Synthesis and GABA uptake inhibitory properties of 6-aryl iminoxymethyl substituted nipecotic acids

Article abstract of DOI:10.1016/j.ejmech.2004.07.003

Nipecotic acid derivatives bearing an aryl iminoxymethyl side chain at the position 6 were synthesised and tested for their GABA uptake inhibitory properties. Contrarily to the N-substituted derivatives 2, 3 the introduction of the oxime function in the s

Full text of DOI:10.1016/j.ejmech.2004.07.003

European Journal of Medicinal Chemistry 39 (2004) 889–895
www.elsevier.com/locate/ejmech
Preliminary communication
Synthesis and GABA uptake inhibitory properties of 6-aryl
iminoxymethyl substituted nipecotic acids
Victor N’Goka a, Tine B. Stenbøl b, Povl Krogsgaard-Larsen b, Gilbert Schlewer a,*
a Faculté de pharmacie, UMR7081 du CNRS, laboratoire de pharmacochimie de la communication cellulaire, 74, route du Rhin, 67401 Illkirch, France
b Royal Danish School of Pharmacy, Department of Medicinal Chemistry, 2 Universitetsparken, DK-2100 Copenhagen, Denmark
Received 26 March 2004; received in revised form 12 July 2004
Available online 09 September 2004
Abstract
Nipecotic acid derivatives bearing an aryl iminoxymethyl side chain at the position 6 were synthesised and tested for their GABA uptake
inhibitory properties. Contrarily to the N-substituted derivatives 2, 3 the introduction of the oxime function in the side chain of analogues of
the active nipecotic derivative 4 does neither increase, nor maintain the activity.
© 2004 Elsevier SAS. All rights reserved.
Keywords: Nipecotic acid; c-Aminobutyric acid; GABA; GABA uptake inhibitors; 6-Aryliminoxymethyl nipecotic acid
1. Introduction
equipotent activity compared to SKF derivatives 2 and 3
[4,15,16]. More, recently, one group of the Novo Nordisk
company directed by Andersen developed an interesting pro-
gram for the optimisation of the structure activity around the
compounds 2 and 3. These investigations led to compounds 6
and 7 (Scheme 1) with significant increase of the activity
compared to the parent compound. Particularly, this program
c-Aminobutyric acid (GABA) 1, a major inhibitory neu-
rotransmitter of the mammal central nervous system [1–4],
seems to be implicated in pathologies such as Parkinson
disease [5], epilepsy [6,7], Huntington chorea [8], schi-
zophrenia [9] or Alzheimer disease [10]. GABA uptake inhi-
bition is one of the possible pathways to maintain the optimal
synaptic concentration of the neurotransmitter.
A major development in the GABA uptake inhibitor field
was the synthesis of SKF 100300-A 2 and SKF 89976-A 3,
which are active in vitro at 0.34 µM and in vivo at around
20 mg/kg [11–13].
A pharmacophore model was proposed [14] suggesting
the synthesis of the 6-substituted guvacine derivative 4 which
was active in vitro at 0.1 µM in the racemic form. Compared
to SKF 89976-A 3, the analogue 4 does not show the double
bound in the side chain. As this insaturation seemed favoura-
ble for the activity [11–13], we were interested in the synthe-
sis of an analogue of 4 containing a diphenylpropenyl side
chain. In the meantime, it has been shown that the p electrons
of the double bound could be replaced by p electrons such as
oxygen electron lone pairs since the ether analogue 5 has
* Corresponding author. Tel.: +33-390-24-42-19; fax: +33-390-24-43-10.
E-mail address: schlewer@pharma.u-strasbg.fr (G. Schlewer).
Scheme 1. Structures of GALA and known GABA uptake inhibitors.
0223-5234/$ - see front matter © 2004 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2004.07.003

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V. N’Goka et al. / European Journal of Medicinal Chemistry 39 (2004) 889–895
concerned the replacement of the side chain double bound by
oximes [17,18]. It seemed interesting to us to see if this
modification could be transposed from the position N-1 to
position 6.
We report the synthesis and the inhibitory properties of
6-substituted nipecotic acids bearing, oxime side chains.
2. Results and discussion
The synthesis of oxime analogues started from 2,5-
Dicarboxypyridine (8) which was treated with ethanol in the
presence of catalytic sulfuric acid to yield the diester 9
[19,20], which was selectively reduced at the position 2 by
treatment with NaBH4 and CaCl2 leading to the hydroxym-
ethyl nicotinate 10 [20–22]. The alcohol 10 treated with
CCl4/nBu3P [23] gave the halide 11, which was coupled with
the oximes 12–19 prepared by reaction of the corresponding
ketones and hydroxylamine giving the intermediates 20–27.
The pyridinic ring was then reduced by means of NaBH3CN
leading to a diastereomeric mixture of the nipecotates. The
diastereomers were separated by classical column chroma-
tography giving the trans-(28–35) and cis-(36–43) ethyl
nipecotates. Finally, the esters were hydrolysed and the
trans-(44–51) and cis-(52–59) nipecotic acid derivatives kept
as hydrochloride salts (Scheme 2).
The GABA uptake inhibitory properties of the final prod-
ucts were tested in vitro on rat brain synaptosome prepara-
tions [24]. The results are reported in Table 1. Compared with
the reference compounds, none of the synthesised product
possesses significant activity. Curiously the esters showed
sometimes slightly more activity than the corresponding ac-
ids. The loss of activity is observed either for the trans or the
cis relative configuration of the side chain in position 6 and
the carboxylic function in position 3.
It is noticeable to observe that the introduction of an
oxime in the side chain of analogues of the potent N-1
substituted compounds 2 and 3 results in powerful deriva-
tives while this modification, transposed at the position
6 transforms the active compounds 4 in poor GABA uptake
inhibitors.
In this series of derivatives the secondary amine in posi-
tion 1 shows an hydrogen atom which could establish an
hydrogen bond with the side chain and thus, induces an
inappropriate conformation of the side chain. However,
N-methyl 6-ether substituted analogues, where this hydrogen
bound is no more possible, do not possess more significant
affinity compared with the N-unsubstituted analogues [20].
An hydrogen bound between the NH group and the side
chain heteroatoms seemed not responsible for the poor ob-
served affinities. These results, concerning the oximes de-
rivatives, confirm the observations made on 6-ether and
6-enol ether nipecotic acids derivatives. One can conclude
that the electronegative area concept cannot be transferred
from position 1 to position 6 [24]. More work is in progress,
particularly, conformational analyses using molecular mod-
Scheme 2 Synthesis of 6-aryl oximinoymethyl nipecotic acids: (a) EtOH,
H2SO4; (b) NaBH4, CaCl2; (c) Bu3P, CCl4; (d) K2CO3; (e) NaBH3CN; (f)
NaOH, then HCl
12 20 28 36 44 52 R1 C6H5R2
C6H5
13 21 29 37 45 53
14 22 30 38 46 54
15 23 31 39 47 55
16 24 32 40 48 56
17 25 33 41 49 57
18 26 34 42 50 58
19 27 35 43 51 59
C6H5
o-CH3-C6H4
H
p-C6H5-C6H4
C6H5
o-Cl-C6H4
a-thienyl
o-CH3-C6H4
Fluorenyl
Dibenzosuberyl
C6H5
o-CH3-C6H4
elling and syntheses of new analogues to understand these
results and to refine the pharmacophore model.
3. Experimental
3.1. General procedures
Melting points were measured on a Mettler PF62 appara-
tus and are uncorrected. NMR spectra were recorded on
BrukerAvance 300 spectrometer using the d scale; the CHCl3
residual signal was fixed at 7.26 ppm. The abbreviations s, d,
t, q, qu, m are related to singlet, doublet, triplet, quadruplet,
quintuplet and multiplet, respectively. All the new com-
pounds gave satisfactory CHN analyses.

V. N’Goka et al. / European Journal of Medicinal Chemistry 39 (2004) 889–895
891
Table 1
Structures and GABA uptake properties of the synthetised 6-substituted nipecotic acids and reference compounds.
Number
44
45
46
47
48
49
50
51
52
53
54
56
57
58
28
29
31
32
33
34
36
37
38
40
41
42
Configuration
trans
trans
trans
trans
trans
trans
trans
trans
cis
R1
R2
R3
Analyses
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
CHN
IC50 µM
>100
>100
>100
>100
66
C6H5
C6H5
H
C6H5
o-CH3-C6H4
H
H
p-C6H5-C6H4
C6H5
H
o-Cl-C6H4
a-thienyl
o-CH3-C6H4
H
C6H5
H
o-CH3-C6H4
Fluorenyl
Dibenzosuberyl
C6H5
H
>100
>100
>100
>100
>100
>100
53
H
H
C6H5
H
cis
C6H5
o-CH3-C6H4
H
H
cis
p-C6H5-C6H4
C6H5
H
cis
a-thienyl
o-CH3-C6H4
H
cis
o-CH3-C6H4
Fluorenyl
C6H5
H
68
cis
H
60.4
>100
105
33
trans
trans
trans
trans
trans
trans
cis
C6H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C6H5
o-CH3-C6H4
o-Cl-C6H4
a-thienyl
C6H5
C6H5
66
o-CH3-C6H4
Fluorenyl
C6H5
o-CH3-C6H4
66
32
C6H5
55
cis
C6H5
o-CH3-C6H4
H
65
cis
p-C6H5-C6H4
C6H5
80
cis
a-thienyl
o-CH3-C6H4
>100
40
cis
o-CH3-C6H4
Fluorenyl
cis
23
2
3
4
5
6
7
SKF100300-A
SKF 89976-A
0.60
0.33
0.10
0.44
0.07
0.08
CI966
Thiagabine
3.1.1. Ethyl 2-chloromethyl-nicotinate (11)
the mixture was refluxed for 3 h. The solvent was evaporated
and the residue was partitioned between water (30 ml) and
ethyl acetate (3 × 50 ml). The organic layer was dried over
MgSO4, filtered and concentrated in vacuo. The crude prod-
uct was flash chromatographed on a silica gel column. The
product was eluted with a mixture of CH2Cl2–CH3OH (97:3)
giving 20 (3.10 g, 82%). 1H NMR (CDCl3): 1.43 (t, J = 7.1,
3H, OCH2CH3), 4.43 (q, J = 6.8, 2H, OCH2CH3), 5.16 (s,
2H, =NOCH2), 7.3–7.6 (m, 11H, 2C6H5 et H-3), 8.33 (dd,
J = 8.0, J = 2.0, H-4), 9.17 (d, J = 2.0, 1H, H-6).
Alcohol 10 [19–22] (10.0 g, 55.3 mmol) was dissolved in
CCl4 (250 ml) and placed under argon. Bu3P (20.6 ml,
82.9 mmol) was slowly added under stirring; stirring was
maintained for an additional 15 min. The mixture was ad-
sorbed on silica gel and chromatographied. The product was
eluted with hexane/ethyl acetate (8:2). Evaporation of the
solvent gave the chloromethyl derivative 11 as an orange
coloured oil (10.4 g, 94%). 1H NMR (CDCl3): 1.39 (t,
J = 7.1, 3H, OCH2CH3), 4.40 (q, J = 7.2, 2H, OCH2CH3),
4.70 (s, 2H, CH2Cl), 7.56 (d, J = 8.0, 1H, H-3), 8.31 (dd,
J = 8.1, J = 2.2, 1H, H-4), 9.15 (d, J = 2.1, 1H, H-6).
3.1.3. Ethyl 2-((o-methylphenyl, phenyl-iminooxy)-methyl)-
nicotinate (21)
3.1.2. Ethyl 2-(diphenyl-iminooxymethyl)-nicotinate (20)
Ethyl 2-chloromethyl-nicotinate 11 (2.1 g, 10.1 mmol),
benzophenone-oxime (1.97 g, 10.0 mmol) were dissolved in
CH3CN (30 ml); K2CO3 (2.76 g, 20.0 mmol) was added and
Same procedure as for 20; yield: 71%; 1H NMR (CDCl3):
1.43 (t, J = 6.8, 3H, OCH2CH3), 2.23 (s, 3H, o-CH3), 4.40 (q,
J = 6.8, 2H, OCH2CH3), 5.39 (s, 2H, =NOCH2–), 7.0–7.6 (m,

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V. N’Goka et al. / European Journal of Medicinal Chemistry 39 (2004) 889–895
10H, C6H4, C6H5 and H-3), 8.33(dd, J = 8.0, J = 2.0, H-4);
9.17(d, J = 2.0, 1H, H-6).
graphed on a silica gel column. We obtained 0.54 g of the less
polar trans-isomer 28 (51.5%), and 0.30 g (29%) of the more
polar cis-isomer 36.
Trans-Diastereomer 28: m.p. (as hydrochloride):184 °C;
1H NMR (CDCl3) (free base): 0.8–0.9 (m, 1H, H-5ax), 1.23
(t, J = 7.1, 3H, OCH2CH3), 1.5–1.7 (m, 1H, H-4ax), 1.8–2.1
(m, 2H, H-1, H-5eq), 2.2–2.4 (m, 1H, H-4eq), 2.91 (t,
J = 10.0, 1H, H-2ax), 3.14 (tt, J =10.0, J =3.5, 1H, H-3ax),
3.4–3.6 (m, 1H, H-6), 3.76 (ddd, J = 9.0, J = 3.5, J = 1.5, 1H,
H-2eq), 4.12 (q, J = 7.1, 2H, OCH2CH3), 4.32(AB part of an
ABX system, Dd = 0.34, JAB = 11.3, JAX = 6.8, JBX = 3.8, 2H,
CH2-7), 7.2–7.6 (m, 10H, (C6H5)2).
3.1.4. Ethyl 2-(((p-phenyl-phenyl)-iminooxy)-methyl)-
nicotinate (22)
Same procedure as for 20,Yield: 69%; 1H NMR (CDCl3):
1.44 (t, J = 7.1, 3H, OCH2CH3), 4.44 (q, J = 7.1, 2H,
OCH2CH3), 5.34 (s, 1H, HC=NO), 5.45 (s, 2H, =NOCH2–),
7.3–7.6 (m, 10H, C6H4, C6H5 and H-3), 8.35 (dd, J = 7.8,
J = 1.9, H-4); 9.20 (d, J = 1.7, 1H, H-6).
3.1.5. Ethyl 2-((o-Chlorophenyl, phenyl-iminooxy)-
methyl)-nicotinate (23)
1
Cis diastereomer 36: CNH mp 154 °C (free base); H
Same procedure as for 20;Yield: 51%; 1H NMR (CDCl3):
1.45 (t, J = 7.2, 3H, OCH2CH3), 4.41 (q, J = 7.2, 2H,
OCH2CH3), 5.42 (s, 2H, =NOCH2–), 7.2–7.5 (m, 10H, C6H4,
C6H5 and H-3), 8.31 (dd, J = 7.9, J = 1.9, H-4), 9.18 (d,
J = 1.9, 1H, H-6).
NMR (CDCl3): 0.8–1.0 ((m, 1H, H-5ax), 1.30 (t, J = 7.1, 3H,
OCH2CH3), 1.8–2.0 (m, 3H, H-4ax, H-5eq, H-1), 2.1–2.3
(m, 1H, H-4eq), 2.65(qu, J = 4.0, 1H, H-3eq), 2.94 (dd,
J = 12.0, J = 4.0, 1H, H-2ax), 3.5–3.7 (m, 2H, H-6 and
H-2eq), 4.05(q, J = 7.0, 2H, OCH2CH3), 4.34(AB part of an
ABX system, Dd = 0.17, JAB = 10.3, JAX = 6.2, JBX = 3.4, 2H,
CH2-7), 7.2–7.6 (m, 10H, (C6H5)2).
3.1.6. Ethyl 2-((␣-thienyl, phenyl-iminooxy)-methyl)-
nicotinate (24)
3.1.10. Ethyl 6-((o-methylphenyl, phenyl-iminooxy)-
methyl)-nipecotates (29) and (37)
Same procedure as for 20,Yield: 74%, mixture of syn- and
anti-isomers (ratio 8/2); 1H NMR (CDCl3): 1.43 (t, J = 7.0,
3H, OCH2CH3), 4.43 (q, J = 7.0, 2H, OCH2CH3), 5.39 and
5.60 (2s, 2H, =NOCH2–), 6.8–7.5 (m, 9H, C6H3S, C6H5 and
H-3), 8.29 and 8.33 (2dd, J = 8.0, J = 2.0, H-4); 9.13 and 9.17
(2d, J = 2.0, 1H, H-6).
Same procedure as for 28 and 36 starting from ethyl
2-((o-methylphenyl, phenyl-iminooxy)-methyl)-nicotinate
(21) (2.0 g, 5.34 mmol). We obtained 0.65 g of the less polar
trans-isomer 29 (32.5%), and 0.57 g (28.5%) of the more
polar cis-isomer 37.
Trans-Diastereomer 29 (as hydrochloride): CHN; m.p.
143 °C; 1H NMR (CDCl3) (free base): 1.25 (t, J = 7.0, 3H,
OCH2CH3), 1.5–1.7 (m, 3H, H-5ax, H-4ax, H-5eq), 2.10(s,
3H, CH3), 2.15 (broad d, J = 11.0, 1H, H-4eq), 2.80 (t,
J = 10.0, 1H, H-2ax), 3.14 (tt, J = 11.0, J = 3.5, 1H, H-3ax),
3.4–3.6 (m, 1H, H-6), 3.70 (broad dd, J = 10.0, 1H, H-2eq),
4.1–4.3 (m, 4H, containing at 4.10 (q, J = 7.0, 2H,
OCH2CH3), and CH2-7), 7.2–7.6 (m, 9H, C6H5 and C6H4).
Cis diastereomer 37 (as hydrochloride): CHN; m.p.
154 °C (free base); 1H NMR (CDCl3): 1.25 (t, J = 7.0, 3H,
OCH2CH3), 1.6–2.1 (m, 4H, H-5ax, H-4ax, H-5eq, H-4eq),
2.10 (s, 3H, CH3), 2.95 (broad s, 1H, H-3eq), 3.44(broadAB,
Dd = 0.14, JAB = 10.3, 2H, CH2-2), 3.62 (broad s, 1H, H-6),
4.10 (q, J = 7.0, 2H, OCH2CH3),4.49(broad AB, Dd = 0.45,
JAB = 10.0, 2H, CH2-7), 7.2–7.7 (m, 9H, C6H5 and C6H4).
3.1.7. Ethyl 2-((di-o-methylphenyl-iminooxy)-methyl)-
nicotinate (25)
Same procedure as for 20; yield: 70%; 1H NMR (CDCl3):
1.43 (t, J = 7.0, 3H, OCH2CH3), 2.28 and 2.32 (2s, 6H,
(o-CH3)2), 4.43 (q, J = 7.0, 2H, OCH2CH3), 5.39 (2s,
2H, =NOCH2–), 7.0–7.4 (m, 9H, (C6H4)2 and H-3), 8.33 (dd,
J = 8.0, J = 2.0, H-4); 9.17 (d, J = 2.0, 1H, H-6).
3.1.8. Ethyl 2-((fluorenyl-iminooxy)-methyl)-nicotinate (26)
Same procedure as for 20; yield: 83%; 1H NMR (CDCl3):
1.40 (t, J = 7.0, 3H, OCH2CH3), 4.40(q, J = 7.0, 2H,
OCH2CH3), 5.39 (s, 2H, =NOCH2–), 7.3–8.2 (m, 9H, fluo-
renyl and H-5), 8.33 (dd, J = 8.0, J = 2.0, H-4); 9.20 (d,
J = 2.0, 1H, H-2).
3.1.9. Ethyl 6-(diphenyl-iminooxymethyl)-nipecotates (28)
and (36)
3.1.11. Ethyl 6-((o-chlorophenyl, phenyl-iminooxy)-
methyl)-nipecotates (31) and (39)
The substituted pyridine 20 (1.03 g, 2.86 mmol) was
dissolved in glacial acetic acid (10 ml) at room temperature
and placed under an argon atmosphere. NaBH3CN (0.74 g,
11.9 mmol) was slowly added and the mixture was stirred for
2 h at room temperature and then heated at 50 °C for 1 h, kept
at room temperature overnight and finally ice cooled. Water
(50 ml), and concentrated sodium hydroxide until the mix-
ture was strongly basic were added. The mixture was ex-
tracted with ethyl acetate, the organic layer was washed with
NaCl saturated water, dried over MgSO4, filtered and con-
centrated in vacuo. The crude product was flash chromato-
Same procedure as for 28 and 36 starting from ethyl
2-((o-Chlorophenyl, phenyl-iminooxy)-methyl)-nicotinate
(23) (1.8 g, 4.56 mmol). We obtained 0.40 g of the less polar
1
trans diastereomer 31: H NMR (CDCl3): 1.1–1.3 (m, 4H,
containing at 1.26 (t, J = 7.0, 3H, OCH2CH3) and H-5ax),
1.55(qd, J = 13.0, J = 4.0, 1H, H-4ax), 1.71 (dq, J = 13.0,
J = 3.0, 1H, H-5eq), 2.11 (broad d, J = 12.6, 1H, H-4eq), 2.46
(tt, J = 12.0, J = 4.0, 1H, H-3ax), 2.70(t, J = 11.3, 1H, H-2ax),
2.93 (broad t, J = 10.8, 1H, H-6ax), 3.28 (ddd, J = 12.0,
J = 4.0, J = 1.5, 1H H-2eq), 4.0–4.3 (m 4H, containing at 4.13

V. N’Goka et al. / European Journal of Medicinal Chemistry 39 (2004) 889–895
893
(q, J = 7.0, 2H, OCH2CH3) and N-OCH2), 7.1–7.6 (m, 9H,
C6H5 and C6H4Cl).The cis-isomer was not obtained pure.
H-2ax), 2.9–3.1 (m, 1H, H-6), 3.43 (dt, J = 12.4, J = 1.9, 1H,
H-2eq), 4.0–4.3 (m, 4H, OCH2CH3, and CH2-7), 7.0–7.3 (m,
8H, (C6H4)2).
3.1.12. Ethyl 6-((␣-thienyl, phenyl-iminooxy)-methyl)-
nipecotates (32) and (40)
Same procedure as for 28 and 36 starting from ethyl
2-((a-thienyl, phenyl-iminooxy)-methyl)-nicotinate (24)
(1.20 g, 3.27 mmol). trans-Isomer 32 (0.40 g, 33%), and
cis-isomer 40 (0.30 g, 25%) were obtained.
3.1.14. Ethyl 6-((fluorenyl-iminooxy)-methyl)-nipecotates
(34) and (42)
Same procedure as for 28 and 36 starting from ethyl
2-((fluorenyl-iminooxy)-methyl)-nicotinate (26) (2.0 g,
5.58 mmol). trans-Isomer 34 (0.95 g 47%), and cis-isomer
42 (0.50 g, 24%) were obtained.
Trans-Diastereomer 32: m.p. (hydrochloride): 84 °C;
CHN (hydrochloride); 1H NMR (CDCl3) (free base): 1.2–1.4
(m, 4H, containing at 1.27 (t, J = 7.0, 3H, OCH2CH3) and
H-5ax), 1.59(qd, J = 12.4, J = 3.8, 1H, H-4ax), 1.80 (dq,
J = 9.8, J = 3.0, 1H, H-5eq), 1.94 (broad s, 1H exchangeable,
H-1), 2.14 (broad d, J = 12.6, 1H, H-4eq), 2.51 (tt, J = 11.7,
J = 3.4, 1H, H-3ax), 2.79 (t, J = 11.7, 1H, H-2ax), 2.9–3.2 (m,
1H, H-6ax), 3.40 (ddd, J = 11.6, J = 4.1, J = 1.9, 1H, H-2eq),
4.14(q, J = 7.0, 2H, OCH2CH3), 4.34(AB part of an ABX
system, Dd = 0.12, JAB = 10.9, JAX = 7.9, JBX = 3.8 2H,
CH2-7), 7.0–7.7 (m, 8H, C6H5 and C4H3S).
Cis diastereomer 40: m.p. (hydrochloride): 200 °C; CHN
(hydrochloride); 1H NMR (CDCl3) (free base): 1.2–1.4 (m,
4H, containing at 1.23 and 1.27 (2t, J = 6.8, 3H, OCH2CH3
syn and anti isomers), and H-5ax), 1.5–1.8 (m, 3H, H-4ax,
H-5eq, and H-4eq), 2.02 (s, exchangeable 1H, H-1), 2.51 and
2.55 (2qu, J = 3.8, 1H, H-3eq, syn and anti isomers), 2.86 and
2.90 (2dd, J = 12.0, J = 4.0, 1H, H-2ax syn and anti isomers),
3.0–3.2 (m, 1H, H-6) 3.4–3.6 (m, 1H, H-2eq), 4.15 and 4.22
(2q, J = 7.0, 2H, OCH2CH3, syn and anti isomers), 4.22(AB
part of an ABX system, Dd = 0.07, JAB = 12.3, JAX = 6.2,
JBX = 3.4, 2H, CH2-7), 6.7–7.6 (m, 8H, C6H5 and C4H3S).
Trans-Diastereomer 34: CHN (as hydrochloride); m.p. (as
hydrochloride): 148 °C; 1H NMR (CDCl3) (free base): 1.26
(t, J = 7.1, 3H, OCH2CH3), 1.44 (qd, J = 10.4, J = 3.7, 1H,
H-5ax), 1.62 (qd, J = 12.4, J =3.4, 1H, H-4ax), 1.89 (dq,
J = 10.2, J = 3.0, 1H, H-5eq), 2.1–2.3 (m, 1H, H-4eq), 2.59
(tt, J = 11.7, J = 4.0, 1H, H-3ax), 2.81 (t, J = 11.7, 1H, H-2ax),
3.1–3.3 (m, 2H, H-1, and H-6ax), 3.44 (ddd, J=12.1, J=3.8,
J=1.9, 1H, H-2eq), 4.15 (q, J = 6.9, 2H, OCH2CH3), 4.41(AB
part of an ABX system, Dd = 0.08, JAB = 12.3, JAX = 7.9,
JBX = 4.1, 2H, CH2-7)), 7.3–7.3 (m, 8H, (fluorenyl).
Cis diastereomer 42: CNH (as hydrochloride); m.p. (as
1
hydrochloride) 182 °C; H NMR (CDCl3) (free base): 1.2–
1.4 (m, 4H, containing at 1.22 (t, J = 7.1, 3H, OCH2CH3), and
H-5ax), 1.5–1.8 (m, 2H, H-4ax, H-5eq), 2.1–2.3 (m, 1H,
H-4eq), 2.65(qu, J = 3.8, 1H, H-3eq), 2.96(dd, J = 12.4,
J = 3.8, 1H, H-2ax), 3.2–3.4 (m, 1H, H-6), 3.4–3.6 (m, 2H,
containing at 3.56 (dt, J = 12.8, J = 2.2, 1H, H-2eq) and H-1),
4.1–4.2 (m, 2H, OCH2CH3), 4.42(AB part of an ABX sys-
tem, Dd = 0.07, JAB = 11.7, JAX = 6.4, JBX = 3.8, 2H, CH2-7),
7.3–7.3 (m, 8H, (fluorenyl)).
3.1.13. Ethyl 6-((di-o-methylphenyl-iminooxy)-methyl)-
nipecotates (33) and (41)
Same procedure as for 28 and 36 starting from ethyl
2-((di-o-methylphenyl-iminooxy)-methyl)-nicotinate (25)
(1.30 g, 3.35 mmol). trans-Isomer 33 (0.60 g, 46%), and
cis-isomer 41 (0.30 g, 23%) were obtained.
3.1.15. Ethyl 6-((dibenzosuberyl-iminooxy)-methyl)-
nipecotates (35) and (43)
Same procedure as for 16 and 17 starting from ethyl
2-((dibenzosuberyl-iminooxy)-methyl)-nicotinate
(2.0 g, 5.15 mmol). trans-Isomer 35 (0.90 g, 44%), and
cis-isomer 43 (0.50 g, 25%) were obtained.
(27)
trans-Diastereomer 33: CHN (as hydrochloride); m.p. (as
hydrochloride): 85 °C; 1H NMR (CDCl3) (free base): 1.1–1.4
(m, 4H, containing at, 1.23 (t, J = 7.1, 3H, OCH2CH3), and
H-5ax), 1.53 (qd, J = 12.4, J = 3.8, 1H, H-4ax), 1.67 (dq,
J = 12.8, J = 2.6, 1H, H-5eq), 1.88 (broad s, 1H, H-1), 2.09
((broad d, J = 13.2, 1H, H-4eq), 2.23 (s, 3H, CH3), 2.3–2.4
(m, 4H, containing at 2.44 (s, 3H, CH3), and H-3ax), 2.68 (t,
J = 11.3, 1H, H-2ax), 2.89 (tt, J = 11.0, J = 3.5, 1H, H-6ax),
3.28 (ddd, J = 11.5, J = 3.8, J = 1.5, 1H, H-2eq), 4.0–4.3 (m,
4H containing at, 4.13 (q, J = 6.5, 2H, OCH2CH3), and at
4.08(AB part of an ABX system, Dd = 0.16, JAB = 10.9,
JAX=7.9, JBX=3.8, 2H, CH2-7)), 7.0–7.4(m, 8H, (C6H4)2).
cis diastereomer 41: CNH (as hydrochloride); m.p. (as
hydrochloride) 112 °C; 1H NMR (CDCl3): 1.1–1.5 (m, 4H,
containing at 1.25 (t, J = 7.1, 3H, OCH2CH3), and H-5ax),
1.6–1.9 (m, 3H, H-4ax, H-5eq, H-4eq), 2.1–2.3 (m, 4H
containing at 2.23 (s, 3H, CH3) and H-1), 2.44 (s, 3H, CH3),
2.51 (qu, J = 3.8, 1H, H-3eq), 2.82 (dd, J = 12.4, J = 3.4, 1H,
Trans-Diastereomer 35: CHN (as hydrochloride); 1H
NMR (CDCl3) (free base): 1.27 (t, J = 7.1, 3H, OCH2CH3),
1.54 (qd, J = 10.4, J = 3.7, 1H, H-5ax), 1.74 (qd, J = 12.4,
J = 3.4, 1H, H-4ax), 2.1–2.4 (m, 2H, H-4eq, H-5eq), 2.50 (tt,
J = 11.9, J = 4.0, 1H, H-3ax), 2.74 (t, J = 11.6, 1H, H-2ax),
2.9–3.1 (m, 1H, H-6ax), 3.1–3.3 (m, 4H, CH2-CH2), 3.44
(ddd, J = 13.4, J = 4.05, J = 1.6, 1H, H-2eq), 4.0–4.3 (m, 4H,
OCH2CH3, CH2-7), 7.1–7.6 (m, 8H, (C6H4)2).
Cis diastereomer 43: CNH (as hydrochloride); m.p. (as
hydrochloride) 182 °C; 1H NMR (CDCl3) (free base): 1.24 (t,
J = 7.1, 3H, OCH2CH3), 1.3–1.5 (m, 1H, H-5ax), 1.5–1.7 (m,
2H, H-4ax, H-5eq), 2.21 (broad d, J = 14, 1H, H-4eq), 2.54
(broad qu, J = 4.0, 1H, H-3eq), 2.84 (dd, J = 12.5, J = 3.4, 1H,
H-2ax), 2.9–3.2 (m, 5H, H-6, CH2–CH2), 3.4–3.6 (m, 1H,
H-2eq), 4.0–4.3 (m, 4H, OCH2CH3, CH2-7), 7.1–7.7 (m, 8H,
(C6H4)2).

894
V. N’Goka et al. / European Journal of Medicinal Chemistry 39 (2004) 889–895
3.1.16. trans-6-(Diphenyl-iminooxymethyl)-nipecotic acid
(44) (hydrochloride)
3.1.21. trans-6-((␣-Thienyl, phenyl-iminooxy)-methyl)-
nipecotic acid (48)
Same procedure as for 44 starting from ester 32 (200 mg)
gave the acid 48 (59%), CHN; 1H NMR (CD3OD): 1.6–1.8
(m, 2H, H-5ax, H-4ax), 2.0–2.3 (m, 2H, H-5eq, H-4eq), 2.56
(broad t, J = 12.2, 1H, H-3ax), 3.04 (t, J = 12.4, 1H, H-2ax),
3.5–3.7 (m, 2H, H-6ax and H-2eq), 4.44(AB part of an ABX
system, Dd = 0.09, JAB = 12.4, JAX = 7.2, JBX = 4.1, 2H,
CH2-7), 6.8–7.9 (m, 8H, C6H5 and C4H3S).
The ester 28 (220 mg, 0.60 mmol) NaOH (28 mg,
0.68 mmol), water (12.5 ml), and THF (6 ml) was stirred
overnight at room temperature. The mixture was evaporated
to dryness and the residue was washed with ether. Water
(1.0 ml) and HCl 37% (0.2 ml, 1.6 mmol) were added to the
residue. The solution was, again, evaporated and isopropanol
was added to the residue. This solution was filtered and
dropped in anhydrous ether (100 ml). The precipitate was
1
3.1.22. cis-6-((␣-thienyl, phenyl-iminooxy)-methyl)-
nipecotic acid (56)
Same procedure as for 44 starting from ester 40 (200 mg)
gave the acid 56 (42%) CHN; m.p. 112 °C.
filtered and dried giving the acid 44 (200 mg), H NMR
(CD3OD): 0.91 (dd, J = 10.5, J = 8.0, 1H, H-5ax), 1.5–1.7
(m, 1H, H-4ax), 1.8–2.1 (m, 2H, H-1, H-5eq), 2.2–2.4 ((m,
1H, H-4eq), 2.91 (t, J = 11.0, 1H, H-2ax), 3.14 (tt, J = 10.0,
J = 3.5, 1H, H-3ax), 3.4–3.6 (m, 1H, H-6), 3.76 (ddd, J = 9.0,
J = 3.5, J = 1.5, 1H, H-2eq), 4.30(AB part of anABX system,
Dd = 0.09, JAB = 12.8, JAX = 6.9, JBX = 3.7, 2H, CH2-7),
7.2–7.6 (m, 10H, (C6H5)2).
3.1.23. trans-6-((Di-o-methylphenyl-iminooxy)-methyl)-
nipecotic acid (49)
Same procedure as for 44 starting from ethyl trans-6-((di-
o-methylphenyl-iminooxy)-methyl)-nipecotate (33), yield:
1
59%, CHN; m.p. 203 °C; H NMR (CD3OD): 1.5–1.9 (m,
3.1.17. trans-6-((o-Methylphenyl, phenyl-iminooxy)-
methyl)-nipecotic acid (45)
2H, H-5ax, H-4ax), 2.0–2.1 (m, 1H, H(5eq), 2.2–2.5 (m, 7H,
containing at 2.36 and 2.38 (2s, 6H, (CH3)2) and H-4eq), 2.72
(tt, J = 12.2, J = 3.8, 1H, H-3ax), 3.09(t, J = 12.5, 1H, H-2ax),
3.4–3.7 (m, 2H, H-2eq and H-6ax), 4.31(AB part of anABX,
Dd = 0.04, JAB = 12.8, JAX = 6.6, JBX = 4.4, 2H, CH2-7),
7.1–7.4 (m, 8H, (C6H4)2).
Same procedure as for 44 starting from ester 29 (200 mg)
1
gave the acid 45 CHN; m.p. 183 °C; H NMR (CD3OD):
1.5–1.7 (m, 2H, H-4ax, H-5ax), 1.9–2.4 (m, 5H, containing
at 2.10 (s, 3H, CH3) and H-5eq, H-4eq), 2.71 (tt, J = 12.5,
J = 4.5, 1H, H-3ax), 3.11 (t, J = 13.0, 1H, H-2ax), 3.5–3.7 (m,
2H, H-6ax and H-2eq), 4.2–4.4 (m, 2H, CH2-7), 7.0–7.6 (m,
9H, C6H5 and C6H4).
3.1.24. cis-6-((di-o-methylphenyl-iminooxy)-methyl)-nipe-
cotic acid (57)
Same procedure as for 44 starting from ethyl cis-6-((di-o-
methylphenyl-iminooxy)-methyl)-nipecotate (41) yield:
59%, CHN; m.p. 169 °C; H NMR (CD3OD): 1.5–1.8 (m,
1H, H-5ax), 1.8–2.1 (m, 2H, H-4ax, H-5eq); 2.1–2.3 (m, 4H,
containing at 2.20 (s, 3H, CH3) and H-4eq), 2.39 (s, 3H,
CH3), 2.9–3.0 (m, 1H, H-3eq), 3.18 (dd, J = 13.1, J = 4.1, 1H,
H-2ax), 3.5–3.7 (m, 2H, H-2eq, H-6ax), 4.3–4.5 (m, 2H,
CH2-7), 7.0–7.4 (m, 8H, (C6H4)2).
3.1.18. cis-6-((o-methylphenyl, phenyl-iminooxy)-methyl)-
nipecotic acid (53)
1
Same procedure as for 44 starting from ester 37 (200 mg)
1
gave the acid 53 CHN; m.p. 130 °C; H NMR (CD3OD):
0.8–1.0 (m, 1H, H-5ax), 1.5-2.4 (m, 6H, containing at 2.14 (s,
3H, CH3) and H-4ax, H-5eq, H-4eq), 2.98 (qu J = 4.1, 1H,
H-3eq), 3.22 (dd, J = 13.0, J = 3.8, 1H, H-2ax), 3.5–3.7 (m,
2H, containing at 3.68 (dt, J = 11.3, J = 1.9, H-2eq) and
H-6ax), 4.34(AB part of an ABX system, Dd = 0.07,
JAB = 12.7, JAX = 4.9, JBX = 3.8, 2H, CH2-7), 7.1–7.6 (m, 9H,
C6H5 and C6H4).
3.1.25. trans-6-((Fluorenyl-iminooxy)-methyl)-nipecotic
acid (50)
Same procedure as for 44 starting from ethyl trans-6-
((fluorenyl-iminooxy)-methyl)-nipecotate (34) yield: 49%;
1
3.1.19. cis-6-(((p-phenyl-phenyl)-iminooxy)-methyl)-nipe-
cotic acid (54)
Same procedure as for 44 starting from ester 55 (200 mg)
gave the acid 54 (80 mg, 38%), CHN; m.p. 120 °C;
CHN; H NMR (CD3OD): 1.3–1.6 (m, 2H, H-5ax, H-4ax),
1.99 (broad d, J = 9.5, 1H, H(5eq), 2.1–2.2 (m, 1H, H-4eq),
2.45 (broad t, J = 11.3, 1H, H-3ax), 2.92 (t, J = 12.6, 1H,
H-2ax), 3.3–3.6 (m, 2H, H-2eq and H-6ax), 4.34(AB part of
an ABX, Dd = 0.08, JAB = 12.6, JAX = 7.0, JBX = 4.1, 2H,
CH2-7), 7.2–8.4 (m, 8H, (C6H4)2).
3.1.20. trans-6-((o-Chlorophenyl, phenyl-iminooxy)-
methyl)-nipecotic acid (47)
Same procedure as for 44 starting from ester 31 (200 mg)
gave the acid 47 (85 mg, 39%), CHN; H NMR (D2O):
3.1.26. cis-6-((fluorenyl-iminooxy)-methyl)-nipecotic acid
(58)
1
0.8–1.0 (m, 1H, H-5ax), 1.2–1.5 (m, 1H, H-4ax,), 1.5–1.8
(m, 2H, H-5eq, H-4eq), 2.71 (tt, J = 12.5, J = 4.5, 1H, H-3ax),
3.11 (t, J = 12.8, 1H, H-2ax), 3.5–3.7 (m, 2H, H-6ax and
H-2eq), 4.2–4.4 (m, 2H, CH2-7), 7.2–7.7 (m, 9H, C6H5 and
C6H4).
Same procedure as for 44 starting from ethyl cis-6-
((fluorenyl-iminooxy)-methyl)-nipecotate (42); yield: 52%;
CHN; 1H NMR (CD3OD): 1.9–2.18 (m, 2H, H-5ax, H-4ax),
2.2–2.3 (m, 1H, H-5eq), 2.65–2.75 (m, 1H, H-4eq), 3.09 (dd,
J = 13.0, J = 4.0, 1H, H-2ax), 3.24 (qu, J = 2.8, 1H, H-3eq),

V. N’Goka et al. / European Journal of Medicinal Chemistry 39 (2004) 889–895
895
3.4–3.7 (m, 2H, H-2eq, H-6ax), 4.4–4.6 (m, 2H, CH2-7),
References
7.2–8.4 (m, 8H, (C6H4)2).
[1] S.J. Enna, The GABA Receptors, Humana Press, Clifton, New York,
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3.1.27. trans-6-((Dibenzosuberyl-iminooxy)-methyl)-nipe-
cotic acid (51)
[2] E. Roberts, T.N. Chase, D.B. Tower, GABA in Nervous System
Function, Raven Press, New York, 1976 554 pp.
Same procedure as for 44 starting from ethyl trans-6-
((dibenzosuberyl-iminooxy)-methyl)-nipecotate (35), yield:
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1
59%; CHN; H NMR (CD3OD): 1.5–1.8 (m, 2H, H-5ax,
H-4ax), 2.0–2.1 (m, 1H, H(5eq), 2.2–2.4 (m, 1H, H-4eq) 2.73
(tt, J = 11.8, J = 4.4, 1H, H-3ax), 3.0–3.3 (m, 5H, H-2ax,
CH2–CH2 suberyl), 3.5–3.7 (m, 2H, H-2eq and H-6ax),
4.31(AB part of an ABX, Dd = 0.07, JAB = 12.5, JAX = 6.9,
JBX =4.1, 2H, CH2-7), 7.1–7.7 (m, 8H, (C6H4)2).
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3.1.28. cis-6-((dibenzosuberyl-iminooxy)-methyl)-nipecotic
acid (59)
Same procedure as for 44 starting from ethyl cis-6-
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39%; CHN.
[8] S.J. Enna, E.D. Bird, J.P. Bennett, D.B. Bylund, L.L. Iversen,
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supplemented with NaCl (0.15 M), and 100 µl of [3H]-
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Acknowledgements
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We thank INSERM contract 892017 and CNRS for giving
a grant to VN and Mary Richards for proofreading the manu-
script.
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