CA2665849A1 - Spiro benzazepines used as vasopressin antagonists - Google Patents
Spiro benzazepines used as vasopressin antagonists Download PDFInfo
- Publication number
- CA2665849A1 CA2665849A1 CA002665849A CA2665849A CA2665849A1 CA 2665849 A1 CA2665849 A1 CA 2665849A1 CA 002665849 A CA002665849 A CA 002665849A CA 2665849 A CA2665849 A CA 2665849A CA 2665849 A1 CA2665849 A1 CA 2665849A1
- Authority
- CA
- Canada
- Prior art keywords
- phenyl
- compound
- benzazepine
- spiro
- carbonyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- -1 Spiro benzazepines Chemical class 0.000 title claims description 90
- 229940116211 Vasopressin antagonist Drugs 0.000 title description 5
- 239000003038 vasopressin antagonist Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 196
- 238000000034 method Methods 0.000 claims abstract description 51
- 206010019280 Heart failures Diseases 0.000 claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
- 102000004136 Vasopressin Receptors Human genes 0.000 claims abstract description 18
- 108090000643 Vasopressin Receptors Proteins 0.000 claims abstract description 18
- 208000001647 Renal Insufficiency Diseases 0.000 claims abstract description 17
- 201000006370 kidney failure Diseases 0.000 claims abstract description 17
- 206010007559 Cardiac failure congestive Diseases 0.000 claims abstract description 15
- 206010020772 Hypertension Diseases 0.000 claims abstract description 15
- 206010021036 Hyponatraemia Diseases 0.000 claims abstract description 14
- 230000000694 effects Effects 0.000 claims abstract description 13
- 206010048962 Brain oedema Diseases 0.000 claims abstract description 8
- 208000006011 Stroke Diseases 0.000 claims abstract description 8
- 208000006752 brain edema Diseases 0.000 claims abstract description 8
- 208000019425 cirrhosis of liver Diseases 0.000 claims abstract description 8
- 206010003225 Arteriospasm coronary Diseases 0.000 claims abstract description 7
- 201000006474 Brain Ischemia Diseases 0.000 claims abstract description 7
- 206010008120 Cerebral ischaemia Diseases 0.000 claims abstract description 7
- 208000003890 Coronary Vasospasm Diseases 0.000 claims abstract description 7
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims abstract description 7
- 206010016807 Fluid retention Diseases 0.000 claims abstract description 7
- 206010047163 Vasospasm Diseases 0.000 claims abstract description 7
- 206010008118 cerebral infarction Diseases 0.000 claims abstract description 7
- 201000011634 coronary artery vasospasm Diseases 0.000 claims abstract description 7
- 208000033679 diabetic kidney disease Diseases 0.000 claims abstract description 7
- 208000031225 myocardial ischemia Diseases 0.000 claims abstract description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 106
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 85
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 70
- GTKIGDZXPDCIKR-UHFFFAOYSA-N 2-phenylbenzamide Chemical compound NC(=O)C1=CC=CC=C1C1=CC=CC=C1 GTKIGDZXPDCIKR-UHFFFAOYSA-N 0.000 claims description 69
- 125000000217 alkyl group Chemical group 0.000 claims description 50
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 claims description 45
- 229960003726 vasopressin Drugs 0.000 claims description 38
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 claims description 37
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- 125000003118 aryl group Chemical group 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
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- 229910052736 halogen Inorganic materials 0.000 claims description 11
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 6
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
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- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 34
- 101150041968 CDC13 gene Proteins 0.000 description 29
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- 238000003756 stirring Methods 0.000 description 24
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
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- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 235000015320 potassium carbonate Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 230000009329 sexual behaviour Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
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- ZKZOIWBLOYDXCP-UHFFFAOYSA-N spiro[1-benzazepine-4,3'-cyclopentane]-1'-carboxylic acid Chemical compound C1C(C(=O)O)CCC21C=C1C=CC=CC1=NC=C2 ZKZOIWBLOYDXCP-UHFFFAOYSA-N 0.000 description 1
- OKTZGZFCMGOBLM-UHFFFAOYSA-N spiro[1-benzazepine-4,3'-piperidine]-2'-one Chemical compound O=C1NCCCC11C=C2C=CC=CC2=NC=C1 OKTZGZFCMGOBLM-UHFFFAOYSA-N 0.000 description 1
- DIFPAMJXWONROD-UHFFFAOYSA-N spiro[1-benzazepine-4,3'-pyrrolidine] Chemical compound C1NCCC21C=C1C=CC=CC1=NC=C2 DIFPAMJXWONROD-UHFFFAOYSA-N 0.000 description 1
- SREGKYXRHUESFN-UHFFFAOYSA-N spiro[1-benzazepine-4,6'-piperidine]-2'-one Chemical compound N1C(=O)CCCC21C=C1C=CC=CC1=NC=C2 SREGKYXRHUESFN-UHFFFAOYSA-N 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- GYHCTFXIZSNGJT-UHFFFAOYSA-N tolvaptan Chemical compound CC1=CC=CC=C1C(=O)NC(C=C1C)=CC=C1C(=O)N1C2=CC=C(Cl)C=C2C(O)CCC1 GYHCTFXIZSNGJT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
- C07D487/10—Spiro-condensed systems
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- 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
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Psychiatry (AREA)
- Obesity (AREA)
- Anesthesiology (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US82665406P | 2006-09-22 | 2006-09-22 | |
| US60/826,654 | 2006-09-22 | ||
| PCT/US2007/078917 WO2008036755A1 (en) | 2006-09-22 | 2007-09-19 | Spiro benzazepines used as vasopressin antagonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2665849A1 true CA2665849A1 (en) | 2008-03-27 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002665849A Abandoned CA2665849A1 (en) | 2006-09-22 | 2007-09-19 | Spiro benzazepines used as vasopressin antagonists |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US7825110B2 (enExample) |
| EP (1) | EP2078022B1 (enExample) |
| JP (1) | JP2010504351A (enExample) |
| CN (1) | CN101541806A (enExample) |
| AT (1) | ATE532786T1 (enExample) |
| AU (1) | AU2007299818B2 (enExample) |
| CA (1) | CA2665849A1 (enExample) |
| CY (1) | CY1112270T1 (enExample) |
| DK (1) | DK2078022T3 (enExample) |
| ES (1) | ES2374582T3 (enExample) |
| PL (1) | PL2078022T3 (enExample) |
| PT (1) | PT2078022E (enExample) |
| SI (1) | SI2078022T1 (enExample) |
| WO (1) | WO2008036755A1 (enExample) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8921576B2 (en) | 2011-10-19 | 2014-12-30 | Kowa Company, Ltd. | Spiroindoline compound, and medicinal agent comprising same |
| TW201607923A (zh) | 2014-07-15 | 2016-03-01 | 歌林達有限公司 | 被取代之氮螺環（４．５）癸烷衍生物 |
| ES2686326T3 (es) | 2014-07-15 | 2018-10-17 | Grünenthal GmbH | Derivados de azaspiro(4,5)decano sustituidos |
| BR112017026173A2 (pt) | 2015-07-07 | 2018-08-14 | Japan Tobacco, Inc. | Método para produção de derivado de 7h-pirrolo [2,3-d]pirimidina e intermediário do mesmo |
| PL3560932T3 (pl) | 2016-12-21 | 2026-06-29 | Japan Tobacco Inc. | Sposób wytwarzania pochodnych 7H‑pirolo[2,3‑d]pirymidyny i ich syntetycznych produktów pośrednich |
| KR102790657B1 (ko) * | 2017-09-15 | 2025-04-02 | 아제반 파마슈티칼스, 인코퍼레이티드 | 뇌 손상을 치료하기 위한 조성물 및 방법 |
| WO2019141575A1 (de) | 2018-01-16 | 2019-07-25 | Bayer Aktiengesellschaft | Unterstützung bei der behandlung von herzinsuffizienz |
| US12698266B2 (en) | 2019-12-19 | 2026-08-04 | Casma Therapeutics, Inc. | TRPML modulators |
| TW202220958A (zh) * | 2020-08-07 | 2022-06-01 | 美商卡司馬療法公司 | Ｔｒｐｍｌ調節劑 |
| JP7627343B2 (ja) * | 2020-11-26 | 2025-02-05 | シャンハイ ジェミンケア ファーマシューティカル カンパニー，リミティド | 新規ベンズアゼピンスピロ環式誘導体 |
| CN112939864B (zh) * | 2021-01-29 | 2022-05-06 | 中国医科大学 | 螺[苯并[c]氮杂-1,1’-环己基]-3-酮类化合物 |
| EP4491699A1 (de) | 2023-07-13 | 2025-01-15 | Klueber Lubrication München GmbH & Co. KG | Phthalimidverbindungen als basisöl für schmierstoffzusammensetzungen |
| WO2026002248A1 (zh) * | 2024-06-28 | 2026-01-02 | 上海济煜医药科技股份有限公司 | 作为v2受体拮抗剂的苯并氮杂卓并环衍生物 |
Family Cites Families (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4617302A (en) * | 1984-10-15 | 1986-10-14 | Eli Lilly And Company | Inotropic agents |
| US5258510A (en) * | 1989-10-20 | 1993-11-02 | Otsuka Pharma Co Ltd | Benzoheterocyclic compounds |
| KR0167349B1 (ko) | 1989-10-20 | 1999-02-18 | 오스카 아끼히꼬 | 벤조헤테로 고리 화합물 |
| US5985869A (en) * | 1989-10-20 | 1999-11-16 | Otsuka Pharmaceutical Company, Limited | Benzoheterocyclic compounds |
| JP2905909B2 (ja) * | 1991-04-19 | 1999-06-14 | 大塚製薬株式会社 | バソプレシン拮抗剤 |
| US5663431A (en) * | 1992-01-30 | 1997-09-02 | Sanofi | 1-benzenesulfonyl-1,3-dihydro-indol-2-one derivatives, their preparation and pharmaceutical compositions in which they are present |
| FR2686878B1 (fr) * | 1992-01-30 | 1995-06-30 | Sanofi Elf | Derives du n-sulfonyl oxo-2 indole, leur preparation, les compositions pharmaceutiques en contenant. |
| US5686624A (en) * | 1992-01-30 | 1997-11-11 | Sanofi | 1-benzenesulfonyl-1,3-dihydro-indol-2-one derivatives, their preparation and pharmaceutical compositions in which they are present |
| US5849780A (en) * | 1992-01-30 | 1998-12-15 | Sanofi | 1-benzenesulfonyl-1-1,3-dihydroindol-2-one derivatives, their preparation and pharmaceutical compositions in which they are present |
| FR2708605A1 (fr) | 1993-07-30 | 1995-02-10 | Sanofi Sa | Dérivés du N-sulfonylindol-2-one, leur préparation, les compositions pharmaceutiques en contenant. |
| JPH08502474A (ja) | 1992-10-07 | 1996-03-19 | メルク エンド カンパニー インコーポレーテッド | トコリティックオキシトシンレセプターアンタゴニスト |
| US5512563A (en) | 1993-07-29 | 1996-04-30 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
| FR2708606B1 (fr) * | 1993-07-30 | 1995-10-27 | Sanofi Sa | Dérivés du N-phénylalkylindol-2-one, leur préparation, les compositions pharmaceutiques en contenant. |
| US5464788A (en) | 1994-03-24 | 1995-11-07 | Merck & Co., Inc. | Tocolytic oxytocin receptor antagonists |
| US5753648A (en) | 1995-01-17 | 1998-05-19 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
| AUPP150098A0 (en) | 1998-01-27 | 1998-02-19 | Fujisawa Pharmaceutical Co., Ltd. | Benzamide derivatives |
| ES2250432T3 (es) * | 2000-07-05 | 2006-04-16 | Ortho-Mcneil Pharmaceutical, Inc. | Espirobenzoazepinas no peptidicas sustituidas, antagonistas de la vasopresina. |
| AU2002231098A1 (en) * | 2000-12-15 | 2002-06-24 | Emory University | Nonpeptide agonists and antagonists of vasopressin receptors |
| US7011898B2 (en) * | 2003-03-21 | 2006-03-14 | Air Products And Chemicals, Inc. | Method of joining ITM materials using a partially or fully-transient liquid phase |
| CA2529513A1 (en) * | 2003-06-17 | 2005-01-06 | Janssen Pharmaceutica N.V. | Process for the preparation of nonpeptide substituted spirobenzoazepine derivatives |
| SI1633719T1 (sl) * | 2003-06-17 | 2010-01-29 | Janssen Pharmaceutica Nv | Substituirani spirobenzazepini |
| EP1984342A2 (en) * | 2006-01-20 | 2008-10-29 | Janssen Pharmaceutica, N.V. | Novel solid forms of (4r)-1-[4-(2-chloro-5-fluorobenzoyl)amino-3-methoxybenzoyl]-1,2,3,5-tetrahydro-spiro[4h-1-benzazepine-4,1'-[2]cyclopentene]-3'-carboxylic acid |
-
2007
- 2007-09-19 WO PCT/US2007/078917 patent/WO2008036755A1/en not_active Ceased
- 2007-09-19 CN CNA2007800432003A patent/CN101541806A/zh active Pending
- 2007-09-19 PT PT07842799T patent/PT2078022E/pt unknown
- 2007-09-19 JP JP2009529369A patent/JP2010504351A/ja active Pending
- 2007-09-19 US US11/857,891 patent/US7825110B2/en not_active Expired - Fee Related
- 2007-09-19 SI SI200730800T patent/SI2078022T1/sl unknown
- 2007-09-19 ES ES07842799T patent/ES2374582T3/es active Active
- 2007-09-19 EP EP07842799A patent/EP2078022B1/en not_active Not-in-force
- 2007-09-19 AT AT07842799T patent/ATE532786T1/de active
- 2007-09-19 PL PL07842799T patent/PL2078022T3/pl unknown
- 2007-09-19 CA CA002665849A patent/CA2665849A1/en not_active Abandoned
- 2007-09-19 DK DK07842799.4T patent/DK2078022T3/da active
- 2007-09-19 AU AU2007299818A patent/AU2007299818B2/en not_active Expired - Fee Related
-
2012
- 2012-01-24 CY CY20121100081T patent/CY1112270T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PT2078022E (pt) | 2012-01-11 |
| CN101541806A (zh) | 2009-09-23 |
| AU2007299818B2 (en) | 2012-08-02 |
| ATE532786T1 (de) | 2011-11-15 |
| PL2078022T3 (pl) | 2012-04-30 |
| WO2008036755A1 (en) | 2008-03-27 |
| DK2078022T3 (da) | 2012-02-13 |
| EP2078022A1 (en) | 2009-07-15 |
| JP2010504351A (ja) | 2010-02-12 |
| ES2374582T3 (es) | 2012-02-20 |
| CY1112270T1 (el) | 2015-12-09 |
| US7825110B2 (en) | 2010-11-02 |
| SI2078022T1 (sl) | 2012-01-31 |
| AU2007299818A1 (en) | 2008-03-27 |
| EP2078022B1 (en) | 2011-11-09 |
| US20080076753A1 (en) | 2008-03-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |
Effective date: 20140919 |