Synthesis of imidazole phosphinic acids as I4AA analogues

Article abstract of DOI:10.1016/j.tetlet.2005.12.086

The GABA_C receptor has been identified as a potentially attractive target involved in a number of eye diseases. TPMPA is the best antagonist reported so far. The synthesis of two new pharmacophores based on imidazole phosphinic acid core structure will be presented.

Full text of DOI:10.1016/j.tetlet.2005.12.086

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1253–1255
Synthesis of imidazole phosphinic acids as I4AA analogues
David Orain* and Henri Mattes
Global Discovery Chemistry-Neuroscience, Novartis Institute for Biomedical Research Basel, CH-4002 Basel, Switzerland
Received 3 October 2005; revised 15 December 2005; accepted 16 December 2005
Available online 10 January 2006
Abstract—The GABAC receptor has been identified as a potentially attractive target involved in a number of eye diseases. TPMPA
is the best antagonist reported so far. The synthesis of two new pharmacophores based on imidazole phosphinic acid core structure
will be presented.
Ó 2006 Elsevier Ltd. All rights reserved.
c-Aminobutyric acid, GABA, is the major inhibitory
neurotransmitter in the mammalian central nervous
system. Currently, three classes of GABA receptors
have been characterized: two ion channels (GABAA and
modulating the linker chain between the imidazole and
the phosphinic acid (Fig. 1).
For the synthesis of the 4-imidazole phosphinic acid ana-
logue 1, commercial 4-carboxyimidazole was used as the
starting point. Imidazole was protected with a trityl
group in a 65% yield. Introduction of the phosphorus
in a pseudo benzylic position was not possible by direct
nucleophilic substitution of a phosphinate on activated
imidazoles (–CH2Br, –CH2Cl or –CH2OMs) most prob-
ably due to the high instability of these compounds.
Therefore the phosphinic ester was introduced through
a Pudovik condensation between aldehyde 4 and butyl
GABAC) and
a
GPCR related (GABAB). The
GABAC receptors are composed of three subunits q1,
q2 and q3 and the q1 GABAC subunit is essentially
expressed in the eye. In addition, GABAC receptors
appear to be involved in a number of inherited diseases
of the eye. These aspects have focused an interest on
the GABAC receptor as a novel therapeutic target.1
A number of compounds have been synthesized in order
to get inhibitory effect on q1 GABAC receptors. So far,
the best compound in the area seems to be TPMPA with
a Ki of 3.2 lM. TPMPA2 was designed by selecting the
core structure of isoguvacine (a known GABAA/C
ligand) in which the carboxylic acid was replaced by a
phosphinic acid in order to increase activity and selectiv-
ity towards GABAC. Following the same design, imid-
azole-4-acetic acid (I4AA), which is already known as
a q1 GABAC antagonist/partial agonist3 was selected
as a template. Little is known about the GABAC recep-
tor ligands’ binding site but the trend is that GABAC
binding affinity seems to require a basic and an acidic
group ideally arranged in the median plane of the mol-
ecule and separated by roughly three carbons.4 We wish
to report herein the synthesis of two new classes of imid-
azole phosphinic acids 1 and 2, as I4AA analogues, by
replacing the carboxylic acid by a phosphinic acid and
–
H3N+
O
O
GABA
O
O
HN
HN
P
OH
OH
Isoguvacine
TPMPA
H
O
N
1
P R
OH
H
N
N
OH
N
O
H
O
N
I4AA
P R
OH
2
N
Keywords: Phosphinic acid; Imidazole; GABA; TPMPA.
*
Figure 1. Structure of GABA, isoguvacine, TPMPA, I4AA and
imidazole phosphinic acids 1 and 2.
Corresponding author. Tel.: +41 61 696 15 64; fax: +41 61 696 24
55; e-mail: david.orain@novartis.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.086

1254
D. Orain, H. Mattes / Tetrahedron Letters 47 (2006) 1253–1255
ethylphosphinate 55 in neat triethylamine.6 The corre-
sponding imidazole phosphinic ester 6 was obtained in
a moderate yield of 35%. Addition of a co-solvent such
as toluene or changing the base did not improve the yield.
Deoxygenation was realized by a modified Barton-type
reaction as described by Kehler.4 The deoxy derivative
7 was obtained in an isolated yield ranging from 15%
to 25% together with 4-hydroxymethyl tritylimidazole,
which was detected by LC/MS analysis. Utilization of
diphenylchlorosilane in the presence of catalytic amounts
of indium chloride as an alternative pathway for this
deoxygenation, gave no reaction.7 Finally, removal of
the acid labile groups was carried out in refluxing HCl
6 N. Purification was achieved by filtration over
DOWEX resin8 to afford 4-imidazolmethyl-n-butylphos-
phinic acid 19 in a 75% yield (Scheme 1).
ever did not proceed between vinyl tritylimidazole11
and 5 under several conditions (Scheme 2).
As an alternative pathway, nucleophilic substitution of a
phosphinate on an alkyl bromide was chosen. N-Benzyl
imidazole carboxylic acid 8 was used as the starting
point. After esterification under acidic catalysis, ester 9
was reduced with LAH to the corresponding alcohol.
Bromination of the alcohol was achieved with triphenyl
phosphine and bromine in low yield. This was probably
due to the relative instability of 11, which had to be used
quickly for the next step. Four equivalents of phosphin-
ate 5 were used for the nucleophilic substitution afford-
ing compound 12 in a 65% yield. Removal of the benzyl
group by hydrogenation over Pd/C was quantitative.
Finally, imidazole phosphinic acid 212 was obtained in
a 61% isolated yield after refluxing in HCl 6 N and puri-
fication over DOWEX resin (Scheme 3).
For the introduction of an ethylene spacer between the
imidazole and the phosphinic acid, the first approach
was based on the addition of a phosphinate onto a dou-
ble bond as previously reported.10 This reaction how-
In conclusion, using I4AA as template, the carboxylic
group has been replaced by a phosphinic group leading
H
Trt-Cl (1 eq), TEA (2 eq)
DMF, rt, 16 hrs
N
BuP(O)(OEt) 5 (1 eq)
TEA, 100 deg, 16 hrs
N
H
N
35%
N
65%
O
4
O
P
N
N
3
H
HO
O
O
6
i) MeOCOCOCl (1.5 eq)
DMAP (1.6 eq), CH3CN
0oC and then rt, 2 hrs
ii) Bu3SnH (1.5 eq)
15-25%
toluene, 90oC, 3 hrs
H
N
i) HCl 6N, reflux, 16 hrs
ii) Purification DOWEX 50WX4
OH
P
N
N
75%
O
O
P
N
1
O
7
Scheme 1. Synthesis of imidazole phosphinic acid 1.
N
O
H P
O
+
N
N
O
N
P
O
Scheme 2. Addition of phosphinate onto double bond.

D. Orain, H. Mattes / Tetrahedron Letters 47 (2006) 1253–1255
1255
HClconc, MeOH
reflux, 6 hrs
LAH (1.5 eq), THF
reflux, 3 hrs
N
N
N
O
O
O
N
N
N
78%
96%
10
8
9
OH
OH
PPh3 (1.27 eq)
Br2 (1.25 eq)
30%
DCM
rt, 2 hrs
i) BuP(O)(OEt)H (4 eq), NaH (4 eq)
THF, rt, 2 hrs
ii) 11, reflux, 2 hrs
N
N
O
N
P
N
O
65%
11
12
Br
Pd/C, H2
MeOH
100%
H
N
H
i) HCl 6N, reflux, 16 hrs
ii) Purification DOWEX 50WX4
N
O
O
P
N
P
N
O
OH
61%
13
Scheme 3. Synthesis of imidazole phosphinic acid 2.
2
4. Chebib, M.; Vandenberg, R. J.; Johnston, G. A. R. Br. J.
Pharmacol. 1997, 122, 1551–1560.
to the synthesis of two new imidazole phosphinic acids.
Biological results will be reported in due course.
5. Froestl, W.; Mickel, S. J.; von Sprecher, G.; Diel, P. J.;
Hall, R. G.; Maier, L.; Strub, D.; Melillo, V.; Baumann, P.
A.; Bernasconi, R.; Gentsch, C.; Hauser, K.; Jaekel, J.;
Karlsson, G.; Klebs, K.; Maitre, L.; Marescaux, C.;
Pozza, M. F.; Schmutz, M.; Steinmann, M. W.; van
Riezen, H.; Vassout, A.; Mondadori, C.; Ople, H.-R.;
Waldmeier, P. C.; Bittiger, H. J. Med. Chem. 1995, 38,
3313–3331.
6. Kehler, J.; Ebert, B.; Dahl, O.; Krogsgaard-Larsen, P.
J. Chem. Soc., Perkin Trans. 1 1998, 3241–3243.
7. Yasuda, M.; Onishi, Y.; Ueba, M.; Miyai, T.; Baba, A.
J. Org. Chem. 2001, 66, 7741–7744.
Acknowledgements
The authors thank Dr. U. Trendelenburg, M. Bernhard,
Dr. J. Mosbacher, Dr. I. Vranesic and N. Reyman for
fruitful discussion, R. Denay for the NMR experiments.
References and notes
8. Protocol for purification over DOWEX resin see: Dumon,
Y. R.; Montchamp, J.-L. J. Organomet. Chem. 2002, 653,
252–260.
1. Most recent reviews on GABAC and references herein: (a)
Johnston, G. A. R.; Chebib, M.; Hanrahan, J. R.; Mewett,
K. N. Curr. Drug Targets—CNS Neurol. Disorders 2003,
2, 260–268; (b) Johnston, G. A. R. Curr. Top. Med. Chem.
2002, 2, 903–913.
2. Hanrahan, J. R.; Mewett, K. N.; Chebib, M.; Burden, P.
M.; Johnston, G. A. R. J. Chem. Soc., Perkin Trans 1
2001, 2389–2392.
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Pharmacol. Sect. 1993, 245, 83–84.
9. 1H NMR (400 MHz, D2O): d 8.34 (d, J = 1.0 Hz, 1H),
7.12 (d, J = 1.5 Hz, 1H), 2.94 (d, J = 14.6 Hz, 2H), 1.41
(m, 4H), 1.27 (m, 2H), 0.79 (t, J = 7.1 Hz, 3H).
10. Liu, X.; Hu, E.; Tian, X.; Mazur, A.; Ebetino, F. H.
J. Organomet. Chem. 2002, 646, 212–222.
11. Kokosa, J. M.; Szafasz, R. A.; Tagupa, E. J. Org. Chem.
1983, 48, 3605–3607.
12. 1H NMR (400 MHz, D2O): d 7.50 (s, 1H), 6.82 (br s, 1H),
3.92 (m, 2H), 2.66 (m, 2H), 1.97 (m, 2H), 1.62 (m, 2H),
1.36 (m, 4H), 1.21 (t, J = 7.1 Hz, 3H), 0.86 (t, J = 7.0 Hz,
3H).