Synthesis and pharmacological characterization of novel xanthine carboxylate amides as A2A adenosine receptor ligands exhibiting bronchospasmolytic activity

Article abstract of DOI:10.1016/j.bioorg.2016.01.003

The carboxylate amides of 8-phenyl-1,3-dimethylxanthine described herein represent a new series of selective ligands of the adenosine A_2A receptors exhibiting bronchospasmolytic activity. The effects of location of 8-phenyl substitutions on the

Full text of DOI:10.1016/j.bioorg.2016.01.003

Accepted Manuscript
Synthesis and pharmacological characterization of novel xanthine carboxylate
amides as A2A adenosine receptor ligands exhibiting bronchospasmolytic activ-
ity
Rakesh Yadav, Ranju Bansal, Sonja Kachler, Karl-Norbert Klotz
PII:
S0045-2068(16)30003-7
DOI:
http://dx.doi.org/10.1016/j.bioorg.2016.01.003
YBIOO 1871
Reference:
Bioorganic Chemistry
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Revised Date:
Accepted Date:
27 October 2015
15 January 2016
16 January 2016
Please cite this article as: R. Yadav, R. Bansal, S. Kachler, K-N. Klotz, Synthesis and pharmacological
characterization of novel xanthine carboxylate amides as A2A adenosine receptor ligands exhibiting
bronchospasmolytic activity, Bioorganic Chemistry (2016), doi: http://dx.doi.org/10.1016/j.bioorg.2016.01.003
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Synthesis and pharmacological characterization of novel xanthine
carboxylate amides as A2A adenosine receptor ligands exhibiting
bronchospasmolytic activity
Rakesh Yadav1, Ranju Bansal1*, Sonja Kachler2 and Karl-Norbert Klotz2
1University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh – 160014, India
2Institut für Pharmakologie und Toxikologie, Universität Würzburg, Germany
*Corresponding author:
Prof. Ranju Bansal
University Institute of Pharmaceutical Sciences
Panjab University, Chandigarh-160 014, India
Email: ranju29in@yahoo.co.in
Tel.: 0172-2541142; Fax: 0172-2543101
1

Abstract
The carboxylate amides of 8-phenyl-1,3-dimethylxanthine described herein represent a
new series of selective ligands of the adenosine A2A receptors exhibiting
bronchospasmolytic activity. The effects of location of 8-phenyl substitutions on the
adenosine receptor (AR) binding affinities of the newly synthesized xanthines have also
been studied. The compounds displayed moderate to potent binding affinities
towards various adenosine receptor subtypes when evaluated through radioligand
binding studies. However, most of the compounds showed the maximum affinity
for the A2A subtype, some with high selectivity versus all other subtypes
.
Xanthine carboxylate amide 13b with a diethylaminoethylamino moiety at the para-
position of the 8-phenylxanthine scaffold was identified as the most potent A2A
adenosine receptor ligand with Ki = 0.06 µM. Similarly potent and highly A2A-selective
are the isovanillin derivatives 16a and 16d. In addition, the newly synthesized xanthine
derivatives showed good in vivo bronchospasmolytic activity when tested in guinea pigs.
Keywords:
Adenosine receptor ligands, Bronchospasmolytic agents, 8-Phenylxanthine carboxylate
amides, Partition coefficient
2

1. Introduction
The development of potent and selective ligands of adenosine receptors (ARs) has
been the subject of medicinal chemistry research for more than three decades. The
expression and activation of the four adenosine receptor subtypes A1, A2A, A2B, and A3
are associated with the control of gene expression, cell growth, intestinal function,
neurosecretion, vascular tone and asthma. Therefore all AR subtypes have been
considered as potential targets for therapies of neurodegenerative, cardiac, immune
and inflammatory disorders [1,2]. Although several adenosine receptor-specific
compounds have entered clinical trials and an A2A AR selective agonist Regadenosan®
has gained approval from US Food and Drug Administration (FDA), in practice this goal
remains elusive even today [3,4]. The possibility of side effects due to the ubiquitous
nature of ARs suggests subtype selectivity to be of significance for numerous
therapeutic applications [5].
A2A receptor subtype represents a fascinating target for the development of small
molecules as antiasthmatic agents as these receptors are expressed in lungs and in
inflammatory cells involved in asthma. Therefore selective ligands of this subtype are
being widely explored by a large number of research bodies to generate novel therapies
for asthma and chronic obstructive pulmonary disease (COPD) [6,7].
Substituted xanthines represent the first potent class of adenosine receptor
antagonists reported till date [8]. It has been established that appropriate substitutions
as well as location of 8-phenyl substituents affects the potency and selectivity of
xanthines towards ARs and thus their pharmacological effects [9,10]. The progressive
studies on alkylxanthines led to the development of 8-phenylxanthine carboxylic acid
congeners as potent and selective adenosine A2 receptor antagonists. In particular, the
derivative named MRS-1754 (1) has emerged as a potent and selective xanthine based
A2B adenosine receptor antagonist [11,12] (fig 1). Jacobson and co-workers
demonstrated the increased affinity of xanthine amides at A2 receptors with the
introduction of an 8-phenyl group functionalized in the para-position with a
carboxymethoxy chain [13]. However the effect of this moiety on other positions of the
8-phenyl group remains relatively unexplored. In continuation of our earlier
3

investigations [14-16] directed towards finding therapeutically useful molecules through
the preparation of substituted xanthines, we considered it worthwhile to synthesize and
study additional amide derivatives of xanthine carboxylates as represented by structure
2 in figure 1.
Taking into consideration the related interesting literature reports, an acetyloxy
group linked through a nitrogen atom to a variety of cyclic and acyclic substituents was
introduced on the 8-phenyl ring in this series of xanthine derivatives. Previous studies
have indicated that suitable selection and positioning of aryl substituents lead to the
development of potent and selective xanthine based AR ligands [14]. Shifting of para
substituents to meta position of 8-phenyl ring resulted into xanthines with almost equal
affinity for A1 and A2A subtypes while the former were more selective for A2A receptors.
Therefore, the effects of varying the location of 8-phenyl substituent in the current series
of xanthine carboxylate amides on the biological properties were also examined. It is
also anticipated that coupling of a carboxylic group with various polar groups such as
amines may improve the water solubility of xanthines, so one of the series was also
selected randomly to evaluate the hydrophobicity of the synthesized compounds [17,18].
H
O
CN
N
O
H
N
N
O
N
O
N
(1)
O
H
N
OCH2COR
N
N
O
N
(2)
Figure 1: Structures of potent xanthine based A2B adenosine receptor antagonist MRS-1754 (1) and
general structure (2) of proposed xanthine derivatives
4

The synthesized compounds have been biologically evaluated using radioligand
binding to membranes prepared fom CHO cells transfected with human A1, A2A, A2B and
A3 adenosine receptor subtypes [19,20]. In vivo experiment using a histamine chamber
was also performed to study the bronchospasmolytic activity of the new compounds
using theophylline as a standard drug [21].
2. Results and Discussion
2.1. Chemistry
5,6-Diaminouracil (4), the intermediate used for the preparation of new xanthine
derivatives was prepared according to the reported method [22,23]. Synthesis of
substituted aldehydes 5-8, Schiff bases 9-12 and xanthine carboxylate esters 13-16 is
presented in scheme 1. The starting aldehydes such as 4-hydroxybenzaldehyde, 3-
hydroxybenzaldehyde, vanillin and isovanillin, possessing a vulnerable para or meta
hydroxy group on the 8-phenyl ring for derivatization, were selected to study the effect
of such substitution pattern on affinity and selectivity of xanthine derivatives for various
adenosine receptor subtypes. This choice is not only characterized by ease of
substitution but also helped to evaluate the impact of various substituting groups in para
or meta positions of the 8-phenyl ring, with or without an ortho methoxy group, on
adenosine binding affinity and selectivity.
Condensation of various substituted aldehydes 5-8 with 5,6-diaminouracil (4) in
the presence of MeOH:AcOH (4:1) at room temperature afforded Schiff bases 9-12,
oxidative cyclization of which in refluxing thionyl chloride formed xanthine carboxylates
13-16 as shown in scheme 1. A singlet integrating for one proton appeared at ~  9.7
ppm for N=CH in 1H NMR all the benzylidene derivatives 9-12.
Amide derivatives 13a-i─16a-i of parent xanthine carboxylate esters 13-16 were
prepared according to scheme 1 by fusing them with appropriate acyclic and cyclic
amines. A prominent singlet for -OCH2- ranging from  4.5 to 4.8 and presence of two
N-methyl of xanthine ring at ~ 3.40 and ~ 3.50 ppm were observed in the nuclear
magnetic resonance spectra of all the amide derivatives 13a-i─16a-i. Three N-
methylenes of –CH2-N(CH2CH3)2 moiety appeared together as a multiplet at  2.5-2.6
for diethylamino derivatives 13b-16b, whereas protons of –CH2-N of dimethylamino
5

a
f
b
g
c
d
e
N
N
H
H
N
N
O
N
N
N
N
R2
h
i
O
N
N
N
N
N
H
O
Scheme-1- Synthetic route to the synthesis of xanthine carboxylate amides 13a-i, 14a-i, 15a-i and 16a-i
derivatives 13a-16a resonated separately at ~ 2.5 ppm. Two N-methylenes of the
heterocyclic ring for pyrrolidino xanthines 13c-16c were found a little upfield than those
of piperidino derivatives 13d-16d. The compounds 13-16 were also fused with
6

homoveratrylamine to observe the effect of such functionality on the pharmacological
profile of xanthines since this type of moiety form an integral part of a potent and
selective A2B adenosine receptor antagonist, MRE-2028F20 [18].
2.2. Partition Coefficient
The partition coefficient values of xanthine carboxylate ester 14 and its amidic
congeners 14a-i belonging to 3-hydroxybenzaldehyde series were measured using the
shake flask method and an in silico (ChemDraw Ultra 8.0.3 and Biotage Path Finder)
method [18]. Partition coefficient data (Log PC) of various xanthine derivatives have
been compiled in table 1. In general, the compounds displayed good hydrophobicity
except the compounds 14a-b and 14h.
Table 1: Partition coefficient values of some 8-substituted-phenylxanthine derivatives
Partition Coefficient (Log PC)
Comp. No.
Calculated
Measured
LogPCCH
(Code)
Biotage
Chem Draw
LogPCOC
14
(RB-374)
14a
(RB-379)
14b
(RB-378)
14c
(RB-381)
14d
(RB-382)
14e
(RB-376)
14f
(RB-375)
14g
(RB-380)
14h
(RB-445)
14i
(RB-377)
1.06
0.27
0.26
-0.41
0.14
0.56
0.97
-0.58
-0.42
-0.41
1.35
0.865
-0.094
-1.144
1.776
2.339
1.710
1.094
0.240
-1.037
1.82
1.051
1.08
0.39
0.99
1.38
1.78
0.32
0.46
0.94
1.94
0.064
-0.396
1.509
1.506
2
0.526
0.655
-1.735
0.089
There is also a significant correlation between chloroform/phosphate buffer and
n-octanol/phosphate buffer partition coefficient values of these derivatives (r2 = 0.64; p
<0.05) as shown in figure 2. The regression line (solid line) was calculated by the least-
7

squares method. The dotted lines indicate 95% confidence limits for the regression line.
The three xanthine amides 14c-e, substituted with 5-, 6-, and 7-membered heterocyclic
ring, respectively, exhibited higher partition coefficient values, which indicate their
preferential distribution to hydrophobic compartments such as the lipid bilayers of cells.
The ideal not too hydrophobic nor too hydrophilic character of the new xanthines
predicts their good bioavailability. It is assumed that these compounds might produce
good bronchodilating effects as the potency of relaxant effects of xanthines depends on
the cell membrane permeability based on their hydrophobic property. The
hydrophobicity may also be the major factor for the molecules to bind to the receptors.
2.3. Radioligand binding assays
Table 2 summarizes the observed binding affinities of newly synthesized
8-(carboxymethyloxyphenyl)xanthine derivatives towards the four human
adenosine receptor subtypes (A1, A2A, A2B and A3). In general, the 8-
phenylsubstituted xanthine carboxylate esters 13-16 and their amidic congeners
13a-i─16a-i displayed moderate to potent binding affinities towards various
adenosine receptor subtypes, however, augmented affinity and thus resulting in
selectivity was markedly present for the A2A subtype in the majority of the cases.
Overall the binding selectivity for A2A is somewhat more pronounced versus A3
receptors (up to > 400 fold) as compared to the A1 (maximally about 60 fold)
and A2B (up to > 130 fold) subtypes. Monosubstituted 8-phenylxanthine
carboxylate esters 13 and 14 with a polar side chain present at para or meta
positions of the 8-phenyl ring, respectively, displayed higher binding affinity for all
AR subtypes and more notably for A2A receptors in comparison to disubstituted
analogues 15 and 16, which possess an additional methoxy group ortho to the
methoxycarbonylmethoxy side chain. Incorporation of a methoxy substituent
significantly improves the A2A selectivity of disubstituted xanthines 15 and 16
versus A1 subtype in comparison to their monosubstituted counterparts,
however reduced selectivity is observed versus A2B and A3 adenosine
receptors. The results are in agreement with the adenosine binding affinity data
of a series of 8-(4-aminoethoxy)phenylxanthines previously reported from our
8

laboratory [14]. Conversion of xanthine carboxylates into amides enhances the
A2A binding affinity in general, but the selectivity pattern remains the same as
seen with their precursors. While comparing the two series of monosubstituted 8-
phenylxanthine derivatives 13a-i and 14a-i, it was observed that both para and meta
substituted 8-phenylxanthines showed pronounced affinity for A2A receptors. However,
the meta substituted products 14a-i exhibited markedly decreased affinity for A2B
receptors in comparison to their para phenyl substituted counterparts 13a-i. 1,3-
Dimethyl-8-[4-{2-(diethylaminoethylamino)-2-oxoethoxy}phenyl]xanthine (13b) with the
Ki = 63 nM at A2A receptors remains the most potent compound of the two series.
The binding affinity of disubstituted 8-phenylxanthine analogues 15a-i
possessing a methoxy group ortho to the meta substituted polar side chain was found to
be lower for A2A in comparison to monosubstituted compounds. The isovanilloid based
compounds 16a-i with the rearrangement of the side substitutions of the 8-phenyl ring
so that methoxy is at 4-position and polar substituents are at 3-position on the 8-phenyl
ring, showed high affinity for A2A receptors. This resulted in a higher level of selectivity
for A2A versus other receptor subtypes compared to the vanilloid series 15a-i.1,3-
Dimethyl-8-[4-methoxy-3-{2-(-(dimethylaminoethylamino)-2-oxoethoxy}phenyl]xanthine
(16a) emerged as the most potent compound of the disubstituted series with a Ki = 75
nM. No systematic differences were observed in binding affinity of 8-
(carboxymethyloxyphenyl) substituted xanthines bearing open (13a-b─16a-b
)
and cyclisized heterocyclic ring systems (13c-i─16c-i) in their side chains for
individual adenosine receptors. In contrast to earlier reported xanthine
carboxylate amides such as MRS-1754 with high A2B receptor selectivity [11], the
new compounds depicted higher affinity for A2A AR versus the other human adenosine
receptor subtypes.
Table. 2 Binding profile of various xanthine derivatives at adenosine receptors (A1, A2, A2B and A3
)
Ki (µM)
A2A selectivity
COMP.
NO.
(CODE)
b
c
(A1)a
(A2A
)
(A2B
)
(A3)d
5.86
A1/A2A
A2B/A2A
A3/A2A
13
0.319
0.170
0.980
1.9
5.8
34
(RB-419) (0.273-0.374) (0.124-0.233) (0.866-1.11) (5.01-6.85)
9

Ki (µM)
A2A selectivity
COMP.
NO.
(CODE)
b
c
(A1)a
(A2A
)
(A2B
>10
>10
>10
)
(A3)d
3.81
A1/A2A
A2B/A2A
A3/A2A
14
(RB-374)
3.95
0.375
11
>26
10
(2.36-6.63) (0.236-0.597)
(2.90-5.00)
15
(RB-384)
4.38
>30
>6.8
16
>2.3
>14
9.0
15
>2.3
15
>10
(2.35-8.15)
16
(RB-410)
11.8
0.717
10.7
(8.62-13.4)
(7.76-18.0) (0.547-0.939)
13a
0.220
0.100
0.903
10.5
2.2
4.7
6.5
2.4
2.2
4.4
2.6
1.5
13
105
132
47
(RB-420) (0.194-0.249) (0.046-0.216) (0,760+1,07) (6.59-16.8)
13b
0.298
0.063
0.968
8.35
(RB-421) (0.233-0.380) (0.042-0.096) (0.851-1.10) (7.25-9.61)
13c
(RB-426)
0.796
0.122
1.49
5.68
12
(0.622-1.02) (0.082-0.182) (1.25-1.78) (3.91-8.24)
13d
0.419
0.178
0.401
13.0
1.5
1.6
8.1
4.9
2.4
4.0
73
(RB-427) (0.369-0.476) (0.101-0.313) (0,232-0,696) (11.8-14.4)
13e
(RB-424)
0.609
0.273
0.443
4.15
15
(0.456-0.813) (0.196-0.381) (0.406-0.486) (2.61-6.59)
13f
(RB-423)
1.25
0.283
2.29
7.11
25
(0.996-1.62) (0.195-0.411) (1.85-2.83) (5.62-8.99)
13g
0.499
0.193
0.954
10.1
52
(RB-425) (0.450-0.553) (0.098-0.378) (0,645-1,41) (9.83-10.3)
13h
(RB-447)
3.99
2.69
6.38
>11
47
>30
6,0
(2.83-5.63) (1.71-4.21) (4.75-8.58)
13i
(RB-422)
1.68
0.128
0.516
(1.34-2.10) (0.102-0.161) (0.468-0.571) (5.46-6.58)
14a
0.683 0.163 2.83 8.97
4.2
6.8
14
17
27
55
47
20
20
16
12
10
9.6
(RB-379) (0.627-0.744) (0.079-0.339) (1,78-4,50) (5.73-14.0)
14b
(RB-378)
1.22
0.179
4.91
8.39
(0.983-1.52) (0.143-0.223) (3.32-7.30) (6.58-10.70)
14c
(RB-381)
3.29
0.237
4.64
(4.27-5.04)
>10
4.04
>42
19
(3.10-3.49) (0.167-0.338)
14d
(RB-382)
1.52
0.209
4.16
7.3
11
(1.37-1.69) (0.102-0.430) (2,00-6,51) (2.90-5.00)
14e
(RB-376)
2.43
0.226
6.28
3.69
28
(2.20-2.69) (0.133-0.384) (3.49-11.3) (2.85-4.78)
14f
(RB-375)
5.37
0.679
7.90
(5.81-10.70)
>10
7.9
3.4
>59
>15
15
(4.89-5.89) (0.657-0.702)
14g
(RB-380)
1.90
0.561
8.21
5.67
(1.75-2.06) (0.296-1.07) (1,80-14,0) (6.12-14.4)
14h
(RB-445)
0.509
(0.310-0.836)
4.89
(4.35-5.49)
>30
>30
>59
10

Ki (µM)
A2A selectivity
A2B/A2A
>7.2
12
COMP.
NO.
(CODE)
b
c
(A1)a
(A2A
)
(A2B
)
(A3)d
9.25
A1/A2A
4.3
A3/A2A
6.7
14i
(RB-377)
5.98
(4.27-8.38)
1.39
>10
10.0
(0.80-2.41)
(6.95-12.3)
15a
(RB-386)
9.25
0.821
>10
11
>12
>43
>6.6
>3.0
3.7
(6.66-12.8) (0.462-1.46) (8,93-11,3)
15b
(RB-388)
0.692
(0.582-0.823)
>10
>30
>30
>10
>30
>30
>30
>10
>30
>30
>30
>14
>6.6
>8.9
>4.1
>11
>7.1
>3.9
>36
11
>14
15c
(RB-392)
4.57
(3.48-6.00)
>6.6
>3,0
3.2
15d
(RB-391)
3.35
(1.66-6.73)
>10
>10
15e
(RB-387)
2.41
7.82
9.01
(1.49-3.90) (4.38-13.9) (4.76-17.0)
15f
(RB-385)
2.74
(2.05-3.67)
>30
>10
>30
>30
>30
>30
>30
>30
>30
>11
>11
>7.1
>3.9
>36
>400
>240
35
15g
(RB-446)
4.21
(2.77-6.39)
>2.4
>3.9
>36
15h
(RB-390)
7.74
(7.17-8.35)
15i
(RB-389)
0.843
(0.559-1.27)
>30
>30
16a
(RB-413)
0.847
0.075
4.80
64
(0.605-1.18) (0.042-0.132) (3,72-6,19)
16b
(RB-411)
1.97
0.126
8.05
16
64
(1.68-2.30) (0.076-0.208) (6.43-10.0)
16c
(RB-414)
5.94
0.259
8.98
(7.25-11.1)
>10
23
>39
(4.17-8.45) (0.194-0.345)
16d
(RB-417)
1.62
0.076
1.97
(1.49-2.61)
>10
21
>130
42
26
(1.48-1.77) (0.040-0.145)
16e
(RB-449)
1.91
0.094
3.94
0.797
20
8.5
(1.55-2.34) (0.057-0.156) (3.00-5.16) (0.790-0.836)
16f
(RB-415)
3.51
0.466
14.30
(8.60-23.8)
>10
7.5
>21
31
(2.48-4.96) (0.348-0.624)
16g
(RB-416)
3.64
0.685
6.54
>10
5.3
9.5
>15
3.7
(3.41-3.89) (0.428-1.10) (4,62-9,27)
16h
(RB-450)
1.12
(0.91-1.38)
4.10
(3.70-4.55)
>30
>30
>30
>30
>27
>39
>27
16i
(RB-412)
0.772
(0.607-0.981)
>30
>39
>39
11

Shown values are geometric means from 3–5 experiments in µM with 95% confidence intervals in parentheses, where:-
aDisplacement of specific (3H)CCPA binding in CHO cells, stably transfected with human recombinant A1 adenosine receptor,
expressed as Ki (nM).
bDisplacement of specific (3H)NECA binding in CHO cells, stably transfected with human recombinant A2A adenosine receptor,
expressed as Ki (nM).
cAntagonist affinities were determined by inhibition of NECA-stimulated adenylyl cyclase activity in membrane preparations.
dDisplacement of specific (3H)HEMADO binding in CHO cells, stably transfected with human recombinant A3 adenosine receptor,
expressed as Ki (nM).
2.4. Bronchospasmolytic activity
All the newly synthesized 8-(carboxymethyloxyphenyl) derived xanthine amides
13a-i─16a-i displayed significant protection against histamine aerosol induced
bronchospasm in guinea pigs (Table 3). Many compounds showed more
bronchospasmolytic potency in comparison to the standard drug theophylline as
apparent from enhanced time of onset of bronchospasm in case of test compounds
compared to theophylline. In the 4-hydroxybenzaldehyde series the most effective
compounds with negligible jerks, least severity of bronchospasm and 100% survival of
animals were xanthenes 13b, 13c and 13f. The compounds 14d, 14g and 14h from the
3-hydroxybenzaldehyde series displayed a similar pattern of bronchospasmolytic
activity along with markedly increased time for onset of bronchospasm. In the vanillin
substituted series (15a-15i) comparable bronchospasmolytic effects as that of standard
theophylline were observed, but the survival of animals was reduced to 60%. Only the
imidazole substituted compound 15h of this series showed a 100% survival of animals
with onset of bronchospasm equivalent to theophylline. The 16d and 16g of the
isovanillin series showed prominent protection against histamine induced
bronchospasm with 100% survival of animals.
Table 3: Protection by newly synthesized xanthine derivatives against bronchospasm
induced by histamine aerosol (5 ml of 1% w/v aerosoled in 1 min) in guinea
pigs
Duration of
jerks in
seconds
Mean time in seconds for
onset of bronchospasm
Mean ± S.E.M
Comp. No.
(Code)
Severity of
bronchospasm
Survival
(%)
Mean ± S.E.M
Control
67±2*
92±3
172±4*
89±7
+++
+
0
Theophylline
100
12

Duration of
jerks in
seconds
Mean time in seconds for
onset of bronchospasm
Mean ± S.E.M
Comp. No.
(Code)
Severity of
bronchospasm
Survival
(%)
Mean ± S.E.M
13a
(RB-420)
76±5
95±3
17±4*
32±5*
32±3*
34±6*
41±2*
38±3*
38±4*
26±3*
115±5*
24±5*
74±2
++
+
40
100
100
40
13b
(RB-421)
13c
(RB-426)
131±4*
74±4
+
13d
(RB-427)
++
+
13e
(RB-424)
92±2
80
13f
(RB-423)
86±3
+
100
40
13g
(RB-425)
80±2
++
++
++
++
+
13h
(RB-447)
79±5
60
13i
(RB-422)
86±5
40
14a
(RB-379)
71±4
60
14b
(RB-378)
98±4
80
14c
(RB-381)
71±5
33±2*
38±3*
60±5*
46±3*
42±2*
++
+
40
14d
(RB-382)
121±6*
120±5*
94±4
100
80
14e
(RB-376)
+
14f
(RB-375)
+
80
14g
(RB-380)
102±3
+
100
13

Duration of
jerks in
seconds
Mean time in seconds for
onset of bronchospasm
Mean ± S.E.M
Comp. No.
(Code)
Severity of
bronchospasm
Survival
(%)
Mean ± S.E.M
14h
(RB-445)
130±5*
100±4
110±4
81±4
30±4*
68±2*
90±4
+
100
80
60
60
60
40
60
60
60
100
40
40
40
60
100
40
14i
(RB-377)
+
15a
(RB-386)
++
++
++
++
++
++
++
+
15b
(RB-388)
34±6*
38±2*
65±2*
34±2*
82±2
15c
(RB-392)
84±4
15d
(RB-391)
112±4
99±3
15e
(RB-387)
15f
(RB-385)
92±2
15g
(RB-446)
126±3*
97±4
66±4*
20±3*
19±1*
80±3
15h
(RB-390)
15i
(RB-389)
86±4
++
++
++
++
+
16a
(RB-413)
84±5
16b
(RB-411)
72±3
50±2*
53±4*
60±3*
41±3*
16c
(RB-414)
68±2
16d
(RB-417)
103±5
64±4*
16e
(RB-449)
++
14

Duration of
jerks in
seconds
Mean time in seconds for
onset of bronchospasm
Mean ± S.E.M
Comp. No.
(Code)
Severity of
bronchospasm
Survival
(%)
Mean ± S.E.M
16f
(RB-415)
96±5
116±5*
73±3
113±3*
59±2*
42±4*
51±2*
++
+
60
100
40
16g
(RB-416)
16h
(RB-450)
+
16i
(RB-412)
71±2
++
60
Number of animals in each group (N) = 4
Dose of standard and tested compounds = 50 mg/kg
*Tukey’s test; p<0.05
All compounds exhibited A2A AR binding affinity ranging from about 60 nM to 8
µM along with prominent bronchospasmolytic effects. Imidazole substituted 8-
(carboxymethyloxyphenyl) xanthine 15h shows the lowest affinity for A2A but the
bronchospasmolytic effects are prominent. Although a causal relationship between A2A
antagonism and broncholysis seems very likely other contributing mechanisms cannot
be ruled out in this case.
3. Conclusions
The newly synthesized 8-(carboxymethyloxyphenyl)xanthine amides display
significant binding affinity for adenosine receptors with maximum potency for
A2A receptors and varying degree of selectivity versus other AR subtypes. The
effects of varying substituents and their location on the 8-phenyl ring are clearly
visible in the pharmacological characteristics of these novel xanthine
derivatives. Suitable introduction of 8-phenyl substituents on the xanthine
scaffold results in potent and selective binding with A2A adenosine receptors,
which seems to be an important trait for potent bronchospasmolytic effects.
Further the partition coefficient values predict the ideal not too hydrophobic nor too
hydrophilic character of the new xanthines for good bioavailability.
15

4. Experimental section
4.1. Chemistry
All melting points were obtained using glass capillary tubes on Veego melting point
apparatus and are uncorrected. Infrared (IR) spectra were recorded on Perkin-Elmer
RX1 Fourier Transform-Infrared spectrophotometer using potassium bromide pellets
(max in cm-1). Proton (1H) and carbon (13C) nuclear magnetic resonance spectroscopy
were performed using a Bruker AC-400F, 400 MHz spectrometer for solutions in
deuteriochloroform (CDCl3), deuterated dimethylsulfoxide (DMSO-d6) and mixture of
CDCl3-DMSO-d6 (2:1) and are reported in parts per million (ppm) downfield from
tetramethylsilane (Me4Si) as internal standard. The spin multiplicities are indicated by
the symbols, s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), m (multiplet), br
(broad) and the coupling constants (J) are given in Hertz (Hz). Elemental analyses were
carried out on a Thermo-Flash EA-1112 CHNS-O analyzer. The results are within 0.4%
of the theoretical values. Precoated plates with silica gel G (E. Merck 60 F254, 0.25 mm)
were used for thin layer chromatography (TLC). Chromatographic spots were visualized
by ultra-violet light in the UV cabinet (Perfit, India). Anhydrous sodium sulfate was
utilized as drying agent. All solvents were freshly distilled and dried prior to use
according to standard procedures. Synthesis of substituted aldehydes 5-8 by a two step
method is reported in literature [24], however we performed the reaction in a single step.
4.1.1. General method for the synthesis of compounds 5-8
Methyl chloroacetate (4.0 ml) was added to a stirred and refluxing suspension of
desired aromatic aldehyde [4-hydroxybenzaldehyde (1.0 g, 8.19 mmol) / 3-
hydroxybenzaldehyde (1.0 g, 8.19 mmol) / vanillin (1.0 g, 6.57 mmol) / isovanillin (1.0 g,
6.57 mmol] and anhydrous potassium carbonate (2.0 g) in ethyl methyl ketone (40 ml).
The reaction mixture was further refluxed for 4 h with continuous stirring until the
reaction was complete. (monitored by TLC). The reaction mixture was cooled, filtered
and solvent was removed under reduced pressure to obtain the corresponding oily
residues 5-8, which were used as such for subsequent reaction.
4.1.2. General method for the synthesis of various benzylidene derivatives 9-12
16

To a stirred solution of 5,6-diamino-1,3-dimethyluracil (4) (1.0 g, 5.87 mmol) in MeOH–
AcOH (4:1, 40 mL) was slowly added the solution of above obtained oily residues of
requisite substituted aldehydes 5-8 in methanol (24 ml). Yellow colored precipitate
appeared during addition. The reaction mixture was further stirred overnight at room
temperature and the completion of reaction was monitored by thin layer
chromatography. The precipitate obtained was filtered off, washed with methanol and
dried to obtain corresponding benzylidene derivatives 9-12.
4.1.2.1. 6-Amino-5-[{4-(2-methoxy-2-oxoethoxy)benzylidene}amino]-1,3-dimethyluracil
1
(9) (1.2 g; 65 %), mp: 236-238 C; H NMR (400 MHz, CDCl3-DMSO-d6):  = 3.33 (s,
3H, N-CH3), 3.51 (s, 3H, N-CH3), 3.81 (s, 3H, -OCH2COOCH3), 4.71 (s, 2H, -OCH2),
6.87 (s(br), 2H, -NH2), 6.92 (d, 2H, 2-CH and 6-CH, aromatic, Jo = 8.68 Hz), 7.73 (d, 2H,
3-CH and 5-CH, aromatic, Jo = 8.68 Hz) and 9.71 ppm (s, 1H, N=CH); FT-IR (KBr): max
= 3331, 2955, 1755, 1696, 1627, 1510, 1437, 1301, 1230, 1080, 965, 830 and 755 cm-1;
Anal. calcd. for C16H18N4O5: C, 55.49; H, 5.24; N, 16.18. Found: C, 55.60; H, 5.25; N,
16.29.
4.1.2.2. 6-Amino-5-[{3-(2-methoxy-2-oxoethoxy)benzylidene}amino]-1,3-dimethyluracil
(10) (0.76 g; 75 %), mp: 198-200 C; 1H NMR (400 MHz, CDCl3-DMSO-d6):  = 3.34 (s,
3H, N-CH3), 3.51 (s, 3H, N-CH3), 3.81 (s, 3H, -OCH2COOCH3), 4.71 (s, 2H, -OCH2-),
6.85 (s, 2H, -NH2), 6.88 (d, 1H, 4-CH, aromatic, Jo = 7.68 Hz), 7.31 (t, 1H, 5-CH,
aromatic, Jo = 7.96 Hz), 7.36 (m, 2H, 2-CH and 6-CH, aromatic) and 9.72 ppm (s, 1H,
N=CH); FT-IR (KBr): max = 3312, 2957, 1772, 1738, 1692, 1588, 1438 and 860 cm-1;
Anal. calcd. for C16H18N4O5: C, 55.49; H, 5.24; N, 16.18. Found: C, 55.65; H, 5.31; N,
16.08.
4.1.2.3.
6-Amino-5-[{(4-(2-methoxy-2-oxoethoxy)-3-methoxy)benzylidene}amino]-1,3-
dimethyl- uracil (11) (1.1 g, 99 %), mp: 218-220 C; 1H NMR (400 MHz, CDCl3-DMSO-
d6):  = 3.27 (s, 3H, N-CH3), 3.48 (s, 3H, N-CH3), 3.77 (s, 3H, -OCH2COOCH3), 3.93 (s,
3H, -OCH3), 4.75 (s, 2H, -OCH2-), 6.85 (d, 1H, 5-CH, aromatic, Jo = 8.28 Hz), 7.07 (s,
17

2H, -NH2), 7.24 (d, 1H, 6-CH, aromatic, Jo = 8.24 Hz), 7.48 (s, 1H, 2-CH, aromatic) and
9.68 ppm (s, 1H, N=CH); FT-IR (KBr): max = 3329, 2922, 2851, 1763, 1691, 1621,
1507, 1438, 1221 and 758 cm-1; Anal. calcd. for C17H20N4O6: C, 54.25; H, 5.36; N,
14.89. Found: C, 55.12; H, 5.16; N, 15.25.
4.1.2.4.
6-Amino-5-[{(3-(2-methoxy-2-oxoethoxy)-4-methoxy)benzylidene}amino]-1,3-
dimethyluracil (12) (0.74 g, 67 %), mp: 208-210 C; 1H NMR (400 MHz, CDCl3):  = 3.30
(s, 3H, N-CH3), 3.50 (s, 3H, N-CH3), 3.78 (s, 3H, -OCH2COOCH3), 3.90 (s, 3H, -OCH3),
4.80 (s, 2H, -OCH2-), 6.95 (d, 1H, 5-CH, aromatic, Jo = 8.32 Hz), 7.00 (s(br), 2H, -NH2),
7.29 (dd, 1H, 6-CH, aromatic, Jm = 1.80 Hz; Jo = 8.22 Hz), 7.42 (d, 1H, 2-CH, aromatic,
Jm = 1.60 Hz) and 9.65 ppm (s, 1H, N=CH); FT-IR (KBr): max = 3318, 2942, 1762,
1677, 1620, 1507, 1432, 1262, 1219, 1135, 1065, 868 and 761 cm-1; Anal. Calcd. for
C17H20N4O6: C, 54.25; H, 5.36; N, 14.89. Found: C, 54.27; H, 5.27; N, 14.74.
4.1.3. General method for synthesis of various 8-(substitutedphenyl)xanthine
derivatives 13-16
Benzylidene derivatives 9-12 (1.0 g, 2.88 mmol) thus obtained were refluxed individually
in thionyl chloride (20 ml) for 30-40 min to affect cyclization. The excess thionyl chloride
was removed under reduced pressure to obtain a solid product. Ice cold water was
added to it and resultant suspension was neutralized with ammonium hydroxide
solution. The precipitate obtained was collected by filtration, dried and crystallized from
a mixture of methanol and chloroform to afford the desired products 13-16, respectively.
4.1.3.1. 1,3-Dimethyl-8-[4-(2-methoxy-2-oxoethoxy)-phenyl]xanthine (13) (0.94 g, 94 %),
1
mp: 260 ºC (decomp.); H-NMR (400 MHz, DMSO-d6):  = 3.42 (s, 3H, N-CH3), 3.64 (s,
3H, N-CH3), 3.82 (s, 3H, -OCH2COOCH3), 4.72 (s, 2H, -OCH2-), 6.98 (s, 2H, 2-CH and
6-CH, aromatic) and 8.13 ppm (s, 2H, 3-CH and 5-CH, aromatic); FT-IR (KBr): max
=
3165, 2953, 1749, 1691, 1647, 1479, 1232, 1065, 988, 839 and 747 cm-1; Anal. calcd.
for C16H16N4O5: C, 55.81; H, 4.68; N, 16.27. Found: C, 55.79; H, 4.71; N, 16.12.
18

4.1.3.2. 1,3-Dimethyl-8-[3-(2-methoxy-2-oxoethoxy)-phenyl]xanthine (14) (0.92 g, 92 %),
mp: 280 ºC (decomp.); 1H NMR (400 MHz, CDCl3):  = 3.43 (s, 3H, N-CH3), 3.66 (s, 3H,
N-CH3), 3.82 (s, 3H, -OCH2COOCH3), 4.77 (s, 2H, -OCH2-), 7.02 (dd, 1H, 4-CH,
aromatic, Jm = 2.74 Hz; Jo = 7.44 Hz), 7.38 (m, 1H, 5-CH, aromatic), 7.76 (s, 1H, 2-CH,
aromatic) and 7.82 ppm (d, 1H, 6-CH, aromatic, Jo = 7.44 Hz); FT-IR (KBr): max
=
3183, 1760, 1703, 1655, 1594, 1522, 1481 and 1297 cm-1; Anal calcd. for C16H16N4O5:
C, 55.81; H, 4.68; N, 16.27. Found: C, 55.76; H, 4.55; N, 16.32.
4.1.3.3. 1,3-Dimethyl-8-[{4-(2-methoxy-2-oxoethoxy)-3-methoxy}-phenyl]xanthine (15)
(0.95 g, 95 %), mp: 212-214 ºC; 1H NMR (400 MHz, DMSO-d6):  = 3.39 (s, 3H, N-CH3),
3.61 (s, 3H, N-CH3), 3.80 (s, 3H, -OCH2COOCH3), 3.93 (s, 3H, -OCH3), 4.80 (s, 2H, -
OCH2-), 6.98 (s, 1H, 5-CH, aromatic), 7.36 (s, 1H, 6-CH, aromatic), 7.81 (s, 1H, 2-CH,
aromatic) and 13.36 ppm (s, 1H, N-H); FT-IR (KBr): max = 2960, 1757, 1694, 1649,
1488, 1266, 1080, 992, 879, 760 and 746 cm-1; Anal. calcd. for C17H18N4O6: C, 54.54;
H, 4.85; N, 14.97. Found: C, 54.35; H, 4.95; N, 14.79.
4.1.3.4. 1,3-Dimethyl-8-[{3-(2-methoxy-2-oxoethoxy)-4-methoxy}-phenyl]xanthine (16)
1
(0.97 g, 97 %), mp: 238-240 ºC; H NMR (400 MHz, CDCl3):  = 3.38 (s, 3H, N-CH3),
3.60 (s, 3H, N-CH3), 3.80 (s, 3H, -OCH2COOCH3), 3.92 (s, 3H, -OCH3), 4.83 (s, 2H, -
OCH2-), 7.01 (d, 1H, 5-CH, aromatic, Jo = 8.56 Hz), 7.74 (d, 1H, 2-CH, aromatic, Jm =
2.00 Hz) and 7.82 ppm (dd, 1H, 6-CH, aromatic, Jo = 8.56 Hz; Jm = 1.96 Hz); FT-IR
(KBr): max = 3159, 2952, 1757, 1697, 1645, 1557, 1486, 1438, 1372, 1274, 1108, 983,
867, and 753 cm-1; Anal. Calcd. for C17H18N4O6: C, 54.54; H, 4.85; N, 14.97. Found: C,
54.74; H, 4.77; N, 14.84.
4.1.4. General method for the synthesis of 8-(carboxymethyloxyphenyl)xanthine
amides 13a-i─16a-i
The mixtures of cyclized xanthine esters 13-16 (1.0 g, 2.90 mmol) with appropriate
amines a-i (in excess) were heated at 80-100 ºC for 30-40 min. The completion of
reaction was monitored by TLC. The excess of amine was removed under vacuum and
19

residue so obtained was washed thoroughly with diethyl ether. The solid so obtained
was filtered, and dried to afford the respective products 13a-i─16a-i, which were
crystallized in methanol.
4.1.4.1. 1,3-Dimethyl-8-[4-{2-(dimethylaminoethylamino)-2-oxoethoxy}-phenyl]xanthine
(13a) (0.62 g, 53 %), mp: 270-272 ºC; 1H NMR (400 MHz, CDCl3-DMSO-d6):  = 2.41 (s,
6H, -N(CH3)2), 2.58-2.60 (m, 2H, -CH2-N<), 3.49-3.52 (s, 3H, N-CH3), 3.48-3.52 (m, 2H,
-CONHCH2), 3.65 (s, 3H, N-CH3), 4.57 (s, 2H, -OCH2-), 7.04 (d, 2H, 2-CH and 6-CH,
aromatic, Jo = 8.96 Hz) and 8.13 ppm (d, 2H, 3-CH and 5-CH, aromatic, Jo = 8.88 Hz);
13C NMR (CDCl3-DMSO-d6): δ = 27.61 (N-CH3), 29.57 (N-CH3), 35.93 (HN-CH2), 44.60
(2×N-CH3), 57.52 (N-CH2), 66.87 (O-CH2), 107.23 (ArC), 114.86 (2×ArCH), 121.90
(ArC), 127.91 (2×ArCH), 148.39 (ArC), 149.70 (ArC), 151.08 (ArC), 153.99 (C=O),
159.00 (C=O), 167.28 (C=O); FT-IR (KBr): max = 3152, 2947, 1693, 1650, 1477, 1250,
1049, 839 and 744 cm-1.; Anal. calcd. for C19H24N6O4: C, 56.99; H, 6.04; N, 20.99.
Found: C, 56.93; H, 6.17; N, 21.06.
4.1.4.2.
8-[4-{2-(Diethylaminoethylamino)-2-oxoethoxy}-phenyl]-1,3-dimethylxanthine
(13b) (0.22 g, 17 %), mp: 258-260 ºC; 1H NMR (400 MHz, CDCl3-DMSO-d6):  = 1.03
(t, 6H, -N(CH2CH3)2; J = 7.06 Hz), 2.56-2.62 (m, 6H, -N(CH2CH3)2 and -CH2N<), 3.38
(s(br), 5H, -CONHCH2 and N-CH3), 3.57 (s, 3H, N-CH3), 4.54 (s, 2H, -OCH2-), 7.03 (d,
2H, 2-CH and 6-CH, aromatic, Jo = 8.44 Hz), 7.81 (s, 1H, -CONHCH2-), 8.11 ppm (d,
13
2H, 3-CH and 5-CH, aromatic, Jo = 8.68 Hz) and 13.38 ppm (s, 1H, N-H); C NMR
(CDCl3-DMSO-d6): δ = 11.47 (2×CH3), 27.59 (N-CH3), 29.55 (N-CH3), 36.23 (HN-CH2),
46.51 (2×N-CH2), 51.10 (N-CH2), 66.89 (O-CH2), 107.25 (ArC), 114.79 (2×ArCH),
121.95 (ArC), 127.89 (2×ArCH), 148.35 (ArC), 149.67 (ArC), 151.05 (ArC), 153.97
(C=O), 158.91 (C=O), 167.15 (C=O); FT-IR (KBr): max = 3187, 2964, 1695, 1656, 1477,
1253, 1049, 983, 842 and 738 cm-1; Anal. calcd. for C21H28N6O4: C, 58.86; H, 6.59; N,
19.61. Found: C, 58.98; H, 6.48; N, 19.73.
4.1.4.3. 1,3-Dimethyl-8-[4-{2-(pyrrolidin-1-yl)-2-oxoethoxy}-phenyl]xanthine (13c) (0.9 g,
80 %), mp: 215-217 ºC; 1H NMR (400 MHz, CDCl3-DMSO-d6):  = 1.88 (p, 2H, -CH2-,
20

pyrrolidine), 2.01 (p, 2H, -CH2-, pyrrolidine), 3.37 (s, 3H, N-CH3), 3.47 (t, 2H, N-CH2,
pyrrolidine, J = 6.76 Hz), 3.53 (t, 2H, N-CH2, pyrrolidine, J = 6.9 Hz), 3.59 (s, 3H, N-
CH3), 4.73 (s, 2H, -OCH2-), 7.00 (d, 1H, 2-CH and 6-CH, aromatic, Jo = 8.92 Hz), 8.09
13
(d, 1H, 3-CH and 5-CH, aromatic, Jo = 8.92 Hz) and 13.43 ppm (s, 1H, N-H); C NMR
(CDCl3-DMSO-d6): δ = 23.46 (2×CH2), 25.67 (HN-CH2), 27.60 (N-CH3), 29.58 (N-CH3),
44.73 (N-CH2), 45.53 (2×N-CH2), 66.15 (O-CH2), 107.18 (ArC), 114.72 (2×ArCH),
121.52 (ArC), 127.82 (2×ArCH), 148.43 (ArC), 149.85 (ArC), 151.10 (ArC), 153.99
(C=O), 159.56 (C=O), 165.23 (C=O); FT-IR (KBr): max = 3168, 2954, 2881, 1687, 1647,
1481, 1357, 1189, 1080 and 984 cm-1; Anal. calcd. for C19H21N5O4: C, 59.52; H, 5.52; N,
18.27. Found: C, 59.61; H, 5.61; N, 18.12.
4.1.4.4. 1,3-Dimethyl-8-[4-{2-(piperidin-1-yl)-2-oxoethoxy}-phenyl]xanthine (13d) (0.70
g, 61 %), mp: 288-290 ºC; 1H NMR (400 MHz, CDCl3-DMSO-d6):  = 1.55-1.68 (m, 6H,
3 x -CH2-, piperidine), 3.40 (s, 3H, N-CH3), 3.49 (t, 2H, N-CH2, piperidine, J = 5.2 Hz),
3.54 (t, 2H, N-CH2, piperidine, J = 5.34 Hz), 3.63 (s, 3H, N-CH3), 4.78 (s, 2H, -OCH2-),
7.02 (d, 2H, 2-CH and 6-CH, aromatic, Jo = 8.68 Hz) and 8.11 ppm (d, 2H, 3-CH and 5-
CH, aromatic, Jo = 8.68 Hz); 13C NMR (CDCl3-DMSO-d6): δ = 23.93 (CH2), 25.22
(2×CH2), 25.91 (HN-CH2), 27.66 (N-CH3), 29.64 (N-CH3), 42.19 (N-CH2), 45.17 (2×N-
CH2), 65.99 (O-CH2), 107.21 (ArC), 114.81 (2×ArCH), 121.51 (ArC), 127.86 (2×ArCH),
148.48 (ArC), 149.86 (ArC), 151.14 (ArC), 154.04 (C=O), 159.60 (C=O), 165.01 (C=O);
FT-IR (KBr): max = 3165, 2939, 2861, 1680, 1649, 1479, 1240, 1188, 1062, 841 and
749 cm-1; Anal. calcd. for C20H23N5O4: C, 60.44; H, 5.83; N, 17.62. Found: C, 60.57; H,
5.72; N, 17.76.
4.1.4.5.
1,3-Dimethyl-8-[4-{2-(hexamethyleneimin-1-yl)-2-oxoethoxy}-phenyl]xanthine
(13e) (0.6 g, 50 %), mp: 196-198 ºC; 1H NMR (400 MHz,CDCl3-DMSO-d6):  1.52 (p,
4H, 2 x -CH2-, hexamethyleneimine), 1.64 (p, 2H, -CH2-, hexamethyleneimine), 1.72 (p,
2H, -CH2-, hexamethyleneimine), 3.30 (s, 3H, N-CH3), 3.45 (t, 4H, N-(CH2)2,
hexamethylene imine, J = 5.84 Hz), 3.52 (s, 3H, N-CH3), 4.75 (s, 2H, -OCH2-), 6.94 (d,
2H, 2-CH and 6-CH, aromatic, Jo = 8.84 Hz), 8.05 (d, 2H, 3-CH and 5-CH, aromatic, Jo
13
= 8.84 Hz) and 13.42 ppm (s, 1H, N-H); C NMR (CDCl3-DMSO-d6): δ = 26.09 (CH2),
26.89 (CH2), 26.95 (HN-CH2), 27.58 (N-CH3), 28.51 (2×CH2), 29.55 (N-CH3), 45.34 (N-
21

CH2), 46.33 (2×N-CH2), 65.88 (O-CH2), 107.18 (ArC), 114.65 (2×ArCH), 121.53 (ArC),
127.82 (2×ArCH), 148.41 (ArC), 149.84 (ArC),151.10 (ArC), 153.99 (C=O), 159.53
(C=O), 166.24 (C=O); FT-IR (KBr): max = 3170, 2931, 1691, 1650, 1480, 1244, 1064
and 839 cm-1; Anal. calcd. for C21H25N5O4: C, 61.30; H, 6.12; N, 17.02.Found: C, 61.38;
H, 6.20; N, 16.91.
4.1.4.6. 1,3-Dimethyl-8-[4-{2-(morpholin-1-yl)-2-oxoethoxy}-phenyl]xanthine (13f) (0.84
g, 72 %), mp: 262-264 ºC; 1H-NMR (400 MHz, CDCl3-DMSO-d6):  = 3.32 (s, 3H, N-
CH3), 3.50-3.55 (m, 7H, N-(CH2)2, morpholine and N-CH3), 3.60-3.67 (m, 4H, O-(CH2)2,
morpholine), 4.86 (s, 2H, -OCH2-), 7.01 (d, 2H, 2-CH and 6-CH, aromatic, Jo = 8.88 Hz)
and 8.08 ppm (d, 2H, 3-CH and 5-CH, aromatic, Jo = 8.88 Hz); 13C NMR (CDCl3-DMSO-
d6): δ = 27.66 (N-CH3), 29.64 (N-CH3), 41.56 (N-CH2), 44.66 (N-CH2), 65.69 (2×O-CH2),
66.03 (O-CH2), 107.22 (ArC), 114.67 (ArCH), 114.86 (ArCH), 121.58 (ArC), 127.84
(2×ArCH), 148.47 (ArC), 149.82 (ArC), 151.11 (ArC), 154.03 (C=O), 159.51 (C=O),
165.63 (C=O); FT-IR (KBr): max = 3172, 2956, 1690, 1649, 1481, 1237, 1111, 1031,
984, 846 and 754 cm-1; Anal. Calcd. for C19H21N5O5: C, 57.14; H, 5.30; N, 17.53. Found:
C, 57.29; H, 5.23; N, 17.46.
4.1.4.7.
1,3-Dimethyl-8-[4-{2-(1-methylpiperazin-4-yl)-2-oxoethoxy}-phenyl]xanthine
(13g) (0.80 g, 66 %), mp: 230 ºC (decomp.). 1H NMR (400 MHz, CDCl3-DMSO-d6):  =
2.28 (s, 3H, >N-CH3, N-methylpiperazine), 2.36 (t(br), 2H, N-CH2, N-methylpiperazine),
2.42 (t(br), 2H, N-CH2, N-methylpiperazine), 3.35 (s, 3H, N-CH3), 3.57 (s(br), 7H, N-CH3
and -N(CH2)2, N-methylpiperazine), 4.84 (s, 2H, -OCH2-), 7.0 (d, 2H, 2-CH and 6-CH,
aromatic, Jo = 8.88 Hz), 8.09 (d, 2H, 3-CH and 5-CH, aromatic, Jo = 8.84 Hz) and 13.46
ppm (s, 1H, N-H); 13C NMR (CDCl3-DMSO-d6): δ = 27.64 (N-CH3), 29.61 (N-CH3), 41.10
(N-CH3), 43.96 (N-CH2), 45.58 (N-CH2), 54.15 (N-CH2), 54.53 (N-CH2), 65.77 (O-CH2),
107.17 (ArC), 114.79 (2×ArCH), 121.51 (ArC), 127.81 (2×ArCH), 148.39 (ArC), 149.78
(ArC), 151.07 (ArC), 153.97 (C=O), 159.49 (C=O), 165.37 (C=O); FT-IR (KBr): max
=
3170, 2946, 1680, 1648, 1560, 1481, 1292, 1187, 1032, 987, 841 and 753 cm-1; Anal.
Calcd. for C20H24N6O4: C, 58.24; H, 5.87; N, 20.38. Found: C, 58.44; H, 5.78; N, 20.41.
22

4.1.4.8. 1,3-Dimethyl-8-[4-{2-(imidazol-1-yl)-2-oxoethoxy}-phenyl]xanthine (13h) (0.4 g,
36 %), mp: 250 ºC (decomp.); 1H NMR (400 MHz, CDCl3-DMSO-d6):  = 3.42 (s, 3H, N-
CH3), 3.69 (s, 3H, N-CH3), 4.65 (s, 2H, -OCH2-), 6.99 (d, 2H, 2-CH and 6-CH, aromatic,
Jo = 8.88 Hz), 7.32 (s(br), 2H, CH, imidazole), 8.11 (d, 2H, 3-CH and 5-CH, aromatic, Jo
= 8.88 Hz), 8.69 (s(br), 1H, CH, imidazole) and 13.32 ppm (s, 1H, N-H); 13C NMR
(DMSO-d6): δ = 27.75 (N-CH3), 29.73 (N-CH3), 56.83 (O-CH2), 99.49 (2×ArCH), 107.23
(ArC), 114.84 (2×ArCH), 121.52 (ArC), 127.95 (3×ArCH), 148.51 (ArC), 149.80 (2×ArC),
151.16 (C=O), 154.07 (C=O), 159.40 (C=O); FT-IR (KBr): max = 3179, 2951, 2562,
1685, 1648, 1481, 1306, 1244, 1189, 1058, 987, 840 and 754 cm-1; Anal. calcd. for
C18H16N6O4: C, 56.84; H, 4.24; N, 22.10. Found: C, 56.70; H, 4.16; N, 21.94.
4.1.4.9. 1,3-Dimethyl-8-[4-{2-(homoveratrylamino)-2-oxoethoxy}-phenyl]xanthine (13i)
(0.92 g, 64 %), mp: 283-285 ºC; 1H NMR (400 MHz, CDCl3-DMSO-d6):  = 2.77 (t, 2H, -
CONHCH2CH2-), 3.36 (s, 3H, N-CH3), 3.47 (q, 2H, -CONHCH2CH2-), 3.59 (s, 3H, N-
CH3), 3.80 (s, 6H, 2 x OCH3), 4.52 (s, 2H, -OCH2-), 6.70 (dd, 1H, 5-CH, aromatic, Jm =
1.74 Hz, homoveratrylamine), 6.76-6.80 (m, 2H, 2-CH and 6-CH, aromatic,
homoveratrylamine), 6.99 (d, 2H, 2-CH and 6-CH, aromatic, Jo = 8.84 Hz), 7.74 (s, 1H, -
CONHCH2CH2-), 8.11 (d, 2H, 3-CH and 5-CH, aromatic, Jo = 8.88 Hz) and 13.49 ppm
(s, 1H, N-H); 13C NMR (DMSO-d6): δ = 27.72 (N-CH3), 29.70 (N-CH3), 34.58 (CH2),
40.07 (HN-CH2), 55.29 (O-CH3), 55.40 (O-CH3), 66.91 (O-CH2), 107.34 (ArC), 111.73
(ArCH), 112.34 (ArCH), 115.02 (2×ArCH), 120.39 (ArC), 121.87 (ArCH), 127.92
(2×ArCH), 131.61 (ArC), 147.16 (ArC), 148.49 (ArC), 148.55 (ArC), 149.74 (ArC),
151.13 (ArC), 154.08 (C=O), 159.15 (C=O), 167.13 (C=O); FT-IR (KBr): max = 3171,
2940, 1702, 1654, 1478, 1235, 839 and 744 cm-1; Anal. calcd. for C25H27N5O6: C, 60.84;
H, 5.51; N, 14.19. Found: C, 60.81; H, 5.66; N, 14.26.
4.1.4.10. 1,3-Dimethyl-8-[3-{2-(dimethylaminoethylamino)-2-oxoethoxy}-phenyl]xanthine
(14a) (0.86 g, 69 %), mp: 215-217 ºC; 1H NMR (400 MHz, DMSO-d6):  = 2.33 (s, 6H, -
N(CH3)2), 2.58 (s, 2H, -CH2N<), 3.39 (s, 3H, N-CH3), 3.44 (q, 2H, -CONHCH2CH2-),
3.62 (s, 3H, N-CH3), 4.60 (s, 2H, -OCH2-), 7.05 (dd, 1H, 4-CH, aromatic, Jm = 1.88 Hz;
Jo = 8.00 Hz), 7.38 (t, 1H, 5-CH, aromatic, Jo = 7.96 Hz), 7.61 (s(br), 1H, N-H), 7.73 (d,
23

1H, 2-CH, aromatic, Jm = 2.08 Hz) and 7.81 ppm (dd, 1H, 6-CH, aromatic, Jm = 2.20 Hz;
Jo = 8.40 Hz); 13C NMR (DMSO-d6): δ = 27.78 (N-CH3), 29.78 (N-CH3), 35.86 (HN-CH2),
44.59 (2×N-CH3), 57.56 (N-CH2), 66.95 (O-CH2), 107.82 (ArC), 112.14 (ArCH), 116.83
(ArCH), 119.30 (ArC), 129.96 (ArCH), 130.14 (ArCH), 148.34 (ArC), 149.31 (ArC),
151.16 (ArC), 154.23 (C=O), 157.91 (C=O) and 167.44 ppm (C=O); FT-IR (KBr): max
=
3170, 2947, 1699, 1661, 1521, 1446, 1279, 1225, 1054, 792 and 724 cm-1; Anal. calcd.
for C19H24N6O4: C, 56.99; H, 6.04; N, 20.99. Found: C, 56.80; H, 6.10; N, 21.03.
4.1.4.11. 8-[3-{2-(Diethylaminoethylamino)-2-oxoethoxy}-phenyl]-1,3-dimethylxanthine
(14b) (0.6 g, 51 %), mp: 240 ºC (decomp.); 1H NMR (400 MHz, DMSO-d6):  = 1.0 (t,
6H, -N(CH2CH3)2, J = 7.01 Hz), 2.51-2.61 (m, 6H, -N(CH2CH3)2 and -CH2N<), 3.34 (q,
2H, -CONHCH2CH2-), 3.40 (s, 3H, N-CH3), 3.62 (s, 3H, N-CH3), 4.58 (s, 2H, -OCH2-),
7.03 (dd, 1H, 4-CH, aromatic, Jm = 1.74 Hz; Jo = 8.22 Hz), 7.39 (t, 1H, 5-CH, aromatic,
Jo = 8.16 Hz), 7.50 (s(br), 1H, N-H) and 7.82-7.84 ppm (m, 2H, 2-CH and 6-CH,
aromatic); 13C NMR (DMSO-d6): δ = 11.65 (2×CH3), 27.69 (N-CH3), 29.67 (N-CH3),
36.34 (HN-CH2), 46.55 (2×N-CH2), 51.17 (N-CH2), 66.94 (O-CH2), 108.04 (ArC), 111.88
(ArCH), 116.56 (ArCH), 119.23 (ArC), 129.96 (ArCH), 130.22 (ArCH), 148.28 (ArC),
149.41 (ArC), 151.07 (ArC), 154.23 (C=O), 157.77 (C=O) and 167.24 ppm (C=O); FT-IR
(KBr): max = 3178, 2968, 1700, 1669, 1523, 1479 and 1216 cm-1; Anal. calcd. for
C21H28N6O4: C, 58.86; H, 6.59; N, 19.61. Found: C, 58.98; H, 6.72; N, 19.52.
4.1.4.12. 1,3-Dimethyl-8-[3-{2-(pyrrolidin-1-yl)-2-oxoethoxy}-phenyl]xanthine (14c) (0.79
g, 70 %), mp: 280 ºC (decomp.); 1H NMR (400 MHz, DMSO-d6):  = 1.87 (p, 2H, -CH2-,
pyrrolidine), 2.00 (p, 2H, -CH2-, pyrrolidine), 3.35 (s, 3H, N-CH3), 3.45 (t, 2H, N-CH2,
pyrrolidine, J = 6.94 Hz), 3.56 (t, 2H, N-CH2, pyrrolidine, J = 6.84 Hz), 3.58 (s, 3H, N-
CH3), 4.75 (s, 2H, -OCH2-), 7.00 (dd, 1H, 4-CH, aromatic, Jm = 2.26 Hz; Jo = 8.22 Hz),
7.36 (t, 1H, 5-CH, aromatic, Jo = 7.96 Hz), 7.75 (d, 1H, 2-CH, aromatic, Jm = 2.16 Hz),
7.77 (d, 1H, 6-CH, aromatic, Jo = 7.88 Hz) and 13.63 ppm (s, 1H, N-H); 13C NMR
(DMSO-d6): δ = 23.49 (CH2), 25.67 (CH2), 27.78 (N-CH3), 29.76 (N-CH3), 44.77 (N-
CH2), 45.57 (N-CH2), 66.17 (O-CH2), 107.64 (ArC), 112.26 (ArCH), 116.48 (ArCH),
118.99 (ArC), 129.99 (2×ArCH), 144.99 (ArC), 149.61 (ArC), 151.17 (ArC), 154.30
(C=O), 158.44 (C=O) and 165.41 ppm (C=O); FT-IR (KBr): max = 3154, 2953, 1699,
24

1653, 1520, 1476 and 1218 cm-1; Anal. calcd. for C19H21N5O4: C, 59.52; H, 5.52; N,
18.27. Found: C, 59.66; H, 5.45; N, 18.44.
4.1.4.13. 1,3-Dimethyl-8-[3-{2-(piperidin-1-yl)]-2-oxoethoxy}-phenyl]xanthine (14d) (0.72
1
g, 62 %), mp: 240 ºC (decomp.); H NMR (400 MHz, CDCl3-DMSO-d6):  = 1.57 (t(br),
2H, -CH2, piperidine), 1.67 (p(br), 4H, -(CH2)2, piperidine), 3.42 (s, 3H, N-CH3), 3.50 (t,
2H, -N-CH2, piperidine, J = 4.94 Hz), 3.57 (t, 2H, -N-CH2, piperidine, J = 5.44 Hz), 3.64
(s, 3H, N-CH3), 4.79 (s, 2H, -OCH2-), 7.03 (dd, 1H, 4-CH, aromatic, Jm = 2.50 Hz; Jo =
7.54 Hz), 7.37 (t, 1H, 5-CH, aromatic, Jo = 7.96 Hz), 7.78 (d, 1H, 2-CH, aromatic, Jm =
2.88 Hz) and 7.80 ppm (d, 1H, 6-CH, aromatic, Jo = 7.84 Hz); 13C NMR (DMSO-d6): δ =
23.95 (CH2), 25.29 (CH2), 25.98 (CH2), 27.75 (N-CH3), 29.68 (N-CH3), 42.18 (N-CH2),
45.23 (N-CH2), 65.92 (O-CH2), 107.73 (ArC), 112.10 (ArCH), 116.48 (ArCH), 118.91
(ArC), 129.82 (ArCH), 129.96 (ArCH), 148.30 (ArC), 149.40 (ArC), 151.10 (ArC), 154.19
(C=O), 158.36 (C=O) and 165.11 ppm (C=O); FT-IRmax (KBr): 3164, 2936, 1695, 1647,
1522, 1450, 985 and 791 cm-1; Anal. calcd. for C20H23N5O4: C, 60.44; H, 5.83; N, 17.62.
Found: C, 60.34; H, 5.76; N, 17.79.
4.1.4.14. 1,3-Dimethyl-8-[3-{2-(hexamethyleneimin-1-yl)-2-oxoethoxy}-phenyl]xanthine
(14e) (0.6 g, 50 %), mp: 210 ºC (decomp.). 1H NMR (400 MHz, CDCl3-DMSO-d6):  =
1.60 (p, 4H, 2 x -CH2-, hexamethyleneimine), 1.73 (p, 2H, -CH2-, hexamethyleneimine),
1.82 (p, 2H, -CH2-, hexamethyleneimine), 3.40 (s, 3H, N-CH3), 3.55 (t, 4H, -N-(CH2)2,
hexamethyleneimine), 3.63 (s, 3H, N-CH3), 4.81 (s, 2H, -OCH2-), 7.02 (dd, 1H, 4-CH,
aromatic, Jm = 2.20 Hz; Jo = 8.16 Hz), 7.37 (t, 1H, 5-CH, aromatic, Jo = 7.98 Hz), 7.76
(d, 1H, 2-CH, aromatic, Jm = 2.08 Hz), 7.79 (d, 1H, 6-CH, aromatic, Jo = 7.80 Hz) and
13
13.52 ppm (s, 1H, N-H); C NMR (DMSO-d6): δ = 26.11 (CH2), 26.83 (CH2), 27.03
(CH2), 27.75 (CH2), 28.48 (N-CH3), 29.67 (N-CH3), 45.21 (N-CH2), 46.24 (N-CH2), 65.71
(O-CH2), 107.82 (ArC), 112.00 (ArCH), 116.48 (ArCH), 118.83 (ArC), 129.90 (2×ArCH),
148.32 (ArC), 149.47 (ArC), 151.11 (ArC), 154.22 (C=O), 158.42 (C=O) and 166.37
ppm (C=O); FT-IR (KBr): max = 3160, 2928, 1698, 1649, 1477, 1288, 1223 and 752
cm-1. Anal. calcd. for C21H25N5O4: C, 61.30; H, 6.12; N, 17.02. Found: C, 61.53; H, 5.99;
N, 17.18.
25

4.1.4.15. 1,3-Dimethyl-8-[3-{2-(morpholin-1-yl)-2-oxoethoxy}-phenyl]xanthine (14f) (0.78
g, 67 %), mp 250 ºC (decomp.); 1H NMR (400 MHz, CDCl3-DMSO-d6):  3.43 (s, 3H, N-
CH3), 3.65 (s, merged with multiplet, 7H, -N-(CH2)2, morpholine and N-CH3), 3.70-3.73
(m, 4H, O-(CH2)2, morpholine), 4.81 (s, 2H, -OCH2-), 7.35 (dd, 1H, 4-CH, aromatic, Jm =
2.12 Hz; Jo = 7.88 Hz), 7.38 (t, 1H, 5-CH, aromatic, Jo = 7.96 Hz), 7.79-7.83 (m, 2H, 2-
13
CH and 6-CH, aromatic) and 9.98 ppm (s, 1H, N-H); C NMR (CDCl3-DMSO-d6): δ =
27.76 (N-CH3), 29.75 (N-CH3), 41.63 (N-CH2), 44.80 (N-CH2), 57.63 (O-CH2), 65.70 (O-
CH2), 66.07 (O-CH2), 108.44 (ArC), 112.18 (ArCH), 116.20 (ArCH), 118.97 (ArC),
129.93 (ArCH), 130.48 (ArCH), 148.52 (ArC), 149.79 (ArC), 151.20 (ArC), 154.47
(C=O), 158.27 (C=O) and 165.79 ppm (C=O); FT-IR (KBr): max = 3148, 2926, 1699,
1652, 1519, 1478, 1211 and 795 cm-1; Anal. calcd. for C19H21N5O5: C, 57.14; H, 5.30; N,
17.53. Found: C, 57.24; H, 5.35; N, 17.60.
4.1.4.16.
1,3-Dimethyl-8-[3-{2-(1-methylpiperazin-4-yl)-2-oxoethoxy}-phenyl]xanthine
(14g) (0.6 g, 50 %), mp: 218-220 ºC; 1H-NMR (400 MHz, DMSO-d6):  2.28 (s, 3H, >N-
CH3, N-methylpiperazine), 2.37 (t(br), 2H, N-CH2, N-methylpiperazine Jo = 4.0 Hz), 2.44
(t(br), 2H, N-CH2, N-methylpiperazine), 3.36 (s, 3H, N-CH3), 3.59 (s(br), 7H, N-CH3 and
-N-(CH2)2, N-methylpiperazine), 4.83 (s, 2H, -OCH2-), 7.01 (dd, 1H, 4-CH, aromatic, Jm
= 2.04 Hz; Jo = 8.16 Hz), 7.36 (t, 1H, 5-CH, aromatic, Jo = 7.98 Hz), 7.75-7.79 (m, 2H,
2-CH and 6-CH, aromatic) and 13.62 ppm (s, 1H, N-H); 13C NMR (DMSO-d6): δ = 27.78
(N-CH3), 29.77 (N-CH3), 41.15 (N-CH3), 45.52 (2×N-CH2), 54.55 (2×N-CH2), 65.78 (O-
CH2), 107.76 (ArC), 112.24 (ArCH), 116.52 (ArCH), 119.02 (ArC), 129.75 (ArCH),
130.04 (ArCH), 148.27 (ArC), 149.38 (ArC), 151.16 (ArC), 154.22 (C=O), 158.37 (C=O)
and 165.53 ppm (C=O); FT-IR (KBr): max = 3163, 2938, 1695, 1648, 1522, 1478, 1221
and 717 cm-1; Anal. calcd. for C20H24N6O4: C, 58.24; H, 5.87; N, 20.38. Found: C, 58.14;
H, 5.97; N, 20.14.
4.1.4.17. 1,3-Dimethyl-8-[3-{2-(imidazol-1-yl)-2-oxoethoxy}-phenyl]xanthine (14h) (0.720
g, 65 %), mp: 250 ºC (decomp.); 1H NMR (400 MHz, CDCl3-DMSO-d6):  = 3.40 (s, 3H,
N-CH3), 3.63 (s, 3H, N-CH3), 4.71 (s, 2H, -OCH2-), 7.01 (dd, 1H, 4-CH, aromatic, Jm =
2.04 Hz; Jo = 8.00 Hz), 7.27 (s, 1H, CH, imidazole), 7.37 (t, 1H, 5-CH, aromatic, Jo =
26

7.94 Hz), 7.78 (d, 2H, 2-CH and 6-CH, aromatic, Jm = 2.44 Hz), 7.82 (s, 1H, CH,
13
imidazole), 8.42 (s, 1H, CH, imidazole) and 13.56 ppm (s, 1H, N-H); C NMR (DMSO-
d6): δ = 27.78 (N-CH3), 29.77 (N-CH3), 64.56 (O-CH2), 105.64 (ArCH), 105.96 (ArCH),
107.71 (ArC), 111.48 (ArCH), 116.81 (ArCH), 119.16 (ArC), 129.80 (2×ArCH), 130.12
(ArCH), 148.33 (ArC), 149.32 (ArC), 151.16 (ArC), 154.22 (C=O), 158.13 (C=O) and
170.03 ppm (C=O); FT-IR (KBr): max = 3161, 2950, 1692, 1647, 1523, 1479, 1364,
1289, 984 and 754 cm-1; Anal. calcd. for C18H16N6O4: C, 56.84; H, 4.24; N, 22.10.
Found: C, 56.98; H, 4.32; N, 22.00.
4.1.4.18. 1,3-Dimethyl-8-[3-{2-(homoveratrylamino)-2-oxoethoxy}-phenyl]xanthine (14i)
(0.91 g, 63 %), mp: 220 ºC (decomp.); 1H NMR (400 MHz, CDCl3-DMSO-d6):  = 2.97 (t,
2H, -CONHCH2CH2-), 3.40 (s, 3H, N-CH3), 3.53 (q, 2H, -CONHCH2CH2-), 3.63 (s, 3H,
N-CH3), 3.81 (s, 3H, -OCH3), 3.82 (s, 3H, -OCH3), 4.57 (s, 2H, -OCH2-), 6.69-6.78 (m,
3H, CH, aromatic, homoveratrylamine), 6.99 (dd, 1H, 4-CH, aromatic, Jm = 2.06 Hz; Jo =
8.22 Hz), 7.38 (t merged with br(s), 2H, 5-CH, aromatic, Jo = 8.00 Hz and N-H) and
13
7.81-7.84 ppm (m, 2H, 2-CH and 6-CH, aromatic); C NMR (DMSO-d6): δ = 27.75 (N-
CH3), 29.76 (N-CH3), 34.63 (CH2), 40.08 (HN-CH2), 55.28 (O-CH3), 55.40 (O-CH3),
66.97 (O-CH2), 111.74 (ArC), 112.11 (ArCH), 112.33 (2×ArCH), 116.43 (ArCH), 119.20
(2×ArC), 120.37 (ArCH), 130.02 (ArCH), 131.65 (ArCH), 147.15 (ArC), 148.51 (ArC),
148.55 (ArC), 149.72 (ArC), 151.20 (ArC), 154.46 (C=O), 157.95 (C=O) and 167.25
ppm (C=O); FT-IR (KBr): max = 3184, 3096, 2933, 1704, 1668, 1518, 1448 and 1264
cm-1; Anal. calcd. for C25H27N5O6: C, 60.84; H, 5.51; N, 14.19. Found: C, 60.71; H, 5.61;
N, 14.11.
4.1.4.19.
1,3-Dimethyl-8-[{4-(2-(dimethylaminoethylamino)-2-oxoethoxy)-3-methoxy}-
1
phenyl]-xanthine (15a) (0.44 g, 38 %), mp: 190 ºC (decomp.); H NMR (400 MHz,
CDCl3-DMSO-d6):  = 2.30 (s, 6H, -N(CH3)2), 2.51-2.54 (m, 2H, -CH2N<), 3.45 (s
merged with triplet, 5H, -CONHCH2- and N-CH3), 3.67 (s, 3H, N-CH3), 3.96 (s, 3H, -
OCH3), 4.57 (s, 2H, -OCH2-), 6.98 (s, 1H, 5-CH, aromatic), 7.35 (s, 1H, 2-CH, aromatic),
13
7.37 (s(br), 1H, N-H) and 7.55 ppm (s, 1H, 6-CH, aromatic); C NMR (CDCl3-DMSO-
d6): δ = 27.70 (N-CH3), 29.74 (N-CH3), 36.09 (HN-CH2), 44.80 (2×N-CH3), 55.93 (N-
CH2), 57.60 (O-CH3), 67.95 (O-CH2), 107.45 (ArC), 114.13 (ArCH), 115.56 (ArCH),
27

121.12 (ArC), 123.37 (ArCH), 147.69 (ArC), 147.74 (ArC), 147.88 (ArC), 148.78 (ArC),
151.11 (C=O), 154.23 (C=O) and 166.96 ppm (C=O); FT-IR (KBr): max = 2939, 2820,
2775, 1694, 1655, 1526, 1491, 1262, 1047, 824 and 747 cm-1; Anal. calcd. for
C20H26N6O5: C, 55.80; H, 6.09; N, 19.52. Found: C, 55.97; H, 5.97; N, 19.66.
4.1.4.20.
8-[{4-(2-(Diethylaminoethylamino)-2-oxoethoxy)-3-methoxy}-phenyl]-1,3-
dimethyl- xanthine (15b) (0.62 g, 50.65%), mp: 188-190 ºC; 1H NMR (CDCl3):  = 1.00
(t, 6H, -N(CH2CH3)2, J = 7.14 Hz), 2.54 (q, 4H, -N(CH2CH3)2), 2.59 (t, 2H, -CH2N<, J =
6.0 Hz), 3.39-3.42 (m, 2H, -CONHCH2CH2-), 3.45 (s, 3H, N-CH3), 3.68 (s, 3H, N-CH3),
3.98 (s, 2H, -OCH3), 4.57 (s, 2H, -OCH2-), 6.93 (s, 1H, 5-CH, aromatic), 7.27 (s, 1H, 2-
CH, aromatic), 7.36 (s, 1H, N-H) and 7.82 ppm (s, 1H, 6-CH, aromatic); 13C NMR
(CDCl3-DMSO-d6): δ = 11.66 (2×CH3), 27.72 (N-CH3), 29.76 (N-CH3), 36.39 (HN-CH2),
46.48 (2×N-CH2), 51.12 (N-CH2), 55.92 (O-CH3), 67.94 (O-CH2), 107.59 (ArC), 114.08
(ArCH), 115.46 (ArCH), 121.24 (ArC), 123.46 (ArCH), 147.73 (ArC), 147.77 (ArC),
147.94 (ArC), 148.59 (ArC), 151.17 (C=O), 154.29 (C=O) and 166.81 ppm (C=O); FT-IR
(KBr): max = 2976, 2822, 1693, 1653, 1537, 1486, 1387, 1236, 1041, 880 and 750 cm-1;
Anal. calcd. for C22H30N6O5: C, 57.63; H, 6.59; N, 18.33. Found: C, 57.86; H, 6.47; N,
18.22.
4.1.4.21. 1,3-Dimethyl-8-[3-methoxy-4-{2-(pyrrolidin-1-yl)-2-oxoethoxy}-phenyl]xanthine
(15c) (0.6 g, 54 %), mp: 215-217 ºC; 1H NMR (400 MHz, CDCl3):  = 1.88 (p, 2H, -CH2-,
pyrrolidine), 2.01 (p, 2H, -CH2-, pyrrolidine), 3.39 (s, 3H, N-CH3), 3.47 (t, 2H, N-CH2,
pyrrolidine, J = 6.92 Hz), 3.53 (t, 2H, N-CH2, pyrrolidine, J = 6.80 Hz), 3.62 (s, 3H, N-
CH3), 3.92 (s, 3H, -OCH3), 4.77 (s, 2H, -OCH2-), 7.02 (s, 1H, 5-CH, aromatic), 7.35 (s,
13
1H, 2-CH, aromatic) and 7.80 ppm (s, 1H, 6-CH, aromatic); C NMR (DMSO-d6): δ =
23.49 (CH2), 25.60 (CH2), 27.79 (N-CH3), 29.84 (N-CH3), 44.55 (N-CH2), 45.55 (N-CH2),
55.95 (O-CH3), 66.47 (O-CH2), 107.35 (ArC), 114.09 (ArCH), 114.73 (ArCH), 120.32
(ArC), 123.25 (ArCH), 147.48 (2×ArC), 147.92 (ArC), 149.33 (ArC), 151.15 (C=O),
154.28 (C=O) and 164.94 ppm (C=O); FT-IR (KBr): max = 2953, 1706, 1663, 1550,
1484, 1178, 1073 and 988 cm-1; Anal. calcd. for C20H23N5O5: C, 58.10; H, 5.61; N,
16.94. Found: C, 57.97; H, 5.73; N, 16.86.
28

4.1.4.22. 1,3-Dimethyl-8-[3-methoxy-4-{2-(piperidin-1-yl)-2-oxoethoxy}-phenyl]xanthine
(15d)
(0.32 g, 28 %), mp: 218-220 ºC; 1H NMR (400 MHz, CDCl3):  = 1.57-1.67 (m, 6H, 3 x -
CH2-, piperidine), 3.45 (s, 3H, N-CH3), 3.48 (t, 2H, N-CH2, piperidine, J = 5.22 Hz), 3.58
(t, 2H, N-CH2, piperidine, J = 5.42 Hz), 3.68 (s, 3H, N-CH3), 3.97 (s, 3H, -OCH3), 4.82
(s, 2H, -OCH2-), 6.97 (s, 1H, 5-CH, aromatic), 7.27 (s, 1H, 2-CH, aromatic) and 7.79
ppm (s, 1H, 6-CH, aromatic); FT-IR (KBr): max = 2937, 1705, 1659, 1551, 1486, 1259,
1065 and 990 cm-1; Anal. calcd. for C21H25N5O5: C, 59.01; H, 5.90; N, 16.38. Found: C,
58.90; H, 5.85; N, 16.25.
4.1.4.23.
1,3-Dimethyl-8-[{4-(2-(hexamethyleneimin-1-yl)-2-oxoethoxy)-3-methoxy}-
phenyl]-xanthine (15e) (0.5 g, 42 %), mp 114 ºC (decomp.); 1H NMR (400 MHz, CDCl3):
 = 1.58-1.60 (m, 4H, 2 x -CH2-, hexamethyleneimine), 1.72-1.76 (m, 2H, -CH2-,
hexamethyleneimine), 1.79 (m, 2H, -CH2-, hexamethyleneimine), 3.46 (s, 3H, N-CH3),
3.51 (t, 2H, N-CH2, hexamethyleneimine, J = 6.06 Hz), 3.57 (t, 2H, N-CH2,
hexamethyleneimine, J = 5.96 Hz), 3.68 (s, 3H, N-CH3), 3.95 (s, 2H, -OCH3), 4.85 (s,
2H, -OCH2-), 6.94 (s, 1H, 5-CH, aromatic), 7.26 (s, 1H, 2-CH, aromatic) and 7.79 ppm
(s, 1H, 6-CH, aromatic); 13C NMR (CDCl3-DMSO-d6): δ 26.04 (CH2), 26.82 (CH2), 27.05
(CH2), 27.77 (N-CH3), 28.31 (CH2), 29.83 (N-CH3), 45.21 (N-CH2), 46.15 (N-CH2), 55.93
(O-CH3), 66.10 (O-CH2), 107.61 (ArC), 114.07 (ArC), 114.63 (ArCH), 120.42 (ArC),
123.17 (ArCH), 147.46 (ArC), 147.96 (ArC), 148.02 (ArC), 149.23 (ArC), 151.15 (C=O),
154.33 (C=O) and 165.94 ppm (C=O); FT-IR (KBr): max = 2926, 2855, 1706, 1653,
1551, 1487, 1263, 1058, 877 and 744 cm-1; Anal. calcd. for C22H27N5O5: C, 59.85; H,
6.16; N, 15.86. Found: C, 59.72; H, 6.26; N, 15.72.
4.1.4.24. 1,3-Dimethyl-8-[3-methoxy-4-{2-(morpholin-1-yl)-2-oxoethoxy}-phenyl]xanthine
1
(15f) (0.78 g, 68 %), mp: 238-240 ºC; H NMR (400 MHz, CDCl3):  = 3.43 (s, 3H, N-
CH3), 3.59-3.63 (m, 4H, N-(CH2)2, morpholine), 3.65 (s, 3H, N-CH3), 3.68-3.70 (m, 4H,
O-(CH2)2, morpholine), 3.93 (s, 3H, -OCH3), 4.84 (s, 2H, -OCH2-), 7.04 (s, 1H, 5-CH,
aromatic), 7.41 (s, 1H, 2-CH, aromatic), 7.56 (s, 1H, 6-CH, aromatic) and 13.09 ppm (s,
13
1H, N-H); C NMR (CDCl3-DMSO-d6): δ = 27.79 (N-CH3), 29.83 (N-CH3), 41.59 (N-
CH2), 44.64 (N-CH2), 55.98 (O-CH3), 65.97 (O-CH2), 66.06 (O-CH2), 66.12 (O-CH2),
29