I kmethylation Studies. VII.
A Unique Ett'ec-t of' the N-Cyclopropyl Group in a New Series of Inhibitors of Oxidative Ylicrosomal Demethylation
?HCH.CHJHR
R = Me b. R = cyclopropyl c. R = H
2a.
111 the\? studies it was found that while 2a wab demethylated much more SIOIV~J than the corresponding tertiary amine,h2a appeared to ha ,.e higher dfiriit\ tor t h r rnz! mc aiid to ha\.e : ~ i iinhibitory effect. In order to t b s p l o i t thih lead, :i number of :~ii:~log.of 2a 1i:tb.e been p w p a r d arid their : i c t i r i t \ a. 01 i7tio de' inhibitor. ha. br.c.11 itutlied. Theye itudiri. I\ hich : t r ~devmbt4 brlon , lrd to tht. d i ~ c o w r \ ot i~ rivw i i i z w h microwimil inhibitor, t h c .Y-cycloprop~I :triulog 2b, nhich \va- mort. potent than a i i i ot thc 111hibitor5 ho far r e p o r t d . Experimental Section Compounds.--The c.onipourids \\-ere prepai,ed hy staiidard iahoratory pi.oc.edrirel and purified h y re tallizatioii of the EIC'I .-:iltii. h l l of them gave a single spot w chromatographed I :I> the free baqe) on d i m gel i r i a system of CaHa ( 4 parts) and I800; 0 = inactive at any dose. Activity [E. J. Cragoe, Jr., 0. W. Woltersdorf, Jr., J. E. Baer, and J. M.Sprague, J. Med. C h e m , 5 , 896 (1962)l is based upon increase in urinary electrolyte and volume over controlvalues referred to standards: $3 = activity of 100 mg/kg hydrochlorothiazide; + 2 = activity of 100mg/kgof chlorothiazide, 0 = controls. Compounds with activities betweeii chlorothiazide and controls are scored +1 or +. e J. B. Bicking, C. XI. Robb, S. F. Kwong, and E. J. Cragoe, Jr., J . W e d . Chem., 10,598 (1967). See ref 1. 0 K. L. Shepard, J. W. Mason, 0. W. Woltersdorf, Jr., J. H. Jones, and E. J. Cragoe, Jr., J . Mcd. Chem., 12, 280 (1969). (1
3
The basis for the effect of cyclopropyl substitution in the two series of microsomal inhibitors remains obscure. The effect is not simply the effect of branching on the a-C since the i-Pr compound is no more active than n-Pr. The electron-attracting properties of cyclopropyl would be expected to lower the pK, of the amine. However, this effect alone cannot explain the unique effect of cyclopropyl since other electron-withdrawing groups such as benzyl, allyl, and dimethylpropargy18 have a very minimal effect. A number of other workersg (8)R. E. McMahon and K. R. Easton, J . M e d . Pharm. Chem., 4, 437 (1961). (9) A. Burger, R. T. Standridge, and E. J. Ariens, ibid., 6 , 221 (1963); J. Mills, R . Tiattail, I. H. Slater, and R .W.FtilIer,
