Synthesis of 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1H-β- carbolinesas antileishmanial agents

Article abstract of DOI:10.1016/j.ejmech.2010.04.004

A series of 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1H-β- carboline derivatives has been synthesized and evaluated for antileishmanial activity against Leishmania donovani. Compound 8 exhibited best antileishmanial activity with IC₅₀ val

Full text of DOI:10.1016/j.ejmech.2010.04.004

European Journal of Medicinal Chemistry 45 (2010) 3274e3280
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1H-b-carbolines as
antileishmanial agents
Ravi Kumar a, Shahnawaz Khan a, Aditya Verma b, Saumya Srivastava b, Preeti Viswakarma b,
,
Suman Gupta b, Sanjeev Meena c, Neetu Singh c, Jayanta Sarkar c, Prem M.S. Chauhan a
*
a Medicinal & Process Chemistry Division, Central Drug Research Institute, CSIR, Lucknow, India
b Parasitology Division, Central Drug Research Institute, CSIR, Lucknow, India
c Drug Target Discovery & Development Division, Central Drug Research Institute, CSIR, Lucknow, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1H-b-carboline derivatives has been synthe-
Received 21 August 2009
Received in revised form
17 March 2010
Accepted 7 April 2010
Available online 14 April 2010
sized and evaluated for antileishmanial activity against Leishmania donovani. Compound 8 exhibited best
antileishmanial activity with IC50 value of 1.93 g/ml against amastigotes, high selectivity index, and was
more active than reference drugs sodium stilbogluconate and pentamidine.
Ó 2010 Elsevier Masson SAS. All rights reserved.
m
Keywords:
Antileishmanial
2-Amino-4,6-dichloropyrimidine
2,4,6-Triaminopyrimidine
Tetrahydro-b-carboline
1. Introduction
[7]. Only recently amphotericin B, pentamidine, and miltefosin
have been discovered as effective antileishmanial drugs. All these
drugs suffer also from serious side effects associated with them.
Major drawbacks associated with amphotericin B are, it’s prohibi-
tively high cost, life threatening first dose anaphylaxis, nephro-
toxicity and hypokalemicity [8]. Pentamidine is orally inactive and
may show renal, hepatic and pancreatic toxicity along with hypo-
tension and dysglycemia [9]. Miltefosine, originally developed as
anticancer drug, is the first orally active antileishmanial agent,
which have good efficacy against both visceral as well as cutaneous
leishmaniases but suffers from low therapeutic index, teratoge-
nicity in animals, extremely long half life (6e8 days), and relative
low efficacy in HIV coinfected patients [10].
Leishmaniasis [1], a group of vector-borne parasitic diseases
caused by several protozoan parasite of genus Leishmania, are
endemic in large areas of the tropics, subtropics and Mediterranean
basin. Phlebotomine sand fly transmits the parasitic agents by
inoculation of the flagellate promastigotes in to mammalian host,
where they enter macrophages differentiating and multiplying into
immobile amastigotes [2]. Visceral Leishmaniasis [3] or Kala Azar is
most common pathological form of the disease and caused by
Leishmania donovani. From the socioeconomic point of view,
Leishmaniasis are the second most important among all the para-
sitic diseases [4]. More than 12 million people around the world are
affected by Leishmaniasis, with 1.5e2 million new cases and 51,000
deaths reported each year [5].
Chemotherapy of patients with Leishmaniasis is still a serious
problem as the treatment options are very limited. Pentavalent
antimonial compounds were widely used as primary therapy for 50
years but resistance has developed to them to such an extent in
India that they can no longer be used in some regions [6]. Anti-
monials may also cause acute pancreatitis and cardiac arrhythmia
In the light of above facts, there is an urgent need for the deve-
lopment of more efficient, inexpensive, nontoxic, and innovative
drugs based on new molecular scaffold for the treatment of leish-
maniases. In 1998, a tetrahydro-
[11] 1 (Fig. 1) was isolated from Kopsia griffithii and found to have
good antileishmanial activity (0.30 > IC50 > 1.56 g/ml) against
L. donovani. A few years later, antileishmanial activity of harmine 2
(Fig. 1), a -carboline amine alkaloid [12] isolated from Peganum
harmala, was also reported. Pinheiro’s group isolated the pyrimi-
dine- -carboline alkaloid annomontine 3 (Fig. 1) from the bark of
a Brazilian tree Annona foetida [13] having antileishmanial activity
against Leishmania braziliensis with IC50 value of 34.8 ꢀ 1.5 g/ml.
b-carboline alkaloid buchtienine
m
b
b
* Corresponding author. Tel.: þ91 522 2262411; fax: þ91 522 2623405.
E-mail addresses: premsc58@hotmail.com, prem_chauhan_2000@yahoo.com
(P.M.S. Chauhan).
m
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.04.004

R. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 3274e3280
3275
N
N
H
N
H
H
N
N
H
MeOOC
N
HN
H
N
H
O
H
N
H2N
HN
Buchtienine 1
2
Annomontine 3
Harmine
Fig. 1. Natural b-carboline alkaloids with antileishmanial activity.
In addition, synthetic 2-aminopyrimidines with hydrophobic
handle at 4-position has also been reported as good antileishmanial
agents [14]. Prompted by this and in continuation of our efforts
towards design and synthesis of novel nitrogen heterocylces as
antileishmanial agent [15], a series of 2-(pyrimidin-2-yl)-1-phenyl-
dichloropyrimidine 4 with m-chloroperbenzoic acid to its sulfone
derivative 5. Nucleophilic substitution of methane sulfonyl group
of 5 with tryptamine furnished N-(2-(1H-indol-3-yl)ethyl)-4,6-
dichloropyrimidin-2-amine 6 in good yield. Pictet Spengler cycli-
zation [16] of 6 with variously substituted benzaldehydes under
acidic conditions gave 2-(4,6-dichloropyrimidin-2-yl)-1-phenyl-
2,3,4,9-tetrahydro-1H-b-carbolines has been synthesized and
evaluated for antileishmanial activity against L. donovani.
2. Chemistry
2,3,4,9-tetrahydro-1H-
2-(4,6-Diaminopyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1H-
carboline derivatives 20e23 and (4,6-Diaminopyrimidin-2-yl)-[2-
(1H-indol-3-yl)-ethyl]-amines 24e25 were obtained in good to
excellent yields bytreating the corresponding dichloroderivatives 6,
b-carboline derivatives 7e19 in high yields.
b
-
The synthetic strategy followed for synthesis of 2-(pyrimidin-
2-yl)-1-phenyl-2,3,4,9-tetrahydro-1H-
picted in Scheme 1. It involves oxidation of 2-thiomethyl-4,6-
b
-carbolines 7e25 is de-
8, 9 and 13 with amine nucleophiles. All the tetrahydro-
derivatives 7e23 were obtained as racemic mixtures.
b-carboline
Cl
Tryptamine
N
(d)
O
HN
N
Cl
HN
N
R1
N
H
(b)
Cl
N
S
N
H
CH3
O
N
N
6
24-25
5
Cl
R1
R
For 24 R1 = Morpholine,
25 R1 = N-methylpiperazine.
(a)
(c)
CHO
m-CPBA
Cl
N
N
Cl
N
N
R1
N
N
H
(d)
N
H
N
N
Cl
N
4
S
CH3
Cl
R1
R
( ) 20-23
R
( ) 7-19
For
20 R = 3,4-dioxymethylene,
R =
For
7 R = 3,4,5-trimethoxy,
8 R= 3,4-dimethoxy
9 R = 4-methoxy,
10 R = 2-methoxy,
11 R = 3-methoxy,
12 R = 3-bromo,
N-methylpiperazine.
1
21 R = 3,4-dioxymethylene,
R1 = N-ethylpiperazine.
22 R = 4-methoxy,
R1 = morpholine,
13 R = 3,4-dioxymethylene,
14 R = 4-benzyloxy.
15 R = 4-ethyl,
23 R = 3,4-dimethoxy,
R1 = morpholine.
16 R = 4-methyl,
17 R = 3,5-dimethoxy,
18 R = 2,4-dimethoxy,
19 R = 2,5-dimethoxy,
Scheme 1. Reagents and conditions: (a) DCM, 0 ꢁC to rt, 4 h; (b) Ethanol, reflux, 2 h; (c) PTSA, ethanol, reflux, 3 h; (d) Neat Amine, reflux, 10 h.

3276
R. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 3274e3280
3. Antileishmanial activity
filtration were added to each well and incubated at 37 ꢁC for 2 h. At
the end of the incubation period, the supernatant was removed by
tilting plate completely without disturbing cell layer and 150 l of
3.1. Antipromastigote activity
m
pure DMSO are added to each well. After 15 min of shaking the
readings were recorded as absorbance at 544 nm on a microplate
reader. The cytotoxic effect was expressed as 50% lethal dose, i.e. as
the concentration of a compound which provoked a 50% reduction
in cell viability compared to cell in culture medium alone. IC50
values were estimated through the preformed template as
described by Huber and Koella [18].
The L. donovani promastigotes (MHOM/IN/80/Dd8; originally
obtained from Imperial College, London) were transfected with
firefly luciferase gene and the transfectants were maintained in
medium 199 (Sigma Chemical Co., USA) supplemented with 10%
foetal calf serum (GIBCO) and 1% penicillin (50 U/ml), streptomycin
(50 mg/ml) solution (Sigma) under pressure of G418 (Sigma). The in
vitro effect of the compounds on the growth of promastigotes was
assessed by monitoring the luciferase activity of viable cells after
treatment. The transgenic promastigotes of late log phase were
ml medium 199 in 96-well flat-bottomed
microtiter (MT) plates (CELLSTAR) and incubated for 72 h in
medium alone or in the presence of serial dilutions of drugs
4. Results and discussion
seeded in 5 ꢂ 105/100
In vitro antileishmanial evaluation of the 2-(4,6-dichloro-
pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1H-
vatives 7e19, 2-(4,6-diaminopyrimidin-2-yl)-1-phenyl-2,3,4,9-
tetrahydro-1H- -carbolines 20e23, and 2,4,6-triaminopyrimidines
b-carboline deri-
(1e10
mg/ml) in DMSO [17]. Parallel dilutions of DMSO were used as
b
controls. After incubation, an aliquot (50
m
l) of promastigote
24e25showedencouragingresults asdisplayed inTable 1. Amongthe
synthesized compounds 7e25, twelve compounds exhibited more
than 80% inhibition against promastigotes at 10 mg/ml while seven
compounds i.e. 10e15 and 18 showed inhibition in the range of
33.57e79.65%. N-(2-(1H-indol-3-yl)ethyl)-4,6-dichloropyrimidin-2-
amine 6 was also screened and found to be exhibit 99.78% inhibition
against promastigotes, but against amastigotes it showed poor
suspension was aspirated from each well of a 96-well plate and
mixed with an equal volume of Steady GloÒ reagent (Promega) and
luminescence was measured by a luminometer. The values were
expressed as relative luminescence unit (RLU). The inhibition of
parasitic growth is determined by comparison of the luciferase
activity of drug treated parasites with that of untreated controls by
the general formula:
activity with IC50 value of 7.34
Interestingly, the derivative 8 having 3,4-dimethoxyphenyl
group at C-1 of tetrahydro- -carboline ring system, exhibited IC50
value of 1.93 g/ml against amastigotes and selectivity index of
mg/ml and selectivity index of 2.80.
Percentage inhibition ¼ ðN ꢃ n ꢂ 100Þ=N
where N is average relative luminescence unit (RLU) of control
wells and n is average RLU of treated wells.
b
m
15.43. Both selectivity index and IC50 value of 8 were much better
than that of reference drugs sodium stilbogluconate (SSG) and
pentamidine. It can be observed in Table 1 that antileishmanial
activity is dependent on nature and position of substituents on aryl
3.2. Antiamastigote activity
ring at C-1 of tetrahydro-b-carboline ring system. In comparison to
8, presence of one more methoxy group as in 7 or one less methoxy
For assessing the activity of compounds against the amastigote
stage of the parasite, mouse macrophage cell line (J774A.1) infected
with promastigotes expressing luciferase firefly reporter gene was
Table 1
used. Cells were seeded in a 96-well plate (1.5 ꢂ 104 cells/100
ml/
In vitro antileishmanial acitivity of compounds 6e25.
well) in RPMI-1640 containing 10% foetal calf serum and the plates
were incubated at 37 ꢁC in a CO2 incubator. After 24 h, the medium
was replaced with fresh medium containing stationary phase
Compound
no.
In vitro screening
Cytotoxicity Selectivity
CC50
(m
g/ml) indexa (SI)
Antipromastigote Antiamastigote
promastigotes (2.25 ꢂ 105/100
ml/well). Promastigotes invade the
macrophage and are transformed into amastigotes. The test material
activity
(% inhibition
activity MQ/amast.
Model IC50
at 10
m
g/ml)
(mg/ml)
in appropriate concentrations (0.25e10 mg/ml) in complete medium
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
99.78
81.68
93.06
81.68
38.79
44.33
79.65
33.57
36.85
60.24
84.15
90.57
54.14
85.34
99.96
99.94
97.25
85.31
99.72
7.34
3.81
1.93
3.57
NA
NA
7.79
NA
20.59
ND
29.78
ND
ND
ND
14.03
ND
ND
30.66
24.59
ND
2.80
N/A
15.43
N/A
N/A
N/A
1.81
N/A
N/A
6.87
4.09
N/A
was added after replacing the previous medium and the plates were
incubated at 37 ꢁC in a CO2 incubator for 72 h. After incubation, the
drug containing medium was decanted and 50 ml PBS was added in
each well and mixed with an equal volume of Steady GloÒ reagent.
After gentle shaking for 1e2 min, the reading was taken in
a luminometer [17]. The inhibition of parasitic growth is determined
by comparison of the luciferase activity of drug treated parasites
with that of untreated controls as described above.
NA
4.46
6.00
NA
NA
NA
0.49
0.48
4.48
NA
3.05
1.74
53.62
12.11
IC50 of antileishmanial activity were evaluated by logit regres-
sion analysis.
ND
ND
N/A
N/A
2.80
2.50
67.67
ND
19.35
18.37
5.71
5.20
15.10
N/A
6.34
10.55
6.38
2.07
3.3. Cytotoxicity assay
22
23
24
25
The cell viability was determined using the MTT assay. J774A.1
cell line was maintained in RPMI medium (Sigma), supplemented
with 10% foetal calf serum and 40 mg/ml gentamycin. Exponen-
100
SSG
Pentamidine
40e50b
297.38
25.15
tially growing cells (1 ꢂ 104 cells/100
ml/well) were incubated with
100
different drug concentrations for 72 h and were incubated at 37 ꢁC
in a humidified mixture of CO2 and 95% air in an incubator. Stock
solutions of compounds were initially dissolved in DMSO and
NA: not active. ND: not determined.
a
Selectivity index (SI) defined by the ratio CC50 (J-774 A-1 cells)/IC50 (Leishmania
amastigotes). SSG: sodium stilbogluconate.
b
further diluted with fresh complete medium. After incubation, 25
ml
SSG shows 40e50% inhibition against promastigotes at 500
mg/ml. N/A: not
of MTT reagent (5 mg/ml) in PBS medium, followed by syringe
applicable.

R. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 3274e3280
3277
group as in 9 led to approximately two folds decrease in activity
against amastigotes. Compounds 7 and 9 were highly toxic against
J774A.1 cells, so were not selective against amastigotes. Similarly
compounds 10 and 11 having 2-methoxy and 3-methoxy substit-
uent, respectively were also found to be inactive against amasti-
gotes. 3-Bromophenyl substituent in compound 12 was also
detrimental to antiamastigote activity. 3,4-Dioxymethylenephenyl
and benzyloxyphenyl derivatives 13 and 14 were inactive against
amastigotes. Higher IC50 values and lower selectivity indices for
compounds 15 and 16 indicated that 4-methyl or ethyl substituents
were not good for antiamastigote activity. Excited by the good
antileishmanial activity of compound 8 and to extend the structure
activity relationship around phenyl ring compounds 17e19 having
two methoxy substituents at different positions on the phenyl ring
Nuclear magnetic resonance (NMR) spectra were recorded on
Bruker Avance DRX-300 MHz FT spectrometer using TMS as an
internal reference. Mass spectra were recorded on JEOL SX 102/DA
6000 mass spectrometer using Argon/Xenon (6 kV, 10 mA).
Chemical analysis was carried out on Carlo-Erba-1108 instrument.
5.1. Typical procedure for synthesis of compound 6
To
a solution of 2-thiomethyl-3,5-dichloropyrimidine 4 (1
equivalent) in dry DCM was added m-chloroperbenzoic acid (3
equivalent) at 0 ꢁC and stirred for 3 h with gradual rise in temper-
ature to room temperature. Then, reaction was quenched by satu-
rated solution of sodium bicarbonate and diluted with DCM. Organic
phase was separated, dried by Na2SO4 and evaporated in vacuo.
White solid so obtained was refluxed with equivalent amount of
tryptamine in ethanol for 2 h. After TLC analysis showed completion
of the reaction, ethanol was evaporated at reduced pressure and
purified by column chromatography to obtain pure compound 6.
at the C-1 position of b-carboline ring system were synthesized and
evaluated for antileishmanial activity but were inactive against
amastigotes. It indicates that 3,4-dimethoxyphenyl substituent at
C-1 of tetrahydro-b-carboline ring system is necessary for the
antileishmanial activity.
Amongst 2-(4,6-diaminopyrimidin-2-yl)-1-phenyl-2,3,4,9-tet-
5.1.1. N-(2-(1H-indol-3-yl)ethyl)-4,6-dichloropyrimidin-2-amine
rahydro-1H-
b
-carboline derivatives 20e22, antiamastigote activi-
(6)
ties of compounds 20 and 21 were good, but they didn’t have
selectivity indices comparable to that of 8. Inhibitory potency of
compound 22 against amastigotes was less, but value of selectivity
index was comparable to compound 8. Compounds 20e23 were
more active than their corresponding dichloro analogues (i.e. 9 and
13) and showed better selectivity indices. Taking a clue from above
observations, compound 23 was synthesized by substituting both
the chloro groups in compound 8 by morpholine. But to our
surprise it was found to be inactive against amastigotes. Compound
Yield: 68%, mp 132e134 ꢁC; IR (KBr): 3692, 3477, 3019, 2928,
2857, 1573, 1522, 1430, 1216, 1093, 1044 cmꢃ1 1H NMR (CDCl3,
;
300 MHz):
d
(ppm) 8.00 (s, 1H), 7.66 (d, 1H, J ¼ 8.1 Hz), 7.37 (d, 1H,
J ¼ 9.6 Hz), 7.16 (t, 1H, J ¼ 7.8 Hz), 7.22 (t, 1H, J ¼ 6.9 Hz), 7.04 (s, 1H),
6.59 (s, 1H), 5.67 (s, 1H), 3.78 (q, 2H, J ¼ 6.6 Hz), 3.08 (t, 2H,
J ¼ 6.9 Hz); 13C NMR (CDCl3, 75 MHz): 161.57, 136.46, 127.24, 122.27,
122.10, 119.62, 119.55, 118.81, 112.61, 111.23, 108.72, 96.18, 41.73,
25.08. Anal. calcd. for C14H12Cl2N4: C 54.74, H 3.94, N 18.24; Found:
C 54.37, H 3.56, N 17.93%.
24 also inhibited amastigotes with IC50 value of 3.05 mg/ml and poor
selectivity index. Similarly, compound 25 was as effective against
amastigotes as compound 8 but has lower selectivity index.
Structure activity relationship reveals that 3,4-dimethox-
5.2. General procedure for synthesis of compounds 7e19
The mixture of compound 6 (1 equivalent) and substituted
benzaldehyde (1 equivalent) was refluxed in ethanol in presence of
catalytic amount of PTSA for 3 h. After completion of reaction,
solvent was removed in vacuo and resulting solid residue was
column chromatographed to afford respective compounds with
yields in the range of 65e75%.
yphenyl substituent at C-1 of tetrahydro-b-carboline ring system in
2-(4,6-dichloropyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1H-
b
-
carboline derivatives increase the antileishmanial activity and
these results will be used as basis strategy point for the design of
new molecules with improved antileishmanial activity.
Effectiveness of certain molecules as both antiprotozoal and
anticancer agents [19], antileishmanial and anticancer activities of
5.2.1. 2-(4,6-Dichloropyrimidin-2-yl)-1-(3,4,5-trimethoxyphenyl)-
tetrahydro-
b
-carboline derivatives [20] led us to screen all the
2,3,4,9-tetrahydro-1H-b-carboline (7)
synthesized compounds 6e25 for their cytotoxicity against a panel
of human cancer cell lines. Only compound 20 showed moderate
cytotoxicity against C33A, MCF7, DU145, and KB cancer cell lines
Yield: 75%; mp: 198e200 ꢁC; IR (KBr): 3289, 3101, 2994, 2937,
2843, 1579, 1509, 1457, 1350, 1324, 1298, 1247, 1183, 1120 cmꢃ1; 1H
NMR (CDCl3, 300 MHz):
d (ppm) 8.05 (bs, 1H), 7.57 (d, 1H,
with IC50 values of 1.1, 1.2, 1.5, and 2.0
In summary, synthesis and biological evaluation of the series 2-
(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1H- -carboline
derivatives led us to discovery of compound 8 as good anti-
leishmanial agent which is more active than SSG and pentamidine
in vitro. Selectivity index of compound 8 is 2.4, and 7.4 folds higher
than SSG and pentamidine, respectively. These preliminary inves-
tigations revealed that 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetra-
m
g/ml, respectively.
J ¼ 7.5 Hz), 7.31 (d, 1H, J ¼ 7.5 Hz), 7.20e7.13 (m, 2H), 6.91 (s, 1H),
6.71 (s, 2H), 6.58 (s, 1H), 5.07 (dd, 1H, J ¼ 13.2, 3.3 Hz), 3.85 (s, 3H),
3.77 (s, 6H), 3.49e3.39 (m, 1H), 3.09e2.92 (m, 2H); 13C (CDCl3,
75 MHz): 163.9, 160.30,152.91, 137.58,136.56, 135.19,131.44,126.57,
122.08, 119.58, 118.29, 111.08, 110.60, 108.05, 105.99, 60.61, 55.97,
54.64, 38.64, 21.24. Anal. calcd. for C24H22Cl2N4O2: C 59.39, H 4.57,
N 11.54; Found: C 59.02, H 4.28, N 11.33%.
b
hydro-1H-
b
-carboline class can be served as prototype for
5.2.2. 2-(4,6-Dichloropyrimidin-2-yl)-1-(3,4-dimethoxyphenyl)-
development of more efficacious antileishmanial agents. In vivo
studies and efforts directed towards SAR of the pyrimidine ring,
mode of action are in progress in our lab and will be reported in due
course.
2,3,4,9-tetrahydro-1H-b-carboline (8)
Yield: 72%, mp 209e211 ꢁC; IR (KBr): 3371, 3105, 3007, 2945,
2838, 1682, 1581, 1512, 1459, 1384, 1346, 1304, 1269, 1245,
1136 cmꢃ1; 1H NMR (CDCl3, 300 MHz):
d (ppm) 7.81 (s, 1H), 7.59 (d,
1H, J ¼ 7.5 Hz), 7.33e7.14 (m, 4H), 7.16 (s, 1H), 6.84e6.74 (m, 2H),
6.58 (s, 1H), 5.01 (dd, 1H, J ¼ 13.4, 4.2 Hz), 3.86 (s, 3H), 3.85 (s, 3H),
3.49e3.40 (m, 1H), 3.12e2.96 (m, 2H); 13C NMR (CDCl3, 75 MHz):
160.30, 148.95, 148.81, 136.38, 132.07, 131.76, 126.65, 122.17, 120.91,
119.61, 118.33, 112.32, 111.03, 110.76, 110.59, 108.04, 55.84, 55.78,
54.13, 38.21, 21.14. Anal. calcd. for C23H20Cl2N4O2: C 60.67, H 4.43, N
12.30; Found: C 60.48, H 4.14, N 12.11%.
5. Experimental
The melting points were recorded on an electrically heated
melting point apparatus and are uncorrected. IR spectra were
recorded on Beckman Aculab-10, Perkin Elmer 881 and FTIR Shi-
madzu 8201PC spectrophotometers either on KBr discs or in neat.

3278
R. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 3274e3280
5.2.3. 2-(4,6-Dichloropyrimidin-2-yl)-1-(4-methoxyphenyl)-
2,3,4,9-tetrahydro-1H- -carboline (9)
Yield: 69%; mp: 191e193 ꢁC; IR (KBr): 3872, 3399, 2930, 2844,
1586, 1511, 1454, 1369, 1304, 1249, 1178 cmꢃ1 1H NMR (CDCl3,
300 MHz):
(ppm) 7.43 (d, 1H, J ¼ 7.5 Hz), 7.23e7.17 (m, 3H),
1H), 7.55 (d,1H, J ¼ 7.2 Hz), 7.42e7.29 (m, 8H), 7.21e7.11 (m, 2H), 7.02
(s, 1H), 6.90 (d, 2H, J ¼ 8.7 Hz), 6.55 (s, 1H), 5.03 (s, 2H), 4.94 (dd, 1H,
J ¼ 13.8, 4.5 Hz), 3.38e3.31 (m, 1H), 2.99e2.91 (m, 2H); 13C (CDCl3,
75 MHz): 160.30,158.81,136.82,136.28,132.01,131.84,130.00,128.64,
128.06, 127.46, 126.71, 122.21, 119.72, 118.35, 114.82, 111.00, 110.75,
108.11, 70.03, 53.66, 38.04, 21.07. Anal. calcd. for C28H22Cl2N4O: C
67.07, H 4.42, N 11.17; Found: C 66.83, H 4.18, N 10.98%.
b
;
d
7.07e6.97(m, 2H),6.90(s,1H), 6.70(d,2H, J¼ 8.4Hz), 6.44(s,1H),4.80
(dd,1H, J ¼ 13.2, 4.8 Hz), 3.65 (s, 3H), 3.28e3.18 (m,1H), 2.88e2.74 (m,
2H); 13C (CDCl3 þ CD3OD, 75 MHz): 164.78, 163.65, 162.73, 139.76,
135.45, 135.29, 133.21, 129.90, 125.14, 122.58, 121.46, 117.06, 114.44,
113.33,111.28, 58.58, 57.06, 41.37, 24.36. Anal. calcd. for C22H18Cl2N4O:
C 62.13, H 4.27, N 13.17; Found: C 61.83, H 4.02, N 12.93%.
5.2.9. 2-(4,6-Dichloropyrimidin-2-yl)-1-(4-ethylphenyl)-2,3,4,9-
tetrahydro-1H-
Yield: 72%; mp: 187e189 ꢁC; IR (KBr): 3396, 3123, 3055, 2926,
1581, 1509, 1436, 1372, 1303, 1237, 1188 cmꢃ1 1H NMR (CDCl3,
300 MHz):
(ppm) 7.73 (s,1H), 7.58 (d,1H, J ¼ 7.5 Hz), 7.36e7.29 (m,
b-carboline (15)
;
5.2.4. 2-(4,6-Dichloropyrimidin-2-yl)-1-(2-methoxyphenyl)-
d
2,3,4,9-tetrahydro-1H-
Yield: 65%; mp: 182e184 ꢁC; IR (KBr): 3426, 3399, 3022, 1644,
1587, 1512, 1453, 1217 cmꢃ1 1H NMR (CDCl3, 300 MHz):
(ppm)
b-carboline (10)
2H), 7.23e7.15 (m, 4H), 7.06 (s, 1H), 6.57 (s, 1H), 4.98 (dd, 1H,
J ¼ 13.2, 4.5 Hz), 3.49e3.35 (m, 1H), 3.12e2.93 (m, 2H), 2.64 (q, 2H,
J ¼ 7.8 Hz), 1.23 (t, 3H, J ¼ 7.8 Hz); 13C (CDCl3, 75 MHz): 160.37,
144.57, 136.85, 136.31, 131.84, 128.75, 128.08, 126.74, 122.20, 119.72,
118.35, 111.01, 110.72, 108.12, 54.02, 38.19, 28.57, 21.08, 15.51. Anal.
calcd. for C23H20Cl2N4: C 65.25, H 4.76, N 13.23; Found: C 64.95, H
4.52, N 12.97%.
;
d
7.63 (d, 1H, J ¼ 7.5 Hz), 7.23e7.17 (m, 3H), 7.07e6.87 (m, 5H), 6.45 (s,
1H), 4.83 (dd, 1H, J ¼ 12.4, 4.2 Hz), 3.89 (s, 3H), 3.34e3.23 (m, 1H),
2.89e2.77 (m, 2H); 13C (CDCl3 þ CD3OD, 75 MHz): 165.16, 163.25,
160.58, 139.23, 138.47, 135.42, 135.28, 133.21, 129.94, 125.15, 122.52,
121.44,117.06,114.47,113.33,111.48, 56.58, 54.06, 40.34, 23.98. Anal.
calcd. for C22H18Cl2N4O: C 62.13, H 4.27, N 13.17; Found: C 61.86, H
4.07, N 13.02%.
5.2.10. 2-(4,6-Dichloropyrimidin-2-yl)-1-p-tolyl-2,3,4,9-
tetrahydro-1H-
Yield: 70%; mp: 216e218 ꢁC; IR (KBr): 3691, 3401, 3020, 1728,
1569, 1510, 1445, 1372, 1217 cmꢃ1 1H NMR (CDCl3, 300 MHz):
b-carboline (16)
5.2.5. 2-(4,6-Dichloropyrimidin-2-yl)-1-(3-methoxyphenyl)-
;
2,3,4,9-tetrahydro-1H-
Yield: 73%; mp: 175e177 ꢁC; IR (KBr): 3451, 3399, 3023, 2844,
1642, 1511, 1454, 1217 cmꢃ1 1H NMR (CDCl3, 300 MHz):
(ppm)
7.42e7.23 (m, 4H), 7.13e6.97 (m, 3H), 6.85 (d, 1H, J ¼ 7.2 Hz), 6.73
(d, 1H, J ¼ 7.8 Hz), 6.46 (s, 1H), 4.81 (dd, 1H, J ¼ 13.2, 4.8 Hz), 3.65 (s,
3H), 3.31e3.23 (m, 1H), 2.89e2.84 (m, 2H); 13C (CDCl3 þ CD3OD,
75 MHz): 161.25, 159.60, 159.19, 141.18, 136.24, 131.31, 128.95,
126.04, 121.13, 120.28, 118.53, 117.56, 114.18, 112.77, 110.94, 108.96,
107.53, 54.72, 53.80, 37.80, 20.51. Anal. calcd. for C22H18Cl2N4O: C
62.13, H 4.27, N 13.17; Found: C 61.78, H 4.16, N 12.99%.
b
-carboline (11)
d
(ppm) 7.70 (s, 1H), 7.58 (d, 1H, J ¼ 7.5 Hz), 7.31e7.25 (m, 3H),
7.24e7.11 (m, 4H), 7.05 (s, 1H), 6.57 (s, 1H), 4.98 (dd, 1H, J ¼ 13.2,
4.2 Hz), 3.43e3.35 (m, 1H), 3.03e2.94 (m, 2H), 2.33 (s, 3H); 13C
(CDCl3, 75 MHz): 161.92, 160.35, 138.23, 136.61, 136.31, 131.81,
129.26, 128.64, 126.72, 122.19, 119.70, 118.34, 110.99, 110.72, 108.12,
54.01, 38.19, 21.16, 21.06. Anal. calcd. for C22H18Cl2N4: C 64.56, H
4.43, N 13.69; Found: C 64.36, H 4.15, N 13.43%.
;
d
5.2.11. 2-(4,6-Dichloropyrimidin-2-yl)-1-(3,5-dimethoxyphenyl)-
2,3,4,9-tetrahydro-1H-
Yield: 75%, mp 194e196 ꢁC; IR (KBr): 3418, 3105, 3010, 2945,
1640, 1511, 1218, 1136 cmꢃ1 1H NMR (CDCl3, 300 MHz):
(ppm)
b-carboline (17)
5.2.6. 1-(3-Bromophenyl)-2-(4,6-dichloropyrimidin-2-yl)-2,3,4,9-
;
d
tetrahydro-1H-
Yield: 65%; mp: 158e160 ꢁC; IR (KBr): 3686, 3459, 3019, 1727,
1569, 1510, 1445, 1375, 1216 cmꢃ1 1H NMR (CDCl3, 300 MHz):
b
-carboline (12)
8.93 (s, 1H), 7.53 (d, 1H, J ¼ 7.2 Hz), 7.32e7.29 (m, 1H), 7.28e6.97 (m,
4H), 6.88e6.78 (m, 2H), 6.56 (s, 1H), 5.40 (dd, 1H, J ¼ 9.7, 3.6 Hz),
4.19 (s, 3H), 4.02e3.73 (m, 4H), 2.98e2.96 (m, 2H); 13C NMR (CDCl3,
75 MHz): 161.67, 160.71, 153.04, 145.87, 136.16, 135.25, 133.01,
126.49, 125.08, 121.91, 119.38, 118.19, 117.46, 111.52, 111.20, 108.51,
108.04, 60.84, 55.90, 50.94, 41.65, 21.28. Anal. calcd. for
C23H20Cl2N4O2: C 60.67, H 4.43, N 12.30; Found: C 60.39, H 4.21, N
12.14%.
;
d
(ppm) 7.59 (m, 2H), 7.45 (d, 1H, J ¼ 7.8 Hz), 7.39e7.32 (m, 2H),
7.25e7.14 (m, 3H), 7.03 (s, 1H), 6.61 (s, 1H), 4.94 (dd, 1H, J ¼ 13.2,
4.5 Hz), 3.46e3.34 (m, 1H), 3.15e2.86 (m, 2H); 13C (CDCl3, 75 MHz):
160.35, 141.85, 136.39, 131.57, 131.54, 130.68, 130.19, 127.29, 126.63,
122.81 122.50, 119.89, 118.48, 111.16, 111.13, 108.63, 53.78, 38.33,
20.94. Anal. calcd. for C21H15BrCl2N4: C 53.19, H 3.19, N 11.82;
Found: C 52.84, H 2.92, N 11.66%.
5.2.12. 2-(4,6-Dichloropyrimidin-2-yl)-1-(2,4-dimethoxyphenyl)-
2,3,4,9-tetrahydro-1H-b-carboline (18)
5.2.7. 1-(Benzo[d][1,3]dioxol-5-yl)-2-(4,6-dichloropyrimidin-2-yl)-
Yield: 69%, mp 205e207 ꢁC; IR (KBr): 3374, 3105, 2838, 1673,
2,3,4,9-tetrahydro-1H-
Yield: 68%; mp: 173e175 ꢁC; IR (KBr): 3404, 2922, 1572, 1509,
1435,1304, 1240 cmꢃ1; 1H NMR (CDCl3, 300 MHz):
(ppm) 7.73 (bs,
b-carboline (13)
1570,1501, 1459,1384,1273,1220 cmꢃ1; 1H NMR (CDCl3, 300 MHz):
d
(ppm) 8.18 (s, 1H), 7.53 (d, 1H, J ¼ 7.2 Hz), 7.18e7.09 (m, 3H), 6.96
d
(d, 1H, J ¼ 8.4 Hz), 6.55 (s, 1H), 6.57 (d, 2H, J ¼ 2.4 Hz), 6.38 (dd, 1H,
J ¼ 8.4, 2.4 Hz), 5.09 (dd,1H, J ¼ 8.4, 2.2 Hz), 3.96 (s, 3H), 3.79 (s, 3H),
3.59e3.55 (m, 1H), 2.94e2.91 (m, 2H); 13C NMR (CDCl3, 75 MHz):
161.51, 160.69, 158.52, 136.13, 133.22, 129.01, 126.80, 121.94, 121.15,
119.54, 118.26, 111.05, 109.44, 108.25, 104.66, 99.70, 56.30, 55.50,
50.15, 40.08, 21.16. Anal. calcd. for C23H20Cl2N4O2: C 60.67, H 4.43, N
12.30; Found: C 60.43, H 4.22, N 12.19%.
1H), 7.55 (d, 1H, J ¼ 7.5 Hz), 7.30 (d, 1H, J ¼ 7.8 Hz), 7.22e7.11 (m,
2H), 6.99e6.93 (m, 2H), 6.88 (d, 1H, J ¼ 8.1 Hz), 6.73 (d, 1H,
J ¼ 7.8 Hz), 6.56 (s, 1H), 5.93 (d, 2H, J ¼ 1.8 Hz), 4.95 (dd, 1H, J ¼ 13.2,
4.8 Hz), 3.41e3.32 (m, 1H), 2.99e2.85 (m, 2H); 13C (CDCl3 þ CD3OD,
75 MHz): 164.18, 151.60, 151.28, 140.39, 137.70, 136.73, 135.59,
133.57, 130.36, 126.07, 125.65, 123.01, 121.95, 112.85, 112.28, 111.87,
111.80, 104.98, 57.86, 41.86, 24.82. Anal. calcd. for C22H16Cl2N4O2: C
60.15, H 3.67, N 12.75; Found: C 59.91, H 3.46, N 12.54%.
5.2.13. 2-(4,6-Dichloropyrimidin-2-yl)-1-(2,5-dimethoxyphenyl)-
2,3,4,9-tetrahydro-1H-b-carboline (19)
5.2.8. 1-(4-(Benzyloxy)phenyl)-2-(4,6-dichloropyrimidin-2-yl)-
Yield: 72%, mp 186e188 ꢁC; IR (KBr): 3370, 3009, 2948, 2838,
2,3,4,9-tetrahydro-1H-
Yield:74%;mp:184e186 ꢁC;IR(KBr): 3407, 2924, 2845,1571,1508,
1446, 1238, 1172 cmꢃ1; 1H NMR (CDCl3, 300 MHz):
(ppm) 7.68 (s,
b-carboline (14)
1682,1581,1386,1346,1273,1220 cmꢃ1; 1H NMR (CDCl3, 300 MHz):
d
(ppm) 8.59 (s, 1H), 7.51 (d, 1H, J ¼ 7.5 Hz), 7.30e7.28 (m, 1H),
d
7.16e7.09 (m, 3H), 7.00e93 (m, 1H), 6.79e6.71 (m, 2H), 6.55 (s, 1H),

R. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 3274e3280
3279
5.28 (dd, 1H, J ¼ 11.1, 1.2 Hz), 4.01 (s, 3H), 3.72 (s, 3H), 3.69e3.64 (m,
1H), 2.97e2.93 (m, 2H); 13C NMR (CDCl3, 75 MHz): 161.56, 160.65,
154.42, 151.32, 136.08, 132.92, 131.02, 126.61, 125.01, 121.89, 119.42,
118.22, 114.37, 113.83, 112.59, 111.07, 108.50, 57.86, 55.72, 50.65,
40.98, 21.16. Anal. calcd. for C23H20Cl2N4O2: C 60.67, H 4.43, N 12.30;
Found: C 60.33, H 4.08, N 12.09%.
2H), 7.11e7.07 (m, 3H), 6.76e6.68 (m, 2H), 5.08 (s, 1H), 4.88 (dd, 1H,
J ¼ 12.8, 4.2 Hz), 3.79 (s, 3H), 3.73 (bs, 8H), 3.65 (s, 3H), 3.52 (bs, 8H),
3.27e3.15 (m, 1H), 2.77e2.55 (m, 2H); 13C (DMSO-d6, 75 MHz):
164.22, 161.35, 158.43, 136.64, 135.19, 134.28, 129.56, 127.10, 121.33,
118.62, 118.17, 114.25, 111.38, 109.01, 73.87, 66.52, 55.53, 54.54, 52.63,
44.82, 37.20, 21.14. Anal. calcd. for C31H36N6O4: C 66.89, H 6.52, N
15.10; Found: C 66.62, H 6.28, N 14.91%.
5.3. General procedure for synthesis of compounds 20e25
5.3.5. (4,6-Dimorpholin-4-yl-pyrimidin-2-yl)-[2-(1H-indol-3-yl)
ethyl]amine (24)
To synthesize 2,4,6-triaminopyrimidine derivatives 20e25 cor-
responding dichloro derivative were refluxed in neat amine for
10 h. After completion of the reaction, amine was evaporated in
vacuo and resulting solid was dissolved in CHCl3, washed with 2%
HCl in water and purified by column chromatography to afford pure
compounds with yields ranging from 73 to 85%.
Yield: 82%; mp: 190e192 ꢁC; ESMS: 409 (M þ 1); IR (KBr): 3695,
3395, 3355, 3046, 2956, 2921, 2850, 1722, 1579, 1549, 1460, 1439,
1360,1333,1299,1259,1222,1186 cmꢃ1; 1H NMR (CDCl3, 300 MHz):
d
(ppm) 8.08 (bs, 1H), 7.66 (d, 1H, J ¼ 7.8 Hz), 7.38 (d, 1H, J ¼ 7.8 Hz),
7.24e7.10 (m, 2H), 7.05 (s, 1H), 5.11 (s, 1H), 3.77 (t, 8H, J ¼ 4.5 Hz),
3.71 (t, 2H, J ¼ 6.6 Hz), 3.51 (t, 8H, J ¼ 4.5 Hz), 3.05 (t, 2H, J ¼ 6.6 Hz);
13C (CDCl3 þ CD3OD, 75 MHz): 168.80, 165.57, 140.35, 131.35,
126.20, 126.04, 125.52, 122.71, 122.57, 117.04, 115.11, 70.57, 48.69,
45.60, 29.65. Anal. calcd. for C22H28N6O2: C 64.68, H 6.91, N 20.57;
Found: C 64.53, H 6.76, N 20.23%.
5.3.1. 1-(Benzo[d][1,3]dioxol-5-yl)-2-(4,6-bis(4-methylpiperazin-1-
yl)pyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-b-carboline (20)
Yield: 73%; mp: 204e206 ꢁC; ESMS: 567 (M þ 1); IR (KBr): 3783,
3689, 3619, 3413, 3020, 2927, 2361, 1561, 1426, 1371, 1216 cmꢃ1; 1H
NMR (CDCl3, 300 MHz):
d
(ppm) 8.74 (s, 1H), 7.55 (d, 1H, J ¼ 7.2 Hz),
7.27 (d, 1H, J ¼ 6.23 Hz), 7.17e7.11 (m, 3H), 7.01 (s, 1H), 6.82 (d, 1H,
J ¼ 7.8 Hz), 6.68 (d, 1H, J ¼ 7.8 Hz), 5.89e5.87 (m, 2H), 5.12 (s, 1H),
4.97 (dd, 1H, J ¼ 13.2, 4.3 Hz), 3.61 (bs, 8H), 3.19e3.11 (m, 1H),
2.99e2.89 (m, 1H), 2.79 (dd, 1H, J ¼ 14.7, 2.7 Hz), 2.50 (bs, 8H), 2.31
(s, 6H); 13C (CDCl3, 75 MHz): 164.53, 160.35, 147.64, 146.87, 136.19,
136.12, 133.21, 127.22, 121.72, 121.50, 119.13, 118.23, 111.16, 110.72,
109.08, 107.69, 100.90, 73.04, 54.82, 52.86, 46.11, 44.20, 37.06, 21.14.
Anal. calcd. for C32H38N8O2: C 67.82, H 6.76, N 19.77; Found: C
67.66, H 6.39, N 19.52%.
5.3.6. [4,6-Bis(4-methylpiperazin-1-yl)pyrimidin-2-yl][2-(1H-
indol-3-yl)ethyl]amine (25)
Yield: 85%; mp 162e164 ꢁC; ESMS: 435 (M þ 1); IR (KBr): 3781,
3691, 3475, 3019, 2927, 2852, 2805, 1573, 1445, 1364, 1281,
1216 cmꢃ1 1H NMR (CDCl3, 300 MHz):
; d (ppm) 8.19 (bs, 1H), 7.66
(d, 1H, J ¼ 7.8 Hz), 7.36 (d, 1H, J ¼ 7.8 Hz), 7.23e7.08 (m, 2H), 7.05 (s,
1H), 5.12 (s, 1H), 4.83 (bs, 1H), 3.74e3.68 (m, 2H), 3.57 (t, 8H,
J ¼ 4.8 Hz), 3.05 (t, 2H, J ¼ 6.9 Hz), 2.47 (t, 8H, J ¼ 4.8 Hz), 2.33 (s,
6H); 13C NMR (CDCl3, 75 MHz): 164.65, 161.66, 136.41, 127.60,
121.99, 121.89, 119.13, 118.95, 113.90, 111.13, 73.48, 54.83, 46.17,
44.28, 41.78, 29.69. Anal. calcd. for C24H34N8: C 66.33, H 7.89, N
25.78; Found: C 66.07, H 7.58, N 25.42%.
5.3.2. 1-(Benzo[d][1,3]dioxol-5-yl)-2-(4,6-bis(4-ethylpiperazin-1-
yl)pyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-b-carboline (21)
Yield: 81%; mp: 179e181 ꢁC; ESMS: 595 (M þ 1); IR (KBr): 3693,
3463, 3019, 2927, 2848,1560,1427,1350,1304,1216,1166,1124 cmꢃ1
;
Acknowledgements
1H NMR (CDCl3, 300 MHz):
d
(ppm) 8.65(s,1H), 7.55 (d,1H, J ¼ 7.2 Hz),
7.27 (d, 1H, J ¼ 6.24 Hz), 7.19e7.09 (m, 3H), 7.01 (s, 1H), 6.83 (m, 1H),
6.68 (d, 1H, J ¼ 8.1 Hz), 5.91e5.89 (m, 2H), 5.12 (s, 1H), 4.98 (dd, 1H,
J ¼ 13.2, 4.8 Hz), 3.62 (bs, 8H), 3.22e3.14 (m, 1H), 2.95e2.92 (m, 1H),
2.75 (dd, 1H, J ¼ 15.0, 3.0 Hz), 2.55 (bs, 8 Hz), 2.44 (q, 4H, J ¼ 6.9 Hz),
0.91 (t, 6H, J ¼ 6.9 Hz); 13C (CDCl3, 75 MHz): 164.50, 160.32, 147.61,
146.86, 136.19, 136.15, 133.21, 127.22, 121.79, 121.44, 119.06, 118.23,
111.10, 110.69, 109.14, 107.70, 100.89, 72.95, 52.84, 52.57, 52.37, 44.19,
36.97, 21.16,11.76. Anal. calcd. forC34H42N8O2:C 68.66, H7.12, N18.84;
Found: C 68.34, H 6.92, N 18.69%.
R.K. and S.K. are grateful to the CSIR and UGC, New Delhi for
senior and junior research fellowships respectively and to the
Sophisticated Analytical Instrument Facility, CDRI Lucknow for
providing spectroscopic data. CDRI Communication No. 7822.
Appendix. Supporting information
Supplementary data associated with this article can be found in
the on-line version, at doi:10.1016/j.ejmech.2010.04.004.
5.3.3. 2-(4,6-Dimorpholin-4-yl-pyrimidin-2-yl)-1-(4-methoxy-
phenyl)-2,3,4,9-tetrahydro-1H-b-carboline (22)
References
Yield: 76%; mp: 145e147 ꢁC; ESMS: 527 (M þ 1); IR (KBr): 3781,
[1] (a) M.H. Gelb, W.G. Hol, Science 297 (2002) 343e344;
(b) Tropical Disease Research: Progress 1999e2000. World Health Organiza-
tion, Geneva, 2001.
3692, 3405, 3020, 2923, 2852, 1560, 1509, 1421, 1368, 1300,
1216 cmꢃ1 1H NMR (CDCl3, 300 MHz):
; d (ppm) 10.85 (s, 1H), 7.44
(d, 1H, J ¼ 7.8 Hz), 7.28 (d, 1H, J ¼ 8.1 Hz), 7.22 (d, 2H, J ¼ 8.1 Hz),
7.09e6.96 (m, 3H), 6.88 (d, 2H, J ¼ 8.7 Hz), 5.40 (s, 1H), 4.82 (dd, 1H,
J ¼ 12.6, 3.9 Hz), 3.76 (s, 3H), 3.71 (bs, 8H), 3.52 (bs, 8H), 3.18e3.06
(m, 1H), 2.81e2.69 (m, 2H); 13C (DMSO-d6, 75 MHz): 164.81, 160.31,
158.97, 136.60, 134.49, 134.22, 129.45, 126.99, 121.33, 118.84, 118.16,
114.03, 111.48, 109.16, 73.79, 66.43, 55.53, 52.74, 44.94, 37.16, 21.10.
Anal. calcd. for C30H34N6O3: C 68.42, H 6.51, N 15.96; Found: C
68.08, H 6.25, N 15.62%.
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5.3.4. 2-(4,6-Dimorpholin-4-yl-pyrimidin-2-yl)-1-(3,4-dimethoxy-
phenyl)-2,3,4,9-tetrahydro-1H-b-carboline (23)
Yield: 78%; mp: 162e164 ꢁC; ESMS: 557 (M þ 1); IR (KBr): 3441,
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