Design, synthesis and evaluation of carbazole derivatives as PPARα/γ dual agonists and antioxidants

Article abstract of DOI:10.1016/j.bmc.2005.04.018

A series of hydroxycarbazole derivatives were synthesized and evaluated for PPARα/γ dual agonist as well as antioxidant activities. While most compounds showed good antioxidant activity, some compounds were identified as potential PPARα/γ dual agonists as well. Compounds 10a and 16 were found to be active in animal studies.

Full text of DOI:10.1016/j.bmc.2005.04.018

Bioorganic & Medicinal Chemistry 13 (2005) 4279–4290
Design, synthesis and evaluation of carbazole derivatives as
PPARa/c dual agonists and antioxidantsI
Rakesh Kumar,a Uma Ramachandran,a,* Krishnamoorthy Srinivasan,b Poduri Ramarao,b
Suryaprakash Raichurc and Ranjan Chakrabartic
aDepartment of Pharmaceutical Technology, National Institute of Pharmaceutical Education and Research (NIPER),
Sector 67, S.A.S. Nagar 160 062, India
bDepartment of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER),
Sector 67, S.A.S. Nagar 160 062, India
cDr. ReddyÕs Laboratories-Discovery Research, Bollaram Road, Miyapur, Hyderabad 500 050, India
Received 17 January 2005; revised 1 April 2005; accepted 10 April 2005
Abstract—A series of hydroxycarbazole derivatives were synthesized and evaluated for PPARa/c dual agonist as well as antioxidant
activities. While most compounds showed good antioxidant activity, some compounds were identified as potential PPARa/c dual
agonists as well. Compounds 10a and 16 were found to be active in animal studies.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
which is linked to the pathogenesis of diabetes.4–6 The
role of PPARc activators in reducing hyperglycemia
associated with type 2 diabetes was proved initially by
use of thiazolidinediones (TZDs), which were already
known to be normoglycemic.7 Likewise, fibrates like
WY 14643, which were shown to reduce triglycerides
(TG) and free fatty acids (FFA) and increase high den-
sity lipoproteins (HDL) were found to activate PPARa.8
Non-insulin dependent diabetes mellitus or type 2 diabe-
tes is characterized by hyperglycemia due to insulin
resistance.1 A sharp increase in the incidence of type 2
diabetes especially in the developed and fast developing
countries is a matter of serious concern. It is predicted
that the worldÕs diabetic population will be doubled to
300 million before 2025. Insulin resistance is a primary
risk factor for type 2 diabetes mellitus.2 Besides, these
patients have elevated serum levels of fatty acids. Type
2 diabetic patients have an increased risk of developing
various clinical complications due to microvascular or
macrovascular diseases that include nephropathy, reti-
nopathy and neuropathy.3
Though currently marketed TZDs, pioglitazone and rosi-
glitazone are effective in reducing glucose levels and
have beneficial effects to some extent on TG, FFA and
HDL cholesterol levels, they exhibit some undesirable
effects like weight gain and edema.9
It was quickly realized that if ligands were designed to
activate both PPARa and PPARc, there could be a
simultaneous control of both glucose and lipid levels
in type 2 diabetic patients.10 So the inference that
PPARa/c dual agonists could provide additive and pos-
sibly synergistic efficacy relative to selective activation of
one subtype alone, lead to the reporting of many com-
pounds having dual activation.11–13 The compounds of
this class have a few essential pharmacophore elements.
These comprise of an acidic group linked to a central flat
ring and a large lipophilic substructure. Earlier, we had
studied a series of glitazones replacing central phenyl
ring by pyridine ring.14
Since the identification of peroxisome proliferator acti-
vated receptors (PPARa, c and d) of the nuclear recep-
tor superfamily, rapid progress has been made in
understanding their functions. Besides sensitizing insulin
receptors, it has been established that they play a central
role in regulating the storage and catabolism of lipids,
Keywords: PPAR dual agonists; Hydroxycarbazoles; Hypoglycemic;
Antioxidant; Transactivation; Lipid peroxidation.
q NIPER communication number.
*
Corresponding author. Tel.: +91 (0) 172 2214682/87; fax: +91 (0) 172
2214692; e-mail: umaram54@yahoo.com
0968-0896/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.04.018

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R. Kumar et al. / Bioorg. Med. Chem. 13 (2005) 4279–4290
Another dimension to the complexity of the disease like
diabetes is the role of oxidative stress right from its onset
and all through the progression of this disease. It has
been shown beyond doubt that diabetic subjects exhibit
high lipid peroxides and other forms of oxidative
stress.15 Oxidative stress seems to be caused by increased
production of reactive oxygen species (ROS) and altered
cellular redox states. Antioxidants are known to be
interceptors of peroxy radicals and singlet oxygen and
hence inhibit lipid peoxidation, which is implicated in
the alternation of glucose transport and microangio-
pathic disease in diabetes. Supplementation with an
antioxidant is a promising complimentary treatment,
which exerts beneficial effects in diabetes and provides
further support for implications of oxidative stress in
beta cell dysfunction in diabetes.16,17
Figure 2. Designing of hydroxycarbazole derivatives.
we hoped, would show dual PPARa/c agonistic as well
as antioxidant activities.
3. Chemistry
Starting with either 4- or 2-hydroxy carbazoles, their al-
kyl or aralkyl derivatives (5a–f) were synthesized using
alkyl halides or aralkyl halides as shown in Scheme 1.
These were then condensed with 4-(2-bromoethoxy)
benzaldehyde (3), to obtain corresponding aldehyde 6.
Horner Wadsworth–Emmons reaction on these alde-
hydes using phosphonate (4),22,23 gave 7. These esters
were hydrogenated to get 8 and then hydrolyzed to acid
9. The acids were then converted to their L-lysine salts
10.
After troglitazone, which had a beneficial antioxidant
activity, was withdrawn due to hepatic dysfunction
and increase in lipoproteins, not much work has been
carried out in designing antidiabetic compounds with
antioxidant activity. Lohray et al. reported TZDs hav-
ing chroman moieties and evaluated them for their
euglycemic and hypolipidemic activities.18 They also
found that when hydroxy group of chroman moiety of
troglitazone was protected, it led to a decrease in metab-
olism and superior pharmacological profile.19
In Scheme 2, we have shown the synthesis of N-substi-
tuted L-tyrosine based derivative. Compound 13 was ob-
tained by condensing L-tyrosine methyl ester 12 and
benzoyl acetone (11).24–27 Condensing 13 with 4-(2-
bromoethoxy)-9H-carbazole (17), gave 14, which was
then hydrolyzed to 15. This was converted to its L-lysine
salt 16.
In a previous study, potent b- and selective a-adrenocep-
tor blocker carvedilol, which has hydoxycarbazole moi-
ety, was shown to have potent antioxidant activity.
Antioxidant effect of carvedilol mainly resides in carb-
azole moiety and substitution of hydroxyl group of carb-
azole resulted in an increase in antioxidant activity. The
apparent mechanism of carvedilolÕs inhibition of lipid
peroxidation was shown to be through scavenging free
radicals.20
In another series, we explored some changes in the linker
unit and the receptor binding unit when they are at-
tached to oxygen of 4-hydroxycarbazole. Thus, starting
from 4-(2-bromoethoxy)-9H-carbazole (17) various
hydroxyesters like 18, 20, 22 and 25 were condensed to
obtain compounds 19, 21, 23 and 26, respectively. Com-
pound 23 was hydrogenated to 24 and then hydrolyzed
and made into L-lysine salt 24a. Compounds 19, 21, 26
were hydrolyzed to give their respective carboxylic acid
19a, 21a and 26a (Scheme 3).
2. Design concept
Compounds having tricyclic unit and a-ethoxy propi-
onic acid group have shown good PPARa/c dual agonis-
tic activity and some reached up to phase II clinical
trials. Among these, carbazole analogue 1 (Fig. 1),
which showed improved insulin sensitizing and lipid
lowering effects in in vivo studies as compared to known
TZDs, attracted us.21
4. Biological screening
In vitro screening of compounds was done to evaluate
their PPARa/c dual agonistic as well as their antioxi-
dant potential.
By taking hydroxycarbazole as starting synthons, we at-
tached the linker and receptor binding unit at oxygen
and in some cases at nitrogen (Fig. 2). These compounds
4.1. Lipid peroxidation
Aerobic incubation of rat brain homogenates with
agents known to produce reactive oxygen species
(ROS) like ferrous chloride and ascorbate, induce the
process of lipid peroxidation, leading to the formation
of degradation products of peroxidized lipids including
malondialdehyde. This reacts with barbituric acid to
yield a pink colour, whose intensity is read spectropho-
tometrically. The antioxidant activities of the com-
pounds in their ester, acid and/or their L-lysine salt
forms is shown in Table 1. Trolox was used as positive
Figure 1. Some selected PPAR agonists.

R. Kumar et al. / Bioorg. Med. Chem. 13 (2005) 4279–4290
4281
Scheme 1. Reagents and conditions: (a) 4-(2-bromoethoxy)-benzaldehyde (3), NaH, THF; (b) ethyl-2-ethoxy-2-diethyl phosphonoacetate (4), NaH,
THF; (c) H2, 10% Pd/C, ethyl acetate, 5 h; (d) 20% NaOH, ethanol, rt, 2 h; (e) L-lysine, ethanol, 1 h.
˚
Scheme 2. Reagents and conditions: (a) benzoyl acetone (11), toluene, 4 A molecular sieve, reflux; (b) 4-(2-bromoethoxy)-9H-carbazole (17), K2CO3,
acetone, reflux; (c) 20% NaOH, ethanol, (d) L-lysine, ethanol.
was measured. Potencies of PPAR gene activation were
evaluated in cell based transcription assays using GAL4-
PPAR chimeric receptors.28,29 Transactivation studies
were done for all the compounds in 3 concentrations
both for PPARc and PPARa using rosiglitazone and
WY 14,643 as references, respectively (fold activation
for 2 concentrations are shown in Table 1). PPARa fold
activation for fenofibrate was found to be 3.2 at 100 lM
concentration.
4.3. In vivo studies
In vivo studies were done on db/db mice, which were
used as a type 2 diabetic animal model. Male db/db mice
at 12–13 weeks of age (seven per group) received a daily
oral dosing of vehicle or test compounds for 14 days.
The blood was collected on the 14th day for measure-
ment of plasma glucose level. Cholesterol fed male Spra-
gue–Dawley (SD) rats was used as another model to
evaluate hypolipidemic effect of compound 16, 10a and
1. Compounds were given through oral gavage and on
Scheme 3. Reagents and conditions: (a) K2CO3, acetone, reflux; (b) 20%
NaOH, ethanol; (c) H2, 10% Pd/C, ethyl acetate; (d) L-lysine, ethanol.
3rd day of treatment, TG, TC, HDL, LDL and VLDL
levels were measured.
control and compound 1, which is also a carbazole
derivative without hydroxyl group is another control.
4.4. Results and discussion
4.2. PPAR transactivation
All compounds with hydroxycarbazole structural motif,
showed antioxidant activity as determined by lipid per-
The cells were transfected with an expression plasmid
for PPAR receptors and activation of luciferase gene
oxidation test. Compound
>300 lM, while the rest, which were derivatives of
1 showed activity at

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R. Kumar et al. / Bioorg. Med. Chem. 13 (2005) 4279–4290
Table 1. Lipid peroxidation and PPAR fold activation
Sr. No.
Compound
Lipid peroxidation IC50 (lM)
PPARa Fold
activation
PPARc Fold
activation
1 lM
50 lM
1 lM
50 lM
1
10a
10b
41.88
49.15
07.28
16.59
24.09
ND
3.3
2.9
1.0
1.9
1.2
1.1
3.2
2.7
1.2
1.3
1.0
ND
1.1
ND
1.1
ND
ND
2.5
—
9.7
5.6
3.7
4.0
2.4
1.9
4.4
5.4
2.5
1.3
2.0
ND
4.2
ND
2.2
ND
ND
6.2
—
6.7
6.4
40.4
18.0
14.2
16.9
11.8
4.1
2
3
10c
10d
5.2
4
11.8
2.2
5
10e
10f
6
0.7
7
14
16
ND
12.9
20.9
0.5
29.4
47.6
5.8
8
00.35
01.28
01.85
17.09
01.29
ND
9
23
24
10
11
12
13
14
15
16
17
18
19
20
21
0.7
0.6
5.8
24a
19
10.2
ND
2.0
ND
0.9
19a
21
04.71
ND
ND
3.0
ND
3.7
21a
26
20.01
ND
0.6
1.1
1.8
1.8
26a
1
P300
07.43
—
11.5
—
18.3
—
Trolox
WY 14643
Rosiglitazone
1.3
—
4.0
—
—
15.4
—
22.5
—
ND—Not done.
hydroxycarbazole exhibited an antioxidant IC50 value
ranging from 49.0 lM to 0.35 lM. Among these, 4-
hydroxycarbazole based compounds exhibited better
antioxidant activity as compared to 2-hydroxycarbazole
derivatives. Compound 16 having IC50 = 0.35 lM
turned out to be around 20-fold more potent than refer-
ence trolox (IC50 = 7.48 lM). Compounds 19a and 20a,
which have carboxylic acid group attached directly to
the aromatic ring also exhibited good antioxidant activ-
ity (Table 1).
Transactivation studies exhibited that a-alkoxyprop-
ionic acid series showed good PPARa activity (around
2-fold higher than WY) but PPARc activity was seen
only at higher concentrations. L-Tyrosine based com-
pound 14 and its L-lysine salt 16 have good PPARa/c
dual activity. They exhibited better activity than WY
and equipotency with rosiglitazone. Comparative dose
response studies of compounds 10a and 16 were per-
formed with rosiglitazone for PPARc and WY for
PPARa (Fig. 3). Compounds 10a and 16 showed less
potency (EC50 = 11.48 lM) and (EC50 = 1.68 lM),
respectively, as compared to rosiglitazone (EC50
=
0.78 lM). However both these compounds show more
potency (EC50 = 8.27 lM) and (EC50 = 8.10 lM),
respectively, for PPARa activation than WY 14,643
(EC50 = 23.92 lM). Rest of the compounds, with varia-
tions in linker and acid chain length did not show much
activity.
It is interesting to note that when the a-alkoxy propionic
acid derivative 24a, having linkage at O-atom, showed
lower activity as compared to 10a, where it is linked to
N-atom of hydroxycarbazole. Compound 10a of a-alk-
oxy propionic series and 16, which is of L-tyrosine series,
were chosen for in vivo studies.
Figure 3. Note: Each compound was tested in 10 concentrations
ranging from 0.01 to 50 lM.
In vivo experiments done in db/db mice for 10a, 16 and
1 gave some very interesting results. While PG level was

R. Kumar et al. / Bioorg. Med. Chem. 13 (2005) 4279–4290
4283
significantly reduced by 10a when given orally on 14th
day by about 70%, compound 16 did not show signifi-
cant reduction. Similarly, 10a significantly reduced TG
level in db/db mice by 45% when given orally while 16
did not show any TG lowering effect (Table 2).
used for hydrogenation is from Perfit-India. Infrared
(IR) spectra were recorded on a Nicolet Impact-410 FTIR
spectrometer. Proton magnetic resonance (NMR) spectra
were recorded on a Bruker 300 MHz spectrometer in
CDCl3, CD3OD, D2O or DMSO-d6 solution. The chemi-
cal shifts are reported in d (ppm) relative to internal stan-
dard tetramethylsilane (TMS) and coupling constants J
are given in Hz. Mass spectroscopy was conducted using
Shimadzu QP5000 mass spectrometer, LCQ Finnigan
MAT and Bruker Daltonics MALDI Tandem TOF mass
spectrometer. Elemental analyses were obtained from
Elementar VarioÒEL.
Surprisingly, the results of PPAR transactivation assays
do not correlate with the plasma glucose and triglyceride
lowering activities in orally fed db/db mice studies of 16.
However, when 16 was tested in cholesterol fed SD rats
orally, it showed significant lowering in TC, TG, LDL
and VLDL levels and increase in HDL level (Table 3).
These results can be attributed to species differ-
ences, which need to be confirmed through further
studies.
6.2. Biological study
PPAR transactivation: The response element (UAS-
GAL4*5) was cloned upstream of the Pgl2-sv 40-Luc re-
porter (Promega, Madison, WI, USA), which contains
the Simian virus early promoter for luciferase assay.
GAL4 fusions were made by fusing human PPARc1
or PPARa ligand-binding domain (amino acids: 174–
475) to the C-terminal end of the yeast GAL4 DNA-
binding domain (amino acids: 1–147) of the pM1 vector.
PadVantage (Promega, Madison, WI, USA) vector was
used to enhance luciferase expression.
Compounds 16 and 10a show better profile than com-
pound 1 regarding TC and LDL lowering and increase
in HDL.
5. Conclusion
Our studies have shown that many hydroxycarbazole
derivatives are both PPARa/c dual agonists as well as
antioxidants. In vivo studies in fat fed SD rats show that
compounds 10a and 16 to have better profile than com-
pound 1. We have studied compounds linked at O-atom
of hydroxycarbazole for the first time. Further pharma-
cological studies on these compounds are underway.
HEK 293T cells were grown in DulbeccoÕs modified Ea-
gleÕs medium supplemented with 10% foetal bovine ser-
um (DMEM-FBS) at 37 °C in 5% CO2. At 1 day prior
to transfection, cells were plated to 50–60% confluence
in DMEM containing 10% delipidated FBS (DMEM-
DFBS). Cells were transfected by Superfect as per the
manufacturerÕs protocol. At 3 h after transfection, the
reagent was removed and cells maintained in DMEM-
DFBS. At 42 h after transfection, the cells were placed
in phenol red-free DMEM-DFBS, and treated for 18 h
with the test compounds or vehicle alone. The cells were
lysed and assayed for luciferase activity. Luciferase
activity was determined by using Lucite kit (Packard,
CT, USA) in a Packard Top count and expressed as fold
activation relative to untreated cells.
6. Experimental
6.1. General experimental details
Thin layer chromatography analyses were performed on
precoated silica gel plates (GF254, Merck). Chromato-
graphy was performed on flash silica gel (230–400 mesh).
Melting points were recorded on a Buchi capillary melt-
ing point apparatus and are uncorrected. Parr shaker
Table 2. Effect of 10a, 16 and 1 on plasma glucose and plasma triglyceride in db/db mice
Group
0 day PG
14 day PG
% Reduction
0 day TG
14 day TG
% Reduction
Control
494.83 37.36
495.97 32.89
477.12 38.60
498.57 25.67
454.56 59.50
136.16 10.46*
401.36 30.23*
200.31 12.78*
—
70
8
141.12 30.48
110.01 24.59
87.14 7.36
154.13 26.84
66.31 8.07*
170.01 12.32*
80.08 5.56*
—
45
10a
16
1
NE
44
56
130.18 11.25
Note: N = 7/group. Values are mean SEM. All compounds were used at 10 mg/kg, p.o.
* P < 0.05 versus control group.
Table 3. Hypolipidemic effect of 16 in cholesterol fed SD rats: TC, TG, HDL, LDL and VLDL levels on 3rd day of treatment
Parameter/ TC (mg/dl)
compd
% Red TG (mg/dl)
% Redn HDL (mg/dl) % Incr LDL (mg/dl)
% Redn VLDL
(mg/dl)
% Redn
Control
607.43 80.39
—
160.19 26.91
—
12.29 0.73
—
563.11 79.64
—
32.04 5.38
—
18.30 0.36* 43
16.19 0.81 48
16.96 1.58 48
16
10a
1
136.54 3.37* 78
255.84 10.32 58
324.79 22.51 46
91.49 1.81* 43
24.82 2.36* 102
93.43 5.88* 83
220.23 15.86 61
292.76 10.29 48
83.2 5.32
106.23 9.57
48
34
19.42 1.25
15.07 1.98
58
23
Note: N = 7/group. Values are mean SEM. All compounds were used at 3 mg/kg, p.o.
* P < 0.05 versus control group.

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R. Kumar et al. / Bioorg. Med. Chem. 13 (2005) 4279–4290
In vivo studies: Animals C57 BL/6J-db/db mice were
obtained from Jackson Laboratory, Bar Harbour,
ME, USA at 6 weeks of age. Sprague–Dawley rats were
bred at Dr. ReddyÕs Laboratories-Discovery Research
(DRL-DR) animal house. All animals were maintained
under 12 h light and 12 h dark cycle at 25 1 °C. All
animals were given standard laboratory chow (National
Institute of Nutrition, Hyderabad, India) and water ad
libitum. Male Sprague–Dawley rats weighing 157–
253 g were made hyperlipidemic by feeding a high-fat
diet containing 2% cholesterol and 1% sodium cholate
mixed with standard laboratory chow. All animal exper-
iments were carried out in accordance with internation-
ally valid guidelines, and the experimental protocols
were approved by DRL-DR animal ethics committee.
(inhibitory concentration at which occurs 50% inhibi-
tion of TBARS formation) value for each compound
was found out by nonlinear regression curve fitting
using Graph Pad Prism software. Each measurement
was the average of 2 or 3 experiments performed in
duplicates. Similarly, EC50 value of the comp-
ounds 10a and 16 were calculated in transactivation
assays.
6.3. Synthetic procedures
6.3.1. General procedure for synthesis of 5a,b,d,f. To an
ethyl acetate solution of 4-hydroxycarbazole (1.0 equiv)
for 5a,b,d or 2-hydroxycarbazole (for 5f), tetrabutyl
ammonium hydrogen sulfate (0.01 equiv), alkyl halide
(1.5 equiv) was added potassium carbonate (1.2 equiv).
The resulting suspension was refluxed for 12–14 h. The
reaction mixture was diluted with ethyl acetate and
water. The organic layer was separated and dried over
anhydrous sodium sulfate, decanted, concentrated and
chromatographed on silica gel. Elution with a gradient
mixture of ethyl acetate/hexane yielded the title com-
pounds (60–80%).
6.2.1. Lipid peroxidation. Preparation of rat brain
homogenates: The male SD rats weighing 280–350 g
were sacrificed by decapitation and the brains were
immediately taken out and cleaned with ice cold 0.9%
saline. Whole brain, except cerebellum, was homoge-
nized with a polytron homogenizer in 10 vol of ice-cold
saline. Then, homogenate volume was adjusted/diluted
with ice-cold saline so as to give a final concentration
of 10 mg/0.8 ml and frozen as aliquots at À20 °C, if
studied later (within 2 days).
6.3.1.1. 4-Methoxy carbazole (5a). White solid. Mp
135 °C. IR (KBr, cmÀ1) 3393, 1599, 1452, 1260, 1100.
1H NMR (CDCl3) d 4.07 (s, 3H), 6.68 (d, J = 9 Hz,
1H), 7.04 (d, J = 8.1 Hz, 1H), 7.05–7.39 (m, 4H),
8.05 (s, 1H), 8.31 (d, J = 7.8 Hz, 1H). MS (EI): 197
(m/z M+).
Measurement of lipid peroxidation in rat brain homoge-
nate: The rates of membrane lipid peroxidation were
measured by the formation of thiobarbituric acid reac-
tive substances (TBARS) by the methodology reported
by Yue et al.,30 with some modification. The rat brain
homogenates (10 mg tissue/0.8 ml) were incubated at
37 °C for 15 min with 6–8 different concentrations of
10 ll of a test compound or vehicle. Lipid peroxidation
was initiated by addition of 0.1 ml each of 0.25 mM of
FeCl2 and 1 mM ascorbic acid. A final volume of 1 ml
reaction mixture was further incubated for 30 min at
37 °C in water bath and then the reaction was stopped
by addition of 0.1 ml of 0.2% butylated hydroxytoluene.
Thiobarbituric acid (0.67%) (TBA) reagent, 1 ml was
then added and the mixture heated for 30 min at 95 °C
in water bath. The mixture then cooled on ice for
5 min. The TBARS were extracted by adding 2.0 ml of
n-butanol and vortexed well for a minute and centri-
fuged for 5 min at 3000 rpm and the 1 ml aliquot of n-
butanol phase was taken for measuring absorbance at
535 nm. Reactions without TBA were taken as blank.
The antioxidant activity of test compounds was deter-
mined as percent inhibition of TBARS formation from
the control absorbance values (i.e., in the absence of
the test compound), which is assumed as 100%. The ref-
erence compound used is a well known antioxidant,
trolox.
6.3.1.2. 4-Ethoxy carbazole (5b). White solid. Mp
150 °C. IR (KBr, cmÀ1) 3395, 1601, 1454, 1262, 1100.
1H NMR (CDCl3) d 1.62 (m, 3H), 4.25 (q, J = 6 Hz,
2H), 6.66 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 9.3 Hz, 1H),
7.20–7.38 (m, 4H), 8.03 (s, 1H), 8.33 (d, J = 7.8 Hz,
1H). MS (EI): 211 (m/z M+).
6.3.1.3. 4-Benzyloxycarbazole (5d). Off-white solid.
Mp 180 °C. IR (KBr, cmÀ1) 3400, 1584, 1439, 1258,
1099. 1H NMR (CDCl3) d 5.35 (s, 2H), 6.75 (d,
J = 7.8 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 7.25–7.43
(m, 8H), 7.59 (d, J = 7.2 Hz, 1H), 8.06 (s, 1H), 8.31 (d,
J = 7.8 Hz, 1H). MS (EI): 273 (m/z M+).
6.3.1.4. 2-Benzyloxycarbazole (5f). Light yellow solid.
1
Mp 175 °C. H NMR (CDCl3) d 5.11 (s, 2H), 6.91–6.97
(m, 2H), 7.14 (m, 1H), 7.23 (m, 2H), 7.32–7.46 (m, 6H),
7.95–8.03 (m, 2H). MS (EI): 273 (m/z M+).
6.3.2. General procedure for synthesis of 6a,b,d,f. A dry
THF solution of 5a,b,d,f (1.0 equiv) under nitrogen
was cooled to 0 °C. Sodium hydride (60% dispersion
in oil, 1.5 equiv) was added and the solution stirred
for 30 min at 0 °C. 4-(2-Bromoethoxy)-benzaldehyde
(3), (1.1 equiv) was added and solution stirred at room
temp over night. The reaction mixture was concentrated,
poured in water and extracted in diethyl ether. The
organic layer was separated and dried over anhydrous
sodium sulfate, decanted, concentrated and chromato-
graphed on silica gel. Elution with a gradient mixture
of ethyl acetate/hexane yielded the title compounds as
yellowish oil (50–65%).
6.2.2. Statistical analysis. For in vivo studies, the data
were represented as mean SEM and analyzed by un-
paired Student ÔtÕ test if two groups and one way ANO-
VA if more than two groups, followed by multiple
comparison test (TukeyÕs test). A value of P < 0.05
was considered statistically significant. For in vitro lipid
peroxidation studies, a sigmoidal curve was plotted as
percent inhibition versus log concentration and IC50

R. Kumar et al. / Bioorg. Med. Chem. 13 (2005) 4279–4290
4285
6.3.2.1. 4-(2-(4-Methoxycarbazole)-ethoxy)-benzalde-
J = 8.4 Hz, 2H), 8.35 (d, J = 7.2 Hz, 1H). MS (APCI):
474 (m/z M+1).
1
hyde (6a). IR (cmÀ1) 1691, 1601, 1262, 1157, 740. H
NMR (CDCl3) d 4.07 (s, 3H), 4.39 (t, J = 6 Hz, 2H),
4.71 (t, J = 6 Hz, 2H), 6.7 (d, J = 8.1 Hz, 1H), 6.86 (d,
J = 8.7 Hz, 2H), 7.1 (d, J = 8.1 Hz, 1H), 7.23–7.28 (m,
1H), 7.37–7.75 (m, 3H), 7.74 (d, J = 8.7 Hz, 2H), 8.34
(d, J = 7.8 Hz, 1H), 9.82 (s, 1H). MS (EI): 345 (m/z M+).
6.3.3.3. Ethyl-2-ethoxy-3-{4-[2-(4-benzyloxycarbazole)-
ethoxy]-phenyl}-2-propenoate (7d). H NMR (CDCl3) d
1
1.28–1.42 (tt, J = 6, 6 Hz, 6H), 3.93 (q, J = 6.9 Hz,
2H), 4.27 (q, J = 6.9 Hz, 2H), 4.36 (t, J = 6 Hz, 2H),
4.71 (t, J = 6 Hz, 2H), 5.35 (s, 2H), 6.78 (m, 4H), 6.92
(s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.23 (m, 1H), 7.36–
7.47 (m, 5H), 7.57 (d, J = 7.5 Hz, 2H), 7.68 (d,
J = 8.7 Hz, 2H), 8.34 (d, J = 7.2 Hz, 1H). MS (APCI):
536 (m/z M+1).
6.3.2.2. 4-(2-(4-Ethoxycarbazole)-ethoxy)-benzaldehyde
(6b). 1H NMR (CDCl3) d 1.59 (t, J = 6.9 Hz, 3H), 4.3 (q,
J = 7.2 Hz, 2H), 4.41 (t, J = 6 Hz, 2H), 4.71 (t, J = 6 Hz,
2H), 6.68 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 9 Hz, 1H), 6.98
(d, J = 9 Hz, 2H), 7.07 (d, J = 8.1 Hz, 1H), 7.24–7.44 (m,
2H), 7.73 (d, J = 9 Hz, 2H), 8.35 (d, J = 8.1 Hz, 2H), 9.8
(s, 1H). MS (APCI): 360 (m/z M+1).
6.3.3.4. Ethyl-2-ethoxy-3-{4-[2-(2-benzyloxycarbazole)-
1
ethoxy]-phenyl}-2-propenoate (7f). H NMR (CDCl3) d
1.12–1.57 (m, 6H), 3.63–3.75 (m, 1H), 3.9 (m, 1H),
4.34 (q, J = 3.3 Hz, 2H), 4.41 (m, 2H), 4.69 (m, 2H),
5.11 (s, 2H), 6.65 (m, 1H), 6.9 (s, 1H), 6.92–7.0 (m,
3H), 7.23 (m, 2H), 7.28–7.34 (m, 5H), 7.37–7.43 (m,
2H), 8.02 (m, 3H). MS (APCI): 536 (m/z M+1).
6.3.2.3. 4-(2-(4-Benzyloxycarbazole)-ethoxy)-benzal-
dehyde (6d). 1H NMR (CDCl3) d 4.36 (t, J = 6 Hz,
2H), 4.68 (t, J = 6 Hz, 2H), 5.35 (s, 2H), 6.62 (m, 1H),
6.77 (d, J = 9 Hz, 2H), 6.85 (d, J = 8.1 Hz, 1H), 6.98
(d, J = 8.4 Hz, 2H), 7.11 (d, J = 8 Hz, 1H), 7.28–7.45
(m, 5H), 7.56 (d, J = 7.2 Hz, 2H), 7.9 (d, J = 8.4 Hz,
1H), 8.34 (d, J = 7.5 Hz, 1H), 9.79 (s, 1H). MS (APCI):
422 (m/z M+1).
6.3.4. General procedure for synthesis of 8a,b,d,f. To a
10 ml ethyl acetate solution of compounds (7a,b,d,f)
(1.0 equiv), was added 10% Pd/C (0.1 equiv). The result-
ing suspension was placed in a Parr shaker and hydroge-
nated under hydrogen atmosphere at 60 psi for 5 h. The
reaction suspension was then filtered through a pad of
Celite, concentrated and chromatographed on silica
gel. Elution with a gradient mixture of ethyl acetate/hex-
ane yielded the title compounds as colourless oil (80–
95%).
6.3.2.4. 4-(2-(2-Benzyloxycarbazole)-ethoxy)-benzal-
dehyde (6f). 1H NMR (CDCl3) d 4.42 (m, 2H), 4.67
(m, 2H), 5.11 (s, 2H), 6.65 (m, 1H), 7.03 (m, 2H), 7.34
(m, 3H), 7.37–7.48 (m, 5H), 7.86 (d, J = 7.2 Hz, 2H),
7.97 (m, 3H), 9.83 (s, 1H). MS (APCI): 422 (m/z M+1).
6.3.3. General procedure for synthesis of 7a,b,d,f. A dry
THF solution of 6a,b,d,f (1.0 equiv) under nitrogen
was cooled to 0 °C. Sodium hydride (60% dispersion
in oil, 1.5 equiv) was added and the solution stirred
for 30 min at 0 °C. Ethyl-2-ethoxy-2-diethyl phospho-
noacetate (4) (1.5 equiv) was added and solution stirred
at room temp overnight. The reaction mixture was con-
centrated, poured in water and extracted in diethyl
ether. The organic layer was separated and dried over
anhydrous sodium sulfate, decanted, concentrated and
chromatographed on silica gel. Elution with a gradient
mixture of ethyl acetate/hexane yielded the title com-
pounds as yellowish oil (50–65%).
6.3.4.1. Ethyl-2-ethoxy-3-{4-[2-(4-methoxycarbazole)-
ethoxy]-phenyl}propionate (8a). 1H NMR (CDCl3) d
1.13 (t, J = 6.9 Hz, 3H), 1.34 (t, J = 6 Hz, 3H), 2.9 (d,
J = 6 Hz, 2H), 3.3 (m, 1H), 3.58 (m, 1H), 3.91 (t,
J = 6 Hz, 1H), 4.08 (s, 3H), 4.16 (q, J = 6 Hz, 2H),
4.30 (t, J = 6 Hz, 2H), 4.68 (t, J = 6 Hz, 2H), 6.71 (t,
J = 9 Hz, 2H), 7.10 (t, J = 6 Hz, 2H), 7.27 (m, 2H),
7.37–7.45 (m, 3H), 8.34 (d, J = 9 Hz, 2H). MS (APCI):
462 (m/z M+1).
6.3.4.2. Ethyl-2-ethoxy-3-{4-[2-(4-ethoxycarbazole)-
ethoxy]-phenyl}propionate (8b). 1H NMR (CDCl3) d
1.31 (t, J = 7.2 Hz, 3H), 1.41 (t, J = 6.9 Hz, 3H), 1.61
(t, J = 6.6 Hz, 3H), 2.90 (d, J = 6 Hz, 2H), 3.27–3.33
(m, 1H), 3.51–3.59 (m,1H), 3.93 (t, J = 6.6 Hz, 1H),
4.05 (q, J = 6.9 Hz, 2H), 4.14 (q, J = 6 Hz, 2H), 4.30
(t, J = 6 Hz, 2H), 4.67 (t, J = 6 Hz, 2H), 6.73 (d,
J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 7.9 (d,
J = 7.8 Hz, 2H), 7.20 (m, 2H), 7.37–7.45 (m, 2H), 8.35
(d, J = 7.5 Hz, 1H). MS (APCI): 476 (m/z M+1).
6.3.3.1. Ethyl-2-ethoxy-3-{4-[2-(4methoxycarbazole)-
1
ethoxy]-phenyl}-2-propenoate (7a). H NMR (CDCl3) d
1.12–1.57 (m, 6H), 3.94 (q, J = 6 Hz, 2H), 4.11 (s, 3H),
4.27 (q, J = 6 Hz, 2H), 4.35 (t, J = 6 Hz, 2H), 4.70 (t,
J = 6 Hz, 2H), 6.71 (d, J = 7.5 Hz, 1H), 6.79 (d,
J = 8.7 Hz, 1H), 6.90 (s,1H), 7.12 (d, J = 9 Hz, 2H),
7.27 (m, 1H), 7.37–7.46 (m, 2H), 7.60 (d, J = 9 Hz, 2H),
8.34 (d, J = 7.5 Hz, 2H). MS (EI): 459 (m/z M+).
6.3.4.3. Ethyl-2-ethoxy-3-{4-[2-(4-benzyloxycarbazole)-
ethoxy]-phenyl}propionate (8d). 1H NMR (CDCl3) d 1.15
(t, J = 6 Hz, 3H), 1.41 (t, J = 6 Hz, 3H), 2.91 (d,
J = 6 Hz, 2H), 3.3 (m, 1H), 3.6 (m, 1H), 3.9 (t,
J = 6.9 Hz, 1H), 4.03 (q, J = 6 Hz, 2H), 4.31 (t, J =
6 Hz, 2H), 4.68 (t, J = 6 Hz, 2H), 5.35 (s, 2H), 6.65 (d,
J = 8.4 Hz, 1H), 6.73 (d, J = 9 Hz, 2H), 6.88 (d,
J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 7.25 (m,
2H), 7.38–7.47 (m, 5H), 7.68 (d, J = 8.7 Hz, 1H), 8.32
(d, J = 7.2 Hz, 1H). MS (APCI): 538 (m/z M+1).
6.3.3.2. Ethyl-2-ethoxy-3-{4-[2-(4-ethoxy-carbazole)-
1
ethoxy]-phenyl}-2-propenoate (7b). H NMR (CDCl3) d
1.29–1.35 (tt, J = 6.9, 6.9 Hz, 6H), 1.59 (t, J = 6.9 Hz,
3H), 3.94 (m, 1H), 4.08 (m, 1H), 4.25–4.37 (qq,
J = 6.6, 6.6 Hz, 4H), 4.41 (t, J = 6 Hz, 2H), 4.65 (t,
J = 6 Hz, 2H), 6.68 (d, J = 8.4 Hz, 1H), 6.78 (d, J =
9 Hz, 1H), 6.89 (s, 1H), 6.98 (d, J = 7.5 Hz, 2H), 7.07
(d, J = 8.1 Hz, 1H), 7.29–7.43 (m, 3H), 7.65 (d,

4286
R. Kumar et al. / Bioorg. Med. Chem. 13 (2005) 4279–4290
6.3.4.4. Ethyl-2-ethoxy-3-{4-[2-(2-benzyloxycarbazole)-
J = 6 Hz, 2H), 6.71 (m, 2H), 6.88 (d, J = 8.4 Hz, 2H),
7.09 (d, J = 8.4 Hz, 2H), 7.26 (m, 1H), 7.37–7.45 (m,
2H), 8.35 (d, J = 7.5 Hz, 1H). MS (EI): 447 (m/z M+).
ethoxy]-phenyl}propionate (8f). 1H NMR (CDCl3) d
1.12–1.57 (m, 6H), 2.91 (d, J = 6 Hz, 2H), 3.33 (m,
1H), 3.68 (m, 1H), 3.94 (t, J = 6.9 Hz, 1H), 4.03 (q,
J = 6 Hz, 2H), 4.31 (t, J = 6 Hz, 2H), 4.68 (t, J = 6 Hz,
2H), 5.11 (s, 2H), 6.65 (m, 1H), 7.03 (m, 4H), 7.34 (m,
4H), 7.37–7.48 (m, 5H), 8.02 (m, 2H). MS (APCI): 538
(m/z M+1).
6.3.5.3. 3-(4-(2-(4-Benzyloxycarbazole)-9-yl-ethoxy)-
phenyl)-2-ethoxy propionic acid (9d). H NMR (CDCl3)
1
d 1.39 (t, J = 6 Hz, 3H), 2.91 (m, 2H), 3.30 (m, 1H),
3.61 (m, 1H), 3.90 (t, J = 6.9 Hz, 1H), 4.31 (t,
J = 6 Hz, 2H), 4.68 (t, J = 6 Hz, 2H), 5.35 (s, 2H), 6.73
(m, 1H), 6.88 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz,
2H), 7.25 (m, 2H), 7.38–7.47 (m, 5H), 7.57 (m, 1H),
7.68 (d, J = 8.7 Hz, 2H), 8.32 (d, J = 7.2 Hz, 1H). MS
(EI): 509 (m/z M+).
6.3.4.5. Ethyl-2-ethoxy-3-{4-[2-(4-hydroxycarbazole)-
ethoxy]-phenyl}propionate (8c). To a 10 ml ethyl acetate
solution of compound 7d (1.0 equiv) was added 10% Pd/
C (0.1 equiv). The resulting suspension was placed in a
Parr shaker and debenzylated via hydrogenation under
hydrogen atmosphere at 60 psi for 6 h at 50 °C. The
reaction suspension was then filtered through a pad of
Celite, concentrated and chromatographed on silica
gel. Elution with a gradient mixture of ethyl acetate/hex-
ane yielded the title compounds as colourless oil (80–
6.3.5.4. 3-(4-(2-(2-Benzyloxycarbazole)-ethoxy)-phenyl)-
2-ethoxy propionic acid (9f). 1H NMR (CDCl3) d 1.41 (t,
J = 6 Hz, 3H), 2.92 (m, 2H), 3.32 (m, 1H), 3.60 (m, 1H),
3.91 (t, J = 6.9 Hz, 1H), 4.32 (t, J = 6 Hz, 2H), 4.69 (t,
J = 6 Hz, 2H), 5.11 (s, 2H), 6.72 (m, 1H), 6.87 (d,
J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 7.24 (m,
2H), 7.38–7.48 (m, 5H), 7.58 (m, 1H), 7.67 (d,
J = 8.7 Hz, 2H), 8.33 (d, J = 7.2 Hz, 1H). MS (EI): 509
(m/z M+).
1
95%). H NMR (CDCl3) d 1.12–1.57 (m, 6H), 2.89 (d,
J = 6 Hz, 2H), 3.4 (m, 1H), 3.6 (m, 1H), 3.9 (t,
J = 6.9 Hz, 1H), 4.13 (q, J = 6 Hz, 2H), 4.31 (t, J =
6 Hz, 2H), 4.6 (s, 1H), 4.66 (t, J = 6 Hz, 2H), 6.72 (d,
J = 8.7, 1H), 7.01 (d, J = 8.4 Hz, 2H), 7.08 (d,
J = 8.4 Hz, 2H), 7.25 (m, 1H), 7.44 (m, 2H), 7.5 (m,
2H), 8.32 (d, J = 7.2 Hz, 1H). MS (APCI): 448 (m/z
M+1).
6.3.5.5. 3-(4-(2(4-Hydroxycarbazole)-ethoxy)-phenyl)-
2-ethoxy propionic acid (9c). 1H NMR (CDCl3) d 1.40 (t,
J = 6 Hz, 3H), 2.89 (m, 2H), 3.40 (m, 1H), 3.60 (m, 1H),
3.90 (t, J = 6.9 Hz, 1H), 4.31 (t, J = 6 Hz, 2H), 4.6 (s,
1H), 4.66 (t, J = 6 Hz, 2H), 6.72 (d, J = 8.7, 1H), 7.01
(d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 7.25 (m,
2H), 7.44 (m, 1H), 7.5 (m, 2H), 8.32 (d, J = 7.2 Hz,
1H). MS (EI): 419 (m/z M+).
6.3.4.6. Ethyl-2-ethoxy-3-{4-[2-(2-hydroxycarbazole)-
ethoxy]-phenyl} propionate (8e). This compound was
prepared from 7f according to a procedure similar to
the one used for the synthesis of compound 8c. 1H
NMR (CDCl3) d 1.12–1.57 (m, 6H), 2.89 (d, J = 6 Hz,
2H), 3.4 (m, 1H), 3.6 (m, 1H), 3.9 (t, J = 6.9 Hz, 1H),
4.13 (q, J = 6 Hz, 2H), 4.31 (t, J = 6 Hz, 2H), 4.66 (t,
J = 6 Hz, 2H), 4.8 (s, 1H), 6.72 (d, J = 8.7, 1H), 7.01
(d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 7.25 (m,
1H), 7.44 (m, 2H), 7.5 (m, 2H), 8.02 (d, J = 7.2 Hz,
1H). MS (APCI): 448 (m/z M+1).
6.3.5.6. 3-(4-(2-(2-Hydroxycarbazole)-ethoxy)-phenyl)-
2-ethoxy propionic acid (9e). 1H NMR (CDCl3) d 1.41 (t,
J = 6 Hz, 3H), 2.91 (m, 2H), 3.30 (m, 1H), 3.61 (m, 1H),
3.92 (t, J = 6.9 Hz, 1H), 4.31 (t, J = 6 Hz, 2H), 4.56 (s,
1H), 4.68 (t, J = 6 Hz, 2H), 6.73 (m, 1H), 6.88 (d,
J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 7.25 (m,
2H), 7.57 (m, 1H), 7.68 (d, J = 8.7 Hz, 2H), 8.32 (d,
J = 7.2 Hz, 1H). MS (EI): 419 (m/z M+).
6.3.5. General procedure for synthesis of 9a–f. To ethanol
solution of compounds (8a–f) (1.0 equiv) was added
20% aqueous sodium hydroxide (1.0 equiv) and stirred
at room temperature overnight. The reaction mixture
was concentrated, acidified with acetic acid (pH 4).
The acidic solution was extracted with ethyl acetate.
The organic layer was separated and dried over anhy-
drous sodium sulfate, decanted and concentrated to
yield the title compounds (90–95%).
6.3.6. General procedure for synthesis of 10a–f. L-Lysine
monohydrochloride was passed through a cation ex-
change resin (Dowex) bed with help of water. The aque-
ous ammonia solution was eluted through the resin and
concentrated under high vacuum to give free L-lysine.
To a suspension of compounds 9a–f, (1.0 equiv) in eth-
anol was added L-lysine (1.0 equiv) and stirred for 2 h.
Solvent removed and residue washed with diethyl ether.
6.3.5.1. 3-(4-(2-(4-Methoxycarbazole)-ethoxy)-phenyl)-
2-ethoxy propionic acid (9a). 1H NMR (CDCl3) d 1.41 (t,
J = 6.9 Hz, 3H), 2.9–3.02 (m, 2H), 3.39 (m, 2H), 3.54
(m, 2H), 3.99 (m, 1H), 4.08 (s, 3H), 4.30 (t, J = 6 Hz,
2H), 4.68 (t, J = 6 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H),
7.10 (t, J = 7.5 Hz, 2H), 7.25 (m, 1H), 7.37–7.48 (m,
4H), 8.34 (d, J = 7.8 Hz, 1H). MS (EI): 433 (m/z M+).
6.3.6.1. 3-(4-(2-(4-Methoxycarbazole)-ethoxy)-phenyl)-
2-ethoxy propionic acid, L-lysine salt (10a). 1H NMR
(CD3OD) d 1.05 (t, J = 6.9 Hz, 3H), 1.27 (m, 4H), 1.50
(m, 2H), 1.68 (m, 2H), 1.87 (m, 2H), 2.75 (m, 1H),
2.85–2.94 (m, 3H), 3.29 (m, 1H), 3.57 (m, 2H), 3.75
(m, 1H), 4.06 (s, 3H), 4.34 (t, J = 6 Hz, 2H), 4.70
(t, J = 6 Hz, 2H), 6.75 (d, J = 7.8 Hz, 1H), 6.67 (d,
J = 9 Hz, 2H), 7.16 (m, 4H), 7.40 (m, 2H), 7.53 (d,
J = 8.4 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H). IR (KBr,
cmÀ1) 3416, 2928, 1583, 1511, 1459, 1402. MS (APCI):
579 (m/z M+1). Anal. Calcd for C32H41N3O7 (579.29):
6.3.5.2. 3-(4-(2-(4-Ethoxycarbazole)-9-yl-ethoxy)-phe-
1
nyl)-2-ethoxy propionic acid (9b). H NMR (CDCl3) d
1.41 (t, J = 6.9 Hz, 3H), 1.60 (t, J = 6.9 Hz, 3H), 2.95–
3.05 (m, 2H), 3.34 (m, 1H), 3.65 (m, 1H), 4.01 (m,
1H), 4.14 (q, J = 6 Hz, 2H), 4.28 (m, 4H), 4.67 (t,

R. Kumar et al. / Bioorg. Med. Chem. 13 (2005) 4279–4290
4287
C, 66.30; H, 7.13; N, 7.25. Found: C, 66.13; H, 7.11; N,
7.19.
J = 6.9 Hz, 1H), 4.31 (t, J = 6 Hz, 2H), 4.71 (s, 1H),
4.8 (t, J = 6 Hz, 2H), 6.52 (m, 2H), 6.95 (m, 2H), 7.18
(m, 2H), 7.42 (m, 3H), 8.03 (m, 2H). IR (KBr, cmÀ1
)
6.3.6.2. 3-(4-(2-(4-Ethoxycarbazole)-ethoxy)-phenyl)-
2-ethoxy propionic acid, L-lysine salt (10b). 1H NMR
(CD3OD) d 1.06 (t, J = 6.9 Hz, 3H), 1.48 (m, 2H),
1.56–1.68 (m, 5H), 1.82 (m, 2H), 2.6 (m, 1H), 2.86–
2.90 (m, 2H), 3.25 (m, 1H), 3.50 (m, 3H), 3.75 (m,
1H), 4.28–4.36 (m, 4H), 4.67 (t, J = 6 Hz, 2H), 6.70 (t,
J = 7.8 Hz, 3H), 7.09–7.19 (m, 4H), 7.32–7.39 (m, 2H),
7.53 (d, J = 8.1 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H). IR
(KBr, cmÀ1) 3909, 2929, 1586, 1505, 1458, 1402, 1336,
1244. MS (APCI): 593 (m/z M+1). Anal. Calcd for
C33H43N3O7 (593.31): C, 66.76; H, 7.30; N, 7.08. Found:
C, 66.59; H, 7.23; N, 6.89.
3420, 2922, 1583, 1402, 1347. MS (APCI): 567 (m/z
M+). Anal. Calcd for C31H39N3O7 (565.28): C, 65.82;
H, 6.95; N, 7.43. Found: C, 65.71; H, 6.83; N, 7.33.
6.3.7. (S)3-{4-[2-(9H-Carbazol-4-yloxy)-ethoxy]-phenyl}-
2-(1-methyl-3-oxo-3-phenyl-propenylamino)-propionic acid
methyl ester (14). Step (A): Synthesis of (13) (S)3-(4-Hy-
droxy-phenyl)-2-(1-methyl-3-oxo-3-phenyl-propenylamino)-
propionic acid methyl ester: To a 10 ml dry toluene sus-
pension of L-tyrosine methyl ester (2.0 g, 10.2 mmol),
benzoylacetone (1.7 g, 10.2 mmol) was added in pres-
˚
ence of 4 A molecular sieve. The suspension was re-
fluxed overnight. Toluene was removed and residue
was extracted with dichloromethane. The organic layer
was separated and dried over anhydrous sodium sulfate,
decanted, concentrated and chromatographed on silica
gel. Elution with a gradient mixture of ethyl acetate/hex-
ane yielded the title compounds (90–95%). IR (KBr,
6.3.6.3. 3-(4-(2-(4-Benzyloxycarbazole)-ethoxy)-phenyl)-
2-ethoxy propionic acid, L-lysine salt (10d). 1H NMR
(CD3OD) d 1.01 (t, J = 6.9 Hz, 3H), 1.27 (m, 2H), 1.48
(m, 2H), 1.69 (m, 2H), 1.78 (m, 2H), 2.91 (m, 2H), 3.3
(m, 1H), 3.49 (m, 2H), 3.6 (m, 1H), 3.75 (m, 1H), 3.9
(t, J = 6.9 Hz, 1H), 4.38 (t, J = 6 Hz, 2H), 4.68 (t,
J = 6 Hz, 2H), 5.35 (s, 2H), 6.69 (m, 2H), 6.84 (d,
J = 7.8 Hz, 1H), 7.10–7.21 (m, 4H), 7.39–7.54 (m, 5H),
1
cmÀ1) 3177.8, 1744.1, 1596.1, 1438.5, 1118.2, 745.6. H
NMR CDCl3 d 1.81 (s, 3H), 2.99–3.16 (m, 4H), 3.72
(s, 3H), 5.65 (m, 1H), 6.74 (d, J = 8.34 Hz, 1H), 7.02
(d, J = 6.57 Hz, 1H), 7.38 (d, J = 6.78 Hz, 1H), 7.84
(d, J = 7.02 Hz, 1H). MS (APCI): 339 (m/z M+1). Step
(B): Synthesis of (17) 4-(2-bromo-ethoxy)-9H-carbazole:
To a 10 ml acetone solution of 4-hydroxycarbazole
(2.0 g, 10.8 mmol) and dibromoethane (2.0 g,
12.0 mmol) was added K2CO3 (2.2 g, 12.0 mmol). The
suspension was refluxed overnight. Acetone was re-
moved and residue was extracted with ethyl acetate.
The organic layer was separated and dried over anhy-
drous sodium sulfate, decanted, concentrated and chro-
matographed on silica gel. Elution with a gradient
mixture of ethyl acetate/hexane yielded the title com-
7.57 (m, 3H), 8.20 (d, J = 7.8 Hz, 1H). IR (KBr, cmÀ1
)
3413, 2922, 1637, 1505, 1406, 1244. MS (APCI): 656
(m/z M+1). Anal. Calcd for C38H45N3O7 (655.33): C,
69.60; H, 6.92; N, 6.41. Found: C, 69.29; H, 6.87; N,
6.28.
6.3.6.4. 3-(4-(2-(2-Benzyloxycarbazole)-ethoxy)-phenyl)-
2-ethoxy propionic acid, L-lysine salt (10f). 1H NMR
(CD3OD) d 1.08 (t, J = 6.9 Hz, 3H), 1.27 (m, 2H), 1.48
(m, 2H), 1.69 (m, 2H), 1.78 (m, 2H), 2.91 (m, 2H), 3.3
(m, 1H), 3.49 (m, 2H), 3.6 (m, 1H), 3.75 (m, 1H), 3.9
(t, J = 6.9 Hz, 1H), 4.31 (t, J = 6 Hz, 2H), 4.68 (t,
J = 6 Hz, 2H), 5.11 (s, 2H), 6.71 (m, 2H), 6.84 (d,
J = 7.8 Hz, 1H), 7.10–7.21 (m, 4H), 7.39–7.54 (m, 5H),
1
pounds white powder mp 115 °C (60–70%). H NMR
(CDCl3) d 3.84 (t, J = 6 Hz, 2H), 4.55 (t, J = 6 Hz,
2H), 6.64 (d, J = 8.1 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H),
7.25 (m, 2H), 7.36 (d, J = 9 Hz, 1H), 8.06 (s, 1H), 8.38
(d, J = 6.9 Hz, 1H). MS (EI): 289, 291 (m/z M+1,
M+2). Step (C): To a 10 ml acetone solution of 13
(1.0 g, 2.9 mmol) and 17 (0.9 g, 3.19 mmol) was added
K2CO3 (0.6 g, 4.35 mmol). The suspension was refluxed
overnight. Acetone was removed and residue was ex-
tracted with ethyl acetate. The organic layer was sepa-
rated and dried over anhydrous sodium sulfate,
decanted, concentrated and chromatographed on silica
gel. Elution with a gradient mixture of ethyl acetate/hex-
7.57 (m, 3H), 8.12 (d, J = 7.8 Hz, 1H). IR (KBr, cmÀ1
)
3415, 2928, 1632, 1505, 1406, 1344. MS (APCI): 656
(m/z M+1). Anal. Calcd for C38H45N3O7 (655.33): C,
69.60; H, 6.92; N, 6.41. Found: C, 69.52; H, 6.88; N,
6.37.
6.3.6.5. 3-(4-(2-(4-Hydroxycarbazole)-ethoxy)-phenyl)-
2-ethoxy propionic acid, L-lysine salt (10c). 1H NMR
(CD3OD) d 1.02 (t, J = 6.9 Hz, 3H), 1.26 (m, 2H), 1.49
(m, 2H), 1.69 (m, 2H), 1.84 (m, 2H), 2.75 (m, 2H),
2.95 (m, 2H), 3.2 (m, 1H), 3.5 (m, 2H), 3.6 (m, 1H),
3.76 (m, 1H), 4.02 (t, J = 6.9 Hz, 1H), 4.37 (t,
J = 6 Hz, 2H), 4.6 (s, 1H), 4.69 (t, J = 6 Hz, 2H), 6.68
(t, J = 9 Hz, 2H), 7.12 (m, 3H), 7.20 (m, 2H), 7.25 (m,
1H), 7.44 (m, 1H), 7.6 (m, 1H), 8.24 (d, J = 8.4 Hz,
1H). IR (KBr, cmÀ1) 3416, 2929, 2863, 1586, 1406,
1107. MS (APCI): 567 (m/z M+1). Anal. Calcd for
C31H39N3O7 (565.28): C, 65.82; H, 6.95; N, 7.43. Found:
C, 65.69; H, 6.83; N, 7.38.
1
ane yielded the title compounds. H NMR (CDCl3) d
1.94 (s, 3H), 3.16 (m, 1H), 3.20 (m, 1H), 3.54 ( t,
J = 6 Hz, 1H), 3.76 (s, 3H), 4.49 (t, J = 6 Hz, 2H), 4.57
(t, J = 6 Hz, 2H), 4.74 (m, 1H), 5.6 (s, 1H), 6.74 (d,
J = 8.4 Hz, 2H), 6.93 (t, J = 8.4 Hz, 1H), 7.09 (d,
J = 8.4 Hz, 2H), 7.20 (m, 5H), 7.33 (d, J = 9 Hz, 2H),
7.87 (m, 3H), 8.01 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H).
MS (EI): 548 (m/z M+). Anal. Calcd for C34H32N2O5
(548.23): C, 74.43; H, 5.88; N, 5.11. Found: C, 74.27;
H, 5.76; N, 5.08.
6.3.6.6. 3-(4-(2-(2-Hydroxycarbazole)-ethoxy)-phenyl)-
2-ethoxy propionic acid, L-lysine salt (10e). 1H NMR
(D2O) d 0.95 (t, J = 6 Hz, 3H), 1.38 (m, 2H), 1.63 (m,
2H), 1.78 (m, 2H), 2.91 (m, 4H), 3.18 (m, 1H), 3.40
(m, 1H), 3.54 (m, 2H), 3.76 (m, 1H), 3.91 (t,
6.3.8. (S)3-{4-[2-(9H-Carbazol-4-yloxy)-ethoxy]-phenyl}-
2-(1-methyl-3-oxo-3-phenyl-propenylamino)-propionic acid,
L-lysine salt (16). To ethanol solution of compound 14

4288
R. Kumar et al. / Bioorg. Med. Chem. 13 (2005) 4279–4290
(1.0 g, 1.8 mmol) was added 20% aqueous sodium
hydroxide and stirred at room temperature overnight.
The reaction mixture was concentrated, acidified with
acetic acid (pH 4). The acidic solution was extracted with
ethyl acetate. The organic layer was separated and dried
over anhydrous sodium sulfate, decanted and concen-
trated to yield the title compounds 15 (75%). Chiral
added 50 mg 10% Pd/C. The resulting suspension was
placed in a Parr shaker and debenzylated via hydrogena-
tion under hydrogen atmosphere at 60 psi for 5 h at
50 °C. The reaction suspension was then filtered through
a pad of Celite, concentrated and chromatographed on
silica gel. Elution with a gradient mixture of ethyl ace-
tate/hexane yielded the title compounds as colourless
1
HPLC (chiral-AGP, 150 4 mm, 5 lM, hexane–isopro-
oil (80–95%). H NMR (CDCl3) d 1.23 (t, J = 6.6 Hz,
*
panol (4:1), 1 ml/min), tR = 8.2, 98% ee. MS (MALDI):
535 M+. To a suspension of compounds (15, 0.5 g,
1.0 mmol) in ethanol was added L-lysine (0.14 g,
1.0 mmol) and stirred for 2 h. Solvent removed and resi-
3H), 1.37 (t, J = 6.6 Hz, 3H), 2.9 (d, J = 6 Hz, 2H),
3.85 (m, 1H), 3.95 (m, 2H), 4.01 (m, 2H), 4.25 (t,
J = 6 Hz, 2H), 4.56 (t, J = 6 Hz, 2H), 6.84 (d,
J = 9 Hz, 2H), 6.96 (s, 1H), 7.08 (d, J = 8.4 Hz, 2H),
7.39 (m, 4H), 7.69 (d, J = 9 Hz, 2H), 8.06 (s, 1H), 8.30
(d, J = 8.4 Hz, 1H). MS (EI): 447 (m/z M+). Anal. Calcd
for C27H29NO5 (447.20): C, 72.46; H, 6.53; N, 3.13.
Found: C, 72.39; H, 6.55; N, 3.11.
1
due crystallized with diethyl ether. H NMR CDCl3 d
1.48 (m, 2H), 1.68 (m, 2H), 1.86 (m, 2H), 1.94 (s, 3H),
2.97 (m, 2H), 3.16 (m, 1H), 3.20–3.30 (m, 5H), 3.54 ( t,
J = 6 Hz, 1H), 3.60 (m, 1H), 4.49 (t, J = 6 Hz, 2H), 4.57
(t, J = 6 Hz, 2H), 5.6 (s, 1H), 6.74 (d, J = 8.4 Hz, 2H),
6.93 (t, J = 8.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.20
(m, 5H), 7.33 (d, J = 9 Hz, 2H), 7.87 (m, 3H), 8.01 (s,
1H), 8.25 (d, J = 8.4 Hz, 1H). MS (MALDI): 680 (m/z
M+). Anal. Calcd for C39H44N4O7 (680.32): C, 68.81; H,
6.51; N, 8.23. Found: C, 68.58; H, 6.47; N, 8.12.
6.3.11. 3-{4-[2-(9H-Carbazole-4-yloxy)-ethoxy]-phenyl}-
2-ethoxy propionic acid L-lysine salt (24a). To ethanol
solution of compound 24 (0.5 g, 1.1mmol) was added
20% aqueous sodium hydroxide (1.1 equiv) and stirred
at room temperature overnight. The reaction mixture
was concentrated, acidified with acetic acid (pH 4).
The acidic solution was extracted with ethyl acetate.
The organic layer was separated and dried over anhy-
drous sodium sulfate, decanted and concentrated to
yield the carboxylic acid (70–80%). The carboxylic acid
(0.25 g, 0.5 mmol) in ethanol was added L-lysine
(0.09 g, 0.5 mmol) and stirred for 2 h. Solvent removed
and residue crystallized with diethyl ether. 1H NMR
CDCl3 d 1.35 (t, J = 6.6 Hz, 3H), 1.48 (m, 2H), 1.65
(m, 2H), 1.87 (m, 2H), 2.95 (m, 4H), 3.32 (m, 4H),
3.57 (m, 1H), 3.85 (m, 1H), 4.01 (m, 2H), 4.25 (t,
J = 6 Hz, 2H), 4.56 (t, J = 6 Hz, 2H), 6.84 (d,
J = 9 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 7.39 (m, 4H),
7.71 (d, J = 9 Hz, 2H), 8.08 (s, 1H), 8.32 (d,
J = 8.4 Hz, 1H). MS (MALDI): 564 (m/z M+). Anal.
Calcd for C31H39N3O7 (565.28): C, 65.82; H, 6.95; N,
7.43. Found: C, 65.68; H, 6.87; N, 7.41.
6.3.9. 3-{4-[2-(9H-carbazole-4-yloxy)-ethoxy]-phenyl}-2-
ethoxy acrylic acid ethyl ester (23). Step (A): Synthesis of
(22) ethyl-3-(4-hydroxyphenyl) 2-ethoxy prop-2-enoate.
A dry THF solution of 4-hydroxybenzaldehyde (1.0 g,
8.1 mmol) under nitrogen was cooled to 0 °C. Sodium
hydride (60% dispersion in oil, 0.6 g, 24 mmol) was
added and the solution stirred for 30 min at 0 °C.
Ethyl-2-ethoxy-2-diethyl phosphonoacetate (4) (3.2 g,
12.1 mmol) was added and solution stirred at room
temp overnight. The reaction mixture was concentrated,
poured in water and extracted in diethyl ether. The or-
ganic layer was separated and dried over anhydrous so-
dium
sulfate,
decanted,
concentrated
and
chromatographed on silica gel. Elution with a gradient
mixture of ethyl acetate/hexane yielded the title com-
1
pounds as yellowish oil (50%). H NMR CDCl3 d 1.3–
1.42 (m, 6H), 3.95 (m, 1H), 4.14 (m, 2H), 4.28 (m,
1H), 6.83 (d, J = 8.7 Hz, 2H), 6.95 (s, 1H), 7.7 (d,
J = 8.4 Hz, 2H). MS (EI): 236 (m/z M+). Step (B): To
a 10 ml acetone solution of 17 (1.0 g, 3.4 mmol) and
22 (0.76 g, 3.23 mmol) was added K2CO3 (0.7 g,
5.1 mmol). The suspension was refluxed overnight. Ace-
tone was removed and residue was extracted with ethyl
acetate. The organic layer was separated and dried over
anhydrous sodium sulfate, decanted, concentrated and
chromatographed on silica gel. Elution with a gradient
mixture of ethyl acetate/hexane yielded the title com-
6.3.12. 4-Hydroxy-3-methoxy-benzoic acid ethyl ester
(18).
4-Hydroxy-3-methoxy-benzoic
acid
(2.0 g,
11.9 mmol) was refluxed with SOCl2 in ethanol for
30 min. The reaction mixture was concentrated, ex-
tracted with ethyl acetate. The organic layer was sepa-
rated and dried over anhydrous sodium sulfate;
decanted and concentrated to yield the title compounds
1
24a (70–80%). H NMR CDCl3 d 1.38 (t, J = 7.2 Hz,
3H), 4.35 (q, J = 7.2 Hz, 2H), 6.44 (s, 1H), 6.93 (d,
J = 8.1 Hz, 1H), 7.55 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H).
MS (EI): 196 (m/z M+).
1
pounds. H NMR (CDCl3) d 1.25 (t, J = 6.6 Hz, 3H),
1.38 (t, J = 6.6 Hz, 3H), 3.85 (m, 1H), 3.96 (m, 2H),
4.01 (m, 1H), 4.25 (t, J = 6 Hz, 2H), 4.56 (t, J = 6 Hz,
2H), 6.84 (d, J = 9 Hz, 2H), 6.96 (s, 1H), 7.08 (d,
J = 8.4 Hz, 2H), 7.39 (m, 4H), 7.71 (d, J = 9 Hz, 2H),
8.08 (s, 1H), 8.32 (d, J = 8.4 Hz, 1H). MS (EI): 445
(m/z M+). Anal. Calcd for C27H27NO5 (445.19): C,
72.79; H, 6.11; N, 3.14. Found: C, 72.47; H, 5.78; N,
3.02.
6.3.13. 6-Hydroxy-naphthalene-2-carboxylic acid ethyl
ester (20). The title compound 20 was prepared from 6-
hydroxy
naphthalene-2-carboxylic
acid
(2.0 g,
10.6 mmol) by a procedure similar to followed for syn-
thesis of 18. 1H NMR CDCl3 d 1.44 (t, J = 7.2 Hz,
3H), 4.43 (q, J = 7.2 Hz, 2H), 5.6 (s, 1H), 7.15 (d,
J = 8.7 Hz, 1H), 7.18 (s, 1H), 7.69 (d, J = 8.7 Hz, 1H),
7.86 (d, J = 8.7 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 8.53
(s, 1H). MS (EI): 216 (m/z M+).
6.3.10. 3-{4-[2-(9H-Carbazole-4-yloxy)-ethoxy]-phenyl}-
2-ethoxy propionic acid ethyl ester (24). To a 10 ml ethyl
acetate solution of compound 23 (1.0 g, 2.2 mmol) was

R. Kumar et al. / Bioorg. Med. Chem. 13 (2005) 4279–4290
4289
6.3.14. 3-(4-Hydroxy phenyl)-propionic acid ethyl ester
(25). The title compound 25 was prepared from 3-(4-hy-
droxy phenyl)-propionic acid (2.0 g, 12.0 mmol) by a
1H), 7.85 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 9 Hz, 1H),
8.12 (m, 1H), 8.20 (d, J = 9 Hz, 1H), 8.50–8.55 (m,
2H). MS: 397 (m/z M+). Anal. Calcd for C25H19NO4
(397.13): C, 75.55; H, 4.82; N, 3.52. Found: C, 75.58;
H, 4.77; N, 3.41.
1
procedure similar to followed for synthesis of 18. H
NMR CDCl3 d 1.23 (t, J = 7.2 Hz, 3H), 2.58 (t,
J = 7.8 Hz, 2H), 2.87 (t, J = 7.5 Hz, 2H), 4.12 (q,
J = 6.9 Hz, 2H), 5.30 (s, 1H). MS (EI): 194 (m/z M+).
6.3.19. 3-{4-[2-(9H-Carbazol-4-yloxy)-ethoxy]-phenyl}-
propionic acid ethyl ester (26). This compound was pre-
pared from 17 (1.0 g, 3.4 mmol) and 3-(4-hydroxy phen-
yl)-propionic acid ethyl ester 25 (0.6 g, 3.23 mmol)
according to a procedure similar to the used for synthe-
6.3.15. 4-[2-(9H-Carbazol-4-yloxy)-ethoxy]-3-methoxy-
benzoic acid ethyl ester (19). To a 10 ml acetone solution
of 17 (1.0 g, 3.4 mmol) and 18 (0.6 g, 3.1 mmol) was
added K2CO3 (0.7 g, 5mmol). The suspension was re-
fluxed overnight. Acetone was removed and residue
was extracted with ethyl acetate. The organic layer was
separated and dried over anhydrous sodium sulfate, dec-
anted, concentrated and chromatographed on silica gel.
Elution with a gradient mixture of ethyl acetate/hexane
1
sis of compound 19. H NMR CDCl3 d 1.25 (t, J =
6.9 Hz, 3H), 2.60 (t, J = 6 Hz, 2H), 2.87 (t, J = 6 Hz,
2H), 4.12 (q, J = 6 Hz, 2H), 4.49 (t, J = 6 Hz, 2H),
4.56 (t, J = 6 Hz, 2H), 6.69 (d, J = 9 Hz, 2H), 6.95 (d,
J = 9 Hz, 2H), 7.04 (d, J = 9 Hz, 2H), 7.15 (d, J =
9 Hz, 2H), 7.25 (s, 1H), 7.35 (m, 2H), 8.26 (m, 1H).
MS (MALDI): 403 (m/z M+). Anal. Calcd for
C25H25NO4 (403.18): C, 74.42; H, 6.25; N, 3.47. Found:
C, 74.28; H, 6.19; N, 3.40.
1
yielded the title compounds. H NMR CDCl3 d 1.25 (t,
J = 6.6 Hz, 3H), 3.91 (s, 3H), 4.13 (q, J = 6 Hz, 2H),
4.36 (t, J = 6 Hz, 2H), 4.64 (t, J = 6 Hz, 2H), 6.73 (m,
1H), 6.93 (d, J = 9 Hz, 1H), 7.07 (m, 2H), 7.18 (m,
2H), 7.36–7.41 (m, 2H), 7.55 (s, 1H), 7.64 (d, J = 9 Hz,
1H), 8.25 (m, 1H). MS: 405 (m/z M+). Anal. Calcd for
C24H23NO5 (405.19): C, 71.10; H, 5.72; N, 3.45. Found:
C, 71.03; H, 5.63; N, 3.32.
6.3.20. 3-{4-[2-(9H-Carbazol-4-yloxy)-ethoxy]-phenyl}-
propionic acid (26a). This compound was prepared from
26 according to a procedure similar to the used for syn-
thesis of compound 19a. 1H NMR CDCl3 d 2.61 (t,
J = 6 Hz, 2H), 2.87 (t, J = 6 Hz, 2H), 4.49 (t, J = 6 Hz,
2H), 4.56 (t, J = 6 Hz, 2H), 6.69 (d, J = 9 Hz, 2H),
6.95 (d, J = 9 Hz, 2H), 7.04 (d, J = 9 Hz, 2H), 7.16 (d,
J = 9 Hz, 2H), 7.25 (s, 1H), 7.35 (m, 2H), 8.26 (m,
1H). MS: 375 (m/z M+). Anal. Calcd for C23H21NO4
(375.15): C, 73.58; H, 5.64; N, 3.73. Found: C, 73.47;
H, 5.58; N, 3.71.
6.3.16. 4-[2-(9H-Carbazol-4-yloxy)-ethoxy]-3-methoxy-
benzoic acid (19a). To ethanol solution of compound
19 was added 20% aqueous sodium hydroxide and re-
fluxed for 30 min. The reaction mixture was concen-
trated and extracted with ethyl acetate. The organic
layer was separated and dried over anhydrous sodium
sulfate, decanted and concentrated to yield the title com-
1
pounds 19a. H NMR CDCl3 d 3.96 (s, 3H), 4.36 (t,
J = 6 Hz, 2H), 4.64 (t, J = 6 Hz, 2H), 6.73 (m, 1H),
6.96 (d, J = 9 Hz, 1H), 7.07 (m, 2H), 7.18 (m, 2H),
7.36–7.41 (m, 2H), 7.62 (s, 1H), 7.73 (d, J = 9 Hz, 1H),
8.24 (m, 1H). MS: 377 (m/z M+). Anal. Calcd for
C22H19NO5 (377.13): C, 70.02; H, 5.07; N, 3.71. Found:
C, 70.05; H, 5.01; N, 3.68.
Acknowledgements
We wish to thank CSIR and DST, New Delhi for fund-
ing this project. R.K. thanks CSIR for his senior re-
search fellowship.
6.3.17. 6-[2-(9H-Carbazol-4-yloxy)-ethoxy]-naphthalene-
2-carboxylic acid ethyl ester (21). This compound was
prepared from 17 (1.0 g, 3.4 mmol) and 6-hydroxy-
naphthalene-2-carboxylic acid ethyl ester (20) (0.7 g,
3.0 mmol) according to a procedure similar to the used
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