J. zyxwvutsrq Med. Chem. zyxwvu 1984,27, zyxwvu 1215-1219 1215 transferred to two 2000-wm silica gel chromatography plates and developed once with 35% EtOAcIhexane. The Rf0.6 band was isolated (0.003 9): NMR (CDC13/Me4Si) 7.45-7.0 (m, 4 H aromatic H), 5.02(s,2 H, methylene), 3.8 (e, 3 H methoxy H); IR (CH2C12) 1780 cm-l (C=O); MS, 179.0578 (parent). Antimicrobial Activity: Minimum Inhibitory Concen- tration. Minimum inhibitory concentration (MIC) for various bacteria was determined by a microplate broth dilution technique. Serial twofold dilutions of the antibiotics were prepared in zyxwvutsr 50 KL of modified brain heart infusion broth medium (reference) in the wells of a microplate. Each well was then inoculated with 50 wL of standardized cell suspension to yield a final concentration of zyxwvu - lo6 viable cells per mililiter of drug-supplemented medium. The microplates were incubated at 37 “C for 20 h, and the MIC was read as the lowest concentration of drug that inhibited the visible growth of the organism. Acknowledgment. We express our appreciation to S. L. Kuentzel for the L1210 assay data, T. F. DeKoning and J. P. McGovren for the P388 in vivo evaluation, and C. W. Ford and K. Stern for the in vivo P. aeruginosa and K. pneumoniae data. Registry No. 1, 39830-70-1; 2, 88057-16-3; 3, 31499-90-8; 6, 33047-12-0; 7, 23091-67-0; 8, 90720-08-4; 9, 90720-09-5; 10, 90720-10-8; 11, 90720-11-9; 12, 90720-12-0; 13, 90720-13-1; 14, 90720-14-2; 15, 90720-15-3; 16, 90720-16-4; 17, 90720-17-5; 18, 90720-18-6; 19,90720-19-7. Synthesis and Pharmacological Evaluation of Indanpropionic Acids as Uterine Relaxant s1 Donald T. Witiak,* Ahmed M. Hassan, Franziska R. Del Vecchio, Richard J. Brumbaugh, and Ralf G. Rahwan Divisions of Medicinal Chemistry and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210. Received November 23, 1983 The PGF2uantagonist 5,6-bis(benzyloxy)-l-oxo-2-propyl-2-indanpropionic acid (1) had previously been shown to provide significant protection against the abortifacient actions of PGFk in mice. To explore further structural concepts in drug design employed for the development of 1, several mono(benzy1oxy) ketones (3-10) and alcohols ( 11-15) as well as a diacid (22) were prepared. None of these structural modifications resulted in compounds of greater superiority to 1 as uterine relaxants and 22 was void of any antagonistic properties, suggesting that the original rationale requiring one carboxyl group and two benzyloxy functions appropriately placed for maximum PGFZa antagonism in this series was a good assumption. A carbonyl rather than hydroxyl group at position C-1 of the indan is most beneficial for reversible antagonism. Reduction of the ketone to the alcohol is of synthetic interest and discussed in some detail. Previous reports2v3 from these laboratories describe our rationale for the design of keto-DIPA [5,6-bis(benzyl- oxy)-l-oxo-Bpropyl-2-indanpropionic acid; 11 as a PGF2a receptor antagonist. Noteworthy, the 15a-hydroxyl group of PGF2a, which is important for its agonist a~tivity,~ is replaced in 1 by a keto function having a juxtaposition to the carboxyl group similar to the juxtaposition of the 15a-hydroxyl function to the carboxyl group of PGF2, but about one staggered ethylene moiety short of the distance between these groups in the proposed “active” hairpin conformation5 of the prostaglandin. Studies in vitro6 confirmed the ability of 1 to block PGFza-induced con- tractions of the isolated uterus with an IC50 of 3.8 X M. Investigations in vivo demonstrated the significant protective effects of 1 against the abortifacient actions of PGF,, in mice,3 as well as the absence of teratogenic ac- ti~ity.~ To explore further structural requirements for anta- gonistic activity in vitro, we prepared bis(benzy1oxy) al- cohol 2, a series of mono(benzy1oxy) ketones (3-10) and alcohols (11-151, and diacid 22. Selected compounds were assessed for their pharmacological activity on the isolated rat uterus. Supported by USPHS Grant HD-14853 from the National Institute of Child Health and Human Development. Witiak, D. T.; Kakodkar, S. V.; Johnson, T. P.; Baldwin, J. R.; Rahwan, R. G. J. Med. Chem. 1979,22, 77-81. Rahwan, R. G.; Del Vecchio, F. R.; Azzolin, G.; Witiak, D. T. Prostaglandins 1983, 25, 519-530. Anderson, N. Ann. N.Y. Acad. Sei. 1971,180, 104. Langs, D. A.; Erman, M.; DeTitta, G. TI Science 1977,197, 1003-1005. Heaslip, R. J.; Rahwan, R. G.; Hassan, A. M. M.; Witiak, D. T. Res. Commun. Chem. Pathol. Pharmacol. 1981,32,251-259. Del Vecchio, F. R.; Rahwan, R. G. Toxicologist 1984, zyxwvuts 4, ab- stract 332. 0022-262318411827-1215$01.50/0 Chemistry. Keto acids 3,4, and 6 were synthesized by using methods similar to those employed in the synthesis of keto acid !l2l6 Reduction of intermediate ester 9 with NaBH4 in MeOH, however, did not afford the desired epimeric indanols 11 but rather two tricyclic compounds 17 (30%) and 18 (50%), which were separated by chro- matography on silica gel using CHC13/i-PrOH (96:4) as eluting solvent. The indan C-1 proton resonance signals for 17 (6 5.38) and 18 (6 4.54) were particularly diagnostic. For lactones, the indan C-1 H resonance signal was con- sistently found to be downfield at approximately 6 5.4. Also, for 18, the additional two-proton resonance signal multiplets (X) bonded to the C a to oxygen appeared at 6 3.5-3.7. The [13C]carbonylresonance signal for 17 ap- peared at 172.4 ppm and the equivalent I3C signal for 18 appeared at 63.5 ppm. Such a difference in chemical shift can be attributed to removal of electronegative oxygen. On the other hand, the C-1 indan 13C resonance signals for 17 and 18 were identical (70.36 ppm). No OH stretching absorption was observed for 18 in the IR. Interestingly, when 17 was subjected to NaBH4/MeOH reduction under conditions similar to those employed in the reduction of 9, a compound of identical Rf (0.34) [silica gel plates (5% hexane in CHC13)]with that of 18 was obtained as well as starting 17 (Rf 0.16). Further work would be necessary to elucidate the pathway of formation of 18 from 17. Thus, 17 may undergo solvolysis to ester 9 serving as intermediate to a diol precursor to 18. Reduction of other esters under similar conditions have previously been reported.1° (8) House, H. 0.; Carlson, R. G.; Muller, H.; Noltes, A. W.; Slater, (9) Chinn, L. J.; Brown, E. A.; Mikulec, R. A.; Garland, R. B. J. (10) House, H. 0.; Barda, H.; Toothill, R. B.; Noltes, A. W. J. Org. C. D. J. Am. Chem. SOC. 1962,84, 2614-2620. Org. Chem. 1962,27, 1733-1741. Chem. 1962,27,4141-4146. 0 1984 American Chemical Society