Synthetic 2-aroylindole derivatives as a new class of potent tubulin-inhibitory, antimitotic agents

Article abstract of DOI:10.1021/jm010940+

A new class of simple synthetic antimitotic compounds based on 2-aroylindoles was discovered. (5-Methoxy-1H-2-indolyl)-phenylmethanone (1) as well as analogous 3-fluorophenyl- (36) and 3-methoxyphenyl (3) derivatives displayed high cytotoxicity of IC

Full text of DOI:10.1021/jm010940+

J . Med. Chem. 2001, 44, 4535-4553
4535
Syn th etic 2-Ar oylin d ole Der iva tives a s a New Cla ss of P oten t
Tu bu lin -In h ibitor y, An tim itotic Agen ts|
Siavosh Mahboobi,*,† Herwig Pongratz,† Harald Hufsky,† J o¨rg Hockemeyer,† Markus Frieser,† Alexei Lyssenko,†
Dietrich H. Paper,† J utta Bu¨rgermeister,† Frank-D. Bo¨hmer,‡ Heinz-Herbert Fiebig,§ Angelika M. Burger,§
Silke Baasner,# and Thomas Beckers*,#
Faculty of Chemistry and Pharmacy, Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany,
Research Unit Molecular Cell Biology, Medical Faculty, Friedrich Schiller University, D-07747 J ena, Germany,
Oncotest GmbH, Am Flughafen 12-14, D-79108 Freiburg, Germany, ASTA Medica AG, Department of Cancer Research,
D-60314 Frankfurt/ Main, Germany
Received May 29, 2001
A new class of simple synthetic antimitotic compounds based on 2-aroylindoles was discovered.
(5-Methoxy-1H-2-indolyl)-phenylmethanone (1) as well as analogous 3-fluorophenyl- (36) and
3-methoxyphenyl (3) derivatives displayed high cytotoxicity of IC50 ) 20 to 75 nM against the
human HeLa/KB cervical, SK-OV-3 ovarian, and U373 astrocytoma carcinoma cell lines. The
inhibition of proliferation correlated with the arrest in the G2/M phase of the cell cycle. In in
vitro assays with tubulin isolated from bovine brain, in general antiproliferative activity
correlated with inhibition of tubulin polymerization. Thus, the antimitotic activity of 2-aroyl-
indoles is explained by interference with the mitotic spindle apparatus and destabilization of
microtubules. In contrast to colchicine, vincristine, nocodazole, or taxol, 1 did not significantly
affect the GTPase activity of â-tubulin. Interestingly, selected compounds inhibited angiogenesis
in the chorioallantoic membrane (CAM) assay. In xenograft experiments, 1 was highly active
after oral administration at 200 mg/kg against the human amelanocytic melanoma MEXF 989
in athymic nude mice. We conclude, that 2-aroylindoles constitute an interesting new class of
antitubulin agents with the potential to be clinically developed for cancer treatment.
In tr od u ction
as the microtubule associated proteins (MAPs) bind to
and modify microtubule properties.5,8 In the absence of
MAPs, Râ-tubulin heterodimers polymerize only by
treatment with high concentrations of glycerol or or-
ganic acids.9
The discovery of various compounds from natural
sources as being cytotoxic by interfering with the mitotic
spindle apparatus has attracted much attention within
the last two decades, and microtubles have become an
attractive pharmacological target for anticancer drug
discovery.1-4 Microtubules are hollow tubes consisting
of heterodimers of R- and â-tubulin that polymerize
parallel to a cylindrical axis, playing important roles
in processes such as cell shape, intracellular transport,
and mitosis.5 In cell mitosis, microtubules are forming
the mitotic spindle, a bipolar, self-organizing machine
that uses energy from nucleotide hydrolysis to segregate
sister chromatids accurately into daughter cells.6 The
rapid switch between growing and shortening states of
microtubules, a process known as dynamic instability
and driven by â-tubulin dependent GTP hydrolysis, is
essential for movement of chromosomes.7 Proteins such
Interfering with the dynamic instability of micro-
tubules, spindle poisons arrest dividing cells in G2/M
phase of the cell cycle, causing mitotic catastrophy and
finally apoptotic cell death. The well-known natural
tubulin binding molecules affecting microtubule dynam-
ics are colchicine, the vinca alkaloids vinblastine and
vincristine, rhizoxin, maytansine, combretastatin A4,
epothilone, and taxanes.10 They bind to distinct sites
within â-tubulin and, by destabilization or stabilization
of microtubules, lead to mitotic catastrophy.11 Taxol
(INN: paclitaxel) and the semisynthetic analogue Taxo-
tere (INN: docetaxel) are stabilizing tubulin inhibitors
used routinely for treatment of advanced cancer pa-
tients. New studies now convincingly show that tubulin
inhibitors might also target proliferating endothelial
cells and thereby affect tumor vascularization.12 Most
solid tumors can only grow beyond a critical size by
inducing the formation of new blood vessels, a process
called tumor neovascularization.13,14 Antiangiogenic
compounds, however, might also be used for the treat-
ment of several nonmalignant diseases, like macular
degeneration, arthritis, or psoriasis.15
| Abbreviations: MAP - microtubule associated protein, XTT-sodium
3′-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis-(4-methoxy-6-nitro)-
benzene sulfonic acid hydrate, DMSO - dimethyl sulfoxide, FACS -
fluorescence activated cell sorting, CAM - chorioallantoic membrane,
GTP - guanosine trisphosphate, PBS - phosphate buffered saline,
PI - propidium iodide, EDTA - ethylendiamine-N,N,N′,N′-tetraacetic
acid.
* Correspondence to S. Mahboobi, Institute of Pharmacy, University
of Regensburg, D-93040 Regensburg, Germany (Fax: +49-941-
9431737, e-mail: siavosh.mahboobi@chemie.uni-regensburg.de) and to
T. Beckers, ASTA Medica AG, Department of Cancer Research,
D-60314 Frankfurt/Main, Germany (e-mail: T.Beckers@vff.uni-frank-
furt.de).
As said, by antagonizing tumor cell proliferation and
neovascularization, tubulin inhibitors are potent anti-
cancer drugs. Nevertheless, clinically available com-
pounds such as paclitaxel or vincristine are facing
severe disadvantages, namely, (i) high toxicity, (ii)
† University of Regensburg.
‡ Friedrich Schiller University.
§ Oncotest GmbH.
#
ASTA Medica AG.
10.1021/jm010940+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/17/2001

4536 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26
Mahboobi et al.
Ch a r t 1. Indole Derivatives as Inhibitors of Tubulin
Polymerization
and the acid chloride III in THF at -78 °C. Alkali
hydrolysis of the resulting N-phenylsulfonyl-protected
ketone IVb yielded IV in good yields. In some cases,
however, if the acid chloride III was not easily available,
the ketone IVb was prepared from the aldehyde II
followed by oxidation of the resulting carbinol IVa using
PDC/PTFA in CH2Cl2. According to Scheme 1, we
prepared (5-methoxy-1H-2-indolyl)-phenylmethanone 1
and phenyl-substituted derivatives 2-22, 24, 26, and
28-40. When various N-protected ketones IVb with
electron-withdrawing substituents (e.g., F, Cl, NO2) in
the phenylring ortho to the carbonyl-group (22a , 35a ,
38a , 39a ) were used as starting material for hydrolysis
by NaOH in ethanol at 75 °C, 3-ethoxy substituted
indole-derivatives IV were isolated in small amounts
additionally to the desired product (not shown in
Scheme 1 and Table 1). The amino-compounds 23, 25,
and 27 were synthesized by catalytic reduction of the
corresponding nitro-compounds 22, 24, and 26 with
palladium on charcoal (Pd/C) in methanol at room
temperature. Removing the benzyl-group from com-
pound 15 by heating with Pd/C and ammonium formate
in methanol/THF 1/1 afforded the alcohol 16, which was
reacted with butanoic acid chloride to yield the ester-
derivative 17.
To evaluate the role of the indole substitution pattern
in IV, we synthesized various derivatives of the indole
building block (41-59), i.e., instead of lithiated 5-
methoxyindole (Ia ), various other indoles [5-methyl-
indole (Ib), 5-benzyloxyindole (Ic), 4-methoxyindole (Id ),
3-methylindol (Ie), and metalated unsubstituted indole
(If)] were used for coupling with some of the acid
chlorides III or aldehydes II according to the general
reaction procedure described in Scheme 1. Furthermore,
replacing the indole structure in Scheme 1 with lithiated
aza-indoles Ig and Ih , yielded compounds 60-63 and
64-67, respectively.
Additionally, we substituted the phenylring in 1 by
other cyclic systems. Thus, compounds 68-76 of type
V (Scheme 2) were prepared by the same methodology
as described in Scheme 1, employing Ia and various
cyclic aldehydes and acid chlorides instead of benzal-
dehydes II and benzoyl chlorides III, respectively.
marginal oral bioavailability and poor solubility, (iii)
complex synthesis or isolation procedures, and finally
(iv) development of drug resistance in patients. There-
fore, synthetic low molecular weight compounds with
oral bioavailability and high therapeutic index for first
and second line therapy are urgently needed.
By screening for new antimitotic drugs, we identified
2-aroylindoles representing a novel class of simple
compounds with high cytotoxicity. In this paper, we
describe that more than 150 compounds were synthe-
sized and tested in different biological assays, identify-
ing derivatives with a potency comparable to paclitaxel.
2-Aroylindoles are antimitotic in a cell cycle specific
manner by binding to â-tubulin and destabilization of
microtubules. Together with 3-formyl-2-phenylindoles,16
heterocombretastatins or diarylindoles,17,18 and N-
(pyridin-4-yl)-(1-(4-chlorbenzyl)-indol-3-yl)-glyoxyl-
amid,19 they constitute a class of tubulin inhibitors with
the indole moiety as a core structure (Chart 1). In the
present paper, structure-activity-relationship (SAR) as
well as biological properties of selected 2-aroylindoles
are presented.
Finally, starting from 1, some N-alkylated species
77-81 of type VI were prepared in good yields by
reaction with NaH and alkylhalides in DMF at room
temperature (Scheme 3).
The parent compound 2-benzoylindole 1 and all the
substituted derivatives 2-67 as well as the precursor
compounds 1a -15a , 18a -22a , 24a , 26a , 28a -76a , and,
if prepared, the carbinols of type IVb were assayed in
a screening for cytotoxicity against the human cervical
epitheloid carcinoma HeLa/KB and the human ovarian
adenocarcinoma SK-OV-3 cell line. As shown in Table
1, many 2-benzoylindole derivatives IV exhibited strong
cytotoxicity with IC50 values of e 1 to g 0.02 µg/mL (6,
7, 9, 12-14, 16-20, 23-25, 33-35, 40) or <0.02 µg/
mL (1-3, 8, 11, 21, 36). From all other 2-aroylindole
derivatives tested, only the two 5-methylindole species
50 and 52, the 1-naphthyl-species 70, the 4-isochinolinyl
derivative 72, and the N-alkylated species 81 showed
noteworthy cytotoxic activity (Tables 2-4). In general,
all precursor compounds except 8b, 9b, and 36b proved
to be inactive. However, removal of the N-phenylsulfo-
Resu lts a n d Discu ssion
Syn th esis of 2-Ar oylin d ole Der iva tives a n d SAR
for An tim itotic Activity in Hu m a n Ca n cer Cells.
Substituted 2-aroylindole derivatives IV were easily
prepared as shown in the general reaction sequence in
Scheme 120,21 by coupling the lithiated indole species I

2-Aroylindole Derivatives as Tubulin-Inhibitory Agents
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26 4537
Ta ble 1. Tubulin-Inhibitory Activity and In Vitro Cytotoxicity of 2-Aroylindole Analogs 1-40, 42, 44, and 50-52
ITPa
IC50 [µM]
HeLa/KBb
IC50 [µM]
SK-OV-3b
IC50 [µM]
compd
R1
R5
R6
R7
R8
R9
1
2
3
4
5
6
7
8
9
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H
H
OCH3
H
H
H
OCH3
H
OCH3
H
OCH3
OCH3
OCH3
OCH3
OCH3
H
H
H
H
OCH3
H
OCH3
OCH3
H
OCH3
H
OCH3
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
H
OCH3
OCH3
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
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
0.53
1.29
0.53
NEc
>10d
5.6
0.81
0.81
g10
NE
0.99
4.8
1.5
5.2
NE
0.66
0.85
1.7
g10
2.1
1.5
>10
6.7
0.85
0.99
>10
>10
>10
g10
>10
NE
NE
5.0
4.3
1.0
0.39
n.d.
NE
>10
2.5
>10
NE
3.5
>10
0.86
0.068
0.036
0.011
11.4
6.4
0.10
0.68
0.11
0.011
11.4
3.2
1.03
1.64
0.019
0.088
9.37
0.058
0.38
1.88
0.72
>8.6
0.22
0.24
0.21
0.63
0.36
0.03
>10.8
3.76
0.10
0.23
>10.3
11.4
>9.8
11.5
>10.9
>10.4
>9.5
1.75
0.91
0.74
0.015
7.43
8.70
H
OCH3
OCH3
H
1.32
H
0.019
0.059
8.79
0.029
1.21
0.38
0.72
>8.6
0.22
0.27
0.27
0.88
0.39
0.03
>10.8
3.76
0.10
0.34
OCH3
OCH3
H
CH3
H
CH3
H
H
H
H
H
H
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
42
44
50
51
52
colchicine
H
H
OCH2Ph
OH
O(CO)(CH2)2CH3
OCF3
SCF3
SCF2H
CF3
H
H
NO2
NH2
H
H
NO2
NH2
NO2
NH2
OCH3
H
H
H
H
H
H
H
F
H
H
H
Cl
H
H
CH3
CH3
NO2
H
H
H
H
H
H
F
H
H
F
Cl
H
OCH3
H
OCH3
H
H
H
H
H
>10.3
11.4
>9.8
8.9
>10.9
>10.4
>9.5
3.50
0.91
0.37
0.026
5.57
6.96
>10.5
0.10
>12.7
6.42
0.38
>12.1
0.03
0.023
CH2CH3
CH2CH2CH3
C(CH3)3
O(CH2)4CH3
Cl
Br
H
H
F
H
H
Cl
H
OCH3
H
H
H
H
H
OCH3
H
H
F
>10.5
0.10
>12.7
9.64
0.75
>12.1
0.03
0.020
H
H
H
H
H
H
H
CH3
CH3
CH3
OCH3
H
OCH3
OCH3
H
OCH3
OCH3
a
b
ITP ) inhibition of tubulin polymerization. IC50 values were determined in the initial screening from XTT proliferation assays,
after incubation with test compound for 48 h. A detailed analysis of the antitumor activity of selected compounds 1-3, 6, 9, 11, 23, 24,
34, and 40 is summarized in Table 4. Each experiment was performed at least in duplicate. c No effect was observed at a concentration
d
up to 10 µM. Weak inhibitory activity.
nyl-protection group yielding compounds 8, 9, and 36
resulted in 40- to 100-fold higher activity (Table 1).
In terms of SAR information, substituting the indole
structure (azaindole-derivatives 60-67) yielded inactive
compounds, except 64 and 65 with low cytotoxicity. The
substitution of C by N at the 5-methoxyindole-C4- (64-
67) or 5-methoxyindole-C7-position (60-63) results in
conformational changes in the relative positions of the
aromatic rings A and C, which might be responsible for
this loss of activity. However, also some simple changes
in the indole-substitution pattern (41-59) generally
resulted in loss of activity. The N-alkylated compounds
77-81 depicted reduced cytotoxicity in comparison to
their parent compound 1. In summary, these results
from the cellular cytotoxicity screen suggested that the
5-methoxyindole group seems to be beneficial for potent
antitumor activity. It is noteworthy, that the 5-meth-
ylindole derivative 51 is inactive, whereas its cognate
5-methoxyindole derivative 3 showed the highest anti-
proliferative activity of all compounds tested so far (IC50
e 0.0032 nM). In contrast, the 3,4,5-trimethoxyben-
zoylindole derivatives 11 (on the basis of 5-methoxy-
indole) and 52 (on the basis of 5-methylindole) are
cytotoxic with comparable potency. In the biochemical
tubulin polymerization assay, however, a surprising
difference in the IC50 values of these substances could
be noted. The 5-methylindole compound 52 was about
11-fold more active in inhibiting tubulin polymerization
than the 5-methoxyindole derivative 11 (see next section
for details).

4538 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26
Mahboobi et al.
Sch em e 1. Synthesis of 2-Aroylindole Derivatives IV and the Respective Precursors IVa /IVba

2-Aroylindole Derivatives as Tubulin-Inhibitory Agents
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26 4539
Sch em e 1. (Continued)
a
Reactions and conditions: i: procedure A (THF, -78 °C); ii: procedure B (PDC, CH2Cl2, R. T.); iii: procedure C (THF, -78 °C); iv:
procedure D (NaOH, EtOH, reflux); v: procedure E (TBAF, THF/MeOH 1/1, reflux).
Many active compounds were found among the 2-ben-
zoyl-5-methoxyindole derivatives 1-40 with the 3-meth-
oxyphenyl derivative 3 being the most active. In general,
single substitutions at the phenyl-3-position (R6) re-
sulted in a number of active compounds (e.g., 3, 15, 16,
17-21, 24, 25, and 36). However, only the 3-fluorophen-
yl- (36) and the 3-methoxyphenyl derivative (3) showed
higher cytotoxic activity than the unsubstituted com-
pound 1; their effect is similar to that of paclitaxel, the
standard agent for treatment of advanced breast and
ovarian cancer.
By comparing the effect of electron-donating or -with-
drawing groups at the phenyl-3-position (R6), no clear
influence can be noted. For example, compound 3 with
the electron-donating 3-OCH3 and compound 36 with
the electron-withdrawing 3-F are both high cytotoxic
compounds. In contrast, 25 with the electron donating
NH2-substituent at the phenyl-3-position is less cyto-
toxic than 24 with the electron-withdrawing NO2 group
at the same position.
Cell Cycle Sp ecific Mod e of Action , Effect on
Tu bu lin P olym er iza tion a n d GTP a se Activity in
Vitr o. Compounds 1, 3, and 11 were selected for mode-
of-action studies to elucidate the molecular target
leading to cytotoxicity. By using fluorescence activated
cell sorting (FACS) analysis, a concentration-dependent
arrest of U373 human astrocytoma cells in the G2/M
phase with 4N chromosomes was observed (Figure 1A/
B), correlating nicely with the cytoxicity against this cell
line (Table 2). From this result, we hypothesized that
2-aroylindoles are acting in a cell cycle specific manner
by interfering with the mitotic spindle apparatus. To
prove this hypothesis, selected compounds were tested
for inhibition of Râ tubulin polymerization. As sum-
marized in Tables 1-5, with the exception of 6, 7, 9,
and 19 all compounds having significant cytotoxicity
inhibited tubulin polymerization with IC50 < 10 µM.
Thus, we conclude that the spindle apparatus formed
by tubulin Râ heterodimers is the cellular target of
2-aroylindoles. For compounds 6, 7, 9, and 19, showing
only marginal inhibition of tubulin polymerization (IC50
g 10 µM), the cytotoxic effect might be explained by a
target different from tubulin. Nevertheless, in general
the IC50 values determined in the cellular cytotoxicity
and biochemical polymerization assay did correlate. One
exception is compound 3, being highly cytotoxic but less
active in inhibition of tubulin polymerization as com-
pared to 8 and 36. In contrast to the cellular assay, the
dynamic range of the biochemical assay is narrow, and
50-100 times higher concentrations are needed to
achieve the same half-maximal biological effect. Most
likely, the intracellular milieu and compound concen-
tration, which is effected by the efficiency of cellular
uptake, as well as the target concentration within the
cell are quite different from the in vitro situation and
not easily transferable. Since similar results were
obtained with the well-known tubulin inhibitory drugs
paclitaxel and vincristine,19 this phenomenon is not
limited to 2-aroylindol derivatives. Again, as with the
investigation of cytotoxicity, no electronic effect of the
substituents at the phenyl ring can be noted: compound
24 (R6dNO2) resulted in nearly the same IC50 value as
compound 25 (R6dNH2).
The assembly of microtubules requires GTP hydroly-
sis, catalyzed by the GTPase activity of â-tubulin.7 All
tubulin inhibitors studied so far are GTPase effectors,

4540 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26
Mahboobi et al.
Ta ble 3. Effect of 1 and Well-Known Tubulin-Inhibitory
Agents on GTPase Activity of ss-Tubulina
Sch em e 2. 5-Methoxy-2-aroylindole Derivatives V
(68-76)
â-tubulin GTPase activitya
compound
10 µM
1 µM
DMSO (0 °C)
DMSO (37 °C)
colchicine
nocodazole
vincristine
taxol
0.12
3.3
10.1
9.0
0.09
1.4
3.5
6.7
4.9
5.3
3.3
3.2
1
a
â-Tubulin GTPase activity is shown as the quotient of GDP/
GTP concentrations, determined by phosphorimager analysis.
Tubulin polymerization was induced by 1 M glutamate and
incubation for 2 h at 37 °C. All compounds were added before
starting the polymerization reaction.
Ta ble 4. Mean Cytotoxic Activity for Selected, Most Active
Compoundsa
mean
mean
compound
IC70 [µg/mL]
compound
IC70 [µg/mL]
1
2
3
6
9
0.22
0.35
0.27
1.74
0.73
0.17
1.44
24
34
40
50
52
70
81
1.40
2.56
1.34
2.03
1.17
0.88
2.95
11
23
a
Cytoxicity of 16 selected 2-aroylindoles was studied using a
panel of human tumor cell lines, namely, MCF-7, MAXF 401NL
(breast), HT29 (colon), GXF 251L (stomach), LXFA 529L, LXF
66NL, LXFL 629L, MEXF 462NL, MEXF 462NL, MEXF 514L
(skin/melanocyten), OVCAR3 (ovary), RXF 393NL, RXF 944L
(renal), and UXF 1138L (soft tissue). The mean IC70 values in [µg/
mL] are shown.
Ta ble 2. Cell Cycle Arrest and Cyctotoxicity of Analogs 1, 3,
and 11 in U373 Astrocytoma Cellsa
U373 proliferation
IC50 [nM]
U373 cell cycle
IC50 [nM]
compd
1
3
11
74
28
73
62.7
10.7
36.1
highly purified tubulin free of contaminating GTPase
activity. Whereas colchicine or nocodazole stimulated
and vincristine inhibited GTP hydrolysis, 1 had no
significant effect at 1 and 10 µM concentration (Table
3). In summary, these results confirmed that 2-aroyl-
indoles are constituting a new class of cell cycle specific
small molecule tubulin inhibitors with high cytotoxicity
toward cancer cells.
An tia n giogen ic Activity. It is well-known, that
tubulin inhibitors such as combretastatin-A4 phosphate
are tumor vascular-targeting agents, aimed at a rapid
and extensive shut-down of the established tumor
a
The IC50 values for compounds 1, 3 and 11 were calculated
from respective dose-response curves for cytotoxicity or cell-cycle
arrest (Figure 1).
either stimulating or inhibiting GTP hydrolysis.22,23
Since preliminary experiments with [3H]colchicine
showed that 1 bound to â-tubulin with the same potency
than colchicine [IC50 [colchicine] 0.53 µM vs IC50 [1] 0.51
µM; compound 3 (IC50 0.28) bound even a bit better],
we studied the effect of 1 on GTPase hydrolysis by using
Sch em e 3. Preparation of N-Alkylated Derivatives VI (77-81) (procedure F)

2-Aroylindole Derivatives as Tubulin-Inhibitory Agents
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26 4541
Ta ble 5. In Vivo Tumor Activity and Toxicity Data for 1a
tumor desig.
MEXF 989
dose [mg/kg]
sched
route
opt. T/C (d) [%]
GD 200% [d]
BWC [%]
drug rel. deaths [%]
100
200
100
200
d1-5, 8-12
d1-5, 8-12
d1-5, 8-12
d1-5, 8-12
o.
p.o.
o.
34 (28)
19 (17)
100 (1)
100 (1)
4.8
12.9
-0.4
-0.4
+11
+3
+11
+1
0
0
0
0
RXF 944LX
p.o.
a
Opt. T/C (d): Optimum tumor weight of treated animals/control animals in % (deviation); GD 200%: growth delay until tumor doubling
in days; BWC: medium maximum body weight change in %; group size: 6-12 tumors.
F igu r e 2. Antiangiogenic potency of selected compounds in
the CAM test. The CAM test was performed as described in
Materials and Methods. For evaluation of the antiangiogenic
effect, a score system was used:
F igu r e 1. Cell cycle arrest of U373 astrocytoma cells induced
by 2-aroylindole analogues 1, 3, and 11. The distribution of
U373 astrocytoma cells within the cell cycle was analyzed by
FACS as described in Materials and Methods. Selected FACS
histograms of cells treated with DMSO or 1 are shown in A
(at 0, 0.01, and 1 µM, 17, 30, and 78% of all cells are in G2/
M), the dose-response-curves for 1, 3, and 11 are shown in
B. IC50 values for arresting cells in G2/M as well as cytotoxicity
are summarized in Table 2.
vasculature, leading to tumor cell necrosis.12 Thus, a
variety of 2-aroylindoles (Figure 2) were tested for their
in vivo antiangiogenic activity in the chick embryo
chorioallantoic membrane (CAM) assay.24 An agarose
pellet containing the compound was placed on the
germination layer of artificially incubated fertilized
hens’ eggs, and after 24 h the development of new blood
vessels was determined under the stereo microscopi-
As a negative control, CAMs were treated with agarose
cally. For evaluation of antiangiogenic effects, a score
solution only; suramin A (50 µg/pellet) served as a positive
system was defined,25 and the compounds were classi-
control. The â-1,4-galactan sulfate LuPS S525 as a potent
antiangiogenic compound is shown, too. Each experiment was
fied due to their respective effect on the chorioallantoic
membrane. Compounds 7 and 25 exhibited strong
antiangiogenic activity, whereas 28 and 61 had almost
no activity. Therefore, the antiangiogenic effect might
be explained by a target different from tubulin. As far
as the most cytotoxic compound 1 (weak anti-angiogenic
effect) is concerned, substitution at the meta-position
in the phenyl ring seemed to be beneficial for anti-
angiogenic activity. However, the most potent compound
in the tubulin polymerization assay, 36, resulted in the
CAM-assay in membrane irritation in more than 80%
of the eggs with more than 50% of the embryos dying.
As many compounds (1, 16, 3, 18, and 65) were not
performed at least in duplicate. All samples were tested at
the concentration of 50 µg/pellet. Footnote a: substance was
tested in suspension; due to diffusion processes, the standard
deviation was 0.3.
easily soluble in the agarose buffer and thus had to be
tested in suspension, some score-values have a large
standard deviation (up to 0.3) due to variable diffusion
processes, which have to be considered in these specific
cases.
In Vivo Activity a ga in st Hu m a n Tu m or Xe-
n ogr a ft s. To evaluate whether the potent in vitro

4542 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26
Mahboobi et al.
Con clu sion s
In conclusion, we have identified (5-methoxy-1H-2-
indolyl)-phenyl-methanones as a novel class of highly
potent anticancer agents and, by targeting microtubules,
leading to mitotic catastrophy and finally apoptotic cell
death. Although interfering with the colchicine binding
site of â-tubulin, they do not affect â-tubulin GTPase
activity. Selected compounds are as active as paclitaxel,
the standard tubulin inhibitor used for advanced cancer
treatment, and depicted antiangiogenic activity, too.
Being orally bioavailable with marked in vivo antitumor
activity, certain 2-aroylindoles may have potential for
clinical development as anticancer drugs.
F igu r e 3. Chemosensitivity profile of compound 1 against
human tumor cell lines. Bars to the left represent more
sensitive; bars to the right more resistant tumor lines.
Exp er im en ta l Section
Ch em ica ls a n d Biologica ls. General chemicals, XTT as
well as tubulin inhibitors paclitaxel, vincristine, colchicine, and
nocodazole were purchased from Sigma (Munich, Germany),
and glutamate monohydrate was from Merck (Darmstadt,
Germany). R[32P]GTP was obtained from Amersham Pharma-
cia (Freiburg, Germany).
Hu m a n Tu m or Cell Lin es. The cell lines SKOV3 (ovary/
HTB-77), KB/HeLa (cervix/CCL-17), U373 (astrocytoma/HTB-
17), CCL HT29 (colon adenocarcinoma/HTB-38), and MACL
MCF7 (breast adenocarcinoma/HTB-22) were obtained from
ATCC. The cell line OVCAR3 (ovarian adenocarcinoma) is from
the NCI tumor cell repository.26,27 The cell lines MAXF 401NL
(papillary breast adenocarcinoma), GXF 251L (stomach ad-
enocarcinoma), LXFE 66NL (lung epidermoid carcinoma),
LXFL 529L (large cell lung cancer), LXFA 629L (adenocarci-
noma), MEXF 462NL (amelanotic melanoma), MEXF 514L
(melanotic melanoma), MEXF 989 (amelanotic melanoma),
RXF 944L (renal hypernephroma), RXF 393NL (renal hyper-
nephroma), and UXF 1138L (carcinoma of the corpus uteri)
were established at the University of Freiburg/Oncotest GmbH,
Freiburg.
Cyt ot oxicit y Assa ys. The compounds were dissolved in
dimethyl sulfoxide (DMSO) at a final concentration of 1 mg/
mL and stored at -20 °C or, alternatively, 8 °C. The XTT
(sodium 3′-[1-(phenylaminocarbonyl)-3,4-tetrazolium]bis(4-
methoxy-6-nitro)benzene sulfonic acid hydrate) assay was used
as described28 to determine proliferation by quantification of
cellular metabolic activity. Half-maximal inhibition constants
(IC50) or estimates thereof were obtained by nonlinear regres-
sion analysis (program GraphPad Prism).
F igu r e 4. In vivo activity of 1 in the human MEXF 989
melanoma xenograft model. Drug was given daily orally on
days 1-5 and 8-12. The therapy was well tolerated at the
dose administered, and no toxicity (0/6) nor body weight loss
were seen. The arrow indicates the termination of therapy.
The optimal T/C in the 200 mg/kg group was 19%, correspond-
ing to a 81% inhibition of tumor growth as compared to the
vehicle control.
activity of 2-aroylindole derivatives can be translated
into anticancer efficacy in human tumor xenografts in
vivo, compound 1, which was one of the most potent
agents in the propidium iodide assay (Table 4), was
selected. The in vitro chemosensitive profile (Figure 3)
for compound 1 showed different cytotoxicities of 1 in a
panel of human tumor cell lines. Melanomas (2/2),
ovarian (1/1), and colon (1/1) cancers were the more
sensitive, and gastric (1/1), lung (2/3), and renal (2/2)
cancers were the more resistant tumor types. According
to this in vitro chemosensitive profile, the human
melanoma xenograft MEXF 989 was selected as a
potentially sensitive tumor type. Additionally, the hu-
man hypernephroma xenograft RXF 944L was em-
ployed, too.
A modified propidium iodide (PI) assay, quantifying dead
cells by staining of DNA and RNA, was applied for determi-
nation of cytotoxicity toward the human tumor cell panel.29
Growth inhibition was expressed as treated/control × 100 (%
T/C); inhibiting concentrations (IC) were determined by plot-
ting compound concentration versus cell viability. Mean IC50
and IC70 values were calculated for each individual cell line.
For compound 1, a chemosensitivity profile was determined
(Figure 3).
From all IC70 values, the mean IC70 was calculated according
to the formula:
n
log (IC50/70
10
)
x
∑
x)1
(
)
mean IC50,70
)
10
For oral dosing, 100 and 200 mg/kg 1 were adminis-
tered Qd×5 over 2 weeks (Table 5). Both p.o. dosages
were very well tolerated and showed no signs of toxicity
(0/6) or body weight loss. Treatment with 1 resulted in
growth inhibition of 81% of control at 200 mg/kg/day
and 66% at 100 mg/kg/day in the human melanoma
xenograft model MEXF 989 (Figure 4). The renal cell
carcinoma RXF 944, however, was resistant toward
therapy with compound 1.
with x ) value of specific tumor cell line and n ) total number
of tumor cell lines studied. If IC50 or IC70 values could not be
determined within the examined concentration range, the
lowest or highest concentration studied was used for calcula-
tion.
F low Cytom etr y. U373 cells (5 × 106 cells) were exposed
to the cytotoxic agents for 24 h at 37 °C, briefly treated with
trypsin and collected by centrifugation. After the cells were
washed twice with PBS, they were fixed in 80% v:v methanol

2-Aroylindole Derivatives as Tubulin-Inhibitory Agents
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26 4543
for 30 min on ice. Subsequently, cells were washed three times
with PBS containing 0.1% saponin and incubated with PBS/
saponin buffer containing 20 µg/mL propidium iodide and 1
mg/mL RNAse A for 30 min at 37 °C. Now, cells were washed
once again with PBS/saponin and then resuspended in PBS.
The DNA content of the cells was determined using fluores-
cence-activated cell sorting (FACS) with a Calibur flow cy-
tometer (Becton Dickinson, Heidelberg, Germany). The num-
ber of cells in G2/M phase was calculated using Mod Fit LT
cell cycle analysis software (VERITY). Data points were
connected, and the respective IC50 value was calculated using
a nonlinear regression program (GraphPad Prism).
test compound, 15-20 eggs were utilized and for the evalua-
tion of the antiangiogenic effect, a score system was used (see
Figure 2).
Tu bu lin P olym er iza tion Assa y. The assay was basically
performed according to Bollag et al.31 Tubulin heterodimers
with MAPs (0.8 mg/mL; 80 µg/assay), isolated by cycles of
polymerization and depolymerization from fresh bovine brain,
were incubated with test compounds (4 µg/mL in the initial
screening, different concentrations in the final IC50 determi-
nation scheme) in PEM (100 mM PIPES, 1 mM EGTA, 1 mM
MgCl2) buffer pH 6.6 containing 1 mM GTP in a total volume
of 100 µL at 37 °C for 1 h. Samples (75 µL) were then
transferred to a 96-well Millipore Multiscreen Durapore hy-
drophilic 0.22 µm pore size filtration plate. Recovered micro-
tubules on the filters were stained with 50 µL amido black
solution (0.1% w/v naphthol blue black (Sigma), 45% v:v
methanol, 10% v/v acetic acid) for 2 min. Vacuum was applied
and unbound dye was removed by two additions of 200 µL
destain solution (90% v/v methanol, 2% v/v acetic acid). The
microtubule bound dye was then eluted by incubation with
200 µL elution solution (25 mM NaOH, 0.05 mM EDTA, 50%
v/v ethanol) for 20 min. 160 µL elution solution were then
transferred to a 96-well plate, and the absorbance was
measured at 600 nm using the Wallac Victor Multilabel
counter (PerkinElmer, Freiburg).
Tu bu lin GTP a se Assa y. The tubulin GTPase assay was
performed with slight modifications according to Roychowdhury
et al.32 Highly purified, lyophilized MAP-free bovine brain
tubulin (Cytoskeleton Inc./Denver, USA) was reconstituted in
PEM (100 mM PIPES, 1 mM EGTA, 1 mM MgCl2) buffer pH
6.6 and stored in aliquots at -80 °C. The reaction mixture
used for the GTPase assay contained 1 mg/mL tubulin, 1 mM
MgCl2, 100 µM R[32P]GTP (specific activity 3000 Ci/mmol), and
1 M monosodium glutamate in PEM buffer. Test compounds,
dissolved in 10% v/v DMSO, were added prior to addition of
glutamate and R[32P]GTP (final 1% DMSO). Tubulin polym-
erization was started by incubation at 37 °C for 1 h and
terminated by addition of sodium dodecyl sulfate at 1% final
concentration. GTP hydrolysis was measured by thin-layer
chromatography of the reaction mixture using polyethylene-
imine-(PEI) cellulose plates. The chromatograms were devel-
oped with 0.35 M (NH4)2CO3. Chromatography plates were
exposed to X-ray films and quantified by phosphorimager
analysis using a Fuji BAS-1800II device.
Hu m a n Tu m or Xen ogr a ft Exp er im en ts. For animal
experiments, 1 was dissolved in DMSO and diluted with PBS
containing 0.05% v:v Tween 80 to obtain a final DMSO
concentration of 10%. Six to eight-week-old outbred nude mice
of NMRI genetic background were used for all experiments.
The animals were bred in-house and kept under laminar air
flow on natural day light cycles. Diet (altromin, Lage, Ger-
many) and water were provided ad libitium and room tem-
perature (25 ( 2 °C) as well as humidity (60 ( 10%) were
maintained. The gender of the mice was chosen according to
the gender of the patients from which the tumors were
originally derived. For the experiments the RXF944L and
MEXF989 tumor xenograft models were selected and engrafted
from tumors in serial passage growing s.c. in nude mice.
Fragments of approximately 25 mg were implanted s.c. in both
flanks of the animals. When the tumors were clearly palpable
and had reached a volume of 100-200 mm3, animals (6-12
tumors) were randomly allocated into treatment groups.
Tumor growth was followed twice weekly by serial caliper
measurement. Tumor volumes were calculated using the
formula length × width2/2, where length (a) is the largest
dimension, and width (b) is the smallest dimension perpen-
dicular to the length (ab2/2).30 Data evaluation was performed
using specifically designed software by plotting relative tumor
volume against time. Relative tumor volumes were calculated
for each single tumor by dividing the tumor volume on day X
by the tumor volume on day 0 at the time of randomization.
Tumor doubling time of test and control groups was defined
as the period required to double the initial tumor volume
(200%). Growth curves were analyzed in terms of maximal
tumor inhibition (treated/control, T/C, calculated as median
tumor weight of treated divided by median tumor weight of
control animals × 100) and growth delay (the difference in
days to double the initial tumor volume of the test minus the
control groups). Statistical data analysis was performed using
nonparametrical Mann-Whitney statistics. Median relative
tumor volumes of each treatment group were compared to
those of the control group. Human tumors growing s.c. in nude
mice were treated orally with doses of 100 and 200 mg/kg/day
1 on days 1-5 and 8-12. The drug doses and treatment
schedule used proved to be well tolerated in nontumor bearing
nude mice prior to initiation of tumor experiments.
Syn th esis. Elemental Analyses: Analytical Lab. University
Regensburg. - mp: Bu¨chi 512, Reichert hot-stage microscope.
- IR: FT, Nicolet 510. - 1H-NMR: Bruker 250 (250 MHz). -
MS: Varian MAT 311A (EI, 70 eV). All reactions were carried
out under nitrogen and dried over self-indicating silica gel,
concentrated H2SO4 and KOH.
P r oced u r e A: Syn th esis of Su bstitu ted (1-P h en ylsu l-
fon yl-1H-2-in d olyl)-p h en ylm eth a n oles (IVb): n-Butyllith-
ium (9.9 mL, 15.9 mmol in hexane) was added dropwise to a
solution of anhydrous diisopropylamine (2.23 mL, 15.9 mmol)
in dry THF (15 mL) at -78 °C. After the sample was stirred
for 10 min, the mixture was allowed to warm to 0 °C, and then
it was stirred for 30 min. A solution of the appropriate
1-phenylsulfonyl indole (14.0 mmol) in dry THF (22 mL) was
added within 10 min, and the reaction mixture was kept
stirring at 0 °C for 30 min. Then the solution of the respective
(1-phenylsulfonyl-1H-2-indolyl)lithium so obtained was cooled
to -78 °C again, and the aldehyde III (4.39 g, 15.4 mmol) in
dry THF (15 mL) was added slowly. After the sample was
warmed to room-temperature overnight, the mixture was
poured into 1% aq HCl (100 mL), and the organic layer was
separated. The water layer was extracted with ethyl acetate
(3 × 50 mL), and the combined organic layers were washed
successively with bicarbonate and brine. After the sample was
dried (Na2SO4), the solvent was evaporated under reduced
pressure to leave a foamy solid, which was subjected to column
chromatography (SiO2; ethyl acetate/hexane 4/1) or recrystal-
lized from ethanol, yielding the product as light yellowish
crystals. Thus, compounds 1b-4b, 6b, 15b, and 72b were
prepared.
CAM Assa y for An tia n giogen ic P oten cy. All preliminary
steps were performed at approximately 60 °C. Test compounds
were dissolved in a 2.5% aq agarose solution (final concentra-
tion: 1-20 mg/mL). For the preparation of the pellets, 10 µL
of these solutions were applied dropwise on circular Teflon
supports of 3 mm in diameter and then cooled to room
temperature at once. After incubation at 37 °C and relative
humidity of 80% for 65-70 h, the fertilized hens’ eggs were
positioned in a horizontal position and rotated several times.
Before the opening on the snub side, 10 mL of albumin were
aspirated from a hole on the pointed side. At two-third of the
height (from the pointed side), the eggs were traced with a
scalpel, and the shells were removed with forceps. The
aperture (cavity) was covered with keep-fresh film, and the
eggs were incubated at 37 °C at a relative humidity of 80%
for 75 h. When the formed chorioallantoic membrane (CAM)
had approximately a diameter of 2 cm, one pellet (1 pellet/
egg) was placed on it. The eggs were incubated for 1 day and
subsequently evaluated under the stereo microscope. For every

4544 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26
Mahboobi et al.
(5-Me t h oxy-1-p h e n ylsu lfon yl-1H -2-in d olyl)-p h e n yl-
m eth a n ol (1b): colorless crystals, 86%, mp 51-52 °C. IR
leading to light yellow cristals. Thus, compounds 1a -4a , 6a ,
15a , and 72a were prepared.
(KBr): 3429, 3064, 2937, 2834, 1615, 1368, 1159 cm-1 1H-
.
P r oced u r e C: P r ep a r a tion of (1-P h en ylsu lfon yl-1H-
2-in d olyl)-p h en yl-m eth a n on es (IVa ) by r ea ction of (1-
p h en ylsu lfon yl-1H-in d olyl)-2-lith iu m w ith Ca r boxylic
Acid Ch lor id es: At -78 °C a solution of the respective (1-
phenylsulfonyl-1H-indolyl)-2-lithium (I) (5.0 mmol) was added
to the appropriate benzoic acid chloride (II) (5.5 mmol) in dry
THF (15.0 mL). The mixture was allowed to warm to room-
temperature overnight, hydrolyzed with aqueous NaHCO3 (300
mL; 2%), extracted with ethyl acetate (3 × 50 mL), and the
combined organic layers were dried (Na2SO4). Column chro-
matography (SiO2/CH2Cl2) or crystallization from ethyl acetate/
light petrol (4:1) afforded the products as colorless to faintly
yellowish crystals. Thus, compounds 5a , 7a -14a , and 16a -
71a were prepared.
(5-Me t h oxy-1-p h e n ylsu lfon yl-1H -2-in d olyl)-p h e n yl-
m eth a n on e (1a ): colorless needles, 61%, mp 148 °C. IR
(KBr): 3064, 3008, 2964, 2838, 1663, 1613, 1598, 1368, 1164
cm-1. 1H-NMR (DMSO-d6): δ 3.77 (s, 3 H), 7.09-7.14 (m, 1H),
7.19-7.21 (m, 2H), 7.57-7.65 (m, 4H), 7.68-7.77 (m, 2H),
7.88-7.96 (m, 5H). EI-MS (70 eV); m/z (%): 391 (82) [M+•],
250 (100), 236 (8), 222 (14), 207 (20), 179 (24), 105 (32), 77
(51). Anal. (C22H17NO4S) C, H, N.
NMR (DMSO-d6): δ 3.72 (s, 3H), 6.15-6.18 (m, 1H, exchange-
able), 6.37-6.39 (m, 1H), 6.60 (s, 1H), 6.86-6.9 (m, 1H), 7.06-
7.07 (m, 1H), 7.28-7.39 (m, 5H), 7.47-7.53 (m, 2H), 7.60-
7.67 (m, 1H), 7.73-7.76 (m, 2H), 7.84-7.87 (m, 1H). EI-MS
(70 eV); m/z (%): 393 (63) [M+•], 251 (100), 236 (13), 224 (21),
105 (61), 77 (44). Anal. (C22H19NO4S) C, H, N.
2-Meth oxyp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-
in d olyl)-m eth a n ol (2b): light red crystals, 41%, mp 75-76
°C. IR (KBr): 3414, 3068, 2961, 2836, 1603, 1589, 1368, 1177
1
cm-1. H-NMR (DMSO-d6): δ 3.70 (s, 3H), 3.75 (s, 3H), 6.10-
6.12 (m, 1H, exchangeable), 6.68-6.77 (m, 2H), 6.86-6.91 (m,
2H), 6.94-7.05 (m, 3H), 7.45-7.49 (m, 1H), 7.54-7.70 (m, 3H),
7.86-7.95 (m, 3H). EI-MS (70 eV); m/z (%): 423 (27) [M+•],
281 (35), 135 (100), 77 (34). Anal. (C23H21NO5S) C, H, N.
3-Meth oxyp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-
in d olyl)-m eth a n ol (3b): light yellow crystals, 68%, mp 121-
122 °C. IR (KBr): 3435, 3095, 2958, 2836, 1605, 1358, 1160
1
cm-1. H-NMR (DMSO-d6): δ 3.72 (s, 6H), 6.16-6.18 (m, 1H,
exchangeable), 6.34-6.36 (m, 1H), 6.56 (s, 1H), 6.84-6.95 (m,
4H), 7.06-7.07 (m, 1H), 7.23-7.29 (m, 1H), 7.47-7.53 (m, 2H),
7.61-7.67 (m, 1H), 7.79-7.79 (m, 2H), 7.85-7.88 (m, 1H). EI-
MS (70 eV); m/z (%): 423 (72) [M+•], 266 (100), 250 (23), 135
(45), 77 (27). Anal. (C23H21NO5S) C, H, N.
2-Meth oxyp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-
in d olyl)-m eth a n on e (2a ): colorless crystals, 62%, mp 179 °C.
IR (KBr): 3067, 3015, 2985, 2936, 1648, 1596, 1474, 1374, 1167
4-Meth oxyp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-
in d olyl)-m eth a n ol (4b): light red crystals, 77%, mp 78-79
°C. IR (KBr): 3442, 3068, 2935, 2836, 1513, 1474, 1368, 1175
cm-1 1H-NMR (DMSO-d6): δ 3.67 (s, 3H), 3.75 (s, 3H), 7.01
.
(s, 1H), 7.06-7.21 (m, 4H), 7.55-7.74 (m, 5H), 7.90-7.96 (m,
3H). EI-MS (70 eV); m/z (%): 421 (100) [M+•], 280 (58), 265
(49), 249 (90), 160 (78), 135 (56), 77 (86). Anal. (C23H19NO5S)
C, H, N.
1
cm-1. H-NMR (DMSO-d6): δ 3.72 (s, 3H), 3.74 (s, 3H), 6.03-
6.05 (m, 1H, exchangeable), 6.31-6.33 (m, 1H), 6.63 (s, 1H),
6.85-6.90 (m, 3H), 7.06-7.07 (m, 1H), 7.23-7.29 (m, 2H),
7.45-7.51 (m, 2H), 7.60-7.73 (m, 3H), 7.83-7.87 (m, 1H). EI-
MS (70 eV); m/z (%): 423 (27) [M+•], 281 (100), 265 (18), 250
(17), 173 (18), 135 (31), 77(25). Anal. (C23H21NO5S) C, H, N.
2,4-Dim et h oxyp h en yl-(5-m et h oxy-1-p h en ylsu lfon yl-
1H-2-in d olyl)-m eth a n ol (6b): colorless crystals, 61%, mp
119-120 °C. IR (KBr): 3450, 3002, 2941, 2836, 1591, 1508,
3-Meth oxyp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-
in d olyl)-m eth a n on e (3a ): colorless needles, 67%, mp 181 °C.
IR (KBr): 3083, 3014, 2958, 2842, 1663, 1603, 1366, 1152 cm-1
.
1H-NMR (DMSO-d6): δ 3.77 (s, 3H), 3.84 (s, 3H), 7.10-7.14
(m, 1H), 7.19-7.22 (m, 2H), 7.29-7.34 (m, 1H), 7.40-7.64 (m,
5H), 7.69-7.76 (m, 1H), 7.89-7.96 (m, 3 H). EI-MS (70 eV);
m/z (%): 421 (72) [M+•], 280 (100), 265 (20), 249 (31), 135 (20),
77 (49). Anal. (C23H19NO5S) C, H, N.
1
1364, 1179 cm-1. H-NMR (DMSO-d6): δ 3.69 (s, 3H), 3.73 (s,
3H), 3.78 (s, 3H), 5.75-5.77 (m, 1H, exchangeable), 6.15 (s,
1H), 6.51-6.60 (m, 3H), 6.85-6.89 (m, 1H), 7.00-7.01 (m, 1H),
7.26-7.29 (m, 1H), 7.51-7.68 (m, 3H), 7.84-7.90 (m, 3H). EI-
MS (70 eV); m/z (%): 453 (23) [M+•], 311 (60), 284 (25), 173
(67), 165 (100), 77 (39). Anal. (C24H23NO6S) C, H, N.
4-Meth oxyp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-
in d olyl)-m eth a n on e (4a ): beige crystals, 64%, mp 129-130
°C. IR (KBr): 3066, 3002, 2937, 2937, 1611, 1512, 1370, 1162
cm-1 1H-NMR (DMSO-d6): δ 3.77 (s, 3H), 3.80 (s, 3H), 6.16
.
3-Ben zyloxyp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-
2-in d olyl)-m eth a n ol (15b): colorless crystals, 72%, mp 61 °C.
IR (KBr): 3440, 3064, 2937, 2834, 1609, 1486, 1368 cm-1. 1H-
NMR (DMSO-d6): δ 3.71 (s, 3H), 5.05 (s, 2H), 6.16-6.18 (m,
1H), 6.32-6.35 (m, 1H), 6.55 (s, 1H), 6.86-6.87 (m, 1H), 6.89-
6.98 (m, 3H), 7.04-7.05 (m, 1H), 7.21-7.51 (m, 8H), 7.60-
7.66 (m, 1H), 7.72-7.76 (m, 2H), 7.84-7.88 (m, 1H). EI-MS
(70 eV); m/z (%): 499 (20) [M+•], 359 (13), 267 (17), 250 (25),
91 (100), 77 (30). Anal. (C29H25NO5S) C, H, N.
4-Isoch in olin yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-in -
d olyl)-m eth a n ol (72b): colorless crystals, 64%, mp 138-139
°C. IR (KBr): 3424, 3060, 2958, 2834, 1623, 1590, 1505, 1366,
1177 cm-1. 1H-NMR (DMSO-d6): δ 3.72 (s, 3H), 6.46-6.49 (m,
1H), 6.57 (s, 1H), 6.92-6.96 (m, 1H), 7.06-7.10 (m, 2H), 7.53-
7.59 (m, 2H), 7.66-7.74 (m, 2H), 7.78-7.84 (m, 1H), 7.89-
7.95 (m, 3H), 8.05-8.09 (m, 1H), 8.17-8.20 (m, 1H), 8.28 (s,
1H), 9.29 (s, 1H). EI-MS (70 eV); m/z (%): 444 (41) [M+•], 302
(100), 286 (28), 271 (26), 156 (29), 128 (37), 77 (40). Anal.
(C25H20N2O4S) C, H, N.
P r oced u r e B: P r ep a r a tion of (1-p h en ylsu lfon yl-1H-
in d olyl)-p h en yl-m eth a n on es (IVa ) fr om IVb: PDC (pyri-
dinium dichromate) (11.66 g, 31.0 mmol) and PTFA (pyridin-
ium trifluoroacetate) (2.48 g, 155 mmol) were added to a
solution of the (1-phenylsulfonyl-1H-indolyl)methanol deriva-
tive IVb (6.2 mmol) in 40 mL of dry CH2Cl2. When the
oxidation was completed (2 h to 3 weeks, TLC-control), solid
chromium waste was removed by filtration through SiO2.
Evaporation of the solvent left a foamy material, which was
purified by column chromatography on silica gel with CH2Cl2
as eluent or recrystallized from ethyl acetate/light petrol (4:1)
(s, 1H), 6.88-6.93 (m, 1H), 7.01-7.04 (m, 2H), 7.12-7.40 (m,
8H), 7.55-7.61 (m, 1H), 7.82-7.86 (m, 1H). EI-MS (70 eV);
m/z (%): 421 (72) [M+•], 357 (22), 280 (100), 252 (32), 173 (42),
135 (56), 77 (57). Anal. (C23H19NO5S): C, H, N.
2,3-Dim eth oxyp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1-
H-2-in d olyl)-m et h a n on e (5a ): colorless crystals, 80%, mp
128 °C. IR (KBr): 3081, 3004, 2941, 2838, 1663, 1615, 1368,
1
1171 cm-1. H-NMR (DMSO-d6): δ 3.57 (s, 3H), 3.75 (s, 3H),
3.87 (s, 3H), 7.06-7.24 (m, 5H), 7.32-7.35 (dd,1.7, 8.1 Hz, 1H),
7.59-7.65 (m, 2H), 7.69-7.76 (m, 1H), 7.91-8.00 (m, 3H). EI-
MS (70 eV); m/z (%): 451 (49) [M+•], 311 (29), 279 (100), 264
(33), 160 (32), 77 (27). Anal. (C24H21NO6S) C, H, N.
2,4-Dim et h oxyp h en yl-(5-m et h oxy-1-p h en ylsu lfon yl-
1H-2-in d olyl)-m eth a n on e (6a ): colorless crystals, 53%, mp
62-64 °C. IR (KBr): 3046, 2943, 2943, 1653, 1601, 1573, 1370,
1
1165 cm-1. H-NMR (DMSO-d6): δ 3.64 (s, 3H), 3.75 (s, 3H),
3.88 (s, 3H), 6.64-6.69 (m, 2H), 6.92 (s, 1H), 7.02-7.07 (m,
1H), 7.13-7.14 (m, 1H), 7.57-7.74 (m, 4H), 7.85-7.95 (m, 3H).
EI-MS (70 eV); m/z (%): 451 (100) [M+•], 311 (74), 295 (40),
279 (76), 264 (34), 173 (97), 165 (72), 160 (62), 77 (72). Anal.
(C24H21NO6S) C, H, N.
3,4-Dim et h oxyp h en yl-(5-m et h oxy-1-p h en ylsu lfon yl-
1H-2-in d olyl)-m eth a n on e (7a ): light red crystals, 58%, mp
75 °C (dec). IR (KBr): 3068, 3004, 2939, 2838, 1652, 1615,
1
1596, 1513, 1372, 1175 cm-1. H-NMR (DMSO-d6): δ 3.76 (s,
3H), 3.83 (s, 3H), 3.87 (s, 3H), 7.06-7.17 (m, 4H), 7.43-7.71
(m, 5H), 7.91-7.95 (m, 3H). EI-MS (70 eV); m/z (%): 451 (89)
[M+•], 387 (18), 310(63), 279 (100), 264 (39), 165 (32), 77 (70),
51 (24). Anal. (C24H21NO6S) C, H, N.

2-Aroylindole Derivatives as Tubulin-Inhibitory Agents
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26 4545
1339, 1220 cm-1 1H-NMR (CDCl3): δ 3.83 (s, 3H), 6.94 (d,
3,5-Dim et h oxyp h en yl-(5-m et h oxy-1-p h en ylsu lfon yl-
1H-2-in d olyl)-m eth a n on e (8a ): light red crystals, 64%, mp
122-123 °C (dec). IR (KBr): 3087, 2968, 2838, 1667, 1594,
.
0.8 Hz, 1H), 6.99 (dd, 2.6 Hz, 0.5 Hz, 1H), 7.12 (d, 2.6 Hz, 1H),
7.44-7.61 (m, 4H), 7.88-8.10 (m, 5H), 8.25 (m,1H). EI-MS (70
eV); m/z (%): 491 (52) [M+•], 287 (19), 249 (100), 234 (29), 146
(54), 77 (34), 28 (22). Anal. (C23H16F3NO4S2) C, H, N.
3-(Diflu or om et h ylt h io)p h en yl-(5-m et h oxy-1-p h en yl-
su lfon yl-1H-2-in d olyl)-m eth a n on e (20a ): colorless crystals,
42%, mp 188-195 °C. IR (KBr): 1649, 1481, 1387, 765, 562
cm-1. 1H-NMR (DMSO-d6): δ 3.70 (s, 3H), 6.92-7.92 (m, 14H).
EI-MS (70 eV); m/z (%): 473 (30) [M+•]. Anal. (C23H17F2-
NO4S2): C, H, N.
1
1368, 1179 cm-1. H-NMR (DMSO-d6): δ 3.76 (s, 3H), 3.80 (s,
6H), 6.97 (s, 2H), 7.08-7.22 (m, 3H), 7.57-7.63 (m, 2H), 7.67-
7.74 (m, 1H), 7.88-7.96 (m, 3H). EI-MS (70 eV); m/z (%): 451
(38) [M+•], 311 (100), 295 (27), 279 (27), 264 (17), 77 (40). Anal.
(C24H21NO6S) C, H, N.
5-Me t h oxy-1-p h e n ylsu lfon yl-1H -2-in d olyl-(2,3,4-t r i-
m eth oxyp h en yl)-m eth a n on e (9a ): colorless crystals, 45%,
mp 57-59 °C. IR (KBr): 3103, 3000, 2944, 2840, 1656, 1615,
1495, 1372, 1175 cm-1 1H-NMR (DMSO-d6): δ 3.63 (s, 3H),
.
3-Tr iflu or om eth ylph en yl-(5-m eth oxy-1-ph en ylsu lfon yl-
1H-2-in d olyl)-m eth a n on e (21a ): colorless crystals, 29%, mp
175-177 °C. IR (KBr): 1670, 1474, 1449, 1331, 812, 725, 596,
575 cm-1. 1H-NMR (CDCl3): δ 3.70 (s, 3H), 6.92-7.02 (m, 2H),
7.49 (s, 1H), 7.48-7.99 (m, 10H). EI-MS (70 eV); m/z (%): 457
(7) [M+•], 318 (14), 141 (24). Anal. (C23H16F3NO4S) C, H, N.
5-Meth oxy-1-ph en ylsu lfon yl-1-H-2-in dolyl-(2-n itr oph en -
yl)-m eth a n on e (22a ): beige needles, 47%, mp 190-191 °C.
IR (KBr): 3070, 3012, 2935, 2838, 1673, 1650, 1613, 1532,
3.76 (s, 3H), 3.77 (s, 3H), 3.90 (s, 3H), 6.95-7.09 (m, 3H), 7.14-
7.15 (m, 1H), 7.37-7.40 (m, 1H), 7.58-7.75 (m, 3H), 7.88-
7.98 (m, 3H). EI-MS (70 eV); m/z (%): 481 (67) [M+•], 341, 309
(100), 294 (26), 195 (19), 181 (44), 173 (37), 160 (60), 77 (30).
Anal. (C25H23NO7S) C, H, N.
5-Me t h oxy-1-p h e n ylsu lfon yl-1H -2-in d olyl-(2,3,5-t r i-
m eth oxyp h en yl)-m eth a n on e (10a ): colorless crystals, 78%,
mp 79-81 °C. IR (KBr): 3465, 3004, 2942, 2836, 1642, 1603,
1
1368, 1171 cm-1. H-NMR (DMSO-d6): δ 3.56 (s, 3H), 3.74 (s,
1320, 1352, 1169 cm-1 1H-NMR (DMSO-d6): δ 3.77 (s, 3H),
.
3H), 3.75 (s, 3H), 3.90 (s, 3H), 6.74 (s, 1H), 6.88 (m, 1H), 6.99-
7.04 (m, 1H), 7.11-7.12 (m, 1H), 7.24 (s, 1H), 7.55-7.71 (m,
3H), 7.83-7.93 (m, 3H). EI-MS (70 eV); m/z (%):481 (47) [M+•],
341 (35), 325 (21), 309 (100), 294 (38), 168 (34), 160 (30), 77
(39). Anal. (C25H23NO7S) C, H, N.
3,4,5-Tr im eth oxyp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-
1H-2-in d olyl)-m eth a n on e (11a ): colorless crystals, mp 140-
142 °C. IR (KBr): 3098, 2996, 2942, 1653, 1584 cm-1. 1H-NMR
(DMSO-d6): δ 3.78 (s, 3H), 3.81 (s, 3H), 3.82 (s, 6H), 7.10-
7.25 (m, 5H), 7.60-7.78 (m, 3H), 7.95-8.00 (m, 3H). EI-MS
(70 eV); m/z (%): 481 (100) [M+•], 341 (60), 309 (62), 294 (18),
173 (17). Anal. (C25H23NO7S) C, H, N.
7.19-7.24 (m, 3H), 7.64-7.80 (m, 4H), 7.86-7.94 (m, 2H),
8.05-8.13 (m, 3H), 8.16-8.23 (m, 1H). EI-MS (70 eV); m/z
(%): 436 (24) [M+•], 134 (100), 104 (57), 77 (41). Anal.
(C22H16N2O6S) C, H, N.
5-Meth oxy-1-ph en ylsu lfon yl-1-H-2-in dolyl-(3-n itr oph en -
yl)-m eth a n on e (24a ): beige needles, 53%, mp 228-230 °C.
IR (KBr): 3074, 2838, 1659, 1613, 1326, 1368, 1167 cm-1. 1H-
NMR (DMSO-d6): δ 3.78 (s, 3 H), 7.14-7.22 (m, 2H), 7.39 (s,
1H), 7.58-7.64 (m, 2H), 7.69-7.76 (m, 1H), 7.86-8.00 (m, 4H),
8.30-8.95 (m, 2H), 8.55-8.59 (m, 2H). EI-MS (70 eV); m/z
(%): 436 (87) [M+•], 372 (9), 295 (25), 249 (100), 234 (37), 206
(24), 178 (22), 150 (18), 141 (16), 77 (59). Anal. (C22H16
N2O6S): C, H, N.
-
2-Meth ylp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-in -
d olyl)-m eth a n on e (12a ): colorless crystals, 30%, mp 149-
5-Met h oxy-1-p h en ylsu lfon yl-1-H -2-in d olyl-(2-m et h yl-
3-n itr op h en yl)-m eth a n on e (26a ): colorless crystals, 73%,
mp 210-211 °C. IR (KBr): 3085, 2971, 2838, 1659, 1615, 1530,
153 °C. IR (KBr): ν ) 1659, 1472, 1368, 748, 725 cm-1 1H-
.
NMR (DMSO-d6): δ 2.49 (s, 3H), 3.75 (s, 3H), 7.08-7.18 (m,
3H), 7.25-7.49 (m, 3H), 7.47-7.76 (m, 4H), 7.89-7.93 (m, 3H).
EI-MS (70 eV); m/z (%): 405 (41) [M+•], 264 (100). Anal.
(C23H19NO4S) C, H, N.
1322, 1356, 1167 cm-1 1H-NMR (DMSO-d6): δ 2.48 (s, 3H),
.
3.77 (s, 3H), 7.15-7.22 (m, 2H), 7.31 (s, 1H), 7.52-7.76 (m,
5H), 7.93-7.99 (m, 3H), 8.08-8.11 (m, 1H). EI-MS (70 eV);
m/z (%): 450 (100) [M+•], 310 (20), 292 (22), 262 (36), 77 (22).
Anal. (C23H18N2O6S) C, H, N.
5-Me t h oxy-1-p h e n ylsu lfon yl-1-H -2-in d olyl-(4-m e t h -
ylp h en yl)-m eth a n on e (13a ): colorless needles, 77%, mp
126-127 °C. IR (KBr): 3074, 2962, 2836, 1648, 1605, 1586,
5-Meth oxy-1-p h en ylsu lfon yl-1-H-2-in d olyl-(3-m eth oxy-
2-n itr op h en yl)-m eth a n on e (28a ): light yellow crystals, 55%,
mp 180 °C. IR (KBr): 3068, 2973, 2842, 1669, 1650, 1605, 1580,
1
1368, 1177 cm-1. H-NMR (DMSO-d6): δ 2.43 (s, 3H), 3.77 (s,
3H), 7.08-7.13 (m, 1H), 7.17-7.19 (m, 2H), 7.39-7.42 (m, 2H),
7.57-7.64 (m, 2H), 7.68-7.74 (m, 1H), 7.78-7.81 (m, 2H),
7.88-7.95 (m, 3H). EI-MS (70 eV); m/z (%): 405 (90) [M+•],
341, 264 (100), 250 (23), 236 (18), 119 (46), 91 (34), 77 (37), 51
(12). Anal. (C23H19NO4) C, H, N.
1538, 1374, 1178 cm-1 1H-NMR (DMSO-d6): δ 3.77 (s, 3H),
.
3.98 (s, 3H), 7.16-7.21 (m, 2H), 7.33-7.39 (m, 2H), 7.60-7.74
(m, 5H), 7.89-7.99 (m, 3H). EI-MS (70 eV); m/z (%): 466 (46)
[M+•], 326 (29), 302 (88) 164 (100), 125 (43), 77 (99). Anal.
(C23H18N2O7S) C, H, N.
2,5-Dim eth ylp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1-H-
2-in d olyl)-m eth a n on e (14a ): colorless crystals, 80%, mp 164
°C. IR (KBr): 3068, 3027, 2989, 2927, 2834, 1665, 1615, 1532,
4-Eth ylp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1-H-2-in -
d olyl)-m eth a n on e (29a ): colorless crystals, 52%, mp 107-
108 °C. IR (KBr): 3070, 2970, 2836, 1656, 1605, 1586, 1370,
1
1372, 1180 cm-1. H-NMR (DMSO-d6): δ 2.24 (s, 3H), 2.44 (s,
1162 cm-1 1H-NMR (DMSO-d6): δ 1.23 (t, J ) 7.6 Hz, 3H),
.
3H), 3.77 (s, 3H), 7.09-7.20 (m, 4H), 7.27-7.35 (m, 2H), 7.59-
7.65 (m, 2H), 7.70-7.77 (m, 1H), 7.91-7.97 (m, 3H). EI-MS
(70 eV); m/z (%): 419 (35) [M+•], 278 (100), 263 (25), 248 (17),
234 (11), 105 (9), 77 (21). Anal. (C24H21NO4S) C, H, N.
3-Ben zyloxyp h en yl-(5-Meth oxy-1-p h en ylsu lfon yl-1-H-
2-in d olyl)-m eth a n on e (15a ): colorless crystals, 63%, mp 121
°C. IR (KBr): 3448, 3068, 2935, 2836, 1659, 1594, 1366, 1183
2.73 (q, J ) 7.6 Hz, 2 H), 3.77 (s, 3H), 7.11 (dd, J ) 2.6, 9.1
Hz, 1H), 7.18-7.19 (m, 2H), 7.42-7.45 (m, 2H), 7.57-7.64 (m,
2H), 7.68-7.75 (m, 1H), 7.81-7.84 (m, 2H), 7.89-7.95 (m, 3H).
EI-MS (70 eV); m/z (%): 419 (100) [M+•], 355 (20), 279(97),
250 (50), 234 (32), 133 (45), 77 (62), 51 (15). Anal. (C25H23
NO4S) C, H, N.
-
1
cm-1. H-NMR (DMSO-d6): δ 3.75 (s, 3H), 5.18 (s, 2H), 7.08-
5-Met h oxy-1-p h en ylsu lfon yl-1-H -2-in d olyl-(4-p r op yl-
p h en yl)-m eth a n on e (30a ): colorless crystals, 67%, mp 112-
114 °C. IR (KBr): 3070, 2970, 2935, 2838, 1652, 1605, 1586,
7.12 (m, 1H), 7.15-7.16 (m, 2H), 7.31-7.51 (m, 9H), 7.54-
7.62 (m, 2H), 7.66-7.73 (m, 1H), 7.87-7.84 (m, 3H). EI-MS
(70 eV); m/z (%): 497 (17) [M+•], 357 (22), 91 (100), 77 (26).
Anal. (C29H23NO5S) C, H, N.
1
1370, 1177 cm-1. H-NMR (DMSO-d6): δ 2.43 (s, 3H), 3.77 (s,
3H), 7.08-7.13 (m, 1H), 7.17-7.19 (m, 2H), 7.39-7.42 (m, 2H),
7.57-7.64 (m, 2H), 7.68-7.74 (m, 1H), 7.78-7.81 (m, 2H),
7.89-7.95 (m, 3H). EI-MS (70 eV); m/z (%): 433 (100) [M+•],
369 (32), 292 (82), 264 (33), 250 (64), 234 (30), 220 (37), 147
(42), 91 (25), 77 (57). Anal. (C25H23NO4S) C, H, N.
5-Met h oxy-1-p h en ylsu lfon yl-1H -2-in d olyl-(3-t r iflu o-
r om eth oxyp h en yl)-m eth a n on e (18a ): colorless crystals,
55%, mp 188-192 °C. IR (KBr): 1656, 1477, 1453, 1329, 734,
1
589 cm-1. H-NMR (DMSO-d6): δ 3.70 (s, 3H), 6.92-6.97 (m,
2H), 7.12 (s, 1H), 7.41-7.95 (m, 10H). EI-MS (70 eV); m/z (%):
475 (99) [M+•], 334 (100). Anal. (C23H16F3NO5S) C, H, N.
3-(Tr iflu or om et h ylt h io)p h en yl-(5-m et h oxy-1-p h en yl-
su lfon yl-1H-2-in d olyl)-m eth a n on e (19a ): colorless powder,
76%, mp 123-124 °C. IR (KBr): 3070, 3006, 2940, 2842, 1669,
4-ter t-Bu tylp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-
in d olyl)-m eth a n on e (31a ): colorless crystals, mp 161-163
°C. IR (KBr): 3071, 2973, 2867, 1670, 1603, cm-1 1H-NMR
.
(DMSO-d6): δ 1.33 (s, 9H), 3.77 (s, 3H), 7.08-7.19 (m, 3H),
7.57-7.76 (m, 5H), 7.82-7.91 (m, 5H). EI-MS (70 eV); m/z

4546 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26
Mahboobi et al.
(%): 447 (58) [M+•], 383 (14), 307 (87), 250 (80), 77 (89), 57
(100). Anal. (C26H25NO4S) C, H, N.
2-Meth oxyph en yl-(1-ph en ylsu lfon yl-1H-2-in dolyl)-m eth -
a n on e (42a ): colorless crystals, mp 141-143 °C. IR (KBr):
3070, 3008, 2940, 1640, 1595 cm-1 1H-NMR (DMSO-d6): δ
.
4-P en tyloxyp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-
in d olyl)-m eth a n on e (32a ): colorless crystals, mp 118-120
3.75 (s, 3H), 6.85 (s, 1H), 6.95-7.07 (m, 2H), 7.23-7.30 (m,
1H), 7.40-7.69 (m, 7H), 8.09-8.17 (M, 3H). EI-MS (70 eV);
m/z (%): 391 (100) [M+•], 250 (49), 219 (77), 130 (83), 77 (93).
Anal. (C22H17NO4S): C, H, N.
°C. IR (KBr): 3063, 2956, 2869, 1638, 1601 cm-1 1H-NMR
.
(DMSO-d6): δ 0.90 (t, J ) 6.9 Hz, 3H), 1.30-1.45 (m, 4H),
1.75 (quint, J ) 6.8 Hz, 2H), 3.77 (s, 3H), 4.10 (t, J ) 6.5 Hz,
2H), 7.06-7.18 (m, 5H), 7.55-7.75 (m, 3H), 7.83-7.94 (m, 5H).
EI-MS (70 eV); m/z (%): 477 (84) [M+•], 413 (41), 337 (54), 336
(63), 266 (100). Anal. (C27H27NO5S) C, H, N.
2,4-Dim eth oxyp h en yl-(1-p h en ylsu lfon yl-1H-2-in d olyl)-
m et h a n on e (43a ): colorless crystals, mp 66-68 °C. IR
1
(KBr): 3060, 2996, 2930, 1634, 1597 cm-1. H-NMR (DMSO-
d6): δ 3.73 (s, 3H); 3.88 (s, 3H), 6.46-6.58 (m, 2H), 6.79 (s,
1H), 7.22-7.58 (m,6H), 7.53-7.58 (m, 1H), 8.40-8.52 (m, 3H).
EI-MS (70 eV); m/z (%): 421 (84) [M+•], 281 (72), 249 (53), 165
(100), 130 (82), 77 (90). Anal. (C23H19NO5S) C, H, N.
3,4,5-Tr im e t h oxyp h e n yl-(1-p h e n ylsu lfon yl-1H -2-in -
d olyl)-m eth a n on e (44a ): colorless crystals, mp 152-153 °C.
IR (KBr): 3073, 3058, 2971, 1646, 1584 cm-1. 1H-NMR (DMSO-
d6): δ 3.88 (s, 6H), 3.97 (s, 3H), 6.95 (s, 1H), 7.25-7.37 (m,
3H), 7.43-7.65 (m, 5H), 8.11-8.17 (m, 3H). EI-MS (70 eV);
m/z (%): 451 (100) [M+•], 387 (9), 311 (78), 295 (30), 279 (44).
Anal. (C24H21NO6S) C, H, N.
4-Ch lor op h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-in -
d olyl)-m eth a n on e (33a ): colorless crystals, mp 146-148 °C.
1
IR (KBr): 3085, 2938, 1660, 1586 cm-1. H-NMR (DMSO-d6):
δ 3.75 (s, 3H), 7.09-7.20 (m, 2H), 7.26 (d, J ) 0.5 Hz, 1H),
7.56-7.75 (m, 5H), 7.85-7.97 (m, 5H). EI-MS (70 eV); m/z
(%): 425 (90) [M+•], 361 (16), 284 (68), 249 (100), 234 (27), 139
(40). Anal. (C22H16ClNO4S) C, H, N.
4-Br om op h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-in -
d olyl)-m eth a n on e (34a ): colorless crystals, mp 145-148 °C.
IR (KBr): 3081, 2959, 2834, 1659, 1613 cm-1. 1H-NMR (DMSO-
d6): δ 3.75 (s, 3H), 6.95-7.20 (m, 2H), 7.26-7.27 (m, 1H),
7.57-7.64 (m, 2H), 7.68-7.75 (m, 1H), 7.81-7.96 (m, 7H). EI-
MS (70 eV); m/z (%): 469 (43) [M+•], 405 (10), 328 (19), 249
(100), 234(39). Anal. (C22H16BrNO4S × 0.15 CH2Cl2): calcd. C
55.07, H 3.40, N 2.90; found C 55.16, H 3.79, N 2.76.
2-F lu or op h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-in -
d olyl)-m eth a n on e (35a ): colorless crystals, 29%, mp 199-
2-Meth oxyp h en yl-(3-m eth yl-1-p h en ylsu lfon yl-1H-2-in -
d olyl)-m eth a n on e (45a ): colorless crystals, 51%, mp 167-
169 °C. IR (KBr): 1657, 1573, 1451 cm-1 1H-NMR (DMSO-
.
d6): δ 2.07 (s, 3H), 3.57 (s, 3H), 7.05-7.93 (m, 13H). EI-MS
(70 eV); m/z (%): 405 (100) [M+•], 264 (70). Anal. (C23H19NO4S)
C, H, N.
205 °C. IR (KBr): 1613, 1472, 1449, 1205, 1173, 725, 602 cm-1
.
3-Meth oxyp h en yl-(3-m eth yl-1-p h en ylsu lfon yl-1H-2-in -
d olyl)-m eth a n on e (46a ): colorless crystals, 43%, mp 113 °C.
1H-NMR (DMSO-d6): δ 3.70 (s, 3H), 6.92-6.96 (m, 1H), 7.11-
7.13 (m, 1H), 7.44-7.68 (m, 5H), 7.85-7.95 (m, 1H). EI-MS
(70 eV); m/z (%): 409 (54) [M+•], 268 (72), 141 (48). Anal.
(C22H16FNO4S) C, H, N.
IR (KBr): 1660, 1588, 1448, 1233, 1116, 793, 734 cm-1 1H-
.
NMR (DMSO-d6): δ 2.12 (s, 3H), 3.81 (s, 3H), 7.25-8.00 (m,
13H). EI-MS (70 eV); m/z (%): 405 (91) [M+•], 264 (100). Anal.
(C23H19NO4S): C, H, N.
3-(F lu or om eth ylth io)p h en yl-(5-m eth oxy-1-p h en ylsu l-
fon yl-1H-2-in d olyl)-m eth a n on e (36a ): colorless crystals,
47%, mp 149 °C. IR (KBr): 1676, 1491, 1342, 1298, 733, 524
cm-1. 1H-NMR (DMSO-d6): δ 3.76 (s, 3H), 7.09-7.19 (m, 2H),
7.27 (s, 1H), 7.56-7.73 (m, 7H), 7.85-7.95 (m, 3H). EI-MS (70
eV); m/z (%): 409 (62) [M+•], 268 (100). Anal. (C22H16FNO4S2)
C, H, N.
2,4-Dim eth oxyp h en yl-(3-m eth yl-1-p h en ylsu lfon yl-1H-
2-in d olyl)-m eth a n on e (47a ): colorless crystals, 34%, mp
155-157 °C. IR (KBr): 1663, 1546, 1482, 1149, 1306, 765, 694
cm-1 1H-NMR (DMSO-d6): δ 2.49 (s, 3H), 3.58 (s, 3H), 3.86
.
(s, 3H), 6.60-6.69 (m, 2H), 7.24-7.65 (m, 7H), 7.79-7.97 (m,
3H). EI-MS (70 eV); m/z (%): 435 (100) [M+•], 294 (71). Anal.
(C24H21NO5S) C, H, N.
4-F lu or op h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-in -
d olyl)-m et h a n on e (37a ): colorless crystals 44%, mp 123-
3,4,5-Tr im et h oxyp h en yl-(3-m et h y-1-p h en ylsu lfon yl-
1H-2-in d olyl)-m eth a n on e (48a ): pale beige powder, 83%, mp
149.5-151 °C. IR (KBr): 3068, 3020, 2942, 2836, 1648, 1611,
1592, 1366 cm-1. 1H-NMR (CDCl3): δ 2.18 (s, 3H), 3.86 (s, 6H),
3.95 (s, 3H), 7.23 (s, 2H), 7.25-7.55 (m, 6H), 7.85-7.90 (m,
2H), 8.08 (m, 1H). EI-MS (70 eV); m/z (%): 465 (68) [M+•], 324
(49), 293 (100), 278 (31), 195 (44), 28 (76). Anal. (C25H23NO6S
× 0.33 H2O): calcd. C 63.68, H 5.06, N 2.97; found C 63.52, H
4.99, N 2.76.
128 °C. IR (KBr): 1672, 1599, 1472, 1219, 1159, 725, 598 cm-1
.
1H-NMR (DMSO-d6): δ 3.70 (s, 3H), 6.91-6.96 (m, 1H), 7.08-
7.76 (m, 9H), 7.81-7.99 (m, 3H). EI-MS (70 eV); m/z (%): 409
(54) [M+•], 268 (72), 141 (48). Anal. (C22H16FNO4S) C, H, N.
2,6-Diflu or p h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-
in d olyl)-m eth a n on e (38a ): colorless crystals, 29%, mp 124
°C. IR (KBr): 1674, 1466, 1217, 1175, 723, 598, 565 cm-1. 1H-
NMR (CDCl3): δ 3.81 (s, 3H), 6.92-7.14 (m, 5H), 7.40-7.60
(m, 4H), 7.95-7.98 (m, 2H), 8.00-8.01 (m, 1H). EI-MS (70 eV);
m/z (%): 427 (57) [M+•], 286 (100), 141 (33). Anal. (C22H15F2-
NO4S) C, H, N.
3-Meth oxyp h en yl-(4-m eth oxy-1-p h en ylsu lfon yl-1H-2-
in d olyl)-m eth a n on e (49a ): colorless crystals, 74%, mp 132
°C (dec). IR (KBr): 3062, 2943, 2842, 1652, 1611, 1592, 1366
1
cm-1. H-NMR (DMSO-d6): δ 3.82 (s, 3H), 3.85 (s, 3H), 6.86-
2-Ch lor o-6-flu or op h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-
1-H-2-in d olyl)-m eth a n on e (39a ): beige crystals, 27%, mp
130 °C. IR (KBr): 3014, 2958, 2834, 1679, 1605, 1530, 1372,
6.89 (m, 1H), 7.15 (m, 1H), 7.27-7.32 (m, 1H), 7.38-7.50 (m,
4H), 7.59-7.65 (m, 3H), 7.69-7.73 (m, 1H), 7.94-7.98 (m, 2H).
EI-MS (70 eV); m/z (%): 421 (42) [M+•], 357 (7), 280 (100), 265
(36), 250 (22), 135 (17), 121(24), 77 (48). Anal. (C23H19NO5S)
C, H, N.
1177, 1221, 1048 cm-1 1H-NMR (DMSO-d6): δ 3.77 (s, 3H),
.
7.21-7.26 (m, 2H), 7.37 (s, 1H), 7.39-7.51 (m, 2H), 7.61-7.79
(m, 4H), 8.02-8.10 (m, 3H). EI-MS (70 eV); m/z (%): 443 (80)
[M+•], 379 (9), 303 (62), 267 (100), 252 (46), 224 (31), 157 (41),
130 (21), 77 (61). Anal. (C22H15ClFNO4S) C, H, N.
2-Meth oxyp h en yl-(5-m eth yl-1-p h en ylsu lfon yl-1H-2-in -
d olyl)-m eth a n on e (50a ): colorless crystals, 48%, mp 157-
158 °C. IR (KBr): 1652, 1586, 1232, 1115 cm-1 1H-NMR
.
3,4-Dich lor op h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-
2-in d olyl)-m eth a n on e (40a ): colorless crystals, mp 141-144
(DMSO-d6): δ 2.34 (s, 3H), 3.64 (s, 3H), 7.00 (s, 1H), 7.05-
7.31 (m, 3H), 7.42 (s, 1H), 7.54-7.72 (m, 5H), 7.87-7.96 (m,
3H). EI-MS (70 eV); m/z (%): 405 (100) [M+•], 264 (49). Anal.
(C23H19NO4S) C, H, N.
°C. IR (KBr): 3091, 3008, 2929, 2836, 1663, 1615 cm-1 1H-
.
NMR (DMSO-d6): δ 3.78 (s, 3H), 7.10-7.21 (m, 2H), 7.33 (s,
1H), 7.56-7.75 (m, 3H), 7.80-7.98 (m, 5H), 8.04 d, J ) 1.8
Hz, 1H). EI-MS (70 eV); m/z (%): 459 (58) [M+•], 395 (9), 318
(27), 283 (100), 268 (27), 173 (26). Anal. (C22H15Cl2NO4S) C,
H, N.
3-Meth oxyp h en yl-(5-m eth yl-1-p h en ylsu lfon yl-1H-2-in -
d olyl)-m eth a n on e (51a ): colorless crystals, 39%, mp 124-
127 °C. IR (KBr): 1657, 1554, 1236, 1165 cm-1 1H-NMR
.
(DMSO-d6): δ 2.36 (s, 3H), 3.82 (s, 3H), 7.21 (s, 1H), 7.28-
7.74 (m, 9H), 7.90-7.95 (m, 3H). EI-MS (70 eV); m/z (%): 405
(56) [M+•], 264 (100). Anal. (C23H19NO4S) C, H, N.
3,4,5-Tr im et h oxyp h en yl-(5-m et h y-1-p h en ylsu lfon yl-
1H-2-in d olyl)-m eth a n on e (52a ): pale beige powder, 63%, mp
152-153 °C. IR (KBr): 3060, 2996, 2838, 1648, 1611, 1592,
1-P h en ylsu lfon yl-1H-2-in dolyl-ph en yl-m eth an on e (41a):
colorless crystals, mp 142-143 °C. IR (KBr): 3071, 1661, 1599,
1533, 1364, 1342 cm-1. 1H-NMR (DMSO-d6): δ 7.29-7.41 (m,
2H), 7.49-7.80 (m, 8H), 7.91-8.09 (m, 5H). EI-MS (70 eV);
m/z (%): 361 (68) [M+•], 297 (37), 220 (100), 192 (30), 165 (34),
105(39), 77 (95). Anal. (C21H15NO3S) C, H, N.

2-Aroylindole Derivatives as Tubulin-Inhibitory Agents
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26 4547
1366 cm-1. 1H-NMR (CDCl3): δ 2.44 (s, 3H), 3.88 (s, 6H), 3.96
(s, 3H), 6.88 (d, 0.8 Hz, 1H), 7.26 (s, 2H), 7.20-7.38 (m, 2H),
7.45-7.64 (m, 3H), 8.01 (m, 1H), 8.06-8.11 (m, 2H). EI-MS
(70 eV); m/z (%): 465 (100) [M+•], 401 (30), 324 (73), 293 (93),
278 (37), 195 (24), 28 (80). Anal. (C25H23NO6S × 0.25 H2O):
calcd. C 63.88, H 5.04, N 2.98; found C 63.92, H 5.04, N 2.74.
5-Ben zyloxy-1-p h en ylsu lfon yl-1H -2-in d olyl-p h en yl-
m eth a n on e (53a ): colorless crystals, mp 205-207 °C. IR
8.2 Hz, J ) 8.0 Hz, J ) 0.3 Hz, 1H), 7.10-7.18 (m, 2H), 7.35-
7.50 (m, 3H), 7.84 (dd, J ) 8.0 Hz, J ) 1.7 Hz), 8.27-8.35 (m,
2H), 8.53 (dd, J ) 4.8 Hz, J ) 1.7 Hz, 1H). EI-MS (70 eV); m/z
(%): 392 (64) [M+•], 251 (100), 135 (27), 77 (96). Anal.
(C21H16N2O4S) C, H, N.
2,4-Dim eth oxyp h en yl-(1-p h en ylsu lfon yl-1H-(p yr r olo-
[2,3-b]p yr id in -2-yl))-m eth a n on e (62a ): light beige powder,
mp 180-190 °C (dec). IR (KBr): 3064, 3016, 2968, 2838, 1611,
1586, 1339 cm-1. 1H-NMR (CDCl3): δ 3.30 (s, 3H), 3.78 (s, 3H),
6.28 (s, 1H), 6.34 (d, J ) 2.5 Hz, 1H), 6.56 (dd, J ) 8.6 Hz, J
) 2.4 Hz, 1H), 7.14 (dd, J ) 7.9 Hz, J ) 4.8 Hz, 1H), 7.30-
7.40 (m, 2H), 7.44-7.50 (m, 2H), 7.71 (d, J ) 8.6 Hz, 1H), 7.73
(dd, J ) 7.9 Hz, J ) 1.6 Hz), 8.05-8.18 (m, 1H), 8.44 (dd, J )
4.8 Hz, J ) 1.6 Hz, 1H). EI-MS (70 eV); m/z (%): 422 (65) [M+•],
405 (30), 254 (24), 165 (27), 138 (100). Anal. (C22H18N2O5S) ×
1/3 H2O: calcd. C 61.67, H 4.39, N 6.54; found C 61.79, H 4.37,
N 6.25.
1
(KBr): 3179, 2977, 1654, 1599 cm-1. H-NMR (DMSO-d6): δ
5.10 (s, 2H), 7.15-7.45 (m, 8H), 7.55-7.80 (m, 6H), 7.85-8.00
(m, 5H). EI-MS (70 eV); m/z (%): 467 (30) [M+•], 376 (18), 236
(18), 141 (23), 91 (100). Anal. (C28H21NO4S × 0.2 ethyl
acetate): calcd. C 71.30, H 4.70, N 2.89; found C 71.13, H 4.65,
N 2.86.
5-Ben zyloxy-1-ph en ylsu lfon yl-1H-2-in dolyl-(2-m eth oxy-
p h en yl)-m eth a n on e (54a ): colorless crystals, mp 114.5-116
°C. IR (KBr): 3066, 2940, 2842, 1652, 1599, 1168 cm-1 1H-
.
NMR (CDCl3): δ 3.68 (s, 3H), 4.99 (s, 2H), 6.71 (d, J ) 0.8
Hz, 1H), 6.92 (m, 2H), 7.06 (dd, J ) 9.1 Hz, J ) 2.6 Hz, 1H),
7.25-7.60 (m, 11H), 7.97-8.02 (m, 2H). EI-MS (70 eV); m/z
3,4,5-Tr im eth oxyph en yl-(1-ph en ylsu lfon yl-1H-(pyr r olo-
[2,3-b]p yr id in -2-yl))-m eth a n on e (63a ): pale yellow powder,
mp 180-181 °C. IR (KBr): 3060, 2973, 1653, 1584, 1344 cm-1
.
(%): 497 (19) [M+•], 266 (17), 135 (28), 91 (100). Anal. (C29H23
NO5S) C, H, N.
-
1H-NMR (CDCl3): δ 3.88 (s, 6H), 3.97 (s, 3H), 6.84 (s, 1H),
7.25-7.31 (m, 2H), 7.29 (s, 2H), 7.53-7.68 (m, 3H), 8.42-8.47
(m, 2H), 8.44 (dd, J ) 4.8 Hz, J ) 1.6 Hz, 1H). EI-MS (70 eV);
m/z (%): 452 (100) [M+•], 312 (75), 281 (39), 77 (42). Anal.
(C23H20N2O6S) C, H, N.
5-Ben zyloxy-1-ph en ylsu lfon yl-1H-2-in dolyl-(3-m eth oxy-
p h en yl)-m eth a n on e (55a ): grey powder, mp 129-131 °C. IR
(KBr) 3066, 2948, 2842, 1659, 1545, 1175 cm-1 1H-NMR
.
(CDCl3): δ 3.79 (s, 3H), 5.01 (s, 2H), 6.80 (d, J ) 0.8 Hz, 1H),
6.97 (dd, J ) 2.5 Hz, J ) 0.3 Hz, 1H), 7.08 (dd, J ) 9.1 Hz, J
) 2.5 Hz, 1H), 7.09 (ddd, J ) 8.1 Hz, J ) 2.5 Hz, J ) 1.4 Hz,
1H), 7.23-7.62 (m, 12H), 7.92-7.99 (m, 2H). EI-MS (70 eV);
m/z (%): 497 (15) [M+•], 357 (14), 266 (20), 91 (100). Anal.
(C29H23NO5S) C, H, N.
2-Meth oxyph en yl-(5-m eth oxy-1-ph en ylsu lfon yl-1H-pyr -
r olo[3,2-b]p yr id in -2-yl)-m eth a n on e (64a ): colorless crys-
tals, 44%, mp 197-198 °C. IR (KBr): 3095, 2975, 2838, 1659,
1595, 1376, 1171 cm-1 1H-NMR (DMSO-d6): δ 3.83 (s, 3H),
.
3.85 (s, 3H), 6.90-6.93 (m, 1H), 6.96 (s, 1H), 7.09-7.18 (m,
2H), 7.59-7.66 (m, 4H), 7.71-7.78 (m, 1H), 7.96-7.80 (m, 2H),
8.31-8.35 (m, 1H). EI-MS (70 eV); m/z (%): 422 (100) [M+•],
5-Ben zyloxy-1-ph en ylsu lfon yl-1H-2-in dolyl-(4-m eth oxy-
p h en yl)-m eth a n on e (56a ): colorless crystals, mp 70-72 °C.
IR (KBr): 3067, 3033, 2925, 1653, 1599 cm-1. 1H-NMR (DMSO-
d6): δ 3.75 (s, 3H), 5.09 (s, 2H), 7.07-7.46 (m, 10H), 7.55-
7.75 (m, 3H), 7.84-7.94 (m, 5H). EI-MS (70 eV); m/z (%): 497
281 (38), 250 (51), 161 (56), 135 (44), 77 (68). Anal. (C22H18
N2O5S) C, H, N.
-
3-Meth oxyph en yl-(5-m eth oxy-1-ph en ylsu lfon yl-1H-pyr -
r olo[3,2-b]p yr id in -2-yl)-m eth a n on e (65a ): colorless crys-
tals, 66%, mp 147-149 °C. IR (KBr): 3089, 2946, 2840, 1663,
(24) [M+•], 357 (20), 266 (23), 158 (39), 91 (100). Anal. (C29H23
NO5S) C, H, N.
-
5-Ben zyloxy-1-p h en ylsu lfon yl-1H -2-in d olyl-(3,4,5-t r i-
m eth oxyp h en yl)-m eth a n on e (57a ): colorless crystals, mp
1596, 1376, 1169 cm-1 1H-NMR (DMSO-d6): δ 3.84 (s, 3H),
.
3.88 (s, 3H), 6.95-6.99 (m, 1H), 7.25 (s, 1H), 7.31-7.36 (m,
1H), 7.42-7.55 (m, 3H), 7.62-7.69 (m, 2H), 7.74-7.80 (m, 1H),
7.97-8.01 (m, 2H), 8.36-8.40 (m, 1H). EI-MS (70 eV); m/z
(%): 422 (51) [M+•], 281 (100), 265 (14), 135 (24), 77 (55). Anal.
(C22H18N2O5S) C, H, N.
150-152 °C. IR (KBr): 3066, 2938, 2873, 1659, 1611 cm-1
.
1H-NMR (DMSO-d6): δ 3.80 (s, 3H), 3.81 (s, 6H), 5.10 (s, 2H),
7.17-7.46 (m, 10H), 7.58-7.71 (m, 3H), 7.94-8.00 (m, 3H).
EI-MS (70 eV); m/z (%): 557 (19) [M+•], 466 (9), 417 (22), 294
(42), 195 (31), 91 (100). Anal. (C31H27NO7S) C, H, N.
2,4-Dim et h oxyp h en yl-(5-m et h oxy-1-p h en ylsu lfon yl-
1H-p yr r olo[3,2-b]p yr id in -2-yl)-m eth a n on e (66a ): colorless
crystals, 14%, mp 132 °C. IR (KBr): 3062, 2944, 2852, 1634,
5-Be n zyloxy-1-p h e n ylsu lfon yl-1H -2-in d olyl-(3-ch lo-
r op h en yl)-m eth a n on e (58a ): colorless crystals, mp 150-152
1
°C. IR (KBr): 3087, 2860, 1657, 1566 cm-1. H-NMR (DMSO-
1582, 1366, 1171 cm-1 1H-NMR (DMSO-d6): δ 3.60 (s, 3H),
.
d6): δ 5.11 (s, 2H), 7.19-7.48 (m, 8H), 7.58-7.99 (m, 10H).
EI-MS (70 eV); m/z (%): 501 (18) [M+•], 410 (6), 361 (7), 141
(19), 91 (100). Anal. (C28H20ClNO4S) C, H, N.
3.84 (s, 3H), 3.87 (s, 3H), 6.63-6.69 (m, 2H), 6.85-6.89 (m,
2H), 7.59-7.76 (m, 4H), 7.64-7.99 (m, 2H), 8.27-8.31 (m, 1H).
EI-MS (70 eV); m/z (%): 452 (83) [M+•], 311 (100), 280 (78),
173 (92), 77 (37). Anal. (C23H20N2O6S) C, H, N.
5-Be n zyloxy-1-p h e n ylsu lfon yl-1H -2-in d olyl-(4-ch lo-
r op h en yl)-m eth a n on e (59a ): colorless crystals, mp 63-65
5-Meth oxy-1-p h en ylsu lfon yl-1H-p yr r olo[3,2-b]p yr id in -
2-yl-(3,4,5-tr im eth oxyp h en yl)-m eth a n on e (67a ): colorless
crystals, 73%, mp 190-191 °C. IR (KBr): 3072, 2946, 2840,
1
°C. IR (KBr): 3064, 2871, 1661, 1588 cm-1. H-NMR (DMSO-
d6): δ 5.11 (s, 2H), 7.18-7.48 (m, 8H), 7.57-7.71 (m, 5H),
7.86-7.98 (m, 5H). EI-MS (70 eV); m/z (%): 501 (7) [M+•], 361
(5), 270 (6), 141 (14), 91 (100). Anal. (C28H20ClNO4S) C, H, N.
2-Meth oxyp h en yl-(1-p h en ylsu lfon yl-1H-(p yr r olo[2,3-b]-
p yr id in -2-yl))-m et h a n on e (60a ): beige crystals, mp 124-
125 °C. IR (KBr): 3066, 2945, 2842, 1636, 1600, 1392, 1182
1
1659, 1580, 1374, 1174 cm-1. H-NMR (DMSO-d6): δ 3.82 (s,
9H), 3.89 (s, 3H), 6.96-6.99 (m, 1H), 7.23 (s, 2H), 7.29 (s, 1H),
7.64-7.70 (m, 3H), 7.75-7.80 (m, 1H), 8.01-8.05 (m, 2H),
8.39-8.43 (m, 1H). EI-MS (70 eV); m/z (%): 482 (94) [M+•],
342 (100), 326 (22), 310 (49), 77 (46). Anal. (C24H22N2O7S) C,
H, N.
1
cm-1. H-NMR (CDCl3): δ 3.61 (s, 3H), 6.64 (dd, J ) 7.9 Hz,
J ) 1.0 Hz, 1H), 6.82-7.08 (m, 2H), 6.99 (dd, J ) 7.5 Hz, J )
1.6 Hz, 1H), 7.16 (dd, J ) 7.9 Hz, J ) 4.7 Hz, 1H), 7.41-7.77
(m, 4H), 7.79 (dd, J ) 7.9 Hz, J ) 1.7 Hz), 8.36-8.40 (m, 2H),
8.49 (dd, J ) 4.7 Hz, J ) 1.7 Hz, 1H). EI-MS (70 eV); m/z (%):
392 (43) [M+•], 251 (25), 131 (73), 77 (100). Anal. (C21H16N2O4S)
× 1/2 Et2O: calcd. C 64.29, H 4.54, N 6.81; found C 6.27, H
4.27, N 6.58.
Cyclopr opyl-(5-m eth oxy-1-ph en ylsu lfon yl-1H-2-in dolyl)-
m eth a n on e (68a ): colorless crystals, mp 118-120 °C. IR
1
(KBr): 3064, 2934, 1669, 1615 cm-1. H-NMR (DMSO-d6): δ
1.05-1.14 (m, 4H), 2.63-2.74 (m, 1H), 3.70 (s, 3H), 7.08-7.20
(m, 2H), 7.49-7.72 (m, 4H), 7.85-7.99 (m, 3H). EI-MS (70 eV);
m/z (%): 355 (100) [M+•], 287 (40), 214 (51), 146 (39), 77 (38).
Anal. (C19H17NO4S) C, H, N.
3-Meth oxyp h en yl-(1-p h en ylsu lfon yl-1H-(p yr r olo[2,3-b]-
p yr id in -2-yl))-m eth a n on e (61a ): colorless crystals, mp 138-
Cyclobu tyl-(5-m eth oxy-1-ph en ylsu lfon yl-1H-2-in dolyl)-
m eth a n on e (69a ): colorless crystals, mp 146-147 °C. IR
140 °C. IR (KBr): 3031, 2964, 2836, 1656, 1605, 1256 cm-1
.
1
(KBr): 3023, 2990, 2944, 1676, 1615 cm-1. H-NMR (DMSO-
1H-NMR (CDCl3): δ 3.80 (s, 3H), 6.76 (s, 1H), 6.82-7.08 (m,
2H), 7.12 (dddd, J ) 8.2 Hz, J ) 2.6 Hz, J ) 1.1 Hz, J ) 0.3
Hz, 1H), 7.20 (dd, J ) 8.0 Hz, J ) 4.8 Hz, 1H), 7.33 (ddd, J )
d6): δ 1.72-2.34 (m, 6H), 4.06 (quint, J ) 8.3 Hz, 1H), 7.08-
7.19 (m, 2H), 7.39 (d, J ) 0.5 Hz, 1H), 7.57-7.75 (m, 3H),

4548 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26
Mahboobi et al.
7.90-7.97 (m, 3H). EI-MS (70 eV); m/z (%): 369 (85) [M+•],
314 (30), 287 (15), 229 (28), 174 (100). Anal. (C20H19NO4S) C,
H, N.
2H), 7.47-7.51 (m, 2H), 11.85 (s, 1H). EI-MS (70 eV); m/z (%):
281 (100) [M+•], 266 (23), 158 (19), 130 (14). Anal. (C17H15NO3)
C, H, N.
5-Me t h oxy-1H -2-in d olyl-(4-m e t h oxyp h e n yl)-m e t h a -
n on (4): beige crystals, 86%, mp 165 °C. IR (KBr): 3276, 3062,
5-Meth oxy-1-p h en ylsu lfon yl-1H-2-in d olyl-(1-n a p h th a -
len yl)-m eth a n on e (70a ): colorless crystals, mp 225-228 °C.
IR (KBr): 3071, 3008, 2961, 1652, 1613 cm-1. 1H-NMR (DMSO-
d6): δ 3.75 (s, 3H), 7.11-7.23 (m, 3H), 7.56-7.79 (m, 7H),
7.92-7.99 (m, 3H), 8.07-8.12 (m, 1H), 8.20-8.27 (m, 1H),
8.60-8.67 (m, 1H). EI-MS (70 eV); m/z (%): 441 (24) [M+•],
300 (100), 257 (19), 228 (12). Anal. (C26H19NO4S) C, H, N.
2956, 2836, 1625, 1572, 1509 cm-1 1H-NMR (DMSO-d6): δ
.
3.77 (s, 3H), 3.88 (s, 3H), 6.94-6.99 (m, 1H), 7.02-7.03 (m,
1H), 7.09-7.16 (m, 3H), 7.39-7.41 (m, 1H), 7.92-7.98 (m, 2H),
11.78 (s, 1H). EI-MS (70 eV); m/z (%): 281 (100) [M+•], 173
(54), 158 (42), 77 (13). Anal. (C17H15NO3) C, H, N.
2,3-Dim eth oxyp h en yl-(5-m eth oxy-1H-2-in d olyl)-m eth -
a n on e (5): yellow crystals, 88%, mp 172-173 °C. IR (KBr):
5-Meth oxy-1-ph en ylsu lfon yl-1H-2-in dolyl-(2-pyr idin yl)-
m eth a n on e (71a ): colorless crystals, 75%, mp 207 °C. IR
3317, 2943, 2840, 1629, 1580, 1268 cm-1 1H-NMR (DMSO-
.
(KBr): 3073, 2966, 2836, 1671, 1615, 1584, 1370, 1169 cm-1
.
1H-NMR (DMSO-d6): δ 3.75 (s, 3H), 7.04-7.09 (m, 1H), 7.16-
7.17 (m, 1H), 7.27 (s, 1H), 7.53-7.59 (m, 2H), 7.63-7.72 (m,
2H), 7.79-7.85 (m, 3H), 8.05-8.16 (m, 2H), 8.70-8.73 (m, 1H).
EI-MS (70 eV); m/z (%): 492 (9) [M+•], 251 (100), 208 (11), 179
(9), 77 (15). Anal. (C21H16N2O4S) C, H, N.
d6): δ 3.67 (s, 3H), 3.72 (s, 3H), 3.87 (s, 3H), 6.68-6.69 (m,
1H), 6.94-7.01 (m, 2H), 7.08-7.09 (m, 1H), 7.15-7.26 (m, 2H),
7.35-7.38 (m, 1H), 11.82 (br. s, 1H). EI-MS (70 eV); m/z (%):
311 (100) [M+•], 293 (35), 280 (27), 119 (23). Anal. (C18H17NO4)
C, H, N.
2,4-Dim eth oxyp h en yl-(5-m eth oxy-1H-2-in d olyl)-m eth -
a n on e (6): colorless crystals, 81%, mp 160-161 °C. IR (KBr):
4-Isoch in olin yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-in -
d olyl)-m eth a n on e (72a ): yellow crystals, 36%, mp 189-190
°C. IR (KBr): 3064, 2962, 2836, 1652, 1615, 1569, 1362, 1175
cm-1. 1H-NMR (DMSO-d6): δ 3.78 (s, 3H), 7.16-7.21 (m, 2H),
7.37 (s, 1H), 7.60-7.67 (m, 2H), 7.71-7.77 (m, 1H), 7.82-8.03
(m, 5H), 8.31-8.34 (m, 1H), 8.59-8.64 (m, 2H), 9.58 (s, 1H).
EI-MS (70 eV); m/z (%): 442 (34) [M+•], 301 (100), 285 (14),
258 (25), 77 (27). Anal. (C25H18N2O4S) C, H, N.
Rem ova l of th e P h en ylsu lfon yl P r otection Gr ou p to
F or m (1H-2-In d olyl)-p h en yl-m eth a n on es (IV): P r oced u r e
D: The N-protected methanone derivative IVa (1.8 mmol) was
heated in ethanol (40 mL) and 10% aq NaOH (20 mL) under
reflux for 12 h. After the sample was cooled, the solution was
poured into brine (100 mL) and extracted with ethyl acetate
(3 × 50 mL). The combined organic layers were dried (Na2-
SO4) and evaporated under reduced pressure to leave the crude
product, which was subjected to column chromatography (SiO2;
CH2Cl2). Thus, compounds 1-21, 28-34, 36, 37, 40-76 were
prepared.
P r oced u r e E: A mixture of the N-protected methanone
derivative IVa (1.8 mmol) and TBAF (tetrabutylammonium
fluoride trihydrate) (0.79 g, 2.5 mmol) in THF/MeOH 1:1 (20
mL) was gently refluxed. When TLC indicated that the
reaction was completed (30 min - 4 h), part of the solvent
was removed to allow precipitation of the yellow product. Thus,
compounds 22, 24, 26, 35, 38, and 39 were prepared.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Am in o
Com p ou n d s 23, 25, a n d 27: The respective nitro compound
(22, 24, or 26) (1.7 mmol) was dissolved in dry methanol (5
mL). 10% Pd/C (0.4 g) was added, and the flask was connected
to a balloon, filled with dry hydrogen. The mixture was stirred
for 24 h at room temperature. When TLC analysis proved that
the reaction was completed, the mixture was filtered and the
solvent was removed in vacuo. The residue was purified by
chromatography (SiO2, CH2Cl2) to give the desired amino
compound.
3286, 2960, 2836, 1623, 1599, 1501 cm-1 1H-NMR (DMSO-
.
d6): δ 3.74 (s, 3H), 3.75 (s, 3H), 3.86 (s, 3H), 6.61-6.66 (m,
1H), 6.71 (s, 2H), 6.92-6.96 (m, 1H), 7.08-7.09 (m, 1H), 7.34-
7.42 (m, 2H), 11.69 (br. s, 1H). EI-MS (70 eV); m/z (%): 311
(86) [M+•], 280 (6), 173 (100), 165 (18). Anal. (C18H17NO4) C,
H, N.
3,4-Dim eth oxyp h en yl-(5-m eth oxy-1H-2-in d olyl)-m eth -
a n on e (7): yellow crystals, 59%, mp 187 °C. IR (KBr): 3298,
3089, 2964, 2834, 1596, 1515 cm-1 1H-NMR (DMSO-d6): δ
.
3.76 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H) 6.93-6.97 (m, 1H), 7.06
(s, 1H), 7.11-7.14 (m, 2H), 7.37-7.40 (m, 1H), 7.46-7.47 (m,
1H), 7.59-7.64 (m, 1H), 11.77 (br. s, 1H). EI-MS (70 eV); m/z
(%): 311 (100) [M+•], 173 (60), 158 (32), 130 (14). Anal. (C18H17
NO4) C, H, N.
-
3,5-Dim eth oxyp h en yl-(5-m eth oxy-1H-2-in d olyl)-m eth -
a n on e (8): yellow needles, 67%, mp 141-142 °C. IR (KBr):
3309, 3008, 2943, 2840, 1611, 1592 cm-1 1H-NMR (DMSO-
.
d6): δ 3.75 (s, 3H), 3.82 (s, 6H), 6.78-6.80 (m, 1H), 6.98-7.00
(m, 3H), 7.07 (s, 1H), 7.15-7.16 (m, 1H), 7.37-7.40 (m, 1H),
11.83 (br. s, 1H). EI-MS (70 eV); m/z (%): 311 (100) [M•+], 296
(21), 158 (22), 130 (11). Anal. (C18H17NO4) C, H, N.
5-Meth oxy-1H-2-in dolyl-(2,3,4-tr im eth oxyph en yl)-m eth -
a n on e (9): yellow crystals, 85%, mp 156 °C. IR (KBr): 3298,
3064, 2941, 2842, 2833, 1623, 1596, cm-1 1H-NMR (DMSO-
.
d6): δ 3.75 (s, 6H), 3.80 (s, 3H), 3.88 (s, 3H), 6.76 (s, 1H), 6.90-
6.99 (m, 2H), 7.10-7.12 (m, 1H), 7.21-7.25 (m, 1H), 7.36-
7.39 (m, 1H), 11.77 (br. s, 1H). EI-MS (70 eV); m/z (%): 341
(100) [M•+], 323 (23), 173 (55), 161 (37). Anal. (C19H19NO5) C,
H, N.
5-Meth oxy-1H-2-in dolyl-(2,3,5-tr im eth oxyph en yl)-m eth -
a n on e (10): yellow crystals, 84%, mp 198 °C. IR (KBr): 3355,
3068, 2954, 2834, 1686, 1636, 1528 cm-1.1H-NMR (DMSO-
d6): δ 3.72 (s, 3H), 3.73 (s, 6H), 3.88 (s, 3H), 6.75-6.76 (m,
1H), 6.82 (s, 1H), 6.90-6.95 (m, 1H), 7.02 (s, 1H), 7.07-7.08
(m, 1H), 7.33-7.36 (m, 1H), 11.67 (br. s., 1H). EI-MS (70 eV);
m/z (%): 341 (100) [M•+], 323 (41), 310 (17), 173 (36), 168 (89),
161 (33). Anal. (C19H19NO5) C, H, N.
5-Meth oxy-1H-2-in d olyl-p h en yl-m eth a n on e (1): light
yellow needles, 90%, mp 162 °C. IR (KBr): 3311, 2836, 1625,
1600 cm-1. 1H-NMR (DMSO-d6): δ 3.77 (s, 3H), 6.96-7.03 (m,
2H), 7.15-7.16 (m, 1H), 7.39-7.43 (m, 1H), 7.56-7.72 (m, 3H),
7.90-7.94 (m, 2H), 11.86 (br. s, 1H). EI-MS (70 eV); m/z (%):
251 (100) [M+•]. Anal. (C16H13NO2) C, H, N.
5-Meth oxy-1H-2-in dolyl-(3,4,5-tr im eth oxyph en yl)-m eth -
a n on e (11): yellow crystals, mp 210-211 °C. IR (KBr): 3291,
1
3073, 2952, 1605, 1574 cm-1. H-NMR (DMSO-d6): δ 3.77 (s,
3H), 3.79 (s, 3H), 3.88 (s, 6H), 6.95-7.00 (m, 1H), 7.14-7.17
(m, 2H), 7.22 (s, 2H), 7.38-7.42 (m, 1H), 11.85 (s, 1H). EI-MS
(70 eV); m/z (%): 341 (100) [M•+], 310 (6), 195 (5), 173 (32),
158 (14). Anal. (C19H19NO5) C, H, N.
5-Me t h oxy-1H -2-in d olyl-(2-m e t h oxyp h e n yl)-m e t h a -
n on e (2): beige crystals, 87%, mp 127 °C. IR (KBr): 3303,
3070, 2964, 2834, 1620, 1524 cm-1 1H-NMR (DMSO-d6): δ
.
3.73 (s, 3H), 3.75 (s, 3H), 6.67 (s, 1H), 6.93-6.98 (m, 1H), 7.04-
7.10 (m, 2H), 7.17-7.21 (m, 1H), 7.35-7.41 (m, 2H), 7.50-
7.57 (m, 1H), 11.77 (s, 1H). EI-MS (70 eV); m/z (%): 281 (100)
[M+•], 263 (14), 173 (27), 161 (29), 77 (19). Anal. (C17H15NO3)
C, H, N.
5-Me t h oxy-1H -2-in d olyl(2-m e t h ylp h e n yl)-1-m e t h a -
n on e (12): yellow crystals, 83%, mp 120 °C. IR (KBr): 3309,
1
1742, 1634 cm-1. H-NMR (DMSO-d6): δ 2.30 (s, 3H), 3.72 (s,
3H), 6.67 (s, 1H), 6.44-6.99 (m, 1H), 7.08-7.09 (m, 1H), 7.42-
7.52 (m, 5H), 11.85 (s, 1H). EI-MS (70 eV); m/z (%): 265 (100)
[M+•], 250 (25), 158 (9). Anal. (C17H15NO2) C, H, N.
5-Me t h oxy-1H -2-in d olyl-(3-m e t h oxyp h e n yl)-m e t h a -
n on e (3): yellow crystals, 8%, mp 147-148 °C. IR (KBr): 3294,
5-Me t h o x y -1H -2-in d o ly l-(4-m e t h y lp h e n y l)-m e t h a -
n on e (13): light yellow needles, 56%, mp 200 °C. IR (KBr):
3066, 2962, 2834, 1630, 1605, 1576 cm-1 1H-NMR (DMSO-
.
d6): δ 3.77 (s, 3H), 3.86 (s, 3H), 6.96-7.01 (m, 1H), 7.05-7.06
(m, 1H), 7.16-7.17 (m, 1H), 7.22-7.27 (m, 1H), 7.38-7.42 (m,
3295, 3066, 2968, 2838, 1624, 1609, 1522 cm-1 1H-NMR
.
(DMSO-d6): δ 2.42 (s, 3H), 3.75 (s, 3H), 6.96 (dd, J ) 2.4, 9.0

2-Aroylindole Derivatives as Tubulin-Inhibitory Agents
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26 4549
Hz, 1H), 7.01 (s, 1H), 7.14 (d, J ) 2.4 Hz, 1H), 7.37-7.41 (m,
3H), 7.81 (s, 1H), 7.84 (s, 1H), 11.81 (br. s, 1H). EI-MS (70
eV); m/z (%): 265 (100) [M+•], 250 (22), 130 (10), 91 (12). Anal.
(C17H15NO2) C, H, N.
7.38-8.04 (m, 5H), 7.60 (t, SCHF2, J HF ) 55.73 Hz, 1H), 11.92
(s, 1H). EI-MS (70 eV); m/z (%): 333 (100) [M+•]. Anal.
(C17H13F2NO2 S) C, H, N.
3-Tr iflu or om et h ylp h en yl-(5-m et h oxy-1H -2-in d olyl)-
m eth a n on e (21): yellow crystals, 24%, mp 193-195 °C. IR
2,5-Dim eth ylp h en yl-(5-m eth oxy-1H-2-in d olyl)-m eth a -
n on e (14): yellow needles, 64%, mp 152-153 °C. IR (KBr):
(KBr): 3307, 1622, 1526, 764 cm-1 1H-NMR (DMSO-d6): δ
.
3328, 3060, 2993 2833, 1634, 1620, 1522 cm-1
.
1H-NMR
3.74 (s, 3H), 6.96-7.03 (m, 2H), 7.15-7.16 (m, 1H), 7.38-7.42
(m, 1H), 7.78-7.85 (m, 1H), 8.02-8.05 (m, 1H), 8.13 (s, 1H),
8.18-8.22 (m, 1H), 11.96 (s, 1H). EI-MS (70 eV); m/z (%): 319
(100) [M•+], 304 (37), 173 (15), 145 (20). Anal. (C17H12F3NO2)
C, H, N.
(DMSO-d6): δ 2.26 (s, 3H), 2.34 (s, 3H), 3.74 (s, 3H), 6.70 (d,
J ) 3.9 Hz, 1H), 6.98 (dd, J ) 2.4, 9.0 Hz, 1H), 7.11 (d, J )
2.4 Hz, 1H), 7.22-7.41 (m, 4H), 11.82 (br. s, 1H). EI-MS (70
eV); m/z (%): 279 (100) [M+•], 262 (26), 132 (13), 77 (7). Anal.
(C18H17NO2) C, H, N.
5-Met h oxy-1H -2-in d olyl-(2-n it r op h en yl)-m et h a n on e
(22): yellow crystals, 40%, mp 185-187 °C. IR (KBr): 3299,
3-Ben zyloxyp h en yl-(5-m et h oxy-1H -2-in d olyl)-m et h a -
n on e (15): light yellow crystals, 92%, mp 150-151 °C. IR
3072, 2985, 2838, 1609, 1530, 1345 cm-1 1H-NMR (DMSO-
.
(KBr): 3294, 3068, 2956, 2832, 1629, 1600, 1528 cm-1
.
1H-
d6): δ 3.73 (s, 3H), 6.69 (s, 1H), 7.01 (dd, J ) 2.4, 9.0 Hz, 1H),
7.07-7.08 (m, 1H), 7.40 (d, J ) 9.0 Hz, 1H), 7.79-7.95 (m,
3H), 8.23-8.27 (m, 1H), 12.04 (br. S, 1H). EI-MS (70 eV); m/z
(%): 296 (65) [M•+], 162 (100), 134 (22), 104 (37), 76 (17). Anal.
(C16H12N2O4) C, H, N.
NMR (DMSO-d6): δ 3.76 (s, 3H), 5.22 (s, 2H), 6.88-6.89 (m,
1H), 6.95-6.99 (m, 1H), 7.10-7.11 (m, 1H), 7.30-7.50 (m,
10H), 11.82 (br. s, 1H). EI-MS (70 eV); m/z (%): 357 (32) [M•+],
266 (4), 91 (100). Anal. (C23H19NO3) C, H, N.
3-H yd r oxyp h e n yl-(5-m e t h oxy-1H -2-in d olyl)-m e t h a -
n on e (16): Compound 17 (1.00 g, 2.8 mmol) was dissolved in
THF/methanol 1/1 (20 mL). Ammonium formate (0.5 g, 8
mmol) and 10% Pd/C (0.8 g) was added and the reaction
mixture was stirred at 70 °C for 2 h. The catalyst was removed
by filtration through a Celite pad and washed with dry
methanol (10 mL). The filtrate was washed successively with
sat. sodium bicarbonate solution (40 mL) and water (3 × 30
mL), and the product was extracted with CH2Cl2 (3 × 30 mL).
After the sample was dried (Na2SO4), evaporation left the
desired alcohol, which was recrystallized from ethyl acetate/
ether/petrol ether.
2-Am in o p h e n y l-(5-m e t h o x y -1H -2-in d o ly l)-m e t h a -
n on e (23): yellow needles, 83%, mp 144-145 °C. IR (KBr):
3486, 3311, 3062, 2952, 2830, 1615, 1584 cm-1 1H-NMR
.
(DMSO-d6): δ 3.76 (s, 3 H), 6.60-6.67 (m, 3H), 6.83-6.96 (m,
3H), 7.15 (d, J ) 2.4 Hz, 1H), 7.26-7.41 (m, 2H), 7.82-7.86
(m, 1H), 11.69 (br. s, 1H). EI-MS (70 eV); m/z (%): 266 (100)
[M•+], 238 (49), 223 (26), 195 (14), 120 (17), 92 (21), 84 (32).
Anal. (C16H14N2O2) C, H, N.
5-Met h oxy-1H -2-in d olyl-(3-n it r op h en yl)-m et h a n on e
(24): yellow crystals, 85%, mp 221-222 °C. IR (KBr): 3326,
3089, 2950, 2832, 1603, 1520, 1343 cm-1 1H-NMR (DMSO-
.
d6): δ 3.76 (s, 3H), 6.98-7.03 (m, 1H), 7.11-7.15 (m, 2H),
7.39-7.43 (m, 1H), 7.84-7.90 (m, 1H), 8.31-8.35 (m, 1H),
8.48-8.52 (m, 1H), 8.59-8.61 (m, 1H), 12.00 (br. s, 1H). EI-
MS (70 eV); m/z (%): 296 (100) [M•+], 281 (31), 174 (23), 119
(14). Anal. (C16H12N2O4) C, H, N.
light yellow crystals, 74%, mp 167-168 °C. IR (KBr). ν 3363,
3288, 3070, 2960, 2833, 1619, 1590, 1522 cm-1 1H-NMR
.
(DMSO-d6): δ 3.75 (s, 3H), 6.94-7.07 (m, 3H), 7.15 (m, 1H),
7.28-7.29 (m, 1H), 7.31-7.40 (m, 3H), 9.83 (s, 1H), 11.80 (br.
s, 1H). EI-MS (70 eV); m/z (%):267 (100) [M+•], 252 (41), 174
3-Am in o p h e n y l-(5-m e t h o x y -1H -2-in d o ly l)-m e t h a -
n on e (25): orange crystals, 79%, mp 221-222 °C. IR (KBr):
3419, 3327, 3056, 2997, 2833, 1619, 1600, 1490 cm-1. 1H-NMR
(DMSO-d6): δ 3.75 (s, 3 H), 5.39 (s, 2H), 6.80-6.84 (m, 1H),
6.93-7.05 (m, 3H), 7.10-7.22 (m, 3H), 7.36-7.39 (m, 1H),
11.75 (s, 1H). EI-MS (70 eV); m/z (%): 266 (100) [M+•], 251
(17), 158 (16), 130 (14), 92 (16). Anal. (C16H14N2O2) C, H, N.
5-Meth oxy-1H-2-in dolyl-(2-m eth yl-3-n itr oph en yl)-m eth -
a n on e (26): yellow crystals, 55%, mp 199-200 °C. IR (KBr):
(10), 158 (21), 130 (29), 121 (23), 93 (22), 65 (26). Anal. (C16H13
NO3) C, H, N.
-
(3-(5-Me t h o x y -1H -2-in d o ly lc a r b o n y l)p h e n y l)p r o -
p a n oa te (17): Butanoic acid (0.11 g, 1.0 mmol) and pyridin
(1 mL) were added to a solution of 16 in dry ethyl acetate (20
mL). After the sample was stirred for 4 h at room temperature,
the mixture was quenched with concentrated hydrochloric acid
(5 mL) on ice (20 mL), and the product was extracted with
CH2Cl2 (3 × 20 mL). The combined organic phases were dried
(NaSO4), and the solvent was removed under reduced pressure.
The residue was chromatographed (SiO2, CH2Cl2) to give the
title compound, which was crystallized from CH2Cl2/hexane.
yellow crystals, 86%, mp. 124 °C. IR (KBr): 3299, 2964,
3340, 3076, 2935, 2833, 1622, 1524, 1358 cm-1 1H-NMR
.
(DMSO-d6): δ 2.36 (s, 3H), 3.74 (s, 3 H), 6.74 (s, 1H), 6.99-
7.03 (m, 1H), 7.09-7.10 (m, 1H), 7.39-7.42 (m, 1H), 7.58-
7.64 (m, 1H), 7.81-7.85 (m, 1H), 8.08-8.12 (m, 1H), 12.02 (br.
s, 1H). EI-MS (70 eV); m/z (%): 310 (100) [M+•], 293 (14), 147
(14), 119 (12). Anal. (C17H14N2O4) C, H, N.
2842, 1760, 1627, 1586, 1522 cm-1 1H-NMR (DMSO-d6): δ
.
0.95-1.01 (t, J ) 7.4 Hz, 3H), 1.61-1.75 (m, J ) 7.4, 7.3 Hz,
2H), 2.57-2.63 (t, J ) 7.3 Hz, 2H), 3.76 (s, 3H), 6.96-7.04 (m,
2H), 7.15-7.16 (m, 1H), 7.37-7.45 (m, 2H), 7.59-7.66 (m, 2H),
7.78-7.83 (m, 1H), 11.90 (br. s, 1H). EI-MS (70 eV); m/z (%):
337 (95) [M+•], 267 (94), 71 (75), 43 (100). Anal. (C20H19NO4):
C, H, N.
3-Am in o-2-m et h ylp h en yl-(5-m et h oxy-1H -2-in d olyl)-
m eth a n on e (27): brown crystals, 56%, mp 163-165 °C. IR
(KBr): 3431, 3317, 3074, 2935, 2840, 1617, 1590 cm-1 1H-
.
NMR (DMSO-d6): δ 1.97 (s, 3H), 3.72 (s, 3H), 5.08 (s, 2H),
6.63-6.67 (m, 2H), 6.77-6.81 (m, 1H), 6.93-7.09 (m, 3H),
7.27-7.38 (m, 1H), 11.75 (s, 1H). EI-MS (70 eV); m/z (%): 280
(100) [M+•], 265 (19), 106 (17). Anal. (C17H16N2O2) C, H, N.
5-Met h oxy-1H -2-in d olyl-(3-m et h oxy-2-n it r op h en yl)-
m eth a n on e (28): yellow crystals, 83%, mp 212 °C (dec). IR
(KBr): 3332, 3101, 3004, 2956, 2844, 1615, 1603, 1524, 1354
5-Met h oxy-1H -2-in d olyl-(3-t r iflu or om et h oxyp h en yl)-
m eth a n on e (18): yellow crystals, 31%, mp 145-149 °C. IR
(KBr): 3294, 1631, 1533, 1289, 841 cm-1 1H-NMR (DMSO-
.
d6): δ 3.75 (s, 3H), 6.97-7.04 (m, 2H), 7.14-7.16 (m, 1H),
7.38-7.41 (m, 1H), 7.66-7.79 (m, 3H), 7.92-7.96 (m, 1H),
11.92 (s, 1H). EI-MS (70 eV); m/z (%): 335 (100) [M+•]. Anal.
(C17H12F3NO3) C, H, N.
1
cm-1. H-NMR (DMSO-d6): δ 3.76 (s, 3H), 3.98 (s, 3 H), 6.94
(m, 1H), 7.02 (dd, J ) 2.4, 9.0 Hz, 1H), 7.13 (d, J ) 2.4 Hz,
1H), 7.39 (d, J ) 9.0 Hz, 1H), 7.44-7.48 (m, 1H), 7.60-7.64
(m, 1H), 7.73-7.79 (m, 1H), 11.98 (br. s, 1H). EI-MS (70 eV);
m/z (%): 326 (42) [M+•], 162 (100), 119 (20), 76 (13). Anal.
(C17H14N2O5) C, H, N.
3-(Tr iflu or om et h ylt h io)p h en yl-(5-m et h oxy-1H -2-in -
d olyl)-m eth a n on e (19): yellow crystals, 48%, mp >145 °C.
IR (KBr): 3291, 1652, 1518, 1323, 1176, 754 cm-1 1H-NMR
.
(DMSO-d6): δ 3.75 (s, 3H), 6.97-7.03 (m, 2H), 7.14-7.15 (m,
1H), 7.38-7.42 (m, 1H), 7.72-7.78 (m, 1H), 8.00-8.03 (m, 1H),
8.10-8.14 (m, 2H), 11.94 (s, 1H). EI-MS (70 eV); m/z (%): 351
(100) [M+•]. Anal. (C17H12F3NO2S) C, H, N.
4-E t h ylp h en yl-(5-m et h oxy-1H -in d ol-2-yl)-m et h a n on e
(29): yellow crystals, 52%, mp 154-155 °C. IR (KBr): ν ) 3317,
1
2833, 1613, 1601, 1522 cm-1. H-NMR (DMSO-d6): δ 1.25 (t,
J ) 7.6 Hz, 3H), 2.73 (q, J ) 7.6 Hz, 2H), 3.77 (s, 3H), 6.98
(dd, J ) 2.4, 9.0 Hz, 1H), 7.04 (s, 1H), 7.15 (d, J ) 2.4 Hz,
1H), 7.38-7.44 (m, 3H), 7.85 (s, 1H), 7.88 (s, 1H), 11.82 (br. s,
1H). EI-MS (70 eV); m/z (%): 279 (100) [M+•], 264 (20), 250
(40), 158 (41), 130 (25). Anal. (C19H19NO2) C, H, N.
3-(Diflu or om eth ylth io)ph en yl-(5-m eth oxy-1H-2-in dolyl)-
m eth a n on e (20): yellow crystals, 54%, mp 128-129 °C. IR
(KBr): 3305, 1647, 1514, 1302, 748 cm-1 1H-NMR (DMSO-
.
d6): δ 3.75 (s, 3H), 6.96-7.04 (m, 2H), 7.14-7.15 (m, 1H),

4550 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26
Mahboobi et al.
5-Me t h o x y -1H -2-in d o ly l-(4-p r o p y lp h e n y l)-m e t h a -
n on e (30): yellow needles, 70%, mp 145-146 °C. IR (KBr):
3299, 3068, 3035, 2989, 2833, 1624, 1609, 1524 cm-1. 1H-NMR
(DMSO-d6): δ 0.94 (t, J ) 7.3 Hz, 3H), 1.66 (m, 2H), 2.68 (t,
J ) 7.6 Hz, 2H), 3.77 (s, 3H), 6.98 (dd, J ) 2.4, 9.9 Hz, 1H),
7.04 (s, 1H), 7.16 (d, J ) 2.4 Hz, 1H), 7.39-7.42 (m, 3H), 7.84
(s, 1H), 7.88 (s, 1H), 11.82 (br. s, 1H). EI-MS (70 eV); m/z (%):
293 (100) [M+•], 278 (15), 250 (46), 158 (40), 130 (24), 91 (13).
Anal. (C19H19NO2) C, H, N.
3,4-Dich lor op h en yl-(5-m et h oxy-1H -2-in d olyl)-m et h a -
n on e (40): yellow crystals, mp 190-192 °C. IR (KBr): 3316,
1
2988, 2830, 1620, 1549 cm-1. H-NMR (DMSO-d6): δ 3.80 (s,
3H), 6.93-7.18 (m, 4H), 7.80-7.92 (m, 2H), 8.03-8.12 (m, 1H),
11.95 (s, 1H). EI-MS (70 eV); m/z (%): 319 (100) [M+•], 304
(31), 241 (10), 173 (16), 130 (15). Anal. (C16H11Cl2NO2 × 0.4
CH2Cl2) C, H, N.
1H-2-In d olyl-p h en yl-m eth a n on e (41): yellow crystals, mp
145-147 °C. IR (KBr): 3314, 3081, 1669, 1616 cm-1. 1H-NMR
(DMSO-d6): δ 7.08-7.16 (m, 2H), 7.29-7.37 (m, 1H), 7.48-
7.75 (m, 5H), 7.91-7.97 (m, 2H), 11.90 (s, 1H). EI-MS (70 eV);
m/z (%): 221 (100) [M+•], 204 (13), 144 (36), 89 (28), 77 (30).
Anal. (C15H11NO) C, H, N.
4-ter t-Bu t ylp h en yl-(5-m et h oxy-1H -2-in d olyl)-m et h a -
n on e (31): yellow crystals, mp 204-207 °C. IR (KBr): 3293,
3129, 3006, 2965, 1605, 1522 cm-1 1H-NMR (DMSO-d6): δ
.
1.35 (s, 9H), 3.76 (s, 3H), 6.95-7.06 (m, 3H), 7.40 (d, J ) Hz,
1H), 7.58-7.64 (m, 2H), 7.84-7.91 (m, 2H), 11.82 (s, 1H). EI-
MS (70 eV); m/z (%): 307 (100) [M+•], 292 (17), 250 (15), 174
(11), 158 (12). Anal. (C20H21NO2) C, H, N.
1H-2-In d olyl-(2-m eth oxyp h en yl)-m eth a n on e (42): yel-
low crystals, mp 129-130 °C. IR (KBr): 3305, 3064, 1634,
1
1620, 1595 cm-1. H-NMR (DMSO-d6): δ 3.75 (s, 3H), 6.76-
6.79 (m, 1H), 7.02-7.11 (m, 2H), 7.17-7.33 (m, 2H), 7.39-
7.58 (m, 3H), 7.64 (d, J ) 7.9 Hz, 1H), 11.91 (s, 1H). EI-MS
(70 eV); m/z (%): 251 (100) [M+•], 233 (73), 204 (32), 131 (69),
89 (50). Anal. (C16H13NO2 × 0.5 ethyl acetate): calcd. C 73.20,
H 5.80, N 4.74; found C 72.97, H 5.48, N 4.92.
5-Met h oxy-1H -2-in d olyl-(4-p en t yloxyp h en yl)-m et h a -
n on e (32): yellow crystals, mp 139-141 °C. IR (KBr): 3290,
1
3064, 2930, 1624, 1601 cm-1. H-NMR (DMSO-d6): δ 0.90 (t,
J ) 6.9 Hz, 3H), 1.30-1.47 (m, 4H), 1.75 (quint, J ) 6.9 Hz,
2H), 3.77 (s, 3H), 4.09 (t, J ) 6.8 Hz, 2H), 6.93-7.04 (m, 2H),
7.07-7.17 (m, 3H), 7.40 (m, 1H), 7.89-7.96 (m, 2H), 11.75 (s,
1H). EI-MS (70 eV); m/z (%): 337 (100) [M+•], 267 (9), 173 (37),
158 (17). Anal. (C21H23NO3) C, H, N.
1H-2-In d olyl-(2,4-d im eth oxyp h en yl)-m eth a n on e (43):
yellow crystals, mp 134-135 °C. IR (KBr): 3313, 3060, 2946,
1
1617, 1591 cm-1. H-NMR (DMSO-d6): δ 3.83 (s, 3H), 3.89 (s,
3H), 6.53-6.58 (m, 2H), 6.93-6.97 (m, 1H), 7.10-7.18 (m, 1H),
7.25-7.68 (m, 4H), 9.25 (bs, 1H). EI-MS (70 eV); m/z (%): 281
(100) [M+•], 263 (46), 250 (10), 165 (32), 143 (48), 131 (25). Anal.
(C17H15NO3 × 0.25 ethyl acetate): calcd. C 71.27, H 5.65, N
4.62; found C 71.19, H 5.44, N 4.81.
4-C h lo r o p h e n y l-(5-m e t h o x y -1H -2-in d o ly l)-m e t h a -
n on e (33): yellow crystals, mp 191-193 °C. IR (KBr): 3305,
1
3067, 2952, 1629, 1591 cm-1. H-NMR (DMSO-d6): δ 3.75 (s,
3H), 6.96-7.07 (m, 2H), 7.15 (d, J ) 2.3 Hz, 1H), 7.40 (d, J )
9.0 Hz, 1H), 7.62-7.69 (m, 2H), 7.90-7.97 (m, 2H), 11.90 (s,
1H). EI-MS (70 eV); m/z (%): 285 (100) [M+•], 270 (30), 158
(18), 139 (16). Anal. (C16H12ClNO2) C, H, N.
1H-2-In dolyl-(3,4,5-tr im eth oxyph en yl)-m eth an on e (44):
yellow crystals, mp 148-150 °C. IR (KBr): 3319, 3011, 2942,
1
1619, 1582 cm-1. H-NMR (DMSO-d6): δ 3.95 (s, 6H), 3.96 (s,
4-B r o m o p h e n y l-(5-m e t h o x y -1H -2-in d o ly l)-m e t h a -
n on e (34): yellow crystals, mp 188-190 °C. IR (KBr): 3305,
3H), 7.15-7.22 (s, 2H), 7.25-7.28 (m, 2H), 7.35-7.52 (m, 2H),
7.72-7.78 (m,1H), 9.31 (bs, 1H). EI-MS (70 eV); m/z (%): 311
1
3052, 2950, 1630, 1588 cm-1. H-NMR (DMSO-d6): δ 3.75 (s,
(100) [M+•], 296 (8), 168 (15), 144 (17). Anal. (C18H17NO4
0.25 ethyl acetate): calcd. C 68.46, H 5.75, N 4.20; found C
68.11, H 5.39, N 4.42.
×
3H), 6.97-7.06 (m, 2H), 7.14 (d, J ) 2.4 Hz, 1H), 7.41 (d, J )
9.0 Hz, 1H), 7.76-7.89 (m, 4H), 11.90 (s, 1H). EI-MS (70 eV);
m/z (%): 329 (100) [M+•], 314 (28), 250 (13), 207 (19), 158 (30).
Anal. (C16H12BrNO2) C, H, N.
2-Me t h o x y p h e n y l-(3-m e t h y l-1H -2-in d o ly l)-m e t h a -
n on e (45): pale yellow-reddish crystals, 62%, mp 152-153 °C.
IR (KBr): 3319, 1637, 1562 cm-1. 1H-NMR (DMSO-d6): δ 1.99
(s, 3H), 3.71 (s, 3H), 7.00-7.63 (m, 8H), 11.39 (s, 1H). EI-MS
(70 eV); m/z (%): 265 (100) [M+•], 250 (34). Anal. (C17H15NO2)
C, H, N.
2-F lu o r o p h e n y l-(5-m e t h o x y -1H -2-in d o ly l)-m e t h a -
n on e (35): yellow crystals, 30%, mp 145 °C. IR (KBr): 3313,
1632, 1526, 1231, 754 cm-1 1H-NMR (DMSO-d6): δ 3.73 (s,
.
3H), 6.84 (s, 1H), 6.96-7.00 (m, 1H), 7.10-7.11 (m, 1H), 7.33-
7.43 (m, 3H), 7.60-7.71 (m, 2H), 11.94 (s, 1H). EI-MS (70 eV);
m/z (%): 269 (100) [M+•], 254 (36), 123 (19). Anal. (C16H12FNO2)
C, H, N.
3-Me t h o x y p h e n y l-(3-m e t h y l-1H -2-in d o ly l)-m e t h a -
n on e (46): pale yellow-reddish crystals, 80%, mp 131 °C. IR
(KBr): 3340, 1636, 1524 cm-1 1H-NMR (DMSO-d6): δ 2.25
.
3-F lu o r o p h e n y l-(5-m e t h o x y -1H -2-in d o ly l)-m e t h a -
n on e (36): yellow crystals, 49%, mp 154-156 °C. IR (KBr):
3319, 1630, 1519, 1234, 752 cm-1. 1H-NMR (DMSO-d6): δ 3.75
(s, 3H), 6.95-7.00 (m, 1H), 7.05 (s, 1H), 7.13-7.14 (m, 1H),
7.37-7.40 (m, 1H), 7.48-7.77 (m, 4H), 11.88 (s, 1H). EI-MS
(70 eV); m/z (%): 269 (100) [M+•]. Anal. (C16H12FNO2) C, H,
N.
4-F lu o r o p h e n y l-(5-m e t h o x y -1H -2-in d o ly l)-m e t h a -
n on e (37): yellow crystals, 88%, mp 168 °C. IR (KBr): 3397,
1626, 1601, 1588, 1236, 762 cm-1. 1H-NMR (DMSO-d6): δ 3.75
(s, 3H), 6.95-7.03 (m, 2H), 7.13-7.14 (m, 1H), 7.37-7.43 (m,
3H), 7.96-8.02 (m, 2H), 11.85 (s, 1H). EI-MS (70 eV); m/z (%):
269 (100) [M+•], 254 (34), 123 (21). Anal. (C16H12FNO2) C, H,
N.
(s, 3H), 3.81 (s, 3H), 7.04-7.10 (m, 1H), 7.19-7.52 (m, 6H),
7.64-7.67 (m, 1H), 11.44 (s, 1H). EI-MS (70 eV); m/z (%): 265
(100) [M+•], 158 (14). Anal. (C17H15NO2) C, H, N.
2,4-Dim eth oxyp h en yl-(3-m eth yl-1H-2-in d olyl)-m eth a -
n on e (47): pale yellow crystals, 33%, mp 124-126 °C. IR
(KBr): 3327, 1629, 1572 cm-1 1H-NMR (DMSO-d6): δ 2.07
.
(s, 3H), 3.70 (s, 3H), 3.84 (s, 3H). 6.62-6.69 (m, 2H), 6.99-
7.06 (m, 1H), 7.21-7.28 (m, 2H), 7.37-7.40 (m, 1H), 7.58-
7.63 (m, 1H), 11.30 (s, 1H). EI-MS (70 eV); m/z (%): 295 (100)
[M+•], 165 (23). Anal. (C18H17NO3) C, H, N.
3,4,5-Tr im eth oxyp h en yl-(3-m eth yl-1H-2-in d olyl)-m eth -
a n on e (48): pale yellow crystals, 6%, mp 138-144 °C. IR
(KBr): 3324, 1639, 1534 cm-1 1H-NMR (DMSO-d6): δ 2.32
.
(s, 3H), 3.76 (s, 3H), 3.82 (s, 6H), 7.05 (s,2H) 7.06-7.10 (m,
1H), 7.24-7.28 (m, 1H), 7.30-7.7.44 (m, 1H), 7.64-7.68 (m,
1H), 11.44 (s, 1H). EI-MS (70 eV); m/z (%): 325 (100) [M+•],
294 (35). Anal. (C19H19NO4) C, H, N.
2,6-Diflu or op h en yl-(5-m eth oxy-1-1H-2-in d olyl)-m eth a -
n on e (38): yellow crystals, 59%, mp 165-172 °C. IR (KBr):
3336, 1626, 1234, 793 cm-1 1H-NMR (DMSO-d6): δ 3.72 (s,
.
3H), 6.88 (s, 1H), 6.99-7.04 (m, 1H), 7.09-7.11 (m, 1H), 7.25-
7.41 (m, 3H), 7.60-7.73 (m, 1H), 12.07 (s, 1H). EI-MS (70 eV);
m/z (%): 287 (100) [M+•], 272 (24), 158 (18). Anal. (C16H11F2-
NO2) C, H, N.
4-Me t h oxy-1H -2-in d olyl-(3-m e t h oxyp h e n yl)-m e t h a -
n on e (49): yellow needles, 90%, mp 148 °C. IR (KBr): 3315,
3060, 2941, 2838, 1615, 1574 cm-1 1H-NMR (DMSO-d6): δ
.
3.84 (s, 3H), 3.87 (s, 3H), 6.53-6.56 (m, 1H), 7.02-7.08 (m,
2H), 7.20-7.27 (m, 2H), 7.35-7.37 (m, 1H), 7.48-7.51 (m, 2H),
12.00 (br. s, 1H). EI-MS (70 eV); m/z (%): 281 (100) [M+•], 266
(35), 158 (28), 130 (21), 77 (15). Anal. (C17H15NO3) C, H, N.
2-Me t h o x y p h e n y l-(5-m e t h y l-1H -2-in d o ly l)-m e t h a -
n on e (50): pale yellow crystals, 85%, mp 165-167 °C. IR
2-Ch lor o-6-flu or op h e n yl-(5-m e t h oxy-1H -2-in d olyl)-
m eth a n on e (39): yellow crystals, 32%, mp 168-170 °C. IR
(KBr): 3328, 3078, 2958, 2834, 1618, 1528 cm-1 1H-NMR
.
(DMSO-d6): δ 3.73 (s, 3H), 6.81 (s, 1H), 7.03 (dd, J ) 2.5, 9.0
Hz, 1H), 7.10 (d, J ) 2.5 Hz, 1H), 7.37-7.53 (m, 3H), 12.09
(br. s, 1H). EI-MS (70 eV); m/z (%): 303 (100) [M+•], 288 (19),
158 (24), 130 (20). Anal. (C16H11NO2ClF) C, H, N.
(KBr): 3325, 1638, 1574 cm-1 1H-NMR (DMSO-d6): δ 2.33
.
(s, 3H), 3.72 (s, 3H), 6.65 (s, 1H), 7.02-7.19 (m, 3H), 7.33-

2-Aroylindole Derivatives as Tubulin-Inhibitory Agents
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26 4551
7.40 (m, 3H), 7.48-7.55 (m, 1H), 11.78 (s, 1H). EI-MS (70 eV);
m/z (%): 265 (100) [M+•], 158 (12). Anal. (C17H15NO2) C, H, N.
3-Me t h o x y p h e n y l-(5-m e t h y l-1H -2-in d o ly l)-m e t h a -
n on e (51): pale yellow crystals, 25%, mp 192-202 °C. IR
252 (100) [M+•], 234 (35), 135 (34), 133 (52), 77 (31). Anal.
(C15H12N2O2) C, H, N.
(1H -P yr r olo[2,3-b ]p yr id in -2-yl)-(3-m et h oxyp h en yl)-
m eth a n on e (61): colorless crystals, mp 166-168 °C. IR
(KBr): 3250-2700, 3066, 2971, 2890, 2834, 1644, 1605, 1578
(KBr): 3316, 1632, 1516 cm-1 1H-NMR (DMSO-d6): δ 2.42
.
cm-1 1H-NMR (CDCl3): δ 3.91 (s, 3H), 7.14 (d, J ) 2.1 Hz,
.
(s, 3H), 3.82 (s, 3H), 7.05-7.17 (m, 2H), 7.23-7.25 (m, 1H),
7.30-7.47 (m, 3H), 7.87-7.88 (m, 1H), 8.05 (s, 1H), 11.92 (s,
1H). EI-MS (70 eV); m/z (%): 265 (66) [M+•], 158 (100). Anal.
(C17H15NO2) C, H, N.
1H), 7.18 (ddd, J ) 8.2 Hz, J ) 2.6 Hz, J ) 1.1 Hz, 1H), 7.21
(dd, J ) 8.0 Hz, J ) 4.7 Hz, 1H), 7.46 (ddd, J ) 8.2 Hz, J )
7.6 Hz, J ) 0.4 Hz, 1H), 7.52 (dd, J ) 2.6 Hz, J ) 1.4 Hz, 1H),
7.61 (ddd, J ) 7.6 Hz, J ) 1.4 Hz, J ) 1.1 Hz, 1H), 8.11 (dd,
J ) 8.0 Hz, J ) 1.6 Hz, 1H), 8.83 (dd, J ) 4.7 Hz, J ) 1.6 Hz,
1H), 12.52 (br. s, 1H). EI-MS (70 eV); m/z (%): 252 (100) [M+•],
237 (16), 211 (29), 145 (29), 77 (11). Anal. (C15H12N2O2 × 1/6
H2O): calcd. C 70.58, H 4.87, N 10.97; found C 70.62, H 4.93,
N 10.95.
3,4,5-Tr im eth oxyp h en yl-(5-m eth yl-1H-2-in d olyl)-m eth -
a n on e (52): pale yellow crystals, 60%, mp 202-203 °C. IR
(KBr): 3315, 1627, 1522, 1028, 841, 756 cm-1 1H-NMR
.
(DMSO-d6): δ 2.36 (s, 3H), 3.76 (s, 3H), 3.86 (s, 6H), 7.11-
7.15 (m 2H), 7.20 (s, 2H), 7.36-7.39 (m, 1H), 7.47 (s, 1H), 11.82
(s, 1H). EI-MS (70 eV); m/z (%): 325 (100) [M+•], 168 (34), 158
(32). Anal. (C19H19NO4) C, H, N.
(1H-P yr r olo[2,3-b]pyr idin -2-yl)-(2,4-dim eth oxyph en yl)-
m eth a n on e (62): colorless powder, mp 206-210 °C (dec). IR
5-Ben zyloxy-1H-2-in d olyl-p h en yl-m eth a n on e (53): yel-
low crystals, mp 187-188 °C. IR (KBr): 3299, 3031, 2861,
(KBr): 3300-2700, 3289, 3068, 2967 1634, 1609, 1559 cm-1
.
1
1600, 1570 cm-1. H-NMR (DMSO-d6): δ 5.10 (s, 2H), 7.00-
1H-NMR (CDCl3): δ 3.30 (s, 3H), 3.78 (s, 3H), 6.28 (s, 1H),
6.34 (d, J ) 2.5 Hz, 1H), 6.56 (dd, J ) 8.6 Hz, J ) 2.4 Hz, 1H),
7.14 (dd, J ) 7.9 Hz, J ) 4.8 Hz, 1H), 7.30-7.40 (m, 2H), 7.44-
7.50 (m, 2H), 7.71 (d, J ) 8.6 Hz, 1H), 7.73 (dd, J ) 7.9 Hz, J
) 1.6 Hz, 1H), 8.05-8.18 (m, 1H), 8.44 (dd, J ) 4.8 Hz, J )
1.6 Hz, 1H). EI-MS (70 eV); m/z (%): 282 (100) [M+•], 264 (38),
165 (46), 150 (17), 132 (34). Anal. (C16H14N2O3) C, H, N.
7.10 (m, 2H), 7.22-7.50 (m, 6H), 7.54-7.72 (m, 4H), 7.88-
7.94 (m, 2H); 11.90 (s, 1H). EI-MS (70 eV); m/z (%): 327 (60)
[M+•], 236 (100), 158 (15), 130 (17), 105 (22), 91 (98). Anal.
(C22H17NO2 × 0.15 ethyl acetate): calcd. C 79.70, H 5.39, N
4.11; found C 79.79, H 5.32, N 4.24.
5-Ben zyloxy-1H -2-in d olyl-(2-m et h oxyp h en yl)-m et h a -
n on e (54): colorless powder, mp 150-151 °C. IR (KBr): 3276,
(1H-P yr r olo[2,3-b]pyr idin -2-yl)-(3,4,5-tr im eth oxyph en -
yl)-m eth a n on e (63): colorless crystals, mp 204-206 °C. IR
1
3069, 2937, 2836, 1628, 1518 cm-1. H-NMR (CDCl3): δ 3.83
(s, 3H), 5.08 (s, 2H), 6.82 (d, J ) 1.2 Hz, 1H), 7.01-7.10 (m,
4H), 7.28-7.52 (m, 8H), 9.18 (br. s, 1H). EI-MS (70 eV); m/z
(KBr): 3250-2700, 3068, 2962, 2836, 1642, 1605, 1586 cm-1
.
1H-NMR (CDCl3): δ 3.96 (s, 6H), 3.98 (s, 3H), 7.16 (d, J ) 1.9
Hz, 1H), 7.23 (dd, J ) 8.0 Hz, J ) 4.7 Hz, 1H), 7.30 (s, 2H),
8.13 (dd, J ) 4.7 Hz, J ) 1.6 Hz, 1H), 8.82 (dd, J ) 4.7 Hz, J
) 1.6 Hz, 1H), 12.70 (br. s, 1H). EI-MS (70 eV); m/z (%): 312
(100) [M+•], 297 (16), 281 (25), 145 (16). Anal. (C17H16N2O4) C,
H, N.
(%): 357 (67) [M+•], 268 (87), 158 (71), 91 (100). Anal. (C23H19
NO3) C, H, N.
-
5-Ben zyloxy-1H -2-in d olyl-(3-m et h oxyp h en yl)-m et h a -
n on e (55): colorless powder, mp 153-154 °C. IR (KBr): 3303,
1
3062, 2905, 2861, 1629, 1520 cm-1. H-NMR (CDCl3): δ 3.89
(s, 3H), 5.10 (s, 2H), 7.04-7.18 (m, 4H), 7.30-7.49 (m, 8H),
7.56 (m, 1H), 9.24 (br. s, 1H). EI-MS (70 eV); m/z (%): 357
(67) [M+•], 268 (87), 158 (71), 91 (100). Anal. (C23H19NO3) C,
H, N.
2-Meth oxyph en yl-(5-m eth oxy-1H-pyr r olo[3,2-b]pyr idin -
2-yl)-m eth a n on e (64): colorless needles, 53%, mp 190 °C. IR
(KBr): 3294, 3076, 2944, 2840, 1627, 1600, 1522 cm-1 1H-
.
NMR (DMSO-d6): δ 3.75 (s, 3H), 3.83 (s, 3H), 6.64 (s, 1H),
6.77-6.81 (m, 1H), 7.04-7.10 (m, 1H), 7.17-7.21 (m, 1H),
7.39-7.43 (m, 1H), 7.50-7.54 (m, 1H), 7.76-7.80 (m, 1H),
12.02 (br. s, 1H). EI-MS (70 eV); m/z (%): 282 (100) [M+•], 263
(31), 251 (11), 173 (26), 162 (26), 135 (23), 77 (30). Anal.
(C16H14N2O3) C, H, N.
5-Ben zyloxy-1H -2-in d olyl-(4-m et h oxyp h en yl)-m et h a -
n on e (56): yellow crystals, mp 155-157 °C. IR (KBr): 3318,
1
3017, 2929, 1622, 1589 cm-1. H-NMR (DMSO-d6): δ 3.85 (s,
3H), 5.08 (s, 2H), 6.96-7.50 (m, 11H), 7.91 (s, 1H), 7.97 (s,
1H), 11.80 (s, 1H). EI-MS (70 eV); m/z (%): 357 (78) [M+•], 266
(100), 158 (70) 135 (28), 130 (29), 91 (91). Anal. (C23H19NO3 ×
0.5 ethyl acetate): calcd. C 74.79, H 5.77, N 3.49; found C
74.73, H 5.24, N 3.77.
3-Meth oxyph en yl-(5-m eth oxy-1H-pyr r olo[3,2-b]pyr idin -
2-yl)-m eth a n on e (65): light yellow crystals, 77%, mp 150 °C.
1
IR (KBr): 3297, 3074, 2983, 2836, 1623, 1522 cm-1. H-NMR
5-Ben zyloxy-1H -2-in d olyl-(3,4,5-t r im et h oxyp h en yl)-
m eth a n on e (57): yellow crystals, mp 165-167 °C. IR (KBr):
(DMSO-d6): δ 3.85 (s, 3H), 3.87 (s, 3H), 6.80-6.84 (m, 1H),
7.04 (s, 1H), 7.23-7.27 (m, 1H), 7.39-7.40 (m, 1H), 7.49-7.56
(m, 2H), 7.79-7.83 (m, 1H), 12.10 (br. s, 1H). EI-MS (70 eV);
m/z (%): 282 (100) [M+•], 253 (29), 173 (13), 145 (14), 135 (20),
77 (17). Anal. (C16H14N2O3) C, H, N.
3299, 3067, 2977, 1605, 1582 cm-1 1H-NMR (DMSO-d6): δ
.
3.77 (s, 3H), 3.87 (s, 6H), 5.08 (s, 2H), 7.02-7.07 (m, 1H), 7.13-
7.16 (m, 1H), 7.20-7.49 (m, 9H), 11.81 (s, 1H). EI-MS (70 eV);
m/z (%): 417 (61) [M+•], 326 (90), 158 (67), 130 (28), 91 (100).
Anal. (C25H23NO5) C, H, N.
2,4-Dim eth oxyp h en yl(5-m eth oxy-1H-p yr r olo[3,2-b]p y-
r id in -2-yl)-m eth a n on e (66): colorless needles, 46%, mp 100
°C (dec). IR (KBr): 3299, 3095, 3004, 2970, 2840, 1607, 1520
5-Be n zyloxy-1H -2-in d olyl-(3-ch lor op h e n yl)-m e t h a -
n on e (58): yellow crystals, mp 163-165 °C. IR (KBr): 3301,
1
cm-1 1H-NMR (DMSO-d6): δ 3.75 (s, 3H), 3.84 (s, 3H), 3.85
.
3062, 2861, 1629, 1566 cm-1. H-NMR (DMSO-d6): δ 5.10 (s,
(s, 3H), 6.61-6.65 (m, 1H), 6.69-6.71 (m, 2H), 6.75-6.78 (m,
1H), 7.41-7.44 (m, 1H), 7.74-7.78 (m, 1H), 11.92 (br. s, 1H).
EI-MS (70 eV); m/z (%): 312 (100) [M+•], 294 (37), 265 (16),
138 (36), 77 (13). Anal. (C17H16N2O4) C, H, N.
2H), 7.02-7.50 (m, 8H), 7.57-7.98 (m, 5H), 11.95 (s, 1H). EI-
MS (70 eV); m/z (%): 361 (39) [M+•], 270 (37), 207 (8), 91 (100).
Anal. (C22H16ClNO2 × 0.4 CH2Cl2): calcd. C 67.97, H 4.28, N
3.54; found C 67.51, H 4.42, N 3.53.
3,4,5-Tr im eth oxyp h en yl-(5-m eth oxy-1H-p yr r olo[3,2-b]-
p yr id in -2-yl)-m eth a n on e (67): light yellow needles, 68%, mp
5-Be n zyloxy-1H -2-in d olyl-(4-ch lor op h e n yl)-m e t h a -
n on e (59): yellow crystals, mp 188-190 °C. IR (KBr): 3303,
233 °C. IR (KBr): 3303, 2943, 2838, 1623, 1582, 1506 cm-1
.
1
3035, 2859, 1618, 1589 cm-1. H-NMR (DMSO-d6): δ 5.10 (s,
1H-NMR (DMSO-d6): δ 3.77 (s, 3H), 3.88 (s, 9H), 6.79-6.83
(m, 1H), 7.15 (s, 1H), 7.23 (s, 2H), 7.79-7.83 (m, 1H), 12.08
(br. s, 1H). EI-MS (70 eV); m/z (%): 342 (100) [M+•], 175 (11).
Anal. (C18H18N2O5) C, H, N.
2H), 7.02-7.11 (m, 2H), 7.22-7.49 (m, 7H), 7.65 (m, 2H), 7.93
(m, 2H), 11.92 (s, 1H). EI-MS (70 eV); m/z (%): 361 (28) [M+•],
270 (31), 207 (6), 139 (9), 91 (100). Anal. (C22H16ClNO2) C, H,
N.
(1H -P yr r olo[2,3-b ]p yr id in -2-yl)-(2-m et h oxyp h en yl)-
m eth a n on e (60): beige crystals, mp 211-213 °C. IR (KBr):
3250-2700, 3079, 2980, 2838, 1646, 1602, 1578 cm-1. 1H-NMR
(CDCl3): δ 3.84 (s, 3H), 6.88 (d, J ) 2.1 Hz, 1H), 7.01-7.10
(m, 2H), 7.17 (dd, J ) 8.0 Hz, J ) 4.7 Hz, 1H), 7.40-7.56 (m,
2H), 8.03 (dd, J ) 8.0 Hz, J ) 1.6 Hz, 1H), 8.82 (dd, J ) 4.7
Hz, J ) 1.6 Hz, 1H), 12.49 (br. s, 1H). EI-MS (70 eV); m/z (%):
Cyclopr opyl-(5-m eth oxy-1H-2-in dolyl)-m eth an on e (68):
yellow crystals, mp 205-207 °C. IR (KBr): 3307, 2965, 1634,
1
1526 cm-1. H-NMR (DMSO-d6): δ 0.97-1.08 (m, 4H), 2.76-
2.87 (m, 1H), 3.77 (s, 3H), 6.91-6.97 (m, 1H), 7.11-7.15 (m,
1H), 7.31-7.42 (m, 2H), 11.6 (s, 1H). EI-MS (70 eV); m/z (%):
215 (100) [M+•], 200 (21), 174 (22), 172 (8), 119 (19). Anal.
(C13H13NO2) C, H, N.

4552 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26
Mahboobi et al.
Cyclobu tyl-(5-m eth oxy-1H-2-in d olyl)-m eth a n on e (69):
yellow crystals, mp 175-179 °C. IR (KBr): 3299, 3066, 2938,
7H), 6.68-6.70 (m, 1H), 6.80-6.87 (m, 1H), 7.04-7.07 (m, 1H),
7.23-7.38 (m, 6H), 11.40 (s, 1H). EI-MS (70 eV); m/z (%): 349
(28) [M+•], 216 (15), 174 (30), 146 (74), 91 (100). Anal.
(C21H23N3O2 × 0.2 ethyl acetate): calcd. C 71.34, H 6.76, N
11.45; found C 71.69, H 6.66, N 11.68.
P r oced u r e F : P r ep a r a tion of N-Su bstitu ted Der iva -
tives 77-81: At 0 °C, sodium hydride (60% suspension in
paraffin oil) (80 mg, 2.0 mmol) was added to 1 (0.35 g, 1.4
mmol) in 10 mL of anhydrous THF. After 30 min, the alkyl
chloride (5.0 mmol) was added, and the reaction mixture was
stirred for 10 h at room temperature. Water was carefully
added, and the mixture was poured into sat. sodium bicarbon-
ate solution (50 mL). The organic layer was separated, the
aqueous layer was extracted with ethyl acetate (3 × 15 mL),
and the combined organic layers were dried (Na2SO4). Removal
of the solvent resulted in yellow crystals that were subjected
to flash chromatography (SiO2; ethyl acetate/hexane).
1
1642, 1524 cm-1. H-NMR (DMSO-d6): δ 1.75-2.35 (m, 6H),
3.76 (s, 3H), 3.97-4.12 (m, 1H), 6.89-6.96 (m, 1H), 7.10-7.18
(m, 2H), 7.32-7.38 (m, 1H), 11.55 (s, 1H). EI-MS (70 eV); m/z
(%): 229 (100) [M+•], 201 (9), 186 (10), 174 (70), 146 (12). Anal.
(C14H15NO2) C, H, N.
(5-Me t h o x y -1H -2-in d o ly l)-1-n a p h t h a le n y l-m e t h a -
n on e (70): yellow crystals, mp 174-175 °C. IR (KBr): 3301,
1
3050, 1611, 1574, 1518 cm-1. H-NMR (DMSO-d6): δ 3.72 (s,
3H), 6.76 (s, 1H), 6.98-7.12 (m, 2H), 7.40-7.47 (m, 1H), 7.53-
7.70 (m, 3H), 7.82-7.89 (m, 1H), 8.03-8.20 (m, 3H), 12.02 (s,
1H). EI-MS (70 eV); m/z (%): 301 (100) [M+•], 300 (47), 284
(13); 158 (11), 127 (26). Anal. (C20H15NO2) C, H, N.
(5-Meth oxy-1H-in d ol-2-yl)-2-p yr id in yl-m eth a n on e (71):
yellow crystals, 65%, mp 201 °C. IR (KBr): 3328, 3067, 1649
cm-1. 1H-NMR (DMSO-d6): δ 3.73 (s, 3H), 7.98-8.04 (m, 1H),
8.12-8.22 (m, 2H), 8.31-8.39 (m, 2H), 8.53-8.60 (m, 1H),
8.69-8.71 (m, 1H), 8.83-8.85 (m, 1H), 11.84 (s, 1H). EI-MS
(70 eV); m/z (%): 252 (100) [M+•], 237 (18), 173 (88), 158 (49),
77 (13). Anal. (C15H12N2O2) C, H, N.
(5-Met h oxy-1-(2-d im et h yla m in oet h yl)-1H -2-in d olyl)-
p h en yl-m eth a n on e (77): yellow wax, mp 38-40 °C. IR
1
(KBr): 3023, 2948, 2822, 1638, 1597 cm-1. H-NMR (DMSO-
d6): δ 2.10 (s, 6H), 2.51 (t, J ) 6.7 Hz, 2H), 3.76 (s, 3H), 4.61
(t, J ) 6.7 Hz, 2H), 6.85 (s, 1H), 7.01-7.09 (m, 1H), 7.13-7.18
(m, 1H), 7.53-7.73 (m, 4H), 7.82-7.87 (m, 2H). EI-MS (70 eV);
m/z (%): 322 (7) [M+•], 264 (1), 251 (6), 58 (100). Anal.
(C20H22N2O2) C, H, N.
4-I s o q u in o lin y l-(5-m e t h o x y -1-H -2-in d o ly l)-m e t h a -
n on e (72): yellow crystals, 75%, mp 228-230 °C. IR (KBr):
3058, 2952, 2827, 1630, 1503 cm-1 1H-NMR (DMSO-d6): δ
.
3.73 (s, 3H), 6.88 (m, 1H), 6.98-7.03 (m, 1H), 7.09-7.10 (m,
1H), 7.40-7.44 (m, 1H), 7.75-7.90 (m, 2H), 8.10-8.13 (m, 1H),
8.26-8.30 (m, 1H), 8.83 (s, 1H), 9.53 (s, 1H), 12.07 (br. s, 1H).
EI-MS (70 eV); m/z (%): 302 (100) [M+•], 287 (13), 128 (22).
Anal. (C19H14N2O2) C, H, N.
(5-Meth oxy-1-(3-d im eth yla m in op r op yl)-1H-2-in d olyl)-
p h en yl-m eth a n on e (78): yellow wax, mp 51-52 °C. IR
1
(KBr): 3050, 2927, 1643, 1597, 1576 cm-1. H-NMR (DMSO-
d6): δ 1.86 (quint, J ) 6.9 Hz, 2H), 2.08 (s, 6H), 2.19 (t, J )
6.9 Hz, 2H), 3.75 (s, 3H), 4.55 (t, J ) 7.0 Hz, 2H), 6.90 (s. 1H),
7.02-7.08 (m, 1H),7.17 (d, J ) 3.6 Hz, 1H), 7.53-7.72 (m, 4H),
7.82-7.88 (m, 2H). EI-MS (70 eV); m/z (%): 336 (31) [M+•],
265 (57), 160 (18), 84 (30), 72 (19), 58 (100). Anal. (C21H24N2O2
× 0.4 ethyl acetate): calcd. C 73.03, H 7.38, N 7.54; found C
72.75, H 7.23, N 7.71.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e 5-Meth -
oxy-1H-2-in d oleca r boxa m id es 73-76: The respective pip-
erazine derivative (2.0 mmol) was dissolved in diethyl ether
(15 mL). A solution of 0.49 g (2.33 mmol) 5-methoxy-1H-2-
indolecarboxylic acid chloride in benzene (10 mL) was added,
and the reaction mixture was stirred for 20 h at room
temperature. The mixture was poured in 5% aq NaOH (100
mL), and the product was extracted with ethyl acetate (150
mL). After the sample was dried (Na2SO4), 95% of the solvent
was removed in vacuo and the residue was treated with diethyl
ether (50 mL). The resulting colorless crystals were collected
by filtration and washed with diethyl ether.
(5-Meth oxy-1-(2-p yr r olid in oeth yl)-1H-2-in d olyl)-p h en -
yl-m eth a n on e (79): yellow wax, mp 68-71 °C. IR (KBr):
3066, 2971, 2956, 1638, 1578 cm-1 1H-NMR (DMSO-d6): δ
.
1.43-1.54 (m, 4H), 2.37-2.48 (m, 4 H), 2.69 (t, J ) 6.5 Hz,
2H), 4.63 (t, J ) 6.5 Hz, 2H), 6.83 (s, 1H),7,00-7.07 (m, 1H),
7.14-7.18 (m, 1H), 7.52-7.73 (m, 4H), 7.83-7.89 (m, 2H). EI-
MS (70 eV); m/z (%): 348 (14) [M+•], 97 (6), 84 (100). Anal.
(C22H24N2O2) C, H, N.
N-4-(2-Meth oxyp h en yl)p er h yd r o-1-p yr a zin yl-5-m eth -
oxy-1H-2-in d oleca r boxa m id e (73): colorless crystals, mp
186.189 °C. IR (KBr): 3284, 2836, 1601 cm-1 1H-NMR
.
(5-Meth oxy-1-(2-p ip er id in oeth yl)-1H-2-in d olyl)-p h en -
yl-m eth a n on e (80): yellow wax, mp 55-57 °C. IR (KBr):
(DMSO-d6): δ 2.98-3.05 (m, 4H), 3.75 (s, 3H), 3.80 (s, 3H),
3.83-3.95 (m, 4H), 6.72-6.77 (m, 1H), 6.82-7.08 (m, 6H),
7.29-7.37 (m, 1H), 11.45 (s, 1H). EI-MS (70 eV); m/z (%): 365
(39) [M+•], 216 (7), 175 (34), 162 (100), 134 (29). Anal.
(C21H23N3O3 × 0.33 ethyl acetate): calcd. C 67.95, H 6.55, N
10.65; found C 67.74, H 6.21, N 10.98.
3067, 2929, 2834, 1636, 1597 cm-1 1H-NMR (DMSO-d6): δ
.
1.20-1.34 (m, 6H), 2.23-2.35 (m, 4H), 2.53 (t, J ) 6.5 Hz, 2H),
3.75 (m, 3H), 4.65 (t, J ) 6.5 Hz, 2H), 6.83 (s, 1H),7,00-7.07
(m, 1H), 7.14-7.18 (m, 1H), 7.52-7.73 (m, 4H), 7.83-7.89 (m,
2H). EI-MS (70 eV); m/z (%): 362 (9) [M+•], 251 (2), 99 (8), 98
(100). Anal. (C23H26N2O2 × 0.15 ethyl acetate): calcd. C 75.45,
H 7.30, N 7.46; found C 75.44, H 7.22, N 7.57.
N-4-(2-P yr a zin yl)p er h yd r o-1-p yr a zin yl-5-m eth oxy-1H-
2-in d oleca r boxa m id e (74): colorless crystals, mp 180-183
1
°C. IR (KBr): 3268, 2834, 1598 cm-1. H-NMR (DMSO-d6): δ
(5-Meth oxy-1-(2-m or p h olin oeth yl)-1H-2-in d olyl)-p h en -
yl-m eth a n on e (81): yellow wax, mp 66-68 °C. IR (KBr):
3.67-3.76 (m, 4H), 3.77 (s, 3H), 3.83-3.94 (m, 4H), 6.74-6.79
(m, 1H), 6.86 (dd, J 1 ) 2.5 Hz, J 2 ) 8.9 Hz, 1H), 7.08 (d, J )
2.5 Hz, 1H), 7.32 (d, J ) 8.9 Hz, 1H), 7.88 (d, J ) 2.6 Hz, 1H),
8.12 (dd, J 1 ) 2.6 Hz, J 2 ) 1.5 Hz, 1H), 8.35 (d, J ) 1.5 Hz,
1H), 11.48 (s, 1H). EI-MS (70 eV); m/z (%): 337 (100) [M+•],
216 (12), 190 (32), 174 (60), 134 (42). Anal. (C18H19N5O2 × 0.15
CH2Cl2): calcd. C 62.26, H 5.56, N 20.00; found C 62.51, H
5.43, N 20.21.
3071, 2965, 2942, 1630, 1597 cm-1 1H-NMR (DMSO-d6): δ
.
2.32 (t, J ) 4.8 Hz, 4H), 2.52 (t, J ) 6.2 Hz, 2H), 3.31 (t, J )
4.8 Hz, 4H), 4.65 (t, J ) 6.2 Hz, 2H), 6.85 (s, 1H), 7.00-7.06
(m, 1H), 7.13-7.18 (m, 1H), 7.54-7.74 (m, 4H), 7.85-7.92 (m,
2H). EI-MS (70 eV); m/z (%): 364 (6) [M+•], 287 (3), 259 (8),
146 (8), 100 (100). Anal. (C22H24N2O3 × 0.15 ethyl acetate):
calcd. C 71.88, H 6.73, N 7.42; found C 71.93, H 6.70, N 7.62.
N-4-Met h ylp er h yd r o-1-p yr a zin yl-5-m et h oxy-1H -2-in -
d oleca r boxa m id e (75): colorless crystals, mp 155-157 °C.
IR (KBr): 3237, 2994, 1600 cm-1. 1H-NMR (DMSO-d6): δ 2.21
(s, 3H), 2.37 (t, J ) 5.1 Hz, 4H), 3.68-3.79 (m, 7H), 6.65-6.70
(m, 1H), 6.80-6.88 (m, 1H), 7.03-7.09 (m, 1H), 7.28-7.36 (m,
1H), 11.43 (s, 1H). EI-MS (70 eV); m/z (%): 273 (28) [M+•], 174
(17), 119 (15), 99 (21), 70 (100). Anal. (C15H19N3O2 × 0.2 CH2-
Cl2): calcd. C 62.88, H 6.74, N 14.47; found C 63.03, H 6.72,
N 14.06.
Ack n ow led gm en t. We acknowledge the excellent
technical assistance of C. Lang, A. Masch, E. Thoenes,
C. Trauner, and K. Ziereis. This work was supported
by the Federal Ministry of Education, Science, Research
and Technology (BMBF), Grant 0311334/new natural
products.
N-4-P h en ylm et h ylp er h yd r o-1-p yr a zin yl-5-m et h oxy-
1H-2-in d oleca r boxa m id e (76): colorless crystals, mp 164-
Su p p or tin g In for m a tion Ava ila ble: Combustion ana-
lytical data, tubulin-inhibitory activity data, and in vitro
cytotoxicity data of all prepared compounds that have not been
presented in Table 1 because of inactivity or very weak
166 °C. IR (KBr): 3245, 2938, 1603 cm-1 1H-NMR (DMSO-
.
d6): δ 2.43 (t, J ) 5.9 Hz), 4H), 3.52 (s, 2H), 3.70-3.80 (m,

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