136 Journal o j Nedicinal Chenmtry, 1971, Vol. 14, LYO.2
Lu, KOHEN, AND COUNSELL
8.l Synthesis of 25-ilzadihydrolanosterol and Derivatives'
Hypocholesterolemic Agents.
llL4TTHIAS
c. I,C,
F O R T U N E K O H E N , AND
R. E.
cOUNSELLX.
Laboratory of Xeclzcznal Chemzstry, Collegd o j Pharmacy, Unzverszty oj Nachzgan, Ann Arbor, Xachagan 48104 Recezved June 9, 1970 Continued interest in azasteroids as inhibitors of cholesterogenesis prompted the synthesis of 25-azadihydrolanosterol (3d) and derivatives. This was achieved by ozonolysis of lanosterol acetate Fc-hich afforded the trisiioracid 2a n-hich upon treatment with SOC1, follosed by (CH,),NH and subsequent reduction of the amide 2d gave 3d in good yield. Compound 3d could also be obtained directly by the action of DMF and formic acid on the trisnoraldehyde 5. Compounds 3a and 3c were also prepared for biological testing. Compound 3d ihowed a marked inhibitory effect on the growth and development of tobacco hornworms.
Cholesterol synthesis in the liver of men and mammals is known to be inhibited by exogenous cholesterol in ;L feedback mechanism. I'revious papers in t,his series describe a variet'y of synthet,ic aza- and diazacholesterol analogs3 n-hich were prepared in an effort t o simulate cholesterol in this feedback mechanism. I n addition to the desired inhibit'ion of 3-hydroxy-3-methylglutaryl-coenzyme A reductase* with concomitant decrease in plasma total sterol levels, these azasteroids also inhibited desmosterol reductase.5 Since lanosterol is the init,ial steroid product resulting from tlie cyclization of squalene, it \vas of interest to examine aza analogs of lanosterol not only as possible feedback inhibitors, but also as inhibitors of squalene oxidocyclase. This paper represents a continuation in part of our structureact'ivity relationship studies and describes the synthesis and biological activities of a number of modified nzalanosterol analogs. The most' direct approach to 25azadihydrol:tnosterol (3d) appeared to be ozonolysis of lanosterol acetate (1) n-ith formation of a t'risnoracid (2a) which is suitably functionalized for furt'her transformations. The ozonolysis of lanosterol acetate rixs first reported by Ruzicka.6 The isolation of 2a, liowever, was quite tedious since the product could not be isolated directly from the reaction mixture. ConscquentlF, these worker> resortcd to c1ironi:atograpliy of methyl ester 2b and Pu bse que 11t h ydrol? to the free alcohol of 2a. I n oui' limcls, however, 2a \\-as obtained directly in 857; yield bj- performing the ozonolysis of 1:mosterol acetate it1 * To
ii-lion1 currespondence should be a d d r e s x d . V. V, Ranade, F. Iiolien, a n d R . E . Counsell, J . .Urd.
(1) P a r t 7 . C h c m . , 14, 3 8 .
(2) This Ivork v a s supported by Grants HE-11274 from t h e S a t i o n a l Institutes of Health a n d PR.1-18 from the American Cancer Societs. ( 3 ) (a) I-'. 11. Iilimstra, It. E . Rannoy, a n d R.E . Counsell, J . M e d . Chem., 9 , 7 2 3 11066). (I)) R . E. Counsell. P . D. lilimstra, L . h-,: ' ) : nmr 6 1.25 and 1.30 (C-26 and C-27 hle protons). Lanost-8-ene-3p,245,25-triol 3-Acetate (4c).--HC104 (0,28 .\., 10 ml) was added to a 3oln of the monoeposide 4b (1 g ) i l l iliosaire (100 nil), and the mistiire was stirred a t room temp for 1 1lr prior t o poiiring into I 1 2 0 . The ppt wa3 filtered, dried, from hexaiie-CII~Cl?tu give diol 4c (800 mg): I [alu S43'; 6 1.l.i niid 1.20 (C-26 rtird C-27 ;\le pro iCazHaiOr) C , €1. 3~-Acetoxg-25,26,27-trisnorlanost-8-en-24-al (5).---l'b(Ohcja (h00 m g ) WRS added to a soln of diol 4c (1 g ) in TfIF ( 2 5 mlj, : ~ n d the mixture xi-.stirred at room temp for 1 hr, filtered, and evapd, The residiie was then extd irii o CHC13. The org layer was washed with Sa2S20r w l n aiid R,O, dried, aiid evapd. The residue a a s chroniaiographed oii K w l m neutral AI& (.\ctivity 11). with hexane-Et20 ( 1 : l ) gave the desired aldehyde 5 ( which was crystd from hexane: mi, 144-14*5'; [ a ]+.5,3" ~ (lit.7 mp 144-146'; [ n ] +~3 8 ' ) ; 6 9.72 (t, 111, J = 2 cps, CHO). Leuckart Reductive Amination of 5.--A .mlii of aldehyde 5 (200 mg) in IIMF i l ml) a n d IICOlH (90 , 1 ml) \vas heated at 140" for 2 hi. The mixture \+-:isthcii 1'0 ed, poured into 1120, anti estd i i i t o CHCII. The org layer s-as then washed with SaIICO3 and H 2 0 , dried i31gS04), and evapd. The iesidiie graphed on h120,,and elutioii wiih hexane--I':tpO desired aznlanosterol derivative (120 mg). llecrystil from hexane gave n p r d u c t identical In si1 r c y e c t < with thiit uhtniiied by xcetylatioii of 3d.
Centrally Acting Cyclic Urea, Thiourea, and Their K,N'-Dialkyl Derivatives. Structure-Activity Correlations1" A \ IH.~HUSSAIN'~ ~ ~ ~ AND ERICJ. LIEN" Sciiool of Pharmacy, L'nzverszty of Southein Calzfornzn, Los dngtles, Calzfornza 90007
Received July 27, 1970 Sixteen cyclic urea and thiourea derivatives were synthesized, 12 of which were new compounds and had not been reported previously. Six of the compounds showed potent convulsant activity, 3 showed potent CNS depressant activity, and 7 of them were found to possess potent respiratory stimulation activity. For these compoiinds the respiratory stimulation effect was tested in pentobarbital-depressed mice. The pharmacological activities, LDw, HDa, and CD,, xere correlated with the partition coefficient (log P ) and the dipole moment ( g ) by multiple regresbion analysis using an IBM 360/6.? computer. The correlations obtained indicate that there is a parabolic relationship between the pharmacological activity and the partition coefficient of the congeneric cyclic ureas and thioureas. Inclusion of dipole moment further improves the correlations at the 99 percentile level.
,\Ian;\. of the CXS-acting drugs have amide or t'hioamide linkage :is the conimon niolecular structural unit's.* ' Cyclic urea and t,liiourea derivatives, ~vhicli :tlso have the same st'ructural features, may be expect,ed t o possess C S S activities, although urea and thiourea molecules themselves do not have significant pharmacological activity. It appears that' the pharniacological inertness of urea and thiourea can be attributed to their very high solubility in water and poor solubility in lipid. If appropriate molecular modificat'ions are made on the parent urea and thiourea molecules to raise their lipophilic character, ph:irmacologically active compounds may result. Relationship between biological activity of T o ivliom correspondence shoiild be addressed. 11) (a) Taken i n p a r t from t h e dissertation presented IJY 3Iehdi H . Hussain, .June 1970, t o the Graduate School, IJniversity of Southern California, in partial fulfillment of the requirements for the Doctor of Philosophy Degree. (11) R . A I , and J. L. Converse F u n d Fellon.. (2) .I. Ilurger, "I\Iedicinal Chemistry." 2nd ed, Interscience Publislier.;, 1960. Inc., S e n York, N. 1., 1 3 ) C . 0. \\'ikon, 0 . Gisvold. arid li. E . Lloerge. "Texthook of Organic Medicinal a n d Pharmaceutical Chemistry," 5 t h ed, J . K Ligpincott Co.. I'liiladelpliia, P a . , 1966.
different classej of compounds aiid their lipid solubility has been demonstrated in many case^.^-^ JIeyer and Overton's classical work has been extended by Hansch :ind his co~vorkers.~In T h q have shown that in geriera1 a parabolic relationship exists between the biological activity and partition coefficient of a n-ide variety of compounds. Linear relationship lins been considered only as a special case. Lien and 1iumler1l have reported the CSS xtivities of 3-, G - , and :-membered cyclic ured', thioureas, and their N,N'-dimethyl derivatives. The methylated compounds 11 ere reported to be significantly more potent than the unmethylated ones. Also, they showed a (4) 1%. l l e y e r , A r c h . Exp. Pathol. Pharmakol., 44, 109 (1899). ( 5 ) E . Overton, V z e r t e l i a h ~ e s s c h r.?iatur/orsck. . G e s . Zuerich, 44, 88 (1899;. (6) A . Alhert, "Selective Toxicity," 4th ed, Methuen B C o . , London. 1968.
(7) T. F u j i t a , .J. Iii-asa. and C . Hanscii, J . Amer. Ciiern. Suc.. 86, 5157 (1964). (8) J. Ill-asa, T . Fujita, and C. Iiansch, J . .Wed. Chem., 8 , 160 (1!165), (9) C:. Hansch and T. Fujita, J . Amer. Chem. Sac., 86, 1616 (1961). fl0) E. .J. Lien, C. Hansch, and S. Anderson, J . .?fed. C h e m . , 11, ,430 (1968). (11) E. J. Lien and IY. 11. Kumler, ibzd., 11, 214 (1968).
