(Fluorocyclopropyl)quinolones. 2. Synthesis and Stereochemical Structure-Activity Relationships of Chiral 7-(7-Amino-5-azaspiro[2.4]heptan-5-yl)-1-(2-fluorocyclopropyl)quinolone Antibacterial Agents
A series of novel chiral 7-(7-amino-5-azaspiro[2.4]heptan-4-yl)-8-chloro-1-(2-fluo rocyclopropyl)- quinolones were synthesized as a continuation of a research project of 1-(2-fluorocyclopropyl)-quinolones by considering stereochemical and physicochemical properties of the molecule. Absolute configur...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 1994-09, Vol.37 (20), p.3344-3352 |
|---|---|
| Hauptverfasser: | , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 3352 |
|---|---|
| container_issue | 20 |
| container_start_page | 3344 |
| container_title | Journal of medicinal chemistry |
| container_volume | 37 |
| creator | Kimura, Youichi Atarashi, Shohgo Kawakami, Katsuhiro Sato, Kenichi Hayakawa, Isao |
| description | A series of novel chiral 7-(7-amino-5-azaspiro[2.4]heptan-4-yl)-8-chloro-1-(2-fluo rocyclopropyl)- quinolones were synthesized as a continuation of a research project of 1-(2-fluorocyclopropyl)-quinolones by considering stereochemical and physicochemical properties of the molecule. Absolute configurations of the 1-(cis-2-fluorocyclopropyl) moiety and the 7-(7-amino-5-azaspiro-[2.4]heptan-5-yl) moiety were determined by X-ray crystallographic analysis. Stereochemical structure-activity relationship studies indicated that 1-[(1R,2S)-2-fluorocyclopropyl] and 7-[(7S)-amino-5-azaspiro[2.4]heptan-5-yl] derivatives are more potent against Gram-positive and Gram-negative bacteria than the other stereoisomers and 7-[(7S)-7-amino-5-azaspiro[2.4]-heptan-5-yl]-8-chloro-1-[(1R ,2S)-2- fluorocyclopropyl]quinolone (33) is the most potent of all stereoisomers. Pharmacokinetic profiles and physicochemical properties of the selected compounds were also examined, and it was found that 33 (DU-6859a) possesses moderate lipophilicity and good pharmacokinetic profiles. |
| doi_str_mv | 10.1021/jm00046a019 |
| format | Article |
| fullrecord | <record><control><sourceid>acs_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1021_jm00046a019</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>b889226559</sourcerecordid><originalsourceid>FETCH-LOGICAL-a389t-1793de294a8ba0de6e151371abdba1c90f3f885a3fb24881227fe60b7f0d49fc3</originalsourceid><addsrcrecordid>eNp1kVtrFDEUx4Moda0--SzMmyslay5zfRwWq6X1QreCIBLOZBIn68xkTDLF8QP2czWypfigT4dz_j_-54bQc0o2lDD6ej8QQtIcCK0eoBXNGMFpSdKHaEUIY5jljD9GT7zfR4xTxo_QUVFxluVshW7Wp_1snZWL7O3k7LT0r37OZrS9HZXfJGyT7JYxdMobn8DYJrugnLKyU4OR0MfUzTLMTuFaBnNtwpJcqh6CsaPvzOQTq5NtZ1xEC7wucD1Eb5xh-A1-Ms5-ZZv0W6emAGOsxuaY4jXD-v9DJfUYTAMyzmGia_1djcE_RY809F49u4vH6PPpm6vtO3zx8e3Ztr7AwMsqYBr3bhWrUigbIK3KFc0oLyg0bQNUVkRzXZYZcN2wtCwpY4VWOWkKTdq00pIfo5ODr3TWe6e0mJwZwC2CEvHnGeKvZ0T6xYGe5mZQ7T17d_2o44NufFC_7mVwP0Re8CITV592glx-eP-FsJ04j_zLAw_Si72d3Rh3_WfnWxfYpEs</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>(Fluorocyclopropyl)quinolones. 2. Synthesis and Stereochemical Structure-Activity Relationships of Chiral 7-(7-Amino-5-azaspiro[2.4]heptan-5-yl)-1-(2-fluorocyclopropyl)quinolone Antibacterial Agents</title><source>ACS Publications</source><source>MEDLINE</source><creator>Kimura, Youichi ; Atarashi, Shohgo ; Kawakami, Katsuhiro ; Sato, Kenichi ; Hayakawa, Isao</creator><creatorcontrib>Kimura, Youichi ; Atarashi, Shohgo ; Kawakami, Katsuhiro ; Sato, Kenichi ; Hayakawa, Isao</creatorcontrib><description>A series of novel chiral 7-(7-amino-5-azaspiro[2.4]heptan-4-yl)-8-chloro-1-(2-fluo rocyclopropyl)- quinolones were synthesized as a continuation of a research project of 1-(2-fluorocyclopropyl)-quinolones by considering stereochemical and physicochemical properties of the molecule. Absolute configurations of the 1-(cis-2-fluorocyclopropyl) moiety and the 7-(7-amino-5-azaspiro-[2.4]heptan-5-yl) moiety were determined by X-ray crystallographic analysis. Stereochemical structure-activity relationship studies indicated that 1-[(1R,2S)-2-fluorocyclopropyl] and 7-[(7S)-amino-5-azaspiro[2.4]heptan-5-yl] derivatives are more potent against Gram-positive and Gram-negative bacteria than the other stereoisomers and 7-[(7S)-7-amino-5-azaspiro[2.4]-heptan-5-yl]-8-chloro-1-[(1R ,2S)-2- fluorocyclopropyl]quinolone (33) is the most potent of all stereoisomers. Pharmacokinetic profiles and physicochemical properties of the selected compounds were also examined, and it was found that 33 (DU-6859a) possesses moderate lipophilicity and good pharmacokinetic profiles.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00046a019</identifier><identifier>PMID: 7932562</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Anti-Infective Agents - chemical synthesis ; Anti-Infective Agents - pharmacokinetics ; Anti-Infective Agents - pharmacology ; Chemical Phenomena ; Chemistry, Physical ; Crystallography, X-Ray ; Fluoroquinolones ; Gram-Negative Bacteria - drug effects ; Gram-Positive Bacteria - drug effects ; Molecular Conformation ; Molecular Structure ; Quinolones - chemical synthesis ; Quinolones - pharmacokinetics ; Quinolones - pharmacology ; Rats ; Spiro Compounds - chemical synthesis ; Spiro Compounds - pharmacokinetics ; Spiro Compounds - pharmacology ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1994-09, Vol.37 (20), p.3344-3352</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a389t-1793de294a8ba0de6e151371abdba1c90f3f885a3fb24881227fe60b7f0d49fc3</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/jm00046a019$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00046a019$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7932562$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kimura, Youichi</creatorcontrib><creatorcontrib>Atarashi, Shohgo</creatorcontrib><creatorcontrib>Kawakami, Katsuhiro</creatorcontrib><creatorcontrib>Sato, Kenichi</creatorcontrib><creatorcontrib>Hayakawa, Isao</creatorcontrib><title>(Fluorocyclopropyl)quinolones. 2. Synthesis and Stereochemical Structure-Activity Relationships of Chiral 7-(7-Amino-5-azaspiro[2.4]heptan-5-yl)-1-(2-fluorocyclopropyl)quinolone Antibacterial Agents</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of novel chiral 7-(7-amino-5-azaspiro[2.4]heptan-4-yl)-8-chloro-1-(2-fluo rocyclopropyl)- quinolones were synthesized as a continuation of a research project of 1-(2-fluorocyclopropyl)-quinolones by considering stereochemical and physicochemical properties of the molecule. Absolute configurations of the 1-(cis-2-fluorocyclopropyl) moiety and the 7-(7-amino-5-azaspiro-[2.4]heptan-5-yl) moiety were determined by X-ray crystallographic analysis. Stereochemical structure-activity relationship studies indicated that 1-[(1R,2S)-2-fluorocyclopropyl] and 7-[(7S)-amino-5-azaspiro[2.4]heptan-5-yl] derivatives are more potent against Gram-positive and Gram-negative bacteria than the other stereoisomers and 7-[(7S)-7-amino-5-azaspiro[2.4]-heptan-5-yl]-8-chloro-1-[(1R ,2S)-2- fluorocyclopropyl]quinolone (33) is the most potent of all stereoisomers. Pharmacokinetic profiles and physicochemical properties of the selected compounds were also examined, and it was found that 33 (DU-6859a) possesses moderate lipophilicity and good pharmacokinetic profiles.</description><subject>Animals</subject><subject>Anti-Infective Agents - chemical synthesis</subject><subject>Anti-Infective Agents - pharmacokinetics</subject><subject>Anti-Infective Agents - pharmacology</subject><subject>Chemical Phenomena</subject><subject>Chemistry, Physical</subject><subject>Crystallography, X-Ray</subject><subject>Fluoroquinolones</subject><subject>Gram-Negative Bacteria - drug effects</subject><subject>Gram-Positive Bacteria - drug effects</subject><subject>Molecular Conformation</subject><subject>Molecular Structure</subject><subject>Quinolones - chemical synthesis</subject><subject>Quinolones - pharmacokinetics</subject><subject>Quinolones - pharmacology</subject><subject>Rats</subject><subject>Spiro Compounds - chemical synthesis</subject><subject>Spiro Compounds - pharmacokinetics</subject><subject>Spiro Compounds - pharmacology</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1994</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kVtrFDEUx4Moda0--SzMmyslay5zfRwWq6X1QreCIBLOZBIn68xkTDLF8QP2czWypfigT4dz_j_-54bQc0o2lDD6ej8QQtIcCK0eoBXNGMFpSdKHaEUIY5jljD9GT7zfR4xTxo_QUVFxluVshW7Wp_1snZWL7O3k7LT0r37OZrS9HZXfJGyT7JYxdMobn8DYJrugnLKyU4OR0MfUzTLMTuFaBnNtwpJcqh6CsaPvzOQTq5NtZ1xEC7wucD1Eb5xh-A1-Ms5-ZZv0W6emAGOsxuaY4jXD-v9DJfUYTAMyzmGia_1djcE_RY809F49u4vH6PPpm6vtO3zx8e3Ztr7AwMsqYBr3bhWrUigbIK3KFc0oLyg0bQNUVkRzXZYZcN2wtCwpY4VWOWkKTdq00pIfo5ODr3TWe6e0mJwZwC2CEvHnGeKvZ0T6xYGe5mZQ7T17d_2o44NufFC_7mVwP0Re8CITV592glx-eP-FsJ04j_zLAw_Si72d3Rh3_WfnWxfYpEs</recordid><startdate>19940901</startdate><enddate>19940901</enddate><creator>Kimura, Youichi</creator><creator>Atarashi, Shohgo</creator><creator>Kawakami, Katsuhiro</creator><creator>Sato, Kenichi</creator><creator>Hayakawa, Isao</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></search><sort><creationdate>19940901</creationdate><title>(Fluorocyclopropyl)quinolones. 2. Synthesis and Stereochemical Structure-Activity Relationships of Chiral 7-(7-Amino-5-azaspiro[2.4]heptan-5-yl)-1-(2-fluorocyclopropyl)quinolone Antibacterial Agents</title><author>Kimura, Youichi ; Atarashi, Shohgo ; Kawakami, Katsuhiro ; Sato, Kenichi ; Hayakawa, Isao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a389t-1793de294a8ba0de6e151371abdba1c90f3f885a3fb24881227fe60b7f0d49fc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1994</creationdate><topic>Animals</topic><topic>Anti-Infective Agents - chemical synthesis</topic><topic>Anti-Infective Agents - pharmacokinetics</topic><topic>Anti-Infective Agents - pharmacology</topic><topic>Chemical Phenomena</topic><topic>Chemistry, Physical</topic><topic>Crystallography, X-Ray</topic><topic>Fluoroquinolones</topic><topic>Gram-Negative Bacteria - drug effects</topic><topic>Gram-Positive Bacteria - drug effects</topic><topic>Molecular Conformation</topic><topic>Molecular Structure</topic><topic>Quinolones - chemical synthesis</topic><topic>Quinolones - pharmacokinetics</topic><topic>Quinolones - pharmacology</topic><topic>Rats</topic><topic>Spiro Compounds - chemical synthesis</topic><topic>Spiro Compounds - pharmacokinetics</topic><topic>Spiro Compounds - pharmacology</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kimura, Youichi</creatorcontrib><creatorcontrib>Atarashi, Shohgo</creatorcontrib><creatorcontrib>Kawakami, Katsuhiro</creatorcontrib><creatorcontrib>Sato, Kenichi</creatorcontrib><creatorcontrib>Hayakawa, Isao</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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kimura, Youichi</au><au>Atarashi, Shohgo</au><au>Kawakami, Katsuhiro</au><au>Sato, Kenichi</au><au>Hayakawa, Isao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>(Fluorocyclopropyl)quinolones. 2. Synthesis and Stereochemical Structure-Activity Relationships of Chiral 7-(7-Amino-5-azaspiro[2.4]heptan-5-yl)-1-(2-fluorocyclopropyl)quinolone Antibacterial Agents</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1994-09-01</date><risdate>1994</risdate><volume>37</volume><issue>20</issue><spage>3344</spage><epage>3352</epage><pages>3344-3352</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>A series of novel chiral 7-(7-amino-5-azaspiro[2.4]heptan-4-yl)-8-chloro-1-(2-fluo rocyclopropyl)- quinolones were synthesized as a continuation of a research project of 1-(2-fluorocyclopropyl)-quinolones by considering stereochemical and physicochemical properties of the molecule. Absolute configurations of the 1-(cis-2-fluorocyclopropyl) moiety and the 7-(7-amino-5-azaspiro-[2.4]heptan-5-yl) moiety were determined by X-ray crystallographic analysis. Stereochemical structure-activity relationship studies indicated that 1-[(1R,2S)-2-fluorocyclopropyl] and 7-[(7S)-amino-5-azaspiro[2.4]heptan-5-yl] derivatives are more potent against Gram-positive and Gram-negative bacteria than the other stereoisomers and 7-[(7S)-7-amino-5-azaspiro[2.4]-heptan-5-yl]-8-chloro-1-[(1R ,2S)-2- fluorocyclopropyl]quinolone (33) is the most potent of all stereoisomers. Pharmacokinetic profiles and physicochemical properties of the selected compounds were also examined, and it was found that 33 (DU-6859a) possesses moderate lipophilicity and good pharmacokinetic profiles.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>7932562</pmid><doi>10.1021/jm00046a019</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1994-09, Vol.37 (20), p.3344-3352 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_crossref_primary_10_1021_jm00046a019 |
| source | ACS Publications; MEDLINE |
| subjects | Animals Anti-Infective Agents - chemical synthesis Anti-Infective Agents - pharmacokinetics Anti-Infective Agents - pharmacology Chemical Phenomena Chemistry, Physical Crystallography, X-Ray Fluoroquinolones Gram-Negative Bacteria - drug effects Gram-Positive Bacteria - drug effects Molecular Conformation Molecular Structure Quinolones - chemical synthesis Quinolones - pharmacokinetics Quinolones - pharmacology Rats Spiro Compounds - chemical synthesis Spiro Compounds - pharmacokinetics Spiro Compounds - pharmacology Stereoisomerism Structure-Activity Relationship |
| title | (Fluorocyclopropyl)quinolones. 2. Synthesis and Stereochemical Structure-Activity Relationships of Chiral 7-(7-Amino-5-azaspiro[2.4]heptan-5-yl)-1-(2-fluorocyclopropyl)quinolone Antibacterial Agents |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T09%3A38%3A44IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-acs_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=(Fluorocyclopropyl)quinolones.%202.%20Synthesis%20and%20Stereochemical%20Structure-Activity%20Relationships%20of%20Chiral%207-(7-Amino-5-azaspiro%5B2.4%5Dheptan-5-yl)-1-(2-fluorocyclopropyl)quinolone%20Antibacterial%20Agents&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Kimura,%20Youichi&rft.date=1994-09-01&rft.volume=37&rft.issue=20&rft.spage=3344&rft.epage=3352&rft.pages=3344-3352&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/jm00046a019&rft_dat=%3Cacs_cross%3Eb889226559%3C/acs_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/7932562&rfr_iscdi=true |