MD4793C1 - Noi compuşi de izoindolină sau izochinolină, procedeu de obţinere a lor şi compoziţii farmaceutice care le conţin - Google Patents

Noi compuşi de izoindolină sau izochinolină, procedeu de obţinere a lor şi compoziţii farmaceutice care le conţin Download PDF

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Publication number
MD4793C1
MD4793C1 MDA20160018A MD20160018A MD4793C1 MD 4793 C1 MD4793 C1 MD 4793C1 MD A20160018 A MDA20160018 A MD A20160018A MD 20160018 A MD20160018 A MD 20160018A MD 4793 C1 MD4793 C1 MD 4793C1
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MD
Moldova
Prior art keywords
methyl
carbonyl
phenyl
tetrahydroisoquinoline
carboxamide
Prior art date
Application number
MDA20160018A
Other languages
English (en)
Romanian (ro)
Russian (ru)
Other versions
MD20160018A2 (ro
MD4793B1 (ro
Inventor
Джеймс Эдвард Пол Дэвидсон
Джеймс Брук МЮРРЕЙ
Ай-Джен ЧЕНЬ
Клэр Уолмсли
Марк ДОДСУОРТ
Йоханнес В.Г. МЕЙССНЕР
Пол БРОГ
Имре ФЕЕШ
Янош Татаи
Миклош Ньергеш
Андрас КОЦКИ
Золтан Славик
Оливье Женест
Тиран Арно Ле
Дигуарье Тьерри Ле
Жан-Мишель ХЕНЛИН
Жером-Бенуа Старк
Анна-Франсуаза ГИЙЮЗИС
Нантей Гийом Де
Original Assignee
Les Laboratoires Servier
Vernalis (R&D) Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Les Laboratoires Servier, Vernalis (R&D) Limited filed Critical Les Laboratoires Servier
Publication of MD20160018A2 publication Critical patent/MD20160018A2/ro
Publication of MD4793B1 publication Critical patent/MD4793B1/ro
Publication of MD4793C1 publication Critical patent/MD4793C1/ro

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/04Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/14Heterocyclic 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 three or more hetero rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/472Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/496Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/4965Non-condensed pyrazines
    • A61K31/497Non-condensed pyrazines containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • A61K31/53771,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/66Phosphorus compounds
    • A61K31/675Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/10X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic 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
    • C07D471/02Heterocyclic 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 two hetero rings
    • C07D471/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02Phosphorus compounds
    • C07F9/547Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pathology (AREA)
  • Radiology & Medical Imaging (AREA)
  • Transplantation (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Indole Compounds (AREA)
MDA20160018A 2013-07-23 2014-07-22 Noi compuşi de izoindolină sau izochinolină, procedeu de obţinere a lor şi compoziţii farmaceutice care le conţin MD4793C1 (ro)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR1357276A FR3008977A1 (fr) 2013-07-23 2013-07-23 Nouveaux derives d'isoindoline ou d'isoquinoline, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
PCT/EP2014/065764 WO2015011164A1 (en) 2013-07-23 2014-07-22 New isoindoline or isoquinoline compounds, a process for their preparation and pharmaceutical compositions containing them

Publications (3)

Publication Number Publication Date
MD20160018A2 MD20160018A2 (ro) 2016-07-31
MD4793B1 MD4793B1 (ro) 2022-02-28
MD4793C1 true MD4793C1 (ro) 2022-09-30

Family

ID=49911606

Family Applications (1)

Application Number Title Priority Date Filing Date
MDA20160018A MD4793C1 (ro) 2013-07-23 2014-07-22 Noi compuşi de izoindolină sau izochinolină, procedeu de obţinere a lor şi compoziţii farmaceutice care le conţin

Country Status (49)

Country Link
US (3) US9809574B2 (https=)
EP (1) EP3024826B1 (https=)
JP (1) JP6395829B2 (https=)
KR (1) KR102008431B1 (https=)
CN (2) CN105431422B (https=)
AP (1) AP2016008989A0 (https=)
AR (1) AR097009A1 (https=)
AU (1) AU2014295101B2 (https=)
BR (1) BR112016001080B1 (https=)
CA (1) CA2919572C (https=)
CL (1) CL2016000148A1 (https=)
CR (1) CR20160030A (https=)
CU (1) CU24352B1 (https=)
CY (1) CY1121247T1 (https=)
DK (1) DK3024826T3 (https=)
DO (1) DOP2016000009A (https=)
EA (1) EA032301B1 (https=)
ES (1) ES2711371T3 (https=)
FR (1) FR3008977A1 (https=)
GE (2) GEP20207070B (https=)
HK (1) HK1218754A1 (https=)
HR (1) HRP20190277T1 (https=)
HU (1) HUE041443T2 (https=)
IL (1) IL243449A0 (https=)
JO (1) JO3457B1 (https=)
LT (1) LT3024826T (https=)
MA (1) MA38801B1 (https=)
MD (1) MD4793C1 (https=)
ME (1) ME03346B (https=)
MX (1) MX365373B (https=)
MY (1) MY193619A (https=)
NI (1) NI201600016A (https=)
NZ (1) NZ716155A (https=)
PE (1) PE20160241A1 (https=)
PH (1) PH12016500034A1 (https=)
PL (1) PL3024826T3 (https=)
PT (1) PT3024826T (https=)
RS (1) RS58344B1 (https=)
RU (1) RU2689305C2 (https=)
SA (1) SA516370439B1 (https=)
SG (1) SG11201600205XA (https=)
SI (1) SI3024826T1 (https=)
TN (1) TN2016000003A1 (https=)
TR (1) TR201819155T4 (https=)
TW (1) TWI560184B (https=)
UA (1) UA117490C2 (https=)
UY (1) UY35664A (https=)
WO (1) WO2015011164A1 (https=)
ZA (1) ZA201600198B (https=)

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FR3008977A1 (fr) * 2013-07-23 2015-01-30 Servier Lab Nouveaux derives d'isoindoline ou d'isoquinoline, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
BR112018071548A2 (pt) 2016-04-20 2019-04-16 Bristol-Myers Squibb Company compostos heterocíclicos bicíclicos substituídos
BR112020026580A2 (pt) 2018-06-27 2021-03-23 Proteostasis Therapeutics, Inc. (Fem) Compostos, composição farmacêutica e métodos para tratar um paciente
KR20220102622A (ko) * 2019-11-15 2022-07-20 우한 엘엘 사이언스 앤드 테크놀로지 디벨롭먼트 컴퍼니, 리미티드 Rock 억제제 및 이의 제조 방법과 용도
CN112010796B (zh) * 2020-09-17 2022-04-22 浙江大学 光学活性3-(1,1-二氟-2-氧-2-芳基乙基)异吲哚啉-1-酮衍生物制备方法
JP2024511277A (ja) 2021-02-19 2024-03-13 メビオン・メディカル・システムズ・インコーポレーテッド 粒子線治療システムのためのガントリー
CN116997544A (zh) * 2021-03-24 2023-11-03 法国施维雅药厂 用于合成5-{5-氯-2-[(3s)-3-[(吗啉-4-基)甲基]-3,4-二氢异喹啉-2(1h)-羰基]苯基}-1,2-二甲基-1h-吡咯-3-甲酸衍生物的新方法及其在生产药物化合物中的应用
US20250179047A1 (en) 2022-02-24 2025-06-05 Les Laboratoires Servier 5-[7-(3,4-dihydro-1h-isoquinoline-2-carbonyl)-1,2,3,4 tetrahydroisoquinolin-6-yl]-1h-pyrrole-3-carboxamide derivatives, pharmaceutical compositions containing them and their uses as pro-apoptotic agents
CN120787162A (zh) 2022-05-20 2025-10-14 诺华股份有限公司 抗肿瘤化合物的抗体-药物缀合物及其使用方法
WO2024204846A1 (ja) * 2023-03-31 2024-10-03 三井化学株式会社 カルバメート化合物
PY24103486A (es) 2023-11-22 2025-06-06 Servier Lab Conjugados de anticuerpo anti-cd74-fármaco y métodos de uso de los mismos
TW202540186A (zh) 2023-11-22 2025-10-16 瑞士商諾華公司 抗cd7抗體藥物結合物及其使用方法

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JP5496915B2 (ja) 2008-02-13 2014-05-21 シージーアイ ファーマシューティカルズ,インコーポレーテッド 6−アリール−イミダゾ[1,2−a]ピラジン誘導体、その製造方法、及びその使用方法
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CN103732589B (zh) * 2011-05-25 2016-03-30 百时美施贵宝公司 可用作抗细胞凋亡bcl抑制剂的取代的磺酰胺
JP2015503518A (ja) * 2011-12-23 2015-02-02 ノバルティス アーゲー Bcl2と結合相手の相互作用を阻害するための化合物
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FR2986002B1 (fr) * 2012-01-24 2014-02-21 Servier Lab Nouveaux derives d'indolizine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR3008977A1 (fr) * 2013-07-23 2015-01-30 Servier Lab Nouveaux derives d'isoindoline ou d'isoquinoline, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR3008979B1 (fr) * 2013-07-23 2015-07-24 Servier Lab Nouveaux derives phosphates, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

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US20180002313A1 (en) 2018-01-04
MY193619A (en) 2022-10-20
SA516370439B1 (ar) 2019-06-27
EP3024826A1 (en) 2016-06-01
CY1121247T1 (el) 2020-05-29
ME03346B (me) 2019-10-20
SG11201600205XA (en) 2016-02-26
RU2689305C2 (ru) 2019-05-27
CA2919572A1 (en) 2015-01-29
PH12016500034B1 (en) 2016-03-28
MX365373B (es) 2019-05-31
CN105431422A (zh) 2016-03-23
HK1218754A1 (zh) 2017-03-10
AU2014295101B2 (en) 2018-05-31
CN109456324B (zh) 2022-04-22
ES2711371T3 (es) 2019-05-03
CN105431422B (zh) 2019-08-30
ZA201600198B (en) 2019-07-31
AP2016008989A0 (en) 2016-01-31
PT3024826T (pt) 2019-01-28
JP6395829B2 (ja) 2018-09-26
CA2919572C (en) 2017-06-20
KR20160033224A (ko) 2016-03-25
CU24352B1 (es) 2018-07-05
TN2016000003A1 (en) 2017-07-05
HK1222856A1 (en) 2017-07-14
PE20160241A1 (es) 2016-04-30
MX2016000904A (es) 2016-04-25
CU20160010A7 (es) 2016-06-29
TWI560184B (en) 2016-12-01
RS58344B1 (sr) 2019-03-29
EA032301B1 (ru) 2019-05-31
JP2016525529A (ja) 2016-08-25
PH12016500034A1 (en) 2016-03-28
LT3024826T (lt) 2019-02-25
MD20160018A2 (ro) 2016-07-31
DK3024826T3 (en) 2019-03-04
US9809574B2 (en) 2017-11-07
SI3024826T1 (sl) 2019-03-29
US20200262816A1 (en) 2020-08-20
CN109456324A (zh) 2019-03-12
RU2016106003A (ru) 2017-08-28
GEP20207070B (en) 2020-02-25
UY35664A (es) 2015-01-30
AR097009A1 (es) 2016-02-10
CR20160030A (es) 2016-03-09
EP3024826B1 (en) 2018-11-14
PL3024826T3 (pl) 2019-05-31
AU2014295101A1 (en) 2016-02-04
US11028070B2 (en) 2021-06-08
MA38801A1 (fr) 2018-05-31
GEAP201914063A (en) 2019-10-25
US20160194304A1 (en) 2016-07-07
TR201819155T4 (tr) 2019-01-21
CL2016000148A1 (es) 2016-08-12
NZ716155A (en) 2019-05-31
JO3457B1 (ar) 2020-07-05
WO2015011164A1 (en) 2015-01-29
KR102008431B1 (ko) 2019-08-07
HRP20190277T1 (hr) 2019-04-05
MA38801B1 (fr) 2019-03-29
MD4793B1 (ro) 2022-02-28
BR112016001080A2 (https=) 2017-07-25
UA117490C2 (uk) 2018-08-10
BR112016001080B1 (pt) 2022-04-05
FR3008977A1 (fr) 2015-01-30
NI201600016A (es) 2016-02-11
TW201504228A (zh) 2015-02-01
US10689364B2 (en) 2020-06-23
IL243449A0 (en) 2016-02-29
DOP2016000009A (es) 2016-03-15
EA201600122A1 (ru) 2016-07-29
HUE041443T2 (hu) 2019-05-28

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