Synthesis of new 4-heteroaryl-2-phenylquinolines and their pharmacological activity as NK-2/NK-3 receptor ligands

Article abstract of DOI:10.1002/ardp.200600113

Substituted 4-heteroaryl-2-phenylquinolines were synthesized and tested on NK-2 and NK-3 receptors in order to get a better insight in the structure-activity relationship. On the whole, these molecules, which can be regarded as bioisosters of the NK-3 ant

Full text of DOI:10.1002/ardp.200600113

Arch. Pharm. Chem. Life Sci. 2007, 340, 17–25
A. Borioni et al.
17
Full Paper
Synthesis of New 4-Heteroaryl-2-Phenylquinolines and Their
Pharmacological Activity as NK-2/NK-3 Receptor Ligands
Anna Borioni, Carlo Mustazza, Isabella Sestili, Maria Sbraccia, Luciana Turchetto,
and Maria Rosaria Del Giudice
Dipartimento del Farmaco, Istituto Superiore di Sanitꢀ, Roma, Italy
Substituted 4-heteroaryl-2-phenylquinolines were synthesized and tested on NK-2 and NK-3
receptors in order to get a better insight in the structure-activity relationship. On the whole,
these molecules, which can be regarded as bioisosters of the NK-3 antagonist SB 218795, dis-
played a lower activity than the template. Ring electronic distribution and H-bond donor and
acceptor positions played some role in selectivity, 2-imidazolyl substituted 2a showing affinity
mainly towards NK-3 while 3-pyrazolyl substituted 4 displayed a preferential interaction with
NK-2 receptor. Structural characterization of the synthesized compounds was achieved by NMR
1
and mass techniques. Bidimensional H-NOESY experiments were a helpful tool for the assi-
gnment of the isomeric structures of compounds 9 and 11b–c.
Keywords: 4-Heteroaryl-2-phenylquinolines / Neurokinin receptors / NK-2 / NK-3 /
Received: July 13, 2006; accepted: October 13, 2006
DOI 10.1002/ardp.200600113
system and is involved in the modulation of the central
monoaminergic system [2]. NK-3 antagonists have been
proposed for the treatment of irritable bowel syndrome
[3], asthma and chronic obstructive pulmonary disease
[4], urinary incontinence [5], anxiety and depression [6],
hypertension and tachycardia [7], psychotic symptoms of
schizophrenia [8], and panic disorders [9].
At present, only few chemical classes of selective non-
peptidic NK-3 receptor antagonists have been developed:
2-arylalkylcarbamates as PD 161182 [10], 1-acylpiperi-
dines like osanetant [11] and its analogues [12], and 2-aryl-
quinoline-4-carboxamides including the potent and
selective antagonist SB 218795 (Fig. 1) which led to the
development of talnetant [13–17].
The importance of the arylquinoline class of ligands
also lies in the fact that these molecules were rather sim-
ple to synthesize so that many different substituents
could be introduced in the basic skeleton. Hence, a good
and rather complete study on the structural key points
for receptor binding and selectivity was achieved and
information was obtained on the binding site of the NK-3
receptor [14].
Introduction
Tachykinins are peptidic neurotransmitters character-
ized by the common C-terminal sequence Phe-X-Gly-Leu-
MetNH2; they include substance P (SP), neurokinin A
(NKA), and neurokinin B (NKB), along with the recently
discovered hemokinin-1 (HK-1). The physiological role of
tachykinins is exerted through the transmembrane G-
protein coupled receptors designated neurokinin-1 (NK-
1), NK-2, and NK-3. Although tachykinins do not show
complete selectivity to their receptors, SP binds mainly
to NK-1, NKA to NK-2, and NKB to NK-3. These receptors
are widely distributed within both the central and per-
ipheral nervous system, and also in non-neural tissues,
and are involved in many physiological and pathological
processes including pain, neurogenic inflammation,
smooth muscle contraction, neuro immunomodulation,
blood pressure control, anxiety, and depression [1]. The
NK-3 receptor is mainly expressed in the central nervous
Correspondence: Anna Borioni, Dipartimento del Farmaco, Istituto
Superiore di Sanitꢀ, Viale Regina Elena 299, 00161 Roma, Italy
E-mail: anna.borioni@iss.it
The purpose of this publication is to extend the struc-
ture-activity studies of the 2-phenylquinolines on NK-3
Fax: +39 6 4990-2516
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A. Borioni et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 17–25
3-yl)-2-phenylquinoline 7a which afforded 7b by reaction
with benzaldehyde and subsequent reduction with
sodium borohydride (Scheme 1).
2-Phenyl-4-(3-phenyl-[1,2,4]triazol-5-yl)quinoline 8 was
obtained from 2-phenyl-4-quinolinecarbonitrile and
benzhydrazide in diphenyl ether at 2208C. Condensation
of 2-phenyl-4-quinolinecarboxamide with dimethylfor-
mamide dimethyl acetal and subsequent reaction of the
resulting amidine with phenylhydrazine afforded 2-phe-
nyl-4-(1-phenyl-[1,2,4]triazol-5-yl)quinoline 9 whose struc-
Figure 1. Chemical structure of SB 218795 and the bioisosters
4-heteroaryl-2-phenylquinolines.
1
ture was elucidated by H-NOE experiments. The study
was aimed to ascertain if an 1,3- or 1,5-disubstitution
1
occurred on triazole ring. H-NOESY spectrum showed
and NK-2 receptors by the synthesis and the pharmacolo-
gical characterization of new substituted 4-heteroaryl-2-
phenylquinolines where the amidic group of the tem-
plate (Fig. 1) has been replaced by a series of substituted
heterocyclic rings such as imidazole, pyrazole, triazole,
oxazole, some of which can be regarded as amide bioisos-
ters.
A docking study of the 2-phenylcarboxamides in inter-
action with NK-3 receptor [14] evidenced that the amide
group is surrounded by aromatic residues. In our com-
pounds more p-interaction with the aromatic gorge
could be provided by the heteroaryl moiety and its differ-
ent aromatic substituents.
consistent NOEs between the protons of the phenylic sub-
stituent of triazole and the quinoline H-3 and H-5 while
no interaction between the triazole C–H and the same
phenyl protons was observed. These data indicate the
proximity of the phenylic substituent of the triazole ring
to the quinoline moiety confirming the structure of com-
pound 9. Reaction between 4-(bromoacetyl)-2-phenylqui-
noline and benzamidine in absolute ethanol gave 2-phe-
nyl-4-(2-phenylimidazol-4-yl)quinoline 10; the condensa-
tion of 4-acetyl-2-phenylquinoline with dimethylforma-
mide dimethyl acetal and the reaction of the resulting
enamine with hydrazine gave 2-phenyl-4-(pyrazol-3-
yl)quinoline 11a, which by a Mannich reaction with for-
maldehyde and anilines gave products 11b–c (Scheme 2).
NOE experiments indicated that the aminomethyl group
was selectively directed to the pyrazole nitrogen away
Results and discussion
1
from the quinoline ring. H NOESY spectrum showed
Chemistry
NOEs between the CH2 group and the pyrazole H-4 and H-
5, no NOE with the quinoline protons being observed.
2-Phenyl-4-(4-phenylimidazol-2-yl)quinoline 2a, along
with 2-phenyl-4-(4-phenyloxazol-2-yl)quinoline 2b as sec-
ondary product, was obtained by converting 2-phenyl-4-
quinolinecarboxylic acid into its phenacyl ester 1 and by
treating the latter with ammonium acetate in refluxing
acetic acid. The synthesis of compound 4 was accom-
plished in two steps: first ethyl 2-phenyl-4-quinolinecar-
boxylate and acetophenone were condensated in the pre-
sence of sodium hydride to afford the intermediate 4-
(benzoylacetyl)-2-phenylquinoline 3. Subsequent reac-
tion of 3 with hydrazine afforded 2-phenyl-4-(5-phenyl-
pyrazol-3-yl)quinoline 4. Ethyl 2-phenyl-4-quinolinecar-
boxylate gave also condensation with acetonitrile to
form 4-(cyanacetyl)-2-phenylquinoline 5, which afforded
4-(3-aminopyrazol-5-yl)-2-phenylquinoline 6a by hydra-
zine addiction; introduction of a benzyl, 3-thienylmethyl
or a-phenylpropyl substituent on the aminic group to
give 6b–d was performed via azomethinic intermediates;
acylation with benzoyl chloride in pyridine gave 6e.
Condensation of ethyl 2-phenyl-4-quinolinecarboxy-
late with aminoguanidine gave 4-(5-amino-[1,2,4]triazol-
Pharmacology and structure-activity studies
The binding affinities of the synthesized compounds for
the human cloned neurokinin receptors subtype 2 and 3
expressed in CHO cells (Perkin Elmer Life Sciences) were
measured employing [125I]-neurokinin A and B as radiotra-
cers. Concentration-response curves for the compounds
were first run in duplicate; for compounds which dis-
played IC50 a 10 lM tests were repeated in three indepen-
dent experiments. IC50 values were obtained by fitting
the competition curves according to a 4-parameter logis-
tic model (ALLFIT program) [18]. The apparent inhibition
constants (Ki) were calculated fitting the competition
curves according to LIGAND program [19] and are
reported in Table 1.
The synthesized structures resulted to be less potent
than the lead compounds; their activity has been found
in the micromolar concentration range (Table 1).
The carbamide of the template (Fig. 1) was reported to
form a hydrogen bond with a tyrosine or a histidine in
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Arch. Pharm. Chem. Life Sci. 2007, 340, 17–25
NK-2/NK-3 Receptor Ligands
19
Reagents: A:a) KOH, PhCOCH2Br, DMF; B: NH4OAc, HOAc, reflux; C: PhCOCH3, NaH, THF; D: N2H4.H2O, EtOH, HOAc,
808C; E: CH3CN, NaH, DMF; F: N2H4.H2O, EtOH, HOAc, reflux; G: PhCHO for 6b, 3-thiophenecarboxaldehyde for 6c,
PhCOCH2CH3 for 6d; b) NaBH4, EtOH. H: a) PhCOCl pyridine; I: H2NC(=NH)NHNH2, H2CO3, NaOCH3, MeOH, reflux; J: a)
PhCHO, EtOH; b) NaBH4, EtOH.
Scheme 1. Synthesis route of compounds 1–7.
the TM6 section of the NK-3 receptor and with the same nitrogen atoms could act as H-bond donors and accep-
residues in the NK-2 receptor [14]. Our synthesized struc- tors, were confirmed to be peculiar for NK-3 affinity and
tures maintained the possibility of acting as hydrogen- the introduction of an additional nitrogen in the c posi-
bond donor or acceptor although the strength and the tion (triazole 8) did not substantially alter binding fea-
direction of the hydrogen bond could be altered because tures. Shifting of the phenyl ring onto the triazole nitro-
of the delocalization of the hydrogen on different nitro- gen (compound 9) was more detrimental for NK-2 than
gen atoms. On the whole, the heterocyclic structure for NK-3 affinity and led to an enhancement of NK-3 vs.
seemed not to have the proper shape for affinity, how- NK-2 selectivity. Lack of the Na –C(–Q)–Nb sequence
ever, some structural aspects could be emphasized.
resulted in a loss of NK-3 affinity: going deep, the shift of
We considered compound 2a bearing the isosteric 2- the a nitrogen atom to the c position led to an inversion
imidazolyl group as structural reference (Fig. 2). 2a dis- of selectivity (compounds 4 and 6b–d). The sequence Nb –
played a Ki = 1.1 lM for NK-3 and a threefold lower activ- Nc working as H-bond donors and acceptors seemed to be
ity for NK-2 receptor. The a and b positions, where the more suitable for NK-2 interaction. Absence of Nb (imida-
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A. Borioni et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 17–25
Reagents: A: PhCONHNH2, (Ph)2O, 2208C; B: a) (CH3)2NCH(OCH3)2, reflux; b) Ph NHNH2, AcOH, 908C; C: PhC(=NH)NH2,
Na2CO3, EtOH; D: a) (CH3)2NCH(OCH3)2, reflux; b) N2H4.H2O, AcOH, 908C; E: RNH2, HCHO, toluene, 808C.
Scheme 2. Synthesis route of compounds 8–11.
Figure 2. Structure-activity relationship of synthesized compounds.
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Arch. Pharm. Chem. Life Sci. 2007, 340, 17–25
NK-2/NK-3 Receptor Ligands
21
Table 1. In vitro affinity of compounds 2, 4, and 6–11.
former showing NK-2 Ki = 6.1 lM, NK-3 Ki A 10 lM, the lat-
ter NK-2 Ki = 3.4 lM, NK-3 Ki = 1.6 lM.
More distance of the exo nitrogen atom from the het-
eroaryl ring gave rise to the inactive compounds 11. Sub-
stitution of a nitrogen with an oxygen atom (oxazole 2b)
led to a weakening of the biological interaction.
Structure
Ki [lM]
NK-2
NK-3
In conclusion, the pharmacological study of the mod-
erate NK-2/NK-3 ligands 4-heteroaryl-2-phenylquinolines
suggested that the interaction of small molecules with
the neurokinin receptors is very strictly ruled by struc-
tural and electronic requirements. Isosteric replacement
of the amide group by the slightly more restricted hetero-
aryl rings did not assure an effective contact with the
receptor. Different ring electronic distribution joined to
H-bond donor and acceptor positions seemed to play
some role in selectivity and might be an intriguing sub-
ject to elucidate differences and requirements for selec-
tive neurokinins ligands. The interest of this study lies
also in the feasible synthesis and in the structural charac-
terization of these new heterocyclic molecules. Inter-
mediate compounds 1, 3, and 5 which have never been
synthesized previously were characterized and represent
potential starting material for the preparation of substi-
tuted quinolinic structures.
2a Z = NH
2b Z = O
3.6 l 0.9
7.2 l 1.4
1.1 l 0.5
7.7 l 1.3
4
0.47 l 0.03 2.9 l 0.3
6b R = CH2Ph
9.4 l 1.5
4.8 l 1.2
8.2 l 2.0
10.5 l 0.6
A10
A10
A10
A10
6c R = CH2(thienyl)
6d R = CH(C2H5)Ph
6e R = COPh
7b
8
6.1 l 0.1
3.4 l 0.5
A10
>10
1.6 l 0.3
2.4 l 0.2
A10
9
The authors wish to thank Mr. Antonino Puccio for technical
assistance.
10
A10
Experimental
11b R1 = H
11c R1 = F
A10
A10
A10
A10
Chemistry
SB-218795
1.2 l 0.2
0.013 l 0.003
General
Melting points were determined on a Kofler hot stage apparatus
(C. Reichert, Vienna, Austria) and are uncorrected. Column chro-
matographic separations were accomplished on Merck silica gel
(70–230 mesh) or on Merck aluminium oxide 90 (Merck, Darm-
stadt, Germany). The purity of each compound was checked on
silica gel C. Erba 60 F254 (Carlo Erba, Milan, Italy) or Merck alumi-
nium oxide 60 F254 (type E; Merck) plates and spots were located
by UV light. Sodium sulfate was used to dry organic solutions.
Elemental analyses were within l0.4% of the theoretical values.
1H-NMR spectra and 2D-COSY and NOESY experiments were
performed on Bruker Avance 700 and 400 instruments (Bruker)
in CDCl3 or DMSO-d6 solution; all values are reported in ppm (d)
and standard abbreviations were used (a = apparent; b = broad; d
= doublet; dd = doublet of doublets; dt = doublet of triplets; m =
multiplet; q = quadruplet; s = singlet). Electron Ionisation Mass
spectra were recorded on a HP 59980 B spectrometer operating
at 70 eV (Hewlett-Packard, Palo Alto, CA, USA).
Data are given as mean lSD (n = 3).
zole 10) as well as Nc-substitution (pyrazole 11) led to a
loss of affinity. Considering the nitrogen atom in the b
position as an indispensable requirement for some affi-
nity, the selectivity ratio NK-3/NK-2 seemed to be modu-
lated by the key positions a and c.
The addition of an exo nitrogen atom directly bound to
the pyrazolyl moiety (derivatives 6), aimed to provide an
addictive hydrogen bond to the receptor and to build a
more extended and flexible aromatic substituent, main-
tained a preferential although lower affinity for NK-2
binding. The most active compound in this series was 6c
which displayed NK-2 Ki = 4.8 lM. The presence of this
aminic side chain in the triazole moiety (compound 7b),
changed the selectivity of the related compound 8, the
The 2-phenyl-4-quinolinecarboxylic acid [20], the correspond-
ing amide [21] and nitrile [20], 4-acetyl-2-phenylquinoline [22],
and 4-(bromoacetyl)-2-phenylquinoline hydrobromide [23] were
prepared according to literature methods; ethyl 2-phenyl-4-qui-
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A. Borioni et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 17–25
nolinecarboxylate was obtained from the acid by a conventional
esterfication with absolute ethanol and sulphuric acid.
2-Phenyl-4-(5-phenylpyrazol-3-yl)quinoline 4
A solution of 3 (0.5 g, 1.4 mmol) and hydrazine hydrate (0.15 mL,
3.1 mmol) in absolute ethanol (5 mL) and acetic acid (1 mL) was
heated at 808C for 1.5 h, cooled to room temperature, diluted
with water, and extracted with ethyl acetate. Compound 4 was
obtained by evaporation of the organic layer and was purified by
crystallization, m. p. 112–1158C (ethyl acetate/hexane), yield
59%. 1H-NMR (DMSO-d6): d 8.45 (d, 1H, H-8, J8,7 = 8.2 Hz), 8.25 (d,
2H, H-29, H-69, J29,39 = J69,59 = 7.5 Hz), 8.06 (d, 1H, H-5, J5,6 = 8.4 Hz), 8.00
(s, 1H, H-3), 7.84 (m, 2H, H-39, H-59), 7.73 (dd, 1H, H-6, J6,5 = 8.4 Hz,
J6,7 = 7.8 Hz), 7.52 (m, 4H, H-7, H-49, H-299, H-699), 7.35 (m, 3H, H-399,
H-499, H-599), 6.07 (s, 1H, pyrazole H-4). MS: (m/z) 347 [M+], 271, 229,
174. Anal. C24H17N3.
Phenacyl 2-phenyl-4-quinolinecarboxylate 1
Phenacyl bromide (2.0 g, 0.010 mol) was added portion-wise to a
solution of potassium 2-phenyl-4-quinolinecarboxylate (3.0 g,
0.010 mol) at 0–58C in anhydrous dimethylformamide (20 mL)
and the mixture was kept overnight at room temperature. After
addition of water (3 mL), the mixture was vigorously stirred at
5–108C for 1 h; a solid separated which was collected by filtra-
tion and washed with water and diethyl ether; m. p. 120–1228C
1
(ethyl acetate/hexane), yield 76%. H-NMR (DMSO-d6): d 8.68 (d,
1H, H-8, J8,7 = 8.4 Hz), 8.55 (s, 1H, H-3), 8.30 (d, 2H, H-29, H-69, J29,39
=
J
J
69,59 = 8.0 Hz), 8.26 (d, 1H, H-5, J5,6 = 8.6 Hz), 8.08 (d, 2H, H-29, H-69,
29,39 = J69,59 = 7.4 Hz), 7.90 (dd, 1H, H-6, J6,5 = 8.6 Hz, J6,7 = 7.2 Hz), 7.75
4-(Cyanacetyl)-2-phenylquinoline 5
(dd, 1H, H-7, J7,8 = 8.4 Hz, J7,6 = 7.1 Hz), 7.70-7.57 (m, 6H, H-39, H-49,
H-59, H-39, H-499, H-599), 5.96 (s, 2H, OCH2CO). MS: (m/z) 367 [M+],
309, 232, 204. Anal. C24H17NO3.
Ethyl 2-phenyl-4-quinolinecarboxylate (5.54 g, 0.020 mol) and
then acetonitrile (1.9 mL, 0.036 mol) were added drop-wise to a
suspension of sodium hydride (0.96 g, 60% in mineral oil,
0.024 mol) in anhydrous dimethylformamide (50 mL) at 08C. The
mixture was kept overnight at room temperature, then concen-
trated in vacuo, diluted with water, and extracted with ethyl
acetate; the aqueous phase was neutralized with diluted hydro-
chloric acid and extracted again, the combined organic layers
were evaporated and the residue purified by chromatography
on a silica gel column, by eluting with an ethyl acetate/hexane
2-Phenyl-4-(4-phenylimidazol-2-yl)quinoline and 2-
Phenyl-4-(4-phenyloxazol-2-yl)quinoline 2a and 2b
A solution of 1 (0.8 g, 2.2 mmol) and ammonium acetate (1.5 g,
19.5 mmol) was refluxed in acetic acid (12.5 mL) for 3 h. Most of
the acetic acid was removed in a rotary evaporator and the resi-
due was diluted with water and alkalinized with aqueous ammo-
nium hydroxide. The solid which separated was collected by fil-
tration, dried under vacuum and was chromatographed on a
silica gel column, eluent 1 : 3 ethyl acetate/hexane; 2b eluted
first followed by 2a.
1
mixture (1:8), m. p. 142–1448C (methanol), yield 81%. H-NMR
(DMSO-d6): d 8.32 (two overlapped doublets, 3H, H-8, H-29, H-69),
8.16 (d, 1H, H-5, J5,6 = 8.4 Hz), 8.14 (s, 1H, H-3), 7.86 (dd, 1H, H-6, J6,5
= 8.4 Hz, J6,7 = 7.0 Hz), 7.69 (dt, 1H, H-7, J7,8 =8.4 Hz, J7,6 = 7.0 Hz),
7.60–7.50 (m, 3H, H-39, H-49, H-59), 5.10 (broad, 2H, COCH2CN).
MS: (m/z) 272 [M+], 232, 204, 176. Anal. C18H12N2O.
2a: This compound was obtained from 1 in 59% yield, m. p.
114–1168C (ethyl acetate/hexane). 1H-NMR (CDCl3): d 8.72 (d, 1H,
H-8, J8,7 = 8.4 Hz), 8.15 (d, 1H, H-5, J5,6 = 8.4 Hz), 8.08 (d, 2H, H-29, H-
69, J29,39= J69,59 = 7.9 Hz), 7.94 (s, 1H, H-3), 7.81 (bm, 2H, H-6, NH), 7.70
(t, 1H, H-7, J7,8 = J7,6 = 8.4 Hz), 7.54 (overlapped d and s, 3H, H-299, H-
699, imidazole H-5), 7.50–7.29 (m, 6H, H-39, H-49, H-59, H-39, H-499, H-
599). MS: (m/z) 347 [M+], 270, 229, 174. Anal. C24H17N3.
4-(3-Aminopyrazol-5-yl)-2-phenylquinoline 6a
A solution of 5 (2.0 g, 7.4 mmol) and hydrazine hydrate (0.8 mL,
16.5 mmol) in ethanol (10 mL) and acetic acid (0.8 mL) was
refluxed for 6 h; then cooled to room temperature, diluted with
water and alkalinized with aqueous ammonia. The resulting pre-
cipitate was collected by filtration and chromatographed on a
silica gel column by eluting with 5% methanol in ethyl acetate,
m. p. 130–1328C (ethyl acetate), yield 17%. 1H-NMR (CDCl3): d
8.24 (dd, 2H, H-29, H-69, J29,39 = J69,59 = 8.4 Hz), 8.16 (d, 1H, H-8, J8,7 = 8.0
Hz), 8.15 (d, 1H, H-5, J5,6 = 7.2 Hz), 7.89 (s, 1H, H-3), 7.77 (dt, 1H, H-
6, J6,7 = 8.2 Hz, J6,5 = 7.2 Hz, J6,8 = 1.5 Hz), 7.56-7.50 (m, 4H, H-7, H-39,
H-49, H-59), 6.11 (s, 1H, pyrazole H-4), 3.05 (broad, 2H, NH2). MS:
(m/z) 286 [M+], 257, 244, 230, 152. Anal. C18H14N4.
2b: This compound was obtained from 1 in 6% yield, m. p.
1
127–1298C (ethyl acetate / hexane). H-NMR (CDCl3): d 9.43 (d,
1H, H-8, J8,7 = 8.4 Hz), 8.58 (s, 1H, oxazole H-5), 8.24 (two over-
lapped d, 3H, H-5, H-29, H-69, J29,39 = J69,59 = 8.2 Hz), 8.15 (s, 1H, H-3),
7.92 (d, 2H, H-299, H-699, J299,399 = J699,599 = 8.4 Hz), 7.80 (t, 1H, H-6, J6,5
=
8.2 Hz, J6,7 = 8.2 Hz), 7.69 (t, 1H, H-7, J7,8 = 8.4 Hz, J7,6 = 8.2 Hz),
7.60–7.34 (m, 6H, H-39, H-49, H-59, H-39, H-499, H-599). MS: (m/z) 348
[M+], 319, 204. Anal. C24H16N2O.
4-(Benzoylacetyl)-2-phenylquinoline 3
4-(3-Benzylaminopyrazol-5-yl)-2-phenylquinoline 6b
Benzaldehyde (0.17 mL, 1.7 mmol) was added to a solution of 6a
(0.5 g, 1.7 mmol) in absolute ethanol (5 mL) and the mixture was
kept at 458C for 2 h. After cooling to room temperature sodium
borohydride (0.1 g, 2.6 mmol) was slowly added and after 1 h of
additional stirring, the mixture was concentrated in vacuo,
diluted with water, and extracted with ethyl acetate. Evapora-
tion of the organic layer gave 8c, m. p. 158–1608C (ethyl acetate/
hexane), yield 91%. 1H-NMR (CDCl3): d 8.24 (d, 1H, H-8, J8,7 = 8.0
Hz), 8.20 (d, 1H, H-5, J5,6 = 8.0 Hz), 8.10 (dd, 2H, H-29, H-69, J29,39 = J69,59
= 7.9 Hz), 7.86 (s, 1H, H-3), 7.72 (dt, 1H, H-6, J6,5 = 8.0 Hz, J6,7 = 7.0
Hz, J6,8 = 1.4 Hz), 7.55–7.30 (m, 10H, H-7, H-39, H-49, H-59, benzyl
aromatics, NH), 5.99 (s, 1H, pyrazole H-4), 4.41 (s, 2H, benzyl CH2).
MS: (m/z) 376 [M+], 348, 299, 230. Anal. C25H20N4.
Acetophenone (5.5 mL, 0.047 mol) was added drop-wise to a sus-
pension of ethyl 2-phenyl-4-quinolinecarboxylate (13.0 g,
0.047 mol) and sodium hydride (1.9 g, 60% in mineral oil,
0.047 mol) in anhydrous tetrahydrofuran (100 mL) at 08C. The
mixture was kept overnight at room temperature under stir-
ring, then concentrated in vacuo, diluted with water, and
extracted with ethyl acetate; the solvent was evaporated and the
residue purified by crystallization, m. p. 193–1958C (ethyl acet-
ate/hexane), yield 92%. 1H-NMR (DMSO-d6): d 8.46 (d, 1H, H-8, J8,7
=
8.2 Hz), 8.25 (dd, 2H, H-29, H-69, J29,39 = J69,59 = 8.2 Hz), 8.05 (d, 1H, H-5,
J5,6 = 8.2 Hz), 8.00 (s, 1H, H-3), 7.83 (m, 2H, H-299, H-699), 7.72 (t, 1H,
H-6, J6,5 = J6,7 = 8.2 Hz), 7.60–7.40 (m, 4H, H-7, H-39, H-49, H-59), 7.34
(m, 3H, H-399, H-499, H-599), 6.06 (s, 2H, COCH2CO). MS: (m/z) 351
[M+], 263, 205,176 Anal. C24H17NO2.
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Arch. Pharm. Chem. Life Sci. 2007, 340, 17–25
NK-2/NK-3 Receptor Ligands
23
H-8, J8,7 = 8.4 Hz), 8.23 (d, 2H, H-29, H-69, J29,39 = J69,59 = 8.0 Hz), 8.13 (s,
1H, H-3), 8.03 (d, 1H, H-5, J5,6 = 8.4 Hz), 7.72 (dt, 1H, H-6, J6,5 = 8.4
Hz, J6,7 = 7.2 Hz, J6,8 = 1.4 Hz), 7.60–7.49 (m, 4H, H-7, H-39, H-49, H-
59), 4.69 (s, 2H, NH2). MS: (m/z) 287. Anal. C17H13N5.
4-[3-(3-Thienylmethyl)aminopyrazol-5-yl]-2-
phenylquinoline 6c
This compound was obtained from 6a and 3-thiophenecarboxal-
dehyde analogously to the above compound, m. p. 133–1358C
(ethyl acetate/hexane), yield 67%. 1H-NMR (CDCl3): d 8.23 (d, 1H,
H-8, J8,7 = 7.5 Hz), 8.17 (d, 1H, H-5, J5,6 = 7.8 Hz), 8.09 (dd, 2H, H-29,
H-69, J29,39 = J69,59 = 8.2 Hz), 7.86 (s, 1H, H-3), 7.73 (dt, 1H, H-6, J6,5 = 7.8
Hz, J6,7 = 7.1 Hz, J6,8 = 1.4 Hz), 7.55–7.40 (m, 4H, H-7, H-39, H-49, H-59
Hz), 7.28 (q, 1H, thiophene H-5), 7.22 (bs, 1H, thiophene H-2), 7.11
(d, 1H, thiophene H-4), 6.01 (s, 1H, pyrazole H-4), 4.42 (s, 2H, thie-
nylmethyl CH2). MS: (m/z) 382 [M+], 381, 380, 286, 271. Anal.
C23H18N4S.
4-(3-Benzylamino-[1,2,4]triazol-5-yl)-2-phenylquinoline
7b
Benzaldehyde (0.17mL, 1.7 mmol) was added to a solution of 7a
(0.5 g, 1.7 mmol) in absolute ethanol (5 mL) and the mixture was
refluxed for 2 h. After cooling to room temperature, sodium bor-
ohydride (0.1 g, 2.6 mmol) was slowly added and stirring was
continued for 1 h. Then water was added and the resulting preci-
pitate was collected by filtration, washed with water, and dried
in vacuo to give 7b, m. p. 130–1328C (ethyl acetate/hexane), yield
76%. 1H-NMR (CDCl3): d 8.19 (d, 1H, H-8, J8,7 = 8.2 Hz), 8.15 (d, 1H,
H-5, J5,6 = 8.2 Hz), 8.06 (dd, 2H, H-29, H-69, J29,39 = J69,59 = 8.0 Hz), 7.81 (s,
1H, H-3), 7.67 (dt, 1H, H-6, J6,5 = 8.2 Hz, J6,7 = 7.0 Hz, J6,8 = 1.5 Hz),
7.50–7.27 (m, 9H, H-7, H-39, H-49, H-59, benzyl aromatics), 5.95 (s,
1H, NH), 4.67 (s, 1H, NH), 4.37 (s, 2H, benzyl CH2). MS: (m/z) 377
[M+]. Anal. C24H19N5.
4-[3-(1-Phenylpropyl)aminopyrazol-5-yl]-2-
phenylquinoline 6d
A mixture of 6a (0.5 g, 1.7 mmol) and propiophenone (0.23 mL,
1.7 mmol) in toluene (20 mL) was refluxed for two days; then
toluene was removed in vacuo and the residue dissolved in abso-
lute ethanol (20 mL); sodium borohydride (0.15 g, 4.0 mmol) was
portion-wise added under stirring at room temperature. After
3 h stirring, the mixture was concentrated in vacuo, added with
water, and extracted with ethyl acetate; the organic layer was
evaporated in vacuo and the residue chromatographed on an alu-
minium oxide column, by eluting with a 1:1 ethyl acetate/hex-
2-Phenyl-4-(5-phenyl-[1,2,4]triazol-3-yl)quinoline 8
Benzhydrazide (2.5 g, 18.4 mmol) was added portion-wise to a
solution of 2-phenyl-4-quinolinecarbonitrile (2.0 g, 8.7 mmol) in
diphenyl ether (50 g) at 2208C. The mixture was maintained at
the same temperature for 4 h and, after cooling to room tem-
perature, hexane (200 mL) was added. The solid which separated
was collected by filtration and chromatographed on an alumi-
nium oxide column, by eluting with an ethyl acetate/hexane
mixture (1:3), m. p. 180–1828C (ethyl acetate / hexane), yield
13%. 1H-NMR (DMSO-d6): d 9.26 (d, 1H, H-8, J8,7 = 8.2 Hz), 8.71 (s,
1H, H-3), 8.33 (d, 2H, H-299, H-699, J299,399 = J699,599 = 6.6 Hz), 8.18 (two over-
1
ane mixture, resinous solid, yield 28%. H-NMR (CDCl3): d 8.15
(two overlapped d, 2H, H-8, H-5, J8,7 = 8.4 Hz, J5,6 = 8.4 Hz), 8.08 (d,
2H, H-29, H-69, J29,39 = J69,59 = 8.1 Hz), 7.80 (s, 1H, H-3), 7.68 (dt, 1H, H-6,
J6,5 = 8.4 Hz, J6,7 = 7.2 Hz, J6,8 = 1.3 Hz), 7.50–7.25, (m, 9H, H-7, H-39,
H-49, H-59, H-299, H-399, H-4”, H-5”, H-699), 5.76 (s, 1H, pyrazole H-4),
4.26 (t, 1H, CH3CH2CH), 1.81 (m, 2H, CH3CH2CH), 0.91 (t, 3H,
CH3CH2CH). MS: (m/z) 404 [M+], 376, 375, 286. Anal. C27H24N4.
4-(3-Benzoylaminopyrazol-5-yl)-2-phenylquinoline 6e
A solution of 6a (0.5 g, 1.7 mmol) and benzoyl chloride (0.39 mL,
3.4 mmol) in pyridine (7 mL) was stirred overnight at room tem-
perature; pyridine was then evaporated in vacuo and the residue
dispended in water and extracted with ethyl acetate. After eva-
poration, the organic layer gave a solid which was dissolved in
ethanol (5 mL) and added with the same volume of 40% aqueous
sodium hydroxide. The resulting slurry was kept under stirring
for 1 h and after addition of water a solid separated which was
collected by filtration, washed with water, and dried in vacuo,
m. p. 140–1428C (ethyl acetate/hexane), yield 91%. 1H-NMR
(DMSO-d6): d 8.53 (d, 1H, H-8, J8,7 = 8.4 Hz), 8.34 (d, 2H, H-29, H-69,
lapped d, 3H, H-5, H-29, H-69), 7.86 (dt, 1 H, H-6, J6,5 = 8.2 Hz, J6,7
6.7 Hz, J6,8 = 1.4 Hz), 7.73 (dt, 1H, H-7, J7,8 = 8.2 Hz, J7,6 = 6.7 Hz, J7,5
=
=
1.2 Hz), 7.60–7.45 (m, 7H, H-39, H-49, H-59, H-399, H-499, H-599, NH).
MS: (m/z) 348 [M+], 320, 245, 229, 217, 174. Anal. C23H16N4.
2-Phenyl-4-(1-phenyl-[1,2,4]triazol-5-yl)quinoline 9
A
mixture of 2-phenyl-4-quinolinecarboxamide (5.5 g,
0.022 mol) in dimethylformamide dimethyl acetal (20 mL) was
refluxed for 1 h; the acetal was then removed in vacuo and the
residue dissolved in acetic acid (7 mL), added with phenylhydra-
zine (2.36 mL, 0.024 mol) and heated at 908C for 2 h. The mix-
ture was dried in vacuo and chromatographed on a silica gel col-
umn, by eluting with an ethyl acetate/hexane mixture (9:1),
J
29,39 = J69,59 = 8.0 Hz), 8.25 (s, 1H, H-3), 8.16 (d, 1H, H-5, J5,6 = 8.4 Hz),
8.07 (d, 2H, H-299, H-699, J299,399 = J699,599 = 7.2 Hz), 7.84 (at, 1H, H-6, J6,5
=
1
m. p. 125–1278C (methanol), yield 26%. H-NMR (DMSO-d6): d
8.4 Hz, J6,7 = 7.4 Hz), 7.69 (at, 1H, H-7, J7,8 = 8.4 Hz, J7,6 = 7.4 Hz),
7.60-7.45 (m, 6H, H-39, H-49, H-59, H-39, H-499, H-599), 7.17 (s, 1H, pyra-
zole H-4). MS: (m/z) 390 [M+], 363, 362, 361, 230. Anal. C25H18N4O.
8.53 (s, 1H, triazole H-3), 8.15 (s, 1H, H-3), 8.14 (d, 1H, H-8, J8,7 = 7.7
Hz), 8.09 (dd, 2H, H-29, H-69, J29,39 = J69,59 = 7.8 Hz), 7.83 (d, 1H, H-5, J5,6
= 7.6 Hz), 7.82 (dt, 1H, H-7, J7,8 = 7.7 Hz, J7,6 = 7.6 Hz, J7,5 = 1.5 Hz),
7.57 (dt, 1H, H-6, J6,5 = J6,7 = 7.6 Hz, J6,8 = 1.2 Hz), 7.50 (m, 3H, H-39,
H-59, H-49), 7.42–7.32 (m, 5H, H-299, H-399, H-499, H-599, H699). MS: (m/z)
348 [M+], 271, 229, 174. Anal. C23H16N4.
4-(3-Amino-[1,2,4]triazol-5-yl)-2-phenylquinoline 7a
Aminoguanidine bicarbonate (2.5 g, 18.4 mmol) was added to a
solution of sodium methoxide (17.4 mmol) in methanol (25 mL)
at 08C, ethyl 2-phenyl-4-quinolinecarboxylate (1.3g, 4.7 mmol)
was then portion-wise added at the same temperature and the
mixture was refluxed for 18 h. After cooling to room tempera-
ture, the reaction was poured onto crushed ice and neutralized
with diluted hydrochloric acid; about 1 h later, the solid prod-
uct was collected by filtration, washed with water and diethyl
ether, and dried in vacuo; m. p. 190–1928C (ethyl acetate), yield
72%. 1H-NMR (DMSO-d6): d 9.67 (bs, 1H, triazole NH), 8.73 (d, 1H,
2-Phenyl-4-(2-phenylimidazol-4-yl)quinoline 10
A mixture of 4-(bromoacetyl)-2-phenylquinoline hydrobromide
(1.0 g, 2.5 mmol), benzamidine (0.5 g, 4.2 mmol) and sodium car-
bonate (0.4 g, 3.8 mmol) in absolute ethanol (20 mL) was kept at
room temperature for 24 h under stirring. After the solvent eva-
poration, water was added to the mixture and stirring was con-
tinued for 2 h. The solid which separated was filtered, washed
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www.archpharm.com

24
A. Borioni et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 17–25
with water, and dried in vacuo, m. p. 200–2028C (ethyl acetate/
hexane), yield 70%. 1H-NMR (DMSO-d6): d 9.90 (broad, 1H, imida-
Pharmacology
[
125I]NKB (specific activity, 2200 Ci/mmol) and [125I]NKA (specific
zole NH), 8.72 (d, 1H, H-8, J8,7 = 8.4 Hz), 8.24 (d, 2H, H-29, H-69, J29,39
=
activity, 2200 Ci/mmol) were obtained from Perkin Elmer Life
Sciences (USA). The tachykinin peptides NKA and NKB were pur-
chased from Bachem AG (Weil am Rhein, Germany).
J
69,59 = 8.2 Hz), 8.12 (s, 1H, H-3), 8.03 (d, 1H, H-5, J5,6 = 8.3 Hz), 7.83
(d, 2H, H-299, H-699, J299,399 = J699,599 = 6.7 Hz), 7.70 (m, 2H, H-6, H-499), 7.60-
7.45 (m, 7H, H-7, triazole H-5, H-39, H-49, H-59, H-39, H-599). MS: (m/z)
347. Anal. C24H17N3.
The binding of [125I]NKB and [125I]NKA (Perkin Elmer Life
Sciences) was measured in 1 mL reaction mixture containing
50 mM Hepes-Tris pH 7.4, 1 mM MnCl2, 0.1% (w/v) bovine serum
albumin (BSA) and 5 or 10 lg of membrane proteins from CHO
cells, expressing the hNK-3 and the hNK-2 receptors, respectively.
The concentration of radiotracer was maintained constant at
l50000 cpm in the presence of increasing concentrations of
compounds to be tested. Reactions lasted 90 min at room tem-
perature and were terminated by rapid filtration onto GF/B glass
fiber filtering microplates pretreated with 0.1% Ethylene Imine
Polymer (PEI) (Filtermate 196; Packard Instruments, Meriden,
CT, USA). Filters were washed three times with 1 mL of ice-cold
50 mM Tris-HCl pH 7.4 and allowed to dry for 30 min at 378C.
The plates were counted in a Top Count (Packard Instruments)
after the addition (50 lL) of Microscint 20 (Packard) to each well.
Concentration-response curves for each compound were run
using duplicate samples in at least three independent experi-
ments. The reported values are the apparent inhibition con-
stants (Ki) which were obtained by fitting the competition curves
according to Ligand Programm [19].
2-Phenyl-4-(pyrazol-3-yl)quinoline 11a
A solution of 4-acetyl-2-phenylquinoline (1.6 g, 6.5 mmol) in
dimethylformamide dimethyl acetal (6 mL) was refluxed for
1.5 h; afterwards the acetal was evaporated and the residue dis-
solved in acetic acid (2 mL), added with hydrazine hydrate
(0.35 mL, 7.1 mmol) and heated at 908C for 2 h. The mixture was
then cooled, diluted with water, and alkalinized with sodium
carbonate. A precipitate formed which was collected by filtra-
tion, and washed with water and diethyl ether, m. p. 145–1468C
(ethyl acetate/hexane), yield 91%. 1H-NMR (CDCl3): d 8.86 (d, 1H,
H-8, J8,7 = 8.4 Hz), 8.33 (d, 2H, H-29, H-69, J29,39 = J69,59 = 8.1 Hz), 8.30 (s,
1H, H-3), 8.13 (d, 1H, H-5, J5,6 = 8.3 Hz), 7.97 (d, 1H, pyrazole H-5,
J = 2.0 Hz), 7.79 (t, 1H, H-6, J6,5 = J6,7 = 8.3 Hz), 7.62 (t, 1H, H-7, J7,6
=
J7,8 = 8.4 Hz), 7.53 (m, 3H, H-39, H-49, H-59), 7.08 (d, 1H, pyrazole H-
4, J = 2.0 Hz). MS: (m/z) 271 [M+], 270, 244. Anal. C18H13N3.
General method for the preparation of the 2-phenyl-4-[1-
(arylaminomethyl)pyrazol-3-yl]quinolines 11b–c
A mixture of 11a (1.0 g, 3.7 mmol), the appropriate aniline
(3.7 mmol) and 37% aqueous formaldehyde (0.28 mL, 3.7 mmol)
in toluene (7 mL) was heated at 808C for 4 h. The mixture was
then evaporated to dryness and chromatographed on an alumi-
nium oxide column, by eluting with an ethyl acetate/hexane
mixture.
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Hz), 6.64 (t, 1H, CH2NHC6H5, J = 7.2 Hz), 5.65 (d, 2H, CH2 NH C6H5, J
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29,39 = J69,59 = 7.1 Hz), 8.25 (s, 1H, H-3), 8.11 (d, 1H, H-5, J5,6 = 8.4 Hz),
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8.07 (d, 1H, pyrazole H-5, J = 2.3 Hz), 7.80 (at, 1H, H-6, J6,5 = 8.4 Hz,
J6,7 = 7.2 Hz), 7.62–7.48 (m, 4H, H-7, H-39, H-49, H-59), 7.41 (t, 1H,
CH2NHC6H5, J = 7.1 Hz), 7.14 (m, 1H, H-599), 7.07 (d, 1H, pyrazole H-
4, J = 2.3 Hz), 6.78 (dt, 1H, H-499), 6.71 (dd, 1H, H-699), 6.43 (dt, 1H,
H-299), 5.67 (d, 2H, CH2 NH C6H5, J = 7.1 Hz). MS: (m/z) 394 [M+], 271,
244, 165. Anal. C25H19FN4.
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