JP3637961B2 - Aromatic nitrogen-containing six-membered ring compounds - Google Patents
Aromatic nitrogen-containing six-membered ring compounds Download PDFInfo
- Publication number
- JP3637961B2 JP3637961B2 JP2000277652A JP2000277652A JP3637961B2 JP 3637961 B2 JP3637961 B2 JP 3637961B2 JP 2000277652 A JP2000277652 A JP 2000277652A JP 2000277652 A JP2000277652 A JP 2000277652A JP 3637961 B2 JP3637961 B2 JP 3637961B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- containing heterocyclic
- methoxybenzylamino
- nitrogen
- chloro
- 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 - Lifetime
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- 150000001875 compounds Chemical class 0.000 title claims description 300
- -1 pyrimidinyloxy group Chemical group 0.000 claims description 116
- 125000000623 heterocyclic group Chemical group 0.000 claims description 81
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 81
- 125000000217 alkyl group Chemical group 0.000 claims description 61
- 150000003839 salts Chemical class 0.000 claims description 40
- 125000003545 alkoxy group Chemical group 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 23
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 18
- 125000003282 alkyl amino group Chemical group 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 16
- WEAJZXNPAWBCOA-INIZCTEOSA-N avanafil Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NCC1=NC=CC=N1 WEAJZXNPAWBCOA-INIZCTEOSA-N 0.000 claims description 9
- 125000004043 oxo group Chemical group O=* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- ZUOSZNKVOBXTON-UHFFFAOYSA-N 4-[(3-chloro-4-methoxyphenyl)methylamino]-2-(6,8-dihydro-5h-1,7-naphthyridin-7-yl)-n-(2-morpholin-4-ylethyl)pyrimidine-5-carboxamide Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2CC3=NC=CC=C3CC2)=NC=C1C(=O)NCCN1CCOCC1 ZUOSZNKVOBXTON-UHFFFAOYSA-N 0.000 claims description 8
- 125000002619 bicyclic group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000002757 morpholinyl group Chemical group 0.000 claims description 8
- BZIKYOBRYFDAQS-KRWDZBQOSA-N 4-[(3-chloro-4-methoxyphenyl)methylamino]-2-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]-n-(1,3,5-trimethylpyrazol-4-yl)pyrimidine-5-carboxamide Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NC1=C(C)N(C)N=C1C BZIKYOBRYFDAQS-KRWDZBQOSA-N 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- JDEHGBFVLSFNQF-INIZCTEOSA-N 3-[(3-chloro-4-methoxyphenyl)methylamino]-5-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]-n-(pyrimidin-2-ylmethyl)pyrazine-2-carboxamide Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=CN=C1C(=O)NCC1=NC=CC=N1 JDEHGBFVLSFNQF-INIZCTEOSA-N 0.000 claims description 6
- AMUQMYUCCDGCBH-KRWDZBQOSA-N 4-[(3-chloro-4-methoxyphenyl)methylamino]-2-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]-n-(pyrimidin-5-ylmethyl)pyrimidine-5-carboxamide Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NCC1=CN=CN=C1 AMUQMYUCCDGCBH-KRWDZBQOSA-N 0.000 claims description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims description 5
- PDKSTSHJWLVVPD-SFHVURJKSA-N 3-[(3-chloro-4-methoxyphenyl)methylamino]-5-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]-n-(2-morpholin-4-ylethyl)pyrazine-2-carboxamide Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=CN=C1C(=O)NCCN1CCOCC1 PDKSTSHJWLVVPD-SFHVURJKSA-N 0.000 claims description 4
- QEZPSGKEUQYEJJ-SFHVURJKSA-N 4-[(3-chloro-4-methoxyphenyl)methylamino]-2-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]-n-(2-morpholin-4-ylethyl)pyrimidine-5-carboxamide Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NCCN1CCOCC1 QEZPSGKEUQYEJJ-SFHVURJKSA-N 0.000 claims description 4
- YRUWWUCFHIDILY-KRWDZBQOSA-N 4-[(3-chloro-4-methoxyphenyl)methylamino]-2-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]-n-(pyrimidin-4-ylmethyl)pyrimidine-5-carboxamide Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NCC1=CC=NC=N1 YRUWWUCFHIDILY-KRWDZBQOSA-N 0.000 claims description 4
- DKEPQDALHOKEMO-QAQDUYKDSA-N C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2CC(=O)N(C)CC2)=NC=C1C(=O)N[C@@H]1CC[C@@H](O)CC1 Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2CC(=O)N(C)CC2)=NC=C1C(=O)N[C@@H]1CC[C@@H](O)CC1 DKEPQDALHOKEMO-QAQDUYKDSA-N 0.000 claims description 4
- DRDRFIHQQVYKOQ-IYARVYRRSA-N C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2CCN(CC2)C=O)=NC=C1C(=O)N[C@@H]1CC[C@@H](O)CC1 Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2CCN(CC2)C=O)=NC=C1C(=O)N[C@@H]1CC[C@@H](O)CC1 DRDRFIHQQVYKOQ-IYARVYRRSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- ZKVBUXINNNFHDQ-AWEZNQCLSA-N 1-[4-[(3-chloro-4-methoxyphenyl)methylamino]-2-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidin-5-yl]ethanone Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(C)=O ZKVBUXINNNFHDQ-AWEZNQCLSA-N 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 3
- UWBVOGVFKRJBOW-HNNXBMFYSA-N 1-[4-[(3-chloro-4-methoxyphenyl)methylamino]-2-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidin-5-yl]-3-methoxypropan-1-one Chemical compound COCCC(=O)C1=CN=C(N2[C@@H](CCC2)CO)N=C1NCC1=CC=C(OC)C(Cl)=C1 UWBVOGVFKRJBOW-HNNXBMFYSA-N 0.000 claims description 2
- YNNKKCCWMQZSKY-SFHVURJKSA-N 1-[4-[(3-chloro-4-methoxyphenyl)methylamino]-2-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidin-5-yl]-3-morpholin-4-ylpropan-1-one Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)CCN1CCOCC1 YNNKKCCWMQZSKY-SFHVURJKSA-N 0.000 claims description 2
- UJGJGLRWBIDXDS-CALCHBBNSA-N 2-[(2s,5r)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-4-[(3-chloro-4-methoxyphenyl)methylamino]-n-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CC[C@@H]2CO)CO)=NC=C1C(=O)NCC1=NC=CC=N1 UJGJGLRWBIDXDS-CALCHBBNSA-N 0.000 claims description 2
- HYKWSWIXOFMTGB-UHFFFAOYSA-N 3-[(3-chloro-4-methoxyphenyl)methylamino]-5-(6,8-dihydro-5h-imidazo[1,2-a]pyrazin-7-yl)-n-(pyrimidin-2-ylmethyl)pyrazine-2-carboxamide Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2CC3=NC=CN3CC2)=CN=C1C(=O)NCC1=NC=CC=N1 HYKWSWIXOFMTGB-UHFFFAOYSA-N 0.000 claims description 2
- VFUOOSBEUXOHJA-UHFFFAOYSA-N 4-[(3-chloro-4-methoxyphenyl)methylamino]-2-(6,8-dihydro-5h-imidazo[1,2-a]pyrazin-7-yl)-n-[(4-methylmorpholin-2-yl)methyl]pyrimidine-5-carboxamide Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2CC3=NC=CN3CC2)=NC=C1C(=O)NCC1OCCN(C)C1 VFUOOSBEUXOHJA-UHFFFAOYSA-N 0.000 claims description 2
- JBMBVESUUWXWDY-KRWDZBQOSA-N 4-[(3-chloro-4-methoxyphenyl)methylamino]-2-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]-n-(pyridazin-4-ylmethyl)pyrimidine-5-carboxamide Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NCC1=CC=NN=C1 JBMBVESUUWXWDY-KRWDZBQOSA-N 0.000 claims description 2
- BGQRCENSNLFTCS-SFHVURJKSA-N 4-[(3-chloro-4-methoxyphenyl)methylamino]-2-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]-n-(pyridin-2-ylmethyl)pyrimidine-5-carboxamide Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NCC1=CC=CC=N1 BGQRCENSNLFTCS-SFHVURJKSA-N 0.000 claims description 2
- CFQCGXUAGOJKPS-ZWKOTPCHSA-N 4-[(3-chloro-4-methoxyphenyl)methylamino]-2-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]-n-[[(2r)-4-methylmorpholin-2-yl]methyl]pyrimidine-5-carboxamide Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NC[C@H]1OCCN(C)C1 CFQCGXUAGOJKPS-ZWKOTPCHSA-N 0.000 claims description 2
- CFQCGXUAGOJKPS-ROUUACIJSA-N 4-[(3-chloro-4-methoxyphenyl)methylamino]-2-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]-n-[[(2s)-4-methylmorpholin-2-yl]methyl]pyrimidine-5-carboxamide Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NC[C@@H]1OCCN(C)C1 CFQCGXUAGOJKPS-ROUUACIJSA-N 0.000 claims description 2
- SESDYPVYQSBTDT-MEMLXQNLSA-N C1=C(C#N)C(OC)=CC=C1CNC1=NC(N2CC3=NC=CC=C3C2)=NC=C1C(=O)N[C@@H]1CC[C@@H](O)CC1 Chemical compound C1=C(C#N)C(OC)=CC=C1CNC1=NC(N2CC3=NC=CC=C3C2)=NC=C1C(=O)N[C@@H]1CC[C@@H](O)CC1 SESDYPVYQSBTDT-MEMLXQNLSA-N 0.000 claims description 2
- UAMDGRULSTUHIJ-IYARVYRRSA-N C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2CC3=NC=CN3CC2)=NC=C1C(=O)N[C@@H]1CC[C@@H](O)CC1 Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2CC3=NC=CN3CC2)=NC=C1C(=O)N[C@@H]1CC[C@@H](O)CC1 UAMDGRULSTUHIJ-IYARVYRRSA-N 0.000 claims description 2
- QGPZRJMJDWTBPK-WGSAOQKQSA-N C1C[C@@H](OC)CC[C@@H]1NC(=O)C1=CN=C(N2CC3=NC=CN3CC2)N=C1NCC1=CC=C(OC)C(Cl)=C1 Chemical compound C1C[C@@H](OC)CC[C@@H]1NC(=O)C1=CN=C(N2CC3=NC=CN3CC2)N=C1NCC1=CC=C(OC)C(Cl)=C1 QGPZRJMJDWTBPK-WGSAOQKQSA-N 0.000 claims description 2
- ZGHZWTAAERHCMZ-UHFFFAOYSA-N COCCC(C1=CN=C(NCC(C=C2)=CC(Cl)=C2OC)N=C1)=O Chemical compound COCCC(C1=CN=C(NCC(C=C2)=CC(Cl)=C2OC)N=C1)=O ZGHZWTAAERHCMZ-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 168
- 238000006243 chemical reaction Methods 0.000 description 104
- 239000002904 solvent Substances 0.000 description 84
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 72
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 70
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 60
- 239000000243 solution Substances 0.000 description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 46
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 46
- 239000000203 mixture Substances 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 40
- 239000011541 reaction mixture Substances 0.000 description 40
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 35
- 230000002829 reductive effect Effects 0.000 description 32
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 238000002844 melting Methods 0.000 description 26
- 230000008018 melting Effects 0.000 description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 24
- 238000000034 method Methods 0.000 description 24
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 23
- 235000017557 sodium bicarbonate Nutrition 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 22
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 21
- 239000012267 brine Substances 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
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- 230000001590 oxidative effect Effects 0.000 description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 16
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 14
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 239000002585 base Substances 0.000 description 14
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- 125000006239 protecting group Chemical group 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 11
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
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- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 8
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
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- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
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- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 6
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- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
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- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
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- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- CHDFNIZLAAFFPX-UHFFFAOYSA-N ethoxyethane;oxolane Chemical compound CCOCC.C1CCOC1 CHDFNIZLAAFFPX-UHFFFAOYSA-N 0.000 description 1
- JDLZATZOHSKDTL-ZDUSSCGKSA-N ethyl 2-[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-phenylsulfanylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(N2[C@@H](CCC2)CO)N=C1SC1=CC=CC=C1 JDLZATZOHSKDTL-ZDUSSCGKSA-N 0.000 description 1
- JXDHLYZHVMLIGM-UHFFFAOYSA-N ethyl 6-[(3-chloro-4-methoxyphenyl)methylamino]-2-oxo-1h-pyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(O)N=C1NCC1=CC=C(OC)C(Cl)=C1 JXDHLYZHVMLIGM-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
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- FVLAYJRLBLHIPV-UHFFFAOYSA-N pyrimidin-5-amine Chemical compound NC1=CN=CN=C1 FVLAYJRLBLHIPV-UHFFFAOYSA-N 0.000 description 1
- DRGCXLJWMQGVJA-UHFFFAOYSA-N pyrimidine;dihydrochloride Chemical compound Cl.Cl.C1=CN=CN=C1 DRGCXLJWMQGVJA-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明はｃＧＭＰ特異的ホスホジエステラーゼ(ＰＤＥ)阻害作用(ＰＤＥ Ｖ阻害作用)を有し医薬として有用な新規芳香族含窒素六員環化合物及びその製法に関する。
【０００２】
【従来の技術】
一般に、細胞内セカンドメッセンジャーであるｃＧＭＰは、生体内の組織に広く分布するホスホジエステラーゼにより分解され不活性化されるが、該ＰＤＥ活性を阻害すると、細胞内のｃＧＭＰの濃度が上昇し、その結果、種々の薬理作用、例えば、血管平滑筋弛緩作用、気管支平滑筋弛緩作用、血小板凝集抑制作用等が発現することが知られている。
また、このようなｃＧＭＰ特異的ＰＤＥ阻害作用(即ち、ＰＤＥ Ｖ阻害作用)を有する化合物は、ｃＧＭＰ系シグナル伝達の機能障害に起因する各種疾患、例えば、高血圧症、狭心症、心筋梗塞、慢性及び急性心不全、肺高血圧症(ＷＯ９６／０５１７６等)、前立腺肥大(オーストラリア特許公開９９５５９７７)等の治療に有用であることが知られており、更に女性性機能不全〔Vemulapalli ら、ライフ・サイエンシーズ、第６７巻、第２３−２９頁(２０００年) (Life Sciences)〕、糖尿病性胃不全麻痺〔Watkins ら、ジャーナル・オブ・クリニカル・インベスティゲーション、第１０６巻、第３７３−３８４頁(２０００年) (J. Clin. Invest.)〕、アカラシア〔Bortolotti ら、ガストロエンテロロジー、第１１８巻、第２５３−２５７頁(２０００年) (Gastroenterology)〕、下痢 〔Mule ら、ブリティッシュ・ジャーナル・オブ・ファーマコロジー、第１２７巻、第５１４−５２０頁(１９９９年) (Br. J. Pharmacol.)〕、便秘〔Bakre ら、ジャーナル・オブ・セルラー・バイオケミストリー、第７７巻、第１５９−１６７頁(２０００年) (J. Cell. Biochem.)〕、喘息〔Turner ら、ブリティッシュ・ジャーナル・オブ・ファーマコロジー、第１１１巻、第１１９８−１２０４頁(１９９４年) (Br. J. Pharmacol.)〕の治療に用いうる可能性も報告されている。
【０００３】
更に、ＰＤＥ Ｖ阻害作用を有する１−〔４−エトキシ−３−(６,７−ジヒドロ−１−メチル−７−オキソ−３−プロピル−１Ｈ−ピラゾロ〔４,３−ｄ〕ピリミジン−５−イル)フェニルスルホニル〕−４−メチルピペラジン〔一般名；シルデナフィル(Sildenafil)〕が陰茎勃起不全等の疾患の治療に有用であることも報告されている〔Boolell ら、ザ・ジャーナル・オブ・ウロロジー サプリメント、第１５５巻、第５号、第４９５Ａ頁７３９ (１９９６年) (The Journal of Urology, Supplement)、Terrett ら、バイオオルガニック・アンド・メディシナル・ケミストリー・レターズ、第６巻、第１５号、第１８１９頁 (１９９６年) (Bioorganic & Medicinal Chemistry Letters) 及びBallard ら、ブリティシュ・ジャーナル・オブ・ファーマコロジー プロシーディング・サプリメント、第１１８巻、１５３Ｐ (１９９６年) (British Journal of Pharmacology, Proceeding Supplement)〕。
【０００４】
しかしながら、シルデナフィルには、頭痛、顔面紅潮、消化管障害、鼻炎、色覚異常及び勃起持続症等の副作用があることも報告されている〔Irwin ら、ザ・ニュー・イングラド・ジャーナル・オブ・メディシン、第３３８巻、第２０号、第１３９７−１４０４頁 (１９９８年) (The New England Journal of Medicine)、Morales ら、インターナショナル・ジャーナル・オブ・インポテンス・リサーチ、第１０巻、第２号、第６９−７３頁 (１９９８年) (International Journal of Impotence Research) 及び Goldenberg、クリニカル・セラピューティクス、第２０巻、第６号、第１０３３−１０４８頁 (１９９８年) (Clinical Therapeutics)〕。
【０００５】
また、イヌの実験において、シルデナフィルは網膜組織の光応答の影響に関してＰＤＥ ＶＩ阻害作用と相関していることが報告されており〔Morales ら、インターナショナル・ジャーナル・オブ・インポテンス・リサーチ、第１０巻、第２号、第６９−７３頁 (１９９８年) (International Journal of Impotence Research)〕、一方、網膜のＰＤＥ ＶＩが視覚機能において重要な役割を奏していることも報告されている〔Morales ら、インターナショナル・ジャーナル・オブ・インポテンス・リサーチ、第１０巻、第２号、第６９−７３頁 (１９９８年) (International Journal of Impotence Research) 及び Estrade ら、ヨーロピアン・ジャーナル・オブ・ファーマコロジー、第３５２巻、第１５７−１６３頁 (１９９８年) (European Journal of Pharmacology)〕。
【０００６】
【発明が解決しようとする課題】
本発明は、優れたホスホジエステラーゼＶ(ＰＤＥ Ｖ)阻害作用を有し、かつ副作用の少ない陰茎勃起不全の予防・治療薬として有用な新規芳香族含窒素六員環化合物を提供するものである。更に、本発明は、このような新規芳香族含窒素六員環化合物の製法をも提供するものである。
【０００７】
【課題を解決するための手段】
本発明は、一般式(Ｉ)
【化２９】
−ＮＨ−Ｑ−Ｒ3
（式中、Ｒ3は置換されていてもよい含窒素複素環式基、Ｑは低級アルキレン基又は単結合を表す)
で示される基又は式：
−ＮＨ−Ｒ4
（式中、Ｒ4は置換されていてもよいシクロアルキル基を表す)
で示される基、Ｒ2は置換されていてもよいアリール基、Ｙ及びＺは一方が式：＝ＣＨ−であり、他方が式：＝Ｎ−を表す)
で示される芳香族含窒素六員環化合物又はその薬理的に許容し得る塩及びその製法である。
【０００８】
【発明の実施の形態】
本発明の化合物(Ｉ)において、環Ａで示される「置換されていてもよい含窒素複素環式基」の含窒素複素環式基としては、５〜１０員単環式もしくは二環式含窒素複素環式基、より具体的には、５〜６員の単環式含窒素複素環式基及び８〜１０員の二環式含窒素複素環式基があげられ、さらに具体的には、ピロリジニル基、ピペラジニル基、ピペリジル基、モルホリノ基等の５〜６員の非芳香族単環式含窒素複素環式基、イミダゾリル基、ピロリル基等の５〜６員の芳香族単環式含窒素複素環式基、６,７−ジヒドロ−５Ｈ−ピロロ[３,４−ｂ]ピリジン−６−イル基、５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル基、５,６,７,８−テトラヒドロ−１,７−ナフチリジン−７−イル基、１,２,３,４−テトラヒドロ−２−イソキノリニル基、１Ｈ−２,３,４,５,６,７−ヘキサヒドロピラゾロ[４,３−ｃ]ピリジン−５−イル基、４,５,６,７−テトラヒドロチアゾロ[５,４−ｃ]ピリジン−６−イル基、５,６,７,８−テトラヒドロピリド[４,３−ｄ]ピリミジン−６−イル基、４,５,６,７−テトラヒドロ−３Ｈ−イミダゾ[４,５−ｃ]ピリジン−３−イル基等の二環式含窒素複素環式基が挙げられる。
【０００９】
Ｒ3で示される「置換されていてもよい含窒素複素環式基」における含窒素複素環式基としては、５〜６員の単環式含窒素複素環式基又は８〜１０員の二環式含窒素複素環式基があげられ、具体的には、モルホリニル基、ピペラジニル基、ピペリジル基、チアジアゾリル基、ジヒドロピリミジニル基、ジヒドロピラゾリル基等の５〜６員の非芳香族単環式含窒素複素環式基や、ピリミジニル基、ピリダジニル基、ピリジル基、ピラゾリル基、イミダゾリル基、オキサゾリル基、チアゾリル基、ピラジニル基等の５〜６員の芳香族単環式含窒素複素環式基、ベンゾチアゾリル基、キノリル基、ジヒドロベンゾオキサゾリル基等の８〜１０員の二環式含窒素複素環式基があげられる。
【００１０】
環Ａ及びＲ3で示される「置換されていてもよい含窒素複素環式基」の置換基としては、
(１)低級アルキル基、
(２)水酸基置換低級アルキル基、
(３)ホルミル基、
(４)オキソ基、
(５)アミノ基、
(６)ジ低級アルキルアミノ基、
(７)水酸基、
(８)低級アルコキシ基、
(９)低級アルコキシカルボニル基、
(１０)低級アルコキシ置換低級アルカノイル基、
(１１)低級アルカノイル基、
(１２)シアノ基置換低級アルキル基、及び
(１３)(ｉ)ハロゲン原子と低級アルコキシ基とで置換されたベンジルアミノ基及び(ｉｉ)水酸基置換シクロアルキルカルバモイル基で置換されたピリミジニル基、
等があげられる。
【００１１】
Ｒ2で示される「置換されていてもよいアリール基」のアリール基としては、５〜１０員単環もしくは二環式芳香族炭化水素基があげられ、具体的には、フェニル基、ナフチル基等があげられる。
【００１２】
Ｒ2で示される「置換されていてもよいアリール基」の置換基としては、例えば、低級アルコキシ基、ハロゲン原子、シアノ基、ニトロ基、水酸基、低級アルキル基等があげられる。
【００１３】
Ｒ1で示される「置換されていてもよい低級アルキル基」及びＲ4で示される「置換されていてもよいシクロアルキル基」の置換基としては、低級アルコキシ基、水酸基、モルホリニル基、低級アルキルスルホニル基、ジ低級アルキルホスフィノ基、ジ低級アルキルアミノ基、ピリミジニル基置換低級アルキルアミノ基、ピリジル基、ピリジルアミノ基、低級アルキル基置換ピペラジニル基及びピリミジニルオキシ基等があげられる。
【００１４】
本明細書を通じて、低級アルキル基とは、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｔｅｒｔ−ブチル等の炭素数１〜６の直鎖又は分岐鎖アルキル基を意味する。低級アルコキシ基とは、メトキシ、エトキシ、プロポキシ、イソプロピルオキシ、ブチルオキシ、イソブチルオキシ、ｔｅｒｔ−ブチルオキシ等の炭素数１〜６の直鎖又は分岐鎖アルコキシ基を意味する。シクロアルキル基とは、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、シクロヘプチル等の炭素数３〜８のシクロアルキル基を意味する。低級アルキレン基とは、メチレン、エチレン、トリメチレン等の炭素数１〜６の直鎖又は分岐鎖アルキレン基を意味する。又ハロゲン原子とはフッ素原子、塩素原子、臭素原子、ヨウ素原子を意味する。
【００１５】
本発明の化合物(Ｉ)のうち、好ましい化合物としては、一般式(Ｉ)において、環Ａで示される「置換されていてもよい含窒素複素環式基」における含窒素複素環式基が、５〜６員の単環式含窒素複素環式基又は８〜１０員の二環式含窒素複素環式基であり、前記の「置換されていてもよい含窒素複素環式基」の置換基が、
(１)低級アルキル基、
(２)水酸基置換低級アルキル基、
(３)ホルミル基、
(４)オキソ基、
(５)アミノ基、
(６)水酸基、
(７)低級アルコキシカルボニル基、及び
(８)(ｉ)ハロゲン原子と低級アルコキシ基とで置換されたベンジルアミノ基及び(ｉｉ)水酸基置換シクロアルキルカルバモイル基で置換されたピリミジニル基
から選ばれる基であり、Ｒ1が低級アルコキシ基、水酸基、モルホリニル基、低級アルキルスルホニル基、ジ低級アルキルホスフィノ基、ジ低級アルキルアミノ基、ピリミジニル基置換低級アルキルアミノ基、ピリジル基、ピリジルアミノ基及び低級アルキル基置換ピペラジニル基から選ばれる基で置換されていてもよい低級アルキル基、式：
−ＮＨ−Ｑ−Ｒ3
で示される基又は式：
−ＮＨ−Ｒ4
で示される基であり、Ｒ3で示される「置換されていてもよい含窒素複素環式基」における含窒素複素環式基が５〜６員の単環式含窒素複素環式基又は８〜１０員の二環式含窒素複素環式基から選ばれる基であり、前記の「置換されていてもよい含窒素複素環式基」の置換基が、低級アルキル基、水酸基置換低級アルキル基、オキソ基、アミノ基、ジ低級アルキルアミノ基、低級アルカノイル基及びシアノ基置換低級アルキル基から選ばれる基であり、Ｒ4が水酸基、低級アルコキシ基及びピリミジニルオキシ基から選ばれる基で置換されたシクロアルキル基であり、Ｒ2が低級アルコキシ基、ハロゲン原子、シアノ基、ニトロ基、水酸基及び低級アルキル基から選ばれる基で置換されたフェニル基である化合物があげられる。
【００１６】
より具体的には、環Ａで示される「置換されていてもよい含窒素複素環式基」における含窒素複素環式基が、式：
【化３０】
【化３１】
【化３２】
【化３３】
【００１７】
本発明の化合物(Ｉ)のうち、他の好ましい化合物としては、一般式(Ｉ)において、環Ａで示される「置換されていてもよい含窒素複素環式基」における含窒素複素環式基が、５〜６員の単環式含窒素複素環式基又は８〜１０員の二環式含窒素複素環式基であり、前記の「置換されていてもよい含窒素複素環式基」の置換基が、低級アルキル基、水酸基置換低級アルキル基、ホルミル基及びオキソ基から選ばれる基であり、Ｒ1が低級アルコキシ基及びモルホリニル基から選ばれる基で置換されていてもよい低級アルキル基、式：
−ＮＨ−Ｑ−Ｒ3
で示される基又は式：
−ＮＨ−Ｒ4
で示される基であり、Ｒ3で示される「置換されていてもよい含窒素複素環式基」が、低級アルキル基で置換されていてもよい５〜６員の単環式含窒素複素環式基であり、Ｒ4が水酸基及び低級アルコキシ基から選ばれる基で置換されたシクロアルキル基であり、Ｒ2が低級アルコキシ基、ハロゲン原子及びシアノ基から選ばれる基で置換されたフェニル基である化合物があげられる。
【００１８】
より具体的には、環Ａで示される「置換されていてもよい含窒素複素環式基」における含窒素複素環式基が、式：
【化３４】
【化３５】
【化３６】
【化３７】
【００１９】
更に具体的には、環Ａが式：
【化３８】
−ＮＨ−Ｑ−Ｒ3
で示される基又は式：
−ＮＨ−Ｒ4
で示される基であり、Ｒ3が、式：
【化３９】
【化４０】
【化４１】
【００２０】
本発明の化合物(Ｉ)のうち、より好ましい化合物としては、一般式(Ｉ)において、環Ａで示される「置換されていてもよい含窒素複素環式基」における含窒素複素環式基が、５〜６員の単環式含窒素複素環式基又は８〜１０員の二環式含窒素複素環式基であり、前記の「置換されていてもよい含窒素複素環式基」の置換基が、低級アルキル基、水酸基置換低級アルキル基、ホルミル基及びオキソ基から選ばれる基であり、Ｒ1が低級アルコキシ基で置換された低級アルキル基、式：
−ＮＨ−Ｑ−Ｒ3
で示される基又は式：
−ＮＨ−Ｒ4
で示される基であり、Ｒ3で示される「置換されていてもよい含窒素複素環式基」が低級アルキル基で置換されていてもよい５〜６員の単環式含窒素複素環式基であり、Ｒ4が水酸基で置換されたシクロアルキル基であり、Ｒ2が低級アルコキシ基及びハロゲン原子から選ばれる基で置換されたフェニル基である化合物があげられる。
【００２１】
より具体的には、環Ａで示される「置換されていてもよい含窒素複素環式基」における含窒素複素環式基が、式：
【化４２】
【化４３】
【化４４】
【化４５】
【００２２】
更に具体的には、環Ａが式：
【化４６】
−ＮＨ−Ｑ−Ｒ3
で示される基又は式：
−ＮＨ−Ｒ4
で示される基であり、Ｒ3が式：
【化４７】
【化４８】
【化４９】
【００２３】
本発明の化合物(Ｉ)のうち、さらに好ましい化合物としては、一般式(Ｉ)において、環Ａで示される「置換されていてもよい含窒素複素環式基」における含窒素複素環式基が、５〜６員の単環式含窒素複素環式基又は８〜１０員の二環式含窒素複素環式基であり、前記の「置換されていてもよい含窒素複素環式基」の置換基が水酸基置換低級アルキル基であり、Ｒ1が式：
−ＮＨ−Ｑ−Ｒ3
で示される基であり、Ｒ3で示される「置換されていてもよい含窒素複素環式基」が低級アルキル基で置換されていてもよい５〜６員の単環式含窒素複素環式基であり、Ｒ2が低級アルコキシ基及びハロゲン原子から選ばれる基で置換されたフェニル基である化合物があげられる。
【００２４】
より具体的には、環Ａで示される「置換されていてもよい含窒素複素環式基」における含窒素複素環式基が、式：
【化５０】
【化５１】
【化５２】
【化５３】
【００２５】
更に具体的には、環Ａが式：
【化５４】
−ＮＨ−Ｑ−Ｒ3
で示される基であり、Ｒ3が式：
【化５５】
【化５６】
【００２６】
本発明の化合物(Ｉ)のうち、とりわけ好ましい化合物としては、Ｙが式：＝Ｎ−であり、Ｚが式：＝ＣＨ−である化合物があげられる。
【００２７】
本発明の化合物(Ｉ)のうち、薬効上好ましい化合物としては、下記の群から選ばれる化合物又はその薬理的に許容し得る塩が挙げられる。
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジニルメチル)カルバモイル]ピリミジン；
２−(６,７−ジヒドロ−５Ｈ−ピロロ[３,４−ｂ]ピリジン−６−イル)−４−(３−シアノ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジニルメチル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(トランス−４−メトキシシクロヘキシル)カルバモイル]ピリミジン；
２−(６,７−ジヒドロ−５Ｈ−ピロロ[３,４−ｂ]ピリジン−６−イル)−４−(３−シアノ−４−メトキシベンジルアミノ)−５−[Ｎ−(トランス−４−ヒドロキシシクロヘキシル)カルバモイル]ピリミジン；
２−(６,７−ジヒドロ−５Ｈ−ピロロ[３,４−ｂ]ピリジン−６−イル)−４−(３−シアノ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−モルホリノエチル)カルバモイル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−モルホリノエチル)カルバモイル]ピリミジン；
２−[(２Ｓ)−２−ヒドロキシメチル−１−ピロリジニル]−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−[[(２Ｒ)−４−メチル−２−モルホリニル]メチル]カルバモイル]ピリミジン；
２−[(２Ｓ)−２−ヒドロキシメチル−１−ピロリジニル]−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−[[(２Ｓ)−４−メチル−２−モルホリニル]メチル]カルバモイル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(４−ピリミジニルメチル)カルバモイル]ピリミジン；
２−(４−メチル−３−オキソ−１−ピペラジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(トランス−４−ヒドロキシシクロヘキシル)カルバモイル]ピリミジン；
２−(４−ホルミル−１−ピペラジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(トランス−４−ヒドロキシシクロヘキシル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(トランス−４−ヒドロキシシクロヘキシル)カルバモイル]ピリミジン；
２−[シス−２,５−ビス(ヒドロキシメチル)−１−ピロリジニル]−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジニルメチル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジニルメチル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−モルホリノエチル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロ−１,７−ナフチリジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−モルホリノエチル)カルバモイル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−アセチルピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(４−ピリダジニルメチル)カルバモイル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(５−ピリミジニルメチル)カルバモイル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリジルメチル)カルバモイル]ピリミジン；
(Ｓ)−２−[Ｎ−(２−ピリミジニルメチル)カルバモイル]−３−(３−クロロ−４−メトキシベンジルアミノ)−５−[２−ヒドロキシメチル−１−ピロリジニル]ピラジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[(２−モルホリノエチル)カルボニル]ピリミジン；
２−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−[(４−メチル−２−モルホリニル)メチル]カルバモイル]ピリミジン；
(Ｓ)−２−[Ｎ−(２−モルホリノエチル)カルバモイル]−３−(３−クロロ−４−メトキシベンジルアミノ)−５−(２−ヒドロキシメチル−１−ピロリジニル)ピラジン；
２−[Ｎ−(２−ピリミジニルメチル)カルバモイル]−３−(３−クロロ−４−メトキシベンジルアミノ)−５−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)ピラジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[(２−メトキシエチル)カルボニル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(１,３,５−トリメチル−４−ピラゾリル)カルバモイル]ピリミジン、
又はその薬理学的に許容し得る塩が挙げられる。
【００２８】
本発明の化合物(Ｉ)のうち、より薬効上好ましい化合物としては、下記の群から選ばれる化合物又はその薬理的に許容し得る塩が挙げられる。
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジニルメチル)カルバモイル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(４−ピリミジニルメチル)カルバモイル]ピリミジン；
２−(４−メチル−３−オキソ−１−ピペラジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(トランス−４−ヒドロキシシクロヘキシル)カルバモイル]ピリミジン；
２−(４−ホルミル−１−ピペラジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(トランス−４−ヒドロキシシクロヘキシル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジニルメチル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−モルホリノエチル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロ−１,７−ナフチリジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−モルホリノエチル)カルバモイル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(５−ピリミジニルメチル)カルバモイル]ピリミジン；
(Ｓ)−２−[Ｎ−(２−ピリミジニルメチル)カルバモイル]−３−(３−クロロ−４−メトキシベンジルアミノ)−５−[２−ヒドロキシメチル−１−ピロリジニル]ピラジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[(２−メトキシエチル)カルボニル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(１,３,５−トリメチル−４−ピラゾリル)カルバモイル]ピリミジン、
又はその薬理学的に許容し得る塩が挙げられる。
【００２９】
本発明の化合物(Ｉ)のうち、他の薬効上好ましい化合物としては、下記の群から選ばれる化合物又はその薬理的に許容し得る塩が挙げられる。
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジニルメチル)カルバモイル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−モルホリノエチル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジニルメチル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロ−１,７−ナフチリジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−モルホリノエチル)カルバモイル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(５−ピリミジニルメチル)カルバモイル]ピリミジン；
(Ｓ)−２−[Ｎ−(２−ピリミジニルメチル)カルバモイル]−３−(３−クロロ−４−メトキシベンジルアミノ)−５−[２−ヒドロキシメチル−１−ピロリジニル]ピラジン；
(Ｓ)−２−[Ｎ−(２−モルホリノエチル)カルバモイル]−３−(３−クロロ−４−メトキシベンジルアミノ)−５−(２−ヒドロキシメチル−１−ピロリジニル)ピラジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(１,３,５−トリメチル−４−ピラゾリル)カルバモイル]ピリミジン、
又はその薬理学的に許容し得る塩が挙げられる。
【００３０】
本発明の化合物(Ｉ)のうち、特に薬効上好ましい化合物としては、下記の化合物又はその薬理的に許容し得る塩が挙げられる。
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジニルメチル)カルバモイル]ピリミジン、又はその薬理学的に許容し得る塩、並びに２−(５,６,７,８−テトラヒドロ−１,７−ナフチリジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−モルホリノエチル)カルバモイル]ピリミジン、又はその薬理学的に許容し得る塩、及び(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(１,３,５−トリメチル−４−ピラゾリル)カルバモイル]ピリミジン、又はその薬理学的に許容し得る塩が挙げられる。
【００３１】
本発明の化合物(Ｉ)又はその薬理的に許容し得る塩は、環Ａ、Ｒ1及び／又はＲ2が不斉原子を有する場合、当該不斉原子に基づく光学異性体として存在しうるが、本発明はこれらの光学異性体及びその混合物のいずれをも含むものである。
【００３２】
本発明の化合物(Ｉ)又はその薬理的に許容し得る塩は、優れた選択的ＰＤＥ Ｖ阻害作用を有するため、色覚異常等の副作用を実質的に示さず、陰茎勃起不全の予防、治療に用いることができる。
【００３３】
本発明の化合物(Ｉ)は、遊離の形でも、また、薬理的に許容し得る塩の形でも医薬用途に使用することができる。化合物(Ｉ)の薬理的に許容し得る塩としては、例えば塩酸塩、硫酸塩、硝酸塩又は臭化水素酸塩の如き無機酸塩、酢酸塩、フマル酸塩、シュウ酸塩、クエン酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、トシル酸塩又はマレイン酸塩の如き有機酸塩等が挙げられる。
本発明の化合物(Ｉ)又はその塩は、その分子内塩や付加物、それらの溶媒和物あるいは水和物等をいずれも含むものである。
【００３４】
本発明の化合物(Ｉ)又はその薬理的に許容し得る塩は、経口的にも非経口的にも投与することができ、また、錠剤、顆粒剤、細粒剤、丸剤、カプセル剤、散剤、注射剤、吸入剤、バッカル製剤、舌下製剤、シロップ剤、ドライシロップ剤、ゼリー剤、坐剤、軟膏剤、エリキシル剤、リニメント剤、ローション剤、ドリンク剤、点鼻剤、経皮製剤、口腔内速崩壊製剤等の慣用の医薬製剤として用いることができる。これら医薬製剤は、医薬上許容される賦形剤、結合剤、湿潤剤、崩壊剤、増量剤等の添加剤と共に、常法により製剤化することにより調製される。本発明の化合物(Ｉ)又はその薬理的に許容し得る塩の投与量は、投与方法、患者の年令、体重、状態によっても異なるが、注射剤とすれば、通常、１日当り約０.００１〜１００ｍｇ／ｋｇ、とりわけ約０.１〜１０ｍｇ／ｋｇ程度、経口剤とすれば、通常、１日当り約０.１〜２００ｍｇ／ｋｇ、とりわけ約０.１〜８０ｍｇ／ｋｇ程度とするのが好ましい。
【００３５】
なお、本発明の化合物(Ｉ)又はその薬理学的に許容しうる塩は、優れた選択的ＰＤＥ Ｖ阻害作用を有するので、前述した勃起不全のほかに、ｃＧＭＰ系シグナル伝達の機能障害に起因する各種疾患(例えば、肺高血圧症、糖尿病性胃不全麻痺、高血圧症、狭心症、心筋梗塞、慢性及び急性心不全、女性性機能不全、前立腺肥大、喘息、下痢、便秘、アカラシアなど)の予防・治療にも適用できる。
【００３６】
本発明によれば、化合物(Ｉ)は、下記[Ａ法]〜[Ｆ法]によって製造することができる。
[Ａ法]
本発明の化合物(Ｉ)のうち、Ｒ1が式：−ＮＨ−Ｑ−Ｒ3又は−ＮＨ−Ｒ4で示される基である化合物、即ち、一般式(Ｉ−ａ)：
【化５７】
【化５８】
で示される化合物と一般式(ＩＩＩ)
Ｒ2−ＣＨ2−ＮＨ2 (ＩＩＩ)
（但し、記号は前記と同一意味を有する)
で示される化合物とを反応させ、得られる一般式(ＩＶ)
【化５９】
で示される化合物を酸化して一般式(Ｖ)
【化６０】
で示されるスルホニル(又はスルフィニル)化合物とし、さらに一般式(ＶＩ)
【化６１】
で示される化合物又はその塩と反応させて一般式(ＶＩＩ)
【化６２】
で示される化合物としたのち、カルボキシル基の保護基Ｒ5を脱離して一般式(ＶＩＩＩ)
【化６３】
で示される化合物とし、さらに一般式(ＩＸ−ａ)
Ｒ11−Ｈ (ＩＸ−ａ)
（但し、Ｒ11は前記と同一意味を有する)
で示される化合物と反応させることにより製造することができる。
【００３７】
また、化合物(Ｉ−ａ)は、化合物(ＶＩＩＩ)をハロゲン化して一般式(Ｘ)
【化６４】
で示される化合物としたのち、化合物(ＩＸ−ａ)と反応させることによっても製造することができる。
【００３８】
なお、上記化合物(ＶＩＩ)は、一般式(ＸＩ)
【化６５】
【化６６】
で示される化合物のカルボキシル基を保護して一般式(ＸＩＩＩ)
【化６７】
で示される化合物としたのち、化合物(ＩＩＩ)と反応させて一般式(ＸＩＶ)
【化６８】
で示される化合物とし、さらに化合物(ＶＩ)と反応させることによっても製造することができる。
【００３９】
また、上記化合物(ＸＩＶ)は、化合物(Ｖ)を加水分解し、得られる一般式(ＸＶ)
【化６９】
で示される化合物をハロゲン化することによっても製造することができる。
【００４０】
[Ｂ法]
本発明の化合物(Ｉ)のうち、Ｒ1が置換されていてもよい低級アルキル基である化合物、即ち一般式(Ｉ−ｂ)
【化７０】
【化７１】
で示される化合物を酸化して一般式(ＸＶＩＩ)
【化７２】
で示される化合物とし、さらに酸化して一般式(ＸＶＩＩＩ)
【化７３】
で示される化合物としたのち、化合物(ＶＩ)と反応させて一般式(ＸＩＸ)
【化７４】
で示される化合物を得、さらに一般式(ＩＸ−ｂ)
Ｒ12−Ｈ (ＩＸ−ｂ)
（但し、Ｒ12は前記と同一意味を有する)
で示される化合物の金属塩と反応させて一般式(ＸＸ)
【化７５】
で示される化合物とし、ついで酸化することにより製造することができる。
【００４１】
また、本発明の化合物(Ｉ)のうち、基Ｒ1が低級アルコキシ基置換エチル基、モルホリノ基置換エチル基、４−低級アルキルピペラジニル基置換エチル基、３−ピリジルアミノ基置換エチル基、２−ピリジル低級アルキルアミノ基置換エチル基、ジ低級アルキルアミノエチル基もしくはヒドロキシエチル基である化合物、即ち、一般式(Ｉ−ｃ)
【化７６】
で示される化合物は、化合物(ＸＩＸ)と式
ＣＨ2＝ＣＨＭｇＢｒ (ＸＸＩ)
で示されるグリニャール化合物とを反応させ、得られる一般式(ＸＸＩＩ)
【化７７】
で示される化合物を酸化して一般式(ＸＸＩＩＩ)
【化７８】
で示される化合物とし、さらに一般式(ＸＸＩＶ)
Ｒ6−Ｈ (ＸＸＩＶ)
（但し、記号は前記と同一意味を有する)
で示される化合物と反応させることによっても製造することができる。
【００４２】
[Ｃ法]
化合物(Ｉ−ａ)は、化合物(ＩＶ)のカルボキシル基の保護基Ｒ5を脱離して得られる一般式(ＸＸＶ)
【化７９】
で示される化合物と化合物(ＩＸ−ａ)とを反応させて一般式(ＸＸＶＩ−ａ)
【化８０】
で示される化合物とし、さらに酸化して一般式(ＸＸＶＩＩ−ａ)
【化８１】
で示される化合物としたのち、化合物(ＶＩ)と反応させることによっても製造することができる。
【００４３】
[Ｄ法]
化合物(Ｉ−ｂ)は、化合物(ＸＶＩＩ)と化合物(ＩＸ−ｂ)の金属塩とを反応させて得られる一般式(ＸＸＶＩＩＩ)
【化８２】
で示される化合物を酸化し、一般式(ＸＸＶＩ−ｂ)
【化８３】
で示される化合物とし、さらに酸化して一般式(ＸＸＶＩＩ−ｂ)
【化８４】
で示される化合物としたのち、化合物(ＶＩ)と反応させることによっても製造することができる。
【００４４】
[Ｅ法]
化合物(Ｉ−ｂ)は、ジハロゲノ化合物(ＸＩ)と、一般式(ＸＸＩＸ)
Ｒ12−ＣＨＯ (ＸＸＩＸ)
（但し、記号は前記と同一意味を有する)
で示される化合物とを反応させて得られる一般式(ＸＸＸ)
【化８５】
で示される化合物を酸化して、一般式(ＸＸＸＩ)
【化８６】
で示される化合物に導き、これに化合物(ＩＩＩ)を反応させて一般式(ＸＸＸＩＩ)
【化８７】
で示される化合物とし、さらに化合物(ＶＩ)を反応させることによっても製造することができる。
【００４５】
なお、上記化合物(ＸＸＸＩＩ)は、化合物(ＸＸＸ)と化合物(ＩＩＩ)とを反応させ、得られる一般式(ＸＸＸＩＩＩ)
【化８８】
で示される化合物を酸化することによっても製造することができる。
【００４６】
[Ｆ法]
化合物(Ｉ−ａ)は、化合物(ＸＩＩＩ)と一般式(ＸＸＸＩＶ)
ＲＳＨ (ＸＸＸＩＶ)
（但し、Ｒは置換されていてもよい低級アルキル基又は置換されていてもよいアリール基を表す)
で示される化合物とを反応させて一般式(ＸＸＸＶ)
【化８９】
とし、ついで化合物(ＶＩ)又はその塩と反応させて一般式(ＸＸＸＶＩ)
【化９０】
で示される化合物としたのち、カルボキシル基の保護基Ｒ5を脱離して一般式(ＸＸＸＶＩＩ)
【化９１】
で示される化合物とし、さらに化合物(ＩＸ−ａ)と反応させて一般式(ＸＸＸＩＸ)
【化９２】
で示される化合物とし、ついでスルホニル又はスルフィニル化合物へ酸化したのち、化合物(ＩＩＩ)と反応させることにより製造することができる。
【００４７】
上記[Ａ法]〜[Ｆ法]は以下のようにして実施することができる。
[Ａ法]
化合物(ＩＩ)と化合物(ＩＩＩ)との反応は、脱酸剤の存在下又は非存在下、溶媒中で実施することができる。脱酸剤としては、Ｎ,Ｎ−ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、トリエチルアミン、ピリジン等の有機塩基、水素化ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム等の無機塩基等を好適に用いることができる。溶媒としては、ジメチルスルホキシド、テトラヒドロフラン、トルエン、酢酸エチル、クロロホルム、ジメトキシエタン、キシレン、Ｎ,Ｎ−ジメチルホルムアミド等の該反応を阻害しない溶媒をいずれも好適に用いることができる。本反応は、−１０℃〜室温、とりわけ０℃〜室温で好適に進行する。
【００４８】
化合物(ＩＶ)を酸化してスルホニル(又はスルフィニル)化合物(Ｖ)に導く反応は、酸化剤の存在下、溶媒中で実施することができる。酸化剤としては、ｍ−クロロ過安息香酸、過酢酸等の過酸類、二酸化マンガン、過ヨウ素酸ナトリウム、過酸化水素、四酸化二窒素、ハロゲン、ヒドロペルオキシド、酢酸ヨードベンゼン、次亜塩素酸ｔ−ブチル、塩化スルフリル、パーオキシモノ硫酸カリウム等の無機酸化剤を好適に用いることができる。溶媒としては、クロロホルム、塩化メチレン、ジクロロエタン、酢酸等の該反応を阻害しない溶媒を適宜用いることができる。本反応は、−７８℃〜５０℃、とりわけ−１０〜１０℃で好適に進行する。
【００４９】
化合物(Ｖ)と化合物(ＶＩ)又はその塩との反応は、脱酸剤の存在下もしくは非存在下、溶媒中で実施することができる。脱酸剤としては、Ｎ,Ｎ−ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、トリエチルアミン、ピリジン等の有機塩基、水素化ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム等の無機塩基等を好適に用いることができる。化合物(ＶＩ)の塩としては、ナトリウム塩、カリウム塩等のアルカリ金属塩を好適に用いることができる。溶媒としては、Ｎ,Ｎ−ジメチルホルムアミド、テトラヒドロフラン、ジメトキシエタン、ジメチルスルホキシド等の該反応を阻害しない溶媒をいずれも好適に用いることができる。本反応は、０〜１５０℃、とりわけ室温〜６０℃で好適に進行する。
【００５０】
化合物(ＶＩＩ)のカルボキシル基の保護基Ｒ5を脱離して化合物(ＶＩＩＩ)を得るには、カルボキシル基の保護基の種類に応じて通常用いられる方法(加水分解、接触還元等)を適宜利用することができ、加水分解によりカルボキシル基の保護基を脱離する場合には、例えば、塩基の存在下、溶媒中で実施することができる。塩基としては、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等のアルカリ金属水酸化物、炭酸ナトリウム、炭酸カリウム等のアルカリ金属炭酸塩等を好適に用いることができる。溶媒としては、水又はメタノール、エタノール、テトラヒドロフラン、ジオキサン、Ｎ,Ｎ−ジメチルホルムアミド、ジメチルスルホキシド等と水との混合溶媒を適宜用いることができる。本反応は、０〜８０℃、とりわけ５〜６０℃で好適に進行する。なお、カルボキシル基の保護基Ｒ5としては、低級アルキル基、ベンジル基等の通常一般的に用いられるカルボキシル基の保護基を用いることができる。
【００５１】
化合物(ＶＩＩＩ)と化合物(ＩＸ−ａ)との反応は、縮合剤、塩基或いは活性化剤の存在下又は非存在下、適当な溶媒中で実施することができる。縮合剤としては、ペプチド合成で一般的に用いられるジシクロヘキシルカルボジイミド、１−エチル−３−(３−ジメチルアミノプロピル)カルボジイミド、ジフェニルホスホリルアジド、ジエチルシアノホスホネート等を好適に用いることができる。塩基としては、トリエチルアミン、Ｎ−メチルモルホリン等の有機塩基を、活性化剤としては、１−ヒドロキシベンゾトリアゾール等を、それぞれ好適に用いることができる。溶媒としては、塩化メチレン、テトラヒドロフラン、Ｎ,Ｎ−ジメチルホルムアミド、アセトニトリル、Ｎ,Ｎ−ジメチルアセトアミド、酢酸エチル等の該反応を阻害しない溶媒をいずれも好適に用いることができる。本反応は、−３０〜５０℃、とりわけ−１０〜１０℃で好適に進行する。
【００５２】
また、別法としての化合物(ＶＩＩＩ)を化合物(Ｘ)とした後、化合物(ＩＸ−ａ)を反応させる方法は、まず、該化合物(ＶＩＩＩ)を、常法により、活性化剤の存在下又は非存在下、ハロゲン化剤と反応させて化合物(Ｘ)とし、ついで化合物(ＩＸ−ａ)を反応させる。化合物(ＶＩＩＩ)とハロゲン化剤との反応は、溶媒中で実施することができる。ハロゲン化剤としては、例えば、チオニルクロリド、オキザリルクロリド、五塩化リン等を好適に用いることができる。活性化剤としては、Ｎ,Ｎ−ジメチルホルムアミド等のアミド化合物を好適に用いることができる。溶媒としては、塩化メチレン、クロロホルム、テトラヒドロフラン、ベンゼン、トルエン、ジオキサン等の該反応を阻害しない溶媒をいずれも好適に用いることができる。本反応は、−３０〜１００℃、とりわけ−５〜１０℃で好適に進行する。
【００５３】
引き続く、化合物(ＩＸ−ａ)との反応は、脱酸剤の存在下、溶媒中で実施することができる。脱酸剤としては、Ｎ,Ｎ−ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、トリエチルアミン、ピリジン、ジメチルアミノピリジン等の有機塩基、水素化ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム等の無機塩基を好適に用いることができる。溶媒としては、テトラヒドロフラン、塩化メチレン、クロロホルム、トルエン、ベンゼン、ジオキサン、酢酸エチル等の該反応を阻害しない溶媒をいずれも好適に用いることができる。本反応は、−３０〜１００℃、とりわけ−５〜１０℃で好適に進行する。
【００５４】
また、ジハロゲノ化合物(ＸＩ)を二酸化炭素で処理し、化合物(ＸＩＩ)を得る反応は、塩基の存在下、溶媒中で実施することができる。塩基としては、リチウムジイソプロピルアミド、リチウム２,２,６,６−テトラメチルピペリジドなどの有機塩基のアルカリ金属塩等を好適に用いることができる。溶媒としては、テトラヒドロフラン、１,２−ジメトキシエタン、ジエチルエーテル等の該反応を阻害しない溶媒を適宜用いることができる。本反応は、−１００℃〜−３０℃、とりわけ−１００℃〜−７０℃で好適に進行する。
【００５５】
化合物(ＸＩＩ)のカルボキシル基を保護して、化合物(ＸＩＩＩ)を得る反応は、常法により実施することができるが、例えば保護基が低級アルキル基の場合には、塩基及び溶媒の存在下、アルキル化剤と反応させることにより実施することができる。アルキル化剤としては、ヨウ化メチルの如き低級アルキルハライドを好適に用いることができる。塩基としては、炭酸水素ナトリウムの如き炭酸水素アルカリ金属を、溶媒としては、Ｎ,Ｎ−ジメチルホルムアミド、テトラヒドロフラン等の該反応を阻害しない溶媒を好適に用いることができる。本反応は、０℃〜１００℃、とりわけ室温〜７０℃で好適に進行する。
【００５６】
化合物(ＸＩＩＩ)に化合物(ＩＩＩ)を反応させ化合物(ＸＩＶ)を得る反応は、化合物(ＩＩ)と化合物(ＩＩＩ)との反応と同様に実施することができる。
化合物(ＸＩＶ)に化合物(ＶＩ)を反応させ化合物(ＶＩＩ)を得る反応は、化合物(Ｖ)と化合物(ＶＩ)との反応と同様に実施することができる。
また、化合物(Ｖ)を加水分解して化合物(ＸＶ)を得る反応は、塩基の存在下、溶媒中で実施することができる。塩基としては、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等のアルカリ金属水酸化物、炭酸ナトリウム、炭酸カリウム等のアルカリ金属炭酸塩等を好適に用いることができる。溶媒としては、水又はメタノール、エタノール、テトラヒドロフラン、ジオキサン、Ｎ,Ｎ−ジメチルホルムアミド、ジメチルスルホキシド等と水との混合溶媒を適宜用いることができる。本反応は、−２０〜８０℃、とりわけ−５〜６０℃で好適に進行する。化合物(ＸＶ)をハロゲン化して化合物(ＸＩＶ)を得る反応は、化合物(ＶＩＩＩ)をハロゲン化剤によりハロゲン化して化合物(Ｘ)を得る反応と同様に実施することができる。
【００５７】
[Ｂ法]
化合物(ＩＶ)を還元して化合物(ＸＶＩ)に導く反応は、還元剤の存在下、適当な溶媒中で実施することができる。還元剤としては、水素化アルミニウムリチウムの如き水素化アルミニウムアルカリ金属、水素化ホウ素リチウムの如き水素化ホウ素アルカリ金属等を好適に用いることができる。溶媒としては、テトラヒドロフラン、ジオキサン 、ジエチルエーテル、ジメトキシエタン等の該反応を阻害しない溶媒等を好適に用いることができる。本反応は、−７８℃〜用いる溶媒の沸点、とりわけ、−１０℃〜室温で好適に進行する。
【００５８】
化合物(ＸＶＩ)を酸化して化合物(ＸＶＩＩ)に導く反応は、酸化剤の存在下、溶媒中で実施することができる。酸化剤としては、アルコールを対応するカルボニル化合物ヘ誘導できるものであれば特に制限はないが、例えば二酸化マンガン、過マンガン酸バリウム、過マンガン酸カリウム、２,３−ジクロロ−５,６−ジシアノ−１,４−ベンゾキノン、ピリジニウムクロロクロメイト、ピリジニウムジクロメイト等を好適に用いることができる。溶媒としては、クロロホルム、トルエン、酢酸エチル、１,２−ジクロロエタン、塩化メチレン、テトラヒドロフラン等の該反応を阻害しない溶媒を適宜用いることができる。本反応は、０℃〜１００℃、とりわけ室温〜７０℃で好適に進行する。
【００５９】
化合物(ＸＶＩＩ)を酸化して化合物(ＸＶＩＩＩ)に導く反応は、化合物(ＩＶ)を酸化して化合物(Ｖ)に導く反応と同様に実施することができる。
化合物(ＸＶＩＩＩ)に化合物(ＶＩ)を反応させ化合物(ＸＩＸ)に導く反応は、化合物(Ｖ)と化合物(ＶＩ)の反応と同様に実施することができる。
化合物(ＸＩＸ)に化合物(ＩＸ−ｂ)の金属塩を反応させ化合物(ＸＸ)に導く反応は、適当な溶媒中で実施することができる。化合物(ＩＸ−ｂ)の金属塩としては、リチウム塩等を好適に用いることができる。溶媒としては、テトラヒドロフラン、ジオキサン、ジエチルエーテル、ジメトキシエタン等の該反応を阻害しない溶媒を適宜用いることができる。本反応は、−７８℃〜室温で好適に進行する。
【００６０】
化合物(ＸＸ)を酸化して化合物(Ｉ−ｂ)に導く反応は、化合物(ＸＶＩ)を酸化して化合物(ＸＶＩＩ)に導く反応と同様に実施することができる。
また、化合物(ＸＩＸ)とグリニャール化合物(ＸＸＩ)との反応は、適当な溶媒中で実施することができる。溶媒としては、テトラヒドロフラン、ジオキサン、ジエチルエーテル等を好適に用いることができる。本反応は、−７８℃〜６０℃、とりわけ、−７８℃〜室温で好適に進行する。
【００６１】
化合物(ＸＸＩＩ)を酸化して化合物(ＸＸＩＩＩ)に導く反応は、化合物(ＸＶＩ)を酸化して化合物(ＸＶＩＩ)に導く反応と同様に実施することができる。
化合物(ＸＸＩＩＩ)にＲ6がモルホリノ基、４−低級アルキルピペラジニル基、３−ピリジルアミノ基、２−ピリミジニル低級アルキルアミノ基又はジ低級アルキルアミノ基である化合物(ＸＸＩＶ)を反応させてＲ6がモルホリノ基、４−低級アルキルピペラジニル基、３−ピリジルアミノ基、２−ピリミジニル低級アルキルアミノ基又はジ低級アルキルアミノ基である化合物(Ｉ−ｃ)を得る反応は、塩基の存在下もしくは非存在下、適当な溶媒中で実施することができる。塩基としては、Ｎ,Ｎ−ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、トリエチルアミン、ピリジン等の有機塩基、水素化ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム等の無機塩基等を好適に用いることができる。溶媒としては、エタノール、Ｎ,Ｎ−ジメチルホルムアミド、テトラヒドロフラン、ジメトキシエタン、ジメチルスルホキシド等をいずれも好適に用いることができる。本反応は、０〜１５０℃、とりわけ室温〜６０℃で好適に進行する。
【００６２】
一方、化合物(ＸＸＩＩＩ)にＲ6が水酸基又は低級アルコキシ基である化合物(ＸＸＩＶ)を反応させＲ6が水酸基又は低級アルコキシ基である化合物(ＸＸＩ)に導く反応は、酸の存在下、無溶媒もしくは適当な溶媒中で実施することができる。酸としては、硫酸等の無機酸及びメタンスルホン酸、カンファースルホン酸、トルエンスルホン酸、ベンゼンスルホン酸等の有機酸を好適に用いることができる。溶媒としては、ジエチルエーテル、トルエン、ベンゼン、Ｎ,Ｎ−ジメチルホルムアミド、ジメトキシエタン、ジメチルスルホキシド等をいずれも好適に用いることができる。本反応は、０〜１５０℃、とりわけ室温〜６０℃で好適に進行する。
【００６３】
[Ｃ法]
化合物(ＩＶ)のカルボキシル基の保護基Ｒ5を脱離し化合物(ＸＸＶ)を得る反応は、化合物(ＶＩＩ)のカルボキシルの保護基Ｒ5を脱離して化合物(ＶＩＩＩ)を得る反応と同様に実施することができる。
化合物(ＸＸＶ)に化合物(ＩＸ−ａ)を反応させ化合物(ＸＸＶＩ−ａ)に導く反応は、化合物(ＶＩＩＩ)と化合物(ＩＸ−ａ)との反応と同様に実施することができる。
化合物(ＸＸＶＩ−ａ)を酸化して化合物(ＸＸＶＩＩ−ａ)に導く反応は、上記化合物(ＩＶ)を酸化して化合物(Ｖ)に導く反応と同様に実施することができる。化合物(ＸＸＶＩＩ−ａ)に化合物(ＶＩ)を反応させ本発明の化合物(Ｉ−ａ)に導く反応は、上記化合物(Ｖ)と化合物(ＶＩ)の反応と同様に実施することができる。
【００６４】
[Ｄ法]
化合物(ＸＶＩＩ)に化合物(ＩＸ−ｂ)の金属塩を反応させ化合物(ＸＸＶＩＩＩ)に導く反応は、化合物(ＸＩＸ)と化合物(ＩＸ−ｂ)の金属塩との反応と同様に実施することができる。
化合物(ＸＸＶＩＩＩ)を酸化して化合物(ＸＸＶＩ−ｂ)に導く反応は、化合物(ＸＶＩ)を酸化して化合物(ＸＶＩＩ)に導く反応と同様に実施することができる。
化合物(ＸＸＶＩ−ｂ)を酸化して化合物(ＸＸＶＩＩ−ｂ)に変換後、本発明の化合物(Ｉ−ｂ)に導く反応は、化合物(ＸＸＶＩ−ａ)を酸化して化合物(ＸＸＶＩＩ−ａ)に変換後、本発明の化合物(Ｉ−ａ)に導く反応と同様に実施することができる。
【００６５】
[Ｅ法]
化合物(ＸＩ)に化合物(ＸＸＩＸ)を反応させ化合物(ＸＸＸ)に導く反応は、塩基の存在下、適当な溶媒中で実施することができる。塩基としては、リチウムジイソプロピルアミド、リチウム２,２,６,６−テトラメチルピペリジドなどの有機塩基のアルカリ金属塩等を好適に用いることができる。溶媒としては、テトラヒドロフラン、１,２−ジメトキシエタン、ジエチルエーテル等の該反応を阻害しない溶媒を適宜用いることができる。本反応は、−１００℃〜−３０℃、とりわけ−１００℃〜−７０℃で好適に進行する。
【００６６】
化合物(ＸＸＸ)を酸化して化合物(ＸＸＸＩ)に導く反応は、上記化合物(ＸＶＩ)を酸化して化合物(ＸＶＩＩ)に導く反応と同様に実施することができる。
上記化合物(ＸＸＸＩ)に化合物(ＩＩＩ)を反応させ化合物(ＸＸＸＩＩ)に導く反応は、上記化合物(ＩＩ)と化合物(ＩＩＩ)の反応と同様に実施することができる。
【００６７】
さらに、化合物(ＸＸＸＩＩ)に化合物(ＶＩ)又はその塩を反応させ本発明の化合物(Ｉ−ｂ)に導く反応は、上記化合物(Ｖ)と化合物(ＶＩ)の反応と同様に実施することができる。
【００６８】
なお、化合物(ＸＸＸ)に化合物(ＩＩＩ)を反応させ化合物(ＸＸＸＩＩＩ)に導く反応は、上記化合物(ＩＩ)と化合物(ＩＩＩ)との反応と同様に実施することができる。また、化合物(ＸＸＸＩＩＩ)を酸化して化合物(ＸＸＸＩＩ)に導く反応は、上記化合物(ＸＶＩ)を酸化して化合物(ＸＶＩＩ)に導く反応と同様に実施することができる。
【００６９】
[Ｆ法]
化合物(ＸＩＩＩ)と化合物(ＸＸＸＩＶ)との反応は、脱酸剤の存在下又は非存在下、溶媒中で実施することができる。脱酸剤としては、Ｎ,Ｎ−ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、トリエチルアミン、ピリジン等の有機塩基、水素化ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム等の無機塩基等を好適に用いることができる。溶媒としては、Ｎ,Ｎ−ジメチルホルムアミド、テトラヒドロフラン、トルエン、酢酸エチル、クロロホルム、ジメトキシエタン、キシレン、Ｎ,Ｎ−ジメチルホルムアミド等の該反応を阻害しない溶媒をいずれも好適に用いることができる。本反応は、−１０℃〜室温、とりわけ０℃〜室温で好適に進行する。
【００７０】
化合物(ＸＸＸＶ)と化合物(ＶＩ)又はその塩との反応は、化合物(Ｖ)と化合物(ＶＩ)との反応と同様に実施することができる。
化合物(ＸＸＸＶＩ)のカルボキシル基の保護基Ｒ5を脱離して化合物(ＸＸＸＶＩＩ)を得る反応は、化合物(ＶＩＩ)のカルボキシル基の保護基Ｒ5を脱離して化合物(ＶＩＩＩ)を得る反応と同様に実施することができる。
化合物(ＸＸＸＶＩＩ)と化合物(ＩＸ−ａ)との反応は、化合物(ＶＩＩＩ)と化合物(ＩＸ−ａ)との反応と同様に実施することができる。
【００７１】
化合物(ＸＸＸＩＸ)の酸化反応は、化合物(ＩＶ)から(Ｖ)への反応と同様に実施でき、酸化剤としては、ｍ−クロロ過安息香酸等を好適に用いることができる。溶媒としては、クロロホルム、塩化メチレン、ジクロロエタン、酢酸等の該反応を阻害しない溶媒を適宜用いることができる。本反応は、−７８℃〜５０℃、とりわけ−１０℃〜１０℃で好適に進行する。
【００７２】
引き続く化合物(ＩＩＩ)との反応は、化合物(ＩＩ)と化合物(ＩＩＩ)との反応と同様に実施することができる。
かくして得られる化合物(Ｉ)は、所望により、その薬理的に許容し得る塩とすることができる。
なお、出発化合物(ＩＩ)は、例えば、ジャーナル・オブ・アメリカン・ケミカル・ソサイエティ、３５０頁、６５巻、１９４３年に記載されている方法に準じて製造することができる。
【００７３】
【実施例】
上記例示の各方法で合成される本発明化合物(Ｉ)の具体例(実施例)を下記に示すが、これにより本発明が限定されるものではない。
【００７４】
実施例１
(１)４−クロロ−５−エトキシカルボニル−２−メチルチオピリミジン２５.３３ｇのＮ,Ｎ−ジメチルホルムアミド８５ｍｌ溶液に、氷冷下３−クロロ−４−メトキシベンジルアミン１９.６２ｇのＮ,Ｎ−ジメチルホルムアミド１５ｍｌの溶液及びトリエチルアミン１６.７ｍｌを加える。室温下２０分攪拌後、３−クロロ−４−メトキシベンジルアミン９４０ｍｇを加え１５分攪拌後、さらに該アミン９４０ｍｇを加え１５分攪拌する。反応混合物を氷水−クエン酸混合物に注ぎ、酢酸エチルで抽出し、１０％クエン酸水溶液、水、食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥する。溶媒を減圧下留去し、残渣をｎ−ヘキサンで洗浄し、４−(３−クロロ−４−メトキシベンジルアミノ)−５−エトキシカルボニル−２−メチルチオピリミジン３８.３４ｇを得る。融点：８６℃。
【００７５】
(２)上記(１)で得られる化合物５.００ｇのクロロホルム５０ｍｌ溶液に、氷冷下ｍ−クロロ過安息香酸４.００ｇのクロロホルム５０ｍｌ溶液を加え、２時間攪拌する。反応混合物を飽和炭酸水素ナトリウム水溶液及び食塩水で洗浄し、有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去し、４−(３−クロロ−４−メトキシベンジルアミノ)−５−エトキシカルボニル−２−メチルスルフィニルピリミジンの粗成物を得る。ＭＳ(m/z)：４４７(ＭＨ+)。
【００７６】
(３)上記(２)で得られる粗成物をテトラヒドロフラン４０ｍｌに溶解し、室温下Ｌ−プロリノール１.５０ｇ及びトリエチルアミン１.６０ｇのテトラヒドロフラン１０ｍｌ溶液を加える。一晩攪拌後、反応混合物を酢酸エチルで希釈し、炭酸水素ナトリウム水溶液及び食塩水で洗浄後、有機層を無水硫酸ナトリウムで乾燥する。溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィー(溶媒：クロロホルム)にて精製し、エーテル−n−ヘキサンより結晶化し、(Ｓ)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−エトキシカルボニル−２−(２−ヒドロキシメチル−１−ピロリジニル)ピリミジン４.７２ｇを得る。融点：８８−９０℃。ＭＳ(m/z)：４２１(ＭＨ+)。
【００７７】
(４)上記(３)で得られる化合物３.４ｇ、１０％水酸化ナトリウム水溶液２３ｍｌ、及びジメチルスルホキシド３４ｍｌを室温下１５時間攪拌する。反応混合物を１０％クエン酸水溶液に注ぎ、析出物をテトラヒドロフラン−エーテルより結晶化させ、(Ｓ)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−カルボキシ−２−(２−ヒドロキシメチル−１−ピロリジニル)ピリミジン２.５２ｇを得る。融点：２０５−２０８℃。ＭＳ(m/z)：３９１(Ｍ−Ｈ)-。
【００７８】
(５)上記(４)で得られる化合物６００ｍｇ、２−アミノメチルピリミジン２１７ｍｇ、１−(３−ジメチルアミノプロピル)−３−エチルカルボジイミド・塩酸塩３２３ｍｇ、１−ヒドロキシベンズトリアゾール・一水和物２２７ｍｇ、及びＮ,Ｎ−ジメチルホルムアミド１２ｍｌの混合物を室温下８時間攪拌後、反応混合物を炭酸水素ナトリウム水溶液に注ぐ。酢酸エチルで抽出し、食塩水で洗浄後、無水硫酸ナトリウムで乾燥する。溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィー(溶媒；クロロホルム：メタノール＝５０：１)にて精製し、(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジルメチル)カルバモイル]ピリミジン６１０ｍｇを得る。融点：１６０−１６３℃。
【００７９】
実施例２
(１)水素化リチウムアルミニウム４.１５ｇのテトラヒドロフラン１５０ｍｌ懸濁液に２−メチルチオ−４−(３−クロロ−４−メトキシベンジルアミノ)−５−エトキシカルボニルピリミジン３８.３２ｇのテトラヒドロフラン１００ｍｌ溶液を氷冷下５〜１０℃で１時間かけて加える。添加完了後、氷浴を除き、反応混合物を室温で１時間攪拌する。反応混合物に水４.１５ｍｌを氷冷下で加え、ついで３Ｎ水酸化ナトリウム水溶液４.１５ｍｌを加える。水４.１５ｍｌを３回混合物に加え、室温で１時間攪拌する。反応混合物を硫酸マグネシウムで処理したのち析出した固体を濾別し、固体をテトラヒドロフランで洗浄する。濾液と洗液を合せた後減圧下濃縮し、酢酸エチル−イソプロピルエーテルでトリチュレーションする。得られた結晶を濾取し、イソプロピルエーテルで充分洗浄して淡黄色結晶性粉末の２−メチルチオ−４−(３−クロロ−４−メトキシベンジルアミノ)−５−ヒドロキシメチルピリミジンを得る。
第１回生成；収量：２５.１０ｇ、融点：１６２−１６３℃
第２回生成；収量：２.３２ｇ、融点：１５９−１６０℃
さらに、析出固体をイソプロピルエーテルで再度洗浄し、濾液を減圧下濃縮し無色結晶物を得る。得られた固体をイソプロピルエーテルに懸濁し、濾過し、ついで沈澱物をイソプロピルエーテルとヘキサンで充分に洗浄して、４.２６ｇの無色結晶２−メチルチオ−４−(３−クロロ−４−メトキシベンジルアミノ)−５−ヒドロキシメチルピリミジンを得る。融点：１６１−１６２℃。
【００８０】
(２)上記(１)で得られる２−メチルチオ−４−(３−クロロ−４−メトキシベンジルアミノ)−５−ヒドロキシメチルピリミジン２５.１０ｇのクロロホルム１５０ｍｌ懸濁液に二酸化マンガン粉末３７.６ｇを加え、反応混合物を室温で１日激しく攪拌する。さらに二酸化マンガン粉末１２.６ｇ(原料化合物の０.５倍量)で処理し、３晩攪拌する。不溶物をすばやくセライト濾過して除き、濾液を減圧下濃縮し、残渣を酢酸エチル−イソプロピルエーテルに懸濁する。沈澱物を濾過し、イソプロピルエーテルとヘキサンで順次洗浄して無色結晶状の２−メチルチオ−４−(３−クロロ−４−メトキシベンジルアミノ)−５−ホルミルピリミジン２２.４３ｇを得る。融点：１２４−１２５℃。
【００８１】
(３)２−メチルチオ−４−(３−クロロ−４−メトキシベンジルアミノ)−５−ホルミルピリミジン２.０５７ｇのクロロホルム２０ｍｌ溶液をｍ−クロロ過安息香酸(８０％)１.４６８ｇで０℃で３０分間処理する。その反応混合物にＬ−プロリノール０.９０１ｇ、ついでトリエチルアミン１.３３ｍｌを加え、０℃で１時間反応させる。その反応混合物を室温まで昇温し、酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、沈澱物をシリカプラグで濾過して除く。濾液を減圧下濃縮して、無色アモルファス状の(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−ホルミルピリミジン１.９９９０ｇを得る。ＭＳ(m/z)：３７７(ＭＨ+)。
【００８２】
(４)(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−ホルミルピリミジン９１.０ｍｇのテトラヒドロフラン２０ｍｌ溶液に、メチルリチウムのエーテル溶液１.１ｍｌ(１.１０Ｍ)を−７８℃で１０分間反応させた後、炭酸水素ナトリウム水溶液を加える。その反応混合物を酢酸エチルで抽出して、(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−(１−ヒドロキシエチル)ピリミジンの粗成物を得る。ＭＳ(m/z)：３９３(ＭＨ+)。
【００８３】
(５)上記(４)で得られる粗成物を二酸化マンガン０.５ｇで室温下処理し、混合物を一晩攪拌する。その反応混合物を５時間還流下加熱し、不溶物を濾過して除き、濾液を減圧下濃縮し、シリカゲルカラムクロマトグラフィー(溶媒：クロロホルム：酢酸エチル＝３：１)で精製し、無色油状物の(Ｓ)−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−アセチルピリミジン５６.７ｍｇを得る。ＭＳ(m/z)：３９１(ＭＨ+)。
【００８４】
実施例３
(１)(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−ホルミルピリミジン８４ｍｇのテトラヒドロフラン約１ｍｌ溶液に１.０Ｍビニルマグネシウムブロミドのテトラヒドロフラン溶液をドライアイス−アセトン槽上で冷却しながら滴下する。反応混合物を−７８℃で１０分間、ついで室温下で１０分間攪拌する。反応混合物を氷−飽和炭酸水素ナトリウム水溶液中に注ぎ、酢酸エチルで抽出する。有機層を水と食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥、ついで減圧下濃縮する。
得られた粗生成物を分取用薄層クロマトグラフィー(溶媒；酢酸エチル：メタノール＝２０：１)に付して、無色油状物の(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−(１−ヒドロキシ−２−プロペン−１−イル)ピリミジン３０ｍｇを得る。ＭＳ(m/z)：４０５(ＭＨ+)。
【００８５】
(２)(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−(１−ヒドロキシ−２−プロペン−１−イル)ピリミジン１４４ｍｇのクロロホルム２.５ｍｌ溶液に二酸化マンガン４３２ｍｇを加え、室温下激しく三晩攪拌する。不溶物をセライトで濾過して除き、濾液を減圧下濃縮して、淡黄色油状物１２４ｍｇを得る。得られた粗生成物をシリカゲルカラムクロマトグラフィー(シリカゲル２０ｇ、溶媒；クロロホルム：酢酸エチル＝２：１)で精製して、無色結晶の(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−(アクリロイル)ピリミジン９０ｍｇを得る。融点：１１３−１１５℃。ＭＳ(m/z)：４０３(ＭＨ+)。
【００８６】
(３)(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−(アクリロイル)ピリミジン７２ｍｇのエタノール２ｍｌ溶液に室温下モルホリン７８μｌを加え、その混合物を室温下４０分間攪拌する。反応混合物を減圧下濃縮し、残渣を水中に注ぎ、酢酸エチルで抽出する。有機層を水と食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧下で蒸発乾固して、(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[(２−モルホリノエチル)カルボニル]ピリミジン９１ｍｇを得る。
【００８７】
得られた粗生成物を酢酸エチル１０ｍｌに溶解し、その溶液を塩酸／メタノール飽和溶液５ｍｌで処理し、減圧下濃縮する。残渣に酢酸エチルを加え、濾過し、得られた固体をヘキサンで充分に洗浄して、(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[(２−モルホリノエチル)カルボニル]ピリミジン２塩酸塩６５ｍｇを得る。ＭＳ(m/z)：４９０(ＭＨ+)。
【００８８】
実施例４
(１)上記実施例１(１)で得られる４−(３−クロロ−４−メトキシベンジルアミノ)−５−エトキシカルボニル−２−メチルチオピリミジン９７２ｍｇのクロロホルム８ｍｌ溶液にｍ−クロロ過安息香酸(８０％)５９８ｍｇのクロロホルム１０ｍｌ溶液を氷冷下３０分間で加える。反応混合物を氷冷下１時間攪拌する。反応混合物を飽和炭酸水素ナトリウム水溶液で希釈し、クロロホルム層を分離し、飽和炭酸水素ナトリウム水溶液、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、減圧下濃縮して無色カラメル状の２−メチルスルフィニル−４−(３−クロロ−４−メトキシベンジルアミノ)−５−エトキシカルボニルピリミジンを定量的に得る。ＭＳ(m/ｚ)：３８４(ＭＨ+)。
【００８９】
(２)上記(１)で得られる２−メチルスルフィニル−４−(３−クロロ−４−メトキシベンジルアミノ)−５−エトキシカルボニルピリミジン全量のテトラヒドロフラン６ｍｌ溶液に、氷冷下２Ｎ水酸化ナトリウム１.３２ｍｌを氷冷下２分間で滴下し、反応混合物を氷冷下３０分間攪拌する。さらにテトラヒドロフラン８ｍｌとＮ,Ｎ−ジメチルアセトアミド６ｍｌを加え、反応混合物を氷冷下３０分間攪拌する。水５ｍｌとＮ,Ｎ−ジメチルアセトアミド２ｍｌを加え、反応液を氷冷下で１時間攪拌する。反応混合液を１０％クエン酸水溶液で酸性とし、水で希釈し、酢酸エチルで２回抽出する。抽出液を集め、水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥、減圧下濃縮する。残渣をシリカゲルカラムクロマトグラフィー(シリカゲル２０ｇ、溶媒；クロロホルム：酢酸エチル＝５：１→クロロホルム：イソプロパノ−ル＝３０：１)で分離してわずかに黄色の結晶粉末状の２−ヒドロキシ−４−(３−クロロ−４−メトキシベンジルアミノ)−５−エトキシカルボニルピリミジン６１８ｍｇを得る。融点：１９５−１９７℃。
【００９０】
(３)上記(２)で得られる２−ヒドロキシ−４−(３−クロロ−４−メトキシベンジルアミノ)−５−エトキシカルボニルピリミジン５００ｍｇ、ジエチルアミノベンゼン２ｍｌ及びオキシ塩化リン４ｍｌの混合液を８０℃で３０分間、ついで１００℃で５時間攪拌する。冷却後、反応液を氷−水中に注ぎ、混合物を室温で３０分間攪拌する。得られた生成物を酢酸エチルで抽出し、有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥、減圧濃縮する。残渣をシリカゲルカラムクロマトグラフィー(シリカゲル７ｇ、溶媒；クロロホルム)で精製してわずかに黄色の結晶粉末の２−クロロ−４−(３−クロロ−４−メトキシベンジルアミノ)−５−エトキシカルボニルピリミジン３７５ｍｇを得る。融点：１１４−１１５℃。ＭＳ(m/z)：３５６(ＭＨ+)。
【００９１】
(４)上記(３)で得られる２−クロロ−４−(３−クロロ−４−メトキシベンジルアミノ)−５−エトキシカルボニルピリミジン２８５ｍｇ、５,６,７,８−テトラヒドロイミダゾ[１,２−a]ピラジン１９７ｍｇ、トリエチルアミン０.２２ｍｌ及びクロロホルム３ｍｌの混合物を室温で２.５時間攪拌し、ついで６０℃で２.５時間攪拌する。反応混合物を酢酸エチルで希釈し、水洗する。水層を酢酸エチルで抽出し、有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下濃縮する。残渣をシリカゲルカラムクロマトグラフィー(シリカゲル１０ｇ、クロロホルム：メタノール＝５０：１)で精製し、減圧下濃縮する。イソプロピルエーテルでトリチュレーションして無色結晶粉末状の２−(５,６,７,８−テトラヒドロイミダゾ[１,２−a]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−エトキシカルボニルピリミジン２９０ｍｇを得る。融点：１７９−１８２℃。ＭＳ(m/z)：４４３(ＭＨ+)。
【００９２】
(５)上記(４)で得られる２−(５,６,７,８−テトラヒドロイミダゾ[１,２−a]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−エトキシカルボニルピリミジン２９０ｍｇと２Ｎ水酸化ナトリウム１.６４ｍｌのジメチルスルホキシド−水(５ｍｌ−１ｍｌ)中懸濁液を室温で１時間攪拌する。テトラヒドロフラン５ｍｌを添加し、混合物を室温で１３時間で攪拌する。テトラヒドロフランを減圧下留去し、得られた溶液を水で希釈し、１０％クエン酸水溶液で中和する。生じた沈澱物を分取し、水、メタノール、及びイソプロピルエーテルで洗浄して無色結晶粉末の２−(５,６,７,８−テトラヒドロイミダゾ[１,２−a]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−カルボキシピリミジン１８７ｍｇを得る。融点：２２３−２２６℃(分解)。ＭＳ(m/z)：４１３(Ｍ−Ｈ)-。
【００９３】
(６)２−(５,６,７,８−テトラヒドロイミダゾ[１,２−a]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−カルボキシピリミジン６０ｍｇ、４−メチル−２−アミノメチルモルホリン２２.７ｍｇ、１−(３−ジメチルアミノプロピル)−３−エチルカルボジミド・塩酸塩３０.６ｍｇ、１−ヒドロキシベンゾトリアゾール２１.６ｍｇ及びＮ,Ｎ−ジメチルホルムアミド３ｍｌの混合物を室温で２２時間攪拌する。水を反応混合物に注ぎ、酢酸エチルで抽出する。有機層を水、飽和炭酸水素ナトリウム水溶液、水及び食塩水で洗浄し、無水硫酸ナトリウムで乾燥、ついで減圧下濃縮して、無色結晶７０.０ｍｇを得る。これをクロロホルム−ヘキサンから再結晶して無色針状結晶の２−(５,６,７,８−テトラヒドロイミダゾ[１,２−a]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−[(４−メチル−２−モルホリニル)メチル]カルバモイル]ピリミジン５１.７ｍｇを得る。融点：１３２−１３４℃。ＭＳ(m/z)：５２７(ＭＨ+)。
【００９４】
実施例５〜６
対応する出発物質を実施例４(６)と同様に処理して、下記第１表記載の化合物を得る。
【００９５】
【表１】
実施例７〜２１
対応する出発物質より同様に処理して、下記第２表記載の化合物を得る。
【００９７】
【表２】
【表３】
実施例２２
(１)ジイソプロピルアミン０.７８ｇのテトラヒドロフラン４０ｍｌ溶液に１.６Ｍ ｎ−ブチルリチウムのヘキサン溶液４.８２ｍｌをドライアイス−アセトン浴で冷却しながら３分間で滴下する。混合物を同浴上で３０分間攪拌する。２,６−ジクロロピラジン０.５０ｇのテトラヒドロフラン５ｍｌ溶液を同温度で１５分間で滴下し、混合物を１時間攪拌する。反応混合物をドライアイス中に注ぎ、室温で１時間攪拌する。反応混合物を１０％塩酸水溶液で希釈してｐＨ値を約２とし、酢酸エチルで抽出する。集めた有機層を飽和炭酸水素ナトリウム水溶液で抽出し、水抽出液を酢酸エチルで洗浄し、１０％塩酸水溶液で酸性とし、酢酸エチルで抽出する。集めた有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥、減圧下濃縮する。残渣をクロロホルム−ヘキサン(１：１)でトリチュレーションして、わずかに褐色の結晶性粉末状の２−カルボキシ−３,５−ジクロロピラジン２３４ｍｇを得る。融点：１３９−１４１℃。ＭＳ(m/z)：１９１(Ｍ−Ｈ)-。
【０１００】
(２)上記(１)で得られる２−カルボキシ−３,５−ジクロロピラジン２２６ｍｇ、炭酸水素ナトリウム１１８ｍｇ、沃化メチル０.５ｍｌ及びＮ,Ｎ−ジメチルホルムアミド１.８ｍｌの混合物を室温で１４時間攪拌する。混合物を１０％クエン酸水溶液で希釈し、酢酸エチルで抽出する。集めた有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下濃縮して、淡褐色結晶性粉末状の２−メトキシカルボニル−３,５−ジクロロピラジン２４５ｍｇを得る。融点：６０−６３℃。ＭＳ(m/z)：２０６(Ｍ+)。
【０１０１】
(３)上記(２)で得られる２−メトキシカルボニル−３,５−ジクロロピラジン２３４ｍｇ、３−クロロ−４−メトキシベンジルアミン２０４ｍｇ、トリエチルアミン０.１７ｍｌ及び無水トルエン３ｍｌの混合物を室温で７時間攪拌する。反応混合物を１０％クエン酸水溶液で希釈し、酢酸エチルで抽出する。抽出液を水と飽和食塩水で洗浄、硫酸ナトリウムで乾燥、ついで減圧下濃縮する。残渣をシリカゲルカラムクロマトグラフィー(シリカゲル５ｇ、溶媒；ヘキサン：クロロホルム＝１：１)で精製・分離し、所望の分画を減圧下濃縮して淡黄色結晶粉末状の２−メトキシカルボニル−３−(３−クロロ−４−メトキシベンジルアミノ)−５−クロロピラジン１０２ｍｇを得る。融点：１４９−１５１℃。ＭＳ(m/z)：３４２(ＭＨ+)。
【０１０２】
(４)２−メトキシカルボニル−３−(３−クロロ−４−メトキシベンジルアミノ)−５−クロロピラジン１５０ｍｇ、２−ヒドロキシメチルピロリジン８８.６ｍｇ、トリエチルアミン０.１２ｍｌのテトラヒドロフラン５ｍｌ混合物を室温で４時間攪拌し、ついで５０℃で２時間加熱する。ついで２−ヒドロキシメチルピロリジン４４.３ｍｇを加え、混合物を５０℃で１時間攪拌する。冷却後、水を混合物に加え、酢酸エチルで抽出する。抽出液を水、食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮する。得られた黄色油状物をシリカゲルフラッシュカラムクロマトグラフィー(溶媒；クロロホルム：ヘキサン＝１：１)で精製して、淡黄色粉末状の(Ｓ)−２−メトキシカルボニル−３−(３−クロロ−４−メトキシベンジルアミノ)−５−(２−ヒドロキシメチル−１−ピロリジニル)ピラジン１２３ｍｇを得る。ＭＳ(m/z)：４０７(ＭＨ+)。
【０１０３】
(５)上記(４)で得られる(Ｓ)−２−メトキシカルボニル−３−(３−クロロ−４−メトキシベンジルアミノ)−５−(２−ヒドロキシメチル−１−ピロリジニル)ピラジン７７５ｍｇのエタノール８ｍｌ溶液に４Ｎ水酸化ナトリウム水溶液１.４３ｍｌを加え、混合液を室温で２４時間攪拌する。反応混合液を１０％塩酸で酸性とし、酢酸エチルで抽出し、有機層を水と食塩水で洗浄、無水硫酸ナトリウムで乾燥、ついで減圧濃縮し、イソプロピルアルコールで洗浄して、黄色結晶の(Ｓ)−２−カルボキシ−３−(３−クロロ−４−メトキシベンジルアミノ)−５−(２−ヒドロキシメチル−１−ピロリジニル)ピラジン５３７ｍｇを得る。融点：１６９−１７１℃。ＭＳ(m/z)：３９１(Ｍ−Ｈ)-。
【０１０４】
(６)上記(５)で得られる(Ｓ)−２−カルボキシ−３−(３−クロロ−４−メトキシベンジルアミノ)−５−(２−ヒドロキシメチル−１−ピロリジニル)ピラジン８０ｍｇ、２−アミノメチルピリミジン２６.７ｍｇ、１,２−ジクロロエタン４３ｍｇ、１−ヒドロキシベンゾトリアゾール３０.３ｍｇのＮ,Ｎ−ジメチルホルムアミド３ｍｌ混合物を室温で１８時間攪拌する。反応混合物中に水を注ぎ、酢酸エチルで抽出する。抽出液を水、飽和炭酸水素ナトリウム水溶液及び食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、ついで減圧濃縮する。残渣をシリカゲルフラッシュカラムクロマトグラフィー(溶媒；酢酸エチル)で精製して、(Ｓ)−２−[Ｎ−(２−ピリミジニルメチル)カルバモイル]−３−(３−クロロ−４−メトキシベンジルアミノ)−５−(２−ヒドロキシメチル−１−ピロリジニル)ピラジン８７.６ｍｇを得る。ＭＳ(m/z)：４８４(ＭＨ+)。
【０１０５】
実施例２３〜２４
対応する出発物質を実施例２２と同様に処理して、下記第３表記載の化合物を得る。
【０１０６】
【表４】
実施例２５
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−(アクリロイル)ピリミジン３１ｍｇ、メタノール１ｍｌ及び濃硫酸１滴の混合物を２日間加熱還流する。反応後溶媒を留去し、残さをシリカゲル薄層クロマトグラフィー(溶媒：クロロホルム：メタノール＝３０：１)で分離することにより、(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[(２−メトキシエチル)カルボニル]ピリミジン２７ｍｇを無色油状物として得る。ＭＳ(m/z)：４３５(ＭＨ+)。
【０１０８】
実施例２６
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジニルメチル)カルバモイル]ピリミジン８２.４８ｇ及びベンゼンスルホン酸１水和物６０.０６ｇのメタノール１０００ｍｌ溶液を濃縮し、メタノール−アセトン混液より再結晶することにより、(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジニルメチル)カルバモイル]ピリミジン・２ベンゼンスルホン酸塩１２１.８ｇを無色結晶として得る。融点：１５８.５−１６１.５℃。
【０１０９】
実施例２７
実施例１(４)で得られた(Ｓ)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−カルボキシ−２−(２−ヒドロキシメチル−１−ピロリジニル)ピリミジン１００ｍｇ、４−アミノ−１,３,５−トリメチルピラゾール４７.９ｍｇ、１−(３−ジメチルアミノプロピル)−３−エチルカルボジイミド・塩酸塩５８.７ｍｇ、１−ヒドロキシベンズトリアゾール・１水和物４１.３ｍｇ、及びＮ,Ｎ−ジメチルホルムアミド３ｍｌの混合物を室温下８時間攪拌後、反応混合物を炭酸水素ナトリウム水溶液に注ぐ。酢酸エチルで抽出後、有機層を水、および飽和食塩水にて洗浄し、無水硫酸ナトリウムで乾燥する。溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィー(溶媒；クロロホルム：メタノール＝５：１)にて精製し、(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(１,３,５−トリメチル−４−ピラゾリル)カルバモイル]ピリミジン１１５ｍｇを得る。ＭＳ(m/z)：５００(ＭＨ+)。
【０１１０】
実施例２８
(１)４−クロロ−５−エトキシカルボニル−２−メチルチオピリミジン５.０ｇのスルフリルクロリド２０ｍｌ溶液を５０℃で１時間加熱する。反応混合液を濃縮し、飽和炭酸水素ナトリウム水溶液を注ぐ。混合液を酢酸エチルで抽出し、有機層を水、食塩水で洗浄し、硫酸ナトリウムで乾燥し、濃縮する。残渣をシリカゲルフラッシュカラムクロマトグラフィー(溶媒；酢酸エチル：ヘキサン＝１：１０)で精製して、黄色油状物の２,４−ジクロロ−５−エトキシカルボニルピリミジン４.８７ｇを定量的に得る。ＭＳ(m/z)：２２０(Ｍ+)。
【０１１１】
(２)上記(１)で得られる２,４−ジクロロ−５−エトキシカルボニルピリミジン４.２ｇとメルカプトベンゼン２.３０ｇのトルエン４０ｍｌ溶液に０℃で炭酸カリウム３.９４ｇを加え、室温で１時間、ついで５０℃で１時間、さらに１００℃で１０分間攪拌する。水を注ぎ、酢酸エチルで抽出する。有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥、ついで濃縮する。残渣をシリカゲルフラッシュカラムクロマトグラフィー(溶媒；酢酸エチル：ヘキサン＝１：２０〜酢酸エチル：ヘキサン＝１：１０)で精製して、無色結晶の２−クロロ−４−フェニルチオ−５−エトキシカルボニルピリミジン４.１６ｇを得る。ＭＳ(m/z)：２９５(ＭＨ+)。
【０１１２】
(３)上記(２)で得られる２−クロロ−４−フェニルチオ−５−エトキシカルボニルピリミジン４.０５ｇのテトラヒドロフラン４０ｍｌ溶液にＬ−プロリノール１.６６ｇとトリエチルアミン２.７７ｇを加え、混合物を室温で２０時間攪拌する。反応混合物に水を注ぎ、酢酸エチルで抽出する。有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥、ついで濃縮する。残渣をシリカゲルフラッシュカラムクロマトグラフィー(溶媒；酢酸エチル：ヘキサン＝１：２)で精製して、無色粘稠油状物の(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−フェニルチオ−５−エトキシカルボニルピリミジン４.１６ｇを得る。ＭＳ(m/z)：３６０(ＭＨ+)。
【０１１３】
(４)上記(３)で得られる(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−フェニルチオ−５−エトキシカルボニルピリミジン４.１０ｇのエタノール５０ｍｌ溶液に４Ｎ水酸化ナトリウム水溶液８.６ｍｌを加え、混合物を室温で１５時間攪拌する。反応溶液が弱酸性になるまで、１０％クエン酸水溶液３０ｍｌを加え、ついで酢酸エチルで抽出する。有機層を水、食塩水で洗浄し、硫酸ナトリウムで乾燥し、濃縮して、無色結晶の(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−フェニルチオ−５−カルボキシピリミジン３.６５ｇを得る。ＭＳ(m/z)：３３０(Ｍ−Ｈ)-。
【０１１４】
(５)上記(４)で得られる(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−フェニルチオ−５−カルボキシピリミジン２.５５ｇ、２−アミノメチルピリミジン１.０９ｇ、１,２−ジクロロエタン１.７７ｇ及び１−ヒドロキシベンズトリアゾール１.２５ｇのＮ,Ｎ−ジメチルホルムアミド４０ｍｌの混合物を室温で１６時間攪拌する。水を注ぎ、酢酸エチルで抽出する。有機層を水、飽和炭酸水素ナトリウム水溶液及び食塩水で洗浄し、硫酸ナトリウムで乾燥し、濃縮して、淡黄色結晶４.０５ｇを得る。これをシリカゲルフラッシュカラムクロマトグラフィー(溶媒；酢酸エチル)で精製して、無色結晶の２−(２−ヒドロキシメチル−１−ピロリジニル)−４−フェニルチオ−５−[Ｎ−(２−ピリミジルメチル)カルバモイル]ピリミジン２.３９ｇを得る。融点：１５４−１５６℃。ＩＲ(Nujol)：１６３３ｃｍ-1。ＭＳ(m/z)：４２３(ＭＨ+)。
【０１１５】
(６)上記(５)で得られる(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−フェニルチオ−５−[Ｎ−(２−ピリミジルメチル)カルバモイル]ピリミジン１００ｍｇのクロロホルム３ｍｌ溶液にｍ−クロロ過安息香酸７０.１ｍｇを０℃で加え、混合物を０℃で３０分間攪拌する。ついで、３−クロロベンジルアミン５０.３ｍｇとトリエチルアミン４８.０ｍｇを０℃で加え、混合物を室温で１７時間攪拌する。水を注ぎ、クロロホルムで抽出し、有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥、ついで濃縮して黄色油状物１６９ｍｇを得る。これをシリカゲルフラッシュカラムクロマトグラフィー(溶媒；酢酸エチル)で精製し、酢酸エチル−ヘキサンでトリチュレーションして、無色粉末状の(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロベンジルアミノ)−５−[Ｎ−(２−ピリミジルメチル)カルバモイル]ピリミジン９５.３ｍｇを得る。融点：１５３−１５６℃。ＩＲ(Nujol)：３２４１、１６３７ｃｍ-1。ＭＳ(m/z)：４５４(ＭＨ+)。
【０１１６】
(７)上記(５)で得られる(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−フェニルチオ−５−[Ｎ−(２−ピリミジルメチル)カルバモイル]ピリミジン１００ｍｇのクロロホルム３ｍｌ溶液にｍ−クロロ過安息香酸(７０％)７０.１ｍｇを０℃で加え、混合物を０℃で３０分間攪拌する。ついで、４−メトキシベンジルアミン４８.８ｍｇとトリエチルアミン４８.０ｍｇを０℃で加え、混合物を室温で２０時間攪拌する。水を注ぎ、クロロホルムで抽出し、有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥、ついで濃縮して黄色油状物１４３ｍｇを得る。これをシリカゲルフラッシュカラムクロマトグラフィー(溶媒；酢酸エチル)で精製して、無色粉末状の(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジルメチル)カルバモイル]ピリミジン８８.２ｍｇを得る。ＩＲ(Neat)：３２９６、１６３３ｃｍ-1。ＭＳ(m/z)：４５０(ＭＨ+)。
【０１１７】
実施例２９
(１)実施例２(３)で得られる(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−ホルミルピリミジン１０.０ｍｇのテトラヒドロフラン１.０ｍｌ溶液を１.６Ｍ ｎ−ブチルリチウムヘキサン溶液８３μｌで−７８℃にて３分間処理した後、炭酸水素ナトリウム水溶液を加える。その反応混合物を酢酸エチルで抽出して油状の(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−(１−ヒドロキシペンチル)ピリミジン１３.７ｍｇを得る。
【０１１８】
(２)上記で得た(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−(１−ヒドロキシペンチル)ピリミジンを二酸化マンガン２５ｍｇで室温下処理し、さらに、二酸化マンガン１００ｍｇをゆっくりと加え、混合物を一晩攪拌する。その反応混合物を５時間還流下加熱し、不溶物を濾過して除き、濾液を減圧下に濃縮し、分取用薄層クロマトグラフィーで分離して、無色油状の(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−ペンタノイルピリミジン５.８ｍｇを得る。ＭＳ(m/z)：４３３(ＭＨ+)。
【０１１９】
実施例３０〜８３
対応する出発物質より同様に処理して、下記第４表記載の化合物を得る。
【０１２０】
【表５】
【表６】
【表７】
【表８】
【表９】
実施例８４〜８６
対応する出発物質より同様に処理して、下記第５表記載の化合物を得る。
【表１０】
実施例８７
実施例２２(５)で得られる(Ｓ)−２−カルボキシ−３−(３−クロロ−４−メトキシベンジルアミノ)−５−(２−ヒドロキシメチル−１−ピロリジニル)ピラジン８０ｍｇ、２−アミノメチル−４−メチルモルホリン３１.９ｍｇ、１−エチル−３−(３−ジメチルアミノプロピル)カルボジイミド・塩酸塩４３ｍｇ、１−ヒドロキシベンゾトリアゾール３０.３ｍｇのＮ,Ｎ−ジメチルホルムアミド３ｍｌ混合物を室温で１８時間攪拌する。反応混合物中に水を注ぎ、酢酸エチルで抽出する。抽出液を水、飽和炭酸水素ナトリウム水溶液及び食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、ついで減圧濃縮する。残渣をシリカゲルフラッシュカラムクロマトグラフィー(溶媒；酢酸エチル)で精製して、(Ｓ)−２−[Ｎ−(４−メチル−２−モルホリニル)メチルカルバモイル]−３−(３−クロロ−４−メトキシベンジルアミノ)−５−(２−ヒドロキシメチル−１−ピロリジニル)ピラジン８０.５ｍｇを得る。ＭＳ(m/z)：５０５(ＭＨ+)、ＩＲ(Nujol)：３２９５、１６３５ｃｍ-1。
【０１２７】
実施例８８〜９１
対応する出発物質より同様に処理して、下記第６表記載の化合物を得る。
【表１１】
実施例９２〜１４５
対応する出発物質より同様に処理して、下記第７表記載の化合物を得る。
【表１２】
【表１３】
【表１４】
【表１５】
【表１６】
【表１７】
実施例１４６
対応する出発物質より同様に処理して、泡状物の下記式の化合物を得る。ＭＳ(m/z)：４６４(ＭＨ+)。
【化９３】
実施例１４７
対応する出発物質より同様に処理して、下記式の化合物を得る。融点：１４０−１４４℃。
【化９４】
実施例１４８
実施例１(５)で得られる(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジルメチル)カルバモイル]ピリミジン３０７ｍｇの塩化メチレン６ｍｌ溶液に、臭化ホウ素３００μｌを氷冷下滴下する。反応混合液を０℃で４時間攪拌する。反応混合物にメタノール、ついで飽和炭酸水素ナトリウム水溶液を氷冷下加える。混合物を酢酸エチルとテトラヒドロフランの混合溶媒で抽出し、有機層を水、食塩水で順次洗浄、硫酸ナトリウムで乾燥、真空濃縮してわずかに茶色のアモルファス状物２２７ｍｇを得る。これをクロロホルムに懸濁し、生じた不溶物を濾過して除き、濾液をシリカゲルカラムクロマトグラフィーに供し、ついでＮＨ−シリカゲルカラムクロマトグラフィーで精製して、無色泡状物の(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−ヒドロキシベンジルアミノ)−５−[Ｎ−(２−ピリミジルメチル)カルバモイル]ピリミジン１２９ｍｇを得る。ＭＳ(m/z)：４７０(ＭＨ+)。ＩＲ(Nujol)：３２７９、１６３２、１５９３、１５６９、１５１８、１４６３ｃｍ-1。
【０１３７】
実施例１４９
(１)実施例１(１)で得られる２−メチルチオ−４−(３−クロロ−４−メトキシベンジルアミノ)−５−エトキシカルボニルピリミジン２.００ｇをジメチルスルホキシド１０ｍｌに懸濁し、室温下１０％水酸化ナトリウム水溶液１０ｍｌで処理する。ジメチルスルホキシド５ｍｌを加え、反応混合物を室温下一晩攪拌する。得られる透明な反応液にクエン酸を加え酸性とする。過剰量の水(約５０ｍｌ)を加え、生じた沈殿物を濾取し、イソプロピルアルコールで洗浄し、ついでイソプロピルエーテルでさらに洗浄し、減圧乾燥して、淡黄色微粉末状の、２−メチルチオ−４−(３−クロロ−４−メトキシベンジルアミノ)−５−カルボキシピリミジン１.８６４ｇを得る。融点：２３８−２４０℃(分解)。
【０１３８】
(２)４−(３−クロロ−４−メトキシベンジルアミノ)−５−カルボキシ−２−メチルチオピリミジン２００ｍｇの塩化メチレン５ｍｌ懸濁液にオキサリルクロリド１５０ｍｇとＮ,Ｎ−ジメチルホルムアミドを加え、混合物を室温で３０分間攪拌した。反応混合物を濃縮し、得られた酸クロリド化合物と５−アミノピリミジン８４.０ｍｇの塩化メチレン５ｍｌ懸濁液にジメチルアミノピリジン１４４ｍｇを室温下加え、混合物を室温で攪拌する。水を注ぎ、酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム水溶液、水、食塩水で洗浄、硫酸ナトリウムで乾燥、ついで濃縮する。残渣を酢酸エチルとｎ−ヘキサンの混合溶媒でトリチュレーションして、淡黄色針状結晶の４−(３−クロロ−４−メトキシベンジルアミノ)−５−(５−ピリミジニルアミノカルボニル)−２−メチルチオピリミジン２１６ｍｇを得る。融点：２３８−２４０℃。ＩＲ(Nujol)：３２５１、１６６６ｃｍ-1。ＭＳ(m/z)：４１６(Ｍ+)。
【０１３９】
(３)上記(２)で得られる化合物１５０ｍｇのクロロホルム１０ｍｌ懸濁液にｍ−クロロ過安息香酸１０７ｍｇを０℃で加え、混合物を０℃で１時間、室温で１時間攪拌し、ついでｍ−クロロ過安息香酸５３ｍｇを０℃で加え、０℃で３０分間攪拌する。Ｌ−プロリノール４３.７ｍｇとトリエチルアミン７２.９ｍｇを０℃で加え、混合物を室温で２０時間攪拌する。水を注ぎ、クロロホルムで抽出し、有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥、ついで濃縮して、黄色粘稠油状物２０１ｍｇを得、これをＮＨ−シリカゲルフラッシュカラムクロマトグラフィー(溶媒；酢酸エチル)で精製し、酢酸エチルとヘキサンの混合溶媒で洗浄して、無色針状結晶の(Ｓ)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−(５−ピリミジニルアミノカルボニル)−２−(２−ヒドロキシメチル−１−ピロリジニル)ピリミジン８１ｍｇを得る。融点：１９２−１９５℃。ＩＲ(Nujol)：３２７９、１６６９ｃｍ-1。ＭＳ(m/z)：４７０(ＭＨ+)。
【０１４０】
実施例１５０〜１５７
実施例１４９と同様に、対応する出発物質より下記第８表記載の化合物を得る。
【表１８】
実施例１５８
(１)実施例１４９(１)で得られる４−(３−クロロ−４−メトキシベンジルアミノ)−５−カルボキシ−２−メチルチオピリミジン１５４.０ｍｇの塩化メチレン５ｍｌ懸濁液をオキサリルクロリド１１９μｌで室温下処理し、Ｎ,Ｎ−ジメチルホルムアミドを加える。混合物を１時間攪拌し、溶媒を真空除去する。残渣をエーテルで処理し、一晩冷蔵する。揮発性物質を真空除去し、残渣を過剰量のジアゾメタンで０℃で処理し、ついで一晩冷蔵する。メタノールを加えて反応を止める。シリカゲルクロマトグラフィー(溶媒；ヘキサン：酢酸エチル＝２：１)で精製して、４−(３−クロロ−４−メトキシベンジルアミノ)−５−(ジアゾメチルカルボニル)−２−メチルチオピリミジン２１.５ｍｇを淡黄色固体物として得る。ＩＲ(Nujol)：３２７７、２１１５、１６０７、１５６７、１４６１、１３７７、１３５７、１１４１ｃｍ-1。ＭＳ(m/z)：３６４(ＭＨ+)。融点：１６２−１６５℃(分解)。
【０１４２】
(２)上記(１)で得られる化合物１６.５ｍｇのメタノール３ｍｌ懸濁液をトルエンスルホン酸１水和物１６.５ｍｇで室温下処理する。溶媒を真空除去し、残渣をプレパラティブＴＬＣ(溶媒；ヘキサン：酢酸エチル＝２：１)で精製して、４−(３−クロロ−４−メトキシベンジルアミノ)−５−(メトキシメチルカルボニル)−２−メチルチオピリミジン１１.０ｍｇを無色油状物で得る。
【０１４３】
(３)上記(２)で得られる化合物１１.０ｍｇのクロロホルム１.０ｍｌ溶液をｍ−クロロ過安息香酸７.４ｍｇで０℃で処理する。混合物を室温下トリエチルアミン８.３μｌとＬ−プロリノール３６ｍｇで処理し、反応混合物を一晩攪拌する。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥する。残渣をプレパラティブＴＬＣ(溶媒；クロロホルム：酢酸エチル＝１：１)で精製して、無色油状物の(Ｓ)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−(メトキシメチルカルボニル)−２−(２−ヒドロキシメチル−１−ピロリジニル)ピリミジン８.５ｍｇを得る。ＭＳ(m/z)：４２１(ＭＨ+)。
【０１４４】
【発明の効果】
本発明の化合物(Ｉ)及びその薬理的に許容し得る塩は、優れたＰＤＥ Ｖ阻害作用を有し、陰茎勃起不全等の予防・治療剤として有用な医薬化合物である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel aromatic nitrogen-containing six-membered ring compound having a cGMP-specific phosphodiesterase (PDE) inhibitory action (PDE V inhibitory action) and useful as a medicament, and a process for producing the same.
[0002]
[Prior art]
In general, cGMP, which is an intracellular second messenger, is degraded and inactivated by phosphodiesterase widely distributed in tissues in the living body, but when the PDE activity is inhibited, the concentration of intracellular cGMP increases. It is known that various pharmacological actions such as vascular smooth muscle relaxing action, bronchial smooth muscle relaxing action, platelet aggregation inhibitory action and the like are expressed.
In addition, a compound having such cGMP-specific PDE inhibitory action (ie, PDE V inhibitory action) is used in various diseases caused by cGMP system signaling dysfunction such as hypertension, angina pectoris, myocardial infarction, chronic And known to be useful for the treatment of acute heart failure, pulmonary hypertension (WO96 / 05176, etc.), prostatic hypertrophy (Australian Patent Publication 9559777), etc., and female sexual dysfunction [Vemulapalli et al., Life Sciences, 67, 23-29 (2000) (Life Sciences)], diabetic gastric paresis [Watkins et al., Journal of Clinical Investment, 106, 373-384 (2000) (J. Clin. Invest.)], Achalasia [Bortolotti et al., Gastroenterology, 118, 253-257 (2000) (Gastroenterology) Diarrhea [Mule et al., British Journal of Pharmacology, 127, 514-520 (1999) (Br. J. Pharmacol.)], Constipation [Bakre et al., Journal of Cellular Bio Chemistry, 77, 159-167 (2000) (J. Cell. Biochem.)], Asthma [Turner et al., British Journal of Pharmacology, 111, 1981-204 (1994). (Year) (Br. J. Pharmacol.)] Has also been reported for possible use.
[0003]
Furthermore, 1- [4-ethoxy-3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidine-5 having PDE V inhibitory action Yl) phenylsulfonyl] -4-methylpiperazine (generic name: Sildenafil) has also been reported to be useful in the treatment of diseases such as penile erectile dysfunction [Boolell et al., The Journal of Urology Supplements. 155, No. 5, 495A, page 739 (1996) (The Journal of Urology, Supplement), Terrett et al., Bio-Organic and Medicinal Chemistry Letters, Vol. 6, No. 15, 1819 (1996) (Bioorganic & Medicinal Chemistry Letters) and Ballard et al., British Journal of Pharmacology Proceeding Supplements 118, 153P (1996) (British Journal of Pharmacology, Proceeding Supplement)].
[0004]
However, sildenafil has also been reported to have side effects such as headache, flushing of the face, gastrointestinal dysfunction, rhinitis, color blindness, and persistent erection [Irwin et al., The New Ingrad Journal of Medicine, 338, No. 20, pp. 1397-1404 (1998) (The New England Journal of Medicine), Morales et al., International Journal of Impotence Research, Vol. 10, No. 2, 69- 73 (1998) (International Journal of Impotence Research) and Goldenberg, Clinical Therapeutics, Vol. 20, No. 6, pages 1033-1048 (1998) (Clinical Therapeutics)].
[0005]
In dog experiments, sildenafil has been reported to correlate with PDE VI inhibitory effects on the effects of light response on retinal tissue [Morales et al., International Journal of Impotence Research, Vol. 10, 2, 69-73 (1998) (International Journal of Impotence Research)], on the other hand, it has also been reported that retinal PDE VI plays an important role in visual function [Morales et al., International Journal of Impotence Research, Vol. 10, No. 2, pp. 69-73 (1998) (International Journal of Impotence Research) and Estrade et al., European Journal of Pharmacology, Vol. 352, 157-163 (1998) (European Journal of Pharmacology)].
[0006]
[Problems to be solved by the invention]
The present invention provides a novel aromatic nitrogen-containing six-membered ring compound which has an excellent phosphodiesterase V (PDE V) inhibitory action and is useful as a prophylactic / therapeutic agent for penile erectile dysfunction. Furthermore, the present invention also provides a method for producing such a novel aromatic nitrogen-containing six-membered ring compound.
[0007]
[Means for Solving the Problems]
The present invention relates to general formula (I)
Embedded image
-NH-Q-RThree
(Wherein RThreeIs an optionally substituted nitrogen-containing heterocyclic group, Q represents a lower alkylene group or a single bond)
Or a group represented by:
-NH-RFour
(Wherein RFourRepresents an optionally substituted cycloalkyl group)
A group represented by R2Is an optionally substituted aryl group, one of Y and Z represents the formula: = CH-, and the other represents the formula: = N-)
Or a pharmacologically acceptable salt thereof and a process for producing the same.
[0008]
DETAILED DESCRIPTION OF THE INVENTION
In the compound (I) of the present invention, the nitrogen-containing heterocyclic group of the “optionally substituted nitrogen-containing heterocyclic group” represented by ring A includes a 5- to 10-membered monocyclic or bicyclic group. Nitrogen heterocyclic groups, more specifically, 5- to 6-membered monocyclic nitrogen-containing heterocyclic groups and 8- to 10-membered bicyclic nitrogen-containing heterocyclic groups, and more specifically, 5- to 6-membered non-aromatic monocyclic nitrogen-containing heterocyclic group such as pyrrolidinyl group, piperazinyl group, piperidyl group, morpholino group, imidazolyl group, pyrrolyl group, etc. Nitrogen heterocyclic group, 6,7-dihydro-5H-pyrrolo [3,4-b] pyridin-6-yl group, 5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine-7- Yl group, 5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl group, 1,2,3,4-tetrahydro-2-isoxy group Norinyl group, 1H-2,3,4,5,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl group, 4,5,6,7-tetrahydrothiazolo [5.4] -C] pyridin-6-yl group, 5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-6-yl group, 4,5,6,7-tetrahydro-3H-imidazo [4 , 5-c] pyridin-3-yl group and the like.
[0009]
RThreeAs the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by the formula, a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8 to 10-membered bicyclic group Specific examples include nitrogen-containing heterocyclic groups such as morpholinyl group, piperazinyl group, piperidyl group, thiadiazolyl group, dihydropyrimidinyl group, dihydropyrazolyl group, etc. Cyclic groups, 5- to 6-membered aromatic monocyclic nitrogen-containing heterocyclic groups such as pyrimidinyl group, pyridazinyl group, pyridyl group, pyrazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, pyrazinyl group, benzothiazolyl group, Examples thereof include 8- to 10-membered bicyclic nitrogen-containing heterocyclic groups such as a quinolyl group and a dihydrobenzoxazolyl group.
[0010]
Ring A and RThreeAs the substituent of the “optionally substituted nitrogen-containing heterocyclic group” represented by
(1) a lower alkyl group,
(2) a hydroxyl group-substituted lower alkyl group,
(3) formyl group,
(4) an oxo group,
(5) amino group,
(6) Di-lower alkylamino group,
(7) hydroxyl group,
(8) a lower alkoxy group,
(9) a lower alkoxycarbonyl group,
(10) a lower alkoxy-substituted lower alkanoyl group,
(11) a lower alkanoyl group,
(12) a cyano group-substituted lower alkyl group, and
(13) (i) a benzylamino group substituted with a halogen atom and a lower alkoxy group, and (ii) a pyrimidinyl group substituted with a hydroxyl group-substituted cycloalkylcarbamoyl group,
Etc.
[0011]
R2Examples of the aryl group of the “optionally substituted aryl group” represented by the above include 5- to 10-membered monocyclic or bicyclic aromatic hydrocarbon groups, specifically, phenyl group, naphthyl group and the like. can give.
[0012]
R2Examples of the substituent of the “optionally substituted aryl group” represented by the formula include a lower alkoxy group, a halogen atom, a cyano group, a nitro group, a hydroxyl group, and a lower alkyl group.
[0013]
R1“An optionally substituted lower alkyl group” and RFourSubstituents of the “optionally substituted cycloalkyl group” represented by the formula: lower alkoxy group, hydroxyl group, morpholinyl group, lower alkylsulfonyl group, di-lower alkylphosphino group, di-lower alkylamino group, pyrimidinyl group substitution Examples thereof include a lower alkylamino group, a pyridyl group, a pyridylamino group, a lower alkyl group-substituted piperazinyl group, and a pyrimidinyloxy group.
[0014]
Throughout this specification, a lower alkyl group means a straight or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like. The lower alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy and the like. A cycloalkyl group means a C3-C8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The lower alkylene group means a linear or branched alkylene group having 1 to 6 carbon atoms such as methylene, ethylene, trimethylene and the like. The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0015]
Among the compounds (I) of the present invention, preferred compounds include the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by ring A in general formula (I), A 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic nitrogen-containing heterocyclic group, the substitution of the above-mentioned “optionally substituted nitrogen-containing heterocyclic group” The group is
(1) a lower alkyl group,
(2) a hydroxyl group-substituted lower alkyl group,
(3) formyl group,
(4) an oxo group,
(5) amino group,
(6) hydroxyl group,
(7) a lower alkoxycarbonyl group, and
(8) (i) a benzylamino group substituted with a halogen atom and a lower alkoxy group and (ii) a pyrimidinyl group substituted with a hydroxyl group-substituted cycloalkylcarbamoyl group
R is a group selected from R1Is selected from a lower alkoxy group, a hydroxyl group, a morpholinyl group, a lower alkylsulfonyl group, a dilower alkylphosphino group, a dilower alkylamino group, a pyrimidinyl group substituted lower alkylamino group, a pyridyl group, a pyridylamino group, and a lower alkyl group substituted piperazinyl group. A lower alkyl group optionally substituted with a group represented by the formula:
-NH-Q-RThree
Or a group represented by:
-NH-RFour
And a group represented by RThreeIn which the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” is a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic nitrogen-containing group A group selected from a heterocyclic group, wherein the substituent of the “optionally substituted nitrogen-containing heterocyclic group” is a lower alkyl group, a hydroxyl group-substituted lower alkyl group, an oxo group, an amino group, a di-lower group; A group selected from an alkylamino group, a lower alkanoyl group, and a cyano group-substituted lower alkyl group, and RFourIs a cycloalkyl group substituted with a group selected from a hydroxyl group, a lower alkoxy group and a pyrimidinyloxy group, and R2Is a phenyl group substituted with a group selected from a lower alkoxy group, a halogen atom, a cyano group, a nitro group, a hydroxyl group and a lower alkyl group.
[0016]
More specifically, the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by ring A is represented by the formula:
Embedded image
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Embedded image
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[0017]
Among the compounds (I) of the present invention, other preferable compounds include nitrogen-containing heterocyclic groups in the “optionally substituted nitrogen-containing heterocyclic group” represented by ring A in general formula (I). Is a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic nitrogen-containing heterocyclic group, and the above-mentioned “optionally substituted nitrogen-containing heterocyclic group” Is a group selected from a lower alkyl group, a hydroxyl group-substituted lower alkyl group, a formyl group, and an oxo group, and R1Is a lower alkyl group which may be substituted with a group selected from a lower alkoxy group and a morpholinyl group, the formula:
-NH-Q-RThree
Or a group represented by:
-NH-RFour
And a group represented by RThreeThe “optionally substituted nitrogen-containing heterocyclic group” represented by the above is a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group which may be substituted with a lower alkyl group, and RFourIs a cycloalkyl group substituted with a group selected from a hydroxyl group and a lower alkoxy group, and R2Is a phenyl group substituted with a group selected from a lower alkoxy group, a halogen atom and a cyano group.
[0018]
More specifically, the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by ring A is represented by the formula:
Embedded image
Embedded image
Embedded image
Embedded image
[0019]
More specifically, ring A is represented by the formula:
Embedded image
-NH-Q-RThree
Or a group represented by:
-NH-RFour
And a group represented by RThreeBut the formula:
Embedded image
Embedded image
Embedded image
[0020]
Among the compounds (I) of the present invention, more preferred compounds include the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by ring A in general formula (I). , A 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic nitrogen-containing heterocyclic group, and the above-mentioned “optionally substituted nitrogen-containing heterocyclic group” The substituent is a group selected from a lower alkyl group, a hydroxyl group-substituted lower alkyl group, a formyl group, and an oxo group;1A lower alkyl group substituted with a lower alkoxy group, the formula:
-NH-Q-RThree
Or a group represented by:
-NH-RFour
And a group represented by RThreeThe “optionally substituted nitrogen-containing heterocyclic group” represented by is a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group which may be substituted with a lower alkyl group, and RFourIs a cycloalkyl group substituted with a hydroxyl group, and R2Is a phenyl group substituted with a group selected from a lower alkoxy group and a halogen atom.
[0021]
More specifically, the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by ring A is represented by the formula:
Embedded image
Embedded image
Embedded image
Embedded image
[0022]
More specifically, ring A is represented by the formula:
Embedded image
-NH-Q-RThree
Or a group represented by:
-NH-RFour
And a group represented by RThreeIs the formula:
Embedded image
Embedded image
Embedded image
[0023]
Among the compounds (I) of the present invention, more preferred compounds include the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by ring A in general formula (I). , A 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic nitrogen-containing heterocyclic group, and the above-mentioned “optionally substituted nitrogen-containing heterocyclic group” The substituent is a hydroxyl group-substituted lower alkyl group, and R1Is the formula:
-NH-Q-RThree
And a group represented by RThreeThe “optionally substituted nitrogen-containing heterocyclic group” represented by is a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group which may be substituted with a lower alkyl group, and R2Is a phenyl group substituted with a group selected from a lower alkoxy group and a halogen atom.
[0024]
More specifically, the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by ring A is represented by the formula:
Embedded image
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Embedded image
Embedded image
[0025]
More specifically, ring A is represented by the formula:
Embedded image
-NH-Q-RThree
And a group represented by RThreeIs the formula:
Embedded image
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[0026]
Among the compounds (I) of the present invention, particularly preferred compounds include those in which Y is the formula: = N- and Z is the formula: = CH-.
[0027]
Among the compounds (I) of the present invention, compounds that are preferable in terms of medicinal effects include compounds selected from the following groups or pharmacologically acceptable salts thereof.
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine;
2- (6,7-Dihydro-5H-pyrrolo [3,4-b] pyridin-6-yl) -4- (3-cyano-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) ) Carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4 -Methoxycyclohexyl) carbamoyl] pyrimidine;
2- (6,7-Dihydro-5H-pyrrolo [3,4-b] pyridin-6-yl) -4- (3-cyano-4-methoxybenzylamino) -5- [N- (trans-4- Hydroxycyclohexyl) carbamoyl] pyrimidine;
2- (6,7-Dihydro-5H-pyrrolo [3,4-b] pyridin-6-yl) -4- (3-cyano-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) ) Carbamoyl] pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl] pyrimidine;
2-[(2S) -2-hydroxymethyl-1-pyrrolidinyl] -4- (3-chloro-4-methoxybenzylamino) -5- [N-[[(2R) -4-methyl-2-morpholinyl] Methyl] carbamoyl] pyrimidine;
2-[(2S) -2-hydroxymethyl-1-pyrrolidinyl] -4- (3-chloro-4-methoxybenzylamino) -5- [N-[[(2S) -4-methyl-2-morpholinyl] Methyl] carbamoyl] pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (4-pyrimidinylmethyl) carbamoyl] pyrimidine;
2- (4-Methyl-3-oxo-1-piperazinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4-hydroxycyclohexyl) carbamoyl] pyrimidine;
2- (4-formyl-1-piperazinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4-hydroxycyclohexyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4 -Hydroxycyclohexyl) carbamoyl] pyrimidine;
2- [cis-2,5-bis (hydroxymethyl) -1-pyrrolidinyl] -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinyl) Methyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholino) Ethyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl ] Pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-acetylpyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (4-pyridazinylmethyl) carbamoyl] pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (5-pyrimidinylmethyl) carbamoyl] pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyridylmethyl) carbamoyl] pyrimidine;
(S) -2- [N- (2-pyrimidinylmethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- [2-hydroxymethyl-1-pyrrolidinyl] pyrazine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-[(2-morpholinoethyl) carbonyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N-[(4- Methyl-2-morpholinyl) methyl] carbamoyl] pyrimidine;
(S) -2- [N- (2-morpholinoethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine;
2- [N- (2-pyrimidinylmethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine- 7-yl) pyrazine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-[(2-methoxyethyl) carbonyl] pyrimidine;
(S) -2- (2-Hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (1,3,5-trimethyl-4-pyrazolyl) carbamoyl ] Pyrimidine,
Or a pharmacologically acceptable salt thereof.
[0028]
Among the compounds (I) of the present invention, compounds more preferred in terms of pharmacological effects include compounds selected from the following groups or pharmacologically acceptable salts thereof.
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (4-pyrimidinylmethyl) carbamoyl] pyrimidine;
2- (4-Methyl-3-oxo-1-piperazinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4-hydroxycyclohexyl) carbamoyl] pyrimidine;
2- (4-formyl-1-piperazinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4-hydroxycyclohexyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinyl) Methyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholino) Ethyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl ] Pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (5-pyrimidinylmethyl) carbamoyl] pyrimidine;
(S) -2- [N- (2-pyrimidinylmethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- [2-hydroxymethyl-1-pyrrolidinyl] pyrazine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-[(2-methoxyethyl) carbonyl] pyrimidine;
(S) -2- (2-Hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (1,3,5-trimethyl-4-pyrazolyl) carbamoyl ] Pyrimidine,
Or a pharmacologically acceptable salt thereof.
[0029]
Among the compounds (I) of the present invention, other pharmaceutically effective compounds include compounds selected from the following groups or pharmacologically acceptable salts thereof.
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinyl) Methyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl ] Pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (5-pyrimidinylmethyl) carbamoyl] pyrimidine;
(S) -2- [N- (2-pyrimidinylmethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- [2-hydroxymethyl-1-pyrrolidinyl] pyrazine;
(S) -2- [N- (2-morpholinoethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine;
(S) -2- (2-Hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (1,3,5-trimethyl-4-pyrazolyl) carbamoyl ] Pyrimidine,
Or a pharmacologically acceptable salt thereof.
[0030]
Among the compounds (I) of the present invention, particularly preferred compounds in terms of medicinal effects include the following compounds or pharmacologically acceptable salts thereof.
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine, or pharmacology thereof Acceptable salts as well as 2- (5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N -(2-morpholinoethyl) carbamoyl] pyrimidine, or a pharmaceutically acceptable salt thereof, and (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxy) Benzylamino) -5- [N- (1,3,5-trimethyl-4-pyrazolyl) carbamoyl] pyrimidine, or a pharmaceutically acceptable salt thereof.
[0031]
Compound (I) of the present invention or a pharmaceutically acceptable salt thereof is represented by ring A, R1And / or R2When A has an asymmetric atom, it may exist as an optical isomer based on the asymmetric atom, but the present invention includes any of these optical isomers and mixtures thereof.
[0032]
Since the compound (I) or a pharmacologically acceptable salt thereof of the present invention has an excellent selective PDE V inhibitory action, it does not substantially show side effects such as color blindness, and can be used for the prevention and treatment of penile erectile dysfunction. Can be used.
[0033]
The compound (I) of the present invention can be used for pharmaceutical use either in a free form or in the form of a pharmacologically acceptable salt. Examples of the pharmaceutically acceptable salt of compound (I) include inorganic acid salts such as hydrochloride, sulfate, nitrate, and hydrobromide, acetate, fumarate, oxalate, citrate, Examples thereof include organic acid salts such as methanesulfonate, benzenesulfonate, tosylate and maleate.
The compound (I) or a salt thereof of the present invention includes any of its internal salts and adducts, solvates or hydrates thereof.
[0034]
The compound (I) of the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally, and can also be used for tablets, granules, fine granules, pills, capsules, Powder, injection, inhalation, buccal formulation, sublingual formulation, syrup, dry syrup, jelly, suppository, ointment, elixir, liniment, lotion, drink, nasal, transdermal formulation, It can be used as a conventional pharmaceutical preparation such as an intraoral rapidly disintegrating preparation. These pharmaceutical preparations are prepared by formulation according to a conventional method together with pharmaceutically acceptable excipients, binders, wetting agents, disintegrating agents, fillers and the like. The dose of the compound (I) of the present invention or a pharmacologically acceptable salt thereof varies depending on the administration method, the age, body weight and condition of the patient, but usually about 0. 001 to 100 mg / kg, especially about 0.1 to 10 mg / kg, and oral dosage is usually about 0.1 to 200 mg / kg, especially about 0.1 to 80 mg / kg per day. preferable.
[0035]
In addition, since the compound (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent selective PDE V inhibitory action, in addition to the above-mentioned erectile dysfunction, Prevention of various diseases (for example, pulmonary hypertension, diabetic gastric paralysis, hypertension, angina pectoris, myocardial infarction, chronic and acute heart failure, female sexual dysfunction, prostatic hypertrophy, asthma, diarrhea, constipation, achalasia, etc.)・ Applicable to treatment.
[0036]
According to the present invention, compound (I) can be produced by the following [Method A] to [Method F].
[Method A]
Among the compounds (I) of the present invention, R1Is of the formula: -NH-QRThreeOr -NH-RFourA compound represented by the general formula (Ia):
Embedded image
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And a compound of the general formula (III)
R2-CH2-NH2 (III)
(However, the symbols have the same meaning as above)
Is reacted with a compound represented by the general formula (IV)
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Is oxidized to a compound of the general formula (V)
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A sulfonyl (or sulfinyl) compound represented by general formula (VI)
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And a compound represented by the general formula (VII)
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After the compound represented by the following formula, the protective group R for the carboxyl groupFiveAnd general formula (VIII)
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And a compound represented by the general formula (IX-a)
R11-H (IX-a)
(However, R11Has the same meaning as above)
It can manufacture by making it react with the compound shown by these.
[0037]
In addition, compound (Ia) is obtained by halogenating compound (VIII) to give a compound of general formula (X)
Embedded image
And then reacting with compound (IX-a).
[0038]
The compound (VII) is represented by the general formula (XI)
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Protecting the carboxyl group of the compound represented by formula (XIII)
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And then reacting with compound (III) to give a compound of general formula (XIV)
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It can be also produced by reacting with the compound (VI).
[0039]
In addition, the compound (XIV) is obtained by hydrolyzing the compound (V) to obtain the general formula (XV)
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It can also be produced by halogenating the compound represented by
[0040]
[Method B]
Among the compounds (I) of the present invention, R1Is a lower alkyl group which may be substituted, that is, the compound represented by the general formula (Ib)
Embedded image
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Is oxidized to give a compound of the general formula (XVII)
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And further oxidized to give a compound of the general formula (XVIII)
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And then reacting with compound (VI) to give a compound of general formula (XIX)
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And a compound represented by the general formula (IX-b)
R12-H (IX-b)
(However, R12Has the same meaning as above)
Is reacted with a metal salt of a compound represented by the general formula (XX)
Embedded image
It can manufacture by making it into the compound shown by following, and oxidizing.
[0041]
Among the compounds (I) of the present invention, the group R1Is a lower alkoxy group-substituted ethyl group, morpholino group-substituted ethyl group, 4-lower alkyl piperazinyl group-substituted ethyl group, 3-pyridylamino group-substituted ethyl group, 2-pyridyl lower alkylamino group-substituted ethyl group, di-lower alkylaminoethyl Or a hydroxyethyl group, ie a compound of the general formula (Ic)
Embedded image
The compound represented by the formula is the compound (XIX) and the formula
CH2= CHMgBr (XXI)
Is reacted with a Grignard compound represented by the general formula (XXII)
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The compound represented by the general formula (XXIII)
Embedded image
And a compound represented by the general formula (XXIV)
R6-H (XXIV)
(However, the symbols have the same meaning as above)
It can manufacture also by making it react with the compound shown by these.
[0042]
[Method C]
Compound (Ia) is a protective group R for the carboxyl group of compound (IV).FiveGeneral formula (XXV) obtained by desorbing
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And the compound (IX-a) is reacted with a compound represented by the general formula (XXVI-a)
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And is further oxidized to give a compound of the general formula (XXVII-a)
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And then reacting with the compound (VI).
[0043]
[Method D]
Compound (Ib) is obtained by reacting Compound (XVII) with a metal salt of Compound (IX-b).
Embedded image
And the compound represented by the general formula (XXVI-b)
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And is further oxidized to give a compound of the general formula (XXVII-b)
Embedded image
And then reacting with the compound (VI).
[0044]
[E method]
Compound (Ib) includes dihalogeno compound (XI) and general formula (XXIX)
R12-CHO (XXIX)
(However, the symbols have the same meaning as above)
General formula (XXX) obtained by reacting with a compound represented by formula (XXX)
Embedded image
Is oxidized to give a compound of the general formula (XXXI)
[Chemical Formula 86]
To a compound represented by general formula (XXXII)
Embedded image
It can also be produced by reacting compound (VI) with the compound represented by
[0045]
The compound (XXXII) is obtained by reacting the compound (XXX) with the compound (III) to obtain the general formula (XXXIII)
Embedded image
It can also manufacture by oxidizing the compound shown by these.
[0046]
[F method]
Compound (Ia) is compound (XIII) and general formula (XXXIV)
RSH (XXXIV)
(However, R represents a lower alkyl group which may be substituted or an aryl group which may be substituted.)
Is reacted with a compound represented by the general formula (XXXV)
Embedded image
And then reacting with compound (VI) or a salt thereof to give a compound of the general formula (XXXVI)
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After the compound represented by the following formula, the protective group R for the carboxyl groupFiveGeneral formula (XXXVII)
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And further reacting with compound (IX-a) to give a compound of general formula (XXXIX)
Embedded image
And then oxidized to a sulfonyl or sulfinyl compound and then reacted with compound (III).
[0047]
[Method A] to [Method F] can be carried out as follows.
[Method A]
The reaction of compound (II) and compound (III) can be carried out in a solvent in the presence or absence of a deoxidizing agent. As the deoxidizer, organic bases such as N, N-diisopropylethylamine, N-methylmorpholine, triethylamine and pyridine, and inorganic bases such as sodium hydride, sodium carbonate, potassium carbonate and sodium bicarbonate are preferably used. it can. As the solvent, any solvent that does not inhibit the reaction, such as dimethyl sulfoxide, tetrahydrofuran, toluene, ethyl acetate, chloroform, dimethoxyethane, xylene, N, N-dimethylformamide, can be preferably used. This reaction suitably proceeds at −10 ° C. to room temperature, particularly 0 ° C. to room temperature.
[0048]
The reaction of oxidizing compound (IV) to give sulfonyl (or sulfinyl) compound (V) can be carried out in a solvent in the presence of an oxidizing agent. Examples of the oxidizing agent include peracids such as m-chloroperbenzoic acid and peracetic acid, manganese dioxide, sodium periodate, hydrogen peroxide, dinitrogen tetroxide, halogen, hydroperoxide, iodobenzene acetate, hypochlorous acid t. -An inorganic oxidizing agent such as butyl, sulfuryl chloride or potassium peroxymonosulfate can be preferably used. As the solvent, a solvent that does not inhibit the reaction, such as chloroform, methylene chloride, dichloroethane, and acetic acid, can be used as appropriate. This reaction suitably proceeds at −78 ° C. to 50 ° C., particularly −10 to 10 ° C.
[0049]
The reaction of compound (V) with compound (VI) or a salt thereof can be carried out in a solvent in the presence or absence of a deoxidizing agent. As the deoxidizer, organic bases such as N, N-diisopropylethylamine, N-methylmorpholine, triethylamine and pyridine, and inorganic bases such as sodium hydride, sodium carbonate, potassium carbonate and sodium bicarbonate are preferably used. it can. As the salt of compound (VI), alkali metal salts such as sodium salt and potassium salt can be preferably used. As the solvent, any solvent that does not inhibit the reaction, such as N, N-dimethylformamide, tetrahydrofuran, dimethoxyethane, dimethyl sulfoxide, and the like can be suitably used. This reaction suitably proceeds at 0 to 150 ° C, particularly at room temperature to 60 ° C.
[0050]
Protecting group R of carboxyl group of compound (VII)FiveIn order to obtain the compound (VIII) by removing the compound, a method usually used (hydrolysis, catalytic reduction, etc.) can be appropriately used depending on the kind of the protective group of the carboxyl group, and the carboxyl group can be protected by hydrolysis. When the group is removed, it can be carried out in a solvent in the presence of a base, for example. As the base, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and the like can be suitably used. As the solvent, water or a mixed solvent of water, methanol, ethanol, tetrahydrofuran, dioxane, N, N-dimethylformamide, dimethyl sulfoxide, and the like and water can be appropriately used. This reaction suitably proceeds at 0 to 80 ° C, particularly 5 to 60 ° C. In addition, carboxyl protecting group RFiveAs such, a commonly used protective group for a carboxyl group such as a lower alkyl group or a benzyl group can be used.
[0051]
The reaction of compound (VIII) and compound (IX-a) can be carried out in a suitable solvent in the presence or absence of a condensing agent, base or activator. As the condensing agent, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, diethylcyanophosphonate and the like generally used in peptide synthesis can be preferably used. An organic base such as triethylamine or N-methylmorpholine can be suitably used as the base, and 1-hydroxybenzotriazole or the like can be suitably used as the activator. As the solvent, any solvent that does not inhibit the reaction, such as methylene chloride, tetrahydrofuran, N, N-dimethylformamide, acetonitrile, N, N-dimethylacetamide, and ethyl acetate can be preferably used. This reaction suitably proceeds at -30 to 50 ° C, particularly -10 to 10 ° C.
[0052]
Alternatively, after compound (VIII) as an alternative method is converted to compound (X), compound (IX-a) is reacted with compound (VIII) in the presence of an activating agent by a conventional method. Alternatively, in the absence, it is reacted with a halogenating agent to give compound (X), and then compound (IX-a) is reacted. The reaction of compound (VIII) with a halogenating agent can be carried out in a solvent. As the halogenating agent, for example, thionyl chloride, oxalyl chloride, phosphorus pentachloride and the like can be suitably used. As the activator, an amide compound such as N, N-dimethylformamide can be suitably used. As the solvent, any solvent that does not inhibit the reaction such as methylene chloride, chloroform, tetrahydrofuran, benzene, toluene, dioxane and the like can be suitably used. This reaction suitably proceeds at −30 to 100 ° C., particularly −5 to 10 ° C.
[0053]
The subsequent reaction with compound (IX-a) can be carried out in a solvent in the presence of a deoxidizing agent. As the deoxidizer, organic bases such as N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, pyridine, dimethylaminopyridine, and inorganic bases such as sodium hydride, sodium carbonate, potassium carbonate, sodium hydrogen carbonate are preferably used. Can be used. As the solvent, any solvent that does not inhibit the reaction, such as tetrahydrofuran, methylene chloride, chloroform, toluene, benzene, dioxane, and ethyl acetate can be preferably used. This reaction suitably proceeds at −30 to 100 ° C., particularly −5 to 10 ° C.
[0054]
In addition, the reaction in which the dihalogeno compound (XI) is treated with carbon dioxide to obtain the compound (XII) can be carried out in a solvent in the presence of a base. As the base, alkali metal salts of organic bases such as lithium diisopropylamide and lithium 2,2,6,6-tetramethylpiperidide can be preferably used. As the solvent, a solvent that does not inhibit the reaction, such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, and the like can be appropriately used. This reaction suitably proceeds at -100 ° C to -30 ° C, particularly -100 ° C to -70 ° C.
[0055]
The reaction to obtain compound (XIII) by protecting the carboxyl group of compound (XII) can be carried out by a conventional method. For example, when the protecting group is a lower alkyl group, in the presence of a base and a solvent, It can be carried out by reacting with an alkylating agent. As the alkylating agent, a lower alkyl halide such as methyl iodide can be suitably used. As the base, an alkali metal hydrogencarbonate such as sodium hydrogencarbonate can be suitably used, and as the solvent, a solvent that does not inhibit the reaction, such as N, N-dimethylformamide and tetrahydrofuran, can be suitably used. This reaction suitably proceeds at 0 to 100 ° C, particularly at room temperature to 70 ° C.
[0056]
The reaction for obtaining compound (XIV) by reacting compound (XIII) with compound (III) can be carried out in the same manner as the reaction of compound (II) with compound (III).
The reaction to obtain compound (VII) by reacting compound (XIV) with compound (VI) can be carried out in the same manner as the reaction between compound (V) and compound (VI).
Moreover, the reaction which hydrolyzes compound (V) to obtain compound (XV) can be carried out in a solvent in the presence of a base. As the base, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and the like can be suitably used. As the solvent, water or a mixed solvent of water, methanol, ethanol, tetrahydrofuran, dioxane, N, N-dimethylformamide, dimethyl sulfoxide, and the like and water can be appropriately used. This reaction suitably proceeds at -20 to 80 ° C, particularly -5 to 60 ° C. The reaction to obtain compound (XIV) by halogenating compound (XV) can be carried out in the same manner as the reaction to obtain compound (X) by halogenating compound (VIII) with a halogenating agent.
[0057]
[Method B]
The reaction for reducing compound (IV) to compound (XVI) can be carried out in a suitable solvent in the presence of a reducing agent. As the reducing agent, an alkali metal aluminum hydride such as lithium aluminum hydride, an alkali metal borohydride such as lithium borohydride, or the like can be suitably used. As the solvent, a solvent that does not inhibit the reaction, such as tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, or the like can be preferably used. This reaction suitably proceeds from −78 ° C. to the boiling point of the solvent used, particularly from −10 ° C. to room temperature.
[0058]
The reaction for oxidizing compound (XVI) to lead to compound (XVII) can be carried out in a solvent in the presence of an oxidizing agent. The oxidizing agent is not particularly limited as long as it can induce alcohol to the corresponding carbonyl compound. For example, manganese dioxide, barium permanganate, potassium permanganate, 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone, pyridinium chlorochromate, pyridinium dichromate and the like can be suitably used. As the solvent, a solvent that does not inhibit the reaction, such as chloroform, toluene, ethyl acetate, 1,2-dichloroethane, methylene chloride, tetrahydrofuran, and the like can be appropriately used. This reaction suitably proceeds at 0 to 100 ° C, particularly at room temperature to 70 ° C.
[0059]
The reaction for oxidizing compound (XVII) to lead to compound (XVIII) can be carried out in the same manner as the reaction for oxidizing compound (IV) to lead to compound (V).
The reaction leading to the compound (XIX) by reacting the compound (XVIII) with the compound (VI) can be carried out in the same manner as the reaction of the compound (V) and the compound (VI).
The reaction leading to compound (XX) by reacting compound (XIX) with the metal salt of compound (IX-b) can be carried out in a suitable solvent. As the metal salt of compound (IX-b), a lithium salt or the like can be preferably used. As the solvent, a solvent that does not inhibit the reaction, such as tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, and the like can be appropriately used. This reaction suitably proceeds at −78 ° C. to room temperature.
[0060]
The reaction for oxidizing compound (XX) to lead to compound (Ib) can be carried out in the same manner as the reaction for oxidizing compound (XVI) to lead to compound (XVII).
The reaction of compound (XIX) and Grignard compound (XXI) can be carried out in a suitable solvent. As the solvent, tetrahydrofuran, dioxane, diethyl ether and the like can be suitably used. This reaction suitably proceeds at −78 ° C. to 60 ° C., particularly at −78 ° C. to room temperature.
[0061]
The reaction for oxidizing compound (XXII) to lead to compound (XXIII) can be carried out in the same manner as the reaction for oxidizing compound (XVI) to lead to compound (XVII).
Compound (XXIII) is converted to R6Wherein R is a morpholino group, a 4-lower alkylpiperazinyl group, a 3-pyridylamino group, a 2-pyrimidinyl lower alkylamino group, or a di-lower alkylamino group (XXIV)6Is a morpholino group, a 4-lower alkylpiperazinyl group, a 3-pyridylamino group, a 2-pyrimidinyl lower alkylamino group or a di-lower alkylamino group, in the presence or absence of a base. It can be carried out in a suitable solvent in the presence. As the base, organic bases such as N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, and pyridine, and inorganic bases such as sodium hydride, sodium carbonate, potassium carbonate, and sodium bicarbonate can be preferably used. As the solvent, any of ethanol, N, N-dimethylformamide, tetrahydrofuran, dimethoxyethane, dimethyl sulfoxide and the like can be suitably used. This reaction suitably proceeds at 0 to 150 ° C, particularly at room temperature to 60 ° C.
[0062]
On the other hand, compound (XXIII) is converted to R6Is reacted with a compound (XXIV) in which is a hydroxyl group or a lower alkoxy group.6The reaction leading to the compound (XXI) in which is a hydroxyl group or a lower alkoxy group can be carried out in the presence of an acid, without solvent, or in a suitable solvent. As the acid, inorganic acids such as sulfuric acid and organic acids such as methanesulfonic acid, camphorsulfonic acid, toluenesulfonic acid, and benzenesulfonic acid can be suitably used. As the solvent, any of diethyl ether, toluene, benzene, N, N-dimethylformamide, dimethoxyethane, dimethyl sulfoxide and the like can be suitably used. This reaction suitably proceeds at 0 to 150 ° C, particularly at room temperature to 60 ° C.
[0063]
[Method C]
Protecting group R of carboxyl group of compound (IV)FiveThe reaction for obtaining the compound (XXV) by removing the carboxyl group R is a carboxyl protecting group R of the compound (VII).FiveCan be carried out in the same manner as in the reaction for obtaining compound (VIII).
The reaction of reacting compound (XXV) with compound (IX-a) to give compound (XXVI-a) can be carried out in the same manner as in the reaction of compound (VIII) with compound (IX-a).
The reaction for oxidizing compound (XXVI-a) to lead to compound (XXVII-a) can be carried out in the same manner as the reaction for oxidizing compound (IV) to lead to compound (V). The reaction leading to the compound (Ia) of the present invention by reacting the compound (XXVII-a) with the compound (VI) can be carried out in the same manner as the reaction of the compound (V) and the compound (VI).
[0064]
[Method D]
The reaction leading to compound (XXVIII) by reacting compound (XVII) with the metal salt of compound (IX-b) can be carried out in the same manner as the reaction of compound (XIX) with the metal salt of compound (IX-b). it can.
The reaction for oxidizing compound (XXVIII) to lead to compound (XXVI-b) can be carried out in the same manner as the reaction for oxidizing compound (XVI) to lead to compound (XVII).
After converting compound (XXVI-b) to compound (XXVII-b) and converting to compound (XXVII-b), the reaction leading to compound (Ib) of the present invention involves oxidation of compound (XXVI-a) and compound (XXVII-a). After conversion to, the reaction can be carried out in the same manner as in the reaction leading to the compound (Ia) of the present invention.
[0065]
[E method]
The reaction of reacting compound (XI) with compound (XXIX) to give compound (XXX) can be carried out in a suitable solvent in the presence of a base. As the base, alkali metal salts of organic bases such as lithium diisopropylamide and lithium 2,2,6,6-tetramethylpiperidide can be preferably used. As the solvent, a solvent that does not inhibit the reaction, such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, and the like can be appropriately used. This reaction suitably proceeds at -100 ° C to -30 ° C, particularly -100 ° C to -70 ° C.
[0066]
The reaction for oxidizing compound (XXX) to lead to compound (XXXI) can be carried out in the same manner as the reaction for oxidizing compound (XVI) to lead to compound (XVII).
The reaction leading to compound (XXXII) by reacting compound (XXXI) with compound (III) can be carried out in the same manner as the reaction of compound (II) and compound (III).
[0067]
Further, the reaction leading to compound (Ib) of the present invention by reacting compound (XXXII) with compound (VI) or a salt thereof can be carried out in the same manner as the reaction of compound (V) and compound (VI). it can.
[0068]
The reaction leading to compound (XXXIII) by reacting compound (XXX) with compound (III) can be carried out in the same manner as in the reaction of compound (II) with compound (III). The reaction for oxidizing compound (XXXIII) to lead to compound (XXXII) can be carried out in the same manner as the reaction for oxidizing compound (XVI) to lead to compound (XVII).
[0069]
[F method]
The reaction of compound (XIII) and compound (XXXIV) can be carried out in a solvent in the presence or absence of a deoxidizing agent. As the deoxidizer, organic bases such as N, N-diisopropylethylamine, N-methylmorpholine, triethylamine and pyridine, and inorganic bases such as sodium hydride, sodium carbonate, potassium carbonate and sodium bicarbonate are preferably used. it can. As the solvent, any solvent that does not inhibit the reaction, such as N, N-dimethylformamide, tetrahydrofuran, toluene, ethyl acetate, chloroform, dimethoxyethane, xylene, N, N-dimethylformamide, can be preferably used. This reaction suitably proceeds at −10 ° C. to room temperature, particularly 0 ° C. to room temperature.
[0070]
The reaction between compound (XXXV) and compound (VI) or a salt thereof can be carried out in the same manner as the reaction between compound (V) and compound (VI).
Protecting group R of carboxyl group of compound (XXXVI)FiveIn the reaction to obtain compound (XXXVII) is a protective group R for the carboxyl group of compound (VII).FiveCan be carried out in the same manner as in the reaction for obtaining compound (VIII).
The reaction between compound (XXXVII) and compound (IX-a) can be carried out in the same manner as in the reaction between compound (VIII) and compound (IX-a).
[0071]
The oxidation reaction of compound (XXXIX) can be carried out in the same manner as the reaction from compound (IV) to (V), and m-chloroperbenzoic acid or the like can be suitably used as the oxidizing agent. As the solvent, a solvent that does not inhibit the reaction, such as chloroform, methylene chloride, dichloroethane, and acetic acid, can be used as appropriate. This reaction suitably proceeds at −78 ° C. to 50 ° C., particularly −10 ° C. to 10 ° C.
[0072]
The subsequent reaction with compound (III) can be carried out in the same manner as the reaction between compound (II) and compound (III).
The compound (I) thus obtained can be converted to a pharmacologically acceptable salt thereof as desired.
The starting compound (II) can be produced, for example, according to the method described in Journal of American Chemical Society, page 350, volume 65, 1943.
[0073]
【Example】
Specific examples (Examples) of the compound (I) of the present invention synthesized by each of the above exemplified methods are shown below, but the present invention is not limited thereby.
[0074]
Example 1
(1) 4-Chloro-5-ethoxycarbonyl-2-methylthiopyrimidine To a solution of 25.33 g of N, N-dimethylformamide in 85 ml of ice-cooled 3-chloro-4-methoxybenzylamine 19.62 g of N, N- Add a solution of 15 ml of dimethylformamide and 16.7 ml of triethylamine. After stirring for 20 minutes at room temperature, 940 mg of 3-chloro-4-methoxybenzylamine is added and stirred for 15 minutes, and then further 940 mg of the amine is added and stirred for 15 minutes. The reaction mixture is poured into an ice-water-citric acid mixture, extracted with ethyl acetate, washed successively with 10% aqueous citric acid solution, water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with n-hexane to obtain 38.34 g of 4- (3-chloro-4-methoxybenzylamino) -5-ethoxycarbonyl-2-methylthiopyrimidine. Melting point: 86 ° C.
[0075]
(2) To a solution of 5.00 g of the compound obtained in (1) above in 50 ml of chloroform, add a solution of 4.00 g of m-chloroperbenzoic acid in 50 ml of chloroform under ice cooling and stir for 2 hours. The reaction mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 4- (3-chloro-4-methoxybenzylamino) -5-ethoxy. A crude product of carbonyl-2-methylsulfinylpyrimidine is obtained. MS (m / z): 447 (MH+).
[0076]
(3) The crude product obtained in (2) above is dissolved in 40 ml of tetrahydrofuran, and a solution of 1.50 g of L-prolinol and 1.60 g of triethylamine in 10 ml of tetrahydrofuran is added at room temperature. After stirring overnight, the reaction mixture is diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and brine, and the organic layer is dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: chloroform), crystallized from ether-n-hexane, and (S) -4- (3-chloro-4-methoxybenzylamino). 4.72 g of -5-ethoxycarbonyl-2- (2-hydroxymethyl-1-pyrrolidinyl) pyrimidine is obtained. Melting point: 88-90 ° C. MS (m / z): 421 (MH+).
[0077]
(4) 3.4 g of the compound obtained in (3) above, 23 ml of a 10% aqueous sodium hydroxide solution and 34 ml of dimethyl sulfoxide are stirred at room temperature for 15 hours. The reaction mixture was poured into 10% aqueous citric acid solution, the precipitate was crystallized from tetrahydrofuran-ether, and (S) -4- (3-chloro-4-methoxybenzylamino) -5-carboxy-2- (2-hydroxy). 2.52 g of methyl-1-pyrrolidinyl) pyrimidine are obtained. Melting point: 205-208 ° C. MS (m / z): 391 (M-H)-.
[0078]
(5) 600 mg of the compound obtained in the above (4), 217 mg of 2-aminomethylpyrimidine, 323 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 227 mg of 1-hydroxybenztriazole monohydrate , And 12 ml of N, N-dimethylformamide are stirred at room temperature for 8 hours, and then the reaction mixture is poured into an aqueous sodium bicarbonate solution. Extract with ethyl acetate, wash with brine, and dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent; chloroform: methanol = 50: 1), and (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- ( 610 mg of 3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidylmethyl) carbamoyl] pyrimidine are obtained. Melting point: 160-163 ° C.
[0079]
Example 2
(1) A solution of 4.15 g of lithium aluminum hydride in 150 ml of tetrahydrofuran and a solution of 38.32 g of 2-methylthio-4- (3-chloro-4-methoxybenzylamino) -5-ethoxycarbonylpyrimidine in 100 ml of tetrahydrofuran were ice-cooled. Add at 5-10 ° C under 1 hour. After the addition is complete, the ice bath is removed and the reaction mixture is stirred at room temperature for 1 hour. 4.15 ml of water is added to the reaction mixture under ice cooling, followed by 4.15 ml of 3N aqueous sodium hydroxide solution. 4.15 ml of water is added to the mixture three times and stirred at room temperature for 1 hour. After treating the reaction mixture with magnesium sulfate, the precipitated solid is filtered off and the solid is washed with tetrahydrofuran. The filtrate and washings are combined, concentrated under reduced pressure, and triturated with ethyl acetate-isopropyl ether. The obtained crystals are collected by filtration and sufficiently washed with isopropyl ether to obtain 2-methylthio-4- (3-chloro-4-methoxybenzylamino) -5-hydroxymethylpyrimidine as a pale yellow crystalline powder.
1st generation; yield: 25.10 g, melting point: 162-163 ° C.
2nd generation; yield: 2.32 g, melting point: 159-160 ° C.
Further, the precipitated solid is washed again with isopropyl ether, and the filtrate is concentrated under reduced pressure to obtain colorless crystals. The obtained solid was suspended in isopropyl ether, filtered, and the precipitate was washed thoroughly with isopropyl ether and hexane to give 4.26 g of colorless crystalline 2-methylthio-4- (3-chloro-4-methoxybenzyl). Amino) -5-hydroxymethylpyrimidine is obtained. Melting point: 161-162 ° C.
[0080]
(2) 37.6 g of manganese dioxide powder was added to a suspension of 25.10 g of 2-methylthio-4- (3-chloro-4-methoxybenzylamino) -5-hydroxymethylpyrimidine obtained in (1) above in 150 ml of chloroform. In addition, the reaction mixture is stirred vigorously at room temperature for 1 day. Further, it is treated with 12.6 g of manganese dioxide powder (0.5 times the amount of the raw material compound) and stirred for 3 nights. The insoluble material is quickly removed by Celite filtration, the filtrate is concentrated under reduced pressure, and the residue is suspended in ethyl acetate-isopropyl ether. The precipitate is filtered and washed successively with isopropyl ether and hexane to give 22.43 g of colorless crystalline 2-methylthio-4- (3-chloro-4-methoxybenzylamino) -5-formylpyrimidine. Melting point: 124-125 ° C.
[0081]
(3) A solution of 2.057 g of 2-methylthio-4- (3-chloro-4-methoxybenzylamino) -5-formylpyrimidine in 20 ml of chloroform was added to 1.468 g of m-chloroperbenzoic acid (80%) at 0 ° C. Process for 30 minutes. To the reaction mixture, 0.901 g of L-prolinol and then 1.33 ml of triethylamine are added and reacted at 0 ° C. for 1 hour. The reaction mixture is warmed to room temperature, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, water, saturated brine, dried over anhydrous sodium sulfate, and the precipitate is removed by filtration through a silica plug. The filtrate was concentrated under reduced pressure to give 1.9990 g of colorless amorphous (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-formylpyrimidine. Get. MS (m / z): 377 (MH+).
[0082]
(4) (S) -2- (2-Hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-formylpyrimidine in 10 ml of tetrahydrofuran was added to 20 ml of tetrahydrofuran. After reacting 1.1 ml (1.10 M) of an ether solution at −78 ° C. for 10 minutes, an aqueous sodium hydrogen carbonate solution is added. The reaction mixture was extracted with ethyl acetate and (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- (1-hydroxyethyl) A crude pyrimidine product is obtained. MS (m / z): 393 (MH+).
[0083]
(5) The crude product obtained in (4) above is treated with 0.5 g of manganese dioxide at room temperature, and the mixture is stirred overnight. The reaction mixture was heated under reflux for 5 hours, insolubles were removed by filtration, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (solvent: chloroform: ethyl acetate = 3: 1) to give a colorless oil. 56.7 mg of (S)-(2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-acetylpyrimidine are obtained. MS (m / z): 391 (MH+).
[0084]
Example 3
(1) (S) -2- (2-Hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-formylpyrimidine 1.0 M vinylmagnesium in about 1 ml of tetrahydrofuran The tetrahydrofuran solution of bromide is added dropwise while cooling on a dry ice-acetone bath. The reaction mixture is stirred at −78 ° C. for 10 minutes and then at room temperature for 10 minutes. The reaction mixture is poured into ice-saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer is washed successively with water and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure.
The obtained crude product was subjected to preparative thin layer chromatography (solvent; ethyl acetate: methanol = 20: 1) to give (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) as a colorless oil. ) -4- (3-Chloro-4-methoxybenzylamino) -5- (1-hydroxy-2-propen-1-yl) pyrimidine 30 mg is obtained. MS (m / z): 405 (MH+).
[0085]
(2) (S) -2- (2-Hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- (1-hydroxy-2-propen-1-yl) pyrimidine Add 432 mg of manganese dioxide to a solution of 144 mg of chloroform in 2.5 ml and stir vigorously at room temperature overnight. The insoluble material was removed by filtration through celite, and the filtrate was concentrated under reduced pressure to give 124 mg of a pale yellow oil. The obtained crude product was purified by silica gel column chromatography (silica gel 20 g, solvent; chloroform: ethyl acetate = 2: 1) to give colorless crystals of (S) -2- (2-hydroxymethyl-1-pyrrolidinyl). 90 mg of -4- (3-chloro-4-methoxybenzylamino) -5- (acryloyl) pyrimidine is obtained. Melting point: 113-115 ° C. MS (m / z): 403 (MH+).
[0086]
(3) (S) -2- (2-Hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- (acryloyl) pyrimidine in 72 ml of ethanol was dissolved in 78 ml of morpholine at room temperature. And the mixture is stirred for 40 minutes at room temperature. The reaction mixture is concentrated under reduced pressure, the residue is poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, evaporated to dryness under reduced pressure, and (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3- 91 mg of chloro-4-methoxybenzylamino) -5-[(2-morpholinoethyl) carbonyl] pyrimidine are obtained.
[0087]
The obtained crude product is dissolved in 10 ml of ethyl acetate, the solution is treated with 5 ml of a hydrochloric acid / saturated methanol solution and concentrated under reduced pressure. Ethyl acetate was added to the residue, filtered, and the resulting solid was washed thoroughly with hexane to give (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxy). 65 mg of benzylamino) -5-[(2-morpholinoethyl) carbonyl] pyrimidine dihydrochloride are obtained. MS (m / z): 490 (MH+).
[0088]
Example 4
(1) To a solution of 972 mg of 4- (3-chloro-4-methoxybenzylamino) -5-ethoxycarbonyl-2-methylthiopyrimidine obtained in Example 1 (1) above in 8 ml of chloroform, m-chloroperbenzoic acid (80 %) 598 mg of chloroform in 10 ml is added over 30 minutes under ice cooling. The reaction mixture is stirred for 1 hour under ice cooling. The reaction mixture was diluted with a saturated aqueous sodium bicarbonate solution, the chloroform layer was separated, washed with a saturated aqueous sodium bicarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a colorless caramel-like 2 -Methylsulfinyl-4- (3-chloro-4-methoxybenzylamino) -5-ethoxycarbonylpyrimidine is obtained quantitatively. MS (m / z): 384 (MH+).
[0089]
(2) To a solution of 2-methylsulfinyl-4- (3-chloro-4-methoxybenzylamino) -5-ethoxycarbonylpyrimidine obtained in (1) above in 6 ml of tetrahydrofuran, 2N sodium hydroxide 1. 32 ml are added dropwise over 2 minutes under ice cooling and the reaction mixture is stirred for 30 minutes under ice cooling. Further, 8 ml of tetrahydrofuran and 6 ml of N, N-dimethylacetamide are added, and the reaction mixture is stirred for 30 minutes under ice cooling. 5 ml of water and 2 ml of N, N-dimethylacetamide are added, and the reaction solution is stirred for 1 hour under ice cooling. The reaction mixture is acidified with 10% aqueous citric acid solution, diluted with water and extracted twice with ethyl acetate. The extracts are collected, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (silica gel 20 g, solvent; chloroform: ethyl acetate = 5: 1 → chloroform: isopropanol = 30: 1) to give 2-hydroxy-4- ( 618 mg of 3-chloro-4-methoxybenzylamino) -5-ethoxycarbonylpyrimidine are obtained. Melting point: 195-197 ° C.
[0090]
(3) A mixture of 2-hydroxy-4- (3-chloro-4-methoxybenzylamino) -5-ethoxycarbonylpyrimidine (500 mg), diethylaminobenzene (2 ml) and phosphorus oxychloride (4 ml) obtained in (2) above at 80 ° C. Stir for 30 minutes and then at 100 ° C. for 5 hours. After cooling, the reaction is poured into ice-water and the mixture is stirred at room temperature for 30 minutes. The obtained product is extracted with ethyl acetate, and the organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 7 g, solvent; chloroform) to obtain 375 mg of 2-chloro-4- (3-chloro-4-methoxybenzylamino) -5-ethoxycarbonylpyrimidine as a slightly yellow crystalline powder. obtain. Melting point: 114-115 ° C. MS (m / z): 356 (MH+).
[0091]
(4) 2-Chloro-4- (3-chloro-4-methoxybenzylamino) -5-ethoxycarbonylpyrimidine obtained in the above (3) 285 mg, 5,6,7,8-tetrahydroimidazo [1,2- a] A mixture of 197 mg of pyrazine, 0.22 ml of triethylamine and 3 ml of chloroform is stirred at room temperature for 2.5 hours and then at 60 ° C. for 2.5 hours. The reaction mixture is diluted with ethyl acetate and washed with water. The aqueous layer is extracted with ethyl acetate, and the organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel 10 g, chloroform: methanol = 50: 1) and concentrated under reduced pressure. Triturated with isopropyl ether to give 2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxy) as a colorless crystalline powder 290 mg of (benzylamino) -5-ethoxycarbonylpyrimidine are obtained. Melting point: 179-182 ° C. MS (m / z): 443 (MH+).
[0092]
(5) 2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) obtained in (4) above A suspension of 290 mg of -5-ethoxycarbonylpyrimidine and 1.64 ml of 2N sodium hydroxide in dimethyl sulfoxide-water (5 ml-1 ml) is stirred at room temperature for 1 hour. 5 ml of tetrahydrofuran are added and the mixture is stirred at room temperature for 13 hours. Tetrahydrofuran is distilled off under reduced pressure, and the resulting solution is diluted with water and neutralized with a 10% aqueous citric acid solution. The resulting precipitate was separated, washed with water, methanol, and isopropyl ether to give 2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) as a colorless crystalline powder. 187 mg of -4- (3-chloro-4-methoxybenzylamino) -5-carboxypyrimidine is obtained. Melting point: 223-226 ° C. (decomposition). MS (m / z): 413 (MH)-.
[0093]
(6) 2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5-carboxypyrimidine 60 mg, 4-methyl-2-aminomethylmorpholine 22.7 mg, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 30.6 mg, 1-hydroxybenzotriazole 21.6 mg and N, N-dimethyl A mixture of 3 ml formamide is stirred at room temperature for 22 hours. Water is poured into the reaction mixture and extracted with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium hydrogen carbonate solution, water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 70.0 mg of colorless crystals. This was recrystallized from chloroform-hexane to give colorless needle-like crystals of 2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4 51.7 mg of -methoxybenzylamino) -5- [N-[(4-methyl-2-morpholinyl) methyl] carbamoyl] pyrimidine are obtained. Melting point: 132-134 ° C. MS (m / z): 527 (MH+).
[0094]
Examples 5-6
The corresponding starting material is treated in the same manner as in Example 4 (6) to give the compounds listed in Table 1 below.
[0095]
[Table 1]
Examples 7-21
The corresponding starting materials are treated in the same manner to give the compounds listed in Table 2 below.
[0097]
[Table 2]
[Table 3]
Example 22
(1) To a solution of 0.78 g of diisopropylamine in 40 ml of tetrahydrofuran, 4.82 ml of 1.6M n-butyllithium in hexane is added dropwise over 3 minutes while cooling in a dry ice-acetone bath. The mixture is stirred for 30 minutes on the same bath. A solution of 0.50 g of 2,6-dichloropyrazine in 5 ml of tetrahydrofuran is added dropwise at the same temperature over 15 minutes, and the mixture is stirred for 1 hour. The reaction mixture is poured into dry ice and stirred at room temperature for 1 hour. The reaction mixture is diluted with 10% aqueous hydrochloric acid to a pH value of about 2, and extracted with ethyl acetate. The collected organic layer is extracted with a saturated aqueous solution of sodium bicarbonate, the aqueous extract is washed with ethyl acetate, acidified with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The collected organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is triturated with chloroform-hexane (1: 1) to give 234 mg of 2-carboxy-3,5-dichloropyrazine as a slightly brown crystalline powder. Melting point: 139-141 ° C. MS (m / z): 191 (M-H)-.
[0100]
(2) A mixture of 226 mg of 2-carboxy-3,5-dichloropyrazine obtained in the above (1), 118 mg of sodium bicarbonate, 0.5 ml of methyl iodide and 1.8 ml of N, N-dimethylformamide at room temperature for 14 hours. Stir. The mixture is diluted with 10% aqueous citric acid and extracted with ethyl acetate. The collected organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 245 mg of 2-methoxycarbonyl-3,5-dichloropyrazine as a light brown crystalline powder. Melting point: 60-63 ° C. MS (m / z): 206 (M+).
[0101]
(3) A mixture of 2-methoxycarbonyl-3,5-dichloropyrazine (234 mg), 3-chloro-4-methoxybenzylamine (204 mg), triethylamine (0.17 ml) and anhydrous toluene (3 ml) obtained in (2) above was stirred at room temperature for 7 hours. To do. The reaction mixture is diluted with 10% aqueous citric acid and extracted with ethyl acetate. The extract is washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified and separated by silica gel column chromatography (silica gel 5 g, solvent; hexane: chloroform = 1: 1), and the desired fraction was concentrated under reduced pressure to give 2-methoxycarbonyl-3- ( 102 mg of 3-chloro-4-methoxybenzylamino) -5-chloropyrazine are obtained. Melting point: 149-151 ° C. MS (m / z): 342 (MH+).
[0102]
(4) A mixture of 150 ml of 2-methoxycarbonyl-3- (3-chloro-4-methoxybenzylamino) -5-chloropyrazine, 88.6 mg of 2-hydroxymethylpyrrolidine and 0.12 ml of triethylamine in 5 ml of tetrahydrofuran at room temperature for 4 hours. Stir and then heat at 50 ° C. for 2 hours. Then 44.3 mg of 2-hydroxymethylpyrrolidine are added and the mixture is stirred at 50 ° C. for 1 hour. After cooling, water is added to the mixture and extracted with ethyl acetate. The extract is washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained yellow oil was purified by silica gel flash column chromatography (solvent; chloroform: hexane = 1: 1) to give (S) -2-methoxycarbonyl-3- (3-chloro-4) in the form of a pale yellow powder. 123 mg of -methoxybenzylamino) -5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine are obtained. MS (m / z): 407 (MH+).
[0103]
(5) (S) -2-methoxycarbonyl-3- (3-chloro-4-methoxybenzylamino) -5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine 775 mg ethanol 8 ml obtained in (4) above To the solution is added 1.43 ml of 4N aqueous sodium hydroxide and the mixture is stirred at room temperature for 24 hours. The reaction mixture was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, washed with isopropyl alcohol, and washed with (S 537 mg of) -2-carboxy-3- (3-chloro-4-methoxybenzylamino) -5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine is obtained. Melting point: 169-171 [deg.] C. MS (m / z): 391 (M-H)-.
[0104]
(6) (S) -2-carboxy-3- (3-chloro-4-methoxybenzylamino) -5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine 80 mg, 2-amino obtained in (5) above A mixture of 26.7 mg of methylpyrimidine, 43 mg of 1,2-dichloroethane, 30.3 mg of 1-hydroxybenzotriazole and 3 ml of N, N-dimethylformamide is stirred at room temperature for 18 hours. Water is poured into the reaction mixture and extracted with ethyl acetate. The extract is washed with water, saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent; ethyl acetate) to give (S) -2- [N- (2-pyrimidinylmethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino)- There are obtained 87.6 mg of 5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine. MS (m / z): 484 (MH+).
[0105]
Examples 23-24
The corresponding starting material is treated in the same manner as in Example 22 to give the compounds listed in Table 3 below.
[0106]
[Table 4]
Example 25
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- (acryloyl) pyrimidine 31 mg, methanol 1 ml and concentrated sulfuric acid 1 drop Heat to reflux for days. After the reaction, the solvent was distilled off, and the residue was separated by silica gel thin layer chromatography (solvent: chloroform: methanol = 30: 1) to give (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4. 27 mg of-(3-chloro-4-methoxybenzylamino) -5-[(2-methoxyethyl) carbonyl] pyrimidine are obtained as a colorless oil. MS (m / z): 435 (MH+).
[0108]
Example 26
82.48 g of (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine and benzene A solution of 60.06 g of sulfonic acid monohydrate in 1000 ml of methanol was concentrated and recrystallized from a methanol-acetone mixture to obtain (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3- Chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine-2benzenesulfonate 121.8 g is obtained as colorless crystals. Melting point: 158.5-161.5 ° C.
[0109]
Example 27
(S) -4- (3-Chloro-4-methoxybenzylamino) -5-carboxy-2- (2-hydroxymethyl-1-pyrrolidinyl) pyrimidine 100 mg, 4-amino obtained in Example 1 (4) -1,3,5-trimethylpyrazole 47.9 mg, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 58.7 mg, 1-hydroxybenztriazole monohydrate 41.3 mg, and N , N-dimethylformamide (3 ml) was stirred at room temperature for 8 hours, and the reaction mixture was poured into an aqueous sodium bicarbonate solution. After extraction with ethyl acetate, the organic layer is washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent; chloroform: methanol = 5: 1), and (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- ( 115 mg of 3-chloro-4-methoxybenzylamino) -5- [N- (1,3,5-trimethyl-4-pyrazolyl) carbamoyl] pyrimidine are obtained. MS (m / z): 500 (MH+).
[0110]
Example 28
(1) A solution of 5.0 g of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine in 20 ml of sulfuryl chloride is heated at 50 ° C. for 1 hour. Concentrate the reaction mixture and pour in saturated aqueous sodium bicarbonate. The mixture is extracted with ethyl acetate and the organic layer is washed with water, brine, dried over sodium sulfate and concentrated. The residue is purified by silica gel flash column chromatography (solvent; ethyl acetate: hexane = 1: 10) to quantitatively obtain 4.87 g of 2,4-dichloro-5-ethoxycarbonylpyrimidine as a yellow oily substance. MS (m / z): 220 (M+).
[0111]
(2) To a solution of 4.2 g of 2,4-dichloro-5-ethoxycarbonylpyrimidine obtained in the above (1) and 2.30 g of mercaptobenzene in 40 ml of toluene, 3.94 g of potassium carbonate was added at 0 ° C. The mixture is then stirred at 50 ° C. for 1 hour and further at 100 ° C. for 10 minutes. Pour water and extract with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate and then concentrated. The residue was purified by silica gel flash column chromatography (solvent; ethyl acetate: hexane = 1: 20 to ethyl acetate: hexane = 1: 10) to give colorless crystals of 2-chloro-4-phenylthio-5-ethoxycarbonylpyrimidine 4 Obtain .16 g. MS (m / z): 295 (MH+).
[0112]
(3) To a solution of 4.05 g of 2-chloro-4-phenylthio-5-ethoxycarbonylpyrimidine obtained in (2) above in 40 ml of tetrahydrofuran were added 1.66 g of L-prolinol and 2.77 g of triethylamine, and the mixture was stirred at room temperature. Stir for 20 hours. Water is poured into the reaction mixture and extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate and then concentrated. The residue was purified by silica gel flash column chromatography (solvent; ethyl acetate: hexane = 1: 2) to give (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4-phenylthio as a colorless viscous oil. 4.16 g of -5-ethoxycarbonylpyrimidine are obtained. MS (m / z): 360 (MH+).
[0113]
(4) (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4-phenylthio-5-ethoxycarbonylpyrimidine obtained in (3) above in 4 ml of ethanol in 4.10 g of 4N aqueous sodium hydroxide solution 8 .6 ml is added and the mixture is stirred at room temperature for 15 hours. Add 30 ml of 10% aqueous citric acid solution until the reaction solution is slightly acidic, then extract with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, concentrated and colorless crystals of (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4-phenylthio-5-carboxypyrimidine 3 Obtain .65 g. MS (m / z): 330 (M-H)-.
[0114]
(5) 2.55 g of (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4-phenylthio-5-carboxypyrimidine obtained in (4) above, 1.09 g of 2-aminomethylpyrimidine, A mixture of 1.77 g of 2-dichloroethane and 1.25 g of 1-hydroxybenztriazole and 40 ml of N, N-dimethylformamide is stirred at room temperature for 16 hours. Pour water and extract with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium hydrogen carbonate solution and brine, dried over sodium sulfate and concentrated to give 4.05 g of pale yellow crystals. This was purified by silica gel flash column chromatography (solvent; ethyl acetate) to give colorless crystals of 2- (2-hydroxymethyl-1-pyrrolidinyl) -4-phenylthio-5- [N- (2-pyrimidylmethyl) carbamoyl] 2.39 g of pyrimidine are obtained. Melting point: 154-156 ° C. IR (Nujol): 1633cm-1. MS (m / z): 423 (MH+).
[0115]
(6) (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4-phenylthio-5- [N- (2-pyrimidylmethyl) carbamoyl] pyrimidine (100 mg) obtained in (5) above was added to a chloroform 3 ml solution. 70.1 mg of m-chloroperbenzoic acid are added at 0 ° C. and the mixture is stirred at 0 ° C. for 30 minutes. Then 50.3 mg of 3-chlorobenzylamine and 48.0 mg of triethylamine are added at 0 ° C. and the mixture is stirred at room temperature for 17 hours. Pour water, extract with chloroform, wash the organic layer with brine, dry over sodium sulfate, and concentrate to give 169 mg of a yellow oil. This was purified by silica gel flash column chromatography (solvent; ethyl acetate) and triturated with ethyl acetate-hexane to give (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4 as colorless powder. 95.3 mg of-(3-chlorobenzylamino) -5- [N- (2-pyrimidylmethyl) carbamoyl] pyrimidine are obtained. Melting point: 153-156 ° C. IR (Nujol): 3241, 1637cm-1. MS (m / z): 454 (MH+).
[0116]
(7) (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4-phenylthio-5- [N- (2-pyrimidylmethyl) carbamoyl] pyrimidine (100 mg) obtained in (5) above was added to a chloroform 3 ml solution. 70.1 mg of m-chloroperbenzoic acid (70%) are added at 0 ° C. and the mixture is stirred at 0 ° C. for 30 minutes. Then 48.8 mg of 4-methoxybenzylamine and 48.0 mg of triethylamine are added at 0 ° C. and the mixture is stirred at room temperature for 20 hours. Pour water, extract with chloroform, wash the organic layer with brine, dry over sodium sulfate, and concentrate to give 143 mg of a yellow oil. This was purified by silica gel flash column chromatography (solvent; ethyl acetate) to give (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (4-methoxybenzylamino) -5 as colorless powder. 88.2 mg of-[N- (2-pyrimidylmethyl) carbamoyl] pyrimidine are obtained. IR (Neat): 3296, 1633cm-1. MS (m / z): 450 (MH+).
[0117]
Example 29
(1) 10.0 mg of (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-formylpyrimidine obtained in Example 2 (3) 1.0 ml of tetrahydrofuran is treated with 83 μl of 1.6 M n-butyllithium hexane solution at −78 ° C. for 3 minutes, and then an aqueous sodium hydrogen carbonate solution is added. The reaction mixture was extracted with ethyl acetate to give an oily (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- (1-hydroxypentyl). ) 13.7 mg of pyrimidine is obtained.
[0118]
(2) (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- (1-hydroxypentyl) pyrimidine obtained above was converted to manganese dioxide Treat with 25 mg at room temperature, add 100 mg of manganese dioxide slowly and stir the mixture overnight. The reaction mixture was heated at reflux for 5 hours, the insoluble material was filtered off, the filtrate was concentrated under reduced pressure, separated by preparative thin layer chromatography, and purified as a colorless oil (S) -2- (2 5.8 mg of -hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-pentanoylpyrimidine are obtained. MS (m / z): 433 (MH+).
[0119]
Examples 30-83
The corresponding starting materials are treated in the same manner to give the compounds listed in Table 4 below.
[0120]
[Table 5]
[Table 6]
[Table 7]
[Table 8]
[Table 9]
Examples 84-86
The corresponding starting materials are treated in the same manner to give the compounds listed in Table 5 below.
[Table 10]
Example 87
80 mg of (S) -2-carboxy-3- (3-chloro-4-methoxybenzylamino) -5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine obtained in Example 22 (5), 2-aminomethyl A mixture of 31.9 mg of 4-methylmorpholine, 43 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 30.3 mg of 1-hydroxybenzotriazole in 3 ml of N, N-dimethylformamide at room temperature for 18 hours. Stir. Water is poured into the reaction mixture and extracted with ethyl acetate. The extract is washed with water, saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent; ethyl acetate) to give (S) -2- [N- (4-methyl-2-morpholinyl) methylcarbamoyl] -3- (3-chloro-4-methoxy 80.5 mg of (benzylamino) -5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine are obtained. MS (m / z): 505 (MH+), IR (Nujol): 3295, 1635 cm-1.
[0127]
Examples 88-91
The corresponding starting materials are treated in the same manner to give the compounds listed in Table 6 below.
[Table 11]
Examples 92-145
Similar treatment from the corresponding starting material gives the compounds listed in Table 7 below.
[Table 12]
[Table 13]
[Table 14]
[Table 15]
[Table 16]
[Table 17]
Example 146
Treatment in a similar manner from the corresponding starting material gives a foam of the formula MS (m / z): 464 (MH+).
Embedded image
Example 147
The same treatment from the corresponding starting material gives the compound of formula Melting point: 140-144 ° C.
Embedded image
Example 148
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidylmethyl) obtained in Example 1 (5) To a solution of carbamoyl] pyrimidine (307 mg) in methylene chloride (6 ml) is added dropwise boron bromide (300 μl) under ice cooling. The reaction mixture is stirred at 0 ° C. for 4 hours. Methanol and then saturated aqueous sodium hydrogen carbonate solution are added to the reaction mixture under ice cooling. The mixture is extracted with a mixed solvent of ethyl acetate and tetrahydrofuran, and the organic layer is washed successively with water and brine, dried over sodium sulfate, and concentrated in vacuo to give 227 mg of a slightly brown amorphous product. This was suspended in chloroform, and the resulting insoluble matter was removed by filtration. The filtrate was subjected to silica gel column chromatography and then purified by NH-silica gel column chromatography to obtain (S) -2- ( 129 mg of 2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-hydroxybenzylamino) -5- [N- (2-pyrimidylmethyl) carbamoyl] pyrimidine are obtained. MS (m / z): 470 (MH+). IR (Nujol): 3279, 1632, 1593, 1569, 1518, 1463 cm-1.
[0137]
Example 149
(1) 2.00 g of 2-methylthio-4- (3-chloro-4-methoxybenzylamino) -5-ethoxycarbonylpyrimidine obtained in Example 1 (1) was suspended in 10 ml of dimethyl sulfoxide and 10% at room temperature. Treat with 10 ml of aqueous sodium hydroxide. 5 ml of dimethyl sulfoxide are added and the reaction mixture is stirred overnight at room temperature. Citric acid is added to the resulting transparent reaction solution to make it acidic. An excess amount of water (about 50 ml) was added, and the resulting precipitate was collected by filtration, washed with isopropyl alcohol, then further washed with isopropyl ether, and dried under reduced pressure to give 2-methylthio- 1.864 g of 4- (3-chloro-4-methoxybenzylamino) -5-carboxypyrimidine are obtained. Melting point: 238-240 ° C. (decomposition).
[0138]
(2) 4- (3-Chloro-4-methoxybenzylamino) -5-carboxy-2-methylthiopyrimidine 200 mg of oxalyl chloride and N, N-dimethylformamide were added to a suspension of 200 mg of methylene chloride and the mixture was stirred at room temperature. For 30 minutes. The reaction mixture is concentrated, 144 mg of dimethylaminopyridine is added at room temperature to a suspension of the obtained acid chloride compound and 5-aminopyrimidine 84.0 mg in methylene chloride at room temperature, and the mixture is stirred at room temperature. Water is poured and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine, dried over sodium sulfate, and concentrated. The residue was triturated with a mixed solvent of ethyl acetate and n-hexane to give pale yellow needles of 4- (3-chloro-4-methoxybenzylamino) -5- (5-pyrimidinylaminocarbonyl) -2- 216 mg of methylthiopyrimidine are obtained. Melting point: 238-240 ° C. IR (Nujol): 3251, 1666cm-1. MS (m / z): 416 (M+).
[0139]
(3) To a suspension of 150 mg of the compound obtained in (2) above in 10 ml of chloroform, 107 mg of m-chloroperbenzoic acid was added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 1 hour, and then m- Add 53 mg of chloroperbenzoic acid at 0 ° C. and stir at 0 ° C. for 30 minutes. 43.7 mg of L-prolinol and 72.9 mg of triethylamine are added at 0 ° C. and the mixture is stirred at room temperature for 20 hours. Water was poured and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give 201 mg of a yellow viscous oil, which was subjected to NH-silica gel flash column chromatography (solvent; acetic acid). Ethyl) and washed with a mixed solvent of ethyl acetate and hexane to give colorless needle-like crystals of (S) -4- (3-chloro-4-methoxybenzylamino) -5- (5-pyrimidinylaminocarbonyl) 81 mg of 2- (2-hydroxymethyl-1-pyrrolidinyl) pyrimidine are obtained. Melting point: 192-195 ° C. IR (Nujol): 3279, 1669cm-1. MS (m / z): 470 (MH+).
[0140]
Examples 150-157
In the same manner as in Example 149, the compounds shown in Table 8 below are obtained from the corresponding starting materials.
[Table 18]
Example 158
(1) A suspension of 154.0 mg of 4- (3-chloro-4-methoxybenzylamino) -5-carboxy-2-methylthiopyrimidine obtained in Example 149 (1) in 5 ml of methylene chloride was dissolved in 119 μl of oxalyl chloride at room temperature. Work up and add N, N-dimethylformamide. The mixture is stirred for 1 hour and the solvent is removed in vacuo. Treat the residue with ether and refrigerate overnight. Volatiles are removed in vacuo and the residue is treated with excess diazomethane at 0 ° C. and then refrigerated overnight. Methanol is added to stop the reaction. Purification by silica gel chromatography (solvent: hexane: ethyl acetate = 2: 1) gave 21.5 mg of 4- (3-chloro-4-methoxybenzylamino) -5- (diazomethylcarbonyl) -2-methylthiopyrimidine. Obtained as a pale yellow solid. IR (Nujol): 3277, 2115, 1607, 1567, 1461, 1377, 1357, 1141 cm-1. MS (m / z): 364 (MH+). Melting point: 162-165 [deg.] C. (decomposition).
[0142]
(2) A suspension of 16.5 mg of the compound obtained in (1) above in 3 ml of methanol is treated with 16.5 mg of toluenesulfonic acid monohydrate at room temperature. The solvent was removed in vacuo and the residue was purified by preparative TLC (solvent; hexane: ethyl acetate = 2: 1) to give 4- (3-chloro-4-methoxybenzylamino) -5- (methoxymethylcarbonyl)- 11.0 mg of 2-methylthiopyrimidine is obtained as a colorless oil.
[0143]
(3) A 1.0 ml solution of 11.0 mg of the compound obtained in (2) above is treated with 7.4 mg of m-chloroperbenzoic acid at 0 ° C. The mixture is treated with 8.3 μl triethylamine and 36 mg L-prolinol at room temperature and the reaction mixture is stirred overnight. The reaction mixture is diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The residue was purified by preparative TLC (solvent; chloroform: ethyl acetate = 1: 1) to give (S) -4- (3-chloro-4-methoxybenzylamino) -5- (methoxymethylcarbonyl) as a colorless oil. 8.5 mg of) -2- (2-hydroxymethyl-1-pyrrolidinyl) pyrimidine is obtained. MS (m / z): 421 (MH+).
[0144]
【The invention's effect】
The compound (I) of the present invention and a pharmacologically acceptable salt thereof are pharmaceutical compounds that have an excellent PDE V inhibitory action and are useful as preventive and therapeutic agents for penile erectile dysfunction.
Claims (19)
−ＮＨ−Ｑ−Ｒ3
（式中、Ｒ3は置換されていてもよい含窒素複素環式基、Ｑは低級アルキレン基又は単結合を表す)
で示される基又は式：
−ＮＨ−Ｒ4
（式中、Ｒ4は置換されていてもよいシクロアルキル基を表す)
で示される基、Ｒ2は置換されていてもよいアリール基、Ｙ及びＺは一方が式：＝ＣＨ−であり、他方が式：＝Ｎ−を表す)
で示される芳香族含窒素六員環化合物又はその薬理的に許容し得る塩。Formula (I)
-NH-Q-R 3
(Wherein R 3 represents an optionally substituted nitrogen-containing heterocyclic group, Q represents a lower alkylene group or a single bond)
Or a group represented by:
-NH-R 4
(Wherein R 4 represents an optionally substituted cycloalkyl group)
Wherein R 2 is an optionally substituted aryl group, Y and Z are each represented by the formula: ═CH— and the other represents the formula: ═N—)
Or a pharmacologically acceptable salt thereof.
(１)低級アルキル基、
(２)水酸基置換低級アルキル基、
(３)ホルミル基、
(４)オキソ基、
(５)アミノ基、
(６)水酸基、
(７)低級アルコキシカルボニル基、及び
(８)(ｉ)ハロゲン原子と低級アルコキシ基とで置換されたベンジルアミノ基及び(ｉｉ)水酸基置換シクロアルキルカルバモイル基で置換されたピリミジニル基から選ばれる基であり、Ｒ1が低級アルコキシ基、水酸基、モルホリニル基、低級アルキルスルホニル基、ジ低級アルキルホスフィノ基、ジ低級アルキルアミノ基、ピリミジニル基置換低級アルキルアミノ基、ピリジル基、ピリジルアミノ基及び低級アルキル基置換ピペラジニル基から選ばれる基で置換されていてもよい低級アルキル基、式：
−ＮＨ−Ｑ−Ｒ3
で示される基又は式：
−ＮＨ−Ｒ4
で示される基であり、Ｒ3で示される「置換されていてもよい含窒素複素環式基」における含窒素複素環式基が５〜６員の単環式含窒素複素環式基又は８〜１０員の二環式含窒素複素環式基から選ばれる基であり、前記の「置換されていてもよい含窒素複素環式基」の置換基が、低級アルキル基、水酸基置換低級アルキル基、オキソ基、アミノ基、ジ低級アルキルアミノ基、低級アルカノイル基及びシアノ基置換低級アルキル基から選ばれる基であり、Ｒ4が水酸基、低級アルコキシ基及びピリミジニルオキシ基から選ばれる基で置換されたシクロアルキル基であり、Ｒ2が低級アルコキシ基、ハロゲン原子、シアノ基、ニトロ基、水酸基及び低級アルキル基から選ばれる基で置換されたフェニル基である請求項１記載の化合物。The nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by ring A is a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic ring A substituent of the above-mentioned “optionally substituted nitrogen-containing heterocyclic group”,
(1) a lower alkyl group,
(2) a hydroxyl group-substituted lower alkyl group,
(3) formyl group,
(4) an oxo group,
(5) amino group,
(6) hydroxyl group,
(7) a lower alkoxycarbonyl group, and
(8) a group selected from (i) a benzylamino group substituted with a halogen atom and a lower alkoxy group and (ii) a pyrimidinyl group substituted with a hydroxyl group-substituted cycloalkylcarbamoyl group, and R 1 is a lower alkoxy group, Substituted with a group selected from a hydroxyl group, a morpholinyl group, a lower alkylsulfonyl group, a dilower alkylphosphino group, a dilower alkylamino group, a pyrimidinyl group substituted lower alkylamino group, a pyridyl group, a pyridylamino group and a lower alkyl group substituted piperazinyl group. Optionally lower alkyl group, formula:
-NH-Q-R 3
Or a group represented by:
-NH-R 4
Or a monocyclic nitrogen-containing heterocyclic group having a 5- to 6-membered nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by R 3 or 8 A group selected from a 10-membered bicyclic nitrogen-containing heterocyclic group, wherein the substituent of the “optionally substituted nitrogen-containing heterocyclic group” is a lower alkyl group, a hydroxyl group-substituted lower alkyl group , An oxo group, an amino group, a di-lower alkylamino group, a lower alkanoyl group and a cyano group-substituted lower alkyl group, wherein R 4 is substituted with a group selected from a hydroxyl group, a lower alkoxy group and a pyrimidinyloxy group The compound according to claim 1, which is a cycloalkyl group, and R 2 is a phenyl group substituted with a group selected from a lower alkoxy group, a halogen atom, a cyano group, a nitro group, a hydroxyl group and a lower alkyl group.
−ＮＨ−Ｑ−Ｒ3
で示される基又は式：
−ＮＨ−Ｒ4
で示される基であり、Ｒ3で示される「置換されていてもよい含窒素複素環式基」が、低級アルキル基で置換されていてもよい５〜６員の単環式含窒素複素環式基であり、Ｒ4が水酸基及び低級アルコキシ基から選ばれる基で置換されたシクロアルキル基であり、Ｒ2が低級アルコキシ基、ハロゲン原子及びシアノ基から選ばれる基で置換されたフェニル基である請求項１記載の化合物。The nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by ring A is a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic ring A group selected from the group consisting of a lower alkyl group, a hydroxyl group-substituted lower alkyl group, a formyl group, and an oxo group, wherein the substituent of the aforementioned “optionally substituted nitrogen-containing heterocyclic group” is a nitrogen-containing heterocyclic group Wherein R 1 is a lower alkyl group optionally substituted with a group selected from a lower alkoxy group and a morpholinyl group,
-NH-Q-R 3
Or a group represented by:
-NH-R 4
A 5- to 6-membered monocyclic nitrogen-containing heterocycle optionally represented by a "optionally substituted nitrogen-containing heterocyclic group" represented by R 3 and a lower alkyl group R 4 is a cycloalkyl group substituted with a group selected from a hydroxyl group and a lower alkoxy group, and R 2 is a phenyl group substituted with a group selected from a lower alkoxy group, a halogen atom and a cyano group A compound according to claim 1.
−ＮＨ−Ｑ−Ｒ3
で示される基又は式：
−ＮＨ−Ｒ4
で示される基であり、Ｒ3が、式：
-NH-Q-R 3
Or a group represented by:
-NH-R 4
R 3 is a group represented by the formula:
−ＮＨ−Ｑ−Ｒ3
で示される基又は式：
−ＮＨ−Ｒ4
で示される基であり、Ｒ3で示される「置換されていてもよい含窒素複素環式基」が低級アルキル基で置換されていてもよい５〜６員の単環式含窒素複素環式基であり、Ｒ4が水酸基で置換されたシクロアルキル基であり、Ｒ2が低級アルコキシ基及びハロゲン原子から選ばれる基で置換されたフェニル基である請求項１記載の化合物。The nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by ring A is a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic ring A group selected from the group consisting of a lower alkyl group, a hydroxyl group-substituted lower alkyl group, a formyl group, and an oxo group, which is a nitrogen-containing heterocyclic group of formula Wherein R 1 is a lower alkyl group substituted by a lower alkoxy group, the formula:
-NH-Q-R 3
Or a group represented by:
-NH-R 4
A 5- or 6-membered monocyclic nitrogen-containing heterocyclic group in which the “optionally substituted nitrogen-containing heterocyclic group” represented by R 3 may be substituted with a lower alkyl group The compound according to claim 1, wherein R 4 is a cycloalkyl group substituted with a hydroxyl group, and R 2 is a phenyl group substituted with a group selected from a lower alkoxy group and a halogen atom.
−ＮＨ−Ｑ−Ｒ3
で示される基又は式：
−ＮＨ−Ｒ4
で示される基であり、Ｒ3が式：
-NH-Q-R 3
Or a group represented by:
-NH-R 4
R 3 is a group represented by the formula:
−ＮＨ−Ｑ−Ｒ3
で示される基であり、Ｒ3で示される「置換されていてもよい含窒素複素環式基」が低級アルキル基で置換されていてもよい５〜６員の単環式含窒素複素環式基であり、Ｒ2が低級アルコキシ基及びハロゲン原子から選ばれる基で置換されたフェニル基である請求項１記載の化合物。The nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by ring A is a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic ring A nitrogen-containing heterocyclic group, the substituent of the “optionally substituted nitrogen-containing heterocyclic group” is a hydroxyl group-substituted lower alkyl group, and R 1 is a group represented by the formula:
-NH-Q-R 3
A 5- or 6-membered monocyclic nitrogen-containing heterocyclic group in which the “optionally substituted nitrogen-containing heterocyclic group” represented by R 3 may be substituted with a lower alkyl group The compound according to claim 1, wherein R 2 is a phenyl group substituted with a group selected from a lower alkoxy group and a halogen atom.
−ＮＨ−Ｑ−Ｒ3
で示される基であり、Ｒ3が式：
-NH-Q-R 3
R 3 is a group represented by the formula:
２−(６,７−ジヒドロ−５Ｈ−ピロロ[３,４−ｂ]ピリジン−６−イル)−４−(３−シアノ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジニルメチル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(トランス−４−メトキシシクロヘキシル)カルバモイル]ピリミジン；
２−(６,７−ジヒドロ−５Ｈ−ピロロ[３,４−ｂ]ピリジン−６−イル)−４−(３−シアノ−４−メトキシベンジルアミノ)−５−[Ｎ−(トランス−４−ヒドロキシシクロヘキシル)カルバモイル]ピリミジン；
２−(６,７−ジヒドロ−５Ｈ−ピロロ[３,４−ｂ]ピリジン−６−イル)−４−(３−シアノ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−モルホリノエチル)カルバモイル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−モルホリノエチル)カルバモイル]ピリミジン；
２−[(２Ｓ)−２−ヒドロキシメチル−１−ピロリジニル]−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−[[(２Ｒ)−４−メチル−２−モルホリニル]メチル]カルバモイル]ピリミジン；
２−[(２Ｓ)−２−ヒドロキシメチル−１−ピロリジニル]−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−[[(２Ｓ)−４−メチル−２−モルホリニル]メチル]カルバモイル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(４−ピリミジニルメチル)カルバモイル]ピリミジン；
２−(４−メチル−３−オキソ−１−ピペラジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(トランス−４−ヒドロキシシクロヘキシル)カルバモイル]ピリミジン；
２−(４−ホルミル−１−ピペラジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(トランス−４−ヒドロキシシクロヘキシル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(トランス−４−ヒドロキシシクロヘキシル)カルバモイル]ピリミジン；
２−[シス−２,５−ビス(ヒドロキシメチル)−１−ピロリジニル]−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジニルメチル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジニルメチル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−モルホリノエチル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロ−１,７−ナフチリジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−モルホリノエチル)カルバモイル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−アセチルピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(４−ピリダジニルメチル)カルバモイル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(５−ピリミジニルメチル)カルバモイル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリジルメチル)カルバモイル]ピリミジン；
(Ｓ)−２−[Ｎ−(２−ピリミジニルメチル)カルバモイル]−３−(３−クロロ−４−メトキシベンジルアミノ)−５−[２−ヒドロキシメチル−１−ピロリジニル]ピラジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[(２−モルホリノエチル)カルボニル]ピリミジン；
２−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−[(４−メチル−２−モルホリニル)メチル]カルバモイル]ピリミジン；
(Ｓ)−２−[Ｎ−(２−モルホリノエチル)カルバモイル]−３−(３−クロロ−４−メトキシベンジルアミノ)−５−(２−ヒドロキシメチル−１−ピロリジニル)ピラジン；
２−[Ｎ−(２−ピリミジニルメチル)カルバモイル]−３−(３−クロロ−４−メトキシベンジルアミノ)−５−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)ピラジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[(２−メトキシエチル)カルボニル]ピリミジン、
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(１,３,５−トリメチル−４−ピラゾリル)カルバモイル]ピリミジン、
又はその薬理学的に許容し得る塩。(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine;
2- (6,7-Dihydro-5H-pyrrolo [3,4-b] pyridin-6-yl) -4- (3-cyano-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) ) Carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4 -Methoxycyclohexyl) carbamoyl] pyrimidine;
2- (6,7-Dihydro-5H-pyrrolo [3,4-b] pyridin-6-yl) -4- (3-cyano-4-methoxybenzylamino) -5- [N- (trans-4- Hydroxycyclohexyl) carbamoyl] pyrimidine;
2- (6,7-Dihydro-5H-pyrrolo [3,4-b] pyridin-6-yl) -4- (3-cyano-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) ) Carbamoyl] pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl] pyrimidine;
2-[(2S) -2-hydroxymethyl-1-pyrrolidinyl] -4- (3-chloro-4-methoxybenzylamino) -5- [N-[[(2R) -4-methyl-2-morpholinyl] Methyl] carbamoyl] pyrimidine;
2-[(2S) -2-hydroxymethyl-1-pyrrolidinyl] -4- (3-chloro-4-methoxybenzylamino) -5- [N-[[(2S) -4-methyl-2-morpholinyl] Methyl] carbamoyl] pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (4-pyrimidinylmethyl) carbamoyl] pyrimidine;
2- (4-Methyl-3-oxo-1-piperazinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4-hydroxycyclohexyl) carbamoyl] pyrimidine;
2- (4-formyl-1-piperazinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4-hydroxycyclohexyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4 -Hydroxycyclohexyl) carbamoyl] pyrimidine;
2- [cis-2,5-bis (hydroxymethyl) -1-pyrrolidinyl] -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinyl) Methyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholino) Ethyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl ] Pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-acetylpyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (4-pyridazinylmethyl) carbamoyl] pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (5-pyrimidinylmethyl) carbamoyl] pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyridylmethyl) carbamoyl] pyrimidine;
(S) -2- [N- (2-pyrimidinylmethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- [2-hydroxymethyl-1-pyrrolidinyl] pyrazine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-[(2-morpholinoethyl) carbonyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N-[(4- Methyl-2-morpholinyl) methyl] carbamoyl] pyrimidine;
(S) -2- [N- (2-morpholinoethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine;
2- [N- (2-pyrimidinylmethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine- 7-yl) pyrazine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-[(2-methoxyethyl) carbonyl] pyrimidine,
(S) -2- (2-Hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (1,3,5-trimethyl-4-pyrazolyl) carbamoyl ] Pyrimidine,
Or a pharmacologically acceptable salt thereof.
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(４−ピリミジニルメチル)カルバモイル]ピリミジン；
２−(４−メチル−３−オキソ−１−ピペラジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(トランス−４−ヒドロキシシクロヘキシル)カルバモイル]ピリミジン；
２−(４−ホルミル−１−ピペラジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(トランス−４−ヒドロキシシクロヘキシル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジニルメチル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−モルホリノエチル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロ−１,７−ナフチリジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−モルホリノエチル)カルバモイル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(５−ピリミジニルメチル)カルバモイル]ピリミジン；
(Ｓ)−２−[Ｎ−(２−ピリミジニルメチル)カルバモイル]−３−(３−クロロ−４−メトキシベンジルアミノ)−５−[２−ヒドロキシメチル−１−ピロリジニル]ピラジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[(２−メトキシエチル)カルボニル]ピリミジン、
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(１,３,５−トリメチル−４−ピラゾリル)カルバモイル]ピリミジン、
又はその薬理学的に許容し得る塩。(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (4-pyrimidinylmethyl) carbamoyl] pyrimidine;
2- (4-Methyl-3-oxo-1-piperazinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4-hydroxycyclohexyl) carbamoyl] pyrimidine;
2- (4-formyl-1-piperazinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4-hydroxycyclohexyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinyl) Methyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholino) Ethyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl ] Pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (5-pyrimidinylmethyl) carbamoyl] pyrimidine;
(S) -2- [N- (2-pyrimidinylmethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- [2-hydroxymethyl-1-pyrrolidinyl] pyrazine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-[(2-methoxyethyl) carbonyl] pyrimidine,
(S) -2- (2-Hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (1,3,5-trimethyl-4-pyrazolyl) carbamoyl ] Pyrimidine,
Or a pharmacologically acceptable salt thereof.
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−モルホリノエチル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロイミダゾ[１,２−ａ]ピラジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−ピリミジニルメチル)カルバモイル]ピリミジン；
２−(５,６,７,８−テトラヒドロ−１,７−ナフチリジン−７−イル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(２−モルホリノエチル)カルバモイル]ピリミジン；
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(５−ピリミジニルメチル)カルバモイル]ピリミジン；
(Ｓ)−２−[Ｎ−(２−ピリミジニルメチル)カルバモイル]−３−(３−クロロ−４−メトキシベンジルアミノ)−５−[２−ヒドロキシメチル−１−ピロリジニル]ピラジン；
(Ｓ)−２−[Ｎ−(２−モルホリノエチル)カルバモイル]−３−(３−クロロ−４−メトキシベンジルアミノ)−５−(２−ヒドロキシメチル−１−ピロリジニル)ピラジン、
(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−４−(３−クロロ−４−メトキシベンジルアミノ)−５−[Ｎ−(１,３,５−トリメチル−４−ピラゾリル)カルバモイル]ピリミジン、
又はその薬理学的に許容し得る塩。(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinyl) Methyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl ] Pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (5-pyrimidinylmethyl) carbamoyl] pyrimidine;
(S) -2- [N- (2-pyrimidinylmethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- [2-hydroxymethyl-1-pyrrolidinyl] pyrazine;
(S) -2- [N- (2-morpholinoethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine,
(S) -2- (2-Hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (1,3,5-trimethyl-4-pyrazolyl) carbamoyl ] Pyrimidine,
Or a pharmacologically acceptable salt thereof.
又はその薬理学的に許容し得る塩。(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine,
Or a pharmacologically acceptable salt thereof.
又はその薬理学的に許容し得る塩。2- (5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl ] Pyrimidine,
Or a pharmacologically acceptable salt thereof.
又はその薬理学的に許容し得る塩。(S) -2- (2-Hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (1,3,5-trimethyl-4-pyrazolyl) carbamoyl ] Pyrimidine,
Or a pharmacologically acceptable salt thereof.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000277652A JP3637961B2 (en) | 1999-09-16 | 2000-09-13 | Aromatic nitrogen-containing six-membered ring compounds |
| US10/699,804 US7273868B2 (en) | 2000-04-28 | 2003-11-04 | Pyrazine derivatives |
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| Application Number | Priority Date | Filing Date | Title |
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| JP26185299 | 1999-09-16 | ||
| JP2000130371 | 2000-04-28 | ||
| JP2000-130371 | 2000-04-28 | ||
| JP11-261852 | 2000-04-28 | ||
| JP2000277652A JP3637961B2 (en) | 1999-09-16 | 2000-09-13 | Aromatic nitrogen-containing six-membered ring compounds |
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| JP3637961B2 true JP3637961B2 (en) | 2005-04-13 |
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| CA2508914A1 (en) * | 2002-12-04 | 2004-06-17 | Gene Logic Inc. | Modulators of melanocortin receptor |
| US7759348B2 (en) | 2003-07-30 | 2010-07-20 | Xenon Pharmaceuticals Inc. | Pyridazine derivatives and their use as therapeutic agents |
| TW201038270A (en) * | 2003-07-30 | 2010-11-01 | Xenon Pharmaceuticals Inc | Pyridazine derivatives and their use in the inhibition of stearoyl-CoA desaturase |
| EP2202228B1 (en) * | 2007-10-15 | 2014-12-10 | Takeda Pharmaceutical Company Limited | Amide compounds and use of the same |
| EP2735567B1 (en) * | 2011-07-21 | 2016-10-26 | Xuanzhu Pharma Co., Ltd. | Heterocyclic substituted pyrimidine compound |
| KR101794321B1 (en) * | 2012-08-14 | 2017-12-01 | 수안주 파마 코포레이션 리미티드 | Bicyclic Group Substituted Pyrimidine Compounds |
| US9527876B2 (en) * | 2013-03-29 | 2016-12-27 | Xuanzhu Pharma Co., Ltd. | Prodrugs of bicyclic substituted pyrimidine type PDE-5 inhibitors |
| GB201321748D0 (en) * | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
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