Diaryloxy methano phenanthrenes: A new class of antituberculosis agents

Article abstract of DOI:10.1016/j.bmc.2004.07.058

A new series of diaryloxy methano phenanthrenes were prepared through tertiary-aminoalkylations of [(methoxy-phenyl)-phenanthren-9-yl-methyl]-phenols obtained from Friedel-Crafts alkylations on (methoxy-phenyl)-phenanthren-9-yl- methanols. These series of

Full text of DOI:10.1016/j.bmc.2004.07.058

Bioorganic& Medicinal Chemistry 12 (2004) 5269–5276
Diaryloxy methano phenanthrenes: a new class of
antituberculosis agentsq
a
a
b
Gautam Panda,a, Shagufta , Jitendra Kumar Mishra, Vinita Chaturvedi,
*
Anil K. Srivastava,b Ranjana Srivastavab and Brahm S. Srivastavab
aMedicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, UP, India
bMicrobiology Division, Central Drug Research Institute, Lucknow 226001, UP, India
Received 17 May 2004; revised 27 July 2004; accepted 27 July 2004
Available online 9 September 2004
Dedicated to Professor Goverdhan Mehta on the occasion of his 60th birthday
Abstract—A new series of diaryloxy methano phenanthrenes were prepared through tertiary-aminoalkylations of [(methoxy-phen-
yl)-phenanthren-9-yl-methyl]-phenols obtained from Friedel–Crafts alkylations on (methoxy-phenyl)-phenanthren-9-yl-methanols.
These series of compounds were evaluated against Mycobacterium tuberculosis H37Rv and showed the desired activity in the range
of 6.25lg/mL in vitro. One of the compound 12j protects the mice from the challenge of M. tuberculosis in vivo, as 30% of the mice
were survived at treatment of 50mg/kg body weight.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
pyrazinamide, ethambutol and streptomycin) and for
several second-line and newer drugs (ethionamide, fluoro-
quinolones, macrolides, nitroimidazopyrans).4 The
search for more effective agents against M. tuberculosis
(MT) and M. avium complex (MAC) is ongoing in an
attempt to enhance survival and reduce morbidity, as
proven by the high number of patents of new antituber-
culous agents recently published.5,6
Tuberculosis, a leading infectious disease caused by
Mycobacterium tuberculosis is major concern of death
in the world today.1 It is estimated that worldwide 100
million people are infected annually. Approximately 10
million develop the disease, with 5 million of these pro-
gressing to the infectious stage and ultimately 3 million
dying. Even though improved methods of prevention,
detection, diagnosis and modern treatment have greatly
reduced the number of people getting infected and dying
from it, the emergence of multi-drug-resistant (MDR)
strains, its synergy with global human immunodefi-
ciency virus (HIV) and many socioeconomic problem
has led to declare this disease as ꢀglobal emergencyꢁ by
WHO (World Health Organization). In spite of modern
sophisticated developments in improved methods of
diagnosis, prevention and treatment, the gloomy picture
of this disease is still alarming.2,3 Resistance has been
described for all first-line drugs (isoniazid, rifampin,
Because of this, there is an urgent need for anti-TB
drugs with improved properties such as enhanced activ-
ity7,8 against MDR strains, reduced toxicity, shortened
duration of therapy, rapid mycobactericidal mechanism
of action and the ability to penetrate host cells and
exert anti-mycobacterial effects in the intracellular
environment.9,10
Diaryl naphthalenes are known for a number of biolog-
ical activities such as anti-inflammatory, antichagasic
etc. This class of molecule is known to alter the cellular
machinery processes. Biphenyl methanone derivatives
are known to possess antimycobacterial activity. Keep-
ing that in mind, we were prompted to see the effect of
diaryloxy methano phenanthrenes on the growth of M.
tuberculosis as this class of compounds possess enough
hydrophobicity, a requirement for good antituberculosis
agents.11 Thus we have identified 1 as a potential target
Keywords: Diaryloxy methano-phenanthrenes; Antituberculosis
agents.
q CDRI Communication no. 6514.
*
Corresponding author. Tel.: +91 5222364635; fax: +91 5222223938;
e-mail addresses: gautam_panda@lycos.com; bapi.rm@yahoo.com
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.07.058

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G. Panda et al. / Bioorg. Med. Chem. 12 (2004) 5269–5276
NMR and mass spectrum fragmentation analysis. In
R
R
this competitive reaction, the generation of compound
9a–c and 10a–c could be attributed to the fact that
Friedel–Crafts alkylation occurs via attack of phenol
at both ortho and para position of the benzene nucleus
with the carbinol 2a–c.
Ha
Hb
R
Hc
+
X
Y
OH
( )n
O
N
( )n
3a, X= MgX
3b, X= CHO
4a, Y= MgX
4b, Y= CHO
2
R = OCH3
1
The reaction between 9a–c with different alkylamino-
hydrochloride chains in the presence of K2CO3 and ace-
tone led to the formation of compounds 11a–l in good
yields (Scheme 3). Similarly, compounds 10a–c also on
reaction with alkylaminohydrochlorides gave 13a–d in
respectable yields (Scheme 4). Diaryloxy methano
phenanthrenes 12a–l and 14a–d were prepared as amino-
hydrochloride salts through treating their corresponding
amines 11a–l and 13a–d with ethanolicHCl. All the
hydrochloride salts were good crystalizable solid
compounds.
Scheme 1. Retrosynthesis of target compounds.
molecule for antituberculosis agents. Retrosynthetic
analysis of 1 leads to compound 2 as the precursor,
which can be obtained from nucleophilic addition of
Grignard reagent 3a, 4a onto carbaldehyde 4b, 3b,
respectively (Scheme 1).
2. Results and discussion
2.1. Chemistry
R
R
K2CO3,
Acetone
Ethanolic
HCl
The compounds were synthesized essentially following
the steps as depicted below. The reaction between Grig-
nard reagent 3a, 4a and aldehyde 4b, 3b in dry THF fur-
nished the carbinol7 2a–c in 70% isolated yield. IR
frequency at 3431cmÀ1 indicated the presence of hydr-
oxyl group in 2a–c. The characteristic peaks of 2a–c at
Hydrochloride
Salts
12a-l
Amino
hydrochloride
R1Cl.HCl
OH
OR1
9a, 9b, 9c
11
Name of the Amino
hydrochloride Chain
R1Cl. HCl
1
Compound
Yields (%)
d 8.66, 8.62 and 6.39ppm in its H NMR spectra were
R group
R1 group
No.
assigned for phenanthrene (Ha, Hb) and benzylic
methine proton (Hc), respectively. 13C NMR and mass
spectral data (molecular ion peak at 314amu) further
confirmed the structural identity of 2a–c (Scheme 2).
ClCH2CH2N(CH3)2.HCl
o-OCH3
CH2CH2N(CH3)2
12a
12b
12c
67
62
ClCH2CH2N(CH2CH3)2.HCl o-OCH3
o-OCH3
CH2CH2N(CH2CH3)2
CH2CH2N
72
70
.HCl
ClCH2CH2N
ClCH2CH2N
o-OCH3
m-OCH3
12d
.HCl
.HCl
CH2CH2N
Friedel–Crafts alkylation of the compounds 2a–c with
phenol 8 in the presence of AlCl3 and SnCl4 led to enan-
tiomericmixtures of 9a–c as major and 10a–c as minor
products. The compound 9a–c was characterized from
77
77
ClCH2CH2N(CH3)2.HCl
ClCH2CH2N(CH2CH3)2.HCl m-OCH3
CH2CH2N(CH3)2
CH2CH2N(CH2CH3)2
12e
12f
ClCH2CH2N
ClCH2CH2N
m-OCH3
CH2CH2N
.HCl
12g
12h
.HCl
72
70
its deshielded doublet aromaticprotons H , He (d 8.68
d
m-OCH3
p-OCH3
CH2CH2N
.HCl
.HCl
and 8.62ppm) and singlet methine proton Hf (d
6.11ppm) resonances, respectively. Whereas in 1H
NMR of 10a–c, the singlet methine proton Hg appears
at d 6.37ppm due to ÀI inductive effect of ortho-hydroxy
group of the benzene nucleus. The structural identity of
9a–c and 10a–c were further confirmed by their 13C
ClCH2CH2N(CH3)2.HCl
CH2CH2N(CH3)2
93
83
12i
12j
ClCH2CH2N(CH2CH3)2.HCl p-OCH3
CH2CH2N(CH2CH3)2
.HCl
80
77
ClCH2CH2N
ClCH2CH2N
p-OCH3
p-OCH3
CH2CH2N
12k
12l
.HCl
.HCl
CH2CH2N
.HCl
Scheme 3. Synthesis of phenolicderivatives 12a–l.
CHO
Mg, THF
R
Hd
He
R
R
Hf
K2CO3,
Acetone
R
Br
6a, R = o-OCH3
6b, R = m-OCH3
6c, R = p-OCH3
Ethanolic Hydrochloride
OH
Amino
hydrochloride
R1Cl. HCl
HCl
Salts
14a-d
5
OH
R
OR1
Ha
Hb
AlCl3, SnCl4,
8
Hc
Benzene/pentane, 0-5oC
OH
BuLi
THF
DMF
9a, R = o-OCH3
9b, R = m-OCH3
9c, R = p-OCH3
10a, 10b, 10c
OH
or
13
Name of the Amino
hydrochloride Chain
Yield (%)
Compound
No.
Conc. H2SO4, phenol 8
R group
R
1 group
2a, R = ortho-OCH3
2b, R = meta-OCH3
2c, R = para-OCH3
Benzene, 80oC, 1-2 h
+
R1Cl. HCl
R
80
92
p-OCH3
p-OCH3
p-OCH3
14a
14b
14c
CH2CH2N(CH3)2
ClCH2CH2N(CH3)2.HCl
Hg
CH2CH2N(CH2CH3)2
CHO
ClCH2CH2N(CH2CH3)2.HCl
Mg, THF
Br
OH
CH2CH2N
.HCl
78
65
ClCH2CH2N
7a, R = o-OCH3
7b, R = m-OCH3
7c, R = p-OCH3
3b
R
10a, R = o-OCH3
10b, R = m-OCH3
10c, R = p-OCH3
p-OCH3
14d
.HCl
CH2CH2N
.HCl
ClCH2CH2N
Scheme 2. Synthesis of carbinols.
Scheme 4. Synthesis of phenolicderivatives 14a–d.

G. Panda et al. / Bioorg. Med. Chem. 12 (2004) 5269–5276
5271
Table 1. In vitro antituberculosis activity of 12a–l, 14a–d and 18a–c
against M. tuberculosis H37Rv
Mg, THF
CHO
OBn
Compound no. MIC (lg/mL), Agar micro MIC (lg/mL),
Br
dilution method
BACTEC method
OH
16
12a
12b
12.5
12.5
12.5
12.5
––
12.5
12.5
12.5
12.5
––
OBn
5
AlCl3, SnCl4,
Phenol
Benzene,
pentane
15
12c
12d
OH
12e
12f
OR1
12.5
25.0
12.5
25.0
6.25
6.25
6.25
25.0
25.0
12.5
12.5
6.25
6.25
6.25
0.75
0.05
12.5
12.5
12.5
12.5
6.25
6.25
6.25
25.0
25.0
12.5
12.5
6.25
6.25
6.25
1.00
0.025
K2CO3, Acetone
12g
12h
Aminohydrochloride
R1Cl.HCl
12i
12j
OH
17
OR1
18
12k
12l
14a
14b
Compound
No.
R1 group
Name of the Chain
R1Cl. HCl
18a
CH2CH2N(CH3)2
ClCH2CH2N(CH3)2.HCl
14c
14d
18b
ClCH2CH2N(CH2CH3)2.HCl
CH2CH2N(CH2CH3)2
18a
18b
CH2CH2N
18c
.HCl
ClCH2CH2N
18c
SPAR
Isoniazid (INH)
Scheme 5. Synthesis of phenolicderivatives 18a–c.
–– means not active at 25lg/mL.
While the mono-aminohydrochloride salts 14a–l and
14a–d are active against M. tuberculosis, we became
interested in synthesizing their bis-aminohydrochloride
salts and evaluate their antitubercular activity. Towards
this objective, the Grignard reagent 3a derived from 5
was reacted with benzyloxy benzaldehyde 15 to furnish
the carbinol 16. The identity of 16 was characterized
through 1H and 13C NMR data analysis. Upon
Friedel–Crafts reaction on 16, the bis-phenolicderiva-
tive 17 was obtained with disappearance of benzyl
group. The compound 17 was reacted with three amino-
hydrochlorides to furnish the bis-phenolic derivatives
18a–c (Scheme 5). The compounds were evaluated
against M. tuberculosis H37Rv in vitro and the results
are shown below.
substituents except in case of 12i showed desired activity
with MIC 6.25lg/mL in comparison to other ortho and
meta substituted methoxy derivatives possibly due to
better exposition of p-methoxy groups in the hydro-
phobicity of central pharmacophore skeleton. Effect of
difference in ortho and meta methoxy substituents on
MIC value was marginal. Increasing the alkyl chain on
nitrogen resulted into better activity. Compound 12i
with dimethyl substituents on nitrogen is having MIC
12.5 (BACTEC method) whereas 12j, 12k and 12l with
diethyl, pyrrolidine and piperidine rings, respectively,
are having MIC 6.25 (BACTEC method). Interestingly,
increasing the alkylaminohydrochloride chains on the
central pharmacophore gave better results. Compounds
18a–c with bis-alkylaminohydrochloride chains at the
para position of the benzene ring are having MIC 6.25
evaluated in both methods (Agar microdilution and
BACTEC). Thus, methanophenanthrenes with para-
methoxy group on one benzene nucleus and alkylamino-
hydrochloride chains on other benzene nucleus gave
better antitubercular activity in vitro. On the basis of
MIC, three compounds (12j, 12k, 12l) were selected
for further evaluation of their activity. Out of them,
compound 12j was selected as a representative to evalu-
ate its activity in vivo.
3. Biology
3.1. Determination of activity in vitro and in vivo
The activity of the compounds against M. tuberculosis
H37Rv was determined by agar micro dilution technique
and standard BACTEC radiometricgrowth assay. 12 (de-
tails are described in experimental section). The activity
of the compounds 12a–l, 14a–d and 18a–c in vitro are
shown in Table 1.
Forty inbred female AKR mice, weighing 18–20g were
infected i.v. via lateral vein with 107 colony forming
units of M. tuberculosis H37Rv. Mice were divided into
four groups after two days comprising 10 mice each.
One group received the aqueous suspension of the test
agent 12j by oral route daily for 14 days at the dose of
50mg/kg body weight. The second group received spar-
floxacin at 25mg/kg body weight (ED90) for 14 days or-
ally. The third group received the test compound 12j at
the dose of 100mg/kg body weight whereas the fourth
group served as control receiving no drug. Mice were
All the alkylaminohydrochloride derivatives (12a–l,
14a–d and 18a–c) displayed activity against M. tubercu-
losis with minimum inhibitory concentrations (MIC)
ranging from 6.25 to 25lg/mL. These compounds were
synthesized to evaluate the effect of ortho, meta and para
methoxy substituents of benzene ring on the central
methano-phenanthrene nucleus and also the effect of
increasing the alkyl substituents of nitrogen ring on anti-
tubercular activity. It is noteworthy that all the diaryl-
oxy methano phenanthrenes with para methoxy

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G. Panda et al. / Bioorg. Med. Chem. 12 (2004) 5269–5276
4. Conclusion
120
100
80
60
40
20
0
The analysis of in vitro and in vivo data for the com-
pounds 12a–l and 18a–c clearly suggests that these class
of compounds are indeed antitubercular. The compound
12j seems to protect the mice from the challenge of M.
tuberculosis, as 30% of mice were survived and this pro-
tection is dose dependent. Since the mice receiving
100mg/kg dose were not protected and there was no
inhibition of growth of infection, the logical assumption
was that the immune system of the mice was compro-
mised by treatment of the compound for several days.
This class of compounds appears to have antitubercular
activity. We are reporting for the first time that diaryl-
oxy methano phenanthrenes might be a suitable phar-
macophore for developing novel antitubercular agents.
Compounds containing biphenyl and related hydro-
phobic groups are known to act through fatty-acid bio-
synthesis and offer antitubercular activity.14 Our
compounds also bear the similar chemical moieties.
Therefore, it can reasonably be assumed that this class
of compounds having related hydrophobicity might be
acting through inhibition of fatty acid biosynthesis of
M. tuberculosis. A rational and logical design of a com-
pound retaining the antitubercular activity without tox-
icity may be a favourable molecule. Synthesis of the
compounds and their biological evaluation towards this
direction is currently underway.
0
10
20
30
40
Time (days)
Figure 1. Plot of % survival of mice. (Å) No drug; (+) 100mg/kg of 12j;
(À) 50mg/kg of 12j.
observed for 35days. Antitubercular activity was meas-
ured by general health of the mice, mean survival time,
lesions in lung and spleen, load of bacilli (Fig. 1).
All the mice in the untreated group died of tuberculosis
within 20days of receiving infection. These mice were
weak with ruffled hairs. The mean survival time (MST)
was 13.7days. The lungs were full of tubercles and
spleen was enlarged. The load of the bacilli was esti-
mated around 3 · 107/g of lung. All the mice treated
with sparfloxacin survived with normal appearance of
lung and spleen. Hardly few acid-fast bacilli were seen
in lung smears under microscope.
In the group treated with 50mg/kg dose of 12j, 30% of
the mice survived. The survival rate was not significantly
different from the control group up to day 18. However,
the number of survivors in the 50mg/kg dose group was
significantly greater than zero on day 19 onwards when
compared by the test of proportion (p < 0.05). The mean
survival time (MST) was found to be 18.5days, hence
MST increased compared to that of control group
(13.7days). There were few tubercles in the lung and
the spleen was looking normal in the surviving mice.
The load of the bacilli in the lungs of surviving mice
was significantly less (approx. 103–7 · 103 bacilli/g
of lung). However, it was surprising that increasing the
dose of the compound from 50 to 100mg/kg could not
give better protection against M. tuberculosis infection.
The mice receiving 100mg/kg of the test compound 12j
died earlier than the control (untreated infected mice).
The mice were weak and there were tubercles in the
lung. Microscopic examination of the lung smear
showed a large number of acid-fast bacilli (AFB) as
those seen in the lung of control group of mice. It, there-
fore, appears that in M. tuberculosis infected mice, the
compound may have become toxic. It is already known
that mice with tubercular infection are prone to immu-
nological disorders and loss immune function.13 This
observation suggest that flaring up of the infection is
much faster due to toxicity of the compound in immu-
nologically weak mice at 100mg/kg dose and protection
in mice at 50mg/kg dose appears to be due to the fine
balance between toxicity and efficacy of the compound.
In 25mg/kg dose group, infection load was the same as
that in the untreated control group (data not shown).
This may be due to inefficacy of the compound at a
lower dose.
5. Experimental details
5.1. Representative Grignard reaction
To a solution of bromoanisole 7a–c (3.6mL, 29.1mmol)
in dry THF (15mL) was added activated magnesium
(0.79g, 32.98mmol) and was stirred at room tempera-
ture under dry nitrogen for 2h. To Grignard reagent
thus formed was added phenanthrene-9-carbaldehyde
3b (2g, 9.7mmol) in THF (15mL) and stirring was con-
tinued for another 3–4h. The reaction mixture was
quenched by gradual addition of saturated NH4Cl
(ꢀ10mL) and THF was removed in vacuo. The mixture
was extracted thrice with ethyl acetate, washed with
brine and dried over sodium sulfate. It was concentrated
and charged over silica gel. Elution with 10% ethylacet-
ate in hexane furnished carbinol product 2a–c.
5.1.1.
Pale yellow solid, 2c (2.57g, 85%), mp 70ꢁC, IR (neat):
3409, 1597, 1485, 1256, 1045, 760cmÀ1 1H NMR
(4-Methoxy-phenyl)-phenanthren-9-yl-methanol.
,
(CDCl3, 200MHz): d 8.66 (d, 1H, J = 8.3Hz), 8.62 (d,
1H, J = 8.3Hz), 7.94 (s, 1H), 7.90 (d, 1H, J = 8Hz),
7.86 (d, 1H, J = 8Hz), 7.69–7.40 (m, 4H), 7.28 (d, 2H,
J = 8.8Hz), 6.78 (d, 2H, J = 8.6Hz), 6.39 (s, 1H), 3.70
(s, 3H), 2.50 (bs, 1H); 13C NMR: d 159.6, 137.4, 135.5,
131.8, 131.2, 130.7, 130.1, 129.4, 129.0, 127.1, 126.9,
126.6, 125.5, 125.3, 123.5, 122.8, 114.4, 73.9, 55.6; MS
(EI): m/z 314 (M+); Anal. Calcd for C22H18O2: C,
84.05; H, 5.77. Found: C, 84.57; H, 5.62.
5.1.2.
(3-Methoxy-phenyl)-phenanthren-9-yl-methanol.
Pale yellow solid, 2b (2.5g, 85%), mp 123ꢁC, IR (neat):

G. Panda et al. / Bioorg. Med. Chem. 12 (2004) 5269–5276
5273
3409, 1599, 1488, 1256, 1045, 760cmÀ1
,
1H NMR
IR (neat): 3391, 3017, 2928, 1605, 1506, 1449, 1245,
1033, 833, 753cmÀ1 1H NMR (CDCl3, 200MHz): d
(CDCl3, 200MHz): d 8.66 (d, 1H, J = 8.6Hz), 8.62 (d,
1H, J = 8.4Hz), 7.98 (d, 1H, J = 8Hz), 7.87 (s, 1H),
7.84 (d, 1H, J = 8Hz), 7.66–7.40 (m, 4H), 7.19 (t, 1H,
J = 8Hz), 6.98 (s, 1H), 6.96 (d, 1H, J = 8.4Hz), 6.76
(d, 1H, J = 8Hz), 6.39 (s, 1H), 3.69 (s, 3H), 2.56 (bs,
1H); MS: 314 (M+); Anal. Calcd for C22H18O2: C,
84.05; H, 5.77. Found: C, 83.94; H, 6.00.
,
8.68 (d, 1H, J = 8.2Hz), 8.62 (d, 1H, J = 8.2Hz), 8.01
(d, 1H, J = 7.9Hz), 7.72–7.45 (m, 5H), 7.14 (s, 1H),
7.04 (d, 2H, J = 8.6Hz), 6.98 (d, 2H, J = 7.6Hz), 6.83
(d, 2H, J = 7.7Hz), 6.70 (d, 2H, J = 8Hz), 6.11 (s,
1H), 5.08 (bs, 1H), 3.74 (s, 3H); MS: 390 (M+); Anal.
Calcd for C28H22O2: C, 86.13; H, 5.68. Found: C,
86.18; H, 5.99.
5.1.3.
(2-Methoxy-phenyl)-phenanthren-9-yl-methanol.
Pale yellow solid, 2a (3.2g, 70%), mp 162ꢁC, IR (neat):
5.3.2. 4-[(3-Methoxy-phenyl)-phenanthren-9-yl-methyl]-
phenol. Pale yellow solid, 9b (1.92g, 49%). mp 70ꢁC,
1
3262, 1593, 1456, 1237, 1035cmÀ1, H NMR (CDCl3,
1
200MHz): d 8.69 (d, 1H, J = 8.6Hz), 8.64 (d, 1H,
J = 8.6Hz), 7.97 (s, 1H), 7.92 (d, 1H, J = 8.6Hz), 7.87
(d, 1H, J = 8.4Hz), 7.70–7.40 (m, 4H), 7.23 (t, 1H,
J = 7.8Hz), 7.0–6.7 (m, 3H), 6.95 (s, 1H), 3.90 (s, 3H),
3.10 (d, 1H, J = 4.2Hz); 13C NMR: d 132.0, 131.5,
130.6, 130.5, 129.6, 129.4, 129.0, 127.09, 127.04, 126.9,
126.5, 125.5, 125.3, 123.5, 122.8, 121.3, 68.6, 56.0; MS:
314 (M+); Anal. Calcd for C22H18O2: C, 84.05; H,
5.77. Found: C, 84.25; H, 5.98.
IR (neat): 3400, 1599, 1488, 1259, 756cmÀ1, H NMR
(CDCl3, 200MHz): d 8.71 (d, 1H, J = 8.2Hz), 8.64 (d,
1H, J = 8.2Hz), 8.02 (d, 1H, J = 7.9Hz), 7.70–7.48 (m,
5H), 7.22 (d, 1H, J = 8Hz), 7.16 (s, 1H), 7.02 (d, 2H,
J = 8.2Hz), 6.80–6.73 (m, 5H), 6.15 (s, 1H), 4.73 (s,
1H), 3.71 (s, 3H); MS: 390 (M+); Anal. Calcd for
C28H22O2: C, 86.13; H, 5.68. Found: C, 86.68; H, 5.66.
5.3.3. 4-[(2-Methoxy-phenyl)-phenanthren-9-yl-methyl]-
phenol. Pale yellow solid, 9a (3g, 40%), mp 80ꢁC, IR
1
5.1.4. (4-Benzyloxy-phenyl)-phenanthren-9-yl-methanol.
Pale yellow solid, 16 (1.32g, 87%), mp 131ꢁC, 1H
NMR (CDCl3, 200MHz): d 8.72 (d, 1H, J = 8.4Hz),
8.67 (d, 1H, J = 8.4Hz), 8.01 (s, 1H), 7.93 (d, 2H,
J = 8.6Hz), 7.66–7.40 (m, 4H), 7.40–7.29 (m, 7H), 6.92
(d, 2H, J = 8.6Hz), 6.50 (d, 1H, J = 2.8Hz), 5.02 (s,
2H), 2.30 (d, 1H, J = 3.8Hz); MS: 373 (M+); Anal.
Calcd for C28H22O2: C, 86.13; H, 5.68. Found: C,
86.93; H, 5.99.
(neat): 3390, 1500, 1241, 758cmÀ1, H NMR (CDCl3,
200MHz): d 8.70 (d, 1H, J = 8.2Hz), 8.64 (d, 1H,
J = 8.2Hz), 8.01 (d, 1H, J = 8Hz), 7.69–7.43 (m, 5H),
7.27–7.18 (m, 2H), 7.15 (s, 1H), 7.02 (d, 2H,
J = 8.4Hz), 6.96–6.70 (m, 4H), 6.53 (s, 1H), 4.70 (bs,
1H), 3.74 (s, 3H); MS: 390 (M+); Anal. Calcd for
C28H22O2: C, 86.13; H, 5.68. Found: C, 86.75; H, 5.63.
5.3.4. 2-[(4-Methoxy-phenyl)-phenanthren-9-yl-methyl]-
phenol. Pale yellow solid, 10c (0.8g, 12%), mp 80ꢁC,
IR (neat): 3391, 3017, 2928, 1605, 1506, 1449, 1245,
5.2. Representative Friedel–Crafts reaction
1033, 833, 753cmÀ1 1H NMR (CDCl3, 200MHz): d
,
To a solution of carbinol 2a–c (6.0g, 19.11mmol) taken
in dry benzene (60mL) and pentane (120mL) at room
temperature was gradually added phenol (2.37mL,
28.66mmol) and the reaction mixture was stirred at
0ꢁC for 15min. AlCl3 (2.56g, 19.11mmol) was added
followed by SnCl4 (4.56mL, 24.84mmol) and stirring
was continued for another 1h. Water was slowly added
and the mixture was extracted with ethylacetate. The or-
ganiclayer was washed with water, brine and dried over
anhydrous Na2SO4. It was concentrated to give an oily
residue that was charged over silica gel. Elution with
15% ethylacetate in hexane furnished the compound
9a–c, 10a–c.
8.72 (d, 1H, J = 8Hz), 8.65 (d, 1H, J = 8Hz), 8.01 (d,
1H, J = 8Hz), 7.65–7.40 (m, 5H), 7.24–7.08 (m, 3H),
7.14 (s, 1H), 6.88–6.78 (m, 5H), 6.37 (s, 1H), 4.81 (bs,
1H), 3.78 (s, 3H); MS: 390 (M+); Anal. Calcd for
C28H22O2: C, 86.13; H, 5.68. Found: C, 86.28; H, 6.00.
5.3.5. 4-[(4-Hydroxy-phenyl)-phenanthren-9-yl-methyl]-
phenol. Dark orange solid, 17 (1.2g, 52%), mp 112ꢁC,
IR (neat): 3323, 1602, 1505, 1441, 1365, 1230,
1170cmÀ1 1H NMR (CDCl3, 200MHz): d 8.72 (d,
,
1H, J = 8.2Hz), 8.65 (d, 1H, J = 8.2Hz), 8.02 (d, 1H,
J = 9Hz), 7.69–7.48 (m, 5H), 7.14 (s, 1H), 7.01 (d, 4H,
J = 8.2Hz), 6.75 (d, 4H, J = 8.2Hz), 6.12 (s, 1H), 4.67
(bs, 2H); 13C NMR: 154.4, 139.1, 136.4, 131.8, 131.6,
131.2, 130.2, 129.1, 128.7, 127.0, 126.8, 126.5, 125.6,
123.4, 122.7, 115.7, 109.9, 52.2; MS: 376 (M+); Anal.
Calcd for C27H20O2: C, 86.14; H, 5.36. Found: C,
86.45; H, 5.78.
5.3. Alternative procedure
To a solution of carbinol 2a–c (2.85g, 9.07mmol) and
phenol (1.28g, 13.61mmol) in dry benzene (40mL) cat-
alytic amount of conc. H2SO4 was added and the reac-
tion mixture was refluxed at 80ꢁC for 1h. It was
cooled to room temperature, treated with saturated
NaHCO3 and extracted with ethylacetate. The organic
layer was washed with water and dried over anhydrous
Na2SO4. Column chromatography over silica gel and
elution with 15% ethyl acetate in hexane furnished the
desired compound.
5.4. Representative chain reaction
A mixture of compounds 9a–c (1g, 2.564mmol), anhy-
drous K2CO3 (1.77g, 12.82mmol), 1-(2-chloroethyl)-
piperidine hydrochloride (0.708g, 3.84mmol) and dry
acetone (50mL) was refluxed for 7h. K2CO3 was filtered
off and acetone was removed. The residue was diluted
with water and extracted with ethyl acetate. The organic
layer was washed with water, brine and dried over anhy-
drous Na2SO4. Column chromatography over silica gel
5.3.1. 4-[(4-Methoxy-phenyl)-phenanthren-9-yl-methyl]-
phenol. Pale yellow solid, 9c (2.4g, 32.2%) mp 64ꢁC,

5274
G. Panda et al. / Bioorg. Med. Chem. 12 (2004) 5269–5276
and elution with 35% ethylacetate in hexane furnished
the compound. The product was dissolved in absolute
ethanol (25mL) and ethanolicHCl was added dropwise
till the pH of the mixture was acidic. Ethanol was re-
moved in vacuo. The residue was recrystallized from a
mixture of absolute ethanol and dry ether to give com-
pound as hydrochloride salt.
(450mg, 72%), mp 60ꢁC (HCl salt), IR (neat): 2927,
1219, 761cmÀ1 1H NMR (CDCl3, 200MHz): d 8.72
,
(d, 1H, J = 8Hz), 8.65 (d, 1H, J = 7.8Hz), 8.01 (d, 1H,
J = 8.2Hz), 7.71 (d, 1H, J = 7.6Hz), 7.66–7.45 (m,
4H), 7.20 (d, 1H, J = 8Hz), 7.15 (s, 1H), 7.04 (d, 2H,
J = 8Hz), 6.84 (s, 1H), 6.82–6.70 (m, 4H), 6.16 (s, 1H),
4.08 (t, 2H, J = 6Hz), 3.71 (s, 3H), 2.89 (t, 2H,
J = 6Hz), 2.63 (m, 4H), 1.80 (m, 4H); MS: 488 (M+);
Anal. Calcd for HCl salt, C34H34ClNO2: C, 77.92; H,
6.54; N, 2.67. Found: C, 77.62; H, 6.78; N, 2.27.
5.4.1.
1-(2-{4-[(4-Methoxy-phenyl)-phenanthren-9-yl-
methyl]-phenoxy}-ethyl)-piperidine. White solid, 11l (1g,
77%), mp 80ꢁC (HCl salt), IR (neat): 2929, 1507,
1246, 755cmÀ1
,
1H NMR (CDCl3, 200MHz): d 8.71
5.4.6.
1-(2-{4-[(3-Methoxy-phenyl)-phenanthren-9-yl-
(d, 1H, J = 8Hz), 8.65 (d, 1H, J = 8Hz), 8.03 (d, 1H,
J = 8Hz), 7.65–7.48 (m, 5H), 7.15 (s, 1H), 7.07 (d, 4H,
J = 8.2Hz), 6.82 (d, 4H, J = 8.6Hz), 6.14 (s, 1H), 4.08
(t, 2H, J = 6Hz), 3.78 (s, 3H), 2.77 (t, 2H, J = 6Hz),
2.51 (m, 4H), 1.60 (m, 4H), 1.45 (m, 2H); MS: 502
(M+); Anal. Calcd for HCl salt, C35H36ClNO2: C,
78.12; H, 6.74; N, 2.66. Found: C, 78.26; H; 6.56; N,
2.49.
methyl]-phenoxy}-ethyl)-piperidine. White solid, 11h
(450mg, 70%), mp 90ꢁC (HCl salt), IR (neat): 2927,
1652, 1505, 1219, 761cmÀ1
,
1H NMR (CDCl3,
200MHz): d 8.71 (d, 1H, J = 8.2Hz), 8.64 (d, 1H,
J = 8.2Hz), 8.03 (d, 1H, J = 8Hz), 7.70–7.40 (m, 5H),
7.22 (d, 1H, J = 7.8Hz), 7.17 (s, 1H), 7.06 (d, 1H,
J = 8Hz), 7.02 (d, 1H, J = 8.2Hz), 6.84 (s, 1H), 6.80–
6.67 (m, 4H), 6.16 (s, 1H), 4.07 (t, 2H, J = 6Hz), 3.70
(s, 3H), 2.75 (t, 2H, J = 6Hz), 2.52–2.46 (m, 4H),
1.70–1.56 (m, 4H), 1.46–1.44 (m, 2H); MS: 488 (M+);
Anal. Calcd for HCl salt, C35H36ClNO2: C, 78.12; H,
6.74; N, 2.60. Found: C, 78.50; H, 6.99; N, 2.94.
5.4.2.
1-(2-{4-[(4-Methoxy-phenyl)-phenanthren-9-yl-
methyl]-phenoxy}-ethyl)-pyrrolidine. White solid, 11k
(1g, 80%), mp 90ꢁC (HCl salt), IR (neat): 2926, 1507,
1246, 756cmÀ1 1H NMR (CDCl3, 200MHz): d 8.72
,
(d, 1H, J = 7.6Hz), 8.65 (d, 1H, J = 7.8Hz), 8.03 (d,
1H, J = 7.2Hz), 7.69–7.45 (m, 5H), 7.14 (s, 1H), 7.06
(d, 4H, J = 8.8Hz), 6.82 (d, 4H, J = 8.8Hz), 6.14 (s,
1H), 4.08 (t, 2H, J = 6Hz), 3.79 (s, 3H), 2.89 (t, 2H,
J = 6Hz), 2.62 (m, 4H), 1.79 (m, 4H); MS: 488 (M+);
Anal. Calcd for HCl salt, C34H34ClNO2ÆH2O: C,
77.92; H, 6.54; N, 2.67. Found: C, 78.22; H, 6.78; N,
2.27.
5.4.7. (2-{4-[(3-Methoxy-phenyl)-phenanthren-9-yl-meth-
yl]-phenoxy}-ethyl)-dimethylamine. White solid, 11e
(460mg, 77%), mp 70ꢁC (HCl salt), IR (neat): 2926,
1604, 1460, 1244, 758cmÀ1
,
1H NMR (CDCl3,
200MHz): d 8.71 (d, 1H, J = 8Hz), 8.64 (d, 1H,
J = 8Hz), 8.03 (d, 1H, J = 8Hz), 7.70–7.43 (m, 5H),
7.22 (d, 1H, J = 8.6Hz), 7.16 (s, 1H), 7.06 (d, 1H,
J = 8.8Hz), 7.02 (d, 1H, J = 8.6Hz), 6.86 (s, 1H),
6.83–6.68 (m, 4H), 4.02 (t, 2H, J = 6Hz), 3.71 (s, 3H),
2.72 (t, 2H, J = 6Hz), 2.33 (s, 6H); MS: 462 (M+ À1);
Anal. Calcd for HCl salt, C32H32ClNO2: C, 77.17; H,
6.48; N, 2.81. Found: C, 76.84; H, 6.12; N, 2.58.
5.4.3.
1-(2-{4-[(4-Methoxy-phenyl)-phenanthren-9-yl-
methyl]-phenoxy}-ethyl)-dimethyl-amine. White solid,
11i (1.1g, 93%), mp 110ꢁC (HCl salt), IR (Neat): 3440,
1633, 769cmÀ1
, d
1H NMR (CDCl3, 200MHz):
8.72 (d, 1H, J = 8Hz), 8.65 (d, 1H, J = 8.2Hz), 8.03
(d, 1H, J = 8Hz), 7.69–7.44 (m, 5H), 7.14 (s, 1H), 7.05
(d, 4H, J = 8Hz), 6.83 (d, 4H, J = 8Hz), 6.14 (s, 1H),
4.04 (t, 2H, J = 6Hz), 3.78 (s, 3H), 2.71 (t, 2H,
J = 6Hz), 2.32 (s, 6H); MS: 462 (M+); Anal. Calcd for
HCl salt, C32H32ClNO2: C, 77.17; H, 6.48; N, 2.81.
Found: C, 77.87; H, 6.75; N, 2.69.
5.4.8. Diethyl-(2-{4-[(3-methoxy-phenyl)-phenanthren-9-
yl-methyl]-phenoxy}-ethyl)-amine. White solid, 11f
(448mg, 77%), mp 65ꢁC (HCl salt), IR (neat): 2926,
1602, 1241, 1046, 758cmÀ1
,
1H NMR (CDCl3,
200MHz): d 8.71 (d, 1H, J = 8Hz), 8.64 (d, 1H,
J = 8.2Hz), 8.03 (d, 1H, J = 8Hz), 7.70–7.40 (m, 5H),
7.22 (d, 1H, J = 8.2Hz), 7.16 (s, 1H), 7.06 (d, 1H,
J = 8.4Hz), 7.02 (d, 1H, J = 8.4Hz), 6.84 (s, 1H),
6.82–6.70 (m, 4H), 6.16 (s, 1H), 4.02 (t, 2H, J = 6Hz),
3.71 (s, 3H), 2.86 (t, 2H, J = 6Hz), 2.61 (q, 4H,
J = 6Hz), 1.05 (t, 2H, J = 7.2Hz); MS: 490 (M+); Anal.
Calcd for HCl salt, C34H36ClNO2: C, 77.62; H, 6.92; N,
2.66. Found: C, 77.83; H, 6.39; N, 2.13.
5.4.4. Diethyl-(2-{4-[(4-methoxy-phenyl)-phenanthren-9-
yl-methyl]-phenoxy}-ethyl)-amine. White solid, 11j
(1.05g, 83%), mp 85ꢁC (HCl salt), IR (Neat): 2927,
1
1507, 1244, 759cmÀ1, H NMR (CDCl3, 200MHz): d
8.73 (d, 1H, J = 8Hz), 8.66 (d, 1H, J = 8Hz), 8.06 (d,
1H, J = 8.2Hz), 7.94–7.49 (m, 5H), 7.17 (s, 1H), 7.09
(d, 4H, J = 8.4Hz), 6.84 (d, 4H, J = 8.4Hz), 6.16 (s,
1H), 4.05 (t, 2H, J = 6Hz), 3.78 (s, 3H), 2.89 (t, 2H,
J = 6Hz), 2.66 (q, 4H), 1.08 (t, 6H); 13C NMR: d
139.3, 136.3, 131.9, 131.8, 131.0, 130.0, 129.1, 128.8,
127.0, 126.9, 126.4, 125.7, 123.4, 122.7, 114.8, 114.2,
66.8, 55.6, 52.2, 48.2, 12.2; MS: 490 (M+); Anal. Calcd
for HCl salt, C34H36ClNO2: C, 77.62; H, 6.92; N, 2.66.
Found: C, 77.64; H, 6.47; N, 2.60.
5.4.9.
1-(2-{4-[(2-Methoxy-phenyl)-phenanthren-9-yl-
methyl]-phenoxy}-ethyl)-piperidine. White solid, 11d
(450mg, 70%), mp 90ꢁC (HCl salt), IR (neat): 2930,
1
1604, 1242, 758cmÀ1, H NMR (CDCl3, 200MHz): d
8.70 (d, 1H, J = 8.2Hz), 8.64 (d, 1H, J = 8.2Hz), 8.01
(d, 1H, J = 8Hz), 7.70–7.43 (m, 5H), 7.23 (d, 1H,
J = 8Hz), 7.15 (s, 1H), 7.05 (d, 2H, J = 8.2Hz), 6.92
(d, 1H, J = 8.2Hz), 6.88–6.78 (m, 4H), 6.54 (s, 1H),
4.11 (t, 2H, J = 6Hz), 3.73 (s, 3H), 2.86 (t, 2H,
J = 6Hz), 2.61 (t, 4H, J = 6Hz), 1.66 (m, 4H), 1.47 (m,
2H); MS: 502 (M+À1); Anal. Calcd for HCl salt,
5.4.5. 1-(2-4-[(3-Methoxy-phenyl)-phenanthren-9-yl-
methyl]-phenoxy-ethyl)-pyrrolidine. White solid, 11g

G. Panda et al. / Bioorg. Med. Chem. 12 (2004) 5269–5276
5275
C35H36ClNO2: C, 78.12; H, 6.74; N, 2.60. Found: C,
78.81; H, 6.38; N, 2.76.
J = 6.8Hz), 7.08 (s, 1H), 7.01 (d, 2H, J = 8.6Hz),
6.84–6.71 (m, 5H), 6.45 (s, 1H), 3.96 (t, 2H, J = 6Hz),
3.70 (s, 3H), 2.43 (t, 2H, J = 6.2Hz), 2.09–2.08 (m,
4H), 1.21–1.18 (m, 6H), MS: 502 (M+ÀClÀ); Anal.
Calcd for HCl salt, C35H36ClNO2: C, 78.12; H, 6.74;
N, 2.66. Found: C, 78.91; H, 6.99; N, 2.87.
5.4.10.
1-(2-{4-[(2-Methoxy-phenyl)-phenanthren-9-yl-
methyl]-phenoxy}-ethyl)-pyrrolidine. White solid, 11c
(450mg, 72%), mp 97ꢁC (HCl salt), IR (neat): 3017,
2929, 1505, 1218, 758cmÀ1
,
1H NMR (CDCl3,
200MHz): d 8.69 (d, 1H, J = 8.2Hz), 8.64 (d, 1H,
J = 8.4Hz), 8.01 (d, 1H, J = 8Hz), 7.70–7.43 (m, 5H),
7.24 (d, 1H, J = 8Hz), 7.15 (s, 1H), 7.05 (d, 2H,
J = 8.4Hz), 6.91 (d, 1H, J = 8.2Hz), 6.90–6.75 (m,
4H), 6.54 (s, 1H), 4.07 (t, 2H, J = 6Hz), 3.73 (s, 3H),
2.88 (t, 2H, J = 6Hz), 2.65–2.56 (m, 4H), 1.79–1.77
(m, 4H), MS: 488 (M+); Anal. Calcd for HCl salt,
C34H34ClNO2: C, 77.92; H, 6.54; N, 2.67. Found: C,
77.44; H, 6.43; N, 2.38.
5.4.15.
1-(2-{2-[(4-Methoxy-phenyl)-phenanthren-9-yl-
methyl]-phenoxy}-ethyl)-pyrrolidine. White solid, 13c
(390mg, 78%), mp 80ꢁC (HCl salt), IR (neat): 2938,
1244, 754cmÀ1 1H NMR (CDCl3, 200MHz): d 8.67
,
(d, 1H, J = 8.2Hz), 8.63 (d, 1H, J = 8.0Hz), 8.00 (d,
1H, J = 8.2Hz), 7.65–7.48 (m, 5H), 7.18 (d, 1H,
J = 6.8Hz), 7.05 (s, 1H), 7.02 (d, 2H, J = 8.2Hz),
6.93–6.80 (m, 5H), 6.54 (s, 1H), 4.03 (t, 2H, J = 6Hz),
3.78 (s, 3H), 2.63 (t, 2H, J = 6Hz), 2.25 (m, 4H), 1.45
(m, 4H), MS: 488 (M+ÀClÀ); Anal. Calcd for HCl salt,
C34H34ClNO2: C, 77.92; H, 6.54; N, 2.67. Found: C,
77.98; H, 6.29; N, 2.41.
5.4.11.
(2-{4-[(2-Methoxy-phenyl)-phenanthren-9-yl-
methyl]-phenoxy}-ethyl)-dimethylamine. White solid,
11a (400mg, 67%), mp 95ꢁC (HCl salt), 1H NMR
(CDCl3, 200MHz): d 8.69 (d, 1H, J = 8.4Hz), 8.63 (d,
1H, J = 8.4Hz), 8.02 (d, 1H, J = 8Hz), 7.70–7.45 (m,
5H), 7.22 (d, 1H, J = 8.2Hz), 7.15 (s, 1H), 7.05 (d, 2H,
J = 8.6Hz), 6.95–6.80 (m, 5H), 6.54 (s, 1H), 4.03 (t,
2H, J = 6Hz), 3.72 (s, 3H), 2.70 (t, 2H, J = 6Hz), 2.33
(s, 6H), MS: 462 (M+À1), IR (neat): 2930, 1600, 1496,
1461, 1240, 761cmÀ1; Anal. Calcd for HCl salt,
C32H32ClNO2: C, 77.17; H, 6.48; N, 2.81. Found: C,
76.85; H, 6.88; N, 2.34.
5.4.16.
1-(2-{2-[(4-Methoxy-phenyl)-phenanthren-9-yl-
methyl]-phenoxy}-ethyl)-dimethylamine. White solid,
13a (380mg, 80%), mp 210ꢁC (HCl salt), IR (neat):
2938, 1244, 754cmÀ1 1H NMR (CDCl3, 200MHz):
,
d 8.67 (d, 1H, J = 8.2Hz), 8.64 (d, 1H, J = 8.0Hz),
8.01 (d, 1H, J = 8.2Hz), 7.65–7.48 (m, 5H), 7.22 (d,
1H, J = 6.9Hz), 7.15 (s, 1H), 7.08 (d, 2H, J = 8.0Hz),
6.93–6.78 (m, 5H), 6.54 (s, 1H), 3.97 (t, 2H, J = 6Hz),
3.78 (s, 3H), 2.39 (t, 2H, J = 6Hz), 2.05 (s, 6H), MS:
462 (M+ÀClÀ); Anal. Calcd for HCl salt, C32H32ClNO2:
C, 77.17; H, 6.48; N, 2.81. Found: C, 76.90; H, 6.98; N,
2.76.
5.4.12. Diethyl-(2-{4-[(2-methoxy-phenyl)-phenanthren-9-
yl-methyl]-phenoxy}-ethyl)-amine. White solid, 11b
(390mg, 62%), mp 78ꢁC (HCl salt), IR (neat): 3019,
1216, 765cmÀ1
,
1H NMR (CDCl3, 200MHz): d 8.70
5.4.17. Bis-1-(2-{2-[(4-methoxy-phenyl)-phenanthren-9-
yl-methyl]-phenoxy}-ethyl)-dimethylamine. White solid,
18a (200mg, 48%), mp 192ꢁC (HCl salt), IR (neat):
(d, 1H, J = 8.2Hz), 8.64 (d, 1H, J = 8.2Hz), 8.02 (d,
1H, J = 8Hz), 7.69–7.42 (m, 5H), 7.25 (d, 1H,
J = 8Hz), 7.15 (s, 1H), 7.05 (d, 2H, J = 8.4Hz), 6.91
(d, 1H, J = 8.2Hz), 6.90–6.78 (m, 4H), 6.54 (s, 1H),
4.01 (t, 2H, J = 6Hz), 3.73 (s, 3H), 2.85 (t, 2H,
J = 6Hz), 2.62 (q, 4H, J = 7Hz), 1.05 (t, 6H); MS: 490
(M+À1); Anal. Calcd for HCl salt, C34H36ClNO2: C,
77.62; H, 6.92; N, 2.66. Found: C, 77.17; H, 6.88; N,
2.66.
2930, 2862, 2822, 2773, 1461, 1245cmÀ1 1H NMR
,
(CDCl3, 200MHz): d 8.71 (d, 1H, J = 8.4Hz), 8.65 (d,
1H, J = 8.4Hz), 8.01 (d, 1H, J = 8.2Hz), 7.70–7.46 (m,
5H), 7.14 (s, 1H), 7.04 (d, 4H, J = 8.2Hz), 6.82 (d, 4H,
J = 8.2Hz), 6.13 (s, 1H), 4.03 (t, 4H, J = 6.2Hz), 2.71
(t, 4H, J = 6.2Hz), 2.34 (s, 12H), MS: 519 (M+); Anal.
Calcd for HCl salt, C35H40Cl2N2O2: C, 71.06; H, 6.81;
N, 4.74. Found: C, 71.66; H, 6.71; N, 4.99.
5.4.13. Diethyl-(2-{2-[(4-methoxy-phenyl)-phenanthren-9-
yl-methyl]-phenoxy}-ethyl)-amine. White solid, 13b
(250mg, 91%), mp 150ꢁC (HCl salt), IR (neat): 2942,
5.4.18.
Bis-diethyl-(2-{2-[(4-methoxy-phenyl)-phenan-
thren-9-yl-methyl]-phenoxy}-ethyl)-amine. White solid,
18b (215mg, 47%), mp 220ꢁC (HCl salt), IR (neat):
1241, 756cmÀ1 1H NMR (CDCl3, 200MHz): d 8.70
,
1
(d, 1H, J = 8.4Hz), 8.64 (d, 1H, J = 8.4Hz), 8.03 (d,
1H, J = 8.2Hz), 7.68–7.47 (m, 5H), 7.22 (d, 1H,
J = 6.8Hz), 7.16 (s, 1H), 7.08 (d, 2H, J = 8.2Hz), 6.91
(d, 1H, J = 8Hz), 6.83–6.78 (m, 4H), 6.54 (s, 1H), 3.95
(t, 2H, J = 6Hz), 3.78 (s, 3H), 2.53 (t, 2H, J = 6Hz),
2.36 (q, 4H), 0.8 (t, 6H), MS: 490 (M+ÀClÀ); Anal.
Calcd for HCl salt, C34H36ClNO2: C, 77.62; H, 6.92;
N, 2.66. Found: C, 76.20; H, 6.80; N, 2.39.
2970, 2932, 2820, 1604, 1506, 1243, 1042, 758cmÀ1, H
NMR (CDCl3, 200MHz): d 8.71 (d, 1H, J = 8.2Hz),
8.65 (d, 1H, J = 8.0Hz), 8.03 (d, 1H, J = 8.2Hz), 7.70–
7.46 (m, 5H), 7.14 (s, 1H), 7.04 (d, 4H, J = 8.2Hz),
6.82 (d, 4H, J = 8.2Hz), 6.13 (s, 1H), 4.01 (t, 4H,
J = 6.2Hz), 2.85 (t, 4H, J = 6.2Hz), 2.61 (q, 8H,
J = 6.2Hz), 1.05 (t, 12H, J = 6.2Hz), MS: 575 (M+);
Anal. Calcd for HCl salt, C39H48Cl2N2O2: C, 72.32;
H, 7.47; N, 4.32. Found: C, 72.91; H, 7.99; N, 4.65.
5.4.14.
1-(2-{2-[(4-Methoxy-phenyl)-phenanthren-9-yl-
methyl]-phenoxy}-ethyl)-piperidine. White solid, 13d
(450mg, 65%), mp 110ꢁC (HCl salt), IR (neat): 2938,
5.4.19. Bis-1-(2-{4-[(3-methoxy-phenyl)-phenanthren-9-
yl-methyl]-phenoxy}-ethyl)-piperidine. White solid, 18c
(98mg, 30%), mp 146ꢁC (HCl salt), IR (neat): 2929,
1244, 754cmÀ1 1H NMR (CDCl3, 200MHz): d 8.60
,
(d, 1H, J = 8.2Hz), 8.56 (d, 1H, J = 8.1Hz), 7.95 (d,
1H, J = 8.2Hz), 7.60–7.40 (m, 5H), 7.17 (d, 1H,
2853, 2783, 1505, 1242, 1036, 758cmÀ1 1H NMR
,
(CDCl3, 200MHz): d 8.71 (d, 1H, J = 8.0Hz), 8.65 (d,

5276
G. Panda et al. / Bioorg. Med. Chem. 12 (2004) 5269–5276
1H, J = 8.2Hz), 8.03 (d, 1H, J = 8.2Hz), 7.70–7.46 (m,
5H), 7.14 (s, 1H), 7.04 (d, 4H, J = 8.2Hz), 6.82 (d, 4H,
J = 8.4Hz), 6.13 (s, 1H), 4.08 (t, 4H, J = 6.2Hz), 2.76
(t, 4H, J = 6.2Hz), 2.52–2.48 (m, 8H), 1.60–1.56 (m,
8H), 1.45–1.42 (m, 4H), MS: 600 (M+); Anal. Calcd
for HCl salt, C41H48Cl2N2O2: C, 73.31; H, 7.20; N,
4.17. Found: C, 73.69; H, 7.98; N, 3.99.
J.K.M. and Shagufta thank CSIR for providing
fellowship.
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Acknowledgements
The authors thank Director, Central Drug Research
Institute (CDRI) for his encouragement and support.
Instrumentation facilities from R.S.I.C., CDRI is grate-
fully acknowledged. This research project was supported
by Department of Science and Technology (SR/FTP/
CSA-05/2002), New Delhi, India. We thank Mr.
Pramod Kumar for his technical assistance and Mr.
Mukesh Srivastava for statistical analysis in this project.