Isosteric N-arylpiperazine replacements in a series of dihydropyridine NPY1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2004.10.005

4-Amino-N-arylpiperidines serve as effective bioisosteres for N-arylpiperazines in the series of dihydropyridine NPY₁ receptor antagonists. These were prepared by a ZnCl₂-mediated reductive amination reaction between elaborated primary amines and 4-arylpiperidones. 4-Amino-N-arylpiperidines serve as effective bioisosteres for N-arylpiperazines in the series of dihydropyridine NPY₁ receptor antagonists. These were prepared by a ZnCl₂-mediated reductive amination reaction between elaborated primary amines, 2 or 5, and 4-arylpiperidones.

Full text of DOI:10.1016/j.bmcl.2004.10.005

Bioorganic & Medicinal Chemistry Letters 14 (2004) 5975–5978
Isosteric N-arylpiperazine replacements in a series of
dihydropyridine NPY1 receptor antagonists
Guanglin Luo,a,* Gail K. Mattson,b Marc A. Bruce,a Henry Wong,a Brian J. Murphy,c
Daniel Longhi,c Ildiko Antal-Zimanyic and Graham S. Poindextera
aBristol-Myers Squibb Pharmaceutical Research Institute, Department of Chemistry, 5 Research Parkway, Wallingford, CT, USA
bBristol-Myers Squibb Pharmaceutical Research Institute, Department of CNS Biology, 5 Research Parkway, Wallingford, CT, USA
cBristol-Myers Squibb Pharmaceutical Research Institute, Department of Metabolic Research, PO Box 5400, Princeton, NJ, USA
Received 10 September 2002; revised 28 September 2004; accepted 2 October 2004
Available online 26 October 2004
Abstract—4-Amino-N-arylpiperidines serve as effective bioisosteres for N-arylpiperazines in the series of dihydropyridine NPY1
receptor antagonists. These were prepared by a ZnCl2-mediated reductive amination reaction between elaborated primary amines,
2 or 5, and 4-arylpiperidones.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
A number of small molecule Y1 receptor antagonists have
been described over the last several years (Fig. 1).1–3
Some of them (e.g., LY357879 and J-104870) are very
potent Y1 antagonists, which have reported inhibitory
effects on feeding in rodents and clearly support the
involvement of the Y1 receptor on food intake.2c,d
Neuropeptide Y (NPY), a 36-amino acid, single-chain
polypeptide, is one of the most abundant neurotransmit-
ters in the central nervous system. Because of its abund-
ance, homology across the species, and ubiquitous
presence in the central nervous system, it has been impli-
cated in a variety of physiological processes and behav-
iors, such as feeding, energy homeostasis, cardiovascular
regulation, anxiety, seizures, memory, circadian
rhythms, and sexual functions.1
In a previous publication, we disclosed the synthesis of
1,4-dihydropyridine-derived Y1 receptor antagonist con-
taining N-arylpiperazine functionality.3a Two of the rep-
resentative N-arylpiperazines in the series, BMS-189323
(urea)3a and BMS-245782 (cyanoguanidine)3b,c,4 (Fig.
1), display Y1 receptor binding affinities IC50 of 12 nM
and 39 nM, respectively. We were interested in modify-
ing the right-side arylpiperazine portion of the urea and
cyanoguanidine chemotypes and determining whether
the piperazine was required for affinity, as shown in Fig-
ure 2. In this regard, a recent patent application from
Merckhas demonstrated that the 4-amino- N-arylpiperi-
dine moiety can serve as a bioisotere for N-arylpiper-
azine.5 This paper will document our synthetic and
structure–activity efforts around the 4-amino-N-arylpi-
peridine moiety as a replacement for N-arylpiperazine
in our chemotype series.
With regard to feeding, NPY is the most potent orexi-
genic agent known. Central administration of NPY
greatly increases food intake in a variety of animal spe-
cies.1,2 There are six known NPY receptors, of which
five have been cloned (Y1, Y2, Y4, Y5, and y6). Among
them both Y1 and Y5 receptors are thought to be in-
volved in the regulation of feeding and energy homeo-
stasis.1,2 Both Y1 and Y5 receptor antagonists have been
shown to reduce food intake in rodents, although the ef-
fect of Y5 receptor antagonists is not quite clear, and
therefore they both may have potential utility in the
treatment of obesity.1,2
2. Chemistry
Keywords: Bioisostere; N-arylpiperazine; NPY1 receptor antagonists.
*
As shown in Scheme 1, both cyanoguanidine and urea
intermediates, 2 and 5, were prepared from known
Corresponding author. Tel.: +1 203 677 6640; fax: +1 203 677
7702; e-mail: guanglin.luo@bms.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.10.005

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G. Luo et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5975–5978
N
Et
N
S
S
O
N
N
R
N
H
N
H
N
O
N
N
HN
X
N
O
Cl
MeO2C
Me
CO2Me
Me
MeO
NH
OAllyl
N
H
NH
O
J-104870
X = O, R = 2-OMe:
X = NCN, R = 3-OMe: BMS-245782
BMS-189323
LY357897
Figure 1. Y1 Receptor antagonists.
Ar
Ar
N
N
H
N
H
N
H
N
H
N
MeO C
2
CO Me
2
N
N
H
DHP =
X
X
Me
N
H
Me
DHP
DHP
X = O, N-CN
X = O, N-CN
Figure 2. 4-Aminopiperidine as a bioisostere of piperazine.
R
N
H
N
H
N
H
N
H
N
H
N
-
+
S Na
a
d
N
H
NH
NH
2
N
N
N
CN
CN
CN
DHP
1
DHP
DHP
2
3
R
N
H
N
H
N
H
N
H
N
NH
2
b, c
d
N
H
2
O
O
DHP
DHP
DHP
6
4
5
Scheme 1. Reagents and conditions: (a) ethylene diamine (8equiv), HgCl2 (2.0equiv), THF, rt, 3h, 58%; (b) phenyl chloroformate (1.05equiv),
pyridine; (c) ethylene diamine (10equiv), CH3CN, 93% (two steps); (d) 4-arylpiperidone (1.0equiv), amine (2 or 5, 1.02equiv), NaBH3CN (0.5equiv),
ZnCl2 (0.5equiv), MeOH, rt, 20min.
intermediates, 1 and 4 respectively.3 Treatment of 1 with
excess ethylene diamine provided 2 in good yield and of-
fered almost none of the bis-functionalized product. For
the synthesis of 5, aniline 4 was treated with phenyl chlo-
roformate followed by treatment of the crude intermedi-
ate with excess ethylene diamine to provide the product
in excellent yield after purification by silica gel
chromatography.
Use of the Mattson procedure in which Ti(OiPr)4 was
utilized in place of protic acid afforded good yields of
4-aminopiperidines through a proposed chelated aminal
intermediate with subsequent NaBH3CN reduction.6
However, the stepwise reaction proved to be very mois-
ture sensitive and somewhat tedious, especially for our
desired parallel synthesis conditions.
We next employed ZnCl2, which is less hygroscopic, as
the Lewis acid in promoting the reductive aminations.
Instead of stepwise reaction, the reduction by
NaBH3CN tookplace in a one-pot procedure. The pro-
cedure afforded high yields of desired secondary amine
products without formation of tertiary amines. Further-
more, it was found that ZnCl2 could be employed in cata-
lytic amounts. Additionally, the reaction was very fast
With 2 and 5 readily available, we intended to prepare
the series of aminopiperidines via reductive amination
with various 4-arylpiperidones. However, simple protic
acid promoted reductive amination of 2 with 4-arylpi-
peridones using NaBH3CN gave either intractable mix-
tures or low isolated yields (3c and 3d, Table 1), even
when excess amines were used.

G. Luo et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5975–5978
5977
Table 1. Reaction yields and Y1 receptor binding data for the
cyanoguanidine series of compounds 3a–j
spect to the N-aryl piperidines, substitution at both
ortho and meta positions of the phenyl ring is well toler-
ated for the binding, as has been shown earlier in the
urea series. Fluorine containing substituents (3d, 3g, 6d
and 6g) were somewhat less potent than other types of
substitution. However, the electronic nature of the sub-
stituents did not appear to influence the binding results.
Both electron-withdrawing (nitro- or cyano-) and elec-
tron-donating (methoxy- or hydroxy-) substituents gave
very potent receptor binding in both cyanoguanidine
and urea series.
Compdsa
R
Reductive amination
Yieldsb (%)
Y1
IC50, nMc
3a
3b
3c
3d
3e
3f
H
– (66)
90
10
4
2-NO2
2-CH3
2-CF3
2-CN
2-OCH3
2-OCF3
2-OH
3-Cl
70 (0)
– (31)
85
4
14
3
84
82
4
3g
3h
3i
28
5
82
87
8
The Y1 receptor potencies of 3 and 6 also trackwell with
the piperazine series reported earlier.3 For example, the
corresponding piperazine analogs of 3a (R = H) and 6f
(R = 2-OMe) have Y1 binding affinities (IC50ꢀs) of 13
nM3b,4 and 12 nM (BMS-189323),3a respectively. The
binding results show that 4-amino piperidines effectively
serve as bioisosteres for piperazines in this series of Y1
receptor ligands. To further test the functional antago-
nism of the piperazine series, an apparent Kb determina-
tion had been carried out by measuring the inhibition of
the forskolin-stimulated cAMP production inhibited by
NPY by compounds 3f and 6f3. These compounds are
full functional antagonists of the Y1 receptor (3f:
Ki = 3.6nM, Kb = 9.4nM; 6f: Ki = 1.9nM, Kb = 20nM).
3j
2-SCH3
86
3
a The geometry of the cyanoguanidine group is not known.
b Purified yields based on starting piperidone. Some yields with protic
acid reaction conditions are listed in the parenthesis. All compounds
are fully characterized by 1H NMR, 13C NMR, LCMS, and ele-
mental analysis.
c 125I-PYY binding to membranes of SK-N-MC cells expressing the
human Y1 receptors (average of at least two duplicated experiments).
Table 2. Reaction yields and Y1 receptor binding data for the urea
series of compounds 6a–j
Compds
R
Reductive amination
Yieldsa (%)
Y1
IC50, nMb
6a
6b
6c
6d
6e
6f
H
79
81
80
74
84
82
85
85
74
85
2
2
2-NO2
2-CH3
2-CF3
2-CN
2-OCH3
2-OCF3
2-OH
3-Cl
4. Conclusion
4
31
3
A series of N-arylpiperidine derivatives were prepared
by reductive amination with ZnCl2 in a parallel fashion.
The potency of these compounds demonstrates that the
4-aminopiperidine group can serve as an effective piper-
azine replacement in our series of NPY receptor antag-
onists and supports earlier results by Patane et al.5
These highly potent small molecule Y1 receptor antago-
nists will be useful in further evaluating the role of NPY
in the regulation of energy homeostasis.
2
6g
6h
6i
25
6
8
6j
2-SCH3
5
a Purified yields based on starting piperidone. All compounds are fully
characterized by 1H NMR, 13C NMR, LCMS, and elemental
analysis.
b See footnote c in Table 1.
References and notes
and not very sensitive to moisture, which made it
amendable for use in parallel synthesis. Although this
method has been reported earlier by Kim et al.,7 it has
not been widely used. Thus, we were able to utilize high
throughput techniques to obtain our final products (3
and 6) in good yields using this very simple reductive
amination process (Scheme 1, Tables 1 and 2).8
1. For recent reviews, see: (a) Herzog, H. Eur. J. Pharmacol.
2003, 480, 21; (b) Levens, N. R.; Dela-Zuana, O. Curr.
Opin. Inv. Drugs 2003, 4, 1198; (c) Chamorro, S.; Della-
Zuana, O.; Fauchere, J.-L.; Feletou, M.; Galizzi, J.-P.;
Levens, N. Int. J. Obes. 2002, 26, 281; (d) Parker, E.; Heek,
M. V.; Stamford, A. Eur. J. Pharmacol. 2002, 440, 173; (e)
Antal-Zimanyi, I.; Poindexter, G. S. Drug Dev. Res. 2000,
51, 94; (f) Antal-Zimanyi, I.; Fathi, Z.; Poindexter, G. S.
Curr. Pharm. Des. 1998, 4, 349.
3. Results and discussion
2. For a recent review, see: (a) Stamford, A. W.; Parker, E. M.
In Ann. Rep. Med. Chem.; Academic Press, 1999; 34, p 31;
NPY1 receptor antagonists: (b) Aiglstorfer, I. A.; Hendrich,
I.; Moser, C.; Bernhardt, G.; Dove, S.; Buschauer, A.
Bioorg. Med. Chem. Lett. 2000, 10, 1597; (c) Hipskind, P.
A.; Lobb, K. L.; Nixon, J. A.; Britton, T. C.; Bruns, R. F.;
Catlow, J.; Dieckman-McGinty, D. K.; Gackenheimer, S.
L.; Gitter, B. D.; Iyengar, S.; Schober, D. A.; Simmons, R.
M. A.; Swanson, S.; Zarrinmayeh, H.; Zimmerman, D. M.;
Gehlert, D. R. J. Med. Chem. 1997, 40, 3712; (d) Kanatani,
A.; Kanno, T.; Ishihara, A.; Hata, M.; Sakuraba, A.;
Tanaka, T.; Tsuchiya, Y.; Mase, T.; Fukuroda, T.; Fukami,
T.; Ihara, M. Biochem. Biophys. Res. Commun. 1999, 266,
All of the final products, 3a–j and 6a–j, were examined
in a Y1 receptor binding assay as previously described.3
The binding results are shown in Tables 1 and 2 for the
cyanoguanidine and urea series, respectively.
The dihydropyridine chemotype represents one of the
most potent Y1 receptor antagonists reported to date.3
In the new series 3 and 6, the 4-aminopiperidine moiety
appears to effectively function as piperazine replacement
with both cyanoguanidine and urea analogs. With re-

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G. Luo et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5975–5978
88; Recent NPY5 receptor antagonists: (e) Sato, N.;
(0.1M with regard to the amine) was added ZnCl2
(0.5equiv) in one portion. The mixture was stirred at room
temperature for 20min. MeOH was then evaporated and
the residue was partitioned between 1N NaOH and
CH2Cl2. The phases were separated and the aqueous layer
was extracted with CH2Cl2. The combined organic layers
were dried (Na2SO4), concentrated in vacuo, and the
residue purified by flash column chromatography to afford
3 or 6. Analytical data for representative compounds 3j: IR
(KBr): 3300, 2946, 2170, 1686, 1606, 1582,1566, 1433, 1216
Takahashi, T.; Shibata, T.; Haga, Y.; Sakuraba, A.; Hirose,
M.; Sato, M.; Nonoshita, K.; Koike, Y.; Kitazawa, H.;
Fujino, N.; Ishii, Y.; Ishihara, A.; Kanatani, A.; Fukami,
T. J. Med. Chem. 2003, 46, 666; (f) Elliott, R. L.; Oliver, R.
M.; Hammond, M.; Patterson, T. A.; She, L.; Hargrove, D.
M.; Martin, K. A.; Maurer, T. S.; Kalvass, J. C.; Morgan,
B. P.; DaSilva-Jardine, P. A.; Stevenson, R. W.; Mack, C.
M.; Cassella, J. V. J. Med. Chem. 2003, 46, 670, and
references cited therein.
1
3. (a) Poindexter, G. S.; Bruce, M. A.; LeBoulluec, K. L.;
Monkovic, I.; Martin, S. W.; Parker, E. M.; Iben, L. G.;
McGovern, R. T.; Ortiz, A. A.; Stanley, J. A.; Mattson, G.
K.; Kozlowski, M.; Arcuri, M.; Antal-Zimanyi, I. Bioorg.
Med. Chem. Lett. 2002, 12, 379; (b) Poindexter, G. S.;
Swann, T. R.; Bruce, M. A.; Morton, M. A.; Huang, Y.;
Sit, S.-Y.; Breitenbucher, J. G. U.S. Patent 6,001,836; (c)
Poindexter, G. S.; Bruce, M.; Johnson, G.; Kozlowski, M.;
Leboulluec, K.; Monkoviv, I.; Seethala, R.; Sloan, C. P.
U.S. Patent 5,635,503; (d) Sit, S.-Y.; Huang, Y.; Antal-
Zimanyi, I.; Ward, S.; Poindexter, G. S. Bioorg. Med.
Chem. Lett. 2002, 12, 337; (e) Poindexter, G. S.; Bruce, M.
A.; Breitenbucher, J. G.; Higgens, M. A.; Sit, S.-Y.;
Romine, J. L.; Martin, S. W.; Ward, S. A.; McGovern,
R. T.; Clarke, W.; Russell, J.; Antal-Zimanyi, I. Bioorg.
Med. Chem. 2004, 12, 507.
4. Poindexter, G. S.; Bruce, M., unpublished results.
5. Patane, M. A.; Bock, M. G.; Newton, R. A. WO patent
9857638.
6. Mattson, R. J.; Pham, K. M.; Leuck, D. J.; Cowen, K. A. J.
Org. Chem. 1990, 55, 2552.
7. Kim, S.; Oh, C. H.; Ko, J. S.; Ahn, K. H.; Kim, Y. J. J.
Org. Chem. 1995, 50, 1927.
8. Typical procedure for the synthesis of aminopiperidines: To
a mixture of the starting amine (2 or 5, 1.05equiv), 4-
arylpiperidone (1.0equiv), NaBH3CN (0.5equiv) in MeOH
cmÀ1; H NMR (CDCl3, 300MHz): d 7.25–6.95 (m, 8H),
6.50–6.42 (br, 1H), 6.14–6.03 (br, 1H), 4.98 (s, 1H), 3.63 (s,
6H), 3.40–3.31 (m, 2H), 3.26–3.14 (m, 2H), 2.90–2.83 (m,
2H), 2.69–2.51 (m, 3H), 2.39 (s, 3H), 2.32 (s, 6H), 2.04–1.92
(m, 2H), 1.91–1.62 (br, 2H), 1.59–1.42 (m, 2H); 13C NMR
(CDCl3, 75.5MHz): d 168.1, 159.5, 149.7, 149.4, 145.1,
134.9, 129.0 (CH), 124.9 (CH), 124.5 (CH), 124.1 (CH),
119.7 (CH), 118.5, 103.2, 55.1 (CH), 51.22 (CH3), 51.18
(CH2), 39.4 (CH), 33.3 (CH2), 27.7 (CH2), 19.5 (CH3), 14.4
(CH3); MS: [M+H] = 632; Elemental analysis calcd for
C33H41N7O4S1Æ0.30CH2Cl2: C, 60.85; H, 6.38; N, 14.92.
Found: C, 60.90; H, 6.64; N, 14.90. 6b: IR (KBr): 3346,
2947, 1683, 1490, 1217, 1120 cmÀ1 1H NMR (CDCl3,
;
300MHz): d 7.75 (dd, J = 1.7 and 8.2Hz, 1H), 7.44 (dt,
J = 1.7 and 7.8Hz, 1H), 7.23–7.16 (m, 2H), 7.14–7.08 (m,
2H), 7.04–6.93 (m, 2H), 6.53 (s, 1H), 5.65 (t, J = 5.3Hz,
1H), 4.98 (s, 1H), 3.62 (s, 6H), 3.31–3.17 (m, 4H), 2.84–2.71
(m, 4H), 2.63–2.49 (m, 1H), 2.25 (s, 6H), 1.94–1.60 (br, 4H),
1.55–1.38 (m, 2H); 13C NMR (CDCl3, 75.5MHz): d 168.5,
156.9, 148.8, 146.6, 145.2, 143.0, 139.2, 133.8 (CH), 128.9
(CH), 126.2 (CH), 122.9 (CH), 121.4 (CH), 121.3 (CH),
119.6 (CH), 118.4 (CH), 103.4, 54.5 (CH), 51.2 (CH3), 51.1
(CH2), 46.7 (CH2), 41.0 (CH2), 39.4 (CH), 32.9 (CH2), 19.4
(CH3); MS: [M+H] = 607; Elemental analysis calcd for
C31H38N6O7Æ0.25CH2Cl2: C, 59.78; H, 6.18; N, 13.38.
Found: C, 59.75; H, 6.28; N, 13.45.