X-ray structure analysis of iso-sildenafil (iso-viagra)

Article abstract of DOI:10.1515/znb-1999-1016

For structure-activity reasons, an isomeric compound of Viagra, methylated at N-2 at the pyroazolo[4,3-d]pyrimidine-7-one nucleus, was synthesized and its X-ray structure performed. The crystallographic data show that the phenyl and condensed pyrazolo-pyrimidone ring systems are not coplanar to each other.

Full text of DOI:10.1515/znb-1999-1016

X-Ray Structure Analysis of wo-Sildenafil (iso-Viagra) [1]
M ustafa M. E l-A badelah3 *, Salim S. Sabria, M onther A. K hanfar3,
W olfgang V oelterb-*, and Cäcilia M aichle-M össm erc
a Chemistry Department, Faculty of Science, University of Jordan, Amman, Jordan
b Abteilung für Physikalische Biochemie, Physiologisch-chemisches Institut der
Universität Tübingen, Hoppe-Seyler-Straße 4, D-72076 Tübingen, Germany
c Institut für Anorganische Chemie auf der Morgenstelle 18, Universität Tübingen,
D-72076 Tübingen, Germany. Fax: (+49) 7071-293348.
E-mail: wolfgang.voelter@uni-tuebingen.de
* Reprint requests to Prof. M. M. El-Abadelah or to Prof. W. Voelter
Z. Naturforsch. 54b, 1323-1326 (1999); received December 28, 1998
X-Ray Data, wo-Viagra, Cyclic Guanosine Monophosphate, Viagra, Phosphodiesterase
For structure-activity reasons, an isomeric compound of Viagra, methylated at N-2 at the
pyroazolo[4,3-d]pyrimidine-7-one nucleus, was synthesized and its X-ray structure per-
formed. The crystallographic data show that the phenyl and condensed pyrazolo-pyrimidone
ring systems are not coplanar to each other.
Introduction
Results and Discussion
A key feature of 1 is the existence of an intra-
m olecular hydrogen bond betw een the pyrim idone
N H and the oxygen lone pair of the 2'-ethoxy
group. This hydrogen bonding m aintains coplanar-
ity betw een the 5-(substituted)phenyl ring and the
condensed heterocyclic system ( confirm ed by an
X -ray crystal structure) [2]. S A R studies suggested
that this coplanarity appeared to be an im portant
requirem ent for optim al bioactivity [2].
Q uite recently, Sildenafil citrate (V iagra) (1), a
potent inhibitor of cyclic guanosine m onophos-
phate (cG M P)-specific phosphodiesterase (PD E-
type V) isozyme, has been m arketed as an orally
active therapeutic drug for the enhancem ent of
m ale erectile response [2]. The isom eric com -
pound 2 (we call it ‘i'so-Viagra’), having the pyra-
zolo[4,3-d]pyrim idine-7-one nucleus m ethylated at
N-2, is hitherto undescribed in the literature. A c-
cordingly we thought it m ight be w orth investigat-
ing the bioproperties of iso-Viagra [3] com pared
to Viagra.
In the present w ork, an X -ray crystal structure
determ ination of wo-Viagra (2) has been done.
The m olecular structure of 2 is displayed in Fig. 1.
The atom ic coordinates, bond lengths and angles
are given in Tables I and II, respectively. The crys-
o = s = o
6
N
1
CH,
2
0932-0776/99/1000-1323 $06.00 © 1999 Verlag der Zeitschrift für Naturforschung, Tübingen • www.znaturforsch.com
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M. M. El-Abadelah et al. ■X-Ray Structure Analysis of iso-Sildenafil (/so-Viagra)
Fig. 1. ORTEP-plot of the molecular structure of 2.
Experimental
tallographic data reveal that the phenyl and con-
densed pyrazolo-pyrim idone ring systems show no
coplanarity. The interplanar angle is 42.4 degrees
[across their joint C (5 )-C (ll) axis]. The spatial in-
teratom ic distance, as determ ined for 0(12)-N (6)
as 2.76 A , allows an intram olecular hydrogen bond
involving the pyrim idone N H [H (6)] and the 2'-
ethoxy oxygen lone pair [0(12)]. The hydrogen
atom H (6) was found in the difference fourier m ap
and refined isotropically. H ow ever, non-coplanar-
ity betw een the tw o biophoric ring systems, at least
in the solid state, im plies that the electrostatic
attraction and the associated hydrogen-bridge, in-
volving H (6) and 0 (1 2 ), are rather weak. It re-
m ains to establish, by SA R studies, w hether N-2
m ethylation (in 2) has im pact on the potency of
“w o-V iagra“ as cG M P -PD E V inhibitor [3].
Synthesis
/so-V iagra (2) has been synthesized as outlined
in Schem e 1. The physical properties and spectral
characteristics of the interm ediate com pounds,
leading to 2, will be reported separately in a full
publication.
Crystal structure determination o f 2
Crystals were obtained by slow evaporating of
the solvent ethanol from the solution. Crystal data
for C 2 H 30N6O 4S: FW = 474.58, m onoclinic, space
2
group P ^ /n with a = 9.7550(13), b = 7.6070(7), c =
32.568(5) Ä, ß = 94.741(13) °, V = 2408.5(6) A 3,
Z = 4, D calc = 1.309, F(000) = 1008. D ata collection
was m ade at -6 0 °C, using an E N R A F-N O N IU S
C A D 4 diffractom eter operating in the om ega
PPA
120°C/2h
i) CISOjH, 60°C, lh
ii) N-Methylpiperazine
Scheme 1.
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1325
M. M. El-Abadelah et al. ■X-Ray Structure Analysis of /so-Sildenafil (/so-Viagra)
Table I. Atomic coordinates o(xl04) and equivalent isot- Table II. Relevant bond lengths (A), and angles (°) for 2.
ropic displacement factors (A2xl03) for 2.
1.426(3)
1.436(3)
1.632(3)
1.760(3)
1.229(4)
1.360(4)
1.440(4)
2.35(4)
S (l)-0 ( 1 )
S (l)-0 ( 2 )
S (l)-N (2 1 )
S (l)-C (15)
0 (7 )-C (7 )
0(12)-C (12)
0(12)-C (121)
0 (1 2 )-H (6 )
0 (1 2 )-N (6 )
N (l)-C (8 )
N (l)-N (2 )
N (2)-C (3)
N (2)-C (20)
N (4)-C (5)
N (4)-C (9)
N (6)-C (5)
N (6)-C (7)
Atom
X
U(eq)
z
y
877(1)
6373(1)
6463(4)
4774(4)
9614(4)
11981(3)
8015(4)
7278(4)
8029(4)
9303(4)
6855(4)
8311(4)
7106(5)
8795(4)
9125(4)
8345(5)
7808(4)
9124(4)
10712(5)
10958(5)
9627(5)
8054(5)
7815(5)
6783(6)
6751(6)
6747(6)
8340(8)
8399(6)
8439(6)
6286(6)
7568(7)
8897(13)
13505(5)
14619(6)
2152(1)
2301(1)
1973(1)
-287(1)
917(1)
35(1)
48(1)
50(1)
33(1)
27(1)
31(1)
31(1)
26(1)
24(1)
32(1)
37(1)
28(1)
23(1)
24(1)
25(1)
25(1)
24(1)
24(1)
30(1)
31(1)
28(1)
27(1)
40(1)
39(1)
43(1)
51(1)
S(l)
2291(3)
320(3)
0 (1 )
0 (2 )
0 (7 )
0(12)
N (l)
N(2)
N(4)
N(6)
N(21)
N(24)
C(3)
-1561(2)
-141(2)
-4348(3)
-5300(3)
-2725(3)
-1190(3)
-10(3)
-1700(3)
-4912(3)
-1574(3)
-1987(3)
-3303(3)
-3589(3)
-561(3)
160(3)
-182(1)
2.767(4)
1.340(4)
1.355(4)
1.357(4)
1.459(4)
1.294(4)
1.384(4)
1.384(4)
1.387(4)
0.949(6)
1.393(4)
1.489(5)
1.486(4)
1.444(4)
1.403(4)
118.1(2)
90.5(11)
124.9(12)
102.6(3)
115.2(3)
118.1(3)
126.7(3)
113.8(3)
125.6(3)
104.2(3)
124.9(3)
130.9(3)
124.4(3)
119.0(3)
116.6(3)
121.1(3)
127.8(3)
111.0(3)
112.3(3)
128.0(3)
119.7(3)
128.9(3)
125.4(3)
105.6(3)
45(1)
852(1)
409(1)
2540(1)
3121(1)
453(1)
792(1)
C(5)
C(7)
C(8)
C(9)
39(1)
101(1)
N (6)-H (6)
C (3)-C (9)
C (3)-C (31)
C (5 )-C (ll)
C (7)-C (8)
C (8)-C (9)
497(1)
1150(1)
1205(1)
1550(1)
1835(1)
1784(1)
1446(1)
-164(2)
2471(1)
2888(1)
3516(1)
3183(1)
2776(1)
760(1)
C (ll)
C(12)
C(13)
C(14)
C(15)
C(16)
C(20)
C(22)
C(23)
C(24)
C(25)
C(26)
C(31)
C(32)
C(33)
C(121)
C(122)
1082(3)
1307(4)
588(3)
C (12)-0(12)-C (121)
C (1 2 )-0 (1 2 )-H (6 )
C (1 2 1 )-0 (1 2 )-H (6 )
C (8 )-N (l)-N (2 )
N (l)-N (2 )-C (3 )
N (l)-N (2 )-C (2 0 )
C (3)-N (2)-C (20)
C (5)-N (4)-C (9)
C (5)-N (6)-C (7)
N (2)-C (3)-C (9)
N (2)-C (3)-C (31)
C (9)-C (3)-C (31)
N (4 )-C (5 )-N (6 )
N (4 )-C (5 )-C (ll)
N (6 )-C (5 )-C (ll)
0 (7 )-C (7 )-N (6 )
0 (7 )-C (7 )-C (8 )
N (6 )-C (7 )-C (8 )
N (l)-C (8 )-C (9 )
N (l)-C (8 )-C (7 )
C (9)-C (8)-C (7)
N (4)-C (9 )-C (3 )
N (4)-C (9 )-C (8 )
C (3)-C (9)-C (8)
-369(3)
-6623(4)
-1518(4)
-2114(4)
-2313(5)
-204(4)
429(4)
-5763(4)
-6619(4)
-5748(8)
735(4)
40(1)
36(1)
39(1)
53(1)
98(3)
32(1)
45(1)
989(2)
1231(3)
921(1)
562(1)
211(5)
m ode. 5231 independent data were collected
w ithin the range of 3.2 to 26.9° using graphite mo-
nochrom ated M oK ct radiation X = 0.7107Ä). The
cell param eters and orientation m atrix for the data
collection w ere obtained using the setting angles
of 25 reflections in the range of 6 to 15.26 degrees.
The structure was solved by direct m ethods using
the program SHELX S86 [4]. All non-hydrogen
atom s w ere refined anisotropically by full-m atrix
least-squares based on F2 with SHELX L93 [5].
The hyrogen atom s have been found in the differ-
ence F ourier syntheses and were refined isotropi-
cally. This results in an R value Rj = 0.0484 and
w R 2 = 0.1225 for the observed data and 418
param eter. G O F = 0.836, largest peak in final F ou-
rier difference m ap was 0.261 e/A 3.
A know ledgem ent
We wish to thank Forschungszentrum Jülich
G m bH , D-52425 Jülich, Public R elations and In-
dustrial A ffairs for financial support.
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1326
M. M. El-Abadelah et al. • X-Ray Structure Analysis of /so-Sildenafil (iso-Viagra)
[1] IUPAC Name: 5-[2-Ethoxy-5-(4-methylpiperazin-l-
[3] The total synthesis and biodata of “iso-Viagra“ (2)
will be published separately.
[4] G. M. Sheldrick, Acta Crystallogr. A46, 467(1990).
[5] G. M. Sheldrick, SHELXL93, Program for Crystal
Structure Refinement Universität Gottingen, Ger-
many (1993).
ylsulfonyl)phenyl]-2-methyl-3-propyl-6,7-dihydro-
2//-pyrazolo[4,3-d]pyrimidin-7-one.
[2] N. K. Terrett, A. S. Bell, D. Brown. P. Ellis, Bioorg.
Med. Chem. Lett. 6, 1819 (1996), and references
therein.
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