CA2805294A1 - Compounds for the reduction of beta-amyloid production - Google Patents
Compounds for the reduction of beta-amyloid production Download PDFInfo
- Publication number
- CA2805294A1 CA2805294A1 CA2805294A CA2805294A CA2805294A1 CA 2805294 A1 CA2805294 A1 CA 2805294A1 CA 2805294 A CA2805294 A CA 2805294A CA 2805294 A CA2805294 A CA 2805294A CA 2805294 A1 CA2805294 A1 CA 2805294A1
- Authority
- CA
- Canada
- Prior art keywords
- cyclopenta
- azeno
- metheno
- methyl
- mmol
- 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.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims description 247
- 238000004519 manufacturing process Methods 0.000 title claims description 18
- 230000009467 reduction Effects 0.000 title claims description 17
- 102000013455 Amyloid beta-Peptides Human genes 0.000 title description 2
- 108010090849 Amyloid beta-Peptides Proteins 0.000 title description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 213
- 229910052757 nitrogen Inorganic materials 0.000 claims description 113
- -1 haloC1-6alkyl Chemical group 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 27
- 208000024827 Alzheimer disease Diseases 0.000 claims description 26
- 229910052739 hydrogen Chemical group 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 14
- 208000035475 disorder Diseases 0.000 claims description 13
- 206010067889 Dementia with Lewy bodies Diseases 0.000 claims description 12
- 201000002832 Lewy body dementia Diseases 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 11
- 201000008319 inclusion body myositis Diseases 0.000 claims description 11
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 10
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 201000010374 Down Syndrome Diseases 0.000 claims description 7
- 208000010877 cognitive disease Diseases 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Chemical group 0.000 claims description 6
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- 208000027061 mild cognitive impairment Diseases 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 5
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000002560 nitrile group Chemical group 0.000 claims description 3
- 229910052717 sulfur Chemical group 0.000 claims description 3
- 239000011593 sulfur Chemical group 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
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- VOYSMHPUJVBEPX-UHFFFAOYSA-N 18-(2,4-difluorophenyl)-6-(3-methyl-1,2,4-triazol-1-yl)-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene Chemical compound N1=C(C)N=CN1C1=CC=C(N2)C=C1OCCCCNC1=NC2=NC2=C1CCC2C1=CC=C(F)C=C1F VOYSMHPUJVBEPX-UHFFFAOYSA-N 0.000 claims description 2
- QSMJRYHHVJROJR-UHFFFAOYSA-N 18-phenyl-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene-6-carbonitrile Chemical compound C1CC=2C(=N3)NCCCCOC(=C4)C(C#N)=CC=C4NC3=NC=2C1C1=CC=CC=C1 QSMJRYHHVJROJR-UHFFFAOYSA-N 0.000 claims description 2
- PSZBZYMYLJGTIV-UHFFFAOYSA-N 19-(4-fluorophenyl)-17-methyl-6-(3-methyl-1,2,4-triazol-1-yl)-8-oxa-2,13,17,21,22-pentazatetracyclo[12.7.1.13,7.015,20]tricosa-1(21),3(23),4,6,14(22),15(20)-hexaene Chemical compound C12=NC(=N3)NC(C=4)=CC=C(N5N=C(C)N=C5)C=4OCCCCNC3=C2CN(C)CC1C1=CC=C(F)C=C1 PSZBZYMYLJGTIV-UHFFFAOYSA-N 0.000 claims description 2
- VZPNBCNIDYHWME-UHFFFAOYSA-N 19-(4-fluorophenyl)-17-methyl-8-oxa-2,13,17,21,22-pentazatetracyclo[12.7.1.13,7.015,20]tricosa-1(21),3(23),4,6,14(22),15(20)-hexaene-6-carbonitrile Chemical compound C12=NC(=N3)NC(C=4)=CC=C(C#N)C=4OCCCCNC3=C2CN(C)CC1C1=CC=C(F)C=C1 VZPNBCNIDYHWME-UHFFFAOYSA-N 0.000 claims description 2
- FXRRQMQWRDATBM-UHFFFAOYSA-N 6-(4-chloroimidazol-1-yl)-18-(2,4-difluorophenyl)-13-methyl-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene Chemical compound C1CC=2C(=N3)N(C)CCCCOC(C(=CC=4)N5C=C(Cl)N=C5)=CC=4NC3=NC=2C1C1=CC=C(F)C=C1F FXRRQMQWRDATBM-UHFFFAOYSA-N 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- AFJYYTUXRGZTLI-UHFFFAOYSA-N 13-methyl-6-(3-methyl-1,2,4-triazol-1-yl)-18-phenyl-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene Chemical compound C1CC=2C(=N3)N(C)CCCCOC(C(=CC=4)N5N=C(C)N=C5)=CC=4NC3=NC=2C1C1=CC=CC=C1 AFJYYTUXRGZTLI-UHFFFAOYSA-N 0.000 claims 1
- UYQVMWNJHMWEFE-UHFFFAOYSA-N 13-methyl-6-(5-methyl-1,2,4-triazol-1-yl)-18-phenyl-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene Chemical compound C1CC=2C(=N3)N(C)CCCCOC(C(=CC=4)N5C(=NC=N5)C)=CC=4NC3=NC=2C1C1=CC=CC=C1 UYQVMWNJHMWEFE-UHFFFAOYSA-N 0.000 claims 1
- SMUZICWNTQGWQT-UHFFFAOYSA-N 18-(2,4-difluorophenyl)-12-methyl-6-(3-methyl-1,2,4-triazol-1-yl)-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene Chemical compound C1CC=2C(=N3)NC(C)CCCOC(C(=CC=4)N5N=C(C)N=C5)=CC=4NC3=NC=2C1C1=CC=C(F)C=C1F SMUZICWNTQGWQT-UHFFFAOYSA-N 0.000 claims 1
- LDSBODUYGTVSJP-UHFFFAOYSA-N 18-(2,4-difluorophenyl)-13-methyl-6-(3-methyl-1,2,4-triazol-1-yl)-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene Chemical compound C1CC=2C(=N3)N(C)CCCCOC(C(=CC=4)N5N=C(C)N=C5)=CC=4NC3=NC=2C1C1=CC=C(F)C=C1F LDSBODUYGTVSJP-UHFFFAOYSA-N 0.000 claims 1
- DYCBEOLLILVMRH-UHFFFAOYSA-N 18-(2,4-difluorophenyl)-13-methyl-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene-6-carbonitrile Chemical compound C1CC=2C(=N3)N(C)CCCCOC(C(=CC=4)C#N)=CC=4NC3=NC=2C1C1=CC=C(F)C=C1F DYCBEOLLILVMRH-UHFFFAOYSA-N 0.000 claims 1
- BAGGKXHJFUXZLY-UHFFFAOYSA-N 18-(4-fluorophenyl)-6-(3-methyl-1,2,4-triazol-1-yl)-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaen-10-ol Chemical compound N1=C(C)N=CN1C1=CC=C(N2)C=C1OCC(O)CCNC1=NC2=NC2=C1CCC2C1=CC=C(F)C=C1 BAGGKXHJFUXZLY-UHFFFAOYSA-N 0.000 claims 1
- GOQPGHPDMIWJAR-UHFFFAOYSA-N 18-phenyl-8-oxa-2,20,21-triazatetracyclo[12.6.1.13,7.015,19]docosa-1(21),3(22),4,6,14,19-hexaene-6-carbonitrile Chemical compound C1CC=2C(=N3)CCCCCOC(=C4)C(C#N)=CC=C4NC3=NC=2C1C1=CC=CC=C1 GOQPGHPDMIWJAR-UHFFFAOYSA-N 0.000 claims 1
- RYMSIBOTNUIQAP-UHFFFAOYSA-N 6-(3-methyl-1,2,4-triazol-1-yl)-18-phenyl-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene Chemical compound N1=C(C)N=CN1C1=CC=C(N2)C=C1OCCCCNC1=NC2=NC2=C1CCC2C1=CC=CC=C1 RYMSIBOTNUIQAP-UHFFFAOYSA-N 0.000 claims 1
- VRXLUWYIOGBPCL-UHFFFAOYSA-N 6-(3-methyl-1,2,4-triazol-1-yl)-18-phenyl-8-oxa-2,20,21-triazatetracyclo[12.6.1.13,7.015,19]docosa-1(21),3(22),4,6,14,19-hexaene Chemical compound N1=C(C)N=CN1C1=CC=C(N2)C=C1OCCCCCC1=NC2=NC2=C1CCC2C1=CC=CC=C1 VRXLUWYIOGBPCL-UHFFFAOYSA-N 0.000 claims 1
- XUKDMGUYWYRQCF-UHFFFAOYSA-N 6-(4-chloroimidazol-1-yl)-13-methyl-18-phenyl-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene Chemical compound C1CC=2C(=N3)N(C)CCCCOC(C(=CC=4)N5C=C(Cl)N=C5)=CC=4NC3=NC=2C1C1=CC=CC=C1 XUKDMGUYWYRQCF-UHFFFAOYSA-N 0.000 claims 1
- ALGVYGXLKJUZTA-UHFFFAOYSA-N 6-(4-chloroimidazol-1-yl)-18-phenyl-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene Chemical compound C1=NC(Cl)=CN1C1=CC=C(N2)C=C1OCCCCNC1=NC2=NC2=C1CCC2C1=CC=CC=C1 ALGVYGXLKJUZTA-UHFFFAOYSA-N 0.000 claims 1
- QJDUZIDYDFIENI-UHFFFAOYSA-N 6-(5-methyl-1,2,4-triazol-1-yl)-18-phenyl-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene Chemical compound CC1=NC=NN1C1=CC=C(N2)C=C1OCCCCNC1=NC2=NC2=C1CCC2C1=CC=CC=C1 QJDUZIDYDFIENI-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- 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
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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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
- C07D487/12—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 three hetero rings
- C07D487/16—Peri-condensed systems
-
- 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
- C07D498/06—Peri-condensed systems
-
- 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
- C07D498/12—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 three hetero rings
- C07D498/16—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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| US36442510P | 2010-07-15 | 2010-07-15 | |
| US61/364,425 | 2010-07-15 | ||
| PCT/US2011/043628 WO2012009309A1 (en) | 2010-07-15 | 2011-07-12 | Compounds for the reduction of beta-amyloid production |
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| CA2805294A1 true CA2805294A1 (en) | 2012-01-19 |
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| CA2805294A Abandoned CA2805294A1 (en) | 2010-07-15 | 2011-07-12 | Compounds for the reduction of beta-amyloid production |
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| WO (1) | WO2012009309A1 (enExample) |
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| JPH0696663B2 (ja) | 1986-08-04 | 1994-11-30 | 東レ株式会社 | 樹脂組成物 |
| US8754114B2 (en) | 2010-12-22 | 2014-06-17 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3 |
| PE20190736A1 (es) | 2012-06-13 | 2019-05-23 | Incyte Holdings Corp | Compuestos triciclicos sustituidos como inhibidores del receptor del factor de crecimiento de fibroblastos (fgfr) |
| WO2014026125A1 (en) | 2012-08-10 | 2014-02-13 | Incyte Corporation | Pyrazine derivatives as fgfr inhibitors |
| US9266892B2 (en) | 2012-12-19 | 2016-02-23 | Incyte Holdings Corporation | Fused pyrazoles as FGFR inhibitors |
| KR101473081B1 (ko) | 2013-01-25 | 2014-12-16 | 영남대학교 산학협력단 | 고리형 2-다이아조-1,3-다이카보닐 화합물을 출발물질로 하는 고리형 베타-엔아미노아마이드 유도체 및 우라실 유도체의 합성방법 |
| KR102269032B1 (ko) | 2013-04-19 | 2021-06-24 | 인사이트 홀딩스 코포레이션 | Fgfr 저해제로서 이환식 헤테로사이클 |
| WO2014180524A1 (en) * | 2013-05-06 | 2014-11-13 | Merck Patent Gmbh | Macrocycles as kinase inhibitors |
| WO2014195322A1 (en) | 2013-06-04 | 2014-12-11 | Acturum Life Science AB | Triazole compounds and their use as gamma secretase modulators |
| NO3004079T3 (enExample) | 2013-06-04 | 2018-06-16 | ||
| CN105308037B (zh) | 2013-06-04 | 2017-09-19 | 阿克图拉姆生命科学股份公司 | 三唑化合物及其作为γ分泌酶调节剂的用途 |
| US9833454B2 (en) | 2014-04-02 | 2017-12-05 | Bristol-Myers Squibb Company | Difluoromethoxy compound with low bioactivation potential for the reduction of beta-amyloid production |
| US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
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| WO2020151682A1 (zh) * | 2019-01-23 | 2020-07-30 | 成都先导药物开发股份有限公司 | 一种大环类免疫调节剂 |
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| WO2021067374A1 (en) | 2019-10-01 | 2021-04-08 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
| US11607416B2 (en) | 2019-10-14 | 2023-03-21 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
| US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
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| WO2021113462A1 (en) | 2019-12-04 | 2021-06-10 | Incyte Corporation | Derivatives of an fgfr inhibitor |
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| CN101365703B (zh) * | 2005-11-16 | 2013-11-06 | S*Bio私人有限公司 | 杂烷基连接的嘧啶衍生物 |
| US7932261B2 (en) * | 2006-02-06 | 2011-04-26 | Janssen Pharmaceutica Nv | Macrocycle derivatives useful as inhibitors of β-secretase (BACE) |
| ITMI20061513A1 (it) | 2006-07-31 | 2008-02-01 | Poli Costruzione Materiali Trazione Spa | Unita' frenante compatta a disco per veicoli su rotaia |
| AU2008333865A1 (en) * | 2007-12-06 | 2009-06-11 | Schering Corporation | Gamma secretase modulators |
| US8426595B2 (en) * | 2007-12-11 | 2013-04-23 | Xianhai Huang | Gamma secretase modulators |
| ATE535515T1 (de) | 2008-01-11 | 2011-12-15 | Hoffmann La Roche | Modulatoren für amyloid beta |
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- 2011-07-12 KR KR1020137003728A patent/KR20130041944A/ko not_active Withdrawn
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- 2011-07-12 SG SG2012093274A patent/SG186392A1/en unknown
- 2011-07-12 CA CA2805294A patent/CA2805294A1/en not_active Abandoned
- 2011-07-12 EA EA201270824A patent/EA021527B1/ru not_active IP Right Cessation
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| KR20130041944A (ko) | 2013-04-25 |
| CO6670589A2 (es) | 2013-05-15 |
| EP2593461A1 (en) | 2013-05-22 |
| EA021527B1 (ru) | 2015-07-30 |
| NZ606950A (en) | 2014-08-29 |
| IL224202A (en) | 2016-04-21 |
| CN102971325A (zh) | 2013-03-13 |
| ZA201301178B (en) | 2014-07-30 |
| SG186392A1 (en) | 2013-02-28 |
| MX2013000514A (es) | 2013-02-27 |
| US8637523B2 (en) | 2014-01-28 |
| AU2011279412A1 (en) | 2013-03-07 |
| WO2012009309A1 (en) | 2012-01-19 |
| JP5755739B2 (ja) | 2015-07-29 |
| BR112013000920A2 (pt) | 2016-05-17 |
| TW201206946A (en) | 2012-02-16 |
| EP2593461B1 (en) | 2016-08-17 |
| US20120184565A1 (en) | 2012-07-19 |
| JP2013531040A (ja) | 2013-08-01 |
| CN102971325B (zh) | 2016-01-20 |
| EA201270824A1 (ru) | 2013-04-30 |
| AU2011279412B2 (en) | 2014-12-11 |
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