A new synthesis of sulfonamides by aminolysis of p-nitrophenylsulfonates yielding potent and selective adenosine A2B receptor antagonists

Article abstract of DOI:10.1021/jm060277v

1-Propyl- and 1,3-dimethyl-8-p-sulfophenylxanthine (PSB-1115 and SPT) were used as starting compounds for the development of adenosine A_2B receptor antagonists with a sulfonamide structure. Since standard reactions for sulfonamide formation fai

Full text of DOI:10.1021/jm060277v

4384
J. Med. Chem. 2006, 49, 4384-4391
A New Synthesis of Sulfonamides by Aminolysis of p-Nitrophenylsulfonates Yielding Potent and
Selective Adenosine A2B Receptor Antagonists
Luo Yan,§ Daniela C. G. Bertarelli,§ Alaa M. Hayallah,§,† Heiko Meyer,§ Karl-Norbert Klotz,‡ and Christa E. Mu¨ller*,§
Pharmaceutical Institute, Pharmaceutical Chemistry Poppelsdorf, UniVersity of Bonn, Kreuzbergweg 26, D-53115 Bonn, Germany, Faculty of
Pharmacy, Assiut UniVersity, Egypt, and Institute of Pharmacology and Toxicology, UniVersity of Wu¨rzburg, D-97078 Wu¨rzburg, Germany
ReceiVed March 13, 2006
1-Propyl- and 1,3-dimethyl-8-p-sulfophenylxanthine (PSB-1115 and SPT) were used as starting compounds
for the development of adenosine A2B receptor antagonists with a sulfonamide structure. Since standard
reactions for sulfonamide formation failed or resulted in very low yields, we developed a new method for
the preparation of sulfonamides. p-Nitrophenoxide was used as a suitable leaving group with well balanced
stability-reactivity properties. A large variety of amines, including aniline, benzylamine, phenethylamine,
propylamine, butylamine, 2-hydroxyethylamine, aminoacetic acid, and N-benzylpiperazine reacted with
p-nitrophenoxysulfonylphenylxanthine derivatives yielding the desired sulfonamides in satisfying to very
good yields. The obtained sulfonamides were much more potent at A2B receptors than the parent sulfonates.
The most active compound of the present series was 8-[4-(4-benzylpiperazide-1-sulfonyl)phenyl]-1-
propylxanthine (11, PSB-601) exhibiting a Ki value of 3.6 nM for the human A2B receptor combined with
high selectivity versus the other human adenosine receptor subtypes (575-fold versus A1, 134-fold versus
A2A, and >278-fold versus A3).
Introduction
Sulfonamide derivatives belong to the most important struc-
tural classes of drug molecules. Antibacterial agents with a
sulfonamide structure, e.g. sulfadiazine, and diuretics, such as
hydrochlorothiazide, have been therapeutically used for many
decades.1 Examples for recently approved drugs with a sul-
fonamide structure are the antihypertensive agent bosentan,2 the
antiviral HIV protease inhibitor amprenavir,3 and the phos-
phodiesterase-5 inhibitor sildenafil.4 In addition, numerous
sulfonamide derivatives have been in preclinical development.
The sulfonamide partial structure appears to belong to the so-
called “privileged structures” in medicinal chemistry,5 and it
exhibits favorable pharmacokinetic properties including meta-
bolic stability.
Xanthine derivatives were the first and still are one of the
most important classes of adenosine receptor antagonists.6
Figure 1. Structures of sulfostyryl- and sulfophenylxanthine deriva-
tives.
Adenosine receptors (AR) are subdivided into four different
subtypes, A1, A2A, A2B, and A3. Xanthine derivatives with high
potency at either A1 or A2 receptors were developed by
introducing certain lipophilic substituents into the 8-position of
the xanthine nucleus (e.g., cycloalkyl for A1, phenyl for A1 and
A2) and by variation of the substituents at the purine ring
nitrogen atoms. The resulting compounds, for example, 1,3-
dipropyl-8-phenylxanthine, generally exhibit rather low water
solubility. To increase their hydrophilicity, compounds bearing
a sulfonate group, such as 3,7-dimethyl-1-propargyl-8-(p-sul-
fostyryl)xanthine (1, SS-DMPX), 8-p-sulfophenyltheophylline
(2, SPT), 1,3-dipropyl-8-p-sulfophenylxanthine (3, DPSPX), and
1-propyl-8-p-sulfophenylxanthine (4) were introduced (Figure
1).7-9 Xanthin-8-ylbenzenesulfonates have become useful phar-
macological tools, although the sulfonate group generally led
to a decrease in adenosine receptor affinity. 1,3-Dialkylxanthin-
8-yl-benzenesulfonamides were first introduced by Hamilton et
al.8 Because of their amphoteric nature, they are soluble across
a wide pH range and can be perorally absorbed in contrast to
the highly polar sulfophenylxanthine derivatives.
We have recently discovered that 3-unsubstituted 1-alkyl-8-
phenylxanthine derivatives, such as 1-propyl-8-p-sulfophenyl-
xanthine (4), are potent and selective A2B adenosine receptor
antagonists.10 A2B-selective antagonists are of considerable
interest as novel drugs: they have been found to exhibit
analgesic, antiinflammatory, antiallergic, antiasthmatic, and
antidiabetic activity in vitro and in vivo.10-19 They seem to have
great potential, for example, for the treatment of asthma and
related pulmonary diseases17,19 and as novel antidiabetic drugs.15,16
Furthermore, A2B antagonists that are able to cross the blood-
brain barrier might attenuate neurodegenerative processes in the
brain and thus may be useful novel therapeutics, for example,
for Alzheimer’s disease.18,20 Due to their clinical relevance there
have been a number of efforts to develop A2B-selective
adenosine receptor antagonists,13 derived from xanthines, ad-
* Address correspondence to: Mailing address: Pharmazeutisches In-
stitut, Pharmazeutische Chemie Poppelsdorf, Kreuzbergweg 26, D-53115
Bonn, Germany. Phone: +49-228-73-2301. Fax: +49-228-73-2567. E-
mail: christa.mueller@uni-bonn.de.
§ University of Bonn.
† Assiut University.
‡ University of Wu¨rzburg.
10.1021/jm060277v CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/13/2006

Adenosine A2B Receptor Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14 4385
Scheme 1. Synthesis of 8-[4-(Benzylamidosulfonyl)phenyl]-1-propylxanthine (5)a
a Reagents and conditions: (a) chlorosulfonic acid, r.t. overnight; (b) benzylamine, anhydrous pyridine/DMF, r.t., 3 days; reflux, 3 h.
Scheme 2. Synthesis of Xanthin-8-yl-benzenesulfonamide Derivativesa
a Reagents and conditions: (a) primary or secondary amine; method A ) DMSO, 150 °C, 3 h; method B ) DMSO, 150 °C, 5 h; method C ) DMSO,
r.t., 72 h, argon; method D ) DMF, r.t., 48 h; reflux, 1 h. For R1, R2, R3, and R4, see Table 1.
enine, or other heterocyclic lead structures that had been
identified by screening approaches. Major problems with many
of the published and currently available A2B antagonists are (i)
moderate or no selectivity versus other AR subtypes,16,21-25 (ii)
high lipophilicity and low water solubility,26-29 (iii) insufficient
peroral bioavailability and lack of brain penetration (e.g., 4),10
and (iv) metabolic instability (e.g., anilides such as compound
17 (see Figure 2)26 (Kalla R., Zablocki J. et al., poster
presentation at Purines 2004, Chapel Hill, NC).
To increase the A2B affinity and selectivity of our lead
structure 1-propyl-8-p-sulfophenylxanthine (4)10,11 and to obtain
perorally bioavailable drugs, we planned to synthesize a series
of sulfonamide derivatives of 4 and the related 8-p-sulfophen-
yltheophylline (2) with broad variation of the substitution pattern
at the sulfonamide nitrogen. Since initially examined standard
procedures for the preparation of the target sulfonamide deriva-
tives failed or gave only poor yields, we developed a new
strategy employing p-nitrophenoxide as a leaving group in
nucleophilic substitution. Thereby we obtained some novel
sulfonamides with high affinity and selectivity for adenosine
A2B receptors.
conversion of the chlorosulfophenyl xanthine to the fluorosul-
fophenyl derivative using potassium fluoride32 failed.
Another approach was to prepare the p-sulfonamidobenzoic
acid derivatives as precursor molecules.33,34 However, coupling
of 5,6-diamino-3-propyluracil with p-sulfonamidobenzoic acid
derivatives in the presence of N-(3-dimethylaminopropyl)-N′-
ethylcarbodiimide hydrochloride (EDC) failed under various
conditions.
Since the first approach starting from the p-sulfophenylxan-
thine derivative had been somewhat more successful so far
(Scheme 1), we decided to follow the same strategy but to
investigate whether nitrophenoxides would be more suitable
leaving groups than halogenides. Nitrophenoxysulfonylben-
zenexanthine derivatives can easily be prepared in high yields;21
they are crystalline compounds, highly lipophilic, and well
soluble in a number of generally used organic solvents; in
addition, they are quite stable and easy to handle.21 In initial
experiments, 1,3-dimethyl-8-[4-[[m-nitrophenoxy]sulfonyl]phen-
yl]xanthine21 was treated with benzylamine under various
reaction conditions. However, no substitution reaction was
observed, even though different bases, for example, sodium
hydride and (dimethylamino)pyridine, were tried as catalysts.
Thus the m-nitrophenoxide was not a suitable leaving group
for the aminolysis. Since p-nitrophenylsulfonate esters are less
stable than m-nitrophenylsulfonate ester toward nucleophilic
attack, for example, by hydroxide ions,21 we expected p-
nitrophenoxide to be a more suitable leaving group. Initial
experiments were performed with 1,3-dimethyl-8-[4-[[p-nitro-
phenoxy]sulfonyl]phenyl]xanthine,21 which was treated with the
appropriate amine in dimethyl sulfoxide (DMSO) at r.t. for 30
min followed by heating at 150 °C for 3 h (method A), yielding
the desired sulfonamides in good yields (Scheme 2). Since the
3-unsubstituted xanthine derivatives were less reactive, harder
reaction conditions had to be applied to achieve aminolysis. The
desired sulfonamide derivatives of the lead structure 4 could
be obtained by prolongation of the heating time to 5 h at 150
°C in DMSO (method B), by stirring at r.t. for 72 h in DMSO
under an atmosphere of argon (method C), or by stirring for 48
h in dimethylformamide (DMF) followed by refluxing for 1 h
(method D). The sulfonamide derivatives could be successfully
obtained and purified by column chromatography. In Table 1
the yields of the synthesized xanthin-8-yl-benzenesulfonamide
derivatives are collected. Nitrophenoxide has turned out to be
a suitable leaving group for a very efficient synthesis of
Synthesis
Initially, we investigated various standard methods for the
synthesis of the target sulfonamide derivatives. The most
frequently used method for the preparation of sulfonamides is
the conversion of a sulfonic acid to the corresponding chloro-
sulfonyl derivatives with thionyl chloride, chlorosulfonic acid,
phosphorus oxychloride, or phosphorus pentachloride, followed
by reaction of the chlorosulfonyl derivative with the appropriate
amine.30 This method usually gives good yields of sulfonamides
at ambient temperature or under reflux conditions. However,
when this method was applied to our lead compound 1-propyl-
8-p-sulfophenylxanthine (4), the desired sulfonamides could not
be isolated in most cases, with the exception of 8-[4-(benzyl-
amidosulfonyl)phenyl]-1-propylxanthine (5). 1-Propyl-8-p-sul-
fophenylxanthine was converted to its sulfonyl chloride deriva-
tive by reaction with chlorosulfonic acid, which was subse-
quently treated with benzylamine (Scheme 1). A moderate yield
of 14% of compound 5 was obtained, after tedious purification
by column chromatography. Attempts to increase the reactivity
of the sulfophenylxanthine derivative either by introduction of
a fluorosulfonic moiety at the para-position of 8-phenyl-1-
propylxanthine by reaction with fluorosulfonic acid31 or by

4386 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Yan et al.
Table 1. Methods and Yields of Synthesized
Xanthin-8-yl-benzenesulfonamide Derivatives
new method for the preparation of sulfonamides, which may
be generally applicable and useful, has the following advan-
tages: (i) good yields, (ii) relatively short reaction times, (iii)
easy handling and purification, (iv) avoidance of the use of
pyridine, and (v) broad applicability to a wide range of amines
with different degrees of nucleophilicity. p-Nitrophenylsul-
fonates may be a useful replacement for the more reactive,
unstable sulfonyl chlorides, which are sometimes difficult to
prepare and to handle. They could be employed in combinatorial
solid-phase synthesis approaches to produce chemical libraries
of sulfonamides.
yield
R4 methoda (%)c
compd R1 R2
R3
5
Pr
H
Bn
H
D
b
B
B
C
b
51
14
88
28
53
0
6
7
Pr
Pr
H
H
-CH2CH2Ph
-CH2CH2OH
H
H
8
9
Pr
Pr
H
H
-CH2COOH
Pr
H
Pr
B
B
b
34
33
0
10
11
12
13
14
15
16
Pr
Pr
H
H
Ph
H
B
D
A
A
A
A
A
40
57
61
42
44
51
28
Biological Activity
-CH2-CH2-N(Bn)CH2-CH2-
Me Me iPr
H
H
H
H
H
The xanthine sulfonamide derivatives were investigated in
radioligand binding studies at A1, A2A, A2B, and A3 adenosine
receptors using [3H]2-chloro-N6-cyclopentyladenosine ([3H]-
CCPA), [3H](E)-3-(3-hydroxypropyl)-8-[2-(3-methoxphenyl)-
vinyl]-7-methyl-1-prop-2-ynyl-3,7-dihydropurine-2,6-dione ([3H]-
MSX-2), [3H]8-((4-(2-hydroxyethylamino)-2-oxoethoxy)phenyl)-
1-propylxanthine ([3H]PSB-298), and [3H]2-phenyl-8-ethyl-4-
methyl-(8R)-4,5,7,8-tetrahydro-1H-imidazo[2.1-i]purin-5-one
([3H]PSB-11), respectively.21,39 Rat brain membrane preparations
were used for A1 (cortex) and A2A (striatum) assays. Selected
compounds were additionally investigated at human A1 and A2A
receptors recombinantly expressed in Chinese hamster ovary
(CHO) cells. For A2B and A3 assays, human recombinant
receptors expressed in CHO cells were used.
Me Me -CH2CH2Ph
Me Me Bu
Me Me -CH2CH2OH
Me Me -CH2COOH
a For methods, see Results and Discussion and Experimental Section.
b Preparation via the chlorosulfonate (standard method, see Scheme 1).8,30
c Yields after purification by column chromatography.
sulfonamides. Yields of chromatographically purified products
were in most cases higher than 30%, in one case even 88%
was achieved (6). Not only primary amines could easily be
reacted but also secondary amines could be employed, as well
as amino alcohols, amino acids, aniline, and piperazine deriva-
tives (Table 1).
It has been reported that nucleophilic substitution reactions
of such phenyl benzenesulfonates may proceed via competing
pathways: (a) attack at the electron-deficient sulfur atom or
(b) attack at the electron-deficient carbon atom of the phenyl
ester.35,36 In our investigations, we have observed nucleophilic
attack of amines only at the sulfur atom of p-nitrophenyl
xanthinebenzenesulfonic acid esters yielding the desired sul-
fonamides. The competing reaction, which would result in the
formation of p-nitrophenylamines was not observed under the
applied reaction conditions. According to investigations by Choi
et al.35 with model compounds, the described nucleophilic
substitution reaction is likely to proceed via an SN2 mechanism
in which the attack of the nucleophile and thus the formation
of intermediate 17 is the rate-limiting step (Scheme 3). Recently,
Caddick et al. introduced pentafluorophenoxide as a leaving
group for sulfonamide synthesis, but in the reported reaction,
strong bases (DBU, NaH) were required even with nucleophilic
amines present pointing to a different reaction mechanism via
a sulfene intermediate.37,38
The optimized, balanced chemical reactivity of the p-
nitrophenylsulfonates (p-nosylates) is important for the success
of this reaction. The chemical reactivity is determined by the
nature of the sulfur center and the characteristics as a leaving
group (nucleofugality) of the group displaced. The reactivity
of m-nosylates is too low; however, compounds with a higher
reactivity than the p-nosylates may lead to greater hydrolytic
instability and would produce lower reaction selectivity.35 The
Structure-Activity Relationships
Information from several previous structure-activity relation-
ship studies10,21,40 allowed us to focus this investigation on a
well-defined set of compounds, namely, a series of diverse
variations of the substituent at the sulfonamide group. Starting
from 8-p-sulfophenylxanthine derivatives as lead structures, two
series of compounds were investigated, 1,3-dimethyl-substituted
xanthines derived from 2, and 1-propyl-3-unsubstituted xan-
thines derived from 4. The two lead structures 2 and 4 were
selected for sulfonamide formation since these two substitution
patterns for the xanthine N1- and N3-position conferred A2B
selectivity (see Table 2).10 The N7-position was unsubstituted
because the N7-hydrogen atom appears to be required for
hydrogen bond formation with the receptor protein.40
All of the compounds showed low affinity for human A3 ARs
as expected. It had been previously shown that the A3 receptor
prefers 1,3-dipropyl-substituted xanthine derivatives,21 and this
was confirmed in the present study. The 1,3-dimethyl-substituted
xanthines were generally somewhat less potent at A2B ARs than
the 1-propyl-substituted analogues (compare 7/15, 8/16), but
no significant difference was observed in the case of the
phenylethyl-substituted compounds 6 and 13, a substituent that
was very favorable for high A2B affinity. However, the propyl
derivative was still superior due to its higher selectivity versus
A2A ARs. Alkyl substitutents at the sulfonamide group (isopro-
pyl, butyl, dipropyl) were tolerated by the A2B AR, but even
Scheme 3. Proposed Mechanism of Aminolysis

Adenosine A2B Receptor Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14 4387
Table 2. Adenosine Receptor Affinity of Sulfonamidophenylxanthine Derivatives and Parent Sulfophenylxanthines
Ki ( SEM [nM]
(or % inhibition of radioligand binding
at indicated concentration)
A1
A2A
rat brain
cortical
membranes
vs.
A1
human
rat brain
striatal
A2A
human
A2B
human
A3
human
recombinant
vs
membranes
vs.
recombinant
vs
recombinant
vs.
recombinant
vs.
[3H]CCPA
(n ) 3)
[3H]CCPA
(n ) 3)
[3H]MSX-2
(n ) 3)
[3H]MSX-2
(n ) 3)
[3H]PSB-298
(n ) 3)
[3H]PSB-11
(n ) 2)
compd
R1
R2
R3
R4
2
3
4
5
6
7
8
9
methyl
propyl
propyl
propyl
propyl
propyl
propyl
propyl
propyl
propyl
methyl
propyl
H
H
H
H
H
H
H
1400043,a
21043,a
g
g
1400043,a
140043,a
g
g
g
133040,b
589044,c
25040,b
18345,c,d
220046,a
4.6 ( 0.5
10 ( 2
>1000010
2400046,a
26.7 ( 3.2
297 ( 81
287 ( 15
320 ( 32
42 ( 3
53.410,e
>1000010
-CH2Ph
H
H
H
H
propyl
H
54.8 ( 3.2
162 ( 64
769 ( 206
g
g
g
g
4.2 ( 2.5
3.62 ( 0.54
27.1 ( 8.0
101 ( 35
53.8 ( 36.3f
31.4 ( 0.9f
3.6 ( 0.4
g1000 (41%)
g10000 (37%)
g10000 (36%)
>10000 (25%)
>1000 (18%)
g1000 (48%)
>1000 (29%)
-CH2CH2Ph
-CH2CH2OH
-CH2COOH
propyl
183 ( 22
45 ( 7
g
g
g
g
100 ( 15
5.5 ( 2.0
1.8 ( 1.0
260 ( 0
10
11
phenyl
see structure above
23 ( 13
93.7 ( 32.1
H
2067 ( 261
484 ( 115
(PSB-601)
12
13
14
15
16
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
isopropyl
-CH2CH2Ph
butyl
-CH2CH2OH
-CH2COOH
H
H
H
H
H
75 ( 9
12 ( 1
27 ( 2
98 ( 2
64 ( 4
g
283 ( 13
113 ( 9
165 ( 69
347 ( 37
182 ( 65
g
102 ( 3
>10000 (27%)
1083 ( 25
g10000 (43%)
g10000 (49%)
g10000 (41%)
185 ( 63
32.6 ( 14
4.48 ( 2.24
122 ( 20
250 ( 169
154 ( 9
g
g
g
g
g
g
a Determined with [3H]R-PIA (A1) and [3H]NECA (A2A) as radioligands. b Determined with [125I]ABOPX as radioligand. c Determined with [125I]AB-
MECA. d Determined at the sheep receptor. e Determined with [3H]ZM241385 as radioligand. f n ) 2. g Not determined.
Table 3. Calculated log P Values and Polar Surface Areas (PSA) for
better by the A1 AR leading to A1-selective compounds (9, 12,
Compound 11 and Standard A2B Antagonists
14). Phenyl, benzyl, and phenylethyl substitution was investi-
calcd log P
uncharged/protonated
calcd PSA
uncharged/protonated
gated in the 1-propylxanthine series. The phenyl derivative 10
was the most potent A1 antagonist of the present series (Ki )
1.8 nM, rat A1 AR); it was 13-17-fold selective versus A2A
and A2B and highly selective versus A3 ARs. Replacement of
the phenyl group by a benzyl residue (5) increased A2B affinity
7.5-fold, while A1 affinity was reduced and A2A and A3 affinities
were virtually unaltered leading to a potent A2B antagonist with
some selectivity in a comparison of the human receptor subtypes
(Ki A2B 4.2 nM, 13-fold selective vs human A1, 39-fold versus
human A2A, >200-fold vs human A3 ARs). It is interesting to
note that the compound is 12-fold more potent at the rat A1
than at the human A1 AR and 6-fold more potent at the rat A2A
in comparison to the human A2A AR. Further extension of the
alkyl chain that connects the aromatic ring by one methylene
unit yields the phenylethyl derivative 6, which was a similarly
potent A2B antagonist (Ki 3.62 nM) but showed increased
selectivity over the other human AR subtypes (50-fold vs A1,
212-fold vs A2A, >2700-fold vs A3). In analogy to the
observation with the benzyl derivative 5, compound 6 was also
more potent at rat A1 as compared to human A1 (18-fold) and
at rat A2A in comparison with human A2A ARs (2.6-fold).
Compound 9 was synthesized to investigate whether disubsti-
tution of the sulfonamide nitrogen atom was tolerated. The
dipropylamino derivative was moderately potent at A2B (Ki 53.8
nM) and had a reasonable to high affinity for A2A ARs (Ki 42
nM) and A1 ARs (Ki 5.5 nM).
compda
11
3.31/-0.51b
3.53/0.562c
3.18b
127/128b
124/125c
131b
17
18
19
20
4.48c
134c
2.58/-1.24b
3.69/0.527c
1.79b
106/105b
106/107b
144b
3.07c
147c
2.24b
126b
3.95c
129c
a For structures, see Figure 2. b Software Marvin tools: www.chemax-
on.com; log P;49 PSA.50 c www.molinspiration.com.
tion, including hydroxyethylamine, aminoacetic acid, and N-
benzylpiperazine. A hydroxyl group (7, 15) will somewhat
increase water solubility, and it would allow for the formation
of water-soluble prodrugs, for example, phosphate or amino acid
ester prodrugs.41,42 A carboxylic acid function (8, 16) will be
largely deprotonated at physiological pH value and will therefore
result in an increased water solubility. The N-benzylpiperazine
structure (11) was chosen due to its basic nitrogen atom, which
can be protonated under physiological conditions. The benzyl
residue was expected to increase A2B affinity and selectivity
since it had been found that an aromatic residue is favorable
for selective binding to A2B ARs.13,26,28 Indeed, both the
hydroxyethyl and the acetic acid residue were tolerated by the
A2B receptor; however, the compounds were similarly (1-
propylxanthine derivatives 7 and 8) or somewhat more potent
(1,3-dimethylxanthine derivatives 15 and 16) at A1 ARs.
Our goal was reached with the benzylpiperazinylsulfonamide
derivative 11: the compound showed high affinity for A2B ARs
A major problem of many A2B antagonists that have been
developed is their frequently very low water solubility, which
limits their applicability as drugs or pharmacological tools due
to a limited bioavailability. Therefore we introduced polar
residues by using functionalized amines for sulfonamide forma-

4388 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Yan et al.
Figure 2. Structures and adenosine receptor affinities of potent adenosine A2B receptor antagonists in comparison with the newly developed
sulfonamide derivative 11 and common pharmacophore model: h indicates human; r indicates rat.
(Ki 3.6 nM) combined with high selectivity versus all other AR
subtypes, 574-fold versus human A1, 134-fold versus human
A2A, and >278-fold versus human A3 ARs. Compound 11 shows
good A2B selectivity in comparison with the rat A1 and A2A
receptors. Because it is 8-fold more potent at rat A1 and 5-fold
more potent at rat A2A as compared to the orthologous human
receptor subtypes, it is even more A2B selective if the thera-
peutically relevant human subtypes are compared. The pipera-
zine nitrogen atom makes this ligand a weak base similar to
many alkaloids (e.g., morphine, atropine), which are known to
have excellent pharmacokinetic properties and can penetrate the
blood-brain barrier.
Lipophilicity (log P value) and polar surface area (PSA)
values are two important predictors of peroral bioavailability
of drug molecules.47,48 Therefore we calculated log P and PSA
values for compound 11 using two different software programs
and compared them to the values obtained for a selection of
previously published potent and selective A2B antagonists (see
Table 3).
Compounds 11 and 18 are both basic molecules, and
therefore, we calculated the values for the neutral as well as
for the protonated form. The log P values calculated with the
two different programs differed considerably, the Marvin
program generally yielding lower log P values. For all com-
pounds the calculated log P values were lower than 5, which is
the upper limit for drugs to be able to penetrate biomembranes
according to Lipinsky’s rules. The highest degree of lipophilicity
was exhibited by compound 17 (c log P ) 3.18 (Marvin), )
4.48 (molinspiration)). The two compounds containing a basic
piperazine ring, 11 and 18, which are largely protonated at pH
7, exhibit the lowest log P values in the protonated form, which
is an indication for good water solubility. The polar surface
area (PSA) is calculated from the surface areas that are occupied
by oxygen and nitrogen atoms and by hydrogen atoms attached
to them. Thus, the PSA is closely related to the hydrogen
bonding potential of a compound.48,51 Both programs that were
used to calculate PSA values gave nearly identical results.
Neutral and protonated species of a molecule showed only minor

Adenosine A2B Receptor Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14 4389
followed by heating under reflux for 1 h. The progress of all
reactions was monitored by TLC. After the starting xanthines had
been consumed, the solvent was evaporated under reduced pressure,
and the residue was purified by flash column chromatography on
silica gel using dichloromethane/methanol (40:1 for compounds 5,
6, 9, and 11-13, 20:1 for compounds 7, 8, 10, 15, and 16, or 9:1
for 11). All compounds gave only a single spot on TLC.
8-[4-(Benzylamidosulfonyl)phenyl]-1-propylxanthine (5). Prepa-
ration via the Chlorosulfonate (Standard Procedure). 1-Propyl-
8-p-sulfophenylxanthine21,46 (0.57 mmol) was dissolved in chlo-
rosulfonic acid (5 mL) and stirred overnight. The reaction mixture
was poured into ice water; the formed white precipitate was filtered
off and dried affording the corresponding sulfonyl chloride deriva-
tive. 1-Propyl-8-p-chlorosulfophenylxanthine (0.49 mmol) was
dissolved in anhydrous DMF/pyridine (1:1, 25 mL), benzylamine
(1.46 mmol) was added, and the reaction mixture was stirred under
argon for 3 days and then refluxed for 2 h. The solvent was distilled
off in vacuo, and the residue was suspended in a small amount of
methanol and filtered off. The product was purified by column
chromatography on silica gel using dichloromethane/methanol (9:
1) to give compound 5.
differences as is to be expected from the difference of only one
hydrogen atom. Molecules with PSAs of 140 Å2 or more are
expected to exhibit poor intestinal absorption.48 Table 3 shows
that compound 19 is above this limit, while all other molecules,
including compound 11, are below. It has to be kept in mind
that log P and PSA values are only two s important, although
not sufficient s criteria for predicting oral absorption of a drug.49
By comparison of the structures of some of the most potent
A2B antagonists, a pharmacophore model can be deduced (Figure
2), which partly also applies to antagonists at the other adenosine
receptor subtypes. A central core structure (xanthine in many
compounds, pyrrolo[2,3-d]pyrimidine in 18)52 containing a
hydrogen bond acceptor-hydrogen bond donor motif has been
found to be typical also for A1 AR ligands.53 In xanthines, this
motif is formed by the C6-carbonyl group (acceptor) and the
N7-hydrogen (donor). In compound 18, a pyrimidine ring
nitrogen atom and the pyrrole N-H function form the same
motif (Figure 2). A lipophilic pocket (L1) can be filled with an
alkyl (preferably propyl) or a phenyl residue. A second pocket
(L2) is present, but this is more important for A1 and A3 ARs
and therefore reduces selectivity.10 Since a free, unsubstituted
N3-H atom in xanthines not only increases A2B selectivity but
also affinity,10 it can be speculated that the A2B AR prefers a
hydrogen donor group in that positon (N3-H in 11, exocyclic
NH in 18). Connected to C8 of xanthine derivatives or to the
respective position in the pyrrolopyrimidine is a long spacer,
ca. 7-10 atoms long, that may contain cyclic, aromatic, or
nonaromatic structures, as well as various hydrogen bond-
accepting functional groups. At the terminus of the spacer, an
aromatic ring is attached, and this appears to increase selectivity
for the A2B AR. In the new sulfonamide derivative 11, the spacer
is sterically highly restricted due to the piperazine ring connected
via a sulfone to the 8-phenyl residue.
8-[4-(Benzylamidosulfonyl)phenyl]-1-propylxanthine (5). Mp
1
292 °C; H NMR (500 MHz, DMSO-d6) δ 0.88 (t, J ) 7.40 Hz,
3H), 1.58 (m, J ) 7.40 Hz, 2H), 3.82 (t, J ) 7.40 Hz, 2H), 4.03 (s,
2H), 7.21 (m, 5H), 7.87 (d, J ) 8.50 Hz, 2H), 8.23 (d, J ) 8.50
Hz, 2H), 12.05 (s, 1H), 13.88 (s, 1H); 13C NMR (125 MHz, DMSO-
d6) δ 11.31, 21.01, 41.60, 46.30, 108.69, 126.92, 127.26, 127.30,
127.74, 128.36, 132.50, 137.69, 141.69, 147.69, 148.42, 151.11,
155.14. Anal. (C21H21N5O4S‚0.2H2O) C, H, N.
8-[4-(Phenylethylamidosulfonyl)phenyl]-1-propylxanthine (6).
Mp >300 °C. HRMS (C22H23N5O4S) calcd, 453.1470; found,
453.1469.
8-[4-(2-Hydroxyethylamidosulfonyl)phenyl]-1-propylxan-
thine (7). Mp >300 °C. Anal. (C16H19N5O5S‚2.5 H2O) C, H, N.
4-(1-Propylxanthin-8-yl)phenylsulfonamidoacetic Acid (8).
Mp >300 °C; 1H NMR (500 MHz, DMSO-d6) δ 0.88 (t, J ) 7.41
Hz, 3H), 1.58 (m, 2H), 2.44 (s, J ) 5.04 Hz, 2H), 3.84 (t, J ) 7.4
Hz, 2H), 7.51 (t, 1H), 7.89 (d, J ) 8.51 Hz, 2H), 8.30 (d, J ) 8.2
Hz, 2H), 11.94 (s, 1H). Anal. (C16H17N5O6S) C, H, N calcd, 17.19;
found, 18.02.
Conclusions
In conclusion, we have developed a new strategy for the
preparation of sulfonamides using p-nitrophenoxide as a leaving
group in nucleophilic substitution of 8-[4-[[[p-nitrophenyl]oxy]-
sulfonyl]phenyl]xanthine by amines. The new method allowed
the preparation of xanthin-8-yl-benzenesulfonamides that could
not be obtained at all or only in very low yields by standard
synthetic procedures. It may not be limited to xanthinylben-
zenesulfonamides, but generally applicable and it thereby
extends the current repertoire of methods for preparing sul-
fonamides, one of the most important classes of drugs. The new
method allowed us to synthesize a series of xanthin-8-ylben-
zenesulfonamides and to investigate their structure-activity
relationships at adenosine receptors with the goal to improve
affinity and selectivity for A2B ARs. A highly potent and
selective A2B AR antagonist (11) was identified, which contains
a basic piperazine partial structure that can be protonated at
physiological pH values conferring increased water solubility.
8-[4-(Dipropylamidosulfonyl)phenyl]-1-propylxanthine (9).
Mp >300 °C. HRMS (C20H27N5O4S) calcd, 433.1784; found,
433.1787.
8-[4-(Phenylamidosulfonyl)phenyl]-1-propylxanthine (10). Mp
>300 °C. HRMS (C20H19N5O4S) calcd, 425.1157; found, 425.1145.
8-[4-(4-Benzylpiperazide-1-sulfonyl)phenyl]-1-propylxan-
1
thine (11). Mp >300 °C; H NMR (500 MHz, DMSO-d6) δ 0.88
(t, J ) 7.40 Hz, 3H), 1.58 (sext, J ) 7.40 Hz, 2H,), 2.41 (bs, 4H),
2.94 (bs, 4H), 3.44 (s, 2H), 3.82 (t, J ) 7.40 Hz, 2H), 7.22 (m,
5H), 7.83 (d, J ) 8.51 Hz, 2H), 8.32 (d, J ) 8.50 Hz, 2H), 11.93
(s, 1H), 13.90 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 11.32,
21.00, 41.63, 46.30, 51.56, 61.46, 108.81, 127.07, 127.12, 128.30,
128.39, 128.83, 128.97, 133.25, 135.77, 137.79, 147.70, 148.16,
151.09, 155.12. Anal. (C25H28N6O4S‚0.5 H2O) C, H, N.
8-[4-(Isopropylamidosulfonyl)phenyl]-1,3-dimethylxanthine
(12). Mp >300 °C. Anal. (C16H19N5O4S) C, H, N calcd, 18.58;
found, 18.04.
8-[4-(Phenylethylamidosulfonyl)phenyl]-1,3-dimethylxan-
thine (13). Mp >300 °C. Anal. (C21H21N5O4S) C, H, N.
8-[4-(Butylamidosulfonyl)phenyl]-1,3-dimethylxanthine (14).
Mp >300 °C. Anal. (C17H21N5O4S) C, H, N.
8-[4-(2-Hydroxyethylamidosulfonyl)phenyl]-1,3-dimethylxan-
thine (15). Mp >300 °C. Anal. (C15H17N5O5S‚0.8 H2O) C, H, N
calcd, 17.78; found: 17.33.
Experimental Section
General Procedure for the Preparation of Sulfonamides
5-16. To a stirred solution of 1-propyl-8-[4-[[[p-nitrophenyl]oxy]-
sulfonyl]phenyl]xanthine21 (1 equiv) for 5-11 or 1,3-dimethyl-8-
[4-[[[p-nitrophenyl]oxy]sulfonyl]phenyl]xanthine21 (1 equiv) for
12-15 in DMSO (5 mL) the appropriate amine (10-50 equiv) was
added at room temperature. In method A, the reaction mixture was
stirred for 30 min at room temperature, then heated under reflux
for 3-5 h. In method B, the mixture was heated at 150 °C for 5 h.
In method C, the mixture was stirred for 72 h at r.t. under an
atmosphere of argon. In method D, DMF instead of DMSO was
used as a solvent. The reaction mixture was stirred for 48 h at r.t.
4-(1,3-Dimethylxanthin-8-yl)phenylsulfonamidoacetic Acid
(16). Mp >300 °C. Anal. (C15H15N5O6S) C, H, N.
Biological Studies. Radioligand binding studies were performed
as recently described.21,39
Computer Calculations. The molecules were built with the
SYBYL software, version 7.0 (Tripos, Inc., St. Louis, MO). The
structures were energy-minimized using the maximin2 minimizer

4390 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Yan et al.
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in SYBYL running on default options. Minimization was terminated
either after 1000 iterations or when a gradient of less than 0.05
kcal/(mol‚Å) was attained. To find conformations with low energy,
the systematic search intergrated in SYBYL was performed. Partial
electrostatic potentials were calculated using the Gasteiger-Hu¨ckel
method. Low-energy conformations were used for calculations of
log P49 and PSA values50 with Marvin (www.chemaxon.com), while
calculations with molinspiration (www.molinspiration.com) could
only be performed using nonoptimized structures.
Acknowledgment. L.Y. was supported by a STIBET
scholarship by the Deutscher Akademischer Austauschdienst
(DAAD). We thank the Deutsche Forschungsgemeinschaft for
support (Grant GRK677, scholarships for D.C.G.B. and H.M.).
Supporting Information Available: 1H and 13C NMR spectral
data, elemental analyses, and HRMS data for the synthesized
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
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