314 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1
Frost et al.
10 mL of THF were processed as described in the procedure for 2-
morpholin-4-ylethyl methanesulfonate to provide 2-(4-methyl-
thiazol-5-yl)ethyl methanesulfonate which was carried on with-
out purification or characterization.
Sharkey, K. A.; Makriyannis, A. Should peripheral CB1 cannabinoid
receptors be selectively targeted for therapeutic gain? Trends Pharma-
col. Sci. 2008, 30, 1–7.
(8) (a) Lotersztajn, S.; Teixeira-Clerc, F.; Julien, B.; Deveaux, V.;
Ichigotani, Y.; Manin, S.; Tran-Van-Nhieu, J.; Karsak, M.;
Zimmer, A.; Mallat, A. CB2 receptors as new therapeutic targets
for liver diseases. Br. J. Pharmacol. 2008, 153, 286–289. (b) Julien,
B.; Grenard, P.; Teixeira-Clerc, F.; van Nhieu, J.; Li, L.; Karsak, M.;
Zimmer, A.; Mallat, A.; Lotersztajn, S. Antifibrogenic role of the
cannabinoid receptor CB2 in the liver. Gastroenterology 2005, 128,
The 2-(4-methylthiazol-5-yl)ethyl methanesulfonate (1.2
mmol), 1H-indol-3-yl(2,2,3,3-tetramethylcyclopropyl)methan-
one (0.15 g, 0.62 mmol), and NaH (60% dispersion in mineral
oil, 0.12 g, 3.1 mmol) in DMF (8 mL) were processed as
described in the procedure for 5 to provide 69 (73 mg, 0.20
mmol, 32% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.26 (s,
6 H), 1.32 (s, 6 H), 1.81 (s, 1 H), 2.15 (s, 3 H), 3.33 (t, J = 5.8 Hz,
2 H), 4.39 (t, J = 6.3 Hz, 2 H), 7.26-7.31 (m, 3 H), 7.39 (s, 1 H),
8.36-8.46 (m, 1 H), 8.57-8.71 (m, 1 H); MS (DCI/NH3) m/z 367
(M þ H)þ. Anal. (C22H26N2OS) C, H, N.
ꢀ
742–755. (c) Batkai, S.; Osei-Hyiaman, Pan, H.; el-Assal, O.; Rajesh,
ꢀ
M.; Mukhopadhyoy, P.; Hong, F.; Harvey-White, J.; Jafri, A.; Hasko,
G.; Huffman, J. W.; Gao, B.; Kunos, G.; Pacher, P. Cannabinoid-2
receptor mediates protection against hepatic ischemia/reperfusion in-
jury. FASEB J. 2007, 21, 1788–1800.
(9) (a) Idris, A. I; Sophocleous, A.; Landao-Bassonga, E.; van’t Hof,
R. J; Ralston, S. H. Regulation of bone mass, osteoclast function,
and ovariectomy-induced bone loss by the type 2 cannabinoid
receptor. Endocrinology 2008, 149, 5619–5626. (b) Ofek, O.; Karsak,
M.; Leclerc, N; Fogel, M.; Frenkel, B.; Wright, K.; Tam, J.; Attar-
Namdar, M.; Kram, V.; Shohami, E.; Mechoulam, R.; Zimmer, A.; Bab,
I. Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc.
Natl. Acad. Sci. U.S.A. 2006, 103, 696–701.
(1-(2-(5-Chloro-1,2,4-thiadiazol-3-yl)ethyl)-1H-indol-3-yl)(2,2,3,-
3-tetramethylcyclopropyl)methanone (70). The 5-chloro-3-(chloro-
methyl)-1,2,4-thiadiazole (0.21 g, 1.2 mmol), 1H-indol-3-yl(2,2,3,3-
tetramethylcyclopropyl)methanone (0.15 g, 0.62 mmol), and NaH
(60% dispersion in mineral oil, 0.12 g, 3.1 mmol) in DMF (10 mL)
were processed as described in the procedure for 5 to provide 70 (50
mg, 0.13 mmol, 22% yield). 1H NMR (300 MHz, CD3OD) δ ppm
1.36 (s, 6 H), 1.37 (s, 6 H), 2.07 (s, 1 H), 4.79 (s, 2 H), 7.43 (dt, J =
7.5, 1.2 Hz, 1 H), 7.50 (dt, J=7.7, 1.5 Hz, 1H), 7.83-7.91 (m, 1 H),
8.34 (s, 1 H), 8.47-8.52 (m, 1 H); MS (DCI/NH3) m/z 373 (M þ
ꢀ~
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(10) Benito, C.; Nunez, E.; Tolon, R. M.; Carrier, E. J.; Rabano, A.;
Hillard, C. J.; Romero, J. Cannabinoid CB2 receptors and fatty
acid amide hydrolase are selectively overexpressed in neuritic
plaque-associated glia in Alzheimer’s disease brains. J. Neurosci.
2003, 23, 11136–11141.
H)þ. Anal. (C19H20ClN3OS 0.4H2O) C, H, N.
(11) (a) Shi, Y.; Zou, M.; Baitei, E. Y.; Alzahrani, A. S.; Parhar, R. S.;
Al-Makhalafi, Z.; Al-Mohanna, F. A. Cannabinoid 2 receptor
induction by IL-12 and its potential as a therapeutic target for the
treatment of anaplastic thyroid carcinoma. Cancer Gene Ther.
2008, 15, 101–107. (b) Flygar, J.; Gustafsson, K.; Kimby, E.;
Christensson, B.; Sander, B. Cannabinoid receptor ligands mediate
growth inhibition and cell death in mantel cell lymphoma. FEBS Lett.
2005, 579, 6885–6889. (c) Herrera, B.; Carracedo, A.; Diez-Zaera, M.;
Guzman, M.; Velasco, G. p38 MAPK is involved in CB2 receptor-
induced apoptosis of human leukaemia cells. FEBS Lett. 2005, 579,
5084–5088.
3
References
(1) (a) Cabral, G. A.; Marciano-Cabral, F. Cannabinoid receptors in
microglia of the central nervous system: immune functional rele-
vance. J. Leukocyte Biol. 2005, 78, 1192–1197. (b) Van Sickle, M. D.;
Duncan, M.; Kingsley, P. J.; Mouihate, A.; Urbani, P.; Mackie, K.;
Stella, N.; Makriyannis, A.; Piomelli, D.; Davison, J. S.; Marnett, L. J.;
Marzo, V. D.; Pittman, Q. J.; Patel, K. D.; Sharkey, K. A. Identification
and functional characterization of brainstem cannabinoid CB2 recep-
tors. Science 2005, 310, 329–332. (c) Beltramo, M.; Bernardini, N.;
Bertorelli, R.; Campanella, M.; Nicolussi, E.; Fredduzzi, S.; Reggiani,
A. CB2 receptor-mediated antihyperalgesia: possible direct involve-
ment of neural mechanisms. Eur. J. Neurosci. 2006, 23, 1530–1538.
(2) Munro, S.; Thomas, K. L.; Abu-Shaar, M. Molecular character-
ization of a peripheral receptor for cannabinoids. Nature 1993, 365,
61–65.
(12) (a) Docagne, F.; Mestre, L.; Loria, F.; Hernangomez, M.; Correa,
F.; Guaza, C. Therapeutic potential of CB2 targeting in multiple
sclerosis. Expert Opin. Ther. Targets 2008, 12, 185–195. (b) Pryce,
G.; Baker, D. Emerging properties of cannabinoid medicines in man-
agement of multiple sclerosis. Trends Neurosci. 2005, 28, 272–276. (c)
ꢀ
Benito, C.; Romero, J. P.; Tolon, R. M.; Clemente, D.; Docagne, F.;
Hillard, C. J.; Guaza, C.; Romero, J. Cannabinoid CB1 and CB2
receptors and fatty acid amide hydrolase are specific markers of plaque
cell subtypes in human multiple sclerosis. J. Neurosci. 2007, 27, 2396–
2402. (d) Baker, D.; Pryce, G.; Croxford, J. L.; Brown, P.; Pertwee,
R. G.; Huffman, J. W.; Layward, L. Cannabinoids control spasticity and
tremor in a multiple sclerosis model. Nature 2000, 404, 84–87.
(3) Chapman, V.; Finn, D. P. Analgesic effects of cannabinoids: sites
and mechanisms of action. Rev. Analg. 2003, 7, 25–39.
(4) (a) Hanus, L.; Breuer, A.; Tchilibon, S.; Shiloah, S.; Goldenberg,
D.; Horowitz, M.; Pertwee, R. G.; Ross, R. A.; Mechoulam, R.;
Fride, E. HU-308: a specific agonist for CB2, a peripheral canna-
binoid receptor. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 14228–
14233. (b) Malan, T. P., Jr.; Ibrahim, M. M.; Lai, J.; Vanderah, T. W.;
Makriyannis, A.; Porreca, F. CB2 cannabinoid receptor agonists: pain
relief without psychoactive effects? Curr. Opin. Pharmacol. 2003, 3,
62–67. (c) Clayton, N.; Marshall, F. H.; Bountra, C.; O'Shaughnessy,
C. T. CB1 and CB2 cannabinoid receptors are implicated in inflamma-
tory pain. Pain 2002, 96, 253–260.
(5) Quartiho, A.; Mata, H. P.; Ibrahim, M. M.; Vanderah, T. W.;
Porreca, F.; Makriyannis, A.; Malan, T. P., Jr. Inhibition of
inflammatory hyperalgesia by activation of peripheral CB2 canna-
binoid receptors. Anesthesiology 2003, 99, 955–960.
(6) (a) Hanus, L.; Breuer, A.; Tchilibon, S.; Shiloah, S.; Goldenberg,
D.; Horowitz, M.; Pertwee, R. G.; Ross, R. A.; Mechoulam, R.;
Fride, E. HU-308: a specific agonist for CB2, a peripheral canna-
binoid receptor. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 14228–
14233. (b) Malan, T. P., Jr.; Ibrahim, M. M.; Lai, J.; Vanderah, T. W.;
Makriyannis, A.; Porreca, F. CB2 cannabinoid receptor agonists: pain
relief without psychoactive effects? Curr. Opin. Pharmacol. 2003, 3,
62–67. (c) Clayton, N.; Marshall, F. H.; Bountra, C.; O'Shaughnessy,
C. T. CB1 and CB2 cannabinoid receptors are implicated in inflamma-
tory pain. Pain 2002, 96, 253–260.
(7) (a) Dziadulewicz, E. K.; Bevan, S. J.; Brain, C. T.; Coote, P. R.;
Culshaw, A. J.; Davis, A. J.; Edwards, L. J.; Fisher, A. J.; Fox,
A. J.; Gentry, C.; Groarke, A.; Hart, T. W.; Werner Huber, W.;
James, I. F.; Kesingland, A.; Vecchia, L. L.; Loong, Y.; Lyothier,
I.; McNair, K.; O’Farrell, C.; Peacock, M.; Portmann, R.;
Schopfer, U.; Yaqoob, M.; Zadrobilek, J. Naphthalen-1-yl-(4-
pentyloxynaphthalen-1-yl)methanone: a potent, orally bioavail-
able human CB1/CB2 dual agonist with antihyperalgesic properties
and restricted central nervous system penetration. J. Med. Chem.
ꢀ
(13) Bermudez-Silva, F. J.; Sanches-Vera, I.; Suarez, J.; Serrano, A.;
Fuentes, E.; Juan-Pico, P.; Nadal, A.; de Fonseca, F. R. Role of
cannabinoid CB2 receptors in glucose homeostasis in rats. Eur. J.
Pharmacol. 2007, 565, 207–211.
(14) D’Ambra, T. E.; Estep, K. G.; Bell, M. A.; Eissenstat, M. A.; Josef,
K. A.; Ward, S. J.; Haycock, D. A.; Baizman, E. R.; Casiano,
F. M.; Beglin, N. C.; Chippari, S. M.; Grego, J. D.; Kullnig, R. K.;
Daley, G. T. Conformationally restrained analogues of pravado-
line: nanomolar potent, enantioselective, (aminoalkyl)indole ago-
nists of the cannabinoid receptor. J. Med. Chem. 1992, 35, 124–135.
(15) (a) Huffman, J. W.; Dai, D.; Martin, B. R.; Compton, D. R.
Design, synthesis and pharmacology of cannabimimetic indoles.
Bioorg. Med. Chem. Lett. 1994, 4, 563–566. (b) Huffman, J. W.;
Zengin, G.; Wu, M.-J.; Lu, J.; Hynd, G.; Bushell, K.; Thompson,
A. L. S.; Bushell, S.; Tartal, C.; Hurst, D. P.; Reggio, P. H.; Selley, D. E.;
Cassidy, M. P.; Wiley, J. L.; Martin, B. R. Structure-activity relation-
ships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and
CB2 receptors: steric and electronic effects of naphthoyl substituents.
New highly selective CB2 receptor agonists. Bioorg. Med. Chem.
2005, 13, 89–112.
(16) (a) Gallant, M.; Dufresne, C.; Gareau, Y.; Guay, D.; Leblanc, Y.;
Prasit, P.; Rochette, C.; Sawyer, N.; Slipetz, D. M.; Tremblay, N.;
Metters, K. M.; Labelle, M. New class of potent ligands for the
human peripheral cannabinoid receptor. Bioorg. Med. Chem. Lett.
1996, 9, 2263–2268. (b) Gallant, M.; Gareau, Y.; Guay, D.; Labelle, M.;
Prasit, P. U.S. Patent 5,532,237, 1996. (c) Valenzano, K. J.; Tafesse, L.;
Lee, G.; Harrison, J. E.; Boulet, J. M.; Gottshall, S. L.; Mark, L.;
Pearson, M. S.; Miller, W.; Shan, S.; Rabadi, L.; Rotshteyn, Y.; Chaffer,
S. M.; Turchin, P. I.; Elsemore, D. A.; Toth, M.; Koetzner, L.; Whiteside,
G. T. Pharmacological and pharmacokinetic characterization of the
cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of
ꢀ
2007, 50, 3851–3856. (b) Kunos, G.; Osei-Hyiaman, D.; Batkai, S.;