MX2013003093A - Compuestos de imidazotriazinona. - Google Patents
Compuestos de imidazotriazinona.Info
- Publication number
- MX2013003093A MX2013003093A MX2013003093A MX2013003093A MX2013003093A MX 2013003093 A MX2013003093 A MX 2013003093A MX 2013003093 A MX2013003093 A MX 2013003093A MX 2013003093 A MX2013003093 A MX 2013003093A MX 2013003093 A MX2013003093 A MX 2013003093A
- Authority
- MX
- Mexico
- Prior art keywords
- carbon atoms
- alkyl
- imidazo
- trans
- triazin
- Prior art date
Links
- IJYHVZICHKCLMQ-UHFFFAOYSA-N imidazo[4,5-d]triazin-4-one Chemical class O=C1N=NN=C2N=CN=C12 IJYHVZICHKCLMQ-UHFFFAOYSA-N 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 182
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 133
- 201000010099 disease Diseases 0.000 claims abstract description 67
- 208000035475 disorder Diseases 0.000 claims abstract description 64
- 238000000034 method Methods 0.000 claims abstract description 52
- 101100407341 Drosophila melanogaster Pde9 gene Proteins 0.000 claims abstract description 46
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 29
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 651
- 125000000217 alkyl group Chemical group 0.000 claims description 416
- -1 for example Chemical group 0.000 claims description 323
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 126
- 125000003545 alkoxy group Chemical group 0.000 claims description 93
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 77
- 229910052736 halogen Inorganic materials 0.000 claims description 74
- 229910052799 carbon Inorganic materials 0.000 claims description 72
- 150000002367 halogens Chemical group 0.000 claims description 71
- 125000001424 substituent group Chemical group 0.000 claims description 68
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 65
- NIHUZJPITMUICY-UHFFFAOYSA-N 1h-imidazo[5,1-f][1,2,4]triazin-4-one Chemical compound O=C1NC=NN2C=NC=C12 NIHUZJPITMUICY-UHFFFAOYSA-N 0.000 claims description 60
- QMNWYGTWTXOQTP-UHFFFAOYSA-N 1h-triazin-6-one Chemical compound O=C1C=CN=NN1 QMNWYGTWTXOQTP-UHFFFAOYSA-N 0.000 claims description 53
- 125000001072 heteroaryl group Chemical group 0.000 claims description 51
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 49
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 45
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 40
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 38
- 125000004429 atom Chemical group 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 229910052731 fluorine Inorganic materials 0.000 claims description 29
- 239000011737 fluorine Substances 0.000 claims description 25
- 239000000460 chlorine Substances 0.000 claims description 24
- 229910052801 chlorine Inorganic materials 0.000 claims description 23
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 20
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 125000002950 monocyclic group Chemical group 0.000 claims description 19
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 14
- 125000003386 piperidinyl group Chemical group 0.000 claims description 11
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 11
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 230000001225 therapeutic effect Effects 0.000 claims description 9
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 8
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims description 7
- 230000005764 inhibitory process Effects 0.000 claims description 7
- 208000015114 central nervous system disease Diseases 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
- 125000002619 bicyclic group Chemical group 0.000 claims description 5
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 4
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 4
- 208000012902 Nervous system disease Diseases 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- SSFMPMMQRUJHMN-UHFFFAOYSA-N 2-(1-ethylsulfonylpiperidin-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one Chemical compound C(C)S(=O)(=O)N1CCC(CC1)C1=NN2C(C(N1)=O)=CN=C2 SSFMPMMQRUJHMN-UHFFFAOYSA-N 0.000 claims 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 24
- 230000008569 process Effects 0.000 abstract description 16
- 241000124008 Mammalia Species 0.000 abstract description 9
- 239000003112 inhibitor Substances 0.000 abstract description 7
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 4
- 101001117256 Drosophila melanogaster High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A Proteins 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 211
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 195
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 177
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 111
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 103
- 239000000243 solution Substances 0.000 description 102
- 239000011541 reaction mixture Substances 0.000 description 91
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 87
- 238000004809 thin layer chromatography Methods 0.000 description 84
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 81
- 235000019439 ethyl acetate Nutrition 0.000 description 73
- 239000000203 mixture Substances 0.000 description 67
- 230000015572 biosynthetic process Effects 0.000 description 64
- 238000003786 synthesis reaction Methods 0.000 description 62
- 239000007787 solid Substances 0.000 description 61
- ZHGNHOOVYPHPNJ-UHFFFAOYSA-N Amigdalin Chemical compound FC(F)(F)C(=O)OCC1OC(OCC2OC(OC(C#N)C3=CC=CC=C3)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C2OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C1OC(=O)C(F)(F)F ZHGNHOOVYPHPNJ-UHFFFAOYSA-N 0.000 description 53
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 53
- 125000004076 pyridyl group Chemical group 0.000 description 51
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 47
- 239000000463 material Substances 0.000 description 46
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 46
- 230000002829 reductive effect Effects 0.000 description 44
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 43
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 42
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 42
- 238000005481 NMR spectroscopy Methods 0.000 description 41
- 239000012044 organic layer Substances 0.000 description 41
- 230000014759 maintenance of location Effects 0.000 description 40
- 239000000741 silica gel Substances 0.000 description 40
- 229910002027 silica gel Inorganic materials 0.000 description 40
- 235000002639 sodium chloride Nutrition 0.000 description 40
- 239000012298 atmosphere Substances 0.000 description 39
- 229910052938 sodium sulfate Inorganic materials 0.000 description 38
- 235000011152 sodium sulphate Nutrition 0.000 description 38
- 238000005160 1H NMR spectroscopy Methods 0.000 description 37
- 239000013058 crude material Substances 0.000 description 37
- 239000012043 crude product Substances 0.000 description 37
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 32
- 230000003287 optical effect Effects 0.000 description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- 238000004440 column chromatography Methods 0.000 description 30
- 239000003814 drug Substances 0.000 description 28
- 101150041968 CDC13 gene Proteins 0.000 description 27
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 27
- 125000003118 aryl group Chemical group 0.000 description 26
- 239000000725 suspension Substances 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 24
- 239000012071 phase Substances 0.000 description 22
- 208000024827 Alzheimer disease Diseases 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
- 238000009472 formulation Methods 0.000 description 21
- 239000000651 prodrug Substances 0.000 description 20
- 229940002612 prodrug Drugs 0.000 description 20
- 239000007858 starting material Substances 0.000 description 19
- 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 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 18
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 17
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 238000004296 chiral HPLC Methods 0.000 description 17
- 229910052805 deuterium Inorganic materials 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 16
- PGJLOGNVZGRMGX-UHFFFAOYSA-L iron(2+);trifluoromethanesulfonate Chemical compound [Fe+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F PGJLOGNVZGRMGX-UHFFFAOYSA-L 0.000 description 16
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 16
- 235000019341 magnesium sulphate Nutrition 0.000 description 16
- 125000004043 oxo group Chemical group O=* 0.000 description 16
- 238000006467 substitution reaction Methods 0.000 description 16
- 206010012289 Dementia Diseases 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- 229910000024 caesium carbonate Inorganic materials 0.000 description 15
- 239000001993 wax Substances 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 14
- 229940079593 drug Drugs 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
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- 208000024891 symptom Diseases 0.000 description 14
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- 125000006413 ring segment Chemical group 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 230000003956 synaptic plasticity Effects 0.000 description 13
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 12
- 229910017711 NHRa Inorganic materials 0.000 description 12
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 12
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
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- 238000003818 flash chromatography Methods 0.000 description 11
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- 150000002148 esters Chemical class 0.000 description 10
- 238000010348 incorporation Methods 0.000 description 10
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- 235000019198 oils Nutrition 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 9
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 9
- 125000003282 alkyl amino group Chemical group 0.000 description 9
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
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- 125000005842 heteroatom Chemical group 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 8
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 8
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 8
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- 125000004446 heteroarylalkyl group Chemical group 0.000 description 8
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- 125000004193 piperazinyl group Chemical group 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
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- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 6
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- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 6
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 6
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
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- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 6
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 235000015424 sodium Nutrition 0.000 description 6
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- 239000011593 sulfur Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 125000004001 thioalkyl group Chemical group 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
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- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
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| US38469410P | 2010-09-20 | 2010-09-20 | |
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| PL2619208T3 (pl) * | 2010-09-20 | 2017-03-31 | Ironwood Pharmaceuticals, Inc. | Związki imidazotriazynonu |
| HK1211023A1 (zh) * | 2011-10-10 | 2016-05-13 | H. Lundbeck A/S | 具有咪唑并吡嗪骨架pde9i |
| EP3178820B1 (en) | 2012-01-26 | 2017-12-20 | H. Lundbeck A/S | Pde9- inhibitors with imidazo triazinone backbone |
| HK1206726A1 (en) | 2012-03-19 | 2016-01-15 | Ironwood Pharmaceuticals, Inc. | Imidazotriazinone compounds |
| 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 |
| WO2014024125A1 (en) | 2012-08-08 | 2014-02-13 | Celon Pharma S.A. | Pyrazolo[4,3-d]pyrimidin-7(6h)-one derivatives as pde9 inhibitors |
| JP2016503395A (ja) | 2012-10-31 | 2016-02-04 | バイエル・クロップサイエンス・アクチェンゲゼルシャフト | 病害生物防除剤としての複素環化合物 |
| TW201629064A (zh) | 2014-10-10 | 2016-08-16 | Ｈ 朗德貝克公司 | 作爲ｐｄｅ１抑制劑之三唑並吡酮 |
| WO2016147659A1 (en) * | 2015-03-16 | 2016-09-22 | Sumitomo Dainippon Pharma Co., Ltd. | Bicyclic imidazolo derivative |
| TW201643167A (zh) * | 2015-04-22 | 2016-12-16 | Ｈ 朗德貝克公司 | 作爲ｐｄｅ１抑制劑之咪唑並三酮 |
| JO3627B1 (ar) | 2015-04-30 | 2020-08-27 | H Lundbeck As | إيميدازو بيرازينونات على هيئة مثبطات pde1 |
| AU2016289856B2 (en) | 2015-07-07 | 2020-11-26 | H. Lundbeck A/S | PDE9 inhibitors with imidazo triazinone backbone and imidazo pyrazinone backbone for treatment of peripheral diseases |
| WO2017070293A1 (en) * | 2015-10-20 | 2017-04-27 | Ironwood Pharmaceuticals, Inc. | Phosphodiesterase 9 inhibitor and levodopa therapy |
| CN105669680B (zh) * | 2016-03-24 | 2018-02-23 | 南京药捷安康生物科技有限公司 | 吡咯并[2,1‑f][1,2,4]三嗪‑4(1H)‑酮衍生物类PDE9A抑制剂 |
| TWI729109B (zh) | 2016-04-12 | 2021-06-01 | 丹麥商Ｈ 朗德貝克公司 | 作爲PDE1抑制劑的1,5-二氫-4H-吡唑并[3,4-d]嘧啶-4-酮和1,5-二氫-4H-吡唑并[4,3-c]吡啶-4-酮 |
| TN2018000383A1 (en) | 2016-07-06 | 2020-06-15 | H Lundbeck As | Pde9 inhibitors for treatment of peripheral diseases. |
| EP3529250B1 (en) | 2016-10-18 | 2023-12-06 | H. Lundbeck A/S | Imidazopyrazinones, pyrazolopyrimidinones and pyrazolopyridinones as pde1 inhibitors |
| JP2019536762A (ja) | 2016-10-28 | 2019-12-19 | ハー・ルンドベック・アクチエゼルスカベット | 精神疾患及び／又は認知障害の治療のためのイミダゾピラジノンを含む併用療法 |
| KR20190077349A (ko) | 2016-10-28 | 2019-07-03 | 하. 룬드벡 아크티에셀스카브 | 이미다조피라지논의 투여를 포함하는 병용 치료 |
| CN115746003B (zh) * | 2017-05-26 | 2024-08-09 | 卡都瑞恩医药公司 | 制备和使用pde9抑制剂的方法 |
| ES2975792T3 (es) | 2018-05-25 | 2024-07-15 | Cardurion Pharmaceuticals Inc | Monohidrato y formas cristalinas de 6-[(3s,4s)-4-metil-1- (pirimidin-2-ilmetil)pirrolidin-3-il]-3-tetrahidropiran-4-il-7H-imidazo[1,5-a]pirazin-8-ona |
| KR20250108770A (ko) | 2018-08-31 | 2025-07-15 | 카듀리온 파마슈티칼스, 인크. | 겸상 세포 질환의 치료를 위한 pde9 억제제 |
| WO2020102374A1 (en) * | 2018-11-14 | 2020-05-22 | The Board Of Trustees Of The Leland Stanford Junior University | Targeting of makap-pde4d3 complexes in neurodegenerative disease |
| KR102712818B1 (ko) * | 2018-12-06 | 2024-09-30 | 한국화학연구원 | Pde9a 저해 활성을 가지는 화합물 및 이들의 의약 용도 |
| CN114929231B (zh) * | 2019-10-21 | 2024-11-29 | 爱思开生物制药株式会社 | 咪唑并嘧啶或咪唑并三嗪化合物用于预防、减轻或治疗发育性残疾的用途 |
| CN112724079A (zh) * | 2021-02-04 | 2021-04-30 | 康化（上海）新药研发有限公司 | 一种6-甲氧基吡啶甲酸甲酯的合成方法 |
| GB2632307A (en) * | 2023-08-02 | 2025-02-05 | Duke Street Bio Ltd | PARP1 inhibitor compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| PT72878B (en) | 1980-04-24 | 1983-03-29 | Merck & Co Inc | Process for preparing mannich-base hydroxamic acid pro-drugs for the improved delivery of non-steroidal anti-inflammatory agents |
| DE19750085A1 (de) * | 1997-11-12 | 1999-05-20 | Bayer Ag | 2-Phenyl-substituierte Imidazotriazinone |
| SK287161B6 (sk) | 1997-11-12 | 2010-02-08 | Bayer Healthcare Ag | 2-Fenylsubstituované imidazotriazinóny, spôsob ich výroby, liečivá obsahujúce tieto látky a ich použitie |
| US7087605B2 (en) | 2001-06-01 | 2006-08-08 | Bayer Aktiengesellschaft | 5-Ethyl-imidazotriazinones |
| GB0113343D0 (en) * | 2001-06-01 | 2001-07-25 | Bayer Ag | Novel Heterocycles 2 |
| CA2465632A1 (en) * | 2001-11-02 | 2003-05-08 | Pfizer Products Inc. | Treatment of insulin resistance syndrome and type 2 diabetes with pde9 inhibitors |
| WO2004078163A2 (en) | 2003-02-28 | 2004-09-16 | Transform Pharmaceuticals, Inc. | Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen |
| DE10229778A1 (de) * | 2002-07-03 | 2004-01-29 | Bayer Ag | Neue Verwendung von Imidazotriazinonen |
| US20040220186A1 (en) * | 2003-04-30 | 2004-11-04 | Pfizer Inc. | PDE9 inhibitors for treating type 2 diabetes,metabolic syndrome, and cardiovascular disease |
| US20060264624A1 (en) | 2005-05-20 | 2006-11-23 | Alexander Heim-Riether | Methods for synthesizing imidazotriazinones |
| JP2008543968A (ja) | 2005-06-28 | 2008-12-04 | オーキッド リサーチ ラボラトリーズ リミテッド | 新規なピラゾロピリミジノン誘導体 |
| HRP20120105T1 (hr) * | 2007-05-11 | 2012-02-29 | Pfizer Inc. | Aminoheterociklički spojevi |
| CN102131801B (zh) | 2008-06-25 | 2015-04-08 | 福拉姆医药股份有限公司 | 1,2-二取代的杂环化合物 |
| PL2619208T3 (pl) | 2010-09-20 | 2017-03-31 | Ironwood Pharmaceuticals, Inc. | Związki imidazotriazynonu |
| EP3178820B1 (en) | 2012-01-26 | 2017-12-20 | H. Lundbeck A/S | Pde9- inhibitors with imidazo triazinone backbone |
| HK1206726A1 (en) | 2012-03-19 | 2016-01-15 | Ironwood Pharmaceuticals, Inc. | Imidazotriazinone compounds |
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| RU2013118362A (ru) | 2014-10-27 |
| BR112013008140A2 (pt) | 2017-12-05 |
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| EP3181566A1 (en) | 2017-06-21 |
| US20170152265A1 (en) | 2017-06-01 |
| HK1187908A1 (en) | 2014-04-17 |
| JP5855109B2 (ja) | 2016-02-09 |
| RU2603140C2 (ru) | 2016-11-20 |
| BR112013008140A8 (pt) | 2018-04-03 |
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| AR083058A1 (es) | 2013-01-30 |
| EP2619208A1 (en) | 2013-07-31 |
| CA2811714C (en) | 2017-11-21 |
| AU2011305568A1 (en) | 2013-04-04 |
| CN103313988A (zh) | 2013-09-18 |
| US20140330014A1 (en) | 2014-11-06 |
| CA2811714A1 (en) | 2012-03-29 |
| JP2016104747A (ja) | 2016-06-09 |
| US20120157458A1 (en) | 2012-06-21 |
| CN103313988B (zh) | 2016-06-08 |
| JP2013540755A (ja) | 2013-11-07 |
| DK2619208T3 (en) | 2017-01-30 |
| ES2610360T3 (es) | 2017-04-27 |
| AU2016200970A1 (en) | 2016-03-03 |
| TWI541244B (zh) | 2016-07-11 |
| US9540380B2 (en) | 2017-01-10 |
| UY33616A (es) | 2012-04-30 |
| EP2619208B1 (en) | 2016-11-09 |
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