PT3818065T - Derivados fosfato e fosfonato de 7-amino-5-tio-tiazolo[4,5-d]pirimidinas e sua utilização no tratamento de condições associadas a níveis elevados de cx3cr1 e/ou de cx3cl1 - Google Patents
Derivados fosfato e fosfonato de 7-amino-5-tio-tiazolo[4,5-d]pirimidinas e sua utilização no tratamento de condições associadas a níveis elevados de cx3cr1 e/ou de cx3cl1Info
- Publication number
- PT3818065T PT3818065T PT197392343T PT19739234T PT3818065T PT 3818065 T PT3818065 T PT 3818065T PT 197392343 T PT197392343 T PT 197392343T PT 19739234 T PT19739234 T PT 19739234T PT 3818065 T PT3818065 T PT 3818065T
- Authority
- PT
- Portugal
- Prior art keywords
- cx3cl1
- cx3cr1
- thiazolo
- pyrimidines
- thio
- Prior art date
Links
- 229910019142 PO4 Inorganic materials 0.000 title 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title 1
- 239000010452 phosphate Substances 0.000 title 1
- 150000003230 pyrimidines Chemical class 0.000 title 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic 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
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- 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
- A61P25/28—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
- 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
- A61P35/00—Antineoplastic agents
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurology (AREA)
- Biochemistry (AREA)
- Urology & Nephrology (AREA)
- Pulmonology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Vascular Medicine (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB1811169.0A GB201811169D0 (en) | 2018-07-06 | 2018-07-06 | New compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
PT3818065T true PT3818065T (pt) | 2023-05-30 |
Family
ID=63273083
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PT197392343T PT3818065T (pt) | 2018-07-06 | 2019-07-05 | Derivados fosfato e fosfonato de 7-amino-5-tio-tiazolo[4,5-d]pirimidinas e sua utilização no tratamento de condições associadas a níveis elevados de cx3cr1 e/ou de cx3cl1 |
Country Status (23)
Country | Link |
---|---|
US (2) | US12060380B2 (pt) |
EP (1) | EP3818065B1 (pt) |
JP (1) | JP7506653B2 (pt) |
KR (1) | KR20210032403A (pt) |
CN (1) | CN112867725B (pt) |
AU (1) | AU2019297572A1 (pt) |
CA (1) | CA3105566A1 (pt) |
CY (1) | CY1126070T1 (pt) |
DK (1) | DK3818065T3 (pt) |
ES (1) | ES2945561T3 (pt) |
FI (1) | FI3818065T3 (pt) |
GB (1) | GB201811169D0 (pt) |
HR (1) | HRP20230532T1 (pt) |
HU (1) | HUE062011T2 (pt) |
IL (1) | IL279818B2 (pt) |
LT (1) | LT3818065T (pt) |
MX (1) | MX2021000011A (pt) |
PL (1) | PL3818065T3 (pt) |
PT (1) | PT3818065T (pt) |
SG (1) | SG11202100014RA (pt) |
SI (1) | SI3818065T1 (pt) |
WO (1) | WO2020008064A1 (pt) |
ZA (1) | ZA202100192B (pt) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB201811169D0 (en) * | 2018-07-06 | 2018-08-29 | Kancera Ab | New compounds |
GB202006849D0 (en) | 2020-05-08 | 2020-06-24 | Kancera Ab | New use |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE0101082D0 (sv) * | 2001-03-27 | 2001-03-27 | Astrazeneca Ab | Novel use |
ATE403428T1 (de) * | 2003-06-27 | 2008-08-15 | Pfizer Prod Inc | Pyrazoloä3,4-büpyridin-6-one als gsk-3 inhibitoren |
KR20060120014A (ko) | 2003-10-07 | 2006-11-24 | 아스트라제네카 아베 | 케모킨, 특히 cx3cr1 수용체 길항제로서 유용한 신규한2-치환된 4-아미노-티아졸로[4,5-d]피리미딘 |
ATE417830T1 (de) | 2004-11-02 | 2009-01-15 | Pfizer | Sulfonylbenzimidazolderivate |
AR053347A1 (es) * | 2005-04-06 | 2007-05-02 | Astrazeneca Ab | Derivados de [1,3]tiazolo[4,5-d]pirimidin-2(3h)-ona 5,7-sustituidos |
UA90707C2 (en) | 2005-04-06 | 2010-05-25 | Астразенека Аб | Novel 5-substituted 7-amino-[1,3]thiazolo[4,5-d]pyrimidine derivatives |
WO2008005555A1 (en) | 2006-07-07 | 2008-01-10 | Gilead Sciences, Inc. | Modulators of toll-like receptor 7 |
AU2007300749B2 (en) * | 2006-09-29 | 2011-08-25 | Astrazeneca Ab | Novel 5,7-disubstituted [1, 3] thiazolo [4, 5] pyrimidin-2 (3H)-amine derivatives and their use in therapy |
UA95811C2 (en) * | 2006-09-29 | 2011-09-12 | Астразенека Аб | 5,7-disubstituted [1,3]thiazolo [4,5-d] pyrimidin-2 (3h)-one derivatives and their use in therapy |
TW200820973A (en) * | 2006-09-29 | 2008-05-16 | Astrazeneca Ab | Novel compounds 480 |
TW200942549A (en) * | 2007-12-17 | 2009-10-16 | Janssen Pharmaceutica Nv | Imidazolo-, oxazolo-, and thiazolopyrimidine modulators of TRPV1 |
PL2254869T3 (pl) | 2008-03-07 | 2017-10-31 | Acraf | Nowe pochodne 1-benzylo-3-hydroksymetyloindazolu i ich zastosowanie w leczeniu chorób bazujących na ekspresji CX3CR1 i p40 |
AR071036A1 (es) | 2008-03-26 | 2010-05-19 | Astrazeneca Ab | Derivados 5, 7-disustituidos de [1, 3]tiazolo[4, 5-d]pirimidin-2 (3h)-ona, una composicion farmaceutica que los comprende y su uso en el tratamiento de enfermedades mediadas por el receptor cx3cr1. |
CN103118682A (zh) * | 2010-04-30 | 2013-05-22 | 加利福尼亚大学校务委员会 | 合成tlr7激动剂的磷脂缀合物的用途 |
WO2013187978A1 (en) | 2012-06-16 | 2013-12-19 | Nanjing Molecular Research, Inc. | Double-liver-targeting phosphoramidate and phosphonoamidate prodrugs |
US20180222922A1 (en) | 2015-06-08 | 2018-08-09 | The Johns Hopkins University | Radiofluorinated 7-amino-5-thio-thiazolo[4,5-d]pyrimidines for imaging fractalkine receptor (cx3cr1) |
GB201811169D0 (en) * | 2018-07-06 | 2018-08-29 | Kancera Ab | New compounds |
-
2018
- 2018-07-06 GB GBGB1811169.0A patent/GB201811169D0/en not_active Ceased
-
2019
- 2019-07-05 CA CA3105566A patent/CA3105566A1/en active Pending
- 2019-07-05 WO PCT/EP2019/068169 patent/WO2020008064A1/en unknown
- 2019-07-05 PL PL19739234.3T patent/PL3818065T3/pl unknown
- 2019-07-05 FI FIEP19739234.3T patent/FI3818065T3/fi active
- 2019-07-05 LT LTEPPCT/EP2019/068169T patent/LT3818065T/lt unknown
- 2019-07-05 DK DK19739234.3T patent/DK3818065T3/da active
- 2019-07-05 KR KR1020217003104A patent/KR20210032403A/ko not_active Application Discontinuation
- 2019-07-05 US US17/257,917 patent/US12060380B2/en active Active
- 2019-07-05 HR HRP20230532TT patent/HRP20230532T1/hr unknown
- 2019-07-05 SI SI201930537T patent/SI3818065T1/sl unknown
- 2019-07-05 EP EP19739234.3A patent/EP3818065B1/en active Active
- 2019-07-05 AU AU2019297572A patent/AU2019297572A1/en active Pending
- 2019-07-05 JP JP2021500175A patent/JP7506653B2/ja active Active
- 2019-07-05 PT PT197392343T patent/PT3818065T/pt unknown
- 2019-07-05 MX MX2021000011A patent/MX2021000011A/es unknown
- 2019-07-05 SG SG11202100014RA patent/SG11202100014RA/en unknown
- 2019-07-05 CN CN201980057603.6A patent/CN112867725B/zh active Active
- 2019-07-05 HU HUE19739234A patent/HUE062011T2/hu unknown
- 2019-07-05 IL IL279818A patent/IL279818B2/en unknown
- 2019-07-05 ES ES19739234T patent/ES2945561T3/es active Active
-
2021
- 2021-01-12 ZA ZA2021/00192A patent/ZA202100192B/en unknown
- 2021-07-09 US US17/372,125 patent/US11339183B2/en active Active
-
2023
- 2023-06-15 CY CY20231100281T patent/CY1126070T1/el unknown
Also Published As
Publication number | Publication date |
---|---|
WO2020008064A1 (en) | 2020-01-09 |
AU2019297572A1 (en) | 2021-01-28 |
DK3818065T3 (da) | 2023-05-15 |
FI3818065T3 (fi) | 2023-06-13 |
IL279818A (en) | 2021-03-01 |
JP2021530474A (ja) | 2021-11-11 |
US12060380B2 (en) | 2024-08-13 |
CY1126070T1 (el) | 2023-11-15 |
SI3818065T1 (sl) | 2023-08-31 |
US20210292349A1 (en) | 2021-09-23 |
LT3818065T (lt) | 2023-06-26 |
EP3818065A1 (en) | 2021-05-12 |
SG11202100014RA (en) | 2021-01-28 |
US11339183B2 (en) | 2022-05-24 |
CN112867725B (zh) | 2024-09-27 |
PL3818065T3 (pl) | 2023-10-09 |
HUE062011T2 (hu) | 2023-09-28 |
ZA202100192B (en) | 2023-07-26 |
KR20210032403A (ko) | 2021-03-24 |
ES2945561T3 (es) | 2023-07-04 |
IL279818B2 (en) | 2024-06-01 |
HRP20230532T1 (hr) | 2023-08-04 |
EP3818065B1 (en) | 2023-03-15 |
GB201811169D0 (en) | 2018-08-29 |
CA3105566A1 (en) | 2020-01-09 |
CN112867725A (zh) | 2021-05-28 |
US20210340167A1 (en) | 2021-11-04 |
JP7506653B2 (ja) | 2024-06-26 |
MX2021000011A (es) | 2021-05-12 |
IL279818B1 (en) | 2024-02-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
IL246564A (en) | 3-aryl-1-heterocyclic-pyrazolo [4,3- d] pyrimidine derivatives and their use in the treatment of diseases | |
MX2019005834A (es) | Compuestos con actividad antitumoral contra células cancerosas que tienen mutaciones en el exón 20 de egfr o her2. | |
ZA202100192B (en) | Phosphate and phosphonate derivatives of 7-amino-5-thio-thiazolo[4,5-d]pyrimidines and their use in treating conditions associated with elevated levels of cx3cr1 and/or cx3cl1 | |
PH12015502780B1 (en) | Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases | |
NZ751284A (en) | Novel jak1 selective inhibitors and uses thereof | |
MX2019004070A (es) | Sistema de extraccion de un sistema de circuito cerrado. | |
IL246579B (en) | Compounds that inhibit the activity of 2lrrk and their use in the treatment of Parkinson's disease | |
MX2020008680A (es) | Terapia de combinacion con apilimod y agentes glutamatergicos. | |
TW201613919A (en) | Inhibitors of Bruton's tyrosine kinase | |
SG10201908697XA (en) | A pharmaceutical composition for use in the treatment or prevention of a c5-related disease and a method for treating or preventing a c5-related disease | |
MX363950B (es) | Derivados de urea utiles como inhibidores de quinasa. | |
IL262177B (en) | Pyrimidinyl Carboxamide, 5-a] compounds and their use for the treatment of medical disorders | |
AU2017261291A1 (en) | Substituted imidazo[1,2-b]pyridazines, substituted imidazo[1,5-b]pyridazines, related compounds, and their use in the treatment of medical disorders | |
MX2022007994A (es) | Derivados de arilciclohexilamina y su uso en el tratamiento de trastornos psiquiátricos. | |
EP3452480A4 (en) | SUBSTITUTED PYRROLO [1,2-] TRIAZINES AND RELATED COMPOUNDS AND THEIR USE IN THE TREATMENT OF MEDICAL DISORDERS | |
MX2019009190A (es) | Uso de gaboxadol en el tratamiento de tinnitus. | |
MX2021007260A (es) | Inhibidores de la vía de cinasa janus 1 (jak1) para el tratamiento de enfermedades gastrointestinales. | |
MX2019012176A (es) | Metodos de combinacion de chk1(sra737)/parpi para inhibir el crecimiento tumoral. | |
MX2020003400A (es) | Profarmacos de dantroleno y metodos de su uso. | |
MX2019008124A (es) | Metodos para el tratamiento de trastornos neurologicos. | |
EP3344632A4 (en) | Heterocyclic pyrimidine compounds and their use in the treatment of medical disorders | |
NZ756936A (en) | Composition and method for preventing or delaying onset of myopia comprising atropine | |
DK3292867T3 (da) | Ny brug af triazol(4,5-d)pyrimidinderivater til brug i forebyggelsen og behandlingen af bakteriel infektion | |
NZ745186A (en) | 8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives | |
NZ771525A (en) | Methods of treating hfpef employing dapagliflozin and compositions comprising the same |