Synthesis of a novel class of non-peptide NK-2 receptor ligand, derived from 1-phenyl-3-pyrrol-1-ylindan-2-carboxamides

Article abstract of DOI:10.1016/S0968-0896(01)00360-1

A series of trans,trans-1-phenyl-3-pyrrol-1-ylindan-2-carboxamide derivatives has been synthesized in eight steps starting from cinnamic acid or 3,3-diphenylpropionic acid. The trans,trans configuration of these carboxamides has been established by X-ray analysis and by NOE experiments in NMR. These new compounds were evaluated for their potential NK-1, NK-2 and NK-3 receptors binding affinity. The N,N-disubstituted carboxamides bound selectively on NK-2 receptors. Copyright

Full text of DOI:10.1016/S0968-0896(01)00360-1

Bioorganic & Medicinal Chemistry10 (2002) 1043–1050
Synthesis of a Novel Class of Non-Peptide NK-2 Receptor Ligand,
Derived from 1-Phenyl-3-pyrrol-1-ylindan-2-carboxamides
Jean Guillon,a Patrick Dallemagne,b,* Jean-Michel Leger,a Jana Sopkova,b
Philippe R. Bovy,c Christian Jarrya and Sylvain Raultb
a
´
EA 2962—Pharmacochimie, UFR des Sciences Pharmaceutiques, Universite Victor Segalen Bordeaux 2,
´
146, rue Leo Saignat, 33076 Bordeaux Cedex, France
´
b
Centre d’Etudes et de Recherche sur le Medicament de Normandie, UFR des Sciences Pharmaceutiques,
´
´
Universite de Caen, 1, rue Vaubenard, 14032 Caen Cedex, France
Synthelabo, 10, rue des Carrieres, 92500 Rueil-Malmaison, France
c
´
`
Received 3 July2001; accepted 8 October 2001
Abstract—A series of trans,trans-1-phenyl-3-pyrrol-1-ylindan-2-carboxamide derivatives has been synthesized in eight steps starting
from cinnamic acid or 3,3-diphenylpropionic acid. The trans,trans configuration of these carboxamides has been established byX-
rayanalysis and byNOE experiments in NMR. These new compounds were evaluated for their potential NK-1, NK-2 and NK-3
receptors binding affinity. The N,N-disubstituted carboxamides bound selectivelyon NK-2 receptors. # 2002 Elsevier Science Ltd.
All rights reserved.
Introduction
SR-4896815,16 and some phenylpiperonylindan-2-car-
boxamides 1,17 are representative of the large structural
diversityfound in this class of compounds (Fig. 1).
Taking into account all the recent SAR studies realized
on theses various series,10ꢀ17 we designed a number of
chemical models which could offer, in principle, realistic
opportunities to be potent NK-1, NK-2 or NK-3
receptor antagonists. In this report, we described the
synthesis and the first preliminary in vitro evaluation of
new trans,trans-1-phenyl-3-pyrrol-1-ylindan-2-carbox-
amides 2, a novel chemical class of potential non-pep-
tide antagonists for the NK-2 receptors (Fig. 2).
The tachykinins,1 a group of small peptides which are
released from sensorynerves, are implicated in a wide
range of pathophysiological conditions (including noci-
ceptive, inflammatory, and immunoregulatory pro-
cesses, airwayobstruction and asthma, skin disorders,
inflammatorybowel disease, emesis, and various CNS
disorders).2ꢀ6 The three main endogenous tachykinins
identified to date, substance P, neurokinin A (NKA),
and neurokinin B (NKB), interact with three neurokinin
receptors (NK-1, NK-2 and NK-3). These receptors,
widelydistributed in both the central nervous system
(CNS) and periphery,7 belong to the seven transmem-
brane G-protein-coupled receptors superfamily(7TM-
GPCR).2 Since the discoveryin 1991 of CP-96,345, 8 the
first potent non-peptide human neurokinin-1 (NK-1)
receptor antagonist from Pfizer, and of RP-67,580,9
another potent NK-1 receptor antagonist identified
from random screening byRho ne-Poulenc in 1992,
interest in the tachykinin area has widely increased and
manyresearch groups dedicated efforts to the identifi-
cation of non-peptide antagonists selective for the three
neurokinin receptors. Among the most interesting
described antagonists,10 CP-99,994,11 SB-223412,12ꢀ14
Chemistry
The general methodologyadopted for the synthesis of
carboxamides 2 is summarized in Scheme 1.18 Con-
densation between benzene and cinnamic acid in the
presence of AlCl3 or cyclization of 3,3-diphenylpro-
pionic acid with polyphosphoric acid (PPA) afforded
the 3-phenylindan-1-one 4. The reaction of 4 with ethyl
carbonate gave the cetoester 5, subsequentlyfunctiona-
lized on the 1-position with ammonium acetate to afford
the enaminoester 6. A mixture of the isomers 7 and 8
was obtained from 6 through a Clauson–Kaas reaction
involving probablya thermal [1,3] sigmatropic rearran-
gement. The hydrogenation of the indenes 7 and 8 by
using NaBH4–NiCl2, 6H2O yielded a mixture of the all-
*Corresponding author. Fax: +33-2-3193-1188; e-mail: dallemagne@
pharmacie.unicaen.fr
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00360-1

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J. Guillon et al. / Bioorg. Med. Chem. 10 (2002) 1043–1050
Figure 1. Structures of CP-96,345, RP-67,580, CP-99,994, SB-223412, SR 48968 and compounds 1.
trans 9 and all-cis 10 epimers. Finallythe saponification
of the two diastereomers 9 and 10 afforded the trans–
trans acid 3 via an epimerization at C-2. The trans–trans
configuration of 3 was established byX-raycrsytal-
NK-3 receptors.19ꢀ21 The results expressed as IC50 and
Ki are reported in Table 2. Although 2a, 2b and 2g
bound selectivelyon NK-2 receptors with Ki varying
from 0.633 (2b) to 0.733 mM (2g), none of the test com-
pounds exerted affinityagainst NK-1 and NK-3 recep-
tors. From a structure–activityrelationship point of
view, these results seem to indicate that the disubstitu-
tion of the carboxamide nitrogen atom was essential for
a selective NK-2 binding affinity. These results could be
related to the X-raycrystallographydata established for
a secondaryamide ( 2d). The oxygen atom of the amide
group O(22) pointed away from the pyrrole and phenyl
rings. The crystalline cohesion was ensured by one
intermolecular H-bond between N(23) of molecule I (x,
y, z) and O(22) of molecule II (1+x, y, z): N(23, I) . . .
O(22, II)=2.866(4) A, H(123, I) . . . O(22, II)=2.04 A,
N(23, I) ꢀ H(123, I) . . . O(22, II)=162.4ꢁ. This H-bond,
lography(Fig. 3, Table 1). The crystal structure for
3
revealed a particular spatial conformation of the phenyl
and pyrrole rings allowing an easy and free access to the
acid function.
Acid 3 treated by triethylamine and then by ethyl
chloroformate gave in situ the carbonic mixed anhy-
dride 11 which was reacted with various primaryor
secondaryamines to afford the trans,trans-1-phenyl-3-
pyrrol-1-ylindan-2-carboxamides 2a–h purified bycrys-
tallization from diethyl ether or by chromatography on
silica gel (Scheme 1). Assignment of the relative config-
uration of carboxamides 2 was made on the basis of
NOE experiments. Specifically, irradiation of H-2 in 2
led to an NOE with H-20 and H-60 of the 1-phenyl group
and H-a of the pyrrole. These observations were con-
sistent with a trans stereochemical relationship between
H-2 and the H-1 and H-3 in 2. For 2d, this all-trans
configuration was confirmed from the X-rayanalsyis
data (Fig. 4, Table 1).
onlydefined for the secondarycarboxamides
2c–f,h,
seems to be the necessarycohesion factor for obtaining
a solid form. Inversely, the tertiary amides 2a–b,g were
always isolated as oily compounds. Moreover, the lack
of such a H-bond in tertiarycarboxamides 2a–b,g could
offer a better flexibilitythan for the secondaryones.
This structural discrimination could have some con-
sequences on the pharmacological activityof 2a–b,g via
their possible fixation on NK-2 receptor versus the
inabilityfor establishing such fixation for the pharma-
cological inactive secondaryamides 2c–f,h. Evaluation
of the antagonistic potencyof 2a–b,g on specific isolated
organs as well as their in vivo activityare currently
under investigation.
Results and Discussion
The synthesized compounds 2a–h were tested for their
in vitro binding affinityon tachykinin NK-1, NK-2 and
Experimental
Chemistry
Melting points were determinated on a Kofler block and
are uncorrected. IR spectra were recorded on a Unicam
Mattson 1000 FTIR spectrophotometer. NMR spectra
(1H, 13C, 1H-COSY, NOE) were recorded at 400 or
Figure 2. Identification of the trans,trans-1-phenyl-3-pyrrol-1-ylindan-
2-carboxamides 2.

J. Guillon et al. / Bioorg. Med. Chem. 10 (2002) 1043–1050
1045
Scheme 1. Reagents: (i) AlCl3, C6H6, 38%; (ii) PPA, 30%; (iii) (C2H5O)2CO, Na, 82%; (iv) CH3COONH4, C2H5OH, 94%; (v) 2,5-diMeOTHF,
.
.
C5H4ClN HCl, 1,4-dioxane, 90% (7/8: 1/1); (vi) NiCl2 6H2O, NaBH4, CH3OH, 87% (9/10: 3/1); (vii) (a) NaOH, C2H5OH, H2O; (b) HCl, H2O, 79%
from 9 and 10; (viii) Et3N, ClCOOEt; (ix) HNR1R2, 36–57%.
100 MHz with tetramethylsilane as an internal standard
using a JEOL JNM-LA 400 spectrometer. Splitting
patterns have been designated as follows: s=singlet;
bs=broad singlet; d=doublet; t=triplet; q=quartet;
dd=double doublet; m=mutiplet. The samples used for
NOE experiments were degassed bybubbling nitrogen
through the solution. Mass spectra were recorded on a
JEOL GC mate instrument using direct inlet system and
electron impact ionisation. Analytical TLC was carried
out on 0.25 precoated silica gel plates (Polygram SIL G/
UV254) with visualisation byirradiation with a UV
lamp. Silica gel 60 (70–230 mesh) was used for column
chromatography. Analyses indicated by the symbols of
the elements were within ꢂ0.3% of the theoretical
values.
Ethyl 3-amino-1-phenyl-1H-inden-2-carboxylate (6). To
a solution of 5 (0.043 mol) in 120 mL of ethanol were
added portionwise ammonium acetate (1.07 mol). The
reaction mixture was refluxed for 20 h then evaporated
to dryness. The residue was triturated in water and
made alkaline with sodium hydrogenocarbonate. The

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J. Guillon et al. / Bioorg. Med. Chem. 10 (2002) 1043–1050
Figure 3. The ORTEP drawing of carboxylic acid 3 with thermal ellipsoids at 30% level.
Table 1. The crystallographic data of compounds 3 and 2d
X-raydata
Cryst syst
Space group
Cell dimension
3
Triclinic
P-1
9.809(1) A
2d
Monoclinic
P21/n
a
b
c
5.018(2) A
27.242(5) A
18.977(5) A
96.33(3) ꢁ
11.113(1) A
16.090(2) A
b
95.14(1) ꢁ
V
Z
Dx
F(000)
Crystal size
1642.4(3) A3
2578.3(13) A3
4
2
1.227 Mg mꢀ3
640
1.361 Mg mꢀ3
1088
0.32ꢃ0.25ꢃ0.10 mm3
0.70ꢃ0.20ꢃ0.05 mm3
No. of unique refl. Meads
Refinement method
Goodness-of-fit on F2
R[I>2S(I)]
4776
3243
Full-matrix least-squares on F2
Full-matrix least-squares on F2
1.081
0.0666
1.020
0.0748
0.1956
WR2
0.1751
General procedure for ethyl phenyl-pyrrolyl-1H-inden-2-
carboxylate (7) and (8)
precipitate was filtered, washed with water and dis-
solved in dichloromethane. The organic layer was
washed with a saturated aqueous sodium hydro-
genocarbonate solution, dried over calcium chloride,
filtered and evaporated to dryness to yield compound 6
as white crystals (94%); mp 118 ꢁC. IR (KBr) 3460,
To a solution of 6 (0.045 mol) in 170 mL of dioxane
were added 2,5-dimethoxytetrahydrofuran (0.045 mol)
and then 4-chloropyridine hydrochloride (0.045 mol).
The reaction mixture was refluxed for 3 h then evapo-
rated to dryness under reduced pressure. After cooling,
the residue was extracted with diethyl ether and filtered.
The organic layer was washed with a 1 N hydrochloric
acid solution then with a saturated aqueous solution of
sodium hydrogenocarbonate, dried over magnesium
sulfate and evaporated to dryness to give an orange oil
(90%) which was purified bychromatographyon silica
gel with methylene chloride as eluant.
1
3360 (NH), 1655 (CO); H NMR (CDCl3) d 7.41 (m,
1H, H-4), 7.30 (m, 2H, ArH), 7.27–7.14 (m, 4H, ArH),
7.09 (m, 2H, ArH), 6.12 (bs, 2H, NH2), 4.78 (s, 1H, H-
1), 4.04 (m, 2H, CH2), 1.05 (t, 3H, J=7.05 Hz, CH3);
13C NMR (CDCl3) d 167.5 (CO), 156.7 (C-3), 149.3 (C-
10), 141.5 (C-7a), 136.9 (C-3a), 129.3 (C-30 and C-50),
127.9 (C-20 and C-60), 127.7 (C-7), 126.6 (C-6), 126.1 (C-
4), 124.8 (C-40), 118.8 (C-5), 102.9 (C-2), 58.7 (CH2),
52.1 (C-1), 14.1 (CH3); MS (EI): m/z 280 (M++1, 24),
279 (M+, 100), 234 (17), 206 (100), 128 (30). Anal. calcd
for C18H17NO2: C, 77.40; H, 6.13; N, 5.01. Found: C,
77.37; H, 6.02; N, 4.95.
Ethyl 3-phenyl-1-pyrrolyl-1H-inden-2-carboxylate (7).
1
Orange oil (44%); Rf=0.66. IR (KBr) 1725 (CO); H
NMR (CDCl3) d 7.41 (m, 5H, ArH), 7.28 (m, 2H, ArH),

J. Guillon et al. / Bioorg. Med. Chem. 10 (2002) 1043–1050
1047
Figure 4. The ORTEP drawing of carboxamide 2d with thermal ellipsoids at 30% level.
Table 2. Binding affinities for compounds 2a–h
and NaBH4 (0.57 mol) was added in portions with stir-
ring under cooling for 2 h. The stirring was continued
for 48 h at room temperature. After the removal of
methanol bydistillation, the black precipitate was dis-
solved in 5% hydrochloric acid, the acidic solution was
extracted with diethyl ether. The extracts were collected,
washed with water, dried over magnesium sulfate and
evaporated to dryness under reduced pressure to give 5
as a yellow oil (87%). A sample of the two diastereo-
isomers 9 and 10 was readilyseparated bychromato-
graphyusing methylene chloride as eluant.
Compound
NK1
NK2
NK3
IC50 (mM) IC50 (mM) Ki (mM)
nH
IC50 (mM)
2a
2b
2c
2d
2e
2f
> 10
> 10
> 10
> 10
> 10
> 10
> 10
> 10
2.0
1.9
> 10
> 10
> 10
> 10
2.2
> 10
0.667
0.633
—
—
—
—
0.733
—
0.66
1.18
—
—
—
—
0.67
—
> 10
> 10
> 10
> 10
> 10
> 10
> 10
> 10
2g
2h
trans,trans Ethyl 1-phenyl-3-pyrrol-1-ylindan-2-carboxy-
late (9). Yellow crystals (65%); mp 62 ꢁC; Rf=0.84. IR
(KBr) 1730 (CO); H NMR (CDCl3) d 7.35 (m, 2H,
7.19 (m, 2H, ArH), 6.64 (dd, 2H, J=1.96, 1.96 Hz, H-
a), 6.08 (dd, 2H, J=1.96, 1.96 Hz, H-b), 5.97 (s, 1H, H-
1), 4.04–3.85 (m, 2H, CH2), 0.93 (t, 3H, J=7.30 Hz,
CH3). Anal. calcd for C22H19NO2: C, 80.22; H, 5.81; N,
4.25. Found: C, 79.91; H, 5.77; N, 4.21.
1
ArH), 7.27 (m, 5H, ArH), 7.12 (m, 1H, H-5), 6.95 (m,
1H, H-6), 6.77 (dd, 2H, J=1.90, 1.90 Hz, H-a), 6.20
(dd, 2H, J=1.90, 1.90 Hz, H-b), 5.94 (d, 1H,
J=8.70 Hz, H-3), 4.58 (d, 1H, J=9.80 Hz, H-1), 4.21–
4.02 (m, 2H, CH2), 3.39 (dd, 1H, J=9.80, 8.70 Hz, H-2),
1.13 (t, 3H, J=7.30 Hz, CH3); 13C NMR (CDCl3) d
172.9 (CO), 143.7 (C-10), 142.1 (C-7a), 140.5 (C-3a),
128.9 (C-30 and C-50), 128.7 (C-4), 128.5 (C-20 and C-60),
127.9 (C-7), 127.3 (C-6), 125.1 (C-40), 124.4 (C-5), 119.8
(C-a), 108.7 (C-b), 66.1 (C-3), 64.0 (CH2), 60.9 (C-2),
52.9 (C-1), 14.2 (CH3); MS (EI): m/z 332 (M+.+1, 21),
331 (M+, 100), 286 (6), 264 (28), 191 (65). Anal. calcd
for C22H21NO2: C, 79.73; H, 6.39; N, 4.23. Found: C,
80.03; H, 6.35; N, 4.19.
Ethyl 1-phenyl-3-pyrrolyl-1H-inden-2-carboxylate (8).
1
Orange oil (46%); Rf=0.74. IR (KBr) 1730 (CO); H
NMR (CDCl3) d 7.47 (m, 1H, ArH), 7.25 (m, 3H, ArH),
7.16 (m, 3H, ArH), 7.10 (m, 2H, ArH), 7.03 (dd, 2H,
J=1.96, 1.96 Hz, H-a), 6.30 (dd, 2H, J=1.96, 1.96 Hz, H-
b), 4.94 (s, 1H, H-1), 4.03–3.84 (m, 2H, CH2), 0.92 (t, 3H,
J=7.07 Hz, CH3). Anal. calcd for C22H19NO2: C, 80.22;
H, 5.81; N, 4.25. Found: C, 80.17; H, 5.76; N, 4.33.
General procedure for trans,trans and cis,cis ethyl 1-phenyl-
3-pyrrol-1-ylindan-2-carboxylate (9) and (10)
cis,cis Ethyl 1-phenyl-3-pyrrol-1-ylindan-2-carboxylate
(10). Orange oil (22%); Rf=0.78. IR (KBr) 1735 (CO);
1H NMR (CDCl3) d 7.39–7.23 (m, 9H, ArH), 6.84 (dd,
A mixture of compounds 7 and 8 (0.038 mol) and NiCl2,
6H2O (0.114 mol) were dissolved in 240 mL of methanol

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J. Guillon et al. / Bioorg. Med. Chem. 10 (2002) 1043–1050
2H, J=2.20, 2.20 Hz, H-a), 6.15 (dd, 2H, J=2.20,
2.20 Hz, H-b), 5.98 (d, 1H, J=7.45 Hz, H-3), 4.73 (d,
1H, J=7.45 Hz, H-1), 3.99 (t, 1H, J=7.45 Hz, H-2),
3.45 (q, 2H, J=7.20 Hz, CH2), 0.68 (t, 3H, J=7.20 Hz,
CH3); MS (EI): m/z 332 (M+.+1, 10), 331 (M+, 37),
266 (20), 192 (100), 115 (87). Anal. calcd for
C22H21NO2: C, 79.73; H, 6.39; N, 4.23. Found: C,
79.69; H, 6.31; N, 4.38.
40.9 (CH2), 13.7 (CH3), 13.0 (CH3); MS (EI): m/z 359
(M+.+1, 8), 358 (M+, 30), 258 (26), 191 (36), 100 (100),
72 (27). Anal. calcd for C24H26N2O: C, 80.41; H, 7.31;
N, 7.81. Found: C, 80.22; H, 7.24; N, 7.71.
trans,trans-N,N-Pyrrolidinyl-1-phenyl-3-pyrrol-1-ylin-
dan-2-carboxamide (2b). Yellow oil (52%). IR (KBr)
1650 (CO); 1H NMR (CDCl3) d 7.24 (m, 2H, ArH), 7.18
(m, 5H, ArH), 7.05 (m, 1H, H-5), 6.88 (m, 1H, H-6),
6.69 (dd, 2H, J=2.10, 2.10 Hz, H-a), 6.10 (dd, 2H,
J=2.10, 2.10 Hz, H-b), 5.84 (d, 1H, J=9.20 Hz, H-3),
4.65 (d, 1H, J=9.90 Hz, H-1), 3.36 (m, 3H, H-2 and
CH2), 2.33 (m, 1H, CH2), 2.16 (m, 1H, CH2), 1.57 (m,
2H, CH2), 1.41 (m, 2H, CH2); 13C NMR (CDCl3) d
169.9 (CO), 143.9 (C-10), 141.9 (C-7a), 140.4 (C-3a),
128.6 (C-30 and C-50), 128.5 (C-4), 128.2 (C-20 and C-60),
127.5 (C-7), 127.1 (C-6), 124.9 (C-40), 124.0 (C-5), 119.5
(C-a), 108.7 (C-b), 67.0 (C-3), 64.9 (C-2), 52.8 (CH2),
45.8 (CH2), 45.7 (C-1), 25.5 (CH2), 24.0 (CH2); MS (EI):
m/z 356 (M+, 15), 289 (7), 258 (10), 191 (22), 114 (69),
98 (100), 70 (72). Anal. calcd for C24H24N2O: C, 80.87;
H, 6.79; N, 7.86. Found: C, 80.89; H, 6.71; N, 7.66.
1-Phenyl-3-pyrrol-1-ylindan-2-carboxylic acid (3). To a
solution of ethyl 1-phenyl-3-pyrrol-1-ylindan-2-carboxy-
late 9 and 10 (0.032 mol) in 110 mL of ethanol were
added 85 mL of an 2 M aqueous sodium hydroxide
solution and the reaction mixture was heated to reflux
for 4 h. The solvent was eliminated in vacuo and the
residue was dissolved in water. The aqueous layer was
washed with diethyl ether. Acidification with 3 N HCl
solution gave a precipitate which was extracted with
diethyl ether. The organic layer was dried over magne-
sium sulfate, filtered and evaporated to dryness under
reduced pressure to give white crystals (79%); mp
66 ꢁC.18
trans,trans-N-(2-Methoxybenzyl)-1-phenyl-3-pyrrol-1-
ylindan-2-carboxamide (2c). White crystals (42%); mp
142 ꢁC. IR (KBr) 3270 (NH), 1650 (CO); 1H NMR
(CDCl3) d 7.25 (m, 6H, ArH), 7.15 (m, 2H, ArH), 7.09
(m, 2H, ArH), 6.93 (m, 1H, ArH), 6.86 (m, 1H, ArH),
6.77 (m,1H, ArH), 6.71 (dd, 2H, J=2.10, 2.10 Hz, H-a),
6.16 (dd, 2H, J=2.10, 2.10 Hz, H-b), 5.96 (d, 1H,
J=8.90 Hz, H-3), 5.52 (t, 1H, J=6.00 Hz, NH), 4.58 (d,
1H, J=9.80 Hz, H-1), 4.39 (dd, 1H, J=14.40, 6.00 Hz,
CH2), 4.30 (dd, 1H, J=14.40, 6.00 Hz, CH2), 3.62 (s,
3H, OCH3), 3.03 (dd, 1H, J=9.80, 8.90 Hz, H-2); 13C
NMR (CDCl3) d 170.6 (CO), 157.3 (C-200), 143.8 (C-10),
142.3 (C-7a), 140.6 (C-3a), 129.5 (C-600), 128.7 (C-4),
128.5 (C-20 and C-60), 127.7 (C-7), 127.1 (C-400), 125.8
(C-6), 125.1 (C-40), 124.3 (C-5), 120.4 (C-100), 119.7 (C-
500), 114.0 (C-300), 109.9 (C-a), 108.6 (C-b), 67.0 (C-3),
66.0 (OCH3), 54.9 (C-2), 52.6 (CH2), 39.4 (C-1); MS
(EI): m/z 423 (M++1, 29), 422 (M+, 100), 355 (9), 258
(33), 192 (46), 121 (64). Anal. calcd for C28H26N2O2: C,
79.59; H, 6.20; N, 6.63. Found: C, 79.67; H, 6.17; N,
6.62.
General procedure for N,N-alkyl-1-phenyl-3-pyrrol-1-
ylindan-2-carboxamides (2a–h)
To a stirred solution of 1-phenyl-3-pyrrol-1-ylindan-2-
carboxylic acid 3 (3.3 mmol) in 25 mL of anhydrous
acetone at 0 ꢁC was added dropwise triethylamine
(3.3 mmol). After 30 min, ethyl chloroformate
(3.3 mmol) was added dropwise at 0 ꢁC. After an other
30 min, the amine (3.6 mmol) was added dropwise at
0 ꢁC and then the reaction mixture was refluxed for 3 h.
After cooling, the precipitate which formed was filtered
and the filtrate was evaporated to dryness under
reduced pressure. The oilyresidue was dissolved in di-
ethyl ether (70 mL) and the solution was washed with a
2 N aqueous hydrochloric acid solution (2 ꢃ 70 mL) and
then with
a
saturated aqueous sodium hydro-
genocarbonate solution (2 ꢃ 70 mL). The organic layer
was collected, dried over magnesium sulfate, filtered and
the solvent was removed under reduced pressure. The
residue was triturated in diethyl ether and the formed
crystals were filtered and recrystallized in diethyl ether.
In case of oil, the residue was purified bychromato-
graphic column using methylene chloride/methanol (95/
5 v/v) as eluant.
trans,trans-N-(3,5-Bistrifluoromethylbenzyl)-1-phenyl-3-
pyrrol-1-ylindan-2-carboxamide (2d). White crystals
(57%); mp 204 ꢁC. IR (KBr) 3290 (NH), 1645 (CO); H
1
trans,trans-N,N-Diethyl-1-phenyl-3-pyrrol-1-ylindan-2-
carboxamide (2a). Yellow oil (36%). IR (KBr) 1650
(CO); 1H NMR (CDCl3) d 7.26–7.21 (m, 4H, ArH), 7.20
(m, 1H, ArH), 7.17 (m, 1H, ArH), 7.15 (m, 1H, ArH),
7.11 (m, 1H, H-5), 6.95 (m, 1H, H-6), 6.67 (dd, 2H,
J=2.10, 2.10 Hz, H-a), 6.09 (dd, 2H, J=2.10, 2.10 Hz,
H-b), 5.88 (d, 1H, J=8.90 Hz, H-3), 4.63 (d, 1H,
J=9.85 Hz, H-1), 3.35 (dd, 1H, J=9.85, 8.90 Hz, H-2),
3.22 (q, 2H, J=7.10 Hz, CH2), 2.32 (m, 1H, CH2), 2.22
(m, 1H, CH2), 0.98 (t, 3H, J=7.10 Hz, CH3), 0.25 (t,
3H, J=7.10 Hz, CH3); 13C NMR (CDCl3) d 171.0 (CO),
144.0 (C-10), 142.0 (C-7a), 140.6 (C-3a), 128.7 (C-30 and
C-50), 128.6 (C-4), 128.2 (C-20 and C-60), 127.6 (C-7),
127.2 (C-6), 125.1 (C-40), 124.3 (C-5), 119.5 (C-a), 108.8
(C-b), 67.5 (C-3), 63.4 (C-2), 53.6 (C-1), 41.3 (CH2),
NMR (CDCl3) d 7.77 (s, 1H, H-400), 7.57 (s, 2H, H-200
and H-600), 7.31 (m, 5H, ArH), 7.22 (m, 2H, ArH), 7.14
(m, 1H, H-5), 6.96 (m, 1H, H-6), 6.74 (dd, 2H, J=2.10,
2.10 Hz, H-a), 6.19 (dd, 2H, J=2.10, 2.10 Hz, H-b), 5.95
(d, 1H, J=8.80 Hz, H-3), 5.49 (t, 1H, J=6.10 Hz, NH),
4.62 (d, 1H, J=9.65 Hz, H-1), 4.45 (dd, 1H, J=15.30,
6.10 Hz, CH2), 4.36 (dd, 1H, J=15.30, 6.10 Hz, CH2),
3.11 (dd, 1H, J=9.65, 8.80 Hz, H-2); 13C NMR
(CDCl3) d 171.6 (CO), 143.5 (C-10), 141.8 (C-7a), 140.6
(C-3a), 140.2 (C-100), 131.8 (q, J=36 Hz, CF3), 128.9 (C-
300 and C-500), 128.4 (C-30 and C-50), 127.9 (C-4), 127.7
(C-20 and C-60), 127.6 (C-7), 125.1 (C-200 and C-600),
124.8 (C-6), 124.3 (C-40), 124.1 (C-5), 121.4 (C-400),
119.6 (C-a), 109.1 (C-b), 67.3 (C-3), 66.3 (NCH2), 52.6
(C-2), 42.8 (C-1); MS (EI): m/z 529 (M++1, 33), 528

J. Guillon et al. / Bioorg. Med. Chem. 10 (2002) 1043–1050
1049
(M+, 97), 461 (36), 258 (74), 227 (51), 191 (100). Anal.
calcd for C29H22F6N2O: C, 65.89; H, 4.16; N, 5.30.
Found: C, 65.77; H, 4.02; N, 5.22.
7.36 (m, 3H, ArH), 7.31 (m, 2H, ArH), 7.23 (m, 2H,
ArH), 7.10 (m, 1H, H-5), 7.01 (d, 2H, J=8.70 Hz, H-300
and H-500), 6.92 (m, 1H, H-6), 6.77 (dd, 2H, J=2.10,
2.10 Hz, H-a), 6.22 (dd, 2H, J=2.10, 2.100Hz, H-b),
5.94 (d, 1H, J=9.10 Hz, H-3), 5.03 (t, 1H, J=6.30 Hz,
NH), 4.60 (d, 1H, J=10.10 Hz, H-1), 3.44 (m, 2H,
CH2), 3.01 (dd, 1H, J=10.10, 9.10 Hz, H-2), 2.77 (t, 2H,
J=6.30 Hz, CH2); 13C NMR (CDCl3) d 171.1 (CO),
146.6 (C-100), 146.4 (C-400), 143.6 (C-10), 141.9 (C-7a),
140.4 (C-3a), 129.5 (C-30 and C-50), 128.9 (C-200 and C-
600), 128.8 (C-4), 128.5 (C-20 and C-60), 127.8 (C-7),
127.4 (C-6), 125.0 (C-40), 124.2 (C-5), 123.7 (C-300 and
C-500), 119.7 (C-a), 108.9 (C-b), 67.3 (C-3), 66.2 (C-2),
52.6 (CH2), 40.2 (C-1), 35.4 (CH2); MS (EI): m/z 452
(M++1, 37), 451 (M+, 100), 384 (13), 258 (25), 192
(57). Anal. calcd for C28H25N3O3: C, 74.48; H, 5.58; N,
9.31. Found: C, 74.59; H, 5.79; N, 9.24.
trans,trans-N-Phenethyl-1-phenyl-3-pyrrol-1-ylindan-2-
carboxamide (2e). White crystals (45%); mp 143 ꢁC. IR
(KBr) 3350 (NH), 1650 (CO); 1H NMR (CDCl3) d 7.36–
7.16 (m, 10H, ArH), 7.10 (m, 1H, ArH), 6.93 (m, 1H,
ArH), 6.88 (m, 1H, ArH), 6.75 (dd, 2H, J=2.10,
2.10 Hz, H-a), 6.20 (dd, 2H, J=2.10, 2.10 Hz, H-b), 5.96
(d, 1H, J=9.00 Hz, H-3), 4.99 (t, 1H, J=5.30 Hz, NH),
4.61 (d, 1H, J=9.90 Hz, H-1), 3.47 (m, 1H, CH2), 3.36
(m, 1H, CH2), 2.97 (dd, 1H, J=9.90, 9.00 Hz, H-2), 2.64
(m, 2H, CH2); 13C NMR (CDCl3) d 170.9 (CO), 143.8
(C-100), 142.1 (C-7a), 140.5 (C-100), 138.5 (C-3a), 128.9
(C-3 and C-50), 128.8 (C-4), 128.6 (C-20 and C-60), 128.5
(C-300 and C-500), 128.4 (C-7), 127.8 (C-200 and C-600),
127.4 (C-6), 126.3 (C-40), 125.0 (C-5), 124.2 (C-400),
119.7 (C-a), 108.8 (C-b), 67.2 (C-3), 66.2 (C-2), 52.7
(CH2), 40.7 (C-1), 35.6 (CH2); MS (EI): m/z 407
(M++1, 16), 406 (M+, 51), 339 (10), 258 (29), 192
(100), 105 (49). Anal. calcd for C28H26N2O: C, 82.73; H,
6.45; N, 6.89. Found: C, 82.91; H, 6.46; N, 6.78.
X-ray crystallography of 3 and 2d
Colorless single crystals were obtained from a chloro-
form/methanol (80/20) solution of 3 or 2d. Diffraction
data were collected using a Enraf-Nonius CAD-4 dif-
fractometer. An empirical absorption correction was
applied. The data were also corrected for Lorentz and
polarization effect. The program PLATON22,23 was
used for analysis and drawing figures. The positions of
non-H atoms were easilydetermined bythe program
SHELXS8624 and the positions of the H atoms were
deduced from coordinates of the non-H atoms and
confirmed byFourier synthesis. The non-H atoms were
refined with anisotropic temperature parameters. H
atoms were included for structure factor calculations
but not refined. Full crystallographic results have been
deposited at the Cambridge Crystallographic Data
trans,trans-N-[2-(2-Methoxyphenyl)ethyl)]-1-phenyl-3-
pyrrol-1-ylindan-2-carboxamide (2f). White crystals
(37%); mp 132 ꢁC. IR (KBr) 3350 (NH), 1650 (CO); H
1
NMR (CDCl3) d 7.35–7.22 (m, 7H, ArH), 7.21–7.09 (m,
2H, ArH), 6.93 (m, 1H, ArH), 6.75–6.69 (m, 5H, H-a
and ArH), 6.19 (dd, 2H, J=2.10, 2.10 Hz, H-b), 5.96 (d,
1H, J=8.90 Hz, H-3), 5.13 (bs, 1H, NH), 4.61 (d, 1H,
J=9.70 Hz, H-1), 3.68 (s, 3H, OCH3), 3.42 (m, 2H,
CH2), 2.95 (dd, 1H, J=9.70, 8.90 Hz, H-2), 2.65 (m, 2H,
CH2); 13C NMR (CDCl3) d 171.0 (CO), 157.3 (C-200),
143.8 (C-10), 142.3 (C-7a), 140.6 (C-3a), 130.5 (C-30 and
C-50), 128.8 (C-600), 128.7 (C-4), 128.5 (C-20 and C-60),
127.7 (C-7), 127.3 (C-400), 126.8 (C-6), 125.5 (C-100),
125.1 (C-40), 124.3 (C-5), 120.5 (C-500), 119.7 (C-a),
110.2 (C-300), 108.8 (C-b), 67.3 (C-3), 66.3 (OCH3), 55.0
(C-2), 52.8 (CH2), 39.5 (C-1), 30.3 (CH2); MS (EI): m/z
437 (M++1, 21), 436 (M+, 64), 369 (8), 258 (26), 192
(88), 135 (56), 91 (100). Anal. calcd for C29H28N2O2: C,
79.79; H, 6.46; N, 6.42. Found: C, 80.06; H, 6.70; N,
6.45.
25
Centre (CCDC), UK, as SupplementaryMaterial.
Binding assays
The assays were performed using the following general
procedures. For NK1 receptors, human glioblastoma
cells (U373MG) were used with [3H][Sar9, Met(O2)11]-
SP as radiolabelled ligand (concentration 1.2 nM) and
[Sar9, Met(O2)11]-SP (concentration 1 mM) as non-spe-
cific ligand;19 for NK2 receptors, human recombinant
(CHO cells) were used with [125I]NKA as radiolabelled
ligand (concentration 0.1 nM) and [Nle10]-NKA(4-10)
(concentration 10 mM) as non-specific ligand;20 for NK3,
human recombinant (mammalian cells) were used with
[3H]Senktide as radiolabelled ligand and Senktide
(1 mM) as non-specific ligand.21 Following incubation,
the membranes or cells in suspension were rapidlyfil-
tered under vaccum through glass fiber filters (GF/B or
GF/C, Whatman or Packard). The filters were then
washed several times with an ice-cold buffer using a cell
harvester (Brandel, Packard). Bound radioactivitywas
measured with a scintillation counder (LS 6000, Beck-
man, Topcount, Packard) using a liquid scintillation
cocktail (Formula 989, Microscint O, Packard).
trans,trans-N-Methyl-N-phenethyl-1-phenyl-3-pyrrol-1-
ylindan-2-carboxamide (2g). Yellow oil (41%). IR
1
(KBr) 1650 (CO); H NMR (CDCl3) d 7.36 (m, 3H,
ArH), 7.29 (m, 5H, ArH), 7.19 (m, 4H, ArH), 7.02 (m,
1H, H-5), 6.91 (m, 1H, H-6), 6.82 (dd, 2H, J=1.85,
1.85 Hz, H-a), 6.12 (dd, 2H, J=1.85, 1.85 Hz, H-b), 5.90
(d, 1H, J=8.00 Hz, H-3), 4.64 (d, 1H, J=8.90 Hz, H-1),
3.77 (m, 1H, CH2), 3.46 (m, 1H, CH2), 2.80 (m, 4H, H-2
and CH3), 2.55 (m, 2H, CH2); MS (EI): m/z 421
(M++1, 15), 420 (M+, 44), 353 (7), 286 (11), 258 (27),
191 (45), 162 (100), 105 (74). Anal. calcd for
C29H28N2O: C, 82.82; H, 6.71; N, 6.66. Found: C,
82.67; H, 6.65; N, 6.61.
trans,trans-N-(4-Nitrophenethyl)-1-phenyl-3-pyrrol-1-
ylindan-2-carboxamide (2h). White crystals (43%); mp
171 ꢁC. IR (KBr) 3345 (NH), 1650 (CO); 1H NMR
(CDCl3) d 7.99 (d, 2H, J=8.70 Hz, H-200 and H-600),
The compounds were first tested in each assayat 10 mM.
In the assays where compound inhibited the specific
binding bymore than 80% at this concentration, they

1050
J. Guillon et al. / Bioorg. Med. Chem. 10 (2002) 1043–1050
were further tested at eight concentrations ranging from
0.3 nM to 10 mM to obtain full competition curves. Each
determination was made in duplicate.
M. C.; Vinick, F. J.; Spencer, R. W.; Hess, H. J. Science 1991,
251, 435.
9. Peyronel, J. F.; Truchon, A.; Moutonnier, C.; Garret, C.
Bioorg. Med. Chem. Lett. 1992, 2, 37.
10. Swain, C. J. Expert Opin. Ther. Pat. 1996, 6, 367.
11. Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo,
K. P.; Snider, R. M. J. Med. Chem. 1992, 35, 4911.
12. Giardina, G. A. M.; Sarau, H. M.; Farina, C.; Medhurst,
A. D.; Grugni, M.; Raveglia, L. F.; Schmidt, D. B.; Rigolio,
R.; Luttmann, M.; Vecchietti, V.; Hay, D. W. P. J. Med.
Chem. 1997, 40, 1794.
13. Giardina, G. A. M.; Artico, M.; Cavagnera, S.; Cerri, A.;
Consolandi, E.; Gagliardi, S.; Graziani, D.; Grugni, M.; Hay,
D. W. P.; Luttmann, M.; Mena, R.; Raveglia, L. F.; Rigolio,
R.; Sarau, H. M.; Schmidt, D. B.; Zanoni, G.; Farina, C.;
Vecchietti, V. Il Farmaco 1999, 54, 364.
14. Giardina, G. A. M.; Raveglia, L. F.; Grugni, M.; Sarau,
H. M.; Farina, C.; Medhurst, A. D.; Graziani, D.; Schmidt,
D. B.; Rigolio, R.; Luttmann, M.; Cavagnera, S.; Foley, J. J.;
Vecchietti, V.; Hay, D. W. J. Med. Chem. 1999, 42, 1053.
15. Advenier, C.; Roussi, N.; Nguyen, Q. T.; Emonds-Alt, X.;
Breliere, J.-C.; Neliat, G.; Naline, E.; Regoli, D. Biochem.
Biophys. Res. Commun. 1992, 184, 1418.
16. Emonds-Alt, X.; Vilain, P.; Goulaouic, P.; Proietto, V.;
Van Broeck, D.; Advenier, C.; Naline, E.; Neliat, G.; Le Fur,
G.; Breliere, J.-C. Life Sci. 1992, 50, PL.
In each experiment, a reference compound was tested at
eight concentrations in duplicate to obtain a competi-
tion curve in order to validate this experiment. The
specific radioligand binding to the receptors is defined
as the difference between total binding and non-specific
binding determined in the presence of an excess of
unlabelled ligand. Results are expressed as a percent of
control specific binding and as a percent inhibition of
control specific binding obtained in the presence of the
tested compounds. Individual data and mean data are
presented in the Results section. IC50 values (con-
centration causing a half-maximal inhibition of control
specific binding), and Hill coefficients (nH) were deter-
mined bynon-linear regression analysis of the competi-
tion curves. These parameters were obtained byHill
equation curve fitting. The inhibition constants (Ki)
were calculated from the Cheng Prusoff equation [Ki50/
(1+L/KD), where L=concentration of radioligand in
the assay, and KD=affinityof the radioligand for the
receptor).]
17. Girard, G. R.; Weinstock, J. (Smithkline Beecham Cor-
poration). Internat. Patent WO 96/20193, 1996; Chem. Abstr.
1996, 125, 167593g.
18. Guillon, J.; Dallemagne, P.; Stiebing, S.; Bovy, P. R.;
Rault, S. Synlett 1999, 8, 1263.
References and Notes
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Auton. Pharmacol. 1993, 13, 23.
3. Mantyh, P. W.; Vigna, S. R.; Maggio, J. E. In The Tachy-
kinin Receptors; Buck, S. H., Ed.; Humana: Totowa, NJ, 1994;
p. 581.
4. Tattersall, F. D.; Rycroft, W.; Hill, R. G.; Hargreaves, R. J.
Neuropharmacology 1994, 33, 259.
5. Walsh, D. M.; Stratton, S. C.; Harvey, F. J.; Beres-
ford, I. J. M.; Hagan, R. M. Psychopharmacology 1995,
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6. Ishizuka, O.; Mattiasson, A.; Andersson, K.-E. J. Urol.
1995, 154, 257.
7. Nakanishi, S. Annu. Rev. Neurosci. 1991, 14, 123.
8. Snider, R. M.; Constantine, S. J. W.; Lowe, J. A.; Longo,
K. P.; Lebel, W. S.; Woody, H. A.; Drozda, S. E.; Desai,
19. Fardin, V.; Flamand, O.; Bock, M.; Garret, C.; Crespo,
A.; Fallourd, A. M.; Doble, A. J. Neurochem. 1993, 60, 868.
20. Aharony, D.; Little, J.; Hopkins, B.; Bundell, K. R.;
McPheat, W. L.; Gordon, R. D.; Hassal, G.; Hockney, R.;
Griffin, R.; Graham, A. Mol. Pharmacol. 1993, 44, 356.
21. Guard, S.; Watson, S. P.; Maggio, J. E.; Phon Too, H.;
Watling, K. J. Br. J. Pharmacol. 1990, 99, 767.
22. Spek, A. L. Acta Crystallogr. 1990, A46, C.
23. Sluis, P.; Spek, A. L. Acta Crystallogr. 1990, A46, 194.
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drick, G. M., Kroger, C., Goddard, R., Eds.; Oxford Uni-
¨
versityPress: 1985; p. 175.
25. SupplementaryX-raycrsytallographic data: Cambridge
Crystallographic Data Centre, University Chemical Lab,
Lensfield Road, Cambridge, CB2 1EW, UK; e-mail: http:/
www.deposit@chemcrys.cam.ac.uk.