A novel access to arylated and heteroarylated beta-carboline based PDE5 inhibitors

Article abstract of DOI:10.2174/157340610793563992

Starting from a previously reported lead compound GR30040X (a hydantoin tetrahydro-β-carboline derivative with a 4- pyridinyl ring at C- 5), a series of structurally related tetrahydro-β-carboline derivatives were prepared. The tetrahydro- β-carboline skeleton was fused either to a hydantoin or to a piperazindione ring, the pendant aryl group attached to C-5 or C-6 was changed to a 3, 4-dimethoxyphenyl or a 3-pyridinyl ring; different N-substituents on the terminal ring were introduced, a straight chain ethyl group, a branched tert. butyl and P-chlorophenyl group rather than n-butyl group of the lead compound. All four possible diastereomers of target tetrahydro-β-carboline derivatives were prepared, separated by column chromatography and the significance of these stereochemical manipulations was studied. Synthesized compounds were evaluated for their inhibitory effect versus PDE5. Seven hits were obtained with appreciable inhibitory activity versus PDE5 with IC₅₀s 0.14 - 4.99 μM.

Full text of DOI:10.2174/157340610793563992

374
Medicinal Chemistry, 2010, 6, 374-387
A Novel Access to Arylated and Heteroarylated Beta-Carboline Based
PDE5 Inhibitors
Nermin S. Ahmed*,1, Bernard D. Gary2, Gary A. Piazza2, Heather N. Tinsley2, Stefan Laufer3 and Ashraf H.
Abadi1
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo,
Cairo 11835, Egypt
2Division of Drug Discovery, Department of Biochemistry and Molecular Biology, Southern Research Institute, The
University of Alabama at Birmingham, 2000 Ninth Avenue South, Birmingham, AL 35205, USA
3Department of Pharmaceutical and Medicinal Chemistry, Eberhard Karls University Tꢀbingen, Auf der Morgenstelle 8,
72076 Tꢀbingen, Germany
Abstract: Starting from a previously reported lead compound GR30040X (a hydantoin tetrahydro-ꢀ-carboline derivative
with a 4- pyridinyl ring at C- 5), a series of structurally related tetrahydro-ꢀ-carboline derivatives were prepared. The tet-
rahydro-ꢀ-carboline skeleton was fused either to a hydantoin or to a piperazindione ring, the pendant aryl group attached
to C-5 or C-6 was changed to a 3, 4-dimethoxyphenyl or a 3-pyridinyl ring; different N-substituents on the terminal ring
were introduced, a straight chain ethyl group, a branched tert. butyl and P-chlorophenyl group rather than n-butyl group of
the lead compound. All four possible diastereomers of target tetrahydro-ꢀ-carboline derivatives were prepared, separated
by column chromatography and the significance of these stereochemical manipulations was studied. Synthesized com-
pounds were evaluated for their inhibitory effect versus PDE5. Seven hits were obtained with appreciable inhibitory activ-
ity versus PDE5 with IC50s 0.14 - 4.99 ꢁM.
Keywords: 3- pyridine, cGMP, MED, PDE5, tadalafil, tetrahydro-ß-carboline.
1. INTRODUCTION
vasorelaxation in penile tissue, which is predominantly me-
diated by the release of NO in the cavernous nerve endings,
the endothelium of penile arteries and the corpora cavernosa
[4]. The wide, safe use of PDE5 inhibitors, together with an
increasing understanding of cGMP-regulated mechanisms,
have triggered a number of attempts to find new applications
for these agents. It has been shown that besides corpus cav-
ernosum, PDE5 is also expressed in smooth muscles of the
systemic vasculature, prostate, bladder, cardiac tissues, brain
and platelets which imply additional target tissues for PDE5
inhibitors [5, 6]. Recently, PDE5 inhibitors have been re-
ported to be effective in the treatment of various disorders
such as chronic obstructive pulmonary disease, prostate hy-
perplasia, hypertension and coronary heart disease [7]. The
over expression of PDEs has been described in various can-
cer pathologies, inhibition of selective PDE isoforms raises
the level of intracellular cAMP and /or cGMP which in turn
induces apoptosis and cycle arrest in a broad spectrum of
tumor cells and regulates the tumor microenvironment, and
this may provide a whole new class of antitumor therapy
with reduced adverse effects [8, 9].
It is well established that nitric oxide (NO) and natri-
uretic peptides increase intracellular cGMP levels by stimu-
lation of the soluble and membrane bound guanylate cyclase,
respectively. This cGMP formation is the initial step of a
crucial biochemical pathway, regulating the cardiovascular,
central and peripheral nervous system. Phosphodiesterases
(PDEs) are intracellular enzymes that specifically catalyze
the hydrolysis of the second messengers cAMP and cGMP to
the inactive metabolites AMP and GMP. Various degrees of
substrate specificity is reported for this family of enzymes,
the cAMP specific PDEs include PDE7, PDE4 and PDE8
and the cGMP specific PDEs include PDE5, PDE6 and
PDE9, the others are of dual activity [1]. Thus PDE5 inhibi-
tion increases intracellular cGMP levels by preventing its
degradation with subsequent decrease in intracellular cal-
cium levels, thereby promoting relaxation of smooth muscle
cells and a variety of other calcium-dependent processes [2].
Since inhibitors of PDE5 raise intracellular cGMP levels, the
effects will be much more pronounced under conditions
when cGMP formation is already increased for example sex-
ual stimulation [3]. Sexual stimulation induces a selective
The superposition of all PDE5A reported inhibitors has
revealed with outstanding clarity that there is a highly con-
served binding mode among all the inhibitors. All these in-
hibitors share a core binding site that can be characterized by
a planar ring sandwiched by the hydrophobic clamp and the
formation of an H bond with an invariant glutamine 817. The
substructure of the inhibitors that bind to this core represents
*Address correspondence to this author at the Department of Pharmaceutical
Chemistry, Faculty of Pharmacy and Biotechnology, German University in
Cairo, Cairo 11835, Egypt; Tel: +20227590623; Fax: +20227581041;
E-mail: nermin.salah@guc.edu.eg
1573-4064/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

A Novel Access to Arylated and Heteroarylated Beta-Carboline
Medicinal Chemistry, 2010, Vol. 6, No. 6 375
a framework upon which more potent and selective inhibi-
tors can be developed [10].
literature [13, 14]. Signals for C-1 and C-3 in the trans-THBC
isomers appeared at higher field in the carbon spectrum than
the analogous carbons of the corresponding cis-isomer,
probably due to the 1,3-interactions present in the trans-
isomer. Moreover, the 1H-NMR signals for the proton at C-1
appeared at about 5.5 ppm, on cyclization to the hydantoin
and piperazinedione derivatives the same proton which is
now attached to C-5 and C-6 respectively makes a remark-
able downfield shift compared to its respective THBC, this
may be due to the electron withdrawing effect of the neigh-
boring carbonyl. Also, regarding the THBCs a significant
difference has been noted between the 2 isomers regarding
their melting points and Rf values. A correlation exists be-
tween Rf value on TLC and the stereochemistry of the 1, 3-
disubstituted tetrahydro-ꢀ-carbolines. The cis-isomer is sys-
tematically less polar than the trans-isomer; however, in the
hydantoin series, the polarity is reversed, thus, the cis-isomer
becomes more polar than the trans-isomer. The difference in
both Rf and melting point values are not as significant in the
piperazindione series as it is in the hydantoin series. The
presence of a 3-pyridine ring in compounds (I-IV & VIII-
XIX) led to a large chemical shift in the aromatic protons at
ortho and para position; this is due to the deshielding effect
of nitrogen on C2 and C4 of the ring.
Herein, we report about thirty two new tetrahydro-ꢀ-
carboline derivatives, structurally related to the lead com-
pound (5R,11aR)-2-butyl-5-(pyridin-4-yl)-5,6,11,11a-tetra-
hydro-1Himidazo[1’,5’:1,6]pyrido[3,4-b]indole-1,3(2H)-dione
(GR30040X), by replacing its 4-pyridinyl moiety with 3-
pyridinyl, 3,4-dimethoxyphenyl; changing the nature of the
substituent on its terminal nitrogen and manipulating its
stereochemical aspects and the size of the terminal ring.
2. CHEMISTRY
The functional tetrahydro-ß-carboline skeleton can be as-
sembled by the reaction of D- or L-tryptophane methyl ester
( prepared according to a known procedure) [11] with the
selected aldehydes (3 pyridinecarboxaldehyde, 3,4 dimeth-
oxybenzaldehyde) under non stereospecific Pictet-Spengler
conditions (TFA/ CH2Cl2) [12] to furnish the required cis-
and trans- isomers in different yields (I-VIII). The diastereo-
mers are then separated using column chromatography. Each
of the pure diastereomers is then allowed to react with one of
the commercially available isocyanates to allow the fusion of
the THBCs to an imidazolinedione ring (Scheme 1). In order
to expand the substrate types, we turned our attention to en-
large the imiadazolidinedione ring to a piperazindione ring;
this was accomplished through reaction of the pure di-
astereomer of THBCs (V-VIII) with chloroacetyl chloride to
provide the acylated intermediate in almost quantitative yield.
Subsequent cyclization of these intermediates with selected
amines in methanol provided the piperazindione series
(Scheme 2). The attempt to prepare a piperazindione series
from THBCs with a pyridinecarboxaldehyde at position 3
failed, to the best of our knowledge the failure of cyclization
may be attributed to intermolecular reaction involving the 3-
pyridine ring.
3. RESULTS AND DISCUSSION
Table 1 shows the reported IC50 values for PDE5 inhibi-
tion of the reference compound GR30040X compared to
other previously synthesized PDE5 inhibitor, the results
show that GR30040X PDE5 inhibitory activity is much less
than the phenyl congener (XLV). The decrease in the activ-
ity of GR20040X relative to (XLV) was attributed to de-
crease in the electron density on the pendant pyridine due to
the electron withdrawing effect of the N.
Moreover a related structure to (XLV) but with pendant
4-methoxyphenyl (XLVI) and the structurally related 3,4
benzodioxol derivative (tadalafil) were highly potent PDE5
inhibitors, Thus, we designed our new molecules as
The assignment of cis- / trans- stereochemistry for the
tetrahydro-ß-carbolines (I-VIII) was based on detailed study
of 13C-NMR spectroscopy data well established in previous
HOOC
H3COOC
R,S
R,S
H2N
H2N
CH3OH
1-CH3COCl
2-dil.NH4OH
N
H
N
H
D or L-tryptophan
ArCHO
CF3COOH/RT/4 days
O
H3COOC
HN
R
R,S
R,S
R,S
R,S
N
RNCO
N
O
Butanone/ reflux
N
H
Ar
N
Ar
H
I-VIII
IX-XXXII
Ar = 3- pyridinyl
Ar = 3, 4 dimethoxyphenyl
I- IV
V-VIII
Scheme 1.

376 Medicinal Chemistry, 2010, Vol. 6, No. 6
Ahmed et al.
HOOC
H3COOC
H2N
R,S
H2N
CH3OH
1-CH3COCl
2-dil.NH4OH
N
H
N
H
D or L-tryptophan
3,4 dimethoxybenzaldehyde
CF3COOH/RT/4 days
H3COOC
H3COOC
R,S
Cl
N
O
R,S
O
HN
Cl
Cl
R,S
N
R,S
N
H
H
H3CO
OCH3
H3CO
OCH3
XXIII-XXVI
RNH2, CH3OH, Reflux
O
R
N
R,S
N
O
R,S
N
H
H3CO
OCH3
XXXVII-XLIV
R
Compound
C2H5
tert-butyl
XXXVII, XXXVIII, XXIX
XLI, XLII, XLIII, XLIV
Scheme 2.
positional isomers to GR30040X viz the 3- pyridinyl conge-
ner and by trying the 3, 4-dimethoxyphenyl as the pendant
aryl. In the latter case the two methoxy functional groups
increase the electron density on the phenyl ring and may lead
to more active derivatives. Other structural modifications
were: keeping the terminal ring as hydantoin or enlarging it
to piperazinedione; variation of the N-substituent from n-
alkyl (ethyl) to branched (tert-butyl) and finally to an aro-
matic (P-chlorophenyl) and manipulating the stereochemical
aspects of the 2 chiral carbons (C5, C11a in case of hydan-
toin derivatives) and (C6, C12a in case of piperazindione
derivatives).
free rotating groups prevents the optimal orientation of the
phenyl ring, this steric clash is not observed when only 4-
methoxyphenyl moeity is present XLVI.
Seven of our compounds with the 3-pyridinyl substitution
showed PDE5 inhibitory activity with IC50= 0.14 - 4.99 ꢀM
(IX, XII, XIII, XIV, XVI, XVII, XX). The following SAR
conclusions can be withdrawn:
All the active hydantoins were of the R- configuration at
C-5 but C11a was either R or S, thus, the stereochemical
aspect of the carbon derived from the aldehyde is more im-
portant than that of the carbon derived from amino acids e.g.
the 5R, 11aR; 5R, 11aS diastereomers were equiactive e.g.
IX versus XII and in other cases 5R, 11aS was more active
than the 5R, 11aR e.g. XVI versus XIII, the order of activity
in the case of XVI-XIII was 5R, 11aS > 5R, 11aR >5S,
11aR > 5S, 11aS. This opens the horizon towards obtaining
efficient PDE5 inhibitors derived from cheap commercially
available L-tryptophan rather than D-tryptophan, this may be
of an economic advantage.
To our surprise almost all compound with the 3, 4 di-
methoxyphenyl substituent were of marginal PDE5 inhibi-
tory activity (5-7 ꢀM) or were totally inactive despite the
fact that this substitution is very similar to tadalafil (a potent
PDE5 inhibitor with IC50= 7 nM) and XLVI (another potent
PDE5 inhibitor with IC50= 10 nM), and the pendant aryls in
these derivatives have nearly the same electronic properties,
The steric compactness of the 3,4 dimethoxy group com-
pared to the conformationally constrained 3,4-methylene-
dioxy of tadalafil, seems to be a governing factor in activity,
possibly suggesting that the presence of this 3,4 dimethoxy
Regarding the size of substituent on the nitrogen of the
terminal ring; N-substitution seems to slightly affect the ac-
tivity, however compounds with ethyl substitution contrib-

A Novel Access to Arylated and Heteroarylated Beta-Carboline
Medicinal Chemistry, 2010, Vol. 6, No. 6 377
utes most to our hit list and those of P-chlorophenyl contrib-
utes least, but none of these substituent had a deleterious
effect on activity, this may encourage the use of less bulky
groups in the future. It is apparent that a wide range of N-
alkyl groups is tolerated the hydantoin series.
toin, derivatives. It is worthy to mention that all the chloro-
ethanone derivatives (XXXIII-XXXVI) were also among
the least active at the screening dose, this confirms that for
this class of PDE5 inhibitors an integer tetracyclic part is
essential for PDE5 inhibition. The biological screening re-
sults are shown in Tables 2-7.
Surprisingly, all the piperazinedione derivatives were in-
active, thus at least with the respective pendant aryls; the
activity is limited to the hydantoin derivatives.
Docking of IX and tadalafil to the PDE5 binding pocket,
they showed an interaction slightly different from each other,
while like all reported PDE5 inhibitors tadalafil formed a
hydrogen bonding with glutamine 817, IX showed hydrogen
bonding of the oxygen of the carbonyl group of the hydan-
toin ring with tyrosine 612, the lack of this type of interac-
tion may explain its relative lower potency. The results are
displayed in Figs. (1 and 2).
The disubstitued THBCs (I-VIII), did not show appre-
ciable inhibition to PDE5 at the screening dose to justify IC50
determination. As all the active derivatives were of the
THBCs-hydantoin skeleton, thus the PDE5 inhibition is de-
terminately linked to the formation of the respective hydan-
Table 1. Reported % PDE5 Inhibition and IC50 values Versus PDE5 for some Known PDE5 Inhibitors
Code
Structure
%PDE5 Inhibition (50 μM)
IC50 (ꢀM)
O
N
N
GR30040X
75
0.3
O
N
H
N
O
N
N
XLV
102
0.06
O
N
H
O
N
N
O
XLVI
98
0.01
N
H
H3CO
O
N
N
O
Tadalafil
102
0.007
N
H
O
O

378 Medicinal Chemistry, 2010, Vol. 6, No. 6
Ahmed et al.
Table 2. % PDE5 Inhibition and IC50 Values of C-3 (3- pyridinyl) tetrahydro-ß-carbolines
H3COOC
HN
N
H
N
Code
Absolute Stereochemistry
%PDE5 Inhibition (50 μM)
IC50 (μM)
I
1R, 3R
1S, 3R
1S, 3S
1R, 3S
50
30
72
41
*ND
ND
II
III
IV
>10
ND
Table 3. % PDE5 Inhibition and IC50 Values of C-3 (3,4- dimethoxyphenyl) tetrahydro-ß-carbolines
H3COOC
HN
N
H
OCH3
OCH3
Code
Absolute Stereochemistry
%PDE5 Inhibition (50 μM)
IC50 (μM)
V
1R, 3R
1S, 3R
1S, 3S
1R, 3S
48
54
8
ND
ND
ND
ND
VI
VII
VIII
7
Table 4. % PDE5 Inhibition and IC50 Values of C-5 (3- pyridinyl) Hydantoin Derivatives
O
R
N
N
N
H
O
N
Code
R
Absolute Stereochemistry
%PDE5 Inhibition (50 μM)
IC50 (μM)
IX
X
Ethyl
Ethyl
5R, 11aR
5S, 11aR
5S, 11aS
5R, 11aS
5R, 11aR
5S, 11aR
5S, 11aS
5R, 11aS
5R, 11aR
5S, 11aR
5S, 11aS
5R, 11aS
102
58
24
100
90
89
45
90
85
2
0.14
ND
XI
Ethyl
ND
XII
Ethyl
0.15
0.41
4.75
ND
XIII
XIV
XV
tert- butyl
tert- butyl
tert- butyl
tert- butyl
P-chlorophenyl
P-chlorophenyl
P-chlorophenyl
P-chlorophenyl
XVI
XVII
XVIII
XIX
XX
0.18
4.99
ND
1
ND
87
1.25

A Novel Access to Arylated and Heteroarylated Beta-Carboline
Medicinal Chemistry, 2010, Vol. 6, No. 6 379
Table 5. % PDE5 Inhibition and IC50 Values of C-5 (3,4- dimethoxyphenyl) Hydantoin Derivatives
O
R
N
N
N
H
O
OCH3
OCH3
Code
R
Absolute Stereochemistry
% PDE5 Inhibition (50 μM)
IC50 (μM)
XXI
XXII
Ethyl
Ethyl
5R, 11aR
5S, 11aR
5S, 11aS
5R, 11aS
5R, 11aR
5S, 11aR
5S, 11aS
5R, 11aS
5R, 11aR
5S, 11aR
5S, 11aS
5R, 11aS
78
70
52
75
54
52
58
79
22
20
33
87
5.11
7
XXIII
XXIV
XXV
Ethyl
ND
13.73
ND
ND
ND
6.21
ND
ND
ND
5.36
Ethyl
tert- butyl
tert- butyl
tert- butyl
tert- butyl
P-chlorophenyl
P-chlorophenyl
P-chlorophenyl
P-chlorophenyl
XXVI
XXVII
XXVIII
XXIX
XXX
XXXI
XXXII
Table 6. % PDE5 Inhibition and IC50 Values of C-3 (3,4- dimethoxyphenyl) Chloroacetyl Derivatives
H3COOC
N
Cl
N
H
O
OCH3
OCH3
Code
Absolute Stereochemistry
% PDE5 Inhibition (50 μM)
IC50 (μM)
XXXIII
XXXIV
XXXV
1R, 3R
1S, 3R
1S, 3S
1R, 3S
70
75
48
22
>10
>10
ND
ND
XXXVI
Table 7. % PDE5 Inhibition and IC50 Values of C-6 (3,4- dimethoxyphenyl) Piperazinedione Derivatives
O
R
N
N
N
H
O
OCH3
OCH3
Code
R
Absolute Stereochemistry
% PDE5 Inhibition (50 μM)
IC50 (μM)
XXXVII
XXXVIII
XXXIX
Ethyl
Ethyl
Ethyl
6R, 12aR
6S, 12aR
6S, 12aS
68
13
22
4.35
ND
ND

380 Medicinal Chemistry, 2010, Vol. 6, No. 6
Ahmed et al.
Table 7. contd….
Code
R
Absolute Stereochemistry
% PDE5 Inhibition (50 μM)
IC50 (μM)
XL
Ethyl
6R, 12aS
6R, 12aR
6S, 12aR
6S, 12aS
6R, 12aS
10
10
21
18
55
ND
ND
ND
ND
ND
XLI
tert- butyl
tert- butyl
tert- butyl
tert- butyl
XLII
XLIII
XLIV
Fig. (1). Detailed mode view showing the docking and interaction of tadalafil with human PDE5.
Fig. (2). Detailed mode view showing the docking and interaction of IX with human PDE5.

A Novel Access to Arylated and Heteroarylated Beta-Carboline
Medicinal Chemistry, 2010, Vol. 6, No. 6 381
4. EXPERIMENTAL DETAILS
Methyl (1S, 3R)-1-(pyridin-3-yl)-2, 3, 4, 9-tetrahydro-1H-
ꢀ –carboline-3-carboxylate (II)
All reactions were carried out under inert gas (nitrogen).
Reaction progress was monitored by TLC, performed on
precoated silica gel plates (ALUGRAM SIL G/UV254) and
detection of the components was made by short UV light.
Column chromatography was performed using silica-gel (70-
200 μm). Melting points were determined on Buchi Melting
Point apparatus and are uncorrected. FTIR spectra were re-
corded on Nicolet Avatar 380 spectrometer. 1H-NMR spectra
were run at 300 MHz and 13C spectra were run at 75.46 MHz
in deuterated chloroform (CDCl3) and deuterated dimethyl-
sulfoxide (DMSO), chemical shifts are quoted in (ꢀ) and
were related to that of the solvents; chemical shifts (ꢀ) were
reported in parts per million (ppm) downfield from TMS;
multiplicities are abbreviated as s: singlet; d: doublet; t: trip-
let; q: quartret; m: multiplet; dd: doublet of doublet; brs:
broad. Mass spectra were made on Focus GC/ Polaris MS,
model 5890, series II at an ionization potential of 70 ev and
the FAB was done on Finnigan TQS 70 by 70 ev in nitro-
benzylalcohol –matrix at 30°C. Elemental analysis were per-
formed by the Microanalytical Unit, Faculty of Science,
Cairo University; the found values were within + 0.4% of the
theoretical ones, unless otherwise indicated. All starting ma-
terials were commercially available and of general purpose
pure analytical grade.
Yellow powder (13%); m.p.: 180-183 °C; Rf = 0.59
(CH2Cl2/CH3OH 9:1); MS (EI): m/z 307 (M+; 100%); IR
1
(cm-1): 3232, 1734; H-NMR (DMSO): 10.85 (brs,1H, NH),
8.61 (s,1H, Ar), 7.68-7.64 (d,1H, Ar), 7.54-7.51 (d,1H, Ar),
7.29-7.27 (d,1H, Ar), 7.14-7.01 (m, 4H, Ar), 5.78 (s,1H,
CHPh), 3.96-3.81 (m, 1H, CHC(O)N), 3.71 (s, 3H, OCH3),
3.74-3.69 (dd, 1H, CHaHb), 3.15-3.10 (m, 1H, CHaHb);, 13C-
NMR: 171.5, 150.6, 149.7, 137.5, 135.9, 136.9, 126.2, 123.9,
122.1, 121.2, 119.3, 118.5, 111.4, 106.8, 52.8(C1), 52.5(C3),
51.9,23.6; Analysis calcd for C18H17N3O2 C, H, N.
Methyl (1S, 3S)-1-(pyridin-3-yl)-2,3,4,9-tetrahydro-1H-ꢀ
–carboline-3-carboxylate (III)
Orange powder (18%); m.p.: 225-228 °C; Rf = 0.77
(CH2Cl2/CH3OH 9:1); MS (EI): m/z 307 (M+;100%); IR
(cm-1): 3320, 1727; 1H-NMR (DMSO) : 9.22 (brs,1H,
NH),8.62 (s, 1H, Ar), 8.46-8.43 (d, 1H, Ar), 8.28-8.25 (d,
1H, Ar), 7.75-7.73 (d, 1H, Ar), 7.69-7.59 (m, 1H, Ar), 7.49-
7.43 (dd, 1H, Ar), 7.25-7.22 (d, 1H, Ar), 7.09-7.69 (dd, 1H,
Ar), 5.59 (s, 1H, CHPh), 4.67-4.59 (dd, 1H, CHC(O)N), 3.77
(s, 3H, OCH3), 3.74-3.69 (dd, 1H, CHaHb), 3.24-2.98 (m, 1H,
CHaHb);13C-NMR: 171.3, 150.7, 150.1, 149.8, 137.5, 136.9,
129.8, 126.4, 124.0, 121.8, 119.2, 118.3, 111.7, 107.4, 56.2
(C1), 55.8(C3), 52.7, 24.3; Analysis calcd for C18H17N3O2 C,
H, N.
General Procedures for the Preparation of Methyl 1-
(aryl)-2,3,4,9-tetrahydro-1H-ꢀ-carboline-3-carboxylate
(I-VIII)
Methyl (1R,3S)-1-(pyridin-3-yl)-2,3,4,9-tetrahydro-1H-ꢀ
–carboline-3-carboxylate (IV)
The appropriate tryptophane methyl ester (10.76 g, 49.3
mmol) and the appropriate aromatic aldehyde namely 3-pyri-
dinecarboxaldehyde or 3, 4-dimehoxybenzaldehyde (54.23
mmol) were dissolved in CH2Cl2 (70 mL) and cooled to 0 °C
in an ice bath. To this solution was added dropwise TFA (8
mL), and the mixture was stirred at room temperature for 4
days under N2 atmosphere. The reaction mixture was then
basified with dilute NH4OH solution and extracted with
CH2Cl2 (3 x 50 m). The organic layer was washed with wa-
ter, brine, dried over Na2SO4, filtered, and evaporated under
reduced pressure. The residue was purified and the isomers
were separated by column chromatography on silica gel
eluting with CH2Cl2: CH3OH in different ratios to give first
the appropriate cis-isomer followed the trans- one.
Yellow powder (17%); m.p.: 182-185 °C; Rf = 0.57
(CH2Cl2/CH3OH 9:1); MS (EI): m/z 307 (M+;100%); IR
1
(cm-1): 3209, 1726; H-NMR (DMSO) : 9.22 (brs,1H, NH),
8.62 (s,1H, Ar), 8.46-8.43 (d,1H, Ar), 8.28-8.25 (d,1H, Ar),
7.75-7.73 (d,1H, Ar), 7.69-7.59 (m,1H, Ar), 7.49-7.43
(dd,1H, Ar), 7.25-7.22 (d,1H, Ar), 7.09-7.69 (dd,1H, Ar),
5.59 (s, 1H, CHPh), 4.67-4.59 (dd,1H, CHC(O)N), 3.77 (s,
3H, OCH3), 3.74-3.69 (dd,1H, CHaHb), 3.24-2.98 (m, 1H,
CHaHb); 13C-NMR: 169.1, 146.3, 142.3, 137.1, 136.9, 132.7,
127.0, 125.7, 125.6, 122.7, 119.6, 118.7, 111.9, 106.9,
53.2(C3), 51.8, 22.1; Analysis calcd for C18H17N3O2 C, H, N.
Methyl (1R, 3R)-1-(3,4-dimethoxyphenyl)- 2, 3, 4, 9-tetra-
hydro-1H-ꢀ-carboline-3-carboxylate (V)
Orange powder (23 %); m.p.: 174-176 °C; Rf = 0.73
(CH2Cl2/CH3OH 95:5); MS (EI): m/z 366 (M+; 100%); IR
(cm-1): 3341, 1727; 1H-NMR(CDCl3): 8.86 (brs, 1H, NH),
7.57-7.53 (d, 1H, Ar), 7.25-7.22 (d, 1H, Ar), 6.19-6.92 (m,
5H, Ar), 5.21(s, 1H, CHPh), 4.03-3.96 (dd, 1H, CHCOO-
CH3), 3.89 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.81 (s, 3H,
OCH3), 3.74-3.73 (dd, 1H, CHaHb), 3.27-3.03 (m, 1H,
CHaHb); Analysis calcd for C21H22N2O4 C, H, N.
Methyl (1R, 3R)-1-(pyridin-3-yl)- 2, 3, 4, 9-tetrahydro-
1H-ꢀ-carboline-3-carboxylate (I)
Orange powder (28%); m.p.: 224-227; °C; Rf = 0.78
(CH2Cl2/CH3OH 90:10); MS (EI): m/z 307 (M+;100%); IR
1
(cm-1): 3332, 1708; H-NMR (DMSO): 9.21 (brs,1H, NH),
8.97-8.93 (d,1H, Ar), 8.64 (s,1H, Ar), 7.76-7.74 (d,1H, Ar),
7.53-7.46 (dd,1H, Ar), 7.26-7.24 (d,1H, Ar), 7.11-6.99
(m,3H, Ar), 5.64 (s,1H,CHPh), 4.48-4.37 (m,1H,CHC(O)N),
3.79 (s, 3H, OCH3), 3.74-3.69 (dd, 1H, CHaHb),3.13-3.08
(m, 1H, CHaHb); 13C-NMR: 171.1, 151.0, 150.5, 137.8,
137.6, 137.0, 137.2, 126.2, 124.1, 122.1, 119.4, 118.4, 111.8,
107.3, 56.0 (C1), 55.8 (C3), 52.9, 22.4; Analysis calcd for
C18H17N3O2 C, H, N.
Methyl (1S, 3R)-1-(3,4-dimethoxphenyl)-2, 3, 4, 9-tetra-
hydro-1H-ꢀ –carboline-3-carboxylate (VI)
Yellow powder (14 %); m.p. : 163-165 °C; Rf = 0.54
(CH2Cl2/CH3OH 95:5); MS (EI): m/z 366 (M+; 100%); IR
1
(cm-1): 3366, 1724; H-NMR ( CDCl3): 7.66 (s, 1H, NH),

382 Medicinal Chemistry, 2010, Vol. 6, No. 6
Ahmed et al.
7.59-7.54 (d, 1H, Ar), 7.25-7.24 (d, 1H, Ar), 7.21-6.82 (m,
5H, Ar), 5.43 (s, 1H, CHPh), 3.92-3.90 (d, 1H, CHCOO-
CH3), 3.86 (s, 3H, OCH3), 3.83 (s, 3H, OCH3),3.74 (s, 3H,
OCH3), 3.72-3.71 (d, 1H, CHaHb), 3.33-3.32 (dd, 1H,
CHaHb); Analysis calcd for C21H22N2O4 C, H, N.
1H, Ar), 7.35-7.33 (d, 1H, Ar), 7.30-7.14 (m, 4H, Ar), 6.39
(s, 1H, CHPh), 4.29-4.23 (dd, 1H, CHC(O)N), 3.64-3.57 (q,
2H, NCH2), 3.55-3.48 (dd, 1H, CHaCHb), 2.95-2.88 (m, 1H,
CHaHb), 1.14- 1.09 (t, 3H, CH3).13C-NMR : 172.3, 158.4,
148.9, 136.3, 129.1, 122.9, 119.9, 118.3, 111.4, 108.1,
115.6,114.3,113.0,107.8, 106.4, 53.2 (C5), 49.7 (C11a),
35.2, 23.3,13; Analysis calcd for C20H18N4O2 C, H, N.
Methyl (1S, 3S)-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahy-
dro-1H-ꢀ –carboline-3-carboxylate (VII)
(5S,11aS)- 2-ethyl -5-(pyridin-3-yl)-5,6,11,11a-tetrahydro-
1H imidazo[1’,5’:1,6]pyrido[3,4-b]indole-1,3(2H)-dione (XI)
Orange powder (28%); m.p.: 174-177 °C; Rf = 0.71
(CH2Cl2/CH3OH 95:5); MS (EI): m/z 366 (M+; 100%); IR
1
(cm-1): 3341, 1727; H-NMR (CDCl3): 8.87 (s, 1H, NH),
Yellow powder (54%); m.p.: 212-214 °C; Rf =0.36
(CH2Cl2/MeOH 95:5); MS (EI): m/z 346 (M+ 100%); IR (cm-
7.57- 7.53 (d, 1H, Ar), 7.25- 7.23 (d, 1H, Ar), 7.18-6.83 (m,
5H, Ar), 5.30 (brs, 1H, CHPh), 4.06-3.96 (dd, 1H, CHCOO-
CH3), 3.88 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.78 (s, 3H,
OCH3), 3.72-3.69 (d, 1H, CHaHb), 3.29-3.08 (m, 1H,
CHaHb); Analysis calcd for C21H22N2O4 C, H, N.
;
1
1): 3318,1737,1679; H-NMR (DMSO): 10.75 (s, 1H, NH),
8.97 (s, 1H, Ar), 8.82-8.89(d, 1H, Ar),8.83-8.81(dd, 1H, Ar),
8.78-8.76 (d, 1H, Ar), 7.81-6.98 (m, 4H, Ar), 5.65 (brs, 1H,
CHPh), 4.57-4.52 (dd, 1H, CHC(O)N), 3.41-3.37 (m, 2H,
NCH2), 3.03-2.96 (dd, 1H, CHaCHb), 2.51-2.48 (m, 1H,
CHaHb), 1.11-1.07 (t, 3H, CH3); 13C-NMR : 171.1,157.7,
148.7,148.2,136.7, 135.9, 133.6,125.6,123.2,121.4,120.5,
118.7,118.1, 111.1, 105.1,57.3 (C5), 53.3 (C11a), 33.8,
15.4,12.9; Analysis calcd for C20H18N4O2 C, H, N.
Methyl (1R,3S)-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahy-
dro-1H-ꢀ –carboline-3-carboxylate (VIII)
Yellow powder (12 %); m.p.: 164-167 °C ; Rf= 0.53
(CH2Cl2/CH3OH 95:5) ; MS (EI): m/z 366 (M+; 100%); IR
1
(cm-1) : 3366 (-NH-), 1724 (C=O); H-NMR (CDCl3) :7.69
(brs, 1H, NH), 7.57-7.55 (d, 1H, Ar), 7.27-7.24 (d, 1H,
Ar),7.19-7.11(m, 4H, Ar), 6.81(s, 1H, Ar),5.40 (brs, 1H,
CHPh), 4.06- 4.02 (dd, 1H, CHCOOCH3), 3.85 (s, 3H, O-
CH3), 3.81 (s, 3H, OCH3),3.74 (s, 3H, OCH3), 3.35-3.28
(dd,1H,CHaHb), 3.22-3.15 (dd, 1H, CHaHb); Analysis calcd
for C21H22N2O4 C, H, N.
(5R,11aS)- 2-ethyl -5-(pyridin-3-yl)-5,6,11,11a-tetrahydro1-
H-imidazo[1’,5’:1,6]pyrido[3,4-b]indole-1,3(2H)-dione (XII)
Yellow powder (20%); m.p.: 246-249 °C; Rf = 0.45
(CH2Cl2/MeOH 95:5); MS (EI): m/z 346 (M+ 100%); IR
;
1
(cm-1): 3364, 1762, 1703 ; H-NMR (DMSO): 10.25 (s, 1H,
NH), 8.45 (s, 1H, Ar), 8.22- 8.27 (d, 1H, Ar),7.17-7.09
(d,1H, Ar), 7.42-7.30 (m, 1H, Ar), 6.73-6.61 (m, 4H, Ar),
5.93 (brs, 1H, CHPh), 3.92-3.86 (dd, 1H, CHC(O)N), 3.70-
3.63 (q, 2H, NCH2), 2.99-2.82 (dd, 1H, CHaCHb), 2.35-2.11
(m, 1H, CHaHb), 1.02-0.75 (t, 3H, CH3); 13C-NMR (DMSO)
: 172.1, 167.2, 154.4, 149.3, 136.8, 135.5, 135.3, 135.4,
129.5 ,125.6, 123.6, 121.9, 117.8, 111.4, 106.8, 52.8 (C5),
49.5 (C11a), 33.3, 22.8, 13.2; Analysis calcd for C20H18N4O2
C, H, N.
General procedures for the preparation of 2-Alkyl-5-
(pyridin-3-yl)-5,6,11,11a-tetrahydro-1H imidazo[1’,5’:1,6]
pyrido[3,4-b]indole-1,3(2H)-dione
The appropriate isocyanate (1.6 mmol) was added to a
well stirred solution of the appropriate beta carboline I - IV
(0.31 g, 1 mmol) in methyl ethyl ketone (10 ml) and the mix-
ture was stirred at reflux for 16 hours under nitrogen atmos-
phere. The product was purified using by column chromatog-
raphy on silica gel eluting with CH2Cl2:CH3OH (99:1).
(5R,11aR)- 2-tert-butyl -5-(pyridin-3-yl)-5,6,11,11a-tetra-
hydro-1H imidazo[1’,5’:1,6]pyrido[3,4-b] indole-1,3(2H)-
dione (XIII)
(5R,11aR)- 2-ethyl -5-(pyridin-3-yl)-5,6,11,11a-tetrahydro-
1H imidazo[1’,5’:1,6]pyrido[3,4-b]indole-1,3(2H)-dione(IX)
White powder (50%); m.p.: 275-278 °C; Rf = 0.42
(CH2Cl2/MeOH 95:5); MS (EI): m/z 374 (M+), m/z 317
(100%); IR (cm-1): 3180, 1762,1708; 1H-NMR (DMSO):
9.93 (brs, 1H, NH), 8.48 (s, 1H, Ar), 7.84- 7.81 (d, 1H, Ar),
7.56-51 (m, 1H, Ar), 7.35-7.39 (m, 1H, Ar), 7.34-7.13 (m,
4H, Ar), 6.05 (s, 1H, CHPh), 3.76-3.73 (dd, 1H, CHC(O)N),
3.39-3.34 (dd, 1H, CHaCHb), 2.95-2.86 (m, 1H, CHaHb),
1.58 (s, 9H, CH3); Analysis calcd for C22H22N4O2 C, H, N.
Yellow powder (70%); m.p.: 210-212 °C ; Rf = 0.34
(CH2Cl2/MeOH 95:5); MS (EI): m/z 346 (M+ 100%); IR (cm-
;
1
1): 3153, 1767, 1692 ; H-NMR (DMSO): 11.74 (brs, 1H,
NH), 9.89-9.31 (d, 1H, Ar), 8.94 (s, 1H, Ar), 8.49-8.36 (dd,
1H, Ar), 8.32-8.23 (dd, 1H, Ar), 7.62-7.15 (m, 4H, Ar), 5.92
(brs, 1H, CHPh), 4.38-4.33 (dd, 1H, CHC(O)N), 3.58-3.48
(q, 2H, NCH2), 3.21-3.18 (m, 1H, CHaCHb), 3.11-3.01 (m,
1H, CHaHb), 1.23-1.17 (t, 3H,CH3); 13C-NMR : 171.2, 166.5,
154.9, 148.8, 141.8, 137.8, 135.8, 134.7, 132.5, 130.5, 125.9,
124.1, 121.8, 120.1, 112.4, 107.1, 57.9 (C5), 54.1 (C11a),
35.4, 22.5, 13.4. Analysis calcd for C20H18N4O2 C, H, N.
(5S,11aR)- 2-tert-butyl -5-(pyridin-3-yl)-5,6,11,11a-tetra-
hydro-1H-imidazo[1’,5’:1,6]pyrido[3,4-b]indole-1,3(2H)-
dione (XIV)
(5S,11aR)- 2-ethyl -5-(pyridin-3-yl)-5,6,11,11a-tetrahydro-
1H-imidazo[1’,5’:1,6]pyrido[3,4-b]indole-1,3(2H)-dione (X)
Yellow powder (40%); m.p.: 240-242 °C; Rf = 0.58
(CH2Cl2/MeOH 95:5); MS (EI): m/z 374 (M+), m/z 318
(100%); IR (cm-1): 3324, 1761,1726; 1H-NMR (DMSO):
8.75 (brs, 1H, NH), 8.53 (s, 1H, Ar), 7.83- 7.81 (d, 1H, Ar),
7.48-7.38 (m, 1H, Ar), 7.33-7.30 (m, 1H, Ar), 7.26-7.17 (m,
4H, Ar), 6.35 (s, 1H, CHPh), 4.10-4.04 (dd, 1H, CHC(O)N),
Yellowish white powder (40%); m.p.: 248-252 °C , Rf =
0.43 (CH2Cl2/MeOH 95:5); MS (EI): m/z 346 (M+ 100%); IR
;
1
(cm-1): 3333,1760,1620 ; H-NMR ( DMSO): 9.43 (s, 1H,
NH), 8.62 (s, 1H, Ar), 8.52-8.51 (d, 1H, Ar), 7.69-7.55 (dd,

A Novel Access to Arylated and Heteroarylated Beta-Carboline
Medicinal Chemistry, 2010, Vol. 6, No. 6 383
3.47-3.40 (dd, 1H, CHaCHb), 2.88-2.75 (m, 1H, CHaHb),
1.63 (s, 9H, CH3); Analysis calcd for C22H22N4O2 C, H, N.
Ar), 7.43-7.02 (m, 7H, Ar), 6.38 (brs, 1H, CHPh), 4.87-4.81
(dd, 1H, CHC(O)N), 3.48-3.40 (dd, 1H, CHaCHb), 3.12-3.04
(m, 1H, CHaHb); Analysis calcd for C24H17ClN4O2 C, H, N.
(5S,11aS)- 2-tert-butyl -5-(pyridin-3-yl)-5,6,11,11a-tetra-
hydro-1H-imidazo[1’,5’:1,6] pyrido[3,4-b]indole-1,3(2H)-
dione (XV )
(5S,11aS)- 4-chlorophenyl -5-(pyridin-3-yl)-5,6,11,11a-
tetrahydro-1H imidazo[1’,5’:1,6] pyrido [3,4-b]indole-
1,3(2H)-dione (XIX)
White powder (64%); m.p.: 279-282 °C; Rf = 0.42
(CH2Cl2/MeOH 95:5); MS (EI): m/z 374 (M+), m/z 318
(100%); IR (cm-1): 3057, 1762,1692; 1H-NMR (DMSO):
10.79 (brs, 1H, NH), 8.62 (s, 1H, Ar), 8.46-8.44 (d, 1H, Ar),
7.64-7.61 (d, 1H, Ar), 7.56-7.54 (d, 1H, Ar), 7.31-7.27 (dd,
1H, Ar),7.23-7.21 (d, 1H, Ar),7.07-6.97 (m, 2H, Ar), 5.89 (s,
1H, CHPh), 4.44-4.39 (dd, 1H, CHC(O)N), 3.04-2.95 (m,
1H, CHaCHb), 2.51-2.49 (m, 1H, CHaHb), 1.50 (s, 9H, CH3);
Analysis calcd for C22H22N4O2 C, H, N.
Yellow crystals (64%); m.p.: 262-265 °C; Rf = 0.68
(CH2Cl2/MeOH 95:5); MS (EI): m/z 431 (M++2), m/z 429
1
(M+;100%); IR (cm-1): 3430,1776,1716; H-NMR (DMSO):
10.86 (brs, 1H, NH), 8.71 (s, 1H, Ar), 8.47-8.45 (d, 1H, Ar),
7.78-7.79 (d, 1H, Ar), 7.60-7.53 (dd, 1H, Ar),7.43-7.40 (d,
2H, Ar), 7.35-6.99 (m, 6H, Ar), 6.03 (s,1H,CHPh), 4.77-4.72
(dd, 1H, CHC(O)N), 3.44-3.36 (dd, 1H, CHaCHb), 3.27-3.23
(m, 1H, CHaHb); Analysis calcd for C24H17ClN4O2 C, H, N.
(5R,11aS)- 4-chlorophenyl -5-(pyridin-3-yl)-5,6,11,11a-
tetrahydro-1H-imidazo[1’,5’:1,6]pyrido[3,4-b]indole-
1,3(2H)-dione (XX)
(5R,11aS)- 2-tert-butyl -5-(pyridin-3-yl)-5,6,11,11a-tetra-
hydro-1H-imidazo[1’,5’:1,6]pyrido[3,4-b]indole-1,3(2H)-
dione (XVI)
Yellow powder (50%); m.p.: 228-232 °C; Rf =0.74 (CH2
Cl2/MeOH 95:5); MS (EI): m/z 431 (M++2), m/z 429 (M+;
100%); IR (cm-1): 3405, 1776, 1716 ; 1H-NMR ( DMSO): 8.68
(brs, 1H, NH), 8.62 (s, 1H, Ar), 8.54-8.52 (d, 1H, Ar), 7.72-
7.59 (dd, 1H, Ar), 7.42-7.19 (m, 5H, Ar), 7.25-7.24 (d, 2H,
Ar), 7.22-7.21 (d, 2H, Ar), 6.43 (s, 1H, CHPh), 4.47-4.42
(dd, 1H, CHC(O)N), 3.65-3.58 (dd, 1H, CHaCHb), 3.11-3.02
(m, 1H, CHaHb); Analysis calcd for C24H17ClN4O2 C, H, N.
Yellow powder (57%); m.p.: 240-242 °C; Rf = 0.6
(CH2Cl2/MeOH 95:5); MS (EI): m/z 374 (M+), m/z 318
(100%); IR (cm-1): 3320,1762,1703; NMR (DMSO): 8.72
(s,1H, NH), 8.54 (s, 1H, Ar), 7.80- 7.77 (d, 1H, Ar), 7.58-
7.56 (d, 1H, Ar), 7.39-7.35 (dd, 1H, Ar), 7.31-7.19 (m, 4H,
Ar), 6.34 (s, 1H, CHPh), 4.12-4.06 (dd, 1H, CHC(O)N),
3.48-3.41 (dd, 1H, CHaCHb), 2.89-2.81 (m, 1H, CHaHb),1.63
(s, 9H, CH3); Analysis calcd for C22H22N4O2 C, H, N.
General procedures for the preparation of Ethyl-5-(3,4
dimethoxyphenyl)-5,6,11,11a-tetrahydro-1H-imidazo[1’,5’:
1,6]pyrido[3,4-b]indole-1,3(2H)-dione
General procedures for the preparation of 4-Chloro-
phenyl-5-(3-pyridinyl)-5,6,11,11a-tetrahydro-1H-imidazo
[1’,5’:1,6]pyrido[3,4-b]indole-1,3(2H)-dione
Excess ethyl isocyanate (135 ꢀl, 1.6 mmol) was added to
a well stirred solution of the appropriate beta carboline V-
VIII (0.36 g, 1 mmol) in methyl ethyl ketone (10 ml) and the
mixture was stirred at reflux for 16 hours under nitrogen
atmosphere. The product was purified using by column
chromatography on silica gel eluting with CH2Cl2.
4-chlorophenyl isocyanate (0.153 g, 1 mmol, 1 equiv.)
was added to a well stirred solution of the appropriate beta
carboline I-IV (0.31 g, 1 mmol, 1 equiv.) in methyl ethyl
ketone (10 ml) and the mixture was stirred at reflux for 16
hours under nitrogen atmosphere. The product was purified
using by column chromatography on silica gel eluting with
CH2Cl2:CH3OH (99:1).
(5R,11aR)- 2-ethyl -5-(3,4 dimethoxyphenyl)-5,6,11,11a-
tetrahydro-1H-imidazo[1’,5’:1,6]pyrido[3,4-b]indole-1,3
(2H)-dione (XXI)
(5R,11aR)- 4-chlorophenyl -5-(pyridin-3-yl)-5,6,11,11a-
tetrahydro-1H-imidazo[1’,5’:1,6]pyrido[3,4-b]indole-1,3
(2H)-dione (XVII )
Buff powder (54%); m.p.: 222-225 °C; Rf = 0.43
(CH2Cl2/MeOH 99:1); MS (EI): m/z 405 (M+), m/z 374
Yellow crystals (54%); m.p.: 264-268 °C; Rf = 0.66
(CH2Cl2/MeOH 95:5); MS (FAB): m/z 431 (M++2), m/z 429
(M+;100%); IR (cm-1): 3292, 1772, 1709; 1H-NMR (DMSO):
10.26 (s, 1H, NH), 9.41 (s, 1H, Ar), 8.86-8.77 (d, 1H, Ar),
8.63-8.37 (d, 1H, Ar), 7.56-7.86 (d, 1H, Ar), 7.63-7.06 (m,
8H, Ar), 6.31 (s, 1H, CHPh), 4.44-4.39 (dd, 1H, CHC(O)N),
3.62-3.48 (m, 1H, CHaCHb), 3.09-2.99 (m, 1H, CHaHb); A-
nalysis calcd for C24H17ClN4O2 C, H, N.
1
(100%); IR (cm-1): 3325, 1767, 1703; H-NMR (CDCl3):
11.06 (brs, 1H, NH), 7.93-7.90 (d, 1H, Ar), 7.63-7.61 (d, 1H,
Ar), 7.46-7.32 (m, 5H, Ar), 6.18 (brs, 1H, CHPh), 4.93-4.86
(dd, 1H, CHC(O)N), 3.85 (s, 3H, OCH3), 3.78 (s, 3H, O-
CH3), 3.58-3.53 (m, 2H, NCH2), 3.51- 3.48 (m, 1H, CHa-
CHb), 3.10-3.01 (m, 1H, CHaHb), 1.49-1.44 (t, 3H, CH3);
13C-NMR: 171.4, 154.3,148.8,148.4,136.9, 135.3, 133.5,
126.2, 121.8, 119.6, 119.1, 118.4, 112.0, 111.8,111.5 ,105.2,
58.1 (C5), 55.8 (C11a), 55.9, 55.8, 33.6, 22.5,13.5; Analysis
calcd for C23H23N3O4 C, H, N.
(5S,11aR)- 4-chlorophenyl -5-(pyridin-3-yl)-5,6,11,11a-
tetrahydro-1H-imidazo[1’,5’:1,6]pyrido[3,4-b]indole-
1,3(2H)-dione (XVIII)
(5S,11aR)- 2-ethyl -5-(3,4 dimethoxyphenyl)-5,6,11,11a-
tetrahydro-imidazo[1’,5’:1,6] pyrido [3,4-b]indole-1,3(2H)-
dione (XXII)
Buff crystals (54%); m.p.:229-231 °C; Rf = 0.72
(CH2Cl2/MeOH 95:5); MS (FAB): m/z 431 (M++2), m/z 429
(M+;100%); IR (cm-1): 3405, 1765, 1698 ; NMR (DMSO) :
10.94 (s, 1H, NH), 8.69 (s, 1H, Ar), 8.58-8.56 (d, 1H, Ar),
7.79-7.77 (d, 1H, Ar), 7.60-7.58 (d, 1H, Ar), 7.55-7.49 (dd, 1H,
White powder (26%); m.p.:178-180 °C; Rf = 0.58
(CH2Cl2/MeOH 99:1); MS (EI): m/z 405 (M+), m/z 374

384 Medicinal Chemistry, 2010, Vol. 6, No. 6
Ahmed et al.
(100%), IR (cm-1): 3338, 1764, 1703; 1H-NMR :11.23
(brs,1H,NH), 7.93-7.91 (d, 1H, Ar), 7.69-7.66 (d, 1H, Ar),
7.50- 7.19 (m, 5H, Ar), 6.53 (brs, 1H, CHPh), 5.03-4.97 (dd,
1H, CHC(O)N), 4.11 (s, 3H, OCH3), 3.76 (s, 3H, OCH3),
3.88-3.79 (q, 2H, NCH2), 3.23-3.13 (m, 1H, CHaCHb), 2.89-
2.86 (m, 1H, CHaHb), 1.49-1.43 (t, 3H, CH3); 13C-NMR: 171.8,
154.3, 148.9, 148.8, 136.7, 132.6, 131.6, 125.8, 121.6, 120.1,
118.8, 118.2, 111.9, 111.6, 111.4, 105.9, 55.6 ( C5 ), 53.0
(C11a), 51.5, 55.8, 32.9, 22.6, 13.3; Analysis calcd for
C23H23N3O4 C, H, N.
CHPh), 4.25-4.22 (dd, 1H, CHC(O)N), 3.99 (s, 3H, OCH3),
3.97 (s, 3H, OCH3), 3.88-3.81 (m, 1H, CHaCHb), 3.05-2.83
(m, 1H, CHaHb),1.64 (s, 9H, CH3); Analysis calcd for
C25H27N3O4 C, H, N.
(5S,11aR)- 2-tert-butyl-5-(3,4 dimethoxyphenyl)-5,6,11,
11a-tetrahydro-1H-imidazo[1’,5’:1,6]pyrido[3,4-b]indole-
1,3(2H)-dione (XXVI )
Yellow powder (65%); m.p.: 125-128 °C; Rf = 0.89
(CH2Cl2/MeOH 99:1) ; MS (EI): m/z 433 (M+), m/z 346
1
(100%); IR (cm-1): 3334,1760,1703; H-NMR(CDCl3): 7.81
(5S,11aS)- 2-ethyl -5-(3,4 dimethoxyphenyl)-5,6,11,11a-
tetrahydro-1H-imidazo[1’,5’:1,6] pyrido[3,4-b] indole-
1,3(2H)-dione (XXIII)
(brs, 1H, NH), 7.58-7.56 (d, 1H, Ar), 7.32- 7.29 (d, 1H, Ar),
7.25-6.96 (m, 5H, Ar), 6.81 (brs, 1H, CHPh), 4.21-4.15 (dd,
1H, CHC(O)N), 3.86 (s, 3H, OCH3), 3.84 (s, 3H, OCH3),
3.51-3.44 (dd, 1H, CHaCHb), 2.90-2.80 (m, 1H, CHaHb),
1.64 (s, 9H, CH3); Analysis calcd for C25H27N3O4 C, H, N.
Golden yellow powder (65%); m.p.: 224-227 °C; Rf =
0.45 (CH2Cl2/MeOH 99:1) ; MS (EI): m/z 405 (M+), m/z,
374 (100%); IR (cm-1): 3326, 1762, 1708 ; 1H-NMR (CDCl3)
: 8.52 (brs, 1H, NH), 7.73-6.75 (m, 7H, Ar), 5.76 (brs, 1H,
CHPh), 4.24-4.21 (dd, 1H, CHC(O)N), 3.85 (s, 3H, OCH3),
3.77 (s, 3H, OCH3), 3.70-3.63 (q, 2H, NCH2), 3.58-3.51 (dd,
1H, CHaCHb), 3.10-3.01 (m, 1H, CHaHb), 1.23-1.19
(t,3H,CH3); 13C-NMR: 171.4,154.6,148.7,148.4,136.9, 35.3,
133.5,131.9,126.2, 119.6, 119.1, 118.4, 112.1,111.8, 111.6,
105.2, 58.1(C5), 55.7(C11a), 55.9, 55.8, 33.6, 22.4,13.4;
Analysis calcd for C23H23N3O4 C, H, N.
(5S,11aS)- 2-tert-butyl-5-(3,4 dimethoxyphenyl)-5,6,1 1,11a-
tetrahydro-1H-imidazo[1’,5’:1,6] pyrido[3,4-b]indole-1,3
(2H)-dione (XXVII)
Golden yellow powder (50%); m.p.: 222-225 °C; Rf =
0.65 (CH2Cl2/MeOH 99:1); MS (EI): m/z 433 (M+ 25%),
;
m/z 362 (100%); IR (cm-1): 332, 1722, 1710 ; 1H-NMR
(CDCl3): 8.86 (brs, 1H, NH), 8.25-8.22 (d, 1H, Ar),7.73-
7.71 (d, 1H, Ar),7.64-7.04 (m, 5H, Ar), 5.78 (brs, 1H, CH-
Ph), 4.25-4.22 (m, 1H, CHC(O)N),3.99 (s, 3H, OCH3), 3.97
(s, 3H, OCH3), 3.88-3.81 (m, 1H, CHaCHb), 3.35-3.27 (m,
1H, CHaHb), 1.57 (s, 9H, CH3); Analysis calcd for
C25H27N3O4 C, H, N.
(5R,11aS)- 2-ethyl -5-(3,4 dimethoxyphenyl)-5,6,11,11a-
tetrahydro-1H-imidazo[1’,5’:1,6]pyrido[3,4-b]indole 1,3
(2H)-dione (XXIV)
Golden yellow powder (50%); m.p.: 179-182 °C; Rf =
0.56 (CH2Cl2/MeOH 99:1); MS (EI): m/z 405 (M+ 100%); IR
(5R,11aS)- 2-tert-butyl-5-(3,4 dimethoxyphenyl)-5,6,1
1,11a-tetrahydro-1H-imidazo[1’,5’:1,6]pyrido[3,4-
b]indole-1,3(2H)-dione (XXVIII)
;
(cm-1): 3339 ,1764,1703 ; 1H-NMR (CDCl3): 10.84 (brs, 1H,
NH), 7.56-7.52 (d, 1H, Ar), 7.31-7.27 (d, 1H, Ar), 7.24- 6.81
(m, 5H, Ar), 6.14 (brs, 1H, CHPh), 4.33-4.27 (dd, 1H,
CHC(O)N), 3.73 (s, 3H, OCH3), 3.71(s, 3H ,OCH3), 3.49-
3.34 (q, 2H, NCH2), 3.01-2.95 (m, 1H, CHaCHb), 2.50-2.48
(dd, 1H, CHaHb),1.13-1.06 (t, 3H, CH3), 13C-NMR: 172.6,
149.5,136.6,131.8,130.6, 126.3,126.2,126.1,122.9,120.4,120.1,
118.4,111.6,111.3,111.2,108.2, 56.1 (C5), 55.9 (C11a), 53.2,
51.8, 33.7, 23.5,13.5; Analysis calcd for C23H23N3O4 C, H, N.
Yellow powder (56%), m.p.:122-125 °C; Rf = 0.90
(CH2Cl2/MeOH 99:1); MS (EI): m/z 433 (M+), m/z 346
1
(100%); IR (cm-1): 3338, 1760, 1734; H-NMR (CDCl3):
7.86 (brs, 1H, NH), 7.58-7.56 (d, 1H, Ar), 7.32- 7.29 (d, 1H,
Ar), 7.25-6.79 (m, 6H, Ar), 6.22 (brs, 1H, CHPh), 4.21-4.15
(dd, 1H, CHC(O)N), 3.87 (s, 3H, OCH3), 3.83 (s, 3H, OCH3),
3.51-3.43 (dd, 1H, CHaCHb), 2.90-2.80 (m, 1H, CHaHb),
1.64 (s, 9H, CH3); Analysis calcd for C25H27N3O4 C, H, N.
General procedures for the preparation of Tert-butyl-5-
(3,4 dimethoxyphenyl)-5,6,11,11a-tetrahydro-1H-imidazo
[1’,5’:1,6]pyrido[3,4-b]indole-1,3(2H)-dione
General procedures for the preparation of 4-Chloro-
phenyl-5-(3,4 dimethoxyphenyl)-5,6,11,11a- tetrahydro-
1H-imidazo [1’,5’:1,6]pyrido[3,4-b]indole-1,3(2H)-dione
Excess tertiary butyl isocyanate (185 ꢀl, 1.6 mmol) was
added to a well stirred solution of the appropriate beta car-
boline V-VIII (0.36 g, 1 mmol) in methyl ethyl ketone (10
ml) and the mixture was stirred at reflux for 16 hours under
nitrogen atmosphere. The product was purified using column
chromatography on silica gel eluting with CH2Cl2.
4-chlorophenyl isocyanate (0.153 g,1 mmol, 1 equiv.)
was added to a well stirred solution of the appropriate beta
carboline V,VI,VII,VIII (0.36 g, 1 mmol) in methyl ethyl
ketone (10 ml) and the mixture was stirred at reflux for 16
hours under nitrogen atmosphere. The product was purified
using column chromatography on silica gel eluting with
CH2Cl2.
(5R,11aR)- 2-tert-butyl-5-(3,4 dimethoxyphenyl)-5,6,1 1,11a-
tetrahydro-1H Imidazo[1’,5’:1,6] pyrido [3,4-b]indole-1,3
(2H)-dione (XXV)
(5R,11aR)- 4-chlorophenyl-5-(3,4 dimethoxyphenyl)-5,6,
11,11a-tetrahydro-1H-imidazo[1’,5’:1,6]pyrido[3,4-b]indole-
1,3(2H)-dione (XXIX )
Buff powder (54%); m.p. 220-223 °C; Rf = 0.67
(CH2Cl2/MeOH 99:1); MS (EI): m/z 433 (M+), m/z 346
1
(100%); IR (cm-1): 3405, 1765, 1698; H-NMR (CDCl3):
Yellow powder (54%); m.p.: 292-295 °C; Rf = 0.71
(CH2Cl2/MeOH 99:1); MS (EI): m/z 489 (M++2), m/z 487
(M+;100%); IR (cm-1): 3334, 1750, 1721 ; 1H-NMR (CDCl3)
7.89 (brs, 1H, NH), 7.58-7.56 (d, 1H, Ar), 7.32- 7.29 (d, 1H,
Ar), 6.95 (s, 1H, Ar), 6.92-6.71 (m, 4H, Ar), 6.23 (brs, 1H,

A Novel Access to Arylated and Heteroarylated Beta-Carboline
Medicinal Chemistry, 2010, Vol. 6, No. 6 385
1
(M+; 100%); IR (cm -1): 3334, 1737, 1658 ; H-NMR (CD-
:7.94 (s, 1H, Ar), 7.63-7.60 (d, 1H, Ar), 7.43-7.39 (d, 2H,
Ar), 7.24-6.89 (m, 8H, Ar), 6.36 (brs, 1H, CHPh), 4.58-4.47
(m, 1H, CHC(O)N), 3.85 (s, 3H, OCH3),3.79 (s, 3H, OCH3),
3.64-3.58 (dd, 1H, CHaCHb), 3.24-3.02 (m, 1H, CHaHb),
Analysis calcd for C27H22ClN3O4 C, H, N.
Cl3): 7.81 (brs, 1H, NH), 7.63-7.61 (d, 1H, Ar ), 7.32-7.29 (d,
1H, Ar), 7.22-7.20 (d, 1H, Ar), 7.18-6.72 (m, 4H, Ar), 5.31
(s, 1H, CHPh), 4.24-4.20 (d, 1H, CHCOOCH3), 3.99- 3.95
(d, 2H, COCH2Cl), 3.84 (s, 3H, OCH3), 3.78 (s, 3H, OCH3),
3.73 (s, 3H, OCH3), 3.67-3.60 (m, 1H, CHaCHb), 3.62 -3.14
(dd, 1H, CHaHb); Analysis calcd for C23H23ClN2O5 C, H, N.
(5S,11aR)- 4-chlorophenyl-5-(3,4 dimethoxyphenyl)-5,6,
11,11a-tetrahydro-1H-imidazo[1’,5’:1,6]pyrido[3,4-b]indole-
1,3(2H)-dione (XXX)
Methyl (1S, 3R)-1-(3,4- dimethoxyphenyl)-2-(chloroacetyl)-
2, 3, 4, 9-tetrahydro-1H-ꢀ-carboline-3-carboxylate (XXXIV)
Yellowish green powder (54%); m.p.: 270-272 °C; Rf =
0.89 (CH2Cl2/MeOH 99:1); MS (EI): m/z 489 (M++2), m/z
Yellow powder (90%); m.p.: 145-147 °C; Rf = 0.61
(CH2Cl2/MeOH 98:2); MS (EI): m/z 445 (M++2), m/z 443
(M+; 100%); IR (cm -1): 3339, 1740, 1660; 1H-NMR (CDCl3):
7.78 (brs, 1H, NH),7.54-7.52 (d, 1H, Ar),7.24-6.82 (m, 6H, Ar),
6.09 (s, 1H, CHPh), 4.15-4.10 (d, 1H, CHCOOCH3), 3.95- 3.92
(d, 2H, COCH2Cl), 3.83 (s, 3H, OCH3), 3.72 (s, 3H, OCH3),
3.64 (s, 3H, OCH3),3.34-3.32 (m, 1H, CHaCHb), 2.36-2.34
(m, 1H, CHaHb); Analysis calcd for C23H23ClN2O5 C, H, N.
1
487 (M+; 100%); IR (cm -1): 3341, 1772, 1710; H-NMR
(CDCl3): 7.95 (brs, 1H, NH), 7.63-7.60 (d, 2H, Ar), 7.35-
7.33 (d, 2H, Ar), 7.24-7.02 (d, 7H, Ar), 6.81 (brs, 1H, CH-
Ph), 4.52-4.46 (dd, 1H, CHC(O)N), 3.87 (s, 3H, OCH3), 3.84
(s, 3H, OCH3), 3.65-3.58 (dd, 1H, CHaCHb), 3.10-3.01 (m,
1H, CHaHb); Analysis calcd for C27H22ClN3O4 C, H, N.
(5S,11aS)- 4-chlorophenyl-5-(3,4 dimethoxyphenyl)-5,6,
11,11a-tetrahydro-1H-imidazo[1’,5’:1,6]pyrido[3,4-b]indole-
1,3(2H)-dione (XXXI)
Methyl (1S, 3S)-1-(3,4- dimethoxyphenyl)-2-(chloroacetyl)-
2, 3, 4, 9-tetrahydro-1H-ꢀ-carboline-3-carboxylate (XXXV)
Yellow powder (54%); m.p.: 295-298 °C; Rf = 0.70
(CH2Cl2/MeOH 99:1); MS (EI): m/z 489 (M++2), m/z 487
Orange powder (97%); m.p.:178-181 °C; Rf = 0.72
(CH2Cl2/MeOH 98:2); MS (EI): m/z 445 (M++2), m/z 443
(M+; 100%); IR (cm -1): 3345, 1737, 1657; 1H-NMR (CDCl3)
:7.81 (brs, 1H, NH),7.63-7.60 (d, 1H, Ar ),7.56-6.73 (m, 6H,
Ar),5.31 (s, 1H, CHPh), 4.24-4.20 (d, 1H, CHCOOCH3),
3.99- 3.96 (d, 2H, COCH2Cl), 3.92 (s, 3H, OCH3), 3.80 (s,
3H, OCH3), 3.78 (s, 3H, OCH3), 3.75-3.60 (m, 1H, CHaCHb),
3.26-3.18 (m,1H,CHaHb); Analysis calcd for C23H23ClN2O5
C, H, N.
1
(M+; 100%); IR (cm -1): 3285 ,1710, 1624 ; H-NMR (CD-
Cl3): 8.82 (brs, 1H, NH), 8.24-8.21 (d, 2H, Ar), 7.74-7.71(d,
2H, Ar), 7.64-7.20 (m, 7H, Ar), 6.93 (brs, 1H, CHPh), 4.24-
4.21 (dd, 1H, CHC(O)N), 3.93 (s, 3H, OCH3), 3.89 (s, 3H,
OCH3), 3.77-3.62 (m, 1H, CHaCHb), 3.49-3.45 (m, 1H,
CHaHb); Analysis calcd for C27H22ClN3O4 C, H, N.
(5R,11aS)- 4-chlorophenyl-5-(3,4 dimethoxyphenyl)-5,6,
11,11a-tetrahydro-1H-imidazo[1’,5’:1,6]pyrido[3,4-b]indole-
1,3(2H)-dione (XXXII)
Methyl (1R, 3S)-1-(3,4- dimethoxyphenyl)-2-(chloroacetyl)-
2, 3, 4, 9-tetrahydro-1H-ꢀ-carboline-3-carboxylate (XXXVI)
White powder (55%); m.p.:269-272 °C; Rf = 0.90
(CH2Cl2/MeOH 99:1); MS (EI): m/z 489 (M++2), m/z 487
Golden yellow powder (94%); m.p.: 142-145 °C; Rf =
0.62 (CH2Cl2/MeOH 98:2); MS (EI): m/z 445 (M++2), m/z
1
(M+; 100%); IR (cm -1): 3288, 1710, 1628 , H-NMR (CD-
1
443 (M+; 100%); IR (cm -1) 3339, 1738, 1659, H-NMR
Cl3) : 8.01 (brs, 1H, NH), 7.65-7.63 (d, 2H, Ar),7.38-7.35 (d,
2H, Ar), 7.22-7.02 (d, 7H, Ar), 6.79 (brs,1H, CHPh), 4.52-
4.48 (dd, 1H, CHC(O)N), 3.88 (s, 3H, OCH3), 3.84 (s, 3H,
OCH3), 3.69-3.60 (dd, 1H, CHaCHb), 3.10-3.01 (m, 1H,
CHaHb); Analysis calcd for C27H22ClN3O4 C, H, N.
(CDCl3): 7.68 (brs, 1H, NH), 7.55-7.53 (d, 1H, Ar), 7.24-
6.81 (m, 6H, Ar), 6.12 (s, 1H, CHPh), 4.15-4.10 (d, 1H,
CHCOOCH3), 3.96- 3.88 (d, 2H, COCH2Cl), 3.84 (s, 3H,
OCH3), 3.74 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 3.63-3.59
(m, 1H, CHaCHb), 3.33-3.28 (m, 1H, CHaHb); Analysis calcd
for C23H23ClN2O5 C, H, N.
General Procedures for the Preparation of Methyl -1-
(3,4-dimethoxyphenyl)-2-(chloroacetyl)-2,3,4,9-tetrahydro-
1H-ß-carboline-3-carboxylate
General procedures for the preparation of 2-ethyl-6-(3,4
dimethoxyphenyl)-2,3,6,7,12,12a-hexahydropyrazino [1’,
2’:1,6] pyrido[3,4-b]indole-1,4-dione
To a well stirred solution of of the appropriate ß-carboline
V-VIII (2.08 g, 5.7 mmol) and NaHCO3 (0.575 g, 6.89 mmol)
in CHCl3 (40 ml) was added dropwise chloroacetylchloride
(1.1 ml, 13.69 mmol) at 0°C. The mixture was then stirred
under N2 for 1 hr. The mixture was then diluted with CH2Cl2
washed with a solution of NaHCO3, dried over anhydrous Na
2SO4. The residue was then crystallized from diethyl ether.
A solution of the appropriate chloroacetyl derivative
XXXIII-XXXVI (0.62 g, 1.4 mmol, 1 equiv) and the ethyl
amine (2.8 mmol, 2 equiv) in methanol (25 mL) was heated
to reflux under a nitrogen atmosphere for 16 h. The reaction
mixture was cooled to room temperature and evaporated to
dryness under reduced pressure. The residue was dissolved
in CH2Cl2, and the organic layer was washed with water,
dried over Na2SO4, filtered, and concentrated to dryness. The
crude product was then purified using column chromatogra-
phy eluting with CH2Cl2: CH3OH (99.5:0.5). The product
was crystallized from ethanol.
Methyl (1R, 3R)-1-(3,4- dimethoxyphenyl)-2-(chloroacetyl)-
2, 3, 4, 9-tetrahydro-1H-ꢀ-carboline-3-carboxylate (XXXIII)
Yellow powder (92%); m.p.: 179-182 °C; Rf = 0.73
(CH2Cl2/MeOH 98:2); MS (EI): m/z 445 (M++2), m/z 443

386 Medicinal Chemistry, 2010, Vol. 6, No. 6
Ahmed et al.
(6R,12aR) -2- Ethyl-6-(3,4-dimethoxyphenyl)-2,3,6,7,12,12a
hexahydropyrazino[1’,2’:1,6] pyrido[3,4-b]indole-1,4-dione
(XXXVII)
General procedures for the preparation of 2-tert- butyl-6-
(3,4-dimethoxyphenyl)-2,3,6,7,12,12a-hexahydropyrazino
[1’,2’:1,6] pyrido[3,4-b]indole-1,4-dione
A solution of the of the appropriate chloroacetyl deriva-
tive XXXIII-XXXVI (0.62 g,1.4 mmol, 1 equiv) and tertiary
butylamine (2.8 mmol, 2 equiv) in methanol (25 mL) was
heated to reflux under a nitrogen atmosphere for 16 h. The
reaction mixture was cooled to room temperature and evapo-
rated to dryness under reduced pressure. The residue was
dissolved in CH2Cl2, and the organic layer was washed with
water, dried over Na2SO4, filtered, and concentrated to dry-
ness. The crude product was then purified using column
chromatography eluting with CH2Cl2: CH3OH (99:1). The
product was crystallized from ethanol.
Yellow powder (15%), m.p.: 262-265 °C; Rf = 0.75
(CH2Cl2/MeOH 95:5); MS (EI): m/z 419 (M+; 100%); IR
1
(cm -1): 3205, 1666, 1641; H-NMR (CDCl3): 7.88 (brs, 1H,
NH), 7.64-7.62 (d, 1H, Ar), 7.54- 7.44 (d, 1H, Ar), 6.98-6.88 (d,
1H, Ar) ,7.19- 6.72 (m, 4H, Ar), 6.23 (s, 1H, CHPh), 4.33-
4.27 (dd, 1H, CHC(O)N), 4.14-4.08 (d, 1H, CHaHbC(O)N),
3.96-3.91 (d, 1H, CHaHbC(O)N), 3.79 (s, 3H, OCH3), 3.78
(s, 3H, OCH3), 3.73-3.66 (q, 2H, NCH2), 3.41-3.35 (dd, 1H,
CHaCHb), 3.29-3.19 (dd, 1H, CHaHb),1.22-1.18 (t, 3H, CH3);
Analysis calcd for C24H25N3O4 C, H, N.
(6S,12aR) -2- Ethyl-6-(3,4-dimethoxyphenyl) 2,3,6,7,12,12a
hexahydropyrazino[1’,2’:1,6] pyrido[3,4-b]indole-1,4-dione
(XXXVIII)
(6R,12aR) -2- tert-butyl-6-(3,4-dimethoxyphenyl)-2,3,6,7,12,
12ahexahydropyrazino[1’,2’:1,6] pyrido[3,4-b]indole-1,4-
dione (XLI)
Yellow powder (10%); m.p.: 220-223 °C; Rf = 0.79
Buff powder (14%); m.p.:190-192 °C; Rf
= 0.4
(CH2Cl2/MeOH 95:5); MS (EI): m/z 419 (M+ 100%); IR (cm
(CH2Cl2/MeOH 92:8); MS (EI): m/z 447 (M+), m/z 248
(100%); IR (cm -1): 3260, 1658,1649; 1H-NMR (CDCl3):
7.76 (brs,1H,NH),7.62-7.59 (d,1H,Ar), 7.54- 7.51 (d,1H, Ar),
7.23-7.15 (dd,1H,Ar), 6.93-6.85 (d,1H, Ar), 6.82-6.73 (m, 3H,
Ar), 6.67 (s,1H,CHPh), 4.90-4.88 (d,1H,CHC(O)N), 4.37-4.31
(d,1H,CHaHbC(O)N), 3.99-3.95 (d,1H,CHaHbC(O)N), 3.82
(s, 3H, OCH3), 3.77 (s,3H,OCH3), 3.71-3.60 (m,1H,CHaCHb),
3.47-3.37 (dd,1H, CHaHb), 1.31 (s, 9H, CH3); Analysis calcd
for C26H29N3O4 C, H, N.
;
1
-1): 3205 ,1668,1641; H-NMR (CDCl3): 7.85 (brs,1H, NH),
7.58-7.54 (d,1H, Ar), 7.25- 6.99 (m, 6H, Ar), 6.74 (brs, 1H,
CHPh), 4.39-4.37 (dd, 1H, CHC(O)N), 4.18-4.13 (d, 1H,
CHaC(O)N), 4.04-3.99 (d, 1H, CHbC(O)N), 3.86 (s, 3H,
OCH3),3.84 (s, 3H, OCH3),3.61-3.56 (q, 2H, NCH2), 3.44-
3.33 (m,1H, CHaCHb), 3.02-2.99 (m, 1H, CHaHb), 1.26-1.19
(t, 3H, CH3); Analysis calcd for C24H25N3O4 C, H, N.
(6S,12aS) -2- Ethyl-6-(3,4-dimethoxyphenyl)-2,3,6,7,12,12a
hexahydropyrazino[1’,2’:1,6] pyrido[3,4-b]indole-1,4-dione
(XXXIX )
(6S,12aR) -2- tert-butyl-6-(3,4-dimethoxyphenyl)-2,3,6,7,12,
12a hexahydropyrazino [1’,2’:1,6] pyrido[3,4-b] indole-
1,4-dione (XLII)
Yellow powder; m.p.: 264-267 °C; Rf
=
0.74
(CH2Cl2/MeOH 95:5); MS (EI): m/z 419 (M+), m/z 248
Yellow powder (16%); m.p.: 210-212 °C; Rf = 0.27
(CH2Cl2/MeOH 92:8); MS (EI): m/z 447 (M+), m/z 248
(100%); IR (cm -1): 3260,1741,1655; 1H-NMR (CDCl3): 7.90
(brs, 1H, NH), 7.82-7.14 (m, 7H, Ar),6.83 (brs,1H,CHPh),
4.90-4.88 (d,1H,CHC(O)N), 4.37-4.31(d,1H,CHaHbC(O)N),
3.99-3.95(d,1H,CHaHbC(O)N), 3.84 (s, 3H, OCH3),3.63 (s, 3H,
OCH3),3.71-3.60 (m,1H,CHaCHb), 3.47-3.37 (dd,1H,CHaHb),
1.24 (s, 9H, CH3); Analysis calcd for C26H29N3O4 C, H, N.
1
(100%); IR (cm -1): 3285, 1658, 1650; H-NMR (CDCl3):
8.01 (brs, 1H, NH), 7.64-7.61 (d, 1H, Ar), 7.55-7.56 (d, 1H,
Ar), 7.31- 7.30 (d, 1H, Ar), 7.19-7.18 (d, 1H, Ar), 7.17-7.16
(d, 1H, Ar), 6.90-6.89 (d, 1H, Ar), 6.85-6.82 (dd, 1H, Ar),
6.89 (s, 1H, Ar),6.24 (s, 1H, CHPh), 4.33-4.26 (dd, 1H,
CHC(O)N), 4.08-4.03 (d, 1H, CHaC(O)N), 3.95-3.90 (d, 1H,
CHbC(O)N), 3.81 (s, 3H, OCH3),3.79 (s, 3H, OCH3), 3.74-
3.66 (q, 2H, NCH2), 3.41-3.33 (dd, 1H, CHaCHb), 3.29-3.19
(dd, 1H, CHaHb), 1.22-1.17 (t, 3H, CH3); Analysis calcd for
C24H25N3O4 C, H, N.
(6S,12aS) -2- tert-butyl-6-(3,4-dimethoxyphenyl)-2,3,6,7,12,
12a hexahydropyrazino[1’,2’:1,6] pyrido[3,4-b]indole-1,4-
dione (XLIII)
18%, Yellow powder ; m.p.: 192-195 °C; Rf = 0.40
(CH2Cl2/MeOH 92:8); MS (EI): m/z 447 (M+), m/z 248
(6R,12aS) -2- Ethyl-6-(3,4-dimethoxyphenyl)-2,3,6,7,12,12a
hexahydropyrazino[1’,2’:1,6] pyrido[3,4-b]indole-1,4-dione
(XL)
1
(100%); IR (cm -1): 3262,1699, 1654 ; H-NMR (CDCl3):
7.73 (brs, 1H, NH), 7.62-7.59 (d, 1H, Ar), 7.56-7.54 (d, 1H,
Ar), 7.23- 7.16 (dd, 1H, Ar), 6.88-6.81(d, 1H, Ar), 6.79-6.62
(m, 3H, Ar), 6.33 (s, 1H, CHPh), 4.87-4.85 (d, 1H,
CHC(O)N), 4.36-4.32 (dd, 1H, CHaHbC(O)N), 4.10-4.01 (d,
1H, CHaHbC(O)N), 3.81 (s, 3H, OCH3), 3.76 (s, 3H, OCH3),
3.67-3.63 (m, 1H, CHaCHb), 3.55-3.45 (dd, 1H, CHaHb),
1.36 (s, 9H, CH3); Analysis calcd for C26H29N3O4 C, H, N.
Orange powder (10%); m.p.: 218-220 °C; Rf = 0.81
(CH2Cl2/MeOH 95:5); MS (EI): m/z 419 (M+; 100 %); IR
(cm -1): 3280, 1660, 1648; 1H-NMR ( CDCl3): 8.29 (brs, 1H,
NH),7.96-7.94 (d, 1H, Ar), 7.56-7.54 (d, 1H, Ar),7.34-7.31
(d, 1H,Ar), 7.29-7.25 (dd,1H,Ar), 7.17-7.15 (d,1H,Ar), 6.95-
6.93 (d,1H,Ar), 6.78 (s,1H,Ar), 6.68 (brs,1H,CHPh), 4.39-
4.33 (dd,1H,CHC(O)N),3.87 (s,3H,OCH3),3.83 (s,3H,OCH3),
3.82-3.73 (q,2H,NCH2), 3.60-3.53 (m,1H,CHaC(O)N), 3.42-
3.31 (m,1H,CHbC(O)N), 3.23-3.16 (m,1H,CHaCHb), 3.00-
2.91(m,1H,CHaHb), 1.22 -1.17 (t,3H,CH3); Analysis calcd for
C24H25N3O4 C, H, N.
(6R,12aS) -2- tert-butyl-6-(3,4-dimethoxyphenyl)-2,3,6,7,
12,12a hexahydropyrazino [1’,2’:1,6]pyrido[3,4-b] indole-
1,4-dione (XLIV)
Orange powder (15%); m.p.: 212-214 °C; Rf = 0.17
(CH2Cl2/MeOH 92:8); MS (EI): m/z 447 (M+ 94 %), m/z
;

A Novel Access to Arylated and Heteroarylated Beta-Carboline
Medicinal Chemistry, 2010, Vol. 6, No. 6 387
248 (100%); IR (cm -1) 3260, 1657, 1641; 1H-NMR (CDCl3):
7.78 (brs, 1H, NH), 7.54-7.59 (d, 1H, Ar), 7.34- 6.98 (m, 6H,
Ar), 6.82 (s, 1H, CHPh), 4.32-4.27 (d, 1H, CHC(O)N), 4.15.-
4.09(dd, 1H, CHaC(O)N), 4.03-3.99 (d, 1H, CHbC(O)N), 3.87
(s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.75-3.68 (m, 1H, CHa-
CHb), 3.64 -3.58 (dd,1H, CHaHb),1.26 (s, 9H, CH3); Analysis
calcd for C26H29N3O4 C, H, N.
meanwhile the interaction of IX is also displayed and the
difference in mode of binding is observed (Fig. 2).
ACKNOWLEDGMENTS
The authors are indebted to the Faculty of Postgraduate
Studies, The German University in Cairo for partial finance
of the project. Also, some of the instruments used were do-
nated by The Alexander von Humboldt Foundation, Ger-
many.
5. Biological evaluation
All the synthesized compounds were evaluated for their
inhibitory properties versus recombinant PDE5. Most of
compounds were evaluated in 2 steps. The first step was the
determination of the percentage inhibition at a screening
dose of 50 ꢀM performed in triplicate. For compounds dis-
playing a percentage of inhibition > 65%, the IC50 was de-
termined by testing a range of 10 concentrations with at least
two replicates per concentration. For all assays, tadalafil
(PDE5/PDE11 inhibitor) was used for comparison.
REFERENCES
[1]
[2]
[3]
[4]
Conti, M. Phosphodiesterases and cyclic nucleotide signalling in
endocrine signalling in endocrine cells. Mol. Endocrinol., 2000, 14,
1317- 1327.
Lucas, K. A.; Pitari, G. M.; Kazerounian, S.; Ruiz-Stewart, I.; Park,
J.; Schulz, S. Guanylyl cyclases an signaling by cGMP. Pharmacol.
Rev., 2000, 52, 375- 414.
Corbin, J. D.; Francis, S. H.; Webb, D. J. Phosphodiesterase type 5
as a pharmacologic target in erectile dysfunction. Urology, 2002,
60, 4-11.
Champion, H. C.; Bivalacqua, T. J.; Takimoto, E.; Kass, D. A.;
Burnett, A. L. Phosphodiesterase-5A dysregulation in penile erec-
tile tissue is a mechanism of priapism. Proc. Nat.l Acad. Sci. USA,
2005, 102(5), 1661-1666.
Phosphodiesterase Inhibitory Activity
PDE activity was measured using an adaptation of the
IMAP1 fluorescence polarization phosphodiesterase assay
(Molecular Devices, Sunnyvale, CA, USA). PDE hydrolysis
of the fluorescent- labeled substrate allows it to bind the
IMAP1 reagent, which increases fluorescence polarization
(FP). The assay used fluorescein (Fl)-cAMP and tetramethyl-
rhodamine (TAMRA) - cGMP as substrates. The different
excitation and emission spectra of the substrates (485-530
nm for Fl and 530-590 nm for TAMRA) allowed for simul-
taneous measurement of cAMPand cGMP hydrolysis in the
same well. The assays were performed in 96-well microtiter
plates using a reaction buffer containing 10 mM Tris-HCl
(pH 7.2) 10 mM MgCl2, 0.05% NaN3 and 0.1% phosphate-
free bovine serumalbumin as the carrier. Each well contained
20 μL of recombinant enzyme (BPS Biosciences, San Diego,
CA, USA) and 10 μL inhibitor. The reaction was initiated by
the addition of 10 μL of a substrate solution containing 50
nM Fl-cAMP and/or TAMRA-cGMP. After incubating at
room temperature for 60 min. the reaction was terminated by
adding 120 μL of binding solution. FP was measured with a
BioTek Synergy 4 (BioTek Instruments, Winooski, VM,
USA) [15].
[5]
[6]
Stacey, P.; Rulten, S.; Dapling, A.; Phillips, S. C. Molecular clon-
ing and expression of human cGMP-binding cGMP-specific phos-
phodiesterase (PDE5). Biochem. Biophys. Res. Commun., 1998,
247(2), 249-254.
Loughney, K.; Hill, T. R.; Florio, V. A.; Uher, L.; Rosman, G. J.;
Wolda, S. L.; Jones, B. A.; Howard, M. L.; McAllister-Lucas, L.
M.; Sonnenburg, W. K.; Francis, S. H.; Corbin, J. D.; Beavo, J. A.;
Ferguson, K. Isolation and characterization of cDNAs encoding
PDE5A, a human cGMP-binding, cGMP-specific 3',5'-cyclic nu-
cleotide phosphodiesterase. Gene, 1998, 216(1), 139-147.
Van Driel, M. F. Phosphodiesterase inhibitors: effectiveness and
new applications. Ned. Tijdschr. Geneeskd., 2006, 150(29), 1613-
1616.
[7]
[8]
[9]
Bos, J. Epac protiens: multi-purpose cAMP targets. Trends Bio-
chem. Sci., 2006, 31, 680-686.
Hou, Y.; Gupta, N.; Schoenlein, P.; Wong, E.; Worner, R.; Martin-
dale, R.; Ganapathy, V. An anti-tumor role for cGMP -dependant
protien kinase. Cancer Lett., 2006, 240, 60-68.
[10]
Zhang, K. Y.; Card, G. L.; Suzuki, Y.; Artis, D. R.; Fong, D.; Gil-
lette, S.; Hsieh, D.; Neiman, J.; West, B. L.; Zhang, C.; Milbum,
M. V.; Kim, S. V.; J., S.; Bollag, G. A glutamine switch mecha-
nism for nucleotide selectivity by phosphodiesterases. Mol. Cell,
2004, 11, 865-873.
[11]
[12]
[13]
Orme, M. W.; Martinelli, M. J.; Doecke, C. W.; Pawlak, J.M.
Modified Pictet-Spengler reaction and products prepared there-
form. U.S. Patent 7, 550, 479, June, 23, 2009.
Whaley W.M.; Govindachari T.R. The Pictet-Spengler synthesis of
tetrahydroisoquinolines and related compounds. Org. React., 1951,
6, 151-190.
Ungemach, F.; Soerens, D.; Weber, R.; DiPierro, M.; Campos, O.;
Mokry, P.; Cook, J. M.; Silverston, J. V. General method for the
assignement of stereochemistry of 1,3- disubstituted 1,2,3,4 -
tetrahydro-ß-carbolines by Carbon -13 spectroscopy. J. Am. Chem.
Soc., 1980, 102, 6976-6984.
6. IN SILICO STUDY
To reveal the mode of interaction of IX with the residues
lining the binding pocket of PDE5, a docking experiment
was implemented to dock IX into the active site of PDE5
with the program MOE version 2007.09. All ligand atoms
but no protein atoms were allowed to move during the dock-
ing simulation. Before the docking procedure, water mole-
cules, old co-crystallized ligand (tadalafil) and heteroatoms
were removed from the protein (PDB ID code 1UDU) crystal
structure, To ensure more accurate docking procedures, tada-
lafil as an example of potent PDE5 inhibitor was redocked to
the binding pocket under the same MOE settings as com-
pound IX; the interaction of tadalafil is displayed (Fig. 1)
[14]
[15]
Sandrin, J.; Soerens, D.; Cook, J. M. Carbon-13 NMR of 1,3-
disubstituted 1,2,3,4-tetrahydro-ß-carbolines Heterocycles, 1976, 4,
1249-1255.
Huang, W.; Zhang, Y.; Sportsman, J. R. A fluorescence polariza-
tion assay for cyclic nucleotide phosphodiesterases. J. Biomol.
Screen., 2002, 7, 215-219.
Received: August 15, 2010
Revised: September 29, 2010
Accepted: October 04, 2010