HRP20201895T1 - Postupak pripreme (s) -nikotina iz miozmina - Google Patents
Postupak pripreme (s) -nikotina iz miozmina Download PDFInfo
- Publication number
- HRP20201895T1 HRP20201895T1 HRP20201895TT HRP20201895T HRP20201895T1 HR P20201895 T1 HRP20201895 T1 HR P20201895T1 HR P20201895T T HRP20201895T T HR P20201895TT HR P20201895 T HRP20201895 T HR P20201895T HR P20201895 T1 HRP20201895 T1 HR P20201895T1
- Authority
- HR
- Croatia
- Prior art keywords
- nornicotine
- nicotine
- formaldehyde
- aqueous solution
- myosmin
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims 20
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 title claims 9
- DPNGWXJMIILTBS-UHFFFAOYSA-N myosmine Chemical compound C1CCN=C1C1=CC=CN=C1 DPNGWXJMIILTBS-UHFFFAOYSA-N 0.000 title claims 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims 20
- 229930182840 (S)-nicotine Natural products 0.000 claims 8
- MYKUKUCHPMASKF-VIFPVBQESA-N (S)-nornicotine Chemical compound C1CCN[C@@H]1C1=CC=CN=C1 MYKUKUCHPMASKF-VIFPVBQESA-N 0.000 claims 8
- MYKUKUCHPMASKF-UHFFFAOYSA-N Nornicotine Natural products C1CCNC1C1=CC=CN=C1 MYKUKUCHPMASKF-UHFFFAOYSA-N 0.000 claims 8
- 229960002715 nicotine Drugs 0.000 claims 8
- 239000007864 aqueous solution Substances 0.000 claims 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 4
- 102000004190 Enzymes Human genes 0.000 claims 3
- 108090000790 Enzymes Proteins 0.000 claims 3
- 102000004316 Oxidoreductases Human genes 0.000 claims 3
- 108090000854 Oxidoreductases Proteins 0.000 claims 3
- 239000003638 chemical reducing agent Substances 0.000 claims 3
- 230000000694 effects Effects 0.000 claims 3
- 150000002466 imines Chemical class 0.000 claims 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 claims 2
- 235000019253 formic acid Nutrition 0.000 claims 2
- 238000009472 formulation Methods 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- GFAJOMHUNNCCJQ-UHFFFAOYSA-N 1,3-dioxetane Chemical compound C1OCO1 GFAJOMHUNNCCJQ-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims 1
- 239000000654 additive Substances 0.000 claims 1
- 239000003571 electronic cigarette Substances 0.000 claims 1
- -1 formaldehyde acetal Chemical class 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 239000004615 ingredient Substances 0.000 claims 1
- 239000007937 lozenge Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000001035 methylating effect Effects 0.000 claims 1
- 230000011987 methylation Effects 0.000 claims 1
- 238000007069 methylation reaction Methods 0.000 claims 1
- 229910052763 palladium Inorganic materials 0.000 claims 1
- 229920000642 polymer Polymers 0.000 claims 1
- 238000006485 reductive methylation reaction Methods 0.000 claims 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
- A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
- A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
- A24B15/10—Chemical features of tobacco products or tobacco substitutes
- A24B15/16—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes
- A24B15/167—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes in liquid or vaporisable form, e.g. liquid compositions for electronic cigarettes
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/465—Nicotine; Derivatives thereof
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/0004—Oxidoreductases (1.)
- C12N9/0012—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7)
- C12N9/0026—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7) acting on CH-NH groups of donors (1.5)
- C12N9/0028—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7) acting on CH-NH groups of donors (1.5) with NAD or NADP as acceptor (1.5.1)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
- C12P17/165—Heterorings having nitrogen atoms as the only ring heteroatoms
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/002—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by oxidation/reduction reactions
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y105/00—Oxidoreductases acting on the CH-NH group of donors (1.5)
- C12Y105/01—Oxidoreductases acting on the CH-NH group of donors (1.5) with NAD+ or NADP+ as acceptor (1.5.1)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Addiction (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Analytical Chemistry (AREA)
- Molecular Biology (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Claims (15)
1. Postupak dobivanja (S) -nikotina koji obuhvaća korake:
(i) reduciranje miozmina enzimom s imin-reduktaznom aktivnošću da bi se dobio (S) -nornikotin; (i) reduciranje miozmina enzimom s imin-reduktaznom aktivnošću da bi se dobio (S) -nornikotin;
(ii) metiliranje (S) -nornikotina koji nastaje iz koraka (i) da bi se dobio (S) -nikotin.
2. Postupak prema zahtjevu 1, naznačen time što se korak (ii) provodi reduktivnom metilacijom.
3. Postupak prema zahtjevu 2, naznačen time što se u koraku (ii) (S) -nornikotin reduktivno metilira uporabom formaldehida ili spoja na bazi formaldehida u prisutnosti reduktanta.
4. Postupak prema zahtjevu 3, naznačen time što se formaldehid uvodi kao dio vodene otopine.
5. Postupak prema zahtjevu 3, naznačen time što je spoj na bazi formaldehida dimer formaldehida, polimer od formaldehid, ili acetal formaldehida.
6. Postupak prema bilo kojem od zahtjeva 2-4, naznačen time što je reduktant mravlja kiselina, natrijev cijanoborohidrid, ili paladij / vodik.
7. Postupak prema bilo kojem od zahtjeva 2-4, naznačen time što je reduktant mravlja kiselina.
8. Postupak prema bilo kojem od prethodnih zahtjeva, naznačen time što se postupak izvodi bez izolacije (S) -nornikotina nastalog u koraku (i).
9. Postupak prema bilo kojem od prethodnih zahtjeva, naznačen time što se u koraku (i) formira (S) -nornikotin kao dio vodene otopine, i pri čemu korak (ii) obuhvaća metiliranje (S) -nornikotina koji se nalazi u vodenoj otopini.
10. Postupak prema zahtjevu 9, naznačen time što se u koraku (ii) (S) -nornikotin reduktivno metilira uporabom formaldehida uvedenog kao dio vodene otopine.
11. Postupak prema bilo kojem od prethodnih zahtjeva, naznačen time što se (S) -nikotin dobiva s enantiomernim suviškom od najmanje 90%, poželjno najmanje 95%, poželjnije najmanje 98%, najpoželjnije najmanje 99%.
12. Postupak za proizvodnju farmaceutskog pripravka, naznačen time što obuhvaća stvaranje (S) -nikotina prema postupku iz bilo kojeg prethodnog zahtjeva, i uključivanje (S) -nikotina u farmaceutski pripravak zajedno s jednim ili više farmaceutskih pomoćnih sastojaka.
13. Postupak prema zahtjevu 12, naznačen time što je farmaceutski pripravak transdermalni flaster, pastila, ili formulacija za inhaliranje.
14. Postupak za proizvodnju formulacije za uređaj za elektroničku cigaretu, naznačen time što obuhvaća formiranje (S) -nikotina prema postupku iz bilo kojeg od zahtjeva 1-11, i koji uključuje (S) -nikotin u otapalu s jednim ili više aditiva.
15. Uporaba miozmina i enzima s imin reduktaznom aktivnošću u procesu formiranja (S) -nikotina, pri čemu postupak obuhvaća značajke iz bilo kojeg od zahtjeva 1-11.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP18206826.2A EP3653617B1 (en) | 2018-11-16 | 2018-11-16 | Process for the preparation of (s)-nicotin from myosmine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20201895T1 true HRP20201895T1 (hr) | 2021-04-16 |
Family
ID=64331961
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20201895TT HRP20201895T1 (hr) | 2018-11-16 | 2020-11-27 | Postupak pripreme (s) -nikotina iz miozmina |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP3653617B1 (hr) |
| JP (1) | JP7068554B2 (hr) |
| KR (1) | KR102393478B1 (hr) |
| CN (2) | CN113272289A (hr) |
| AU (1) | AU2019382117B2 (hr) |
| BR (1) | BR112021009328B1 (hr) |
| CA (1) | CA3118774C (hr) |
| DK (1) | DK3653617T3 (hr) |
| ES (1) | ES2836481T3 (hr) |
| HR (1) | HRP20201895T1 (hr) |
| HU (1) | HUE051799T2 (hr) |
| MX (1) | MX2021005584A (hr) |
| PL (1) | PL3653617T3 (hr) |
| PT (1) | PT3653617T (hr) |
| SI (1) | SI3653617T1 (hr) |
| WO (1) | WO2020098978A1 (hr) |
| ZA (1) | ZA202103223B (hr) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113373188B (zh) * | 2020-03-10 | 2024-02-20 | 重庆博腾制药科技股份有限公司 | 一种(s)-尼古丁的合成方法 |
| CN112795603B (zh) * | 2020-12-14 | 2022-06-24 | 山东金城医药化工有限公司 | 一种制备(s)-2-(3-吡啶)-吡咯烷的方法 |
| US20220154231A1 (en) * | 2020-11-18 | 2022-05-19 | Shandong Jincheng Pharmaceutical Chemical Co., Ltd | Methods for preparing nicotine and intermediates thereof |
| CN112409327A (zh) * | 2020-11-18 | 2021-02-26 | 山东金城医药化工有限公司 | 一种高光学纯度烟碱的制备方法 |
| CN115404249B (zh) * | 2021-05-29 | 2024-07-05 | 重庆博腾制药科技股份有限公司 | 一种(s)-尼古丁中间体的制备方法及其应用 |
| CN115404250B (zh) * | 2021-05-29 | 2024-08-06 | 重庆博腾制药科技股份有限公司 | 一种利用还原方式制备(s)-尼古丁的方法 |
| CN115491364A (zh) | 2021-06-20 | 2022-12-20 | 陈泽聪 | 亚胺还原酶突变体、亚胺还原酶和葡萄糖脱氢酶共表达酶及其应用 |
| CN115851635A (zh) * | 2021-08-10 | 2023-03-28 | 深圳瑞德林生物技术有限公司 | 一种s-尼古丁的制备方法 |
| CN114195759B (zh) * | 2021-08-26 | 2023-10-20 | 上海零诺生物科技有限公司 | 一种2-甲基-5-（1-甲基吡咯烷-2-基）吡啶制备方法 |
| CN113999084B (zh) * | 2021-11-03 | 2024-04-16 | 成昌梅 | 一种（s）-（-）-尼古丁的合成制备方法 |
| CN114437029A (zh) * | 2022-01-24 | 2022-05-06 | 深圳市华加生物科技有限公司 | 不对称合成手性尼古丁的制备方法及手性尼古丁 |
| CN114807265B (zh) * | 2022-03-31 | 2024-08-20 | 上海锐康生物技术研发有限公司 | 一种s-烟碱的合成方法 |
| CN114671852A (zh) * | 2022-04-24 | 2022-06-28 | 仙居两山生物科技有限公司 | 一种高纯度左旋烟碱医药中间体的制备方法 |
| CN114702475B (zh) * | 2022-05-17 | 2023-12-26 | 大连天源基化学有限公司 | 一种单一构型烟碱的合成工艺 |
| EP4332098A1 (en) | 2022-08-31 | 2024-03-06 | Siegfried AG | Chiral synthesis of nornicotine and nicotine |
| CN116218803B (zh) * | 2023-01-31 | 2024-03-19 | 河北工业大学 | 亚胺还原酶及其制备方法和编码亚胺还原酶的dna |
| CN115820762B (zh) | 2023-02-20 | 2023-05-16 | 山东金城医药化工有限公司 | 合成(s)-烟碱及其中间体的方法 |
| CN117925746A (zh) * | 2023-03-09 | 2024-04-26 | 仙居两山生物科技有限公司 | 一种2-甲基-5-[(2s)-1-甲基吡咯烷-2-基]吡啶的酶转化制备方法 |
| CN116217544B (zh) * | 2023-05-08 | 2023-08-29 | 济南悟通生物科技有限公司 | 一种(s)-降烟碱的合成方法 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102617547B (zh) | 2011-01-27 | 2016-02-10 | 上海特化医药科技有限公司 | 一种制备消旋尼古丁的方法 |
| US8378111B2 (en) | 2011-02-02 | 2013-02-19 | Divi's Laboratories, Ltd. | Process for the resolution of (R,S)-nicotine |
| US8367837B2 (en) * | 2011-02-14 | 2013-02-05 | Divi's Laboratories, Ltd. | Process for the preparation of (R,S)-nicotine |
| DK2847214T3 (en) | 2012-05-11 | 2018-03-12 | Codexis Inc | CONSTRUCTED IMINE REDUCTIONS AND PROCEDURES FOR THE REDUCED AMINING OF KETON AND AMINE COMPOUNDS |
| IL225900A0 (en) | 2013-04-22 | 2014-03-31 | Perrigo Api Ltd | A process for the preparation of nicotine that includes the enzymatic reduction of 4-(methylamino)-1-(3-pyridinyl)-1-butanone |
| EP3068793B1 (en) | 2013-11-13 | 2021-02-17 | Codexis, Inc. | Engineered imine reductases and methods for the reductive amination of ketone and amine compounds |
| EP3209653B1 (en) | 2014-10-22 | 2021-06-09 | Next Generation Labs, LLC | Process for the preparation of (r,s)-nicotine |
-
2018
- 2018-11-16 PL PL18206826T patent/PL3653617T3/pl unknown
- 2018-11-16 EP EP18206826.2A patent/EP3653617B1/en active Active
- 2018-11-16 PT PT182068262T patent/PT3653617T/pt unknown
- 2018-11-16 DK DK18206826.2T patent/DK3653617T3/da active
- 2018-11-16 HU HUE18206826A patent/HUE051799T2/hu unknown
- 2018-11-16 SI SI201830153T patent/SI3653617T1/sl unknown
- 2018-11-16 ES ES18206826T patent/ES2836481T3/es active Active
-
2019
- 2019-03-12 JP JP2021526250A patent/JP7068554B2/ja active Active
- 2019-03-12 MX MX2021005584A patent/MX2021005584A/es unknown
- 2019-03-12 CN CN201980058561.8A patent/CN113272289A/zh active Pending
- 2019-03-12 KR KR1020217018020A patent/KR102393478B1/ko active IP Right Review Request
- 2019-03-12 AU AU2019382117A patent/AU2019382117B2/en active Active
- 2019-03-12 CN CN202410133134.4A patent/CN118005607A/zh active Pending
- 2019-03-12 WO PCT/EP2019/056194 patent/WO2020098978A1/en active Application Filing
- 2019-03-12 CA CA3118774A patent/CA3118774C/en active Active
- 2019-03-12 BR BR112021009328-1A patent/BR112021009328B1/pt active IP Right Grant
-
2020
- 2020-11-27 HR HRP20201895TT patent/HRP20201895T1/hr unknown
-
2021
- 2021-05-12 ZA ZA2021/03223A patent/ZA202103223B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA202103223B (en) | 2022-10-26 |
| JP2022507375A (ja) | 2022-01-18 |
| EP3653617A1 (en) | 2020-05-20 |
| WO2020098978A1 (en) | 2020-05-22 |
| EP3653617B1 (en) | 2020-10-28 |
| KR20210082532A (ko) | 2021-07-05 |
| HUE051799T2 (hu) | 2021-03-29 |
| CA3118774A1 (en) | 2020-05-22 |
| KR102393478B1 (ko) | 2022-05-03 |
| DK3653617T3 (da) | 2020-12-07 |
| CN118005607A (zh) | 2024-05-10 |
| ES2836481T3 (es) | 2021-06-25 |
| MX2021005584A (es) | 2022-02-25 |
| CA3118774C (en) | 2022-02-08 |
| CN113272289A (zh) | 2021-08-17 |
| PT3653617T (pt) | 2020-12-11 |
| SI3653617T1 (sl) | 2021-01-29 |
| PL3653617T3 (pl) | 2021-04-06 |
| AU2019382117B2 (en) | 2021-05-27 |
| JP7068554B2 (ja) | 2022-05-16 |
| BR112021009328B1 (pt) | 2022-05-10 |
| BR112021009328A2 (pt) | 2021-08-17 |
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