JP4531867B2 - 一定のジヌクレオチドおよび粘膜繊毛クリアランスおよび繊毛運動頻度のモジュレーターとしてのそれらの使用 - Google Patents
一定のジヌクレオチドおよび粘膜繊毛クリアランスおよび繊毛運動頻度のモジュレーターとしてのそれらの使用 Download PDFInfo
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- JP4531867B2 JP4531867B2 JP53505598A JP53505598A JP4531867B2 JP 4531867 B2 JP4531867 B2 JP 4531867B2 JP 53505598 A JP53505598 A JP 53505598A JP 53505598 A JP53505598 A JP 53505598A JP 4531867 B2 JP4531867 B2 JP 4531867B2
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- Prior art keywords
- uridine
- pharmaceutically acceptable
- tetraphosphate
- pharmaceutical composition
- treatment
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- RUAYLFCHPJYFJL-HVVPPSBSSA-N n,n'-dicyclohexylmorpholine-4-carboximidamide;[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-morpholin-4-ylphosphinic acid Chemical compound C1CCCCC1NC(N1CCOCC1)=NC1CCCCC1.C([C@@H]1[C@H]([C@H]([C@@H](O1)N1C(NC(=O)C=C1)=O)O)O)OP(O)(=O)N1CCOCC1 RUAYLFCHPJYFJL-HVVPPSBSSA-N 0.000 description 1
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- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
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- 150000003512 tertiary amines Chemical class 0.000 description 1
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- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- 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
- A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- 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
- A61P11/02—Nasal agents, e.g. decongestants
-
- 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
- A61P11/10—Expectorants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- 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
- 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
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/797,472 US5900407A (en) | 1997-02-06 | 1997-02-06 | Method of treating dry eye disease with uridine triphosphates and related compounds |
| US08/797,472 | 1997-02-06 | ||
| US08/798,508 | 1997-02-10 | ||
| US08/798,508 US5837861A (en) | 1997-02-10 | 1997-02-10 | Dinucleotides and their use as modulators of mucociliary clearance and ciliary beat frequency |
| PCT/US1998/002702 WO1998034942A2 (en) | 1997-02-06 | 1998-02-06 | Dinucleotides and their use |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2001526635A JP2001526635A (ja) | 2001-12-18 |
| JP2001526635A5 JP2001526635A5 (https=) | 2005-10-06 |
| JP4531867B2 true JP4531867B2 (ja) | 2010-08-25 |
Family
ID=27121880
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP53505598A Expired - Fee Related JP4531867B2 (ja) | 1997-02-06 | 1998-02-06 | 一定のジヌクレオチドおよび粘膜繊毛クリアランスおよび繊毛運動頻度のモジュレーターとしてのそれらの使用 |
Country Status (16)
| Country | Link |
|---|---|
| US (2) | US6348589B1 (https=) |
| EP (1) | EP0981534B1 (https=) |
| JP (1) | JP4531867B2 (https=) |
| KR (1) | KR100606131B1 (https=) |
| CN (1) | CN1262556C (https=) |
| AT (1) | ATE325129T1 (https=) |
| AU (1) | AU738907C (https=) |
| BR (1) | BR9807169A (https=) |
| CA (1) | CA2279963C (https=) |
| DE (1) | DE69834392T2 (https=) |
| DK (1) | DK0981534T3 (https=) |
| ES (1) | ES2264197T3 (https=) |
| NO (1) | NO326718B1 (https=) |
| NZ (1) | NZ337225A (https=) |
| PT (1) | PT981534E (https=) |
| WO (1) | WO1998034942A2 (https=) |
Families Citing this family (67)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6673779B2 (en) | 1996-03-27 | 2004-01-06 | Inspire Pharmaceuticals, Inc. | Method of treating ciliary dyskinesia with dinucleoside polyphosphate compounds or UTP analogues |
| US6319908B1 (en) | 1996-07-03 | 2001-11-20 | Inspire Pharmaceuticals, Inc. | Method for large-scale production of di(uridine 5′-tetraphosphate) and salts thereof |
| US5763447C1 (en) | 1996-07-23 | 2002-05-07 | Inspire Pharmaceuticals | Method of preventing or treating pneumonia in immobilized patients with uridine triphosphates and related compounds |
| DK0981534T3 (da) | 1997-02-06 | 2006-09-04 | Inspire Pharmaceuticals Inc | Dinukleotider og deres anvendelser |
| US7078391B2 (en) * | 1997-02-10 | 2006-07-18 | Inspire Pharmaceuticals, Inc. | Method of treating edematous retinal disorders |
| US6596725B2 (en) * | 1997-02-10 | 2003-07-22 | Inspire Pharmaceuticals, Inc. | Use of certain dinucleotides to stimulate removal of fluid in retinal detachment and retinal edema |
| US7223744B2 (en) | 1997-02-10 | 2007-05-29 | Inspire Pharmaceuticals, Inc. | Pharmaceutical formulation comprising dinucleoside polyphosphates and salts thereof |
| US6818629B2 (en) * | 1997-02-10 | 2004-11-16 | Inspire Pharmaceuticals, Inc. | Pharmaceutical formulation comprising P1-(2'-deoxycytidine 5'-)P4-(uridine 5'-) tetraphosphate |
| US6462028B2 (en) | 1997-07-25 | 2002-10-08 | Inspire Pharmaceuticals, Inc. | Method of promoting cervical and vaginal secretions |
| TW593331B (en) | 1997-07-25 | 2004-06-21 | Inspire Pharmaceuticals Inc | Method for large-scale production of di(uridine 5')-tetraphosphate and salts thereof |
| US6548658B2 (en) * | 1997-07-25 | 2003-04-15 | Inspire Pharmaceuticals, Inc. | Di-(uridine 5′)-tetraphosphate and salts thereof |
| KR20010013797A (ko) | 1997-07-25 | 2001-02-26 | 인스파이어 파마슈티컬스 인코퍼레이티드 | 디(우리딘 5'-테트라포스페이트) 염 및 그의 제조방법과용도 |
| US6872710B2 (en) | 1997-07-25 | 2005-03-29 | Inspire Pharmaceuticals, Inc. | Di(uridine 5′)-tetraphosphate and salts thereof |
| ID29198A (id) * | 1997-08-29 | 2001-08-09 | Univ North Carolina | Pemakaian uridin 5'-difosfat dan persamaannya untuk mengobati penyakit paru-paru |
| CA2332540A1 (en) * | 1998-05-22 | 1999-12-02 | Benjamin R. Yerxa | Therapeutic dinucleotide and derivatives |
| WO2000039145A1 (en) * | 1998-12-23 | 2000-07-06 | The University Of North Carolina At Chapel Hill | Targeted gene transfer using g protein coupled receptors |
| WO2000050024A2 (en) | 1999-02-26 | 2000-08-31 | Inspire Pharmaceuticals, Inc. | Method of promoting mucosal hydration with certain uridine, adenine and cytidine diphosphates and analogs thereof |
| WO2001002416A1 (en) * | 1999-06-30 | 2001-01-11 | Yamasa Corporation | Dinucleotide crystals |
| WO2001012644A1 (en) * | 1999-08-17 | 2001-02-22 | Adani, Alexander | Dinucleoside 5',5'-tetraphosphates as inhibitors of viral reverse transcriptases and viruses |
| AU2603101A (en) * | 1999-12-22 | 2001-07-03 | Inspire Pharmaceuticals, Inc. | Method of treating gastrointestinal tract disease with purinergic receptor agonists |
| RU2161982C1 (ru) * | 2000-01-20 | 2001-01-20 | Общество с ограниченной ответственностью "Клиника Института биорегуляции и геронтологии" | Тетрапептид, стимулирующий функцию сетчатой оболочки глаза, фармакологическое средство на его основе и способ его применения |
| US6864243B1 (en) * | 2000-05-12 | 2005-03-08 | Inspire Pharmaceuticals, Inc. | Method for treating retinal degeneration with purinergic receptor agonists |
| BR0111297A (pt) * | 2000-05-30 | 2004-01-06 | Santen Pharmaceutical Co Ltd | Promotor de migração epitelial corneana |
| US6867199B2 (en) | 2000-08-21 | 2005-03-15 | Inspire Pharmaceuticals, Inc. | Dinucleoside polyphosphate compositions and their therapeutic use |
| US7132408B2 (en) * | 2000-08-21 | 2006-11-07 | Inspire Pharmaceuticals, Inc. | Composition and method for inhibiting platelet aggregation |
| US7115585B2 (en) * | 2000-08-21 | 2006-10-03 | Inspire Pharmaceuticals, Inc. | Compositions for treating epithelial and retinal tissue diseases |
| US6555675B2 (en) * | 2000-08-21 | 2003-04-29 | Inspire Pharmaceuticals, Inc. | Dinucleoside polyphosphate compositions and their therapuetic use as purinergic receptor agonists |
| US7018985B1 (en) | 2000-08-21 | 2006-03-28 | Inspire Pharmaceuticals, Inc. | Composition and method for inhibiting platelet aggregation |
| US7452870B2 (en) * | 2000-08-21 | 2008-11-18 | Inspire Pharmaceuticals, Inc. | Drug-eluting stents coated with P2Y12 receptor antagonist compound |
| WO2002048165A2 (en) * | 2000-12-15 | 2002-06-20 | Pharmasset Ltd. | Antiviral agents for treatment of flaviviridae infections |
| US20040122223A1 (en) * | 2001-02-07 | 2004-06-24 | Davis Jeremy Martin | Non-natural nucleotides and dinucleotides |
| WO2003000056A1 (en) | 2001-06-25 | 2003-01-03 | Inspire Pharmaceuticals, Inc. | Joint lubrication with p2y purinergic receptor agonists |
| EP1409503A1 (en) * | 2001-07-25 | 2004-04-21 | Celltech R & D Limited | Non-natural carbon-linked nucleotides and dinucleotides |
| WO2003030892A1 (en) * | 2001-10-11 | 2003-04-17 | Alcon, Inc. | Methods for treating dry eye |
| KR20050043761A (ko) | 2001-11-06 | 2005-05-11 | 인스파이어 파마슈티컬스 인코퍼레이티드 | 염증성 질환의 치료 또는 예방 방법 |
| US7084128B2 (en) | 2002-01-18 | 2006-08-01 | Inspire Pharmaceuticals, Inc. | Method for reducing intraocular pressure |
| MXPA05004121A (es) * | 2002-10-18 | 2006-02-17 | Molichem Medicines Inc | Metodos para tratar la enfermedad de ojo reseco con lantibioticos. |
| US6984628B2 (en) * | 2003-07-15 | 2006-01-10 | Allergan, Inc. | Ophthalmic compositions comprising trefoil factor family peptides |
| US7326683B2 (en) * | 2004-05-06 | 2008-02-05 | Molichem Medicines, Inc. | Treatment of membrane-associated diseases and disorders using lantibiotic containing compositions |
| CA2565545A1 (en) * | 2004-05-06 | 2005-12-08 | Molichem Medicines, Inc. | Treatment of ocular diseases and disorders using lantibiotic compositions |
| GB0417886D0 (en) * | 2004-08-11 | 2004-09-15 | Univ Cardiff | Method and means for enhanced pulmonary delivery |
| GB0502250D0 (en) * | 2005-02-03 | 2005-03-09 | Ic Vec Ltd | Use |
| US7368439B2 (en) * | 2005-06-15 | 2008-05-06 | Bar - Ilan University | Dinucleoside poly(borano)phosphate derivatives and uses thereof |
| US7851456B2 (en) * | 2005-06-29 | 2010-12-14 | Inspire Pharmaceuticals, Inc. | P2Y6 receptor agonists for treating lung diseases |
| EP2036567A3 (en) | 2005-12-06 | 2009-12-09 | P2-Science APS | Modulation of the P2Y2 receptor pathway |
| US20070249556A1 (en) * | 2006-04-21 | 2007-10-25 | Brubaker Kurt E | Method of treating inflammation |
| CN101495497B (zh) * | 2006-07-26 | 2012-03-14 | Yamasa酱油株式会社 | 二(嘧啶核苷5’-)多磷酸的制备方法 |
| EP2049665A2 (en) * | 2006-07-28 | 2009-04-22 | Applera Corporation | Dinucleotide mrna cap analogs |
| CA2702094C (en) | 2007-10-10 | 2018-05-01 | Parion Sciences, Inc. | Delivering osmolytes by nasal cannula |
| US8168597B2 (en) * | 2008-10-22 | 2012-05-01 | Inspire Pharmaceuticals, Inc. | Method for treating cystic fibrosis |
| US9067964B2 (en) | 2008-12-18 | 2015-06-30 | Oligomer Sciences Ab | Complex and method for enhancing nuclear delivery |
| WO2012031186A1 (en) | 2010-09-03 | 2012-03-08 | Wisconsin Pharmacal Company, Llc. | Prebiotic suppositories |
| PL2614838T3 (pl) * | 2010-09-10 | 2016-10-31 | Dikwafozol i kwas hialuronowy lub ich sole do zastosowania w leczeniu zespołu suchego oka | |
| EP2717855A4 (en) | 2011-06-07 | 2014-11-12 | Parion Sciences Inc | Methods of Treatment |
| US8945605B2 (en) | 2011-06-07 | 2015-02-03 | Parion Sciences, Inc. | Aerosol delivery systems, compositions and methods |
| AR086745A1 (es) | 2011-06-27 | 2014-01-22 | Parion Sciences Inc | 3,5-diamino-6-cloro-n-(n-(4-(4-(2-(hexil(2,3,4,5,6-pentahidroxihexil)amino)etoxi)fenil)butil)carbamimidoil)pirazina-2-carboxamida |
| EP3431092A1 (en) | 2012-03-26 | 2019-01-23 | Santen Pharmaceutical Co., Ltd. | Ophthalmic solution comprising diquafosol |
| HUE039734T2 (hu) | 2012-05-29 | 2019-01-28 | Parion Sciences Inc | Nátriumcsatorna-blokkoló aktivitású, dendrimerszerû amino-amid-származékok száraz szem és más nyálkahártya-megbetegedések kezelésére |
| CN108658876A (zh) | 2012-12-17 | 2018-10-16 | 帕里昂科学公司 | 3,5-二氨基-6-氯-n-(n-(4-苯基丁基)甲脒基)吡嗪-2-甲酰胺化合物 |
| ES2674665T3 (es) | 2012-12-17 | 2018-07-03 | Parion Sciences, Inc. | Compuestos de 3,5-diamino-6-cloro-N-(N-(4-fenilbutilo)carbamimidoilo)-pirazina-2-carboxamida |
| CA2895512C (en) | 2012-12-17 | 2021-10-19 | Parion Sciences, Inc. | Chloro-pyrazine carboxamide derivatives useful for the treatment of diseases favoured by insufficient mucosal hydration |
| US10323058B2 (en) | 2014-07-24 | 2019-06-18 | W. R. Grace & Co.-Conn. | Crystalline form of nicotinamide riboside |
| EP3268379B1 (en) | 2015-03-09 | 2023-11-01 | W.R. Grace & CO. - CONN. | Crystalline form of nicotinamide riboside |
| US20180125876A1 (en) | 2015-05-20 | 2018-05-10 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and Pharmaceutical Composition for Modulation Polarization and Activation of Macrophages |
| CN112020363A (zh) | 2017-12-22 | 2020-12-01 | 益力舒健康公司 | 烟酰胺核苷氯化物的结晶形式 |
| EP4157288A2 (en) | 2020-06-02 | 2023-04-05 | Institut Gustave-Roussy | Modulators of purinergic receptors and related immune checkpoint for treating acute respiratory distress syndrom |
| EP3919062A1 (en) | 2020-06-02 | 2021-12-08 | Institut Gustave-Roussy | Modulators of purinergic receptors and related immune checkpoint for treating acute respiratory distress syndrom |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4855304A (en) | 1985-01-10 | 1989-08-08 | Repligen Corporation | Dinucleoside pyrophosphates and pyrophosphate homologs as plant antivirals |
| US5049550A (en) | 1987-11-05 | 1991-09-17 | Worcester Foundation For Experimental Biology | Diadenosine 5', 5'"-p1, p4,-tetraphosphate analogs as antithrombotic agents |
| US5292498A (en) | 1991-06-19 | 1994-03-08 | The University Of North Carolina At Chapel Hill | Method of treating lung disease with uridine triphosphates |
| WO1996002554A1 (en) | 1994-07-15 | 1996-02-01 | Gruppo Lepetit S.P.A. | Dinucleoside-5',5'-pyrophosphates |
| US5635160A (en) | 1995-06-07 | 1997-06-03 | The University Of North Carolina At Chapel Hill | Dinucleotides useful for the treatment of cystic fibrosis and for hydrating mucus secretions |
| US5837861A (en) * | 1997-02-10 | 1998-11-17 | Inspire Pharmaceuticals, Inc. | Dinucleotides and their use as modulators of mucociliary clearance and ciliary beat frequency |
| US5681823A (en) | 1996-05-02 | 1997-10-28 | Prp Inc. | P1, P4 -dithio-P2 -P3 -monochloromethylene 5', 5'"-diadenosine P1, P4 -tetraphosphate as antithrombotic agent |
| US5789391A (en) | 1996-07-03 | 1998-08-04 | Inspire Pharmaceuticals, Inc. | Method of treating sinusitis with uridine triphosphates and related compounds |
| US5763447C1 (en) * | 1996-07-23 | 2002-05-07 | Inspire Pharmaceuticals | Method of preventing or treating pneumonia in immobilized patients with uridine triphosphates and related compounds |
| JP4118958B2 (ja) | 1996-10-09 | 2008-07-16 | ファーマセット，リミティド | テトラホスホネート二環式トリス無水物 |
| DK0981534T3 (da) | 1997-02-06 | 2006-09-04 | Inspire Pharmaceuticals Inc | Dinukleotider og deres anvendelser |
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| NZ337225A (en) | 2002-03-28 |
| EP0981534B1 (en) | 2006-05-03 |
| BR9807169A (pt) | 2000-06-06 |
| DE69834392D1 (de) | 2006-06-08 |
| KR20000070807A (ko) | 2000-11-25 |
| JP2001526635A (ja) | 2001-12-18 |
| CN1292795A (zh) | 2001-04-25 |
| US20020082417A1 (en) | 2002-06-27 |
| US6977246B2 (en) | 2005-12-20 |
| CN1262556C (zh) | 2006-07-05 |
| WO1998034942A3 (en) | 2000-01-06 |
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| NO993776D0 (no) | 1999-08-04 |
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| AU738907B2 (en) | 2001-09-27 |
| WO1998034942A2 (en) | 1998-08-13 |
| AU738907C (en) | 2002-05-16 |
| PT981534E (pt) | 2006-09-29 |
| KR100606131B1 (ko) | 2006-07-31 |
| CA2279963A1 (en) | 1998-08-13 |
| AU6324298A (en) | 1998-08-26 |
| NO993776L (no) | 1999-10-06 |
| ATE325129T1 (de) | 2006-06-15 |
| US6348589B1 (en) | 2002-02-19 |
| NO326718B1 (no) | 2009-02-02 |
| DE69834392T2 (de) | 2007-02-08 |
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