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Bull. Soc. Chlrn. Belg. vd. 102 / no 10 / 1993
0037-9646 / 93 I $2.00
EUROPEAN SECTION
0 1993 Cornit6 van Beheer van het Bulletln V.Z.W.
CRYSTAL STRUCTURE OF 4-AMINO-3-(2-BENZOTHlOPHEN) BUTYRIC ACID,
A BACLOFEN ANALOGUE
B. Pirard*’, G. Evrard’, B. Norberg’, P. Berthelo?, C. Vacche?, M. Debaert’ and F. Durant’
’Laboratoire de Chimie Moleculaire Structurale, Facultes Universitaires Notre-Dame de la Paix,
rue de Bruxelles 61, 8-50oO Narnur (Belgium)
*Laboratoire de Pharmacie Chimique, U.F.R. de Pharmacie, 3 rue du Professeur Laguesse,
59006 Lille Cedex (France)
Received : 22/11/1593 -Accepted : 07/01/1994
ABSTRACT
Thc crystal strumre of 4-amino-3-(2-benzothiophen)
butyric acid is qwed and compared with that of 4
smino-3-(2-thi&nyl)butyric acid. For both molecules, the y-aminobutyric acid (GAB)chains show
almost identical conformations.
Cl2H13NO2S,Mw
=
235.0, F21/c, a
=
17.857(2), b
= 5.183(1), c =
12.587(1)A,P=100.07(1)”,V=1147.1A 3 , 2 = 4 , D c = 1 . 3 6 3 g ~ m -R~ ,Cu Kn= 1.54178A, [i
22.6 1 cm- F(000) = 496.0,T = 293 K , R
= 0.075 for
=
1103 observed reflections (I t 2 41)).
INTRODUCRON
Within the central and peripheral nervous sytenls, paminobutyric acid (GABA)can
bind to two different kinds of receptors : GABAA and GABAB receptors. So far, y-amino
chlorophenyl) buryric acid (badofen) has been considered as the reference ago&
BT
least
[email protected]
for GABAB receptors.
Synthesis and binding rmdies of 3-heteroaromatic analogues of baclofen have been recently repatedl .The
nature of the heteroxurnatic moiety is critical for GABAB affinity.
In the crystalline state, 3 heteroaromatic analogues of badofen show different conformations
according to the nature of the heteroarumatic ring (*, 3). As conformation plays a prominent p a t in
biochemical mechanisms, we have investigated the influence of a benzothiophen ring on the y
aminobutyric acid (GAB) chain conformation. So crystal structure of 4 amiao-3-(2-benzothiophen)
buryric acid was studied by X-Raydiffraction and compared with that of 4 amino 3 (2 thienyl) butyric
acid.
I1
I&%+
12
&p l h SrucmUP of 4-amino-3-(2-benzothiophen)
butyric acid and aromic numbering
- 639 -
ExPERIm
[email protected], Mw = 235.0. Colourless platelets were formed after slow evaporation at room
temperature of a 111 methanol ethyl acetate solution.One crystal measuring 0.06 X 0.2 X 0.05 mm was
selectedforx-Raydiffraction.Final cell dimension, a
=
17.857(2), b
= 5.183(1).
c
=
12.587(1) A, ,l?=
100.07(1)” and intensities were measured on a Huber diffractometerwith a Rig& RU200 rotacing mode;
RCu K O = 1.54178 A,,& = 22.61 crn-l, F(000) = 496.0, F’21/C, 2
final R index (Z [Fo
-
=
4, no absorption correaion. The
Fc]/[F]o) was 0.075.’ for 1103 observed reflections (I
2
2 C(1) ). The structure
was solved with SHELXS864 and refined with SHELX76S. The geometric analysis was performed with
XRAY766.
DISCUSSION
The final atomic coordinates and the thermal parameters are presented in Table 1. Hydrogens
are numbwed according to the carrier atom (Fig. 1) and their Bq values are
i- 0.01.
set
to Bq of the heavy atom
In the crystallinestate, 4-amino-3-(2-benzothienyl)
butyric acid is observed ifi a zwitterion. The
bond lengths and valence angles (Table 2) carespond to those observed for similar compounds ( 2 ,3
e7).
Table LFinal coordinates (X lo4) and thermal parameters with e.s.d.’sinparentheses.
( B k = 8 k Uc, = 113 ZiZi uii q * q* q ai)
Acorns
Xla
Ylb
B$
Zlc
7728( 1)
1144(5)
8054(1)
5 58(5)
8396(4)
1288(17)
7226(6)
4 54[17)
8999(5)
-401(19)
7232(9)
6 43(25)
9488( 5 )
4(26)
6532(12)
8 23(35)
9373(5)
20 1 7 ( 2 7 )
5813(9)
7 87(32)
8779(5)
3701(21)
5782(6)
6 24(22)
8267(4)
3355( 1 7 )
6510(5)
4 42(16)
7602(2)
4965( 12)
6588(5)
2 93(13)
7290(4)
3931(13)
7487(5)
3 13(12)
6618(4)
5020( 1 2 )
7921(5)
2 81(12)
6733(4)
4987(13
g161( 5)
3 41(13
6169 ( 4 )
6622 ( 1 2
9634 ( 5 )
2 82(12
5860(2)
8 4 8 1( 9 )
9096(4 )
3 46(9)
6069 ( 2 )
6062(9)
0569(4)
3 75(10
5888(4)
3666(13
7470 ( 5 )
2 82(11
5691(2)
3 8 4 1 ( 10 I
6273(4)
2 83(10)
- 640 -
Bond lengths (A) and valence angles (") fcr4-amino-3-(2-benzothiophen)butyric acid
so1-c02
C02 C03
C03 C03
C03' CO4
CO4 C05
CO5-COG
COG C07
SO 1- C07'
C03'-C07'
c02 C 0 8
CO8-C09
C09 C10
c10 011
c10 012
C08 C13
C13 N14
1.718
1.472
1.500
1.380
1.391
1.377
1.341
1.712
1.396
1.510
1.548
1.510
1.246
1.257
1.516
1.476
C03 CO2-SO1
C03' C03 C02
c 0 4 c03' - c02
co5-cw-co3'
COG -COS-CW
C07-COG-CO5
C07'-CO7-C06
c07 -c07'-s01
co3'-co7'so1
C07'-S01 -C02
co8-co2-co3
C09 C08 C02
C10 C09 C08
0 1 1 ClO-CO9
012 C10 C09
N13 C08-CO2
N14 C13 CO8
e s d . mu./A
0.100
e.s.d. m a . / '
~
The main torsion angles are reputed
iii
115.4
104.5
125.5
118.5
121.5
120.0
120.1
127.1
112.5
92.1
120.7
112.2
113.2
116.5
119.1
111.6
112.6
0.9
Table 3. The molecular conformation is shown in
Figure2 and is compared with the one observed for4 amino 3-(2-thienyl)butyric acid 3. We have focused
on two intramolecular distances : (i) the distance between the nitrogen atom and the mean position of the
carboxylate group (dl), (ii)the distaoce between the nitrogen and the benzothienyl or thienyl sulfur a o m
(d2). The values of d l amount respectively to 4.58 and 4.64 A.
On the other hand, there is no van der Waals contact between the ammonium group and the benzothienyl
or thienyl sulfur atom (d2
=
4.17 and 4.18 A respectively, while the contaa diamce is 3.35 AR).
However,in the c&tdline state, the furyl and benzofuran analogues of baclofen show conformations
with folding of the ammonium group towards the furyl or benzofuran oxygen atoms.(2,3).
T a b l e 3, Main tmion angles (") for 4 amino 3 (2 benzothiopheu) butyric acid
CO8 CO2 C03 C03
C09 C08 C02 C03
CIO C09 CO8 C02
011 CIO C09 C08
012 C10 C09 C08
C13 C08 C02 C03
N14 C13 C08 C02
176 7(6)
139 4(6)
166 3(5)
23 9(9)
157 7(8)
97.0(5)
ORTEP stereoview with vibrational ellipsmde (probabilicy 50 46) of 4-&0-3-(2
benzahiophen) buryric acid
-641 -
In 4-amino-3-(2-benzothienyl)
butyric acid, the crystal packing is assumed by open polymeric
hydrogen bonds betweenthe ammonium and the carboxylate groups (Fig. 3). Their geometrical features
are given in Table 4.
Table 4 Geometrical features of hydrogen bonds for 4-amino-3-(2-benzothiophen)
butyric acid
N-H---0
N( 14)-H(141)i---O( 12)ii
N-H/A
1.070
N(14)-H(142)i---0(1I)iii 1.090
N(14tH(143)i---O(l2)iv
1.090
N--O/A
2.890(4)
2.740(9)
2.830(4)
H--O/A
1.870
1.770
2.000
N-H---Or
158.3
144.4
126.5
In. 2 - 112
iX,Y.Z
ORlW stereoview 01 crystal padung
butyric acid
In the crystalline state, 4-amino-3-(2-benzothienyl)butyric and 4-amino-3-(2-thienyl)butyric
acid show almost identical conformations. So conformation could not account for their different GABAB
affioities (ICso >
M and ICso
=
9.72
M respectively). The size of the heteroaromatic ring
could be decisive for GABAn affinity. To test this latter hypothesis, works are in progress hi our
laboratory.
ACKNOWLEDGMENT
The authors would like to thank Prof. M. Debaerr and Dr. P. Renard for providing the
compounds and for fruitfull scientific oollaboncion, Prof. J.P. Declercq and Dr B. Tinant (UCL) for
collecting the data, IBM Belgium, The Facultes Universitaires Notre-Dame de la Paix and the F.N.R.S.
for the use of the Namur ScientificCompute Facilities.B.P. is also pleased to acknowledge the ADLR
society for financial suppott.
REFERENCES
(1) Beithelot P., Vaccher C., Flouquet N., Debaert M., Luyckx M., and Brunet C., J. Med. Chem.,34
(8) 2557-2560 (1991).
(2) Betthelot P., Vaccher C., Flouquet N., Luyckx M., Brunet C., Boulmger T., Fripiat J.P.,
VercauterenD.P., Debaert M., Evnrd G., and Durant F., Eur. J. Med. Chem., 26 (4) 395-402(1991)
(3) Pimd B.. Evnnl G.,Norberg B., Betthelot P., Vaccher C., Debaert M., Vercauteren D.P.. and D u r n
F., J. Cryst. Spec. Res., =(11)843-848 (1993).
- 642
(4) Sheldrick G., "SHELXS86,Progrm for the Solution of Crystal Struaure". University of Gottingen
(1986).
(5) Sheldrick G., "SHELX76,Program for Crystal Structure Determination", Univmity of Cambridge
(1976).
(6) Stewart J..Editor XRAY-76. Tech. Rep. TF-445,Computer Science Centre. University of Maryland
(1976).
(7) Sutberland H.H., Rawers A,, Acta C r y s t . a ( 6 ) 929 931 (1985).
(8) Weaa R.C. in CRC Handbook of Chemisny and Physics. CRC Press Inc. Boca Raton,
(1 986-1987).
- 643 -
Dl88
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