Triaryl bis-sulfones as cannabinoid-2 receptor ligands: SAR studies

Article abstract of DOI:10.1016/j.bmcl.2005.07.023

We recently reported that compound 1 is a potent inhibitor of the CB2 receptor with high selectivity over CB1. This paper describes the SAR development for this class of compounds. Variation of the substitution pattern on the aromatic rings, as well as th

Full text of DOI:10.1016/j.bmcl.2005.07.023

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4417–4420
Triaryl bis-sulfones as cannabinoid-2 receptor ligands: SAR studies
a,
a
a
Bandarpalle B. Shankar,a,* Brian J. Lavey, Guowei Zhou, James A. Spitler,
*
Ling Tong,a Razia Rizvi,a De-Yi Yang,a Ronald Wolin,a Joseph A. Kozlowski,a
Neng-Yang Shih,a Jie Wu,a R. William Hipkin,b Waldemar Gonsiorekb
and Charles A. Lunnb
aDepartment of Chemistry, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
bDepartment of Immunology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
Received 9 March 2005; revised 19 July 2005; accepted 20 July 2005
Available online 22 August 2005
Abstract—We recently reported that compound 1 is a potent inhibitor of the CB2 receptor with high selectivity over CB1. This paper
describes the SAR development for this class of compounds. Variation of the substitution pattern on the aromatic rings, as well as
the groups linking them together, led to sub-nanomolar inhibitors of the CB2 receptor, with high selectivity over CB1.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
methyl, alternates for the sulfone linkers, and the substi-
tution pattern on the aromatic rings are described.
The CB2 receptor is a G-protein coupled receptor that
was identified in 1993.1 It is located primarily in the
spleen and other immune-related tissues and is 44%
homologous with CB1. The discovery of CB2 offered
the possibility that immune-related biological effects of
cannabinoid compounds could be obtained without
the psychoactive effects typical of cannabinoid ligands
that inhibit the CB1 receptor and enter the CNS, such
as D9-THC.2 Reported functions of CB2 include modu-
lation of B-cell differentiation,3 altered migration,4
altered antigen processing5 in macrophages, and altered
cannabinoid-mediated anti-tumor activity.6 Cannabi-
noid ligands have shown in vivo efficacy in rodent
models of pain,7–9 rheumatoid arthritis,10,11 and multi-
ple sclerosis12, providing support to the idea that CB2
inhibitors might be useful as a new class of drugs to
modulate the immune system.13
Me
H3CO
NHSO2CH3
A
B
S
O2
SO2
C
H3CO
1
2. Chemistry
Changes to the benzylic carbon were made by starting
with the appropriate benzylamine and applying the
chemistry previously reported.14 Sulfone modifications
were effected by chemistry shown in Schemes 1 and 2.
Scheme 1 starts with the assembly of the B and C phenyl
rings by ortholithiation of a 4-substituted benzalde-
hyde,15 and quenching with a substituted phenyl disul-
fide, to provide 3.16 Halogen metal exchange on 4,
followed by reaction with 3, led to 5. Reduction of 5,
oxidation of the B, C-linker to sulfone, amine deprotec-
tion, followed by sulfonylation with methanesulfonyl
chloride, resulted in 6. Alternately, PCC oxidation of
5, followed by oxidation of B, C-linker to sulfone,
hydrolysis of the TFA group, and sulfonylation, led to
compound 7. Conversion of 7 to 8 was carried out via
the Wittig procedure. Compound 7 was also converted
to oxime 9 (1:1 E and Z mixture) with methoxylamine.
We recently disclosed compound 1, a novel CB2-selec-
tive triaryl bis-sulfone.14 Here, we describe SAR studies
on 1, where the impact of varying the nature of benzylic
Keywords: CB2–CB1 receptor ligands; Inverse agonists; Cannabinoid
receptors; Immunomodulatory; Anti-inflammatory.
*
Corresponding authors. Tel.: +1 908 740 3460; fax: +1 908 740 7152
(B.B.S.); tel.: +1 908 740 2329; fax: +1 908 740 7152 (B.J.L.); e-mail
addresses: bandarpalle.shankar@spcorp.com; Brian.Lavey@spcorp.
com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.07.023

4418
B. B. Shankar et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4417–4420
Me
O
O
CF3O
Y
N
CF3
NHSO2Me
Y
c
N
CF3
H
a,b
4
H
S
O
O
S
SO2
F
S
O
21
6
20
O
O
O
Me
4
d, e
O
Z
c, d, e
O O
NHCOCF3
CF3O
Y
S
Me
NHCOCF3
N
Br
CHO
H
CF3O
a
CF3O
b
S
O
S
O
CHO
O
22
Z
OH
3
S
F
2
S
F
5
f, g. h
Scheme 3. (a) 2.1 equiv n-BuLi, THF–hexanes, ꢀ78 °C, (b) Y-phen-
ylsulfonyl fluoride, (c) 2.1 equiv n-BuLi, THF–hexanes, ꢀ78 °C, then
Z-aryl sulfonyl fluoride, ꢀ78 °C to rt overnight, (d) 1.0 M aq LiOH,
dioxane, and (e) methanesulfonyl chloride, Et3N, CH2Cl2.
Me
Me
NHSO2Me
CF3O
CF3O
CF3O
NHSO2Me
j
NOR'
O
SO2
SO2
F
7
by halogen or other moieties.19 (Table 3). Halogen metal
exchange of 4 with n-butyl lithium, followed by trapping
with an aryl sulfonyl fluoride, afforded 20.
9
F
i
Me
NHSO2Me
CH2
SO2
F
8
Compound 20 was treated with two equivalents of
n-butyl lithium and then trapped with an aryl sulfonyl
fluoride to give intermediate 21. Deprotection and sulf-
onylation of the benzylic amine gave 22.
Scheme 1. Reagents and conditions: (a) i. N,N,N-Trimethylethylene-
diamine, n-BuLi, THF, ꢀ20 °C; ii. 4-trifluoromethoxybenzaldehyde;
iii. n-BuLi (3 equiv), bis(2-fluorophenyl)disulfide (2 equiv), THF,
ꢀ40 °C; (b) 4, CH3Li, n-BuLi, THF, ꢀ78 °C; (c) (C2H5)3SiH,
BF3Æ(OEt)2, CH2Cl2, rt; (d) m-chloroperoxybenzoic acid (5 equiv),
CH2Cl2, rt; (e) i. LiOH (3 equiv), dioxane; ii. (C2H5)3N (5 equiv),
CH3SO2Cl (2 equiv); (f) PCC, CH2Cl2, rt; (g) m-chloroperoxybenzoic
acid (5 equiv), CH2Cl2, rt; (h) i. LiOH (3 equiv), dioxane; ii. pyridine
(10 equiv), CH3SO2Cl (4 equiv); (i) LiN(Si(CH3)3)2 (3 equiv),
CH3P(Ph)3Br (2 equiv), THF, 0 °C; (j) R0ONH2ÆHCl (20 equiv),
pyridine, 80 °C.
3. Results and discussion
Table 1 shows the outcome of altering the stereochemis-
try and the substitution on the benzylic carbon. The
antipode of 1 was less active and less selective. Introduc-
tion of an additional methyl group (1b), rendering the
benzylic carbon achiral, decreased affinity and selectivi-
ty. Removal of the methyl group provided the equipo-
tent and more selective compound 1c. However, the
potential increase in metabolic activity at this less hin-
dered benzylic site was not desirable, and the original
substitution and stereochemistry were retained. Trans-
forming L1 from SO2 to CH2 provided compounds with
good affinity for CB2, but with varying selectivity. Com-
pounds 25 vs. 28 show comparable activity for substitu-
tion at the 2-position over the 3-position of the C-ring.
However, compounds 23 and 24 showed the best profile
with respect to CB2 affinity and selectivity, and both of
them retained an oxygen at the 4-position of the B-ring.
Aiming to optimize substitution at L1, additional linkers
were investigated (9, 33, and 34). Sulfone- and methy-
lene-linked (L1) analogs were preferred, as presented in
Table 2.
Me
NHCOCF3
d, e
Me
NHSO2Me
Me
NHCOCF3
Cl
Cl
Cl
a
SO2
SO2
SO2
10
X
M
CHO
11 = OH
F
b
F
F
f
14. M = O
15. M = CH2
16. M = NOR'
Me
g
12 = H
h
c
13
Me
NHCOCF3
Cl
i
Cl
NHSO2Me
Cl
j
Y
SO2
SO2
Y = NH2, OH
Y
I
17
18. Y = NH
19. Y = O
Cl
Scheme 2. Reagents and conditions: (a) n-BuLi, THF, ꢀ78 °C; 2-
fluorobenzaldehyde; (b) (C2H5)3SiH, BF3Æ(OEt)2, CH2Cl2, rt;
(c) i. LiOH, dioxane; ii. (C2H5)3N, CH3SO2Cl; (d) PCC, CH2Cl2, rt;
(e) i. LiOH, dioxane; ii. (C2H5)3N, CH3SO2Cl; (f) LiN(Si(CH3)3)2,
CH3P(Ph)3Br, THF, 0 °C; (g) R0ONH2ÆHCl, pyridine, 80 °C; (h)
n-BuLi,
,
I2, THF, ꢀ78 °C; (i) i. Pd(OAc)2, PtBu3, NaOBut,
4-chloroaniline, toluene, 120 °C (sealed tube); ii. NaH, CuBrÆ(CH3)2S,
4-chlorophenol, toluene, 120 °C (sealed tube); (j) i. LiOH, dioxane; ii.
(C2H5)3N, CH3SO2Cl.
L2 SAR was investigated, and a similar strategy of
screening different functional groups was initiated. The
L2-linkers examined were significantly less active com-
pared to the original sulfone.
Scheme 2 utilizes preassembled17 10. Ortholithiation of
10 followed by treatment with 2-fluorobenzaldehyde,
provided 11, which was transformed to analogs 14, 15,
and 16, as described in Scheme 1. The nitrogen- and
oxygen-linked compounds 18 and 19 were accessed by
palladium- and copper-mediated18 coupling of 2-iodo
derivative 17, which itself was obtained from 10 by
ortholithiation and iodide quenching.
Table 1. Benzylic carbon variant of 1
Compounds Benzyl carbon Kia (CB2 nM) Selectivity
(CB1 Ki/CB2 Ki)
1
CHCH3 (S)
CHCH3 (R)
C(CH3)2
CH2
0.4
30
2262
105
1a
1b
1c
6
1.3
282
2168
a Individual data points for determinations of Ki for CB1 and CB2
were carried out in triplicate, in two separate assays.
Scheme 3 describes compounds that were prepared in
which one or both of the methoxy groups were replaced

B. B. Shankar et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4417–4420
Table 2. Linker (L1; L2) and substitution (X; Y) variants of 1
4419
Me
NHSO2CH3
X
4
A
B
Y
L1
L2
C
4
Compound
L1
L2
X
Y
Kia (CB2 nM)
Selectivity (CB1 Ki/CB2 Ki)
23
8
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH3
CO
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
CH2
CO
4-OCH3
4-Cl
4-OCH3
4-Cl
2-F
0.6
6.7
0.4
1
1300
188
1178
674
584
60
24
25
26
27
28
29
30
31
32
33
9
4-OCF3
4-CF3
4-CF3
4-OCF3
4-CF3
4-OCF3
4-OCH3
4-OCF3
4-Cl
2-F
2, 6-Di F
2-OCF3
3-F
1.8
16
3.5
35
438
27
3-CF3
4-OCH3
2-F
44
108
28
CO
CO
179
410
76
4-Cl
4-Cl
16
48
C(CH3)2
C:CH2
C:NOCH3
SO2
4-Cl
4-OCF3
4-Cl
4-Cl
2-F
4-Cl
86
19
34
35
36
15
37
38
18
19
406
164
192
247
77
5
11
4-Cl
4-Cl
SO2
SO2
4-Cl
4-Cl
284
17
C:CH2
2-F
2-F
SO2
SO2
C(CH3)(OH)
C(CH3)(OH)
NH
4-Cl
4-Cl
111
25
4-Cl
4-Cl
230
278
983
SO2
SO2
4-Cl
4-Cl
5
O
4-Cl
3
a Individual data points for determinations of Ki for CB1 and CB2 were carried out in triplicate, in two separate assays.
After ascertaining that sulfone offered the best in vitro
profile for L1 and L2, with the least metabolic risk, we
revisited substitution on the aromatic rings. A series of
compounds were prepared in which one or both of the
methoxy groups of compound 1 were replaced with
other moieties (Table 3).
Table 3. Substitution (X; Y) variants of 1.
Me
X
4
NHSO2CH3
A
B
Y
S
O2
SO2
C
4
In general, the B-ring methoxy replacements were well-
tolerated, although there seems to be a preference for
smaller substituents. Small alkoxy substituents are high-
ly potent at CB2 and show good selectivity (compound
39–42). When the O-alkyl group becomes too large how-
ever, the affinity at CB2 decreases (compound 42). Small
alkyl substitution (CF3/CH3) gave compounds with sub-
nanomolar activity (compounds 45, 46). Compounds
where X = H are less active than those with substitution
at this position (compounds 44, 47).
Compound
X
Y
Kia (CB2 nM) CB1 Ki/
CB2 Ki
1
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
4-OCH3
4-OCH3
4-OCH3
4-OH
4-OMe
H
0.4
0.6
0.9
2262
2482
1146
2315
11
4-Cl
4-Cl
13
4-O-c-C5H9 4-Cl
232
8
4-CF3
H
4-Cl
4-Cl
2-F
2-F
2-F
H
558
127
58
4-CH3
4-CF3
H
0.5
1741
3552
1449
1941
1778
238
0.9
9
While the in vitro profiles of compounds 39 and 45 are
desirable, we favored 46 due to its putative metabolic
stability. Exploring other putatively stable groups, we
examined chlorine as an alternate to 4-CF3 and varied
substitution on the C-ring (compounds 16–28). A prefer-
ence for smaller groups was observed (compounds 48
and 52 vs. 53). Fluorine substitution gave somewhat
more potent compounds than hydrogen substitution
(compounds 48 vs. 52). The compound with the best
combination of potency and CB2 selectivity was 52,
although 46 was similar. Compound 52 gave an AUC
of 6331 nM h when dosed orally in rats,20 indicating
that the combination of chlorine and fluorine was effec-
tive at decreasing the oxidative metabolism observed for
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
2
2-Cl
3-Cl
4-Cl
2-F
6
23
10
1
687
4387
134
2-OCF3 128
compound 1. Like compound 1, compound 52 is an in-
verse agonist at the CB2 receptor, as indicated by its ef-
fect on the binding of [35S]GTPcS to the CB2 receptor21
(Fig. 1).

4420
B. B. Shankar et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4417–4420
7. Quartilho, A.; Mata, H. P.; Ibrahim, M. M.; Vanderah, T.
9000
7500
6000
4500
3000
1500
0
W.; Porreca, F.; Makriyannis, A.; Malan, T. P. Anesthe-
siology 2003, 99, 955.
8. Kehl, L. J.; Hamamoto, D. T.; Wacnik, P. W.; Croft, D.
L.; Norsted, B. D.; Wilcox, G. L.; Simone, D. A. Pain
2003, 103, 175.
9. Papanastassiou, A. M.; Fields, H. L.; Meng, I. D. Pain
2004, 107, 267.
EC50
EC50
10. Zurier, R. B.; Rossetti, R. G.; Lane, J. H.; Goldberg, J.
M.; Hunter, S. A.; Burstein, S. H. Arthritis Rheum. 1998,
41, 163.
0 -11 -10 -9
-8
-7
-6
11. Malfait, A. M.; Gallily, R.; Sumariwalla, P. F.; Malik, A.
S.; Andreakos, E.; Mechoulam, R.; Feldman, M. Proc.
Natl. Acad. Sci. U.S.A. 2000, 97, 9561.
Cannabinoids Log (M)
Figure 1. Effect of cannabinoids on [35S]GTPgS exchange in SF9
hCB2 membranes.
12. Baker, D.; Pryce, G.; Croxford, J. L.; Brown, P.; Pertwee,
R. G.; Huffman, J. W.; Layward, L. Nature 2000, 404, 84.
13. For some leading references CB2-selective inhibitors see
the following: (a) Huffman, J. W.; Yu, S.; Showalter, V.;
Abood, M. E.; Wiley, J. L.; Compton, D. R., et al. J.
Med. Chem. 1996, 39, 3875; (b) Galland, M.; Dufresne, C.;
Gareau, Y.; Guay, D.; Leblanc, Y., et al. Bioorg. Med.
Chem. Lett. 1996, 6, 2263; (c) Rinaldi-Carmona, M.;
Barth, F.; Millan, J., et al. J. Pharmacol. Exp. Ther. 1998,
284, 644; (d) Wrobleski, S. T.; Chen, P.; Hynes, J.; Lin, S.;
Norris, D. J., et al. J. Med. Chem. 2003, 46, 2110.
14. Lavey, B. J.; Kozlowski, J. A.; Hipkin, R. W.; Gonsiorek,
W.; Lundell, D. J.; Piwinski, J. J.; Narula, S.; Lunn, C. A.
Bioorg. Med. Chem. Lett. 2005, 15, 783.
4. Conclusions
We have studied the SAR of the CB2 antagonist 1, tar-
geting the nature of the chiral benzylic carbon, substitu-
tion on the aromatic rings, and the linkers L1 and L2.
Achiral benzylic analog 1c maintained significant activ-
ity, while all other variations resulted in loss of activity.
Changes at L2 were not tolerated, and sulfone was
judged to be the best overall for L1 and L2. Substitution
on the phenyl rings showed a preference for a small
group at the 2-position of the C-ring and a small alkyl
or halogen at the 4-position of the B-ring.
15. Commins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49,
1078–1083.
16. Preparation of intermediate 3: to a solution of N,N,N-
trimethylethylenediamine (1.2 mL, 8.6 mmol) in THF
(8 mL) at ꢀ20 °C was added n-BuLi (1.6 M, 5.4 mL,
8.6 mmol) dropwise. After 15 min, 4-trifluoromethoxy-
benzaldehyde (1.5 g, 7.8 mmol) in THF (8 mL) was added.
The mixture was stirred for 15 min and additional n-BuLi
(1.6 M, 14.6 mL, and 23 mmol) was added. The reaction
mixture was stirred at ꢀ20 °C for 1 h and then placed in a
freezer at ꢀ20 °C for 20 h. The mixture was cooled to
ꢀ40 °C, and a solution of bis(2-fluorophenyl)disulfide
(4.0 g, 15.7 mmol) in 30 mL THF was added. The reaction
mixture was stirred at ꢀ35 °C for 3 h, poured into 0.5 N
HCl, and extracted with EtOAc. The organic layer was
washed with water and brine, dried over Na2SO4, filtered,
and concentrated to an oil. Purification by silica gel
chromatography (3% EtOAc/hexanes) gave 1.55 g (62%)
of compound 3, as a solid.
Supplementary data
Characterization data and experimental procedures
for the synthesis of 10 and 52 can be found in the online
version at doi:10.1016/j.bmcl.2005.07.023.
References and notes
1. Munro, S.; Thomas, K. L.; Abu-Shaar, M. Nature 1993,
365, 61.
2. For reviews on cannabinoid biology see: (a) Watson, S. J.;
Benson, J. A., Jr.; Joy, J. E. Arch. Gen. Psychiatry 2000,
57, 547; (b) Goutopoulos, A.; Makriyannis, A. Pharmacol.
Ther. 2002, 95, 103; For reviews discussing immune
modulation by cannabinoid ligands see: (c) Klein, T. W.;
Newton, C.; Larsen, K.; Lu, L.; Perkins, I.; Nong, L.;
Friedman, H. J. Leukoc. Biol. 2003, 74; (d) Pertwee, R. G.
Exp. Opin. Invest. Drugs 2000, 9, 1553.
17. See supplemental material for experimental details for key
compounds.
18. (a) Yamamoto, T.; Nishiyama, M.; Koie, Y. Tetrahedron
Lett. 1998, 39, 2367; (b) Boger, D.; Yohannes, D.
Tetrahedron Lett. 1989, 30, 2053.
19. For experimental details of the syntheses and determina-
tion of Ki values, see: Kozlowski, J. A.; Shih, N.-Y.;
Lavey, B. J.; Rizvi, R. K.; Shankar, B. P.; Spitler, J. M.;
Tong, L.; Wolin, R.; Wong, M. K. WO02062750.
20. For experimental details of the measurement of in vivo
drug plasma concentrations, see Korfmacher, W. A.; Cox,
K. A.; Ng, K. J.; Veals, J.; Hsieh, Y.; Wainhaus, S.;
Broske, L.; Prelusky, D.; Nomeir, A.; White, R. E. Rapid
Commun. Mass Spectrom. 2001, 15, 335.
3. Carayon, P.; Marchand, J.; Dussossoy, D.; Derocq, J. M.;
Jbilo, O.; Bord, A.; Bouaboula, M.; Galiegue, S.; Mon-
diere, P.; Penarier, G.; Fur, G. L.; Defrance, T.; Casellas,
P. Blood 1998, 92, 3605.
4. Sacerdote, P.; Massi, P.; Panerai, A. E.; Parolaro, D.
J. Neuroimmunol. 2000, 109, 155.
5. McCoy, K. L.; Matveyeva, M.; Carlisle, S. J.; Cabral, G.
A. J. Pharmacol. Exp. Ther. 1999, 289, 1620.
6. Zhu, L. X.; Sharma, S.; Stolina, M.; Gardner, B.; Roth,
M. D.; Tashkin, D. P.; Dubinett, S. M. J. Immunol. 2000,
165, 373.
21. Gonsiorek, W.; Lunn, C.; Fan, X.; Narula, S.; Lundell,
D.; Hipkin, R. W. Mol. Pharmacol. 2000, 57, 1045.