Novel indole-2-carboxamide and cycloalkeno[1,2-b]indole derivatives. Structure-activity relationships for high inhibition of human LDL peroxidation

Article abstract of DOI:10.1021/jm960542k

Series of indole-2-carboxamide and cycloalkeno[1,2-b]indole derivatives were synthesized and evaluated in order to determine the necessary structural requirements for a high inhibition of human LDL copper-induced peroxidation. Various modulations were sys

Full text of DOI:10.1021/jm960542k

J . Med. Chem. 1997, 40, 1201-1210
1201
Novel In d ole-2-ca r boxa m id e a n d Cycloa lk en o[1,2-b]in d ole Der iva tives.
Str u ctu r e-Activity Rela tion sh ip s for High In h ibition of Hu m a n LDL
P er oxid a tion
Catherine Kuehm-Caubere,† Paul Caubere,*,† Brigitte J amart-Gregoire,† Anne Negre-Salvayre,‡
Dominique Bonnefont-Rousselot,§ J ean-Guy Bizot-Espiard, Bruno Pfeiffer,| Daniel-Henri Caignard,|
Be´atrice Guardiola-Lemaitre, and Pierre Renard*,|
Laboratoire de Chimie Organique I, URA CNRS 457, Faculte´ des Sciences, Universite´ H. Poincare´, Nancy I, BP 239,
F-54506 Vandoeuvre-les-Nancy, France, Adir, 1, rue Carle He´bert, F-92415 Courbevoie, France, De´partement de Biochimie,
Faculte´ de Me´decine a` Margueil, Universite´ Paul Sabatier, 31054 Toulouse, France, De´partement de Biochimie,
Hopital Pitie´-Salpeˆtrie`re, 75651 Paris Ce´dex 13, France, and IRI Servier, 6 place des Ple´¨ıades, 92415 Courbevoie, France
Received J uly 25, 1996X
Series of indole-2-carboxamide and cycloalkeno[1,2-b]indole derivatives were synthesized and
evaluated in order to determine the necessary structural requirements for a high inhibition of
human LDL copper-induced peroxidation. Various modulations were systematically performed
on the indole and cycloalkeno[1,2-b]indole nuclei as well as on the carboxamide moiety. The
best compounds (3c, 3e, 7c, 7f, 7h , 7g, and 7o) are between 5 and 30 times more active than
probucol itself. Two of these compounds (3c and 7o) were selected for complementary in vitro
and in vivo investigations, which have shown additional properties of interest for the treatment
and the prevention of atherosclerosis injuries. Compound 3c was found to have some
antiinflammatory properties while compound 7o was proved to protect endothelial cells from
the direct cytotoxicity of oxidized LDL with some additional calcium channel blocking properties.
In tr od u ction
Numerous available epidemiological, biochemical, and
experimental data have led to the conclusion that
antioxidant compounds able to protect lipids from
peroxidation could be of value for the prevention and/
or the treatment of atherosclerosis by attenuating
foam-cell formation. There are several evidences that
vitamin E (Figure 1), an endogenous antioxidant radical
scavenger, may prevent initiation and propagation of
spontaneous atherosclerosis. The epidemiological stud-
ies also suggest that humans with a high plasma level
of vitamin E have a lower risk of coronary heart
disease.20 In the same way, supplementation of humans
with vitamin E increases the oxidation resistance of
LDL.21
Oxygen-derived free radicals and hydrogen peroxide
have been recognized to be essential mediators in the
appearance and development of numerous human pa-
thologies1 with, among others, cerebral and cardiac
ischemia-reperfusion injury2-5 as well as atherosclero-
sis.6 Atherosclerosis is a severe pathology which can
be implicated, directly or not, in about 50% of all
mortality in western countries and is considered as the
main contributor to the pathogenesis of myocardial and
cerebral infarction, gangrene, and loss of function of the
extremities. Over the past years, evidence has ac-
cumulated to suggest that free radicals, and the lipid
peroxidation they induce, could trigger most of the
factors involved in the atherosclerotic vascular injuries
(cytotoxicity, inflammation, formation of atheromatous
plaques, ...).6-10 Oxidative modifications of the lipopro-
teins, and more particularly of the low density lipopro-
teins (LDL), appeared to be one of the earliest phenom-
enon in the development of atherosclerosis pathology.11-13
Oxidatively modified LDL (ox-LDL) are key components
in endothelial injury. Indeed besides their direct cyto-
toxicity14,15 they stimulate the induction of proteins
responsible for the adhesion as well as chemotaxis of
monocytes at the endothelial cell surface.16 Moreover,
thanks to scavenger receptors and putative ox-LDL
receptors, ox-LDL are taken up in an unregulated
manner by the subendothelial macrophages with, as a
consequence, accumulation of cholesterol esters and
formation of foam cells which accumulate in the ath-
erosclerotic lesions leading to atheromatous plaques.16-19
Studies performed on Watanabe heritable hyperlipi-
demic rabbit showed that probucol, a potent liposoluble
hydroxyl radical scavenger, prevents the progression of
atherosclerosis.22-24
Like vitamin E and probucol, a lot of potent antioxi-
dants have their structure based on hindered phenol or
hydroxy chromane. This is the case for Trolox25 and
some of its analogues such as U-78517 F26,27 as well as
for some hydroxybenzylamine antioxidants28 (Figure 2).
Antioxidant properties were also observed with 5-hy-
droxyindole and 5-hydroxytryptophan29 and especially
with 6-hydroxy-1,4-dimethylcarbazole (HDC) which
proved in vitro to be a very powerful inhibitor of lipid
peroxidation (Figure 3).30
In this paper, we report the synthesis and the
pharmacological evaluation of a series of antioxidant
indole-2-carboxamide and cycloalkeno[1,2-b]indole de-
rivatives having the general formulas given in Figure
4.
Chemical modulations were systematically carried out
on these two structures in order to determine the
necessary structural requirements for high antioxidant
properties and more particularly for high lipid peroxi-
dation inhibition and LDL protection.
† Universite´ H. Poincare´.
‡ Universite´ Paul Sabatier.
§ Hopital Pitie´-Salpeˆtrie`re.
IRI Servier.
| Adir.
X Abstract published in Advance ACS Abstracts, March 15, 1997.
S0022-2623(96)00542-0 CCC: $14.00 © 1997 American Chemical Society

1202 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 8
Kuehm-Caubere et al.
F igu r e 1.
F igu r e 2.
Resu lts a n d Discu ssion
Twenty indole-2-carboxamide and six cycloalkeno[1,2-
b]indole derivatives were synthesized and evaluated. All
were prescreened in vitro for their ability to protect
human LDL against copper-induced peroxidation. Re-
sults were expressed as IC50 (concentration inhibiting
50% of the copper induced lipid peroxidation) deter-
mined using the thiobarbituric acid reactive substance
(TBARS) and expressed as malondialdehyde equivalent
(Tables 1 and 2). To correct slight variations in response
between the same evaluation procedures not performed
with the same batch of human LDL, results were also
expressed as an activity ratio versus probucol (r).
F igu r e 3.
Concerning the cycloalkeno[1,2-b]indoles derivatives
(Table 1), this prescreening procedure showed the fol-
lowing: (i) Methylation of the indole nucleus nitrogen
results in a significant increase in activity. r ) 10 for
compound 3e (R1 ) CH3) compared to r ) 2 for
compound 3d (R1 ) H). (ii) Replacement of the hydroxy
substituent R2 (3b, r ) 3) with an ethylthio group (4b,
r ) 0.1) results in a very clear decrease in activity. (iii)
The size of the cycloalkenyl ring is of a great influence
on the peroxidation inhibition. Very good results are
obtained with compound 3c which is a cycloheptene
derivative 30 times more efficient than probucol. The
order of potency according to the size of the ring is as
follows: 3c (n ) 5, r ) 30) > 3e (n ) 6, r ) 10) > 3b (n
) 4, r ) 3).
Concerning the indole-2-carboxanilides derivatives
(Table 2), the following observations emerged: (i) What-
ever the other substituents, R1, R2, and Ar, 5-methoxy-
indole derivatives 5 are less active than their 5-hydroxy
strict analogues 7. The difference in activity can be very
low between the NH-anilides 5a (r ) 2.2) and 7a (r )
3) or much higher for the N-methylanilide derivatives,
5b (r < 0.001) and 5f (r ) 0.02), which are around 1000
times less active than their 5-hydroxy analogues 7b (r
) 1) and 7f (r ) 10) virtually inactive. (ii) Replacement
of the 5-hydroxy substituent (7d , r ) 0.3) by a 5-SEt
group (6d , r ) 0.03) clearly decreases the antioxidant
properties. (iii) With the exception of 7h which is 2
times less active than 7c, methylation of the indole
nucleus nitrogen (R1 ) CH3) results generally in a
moderate to clear increase of the antioxidant properties
F igu r e 4.
Ch em istr y
Indoles 2 (Scheme 1) were prepared from the corre-
sponding imines 1 by intramolecular arynic cyclization
in the presence of an appropriate complex base31 fol-
lowed by quenching of the anionic intermediates with
an electrophile (H2O or Me2SO4). Yields varied from
60% and 88%. Treatment of 2 with AlCl3 and PhCH2-
SH, a new effective method for demethylation of meth-
oxyindoles,32 provided the corresponding hydroxy de-
rivatives 3 in very good yields. The (ethylthio)indole
4b was synthesized from 2b using AlCl3-EtSH in large
excess as reagent.32 Indoles 5 were obtained in 50-
90% yield according to Scheme 2 from the commercially
available 5-methoxy-2-indolecarboxylic acid. The (eth-
ylthio)indole 6d was synthesized from 5d and AlCl3-
EtSH used in a large excess.32 Hydroxyindolecarboxa-
mides 7 were obtained with an average 70% yield by
demethylation of 5 with the AlCl3-PhCH2SH reagent.
When the N-aryl substituent contained methoxy groups,
another synthetic pathway was adopted (Scheme 3).
Thus the desired amine was condensed on the com-
mercially available (but very expensive) 5-hydroxy-2-
indolecarboxylic acid via its acid chloride with an
average yield of 30%. Compounds 2-7 were tested for
their antioxidant properties.

Indolecarboxamide and Cycloalkenoindole Derivatives
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 8 1203
Sch em e 1a
a
(a) C6H6, ∆; (b) NaNH2-tBuONa, THF, room temperature; (c) H2O for 2a ,d , 0 °C; Me2SO4 for 2b,c,e, 0 °C to room temperature; (d)
AlCl3-PhCH2SH, CH2Cl2, 0 °C; (e) AlCl3-EtSH, CH2Cl2, 0 °C to room temperature.
Sch em e 2a
a
(a) PCl5, Et2O, room temperature; (b) ArNHR, Et2O/dioxane, 0 °C to room temperature; (c) NaH, Me2SO4, DMF, room temperature;
(d)AlCl3-EtSH, CH2Cl2, 0 °C; (e) AlCl3-PhCH2SH, CH2Cl2, 0 °C; (f) KOH, EtOH; (g) H3O+.
(up to 10 times for 7f and 5f compared to 7b and 5b).
(iv) The influence of alkylation on the carboxamide
nitrogen appears to be complex and very dependent on
the other substitutions. Thus in the 5-methoxy-substi-
tuted series 5, methylation of the amide function results
in a drastic decrease in activity (more than 1000 times
for 5b compared to 5a ). In the 5-hydroxy-substituted
series 7, alkylation may result in a clear increase in
activity in a dependent manner according to R1 sub-
stituent on the indole nucleus nitrogen. When R1 ) H,
itself and the order of potency is as follows: 7c (R2 )
n-Hex, r ) 10) > 7a (R2 ) H, r ) 3) > 7b (R2 ) CH3, r
) 1) > 7d (R2 ) n-octyl, r ) 0.3). When R1 ) CH3, the
best results are obtained for compounds 7f and 7j (R2
) CH3) and the orders of potency are as follows: 7f (R2
) CH3, r ) 10) > 7h (R2 ) n-Hex, r ) 5) > 7e (R2 ) H,
r ) 0.3) when Ar ) C6H5 and 7j (R2 ) CH3, r > 20) .
7i (R2 ) H, r ) 0.8) when Ar ) 3-ClC6H4. (v) Concern-
ing the substitution on the aromatic anilide moiety,
compound 7j (Ar ) 3-ClC6H4, r > 20) is more active than
its 3-Br (7l), 3-CF3 (7k ), or nonsubstituted (7f) anilides
direct analogues. (vi) Replacement of the aniline moiety
the best results are obtained for compound 7c (R2
n-hexyl), which is 10 times more potent than probucol
)

1204 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 8
Kuehm-Caubere et al.
Sch em e 3a
Ta ble 1. Inhibition of Copper-Induced Lipid Peroxidation by
Cycloalkeno[1,2-b]indole Derivatives
inhibition of
lipid peroxidation
compd
R1
R2
n
IC50 (M)
ra
2a
3b
3c
3d
3e
4b
H
OCH3
OH
OH
OH
OH
4
4
5
6
6
4
10-6
3
3
30
2
10
CH3
CH3
H
CH3
CH3
6 × 10-7
10-7
5 × 10-7
10-7
a
(a) SOCl2, C6H6, ∆; (b) RNHAr, Et2O/dioxane, room temper-
SEt
2 × 10-5
0,1
ature.
a
Activity ratio versus Probucol.
by azylpiperazines (7n , r ) 1, and 7o, r ) 5) results in
relatively active derivatives. Compound 7o was sub-
stituted with a “flunarizine-like” fluorobenzhydrylpip-
erazine in the aim of providing it with some antagonistic
activity on the calcium channels and consequently with
additional cytoprotective potentialities.
In conclusion to this preliminary evaluation, the
chemical modulations we carried out led us to the
discovery of new compounds much more potent than
probucol in their ability to prevent human LDL from
copper-induced peroxidation.
compound to inhibit, with an IC50 of 1.5 × 10-6 M, the
KCl-induced rat thoracic aorta contraction39 (flunarizine
IC50 ) 2.7 × 10-7 M). In addition to its antioxidant
properties, compound 7o proved to very potently protect
bovine endothelial cells against direct cytotoxicity of
oxidized LDL with an IC50 value of (1.4 ( 0.4) × 10-7
M. This compound is clearly more potent than probucol
and R-tocopherol which only showed IC50 values of
respectively (1.5 ( 0.4) × 10-5 and (2.0 ( 0.6) × 10-5
M
in this test.
P h a r m a cology
Con clu sion
Among the highly potent compounds selected from the
prescreening procedure, compounds 3c and 7o were
selected for complementary pharmacological evaluation.
Due to its very potent antioxidant properties, com-
pound 3c was investigated, in vitro, for its inhibiting
properties on cyclooxygenase and 5-lipoxygenase. In-
deed, inflammatory processes are suspected to be in-
volved in atherosclerosis pathology. This seems to be
more particularly the case for the 15-lipoxygenase
pathway33 which could be implicated in the development
of atherosclerosis lesions by stimulating neovascular-
ization34 and also by its role in the LDL oxidation.35
Due to its fluorobenhydrylpiperazine moiety, interac-
tions of compound 7o with the calcium channels were
investigated. As calcium channel blockers such as
nifedipine, diltiazem, and verapamil have already been
proved cultured lymphoid cells against the toxicity of
oxidized LDL,36 compound 7o was also evaluated for its
direct cytoprotective properties on cultured endothelial
cells exposed to oxidized LDL.
The chemical modulations performed on both indole-
2-carboxamide and cycloalkeno[1,2-b]indole series led
us to new compounds which were very efficient in
preventing human LDL from copper-induced peroxida-
tion. Among the numerous compounds more active than
Probucol, compounds 3c and 7o were selected for
complementary in vitro and in vivo investigations that
showed additional properties of great interest for the
treatment and for the prevention of atherosclerosis and
oxidative injuries. Compound 3c was proved to have
in vitro inhibiting properties on cyclooxygenase and
5-lipoxygenase. This could be predictive of in vivo
antiinflammatory activity. Compound 7o was found to
protect endothelial cells from direct cytotoxicity of
oxidized LDL with additional calcium channel blocking
properties. Both deserve further investigations cur-
rently under exploration.
Exp er im en ta l P a r t
Ch em istr y. Gen er a l Meth od s. Melting points were
determined on a Totoli melting point apparatus and are
uncorrected. 13C NMR spectra were recorded with a Bruker
AM 400 or a Bruker 300 MHz spectrometer (Attached Proton
Test method, APT). 1H NMR spectra were recorded on a J EOL
PMX 60 at 60 MHz, or a Brucker AM 400 instrument at 400
MHz. Me4Si was the internal standard. Infrared (IR) spectra
of thin liquid films between NaCl plates or KBr pellets were
recorded with a Perkin-Elmer 841 instrument. Elemental
analyses were performed by CNRS Laboratory (Vernaison) and
by ENSCM Microanalysis Department of Montpellier. Mass
spectra were recorded on Hewlett-Packard 5971A instrument.
Thin-layer chromatography (TLC) was performed with plates
coated with kieselgel G (Merck). The plates were developed
with petroleum ether (PE)/EtOAc or acetone/hexane as eluents.
The silica gels used for column chromatography and flash
chromatography were kieselgels of 0.063-0.2 and 0.04-0.063
mm particle size, respectively. A capillary HP1(6m) was used
for GPC.
P h a r m a cology Resu lts
The inhibiting properties of compound 3c on cyclooxy-
genase and 5-lipoxygenase were determined in vitro by
measuring the inhibition of the production of PGE2 and
LTB4 from rabbit granulocytes cells stimulated by
calcium ionophore A 23187.37 Compound 3c was found
to be active in inhibiting both cyclooxygenase and
5-lipoxygenase with IC50 values of respectively (4.0 (
0.9) × 10-7 and (1.2 ( 0.3) × 10-6 M. It also proved to
be active against 15-lipoxygenase, by inhibiting, at a
concentration of 10-5 M, 62 ( 3% of the 15-HETE
production by human umbilical vein endothelial cells
(HUVEC) stimulated by calcium ionophore A 23187.38
On another side, calcium channel blocking properties
of compound 7o were demonstrated by the ability of this

Indolecarboxamide and Cycloalkenoindole Derivatives
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 8 1205
Ta ble 2. Inhibition of Copper-Induced Lipid Peroxidation by Indole-2-carboxamide Derivatives
Imines 1 were classically obtained in yields varying from
40% to 75% by azeotropic dehydration of an equimolar amount
of amine and ketone. They were either purified by fast
distillation under vacuum or used as crude product after
classical workup without other purification.
(1) Qu en ch in g w ith E+ ) H2O. The reaction mixture was
poured into ice and extracted with Et2O, the organic phase
was dried on MgSO4, and the solvent was removed under
vacuum. Indoles were isolated by flash chromatography with
AcOEt/PE as eluents.
Ar yn ic Syn th esis: Gen er a l P r oced u r e for th e P r ep a -
r a tion of In d oles 2. To a stirred suspension of 7 equiv of
NaNH2 in THF (1 mL/7 mmol) was slowly added at 0 °C 2
equiv of t-BuOH in the minimum amount of THF. The stirred
reaction mixture was then warmed to 42 °C for 2 h. The
complex base thus obtained was cooled to 0 °C, and a solution
of the imine 1 in THF (3 mL/1 mmole) was dropwise added.
The stirred reaction mixture was then allowed to warm to room
temperature for 24 h, and a quenching with various electro-
philes was done.
1,2,3,4-Tetr a h yd r o-6-m eth oxyca r ba zole (2a ) was ob-
tained with AcOEt/PE (10/90) as eluent. IR (NaCl): 3395
(NH), 2916-2852 (C-H). 1H NMR (CDCl3): δ 6.50-7.55 (4H,
m, arom H + NH), 3.80 (3H, s, OMe), 2.90-2.50 (4H, m, 2 ×
CH2), 2.15-1.60 (4H, m, 2 × CH2). 13C NMR (CDCl3): δ 153.7
(arom COMe), 135.1 (arom C), 130.7 (arom C), 128.1 (arom
C), 110.9 (arom CH), 110.4 (arom CH), 109.8 (arom C), 100.2
(arom CH), 55.9 (OMe), 23.2 (CH2), 23.1 (CH2), 20.9 (2 × CH2).
Mp: 84-87 °C. Anal. Calcd for C13H15NO: C, 77.57; H, 7.51;
N, 6.95. Found: C, 77.04; H, 7.66; N, 6.90.

1206 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 8
Kuehm-Caubere et al.
2-Met h oxy-6,7,8,9,10,11-h exa h yd r o-5H -cyclooct [b]in -
d ole (2d ) was obtained with AcOEt/PE (10/90) as eluent. IR
(NaCl): 3405 (NH), 2922-2848 (C-H). 1H NMR (CDCl3): δ
7.90-6.50 (4H, m, arom H + NH), 3.86 (3H, s, OMe), 3.00-
2.50 (4H m, 2 × CH2), 2.00-1.20 (8H, m, 4 × CH2). 13C NMR
(CDCl3): δ 153.5 (arom COMe), 136.7 (arom C), 130.1 (arom
C), 128.8 (arom C), 111.2 (arom C), 110.9 (arom CH), 110.0
(arom CH), 99.9 (arom CH), 55.8 (OMe), 29.4 (CH2), 29.4 (CH2),
25.8 (CH2), 25.8 (CH2), 25.6 (CH2), 22.1 (CH2). Mp: 100-104
°C. Anal. Calcd for C15H19NO: C, 78.56; H, 8.35; N, 6.10.
Found: C, 78.65; H, 8.43; N, 6.10.
(NMe). Mp: 91-93 °C. Anal. Calcd for C13H15NO: C, 77.57;
H, 7.51; N, 6.95. Found: C, 77.45; H, 7.51; N, 6.86.
2-Hyd r oxy-5-m eth yl-5,6,7,8,9,10-h exa h yd r ocycloh ep t-
[b]in d ole (3c) was obtained after a reaction time of 3.5 h and
isolated with AcOEt/PE (15/85) as eluent. IR (NaCl): 3349
(OH), 2920-2845 (C-H). 1H NMR (CDCl3): δ 6.5-7.3 (3H,
m, arom H), 5.2 (1H, s, OH), 3.6 (3H, s, NMe), 2.5-3.0 (4H,
m, 2 × CH2), 1.5-2.0 (6H, m, 3 × CH2). 13C NMR (CDCl3): δ
148.8 (arom COH), 140.0 (arom C), 131.3 (arom C), 128.1 (arom
C), 112.6 (arom C), 109.7 (arom CH), 109.2 (arom CH), 102.4
(arom CH), 31.4 (CH2), 29.4 (NMe), 28.3 (CH2), 26.9 (CH2), 26.2
(2) Qu en ch in g w ith E+ ) Me2SO4. The reaction mixture
was decanted, and the supernatant liquid was transferred into
a flask containing a stirred solution of 3 equiv of Me2SO4 in
THF at 0 °C. After the mixture was stirred at room temper-
ature, the reaction, monitored by TLC (AcOEt/PE as eluent)
or CPG, was stopped when the unsubstituted indole had
desappeared. The reaction mixture was then poured into ice/
NH4OH (10%) and extracted with Et2O. The organic phase
was washed three times with H2O and dried on MgSO4 and
the solvent removed under vacuum. Indoles were isolated by
flash chromatography with AcOEt/PE as eluent.
(CH2), 24.3 (CH2). Mp: 101-103 °C. Anal. Calcd for C14H17-
NO: C, 78.10; H, 7.96; N, 6.50. Found: C, 77.69; H, 7.85; N,
6.52.
2-H yd r oxy-6,7,8,9,10,11-h exa h yd r o-5H -cyclooct [b]in -
d ole (3d ) was obtained after a reaction time of 1.5 h and
isolated with AcOEt/PE (15/85) as eluent. IR (NaCl): 3404
(OH + NH), 2922-2849 (C-H). 1H NMR (CDCl3): δ 7.25 (s,
1H, NH), 6.90-6.25 (3H, m, arom H), 5.45 (1H, s, OH), 2.70-
2.25 (4H, m, 2 × CH2), 1.90-1.00 (8H, m, 4 × CH2). 13C NMR
(CDCl3): δ 148.88 (arom COH), 137.06 (arom C), 132.24 (arom
C), 129.20 (arom C), 111.03 (arom C), 110.81 (arom CH), 109.92
(arom CH), 102.52 (arom CH), 29.44 (CH2), 29.38 (CH2), 25.91
(CH2), 25.78 (CH2), 25.72 (CH2), 22.08 (CH2). Mp: 90-94 °C.
Anal. Calcd for C14H17NO: C, 78.10; H, 7.96; N, 6.50.
Found: C, 77.57; H, 7.94; N, 6.58.
2-H yd r oxy-5-m et h yl-6,7,8,9,10,11-h ep t a h yd r o-5H -cy-
clooct[b]in d ole (3e) was obtained after a reaction time of
1.5 h and isolated with AcOEt/PE (15/85) as eluent. IR
(NaCl): 3368 (OH), 2925-2847 (C-H). 1H NMR (CDCl3) δ
ppm: 7.00-6.35 (3H, m, arom H), 5.55 (1H, s, OH), 3.50 (3H,
s, NMe), 3.00-2.50 (4H, m, 2 × CH2), 1.90-1.00 (8H, m, 4 ×
CH2). 13C NMR (CDCl3): δ 148.7 (arom COH), 138.0 (arom
C), 132.0 (arom C), 127.7 (arom C), 110.8 (arom C), 109.5 (arom
CH), 109.0 (arom CH), 102.4 (arom CH), 30.4 (CH2), 29.2
(NMe), 28.6 (CH2), 25.8 (2 × CH2), 22.9 (2 × CH2). Mp: 97-
99 °C. Anal. Calcd for C15H19NO: C, 78.56; H, 8.35; N, 6.12.
Found: C, 78.07; H, 8.30; N, 6.12.
Syn th esis of 6-(Eth ylth io)-1,2,3,4-tetr a h yd r o-9-m eth -
ylca r ba zole (4b). To a suspension of 20 equiv of EtSH (6.9
mL) and 1.5 equiv of AlCl3 (930 mg) at 0 °C was slowly added
a solution of 1 equiv of indole 2b (1 g) in CH2Cl2 (25 mL). The
reaction mixture was stirred for 0.5 h at 0 °C, and 20 equiv of
EtSH (6.9 mL) and 1.5 equiv of AlCl3 (930 mg) were added.
After the mixture was stirred for 0.5 h at 0 °C, a third identical
portion of each reagent was added. After 2 h at 0 °C and 48
h at room temperature, an acid hydrolysis with HCl (10%) (50
mL) was done at 0 °C. The mixture was extracted with CH2-
Cl2 (3 × 50 mL), and the organic phase was successively
washed with H2O (100 mL) and a saturated solution of NaCl
(100 mL) and dried over Na2SO4. The solvents were removed
under vacuum, and 6-(ethylthio)-1,2,3,4-tetrahydro-9-methyl-
carbazole (4b) was isolated by flash chromatography with
AcOEt/PE (10/90) as eluent: Yield: 78%. IR (NaCl): 3408
(NH), 2925-2840 (C-H). 1H NMR (CDCl3): δ 7.70-6.80 (4H,
m, arom H + NH), 3.10-2.30 (6H, m + q, SCH2 + 2 × CH2),
2.20-1.50 (4H, m, 2 × CH2), 1.50-1.00 (3H, t, CH3). 13C NMR
(CDCl3): δ 134.9 (arom CS), 134.8 (arom C), 128.4 (arom C),
125.5 (arom CH), 124.2 (arom C), 122.1 (arom CH), 110.6 (arom
CH), 109.88 (arom C), 30.5 (SCH2), 23.1 (CH2), 23.0 (2 × CH2),
20.72 (CH2), 14.7 (CH3). Mp: 58-61 °C. Anal. Calcd for
C14H17SN: C, 72.67; H, 7.40; N, 6.05; S, 13.85. Found: C,
72.40; H, 7.54; N, 6.15; S, 13.59.
Syn th esis of In d oles 5 (Sch em e 2): Typ ica l P r oced u r e
for th e P r ep a r a tion of N-P h en yl-5-m eth oxyin d ole-2-
ca r boxa m id e (5a ). To a suspension of 1 equiv of 5-methoxy-
2-indolecarboxylic acid (1 g) in anhydrous Et2O (60 mL) was
slowly added 1.5 equiv of PCl5 (1.64 g) at room temperature.
When the solution became clear, the solvent was removed
under vacuum. The crude solid was dissolved in CHCl3, the
solvent was removed under vacuum, and this operation was
repeated twice. The solid thus obtained was then dissolved
in anhydrous Et2O (50 mL), and a solution of 2 equiv of aniline
(975 mg) in solution in dioxane (in such amount that Et2O/
dioxane ) 3/1) was added at 0 °C. The reaction mixture was
then allowed to warm to room temperature and maintained
1,2,3,4-Tetr a h yd r o-6-m eth oxy-9-m eth ylca r ba zole (2b)
was obtained with AcOEt/PE (5/95) as eluent. IR (NaCl):
2993, 2930, 2833 (C-H). 1H NMR (CDCl3): δ 7.50-6.60 (3H,
m, arom H), 3.80 (3H, s, OMe), 3.55 (NMe), 3.10-2.50 (4H,
m, 2 × CH2), 2.30-1.70 (4H, m, 2 × CH2). 13C NMR (CDCl3):
δ 153.5 (arom COMe), 136.3 (arom C), 132.0 (arom C), 127.2
(arom C), 109.9 (arom CH), 108.9 (arom CH), 108.7 (arom C),
100.1 (arom CH), 55.9 (OMe), 28.8 (NMe), 23.1 (2 × CH2), 22.0
(CH2), 21.0 (CH2). Mp: 70-72 °C. Anal. Calcd for C14H17
-
NO: C, 78.10; H, 7.96; N, 6.50. Found: C, 78.37; H, 8.10; N,
6.44.
2-Meth oxy-5-m eth yl-5,6,7,8,9,10-h exa h yd r ocycloh ep t-
[b]in d ole (2c) was obtained with AcOEt/PE (5/95) as eluent.
IR (NaCl): 2990, 2920, 2845 (C-H). 1H NMR (CDCl3):
δ
7.30-6.50 (3H, m, arom H), 3.80 (3H, s, OMe), 3.00-2.50 (4H,
m, 2 × CH2), 2.00-1.50 (6 H, m, 3 × CH2). 13C NMR (CDCl3):
δ 153.6 (arom COMe), 139.7 (arom C), 139.7 (arom C), 131.2
(arom C), 127.7 (arom C), 113.0 (arom C), 109.9 (arom CH),
108.9 (arom CH), 99.8 (arom CH), 55.9 (OMe), 31.5 (CH2), 29.3
(NMe), 28.4 (CH2), 26.9 (CH2), 26.2 (CH2), 24.3 (CH2). Mp:
47-49 °C. Anal. Calcd for C15H19NO: C, 78.56; H, 8.35; N,
6.10. Found: C, 78.41; H, 8.51; N, 6.26.
2-Me t h oxy-5-m e t h yl-6,7,8,9,10,11-h e xa h yd r o-5H -cy-
clooct[b]in d ole (2e) was obtained with AcOEt/PE (5/95) as
eluent. IR (NaCl): 2921-2848 (C-H). 1H NMR (CDCl3): δ
7.10-6.50 (3H, m, arom H), 3.78 (3H, s, OMe), 3.68 (3H, s,
NMe), 3.00-2.60 (4H, m, 2 × CH2), 1.90-1.20 (8H, m, 4 ×
CH2). 13C NMR (CDCl3): δ 153.5 (arom COMe), 137.7 (arom
C), 131.9 (arom C), 127.4 (arom C), 111.1 (arom C), 109.7 (arom
CH), 109.1 (arom CH), 99.9 (arom CH), 55.9 (OMe), 30.4 (CH2),
29.2 (NMe), 28.7 (CH2), 25.9 (CH2), 25.8 (CH2), 22.9 (2 × CH2).
Mp: 53-55 °C. Anal. Calcd for C16H21NO: C, 78.96; H, 8.69;
N, 5.75. Found: C, 78.90; H, 8.52; N, 5.82.
Dem eth yla tion of Meth oxyin d oles 2: Typ ica l P r oce-
d u r e for th e P r ep a r a tion of 1,2,3,4-Tetr a h yd r o-6-h y-
d r oxy-9-m eth ylca r ba zole (3b). To a suspension of 20 equiv
of PhCH2SH (10.9 mL) and 1.5 equiv of AlCl3 (930 mg) at 0 °C
was slowly added a solution of 1 equiv of 2b (1 g) in CH2Cl2
(25 mL). The reaction mixture was stirred for 0.5 h at 0 °C,
and 20 equiv of PhCH2SH (10.9 mL) and 1.5 equiv of AlCl3
(930 mg) were added. After the mixture was stirred for 5 h
at 0 °C, acid hydrolysis with HCl (10%) (50 mL) was done at
0 °C. The mixture was extracted with CH2Cl2 (3 × 50 mL),
and the organic phase was successively washed with H2O (100
mL) and brine (100 mL) and dried over Na2SO4. The solvents
were removed under vacuum and 1,2,3,4-tetrahydro-6-hy-
droxy-9-methylcarbazole 3b isolated by flash chromatography
with AcOEt/PE (15/85) as eluent. IR (NaCl): 3356 (OH),
2930-2839 (C-H). 1H NMR (CDCl3): δ 7.00-6.46 (3H, m,
arom H), 6.00 (1H, s, OH), 3.30 (3H, s, NMe), 2.83-2.16 (4H,
m, 2 × CH2), 2.00-1.46 (4H, m, 2 × CH2). 13C NMR (CDCl3):
δ 148.5 (arom COH), 136.4 (arom C), 132.0 (arom C), 127.4
(arom C), 109.7 (arom CH), 108.7 (arom CH), 108.2 (arom C),
102.7 (arom CH), 23.0 (2 × CH2), 21.8 (CH2), 20.8 (CH2), 28.6

Indolecarboxamide and Cycloalkenoindole Derivatives
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 8 1207
under stirring for 12 h. After acidification with 1 N HCl (50
mL) and extraction with CHCl3 (3 × 50 mL), the organic phase
was washed with H2O (3 × 100 mL) and dried over MgSO4.
The solvent was removed under vacuum. N-Phenyl-5-meth-
oxyindole-2-carboxamide (5a ) was obtained in 86% yield after
washing with Et2O. IR (KBr): 3424 (NH), 3295 (NH), 1649
(CO). 1H NMR (CDCl3): δ 8.00-6.90 (11H, m, arom H + 2 ×
NH), 3.80 (3H, s, CH3). 13C NMR (CDCl3/DMSO): δ 158.0
(CO), 152.2 (arom COMe), 138.0 (arom C), 130.5 (arom C),
130.2 (arom C), 126.7 (2 × arom CH), 125.7 (arom C), 121.6 (3
× arom CH), 113.3 (arom CH), 111.4 (arom CH), 102.0 (arom
CH), 100.2 (arom CH), 53.5 (OCH3). Mp: 190-192 °C. Anal.
Calcd for C16H14O2N2: C, 72.16; H, 5.29; N, 10.52; O, 12.01.
Found: C, 71.90; H, 5.44; N, 10.55; O, 12.46.
N-Met h yl-N-p h en yl-5-m et h oxyin d ole-2-ca r b oxa m id e
(5b). Yield: 66%. IR (NaCl/Nujol): 3268 (NH), 1616 (CO).
1H NMR (CDCl3): δ 7.60-6.60 (9H, m, arom H + NH), 5.10
(1H, s, arom H2), 3.70 (3H, s, OCH3), 3.45 (3H, s, NCH3). 13C
NMR (CDCl3): δ 159.4 (CO), 151.6 (arom COMe), 142.3 (arom
C), 128.9 (arom C), 128.3 (arom C), 127.7 (2 × arom CH), 125.9
(2 × arom CH), 125.8 (arom CH), 125.0 (arom C), 113.0 (arom
CH), 111.0 (arom CH), 103.4 (arom CH), 99.5 (arom CH), 53.1
(OCH3), 36.5 (NCH3). Mp: 193-195 °C. Anal. Calcd for
C17H16O2N2: C, 72.83; H, 5.75; N, 9.99; O, 11.41. Found: C,
72.66; H, 5.89; N, 9.85; O, 11.16.
N-(3-Met h oxyp h en yl)-5-m et h oxyin d ole-2-ca r b oxa m -
id e (5p ). Yield: 50%. IR (KBr): 3348 (NH), 3277 (NH), 1650
(CO). 1H NMR (CDCl3): δ 7.70-6.50 (10H, m, arom H + 2 ×
NH), 3.80 (6H, s, 2 × CH3). 13C NMR (CDCl3/DMSO): δ 157.8
(CO), 157.5 (arom COMe), 152.01 (arom COMe), 138.2 (arom
C), 130.3 (arom C), 129.8 (arom C), 127.5 (arom CH), 125.4
(arom C), 113.2 (arom CH), 111.3 (arom CH), 110.5 (arom CH),
106.8 (arom CH), 104.1 (arom CH), 101.7 (arom CH), 100.1
(arom CH), 53.5 (OMe), 53.2 (OMe). Mp: 182-184 °C.
Structure established during an X-ray diffraction study.40
Typ ica l P r oced u r e for th e P r ep a r a tion of N-Meth yl-
N-p h en yl-5-(m eth oxym eth yl)in d ole-2-ca r boxa m id e (5f).
(1) F r om N-P h en yl-5-m eth oxyin d ole-2-ca r boxa m id e (5a ).
To 4 equiv of NaH (15 mmol) was slowly added, at 0 °C, a
solution of 1 equiv of 5a (1 g) in DMF (10 mL). When the
addition was complete, the reaction mixture was allowed to
warm to room temperature and 3 equiv of Me2SO4 (1 mL) was
added. The reaction was monitored by TLC. After completion
of the reaction, the mixture was hydrolyzed with a solution of
NH4OH (50 mL) at 0 °C and extracted with CH2Cl2 (3 × 50
mL). The organic phase was washed with H2O (4 × 100 mL)
and dried over MgSO4. The solvents were removed under
vacuum, and N-methyl-N-phenyl-5-(methoxymethyl)indole-2-
carboxamide (5f) was isolated by flash chromatography with
AcOEt/PE (15/85) as eluent. Yield: 95%.
(2) F r om 5-Meth oxy 2-in d oleca r boxylic Acid . The
5-methoxy-2-indolecarboxylic acid was methylated using the
same procedure as (1). The crude methyl 5-methoxy-N-
methyl-2-indolecarboxylate was isolated with 98% yield and
the corresponding acid obtained by a KOH/EtOH saponifica-
tion. Yield: 94%. Mp: 215 °C (lit.41 mp 215 °C). The desired
amide was obtained by the condensation of N-methylaniline
using the same procedure as described above for indole 5a .
Yield: 65%/5-methoxy-2-indolecarboxylic acid. IR (NaCl):
2941-2832 (C-H), 1638 (CO). 1H NMR (CDCl3): δ 7.40-6.80
(8H, m, arom H), 5.80 (1H, s, arom H2), 3.90 (3H, s, NCH3),
3.70 (3H, s, OCH3), 3.50 (1H, s, NCH3). 13C NMR (CDCl3): δ
163.5 (CO), 154.1 (arom COMe), 144.9 (arom C), 133.2 (arom
C), 132.2 (arom C), 129.2 (2 × arom CH), 126.7 (2 × arom CH),
126.5 (arom CH), 126.2 (arom C), 114.5 (arom CH), 110.5 (arom
CH), 106.7 (arom CH), 102.3 (arom CH), 55.5 (OCH3), 38.0
(NCH3), 31.5 (NCH3). Mp: 93-95 °C. Anal. Calcd for
C18H18O2N2: C, 73.44; H, 6.16; N, 9.51. Found: C, 73.39; H,
6.21; N, 9.45.
was stirred for 0.5 h at 0 °C, a third identical portion of each
reagent was added. After 2 h at 0 °C, an acid hydrolysis with
HCl (10%) (50 mL) was done at 0 °C. The mixture was
extracted with CH2
Cl2 (3 × 50 mL), and the organic phase was
successively washed with H2O (100 mL) and brine (100 mL)
and dried over Na2SO4. The solvents were removed under
vacuum, and N-octyl-N-phenyl-5-(ethylthio)indole-2-carboxa-
mide (6d ) was isolated by flash chromatography with AcOEt/
PE (15/85) as eluent. Yield: 70%. IR (NaCl): 3277 (NH),
1952, 2930, 2853 (C-H), 1615 (CO). 1H NMR (CDCl3): δ 10.20
(1H, s, NH), 7.90-6.90 (8H, m, arom H), 5.20 (1H, s, arom
H2), 4.20-3.70 (2H, m, NCH2), 3.10-2.60 (2H, q, SCH2), 2.20-
0.70 (18H, m + t, 6 × CH2 + 2 × CH3). 13C NMR (CDCl3): δ
161.5 (CO), 142.6 (arom C), 134.6 (arom C), 130.4 (arom C),
129.7 (arom CH), 128.8 (arom CH), 128.4 (arom CH), 128.2
(arom C), 125.9 (arom C), 125.5 (arom CH), 112.1 (arom CH),
106.3 (arom CH), 51.1 (NCH2), 31.7 (CH2), 29.9 (SCH2), 29.3
(CH2), 29.1 (CH2), 27.5 (CH2), 26.9 (CH2), 22.5 (2 × CH2), 14.5
(SCH2CH3), 13.9 (CH3). Mp: 86-88 °C. Anal. Calcd for
C25H32SN2O: C, 73.48; H, 7.89; N, 6.85; S, 7.84. Found: C,
73.23; H, 7.83; N, 6.89; S, 8.09.
Dem eth ylation of Meth oxyin dolecar boxam ides 5: Sam e
Typ ica l P r oced u r e a s for th e Dem eth yla tion of Meth -
oxyin d oles 2. N-P h en yl-5-h yd r oxyin d ole-2-ca r boxa m id e
(7a ) was obtained after a reaction time of 1.5 h and isolated
with AcOEt/PE (35/65) as eluent. IR (NaCl): 3297 (OH + NH),
2961-2932 (C-H), 1655 (CO). 1H NMR (CDCl3): δ 10.00 (1H,
s, NH), 8.70 (1H, s, NH), 8.00-6.60 (10H, m, arom H + OH).
13C NMR (CDCl3): δ 158.3 (CO), 149.6 (arom COH), 137.4
(arom C), 130.3 (arom C), 126.3 (arom C), 126.9 (2 × arom
CH), 121.8 (2 × arom CH), 118.6 (arom CH), 113.6 (arom CH),
111.2 (arom CH), 103.0 (arom CH), 101.6 (arom CH). Mp:
225-228 °C. Anal. Calcd for C15H12O2N2: C, 71.41; H, 4.79;
N, 11.10. Found: C, 70.67; H, 4.90; N, 10.63. (Very sensitive
to air oxidatation.)
N-Met h yl-N-p h en yl-5-h yd r oxyin d ole-2-ca r b oxa m id e
(7b) was obtained after a reaction time of 3 h and isolated
with AcOEt/PE (30/70) as eluent. IR (NaCl): 3275 (OH + NH),
3060-2925 (C-H), 1618 (CO). 1H NMR (CDCl3): δ 10.30-
9.90 (1H, s, NH), 7.50-6.60 (9H, m, arom H), 5.20 (1H, s, arom
H2), 3.50 (3H, s, NMe). 13C NMR (CDCl3): δ 162.1 (CO), 144.0
(2 × arom C), 135.4 (arom C), 129.8 (2 × arom CH), 128.3
(arom CH), 127.9 (2 × arom CH), 127.5 (arom C), 124.2 (arom
CH), 122.0 (arom CH), 120.0 (arom CH), 111.6 (arom CH),
107.0 (arom CH), 38.9 (NMe). Mp: 172-174 °C. Anal. Calcd
for C16H14ON2: C, 76.77; H, 5.63; N, 11.19. Found: C, 76.43;
H, 5.68; N, 11.03.
N-Hexyl-N-ph en yl-5-h ydr oxyin dole-2-car boxam ide (7c)
was obtained after a reaction time of 2.5 h and isolated with
AcOEt/PE (30/70) as eluent. IR (NaCl/Nujol): 3420 (OH), 3269
(NH), 1613 (CO). 1H NMR (CDCl3/DMSO): δ 9.26 (1H, s, NH),
7.56-6.65 (8H, m, arom H), 5.00 (1H, s, arom H2), 4.84 (1H,
s, OH), 4.00-3.78 (2H, m, NCH2), 1.75-0.75 (11H, m, 4 × CH2
+ CH3). 13C NMR (CDCl3/DMSO): δ 160.3 (CO), 149.8 (arom
COH), 141.7 (arom C), 129.4 (arom C), 129.2 (arom C), 128.4
(2 × arom CH), 127.5 (2 × arom CH), 126.9 (arom CH), 126.7
(arom C), 113.9 (arom CH), 111.3 (arom CH), 104.2 (arom CH),
103.4 (arom CH), 49.3 (NCH2), 30.2 (CH2), 26.2 (CH2), 25.2
(CH2), 21.2 (CH2), 12.8 (CH3). Mp: 163-165 °C. Anal. Calcd
for C21H24O2N2: C, 74.96; H, 7.19; N, 8.32. Found: C, 74.70;
H, 7.27; N, 8.27.
N-Octyl-N-ph en yl-5-h ydr oxyin dole-2-car boxam ide (7d)
was obtained after a reaction time of 3 hours and isolated with
AcOEt/PE (30/70) as eluent. IR (NaCl): 3402 (OH), 3275 (NH),
2929-2850 (C-H), 1615 (CO). 1H NMR (CDCl3): δ 10.30 (1H,
s, NH), 7.60-6.50 (9H, m, arom H + OH), 5.10 (1H, s, arom
H2), 4.00-3.60 (2H, m, NCH2), 1.90-0.60 (15H, m, 6 × CH2
+ CH3). 13C NMR (CDCl3): δ 161.5 (CO), 147.7 (arom COH),
142.6 (arom C), 130.7 (arom C), 130.6 (arom C), 129.7 (2 ×
arom CH), 128.9 (arom CH), 128.4 (2 × arom CH), 128.2 (arom
C), 115.1 (arom CH), 112.2 (arom CH), 106.1 (arom CH), 105.6
(arom CH), 51.0 (NCH2), 31.7 (CH2), 29.3 (CH2), 29.2 (CH2),
27.6 (CH2), 26.9 (CH2), 22.6 (CH2), 14.0 (CH3). Mp: 159-161
°C. Anal. Calcd for C23H28O2N2: C, 75.78; H, 7.74; N, 7.68.
Found: C, 76.06; H, 7.76; N, 7.70.
Syn th esis of N-Octyl-N-p h en yl-5-(eth ylth io)in d ole-2-
ca r boxa m id e (6d ). To a suspension of 20 equiv of EtSH (3.9
mL) and 1.5 equiv of AlCl3 (530 mg) was slowly added a
solution of 1 equiv of N-octyl-N-phenyl-5-methoxyindole-2-
carboxamide (1 g) in CH2Cl2 (15 mL). The reaction mixture
was stirred for 0.5 h at 0 °C, and 20 equiv of EtSH (3.9 mL)
and 1.5 equiv of AlCl3 (530 mg) were added. After the mixture

1208 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 8
Kuehm-Caubere et al.
N-P h en yl-5-(h ydr oxym eth yl)in dole-2-car boxam ide (7e)
was obtained after a reaction time of 2 h and isolated with
AcOEt/PE (30/70) as eluent. IR (NaCl): 3284 (OH + NH),
1645 (CO). 1H NMR (CDCl3/DMSO); δ 10.00 (1H, s, NH), 8.60
(1H, s, OH), 7.90-6.70 (9H, m, arom H), 4.00 (3H, s, NMe).
13C NMR (CDCl3/DMSO): δ 159.9 (CO), 150.4 (arom COH),
137.8 (arom C), 133.0 (arom C), 131.3 (arom C), 127.5 (2 ×
arom CH), 122.6 (arom CH), 119.4 (2 × arom CH), 125.4 (arom
C), 114.1 (arom CH), 109.5 (arom CH), 104.0 (arom CH), 103.5
(arom CH), 30.5 (NMe). Mp: 194-196 °C. Anal. Calcd for
C16H14O2N2: C, 72.16; H, 5.29; N, 10.52. Found: C, 71.67; H,
5.31; N, 10.13.
N-Met h yl-N-p h en yl-5-(h yd r oxym et h yl)in d ole-2-ca r -
boxa m id e (7f) was obtained after a reaction time of 5 h and
isolated with AcOEt/PE (30/70) as eluent. IR (NaCl): 3850
(OH), 2926 (C-H), 1619 (CO). 1H NMR (CDCl3): δ 6.60-7.50
(8H, m, arom H), 5.85 (1H, s, OH), 5.00 (1H, s, arom H2), 3.90
(3H, s, NMe), 3.50 (3H, s, NMe). 13C NMR (CDCl3): δ 164.0
(CO), 150.1 (arom COH), 144.5 (arom C), 133.1 (arom C), 132.0
(2 × arom C), 129.2 (2 × arom CH), 126.9 (arom CH), 126.4
(arom CH), 125.3 (arom CH), 114.2 (arom CH), 110.2 (arom
CH), 106.5 (arom CH), 105.3 (arom H), 38.2 (NMe), 31.4 (NMe).
Mp: 138-140 °C. Anal. Calcd for C17H16O2N2: C, 72.83; H,
5.75; N, 9.99. Found: C, 72.99; H, 5.79; N, 9.96.
Calcd for C17H15O2N2Cl: C, 64.86; H, 4.80; N, 8.90; Cl, 11.26.
Found: C, 64.90; H, 4.84; N, 8.87; Cl, 11.55.
N-Met h yl-N-[3-(t r iflu or om et h yl)p h en yl]-5-(h yd r oxy-
m eth yl)in d ole-2-ca r boxa m id e (7k ) was obtained after a
reaction time of 3 h and isolated with AcOEt/PE (30/70) as
eluent. IR (NaCl): 3349 (OH), 2930 (C-H), 1629 (CO). 1H
NMR (CDCl3): δ 7.70-6.50 (7H, m, arom H), 5.80 (1H, s, arom
H), 5.50 (1H, s, OH), 3.80 (3H, s, CH3), 3.50 (3H, s, CH3). 13C
NMR (CDCl3): δ 163.9 (CO), 150.0 (arom COH), 145.2 (arom
C), 131.6 (2 × arom C), 130.1 (arom CH), 129.8 (arom CH),
123.5 (arom CH), 122.8 (arom CH), 126.4 (arom C), 121.6 (CF3),
114.4 (arom CH), 110.4 (arom CH), 106.6 (arom CH), 105.4
(arom CH), 38.2 (NMe), 31.5 (NMe). Mp: 157-159 °C. Anal.
Calcd for C18H15O2N2F3: C, 62.06; H, 4.34; N, 8.04; F, 16.36.
Found: C, 62.32; H, 4.52; N, 7.78; F, 15.99.
N-Meth yl-N-(3-br om oph en yl)-5-(h ydr oxym eth yl)in dole-
2-ca r boxa m id e (71) was obtained after a reaction time of 5
h and isolated with AcOEt/PE (30/70) as eluent. IR (NaCl):
3348 (OH), 2937 (C-H), 1627 (CO). 1H NMR (CDCl3): δ 7.50-
6.60 (7H, m, arom H), 5.90 (1H, s, arom H2), 5.00 (1H, s, OH),
3.80 (3H, s, NMe), 3.40 (3H, s, NMe). 13C NMR (CDCl3): δ
163.9 (CO), 150.1 (arom COH), 145.7 (arom C), 134.5 (arom
C), 133.3 (arom C), 131.5 (arom C), 130.1 (arom CH), 127.0
(arom CH), 126.4 (arom CH), 125.0 (arom CH), 126.3 (arom
C), 114.4 (arom CH), 110.3 (arom CH), 106.7 (arom CH), 105.3
(arom CH), 38.2 (NMe), 31.4 (NMe). Mp: 143-145 °C. Anal.
Calcd for C17H15O2N2Br: C, 56.83; H, 4.20; N, 7.80; Br, 22.24.
Found: C, 57.17; H, 4.26; N, 7.81; Br, 21.60.
N-Bu tyl-N-p h en yl-5-(Hyd r oxym eth yl)in d ole-2-ca r box-
a m id e (7g) was obtained after a reaction time of 2.5 h and
isolated with AcOEt/PE (30/70 as eluent. IR (NaCl): 3373
(OH), 2959-2871 (C-H), 1614 (CO). 1H NMR (CDCl3):
δ
7.40-6.50 (9H, m, arom H + OH), 5.70 (1H, s, arom H2), 4.00-
3.70 (2H, m, NCH2), 3.70 (3H, s, NMe), 1.90-1.10 (4H, m, 2 ×
CH2), 1.10-0.70 (3H, m, CH3). 13C NMR (CDCl3): δ 163.7
(CO), 149.9 (arom COH), 143.1 (arom C), 133.0 (arom C), 132.6
(arom C), 129.1 (2 × arom CH), 127.3 (arom CH), 127.0 (2 ×
arom CH), 126.5 (arom C), 114.0 (arom CH), 110.1 (arom CH),
106.0 (arom CH), 105.4 (arom CH), 50.2 (NCH2), 31.4 (NMe),
29.7 (CH2), 20.0 (CH2), 13.7 (CH3). Mp: 149-151 °C. Anal.
Calcd for C20H22O2N2: C, 74.50; H, 6.87; N, 8.69. Found: C,
74.45; H, 7.18; N, 8.49.
2-[[[Bis(p-flu or op h en yl)m eth yl]p ip er a zin o]ca r bon yl]-
5-(h yd r oxym eth yl)in d ole (7o) was obtained after a reaction
time of 2.5 h and isolated with AcOEt/PE (30/70) as eluent.
IR (NaCl): 3330 (OH), 2922-2812 (C-H), 1605 (CO). 1H NMR
(DMSO): δ 8.80 (1H, s, OH), 7.60-6.60 (11H, m, arom H), 6.40
(1H, s, arom H2), 4.40 (1H, s, NCH), 3.80-3.50 (5H, m, NMe
+ NCH2), 3.30 (2H, s, NCH2), 2.60-2.10 (4H, m, 2 × CH2).
13C NMR (CDCl3): δ 190.9-157.7 (arom CF), 160.15 (CO),
149.5 (arom COH), 136.2 (arom C), 130.3 (arom C), 130.0 (arom
C), 127.5 (2 × arom CH), 127.4 (2 × arom CH), 124.7 (2 ×
arom C), 113.5 (2 × arom CH), 113.2 (2 × arom CH), 111.8
(arom CH), 108.5 (arom CH), 102.6 (arom CH), 100.0 (arom
CH), 71.0 (CH), 49.5 (4 × CH2), 28.9 (NMe). Mp: 219-221
°C. Anal. Calcd for C27H24O2N3F2: C, 70.26; H, 5.46; N, 9.10;
F, 8.23. Found: C, 70.13; H, 5.65; N, 9.40; F, 8.01.
Syn th esis of Hyd r oxyin d oles 6 (Sch em e 3): Typ ica l
P r oced u r e for th e P r ep a r a tion of N-(3,4,5-Tr im eth oxy-
ph en yl)-5-h ydr oxyin dole-2-car boxam ide (7m ). To a stirred
solution of commercially available 5-hydroxy 2-indolecarboxylic
acid (1 g) in benzene (85 mL) was dropwise added 15 equiv of
SOCl2 (6.25 mL). The reaction mixture was refluxed during
24 h and then filtered. The filtrate was evaporated in vacuo
to yield the crude carbonyl chloride that was dissolved in
anhydrous ether (100 mL) at 0 °C, and 2 equiv of 3,4,5-
trimethoxyaniline (2 g) in dioxane (30 mL) was added. Thus
the reaction was performed at room temperature for 12 h. After
classical workup, N-(3,4,5-trimethoxyphenyl)-5-hydroxyindole-
2-carboxamide (7m ) was isolated by flash chromatography
with AcOEt/PE (40/60) as eluent. Yield: 30%. IR (NaCl/
Nujol): 3427 (OH), 3278 (NH), 1594 (CO). 1H NMR (CDCl3/
DMSO): δ 10.20 (1H, s, OH), 8.35 (1H, s, NH), 7.55-6.55 (6H,
m, arom H), 4.10-3.70 (13H, m, 2 × CH2 + 3 × CH3), 3.50
(2H, s, CH2), 2.75-2.45 (4H, m, 2 × CH2). 13C NMR (CDCl3/
DMSO): δ 160.3 (CO), 150.8 (arom COMe), 150.3 (arom
COMe), 149.3 (arom COH), 140.1 (arom COMe), 128.9 (arom
C), 128.2 (arom C), 125.7 (arom C), 123.0 (arom CH), 121.5
(arom C), 112.6 (arom CH), 110.6 (arom CH), 105.5 (arom CH),
102.4 (arom CH), 101.3 (arom CH), 59.1 (OMe), 58.4 (OMe),
54.2 (CH2), 53.9 (OMe), 50.9 (4 × CH2). Mp: 180-182 °C.
Anal. Calcd for C23H27O5N3: C, 64.92; H, 6.39; N, 9.87.
Found: C, 65.33; H, 6.49; N, 10.02.
N-Hexyl-N-p h en yl-5-(h yd r oxym eth yl)in d ole-2-ca r box-
a m id e (7h ) was obtained after a reaction time of 2.5 h and
isolated with AcOEt/PE (30/70) as eluent. IR (NaCl): 3344
(OH), 2931-2857 (C-H), 1619 (CO). 1H NMR (CDCl3):
δ
7.30-6.61 (9H, m, arom H + OH), 5.75 (1H, s, arom H2), 4.00-
3.64 (2H, m, NCH2), 3.78 (3H, s, NMe), 1.71-0.75 (11H, m, 4
× CH2 + CH3). 13C NMR (CDCl3): δ 163.7 (CO), 150.1 (arom
COH), 143.0 (arom C), 133.0 (arom C), 132.4 (arom C), 129.1
(arom CH), 127.2 (arom CH), 126.9 (arom CH), 126.4 (arom
C), 114.0 (arom CH), 110.0 (arom CH), 106.0 (arom CH), 105.3
(arom CH), 50.3 (NCH2), 31.3 (NMe), 31.3 (CH2), 27.5 (CH2),
26.4 (CH2), 22.4 (CH2), 13.8 (CH3). Mp: 89-91 °C. Anal.
Calcd for C22H26O2N2: C, 75.39; H, 7.47; N, 7.99. Found: C,
75.27; H, 7.39; N, 7.89.
N-(3-Ch lor op h en yl)-5-(h yd r oxym et h yl)in d ole-2-ca r -
boxa m id e (7i) was obtained after a reaction time of 5 h and
isolated with AcOEt/PE (30/70) as eluent. IR (NaCl): 3430
(OH), 3272 (NH), 1644 (CdO). 1H NMR (CDCl3): δ 9.1 (s, 1H,
NH), 7.9-6.7 (9H, m, arom H + OH), 4.0 (3H, s, CH3). 13C
NMR (CDCl3): δ 159.24 (CO), 150.08 (arom COH), 138.93
(arom C), 132.43 (arom C), 131.79 (arom C), 130.15 (arom CCl),
128.13 (arom CH), 124.65 (arom C), 121.46 (arom CH), 118.22
(arom CH), 116.75 (arom CH), 113.79 (arom CH), 109.09 (arom
CH), 103.41 (arom CH), 103.20 (arom CH), 29.85 (NCH3).
Mp: 186-188 °C. Anal. Calcd for C16H13O2N2Cl: C, 63.89;
H, 4.35; N, 9.31; Cl, 11.78. Found: C, 63.88; H, 4.25; N, 9.00;
Cl, 11.36.
N-Meth yl-N-(3-ch lor oph en yl)-5-(h ydr oxym eth yl)in dole-
2-ca r boxa m id e (7j) was obtained after a reaction time of 5
h and isolated with AcOEt/PE (30/70) as eluent. IR (NaCl):
3340 (OH), 2930 (C-H), 1619 (CO). 1H NMR (CDCl3): δ 7.40-
6.60 (7H, m, arom H), 5.80 (1H, s, arom H2), 5.10 (1H, s, OH),
3.80 (3H, s, NMe), 3.40 (3H, s, NMe). 13C NMR (CDCl3): δ
163.9 (CO), 150.1 (arom COH), 145.7 (arom C), 134.5 (arom
C), 133.3 (arom C), 131.5 (arom C), 130.1 (arom CH), 127.0
(arom CH), 126.4 (arom CH), 125.0 (arom CH), 126.3 (arom
C), 114.4 (arom CH), 110.3 (arom CH), 106.7 (arom CH), 105.4
(arom CH), 38.2 (NMe), 31.4 (NMe). Mp: 141-143 °C. Anal.
2-[[[(2,3,4-Tr im e t h oxyp h e n yl)m e t h yl]p ip e r a zin o]-
ca r bon yl]-5-h yd r oxyin d ole (7n ). IR (NaCl): 3312 (OH +
NH), 2938 (C-H), 1696 (CO). 1H NMR (CDCl3): δ 10.70 (1H,
s, NH), 9.40 (1H, s, NH), 7.20-6.50 (7H, m, arom H), 3.80 (6H,
s, 2 × OCH3), 3.70 (3H, s, OCH3). 13C NMR (CDCl3): δ 159.4
(CO), 152.2 (arom COH), 150.6 (arom C), 134.3 (2 × arom C),
133.4 (arom C), 131.2 (arom C), 131.1 (arom C), 127.5 (arom

Indolecarboxamide and Cycloalkenoindole Derivatives
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 8 1209
C), 114.8 (arom CH), 112.0 (arom CH), 104.3 (arom CH), 103.1
(arom CH), 97.4 (2 × arom CH), 60.11 (OMe), 55.3 (2 × OMe).
Mp: 219-221 °C. Anal. Calcd for C18H18N2O5: C, 63.14; H,
5.29; N, 8.18. Found: C, 63.40; H, 5.38; N, 8.30.
Ack n ow led gm en t. Cyclooxygenase, 5-lipoxygenase,
and 15-lipoxygenase activities and anticalcic activity
have been performed by CEREP, Le Bois l’Eveˆque,
86600 Celle l’Evescault, France. We thank the review-
ers for constructive comments.
P h a r m a cology. P h a r m a cologica l Meth od s: An tioxi-
d a n t P r op er ty. LDL were isolated by ultracentrifugation
from the pooled plasma of healthy normolipidemic human
subjects. The LDL oxidation was promoted by copper (5
µmol-1, 3 h, t ) 24 °C). The compounds in DMSO are
incubated at 10 concentrations just before the beginning of the
oxidation. For each compound, protection against lipid per-
oxidation formation was estimated by dosing the inhibition of
thiobarbituric acid reactive substance at each concentration
according to the method of Yagi.42 For each compound 10
concentrations between 10-7 and 10-3 M were evaluated in
duplicate. The variability between the duplicate was less than
5% in all cases. IC50 values were calculated using linear
regression analysis.
Cyclooxygen a se a n d 5-Lip oxygen a se Activities. Iso-
lated rabbit granulocytes were preincubated during 15 min
at 37 °C with seven different concentrations of compounds
(between 10-5 and 10-8 M in DMSO). Each concentration was
performed in triplicate. Calcic ionophore A 23187 (5 × 10-6
M in DMSO) was added during 15 min. For each compound,
at each concentration, cyclooxygenase and 5-lipoxygenase
inhibition were evaluated by dosing respectively PGE2 and
LTB4 formation using the enzymoimmunoassay (EIA) method.37
Then the IC50 value was calculated using linear regression
analysis. The reference compounds used were indomethacine
(IC50 ) 2.7 × 10-9 M) and NDGA (IC50 ) 4 × 10-7 M)
respectively for inhibition of PGE2 and LTB4 formation.
15-Lyp oxygen a se Activity. Isolated HUVEC were pre-
incubated during 15 min at 37 °C with each compound (10-5
M in triplicate in DMSO). Stimulation was performed using
A 23187 (5 × 10-6 M) in DMSO. To evaluate 15-lipoxygenase
activity, 15-hydroxyeicosatetraenoique (15-HETE) was mea-
sured by radioimmunoassay (RIA).38 Results are expressed
as a percentage of inhibition of control values. The reference
compound used was eicosatetraynoic acid (ETYA) which
inhibited 45 ( 3% of 15-HETE formation at 10-5 M.
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