HRP20172002T1 - Makrociklički inhibitori faktora xia kondenzirani sa heterociklusima - Google Patents
Makrociklički inhibitori faktora xia kondenzirani sa heterociklusima Download PDFInfo
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- HRP20172002T1 HRP20172002T1 HRP20172002TT HRP20172002T HRP20172002T1 HR P20172002 T1 HRP20172002 T1 HR P20172002T1 HR P20172002T T HRP20172002T T HR P20172002TT HR P20172002 T HRP20172002 T HR P20172002T HR P20172002 T1 HRP20172002 T1 HR P20172002T1
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- alkyl
- pharmaceutically acceptable
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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
- C07D471/12—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 three hetero rings
- C07D471/18—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- 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
- C07D487/08—Bridged systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Claims (12)
1. Spoj sa Formulom (Ia):
[image]
ili stereoizomer, tautomer, njegova farmaceutski prihvatljiva sol, gdje:
--- je opcionalna veza;
prsten A je nezavisno odabran od
[image]
R1 je nezavisno odabrano od H, F, OH, i C1-4 alkil;
R2 je nezavisno odabrano od H, F, i OH;
R3 je nezavisno odabrano od H, C1-4 alkil,
C1-4haloalkil, -(CH2)n-OR5, -(CH2)n-C(O)OR5, C3-6 cikloalkil po izboru supstituiran sa halogenom, i 5- do 6-očlani heteroaril koji sadrži ugljikove atome i 1-2 atoma dušika i po izboru supstituiran sa R1; pod uvjetom da je samo jedna R3 grupa prisutna na prstenu;
R4 je nezavisno odabrano od H, OH, F, OC1-4 alkil, C1-4 alkil, i CN;
R5 je nezavisno odabrano od H i C1-4 alkil;
R6 je nezavisno odabrano od H, F, Cl, Br, CN, OCH3, CH3, C(O)CH3, CHF2, CCH3F2, CF3, OCHF2, NHC(O)C1-4 alkil, C3-6 cikloalkil, i 5-očlani heterociklus supstituiran sa R9;
R7 je nezavisno odabrano od H i F;
R8 je nezavisno odabrano od H, F, Cl, i OCH3;
R9 je nezavisno odabrano od H, cijano, C1-4 alkil, haloalkil, i halogen; i
n, u svakom slučaju, je cijeli broj izabran od 1 i 2.
2. Spoj iz patentnog zahtjeva 1 koji ima Formulu (IIa):
[image]
ili stereoizomer, tautomer, njegova farmaceutski prihvatljiva sol, gdje:
prsten A je nezavisno odabran od
[image]
R1 je nezavisno odabrano od H i C1-3 alkil;
R2 je nezavisno odabrano od H i F;
R3 je nezavisno odabrano od H, C1-3 alkil,
C1-3haloalkil, -(CH2)n-OR5, -(CH2)n-C(O)OR5, i C3-4 cikloalkil po izboru supstituiran sa halogenom;
R4 je nezavisno odabrano od H i F;
R5 je nezavisno odabrano od H i C1-4 alkil;
R6 je nezavisno odabrano od H, F, Cl, Br, CN, CF3, C(O)CH3, CHF2, CCH3F2, CF3, OCHF2,
[image]
R7 je nezavisno odabrano od H i F;
R8 je nezavisno odabrano od H, F, Cl, i OCH3;
R9 je nezavisno odabrano od H, CHF2, i CF3;
R9' je nezavisno odabrano od H, F, Cl, CN, CHF2, i CF3; i
n, u svakom slučaju, je cijeli broj izabran od 1 i 2.
3. Spoj iz patentnog zahtjeva 2, ili stereoizomer, tautomer, njegova farmaceutski prihvatljiva sol, gdje:
R1 je nezavisno odabrano od H, CH3, i CH(CH3)2;
R2 je nezavisno odabrano od H i F;
R3 je nezavisno odabrano od H, CH3, CD3, CH2CH3, -CHF2, -CH2CHF2, -CH2CF3, -CH2CH2OH, CH2CH2OC(CH3)3, -CH2C(O)OH, ciklopropil po izboru supstituiran sa F, i ciklobutil;
R6 je nezavisno odabrano od H, F, Cl, Br, CN, CF3, C(O)CH3, CHF2, CCH3F2, CF3, OCHF2,
[image]
R7 je nezavisno odabrano od H i F;
R8 je nezavisno odabrano od H, F, Cl, i OCH3;
R9 je nezavisno odabrano od H, CHF2, i CF3; i
R9' je nezavisno odabrano od H, F, Cl, CN, CHF2, i CF3.
4. Spoj iz patentnog zahtjeva 1 koji ima Formulu (IIIa):
[image]
ili stereoizomer, tautomer, njegova farmaceutski prihvatljiva sol, gdje:
prsten A je nezavisno odabran od
[image]
R1 je nezavisno odabrano od H, CH3, i CH(CH3)2;
R2 je nezavisno odabrano od H i F;
R3 je nezavisno odabrano od H, CH2C(=O)OH, CH2C(=O)OCH2CH3,
[image]
R4 je nezavisno odabrano od H i F;
R6 je nezavisno odabrano od H, F, Cl, Br, CN, CF3, C(O)CH3, CHF2, CCH3F2, CF3, OCHF2,
[image]
R7 je nezavisno odabrano od H i F;
R8 je nezavisno odabrano od H, F, Cl, i OCH3;
R9 je nezavisno odabrano od H, CHF2, i CF3; i
R9' je nezavisno odabrano od H, F, Cl, CN, CHF2, i CF3.
5. Spoj iz patentnog zahtjeva 1, ili stereoizomer, tautomer, njegova farmaceutski prihvatljiva sol, gdje:
R3 je nezavisno odabrano od H, CH3, CD3, CH2CH3, -CHF2, -CH2CHF2, -CH2CF3, -CH2CH2OH, CH2CH2OC(CH3)3, -CH2C(O)OH, CH2C(=O)OH, CH2C(=O)OCH2CH3, ciklopropil po izboru supstituiran sa F, i ciklobutil,
[image]
R6 je nezavisno odabrano od H, F, Cl, Br, CN, CF3, C(O)CH3, CHF2, CCH3F2, CF3, OCHF2,
[image]
R7 je nezavisno odabrano od H i F;
R8 je Cl;
R9 je nezavisno odabrano od H, CHF2, i CF3; i
R9' je nezavisno odabrano od H, F, Cl, CN, CHF2, i CF3;
6. Spoj koji ima Formulu (IV):
[image]
ili stereoizomer, tautomer, njegova farmaceutski prihvatljiva sol, gdje:
prsten A je nezavisno odabran od
[image]
R1 je nezavisno odabrano od H i C1-3alkil;
R2 je nezavisno odabrano od H i F;
R3 je nezavisno odabrano od H, CD3, CHF2, i CH3;
R4 je nezavisno odabrano od H i halogen;
R7 je nezavisno odabrano od H i F;
R8 je nezavisno odabrano od H, F, Cl, i OCH3; i
R9 je nezavisno odabrano od H, F, Cl, CN, i CF3.
7. Spoj koji ima Formulu (V):
[image]
ili stereoizomer, tautomer, njegova farmaceutski prihvatljiva sol, gdje:
prsten A je nezavisno odabran od
[image]
R1 je nezavisno odabrano od H i C1-3alkil;
R2 je nezavisno odabrano od H i F;
R3 je nezavisno odabrano od H, CD3, CHF2, i CH3;
R4 je nezavisno odabrano od H i halogen;
R6 je nezavisno odabrano od H, F, Cl, Br, CN, CF3, C(O)CH3, CHF2, CCH3F2, CF3, OCHF2,
[image]
R7 je nezavisno odabrano od H i F;
R8 je nezavisno odabrano od H, F, Cl, i OCH3;
R9 je nezavisno odabrano od H, CHF2, i CF3; i
R9' je nezavisno odabrano od H, F, Cl, CN, CHF2, i CF3.
8. Spoj u skladu sa patentnim zahtjevom 1, 6 ili 7 odabran sa liste koja se sastoji od
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ili stereoizomer, tautomer, njegova farmaceutski prihvatljiva sol.
9. Farmaceutska kompozicija koja sadrži jedan ili više spojeva u skladu sa bilo kojim od patentnih zahtjeva 1-8 i farmaceutski prihvatljiv nosač ili razblaživač.
10. Spoj u skladu sa bilo kojim od patentnih zahtjeva 1-8, ili stereoizomer, tautomer, ili njegova farmaceutski prihvatljiva sol ili kompozicija u skladu sa patentnim zahtjevom 9 za primjenu kao medikament.
11. Spoj u skladu sa bilo kojim od patentnih zahtjeva 1-8, ili stereoizomer, tautomer, ili njegova farmaceutski prihvatljiva sol za primjenu u liječenju i/ili profilaksi tromboembolijskog poremećaja, gdje tromboembolijski poremećaj je odabran od arterijskih kardiovaskularnih tromboembolijskih poremećaja, venskih tromboembolijskih poremećaja, i tromboembolijskih poremećaja u komorama srca ili u perifernoj cirkulaciji.
12. Spoj ili stereoizomer, tautomer, ili njegova farmaceutski prihvatljiva sol za primjenu u skladu sa patentnim zahtjevom 11, gdje tromboembolijski poremećaj je odabran od nestabilne angine, akutnog koronarnog sindroma, atrijalne fibrilacije, infarkta miokarda, prolaznog ishemijskog napada, moždanog udara, ateroskleroze, periferne okluzivne arterijske bolesti, venske tromboze, duboke venske tromboze, tromboflebitisa, arterijske embolije, koronarne arterijske tromboze, cerebralne arterijske tromboze, cerebralne embolije, bubrežne embolije, plućne embolije, i tromboze koja nastaje od medicinskih implantata, uređaja, ili procedura u kojima je krv izložena umjetnoj površini koja izaziva trombozu.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201461933948P | 2014-01-31 | 2014-01-31 | |
| PCT/US2015/013647 WO2015116882A1 (en) | 2014-01-31 | 2015-01-30 | Macrocyclic factor xia inhibitors condensed with heterocycles |
| EP15705427.1A EP3099688B1 (en) | 2014-01-31 | 2015-01-30 | Macrocyclic factor xia inhibitors condensed with heterocycles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20172002T1 true HRP20172002T1 (hr) | 2018-02-09 |
Family
ID=52484569
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20172002TT HRP20172002T1 (hr) | 2014-01-31 | 2015-01-30 | Makrociklički inhibitori faktora xia kondenzirani sa heterociklusima |
Country Status (24)
| Country | Link |
|---|---|
| US (3) | US20170057961A1 (hr) |
| EP (1) | EP3099688B1 (hr) |
| JP (1) | JP6419836B2 (hr) |
| CN (1) | CN106459051B (hr) |
| AR (1) | AR099228A1 (hr) |
| BR (1) | BR112016016741B1 (hr) |
| CA (1) | CA2937738C (hr) |
| CY (1) | CY1120534T1 (hr) |
| DK (1) | DK3099688T3 (hr) |
| EA (1) | EA032650B1 (hr) |
| ES (1) | ES2655540T3 (hr) |
| HR (1) | HRP20172002T1 (hr) |
| HU (1) | HUE038060T2 (hr) |
| LT (1) | LT3099688T (hr) |
| MX (1) | MX2016009385A (hr) |
| NO (1) | NO2760821T3 (hr) |
| PL (1) | PL3099688T3 (hr) |
| PT (1) | PT3099688T (hr) |
| RS (1) | RS56785B1 (hr) |
| SI (1) | SI3099688T1 (hr) |
| SM (1) | SMT201800024T1 (hr) |
| TW (1) | TWI703144B (hr) |
| UY (1) | UY35972A (hr) |
| WO (1) | WO2015116882A1 (hr) |
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| WO2014160668A1 (en) | 2013-03-25 | 2014-10-02 | Bristol-Myers Squibb Company | Tetrahydroisoquinolines containing substituted azoles as factor xia inhibitors |
| NO2760821T3 (hr) | 2014-01-31 | 2018-03-10 | ||
| SG10201908467RA (en) | 2014-01-31 | 2019-10-30 | Bristol Myers Squibb Co | Macrocycles with hetrocyclic p2' groups as factor xia inhibitors |
| ES2714283T3 (es) | 2014-09-04 | 2019-05-28 | Bristol Myers Squibb Co | Macrociclos de diamida que son inhibidores de FXIa |
| US9453018B2 (en) | 2014-10-01 | 2016-09-27 | Bristol-Myers Squibb Company | Pyrimidinones as factor XIa inhibitors |
| NO2721243T3 (hr) * | 2014-10-01 | 2018-10-20 | ||
| ES2762987T3 (es) | 2015-06-19 | 2020-05-26 | Bristol Myers Squibb Co | Macrociclos de diamida como inhibidores del factor XIA |
| JP6629958B2 (ja) * | 2015-07-29 | 2020-01-15 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | アルキルまたはシクロアルキルＰ２’基を担持する大員環の第ＸＩａ因子阻害剤 |
| CN114874222B (zh) | 2015-07-29 | 2025-06-06 | 百时美施贵宝公司 | 携带非芳族p2,基团的因子xia新大环 |
| EP3368036B1 (en) * | 2015-10-29 | 2022-07-20 | Merck Sharp & Dohme LLC | Macrocyclic pyridine-n-oxide derivatives as factor xia inhibitors |
| EP3371162B1 (en) | 2015-10-29 | 2022-01-26 | Merck Sharp & Dohme Corp. | Macrocyclic spirocarbamate derivatives as factor xia inhibitors, pharmaceutically acceptable compositions and their use |
| KR20180117156A (ko) | 2016-03-02 | 2018-10-26 | 브리스톨-마이어스 스큅 컴퍼니 | 인자 XIa 억제 활성을 갖는 디아미드 마크로사이클 |
| WO2018039094A1 (en) | 2016-08-22 | 2018-03-01 | Merck Sharp & Dohme Corp. | Pyridine-1-oxide derivatives and their use as factor xia inhibitors |
| BR112019010511A2 (pt) | 2016-11-23 | 2019-09-17 | Bayer Ag | derivados de heterociclo bicíclico fundido como pesticidas |
| UY37556A (es) | 2017-01-10 | 2018-07-31 | Bayer Ag | Derivados heterocíclicos como pesticidas |
| AR113206A1 (es) | 2017-01-10 | 2020-02-19 | Bayer Cropscience Ag | Derivados heterocíclicos como pesticidas |
| CN110062757B (zh) * | 2017-01-18 | 2022-03-04 | 广东东阳光药业有限公司 | 凝血因子XIa抑制剂及其用途 |
| CN110922412A (zh) * | 2018-09-20 | 2020-03-27 | 复旦大学 | 具有抗精神病作用药物化合物的不对称合成方法 |
| WO2020211781A1 (zh) * | 2019-04-16 | 2020-10-22 | 南京明德新药研发有限公司 | 作为XIa因子抑制剂的大环衍生物 |
| CN114341714A (zh) * | 2019-07-08 | 2022-04-12 | 加里夏普创新有限责任公司 | 具有高对比度的紧凑型基于偏振的准直器 |
| CN114008047B (zh) * | 2019-07-23 | 2023-03-21 | 南京明德新药研发有限公司 | 作为XIa因子抑制剂的大环衍生物 |
| TW202229280A (zh) * | 2020-10-12 | 2022-08-01 | 美商必治妥美雅史谷比公司 | （６ｒ，１０ｓ）－１０－｛４－［５－氯－２－（４－氯－１ｈ－１，２，３－三唑－１－基）苯基］－６－側氧基－１（６ｈ）－嘧啶基｝－１－（二氟甲基）－６－甲基－１，４，７，８，９，１０－六氫－１１，１５－（亞甲橋基）吡唑并［４，３－ｂ］［１，７］二氮雜環十四炔－５（６ｈ）－酮之製備方法 |
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-
2012
- 2012-08-31 NO NO12780535A patent/NO2760821T3/no unknown
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- 2015-01-30 US US15/115,319 patent/US20170057961A1/en not_active Abandoned
- 2015-01-30 DK DK15705427.1T patent/DK3099688T3/en active
- 2015-01-30 PT PT157054271T patent/PT3099688T/pt unknown
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- 2015-01-30 LT LTEP15705427.1T patent/LT3099688T/lt unknown
- 2015-01-30 EP EP15705427.1A patent/EP3099688B1/en active Active
- 2015-01-30 HU HUE15705427A patent/HUE038060T2/hu unknown
- 2015-01-30 CN CN201580017759.3A patent/CN106459051B/zh active Active
- 2015-01-30 TW TW104103315A patent/TWI703144B/zh active
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- 2015-01-30 BR BR112016016741-4A patent/BR112016016741B1/pt active IP Right Grant
- 2015-01-30 PL PL15705427T patent/PL3099688T3/pl unknown
- 2015-01-30 WO PCT/US2015/013647 patent/WO2015116882A1/en not_active Ceased
- 2015-01-30 RS RS20180033A patent/RS56785B1/sr unknown
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- 2015-01-30 CA CA2937738A patent/CA2937738C/en active Active
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| BR112016016741B1 (pt) | 2023-01-17 |
| US20170057961A1 (en) | 2017-03-02 |
| AR099228A1 (es) | 2016-07-06 |
| MX2016009385A (es) | 2016-09-16 |
| CY1120534T1 (el) | 2019-07-10 |
| HUE038060T2 (hu) | 2018-09-28 |
| JP6419836B2 (ja) | 2018-11-07 |
| US10273236B2 (en) | 2019-04-30 |
| EP3099688A1 (en) | 2016-12-07 |
| US20180222907A1 (en) | 2018-08-09 |
| CA2937738C (en) | 2023-01-17 |
| ES2655540T3 (es) | 2018-02-20 |
| CN106459051B (zh) | 2018-10-16 |
| LT3099688T (lt) | 2017-12-27 |
| WO2015116882A1 (en) | 2015-08-06 |
| EA201691561A1 (ru) | 2017-01-30 |
| EP3099688B1 (en) | 2017-10-18 |
| PT3099688T (pt) | 2018-01-15 |
| RS56785B1 (sr) | 2018-04-30 |
| US20170342071A1 (en) | 2017-11-30 |
| SI3099688T1 (sl) | 2017-12-29 |
| DK3099688T3 (en) | 2018-01-15 |
| NO2760821T3 (hr) | 2018-03-10 |
| EA032650B1 (ru) | 2019-06-28 |
| JP2017504640A (ja) | 2017-02-09 |
| CN106459051A (zh) | 2017-02-22 |
| TWI703144B (zh) | 2020-09-01 |
| BR112016016741A2 (hr) | 2017-08-08 |
| UY35972A (es) | 2015-07-31 |
| SMT201800024T1 (it) | 2018-03-08 |
| PL3099688T3 (pl) | 2018-03-30 |
| TW201615640A (zh) | 2016-05-01 |
| CA2937738A1 (en) | 2015-08-06 |
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