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Novel Steroidal 14-Diketones and Pyridazine Derivatives as Potential Antiestrogens.

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Full Papers
Novel Steroidal 1,4-Diketones and Pyridazine Derivatives as Potential
Antiestrogens
Khadiga A. Ismaila), Alaa A. El-Tombarya), Omaima M. AboulWafaa)*, A-Mohsen M.E. Omara), and Safaa H. El-Rewinib)
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria
b,
Department of Pharmacology and Drug Toxicology, Faculty of Medicine, University of Alexandria, Alexandria 2121 5, Egypt
Key Words: 2-Acetylestradiol-17P-acetate; substituted phenylglyoxals; 2-(6-arylpyriduzin-3-yl)estradiol derivatives;
uterotrophic activity; antiuterotrophic activity; postcoital antiimplantation activity
Summary
A series of steroidal 1.4-diketone derivatives was synthesized by
acid-catalyzed condensation of 2-acetylestradiol- 17P-acetate with
substituted phenylglyoxals. Conversion of the products into the
corresponding pyridazine derivatives was achieved by reaction
with hydrazine hydrate. The synthesized compounds were evaluated for their uterotrophic, antiuterotrophic, and antifertility activities in mature female albino rats. Among the compounds tested,
the phenyl2, pbromophenyl3, andpmethoxyphenyl5 diketone
derivatives displayed uterotrophic activity of 72%, 72%, and 91%,
respectively. The gradation of antiestrogenic activity was assessed
in vivo by the inhibition of the estrone-stimulated uterine growth.
Compounds 2-5 showed moderate antiestrogenic activity of 5356%. None of the tested compounds elicited antifertility activity
as assessed by the post-coital antiimplantation activity test.
Introduction
Antiestrogen therapy is the most widely used endocrine
manipulation for the treatment of breast cancer, especially in
post-menopausal women. Unfortunately, the compounds
presently available, related t o the nonsteroidal
triphenylethylene group of estrogens, possess mixed
agonist/antagonistic activity, thus potentially limiting their
therapeutic efficacy[']. To overcome such shortcomings, considerable effort has been devoted to the search for steroidal
antiestrogens devoid of partial agonist activity. Recently, it
has been observed that a series of 7a- derivatives of 17P-estradiol 12] displayed significant antagonistic activity in various systems, including the rat uterus and human breast cancer
cells. Among the 7a-alkylamide analogues of estradiol, the
[N-n-butyl-N-methyl- 1 1-(3,I7 dihydroxyestra- 1,3,5(10)-ayl)undecamide](ICI 164,384)19; was entirely devoid of estrogenic activity in the rat and mouse uterus but completely
blocked the uterine stimulatory effects of estradiol and tamoxifen and was considered as a pure antagonist of estrogen
action. Some other compounds possessing a-undecanamide
group and a halogen atom at the a-position possessed potent
in vivo antiestrogenic activity. These new antiestrogens
showed no estrogenic activity on uterine weight at the doses
used while tamoxifen showed full estrogenic activity and was
only a weak partial antiestrogen in the same assay[4]. The
naturally occurring hormone estriol, exhibited a low binding
affinity to the estrogen receptor (ER) and, in short term tests,
Arch. P h a n . Pharm. Med. Chem.
produced an inhibition of estradiol-stimulated increases in
uterine weight. Estriol was apparently sufficiently antiestrogenic to inhibit the induction of hormone-dependent rat mammary tumors with dimethylbenzathracene (DMBA)"], an
action that might be important for the protection of patients
from developing breast cancer. 11a-Methoxy- I7a-ethinylestradiol (RU 161 17) also inhibited carcinogenesis withDMBA
and inhibited the growth of established DMBA-induced tumors[61. The effect of attachment of some other functional
groups at the oneL7],6[71,11[*I, and 1819]positions or replacement of the 3-hydroxyl group['] of the steroidal nucleus was
also studied. The obtained compounds exhibited different
degrees of binding to the ER but failed to suppress the uterine
weight response of immature rats to 17P-estradiol. Searching
in the literature, catechol estrogens were also found to exhibit
an entire spectrum of activity ranging from strong estrogen
agonist to antagonist effects. Although 2-hydroxyestrogens
are very weak estrogen agonists in the female reproductive
tract, they are capable of defiminizing the developing rat
brain and can exert short-term effects on the secretion of
immuno-reactive luteinizing hormone and prolactin[lol.
2-Hydroxyestrone was formerly considered as an endogenous antiestrogen in that it occupied the receptor but failed
to be processed for the expression of biological activity[''].
However, it failed to reduce the uterotrophic impact of estradiol and does not play an antiestrogenic role at the uterine
target site['21. Similarly, the 2-methoxy derivative was nonuterotrophic and its binding exceeded that of its 2-hydroxy
precursor"'].
Based on the above facts and that the effect of changes in
substitution at position 2 of the steroid nucleus on biological
activity has not received extensive study, we have synthesized a number of novel ring A aromatic steroids in which the
nucleus is substituted by various moieties that may lead to
variable pharmacological properties.
Previously, we had an interest in the design and synthesis
of estrogens substituted at the 2-position with five-membered
ring systems as pyrazole, isoxazole[l3I, and thiazole[14] and
with a six-membered pyrimidine ring1151.Many interesting
examples of these compounds have been found to possess
good receptor binding affinityri3],e ~ t r o g e n i c ~ 'and/or
~ ] , antifertility activity[101.The good biological activity elicited by
these compounds convinced us to pursue the 2-position as a
site of attachment of some new 1,4-diketone side chains and
other six-membered heterocyclic ring systems as the pyridazine ring in order to study the effect of structural modula-
0VCH Verlagsgesellschaft mbH, D-6945 1 Weinheim, 1996
0365-6233/96/1010-0433 $5.00 + .25/0
434
Ismail, El-Tomhary. AboulWafa, Omar, and El-Rewini
tion around C-2 in estradiol on its estrogenic, antiestrogenic
and antifertility activities. We now report the synthesis of
2-(4-aryl- 1,4-dioxobut-2-enyl)estradiol3,17P-diacetates (25) and 2-(6-substituted pyridazin-3-y1)estradiol derivatives
(6-11) which combine new structural heterocyclic features
that may achieve a decrease or loss of estrogenic activity and
an increase of antiestrogenic an antifertility properties.
Chemistry
The new pyridazinylestradiol derivatives were prepared
from 2-acetylestradiol p-acetate 1'16317-'91
according to
Scheme 1. Acid-catalyzed condensation of 2-acetylestradiol
1 with substituted phenylglyoxals[201afforded the required
1,4-dicarbonyl compounds. The products were obtained as
oils in relatively good yields after purification by column
chromatography. They were identified by IR, 'H-NMR, and
mass spectra. The IR spectra showed bands for 3- and 17pacetyloxy groups at 1767-1748 and 1730-1720 cm-' respectively in addition to 2 other bands at 1692-1665 and
1670-1640 cm-' for the conjugated diketone moiety. The
'H-NMR spectrum of the steroidal diketones 2 and 3 lacked
the singlet of the 2-acetyl protons present in the starting
material 1 and showed 2 singlets at 6.20-6.28 and 6.39-6.53
ppm included within the multiplet of the aromatic protons and
assigned to the a,P-vinylic protons. The MS spectra showed
a common fragmentation patternr2'] and ions similar to those
previously described (Fig. 1). Conversion of the products into
the corresponding pyridazine derivatives 6-11 was achieved
by reacting the I ,4-dicarbonyl compounds with hydrazine
hydrate in ethanol acidified with a few drops of glacial acetic
acid122,231.
Purification by preparative TLC gave 2 products:
the p-monoacetates 6-8 and the 3,17P-diacetates 9-11. Compounds having low R f values were identified as the 17p-acetates while those possessing high Rf values were substantiated
as the 3,17P-diacetates. This indicated that some h drolysis
has occurred during the reaction as shown by 1R and H-NMR
spectra. The IR spectra of the compounds 6-11 lacked the
bands of the 2 carbonyl groups of the 1,4-diketone function
and showed the ring stretching vibration of pyridazine at
1620-1610, 1600-1580, 1500-1493, and 1545-1530 corresponding to C=N, C=C, and N=N respectively. The 'H-NMR
spectra of the mono-(8) and diacetylated p-tolyl derivative
(ll),as representative examples, showed the 2 protons of the
pyridazine ring included within the aromatic protons at lower
field in addition to the methyl, p-tolyl, C-4, and C-1 protons
at their expected chemical shifts.
Y
9-11
6-8
I
R
Scheme 1
H
CH = CH - C
R
CH3COO
-
-RQM
COCH3
0
- C H I CH
CH3CO0
C23H2704m h 397
ClgH2,03
/
CH3CO0
HO \
C20H2204
m h 326
CzoHzzO,m h 342
C13Hl,0
-+O=
m h 186
HO
C,Hl
Figure 1
m/z 119
Cl1HllOm/z
159
C12H100m h 171
m h 297
HO
C16H1502mlz 239
CsH&
m/z 135
I
"""'0
CH
, sO
m/z 105
Arch. Pharnz. Phann. Med. Chem. 329, 433437 (IY96)
435
Potential Antiestrogens
Results and Discussion
2-(4-Aryl-1,4-dioxobut-2-enyl)estrudiol3,
17P-diucetute2-5
The results showed that at a dose of 0.09 ymolldaylrat, the
phenyl (2), p-bromophenyl (3), and p-methoxyphenyl (5)
lP-diketones exhibited 72%, 72%, and 91 % uterotrophic
activity, respectively. Compounds 2-5 exhibited a modest
antiestrogenic activity in the mouse uterine weight test in vivo
of 53-56%. The pyridazinylestradiol derivatives were devoid
of estrogenic and antiestrogenic activity. Evaluation of the
post-coital contraceptive efficacy of these compounds
showed that none of the tested compounds elicited any significant antiimplantation activity relative to estradiol on a
molar ratio basis.
2-Acetylestradiol 17P-acetate 1 (0.5 g, 1.4 mmol was added to a solution
of phenylglyoxal or 4-substituted phenylglyoxal[!O1(1.4 mmol) in acetic
anhydride ( 5 ml). The reaction mixture was heated under relfux for 10 h,
cooled to room temp, poured onto crushed ice and left in the refrigerator for
an overnight. The product that separated was filtered, washed with water,
dried and purified by column chromatography using benzene-light petroleum (60-80 "C) (60:40, v/v) as eluent.- IR v: 1767-1748 ( G O , C-3-acetate), 1730-1720 (C=O, C-17-acetate), 1692-1665, 1670-1640 (C=O,
diketone), 1600-1586, 1490-1480 (C=C), 1259-1226 and 1052-1050 cm-'
(C-0-C).
Conclusions
The fact that our studies showed that the 1,4-diketone
derivatives (2' 3' and 5, have good uterotrophic activity and
moderate antiuterotrophic activity relative to estradiol
being devoid of antiimplantation activity indicates that introduction of a 1,4-diketone side chain in the 2-position of
estradiol imparted a modest antagonistic effect while still
retaining an agonist effect in rats. Thus these compounds can
be considered as modest antiestrogens due to their high
estrogenic side effects. This behavior again supports our
previously reported results which showed that substitution at
the 2-position of the skeleton may be biologically beneficial
and not as previously thought to be inhibitory for biological
activity. On the other hand, the 2-pyridazinyl derivatives 6-8
were completely devoid of uterotrophic and post-coital antiimplantation activity. The moderate antiestrogenic activity
generated by introduction of a diketone side chain at position
2 was completely destroyed by replacement of the 2-pyridazinyl moiety.
17P-diacetute2
2-(4-Phenq.1-1,4-dio~bi~t-2-enyl)estrudiol3,
This was obtained as viscous oil (38% yield).- 'H-NMR (CDC13) 6 1.22
(s, 3H, 18-CH3),2.28 (s, 3H. 17P-OCOCH3), 2.37 (s, 3H, 3-OCOCH3), 3.82
(t, dist, IH, J = 6 Hz, 17a-H), 6.82 and 6.53 (2s, 2 x IH, vinylic protons),
7.10 (& 1 H, C-4-H),7.12-7.68 (m, 3H, Ar-H),7.90 (s,lH,C-l-H), 8.00-8.12
(m, 2H,Ar-H). MS, m/z (% relative abundance): M+ [C3zH3406,514(0.07)],
408 (1.84), 368 (1.40), 367 (1.42), 356 (0.20), 341 (0.38), 297 (l,12), 265
(1.34), 263 (1.02), 236 (2.62), 187 (1 OO), 183 (1.14), 171 (1.78), 167 (1.37),
159 (1.70), 148 (3.78), 147 (2.841, 13s (4.711, 111 (2.43), 106 (7.941, 10s
(100),97(3.88),95(2.42),91 (2.15).85(3.37),83(4.12),81(2.58),79(3.21),
78 (3.07),77 (34.44),69 (4.86),67 (2.34),57 (5.67).
Z-(l-p-Bromophenyl-1,4-dic~xobut-2-enq.l)estrudiol3,17~-diucetute
3
This was obtained as viscous oil (58% yield).- 'H-NMR (CDC13) 6 0.89
(s, 3H, 18-CH3), 1.28 ( s , 3H, 17P-OCOCH3),2 . 2 0 ( ~2H,
, 3-OCOCH3),4.09
(t. IH, J = 6Hz, 17a-H), 6.20 and 6.39 (2s, 2 x lH, vinylic protons), 7.03 (s,
IH, C-4-H), 7.33 (s, lH, C-I-H), 7.42 (d, 2H, J = 3Hz, Ar-H meta to Br),
7.69 (d, 2H, J = 3Hz, Ar-H ortho to Br).- MS, m/z (% relative abundance):
M+[C32H3~Br06,594(1.29),592(1.36)],552(12.6),550(13.18),422(4.75),
368 (25.3), 367 (loo), 356 (55.17), 341 (11.57), 297 (4.21), 296 (2.70), 267
( 6 3 9 , 2 6 4 (3.72), 239 (6.36), 237 (5.08) 214 (8.45), 188 (5.56), 185 (6.84),
184 (66.49), 183 (6.69), 182 (64.83), 171 (5.02), 167 (6.02), 1.59 (5.06), 156
(20.77), 149 (14.98), 135 (3.54), 128 ( S ) , 111 (2.65), 107 (3.54), 105 (7.62),
97 (4.46), 95 (3.83), 91 (6.08), 85 (3.72), 83 (5.21), 79 (4.85), 76 (10.34), 69
(5.84), 57 (7.30).
Acknowledgment
The authors thank Organon Pharmaceutical Co., Holland, for the generous
donation of estradiol.
Experimental Part
Melting Points: Griffin melting point apparatus, uncorrected.- IR spectra:
Perkin-Elmer 430 ratio recording infrared spectrophotometer (KBr).- 'HNMR spectra: Varian EM-390 spectrometer 90 MHz, TMS as internal
standard. The chemical shifts given in ppm 6 values (s, singlet; d, doublet; t,
triplet; m, multiplet and dist, distorted).- MS: Hewlett-Packard MS 5988
spectrometer.- The homogeneity of the products was checked by ascending
TLC run on silica gel G (Merck 60) coated glass plates.- Preparative TLC
was performed on 20 x 20 cm2 plates coated with 30 g silica gel 60 GF 254
for TLC (Adwic Laboratory Chemicals, Egypt).- A duo-UV lamp (Desaga,
Heidelberg, Germany) was used for location of the spots.- Microanalysis:
Microanalytical Unit, Faculty of Science, Cairo University, Egypt.
2-Acetylestrudioll7P-acetute 1
Compound 1 was prepared from estradiol according to the previously
195-197 "C).- IR v: 3450
described method"41; mp: 195-197 "C (ref.
(OH), 1730 (C=O,C-17-acetate), 1640 (C=O, C-2-acetyl), 1620-1495 (C=C
aromatic), 1265 and 1040 cm-' (C-0-C).
Arch. Phrm. Phurm. Med. Chem. 329,433437 (1996)
2-(4-p-Tolyl-1,4-dioxobut-2-enyl)estradiol3,I
7P-diucetate4
This was obtained as viscous oil (47% yield).- MS, m/z (% relative
abundance): M+ [C33H3606,528(absent)], 423 (0.61), 421 (0.64), 383 (1.4),
368 ( I .63), 367 (0.89), 355 (0.96), 343 (7.23), 342 (8.68), 326 (2.17), 297
(1.23),293 (5.64),292(18.53),283(1.75),279(2.33),265(2.24),264(4.84),
2.51 (2.13), 239 (3.49), 237 (3.16), 236 (4.43), 213 (2.49), 201 (4.23), 200
(23.59), 193 (3.32), 186(3.31), 18.5 (3.27), 184(3.6), 183(2.58), 181 (2.81),
171 (10.99), 167 (7.72), 161 (3.23), 1.59 (2.78), 155 (3.94), 149 (17.39), 13.5
(5.73, 127 (4.57), 126 (4.39), 125 (8.72), 123 (8.04), 119 (IOO), 115 (6.65),
111 (16.43), 107 (5.33), 105 (28.02), 99 (6.53), 98 (lo), 97 (24.85), 95
(15.54),91(36.66),85(19.33),83(22.44),81(14.01),77(11.58),71(23.27),
69 (21.43), 57 (26.22).
2-(4-p-Methoxyphenyl-/,4-dionobut-2-enyl)estrudiol3,
17P-diacetute 5
This was obtained as viscous oil (39% yield). - MS; d z (% relative
abundance): M' [C33H3607, 544 (0.38)], 502 (1.69), 421 (0.22), 368 (1.8),
367 (6.12), 355 (0.34), 343 (0.44), 326 (0.23), 324 (1.84), 297 (1.02), 283
(1.79),279(0.63),267(1.04),264(1.43),253(0.29),239(1.20),236(1.15),
213 (1.04), 199 (l. l), 193 (1.58), 186 (2.67), 185 (2.20), 184 (2.64), 171
(7.13), 167(2.26), 161 (1.57), 159(1.05), 155 (1.48), 152(4.39), 149(5.41),
135 (loo), 129 (3.44), 127 (1.57), 125 (2.28), 113 (2.44), 112 (3.52), 111
(3.151, 109 (3.34), 107 (6.70), 105 (23.94), 98 (3.01), 95 (3.17), 92 (6.56),
91 (3.17), 85(2.85), 83 (5.20), 81(2.99),77 (12.69). 71 (4.81), 69 (4.77), 57
(4.85).
436
Ismail, El-Tombary, AboulWafa, Omar, and El-Rewini
2-(6-A~lpryidazin-.~-yl)estradiol
17P-ucetate 6-8 und 3,17P-ditrcetute
9-1 1
Hydrazine hydrate (0.5 ml, 10 mmol), was added to a solution of the
diketone derivative 2-5 (0.5 mmol) in ethanol ( 1 0 ml) containing 3 drops of
glacial acetic acid. The mixture was heated under reflux for 8 h, concentrated,
and poured onto cold H20. The separated solid was crystallized from aqueous
ethanol to give the substituted pyridazinyl estradiol derivatives 6-11. The
mono- 6-8 and diacetate derivatives 9-11 were separated by preparative TLC
using bensene/EtOAc (80:20 v/v) as developing solvent;- IR of compounds
6 - 8 ~ :3404-3393 (OH), 1620-1610 (C=N), 1600-1580,1500-1493 (C=C),
1545-1 530 (N=N), 1266 and I055 cm-' (C-0-C).- IR of compounds 9-11
lacked the stretching vibrational hand for OH group.
2-(6-Phr1i,ylpyriduzin-3-yl)rstrudiolI7P-ucetate 6
(18% yield), Rf:0.175, mp: 185-187 "C.- Analysis calcd for CmH32N203:
C, 76.92; H, 6.83; N, 5.98. Found: C, 77.12; H, 6.64: N, 5.70.
2-(6-Plzenylpyri~luzin-3-).ljestrudi~~l3,
17P-diacetate 9
(30%yield), Rf:0.365, mp: 226-228 "C.- Analysis calcd for C~Hi4N204:
C, 75.29; H, 6.66; N, 5.49. Found: C, 74.89; H, 6.50: N, 5.22.
2-((i-~~-Broinophenylpq.ridazin-3-~l)estrudiol
17P-acetuteI
2(6-p-Tolylpyridazin-3-yl)estradiol3,17~-diacetate
11
(35% yield), Rf:0.472, mp: 250-252 "C. Analysis calcd for C33H36N204:
C,75.57: H, 6.87; N, 5.34. Found: C, 75.32; H, 6.62; N, 4.93.- 'H-NMR
(CDC13) 6 0.81 (s, 3H, 18-CH3), 1.18 (s, 3H, 17P-OCOCH3), 2.07 (s, 3H,
3-OCOCH3), 2.39 (s, 3H, p-tolyl CH3), 3.63 (t, IH, J = 6 Hz, 17a-H). 6.52
(s, IH, C-4-H), 7.1 1 (s, IH, C-I-H), 7.27 (m, 4H, Ar-H ortho to CH3 + 2
pyridazine-H), 7.84 (d. 2H, J = 3 Hz, Ar-H mefa to CH3).
Biologicul Activity
(JterotrophicActivity
The uterotrophic activity'16'241of the synthesized compounds was evaluated by determining the uterine weight gain in mature ovariectomized female
albino rats (100-180 g) (obtained from the animal house of the Faculty of
Pharmacy, Alexandria). The compounds were administered subcutaneously
once daily over a 4-day period in 0.1 ml DMSO (0.09pmol/day/rat). The rats
were weighed 24 h after the last dose and vaginal smears were taken and
examined under the microscope. The animals were then sacrificed and the
uteri were carefully dissected out, blotted, weighed, dried at 60 "C for 24 h
and weighed again. The gain in uterine weight calculated as mg uterine
weighU100g body weight and the percentage of dry/wet weight are shown in
Table 1.
(19% yield), Rt-: 0.245, mp: 153-155°C.- Analysis calcd for
C3oH~iBrN20j:C.65.81;H,5.66;N.5.22.Found:C,66.l~:H,5.52:N,5.45. AntiuterotroplzicActivify
2-(h-~-Broniophe1iylp~riduzin-3-yl)estradiol.?,I7~-diacetate
10
(38% yield) Ri: 0.472, mp: 215-217 "C.- Analysis calcd for
C32H33BrN204: C, 65.19; H, 5.60; N, 4.75. Found: C, 65.20; H, 5.41; N,
4.66.- 'H-NMR (CDC13) 60.83 (s, 3H, IS-CHI), I .44(s, 3H, 17P-OCOCH3),
2.08 (s, 3H 3-OCOCH?), 3.71 (t, dist, lH, J = 6Hs, 17a-H), 6.69 (s, IH,
C-4-H), 6.84 (d, 2H, J = 3Hz, Ar-H meta to Br), 7.08 (d, 2H, J = 3Hz, Ar- H
ortho to Br), 7.23 (m, 3H, C-1-H + 2 pyridazine-H).
The antiuterotrophic a ~ t i v i t y ' ~ ~of
' ~ 'the
' synthesized compounds was
assessed in mature ovariectomized albino female rats (100-200 g). The
compounds were administered subcutaneously in 0.1 ml DMSO along with
0.1 mg of E2-17P (in 0.1 ml DMSO) at 2 different sites for 3 consecutive
days. Inhibition was expressed as percent inhibition from the formula of
Hartmann et al. '261 (Table 2):
&= [
% inhibition = 100 -
2-(6-p-Tulylpyridu,-in-~?-yl)estrudiol
17P-acetate 8
x 100
(25% yield) Rr: 0.226, mp:201-203 TAnalysis calcd for C ~ I H ~ ~ N Z O ~ .
where:
&;I.= Effect of standard under simultaneous application of test substance.
Es = Effect of cstradiol standard.
C-l -H), 7.12-7.32 (m, 6H, 4Ar-H + 2 pyridazine -H).
Ev =Effect of vehicle.
C, 77.17: H, 7.05; N, 5.81. Found: C, 77.45; H, 7.25; N, 5.95.- 'H-NMR
(CDCI3) 6 0.73 (s, 3H, 18-CH3), 1.18(s, 3H, I7P-OCOCHj ), 2.44 (s, 3H,
p-tolyl CHj), 3.62 (t, IH, J = 6Hz, I ~ ~ L - H
6.57
) , (s, IH, C-4-H), 7.08 (s, IH,
Table 1: Estrogenic potencies and post-coital antiimplantation efficacies of the synthesized cornpounds 2-5 and 9-11 in ovariectomized mature female rats.
Camp.
Wet uterine
weight
mg/ 1 00g
Dry uterine
weight
mg/100g
Dry weight/
wet weight
% (n)a
% Uterotrophic
activity based
on dry wt.
Antiimplantation activity
(number of
implants)(n)
8 Antiimplantation
activity
Control
10.68 f 0.534
3.617f0.319
33.76 k 2.104(4)
-
8.00 f 0.707(4)
-
I100
Estradiol 19.65 f 2.55**
6.708 f I .05
33.51 f 3.08(5)
2
20.64 f 2.21 **
4.85 f 0.613
23.28 f 0.96**(5)
72
4.50 k 1.658(4)
22
3
14.06 f 0.85"
4.80 i 0.36"
34.05 f 0.56(5)
72
3.50k 1.19(4)
29
4
9.21 k 0.67
3.14 f 0.35
35.69 f 1.15(5)
47
5.50 f 1.50(4)
18
5
18.74a 1.29""
6.07 i 0.31 **
32.80 f 2.48(4)
91
4.00 k 1.08(4)
25
9
8.22 2.98""
2.69 f 1.46"*
34. I8 f 0.65**(5)
17
7.00 f 3.50(4)
14
10
9.95 ? 0.57**
3.37 f 0.79**
31.93 k 0.426**(5)
13
4.20 f 1.50(5)
24
11
9.82 i 6.41 **
2.93 f 0.76""
28.47 f 1.073""(5)
13
5.00 f 0.912(4)
20
*
0(5)
100
= number of animals. Minimum effective dose for prevention of pregnancy (0.05 mg/kg body weight for estradiol).
Doses of the tested compounds were calculated on a molar ratio basis. Rats received vehicle (DMSO) and served as control.
Results were expressed as mean f SEM. Data were analyzed by one way variance. Studcnt's t for unpaired observations was used
Differences between means were considered significant if P < 0.05. * P < 0.02. **P < 0.01.
an
Arch Phunn Pharm Med. Chem. 329,433437 (1996)
437
Potential Antiestrogens
Table 2: Antiuterotrophic activity of the synthesized compounds 2-5 and
9-11 in ovariectomized mature female rats.
Comp.
Dry uterine weight
mg/100g
% Antiuterotrophic
activity
[7] E.R. Clarck, A.M.E. Omar, G. Prestwich, J. Med. Chem. 1977, 20,
1095-1099.
[8] X. Qian, Y.J. Abul-Hajj, Steroids 1990, 55, 238-241.
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[ 101 End-Organ Metabolism qf Oestrogens, in: Mechanisms of Steroid
Control a
3.947f0.112
-
Estradiol
47.145 k 3.015
-
2
23.05 f 0.66**
56
3
24.19 k 0.54**
53
4
23.75 f 0.16**
54
1121 C. Martucci, J. Fishman, Endocrinology 1977,101, 1709-1715.
5
24.19 f 0.535**
53
9
44.207 f 0.862
[13] A.M.E. Omar, I.C. Ahmed, O.M. AboulWafa, A.M. Hassan, K.A. Ismail, M.M. Mohy El-Din, N.A. Mansour, Eur. J. Med. Chem. 1994,29,
25-32.
10
38.465 f 1.908*
11
41.15
+ 1.579
7
20
14
Acrion, G.P. Lewis, M. Ginsburg (eds), MacMillan Press Ltd, Chapter 9, pp.123-124 (1981).
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[I41 A.M.E. Omar, O.M. AboulWafa, I.M. Labouta, A.A. El-Tombary,
A.I.El-Mallah,Alex. J. Pharm. Sci. 1996, 10, 19-24.
[I51 K.A. Ismail, A.A. El-Tombary, A.M.E. Omar, O.M. AboulWafa,
N.I. Madi, Eur. J. Med. Chem. 1995,30,423427.
Number of animals in each group = 4.
Doses of the tested compounds were calculated on a molar ratio basis.
a Rats received vehicle (DMSO) and served as control.
Results were expressed as mean k SEM. Data were analyzed by one way
variance. Student’s t for unpaired observations was used.
Differences between means were considered significant if * P < 0.05.
** < 0.001.
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Antiimplantation Activity
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Mature female cycling albino rats (150-200 g) were mated with active
males during the night after the day of proestrus. Animals with evidence of
positive mating (presence of sperm in the vaginal smears) received the test
com ound dissolved in 0.1 ml DMSO subcutaneously on days 1-7 post-coit ~ m ~The
~ animals
- ~ ~ were
~ . examined by laparatomy on day 10 of pregnancy for the number of implantation sites. Results were compared with those
obtained on administration of the standard estradiol (Table 1).
[20] H.A. Riley, A.R. Gray, Org Synthesis ZI 1947, 509-510.
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Received: Februaly 20, 1996 [FP098]
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