EP3119778A1 - Imidazo[1,2-a]pyridine-carboxamides substitués et leur utilisation - Google Patents
Imidazo[1,2-a]pyridine-carboxamides substitués et leur utilisationInfo
- Publication number
- EP3119778A1 EP3119778A1 EP15710528.9A EP15710528A EP3119778A1 EP 3119778 A1 EP3119778 A1 EP 3119778A1 EP 15710528 A EP15710528 A EP 15710528A EP 3119778 A1 EP3119778 A1 EP 3119778A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- substituted
- phenyl
- group
- alkyl
- methyl
- 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.)
- Withdrawn
Links
- BEHYAANJUKYBTH-UHFFFAOYSA-N imidazo[1,2-a]pyridine-2-carboxamide Chemical class C1=CC=CC2=NC(C(=O)N)=CN21 BEHYAANJUKYBTH-UHFFFAOYSA-N 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 188
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 63
- 238000011282 treatment Methods 0.000 claims abstract description 44
- 201000010099 disease Diseases 0.000 claims abstract description 35
- 238000011321 prophylaxis Methods 0.000 claims abstract description 35
- 239000003814 drug Substances 0.000 claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 261
- -1 cyano, monofluoromethyl Chemical group 0.000 claims description 196
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 100
- 150000003839 salts Chemical class 0.000 claims description 100
- 229910052731 fluorine Inorganic materials 0.000 claims description 91
- 239000011737 fluorine Substances 0.000 claims description 91
- 125000001424 substituent group Chemical group 0.000 claims description 88
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 83
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 82
- 229910052739 hydrogen Inorganic materials 0.000 claims description 81
- 239000001257 hydrogen Substances 0.000 claims description 81
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 76
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 66
- 239000012453 solvate Substances 0.000 claims description 64
- 150000002431 hydrogen Chemical class 0.000 claims description 47
- 229910052757 nitrogen Inorganic materials 0.000 claims description 45
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 40
- 239000000460 chlorine Chemical group 0.000 claims description 37
- 229910052801 chlorine Inorganic materials 0.000 claims description 36
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 30
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 29
- 125000004193 piperazinyl group Chemical group 0.000 claims description 29
- 239000002904 solvent Substances 0.000 claims description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- 208000035475 disorder Diseases 0.000 claims description 27
- 125000000623 heterocyclic group Chemical group 0.000 claims description 26
- 125000001624 naphthyl group Chemical group 0.000 claims description 25
- 125000004076 pyridyl group Chemical group 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 21
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 239000012442 inert solvent Substances 0.000 claims description 20
- 125000004043 oxo group Chemical group O=* 0.000 claims description 20
- 239000003112 inhibitor Substances 0.000 claims description 19
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 18
- 125000001153 fluoro group Chemical group F* 0.000 claims description 16
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 16
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 15
- 206010019280 Heart failures Diseases 0.000 claims description 15
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 14
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 13
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 13
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 13
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 12
- 206010020772 Hypertension Diseases 0.000 claims description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 12
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 12
- 125000004549 quinolin-4-yl group Chemical group N1=CC=C(C2=CC=CC=C12)* 0.000 claims description 12
- 125000004262 quinoxalin-2-yl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N=C1* 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 11
- 208000002815 pulmonary hypertension Diseases 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 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 10
- 241001465754 Metazoa Species 0.000 claims description 10
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 10
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 10
- 201000006370 kidney failure Diseases 0.000 claims description 10
- 125000002757 morpholinyl group Chemical group 0.000 claims description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims description 10
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 9
- 206010002383 Angina Pectoris Diseases 0.000 claims description 9
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 9
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 230000008878 coupling Effects 0.000 claims description 8
- 238000010168 coupling process Methods 0.000 claims description 8
- 238000005859 coupling reaction Methods 0.000 claims description 8
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 8
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 8
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 8
- 208000028867 ischemia Diseases 0.000 claims description 8
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 8
- 230000009424 thromboembolic effect Effects 0.000 claims description 8
- 208000019553 vascular disease Diseases 0.000 claims description 8
- 125000006530 (C4-C6) alkyl group Chemical group 0.000 claims description 7
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 claims description 7
- 150000007513 acids Chemical class 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 239000003146 anticoagulant agent Substances 0.000 claims description 6
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 6
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 6
- 150000001735 carboxylic acids Chemical class 0.000 claims description 6
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 6
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 6
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 5
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 125000004521 1,3,4-thiadiazol-2-yl group Chemical group S1C(=NN=C1)* 0.000 claims description 4
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 4
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000006638 cyclopentyl carbonyl group Chemical group 0.000 claims description 4
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 claims description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 4
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 3
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 229940030600 antihypertensive agent Drugs 0.000 claims description 3
- 239000002220 antihypertensive agent Substances 0.000 claims description 3
- 229960004676 antithrombotic agent Drugs 0.000 claims description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- 150000002632 lipids Chemical class 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 229940082615 organic nitrates used in cardiac disease Drugs 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 208000001435 Thromboembolism Diseases 0.000 claims description 2
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- 150000001204 N-oxides Chemical class 0.000 claims 3
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims 1
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims 1
- UPUWMQZUXFAUCJ-UHFFFAOYSA-N 2,5-dihydro-1,2-thiazole Chemical compound C1SNC=C1 UPUWMQZUXFAUCJ-UHFFFAOYSA-N 0.000 claims 1
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 149
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 147
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 138
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 135
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 124
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 119
- 239000000243 solution Substances 0.000 description 99
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 85
- 125000006508 2,6-difluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C(F)=C1[H])C([H])([H])* 0.000 description 74
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 74
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 70
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 68
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 68
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 62
- 238000005481 NMR spectroscopy Methods 0.000 description 62
- 239000000203 mixture Substances 0.000 description 61
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
- 239000011541 reaction mixture Substances 0.000 description 58
- 238000006243 chemical reaction Methods 0.000 description 48
- 239000003480 eluent Substances 0.000 description 46
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 42
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 41
- 239000007787 solid Substances 0.000 description 36
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical class COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 34
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 34
- 235000019253 formic acid Nutrition 0.000 description 34
- 239000000126 substance Substances 0.000 description 34
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 31
- 239000012071 phase Substances 0.000 description 30
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 29
- 239000012074 organic phase Substances 0.000 description 27
- 238000002953 preparative HPLC Methods 0.000 description 27
- 239000000047 product Substances 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 26
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 24
- 239000003643 water by type Substances 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 23
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 22
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- 238000010992 reflux Methods 0.000 description 21
- 238000012360 testing method Methods 0.000 description 21
- 239000007821 HATU Substances 0.000 description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- 239000008346 aqueous phase Substances 0.000 description 20
- 229910052938 sodium sulfate Inorganic materials 0.000 description 20
- 235000011152 sodium sulphate Nutrition 0.000 description 20
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
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- 238000000825 ultraviolet detection Methods 0.000 description 18
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- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 16
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- XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 description 16
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- 230000015572 biosynthetic process Effects 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 14
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- 239000002585 base Substances 0.000 description 13
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 13
- 239000002808 molecular sieve Substances 0.000 description 13
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
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- 230000000694 effects Effects 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 12
- 235000005152 nicotinamide Nutrition 0.000 description 12
- 239000011570 nicotinamide Substances 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- WBBAOGDGSBFBCN-UHFFFAOYSA-N 2,5-dimethylimidazo[1,2-a]pyridine-3-carbohydrazide Chemical compound C1=CC=C(C)N2C(C(=O)NN)=C(C)N=C21 WBBAOGDGSBFBCN-UHFFFAOYSA-N 0.000 description 11
- 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 11
- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 description 11
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 description 11
- 229910052786 argon Inorganic materials 0.000 description 11
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 11
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Definitions
- the present application relates to novel substituted imidazo [1,2-a] pyridine-3-carboxamides, processes for their preparation, their use alone or in combinations for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular for the treatment and / or prophylaxis of cardiovascular diseases.
- cGMP cyclic guanosine monophosphate
- NO nitric oxide
- GTP guanosine triphosphate
- R 6 represents hydrogen, cyano or halogen, and their oxides, salts, solvates, salts of the oxides and solvates of the oxides and salts.
- Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
- prodrugs of the compounds according to the invention.
- prodrugs denotes compounds which themselves are biologically active or may be inactive, but during their residence time in the body to be converted into compounds of the invention (for example, metabolically or hydrolytically).
- R 11 is hydrogen, methyl or ethyl, in which methyl and ethyl may be substituted by phenyl, wherein phenyl may be substituted by fluorine, chlorine or cyano, or
- R 10 is hydrogen
- R 11 is hydrogen or methyl, wherein methyl is substituted with phenyl, wherein phenyl is substituted with chlorine, or
- R 12 is hydrogen, cyclopropyl, methoxy or fluorine
- R 7 is hydrogen, (Ci-Go) alkyl, cyclopentyl, pyrrolidin-1-yl, 1,1-Dioxidotetrahydrothiophen-3-yl), l, l-Dioxidotetrahydro-2H-thiopyran-4-yl, methylcarbonyl, ethylcarbonyl, Cyclopropylcarbonyl, cyclopentylcarbonyl, 1,3-thiazol-2-yl-carbonyl, 1,3-thiazol-2-yl, l, 3-thiazol-4-yl, l, 3,4-thiadiazol-2-yl, pyridyl, Pyrimidin-2-yl, quinolin-4-yl, quinoxalin-2-yl, phenyl or naphthyl, wherein (Ci-Cio) alkyl may be substituted with trifluoromethyl, ethoxycarbonyl, amino or phenyl, wherein cyclopent
- R 10 and R 11 together with the nitrogen atom to which they are attached form a piperazinyl ring in which the piperazinyl ring may be substituted by phenyl, and their oxides, salts, solvates, salts of oxides and solvates of Oxides and salts.
- the hydrolysis of the ester group T 1 of the compounds of formula (II) is carried out by conventional methods by treating the esters in inert solvents with acids or bases, wherein in the latter the initially formed salts are converted by treatment with acid into the free carboxylic acids ,
- the ester cleavage is preferably carried out with acids.
- the ester cleavage is preferably carried out by hydrogenolysis with palladium on activated carbon or Raney nickel.
- Suitable inert solvents for this reaction are water or the organic solvents customary for ester cleavage.
- the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
- LMW low molecular weight
- Method 5 Instrument MS: Waters ZQ 2000; Instrument HPLC: Agilent 1100, 2-column circuit, Autosampler: HTC PAL; Column: YMC-ODS-AQ, 50 mm ⁇ 4.6 mm, 3.0 ⁇ m; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 100% A - 0.2 min 95% A - 1.8 min 25% A - 1.9 min 10% A - 2.0 min 5% A - 3.2 min 5% A - 3.21 min 100% A - 3.35 min 100% A; Oven: 40 ° C; Flow: 3.0 ml / min; UV detection: 210 nm.
- Instrument MS Waters
- instrument HPLC Waters (column Waters X-Bridge C18, 18 mm x 50 mm, 5 ⁇
- eluent A water + 0.05% triethylamine
- eluent B acetonitrile (ULC) + 0.05% triethylamine
- flow 40 ml / min
- UV detection DAD, 210 - 400 nm). respectively.:
- reaction solution was combined with diatomaceous earth, concentrated at low temperature and purified by means of silica gel chromatography (mobile phase: cyclohexane / ethyl acetate: 9/1). 637 mg of the target compound (94% of theory, purity 100%) were obtained.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14161143 | 2014-03-21 | ||
PCT/EP2015/055796 WO2015140254A1 (fr) | 2014-03-21 | 2015-03-19 | Imidazo[1,2-a]pyridine-carboxamides substitués et leur utilisation |
Publications (1)
Publication Number | Publication Date |
---|---|
EP3119778A1 true EP3119778A1 (fr) | 2017-01-25 |
Family
ID=50336220
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP15710528.9A Withdrawn EP3119778A1 (fr) | 2014-03-21 | 2015-03-19 | Imidazo[1,2-a]pyridine-carboxamides substitués et leur utilisation |
Country Status (7)
Country | Link |
---|---|
US (1) | US20170057954A1 (fr) |
EP (1) | EP3119778A1 (fr) |
JP (1) | JP2017508811A (fr) |
CN (1) | CN106103438A (fr) |
CA (1) | CA2943051A1 (fr) |
HK (1) | HK1225723A1 (fr) |
WO (1) | WO2015140254A1 (fr) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9624214B2 (en) | 2012-11-05 | 2017-04-18 | Bayer Pharma Aktiengesellschaft | Amino-substituted imidazo[1,2-a]pyridinecarboxamides and their use |
US9771360B2 (en) | 2014-03-21 | 2017-09-26 | Bayer Pharma Aktiengesellschaft | Cyano-substituted imidazo[1,2-A]pyridinecarboxamides and their use |
CA2969268A1 (fr) | 2014-12-02 | 2016-06-09 | Bayer Pharma Aktiengesellschaft | Imidazo[1,2-a]pyridines a substitution heteroaryle et leur utilisation |
EA201891416A1 (ru) | 2015-12-14 | 2018-12-28 | Айронвуд Фармасьютикалз, Инк. | ПРИМЕНЕНИЕ СТИМУЛЯТОРОВ sGC ДЛЯ ЛЕЧЕНИЯ ДИСФУНКЦИИ ЖЕЛУДОЧНО-КИШЕЧНОГО СФИНКТЕРА |
EP3554488A2 (fr) | 2016-12-13 | 2019-10-23 | Cyclerion Therapeutics, Inc. | Utilisation de stimulateurs de sgc pour le traitement de la motilité sophagienne |
CN106831765B (zh) * | 2016-12-28 | 2018-12-14 | 郑州大学 | 2-(2,6-二氰基苯基)咪唑并[1,2-α]吡啶类化合物及其制备方法 |
WO2018184976A1 (fr) | 2017-04-05 | 2018-10-11 | Bayer Pharma Aktiengesellschaft | Imidazo[1,2-a]pyridine-carboxamides substitués et leur utilisation |
AU2019301683A1 (en) | 2018-07-11 | 2021-02-11 | Tisento Therapeutics Inc. | Use of sGC stimulators for the treatment of mitochonrial disorders |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5976788B2 (ja) * | 2011-05-06 | 2016-08-24 | バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングBayer Intellectual Property GmbH | 置換イミダゾピリジンおよびイミダゾピリダジンならびにそれらの使用 |
PL2716642T3 (pl) * | 2011-05-30 | 2017-01-31 | Astellas Pharma Inc. | Związki imidazopirydyny |
CA2914100A1 (fr) * | 2013-06-04 | 2014-12-11 | Bayer Pharma Aktiengesellschaft | Imidazo[1,2-a]pyridines a substitution 3-aryle et leur utilisation |
US9422285B2 (en) * | 2013-08-08 | 2016-08-23 | Bayer Pharma Aktiengesellschaft | Substituted pyrazolo[1,5-A]-pyridine-3-carboxamides and use thereof |
-
2015
- 2015-03-19 EP EP15710528.9A patent/EP3119778A1/fr not_active Withdrawn
- 2015-03-19 JP JP2017500417A patent/JP2017508811A/ja active Pending
- 2015-03-19 US US15/120,343 patent/US20170057954A1/en not_active Abandoned
- 2015-03-19 CN CN201580015369.2A patent/CN106103438A/zh active Pending
- 2015-03-19 WO PCT/EP2015/055796 patent/WO2015140254A1/fr active Application Filing
- 2015-03-19 CA CA2943051A patent/CA2943051A1/fr not_active Abandoned
-
2016
- 2016-12-08 HK HK16113968A patent/HK1225723A1/zh unknown
Non-Patent Citations (2)
Title |
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None * |
See also references of WO2015140254A1 * |
Also Published As
Publication number | Publication date |
---|---|
HK1225723A1 (zh) | 2017-09-15 |
US20170057954A1 (en) | 2017-03-02 |
JP2017508811A (ja) | 2017-03-30 |
CN106103438A (zh) | 2016-11-09 |
WO2015140254A1 (fr) | 2015-09-24 |
CA2943051A1 (fr) | 2015-09-24 |
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