Nor-statine

Utilizing a postcondensation modification of the Passerini reaction,48 both Banff and workers at Amgen49 recognized the potential for a one-pot, two-step transformation to produce nor-statines with the general structure 104 containing three points of potential diversity. Recognizing their... 

Scheme 13. Application of the Passerini reaction for the preparation of nor-statines. Reagents and conditions (i) 0.1 M solutions in MeOH, 18 h, RT, then PS-TsNHNH2 in CH2C12. (ii) Ten percent trifluoroacetic acid (TFA) in CH2C12. (iii) PS-iV-me thy I morphol i lie in CH2C12.

Scheme 14. Synthetic route to tetrazole analogs of nor-statines using the TMSN3-modified Passerini reaction.

Fig. 12. Representative examples of tetrazole-based nor-statine isosteres.

L. Banfi and co-workers utilized the Passerini three component reaction to prepare a 9600 member hit generation library of nor-statines. " ° These compounds are potential transition state mimetics for the inhibitors of aspartyl proteases. The authors produced the library by starting out from eight A/-Boc-a-aminoaldehydes, twenty isocyanides and sixty carboxylic acids. The key Passerini reaction occurred under mild conditions. This transformation was followed by removal of the Boc protecting group and acyl transfer. Three representative examples of the library are shown. 

K. Izuka, T. Kamijo, T. Kubota, K. Akahane, H. Umeyama, and Y. Kiso. J. Med. Chem., 31, 701 (1988). New Human Renin Inhibitors Containing an Unnatural Amino Acid, Nor-statine. 

Statins interfere with the production of isoprene which is somehow connected with sleep, but there have been neither changes in sleep EEG measures relevant to insomnia nor changes in the quality of sleep (SEDA-13, 1327) (6). However, there has been a report of sleep disturbances (7). 

Daptomycin neither inhibits nor induces CYPs, and there are no important drug-drug interactions. However, caution is recommended when administering daptomycin in conjunction with aminoglycosides or statins because of potential risks of nephrotoxicity and myopathy, respectively. 

The structure of the isopropyl ester of nor-C-statine (952), a statine mimic used in the synthesis of renin inhibitors, suggests that it should be accessible from (/ )-malic acid via alkylation methology. Introduction of the cyclohexylmethyl group (as a benzyl) and differentiation of the carboxyl groups allows selective conversion of the C-4 carboxyl to the desired amino group (Scheme 139) [207]. 

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