Synthesis and biological activities of novel chiral fluorinated β-carboline derivatives

Article abstract of DOI:10.1002/jhet.5570450635

(Chemical Equation Presented) A series of unreported chiral β-carbolines 4 with trifluoromethyl group at position-1 and chiral carboxamide chains or amino acid ester chains at position-3 has been designed and synthesized. The results of bioassay in vitro show that compounds 4e, 4i and 4k show 78.8%, 84.0% and 78.9% inhibition on monoamine oxidase, in 1 mmol/L, respectively, and compound 4e also exhibit 60.9% inhibitory activity on tumor lung cell A-549 in 10^-5 mmol/L. In view of different configuration, the inhibitory activity on monoamine oxidase of S-enantiomer of the target compound is better than that of R-enantiomer.

Full text of DOI:10.1002/jhet.5570450635

Nov-Dec 2008
1783
Synthesis and Biological Activities of Novel Chiral
Fluorinated ꢀ-Carboline Derivatives
Jin Chang Dinga, Xiao Bo Huangb*, Hua Yue Wub, Jie Zhi Chenb,
Ming Tiao Caib and Miao Chang Liub
aWenzhou Vocational & Technical College, Wenzhou, 325035, People’s Republic of China
bSchool of Chemistry and Materials Science, Wenzhou University, Wenzhou, 325027, People’s Republic of China
xiaobhuang@hotmail.com
Received November 24, 2007
H
R1
O
R2
COOCH3
N
H
a
N
b
N
c
CF3
N
CF3
N
H
H
4
1
Conditions: a) NaOH, then HCl
b) SOCl2
c) (S)/(R)-R1CH(NH2)R2, Et3N
A series of unreported chiral ꢀ-carbolines 4 with trifluoromethyl group at position-1 and chiral
carboxamide chains or amino acid ester chains at position-3 has been designed and synthesized. The results
of bioassay in vitro show that compounds 4e, 4i and 4k show 78.8%, 84.0% and 78.9% inhibition on
monoamine oxidase, in 1 mmol/L, respectively, and compound 4e also exhibit 60.9% inhibitory activity on
tumor lung cell A-549 in 10-5 mmol/L. In view of different configuration, the inhibitory activity on
monoamine oxidase of S-enantiomer of the target compound is better than that of R-enantiomer.
J. Heterocyclic Chem., 45, 1783 (2008).
INTRODUCTION
position-3 and the derivatives have been thought of as
promising lead antitumor compounds [10].
Numerous ꢀ-carboline derivatives have been reported
to have various biological properties. Some of them have
been shown to possess CNS (central nervous system)
activities, binding with high affinity to the central
benzodiazepine receptors (BZR) [1] and recent reports
reveal that some ꢀ-carboline compounds, such as, ꢀ-
carboline (norharman) and 1-methyl-ꢀ-carboline (harman)
are potent inhibitors of monoamine oxidase which plays a
significant physiological role in the CNS and peripheral
organs [2]. Some ꢀ-carboline derivatives also exhibit
antitumor [3], anti-HIV [4], antiviral [5], antimicrobial
[6], antiplasmodial [7] and insecticidal activities [8]. In
view of these facts, study of synthesis and biological
activities of ꢀ-carbolines has received increasing
attention. As far as structure-activity relationship is
concerned, series of structure modification on ꢀ-carboline
mother nucleus have been carried out and found that
appropriate substituents introduced to the position-1 and 3
could contribute to enhancing antitumor activities of the
compounds. Side chains at position-3, such as different
carboxylate or carboxamide chains could reinforce the
DNA intercalating ability of the compound and boost the
cytotoxicity to tumor cell lines [4b,9]. Amino acid ester
side chain, having base-specific contacts with DNA bases
and high bioavailability, has also been introduced to the
Organic fluorine compounds play an important role in
various fields such as agrochemicals and pharmaceuticals
presumably due to their intrinsic properties and the
biological activity of a compound may be dramatically
changed by replacement of an appropriate hydrogen atom
by a fluorine atom [11]. As a result, trifluoromethylated
compounds have received special attention. Much current
effort has been devoted to the development of methods for
generating trifluoromethylated analogues [12]. In our
previous research, we have developed a novel synthesis of
introducing trifluoromethyl group to the position-1 of ꢀ-
carbolines [13]. Because chirality is a central factor in
biological phenomena and it is common that the
enantiomers of a chiral drug show striking differences in
terms of biological activity, potency, toxicity and
transport mechanisms, enantiomeric pure products are
therefore desirable ones in drug synthesis in recent years
[14]. Based on the above idea, we now report the
synthesis and biological activities of
a series of
unreported chiral ꢀ-carbolines with trifluoromethyl group
at position-1 and chiral carboxamide chains or amino acid
ester chains at position-3. The preliminary results of
bioassay show that some of them possess good inhibition
activities on tumor lung cell A-549 and monoamine
oxidase.

1784
J. C. Ding, X. B. Huang, H. Y. Wu, J. Z. Chen, M. T. Cai and M. C. Liu
Vol 45
Scheme I
H
R1
R2
O
N
COOH
N
COCl
N
COOCH3
H
N
N
b
c
a
CF3
CF3
CF3
CF3
N
H
N
N
H
N
H
H
4
2
3
1
4a: R1 = CH3, R2 = Ph;
4b: R1 = Ph, R2 = CH3;
Conditions: a) NaOH, then HCl
b) SOCl2
4c: R1 = CH3, R2 = COOCH3;
4e: R1 = Ph, R2 = COOCH3;
4g: R1 = CH2OH, R2 = COOCH3;
4d: R1 = COOCH3, R2 = CH3;
4f: R1 = CH2Ph, R2 = COOCH3;
4h: R1 = CH2COOCH3, R2 = COOCH3;
c) (S)/(R)-R1CH(NH2)R2, Et3N
4i: R1 = CH2CH2COOCH3, R2 = COOCH3; 4j: R1 = CH2CH(CH3)2, R2 = CH2COOCH2CH3;
4k: R1 = CH(CH3)2, R2 = COOCH3;
4l: R1
H2C
=
, R2 = COOCH3
N
H
RESULTS AND DISCUSSION
physiological role in the CNS and peripheral organs,
monoamine oxidase inhibitors are useful as
The synthetic pathway for the title compounds 4 is
shown in Scheme 1. The preparation of ꢀ-carboline-3-
carboxylic acid 2 has previously been reported by
Bergman and coworkers [15]. Herein, compound 2 could
be synthesized by the hydrolysis of ꢀ-carboline 1 in the
alkaline conditions in 88% yield. ꢀ-Carboline 1 was
prepared according to the literature method [13] by one-
pot reaction of tryptophan methyl ester hydrochloride,
trifluoroacetic acid and triphenylphosphine and this is a
facile route to introduce trifluoromethyl group to the basic
ꢀ-carboline ring. The compound 2 was subjected to
chlorination with thionyl chloride to provide the
compound 3. And then novel single chiral ꢀ-carboline-3-
carboxamide derivatives 4 could be synthesized by the
reaction of compound 3 with various easily accessible
(S)/(R)-amino acid methyl esters and (S)/(R)-1-
phenylethylamine in 55-96% yields. It was found that the
whole reactive process of synthesis of compounds 4 could
be quickly finished at mild condition and yielded
satisfactory results. The structures of compounds 4 were
antidepressants or Parkinson’s disease [2b]. The results of
monoamine oxidase assay may indicate that these novel
compounds may be promising head lead compounds to
cure neurodegenerative diseases.
Table 1
Inhibitory Activity on Monoamine Oxidase of Compounds 4 (%)
Compound
0.01 mmol/L
0.1 mmol/L
1 mmol/L
4a
4b
4c
4d
4e
4i
7.4
8.3
9.4
2.6
6.9
8.2
8.9
9.4
25.6
22.9
35.5
28.4
29.0
30.7
22.9
31.4
37.5
31.5
73.6
68.5
78.8
84.0
75.3
78.9
4j
4k
The inhibitory activities of lung cancer cell A-549 of
some target compounds in vitro, such as, compounds 4h,
4i, 4l and 4e were done following the sulforhodamine B
(SRB) protein coloration method [17] and found that
compound 4e exhibit good inhibitory rate, 76.4% in 10-4
mmol/L and 60.9% in 10-5 mmol/L, others only show
weak inhibition in 10-4 mmol/L.
1
confirmed by ir, H nmr, 13C nmr, LC-MS spectroscopy
and elemental analysis.
Monoamine oxidase bioassay in vitro of some target
compounds was investigated according to the previous
literature [16]. The results are summarized in Table 1. The
results of Table 1 show that some compounds exhibit
good inhibitory activity, for example, in 1 mmol/L,
compounds 4e, 4i and 4k showed 78.8%, 84.0% and
78.9% inhibition, respectively. Compared 4a with 4b, 4c
with 4d, it can be found that the inhibitory activity of S-
enantiomer is better than R-enantiomer and the
compounds with amino acid ester side chain lead a better
effect. It may be because amino acids are the fundamental
building blocks of biological system and many natural
products and they are sometimes S-configuration in
nature. Because monoamine oxidase plays a significant
Further study on the biological activities of these
compounds is underway.
In summary, unreported chiral ꢀ-carbolines 4 with
trifluoromethyl group at position-1 and chiral
carboxamide chains or amino acid ester chains at
position-3 have been designed and synthesized. The
preliminary results of bioassay show that some of them
not only possess good inhibitory activities on monoamine
oxidase but also exhibit good antitumor activities on
tumor lung cell A-549. The results of the bioassay
indicate that the inhibitory activity on monoamine oxidase
of S-enantiomer of the target compound is better than

Nov-Dec 2008
Synthesis and Biological Activities of Novel Chiral Fluorinated ꢀ-Carboline Derivatives
1785
(deuteriochloroform): ꢁ 22.24, 48.93, 112.06, 117.14, 121.01,
121.55, 122.02, 126.06, 127.20, 128.60, 130.03, 132.89, 133.06,
139.49, 141.08, 143.28, 163.47; ms: m/z 382 (M+-1); ir (cm-1,
potassium bromide): 3375, 1667, 1599, 1500. Anal. Calcd. for
C21H16F3N3O: C, 65.79; H, 4.21; N, 10.96. Found: C, 65.67; H,
4.22; N, 10.92.
R-enantiomer. The results also indicate that some of the
fluorinated ꢀ-carbolines may be promising lead
compounds of antitumor drugs, antidepressants and curing
Parkinson’s disease. It is worthwhile to optimize the
structures.
(R)-1-(Trifluoromethyl)-N-(1-phenylethyl)-9H-pyrido[3,4-
b]indole-3-carboxamide (4b). This compound was obtained as
EXPERIMENTAL
white solids in 90% yield, mp 183-185°C. [ꢂ]20 = 72.75 (c = 1;
D
1
ethyl acetate). H nmr (deuteriochloroform): ꢁ 1.69 (d, J = 6.9
Nmr spectra were obtained using an AVANCE-300
spectrometer 300 MHz for 1H nmr and 75 MHz for 13C nmr and
reported as parts per million (ppm) from the internal standard
tetramethylsilane. Ir spectra were taken on EQUINOX-55
Infrared spectrometer. Mass spectra were recorded on an Agilent
1100LC/MSD Trap SL spectrometer. Elementary analyses were
taken on an Elementar Vario MICRO analyzer. Optical rotations
were measured with a Rudolph AUTOPOL IV automatic
polarimeter. Melting points were determined on X4 microscopic
melting apparatus (uncorrected).
Hz, 3H, CH3), 5.42-5.47 (m, 1H, CH), 7.23-7.46 (m, 6H), 7.56-
7.61 (m, 2H, 7-H and 8-H), 8.16 (d, J = 7.9 Hz, 1H, 5-H ), 8.34
(d, J = 8.2 Hz, 1H, CONH), 9.07 (s, 1H, 4-H), 9.35 (s, 1H, 9-H);
13C nmr (deuteriochloroform): ꢁ 22.23, 48.91, 112.04, 117.16,
121.02, 121.57, 122.04, 126.07, 127.21, 128.60, 130.04, 132.91,
133.05, 139.54, 141.06, 143.28, 163.45; ms: m/z 382 (M+-1); ir
(cm-1, potassium bromide): 3375, 1667, 1599, 1500. Anal. Calcd.
for C21H16F3N3O: C, 65.79; H, 4.21; N, 10.96. Found: C, 65.69;
H, 4.20; N, 10.93.
(S)-N-[1-(Trifluoromethyl)-9H-pyrido[3,4-b]indole-3-car-
bonyl]alanine Methyl Ester (4c). This compound was obtained
Methyl 1-(trifluoromethyl)-9H-pyrido[3,4-b]indole-3-carbox-
ylate (1) was prepared from tryptophan methyl ester hydro-
chloride according to literature procedure [13] in 69% yield.
Preparation of 1-(Trifluoromethyl)-9H-pyrido[3,4-b]in-
dole-3-carboxylic Acid (2). To a solution of 1 (1.20 g, 3.40
mmoles) in methanol (40 mL) was added 18% aqueous sodium
hydroxide solution (25 mL), and the mixture was stirred at 60°C
as white solids in 92% yield, mp 228-229°C. [ꢂ]20 = -4.09 (c =
D
1; ethyl acetate); 1H nmr (deuteriochloroform): ꢁ 1.63 (d, J = 7.1
Hz, 3H, CH3), 3.85 (s, 3H, OCH3), 4.82-4.86 (m, 1H, CH), 7.40
(t, J = 7.3 Hz, 1H, 6-H), 7.58-7.69 (m, 2H, 7-H and 8-H), 8.11
(d, J = 8.1 Hz, 1H, 5-H), 8.32 (d, J = 6.8 Hz, 1H, CONH), 8.67
(s, 1H, 4-H), 9.27 (s, 1H, 9-H); 13C nmr (deuteriochloroform): ꢁ
18.16, 48.35, 52.59, 112.28, 116.82, 121.01, 121.62, 122.06,
130.16, 132.75, 132.92, 138.91, 141.08, 163.85, 173.69; ms: m/z
364 (M+-1); ir (cm-1, potassium bromide): 3342, 1743, 1663,
1501, 1167, 1122. Anal. Calcd. for C17H14F3N3O3: C, 55.89; H,
3.86; N, 11.50. Found: C, 55.84; H, 3.85; N, 11.47.
for
2 hours. The brown solution was neutralized with
concentrated hydrogen chloride to pH 1, and filtered, and the
white solid was recrystallized from acetone:petroleum (1:4, v/v).
1-(Trifluoromethyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid
1
was obtained in 88% yield, mp 202-203°C. H nmr (deuterio-
chloroform): ꢁ 7.43 (t, J = 7.4 Hz, 1H, 6-H), 7.67-7.87 (m, 2H,
7-H and 8-H), 8.48 (d, J = 7.9 Hz, 1H, 5-H), 9.15 (s, 1H, 4-H),
11.44 (s, 1H, 9-H); ms: m/z 279 (M+-1); ir (cm-1, potassium
bromide): 3285, 1743, 1598, 1507.
(R)-N-[1-(Trifluoromethyl)-9H-pyrido[3,4-b]indole-3-car-
bonyl]alanine Methyl Ester (4d). This compound was obtained
as white solids in 87% yield, mp 228-229°C; [ꢂ]20 = 3.80 (c =
D
1; ethyl acetate); 1H nmr (deuteriochloroform): ꢁ 1.64 (d, J = 7.2
Hz, 3H, CH3), 3.86 (s, 3H, OCH3), 4.78-4.88 (m, 1H, CH),7.40
(t, J = 7.3 Hz, 1H, 6-H), 7.58-7.69 (m, 2H, 7-H and 8-H), 8.09
(d, J = 8.1 Hz, 1H, 5-H ), 8.30 (d, J = 7.4 Hz, 1H, CONH), 8.61
(s, 1H, 4-H), 9.34 (s, 1H, 9-H); 13C nmr (deuteriochloroform): ꢁ
18.16, 48.35, 52.65, 112.32, 116.80, 120.98, 121.60, 122.05,
130.16, 132.71, 132.89, 138.77, 141.08, 163.88, 173.76; ms: m/z
364 (M+-1); ir (cm-1, potassium bromide): 3339, 1744, 1664,
1600, 1501, 1167, 1122. Anal. Calcd. for C17H14F3N3O3: C,
55.89; H, 3.86; N, 11.50. Found: C, 55.80; H, 3.85; N, 11.53.
(S)-ꢀ-{[1-(Trifluoromethyl)-9H-pyrido[3,4-b]indole-3-car-
bonyl]amino}benzeneacetic Acid Methyl Ester (4e). This
Preparation of 1-(Trifluoromethyl)-9H-pyrido[3,4-b]in-
dole-3-carbonyl Chloride (3). To a solution of 2 (0.25 g, 0.90
mmol) in dry chloroform (30 mL) was added thionyl chloride (3
mL). The mixture was refluxed for 4 hours, and then the solvent
was removed under pressure, the residue was purified on a silica
gel column. Elution of the column with acetone:petroleum (1:1,
1
v/v) gave pale yellow solids in 97% yield, mp 88-90°C. H nmr
(deuteriochloroform): ꢁ 7.49 (t, J = 7.2 Hz, 1H, 6-H), 7.61-7.75
(m, 2H, 7-H and 8-H), 8.23 (d, J = 8.0 Hz, 1H, 5-H), 9.02 (s, 1H,
4-H), 9.34 (s, 1H, 9-H); ms: m/z 297 (M+-1); ir (cm-1, potassium
bromide): 3139, 1756, 1592, 1498. Anal. Calcd. for
C13H6ClF3N2O: C, 52.28; H, 2.03; N, 9.38. Found: C, 55.20; H,
2.03; N, 0.35.
General Procedure for the Preparation of Fluorinated ꢀ-
carbolines 4a-l. To a solution of (S)-1-phenylethylamine (0.09
g, 0.90 mmol), chloroform (20 mL) and triethylamine (0.09 g,
0.90 mmol) was added dropwise intermediate 3 in acetone (15
mL) in 0.5 hours at 0°C and then the solution was stirred for 10
minutes at room temperature. After evaporation, the residue was
separated on a silica gel column.
(S)-1-(Trifluoromethyl)-N-(1-phenylethyl)-9H-pyrido[3,4-
b]indole-3-carboxamide (4a). This compound was obtained as
white solids in 81%, mp 183-185°C. [ꢂ]20D = -71.36 (c = 1; ethyl
acetate); 1H nmr (deuteriochloroform): ꢁ 1.69 (d, J = 6.9 Hz, 3H,
CH3), 5.42-5.47 (m, 1H, CH), 7.23-7.46 (m, 6H), 7.56-7.61 (m,
2H, 7-H and 8-H), 8.15 (d, J = 7.9 Hz, 1H, 5-H), 8.34 (d, J = 8.3
Hz, 1H, CONH), 9.06 (s, 1H, 4-H), 9.39 (s, 1H, 9-H); 13C nmr
compound was obtained as white solids in 58% yield, mp 82-
1
84°C. [ꢂ]20 = 97.60 (c = 1; ethyl acetate); H nmr (deuterio-
D
chloroform): ꢁ 3.83 (s, 3H, OCH3), 5.83 (d, J = 7.2 Hz, 1H,
CH), 7.37-7.71 (m, 9H, Ph-H, 5-, 6-, 7-, and 8-H), 8.18 (d, J =
7.9 Hz, 1H, CONH), 8.84 (s, 1H, 4-H), 9.08 (s, 1H, 9-H); 13C
nmr (deuteriochloroform): ꢁ 54.04, 57.70, 114.18, 119.06,
121.74, 122.50, 123.94, 125.07, 128.94, 129.73, 130.23, 131.48,
134.19, 138.19, 139.23, 143.45, 163.45, 172.21; ms: m/z 426
(M+-1); ir (cm-1, potassium bromide): 3392, 3251, 1748, 1670,
1629, 1530, 1499, 1251, 1183, 1125. Anal. Calcd. for
C22H16F3N3O3: C, 61.83; H, 3.77; N, 9.83. Found: C, 61.75; H,
3.76; N, 9.85.
(S)-N-[1-(Trifluoromethyl)-9H-pyrido[3,4-b]indole-3-car-
bonyl]phenylalanine Methyl Ester (4f). This compound was
obtained as white solids in 55% yield, mp 179-180°C. [ꢂ]20
=
D

1786
J. C. Ding, X. B. Huang, H. Y. Wu, J. Z. Chen, M. T. Cai and M. C. Liu
Vol 45
35.56 (c = 1; ethyl acetate); 1H nmr (deuteriochloroform): ꢀ 3.29
(d, J = 6.1 Hz, 2H, CH3), 3.78 (s, 3H, OCH3), 5.05-5.12 (m, 1H,
CH), 7.29-7.35 (m, 5H, Ph-H), 7.47 (t, J = 6.9 Hz, 1H, 6-H),
7.59-7.68 (m, 2H, 7-H and 8-H), 8.19 (d, J = 7.5 Hz, 1H, 5-H ),
8.40 (d, J = 7.9 Hz, 1H, CONH), 8.87 (s, 1H, 4-H), 8.91 (s, 1H,
9-H); 13C nmr (deuteriochloroform): ꢀ 37.68, 52.16, 53.16,
112.02, 116.19, 120.62, 121.22, 121.61, 126.98, 128.50, 128.94,
129.77, 132.28, 132.44, 135.44, 138.29, 140.71, 163.51, 172.06;
ms: m/z 440 (M+-1); ir (cm-1, potassium bromide): 3345, 1745,
1676, 1628, 1535, 1498, 1191, 1123. Anal. Calcd. for
C23H18F3N3O3: C, 62.58; H, 4.11; N, 9.52. Found: C, 62.52; H,
4.10; N, 9.50.
Hz, 1H, 5-H), 8.23 (d, J = 8.0 Hz, 1H, CONH), 8.54 (s, 1H, 4-
H), 9.40 (s, 1H, 9-H); 13C nmr (deuteriochloroform): ꢀ 14.18,
21.97, 22.90, 25.09, 41.36, 51.24, 61.51, 112.36, 116.66, 120.96,
121.52, 121.95, 130.08, 132.65, 132.82, 138.76, 141.10, 164.02,
173.32; ms: m/z 420 (M+-1); ir (cm-1, potassium bromide): 3340,
1745, 1662, 1537, 1500, 1174, 1124. Anal. Calcd. for
C21H22F3N3O3: C, 59.85; H, 5.62; N, 9.97. Found: C, 59.92; H,
5.63; N, 9.92.
(S)-N-[1-(Trifluoromethyl)-9H-pyrido[3,4-b]indole-3-car-
bonyl]valine Methyl Ester (4k). This compound was obtained
as white solids in 60% yield, mp 158-160°C; [ꢁ]20 = 2.40 (c =
D
1; ethyl acetate); 1H nmr (deuteriochloroform): ꢀ 1.10 (d, J = 6.9
Hz, 6H, 2CH3), 2.39-2.46 (m, 1H, CH), 3.87 (s, 3H, OCH3),
4.72-4.76 (m, 1H, CH), 7.40 (t, J = 7.8 Hz, 1H, 6-H), 7.57-7.68
(m, 2H, 7-H and 8-H ), 8.05 (d, J = 7.9 Hz, 1H, 5-H), 8.38 (d, J
= 8.5 Hz, 1H, CONH), 8.47 (s, 1H, 4-H), 9.55 (s, 1H, 9-H); ms:
m/z 392 (M+-1); 13C nmr (deuteriochloroform): ꢀ 17.84, 19.27,
30.98, 52.28, 57.72, 112.40, 116.61, 120.96, 121.49, 121.90,
130.04, 132.66, 132.85, 138.70, 141.16, 164.25, 172.80; ir (cm-1,
potassium bromide): 3345, 1747, 1663, 1534, 1498, 1170, 1124.
Anal. Calcd. for C19H18F3N3O3: C, 58.01; H, 4.61; N, 10.68.
Found: C, 57.94; H, 4.60; N, 10.71.
(S)-N-[1-(Trifluoromethyl)-9H-pyrido[3,4-b]indole-3-car-
bonyl]serine Methyl Ester (4g). This compound was obtained
as white solids in 64% yield, mp 215-217°C; [ꢁ]20D = 17.20 (c =
1
1; ethyl acetate); H nmr (deuteriochloroform): ꢀ 2.68-2.76 (m,
2H, CH2), 3.87 (s, 3H, OCH3), 4.93-4.96 (m, 1H, CH), 7.43 (t, J
= 7.2 Hz, 1H, 6-H), 7.61-7.72 (m, 2H, 7-H and 8-H), 8.23 (d, J =
8.2 Hz, 1H, 5-H), 8.78 (d, J = 7.9 Hz, 1H, CONH), 8.46 (s, 1H,
4-H), 9.05 (s, 1H, 9-H); 13C nmr (dimethyl sulfoxide-d6): ꢀ
52.29, 54.76, 61.39, 112.93, 117.75, 120.52, 121.24, 122.72,
130.21, 132.64, 132.92, 138.25, 142.21, 163.49, 171.04; ms: m/z
380 (M+-1); ir (cm-1, potassium bromide): 3371, 3282, 1744,
1650, 1538, 1502, 1189, 1124. Anal. Calcd. for C17H14F3N3O4:
C, 53.55; H, 3.70; N, 11.02. Found: C, 53.60; H, 3.69; N, 11.05.
(S)-N-[1-(Trifluoromethyl)-9H-pyrido[3,4-b]indole-3-car-
bonyl]aspartic Acid Dimethyl Ester (4h). This compound was
(S)-ꢁ-{[1-(Trifluoromethyl)-9H-pyrido[3,4-b]indole-3-car-
bonyl]amino}-3-(1H-indol-2-yl)propanoic Acid Methyl Ester
(4l). This compound was obtained as white solids in 84% yield,
1
mp 166-167°C; [ꢁ]20 = 59.58 (c = 1; ethyl acetate); H nmr
D
(deuteriochloroform): ꢀ 3.46-3.57 (d, J = 6.5 Hz, 2H, CH2), 3.79
(s, 3H, OCH3), 5.06-5.12 (m, 1H, CH), 7.10-7.60 (m, 2H, 7-H
and 8-H ), 8.06 (d, J = 8.2 Hz, 1H, 5-H), 8.20 (s, 1H, N-H), 8.47
(d, 1H, J = 7.9 Hz, CONH), 8.52 (s, 1H, 4-H), 9.23 (s, 1H, 9-H);
13C nmr (dimethyl sulfoxide-d6): ꢀ 27.09, 52.23, 53.18, 109.08,
111.61, 112.91, 117.68, 118.23, 118.66, 120.50, 121.20, 122.68,
123.96, 127.30, 130.17, 132.53, 132.85, 136.32, 138.15, 142.16,
163.48, 172.13; ir (cm-1, potassium bromide): 3326, 1737, 1663,
1534, 1500, 1188, 1133. ms: m/z 479 (M+-1); Anal. Calcd. for
C25H19F3N4O3: C, 62.50; H, 3.99; N, 11.66. Found: C, 62.62; H,
3.98; N, 11.69.
obtained as white solids in 96% yield, mp 184-186°C. [ꢁ]20
=
D
12.79 (c = 1; ethyl acetate); 1H nmr (deuteriochloroform): ꢀ 3.05
(dd, J = 16.8 Hz, 5.0 Hz, 1H, CH2), 3.20 (dd, J = 16.9 Hz, 4.9
Hz, 1H, CH2), 3.77 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 5.15-
5.20 (m, 1H, CH), 7.41 (t, J = 7.3 Hz, 1H, 6-H), 7.62-7.70 (m,
2H, 7-H and 8-H), 8.14 (d, J = 8.0 Hz, 1H, 5-H ), 8.77-8.80 (m,
2H, 4-H and CONH), 9.21 (s, 1H, 9-H ); 13C nmr (dimethyl
sulfoxide-d6): ꢀ 35.79, 48.83, 51.82, 52.53, 112.92, 117.93,
120.53, 121.22, 122.70, 130.18, 132.57, 132.95, 138.18, 142.18,
163.59, 171.17, 171.22; ms: m/z 422 (M+-1); ir (cm-1, potassium
bromide): 3383, 1736, 1671, 1601, 1520, 1497, 1173, 1134.
Anal. Calcd. for C19H16F3N3O5: C, 53.91; H, 3.81; N, 9.93.
Found: C, 54.03; H, 3.80; N, 9.89.
Acknowledgement. The work was supported by the
Scientific Research Fund of Zhejiang Provincial Natural Science
Foundation of China (grant No. Y405113) and the Scientific
Research Fund of Zhejiang Provincial Education Department
(grant No. 20051292). The authors are grateful to the National
Center for Drug of China for the bioassay of the compounds.
(S)-N-[1-(Trifluoromethyl)-9H-pyrido[3,4-b]indole-3-car-
bonyl]glutamic Acid Dimethyl Ester (4i). This compound was
obtained as white solids in 55% yield, mp 111-113°C. [ꢁ]20
=
D
4.39 (c = 1; ethyl acetate); 1H nmr (deuteriochloroform): ꢀ 2.26-
2.30 (m, 2H, CH2), 2.43-2.57 (m, 2H, CH2), 3.86 (s, 3H, OCH3),
3.84 (s, 3H, OCH3), 7.39 (t, J = 6.9 Hz, 1H, 6-H), 7.59-7.70 (m,
2H, 7-H and 8-H), 8.16 (d, J = 7.8 Hz, 1H, 5-H ), 8.45 (d, J =
8.2 Hz, 1H, CONH), 8.85 (s, 1H, 4-H ), 9.11 (s, 1H, 9-H); 13C
nmr (dimethyl sulfoxide-d6): ꢀ 27.50, 31.28, 52.67, 53.01, 53.51,
114.16, 119.11, 121.77, 122.44, 123.90, 131.40, 133.77, 134.16,
139.62, 143.43, 165.23, 173.25, 174.14; ms: m/z 436 (M+-1); ir
(cm-1, potassium bromide): 3341, 1740, 1659, 1534, 1501, 1200,
1134. Anal. Calcd. for C20H18F3N3O5: C, 54.92; H, 4.15; N, 9.61.
Found: C, 54.75; H, 4.16; N, 9.59.
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