10
A. O. Abdelhamid, M. M. Abdelhalim and G. A. Elmegeed
Vol 44
Synthesis of 10,13-Dimethyl-17-(7-substituted 2-phenyl-
penta[a]phenanthreen-3-one (10b). This compound was
obtained as oil, 2.5 g (53 %). ir (KBr): 3020 (CH-aromatic),
2H-pyrazolo[3,4-d]pyridazin-4-yl)-1,2,6,7,8,9,10,11,12,13,14,
15,16,17-tetradecahydro-cyclopenta[a]phenanthrenes 8a-c.
General Procedure. To a solution of the appropriate 6a-d
(0.005 mole) in absolute ethanol (20 ml) and hydrazine hydrate
(0.5 mL, 0.01 mole) was heated under reflux for 4 h and cooled.
The resulting solid was collected and recrystallized from
benzene to give 8a-c, respectively.
4-(10,13-Dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-
tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-phenyl-
2,5-dihydropyrazolo[3,4-d]pyridazin-4-one (8a). This
compound was obtained as yellow crystals (benzene), 3.40 g (70
%), mp 248-250°. ir This compound was obtained as yellow
crystals (benzene), 3.40 g (70 %), mp 248-250°. iR (KBr):
(KBr): 3030 (CH-aromatic), 2984, 2850 (CH-aliphatic), 1705,
1680 (CO), 1647 (C=N) cm-1. 1H nmr (DMSO-d6): 1.16 (s, 3H),
1.26 (s, 3H), 1.27-1.71 (m, 14H), 1.99-2.01 (t, 3H), 2.35 (t, 1H),
2.99 (t, 2H), 5.85 (s, 1H), 7.50-7.68 (m, 5H, C6H5), 8.15 (s, 1H),
pyrazole C-5), 11.21 (s, br., 1H). ms: m/z: 483 (45) (M++1˙).
Anal. Calcd. for C30H34N4O2: C, 74.66; H, 7.10; N, 11.61.
Found: C, 74.37; H, 6.91; N, 11.72.
10,13-Dimethyl-17-(7-methyl-2-phenyl-2H-pyrazol[3,4-d]-
pyridazin-2-yl)-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradeeca-
hydro-cyclopenta[a]phenanthren-3-one (8b). This compound
was obtained as yellow crystals (benzene), 3.10 g (64 %), mp
160-162°. ir (KBr): 3025 (CH-aromatic), 2980 (CH-aliphatic),
1690 (CO), 1640 (C=N) cm-1. 1H nmr (DMSO-d6): 1.16 (s, 3H),
1.26 (s, 3H), 1.27-1.71 (m, 14H), 1.99-2.01 (t, 3H), 2.35 (t, 1H),
2.38 (s, 3H, CH3) 2.99 (t, 2H), 5.85 (s, 1H), 6.95-7.30 (m, 5H,
C6H5), 8.12 (s, 1H), pyrazole C-5). ms: m/z: 479 (46) (M+-1˙).
Anal. Calcd. for C31H36N4O: C, 77.47; H, 7.55; N, 11.66. Found:
C, 77.65; H, 7.32; N, 11.72.
1
2985, 2835 (CH-aliphatic), 1685 (CO), 1625 (C=N) cm-1. H
nmr (CDCl3): 1.16 (s, 3H), 1.26 (s, 3H), 1.27-1.71 (m, 14H),
1.99-2.01 (t, 3H), 2.35 (t, 1H), 2.99 (t, 2H), 5.85 (s, 1H),
7.13-7.76 (m, 3H, ArH’s), 8.12 (s, 1H), oxazole C-5). ms:
m/z: 471 (28) (M+). Anal. Calcd. for C28H31NO4S: C, 70.41;
H, 6.54; N, 2.93; S, 6.71. Found: C, 70.30; H, 6.32; N, 2.80;
S, 6.82.
Synthesis of Isoxazolo[3,4-d]pyradiazines 11a,b.
General Procedure.
Equimolar amounts of 10a,b and
hydrazine hydrate (0.01 mole) and absolute ethanol (20 mL)
were heated under reflux for 3 h. The resulting solid was
collected by filtration and crystallized from benzene to afford
11a and 11b, respectively.
10,13-Dimethyl-17-(7-phenylisoxazolo[3,4-d]pyridazin-4-
yl)-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrocyclo-
penta[a]phenanthren-3-one (11a). This compound was
obtained as yellow crystals (benzene), 2.60 g (60 %), mp 180-
182°. ir (KBr): 3030 (CH-aromatic), 2960, 2830 (CH-aliphatic),
1710 (CO), 1640 (C=N) cm-1 1H nmr (DMSO-d6): 1.16 (s, 3H),
1.26 (s, 3H), 1.27-1.71 (m, 14H), 1.99-2.01 (t, 3H), 2.35 (t, 1H),
2.99 (t, 2H), 5.85 (s, 1H), 7.13-7.76 (m, 5H, ArH’s), 8.12 (s,
1H), oxazole C-5). Anal. Calcd. for C30H33N3O2: C, 77.06; H,
7.11; N, 8.99. Found: C, 76.90; H, 7.20; N, 8.78.
10,13-Dimethyl-17-(7-(4-thien-2yl)isoxazolo[3,4-d]pyrida-
zin-4-yl)-1,2,6,7,8,9,10,11,-12,13,14,15,16,17-tetradecahydro-
cyclopenta[a]phenanthren-3-one (11b). This compound was
obtained as yellow crystals from (benzene), 3.21 g (68 %), mp
165-167°. ir (KBr): 2984, 2850 (CH3, CH2), 1705, (CO), 1647
1
(C=N). H NMR (ꢀ ppm): 1.16 (s, 3H), 1.26 (s, 3H), 1.27-1.71
(m, 14H), 1.99-2.01 (t, 3H), 2.35 (t, 1H), 2.99 (t, 2H), 5.85 (s,
1H), 6.92-7.31 (m, 3H), 9.25 (s, 1H, isoxazole C-5). Anal.
Calcd. for C28H31N3O2S: C, 71.01; H, 6.60; N, 8.87; S, 6.77.
Found: C, 70.85; H, 6.40; N, 8.78; S, 6.54.
17-(2,7-Diphenyl-2H-pyrazolo[3,4-d]pyridazin-4-yl)-10,13-
dimethyl-1,2,6,7,8,9,10,-11,12,13,14,15,16,17-tetradecahydro-
cyclopenta[a]phenanthren-3-one (8c). This compound was
obtained as yellow crystals (benzene), 3.20 g (59 %), mp 238-
240°. ir (KBr): 3026 (CH-aromatic), 2985, 2835 (CH-aliphatic),
REFERENCES AND NOTES
1
1690 (CO), 1645 (C=N) cm-1. H NMR (DMSO-d6): 1.16 (s,
3H), 1.26 (s, 3H), 1.27-1.71 (m, 14H), 1.99-2.01 (t, 3H), 2.35 (t,
1H), 2.99 (t, 2H), 5.85 (s, 1H), 7.53-7.76 (m, 10H, ArH’s), 8.12
(s, 1H), pyrazole C-5) and characteristic signals of cyclopenta-
noperhydrophenanthrene moiety. ms: m/z: 542 (35) (M+). Anal.
Calcd. for C36H38N4O: C, 79.67; H, 7.06; N, 10.32. Found: C,
79.76; H, 6.90; N, 10.05.
Synthesis of Isoxazoles 10a,b. General Procedure. A
mixture of 3 (3.96 g, 0.01 mol), the appropriate hydroximoyl
chloride 9a,b (0.01 mol) and triethylamine (1.5 mL, 0.01 mole)
in dry toluene (20 mL) was stirred at 0ºC. The stirring was
continued for 3 h. The reaction mixture was concentrated under
vacuum to give the oily products 10a,b respectively.
[1] T. Kwon, A. S. Heiman, E. T. Oriaku, K. Yoon, H. J. Lee, J.
Med. Chem. 38(6), 1048 (1995).
[2] D. P. Jindal, P. Piplani, H. Fajrak, C. Prior, I. G. Marshall, Eur. J.
Med. Chem. 36, 195 (2001).
[3] R. M. Hoyte, J. Zhong, R. Lerum, A. Oluyemi, P. Persaud, C.
O’Connor, D. C., Labaree, R. B. Hochberg, J. Med. Chem., 45 (24), 5397
(2002).
[4] E. J. Jacobsen, M. McCall, D. E. Ayer, F. J. Van Doorink, J. R.
Palmer, K. L. Belonga, M. Broughler, E. D. Hall, D. J. Houser, M. A. Krook,
T. A. Runge, J. Med. Chem., 33, 1145 (1990).
[5] Y. Zhengqing, A. S. Heiman, C. E. Hudson, H. J. Lee, Steroids,
67, 353 (2002).
[6] D. KO, A. S. Heiman, M. Chen, H. J. Lee, Steroids, 65, 210
(2000).
[7] H. J. Lee, J. S. Cooperwood, Z. You, D. Ko, Arch. Pharm. Res.,
25 (2), 111 (2002).
[8] S. H. Doss, N. A. Louca, G. A. Elmegeed, R. M. Mohareb, Arch
Pharm Res, 22, 495 (1999).
[9] G. Hajos, Tetrahedron, Asymetry, 4 (3), 393 (1993).
[10] R. Gupta, D. Pathak, D. P. Jindal, Eur. J. Med. Chem., 34, 659
(1999).
17-(3-Benzoylisoxazole-3-carbonyl)-10,13-dimethyl-1,2,6,7,
8,9,10,11,12,13,14,15,16,-17-tetradecahydrocyclopenta[a]phen-
anthreen-3-one (10a). This compound was obtained as oil, 2.8
g (59 %). ir (KBr): 3026 (CH-aromatic), 2985, 2835 (CH-
1
aliphatic), 1690 (CO), 1645 (C=N) cm-1. H nmr (CDCl3): 1.16
(s, 3H), 1.26 (s, 3H), 1.27-1.71 (m, 14H), 1.99-2.01 (t, 3H), 2.35
(t, 1H), 2.99 (t, 2H), 5.85 (s, 1H), 7.53-7.76 (m, 5H, ArH’s), (s,
1H), oxazole C-5). ms: m/z: 471 (28) (M+). Anal. Calcd. for
C30H33NO4: C, 76.41; H, 7.05; N, 2.97. Found: C, 76.30; H,
6.82; N, 3.12.
[11] G. A. Elmegeed, W. W. Wardakhan, M. Younis, N. A. Louca,
Arch. Pharm. Med. Chem., 337, 140 (2004).
10,13-Dimethyl-(3-(2-thienyl)-2-carbonyl)isoxazole-4-car-
bonyl-1,2,6,7,8,9,10,11,-12,13,14,15,16,17-tetradecahydrocyclo-
[12] W. B. Smith, Mag. Reson. Chem. 37(2), 103 (1999).
[13] N. S. Bhacca, D. H. William, "Application of NMR spectroscopy