Synthesis and biological evaluation of novel 2-(1H-imidazol-4-yl)cyclopropane carboxylic acids: key intermediates for H3 histamine receptor ligands.

Article abstract of DOI:10.1016/S0960-894X(02)00793-X

A new synthetic methodology to provide cis-2-(1H-imidazol-4-yl)-cyclopropane carboxylic acids is described. These cyclopropanes are useful for the preparation of novel H(3) receptor agents.

Full text of DOI:10.1016/S0960-894X(02)00793-X

Bioorganic & Medicinal Chemistry Letters 12 (2002) 3561–3563
Synthesis and Biological Evaluation of
Novel 2-(1H-imidazol-4-yl)cyclopropane Carboxylic Acids:
Key Intermediates for H3 Histamine Receptor Ligands
Miguel F. Brana,a,* Cristina Guisado,a Luis Fernando Alguacil,b Elisa Garrido,b
Carmen Perez-Garcıab and Mariano Ruiz-Gayob
a
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Departamento de Ciencias Quımicas, Seccion de Quımica Organica y Farmaceutica, Universidad San Pablo CEU,
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Urb Monteprıncipe, Boadilla del Monte 28668, Madrid, Spain
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b
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Departamento de Farmacologıa, Tecnologıa y Desarrollo Farmaceutico, Seccion de Farmacologıa y Toxicologıa,
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Universidad San Pablo CEU, Urb Monteprıncipe, Boadilla del Monte 28668, Madrid, Spain
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Received 17 July 2002; revised 9 September 2002; accepted 16 September 2002
Abstract—A new synthetic methodology to provide cis-2-(1H-imidazol-4-yl)-cyclopropane carboxylic acids is described. These
cyclopropanes are useful for the preparation of novel H3 receptor agents.
# 2002 Elsevier Science Ltd. All rights reserved.
The different pharmacological actions of histamine are
mediated via the activation of four distinct receptor
antagonist GT-23318 has been reported (Fig. 1). There-
fore, as part of our medicinal chemistry studies directed
towards the preparation of new H3 receptor ligands, we
have initiated the synthesis of new precursors of cyclo-
propylhistamine derivatives. We have synthesised a
series of novel 2-(1H-imidazol-4-yl)-cyclopropane car-
boxylic acids I (Fig. 2), as key synthetic intermediates,
on which an alkyl or an aryl moiety was attached to the
1
subtypes, namely H1, H2, H3 and H4 receptors.2 The
histamine H3 receptor is responsible for controlling
neuronal synthesis of histamine and regulates its release
into the synaptical cleft.3 Furthermore, this receptor has
been shown to modulate the release of other neuro-
transmitters, such as acethylcoline, dopamine, serotonin
and noradrenaline, in both the central and peripheral
nervous systems.4 Therefore, the H3 receptor can be
considered a potential target for several diseases and
neurological disorders, for example, epilepsy, schizo-
phrenia, eating and drinking behaviour, arousal and sleep
disorders, memory and learning deficits, and Alzheimer’s
disease.5
Figure 1.
It has been demonstrated that potent and selective his-
tamine receptor ligands possess distinct stereochemical
characteristics.6 The development of rigid histamine
analogues will contribute to the determination of the H3
receptor pharmacophore. Due to its structural features,
the cyclopropane ring has been used to improve histamine
H3 receptor affinity. The activity of some cyclopropanic
derivatives like the agonist cyclopropylhistamine7 or the
*Corresponding autor. Tel.:+34-91-372-4771; fax:+34-91-372-4009;
e-mail: mfbrana@ceu.es
Figure 2.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00793-X

3562
M. F. Bran˜a et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3561–3563
C3 position of the cyclopropane ring. We have explored
the cis stereochemical relation between C1 and C2
positions of the cyclopropane ring, as a first approach
to the synthesis of the cis-cyclopropylhistamine
precursor II (Fig. 2).
underwent cyclopropanation to give lactones 3a–e upon
slow addition to a refluxing solution of bis-(N-tert-
butyl-salicyladiminato) copper (II) catalyst.12 The lac-
tones 3a–e were opened with LiOH and converted into
their methyl esters 4a–e by reaction with diazomethane.
Thus, oxidation of the primary alcohol function in 4a–e
rendered the aldehydes 5a–e (Scheme 1).
Chemistry
The imidazole ring moiety was obtained from 5a–e by
reaction with benzylamine and TosMIC in a single
pot.13 The esters 6a,c were hydrolysed under basic con-
ditions and subsequent transfer hydrogenation,14 with
cyclohexene and the Pd-C (10%) catalyst, providing
Ia,c. The hydrogenation of the N-benzyl group in esters
6b,d,e, followed by acidic hydrolysis, furnished Ib,d and
II, respectively (Scheme 2).
The general pathway outlined in Schemes 1 and 2 yiel-
ded the desired compounds I and II. The alcohols 1a–e9
were transformed into their corresponding allylic di-
azocetates 2a–e, by reaction with diketene (or the dike-
tene equivalent 2,2,6-trimethyl-4H-3-dioxin-4-one)10
and subsequent diazo transfer, followed by base-
induced deacylation.11 The unsaturated diazo esters 2a–e
Scheme 1. (a) (i) diketene, THF, Á; (ii) 4-acetamidobenzene-sulfonyl azide, CH3CN, rt; (iii) LiOH, H2O; (b) Cu(TBS)2, toluene; (c) (i) LiOH, H2O;
(ii) CH2N2, Et2O; (d) PCC, CH2Cl2, rt.
Scheme 2. (a) (i) BnNH2, DMF; (ii) TosMIC; (iii) K2CO3; (b) (i) LiOH, H2O; (ii) cyclohexene, Pd-C (10%), absolute EtOH, Á; (c) (i) cyclohexene,
Pd-C (10%), absolute EtOH, Á; (ii) HCl 6N, Á.

M. F. Bran˜a et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3561–3563
Table 1. Histamine H3 receptor-binding affinities for compounds
Ia–d and II
3563
References and Notes
Compd
% Inhibitiona
nb
1. Hill, S. J.; Ganellin, C. R.; Timmerman, H.; Schwartz, J. C.;
Shankley, N. P.; Young, J. M.; Schunack, W.; Levi, R.; Haas,
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2. Oda, T.; Morikawa, N.; Saito, Y.; Masuho, Y.; Matsu-
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3. Arrang, J. M.; Garbarg, M.; Schwartz, J. C. Neuroscience
1987, 23, 149.
4. Schilicker, E.; Malinowska, B.; Kathmann, M.; Gothert,
M. Fundam. Clin. Pharmacol. 1994, 8, 128.
RMHA (1Â10À8 M)
Ia (1Â10À5 M)
Ib (1Â10À5 M)
Ic (1Â10À5 M)
Id (1Â10À5 M)
II (1Â10À5 M)
30.8 (Æ3.4)
33.5 (Æ6.0)
4.3 (Æ1.8)
10.0 (Æ3.1)
3.7 (Æ2.7)
11.6 (Æ5.5)
6
6
6
6
6
6
aMean values given, standard error is given in parentheses.
bn is the number of assays.
5. Leurs, R., Vollinga, R. C., Timmerman, H. In Progress in
Drug Research, Jacker, E., Ed., Birkhausser Verlag. Basel,
1995, pp 107–165.
Biological Evaluation
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J. M.; Pollard, H.; Robba, M. F.; Schunack, W.; Schwartz,
J. C. Nature 1987, 327, 117. (b) Lipp, R.; Arrang, J. M.; Gar-
barg, M.; Luger, P.; Schwartz, J. C.; Schunack, W. J. Med.
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nian, R.; Orlando, S.; Piwinski, J. J.; Green, M. J.; Ganguly,
A. K.; Clark, M. A.; Tozzi, S.; Kreutner, W.; Hey, J. A.
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7. (a) Arrang, J. M.; Garbarg, M.; Schunack, W.; Schwartz,
J. C.; Lipp, R. WO 214058, 1987. (b) De Esch, I. J. P.; Vol-
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903.
The affinity of new compounds for the histamine H3
receptor was assessed by the study of the inhibition of
the specific binding of [3H] (R)-a-methylhistamine ([3H]
RMHA) in rat brain membranes. (R)-a-methylhista-
mine (RMHA) was used as the reference compound.
The procedure used for the [3H] RMHA binding assay
was that described by Arrang et al.,15 with some modi-
fications in centrifugation methodology: 12000 rpm, 30
min, 4 ꢀC, buffer Tris–HCl 0.05 M, pH 7.4.
The results of histamine H3 receptor binding affinities for
Ia–d and II are summarized in Table 1. All the compounds
showed less affinity than RMHA. Although these mole-
cules are just key intermediates in the synthesis of new cis-
cyclopropylhistamine derivatives, the slight affinity of Ia
to the H3 receptor should be noticed. The carboxylic
group of compounds I and II could be transformed into
an amine group or into an apolar group in order to
study their activity as H3 agonists or antagonists.
9. The cis allylic alcohols 1b,d were prepared utilizing stan-
dard literature procedures.
10. Doyle, M. P.; Austin, R. E.; Bailey, A. S.; Dwyer, M. P.;
Dyatkin, A. B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.;
Oalmann, C. J.; Pieters, R. J.; Protopopova, M. N.; Raab,
C. E.; Roos, G. H. P.; Zhou, Q. L.; Martin, S. F. J. Am.
Chem. Soc. 1995, 117, 5763.
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Org. Chem. 1977, 42, 1153. (b) Sisko, J.; Kassick, A. J.; Mel-
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2000, 65, 1516.
In conclusion, we have developed a new synthetic
methodology to provide cis-2-(1H-imidazol-4-yl)-cyclo-
propane carboxilic acids that could be useful for pre-
paring conformationally restricted novel histamine H3
receptor agents.
Acknowledgements
We are grateful to the Universidad San Pablo CEU
(Grant 2/99-01 U.S.P.) for financial support. C. Gui-
sado acknowledges the Ministerio de Educacion y
Ciencia (AP96 33987907) and the Universidad San
Pablo CEU for a predoctoral fellowship.
14. Anantharamaiah, G. M.; Sivanandaiah, K. M. J. Chem.
Soc., Perkin Trans. 1 1977, 490.
15. Arrang, J. M.; Roy, J.; Morgat, J. L.; Schunack, W.;
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