CN108892637A - Ship1调节剂及与其相关的方法 - Google Patents
Ship1调节剂及与其相关的方法 Download PDFInfo
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- CN108892637A CN108892637A CN201810634778.6A CN201810634778A CN108892637A CN 108892637 A CN108892637 A CN 108892637A CN 201810634778 A CN201810634778 A CN 201810634778A CN 108892637 A CN108892637 A CN 108892637A
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- Prior art keywords
- alkyl
- compound
- chain
- hydrogen
- methyl
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- 238000000034 method Methods 0.000 title claims abstract description 93
- 101000616502 Homo sapiens Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1 Proteins 0.000 title claims abstract description 37
- 102100021797 Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1 Human genes 0.000 title claims abstract description 37
- 150000001875 compounds Chemical class 0.000 claims abstract description 670
- 239000000203 mixture Substances 0.000 claims abstract description 159
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 116
- 201000010099 disease Diseases 0.000 claims abstract description 110
- 150000003839 salts Chemical class 0.000 claims abstract description 100
- 239000012453 solvate Substances 0.000 claims abstract description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 310
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 260
- 229910052739 hydrogen Inorganic materials 0.000 claims description 230
- 239000001257 hydrogen Substances 0.000 claims description 226
- -1 cyclic hydrocarbon radical Chemical class 0.000 claims description 191
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 128
- 229910052799 carbon Inorganic materials 0.000 claims description 125
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 118
- 125000003118 aryl group Chemical group 0.000 claims description 106
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 103
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 98
- 125000001072 heteroaryl group Chemical group 0.000 claims description 93
- 125000001118 alkylidene group Chemical group 0.000 claims description 87
- 125000000623 heterocyclic group Chemical group 0.000 claims description 85
- 125000003342 alkenyl group Chemical group 0.000 claims description 75
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 72
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 58
- 150000002240 furans Chemical class 0.000 claims description 54
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 53
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 51
- 125000000304 alkynyl group Chemical group 0.000 claims description 50
- 125000002947 alkylene group Chemical group 0.000 claims description 40
- 125000004450 alkenylene group Chemical group 0.000 claims description 38
- 125000004419 alkynylene group Chemical group 0.000 claims description 33
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 33
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 27
- 241000124008 Mammalia Species 0.000 claims description 26
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 25
- 125000004447 heteroarylalkenyl group Chemical group 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 21
- 229930192474 thiophene Natural products 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 10
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 8
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 206010061218 Inflammation Diseases 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 230000004054 inflammatory process Effects 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 230000008901 benefit Effects 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000005936 piperidyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 4
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 4
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 4
- 235000005152 nicotinamide Nutrition 0.000 claims description 4
- 239000011570 nicotinamide Substances 0.000 claims description 4
- 229960003966 nicotinamide Drugs 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 230000002062 proliferating effect Effects 0.000 claims description 3
- NNBZCPXTIHJBJL-UHFFFAOYSA-N trans-decahydronaphthalene Natural products C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims 38
- 150000003217 pyrazoles Chemical class 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 11
- 241001465754 Metazoa Species 0.000 abstract description 7
- 239000002585 base Substances 0.000 description 309
- 239000000243 solution Substances 0.000 description 147
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 136
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 116
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 109
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 96
- 239000001301 oxygen Substances 0.000 description 91
- 229910052760 oxygen Inorganic materials 0.000 description 91
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 86
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 84
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 80
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 74
- 235000019439 ethyl acetate Nutrition 0.000 description 67
- 229910052786 argon Inorganic materials 0.000 description 58
- 239000007789 gas Substances 0.000 description 58
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 57
- 238000006243 chemical reaction Methods 0.000 description 55
- 238000010898 silica gel chromatography Methods 0.000 description 55
- 238000004519 manufacturing process Methods 0.000 description 52
- 238000002360 preparation method Methods 0.000 description 49
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 46
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 43
- 238000012545 processing Methods 0.000 description 42
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 40
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 37
- 239000012044 organic layer Substances 0.000 description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 35
- 239000006260 foam Substances 0.000 description 35
- UTXBJOTXFNNRDN-UHFFFAOYSA-N CC(C)(C)[Si](C)(C)[O] Chemical compound CC(C)(C)[Si](C)(C)[O] UTXBJOTXFNNRDN-UHFFFAOYSA-N 0.000 description 34
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 33
- 238000003756 stirring Methods 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 25
- 239000007787 solid Substances 0.000 description 24
- KDYHNAUCPVCMSI-UHFFFAOYSA-N phenanthro[9,10-d][1,3]dioxole Chemical compound C12=CC=CC=C2C2=CC=CC=C2C2=C1OCO2 KDYHNAUCPVCMSI-UHFFFAOYSA-N 0.000 description 23
- 230000015572 biosynthetic process Effects 0.000 description 22
- 239000000126 substance Substances 0.000 description 22
- 238000003786 synthesis reaction Methods 0.000 description 22
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 21
- 239000000010 aprotic solvent Substances 0.000 description 21
- 239000007864 aqueous solution Substances 0.000 description 21
- 238000004140 cleaning Methods 0.000 description 21
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 21
- 150000003254 radicals Chemical class 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- 238000000605 extraction Methods 0.000 description 19
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 19
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
- 229940002612 prodrug Drugs 0.000 description 17
- 239000000651 prodrug Substances 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 16
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 16
- 150000001721 carbon Chemical group 0.000 description 16
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 16
- 125000004043 oxo group Chemical group O=* 0.000 description 16
- 239000012071 phase Substances 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 16
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 230000000903 blocking effect Effects 0.000 description 14
- 230000008859 change Effects 0.000 description 14
- 125000004093 cyano group Chemical group *C#N 0.000 description 14
- 235000019441 ethanol Nutrition 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 14
- VUAXHMVRKOTJKP-UHFFFAOYSA-M 2,2-dimethylbutanoate Chemical compound CCC(C)(C)C([O-])=O VUAXHMVRKOTJKP-UHFFFAOYSA-M 0.000 description 13
- 229960000583 acetic acid Drugs 0.000 description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 12
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 12
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 238000011282 treatment Methods 0.000 description 12
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 10
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- 150000001336 alkenes Chemical class 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
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- 238000010790 dilution Methods 0.000 description 10
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
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- 229910000033 sodium borohydride Inorganic materials 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
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- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 5
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- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201361786020P | 2013-03-14 | 2013-03-14 | |
| US61/786,020 | 2013-03-14 | ||
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| CN108752236A (zh) | 2013-01-09 | 2018-11-06 | 阿奎诺克斯药物(加拿大)公司 | Ship1调节剂和与其相关的方法 |
| US9765085B2 (en) | 2013-03-14 | 2017-09-19 | Aquinox Pharmaceuticals (Canada) Inc. | SHIP1 modulators and methods related thereto |
| WO2014143561A1 (en) | 2013-03-14 | 2014-09-18 | Aquinox Pharmaceuticals Inc. | Ship1 modulators and methods related thereto |
| WO2016210146A1 (en) | 2015-06-26 | 2016-12-29 | Aquinox Pharmaceuticals (Canada) Inc. | Crystalline solid forms of the acetate salt of (1s,3s,4r)-4-((3as,4r,5s,7as)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1h-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol |
| AU2017209430A1 (en) | 2016-01-20 | 2018-07-12 | Aquinox Pharmaceuticals (Canada) Inc. | Synthesis of a substituted indene derivative |
| EP3423465A1 (en) * | 2016-03-02 | 2019-01-09 | Patheon Austria GmbH & Co KG | Process and intermediates for the production of 17(20)-ene b-seco steroids |
| WO2018126040A1 (en) | 2016-12-28 | 2018-07-05 | Aquinox Pharmaceuticals (Canada) Inc. | Crystalline solid forms of (1s,3s,4r)-4-((3as,4r,5s,7as)-4- (aminomethyl)-7a-methyl-1-methyleneoctahydro-1h-inden-5-yl)-3- (hydroxymethyl)-4-methylcyclohexanol |
| WO2019195692A1 (en) | 2018-04-06 | 2019-10-10 | Aquinox Pharmaceuticals (Canada) Inc. | Hexadecahydro-1h-cyclopenta[a]phenanthrene derivatives useful in treating pain and inflammation |
| WO2019195777A1 (en) | 2018-04-06 | 2019-10-10 | Aquinox Pharmaceuticals (Canada) Inc. | Indene derivatives useful in treating pain and inflammation |
| WO2019195751A1 (en) | 2018-04-06 | 2019-10-10 | Aquinox Pharmaceuticals (Canada) Inc. | Indene derivatives useful in treating pain and inflammation |
| CN112940062B (zh) * | 2021-02-23 | 2022-09-06 | 浙江神洲药业有限公司 | 一种16-去氢黄体酮的制备方法 |
| CN117024374A (zh) * | 2023-08-08 | 2023-11-10 | 安庆百谊生物科技有限公司 | 一种3-甲基-1,2,4-噻二唑-5-碳酰肼或其盐的合成方法 |
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| CN1805915A (zh) * | 2003-04-15 | 2006-07-19 | 茵弗莱采姆药物有限公司 | 作为药物活性剂的茚衍生物 |
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| JP6407951B2 (ja) | 2018-10-17 |
| RU2679805C2 (ru) | 2019-02-13 |
| WO2014158654A1 (en) | 2014-10-02 |
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| CA2902768A1 (en) | 2014-10-02 |
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| US9765085B2 (en) | 2017-09-19 |
| KR102308319B1 (ko) | 2021-10-06 |
| KR102427491B1 (ko) | 2022-08-01 |
| US20170362250A1 (en) | 2017-12-21 |
| CN105164108A (zh) | 2015-12-16 |
| US20160031899A1 (en) | 2016-02-04 |
| KR20220110337A (ko) | 2022-08-05 |
| BR112015023009A2 (pt) | 2017-08-22 |
| EP2970122A1 (en) | 2016-01-20 |
| KR20210120137A (ko) | 2021-10-06 |
| ZA201506674B (en) | 2016-11-30 |
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| US10174046B2 (en) | 2019-01-08 |
| KR20150127205A (ko) | 2015-11-16 |
| AU2014242041A1 (en) | 2015-09-24 |
| RU2015143676A (ru) | 2017-04-27 |
| EP2970122B1 (en) | 2019-05-08 |
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