HRP20201089T1 - Postupak sinteze inhibitora indolamin 2,3-dioksigenaze - Google Patents
Postupak sinteze inhibitora indolamin 2,3-dioksigenaze Download PDFInfo
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- HRP20201089T1 HRP20201089T1 HRP20201089TT HRP20201089T HRP20201089T1 HR P20201089 T1 HRP20201089 T1 HR P20201089T1 HR P20201089T T HRP20201089T T HR P20201089TT HR P20201089 T HRP20201089 T HR P20201089T HR P20201089 T1 HRP20201089 T1 HR P20201089T1
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- 238000000034 method Methods 0.000 title claims 27
- 229940113303 Indoleamine 2,3-dioxygenase inhibitor Drugs 0.000 title 1
- 230000015572 biosynthetic process Effects 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 47
- 239000003638 chemical reducing agent Substances 0.000 claims 14
- 238000006243 chemical reaction Methods 0.000 claims 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 8
- -1 9-fluorenylmethyloxycarbonyl Chemical group 0.000 claims 7
- 238000010511 deprotection reaction Methods 0.000 claims 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 6
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical group CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 4
- 125000000217 alkyl group Chemical group 0.000 claims 4
- 150000007524 organic acids Chemical class 0.000 claims 4
- 125000006239 protecting group Chemical group 0.000 claims 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims 2
- 230000008878 coupling Effects 0.000 claims 2
- 238000010168 coupling process Methods 0.000 claims 2
- 238000005859 coupling reaction Methods 0.000 claims 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 2
- 239000003223 protective agent Substances 0.000 claims 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- MBYLVOKEDDQJDY-UHFFFAOYSA-N tris(2-aminoethyl)amine Chemical group NCCN(CCN)CCN MBYLVOKEDDQJDY-UHFFFAOYSA-N 0.000 claims 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 1
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 claims 1
- IJIVZRMITPUVAC-UHFFFAOYSA-N 2,2,2-trichloroethyl N-(2,2-dimethoxyethylsulfamoyl)carbamate Chemical compound COC(CNS(=O)(=O)NC(=O)OCC(Cl)(Cl)Cl)OC IJIVZRMITPUVAC-UHFFFAOYSA-N 0.000 claims 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 claims 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims 1
- HUYOMBHZNMTQPT-UHFFFAOYSA-N 9H-fluoren-9-ylmethyl N-(2,2-dimethoxyethylsulfamoyl)carbamate Chemical compound COC(CNS(=O)(=O)NC(=O)OCC1c2ccccc2-c2ccccc12)OC HUYOMBHZNMTQPT-UHFFFAOYSA-N 0.000 claims 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims 1
- 150000001299 aldehydes Chemical class 0.000 claims 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 claims 1
- FEJQZESDPWHUIU-UHFFFAOYSA-N benzyl N-(2,2-dimethoxyethylsulfamoyl)carbamate Chemical compound COC(CNS(=O)(=O)NC(=O)OCc1ccccc1)OC FEJQZESDPWHUIU-UHFFFAOYSA-N 0.000 claims 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- KGVDNTXHSSRDTB-UHFFFAOYSA-N ethyl N-(2,2-dimethoxyethylsulfamoyl)carbamate Chemical compound CCOC(=O)NS(=O)(=O)NCC(OC)OC KGVDNTXHSSRDTB-UHFFFAOYSA-N 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000001188 haloalkyl group Chemical group 0.000 claims 1
- 150000007530 organic bases Chemical class 0.000 claims 1
- JETYSCOMGBXHSL-UHFFFAOYSA-N tert-butyl N-(2,2-dimethoxyethylsulfamoyl)carbamate Chemical compound COC(CNS(=O)(=O)NC(=O)OC(C)(C)C)OC JETYSCOMGBXHSL-UHFFFAOYSA-N 0.000 claims 1
- QFUUIYBSWTYLNT-UHFFFAOYSA-N tert-butyl N-[(4-methoxyphenyl)methyl]-N-[(4-methoxyphenyl)methyl-(2-oxoethyl)sulfamoyl]carbamate Chemical compound COc1ccc(CN(CC=O)S(=O)(=O)N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)cc1 QFUUIYBSWTYLNT-UHFFFAOYSA-N 0.000 claims 1
- VNDJTNFKQAFSLL-UHFFFAOYSA-N tert-butyl N-[2-oxoethyl(prop-2-enyl)sulfamoyl]-N-prop-2-enylcarbamate Chemical compound CC(C)(C)OC(=O)N(CC=C)S(=O)(=O)N(CC=C)CC=O VNDJTNFKQAFSLL-UHFFFAOYSA-N 0.000 claims 1
- 239000011701 zinc Substances 0.000 claims 1
- 229910052725 zinc Inorganic materials 0.000 claims 1
Classifications
-
- A—HUMAN NECESSITIES
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/04—Diamides of sulfuric acids
- C07C307/06—Diamides of sulfuric acids having nitrogen atoms of the sulfamide groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/04—1,2,3-Oxadiazoles; Hydrogenated 1,2,3-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Claims (29)
1. Postupak koji obuhvaća reagiranje spoja formule F5:
[image]
s aldehidom formule F6:
[image]
pri čemu je Pg1amino zaštitna grupa, da se dobije spoj formule F7:
[image]
2. Postupak prema zahtjevu 1, pri čemu je Pg1 :
(a) etoksikarbonil, terc-butoksikarbonil, benziloksikarbonil, ili 9-fluorenilmetiloksikarbonil; ili
(b) terc-butoksikarbonil.
3. Postupak prema bilo kojem zahtjevu 1-2, pri čemu se spomenuta reakcija izvodi u prisustvu redukcijskog sredstva, gdje je spomenuto redukcijsko sredstvo:
(a) borhidridno redukcijsko sredstvo; ili
(b) borhidridno redukcijsko sredstvo koje je natrijev triacetoksiborohidrid.
4. Postupak prema bilo kojem zahtjevu 1-3, koji dalje obuhvaća uklanjanje zaštite spomenutog spoja formule F7 da se dobije spoj formule F8:
[image]
opcionalno gdje spomenuto uklanjanje zaštitne grupe uključuje reagiranje spoja formule F7 sa klorovodičnom kiselinom.
5. Postupak prema zahtjevu 4, koji dalje obuhvaća reagiranje spomenutog spoja formule F8, sa Pg2-NH-SO2-X, u prisustvu organske baze da se dobije spoj formule F9:
[image]
pri čemu:
Pg2 je amino zaštitna grupa; i
X je halo.
6. Postupak prema zahtjevu 5, pri čemu je Pg2 :
(a) etoksikarbonil, terc-butoksikarbonil, benziloksikarbonil, ili 9-fluorenilmetiloksikarbonil; ili
(b) terc-butoksikarbonil; i pri čemu X je klor.
7. Postupak prema bilo kojem zahtjevu 5-6, koji dalje obuhvaća i uklanjanje zaštite spomenutog spoja formule F9 da se dobije spoj formule F10:
[image]
opcionalno gdje spomenuto uklanjanje zaštitne grupe obuhvaća reagiranje spoja formule F9 sa klorovodičnom kiselinom.
8. Postupak prema zahtjevu 7, koji dalje obuhvaća reagiranje spomenutog spoja formule F10 sa bazom da se dobije spoj formule I:
[image]
opcionalno gdje je spomenuta baza natrijev hidroksid.
9. Postupak, koji obuhvaća reagiranje spoja formule F15:
[image]
sa spojem formule F5:
[image]
da se dobije spoj formule F16:
[image]
pri čemu:
svaki R1 je nezavisno amino zaštitna grupa izabrana od C2-4 alkenil-C1-3 alkil ili fenil-C1-3 alkil, pri čemu je spomenuti fenil-C1-3 alkil opcionalno supstituiran sa 1, 2, ili 3 nezavisno izabranih C1-4 alkoksi grupa;
i
R3 je C1-6 alkil ili benzil.
10. Postupak prema zahtjevu 9, pri čemu:
(a) svaki R1 je alil;
(b) svaki R1 je 4-metoksibenzil;
(c) R3 je C1-6 alkil; ili
(d) R3 je terc-butil.
11. Postupak prema bilo kojem zahtjevu 9-10, pri se čemu spomenuta reakcija izvodi u prisustvu redukcijskog sredstva, gdje je spomenuto redukcijsko sredstvo:
(a) borohidridno redukcijsko sredstvo; ili
(b) borohidridno redukcijsko sredstvo koje je natrijev triacetoksiborhidrid; i gdje se spomenuta reakcija izvodi u prisustvu trifluoroctene kiseline.
12. Postupak prema bilo kojem zahtjevu 9-11, koji dalje obuhvaća uklanjanje zaštite spomenutog spoja formule F16 da se dobije spoj formule F10:
[image]
pri čemu spomenuto uklanjanje zaštite obuhvaća:
(a) reagiranje spoja formule F16 sa trifluoroctenom kiselinom; ili
(b) reagiranje spojaformule F16 sa klorovodičnom kiselinom.
13. Postupak prema bilo kojem zahtjevu 9-12, pri čemu je spomenuti spoj formule F15 dobijen postupkom koji obuhvaća tretiranje spoja formule F14:
[image]
sa redukcijskim sredstvom da se dobije spomenuti spoj formule F15; pri čemu R2 je C1-4 alkil; opcionalno gdje je spomenuto redukcijsko sredstvo diizobutilaluminijev hidrid.
14. Postupak prema zahtjevu 13, pri čemu je spomenuti spoj formule F14 dobijen postupkom koji obuhvaća zaštitu spoja formule F13:
[image]
s jednim ili više nezavisno izabranih amino zaštitnih sredstava da se dobije spoj formule F14; opcionalno gdje je spomenuto jedno ili više amino zaštitnih sredstava izabrano od alil bromida i 4-metoksibenzil klorida, i gdje se spomenuta zaštita izvodi u prisustvu baze.
15. Spoj formule F15:
[image]
pri čemu:
R3 je C1-6 alkil ili benzil; i
svaki R1 je nezavisno amino zaštitna grupa.
16. Spoj prema zahtjevu 15, koji je:
(a) terc-butil alil{[alil(2-oksoetil)amino] sulfonil} karbamat; ili
(b) terc-butil(4-metoksibenzil){[(4-metoksibenzil)(2-oksoetil)amino] sulfonil} karbamat.
17. Postupak, koji obuhvaća reagiranje spoja formule F17:
[image]
pri čemu R4 je C1-6 alkil, C1-6 haloalkil, benzil, ili 9H-fluoren-9-ilmetil sa spojem formule F5:
[image]
da se dobije spoj formule F18:
[image]
18. Postupak prema zahtjevu 17, pri čemu R4 je:
(a) terc-butil;
(b) benzil;
(c) etil; ili
(d) 2,2,2-trikloretil.
19. Postupak prema zahtjevu 18, pri čemu se spomenuta reakcija izvodi u prisustvu redukcijskog sredstva; opcionalno gdje je spomenuto redukcijskog sredstvo trietilsilan, i gdje se spomenuta reakcija izvodi u prisustvu organske kiseline; opcionalno gdje je spomenuta organska kiselina trifluoroctena kiselina.
20. Postupak prema bilo kojem zahtjevu 18-19, koji dalje obuhvaća uklanjanje zaštite spomenutog spoja formule F18 da se dobije spoj formule F10:
[image]
opcionalno gdje spomenuto uklanjanje zaštitne grupe uključuje reagiranje spoja formule F18 sa cinkom u prisustvu octenekiseline.
21. Postupak prema zahtjevu 20, koji dalje obuhvaća reagiranje spomenutog spoja formule F10 sa bazom da se dobije spoj formule I:
[image]
opcionalno gdje je spomenuta baza natrijev hidroksid.
22. Postupak prema zahtjevu 17, pri čemu R4 je 9H-fluoren-9-ilmetil.
23. Postupak prema zahtjevu 22, pri čemu se spomenuta reakcija izvodi u prisustvu redukcijskog sredstva; opcionalno gdje je spomenuto redukcijsko sredstvo trietilsilan; i gdje se spomenuta reakcija izvodi u prisustvu organske kiseline; opcionalno gdje je spomenuta organska kiselina metansulfonska kiselina.
24. Postupak prema bilo kojem zahtjevu 22-23, koji dalje obuhvaća pretvaranje spomenutog spoja formule F18 u spoj formule I:
[image]
pri čemu spomenuto pretvaranje obuhvaća spajanje spoja formule F18 sa bazom da bi se formirala prva smjesa; opcionalno gdje je spomenuta baza N,N-bis(2-aminoetil)etan-1,2-diamin.
25. Postupak prema zahtjevu 24, pri čemu spomenuto pretvaranje dalje obuhvaća dodavanje vodene klorovodične kiseline u spomenutu prvu smjesu.
26. Spoj formule F17:
[image]
gdje je R4C1-6 haloalkil, benzil, ili 9H-fluoren-9-ilmetil.
27. Spoj prema zahtjevu 26, koji je:
(a) benzil N-(2,2-dimetoksietil)sulfamoilkarbamat;
(b) 2,2,2-trikloretil N-(2,2-dimetoksietil)sulfamoilkarbamat; ili
(c) (9H-fluoren-9-il)metil N-(2,2-dimetoksietil)sulfamoilkarbamat.
28. Spoj koji je:
(a) terc-butil N-(2,2-dimetoksietil)sulfamoilkarbamat; ili
(b) etil N-(2,2-dimetoksietil)sulfamoilkarbamat.
29. Postupak, koji obuhvaća:
i) reagiranje spoja formule F19:
[image]
sa spojem formule F5:
[image]
u prisustvu trietilsilana i metansulfonske kiseline da se dobije spoj formule F20:
[image]
i
ii) pretvaranje spomenutog spoja formule F20 u spoj formule I:
[image]
gdje spomenuto pretvaranje obuhvaća spajanje spomenutog spoja formule F20 sN,N-bis(2-aminoetil)etan-1,2-diaminom.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201361901689P | 2013-11-08 | 2013-11-08 | |
| EP14812015.7A EP3066085B1 (en) | 2013-11-08 | 2014-11-07 | Process for the synthesis of an indoleamine 2,3-dioxygenase inhibitor |
| PCT/US2014/064531 WO2015070007A1 (en) | 2013-11-08 | 2014-11-07 | Process for the synthesis of an indoleamine 2,3-dioxygenase inhibitor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20201089T1 true HRP20201089T1 (hr) | 2020-10-30 |
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ID=52023608
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20201089TT HRP20201089T1 (hr) | 2013-11-08 | 2020-07-13 | Postupak sinteze inhibitora indolamin 2,3-dioksigenaze |
Country Status (31)
| Country | Link |
|---|---|
| US (3) | US9321755B2 (hr) |
| EP (2) | EP3744715A1 (hr) |
| JP (4) | JP6461953B2 (hr) |
| KR (2) | KR102370067B1 (hr) |
| CN (2) | CN109810104B (hr) |
| AR (1) | AR098343A1 (hr) |
| AU (2) | AU2014346647B2 (hr) |
| BR (2) | BR122020009912B1 (hr) |
| CA (1) | CA2929552C (hr) |
| CL (1) | CL2016001082A1 (hr) |
| CR (2) | CR20160252A (hr) |
| CY (1) | CY1123164T1 (hr) |
| DK (1) | DK3066085T3 (hr) |
| EA (2) | EA033667B1 (hr) |
| ES (1) | ES2799582T3 (hr) |
| HR (1) | HRP20201089T1 (hr) |
| HU (1) | HUE049337T2 (hr) |
| IL (2) | IL245314B (hr) |
| LT (1) | LT3066085T (hr) |
| ME (1) | ME03792B (hr) |
| MX (2) | MX366874B (hr) |
| MY (1) | MY174254A (hr) |
| PE (2) | PE20220430A1 (hr) |
| PH (2) | PH12016500818B1 (hr) |
| PL (1) | PL3066085T3 (hr) |
| PT (1) | PT3066085T (hr) |
| RS (1) | RS60598B1 (hr) |
| SG (2) | SG10201803874PA (hr) |
| SI (1) | SI3066085T1 (hr) |
| TW (4) | TWI696618B (hr) |
| WO (1) | WO2015070007A1 (hr) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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