J.Med. Chem. 1990,33,509-513 80772-30-1; 21, 80772-32-3; 22, 80772-46-9; 23, 80772-34-5; 24, 80772-35-6; 25, 80772-71-0; 26, 80772-36-7; 27, 80772-22-1; 28, 80772-37-8; 29, 80772-38-9; 30, 80772-39-0; 31, 80772-40-3; 32, 80772-41-4; 33, 80772-25-4; 34, 80772-44-7; 35, 80772-45-8; 36, 80772-24-3; 37, 80772-61-8; 38, 80772-52-7; 39, 123963-99-5; 40, 80772-54-9; 41, 80772-55-0; 42, 80772-59-4; 43, 80772-51-6; 44, 80772-56-1; 45,80772-57-2;46,80772-58-3;cis-hexahydrophthalide,
509
6939-71-5; 2-(hydroxymethyl)pyridine, 586-98-1; N-(a-hydroxyethyl)morpholine, 622-40-2;3-(hydroxymethyl)pyridine,100-55-0; 2-(2-hydroxyethyl)pyridine,103-74-2.
Supplementary Material Available: A table listing 'H N M R data for H6a and HlOa of 6a,b-l3a,b (1page). Ordering information is given on any current masthead page.
Aldosterone Antagonists. 3. Synthesis and Activities of Steroidal 7a-(Alkoxycarbonyl)-15,16-methyleneSpirolactones Klaus Nickisch,* Dieter Bittler, Henry Laurent, Wolfgang Losert, Yukishige Nishino, Ekkehard Schillinger, and Rudolf Wiechert Research Laboratories, Schering AG Berlin and Bergkamen, Miillerstrasse 170-1 78, 0-1000 Berlin 65, West Germany. Received March 16, 1989 Several A- and D-ring substituted steroidal 7a-alkoxycarbonyl spirolactones were synthesized with the purpose of increasing the aldosterone antagonistic potency and reducing the endocrinological side effects relative to the standard drug spironolactone. It was found that the 15&16&methylene derivative 17 exhibited a 2-fold higher aldosterone antagonistic activity compared to either spironolactone or the 15,16-unsubstituted derivative 29 while showing remarkably reduced antiandrogenicity.
In a previous paper of this series,' we described the synthesis and pharmacological activity of some spironolactone derivatives. We have shown that introduction of a 15@,16@-cyclopropane ring in the spironolactone molecule enhances the aldosterone antagonistic activity. The endocrinological side effects are reduced by the introduction of a 1,2-double bond. It was known that the replacement of the 7a-acetylthio moiety by the 7a-alkoxycarbonyl function leads also to potent aldosterone antagonists.2 In this paper we report our results with A- and D-ring substituted 7a-alkoxycarbonylspirolactones in regard to their aldosterone antagonistic and endocrinological activity.
dehydes 9-12 gave the carboxylic acid derivatives 13-16. For the subsequent esterification, three different methods were employed. The methyl esters were prepared by reaction of the carboxylic acids with diazomethane. The higher esters were obtained either by preparing the mixed anhydride with butyl chloroformate followed by reaction with the appropriate alcohol2or directly by reaction of the carboxylic acids with an alkyl halide and silver oxide catalysis. The introduction of the 1,2-double bond was achieved by treatment of the a,@-unsaturated ketones 17-19 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to afford 26-28 (Table 11).
Chemistry Although 7a-alkoxycarbonylsteroids have been prepared previously,H the reported methods result in only low yields under drastic conditions. We therefore sought a mild and efficient synthesis of these compounds. As starting material for our efforts we chose the known double unsaturated ketones 1-4.' By reacting these ketones with diethylaluminum cyanide5 in tetrahydrofuran (THF), a cyano group could be introduced stereoselectively at the 7a-position of the steroid framework in high yields (Scheme I, Table I). In case of the la,2a:15@,16/3-dimethylene derivative 2 the introduction of a 7a-cyano group accessed in higher yields by using potassium cyanide in dimethylformamide. The reduction of the cyano ketones 5-8 with diethylaluminum hydride in THF or dichloromethane led directly to the aldehydes 9-12. These compounds were obtained as mixtures of diastereomeric alcohols at the 3- and 5'-positions and were further transformed without purification. Jones oxidation of al-
Biological Results and Discussion In the 15@,16@-methylene series (17-19), the methyl ester 17 showed clearly the highest aldosterone antagonistic activity exhibiting a 2-fold higher potency than spironolactone (Table 111). On the basis of in vitro experiments, 17-19 have similar affinities for the androgen and progesterone receptors. As it was found in other series,'*6the introduction of a 15/3,16@-methylene moiety led to a remarkable enhancement of the aldosterone antagonistic potency (17 compared to 29). The affinity for the androgen receptor was practically the same, whereas the affinity for the progesterone receptor was increased.
d
O-.,*COOCH3
29 (SC25152)
(1) Nickisch, K.; Bittler, D.; Laurent, H.; Casals-Stenzel,J.; h e r t ,
W.; Nishino, Y.; Schillinger, E.; Wiechert, R. J. Med. Chem. 1987,30, 1403. (2) Weier, R. M.; Hofmann, L. M. J. Med. Chem. 1975, 18, 817. (3) Christiansen, R. G.; Johnson, W. S. Steroids 1963, 1 , 620. (4) Rasmusson, G. H.; Chen, A.; Arth, G. E. J. Org. Chem. 1973, 38, 3670. (5) Nagata, W.; Yoshioka, M.; Murakami, M. J. Am. Chem. SOC. 1972, 94, 4654.
By introduction of a 1,2-doublebond (compounds 26-28) the affinities for the androgen and progesterone receptors were significantly decreased; however, the aldosterone (6) Nickisch, K.; Bittler, D.; Casals-Stenzel, J.; Laurent, H.; Nickolson, R.; Nishino, Y.; Petzoldt, K.; Wiechert, R. J. Med. Chem. 1985,28,546.
0022-2623/90/lS33-0509$02.50/00 1990 American Chemical Society
Nickisch et al.
510 Journal of Medicinal Chemistry, 1990, Vol. 33, No. 2 Scheme I’
1 ‘ R.S ”‘C
2: R’ + R” = CHp; 15P,16P-CH2 3: R ’ = R” = H; 15a,lGa-CH~ 4: R‘
+ R“
N
= CH2; 15a,16a-CH2
’
HO
5 : R’ = R ” = H; 15P,16P-CHp 6: R’ + R ” = CHp; 15P,16P-CHp 7: R ’ = R ” = H; 15a.16u-CH2 8: R’ + R ” = CH2; 15a,l€a-CHp
R’ = R” = H; 15P,16P-CH2
0
b
0 1:
1,
-
R”
+
’ 17: R’ 18: R’ 1 9 R’ 20: R’ 21: R’ 22: R’ 23: R’ 24: R’ 25: R’
“THO
9: R’ = R” = H; 15P,16P-CHp IO: R’ + R” = CHp; 15P.16P-CH2 11: R’=R”=H;15a,16a-CH2 12: R’ R” = CHp; 15a,l€a-CH2
”’COOH
13: R’ = R ” = H; 15P,16P-CHp 14: R ’ + R ” = CHp; 15P,16P-CH2 15: R’ = R ” = H; 15a,16a-CHp 16: R ’ + R ” = CH?; 15a,lGa-CH2
-
“’COOR
= R ” = H; 15P,l@-CHp; R = CH3 = R” = H; 15P,16P-CH2; R = CpH5 = R” = H; 15P,I@-CHp; R = CH(CH& + R” = CH?; 15P,16P-CH2; R = CH3 + R” = CHp; 15P,l@-CHp; R = C2H5 R“ = CH2; 15P.16P-CHp; R = C3H7 + R ” = CHp; 15P,16P-CHp; R = CH(CH3)p = R ” = H; 15a,16a-CHp; R = CH3 R” = CH2; 15a,16a-CHp; R = CH3
26: R = CH3 27: R=C2H5 28: R = CH(CH3)2
+
+
a (a) 1. EhAlCN, THF 2. KZCO,, MeOH. (b) (i-Buz)AlH, THF or CH2Clz,-40 “C. (c) Cr03, H#Oc acetone. (d) CH2N2or RX, Ag20, DMF or 1. ROCOCl, NEG, THF; 2. ROH, reflux. (e) DDQ, toluene, reflux.
Table I. 7a-Cyano Carbolactones Prep compd method yield, % mp, “C formula 64 241 C,H,NO, 5 1A
anal. C, H, N
6
1B
89
288
C,H,NO,
C, H, N
7
1A
58
260
C,H,N03
C, H, N
8
1A
68
>300
C=HBN03 C, H, N
‘H NMR (100 MHz, CDClJ, 6 l&CH3 19-CH3 other 1.05 1.21 3.27 (m, 1, H-7), 5.83 (s (br), 1, H-4) 1.05 1.30 3.20 (m, 1, H-7), 5.66 (s (br), 1, H-4) 1.21 1.21 3.32 (m, 1, H-7), 5.80 ( 8 , H-4) 1.10 1.20 3.22 (m, 1, H-7), 5.64 (s (br), 1, H-4)
UV max (MeOH), IR (KBr), cm-’ nm (4 2240, 1765,1675, 1620 236 (15000) 2240, 1775, 1665
232 (13 700)
2220, 1760, 1660, 1620 234 (16000) 2240, 1780,1665
231 (12050)
Table 11. 7a-Alkoxycarbonyl Carbolactones ‘H NMR (100 MHz, CDCl,), 6 prep compd method yield,” % mp, “C formula anal. l&CH3 19-CH3 other 1.22 3.65 (s, 3, CH,OCO), 5.7 (s (br), 1, H-4) 17 PA-B-C 33 266 C=H3205 C, H, 0 1.00 1.30 1.31 (t, 3, CH3CH20CO),4.2 (q, 6, (CH,CH,OCO), 5.75 (s, 18 2A-B-D 34 185 CSHaO5 C, H, 0 1.04 (br). H-4) 1.25 1.23 (d, 6, (CH,),CHOCO), 5.09 (quin, 1, (CH3)2CHOCO), 19 2A-B-D 26 208 CnHXO5 C, H, 0 1.02 5.72 (s (br), H-4) 1.30 3.68 (s, 3, CH,OCO), 5.5 (s (br), 1, H-4) 20 PA-B-E 29 261 CZBH3205C, H, 0 1.00 1.20 1.2 (t, 3, CH&HzOCO), 4.05 (q, 2, (CH&HzOCO), 5.45 (8 21 2A-B-E 34 233 C27H3405 C, H, 0 1.00 (br), H-4) 1.00 1.24 0.9 (t, 3, CH&H&HZOCO), 3.97 (t, 2, (CH3CH&H20CO), 22 PA-B-E 23 181 CDHX05 C, H, 0 5.51 (s (br), H-4) 1.28 1.2 (d, 6, (CH3)2CHOCO),4.97 (quin, 1, (CH3)&H0CO), 5.4 23 2A-B-E 28 214 C28H3805C, H, 0 0.98 (s (br), H-4) 24 PA-B-C 1.17 3.67 (s, 3, CH,OCO), 5.7 (s (br), 1, H-4) 18 187 C,H3205 C, H, 0 1.20 25 2A-B-C 1.25 3.55 (s, 3, CH30CO), 5.45 (s (br), 1, H-4) 40 237 CZBH3,05C, H, 0 1.20 1.25 3.65 (s, 3, CH30CO),6.02 (s (br), 1, H-41, 6.22 (dd, 1, H-l), 26 3 39 273 Cz6HmO5C, H, 0 1.05 7.02 (d, 1, H-1) 27 3 32 238 CBH3205 C, H, 0 1.04 1.27 1.25 (t, 3, CH&HZOCO), 4.08 (q, 2, (CH,CH20CO), 6.00 ( 8 (br), H-4), 6.18 (dd, 1, H-2), 6.95 (d, 1, H-1) 28 3 29 255 CZ7HaO5 C, H, 0 1.02 1.25 1.24 (d, 6, (CH,),CHOCO), 4.95 (quin, 1, (CH3)2CHOCO), 6.00 (s (br), H-4), 6.17 (dd, 1, H-2), 6.96 (d, 1, H-1) The yield was calculated for the transformation of the cyano derivatives 5-8 to the esters 17-25 and for the preparation of 26-28 by DDQ dehydrogenation of 17-19.
Aldosterone Antagonists
Journal of Medicinal Chemistry, 1990, Vol. 33, No. 2 511
Table 111. Biological Activities of Spirolactones antialdosterone act.: maximal re1 potencyO androgen receptor progesterone receptor (spironolactone = 100, competition factorC competition factorS compd 95% confidence limita) (dihydrotestosterone = 1) (progesterone = 1) 112 17 217 (169-309) 25 18
