Synthesis of novel pyrazole derivatives incorporating one dicarba-closo-dodecaborane unit

Article abstract of DOI:10.1016/j.tetlet.2012.06.113

Boron clusters, and especially dicarba-closo-dodecaboranes, can be used as hydrophobic pharmacophores in the design of new drugs. In the current letter, analogs of the CB1 receptor inverse agonist Rimonabant incorporating a carborane cage (either ortho- o

Full text of DOI:10.1016/j.tetlet.2012.06.113

Tetrahedron Letters 53 (2012) 4743–4746
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel pyrazole derivatives incorporating one
dicarba-closo-dodecaborane unit
⇑
Naiara Vázquez, Vanessa Gómez-Vallejo, Jordi Llop
Radiochemistry Department, CIC biomaGUNE, Paseo Miramón 182, San Sebastián 20009, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Boron clusters, and especially dicarba-closo-dodecaboranes, can be used as hydrophobic pharmacophores
in the design of new drugs. In the current letter, analogs of the CB1 receptor inverse agonist Rimonabant
incorporating a carborane cage (either ortho- or meta-carborane) have been synthesized in moderate
Received 16 May 2012
Revised 20 June 2012
Accepted 26 June 2012
Available online 2 July 2012
yields and their structure has been elucidated by means of 1H NMR, C NMR, B NMR, and HPLC-MS.
13
11
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
CB1 receptor
Carborane
Pyrazole
The icosahedral carboranes (dicarba-closo-dodecaboranes) are
molecules with characteristic and unique structural and chemical
properties, that is, rigid geometry, rich derivative chemistry, ther-
mal and chemical stability, and exceptional hydrophobic character.
Due to this fact, they have attracted special interest and derivatives
such carborane structures resulted in good chemical stability un-
der physiologic conditions, especially when 1,7- and 1-methyl-
1,2-dicarba-closo-dodecaborane clusters were used. Therefore,
the incorporation of carborane cages in biologically active mole-
cules, especially in those cases where endogenous ligands already
have a significant hydrophobic character, might be appropriate to
improve both in vivo behavior and pharmacokinetic properties.
1
with potential application in the fields of heat-stable polymers,
2
3
4
non-linear optical, electronic materials, and medicine have been
developed for years. Within the latter application, most of the ef-
forts have been directed toward the development of boron neutron
capture therapy (BNCT) agents by attaching the carborane clusters
9
In continuation of our previous work, we present here the syn-
thesis and characterization of new analogs of Rimonabant incorpo-
rating different carborane cages in their structure (Compounds 1–
5
6
11
to targeting moieties, that is, carbohydrates, porphyrins, or
nucleosides. However, Endo and co-workers8 showed that 1,2-
and 1,7-dicarba-closo-dodecaborane (o- and m-carborane) can also
act as a hydrophobic structure of various biologically active mole-
cules because both their spherical structure and hydrophobic sur-
face facilitate the interaction with hydrophobic residues of the
ligand binding pocket of receptors; in this context, they developed
a series of 1,7-dicarba-closo-carborane (m-carborane) derivatives
3, Fig. 2). Rimonabant, first developed by Sanofi-Aventis, is a CB1
7
receptor antagonist which has recently been approved in the Euro-
pean Union for the treatment of obesity, and its therapeutic func-
12
tion might be extended to the treatment of addiction and
1
3
neuropsychiatric disorders. The key binding interaction of Rimo-
nabant is a hydrogen bond formed between its carbonyl group and
1
4
the Lys192 residue of the CB1 receptor. The binding also involves
direct aromatic stacking interactions between its 2,4-dichloro-
which acted as an ER
a
antagonist in luciferase reporter gene
phenyl and the para-chlorophenyl rings with different amino acid
8
b
15,16
assay.
Based on Endo’s group approach, we recently developed analogs
of D receptor antagonists Raclopride and FLB-457, by replacing
sequences of the receptor,
while the lipophilic piperidinyl moi-
ety fits in a cavity formed by the amino acid residues Val196/
1
6
2
Phe170/Leu387 and Met384 (Fig. 3). Structure Activity Relation-
ship (SAR) studies have demonstrated that the 5-substituent of the
pyrazole is involved in receptor recognition and antagonism and
that a 2,4-dichloro-substituted phenyl ring at the pyrazole 1-posi-
the poly-substituted phenyl moieties by different carborane clus-
ters (o-carborane, m-carborane, and 1-methyl-o-carborane, see
9
Fig. 1). In vitro and ex vivo binding assays have been recently per-
10
14
formed and will be reported shortly. Although the introduction of
the carborane cage led to molecules with strong hydrophobic char-
acter with subsequent nonspecific uptake, the incorporation of
tion is preferred for affinity as well as for the activity. Addition-
ally, replacement of the amino piperidinyl substituent by alkyl
amides, ethers, ketones, alcohols, or alkanes results mostly in de-
creased affinity, while replacement by pentyl or heptyl chain gave
the compounds agonistic properties. These results suggest that the
structural and chemical properties of the substituent at the 3 posi-
⇑
Corresponding author.
E-mail address: jllop@cicbiomagune.es (J. Llop).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.113

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N. Vázquez et al. / Tetrahedron Letters 53 (2012) 4743–4746
Figure 1. Chemical structures of Raclopride (left) and its analog containing one 1,7-dicarba-closo-dodecaborane unit (right). s stands for BH, d stands for C.
Figure 2. Chemical structure of the CB1 receptor antagonist Rimonabant (left) and analogs incorporating one o-carborane cage and one m-carborane cage. s stands for BH, d
stands for C.
The general synthetic strategy for the synthesis of Rimonabant
analogs (1–3) is shown in Scheme 1. The synthesis was carried out
by condensation of 6 with the amino derivatives of the carborane
structures (9, 10, and 12, respectively).
Compound 6 was prepared following the method reported by
2
0
Pertwee and co-workers (Scheme 1); briefly: 4-chloropropiophe-
none was reacted with diethyl oxalate in dry diethyl ether using
lithium bis(trimethylsilyl)amide (LiHMDS) as a base yielding the
lithium salt of the enolate (4), which was further reacted with
the substituted phenylhydrazine in ethanol. After centrifugation,
the isolated solid was refluxed with acetic acid. After quenching
the reaction, the extracted fraction (ethyl acetate, 3 ꢀ 40 mL) was
evaporated and purified by flash chromatography to obtain 5 in
2
0% overall yield. Compound 5 was hydrolyzed with LiOH/water
to give 6 in quantitative yield.
The synthesis of the primary amines 9, 10, and 12 was carried
out following the method reported by Washburne and Peterson
2
1
(
Scheme 1). Acid chlorides (prepared according to the method re-
2
2
ported by Kahl and co-workers) were reacted with trimethylsilyl
azide in toluene to yield the corresponding isocyanates which,
after treatment with tert-butyl alcohol, yielded the protected
amines 7, 8, and 11 via Curtius rearrangement in 34%, 11%, and
36% overall yields, respectively. A second strategy, based on the
isolation of the isocyanate species and further reaction with LiOH
in THF/water was assayed; however, yields mentioned above could
not be improved and the strategy was discarded.
Figure 3. Putative interaction of Rimonabant with amino acid sequences in CB1
receptors.
tion of the pyrazole ring have an important effect both in the affin-
ity and the activity of the drug.17 Thus, in the present work we
decided to incorporate the carborane moiety in substitution of
the piperidine group, while respecting all other substructures.
The carborane cage has a rotating volume similar to the phenyl
group; therefore, its fitting into the cavity formed by the amino
acid residues Val196/Phe170/Leu387 and Met384 can be antici-
pated. Moreover, carborane may show greater resistance to metab-
olism than the replaced piperidinyl ring, which has been shown to
Different experimental conditions were assayed for the prepa-
ration of Rimonabant analogs 1–3. First attempts were performed
using dichloromethane as a solvent and triethylamine as a base,
2
with addition of SOCl for the in situ formation of the correspond-
ing acid chlorides, but no desired product was detected in the reac-
tion mixture in any case. Identical results were obtained when
diisopropylethylamine was used as a base. Activation of the car-
0
boxylic acid using N,N - diisopropylcarbodiimide (DIC) in the pres-
1
8
be the exclusive region of metabolism of Rimonabant in vitro and
ence of additives such as N-hydroxysuccinimide (NHS) or 1-
hydroxy-7-azabenzotriazole (HOAT) was also unsuccessful when
1
8,19
in vivo.

N. Vázquez et al. / Tetrahedron Letters 53 (2012) 4743–4746
4745
Scheme 1. Synthesis of compounds 1–3. Reagents and conditions: (a) LiHMDS/Et
2
O
anhydrous/ꢁ78 °C, then diethyl oxalate, rt. (b) 2,4-Dichlorophenylhidrazine
t
hydrochloride/EtOH; (c) LiOH in THF/H
2
O, 0–25 °C. (d) TMSN
3
, toluene, reflux, then BuOH, reflux; (e) TFA, DCM, 0–25 °C; (f) SOCl on the acid, then addition of 9, 10, or 12 in
2
toluene, 150 °C, 50 min, microwave.
reactions were performed at room temperature. Based on the liter-
in vivo stability as well as modulation of the agonist/antagonist
character of the resulting compounds.
2
3
ature data, microwave heating (150 °C, 50 min) was applied
using toluene as a solvent and compound 1 could be synthesized
and isolated in 43% yield. The same procedure was applied to the
preparation of compounds 2 and 3, which could be also synthe-
sized and isolated in 10% and 33% yields, respectively. Shorter reac-
tion times offered lower yields in all cases; although major
impurities were identified as unreacted amines (9, 10 and 12)
and the hydrolyzed form of acid chloride 6, increasing reaction
time up to 120 min did not lead to significantly improved yields.
The moderate yields obtained can be attributed to the low nucleo-
philic character of the amino group attached to the carborane cage,
which is due to the strong electron-withdrawing effect of the carb-
Acknowledgments
The authors would like to thank Dr. Javier Calvo for providing
mass spectroscopy data as well as the Departamento de Industria,
Comercio y Turismo of the Basque Government and the Ministerio
de Ciencia e Innovación (Grant number CTQ2009-08810) for finan-
cial support.
Supplementary data
2
4
oranyl group. Interestingly, the lowest chemical yield corre-
sponds to compound 2, which might be interpreted as a result of
the steric hindrance due to the presence of the methyl group on
one of the carbon atoms of the carborane cage.
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.tetlet.2012.06.113.
1
11
13
11
1
{
H– B} NMR, C NMR and { B- H} NMR, and Electrospray
References and notes
Mass Spectrometry measurements confirmed the chemical struc-
ture of compounds 1–3.2
5,26
Evaluation of the binding affinity
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In summary, we have designed and synthesized three new ana-
logs of the CB1 receptor antagonist Rimonabant by replacing the
piperidinyl substituent by 1,2-dicarba-closo-docecaborane (1), 1-
methyl-1,2-dicarba-closo-docecaborane (2), and 1,7-dicarba-closo-
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3
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118.85, 126.67, 128.21, 129.25, 129.31, 130.97, 135.58, 136.69, 142.81, 144.14,
160.63; 11B NMR (CDCl
, 160.46 MHz, decoupled): d -13.79, -10.88, -7.08, -
1
3
9
3
, 125.77 MHz): d 9.47, 60.59, 78.91,
2
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1
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22 3 3
3.90; HRMS (ESI): m/z calculated for C19H B10Cl N ONa: 545.1722 [M+Na] ;
found: 545.1721.
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, 500MHz): d 2.02-2.59 (m, 10H, BH), 2.00 (s, 3H,
-C(carborane)), 2.33 (s, 3H, CH ), 7.02–7.43 (m, 7H, Ar), 8.02 (s, 1H, CONH);
, 125.77MHz): d 9.56, 22.55, 79.01, 82.48, 119.10, 126.74,
3
1
1
CH
3
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11
3
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z calculated for C20
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CH ), 2.94 (s, 1H, CH-carborane), 7.00–8.13 (m, 7H, Ar); C NMR (CDCl
125.77MHz): d 9.58, 53.35, 80.00, 118.64, 119.75, 127.01, 127.41, 128.14,
129.18, 130.56, 131.01, 131.11, 143.51, 143.77, 149.57, 160.20, 189.50; 11
NMR (CDCl
B
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24
B10Cl
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N
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ONa: 559.1879 [M+Na] ; found: 559.1916.
1
1
3
, 500MHz): d 2.02–2.62 (m, 10H, BH), 2.32 (s, 3H,
13
3
3
,
1
B
3
, 160.46MHz, decoupled): d ꢁ15.04, ꢁ12.40, ꢁ10.67, ꢁ3.79; HRMS
(ESI): m/z calculated for
C
19
H
21
B10Cl
3 3
N O: 521.1746 [MꢁH]ꢁ; found:
521.1744.
1
1
26. UPLC/ESI-MS analyses were performed using an ACQUITY UPLC separation
module coupled to LCT TOF premier XE mass spectrometer (Waters,
Manchester, UK). An Acquity BEH C18 column (1.7 m, 5 mm, 2.1 mm) was
a
33(4), 508–517.
l
1
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used as the stationary phase. The elution buffers were A (methanol) and B
(0.1% formic acid aqueous solution). The column was eluted with a linear
gradient: t = 0 min, 95% B; t = 3 min, 1% B; t = 4 min, 1% B; t = 5 min, 95% B.
2
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Total run was 5 min, injection volume was 5 lL and the flow rate was 600 lL/
min. The detection was carried out in positive mode, monitoring the most
+
2
abundant isotope peaks from the mass spectra (MꢁH ).