Synthesis and evaluation of novel compounds as potent dipeptidyl peptidase IV inhibitors

Article abstract of DOI:10.1080/00397910902919522

A series of new 2-cyanopyrrolidine derivatives with constrained imidazolidin ring were synthesized, Their structures were confirmed by 1H NMR spectroscopy and/or mass spectrometry, and their activities were evaluated in vitro. They were proven to possess submicromolar inhibitory activities against dipeptidyl peptidase IV.

Full text of DOI:10.1080/00397910902919522

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Synthesis and Evaluation of Novel
Compounds as Potent Dipeptidyl
Peptidase IV Inhibitors
Liutang Wang a b , Bin Zhang b , Jianxin Ji b , Bogang Li b , Jufang Yan
b , Weiyu Zhang b , Yong Wu a , Xuechao Wang a b & Hui Hou b
a West China School of Pharmacy, Sichuan University, Chengdu, China
b Department of Research and Development, Di'ao Co. Ltd, Chengdu,
China
Version of record first published: 09 Dec 2009
To cite this article: Liutang Wang, Bin Zhang, Jianxin Ji, Bogang Li, Jufang Yan, Weiyu Zhang,
Yong Wu, Xuechao Wang & Hui Hou (2009): Synthesis and Evaluation of Novel Compounds as Potent
Dipeptidyl Peptidase IV Inhibitors, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:1, 52-57
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Synthetic Communications1, 40: 52–57, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902919522
SYNTHESIS AND EVALUATION OF NOVEL
COMPOUNDS AS POTENT DIPEPTIDYL
PEPTIDASE IV INHIBITORS
Liutang Wang,1,2 Bin Zhang,2 Jianxin Ji,2 Bogang Li,2
Jufang Yan,2 Weiyu Zhang,2 Yong Wu,1 Xuechao Wang,1,2
and Hui Hou2
1West China School of Pharmacy, Sichuan University, Chengdu, China
2Department of Research and Development, Di’ao Co. Ltd, Chengdu, China
A series of new 2-cyanopyrrolidine derivatives with constrained imidazolidin ring were
synthesized, Their structures were confirmed by 1H NMR spectroscopy and/or mass spec-
trometry, and their activities were evaluated in vitro. They were proven to possess submicro-
molar inhibitory activities against dipeptidyl peptidase IV.
Keywords: Antidiabetic agent; 2-cyanopyrrolidine; dipeptidyl peptidase IV inhibitors; imidazolidin
derivatives
INTRODUCTION
Inhibition of dipeptidyl peptidase IV (DPP-IV) has recently emerged as a
promising new approach for the treatment of type 2 diabetes mellitus.[1] DPP-IV
is the enzyme responsible for inactivation of the incretins glucagon-like peptide 1
(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These two hor-
mones are secreted in response to nutrient ingestion, and each enhances the
glucose-dependent secretion of insulin. Furthermore, in mammals GLP-1 has been
shown to stimulate the secretion of insulin in a glucose-dependent manner, inhibit
glucagon release, slow gastric emptying, induce satiety, and stimulate the regener-
ation and differentiation of islet b-cells, with all of these actions promoting the
control of glucose homeostasis in patients with type 2 diabetes.[2] Thus, inhibition
of DPP-IV could increase the half-life of active GLP-1 and GIP and prolong the ben-
eficial effects of these incretin hormones, which would enhance insulin secretion and
improve glucose tolerance. Therefore, much attention has been paid to DPP-IV as a
Received December 17, 2008.
Address correspondence to Yong Wu and Xuechao Wang, Key Laboratory of Drug Targeting and
Novel Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu 610041,
China. E-mail: pro_wuy_2002@soho.com; huaxiwanglt@163.com
52

SYNTHESIS AND EVALUATION OF NOVEL COMPOUNDS
53
Scheme 1. Reagent and conditions: (i) triphosgene, toluene, heated, 4–8 h; (ii) diethanolamine, CH2Cl2,
rt, overnight; (iii) PBr3, CH2Cl2, 10ꢀC, 5 h; (iv) NaHCO3, pH ꢁ 10, overnight; and (v) (1) (S)-1-
(2-aminoacetyl)pyrrolidine-2-carbonitrile trifluoroacetate, K2CO3, CH3CN, rt, 40–48 h; (2) oxalic acid,
isopropanol.
promising new target for drugs.[3] DPP-IV is a dipeptidase that selectively binds
substrates with alanine or proline at the P1 position.[1a,4] Consequently, many
DPP-IV inhibitors are shaped like dipeptides and contain a basic nitrogen and pro-
line mimic. (S)-1-(2-Aminoacetyl)pyrrolidine-2-carbonitrile is one of the most potent
moieties and contributes significantly to the binding affinity between DPP-IV and its
inhibitors.[5,6] Thus, we have designed and synthesized a series of structurally con-
strained imidazolidin (S)-1-(2-aminoacetyl)pyrrolidine-2-carbonitrile derivatives 1.
RESULTS AND DISCUSSION
The DPP-IV inhibitors were prepared as described in Scheme 1. Amine 2 was
heated with triphosgene in toluene to afford isocyanate compounds (3), which were
then reacted with diethanolamine in dichloromethane (DCM) at room temperature
to provide substituted urea derivatives (4) in excellent yield. Compound 4 was bro-
minated with tribromophosphine in DCM under ice-water conditions to yield the
desired intermediates (5), followed by cyclization at base conditions to obtain the
key imidazolidin-2-one derivatives (6). Compound 6 was coupled with (S)-1-(2-
aminoacetyl)pyrrolidine-2-carbonitrile (prepared in three steps[7] from L-prolinamide)
to provide the desired 2-cyanopyrrolidine derivatives (1).
Compounds 1a–g were evaluated in vitro for their inhibition of DPP-IV
(Table 1). KR-62436[8] was used as a reference compound. All of them were proven
to possess submicromolar inhibitory activities against DPP-IV.

54
L. WANG ET AL.
Table 1. DPP-IV inhibitory activity
Compound
R
IC50 (mM)
1a
1b
H
4-Fluoro
2-Fluoro
0.08
0.10
0.10
0.20
0.12
0.32
0.16
0.26
1c
1d
4-Methoxy
3-Methoxy
3,4-Dimethoxy
3,4-Methylenedioxy
1e
1f
1g
KR-62436
Note. Values are IC50 (mM) expressed as the mean of three independent
determinations.
EXPERIMENTAL
General
Melting points were observed in an open capillary tube and are uncorrected. 1H
NMR spectra were obtained at 600 MHz on a Bruker Avance 600 instrument
using CDCl3 or dimethylsufoxide (DMSO-d6) as solvent and tetramethylsilane
(TMS) as internal standard. Mass spectra (MS) were measured on an Agilent
1946B ESI-MS instrument. Specific rotations were measured on a Perkin-Elmer-341
instrument. All commercially available reagents were used without purification.
General Procedure for the Synthesis of 6
Triphosgene (85 mmol) was dissolved in toluene (200 mL), and the solution of 2
(100 mmol) in toluene was added dropwise with ice cooling. The temperature was
gradually increased. The mixture was stirred for an hour at room temperature and
then heated to 100ꢀC for 3 h. The mixture was concentrated to about 80 mL, then
added to the solution of diethanolamine (200 mmol) in CH2Cl2 (200 mL), and stirred
overnight. The reacting solution was diluted with CH2Cl2, washed with brine, dried
over Na2SO4, and concentrated in vacuo to afford 4, which could be used for the
next reaction without purification.
Tribromophosphine (120 mmol) was added to the solution of 4 in CH2Cl2
(200 mL) dropwise in an ice-water bath. The mixture was stirred for 3 h at room tem-
perature, basified with saturated NaHCO3 solution, and stirred overnight. The
organic phase was isolated, and the aqueous layer was extracted with CH2Cl2 two
times. The combined organic phase was washed with brine and dried over Na2SO4.
Concentration was followed by purification by chromatography using silica gel
(eluting sequentially with petroleum ether=ethyl acetate ¼ 10=1 to 3=1) to afford 6.

SYNTHESIS AND EVALUATION OF NOVEL COMPOUNDS
55
1-(2-Bromoethyl)-3-phenethylimidazolidin-2-one (6a). Yield: 35%. 1H
NMR d (CDCl3): 7.30–7.19 (m, 5H), 3.59 (t, 2H, J ¼ 6.7 Hz), 3.47–3.44 (m, 4H),
3.40 (t, 2H, J ¼ 8.5 Hz), 3.24 (t, 2H, J ¼ 8.3 Hz), 2.83 (t, 2H, J ¼ 7.4 Hz). ESI-MS
(þ): 297, 299 (1:1) (M þ H)þ.
1-(2-Bromoethyl)-3-(4-fluorophenethyl)imidazolidin-2-one (6b). Yield:
1
27%. H NMR d (CDCl3): 7.19–7.17 (m, 2H), 6.98 (t, 2H, J ¼ 8.6 Hz), 3.59 (t, 2H,
J ¼ 6.3 Hz), 3.46 (t, 2H, J ¼ 6.3 Hz), 3.43–3.39 (m, 4H), 3.24 (t, 2H, J ¼ 7.3 Hz),
2.80 (t, 2H, J ¼ 7.6 Hz). ESI-MS (þ): 315, 317 (1:1) (M þ H)þ.
1-(2-Bromoethyl)-3-(2-fluorophenethyl)imidazolidin-2-one (6c). Yield:
30%. 1H NMR d (CDCl3): 7.23–7.17 (m, 2H), 7.09–7.00 (m, 2H); 3.58 (t, 2H,
J ¼ 6.6 Hz), 3.46–3.40 (m, 6H), 3.29 (t, 2H, J ¼ 7.4 Hz), 2.88 (t, 2H, J ¼ 7.4 Hz).
ESI-MS (þ): 315, 317 (1:1) (M þ H)þ.
1-(2-Bromoethyl)-3-(4-methoxyphenethyl)imidazolidin-2-one
(6d). Yield: 23%. 1H NMR d (CDCl3): 7.14 (d, 2H, J ¼ 8.5 Hz), 6.84 (d, 2H,
J ¼ 8.4 Hz), 3.79 (s, 3H), 3.59 (t, 2H, J ¼ 6.5 Hz), 3.46 (t, 2H, J ¼ 6.5 Hz),3.42–3.38
(m, 4H), 3.24 (t, 2H, J ¼ 7.5 Hz), 2.77 (t, 2H, J ¼ 7.6 Hz). ESI-MS (þ): 327,329
(1:1) (M þ H)þ.
1-(2-Bromoethyl)-3-(3-methoxyphenethyl)imidazolidin-2-one
1
(6e). Yield: 26%. H NMR d (CDCl3): 7.21 (t, 1H, J ¼ 7.8 Hz), 6.83–6.75 (m, 3H),
3.79 (s, 3H), 3.59 (t, 2H, J ¼ 6.2 Hz), 3.47–3.44 (m, 4H), 3.40 (t, 2H, J ¼ 8.4 Hz), 3.25
(t, 2H, J ¼ 8.5 Hz), 2.80 (t, 2H, J ¼ 7.9 Hz). ESI-MS (þ): 327, 329 (1:1) (M þ H)þ.
1-(2-Bromoethyl)-3-(3,4-dimethoxyphenethyl)imidazolidin-2-one
(6f). Yield: 19%. 1H NMR d (CDCl3): 6.81–6.76 (m, 3H); 3.87 (s, 3H), 3.86 (s, 3H),
3.59 (t, 2H, J ¼ 6.3 Hz), 3.48–3.39 (m, 6H), 3.25 (t, 2H, J ¼ 8.5 Hz), 2.78 (t, 2H,
J ¼ 7.8 Hz). ESI-MS (þ): 357, 359 (1:1) (M þ H)þ.
1-(2-Bromoethyl)-3-(3,4-methylenedioxyphenethyl)imidazolidin-2-one
(6g). Yield: 15%. 1H NMR d (CDCl3): 6.74–6.66 (m, 3H), 5.92 (s, 2H), 3.59 (t, 2H,
J ¼ 6.3 Hz), 3.46 (t, 2H, J ¼ 6.5 Hz), 3.42–3.38 (m, 4H), 3.25 (t, 2H, J ¼ 7.3 Hz), 2.74
(t, 2H, J ¼ 7.7 Hz). ESI-MS (þ): 341, 343 (1:1) (M þ H)þ.
General Procedure for the Synthesis of 1
(S)-1-(2-Aminoacetyl)pyrrolidine-2-carbonitrile trifluoroacetate (24 mmol)was
dissolved in acetonitrile, K2CO3 (64 mmol) was added, and the mixture was stirred
for 30 min to liberate free amine. Then 6 (8 mmol) was added, and stirring continued
for 48 h at room temperature. The mixture was filtered to remove the insoluble sub-
stance and concentrated in vacuo. Purification by flash-column chromatography
(eluted with CHCl3=MeOH ¼ 10=1) yielded 1 as a viscous oil. The free base was
dissolved in isopropanol, the solution of oxalic acid in isopropanol was added in
drops, and precipitation occurred. Filtration was followed by drying in vacuo over
P2O5.
(S)-1-(2-(2-(3-Phenethyl-2-oxoimidazolidin-1-yl)ethylamino)acetyl)
20
pyrrolidine-2-carbonitrile Oxalate (1a). Yield: 28%. Mp 140–142ꢀC. ½aꢁD ꢂ74ꢀ
(c ¼ 1, H2O). 1H NMR d (DMSO-d6): 7.28 (t, 2H, J ¼ 7.7 Hz), 7.23 (d, 2H,

56
L. WANG ET AL.
J ¼ 7.3 Hz), 7.19 (t, 1H, J ¼ 7.3 Hz), 4.82 (dd, 1H, J ¼ 7.5, 4.0 Hz), 4.00–3.88 (m, 2H),
3.59–3.56 (m, 1H), 3.42–3.38 (m, 1H), 3.34–3.30 (m, 4H), 3.27 (s, 4H), 3.00 (t, 2H,
J ¼ 5.9 Hz), 2.75 (t, 2H, J ¼ 7.6 Hz), 2.18–2.15 (m, 2H), 2.07–2.00 (m, 2H). ESI-MS
(þ): 370 (M þ H)þ.
(S)-1-(2-(2-(3-(4-Fluorophenethyl)-2-oxoimidazolidin-1-yl)ethylamino)-
20
acetyl)pyrrolidine-2-carbonitrile Oxalate (1b). Yield: 23%. Mp 127–129ꢀC. ½aꢁD
ꢂ66ꢀ (c ¼ 1, H2O). 1H NMR d (DMSO-d6): 7.28–7.26 (m, 2H), 7.10 (t, 2H,
J ¼ 8.8 Hz), 4.83 (dd, 1H, J ¼ 7.2, 4.2 Hz), 4.04–3.91 (m, 2H), 3.60–3.57 (m, 1H),
3.45–3.39 (m, 1H), 3.35 (t, 2H, J ¼ 5.8 Hz), 3.32–3.28 (m, 6H), 3.03 (m, 2H,
J ¼ 6.0 Hz),2.75 (t, 2H, J ¼ 7.4 Hz), 2.20–2.17 (m, 2H), 2.06–2.00 (m, 2H). ESI-MS
(þ): 388 (M þ H)þ.
(S)-1-(2-(2-(3-(2-Fluorophenethyl)-2-oxoimidazolidin-1-yl)ethylamino)-
20
acetyl)pyrrolidine-2-carbonitrile Oxalate (1c). Yield: 20%. Mp 139–141ꢀC. ½aꢁD
ꢂ71ꢀ (c ¼ 1, H2O). 1H NMR d (DMSO-d6): 7.34–7.12 (m, 4H), 4.82 (dd, 1H, J ¼ 7.1,
3.8 Hz), 3.99–3.89 (m, 2H), 3.60–3.57 (m, 1H), 3.42–3.38 (m, 1H), 3.34–3.27 (m, 8H),
3.01 (t, 2H, J ¼ 7.4 Hz), 2.79 (t, 2H, J ¼ 7.4 Hz), 2.22–2.16 (m, 2H), 2.06–2.00 (m,
2H). ESI-MS (þ): 388 (M þ H)þ.
(S)-1-(2-(2-(3-(4-Methoxyphenethyl)-2-oxoimidazolidin-1-yl)ethylamino)-
20
acetyl)pyrrolidine-2-carbonitrile Oxalate (1d). Yield: 25%. Mp 108–110ꢀ. ½aꢁD
1
ꢂ64ꢀ (c ¼ 1, H2O). H NMR d (DMSO-d6): 7.15 (d, 2H, J ¼ 8.4 Hz), 6.86 (d, 2H,
J ¼ 8.6 Hz), 4.83 (dd, 1H, J ¼ 6.8, 3.5 Hz), 4.04–3.91 (m, 2H), 3.72 (s, 3H),
3.60–3.57 (m, 1H), 3.43–3.38 (m, 1H), 3.34 (t, 2H, J ¼ 6.1 Hz), 3.29–3.26 (m, 6H),
3.03 (t, 2H, J ¼ 6.3 Hz), 2.68 (t, 2H, J ¼ 7.9 Hz), 2.20–2.16 (m, 2H), 2.07–2.00 (m,
2H). ESI-MS (þ): 400 (M þ H)þ.
(S)-1-(2-(2-(3-(3-Methoxyphenethyl)-2-oxoimidazolidin-1-yl)ethylamino)-
20
acetyl)pyrrolidine-2-carbonitrile Oxalate (1e). Yield: 19%. Mp 114–117ꢀ. ½aꢁD
1
ꢂ65ꢀ (c ¼ 1, H2O). H NMR d (DMSO-d6): 7.20 (t, 1H, J ¼ 8.04 Hz), 6.08–6.76
(m, 3H), 4.82 (s, 1H), 4.00–3.90 (m, 2H), 3.74 (s, 3H), 3.58 (br, 1H), 3.43–3.39 (m,
1H), 3.34–3.28 (m, 8H), 3.02 (s, 2H), 2.72 (t, 2H, J ¼ 7.6 Hz), 2.18 (br, 2H),
2.05–2.02 (m, 2H). ESI-MS (þ): 400 (M þ H)þ.
(S)-1-(2-(2-(3-(3,4-Dimethoxyphenethyl)-2-oxoimidazolidin-1-yl)ethylamino)-
20
acetyl)pyrrolidine-2-carbonitrile Oxalate (1f). Yield: 16%. Mp 103–105ꢀC. ½aꢁD
1
ꢂ54ꢀ (c ¼ 1, H2O). H NMR d (DMSO-d6): 6.86 (d, 1H, J ¼ 8.2 Hz), 6.82 (s, 1H),
6.73 (d, 1H, J ¼ 8.2), 4.82 (dd, 1H, J ¼ 7.3, 3.8 Hz), 4.00–3.90 (m, 2H), 3.74 (s,
3H), 3.71 (s, 3H), 3.60–3.57 (m, 1H), 3.43–3.39 (m, 1H), 3.34 (t, 2H, J ¼ 6.0 Hz),
3.31–3.28 (m, 6H), 3.03 (t, 2H, J ¼ 6.0 Hz), 2.68 (t, 2H, J ¼ 7.6 Hz), 2.22–2.17 (m,
2H), 2.06–2.00 (m, 2H). ESI-MS (þ): 430 (M þ H)þ.
(S)-1-(2-(2-(3-(3,4-Methylenedioxyphenethyl)-2-oxoimidazolidin-1-yl)-
ethylamino)acetyl)pyrrolidine-2-carbonitrile Oxalate (1g). Yield: 17%. Mp
20
1
120–122ꢀC. ½aꢁD ꢂ61ꢀ (c ¼ 1, H2O). H NMR d (DMSO-d6): 6.82–6.69 (m, 3H),
5.96 (s, 2H), 4.82 (dd, 1H, J ¼ 7.0, 3.6 Hz), 3.99–3.89 (m, 2H), 3.60–3.57 (m, 1H),
3.43–3.39 (m, 1H), 3.33 (t, 2H, J ¼ 5.8 Hz), 3.28–3.25 (m, 6H), 3.00 (s, 2H), 2.66
(t, 2H, J ¼ 7.6 Hz), 2.20–2.17 (m, 2H), 2.06–2.00 (m, 2H). ESI-MS (þ): 414
(M þ H)þ.

SYNTHESIS AND EVALUATION OF NOVEL COMPOUNDS
57
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