N-(sulfonamido)alkyl[tetrahydro-1H-benzo[e]indol-2-yl]amines: Potent antagonists of human neuropeptide Y Y5 receptor

Article abstract of DOI:10.1016/S0960-894X(99)00676-9

[3a,4,5,9b-Tetrahydro-1H-benzo[e]indol-2-yl]amines were prepared via reductive amination and concomitant cyclization of α-cyanomethyl-β-aminotetralins. N-acylation with Ω-sulfonamido-carboxylic acids and subsequent reduction afforded a series of N-(sulfonamido)alkyl[tetrahydro-1H-benzo[e]indol-2-yl]amines, which bound to the human neuropeptide Y Y5 receptor with nanomolar affinity. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(99)00676-9

Bioorganic & Medicinal Chemistry Letters 10 (2000) 213±216
N-(Sulfonamido)alkyl[tetrahydro-1H-benzo[e]indol-2-yl]amines:
Potent Antagonists of Human Neuropeptide Y Y5 Receptor
a
a
b
James J. McNally, Mark A. Youngman, Timothy W. Lovenberg,
b
b
a,
Diane H. Nepomuceno, Sandy J. Wilson and Scott L. Dax *
aDrug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Welsh and McKean Roads, Spring House,
PA 19477, USA
Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, 3210 Merry®eld Row, San Diego, CA 92121, USA
b
Received 4 October 1999; accepted 16 November 1999
AbstractÐ[3a,4,5,9b-Tetrahydro-1H-benzo[e]indol-2-yl]amines were prepared via reductive amination and concomitant cyclization
of a-cyanomethyl-b-aminotetralins. N-acylation with ꢀ-sulfonamido-carboxylic acids and subsequent reduction a€orded a series of
N-(sulfonamido)alkyl[tetrahydro-1H-benzo[e]indol-2-yl]amines, which bound to the human neuropeptide Y Y5 receptor with
nanomolar anity. # 2000 Elsevier Science Ltd. All rights reserved.
Neuropeptide Y (NPY), a 36 amino acid protein found
abundantly in the central and peripheral nervous sys-
tems, is a powerful stimulant of feeding. Five di€er-
ent NPY receptor subtypes (Y1, Y2, Y4(PP), Y5, and
Y6) that bind NPY and related peptides (peptide YY
Y5 receptor. Unfortunately, N-aralkylated a-benzyl-b-
aminotetralins homologues were, in general, similarly
hampered by poor aqueous solubility, high lipophilicity
and modest binding anity. We therefore decided to
introduce functional groups into the tetralin ring sub-
stituent in an attempt to improve the physical charac-
teristics of the series and to provide a synthetic handle
upon which other structural modi®cations would be
accessible.
1
±4
(
analogues)
PPY), pancreatic polypeptide (PP) and truncated NPY
±14
5
are recognized today as members of the
superfamily of G-protein coupled receptors. Activation
of the Y1 and Y5 receptor subtypes appears to be
responsible for centrally-mediated NPY-induced feeding
1
3,15±17
responses.
Compounds that antagonize the Y5
b-Tetralones were obtained from phenylacetic acids via
cyclization upon reaction with ethylene gas and alumi-
receptor can be e€ective in reducing food intake in ani-
mal models of feeding.18 Consequently, a host of small
molecule Y5 antagonists have been developed in
attempts to provide a novel therapy for the treatment of
20
num trichloride using the method of Sims. Treatment
of b-tetralone 2 with pyrrolidine a€orded the corre-
sponding enamine 3 which smoothly underwent alkyla-
tion with bromoacetonitrile. The resultant iminium salt
4 was subjected to acid hydrolysis to provide a-cyano-
methyl-b-tetralone 5. Reductive amination (ammonium
acetate, sodium cyanoborohydride in methanol with
heating) induced cyclization to the tricycle and sub-
sequent treatment with acid allowed for isolation of
cis-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-ylamines 6
as stable hydrochloride salts (Scheme 1). Interestingly,
a-cyanomethyl-b-aminotetralin, a putative intermediate
from reductive amination, could not be isolated from
the reaction mixture.
1
9
obesity and other human eating disorders. We wish to
report here that tetrahydro-1H-benzo[e]indol-2-yl-
amines, when substituted with appropriate (sulfonami-
do)alkyl groups, a€ord compounds that bind with
nanomolar anity to the human Y5 receptor. To our
knowledge, the 3a,4,5,9b-tetrahydro-1H-benzo[e]indol-
2-ylamine tricycle is a novel ring system whose structure
we con®rm via X-ray crystallographic analysis.
Screening of our in-house chemical library identi®ed a
novel N-phenethyl-a-benzyl-b-aminotetralin 1 (Fig. 1)
as having low micromolar binding anity for the human
With the tetrahydro-1H-benzo[e]indol-2-ylamine tri-
cycle in-hand, we chose to carry out N-acylations and
alkylations in an attempt to enhance Y5 receptor binding
*
4
Corresponding author. Tel.: +1-215-628-5211; fax: +1-215-628-
985; e-mail: sdax@prius.jnj.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(99)00676-9

2
14
J. J. McNally et al. / Bioorg. Med. Chem. Lett. 10 (2000) 213±216
Figure 1.
Figure 2. X-ray crystal structure of 8c.
anity. Thus cyclic amidines 6 were condensed with a
series of ꢀ-sulfonamido-carboxylic acids derived from
tranexamic acid and lysine. Standard peptide coupling
protocols (HBTU/DMF) cleanly a€orded the desired
precursors 7 were evaluated for binding anity to the
human neuropeptide Y Y5 receptor using a stably-
transfected HEK293 cell line and measuring competitive
inhibition of binding of 1 I-PYY (Table 1). In general,
the arylsulfonamido group was needed for measurable
binding anity; amine precursors 6 were inactive and
simple N-acetylation (7a) failed to signi®cantly enhance
25
2
1
amide adducts 7 in high yield. Subsequent reduction
lithium aluminum hydride), followed by treatment with
acid provided the corresponding amines 8 as acid addi-
(
2
2
tion salts (Scheme 2).
binding. As with other sulfonamide-derived Y5 antago-
8,19
nists,1
the trans-cyclohexylmethyl sca€old (L group)
The structures of the ®nal products were con®rmed by
spectroscopic data and X-ray di€raction analysis of a
crystalline congener (8c).23 The crystal structure (Fig. 2)
reveals the cis-junction of the amidine ring, alkylation
of the exocyclic nitrogen atom and that the endocyclic
C±N bond is shorter (1.25 A) than the exocyclic C±N
Ê
bond (1.34 A). This ring system, the [3a,4,5,9b-tetra-
hydro-1H-benzo[e]indol-2-yl]amine tricycle, is novel, as
are the N-alkylated and acylated derivatives we disclose
here.
gives an optimum spacing between the sulfonamido
group and the basic amine site, as evident by potent
binding anity (7b±7f and 8b±8f). However, the
aminopentyl sca€old, derived from lysine, a€ords
water-soluble compounds with only slightly diminished
anity (7g). A cursory examination of substituents on
the tetrahydro-benzo[e]indol-2-ylamine tricycle and the
benzenesulfonamide terminus indicated that aryl sub-
stituents at these sites have little impact on binding
anity, although the C-7 hydroxy substituent on
the tetrahydro-benzo[e]indole does enhance activity
considerably. A combination of these preferred struc-
tural features gave 8d, which is among the most potent
Ê
The N-(sulfonamido)alkyl-[3a,4,5,9b-tetrahydro-1H-ben-
zo[e]indol-2-yl]amines 8 and the corresponding amide
Scheme 1. Reagents: (a) pyrrolidine (1.3 equiv)/PhH re¯ux (-H
(
2 2 3 2 2 2
O); (b) NCCH Br (1.3 equiv)/CH CN; (c) HOAc, H O, CH Cl /MeOH;
3
d) Na(BH )CN (5 equiv), NH Oac (15 equiv)/MeOH; (e) HCl.
4
H
3
Scheme 2. Reagents: (a) HOOC�L�N�SO2-R , HBTU (1.05 equiv), DIEA (3.3 equiv)/DMF; (b) LAH (5.0 equiv)/THF; (c) HCl.

J. J. McNally et al. / Bioorg. Med. Chem. Lett. 10 (2000) 213±216
215
Table 1. Y5 Receptor binding anitya of N-substituted [3a,4,5,9b-
tetrahydro-1H-benzo[e]indol-2-ylaminesb
Y5 receptor ligands reported to date (IC =1 nM).
50
Compounds 7b, 8c, 7d and 8d were shown to be
antagonists since they did not stimulate binding of labeled
GTPgS in a Bowes melanoma cell line transfected with
the human Y5 receptor, but in the presence of PYY,
were able to inhibit incorporation of 35S label.
Summary
Entry
R
Y
L
Ar
Y5 IC50 (nM)
N-(Sulfonamido)alkyl-[3a,4,5,9b-tetrahydro-1H-benzo-
[
e]indol-2-yl]amines are potent antagonists of the
7
7
a
b
7-OMe CˆO
CH
3
Ð
Ph
>1000
60
human neuropeptide Y Y5 receptor. These compounds
embody a novel heterocyclic core that is prepared via
cyanomethylation of b-tetralones followed by reductive
amination and concomitant cyclization. Subsequent
acylation occurs on the exocyclic nitrogen atom and can
be used to install a pendant arylsulfonamide group.
Amide reduction a€ords N-(sulfonamido)alkylated
tetrahydro-1H-benzo[e]indol-2-yl]amines which exhibit
nanomolar binding anity for the Y5 receptor.
(H)
CˆO
8
7
8
7
8
7
8
7
8
7
b
c
c
d
d
e
e
f
(H)
-CH
2
-
Ph
Ph
39
91
57
9
7-OMe CˆO
7-OMe -CH
2
-
Ph
Acknowledgements
7-OH CˆO
Ph
We thank A. Reitz, V. Day,23 P. McDonnell, D. Gau-
thier and C. Kordik for their help.
7-OH -CH
2
-
Ph
1
References and Notes
7-Cl
7-Cl
CˆO
Ph
111
54
121
35
202
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NaCl, 0.22 mM KH PO , 1.3 mM CaCl , 0.8 mM MgSO at pH 7.4.
1
Membranes were incubated with compounds and 125I-PYY (80 pM)
for 45 minutes at room temperature. After centrifugation and washing,
the remaining membrane radioactivity was measured (counts) using a
gamma counter (Packard Cobra II). The total binding was determined
in the absence of compounds and non-speci®c binding was determined
in the presence of 300 nM NPY. Non-speci®c binding (counts) was
subtracted from the radioactivity (counts) remaining on membranes
after incubation with test compound and this value was divided by the
total speci®c binding (counts) to determine percent (%) speci®c bound.
1
1
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3. Gerald, C.; Walker, M. W.; Criscione, L.; Gustafson, E.
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Speci®c binding was plotted versus log compound concentration
L.; Batzl-Hartmann, C.; Smith, K. E.; Vaysse, P.; Durkin, M.
M.; Laz, T. M.; Linemeyer, D. L.; Scha€hauser, A. O.;
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using the program Prism (Graphpad Software, San Diego, CA). IC50
values were determined as the concentration of compound that inhib-
ited 50% of the total speci®c binding; data in Table 1 are average
values from at least two experiments.
b
Compounds are racemates except for 7g, which is a set of diastereo-
mers.

2
16
J. J. McNally et al. / Bioorg. Med. Chem. Lett. 10 (2000) 213±216
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sulfonyl)amino]methyl]cyclohexyl] methyl]-1H-benz[e]indol-2-
ylamine (8c). Amide 7c (1.6 g, 3.22 mmol) was added in por-
tions, with stirring, to a solution of lithium aluminum hydride
(16.1 mmol) in tetrahydrofuran (36 mL) at ambient tempera-
ture. The resultant solution was heated at re¯ux for 45 min.
The solution was cooled on an ice bath and a solution of water
(0.65 mL) in tetrahydrofuran (5 mL) was carefully added, fol-
lowed by the addition of 10% aqueous sodium hydroxide
(0.65 mL) and water (2.1 mL). The resultant suspension was
stirred at ambient temperature for 30 min and dried over
sodium sulfate. The insoluble material was removed by ®ltra-
tion and washed with tetrahydrofuran. The solvent was evap-
orated in vacuo, the residue was dissolved in a minimum
amount of isopropanol and treated with a concentrated solu-
tion of hydrogen chloride in isopropanol. The solvents were
evaporated in vacuo to give the desired amine hydrochloride
salt 8c as a pale pink solid (1.38 g; ꢁ75% HPLC purity). A
300 mg portion of this material was puri®ed by preparative
HPLC (C18 reverse-phase column (4Â45 cm) eluting with a
gradient of water:acetonitrile:tri¯uoroacetic acid (90:10:0.1 to
10:90:0.1) (v/v)) to give material which was treated with etha-
nolic hydrogen chloride to give pure cis-3a,4,5,9b-tetrahydro-
7-methoxy-N-[[trans-4-[[(phenylsulfonyl)amino]methyl]cyclo-
hexyl]methyl]-1H-benz[e]indol-2-yl amine hydrochloride 8c as
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Cullen, M. J.; Pelleymounter, M. A.; Rivier, J. E. J. Med.
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1. cis-3a,4,5,9b-Tetrahydro-7-methoxy-N-[trans-4-[(phenyl-
sulfonyl)amino]methyl]cyclohexyl]carbonyl]-1H-benz[e]indol-
-ylamine (7c). A solution of trans-4-[(benzenesulfonamido)-
methyl]cyclohexane carboxylic acid (1.16 g, 4.15 mmol), O-
2
0
0
benzotriazol-1-yl-N,N,N ,N -tetramethyluronium hexa¯uoro-
phosphate (1.58 g, 4.15 mmol) and N,N-diisopropylethylamine
(2.41 mL, 13.8 mmol) in N,N-dimethylformamide (15 mL) was
stirred at ambient temperature for 15 min. 3a,4,5,9b-Tetra-
hydro-7-methoxy-1H-benz[e]indol-2-ylamine hydrochloride
(
1.0 g, 3.96 mmol) was added, and the resultant solution was
6
a colorless solid (0.15 g). NMR (DMSO-d ): d 0.70±0.94 (m,
ꢀ
heated to 45 C for 1.5 h. The solution was poured into ice
water and the precipitate collected by ®ltration, washed with
water and air dried. This solid was triturated with diethyl ether
to give cis-3a,4,5,9b-tetrahydro-7-methoxy-N-[trans-4-[(phenyl-
sulfonyl)amino]methyl]cyclohexyl]carbonyl]-1H-benz[e]indol-2-
4H), 1.20±1.50 (m, 2H), 1.62±1.77 (m, 4H), 1.80±1.94 (m, 2H),
2.55±2.73 (m, 5H), 3.03±3.16 (m, 2H), 3.31±3.46 (m, 1H),
3.63±3.73 (m, 1H), 3.71 (s, 3H), 4.24±4.32 (m, 1H), 6.70 (d,
1H), 6.79 (d of d, 1H), 7.14 (d, 1H), 7.55±7.67 (m, 4H), 7.74±
7.82 (m, 2H), 9.66 (br t, 1H) and 10.09 (br s, 1H); MS 482
+
amine 7c as a colorless solid (1.87 g, 95%). NMR (DMSO-d
d 0.69±0.89 (m, 2H), 1.10±1.34 (m, 3H), 1.63±1.88 (m, 5H),
.10±2.27 (m, 1H), 3.24±3.50 (m, 3H), 3.70 (s, 3H), 4.04±4.13
6
):
(M+H) .
23. Cambridge Crystallographic Data Centre deposition num-
ber CCDC 135130; submitted by V. Day, Crystalytics Com-
pany, PO Box 82286, Lincoln, NE 68501, USA.
2
(
(
m, 1H), 6.63 (d, 1H), 6.74 (d of d, 1H), 7.05 (d, 1H), 7.54±7.67
+
m, 4H) and 7.74±7.83 (m, 2H); MS 496 (M+H) .