CA2811714C - Imidazotriazinone compounds - Google Patents
Imidazotriazinone compounds Download PDFInfo
- Publication number
- CA2811714C CA2811714C CA2811714A CA2811714A CA2811714C CA 2811714 C CA2811714 C CA 2811714C CA 2811714 A CA2811714 A CA 2811714A CA 2811714 A CA2811714 A CA 2811714A CA 2811714 C CA2811714 C CA 2811714C
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- compound
- trans
- triazin
- 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.)
- Expired - Fee Related
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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 abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 189
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 149
- 201000010099 disease Diseases 0.000 claims abstract description 73
- 208000035475 disorder Diseases 0.000 claims abstract description 67
- 101100407341 Drosophila melanogaster Pde9 gene Proteins 0.000 claims abstract description 51
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 30
- 238000011282 treatment Methods 0.000 claims abstract description 25
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 306
- -1 pyrimidinylmethyl- Chemical group 0.000 claims description 251
- 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 153
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 82
- 229910052736 halogen Inorganic materials 0.000 claims description 74
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 73
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 70
- 125000001424 substituent group Chemical group 0.000 claims description 67
- 125000003545 alkoxy group Chemical group 0.000 claims description 61
- 150000002367 halogens Chemical class 0.000 claims description 57
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 57
- 125000001072 heteroaryl group Chemical group 0.000 claims description 52
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 37
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 35
- 239000003814 drug Substances 0.000 claims description 33
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 30
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 27
- 208000024827 Alzheimer disease Diseases 0.000 claims description 25
- 125000002950 monocyclic group Chemical group 0.000 claims description 19
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 150000002430 hydrocarbons Chemical class 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims 15
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims 4
- 238000000034 method Methods 0.000 abstract description 47
- 230000008569 process Effects 0.000 abstract description 15
- 241000124008 Mammalia Species 0.000 abstract description 9
- 239000003112 inhibitor Substances 0.000 abstract description 7
- 101001117256 Drosophila melanogaster High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A Proteins 0.000 abstract description 4
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 222
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 180
- 239000000243 solution Substances 0.000 description 145
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 144
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 143
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 134
- 239000011541 reaction mixture Substances 0.000 description 125
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 118
- 238000004809 thin layer chromatography Methods 0.000 description 108
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 96
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 86
- 239000007787 solid Substances 0.000 description 82
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 76
- 238000005160 1H NMR spectroscopy Methods 0.000 description 74
- 230000015572 biosynthetic process Effects 0.000 description 74
- 238000003786 synthesis reaction Methods 0.000 description 74
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 72
- 239000000203 mixture Substances 0.000 description 70
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 69
- 101150041968 CDC13 gene Proteins 0.000 description 67
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 67
- 239000012298 atmosphere Substances 0.000 description 55
- 230000003287 optical effect Effects 0.000 description 53
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 50
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 50
- 239000012071 phase Substances 0.000 description 50
- 239000012044 organic layer Substances 0.000 description 49
- 230000002829 reductive effect Effects 0.000 description 49
- 229910052938 sodium sulfate Inorganic materials 0.000 description 48
- 235000011152 sodium sulphate Nutrition 0.000 description 48
- 239000012043 crude product Substances 0.000 description 46
- 239000013058 crude material Substances 0.000 description 45
- 239000007858 starting material Substances 0.000 description 45
- 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 44
- 229910000024 caesium carbonate Inorganic materials 0.000 description 43
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 40
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 39
- 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 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 37
- 238000004296 chiral HPLC Methods 0.000 description 37
- 238000005481 NMR spectroscopy Methods 0.000 description 36
- 235000002639 sodium chloride Nutrition 0.000 description 36
- 125000000753 cycloalkyl group Chemical group 0.000 description 35
- 238000010898 silica gel chromatography Methods 0.000 description 35
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 29
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 29
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 29
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 27
- 238000010992 reflux Methods 0.000 description 27
- 239000000725 suspension Substances 0.000 description 27
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 25
- 235000019341 magnesium sulphate Nutrition 0.000 description 25
- 239000000741 silica gel Substances 0.000 description 25
- 229910002027 silica gel Inorganic materials 0.000 description 25
- 229960001866 silicon dioxide Drugs 0.000 description 25
- 125000003118 aryl group Chemical group 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 23
- 239000003039 volatile agent Substances 0.000 description 23
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 21
- 229910019201 POBr3 Inorganic materials 0.000 description 21
- 235000011114 ammonium hydroxide Nutrition 0.000 description 21
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 20
- 238000003818 flash chromatography Methods 0.000 description 20
- 238000009472 formulation Methods 0.000 description 20
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 20
- 125000005842 heteroatom Chemical group 0.000 description 19
- 239000000651 prodrug Substances 0.000 description 19
- 229940002612 prodrug Drugs 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 19
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- 238000006467 substitution reaction Methods 0.000 description 18
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 17
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 17
- 229910052805 deuterium Inorganic materials 0.000 description 17
- 229940079593 drug Drugs 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 17
- 238000000746 purification Methods 0.000 description 17
- 125000006413 ring segment Chemical group 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
- 125000004429 atom Chemical group 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 15
- 125000005605 benzo group Chemical group 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
- MSFVEEFXECBJPG-UHFFFAOYSA-N 2-(chloromethyl)pyrimidine Chemical compound ClCC1=NC=CC=N1 MSFVEEFXECBJPG-UHFFFAOYSA-N 0.000 description 14
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- 239000013078 crystal Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 125000005412 pyrazyl group Chemical group 0.000 description 14
- 208000024891 symptom Diseases 0.000 description 14
- 239000001993 wax Substances 0.000 description 14
- 229910052799 carbon Inorganic materials 0.000 description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 230000003956 synaptic plasticity Effects 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 11
- 210000003169 central nervous system Anatomy 0.000 description 11
- 238000002347 injection Methods 0.000 description 11
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- 230000000946 synaptic effect Effects 0.000 description 11
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 10
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- 230000001965 increasing effect Effects 0.000 description 10
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- 229910017711 NHRa Inorganic materials 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 9
- 125000003282 alkyl amino group Chemical group 0.000 description 9
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 description 9
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- 229940124597 therapeutic agent Drugs 0.000 description 9
- QMNWYGTWTXOQTP-UHFFFAOYSA-N 1h-triazin-6-one Chemical compound O=C1C=CN=NN1 QMNWYGTWTXOQTP-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 206010012289 Dementia Diseases 0.000 description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 125000004414 alkyl thio group Chemical group 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 8
- 125000004093 cyano group Chemical group *C#N 0.000 description 8
- 125000005366 cycloalkylthio group Chemical group 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 239000006260 foam Substances 0.000 description 8
- 230000013016 learning Effects 0.000 description 8
- 238000011068 loading method Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 239000012299 nitrogen atmosphere Substances 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- 125000004193 piperazinyl group Chemical group 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 201000011240 Frontotemporal dementia Diseases 0.000 description 7
- 201000004810 Vascular dementia Diseases 0.000 description 7
- 125000002252 acyl group Chemical group 0.000 description 7
- 125000003368 amide group Chemical group 0.000 description 7
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- 208000010877 cognitive disease Diseases 0.000 description 7
- 125000004663 dialkyl amino group Chemical group 0.000 description 7
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- 229910052742 iron Inorganic materials 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 239000012279 sodium borohydride Substances 0.000 description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- 208000036864 Attention deficit/hyperactivity disease Diseases 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
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 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
- 125000004122 cyclic group Chemical group 0.000 description 6
- 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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- 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
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 6
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- YEWPVCUHKJABMV-UHFFFAOYSA-N oxane-3-carboxylic acid Chemical compound OC(=O)C1CCCOC1 YEWPVCUHKJABMV-UHFFFAOYSA-N 0.000 description 6
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
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- 230000000472 traumatic effect Effects 0.000 description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 5
- 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 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
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- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 229960000744 vinpocetine Drugs 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000031836 visual learning Effects 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/22—Anxiolytics
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- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- 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
- 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
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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- Neurosurgery (AREA)
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- Psychiatry (AREA)
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- Psychology (AREA)
- Ophthalmology & Optometry (AREA)
- Hospice & Palliative Care (AREA)
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- Communicable Diseases (AREA)
- Oncology (AREA)
- Anesthesiology (AREA)
- Molecular Biology (AREA)
- AIDS & HIV (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US38469410P | 2010-09-20 | 2010-09-20 | |
| US61/384,694 | 2010-09-20 | ||
| PCT/US2011/052399 WO2012040230A1 (en) | 2010-09-20 | 2011-09-20 | Imidazotriazinone compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2811714A1 CA2811714A1 (en) | 2012-03-29 |
| CA2811714C true CA2811714C (en) | 2017-11-21 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2811714A Expired - Fee Related CA2811714C (en) | 2010-09-20 | 2011-09-20 | Imidazotriazinone compounds |
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| EP (2) | EP3181566A1 (enExample) |
| JP (2) | JP5855109B2 (enExample) |
| CN (1) | CN103313988B (enExample) |
| AR (1) | AR083058A1 (enExample) |
| AU (2) | AU2011305568B2 (enExample) |
| BR (1) | BR112013008140A8 (enExample) |
| CA (1) | CA2811714C (enExample) |
| DK (1) | DK2619208T3 (enExample) |
| ES (1) | ES2610360T3 (enExample) |
| MX (1) | MX2013003093A (enExample) |
| PL (1) | PL2619208T3 (enExample) |
| RU (1) | RU2603140C2 (enExample) |
| TW (1) | TWI541244B (enExample) |
| UY (1) | UY33616A (enExample) |
| WO (1) | WO2012040230A1 (enExample) |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
|---|---|---|---|---|
| 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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2011
- 2011-09-20 PL PL11761793T patent/PL2619208T3/pl unknown
- 2011-09-20 RU RU2013118362/04A patent/RU2603140C2/ru not_active IP Right Cessation
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- 2011-09-20 CN CN201180055157.9A patent/CN103313988B/zh not_active Expired - Fee Related
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- 2011-09-20 CA CA2811714A patent/CA2811714C/en not_active Expired - Fee Related
- 2011-09-20 EP EP16197573.5A patent/EP3181566A1/en not_active Withdrawn
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- 2011-09-20 UY UY0001033616A patent/UY33616A/es unknown
- 2011-09-20 AU AU2011305568A patent/AU2011305568B2/en not_active Ceased
- 2011-09-20 EP EP11761793.6A patent/EP2619208B1/en not_active Not-in-force
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- 2011-09-20 WO PCT/US2011/052399 patent/WO2012040230A1/en not_active Ceased
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- 2016-12-07 US US15/371,935 patent/US20170152265A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012040230A1 (en) | 2012-03-29 |
| RU2013118362A (ru) | 2014-10-27 |
| BR112013008140A2 (pt) | 2017-12-05 |
| PL2619208T3 (pl) | 2017-03-31 |
| TW201217381A (en) | 2012-05-01 |
| 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 |
| AU2011305568B2 (en) | 2015-12-10 |
| AR083058A1 (es) | 2013-01-30 |
| EP2619208A1 (en) | 2013-07-31 |
| 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 |
| MX2013003093A (es) | 2013-10-28 |
| 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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Legal Events
| Date | Code | Title | Description |
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| EEER | Examination request |
Effective date: 20140919 |
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| MKLA | Lapsed |
Effective date: 20190920 |