Design and synthesis of novel pyrazino[2,1-a]isoquinoline derivatives with potent antifungal activity

Article abstract of DOI:10.1002/ardp.200900279

A series of novel pyrazino[2,1-a]isoquinoline compounds were designed, synthesized, and their antifungal activities in vitro were evaluated. The results showed that all of the title compounds exhibited antifungal activities. Most of them exhibited stronge

Full text of DOI:10.1002/ardp.200900279

360
Arch. Pharm. Chem. Life Sci. 2010, 343, 360–366
Full Paper
Design and Synthesis of Novel Pyrazino[2,1-a]isoquinoline
Derivatives with Potent Antifungal Activity
Hui Tang, Can-hui Zheng, Ju Zhu, Bing-yue Fu, You-jun Zhou*, and Jia-guo Lv
School of Pharmacy, Second Military Medical University, Shanghai, P.R. China
A series of novel pyrazino[2,1-a]isoquinoline compounds were designed, synthesized, and their
antifungal activities in vitro were evaluated. The results showed that all of the title compounds
exhibited antifungal activities. Most of them exhibited stronger antifungal activities than the
lead compounds; compound 7c is more potent than fluconazole against two of the three tested
fungal strains. The studies presented here provide a new structural type for the development of
novel antifungal agents.
Keywords: Antifungal / Lanosterol 14a-demethylase / Pyrazino[2,1-a]isoquinoline / Synthesis /
Received: November 19, 2009; Accepted: December 11, 2009
DOI 10.1002/ardp.200900279
Introduction
During the past decades, the incidence of systemic fungal
infections has increased dramatically and became a
major cause of morbidity and mortality in immune com-
promised individuals such as patients undergoing anti-
cancer chemotherapy or organ transplants and patients
with AIDS [1–4]. Although the arsenal of antifungal drugs
has expanded, currently available antifungal drugs do
not meet the increasing requirements of managing infec-
tion in the complex patient population. Therefore, the
development of new antifungal drugs is an ongoing
necessity in clinical therapy.
Figure 1. Some CYP51 inhibitors: Azole antifungals, lanosterol,
and compound L-6.
Lanosterol 14a-demethylase (CYP51) is one of the key
enzymes of sterol biosynthesis in fungi and also a prime
target for the development of antifungal drugs. Azole
antifungals, such as fluconazole [5] and voriconazole [6]
(Fig. 1), are the CYP51 inhibitors widely used in the clini-
cal antifungal therapy, which exert antifungal activity
through inhibiting the lanosterol 14a-demethylase
(CYP51) of fungi by a mechanism in which the heterocy-
clic nitrogen atom [1] (N-3 of imidazole and N-4 of 1,2,4-
triazole) binds to the sixth coordination position of the
heme iron atom of the prophyrin in the substrate-bind-
ing site of the enzyme [7–9]. Unfortunately, the broad use
of azoles has led to development of severe resistance,
which significantly reduced their efficacy [10, 11]. Thus,
the search for new non-azole CYP51 inhibitors is mean-
ingful. In recent years, we focused on the search of non-
azole CYP51 inhibitors. In our previous studies [12–13],
we reported the design of non-azole lead molecules with
a tetrahydroisoquinoline scaffold, based on the con-
structed three-dimensional model of Candida albicans
Correspondence: Prof. You-jun Zhou and Prof. Jia-guo Lv, School of
Pharmacy, Second Military Medical University, Shanghai 200433, P.R.
China.
E-mail: zhouyoujun2006@yahoo.com.cn and
ljg20060508@yahoo.com.cn
Fax: +86 21 818-7123-1 and +86 21 818-7123-4
Abbreviation: Lanosterol 14a-demethylase from Candida albicans (CA-
CYP51)
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Arch. Pharm. Chem. Life Sci. 2010, 343, 360–366
Novel Pyrazino[2,1-a]isoquinoline Derivatives
361
Reagents: a) Chloroacetyl chloride, NaHCO3, CH2Cl2, rt; b) 2,2-dimethoxyethanamine toluene, reflux; c) H2SO4, CH2Cl2; d) RX, K2CO3/KI; e) LiAlH4, THF.
Scheme 1. Synthetic routes for pyrazino[2,1-a]isoquinoline derivatives 5a–8c and 9a–12c.
CYP51 (CA-CYP51). The binding study showed that the tet-
rahydroisoquinoline scaffold was located on the sub-
strate- binding site of fungal CYP51, and the affinity of the
lead molecules for CYP51 was mainly attributed to their
non-bonding interaction with the residues of the apopro-
tein, no binding with the heme, which was different from
Figure 2. Novel pyrazino[2,1-a]isoquinoline derivatives.
that of azole antifungals. L-6 is the most potent compound
discovered (Fig. 1). Considering lanosterol – the natural concentrated H2SO4 provided the key intermediates 4a–c
substrate for CYP51 with a four-ring skeleton in its struc- [14, 15]. Intermediates 4a–c were refluxed with different
ture – apossible increase in affinity for CYP51 and antifun- halides to provide the target compounds 5a–8c. Reduc-
gal activities of the target compounds is expected by tion of 5a–8c with LiAlH4 in THF yields the target com-
expanding the tetrahydroisoquinoline scaffold of thelead pounds 9a–12c. The structures of the synthesized com-
molecules. Therefore, novel pyrazino[2,1-a]isoquinoline pounds were characterized by elemental analysis and
derivatives were designed (Fig. 2), and their antifungal spectral data (IR, MS, and 1H-NMR). The spectral analyses
activities in vitro were evaluated.
were consistent with the assigned structures, and spec-
tral data are listed in the experimental section.
Binding mode of the pyrazino[2,1-a]isoquinoline
The binding mode of the compounds was validated by
flexible molecular docking (Affinity module within
Results and discussion
Chemistry
The synthetic routes of compounds 5a–8c and 9a–12c are InsightII 2000 software package [16]). The active site of
reported in Scheme 1. Treatment of chloroacetyl chloride CYP51 had been constructed in the previous studies [11,
with several arylethylamines afforded compounds 2a–c. 12]. We found that the regions in the active site of CYP51
The aminoalkylation reaction of the readily available 2,2- for non-covalent ligand binding can be divided into four
dimethoxyethanamine with 2a–c gave the amine deriv- subsites, S1–S4, next to the site coordinating with the
atives 3a–c, which were isolated as hydrochloride salts heme. The S1 subsite is a hydrophilic hydrogen-bonding
without using column chromatography. Treatment with region; the S2 subsite is a hydrophobic region; the S3 sub-
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H. Tang et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 360–366
Table 1. In-vitro antifungal activity of compounds 5a–12c.
Compound
MIC (lg/mL)
C. alb.§
C. neo.&
T. rub.#
5a
5b
5c
6a
6b
6c
7a
7b
>64
>64
64
32
32
32
32
16
8
16
16
8
16
16
8
4
8
4
>64
64
32
32
16
16
16
8
7c
8
8a
8b
8c
9a
9b
9c
10a
10b
10c
11a
11b
11c
12a
12b
12c
L-6
>64
>64
>64
64
64
64
32
32
32
32
16
8
>64
>64
>64
64
2
64
32
64
4
>64
32
16
8
64
64
32
8
64
>64
16
32
16
16
8
Figure 3. Docking conformation of compounds 7b in the active
site of CA-CYP51.
16
8
4
site is a narrow hydrophobic cleft formed by the residues
in the helix B9-meander1 loop and the N terminus of helix
I, and the S4 subsite is another hydrogen-bonding region
in the active site. Figure 3 shows the docking conforma-
tion of compounds 7b in the active site of CA-CYP51. The
pyrazino[2,1-a]isoquinoline ring interacts with the S2
subsite. The methoxy group in the benzene ring forms H-
bonding interactions with the residues Tyr69 and Ser378
in the S4 subsite. The long lipophilic side chain was ori-
ented into the S3 pocket. No interaction was found
between the compound and the heme. This suggests that
the affinity of pyrazino[2,1-a]isoquinoline derivatives to
the potential receptor CYP51 might be mainly attributed
4
8
>64
64
64
16
4
64
32
32
32
32
Fluconazole
§ C. alb.: Candida albicans; & C. neo.: Cryptococcus neoformans;
# T. rub.: Trichophyton rubrum.
substituted alkyl or the aromatic side chains (5a–c or
12a–c, respectively) are too short to interact firmly with
the hydrophobic S3 region. The S4 subsite is a hydrogen-
to their non-bonding interaction with the apoprotein bond donor and acceptor region, which interacts with
the functional groups on the phenyl group of the isoqui-
noline ring. The compounds with a fluoro or methoxy
group at positions 9 or 10 in the aromatic ring gave bet-
part of the active site.
In-vitro antifungal activities
All compounds were evaluated for their antifungal activ- ter results than those of none substituents in the aro-
matic ring. Compounds 7a–c were the most potent com-
ities in vitro by the standard broth microdilution method
pounds against all tested strains and exhibited much
of the NCCLS [17]. The tested fungi species included three
pathogenic fungi: dermatomycoses (Trichophyton rubrum) stronger activities than the compounds with other alkyl
and systemic mycoses (Candida albicans and Cryptococcus group, which suggests that the appropriate length of the
substituents on the amino group of target derivatives is
important for antifungal activities.
neoformans). The antifungal activities of all compounds
are listed in Table 1; fluconazole and L-6 were used as con-
trols.
All of the title compounds exhibit potent antifungal
activities against three tested fungal strains. Compounds
6c, 7a–c, 10c, and 11a–c exhibit a higher antifungal activ-
Conclusion
ity than L-6 against the test organisms. Compounds 6a, In conclusion, a series of novel pyrazino[2,1-a]isoquino-
line compounds were prepared and evaluated for anti-
fungal activity in vitro. The results showed that most of
7a–c, 9a, 10a, 10c, and 11b–c showed a stronger antifun-
gal activity against T. rubrum than that of control drug
fluconazole. The antifungal activities of compounds 5a–c the target compounds exhibited more potent antifungal
and 12a–c are very low. That is probably because the N- activities than the lead compound L-6, in which com-
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Arch. Pharm. Chem. Life Sci. 2010, 343, 360–366
Novel Pyrazino[2,1-a]isoquinoline Derivatives
363
for 3.5 h, the reaction mixture was poured into ice-water and
adjusted to pH = 12 with 20% aqueous NaOH solution with cool-
ing. The solution was extracted with CH2Cl2. The CH2Cl2 solution
was washed with brine, dried, and concentrated to afford 4a as a
white solid. Yield 81.4%; m.p.: 116.8 to 118.48C (lit. m.p.: 118 to
1198C); 4b (77.6%): m.p.: 137.1 to 137.88C (lit. m.p.: 136 to
1378C); 4c (93%): m.p.: 116.7 to 119.88C.
pound 7c is more potent than fluconazole against two of
the three testing fungal strains. The affinity of the mole-
cules for CYP51 was mainly attributed to their non-bond-
ing interaction with the residues of the apoprotein –
without binding with the heme – which was different
from that of azole antifungals. The studies presented
here may provide a new structural type for the develop-
ment of novel antifungal agents.
General procedure of the preparation of 5a–8c
To a refluxing mixture of intermediate 4 (5 mmol) and K2CO3 (5
mmol) in acetone, 6 mmol of bromo-compounds were added.
After the mixture was heated to reflux for 6 h, the reaction mix-
ture was treated with water and extracted with Et2O three times.
The Et2O solution was dried and concentrated. The residue was
treated with 1 M HCl and recrystallized with EtOH and Et2O to
afford the target compounds 5a–8c.
Experimental
Chemistry
Melting points were determined on an electrically heated RK-Z
melting point apparatus (Analytical instrument factory in Tian-
jin, China) and are uncorrected. Mass spectra (MS) were meas-
ured on a Micromass QTof-Micro LC-MS instrument (Waters-
Micromass). 1H-NMR spectra were recorded at 300 MHz on a
Bruker AC-300P spectrometer (Bruker Bioscience, USA) with
Me4Si as the internal standard. Chemical shifts are given in ppm
(d), and the spectral data are consistent with the assigned struc-
tures. Elemental analyses were performed with a MOD-1106
instrument (Carl Erba, Italy). Commercial solvents and reagents
were of reagent grade.
2-Pentyl-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]
isoquinolin-4(11bH)-one 5a
White solid; yield: 85.3%; m.p.: 251.28C; 1H-NMR (300 MHz,
CDCl3) d: 0.92–0.95 (t, J = 6 Hz, 3H, CH3), 1.37–1.45 (m, 4H, CH2),
1.66–1.85 (m, 2H, CH2), 2.84–3.22 (t, 4H, CH2), 3.24–3.50 (t, 2H,
CH2), 4.02–4.31 (t, 2H, CH2), 4.32–4.41, 4.51–4.78 (dd, 2H, CH2),
5.82–5.91 (t, 1H, CH), 7.18–7.20 (m, 1H, Ar-H), 7.28–7.35 (t, J = 9
Hz, 3H, Ar-H); MS (ESI) m/z: 273.4 [M + H]. Anal. calcd. for
C17H24N2O N HCl: C, 66.11; H, 8.16; N, 9.07. Found: C, 66.10; H,
8.04; N, 9.13.
General procedure of preparation of N-2-(substituted
phenyl)ethyl chloroacetamide 2a–c
Chloroacetamides 2a–c were obtained by a slight modification
of the known procedure [11] as follows: To a mixture of substi-
tuted phenethylamine (0.1 mol) and NaHCO3 (0.1 mol) in CH2Cl2
(200 mL) chloroacetyl chloride was added dropwise (0.12 mol) at
08C. After stirring at 108C for 2 h, the reaction mixture was
quenched by the slow addition of water at 08C. The organic layer
was separated and washed with 10% aqueous HCl solution and
brine. After evaporation of the solvent, the resulting solid was
recrystallized with EtOH to afford 2a as a light-colored needle
(yield 96.6%); m.p.: 61.7 to 64.98C (lit. m.p.: 678C); 2b (81.9%):
m.p.: 93.6 to 95.28C (lit. m.p.: 968C); 2c (79.3%): m.p.: 113.4 to
115.78C.
2-Pentyl-2,3,6,7-tetrahydro-9,10-dimethoxy-1H-
pyrazino[2,1-a]isoquinolin-4(11bH)-one 5b
White solid; yield: 88.5%; m.p.: 250.18C; 1H-NMR (300 MHz,
CDCl3) d: 0.91–0.95 (t, J = 6 Hz, 3H, CH3), 1.37–1.45 (m, 4H, CH2),
1.81–2.03 (m, 2H, CH2), 2.64–2.78 (t, 2H, CH2), 3.07–3.44 (t, 4H,
CH2), 3.85 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.14–4.32 (m, 2H,
CH2), 4.78 (m, 1H, CH), 5.64–5.74 (dd, J = 9.3 Hz, 1H, Ar-H), 6.61 (s,
1H, Ar-H), 6.76 (s, 1H, Ar-H); MS (ESI) m/z: 333.4 [M + H]. Anal.
calcd. for C19H28N2O3 N HCl: C, 61.86; H, 7.92; N, 7.59. Found: C,
61.79; H, 8.01; N, 7.63.
2-Pentyl-2,3,6,7-tetrahydro-10-fluoro-1H-pyrazino[2,1-a]
General procedure of the preparation of N-2-(substituted
phenyl)ethyl-2-[(2,2-dimethoxyethyl)amino]acetamide
hydrochloride 3a–c
isoquinolin-4(11bH)-one 5c
Yellow solid; yield: 79.2%; m.p.: 260.38C; 1H-NMR (300 MHz,
CDCl3) d: 0.94–1.00 (t, J = 6.5 Hz, 3H, CH3), 1.36–1.91 (m, 6H, CH2),
2.81–2.94 (t, 2H, CH2), 3.01–3.07 (m, 2H, CH2), 3.13–3.24 (t, 2H,
CH2), 3.42–4.07 (m, 2H, CH2), 4.21–4.27, 4.71–4.81 (m, 2H, CH2),
5.71–5.85 (m, 1H, CH), 6.93–7.07 (m, 1H, Ar-H), 7.18–7.21(m, 2H,
To a solution of 2a–c (0.08 mol) in toluene (80 mL) 2,2-dimethoxy-
ethanamine (0.167 mol) was added, and the mixture was heated
to reflux. After cooling of the mixture, the resulting solid was
recovered by filtration. The filtrate was washed with water,
dried, and concentrated to give 3a–c. This product was diluted
with CH2Cl2 (50 mL) and treated with HCl gas at –308C. The
resulting solid was filtered and dried to afford 3a hydrochloride
in 73.8% yield as a white solid; m.p.: 151.58C (lit. m.p.: 152 to
152.58C); 3b (77.7%): m.p.: 96.2 to 99.58C (lit. m.p.: 98 to 998C); 3c
(70.3%): m.p.: 166 to 167.58C.
Ar-H); MS (ESI) m/z: 291.4 [M
C17H23FN2O N HCl: C, 62.47; H, 7.40; N, 8.57. Found: C, 61.54; H,
7.31; N, 8.44.
+ H]. Anal. calcd. for
2-Heptyl-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]
isoquinolin-4(11bH)-one 6a
White solid; yield: 84.5%; m.p.: 261.78C; 1H-NMR (300 MHz,
CDCl3) d: 0.90–0.94 (t, J = 6 Hz, 3H, CH3), 1.29–1.47 (m, 8H, CH2),
1.81–2.09 (m, 2H, CH2), 2.84–3.20 (t, 4H, CH2), 3.25–3.48 (t, 2H,
CH2), 4.03–4.33 (t, 2H, CH2), 4.05–4.11, 4.81–4.85 (dd, 2H, CH2),
5.80–5.87 (t, 1H, CH), 7.14–7.19 (m, 1H, Ar-H), 7.23–7.29 (t, J = 9
Hz, 3H, Ar-H); MS (ESI) m/z: 301.4 [M + H]. Anal. calcd. for
General procedure of the preparation of key intermediates
4a–c
Compound 3a–c hydrochloride (12.1 mmol) was added in small
portions to a solution of conc. H2SO4 (4 mL) at 58C. After stirring
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H. Tang et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 360–366
C19H28N2O N HCl: C, 67.74; H, 8.68; N, 8.32. Found: C, 67.68; H,
2-(4-Fluorobenzyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]
8.73; N, 8.30.
isoquinolin-4(11bH)-one 8a
Yellowish solid; yield: 87.5%; m.p.: 278.18C; 1H-NMR (300 MHz,
CDCl3) d: 2.81–2.96 (m, 4H, CH2), 3.36–3.62 (m, 2H, CH2),3.92–
4.09 (m, 2H, CH2), 4.11–4.28 (m, 2H, CH2), 5.81–5.88 (m, 1H, CH),
7.11–7.31 (m, 4H, Ar-H), 7.65–7.78 (m, 4H, Ar-H); MS (ESI) m/z:
311.4 [M + H]. Anal. calcd. for C19H19FN2O N HCl: C, 65.80; H, 5.81;
N, 8.08. Found: C, 65.1.6; H, 5.78; N, 8.01.
2-Heptyl-2,3,6,7-tetrahydro-9,10-dimethoxy-1H-
pyrazino[2,1-a]isoquinolin-4(11bH)-one 6b
White solid; yield: 89.5%; m.p.: 260.48C; 1H-NMR (300 MHz,
CDCl3) d: 0.85–0.95 (t, J = 6 Hz, 3H, CH3), 1.22–1.41 (m, 8H, CH2),
1.73–2.08 (m, 2H, CH2), 2.69–2.94 (t, 4H, CH2), 3.14–3.33 (t, 2H,
CH2), 3.87 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 4.13–4.19 (m, 2H,
CH2), 4.85 (m, 2H, CH2), 5.72–5.76 (dd, J = 9.3 Hz, 1H, CH), 6.64 (s,
1H, Ar-H), 6.71 (s, 1H, Ar-H); MS (ESI) m/z: 361.5 [M + H]. Anal.
calcd. for C21H32N2O3 N HCl: C, 63.54; H, 8.38; N, 7.06. Found: C,
61.97; H, 8.21; N, 7.03.
2-(4-Fluorobenzyl)-2,3,6,7-tetrahydro-9,10-dimethoxy-
1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one 8b
Yellowish solid; yield: 90.1%; m.p.: 301.28C; 1H-NMR (300 MHz,
CDCl3) d: 2.35–2.62 (m, 2H, CH2), 2.82–2.94 (m, 3H, CH2), 3.42–
3.52 (m, 3H, CH2), 3.52–3.55, 3.64–3.71 (m, 2H, CH2), 3.82 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 4.72–4.85 (m, 1H, CH), 6.49 (s, 1H, Ar-
H), 6.632 (s, 1H, Ar-H), 7.01–7.08 (t, J1 = 2.1 Hz, J2 = 4.8 Hz, 2H, Ar-
H), 7.26–7.38(t, J1 = 2.1 Hz, J2 = 4.8 Hz, 2H, Ar-H); MS (ESI) m/z:
371.4 [M + H]. Anal. calcd. for C21H23FN2O3 N HCl: C, 61.99; H, 5.95;
N, 6.88. Found: C, 61.67; H, 6.76; N, 6.84.
2-Heptyl-2,3,6,7-tetrahydro-10-fluoro-1H-pyrazino[2,1-a]
isoquinolin-4(11bH)-one 6c
Yellow solid; yield: 79.9%; m.p.: 270.68C; 1H-NMR (300 MHz,
CDCl3) d: 0.86–0.96 (t, J = 6.5 Hz, 3H, CH3), 1.25–1.42 (m, 8H, CH2),
1.87–2.03 (t, 2H, CH2), 2.80–3.05 (t, 4H, CH2), 2.99–3.08 (m, 2H,
CH2), 3.42–3.49 (m, 2H, CH2), 4.00–4.24 (m, 2H, CH2), 5.81–5.85
(m, 1H, CH), 6.94–7.00 (m, 2H, Ar-H), 7.17–7.19 (m, 1H, Ar-H); MS
(ESI) m/z: 319.4 [M + H]. Anal. calcd. for C19H27FN2O N HCl: C, 64.30;
H, 7.95; N, 7.89. Found: C, 64.25; H, 7.81; N, 7.74.
2-(4-Fluorobenzyl)-2,3,6,7-tetrahydro-10-fluoro-1H-
pyrazino[2,1-a]isoquinolin-4(11bH)-one 8c
1
Yellowish solid; yield: 81.5%; m.p.: 315.38C; H-NMR (300 MHz,
CDCl3) d: 2.74–3.02 (m, 4H, CH2), 3.32–3.52 (m, 2H, CH2), 3.90–
4.48 (m, 2H, CH2), 4.72–4.85 (m, 2H, CH2), 5.84 (m, 1H, CH), 6.84
(s, 2H, Ar-H), 6.72 (s, 1H, Ar-H), 7.15–7.22 (m, 1H, Ar-H), 7.26 (s,
1H, Ar-H), 7.56–7.78 (t, 2H, Ar-H); MS (ESI) m/z: 330.6 [M + H]. Anal.
calcd. for C19H18F2N2O N HCl: C, 62.55; H, 5.25; N, 7.68. Found: C,
61.45; H, 5.21; N, 7.61.
2-Decyl-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]
isoquinolin-4(11bH)-one 7a
White solid; yield: 82.9%; m. p.: 275.68C; 1H-NMR (300 MHz,
CDCl3) d: 0.83–0.87 (t, J = 6.9 Hz, 3H, CH3), 1.23–1.43 (m, 12H,
CH2), 1.68–1.85 (m, 2H, CH2), 2.68–2.86 (t, 2H, CH2), 2.94–3.36 (t,
4H, CH2), 3.77–3.94, 3.97–4.08 (dd, 2H, CH2), 4.31–4.72 (t, 2H,
CH2), 5.24–5.33 (t, 1H, CH), 7.22–7.28 (m, 3H, Ar-H), 7.37–7.40 (t, J
= 9 Hz, 1H, Ar-H); MS (ESI) m/z: 343.4 [M + H]. Anal. calcd. for
C22H34N2O N HCl: C, 69.72; H, 9.31; N, 7.39. Found: C, 69.67; H,
9.27; N, 7.32.
General procedure of the preparation of 9a–12c
To a solution of 5a–8c (3.89 mmol) in THF, LiAlH4 (15.5 mmol)
was added with stirring. After stirring for 3.5 h, the excess of the
reducing agent was decomposed with water. The organic layer
was decanted and the solid material was extracted with THF. The
combined organic extracts were dried over anhydrous Na2SO4.
After removal of the solvent, the residue was taken up in ether
and treated with 1 M HCl in ether. The salt was filtered and dried
to afford 9a–12c.
2-Decyl-2,3,6,7-tetrahydro-9,10-dimethoxy-1H-
pyrazino[2,1-a]isoquinolin-4(11bH)-one 7b
White solid; yield: 88.6%; m.p.: 276.48C; 1H-NMR (300 MHz,
CDCl3) d: 0.78–0.93 (t, J = 6 Hz, 3H, CH3), 1.18–1.41 (m, 14H, CH2),
1.86 (s, 2H, CH2), 2.64–3.01 (t, 4H, CH2), 3.20–3.24 (t, 2H, CH2),
3.87 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 4.11–4.25 (m, 2H, CH2), 4.87
(m, 2H, CH2), 5.73–5.76 (dd, J = 9.3 Hz, 1H, CH), 6.64 (s, 1H, Ar-H),
6.69 (s, 1H, Ar-H); MS (ESI) m/z: 403.6 [M + H]. Anal. calcd. for
C24H38N2O3 N HCl: C, 65.66; H, 8.95; N, 6.38. Found: C, 64.63; H,
8.81; N, 6.27.
2-Pentyl-2,3,6,7,11b-hetrahydro-1H-pyrazino[2,1-a]
isoquinolin hydrochloride 9a
White solid; yield: 94.1%; m.p.: 234.58C; 1H-NMR (300 MHz,
CDCl3) d: 0.89–0.94 (t, J = 6.1 Hz, 3H, CH3), 1.30–1.37 (m, J = 21.9
Hz, 4H, CH2), 1.74–1.85 (m, 2H, CH2), 3.14–3.20 (m, 4H, CH2),
3.61–3.89 (m, 8H, CH2), 3.90–3.94 (m, 1H, CH), 7.21–7.48 (m, 4H,
Ar-H); MS (ESI) m/z: 259.4 [M + H]. Anal. calcd. for C17H26N2 N 2 HCl:
C, 61.63; H, 8.53; N, 8.45. Found: C, 61.52; H, 8.49; N, 8.37.
2-Decyl-2,3,6,7-tetrahydro-10-fluoro-1H-pyrazino[2,1-a]
2-Pentyl-2,3,6,7,11b-hetrahydro-9,10-dimethoxy-1H-
isoquinolin-4(11bH)-one 7c
pyrazino[2,1-a]isoquinolin hydrochloride 9b
Yellow solid; yield: 80.1%; m.p.: 216.18C; 1H-NMR (300 MHz,
CDCl3) d: 0.88–0.91 (t, J = 6.5 Hz, 3H, CH3), 1.17–1.40 (m, 14H,
CH2), 1.87–2.03 (m, 2H, CH2), 2.86–3.01 (m, 4H, CH2), 3.11–3.22
(m, 2H, CH2), 3.91–4.04 (m, 2H, CH2), 4.79–4.84 (m, 2H, CH2),
5.82–5.85 (m, 1H, CH), 6.91–7.00 (s, 2H, Ar-H), 7.17–7.21 (t, 1H, Ar-
H); MS (ESI) m/z: 361.5 [M + H]. Anal. calcd. for C22H33FN2O N HCl:
C, 66.56; H, 8.63; N, 7.06. Found: C, 66.02; H, 8.52; N, 7.04.
White solid; yield: 89.3%; m.p.: 262.58C; 1H-NMR (300 MHz,
CDCl3) d: 0.91–0.97 (t, J = 6.1 Hz, 3H, CH3), 1.30–1.38 (m, J = 22.8
Hz, 4H, CH2), 1.63–1.78 (m, 2H, CH2), 3.11–3.21 (t, 2H, CH2), 3.71–
3.77 (m, 8H, CH2), 3.78–3.80 (m, 1H, CH), 3.71 (s, 3H, OCH3), 3.73
(s, 3H, OCH3), 6.83 (m, 2H, Ar-H), 6.89 (m, 2H, Ar-H); MS (ESI) m/z:
319.5 [M + H]. Anal. calcd. for C19H30N2O2 N 2 HCl: C, 58.31; H,
8.24; N, 7.16. Found: C, 58.26; H, 8.21; N, 7.19.
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Arch. Pharm. Chem. Life Sci. 2010, 343, 360–366
Novel Pyrazino[2,1-a]isoquinoline Derivatives
365
2-Pentyl-2,3,6,7,11b-hetrahydro-10-fluoro-1H-
2-Decyl-2,3,6,7,11b-hetrahydro-10-fluoro-1H-
pyrazino[2,1-a]isoquinolin hydrochloride 9c
pyrazino[2,1-a]isoquinolin hydrochloride 11c
1
1
Yellowish solid; yield: 92.3%; m.p.: 219.48C; H-NMR (300 MHz,
Yellowish solid; yield: 88.3%; m.p.: 244.58C; H-NMR (300 MHz,
CDCl3) d: 0.91–0.96 (t, J = 6.2 Hz, 3H, CH3), 1.29–1.44 (m, 14H,
CH2), 1.84–2.06 (m, 2H, CH2), 2.91–3.08 (t, 4H, CH2), 3.51–3.85 (t,
6H, CH2), 4.22–4.81 (m, 2H, CH2), 5.49–5.77 (t, 1H, CH), 6.87–7.03
(m, 2H, Ar-H), 7.11–7.16 (t, 1H, Ar-H); MS (ESI) m/z: 347.5 [M + H].
Anal. calcd. for C22H35FN2 N 2 HCl: C, 63.00; H, 8.89; N,
6.68;.Found: C, 62.97; H, 8.81; N, 6.63.
CDCl3) d: 0.95–1.05 (t, J = 6.4 Hz, 3H, CH3), 1.41–1.49 (m, J = 22.2
Hz, 4H, CH2), 1.81–2.05 (m, 2H, CH2), 2.62–2.84 (t, 4H, CH2), 3.12–
3.25 (t, 6H), 4.21–4.34 (m, 2H, CH2), 4.50–4.63 (m, 1H, CH), 6.82–
6.93 (m, 2H, Ar-H), 7.12–7.19 (t, 1H, Ar-H); MS (ESI) m/z: 277.4 [M +
H]. Anal. calcd. for C17H25FN2 N 2 HCl: C, 58.45; H, 7.79; N, 8.02.
Found: C, 58.41; H, 7.71; N, 7.97.
2-(4-Fluorobenzyl)-2,3,6,7,11b-hetrahydro-1H-
pyrazino[2,1-a]isoquinolin hydrochloride 12a
2-Heptyl-2,3,6,7,11b-hetrahydro-1H-pyrazino[2,1-a]
isoquinolin hydrochloride 10a
White solid; yield: 92.5%; m.p.: 304.58C; 1H-NMR (300 MHz,
CDCl3) d: 2.41–2.54 (m, 4H, CH2), 2.84–2.95 (t, 2H, CH2), 3.41–3.57
(m, 1H, CH), 3.78–3.99 (m, 2H, CH2), 3.22–3.41 (m, 2H, CH2), 3.51–
3.71 (m, 2H, CH2), 6.79 (s, 1H, Ar-H), 6.85–6.89 (d, 1H, Ar-H), 7.01–
7.04 (d, 3H, Ar-H), 7.07–7.12 (t, 2H, Ar-H), 7.17 (s, 1H, Ar-H); MS
(ESI) m/z: 297.4 [M + H]. Anal. calcd. for C19H21FN2 N 2 HCl: C,
61.79; H, 6.28; N, 7.59. Found: C, 61.67; H, 6.21; N, 7.50.
White solid; yield: 90.1%; m.p.: 243.58C; 1H-NMR (300 MHz,
CDCl3) d: 0.86–0.91 (t, J = 6.1 Hz, 3H, CH3), 1.32–1.39 (m, 8H, CH2),
1.68–1.79 (m, 2H, CH2), 3.11–3.17 (m, 4H, CH2), 3.54–3.79 (m, 8H,
CH2), 3.90–3.93 (m, 1H, CH), 7.18–7.36 (m, 4H, Ar-H); MS (ESI) m/z:
287.5 [M + H]. Anal. calcd. for C19H30N2 N 2 HCl: C, 63.50; H, 8.98;
N, 7.79. Found: C, 63.47; H, 8.89; N, 7.72.
2-Heptyl-2,3,6,7,11b-hetrahydro-9,10-dimethoxy-1H-
2-(4-Fluorobenzyl)-2,3,6,7,11b-hetrahydro-9,10-
pyrazino[2,1-a]isoquinolin hydrochloride 10b
dimethoxy-1H-pyrazino[2,1-a]isoquinolin hydrochloride
12b
White solid; yield: 91.5%; m.p.: 284.18C; 1H-NMR (300 MHz,
CDCl3) d: 0.93–0.99 (t, J = 6.1 Hz, 3H, CH3), 1.30–1.37 (m, J = 22.8
Hz, 8H, CH2), 1.62–1.79 (m, 2H, CH2), 3.16–3.28 (t, 2H, CH2), 3.69–
3.75 (m, 8H, CH2), 3.80–3.81 (m, 1H, CH), 3.75 (s, 3H, OCH3), 3.77
(s, 3H, OCH3), 6.83 (m, 2H, Ar-H), 6.88 (m, 2H, Ar-H); MS (ESI) m/z:
347.5 [M + H]. Anal. calcd. for C21H34N2O2 N 2 HCl: C, 60.14; H,
8.65; N, 6.68. Found: C, 60.01; H, 8.61; N, 6.64.
White solid; yield: 94.7%; m.p.: 351.58C; 1H-NMR (300 MHz,
CDCl3) d: 2.43–2.51 (m, 4H, CH2), 2.87–2.91 (t, 2H, CH2), 3.41–3.57
(m, 1H, CH), 3.78–3.99 (m, 2H, CH2), 3.22–3.41 (m, 2H, CH2), 3.51–
3.71 (m, 2H, CH2), 3.75 (s, 6H, OCH3), 6.79 (s, 1H, Ar-H), 6.98 (d, 1H,
Ar-H), 7.01 (d, 1H, Ar-H), 7.07–7.12 (t, 2H, Ar-H), 7.19 (s, 1H, Ar-H);
MS (ESI) m/z: 357.4 [M + H]. Anal. calcd. for C21H25FN2O2 N 2 HCl: C,
58.74; H, 6.34; N, 6.52. Found: C, 58.67; H, 6.21; N, 6.47.
2-Heptyl-2,3,6,7,11b-hetrahydro-10-fluoro-1H-
pyrazino[2,1-a]isoquinolin hydrochloride 10c
2-(4-Fluorobenzyl)-2,3,6,7,11b-hetrahydro-10-fluoro-1H-
pyrazino[2,1-a]isoquinolin hydrochloride 12c
Yellowish solid; yield: 88.1%; m.p.: 233.28C; 1H-NMR (300 MHz,
CDCl3) d: 0.97–1.02 (t, J = 6.4 Hz, 3H, CH3), 1.39–1.46 (m, J = 22.2
Hz, 8H, CH2), 1.84–2.07 (m, 2H, CH2), 2.64–2.86 (t, 4H, CH2), 3.14–
3.28 (t, 6H, CH2), 4.22–4.34 (m, 2H, CH2), 4.50–4.62 (m, 1H, CH),
6.86–6.94 (m, 2H, Ar-H), 7.12–7.19 (t, 1H, Ar-H); MS (ESI) m/z:
305.4 [M + H]. Anal. calcd. for C19H29FN2 N 2 HCl: C, 60.47; H, 8.28;
N, 7.42. Found: C, 60.39; H, 8.21; N, 7.37.
Yellowish solid; yield: 89.1%; m.p.: 299.58C; 1H-NMR (300 MHz,
CDCl3) d: 2.74–2.82 (m, 2H, CH2), 2.94–3.12 (m, 2H, CH2), 3.34–
3.68 (t, 2H, CH2), 3.82–3.89 (m, 1H, CH), 4.04–4.27 (m, 2H, CH2),
3.22–3.41 (m, 2H, CH2), 3.51–3.71 (m, 2H, CH2), 6.78–6.88 (s, 2H,
Ar-H), 7.05–7.22 (m, 3H, Ar-H), 7.56–7.78 (t, 2H, Ar-H); MS (ESI)
m/z: 315.4 [M + H]. Anal. calcd. for C19H20F2N2 N 2 HCl: C, 58.92; H,
5.73; N, 7.23. Found: C, 58.87; H, 5.71; N, 7.21.
The work was supported by the National Natural Science Foundation
of China (Grant No. 20972187) and the National 863 Program of China
(No.2008AA02Z302).
2-Decyl-2,3,6,7,11b-hetrahydro-1H-pyrazino[2,1-a]
isoquinolin hydrochloride 11a
White solid; yield: 89.7%; m.p.: 259.18C; 1H-NMR (300 MHz,
CDCl3) d: 0.83–0.88 (t, J = 6.2 Hz, 3H, CH3), 1.03–1.44 (m, 14H,
CH2), 1.74–1.85 (m, 2H, CH2), 3.14–3.20 (m, 4H, CH2), 3.51–3.53
(m, 8H, CH2), 3.96–4.05 (t, 1H, CH), 7.20–7.45 (m, 4H, Ar-H); MS
(ESI) m/z: 329.5 [M + H]. Anal. calcd. for C22H36N2 N 2 HCl: C, 65.82;
H, 9.54,; N, 6.98. Found: C, 65.77; H, 9.51; N, 6.91.
The authors have declared no conflict of interest.
References
2-Decyl-2,3,6,7,11b-hetrahydro-9,10-dimethoxy-1H-
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White solid; yield: 93.2%; m.p.: 309.68C; 1H-NMR (300 MHz,
CDCl3) d: 0.86–0.90 (t, J = 6.3 Hz, 3H, CH3), 1.26–1.35 (m, J = 26.1
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