Notes
Journal o f Medicinal Chemistry, 1976, Vol. 19, No. 5 721
2,8-Dimethyl-1l-hydroxy-1,2,3,4,5,8,9,10-octahydro-5- Chicago, Ill., for the biological test results. oxo-9-n-pentylbenz[d]indeno[5,6-b]pyran(5) and 3,lO-Dimethyl- 1-hydroxy-3,4,5,7,7,8,9,lO-octahydro-7-oxo-4-n- References and Notes (1) For paper 5, see M. Winn, D. Arendsen, P. Dodge, A. Dren, pentylbenz[d]indeno[4,5-b]pyran (6). Pechmann condensation D. Dunnigan, R. Hallas, K. Hwang, J. Kyncl, Y. Lee, N. of 4.68 g (0.02 mol) of 4 and 3.68 g (0.02 mol) of ethyl 4Plotnikoff, P. Young, H, Zaugg, H. C. Dalzell, and R. K. methyl-2-cyclohexanone-I-carboxylate according to the procedure Razdan, J . Med. Chem. 19, 461 (1976). of Adam8 after 1.5h gave a creamy solid 4 g (57%); mp 183-186" (2) R. Adams, M. Harfenist, and S. Loewe, J. Am. Chem. SOC., (ethyl acetate-petroleum ether). The material showed a single 71, 1624 (1949), and earlier papers. spot on TLC (1:4 ethyl acetate-hexane) but the NMR and GLC (3) G. Leaf, A. R. Todd, and W. Wilkinson, J . Chem. SOC.,185 showed it to be a mixture of 5 and 6 (55:45 by GLC). Anal. (1942), and earlier papers. (C22H3003) C, H. (4) (a) R. Dagirmanjian and E. S. Boyd, J . Pharrnacol. Exp. 11-Hydroxy-1,2,3,4,5,8,9,10-octahydro-9-n-pentyl-2,5,5,8Ther., 135, 25 (1962); (b) H. F. Hardman, E. F. Domino, tetramethylbenz[d]indeno[5,6-b]pyran (8) and 1and M. H. Seevers, Pharmacol. Reu., 23, 295 (1971); (c) F. Hydroxy-3,4,5,7,7,8,9,lO-octahydro-4-n-pentyl-3,7,7,10R. Sidell, J. E. Pless, H. Neitlich, P. Sussman, W. W. tetramethylbenz[d]indeno[4,5-b]pyran (9). Grignard addition Copeland, and V. M. Sim, Proc. SOC.Exp. Biol. Med., 142, with CH3MgI was carried out according to the procedure described 867 (1973); (d) B. Loev, P. E. Bender, F. Dowalo, E. Macko, by us earlierSg I t gave a purple gum which by TLC in 10% and P. J. Fowler, J . Med. Chem., 16, 1200 (1973); (e) L. ether-petroleum ether showed the presence of two spots. The Lemberger, R. McMahon, R. Archer, K. Matsumoto, and material was chromatographed on 150 g of Florisil in petroleum H. Rowe, Clin. Pharrnacol. Ther., 15, 380 (1974). ether and eluted with graded ether (0.5-2%)-petroleum ether ( 5 ) H. S. Aaron and C. P. Ferguson, J . Org. Chem., 33, 684 mixtures. Compound 8 was less polar and came off the column (1968). first. It was recrystallized from petroleum ether as colorless (6) R. A. Archer, D. B. Boyd, P. V. Demarco, I. J. Tyminski, crystals, mp 101-103°, which on keeping become a semisolid. Anal. and N. L. Allinger, J . Am. Chem. SOC.,92, 5200 (1970). (C25H3602) C, H. (7) For details regarding these pharmacological tests, see R. K. The later fractions from the chromatography column furnished Razdan, B. Z. Terris, H. G. Pars, N. P. Plotnikoff, P. W. 9 as colorless crystals (C~HSOH-H~O), mp 104-106". Anal. Dodge, A. T. Dren, J. Kyncl, and P. Somani, J . Med. Chem., (C25H3602) C, H. 19, 454 (1976) (paper 2). Both comDounds 8 and 9 on treatment with BF?.EtlO in (8) R. Adams and B. R. Baker, J . Am. Chem. SOC.,62, 2401 CH2C12 at room temperature gave a mixture containing 8 and 9 (1940). (1:1 by GLC). (9) R. K. Razdan, G. R. Handrick, H. C. Dalzell, J. F. Howes, Acknowledgment. We wish to thank Drs. N. P. M. Winn, N. P. Plotnikoff, P. W. Dodge, and A. T. Dren, J . Med. Chem., 19, 552 (1976) (paper 4). Plotnikoff and J. Kyncl of Abbott Laboratories, North
- -
Preparation of 16a-Alkoxy and 16a-Acyloxy Derivatives of 21-Chloro-l7-acyloxy Corticosteroids and Determination of Their Vasoconstrictor Activities in Humans Christopher M. Cimarusti,' Sam T. Chao, and Leo J. Brannick The Squibb Institute for Medical Research, Princeton, New Jersey 08690. Received September 8, 1975
A number of 16a-alkoxy and 16a-acyloxy derivatives of 21-chloro-17-acyloxy corticosteroids have been prepared. The synthetic routes used were (a) reaction of the 16a,l7-disubstituted 21-mesylate with lithium chloride and (b) reaction of the 16a-substituted 17,21-cyclicortho ester with triphenylmethyl chloride. The vasoconstrictor activities in humans exhibited by these compounds were significantly lower than that of a 16P-methyl analogue.
Replacement of the 21-hydroxyl group of certain corHydrolysis of ortho ester 3b gave a mixture containing ticosteroids with a C1 atom had led to the synthesis of large amounts of the corresponding 17,21-diol21-acetate clinically useful, topical antiinflammatory agents, for (TLC analysis) and was not preparatively useful. Vitali example, 21-chloro-9-fluoro-ll/3-hydroxy-l6/3-methyl- and Gardi5 noted a similar disparity between ortho17-(propanoy1oxy)pregna-14-diene-3,20-dione (1,clobetasol pentanoate and orthoacetate hydrolysis, but the effect here propionate)' and 21-chloro-9-fluoro-ll~-hydroxy-2',2'- seems more pronounced. dimethylpregn-Ceno[16a,17-d][ 1,3]dioxolane-3,20-dione Rather than explore alternate procedures6for hydrolysis, (2, halcinonide).2 In order to explore further the relawe chose to apply the elegant conversion of ortho esters tionship between structure and topical antiinflammatory to esters of chlorohydrins utilized by Newman and Chen.7 activity, we undertook to prepare 16a-acyloxy and 16aReaction of the 16-unsubstituted ortho ester 6a with alkoxy derivatives of 21-chloro-17-acyloxycorticoids. This triphenylmethyl chloride in refluxing dichloromethane gave the 21-chloro-17-pentanoate 7a in 27% yield. This note describes the preparation of such derivatives and the determination of their vasoconstrictor3activity in humans. material was identical with a sample prepared via the Chemistry. Hydrolysis of ortho ester 3a (prepared from 21-mesylate.~ the known 16cu-methoxy-17,21-dio14by the standard Application of this method to the ortho esters listed in procedure5) to the 17-ester 4a was complicated by the Table I gave the desired 21-chloro 17-esters in the indiformation of by-products (21-ester and 17,21-diol). After cated yields (of analytically pure, TLC homogeneous chromatography and recrystallization, 4a was obtained in material). Hydrolysis of 9d with potassium carbonate in 31.6% yield. Conversion of 4a to the 21-chloro derivative methanol at 0' gave the parent 21-chloro-ll/3,l6cu,l7-triol, 5a was accomplished via the 21-mesylate. thus establishing unambiguously the assigned structure.
722 Journal of Medicinal Chemistry, 1976, Vol. 19, No. 5
Notes
Table I. 1 6-Substituted ~ 21-Chloro 17-Esters
v ''OR'
/
0
8
9
8
9
Yield: % Mp, "C R R' Yield,b % Mp,"C [aID (CHCl,), deg 10.8 240-242 +92.6 (c 0.57) a 27.5 247-250 CH3 CH, b 43.9 240-241 CH, CH,CH, 37.7 229-230 +41.0 (c 0.63) C 31.0 272-273 CH3(A1*4) CH,W 39.4 296-298 +08.3 (c 0.90)c d 38.6 272-274 CH,CH,( A'*4) CH,W 24.6 285-287 +08.8 (c 0.79) Yield of ortho ester after crystallization from acetone-hexane (prepared as described for 3a and purified by column chromatography on silica gel). Combustion analyses (C, H, C1, F) were within +0.3% of the calculated value for these compounds. Solvent, chloroform-methanol (9:1).
LI
I
HO a
-
-
o
1lo and halcinonide2exhibit activity at least equivalent to BMV in the vasoconstrictor assay. The loss of vasoconstrictor activity that attends the replacement of a l6P-methyl group with a 16a-alkoxy or -acyloxy group in these compounds is dramatic. Since 2 1-chloro-16a,l7-acetonides and 21-chloro- 16unsubstituted 17-esters, such as 7,11also display good vasoconstrictor activity, this lack of activity is unexpected. Perhaps conformational restraints imposed by the 17-ester and 16a,l7-acetonide moieties on the D ring and side chain are compatible with activity, whereas perturbation of such conformations by 16a-dkoxy or -acyloxy groups diminishes activity.
Experimental Section Melting points were determined in open capillaries and are uncorrected. Infrared (mineral oil, Perkin-Elmer 137),NMR (CDC13, Perkin-Elmer R-12B),and mass spectra (70eV,
