Studies of the Synthesis of Condensed Pyridazine Derivatives. IV. Synthesis and Anxiolytic Activity of 2-Aryl-5, 6-dihydro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-ones and Related Compound
A series of 2-aryl-5, 6-dihydro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-ones and related compounds were synthesized and evaluated for their ability to displace 3H-diazepam from rat brain membranes in vitro, and to prevent bicuculline induced convulsions in mice in vivo.Compounds with a 4'-metho...
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| Veröffentlicht in: | Chemical & pharmaceutical bulletin 1991/10/25, Vol.39(10), pp.2556-2563 |
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| creator | NAKAO, Tohru OBATA, Minoru KAWAKAMI, Minoru MORITA, Kenji TANAKA, Hiroshi MORIMOTO, Yasuto TAKEHARA, Shuzo YAKUSHIJI, Takashi TAHARA, Tetsuya |
| description | A series of 2-aryl-5, 6-dihydro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-ones and related compounds were synthesized and evaluated for their ability to displace 3H-diazepam from rat brain membranes in vitro, and to prevent bicuculline induced convulsions in mice in vivo.Compounds with a 4'-methoxyphenyl (36) or 4'-chlorophenyl group (37, 39-42) as 2-aryl substituents showed prominent activities in both the in vitro and in vivo tests. Among them, 2-(4'-chlorophenyl)-5, 6-dihydro- (37) and 2-(4'-chlorophenyl)-5, 6-dihydro-10-fluoro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-one 7-oxides (41) showed activity twice as potent as diazepam in an anticonflict test (Vogel type, rats) while exhibiting less muscle relaxation (rotarod test, mice) and augmentation of γ-aminobutyric acid-induced chloride current (1cl) in isolated frog sensory neurones than diazepam. Compound 37 (Y-23684) was selected from this series as a candidate for further development. The structure-activity relationships are discussed. |
| doi_str_mv | 10.1248/cpb.39.2556 |
| format | Article |
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IV. Synthesis and Anxiolytic Activity of 2-Aryl-5, 6-dihydro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-ones and Related Compound</title><source>MEDLINE</source><source>J-STAGE (Japan Science & Technology Information Aggregator, Electronic) Freely Available Titles - Japanese</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Free Full-Text Journals in Chemistry</source><creator>NAKAO, Tohru ; OBATA, Minoru ; KAWAKAMI, Minoru ; MORITA, Kenji ; TANAKA, Hiroshi ; MORIMOTO, Yasuto ; TAKEHARA, Shuzo ; YAKUSHIJI, Takashi ; TAHARA, Tetsuya</creator><creatorcontrib>NAKAO, Tohru ; OBATA, Minoru ; KAWAKAMI, Minoru ; MORITA, Kenji ; TANAKA, Hiroshi ; MORIMOTO, Yasuto ; TAKEHARA, Shuzo ; YAKUSHIJI, Takashi ; TAHARA, Tetsuya</creatorcontrib><description>A series of 2-aryl-5, 6-dihydro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-ones and related compounds were synthesized and evaluated for their ability to displace 3H-diazepam from rat brain membranes in vitro, and to prevent bicuculline induced convulsions in mice in vivo.Compounds with a 4'-methoxyphenyl (36) or 4'-chlorophenyl group (37, 39-42) as 2-aryl substituents showed prominent activities in both the in vitro and in vivo tests. Among them, 2-(4'-chlorophenyl)-5, 6-dihydro- (37) and 2-(4'-chlorophenyl)-5, 6-dihydro-10-fluoro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-one 7-oxides (41) showed activity twice as potent as diazepam in an anticonflict test (Vogel type, rats) while exhibiting less muscle relaxation (rotarod test, mice) and augmentation of γ-aminobutyric acid-induced chloride current (1cl) in isolated frog sensory neurones than diazepam. Compound 37 (Y-23684) was selected from this series as a candidate for further development. The structure-activity relationships are discussed.</description><identifier>ISSN: 0009-2363</identifier><identifier>EISSN: 1347-5223</identifier><identifier>DOI: 10.1248/cpb.39.2556</identifier><identifier>PMID: 1687209</identifier><identifier>CODEN: CPBTAL</identifier><language>eng</language><publisher>Tokyo: The Pharmaceutical Society of Japan</publisher><subject>Animals ; Anti-Anxiety Agents - chemical synthesis ; Anti-Anxiety Agents - pharmacology ; antibicuculline test ; anticonflict test ; anxiolytic activity ; benzodiazepine receptor ; benzothiepino[5, 4-c]pyridazin-3(2H)-one ; Benzothiepins - chemical synthesis ; Benzothiepins - pharmacology ; binding assay ; Chemistry ; Exact sciences and technology ; Heterocyclic compounds ; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms ; Organic chemistry ; Preparations and properties ; Pyridazines - chemical synthesis ; Pyridazines - pharmacology ; Rats ; Structure-Activity Relationship ; sulfoxide ; X-Ray Diffraction ; γ-aminobutyric acid</subject><ispartof>Chemical and Pharmaceutical Bulletin, 1991/10/25, Vol.39(10), pp.2556-2563</ispartof><rights>The Pharmaceutical Society of Japan</rights><rights>1992 INIST-CNRS</rights><rights>Copyright Japan Science and Technology Agency 1991</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4556-ea819a1a9120572109f0e181d9ffdc7256c957f29b193413d82b67d401b5b8663</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1883,4024,27923,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=5113013$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1687209$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>NAKAO, Tohru</creatorcontrib><creatorcontrib>OBATA, Minoru</creatorcontrib><creatorcontrib>KAWAKAMI, Minoru</creatorcontrib><creatorcontrib>MORITA, Kenji</creatorcontrib><creatorcontrib>TANAKA, Hiroshi</creatorcontrib><creatorcontrib>MORIMOTO, Yasuto</creatorcontrib><creatorcontrib>TAKEHARA, Shuzo</creatorcontrib><creatorcontrib>YAKUSHIJI, Takashi</creatorcontrib><creatorcontrib>TAHARA, Tetsuya</creatorcontrib><title>Studies of the Synthesis of Condensed Pyridazine Derivatives. IV. Synthesis and Anxiolytic Activity of 2-Aryl-5, 6-dihydro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-ones and Related Compound</title><title>Chemical & pharmaceutical bulletin</title><addtitle>Chem. Pharm. Bull.</addtitle><description>A series of 2-aryl-5, 6-dihydro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-ones and related compounds were synthesized and evaluated for their ability to displace 3H-diazepam from rat brain membranes in vitro, and to prevent bicuculline induced convulsions in mice in vivo.Compounds with a 4'-methoxyphenyl (36) or 4'-chlorophenyl group (37, 39-42) as 2-aryl substituents showed prominent activities in both the in vitro and in vivo tests. Among them, 2-(4'-chlorophenyl)-5, 6-dihydro- (37) and 2-(4'-chlorophenyl)-5, 6-dihydro-10-fluoro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-one 7-oxides (41) showed activity twice as potent as diazepam in an anticonflict test (Vogel type, rats) while exhibiting less muscle relaxation (rotarod test, mice) and augmentation of γ-aminobutyric acid-induced chloride current (1cl) in isolated frog sensory neurones than diazepam. Compound 37 (Y-23684) was selected from this series as a candidate for further development. The structure-activity relationships are discussed.</description><subject>Animals</subject><subject>Anti-Anxiety Agents - chemical synthesis</subject><subject>Anti-Anxiety Agents - pharmacology</subject><subject>antibicuculline test</subject><subject>anticonflict test</subject><subject>anxiolytic activity</subject><subject>benzodiazepine receptor</subject><subject>benzothiepino[5, 4-c]pyridazin-3(2H)-one</subject><subject>Benzothiepins - chemical synthesis</subject><subject>Benzothiepins - pharmacology</subject><subject>binding assay</subject><subject>Chemistry</subject><subject>Exact sciences and technology</subject><subject>Heterocyclic compounds</subject><subject>Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms</subject><subject>Organic chemistry</subject><subject>Preparations and properties</subject><subject>Pyridazines - chemical synthesis</subject><subject>Pyridazines - pharmacology</subject><subject>Rats</subject><subject>Structure-Activity Relationship</subject><subject>sulfoxide</subject><subject>X-Ray Diffraction</subject><subject>γ-aminobutyric acid</subject><issn>0009-2363</issn><issn>1347-5223</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1991</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkV-L1DAUxYu4rOPqk89CwUV20Yy5SdM2j8Po_oEFxVVfREqapE6GTlKTdrH72fxwpnbcFV9yIeeXcy45SfIM8BJIVr6RXb2kfEkYyx8kC6BZgRgh9GGywBhzRGhOHyWPQ9hiTBgu6GFyCHlZEMwXya_rflBGh9Q1ab_R6fVo4wjmz8XaWaVt0Cr9MHqjxK2xOn2rvbkRvbnRYZlefln-80RYla7sT-PasTcyXclImX6crAha-bFF7HWaI2U2o_IOncBpre2t6zdGd8a6r1HNkPzW_Q1D9IRcnCJn9ez9Ubeij9us3a5zg1VPkoNGtEE_3c-j5PPZu0_rC3T1_vxyvbpCMot_grQogQsQHAhmBQHMG6yhBMWbRsmCsFxyVjSE18BpBlSVpM4LlWGoWV3mOT1KXs6-nXc_Bh36ameC1G0rrHZDqApSAOCcRfDFf-DWDd7G3SrIckxiNVBE6tVMSe9C8LqpOm92wo8V4GpqtIqNVpRXU6ORfr73HOqdVvfsXGHUj_e6CFK0jRdWmnCHMQCKgUbsbMa2oRff9Z0ufKyq1VMkcFZOsXGL-Zzy74GN8JW29DdBXr_N</recordid><startdate>1991</startdate><enddate>1991</enddate><creator>NAKAO, Tohru</creator><creator>OBATA, Minoru</creator><creator>KAWAKAMI, Minoru</creator><creator>MORITA, Kenji</creator><creator>TANAKA, Hiroshi</creator><creator>MORIMOTO, Yasuto</creator><creator>TAKEHARA, Shuzo</creator><creator>YAKUSHIJI, Takashi</creator><creator>TAHARA, Tetsuya</creator><general>The Pharmaceutical Society of Japan</general><general>Maruzen</general><general>Japan Science and Technology Agency</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>1991</creationdate><title>Studies of the Synthesis of Condensed Pyridazine Derivatives. IV. Synthesis and Anxiolytic Activity of 2-Aryl-5, 6-dihydro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-ones and Related Compound</title><author>NAKAO, Tohru ; OBATA, Minoru ; KAWAKAMI, Minoru ; MORITA, Kenji ; TANAKA, Hiroshi ; MORIMOTO, Yasuto ; TAKEHARA, Shuzo ; YAKUSHIJI, Takashi ; TAHARA, Tetsuya</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4556-ea819a1a9120572109f0e181d9ffdc7256c957f29b193413d82b67d401b5b8663</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1991</creationdate><topic>Animals</topic><topic>Anti-Anxiety Agents - chemical synthesis</topic><topic>Anti-Anxiety Agents - pharmacology</topic><topic>antibicuculline test</topic><topic>anticonflict test</topic><topic>anxiolytic activity</topic><topic>benzodiazepine receptor</topic><topic>benzothiepino[5, 4-c]pyridazin-3(2H)-one</topic><topic>Benzothiepins - chemical synthesis</topic><topic>Benzothiepins - pharmacology</topic><topic>binding assay</topic><topic>Chemistry</topic><topic>Exact sciences and technology</topic><topic>Heterocyclic compounds</topic><topic>Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms</topic><topic>Organic chemistry</topic><topic>Preparations and properties</topic><topic>Pyridazines - chemical synthesis</topic><topic>Pyridazines - pharmacology</topic><topic>Rats</topic><topic>Structure-Activity Relationship</topic><topic>sulfoxide</topic><topic>X-Ray Diffraction</topic><topic>γ-aminobutyric acid</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>NAKAO, Tohru</creatorcontrib><creatorcontrib>OBATA, Minoru</creatorcontrib><creatorcontrib>KAWAKAMI, Minoru</creatorcontrib><creatorcontrib>MORITA, Kenji</creatorcontrib><creatorcontrib>TANAKA, Hiroshi</creatorcontrib><creatorcontrib>MORIMOTO, Yasuto</creatorcontrib><creatorcontrib>TAKEHARA, Shuzo</creatorcontrib><creatorcontrib>YAKUSHIJI, Takashi</creatorcontrib><creatorcontrib>TAHARA, Tetsuya</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Chemical & pharmaceutical bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>NAKAO, Tohru</au><au>OBATA, Minoru</au><au>KAWAKAMI, Minoru</au><au>MORITA, Kenji</au><au>TANAKA, Hiroshi</au><au>MORIMOTO, Yasuto</au><au>TAKEHARA, Shuzo</au><au>YAKUSHIJI, Takashi</au><au>TAHARA, Tetsuya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Studies of the Synthesis of Condensed Pyridazine Derivatives. IV. Synthesis and Anxiolytic Activity of 2-Aryl-5, 6-dihydro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-ones and Related Compound</atitle><jtitle>Chemical & pharmaceutical bulletin</jtitle><addtitle>Chem. Pharm. Bull.</addtitle><date>1991</date><risdate>1991</risdate><volume>39</volume><issue>10</issue><spage>2556</spage><epage>2563</epage><pages>2556-2563</pages><issn>0009-2363</issn><eissn>1347-5223</eissn><coden>CPBTAL</coden><abstract>A series of 2-aryl-5, 6-dihydro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-ones and related compounds were synthesized and evaluated for their ability to displace 3H-diazepam from rat brain membranes in vitro, and to prevent bicuculline induced convulsions in mice in vivo.Compounds with a 4'-methoxyphenyl (36) or 4'-chlorophenyl group (37, 39-42) as 2-aryl substituents showed prominent activities in both the in vitro and in vivo tests. Among them, 2-(4'-chlorophenyl)-5, 6-dihydro- (37) and 2-(4'-chlorophenyl)-5, 6-dihydro-10-fluoro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-one 7-oxides (41) showed activity twice as potent as diazepam in an anticonflict test (Vogel type, rats) while exhibiting less muscle relaxation (rotarod test, mice) and augmentation of γ-aminobutyric acid-induced chloride current (1cl) in isolated frog sensory neurones than diazepam. Compound 37 (Y-23684) was selected from this series as a candidate for further development. The structure-activity relationships are discussed.</abstract><cop>Tokyo</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>1687209</pmid><doi>10.1248/cpb.39.2556</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0009-2363 |
| ispartof | Chemical and Pharmaceutical Bulletin, 1991/10/25, Vol.39(10), pp.2556-2563 |
| issn | 0009-2363 1347-5223 |
| language | eng |
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| source | MEDLINE; J-STAGE (Japan Science & Technology Information Aggregator, Electronic) Freely Available Titles - Japanese; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Animals Anti-Anxiety Agents - chemical synthesis Anti-Anxiety Agents - pharmacology antibicuculline test anticonflict test anxiolytic activity benzodiazepine receptor benzothiepino[5, 4-c]pyridazin-3(2H)-one Benzothiepins - chemical synthesis Benzothiepins - pharmacology binding assay Chemistry Exact sciences and technology Heterocyclic compounds Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms Organic chemistry Preparations and properties Pyridazines - chemical synthesis Pyridazines - pharmacology Rats Structure-Activity Relationship sulfoxide X-Ray Diffraction γ-aminobutyric acid |
| title | Studies of the Synthesis of Condensed Pyridazine Derivatives. IV. Synthesis and Anxiolytic Activity of 2-Aryl-5, 6-dihydro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-ones and Related Compound |
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