US20160376259A1 - Methods for Preparing Oltipraz - Google Patents

Methods for Preparing Oltipraz Download PDF

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Publication number
US20160376259A1
US20160376259A1 US14/823,256 US201514823256A US2016376259A1 US 20160376259 A1 US20160376259 A1 US 20160376259A1 US 201514823256 A US201514823256 A US 201514823256A US 2016376259 A1 US2016376259 A1 US 2016376259A1
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reaction
added
container
stirred
minutes
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US14/823,256
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English (en)
Inventor
Bomi P. Framroze
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ST IP Holding AG
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ST IP Holding AG
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Assigned to ST IP HOLDING AG reassignment ST IP HOLDING AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FRAMROZE, BOMI P.
Priority to KR1020187002139A priority Critical patent/KR20180022838A/ko
Priority to CA2989228A priority patent/CA2989228A1/en
Priority to AU2016283082A priority patent/AU2016283082B2/en
Priority to EP16813869.1A priority patent/EP3313835A4/en
Priority to JP2017565999A priority patent/JP6773693B2/ja
Priority to MA042264A priority patent/MA42264A/fr
Priority to PCT/IN2016/050197 priority patent/WO2016207914A2/en
Publication of US20160376259A1 publication Critical patent/US20160376259A1/en
Priority to US16/041,282 priority patent/US20190084971A1/en
Priority to US16/784,915 priority patent/US20200172522A1/en
Priority to US16/854,480 priority patent/US10968207B2/en
Priority to US17/210,049 priority patent/US20210206752A1/en
Assigned to Foley Hoag LLP reassignment Foley Hoag LLP LIEN (SEE DOCUMENT FOR DETAILS). Assignors: ST IP HOLDING AG
Abandoned legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur 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
    • 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
    • A61K31/495—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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A61P33/12—Schistosomicides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • Oltipraz 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, depicted in Formula I, below, was originally developed as an anti-schistosomal drug that eliminates parasitic worms. Later, it was discovered that oltipraz is a chemopreventive agent. The drug also has other known and unknown uses in the medical field.
  • the invention relates to a method comprising the steps of:
  • the solution is added over a period of time of about 30 minutes while warming the first container to a temperature of about 22° C.; and the second solvent is a mixture of tetrahydrofuran and 1,4-dioxane; and
  • the invention relates to any of the methods described herein, wherein the first base is sodium pentanoate or potassium t-butoxide.
  • the invention relates to any of the methods described herein, wherein the method is a method of synthesizing
  • the invention relates to a method of synthesizing oltipraz, comprising the steps of:
  • the invention relates to any of the methods described herein, wherein the purity of the oltipraz produced by the claimed methods is greater than 97%, greater than 98%, or greater than 99%, as determined by gas chromatography.
  • the invention relates to any of the methods described herein, wherein the overall yield of oltipraz from
  • the invention relates to any of the methods described herein, wherein the overall yield of oltipraz from
  • the invention relates to an improved method of synthesizing oltipraz.
  • the method involves Step 2 or Step 3 (or both Step 2 and Step 3 in succession) as depicted in Scheme 1.
  • the invention relates to any one of the methods described herein, wherein Step 2 does not involve sodium hydride.
  • the invention relates to any one of the methods described herein, wherein the yield of Step 2 is greater than 80%, greater than 81%, greater than 82%, greater than 83%, greater than 84%, greater than 85%, greater than 86%, greater than 87%, greater than 88%, greater than 89%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%.
  • the invention relates to any one of the methods described herein, wherein the overall yield of Step 2 and Step 3 is greater than 21%, greater than 22%, greater than 23%, greater than 24%, greater than 25%, greater than 26%, greater than 27%, greater than 28%, greater than 29%, or greater than 30%.
  • the invention relates to any one of the methods described herein, wherein the purity of the oltipraz produced by the claimed methods is greater than 97%, greater than 98%, or greater than 99%, as determined by gas chromatography.
  • the invention relates to any one of the methods described herein, wherein the overall yield of Step 2 and Step 3 is greater than 21%, and the purity of the resulting oltipraz is greater than 97%, as determined by gas chromatography.
  • the invention relates to a method comprising the steps of:
  • the solution is added over a period of time of about 30 minutes while warming the first container to a temperature of about 22° C.; and the second solvent is a mixture of tetrahydrofuran and 1,4-dioxane; and
  • the invention relates to any of the methods described herein, wherein the first solvent is tetrahydrofuran.
  • the invention relates to any of the methods described herein, wherein the first solvent is a mixture of tetrahydrofuran and 1,4-dioxane. In certain embodiments, the invention relates to any of the methods described herein, wherein the first solvent is about a 5:1, about a 4:1, or about a 3:1 mixture by volume of tetrahydrofuran and 1,4-dioxane. In certain embodiments, the invention relates to any of the methods described herein, wherein the first solvent is about a 4:1 mixture by volume of tetrahydrofuran and 1,4-dioxane.
  • the invention relates to any of the methods described herein, wherein the first base is sodium pentanoate or potassium t-butoxide.
  • the invention relates to any of the methods described herein, wherein the concentration of the first base in the first solvent is from about 1.0 M to about 1.8 M.
  • the invention relates to any of the methods described herein, wherein the concentration of the first base in the first solvent is about 1.0 M, about 1.2 M, about 1.4 M, about 1.6 M, or about 1.8 M. In certain embodiments, the invention relates to any of the methods described herein, wherein the concentration of the first base in the first solvent is about 1.4 M.
  • the invention relates to any of the methods described herein, wherein the mole ratio of first base to methyl propionate is from about 3:1 to about 1:1. In certain embodiments, the invention relates to any of the methods described herein, wherein the mole ratio of first base to methyl propionate is about 3:1, about 2:1, or about 1:1. In certain embodiments, the invention relates to any of the methods described herein, wherein the mole ratio of first base to methyl propionate is about 1:1.
  • the invention relates to any of the methods described herein, wherein the concentration of
  • the invention relates to any of the methods described herein, wherein the concentration of
  • the invention relates to any of the methods described herein, wherein the concentration of
  • the invention relates to any of the methods described herein, wherein the mole ratio of methyl propionate to
  • the invention relates to any of the methods described herein, wherein the mole ratio of methyl propionate to
  • the invention relates to any of the methods described herein, wherein the mole ratio of methyl propionate to
  • the invention relates to any of the methods described herein, wherein the second solvent is from about a 1.2:1 to about a 0.8:1 mixture by volume of tetrahydrofuran and 1,4-dioxane. In certain embodiments, the invention relates to any of the methods described herein, wherein the second solvent is about a 1.2:1, about a 1:1, or about a 0.8:1 mixture by volume of tetrahydrofuran and 1,4-dioxane. In certain embodiments, the invention relates to any of the methods described herein, wherein the second solvent is about a 1:1 mixture by volume of tetrahydrofuran and 1,4-dioxane.
  • the invention relates to any of the methods described herein, wherein the first period of time is from about 2 h to about 10 h. In certain embodiments, the invention relates to any of the methods described herein, wherein the first period of time is about 2 h, about 3 h, about 4 h, about 5 h, about 6 h, about 7 h, about 8 h, about 9 h, or about 10 h. In certain embodiments, the invention relates to any of the methods described herein, wherein the first period of time is about 6 h.
  • the invention relates to any of the methods described herein, wherein the method is a method of synthesizing
  • the invention relates to any of the methods described herein, wherein the method is a method of synthesizing
  • the invention relates to any of the methods described herein, wherein the method is a method of synthesizing
  • the invention relates to any of the methods described herein, wherein the method consists essentially of steps (a)-(f).
  • the invention relates to a method comprising the steps of:
  • the invention relates to a method comprising the steps of:
  • the invention relates to any of the methods described herein, wherein the concentration of P 2 S 5 in the first quantity of toluene is from about 0.2 M to about 0.5 M. In certain embodiments, the invention relates to any of the methods described herein, wherein the concentration of P 2 S 5 in the first quantity of toluene is about 0.2 M, about 0.25 M, about 0.3 M, about 0.35 M, about 0.4 M, about 0.45 M, or about 0.5 M.
  • the invention relates to any of the methods described herein, wherein P 2 S 5 and the first quantity of toluene are combined in the second container under an inert atmosphere. In certain embodiments, the invention relates to any of the methods described herein, wherein P 2 S 5 and the first quantity of toluene are combined in the second container under a nitrogen atmosphere.
  • the invention relates to any of the methods described herein, wherein the volume ratio of the first quantity of toluene to the first quantity of water is about 12:1, about 10:1, or about 8:1. In certain embodiments, the invention relates to any of the methods described herein, wherein the volume ratio of the first quantity of toluene to the first quantity of water is about 10:1.
  • the invention relates to any of the methods described herein, wherein the phase transfer catalyst is a tetraalkylammonium salt or a tetraalkylphosphonium salt. In certain embodiments, the invention relates to any of the methods described herein, wherein the phase transfer catalyst is a tetrabutylphosphonium salt. In certain embodiments, the invention relates to any of the methods described herein, wherein the phase transfer catalyst is tetrabutylphosphonium halide. In certain embodiments, the invention relates to any of the methods described herein, wherein the phase transfer catalyst is tetrabutylphosphonium chloride.
  • the invention relates to any of the methods described herein, wherein the concentration of
  • the invention relates to any of the methods described herein, wherein the concentration of
  • toluene in the second quantity of toluene is about 0.2 M, about 0.3 M, or about 0.4 M.
  • the invention relates to any of the methods described herein, wherein the mole ratio of P 2 S 5 to
  • the invention relates to any of the methods described herein, wherein the mole ratio of P 2 S 5 to
  • the invention relates to any of the methods described herein, wherein the second period of time is from about 2 h to about 10 h. In certain embodiments, the invention relates to any of the methods described herein, wherein the second period of time is about 2 h, about 3 h, about 4 h, about 5 h, about 6 h, about 7 h, about 8 h, about 9 h, or about 10 h. In certain embodiments, the invention relates to any of the methods described herein, wherein the second period of time is about 6 h.
  • the invention relates to any of the methods described herein, wherein the
  • the invention relates to any of the methods described herein, wherein the mole ratio of
  • the invention relates to any of the methods described herein, wherein the mole ratio of
  • the invention relates to any of the methods described herein, wherein the mole ratio of
  • the invention relates to any of the methods described herein, wherein the mole ratio of
  • the invention relates to any of the methods described herein, wherein the method is a method of synthesizing oltipraz.
  • the invention relates to any of the methods described herein, wherein the overall yield of oltipraz from
  • the invention relates to any of the methods described herein, wherein the purity of the oltipraz produced by the claimed methods is greater than 97%, greater than 98%, or greater than 99%, as determined by gas chromatography.
  • the invention relates to any of the methods described herein, wherein the overall yield of oltipraz from
  • the invention relates to any of the methods described herein, wherein the method consists essentially of steps (i)-(iv).
  • the invention relates to any of the methods described herein, wherein the method consists essentially of steps (a)-(f) and steps (i)-(iv).
  • the invention relates to any one of the methods described herein, further comprising the steps outlined in any other method described herein.
  • the invention relates to the use of any one of the compounds described herein in the manufacture of a medicament.
  • the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.
  • Optical isomers may be prepared, for example, by resolving a racemic mixture. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers. Racemates, and Resolutions (John Wiley & Sons, 1981).
  • the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art.
  • the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • the solvents, temperatures, reaction durations, etc. delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired bridged macrocyclic products of the present invention.
  • Synthetic chemistry transformations useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R.
  • the present invention is further illustrated by the following Example which should not be construed as limiting in any way.
  • the Examples and discoveries described herein are representative. As such, the studies and results described in the Examples section herein may be used as a guideline.
  • Methyl propionate 64 g+893 g; Lot#11-2713-56+11-2713-57+R11-1913-101
  • ST-602 (from 1 kg of ST-601 (SM), 1 eq); Lot#2463-52-2
  • Aim Establish baseline for Step 2 using NaH as the base.
  • Aim Carry out Step 3 to study cyclization of crude mixture from potassium t-butoxide condensation.
  • Aim Carry out Step 3 to study cyclization of crude mixture from sodium pentanoate condensation.
  • Aim Carry out Step 3 to study cyclization of crude mixture from sodium pentanoate condensation.
  • Aim Carry out Step 3 in toluene and water under reflux using an ammonium salt as a phase transfer catalyst
  • Aim Carry out Step 3 in toluene and water under reflux using an ammonium salt as a phase transfer catalyst
  • Aim Carry out Step 3 in toluene and water under reflux using an ammonium salt as a phase transfer catalyst
  • Aim Carry out Step 3 in toluene and water under reflux using an ammonium salt as a phase transfer catalyst
  • Aim Carry out Step 3 in toluene and water under reflux using an ammonium salt as a phase transfer catalyst

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Epidemiology (AREA)
  • Toxicology (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US14/823,256 2015-06-25 2015-08-11 Methods for Preparing Oltipraz Abandoned US20160376259A1 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
KR1020187002139A KR20180022838A (ko) 2015-06-25 2016-06-24 올티프라즈를 제조하기 위한 방법
CA2989228A CA2989228A1 (en) 2015-06-25 2016-06-24 Methods for preparing oltipraz
AU2016283082A AU2016283082B2 (en) 2015-06-25 2016-06-24 Methods for preparing oltipraz
EP16813869.1A EP3313835A4 (en) 2015-06-25 2016-06-24 PROCESS FOR THE PREPARATION OF OLTIPRAZ
JP2017565999A JP6773693B2 (ja) 2015-06-25 2016-06-24 オルチプラズを調製する方法
MA042264A MA42264A (fr) 2015-06-25 2016-06-24 Procédé de préparation d'oltipraz
PCT/IN2016/050197 WO2016207914A2 (en) 2015-06-25 2016-06-24 Methods for preparing oltipraz
US16/041,282 US20190084971A1 (en) 2015-06-25 2018-07-20 Methods for preparing oltipraz
US16/784,915 US20200172522A1 (en) 2015-06-25 2020-02-07 Methods for preparing oltipraz
US16/854,480 US10968207B2 (en) 2015-06-25 2020-04-21 Methods for preparing oltipraz
US17/210,049 US20210206752A1 (en) 2015-06-25 2021-03-23 Methods for preparing oltipraz

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1891DE2015 2015-06-25
IN1891/DEL/2015 2015-06-25

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US16/041,282 Continuation US20190084971A1 (en) 2015-06-25 2018-07-20 Methods for preparing oltipraz

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US14/823,256 Abandoned US20160376259A1 (en) 2015-06-25 2015-08-11 Methods for Preparing Oltipraz
US16/041,282 Abandoned US20190084971A1 (en) 2015-06-25 2018-07-20 Methods for preparing oltipraz
US16/784,915 Abandoned US20200172522A1 (en) 2015-06-25 2020-02-07 Methods for preparing oltipraz
US16/854,480 Active US10968207B2 (en) 2015-06-25 2020-04-21 Methods for preparing oltipraz
US17/210,049 Abandoned US20210206752A1 (en) 2015-06-25 2021-03-23 Methods for preparing oltipraz

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US16/041,282 Abandoned US20190084971A1 (en) 2015-06-25 2018-07-20 Methods for preparing oltipraz
US16/784,915 Abandoned US20200172522A1 (en) 2015-06-25 2020-02-07 Methods for preparing oltipraz
US16/854,480 Active US10968207B2 (en) 2015-06-25 2020-04-21 Methods for preparing oltipraz
US17/210,049 Abandoned US20210206752A1 (en) 2015-06-25 2021-03-23 Methods for preparing oltipraz

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US (5) US20160376259A1 (ja)
EP (1) EP3313835A4 (ja)
JP (1) JP6773693B2 (ja)
KR (1) KR20180022838A (ja)
AU (1) AU2016283082B2 (ja)
CA (1) CA2989228A1 (ja)
MA (1) MA42264A (ja)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160376259A1 (en) 2015-06-25 2016-12-29 St Ip Holding Ag Methods for Preparing Oltipraz
EP3509642A1 (en) * 2016-09-12 2019-07-17 ST IP Holding AG Formulations of 4-methyl-5-(pyrazin-2-yl)-3h-1, 2-dithiole-3-thione, and methods of making and using same
CN109996563A (zh) * 2016-09-12 2019-07-09 St知识产权控股公司 4-甲基-5-(吡嗪-2-基)-3h-1,2-二硫杂环戊烯-3-硫酮的制剂、味道改良的制剂及其制备和使用方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL171985C (nl) * 1976-02-10 1983-06-16 Rhone Poulenc Ind Werkwijze voor het bereiden van preparaten met werking tegen schistosomiasis, de aldus verkregen gevormde preparaten en werkwijze voor het bereiden van 1,2-dithioolverbindingen.
AU6462500A (en) * 1999-07-29 2001-02-19 Patrick T. Prendergast Dithiolthione compounds for the treatment of neurological disorders and for memory enhancement
HUP0300221A3 (en) 2000-04-07 2003-09-29 Kim Sang Geon Use of oltipraz as an antifibrotic and anticirrhotic agent in the liver for producing pharmaceutical compositions and pharmaceutical compositions containing oltipraz and process for producing them
ATE540586T1 (de) * 2000-11-20 2012-01-15 Applied Food Sciences Inc Verfahren zur erhöhung des gehalts an zuträglichen verbindungen nach der verarbeitung in getränken, in denen diese verbindungen natürlich vorkommen
KR100491318B1 (ko) * 2002-11-26 2005-05-24 씨제이 주식회사 올티프라즈(Ｏｌｔｉｐｒａｚ) 제조방법
KR100629771B1 (ko) 2004-01-27 2006-09-28 씨제이 주식회사 결정성이 감소되거나 무정형화된 올티프라즈의 제조방법
US20160376259A1 (en) 2015-06-25 2016-12-29 St Ip Holding Ag Methods for Preparing Oltipraz

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EP3313835A4 (en) 2019-01-09
EP3313835A2 (en) 2018-05-02
JP6773693B2 (ja) 2020-10-21
US20200247791A1 (en) 2020-08-06
JP2018520134A (ja) 2018-07-26
US20200172522A1 (en) 2020-06-04
MA42264A (fr) 2018-05-02
US20190084971A1 (en) 2019-03-21
AU2016283082A1 (en) 2018-01-18
KR20180022838A (ko) 2018-03-06
AU2016283082B2 (en) 2020-11-26
CA2989228A1 (en) 2016-12-29
US10968207B2 (en) 2021-04-06
US20210206752A1 (en) 2021-07-08

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