N-Pyridinyl-indole-3-(alkyl)carboxamides and derivatives as potential systemic and topical inflammation inhibitors

Article abstract of DOI:10.1016/S0223-5234(01)01242-9

N-substituted-(indol-3-yl)carboxamides 10-15 and alkanamides 16-18 were prepared starting from the corresponding acids and submitted to screening for evaluation of their anti-inflammatory activity. None of the considered carboxamides exhibited significant inhibitory effect in the carrageenin-induced rat paw oedema after oral administration of 0.1 mM kg^-1; nevertheless introduction of an alkyl chain, leading to alkanamides 16-18, induced moderate to high activity: 46-95% inhibition. The efficacy of these compounds in the inhibition of topical inflammation was confirmed by measuring reduction of ear thickness in the acute tetradecanoyl phorbol acetate (TPA)-induced mouse ear swelling assay. Preliminary pharmacomodulation brought to the fore that toxic effects induced, at 0.4 mM kg^-1, by N-(pyridin-4-yl)(indol-3-yl)propanamide (17) could be attenuated or suppressed by 5-fluorination or introduction of a methoxycarbonylborane moiety, leading to 18 and 21.

Full text of DOI:10.1016/S0223-5234(01)01242-9

Eur. J. Med. Chem. 36 (2001) 545–553
´
© 2001 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved
PII: S0223-5234(01)01242-9/FLA
Short communication
N-Pyridinyl-indole-3-(alkyl)carboxamides and derivatives as potential systemic
and topical inflammation inhibitors
Muriel Duflosa,*, Marie-Rene´e Nourrissona, Jacques Breleta, Jacqueline Couranta,
Guillaume LeBauta, Nicole Grimaudb, Jean-Yves Petitb
aDepartment of Organic and Medicinal Chemistry, Faculty of Pharmacy, 1 rue Gaston Veil, F-44035 Nantes Cedex, France
bDepartment of Pharmacology and Pharmacokinetics, Faculty of Pharmacy, 1 rue Gaston Veil, F-44035 Nantes Cedex, France
Received 8 February 2001; revised 10 May 2001; accepted 16 May 2001
Abstract – N-substituted-(indol-3-yl)carboxamides 10–15 and alkanamides 16–18 were prepared starting from the corresponding
acids and submitted to screening for evaluation of their anti-inflammatory activity. None of the considered carboxamides exhibited
significant inhibitory effect in the carrageenin-induced rat paw oedema after oral administration of 0.1 mM kg−1; nevertheless
introduction of an alkyl chain, leading to alkanamides 16–18, induced moderate to high activity: 46–95% inhibition. The efficacy
of these compounds in the inhibition of topical inflammation was confirmed by measuring reduction of ear thickness in the acute
tetradecanoyl phorbol acetate (TPA)-induced mouse ear swelling assay. Preliminary pharmacomodulation brought to the fore that
toxic effects induced, at 0.4 mM kg−1, by N-(pyridin-4-yl)(indol-3-yl)propanamide (17) could be attenuated or suppressed by
´
5-fluorination or introduction of a methoxycarbonylborane moiety, leading to 18 and 21. © 2001 Editions scientifiques et me´dicales
Elsevier SAS
amino(methyl)pyridines (derivatives of) / 3-indol(alkyl)carboxamides / systemic and topical inflammation inhibitors
1. Introduction
In a previous work we reported on the synthesis
and biological evaluation of N-(4,6-dimethylpyridin-
2-yl)heteroarylcarboxamides and acetamides as a
novel type of non-acidic anti-inflammatory agents [1].
It was also established that incorporation of amino
acid residues, especially glycine and alanine into 2-
amino-4,6-dimethylpyridine led to potent systemic
and topical inflammation inhibitors [2]. The fact that
some indolylcarboxamides act as anti-allergic [3] and
that indole constitutes the central core of numerous
efficient LTD4 antagonists [4, 5] or inhibitors of
FLAP [6] prompted us to envision pharmacomodula-
tion in the series of related N-pyridinyl-indolyl-
(alkyl)carboxamides I (figure 1). As replacement of
* Correspondence and reprints
E-mail address: muriel.duflos@sante.univ-nantes.fr
(M. Duflos).
Figure 1. General structure of indole-3-(alkyl)carboxamides
10–18 and 21.

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M. Duflos et al. / European Journal of Medicinal Chemistry 36 (2001) 545–553
canoyl phorbol acetate (TPA)-induced mouse ear
oedema tests — will be presented in this paper.
the methylene carbon in a-amino-acids or dipeptides
by a boron atom leads to compounds exhibiting sig-
nificant anti-arthritic [7] and anti-inflammatory activi-
ties [8, 9], in rodents, we also studied the incidence of
incorporation of a methoxycarbonylborane residue in
the pyridine moiety of one active amide.
Their synthesis and preliminary structure–activity
relationships, based on two in vivo assays — the
carrageenin-induced rat paw oedema and the tetrade-
2. Chemistry
The synthetic routes to targeting (indol-3-
yl)carboxamides and alkanamides I are outlined in
figures 2 and 3. The starting acids 5–9 were activated
via phosphoric anhydride, acyloxypyridinium salt,
Figure 2. Reagents: (a) POCl3, DMF, 10 °C, 2 h; (b) NaH, DMF, CH3I, room temperature, 2 h; (c) Cs2CO3, 4F-BnCl, CH3CN,
reflux, 3 h; (d) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, THF, room temperature, 15 h; (e) phenyl dichlorophosphate,
CH2Cl2, room temperature, 12–20 h; (f) 2-chloro-1-methylpyridinium iodide, THF, reflux 20 min; (g) CDI, THF, room temperature,
14 h; (h) DCC, THF, reflux, 48 h; (i) Ph3P, CBrCl3, THF, reflux, 3 h.
Figure 3. Reagents: (a) (CH3)3N–HCl, THF, reflux, 48 h; (b) (1) Et3OBF4, CHCl3, reflux, 24 h; (2) H2O, room temperature, 72 h;
(c) DCC, CH3OH, room temperature, 7 days; (d) 17, CH3CN, reflux, 48 h.

M. Duflos et al. / European Journal of Medicinal Chemistry 36 (2001) 545–553
547
imidazolide, isourea ester or acyloxyphosphonium
salt formation (methods e–i), leading to amides 10–
18 in moderate to excellent yields. Their physicochem-
ical data are summarised in table I.
N-substituted-(indol-3-yl)carboxylic acids 5 and 6
were obtained in excellent yields (83 and 94%, respec-
tively) by oxidation of the corresponding carbalde-
hydes 3 and 4 by the couple NaClO2/NaH2PO4 in the
Table I. Physicochemical data and anti-oedema effect of (indol-3-yl)carboxamides 10–15 and alkanamides 16–18 and 21.

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M. Duflos et al. / European Journal of Medicinal Chemistry 36 (2001) 545–553
Table II. Inhibition percentage of the acute TPA-induced
mouse ear swelling after oral administration of 0.1 mM kg−1
of the indolyl(alkyl)carboxamides 16–18 and 21.
(5-bromoindol-3-yl) carboxamides 10–15 elicits signifi-
cant inhibitory effect ( see table I). Nevertheless, intro-
duction of a methylene and especially an ethylene chain
at C-3, leading to acetamide 16 and propanamide 17
induced a marked increase of activity: 41 11 and 95
3% inhibition, respectively. Unfortunately, this potent
amide 17 elicited toxic effects at 0.4 mM kg−1. Toxicity
could be attenuated or suppressed by the introduction of
a fluorine at C-5 or incorporation of a methoxycar-
bonylborane moiety in the pyridinyl nucleus, leading to
18 and 21, respectively, with maintenance of a high level
of inhibitory activity (86 8 and 84 9%) at 0.1
mM kg−1. Determination of their ID50 afforded the
16
17
18
21
5492
7794
7892
5893
presence of 2-methyl-2-butene, according to Ref. [10].
The non-commercially available 3-(5-fluoroindol-3-
yl)propionic acid 9 [11] was prepared in an overall
yield of 25% by the four-step sequence starting from
4-fluoroaniline:diazotation, condensation with ethyl
2-oxocyclopentane carboxylate under Japp–Klinge-
mann reaction conditions, hydrolysis of the diester
and C-2-decarboxylation by the couple Cu/N-
methylpyrrolidinone. The boron derivative 21 was
obtained, via an amine exchange reaction [12], from
N-(pyridin-4-yl)-3-(indol-3-yl)propanamide (17) and
following values: 35 13, 26 5 and 49 14 mM kg−1
.
Thus, N-(pyridin-4-yl)-5-fluoro-indol-3-yl)propanamide
(18) appears as the most potent non-acidic NSAID ever
discovered in our series of N-pyridinyl-heteroary-
l(alkyl)carboxamides. The level of activity is comparable
with that of oxicam derivatives [18].
trimethylaminomethoxycarbonylborane
(20),
in
3.2. Effect in the acute TPA-induced mouse ear swelling
test
refluxing acetonitrile (figure 3); due to delicate purifi-
cation, the yield remained poor (11%); attempts to
improve it by operating in DMF, at different temper-
atures, failed. Compound 20 [12, 13] was synthesised
by the reaction of trimethylamine hydrochloride with
sodium cyanoborohydride leading to trimethy-
laminocyanoborane (19); hydrolysis of the intermedi-
ate nitrilium tetrafluoroborate afforded the acid
which was converted into the corresponding ester 20
after DCC activation.
It is well established that prostaglandin [19] and leu-
cotriene (LTB4, 12-HETE) [20] concentrations are ele-
vated in psoriatic skin. Moreover, evidence was found in
psoriatic tissue of increased expression of human non-
pancreatic phospholipase A2 [21] and of the up-regula-
tion of various cytokines (IL-1, TNFa) stimulating
endothelial cell adhesiveness for lymphocytes [22]. As
psoriatic skin shares many of the pathologic features of
phorbol ester-treated mouse skin [23], the effect of the
most active compounds was evaluated in a model of
topical inflammation, the acute TPA-induced mouse ear
swelling test [24]. After oral administration of 0.1
mM kg−1, the four selected amides 16–18 and 21 ex-
erted a significant reduction in ear thickness (see table
II). The 5-fluorinated propanamide 18, less toxic than
17, exhibited a level of activity comparable to that of the
latter: 78 2 and 77 4%, respectively.
3. Pharmacology
3.1. Effect in the carrageenin paw oedema test
The nine indole(alkyl)carboxamides 10–18 were
tested on carrageenin-induced rat paw oedema, by the
oral route, using 0.1 mM kg−1. Our earlier work in the
field of non-acidic anti-inflammatory aryl(alkyl)carbox-
amides, incorporating different amino groupings,
brought to the fore that 2-amino-4,6-dimethylpyridine
[14], 4-aminopyridine [15], 3-aminomethylpyridine [16]
and N-benzylpiperazine (J. Brelet, personal communica-
tion) represent the most potent pharmacophoric moi-
eties in inflammation process inhibition. Although it was
previously stated that nuclear bromination of N-
pyridinyl(hetero)arylcarboxamides was liable to increase
their anti-oedematous effect [17], none of the six used
4. Conclusions
The present preliminary results suggest that 18 may
prove to be a valuable candidate as the lead structure
for further pharmacomodulation in the series of
amides issued from 3-(indol-3-yl)propionic acids. This
new lead compound and derivatives are now being
evaluated in the multiple TPA-induced model of

M. Duflos et al. / European Journal of Medicinal Chemistry 36 (2001) 545–553
549
chronic inflammation [25] considered to be a relevant
model of human psoriasis. Moreover, a first approach
of the mechanism of action of 18 will be carried out
by in vitro determination of the inhibition of TNFa
production, taking into account that structurally re-
lated compounds inhibit TNFa production from
LPS-activated macrophages [26].
(DMSO-d6, ppm): l 7.43 (dd, 1H, H6, J=8.6, 2.0 Hz),
7.54 (d, 1H, H7), 8.26 (d, 1H, H4), 8.39 (s, 1H, H2), 9.97
(s, 1H, CHO), 12.35 (s, 1H, NH).
5.1.2. (5-Bromo-1-methylindol-3-yl)carboxaldehyde (3)
[28]
Methylation of (5-bromoindol-3-yl) carboxaldehyde
(2) was carried out with methyl iodide after deprotona-
tion by NaH in DMF. The crude N-derivative 3 was
purified by chromatography on silica-gel eluting with
dichloromethane, yield: 98.5%; m.p. 133 °C (CH2Cl2),
lit. [28] 130–133 °C (CH2Cl2–petroleum ether). IR
5. Experimental protocols
5.1. Chemistry
1
(KBr, cm−1): w(CꢀO) 1653. H-NMR (DMSO-d6, ppm):
l 3.93 (s, 3H, H, CH3), 7.50 (dd, 1H, H6, J=8.7, 2.0
Hz), 7.62 (d, 1H, H7), 8.26 (d, 1H, H4), 8.37 (s, 1H, H2),
9.93 (s, 1H, CHO).
Melting points (m.p.) were determined on a Tottoli–
Bu¨chi apparatus and were uncorrected. Structures were
supported by IR and 1H-NMR. IR spectra were
recorded on a Perkin–Elmer Paragon PC 1000 spec-
trometer as potassium bromide discs or as a film on
NaCl plates. 1H-NMR spectra were recorded on a
Bruker AC 250 spectrometer (250 MHz) using CDCl3 or
(CH3)2SO-d6 as solvent. Chemical shifts l (ppm) refer to
tetramethylsilane, which was used as the internal refer-
ence; coupling constants are in Hz. Analytical TLC was
performed on precoated silica-gel aluminium (0.2 mm,
GF254, E. Merck). Spots were located by UV illumina-
tion. Sodium sulfate or phosphorus pentoxide was used
as the drying agent. Column chromatography was con-
ducted on silica-gel (Kieselgel 60, 70–230 mesh, E.
Merck) and for delicate separations, a preparative cen-
trifugally accelerated TLC (Chromatotron 7924 T, Har-
risson Research, Palo Alto, CA) was used.
Microanalyses for C, H, and N, were performed using a
Perkin–Elmer C, H, N 240 apparatus; the analytical
results were within 0.4% of the theoretical values.
(Indol-3-yl)acetic and propionic acids 7 and 8 were
purchased from Aldrich Chimie (Saint-Quentin-
Fallavier, France); (5-fluoroindol-3-yl)propionic acid (9)
was prepared according to Ref. [11]. Other starting
materials and reagents were obtained commercially from
Aldrich Chimie, Acros (Noisy-le Grand, France) or
Interchim (Montluc¸on, France).
5.1.3. [5-Bromo-1-(4-fluorobenzyl)indol-3-yl]-
carboxaldehyde (4)
To a solution of (5-bromoindol-3-yl)carboxaldehyde
(2) (2.5 g, 11.15 mmol) in dry CH3CN (50 mL) was
added Cs2CO3 (7.26 g, 22.3 mmol). The suspension was
stirred for 2 h under reflux and 4-fluorobenzylchloride
(1.5 mL, 12.5 mmol) was progressively added. The
reaction mixture was stirred under reflux for 1 h. After
filtration and addition of water (50 mL), the aqueous
phase was extracted with dichloromethane (3×50 mL);
the organic layers were washed with saturated NaCl
solution, dried (Na2SO4), filtered and concentrated.
Purification by chromatography on silica-gel, eluting
with dichloromethane, afforded 4 (3.7 g) as a pale pink
powder, yield: 99%; m.p. 130 °C (CH2Cl2). IR (KBr,
1
cm−1): w(CꢀO) 1653. H-NMR (DMSO-d6, ppm): l 5.58
(s, 2H, CH2), 7.22 (m, 2H, benz. H2, H6), 7.43 (m, 2H,
benz. H3, H5), 7.46 (dd, 1H, H6, J=8.8, 2.0 Hz), 7.64
(d, 1H, H7), 8.28 (d, 1H, H4), 8.57 (s, 1H, H2), 9.97 (s,
1H, CHO).
5.1.4. (5-Bromo-1-methylindol-3-yl)carboxylic acid (5)
Aldehyde 3 (3 g, 12.6 mmol) was dissolved in a
mixture of THF (225 ml) and t-butanol (63 mL). A 2 M
2-methyl-2-butene solution in THF (72 mL, 14.4 mmol)
was first added, followed by a solution of NaClO2 (3.43
g, 37.9 mmol) and NaH2PO4 (6.86 g, 57.2 mmol) in
water (55 mL). The mixture was stirred overnight at
room temperature (r.t.). A solution of NaClO2 (2.25 g,
25 mmol) and NaH2PO4 (4.5 g, 37.5 mmol) in 90 mL of
water was then added and the reaction medium was
stirred for 2 h. The organic solvents were removed, and
the aqueous phase was filtered. The precipitate contain-
5.1.1. (5-Bromoindol-3-yl)carboxaldehyde (2) [27]
This aldehyde was prepared from 5-bromoindole (1),
by the Vilsmeyer–Hack method (POCl3, DMF). The
precipitate formed by heating in alkaline solution was
separated by filtration, washed with water (4×100 mL)
affording 5.7 g of pure aldehyde 2 as a pale yellow
powder, yield: 99.5%; m.p. 201 °C (H2O), lit. [27]
1
205 °C (H2O). IR (KBr, cm−1): w(CꢀO) 1644. H-NMR

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M. Duflos et al. / European Journal of Medicinal Chemistry 36 (2001) 545–553
ing the expected acid was purified by chromatography
on silica-gel; elution with diethyl ether afforded 5 (2.55
g) as a white powder, yield: 80%; m.p. 270 °C (Et2O).
IR (KBr, cm−1): w(OH) 2924, 2582, w(CꢀO) 1650,
5.1.8. N-(4,6-Dimethylpyridin-2-yl)-
[5-bromo-1-(4-fluorobenzyl)indol-3-yl]carboxamide (12)
Amide 12 was prepared according to procedure ‘e’
and isolated as a white powder; yield: 56%; m.p. 144 °C
(CH2Cl2). IR (KBr, cm−1): w(NH) 3417, w(CꢀO) 1664.
1H-NMR (DMSO-d6, ppm): l 2.34 (s, 3H, g-CH3), 2.42
(s, 3H, a-CH3), 5.50 (s, 2H, CH2), 6.84 (s, 1H, pyr. H5),
7.23 (m, 2H, benz. H2, H6), 7.39 (dd, 1H, H6, J=8.7,
2.0 Hz), 7.45 (m, 2H, benz. H3, H5), 7.65 (d, 1H, H7),
7.96 (s, 1H, pyr. H3), 8.42 (d, 1H, H4) 8.75 (s, 1H, H2),
10.34 (s, 1H, NH). Anal. C23H19BrFN3O (C, H, N).
1
l(OH) 907. H-NMR (DMSO-d6, ppm): l 3.87 (s, 3H,
CH3), 7.40 (dd, 1H, H6, J=8.7, 2.0 Hz), 7.55 (d, 1H,
H7), 8.11 (s, 1H, H2), 8.18 (d, 1H, H4), 12.28 (s, 1H,
COOH).
5.1.5. [5-Bromo-1(4-fluorobenzyl)indol-3-yl]carboxylic
acid (6)
Carboxylic acid 6 was prepared according to the same
procedure ‘d’ and was isolated as a white powder, yield:
94%; m.p. 218 °C (Et2O). IR (KBr, cm−1): w(OH) 2885,
5.1.9. N-(Pyridin-4-yl)-[5-bromo-1-(4-fluorobenzyl)-
indol-3-yl]carboxamide (13)
1
2750, w(CꢀO) 1651, l(OH) 939. H-NMR (DMSO-d6,
Amide 13 was synthesised according to procedure ‘e’
and isolated as white crystals; yield: 42%; m.p. 240 °C
(CH2Cl2). IR (KBr, cm−1): w(NH) 3415, w(CꢀO) 1646.
1H-NMR (DMSO-d6, ppm): l 5.58 (s, 2H, CH2), 7.23
(m, 2H, benz. H2, H6), 7.37 (m, 2H, benz. H3, H5), 7.43
(dd, 1H, H6, J=8.8, 2.1 Hz), 7.64 (d, 1H, H7), 7.77 (m,
2H, pyr. H3, H5), 8.40 (d, 1H, H4), 8.48 (m, 2H, pyr. H2,
H6), 8.53 (s, 1H, H2), 10.24 (s, 1H, NH). Anal.
C21H15BrFN3O (C, H, N).
ppm): l 5.53 (s, 2H, CH2), 7.19 (m, 2H, benz. H2, H6),
7.36 (m, 2H, benz. H3, H5), 7.36 (dd, 1H, H6, J=8.8,
2.0 Hz), 7.58 (d, 1H, H7), 8.19 (d, 1H, H4), 8.34 (s, 1H,
H2), 12.34 (s, 1H, COOH).
5.1.6. N-(4,6-Dimethylpyridin-2-yl)-
(5-bromo-1-methylindol-3-yl)carboxamide (10)
A suspension of 5 (0.9 g, 3.5 mmol), triethylamine
(1.4 mL, 10.5 mmol) and 2-amino-4,6-dimethylpyridine
(0.44 g, 3.5 mmol) in dry CH2Cl2 (20 mL) was cooled to
0 °C. Phenyl dichlorophosphate (0.53 mL, 3.5 mmol)
was then added dropwise. The mixture was stirred at r.t.
for 20 h. After washing with water (2×20 mL) and with
5% aqueous NaHCO3 (30 mL), the organic layer was
dried (Na2SO4) and evaporated under reduced pressure.
The residue was purified by column chromatography
(CH2Cl2–ethanol, 95:5) to afford 0.37 g of 10 which was
recrystallised from CH2Cl2 to provide a white solid,
yield: 27%; m.p. 201 °C (CH2Cl2). IR (KBr, cm−1):
5.1.10. N-[(Pyridin-3-yl)methyl]-
(5-bromo-1-(4-fluorobenzyl)indol-3-yl)carboxamide (14)
Amide 14 was prepared according to procedure ‘e’
and isolated as a white solid; yield: 70%; m.p. 187 °C
(CH2Cl2). IR (KBr, cm−1): w(NH) 3417, w(CꢀO) 1630.
1H-NMR (DMSO-d6, ppm): l 4.52 (d, 2H, CH2ꢁNH,
J=5.7 Hz), 5.50 (s, 2H, CH2), 7.21 (m, 2H, benz. H2,
H6), 7.37 (m, 3H, pyr. H5, benz. H3, H5), 7.40 (dd, 1H,
H6, J=8.8 Hz, 2.0 Hz), 7.60 (d, 1H, H7), 7.78 (d, 1H,
pyr. H6, J=7.8 Hz), 8.24 (s, 1H, pyr. H2), 8.37 (d, 1H,
H4), 8.50 (d, 1H, pyr. H4, J=3.5 Hz), 8.61 (s, 1H, H2),
8.69 (t, 1H, NH, J=5.7 Hz). Anal. C22H17BrFN3O (C,
H, N).
1
w(NH) 3415, w(CꢀO)1657. H-NMR (DMSO-d6, ppm):
l 2.33 (s, 3H, g-CH3), 2.42 (s, 3H, a-CH3), 3.88 (s, 3H,
NꢁCH3), 6.83 (s, 1H, pyr. H5), 7.42 (dd, 1H, H6, J=
8.75, 1.8 Hz), 7.56 (d, 1H, H7), 7.96 (s, 1H, pyr. H3),
8.43 (d, 1H, H4), 8.62 (s, 1H, H2), 10.23 (s, 1H, NH).
Anal. C17H16BrN3O (C, H, N).
5.1.11. 1-{[5-Bromo-1-(4-fluorobenzyl)indol-3-yl]-
carbonyl}-4-benzylpiperazine (15)
5.1.7. N-(4-Pyridinyl)-(5-bromo-1-methylindol-3-yl)-
carboxamide (11)
5.1.11.1. Method f
A solution of 6 (0.5 g, 1.4 mmol), 1-benzylpiperazine
(0.3 mL, 1.4 mmol) triethylamine (0.5 mL, 3.57 mmol)
and 2-chloro-1-methylpyridinium iodide (0.4 g, 1.4
mmol) in dry CH2Cl2 was refluxed for 20 min. The
solvent was evaporated and the residue was purified by
column chromatography (diethyl ether) to give 0.45 g of
15 as a white powder, yield: 62%; m.p. 115 °C (Et2O).
Amide 11 was prepared according to the same proce-
dure ‘e’ and isolated as a white solid; yield:55%; m.p.
308 °C (CH2Cl2). IR (KBr, cm−1): w(NH) 3409, w(CꢀO)
1
1676. H-NMR (DMSO-d6, ppm): l 3.93 (s, 1H, CH3),
7.47 (dd, 1H, H6, J=8.70, 1.9 Hz), 7.61 (d, 1H, H7),
8.32 (m, 2H, pyr. H3, H5), 8.36 (d, 1H, H4), 8.65 (m, 2H,
pyr. H2, H6), 8.88 (s, H, H2), 11.34 (s, 1H, NH). Anal.
C15H12BrN3O (C, H, N).
IR (KBr, cm−1): w(NH) 3445, w(CꢀO) 1600. H-NMR
1

M. Duflos et al. / European Journal of Medicinal Chemistry 36 (2001) 545–553
551
(DMSO-d6, ppm): l 2.45 (m, 4H, pip. H), 3.55 (s, 2H,
benz. CH2), 3.69 (m, 4H, pip. H), 5.48 (s, 2H, benz.
CH2), 7.14–7.37 (m, 8H, H6+7 benz. H), 7.18 (m, 2H,
benz. H3, H5), 7.53 (d, 1H, H7, J=8.7 Hz), 7.92 (d, 1H,
H4, J=1.7 Hz), 8.05 (s, 1H, H2). Anal. C27H25BrFN3O
(C, H, N).
5.1.13. N-(Pyridin-4-yl)-(indol-3-yl)propanamide (17)
Amide 17 was prepared according to procedure ‘h’
and was obtained as a white powder, yield: 66%, m.p.
100 °C (petroleum ether). IR (KBr, cm−1): w(NH) 3300,
1
w(CꢀO) 1700, l(NH) 1520, (comb. NH/CN) 1305. H-
NMR (DMSO-d6, ppm): l 2.80 (t, 2H, CH2CO, J=7
Hz), 3.07 (t, 2H, CH2), 7.00 (ddd, 1H, H6, J=7.95, 6.9,
1.2 Hz), 7.09 (ddd, 1H, H5, J=7.6, 6.9, 1.1 Hz), 7.19 (d,
1H, H2, J=2.3 Hz), 7.36 (d, 1H, H7), 7.60 (d, 1H, H4),
7.81 ( d, 2H, pyr. H3, H5, J=4.5 Hz), 8.60 (d, 2H, pyr.
H2, H6), 10.92 (s, 1H, amid. NH), 11.60 (s, 1H, NH).
Anal. C16H15N3O (C, H, N).
5.1.11.2. Method g
N-N%-Carbonyldiimidazole (0.23 g,1.4 mmol) was
added gradually to a solution of 6 (0.5 g, 1.4 mmol) in
dry THF (20 mL). The mixture was stirred at r.t. for 1
h. N-Benzylpiperazine (0.25 g, 1.4 mmol) was added and
stirring was continued for one night. The solvent was
evaporated and the crude amide 15 was purified by
chromatography on silica-gel eluting with diethyl ether
to give 0.39 g of 15 as white powder, yield: 55%; m.p.
115 °C (Et2O).
This amide was obtained in a higher yield (76%) by
method ‘e’.
5.1.14. N-(Pyridin-4-yl)-(5-fluoroindol-3-yl)propanamide
(18)
Amide 18 was obtained according to procedure ‘h’
and was isolated as a white solid, yield: 58%; m.p.
150–155 °C (AcOEt). IR (KBr, cm−1): w(NH) 3400,
3305, 3260, w(CꢀO) 1675, l(NH) 1525, (comb. NH/CN)
1285. 1H-NMR (DMSO-d6, ppm): l 2.74 (t, 2H,
CH2ꢁCO, J=7.0 Hz), 3.03 (t, 2H, CH2), 6.94 (ddd, 1H,
H6, J=8.5, 1.5 Hz), 7.25 (s, 1H, H2), 7.33–7.39 (m, 2H,
H4, H7), 7.60 (dd, 2H, pyr. H3, H5, J=4.5, 1.2 Hz), 8.45
(d, 2H, pyr. H2, H6), 10.33 (s, 1H, amid. NH), 10.92 (s,
1H, NH). Anal. C16H14FN3O (C, H, N).
5.1.12. N-(Pyridin-4-yl)-indol-3-yl)acetamide (16)
5.1.12.1. Method h
N-N%-Dicyclohexylcarbodiimide (2.1 g, 10.2 mmol)
and 4-aminopyridine (0.99 g, 10 mmol) were added to a
solution of indole-3-acetic acid 7 (1.75 g, 10 mmol) in
anhydrous THF (50 mL). After 48 h reflux under stir-
ring, the white precipitate of dicyclohexylurea was
filtered and washed with AcOEt. The filtrate was evapo-
rated under reduced pressure. The residue was purified
by silica-gel chromatrography (CH2Cl2–EtOH, 95:5) to
afford 1.46 g of pure 16 as pale yellow crystals, yield:
58%; m.p. 230 °C (EtOH). IR (KBr, cm−1): w(NH)
3295, w(CꢀO) 1700, l(NH) 1515, (comb. NH/CN) 1290.
1H-NMR (DMSO-d6, ppm): l 3.78 (s, 1H, CH2), 6.98
(m, 1H, H5), 7.08 (m, 1H, H6), 7.27 (d, 1H, H2, J=1.5
Hz), 7.36 (dd, 1H, H7, J=7.75, 1.0 Hz), 7.55–7.60 (m,
3H, H4, pyr. H3, H5), 8.41 (dd, 2H, pyr. H2, H6, J=4.5,
1.25 Hz), 10.49 (s, 1H, amid. NH), 10.95 (s, 1H, NH).
Anal. C15H13N3O (C, H, N).
5.1.15. N,N,N-Trimethylaminomethoxycarbonylborane
(20) [12]
N,N,N-Trimethylaminocyanoborane (19), obtained
according to Ref. [29] in 74% yield, was refluxed for 24
h in a freshly prepared [30] solution of 1 M triethyloxo-
nium tetrafluoroborate in CH2Cl2. Hydrolysis (H2O)
afforded N,N,N-trimethylaminocarboxyborane as white
crystals; yield: 54%. The waited ester was prepared by
reaction of the previously activated acid 19 with DCC,
in methanol for 7 days at r.t. Recrystallisation from
hexane–CH2Cl2 (9:1) afforded 20 as a white powder in
a quantitative yield; m.p. 98–100 °C, lit. [13] 90–92 °C.
1
5.1.12.2. Method i
IR (KBr, cm−1): w(BH) 2387, w(CꢀO) 1670. H-NMR
Triphenylphosphine (4.49 g, 17.1 mmol), bro-
motrichloromethane (6.8 g, 34.2 mmol) and indole-3-
acetic acid (7) (3 g, 17.1 mmol) were dissolved in dry
THF (100 mL). After 10 min stirring, 4-aminopyridine
(3.22 g, 34.2 mmol) was added and the reaction mixture
was heated under reflux for 3 h. After filtration, the
organic phase was concentrated under vacuum to give a
yellow residue. Purification by column chromatography
afforded pure 16 in 35% yield.
(CDCl3, ppm): l 2.68 (s, 9H, 3CH3), 3.39 (s, 3H, CH3).
5.1.16. 4-{[3-Indol-3-yl)-1-oxopropyl]amino}-
pyridine-methoxycarbonylborane (21)
A solution of amide 17 (1.32 g, 5 mmol) and trimethy-
laminomethoxycarbonylborane (20) (0.65 g, 5 mmol) in
freshly distilled CH3CN was maintained under reflux for
48 h. After evaporation of the solvent under reduced
pressure, the organic residue was purified by column

552
M. Duflos et al. / European Journal of Medicinal Chemistry 36 (2001) 545–553
chromatography; elution with CH2Cl2–ethanol (98:2 up
to 96:4) afforded 0.185 g of pure 21 as a pale yellow
powder, yield: 11%; m.p. 135 °C (CH2Cl2). IR (KBr,
before TPA application. Ear thickness was measured
with a model micrometer gauge (Oditest Kroeplin) 3.5 h
after treatment. Ear oedema was calculated by subtract-
ing the thickness of the left ear (vehicle) from the
thickness of the right ear (treatment) and was expressed
as an increase in ear thickness. The percentage of inhibi-
tion of the inflammatory reaction was determined for
each animal by comparison with controls.
1
cm−1): w(BH) 2399, w(CꢀO) 1628. H-NMR (DMSO-d6,
ppm): l 3.2 (t, 2H, CH2ꢁCO, J=7.0 Hz), 3.5 (t, 2H,
CH2), 3.8 (s, 3H, CH3), 7.38 (s, 1H, H2), 7.42 (dd, 1H,
H5, J=7.6, 6.7 Hz), 7.52 (dd, 1H, H6, J=7.9, 6.7 Hz),
7.6 (d, 1H, H7), 7.91 (d, 1H, H4), 7.97 (d, 2H, pyr. H3,
H5, J=6.7 Hz), 8.40 (d, 2H, pyr. H2, H6), 10.83 (s, 1H,
amid. NH), 11.0 (s, 1H, NH). Anal. C18H20BN3O3 (C,
H, N).
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