ES2555167T3 - Nuevos derivados de indol sustituidos como moduladores de gamma secretasa - Google Patents
Nuevos derivados de indol sustituidos como moduladores de gamma secretasa Download PDFInfo
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- ES2555167T3 ES2555167T3 ES12733754.1T ES12733754T ES2555167T3 ES 2555167 T3 ES2555167 T3 ES 2555167T3 ES 12733754 T ES12733754 T ES 12733754T ES 2555167 T3 ES2555167 T3 ES 2555167T3
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- hydrogen
- alkyloxy
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- VHNYOQKVZQVBLC-RTCGXNAVSA-N (4r,7e,9as)-7-[[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]methylidene]-4-(3,4,5-trifluorophenyl)-1,3,4,8,9,9a-hexahydropyrido[2,1-c][1,4]oxazin-6-one Chemical compound C1([C@@H]2COC[C@@H]3CC\C(C(N32)=O)=C/C=2C=C(C(=CC=2)N2C=C(C)N=C2)OC)=CC(F)=C(F)C(F)=C1 VHNYOQKVZQVBLC-RTCGXNAVSA-N 0.000 title 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 title 1
- 150000002475 indoles Chemical class 0.000 title 1
- 229940124648 γ-Secretase Modulator Drugs 0.000 title 1
- -1 NR7R8 Chemical group 0.000 abstract description 62
- 150000001875 compounds Chemical class 0.000 abstract description 58
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 45
- 239000001257 hydrogen Substances 0.000 abstract description 45
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 41
- 125000003545 alkoxy group Chemical group 0.000 abstract description 40
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 40
- 125000001424 substituent group Chemical group 0.000 abstract description 32
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract description 30
- 150000003839 salts Chemical class 0.000 abstract description 29
- 125000005843 halogen group Chemical group 0.000 abstract description 26
- 125000004076 pyridyl group Chemical group 0.000 abstract description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 17
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 abstract description 16
- 229910052731 fluorine Inorganic materials 0.000 abstract description 14
- 239000011737 fluorine Chemical group 0.000 abstract description 14
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 abstract description 13
- 125000004448 alkyl carbonyl group Chemical group 0.000 abstract description 13
- 125000003226 pyrazolyl group Chemical group 0.000 abstract description 12
- 239000012453 solvate Substances 0.000 abstract description 12
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 10
- 125000001153 fluoro group Chemical group F* 0.000 abstract description 10
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 abstract description 8
- 125000002883 imidazolyl group Chemical group 0.000 abstract description 8
- 125000002971 oxazolyl group Chemical group 0.000 abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 6
- 125000002757 morpholinyl group Chemical group 0.000 abstract description 6
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 abstract description 4
- 102100024650 Carbonic anhydrase 3 Human genes 0.000 description 52
- 101000760630 Homo sapiens Carbonic anhydrase 3 Proteins 0.000 description 52
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 41
- 108010064539 amyloid beta-protein (1-42) Proteins 0.000 description 22
- 230000003287 optical effect Effects 0.000 description 20
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
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- 238000006243 chemical reaction Methods 0.000 description 7
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- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
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- DACWQSNZECJJGG-UHFFFAOYSA-N [1,2,4]triazolo[1,5-a]pyridine Chemical compound C1=CC=CN2N=CN=C21 DACWQSNZECJJGG-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
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- YHYLDEVWYOFIJK-UHFFFAOYSA-N 1h-indole-5-carbonitrile Chemical compound N#CC1=CC=C2NC=CC2=C1 YHYLDEVWYOFIJK-UHFFFAOYSA-N 0.000 description 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 2
- PIAWXNKEFFYUCD-UHFFFAOYSA-N 2-[8-(2-cyclopropylphenyl)-6,8-dihydro-5h-imidazo[2,1-c][1,4]oxazin-2-yl]-4-methoxy-1h-indole-5-carbonitrile Chemical compound C=1C=2C(OC)=C(C#N)C=CC=2NC=1C(N=C12)=CN1CCOC2C1=CC=CC=C1C1CC1 PIAWXNKEFFYUCD-UHFFFAOYSA-N 0.000 description 2
- UMAUKBQUICMSGM-UHFFFAOYSA-N 2-[8-(4-fluoro-2-methylphenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazin-2-yl]-4-propan-2-yloxy-1H-indole-5-carbonitrile Chemical compound C=1C=2C(OC(C)C)=C(C#N)C=CC=2NC=1C(=NN1CCO2)N=C1C2C1=CC=C(F)C=C1C UMAUKBQUICMSGM-UHFFFAOYSA-N 0.000 description 2
- HVSDODQLRPYGML-UHFFFAOYSA-N 2-[8-(4-fluoro-2-methylphenyl)-6,8-dihydro-5h-imidazo[2,1-c][1,4]oxazin-2-yl]-4-methoxy-1h-indole-5-carbonitrile Chemical compound C=1C=2C(OC)=C(C#N)C=CC=2NC=1C(N=C12)=CN1CCOC2C1=CC=C(F)C=C1C HVSDODQLRPYGML-UHFFFAOYSA-N 0.000 description 2
- SWVQFTATJKGKJI-UHFFFAOYSA-N 4-methoxy-2-[8-[5-methyl-2-(2,2,2-trifluoroethyl)pyrazol-3-yl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl]-1h-indole-5-carbonitrile Chemical compound C=1C=2C(OC)=C(C#N)C=CC=2NC=1C(N=C12)=CN1CCCC2C1=CC(C)=NN1CC(F)(F)F SWVQFTATJKGKJI-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000000132 electrospray ionisation Methods 0.000 description 2
- 239000003797 essential amino acid Substances 0.000 description 2
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
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- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
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- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- YNDHMPHNXKLPMA-UHFFFAOYSA-N 2-[5-[2-fluoro-5-(trifluoromethyl)phenyl]-5-methyl-6,8-dihydroimidazo[2,1-c][1,4]oxazin-2-yl]-4-methoxy-1h-indole-5-carbonitrile Chemical compound C=1C=2C(OC)=C(C#N)C=CC=2NC=1C(N=1)=CN2C=1COCC2(C)C1=CC(C(F)(F)F)=CC=C1F YNDHMPHNXKLPMA-UHFFFAOYSA-N 0.000 description 1
- GVCNSJONPNQBSI-UHFFFAOYSA-N 2-[8-(2-chloro-6-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazin-2-yl]-4-methoxy-1H-indole-5-carbonitrile Chemical compound C=1C=2C(OC)=C(C#N)C=CC=2NC=1C(=NN1CCO2)N=C1C2C1=C(F)C=CC=C1Cl GVCNSJONPNQBSI-UHFFFAOYSA-N 0.000 description 1
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- CHLUUWQLDURKRV-UHFFFAOYSA-N 2-[8-(2-chlorophenyl)-6,8-dihydro-5h-imidazo[2,1-c][1,4]oxazin-2-yl]-4-methoxy-1h-indole-5-carbonitrile Chemical compound C=1C=2C(OC)=C(C#N)C=CC=2NC=1C(N=C12)=CN1CCOC2C1=CC=CC=C1Cl CHLUUWQLDURKRV-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- 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
- A61P25/28—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
-
- 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
-
- 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
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- Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Indole Compounds (AREA)
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| ES2431619T3 (es) | 2009-05-07 | 2013-11-27 | Janssen Pharmaceuticals, Inc. | Derivados de indazol y aza-indazol sustituidos como moduladores de gamma-secretasa |
| NZ597505A (en) | 2009-07-15 | 2013-05-31 | Janssen Pharmaceuticals Inc | Substituted triazole and imidazole derivatives as gamma secretase modulators |
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| JP6068464B2 (ja) | 2011-07-15 | 2017-01-25 | ヤンセン ファーマシューティカルズ，インコーポレーテッド | γ−セクレターゼ調節剤としての新規な置換インドール誘導体 |
| ES2585009T3 (es) | 2012-05-16 | 2016-10-03 | Janssen Pharmaceuticals, Inc. | Derivados de 3,4-dihidro-2H-pirido[1,2-a]pirazina-1,6-diona sustituidos útiles para el tratamiento de (inter alia) enfermedad de Alzheimer |
| EP2738172A1 (en) * | 2012-11-28 | 2014-06-04 | Almirall, S.A. | New bicyclic compounds as crac channel modulators |
| CA2889249C (en) | 2012-12-20 | 2021-02-16 | Francois Paul Bischoff | Tricyclic 3,4-dihydro-2h-pyrido[1,2-a]pyrazine-1,6-dione derivatives as gamma secretase modulators |
| AU2014206834B2 (en) | 2013-01-17 | 2017-06-22 | Janssen Pharmaceutica Nv | Novel substituted pyrido-piperazinone derivatives as gamma secretase modulators |
| US10562897B2 (en) | 2014-01-16 | 2020-02-18 | Janssen Pharmaceutica Nv | Substituted 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-diones as gamma secretase modulators |
| GB201506660D0 (en) | 2015-04-20 | 2015-06-03 | Cellcentric Ltd | Pharmaceutical compounds |
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| WO2018026620A1 (en) | 2016-07-30 | 2018-02-08 | Bristol-Myers Squibb Company | Dimethoxyphenyl substituted indole compounds as tlr7, tlr8 or tlr9 inhibitors |
| WO2018049089A1 (en) | 2016-09-09 | 2018-03-15 | Bristol-Myers Squibb Company | Pyridyl substituted indole compounds |
| JOP20190060A1 (ar) | 2016-09-26 | 2019-03-26 | Chugai Pharmaceutical Co Ltd | مشتق بيرازولو بيريدين له تأثير مساعد لمستقبل glp-1 |
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| SG11202003283TA (en) | 2017-10-11 | 2020-05-28 | Hoffmann La Roche | Bicyclic compounds for use as rip1 kinase inhibitors |
| EP3710440B1 (en) * | 2017-11-14 | 2023-04-05 | Bristol-Myers Squibb Company | Substituted indole compounds |
| CN111527080B (zh) | 2017-12-15 | 2023-09-22 | 百时美施贵宝公司 | 取代的吲哚醚化合物 |
| BR112020011771A2 (pt) | 2017-12-18 | 2020-11-17 | Bristol-Myers Squibb Company | compostos 4-azaindol |
| ES2922174T3 (es) | 2017-12-19 | 2022-09-09 | Bristol Myers Squibb Co | Compuestos de indol sustituidos con amida útiles como inhibidores de TLR |
| AU2018390543A1 (en) | 2017-12-19 | 2020-08-06 | Bristol-Myers Squibb Company | 6-azaindole compounds |
| US11878975B2 (en) | 2017-12-19 | 2024-01-23 | Bristol-Myers Squibb Company | Substituted indole compounds useful as TLR inhibitors |
| SG11202005694RA (en) | 2017-12-20 | 2020-07-29 | Bristol Myers Squibb Co | Amino indole compounds useful as tlr inhibitors |
| EA202091530A1 (ru) | 2017-12-20 | 2020-09-14 | Бристол-Маерс Сквибб Компани | Диазаиндольные соединения |
| MX2020005622A (es) | 2017-12-20 | 2020-08-20 | Bristol Myers Squibb Co | Compuestos de indol sustituidos con arilo y heteroarilo. |
| SG11202102137SA (en) | 2018-09-03 | 2021-04-29 | Hoffmann La Roche | Bicyclic heteroaryl derivatives |
| EP3628669A1 (en) * | 2018-09-28 | 2020-04-01 | GenKyoTex Suisse SA | Novel compounds as nadph oxidase inhibitors |
| JP7597709B2 (ja) | 2018-10-24 | 2024-12-10 | ブリストル－マイヤーズ スクイブ カンパニー | 置換インドールおよびインダゾール化合物 |
| US11998537B2 (en) | 2018-10-24 | 2024-06-04 | Bristol-Myers Squibb Company | Substituted indole dimer compounds |
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| JP7621275B2 (ja) | 2019-05-09 | 2025-01-24 | ブリストル－マイヤーズ スクイブ カンパニー | 置換ベンズイミダゾロン化合物 |
| EP4041730A1 (en) | 2019-10-01 | 2022-08-17 | Bristol-Myers Squibb Company | Substituted bicyclic heteroaryl compounds |
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| EP2401276B1 (en) | 2009-02-26 | 2013-06-05 | Eisai R&D Management Co., Ltd. | Nitrogen-containing fused heterocyclic compounds and their use as beta amyloid production inhibitors |
| JP2012051806A (ja) | 2009-02-26 | 2012-03-15 | Eisai R & D Management Co Ltd | イミダゾリルピラジン誘導体 |
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| US9145399B2 (en) | 2010-01-15 | 2015-09-29 | Janssen Pharmaceuticals, Inc. | Substituted bicyclic triazole derivatives as gamma secretase modulators |
| TW201307347A (zh) * | 2010-11-01 | 2013-02-16 | Arqule Inc | 經取代苯並－咪唑並－吡啶並－二氮呯化合物 |
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| JP6068464B2 (ja) | 2011-07-15 | 2017-01-25 | ヤンセン ファーマシューティカルズ，インコーポレーテッド | γ−セクレターゼ調節剤としての新規な置換インドール誘導体 |
-
2012
- 2012-07-12 JP JP2014519557A patent/JP6068464B2/ja not_active Expired - Fee Related
- 2012-07-12 EA EA201490287A patent/EA023045B1/ru not_active IP Right Cessation
- 2012-07-12 IN IN258MUN2014 patent/IN2014MN00258A/en unknown
- 2012-07-12 CN CN201280034912.XA patent/CN103874702B/zh not_active Expired - Fee Related
- 2012-07-12 TW TW101125035A patent/TWI567079B/zh not_active IP Right Cessation
- 2012-07-12 CA CA2841102A patent/CA2841102C/en not_active Expired - Fee Related
- 2012-07-12 AU AU2012285931A patent/AU2012285931B2/en not_active Ceased
- 2012-07-12 BR BR112014000713A patent/BR112014000713A2/pt active Search and Examination
- 2012-07-12 ES ES12733754.1T patent/ES2555167T3/es active Active
- 2012-07-12 EP EP12733754.1A patent/EP2731948B1/en active Active
- 2012-07-12 MX MX2014000626A patent/MX2014000626A/es unknown
- 2012-07-12 US US14/233,078 patent/US9115143B2/en not_active Expired - Fee Related
- 2012-07-12 WO PCT/EP2012/063667 patent/WO2013010904A1/en not_active Ceased
- 2012-07-12 KR KR1020147003465A patent/KR101913135B1/ko not_active Expired - Fee Related
- 2012-07-13 AR ARP120102548A patent/AR087182A1/es not_active Application Discontinuation
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- 2014-01-13 IL IL230422A patent/IL230422B/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| JP2014518286A (ja) | 2014-07-28 |
| CA2841102C (en) | 2019-08-13 |
| EP2731948A1 (en) | 2014-05-21 |
| AR087182A1 (es) | 2014-02-26 |
| TWI567079B (zh) | 2017-01-21 |
| WO2013010904A1 (en) | 2013-01-24 |
| EA023045B1 (ru) | 2016-04-29 |
| US20140148450A1 (en) | 2014-05-29 |
| IL230422B (en) | 2018-03-29 |
| US9115143B2 (en) | 2015-08-25 |
| CN103874702A (zh) | 2014-06-18 |
| EA201490287A1 (ru) | 2014-05-30 |
| JP6068464B2 (ja) | 2017-01-25 |
| AU2012285931B2 (en) | 2017-01-12 |
| KR101913135B1 (ko) | 2018-10-30 |
| BR112014000713A2 (pt) | 2017-01-10 |
| TW201315736A (zh) | 2013-04-16 |
| KR20140063595A (ko) | 2014-05-27 |
| MX2014000626A (es) | 2014-04-30 |
| CA2841102A1 (en) | 2013-01-24 |
| IN2014MN00258A (enExample) | 2015-09-25 |
| NZ619683A (en) | 2015-01-30 |
| EP2731948B1 (en) | 2015-09-09 |
| CN103874702B (zh) | 2015-12-09 |
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