JP4728954B2 - Pde9a阻害剤としての6−アリールアミノ−5−シアノ−4−ピリミジノン化合物 - Google Patents
Pde9a阻害剤としての6−アリールアミノ−5−シアノ−4−ピリミジノン化合物 Download PDFInfo
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- JP4728954B2 JP4728954B2 JP2006515952A JP2006515952A JP4728954B2 JP 4728954 B2 JP4728954 B2 JP 4728954B2 JP 2006515952 A JP2006515952 A JP 2006515952A JP 2006515952 A JP2006515952 A JP 2006515952A JP 4728954 B2 JP4728954 B2 JP 4728954B2
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- 229940122229 Phosphodiesterase 9A inhibitor Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 63
- 238000000034 method Methods 0.000 claims description 52
- -1 C 1 -C 3 - alkyl Chemical group 0.000 claims description 47
- 238000002360 preparation method Methods 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 25
- 239000012453 solvate Substances 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 16
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 239000011737 fluorine Chemical group 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 2
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 1
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 36
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 34
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
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- 101001117259 Homo sapiens High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A Proteins 0.000 description 20
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 18
- 235000019253 formic acid Nutrition 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 102100024227 High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A Human genes 0.000 description 17
- 229910000027 potassium carbonate Inorganic materials 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
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- SJDBEROAEMAOJW-UHFFFAOYSA-N methyl 2-cyano-3,3-bis(methylsulfanyl)prop-2-enoate Chemical compound COC(=O)C(C#N)=C(SC)SC SJDBEROAEMAOJW-UHFFFAOYSA-N 0.000 description 13
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000000825 ultraviolet detection Methods 0.000 description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000013016 learning Effects 0.000 description 9
- SDICDZPPQWKMDS-UHFFFAOYSA-N 2-cyclopentylethanimidamide;hydrochloride Chemical compound Cl.NC(=N)CC1CCCC1 SDICDZPPQWKMDS-UHFFFAOYSA-N 0.000 description 8
- 206010012289 Dementia Diseases 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 description 8
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 230000015654 memory Effects 0.000 description 7
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- 101001098858 Homo sapiens cGMP-dependent 3',5'-cyclic phosphodiesterase Proteins 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 102100038953 cGMP-dependent 3',5'-cyclic phosphodiesterase Human genes 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
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- 239000000126 substance Substances 0.000 description 6
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- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 5
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 5
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 description 5
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 5
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 4
- DUNQXKUMEBBVTL-UHFFFAOYSA-N 2-cyclopentylethanimidamide Chemical compound NC(=N)CC1CCCC1 DUNQXKUMEBBVTL-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 102100024317 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C Human genes 0.000 description 4
- 101001117094 Homo sapiens Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C Proteins 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- WPYWIEUVLKTQED-UHFFFAOYSA-N methyl 2-cyano-3-(2-methylanilino)-3-methylsulfanylprop-2-enoate Chemical compound COC(=O)C(C#N)=C(SC)NC1=CC=CC=C1C WPYWIEUVLKTQED-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
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- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- WCQOBLXWLRDEQA-UHFFFAOYSA-N ethanimidamide;hydrochloride Chemical compound Cl.CC(N)=N WCQOBLXWLRDEQA-UHFFFAOYSA-N 0.000 description 1
- DBSADESEDBCPFO-UHFFFAOYSA-N ethyl 2-cyclopentylacetate Chemical compound CCOC(=O)CC1CCCC1 DBSADESEDBCPFO-UHFFFAOYSA-N 0.000 description 1
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 210000001652 frontal lobe Anatomy 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000003370 grooming effect Effects 0.000 description 1
- 235000013928 guanylic acid Nutrition 0.000 description 1
- 125000004871 hexylcarbonyl group Chemical group C(CCCCC)C(=O)* 0.000 description 1
- 208000024697 human cytomegalovirus infection Diseases 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000006328 iso-butylcarbonyl group Chemical group [H]C([H])([H])C([H])(C(*)=O)C([H])([H])[H] 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- NCBZRJODKRCREW-UHFFFAOYSA-N m-anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000007087 memory ability Effects 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- XOXLCQHAZWDTFX-UHFFFAOYSA-N methyl 2-cyano-3-(4-fluoroanilino)-3-methylsulfanylprop-2-enoate Chemical compound COC(=O)C(C#N)=C(SC)NC1=CC=C(F)C=C1 XOXLCQHAZWDTFX-UHFFFAOYSA-N 0.000 description 1
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 208000027061 mild cognitive impairment Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 125000001298 n-hexoxy 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
- 125000006137 n-hexyl sulfonyl group Chemical group 0.000 description 1
- 125000004718 n-hexylthio group Chemical group C(CCCCC)S* 0.000 description 1
- 125000006129 n-pentyl sulfonyl group Chemical group 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006124 n-propyl sulfonyl group Chemical group 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 230000036403 neuro physiology Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 210000000956 olfactory bulb Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004675 pentylcarbonyl group Chemical group C(CCCC)C(=O)* 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000004673 propylcarbonyl group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
- 229950005741 rolipram Drugs 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000000542 thalamic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 208000018726 traumatic encephalopathy Diseases 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 229960000744 vinpocetine Drugs 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- 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
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
-
- 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
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
WO99/41253は、抗ウイルス効果を有し、特にヒトサイトメガロウイルス感染の処置に用いることができるピリミジン誘導体を記載している。
EP130735は、強心剤として著名なアミノピリミジン誘導体を開示している。
Aは、C1−C8−アルキル、C3−C8−シクロアルキル、テトラヒドロフリルまたはテトラヒドロピラニルであり、C1−C6−アルキル、C1−C6−アルコキシ、ヒドロキシカルボニル、シアノ、トリフルオロメチル、トリフルオロメトキシ、アミノ、ヒドロキシ、C1−C6−アルキルアミノ、ハロゲン、C1−C6−アルキルアミノカルボニル、C1−C6−アルコキシカルボニル、C1−C6−アルキルカルボニル、C1−C6−アルキルスルホニルおよびC1−C6−アルキルチオの群から相互に独立して選択される3個までの基により置換されていることもあり[ここで、C1−C6−アルキル、C1−C6−アルコキシ、C1−C6−アルキルアミノ、C1−C6−アルキルアミノカルボニル、C1−C6−アルコキシカルボニル、C1−C6−アルキルカルボニル、C1−C6−アルキルスルホニルおよびC1−C6−アルキルチオは、ヒドロキシ、シアノ、ハロゲン、ヒドロキシカルボニルおよび式−NR3R4の基(式中、R3およびR4は、相互に独立して水素またはC1−C6−アルキルであるか、または、R3およびR4は、それらが結合している窒素原子と一緒になって、5員ないし8員の複素環である)の群から選択される1個またはそれ以上の基により置換されていることもある]、
Bは、フェニルまたはヘテロアリールであり、C1−C6−アルキル、C1−C6−アルコキシ、ヒドロキシカルボニル、シアノ、トリフルオロメチル、トリフルオロメトキシ、アミノ、ニトロ、ヒドロキシ、C1−C6−アルキルアミノ、ハロゲン、C1−C6−アルキルアミノカルボニル、C1−C6−アルコキシカルボニル、C1−C6−アルキルカルボニル、C1−C6−アルキルスルホニルおよびC1−C6−アルキルチオの群から相互に独立して選択される3個までの基により置換されていることもある[ここで、C1−C6−アルキル、C1−C6−アルコキシ、C1−C6−アルキルアミノ、C1−C6−アルキルアミノカルボニル、C1−C6−アルコキシカルボニル、C1−C6−アルキルカルボニル、C1−C6−アルキルスルホニルおよびC1−C6−アルキルチオは、ヒドロキシ、シアノ、ハロゲン、ヒドロキシカルボニルおよび式−NR3R4の基(R3およびR4は、上述の意味を有する)の群から選択される基により置換されていることもある]、
の化合物およびそれらの塩、溶媒和物および/または塩の溶媒和物に関する。
化合物(I)の生理的に許容し得る塩には、無機酸、カルボン酸およびスルホン酸の酸付加塩、例えば、塩酸、臭化水素酸、硫酸、リン酸、メタンスルホン酸、エタンスルホン酸、トルエンスルホン酸、ベンゼンスルホン酸、ナフタレンジスルホン酸、酢酸、プロピオン酸、乳酸、酒石酸、リンゴ酸、クエン酸、フマル酸、マレイン酸および安息香酸の塩が含まれる。
C 1 −C 8 −アルキル、C 1 −C 6 −アルキル、C 1 −C 5 −アルキルおよびC 1 −C 4 −アルキルは、1個ないし8個、好ましくは1個ないし6個、特に好ましくは1個ないし5個および1個ないし4個の炭素原子を有する直鎖または分枝鎖のアルキル基である。好ましい例には、メチル、エチル、n−プロピル、イソプロピル、2−ブチル、2−ペンチルおよび3−ペンチルが含まれる。
Aが、C1−C5−アルキルまたはC3−C6−シクロアルキルであり、C1−C4−アルキル、C1−C4−アルコキシ、ヒドロキシカルボニル、シアノ、アミノ、ヒドロキシ、C1−C4−アルキルアミノ、フッ素、塩素、臭素、C1−C4−アルコキシカルボニル、C1−C6−アルキルカルボニル、C1−C4−アルキルスルホニルおよびC1−C4−アルキルチオの群から相互に独立して選択される3個までの基により置換されていることもあり[ここで、C1−C4−アルキルおよびC1−C4−アルコキシは、ヒドロキシ、シアノ、フッ素、塩素、臭素、ヒドロキシカルボニルおよび式−NR3R4の基(式中、R3およびR4は、相互に独立して水素またはC1−C4−アルキルであるか、または、R3およびR4は、それらが結合している窒素原子と一緒になって、5員ないし6員の複素環である)の群から選択される基により置換されていることもある]、
Bが、フェニル、チエニルまたはピリジルであり、C1−C4−アルキル、C1−C4−アルコキシ、ヒドロキシカルボニル、シアノ、トリフルオロメチル、トリフルオロメトキシ、アミノ、ヒドロキシ、C1−C4−アルキルアミノ、フッ素、塩素、臭素、C1−C4−アルキルアミノカルボニル、C1−C4−アルコキシカルボニル、C1−C4−アルキルカルボニル、C1−C4−アルキルスルホニルおよびC1−C4−アルキルチオの群から各々相互に独立して選択される3個までの基により置換されていることもある[ここで、C1−C4−アルキルおよびC1−C4−アルコキシは、ヒドロキシ、シアノ、フッ素、塩素、臭素、ヒドロキシカルボニルおよび式−NR3R4の基(R3およびR4は、上述の意味を有する)の群から選択される基により置換されていることもある]、
式(I)の化合物およびそれらの塩、溶媒和物および/または塩の溶媒和物に関する。
Aが上述の意味を有し、そして、
Bがフェニルまたはピリジルであり、メチル、エチル、2−プロピル、トリフルオロメチル、メトキシ、エトキシ、フッ素および塩素の群から各々相互に独立して選択される3個までの基により置換されていることもあり、ここで、フェニルまたはピリジル上の基の1つは、アミノ官能基の結合点に対してオルト位に位置する、
式(I)の化合物およびそれらの塩、溶媒和物および/または塩の溶媒和物に関する。
AがC3−C6−シクロアルキルであり、
Bが上述の意味を有する、
式(I)の化合物およびそれらの塩、溶媒和物および/または塩の溶媒和物に関する。
Aが、2−メチルプロピル、2−ブチル、2−ペンチルまたは3−ペンチルであり、
Bが上述の意味を有する、
式(I)の化合物およびそれらの塩、溶媒和物および/または塩の溶媒和物に関する。
Aが、C3−C5−アルキルまたはC5−C6−シクロアルキルであり、
Bが、フェニル、チエニルまたはピリジルであり、C1−C3−アルキル、トリフルオロメチル、ヒドロキシ、メトキシ、エトキシ、シアノ、ジメチルアミノ、ジエチルアミノ、メトキシカルボニル、エトキシカルボニル、メチルカルボニル、エチルカルボニル、フッ素および塩素の群から各々相互に独立して選択される3個までの基により置換されていることもある、
式(I)の化合物およびそれらの塩、溶媒和物および/または塩の溶媒和物に関する。
H2N−B (III)
(式中、Bは上述の意味を有する)
の化合物を用いて、高温、不活性溶媒中、そうでなければ溶媒の非存在下で、式
の化合物に変換し、次いで、後者を、不活性溶媒中、塩基の存在下、式
(式中、Aは上述の意味を有する)
の化合物と反応させ、
得られる式(I)の化合物を、適するならば適切な(i)溶媒および/または(ii)塩基もしくは酸と反応させ、それらの溶媒和物、塩および/または塩の溶媒和物を得る。
PDE阻害
組換えPDE1C(GenBank/EMBL 受託番号: NM_005020, Loughney et al. J. Biol. Chem. 1996 271, 796-806)、PDE2A(GenBank/EMBL 受託番号: NM_002599, Rosman et al. Gene 1997 191, 89-95)、PDE3B(GenBank/EMBL 受託番号: NM_000922, Miki et al. Genomics 1996, 36, 476-485)、PDE4B(GenBank/EMBL 受託番号: NM_002600, Obernolte et al. Gene. 1993, 129, 239-247)、PDE5A(GenBank/EMBL 受託番号: NM_001083, Loughney et al. Gene 1998, 216, 139-147)、PDE7B(GenBank/EMBL 受託番号: NM_018945, Hetman et al. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 472-476)、PDE8A(GenBank/EMBL 受託番号: AF_056490, Fisher et al. Biochem. Biophys. Res. Commun. 1998 246, 570-577)、PDE9A(Fisher et al., J. Biol. Chem, 1998, 273 (25): 15559-15564)、PDE10A(GenBank/EMBL 受託番号: NM_06661, Fujishige et al. J Biol Chem. 1999, 274, 18438-45)、PDE11A(GenBank/EMBL 受託番号: NM_016953, Fawcett et al. Proc. Natl. Acad. Sci. 2000, 97, 3702-3707)を、Sf9細胞にpFASTBACバキュロウイルス発現系(GibcoBRL)を利用して発現させた。
長期増強は、学習および記憶の過程に対する細胞の相関現象と見なされる。以下の方法を使用して、PDE9阻害が長期増強に影響を与えるか否かを判定できる:
ラットの海馬を切断刃(包丁)に対して約70度の角度に置く。厚さ400μmの海馬切片を調製する。非常に柔らかい、入念に湿らせた刷毛(テンの毛)を使用して切片を刃から取り、95%O2/5%CO2でガス供給した冷たい栄養溶液(124mM NaCl、4.9mM KCl、1.3mM MgSO4x7H2O、2.5mM無水CaCl2+、1.2mM KH2PO4、25.6mM NaHCO3、10mMグルコース、pH7.4)の入ったガラス容器に移す。測定の間、温度制御チャンバー中、高さ1−3mmの液体レベルで切片を維持する。流速は2.5ml/分である。予備的なガス供給は、わずかな加圧下(約1atm)で、微小針(microneedle)を通して、前チャンバー(prechamber)中で行う。切片用チャンバーは、小循環(minicirculation)を維持できるようなやり方で前チャンバーに連結する。小循環は、微小針を通って流れ出す95%O2/5%CO2により押し進める。新たに調製した海馬切片を、切片用チャンバー中、33℃で、少なくとも1時間順応させる。
社会的認識試験
社会的認識試験は、学習力および記憶力の試験である。それは、ラットが同種の既知メンバーと未知メンバーとを区別する能力を測定する。従って、この試験は、本発明の化合物の学習力または記憶力の改善効果を調べるのに適している。
方法1:
器具:HPLC Agilent series 1100 を有する Micromass Quattro LCZ;カラム:Grom-Sil 120 ODS-4 HE, 50 mm x 2.0 mm, 3 μm;溶離剤A:水1l+50%蟻酸1ml、溶離剤B:アセトニトリル1l+50%蟻酸1ml;勾配:0.0分100%A→0.2分100%A→2.9分30%A→3.1分10%A→4.5分10%A;オーブン:55℃;流速:0.8ml/分;UV検出:208−400nm
MS器具タイプ:Micromass ZQ;HPLC器具タイプ:Waters Alliance 2795;カラム:Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm;溶離剤A:水1l+50%蟻酸0.5ml、溶離剤B:アセトニトリル1l+50%蟻酸0.5ml;勾配:0.0分90%A流速1ml/分→2.5分30%A流速2ml/分→3.0分5%A流速2ml/分→4.5分5%A流速2ml/分;オーブン:50℃;UV検出:210nm
MS器具タイプ:Micromass ZQ;HPLC器具タイプ:HP 1100 series, UV DAD; カラム: Grom-Sil 120 ODS-4 HE 50 mm x 2 mm, 3.0 μm;溶離剤A:水+50%蟻酸500μl/l、溶離剤B:アセトニトリル+50%蟻酸500μl/l;勾配:0.0分0%B→2.9分70%B→3.1分90%→4.5分90%B;オーブン:50℃;流速:0.8ml/分;UV検出:210nm
MS器具タイプ:Micromass ZQ;HPLC器具タイプ:Waters Alliance 2795;カラム:Merck Chromolith SpeedROD RP-18e 50 mm x 4.6 mm;溶離剤A:水+50%強度蟻酸500μl/l、溶離剤B:アセトニトリル+50%蟻酸500μl/l、勾配:0.0分10%B→3.0分95%B→4.0分95%B;オーブン:35℃;流速:0.0分1.0ml/分→3.0分3.0ml/分→4.0分3.0ml/分;UV検出:210nm
MS器具タイプ:Micromass ZQ;HPLC器具タイプ:HP 1100 series; UV DAD;カラム:Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm;溶離剤A:水1l+50%蟻酸0.5ml、溶離剤B:アセトニトリル1l+50%蟻酸0.5ml;勾配:0.0分90%A流速1ml/分→2.5分30%A流速2ml/分→3.0分5%A流速2ml/分→4.5分5%A流速2ml/分;オーブン:50℃;UV検出:210nm
器具:HPLC Agilent series 1100 を有する Micromass Quattro LCZ;カラム:Phenomex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm;溶離剤A:水1l+50%蟻酸0.5ml、溶離剤B:アセトニトリル1l+50%蟻酸0.5ml;勾配:0.0分90%A流速1ml/分→2.5分30%A流速2ml/分→3.0分5%A流速2ml/分→4.5分5%A流速2ml/分;オーブン:50℃;UV検出:208−400nm
MS器具タイプ:Micromass ZQ;HPLC器具タイプ:Waters Alliance 2790;カラム:Grom-Sil 120 ODS-4 HE 50 mm x 2 mm, 3.0 μm;溶離剤A:水+50%蟻酸500μl/l、溶離剤B:アセトニトリル+50%蟻酸500μl/l;勾配:0.0分5%B→2.0分40%B→4.5分90%B→5.5分90%B;オーブン:45℃;流速:0.0分0.75ml/分→4.5分0.75ml/分→5.5分1.25ml/分;UV検出:210nm
器具:DAD 検出 を有する HP 1100;カラム:Kromasil RP-18, 60 mm x 2 mm, 3.5 μm; 溶離剤A:HclO45ml/H2O、溶離剤B:アセトニトリル;勾配:0分2%B→0.5分2%B→4.5分90%B→6.5分90%B;流速:0.75ml/分;温度:30℃;UV検出210nm
器具:HPLC Agilent series 1100 を有する Micromass Platform LCZ;カラム:Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm;溶離剤A:水1l+50%蟻酸0.5ml、溶離剤B:アセトニトリル1l+50%蟻酸0.5ml;勾配:0.0分90%A流速1ml/分→2.5分30%A流速2ml/分→3.0分5%A流速2ml/分→4.5分5%A流速2ml/分;オーブン:50℃;UV検出:210nm
MS器具タイプ:Micromass ZQ;HPLC器具タイプ:Waters Alliance 2790;カラム:Grom-Sil 120 ODS-4 HE 50 mm x 2 mm, 3.0 μm;溶離剤A:水+50%蟻酸500μl/l、溶離剤B:アセトニトリル+50%蟻酸500μl/l;勾配:0.0分0%B→0.2分0%B→2.9分70%B→3.1分90%B→4.5分90%B;オーブン:45℃;流速:0.8ml/分;UV検出:210nm
実施例1A
2−シクロペンチルエタンアミジン塩酸塩
MS(ESIpos):m/z=127[M+H]+(遊離塩基)
メチル2−シアノ−3−[(4−フルオロフェニル)アミノ]−3−(メチルスルファニル)−2−プロペノエート
LC−MS(方法1):Rt=2.6分
MS(ESIpos):m/z=267[M+H]+
メチル2−シアノ−3−[(4−メチル−3−ピリジニル)アミノ]−3−(メチルスルファニル)−2−プロペノエート
メチル2−シアノ−3−[(3−フルオロフェニル)アミノ]−3−(メチルスルファニル)−2−プロペノエート
LC−MS(方法1):Rt=2.63分
MS(ESIpos):m/z=267[M+H]+
メチル2−シアノ−3−[(3−クロロフェニル)アミノ]−3−(メチルスルファニル)−2−プロペノエート
LC−MS(方法1):Rt=2.78分
MS(ESIpos):m/z=283[M+H]+
メチル2−シアノ−3−[(3−メトキシフェニル)アミノ]−3−(メチルスルファニル)−2−プロペノエート
LC−MS(方法1):Rt=2.63分
MS(ESIpos):m/z=279[M+H]+
メチル2−シアノ−3−[(3−フルオロ−2−メチルフェニル)アミノ]−3−(メチルスルファニル)−2−プロペノエート
LC−MS(方法6):Rt=2.5分
MS(ESIpos):m/z=281[M+H]+
メチル2−シアノ−3−[(2,5−ジメチルフェニル)アミノ]−3−(メチルスルファニル)−2−プロペノエート
LC−MS(方法1):Rt=2.91分
MS(ESIpos):m/z=277[M+H]+
メチル2−シアノ−3−[(2−メトキシフェニル)アミノ]−3−(メチルスルファニル)−2−プロペノエート
LC−MS(方法7):Rt=3.01分
MS(ESIpos):m/z=279[M+H]+
1H-NMR (300 MHz, DMSO-d6): δ = 2.28 (s, 3H), 3.71 (s, 3H), 3.84 (s, 3H), 7.00 (m, 1H), 7.17 (m, 1H), 7.33 (m, 1H), 7.41 (m, 1H).
メチル2−シアノ−3−[(4−フルオロ−2−メチルフェニル)アミノ]−3−(メチルスルファニル)−2−プロペノエート
LC−MS(方法4):Rt=2.28分
MS(ESIpos):m/z=281[M+H]+
1H-NMR (300 MHz, DMSO-d6): δ = 2.22 (s, 3H), 2.27 (s, 3H), 3.70 (s, 3H), 7.11 (m, 1H), 7.23 (m, 1H), 7.33 (m, 1H), 7.34 (m, 1H).
メチル2−シアノ−3−[(2−メチルフェニル)アミノ]−3−(メチルスルファニル)−2−プロペノエート
LC−MS(方法7):Rt=3.08分
MS(ESIpos):m/z=263[M+H]+
1H-NMR (300 MHz, DMSO-d6): δ = 2.27 (s, 3H), 2.23 (s, 3H), 3.70 (s, 3H), 7.28 (m, 4H).
メチル2−シアノ−3−(メチルスルファニル)−3−[(2−プロピルフェニル)アミノ]−2−プロペノエート
LC−MS(方法3):Rt=3.52分
MS(ESIpos):m/z=291[M+H]+
メチル2−シアノ−3−(メチルスルファニル)−3−(3−ピリジニルアミノ)−2−プロペノエート
HPLC(方法8):Rt=3.06分
MS(ESIpos):m/z=250[M+H]+、272[M+Na]+
(3S)−3−メチルペンタンニトリル
1H-NMR (200 MHz, DMSO-d6): δ = 0.87 (t, 3H), 0.92 (d, 3H), 1.30 (m, 2H), 1.67 (m, 1H), 2.42 (dd, 2H).
(3S)−3−メチルペンタンアミジン塩酸塩
LC−MS(方法2):Rt=0.31分
MS(ESIpos):m/z=115[M+H]+(遊離塩基)
メチル2−シアノ−3−[(5−フルオロ−2−メチルフェニル)アミノ]−3−(メチルスルファニル)−2−プロペノエート
LC−MS(方法6):Rt=2.49分
MS(ESIpos):m/z=281[M+H]+
実施例1
2−(シクロペンチルメチル)−4−[(フルオロフェニル)アミノ]6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法1):Rt=2.86分
MS(ESIpos):m/z=313[M+H]+
1H-NMR (300 MHz, DMSO-d6): δ = 1.13 (m, 2H), 1.56 (m, 6H), 2.15 (m, 1H), 2.44 (d, 2H), 7.15 (dd, 2H), 7.41 (dd, 2H), 9.66 (s, 1H), 12.36 (s, 1H).
2−(シクロペンチルメチル)−4−[(4−メチル−3−ピリジニル)アミノ]−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法5):Rt=1.57分
MS(ESIpos):m/z=310[M+H]+
1H-NMR (300 MHz, DMSO-d6): δ = 1.04 (m, 2H), 1.51 (m, 6H), 2.01 (m, 1H), 2.28 (s, 3H), 2.39 (d, 2H), 7.51 (d, 1H), 8.41 (d, 1H), 8.52 (s, 1H), 12.41 (s, 1H).
2−(シクロヘキシルメチル)−4−[(4−メチル−3−ピリジニル)アミノ]−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法5):Rt=1.47分
MS(ESIpos):m/z=324[M+H]+
1H-NMR (300 MHz, DMSO-d6): δ = 0.88 (m, 2H), 1.09 (m, 3H), 1.56 (m, 6H), 2.28 (d, 2H), 2.32 (s, 3H), 7.68 (s, 1H), 8.53 (d, 1H), 8.61 (s, 1H); 9.79 (s, 1H).
2−(シクロペンチルメチル)−4−[(3−フルオロフェニル)アミノ]−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法1):Rt=2.9分
MS(ESIpos):m/z=313[M+H]+
1H-NMR (300 MHz, DMSO-d6): δ = 1.16 (m, 2H), 1.53 (m, 4H), 1.71 (m, 2H), 2.21 (m, 1H), 2.46 (d, 2H), 6.88 (m, 1H), 7.31 (m, 2H), 7.44 (m, 1H).
4−[(3−クロロフェニル)アミノ]−2−(シクロペンチルメチル)−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法1):Rt=3.06分
MS(ESIpos):m/z=329[M+H]+
1H-NMR (300 MHz, DMSO-d6): δ = 1.14 (m, 2H), 1.55 (m, 4H), 1.71 (m, 2H), 2.19 (m, 1H), 2.46 (d, 2H), 7.19 (m, 1H), 7.38 (m, 2H), 7.63 (m, 1H), 9.78 (br. S, 1H), 12.49 (br. S, 1H).
2−(シクロペンチルメチル)−4−[(3−メトキシフェニル)アミノ]−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法1):Rt=2.84分
MS(ESIpos):m/z=325[M+H]+
2−(シクロペンチルメチル)−4−[(3−フルオロ−2−メチルフェニル)アミノ]−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法6):Rt=2.37分
MS(ESIpos):m/z=327[M+H]+
1H-NMR (300 MHz, DMSO-d6): δ = 1.08 (m, 2H), 1.43 (m, 4H), 1.55 (m, 2H), 2.04 (m, 1H), 2.04 (s, 3H), 2.39 (d, 2H), 7.05 (m, 2H), 7.20 (m, 1H), 9.60 (s, 1H), 12.30 (s, 1H).
2−(シクロペンチルメチル)−4−[(2,5−ジメチルフェニル)アミノ]−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法10):Rt=3.39分
MS(ESIpos):m/z=323[M+H]+
1H-NMR (300 MHz, DMSO-d6): δ = 1.10 (m, 2H), 1.43 (m, 4H), 1.62 (m, 2H), 2.04 (m, 1H), 2.10 (s, 3H), 2.24 (s, 3H), 2.36 (d, 2H), 6.98 (m, 1H), 7.09 (m, 2H), 9.15 (br. s, 1H), 12.19 (br. s, 1H).
2−(シクロペンチルメチル)−4−[(2−メトキシフェニル)アミノ]−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法1):Rt=2.92分
MS(ESIpos):m/z=325[M+H]+
2−(シクロペンチルメチル)−4−[(4−フルオロ−2−メチルフェニル)アミノ]−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法3):Rt=2.98分
MS(ESIpos):m/z=327[M+H]+
1H-NMR (300 MHz, DMSO-d6): δ = 1.09 (m, 2H), 1.53 (m, 6H), 2.10 (m, 1H), 2.14 (s, 3H), 2.28 (d, 2H), 6.98 (m, 1H), 7.08 (m, 1H), 7.29 (m, 1H).
2−(シクロペンチルメチル)−4−[(2−メチルフェニル)アミノ]−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法1):Rt=2.84分
MS(ESIpos):m/z=309[M+H]+
1H-NMR (300 MHz, DMSO-d6): δ = 1.07 (m, 2H), 1.42 (m, 2H), 1.52 (m, 2H), 1.59 (m, 2H), 2.05 (m, 1H), 2.14 (s, 3H), 2.36 (d, 2H), 7.17 (m, 4H), 9.47 (s, 1H), 12.24 (s, 1H).
2−(シクロペンチルメチル)−6−オキソ−4−[(2−プロピルフェニル)アミノ]−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法1):Rt=3.13分
MS(ESIpos):m/z=337[M+H]+
1H-NMR (300 MHz, DMSO-d6): δ = 0.84 (t, 3H), 1.07 (m, 2H), 1.52 (m, 8H), 2.04 (m, 1H), 2.35 (d, 2H), 2.49 (m, 2H), 7.16 (m, 2H), 7.23 (m, 2H), 9.44 (s, 1H), 12.20 (s, 1H).
2−(シクロペンチルメチル)−6−オキソ−4−(3−ピリジニルアミノ)−1,6−ジヒドロ−5−ピリミジンカルボニトリル
HPLC(方法8):Rt=3.36分
MS(ESIpos):m/z=296[M+H]+
1H-NMR (300 MHz, DMSO-d6): δ = 1.05-1.20 (m, 2H), 1.37-1.75 (m, 6H), 2.16 (m, 1H), 2.47 (d, 2H), 7.36 (m, 1H), 7.83 (m, 1H), 8.32 (m, 1H), 8.66 (m, 1H), 9.80 (s, 1H), 12.48 (s, 1H).
2−(2−メチルブチル)−4−[(2−メチルフェニル)アミノ]−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法2):Rt=2.06分
MS(ESIpos):m/z=297[M+H]+
1H-NMR (300 MHz, DMSO-d6): δ = 0.80 (d, 6H), 1.09 (m, 1H), 1.24 (m, 1H), 1.74 (m, 1H), 2.14 (s, 3H), 2.32 (dd, 2H), 7.16 (m, 4H), 9.49 (s, 1H), 12.27 (s, 1H).
2−[(2S)−2−メチルブチル]−4−(2−メチルフェニル)アミノ]−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法5):Rt=2.28分
MS(ESIpos):m/z=297[M+H]+
1H-NMR (300 MHz, DMSO-d6): δ = 0.78 (d, 6H), 1.09 (m, 1H), 1.21 (m, 1H), 1.70 (m, 1H), 2.13 (s, 3H), 2.29 (dd, 2H), 7.16 (m, 4H), 9.49 (s, 1H), 12.25 (s, 1H).
4−[(5−フルオロ−2−メチルフェニル)アミノ]−2−[(2S)−2−メチルブチル]−6−オキソ−1,6−ジヒドロ−5−ピリミジンカルボニトリル
LC−MS(方法5):Rt=2.11分
MS(ESIpos):m/z=315[M+H]+
1H-NMR (200 MHz, DMSO-d6): δ = 0.75 (d, 6H), 1.1 (m, 1H), 1.25 (m, 1H), 1.71 (m, 1H), 2.1 (s, 3H), 2.26 (dd, 2H), 7.03 (m, 2H), 7.28 (m, 1H), 9.51 (s, 1H), 12.36 (s, 1H).
Claims (5)
- 疾患の処置および/または予防のための、請求項1または請求項2に記載の化合物。
- 少なくとも1種の請求項1または請求項2に記載の化合物、および、少なくとも1種の医薬的に許容し得る本質的に非毒性の担体または賦形剤を含む、医薬。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10328479A DE10328479A1 (de) | 2003-06-25 | 2003-06-25 | 6-Arylamino-5-cyano-4-pyrimidinone |
DE10328479.6 | 2003-06-25 | ||
PCT/EP2004/006477 WO2004113306A1 (de) | 2003-06-25 | 2004-06-16 | 6-arylamino-5-cyano-4-pyrimidinone als pde9a-inhibitoren |
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JP4728954B2 true JP4728954B2 (ja) | 2011-07-20 |
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JP2006515952A Expired - Lifetime JP4728954B2 (ja) | 2003-06-25 | 2004-06-16 | Pde9a阻害剤としての6−アリールアミノ−5−シアノ−4−ピリミジノン化合物 |
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US (2) | US7488733B2 (ja) |
EP (2) | EP1905765A1 (ja) |
JP (1) | JP4728954B2 (ja) |
CN (1) | CN1835929A (ja) |
AU (1) | AU2004249392A1 (ja) |
CA (1) | CA2530461A1 (ja) |
DE (2) | DE10328479A1 (ja) |
ES (1) | ES2298769T3 (ja) |
IL (1) | IL172694A0 (ja) |
MX (1) | MXPA05013874A (ja) |
RU (1) | RU2006101824A (ja) |
WO (1) | WO2004113306A1 (ja) |
ZA (1) | ZA200510319B (ja) |
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DE10238724A1 (de) * | 2002-08-23 | 2004-03-04 | Bayer Ag | Alkyl-substituierte Pyrazolpyrimidine |
DE10238723A1 (de) * | 2002-08-23 | 2004-03-11 | Bayer Ag | Phenyl-substituierte Pyrazolyprimidine |
DE10238722A1 (de) | 2002-08-23 | 2004-03-11 | Bayer Ag | Selektive Phosphodiesterase 9A-Inhibitoren als Arzneimittel zur Verbesserung kognitiver Prozesse |
US8044060B2 (en) * | 2003-05-09 | 2011-10-25 | Boehringer Ingelheim International Gmbh | 6-cyclylmethyl- and 6-alkylmethyl pyrazolo[3,4-D]pyrimidines, methods for their preparation and methods for their use to treat impairments of perception, concentration learning and/or memory |
DE10320785A1 (de) * | 2003-05-09 | 2004-11-25 | Bayer Healthcare Ag | 6-Arylmethyl-substituierte Pyrazolopyrimidine |
DE10328479A1 (de) * | 2003-06-25 | 2005-01-13 | Bayer Ag | 6-Arylamino-5-cyano-4-pyrimidinone |
DE102004001873A1 (de) * | 2004-01-14 | 2005-09-29 | Bayer Healthcare Ag | Cyanopyrimidinone |
DE102005024494A1 (de) * | 2005-05-27 | 2006-11-30 | Bayer Healthcare Ag | Verwendung von Cyanopyrimidinen |
JP5498392B2 (ja) * | 2007-11-30 | 2014-05-21 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 1,5−ジヒドロ−ピラゾロ[3,4−d]ピリミジン−4−オン誘導体及びcns障害の治療のためのpde9aモジュレーターとしてのそれらの使用 |
UA105362C2 (en) | 2008-04-02 | 2014-05-12 | Бьорингер Ингельхайм Интернациональ Гмбх | 1-heterocyclyl-1, 5-dihydro-pyrazolo [3, 4-d] pyrimidin-4-one derivatives and their use as pde9a modulators |
PE20110383A1 (es) | 2008-09-08 | 2011-07-15 | Boehringer Ingelheim Int | Pirazolopirimidinonas como inhibidores de la fosfodiesterasa 9a (pde9a) |
KR20120003868A (ko) | 2009-03-31 | 2012-01-11 | 베링거 인겔하임 인터내셔날 게엠베하 | 1―헤테로사이클릴―1,5―디하이드로―피라졸로[3,4―d]피리미딘―4―온 유도체 및 pde9a 조절인자로서의 이의 용도 |
AR077859A1 (es) * | 2009-08-12 | 2011-09-28 | Boehringer Ingelheim Int | Compuestos para el tratamiento de trastornos del snc |
BR112013003097B1 (pt) * | 2010-08-12 | 2021-03-16 | Boehringer Ingelheim International Gmbh | 6-cicloalquil-pirazolopirimidinonas e composição farmacêutica |
US8809345B2 (en) | 2011-02-15 | 2014-08-19 | Boehringer Ingelheim International Gmbh | 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders |
US8716305B2 (en) * | 2011-04-18 | 2014-05-06 | Basf Se | Multicomponent crystalline system of rosuvastatin calcium salt and vanillin |
CN102786525B (zh) | 2012-08-08 | 2014-12-17 | 中山大学 | N-取代吡唑并[3,4-d]嘧啶酮类化合物、其制备方法及其应用 |
WO2016145614A1 (en) * | 2015-03-17 | 2016-09-22 | Merck Sharp & Dohme Corp. | Triazolyl pyrimidinone compounds as pde2 inhibitors |
TW201902898A (zh) | 2017-06-08 | 2019-01-16 | 美商默沙東藥廠 | 吡唑并嘧啶pde9抑制劑 |
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2003
- 2003-06-25 DE DE10328479A patent/DE10328479A1/de not_active Withdrawn
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2004
- 2004-06-16 JP JP2006515952A patent/JP4728954B2/ja not_active Expired - Lifetime
- 2004-06-16 DE DE502004006055T patent/DE502004006055D1/de not_active Expired - Lifetime
- 2004-06-16 AU AU2004249392A patent/AU2004249392A1/en not_active Abandoned
- 2004-06-16 US US10/559,954 patent/US7488733B2/en not_active Expired - Lifetime
- 2004-06-16 WO PCT/EP2004/006477 patent/WO2004113306A1/de active IP Right Grant
- 2004-06-16 EP EP07121390A patent/EP1905765A1/de not_active Withdrawn
- 2004-06-16 CA CA002530461A patent/CA2530461A1/en not_active Abandoned
- 2004-06-16 ES ES04739944T patent/ES2298769T3/es not_active Expired - Lifetime
- 2004-06-16 CN CNA2004800233928A patent/CN1835929A/zh active Pending
- 2004-06-16 RU RU2006101824/04A patent/RU2006101824A/ru not_active Application Discontinuation
- 2004-06-16 EP EP04739944A patent/EP1644339B1/de not_active Expired - Lifetime
- 2004-06-16 MX MXPA05013874A patent/MXPA05013874A/es unknown
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- 2005-12-20 ZA ZA200510319A patent/ZA200510319B/xx unknown
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2008
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WO2003037899A1 (en) * | 2001-11-02 | 2003-05-08 | Pfizer Limited | Pde9 inhibitors for treating cardiovascular disorders |
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US7488733B2 (en) | 2009-02-10 |
MXPA05013874A (es) | 2006-07-06 |
DE502004006055D1 (de) | 2008-03-13 |
EP1644339B1 (de) | 2008-01-23 |
ZA200510319B (en) | 2007-03-28 |
CA2530461A1 (en) | 2004-12-29 |
AU2004249392A1 (en) | 2004-12-29 |
EP1644339A1 (de) | 2006-04-12 |
JP2007506662A (ja) | 2007-03-22 |
CN1835929A (zh) | 2006-09-20 |
US20070105881A1 (en) | 2007-05-10 |
RU2006101824A (ru) | 2006-07-27 |
IL172694A0 (en) | 2006-04-10 |
ES2298769T3 (es) | 2008-05-16 |
WO2004113306A1 (de) | 2004-12-29 |
EP1905765A1 (de) | 2008-04-02 |
US20090111838A1 (en) | 2009-04-30 |
DE10328479A1 (de) | 2005-01-13 |
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