Methodology for the preparation of 7α-12α-dihydroxy-3β- (2) and 7α,12α-dihydroxy-3α-(2-hydroxyethoxy)-5β-cholanic acid (3) is described. Nucleophilic displacement of the 3-mesylate of unprotected cholic acid with ethylene glycol led to the 3β-isomer whereas the 3α-isomer was synthesized via the 7,12-diacetyl protected 3-allyl ether of methyl cholate. Only the 3α-isomer 3 is recognized by the ileal bile acid transport system with affinity comparable to cholic acid.

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A group of 43 optically active sodium carboxylates (11a-qq and the corresponding lactones 4 were prepared from respective phenols 8 according to Schemes I-III. Phenols 8 were synthesized from commercially available compounds according to Schemes IV-IX. A number of these HMG-CoA reductase inhibitors 11 exceeded mevinolin's activity in vitro (Tables II and III). Selected lactones 4 effectively inhibited hepatic "de novo" cholesterol synthesis in rats in vivo (Table IV). After po administration to rabbits, 4ff(11ff), 4hh, and notably 11jj reduced plasma cholesterol levels more potently than mevinolin (Table V). Whereas 4ff(11ff) displayed the slight superiority expected according to in vitro data, 4hh and 11jj were considerably more potent than expected. Each of these compounds had only moderate activity after po administration to dogs (Table VI). Compound di-11ii, a hybrid of the structural elements of probucol and HMG-CoA reductase inhibitors, after po administration to rats decreased serum lipoproteins and increased HDL/LDL ratio better than probucol (Table VII). HMG-CoA reductase inhibitor 11ll and phenolic building blocks 8, notably 8jj and 8kk, inhibited LDL oxidation in vitro (Table VIII). Chemical structure-activity relationships (Table IX) and the pharmacological profile of phenoxy-type inhibitors 11 diverged from those of known HMG-CoA reductase inhibitors.

Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy-6-heptenoic (-heptanoic) acids 2-4 have been synthesized. Extensive exploration of structure-activity relationships led to several compounds exceeding the inhibitory activity of mevinolin (1b) on HMG-CoA reductase, both in vitro and in vivo. First clinical trials with 2i (HR 780) are in preparation.

HR 780 (1) a new HMG-CoA reductase inhibitor has been synthesized stereoselectively starting from L-malic acid. Wittig olefination employing phosphonium halides, phosphonates and phosphane oxides have been investigated.

ChemInformVolume 21, Issue 10 Reviews ChemInform Abstract: Synthesis of Chiral Lipid-Lowering Agents Derived from Natural Products E. BAADER, E. BAADER Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorW. BARTMANN, W. BARTMANN Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorG. BECK, G. BECK Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorA. BERGMANN, A. BERGMANN Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorE. GRANZER, E. GRANZER Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorH. JENDRALLA, H. JENDRALLA Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorB. VON KEREKJARTO, B. VON KEREKJARTO Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorK. KESSELER, K. KESSELER Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorR. KRAUSE, R. KRAUSE Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorET AL. ET AL., ET AL. ET AL. Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this author E. BAADER, E. BAADER Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorW. BARTMANN, W. BARTMANN Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorG. BECK, G. BECK Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorA. BERGMANN, A. BERGMANN Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorE. GRANZER, E. GRANZER Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorH. JENDRALLA, H. JENDRALLA Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorB. VON KEREKJARTO, B. VON KEREKJARTO Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorK. KESSELER, K. KESSELER Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorR. KRAUSE, R. KRAUSE Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorET AL. ET AL., ET AL. ET AL. Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this author First published: March 6, 1990 https://doi.org/10.1002/chin.199010359Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume21, Issue10March 6, 1990 RelatedInformation

A series of 7-(1H-pyrrol-3-yl)-substituted-3,5-dihydroxyhept-6(E)- enoates (-heptanoates) 1 and 2 have been prepared and tested for inhibiti 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The most potent compounds exceeded mevinolin's activity in vitro and in vivo.

Derivatives of 3-~Noro~scquinoline-4-car-lic acid are easily accessible by potassium pmmnganate oxidation of the corresponding aldehydes.Conditions have been developed for selective reduction, substitution and decar!mxylation reactions leading ta 3-substituted iscqnkoline derivatives with, interesting pharmacological pmputies .m continuation of our efforts to define easily accessible routes to isoqulnoline derivatives with special substitution patterns and interesting phamcological properties we directed our attention to the synthesis of 3-substituted isaquinoline-4-carboxylic acids.We have already reported that 3-chlomisoquinoline-4-carbaldehydes 1 are oxidized in good yield to the corresponding 3-chlomisoquinoline-4-carboxylic acids 2 by the action of potassium pemganate in acetone/water at pH 7 2'3.As the aldehydes 1 are easily accessible f m 1 , 4 ~y d r 0 -3 ( 2 ~) -i s o ~o l i n o n e s 2 , the c ~b q l i c acids 2 constitute very versatile s M i n g materials for further elaboration.Schene 1 illustrates xme of the oppartunities starting fron 3-cNoro-l-phenylisoquinoline-4-carwlic acid &.Scheme 1 COOH 2a -COOH 3 -COOH 10 -8 CONR', -Received, 2 4 t h October, 1 9 8 8 l-Phenyl-3-Ipi~razin-l-yl)-5,6,7,8-tetrahvdmi-inoline ( 1 8 ) .Tkis c a p u n d is Obtained frm by the procedure described above for the synthesis o f g.

ChemInformVolume 20, Issue 20 Natural Products ChemInform Abstract: Synthesis of (8RS,9SR,11RS,13E,15R)-(.+-.)-1,2,3,4-Tetranor-9,11,15-trihydroxy-16,16-dimethy# l-18-oxa-13-prostenic Acid. W. BARTMANN, W. BARTMANN Hoechst AG, D-6230 Frankfurt/M. 80Search for more papers by this authorG. BECK, G. BECK Hoechst AG, D-6230 Frankfurt/M. 80Search for more papers by this authorW. FEHLHABER, W. FEHLHABER Hoechst AG, D-6230 Frankfurt/M. 80Search for more papers by this authorJ. PROTIVA, J. PROTIVA Hoechst AG, D-6230 Frankfurt/M. 80Search for more papers by this author W. BARTMANN, W. BARTMANN Hoechst AG, D-6230 Frankfurt/M. 80Search for more papers by this authorG. BECK, G. BECK Hoechst AG, D-6230 Frankfurt/M. 80Search for more papers by this authorW. FEHLHABER, W. FEHLHABER Hoechst AG, D-6230 Frankfurt/M. 80Search for more papers by this authorJ. PROTIVA, J. PROTIVA Hoechst AG, D-6230 Frankfurt/M. 80Search for more papers by this author First published: May 16, 1989 https://doi.org/10.1002/chin.198920312Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume20, Issue20May 16, 1989 RelatedInformation

ChemInformVolume 20, Issue 17 Reviews ChemInform Abstract: New Developments in Diastereoselective Synthesis of Drugs Derived from Natural Products W. BARTMANN, W. BARTMANN Hoechst AG, D-6230 Frankfurt/M.Search for more papers by this authorG. BECK, G. BECK Hoechst AG, D-6230 Frankfurt/M.Search for more papers by this authorR. GEIGER, R. GEIGER Hoechst AG, D-6230 Frankfurt/M.Search for more papers by this authorR. HENNING, R. HENNING Hoechst AG, D-6230 Frankfurt/M.Search for more papers by this authorV. TEETZ, V. TEETZ Hoechst AG, D-6230 Frankfurt/M.Search for more papers by this authorH. URBACH, H. URBACH Hoechst AG, D-6230 Frankfurt/M.Search for more papers by this author W. BARTMANN, W. BARTMANN Hoechst AG, D-6230 Frankfurt/M.Search for more papers by this authorG. BECK, G. BECK Hoechst AG, D-6230 Frankfurt/M.Search for more papers by this authorR. GEIGER, R. GEIGER Hoechst AG, D-6230 Frankfurt/M.Search for more papers by this authorR. HENNING, R. HENNING Hoechst AG, D-6230 Frankfurt/M.Search for more papers by this authorV. TEETZ, V. TEETZ Hoechst AG, D-6230 Frankfurt/M.Search for more papers by this authorH. URBACH, H. URBACH Hoechst AG, D-6230 Frankfurt/M.Search for more papers by this author First published: April 25, 1989 https://doi.org/10.1002/chin.198917361Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume20, Issue17April 25, 1989 RelatedInformation