LT4838B - 1,3,4-oksadiazolono dariniai - Google Patents
1,3,4-oksadiazolono dariniai Download PDFInfo
- Publication number
- LT4838B LT4838B LT2000068A LT2000068A LT4838B LT 4838 B LT4838 B LT 4838B LT 2000068 A LT2000068 A LT 2000068A LT 2000068 A LT2000068 A LT 2000068A LT 4838 B LT4838 B LT 4838B
- Authority
- LT
- Lithuania
- Prior art keywords
- methyl
- phenyl
- chloro
- trifluoromethyl
- oxadiazol
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 21
- 208000035475 disorder Diseases 0.000 claims abstract description 19
- 231100000252 nontoxic Toxicity 0.000 claims abstract description 17
- 230000003000 nontoxic effect Effects 0.000 claims abstract description 17
- 239000012453 solvate Substances 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 100
- -1 4-chloro-2 - [[5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl] methyl] phenyl (dimethylamino) Chemical class 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 22
- 239000011575 calcium Substances 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 208000006011 Stroke Diseases 0.000 claims description 12
- 239000000651 prodrug Substances 0.000 claims description 12
- 229940002612 prodrug Drugs 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 229910052791 calcium Inorganic materials 0.000 claims description 10
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 206010010904 Convulsion Diseases 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
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- 206010027599 migraine Diseases 0.000 claims description 7
- GWVLAXGYZUVAGV-UHFFFAOYSA-N n,n-dimethylmethanamine;methanesulfonic acid Chemical compound C[NH+](C)C.CS([O-])(=O)=O GWVLAXGYZUVAGV-UHFFFAOYSA-N 0.000 claims description 7
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
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- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 102000005702 Calcium-Activated Potassium Channels Human genes 0.000 claims description 2
- 108010045489 Calcium-Activated Potassium Channels Proteins 0.000 claims description 2
- SUGURSDJQFUZOY-UHFFFAOYSA-M [2-[4-chloro-2-[[2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-3-yl]methyl]phenoxy]-2-oxoethyl]-trimethylazanium;methanesulfonate Chemical compound CS([O-])(=O)=O.C[N+](C)(C)CC(=O)OC1=CC=C(Cl)C=C1CN1C(=O)OC(C=2C=CC(=CC=2)C(F)(F)F)=N1 SUGURSDJQFUZOY-UHFFFAOYSA-M 0.000 claims description 2
- 150000001450 anions Chemical group 0.000 claims description 2
- MGOYBMFCELTAHS-UHFFFAOYSA-N methyl 3-(diethylamino)propanoate Chemical compound CCN(CC)CCC(=O)OC MGOYBMFCELTAHS-UHFFFAOYSA-N 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- VEQZOIFDBXAUBE-UHFFFAOYSA-M ethyl(trimethyl)azanium;methanesulfonate Chemical compound CS([O-])(=O)=O.CC[N+](C)(C)C VEQZOIFDBXAUBE-UHFFFAOYSA-M 0.000 claims 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 claims 1
- 108010092555 Large-Conductance Calcium-Activated Potassium Channels Proteins 0.000 abstract description 20
- 102000016469 Large-Conductance Calcium-Activated Potassium Channels Human genes 0.000 abstract description 20
- ZVTQYRVARPYRRE-UHFFFAOYSA-N oxadiazol-4-one Chemical class O=C1CON=N1 ZVTQYRVARPYRRE-UHFFFAOYSA-N 0.000 abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
- 239000000243 solution Substances 0.000 description 32
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
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- 238000000034 method Methods 0.000 description 19
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- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 10
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
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- 239000004480 active ingredient Substances 0.000 description 7
- 210000000170 cell membrane Anatomy 0.000 description 7
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 7
- 230000003834 intracellular effect Effects 0.000 description 7
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- 230000001225 therapeutic effect Effects 0.000 description 7
- WTSXVIMLKCKWIW-UHFFFAOYSA-N 3h-1,3,4-oxadiazol-2-one Chemical compound O=C1NN=CO1 WTSXVIMLKCKWIW-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
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- 238000001704 evaporation Methods 0.000 description 6
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 5
- QKOWACXSXTXRKA-UHFFFAOYSA-N 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-one Chemical class OC1=CC=C(Cl)C=C1CN1C(=O)OC(C=2C=CC(=CC=2)C(F)(F)F)=N1 QKOWACXSXTXRKA-UHFFFAOYSA-N 0.000 description 4
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- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 2
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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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
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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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- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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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
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- 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
- A61P25/06—Antimigraine agents
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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
- A61P25/08—Antiepileptics; Anticonvulsants
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- 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
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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
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (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)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Pulmonology (AREA)
- Neurosurgery (AREA)
- Urology & Nephrology (AREA)
- Gynecology & Obstetrics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7296698P | 1998-01-29 | 1998-01-29 | |
| US10227498P | 1998-09-29 | 1998-09-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| LT2000068A LT2000068A (en) | 2001-03-26 |
| LT4838B true LT4838B (lt) | 2001-08-27 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LT2000068A LT4838B (lt) | 1998-01-29 | 2000-07-14 | 1,3,4-oksadiazolono dariniai |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US6034113A (fr) |
| EP (1) | EP1051173A4 (fr) |
| JP (1) | JP2002527352A (fr) |
| KR (1) | KR20010077838A (fr) |
| CN (1) | CN1150175C (fr) |
| AR (1) | AR010712A1 (fr) |
| AU (1) | AU735704B2 (fr) |
| BG (1) | BG104706A (fr) |
| BR (1) | BR9913010A (fr) |
| CA (1) | CA2318830A1 (fr) |
| CO (1) | CO5090837A1 (fr) |
| EE (1) | EE04089B1 (fr) |
| GE (1) | GEP20032914B (fr) |
| HU (1) | HUP0102025A3 (fr) |
| ID (1) | ID26909A (fr) |
| IL (1) | IL137518A0 (fr) |
| LT (1) | LT4838B (fr) |
| LV (1) | LV12559B (fr) |
| NO (1) | NO317102B1 (fr) |
| NZ (1) | NZ505409A (fr) |
| PL (1) | PL342060A1 (fr) |
| RU (1) | RU2202548C2 (fr) |
| SK (1) | SK10852000A3 (fr) |
| TR (1) | TR200002019T2 (fr) |
| TW (1) | TW550075B (fr) |
| UA (1) | UA58579C2 (fr) |
| WO (1) | WO1999038510A1 (fr) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003525199A (ja) * | 1998-01-29 | 2003-08-26 | ブリストル−マイヤーズ スクイブ カンパニー | ジアリール１，３，４−オキサジアゾロンアミノ酸誘導体 |
| WO2000044745A1 (fr) * | 1999-01-29 | 2000-08-03 | Bristol-Myers Squibb Company | Derives carbamates de 1,3,4-oxadiazolone diaryle |
| US6297241B1 (en) | 1999-01-29 | 2001-10-02 | Bristol-Myers Squibb Company | Carbamate derivatives of diaryl 1,3,4-oxadiazolone |
| US6326388B1 (en) * | 1999-12-21 | 2001-12-04 | Celgene Corporation | Substituted 1,3,4-oxadiazoles and a method of reducing TNF-alpha level |
| JP2005507853A (ja) | 2001-02-20 | 2005-03-24 | ブリストル−マイヤーズ スクイブ カンパニー | Ｋｃｎｑカリウムチャンネルモジュレーター並びに片頭痛および機構的に関連する疾患の治療におけるそれらの使用 |
| CN101519386A (zh) * | 2001-04-16 | 2009-09-02 | 田边三菱制药株式会社 | 高传导率钙-活化k通道开启剂 |
| US6909027B1 (en) * | 2001-08-13 | 2005-06-21 | Perry Robins | Method of forming an in-situ film dressing and the composition of the film-forming material |
| US7119246B2 (en) * | 2002-06-25 | 2006-10-10 | Perry Robins | Method of treating acne |
| IN2014KN02583A (fr) | 2012-05-16 | 2015-05-08 | Techfields Pharma Co Ltd | |
| JP5855599B2 (ja) * | 2013-04-30 | 2016-02-09 | テックフィールズ バイオケム カンパニー リミテッド | 非常に速い皮膚浸透率を有するアセトアミノフェン及び関連化合物の正荷電水溶性プロドラッグ |
| CN104710379B (zh) * | 2015-03-09 | 2017-01-18 | 华南理工大学 | 一种bms‑191011的合成方法 |
| JP6165816B2 (ja) * | 2015-10-01 | 2017-07-19 | テックフィールズ バイオケム カンパニー リミテッド | 非常に速い皮膚浸透率を有するアセトアミノフェン及び関連化合物の正荷電水溶性プロドラッグ |
| AU2018225758A1 (en) * | 2017-02-24 | 2019-09-05 | Ovid Therapeutics Inc. | Methods of treating seizure disorders |
| CN110987847B (zh) * | 2019-12-11 | 2021-02-19 | 苏州今蓝纳米科技有限公司 | 1,3,4-噁二唑衍生物在检测酸以及数据加密和储存中的应用 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3971803A (en) | 1973-05-21 | 1976-07-27 | Ciba-Geigy Corporation | 3-Hydroxybenzyl-oxadiazolone and -thiadiazolone derivatives |
| WO1998004135A1 (fr) | 1996-07-31 | 1998-02-05 | Bristol-Myers Squibb Company | Heterocycles diphenyliques utilises comme modulateurs du canal potassium |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1251488B (it) * | 1991-09-17 | 1995-05-15 | Mini Ricerca Scient Tecnolog | Ossa(tia)diazol- e triazol-oni(tioni) ad attivita' acaricida ed insetticida |
| US5234947A (en) * | 1991-11-07 | 1993-08-10 | New York University | Potassium channel activating compounds and methods of use thereof |
| US5547966A (en) * | 1993-10-07 | 1996-08-20 | Bristol-Myers Squibb Company | Aryl urea and related compounds |
| JP2003525199A (ja) * | 1998-01-29 | 2003-08-26 | ブリストル−マイヤーズ スクイブ カンパニー | ジアリール１，３，４−オキサジアゾロンアミノ酸誘導体 |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3971803A (en) | 1973-05-21 | 1976-07-27 | Ciba-Geigy Corporation | 3-Hydroxybenzyl-oxadiazolone and -thiadiazolone derivatives |
| WO1998004135A1 (fr) | 1996-07-31 | 1998-02-05 | Bristol-Myers Squibb Company | Heterocycles diphenyliques utilises comme modulateurs du canal potassium |
Non-Patent Citations (4)
| Title |
|---|
| NIGEL S. COOK: "The pharmacology of potassium channels and their therapeutic potential", TRENDS IN PHARMACOLOGICAL SCIENCES, 1988, pages 21 - 28 |
| TRIVEDI S ET AL.: "Calcium dependent K-channels in guinea pig and human urinary bladder", BIOCHEM BIOPHYS RES COMMUN., 1995, pages 404 - 409 |
| ULRICH QUAST , NIGEL S. COOK: "Moving together: K+ channel openersand ATP-sensitive K+ channels", TRENDS IN PHARMACOLOGICAL SCIENCES, 1989, pages 431 - 435 |
| WILDER SMITH, A.E.: "Preparation of Some New 4-Substituted Derivatives of p-Amino-o-hydroxy-phenyl-1,3,4-oxadiazolone-5 and Study of their Mycobacteriostatic Activity", ARZNEIM. FORSCH., 1967, pages 768 - 772 |
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