MX377195B - Derivados de morfolina-piridina. - Google Patents
Derivados de morfolina-piridina.Info
- Publication number
- MX377195B MX377195B MX2016013412A MX2016013412A MX377195B MX 377195 B MX377195 B MX 377195B MX 2016013412 A MX2016013412 A MX 2016013412A MX 2016013412 A MX2016013412 A MX 2016013412A MX 377195 B MX377195 B MX 377195B
- Authority
- MX
- Mexico
- Prior art keywords
- disorders
- halogen
- lower alkyl
- sup
- disease
- Prior art date
Links
- QJKBHDRXPAOHSY-UHFFFAOYSA-N morpholine;pyridine Chemical class C1COCCN1.C1=CC=NC=C1 QJKBHDRXPAOHSY-UHFFFAOYSA-N 0.000 title 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 4
- 208000035475 disorder Diseases 0.000 abstract 4
- 229910052736 halogen Inorganic materials 0.000 abstract 4
- 125000000217 alkyl group Chemical group 0.000 abstract 3
- 125000003545 alkoxy group Chemical group 0.000 abstract 2
- 125000005843 halogen group Chemical group 0.000 abstract 2
- 150000002367 halogens Chemical group 0.000 abstract 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract 1
- 208000024827 Alzheimer disease Diseases 0.000 abstract 1
- 208000019901 Anxiety disease Diseases 0.000 abstract 1
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 abstract 1
- 208000020925 Bipolar disease Diseases 0.000 abstract 1
- 208000024172 Cardiovascular disease Diseases 0.000 abstract 1
- 208000017164 Chronobiology disease Diseases 0.000 abstract 1
- 208000020401 Depressive disease Diseases 0.000 abstract 1
- 208000002249 Diabetes Complications Diseases 0.000 abstract 1
- 206010012655 Diabetic complications Diseases 0.000 abstract 1
- 208000032928 Dyslipidaemia Diseases 0.000 abstract 1
- 208000030814 Eating disease Diseases 0.000 abstract 1
- 208000019454 Feeding and Eating disease Diseases 0.000 abstract 1
- 206010020772 Hypertension Diseases 0.000 abstract 1
- 208000017170 Lipid metabolism disease Diseases 0.000 abstract 1
- 208000019695 Migraine disease Diseases 0.000 abstract 1
- 208000012902 Nervous system disease Diseases 0.000 abstract 1
- 208000025966 Neurological disease Diseases 0.000 abstract 1
- 208000008589 Obesity Diseases 0.000 abstract 1
- 208000018737 Parkinson disease Diseases 0.000 abstract 1
- 208000028017 Psychotic disease Diseases 0.000 abstract 1
- 239000002253 acid Substances 0.000 abstract 1
- 230000036760 body temperature Effects 0.000 abstract 1
- 230000027288 circadian rhythm Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 206010012601 diabetes mellitus Diseases 0.000 abstract 1
- 235000014632 disordered eating Nutrition 0.000 abstract 1
- 238000005265 energy consumption Methods 0.000 abstract 1
- 206010015037 epilepsy Diseases 0.000 abstract 1
- 125000001072 heteroaryl group Chemical group 0.000 abstract 1
- 230000013632 homeostatic process Effects 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 150000002431 hydrogen Chemical group 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 230000007257 malfunction Effects 0.000 abstract 1
- 208000030159 metabolic disease Diseases 0.000 abstract 1
- 206010027599 migraine Diseases 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 208000015122 neurodegenerative disease Diseases 0.000 abstract 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
- 235000020824 obesity Nutrition 0.000 abstract 1
- 230000003287 optical effect Effects 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 201000000980 schizophrenia Diseases 0.000 abstract 1
- 230000007958 sleep Effects 0.000 abstract 1
- 201000009032 substance abuse Diseases 0.000 abstract 1
- 231100000736 substance abuse Toxicity 0.000 abstract 1
- 208000011117 substance-related disease Diseases 0.000 abstract 1
Classifications
-
- 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
- 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
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic 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
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- A61P9/12—Antihypertensives
-
- 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
- C07D413/12—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 linked by a chain containing hetero atoms as chain links
-
- 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Psychology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pain & Pain Management (AREA)
- Addiction (AREA)
- Emergency Medicine (AREA)
- Rheumatology (AREA)
- Anesthesiology (AREA)
- Child & Adolescent Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2014/076623 WO2015165085A1 (en) | 2014-04-30 | 2014-04-30 | Morpholin-pyridine derivatives |
| PCT/EP2015/059002 WO2015165835A1 (en) | 2014-04-30 | 2015-04-27 | Morpholin-pyridine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MX2016013412A MX2016013412A (es) | 2017-01-18 |
| MX377195B true MX377195B (es) | 2025-03-07 |
Family
ID=53174989
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX2016013412A MX377195B (es) | 2014-04-30 | 2015-04-27 | Derivados de morfolina-piridina. |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US9840501B2 (enExample) |
| EP (1) | EP3137459B1 (enExample) |
| JP (1) | JP6255516B2 (enExample) |
| KR (1) | KR101842382B1 (enExample) |
| CN (1) | CN106255688B (enExample) |
| AR (1) | AR100210A1 (enExample) |
| BR (1) | BR112016022796B1 (enExample) |
| CA (1) | CA2943575C (enExample) |
| MX (1) | MX377195B (enExample) |
| RU (1) | RU2690154C2 (enExample) |
| TW (1) | TWI576345B (enExample) |
| WO (2) | WO2015165085A1 (enExample) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUE046008T2 (hu) | 2014-07-17 | 2020-02-28 | Sunshine Lake Pharma Co Ltd | I-(5-terc-butil)-izoxazol-3-il)-3-(4-((feniI)-etinil)-fenil)-kabamid származékok, valamint az ezekkel rokon vegyületek FLT-3 inhibitorokként rák kezelésére |
| CR20180443A (es) * | 2016-03-17 | 2018-11-21 | Hoffmann La Roche | Derivado de morfolina |
| WO2017210616A1 (en) * | 2016-06-02 | 2017-12-07 | Purdue Pharma L.P. | Trace amine associated receptor 1 agonists and partial agonists for pain treatment |
| CN113754580B (zh) * | 2020-06-05 | 2023-04-25 | 上海中泽医药科技有限公司 | 一种吡啶吗啉类化合物、其制备方法及其应用 |
| US20250051316A1 (en) | 2021-11-04 | 2025-02-13 | Shanghai Hansoh Biomedical Co., Ltd. | 2-(aryl-2-yl) morpholine and deuterated derivative thereof, preparation method therefor and application thereof |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9425211D0 (en) | 1994-12-14 | 1995-02-15 | Ucb Sa | Substituted 1H-imidazoles |
| GB9520150D0 (en) | 1995-10-03 | 1995-12-06 | Orion Yhtymae Oy | New imidazole derivatives |
| US6841684B2 (en) | 1997-12-04 | 2005-01-11 | Allergan, Inc. | Imidiazoles having reduced side effects |
| US20080146523A1 (en) * | 2006-12-18 | 2008-06-19 | Guido Galley | Imidazole derivatives |
| CN101616902B (zh) | 2007-02-15 | 2013-03-27 | 弗·哈夫曼-拉罗切有限公司 | 作为taar1配体的2-氨基*唑啉类化合物 |
| US9452980B2 (en) * | 2009-12-22 | 2016-09-27 | Hoffmann-La Roche Inc. | Substituted benzamides |
| US9132136B2 (en) * | 2010-08-02 | 2015-09-15 | Hoffmann-La Roche Inc. | Pharmaceutical combination |
| US8802673B2 (en) * | 2011-03-24 | 2014-08-12 | Hoffmann-La Roche Inc | Heterocyclic amine derivatives |
| US9073911B2 (en) * | 2011-06-09 | 2015-07-07 | Hoffmann-La Roche Inc. | Pyrazole derivatives |
| US9029370B2 (en) * | 2011-06-10 | 2015-05-12 | Hoffmann-La Roche Inc. | Substituted benzamide derivatives |
| WO2013173506A2 (en) * | 2012-05-16 | 2013-11-21 | Rigel Pharmaceuticals, Inc. | Method of treating muscular degradation |
-
2014
- 2014-04-30 WO PCT/CN2014/076623 patent/WO2015165085A1/en not_active Ceased
-
2015
- 2015-04-27 JP JP2016564587A patent/JP6255516B2/ja not_active Expired - Fee Related
- 2015-04-27 MX MX2016013412A patent/MX377195B/es active IP Right Grant
- 2015-04-27 RU RU2016146560A patent/RU2690154C2/ru active
- 2015-04-27 WO PCT/EP2015/059002 patent/WO2015165835A1/en not_active Ceased
- 2015-04-27 EP EP15721608.6A patent/EP3137459B1/en active Active
- 2015-04-27 CA CA2943575A patent/CA2943575C/en active Active
- 2015-04-27 KR KR1020167033527A patent/KR101842382B1/ko not_active Expired - Fee Related
- 2015-04-27 CN CN201580022457.5A patent/CN106255688B/zh not_active Expired - Fee Related
- 2015-04-27 BR BR112016022796-4A patent/BR112016022796B1/pt not_active IP Right Cessation
- 2015-04-28 AR ARP150101269A patent/AR100210A1/es unknown
- 2015-04-29 TW TW104113768A patent/TWI576345B/zh not_active IP Right Cessation
-
2016
- 2016-10-26 US US15/334,707 patent/US9840501B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2943575A1 (en) | 2015-11-05 |
| JP6255516B2 (ja) | 2017-12-27 |
| WO2015165085A1 (en) | 2015-11-05 |
| CA2943575C (en) | 2022-08-30 |
| CN106255688A (zh) | 2016-12-21 |
| US9840501B2 (en) | 2017-12-12 |
| AR100210A1 (es) | 2016-09-21 |
| BR112016022796B1 (pt) | 2023-03-07 |
| BR112016022796A2 (enExample) | 2017-08-15 |
| RU2690154C2 (ru) | 2019-05-31 |
| TWI576345B (zh) | 2017-04-01 |
| US20170044145A1 (en) | 2017-02-16 |
| EP3137459B1 (en) | 2018-05-23 |
| MX2016013412A (es) | 2017-01-18 |
| RU2016146560A3 (enExample) | 2018-11-26 |
| RU2016146560A (ru) | 2018-06-01 |
| TW201546067A (zh) | 2015-12-16 |
| WO2015165835A1 (en) | 2015-11-05 |
| CN106255688B (zh) | 2019-11-08 |
| EP3137459A1 (en) | 2017-03-08 |
| KR101842382B1 (ko) | 2018-03-26 |
| JP2017513912A (ja) | 2017-06-01 |
| KR20160147033A (ko) | 2016-12-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FG | Grant or registration |