Pergamon Bioorganic & Medicinal Chemistry Letters 9 (1999) 2621-2624 B1OORGANIC & MEDICINAL CHEMISTRY LETrERS INVESTIGATION OF THE 4-O-ALKYLAMINE SUBSTITUENT OF NON-PEPTIDE QUINOLONE GnRH RECEPTOR ANTAGONISTS Robert J. DeVita, *a Mark T. Goulet,a Matthew J. Wyvratt,a Michael H. Fisher,a Jane-L. Lo, b Yi Tien Yang,b Kang Chengb and Roy G. Smithb Departments of aMedicinal Chemistry and bBiochemistry and Physiology Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065-0900, U.S.A. Received 23 June 1999; accepted 3 August 1999 Abstract: Synthesis and in vitro activity of the enantiomers of quinolone GnRH antagonist (+)-1 are reported. Chiral amino alcohols were prepared from the appropriate cyclic D- or L-amino acids by the Arndt-Eistert homologation followed by reduction of the resulting esters. Incorporation of these pharmacophores was achieved via a novel Mitsunobu alkylation of 4-hydroxyquinolones. The key amine pharmacophore for binding to the rat GnRH receptor was most active in the S-configuration. Ring size was not important for potency with 4, 5, 6, and 7-membered ring amines exhibiting similar potency. © 1999ElsevierScienceLtd. All rights reserved. Introduction: In the previous letter, 1we described the identification of a novel 1H-quinolone structure as a GnRH receptor antagonist and the intial structure activity relationships of this non-peptide lead class. Modifications of the lead established that key substitutions of the 6- and 7-positions of the quinolone core, 3,5-dimethylphenyl group at the 3-position and 2-ethylpiperidine at the 4-position resulted in a potent non- peptide antagonist of the rat GnRH receptor (compound 1, IC50 = 32nM). In this letter, we describe the synthesis of both enantiomers of compound 1 and related analogs and their evaluation as antagonists of the rat GnRH receptor. H•']N-CH 3 CH3 H (+_)-1 rat GnRH Binding ICs0 = 32nM Chemistry: Enantiospecific synthesis of the desired protected 2-piperidinethanols was achieved using the Arndt-Eistert homologation 2 as outlined in Scheme 1. N-BOC Protected (L)-pipecolic acid (2) was converted to the diazoketone by formation of the mixed anhydride followed by addition of excess ethereal diazomethane. The resulting ketone was purified on silica gel and rearranged by treatment with Ag(I)benzoate and triethylamine in methanol to afford the N-BOC-piperidineacetic acid derivative 3. Simple reduction with lithium aluminium hydride in ether at 0°C gave the desired (S)-alcohol 4. Similarly, this route efficiently provided the R-aminoalcohol 5 from D-pipecolic acid, the (R)- and (S)-pyrrolidine derivatives 6 and 7 from D- and L-proline, respectively, and the (S)-azetidinethanol 8 from (S)-azetidinecarboxylic acid. The rearrangement of the azetidinyl diazoketone was performed at carefully controlled temperatures (-10 °- 0°C) in order to prevent base catalyzed [5-elimination of the N-BOC amine of the azetidineacetic ester, which would result in ring opening of the azetidine. The racemic seven membered ring analog (2-azepinethanol) was prepared based on similar literature precedent3 as outlined in Scheme 2 (eq. 1). Ethyl 2-cyclohexanoneacetate 9 was treated with hydrazoic acid to 0960-894X/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved. PH: S0960-894X(99)00447-3