Synthesis and Biological Evaluation of Substituted Pyrazole Constrained Piperazine Derivative Library for Dopamine Receptor Antagonist

Full text of DOI:10.1002/bkcs.11012

Note
DOI: 10.1002/bkcs.11012
BULLETIN OF THE
K. P. Landge et al.
KOREAN CHEMICAL SOCIETY
Synthesis and Biological Evaluation of Substituted Pyrazole
Constrained Piperazine Derivative Library for Dopamine Receptor
Antagonist
Kamalkishor P. Landge,† Hyun Ju Song,† Jung Gook Lee,† Sang Eun Chae,‡ Ae Nim Pae,‡
†,
Woo Kyu Park,§ Vasu Sampath,¶ Hee Yoon Lee,¶, and Hun Yeong Koh
*
*
†Department of Chemistry, Inha University, Incheon 22212, Korea. *E-mail: hykoh@inha.ac.kr
‡Neuro-Medicine Center, Korea Institute of Science and Technology, Seoul, Korea
§Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Korea
¶Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea.
*E-mail: leehy@kaist.ac.kr
Received October 13, 2016, Accepted October 19, 2016, Published online November 21, 2016
Keywords: Dopamine receptor, Serotonin receptors, Reductive amination, Schizophrenia, G-protein-
coupled receptors
The D2-like dopamine receptors including the subtypes D2,
D3, and D4 are members of the large family of G-protein-
coupled receptors (GPCRs), also referred to as seven trans-
membrane receptors. Many central nervous system (CNS)-
related diseases like schizophrenia, Parkinson’s disease,
drug addiction, and erectile dysfunction are associated with
D2-like dopamine receptors.1 D3 receptors are localized in
the limbic areas of the brain, specifically in the group of
neural granule cells located within the ventral striatum in
the brains of most animals.2 The dopamine D4 receptor is
expressed predominantly within the CNS, and despite low
abundance relative to the D2 receptor, localization in the
cortex suggests an important functional role. The role of D4
receptor antagonists in CNS disorders such as schizophre-
nia has been extensively investigated and it has also been
shown that the D4 receptor could be associated with
ADHD, depression, substance abuse, and cognitive disor-
ders.3 In connection with search for selective ligands for
various GPCRs, we have recently reported4 the design and
synthesis of arylpiperazine derivative with isoxazole ring
libraries as dopamine receptor antagonist and serotonine
receptor antagonist. In further continuation of our research,
we developed and synthesized different compounds with
piperazine derivative, pyrazole ring with phenyl, t-butyl,
and benzene derivatives, with isopropyl, propyl as a side
chain.
oxidation of alcohols of the mixture of 4 and 5 afforded
pyrazolyl aldehydes 6 and 7, respectively, in dichloro-
methane at room temperature for 3–5 h in 60–94% yields
and two isomeric aldehydes were separated by column
chromatography. Following the combinatorial chemistry
protocol developed for solution phase combinatorial library
formation,5 reductive amination of the prepared pyrazolyl
aldehydes 6 and 7 with a variety of commercially available
arylpiperazine
derivatives
(Table
1)
by
using
6
NaBH(OAc)3 produced HCl salts of the products 8 and
9 derivatives after acid treatment of the reaction products
in good yields with high purities (Scheme 1, Table 1).
1
Identities and purities of products were confirmed by H
NMR, MS spectroscopies, and HPLC. In the present study,
we synthesized a small focused library of more than
200 pyrazolylpiperazine compounds with different side
chain and were evaluated in vitro for dopamine and seroto-
nin receptors.7 Table 2 shows the binding affinities for
dopamine and serotonin receptors of derivatives from reac-
tion Scheme 1, while Table 3 shows binding affinities only
for dopamine D4 receptor of some selected compounds.
By studying the biological data, syn-isomeric compounds
with 3,4-dimethylphenylpiperazine, 2-OMe-phenylpipera-
zine, 4-F-phenylpiperazine, and 4-Cl-phenyl piperazine
with pyrazole derivatives (8-4, 8-40, 8-5, 8-50, 8-6, 8-60, 8-
7, 8-70) attached to isopropyl and propyl as the side chain
showing binding affinities 29.5, 6.5, 33.8, 39.8, 30.4, 9.7,
24.8, and 6.4 nM, respectively, as selective dopamine D4
receptor antagonists. The anti-isomeric compounds with
2,3-dimethylphenylpiperazine, 3,4-dimethylphenylpipera-
zine, 2-OMe-phenylpiperazine, 4-F-phenylpiperazine, and
4-Cl-phenylpiperazine (9-30, 9-40, 9-50, 9-60,9-70, 9-4, 9-7)
with pyrazole derivatives with isopropyl and propyl as the
side chain also show good binding affinities 49, 11.5,
31.0, 42, 16.2, 17.7, and 19.8 nM. Aside from these
In the synthetic part, diketone 3 was synthesized by
opening γ-butyrolactone or δ-valerolactone ring with acti-
vated ketone 1 in the presence of sodium methoxide as
base in benzene for 12–15 h at room temperature in
57–77% yield. Diketone 3 was easily cyclized with phenyl
hydrazine in methanol solvent for 5–12 h at room tempera-
ture to produce a mixture of two isomeric pyrazoles 4 and
5 in 30–84% yield. By applying Dess–Martin reagent
(when, n = 3) and PCC with SiO2 (when, n = 2) for
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Table 1. A pyrazole library with three points of diversity
Sr.No
R1
i-pra/prb
R2
Ph
R3
n
b
b
01
02
03
04
05
06
07
08
09
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
a
Ph
4
8-1a(70)c/8-10 (75)
9-1a(71)c/9-10 (71)
2-F-Ph
8-2(71)/8-20(80)
8-3(65)/8-30(81)
8-4(68)/8-40(80)
8-5(68)/8-50(75)
8-6(68)/8-60(73)
8-7(65)/8-70(63)
8-8(65)/8-80(68)
8-9(64)/8-90(76)
8-10(70)/8-100(78)
8-11(72)/8-110(64)
8-12(93)
9-2(65)/9-20(71)
9-3(68)/9-30(71)
9-4(70)/9-40(71)
9-5(64)/9-50(71)
9-6(64)/9-60(71)
9-7(70)/9-70(71)
9-8(68)/9-80(71)
9-9(60)/9-90(71)
9-10(73)/9-100(71)
9-11(70)/9-110(71)
2,3-diMe-Ph
3,4-diMe-Ph
2-MeO-Ph
4-F-Ph
4-Cl-Ph
3-CF3-Ph
2-Pyrimidine
2-Pyridine
(4-F-Ph)2CH
4-MeO-Ph
Ph
d
Ph
4-Me-Ph
Ph
t-Bu
3
3
—
8-13(90)
8-14(76)
8-15(84)
8-16(73)
8-17(91)
8-18(55)
8-19(80)
8-20(53)
8-21(82)
8-22(93)
8-23(89)
8-24(87)
8-25(80)
8-26(75)
8-27(58)
8-28(85)
—
2-F-Ph
—
3,4-diMe-Ph
4-MeO-Ph
2-F-Ph
4-Cl-Ph
3,4-diMe-Ph
2-F-Ph
4-Cl-Ph
2,3-diMe-Ph
Ph
3,4-diMe-Ph
4-Cl-Ph
2,3-diMe-Ph
4-MeO-Ph
3,4-diCl-Ph
3,4-diCl-Ph
2,4-diMe-Ph
2,3-diMe-Ph
3,4-diMe-Ph
3,4-diMe-Ph
—
4-MeO-Ph
4-MeO-Ph
t-Bu
3
3
—
—
—
3
—
Ph
—
—
4-Cl-Ph
4-F-Ph
t-Bu
t-Bu
3
3
—
—
—
—
—
—
2-thiophene
Propyl
t-Bu
t-Bu
3
3
8-29(94)
8-30(98)
8-31(92)
8-32(98)
—
9-30(84)
9-31(81)
9-32(69)
9-33(92)
Propyl
Ph
3
8-33(85)
Derivatives with isopropyl.
Derivatives with propyl.
Yield in percentage.
b
c
d
Second isomer does not formed.
selective derivatives, only compounds with phenyl pipera-
zine and 3-CF3 phenyl piperazine attached to pyrazole
derivatives show useful binding affinities as 42.3 and
5.2 nM, respectively.
In some part, we evaluated some compounds only for
dopamine receptor D4 (Table 3) which showed IC50 value
in between 100 and 200 nM and near to a reference com-
pound Haloperidol. From Tables 1 and 3, we can conclude
that compounds with different side chain (Ph-H, 4-Me-Ph,
4-OMe-Ph, 4-Cl-Ph, 4-F-Ph, thiophene, and propyl) with
substituted pyrazole by phenyl and isopropyl group
(8–12 ~ 8–33, 9–30 ~ 9–33) which are attached to different
piperazine compounds are better compounds for dopamine
receptor D4. In addition to the D4 activity, most of the com-
pounds are useful for serotonin receptor with good affinity
for 5HT1a.
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Experimental
General Procedure for the Synthesis of Derivatives
8 and 9: To a solution of syn or anti 4-(3-isopropyl-1-
phenyl-1H-pyrazol-5-yl)butanol (when, R1 = i-pr and
R2 = Ph) (60 mg, 0.234 mmol), 1-phenylpiperazine (when,
R3 = Ph) (31.6 mg, 0.234 mmol) and DIPEA (0.061 ml,
0.351 mmol) in dichloromethane (5 mL) at rt, 4 Å molecu-
lar sieve was added and stirred for 30 min. After the mix-
ture being stirred for 30 min, NaBH(OAc)3 (149 mg,
0.702 mmol) was added and the mixture was stirred for
12 h. Saturated NaHCO3 solution was added and the mix-
ture was extracted with ethyl acetate (5 mL × 5). The
organic layers were dried over anhydrous MgSO4 and con-
centrated. The residue was purified by flash column
Scheme 1. Reagents and reaction conditions: (i) NaOMe, Benzene,
rt, 12–15 h, 57–77%; (ii) PhNHNH2, CH3OH, rt, 5–12 h, 30–84%;
(iii) (a) Dess–Martin periodinane, CH2Cl2, rt, 3 h, 60–67%.
(When, n = 3) (b) PCC, SiO2, rt, 5 h, 55–94% (When, n = 2);
(iv) R3, DIPEA, NaBH(OAc)3, CH2Cl2, 4ÅMS, 12 h, rt, 44–94%.
Table 2. Binding affinity of dopamine and serotonin receptor
Binding affinity (IC50, nM)
Compound
D4
118
102
75
D3
219
D2
582
5-HT1A
5-HT2A
5-HT2C
5-HT6
5-HT7
8-1
8-2
8-3
8-4
8-5
8-6
8-7
8-8
8-10
9-2
9-3
9-4
9-5
62
41
47
129
7.0
93
416
63
218
176
53
24
1219
68
5318
2711
273
>10000
>10000
4536
2624
7419
1984
3261
3635
>10000
6550
1611
1021
>10000
1330
991
10000
2233
10000
>10000
2317
1191
6029
4840
3388
3054
>10000
751
21
23
111
62
7.7
58
99
185
200
1070
498
1799
894
823
2021
220
150
396
103
787
156
942
151
695
228
106
392
414
1467
4216
1812
1146
108
392
476
97
224
359
1029
132
1893
2791
587
4122
941
3107
298
20
1249
399
2725
822
530
146
192
576
119
-
662
529
1435
180
875
444
609
800
87
3133
2055
1344
1084
29.5
239
33.8
30.4
24.8
3479
3671
3256
579
10000
3885
296
58
414
247
989
260
29
24
42
206
133
71
17.7
55
19.8
141
460
1024
36
49
143
6.9
156
26
271
40
146
1861
48
9.8
38
4.9
191
12
42
2276
69
32
8.6
20
4.5
35
235
236
48
1727
18
21
21
85
3.9
24
61
27
4.1
70
274
2167
107
333
2023
38
366
549
46
24
1165
69
48
89
310
29
209
615
104
91
2167
47
48
3377
2088
443
>10000
258
7003
2717
301
9-7
9-8
9-10
9-11
8-10
8-20
8-30
8-40
8-50
8-60
8-70
8-80
8-100
8-110
9-10
9-20
9-30
9-40
9-50
9-60
9-70
9-90
9-100
42.3
135
106
72
13
6.5
230
118
8.0
67
128
150
54
689
75
175
56
230
20
124
281
1204
152
39.8
9.7
6.4
5.2
153
337
84
155
49
11.5
31.0
42
16.2
2508
1612
3806
2357
9637
811
1554
3787
370
5161
5387
943
578
142
834
498
1768
626
529
759
2941
2050
1630
>10000
4112
5377
1268
1357
>10000
9239
302
132
>10000
2375
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BULLETIN OF THE
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Table 3. Binding affinity of dopamine receptor D4
Sr. no.
Compound
IC50, nM
Sr. no.
Compound
IC50, nM
01
02
03
04
05
06
07
08
09
10
11
12
8-12
8-13
8-14
8-15
8-16
8-17
8-18
8-19
8-20
8-21
8-22
8-23
8-24
179
146
142
159
148
117
118
103
151
114
165
174
106
160
14
15
16
17
18
19
20
21
22
23
24
25
26
8-25
8-26
8-27
8-28
8-29
8-30
8-31
8-32
8-33
9-30
9-31
9-32
9-33
120
153
110
179
107
16
62
59
199
123
130
122
8
13
Haloperidol
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chromatography (EtOAc: Hexane = 3:1) to give the com-
pound 8-1 in 70% and 9-1 in 71%.
1H NMR of compound 8-1: 1H NMR (400 MHz,
MeOH-d4) δ 7.73–7.64 (m, 5H), 7.33–7.29 (m, 2H),
7.10–7.07 (m, 2H), 7.00–6.96 (m, 1H), 6.74 (s, 1H),
3.90–3.60 (m, 4H), 3.31–3.26 (m, 7H), 3.00–2.90 (m, 2H),
2.02–1.85 (m, 4H), 1.26 (d, 6H, J = 7.2 Hz).
1H NMR of compound 9-1: 1H NMR (400 MHz,
MeOH-d4) δ 7.71–7.65 (m, 5H), 7.31–7.27 (m, 2H), 7.04
(d, 2H, J = 8 Hz), 6.95 (t, 1H, J = 7.5 Hz), 6.74 (s, 1H),
3.81 (d, 2H, J = 11.6 Hz), 3.64(d, 2H, J = 10 Hz),
3.23–3.14 (m, 7H), 2.77 (t, 2H, J = 7.5 Hz), 1.85–1.77 (m,
4H), 1.40 (d, 6H, J = 6.8 Hz).
4. (a) M. Y. Cha, B. C. Choi, K. H. Kang, A. N. Pae, K. I. Choi,
Y. S. Cho, H. Y. Koh, H. Y. Lee, D. Jung, J. Y. Kong, Bioorg.
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H. Choo, A. N. Pae, Bull. Kor. Chem. Soc. 2009, 30, 1873;
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H. Y. Koh, S. H. Jung, Bull. Kor. Chem. Soc. 2011, 32, 2449.
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J. E. Lee, S. H. Jung, H. Y. Koh, H. Y. Lee, Tetrahedron Lett.
2001, 42, 1057.
6. A. F. Abdel-Magid, K. G. Carson, B. D. Harris,
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M. Y. Cha, A. N. Pae, K. I. Choi, H. Y. Koh, J. Y. Kong,
Pharmacol. Biochem. Behav. 2005, 82, 361; (c)Compounds
were evaluated in vitro for dopamine D2, D3, D4 receptors
binding affinity by measuring their ability to displace radioli-
gand ([3H]Methylspiperone for D2 and D3, [3H]YM-
09151-2 for D4) from the cloned human dopamine recep-
tors D2Long, D3 and D4.2 which were stably expressed in
CHO or Sf9 cells, respectively. For serotonin receptors,
compounds were biologically evaluated against human
recombinant 5-HT1A, 5-HT2A, 5-HT2C, 5-HT6 and 5-HT7
receptors stably expressed by CHO-K1 cell lines through
[3H]8-OH-DPAT, [3H]Ketanserin, [3H]Mesulergine and
[3H]LSD binding assay, respectively).
1H NMR of compound 8-10: 1H NMR (400 MHz, MeOH-
d4) δ 7.61–7.47 (m, 5H), 7.31–7.27 (m, 2H), 7.03–7.11 (m,
2H), 6.96–6.92 (m, 1H), 6.36 (s, 1H), 3.88–3.30 (m, 4H),
3.30–3.23 (m, 4H), 3.20–3.03 (m, 2H), 2.80 (t, 2H,
J = 7.2 Hz), 2.62 (t, 2H, J = 7.6 Hz), 1.95–1.80 (m, 4H),
1.64–1.58 (m, 2H), 0.91 (t, 3H, J = 7.4 Hz).
1H NMR of compound 9-10: 1H NMR (400 MHz, MeOH-
d4) δ 7.65–7.57 (m, 5H), 7.30–7.26 (m, 2H), 7.03–7.00 (m,
2H), 6.95 (m, 1H), 6.55 (s, 1H), 3.80 (d, 2H, J = 11.6 Hz),
3.62 (d, 2H, J = 10.8 Hz), 3.20–3.14 (m, 6H), 2.80–2.72 (m,
4H), 1.83–1.73 (m, 6H), 1.03 (t, 3H, J = 7.4 Hz).
All the derivatives synthesized analogously and identified
by 1H NMR.
Acknowledgment. This work was supported by Inha Uni-
versity Research Grant.
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