Synthesis of 7-benzyl-5-(piperidin-1-yl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-1-ylamine and its analogs as bombesin receptor subtype-3 agonists

Article abstract of DOI:10.1016/j.bmcl.2010.03.065

The original structure of a high-throughput screening hit obtained from an external vendor was revised based on multiple NMR studies. The active compound was re-synthesized via a novel route and its structure and biological activity as a BRS-3 agonist were unambiguously confirmed. Multi-gram quantities of the hit were prepared for pharmacokinetic and efficacy studies. The synthetic strategy allowed for the preparation of multiple analogs for SAR exploration.

Full text of DOI:10.1016/j.bmcl.2010.03.065

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2785–2789
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of 7-benzyl-5-(piperidin-1-yl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]-
[2,7]naphthyridin-1-ylamine and its analogs as bombesin receptor subtype-3
agonists
a
a
a
a
b
b
Cheng Guo a, , Peter R. Guzzo , Mark Hadden , Bruce J. Sargent , Larry Yet , Yanqing Kan , Oksana Palyha ,
Theresa M. Kelly b, Xiaoming Guan b, Kim Rosko b, Karen Gagen b, Joseph M. Metzger c, Jasminka Dragovic d,
Kathryn Lyons d, Linus S. Lin d, Ravi P. Nargund d
*
a AMRI, 26 Corporate Circle, Albany, NY 12212, USA
b Department of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
c Department of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
d Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The original structure of a high-throughput screening hit obtained from an external vendor was revised
based on multiple NMR studies. The active compound was re-synthesized via a novel route and its struc-
ture and biological activity as a BRS-3 agonist were unambiguously confirmed. Multi-gram quantities of
the hit were prepared for pharmacokinetic and efficacy studies. The synthetic strategy allowed for the
preparation of multiple analogs for SAR exploration.
Received 1 March 2010
Revised 12 March 2010
Accepted 12 March 2010
Available online 17 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Bombesin receptor subtype-3
Agonists
Small molecule
Obesity is a serious and chronic medical condition that has be-
come a major global health issue. Current drugs approved for the
chronic treatment of obesity have suboptimal tolerability and lim-
ited efficacy.1 Hence, there is still unmet medical need in this ther-
apeutic area and the search for more effective obesity treatments
continues. Bombesin receptor subtype-3 (BRS-3 or BB3), a G-pro-
tein coupled receptor (GPCR) that belongs to the bombesin recep-
tor family, has been recently validated as a potential target for the
treatment of obesity.2 In this Letter, we will describe part of our
early efforts at identifying small molecule BRS-3 agonists.
Figure 1. Original (1) and revised (2) structure assignments.
A high throughput screening (HTS) campaign of the Merck sam-
ple collection identified an active compound against BRS-3 with
the initial structure assignment 1 (Fig. 1) supplied from a commer-
cial vendor. To confirm the structure, a series of NMR experiments
such as COSY, HSQC, HMBC, and NOE difference, were conducted
on a 500 MHz spectrometer using a microprobe. While a lot of
information from proton NMR and HMBC spectra pointed to an iso-
meric structure 2 (Fig. 2), the strongest evidence came from a ser-
ies of NOE experiments (Fig. 2). The benzyl group was determined
to be on the nitrogen of the naphthyridine moiety rather than on
the pyrazole because NOE effects were observed between the ben-
zylic protons and both methylene groups attached to the nitrogen
(Item a in Fig. 2). The nitrogen in the naphthyridine moiety was
found to be at the 7-position instead of 8-position as depicted in
the structure since there were NOE effects between the methylene
at the 6-position and the
a-methylene on the piperidinyl group
(Item b in Fig. 2). The ring conjunction between the pyrazole and
the pyridine should be pyrazolo[3,4-c]pyridine as suggested by
NOE effects between the amino group and the methylene at the
9-position of the naphthyridine moiety (Item c in Fig. 2).
While compound 2 is also commercially available in milligram
quantities, its synthesis has not been described in the literature.
We needed an efficient route to prepare 2 in multi-gram quantities
* Corresponding author. Tel.: +1 518 5122163; fax: +1 518 5122081.
E-mail address: cheng.guo@amriglobal.com (C. Guo).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.03.065

2786
C. Guo et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2785–2789
Figure 2. Summary of NOE experiments.
in order to confirm the structure of 2, to evaluate it in pharmaco-
kinetic and efficacy studies and for subsequent analog work. Ret-
ro-synthetic analysis indicated that 2 could be prepared in four
steps from commercially available ethyl 1-benzyl-4-oxo-3-piperi-
dinecarboxylate hydrochloride (3) (Scheme 1). However, when
considering the transformation of 5 into 6, the selectivity of SNAr
displacement between 1-chloro and 3-chloro in 5 was difficult to
predict. In related examples, the selectivity of SNAr displacement
between the 2-chloro and 6-chloro positions in 2,6-dichloro-3-cya-
nopyridine was heavily dependent on the substituent at either the
4- or 5-position of the pyridine.3–6 To the best of our knowledge, no
examples have been reported for SNAr displacement for substrates
bearing substituents at both the 4- and 5-positions of the pyridine.
The synthesis of 2 (Scheme 1) began with condensation of the
free base of ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate hydro-
chloride (3) with 2-cyanoacetamide to give 7-benzyl-1,3-dioxo-
1,2,3,4,5,6,7,8-octahydro-2,7-naphthyridine-4-carbonitrile (4)7 in
71% yield, which was converted to 7-benzyl-1,3-dichloro-5,6,7,8-
tetrahydro-2,7-naphthyridine-4-carbonitrile (5)7 using phospho-
rus oxychloride. Both 4 and 5 were used directly in the following
step without purification. We were pleased to find that reaction
of 5 with piperidine was completely selective, producing only the
desired 7-benzyl-3-chloro-1-(piperidin-1-yl)-5,6,7,8-tetrahydro-
2,7-naphthyridine-4-carbonitrile (6)7 in 49% yield over two steps
after purification by recrystallization. The structure of 6 was con-
firmed by an NOE experiment. Treatment of 6 with hydrazine
monohydrate in ethanol provided 7-benzyl-5-(piperidin-1-yl)-
6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-1-ylamine
Scheme 1. Reagents and conditions: (a) (i) aqueous NaHCO3, CH2Cl2; (ii)
NCCH2CONH2, KOH, MeOH, reflux, 71%; (b) POCl3, sealed tube, 180 °C; (c)
piperidine, Et3N, DMF, rt, 49% from 4; (d) NH2NH2ÁH2O, EtOH, reflux, 92%.
(2)7 in 92% yield, purified by trituration with ethanol. The entire
synthesis did not involve column chromatography, thus making
it amenable to multi-gram scale preparation. The structure of 2
was confirmed by NOE experiments and other NMR experiments
(HMBC, HSQC, COSY) to be identical to the structure of the hit from
the HTS.

C. Guo et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2785–2789
2787
Figure 3. Food intake effects of 2 in DIO rats.
Compound 2 was confirmed in vitro for BRS-3 agonist functional
potency in an aequorin bioluminescence assay:2a rEC50 = 380 nM
(105% activation), hEC50 = 4525 nM (60% activation). These EC50
values were consistent with those obtained in the HTS. In a pharma-
cokinetic study in rats, compound 2 showed low bioavailability
(F = 5.7%), short half life (t1/2 = 0.73 h), and high clearance
(Cl = 45 mL/min/kg). Compound 2 achieved good brain/plasma
ratios and respectable brain drug level in rats (1 mg/kg IV) which
was important due to the predominant location of BRS-3 receptors
in the central nervous system:8 4.4 at 0.25 h (1.21
tration in brain), 3.2 at 1 h (0.39 M total concentration in brain),
3.4 at 2 h (0.14 M total concentration in brain). In an efficacy
lM total concen-
l
l
study, significant acute food intake effect of compound 2 (31.6%
suppression vs vehicle) was observed in diet-induced obese rats
at 10 mg/kg IV, using melanotan-II9 as the positive control (Fig. 3).
Figure 4. SAR strategy.
Table 1
SAR results at 5-position in 2
ID
R1R2N
Rat functional EC50 (nM) (%activation)
Human functional EC50 (nM) (%activation)
2
380 (105%)
965 (99%)
4525 (60%)
8a
10,000 (12%)
8b
8c
1442 (100%)
10,000 (51%)
10,000 (9%)
10,000 (3.7%)
8d
8e
854 (96%)
481 (96%)
10,000 (6.8%)
10,000 (10%)
(continued on next page)

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C. Guo et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2785–2789
Table 1 (continued)
ID
R1R2N
Rat functional EC50 (nM) (%activation)
3557 (82%)
Human functional EC50 (nM) (%activation)
10,000 (1.3%)
8f
8g
10,000 (31%)
10,000 (0.1%)
8h
10,000 (21%)
10,000 (0.2%)
8i
8j
(CH3)2N–
i-PrNH–
8954 (59%)
7652 (55%)
10,000 (0.9%)
10,000 (1.8%)
8k
8l
10,000 (50%)
10,000 (60%)
10,000 (1%)
PhNH–
10,000 (1.5%)
Table 2
SAR results at 7-position in 2
ID
R3
Rat functional EC50 (nM) (%activation)
Human functional EC50 (nM) (%activation)
2
Ph
380 (105%)
>10,000 (15%)
346 (94%)
342 (121%)
3859 (64%)
10,000 (8%)
10,000 (38%)
402 (94%)
10,000 (49%)
10,000 (61%)
1057 (91%)
7906 (51%)
>10,000
4525 (60%)
>10,000 (0.3%)
6779 (46%)
97
H*
10a7
10b
10c
10d
10e
10f
10g
10i
10j
10k
10l7
2-Pyridyl
2-Cl-Ph
4-F-Ph
4-MeO-Ph
3-CF3-Ph
Piperonyl
Cyclohexyl
i-Pr
5567 (67%)
10,000 (1.7%)
10,000 (0.55%)
10,000 (0.3%)
10,000 (1.6%)
10,000 (12%)
10,000 (10%)
10,000 (22%)
10,000 (3.3%)
>10,000
t-Bu
PhCH2
4-F-Benzoyl*
*
Directly attached to the 7-nitrogen in compound 10.
Table 3
SAR results at 1-amino in 2
ID
R4
Rat functional EC50 (nM) (%activation)
Human functional EC50 (nM) (%activation)
2
380 (105%)
129 (94%)
123 (103%)
99 (102%)
63 (105%)
433 (93%)
413 (99%)
212 (96%)
471 (105%)
680 (94%)
4525 (60%)
3164 (31%)
3474 (19%)
4763 (37%)
1542 (37%)
1234 (52%)
704 (61%)
543 (78%)
10,000 (53%)
4149 (29%)
11a
11b
11c
11d
11e7
11f
11g
12a
12b
CH3–
CH3CH2–
(CH3)2CH–
(CH3)3C–
(CH3)3CCH2–
Cyclopentyl
CH3CH2C(CH3)2–
CH3–
(CH3)3C–

C. Guo et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2785–2789
2789
H.; Sebhat, I. K.; Lin, L. S.; Goodman, A.; Guo, C.; Guzzo, P. R.; Hadden, M.;
Henderson, A. J.; Pattamana, K.; Ruenz, M.; Sargent, B. J.; Swenson, B.; Yet, L.;
Kelly, T. M.; Palyha, O.; Kan, Y.; Pan, J.; Chen, H.; Marsh, D. J.; Shearman, L. P.;
Strack, A. M.; Metzger, J. M.; Feighner, S. D.; Tan, C.; Howard, A. D.;
Tamvakopoulos, C.; Peng, Q.; Guan, X.; Reitman, M. L.; Patchett, A. A.;
Wyvratt, M. J.; Nargund, N. P. Bioorg. Med. Chem. Lett. 2010, 20, 2074; (c)
Hadden, M.; Goodman, A.; Guo, C.; Guzzo, P. R.; Henderson, A. J.; Pattamana, K.;
Ruenz, M.; Sargent, B. J.; Swenson, B.; Yet, L.; Liu, J.; He, S.; Sebhat, I. K.; Lin, L.
S.; Tamvakopoulos, C.; Peng, Q.; Kan, Y.; Palyha, O.; Kelly, T. M.; Guan, X.;
Reitman, M. L.; Nargund, R. P. Bioorg. Med. Chem. Lett. 2010, 20, in press.
3. Bolhofer, W. A.; Deana, A. A.; Habecker, C. N.; Hoffman, J. M.; Gould, N. P.;
Pietruszkiewicz, A. M.; Prugh, J. D.; Torchiana, M. L.; Cragoe, E. J.; Hirschmann,
R. J. Med. Chem. 1983, 26, 538.
4. Skowronski, R.; Strzyzewski, W. Pol. J. Chem. 1991, 65, 883.
5. Roch, J.; Muller, E.; Narr, B.; Nickl, J.; Haarmann, W. U.S. Patent 4182887, 1980;
Chem. Abstr. 1981, 94, 65677.
6. Miyamoto, T.; Egawa, H.; Matsumoto, J.-I. Chem. Pharm. Bull. 1987, 35, 2280.
7. Analytical data for representative compounds:
Figure 5. SAR results at 3-position in 2.
7-Benzyl-1,3-dioxo-1,2,3,4,5,6,7,8-octahydro-2,7-naphthyridine-4-carbonitrile
(4): A light yellow solid: mp 258–260 °C; 1H NMR (DMSO-d6, 300 MHz) d 9.95
(s, 1H), 9.71 (br s, 1H), 7.51–7.47 (m, 5H), 4.48–4.34 (m, 2H), 3.83 (d, 1H,
J = 14.4 Hz), 3.63–3.56 (m, 2H), 3.24 (m, 1H), 2.71 (m. 2H); 13C NMR (DMSO-d6,
75 MHz) d 163.8, 162.6, 146.0, 131.1, 129.9, 129.6, 129.0, 120.6, 96.7, 73.5, 58.5,
48.4, 48.0, 24.6; MS (ESI): m/z 282 (M+H)+.
The newly established synthetic route provided access to key
analogs of 2 for SAR study in hit-to-lead efforts. Figure 4 outlines
the SAR strategy on compound 2 aiming to improve potency and
pharmacokinetics while maintaining a favorable brain/plasma
ratio.
7-Benzyl-1,3-dichloro-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile (5): An
off-white solid: mp 220–223 °C; 1H NMR (DMSO-d6, 300 MHz) d 7.58–7.31 (m,
5H), 4.30 (s, 2H), 4.11 (s, 2H), 3.30 (t, 2H, J = 5.2 Hz), 3.20 (t, 2H, J = 5.2 Hz); 13C
NMR (DMSO-d6, 75 MHz) d 152.3, 150.3, 149.2, 131.1, 129.5, 128.9, 125.1,
113.0, 109.1, 57.8, 56.0, 48.1, 45.5, 25.2; MS (ESI): m/z 318 (M+H, 2 Â 35Cl)+, 320
(M+H, 35Cl + 37Cl)+, 322 (M+H, 2 Â 37Cl)+.
Selective replacement of the 1-chloro group in versatile inter-
mediate 5 with various amines followed by reaction with hydra-
zine provided analogs 8. These compounds showed tight SAR as
even minor changes resulted in decrease of potency (Table 1).
The benzyl group in 2 was successfully removed by hydrogena-
tion to provide 9. Installation of different groups on the naphthyri-
dine nitrogen in 10 was achieved by either selective reductive
alkylation of 9 with aldehydes or acylation.10,11 Table 2 summa-
rizes the SAR of modifying the 7-position of compound 2. While
minor modification like 2-picolyl (10a), 2-chlorobenzyl (10b) and
piperonyl (10f) retained activities against BRS-3 receptor, other
modifications caused loss of potency. Modification at the linker de-
creased potency (compounds 10k and 10l).
The amino group in 2 could be acylated to give amides 11.
Reduction with lithium aluminum hydride provided analogs 12,
which had various alkyl groups attached to the amino nitrogen.
Moderate improvement in potency (2- to 6-fold) was observed in
amides 11, while potency was retained in alkylated analogs 12
(Table 3).
7-Benzyl-3-chloro-1-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-
carbonitrile (6): An off-white solid: mp 120–122 °C; 1H NMR (DMSO-d6,
300 MHz) d 7.34–7.27 (m, 5H), 3.66 (s, 2H), 3.31 (s, 2H), 3.22 (s, 4H), 2.89 (t,
2H, J = 5.8 Hz,), 2.74 (t, 2H, J = 5.8 Hz), 1.50 (s, 6H); 13C NMR (CDCl3, 75 MHz) d
161.0, 150.6, 149.5, 137.5, 129.3, 128.7, 127.7, 119.3, 115.5, 100.6, 62.6, 53.6,
50.3, 49.3, 29.1, 26.1, 24.5; MS (ESI): m/z 367(M+H, 35Cl)+, 369 (M+H, 37Cl)+;
HPLC tR = 14.3 min, >99% (area percent).
7-Benzyl-5-(piperidin-1-yl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-
c][2,7]naphthyridin-1-ylamine (2):
A
white solid: mp 219–222 °C; 1H NMR
(DMSO-d6, 500 MHz) d 11.51 (s, 1Y), 7.39–7.30 (m, 4Y), 7.30–7.23 (m, 1H), 4.86
(s, 2H), 3.65 (s, 2H), 3.39 (s, 2H), 3.16 (t, 2H, J = 5.6 Hz), 2.94 (s, 4H), 2.71 (t, 2H,
J = 5.9 Hz), 1.51 (s, 6H); 13C NMR (DMSO-d6, 75 MHz) d 161.3, 150.8, 148.3,
140.2, 138.3, 129.6, 128.6, 127.5, 114.5, 100.8, 62.2, 52.8, 51.3, 49.8, 26.6, 26.0,
24.4; MS (ESI): m/z 363 (M+H)+; HPLC tR = 11.7 min, >99% (area percent).
5-(Piperidin-1-yl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-1-
ylamine (9): A light yellow solid: 1H NMR (DMSO-d6, 300 MHz) d 9.14 (br s, 2H),
4.16–4.14 (m, 4H), 3.43–3.40 (m, 4H), 3.06-3.04 (m, 4H), 1.67–1.63 (m, 6H); 13C
NMR (D2O, 125 MHz) d 159.6, 148.0, 146.5, 144.6, 108.8, 98.0, 66.6, 51.1, 42.6,
40.0, 25.3, 23.4, 23.3; MS (ESI): m/z 273 (M+H)+; HPLC tR = 6.5 min, 98.3% (area
percent).
Two 3-substituted analogs 13a and 13b were prepared.12 Nei-
ther compound showed improvement in potency (Fig. 5).
In summary, the revision of the original structure assignment of
compound 2 demonstrated the importance of structure confirma-
tion in the hit-to-lead process. A concise synthesis of 7-benzyl-5-
(piperidin-1-yl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naph-
thyridin-1-ylamine (2) in gram quantity was achieved in four steps
with 32% overall yield starting from commercially available mate-
rials. Preliminary SAR work at the 1-, 3-, 5- and 7-positions of 2
showed a generally tight SAR with only limited improvement in
potency against BRS-3 receptor. Priority for further development
was thus given to other more promising hits within the program.2
5-(Piperidin-1-yl)-7-(pyridin-2-ylmethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-
c][2,7]naphthyridin-1-amine hydrochloride (10a):
A yellow solid: mp 228–
230 °C; 1H NMR (DMSO-d6, 300 MHz) d 12.55 (br s, 1H), 11.00 (br s, 1H), 8.70
(dd, J = 4.7, 0.7 Hz, 1H), 7.97 (td, J = 7.7, 1.7 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H),
7.54–7.50 (m, 1H), 4.63 (s, 2H), 4.29 (s, 2H), 3.69–3.67 (m, 2H), 3.60–3.58 (m,
2H), 3.16 (s, 2H), 2.98 (br s, 4H), 1.54 (br s, 6H); 13C NMR (CDCl3/CD3OD,
125 MHz) d 165.1, 153.2, 150.7, 150.6, 148.2, 140.7, 139.3, 125.8, 125.6, 111.2,
98.0, 59.9, 51.8, 49.8, 49.7, 26.7, 25.1, 24.6; MS (ESI): m/z 364 (M+H)+; HPLC
tR = 8.2 min, >99% (area percent).
7-(4-Fluorobenzoyl)-5-(piperidin-1-yl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-
c][2,7]naphthyridin-1-ylamine (10l): An off-white solid: 1H NMR (DMSO-d6,
300 MHz) d 11.70 (s, 1H), 7.51–7.46 (m, 2H), 7.33–7.26 (m, 2H), 5.01 (br s, 2H),
4.69–4.46 (m, 2H), 4.11 (br s, 2H), 3.88–3.62 (m, 2H), 3.06–2.82 (m, 4H), 1.69–
1.37 (m, 6H); MS (ESI): m/z 395 (M+H)+; HPLC tR = 11.7 min, 98.6% (area
percent).
N-(7-Benzyl-5-(piperidin-1-yl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-
c][2,7]naphthyridin-1-yl)-3,3-dimethylbutanamide (11e): An off-white solid: mp
263–265 °C (dec.); 1H NMR (DMSO-d6, 300 MHz) d 12.85 (s, 1H), 9.72 (s, 1H),
7.38–7.25 (m, 5H), 3.65 (s, 2H), 3.41–3.39 (m, 2H), 3.04–2.99 (m, 6H), 2.71–
2.69 (m, 2H), 2.20 (s, 2H), 1.53 (s, 6H), 1.03 (s, 9H); 13C NMR (DMSO-d6,
125 MHz) d 175.9, 163.6, 140.6, 138.4, 131.0, 130.6, 129.5, 128.7, 118.9, 106.8,
63.6, 54.0, 52.5, 50.8, 50.4, 32.1, 30.4, 27.3, 27.0, 25.7; MS (ESI): m/z 461
(M+H)+; HPLC tR = 12.9 min, >99% (area percent).
Acknowledgment
We thank Dr. Paul Isbester of Pharmaceutical Services at AMRI
for assistance in NMR studies.
8. (a) Ohki-Hamazaki, H.; Wada, E.; Matsui, K.; Wada, K. Brain Res. 1997, 762, 165;
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Ploeg, L. H.; Fong, T. M. Biochemistry 2002, 41, 8954.
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M.; Palyha, O.; Kan, Y.; Pan, J.; Chen, H.; Marsh, D. J.; Shearman, L. P.; Strack, A.
M.; Metzger, J. M.; Feighner, S. D.; Tan, C.; Howard, A. D.; Tamvakopoulos, C.;
Peng, Q.; Guan, X.; Reitman, M. L.; Patchett, A. A.; Wyvratt, M. J.; Nargund, N. P.
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12. Compound 13a was prepared by refluxing of
6 with methylhydrazine in
ethanol. Compound 13b was prepared by acylation of the 3-nitrogen in 2 using
acetyl chloride and triethylamine in dichloromethane at 0 °C.