Synthesis and evaluation of antiinflammatory activities of a series of corticosteroid 17α-esters containing a functional group
A series of 21-desoxy-21-chlorocorticosteroids that contain a functionalized ester group at 17 alpha has been prepared and examined to separate their systemic activity from topical antiinflammatory activity. Introduction of the functionalized ester group at 17 alpha was carried out by an acid-cataly...
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| Veröffentlicht in: | Journal of medicinal chemistry 1991-08, Vol.34 (8), p.2468-2473 |
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| container_end_page | 2473 |
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| container_issue | 8 |
| container_start_page | 2468 |
| container_title | Journal of medicinal chemistry |
| container_volume | 34 |
| creator | UENO, H MARUYAMA, A MIYAKE, M NAKAO, E NAKAO, K UMEZU, K NITTA, I |
| description | A series of 21-desoxy-21-chlorocorticosteroids that contain a functionalized ester group at 17 alpha has been prepared and examined to separate their systemic activity from topical antiinflammatory activity. Introduction of the functionalized ester group at 17 alpha was carried out by an acid-catalyzed formation of cyclic ortho esters with 17 alpha,21-hydroxyl groups of corticosteroids and subsequent acid-catalyzed hydrolysis. As for the functional group, chloro, methoxy, acetoxy, cyano, cyclopropyl, or alkoxycarbonyl group was introduced at the terminal carbon atom of the 17 alpha-alkanoate group. The topical antiinflammatory activity and systemic activity of these compounds were examined and found to be significantly dependent on the functionalities in the 17 alpha-esters. Among these derivatives, a series of 17 alpha-(alkoxycarbonyl)alkanoates (17 alpha-OCO(CH2)nCOOR) showed an excellent separation of the systemic activity from topical activity. The effects of the number of methylene groups (n) and of the alkyl groups of the ester (R) on either topical or systemic activity of the corticosteroid derivatives were also investigated. |
| doi_str_mv | 10.1021/jm00112a023 |
| format | Article |
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Introduction of the functionalized ester group at 17 alpha was carried out by an acid-catalyzed formation of cyclic ortho esters with 17 alpha,21-hydroxyl groups of corticosteroids and subsequent acid-catalyzed hydrolysis. As for the functional group, chloro, methoxy, acetoxy, cyano, cyclopropyl, or alkoxycarbonyl group was introduced at the terminal carbon atom of the 17 alpha-alkanoate group. The topical antiinflammatory activity and systemic activity of these compounds were examined and found to be significantly dependent on the functionalities in the 17 alpha-esters. Among these derivatives, a series of 17 alpha-(alkoxycarbonyl)alkanoates (17 alpha-OCO(CH2)nCOOR) showed an excellent separation of the systemic activity from topical activity. 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Introduction of the functionalized ester group at 17 alpha was carried out by an acid-catalyzed formation of cyclic ortho esters with 17 alpha,21-hydroxyl groups of corticosteroids and subsequent acid-catalyzed hydrolysis. As for the functional group, chloro, methoxy, acetoxy, cyano, cyclopropyl, or alkoxycarbonyl group was introduced at the terminal carbon atom of the 17 alpha-alkanoate group. The topical antiinflammatory activity and systemic activity of these compounds were examined and found to be significantly dependent on the functionalities in the 17 alpha-esters. Among these derivatives, a series of 17 alpha-(alkoxycarbonyl)alkanoates (17 alpha-OCO(CH2)nCOOR) showed an excellent separation of the systemic activity from topical activity. The effects of the number of methylene groups (n) and of the alkyl groups of the ester (R) on either topical or systemic activity of the corticosteroid derivatives were also investigated.</description><subject>Administration, Topical</subject><subject>Adrenal Cortex Hormones - chemical synthesis</subject><subject>Adrenal Cortex Hormones - metabolism</subject><subject>Adrenal Cortex Hormones - therapeutic use</subject><subject>Alicyclic compounds, terpenoids, prostaglandins, steroids</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents - chemical synthesis</subject><subject>Anti-Inflammatory Agents - metabolism</subject><subject>Anti-Inflammatory Agents - therapeutic use</subject><subject>Chemical Phenomena</subject><subject>Chemistry</subject><subject>Croton Oil</subject><subject>Edema - drug therapy</subject><subject>Esterification</subject><subject>Exact sciences and technology</subject><subject>Granuloma - chemically induced</subject><subject>Granuloma - drug therapy</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>Organic chemistry</subject><subject>Otitis - chemically induced</subject><subject>Otitis - drug therapy</subject><subject>Preparations and properties</subject><subject>Rats</subject><subject>Rats, Inbred Strains</subject><subject>Receptors, Glucocorticoid - metabolism</subject><subject>Steroids</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1991</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kDtPwzAUhS0EKqUwMSNlYA34-pHHiCpeUiUGYK5uXLu4SpzIdipl4jfxR_hNpBAx3cd3zhkOIZdAb4AyuN01lAIwpIwfkTlIRlNRUHFM5pQylrKM8VNyFsKOUsqB8RmZQZFLLvicfL4OLn7oYEOCbpPoPdY9Rtu6pDXjJ1rrTI1Ng7H1Q4Iq2r2NVodfnATtp121PlrVhqh9azcJ5N9fqT5cYUQuonXWbUeH6Z06xGOdbH3bd-fkxGAd9MU0F-T94f5t-ZSuXh6fl3ertGNcxlRntMyQV7KETArDjWImM1pWYAojdcmMxKLKYSyirASCEoXQUBgoJMtzqfiCXP3ldn3V6M2687ZBP6ynIkZ-PXEMCmvj0Skb_mWizCgrc_4DsUlvPw</recordid><startdate>19910801</startdate><enddate>19910801</enddate><creator>UENO, H</creator><creator>MARUYAMA, A</creator><creator>MIYAKE, M</creator><creator>NAKAO, E</creator><creator>NAKAO, K</creator><creator>UMEZU, K</creator><creator>NITTA, I</creator><general>American Chemical Society</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>19910801</creationdate><title>Synthesis and evaluation of antiinflammatory activities of a series of corticosteroid 17α-esters containing a functional group</title><author>UENO, H ; MARUYAMA, A ; MIYAKE, M ; NAKAO, E ; NAKAO, K ; UMEZU, K ; NITTA, I</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p235t-e6096a3b591654f3fc2f6fe5b1f8f5e92f5a8b710019b4a1c484e18f1852775c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1991</creationdate><topic>Administration, Topical</topic><topic>Adrenal Cortex Hormones - chemical synthesis</topic><topic>Adrenal Cortex Hormones - metabolism</topic><topic>Adrenal Cortex Hormones - therapeutic use</topic><topic>Alicyclic compounds, terpenoids, prostaglandins, steroids</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents - chemical synthesis</topic><topic>Anti-Inflammatory Agents - metabolism</topic><topic>Anti-Inflammatory Agents - therapeutic use</topic><topic>Chemical Phenomena</topic><topic>Chemistry</topic><topic>Croton Oil</topic><topic>Edema - drug therapy</topic><topic>Esterification</topic><topic>Exact sciences and technology</topic><topic>Granuloma - chemically induced</topic><topic>Granuloma - drug therapy</topic><topic>Liver - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>Organic chemistry</topic><topic>Otitis - chemically induced</topic><topic>Otitis - drug therapy</topic><topic>Preparations and properties</topic><topic>Rats</topic><topic>Rats, Inbred Strains</topic><topic>Receptors, Glucocorticoid - metabolism</topic><topic>Steroids</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>UENO, H</creatorcontrib><creatorcontrib>MARUYAMA, A</creatorcontrib><creatorcontrib>MIYAKE, M</creatorcontrib><creatorcontrib>NAKAO, E</creatorcontrib><creatorcontrib>NAKAO, K</creatorcontrib><creatorcontrib>UMEZU, K</creatorcontrib><creatorcontrib>NITTA, I</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>UENO, H</au><au>MARUYAMA, A</au><au>MIYAKE, M</au><au>NAKAO, E</au><au>NAKAO, K</au><au>UMEZU, K</au><au>NITTA, I</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and evaluation of antiinflammatory activities of a series of corticosteroid 17α-esters containing a functional group</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J Med Chem</addtitle><date>1991-08-01</date><risdate>1991</risdate><volume>34</volume><issue>8</issue><spage>2468</spage><epage>2473</epage><pages>2468-2473</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of 21-desoxy-21-chlorocorticosteroids that contain a functionalized ester group at 17 alpha has been prepared and examined to separate their systemic activity from topical antiinflammatory activity. Introduction of the functionalized ester group at 17 alpha was carried out by an acid-catalyzed formation of cyclic ortho esters with 17 alpha,21-hydroxyl groups of corticosteroids and subsequent acid-catalyzed hydrolysis. As for the functional group, chloro, methoxy, acetoxy, cyano, cyclopropyl, or alkoxycarbonyl group was introduced at the terminal carbon atom of the 17 alpha-alkanoate group. The topical antiinflammatory activity and systemic activity of these compounds were examined and found to be significantly dependent on the functionalities in the 17 alpha-esters. Among these derivatives, a series of 17 alpha-(alkoxycarbonyl)alkanoates (17 alpha-OCO(CH2)nCOOR) showed an excellent separation of the systemic activity from topical activity. The effects of the number of methylene groups (n) and of the alkyl groups of the ester (R) on either topical or systemic activity of the corticosteroid derivatives were also investigated.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>1875343</pmid><doi>10.1021/jm00112a023</doi><tpages>6</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1991-08, Vol.34 (8), p.2468-2473 |
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| subjects | Administration, Topical Adrenal Cortex Hormones - chemical synthesis Adrenal Cortex Hormones - metabolism Adrenal Cortex Hormones - therapeutic use Alicyclic compounds, terpenoids, prostaglandins, steroids Animals Anti-Inflammatory Agents - chemical synthesis Anti-Inflammatory Agents - metabolism Anti-Inflammatory Agents - therapeutic use Chemical Phenomena Chemistry Croton Oil Edema - drug therapy Esterification Exact sciences and technology Granuloma - chemically induced Granuloma - drug therapy Liver - metabolism Male Mice Molecular Structure Organic chemistry Otitis - chemically induced Otitis - drug therapy Preparations and properties Rats Rats, Inbred Strains Receptors, Glucocorticoid - metabolism Steroids Structure-Activity Relationship |
| title | Synthesis and evaluation of antiinflammatory activities of a series of corticosteroid 17α-esters containing a functional group |
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