NO300848B1 - Nye 2-substituerte indan-2-mercaptoacetylamidderivater som er anvendbare som inhibitorer av enkefalinase og ACE - Google Patents
Nye 2-substituerte indan-2-mercaptoacetylamidderivater som er anvendbare som inhibitorer av enkefalinase og ACE Download PDFInfo
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- NO300848B1 NO300848B1 NO923744A NO923744A NO300848B1 NO 300848 B1 NO300848 B1 NO 300848B1 NO 923744 A NO923744 A NO 923744A NO 923744 A NO923744 A NO 923744A NO 300848 B1 NO300848 B1 NO 300848B1
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- GASYAMBJHBRTOE-WHDBNHDESA-N γ-endorphin Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 GASYAMBJHBRTOE-WHDBNHDESA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Genetics & Genomics (AREA)
- Cardiology (AREA)
- Biophysics (AREA)
- Heart & Thoracic Surgery (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US76728691A | 1991-09-27 | 1991-09-27 | |
US92948192A | 1992-08-20 | 1992-08-20 |
Publications (3)
Publication Number | Publication Date |
---|---|
NO923744D0 NO923744D0 (no) | 1992-09-25 |
NO923744L NO923744L (no) | 1993-03-29 |
NO300848B1 true NO300848B1 (no) | 1997-08-04 |
Family
ID=27117891
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO923744A NO300848B1 (no) | 1991-09-27 | 1992-09-25 | Nye 2-substituerte indan-2-mercaptoacetylamidderivater som er anvendbare som inhibitorer av enkefalinase og ACE |
Country Status (16)
Country | Link |
---|---|
US (3) | US5428158A (fi) |
EP (1) | EP0534363B1 (fi) |
JP (1) | JP3173675B2 (fi) |
KR (1) | KR100271239B1 (fi) |
AT (1) | ATE155143T1 (fi) |
AU (1) | AU657166B2 (fi) |
CA (1) | CA2078758C (fi) |
DE (1) | DE69220744T2 (fi) |
DK (1) | DK0534363T3 (fi) |
ES (1) | ES2106112T3 (fi) |
FI (1) | FI101303B (fi) |
GR (1) | GR3024850T3 (fi) |
HU (1) | HU214820B (fi) |
IL (1) | IL103263A (fi) |
NO (1) | NO300848B1 (fi) |
NZ (1) | NZ244461A (fi) |
Families Citing this family (59)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU657793B2 (en) * | 1991-09-27 | 1995-03-23 | Merrell Pharmaceuticals Inc. | Novel 2-substituted indane-2-carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE |
CA2078758C (en) * | 1991-09-27 | 2003-12-09 | Alan M. Warshawsky | 2-substituted indane-2-mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace |
US5552397A (en) * | 1992-05-18 | 1996-09-03 | E. R. Squibb & Sons, Inc. | Substituted azepinone dual inhibitors of angiotensin converting enzyme and neutral exdopeptidase |
US5646276A (en) * | 1992-05-13 | 1997-07-08 | Bristol-Myers Squibb Co. | Diazepine containing dual action inhibitors |
WO1994004531A1 (en) * | 1992-08-24 | 1994-03-03 | Merrell Dow Pharmaceuticals Inc. | Novel 2-substituted indane-2-mercaptoacetylamide tricyclic derivatives useful as inhibitors of enkephalinase |
US5504080A (en) * | 1992-10-28 | 1996-04-02 | Bristol-Myers Squibb Co. | Benzo-fused lactams |
NZ267161A (en) * | 1993-06-11 | 1996-12-20 | Eisai Co Ltd | Dipeptidic benzazepine derivative with ace inhibiting activity |
US5508272A (en) * | 1993-06-15 | 1996-04-16 | Bristol-Myers Squibb Company | Compounds containing a fused bicycle ring and processes therefor |
JPH09500113A (ja) * | 1993-06-30 | 1997-01-07 | チバ−ガイギー アクチェンゲゼルシャフト | エンケファリナーゼ及びaceのインヒビターとして有用な抗高血圧性三環式アゼピン誘導体 |
US5362727A (en) * | 1993-07-26 | 1994-11-08 | Bristol-Myers Squibb | Substituted azepino[2,1-a]isoquinoline compounds |
US5594106A (en) * | 1993-08-23 | 1997-01-14 | Immunex Corporation | Inhibitors of TNF-α secretion |
US5525723A (en) * | 1993-11-18 | 1996-06-11 | Bristol-Myers Squibb Co. | Compounds containing a fused multiple ring lactam |
CN1069317C (zh) * | 1994-02-14 | 2001-08-08 | 默里尔药物公司 | 用作脑啡肽酶抑制剂的新的1,2-二氢化茚-2-巯基乙酰胺二硫化物衍生物 |
WO1995021857A1 (en) * | 1994-02-14 | 1995-08-17 | Merrell Pharmaceuticals Inc. | Novel 2-substituted indane-2-mercaptoacetylamide disulfide derivatives useful as inhibitors of enkephalinase and ace |
EP0750631B1 (en) * | 1994-02-14 | 2000-04-05 | Merrell Pharmaceuticals Inc. | Novel mercaptoacetylamido 1,3,4,5-tetrahydro-benzo(c)azepin-3-one disulfide derivatives useful as inhibitors of enkephalinase and ace |
US5616775A (en) * | 1994-05-05 | 1997-04-01 | Bristol-Myers Squibb Co. | Process for preparing homocystein analogs useful as intermediates for compounds containing a fused bicyclic ring |
US5641880A (en) * | 1994-12-21 | 1997-06-24 | Hoechst Marion Roussel, Inc. | Processes for preparing intermediates of inhibitors of enkephalinase and angiotensin converting enzyme and intermediates thereof |
HU227675B1 (en) * | 1994-12-21 | 2011-11-28 | Aventisub Ii Inc | Novel processes for preparing intermediates of inhibitors of enkephalinase and angiotensin converting enzyme and intermediates thereof |
US5587375A (en) * | 1995-02-17 | 1996-12-24 | Bristol-Myers Squibb Company | Azepinone compounds useful in the inhibition of ACE and NEP |
US5877313A (en) | 1995-05-17 | 1999-03-02 | Bristol-Myers Squibb | Benzo-fused azepinone and piperidinone compounds useful in the inhibition of ACE and NEP |
US5650408A (en) * | 1995-06-07 | 1997-07-22 | Karanewsky; Donald S. | Thiazolo benzazepine containing dual action inhibitors |
US5635504A (en) * | 1995-06-07 | 1997-06-03 | Bristol-Myers Squibb Co. | Diazepine containing dual action inhibitors |
US6777550B1 (en) | 1996-04-12 | 2004-08-17 | Bristol-Myers Squibb Company | N-formyl hydroxylamine containing compounds useful as ACE inhibitors and/or NEP inhibitors |
US6953788B1 (en) | 1996-09-19 | 2005-10-11 | Aventis Pharmaceuticals Inc. | 3-mercaptoacetylamino-1,5-substituted-2-oxo-azepan derivatives useful as inhibitors of matrix metalloproteinase |
US6635632B1 (en) | 1996-12-23 | 2003-10-21 | Athena Neurosciences, Inc. | Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds |
PT1087775E (pt) | 1998-06-17 | 2005-11-30 | Bristol Myers Squibb Co | Prevencao de enfarte cerebral por administracao de uma combinacao de farmacos antiplaquetarios bloqueadores de receptores de adp e anti-hipertensivos |
US6509330B2 (en) | 2000-02-17 | 2003-01-21 | Bristol-Myers Squibb Company | Hydroxamic acid containing compounds useful as ACE inhibitors and/or NEP inhibotors |
GB0119305D0 (en) | 2001-04-12 | 2001-10-03 | Aventis Pharma Gmbh | Mercaptoacetylamide derivatives,a process for their preparation and their use |
CZ299708B6 (cs) * | 2001-04-12 | 2008-10-29 | Sanofi - Aventis Deutschland GmbH | Merkaptoacetylamidové deriváty, zpusob jejich prípravy a farmaceutické prostredky s jejich obsahem k ošetrování kardiovaskulárních onemocnení |
AU2002348276A1 (en) | 2001-11-16 | 2003-06-10 | Bristol-Myers Squibb Company | Dual inhibitors of adipocyte fatty acid binding protein and keratinocyte fatty acid binding protein |
DE10229180A1 (de) * | 2002-06-28 | 2004-01-29 | Aventis Pharma Deutschland Gmbh | Verwendung von Vasopeptidase-Inhibitoren bei der Behandlung von metabolischen Erkrankungen, Nephropathie und mit AGE assoziierten Erkrankungen |
US8404852B2 (en) | 2003-01-31 | 2013-03-26 | Vertex Pharmaceuticals Incorporated | Gyrase inhibitors and uses thereof |
US7582641B2 (en) * | 2003-01-31 | 2009-09-01 | Vertex Pharmaceuticals Incorporated | Gyrase inhibitors and uses thereof |
AR042956A1 (es) * | 2003-01-31 | 2005-07-13 | Vertex Pharma | Inhibidores de girasa y usos de los mismos |
US7459474B2 (en) | 2003-06-11 | 2008-12-02 | Bristol-Myers Squibb Company | Modulators of the glucocorticoid receptor and method |
US7371759B2 (en) | 2003-09-25 | 2008-05-13 | Bristol-Myers Squibb Company | HMG-CoA reductase inhibitors and method |
US7420059B2 (en) | 2003-11-20 | 2008-09-02 | Bristol-Myers Squibb Company | HMG-CoA reductase inhibitors and method |
US7273881B2 (en) | 2004-01-16 | 2007-09-25 | Bristol-Myers Squibb Company | Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof |
US7888381B2 (en) | 2005-06-14 | 2011-02-15 | Bristol-Myers Squibb Company | Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity, and use thereof |
US7592461B2 (en) | 2005-12-21 | 2009-09-22 | Bristol-Myers Squibb Company | Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof |
US7795291B2 (en) | 2006-07-07 | 2010-09-14 | Bristol-Myers Squibb Company | Substituted acid derivatives useful as anti-atherosclerotic, anti-dyslipidemic, anti-diabetic and anti-obesity agents and method |
WO2008057862A2 (en) | 2006-11-01 | 2008-05-15 | Bristol-Myers Squibb Company | MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-ϰB ACTIVITY AND USE THEREOF |
EP2089389A2 (en) | 2006-11-01 | 2009-08-19 | Bristol-Myers Squibb Company | Heterocyclic compounds as modulators of glucocorticoid receptor, ap-1, and/or nf-kappa-b activity |
EP2099767A1 (en) | 2006-11-01 | 2009-09-16 | Brystol-Myers Squibb Company | Modulators of glucocorticoid receptor, ap-1, and/or nf- b activity and use thereof |
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 |
MX354786B (es) | 2007-06-04 | 2018-03-21 | Synergy Pharmaceuticals Inc | Agonistas de guanilato ciclasa utiles para el tratamiento de trastornos gastrointestinales, inflamacion, cancer y otros trastornos. |
CA2726917C (en) | 2008-06-04 | 2018-06-26 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
CN102149710A (zh) | 2008-06-24 | 2011-08-10 | 百时美施贵宝公司 | 糖皮质激素受体、AP-1和/或NF-κB 活性的环戊噻吩调节剂及其用途 |
WO2010009319A2 (en) | 2008-07-16 | 2010-01-21 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
US8546377B2 (en) | 2009-04-23 | 2013-10-01 | Abbvie Inc. | Modulators of 5-HT receptors and methods of use thereof |
US8518933B2 (en) | 2009-04-23 | 2013-08-27 | Abbvie Inc. | Modulators of 5-HT receptors and methods of use thereof |
US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
WO2014151200A2 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
EP2970384A1 (en) | 2013-03-15 | 2016-01-20 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
JP6606491B2 (ja) | 2013-06-05 | 2019-11-13 | 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cの超高純度アゴニスト、その作成および使用方法 |
WO2015027021A1 (en) | 2013-08-22 | 2015-02-26 | Bristol-Myers Squibb Company | Imide and acylurea derivatives as modulators of the glucocorticoid receptor |
CN109071504B (zh) | 2016-02-05 | 2022-03-08 | 戴纳立制药公司 | 受体相互作用蛋白激酶1的抑制剂 |
CN110383066B (zh) | 2016-12-09 | 2023-03-31 | 戴纳立制药公司 | 化合物、组合物和方法 |
AU2023206890A1 (en) | 2022-01-12 | 2024-08-22 | Denali Therapeutics Inc. | Crystalline forms of (s)-5-benzyl-n-(5-methyl-4-oxo-2, 3,4,5- tetrahydropyrido [3,2-b] [l,4]oxazepin-3-yl)-4h-l,2,4-triazole-3-carboxamide |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3334095A (en) * | 1965-02-16 | 1967-08-01 | Sandoz Ag | Novel pyrrolo-oxazines and pyrrolo-oxazoles |
US3334091A (en) * | 1965-03-25 | 1967-08-01 | Sandoz Ag | Sedatives |
GB1525845A (en) * | 1976-07-30 | 1978-09-20 | Ucb Sa | 1,2,4,5-tetrahydro-3h-2-benzazepin-3-ones |
IE50839B1 (en) * | 1980-02-26 | 1986-07-23 | Wyeth John & Brother Ltd | Novel processes for preparing proline derivatives and analogous compounds |
EP0042100A1 (de) * | 1980-06-13 | 1981-12-23 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Pyrazolopyridazin-Derivate, Zwischenprodukte und Verfahren zu deren Herstellung, sowie diese enthaltende Arzneimittel |
US4320057A (en) * | 1980-06-23 | 1982-03-16 | American Home Products Corporation | Aryl--pyrrolo--thiazepin--diones and aryl--piperidino--thiazepin--diones |
US4552889A (en) * | 1983-06-09 | 1985-11-12 | Eli Lilly And Company | 3-Mercaptomethyl-2-oxo-1-pyrrolidine acetic acids and use for hypertension |
US4692438A (en) * | 1984-08-24 | 1987-09-08 | Hoffmann-La Roche Inc. | Pyridazo-diazepines, diazocines, and -triazepines having anti-hypertensive activity |
EP0202046B1 (en) * | 1985-04-30 | 1991-01-30 | Eli Lilly And Company | 7-substituted bicyclic pyrazolidinones |
ZA874106B (en) * | 1986-06-13 | 1987-12-08 | Merrell Dow Pharmaceuticals Inc. | Novel antihypertensive agent |
CA1337654C (en) * | 1986-06-13 | 1995-11-28 | Gary A. Flynn | Fused tricyclic lactams as antihypertensive agents |
GB8629875D0 (en) * | 1986-12-15 | 1987-01-28 | Hoffmann La Roche | Pyridazodiazepine derivatives |
US4824832A (en) * | 1987-12-30 | 1989-04-25 | Merrell Dow Pharmaceuticals Inc. | Sulfhydryl containing tricyclic lactams and their pharmacological methods of use |
CA2053340C (en) * | 1990-10-18 | 2002-04-02 | Timothy P. Burkholder | Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace |
US5208230A (en) * | 1990-12-21 | 1993-05-04 | Merrell Dow Pharmaceuticals | Amino and nitro containing tricyclic compounds useful as inhibitors of ACE |
ATE158303T1 (de) * | 1990-12-21 | 1997-10-15 | Merrell Pharma Inc | Neue trizyklische amino- und nitro verbindungen mit ace-hemmenden eigenschaften |
FR2679564A1 (fr) * | 1991-07-23 | 1993-01-29 | Inst Nat Sante Rech Med | Nouveaux acylmercaptoalcanoldipeptides, leur preparation et les compositions qui les contiennent. |
WO1993005809A1 (en) * | 1991-09-16 | 1993-04-01 | Schering Corporation | Pharmaceutical compositions comprising natriuretic peptides or neutral endopeptidase inhibitors for treating or preventing myointimal proliferation |
AU657793B2 (en) * | 1991-09-27 | 1995-03-23 | Merrell Pharmaceuticals Inc. | Novel 2-substituted indane-2-carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE |
CA2078758C (en) * | 1991-09-27 | 2003-12-09 | Alan M. Warshawsky | 2-substituted indane-2-mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace |
CA2078759C (en) * | 1991-09-27 | 2003-09-16 | Alan M. Warshawsky | Novel carboxyalkyl derivatives useful as inhibitors of enkephalinase and ace |
RU2124503C1 (ru) * | 1992-05-18 | 1999-01-10 | И.Р.Сквибб энд Санз, Инк. | Гетероциклические азотсодержащие производные карбоновой кислоты, способ их получения и фармацевтическая композиция |
US5238932A (en) * | 1992-05-20 | 1993-08-24 | Merrell Dow Pharmaceuticals Inc. | Mercaptoacetylamide tricyclic derivatives useful as inhibitors of enkephalinase |
-
1992
- 1992-09-21 CA CA002078758A patent/CA2078758C/en not_active Expired - Fee Related
- 1992-09-21 DK DK92116180.8T patent/DK0534363T3/da active
- 1992-09-21 AT AT92116180T patent/ATE155143T1/de not_active IP Right Cessation
- 1992-09-21 DE DE69220744T patent/DE69220744T2/de not_active Expired - Fee Related
- 1992-09-21 ES ES92116180T patent/ES2106112T3/es not_active Expired - Lifetime
- 1992-09-21 EP EP92116180A patent/EP0534363B1/en not_active Expired - Lifetime
- 1992-09-22 AU AU25245/92A patent/AU657166B2/en not_active Ceased
- 1992-09-23 IL IL10326392A patent/IL103263A/en not_active IP Right Cessation
- 1992-09-23 NZ NZ244461A patent/NZ244461A/en unknown
- 1992-09-25 HU HU9203074A patent/HU214820B/hu not_active IP Right Cessation
- 1992-09-25 NO NO923744A patent/NO300848B1/no unknown
- 1992-09-25 JP JP28066992A patent/JP3173675B2/ja not_active Expired - Fee Related
- 1992-09-25 FI FI924311A patent/FI101303B/fi not_active IP Right Cessation
- 1992-09-26 KR KR1019920017615A patent/KR100271239B1/ko not_active IP Right Cessation
-
1993
- 1993-11-01 US US08/146,646 patent/US5428158A/en not_active Expired - Lifetime
-
1995
- 1995-03-01 US US08/397,298 patent/US5529996A/en not_active Expired - Fee Related
- 1995-03-01 US US08/396,947 patent/US5486513A/en not_active Expired - Fee Related
-
1997
- 1997-09-24 GR GR970402492T patent/GR3024850T3/el unknown
Also Published As
Publication number | Publication date |
---|---|
US5428158A (en) | 1995-06-27 |
FI924311A0 (fi) | 1992-09-25 |
HUT65192A (en) | 1994-05-02 |
DE69220744T2 (de) | 1997-11-13 |
US5486513A (en) | 1996-01-23 |
DK0534363T3 (da) | 1997-09-22 |
KR930006027A (ko) | 1993-04-20 |
EP0534363A2 (en) | 1993-03-31 |
KR100271239B1 (ko) | 2001-02-01 |
GR3024850T3 (en) | 1998-01-30 |
NO923744L (no) | 1993-03-29 |
NZ244461A (en) | 1994-09-27 |
DE69220744D1 (de) | 1997-08-14 |
IL103263A (en) | 1996-11-14 |
FI101303B1 (fi) | 1998-05-29 |
FI924311A (fi) | 1993-03-28 |
AU2524592A (en) | 1993-04-01 |
CA2078758C (en) | 2003-12-09 |
ATE155143T1 (de) | 1997-07-15 |
ES2106112T3 (es) | 1997-11-01 |
NO923744D0 (no) | 1992-09-25 |
US5529996A (en) | 1996-06-25 |
EP0534363B1 (en) | 1997-07-09 |
JP3173675B2 (ja) | 2001-06-04 |
IL103263A0 (en) | 1993-02-21 |
FI101303B (fi) | 1998-05-29 |
HU214820B (hu) | 1998-06-29 |
EP0534363A3 (en) | 1993-06-09 |
HU9203074D0 (en) | 1992-12-28 |
AU657166B2 (en) | 1995-03-02 |
CA2078758A1 (en) | 1993-03-28 |
JPH05294963A (ja) | 1993-11-09 |
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