ATE175667T1 - Aminobenzofuryl- und -thienylderivate - Google Patents
Aminobenzofuryl- und -thienylderivateInfo
- Publication number
- ATE175667T1 ATE175667T1 AT95107606T AT95107606T ATE175667T1 AT E175667 T1 ATE175667 T1 AT E175667T1 AT 95107606 T AT95107606 T AT 95107606T AT 95107606 T AT95107606 T AT 95107606T AT E175667 T1 ATE175667 T1 AT E175667T1
- Authority
- AT
- Austria
- Prior art keywords
- aminobenzofuryl
- amino
- thienyl derivatives
- thienyl
- derivatives
- Prior art date
Links
- -1 AMINOBENZOFURYL Chemical class 0.000 title abstract 2
- 150000008062 acetophenones Chemical class 0.000 abstract 1
- 208000037976 chronic inflammation Diseases 0.000 abstract 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract 1
- 230000004048 modification Effects 0.000 abstract 1
- 238000012986 modification Methods 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic 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
- C07D405/02—Heterocyclic 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 two hetero rings
- C07D405/06—Heterocyclic 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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
-
- 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
-
- 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
- A61P11/08—Bronchodilators
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61P9/10—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
- C07D307/83—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic 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
- C07D405/02—Heterocyclic 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 two hetero rings
- C07D405/10—Heterocyclic 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 two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic 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
- C07D405/02—Heterocyclic 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 two hetero rings
- C07D405/12—Heterocyclic 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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D409/10—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 linked by a carbon chain containing aromatic rings
-
- 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
- C07D409/12—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 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
- C07D413/02—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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pulmonology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
- Saccharide Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9410879A GB9410879D0 (en) | 1994-05-31 | 1994-05-31 | Amino-benzofuryl-derivatives |
| GB9410868A GB9410868D0 (en) | 1994-05-31 | 1994-05-31 | Amino-substituted-3-methyl-benzofurance derivatives |
| GB9410878A GB9410878D0 (en) | 1994-05-31 | 1994-05-31 | Heterocyclyl-carbonyl substituted amino-benzofuran derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ATE175667T1 true ATE175667T1 (de) | 1999-01-15 |
Family
ID=27267207
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AT95107606T ATE175667T1 (de) | 1994-05-31 | 1995-05-18 | Aminobenzofuryl- und -thienylderivate |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US5622989A (de) |
| EP (1) | EP0685475B1 (de) |
| JP (1) | JPH07330751A (de) |
| AT (1) | ATE175667T1 (de) |
| CA (1) | CA2150300A1 (de) |
| DE (1) | DE69507197T2 (de) |
| DK (1) | DK0685475T3 (de) |
| ES (1) | ES2127966T3 (de) |
| GR (1) | GR3029779T3 (de) |
Families Citing this family (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1100773C (zh) * | 1995-12-05 | 2003-02-05 | 达尔文发现有限公司 | 苯并呋喃羧酸胺和磺酰胺 |
| TR199802386T2 (xx) * | 1996-05-20 | 1999-02-22 | Darwin Discovery Limited | Benzofuran karboksamidler ve bunlar�n terap�tik kullan�m�. |
| JP4373497B2 (ja) | 1996-06-19 | 2009-11-25 | ローン−プーラン・ロレ・リミテツド | 置換されたアザビシクロ化合物、ならびにｔｎｆおよびサイクリックａｍｐホスホジエステラーゼ産生の阻害剤としてのそれらの使用 |
| GB9614718D0 (en) | 1996-07-12 | 1996-09-04 | Bayer Ag | 3-ureido-pyridofurans and -pyridothiophenes |
| DE19642451A1 (de) * | 1996-10-15 | 1998-04-16 | Merck Patent Gmbh | Aminothiophencarbonsäureamide |
| WO2000034262A1 (en) | 1998-12-04 | 2000-06-15 | Takeda Chemical Industries, Ltd. | Benzofuran derivatives, process for the preparation of the same and uses thereof |
| CA2715683A1 (en) | 1999-08-21 | 2001-03-01 | Nycomed Gmbh | Synergistic combination |
| US7144885B2 (en) * | 2002-02-22 | 2006-12-05 | Bayer Pharmaceuticals Corporation | Fused tricyclic heterocycles useful for treating hyper-proliferative disorders |
| AU2003215380B2 (en) * | 2002-02-22 | 2008-10-02 | Bayer Pharmaceuticals Corporation | Fused tricyclic heterocycles useful for treating hyper-proliferative disorders |
| US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
| EA200501548A1 (ru) | 2003-04-01 | 2006-02-24 | Апплайд Резеч Системз Арс Холдинг Н.В. | Ингибиторы фосфодиэстераз при бесплодии |
| US20060074083A1 (en) * | 2004-10-05 | 2006-04-06 | Merz Pharma Gmbh & Co. Kgaa | Cyclic and acyclic propenones for treating CNS disorders |
| CA2666469A1 (en) * | 2006-09-01 | 2008-03-06 | Bayer Healthcare Ag | Benzofuran and benzothiophene derivatives useful in the treatment of cancers of the central nervous system |
| MX2009013293A (es) | 2007-06-04 | 2010-02-15 | Synergy Pharmaceuticals Inc | Agonistas de guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros trastornos. |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| EP2810951B1 (de) | 2008-06-04 | 2017-03-15 | Synergy Pharmaceuticals Inc. | Für die Behandlung von gastrointestinalen Erkrankungen, Entzündungen, Krebs und anderen Erkrankungen geeignete Agonisten von Guanylatcyclase |
| CA2730603C (en) | 2008-07-16 | 2019-09-24 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| SG171914A1 (en) | 2008-12-02 | 2011-07-28 | Chiralgen Ltd | Method for the synthesis of phosphorus atom modified nucleic acids |
| EP2451461A4 (de) | 2009-07-06 | 2013-05-29 | Ontorii Inc | Neuartige nukleinsäure-prodrugs und verwendungsverfahren dafür |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| DK2620428T3 (da) | 2010-09-24 | 2019-07-01 | Wave Life Sciences Ltd | Asymmetrisk hjælpegruppe |
| CA3100941C (en) | 2011-03-01 | 2024-03-05 | Synergy Pharmaceuticals Inc. | Process of preparing guanylate cyclase c agonists |
| US9605019B2 (en) | 2011-07-19 | 2017-03-28 | Wave Life Sciences Ltd. | Methods for the synthesis of functionalized nucleic acids |
| DK2872485T3 (da) | 2012-07-13 | 2021-03-08 | Wave Life Sciences Ltd | Asymmetrisk hjælpegruppe |
| EP3718557A3 (de) | 2013-02-25 | 2020-10-21 | Bausch Health Ireland Limited | Guanylat-cyclase-rezeptoragonist sp-333 zur verwendung in der darmreinigung |
| JP2016514670A (ja) | 2013-03-15 | 2016-05-23 | シナジー ファーマシューティカルズ インコーポレイテッド | 他の薬物と組み合わせたグアニル酸シクラーゼ受容体アゴニスト |
| JP2016514671A (ja) | 2013-03-15 | 2016-05-23 | シナジー ファーマシューティカルズ インコーポレイテッド | グアニル酸シクラーゼのアゴニストおよびその使用 |
| EA201592263A1 (ru) | 2013-06-05 | 2016-05-31 | Синерджи Фармасьютикалз, Инк. | Ультрачистые агонисты гуанилатциклазы c, способ их получения и использования |
| KR20160042039A (ko) | 2013-08-09 | 2016-04-18 | 알데릭스, 인코포레이티드 | 인산염 수송을 억제하기 위한 화합물 및 방법 |
| KR102423317B1 (ko) | 2014-01-16 | 2022-07-22 | 웨이브 라이프 사이언시스 리미티드 | 키랄 디자인 |
| WO2020237096A1 (en) | 2019-05-21 | 2020-11-26 | Ardelyx, Inc. | Combination for lowering serum phosphate in a patient |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE351639B (de) * | 1964-11-11 | 1972-12-04 | Haessle Ab | |
| EP0146243A1 (de) | 1983-10-31 | 1985-06-26 | Merck Frosst Canada Inc. | Lipoxygenase-Inhibitoren |
| US5120742A (en) * | 1984-02-27 | 1992-06-09 | Merck & Co., Inc. | 17 β-acyl-4-aza-5 α-androst-1-ene-3-ones as 5 α-reductase inhibitors |
| GB9200623D0 (en) * | 1992-01-13 | 1992-03-11 | Bayer Ag | Benzofuranyl and thiophenyl-methylthio-alkanecarboxylic acid derivatives |
| GB9309324D0 (en) * | 1993-05-06 | 1993-06-16 | Bayer Ag | Venzofuranyl-and-thiophenyl-alkanecarboxyclic acids derivatives |
-
1995
- 1995-05-18 DK DK95107606T patent/DK0685475T3/da active
- 1995-05-18 ES ES95107606T patent/ES2127966T3/es not_active Expired - Lifetime
- 1995-05-18 DE DE69507197T patent/DE69507197T2/de not_active Expired - Fee Related
- 1995-05-18 EP EP95107606A patent/EP0685475B1/de not_active Expired - Lifetime
- 1995-05-18 AT AT95107606T patent/ATE175667T1/de not_active IP Right Cessation
- 1995-05-23 US US08/449,402 patent/US5622989A/en not_active Expired - Fee Related
- 1995-05-26 CA CA002150300A patent/CA2150300A1/en not_active Abandoned
- 1995-05-29 JP JP7153845A patent/JPH07330751A/ja active Pending
-
1999
- 1999-03-23 GR GR990400867T patent/GR3029779T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0685475B1 (de) | 1999-01-13 |
| US5622989A (en) | 1997-04-22 |
| DE69507197D1 (de) | 1999-02-25 |
| DK0685475T3 (da) | 1999-08-30 |
| ES2127966T3 (es) | 1999-05-01 |
| DE69507197T2 (de) | 1999-05-27 |
| JPH07330751A (ja) | 1995-12-19 |
| CA2150300A1 (en) | 1995-12-01 |
| GR3029779T3 (en) | 1999-06-30 |
| EP0685475A1 (de) | 1995-12-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK0685475T3 (da) | Amino-benzofuryl- og thienylderivater | |
| DE69504753D1 (de) | Oxalylamino-Benzofuran- und Benzothienylderivate | |
| DE69507199D1 (de) | Heterocyclylcarbonylsubstituierte Benzofuranyl- und -thiophenylalkancarbonsäurederivate | |
| UA104987C2 (uk) | Похідні 3-(2,6-диметилбензилокси)фенілоцтової кислоти | |
| ATE227279T1 (de) | Phenyl thiazol derivate mit antiherpesvirus eigenschaften | |
| BR9508057A (pt) | Composto | |
| NO20012995L (no) | Forbindelser nyttige for behandling av inflammatoriske sykdommer | |
| SE9301830D0 (sv) | New compounds | |
| DE50015879D1 (de) | Indolyl-3-glyoxylsäure-derivate mit therapeutisch wertvollen eigenschaften | |
| EA200200876A1 (ru) | Алкилированные производные имидазопиридина | |
| EA200200875A1 (ru) | Пролекарства производных имидазопиридина | |
| NO920395D0 (no) | Terapeutisk aktive benzyloksyfenyl-derivater og fremgangsmaate for deres fremstilling | |
| ES2089136T3 (es) | Tratamiento de enfermedades inflamatorias con la ayuda de derivados 15-ceto-prostaglandinas. | |
| NO20055307D0 (no) | Substituerte isokromanforbindelser for behandling av metabolske forstyrrelser, kreft og andre sykdommer | |
| DE69604071D1 (de) | Oxazolidinone derivate, ihre herstellung und ihre therapeutische verwendung | |
| DE69416191D1 (de) | Spiropyran-Derivate mit photochromischen Eigenschaften | |
| DE10152306A8 (de) | 2-Acylindolderivate mit neuen therapeutisch wertvollen Eigenschaften | |
| DE69126758D1 (de) | Benzamid-Derivate | |
| EA200200883A1 (ru) | Производные пирано[2,3-с]имидазо[1,2-а]пиридина для лечения заболеваний желудочно-кишечного тракта | |
| KR930702990A (ko) | 섬유성 질병 치료제로서의 프로스타사이클린- 및 카르바사이클린 유도체 | |
| ATE293215T1 (de) | Pleuel | |
| NO20003629D0 (no) | Forbindelser med veksthormonfrigjørende egenskaper | |
| DK0625520T3 (da) | Thiazolotriazol- og thiazolodiazolderivater med fungicid aktivitet | |
| NO922428D0 (no) | Heterocykliske forbindelser med reninhemmende egenskaper,deres fremstilling og anvendelse | |
| DK329189A (da) | Glycerolderivat og dets farmakologiske anvendelse |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| UEP | Publication of translation of european patent specification | ||
| REN | Ceased due to non-payment of the annual fee |