Diaryl naphthyl methanes a novel class of anti-implantation agents

Article abstract of DOI:10.1016/j.bmc.2003.12.015

Diaryl naphthyl methanes and the corresponding 1, 2, 3, 4- and 5, 6, 7, 8-tetrahydro naphthyl methane derivatives have been synthesized as novel estrogen receptor binding ligands. The secondary and tertiary amino alkoxy derivatives of diaryl naphthyl and

Full text of DOI:10.1016/j.bmc.2003.12.015

Bioorganic & Medicinal Chemistry 12 (2004) 1011–1021
Diaryl naphthyl methanes a novel class of anti-implantation agents
Neeta Srivastava,a Sangita,a S. Ray,a M. M. Singh,b Anila Dwivedib and Atul Kumara,*
aDivision of Medicinal Chemistry, Central Drug Research Institute, Lucknow-226 001(UP), India
bDivision of Endocrinology, Central Drug Research Institute, Lucknow-226 001(UP), India
Received 20 August 2003;accepted 11 December 2003
Abstract—Diaryl naphthyl methanes and the corresponding 1, 2, 3, 4- and 5, 6, 7, 8-tetrahydro naphthyl methane derivatives have
been synthesized as novel estrogen receptor binding ligands. The secondary and tertiary amino alkoxy derivatives of diaryl naphthyl
and tetrahydro naphthyl methane interact with the estrogen receptor to elicit promising estrogenic, antiestrogenic and implantation
inhibition activities in rats. The most active compounds in this series are 7, 9 and 20, cent percent active in preventing implantation
in rats at 2.5 mgkgꢀ1 dose.
# 2004 Elsevier Ltd. All rights reserved.
1. Introduction
interact with ER and therefore, exhibit estrogen agonistic/
antagonistic activity. Thus, prototypes I and II were
synthesized.9 However, such compounds were found to
be inactive. This inactivity was presumably due to the
presence of hydroxyl functions (OH and OR) at an
inappropriate location (lypophilic sites). This is supported
by the observation that prototype III now reported,
lacking such hydrophilic residues showed significant
antifertility activity.
The importance of estrogen antagonists as pharmaceu-
ticals lies in their tissue selective activity. Although the
molecular requirement for estrogen agonist and antago-
nist actions has been worked out to a large extent, their
tissue selective action is poorly understood. Therefore,
synthesis and biological evaluation of new estrogen
agonists and antagonists continues for an in-depth
understanding of their site and mechanism of action.1ꢀ3
Most of the estrogen antagonists known today including
ormeloxifene,4,5 the first non-steroidal oral contraceptive
introduced by our group, possess triaryl ethylene (TAE)
frame work,6 present in an acyclic or cyclic form. The
estrogen receptor (ER) model proposed by us earlier7
(Fig. 1) and later supported by X-ray studies reported
by Brzozowski et al.,8 suggested presence of subsites on
ER active site corresponding to estrogen agonist and
antagonist actions. Looking for a deviation from TAEs
for a possibly better tissue selective action and utilizing
the above information on receptor model, development
of novel diaryl naphthyl methane molecules was
conceived. We report here our work on diaryl naphthyl
methane and corresponding 1, 2, 3, 4- and 5, 6, 7, 8-tetra-
hydro naphthyl methane derivatives which furnished a
large number of compounds possessing estrogenic,
antiestrogenic and promising antiimplantation activities.
The most promising compounds 7, 9 and 20 were found
to be active at 2.5 mgkgꢀ1 dose in rats when administered
orally on day 1–7 postcoitum. However, in the single
day administration it was active only at a dose of 15
mgkgꢀ1. This reduced activity may be assigned to a
likely metabolism of the triaryl methane residue,
wherein a facile formation of a methane free radical10 is
possible or poor absorption from the gastrointestinal
tract.
In view of the above observation, synthesis of correspond-
ing 1,2,3,4-tetrahydronaphthalenes IV was undertaken.
During this synthesis, 5,6,7,8-tetrahydronaphthalenes V
were also formed.11 Interestingly both these prototypes
were found to be active.
It was conceived that a diaryl naphthyl methane molecule
carrying a basic side chain on an aryl residue may
* Corresponding author. E-mail: atulcdri@yahoo.com
0968-0896/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2003.12.015

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N. Srivastava et al. / Bioorg. Med. Chem. 12 (2004) 1011–1021
Table 1.
S. Prototype
No
R1
R2 R3
4
5
6
7
8
9
III
III
III
III
III
III
III
III
III
III
III
III
IV
IV
IV
IV
IV
IV
IV
IV
V
OH
OH
OH
H
CH3
H
H
CH3
H
H
H
CH3
H
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
H
H
H
H
H
H
H
H
CH3
H
CH3
H
H
CH3
H
CH3
H
H
CH3
H
H
CH3
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
2-Pyrrolidin-1-yl-ethoxy
2-Pyrrolidin-1-yl-ethoxy
2-Pyrrolidin-1-yl-ethoxy
(Butyl-methyl-amino)-methoxy
Dimethylamino-methoxy
2-Diethylamino-ethoxy
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
2-Diethylamino-ethoxy
2-Piperidin-1-yl-ethoxy
2-Piperidin-1-yl-ethoxy
OH
OH
2-Pyrrolidin-1-yl-ethoxy
2-Pyrrolidin-1-yl-ethoxy
2-Piperidin-1-yl-ethoxy
2-Piperidin-1-yl-ethoxy
2-Diethylamino-ethoxy
2-Diethylamino-ethoxy
OH
OH
2-Pyrrolidin-1-yl-ethoxy
2-Pyrrolidin-1-yl-ethoxy
2-Piperidin-1-yl-ethoxy
2-Piperidin-1-yl-ethoxy
2-Diethylamino-ethoxy
2-Diethylamino-ethoxy
Oxiranyl-methyloxy
Oxiranyl-methyloxy
Figure 1. Possible regions of the ligand binding site of oestrogen
receptor involved in binding of the steroidal, stilbene, cis and trans
triarylethylene and triarylethane estrogens.
Compounds substituted with a tertiary aminoethoxy or
a 3-substituted amino-2-hydroxy propyloxy group at
the para position of an aryl residue elicited antifertility
activity at doses varying from 1–10 mgkgꢀ1 dayꢀ1
.
V
V
V
V
V
V
V
2. Chemistry
Synthesis of diaryl naphthyl methane derivatives was
carried out starting with a-naphthoic acid 1. Condensation
of a-naphthoic acid with anisole in the presence of
polyphosphoric acid produced 4-methoxy-naphtho-
phenone 2 which on reduction with sodium borohydride
gave (4-methoxyphenyl)-naphth-1-yl-carbinol 3 (Scheme).
A Friedel-Crafts reaction on the carbinol 3 with phenol
furnished (4-methoxyphenyl)-(4-hydroxyphenyl)-naphth-
1-yl methane 4 as the main product along with other
side products. Similarly, Friedel–Crafts reaction on the
o-cresol generated (4-methoxyphenyl)-(4-hydroxy-3-methyl
phenyl)-naphth-1-yl-methane 5. When m-cresol was
used in the above Friedel–Crafts reaction (4-methoxy-
phenyl)-(4-hydroxy-2-methyl phenyl)-naphth-1-yl methane
6 was obtained in major amounts (Table 1). Carrying
out Friedel–Crafts reaction twice, instead of generating
diaryl naphthyl methane through Friedel–Crafts on
naphthaldehyde was necessary as to have selectivity of
the substituent on the two aryl residues.
III
III
III
III
III
III
III
III
III
III
III
III
IV
IV
IV
IV
IV
V
3-Butylamino-2-hydroxy-1-propyloxy
3-Butylamino-2-hydroxy-1-propyloxy
3-Propylamino-2-hydroxy-1-propyloxy
3-Cyclopropylamino-2-hydroxy-1-propyloxy
3-Pyrrolidin-1-yl-2-hydroxy-1-propyloxy
3-Piperidin-1-yl-2-hydroxy-1-propyloxy
3-Morpholin-4-yl-2-hydroxy-1-propyloxy
3-Piperazin-1-yl-2-hydroxy-1-propyloxy
3-Cyclohexyl-2-hydroxy-1-propyloxy
3-Diethylamino-2-hydroxy-1-propyloxy
Oxiranyl-methyloxy
H
H
H
H
H
H
H
Oxiranyl-methyloxy
3-Butylamino-2-hydroxy-1-propyloxy
3-Butylamino-2-hydroxy-1-propyloxy
3-Dibutylamino-2-hydroxy-1-propyloxy
Oxiranyl-methyloxy
Oxiranyl-methyloxy
3-Butylamino-2-hydroxy-1-propyloxy
3-Butylamino-2-hydroxy-1-propyloxy
H
H
H
H
V
V
V
Catalytic hydrogenation of the above naphthyl deriva-
tives 4, 5 and 6 using Raney nickel as catalyst furnished
corresponding 1, 2, 3, 4- and 5, 6, 7, 8-tetra-
hydronaphth-1-yl-methane derivatives 16–17 and 24–25
respectively (Table 1).
A substituted amino alkyl group, generally a basic
requirement for estrogen antagonistic activity,12ꢀ15 was
introduced in the phenol derivatives 4–6 and their
corresponding tetrahydro derivatives 16–17 and 24–25 for
the preparation of the desired compounds. A tertiary
amino alkyl group was introduced by reacting the
phenol derivative with a tertiary amino alkyl halide
(Table 1). When the substituted phenol was first reacted
with epichlorohydrin and subsequently with a primary
or secondary amine, it yielded 3-substitutedamino-2-
hydroxypropyl derivatives (Table 1).

N. Srivastava et al. / Bioorg. Med. Chem. 12 (2004) 1011–1021
1013
Similarly, aminoalkoxy derivatives of 1, 2, 3, 4- and 5, 6,
7, 8-tetrahydro-naphth-1-yl-methane derivatives were
also prepared (Table 1). Compounds thus prepared
were routinely screened for antiimplantation activity.
Compounds showing cent percent activity at 10 mgkgꢀ1
or lower doses were generally evaluated for the Relative
Binding Affinity (RBA) for ER, estrogenic and anti-
estrogenic activities. Results are shown in Table 2.
binding site where the nitrogen containing basic side
chain of antiestrogens interact.
The validity of this model received support from the
X-ray studies with raloxifene bound receptor8 which sug-
gested that the extent of anti-estrogenicity much depend
upon positioning of the anti-estrogenic basic chain,
which in turn is structure dependent. Therefore, subtle
changes in the molecular structure may bring about
significant changes in the agonist to antagonist ratio of
the compound, which determines its particular pharma-
ceutical usage. Novel diaryl naphthyl methane deriva-
tives were designed to fit into the ER model.
All these compounds thus prepared were obtained as
racemates. An effective separation into pure enantio-
meric forms through optical resolution of their salts
with di-p-toluoyl-d-tartaric acid and di-p-toluolyl-l-
tartaric acid could not be achieved. Also, diastereomeric
forms of prototype IV have not been separated.
A study of the 3-D molecular structure of diaryl naph-
thyl methane, its comparison with estradiol and the
potent antiestrogen centchroman on silicon graphics Indy
R 4000 workstation employing Molecular Simulations
software (Insight II16 and Discover17) was carried out.
Structures were built in builder module of Insight II
software. The 3-D structures were later optimized for
their geometry using CVFF forcefield18 and the energy
minimization was performed using steepest descent,
conjugate gradient, Newton Raphsons algorithms in
sequence followed by Quasi Newton Raphson (va09a)
implemented in the discover module by using 0.001
3. Results and discussion
On the basis of Structure Activity Relationship (SAR)
studies carried out on antiestrogenic molecules prepared
in our laboratory and else where, we had earlier pro-
posed an estrogen receptor model.7 The receptor was
analyzed as composed of four subunits ABCD (Fig. 1),
wherein sub sites A to C presumably interact with
estrogenic component. Sub site D is the antiestrogen
Table 2.
S. No.
Dose
(mgkgꢀ1
Efficacy
(%)
RBA% of
Estradiol
Estrogenicity
(% increase in
uterine weight)
Antiestrogenicity
(% inhibition in ethynyl estradiol
induced uterine weight gain)
)
7
2.5
1
100
75
14
171
42
8
9
14
15
10
2.5
10
10
5
10
7.5
5
2.5
5
2.5
10
10
5
100
100
100
100
Inactive
100
199
75
100
100
67
100
100
100
67
50
100
100
75
100
100
100
Inactive
100
66.6
100
0.078
0.80
0.80
ND
202
120
ND
ND
46
42
0.029
18
6.126
ND
168
ND
29
ND
20
21
5.15
1.15
200
143
41
25
22
23
26
5.158
0.771
14.27
ND
ND
105
ND
ND
26
2.5
1
29
30
10
15
10
10
10
5
2.5
15
10
15
5
0.78
0.62
ND
ND
ND
ND
34
37
38
ND
0.84
0.293
ND
196
159
18
ND
36
34
10
39
40
10.48
0.68
196
31
150
1961
169
34
35
25
14
Inactive
100
100
42
46
10
5
0.76
5.14
119
2.5
5
Inactive
100
47
2.66
132
25
2.5
5
10
Inactive
100
75
48
52
17.28
33.49
129
133
27
20

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N. Srivastava et al. / Bioorg. Med. Chem. 12 (2004) 1011–1021
kcalmolꢀ1 energy gradient convergence and maximum
number of iteration set to 1000. Energy minimized
structures were stored in MDL format.
methanes with other antiestrogens, which explains its
antiestrogenic behavior.
Interestingly, A ring reduced diaryl naphthyl methanes
were found to be equipotent as B ring reduced compounds.
This may be explained on the basis of molecular modeling
studies, which suggest (Fig. 2) that the molecule could
be alternatively superimposed on to estradiol with the D
ring of estradiol overlaying A ring of the diaryl naphthyl
methane, (RMS fit value 0.089109).
The conformational resemblances of the molecules were
assessed using the RMS fitting option of the Search-
Compare19 module. One-to-one correspondences for
atoms in the molecules to be superimposed were specified.
The RMS fit between the superimposed molecules was
noted. Figure 2 shows molecular similarity of diaryl
naphthyl methane with estradiol. The RMS fit value
was found to be 0.665287. This would suggest the bind-
ing of the molecule to the receptor at the active site
where estradiol binds. Superimposition of the diaryl
naphthyl methane molecule on to the antiestrogen cen-
tchroman shown in Figure 2, with RMS fit value of
0.662630, shows that in both the molecules the nitrogen
containing basic residue is similarly disposed.
These compounds were synthesized as antiimplantation
agents wherein antiestrogenic property of the compound
interferes with the implantation process in rats. However,
a weak estrogenic profile may be helpful in proper
regulation of the reproductive processes. Significant
activity was observed only in basic chain added com-
pounds Table 2. Compounds 7, 9 and 20 found to be
active at 2.5 mgkgꢀ1 dose were most active ones of this
series. Unlike 3, 4-diaryl chromenes and chromans21
wherein a 3-substitutedamino-2-hydroxypropyloxy group
added compound showed better activity as compared to
2-tertiary aminoethoxy, in this series the latter group
In our X-ray based studies reported earlier,20 we have
shown that potent antiestrogens like tamoxifen, nafoxidene
and centchroman show similar disposition in space.
Thus, the present study correlates diaryl naphthyl
Figure 2. Superposition of (a) centchroman with diaryl naphthyl methane, (b) diaryl naphthyl methane with estradiol, (c) diaryl naphthyl methane
(A ring reduced) with A ring of estradiol, (d) diaryl naphthyl methane (B ring reduced) with D ring of estradiol and (e) diaryl naphthyl methane
(B ring reduced) with estradiol.

N. Srivastava et al. / Bioorg. Med. Chem. 12 (2004) 1011–1021
1015
was found to be better. Since the compounds did not
possess a free phenolic group, their RBA values were of
low order.
acetate. The organic layer was washed with water, dried
over sodium sulphate and concentrated. This crude
product was purified by flash column chromatography
on silica gel using 5% ethyl acetate in hexane as eluant.
It has been earlier shown22 that a phenolic residue in the
estradiol binding zone, on substitution with a basic
chain, produces compounds with lower RBA value
compared to the phenol whereas a similar substitution
when carried out on a phenolic residue present in anti-
estrogen binding zone enhances the RBA of the
compound. In the present series it was observed that
incorporation of a basic residue in prototype IV resulted
in a decrease of RBA whereas a similar change in
prototype V had a reverse effect. However, hydroxy
compounds in all three prototypes were either less active
or inactive, thereby suggesting that the biological activity
is not through removal of the basic chain and a
consequent estrogenic effect produced by the hydroxy
group thus generated. It is likely that under the present
situation, the diphenyl methyl residue attached to
naphthyl ring enjoys a free rotation thereby the phenolic
residue may occupy a position in the estrogen binding
zone when unsubstituted or on the antiestrogen binding
zone when a basic residue is attached.
4.4. General procedure for preparation of compounds 7–
9, 11–15, 18–23 and 26–31
A mixture of substituted (4-methoxyphenyl)-(4-hydr-
oxyphenyl)-naphth-1-yl-methane (1 mmol), anhydrous
potassium carbonate (3 fold excess by weight), tertiary
amino alkyl halide chain (2 mmol) and dry acetone (as
solvent) was refluxed for 8–12 h. Potassium carbonate
was filtered off, acetone was distilled off and residue was
diluted with water, dried over sodium sulphate and
concentrated. The oil thus obtained was treated with
ethanolic HCl. The solvent was evaporated off and
compound was crystallized from absolute alcohol and
dry ether, filtered under anhydrous condition (hygro-
scopic) and dried in Abderhalden drying apparatus.
4.5. (4-Methoxyphenyl)-(4-pyrrolidinoethoxy-phenyl)-
naphth-1-yl-methane N-methyl iodide (10)
A mixture of (4-methoxyphenyl)-(4-pyrrolodinoethoxy-
phenyl)-naphth-1-yl-methane (0.5 g, 1.14 mmol), methyl
iodide (0.3 mL, 4.81 mmol) anhydrous potassium
carbonate (1 g, 7.24 mmol) in dry acetone (20 mL) was
refluxed for 15 h. Acetone was distilled off. Reaction
mixture was extracted with ethyl acetate, washed with
water, dried over anhydrous sodium sulphate and
concentrated to give the desired product.
4. Experimental
4.1. (4-Methoxy-phenyl)-1-(naphth-1-yl)-ketone (2)
A mixture of naphthoic acid (10 g, 0.057 mol), anisole
(18 mL, 0.165 mol) and polyphosphoric acid (100 g) was
taken in r.b. flask. The reaction mixture was heated for
10–12 h on water bath at 80 ꢁC. The reaction mixture
was then poured onto ice and extracted with ethyl
acetate. Excess of naphthoic acid was washed off with
sodium bicarbonate and then organic layer was washed
with water till neutral, dried over sodium sulphate and
concentrated. The oily residue thus obtained was
crystallized from benzene–hexane.
4.6. General procedure for preparation of compounds
16–17 and 24–25
A
mixture of substituted (4-methoxy-phenyl)-(4-
hydroxyphenyl)-naphth-1-yl-methane (8 mmol) in
methanol (as solvent) and Raney nickel (3 g) was
hydrogenated at 40–50 psi pressure for 6–8 h. Then
catalyst was filtered off and methanol was distilled off.
The crude product was purified by flash column chroma-
tography on silica gel using 5% ethyl acetate–hexane as
eluant.
4.2. (4-Methoxy-phenyl)-1-naphth-1-yl-carbinol (3)
Naphthophenone (10 g, 0.038 mol) was dissolved in 100
mL of methanol. To the stirred reaction mixture,
sodium borohydride (2.5 g, 0.66 mol) was added slowly
and stirring continued for 4–5 h. Then methanol was
distilled off and the reaction mixture was extracted with
ethyl acetate. The organic layer was washed with water,
dried over sodium sulphate and concentrated. The oily
residue thus obtained was crystallized from benzene–
hexane.
4.7. General procedure for preparation of compounds
32–33, 44–45 and 49–50
A
mixture of substituted (4-methoxy-phenyl)-(4-
hydroxyphenyl)-naphth-1-yl-methane (1 mmol), anhy-
drous potassium carbonate (3-fold excess by weight)
and epichlorohydrine (as solvent) was refluxed for 10–
12 h at 120 ꢁC. The reaction mixture was filtered and
solvent was distilled off. The residue was dissolved in
ether, washed with NaOH (10%) and water, dried over
sodium sulphate and concentrated to give oil. This oil
was purified by column chromatography on silica gel
using hexane–chloroform as eluant. General procedure
for preparation of compounds 34–43, 46–48 and 51–52.
A mixture of substituted (4-methoxy phenyl)-(4-(2,3-
4.3. General procedure for preparation of compounds 4–6
A mixture of (4-methoxy-phenyl)-naphth-1-yl-carbinol
(1.0 mmol) and substituted phenol (1.0 mmol) was
taken in a mixture of dry benzene and dry pentane (1:1).
To this stirred solution, AlCl3 (1.0 mmol) was added at
0–4 ꢁC. After 15 min tin (lV) chloride (1.5 mmol)) was
added and stirring continued for 4–5 h. Reaction mix-
ture was decomposed with ice-cold water (200 mL)
containing 0.5 mL concd HCl, and extracted with ethyl
epoxypropyloxy)-phenyl))-naphth-1-yl
methane
(1
mmol), amine (1 mmol) and ethanol (as solvent) was
refluxed for 3–4 h. Ethanol was distilled off and the

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N. Srivastava et al. / Bioorg. Med. Chem. 12 (2004) 1011–1021
residue was passed through basic alumina column using
hexane–benzene as eluant.
2ꢂCH2 pyrrolidine), 2.42–2.6 (m, 4H, 2ꢂN CH2 pyrro-
lidine), 2.77 (t, 2H, CH2N J=5 Hz), 3.65 (s, 3H, OMe),
4.21 (t, 2H, OCH2 J=3.6 Hz), 6.05 (s, 1H, CH), 6.65–
7.65 (m, 15H, ArH);MS m/z 437. Anal. (C30H32O2NCl),
C, 76.01;H, 6.80;N, 2.95 Found: C, 76.23;H, 6.57;N,
2.68.
4.8. Characterization of products
4.8.1. (4-Methoxyphenyl)-1-naphth-1-yl-ketone (2). Yield:
11.5 g (75.5%), mp 97 ꢁC, IR (KBr, cmꢀ1): 1500, 1580,
1
1600 (ArH), 1660 (C¼O); H NMR (d, CDCl3) 3.85 (s,
4.8.7. (4-Methoxyphenyl)-(3-methyl-4-pyrrolidinoethoxy-
phenyl)-naphth-1-yl-methane hydrochloride (8). Yield:
46%, mp 140–143 ꢁC, IR (KBr, cmꢀ1) 1500, 1600
3H, OMe), 6.85–7.15 (m, 4H, ArH), 7.7–7.8 (m, 7H,
ArH), MS m/z 262. Anal. (C18H14O2), C, 82.4;H, 5.38,
Found: C, 82.23;H, 5.31.
1
(ArH), 3320 (amine); H NMR (d, CDCl3) 1.3–1.7 (m,
4H, 2ꢂCH2 pyrrolidine), 2.14 (s, 3H, CH3), 2.4–2.6 (m,
4H, 2ꢂNCH2 pyrrolidine), 2.7 (t, 2H, NCH2), 3.7 (s, 3H,
OMe), 4.1 (t, 2H, OCH2), 6.1 (s, 1H, CH), 6.6–8.0 (m,
14H, ArH);MS m/z 451. Anal. (C31H34O2NCl), C,
82.45;H, 7.37;N, 3.10 Found: C, 82.26;H, 6.97;N, 2.88.
4.8.2. (4-Methoxyphenyl)-1-naphth-1-yl-carbinol (3).
Yield: 9.2 g (91.3%), mp. 92 ꢁC, IR (KBr, cmꢀ1) 1500,
1600 (ArH), 3200 (HO), 1H NMR (d, CDCl3) 2.5 (s, 1H,
OH), 3.7 (s, 3H, OMe), 6.40 (s, 1H, CH), 6.8 (dd, 2H,
ArH), 7.23 (dd, 2H, ArH), 7.23–7.53 (m, 3H, naphth),
7.63 (d, 1H, naphth), 7.74 (d, 1H, naphth), 7.82 (d, 1H,
naphth), 7.92 (d, 1H, naphth);MS m/z 264. Anal.
(C18H16O2), C, 81.79;H, 6.10, Found: C, 81.83;H, 5.94.
4.8.8. (4-Methoxyphenyl)-(2-methyl-4-pyrrolidinoethoxy-
phenyl)-naphth-1-yl-methane (9). Yield: 61.22%, oil;IR
(Neat, cmꢀ1) 1460, 1512, 1606 (ArH), 1215 (OMe),
1
2929 (CH), 3685 (Amine); H NMR (d, CDCl3) 2.85 (t,
4.8.3. (4-Methoxyphenyl)-(4-hydroxy phenyl)-naphth-1-
)
2H, CH2N), 3.77 (s, 3H, OMe), 4.03–4.10 (t, 2H,
OCH2), 6.58–7.84 (m, 14H, ArH), 6.16 (s, 1H, CH), 1.9–
1.29 (m, 4H, 2ꢂCH2 pyrrolidine), 1.79–2.04 (m, 4H,
2ꢂNCH2 pyrrolidine);MS m/z 451.
yl-methane (4). Yield: 73%, mp 140 ꢁC, IR (KBr, cmꢀ1
1244 (OMe), 1444, 1508, 1604 (ArH), 2954 (CH), 3298
1
(OH); H NMR (CDCl3) 6.70–6.74 (dd, 2H, meta to
OH), 6.78–6.82 (dd, 2H, ortho to OH), 6.91–6.93 (dd,
2H, meta to OMe), 6.94 (dd, 2H, ortho to OMe), 7.30
(m, 1H, naphth), 7.34–7.35 (m, 2H, naphth), 7.40–7.41
(dd, 1H, naphth), 7.70–7.74 (d, 1H, naphth), 7.81 (d,
1H, naphth), 7.94 (d, 1H, naphth), 3.76 (s, 3H, MeO),
6.14 (s, 1H, CH), 4.6 (s, 1H, OH);MS m/z 340. Anal.
(C24H20O2), C,84.68;H,5.92. Found: C, 84.55;H, 5.84.
4.8.9. (4-Methoxyphenyl)-(4-pyrrolidinoethoxy-phenyl)-
naphth-1-yl-methane N-methyl iodide (10). Yield: 0.41 g
(63.42%), mp 70 ꢁC, IR (KBr, cmꢀ1) 1461, 1508, 1554,
1
1608 (ArH), 2925 (CH),1244 (OMe), 3759 (amine); H
NMR (d, CDCl3) 6.1 (s, 1H, CH), 6.7–7.8 (m, 15H,
ArH), 2.3 (m, 4H, 2ꢂNCH2 pyrrolidine), 3.36 (s, 3H,
NCH3), 3.8–4.1 (t, 2H, CH2N), 4.3–4.4 (t, 2H, OCH2),
3.78 (s, 3H, OMe), 1.2–1.3 (m, 4H, 2ꢂCH2 pyrrolidine);
MS m/z 452 [M+ꢀ127].
4.8.4. (4-Methoxyphenyl)-(3-methyl-4-hydroxy phenyl)-
naphth-1-yl-methane (5). Yield: 67.16%, mp 126–128 ꢁC,
IR (KBr, cmꢀ1) 1240 (OMe), 1500, 1600 (ArH), 3379
1
(OH); H NMR (CDCl3) 2.14 (s, 3H, CH3) 3.74 (s, 3H,
4.8.10. (4-Methoxyphenyl)-(4-diethylaminoethoxy-phenyl)-
naphth-1-yl-methane (11). Yield: 48.78%, oil;IR (Neat,
OMe), 4.61 (s, 1H, OH), 6.12 (s, 1H, CH), 6.64 (dd, 1H,
ArH, ortho to OH), 6.74 (dd, 1H, ArH, meta to OH),
7.01 (dd, 2H, ArH, meta to OMe), 6.93 (d, 1H, naphth),
6.8 (dd, 2H, ortho to OMe), 6.86 (s, 1H, ArH, ortho to
CH3), 7.32–7.43 (m, 3H, naphth), 7.72 (d, 1H, naphth),
7.84 (d, 1H, naphth), 7.94 (d, 1H, naphth);MS m/z 354.
Anal. (C25H22O2), C, 84.72 and H, 6.26 Found: C,
84.53;H, 6.20.
1
cmꢀ1) 1500, 1580, 1600 (ArH), 3360 (Amine); H NMR
(d, CDCl3): 0.97 (t, 6H, 2ꢂCH3 J=5 Hz), 2.54 (q, 4H,
2ꢂCH2 J=5 Hz), 2.78 (t, 2H, CH2N), 3.65 (s, 3H,
OMe), 3.92 (t, 2H, OCH2 J=5 Hz), 6.05 (s, 1H, CH),
6.65–7.65 (m, 15H, ArH);MS m/z 439.
4.8.11. (4-Methoxyphenyl)-(3-methyl-4-(N-N-diethylamino
ethoxy-phenyl)-naphth-1-yl-methane hydrochloride (12).
Yield: 49.09%;mp 115–116 ꢁC;IR (KBr, cm ꢀ1): 1500,
1600 (ArH), 3370 (amine); 1H NMR (d, CDCl3): 1.1–1.3
(m, 6H, 2ꢂCH3), 2.17 (s, 3H, CH3), 2.5–3.0 (m, 6H,
3ꢂNCH2), 3.7 (s, 3H, OMe), 4.0 (t, 2H, OCH2), 6.1 (s,
1H, CH), 6.7–8.0 (m, 14H, ArH);MS m/z 453.
4.8.5. (4-Methoxyphenyl)-(2-methyl-4-hydroxy phenyl)-
naphtha-1-yl-methane (6). Yield: 73.08%, mp 110 ꢁC, IR
(KBr, cmꢀ2) 1454, 1508, 1584, 1616 (ArH), 2974 (CH),
1
1242 (OMe), 3344 (OH); H NMR (CDCl3) 6.53–6.55
(dd, 1H, meta to OH), 6.58–6.64 (dd, 1H, ortho to OH),
6.65–6.66 (dd, 2H, meta to OMe), 6.93–6.97 (dd, 2H,
ortho to OMe), 7.73–7.77 (d, 1H, naphth), 7.87 (d, 1H,
naphth), 7.83 (d, 1H, naphth), 7.30–7.41 (m, 4H,
naphth), 3.77 (s, 3H, MeO), 4.74 (s, 1H, OH), 6.16 (s,
1H, CH), 2.16 (s, 3H, CH3), 7.27 (s, 1H, ortho to OH);
MS m/z 354. Anal. (C25H22O2), C, 84.72 and H, 6.26
Found: C, 84.42;H, 6.32.
4.8.12. 4-Methoxyphenyl-2-methyl-4-diethylaminoethoxy)-
phenyl-naphth-1-yl-methane (13). Yield: 72.99%, oil;IR
(Neat, cmꢀ1) 1463, 1506, 1583, 1614 (ArH), 2976 (CH),
3225 (OH), 1217 (OMe), 3425 (amine); 1H NMR
(CDCl3) 1.0–1.07 (t, 6H, 2ꢂCH3), 2.58 (t, 2H, NCH2), 3.77
(s, 3H, OMe), 3.96 (t, 2H, OCH2), 6.57–7.86 (m, 14H,
ArH), 6.16 (s, 1H, CH), 2.5 (q, 4H, 2ꢂNCH2);MS m/z 453.
4.8.6. (4-Methoxyphenyl)-(4-pyrrolidinoethoxy-phenyl)-
naphth-1-yl-methane hydrochloride (7). Yield: 56.26%,
mp 212 ꢁC, IR (KBr, cmꢀ1) 1500, 1580, 1600 (ArH),
3380 (Amine); 1H NMR (d, CDCl3) 1.6–1.8 (m, 4H,
4.8.13. (4-Methoxyphenyl)-(4-piperidinoethoxy-phenyl)-
naphth-1-yl-methane (14). Yield: 66.1%, oil;IR (Neat,
1
cmꢀ1) 1510, 1608, 1695 (ArH), 3371 (amine); H NMR

N. Srivastava et al. / Bioorg. Med. Chem. 12 (2004) 1011–1021
1017
(d, CDCl3) 1.60–1.62 (m, 6H, 3ꢂCH2 of piperidine ring),
2.49–2.52 (m, 4H, 2ꢂNCH2 piperidine), 2.78 (t, 2H,
NCH2), 3.79 (s, 3H, OMe), 4.06–4.10 (t, 2H, OCH2), 6.16
(s, 1H, CH), 6.80–7.80 (m, 15H, ArH);MS m/z 451.
72%, oil;IR (Neat, cm ꢀ1) 1458, 1506, 1583, 1610
(ArH), 3400 (amine) 2931 (CH); H NMR (d, CDCl3)
1.25–1.83 (m, 10H, 2ꢂCH2 naphth and 3ꢂCH2 piper-
idine), 2.09–2.19 (2s, 3H, CH3 — due to restricted rota-
tion), 2.51–2.53 (m, 4H, 2ꢂNCH2 piperidine), 2.76–2.81
(m, 4H, N-CH2 and CH2 naphth), 3.49 (m, 1H, CH
naphth), 3.72 (s, 3H, OMe), 3.94 (d, 1H CH), 4.03–4.09
(m, 2H, OCH2), 6.67–7.23 (m, 11H, ArH);MS m/z 469.
1
4.8.14. (4-Methoxyphenyl)-(3-methyl-4-piperidinoethoxy-
phenyl)-naphth-1-yl-methane (15). Yield: 55.23%, oil;IR
1
(Neat, cmꢀ1) 1506 (ArH), 3260 (amine); H NMR (d,
CDCl3) 1.60–1.62 (m, 6H, 3ꢂCH2 of piperidine ring),
2.47–2.51 (m, 4H, 2ꢂNCH2), 2.78 (t, 2H, NCH2), 3.74
(s, 3H, OMe), 4.0 (t, 2H, OCH2), 6.1 (s, 1H, CH), 6.6–
8.0 (m, 14H, ArH);MS m/z 465.
4.8.21. (4-Methoxyphenyl)-(4-N-N-diethylaminoethoxy-
phenyl)-1,2,3,4-tetrahydro naphth-1-yl-methane (22).
Yield: 62.5%, oil;IR (Neat, cm ꢀ1) 1463, 1510, 1581,
1608 (ArH), 3340 (amine); 1H NMR (d, CDCl3) 1.07 (s,
6H, CH3), 1.81–1.82 (m, 4H, 2ꢂCH2 naphth), 2.62–2.64
(m, 4H, 2ꢂNCH2), 2.81–2.88 (m, 4H, N-CH2 and CH2
naphth), 3.46–3.48 (m, 1H, CH naphth), 3.73 (s, 3H,
OMe), 3.97–4.04 (m, 3H, OCH2 and CH), 6.35–7.25 (m,
12H, ArH);MS m/z 443.
4.8.15. (4-Methoxyphenyl)-(4-hydroxyphenyl)-1,2,3,4-tetra-
hydronaphth-1-yl-methane (16). Yield: 29%;oil;IR
1
(Neat, cmꢀ1): 1454, 1510, 1608 (ArH), 3320 (OH); H
NMR (d, CDCl3): 1.55–1.99 (m, 4H, 2ꢂCH2 naphth),
2.73–2.93 (m, 2H, CH2 naphth), 3.46 (m, 1H, CH
naphth), 3.73 (s, 3H, OMe), 4.0 (d, 1H, CH), 4.6 (2s,
1H, OH), 6.33–7.23 (m, 12H, ArH);MS m/z 344.
4.8.22. 4-Methoxyphenyl-3-methyl-4-diethylaminoethoxy
phenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane (23). Yield:
67.6%, oil;IR (Neat, cm ꢀ1) 1510, 1606 (ArH), 2976
4.8.16. (4-Methoxyphenyl)-(3-methyl-4-hydroxyphenyl)-
1,2,3,4-tetrahydronaphth-1-yl-methane (17). Yield: 31.5%;
1
(CH), 1215 (OMe), 3411 (amine), H NMR (d, CDCl3)
1
IR (Neat, cmꢀ1): 1602 (ArH), 3374 (OH); H NMR (d,
1.25–1.26 (m, 6H, 2ꢂCH3), 1.5–2.0 (m, 4H, 2ꢂCH2
naphth), 2.0–2.2 (2s, 3H, CH3 — due o restricted rota-
tion), 2.59–2.63 (m, 4H, 2ꢂNCH2), 2.84–2.92 (m, 4H,
NCH2 and CH2 naphth), 3.49 (m, 1H, CH naphth), 3.73
(s, 3H, OMe), 4.01 (m, 3H, OCH2 and CH), 6.67–7.23
(m, 11H, ArH);MS m/z 457.
CDCl3): 1.5–1.9 (m, 4H, 2ꢂCH2 naphth), 2.16 (s, 3H,
CH3), 2.7–2.8 (m, 2H, CH2 naphth), 3.5 (m, 1H, CH
naphth), 3.7 (s, 3H, OMe), 3.9 (d, 1H, CH), 4.6 (2s, 1H,
OH), 6.3–7.23 (m, 11H, ArH);MS m/z 358.
4.8.17. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-
1,2,3,4-tetrahydronaphth-1-yl-methanehydrochloride (18).
Yield: 68.35%, mp 148 ꢁC;IR (KBr, cm ꢀ1) 1452, 1510,
4.8.23. (4-Methoxyphenyl)-(4-hydroxyphenyl)-5,6,7,8-tet-
rahydronaphth-1-yl-methane (24). Yield: 26%, mp 154–
157 ꢁC;IR (KBr, cm ꢀ1) 1506, 1602 (ArH), 1245 (OMe),
1
1610 (ArH), 3435 (amine); H NMR (d, CDCl3) 1.6–1.8
1
(m, 8H, 2ꢂCH2 naphth and 2ꢂCH2 pyrrolidine), 2.66
(m, 4H, 2ꢂNCH2 pyrrolidine), 2.9–3.0 (m, 4H, N-CH2
and CH2 naphth), 3.52 (m, 1H, CH naphth), 3.74 (s,
3H, OMe), 3.98–4.08 (m, 3H, OCH2 and CH), 6.35–7.26
(m, 12H, ArH);MS m/z 441.
3429 (OH); H NMR (d, CDCl3) 1.73 (m, 4H, 2ꢂCH2
naphth), 2.59 (m, 2H, CH2 naphth), 2.79 (m, 2H,
2ꢂCH2 naphth), 3.79 (s, 3H, OMe), 5.54 (s, 1H, CH),
4.43 (s, 1H, OH), 6.60–7.0 (m, 11H, ArH);MS m/z 344.
4.8.24. (4-Methoxyphenyl)-(3-methyl-4-hydroxyphenyl)-
5,6,7,8-tetrahydronaphth-1-yl-methane (25). Yield: 28.7%,
4.8.18. (4-Methoxyphenyl)-(3-methyl-4-pyrrolidinoethoxy
phenyl)-1,2,3,4-tetrahydro naphth-1-yl-methane (19).
Yield: 44%, oil;mp 148 ꢁC;IR (Neat, cm ꢀ1) 1510,
1
oil;IR (Neat, cm ꢀ1) 1500, 1610 (ArH), 3520 (OH); H
NMR (d, CDCl3) 1.7 (bs, 4H, 2ꢂCH2 naphth), 2.16 (s,
3H, CH3), 2.6 (m, 2H, CH2 naphth), 2.8 (bs, 2H,
2ꢂCH2 naphth), 3.75 (s, 3H, OMe), 5.5 (s, 1H, CH), 4.6
(s, 1H, OH), 6.6–7.0 (m, 10H, ArH);MS m/z 358.
1
1583, 1608 (ArH), 3400 (amine) 2931 (CH); H NMR
(d, CDCl3) 1.26–1.83 (m, 8H, 2ꢂCH2 naphth and
2ꢂCH2 pyrrolidine), 2.1–2.2 (2s, 3H, CH3 — due to
restricted rotation), 2.64 (m, 4H, 2ꢂNCH2 pyrrolidine),
2.86–2.92 (m, 4H, N-CH2 and CH2 naphth), 3.49 (m,
1H, CH naphth), 3.72–3.77 (s, 3H, OMe), 3.94 (d, 1H,
CH), 4.0 (t, 2H, OCH2), 6.28–7.25 (m, 11H, ArH);MS
m/z 455.
4.8.25. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-
5,6,7,8-tetrahydronaphth-1-yl-methane hydrochloride (26).
Yield: 42.30%, mp 196–198 ꢁC;IR (KBr, cm ꢀ1) 1510,
1
1608 (ArH), 1217 (OMe), 3435 (amine); H NMR (d,
CDCl3) 1.71 (m, 4H, 2ꢂCH2 naphth) 2.08–2.24 (broad
m, 4H, 2ꢂCH2 pyrrolidine), 2.57 (m, 2H, CH2 naphth),
2.98 (t, 2H, NCH2), 3.46 (m, 4H, 2ꢂN-CH2 pyrroli-
dine), 3.78 (s, 3H, OMe), 3.86–4.0 (t, 2H, OCH2), 5.54
(s, 1H, CH), 6.58–6.81(m, 11H, ArH);MS m/z 441.
Anal. (C31H34O3NCl), C, 73.87;H, 6.80;N, 2.78
Found: C, 74.12;H, 7.14;N, 2.92.
4.8.19. (4-Methoxyphenyl)-(4-piperidinoethoxyphenyl)-
1,2,3,4-tetrahydronaphth-1-yl-methane (20). Yield: 58.6%,
oil;IR (Neat, cm ꢀ1) 1456, 1508, 1608 (ArH), 3433
1
(amine), 1247 (OMe); H NMR (d, CDCl3) 1.45–1.82
(m, 10H, 2ꢂCH2 naphth and 3ꢂCH2 piperidine), 2.48–
2.49 (m, 4H, 2ꢂNCH2 piperidine), 2.81–2.83 (m, 4H, N-
CH2 and CH2 naphth), 3.51 (m, 1H, CH naphth), 3.75
(s, 3H, OMe), 3.97–4.07 (m, 3H, OCH2 and CH), 6.32–
7.25 (m, 12H, ArH);MS m/z 455.
4.8.26. (4-Methoxyphenyl)-(3-methyl-4-pyrrolidinoethoxy
phenyl)-5,6,7,8-tetrahydro naphth-1-yl-methane (27). Yield:
48.5%, oil;IR (Neat, cm ꢀ1) 1461, 1506, 1583, 1608
(ArH), 1217 (OMe), 3390 (amine); 1H NMR (d, CDCl3)
1.70–1.72 (m, 4H, 2ꢂCH2 naphth), 2.17 (s, 3H, CH3),
4.8.20. (4-Methoxyphenyl)-(3-methyl-4-piperidinoethoxy
phenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane (21). Yield:

1018
N. Srivastava et al. / Bioorg. Med. Chem. 12 (2004) 1011–1021
2.63–2.67 (m, 6H, 2ꢂCH2 pyrrolidine and CH2 naphth),
2.78 (m, 2H, CH2 naphth), 2.91–2.93 (t, 2H, N-CH2),
3.47–3.67 (m, 4H, NCH2), 3.78 (s, 3H, OMe), 4.0–4.1 (t,
2H, OCH2), 5.5 (s, 1H, CH), 6.70–6.99 (m, 10H, ArH);
MS m/z 455.
4.8.33. (4-Methoxyphenyl)-[4-(2-hydroxy-3-n-butylamino
propyloxy)-phenyl]-naphth-1-yl-methane (34). Yield:
58.27%), oil;IR (Neat, cm ꢀ1) 1461, 1508, 1600 (ArH),
1
2974 (CH), 1230 (OMe), 3478 (OH), 3413 (amine). H
NMR (d, CDCl3) 1.4 (m, 9H, NCH2C3H7), 2.7 (d, 2H,
NCH2), 2.9 (m, 1H, NH), 3.95 (d, 2H, OCH2), 3.75 (s,
3H, OMe), 4.0 (m, 1H, CHOH), 6.7–7.8 (m, 15H, ArH),
6.15 (s, 1H, CH);MS m/z 469.
4.8.27. (4-Methoxyphenyl)-(4-piperidinoethoxyphenyl)-
(28).
5,6,7,8-tetrahydronaphth-1-yl-methane
Yield:
55.89%, oil;IR (Neat, cm ꢀ1) 1508, 1583, 1608 (ArH),
1
3306 (amine); H NMR (d, CDCl3) 1.57–1.73 (m, 10H,
4.8.34. (4-Methoxyphenyl)-[3-methyl-4-(2-hydroxy-3-n-
butyl aminopropyloxy)-phenyl]-naphth-1-yl-methane (35).
Yield: 41.6%), mp 138 ꢁC;IR (KBr, cm ꢀ1) 1510, 1600
(ArH), 2980 (CH), 1230 (OMe), 3450 (OH), 3443
(amine); 1H NMR (d, CDCl3) 1.4 (m, 9H, NCH2C3H7),
2.16 (s, 3H, CH3), 2.7 (d, 2H, NCH2), 2.9 (m, 1H, NH),
3.95 (d, 2H, OCH2), 3.75 (s, 3H, OMe), 4.1 (m, 1H,
CHOH), 6.7-8.0 (m, 14H, ArH), 6.15 (s, 1H, CH);MS
m/z 483.
2ꢂCH2 naphth and 3ꢂCH2 piperidine), 2.4–2.5 (m, 4H,
2ꢂNCH2 piperidine), 2.60–2.64 (m, 2H, CH2 naphth),
2.75–2.79 (m, 4H, CH2 naphth and NCH2), 3.79 (s, 3H,
OMe), 4.0–4.1 (t, 2H, OCH2), 5.5 (s, 1H, CH), 6.6–7.0
(m, 11H, ArH);MS m/z 455.
4.8.28. (4-Methoxyphenyl)-(3-methyl-4-piperidinoethoxy
phenyl)-5,6,7,8-tetrahydro naphth-1-yl-methane (29).
Yield: 51.7%, oil;IR (Neat, cm ꢀ1) 1512, 1610 (ArH),
3398 (amine) 2935 (CH), 1215 (OMe); 1H NMR (d,
CDCl3) 1.57–1.73 (m, 10H, 2ꢂCH2 naphth and 3ꢂCH2
piperidine), 2.14 (s, 3H, CH3), 2.4–2.5 (m, 4H, 2ꢂNCH2
piperidine), 2.60–2.64 (m, 2H, CH2 naphth), 2.75–2.79
(m, 4H, CH2 naphth and NCH2), 5.5 (m, 1H, CH), 3.79
(s, 3H, OMe), 3.99 (t, 2H OCH2), 6.6–7.2 (m, 10H,
ArH);MS m/z 469.
4.8.35. (4-Methoxyphenyl)-[4-(2-hydroxy-3-n-propylamino
propyloxy)-phenyl]-naphth-1-yl-methane (36). Yield:
65.27%, oil;IR (Neat, cm ꢀ1) 1473, 1519 (ArH), 2960
(CH), 3685 (OH), 1215 (OMe), 3685 (OH), 1215 (OMe),
1
3766 (amine); H NMR (d, CDCl3) 1.18–1.36 (m, 7H,
C3H7), 3.95 (m, 1H, NH), 2.77 (d, 2H, CH2N), 3.7 (s,
3H, OMe), 3.8 (d, 2H, OCH2), 4.16 (s, 1H, CHOH),
6.71–7.88 (m, 15H, ArH), 6.09 (s, 1H, CH), MS m/z
455.
4.8.29. (4-Methoxyphenyl)-(4-N-N-diethylaminoethoxy-
phenyl)-5,6,7,8-tetrahydro naphth-1-yl-methane (30).
Yield: 69.76%, oil;IR (Neat, cm ꢀ1) 1508, 1583, 1608
(ArH), 3354 (amine); 1H NMR (d, CDCl3) 1.04 (m, 6H,
2ꢂCH3), 1.72 (broad s, 4H, 2ꢂCH2), 2.60–2.67 (m, 6H,
CH2 naphth and 2ꢂNCH2), 2.79–2.89 (m, 4H, N-CH2
and CH2 naphth), 5.5 (s, 1H, CH naphth), 3.74 (s, 3H,
OMe), 4.0 (t, 2H, OCH2), 6.6–7.0 (m, 11H, ArH);MS
m/z 443.
4.8.36. (4-Methoxyphenyl)-[4-(2-hydroxy-3-cyclopropyl-
amino propyloxy)-phenyl]-naphth-1-yl-methane (37). Yield:
46.62%, oil;IR (Neat, cm ꢀ1): 1600 (ArH), 2980 (CH),
1
1230 (OMe), 3451 (OH), 3434 (amine); H NMR (d,
CDCl3) 1.7–2.2 (m, 5H, cyclopropyl), 2.7 (d, 2H,
NCH2), 2.8 (m, 1H, NH), 3.96 (d, 2H, OCH2), 3.7 (s,
3H, OMe), 4.0 (m, 1H, CHOH), 6.7–7.9 (m, 15H, ArH),
6.15 (s, 1H, CH);MS m/z 453.
4.8.30. 4-Methoxyphenyl-2-methyl-4-diethylaminoethoxy
phenyl)-5,6,7,8-tetrahydro naphth-1-yl-methane (31).
Yield: 53.21%, oil;IR (Neat, cm ꢀ1) 1461, 1506, 1608
(ArH), 2972 (CH), 3413 (amine), 1217 (OMe); 1H NMR
(d, CDCl3) 1.23 (m, 6H, 2ꢂCH3), 1.62–1.77 (m, 4H,
2ꢂCH2 naphth), 2.12 (s, 3H, CH3), 2.53–2.69 (m, 6H,
CH2 naphth and 2ꢂNCH2) 2.7–2.8 (m, 2H, CH2
naphth), 3.77 (s, 3H, OMe), 4.0 (t, 2H, OCH2), 6.6–7.0
(m, 10H, ArH), 5.5 (s, 1H, CH), 2.9 (m, 2H, NCH2);
MS m/z 457.
4.8.37. (4-Methoxyphenyl)-[4-(2-hydroxy-3-pyrrolidino
propyloxy)-phenyl]-naphth-1-yl-methane (38). Yield:
83.68%, oil;mp 210 ꢁC;IR (KBr, cm ꢀ1) 1461, 1508,
1612 (ArH), 2929 (CH), 1245 (OMe), 3478 (OH), 3413,
1
3762 (amine); H NMR (d, CDCl3) 1.6–1.77 (m, 4H,
2ꢂCH2 of pyrrolidine), 2.78–2.79 (d, 2H, NCH2), 3.95
(d, 2H, OCH2), 3.7 (s, 3H, OMe), 4.01 (m, 1H, CHOH),
6.79–7.97 (m, 15H, ArH), 6.15 (s, 1H, CH), 2.5–2.6 (m,
4H, 2ꢂNCH2 pyrrolidine);MS m/z 467.
4.8.31. (4-Methoxyphenyl)-[4-(2,3-epoxypropyloxy)-phen-
yl]-naphth-1-yl-methane (32). Yield: 78.99%, oil;IR
(Neat, cmꢀ1) 1483, 1514, 1610 (ArH), 761 (C–O), 2950
4.8.38. (4-Methoxyphenyl)-[4-(2-hydroxy-3-piperidinopro-
pyl oxy)-phenyl]-naphth-1-yl-methane hydrochloride (39).
Yield: 48.33%, mp 220 ꢁC;IR (KBr, cm ꢀ1) 1461, 1512,
1612 (ArH), 2945 (CH), 1245, 1305 (OMe), 3421 (OH),
3705 (amine); 1H NMR (d, CDCl3) 1.5–1.6 (m, 6H,
3ꢂCH2 piperidine), 2.2–2.5 (m, 4H, 2ꢂNCH2 piper-
idine), 2.74 (d, 2H, NCH2), 4.0–4.1 (d, 2H, OCH2), 3.7
(s, 3H, OMe), 5.3 (s, 1H, CHOH), 6.7–7.9 (m, 15H,
ArH), 6.1 (s, 1H, CH);MS m/z 481 [M+ꢀ37]. Anal.
(C32H36O3NCl), C, 74.19;H, 7.00;N, 2.70 Found: C,
74.38;H, 7.26;N 2.79.
1
(CH), 1217 (OMe), H NMR (d, CDCl3) 2.56 (d, 2H,
CH2 epoxide), 3.15 (m, 1H, CH epoxide) 3.65 (s, 3H,
OMe), .9 (d, 2H, OCH2), 6.05 (s, 1H, CH), 6.6–7.8 (m,
15H, ArH);MS m/z 396.
4.8.32. (4-Methoxyphenyl)-[3-methyl-4-(2,3-epoxypropyl-
oxy)-phenyl]-naphth-1-yl-methane (33). Yield: 66.9%,
oil;IR (Neat, cm ꢀ1) 1510, 1604 (ArH), 760 (C–O), 2971
1
(CH), 1217 (OMe), H NMR (d, CDCl3) 2.17 (s, 3H,
CH3), 2.6–3.0 (d, 2H, CH2 epoxide), 3.3 (m, 1H, CH
epoxide), 3.75 (s, 3H, OMe), 3.9 (d, 2H, OCH2), 6.10 (s,
1H, CH), 6.6–8.0 (m, 14H, ArH);MS m/z 410.
4.8.39. (4-Methoxyphenyl)-[4-(2-hydroxy-3-morpholino
hydrochloride
propyloxy)-phenyl]-naphth-1-yl-methane
(40). Yield: 59.36%, mp 207 ꢁC;IR (KBr, cm ꢀ1) 1456,

N. Srivastava et al. / Bioorg. Med. Chem. 12 (2004) 1011–1021
1019
1508, 1608 (ArH), 2935 (CH), 1245, 1301 (OMe), 3417
1
2ꢂCH2 naphth and CH2C3H7), 2.64–2.85 (m, 6H, CH2
naphth and CH2NCH2), 3.48 (m, 1H, CH naphth), 3.74
(s, 3H, OMe), 3.91–4.02 (m, 4H, OCH2, CH and
CHOH), 6.69–7.26 (m, 12H, ArH);MS m/z 473.
(OH), 3759 (amine); H NMR (d, CDCl3) 2.32 (m, 4H,
NCH2), 4.2 (d, 2H, OCH2), 3.7 (s, 3H, OMe), 4.2 (m,
1H, CHOH), 6.76–7.75 (m, 15H, ArH), 3.5–3.6 (m, 4H,
CH2O), 2.8 (d, 2H, CH2N);MS m/z 483 [M+ꢀ37].
Anal. (C31H34O4NCl), C, 71.59;H, 6.59;N, 2.69
Found: C, 71.38;H, 7.00;N, 2.89.
4.8.46. (4-Methoxyphenyl)-[3-methyl-4-(2-hydroxy-3-n-
butyl amino propyloxy)-phenyl]-1,2,3,4-tetrahydronaphꢀth1-
1460, 1506, 1579,1608 (ArH), 2929 (CH), 1217 (OMe),
1-yl-methane (47). Yield: 60.05%), oil;IR (Neat, cm
)
4.8.40. (4-Methoxyphenyl)-[4-(2-hydroxy-3-piperazino pro-
pyloxy)-phenyl]-naphth-1-yl-methane hydrochloride (41).
Yield: 68.78%, mp: 200 ꢁC, IR (KBr, cmꢀ1)1507, 1556,
1607 (ArH), 2932 (CH), 3404 (OH), 1217 (OMe), 3768
1
3377 (OH), 3709 (amine); H NMR (d, CDCl3);1.26–
1.80 (m, 11H, 2ꢂCH2 naphth and CH2C3H7), 2.11–2.21
(2s, 3H, CH3 due to restricted rotation) 2.64–2.88 (m,
6H, CH2 naphth and CH2NCH2), 3.48 (m, 1H, CH
naphth), 3.73 (s, 3H, OMe), 3.91–3.98 (m, 4H, OCH2,
CH and CHOH), 6.3–7.2 (m, 11H, ArH);MS m/z
487.
1
(amine), H NMR (d, CDCl3): 2.81 (m, 1H, NH), 2.83
(d, 2H, CH2N), 3.76 (s, 3H, OMe), 3.94 (d, 2H, OCH2),
4.0 (m, 1H, CHOH), 6.81–7.82 (m, 15H, ArH), 6.1 (s,
1H, CH), 2.79 (m, 8H, 4ꢂCH2 piperazine);MS m/z 482
[M+ꢀ37].
4.8.47. (4-Methoxyphenyl)-[4-(2-hydroxy-3-n-dibutyl
aminopropyloxy)-phenyl]-1,2,3,4-tetra hydronaphth-1-yl-
methane (48). Yield: 49.3%), oil;IR (Neat, cm ꢀ1):
1461, 1510, 1608 (ArH), 2933 (CH), 1217 (OMe), 3375
(OH), 3749 (amine); 1H NMR (d, CDCl3);1.29–1.42 (m,
14H, 2ꢂC3H7), 1.43–1.79 (m, 4H, 2ꢂCH2 naphth),
2.42–2.56 (m, 6H, 3ꢂNCH2), 2.64–2.88 (m, 2H, CH2
naphth) 3.46–3.48 (m, 1H, CH naphth), 3.72 (s, 3H,
OMe), 4.0 (m, 4H, OCH2, CH and CHOH), 6.31–7.20
(m, 12H, ArH);MS m/z 529.
4.8.41. (4-Methoxyphenyl)-[4-(2-hydroxy-3-cyclohexyla-
mino propyloxy)-phenyl]-naphth-1-yl-methane hydrochlo-
ride (42). Yield: 56.44%, mp 140 ꢁC, IR (KBr, cmꢀ1
1461, 1508, 1608 (ArH), 2937 (CH), 1241 (OMe), 3481
)
1
(OH), 3419, 3749 (amine); H NMR (d, CDCl3) 1.17–
1.27 (m, 11H, CH & CH2 of cyclohexyl), 2.8 (d, 2H,
NCH2), 3.76 (s, 3H, OMe), 3.94–3.96 (d, 2H, OCH2),
5.2 (s, 1H, CHOH), 6.75–7.8 (m, 15H, ArH), 6.13 (s,
1H, CH), 4.68 (s, 1H, NH);MS m/z 495.
4.8.42. (4-Methoxyphenyl)-[4-(2-hydroxy-3-diethylamino
propyloxy)-phenyl]-naphth-1-yl-methane (43). Yield:
50.66%, oil;IR (Neat, cm ꢀ1) 1400, 1508, 1608 (ArH),
4.8.48. (4-Methoxyphenyl)-[4-(2,3-epoxypropyloxy)-phen-
yl]-5,6,7,8-tetrahydronaphth-1-yl-methane (49). Yield:
78.39%, oil;IR (Neat, cm ꢀ1) 1461, 1510, 1610 (ArH),
2931 (CH), 1217 (OMe), 1H NMR (d, CDCl3) 1.71–1.73
(m, 4H, 2ꢂCH2 naphth), 2.59 (m, 2H, CH2 naphth),
2.8–2.9 (m, 4H, CH2 naphth and CH2 epoxide), 3.15 (m,
1H, CH epoxide), 3.78 (s, 3H, OMe), 3.9–4.1 (d, 1H,
OCH2, J=5.9 Hz), 4.17–4.19 (d, 1H, OCH2, J=5.9
Hz), 5.53 (s, 1H, CH), 6.6–7.0 (m, 11H, ArH);MS m/z
400.
1
2927 (CH), 3246 (OH), 1249 (OMe), 3371(amine), H
NMR (d, CDCl3) 1.0–1.07 (t, 6H, N(CH2CH3)2), 2.58–
2.65 (q, 4H, N(CH2CH3)2), 3.77 (s, 3H, OMe), 3.95 (d,
2H, OCH2), 4.01 (m, 1H, CHOH), 6.80–7.81 (m, 15H,
ArH), 6.15 (s, 1H, CH), 2.74 (d, 2H, CH2N);MS m/z
469.
4.8.43. (4-Methoxyphenyl)-[4-(2,3-epoxypropyloxy)-phen-
yl]-1,2,3,4-tetrahydronaphth-1-yl-methane (44). Yield:
94.8%, oil;IR (Neat, cm ꢀ1) 1456, 1508, 1583, 1608
4.8.49. (4-Methoxyphenyl)-[3-methyl-4-(2,3-epoxypropyl-
oxy)-phenyl]-5,6,7,8-tetrahydro naphth-1-yl-methane (50).
Yield: 82.37%, oil;IR (Neat, cm ꢀ1) 1458, 1504, 1583,
1608 (ArH), 2927 (CH), 1217 (OMe), 1H NMR (d,
CDCl3) 1.65–1.75 (m, 4H, 2ꢂCH2 naphth), 2.15 (s, 3H,
CH3), 2.53–2.64 (m, 2H, CH2 naphth), 2.7–2.8 (m, 4H,
CH2 naphth and CH2 epoxide), 3.3–3.9 (m, 1H, CH
epoxide), 3.70 (s, 3H, OMe), 3.9–4.0 (d, 1H, OCH2,
J=5.8 Hz), 4.1–4.2 (d, 1H, OCH2, J=5.8 Hz), 5.5 (s,
1H, CH), 6.6–7.0 (m, 10H, ArH);MS m/z 413.
1
(ArH), 2933 (CH), 1217 (OMe), H NMR (d, CDCl3)
1.58–1.83 (m, 4H, 2ꢂCH2 naphth), 2.74–2.88 (m, 4H,
CH2 naphth and CH2 epoxide), 3.48 (m, 1H, CH epox-
ide), 3.51 (m, 1H, CH naphth), 3.75 (s, 3H, OMe), 4.1–
4.3 (m, 3H, OCH2 and CH), 6.37–7.24 (m, 12H, ArH);
MS m/z 400.
4.8.44. (4-Methoxyphenyl)-[3-methyl-4-(2,3-epoxypropyl-
oxy)-phenyl]-1,2,3,4-tetrahydro naphth-1-yl-methane (45).
Yield: 88.4%, oil;IR (Neat, cm ꢀ1) 1461, 1510, 1608
(ArH), 1247 (OMe), 1H NMR (d, CDCl3) 1.59–1.86 (m,
4H, 2ꢂCH2 naphth), 2.13–2.23 (s, 3H, CH3), 2.80–2.92
(m, 4H, CH2 naphth and CH2 epoxide), 3.48 (m, 1H,
CH epoxide), 3.49–3.50 (m, 1H, CH naphth), 3.74 (s,
3H, OMe), 3.93–3.99 (m, 2H, OCH2), 4.17 (d, 1H, CH),
6.3-7.24 (m, 11H, ArH);MS m/z 414.
4.8.50. (4-Methoxyphenyl)-[4-(2-hydroxy-3-n-butyl amino-
propyloxy)-phenyl]-5,6,7,8-tetra hydronaphth-1-yl-methane
(51). Yield: 69.75%), oil;IR (Neat, cm ꢀ1): 1460, 1510,
1581, 1608 (ArH), 2933 (CH), 1230 (OMe), 3377 (OH),
3759 (amine); 1H NMR (d, CDCl3);1.71 (m, 11H,
2ꢂCH2 naphth and C3H7), 2.58–2.78 (m, 2H, CH2
naphth), 2.85–3.0 (m, 6H, CH2 naphth, CH2NCH2), 3.77
(s, 3H, OMe), 3.95–4.0 (m, 3H, OCH2 and CHOH),
6.59–6.99 (m, 11H, ArH), 5.53 (s, 1H, CH);MS m/z 473.
4.8.45. (4-Methoxyphenyl)-[4-(2-hydroxy-3-n-butylamino
propyloxy)-phenyl]-1,2,3,4-tetrahydronaphth-1-yl-methane
(46). Yield: 48.93%), oil;IR (Neat, cm ꢀ1): 1472, 1510,
1608 (ArH), 2931 (CH), 1217 (OMe), 3377 (OH), 3749
(amine); 1H NMR (d, CDCl3);1.26–1.49 (m, 11H,
4.8.51. (4-Methoxyphenyl)-[3-methyl-4-(2-hydroxy-3-n-
butylaminopropyloxy)-phenyl]-5,6,7,8-tetrahydro naphth-
1-yl-methane (52). Yield: 52.79%), oil;IR (Neat, cm ꢀ1):

1020
N. Srivastava et al. / Bioorg. Med. Chem. 12 (2004) 1011–1021
1458, 1506, 1610 (ArH), 2935 (CH), 1230 (OMe), 3367
(OH), 3749 (amine); 1H NMR (d, CDCl3);1.20–1.75 (m,
11H, 2ꢂCH2 naphth and C3H7), 2.14 (s, 3H, CH3),
2.52–2.62 (m, 2H, CH2 naphth), 2.72–2.92 (m, 6H, CH2
naphth, CH2NCH2), 3.74 (s, 3H, OMe), 3.9–4.0 (d, 2H,
OCH2), 4.02–4.17 (m, 1H, CHOH), 6.6–7.0 (m, 10H,
ArH), 5.51 (s, 1H, CH);MS m/z 487.
each rat was taken and uterus was carefully excised,
gently blotted, weighed and fixed for histology. Inhibition
in ethynylestradiol induced cornification of vaginal
epithelium and increase in uterine fresh weight were
taken as parameters for evaluation of estrogen antag-
onistic effect of the compounds. Compounds exhibiting
potent estrogen antagonistic activity in this assay were
identified for further development as antiimplantation
agents.
4.9. Materials and spectroscopic methods
Mps were determined in open capillary with a Buchi-
1
4.12. Antiimplantation screening
530 melting point apparatus and are uncorrected. H
NMR spectra were recorded on a Brucker WM
(400 MHz) spectrometer using TMS as reference. IR
spectra were obtained in neat/KBr discs on a model
Perkin–Elmer Ac-1 spectrophotometer and are expressed
in reciprocal centimeters. EI mass spectra were obtained
at 70 eV using a JEOL JMS-D 300 spectrometer. Ele-
mental analyses (C, H) were carried out on a Carlo
Erba-1108 elemental analyzer. TLC was performed on
7ꢂ3 cm thin layer analytical plates (SRL). Chemicals
were obtained from Fluka, Aldrich and Across and were
used as receive under otherwise noted. The following
experiments represent typical experimental procedures
employed in the preparation of the compounds given in
Table 1.
Antiimplantation activity of the compounds was studied
in sperm positive adult (180–220 g) Sprague–Dawley
female albino rats mated to coeval males of proven
fertility. The compounds were administered orally as a
suspension in gum acacia to colony bread adult mated
female rats on days 1–5 post-coitum using five to seven
animals in each group. The animals were examined by
laprotomy on day 10 of pregnancy for the number and
status of implantations and corpora lutea. The results
were scored as positive only if implantations were
totally absent in both the uterine horns of each animal.
4.13. Estrogen receptor binding affinity
The relative binding affinity (RBA) of the compounds
for estrogen receptor was determined by competition
assay, employing radiolabeled estradiol (3H-E2) as the
reference compound. The test ligands and (3H-E2) were
incubated (4 ꢁC) with cytosol estrogen receptors
obtained from immature 20–21 days old rat uteri. Ali-
quot of the uterine cytosol (200 mL concd 1 uterus per
mL) prepared in TEA buffer (10 mM TRIS, 1.5 mM
EDTA, 0.02% sodium azide, pH 7.4) were incubated in
triplicate with a fixed concentration of radiolabeled
estradiol with or without various concentrations of the
competitor substance dissolved in 60 mL of the TEA
buffer containing DMF as co solvent (final concentration
of DMF in the incubation medium never exceeded 5%)
for 18 h at 4 ꢁC. At the end of this period, dextran
coated charcoal (DCC) (5% Norit 0.5% dextran)
suspension in 100 mL of TEA buffer was added into
each tube, which were briefly vortexed and allowed to
stand for 15 min. DCC was precipitated by centrifugation
(800 gꢂ10 min) and the supernatants counted for
radioactivity in 10 mL of a dioxane-based scintillation
fluid. RBA of the text compound was computed from a
graph plotted between percent bound radioactivity
verses log concentration of the test substance. At 50%
inhibition, log of the competitor concentration relative to
that of estradiol, gave the affinity of the test compound
to estrogen receptor relative to estradiol. This when
multiplied with 100 gave the percentage value desig-
nated as RBA (Table 2).
4.10. Estrogen agonistic activity
Twenty one day old immature female Spraugue–Dawley
rats were bilaterally ovariectomized under light ether
anesthesia and after post-operative rest for 7 days were
randomized into different treatment groups. Each rat
received the compound of the invention once daily for 3
consecutive days on days 28–30 of age by oral route. A
separate group of animals received only the vehicle for
similar duration served as control. At autopsy 24 h after
the last treatment on day 31 of age, vaginal smear of
each rat was taken and uterus was carefully excised,
gently blotted, weighed. Premature opening of vagina,
cornification of vaginal epithelium and increase in
uterine fresh weight were taken as parameters for
evaluation of estrogen agonistic activity in comparison
to rats of vehicle control group. The objective was to
evaluate estrogen agonistic effect of the compounds on
the uterus and vagina. Compounds exhibiting no or
negligible estrogen agonistic activity in this assay were
identified for further development as antiimplantation
agents.
4.11. Estrogen antagonistic activity
Twenty-one-day-old immature female Spraugue–Dawley
rats were bilaterally ovariectomized under light ether
anesthesia and after post-operative rest for 7 days were
randomized into different treatment groups. Each rat
received the compound of the invention and 0.02 mg kgꢀ1
dose of 17 a-ethynylestradiol in 10% ethanol-distilled
water once daily for 3 consecutive days on days 28–30 of
age by oral route. A separate group of animals receiving
only 17 a-ethynylestradiol (0.02 mgkgꢀ1) in 10% ethanol-
distilled water for similar duration were used for com-
parison. At autopsy on day 31 of age vaginal smear of
Acknowledgements
One of the authors (Miss Sangita, SRF) thanks to
CSIR, New Delhi (India) for the award of Senior
Research Fellowship. Authors are thankful to Mr. Philip
Prathipati for computer graphics studies.

N. Srivastava et al. / Bioorg. Med. Chem. 12 (2004) 1011–1021
1021
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