NZ616158B2 - Novel phenylpyridine derivative and drug containing same - Google Patents
Novel phenylpyridine derivative and drug containing same Download PDFInfo
- Publication number
- NZ616158B2 NZ616158B2 NZ616158A NZ61615812A NZ616158B2 NZ 616158 B2 NZ616158 B2 NZ 616158B2 NZ 616158 A NZ616158 A NZ 616158A NZ 61615812 A NZ61615812 A NZ 61615812A NZ 616158 B2 NZ616158 B2 NZ 616158B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- methyl
- pyridinyl
- phenyl
- dihydropyrimidinyl
- oxadiazol
- Prior art date
Links
- 239000003814 drug Substances 0.000 title abstract description 9
- 150000005359 phenylpyridines Chemical class 0.000 title abstract description 9
- 229940079593 drugs Drugs 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 129
- 206010020772 Hypertension Diseases 0.000 claims abstract description 19
- 208000008466 Metabolic Disease Diseases 0.000 claims abstract description 19
- 201000010870 diseases of metabolism Diseases 0.000 claims abstract description 19
- 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 14
- 208000001072 Type 2 Diabetes Mellitus Diseases 0.000 claims abstract description 13
- 201000010238 heart disease Diseases 0.000 claims abstract description 13
- -1 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-methoxypyrimidinyl)methylpyrimidin-4(3 H)-one Chemical compound 0.000 claims description 414
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 237
- 125000004076 pyridyl group Chemical group 0.000 claims description 176
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 102
- 239000011780 sodium chloride Substances 0.000 claims description 69
- 150000003839 salts Chemical class 0.000 claims description 67
- 125000000217 alkyl group Chemical group 0.000 claims description 59
- 239000000126 substance Substances 0.000 claims description 59
- 239000012453 solvate Substances 0.000 claims description 57
- 201000010099 disease Diseases 0.000 claims description 53
- 125000005843 halogen group Chemical group 0.000 claims description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 230000002490 cerebral Effects 0.000 claims description 22
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 16
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 15
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 15
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 208000002249 Diabetes Complications Diseases 0.000 claims description 12
- 206010012655 Diabetic complications Diseases 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 201000010874 syndrome Diseases 0.000 claims description 12
- 206010002383 Angina pectoris Diseases 0.000 claims description 11
- 208000007342 Diabetic Nephropathy Diseases 0.000 claims description 11
- 206010061835 Diabetic nephropathy Diseases 0.000 claims description 11
- 206010060378 Hyperinsulinaemia Diseases 0.000 claims description 11
- 230000003451 hyperinsulinaemic Effects 0.000 claims description 11
- 201000008980 hyperinsulinism Diseases 0.000 claims description 11
- 230000000302 ischemic Effects 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 230000002093 peripheral Effects 0.000 claims description 11
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 10
- 206010059245 Angiopathy Diseases 0.000 claims description 9
- 208000001083 Kidney Disease Diseases 0.000 claims description 9
- 208000001636 Diabetic Neuropathy Diseases 0.000 claims description 8
- 206010012680 Diabetic neuropathy Diseases 0.000 claims description 8
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 8
- 102000004877 Insulin Human genes 0.000 claims description 8
- 108090001061 Insulin Proteins 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
- 230000027455 binding Effects 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims 6
- 230000000694 effects Effects 0.000 abstract description 47
- 230000004913 activation Effects 0.000 abstract description 22
- 230000003042 antagnostic Effects 0.000 abstract description 14
- 102000008873 Angiotensin II receptor Human genes 0.000 abstract description 8
- 108050000824 Angiotensin II receptor Proteins 0.000 abstract description 8
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 abstract description 4
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 abstract description 4
- 206010007541 Cardiac disease Diseases 0.000 abstract 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 abstract 1
- 150000003536 tetrazoles Chemical class 0.000 abstract 1
- 238000000034 method Methods 0.000 description 366
- 238000006243 chemical reaction Methods 0.000 description 152
- 238000005160 1H NMR spectroscopy Methods 0.000 description 100
- 238000002360 preparation method Methods 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1H-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 41
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
- 239000003921 oil Substances 0.000 description 33
- 101700070851 PPARG Proteins 0.000 description 27
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 20
- 102000005862 Angiotensin II Human genes 0.000 description 18
- 229950006323 Angiotensin ii Drugs 0.000 description 18
- 101800000733 Angiotensin-2 Proteins 0.000 description 18
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II dizwitterion Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 239000000203 mixture Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 16
- KXIHDLIEPZOPJA-UHFFFAOYSA-N NCOC1=NC=CC=N1 Chemical compound NCOC1=NC=CC=N1 KXIHDLIEPZOPJA-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 125000004432 carbon atoms Chemical group C* 0.000 description 10
- YURNCBVQZBJDAJ-UHFFFAOYSA-M hept-2-enoate Chemical compound CCCCC=CC([O-])=O YURNCBVQZBJDAJ-UHFFFAOYSA-M 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 9
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 9
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 239000008079 hexane Substances 0.000 description 9
- 125000000714 pyrimidinyl group Chemical group 0.000 description 9
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 9
- OUOPDDNPXZHMDY-UHFFFAOYSA-N 2-pyrimidin-2-yloxyethanamine Chemical compound NCCOC1=NC=CC=N1 OUOPDDNPXZHMDY-UHFFFAOYSA-N 0.000 description 8
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 8
- IMNIMPAHZVJRPE-UHFFFAOYSA-N DABCO Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 8
- RMMXLENWKUUMAY-UHFFFAOYSA-N Telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cells Anatomy 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229960005187 telmisartan Drugs 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 238000004821 distillation Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 229960004586 rosiglitazone Drugs 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N Carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- 206010012601 Diabetes mellitus Diseases 0.000 description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- FVSKHRXBFJPNKK-UHFFFAOYSA-N Propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 5
- 239000005695 Ammonium acetate Substances 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 210000003734 Kidney Anatomy 0.000 description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 5
- 229940043376 ammonium acetate Drugs 0.000 description 5
- 235000019257 ammonium acetate Nutrition 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 239000002609 media Substances 0.000 description 5
- 150000002829 nitrogen Chemical group 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- SSUJUUNLZQVZMO-UHFFFAOYSA-N 1,2,3,4,8,9,10,10a-octahydropyrimido[1,2-a]azepine Chemical compound C1CCC=CN2CCCNC21 SSUJUUNLZQVZMO-UHFFFAOYSA-N 0.000 description 4
- UAOMVDZJSHZZME-UHFFFAOYSA-N Diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 4
- 206010022490 Insulin resistance syndrome Diseases 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M Lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- SRTHRWZAMDZJOS-UHFFFAOYSA-N Lithium hydride Chemical compound [H-].[Li+] SRTHRWZAMDZJOS-UHFFFAOYSA-N 0.000 description 4
- 239000005089 Luciferase Substances 0.000 description 4
- 108060001084 Luciferase family Proteins 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N Trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000005842 heteroatoms Chemical group 0.000 description 4
- 229940011051 isopropyl acetate Drugs 0.000 description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 239000001184 potassium carbonate Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 230000003389 potentiating Effects 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- ZBMJLTTZKPNPAR-UHFFFAOYSA-N 2-[5-(bromomethyl)pyridin-2-yl]benzonitrile Chemical compound N1=CC(CBr)=CC=C1C1=CC=CC=C1C#N ZBMJLTTZKPNPAR-UHFFFAOYSA-N 0.000 description 3
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Substances CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- 241001553178 Arachis glabrata Species 0.000 description 3
- 210000004204 Blood Vessels Anatomy 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 101700058973 GAL4 Proteins 0.000 description 3
- 101710042219 GAL6 Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 102100011539 LGALS4 Human genes 0.000 description 3
- 101710015850 LGALS4 Proteins 0.000 description 3
- HNIMBAXJIKTYOV-UHFFFAOYSA-N N,N-di(propan-2-yl)pentan-1-amine Chemical compound CCCCCN(C(C)C)C(C)C HNIMBAXJIKTYOV-UHFFFAOYSA-N 0.000 description 3
- 208000008589 Obesity Diseases 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 206010038428 Renal disease Diseases 0.000 description 3
- JLTRXTDYQLMHGR-UHFFFAOYSA-N Trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- MFNYBOWJWGPXFM-UHFFFAOYSA-N cyclobutanecarboxamide Chemical compound NC(=O)C1CCC1 MFNYBOWJWGPXFM-UHFFFAOYSA-N 0.000 description 3
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
- 230000001077 hypotensive Effects 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 3
- 229910052808 lithium carbonate Inorganic materials 0.000 description 3
- SJPCQNABHNCLPB-UHFFFAOYSA-N methyl 3-oxohexanoate Chemical compound CCCC(=O)CC(=O)OC SJPCQNABHNCLPB-UHFFFAOYSA-N 0.000 description 3
- 235000020824 obesity Nutrition 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000008177 pharmaceutical agent Substances 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 230000002633 protecting Effects 0.000 description 3
- 239000001187 sodium carbonate Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- XGINAUQXFXVBND-UHFFFAOYSA-N 1,2,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrimidine Chemical compound N1CC=CN2CCCC21 XGINAUQXFXVBND-UHFFFAOYSA-N 0.000 description 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-Aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- ORWYRWWVDCYOMK-HBZPZAIKSA-N Angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 2
- 102400000344 Angiotensin-1 Human genes 0.000 description 2
- 101800000734 Angiotensin-1 Proteins 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 210000001124 Body Fluids Anatomy 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N Boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 2
- 101700060761 COS7 Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 229960001031 Glucose Drugs 0.000 description 2
- 206010022489 Insulin resistance Diseases 0.000 description 2
- YCPOHTHPUREGFM-UHFFFAOYSA-N Irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M Lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 102100017336 NLRP3 Human genes 0.000 description 2
- 206010030124 Oedema peripheral Diseases 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- 208000005333 Pulmonary Edema Diseases 0.000 description 2
- 206010037423 Pulmonary oedema Diseases 0.000 description 2
- 210000002966 Serum Anatomy 0.000 description 2
- SEDZOYHHAIAQIW-UHFFFAOYSA-N Trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000003110 anti-inflammatory Effects 0.000 description 2
- 125000004429 atoms Chemical group 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N cdcl3 Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- XRLDSWLMHUQECH-UHFFFAOYSA-N cyclopentanecarboxamide Chemical compound NC(=O)C1CCCC1 XRLDSWLMHUQECH-UHFFFAOYSA-N 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- JGFBRKRYDCGYKD-UHFFFAOYSA-N dibutyl(oxo)tin Chemical compound CCCC[Sn](=O)CCCC JGFBRKRYDCGYKD-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000003511 endothelial Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 200000000018 inflammatory disease Diseases 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229960002198 irbesartan Drugs 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000003287 optical Effects 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- OCFVSFVLVRNXFJ-UHFFFAOYSA-N potassium hydride Inorganic materials [H-].[K+] OCFVSFVLVRNXFJ-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrugs Drugs 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 125000006513 pyridinyl methyl group Chemical group 0.000 description 2
- 239000003087 receptor blocking agent Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 108090000464 transcription factors Proteins 0.000 description 2
- 102000003995 transcription factors Human genes 0.000 description 2
- 201000011528 vascular disease Diseases 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- RUDQPWNLKJLFJL-UHFFFAOYSA-N 2,2,3-trifluoropropanoic acid Chemical compound OC(=O)C(F)(F)CF RUDQPWNLKJLFJL-UHFFFAOYSA-N 0.000 description 1
- OVSKIKFHRZPJSS-UHFFFAOYSA-N 2,4-Dichlorophenoxyacetic acid Chemical compound OC(=O)COC1=CC=C(Cl)C=C1Cl OVSKIKFHRZPJSS-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-Methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 1
- JBSLANHIBKBQGE-UHFFFAOYSA-N 2-cyclopropylacetamide Chemical compound NC(=O)CC1CC1 JBSLANHIBKBQGE-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- LVFRCHIUUKWBLR-UHFFFAOYSA-N 4,6-dimethoxypyrimidin-2-amine Chemical compound COC1=CC(OC)=NC(N)=N1 LVFRCHIUUKWBLR-UHFFFAOYSA-N 0.000 description 1
- QDTVQKKWZAYRBU-UHFFFAOYSA-N 4-chloro-3-(trifluoromethyl)pyridin-2-amine Chemical compound NC1=NC=CC(Cl)=C1C(F)(F)F QDTVQKKWZAYRBU-UHFFFAOYSA-N 0.000 description 1
- YNXLSFXQTQKQEF-UHFFFAOYSA-N 4-methoxypyrimidin-2-amine Chemical compound COC1=CC=NC(N)=N1 YNXLSFXQTQKQEF-UHFFFAOYSA-N 0.000 description 1
- NGWGYIGTWBAKAN-UHFFFAOYSA-N 5-ethoxypyrimidin-2-amine Chemical compound CCOC1=CN=C(N)N=C1 NGWGYIGTWBAKAN-UHFFFAOYSA-N 0.000 description 1
- 125000003341 7 membered heterocyclic group Chemical group 0.000 description 1
- 102100003500 AGTR1 Human genes 0.000 description 1
- 210000000577 Adipose Tissue Anatomy 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 1
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 1
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 1
- 210000002376 Aorta, Thoracic Anatomy 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- DFFGTPXIHHWDGX-UHFFFAOYSA-M C1=NC(CC(C(=O)CCCC)C([O-])=O)=CC=C1C1=CC=CC=C1C#N Chemical compound C1=NC(CC(C(=O)CCCC)C([O-])=O)=CC=C1C1=CC=CC=C1C#N DFFGTPXIHHWDGX-UHFFFAOYSA-M 0.000 description 1
- DFSQNCGPIIYOOG-UHFFFAOYSA-N CSCCOc1ccnc(N)n1 Chemical compound CSCCOc1ccnc(N)n1 DFSQNCGPIIYOOG-UHFFFAOYSA-N 0.000 description 1
- SGZAIDDFHDDFJU-UHFFFAOYSA-N Candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000008787 Cardiovascular Disease Diseases 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 229940107161 Cholesterol Drugs 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 206010058108 Dyslipidaemia Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N Ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 108090000331 Firefly luciferases Proteins 0.000 description 1
- 229940004296 Formula 21 Drugs 0.000 description 1
- 229960002989 Glutamic Acid Drugs 0.000 description 1
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 1
- JUINSXZKUKVTMD-UHFFFAOYSA-N Hydrazoic acid Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 206010061227 Lipid metabolism disease Diseases 0.000 description 1
- 229960004773 Losartan Drugs 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N Losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 230000036740 Metabolism Effects 0.000 description 1
- 230000035633 Metabolized Effects 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N Methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N N,N-dimethyl-2H-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000005480 Olmesartan Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- HYAFETHFCAUJAY-UHFFFAOYSA-N Pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 1
- 229960005095 Pioglitazone Drugs 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 206010038372 Renal arteriosclerosis Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- OEIMLTQPLAGXMX-UHFFFAOYSA-I Tantalum(V) chloride Chemical compound Cl[Ta](Cl)(Cl)(Cl)Cl OEIMLTQPLAGXMX-UHFFFAOYSA-I 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J Tin(IV) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J Titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 1
- JKVRTUCVPZTEQZ-UHFFFAOYSA-N Tributyltin azide Chemical compound CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-] JKVRTUCVPZTEQZ-UHFFFAOYSA-N 0.000 description 1
- VOITXYVAKOUIBA-UHFFFAOYSA-N Triethylaluminium Chemical compound CC[Al](CC)CC VOITXYVAKOUIBA-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N Triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 108010062481 Type 1 Angiotensin Receptor Proteins 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N Valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000001270 agonistic Effects 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Chemical class 0.000 description 1
- 125000005236 alkanoylamino group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940041158 antibacterial for systemic use Imidazole derivatives Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940042051 antimycotic for systemic use Imidazole derivatives Drugs 0.000 description 1
- 229940054051 antipsychotic Indole derivatives Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- OSJRGDBEYARHLX-UHFFFAOYSA-N azido(trimethyl)stannane Chemical compound [N-]=[N+]=[N-].C[Sn+](C)C OSJRGDBEYARHLX-UHFFFAOYSA-N 0.000 description 1
- BJUSKQNPSWYMEI-UHFFFAOYSA-N azido(triphenyl)stannane Chemical compound C=1C=CC=CC=1[Sn](C=1C=CC=CC=1)(N=[N+]=[N-])C1=CC=CC=C1 BJUSKQNPSWYMEI-UHFFFAOYSA-N 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L cacl2 Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000000271 cardiovascular Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 201000006233 congestive heart failure Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001808 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- JFWMYCVMQSLLOO-UHFFFAOYSA-N cyclobutanecarbonyl chloride Chemical compound ClC(=O)C1CCC1 JFWMYCVMQSLLOO-UHFFFAOYSA-N 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- WEPUZBYKXNKSDH-UHFFFAOYSA-N cyclopentanecarbonyl chloride Chemical compound ClC(=O)C1CCCC1 WEPUZBYKXNKSDH-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 150000002237 fumaric acid derivatives Chemical class 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093910 gyncological antiinfectives Imidazole derivatives Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- LVWBCSKGNSTMNO-UHFFFAOYSA-N hydroxylamine;oxalic acid Chemical compound ON.OC(=O)C(O)=O LVWBCSKGNSTMNO-UHFFFAOYSA-N 0.000 description 1
- NXPHCVPFHOVZBC-UHFFFAOYSA-N hydroxylamine;sulfuric acid Chemical compound ON.OS(O)(=O)=O NXPHCVPFHOVZBC-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000004857 imidazopyridinyl group Chemical class N1C(=NC2=C1C=CC=N2)* 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000002452 interceptive Effects 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- 229940079865 intestinal antiinfectives Imidazole derivatives Drugs 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N iodine atom Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000005921 isopentoxy group Chemical group 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- IPLONMMJNGTUAI-UHFFFAOYSA-M lithium;bromide;hydrate Chemical compound [Li+].O.[Br-] IPLONMMJNGTUAI-UHFFFAOYSA-M 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000002934 lysing Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000035786 metabolism Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- XAWVBWGJVRENRT-UHFFFAOYSA-N methyl 2-[[5-(2-cyanophenyl)pyridin-2-yl]methyl]-3-oxoheptanoate Chemical compound C1=NC(CC(C(=O)CCCC)C(=O)OC)=CC=C1C1=CC=CC=C1C#N XAWVBWGJVRENRT-UHFFFAOYSA-N 0.000 description 1
- CZTKGERSDUGZPQ-UHFFFAOYSA-N methyl 3-oxoheptanoate Chemical compound CCCCC(=O)CC(=O)OC CZTKGERSDUGZPQ-UHFFFAOYSA-N 0.000 description 1
- YKLCWZMIZHQGFV-UHFFFAOYSA-N methyl 3-oxooctanoate Chemical compound CCCCCC(=O)CC(=O)OC YKLCWZMIZHQGFV-UHFFFAOYSA-N 0.000 description 1
- XJMIXEAZMCTAGH-UHFFFAOYSA-N methyl 3-oxopentanoate Chemical compound CCC(=O)CC(=O)OC XJMIXEAZMCTAGH-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 125000005484 neopentoxy group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 229960005117 olmesartan Drugs 0.000 description 1
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000001737 promoting Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- VBWLDYULPOTZEP-UHFFFAOYSA-N pyridin-2-yloxymethanamine Chemical compound NCOC1=CC=CC=N1 VBWLDYULPOTZEP-UHFFFAOYSA-N 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atoms Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002195 synergetic Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 150000003918 triazines Chemical class 0.000 description 1
- CNWZYDSEVLFSMS-UHFFFAOYSA-N tripropylalumane Chemical compound CCC[Al](CCC)CCC CNWZYDSEVLFSMS-UHFFFAOYSA-N 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
Disclosed are phenylpyridine compounds with tetrazole or oxadiazole groups represented by the general formula (I), wherein the variables are as defined in the specification. The compounds of formula (I) have both angiotensin II receptor antagonism and a PPAR? activation effect and are useful as a preventative and/or therapeutic agent for circulatory and metabolic disease such as high blood pressure, cardiac disease, arteriosclerosis, and type-2 diabetes. eventative and/or therapeutic agent for circulatory and metabolic disease such as high blood pressure, cardiac disease, arteriosclerosis, and type-2 diabetes.
Description
DESCRIPTION
NOVEL PHENYLPYRIDINE DERIVATIVE AND DRUG CONTAINING SAME
TECHNICAL FIELD
The present invention relates to novel phenylpyridine
derivatives that have both angiotensin II antagonistic activity
and a PPAR g activation effect, and a pharmaceutical agent
containing the same.
BACKGROUND ART
In recent years, diseases such as diabetes, hypertension,
dyslipidemia and obesity which can be a risk factor for
arteriosclerotic diseases have been rapidly increasing due to
changes in life style with improvements in living standard, i.e.,
high calorie and high cholesterol type diet, obesity, lack of
exercise, aging, and the like. It is known that, although being
a risk factor independent of each other, overlap of the diseases
can cause an occurrence of arteriosclerotic diseases at higher
frequency or aggravation of the diseases. As such, with the
understanding of a condition having a plurality of risk factors
for arteriosclerotic diseases as metabolic syndrome, efforts
have been made to elucidate the cause of the syndrome and to
develop a therapeutic method therefor.
Angiotensin II (herein below, also abbreviated as “AII”)
is a peptide that is found to be an intrinsic pressor substance
produced by renin-angiotensin system (i.e., RA system). It is
believed that pharmacological inhibition of angiotensin II
activity can lead to treatment or prevention of circulatory
diseases such as hypertension. Accordingly, an inhibitor for
angiotensin converting enzyme (ACE) which inhibits the enzyme
for promoting the conversion of angiotensin I (AI) to
angiotensin II has been clinically used as an inhibitory agent
for RA system. Furthermore, an orally administrable AII
receptor blocker (Angiotensin Receptor Blocker: ARB) has been
developed, and losartan, candesartan, telmisartan, valsartan,
olmesartan, irbesartan, and the like are already clinically
used as a hypotensive agent. It is reported by many clinical
or basic studies that, as having not only a hypotensive activity
but also other various activities including an
anti-inflammatory activity, an endothelial function improving
activity, a cardiovascular remodeling inhibiting activity, an
oxidation stress inhibiting activity, a proliferation factor
inhibiting activity, insulin resistance improving activity,
and the like, ARB is useful for cardiovascular diseases, renal
diseases, arteriosclerosis, and the like (Non-Patent Documents
1 and 2). Most recently, it is also reported that ARB
particularly has a kidney protecting activity which does not
depend on a hypotensive activity (Non-Patent Document 3).
Meanwhile, three isoforms, i.e., a, g and d have been
identified so far for peroxisome proliferator-activated
receptors (PPARs) which belong to a nuclear receptor
superfamily. Among them, PPARg is an isoform most abundantly
expressed in an adipose tissue and it plays an important role
in differentiation of adipocytes or metabolism of glycolipids.
Currently, thiazolidinedione derivatives (i.e., TZD) such as
pioglitazone or rosiglitazone are clinically used as a
therapeutic agent for diabetes having a PPARg activation effect,
and they are known to have an activity of improving insulin
resistance, glucose tolerance, lipid metabolism, and the like.
Further, it is recently reported that, based on activation of
PPARg, TZD exhibits various activities including a hypotensive
activity, an anti-inflammatory activity, an endothelial
function improving activity, a proliferation factor inhibiting
activity, an activity of interfering RA system, and the like.
It is also reported that, according to such multiple activities,
TZD shows a kidney protecting activity particularly in diabetic
nephropathy without depending on blood sugar control
(Non-Patent Documents 4, 5, 6, 7, and 8). Meanwhile, there is
also a concern regarding adverse effects of TZD caused by PPARg
activation, such as body fluid accumulation, body weight gain,
peripheral edema, and pulmonary edema (Non-Patent Documents 9
and 10).
It has been recently reported that telmisartan has a PPARg
activation effect (Non-Patent Document 11). It has been also
reported that the irbesartan has the same activity (Non-Patent
Document 12). These compounds have both an RA system inhibiting
activity and a PPARg activation effect, and thus are expected
to be used as an integrated agent for prevention and/or
treatment of circulatory diseases (e.g., hypertension, heart
disease, angina pectoris, cerebral vascular disorder, cerebral
circulatory disorder, ischemic peripheral circulatory
disorder, kidney disease, and the like) or diabetes-related
diseases (e.g., type 2 diabetes mellitus, diabetic complication,
insulin resistant syndrome, metabolic syndrome,
hyperinsulinemia, and the like) without increasing a risk of
body fluid accumulation, body weight gain, peripheral edema,
pulmonary edema, or congestive heart failure that are concerned
over the use of TZD (Patent Document 1). Among them, for
diabetic nephropathy, a synergistic prophylactic and/or
therapeutic effect is expected from composite kidney protecting
activity that is based on activities of RA system inhibition
and PPARg activation.
As a compound having the activities above, pyrimidine and
triazine derivatives (Patent Document 1), imidazopyridine
derivatives (Patent Document 2), indole derivatives (Patent
Document 3), imidazole derivatives (Patent Document 4), and
condensed ring derivatives (Patent Document 5) have been
reported. However, there is no description or suggestion
regarding the phenylpyridine derivatives of the present
invention.
Meanwhile, Patent Document 6 discloses a compound
represented by the following formula (A):
[Chemical Formula 1]
[in the formula, R is an optionally substituted
hydrocarbon residue which is optionally bonded through a hetero
atom, R is an optionally substituted 5 to 7 membered
heterocyclic residue having, as a group capable of constituting
the ring, a carbonyl group, a thiocarbonyl group, an optionally
oxidized sulfur atom or a group convertible into them, X is a
direct bond or bonding via a spacer having an atomic length of
two or less between the ring Y and the ring W, W and Y are an
optionally substituted aromatic hydrocarbon residue
optionally containing a hetero atom or an optionally
substituted heterocyclic residue; n is an integer of 1 or 2,
a and b forming the heterocyclic residue are independently one
or two optionally substituted carbon or hetero atoms, c is an
optionally substituted carbon or hetero atom, and, in the group
of the formula,
[Chemical Formula 2]
substituent groups on adjacent two atoms forming the ring
are optionally bonded to each other to form a 5 to 6 membered
ring together with the two atoms forming the ring]. As a
preferred W-Y ring system, biphenyl is exemplified. In the
Examples, only the biphenyl derivatives are specifically
described. The compounds disclosed in Patent Document 6 are
different from the compounds of the present invention in terms
of the ring bonded to the pyridinyl methyl group. In addition,
Patent Document 6 includes no descriptions or suggestions
relating to a PPARg activation effect as a pharmacological
activity or treatment of diabetes, obesity, or metabolic
syndromes.
PRIOR ART DOCUMENT
PATENT DOCUMENT
Patent Document 1: A
Patent Document 2: A
Patent Document 3: A
Patent Document 4: A
Patent Document 5: A
Patent Document 6: JP 5-271228 A
NON-PATENT DOCUMENT
Non-Patent Document 1: AMER. J. Hypertension, 18, 720
(2005)
Non-Patent Document 2: Current Hypertension Report, 10,
261 (2008)
Non-Patent Document 3: Diabetes Care, 30, 1581 (2007)
Non-Patent Document 4: Kidney Int., 70, 1223 (2006)
Non-Patent Document 5: Circulation, 108, 2941 (2003)
Non-Patent Document 6: Best Pract. Res. Clin. Endocrinol.
Metab., 21 (4), 687 (2007)
Non-Patent Document 7: Diab. Vasc. Dis. Res., 1 (2), 76
(2004)
Non-Patent Document 8: Diab. Vasc. Dis. Res., 2 (2), 61
(2005)
Non-Patent Document 9: J. Clin. Invest., 116 (3), 581
(2006)
Non-Patent Document 10: FASEB J., 20 (8), 1203 (2006)
Non-Patent Document 11: Hypertension, 43, 993 (2004)
Non-Patent Document 12: Circulation, 109, 2054 (2004)
SUMMARY OF THE INVENTION
PROBLEMS TO BE SOLVED BY THE INVENTION
An object of the invention is to provide a novel compound
that is useful as a pharmaceutical agent for preventing and/or
treating hypertension as a circulatory disease, diabetes as a
metabolic disease, and the like, and a pharmaceutical
composition using the novel compound.
MEANS FOR SOLVING THE PROBLEMS
As a result of intensive studies to achieve the purpose
described above, the inventors found that the compound
represented by the formula (I) below has both an excellent
angiotensin II antagonistic activity and an excellent PPARg
activation effect, and therefore completed the invention.
Specifically, the present invention relates to the
following inventions.
A compound represented by the formula (I) below or
a salt thereof, or a solvate thereof:
[Chemical Formula 3]
[in the formula, ring A represents the following formula
(II) or formula (III):
[Chemical Formula 4]
ring B represents the following formula (IV) or formula
(V):
[Chemical Formula 5]
X represents C-R or a nitrogen atom,
R represents a C alkyl group,
R represents a C alkyl group or a C cycloalkyl group,
1-6 3-8
3 4 5
R , R , and R each independently represent a hydrogen atom,
a halogen atom, a C alkyl group, a halo C alkyl group, or
1-6 1-6
a C alkoxy group which may have a substituent group, and the
broken line in the formula indicates the binding site for a
neighboring group].
The compound described in the above [1] or a salt
thereof, or a solvate thereof, in which the ring A in the formula
(I) is the formula (II) described above, and X is a nitrogen
atom.
The compound described in the above [1] or [2] or a
salt thereof, or a solvate thereof, in which the ring B in the
formula (I) is the formula (V) described above.
The compound described in any one of the above [1]
to [3] or a salt thereof, or a solvate thereof, in which R in
the formula (I) is a branched C alkyl group or a C cycloalkyl
3-6 3-8
group.
The compound described in any one of the above [1]
to [4] or a salt thereof, or a solvate thereof, in which R in
the formula (I) is a C alkyl group or a C alkyl group.
1-3 5-6
The compound described in any one of the above [1]
to [5] or a salt thereof, or a solvate thereof, in which the
ring A in the formula (I) is the formula (II) described above
and the ring B is the formula (V) described above.
The compound described in any one of the above [1]
to [6] or a salt thereof, or a solvate thereof, in which X in
the formula (I) is a nitrogen atom and R and R are each
independently a hydrogen atom, a halogen atom, a C alkyl group,
a halo C alkyl group, or a C alkoxy group.
1-6 1-6
The compound described in the above [7] or a salt
thereof, or a solvate thereof, in which R and R in the formula
(I) are each independently a hydrogen atom or a C alkoxy group.
The compound described in the above [1] or a salt
thereof, or a solvate thereof, in which the compound represented
by the formula (I) is a compound selected from a group consisting
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-methoxypyrimidinyl)methylpyrimidin-4(3H)-one
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)methylpyrimidin-4(3H)-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylethyl(5-methoxypyrimidinyl)pyrimidin-4(3H)-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)ethylpyrimidin-4(3H)-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylisopropyl(5-methoxypyrimidinyl)pyrimidin-4(3H)-
one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)isopropylpyrimidin-4(3H)-o
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclopropyl(5-methoxypyrimidinyl)pyrimidin-4(3H
)-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclobutyl(5-methoxypyrimidinyl)pyrimidin-4(3H)
-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclobutyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)-
one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclopentyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)
-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclohexyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)-
one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylmethyl{5-[2-(methylthio)ethoxy]pyrimidinyl}pyri
midin-4(3H)-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylmethyl{5-[2-(methylsulfonyl)ethoxy]pyrimidinyl}
pyrimidin-4(3H)-one,
3-{2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihyd
ropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4-oxadiazo
l-5(4H)-one,
3-{2-{5-{[4-butylmethyl(4-methylpyridinyl)oxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4-
oxadiazol-5(4H)-one,
3-{2-{5-{[4-butyl(5-methoxypyrimidinyl)methylox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2
,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)methyloxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,
4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylethyl(5-methoxypyrimidinyl)oxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,
4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)ethyloxo-
1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4
-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylisopropyl(5-methoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)isopropyl
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1
,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclopropyl(5-methoxypyrimidinyl)
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclopropyl(5-ethoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclobutyl(5-methoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclobutyl(5-ethoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclopentyl(5-ethoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclohexyl(5-ethoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{{4-butylmethyl{5-[2-(methylthio)ethoxy]pyrim
idinyl}oxo-1,6-dihydropyrimidinyl}methyl}pyridin-2
-yl}phenyl}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{{4-butylmethyl{5-[2-(methylsulfonyl)ethoxy]p
yrimidinyl}oxo-1,6-dihydropyrimidinyl}methyl}pyrid
inyl}phenyl}-1,2,4-oxadiazol-5(4H)-one,
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylmethyl(pyridinyl)pyrimidin-4(3H)-one,
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-methoxypyridinyl)methylpyrimidin-4(3H)-one,
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl[3-chloro(trifluoromethyl)pyridinyl]methylpy
rimidin-4(3H)-one,
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-methoxypyrimidinyl)methylpyrimidin-4(3H)-one
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)methylpyrimidin-4(3H)-one,
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(4,6-dimethoxypyrimidinyl)methylpyrimidin-4(3H)
-one,
3-{2-{6-{[4-butyl(5-methoxypyridinyl)methyloxo-
1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4
-oxadiazol-5(4H)-one,
3-{2-{6-{[4-butyl(5-methoxypyrimidinyl)methylox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2
,4-oxadiazol-5(4H)-one,
3-{2-{6-{[4-butyl(5-ethoxypyrimidinyl)methyloxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,
4-oxadiazol-5(4H)-one,
3-{2-{6-{[4-butyl(4,6-dimethoxypyrimidinyl)methyl-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopr
opyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxo
propyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxope
ntyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxo
pentyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[1-(5-ethoxypyrimidinyl)ethylisopropyl
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1
,2,4-oxadiazol-5(4H)-one, and
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)ethyl-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one.
The compound described in the above [1] or a salt
thereof, or a solvate thereof, in which the compound represented
by the formula (I) is a compound selected from a group consisting
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylisopropyl(5-methoxypyrimidinyl)pyrimidin-4(3H)-
one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)isopropylpyrimidin-4(3H)-o
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclopropyl(5-methoxypyrimidinyl)pyrimidin-4(3H
)-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclobutyl(5-methoxypyrimidinyl)pyrimidin-4(3H)
-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclobutyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)-
one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclopentyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)
-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclohexyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)-
one,
3-{2-{5-{[4-butylisopropyl(5-methoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)isopropyl
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1
,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclopropyl(5-methoxypyrimidinyl)
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclopropyl(5-ethoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclobutyl(5-methoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclobutyl(5-ethoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclopentyl(5-ethoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclohexyl(5-ethoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopr
opyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxo
propyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxope
ntyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxo
pentyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[1-(5-ethoxypyrimidinyl)ethylisopropyl
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1
,2,4-oxadiazol-5(4H)-one, and
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)ethyl-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one.
The compound described in the above [1] or a salt
thereof, or a solvate thereof, in which the compound represented
by the formula (I) is a compound selected from a group consisting
3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopr
opyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxo
propyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxope
ntyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxo
pentyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[1-(5-ethoxypyrimidinyl)ethylisopropyl
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1
,2,4-oxadiazol-5(4H)-one, and
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)ethyl-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one.
Meanwhile, the alkyl group such as butyl in the
nomenclature of the above-mentioned compounds represents a
straight (normal) chain unless particularly described.
A pharmaceutical composition containing the
compound described in any one of the above [1] to [11] or a salt
thereof, or a solvate thereof, and a pharmaceutically
acceptable carrier.
The pharmaceutical composition described in the
above [12], in which the ring A in the formula (I) is the formula
(II) described above and X is a nitrogen atom.
The pharmaceutical composition described in the
above [12] or [13], in which the ring B in the formula (I) is
the formula (V) described above.
The pharmaceutical composition described in any one
of the above [12] to [14], in which R in the formula (I) is
a branched C alkyl group or a C cycloalkyl group.
3-6 3-8
The pharmaceutical composition described in any one
of the above [12] to [15], in which R in the formula (I) is
a C alkyl group or a C alkyl group.
1-3 5-6
The pharmaceutical composition described in any one
of the above [12] to [16], in which the ring A in the formula
(I) is the formula (II) described above and the ring B is the
formula (V) described above.
The pharmaceutical composition described in any one
of the above [12] to [17], in which X in the formula (I) is a
nitrogen atom and R and R are each independently a hydrogen
atom, a halogen atom, a C alkyl group, a halo C alkyl group,
1-6 1-6
or a C alkoxy group.
The pharmaceutical composition described in the
above [18], in which R and R in the formula (I) are each
independently a hydrogen atom or a C alkoxy group.
The pharmaceutical composition described in any one
of the above [12] to [19], having both angiotensin II receptor
antagonistic activity and a PPARg activation effect.
The pharmaceutical composition described in any one
of the above [12] to [20], which is an agent for preventing and/or
treating a circulatory disease.
The pharmaceutical composition described in the
above [21], in which the circulatory disease is hypertension,
heart disease, angina pectoris, cerebral vascular disorder,
cerebral circulatory disorder, ischemic peripheral
circulatory disorder, kidney disease, or arteriosclerosis.
The pharmaceutical composition described in any one
of the above [12] to [20], which is an agent for preventing and/or
treating a metabolic disease.
The pharmaceutical composition described in the
above [23], in which the metabolic disease is type 2 diabetes
mellitus, diabetic complication (diabetic retinopathy,
diabetic neuropathy, or diabetic nephropathy), insulin
resistant syndrome, metabolic syndrome, or hyperinsulinemia.
A method of preventing and/or treating a circulatory
disease, the method including administering an effective amount
of the compound described in any one of the above [1] to [11]
or a salt thereof, or a solvate thereof to a patient who is in
need of the treatment.
The method described in the above [25], in which the
circulatory disease is hypertension, heart disease, angina
pectoris, cerebral vascular disorder, cerebral circulatory
disorder, ischemic peripheral circulatory disorder, kidney
disease, or arteriosclerosis.
A method of preventing and/or treating a metabolic
disease, the method including administering an effective amount
of the compound described in any one of the above [1] to [11]
or a salt thereof, or a solvate thereof to a patient who is in
need of the treatment.
The method described in the above [27], in which the
metabolic disease is type 2 diabetes mellitus, diabetic
complication (diabetic retinopathy, diabetic neuropathy, or
diabetic nephropathy), insulin resistant syndrome, metabolic
syndrome, or hyperinsulinemia.
A method of preventing and/or treating a circulatory
disease and a metabolic disease, the method including
administering an effective amount of the compound described in
any one of the above [1] to [11] or a salt thereof, or a solvate
thereof to a patient who is in need of the treatment.
The method described in the above [29], in which the
circulatory disease is hypertension, heart disease, angina
pectoris, cerebral vascular disorder, cerebral circulatory
disorder, ischemic peripheral circulatory disorder, kidney
disease, or arteriosclerosis and the metabolic disease is type
2 diabetes mellitus, diabetic complication (diabetic
retinopathy, diabetic neuropathy, or diabetic nephropathy),
insulin resistant syndrome, metabolic syndrome, or
hyperinsulinemia.
Use of the compound described in any one of the above
to [11] or a salt thereof, or a solvate thereof for producing
a preparation for preventing and/or treating a circulatory
disease.
The use described in the above [31], in which the
circulatory disease is hypertension, heart disease, angina
pectoris, cerebral vascular disorder, cerebral circulatory
disorder, ischemic peripheral circulatory disorder, kidney
disease, or arteriosclerosis.
Use of the compound described in any one of the above
to [11] or a salt thereof, or a solvate thereof for producing
a preparation for preventing and/or treating a metabolic
disease.
The use described in the above [33], in which the
metabolic disease is type 2 diabetes mellitus, diabetic
complication (diabetic retinopathy, diabetic neuropathy, or
diabetic nephropathy), insulin resistant syndrome, metabolic
syndrome, or hyperinsulinemia.
The compound described in any one the above [1] to
or a salt thereof, or a solvate thereof to be used for a
pharmaceutical composition for preventing and/or treating a
circulatory disease.
The compound described in the above [35] or a salt
thereof, or a solvate thereof, in which the circulatory disease
is hypertension, heart disease, angina pectoris, cerebral
vascular disorder, cerebral circulatory disorder, ischemic
peripheral circulatory disorder, kidney disease, or
arteriosclerosis.
The compound described in the above [35] or [36] or
a salt thereof, or a solvate thereof, in which the effective
component of a pharmaceutical composition is a compound or a
salt thereof, or a solvate thereof having both an angiotensin
II receptor antagonistic activity and a PPARg activation effect.
The compound described in any one of the above [1]
to [11] or a salt thereof, or a solvate thereof to be used for
a pharmaceutical composition for preventing and/or treating a
metabolic disease.
The compound described in the above [38] or a salt
thereof, or a solvate thereof, in which the metabolic disease
is type 2 diabetes mellitus, diabetic complication (diabetic
retinopathy, diabetic neuropathy, or diabetic nephropathy),
insulin resistant syndrome, metabolic syndrome, or
hyperinsulinemia.
The compound described in the above [38] or [39] or
a salt thereof, or a solvate thereof, in which the effective
component of a pharmaceutical composition is a compound or a
salt thereof, or a solvate thereof having both an angiotensin
II receptor antagonistic activity and a PPARg activation effect.
The compound described in any one of the above [1]
to [11] or a salt thereof, or a solvate thereof to be used for
a pharmaceutical composition for preventing and/or treating a
circulatory disease or a metabolic disease.
The compound described in the above [41] or a salt
thereof, or a solvate thereof, in which the circulatory disease
is hypertension, heart disease, angina pectoris, cerebral
vascular disorder, cerebral circulatory disorder, ischemic
peripheral circulatory disorder, kidney disease, or
arteriosclerosis and the metabolic disease is type 2 diabetes
mellitus, diabetic complication (diabetic retinopathy,
diabetic neuropathy, or diabetic nephropathy), insulin
resistant syndrome, metabolic syndrome, or hyperinsulinemia.
EFFECTS OF THE INVENTION
The phenylpyridine derivative represented by the formula
(I) of the invention or a salt thereof, or a solvate thereof
exhibits a potent antagonistic activity for an angiotensin II
receptor, and can be appropriately used as an effective
component of an agent for preventing and/or treating a disease
related with angiotensin II, for example a circulatory disease
such as hypertension, heart disease, angina pectoris, cerebral
vascular disorder, cerebral circulatory disorder, ischemic
peripheral circulatory disorder, kidney disease, and
arteriosclerosis.
Further, the phenylpyridine derivative represented by
the formula (I) of the invention or a salt thereof, or a solvate
thereof exhibits a PPARg activation effect and can be
appropriately used as an effective component of an agent for
preventing and/or treating a disease related with PPARg, for
example a metabolic disease such as arteriosclerosis, type 2
diabetes mellitus, diabetic complication (diabetic
retinopathy, diabetic neuropathy, or diabetic nephropathy),
insulin resistance syndrome, syndrome X, metabolic syndrome,
and hyperinsulinemia.
Still further, the phenylpyridine derivative represented
by the formula (I) of the invention or a salt thereof, or a
solvate thereof has both an antagonistic activity for an
angiotensin II receptor and a PPARg activation effect and can
be appropriately used as an effective component of an agent for
preventing and/or treating a disease related with both
angiotensin II and PPARg, for example, arteriosclerosis,
diabetic nephropathy, insulin resistance syndrome, syndrome X,
and metabolic syndrome.
MODES FOR CARRYING OUT THE INVENTION
The “halogen atom” as used herein includes a fluorine atom,
a chlorine atom, a bromine atom, an iodine atom, and the like.
The “C alkyl group” and “C alkyl” as used herein mean
1-6 1-6
a linear or a branched hydrocarbon group having 1 to 6 carbon
atoms, preferably a saturated linear or branched hydrocarbon
group having 1 to 6 carbon atoms, and examples thereof include
a methyl group, an ethyl group, an n-propyl group, an isopropyl
group, an n-butyl group, an isobutyl group, a t-butyl group,
an n-pentyl group, a 2-methylbutyl group, a 2,2-dimethylpropyl
group, and an n-hexyl group. Further, the “branched C alkyl
group” and “branched C alkyl” as used herein mean a branched
hydrocarbon group having 3 to 6 carbon atoms, preferably a
saturated branched hydrocarbon group having 3 to 6 carbon atoms,
and examples thereof include an isopropyl group, an isobutyl
group, a 2-methylbutyl group, a 2-methylpentyl group, and a
2-ethylbutyl group.
The “C cycloalkyl group” and “C cycloalkyl” as used
3-8 3-8
herein mean a saturated or unsaturated and monocyclic,
polycyclic, or fused-cyclic cycloalkyl group having 3 to 8
carbon atoms, and preferably 3 to 6 carbon atoms, and examples
of the cycloalkyl group include a cyclopropyl group, a
cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a
cycloheptyl group, and a cyclooctyl group.
The “halo C alkyl group” and “halo C alkyl” as used
1-6 1-6
herein mean a linear or a branched alkyl group having 1 to 6
carbon atoms which is substituted with one or more to maximally
substitutable number of halogen atoms, and examples thereof
include a fluoromethyl group, a difluoromethyl group, a
trifluoromethyl group, a 2,2,2-trifluoroethyl group, a
1,1,2,2,2-pentafluoroethyl group, and a 3,3,3-trifluoropropyl
group.
The “C alkoxy group” as used herein means a linear or
a branched alkoxy group having 1 to 6 carbon atoms, and examples
thereof include a methoxy group, an ethoxy group, a propoxy
group, an isopropoxy group, a butoxy group, an isobutoxy group,
a sec-butoxy group, a tert-butoxy group, a pentoxy group, an
isopentoxy group, a neopentoxy group, a hexyloxy group, and an
isohexyloxy group.
As used herein, the “substituent group” of the “C alkoxy
group which may have a substituent group” may be the same or
different from each other, and the alkoxy group may be
substituted with one or more to maximally substitutable number
of substituent groups. Examples of the “substituent group”
include a phenyl group, a hydroxyl group, a C alkoxy group,
a C alkylthio group, a C alkylsulfonyl group, an oxazolyl
1-6 1-6
group (the oxazolyl group may be substituted with a C alkyl
group, a C aryl group, or a 5 to 10-memebred heteroaryl group
6-10
which may be substituted with a halogen atom), a pyridyl group
(the pyridyl group may be substituted with a C alkyl group),
a C alkoxycarbonyl group, a carboxyl group, a carbamoyl group,
a mono C alkylcarbamoyl group, a di C alkylcarbamoyl group,
1-6 1-6
a C alkanoylamino group, a C alkylsulfonylamino group, a
1-6 1-6
halo C alkylsulfonylamino group, an amide group, and a
sulfonamide group. Preferred examples of the substituent
group include a C alkylthio group, a C alkylsulfonyl group,
1-6 1-6
a carboxyl group, a carbamoyl group, a mono C alkylcarbamoyl
group, and a di C alkylcarbamoyl group. Still more preferred
examples of the substituent group include a C alkylthio group
and a C alkylsulfonyl group.
Preferred modes of the invention include those described
below.
In the formula (I), the C alkyl group as R is preferably
a C alkyl group except butyl group, that is, a C alkyl group
1-6 1-3
or a C alkyl group, and examples thereof include an ethyl group,
an n-propyl group, and an n-pentyl group.
In the formula (I), the C alkyl group as R is preferably
a C alkyl group, and examples thereof include a methyl group,
an ethyl group, and an isopropyl group. An isopropyl group is
particularly preferable. Preferred examples of the C alkyl
group as R include a branched C alkyl group. An isopropyl
group is particularly preferable.
In the formula (I), preferred examples of the C
cycloalkyl group as R include C cycloalkyl, for example, a
cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and
a cyclohexyl group. A cyclopropyl group is particularly
preferable.
In the formula (I), preferred examples of the C alkyl
group as R and R include a C alkyl group, for example, a
methyl group and an ethyl group.
In the formula (I), preferred examples of the halo C
alkyl group as R and R include a halo C alkyl group, for
example, a difluoromethyl group, a trifluoromethyl group, and
a 2,2,2-trifluoroethyl group. A trifluoromethyl group is more
preferable.
In the formula (I), preferred examples of the “C alkoxy
group” of the C alkoxy group which may have a substituent group
as R and R include a C alkoxy group, for example, a methoxy
group, an ethoxy group, a propoxy group, an isopropoxy group,
and an n-butoxy group. An ethoxy group is particularly
preferable. Preferred examples of the “substituent group”
include a phenyl group, a hydroxyl group, a C alkylthio group
(for example, a methylthio group), and a C alkylsulfonyl group
(for example, a methylsulfonyl group).
More preferred examples of the compound represented by
the formula (I) include a compound selected from a group
consisting of the following compounds:
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-methoxypyrimidinyl)methylpyrimidin-4(3H)-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)methylpyrimidin-4(3H)-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylethyl(5-methoxypyrimidinyl)pyrimidin-4(3H)-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)ethylpyrimidin-4(3H)-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylisopropyl(5-methoxypyrimidinyl)pyrimidin-4(3H)-
one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)isopropylpyrimidin-4(3H)-o
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclopropyl(5-methoxypyrimidinyl)pyrimidin-4(3H
)-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclobutyl(5-methoxypyrimidinyl)pyrimidin-4(3H)
-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclobutyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)-
one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclopentyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)
-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclohexyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)-
one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylmethyl{5-[2-(methylthio)ethoxy]pyrimidinyl}pyri
midin-4(3H)-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylmethyl{5-[2-(methylsulfonyl)ethoxy]pyrimidinyl}
pyrimidin-4(3H)-one,
3-{2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihyd
ropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4-oxadiazo
l-5(4H)-one,
3-{2-{5-{[4-butylmethyl(4-methylpyridinyl)oxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4-
oxadiazol-5(4H)-one,
3-{2-{5-{[4-butyl(5-methoxypyrimidinyl)methylox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2
,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)methyloxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,
4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylethyl(5-methoxypyrimidinyl)oxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,
4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)ethyloxo-
1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4
-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylisopropyl(5-methoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)isopropyl
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1
,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclopropyl(5-methoxypyrimidinyl)
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclopropyl(5-ethoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclobutyl(5-methoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclobutyl(5-ethoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclopentyl(5-ethoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclohexyl(5-ethoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{{4-butylmethyl{5-[2-(methylthio)ethoxy]pyrim
idinyl}oxo-1,6-dihydropyrimidinyl}methyl}pyridin-2
-yl}phenyl}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{{4-butylmethyl{5-[2-(methylsulfonyl)ethoxy]p
yrimidinyl}oxo-1,6-dihydropyrimidinyl}methyl}pyrid
inyl}phenyl}-1,2,4-oxadiazol-5(4H)-one,
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylmethyl(pyridinyl)pyrimidin-4(3H)-one,
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-methoxypyridinyl)methylpyrimidin-4(3H)-one,
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl[3-chloro(trifluoromethyl)pyridinyl]methylpy
rimidin-4(3H)-one,
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-methoxypyrimidinyl)methylpyrimidin-4(3H)-one
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)methylpyrimidin-4(3H)-one,
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(4,6-dimethoxypyrimidinyl)methylpyrimidin-4(3H)
-one,
3-{2-{6-{[4-butyl(5-methoxypyridinyl)methyloxo-
1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4
-oxadiazol-5(4H)-one,
3-{2-{6-{[4-butyl(5-methoxypyrimidinyl)methylox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2
,4-oxadiazol-5(4H)-one,
3-{2-{6-{[4-butyl(5-ethoxypyrimidinyl)methyloxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,
4-oxadiazol-5(4H)-one,
3-{2-{6-{[4-butyl(4,6-dimethoxypyrimidinyl)methyl-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopr
opyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxo
propyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxope
ntyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxo
pentyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[1-(5-ethoxypyrimidinyl)ethylisopropyl
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1
,2,4-oxadiazol-5(4H)-one, and
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)ethyl-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one.
More preferred examples of the
-(pyridinylmethyl)pyrimidin-4(3H)-one derivatives that are
represented by the formula (I) include a compound selected from
a group consisting of the following compounds:
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylisopropyl(5-methoxypyrimidinyl)pyrimidin-4(3H)-
one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)isopropylpyrimidin-4(3H)-o
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclopropyl(5-methoxypyrimidinyl)pyrimidin-4(3H
)-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclobutyl(5-methoxypyrimidinyl)pyrimidin-4(3H)
-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclobutyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)-
one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclopentyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)
-one,
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclohexyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)-
one,
3-{2-{5-{[4-butylisopropyl(5-methoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)isopropyl
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1
,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclopropyl(5-methoxypyrimidinyl)
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclopropyl(5-ethoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclobutyl(5-methoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclobutyl(5-ethoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclopentyl(5-ethoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[4-butylcyclohexyl(5-ethoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopr
opyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxo
propyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxope
ntyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxo
pentyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[1-(5-ethoxypyrimidinyl)ethylisopropyl
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1
,2,4-oxadiazol-5(4H)-one, and
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)ethyl-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one.
Still more preferred examples of the
-(pyridinylmethyl)pyrimidin-4(3H)-one derivatives that are
represented by the formula (I) include a compound selected from
a group consisting of the following compounds:
3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopr
opyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxo
propyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxope
ntyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxo
pentyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one,
3-{2-{5-{[1-(5-ethoxypyrimidinyl)ethylisopropyl
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1
,2,4-oxadiazol-5(4H)-one, and
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)ethyl-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one.
If the compound of the invention has geometrical isomers
or optical isomers, all of such isomers are within the scope
of the invention. Isolation of these isomers is carried out
by an ordinary method.
Salts of the compound represented by the formula (I) are
not particularly limited, if they are pharmaceutically
acceptable salts. When the compound is processed as an acidic
compound, an alkali metal salt or an alkali earth metal salt
such as sodium salt, potassium salt, magnesium salt, and calcium
salt, and the like; and a salt with an organic base such as
trimethylamine, triethylamine, pyridine, picoline, N-methyl
pyrrolidine, N-methyl piperidine, N-methyl morpholine, and the
like can be mentioned. When the compound is processed as a basic
compound, an acid addition salt and the like including a salt
with a mineral acid, for example, hydrochloric acid salt,
hydrobromic acid salt, hydroiodic acid salt, sulfuric acid salt,
nitric acid salt, phosphoric acid salt, and the like; or organic
acid addition salt, for example, benzoic acid salt,
methanesulfonic acid salt, ethanesulfonic acid salt,
benzenesulfonic acid salt, p-toluene sulfonic acid salt, maleic
acid salt, fumaric acid salt, tartaric acid salt, citric acid
salt, and acetic acid salt; or the like can be mentioned.
Examples of the solvate of the compound represented by
the formula (I) or a salt thereof include a hydrate, but not
limited thereto.
In addition, compounds which are metabolized in a living
body and converted into the compounds represented by the
aforementioned formula (I), so called prodrugs, all fall within
the scope of the compounds of the invention. Examples of groups
which form the prodrugs of the compounds of the invention
include the groups described in “Progress in Medicine”, Vol.
, pp. 2157-2161, 1985, Life Science Medica, and the groups
described in “Development of Drugs”, Vol. 7, Molecular Designs,
pp. 163-198, published in 1990, Hirokawa Shoten.
The compounds represented by the formula (I) or salts
thereof, or solvates thereof can be produced according to
various known methods, and the production method is not
specifically limited. For example, the compounds can be
produced according to the following reaction process. Further,
when each reaction described below is performed, functional
groups other than the reaction sites may be protected beforehand
as required, and deprotected in an appropriate stage.
Furthermore, the reaction in each process may be performed by
an ordinarily used method, and isolation and purification can
be performed by a method suitably selected from conventional
methods such as crystallization, recrystallization,
chromatography, or the like, or a combination thereof.
(Production method)
1. Method for production of the compound (Ia) in which the ring
B is the formula (IV)
Among the compounds represented by the formula (I) of the
invention, the compound represented by the formula (Ia) can be
produced according to the following method, but it is not
limited thereto. Specifically, as described in the following
Reaction pathway 1, if pyridinyl methyl halide (VI) and
b-ketoester (VII) are reacted with each other and the obtained
compound (VIII) are reacted with ammonium acetate followed by
reaction with acid anhydride (IX) or acid chloride (X),
acylamino compound (XI) is obtained. If the acylamino compound
(XI) is reacted with amino compound (XII), pyrimidinone
derivative (XIII) is obtained. If the pyrimidinone derivative
(XIII) is reacted with an azide compound, the compound
represented by the formula (Ia) of the invention can be
obtained.
[Reaction pathway 1]
[Chemical Formula 6]
1 2 3 4
(in the formula, ring A, R , R , R , R , and X are as defined
above, R represents a protecting group for carboxyl group such
as C alkyl group, and W represents a leaving group such as
halogen atom).
[Process 1] The reaction between the pyridinyl methyl
halide (VI) and the b-ketoester (VII) may be carried out in a
solvent in the presence of a base and lithium halide (lithium
chloride, lithium bromide, and the like). The solvent is not
specifically limited, and N,N-dimethyl formamide, N-methyl
pyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran,
acetonitrile, and propionitrile may be used either alone or in
combination thereof. The base is not specifically limited, and
examples thereof which may be used include an organic base such
as pyridine, N,N-dimethylaminopyridine (DMAP), collidine,
lutidine, 1,8-diazabicyclo[5.4.0]undecene (DBU),
1,5-diazabicyclo[4.3.0]nonene (DBN),
1,4-diazabicyclo[2.2.2]octane (DABCO), triethylamine,
diisopropylamine, diisopropylethylamine,
diisopropylpentylamine, and trimethylamine, an alkali metal
hydride such as lithium hydride, sodium hydride, and potassium
hydride, an alkali metal hydroxide such as lithium hydroxide,
sodium hydroxide, and potassium hydroxide, an alkali metal
carbonate such as lithium carbonate, sodium carbonate,
potassium carbonate, and cesium carbonate, and an alkali metal
bicarbonate such as sodium hydrogen carbonate. The reaction
condition may vary depending on the reaction materials used.
However, the reaction is generally carried out at -20 to 120C,
and preferably 20C to 100C, for 1 minute to 2 days, and
preferably for 5 minutes to 36 hours to obtain the compound
(VIII).
[Process 2-1] The reaction between the compound (VIII)
and ammonium acetate may be carried out in a solvent in the
presence of an acid. The solvent is not specifically limited,
and methanol, ethanol, isopropanol, ethyl acetate, isopropyl
acetate, toluene, benzene, dioxane, tetrahydrofuran,
acetonitrile, propionitrile, N,N-dimethylformamide,
N-methylpyrrolidone, and dimethyl sulfoxide may be used either
alone or in combination thereof. The acid is not specifically
limited, and examples thereof which may be used include a protic
acid such as acetic acid, trifluoro acetic acid, propionic acid,
and benzoic acid and Lewis acid such as titanium tetrachloride,
boron trifluoride, and stannic chloride. The reaction
condition may vary depending on the reaction materials used.
However, the reaction is generally carried out at 0 to 180C,
and preferably 50C to 150C, for 1 minute to 24 hours, and
preferably for 5 minutes to 18 hours.
[Process 2-2] The reaction between the crude product
obtained after distillation of solvent and the acid anhydride
(IX) may be carried out in the presence of an acid. The acid
is not particularly limited, and examples thereof which may be
used include a protic acid like acetic acid, trifluoroacetic
acid, propionic acid, and benzoic acid. The reaction condition
may vary depending on the reaction materials used. However,
the reaction is generally carried out at 0 to 180C, and
preferably 50C to 120C, for 1 minute to 2 days, and preferably
for 5 minutes to 24 hours to obtain the acylamino compound (XI).
The reaction between the crude product obtained after
distillation of solvent and the acid chloride (X) may be carried
out in a solvent in the presence or absence of a base. The
solvent is not specifically limited, and tetrahydrofuran,
toluene, dioxane, N,N-dimethylformamide, N-methylpyrrolidone,
1,2-dichloroethane, dichloromethane, chloroform,
acetonitrile, and propionitrile may be used either alone or in
combination thereof. The base is not specifically limited, and
examples thereof which may be used include an organic base like
pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO,
triethylamine, diisopropylamine, diisopropylethylamine,
diisopropylpentylamine, and trimethylamine, an alkali metal
hydride like lithium hydride, sodium hydride, and potassium
hydride, an alkali metal hydroxide like lithium hydroxide,
sodium hydroxide, and potassium hydroxide, an alkali metal
carbonate like lithium carbonate, sodium carbonate, potassium
carbonate, and cesium carbonate, and sodium hydrogen carbonate.
The reaction condition may vary depending on the reaction
materials used. However, the reaction is generally carried out
at -20 to 100C, and preferably 15 to 80C, for 5 minutes to
48 hours, and preferably for 5 hours to 36 hours to obtain the
acylamino compound (XI).
[Process 3] The reaction between the acylamino compound
(XI) obtained according to the method above and the amino
compound (XII) may be carried out in a solvent in the presence
of trialkylaluminum. The solvent is not specifically limited,
and 1,2-dichloroethane, chloroform, dichloromethane, ethyl
acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran,
dioxane, acetonitrile, propionitrile, and hexane may be used
either alone or in combination thereof. Examples of the
trialkylaluminum which may be used include trimethylaluminum,
triethylaluminum, and tripropylaluminum. The reaction
condition may vary depending on the reaction materials used.
However, the reaction is generally carried out at 0 to 150C,
and preferably 50C to 120C, for 1 minute to 24 hours, and
preferably for 5 minutes to 20 hours to obtain the pyrimidinone
derivative (XIII).
[Process 4] The reaction between the pyrimidinone
derivative (XIII) and an azide compound may be carried out in
a solvent. Examples of the azide compound which may be used
include trimethyltin azide, tributyltin azide, triphenyltin
azide, sodium azide, and hydrogen azide. Further,
trimethylsilyl azide may be used in the presence of dibutyltin
oxide. The solvent is not specifically limited, and methanol,
ethanol, isopropanol, ethyl acetate, isopropyl acetate,
toluene, benzene, dioxane, tetrahydrofuran, acetonitrile,
propionitrile, N,N-dimethylformamide, N-methylpyrrolidone,
and dimethyl sulfoxide may be used either alone or in
combination thereof. The reaction condition may vary
depending on the reaction materials used. However, the
reaction is generally carried out at 0 to 180C, and preferably
50 to 120C, for 1 minute to 2 weeks, and preferably for 1 hour
to 3 days to obtain the target compound.
2. Method for production of the compound (Ib) in which the ring
B is the formula (V)
Among the compounds represented by the formula (I) of the
invention, the compound represented by the formula (Ib) can be
produced according to the following method, but it is not
limited thereto. Specifically, as described in the following
Reaction pathway 2, if the pyrimidinone derivative (XIII) and
hydroxylamine are reacted with each other, amide oxime product
(XIV) is obtained. If the amide oxime product (XIV) is reacted
with a carbonyl reagent, the compound represented by the formula
(Ib) of the invention can be produced.
[Reaction pathway 2]
[Chemical Formula 7]
1 2 3 4
(in the formula, ring A, R , R , R , R , and X are as defined
above).
[Process 5] The reaction between the pyrimidinone
derivative (XIII) and hydroxylamine may be carried out in a
solvent. The solvent is not specifically limited, and
N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl
pyrrolidone, dimethyl sulfoxide, methanol, ethanol,
isopropanol, 1,4-dioxane, and tetrahydrofuran may be used
either alone or in combination thereof. When an acid salt such
as hydroxylamine hydrochloride, hydroxylamine sulfuric acid,
hydroxylamine oxalic acid, and the like is used as hydroxylamine,
a suitable base, for example, potassium carbonate, sodium
hydrogen carbonate, sodium hydroxide, triethylamine, sodium
methoxide, sodium hydride, and the like may be used in an
equivalent amount or a slightly excess amount for the reaction.
The reaction condition may vary depending on the reaction
materials used. However, the reaction is generally carried out
at 0 to 180C, and preferably 50 to 120C, for 1 minute to 3
days, and preferably for 1 hour to 36 hours. As a result, the
amide oxime product (XIV) is obtained.
[Process 6] Conversion of the amide oxime product (XIV)
to the compound (Ib) can be carried out in a solvent in the
presence of a base by using a carbonyl reagent. The solvent
is not specifically limited, and 1,2-dichloroethane,
chloroform, dichloromethane, ethyl acetate, isopropyl acetate,
toluene, benzene, tetrahydrofuran, dioxane, acetonitrile,
propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidone, diethyl ether, or the like may be used
either alone or in combination thereof. The base is not
specifically limited, and examples thereof which may be used
include pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO,
triethylamine, diisopropylethylamine, diisopropylpentylamine,
trimethylamine, lithium carbonate, sodium carbonate,
potassium carbonate, cesium carbonate, sodium hydrogen
carbonate, potassium hydrogen carbonate, or the like. The
carbonyl reagent is not specifically limited, and
1,1’-carbonyldiimidazole, triphosgene, methyl
chlorocarbonate, ethyl chlorocarbonate, or the like may be used.
The reaction condition may vary depending on the reaction
materials used. However, the reaction is generally carried out
at 0 to 120C, preferably 15 to 80C for 5 minutes to 3 days,
and preferably for 1 hour to 12 hours to obtain the compound
(Ib).
If necessary, the intermediates and target compounds that
are obtained from each of the reaction above can be isolated
and purified by a purification method that is generally used
in a field of organic synthesis chemistry, for example,
filtration, extraction, washing, drying, concentration,
recrystallization, various chromatographic methods, and the
like. Furthermore, the intermediates may be used for the next
reaction without any specific purification.
Various isomers may be isolated by applying a general
method based on a difference in physicochemical properties
among the isomers. For example, a racemic mixture may be
resolved into an optically pure isomer by common racemic
resolution such as optical resolution by which a diastereomer
salt is formed with a common optically active acid such as
tartaric acid or a method of using optically active
chromatography. Further, a mixture of diastereomers can be
resolved by fractional crystallization or various
chromatographic methods, for example. Furthermore, an
optically active compound can be also produced by using an
appropriate starting compound that is optically active.
The compound (I) obtained may be converted into a salt
according to a common method. Furthermore, the compound (I)
or a salt thereof may be converted into a solvate with a hydrate
or a solvate with ethanol according to a common method.
Examples of dosage form or administration type of the
pharmaceutical composition containing the compounds of the
invention or salts thereof, or solvates thereof as an effective
component include, for example, those for oral administration
such as tablet, capsule, granule, powder, syrup, or the like
and those for parenteral administration such as intravenous
injection, intramuscular injection, suppository, inhalant,
transdermal preparation, eye drop, nasal drop, or the like. In
order to prepare a pharmaceutical preparation in the various
dosage forms, the effective component may be used alone, or may
be used in appropriate combination with other pharmaceutically
acceptable carriers such as excipients, binders, extending
agents, disintegrating agents, surfactants, lubricants,
dispersing agents, buffering agents, preservatives,
corrigents, perfumes, coating agents, diluents, and the like
to give a pharmaceutical composition.
Although the administration amount of the pharmaceutical
agent of the invention may vary depending on the weight, age,
sex, symptoms, and the like of a patient, in terms of the compound
represented by the formula (I), generally 0.1 to 1000 mg,
especially 1 to 300 mg, may be administered orally or
parenterally at one time or several times as divided portions
per day for an adult.
EXAMPLES
Herein below, the invention will be described in greater
detail with reference to examples. However, the invention is
not limited to these examples. The abbreviations used in the
examples have the following meanings.
s: singlet
d: doublet
t: triplet
q: quartet
m: multiplet
br: broad
J: coupling constant
Hz: Hertz
CDCl : deuterated chloroform
DMSO-d : deuterated dimethylsulfoxide
H-NMR: proton nuclear magnetic resonance
IR: infrared absorption spectrum
Example 1 Preparation of
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-methoxypyrimidinyl)methylpyrimidin-4(3H)-one
[Chemical Formula 8]
Process 1: Under argon atmosphere, tetrahydrofuran (900
mL) solution of 2-[5-(bromomethyl)pyridinyl]benzonitrile
(31.9 g, 117 mmol), methyl 3-oxoheptanoate (27.8 g, 176 mmol),
diisopropylethylamine (31.0 g, 240 mmol), and lithium chloride
(8.2 g, 193 mmol) was refluxed under heating for 23 hours. The
reaction mixture was added water and extracted with ethyl
acetate. The organic layer was combined, washed with water and
brine, dried over anhydrous sodium sulfate, and concentrated
in vacuo. The obtained residues were subjected to silica gel
column chromatography (hexane/ethyl acetate = 2 : 1) to give
methyl
2-{[6-(2-cyanophenyl)pyridinyl]methyl}oxoheptanoate
(20.9 g, 51%) as brown oil.
H-NMR(CDCl , 400 MHz)d:
0.87(3H, t, J = 7 Hz), 1.18 - 1.32(2H, m), 1.47 - 1.59(2H, m),
2.34 - 2.39(1H, m), 2.55 - 2.67(1H, m), 3.20 - 3.29(2H, m),
3.73(3H, s), 3.84(1H, t, J = 7 Hz), 7.50(1H, td, J = 8, 1 Hz),
7.63 - 7.74(3H, m), 7.76 - 7.87(2H, m), 8.61(1H, s).
Process 2: Toluene (50 mL)-acetic acid (7 mL) solution
of methyl
2-{[6-(2-cyanophenyl)pyridinyl]methyl}oxoheptanoate
(3.50 g, 10.0 mmol) and ammonium acetate (23.2 g, 300 mmol) was
refluxed under heating for 1 hour. To the residues obtained
after distillation of solvent, acetic anhydride (51.2 g) and
acetic acid (5.7 g) were added at room temperature followed by
stirring for 30 minutes at 0C and then stirring for 1.5 hours
at 70C. The reaction mixture was added sodium bicarbonate
water, and then extracted with chloroform. The organic layer
was combined, washed with brine, dried over anhydrous sodium
sulfate, and concentrated in vacuo. The obtained residues were
subjected to silica gel column chromatography (hexane/acetone
= 5 : 1) to give methyl
(Z)acetamide{[6-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate (0.975 g, 25%) as pale yellow oil.
H-NMR(CDCl , 400 MHz)d:
0.91(3H, t, J = 7 Hz), 1.33 - 1.45(2H, m), 1.46 - 1.57(2H, m),
2.18(3H, s), 2.94(2H, t, J = 6 Hz), 3.71(3H, s), 3.75(2H, s),
7.50(1H, t, J = 8 Hz), 7.58(1H, d, J = 8 Hz), 7.63 - 7.72(2H,
m), 7.75 - 7.83(2H, m), 8.60(1H, s), 11.9(1H, s).
Process 3: Under argon atmosphere, trimethylaluminum (2
mol/L hexane solution, 1.45 mL, 2.90 mmol) was added to
1,2-dichloroethane (30 mL) solution of
2-aminomethoxypyrimidine (220 mg, 1.74 mmol) at room
temperature, and stirred at the same temperature for 80 minutes.
1,2-Dichloroethane solution (20 mL) of methyl
(Z)acetamide{[6-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate (227 mg, 0.58 mmol) was added dropwise thereto at
room temperature and refluxed under heating for 17 hours. The
reaction mixture was added an aqueous solution of ammonium
chloride and chloroform and filtered through a pad of celite.
The organic layer was separated from the filtrate and the
aqueous layer was extracted with chloroform. The organic layer
was combined, washed with water and brine, dried over anhydrous
sodium sulfate, and concentrated in vacuo. The obtained
residues were subjected to silica gel column chromatography
(hexane/ethyl acetate = 2 : 1) to give
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
(207 mg, 77%) as yellow oil.
H-NMR(CDCl , 400 MHz)d:
0.95(3H, t, J = 7 Hz), 1.36 - 1.48(2H, m), 1.58 - 1.70(2H, m),
2.16(3H, s), 2.63 - 2.72(2H, m), 3.97(2H, s), 4.01(2H, s),
7.47(1H, m), 7.60 - 7.71(2H, m), 7.72 - 7.83(3H, m), 8.54(2H,
s), 8.70(1H, d, J = 1 Hz).
Process 4: Trimethylsilyl azide (8.68 g, 75.3 mmol) and
dibutyltin oxide (55 mg, 0.221 mmol) were added to toluene (20
mL) solution of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
(200 mg, 0.43 mmol) and stirred for 24 hours at 95C under argon
atmosphere. The residues obtained by removing the reaction
solvent by distillation was separated and purified by silica
gel column chromatography (chloroform : methanol = 100 : 1) to
give
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-methoxypyrimidinyl)methylpyrimidin-4(3H)-one
(174 mg, 80%) as yellow oil.
H-NMR(CDCl , 400 MHz)d:
0.93(3H, t, J = 7 Hz), 1.33 - 1.48(2H, m), 1.55 - 1.73(2H, m),
2.16(3H, s), 2.58 - 2.72(2H, m), 3.95(2H, s), 4.00(3H, s), 7.20
- 7.35(1H, m), 7.38 - 7.58(3H, m), 7.62 - 7.82(1H, m), 8.00 -
8.22(1H, m), 8.54(2H, s), 8.50 - 8.63(1H, m).
Example 2 Preparation of
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)methylpyrimidin-4(3H)-one
[Chemical Formula 9]
Process 1: By using 2-aminoethoxypyrimidine instead
of 2-aminomethoxypyrimidine in the Process 3 of the Example
1, the reaction and the treatment were performed in the same
manner as the Process 3 of the Example 1 to give
2-{5-{[4-butyl(5-ethoxypyrimidinyl)methyloxo-1,
6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
(yield: 46%).
H-NMR(CDCl , 400 MHz) :
0.94(3H, t, J = 7 Hz), 1.38 - 1.46(2H, m), 1.51(3H, t, J = 7
Hz), 1.60 - 1.68(2H, m), 2.16(3H, s), 2.65 - 2.69(2H, m), 3.97(2H,
s), 4.22(2H, q, J = 7 Hz), 7.47(1H, m), 7.64 - 7.81(5H, m),
8.51(2H, s), 8.70(1H, d, J = 1 Hz).
Process 2: By using
2-{5-{[4-butyl(5-ethoxypyrimidinyl)methyloxo-1,
6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
instead of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
in the Process 4 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 4 of the Example
1 to give
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)methylpyrimidin-4(3H)-one
(yield: 46%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.94(3H, t, J = 7 Hz), 1.38 - 1.44(2H, m), 1.51(3H, t, J = 7
Hz), 1.61 - 1.68(2H, m), 2.17(3H, s), 2.66 - 2.70(2H, m), 3.97(2H,
s), 4.22(2H, q, J = 7 Hz), 7.37(1H, m), 7.48 - 7.58(3H, m),
7.78(1H, m), 8.21(1H, m), 8.51(2H, s), 8.62(1H, m).
Example 3 Preparation of
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylethyl(5-methoxypyrimidinyl)pyrimidin-4(3H)-one
[Chemical Formula 10]
Process 1: Toluene (36 mL)-acetic acid (4 mL) solution
of methyl
2-{[6-(2-cyanophenyl)pyridinyl]methyl}oxoheptanoate
(1.03 g, 2.94 mmol) obtained from the Process 1 of the Example
1 and ammonium acetate (6.80 g, 88.2 mmol) was refluxed under
heating for 1 hour. The residues obtained by removing solvent
by distillation were added water and 2 mol/L aqueous solution
of sodium hydroxide and extracted with chloroform. Propionyl
chloride (544 mg, 5.88 mmol) and triethylamine (595 mg, 5.88
mmol) were added to the 1,2-dichloroethane (10 mL) solution of
the residues obtained by removing solvent by distillation and
stirred for 16 hours at 50C. The reaction mixture was added
water and extracted with chloroform. The organic layer was
combined, washed with brine, dried over anhydrous sodium
sulfate, and concentrated in vacuo. The obtained residues were
subjected to silica gel column chromatography (hexane/acetone
= 5 : 1) to give methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}propionamid
eheptenoate (464 mg, 39%) as brown oil.
H-NMR(CDCl , 400 MHz)d:
0.91(3H, t, J = 7 Hz), 1.23(3H, t, J = 8 Hz), 1.34 - 1.51(4H,
m), 2.43 (2H, q, J = 8 Hz), 2.89 - 2.99(2H, m), 3.70(3H, s),
3.75(2H, s), 7.49 (1H, td, J = 8, 1 Hz), 7.58(1H, dd, J = 8,
2 Hz), 7.64 - 7.73(2H, m), 7.77 - 7.86(2H, m), 8.60(1H, s),
11.88(1H, s).
Process 2: By using methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}propionamid
eheptenoate instead of methyl
(Z)acetamide{[6-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate in the Process 3 of the Example 1, the reaction and
the treatment were performed in the same manner as the Process
3 of the Example 1 to give
2-{5-{[4-butylethyl(5-methoxypyrimidinyl)oxo-1,
6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
(yield: 70%) as a pale yellow solid.
H-NMR(CDCl , 400 MHz)d:
0.94(3H, t, J = 7 Hz), 1.18(3H, t, J = 7 Hz), 1.35 - 1.46(2H,
m), 1.62 - 1.74(2H, m), 2.32(2H, q, J = 7 Hz), 2.69(2H, t, J
= 8 Hz), 3.96(2H, s), 4.00(3H, s), 7.47(1H, td, J = 8, 1 Hz),
7.61 - 7.70(2H, m), 7.73 - 7.82(3H, m), 8.53(2H, s), 8.69(1H,
Process 3: By using
2-{5-{[4-butylethyl(5-methoxypyrimidinyl)oxo-1,
6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
instead of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
in the Process 4 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 4 of the Example
1 to give
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylethyl(5-methoxypyrimidinyl)pyrimidin-4(3H)-one
(yield: 60%) as colorless viscous oil.
H-NMR(CDCl , 400 MHz) :
0.94(3H, t, J = 7 Hz), 1.18(3H, t, J = 7 Hz), 1.34 - 1.47(2H,
m), 1.60 - 1.75 (2H, m), 2.32(2H, q, J = 7 Hz), 2.70(2H, t, J
= 8 Hz), 3.96(2H, s), 4.01 (3H, s), 7.29 - 7.38(1H, m), 7.43
- 7.59(3H, m), 7.76(1H, d, J = 8 Hz), 8.18 (1H, s), 8.54(2H,
s), 8.61(1H, br s).
Example 4 Preparation of
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)ethylpyrimidin-4(3H)-one
[Chemical Formula 11]
Process 1: By using 2-aminoethoxypyrimidine instead
of 2-aminomethoxypyrimidine in the Process 3 of the Example
1, the reaction and the treatment were performed in the same
manner as the Process 3 of the Example 1 to give
2-{5-{[4-butyl(5-ethoxypyrimidinyl)ethyloxo-1,6
-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
(yield: 80%) as a pale yellow solid.
H-NMR(CDCl , 400 MHz) :
0.94(3H, t, J = 7 Hz), 1.18(3H, t, J = 7 Hz), 1.37 - 1.47(2H,
m), 1.51(3H, t, J = 7 Hz), 1.62 - 1.72(2H, m), 2.32(2H, q, J
= 7 Hz), 2.66 - 2.72(2H, m), 3.97(2H, s), 4.22(2H, q, J = 7 Hz),
7.47(1H, t, J = 8 Hz), 7.64 - 7.69(2H, m), 7.74 - 7.83(3H, m),
8.51(2H, s), 8.70(1H, d, J = 2 Hz).
Process 2: By using
2-{5-{[4-butyl(5-ethoxypyrimidinyl)ethyloxo-1,6
-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
instead of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
in the Process 4 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 4 of the Example
1 to give
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)ethylpyrimidin-4(3H)-one
(yield: 75%) as colorless viscous oil.
H-NMR(CDCl , 400 MHz) :
0.94(3H, t, J = 7 Hz), 1.18(3H, t, J = 7 Hz), 1.36 - 1.47(2H,
m), 1.51(3H, t, J = 7 Hz), 1.61 - 1.74(2H, m), 2.33(2H, q, J
= 7 Hz), 2.70(2H, t, J = 8 Hz), 3.97(2H, s), 4.22(2H, q, J =
7 Hz), 7.38(1H, d, J = 8 Hz), 7.47 - 7.60(3H, m), 7.78(1H, dd,
J = 8, 2 Hz), 8.20 - 8.28(1H, m), 8.51(2H, s), 8.64(1H, s).
Example 5 Preparation of
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylisopropyl(5-methoxypyrimidinyl)pyrimidin-4(3H)-
[Chemical Formula 12]
Process 1: By using isobutyryl chloride instead of
propionyl chloride in the Process 1 of the Example 3, the
reaction and the treatment were performed in the same manner
as the Process 1 of the Example 3 to give methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}isobutylami
deheptenoate (yield: 49%) as brown oil.
H-NMR(CDCl , 400 MHz)d:
0.90(3H, t, J = 7 Hz), 1.25(6H, d, J = 7 Hz), 1.33 - 1.55(4H,
m), 2.49 - 2.63(1H, m), 2.90 - 2.99(2H, m), 3.71(3H, s), 3.75(2H,
s), 7.49(1H, td, J = 8, 1 Hz), 7.59(1H, dd, J = 8, 2 Hz), 7.64
- 7.73(2H, m), 7.79(1H, dd, J = 8, 1 Hz), 7.83(1H, dd, J = 8,
1 Hz), 8.61(1H, d, J = 1 Hz), 11.90(1H, s).
Process 2: By using methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}isobutylami
deheptenoate instead of methyl
(Z)acetamide{[6-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate in the Process 3 of the Example 1, the reaction and
the treatment were performed in the same manner as the Process
3 of the Example 1 to give
2-{5-{[4-butylisopropyl(5-methoxypyrimidinyl)ox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e (yield: 55%) as yellow oil.
H-NMR(CDCl , 400 MHz)d:
0.94(3H, t, J = 7 Hz), 1.20(6H, d, J = 7 Hz), 1.33 - 1.49(2H,
m), 1.62 - 1.75 (2H, m), 2.21 - 2.35(1H, m), 2.69(2H, t, J =
8 Hz), 3.95(2H, s), 4.00(3H, s), 7.46(1H, td, J = 8, 1 Hz), 7.61
- 7.70(2H, m), 7.74 - 7.83(3H, m), 8.53(2H, s), 8.69(1H, d, J
= 1 Hz).
Process 3: By using
2-{5-{[4-butylisopropyl(5-methoxypyrimidinyl)ox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e instead of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
in the Process 4 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 4 of the Example
1 to give
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylisopropyl(5-methoxypyrimidinyl)pyrimidin-4(3H)-
one (yield: 69%) as colorless viscous oil.
H-NMR(CDCl , 400 MHz)d:
0.94(3H, t, J = 7 Hz), 1.20(6H, d, J = 7 Hz), 1.33 - 1.47(2H,
m), 1.60 - 1.75 (2H, m), 2.22 - 2.35(1H, m), 2.70(2H, t, J =
8 Hz), 3.95(2H, s), 4.01(3H, s), 7.33(1H, d, J = 8 Hz), 7.45
- 7.57(3H, m), 7.77(1H, d, J = 7 Hz), 8.18(1H, br s), 8.53(2H,
s), 8.61(1H, s).
Example 6 Preparation of
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)isopropylpyrimidin-4(3H)-o
[Chemical Formula 13]
Process 1: By using methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}isobutylami
deheptenoate obtained from the Process 1 of the Example 5
instead of methyl
(Z)acetamide{[6-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate in the Process 3 of the Example 1 and also using
2-aminoethoxypyrimidine instead of
2-aminomethoxypyrimidine, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
1 to give
2-{5-{[4-butyl(5-ethoxypyrimidinyl)isopropyloxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
(yield: 79%) as a pale yellow solid.
H-NMR(CDCl , 400 MHz)d:
0.94(3H, t, J = 7 Hz), 1.19(6H, d, J = 7 Hz), 1.35 - 1.45(2H,
m), 1.51 (3H, t, J = 7 Hz), 1.63 - 1.74(2H, m), 2.22 - 2.35(1H,
m), 2.69(2H, t, J = 8 Hz), 3.95(2H, s), 4.22(2H, q, J = 7 Hz),
7.46(1H, td, J = 8, 1 Hz), 7.62 - 7.70(2H, m), 7.75 - 7.83(3H,
m), 8.50(2H, s), 8.67 - 8.71(1H, m).
Process 2: By using
2-{5-{[4-butyl(5-ethoxypyrimidinyl)isopropyloxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
instead of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
in the Process 4 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 4 of the Example
1 to give
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)isopropylpyrimidin-4(3H)-o
ne (yield: 99%) as pale brown viscous oil.
H-NMR(CDCl , 400 MHz)d:
0.94(3H, t, J = 7 Hz), 1.20(6H, d, J = 7 Hz), 1.35 - 1.46(2H,
m), 1.51(3H, t, J = 7 Hz), 1.63 - 1.75(2H, m), 2.22 - 2.35(1H,
m), 2.71(2H, t, J = 7 Hz), 3.96(2H, s), 4.22(2H, q, J = 7 Hz),
7.37 - 7.45(1H, m), 7.48 - 7.63(3H, m), 7.81(1H, dd, J = 8, 2
Hz), 8.25 - 8.33(1H, m), 8.51(2H, s), 8.67 (1H, s).
Example 7 Preparation of
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclopropyl(5-methoxypyrimidinyl)pyrimidin-4(3H
)-one
[Chemical Formula 14]
Process 1: By using cyclopropanecarbonyl chloride
instead of propionyl chloride in the Process 1 of the Example
3, the reaction and the treatment were performed in the same
manner as the Process 1 of the Example 3 to give methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}(cyclopropa
necarboxamide)heptenoate (yield: 69%) as yellow oil.
H-NMR(CDCl , 400 MHz)d:
0.78 - 0.98(5H, m), 1.02 - 1.12(2H, m), 1.31 - 1.65(5H, m), 2.88
- 3.02(2H, m), 3.72(3H, s), 3.76(2H, s), 7.50(1H, t, J = 8 Hz),
7.60(1H, d, J = 8 Hz), 7.63 - 7.74(2H, m), 7.76 - 7.87(2H, m),
8.61(1H, s), 12.2(1H, s).
Process 2: By using methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}(cyclopropa
necarboxamide)heptenoate instead of methyl
(Z)acetamide{[6-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate in the Process 3 of the Example 1, the reaction and
the treatment were performed in the same manner as the Process
3 of the Example 1 to give
2-{5-{[4-butylcyclopropyl(5-methoxypyrimidinyl)
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitr
ile (yield: 63%) as yellow oil.
H-NMR(CDCl , 400 MHz)d:
0.82 - 0.87(2H, m), 0.92(3H, t, J = 7 Hz), 1.07 - 1.15(1H, m),
1.21 - 1.27 (2H, m), 1.32 - 1.41(2H, m), 1.53 - 1.64(2H, m),
2.61(2H, t, J = 8 Hz), 3.94(2H, s), 4.01(3H, s), 7.44 - 7.49(1H,
m), 7.66(2H, t, J = 8 Hz), 7.74 - 7.82(3H, m), 8.56(2H, s),
8.68(1H, d, J = 2 Hz).
Process 3: By using
2-{5-{[4-butylcyclopropyl(5-methoxypyrimidinyl)
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitr
ile instead of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
in the Process 4 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 4 of the Example
1 to give
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclopropyl(5-methoxypyrimidinyl)pyrimidin-4(3H
)-one (yield: 100%) as pale yellow viscous oil.
H-NMR(CDCl , 400 MHz)d:
0.82 - 0.89(2H, m), 0.92(3H, t, J = 7 Hz), 1.06 - 1.15(1H, m),
1.21 - 1.27 (2H, m), 1.31 - 1.43(2H, m), 1.56 - 1.67(2H, m),
2.63(2H, t, J = 8 Hz), 3.94(2H, s), 4.01(3H, s), 7.40(1H, d,
J = 8 Hz), 7.47 - 7.62(3H, m), 7.75 - 7.82(1H, m), 8.23 - 8.32(1H,
m), 8.56(2H, s), 8.65(1H, s).
Example 8 Preparation of
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclobutyl(5-methoxypyrimidinyl)pyrimidin-4(3H)
-one
[Chemical Formula 15]
Process 1: By using cyclobutanecarbonyl chloride instead
of propionyl chloride in the Process 1 of the Example 3, the
reaction and the treatment were performed in the same manner
as the Process 1 of the Example 3 to give methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}(cyclobutan
ecarboxamide)heptenoate (yield: 72%) as brown oil.
H-NMR(CDCl , 400 MHz)d:
0.91(3H, t, J = 7 Hz), 1.33 - 1.54(4H, m), 2.19 - 2.44(6H, m),
2.95(2H, t, J = 8 Hz), 3.12 - 3.25(1H, m), 3.70(3H, s), 3.75(2H,
s), 7.49(1H, td, J = 8, 1 Hz), 7.58(1H, dd, J = 8, 2 Hz), 7.64
- 7.73(2H, m), 7.76 - 7.86(2H, m), 8.60(1H, s), 11.78(1H, s).
Process 2: By using methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}(cyclobutan
ecarboxamide)heptenoate instead of methyl
(Z)acetamide{[6-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate in the Process 3 of the Example 1, the reaction and
the treatment were performed in the same manner as the Process
3 of the Example 1 to give
2-{5-{[4-butylcyclobutyl(5-methoxypyrimidinyl)o
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitri
le (yield: 65%) as a pale yellow solid.
H-NMR(CDCl , 400 MHz)d:
0.96(3H, t, J = 7 Hz), 1.34 - 1.51(2H, m), 1.65 - 1.83(6H, m),
2.36 - 2.51(2H, m), 2.71(2H, t, J = 8 Hz), 3.07 - 3.17(1H, m),
3.96(2H, s), 4.00 (3H, s), 7.46(1H, td, J = 8, 1 Hz), 7.61 -
7.70(2H, m), 7.73 - 7.82(3H, m), 8.52(2H, s), 8.69(1H, d, J =
1 Hz).
Process 3: By using
2-{5-{[4-butylcyclobutyl(5-methoxypyrimidinyl)o
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitri
le instead of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
in the Process 4 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 4 of the Example
1 to give
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclobutyl(5-methoxypyrimidinyl)pyrimidin-4(3H)
-one (yield: 74%) as colorless viscous oil.
H-NMR(CDCl , 400 MHz)d:
0.95(3H, t, J = 7 Hz), 1.34 - 1.50(2H, m), 1.65 - 1.83(6H, m),
2.37 - 2.51 (2H, m), 2.72(2H, t, J = 8 Hz), 3.04 - 3.20(1H, m),
3.96(2H, s), 4.01(3H, s), 7.31(1H, d, J = 8 Hz), 7.45 - 7.56(3H,
m), 7.76(1H, d, J = 8 Hz), 8.16(1H, br s), 8.52(2H, s), 8.59(1H,
Example 9 Preparation of
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclobutyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)-
[Chemical Formula 16]
Process 1: By using methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}(cyclobutan
ecarboxamide)heptenoate obtained from the Process 1 of the
Example 8 instead of methyl
(Z)acetamide{[6-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate in the Process 3 of the Example 1 and also using
2-aminoethoxypyrimidine instead of
2-aminomethoxypyrimidine, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
1 to give
2-{5-{[4-butylcyclobutyl(5-ethoxypyrimidinyl)ox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e (yield: 89%) as a pale yellow solid.
H-NMR(CDCl , 400 MHz)d:
0.96(3H, t, J = 7 Hz), 1.39 - 1.47(2H, m), 1.51(3H, t, J = 7
Hz), 1.61 - 1.84 (6H, m), 2.36 - 2.51(2H, m), 2.67 - 2.75(2H,
m), 3.03 - 3.16(1H, m), 3.96(2H, s), 4.22(2H, q, J = 7 Hz),
7.48(1H, dd, J = 8, 1 Hz), 7.62 - 7.70 (2H, m), 7.72 - 7.83(3H,
m), 8.49(2H, s), 8.69(1H, d, J = 2 Hz).
Process 2: By using
2-{5-{[4-butylcyclobutyl(5-ethoxypyrimidinyl)ox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e instead of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
in the Process 4 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 4 of the Example
1 to give
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclobutyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)-
one (yield: 99%) as pale brown viscous oil.
H-NMR(CDCl , 400 MHz)d:
0.95(3H, t, J = 7 Hz), 1.36 - 1.47(2H, m), 1.51(3H, t, J = 7
Hz), 1.63 - 1.85 (6H, m), 2.37 - 2.50(2H, m), 2.73(2H, t, J =
8 Hz), 3.07 - 3.18(1H, m), 3.97(2H, s), 4.22(2H, q, J = 7 Hz),
7.40(1H, d, J = 8 Hz), 7.48 - 7.62(3H, m), 7.76 - 7.82(1H, m),
8.24 - 8.31(1H, m), 8.49(2H, s), 8.66(1H, s).
Example 10 Preparation of
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclopentyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)
-one
[Chemical Formula 17]
Process 1: By using cyclopentanecarbonyl chloride
instead of propionylchloride in the Process 1 of the Example
3, the reaction and the treatment were performed in the same
manner as the Process 1 of the Example 3 to give methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}(cyclopenta
necarboxamide)heptenoate (yield: 44%) as brown oil.
H-NMR(CDCl , 400 MHz)d:
0.90(3H, t, J = 7 Hz), 1.33 - 2.03(12H, m), 2.70 - 2.82(1H, m),
2.89 - 2.99 (2H, m), 3.71(3H, s), 3.75(2H, s), 7.49(1H, td, J
= 8, 1 Hz), 7.59(1H, dd, J = 8, 2 Hz), 7.64 - 7.73(2H, m), 7.76
- 7.86(2H, m), 8.60(1H, s), 11.89(1H, s).
Process 2: By using methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}(cyclopenta
necarboxamide)heptenoate instead of methyl
(Z)acetamide{[6-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate in the Process 3 of the Example 1 and also using
2-aminoethoxypyrimidine instead of
2-aminomethoxypyrimidine, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
1 to give
2-{5-{[4-butylcyclopentyl(5-ethoxypyrimidinyl)o
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitri
le (yield: 57%) as a pale yellow solid.
H-NMR(CDCl , 400 MHz)d:
0.94(3H, t, J = 7 Hz), 1.34 - 1.54(7H, m), 1.60 - 1.80(6H, m),
1.90 - 2.03 (2H, m), 2.42 - 2.48(1H, m), 2.64 - 2.70(2H, m),
3.95(2H, s), 4.22(2H, q, J = 7 Hz), 7.47(1H, td, J = 8, 1 Hz),
7.63 - 7.69(2H, m), 7.77(2H, dd, J = 8, 1 Hz), 7.80(1H, dd, J
= 8, 1 Hz), 8.51(2H, s), 8.69(1H, d, J = 2 Hz).
Process 3: By using
2-{5-{[4-butylcyclopentyl(5-ethoxypyrimidinyl)o
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitri
le instead of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
in the Process 4 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 4 of the Example
1 to give
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclopentyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)
-one (yield: 40%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.94(3H, t, J = 7 Hz), 1.52(3H, t, J = 7 Hz), 1.57 - 1.78(8H,
m), 1.81 - 1.93(5H, m), 2.70(2H, t, J = 8 Hz), 3.94(2H, s),
4.23(2H, q, J = 7 Hz), 7.38(1H, d, J = 9 Hz), 7.47 - 7.62(3H,
m), 7.78(1H, d, J = 8 Hz), 8.22 - 8.29(1H, m), 8.52(2H, s),
8.65(1H, s).
Example 11 Preparation of
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclohexyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)-
[Chemical Formula 18]
Process 1: By using cyclohexanecarbonyl chloride instead
of propionyl chloride in the Process 1 of the Example 3, the
reaction and the treatment were performed in the same manner
as the Process 1 of the Example 3 to give methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}(cyclohexan
ecarboxyamide)heptenoate (yield: 52%) as brown oil.
H-NMR(CDCl , 400 MHz)d:
0.90(3H, t, J = 7 Hz), 1.16 - 2.03(14H, m), 2.45 - 2.59(1H, m),
2.89 - 2.98(2H, m), 3.71(3H, s), 3.75(2H, s), 7.49(2H, td, J
= 8, 1 Hz), 7.58(1H, dd, J = 8, 2 Hz), 7.63 - 7.74(2H, m), 7.76
- 7.86(2H, m), 8.61(1H, s), 11.84(1H, br s).
Process 2: By using methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}(cyclohexan
ecarboxyamide)heptenoate instead of methyl
(Z)acetamide{[6-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate in the Process 3 of the Example 1 and also using
2-amino 5-ethoxypyrimidine instead of 2-amino
-methoxypyrimidine, the reaction and the treatment were
performed in the same manner as the Process 3 of the Example
1 to give
2-{5-{[4-butylcyclohexyl(5-ethoxypyrimidinyl)ox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e (yield: 80%) as a pale yellow solid.
H-NMR(CDCl , 400 MHz)d:
0.94(3H, t, J = 7 Hz), 1.16 - 1.91(17H, m), 2.65 - 2.71(2H, m),
3.95(2H, s), 4.23(2H, q, J = 7 Hz), 7.47(1H, td, J = 8, 1 Hz),
7.63 - 7.68(2H, m), 7.75 - 7.82(3H, m), 8.51(2H, s), 8.69(1H,
d, J = 1 Hz).
Process 3: By using
2-{5-{[4-butylcyclohexyl(5-ethoxypyrimidinyl)ox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e instead of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
in the Process 4 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 4 of the Example
1 to give
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylcyclohexyl(5-ethoxypyrimidinyl)pyrimidin-4(3H)-
one (yield: 58%) as colorless viscous oil.
H-NMR(CDCl , 400 MHz)d:
0.94(3H, t, J = 7 Hz), 1.51(3H, t, J = 7 Hz), 1.61 - 1.82(8H,
m), 1.90 - 2.05(5H, m), 2.46(2H, t, J = 8 Hz), 2.69(2H, t, J
= 7 Hz), 3.95(2H, s), 4.22(2H, q, J = 7 Hz), 7.39(1H, d, J =
8 Hz), 7.48 - 7.62(3H, m), 7.79(1H, dd, J = 8, 2 Hz), 8.22 -
8.31(1H, m), 8.51(2H, s), 8.65(1H, s).
Example 12 Preparation of
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylmethyl{5-[2-(methylthio)ethoxy]pyrimidinyl}pyri
midin-4(3H)-one
[Chemical Formula 19]
Process 1: By using
2-amino[2-(methylthio)ethoxy]pyrimidine instead of
2-aminomethoxypyrimidine in the Process 3 of the Example 1,
the reaction and the treatment were performed in the same manner
as the Process 3 of the Example 1 to give
2-{5-{{4-butylmethyl{5-[2-(methylthio)ethoxy]pyrimidi
nyl}oxo-1,6-dihydropyrimidinyl}methyl}pyridinyl
}benzonitrile (yield: 64%) as yellow oil.
H-NMR(CDCl , 400 MHz) :
0.95(3H, t, J = 7 Hz), 1.33 - 1.48(2H, m), 1.57 - 1.73(2H, m),
2.17(3H, s), 2.24(3H, s), 2.67(2H, t, J = 8 Hz), 2.96(2H, t,
J = 7 Hz), 3.97(2H, s), 4.33(2H, t, J = 7 Hz), 7.47(1H, t, J
= 8 Hz), 7.62 - 7.70(2H, m), 7.73 - 7.83(3H, m), 8.55(2H, s),
8.70(1H, s).
Process 2: By using
2-{5-{{4-butylmethyl{5-[2-(methylthio)ethoxy]pyrimidi
nyl}oxo-1,6-dihydropyrimidinyl}methyl}pyridinyl
}benzonitrile instead of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
in the Process 4 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 4 of the Example
1 to give
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylmethyl{5-[2-(methylthio)ethoxy]pyrimidinyl}pyri
midin-4(3H)-one (yield: 80%) as yellow oil.
H-NMR(CDCl , 400 MHz)d:
0.82 - 1.00(3H, m), 1.33 - 1.47(2H, m), 1.55 - 1.73(2H, m),
2.15(3H, s), 2.23(3H, s), 2.55 - 2.76(2H, m), 2.95(2H, t, J =
7 Hz), 3.82 - 4.03(2H, m), 4.33(2H, t, J = 7 Hz), 7.07 - 7.33(1H,
m), 7.35 - 7.57(3H, m), 7.59 - 7.80(1H, m), 7.85 - 8.15(1H, m),
8.47 - 8.62(1H, m), 8.55(2H, s).
Example 13 Preparation of
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylmethyl{5-[2-(methylsulfonyl)ethoxy]pyrimidinyl}
pyrimidin-4(3H)-one
[Chemical Formula 20]
Methanol (0.4 mL) solution of hydrogen peroxide (30%
solution, 24 mg, 0.211 mmol) and methanol (0.4 mL) solution of
tantalum chloride (1.5 mg, 0.0042 mmol) were added to methanol
(1.0 mL) solution of
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylmethyl{5-[2-(methylthio)ethoxy]pyrimidinyl}pyri
midin-4(3H)-one (24 mg, 0.042 mmol) which has been obtained in
the Example 12. After stirring for 12 hours at room temperature,
the solvent was removed by distillation. The obtained residues
were subjected to silica gel column chromatography
(chloroform : methanol : triethylamine = 4 : 1 : 0.4) to give
-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylmethyl{5-[2-(methylsulfonyl)ethoxy]pyrimidinyl}
pyrimidin-4(3H)-one (24 mg, 93%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz) :
0.94(3H, t, J = 7 Hz), 1.34 - 1.47(2H, m), 1.54 - 1.71(2H, m),
2.16(3H, s), 2.66(2H, t, J = 8 Hz), 3.09(3H, s), 3.55(2H, t,
J = 5 Hz), 3.93(2H, s), 4.64(2H, t, J = 5 Hz), 7.10 - 7.24(1H,
m), 7.31 - 7.55(3H, m), 7.65 - 7.77(1H, m), 7.92 - 8.04(1H, m),
8.45 - 8.53(1H, m), 8.59(2H, s).
Example 14 Preparation of
3-{2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihyd
ropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4-oxadiazo
l-5(4H)-one
[Chemical Formula 21]
Process 1: By using 2-amino-pyridine instead of
2-aminomethoxypyrimidine in the Process 3 of the Example 1,
the reaction and the treatment were performed in the same manner
as the Process 3 of the Example 1 to give
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile (yield: 61%).
H-NMR(CDCl , 400 MHz)d:
0.95(3H, t, J = 7 Hz), 1.43(2H, sextet, J = 8 Hz), 1.61 - 1.69(2H,
m), 2.17(3H, s), 2.66 - 2.70(2H, m), 3.97(2H, s), 7.36 - 7.50(3H,
m), 7.65 - 7.69(2H, m), 7.76 - 7.81(3H, m), 7.93(1H, m), 8.67
- 8.70(2H, m).
Process 2: Sodium hydrogen carbonate (2.02 mg, 24.0 mmol)
was added to dimethyl sulfoxide solution (20 mL) of
hydroxylamine hydrochloride (1.42 g, 20.4 mmol) and stirred for
1 hour at 40C. Dimethyl sulfoxide solution (3 mL) of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile (430 mg,
0.987 mmol) was added to the reaction mixture and stirred for
19 hours at 90C. The reaction mixture was added water and
extracted with ethyl acetate. The organic layer was combined,
washed with water and brine, dried over anhydrous sodium sulfate,
and concentrated in vacuo. The obtained residues were
subjected to silica gel column chromatography (ethyl acetate)
to give
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
(430 mg, 93%) as a white solid.
Process 3: 1,1’-Carbonyldiimidazole (490 mg, 3.02 mmol)
and 1,8-diazabicyclo[5.4.0]undecene (460 mg, 3.02 mmol)
were added to dimethylformamide solution (25 mL) of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
(430 mg, 0.918 mmol) and stirred for 3 hours at room temperature.
Once the reaction is completed, the reaction mixture was added
water and extracted with ethyl acetate. The organic layer was
combined, washed with water and brine, dried over anhydrous
sodium sulfate, and concentrated in vacuo. The obtained
residues were purified by silica gel column chromatography
(ethyl acetate) to give
3-{2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihyd
ropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4-oxadiazo
l-5(4H)-one (160 mg, 35%, two step yield) as weak yellow oil.
H-NMR(CDCl , 400 MHz)d:
0.94(3H, t, J = 7 Hz), 1.42(2H, sextet, J = 8 Hz), 1.60 - 1.68(2H,
m), 2.17(3H, s), 2.64 - 2.68(2H, m), 3.93(2H, s), 7.33 - 7.56(6H,
m), 7.74 - 7.77(2H, m), 7.95(1H, dd, J = 8, 2 Hz), 8.45(1H, s),
8.67(1H, d, J = 4 Hz).
Example 15 Preparation of
3-{2-{5-{[4-butylmethyl(4-methylpyridinyl)oxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4-
oxadiazol-5(4H)-one
[Chemical Formula 22]
Process 1: By using 2-aminomethylpyridine instead of
2-aminomethoxypyrimidine in the Process 3 of the Example 1,
the reaction and the treatment were performed in the same manner
as the Process 3 of the Example 1 to give
2-{5-{[4-butylmethyl(4-methylpyridinyl)oxo-1,6-
dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
(yield: 61%).
H-NMR(CDCl , 400 MHz)d:
0.95(3H, t, J = 7 Hz), 1.42(2H, sextet, J = 8 Hz), 1.60 - 1.69(2H,
m), 2.17(3H, s), 2.45(3H. s), 2.66 - 2.70(2H, m), 3.96(2H, s),
7.19(1H, s), 7.24 - 7.27(2H, m), 7.48(1H, m), 7.65 - 7.69(2H,
m), 7.76 - 7.82(2H, m), 8.51(1H, d, J = 5 Hz), 8.70(1H, s).
Process 2: By using
2-{5-{[4-butylmethyl(4-methylpyridinyl)oxo-1,6-
dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{5-{[4-butylmethyl(4-methylpyridinyl)oxo-1,6-
dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxybenzim
idamide.
Process 3: By using
2-{5-{[4-butylmethyl(4-methylpyridinyl)oxo-1,6-
dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxybenzim
idamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{5-{[4-butylmethyl(4-methylpyridinyl)oxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4-
oxadiazol-5(4H)-one (yield: 45%, two step yield) as weak yellow
oil.
H-NMR(CDCl , 400 MHz)d:
0.95(3H, t, J = 7 Hz), 1.42(2H, sextet, J = 8 Hz), 1.61 - 1.69(2H,
m), 2.17(3H, s), 2.46(3H, s), 2.65 - 2.69(2H, m), 3.94(2H, s),
7.21(1H, s), 7.24 - 7.28(2H, m), 7.37 - 7.60(3H, m), 7.78(1H,
dd, J = 8, 2 Hz), 7.85(1H, d, J = 7 Hz), 8.50 - 8.51(2H, m).
Example 16 Preparation of
3-{2-{5-{[4-butyl(5-methoxypyrimidinyl)methylox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2
,4-oxadiazol-5(4H)-one
[Chemical Formula 23]
Process 1: By using
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
obtained from the Process 3 of the Example 1 instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxyben
zimidamide.
Process 2: By using
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}-N'-hydroxyben
zimidamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{5-{[4-butyl(5-methoxypyrimidinyl)methylox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2
,4-oxadiazol-5(4H)-one (yield: 48%, two step yield) as
colorless amorphous.
H-NMR(CDCl , 400 MHz)d:
0.94(3H, t, J = 7 Hz), 1.43(2H, quint, J = 8 Hz), 1.61 - 1.68(2H,
m), 2.17(3H, s), 2.65 - 2.69(2H, m), 3.95(2H, s), 4.01(3H, s),
7.36 - 7.69(4H, m), 7.76 - 7.86(2H, m), 8.51(1H, br), 8.54(2H,
Example 17 Preparation of
3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)methyloxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,
4-oxadiazol-5(4H)-one
[Chemical Formula 24]
Process 1: By using
2-{5-{[4-butyl(5-ethoxypyrimidinyl)methyloxo-1,
6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
obtained from the Process 1 of the Example 2 instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{5-{[4-butyl(5-ethoxypyrimidinyl)methyloxo-1,
6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxybenz
imidamide.
Process 2: By using
2-{5-{[4-butyl(5-ethoxypyrimidinyl)methyloxo-1,
6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxybenz
imidamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)methyloxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,
4-oxadiazol-5(4H)-one (yield: 18%, two step yield) as pale
yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.95(3H, t, J = 7 Hz), 1.38 - 1.48(2H, m), 1.51(3H, t, J = 7
Hz), 1.62 - 1.68(2H, m), 2.17(3H, s), 2.66 - 2.70(2H, m), 3.95(2H,
s), 4.22(2H, q, J = 7 Hz), 7.38 - 7.61(4H, m), 7.79(1H, d, J
= 7 Hz), 7.90(1H, d, J = 7 Hz), 8.51(2H, s), 8.54(1H, s).
Example 18 Preparation of
3-{2-{5-{[4-butylethyl(5-methoxypyrimidinyl)oxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,
4-oxadiazol-5(4H)-one
[Chemical Formula 25]
Process 1: By using
2-{5-{[4-butylethyl(5-methoxypyrimidinyl)oxo-1,
6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
obtained from the Process 2 of the Example 3 instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{5-{[4-butylethyl(5-methoxypyrimidinyl)oxo-1,
6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxybenz
imidamide.
Process 2: By using
2-{5-{[4-butylethyl(5-methoxypyrimidinyl)oxo-1,
6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxybenz
imidamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{5-{[4-butylethyl(5-methoxypyrimidinyl)oxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,
4-oxadiazol-5(4H)-one (yield: 53%, two step yield) as white
amorphous.
H-NMR(CDCl , 400 MHz)d:
0.95(3H, t, J = 7 Hz), 1.18(3H, t, J = 7 Hz), 1.36 - 1.50(2H,
m), 1.61 - 1.75(2H, m), 2.32(2H, q, J = 7 Hz), 2.71(2H, t, J
= 8 Hz), 3.95(2H, s), 4.00(3H, s), 4.79(1H, br s), 7.38(1H, d,
J = 8 Hz), 7.45(1H, dd, J = 8, 1 Hz), 7.51(1H, dd, J = 8, 1 Hz),
7.59(1H, td, J = 8, 2 Hz), 7.79(1H, dd, J = 8, 2 Hz), 7.89(1H,
dd, J = 8, 1 Hz), 8.52 - 8.55(3H, m).
Example 19 Preparation of
3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)ethyloxo-
1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4
-oxadiazol-5(4H)-one
[Chemical Formula 26]
Process 1: By using
2-{5-{[4-butyl(5-ethoxypyrimidinyl)ethyloxo-1,6
-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
obtained from the Process 1 of the Example 4 instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{5-{[4-butyl(5-ethoxypyrimidinyl)ethyloxo-1,6
-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxybenzi
midamide.
Process 2: By using
2-{5-{[4-butyl(5-ethoxypyrimidinyl)ethyloxo-1,6
-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxybenzi
midamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)ethyloxo-
1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4
-oxadiazol-5(4H)-one (yield: 73%, two step yield) as white
amorphous.
H-NMR(CDCl , 400 MHz)d:
0.94(3H, t, J = 7 Hz), 1.18(3H, t, J = 7 Hz), 1.34 - 1.47(2H,
m), 1.51(3H, t, J = 7 Hz), 1.60 - 1.74(2H, m), 2.32(2H, q, J
= 7 Hz), 2.70(2H, t, J = 8 Hz), 3.94(2H, s), 4.22(2H, q, J =
7 Hz), 7.36(1H, d, J = 8 Hz), 7.41 - 7.61(3H, m), 7.77(1H, dd,
J = 8, 2 Hz), 7.85(1H, dd, J = 8, 1 Hz), 8.48 - 8.53(3H, m).
Example 20 Preparation of
3-{2-{5-{[4-butylisopropyl(5-methoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one
[Chemical Formula 27]
Process 1: By using
2-{5-{[4-butylisopropyl(5-methoxypyrimidinyl)ox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e obtained from the Process 2 of the Example 5 instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{5-{[4-butylisopropyl(5-methoxypyrimidinyl)ox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxy
benzimidamide.
Process 2: By using
2-{5-{[4-butylisopropyl(5-methoxypyrimidinyl)ox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxy
benzimidamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{5-{[4-butylisopropyl(5-methoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one (yield: 60%, two step yield) as white
amorphous.
H-NMR(CDCl , 400 MHz)d:
0.95(3H, t, J = 7 Hz), 1.19(6H, d, J = 7 Hz), 1.31 - 1.49(2H,
m), 1.60 - 1.75(2H, m), 2.23 - 2.35(1H, m), 2.70(2H, t, J = 8
Hz), 3.93(2H, s), 4.00(3H, s), 7.36(1H, d, J = 8 Hz), 7.43(1H,
dd, J = 7, 1 Hz), 7.49(1H, dd, J = 7, 1 Hz), 7.57(1H, td, J =
8, 1 Hz), 7.79(1H, dd, J = 8, 2 Hz), 7.85(1H, dd, J = 8, 1 Hz),
8.50(1H, d, J = 2 Hz), 8.53(2H, s).
Example 21 Preparation of
3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)isopropyl
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1
,2,4-oxadiazol-5(4H)-one
[Chemical Formula 28]
Process 1: By using
2-{5-{[4-butyl(5-ethoxypyrimidinyl)isopropyloxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
obtained from the Process 1 of the Example 6 instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{5-{[4-butyl(5-ethoxypyrimidinyl)isopropyloxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxyb
enzimidamide.
Process 2: By using
2-{5-{[4-butyl(5-ethoxypyrimidinyl)isopropyloxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxyb
enzimidamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)isopropyl
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1
,2,4-oxadiazol-5(4H)-one (yield: 66%, two step yield) as white
amorphous.
H-NMR(CDCl , 400 MHz)d:
0.95(3H, t, J = 7 Hz), 1.20(6H, d, J = 7 Hz), 1.36 - 1.46(2H,
m), 1.51(3H, t, J = 7 Hz), 1.62 - 1.74(2H, m), 2.23 - 2.35(1H,
m), 2.72(2H, t, J = 8 Hz), 3.94(2H, s), 4.22(2H, q, J = 7 Hz),
7.40(1H, d, J = 9 Hz), 7.46(1H, dd, J = 8, 1 Hz), 7.52(1H, td,
J = 8, 2 Hz), 7.61(1H, td, J = 8, 2 Hz), 7.82(1H, dd, J = 8,
2 Hz), 7.95(1H, dd, J = 8, 1 Hz), 8.51(2H, s), 8.58(1H, d, J
= 2 Hz).
Example 22 Preparation of
3-{2-{5-{[4-butylcyclopropyl(5-methoxypyrimidinyl)
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one
[Chemical Formula 29]
Process 1: By using
2-{5-{[4-butylcyclopropyl(5-methoxypyrimidinyl)
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitr
ile obtained from the Process 2 of the Example 7 instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{5-{[4-butylcyclopropyl(5-methoxypyrimidinyl)
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydro
xybenzimidamide.
Process 2: By using
2-{5-{[4-butylcyclopropyl(5-methoxypyrimidinyl)
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydro
xybenzimidamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{5-{[4-butylcyclopropyl(5-methoxypyrimidinyl)
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one (yield: 84%, two step yield) as
white amorphous.
H-NMR(CDCl , 400 MHz)d:
0.81 - 0.89(2H, m), 0.93(3H, t, J = 7 Hz), 1.06 - 1.15(1H, m),
1.24(2H, t, J = 4 Hz), 1.32 - 1.44(2H, m), 1.55 - 1.67(2H, m),
2.63(2H, t, J = 8 Hz), 3.92(2H, s), 4.00(3H, s), 7.37(1H, d,
J = 8 Hz), 7.45(1H, d, J = 8 Hz), 7.51(1H, dd, J = 8, 1 Hz),
7.59(1H, td, J = 8, 1 Hz), 7.78(1H, dd, J = 8, 2 Hz), 7.89(1H,
d, J = 7 Hz), 8.52(1H, d, J = 2 Hz), 8.56(2H, s).
Example 23 Preparation of
3-{2-{5-{[4-butylcyclopropyl(5-ethoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one
[Chemical Formula 30]
Process 1: By using 2-aminoethoxypyrimidine instead
of 2-aminomethoxypyrimidine in the Process 3 of the Example
1 and also using methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}(cyclopropa
necarboxamide)heptenoate instead of methyl
(Z)acetamide{[6-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate, the reaction and the treatment were performed in
the same manner as the Process 3 of the Example 1 to give
2-{5-{[4-butylcyclopropyl(5-ethoxypyrimidinyl)o
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitri
le (yield: 65%) as yellow oil.
H-NMR(CDCl , 400 MHz) :
0.79 - 0.87(2H, m), 0.92(3H, t, J = 8 Hz), 1.09 - 1.16(1H, m),
1.18 - 1.29(2H, m), 1.30 - 1.43(2H, m), 1.51(3H, t, J = 7 Hz),
1.54 - 1.66(2H, m), 2.61(2H, t, J = 8 Hz), 3.94(2H, s), 4.22(2H,
q, J = 7 Hz), 7.47(1H, t, J = 8 Hz), 7.57 - 7.69(2H, m), 7.71
- 7.83(3H, m), 8.54(2H, s), 8.68(1H, s).
Process 2: By using
2-{5-{[4-butylcyclopropyl(5-ethoxypyrimidinyl)o
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitri
le instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{5-{[4-butylcyclopropyl(5-ethoxypyrimidinyl)o
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydrox
ybenzimidamide.
Process 3: By using
2-{5-{[4-butylcyclopropyl(5-ethoxypyrimidinyl)o
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydrox
ybenzimidamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{5-{[4-butylcyclopropyl(5-ethoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one (yield: 38%, two step yield) as
colorless crystalline powder.
H-NMR(CDCl , 400 MHz)d:
0.76 - 0.87(2H, m), 0.92(3H, t, J = 7 Hz), 1.05 - 1.15(1H, m),
1.16 - 1.28(2H, m), 1.32 - 1.44(2H, m), 1.51(3H, t, J = 7 Hz),
1.54 - 1.66(2H, m), 2.61(2H, t, J = 8 Hz), 3.91(2H, s), 4.22(2H,
q, J = 7 Hz), 7.34(1H, d, J = 8 Hz), 7.38 - 7.50(2H, m), 7.51
- 7.59(1H, m), 7.71 - 7.86(2H, m), 8.46(1H, s), 8.54 (2H, s).
Example 24 Preparation of
3-{2-{5-{[4-butylcyclobutyl(5-methoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one
[Chemical Formula 31]
Process 1: By using
2-{5-{[4-butylcyclobutyl(5-methoxypyrimidinyl)o
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitri
le obtained from the Process 2 of the Example 8 instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{5-{[4-butylcyclobutyl(5-methoxypyrimidinyl)o
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydrox
ybenzimidamide.
Process 2: By using
2-{5-{[4-butylcyclobutyl(5-methoxypyrimidinyl)o
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydrox
ybenzimidamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{5-{[4-butylcyclobutyl(5-methoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one (yield: 65%, two step yield) as
white amorphous.
H-NMR(CDCl , 400 MHz)d:
0.96(3H, t, J = 7 Hz), 1.35 - 1.51(2H, m), 1.64 - 1.85(6H, m),
2.37 - 2.53(2H, m), 2.72(2H, t, J = 8 Hz), 3.04 - 3.20(1H, m),
3.94(2H, s), 4.00(3H, s), 7.34(1H, d, J = 8 Hz), 7.39 - 7.44(1H,
m), 7.44 - 7.49(1H, m), 7.51 - 7.59(1H, m), 7.74 - 7.83(2H, m),
8.48(1H, d, J = 2 Hz), 8.52(2H, s).
Example 25 Preparation of
3-{2-{5-{[4-butylcyclobutyl(5-ethoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one
[Chemical Formula 32]
Process 1: By using
2-{5-{[4-butylcyclobutyl(5-ethoxypyrimidinyl)ox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e obtained from the Process 1 of the Example 9 instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{5-{[4-butylcyclobutyl(5-ethoxypyrimidinyl)ox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxy
benzimidamide.
Process 2: By using
2-{5-{[4-butylcyclobutyl(5-ethoxypyrimidinyl)ox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxy
benzimidamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{5-{[4-butylcyclobutyl(5-ethoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one (yield: 48%, two step yield) as white
amorphous.
H-NMR(CDCl , 400 MHz)d:
0.97(3H, t, J = 7 Hz), 1.35 - 1.47(2H, m), 1.48 - 1.83(9H, m),
2.38 - 2.52(2H, m), 2.74(2H, t, J = 8 Hz), 3.03 - 3.18(1H, m),
3.95(2H, s), 4.22(2H, q, J = 7 Hz), 7.40(1H, d, J = 8 Hz), 7.46(1H,
d, J = 8 Hz), 7.54(1H, dd, J = 8, 2 Hz), 7.61(1H, td, J = 8,
2 Hz), 7.81(1H, dd, J = 8, 2 Hz), 7.95(1H, dd, J = 8, 1 Hz),
8.49(2H, s), 8.58(1H, d, J = 2 Hz).
Example 26 Preparation of
3-{2-{5-{[4-butylcyclopentyl(5-ethoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one
[Chemical Formula 33]
Process 1: By using
2-{5-{[4-butylcyclopentyl(5-ethoxypyrimidinyl)o
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitri
le obtained from the Process 2 of the Example 10 instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{5-{[4-butylcyclopentyl(5-ethoxypyrimidinyl)o
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydrox
ybenzimidamide.
Process 2: By using
2-{5-{[4-butylcyclopentyl(5-ethoxypyrimidinyl)o
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydrox
ybenzimidamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{5-{[4-butylcyclopentyl(5-ethoxypyrimidinyl)-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one (yield: 56%, two step yield) as pale
brown amorphous.
H-NMR(CDCl , 400 MHz)d:
0.94(3H, t, J = 7 Hz), 1.32 - 1.57(7H, m), 1.60 - 1.85(6H, m),
1.90 - 2.06(2H, m), 2.36 - 2.52(1H, m), 2.68(2H, t, J = 7 Hz),
3.93(2H, s), 4.22(2H, q, J = 7 Hz), 7.35(1H, d, J = 8 Hz), 7.40
- 7.60(3H, m), 7.78(1H, dd, J = 8, 2 Hz), 7.83(1H, dd, J = 8,
1 Hz), 8.49(1H, d, J = 2 Hz), 8.51(2H, s).
Example 27 Preparation of
3-{2-{5-{[4-butylcyclohexyl(5-ethoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one
[Chemical Formula 34]
Process 1: By using
2-{5-{[4-butylcyclohexyl(5-ethoxypyrimidinyl)ox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e obtained from the Process 2 of the Example 11 instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{5-{[4-butylcyclohexyl(5-ethoxypyrimidinyl)ox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxy
benzimidamide.
Process 2: By using
2-{5-{[4-butylcyclohexyl(5-ethoxypyrimidinyl)ox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxy
benzimidamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{5-{[4-butylcyclohexyl(5-ethoxypyrimidinyl)-6
-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one (yield: 60%) as pale brown
amorphous.
H-NMR(CDCl , 400 MHz)d:
0.89 - 1.07(5H, m), 1.34 - 1.94(16H, m), 2.68(2H, t, J = 8 Hz),
3.92(2H, s), 4.23(2H, q, J = 7 Hz), 7.34(1H, d, J = 8 Hz), 7.39
- 7.49(2H, m), 7.50 - 7.59(1H, m), 7.74 - 7.83(2H, m), 8.47(1H,
d, J = 2 Hz), 8.51(2H, s).
Example 28 Preparation of
3-{2-{5-{{4-butylmethyl{5-[2-(methylthio)ethoxy]pyrim
idinyl}oxo-1,6-dihydropyrimidinyl}methyl}pyridin-2
-yl}phenyl}-1,2,4-oxadiazol-5(4H)-one
[Chemical Formula 35]
Process 1: By using
2-{5-{{4-butylmethyl{5-[2-(methylthio)ethoxy]pyrimidi
nyl}oxo-1,6-dihydropyrimidinyl}methyl}pyridinyl
}benzonitrile obtained from the Process 1 of the Example 12
instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{5-{{4-butylmethyl{5-[2-(methylthio)ethoxy]pyrimidi
nyl}oxo-1,6-dihydropyrimidinyl}methyl}pyridinyl
}-N’-hydroxybenzimidamide.
Process 2: By using
2-{5-{{4-butylmethyl{5-[2-(methylthio)ethoxy]pyrimidi
nyl}oxo-1,6-dihydropyrimidinyl}methyl}pyridinyl
}-N’-hydroxybenzimidamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{5-{{4-butylmethyl{5-[2-(methylthio)ethoxy]pyrim
idinyl}oxo-1,6-dihydropyrimidinyl}methyl}pyridin-2
-yl}phenyl}-1,2,4-oxadiazol-5(4H)-one (yield: 56%, two step
yield) as weak yellow oil.
H-NMR(CDCl , 400 MHz)d:
0.95(3H, t, J = 7 Hz), 1.40 - 1.46(2H, m), 1.50 - 1.70(2H, m),
2.17(3H, s), 2.24(3H, s), 2.68 - 2.71(2H, m), 2.96(2H, t, J =
7 Hz), 3.96(2H, s), 4.33(2H, t, J = 7 Hz), 7.40 - 7.62(4H, m),
7.66 - 7.97(2H, m), 8.55(2H, s), 8.58(1H, s).
Example 29 Preparation of
3-{2-{5-{{4-butylmethyl{5-[2-(methylsulfonyl)ethoxy]p
yrimidinyl}oxo-1,6-dihydropyrimidinyl}methyl}pyrid
inyl}phenyl}-1,2,4-oxadiazol-5(4H)-one
[Chemical Formula 36]
By using
3-{2-{5-{{4-butylmethyl{5-[2-(methylthio)ethoxy]pyrim
idinyl}oxo-1,6-dihydropyrimidinyl}methyl}pyridin-2
-yl}phenyl}-1,2,4-oxadiazol-5(4H)-one obtained in the Example
28, the reaction and the treatment were performed in the same
manner as the Example 13 to give
3-{2-{5-{{4-butylmethyl{5-[2-(methylsulfonyl)ethoxy]p
yrimidinyl}oxo-1,6-dihydropyrimidinyl}methyl}pyrid
inyl}phenyl}-1,2,4-oxadiazol-5(4H)-one (yield: 63%) as
colorless oil.
H-NMR(CDCl , 400 MHz)d:
0.95(3H, t, J = 7 Hz), 1.40 - 1.46(2H, m), 1.65 - 1.70(2H, m),
2.18(3H, s), 2.67 - 2.71(2H, m), 3.09(3H, s), 3.53 - 3.55(2H,
m), 3.92(2H, s), 4.63 - 4.66(2H, m), 7.36 - 7.60(4H, m), 7.74(1H,
d, J = 8 Hz), 7.88(1H, d, J = 8 Hz), 8.59(1H, s), 8.60(2H, s).
Example 30 Preparation of
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylmethyl(pyridinyl)pyrimidin-4(3H)-one
[Chemical Formula 37]
Process 1: By using
2-[6-(bromomethyl)pyridinyl]benzonitrile instead of
2-[5-(bromomethyl)pyridinyl]benzonitrile in the Process 1
of the Example 1, the reaction and the treatment were performed
in the same manner as the Process 1 of the Example 1 to give
2-{[5-(2-cyanophenyl)pyridinyl]methyl}oxoheptanoate
(yield: 69%) as yellow oil.
H-NMR(CDCl , 400 MHz)d:
0.89(3H, t, J = 7 Hz), 1.24 - 1.34(2H, m), 1.54 - 1.61(2H, m),
2.59 - 2.76(2H, m), 3.37 - 3.55(2H, m), 3.73(3H, s), 4.37(1H,
t, J = 7 Hz), 7.33(1H, d, J = 8 Hz), 7.50(2H, t, J = 7 Hz), 7.66
- 7.70(1H, m), 7.78 - 7.83(2H, m), 8.63(1H, d, J = 2 Hz).
Process 2: By using methyl
2-{[5-(2-cyanophenyl)pyridinyl]methyl}oxoheptanoate
instead of methyl
2-{[6-(2-cyanophenyl)pyridinyl]methyl}oxoheptanoate
in the Process 2 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 2 of the Example
1 to give methyl
(Z)acetamide{[5-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate (yield: 100%) as yellow oil.
H-NMR(CDCl , 400 MHz)d:
0.89(3H, t, J = 7 Hz), 1.27 - 1.40(2H, m), 1.47 - 1.59(2H, m),
2.24(3H, s), 3.14(2H, t, J = 8 Hz), 3.78(3H, s), 3.88(2H, s),
7.42 - 7.56(3H, m), 7.65 - 7.91(3H, m), 8.63(1H, s), 10.9(1H,
Process 3: By using 2-aminopyridine instead of
2-aminomethoxypyrimidine in the Process 3 of the Example 1
and also using methyl
(Z)acetamide{[5-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate instead of methyl
(Z)acetamide{[6-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate, the reaction and the treatment were performed in
the same manner as the Process 3 of the Example 1 to give
2-{6-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile (yield: 35%).
H-NMR(CDCl , 400 MHz) :
0.93(3H, t, J = 7 Hz), 1.42(2H, sextet, J = 8 Hz), 1.60 - 1.75(2H,
m), 2.17(3H, s), 2.74 - 2.78(2H, m), 4.17(2H, s), 7.38 - 7.50(5H,
m), 7.67(1H, m), 7.77 - 7.80(2H, m), 7.93(1H, m), 8.65(1H, d,
J = 2 Hz), 8.68(1H, d, J = 3 Hz).
Process 4: By using
2-{6-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile instead of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
in the Process 4 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 4 of the Example
1 to give
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tylmethyl(pyridinyl)pyrimidin-4(3H)-one (yield:
79%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.89(3H, t, J = 7 Hz), 1.30 - 1.35(2H, m), 1.50 - 1.58(2H, m),
2.18(3H, s), 2.51 - 2.54(2H, m), 3.75(2H, s), 6.99(1H, d, J =
8 Hz), 7.16(1H, d, J = 8 Hz), 7.31 - 7.36(3H, m), 7.48 - 7.56(2H,
m), 7.83 - 7.87(2H, m), 7.97(1H, s), 8.56(1H, d, J = 4 Hz).
Example 31 Preparation of
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-methoxypyridinyl)methylpyrimidin-4(3H)-one
[Chemical Formula 38]
Process 1: By using 2-aminomethoxypyridine instead of
2-aminomethoxypyrimidine in the Process 3 of the Example 1
and also using methyl
(Z)acetamide{[5-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate obtained from the Process 2 of the Example 30
instead of methyl
(Z)acetamide{[6-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate, the reaction and the treatment were performed in
the same manner as the Process 3 of the Example 1 to give
2-{6-{[4-butyl(5-methoxypyridinyl)methyloxo-1,6
-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
(yield: 65%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.93(3H, t, J = 7 Hz), 1.37 - 1.46(2H, m), 1.58 - 1.66(2H, m),
2.18(3H, s), 2.76(2H, t, J = 8 Hz), 3.92(3H, s), 4.16(2H, s),
7.27 - 7.30(1H, m), 7.38 - 7.49(4H, m), 7.65 - 7.69(1H, m), 7.77
- 7.79(2H, m), 8.30(1H, d, J = 3 Hz), 8.65(1H, d, J = 2 Hz).
Process 2: By using
2-{6-{[4-butyl(5-methoxypyridinyl)methyloxo-1,6
-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
instead of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
in the Process 4 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 4 of the Example
1 to give
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-methoxypyridinyl)methylpyrimidin-4(3H)-one
(yield: 72%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.87(3H, t, J = 7 Hz), 1.21 - 1.30(2H, m), 1.40 - 1.48(2H, m),
2.09(3H, s), 2.38(2H, t, J = 8 Hz), 3.60(2H, s), 3.90(3H, s),
7.00(1H, d, J = 8 Hz), 7.14(2H, dd, J = 8, 2 Hz), 7.20(1H, d,
J = 9 Hz), 7.34 - 7.38(2H, m), 7.53 - 7.61(2H, m), 7.84(1H, d,
J = 7 Hz), 7.90(1H, s), 8.21(1H, d, J = 3 Hz).
Example 32 Preparation of
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl[3-chloro(trifluoromethyl)pyridinyl]methylpy
rimidin-4(3H)-one
[Chemical Formula 39]
Process 1: By using
2-aminochloro(trifluoromethyl)pyridine instead of
2-aminomethoxypyrimidine in the Process 3 of the Example 1
and also using methyl
(Z)acetamide{[5-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate obtained from the Process 2 of the Example 30
instead of methyl
(Z)acetamide{[6-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate, the reaction and the treatment were performed in
the same manner as the Process 3 of the Example 1 to give
2-{6-{{4-butyl[3-chloro(trifluoromethyl)pyridinyl]
methyloxo-1,6-dihydropyrimidinyl}methyl}pyridin
yl}benzonitrile (yield: 41%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.94(3H, t, J = 7 Hz), 1.37 - 1.47(2H, m), 1.57 - 1.68(2H, m),
2.16(3H, s), 2.70 - 2.83(2H, m), 4.19(2H, s), 7.38(1H, d, J =
8 Hz), 7.46 - 7.53(2H, m), 7.65 - 7.69(1H, m), 7.77 - 7.83(2H,
m), 7.89(1H, m), 8.65(1H, d, J = 2 Hz), 8.84(1H, s).
Process 2: By using
2-{6-{{4-butyl[3-chloro(trifluoromethyl)pyridinyl]
methyloxo-1,6-dihydropyrimidinyl}methyl}pyridin
yl}benzonitrile instead of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
in the Process 4 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 4 of the Example
1 to give
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl[3-chloro(trifluoromethyl)pyridinyl]methylpy
rimidin-4(3H)-one (yield: 43%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.87(3H, t, J = 7 Hz), 1.22 - 1.30(2H, m), 1.43 - 1.50(2H, m),
2.09(3H, s), 2.35 - 2.43(2H, m), 3.55(2H, dd, J = 19, 16 Hz),
6.95(1H, d, J = 8 Hz), 7.11 - 7.14(1H, m), 7.38 - 7.40(1H, m),
7.54 - 7.61(2H, m), 7.86 - 7.89(1H, m), 7.94(1H, m), 8.18(1H,
d, J = 2 Hz), 8.81(1H, s).
Example 33 Preparation on
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-methoxypyrimidinyl)methylpyrimidin-4(3H)-one
[Chemical Formula 40]
Process 1: By using methyl
(Z)acetamide{[5-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate obtained from the Process 2 of the Example 30
instead of methyl
(Z)acetamide{[6-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate in the Process 3 of the Example 1, the reaction and
the treatment were performed in the same manner as the Process
3 of the Example 1 to give
2-{6-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
(yield: 51%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.93(3H, t, J = 7 Hz), 1.36 - 1.45(2H, m), 1.57 - 1.65(2H, m),
2.16(3H, s), 2.75(2H, t, J = 8 Hz), 4.00(3H, s), 4.17(2H, s),
7.40 - 7.49(3H, m), 7.64 - 7.69(1H, m), 7.77 - 7.79(2H, m),
8.54(2H, s), 8.65(1H, d, J = 2 Hz).
Process 2: By using
2-{6-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
instead of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
in the Process 4 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 4 of the Example
1 to give
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-methoxypyrimidinyl)methylpyrimidin-4(3H)-one
(yield: 52%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.86(3H, t, J = 7 Hz), 1.20 - 1.29(2H, m), 1.41 - 1.49(2H, m),
2.09(3H, s), 2.43(2H, t, J = 8 Hz), 3.62(2H, s), 3.98(3H, s),
7.00(1H, d, J = 8 Hz), 7.13(1H, dd, J = 8, 2 Hz), 7.39(1H, d,
J = 8 Hz), 7.51 - 7.60(2H, m), 7.84(1H, d, J = 8 Hz), 7.95(1H,
d, J = 2 Hz), 8.48(2H, s).
Example 34 Preparation of
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)methylpyrimidin-4(3H)-one
[Chemical Formula 41]
Process 1: By using 2-aminoethoxypyrimidine instead
of 2-aminomethoxypyrimidine in the Process 3 of the Example
1 and also using methyl
(Z)acetamide{[5-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate obtained from the Process 2 of the Example 30
instead of methyl
(Z)acetamide{[6-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate, the reaction and the treatment were performed in
the same manner as the Process 3 of the Example 1 to give
2-{6-{[4-butyl(5-ethoxypyrimidinyl)methyloxo-1,
6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
(yield: 70%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.92(3H, t, J = 7 Hz), 1.36 - 1.45(2H, m), 1.51(3H, t, J = 7
Hz), 1.57 - 1.65(2H, m), 2.16(3H, s), 2.75(2H, t, J = 8 Hz),
4.18(2H, s), 4.22(2H, q, J = 7 Hz), 7.41 - 7.52(3H, m), 7.64
- 7.68(1H, m), 7.77 - 7.81(2H, m), 8.52(2H, s), 8.63 - 8.65(1H,
Process 2: By using
2-{6-{[4-butyl(5-ethoxypyrimidinyl)methyloxo-1,
6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
instead of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
in the Process 4 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 4 of the Example
1 to give
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(5-ethoxypyrimidinyl)methylpyrimidin-4(3H)-one
(yield: 63%) as yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.86(3H, t, J = 7 Hz), 1.18 - 1.29(2H, m), 1.40 - 1.50(2H, m),
1.49(3H, t, J = 7 Hz), 2.09(3H, s), 2.42(2H, t, J = 8 Hz), 3.61(2H,
s), 4.20(q, 2H, J = 7 Hz), 7.00(1H, d, J = 8 Hz), 7.12(1H, dd,
J = 8, 2 Hz), 7.39(1H, d, J = 8 Hz), 7.51 - 7.61(2H, m), 7.86(1H,
d, J = 7 Hz), 7.74(1H, d, J = 2 Hz), 8.46(2H, s).
Example 35 Preparation of
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(4,6-dimethoxypyrimidinyl)methylpyrimidin-4(3H)
-one
[Chemical Formula 42]
Process 1: By using 2-amino-4,6-dimethoxypyrimidine
instead of 2-aminomethoxypyrimidine in the Process 3 of the
Example 1 and also using methyl
(Z)acetamide{[5-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate obtained from the Process 2 of the Example 30
instead of methyl
(Z)acetamide{[6-(2-cyanophenyl)pyridinyl]methyl}-2
-heptenoate, the reaction and the treatment were performed in
the same manner as the Process 3 of the Example 1 to give
2-{6-{[4-butyl(4,6-dimethoxypyrimidinyl)methylo
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitri
le (yield: 49%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.93(3H, t, J = 7 Hz), 1.38 - 1.47(2H, m), 1.56 - 1.67(2H, m),
2.24(3H, s), 2.76(2H, t, J = 8 Hz), 3.96(6H, s), 4.19(2H, s),
6.12(1H, s), 7.45 - 7.50(3H, m), 7.65 - 7.69(1H, m), 7.77 -
7.82(2H, m), 8.66(1H, d, J = 2 Hz).
Process 2: By using
2-{6-{[4-butyl(4,6-dimethoxypyrimidinyl)methylo
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitri
le instead of
2-{5-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
in the Process 4 of the Example 1, the reaction and the treatment
were performed in the same manner as the Process 4 of the Example
1 to give
-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl}bu
tyl(4,6-dimethoxypyrimidinyl)methylpyrimidin-4(3H)
-one (yield: 53%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.88(3H, t, J = 7 Hz), 1.22 - 1.32(2H, m), 1.43 - 1.50(2H, m),
2.17(3H, s), 2.42(2H, t, J = 8 Hz), 3.62(2H, s), 3.89(6H, s),
6.06(1H, s), 7.02(1H, d, J = 8 Hz), 7.14(1H, dd, J = 8, 2 Hz),
7.40(1H, d, J = 8 Hz), 7.53 - 7.62(2H, m), 7.31(1H, d, J = 8
Hz), 7.95(1H, s).
Example 36 Preparation on
3-{2-{6-{[4-butyl(5-methoxypyridinyl)methyloxo-
1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4
-oxadiazol-5(4H)-one
[Chemical Formula 43]
Process 1: By using
2-{6-{[4-butyl(5-methoxypyridinyl)methyloxo-1,6
-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
obtained from the Process 1 of the Example 31 instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{6-{[4-butyl(5-methoxypyridinyl)methyloxo-1,6
-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxybenzi
midamide (yield: 64%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.90(3H, t, J = 7 Hz), 1.34 - 1.43(2H, m), 1.54 - 1.62(2H, m),
2.16(3H, s), 2.71(2H, t, J = 8 Hz), 3.91(3H, s), 4.13(2H, s),
4.50(2H, s), 7.29 - 7.42(5H, m), 7.45 - 7.49(1H, m), 7.55 -
7.57(1H, m), 7.66 - 7.69(1H, m), 8.29(1H, d, J = 3 Hz), 8.60(1H,
d, J = 2 Hz).
Process 2: By using
2-{6-{[4-butyl(5-methoxypyridinyl)methyloxo-1,6
-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxybenzi
midamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{6-{[4-butyl(5-methoxypyridinyl)methyloxo-
1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4
-oxadiazol-5(4H)-one (yield: 70%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.92(3H, t, J = 7 Hz), 1.30 - 1.39(2H, m), 1.49 - 1.57(2H, m),
2.11(3H, s), 2.51(2H, t, J = 8 Hz), 3.62(2H, s), 3.91(3H, s),
7.15(1H, d, J = 8 Hz), 7.23(2H, d, J = 9 Hz), 7.32 - 7.39(2H,
m), 7.48 - 7.52(2H, m), 7.57 - 7.61(1H, m), 7.70(1H, d, J = 8
Hz), 7.99(1H, s), 8.18(1H, d, J = 3 Hz).
Example 37 Preparation of
3-{2-{6-{[4-butyl(5-methoxypyrimidinyl)methylox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2
,4-oxadiazol-5(4H)-one
[Chemical Formula 44]
Process 1: By using
2-{6-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
obtained from the Process 1 of the Example 33 instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{6-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxyben
zimidamide (yield: 50%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.90(3H, t, J = 7 Hz), 1.34 - 1.43(2H, m), 1.54 - 1.62(2H, m),
2.15(3H, s), 2.73(2H, t, J = 8 Hz), 3.99(3H, s), 4.13(2H, s),
4.50(2H, s), 7.28 - 7.42(3H, m), 7.45 - 7.49(1H, m), 7.53 -
7.57(1H, m), 7.66 - 7.69(1H, m), 8.53(2H, s), 8.59(1H, d, J =
2 Hz).
Process 2: By using
2-{6-{[4-butyl(5-methoxypyrimidinyl)methyloxo-1
,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxyben
zimidamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{6-{[4-butyl(5-methoxypyrimidinyl)methylox
o-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2
,4-oxadiazol-5(4H)-one (yield: 85%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.90(3H, t, J = 7 Hz), 1.27 - 1.36(2H, m), 1.45 - 1.53(2H, m),
2.11(3H, s), 2.45(2H, t, J = 8 Hz), 3.56(2H, s), 4.00(3H, s),
7.12(1H, d, J = 8Hz), 7.38(1H, d, J = 8 Hz), 7.50 - 7.60(2H,
m), 7.60 - 7.64(1H, m), 7.72(1H, d, J = 1 Hz), 7.90(1H, s),
8.51(2H, s).
Example 38 Preparation of
3-{2-{6-{[4-butyl(5-ethoxypyrimidinyl)methyloxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,
4-oxadiazol-5(4H)-one
[Chemical Formula 45]
Process 1: By using
2-{6-{[4-butyl(5-ethoxypyrimidinyl)methyloxo-1,
6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
obtained from the Process 1 of the Example 34 instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{6-{[4-butyl(5-ethoxypyrimidinyl)methyloxo-1,
6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxybenz
imidamide (yield: 52%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.90(3H, t, J = 7 Hz), 1.35 - 1.43(2H, m), 1.50(3H, t, J = 7
Hz), 1.51 - 1.62(2H, m), 2.15(3H, s), 2.72(2H, t, J = 8 Hz),
4.13(2H, s), 4.21(2H, q, J = 7 Hz), 4.51(2H, s), 7.28 - 7,49(4H,
m), 7.55 - 7.57(1H, m), 7.66 - 7.69(1H, m), 8.50(2H, s), 8.59
- 8.60(1H, m).
Process 2: By using
2-{6-{[4-butyl(5-ethoxypyrimidinyl)methyloxo-1,
6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxybenz
imidamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{6-{[4-butyl(5-ethoxypyrimidinyl)methyloxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,
4-oxadiazol-5(4H)-one (yield: 89%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz)d:
0.90(3H, t, J = 7 Hz), 1.27 - 1.36(2H, m), 1.45 - 1.52(5H, m),
2.11(3H, s), 2.49(2H, t, J = 8 Hz), 3.59(2H, s), 4.22(2H, q,
J = 7 Hz), 7.18(1H, d, J = 8 Hz), 7.38(1H, d, J = 8 Hz), 7.50
- 7.55(2H, m), 7.60 - 7.64(1H, m), 7.72(1H, d, J = 8 Hz), 7.93
- 7.97(1H, m), 8.49(2H, s).
Example 39 Preparation of
3-{2-{6-{[4-butyl(4,6-dimethoxypyrimidinyl)methyl-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one
[Chemical Formula 46]
Process 1: By using
2-{6-{[4-butyl(4,6-dimethoxypyrimidinyl)methylo
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitri
le in the Process 1 of the Example 35 instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}benzonitrile in the
Process 2 of the Example 14, the reaction and the treatment were
performed in the same manner as the Process 2 of the Example
14 to give
2-{6-{[4-butyl(4,6-dimethoxypyrimidinyl)methylo
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydrox
ybenzimidamide (yield: 47%) as pale yellow amorphous.
H-NMR(CDCl , 400 MHz) :
0.92(3H, t, J = 7 Hz), 1.36 - 1.45(2H, m), 1.56 - 1.64(2H, m),
2.23(3H, s), 2.73(2H, t, J = 8 Hz), 3.95(6H, s), 4.14(2H, s),
4.49(2H, s), 6.12(1H, s), 7.32 - 7.43(3H, m), 7.46 - 7.50(1H,
m), 7.56 - 7.58(1H, m), 7.69 - 7.71(1H, m), 8.57 - 8.61(1H, m).
Process 2: By using
2-{6-{[4-butyl(4,6-dimethoxypyrimidinyl)methylo
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydrox
ybenzimidamide instead of
2-{5-{[4-butylmethyloxo(pyridinyl)-1,6-dihydrop
yrimidinyl]methyl}pyridinyl}-N ’-hydroxybenzimidamide
in the Process 3 of the Example 14, the reaction and the treatment
were performed in the same manner as the Process 3 of the Example
14 to give
3-{2-{6-{[4-butyl(4,6-dimethoxypyrimidinyl)methyl-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one (yield: 52%) as pale yellow
amorphous.
H-NMR(CDCl , 400 MHz)d:
0.92(3H, t, J = 7 Hz), 1.31 - 1.40(2H, m), 1.50 - 1.58(2H, m),
2.18(3H, s), 2.51(2H, t, J = 8 Hz), 3.67(2H, s), 3.92(6H, s),
6.08(1H, s), 7.21(1H, d, J = 8 Hz), 7.41(1H, d, J = 8 Hz), 7.50
- 7.56(2H, m), 7.63(1H, t, J = 8 Hz), 7.74(1H, d, J = 8 Hz),
8.01(1H, d, J = 2 Hz).
Example 40 Preparation of
3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopr
opyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one
[Chemical Formula 47]
Process 1: Under argon atmosphere, tetrahydrofuran (20
mL) mixture containing
2-[5-(bromomethyl)pyridinyl]benzonitrile (1.1 g, 3.9 mmol),
methyl 3-oxohexanoate (0.68 g, 4.7 mmol),
diisopropylethylamine (1.0 g, 7.8 mmol), and lithium bromide
monohydrate (0.49 g, 4.7 mmol) was refluxed under heating for
18 hours. The reaction mixture was added water and extracted
three times with chloroform. The organic layer was combined,
washed with water and brine, dried over anhydrous sodium sulfate,
and concentrated in vacuo. The obtained residues were
subjected to silica gel column chromatography (SNAP100HP
manufactured by Biotage) (hexane/ethyl acetate; 5/1fi1/1) to
give methyl
2-{[6-(2-cyanophenyl)pyridinyl]methyl}oxohexanoate
(1.2 g, 91%) as yellow oil.
H-NMR(CDCl , 400 MHz)d:
0.87(3H, t, J = 7.4 Hz), 1.50 - 1.55(2H, m), 2.36 - 2.68(2H,
m), 3.21 - 3.27(2H, m), 3.73(3H, s), 3.84(1H, t, J = 7.6 Hz),
7.50(1H, td, J = 7.6, 1.4 Hz), 7.64 - 7.73(3H, m), 7.77 - 7.85(2H,
m), 8.61(1H, br s).
Process 2: A toluene (45 mL)-acetic acid (5 mL) mixture
containing methyl
2-{[6-(2-cyanophenyl)pyridinyl]methyl}oxohexanoate
(1.2 g, 3.6 mmol) and ammonium acetate (8.3 g, 108 mmol) was
refluxed under heating for 1 hour. After cooling to room
temperature, saturated aqueous solution of sodium hydrogen
carbonate was added and extraction was carried out with toluene.
After washing with brine, it was dried over anhydrous sodium
sulfate and concentrated in vacuo to give methyl
(Z)amino{[6-(2-cyanophenyl)pyridinyl]methyl}hex
enoate (1.15 g) as brown oil crude product. It was used for
the next process without purification.
Process 3: Isobutyryl chloride (219 mg, 2.06 mmol) and
triethylamine (208 mg, 2.06 mmol) were added to
1,2-dichloroethane (10 mL) solution of methyl
(Z)amino{[6-(2-cyanophenyl)pyridinyl]methyl}hex
enoate (575 mg) and stirred for 16 hours at 50C. The reaction
mixture was added water and extracted with chloroform. The
organic layer was combined, washed with brine, dried over
anhydrous sodium sulfate, and concentrated in vacuo. The
obtained residues were subjected to silica gel column
chromatography (SNAP50HP manufactured by Biotage)
(hexane/ethyl acetate; 5/1fi1/1) to give methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}isobutylami
dehexenoate (158 mg, 23%; two step yield) as black oil.
H-NMR(CDCl , 400 MHz)d:
0.99(3H, t, J = 7.4 Hz), 1.19 - 1.29(8H, m), 2.49 - 2.62(1H,
m), 2.88 - 2.97(2H, m), 3.71(3H, s), 3.76(2H, s), 7.51(1H, dd,
J = 7.6, 1.3 Hz), 7.59(1H, dd, J = 8.1, 2.1 Hz), 7.64 - 7.73(2H,
m), 7.77 - 7.86(2H, m), 8.60(1H, s), 11.90(1H, s).
Process 4: Under argon atmosphere, trimethylaluminum (2
mol/L hexane solution, 0.39 mL, 0.78 mmol) was added to
1,2-dichloroethane (5 mL) solution of
2-aminoethoxypyrimidine (108 mg, 0.78 mmol) at room
temperature and stirred for 70 minutes at room temperature.
1,2-dichloroethane solution (2 mL) of methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}isobutylami
dehexenoate (158 mg, 0.39 mmol) was added dropwise thereto
at room temperature and refluxed under heating for 3 hours. The
reaction mixture was added an aqueous solution of ammonium
chloride and chloroform, and filtered through a pad of celite.
The organic layer in the filtrate was separated and the aqueous
layer was extracted with chloroform. The organic layer was
combined, washed with water and brine, dried over anhydrous
sodium sulfate, and concentrated in vacuo. The obtained
residues were subjected to silica gel column chromatography
(Flash12M manufactured by Biotage) (chloroform/methanol = 40 :
1) to give
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopropy
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e (111 mg, 58%) as yellow oil.
H-NMR(CDCl , 400 MHz)d:
0.97(3H, t, J = 7.4 Hz), 1.17(6H, d, J = 6.6 Hz), 1.49(3H, t,
J = 6.9 Hz), 1.66 - 1.77(2H, m), 2.19 - 2.32(1H, m), 2.60 - 2.70(2H,
m), 3.93(2H, s), 4.10(2H, q, J = 7.1 Hz), 7.45(1H, td, J = 7.7,
1.1 Hz), 7.60 - 7.67(2H, m), 7.73 - 7.80(3H, m), 8.49(2H, s),
8.67(1H, d, J = 1.3 Hz).
Process 5: Sodium hydrogen carbonate (1.19 g, 14.1 mmol)
was added to dimethyl sulfoxide (15 mL) mixture of hydroxylamine
hydrochloride (838 mg, 12.1 mmol) and stirred for 1 hour at 40C.
The reaction mixture was added dimethyl sulfoxide (15 mL)
solution of
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopropy
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e (353 mg, 0.71 mmol) and stirred for 18 hours at 90C. The
reaction mixture was added water (80 mL) and ethyl acetate (20
mL) and stirred for 30 minutes. The precipitated solid was
collected by filtration and washed with water and ethyl acetate.
It was then dried in vacuo to give
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopropy
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxy
benzimidamide (214 mg, 57%) as a white solid.
H-NMR(CDCl , 400 MHz)d:
0.98(3H, t, J = 7.3 Hz), 1.19(6H, d, J = 6.6 Hz), 1.51(3H, t,
J = 7.0 Hz), 1.68 - 1.78(2H, m), 2.25 - 2.32(1H, m), 2.63 - 2.70(2H,
m), 3.92(2H, s), 4.22(2H, q, J = 6.9 Hz), 4.72(2H, br s), 7.40(1H,
td, J = 7.5, 1.3 Hz), 7.43(1H, d, J = 8.5 Hz), 7.49(1H, td, J
= 7.6, 1.5 Hz), 7.55(1H, dd, J = 7.6, 1.2 Hz), 7.58(1H, dd, J
= 7.8, 1.2 Hz), 7.66(1H, dd, J = 8.2, 2.3 Hz), 8.51(2H, s),
8.60(1H, d, J = 1.7 Hz).
Process 6: 1,1’-Carbonyldiimidazole (130 mg, 0.80 mmol)
and 1,8-diazabicyclo[5.4.0]undecaene (122 mg, 0.80 mmol)
were added to dichloromethane (4 mL) and tetrahydrofuran (4 mL)
mixture solution of
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopropy
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxy
benzimidamide (212 mg, 0.40 mmol) and stirred for 3 hours at
room temperature. Once the reaction is completed, 1 M
hydrochloric acid solution was added to the reaction mixture,
which was then extracted with chloroform. The organic layer
was washed with water, dried over anhydrous sodium sulfate, and
concentrated in vacuo. The obtained residues were subjected
to silica gel column chromatography (chloroform/methanol = 20 :
1) to give
3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopr
opyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one (201 mg, 91%) as white amorphous.
H-NMR(CDCl , 400 MHz)d:
1.01(3H, t, J = 7.3 Hz), 1.19(6H, d, J = 6.6 Hz), 1.51(3H, t,
J = 7.0 Hz), 1.71 - 1.82(2H, m), 2.26 - 2.32(1H, m), 2.66 - 2.73(2H,
m), 3.95(2H, s), 4.22(2H, q, J = 7.0 Hz), 7.39(1H, d, J = 8.1
Hz), 7.45(1H, d, J = 8.1 Hz), 7.51(1H, t, J = 7.6 Hz), 7.60(1H,
t, J = 7.7 Hz), 7.83(1H, dd, J = 8.1, 1.7 Hz), 7.93(1H, d, J
= 7.8 Hz), 8.51(2H, s), 8.56(1H, s).
Example 41 Preparation of
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxo
propyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one
[Chemical Formula 48]
Process 1: By using cyclopropylcarbonyl chloride instead
of isobutyryl chloride in the Process 3 of the Example 40, the
reaction and the treatment were performed in the same manner
as the Process 3 of the Example 40 to give methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}cyclopropan
ecarboxyamidehexenoate (yield: 58%).
H-NMR(CDCl , 400 MHz)d:
0.83 - 1.10(8H, m), 1.58 - 1.62(2H, m), 2.87 - 2.96(2H, m),
3.71(3H, s), 3.76(2H, s), 7.49(1H, td, J = 7.6, 1.3 Hz), 7.58(1H,
dd, J = 8.1, 2.1 Hz), 7.65 - 7.72(2H, m), 7.77 - 7.86(2H, m),
8.61(1H, s), 12.15(1H, s).
Process 2: By using methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}(cyclopropa
necarboxyamide)hexenoate instead of methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}isobutylami
dehexenoate in the Process 4 of the Example 40, the reaction
and the treatment were performed in the same manner as the
Process 4 of the Example 40 to give
2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxopro
pyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitr
ile (yield: 58%).
H-NMR(CDCl , 400 MHz)d:
0.80 - 0.87(2H, m), 0.96(3H, t, J = 7.5 Hz), 1.08 - 1.14(1H,
m), 1.21 - 1.25(2H, m), 1.51(3H, t, J = 7.0 Hz), 1.61 - 1.72(2H,
m), 2.57 - 2.61(2H, m), 3.94(2H, s), 4.22(2H, q, J = 6.9 Hz),
7.47(1H, td, J = 7.6, 1.1 Hz), 7.63 - 7.69(2H, m), 7.74 - 7.82(3H,
m), 8.54(2H, s), 8.68(1H, d, J = 1.8 Hz).
Process 3: By using
2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxopro
pyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitr
ile instead of
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopropy
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e in the Process 5 of the Example 40, the reaction and the
treatment were performed in the same manner as the Process 5
of the Example 40 to give
2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxopro
pyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydro
xybenzimidamide (yield: 67%).
H-NMR(CDCl , 400 MHz)d:
0.79 - 0.88(2H, m), 0.94(3H, t, J = 7.4 Hz), 1.06 - 1.15(1H,
m), 1.19 - 1.26(2H, m), 1.51(3H, t, J = 7.1 Hz), 1.59 - 1.71(2H,
m), 2.53 - 2.64(2H, m), 3.91(2H, s), 4.22(2H, q, J = 7.0 Hz),
4.73(2H, s), 7.40(1H, td, J = 7.3, 1.6 Hz), 7.43(1H, d, J = 7.6
Hz), 7.49(1H, td, J = 7.6, 1.5 Hz), 7.55(1H, dd, J = 7.6, 1.0
Hz), 7.58(1H, dd, J = 7.7, 0.9 Hz), 7.64(1H, dd, J = 8.2, 2.3
Hz), 8.54(2H, s), 8.59(1H, d, J = 2.2 Hz).
Process 4: By using
2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxopro
pyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydro
xybenzimidamide instead of
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopropy
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxy
benzimidamide in the Process 6 of the Example 40, the reaction
and the treatment were performed in the same manner as the
Process 6 of the Example 40 to give
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxo
propyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one (yield: 94%) as white amorphous.
H-NMR(CDCl , 400 MHz)d:
0.81 - 0.89(1H, m), 0.97(3H, t, J = 7.4 Hz), 1.06 - 1.15(1H,
m), 1.21 - 1.27(2H, m), 1.51(3H, t, J = 7.0 Hz), 1.66 - 1.70(2H,
m), 2.61(2H, t, J = 7.4 Hz), 3.94(2H, s), 4.22(2H, q, J = 6.8
Hz), 7.39(1H, d, J = 8.3 Hz), 7.45(1H, d, J = 7.6 Hz), 7.52(1H,
t, J = 7.6 Hz), 7.60(1H, t, J = 7.2 Hz), 7.81(1H, dd, J = 7.9,
1.8 Hz), 7.94(1H, d, J = 7.8 Hz), 8.54(2H, s), 8.55(1H, s).
Example 42 Preparation of
3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxope
ntyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one
[Chemical Formula 49]
Process 1: By using methyl 3-oxooctanoate instead of
methyl 3-oxohexanoate in the Process 1 of the Example 40, the
reaction and the treatment were performed in the same manner
as the Process 1 of the Example 40 to give methyl
2-{[6-(2-cyanophenyl)pyridinyl]methyl}oxooctanoate
(yield: 88%).
H-NMR(CDCl , 400 MHz) :
0.86(3H, t, J = 6.9 Hz), 1.19 - 1.32(4H, m), 1.49 - 1.55(2H,
m), 2.35 - 2.67(2H, m), 3.20 - 3.26(2H, m), 3.73(3H, s), 3.84(1H,
t, J = 7.4 Hz), 7.50(1H, td, J = 7.6, 1.3 Hz), 7.64 - 7.73(3H,
m), 7.77 - 7.85(2H, m), 8.61(1H, br s).
Process 2: By using methyl
2-{[6-(2-cyanophenyl)pyridinyl]methyl}oxooctanoate
instead of methyl
2-{[6-(2-cyanophenyl)pyridinyl]methyl}oxohexanoate in
the Process 2 of the Example 40, the reaction and the treatment
were performed in the same manner as the Process 2 of the Example
40 to give methyl
(Z)amino{[6-(2-cyanophenyl)pyridinyl]methyl}oct
enoate (yield: 82%) as brown oil crude product. It was used
for the next process without purification.
Process 3: By using methyl
(Z)amino{[6-(2-cyanophenyl)pyridinyl]methyl}oct
enoate instead of methyl
(Z)amino{[6-(2-cyanophenyl)pyridinyl]methyl}hex
enoate in the Process 3 of the Example 40, the reaction was
performed in the same manner as the Process 3 of the Example
40. According
to a post-treatment carried out in the same manner as the Process
3 of the Example 40, methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}isobutylami
deoctenoate was obtained as a crude product. It was used
for the next process without purification.
Process 4: By using methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}isobutylami
deoctenoate instead of methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}isobutylami
dehexenoate in the Process 4 of the Example 40, the reaction
and the treatment were performed in the same manner as the
Process 4 of the Example 40 to give
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopenty
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e (yield: 86%).
H-NMR(CDCl , 400 MHz)d:
0.90(3H, t, J = 6.8 Hz), 1.20(6H, d, J = 6.8 Hz), 1.32 - 1.39(4H,
m), 1.51(3H, t, J = 7.0 Hz), 1.65 - 1.75(2H, m), 2.24 - 2.33(1H,
m), 2.65 - 2.71(2H, m), 3.95(2H, s), 4.22(2H, q, J = 7.0 Hz),
7.47(1H, td, J = 7.6, 1.1 Hz), 7.63 - 7.69(2H, m), 7.76 - 7.82(3H,
m), 8.51(2H, s), 8.70(1H, d, J = 1.5 Hz).
Process 5: By using
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopenty
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e instead of
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopropy
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e in the Process 5 of the Example 40, the reaction and the
treatment were performed in the same manner as the Process 5
of the Example 40 to give
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopenty
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxy
benzimidamide (yield: 59%).
H-NMR(CDCl , 400 MHz)d:
0.90(3H, t, J = 7.0 Hz), 1.21(6H, t, J = 12.2 Hz), 1.30 - 1.39(4H,
m), 1.51(3H, t, J = 7.0 Hz), 1.65 - 1.74(2H, m), 2.25 - 2.32(1H,
m), 2.68(2H, t, J = 7.6 Hz), 3.92(2H, s), 4.22(2H, q, J = 7.0
Hz), 4.73(2H, br s), 7.40(1H, td, J = 7.6, 1.4 Hz), 7.43(1H,
d, J = 8.5 Hz), 7.49(1H, td, J = 7.5, 1.3 Hz), 7.55(1H, dd, J
= 7.6, 1.2 Hz), 7.58(1H, dd, J = 7.6, 1.2 Hz), 7.66(1H, dd, J
= 8.2, 2.3 Hz), 8.51(2H, s), 8.59(1H, d, J = 2.0 Hz).
Process 6: By using
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopenty
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxy
benzimidamide instead of
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopropy
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxy
benzimidamide in the Process 6 of the Example 40, the reaction
and the treatment were performed in the same manner as the
Process 6 of the Example 40 to give
3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxope
ntyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-
1,2,4-oxadiazol-5(4H)-one (yield: 99%).
H-NMR(CDCl , 400 MHz)d:
0.90(3H, t, J = 7.0 Hz), 1.20(6H, d, J = 6.6 Hz), 1.31 - 1.42(4H,
m), 1.51(3H, t, J = 7.1 Hz), 1.67 - 1.77(2H, m), 2.26 - 2.32(1H,
m), 2.71(2H, t, J = 7.6 Hz), 3.95(2H, s), 4.22(2H, q, J = 7.0
Hz), 7.41(1H, d, J = 8.1 Hz), 7.45(1H, dd, J = 7.8, 1.2 Hz),
7.53(1H, td, J = 7.7, 1.2 Hz), 7.61(1H, td, J = 7.6, 1.5 Hz),
7.84(1H, d, J = 8.3 Hz), 7.97(1H, d, J = 7.6 Hz), 8.51(2H, s),
8.59(1H, s).
Example 43 Preparation of
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxo
pentyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one
[Chemical Formula 50]
Process 1: By using cyclopropanecarbonyl chloride
instead of isobutyryl chloride in the Process 3 of the Example
40 and also using methyl
(Z)amino{[6-(2-cyanophenyl)pyridinyl]methyl}oct
enoate instead of methyl
(Z)amino{[6-(2-cyanophenyl)pyridinyl]methyl}hex
enoate, the reaction was performed in the same manner as the
Process 3 of the Example 40. According to a post-treatment
carried out in the same manner as the Process 3 of the Example
40, methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}cyclopropan
ecarboxamideoctenoate was obtained as a crude product. It
was used for the next process without purification.
Process 2: By using methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}cyclopropan
ecarboxamideoctenoate instead of methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}isobutylami
dehexenoate in the Process 4 of the Example 40, the reaction
and the treatment were performed in the same manner as the
Process 4 of the Example 40 to give
2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxopen
tyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitr
ile (yield: 64%).
H-NMR(CDCl , 400 MHz) :
0.81 - 0.91(5H, m), 1.07 - 1.14(1H, m), 1.21 - 1.26(2H, m), 1.29
- 1.36(4H, m), 1.49 - 1.53(3H, m), 1.60 - 1.65(2H, m), 2.57 -
2.63(2H, m), 3.94(2H, s), 4.22(2H, q, J = 7.1 Hz), 7.44 - 7.50(1H,
m), 7.63 - 7.69(2H, m), 7.73 - 7.83(3H, m), 8.54(2H, s), 8.69(1H,
Process 3: By using
2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxopen
tyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitr
ile instead of
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopropy
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e in the Process 5 of the Example 40, the reaction and the
treatment were performed in the same manner as the Process 5
of the Example 40 to give
2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxopen
tyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydro
xybenzimidamide (yield: 70%).
H-NMR(CDCl , 400 MHz)d:
0.81 - 0.86(2H, m), 0.89(3H, t, J = 6.8 Hz), 1.06 - 1.15(1H,
m), 1.19 - 1.25(2H, m), 1.28 - 1.35(4H, m), 1.51(3H, t, J = 7.1
Hz), 1.58 - 1.65(2H, m), 2.60(2H, t, J = 7.9 Hz), 3.90(2H, s),
4.22(2H, q, J = 7.0 Hz), 4.73(2H, br s), 7.40(1H, td, J = 7.5,
1.5 Hz), 7.43(1H, d, J = 7.8 Hz), 7.49(1H, td, J = 7.6, 1.5 Hz),
7.55(1H, dd, J = 7.6, 1.5 Hz), 7.58(1H, dd, J = 7.9, 1.1 Hz),
7.64(1H, dd, J = 8.1, 2.4 Hz), 8.54(2H, s), 8.58(1H, d, J = 1.7
Hz).
Process 4: By using
2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxopen
tyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydro
xybenzimidamide instead of
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopropy
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxy
benzimidamide in the Process 6 of the Example 40, the reaction
and the treatment were performed in the same manner as the
Process 6 of the Example 40 to give
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)oxo
pentyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl
}-1,2,4-oxadiazol-5(4H)-one (yield: 91%) as white amorphous.
H-NMR(CDCl , 400 MHz)d:
0.82 - 0.93(5H, m), 1.07 - 1.15(1H, m), 1.21 - 1.27(2H, m), 1.29
- 1.38(4H, m), 1.51(3H, t, J = 7.0 Hz), 1.59 - 1.70(2H, m),
2.62(2H, t, J = 7.7 Hz), 3.93(2H, s), 4.22(2H, q, J = 7.0 Hz),
7.40(1H, d, J = 7.8 Hz), 7.45(1H, d, J = 7.6 Hz), 7.53(1H, td,
J = 7.6, 1.2 Hz), 7.61(1H, td, J = 7.7, 1.4 Hz), 7.81(1H, dd,
J = 7.9, 2.1 Hz), 7.96(1H, d, J = 7.8 Hz), 8.54(2H, s), 8.57(1H,
s), 7.60(1H, t, J = 7.2 Hz), 7.81(1H, dd, J = 7.9, 1.8 Hz), 7.94(1H,
d, J = 7.8 Hz), 8.54(2H, s), 8.55(1H, s).
Example 44 Preparation of
3-{2-{5-{[1-(5-ethoxypyrimidinyl)ethylisopropyl
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1
,2,4-oxadiazol-5(4H)-one
[Chemical Formula 51]
Process 1: By using methyl 3-oxopentanoate instead of
methyl 3-oxohexanoate in the Process 1 of the Example 40, the
reaction and the treatment were performed in the same manner
as the Process 1 of the Example 40 to give
2-{[6-(2-cyanophenyl)pyridinyl]methyl}oxopentanoate
(yield: 43%).
H-NMR(CDCl , 400 MHz)d:
1.05(3H, t, J = 7 Hz), 2.44(1H, dq, J = 22, 7 Hz), 2.66(1H, dq,
J = 22, 7 Hz), 3.24(2H, dd, J = 7, 7 Hz), 3.73(3H, s), 3.84(1H,
t, J = 7 Hz), 7.50(1H, dd, J = 8, 1 Hz), 7.67 - 7.70(3H, m),
7.78(1H, d, J = 8 Hz), 7.83(1H, d, J = 8 Hz), 8.60(1H, d, J =
2 Hz).
Process 2: By using methyl
2-{[6-(2-cyanophenyl)pyridinyl]methyl}oxopentanoate
instead of methyl
2-{[6-(2-cyanophenyl)pyridinyl]methyl}oxohexanoate in
the Process 2 of the Example 40, the reaction and the treatment
were performed in the same manner as the Process 2 of the Example
40 to give methyl
(Z)amino{[6-(2-cyanophenyl)pyridinyl]methyl}pen
tenoate as a crude product. It was used for the next process
without purification.
Process 3: By using methyl
(Z)amino{[6-(2-cyanophenyl)pyridinyl]methyl}pen
tenoate instead of methyl
(Z)amino{[6-(2-cyanophenyl)pyridinyl]methyl}hex
enoate in the Process 3 of the Example 40, the reaction was
performed in the same manner as the Process 3 of the Example
40. According to a post-treatment carried out in the same
manner as the Process 3 of the Example 40, methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}isobutylami
depentenoate (two step yield: 3.3%) was obtained as a crude
product.
H-NMR(CDCl , 400 MHz) :
1.17(3H, t, J = 7 Hz), 1.25(6H, d, J = 7 Hz), 2.57(1H, sept,
J = 7 Hz), 3.0(2H, q, J = 7 Hz), 3.71(3H, s), 3.77(2H, s), 7.49(1H,
dd, J = 8, 1 Hz), 7.60(1H, dd, J = 8, 2 Hz), 7.70(2H, m), 7.79(1H,
d, J = 8 Hz), 7.83(1H, d, J = 8 Hz), 8.61(1H, d, J = 2 Hz), 11.9(1H,
Process 4: By using methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}isobutylami
depentenoate instead of methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}isobutylami
dehexenoate in the Process 4 of the Example 40, the reaction
and the treatment were performed in the same manner as the
Process 4 of the Example 40 to give
2-{5-{[1-(5-ethoxypyrimidinyl)ethylisopropyloxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
(yield: 58%).
H-NMR(CDCl , 400 MHz)d:
1.20(6H, d, J = 7 Hz), 1.25(3H, t, J = 8 Hz), 1.52(3H, t, J =
7 Hz), 2.29(1H, sept, J = 7 Hz), 2.72(2H, q, J = 8 Hz), 4.0(2H,
s), 4.21(2H, q, J = 7 Hz), 7.47(1H, dd, J = 8, 1 Hz), 7.64 -
7.68(2H, m), 7.76 - 7.78(3H, m), 8.51(2H, s), 8.70(1H, d, J =
2 Hz).
Process 5: By using
2-{5-{[1-(5-ethoxypyrimidinyl)ethylisopropyloxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitrile
instead of
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopropy
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e in the Process 5 of the Example 40, the reaction and the
treatment were performed in the same manner as the Process 5
of the Example 40 to give
2-{5-{[1-(5-ethoxypyrimidinyl)ethylisopropyloxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxyb
enzimidamide (yield: 61%).
H-NMR(CDCl , 400 MHz)d:
1.19(6H, d, J = 7 Hz), 1.22(3H, t, J = 8 Hz), 1.50(3H, t, J =
7 Hz), 2.29(1H, sept, J = 7 Hz), 2.69(2H, q, J = 8 Hz), 3.91(2H,
s), 4.20(2H, q, J = 7 Hz), 4.78(2H, br), 7.37 - 7.40(2H, m),
7.44 - 7.51(2H, m), 7.56(1H, dd, J = 8, 1 Hz), 7.63(1H, dd, J
= 8, 2 Hz), 8.50(2H, s), 8.57(1H, d, J = 2 Hz).
Process 6: By using
2-{5-{[1-(5-ethoxypyrimidinyl)ethylisopropyloxo
-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxyb
enzimidamide instead of
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopropy
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxy
benzimidamide in the Process 6 of the Example 40, the reaction
and the treatment were performed in the same manner as the
Process 6 of the Example 40 to give
3-{2-{5-{[1-(5-ethoxypyrimidinyl)ethylisopropyl
oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1
,2,4-oxadiazol-5(4H)-one (yield: 56%) as pale yellow
amorphous.
H-NMR(CDCl , 400 MHz) :
1.19(6H, d, J = 7 Hz), 1.24(3H, t, J = 8 Hz), 1.51(3H, t, J =
7 Hz), 2.28(1H, sept, J = 7 Hz), 2.69(2H, q, J = 8 Hz), 3.93(2H,
s), 4.22(2H, q, J = 7 Hz), 7.30(1H, d, J = 8 Hz), 7.37 - 7.41(2H,
m), 7.49(1H, dd, J = 8, 1 Hz), 7.67(1H, d, J = 8 Hz), 7.77(1H,
dd, J = 8, 2 Hz), 8.39(1H, d, J = 2 Hz), 8.51(2H, s).
Example 45 Preparation of
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)ethyl-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one
[Chemical Formula 52]
Process 1: By using cyclopropanecarbonyl chloride
instead of isobutyryl chloride in the Process 3 of the Example
40 and also using methyl
(Z)amino{[6-(2-cyanophenyl)pyridinyl]methyl}pen
tenoate instead of methyl
(Z)amino{[6-(2-cyanophenyl)pyridinyl]methyl}hex
enoate, the reaction was performed in the same manner as the
Process 3 of the Example 40. According to a post-treatment
carried out in the same manner as the Process 3 of the Example
40, methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}cyclopropan
ecarboxamidepentenoate (two step yield: 3.7%) was obtained
as a crude product.
H-NMR(CDCl , 400 MHz) :
0.85 - 0.90(2H, m), 1.05 - 1.08(3H, m), 1.16(3H, t, J = 8 Hz),
2.98(2H, q, J = 8 Hz), 3.72(3H, s), 3.77(2H, s), 7.49(1H, dd,
J = 8, 1 Hz), 7.59(1H, dd, J = 8, 2 Hz), 7.66 - 7.72(2H, m),
7.79(1H, d, J = 8 Hz), 7.83(1H, d, J = 8 Hz), 8.62(1H, d, J =
2 Hz), 12.1(1H, s).
Process 2: By using methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}cyclopropan
ecarboxamidepentenoate instead of methyl
(Z){[6-(2-cyanophenyl)pyridinyl]methyl}isobutylami
dehexenoate in the Process 4 of the Example 40, the reaction
and the treatment were performed in the same manner as the
Process 4 of the Example 40 to give
2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)ethylo
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitri
le (yield: 13%).
H-NMR(CDCl , 400 MHz) :
0.82 - 0.88(2H, m), 1.08 - 1.15(1H, m), 1.18(3H, t, J = 8 Hz),
1.23 - 1.28(2H, m), 1.50(3H, t, J = 7 Hz), 2.63(2H, q, J = 8
Hz), 3.95(2H, s), 4.21(2H, q, J = 7 Hz), 7.44 - 7.48(1H, m),
7.64 - 7.66(2H, m), 7.76 - 7.78(3H, m), 8.53(2H, s), 8.7(1H,
d, J = 2 Hz).
Process 3: By using
2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)ethylo
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitri
le instead of
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopropy
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}benzonitril
e in the Process 5 of the Example 40, the reaction and the
treatment were performed in the same manner as the Process 5
of the Example 40 to give
2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)ethylo
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydrox
ybenzimidamide (yield: 52%).
H-NMR(CDCl , 400 MHz)d:
0.82 - 0.88(2H, m), 1.04 - 1.12(1H, m), 1.15(3H, t, J = 8 Hz),
1.22 - 1.28(2H, m), 1.50(3H, t, J = 7 Hz), 2.62(2H, q, J = 8
Hz), 3.90(2H, s), 4.21(2H, q, J = 7 Hz), 4.76(2H, br), 7.38 -
7.40(2H, m), 7.47 - 7.51(2H, m), 7.57(1H, d, J = 8 Hz), 7.61(1H,
d, J = 8 Hz), 8.53(2H, s), 8.57(1H, s).
Process 4: By using
2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)ethylo
xo-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydrox
ybenzimidamide instead of
2-{5-{[1-(5-ethoxypyrimidinyl)isopropyloxopropy
l-1,6-dihydropyrimidinyl]methyl}pyridinyl}-N’-hydroxy
benzimidamide in the Process 6 of the Example 40, the reaction
and the treatment were performed in the same manner as the
Process 6 of the Example 40 to give
3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl)ethyl-
6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}
-1,2,4-oxadiazol-5(4H)-one (yield: 45%) as pale yellow
amorphous.
H-NMR(CDCl , 400 MHz)d:
0.82 - 0.90(2H, m), 1.08 - 1.11(1H, m), 1.18(3H, t, J = 8 Hz),
1.23 - 1.26(2H, m), 1.51(3H, t, J = 7 Hz), 2.63(2H, q, J = 8
Hz), 3.91(2H, s), 4.21(2H, q, J = 7 Hz), 7.31(1H, d, J = 8 Hz),
7.37 - 7.44(2H, m), 7.51(1H, dd, J = 8, 2 Hz), 7.73(1H, d, J
= 8 Hz), 7.76(1H, dd, J = 8, 2 Hz), 8.40(1H, d, J = 2 Hz), 8.54(2H,
Test example 1: Angiotensin II antagonistic activity in
isolated rabbit blood vessels
By using a specimen of isolated rabbit blood vessels,
antagonistic activity of the compounds of the invention against
angiotensin II type 1 receptor was calculated from a
dose-response curve of angiotensin II-induced blood vessel
contraction. Specifically, the specimen of thoracic aorta
ring of a rabbit (New Zealand White: male, 2.4 to 3.0 kg) was
suspended in a magnus bath filled with Krebs-Henseleite buffer
(composition: 118 mM NaCl, 4.7 mM KCl, 2.55 mM CaCl , 1.18 mM
MgSO , 1.18 mM KH PO , 24.88 mM NaHCO , and 11.1 mM D-glucose),
4 2 4 3
and angiotensin II (10 nM)-induced contraction was obtained in
the presence of each test compound (1 n mol/L to 10 mmol/L).
During the measurement, the inside temperature of the magnus
bath was maintained at 37C and the bath was continuously
ventilated with a sufficient amount of mixed gas (95% O and
% CO ). The angiotensin II-induced contraction was converted
into a relative value (%) that is based on the angiotensin II
(0.1 mM)-induced contraction in the absence of the test
compound.
As a result, it was confirmed that the compounds described
in the Examples have an angiotensin II antagonistic activity
at the concentration of 0.1 mM. The inhibitory rate of
angiotensin II (10 nM) at the test compound concentration of
0.1 mM is shown in the Table 1. As shown in the Table 1, it
was confirmed that the compounds of the invention have a potent
angiotensin II antagonistic activity, which is the same as
telmisartan. Meanwhile, under the same condition, rate of
inhibiting the angiotensin II activity by telmisartan was
85.3%.
[Table 1]
Test example 2: PPARg activation effect
The agonistic activity of the compounds of the invention
on PPARg was measured based on the transfection assay using COS7
cells (DS Pharma Biomedical Co., Ltd., Osaka, Japan), which are
the cell line derived from the kidney of the African green monkey.
COS7 cells were cultured under 5% CO concentration, and DMEM
medium containing 10% fetal bovine serum, glutamic acid, and
antibiotics was used as a medium.
As an expression vector, a chimera in which DNA binding
domain of Gal4, which is a yeast transcription factor, and
ligand binding domain of human PPARg2 are fused, i.e., a fused
product between the amino acids 1 to 147 of Gal4 transcription
factor and the amino acids 182 to 505 of human PPARg2, was used.
Furthermore, as a reporter vector, a firefly luciferase
containing five copies of Gal4 recognition sequence in the
promoter region was used. Plasmid transfection to the cells
was performed according to a method which uses jetPEI (trade
name, manufactured by Funakoshi Co., Ltd., Tokyo, Japan).
Furthermore, b-galactosidase expression vector was employed as
an internal standard.
After the transfection into the cells, the medium was
replaced with a DMEM medium (containing 1% serum) added with
the test compound, and the cells were further cultured for 16
hours. After that, the luciferase activity and
b-galactosidase activity in the cell lysis solution were
measured.
Meanwhile, for the present test, dimethylsulfoxide
(DMSO) was used for dissolution and dilution of the test
compounds, and during the cell treatment, the DMSO
concentration in DMEM medium (containing 1% serum) was adjusted
to 0.1%. As a positive compound, rosiglitazone (trade name,
manufactured by ALEXIS Corporation, Switzerland) was used.
The percentage (%) of the luciferase activity of the each test
compound (1 to 30 mmol/L) was calculated when the luciferase
activity of rosiglitazone (3 to 10 mmol/L) is 100% and the
luciferase activity in the absence of the test compound is 0%.
The 50% effective concentration of the test compound (EC , 50%
effect concentration) was calculated by using SAS Preclinical
Package Ver 5.0 (trade name, manufactured by SAS institute Japan
Co., Tokyo, Japan), which is a statistical analysis program.
As a result, it was confirmed that the compounds described
in the Examples have a PPARg activation effect at the
concentration of 30 mM. The EC results are given in the Table
2. As shown in the Table 2, it was confirmed that the compounds
of the invention have a potent PPARg activation effect. In
particular, several compounds in the Table 2 exhibited EC value
of less than 1 mM, indicating stronger PPARg activation effect
than telmisartan. Maximum activity strength of several
compounds relative to the maximum activity of rosiglitazone is
given in the Table 3. As shown in Table 3, it was confirmed
that the compounds of the invention have an activity that is
to 69% of the maximum activity of rosiglitazone and they have
a sufficient agonist activity on PPARg. In particular, the
maximum activity of the compounds of the Examples 40, 41, 42,
and 43 was 42 to 69%, which is the same or greater than that
of telmisartan. Under the same condition, the PPARg activation
effect of telmisartan, i.e., EC , was 1 to 5 mM, and the maximum
activity strength of telmisartan relative to the maximum
activity of rosiglitazone (i.e., % MAX vs. rosiglitazone) was
to 50%.
[Table 2]
[Table 3]
From the results obtained above, it was confirmed that
the compounds of the present invention have both a potent
angiotensin II receptor antagonistic activity and a PPARg
activation effect. Thus, it was found that the compounds of
the present invention and pharmaceutically acceptable salts
thereof are useful as an effective component of a prophylactic
and/or therapeutic agent for disorders involved with
angiotensin II and PPARg, for example, hypertension, heart
diseases, angina pectoris, cerebral vascular disorders,
cerebral circulatory disorders, ischemic peripheral
circulatory disorders, renal diseases, arteriosclerosis,
inflammatory diseases, type 2 diabetes, diabetic complications,
insulin resistance syndrome, syndrome X, metabolic syndrome,
and hyperinsulinemia.
INDUSTRIAL APPLICABILITY
The phenylpyridine derivatives represented by the
formula (I) of the invention or salts thereof, or solvates
thereof are a novel compound which have both an angiotensin II
receptor antagonistic activity and a PPARg activation effect,
and the present invention provides the novel compounds and a
pharmaceutical composition containing the same. The compounds
of the invention are used as an effective component of a novel
pharmaceutical product, i.e., a prophylactic and/or
therapeutic agent for disorders involved with angiotensin II
and PPARg, for example, hypertension, heart diseases, angina
pectoris, cerebral vascular disorders, cerebral circulatory
disorders, ischemic peripheral circulatory disorders, renal
diseases, arteriosclerosis, inflammatory diseases, type 2
diabetes, diabetic complications, insulin resistance syndrome,
syndrome X, metabolic syndrome, and hyperinsulinemia, and
therefore have an industrial applicability.
Claims (21)
1. A compound represented by the formula (I) below or a salt thereof, or a solvate thereof: wherein, in the formula (I), ring A represents the following formula (II) or formula (III): wherein, ring B represents the following formula (IV) or formula (V): wherein, X represents C-R or a nitrogen atom, wherein, R represents a C alkyl group, wherein, R represents a C alkyl group or a C 1-6 3-8 cycloalkyl group, and 3 4 5 wherein, R , R , and R each independently represent a hydrogen atom, a halogen atom, a C alkyl group, a halo C 1-6 1-6 alkyl group, or a C alkoxy group which is optionally substituted with one or more of substituent groups selected from the group consisting of a phenyl group, a hydroxyl group, a C alkylthio group, a C alkylsulfonyl group, a carboxyl group, a carbamoyl group, a mono C alkylcarbamoyl group, and a di C alkylcarbamoyl group, and the broken line in the formula indicates the binding site for a neighboring group.
2. The compound according to Claim 1 or a salt thereof, or a solvate thereof, wherein the ring A in the formula (I) is the formula (II) and the ring B is the formula (V).
3. The compound according to Claim 1 or 2 or a salt thereof, or a solvate thereof, wherein X in the formula (I) is a nitrogen atom and R and R are each independently a hydrogen atom, a halogen atom, a C alkyl group, a halo C alkyl group, or a 1-6 1-6 C alkoxy group.
4. The compound according to Claim 3 or a salt thereof, or a solvate thereof, wherein R and R in the formula (I) are each independently a hydrogen atom or a C alkoxy group.
5. A compound selected from the group consisting of: 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-methoxypyrimidinyl)methylpyrimidin-4(3 H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-ethoxypyrimidinyl)methylpyrimidin-4(3H )-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylethyl(5-methoxypyrimidinyl)pyrimidin-4(3H )-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-ethoxypyrimidinyl)ethylpyrimidin-4(3H) -one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylisopropyl(5-methoxypyrimidinyl)pyrimidin- 4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-ethoxypyrimidinyl)isopropylpyrimidin-4 (3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylcyclopropyl(5-methoxypyrimidinyl)pyrimidi n-4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylcyclobutyl(5-methoxypyrimidinyl)pyrimidin -4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylcyclobutyl(5-ethoxypyrimidinyl)pyrimidin- 4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylcyclopentyl(5-ethoxypyrimidinyl)pyrimidin -4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylcyclohexyl(5-ethoxypyrimidinyl)pyrimidin- 4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylmethyl{5-[2-(methylthio)ethoxy]pyrimidiny l}pyrimidin-4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylmethyl{5-[2-(methylsulfonyl)ethoxy]pyrimidin yl}pyrimidin-4(3H)-one, 3-{2-{5-{[4-butylmethyloxo(pyridinyl)-1,6 -dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4-ox adiazol-5(4H)-one, 3-{2-{5-{[4-butylmethyl(4-methylpyridinyl)-6 -oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}- 1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butyl(5-methoxypyrimidinyl)methy loxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}pheny l}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)methyl oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl }-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylethyl(5-methoxypyrimidinyl) oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl }-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)ethyl- 6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl} -1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylisopropyl(5-methoxypyrimidin-2 -yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}ph enyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)isopro pyloxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phe nyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclopropyl(5-methoxypyrimidin yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl} phenyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclopropyl(5-ethoxypyrimidin- 2-yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}p henyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclobutyl(5-methoxypyrimidin- 2-yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}p henyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclobutyl(5-ethoxypyrimidin-2 -yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}ph enyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclopentyl(5-ethoxypyrimidin- 2-yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}p henyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclohexyl(5-ethoxypyrimidin-2 -yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}ph enyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{{4-butylmethyl{5-[2-(methylthio)ethoxy ]pyrimidinyl}oxo-1,6-dihydropyrimidinyl}methyl}pyr idinyl}phenyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{{4-butylmethyl{5-[2-(methylsulfonyl)et hoxy]pyrimidinyl}oxo-1,6-dihydropyrimidinyl}methyl }pyridinyl}phenyl}-1,2,4-oxadiazol-5(4H)-one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylmethyl(pyridinyl)pyrimidin-4(3H)-one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-methoxypyridinyl)methylpyrimidin-4(3H) -one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl[3-chloro(trifluoromethyl)pyridinyl]me thylpyrimidin-4(3H)-one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-methoxypyrimidinyl)methylpyrimidin-4(3 H)-one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-ethoxypyrimidinyl)methylpyrimidin-4(3H )-one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(4,6-dimethoxypyrimidinyl)methylpyrimidin -4(3H)-one, 3-{2-{6-{[4-butyl(5-methoxypyridinyl)methyl- 6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl} -1,2,4-oxadiazol-5(4H)-one, 3-{2-{6-{[4-butyl(5-methoxypyrimidinyl)methy loxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}pheny l}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{6-{[4-butyl(5-ethoxypyrimidinyl)methyl oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl }-1,2,4-oxadiazol-5(4H)-one, 3-{2-{6-{[4-butyl(4,6-dimethoxypyrimidinyl)m ethyloxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}p henyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropylox opropyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}ph enyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl) oxopropyl-1,6-dihydropyrimidinyl]methyl}pyridinyl} phenyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropylox opentyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}ph enyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl) oxopentyl-1,6-dihydropyrimidinyl]methyl}pyridinyl} phenyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[1-(5-ethoxypyrimidinyl)ethylisopro pyloxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phe nyl}-1,2,4-oxadiazol-5(4H)-one, and 3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl) ethyloxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}p henyl}-1,2,4-oxadiazol-5(4H)-one, or a salt thereof, or a solvate thereof.
6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
7. Use of a compound represented by the following formula (I) or a salt thereof, or a solvate thereof in the manufacture of an agent for the prevention and/or treatment of a circulatory disease: [Chemical Formula 1] [in the formula, ring A represents the following formula (II) or formula (III): [Chemical Formula 2] ring B represents the following formula (IV) or formula (V): [Chemical Formula 3] X represents C-R or a nitrogen atom, R represents a C alkyl group, R represents a C alkyl group or a C cycloalkyl group, 1-6 3-8 3 4 5 R , R , and R each independently represent a hydrogen atom, a halogen atom, a C alkyl group, a halo C alkyl group, or 1-6 1-6 a C alkoxy group which is optionally substituted with one or more substituent groups selected from the group consisting of a phenyl group, a hydroxyl group, a C alkylthio group, a C 1-6 1-6 alkylsulfonyl group, a carboxyl group, a carbamoyl group, a mono C alkylcarbamoyl group, and a di C alkylcarbamoyl group, 1-6 1-6 and the broken line in the formula indicates the binding site for a neighboring group].
8. The use of the compound according to Claim 7 or a salt thereof, or a solvate thereof, wherein R in the formula (I) is a C alkyl group or a C alkyl group. 1-3 5-6
9. The use of the compound according to Claim 7 or 8 or a salt thereof, or a solvate thereof, wherein the ring A in the formula (I) is the formula (II) and the ring B is the formula (V).
10. The use of the compound according to any one of Claims 7 to 9 or a salt thereof, or a solvate thereof, wherein X in the formula (I) is a nitrogen atom and R and R are each independently a hydrogen atom, a halogen atom, a C alkyl group, a halo C alkyl group, or a C alkoxy group. 1-6 1-6
11. The use of the compound according to Claim 10 or a salt thereof, or a solvate thereof, wherein R and R in the formula (I) are each independently a hydrogen atom or a C alkoxy group.
12. Use of a compound or a salt thereof, or a solvate thereof in the manufacture of an agent for the prevention and/or treatment of a circulatory disease, wherein the compound is selected from the group consisting of: 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-methoxypyrimidinyl)methylpyrimidin-4(3 H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-ethoxypyrimidinyl)methylpyrimidin-4(3H )-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylethyl(5-methoxypyrimidinyl)pyrimidin-4(3H )-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-ethoxypyrimidinyl)ethylpyrimidin-4(3H) -one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylisopropyl(5-methoxypyrimidinyl)pyrimidin- 4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-ethoxypyrimidinyl)isopropylpyrimidin-4 (3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylcyclopropyl(5-methoxypyrimidinyl)pyrimidi n-4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylcyclobutyl(5-methoxypyrimidinyl)pyrimidin -4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylcyclobutyl(5-ethoxypyrimidinyl)pyrimidin- 4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylcyclopentyl(5-ethoxypyrimidinyl)pyrimidin -4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylcyclohexyl(5-ethoxypyrimidinyl)pyrimidin- 4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylmethyl{5-[2-(methylthio)ethoxy]pyrimidiny l}pyrimidin-4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylmethyl{5-[2-(methylsulfonyl)ethoxy]pyrimidin yl}pyrimidin-4(3H)-one, 3-{2-{5-{[4-butylmethyloxo(pyridinyl)-1,6 -dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4-ox adiazol-5(4H)-one, 3-{2-{5-{[4-butylmethyl(4-methylpyridinyl)-6 -oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}- 1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butyl(5-methoxypyrimidinyl)methy loxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}pheny l}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)methyl oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl }-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylethyl(5-methoxypyrimidinyl) oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl }-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)ethyl- 6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl} -1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylisopropyl(5-methoxypyrimidin-2 -yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}ph enyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)isopro pyloxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phe nyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclopropyl(5-methoxypyrimidin yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl} phenyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclopropyl(5-ethoxypyrimidin- 2-yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}p henyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclobutyl(5-methoxypyrimidin- 2-yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}p henyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclobutyl(5-ethoxypyrimidin-2 -yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}ph enyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclopentyl(5-ethoxypyrimidin- 2-yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}p henyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclohexyl(5-ethoxypyrimidin-2 -yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}ph enyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{{4-butylmethyl{5-[2-(methylthio)ethoxy ]pyrimidinyl}oxo-1,6-dihydropyrimidinyl}methyl}pyr idinyl}phenyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{{4-butylmethyl{5-[2-(methylsulfonyl)et hoxy]pyrimidinyl}oxo-1,6-dihydropyrimidinyl}methyl }pyridinyl}phenyl}-1,2,4-oxadiazol-5(4H)-one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylmethyl(pyridinyl)pyrimidin-4(3H)-one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-methoxypyridinyl)methylpyrimidin-4(3H) -one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl[3-chloro(trifluoromethyl)pyridinyl]me thylpyrimidin-4(3H)-one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-methoxypyrimidinyl)methylpyrimidin-4(3 H)-one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-ethoxypyrimidinyl)methylpyrimidin-4(3H )-one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(4,6-dimethoxypyrimidinyl)methylpyrimidin -4(3H)-one, 3-{2-{6-{[4-butyl(5-methoxypyridinyl)methyl- 6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl} -1,2,4-oxadiazol-5(4H)-one, 3-{2-{6-{[4-butyl(5-methoxypyrimidinyl)methy loxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}pheny l}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{6-{[4-butyl(5-ethoxypyrimidinyl)methyl oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl }-1,2,4-oxadiazol-5(4H)-one, 3-{2-{6-{[4-butyl(4,6-dimethoxypyrimidinyl)m ethyloxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}p henyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropylox opropyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}ph enyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl) oxopropyl-1,6-dihydropyrimidinyl]methyl}pyridinyl} phenyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropylox opentyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}ph enyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl) oxopentyl-1,6-dihydropyrimidinyl]methyl}pyridinyl} phenyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[1-(5-ethoxypyrimidinyl)ethylisopro pyloxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phe nyl}-1,2,4-oxadiazol-5(4H)-one, and 3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl) ethyloxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}p henyl}-1,2,4-oxadiazol-5(4H)-one.
13. The use of the compound according to any one of Claims 7 to 12 or a salt thereof, or a solvate thereof, wherein the circulatory disease is hypertension, heart disease, angina pectoris, cerebral vascular disorder, cerebral circulatory disorder, ischemic peripheral circulatory disorder, kidney disease, or arteriosclerosis.
14. Use of a compound represented by the following formula (I) or a salt thereof, or a solvate thereof in the manufacture of an agent for the prevention and/or treatment of a metabolic disease: [Chemical Formula 4] [in the formula, ring A represents the following formula (II) or formula (III): [Chemical Formula 5] ring B represents the following formula (IV) or formula (V): [Chemical Formula 6] X represents C-R or a nitrogen atom, R represents a C alkyl group, R represents a C alkyl group or a C cycloalkyl group, 1-6 3-8 3 4 5 R , R , and R each independently represent a hydrogen atom, a halogen atom, a C alkyl group, a halo C alkyl group, or 1-6 1-6 a C alkoxy group which is optionally substituted with one or more substituent groups which is optionally substituted with one or more of substituent groups selected from the group consisting of a phenyl group, a hydroxyl group, a C alkylthio group, a C alkylsulfonyl group, a carboxyl group, a carbamoyl group, a mono C alkylcarbamoyl group, and a di C 1-6 1-6 alkylcarbamoyl group, and the broken line in the formula indicates the binding site for a neighboring group].
15. The use of the compound according to Claim 14 or a salt thereof, or a solvate thereof, wherein R in the formula (I) is a C alkyl group or a C alkyl group. 1-3 5-6
16. The use of the compound according to Claim 14 or 15 or a salt thereof, or a solvate thereof, wherein the ring A in the formula (I) is the formula (II) and the ring B is the formula (V).
17. The use of the compound according to any one of Claims 14 to 16 or a salt thereof, or a solvate thereof, wherein X in the formula (I) is a nitrogen atom and R and R are each independently a hydrogen atom, a halogen atom, a C alkyl group, a halo C alkyl group, or a C alkoxy group. 1-6 1-6
18. The use of the compound according to Claim 17 or a salt thereof, or a solvate thereof, wherein R and R in the formula (I) are each independently a hydrogen atom or a C alkoxy group.
19. Use of the compound or a salt thereof, or a solvate thereof in the manufacture of an agent for the prevention and/or treatment of a metabolic disease, wherein the compound is selected from the group consisting of: 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-methoxypyrimidinyl)methylpyrimidin-4(3 H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-ethoxypyrimidinyl)methylpyrimidin-4(3H )-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylethyl(5-methoxypyrimidinyl)pyrimidin-4(3H )-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-ethoxypyrimidinyl)ethylpyrimidin-4(3H) -one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylisopropyl(5-methoxypyrimidinyl)pyrimidin- 4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-ethoxypyrimidinyl)isopropylpyrimidin-4 (3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylcyclopropyl(5-methoxypyrimidinyl)pyrimidi n-4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylcyclobutyl(5-methoxypyrimidinyl)pyrimidin -4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylcyclobutyl(5-ethoxypyrimidinyl)pyrimidin- 4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylcyclopentyl(5-ethoxypyrimidinyl)pyrimidin -4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylcyclohexyl(5-ethoxypyrimidinyl)pyrimidin- 4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylmethyl{5-[2-(methylthio)ethoxy]pyrimidiny l}pyrimidin-4(3H)-one, 5-{{6-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylmethyl{5-[2-(methylsulfonyl)ethoxy]pyrimidin yl}pyrimidin-4(3H)-one, 3-{2-{5-{[4-butylmethyloxo(pyridinyl)-1,6 -dihydropyrimidinyl]methyl}pyridinyl}phenyl}-1,2,4-ox adiazol-5(4H)-one, 3-{2-{5-{[4-butylmethyl(4-methylpyridinyl)-6 -oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl}- 1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butyl(5-methoxypyrimidinyl)methy loxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}pheny l}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)methyl oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl }-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylethyl(5-methoxypyrimidinyl) oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl }-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)ethyl- 6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl} -1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylisopropyl(5-methoxypyrimidin-2 -yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}ph enyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butyl(5-ethoxypyrimidinyl)isopro pyloxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phe nyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclopropyl(5-methoxypyrimidin yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl} phenyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclopropyl(5-ethoxypyrimidin- 2-yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}p henyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclobutyl(5-methoxypyrimidin- 2-yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}p henyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclobutyl(5-ethoxypyrimidin-2 -yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}ph enyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclopentyl(5-ethoxypyrimidin- 2-yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}p henyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[4-butylcyclohexyl(5-ethoxypyrimidin-2 -yl)oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}ph enyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{{4-butylmethyl{5-[2-(methylthio)ethoxy ]pyrimidinyl}oxo-1,6-dihydropyrimidinyl}methyl}pyr idinyl}phenyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{{4-butylmethyl{5-[2-(methylsulfonyl)et hoxy]pyrimidinyl}oxo-1,6-dihydropyrimidinyl}methyl }pyridinyl}phenyl}-1,2,4-oxadiazol-5(4H)-one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butylmethyl(pyridinyl)pyrimidin-4(3H)-one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-methoxypyridinyl)methylpyrimidin-4(3H) -one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl[3-chloro(trifluoromethyl)pyridinyl]me thylpyrimidin-4(3H)-one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-methoxypyrimidinyl)methylpyrimidin-4(3 H)-one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(5-ethoxypyrimidinyl)methylpyrimidin-4(3H )-one, 5-{{5-[2-(1H-tetrazolyl)phenyl]pyridinyl}methyl }butyl(4,6-dimethoxypyrimidinyl)methylpyrimidin -4(3H)-one, 3-{2-{6-{[4-butyl(5-methoxypyridinyl)methyl- 6-oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl} -1,2,4-oxadiazol-5(4H)-one, 3-{2-{6-{[4-butyl(5-methoxypyrimidinyl)methy loxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}pheny l}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{6-{[4-butyl(5-ethoxypyrimidinyl)methyl oxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phenyl }-1,2,4-oxadiazol-5(4H)-one, 3-{2-{6-{[4-butyl(4,6-dimethoxypyrimidinyl)m ethyloxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}p henyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropylox opropyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}ph enyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl) oxopropyl-1,6-dihydropyrimidinyl]methyl}pyridinyl} phenyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[1-(5-ethoxypyrimidinyl)isopropylox opentyl-1,6-dihydropyrimidinyl]methyl}pyridinyl}ph enyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl) oxopentyl-1,6-dihydropyrimidinyl]methyl}pyridinyl} phenyl}-1,2,4-oxadiazol-5(4H)-one, 3-{2-{5-{[1-(5-ethoxypyrimidinyl)ethylisopro pyloxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}phe nyl}-1,2,4-oxadiazol-5(4H)-one, and 3-{2-{5-{[2-cyclopropyl(5-ethoxypyrimidinyl) ethyloxo-1,6-dihydropyrimidinyl]methyl}pyridinyl}p henyl}-1,2,4-oxadiazol-5(4H)-one.
20. The use of the compound according to any one of Claims 14 to 19 or a salt thereof, or a solvate thereof, wherein the metabolic disease is type 2 diabetes mellitus, diabetic complication, insulin resistant syndrome, metabolic syndrome, or hyperinsulinemia.
21. The use of the compound according to Claim 20 or a salt thereof, or a solvate thereof, wherein diabetic complication is diabetic retinopathy, diabetic neuropathy, or diabetic nephropathy.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2011055691 | 2011-03-14 | ||
JP2011-055691 | 2011-03-14 | ||
PCT/JP2012/001709 WO2012124311A1 (en) | 2011-03-14 | 2012-03-13 | Novel phenylpyridine derivative and drug containing same |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ616158A NZ616158A (en) | 2015-07-31 |
NZ616158B2 true NZ616158B2 (en) | 2015-11-03 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9315493B2 (en) | Phenylpyridine derivative and drug containing same | |
US20120122906A1 (en) | Novel sulfonamide derivative and pharmaceutical product containing same | |
US20120225896A1 (en) | Novel 2-pyridone derivative and pharmaceutical product containing same | |
EP2484675B1 (en) | Novel phenylpyridine derivative and medicinal agent comprising same | |
NZ616158B2 (en) | Novel phenylpyridine derivative and drug containing same | |
JP2010180183A (en) | New compound having pyrimidin-4(3h)-one structure and medicine containing the same | |
US20120322819A1 (en) | Compound containing a novel 4-alkoxypyrimidine structure and medicine containing same |