α2 adrenoceptor agonists as potential analgesic agents. 3. Imidazolylmethylthiophenes

Article abstract of DOI:10.1021/jm0003891

A series of imidazolylmethylthiophenes has been prepared and evaluated as ligands for the α₂ adrenoceptor. These compounds were tested in two animal models that are predictive of analgesic activity in humans. The 3-thienyl compounds were generally the most potent, particularly those with substitution in the 4-position. A subset of the most active compounds was further evaluated for adverse cardiovascular effects in the anesthetized rat model. In addition to excellent binding at the α_2D adrenoceptor, the 4-bromo analogues 20e and 21e were very active in the rat abdominal irritant test (RAIT) with ED₅₀ doses of 0.38 and 0.31 mg/kg, respectively. We constructed a pharmacophore model based on the biological activity of the present series, dexmedetomidine (1), and conformationally restrained analogues 3 and 4.

Full text of DOI:10.1021/jm0003891

J . Med. Chem. 2001, 44, 863-872
863
r2 Ad r en ocep tor Agon ists a s P oten tia l An a lgesic Agen ts. 3.
Im id a zolylm eth ylth iop h en es
Robert E. Boyd,* C. Royce Rasmussen, J effery B. Press,† Robert B. Raffa,‡ Ellen E. Codd, Charlene D. Connelly,
Quan S. Li, Rebecca P. Martinez, Martin A. Lewis,§ Harold R. Almond, and Allen B. Reitz
Drug Discovery Division, The R. W. J ohnson Pharmaceutical Research Institute, Welsh and McKean Roads,
Spring House, Pennsylvania 19477
Received September 5, 2000
A series of imidazolylmethylthiophenes has been prepared and evaluated as ligands for the R2
adrenoceptor. These compounds were tested in two animal models that are predictive of
analgesic activity in humans. The 3-thienyl compounds were generally the most potent,
particularly those with substitution in the 4-position. A subset of the most active compounds
was further evaluated for adverse cardiovascular effects in the anesthetized rat model. In
addition to excellent binding at the R2D adrenoceptor, the 4-bromo analogues 20e and 21e were
very active in the rat abdominal irritant test (RAIT) with ED50 doses of 0.38 and 0.31 mg/kg,
respectively. We constructed a pharmacophore model based on the biological activity of the
present series, dexmedetomidine (1), and conformationally restrained analogues 3 and 4.
In tr od u ction
Adrenergic receptors belong to the superfamily of
seven-transmembrane G-protein coupled receptors
(GPCR) and are implicated in a variety of pharmaco-
logical functions. The R and â subtypes of this receptor
were characterized by Alquist over 50 years ago.1 Since
that time the pharmacology of adrenoceptors has been
investigated in many laboratories throughout the world.
The molecular biology of the R and â adrenoceptor
subtypes has recently been reviewed.2 It has been
known for many years that an R2 agonist such as
dexmedetomidine (1) can produce antinociception in
laboratory animals and analgesia in humans.3 The R2
adrenoceptor has been further divided into the R2A, R2B
ED50 ) 7.9 mg/kg). On the other hand, unsaturated
compound 4 showed 2000-fold better binding at the R2D
receptor (Ki ) 0.0086 nM) and yet was inactive in the
MAIT paradigm. For comparative purposes, dexmedeto-
midine (1) has an R2 adrenergic receptor binding affinity
(Ki ) 0.39 nM) and good oral activity in the mouse and
rat antinociception models (ED50 ) 0.05 and 0.1 mg/kg,
respectively).6 Thiophene has long been known to be an
effective isostere for benzene with surprising differences
between the 2- and 3-positional substituents.7 We
therefore decided to synthesize a number of imidazoly-
lalkylthiophenes and evaluate these compounds for R2D
receptor binding and antinociceptive activity in rodent
models.
Cardiovascular effects are quite often problematic
with R2 ligands, and the more potent compounds from
this series were evaluated by means of electrocardio-
graph (ECG) in an anesthetized rat model. A subset of
the active and inactive compounds was examined in
modeling experiments to better understand the confor-
mational requirements of R2 adrenergic ligands for
biological activity. Herein are reported the results of
those studies.
,
and R2C subtypes. A fourth subtype, the R2D, is believed
to be a rat homologue of the R2A. More recently, Bylund
and co-workers have used genetically engineered mice
to demonstrate that it is primarily the R2A subtype that
is responsible for antinociception, while hypertensive
responses are believed to be mediated through the R2B
subtype, and several other CNS responses are at-
tributed to the R2C
.
In two previous communications we have described
the synthesis and pharmacological profile of a series of
imidazolylmethylthiazoles and -oxazoles4 and imida-
zolyldihydrothianaphthenes5 as potent R2 agonists. One
active compound from the imidazolylmethylthiazole
series was RWJ 37210 (2), which showed good binding
at the R2D adrenergic receptor (Ki ) 18 nM) and was a
potent antinociceptive agent with an ED50 ) 1.8 mg/kg
po in the mouse abdominal irritant test (MAIT). Simi-
larly, imidazotetrahydrothianaphthene 3 displayed good
binding at the R2D receptor (Ki ) 2.9 nM) and was also
active in the mouse and rat antinociception model (RAIT
* To whom correspondence should be addressed. Tel: 215-628-7818.
Fax: 215-628-4985. E-mail: rboyd@prius.jnj.com.
† Present address: Galenica Pharmaceutical, 30 West Patrick St.,
Suite 310, Fredrick, MD 21701.
Ch em istr y
The synthesis of the imidazomethyl-2-thiophene com-
pounds is shown in Scheme 1. Weinreb amides 6b-d
were readily prepared in good yield from the corre-
sponding acid chloride and N,O-dimethylhydroxylamine
‡ Present address: Department of Pharmacy, Temple University,
Philadelphia, PA 19104.
§ Present address: Bristol-Myers Squibb Pharmaceutical Research
Institute.
10.1021/jm0003891 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/13/2001

864 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6
Boyd et al.
Sch em e 1a
a
Reagents: (i) SOCl2; (ii) HNMe(OMe); (iii) 7; (iv) MnO2; (v) NaBH4; (vi) [H]; (vii) R4MgX; (viii) MeOH, HCl.
hydrochloride. Reaction of these intermediates with
N-tritylimidazole magnesium bromide8 (7) afforded
thiophene ketones 8b-d . These compounds are shown
in Table 1. The ketones were reduced with NaBH4 to
give the intermediate carbinol and then deoxygenated
and deprotected to give the unsubstituted methylene
targets 11b-d . Carbinol intermediates 10e-i (Table 1)-
were obtained from 7 and the appropriately substituted
thiophenecarboxaldehyde. A number of methods for the
deoxygenation of the carbinol intermediates were ex-
plored. Catalytic hydrogenation using Pearlman’s cata-
lyst was the most straightforward. However this pro-
cedure was only applicable to substrates which did not
contain halogen substituents and in general gave only
2-thiophene targets. The ketone and carbinol intermedi-
ates are shown in Table 2.
The preparation of the cyclopropane compound 25 is
shown in Scheme 3. Addition of MeMgBr to imidazole
ketone 8b followed by dehydration gave olefin 24.
Cyclopropanation of this olefin using Simmons-Smith
conditions13 gave 25, albeit in modest yield. This
intermediate was deprotected using MeOH and HCl to
give target compound 26.
The enantiomers of 12b,e were prepared by a classical
resolution of the corresponding dibenzoyltartaric acid
salts. In general 2-3 recrystallizations from 2-PrOH
were required to obtain material of >95% ee (a single
1
enantiomer was detected by H NMR using 1 equiv of
9
modest yields. Reduction with BH(TFA)2 was ap-
Mosher’s acid in CDCl3). The enantiomers of 21e were
obtained by HPLC using a Chiralpak AD column (99.9/
0.1 MeCN/HNEt2). The enantiomeric purity was deter-
mined to be >98% by HPLC. Attempts to resolve 21g
by classical resolution or chiral chromatography were
unsuccessful.
plicable for substrates that contained halogens and gave
acceptable results in most cases. To optimize results
with this reagent, however, longer reaction times were
often required and BH3‚THF was unsuitable due to
polymerization of the THF. The use of BH3‚Me2S10 and
11
NaBH4 proved to offer alternative sources of borane
that allowed for longer reaction times and therefore
higher yields. Finally, the deoxygenation of the ben-
zothiophene 10i with Et3SiH/TFA12 gave an excellent
yield of target compound 11i.
Biologica l Resu lts a n d Discu ssion
The compounds were prepared and tested in vitro in
an R2 adrenergic receptor binding assay. They were also
screened in vivo in the mouse abdominal irritant test
(MAIT) for antinociceptive activity. Compounds with
>80% inhibition in this model were then evaluated in
the rat abdominal irritant test (RAIT), and an ED50 was
determined for those compounds with significant activ-
ity. The data for 2-thiophene and 3-thiophene com-
pounds are presented in Tables 3 and 4, respectively.
Compounds of general structure 12 and 13 were
prepared by addition of the appropriate Grignard re-
agent to the protected imidazole ketone 8 to give the
tertiary carbinol. These intermediates were directly
deoxygenated and deprotected using the methodology
described above. Acid-catalyzed solvolysis of carbinol
10e in methanol gave the corresponding methoxy-
substituted product 14e. The synthesis of imidazolyl-
methyl-3-thiophene compounds is shown in Scheme 2
and is analogous to the chemistry described for the
In the 2-thiophene series of compounds, the unsub-
stituted thiophene compound 11a as well as those
bearing a substituent in the 5-position such as 11c,h ,i

R2 Adrenoceptor Agonists as Analgesic Agents
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6 865
Sch em e 2a
a
Reagents: (i) SOCl2; (ii) HNMe(OMe); (iii) 7; (iv) MnO2; (v) NaBH4; (vi) [H]; (vii) R4MgX; (viii) MeOH, HCl.
Sch em e 3a
Ta ble 1. N-Tritylimidazoalkyl-2-thiophene Intermediates
compd R1 R2
R3
R4 R5 method/yield
formula
8b
8c
8d
8e
10e
10f
10g
10h
10i
Me
H
Me Me
Br
Br
H
Br Br
H
H
H
H
H
Me
H
H
H
dO
dO
dO
dO
A/52
A/50
A/73
C/91
B/70
B/66
B/69
B/80
B/65
C
28H22N2OS
C28H22N2OS
C
C
C
C
C
29H24N2OS
H
H
Br
27H19BrN2OS
27H21BrN2OS
27H21BrN2OS
27H20Br2N2OS
OH
H
H
H
H
H
H
H
OH
OH
-(C4H8)- OH
-(C4H4)- OH
C31H28N2OSa
C31H24N2OS
a
Reagents: (i) 1. MeMgBr, 2. TsOH; (ii) CH2I2, Et2Zn; (iii)
MeOH, HCl.
a
Product was somewhat labile, and attempts to recrystallize
resulted in some decomposition.
showed only modest binding at the R2 receptor (Ki )
1.1-8.7 nM) and were inactive in the mouse model.
Compounds with a substituent (Me or Br) ortho to the
benzylic carbon such as 11b,e were 1 order of magnitude
more potent in binding (Ki ) 0.45 and 0.35 nM,
respectively) and significantly more active in the in vivo
models (RAIT ED50 ) 0.87 and 2.0 mg/kg, respectively).
A lone 3-substituent as in the case of 11f was interme-
diate in both receptor binding and biological activity.
The 3,4-disubstituted compounds 11d ,g had the highest
affinity at the R2D adrenergic receptor (Ki ) 0.17 and
0.07 nM, respectively) but had only modest antinocice-
ptive activity. Alkyl substitution on the benzylic carbon
such as compounds 12b,d ,e,g and 13b led to a modest
decrease in receptor binding relative to their unsubsti-
tuted analogues. In addition, compounds 12b,e had in
vivo activity that was comparable to that of their
unsubstituted analogues. It was interesting to find that
compounds 12d ,g and 13b were inactive in the rat
model despite the fact that there was some activity in
the mouse. The methoxy-substituted compound 14e
showed very little binding at the receptor and had
almost no antinociceptive activity. Finally, the cyclo-
propane analogue 26 had no significant binding to the
receptor and was inactive in vivo.
The 3-substituted thiophene analogues were generally
more potent, and even the unsubstituted thiophene
compound 20a had modest receptor affinity and anti-
nociceptive activity (Ki ) 3.1 nM; RAIT ED50 ) 0.97 mg/
kg). We examined the effects of substitution at either
of the two possible ortho positions in this molecule
(compounds 20b-g) and found that for the Et analogues
both isomers were equally active. However for Me and
Br substituents, the 4-substituted isomer was the more
active. The 2,5-dimethyl and 2,5-diethyl analogues 20h ,i
were equipotent relative to their corresponding mono-

866 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6
Ta ble 2. N-Tritylimidazoalkyl-3-thiophene Intermediates
Boyd et al.
Mod elin g. While it is certainly possible that phar-
macodynamics and bioavailability could play a signifi-
cant role in vivo, we decided to construct models of low-
energy conformations of some of the biologically active
compounds and compare these results with the data
obtained for the RAIT assay. Initially we chose com-
pounds 1, 20e, and (-)21e14 with RAIT ED50 values of
0.12, 0.38, and 0.19 mg/kg respectively, for modeling
studies. The overlay of these structures is shown in
Figure 1a,b. It is quite clear from these models that
these 3-thiophene compounds fit quite well with dexme-
detomidine (1). We attempted to fit 2-thienyl compounds
11b,g to this model. The overlay of these structures is
shown in Figure 2a,b. Compound 11b also fits quite well
into this model and is quite active in the antinociceptive
assay (ED50 ) 0.87 mg/kg). On the other hand compound
11g is quite different in the position of the thiophene
ring and is 10-fold less active in the RAIT assay (ED50
) 7.1 mg/kg) despite being among the most potent
ligands for the R2D receptor. Substitution of the meth-
ylene bridge such as OMe (14e) and cyclopropyl (26)
resulted in no antinociceptive activity and very little
receptor affinity, and as expected 14e and 26 have
almost no overlap with 1 (Figure 3).
Finally we wanted to see if this model would explain
the vast difference between receptor binding and anti-
nociceptive activity that was observed between ana-
logues 3 and 4. These structures are shown in Figure
4. In fact unsaturated compound 4 which is inactive in
the RAIT forces the thiophene ring into a much different
region of space than the aromatic ring of 1. The reduced
compound 3 however does in fact hold the thiophene
ring in much the same orientation as the phenyl ring
of 1 and consequently retains significant biological
activity.
method/
compd R1
R2
R3
R4 R5
yield
formula
28H22N2OS
28H22N2OS
27H19BrN2OS
29H24N2
C27H18Cl2N2OS
27H22N2OS
28H24N2OS
28H24N2OS
17b
17c
17e
17g
17k
19a
19b
19c
19d
19e
19f
19g
19h
19i
Me
H
H
H
Cl
H
Me
H
Br
H
Et
H
Me
Et
i-Pr
Cl
H
H
H
H
H
Cl
H
H
H
H
dO
dO
dO
dO
dO
C/93
C/75
C/64
C/90
A/74
B/50
B/55
B/59
B/64
B/56
B/62
B/62
B/93
B/79
B/66
E/72
B/66
B/45
C
C
C
C
Me
Br
Et
H
H
H
Me
H
Br
H
Et
H
H
OH
OH
OH
OH
OH
OH
OH
OH
OH
H
H
H
H
H
H
H
H
H
H
H
H
H
C
C
C
C
C
C
C
C
C
C
C
C
27H21BrN2OS
H
H
H
Me
Et
i-Pr OH
Cl
H
27H21BrN2OS‚0.25H2O
29H26N2OS‚0.25H2O
29H26N2OS‚0.5H2O
29H26N2OS‚0.25H2O
31H30N2OS‚0.25H2O
33H34N2OS‚0.25H2O
27H20Cl2N2OS
19j
19k
19l
H
H
OH
OH
Me Me
29H26N2OS‚0.5H2O
C31H24N2OS‚H2O
19m
H
-(C4H4)- OH
substituted compounds. However the 2,5-dichloro com-
pound 20k had a significant loss in activity, and the
diisopropyl compound 20j was inactive. The 2,4-dim-
ethyl compound 20l was among the most potent in
binding to the R2 receptor (Ki ) 0.1 nM) and was fully
effective in the MAIT screen (100% inhibition @ 30 mg/
kg). However we were unable to obtain an ED50 in the
rat as a consequence of some behavioral side effects. The
benzothiophene compound 20m showed excellent bind-
ing at the receptor (Ki ) 0.09 nM) and was also very
potent in the RAIT (ED50 ) 0.44 mg/kg). A methyl
substituent on the benzylic carbon, such as 21b,c,e,g,
had only minor effects on receptor binding and anti-
nociceptive activity relative to the unsubstituted com-
pounds. However an ethyl (22c) or methoxy (23c,e)
substituent at the benzylic carbon resulted in a signifi-
cant decrease in biological activity.
The potential for cardiovascular side effects is an
important issue for compounds that bind to adrenergic
receptors. We employed an anesthetized rat model as a
way of evaluating some of the more potent compounds
in this series for cardiovascular liability. After id
administration of compound at a dose of 3× ED50 value,
the ECG of the animal was monitored and changes in
the QT interval (∆QT) were recorded. These data are
shown in Table 5. We used dexmedetomidine (1) as a
standard in this procedure which produced only an 8%
change in the QT interval.
For the imidazolylmethyl-2-thiophene compounds,
11b was the most potent in vivo. However the ∆QT was
significantly higher at 22%. Compounds 12b,e were
resolved, and only the more active enantiomer was
evaluated in CV tests. Again these two compounds
produced a significant QT prolongation. In the imida-
zolylmethyl-3-thiophene series, compounds 20c,e,f,g
were tested and only the 4-bromo compound 20e had a
∆QT (11%) close to that of dexmedetomidine (1). Com-
pound 21e is the R-methyl analogue of 20e and was
comparable in R2 binding and antinociceptive activity.
Unfortunately the more active enantiomer of this com-
pound ((-)21e) actually had a higher QT prolongation
than the unsubstituted compound.
In conclusion, we have prepared some 2-thienyl- and
3-thienyl-4-methylimidazoles that show excellent bind-
ing at the R2D receptor and are quite potent in assays
predictive of analgesic activity. The 3-thienyl compounds
that contained a substituent in the 4-position, such as
20c,e,g and 21c,e,g, were the most active in the RAIT
assay. In addition, those compounds with a 4-Br sub-
stituent, such as in 20e and 21e, have the lowest
cardiovascular side effect potential of all compounds in
this series. Finally molecular modeling techniques
provided insight to better understand these results.
Exp er im en ta l Section
Ch em istr y. All melting points are uncorrected and were
taken on a Thomas-Hoover capillary melting point apparatus
or similar device. 1H NMR spectra were obtained on a 90-MHz
Varian EM-390 NMR spectrometer or a 360-MHz Brucker AM-
360 NMR spectrometer with SiMe4 as the internal standard.
The spectral data for each compound supported the assigned
structure, and all elemental analyses were within 0.4% of the
calculated value, except where indicated. The examples below
represent typical experimental conditions for the preparation
of compounds shown in Schemes 1-3.
Gen er a l P r oced u r es for Th iop h en e Ald eh yd es a n d
Wein r eb Am id es. N,O-Dim eth yl-(3-m eth ylth iop h en e-2-
yl)ca r boxa m id e (6b). To a solution of 3-methylthiophene-2-
carboxylic acid (26.0 g, 0.182 mol) in CHCl3 (150 mL) was
added SOCl2 (15.9 mL, 0.22 mol) and the reaction mixture was
heated at reflux for 2 h and then cooled to room temperature.
This solution was then added dropwise to a mixture of N,O-
dimethylhydroxylamine hydrochloride (26.6 g, 0.273 mol) and
NEt3 (68 mL, 0.49 mol) in CHCl3 (400 mL) cooled in an ice

R2 Adrenoceptor Agonists as Analgesic Agents
Ta ble 3. Imidazoalkyl-2-thiophenes
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6 867
compd
R1
R2
R3
R4
method/yield
formula
mp (°C)/solventa
R
2D Kib (nM) MAITc (%)
RAITd
11a
11b
11c
11d
11e
11f
11g
11h
11i
12b
12d
12e
12g
13b
14e
26
H
Me
H
Me Me
Br
H
Br
H
H
Me
Me Me
Br
Br
Me
Br
Me
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
D/18
E/20
F/20
E/12
G/44
H/30
G/68
H/41
I/93
J /40
K/25
L/55
L/25
K/8
C8H8N2S‚HCl
C9H10N2S‚HCl
C9H10N2S‚HCl
128-129/Acn
127.5-129/Ac
131-133/Ac
180-182/Acn
211.5-213.5/Acn
186-189.5/Acn
224-227/Acn
181-183/Acn
187-188/-
163-165/Ac
127-129/Ac
185-188/Acn
120-123.5/Ac
108.5-109.5/Ac
8.7
0.45
3.6
0.17
0.35
1.4
0.07
3.7
1.1
2.1
0.75
0.96
0.43
8.3
60
100
33
100
100
80
93
7
20
100
87
NT
0.87 (0.4, 1.5)
NT
4.7 (2.3, 9.0)
2.0 (0.9, 4.2)
5.2 (2.3, 8.7)
7.1 (3.4, 13.6)
NT
NT
2.2 (0.8 4.7)
IA
0.97 (0.4, 2.6)
NT
IA
NT
NT
C
10H12N2S‚HCl
H
Br
Br
C8H7BrN2S‚HCl
C8H7BrN2S‚HCl
C8H6Br2N2S‚HCl
C12H14N2S‚HCl
C12H10N2S‚HCl
-(C4H8)-
-(C4H4)-
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Et
OMe
C
C
10H12N2S‚HCl
11H14N2S‚C4H4O4
H
Br
H
H
H
C9H9BrN2S‚HCl
C9H8Br2N2S‚C4H4O4
100
80
100
53
e
C
11H14N2S‚C4H4O4
N/35
-/44
C9H9BrN2OS‚C4H4O4 127.5-129.5/Ac
C11H12N2S‚C4H4O4
39
1000
-CH2CH2-
151-155/Ac
40
a
b
Solvents: Ac ) acetone; Acn ) acetonitrile. Receptor binding Ki’s were determined using 5-8 concentrations in triplicate. c Values
d
reported are % inhibition at the screening dose of 30 mg/kg po. Values expressed are ED50 (95% confidence limits); NT ) not tested; IA
) inactive. e C: calcd, 34.54; found, 35.08.
Ta ble 4. Imidazomethyl-3-thiophenes
compd
R1
R2
R3
R4
method/yield
formula
mp (°C)/solventa
R2D Kib (nM) MAITc (%)
RAITd
20a
20b
20c
20d
20e
20f
20g
20h
20i
H
Me
H
Br
H
Et
H
Me
Et
i-Pr
Cl
Me
H
Me
H
H
H
H
Me
H
Br
H
Et
H
H
H
H
Me
-(C4H4)-
H
Me
Br
Et
Me
Me
Br
H
H
H
H
H
H
H
Me
Et
i-Pr
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
D/32
D/24
D/48
H/65
G/34
D/53
D/47
D/47
G/70
G/46
H/52
G/22
H/62
K/34
K/23
J /40
C8H8N2S‚C4H4O4
C9H10N2S‚C4H4O4
C9H10N2S‚C4H4O4
C8H7BrN2S‚C4H4O4
C8H7BrN2S‚C4H4O4
115-118/Ac
140-141/Ac
142-144/Ac
148-150/Ac
135-137/Ac
148-150/Ac
146-148/Ac
146-148/Ac
123-124/Ac
160-161/Ac
164-166/Ac
160-162/Ac
154-156/Ac
131-133/Ac
125-128/Ac
137-139/Ac
145-147/Ac
101-105Ac
99-102/Ac
3.1
0.44
0.47
ND
0.23
0.07
.29
0.69
0.4
12
0.88
0.1
0.09
2.3
0.39
0.08
0.28
0.97
15.9
ND
100
100
100
100
100
100
100
100
100
40
100
100
100
100
100
100
100
100
100
100
0.97 (0.51, 1.8)
0.89 (0.43, 1.7)
0.35 (0.17, 0.84)
1.1 (0.53, 2.4)
0.38 (0.20, 0.81)
0.27 (0.14, 0.51)
0.32 (0.18, 0.49)
0.9 (0.43, 1.75)
0.31 (0.17, 0.58)
NT
C
C
C
C
C
10H12N2S‚C4H4O4
10H12N2S‚C4H4O4
10H12N2S‚C4H4O4
12H16N2S‚C4H4O4
14H20N2S‚C4H4O4
20j
20k
20l
C8H6Cl2N2S‚C4H4O4
3.2 (1.74, 5.03)
e
C10H12N2S‚C4H4O4
20m
21b
21c
21e
21g
22c
23c
23e
H
C12H10N2S‚C4H4O4
0.44 (0.19, 0.93)
1.6 (0.9, 3.5)
0.27 (0.14, 0.49)
0.31 (0.19, 0.51)
0.48 0.23, 0.97)
2.6 (1.5, 4.4)
4.4 (2.4, 7.8)
3.6 (1.7, 8.5)
H
H
H
H
H
M
H
Me
Me
Me
Me
Et
OMe
OMe
C
C
10H12N2S‚C4H4O4
10H12N2S‚C4H4O4
C9H9BrN2S‚C4H4O4
H
H
H
H
K/39
K/19
N/47
N/21
C
C
C
11H14N2S‚C4H4O4
11H14N2S‚C4H4O4
10H12N2OS‚C4H4O4
f
C9H9BrN2OS‚C4H4O4
111-112/Ac
a
See Table 3 for solvents. b Receptor binding Ki’s were determined using 5-8 concentrations in triplicate. c Values reported as % inhibition
at the screening dose of 30 mg/kg po. Values expressed are ED50 (95% confidence limits); NT ) not tested. e Unable to determine an
ED50
Ta ble 5. Cardiovascular Data for Selected Compounds
d
.
f N: calcd, 8.64; found, 8.12.
liquid was vacuum distilled (109.5-110.5 °C, 0.75 mmHg) to
1
give a clear oil (28.8 g, 85%): H NMR (CDCl3) δ 2.55 (s, 3H),
3.33 (s, 3H), 3.71 (s, 3H), 6.9 (d, 1H, J ) 5 Hz), 7.35 (d, 1H, J
) 5 Hz). Anal. (C8H11O2S) C,H,N.
compd
R2 (nM)
RAIT ED50 (mg/kg)
∆QT (%)
D
11b
0.45
0.78
0.18
0.47
0.23
0.07
0.29
ND
0.87 (0.4, 1.5)
22
24
23
34
11
28
48
20
32
8
(+)12b
(+)12e
20c
20e
20f
20g
(-)21e
21g
1.18 (0.45, 2.6)
0.97 (0.56, 1.59)
0.35 (0.17, 0.84)
0.38 (0.20, 0.81)
0.27 (0.14, 0.51)
0.32 (0.18, 0.49)
0.19 (0.13, 0.26)
0.48 (0.23, 0.97)
0.12 (0.04, 0.17)
2-Meth ylth iop h en e-3-ca r boxa ld eh yd e (18b). To a solu-
tion of 3-bromo-2-methylthiophene (11.8 g, 67.0 mmol) in dry
Et2O (50 mL) cooled to -78 °C was added n-BuLi (1.6 M, 42.0
mL) dropwise. After the addition was complete, the reaction
was stirred at -78 °C for an additional 45 min. A solution of
DMF (9.8 g, 134.0 mmol) in dry Et2O was also cooled to -78
°C and then added via cannula to the reaction mixture. The
reaction was allowed to slowly warm to room temperature and
then quenched with water. The mixture was transferred to a
separatory funnel and the aqueous layer extracted with an
additional portion of Et2O. The combined organic layers were
washed with water and brine and then dried over Na2SO4. The
solution was filtered and the solvent was evaporated in vacuo
to give a yellow oil. Chromatography on silica (2.5 to 5% Et2O
40
0.015
1
bath. After the addition was complete, the reaction was
allowed to warm to room temperature, and then transferred
to a separatory funnel. The organic layer was washed with
water (2×) and then dried over MgSO4. The solution was
filtered and the solvent was evaporated in vacuo. The resulting

868 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6
Boyd et al.
F igu r e 2. Overlay of 1 and 11b,g: (a) side view; (b) top view.
F igu r e 1. Overlay of 1, 20e, and 21e: (a) side view; (b) top
view.
in hexane) gave the title compound as a pale yellow oil (4.2 g,
50%). This material would decompose at room temperature
but could be stored 2-3 days in the refrigerator: 1H NMR
(CDCl3) δ 2.85 (s, 3H), 7.1 (d, 1H, J ) 5 Hz), 7.7 (d, 1H, J ) 5
Hz), 10.1 (s, 1H).
Gen er a l P r oced u r es for Ad d ition of Im id a zole Gr ig-
n a r d R ea gen t t o Th iop h en e Ca r b on yl Com p ou n d s.
N-Tr ip h en ylm eth yl-(3-m eth ylth iop h en e-2-yl)-1H-im id a -
zole-4-m eth a n on e (8b). Meth od A. To a solution of 5 (21.8
g, 50 mmol) in CH2Cl2 (150 mL) under Ar was added 3.0 M
EtMgBr in Et2O (17.0 mL). This solution was stirred at room
temperature for 1 h at which point halogen metal exchange
was complete as judged by TLC analysis of an aliquot. A
solution of N,O-dimethyl-(3-methylthiophene-2-yl)carboxamide
(6b; 9.3 g, 50 mmol) in CH2Cl2 was added dropwise, and the
reaction was stirred overnight at room temperature. The
reaction was quenched by the addition of aqueous NH4Cl and
extracted with CH2Cl2 (2×). The combined organic layers were
washed with water and then dried over Na2SO4. After filtering
the solvent was evaporated in vacuo and the residue was
recrystallized from acetone to give the title compound as a pale
F igu r e 3. Overlay of compounds 1, 11a ,h , 14e, and 26.
δ 2.65 (s, 3H), 6.9 (d, 1H, J ) 5 Hz), 7.15 (m, 6H), 7.35 (m,
9H), 7.5 (m, 2H), 7.75 (d, 1H, J ) 2 Hz). Anal. (C28H22N2OS)
C,H,N.
1
yellow solid (11.1 g, 52%): mp 195-197 °C; H NMR (CDCl3)

R2 Adrenoceptor Agonists as Analgesic Agents
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6 869
directly without further purification. To a solution of TFA (50.8
mL, 0.66 mol) in CH2Cl2 cooled in an ice bath was added BH3‚
THF (330 mL, 0.33 mol) dropwise. After the addition was
complete, a solution of the carbinol in CH2Cl2 (50 mL) was
added in one portion. The reaction mixture was stirred for 2
h at 0 °C and then quenched with water and 3 N HCl. The
solution was basified with solid Na2CO3 and extracted with
CH2Cl2 (2×). The extracts were combined and dried over K2-
CO3, filtered and the solvent evaporated in vacuo. The residue
was dissolved in MeOH and filtered. To this solution was
added 3 N HCl (10 mL) and the mixture heated at reflux 2-3
h until starting material had been consumed. The solvent was
evaporated in vacuo. The residue was dissolved in water and
washed with Et2O (2×), then basifed and extracted with EtOAc
(2×). The extracts were combined and dried over Na2SO4,
filtered and the solvent evaporated in vacuo. The residue was
purified by chromatography on silica (99:0.5:0.5 EtOAc/MeOH/
NH4OH). The appropriate fractions were combined and the
solvent was evaporated in vacuo. The residue was treated with
Et2O‚HCl and the salt was recrystallized from acetone and to
give the title compound as white needles (1.2 g, 20%): mp
127.5-129 °C; 1H NMR (DMSO-d6) δ 2.2 (s, 3H), 4.15 (s, 2H),
6.85 (d, 1H, J ) 5 Hz), 7.3 (d, 1H, J ) 5 Hz), 7.4 (s, 1H), 9.0
(s, 1H), 14.6 (br s, 2H). Anal. (C9H10N2S‚HCl) C,H,N.
4-[(5-Meth ylth iop h en e-2-yl)m eth yl]-1H-im id a zole Hy-
d r och lor id e (11c). Meth od F . A mixture of 8c (3.9 g, 9.0
mmol) and NaBH4 (0.52 g, 14.0 mmol) in 2-PrOH was heated
at reflux for 2 h at which point the starting material had been
consumed. The reaction was quenched by the cautious addition
of cold 3 N HCl. Most of the 2-PrOH was evaporated from the
reaction. The residue was diluted with water, basified with
solid Na2CO3 and extracted with CHCl3 (2×). The extracts
were combined and dried over Na2SO4, and then filtered and
the solvent was evaporated in vacuo. The residue was tritu-
rated with Et2O to give an off-white solid. The solid was
dissolved in MeOH and combined with Pearlman’s catalyst (2
g) and hydrogenated at 50 °C, 50 psi for 48 h. The catalyst
was removed by filtration and the filtrate was evaporated in
vacuo. The reisdue was dissolved in dilute HCl, washed with
Et2O (2×), and then basified with Na2CO3 and extracted with
EtOAc. The extracts were combined and dried over K2CO3,
filtered and the solvent evaporated in vacuo. The residue was
converted to the HCl salt (Et2O‚HCl) and recrystallized from
acetone to give the title compound as a white solid: mp 131-
133 °C; 1H NMR (DMSO-d6) δ 2.4 (s, 3H), 4.2 (s, 2H), 6.65 (s,
1H), 6.8 (d, 1H, J ) 3 Hz), 7.5 (s, 1H), 9.05 (s, 1H), 14.6 (br s,
1H). Anal. (C9H10N2S‚HCl) C,H,N.
4-[(3-Br om oth iop h en e-2-yl)m eth yl]-1H-im id a zole Hy-
d r och lor id e (11e). Meth od G. To a solution of TFA (12.2
mL, 0.16 mol) in CH2Cl2 cooled in an ice bath was added BH3‚
Me2S (90 mL, 0.90 mol) dropwise. After the addition was
complete, 10e (2.0 g, 0.004 mol) was added as a solid in one
portion. The reaction mixture was allowed to warm to room
temperature, stirred an additional 1 h at room temperature
and then quenched with water and 3 N HCl. The solution was
basified with solid Na2CO3 and extracted with CH2Cl2 (2×).
The extracts were combined and dried over K2CO3, filtered and
the solvent evaporated in vacuo. The residue was dissolved in
MeOH (25 mL) containing 3 N HCl (5 mL) and the mixture
heated at reflux 2-3 h. The solvent was evaporated in vacuo.
The residue was dissolved in water and washed with Et2O
(2×), then basifed and extracted with EtOAc (2×). The extracts
were combined and dried over Na2SO4, filtered and the solvent
evaporated in vacuo. The residue was dissolved in Et2O,
charcoaled and filtered through Dicalite. The filtrate was
treated with Et2O‚HCl and the product was collected and then
recrystallized from MeOH/MeCN to give the title compound
as a white crystalline solid (0.49 g, 44%): mp 211.5-213.5 °C;
1H NMR (DMSO-d6) δ 4.2 (s, 2H), 7.1 (d, 1H, J ) 5 Hz), 7.45
(s, 1H), 7.6 (d, 1H, J ) 5 Hz), 9.0 (s, 1H) 14.5 (br s, 1H). Anal.
(C8H7BrN2S‚HCl) C,H,N.
F igu r e 4. Overlay of compounds 1, 3, and 4.
N-Tr ip h en ylm et h yl-(4-b r om ot h iop h en e-2-yl)-1H -im i-
d a zole-4-m eth a n ol (10f). Meth od B. This is essentially the
same procedure as described above except 4-bromothiophene-
2-carboxaldehyde (9f; 3.5 g, 18.3 mmol) was used in place of
Weinreb amide 8b. The crude carbinol product is purified by
chromatography on silica (CHCl3) to give the title compound
as a light yellow solid (6.0 g, 66%): 1H NMR (CDCl3) δ 4.5 (br
s, 1H ex), 5.9 (s, 1H), 6.75 (s, 1H), 6.85 (s, 1H), 7.15 (m, 7H),
7.3 (m, 9H), 7.45 (s, 1H). Anal. (C27H21BrN2OS) C,H,N.
N-Tr ip h en ylm et h yl-(3-b r om ot h iop h en e-2-yl)-1H -im i-
d a zole-4-m eth a n on e (8e). Meth od C. A mixture of 10e (17.3
g, 34.5 mmol) and MnO2 (50 g) in CH2Cl2 (300 mL) was stirred
overnight at room temperature. The solution was filtered
through Dicalite and the solvent was evaporated in vacuo to
give a white solid (15.6 g, 91%). An analytical sample could
be obtained by recrystallization from CH2Cl2/MeOH: 1H NMR
(CDCl3) δ 7.15 (m, 7H), 7.3 (m, 9H), 7.5 (m, 1H), 7.55 (m, 1H),
7.8 (s, 1H). Anal. (C27H19BrN2OS) C,H,N.
Gen er a l P r oced u r es for Deoxygen a tion a n d Dep r o-
tection of Im idazolylth ioph en e Car bin ols. 4-[(Th ioph en e-
2-yl)m eth yl]-1H-im id a zole Hyd r och lor id e (11a ). Meth od
D. A solution of bromothiophene 10f (5.0 g, 10.0 mmol) was
combined with Pd(OH)2 in EtOH and hydrogenated at 50 °C,
50 psi overnight. The catalyst was removed by filtration and
the filtrate was evaporated in vacuo. The residue was dissolved
in dilute HCl and washed with Et2O, and then basified with
Na2CO3 and extracted with EtOAc (2×). The organic layer was
separated and dried over K2CO3, filtered and the solvent
evaporated in vacuo. The residue was chromatographed on
silica (2.5% to 5% of MeOH containing 10% NH4OH in CHCl3).
The appropriate fractions were combined and the solvent was
evaporated in vacuo. The residue was dissolved in acetone and
treated with Et2O‚HCl. The product was collected and recrys-
tallized from MeCN to give a white solid: mp 128-129 °C; 1H
NMR (DMSO-d6) δ 4.3 (s, 2H), 7.0 (s, 2H), 7.4 (m, 1H), 7.5 (s,
1H), 9.05 (s, 1H), 14.7 (br s, 1H). Anal. (C8H8N2S‚HCl) C,H,N.
4-[(3-Meth ylth iop h en e-2-yl)m eth yl]-1H-im id a zole Hy-
d r och lor id e (11b). Meth od E. A mixture of 8b (7.7 g, 18.0
mmol) and NaBH4 (1.0 g, 27.0 mmol) in 2-PrOH was heated
at reflux for 2 h at which point the starting material had been
consumed. The reaction was quenched by the cautious addition
of cold 3 N HCl. Most of the 2-PrOH was evaporated from the
reaction. The residue was diluted with water, basified with
solid Na2CO3 and extracted with CHCl3 (2×). The extracts
were combined and dried over Na2SO4, and then filtered and
the solvent was evaporated in vacuo. The residue was tritu-
rated with EtOAc to give an off-white solid that was used
4-[(4-Br om oth iop h en e-2-yl)m eth yl]-1H-im id a zole Hy-
d r och lor id e (11f). Meth od H. TFA (50 mL) was cooled in
an ice bath under Ar and NaBH4 5/16" pellets (3 pellets, 0.5

870 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6
Boyd et al.
g, 75 mmol) was added and the mixture was stirred 20 min at
0 °C. When pellets were almost gone, 10f (3.5 g, 7.0 mmol)
and 2 additional NaBH4 pellets were added. After 30 min, the
starting material had not been completely consumed and 2
more pellets were added and the mixture was allowed to stir
and slowly warm to room temperature overnight. The reaction
mixture was diluted with water and neutralized with solid Na2-
CO3 and then extracted with CHCl3 (2×). The combined
extracts were dried over K2CO3 and then filtered and the
solvent was evaporated in vacuo. The residue was chromato-
graphed on silica (97/3 CHCl3/10% NH4OH in MeOH) to give
an oil which crystallized on standing. This material was
dissolved in acetone and treated with Et2O‚HCl. The product
was collected by filtration and recrystallized from MeCN to
give the title compound as a white solid (0.6 g, 30%): mp 186-
189.5 °C; 1H NMR (DMSO-d6) δ 4.3 (s, 2H), 7.05 (d, 1H, J ) 1
Hz), 7.5 (d, 1H, J ) 1 Hz), 7.6 (d, 1H, J ) 1 Hz), 9.05 (d, 1H,
J ) 1 Hz), 14.7 (br s, 1H). Anal. (C8H7BrN2S‚HCl) C,H,N.
residue triturated with EtOAc to give an off-white solid. The
solid was combined with 1 N HCl (3.8 mL) and Pd(OH)2 in
EtOH and the mixture was hydrogenated at 50 °C, 50 psi for
24-48 h. The catalyst was removed by filtration and the
solvent was evaporated in vacuo. The residue was chromato-
graphed on silica (97.5/2.5 CHCl3/10% NH4OH in MeOH) to
give the crude product. This was dissolved in 2-PrOH and
treated with fumaric acid (1 equiv). The solvent was evapo-
rated in vacuo and the residue was recrystallized from acetone
to give the desired product (0.36 g, 25%) as a white solid: mp
127-129 °C; 1H NMR (DMSO-d6) δ 1.5 (d, 3H, J ) 7 Hz), 2.05
(2s, 6H), 4.35 (q, 1H, J ) 7 Hz), 6.65 (s, 2H), 6.8 (s, 1H), 6.9 (s,
1H), 7.6 (s, 1H). Anal. (C11H14N2S‚C4H4O4) C,H,N.
4-[(3-Br om ot h iop h en e-2-yl)et h yl]-1H -im id a zole H y-
d r och lor id e (12e). Meth od L. This was essentially the same
procedure as method J except BH3‚Me2S was used in place of
BH3‚THF and the reaction was allowed to go overnight before
quenching. The crude product was purified by chromatography
(98:1:1 EtOAc:MeOH:NH4OH). The appropriate fractions were
combined and the solvent was evaporated in vacuo. The
residue converted to the HCl salt (Et2O‚HCl) and recrystallized
from MeCN to give a pale yellow solid: mp 185-188 °C; 1H
NMR (DMSO-d6) δ 1.65 (d, 3H, J ) 7 Hz), 4.6 (q, 1H, J ) 7
Hz), 7.0 (d, 1H, J ) 5 Hz), 7.5 (s, 1H), 7.6 (d, 1H, J ) 5 Hz),
9.1 (s, 1H), 14.8 (br s, 1H). Anal. (C9H9BrN2S‚HCl) C,H,N.
4-[(4-Br om oth iop h en e-3-yl)eth yl]-1H-im id a zole F u m a -
r a te (21e). Meth od M. To a solution of 17e (10.3 g, 20.0 mmol)
in THF (150 mL) was added MeMgBr (3.0 M, 8 mL) and the
reaction mixture was stirred at room temperature overnight.
An additional 1.0 mL of MeMgBr was added and the reaction
was stirred an additional 1 h and then quenched with aqueous
NH4Cl and extracted with EtOAc (2×). The combined extracts
were washed with water and then brine and then dried over
Na2SO4. The solution was filtered and the solvent was evapo-
rated in vacuo and the residue was recrystallized from EtOAc
to give a beige solid. To this solid (7.2 g, 14.0 mmol) was added
Et3SiH (45 mL, 280 mmol) and the reaction mixture was cooled
to -10 °C (ice/MeOH). To this was added TFA (43 mL) and
the reaction mixture was allowed to warm to room tempera-
ture overnight. The mixture was poured into 10% Na2CO3 and
extracted with EtOAc (2×). The combined extracts were dried
over K2CO3 and then filtered, and the solvent was evaporated
in vacuo. The residue was chromatographed on silica starting
with 60:39:1 and increasing to 50:49:1 CH2Cl2/EtOAc/10% NH4-
OH in MeOH. The appropriate fractions were combined and
the solvent was evaporated in vacuo. The residue was com-
bined with 1 equiv of fumaric acid in 2-PrOH, the solvent was
evaporated in vacuo and the residue was recrystallized from
acetone to give a white solid (2.1 g, 40%): mp 137-139 °C; 1H
NMR (DMSO-d6) δ 1.49 (d, 3H, J ) 7.1 Hz), 4.1 (q, 1H, J )
7.1 Hz), 6.6 (s, 2H), 6.75 (s, 1H), 7.25 (d, 1H, J ) 3.2 Hz), 7.65
(d, 1H, J ) 3.2 Hz). Anal. (C9H9BrN2S‚C4H4O4) C,H,N.
4-[(Ben zo[b]th iop h en e-2-yl)m eth yl]-1H-im id a zole Hy-
d r och lor id e (11i). Meth od I. To a solution of 10i (4.7 g, 10
mmol) in CH2Cl2 (50 mL) was added TFA (24.6 mL, 320 mmol).
To this was added Et3SiH (12.7 mL, 80 mmol) dropwise from
a syringe and the reaction mixture was stirred overnight at
room temperature. The reaction was quenched with water and
the aqueous layer was basified with solid Na2CO3. The organic
layer was separated washed with brine and dried over K2CO3.
The solution was filtered and the solvent was evaporated in
vacuo. The residue was chromatographed on silica (50% to 90%
EtOAc/hexane) to afford a colorless oil. This was treated with
Et2O‚HCl to give the title compound (2.3 g, 93%) as a pale
1
yellow solid: H NMR (CD3OD) δ 4.3 (s, 2H), 7.1 (s, 1H), 7.2
(s, 1H), 7.35 (m, 2H), 7.65 (d, 1H), 7.75 (d, 1H), 8.2 (s, 1H).
Anal. (C12H10N2S‚HCl) C,H,N.
4-[(3-Met h ylt h iop h en e-2-yl)et h yl]-1H -im id a zole H y-
d r och lor id e (12b). Meth od J . To a solution of 8b (10.1 g,
24.0 mmol) in THF (100 mL) under Ar was added MeMgBr
(10.5 mL, 31.5 mmol), and the reaction was stirred at room
temperature for 2 h. The reaction was quenched with saturated
NH4Cl and extracted with EtOAc (2×). The combined organic
layers were washed with water and brine and then dried over
Na2SO4. After filtering, the solvent was evaporated in vacuo.
The residue was triturated with acetone to give the carbinol
as an off-white solid. To a solution of TFA (58.5 mL, 0.76 mol)
in CH2Cl2 (100 mL) cooled in an ice bath, was added BH3‚THF
(380 mL, 0,38 mol) maintaining a temperature <10 °C. The
mixture was stirred an additional 1 h after the addition was
complete and then the carbinol was added in one portion. The
reaction was stirred in an ice bath for 90 min and then
quenched with water. The aqueous layer was basified with
solid Na2CO3 and extracted with an additional portion of CH2-
Cl2. The organic layers were combined and dried over Na2-
SO4. The mixture was filtered and the solvent evaporated in
vacuo. The residue was dissolved in MeOH (100 mL) and 3 N
HCl (25 mL) was added and the mixture was heated at reflux
for 3 h. The solvent was evaporated in vacuo and the residue
partitioned between water and Et2O. The aqueous layer was
washed with a second portion of Et2O, and then basified and
extracted with EtOAc. The extracts were dried over K2CO3,
filtered and the solvent evaporated in vacuo. The residue was
dissolved in Et2O and treated with Et2O‚HCl to give a white
solid which was recrystallized from acetone to give the product
4-[(3-Br om oth iop h en e-2-yl)m eth oxym eth yl]-1H-im id a -
zole F u m a r a te (14e). Meth od N. To a solution of 10e (1.1
g, 2.2 mmol) in MeOH (25 mL) was added 5-6 drops of
concentrated HCl and the mixture was heated at reflux
overnight. The solvent was evaporated in vacuo. The residue
was partitioned between water and Et2O. The aqueous layer
was washed with an additional portion of Et2O and then
basified with Na2CO3 and extracted with EtOAc. The extracts
were dried over Na2SO4 and then filtered and the solvent was
evaporated in vacuo. The residue was dissolved in 2-PrOH and
treated with 1 equiv of fumaric acid. The solvent was evapo-
rated in vacuo and the residue was recrystallized from acetone
to give the title compound (0.30 g, 35%) as a white solid: mp
1
as a white crystalline solid (2.2 g, 40%): mp 164-166 °C; H
NMR (DMSO-d6) δ 1.6 (d, 3H, J ) 7 Hz), 2.2 (s, 3H), 4.6 (q,
1H, J ) 7 Hz), 6.9 (d, 1H, J ) 5 Hz), 7.3 (d, 1H, J ) 5 Hz),
7.45 (s, 1H), 9.1 (s, 1H), 14.7 (s, 1H). Anal. (C10H12N2S‚HCl)
C,H,N.
1
127.5-129.5 °C; H NMR (DMSO-d6) δ 3.25 (s, 3H), 5.55 (s,
1H), 6.65 (s, 2H), 7.05 (m, 2H), 7.65 (m, 2H). Anal. (C9H9N2-
4-[(3,4-Dim eth ylth ioph en e-2-yl)eth yl]-1H-im idazole Fu -
m a r a te (12d ). Meth od K. To a solution of 8d (2.0 g, 4.5 mmol)
in THF (20 mL) was added MeMgBr in Et2O(1.5 mL, 4.5 mmol)
and the reaction was stirred overnight at room temperature.
The reaction was quenched with aqueous NH4Cl and the
aqueous layer was extracted with an additional portion of
EtOAc. The combined organic layers were dried over Na2SO4,
filtered and the solvent was evaporated in vacuo and the
OS‚C4H4O4) C, H, N.
N-Tr ip h en ylm eth yl-4-[(3-m eth ylth iop h en e-2-yl)eth yl-
en e]-1H-im id a zole (24). To a solution of 8b (4.2 g, 9.7 mmol)
in THF (40 mL) under Ar was added MeMgBr (6.0 mL, 18
mmol), and the mixture was stirred overnight at room tem-
perature. The reaction was quenched with saturated NH4Cl
and extracted with EtOAc (2×). The combined organic layers

R2 Adrenoceptor Agonists as Analgesic Agents
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6 871
were washed with water and brine and then dried over Na2-
SO4. After filtering, the solvent was evaporated in vacuo. The
residue was dissolved in toluene and TsOH (250 mg) was
added and the mixture heated at reflux overnight. The solution
was allowed to cool and then washed with water and brine
and dried over Na2SO4. The solution was filtered and the
filtrate was evaporated in vacuo. The residue was recrystal-
lized from Et2O to give the title compound as an off white solid
glass homogenizer. The homogenate was centrifuged at 1000g
for 10 min, and the resulting supernatant centrifuged at
42000g for 10 min. The pellet was resuspended in 30 volumes
of 3 mM potassium phosphate buffer, pH 7.5, preincubated at
25 °C for 30 min and recentrifuged. The pellet was resus-
pended as described above and used for the receptor binding
assay. Incubation (20 min at 25 °C) was performed in test
tubes containing phosphate buffer, 0.1 mL of the synaptic
membrane fraction, tritiated p-aminoclonidine (0.1 nM) and
test drug. The incubation was terminated by filtration of the
tube contents through Whatman GF/B filter sheets on a
Brandel cell harvester. Following washing of the sheets with
2 × 2 mL of cold 10 mM HEPES buffer (pH 7.5), the adhering
radioactivity was quantified by liquid scintillation spectrom-
etry.
Da ta An a lysis. Data were analyzed using LIGAND, a
nonlinear curve-fitting program designed specifically for the
analysis of ligand binding data.15 Nonspecific binding was
computed by LIGAND as a fitted parameter. The Ki values
were derived from single-site models of the data, which in each
case provided the best fit. Each concentration curve included
8-10 concentrations of the investigational compound, each
concentration run in triplicate. Replicate determinations of the
inhibition constants usually differed from each other by less
than 10%.
2. In Vivo Stu d ies: An im a ls. Male 18-24 g pathogen-
free albino CD-1 mice (Charles River Laboratories, Kingston
Facility, Stone Ridge, NY) were maintained in a climate-
controlled room on a 12-h light/dark cycle (lights on at 06:00
h) with food and water available ad libitum up to the time of
the test. All tests were performed in accordance with the
recommendations and policies of the International Association
for the Study of Pain (IASP), the National Institutes of Health
(NIH), and J ohnson & J ohnson guidelines for the use of
laboratory animals.
3. Acetylch olin e-In d u ced MAIT. The procedure with
minor modifications was that described by Collier.16 Test
compounds or appropriate vehicle was administered po by
gavage, and at specified intervals later, the animals received
an ip injection of 5.5 mg/kg of acetylcholine bromide. The mice
were then placed into large glass bell jars and observed for
the occurrence a response to the noxious stimulus such a
writhing. The percent inhibition of this response (equal to
percent antinociception) was calculated for each dose as
follows: % antinociception ) 100 × (no. of responders)/(no. of
mice in group). The ED50 value (dose of agonists that produced
50% antinociception) and the corresponding 95% confidence
intervals were determined using the probit anaylsis of Litch-
field and Wilcoxon,17 including a ø-square test for linearity.
4. Ra t Ca r d iova scu la r EKG (∆QT). Pathogen-free, nor-
motensive male albino Long-Evans rats (350-450 g at time
of testing) were purchased from Charles River Laboratories
(Raleigh, NC) and were maintained on a 12-h light/dark cycle
(lights on at 06:00 h) in climate-controlled room with food and
water available ad libitum until the time of the testing. All
housing, treatment, and testing were in accordance with the
recommendations and policies of the National Institutes of
Health (NIH) guidelines for the care and use of laboratory
animals.
5. Ca r d iova scu la r Tests. The rats were anesthetized using
sodium pentobarbital injection (50 mg/kg ip) and were allowed
to respire spontaneously. Body temperature was monitored by
rectal thermometer and maintained constant under a heat
lamp equipped with feedback control. A midline incision was
made in the upper abdominal area and a thread was placed
under the duodenum for the convenience of drug administra-
tion. The carotid artery was isolated and cannulated for
measurement of arterial blood pressure. The surface electro-
cardiogram was recorded using standard limb leads II. Mean
arterial pressure, pulse pressure, heart rate and EKG param-
eters (including QT interval) were measured using an MI2
(Malvern, PA) data acquisition system and Biowindows soft-
ware. The rats were allowed to acclimate for 5-20 min after
being instrumented and then R2 agonist or vehicle was directly
1
(2.0 g, 48%): H NMR (CDCl3) δ 2.0 (s, 3H), 5.2 (d, 1H, J ) 2
Hz), 6.1 (d, 1H, J ) 2 Hz), 6.6 (s, 1H), 6.75 (d, 1H, J ) 5 Hz),
7.1 (d, 1H, J ) 5 Hz), 7.15 (m, 6H), 7.3 (m, 9H), 7.45 (s, 1H).
Anal. (C29H24N2S‚0.5H2O) C,H,N.
1-(N-Tr iph en ylm eth yl-1H-im idazol-4-yl)-1-(3-m eth ylth -
iop h en e-2-yl)cyclop r op a n e (25). To a solution of 24 (0.85
g, 2.0 mmol) in toluene (10 mL) were added CH2I2 (1.6 g, 6.0
mmol) and 1.1 M Et2Zn (6.0 mL, 6.0 mmol) and the mixture
was heated at 90 °C overnight. An additional 1.6 g of CH2I2
and 6.0 mL of Et2Zn were added and the mixture again heated
at 90 °C overnight. The reaction was quenched with saturated
NH4Cl and filtered. The aqueous layer was extracted with
EtOAc (2×). The organic extracts were combined and dried
over Na2SO4. The solution was filtered and the solvent was
evaporated in vacuo to give the crude product. The residue
was chromatographed on silica (CHCl3) to give the title
compound (0.3 g, 33%): 1H NMR (CDCl3) δ 1.2 (t, 2H, J ) 2.5
Hz), 1.5 (m, 2H), 2.0 (s, 3H), 6.2 (s, 1H), 6.65 (d, 1H, J ) 5
Hz), 6.95 (d, 1H, J ) 5 Hz), 7.1 (m, 6H), 7.22 (m, 9H). Anal.
(C30H26N2S) H,N; C: calcd, 80.68; found, 79.77.
1-(1H-Im id a zolyl)-1-(3-m eth ylth iop h en e-2-yl)cyclop r o-
p a n e (26). To a solution of 25 (0.55 g, 1.23 mmol) in MeOH
(40 mL) was added 1 N HCl (3 mL) and the mixture was
stirred at room temperature until the starting material had
been consumed as judged by TLC. The solvent was evaporated
in vacuo. The residue was dissolved in water and washed with
Et2O. The aqueous layer was basified with Na2CO3 and
extracted with EtOAc. The combined extracts were dried over
K2CO3 and then filtered and the filtrate was evaporated in
vacuo. The residue was dissolved in 2-PrOH and combined
with 1 equiv of fumaric acid. The solvent was evaporated and
the residue was recrystallized from acetone to give the desired
compound (0.17 g, 44%) as a tan soli: mp 151-155 °C; 1H NMR
(DMSO-d6) δ 1.1 (d, 2H, J ) 3 Hz), 1.35 (d, 2H, J ) 3 Hz), 2.1
(s, 3H), 6.35 (s, 1H), 6.6 (s, 2H), 6.8 (d, 1H, J ) 5 Hz), 7.2 (d,
1H, J ) 5 Hz), 7.5 (s, 1H). Anal. (C11H12N2S‚C4H4O4) C,H,N.
(+)-4-[(3-Meth ylth ioph en e-2-yl)eth yl]-1H-im idazole Hy-
d r och lor id e ((+)12b). To a solution of (()12b (0.98 g, 5.1
mmol) in 2-PrOH was added a solution of dibenzoyl-L-tartaric
acid (1 equiv) in 2-PrOH and the final volume was brought to
75 mL. After stirring overnight at room temperature the
product was collected by filtration and then recrystallized from
2-PrOH (2×). The enantiomeric excess (ee) was measured by
1H NMR in CDCl3 to be >98% (the other enantiomer could
not be detected) using 1 equiv of Mosher’s acid. The salt was
converted back to free base and the treated with Et2O‚HCl to
give the title compound (0.21 g) as a white solid: mp 167-169
°C; [R] ) +45.8 (c ) 1.0, MeOH).
(+)-4-[(3-Br om oth ioph en e-2-yl)eth yl]-1H-im idazole Hy-
d r och lor id e ((+)12e). Same procedure as described above
except started with racemic 12e: [R] ) +52.6 (c ) 1.0, MeOH).
Anal. (C9H9BrN2S‚HCl) C,H,N.
(-)-4-[(4-Br om oth ioph en e-3-yl)eth yl]-1H-im idazole Fu -
m a r a te ((-)21e). Racemic material was separated on a
Chiracel AD column. Free base was combined with 1 equiv of
fumaric acid in 2-PrOH and the solvent was evaporated in
vacuo. The residue was recrystallized from acetone to give the
title compound as a white solid: mp 132-134 °C; [R] ) -3.6 (c
) 1.0, MeOH). Anal. (C9H9BrN2S‚C4H4O4) C,H,N.
Biologica l Meth od s. 1. In Vitr o R2D Ad r en ocep tor
Bin d in g Assa y. Male Wistar rats (150-250 g, VAF; Charles
River, Kingston, NY) were sacrificed by cervical dislocation
and their brains removed and placed immediately in ice-cold
HEPES-sucrose (10 mM HEPES, 300 mM sucrose, pH 7.4, 23
°C). Tissue from the cerebral cortex was dissected out and
homogenized in 20 volumes of HEPES-sucrose in a Teflon-

872 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6
Boyd et al.
other Thiophene Derivitives. In Thiophene and Its Derivitives,
Part 1; Gronowitz, S., Ed.; J ohn Wiley and Sons: New York,
1985; pp 353-456. (c) Press, J . B. Pharmacologically Active
Thiophene Derivitives Revisited: 1983-1988. In Thiophene and
its Derivitives, Volume 44, Part 4; Gronowitz, S., Ed.; J ohn Wiley
and Sons: New York, 1991.
injected into the duodenum by 1-mL syringe with 26th gauge
needle. The total volume of solution injected was around 0.5
mL. The R2 adrenoceptor agonist doses were 1-, 3-, or 10-fold
the ED50 in the analgesic test described above. Three doses
were injected intraduodenum at 0, 20, and 40 min separately.
The cardiovascular parameters were then monitored from
drug-treated rats (n ) 3-5) and vehicle-treated rats (n ) 3-5)
continuously for 60 min.
(8) Turner, R. M.; Lindell, S. D.; Ley, S. V. A Facile Route to
Imidazol-4-yl Anions and Their Reactions with Carbonyl Com-
pounds. J . Org. Chem. 1991, 56, 5739-5740.
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Bis(trifluoroacetoxy)-borane as a Reducing Agent of Organic
Compounds. J . Org. Chem. 1981, 46, 355-360.
(10) Maryanoff, B. E.; McComsey, D. F. Borane complexes in Trif-
luoroacetic acid. Reduction of Indoles and generation of Bis-
(trifluoroacetoxy)borane. J . Org. Chem. 1978, 43, 2733-2735.
(11) Gribble, G. W.; Leese, R. M.; Evans, B. E. Reactions of Sodium
Borohydride in Acidic Media: VI. Reduction of Diarylmethanols
in Trifluoroacetic Acid. Synthesis 1977, 172.
(12) Olah, G. A.; Wang, Q.; Prakash, G. K. Ionic Hydrogenation with
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(13) Simmons, H. E.; Smith, R. D. J . Am. Chem. Soc. 1958, 80, 5323.
(14) The S enantiomer was chosen for modeling purposes; however
we were unable to determine the absolute configuration of this
compound.
(15) Munson, P. J .; Rodbard, D. LIGAND: A Versatile Computerized
Approach for Characterization of Ligand-Binding Systems. Anal.
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Su p p or tin g In for m a tion Ava ila ble: Analytical data.
This material is available free of charge via the Internet at
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