α2 Adrenoceptor agonists as potential analgesic agents. 1. (Imidazolylmethyl)oxazoles and -thiazoles

Article abstract of DOI:10.1021/jm990005a

A series of (imidazolylmethyl)oxazoles and -thiazoles were prepared and evaluated as α₂ adrenoceptor agonists. These compounds were also tested in in vivo paradigms that are predictive of analgesic activity. Variations in both the imidazole and thiazole portions of the molecule were investigated. Some of the more potent compounds such as 22, 26, 45, and 53 displayed α₂ receptor binding in the 10-20 nM range and also had significant antinociceptive activity in the mouse abdominal irritant test (MAIT).

Full text of DOI:10.1021/jm990005a

5064
J . Med. Chem. 1999, 42, 5064-5071
Articles
r2 Ad r en ocep tor Agon ists a s P oten tia l An a lgesic Agen ts. 1.
(Im id a zolylm eth yl)oxa zoles a n d -th ia zoles
Robert E. Boyd,* J effery B. Press,† C. Royce Rasmussen, Robert B. Raffa,‡ Ellen E. Codd, Charlene D. Connelly,
Debra J . Bennett, Alex L. Kirifides, J oseph F. Gardocki, Brian Reynolds, J ohn T. Hortenstein, and
Allen B. Reitz
Drug Discovery Division, The R. W. J ohnson Pharmaceutical Research Institute, Welsh and McKean Roads,
Spring House, Pennsylvania 19477
Received J anuary 4, 1999
A series of (imidazolylmethyl)oxazoles and -thiazoles were prepared and evaluated as R2
adrenoceptor agonists. These compounds were also tested in in vivo paradigms that are
predictive of analgesic activity. Variations in both the imidazole and thiazole portions of the
molecule were investigated. Some of the more potent compounds such as 22, 26, 45, and 53
displayed R2 receptor binding in the 10-20 nM range and also had significant antinociceptive
activity in the mouse abdominal irritant test (MAIT).
In tr od u ction
Unrelieved pain continues to be a medical problem
and, hence, research on new analgesic agents occupies
a prominent position in the pharmaceutical industry.
The design of compounds that interact with receptors
that mediate the effects of opioids (morphine-like com-
pounds) represents one approach. Another is the design
of compounds directed at nonopioid receptor mecha-
nisms. Compounds that act as agonists at R2-adreno-
S
ceptors for which norepinephrine (1) is the endogenous
ligand produce antinociception in animals (and analge-
sia in humans1) with reduced risk of the abuse liability
or side effects typically associated with opioids.2 Re-
cently developed compounds such as medetomidine (2)
been prompted by the results of in vivo and in vitro
and the more potent (+)-enantiomer dexmedetomidine
studies.8 All of the adrenoceptors are members of the
seven-transmembrane G protein-coupled superfamily
and mediate their effects, including antinociception,
through a variety of second messenger systems, includ-
ing adenylate cyclase and phosphatidyl inositide path-
ways.9 Pertussis toxin, which ADP-ribosylates a Cys
residue in the R subunit of Gi proteins, attenuates R2-
adrenoceptor-induced antinociception.10 In addition, R2-
adrenoceptor agonists increase membrane conductance
of K+ (a mechanism that might result in inhibition of
neurotransmitter release), and in vivo studies have
demonstrated that glibenclamide (a blocker of ATP-
dependent K+ channels) antagonizes the antinociception
induced by R2-adrenoceptor agonists.11 It has been
proposed that R2-adrenoceptor-mediated antinociception
might result from the inhibition of release of primary
afferent neurotransmitters (e.g., substance P and
glutamate) at synapses within the spinal cord. The
association of antinociception with R2-adrenoceptors has
been demonstrated in vivo by Takano and Yaksh,12 who
reported that clonidine- and dexmedetomidine-induced
antinociception in rats was antagonized by the R2-
adrenoceptor antagonists idazoxan, yohimbine, and
(3) have been shown to have analgesic effects.3 These
compounds bind with high affinity to the R2-adrenergic
receptor and are very potent in a number of in vivo
analgesic paradigms. However, a number of unwanted
side effects such as sedation, have limited the usefulness
of these compounds.
There has recently been some indication that adren-
ergic receptor subtype selectivity may be key in the
separation of side effects from analgesia.4 Adrenoceptors
were first recognized by Ahlquist as divided into two
types (designated as R and â), based on different rank
orders of potency for a series of adrenergic compounds
in different physiological functions.5 The â-adrenoceptor
category subsequently has been subdivided further and
subtype-selective agents became clinically useful as
antihypertensives (â1 blockers, such as metoprolol) and
in asthma therapy (â2 agonists, such as terbutaline).6
Subtypes of R-adrenoceptors were identified in 1974 and
were designated R1 and R2.7 Further subdivision has
† Present address: Galenica Pharmaceutical, 30 West Patrick St.,
Suite 310, Frederick, MD 21701.
‡ Present address: Temple University, Philadelphia, PA.
10.1021/jm990005a CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/01/1999

R2 Adrenoceptor Agonists as Potential Analgesics
Ta ble 1. Chemical Data for Amidoketones
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25 5065
entry
R1
R2
recrys. sol.a
% yield
formula
C9H13N3O2
C11H17N3O2
C13H21N3O2‚HNO3
C13H21N3O2
mp (°C)
5
6
7
8
9
11
12
13
14
15
16
17
Me
Et
n-Pr
i-Pr
n-Bu
Et
Et
Et
Et
Me
Et
Acn
Ac
Ac
EA
Acn
27b
53b
53b,c
38
141-144
112.5-113.5
99.5-100.5
135.5-137.5
107-109.5
n-Pr
i-Pr
n-Bu
Me
n-Pr
i-Pr
CF3
Et
53b
71
53
67
13
57
25
48
C15H25N3O2
d
C
10H15N3O2
C12H19N3O2
12H19N3O2
C10H12F3N3O2
Ac/EA
Ac
Ac/Et
107-108
146-147
122.5-123.5
C
d
Me
n-Pr
i-Pr
C
10H15N3O2
C12H19N3O2
12H19N3O2‚HNO3
Et
Et
Ac/Et
Ac
120-122
117-118
C
a
b
Solvents: Ac ) acetone; Acn ) acetonitrile; EA ) ethyl acetate; Et ) diethyl ether. No DMAP used in reaction. c Product isolated
d
as HNO3 salt. Products were difficult to purify and were therefore carried on directly to the next step.
Sch em e 1a
atipamezole but not by the R1-adrenoceptor antagonist
prazosin. The R2-adrenoceptors are further subdivided
into R2A (gene/chromosome ADRA2A/10q2325; also des-
ignated R2-C-10), R2B (ADRA2A/2; R2-C-2) and R2C
(ADRA2A/4; R2-C-4). The R2A subtype has relatively low
affinity for prazosin and for ARC-239 2-[2-[4-(2-meth-
oxyphenyl)-1-piperazinyl]ethyl]-4,4-dimethyl-1,3(2H,4H)-
isoquinolinedione, whereas R2B and R2C subtypes have
relatively high affinity for prazosin and ARC-239.
Species variation gives rise to R2A subtype orthologues.
The R2D receptor is a rat orthologue of the human R2A
adrenoceptor. Millan and colleagues13 have further
suggested that the R2A/D subtype is primarily responsible
a
Reagents: (i) (R1CO)2O, R1CO2H, DMAP. (ii) (R1CO)2O or
for the antinociceptive effect, and genetically modified
mice lacking functional R2A/D receptor are not responsive
to R2-agonist-mediated analgesia. A “hit and run” gene
targeting model also suggests that the relevant subtype
POCl3 (X ) O); Lawesson’s reagent: (X ) S). (iii) 6 N HCl. (iv)
(R2CO)2O, NEt3.
Sch em e 2a
that mediates the antinociceptive response is the R2A/D
-
adrenoceptor subtype.14
In this paper we describe the synthesis of a number
of imidazole compounds and the evaluation of selected
compounds for analgesic activity. A number of dialkyl
thiazole analogues were effective in a broad range of
antinociceptive paradigms and far less sedating in dogs
than the other compounds tested.
Ch em istr y
The initial targets in this series were prepared as
shown in Scheme 1.15 Reaction of histidine (4) with an
acid anhydride in the presence of a base16 afforded the
desired amidoketones (5-9; Table 1). Cyclization of
these intermediates was carried out with the appropri-
ate anhydride to give the symmetrically substituted
oxazoles 18-20. Compound 20 was isolated directly
from the Dakin-West reaction mixture. The correspond-
ing thiazoles 21-25 were obtained by cyclization of the
amidoketone with Lawesson’s reagent in refluxing
CHCl3 or toluene.
a
Reagents: (i) NaNO2, HCl. (ii) H2, (R2CO)2O. (iii) P4S10. (iv)
6N HCl. (v) SOCl2, HNMe(OMe). (vi) MeMgBr or BnMgBr. (vii)
Pd(OH)2, H2.
presence of NEt3 to afford unsymmetrical amidoketones
11-17. These amidoketones were cyclized with Lawes-
son’s reagent to afford thiazoles 26-31.
Targets with unsymmetrical alkyl substitution were
prepared by acid hydrolysis of the amidoketone to give
aminoketone 10. These compounds were often difficult
to isolate and purify and therefore were taken without
purification and treated with an acid anhydride in the
An alternate route that allowed for the incorporation
of alkyl substitution at the methylene bridge is shown
in Scheme 2. Nitrosation of â-ketoester 34 followed by
catalytic reduction of the oxime in the presence of an
acid anhydride gave amidoketoester 35. This was cy-

5066 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Boyd et al.
Sch em e 3a
Sch em e 5a
a
Reagents (i) 3N NaOH; H+. (ii) CDI, HNMe(OMe) or (COCl)2,
a
Reagents: (i) NaH, DMF. (ii) 6 N HCl. (iii) (EtCO)2O, EtCO2H,
HNMe(OMe). (iii) MeOH/HCl. (iv) NaBH4. (v) R3MgBr. (vi) HCl,
Pd(OH)2, H2.
pyridine, DMAP. (iv) NaH, 63e or 63f. (v) H2/Pd(OH)2. (vi) P4S10
.
Sch em e 4a
The synthesis of the requisite regiospecific R-bromoke-
tones has recently been reported from this laboratory.21
Benzothiazole 62 was prepared, albeit in low yield, from
imidazolylacetonitrile and 2-aminothiophenol.
Finally, we wanted to explore variations in the
imidazole portion of the molecule. The synthesis of these
compounds is shown in Scheme 5. The first approach
was to prepare the appropriate histidine analogue such
as 65a ,22 followed by a Dakin-West reaction to provide
the requisite amidoketone. Yields of these intermedi-
ates, however, were quite poor and an alternative route
was explored. The anion of ketoamide 66 was alkylated
with a benzyl-protected heteroarylmethyl chloride to
furnish the protected amidoketone. Debenzylation of
these compounds was accomplished by catalytic hydro-
genation with Pearlman’s catalyst [Pd(OH)2]. Finally,
the target compounds were obtained by cyclization of
these intermediates to thiazoles as previously described.
a
Reagents: (i) HCl, MeCSNH2.
clized with P4S10 to give thiazole ester 36 in good yield.
Hydrolysis of 36 afforded the carboxylic acid, which was
quite insoluble in organic solvents. Consequently the
reaction with carbonyldiimidazole (CDI) and N,O-di-
methylhydroxylamine gave only a modest yield of Wein-
reb amide 37. Addition of 37 to the Grignard reagent
prepared from N-trityl-4-iodoimidazole17 (38) afforded
a good yield of 39. Branched compounds such as 32 and
33 were obtained by addition of a Grignard reagent to
give the tertiary carbinol, followed by hydrogenation
with Pearlman’s catalyst [Pd(OH)2].
To further explore the SAR of these compounds, the
5-thiazole and 2-thiazole isomers were prepared as
shown in Schemes 3 and 4, respectively. The synthesis
of 5-thiazolecarboxylates has been documented in the
literature.18 Accordingly, 2-chloroketoester 40 and thio-
amide 41 were reacted in EtOH to give thiazole ester
42. Conversion to the Weinreb amide 43 and addition
of the imidazole Grignard reagent 38 afforded the
tritylated imidazole ketone 44. After removal of the
trityl protecting group with HCl/MeOH, these ketones
were reduced in a two-step process of NaBH4 in reflux-
ing 2-PrOH, followed by catalytic hydrogenation to give
the unsubstituted methylene compounds. Alternatively,
the addition of a Grignard reagent to 44, followed by
reduction and deprotection, afforded targets that were
substituted on the methylene bridge. The 2-thiazole
targets were prepared from imidazolylacetonitrile 5019
that was converted to thioamide 51 by reaction with HCl
and thioacetamide in DMF.20 Cyclization of this thio-
amide with an R-bromoketone 52 gave the 2-thiazolyl
targets 53-60, although the yields were quite variable.
Biologica l Resu lts a n d Discu ssion
Following the identification of the initial lead struc-
ture, diethyloxazole 19, a number of other oxazole and
thiazole analogues were prepared and evaluated in the
rat R2A/D radioligand binding assay (Table 2). Evaluation
in vivo was based on the fact that R2-adrenoceptor
agonists are known to produce potent, dose-dependent
analgesia in a variety of tests across species.23 The
mouse abdominal irritant test (MAIT) was selected for
the present study because it is well established as a
model sensitive to spinal, supraspinal,24 and peripher-
ally25 mediated adrenergic antinociception. The results
of this testing are also shown in Table 2. The antino-
ciceptive activity of several of the novel compounds
shown is blocked by preadministration of the R2-adreno-
ceptor antagonist idazoxan (data not shown), supporting
adrenergic mediation of the antinociception observed.
The data reveal that the thiazoles generally bind to
the R2-adrenoceptor with higher affinity than the cor-
responding oxazoles. For example, thiazoles 22 and 24
had 2-3-fold higher affinities than oxazoles 19 and 20.
For this reason, additional targets were designed to
focus on the thiazole moiety.
Longer chain alkyl groups, such as in the di-n-Pr and
di-n-Bu thiazoles (23 and 25, respectively), resulted in
a modest reduction in R2A/D binding. The di-i-Pr side
chain compound 24 had a more dramatic effect on this

R2 Adrenoceptor Agonists as Potential Analgesics
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25 5067
Ta ble 2. Chemical and Biological Data for (Imidazolylmethyl)oxazoles and -thiazoles
recrys.
R2A/D KIb
(nM)
MAIT
compd
R1
R2
R3
X
% yield
sol.a
formula
mp
(ED50)c mpk
18d
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
45
46
47
48
49
53
54
55
55
57
58
59
60
62
3
Me
Et
i-Pr
Me
Et
n-Pr
i-Pr
n-Bu
Et
Me
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Bn
H
Me
Ph
H
Me
H
H
H
H
H
H
O
O
O
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
>1000
58
>30
60
42e
39
48
57
46
53c
37
52d
21
49
20g
55g
42
18
76
42
5
36
10
66
23
59
33
44
3
Ac
Acn
Ac
C
11H15N3O‚HCl‚H2O
79-81
130-131
163-164
102-103
84-85
2.8 (2.0, 3.8)
6.9 (3.5, 14.7)
i-Pr
Me
EtÅ
n-Pr
i-Pr
n-Bu
Me
i-Pr
Et
Et
CF3
Ph
Et
Et
C13H19N3O‚HNO3
C9H11N3S‚1.5C4H4O4
C
C
C
C15H23N3S‚2HNO3
C
C12H17N3O‚HNO3
C
C
714
38
17
97
285
35
10
28
57
235
320
13
407
37
8
60
269
23
97
11
18
18
86
36
381
28
110
18
0.015
f
>30
Ac
11H15N3S‚HNO3
13H19N3S‚HNO3
13H19N3S‚HNO3
1.8 (1.3, 3.1)
EA/Ac
Ac/Et
Ac/Et
Ac
Ac/Et
Et
Ac/Et
Ac/Et
Acn
Ac
Acn
Acn
Acn
Et
30.0 (15.3, 48.9)
23.8 (23.8, 155.9)
136-137
88-89
>30
10H13N3S
145-146
118.5-119
86-87
2.3 (1.1, 4.1)
7.5 (4.9, 10.4)
Et
Me
i-Pr
Et
Et
Et
10H13N3S
>30
12H17N3O‚HNO3
112-114
140.5-141
202-204
139-141
185-188
201-203
194-196
169-171
139-141
94-97
188-200
154-157
90-98
109-111
133-134
90-95
25.3 (12.7, 46.4)
20.3 (9.8, 35.5)
15.0 (8.8, 25.2)
16.0 (8.8, 40.0)
h
C10H10F3N3S‚HNO3
C15H15N3S‚HCl
C
C
12H17N3S‚C4H4O4
18H21N3S‚HCl
Et
>30
1.0 (0.6, 1.5)
>30
>30
>30
>30
1.7 (1.1, 2.4)
>30
2.8 (1.8, 3.8)
Me
Me
Me
Et
Et
Me
Et
Me
Et
Et
Me
Me
Me
Et
C9H11N3S‚HCli
C
C
C
C
10H13N3S‚HCl
15H15N3S
11H15N3S‚HCl
12H17N3S‚C4H4O4‚0.5H2O
Ac
Et
EA
Acn
Ac
Ac
Ac
Ac
Ac
Ac
IP
Me
Me
Et
Et
H
C9H11N3S‚1.3HCl‚0.3H2O
C
C
C
10H13N3S‚1.5C4H4O4
10H13N3S‚HCl‚H2O
11H15N3S‚C4H4O4
>30
>30
>30
>30
>30
>30
C9H11N3S‚C4H4O4
H
Et
C9H11N3S‚C4H4O4‚0.25H2Oj
k
-(CH2)3-
-(CH2)4-
-(CH)4-
H
H
H
33
10
11
C10H11N3S‚1.5C4H4O4
168-170
169-171
186-187
C11H13N3S‚1.5C4H4O4
C11H9N3S‚1.5C4H4O4
Ac
0.09
a
b
Solvents; see Table 1. IP is isopropanol. Ki values are determined in duplicate and generally agree within 10%. c Values expressed
d
are ED50 (95% confidence limit). Compounds with <50% inhibition at the screening dose of 30 mpk are recorded as >30. Reference 15.
e Isolated from Dakin-West reaction. f N, Calcd, 11.44; Found, 11.90. g Toluene used as solvent. N, Calcd, 17.28; Found, 17.78. H, Calcd,
h
i
j
k
4.83; Found, 5.25. N, Calcd, 13.39; Found, 12.95. N, Calcd, 4.52; Found, 4.10.
binding, and all three analogues had significantly less
in vivo activity than the diethyl compound. It would also
appear from these data that R1 ) Et is a key element
of the R2 pharmacophore. For example, when the R1
group is Et, substitution of Me or i-Pr for R2 (com-
pounds 26 and 27) has only minor effects on in vitro
and in vivo activity. The reverse situation (compounds
28 and 29), in which R2 ) Et and R1 is Me or i-Pr,
resulted in a more dramatic decrease in binding and
biological activity. The substitution of an electron-
withdrawing group such as CF3 or a phenyl group at
the R2 position, such as in 30 and 31, respectively,
significantly diminishes MAIT activity. There is also a
significant decrease in MAIT activity for compounds 32
and 33 in which the methylene bridge is substituted
with Me or Bn.
The orientation of the thiazole ring appears to be
moderately important for biological activity. In the
5-thiazole series, for example, the dimethyl analogue 45
has good in vivo activity, while the diethyl thiazole 48
has very little antinociceptive activity. This contrasts
with the 4-thiazole series, in which the diethyl com-
pound was the most potent analogue. Once again for
this series, any substitution on the methylene bridge
such as compounds 46, 47, and 49 results is a significant
loss of biological activity. It is also noteworthy that most
of the compounds in the 2-thiazole series had little or
no antinociceptive activity despite their high affinity for
the R2A/D adrenoceptor. The MAIT activity of compounds
53 and 55 would seem to indicate that R1 ) Me is a
necessary criterion for the pharmacophore, and any
variation in R1, such as either H or Et (54, 57, and 58),
resulted in a significant loss of activity, R2A/D binding,
or both. It is also noteworthy that incorporation of these
alkyl groups into a five- or six-membered ring (59, 60,
and 62) also results in loss of antinociceptive activity.
Moreover, in vivo studies with several of these com-
pounds (e.g., 57, 59, 60, and 62) revealed that they
attenuate the antinociceptive action of the R2-adrenergic
agonist clonidine (data not shown), suggesting their
antagonist function.
Finally, the importance of the imidazole portion of the
molecule was investigated. The thiazole portion was
held constant as the 2,5-diethylthiazol-4-yl and the
methylene bridge was unsubstituted. These results are
shown in Table 3. It can be seen from these data that
any variation in this portion of the molecule results in

5068 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Ta ble 3. Chemical and Biological Data for Imidazole Isosteres
Boyd et al.
1
solid. H NMR δ (CDCl3) 0.85 (t, 3H), 0.95 (t, 3H), 2.0 (s, 3H),
2.1 (m, 2H), 2.3 (m, 2H), 2.75 (m, 2H), 4.4 (q, 1H), 7.4 (s, 1H),
8.15 (d, 1H), 11.7 (br s, 1H). Anal. (C12H19N3O2) C, H, N. C:
Calcd, 60.74; Found, 59.73.
2-Am in o-1-(1H -im id a zol-4-yl)p en t a n -3-on e Dih yd r o-
ch lor id e (10). A solution of 6 (19.5 g, 0.1 mol) in 6 N HCl (35
mL) was heated at reflux for 90 min. The solvent was
evaporated in vacuo and the residue was triturated with
acetone and then 2-PrOH to give an off-white solid (R1 ) Et;
3.8 g, 79%), which was pure enough to be used without further
purification. 1H NMR (DMSO-d6) δ 1.0 (t, 3H), 2.7 (m, 2H),
3.2 (m, 1H), 3.4 (m, 1H), 4.6 (m, 1H), 7.5 (s, 1H), 8.6 (br s,
2H), 9.1 (s, 1H), 14.5 (br s, 1H).
%
R2A/D Ki MAIT
entry yield
formula
mp (°C)
(nM)
(ED50)
68a
68b
68c
68d
14
12
24
7
C
C
C
C
12H17N3S‚HNO3
10H14N4S‚HNO3
10H14N4S
125.5-127
53
102-104 >1000
>30
>30
>30
63.5-65
153-155 >1000
>1000
11H15N3S‚C4H4O4
a drastic reduction in receptor binding and antino-
ciceptive activity.
Con clu sion
N-[1-(1H -Im id a zol-4-yl)-3-oxo-2-p en t yl]-2-m et h ylp r o-
p a n a m id e (13). To a mixture of aminoketone 10 (R1 ) Et)
(3.6 g, 15 mmol) and butyric anhydride (9.5 g, 60 mmol) in
CHCl3 (40 mL) was added NEt3 (4.0 g, 40.0 mmol) in CHCl3
(10 mL). The mixture was stirred for 2 h at room temperature
and then poured into ice-water and stirred for 2 h to
decompose the excess anhydride. The aqueous solution was
basified with Na2CO3 and extracted with CHCl3. The extracts
were combined and dried over K2CO3. The solution was filtered
and the solvent was evaporated in vacuo to give a crude solid,
which was recrystallized from acetone to give the title com-
We have prepared and evaluated a series of (imid-
azolylmethyl)oxazoles and -thiazoles. Several of these
compounds possess significant R2A/D adrenoceptor bind-
ing affinity and in vivo antinociceptive activity in mice.
The importance of the 4-imidazole moiety has been
clearly demonstrated and only small alkyl side chains
are permitted in order to maintain biological activity.
In particular, compounds 22, 26, 45, and 53 were
efficacious in an animal model predictive of analgesic
activity. While some safety issues precluded the devel-
opment of any of these compounds as a clinical candi-
date, we were encouraged to pursue other structural
types in this general area and the results of these
studies will be reported in due course.
1
pound (2.4 g, 67%) as an off-white solid. H NMR (DMSO-d6)
δ 0.9 (m, 3H), 1.0 (m, 6H), 2.45 (m, 3H), 2.8 (m, 1H), 2.9 (m,
1H), 4.45 (q, 1H), 6.8 (s, 1H), 7.55 (s, 1H), 8.2 (d, 1H), 11.85
(br s, 1H). Anal. (C12H19N3O2) C, H, N.
N-[1-[1-Ben zyl-1,2,3-(1H)-tr ia zol-5-yl]-3-oxo-2-p en tyl]-
p r op a n a m id e (67e). NaH (80% mineral oil, 6.75 g, 0.225 mol)
was washed with hexane (2×) and then suspended in DMF
(200 mL) and cooled to -20 °C in an ice/salt/water bath. To
this was added ketoamide 66 (32.1 g, 0.225 mol) in portions,
with the temperature maintained below 5 °C. The mixture was
stirred for an additional 30 min, and then a solution of 63e
(22.3 g, 0.09 mol) in DMF (100 mL) was added dropwise and
the reaction was allowed to stir and slowly warm to room
temperature overnight. Most of the DMF was evaporated in
vacuo (40-50 °C), and the residue was dissolved in dilute HCl
and washed with Et2O (2×). The solution was made basic and
extracted with EtOAc (2×). The extracts were combined and
dried over K2CO3. The solution was filtered and the solvent
was evaporated in vacuo. The residue was chromatographed
on silica (CHCl3/MeOH/NH4OH 98/1.8/0.2) and the residue was
recrystallized from acetone/Et2O to give the title compound
(7.4 g, 26%) as a white solid, mp 95.5-97 °C. 1H NMR (DMSO-
d6) δ 1.0 (t, 3H), 1.1 (t, 3H), 2.25 (m, 2H), 2.55 (m, 2H), 3.15
(m, 2H), 4.8 (q, 1H), 5.5 (s, 2H), 6.85 (d, 1H), 7.3 (m, 6H). Anal.
(C17H22N4O2) C, H, N. N: Calcd, 17.82; Found, 18.26.
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 analysis were within 0.4% of the
calculated value, except where indicated. Et2O‚NHO3 is pre-
pared by adding a few drops of concentrated nitric acid to
diethyl ether.
Gen er a l P r oced u r es for t h e Syn t h esis of Am id o-
k eton es: N-[1-(1H-Im id a zol-4-yl)-3-oxo-4-m eth yl-2-p en -
tyl]-2-m eth ylp r op a n a m id e (8). A mixture of histidine hy-
drochloride hydrate (10.5 g, 0.05 mol), anhydrous sodium
isobutyrate (8.3 g, 0.075 mol), isobutyric anhydride (55.4 g,
0.35 mol), and 0.1 g of (dimethylamino)pyridine (DMAP) was
heated at 115-120 °C for 4 h. The mixture was cooled in an
ice bath and diluted with Et2O (300 mL). The organic layer
was extracted with 3 N HCl (3×) and then water. The
combined aqueous layers were washed once with Et2O and
then made basic with cold NaOH and extracted with CHCl3
(3×). The extracts were combined, dried over K2CO3, and
filtered and the solvent was evaporated in vacuo. The residue
was recrystallized from EtOAc to give the title compound as
N -[1-(1H -1,2,3-Tr ia zol-4-yl)-3-oxo-2-p e n t yl]p r op a n -
a m id e (67c). To a solution of 67e (7.3 g, 23 mmol) in MeOH
(50 mL) was added Pd(OH)2 (1.5 g) and the mixture was
hydrogenated at 50 °C and 55 psi until H2 uptake had stopped.
The solution was filtered through dicalite and the solvent was
evaporated in vacuo. The residue was recrystallized from Et2O
to give the title compound (3.4 g, 67%) as a white solid, mp
1
1
82.5-84 °C. H NMR (CDCl3) δ 1.05 (t, 3H), 1.15 (t, 3H), 2.25
a free base (4.8 g. 38%). H NMR (DMSO-d6) δ 0.95 (m, 12H),
(q, 2H), 2.6 (m, 2H), 3.2 (m, 2H), 4.95 (q, 1H), 6.75 (br s, 1H),
7.5 (s, 1H), 12.85 (br s, 1H). Anal. (C10H16N4O2) C, H, N. H:
Calcd, 7.19; Found, 7.70.
2.4 (m, 1H), 2.8 (m, 2H), 2.95 (m, 1H), 4.7 (m, 1H), 6.75 (s,
1H), 7.55 (s, 1H), 8.15 (d, 1H), 11.8 (br s, 1H). Anal. (C13H21N3O2)
C, H, N.
Gen er a l P r oced u r es for th e Syn th esis of 4-Oxa zoles
a n d 4-Th ia zoles: 4-[(2,5-Dieth yloxa zol-4-yl)m eth yl]-1H-
im id a zole Hyd r och lor id e Hyd r a te (19). Amidoketone 9 (6.7
g, 30.0 mmol) was converted to the HCl salt and then heated
at reflux in propionic anhydride (25 mL) for 90 min. The
mixture was cooled and diluted with Et2O and the crude
product was collected by filtration. The residue was recrystal-
lized from 1% aqueous acetone to give the title compound (4.7
g, 60%) as a white solid. 1H NMR (DMSO-d6) δ 1.2 (m, 6H),
2.7 (m, 4H), 3.85 (s, 2H), 7.4 (s, 1H), 9.0 (s, 1H), 14.5 (br s,
1H). Anal. (C11H15N3O‚HCl‚H2O) C, H, N.
N-[1-(5-Met h yl-1H -im id a zol-4-yl)-3-oxo-2-p en t yl]p r o-
p a n a m id e (67a ). A mixture of 5-methylhistidine (15.0 g, 58
mmol), NEt3 (30 mL), propionic anhydride (30 mL), and DMAP
(0.15 g) was heated in an oil bath at 90-100 °C. After the
vigorous reaction and CO2 evolution had subsided, the mixture
was heated for an additional 1 h at 100 °C and then cooled to
room temperature. Propionic anhydride (50 mL) was added
and the mixture was stirred at room temperature for 1 h and
then was evaporated in vacuo. The residue was dissolved in 3
N NaOH and extracted with CHCl3 (3×). The combined
extracts were washed with dilute NaOH and water and then
dried over Na2SO4. The solution was filtered, the solvent was
evaporated in vacuo, and the residue was recrystallized from
EtOAc to give the title compound (5.0 g, 36%) as a light yellow
4-[[2,5-Di(1-m eth yleth yl)th ia zol-4-yl]m eth yl]-1H-im id -
a zole Nitr a te (24). A solution of 8 (3.77 g, 15.0 mmol) and
Lawesson’s reagent (9.1 g, 22.5 mmol) in CHCl3 (100 mL) was

R2 Adrenoceptor Agonists as Potential Analgesics
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25 5069
heated at reflux overnight. The reaction mixture was cooled
and then extracted with dilute HCl (2×) and then water (1×),
and the aqueous extracts were combined and washed with
Et2O. The solution was then basified and extracted with Et2O
(2×). The organic extracts were combined, dried over K2CO3,
and filtered and the solvent was evaporated in vacuo. The
residue was dissolved in EtOAc and treated with Et2O‚HNO3.
The solid was collected and recrystallized from acetone to give
the title compound (2.2 g, 46%) as an off-white solid. 1H NMR
(DMSO-d6) δ 1.2 (m, 6H),1.35 (d, 6H), 3.2 (m, 2H), 4.1 (s, 2H),
7.0 (s, 1H), 8.6 (s, 1H). Anal. (C13H19N3S‚HNO3) C, H, N.
4-[(2,5-Dim eth ylth iazol-4-yl)m eth yl]-5-m eth yl-1H-im id-
a zole Nitr a te (68a ). A mixture of amidoketone 67a (3.5 g,
15 mmol) and P4S10 (6.5 g, 15 mmol) in CHCl3 (50 mL) was
heated at reflux for 3 h. The reaction mixture was diluted with
Et2O and dilute NaOH. The aqueous layer was extracted with
two additional portions of Et2O. The organic layers were
combined, washed sequentially with dilute NaOH and brine,
and then dried over K2CO3. The solution was filtered and the
solvent was evaporated in vacuo. The residue was chromato-
graphed on silica (EtOAc/MeOH/NH4OH 98/2/2) to give the
crude product. The residue was dissolved in EtOAc and treated
with Et2O‚HNO3. A white solid was filtered and recrystallized
from acetone to give the title compound (0.64 g, 14%) as a white
solid. 1H NMR (DMSO-d6) δ 1.15-1.3 (2t, 6H), 2.2 (s, 3H), 2.85
(m, 4H), 3.95 (s, 2H), 8.85 (s, 1H), 13.9 (br s, 2H). Anal.
(C12H17N3S‚HNO3) C, H, N.
3-[(2,5-Diethylthiazol-4-yl)methyl]-1H-1,2,4-triazole Mono-
n itr a te (68b). A solution of 67b (3.4 g, 15 mmol) and
Lawesson’s reagent (7.1 g, 17.5 mmol) in toluene (100 mL) was
heated at reflux overnight (14 h). The reaction mixture was
diluted with EtOAc and extracted with dilute HCl (3×). These
extracts were basified with solid Na2CO3 and extracted with
Et2O (2×). The combined extracts were dried over K2CO3 and
filtered, and the solvent was evaporated in vacuo. The residue
was chromatographed on silica (98/1/1 EtOAc/MeOH/NH4OH)
to give a residue that was dissolved in MeCN and treated with
Et2O‚HNO3. The solid was collected by filtration and recrystal-
lized from MeCN to afford 42 (0.50 g, 12%) as fine white
needles. 1H NMR (DMSO-d6) δ 1.25 (m, 6H), 2.85 (m, 4H), 4.3
(s, 2H), 8.95 (s, 1H). Anal. (C10H14N4S‚HNO3) C, H, N.
Eth yl 2,5-Dim eth ylth ia zole-4-ca r boxyla te (36). A mix-
ture of 35 (31.5 g, 0.146 mol) and P4S10 (16.3 g, 0.073 mol) in
toluene (200 mL) was heated in an oil bath at 50-60 °C until
the starting material had been consumed as judged by TLC.
The reaction mixture was diluted with EtOAc and water. The
aqueous layer was extracted with a second portion of EtOAc,
and the combined organic extracts were dried over MgSO4 and
filtered and the solvent was evaporated in vacuo. Chromatog-
raphy on silica (3/1 hexane/Et2O) afforded the title compound
(23.3 g, 75%) as an orange oil. 1H NMR (CDCl3) δ 1.4 (m, 9H),
3.05 (q, 2H), 3.25 (q, 2H), 4.45 (q, 2H). Anal. (C10H15NO2S) C,
H, N.
hydroxylamine hydrochloride (24.4 g, 250 mmol) and NEt3
(25.3 g, 250 mmol) in DMF (75 mL). The reaction was allowed
to stir overnight at room temperature, and then diluted with
water and extracted with Et2O (4×). The combined extracts
were washed with (3) small portions of water and then brine
and then dried over MgSO4. The solution was filtered and the
solvent was evaporated to give a viscous oil, which was
chromatographed on silica (4/1 hexane/Et2O) to afford the title
1
compound (4.7 g, 41%) as a pale yellow oil. H NMR (CDCl3)
δ 1.3 (2t, 6H), 3.0 (q, 4H), 3.35 (s, 3H), 3.8 (s, 3H). Anal.
(C10H16N2O2S) C, H, N. C: Calcd, 52.61; Found, 53.30. N:
Calcd, 12.27; Found, 11.70.
N-Met h yl-N-m et h oxy-2,4-d im et h ylt h ia zole-5-ca r b ox-
a m id e (43a ). A mixture of 42a as the HCl salt (104.0 g, 0.47
mol) and 500 mL of 3 N NaOH was stirred overnight at room
temperature. The solution was acidified with concentrated HCl
and a white solid was filtered, air-dried, and then recrystal-
lized from acetone. A portion of this material (15.7 g, 0.1 mol)
was combined with CDI (24.3 g, 0.15 mol) in DMF (75 mL)
and stirred 3 h at room temperature. In a separate flask, NEt3
(84 mL, 0.6 mol) was added dropwise to a solution of N,O-
dimethylhydroxylamine hydrochloride (48.8 g, 0.5 mol) in DMF
(400 mL) cooled in an ice bath. To this cooled suspension was
added the activated carboxylic acid reagent prepared above.
The reaction was stirred at room temperature for 3 h. Most of
the DMF was evaporated in vacuo and the residue was diluted
with water and extracted with Et2O (3×). The combined
extracts were dried over MgSO4 and then filtered, and the
solvent was evaporated in vacuo. The residue was purified by
chromatography on silica (2/1 hexane/Et2O, then 1/1 hexane/
Et2O) to give the title compound as an orange oil. 1H NMR
(CDCl3) δ 2.7 (2t, 6H), 3.35 (s, 3H), 3.7 (s, 3H). Anal.
(C8H12N2O2S): C, H, N. C: Calcd, 47.98; Found, 47.52.
N -Me t h yl-N -m e t h oxy-2,4-d ie t h ylt h ia zole -5-ca r b ox-
a m id e (43b). A mixture of 42b (33.7 g, 0.158 mol) and 200
mL of 1 N NaOH was stirred overnight at room temperature.
The solution was acidified with concentrated HCl and a white
solid was filtered, air-dried, and then recrystallized from
acetone. This material was then converted to the sodium salt
with 1 N NaOH, the water was evaporated, and the salt was
dried under vacuum. To this salt was added 250 mL of
benzene, followed by oxalyl chloride (11.2 mL, 0.129 mol). The
reaction mixture was stirred for 2 h and then filtered, and the
solvent was evaporated in vacuo. The residue was dissolved
in CHCl3, and N,O-dimethylhydroxylamine hydrochloride was
added, and the reaction mixture was cooled in an ice bath. To
this was added NEt3 (43 mL, 0.31 mol) in CHCl3 (200 mL)
from a dropping funnel. The reaction was allowed to warm to
room temperature and stirred for 1 h. The mixture was
transferred to a separatory funnel and washed with water and
dilute HCl, and then dried over NaSO4. The solution was
filtered and the solvent was evaporated in vacuo, and the
residue was distilled on a Kugelrohr to give the title compound
1
(19.6 g, 64%) as a colorless oil. H NMR (CDCl3) δ 1.3 (t, 3H),
Eth yl 2,4-Dieth ylth ia zole-5-ca r boxyla te (42b). A solu-
tion of propionic thioamide (16.5 g, 0.185 mol) and ethyl-2-
chloro-3-oxopentanoate (33.1 g, 0.185 mol) in absolute EtOH
(200 mL) was stirred at room-temperature overnight. The
solvent was evaporated in vacuo and the residue was dissolved
in water and extracted with Et2O (3×). The combined extracts
were washed 2× with saturated NaHCO3 and dried over
MgSO4. The solution was filtered and the solvent was evapo-
rated in vacuo to give an oil. This material was distilled (0.75
mmHg/100-105 °C) to give the title compound (34.0 g, 86%)
as a pale yellow oil. 1H NMR (CDCl3) δ 1.35 (3t, 9H), 3.15 (2q,
4H), 4.3 (q, 2H). Anal. (C10H15NO2S) C, H, N.
Gen er a l P r oced u r es for t h e Syn t h esis of Wein r eb
Am id es: N-Meth yl-N-m eth oxy-2,5-d ieth ylth ia zole-4-ca r -
boxa m id e (37). A mixture of 36 (22.9 g, 0.107 mol) and 150
mL of 1 N NaOH was stirred overnight at room temperature.
The solution was acidified with concentrated HCl, and a white
solid was filtered and dried. To a suspension of this solid (9.3
g, 50 mmol) in DMF (75 mL) was added carbonyldiimidazole
(CDI) (12.2 g, 75 mmol). This mixture was stirred for 30 min
and then added in one portion to a mixture of N,O-dimethyl-
1.4 (t, 3H), 3.0 (2q, 4H), 3.35 (s, 3H), 3.7 (s, 3H). Anal.
(C10H16N2O2S) C, H, N.
Gen er a l P r oced u r e for th e Rea ction of Im id a zole
Gr ign a r d Rea gen ts w ith Th ia zole Ester s: 1-(Tr ip h en yl-
m eth yl)-1H-im id a zol-4-yl-(2,5-d ieth ylth ia zol-4-yl)m eth a -
n on e (39). To a solution of 1-(triphenylmethyl)-4-iodoimidazole
(10.9 g, 25 mmol) in CH2Cl2 (100 mL) under Ar was added 3.0
M EtMgBr in Et2O (8.5 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 37 (5.7 g, 25 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 yellow solid (8.6 g, 67%). 1H NMR (CDCl3) δ 1.2 (t, 3H),
1.3 (t, 3H), 2.8 (q, 2H), 3.3 (q, 2H), 7.25 (m, 15H), 7.45 (s, 1H),
8.4 (s, 1H). Anal. (C30H27N3OS) C, H, N.

5070 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Boyd et al.
Gen er a l P r oced u r e for th e Ad d ition of Gr ign a r d
Rea gen ts to Im id a zole Keton es: 4-[1-(2,5-Dieth ylth ia zol-
4-yl)-2-p h en yleth yl]-1H-im id a zole Hyd r och lor id e (33). To
a solution of 39 (2.3 g, 5.0 mmol) in dry THF (50 mL) was
added 2.0 M BnMgCl in THF (3.75 mL), and the reaction was
stirred at room temperature. After the starting material had
been consumed as judged by TLC, the reaction was quenched
with NH4Cl and extracted with EtOAc (2×). The combined
extracts were dried over Na2SO4 and filtered, and the solvent
was evaporated in vacuo. The residue was dissolved in MeOH,
1.0 N HCl (5.0 mL) was added, and the mixture was stirred
overnight at room temperature. The solvent was evaporated
in vacuo, and the residue was dissolved in water and washed
with Et2O (2×). The aqueous layer was basified with Na2CO3
and extracted with EtOAc. After drying over Na2SO4, the
solution was filtered and the solvent was evaporated in vacuo.
The residue was chromatographed on silica (96/3.6/0.4 CHCl3/
MeOH/NH4OH) to give the carbinol intermediate (0.93 g, 57%).
These compounds were often hydrates and difficult to fully
characterize and were generally taken on directly to the next
step. To a solution of the carbinol intermediate in EtOH was
added 1-1.25 equiv of HCl and Pearlman’s catalyst (1.0 g),
and the mixture was hydrogenated at 50 °C and 50 psi. After
the starting material had been consumed, the catalyst was
removed by filtration and the filtrate was evaporated in vacuo.
The residue was chromatographed on silica (97.5/2.25/0.25
CHCl3/MeOH/NH4OH). The appropriate fractions were com-
bined and the solvent was evaporated in vacuo. The residue
was dissolved in Et2O and treated with Et2O‚HCl, and the
crude salt was recrystallized from MeCN to give the title
heated at reflux. After the starting material had been con-
sumed as judged by TLC, the reaction mixture was cooled and
the crude product was collected by filtration. Flash chroma-
tography on silica (90/9/1 CHCl3/MeOH/NH4OH) yielded a
yellow oil (3.3 g, 66%), which was dissolved in MeCN and
treated with Et2O‚HCl. A white solid was collected and
recrystallized from MeCN to yield the title compound as a
mixture of C9H11N3S‚HCl and C9H11N3S‚2HCl‚H2O (7:3), as
judged by elemental analysis. 1H NMR (DMSO-d6) δ 2.3 (s,
3H), 2.35 (s, 3H), 4.4 (s, 2H), 4.8 (br s, 1H), 7.6 (s, 1H), 9.1 (s,
1H), 14.8 (br s, 1H). Anal. (C9H11N3S‚1.3 HCl‚0.3 H2O) C,H,N,
Cl,H2O(KF).
4-[(Ben zoth ia zol-2-yl)m eth yl]-1H-im id a zole F u m a r a te
2:3 (62). A solution of (imidazol-4-yl)acetonitrile (3.0 g, 28
mmol) and 2-aminobenzenethiol hydrochloride (5.0 g, 30 mmol)
in EtOH (75 mL) was heated at reflux overnight. The solvent
was evaporated in vacuo, and the residue was dissolved in 3
N HCl and washed with Et2O (2×). The aqueous layer was
basified with solid Na2CO3 and extracted with CHCl3 (2×). The
organic extracts were combined, dried over K2CO3, and filtered
and the solvent was evaporated in vacuo. The residue was
dissolved in acetone and treated with 1 equiv of fumaric acid,
which was dissolved in a minimum amount of 2-PrOH. The
solid was collected and recrystallized from acetone to give the
title compound as an off-white solid (1.27 g, 11%). 1H NMR
(DMSO-d6) δ 4.4 (s, 2H), 6.65 (s, 3H), 7.1 (s, 1H), 7.45 (2t, 2H),
7.7 (s, 1H), 8.0 (2d, 2H). Anal. (C11H9N3S‚1.5C4H4O4) 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 Laboratories, Kingston Facility, Stone Ridge, NY) were
sacrificed by cervical dislocation, and their brains were
removed and placed immediately in ice-cold HEPES-sucrose
(10 mM HEPES and 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-glass homog-
enizer. The homogenate was centrifuged at 1000g for 10 min,
and the resulting supernatant was 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 resuspended 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 nL
of cold 10 mM HEPES buffer (pH 7.5), the adhering radio-
activity was quantified by liquid scintillation spectrometry.
Da ta An a lysis. Data were analyzed with LIGAND, a
nonlinear curve-fitting program designed specifically for the
analysis of ligand binding data.26 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, with
each concentration run in triplicate. Replicate determinations
of the inhibition constants usually differed from each other
by less than 10%.
1
compound (0.17 g, 18%) as a white solid. H NMR (DMSO-d6)
δ 0.85 (t, 3H), 1.3 (t, 3H), 2.3 (m, 1H), 2.6 (m, 1H), 2.95 (q,
2H), 3.2 (m, 1H), 3.4 (m, 1H), 4.45 (q, 1H), 7.15 (m, 2H), 7.25
(m, 3H), 7.5 (s, 1H), 9.0 (s, 1H), 14.35 (br s, 1H). Anal.
(C18H21N3S‚HCl) C, H, N.
4-[(2,4-Dim eth ylth ia zol-5-yl)m eth yl]-1H-im id a zole Hy-
d r och lor id e (45). A mixture of NaBH4 (0.75 g, 20 mmol) and
44a (6.0 g, 13.3 mmol) in 2-PrOH (50 mL) was heated at reflux
for 3 h and then left to cool overnight. The solvent was
evaporated in vacuo, and 3 N HCl was added to the residue.
When the remaining NaBH4 had been consumed, the solution
was basified and extracted with EtOAc (2×). The combined
extracts were dried over Na2SO4 and filtered, and the solvent
was evaporated in vacuo. The residue was recrystallized from
acetone to give a white solid. This material was refluxed
overnight in EtOH (100 mL) containing 3 N HCl (15 mL). The
solvent was evaporated in vacuo and the residue was dissolved
in water and extracted with Et2O (2×). The aqueous layer was
separated and evaporated to dryness, and the residue was
dissolved in EtOH, combined with Pd(OH)2, and hydrogenated
at 50 °C and 50 psi overnight. The catalyst was removed by
filtration and the filtrate was evaporated to dryness. The
residue was chromatographed on silica (96/3.6/0.4 CHCl3/
MeOH/NH4OH). The residue was converted to the hydrochlo-
ride salt with 1 N HCl. The solvent was evaporated in vacuo
and the residue was recrystallized from MeCN to give the title
compound as a white solid. 1H NMR (DMSO-d6) δ 2.23 (s, 3H),
2.3 (s, 3H), 4.4 (s, 2H), 4.7 (br s, 1H), 7.6 (s, 1H), 9.1 (s, 1H),
14.5-15.0 (br s, 1H). Anal. (C9H11N3S‚HCl) C, H, N.
Gen er a l P r oced u r es for th e Syn th esis of 2-Th ia zole
Com p ou n d s: (4-Im id a zolyl)th ioa ceta m id e Hyd r och lo-
r id e (51). A solution of (4-imidazolyl)acetonitrile (12.8 g, 120
mmol) and thioacetamide (18.0 g, 40 mmol) in DMF (75 mL)
was heated in an oil bath to 90-100 °C for about 2 h, while
HCl(g) was being bubbled into the reaction mixture. The
solvent was evaporated in vacuo, and the residue was tritu-
rated with acetone to give crude product. This material was
recrystallized from 2-PrOH to give the title compound (16.2
g, 76%) as a tan solid, mp 199-201 °C. H NMR (DMSO-d6) δ
4.05 (s, 2H), 7.5 (s, 1H), 9.05 (s, 1H), 9.7 (d, 2H), 14.5 (br s,
2H). Anal. (C5H7N3S‚HCl) C, H, N.
4-[(4,5-Dim eth ylth ia zol-2-yl)m eth yl]-1H-im id a zole Hy-
d r och lor id e (53). A solution of 51 (4.6 g, 26 mmol) and
3-bromo-2-butanone (6.9 g, 45.6 mmol) in 2-PrOH (25 mL) was
(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) Mou se Acetylch olin e-In d u ced Abd om in a l Ir r ita n t
Test (MAIT). The procedure with minor modifications was
that described by Collier.27 Test compounds or appropriate
vehicle were administered p.o. by gavage and at specified
intervals later, the animals received an i.p. injection of 5.5 mg/
1

R2 Adrenoceptor Agonists as Potential Analgesics
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25 5071
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glass bell jars and observed for the occurrence of a single
response. The percent inhibition of this response (equated to
percent antinociception) was calculated for each dose as
follows: % antilnociception ) 100(no. of responders)/(no. of
mice in Group). The ED50 value (dose of agonists that produced
50% antinociception) and the corresponding 95% confidence
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Ack n ow led gm en t. We thank Drs. Ellen W. Baxter
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