DK77090A - Immunmodulerende azaspiraner - Google Patents
Immunmodulerende azaspiraner Download PDFInfo
- Publication number
- DK77090A DK77090A DK077090A DK77090A DK77090A DK 77090 A DK77090 A DK 77090A DK 077090 A DK077090 A DK 077090A DK 77090 A DK77090 A DK 77090A DK 77090 A DK77090 A DK 77090A
- Authority
- DK
- Denmark
- Prior art keywords
- azaspiran
- azaspirans
- immunomodulatory
- animal
- derivative
- Prior art date
Links
- 230000002519 immonomodulatory effect Effects 0.000 title abstract 2
- 239000003085 diluting agent Substances 0.000 abstract 1
- 239000008177 pharmaceutical agent Substances 0.000 abstract 1
- 239000000546 pharmaceutical excipient Substances 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/435—Heterocyclic 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
-
- 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
- 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
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
- C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
- C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
- C04B35/01—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics
- C04B35/45—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics based on copper oxide or solid solutions thereof with other oxides
- C04B35/4504—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics based on copper oxide or solid solutions thereof with other oxides containing rare earth oxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/54—Spiro-condensed
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/96—Spiro-condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Immunology (AREA)
- Ceramic Engineering (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Materials Engineering (AREA)
- Structural Engineering (AREA)
- Manufacturing & Machinery (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Transplantation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Saccharide Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10170487A | 1987-09-28 | 1987-09-28 | |
| US10170487 | 1987-09-28 | ||
| US07/244,229 US4963557A (en) | 1987-09-28 | 1988-09-13 | Immunomodulatory azaspiranes |
| US24422988 | 1988-09-13 | ||
| US8803323 | 1988-09-27 | ||
| PCT/US1988/003323 WO1989002889A1 (en) | 1987-09-28 | 1988-09-27 | Immunomodulatory azaspiranes |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK77090D0 DK77090D0 (da) | 1990-03-23 |
| DK77090A true DK77090A (da) | 1990-03-23 |
| DK170042B1 DK170042B1 (da) | 1995-05-08 |
Family
ID=26798539
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK077090A DK170042B1 (da) | 1987-09-28 | 1990-03-23 | Immunmodulerende azaspiraner, farmaceutiske midler, der indeholder dem, samt anvendelse af azaspiranerne til fremstilling af et immunmodulerende middel |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US4963557A (da) |
| EP (1) | EP0310321B1 (da) |
| JP (1) | JP2582888B2 (da) |
| KR (1) | KR0166336B1 (da) |
| CN (1) | CN1031618C (da) |
| AT (1) | ATE114463T1 (da) |
| AU (1) | AU619780B2 (da) |
| CA (1) | CA1313189C (da) |
| CY (1) | CY1955A (da) |
| DE (1) | DE3852266T2 (da) |
| DK (1) | DK170042B1 (da) |
| ES (1) | ES2064356T3 (da) |
| FI (1) | FI93006C (da) |
| GR (1) | GR3014931T3 (da) |
| HU (1) | HU208809B (da) |
| IE (1) | IE67891B1 (da) |
| IL (1) | IL87908A (da) |
| MX (1) | MX9203765A (da) |
| NO (1) | NO173824C (da) |
| NZ (1) | NZ226354A (da) |
| PT (1) | PT88603B (da) |
| WO (1) | WO1989002889A1 (da) |
| ZW (1) | ZW12388A1 (da) |
Families Citing this family (55)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6051596A (en) * | 1990-08-10 | 2000-04-18 | Anormed, Inc. | Immunosuppressive compositions |
| AU658577B2 (en) * | 1990-08-10 | 1995-04-27 | Smithkline Beecham Corporation | Immunosuppressive compositions |
| WO1992004899A1 (en) * | 1990-09-24 | 1992-04-02 | Smithkline Beecham Corporation | Methods |
| ZA921120B (en) * | 1991-02-19 | 1993-01-27 | Smithkline Beecham Corp | Cytokine inhibitors |
| PT100566B (pt) * | 1991-06-07 | 1999-06-30 | Smithkline Beecham Corp | Azaspiranos imunomoduladores, composicoes farmaceuticas que os contem, sua preparacao e seu uso |
| US5591748A (en) * | 1991-06-07 | 1997-01-07 | Smithkline Beecham Corporation | Immunomodulatory azaspiranes |
| GB9122721D0 (en) * | 1991-10-25 | 1991-12-11 | Smithkline Beecham Corp | Methods |
| GB9122735D0 (en) * | 1991-10-25 | 1991-12-11 | Smithkline Beecham Corp | Methods |
| US5455247A (en) * | 1991-10-25 | 1995-10-03 | Smithkline Beecham Corporation | Methods for the treatment of hyperlipidemia using azaspiranes |
| US7105152B1 (en) | 1991-12-18 | 2006-09-12 | 3M Innovative Properties Company | Suspension aerosol formulations |
| AU675633B2 (en) * | 1991-12-18 | 1997-02-13 | Minnesota Mining And Manufacturing Company | Suspension aerosol formulations |
| US7101534B1 (en) | 1991-12-18 | 2006-09-05 | 3M Innovative Properties Company | Suspension aerosol formulations |
| GB9201803D0 (en) * | 1992-01-28 | 1992-03-11 | Smithkline Beecham Corp | Methods |
| US5482959A (en) * | 1992-01-28 | 1996-01-09 | Smithkline Beecham Corporation | Method for delaying aids in an HIV infected individual by administration of substituted azaspirane compounds |
| GB9201804D0 (en) * | 1992-01-28 | 1992-03-11 | Smithkline Beecham Corp | Methods |
| DE4222459C2 (de) * | 1992-07-08 | 1995-09-14 | Sigma Tau Ind Farmaceuti | 3,9-disubstituierte-Spiro[5.5]undecane, ein Verfahren zu deren Herstellung und pharmazeutische Zusammensetzungen, die diese enthalten |
| GB9217121D0 (en) * | 1992-08-13 | 1992-09-23 | Smithkline Beecham Corp | Methods |
| GB9217116D0 (en) * | 1992-08-13 | 1992-09-23 | Smithkline Beecham Corp | Methods |
| US5484788A (en) * | 1993-03-26 | 1996-01-16 | Beth Israel Hospital Association | Buspirone as a systemic immunosuppressant |
| DK0690715T3 (da) * | 1993-03-26 | 2003-09-22 | Beth Israel Hospital | Topisk og systemisk applikation af busphiron eller derivater deraf til behandling af pathologiske tilstande associeret med immunreaktioner |
| US5631017A (en) * | 1993-03-26 | 1997-05-20 | Beth Israel Deaconess Medical Center, Inc. | Topical application of buspirone for treatment of pathological conditions associated with immune responses |
| GB9308780D0 (en) * | 1993-04-28 | 1993-06-09 | Smithkline Beecham Corp | Methods |
| US5708019A (en) * | 1993-04-28 | 1998-01-13 | Smithkline Beecham Corporation | Methods of treating hyperlipidemia using azaspirane derivatives |
| US5505948A (en) * | 1993-06-01 | 1996-04-09 | Dermatology Home Products, Inc. | Home skin peel composition for producing healthy and attractive skin |
| GB9315340D0 (en) * | 1993-07-23 | 1993-09-08 | Smithkline Beecham Corp | Methods |
| GB9315351D0 (en) * | 1993-07-23 | 1993-09-08 | Smithkline Beecham Corp | Methods |
| GB9315306D0 (en) * | 1993-07-23 | 1993-09-08 | Smithkline Beecham Corp | Methods |
| GB9315341D0 (en) * | 1993-07-23 | 1993-09-08 | Smithkline Beecham Corp | Methods |
| GB9315271D0 (en) * | 1993-07-23 | 1993-09-08 | Smithkline Beecham Corp | Methods |
| GB9315298D0 (en) * | 1993-07-23 | 1993-09-08 | Smithkline Beecham Corp | Methods |
| US5461054A (en) * | 1993-12-09 | 1995-10-24 | Bayer Aktiengesellschaft | Anthracene-spiro-pyrrolindines |
| GB9325854D0 (en) * | 1993-12-17 | 1994-02-23 | Smithkline Beecham Corp | Porcess |
| GB9414902D0 (en) * | 1994-07-23 | 1994-09-14 | Smithkline Beecham Corp | Methods |
| US5786376A (en) * | 1994-07-23 | 1998-07-28 | Smithkline Beecham Corporation | Methods of treating opportunistic infections with azaspiranes |
| GB9414901D0 (en) * | 1994-07-23 | 1994-09-14 | Smithkline Beecham Corp | Methods |
| US5734061A (en) * | 1994-12-07 | 1998-03-31 | Smithkline Beecham Corporation | Process for preparing spirocyclic lactams |
| US5637314A (en) * | 1995-06-07 | 1997-06-10 | Beth Israel Deaconess Medical Center, Inc. | Topical and systemic application of buspirone or derivatives thereof for treating atopic dermatitis |
| JP3195364B2 (ja) * | 1995-07-13 | 2001-08-06 | アノーメッド インコーポレイティド | N,n−ジメチル−8,8−ジプロピル−2−アザスピロ〔4.5〕デカン−2−プロパンアミン・ジマレエート |
| JP2001519754A (ja) * | 1995-07-13 | 2001-10-23 | アノーメッド・インコーポレイテッド | 2−[2−(ジメチルアミノ)エチル]−8,8−ジプロピル−2−アザスピロ[4.5]デカンジマレイン酸塩 |
| BG62359B1 (bg) * | 1995-07-13 | 1999-09-30 | Anormed | N,n-диетил-8,8-дипропил-2-азаспиро[4,5]декан-2-пропанаминдималеат |
| BR9601909A (pt) * | 1995-07-13 | 1999-10-13 | Smithkline Beecham Corp | N,n-dietil-8,8-dipropil-2-azaspiro(4,5)decano-2-propan amina dimaleato |
| KR20000010933A (ko) * | 1996-05-17 | 2000-02-25 | 위샤르트 아이 시 | 천식 치료용으로서의 치환 아자스피란의 용도 |
| US5843936A (en) * | 1996-06-28 | 1998-12-01 | Bernstein; Lawrence R. | Topical administration of azaspiranes to prevent or treat skin conditions associated with hyperproliferation of keratinocytes |
| GB0208742D0 (en) | 2002-04-17 | 2002-05-29 | Bradford Particle Design Ltd | Particulate materials |
| US7582284B2 (en) | 2002-04-17 | 2009-09-01 | Nektar Therapeutics | Particulate materials |
| JP4458514B2 (ja) | 2002-07-18 | 2010-04-28 | 第一三共株式会社 | 高純度のエナミン類の製造方法 |
| US20050250801A1 (en) * | 2003-03-10 | 2005-11-10 | Kunwar Shailubhai | Method of treating cancer with azaspirane compositions |
| US20110104186A1 (en) | 2004-06-24 | 2011-05-05 | Nicholas Valiante | Small molecule immunopotentiators and assays for their detection |
| WO2006010379A1 (en) | 2004-07-29 | 2006-02-02 | Actelion Pharmaceuticals Ltd. | Novel thiophene derivatives as immunosuppressive agents |
| CN101044134A (zh) * | 2004-09-20 | 2007-09-26 | 塔加西普特公司 | 具有烟碱性胆碱能受体活性的氮杂螺烯和氮杂螺烷化合物 |
| WO2006100631A1 (en) | 2005-03-23 | 2006-09-28 | Actelion Pharmaceuticals Ltd | Hydrogenated benzo (c) thiophene derivatives as immunomodulators |
| AR057894A1 (es) | 2005-11-23 | 2007-12-26 | Actelion Pharmaceuticals Ltd | Derivados de tiofeno |
| CN101370805B (zh) | 2006-01-24 | 2011-04-27 | 埃科特莱茵药品有限公司 | 吡啶衍生物 |
| WO2007095202A2 (en) | 2006-02-13 | 2007-08-23 | The Board Of Trustees Of The Leland Stanford Junior University | Blockade of gamma-secretase activity to promote myelination by oligodendrocytes |
| CA2677838C (en) | 2007-02-11 | 2017-08-01 | Map Pharmaceuticals, Inc. | Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3256277A (en) * | 1966-06-14 | Azaspiro alkanes | ||
| GB823338A (en) * | 1956-11-07 | 1959-11-11 | Thomae Gmbh Dr K | Diquaternary salts of aminoalkyl piperidines |
| US3106552A (en) * | 1960-07-19 | 1963-10-08 | Geschickter Fund Med Res | Nu-substituted azaspiranes and azaspirane-diones and processes for their preparation |
| US3418324A (en) * | 1961-03-13 | 1968-12-24 | Geschickter Fund Med Res | Heterocyclic secondary amines |
| US3282947A (en) * | 1962-05-17 | 1966-11-01 | Geschickter Fund Med Res | Unsymmetrically substituted 3, 9-diazaspiro(5, 5)undecane compounds |
| NL124128C (da) * | 1963-05-27 | |||
| US3424755A (en) * | 1964-03-09 | 1969-01-28 | Rolf Denss | 4-piperidine-p-fluorobutyrophenones and related compounds |
| US3432499A (en) * | 1965-04-02 | 1969-03-11 | Geschickter Fund Med Res | Trifluoromethylazaspiranes and azaspirane diones |
| DE1770697C3 (de) * | 1967-07-06 | 1981-04-23 | Dupher International Research B.V., Weesp | 2,2-(N-Methyl-2-azatetramethylen)- -adamantan, dessen Salze, Verfahren zu deren Herstellung und Arzneimittel |
| BE759371A (fr) * | 1969-11-24 | 1971-05-24 | Bristol Myers Co | Azaspirodecanediones heterocycliques et procedes pour leur preparation |
| BE788490A (fr) * | 1971-09-08 | 1973-01-02 | Geschickter Fund Med Res | Azaspiranes substitues par du silicium ou du germanium, leur preparation et compositions pharmaceutiques les contenant |
| US4468393A (en) * | 1982-12-06 | 1984-08-28 | Unimed, Inc. | Treatment of arthritis |
| JPS61502124A (ja) * | 1984-05-09 | 1986-09-25 | ジ オ−ストラリアン ナシヨナル ユニヴア−シテイ− | 免疫応答の調節方法 |
| JPH0662407B2 (ja) * | 1984-12-25 | 1994-08-17 | 株式会社三和化学研究所 | 安定化された3―オキシゲルミルプロピオン酸ポリマーを有効成分とする免疫調整剤 |
| US4654333A (en) * | 1986-02-18 | 1987-03-31 | Unimed, Inc. | Treatment of multiple sclerosis |
-
1988
- 1988-09-13 US US07/244,229 patent/US4963557A/en not_active Expired - Lifetime
- 1988-09-21 ZW ZW123/88A patent/ZW12388A1/xx unknown
- 1988-09-25 IL IL87908A patent/IL87908A/xx not_active IP Right Cessation
- 1988-09-26 ES ES88308914T patent/ES2064356T3/es not_active Expired - Lifetime
- 1988-09-26 EP EP88308914A patent/EP0310321B1/en not_active Expired - Lifetime
- 1988-09-26 AT AT88308914T patent/ATE114463T1/de not_active IP Right Cessation
- 1988-09-26 DE DE3852266T patent/DE3852266T2/de not_active Expired - Lifetime
- 1988-09-27 JP JP63508105A patent/JP2582888B2/ja not_active Expired - Lifetime
- 1988-09-27 NZ NZ226354A patent/NZ226354A/xx unknown
- 1988-09-27 HU HU885889A patent/HU208809B/hu not_active IP Right Cessation
- 1988-09-27 KR KR1019890700907A patent/KR0166336B1/ko not_active Expired - Fee Related
- 1988-09-27 AU AU25333/88A patent/AU619780B2/en not_active Expired
- 1988-09-27 CA CA000578528A patent/CA1313189C/en not_active Expired - Lifetime
- 1988-09-27 PT PT88603A patent/PT88603B/pt not_active IP Right Cessation
- 1988-09-27 WO PCT/US1988/003323 patent/WO1989002889A1/en not_active Ceased
- 1988-09-28 IE IE292988A patent/IE67891B1/en not_active IP Right Cessation
- 1988-09-28 CN CN88109032A patent/CN1031618C/zh not_active Expired - Lifetime
-
1990
- 1990-03-23 DK DK077090A patent/DK170042B1/da not_active IP Right Cessation
- 1990-03-27 FI FI901530A patent/FI93006C/fi not_active IP Right Cessation
- 1990-03-27 NO NO901392A patent/NO173824C/no not_active IP Right Cessation
-
1992
- 1992-06-29 MX MX9203765A patent/MX9203765A/es unknown
-
1995
- 1995-02-01 GR GR950400195T patent/GR3014931T3/el unknown
-
1997
- 1997-05-16 CY CY195597A patent/CY1955A/xx unknown
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