JP5855109B2 - イミダゾトリアジノン化合物 - Google Patents
イミダゾトリアジノン化合物 Download PDFInfo
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- JP5855109B2 JP5855109B2 JP2013530234A JP2013530234A JP5855109B2 JP 5855109 B2 JP5855109 B2 JP 5855109B2 JP 2013530234 A JP2013530234 A JP 2013530234A JP 2013530234 A JP2013530234 A JP 2013530234A JP 5855109 B2 JP5855109 B2 JP 5855109B2
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- Prior art keywords
- alkyl
- cycloalkyl
- alkoxy
- substituted
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- IJYHVZICHKCLMQ-UHFFFAOYSA-N imidazo[4,5-d]triazin-4-one Chemical class O=C1N=NN=C2N=CN=C12 IJYHVZICHKCLMQ-UHFFFAOYSA-N 0.000 title description 4
- -1 N-Me-piperazinyl Chemical group 0.000 claims description 354
- 150000001875 compounds Chemical class 0.000 claims description 185
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 123
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 107
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 105
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 80
- 229910052736 halogen Inorganic materials 0.000 claims description 78
- 150000002367 halogens Chemical class 0.000 claims description 77
- 239000000203 mixture Substances 0.000 claims description 71
- 125000001424 substituent group Chemical group 0.000 claims description 65
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 58
- QMNWYGTWTXOQTP-UHFFFAOYSA-N 1h-triazin-6-one Chemical compound O=C1C=CN=NN1 QMNWYGTWTXOQTP-UHFFFAOYSA-N 0.000 claims description 57
- 125000000217 alkyl group Chemical group 0.000 claims description 57
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 56
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 55
- 201000010099 disease Diseases 0.000 claims description 54
- 208000035475 disorder Diseases 0.000 claims description 52
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 49
- 150000003839 salts Chemical class 0.000 claims description 45
- 125000001072 heteroaryl group Chemical group 0.000 claims description 43
- 101100407341 Drosophila melanogaster Pde9 gene Proteins 0.000 claims description 41
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 35
- 125000003545 alkoxy group Chemical group 0.000 claims description 33
- 239000008194 pharmaceutical composition Substances 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 28
- 229910052801 chlorine Inorganic materials 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 24
- 229910052731 fluorine Inorganic materials 0.000 claims description 24
- 125000004429 atom Chemical group 0.000 claims description 19
- 125000002950 monocyclic group Chemical group 0.000 claims description 19
- 208000024827 Alzheimer disease Diseases 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 15
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 14
- 125000003386 piperidinyl group Chemical group 0.000 claims description 14
- 125000005366 cycloalkylthio group Chemical group 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 12
- 125000004414 alkyl thio group Chemical group 0.000 claims description 11
- 125000004193 piperazinyl group Chemical group 0.000 claims description 11
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 8
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 125000002757 morpholinyl group Chemical group 0.000 claims description 8
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 8
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- CKUAXEQHGKSLHN-UHFFFAOYSA-N [C].[N] Chemical compound [C].[N] CKUAXEQHGKSLHN-UHFFFAOYSA-N 0.000 claims description 7
- CSJDCSCTVDEHRN-UHFFFAOYSA-N methane;molecular oxygen Chemical compound C.O=O CSJDCSCTVDEHRN-UHFFFAOYSA-N 0.000 claims description 7
- 208000015114 central nervous system disease Diseases 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 306
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 201
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 196
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 182
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 163
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 153
- 239000000243 solution Substances 0.000 description 145
- 239000011541 reaction mixture Substances 0.000 description 129
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 124
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 113
- 239000000460 chlorine Substances 0.000 description 112
- 235000019439 ethyl acetate Nutrition 0.000 description 81
- 238000005481 NMR spectroscopy Methods 0.000 description 80
- 230000015572 biosynthetic process Effects 0.000 description 78
- 238000003786 synthesis reaction Methods 0.000 description 78
- 238000005160 1H NMR spectroscopy Methods 0.000 description 76
- 239000007787 solid Substances 0.000 description 72
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 70
- 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 description 69
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 68
- 230000003287 optical effect Effects 0.000 description 57
- 239000012071 phase Substances 0.000 description 57
- 239000012298 atmosphere Substances 0.000 description 53
- 230000002829 reductive effect Effects 0.000 description 53
- 239000012043 crude product Substances 0.000 description 51
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 49
- 239000012044 organic layer Substances 0.000 description 49
- 239000013058 crude material Substances 0.000 description 45
- 238000000034 method Methods 0.000 description 45
- 239000007858 starting material Substances 0.000 description 44
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 43
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 42
- 238000004296 chiral HPLC Methods 0.000 description 42
- 229910052938 sodium sulfate Inorganic materials 0.000 description 38
- 235000011152 sodium sulphate Nutrition 0.000 description 38
- 238000010898 silica gel chromatography Methods 0.000 description 36
- 235000002639 sodium chloride Nutrition 0.000 description 36
- 229920006395 saturated elastomer Polymers 0.000 description 29
- 239000000741 silica gel Substances 0.000 description 28
- 229910002027 silica gel Inorganic materials 0.000 description 28
- 239000002904 solvent Substances 0.000 description 28
- 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 27
- 239000000725 suspension Substances 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- 239000007864 aqueous solution Substances 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000003039 volatile agent Substances 0.000 description 23
- 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 22
- 239000000706 filtrate Substances 0.000 description 21
- 238000011282 treatment Methods 0.000 description 21
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 20
- 125000000753 cycloalkyl group Chemical group 0.000 description 20
- 238000003818 flash chromatography Methods 0.000 description 20
- 238000009472 formulation Methods 0.000 description 20
- 239000000651 prodrug Substances 0.000 description 19
- 229940002612 prodrug Drugs 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 18
- 229910052739 hydrogen Inorganic materials 0.000 description 18
- 239000001257 hydrogen Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 229910052799 carbon Inorganic materials 0.000 description 17
- 229910052805 deuterium Inorganic materials 0.000 description 17
- 238000000746 purification Methods 0.000 description 17
- 125000006413 ring segment Chemical group 0.000 description 17
- 238000006467 substitution reaction Methods 0.000 description 17
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 125000005605 benzo group Chemical group 0.000 description 16
- MSFVEEFXECBJPG-UHFFFAOYSA-N 2-(chloromethyl)pyrimidine Chemical compound ClCC1=NC=CC=N1 MSFVEEFXECBJPG-UHFFFAOYSA-N 0.000 description 15
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 125000004043 oxo group Chemical group O=* 0.000 description 15
- 230000008569 process Effects 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 125000005412 pyrazyl group Chemical group 0.000 description 14
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 13
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- 208000024891 symptom Diseases 0.000 description 13
- 239000001993 wax Substances 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 12
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 230000003956 synaptic plasticity Effects 0.000 description 12
- 230000008901 benefit Effects 0.000 description 11
- 210000003169 central nervous system Anatomy 0.000 description 11
- 238000010348 incorporation Methods 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 230000001965 increasing effect Effects 0.000 description 10
- 238000011068 loading method Methods 0.000 description 10
- 230000000946 synaptic effect Effects 0.000 description 10
- 229940124597 therapeutic agent Drugs 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- 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
- 239000008346 aqueous phase Substances 0.000 description 9
- 238000012512 characterization method Methods 0.000 description 9
- 208000010877 cognitive disease Diseases 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- 239000012299 nitrogen atmosphere Substances 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 206010012289 Dementia Diseases 0.000 description 8
- 241000124008 Mammalia Species 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 125000004093 cyano group Chemical group *C#N 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 8
- 238000001802 infusion Methods 0.000 description 8
- 230000013016 learning Effects 0.000 description 8
- 230000015654 memory Effects 0.000 description 8
- 125000004076 pyridyl group Chemical group 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 7
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 7
- 201000004810 Vascular dementia Diseases 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 7
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 description 7
- 230000007423 decrease Effects 0.000 description 7
- 125000004663 dialkyl amino group Chemical group 0.000 description 7
- 239000006260 foam Substances 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- INLTVLRKFVBWPU-UHFFFAOYSA-N 6-(chloromethyl)imidazo[1,2-b]pyridazine Chemical compound N1=C(CCl)C=CC2=NC=CN21 INLTVLRKFVBWPU-UHFFFAOYSA-N 0.000 description 6
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 241000282412 Homo Species 0.000 description 6
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000002159 abnormal effect Effects 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 6
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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 6
- 235000014113 dietary fatty acids Nutrition 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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- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-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
- DGOYLVBDCVINQZ-UHFFFAOYSA-N oxane-4-carboxamide Chemical compound NC(=O)C1CCOCC1 DGOYLVBDCVINQZ-UHFFFAOYSA-N 0.000 description 6
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- 125000004001 thioalkyl group Chemical group 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- NNOVNCLITMBYRW-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) oxane-4-carboxylate Chemical compound C1COCCC1C(=O)ON1C(=O)CCC1=O NNOVNCLITMBYRW-UHFFFAOYSA-N 0.000 description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 5
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- 238000001727 in vivo Methods 0.000 description 5
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
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- 208000027061 mild cognitive impairment Diseases 0.000 description 5
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 5
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 5
- 238000002953 preparative HPLC Methods 0.000 description 5
- 230000000069 prophylactic effect Effects 0.000 description 5
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- UQJPFFZFTQYRHY-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4,4-difluorocyclohexane-1-carboxylate Chemical compound C1CC(F)(F)CCC1C(=O)ON1C(=O)CCC1=O UQJPFFZFTQYRHY-UHFFFAOYSA-N 0.000 description 4
- GFHPSQFCHUIFTO-UHFFFAOYSA-N 2-(chloromethyl)pyrazine Chemical compound ClCC1=CN=CC=N1 GFHPSQFCHUIFTO-UHFFFAOYSA-N 0.000 description 4
- MIBCYYGVLHFYSD-UHFFFAOYSA-N 3,4-dihydro-2h-pyran-5-carboxylic acid Chemical compound OC(=O)C1=COCCC1 MIBCYYGVLHFYSD-UHFFFAOYSA-N 0.000 description 4
- WKSLUZTZBSDWDE-UHFFFAOYSA-N 5-chloro-2-methylbenzoyl chloride Chemical compound CC1=CC=C(Cl)C=C1C(Cl)=O WKSLUZTZBSDWDE-UHFFFAOYSA-N 0.000 description 4
- QSLLFYVBWXWUQT-UHFFFAOYSA-N 7-Azaindolizine Chemical compound C1=NC=CN2C=CC=C21 QSLLFYVBWXWUQT-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 241000416162 Astragalus gummifer Species 0.000 description 4
- 208000020925 Bipolar disease Diseases 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 208000014094 Dystonic disease Diseases 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
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Landscapes
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Cited By (1)
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| JP2016104747A (ja) * | 2010-09-20 | 2016-06-09 | フォーラム・ファーマシューティカルズ・インコーポレイテッドＦｏｒｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃ． | イミダゾトリアジノン化合物 |
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| 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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| SK287161B6 (sk) | 1997-11-12 | 2010-02-08 | Bayer Healthcare Ag | 2-Fenylsubstituované imidazotriazinóny, spôsob ich výroby, liečivá obsahujúce tieto látky a ich použitie |
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| 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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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2016104747A (ja) * | 2010-09-20 | 2016-06-09 | フォーラム・ファーマシューティカルズ・インコーポレイテッドＦｏｒｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃ． | イミダゾトリアジノン化合物 |
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| WO2012040230A1 (en) | 2012-03-29 |
| RU2013118362A (ru) | 2014-10-27 |
| BR112013008140A2 (pt) | 2017-12-05 |
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| TW201217381A (en) | 2012-05-01 |
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| US20170152265A1 (en) | 2017-06-01 |
| HK1187908A1 (en) | 2014-04-17 |
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| AU2011305568B2 (en) | 2015-12-10 |
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| 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 |
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| DK2619208T3 (en) | 2017-01-30 |
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| 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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