Synthesis of novel 5-substituted pyrazole derivatives as cannabinoid antagonists

Article abstract of DOI:10.1016/j.tetlet.2005.01.165

A facile seven-step sequence was developed from 4′- bromopropiophenone, utilizing a Suzuki-type coupling with an alkene, to give several novel 5-substituted pyrazole derivatives in overall yields of 11-31%. They are potent CB1 antagonists and have binding

Full text of DOI:10.1016/j.tetlet.2005.01.165

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2159–2161
Synthesis of novel 5-substituted pyrazole derivatives as
cannabinoid antagonists
Olga O. Alekseeva,a Anu Mahadevan,a Jenny L. Wiley,b Billy R. Martinb and
Raj K. Razdana,*
aOrganix, Inc., 240 Salem Street, Woburn, MA 01801, USA
bDepartment of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond,
VA 23298, USA
Received 6 December 2004; accepted 11 January 2005
Abstract—A facile seven-step sequence was developed from 40-bromopropiophenone, utilizing a Suzuki-type coupling with an
alkene, to give several novel 5-substituted pyrazole derivatives in overall yields of 11–31%. They are potent CB1 antagonists and
have binding affinities similar to SR 141716A. Like SR 141716A, they may prove to be clinically useful for the treatment of obesity.
Ó 2005 Elsevier Ltd. All rights reserved.
Great progress has been made in cannabinoid research
O
since the Sanofi groupꢀs 1994 discovery1 of the CB1
antagonist SR 141716A. This compound is a pyrazole
derivative (Fig. 1) with substituents in the 1-, 3-, 4-,
and 5-positions. The fact that it binds selectively to
CB1 receptors without producing cannabimimetic activ-
ity in in vivo experiments in mice2 suggests that the
binding and activation of cannabinoid receptors are sep-
arable events. To examine this hypothesis we embarked
on a program to synthesize cannabinoids with a pyraz-
ole template and study their pharmacological proper-
ties.3,4 In summary, we prepared SR 141716A analogs
in which the 1-, 3-, 4-, and 5-positions of the pyrazole
core were replaced by other substituents known to im-
part agonist activity in THCs (tetrahydrocannabinols).
Our results suggested that the 3-position is involved in
agonism and receptor activation whereas the 1-, 4-,
and 5-positions seem to be involved with antagonism.
They support the hypothesis that binding and activation
are separate events and that the substituents at 1- and 5-
positions are primarily responsible for the antagonist
activity of SR 141716A. Further examination4 of the
5-substituents revealed that the retention of the phenyl
group is critical for both receptor affinity and antago-
N
NH
N
N
R
Cl
Cl
SR 141716A
O-1302
R = Cl
R =
Figure 1. Structures of SR 141716A and O-1302.
nism since they decreased when the phenyl was replaced
by an alkyl chain. It was also found that substitution of
the para-position of the phenyl by an alkyl chain (pen-
tyl) increased binding affinity and antagonism. Our
structure activity relationships (SAR) studies were con-
sistent with those of others5–10 as discussed in our paper4
and supported the molecular modeling studies of Tho-
mas et al.5,11 who had suggested a superpositioning of
the para-position of the 5-substituent in SR 141716A
with the pentyl side chain in D9-THC. Based on these
findings an analog (Fig. 1) with a para-pentylphenyl
substituent at the 5-position, O-1302 (Ki =
2.1 0.08 nM for CB1 receptors) was selected for
further study. Previous work on the development of
antagonists in our laboratory had shown that the alkyl
side chain of D8-THC has a fundamental effect on the
pharmacological activity. It was found12 that the side
Keywords: Cannabinoid receptors; Antagonists; Synthesis; Substituted
pyrazoles.
*
Corresponding author. Tel.: +1 781 932 4142; fax: +1 781 933
6695; e-mail: razdan@organixinc.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.165

2160
O. O. Alekseeva et al. / Tetrahedron Letters 46 (2005) 2159–2161
chain can be modified effectively to produce high affinity
ligands at the CB1 receptor, with antagonist, partial
agonist or full agonist effects. With this background
we undertook to synthesize analogs of O-1302, which
had various substituents at the terminal carbon of the
pentyl chain. The importance of this class of compounds
is enhanced by the reported success of SR 141716A
(Romonabant) in Phase III clinical trials13 for obesity.
Another compound SLV 319, based on a closely related
template (pyrazoline derivative) is also in Phase I trials
for obesity.14
derivative 6, obtained by using a Suzuki-type coupling18
of the alkene 5 (prepared from the commercially avail-
able 4-pentene-1-ol by treatment with dihydropyran/cat-
alytic amount of HCl) with the known6 pyrazole 4
(Scheme 1). Treatment of the ester 6 with a mixture of
1-aminopiperidine and trimethylaluminum19 in CH2Cl2
formed the desired amide 7 in 78% yield. Other methods
via the acid (acid chloride, mixed anhydride, DCC etc.)
did not prove satisfactory. Deprotection (PTSA/metha-
nol) followed by mesylation gave the key intermediate
9. The seven-step sequence from 1 to 9 was achieved
in an overall yield of 36%. The treatment of 9 with
NaCN (DMF, 23 °C, 2 d)20 formed the target com-
pound 10 (63%). Similarly, treatment with NaN3 or
LiBr or NaNO2 gave the respective compounds 11
(69%), 12 (70%), and 13 (30%). In the case of 13 a nitr-
oso derivative was also isolated (35%) but it proved to
be unstable. The sulfonamide analog 14 was also pre-
pared (86%) from the mesylate 9 by treatment with
NaH/NH2SO2CH3 in DMF/benzene. The reduction of
11 with LiAlH4 in THF formed the amine 15 (100%).
The target compounds 10–15 were thus obtained from
1 in overall yields of 11–31%.
We have developed a flexible route to the synthesis of O-
1302 analogs, which allows the introduction of a variety
of substituents on the terminal carbon of the pentyl
chain. The compounds prepared were 8 and 10–15
(Scheme 1). All the analogs except 15 (Ki = 38 nM)
showed CB1 binding affinities in the range of 1–
5.5 nM and some of the compounds (8 and 10–12)
showed better CB2/CB1 selectivity (CB2/CB1 ratio,
64–137) than SR 141716A (Ki = 12 nM for CB1;
Ki = 702 nM for CB2; CB2/CB1 ratio, 57).15 The bind-
ing affinities were determined using the procedures
described by us4,15,16 elsewhere. A detailed pharmaco-
logical profile of these analogs as antagonists is ongoing
and will be published elsewhere. In this paper the
synthetic route to these analogs is presented.
In summary, we have developed a facile seven-step se-
quence for the synthesis of the key intermediate 9 from
commercially available 40-bromopropiophenone (1) in
an overall yield of 36%. This key intermediate was used
to synthesize the novel 5-substituted pyrazole analogs
10–15, which have CB1 binding affinities similar to SR
The synthesis17 of the target compounds 8 and 10–15
was achieved via the tetrahydropyranyl-carbethoxy
COOEt
COOEt
Li
b
a
Br
NNH
Cl
Br
Br
O
O
O
O
Cl
3
2
1
O
N
O
OEt
OEt
THPO
d
c
5
THPO
N
N
N
Br
Cl
Cl
6
Cl
Cl
4
O
O
N
N
NH
NH
f
THPO
N
HO
N
e
N
N
Cl
Cl
8
7
Cl
O
Cl
O
N
N
NH
NH
g
MsO
N
R
N
N
N
Cl
Cl
10 R = CN
11 R = N3
12 R = Br
13 R = NO2
14 R = NHSO2CH3
15 R = NH2
9
Cl
Cl
Scheme 1. (a) Reagents and conditions: (a) LiN(SiMe3), ether, 23 °C, 0.75 h; (COOEt)2, 23 °C 16 h, 97%; (b) 2,4-dichlorophenyl hydrazine
hydrochloride, ethanol, 23 °C, 16 h, 72%; (c) AcOH, reflux, 2 d, 99%; (d) 5, 9-BBN, 23 °C, 16 h; K3PO4, Pd(PPh3)4, anhydrous dioxane, 120 °C,
2.5 d, 75%; (e) 1-aminopiperidine, Me3Al, CH2Cl2, 1 h, 6, CH2Cl2, 23 °C, 2 d, 78%; (f) PTSA, overall yield to 9 = 36% and to target compounds 10–
15 = 11–31%.

O. O. Alekseeva et al. / Tetrahedron Letters 46 (2005) 2159–2161
2161
10. Krishnamurthy, M.; Li, W.; Moore, B. M., II. Bioorg.
Med. Chem. 2004, 12, 393–404.
141716A and are presently undergoing pharmacological
study as antagonists of CB1 receptors like SR 141716A.
They may prove to be clinically useful for the treatment
of obesity.
11. Shim, J.-Y.; Welsh, W. J.; Cartier, E.; Edwards, J. L.;
Howlett, A. C. J. Med. Chem. 2002, 45, 1447–1459.
12. Martin, B. R.; Jefferson, R.; Winckler, R.; Wiley, J. L.;
Huffman, J. W.; Crocker, P. J.; Saha, B.; Razdan, R. K. J.
Pharmacol. Exp. Ther. 1999, 290, 1065–1079.
13. Le Fur, G. International Cannabinoid Research Society
(ICRS), 14th Annual Symposium on the Cannabinoids,
Paestum, Italy. 2004; Abstract, p 67.
14. Lange, J. H. M.; Coolen, H. K. A. C.; Stuivenberg, H. H.
V.; Dijksman, J. A. R.; Herremans, A. H. J.; Ronken, E.;
Keizer, H. G.; Tipker, K.; McCreary, A. C.; Veerman, W.;
Wals, H. C.; Stork, B.; Verveer, P. C.; den Hartog, A. P.;
de Jong, N. M.; Adolfs, T. J.; Hoogendoorn, J.; Kruse, C.
G. J. Med. Chem. 2004, 47, 627–643.
15. Showalter, V. M.; Compton, D. R.; Martin, B. R.; Abood,
M. E. J. Pharmacol. Exp. Ther. 1996, 278, 989–999.
16. Compton, D. R.; Rice, K. C.; DeCosta, B.; Razdan, R.
K.; Melvin, L. S.; Johnson, M. R.; Martin, B. R. J.
Pharmacol. Exp. Ther. 1993, 265, 218–226.
Acknowledgements
The authors are grateful to NIDA Grants DA-09789
and DA-05488 for the support of this work.
Supplementary data
Supplementary data associated with this article can be
found, in the online version at doi:10.1016/
j.tetlet.2005.01.165.
17. All new compounds were fully characterized. 1H NMR
spectra were recorded on a JEOL Eclipse 300 spectropho-
tometer using CDCl3 as the solvent with tetramethylsilane
as an internal standard. Similarly, 13C NMR were
recorded at 75 MHz using CDCl3. Mass spectra were
obtained with Agilent 1100 Series LC/MSD spectrometer.
Elemental analyses were performed by Atlantic Microlab,
Inc., Atlanta, GA, and were found to be within 0.4% of
calculated values. The data for target compound 10 is
References and notes
1. Rinaldi-Carmona, M.; Barth, F.; Healume, M.; Shire, D.;
Calendra, B.; Congy, C.; Martinez, S.; Maruani, J.; Neliat,
G.; Caput, D.; Ferrara, P.; Soubrie, P.; Breliere, J. C.; Le
Fur, G. FEBS Lett. 1994, 350, 240–244.
2. Compton, D. R.; Aceto, M. D.; Lowe, J.; Martin, B. R. J.
Pharmacol. Exp. Ther. 1996, 277, 586–594.
3. Dutta, A. K.; Sard, H.; Ryan, W.; Razdan, R. K.;
Compton, D. R.; Martin, B. R. Med. Chem. Res. 1995, 5,
54–62.
4. Wiley, J. L.; Jefferson, R. G.; Grier, M. C.; Mahadevan,
A.; Razdan, R. K.; Martin, B. R. J. Pharmacol. Exp. Ther.
2001, 296, 1013–1022.
5. Thomas, B. F.; Gilliam, A. F.; Burch, D. F.; Roche, M. J.;
Seltzman, H. H. J. Pharmacol. Exp. Ther. 1998, 285, 285–
292.
6. Lan, R.; Liu, Q.; Fan, P.; Lin, S.; Fernando, S. R.;
McCallion, D.; Pertwee, R. G.; Makriyannis, A. J. Med.
Chem. 1999, 42, 769–776.
7. Francisco, M. E. Y.; Seltzman, H. H.; Gilliam, A. F.;
Mitchell, R. A.; Rider, S. L.; Pertwee, R. G.; Stevenson, L.
A.; Thomas, B. F. J. Med. Chem. 2002, 45, 2708–
2719.
8. Katoch-Rouse, R.; Pavlova, O. A.; Caulder, T.; Hoffman,
A. F.; Mukhin, A. G.; Horti, A. G. J. Med. Chem. 2003,
46, 642–645.
1
included as an example; oil: H NMR d 7.65 (s, 1H), 7.42
(dd, 1H, J = 1.7, 0.8 Hz), 7.27 (m, 2H, J = 1–3 Hz), 7.10
(d, 2H, J = 8.1 Hz), 7.02 (d, 2H, J = 8.1 Hz), 2.34 (t, 2H,
J = 7.0 Hz), 2.87 (br t, 4H, J = 5.5 Hz), 2.60 (t, 2H,
J = 7.6 Hz), 2.37 (s, 3H), 1.75 (quint, 4H, J = 5.5 Hz), 1.66
(m, 2H), 1.64 (m, 2H), 1.48 (m, 2H), 1.44 (m, 2H); 13C
NMR d 160.1, 144.3, 144.0, 142.5, 136.3, 135.6, 133.1,
130.6, 130.1, 129.4, 128.4, 127.7, 126.2, 119.6, 117.8, 57.0,
35.3, 30.1, 28.3, 25.1, 25.4, 23.3, 17.0, 9.4. MS, m/z: 524
(M+1). Anal. Calcd for C28H31Cl2N5OÆ0.1EtOAc: C,
63.96; H, 6.01; N, 13.13. Found: C, 63.99; H, 6.14; N,
12.99. The presence of the solvent was confirmed by 1H
NMR.
18. Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.;
Satoh, M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314–
321.
19. Lipton, M. F.; Basha, A.; Weinreb, S. M. Org. Synth. Coll.
Vol. VI 1988, 492–495.
9. Ruiu, S.; Pinna, G. A.; Marchese, G.; Mussinu, J.-M.;
Saba, P.; Tambaro, S.; Casti, P.; Vargiu, R.; Pani, L. J.
Pharmacol. Exp. Ther. 2003, 306, 363–370.
20. Crocker, P. J.; Saha, B.; Ryan, W. J.; Wiley, J. L.; Martin,
B. R.; Ross, R. A.; Pertwee, R. G.; Razdan, R. K.
Tetrahedron 1999, 55, 13907–13926.