Synthesis and antihypertensive activity of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones
A series of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones was prepared and evaluated for antihypertensive activity in the spontaneously hypertensive rat (SHR). The basic ring system was prepared in one step by condensation of dilithiated (tert-butoxycarbonyl)aniline (3...
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| Veröffentlicht in: | Journal of medicinal chemistry 1983-05, Vol.26 (5), p.657-661 |
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| container_end_page | 661 |
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| container_issue | 5 |
| container_start_page | 657 |
| container_title | Journal of medicinal chemistry |
| container_volume | 26 |
| creator | Clark, Robin D Caroon, Joan M Kluge, Arthur F Repke, David B Roszkowski, Adolph P Strosberg, Arthur M Baker, Stephen Bitter, Susan M Okada, Marlys D |
| description | A series of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones was prepared and evaluated for antihypertensive activity in the spontaneously hypertensive rat (SHR). The basic ring system was prepared in one step by condensation of dilithiated (tert-butoxycarbonyl)aniline (3) with (tert-butoxycarbonyl)piperidinone. Deprotection afforded 6, which was condensed with expoxides or alkyl halides to furnish the title compounds. The most active compound was dl-erythro-4'-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]spiro [4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-one (9), and various modifications of this compound were made in order to elucidate the structure-activity relationships in the series. Preliminary indications are that 9 may act by both central and peripheral mechanisms. |
| doi_str_mv | 10.1021/jm00359a007 |
| format | Article |
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The basic ring system was prepared in one step by condensation of dilithiated (tert-butoxycarbonyl)aniline (3) with (tert-butoxycarbonyl)piperidinone. Deprotection afforded 6, which was condensed with expoxides or alkyl halides to furnish the title compounds. The most active compound was dl-erythro-4'-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]spiro [4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-one (9), and various modifications of this compound were made in order to elucidate the structure-activity relationships in the series. Preliminary indications are that 9 may act by both central and peripheral mechanisms.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00359a007</identifier><identifier>PMID: 6842505</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Hypertension - drug therapy ; Male ; Oxazines - therapeutic use ; Piperidines - therapeutic use ; Piperidones - therapeutic use ; Rats ; Spiro Compounds - therapeutic use ; Structure-Activity Relationship ; Systole - drug effects</subject><ispartof>Journal of medicinal chemistry, 1983-05, Vol.26 (5), p.657-661</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a352t-7750aec18b5a736b2630f80b53f9e938400974c0c381f0b7bb9eb6bee8f3932d3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00359a007$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00359a007$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27055,27903,27904,56716,56766</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/6842505$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Clark, Robin D</creatorcontrib><creatorcontrib>Caroon, Joan M</creatorcontrib><creatorcontrib>Kluge, Arthur F</creatorcontrib><creatorcontrib>Repke, David B</creatorcontrib><creatorcontrib>Roszkowski, Adolph P</creatorcontrib><creatorcontrib>Strosberg, Arthur M</creatorcontrib><creatorcontrib>Baker, Stephen</creatorcontrib><creatorcontrib>Bitter, Susan M</creatorcontrib><creatorcontrib>Okada, Marlys D</creatorcontrib><title>Synthesis and antihypertensive activity of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones was prepared and evaluated for antihypertensive activity in the spontaneously hypertensive rat (SHR). The basic ring system was prepared in one step by condensation of dilithiated (tert-butoxycarbonyl)aniline (3) with (tert-butoxycarbonyl)piperidinone. Deprotection afforded 6, which was condensed with expoxides or alkyl halides to furnish the title compounds. The most active compound was dl-erythro-4'-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]spiro [4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-one (9), and various modifications of this compound were made in order to elucidate the structure-activity relationships in the series. Preliminary indications are that 9 may act by both central and peripheral mechanisms.</description><subject>Animals</subject><subject>Hypertension - drug therapy</subject><subject>Male</subject><subject>Oxazines - therapeutic use</subject><subject>Piperidines - therapeutic use</subject><subject>Piperidones - therapeutic use</subject><subject>Rats</subject><subject>Spiro Compounds - therapeutic use</subject><subject>Structure-Activity Relationship</subject><subject>Systole - drug effects</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1983</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkEtrFEEUhQtR4hhduRZ6ZQym9NarH0sJxhEGjE7EhUhR1X2b1Dhd3amqDpn8ektmCC5cXM7ifJwLHyEvGbxjwNn7zQAgVGMAqkdkwRQHKmuQj8kCgHPKSy6ekmcxbiBzjIsjclTWkitQCzKsdz5dY3SxML7Ll9z1bsKQ0Ed3i4Vpk7t1aVeMfSFPaJxtTC7NCbsiTi6MP-WSijNGLfr78c7cO49UnmVycnnFdc7_ovwNW57S0WN8Tp70ZhvxxSGPyfeLj1fnS7r68unz-YcVNULxRKtKgcGW1VaZSpSWlwL6GqwSfYONqCVAU8kWWlGzHmxlbYO2tIh1LxrBO3FMXu93pzDezBiTHlxscbs1Hsc56mxHlbKsM_h2D7ZhjDFgr6fgBhN2moH-K1f_IzfTrw6zsx2we2APNnNP972LCe8eahN-67ISldJXl2v9DdR69ePyq4bMn-x500a9Gefgs5T_fv4DxjSPOA</recordid><startdate>198305</startdate><enddate>198305</enddate><creator>Clark, Robin D</creator><creator>Caroon, Joan M</creator><creator>Kluge, Arthur F</creator><creator>Repke, David B</creator><creator>Roszkowski, Adolph P</creator><creator>Strosberg, Arthur M</creator><creator>Baker, Stephen</creator><creator>Bitter, Susan M</creator><creator>Okada, Marlys D</creator><general>American Chemical Society</general><scope>BSCLL</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>7X8</scope></search><sort><creationdate>198305</creationdate><title>Synthesis and antihypertensive activity of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones</title><author>Clark, Robin D ; Caroon, Joan M ; Kluge, Arthur F ; Repke, David B ; Roszkowski, Adolph P ; Strosberg, Arthur M ; Baker, Stephen ; Bitter, Susan M ; Okada, Marlys D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a352t-7750aec18b5a736b2630f80b53f9e938400974c0c381f0b7bb9eb6bee8f3932d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1983</creationdate><topic>Animals</topic><topic>Hypertension - drug therapy</topic><topic>Male</topic><topic>Oxazines - therapeutic use</topic><topic>Piperidines - therapeutic use</topic><topic>Piperidones - therapeutic use</topic><topic>Rats</topic><topic>Spiro Compounds - therapeutic use</topic><topic>Structure-Activity Relationship</topic><topic>Systole - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Clark, Robin D</creatorcontrib><creatorcontrib>Caroon, Joan M</creatorcontrib><creatorcontrib>Kluge, Arthur F</creatorcontrib><creatorcontrib>Repke, David B</creatorcontrib><creatorcontrib>Roszkowski, Adolph P</creatorcontrib><creatorcontrib>Strosberg, Arthur M</creatorcontrib><creatorcontrib>Baker, Stephen</creatorcontrib><creatorcontrib>Bitter, Susan M</creatorcontrib><creatorcontrib>Okada, Marlys D</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Clark, Robin D</au><au>Caroon, Joan M</au><au>Kluge, Arthur F</au><au>Repke, David B</au><au>Roszkowski, Adolph P</au><au>Strosberg, Arthur M</au><au>Baker, Stephen</au><au>Bitter, Susan M</au><au>Okada, Marlys D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and antihypertensive activity of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1983-05</date><risdate>1983</risdate><volume>26</volume><issue>5</issue><spage>657</spage><epage>661</epage><pages>657-661</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>A series of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones was prepared and evaluated for antihypertensive activity in the spontaneously hypertensive rat (SHR). The basic ring system was prepared in one step by condensation of dilithiated (tert-butoxycarbonyl)aniline (3) with (tert-butoxycarbonyl)piperidinone. Deprotection afforded 6, which was condensed with expoxides or alkyl halides to furnish the title compounds. The most active compound was dl-erythro-4'-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]spiro [4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-one (9), and various modifications of this compound were made in order to elucidate the structure-activity relationships in the series. Preliminary indications are that 9 may act by both central and peripheral mechanisms.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>6842505</pmid><doi>10.1021/jm00359a007</doi><tpages>5</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1983-05, Vol.26 (5), p.657-661 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | ACS Publications; MEDLINE |
| subjects | Animals Hypertension - drug therapy Male Oxazines - therapeutic use Piperidines - therapeutic use Piperidones - therapeutic use Rats Spiro Compounds - therapeutic use Structure-Activity Relationship Systole - drug effects |
| title | Synthesis and antihypertensive activity of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones |
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