Synthesis and evaluation of 2-(arylamino)imidazoles as α2-adrenergic agonists

Article abstract of DOI:10.1021/jm9605142

A series of 2-(arylamino)imidazoles was synthesized and evaluated for activity at α₁- and α₂-adrenoceptors. This class of agents has been shown to have potent and selective agonist activity at the α₂-adrenoceptors. The mos

Full text of DOI:10.1021/jm9605142

18
J . Med. Chem. 1997, 40, 18-23
Articles
Syn th esis a n d Eva lu a tion of 2-(Ar yla m in o)im id a zoles a s r2-Ad r en er gic Agon ists
Stephen A. Munk,* Dale A. Harcourt, Premilla N. Arasasingham, J ames A. Burke, Alexander B. Kharlamb,
Cynthia A. Manlapaz, Edwin U. Padillo, Donald Roberts, Eileen Runde, Linda Williams, Larry A. Wheeler, and
Michael E. Garst
Allergan Pharmaceuticals, 2525 Dupont Drive, Irvine, California 92612
Received J uly 16, 1996X
A series of 2-(arylamino)imidazoles was synthesized and evaluated for activity at R1- and R2-
adrenoceptors. This class of agents has been shown to have potent and selective agonist activity
at the R2-adrenoceptors. The most potent member of this class, 2-[(5-methyl-1,4-benzodioxan-
6-yl)amino]imidazole, proved efficacious for the reduction of intraocular pressure upon topical
administration and for the reduction of blood pressure upon intravenous administration. During
the course of our studies, we developed a new reagent that allowed rapid assembly of the target
compounds. This reagent, N-(2,2-diethoxyethyl)carbodiimide, was convenient to prepare and
was stable under low-temperature storage conditions.
Ch a r t 1
In tr od u ction
Agents stimulating R2-adrenoceptors have been shown
to mediate a variety of physiological functions including
reduction of blood pressure, sedation, and inhibition of
intestinal fluid secretion.1,2 We were interested in
designing novel R2-adrenoceptor agonists to reduce
elevated intraocular pressure (IOP), a condition often
associated with glaucoma.3 Reduction in IOP is the only
currently accepted outcome for a glaucoma medication.
Studies conducted by Makabe4 have demonstrated that
agents acting at R2-adrenoceptors such as clonidine,
shown in Chart 1, are potent ocular antihypertensive
agents. Many investigators have subsequently con-
firmed this observation.5 The R2-adrenoceptor therefore
represents an attractive therapeutic target for the
treatment of glaucoma. The ideal agent would reduce
elevated intraocular pressure without other biological
action. The R2-adrenoceptors, however, can modulate
many biological processes.1 The most limiting side
effects for the topical treatment of glaucoma with R2-
adrenoceptor agonists are those responses mediated
within the central nervous system (CNS).
One approach toward glaucoma drugs possessing an
enhanced therapeutic index relative to clonidine is to
minimize access to the CNS. That approach led to the
design of p-aminoclonidine and AGN 193080.6,7 Both
of these agents have limited access to the CNS and can
reduce intraocular pressure upon topical administration
while inducing minimal centrally mediated responses.
An alternative approach to agents possessing en-
hanced therapeutic indices relies on the recent recogni-
tion that the R2-adrenoceptor has multiple subtypes.8
Correlation of a given R2-adrenoceptor subtype with
biological function is a promising area of research;
however, few subtype specific agonists have been de-
scribed in the literature. Discovery of subtype selective
ligands may allow development of R2-adrenrgic drugs
with enhanced therapeutic indices relative to currently
available compounds.
We initially prepared and evaluated 2-(arylamino)-
imidazoles as potential metabolites of brimonidine and
4.9 Those agents proved to have modest affinity and
selectivity for the R2A-adrenoceptor. We therefore pre-
pared and evaluated a set of compounds to define the
features of the class responsible for activity. We devel-
oped N-(2,2-diethoxyethyl)carbodiimide as a convenient,
new reagent for the assembly of these compounds.
Agent 5 proved to be the most potent compound in the
series. Herein, we describe the synthesis and evalua-
tion of 5 and related agents as R2-adrenergic receptor
agonists. Binding assays demonstrated that 5 was
1200-fold selective for the R2A-receptor relative to the
R1-receptor, 50-fold selective for the R2A-receptor relative
to the R2B-receptor, and 10-fold selective for the R2A
-
receptor relative to the R2C-receptor. We provide details
of the in vitro studies conducted with 5 and related
analogs. Results of the preliminary in vivo evaluation
of this agent demonstrated that 5 lowers both IOP and
blood pressure.
Agen t Syn th esis
We used two approaches to assemble 2-(arylamino)-
imidazoles. We utilized a multistep route to assemble
the imidazole subunit of that class during the course of
our synthetic studies toward brimonidine metabolites.9
The 2-(arylamino)imidazoles showed promise as R2-
adrenergic receptor agonists. As a consequence of that
activity, we developed a convergent route that would
enhance the efficiency of the preparation.
The multistep approach to the synthesis is illustrated
in Scheme 1 for the assembly of 16 and was also used
X Abstract published in Advance ACS Abstracts, December 15, 1996.
S0022-2623(96)00514-6 CCC: $14.00 © 1997 American Chemical Society

(Arylamino)imidazoles as R2-Adrenergic Agonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1 19
Sch em e 4a
Sch em e 1a
a
Reagents and conditions: (i) NaH; (ii) phenyl cyanate; (iii)
a
aminoacetaldehyde diethyl acetal, methanesulfonic acid; (iv) HCl-
H2O, then NaOH.
Reagents and conditions: (i) methanesulfonic acid; (ii) HCl-
H2O, then NaOH.
Sch em e 2a
bromide. The solid amine hydrobromide was removed
by filtration followed by rapid chromatography to afford
the desired reagent of sufficient purity to be used in
subsequent reactions. The reagent was stored in an
anhydrous ether solution at -78 °C as it was unstable
at room temperature. The reagent solution was stable
for 3 months at -78 °C.
An example of the application of reagent 14 in the
synthesis of 2-(arylamino)imidazoles is illustrated in
Scheme 4. Treatment of amine 12 with carbodiimide
14 in the presence of methanesulfonic acid provided
intermediate N-(diethoxyethyl)-N′-arylguanidine 15 in
good yield. This intermediate was then treated as
described previously to afford the 2-(arylamino)imida-
zole 5. In addition to the preparation of 5, the new
reagent was used for the synthesis of 17 and also for
21-26.
a
Reagents and conditions: (i) 1,2-dibromoethane, NaI, K2CO3;
(ii) Ac2O, polyphosphoric acid; (iii) NaOCl; (iv) ethyl chloroformate;
(v) NaN3; (vi) benzyl alcohol, toluene, reflux; (vii) H2, Pd-C.
Sch em e 3a
a
Reagents and conditions: (i) CNBr.
to construct 18-20. 6-Amino-5-bromoquinoxaline was
treated with sodium hydride and then phenyl cyanate,
which was derived from cyanogen bromide and phenol,
to afford an electrophilic intermediate carbodiimide.10,11
This intermediate is analogous to the intermediate
isothiourea that Leonard employed during his assembly
of 2-(arylamino)imidazoles.12 The carbodiimide was
treated with aminoacetaldehyde diethyl acetal to give
guanidine 8. Liberation of the aldehyde with aqueous
hydrochloric acid and then treatment with base afforded
the desired imidazole 16 in good overall yield.
Synthesis of the intermediate amine 12 for assembly
of 5, the most potent agent in the series, is presented
in Scheme 2. 3-Methylcatechol, 9, was treated with 1,2-
dibromoethane to afford the benzodioxane core. The
amine functionality was introduced by first acylating
the aromatic ring and then oxidizing the newly intro-
duced methyl ketone to the corresponding carboxylic
acid.13,14 The regiochemistry was confirmed at the
methyl ketone stage by single-crystal X-ray analysis.
Treatment of the carboxylic acid under standard Curtius
conditions provided amine 12.15
We prepared N-(2,2-diethoxyethyl)carbodiimide, 14,
as a reagent that could be used for the conversion of
amines into the same N-(diethoxyethyl)guanidine in-
termediate previously discussed for the synthesis of
2-(arylamino)imidazoles. That reagent afforded a con-
vergent approach to the agents. The reagent was
prepared from aminoacetaldehyde diethyl acetal and
cyanogen bromide, Scheme 3. Aminoacetaldehyde di-
ethyl acetal was treated with 100 mol % of cyanogen
In Vitr o Eva lu a tion of Agen ts
Membrane suspensions for R1-adrenoceptor binding
assays were prepared from human cerebral cortex
(HCC). This preparation provided a mixed population
of R1-adrenoceptor subtypes, and affinities were deter-
mined relative to the displacement of radiolabeled
prazosin. Membranes from Chinese hamster ovary
(CHO) cells expressing the human R2A-adrenoceptor
(CHO-C10) and R2C-adrenoceptor (CHO-C4) as well as
the rat R2B-adrenoceptor (CHO-RNG) were used for R2
binding assays.8 The rat R2B-adrenoceptor was em-
ployed in our studies as the human ortholog has been
patented.16 Affinity constants were measured relative
to radiolabeled rauwolscine. The data were analyzed
using the Beckman nonlinear least-squares curve-fitting
program AccuFit Competition/Saturation. Table 1 sum-
marizes the in vitro binding affinities of the agents
resulting from at least three separate determinations.
Potent agents were evaluated for functional activity
using the Cytosensor microphysiometer.17 That tech-
nique has been applied in related G-protein-coupled
receptor systems for the generation of functional re-
sponses of receptors to agonists.18 The methodology
allows the generation of functional response data for all
three R2-adrenergic receptor subtypes. We were not
able to generate data for all of the agents as the assay
is not amenable to a high-throughput format. Receptor
expression vectors were identical with those utilized in
the binding assays. Table 2 summarizes the EC50s from

20 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1
Ta ble 1. Binding Affinities (Kis) for R-Adrenergic Receptorsa
Munk et al.
Ta ble 2. Functional Activity (EC50s) at R2-Adrenergic
Receptors
In Vivo Eva lu a tion of Agen ts
A single drop of either brimonidine or 5 was applied
unilaterally to rabbit eyes, and the intraocular pressure
was monitored for 6 h postadministration. Figure 1,
panel A, details the effect that 5 had on intraocular
pressure in the rabbit following topical administration
of the agent. Comparative data for brimonidine are also
shown. Brimonidine and 5 proved to be potent hy-
potensive agents following intravenous administration
to cynomolgus monkeys. These results, Figure 1, panel
B, demonstrated that 5 and brimonidine are both able
to cross the blood-brain barrier.
Discu ssion
Table 1 summarizes the binding affinities of the
agents for the R-adrenergic receptors. Comparison of
the binding affinities for brimonidine (3) and methyl-
substituted analog 4 suggested that the substitution of
an electron-withdrawing subunit for an electron-releas-
ing subunit of comparable size has little effect on the
R2A-adrenoceptor activity of the imidazoline-based agents.
This is in contrast to the comparison of the imidazoles.
Agents 16-18 all have electron-withdrawing substitu-
ents ortho to the aminoimidazole subunit. These agents
are all less potent than 19 which has the same quinoxa-
line subunit found in 4. In this case, the substitution
of an electron-releasing methyl group for an electron-
withdrawing bromine afforded an agent that had over
a 10-fold greater affinity for the R2A-adrenoceptor than
the corresponding bromo analog 16. A dramatic de-
crease in potency was observed upon removal of the
ortho substituent, 20. Substitution at the ortho position
has been shown to facilitate a twist of the imidazoline
relative to the quinoxaline nucleus in a series of bri-
monidine analogs.12 Further enhancements in potency
are obtained upon incorporation of additional electron-
donating substituents onto the aromatic core. Incorpo-
ration of a para methoxy group, 21, afforded a 3-fold
enhancement in potency relative to 19. Addition of a
a
Affinities were determined relative to prazosin for the R1-
adrenoceptors and relative to rauwolscine for the R2-adrenoceptors.
functional studies with some of the most potent 2-(aryl-
amino)imidazoles. Intrinsic activities relative to nore-
pinephrine are also included. The data shown are the
results from at least three separate experiments.

(Arylamino)imidazoles as R2-Adrenergic Agonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1 21
F igu r e 1. In vivo evaluation of brimonidine and 5 (AGN 192836). Panel A: Intraocular pressure (IOP) upon topical, unilateral
administration of a single drop of a 0.001% solution of the specified agent to the rabbit eye. The mean values reported are the
result from six animals in each group. Panel B: Mean arterial blood pressure (MABP) versus time upon intravenous administration
of the specified agent to the cynomolgus monkey. Saline served as a control. Each agent was evaluated at a concentration of 50
µg/kg. The mean values reported are the result from six animals in each group.
second methoxy substituent, 22, afforded an agent of
decreased potency and selectivity relative to 21. The
most potent R2A-adrenoceptor agent in this series was
obtained upon preorganization of the methoxy subunits
(a benzodioxane nucleus), agent 5. This compound was
over 40-fold selective for the R2A-adrenoceptor relative
to the R2B-adrenoceptor and over 10-fold selective for
the R2A-adrenoceptor relative to the R2C-adrenoceptor
in binding studies. Agent 5 proved over 1000-fold
selective for the R2A-adrenoceptor relative to the R1-
adrenoceptor in binding studies. This agent was also
agents displayed modest to good selectivity for R2Α-
adrenoceptors in binding studies. Binding affinity has
not proved an accurate measure of functional activity
in this study. Data presented herein highlight the
requirement for both binding and functional assay
systems for the selection of viable candidates for sub-
sequent in vivo evaluation.
The most potent member of the class of compounds
synthesised, 2-[(5-methyl-1,4-benzodioxan-6-yl)amino]-
imidazole, 5, proved very selective for the R2Α-adreno-
ceptor relative to the R1-adrenoceptor preparation in
binding assays. The compound was comparable in
activity to brimonidine in R2-adrenoceptor functional
assay systems. Agent 5 was equally efficacious when
compared to brimonidine for the reduction of intraocular
pressure upon topical administration to the rabbit and
more efficacious than brimonidine for the reduction of
blood pressure upon intravenous administration to
monkey. During the course of our studies, we developed
a new reagent that allowed rapid assembly of the target
2-(arylamino)imidazoles from arylamines. This reagent,
N-(2,2-diethoxyethyl)carbodiimide, will prove of value
for the preparation of related compounds.
selective for the the R2A-adrenoceptor relative to the R2B
-
adrenoceptor in the functional assay system, Table 2.
The agent did not, however, prove selective for the the
R
2A-adrenoceptor relative to R2C-adrenoceptor in the
functional system. Utilization of an aromatic core
incorporating bulk and related oxymetazoline, 23, Table
1, afforded a very selective R2A-adrenoceptor probe in
binding assays; however, that agent proved inactive in
the functional assay systems, Table 2. Agent 24 is an
analog of 21 with the addition of a bulky substituent in
the 5-position of the phenyl nucleus. This agent had
both reduced selectivity and potency relative to 21.
Incorporation of the benzoxazine subunit, 25, afforded
an agent that proved selective for the R2A-adrenoceptor
in binding studies but possessed reduced potency and
efficacy in functional assay systems, Table 2. The
difference between binding and functional results was
similar to the observations with 23. The benzimidazole
nucleus, 26, had enhanced binding activity relative to
the corresponding quinoxaline nucleus, 20, but reduced
binding selectivity compared to the ortho-substituted
benzodioxanyl nucleus, 5.
Exp er im en ta l Section
Gen er a l. Reagents used were the highest quality available
commercially. Reaction solvents were anhydrous and were
obtained from Aldrich in Sure-Seal bottles. Unless otherwise
noted, all reactions were carried out under an argon atmo-
sphere and temperatures refer to the temperature of the bath.
Organic extracts were dried with magnesium sulfate (MgSO4)
or potassium carbonate (K2CO3). Flash chromatography was
conducted using the procedure described by Still.20 Proton and
carbon NMR spectra were measured on either a Varian Gemini
300 or a Varian Unity Plus 500 spectrometer in the solvents
specified. Chemical shifts are reported in ppm downfield from
TMS as an internal standard, and coupling constants are
reported in hertz. Mass spectra (LRMS and HRMS) were
recorded on a VG 7070E Sector Magnetic 70 eV mass spec-
trometer. Combustion analyses were conducted by Robertson
Microlit Laboratories, Madison, NJ .
J eon et al. have evaluated a series of iminoimidazo-
lines related to brimonidine (3) using subtype specific
R-adrenergic assay systems.19 The results that we
obtained with brimonidine are similar to the reported
values. Both studies serve to illustrate the require-
ments for subtype specific functional assay systems as
binding affinities do not always correlate with the
results obtained from functional studies within related
series of agents.
N-(5-Br om oq u in oxa lin -6-yl)ca r b od iim id e (7). To
6-amino-5-bromoquinoxaline (1.55 g, 6.92 mmol) in dry THF
(150 mL) was added NaH (0.61 g, 60% in oil, 15.2 mmol) in
portions. The mixture turned from clear yellow/orange to red,
but no H2 liberation was observed. The reaction mixture was
Con clu sion s
then warmed at 55 °C until H2 was no longer liberated.
A
We have synthesized and evaluated a series of 2-(aryl-
amino)imidazoles as R2-adrenoceptor agonists. These
cherry red solution resulted. The reaction mixture was cooled
to room temperature, and phenyl cyanate (1.81 g, 15.2 mmol)

22 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1
Munk et al.
was added. The solution gradually lightened to yellow brown,
and a precipitate was observed. After 2 h at room tempera-
ture, the mixture was warmed at reflux for 2 h. The solid was
with 10% EtOAc in hexane afforded 4.0 g (35%) of the desired
product as the most mobile product. Recrystallization of a
sample from ethanol afforded crystalline material which was
used for confirmation of the regiochemistry via single-crystal
X-ray analysis. 1H NMR (CDCl3): 2.38 (s, 3H), 2.53 (s, 3H),
4.28 (s, 4H), 6.75 (d, J ) 8.6 Hz, 1H), 7.25-7.27 (d, J ) 8.6
Hz, 1H).
isolated by filtration. The solid was then slurried in
a
minimum amount of water, and HCl (6 M) was added dropwise
until the pH reached 6. Filtration and drying afforded 860
mg (50%) of the carbodiimide. 1H NMR (DMSO): 7.77 (d, J
) 9.1 Hz, 1H), 8.18 (d, J ) 9.1 Hz, 1H), 8.91 (d, J ) 1.8 Hz,
1H), 9.01 (d, J ) 1.8 Hz, 1H), 10.35 (br s, 1H). 13C NMR
(DMSO): 107.5, 111.3, 120.1, 130.3, 138.5, 139.4, 140.4, 144.6,
5-Met h yl-1,4-b en zod ioxa n e-6-ca r b oxylic Acid (11).
Fresh sodium hypochlorite was prepared by slurrying Ca(ClO)2
(11.4 g, 80 mmol) in H2O (50 mL) and treating the mixture
with Na2CO3 (8.05 g, 76 mmol) and NaOH (0.96 g, 24 mmol)
in H2O (25 mL). The slurry was warmed and then filtered
through a plug of glass wool to afford a homogeneous solution.
Solid 6-acetyl-5-methyl-1,4-benzodioxane (3.84 g, 20 mmol) was
added, and the resulting slurry was warmed at 60 °C over-
night, at which point a homgeneous solution was observed.
The aqueous reaction mixture was washed with CH2Cl2 (2×).
The aqueous solution was treated dropwise with concentrated
HCl until the pH reached 3. The solid was collected by
filtration and washed well with water. The solid, 3.95 g
(quantitative yield), was dried and used for the subsequent
Curtius reaction without further purification. 1H NMR
(CDCl3): 2.50 (s, 3H), 4.29 (s, 4H), 6.75 (d, J ) 8.7 Hz, 1H),
7.61 (d, J ) 8.7 Hz, 1H).
6-Am in o-5-m eth yl-1,4-ben zod ioxa n e (12). Acid 11 (3.95
g, 20 mmol) was dissolved in acetone (25 mL) and Hunig’s base
(4.35 mL, 25 mmol). The reaction mixture was chilled to 0
°C, and ethyl chloroformate (2.01 mL, 21 mmol) was added
dropwise and then stirred for 1 h. Sodium azide (2.6 g, 40
mmol) in H2O (6 mL) was added, and the reaction mixture
was stirred for an additional 1 h. The reaction mixture was
poured into ice-water, and the organic material was extracted
with CH2Cl2. Drying and concentration afforded the azide
(IR: 2139, 2038 cm-1). The product was dissolved in toluene
(40 mL), and benzyl alcohol (2.16 g, 20 mmol) was added. After
warming at reflux overnight, the reaction mixture was poured
into ether and the organic solution was washed once with H3-
PO4 and once with NaHCO3 (saturated), dried, and concen-
trated to afford a solid. Recrystallization from ethanol afforded
3.7 g (47%) of the protected amine. The carbamate was an
excellent point to store the intermediate as aniline 12 dark-
ened on standing. In a typical procedure, amine 12 was
liberated upon treatment of the carbamate (1.0 g) in THF (20
mL, degassed using a Firestone valve) with an atmosphere of
H2 and 10% Pd-C (200 mg) overnight. The catalyst was
removed by filtration through Celite. Concentration of the
solution led to the amine 12 (550 mg, 95%) that rapidly turned
purple on standing in air. 1H NMR (CDCl3): 2.0 (s, 3H), 3.35
(br s, 2H), 4.19 (m, 2H), 4.25 (m, 2H), 6.21 (d, J ) 8.7 Hz, 1H),
6.58 (d, J ) 8.7 Hz, 1H).
2-[(5-Meth yl-1,4-ben zodioxan -6-yl)am in o]im idazole (5).
Amine 12 (350 mg, 2.11 mmol) was dissolved in ethanol (25
mL), and N-(2,2-diethoxyethyl)carbodiimide, 14 (2.4 mL of a
1 M solution in ether), was added dropwise. Methanesulfonic
acid (208 mg, 2.11 mmol) was then added, and the mixture
was warmed at reflux for 24 h. The reaction mixture was
poured into NaOH (0.5 M) and extracted with CH2Cl2. Drying
and concentration afforded a product that was subjected to
flash chromatography (5% MeOH in CH2Cl2 to remove mobile
impurities and then 5% NH3-saturated MeOH in CH2Cl2) to
give the intermediate guanidine. The guanidine was dissolved
in HCl (5 mL, 6 M) at 0 °C and then stirred for 2 h. After the
starting material was consumed, NaOH (25%) was added until
a precipitate formed (pH ) 14). This mixture was stirred for
30 min. The reaction was then poured into NaOH (0.5 M),
extracted with CH2Cl2, dried, and concentrated. Flash chro-
matography (5% NH3-saturated MeOH in CH2Cl2) afforded 5
(292 mg, 60%). 1H NMR (DMSO): 2.00 (s, 3H), 4.22 (m, 4H),
6.55-6.59 (m, 3H), 7.13 (d, J ) 8.8 Hz, 1H), 7.45 (s, 1H), 10.4
(s, 1H). 13C NMR (DMSO): 9.7, 63.5, 64.37, 110.8, 113.7,
114.6, 134.8, 137.6, 141.3, 146.5. Anal. Calcd (C12H13N3O2)
C, H, N.
146.8. IR (KBr): 2227 cm-1
.
2-[(5-Br om oqu in oxalin -6-yl)am in o]im idazole (16). Car-
bodiimide 7 (0.255 g, 0.94 mmol) and aminoacetaldehyde
diethyl acetal (0.163 g, 1.22 mmol) were dissolved in ethanol
(25 mL) and treated with methanesulfonic acid (0.109 g, 1.13
mmol). The reaction mixture was warmed at reflux overnight.
Traces of the starting material remained. An additional
portion of aminoacetaldehyde diethyl acetal (0.032 g, 0.24
mmol) and methanesulfonic acid (1 drop) were added. After
an additional 2 h warming at reflux, no further starting
material remained. The reaction mixture was concentrated
to dryness, dissolved in ethyl acetate, and then washed with
NaOH (0.5 M). The organic layer was dried, concentrated, and
subjected to flash chromatography (gradient: EtOAc f 40%
THF in EtOAc) to afford a foam that was dissolved in HCl (5
mL, 6 M) at 0 °C and then stirred for 2 h. After the starting
material was consumed (2 h), NaOH (25%) was added until a
precipitate formed (pH of 14). This mixture was stirred for
30 min. The reaction mixture was then acidified to a pH of 5
using concentrated HCl. The resulting yellow solid was
collected and dried. Chromatography over basic alumina
(gradient: EtOAc f THF) afforded pure 16 (0.109 g, 40%
overall) as a yellow solid. 1H NMR (DMSO): 6.65-7.00 (br s,
2H), 7.99 (d, J ) 9.3 Hz, 1H), 8.62 (s, 1H), 8.73 (d, J ) 9.3 Hz,
1H), 8.74 (d, J ) 1.9 Hz, 1H), 8.89 (d, J ) 1.9 Hz, 1H), 11.29
(br s, 1H). 13C NMR (DMSO): 104.3, 121.3, 128.8, 138.3, 140.8,
142.4, 142.5, 142.8, 146.0. Anal. Calcd (C11H8BrN5) C, H, N.
N-(2,2-Dieth oxyeth yl)ca r bod iim id e (14). A solution of
the aminoacetaldehyde diethyl acetal (2.66 g, 20 mmol) was
dissolved in a mixture of ether (10 mL) and pentane (10 mL).
This was then treated with solid CNBr (2.11 g, 20 mmol). A
solid precipitated from solution. The reaction mixture was
magnetically mixed for 18 h at room temperature. The solid
was removed by filtration, and the reaction mixture was
concentrated. Flash chromatography of the concentrated
residue (5% MeOH in CH2Cl2) afforded 1.2 g of the reagent
(38%; note that one-half of the starting amine served as a
sacrificial base in the reaction). After analysis by 1H NMR
and IR, the material was dissolved in anhydrous ether to afford
a 1 M solution that was stable to storage at -78 °C for 3
months. 1H NMR (CDCl3): 1.24 (t, J ) 7 Hz, 3H), 3.17 (app
t, J ) 5.4 Hz, 2H), 3.57 (m, 2H), 3.74 (m, 2H), 3.85 (br s, 1H),
4.59 (t, J ) 5.4 Hz, 1H). IR (cm-1): 1064 (s, s), 1130 (s, s),
2227 (s, s), 2978 (s, m), 3226 (br, m).
5-Meth yl-1,4-ben zod ioxa n e (10). A mixture of 3-meth-
ylcatechol, 9 (12.4 g, 100 mmol), 1, 2-dibromoethane (9.5 mL,
110 mmol), potassium carbonate (34.6 g, 250 mmol), and
sodium iodide (0.75 g, 5.0 mmol) in acetone (200 mL) was
warmed at reflux with mechanical stirring in a Morton flask
overnight. The black slurry was poured into water and
extracted with ether three times. The ether layer was washed
with 5% sodium thiosulfate, dried, and distilled via Kugelrohr
(80 °C, 0.05 mmHg) to afford 10.5 g of a gold oil. Flash
chromatography (SiO2, 2 in. × 4 in., 5% EtOAc in hexane)
afforded 9.0 g (60%) of pure 5-methyl-1,4-benzodioxane. 1H
NMR (CDCl3): 2.20 (s, 3H), 4.23-4.29 (m, 4H), 6.72 (br s, 3H).
6-Acet yl-5-m et h yl-1,4-b en zod ioxa n e. A mixture of 5-
methyl-1,4-benzodioxane, 10 (9.0 g, 60 mmol), and acetic
anhydride (6.14 g, 60 mmol) was warmed at 60 °C with
polyphosphoric acid (70 g) using mechanical mixing in a
Morton flask for 2 h. The reaction mixture was cooled and
then the reaction quenched by the slow addition of H2O (100
mL). The mixture was poured into water (200 mL) and
extracted with ether. The ether was washed with NaHCO3
(saturated) and then NaCl (saturated). The ether was dried
and concentrated to afford a black oil. Flash chromatography
2-[(2-Br om op h en yl)a m in o]im id a zole (17). 1H NMR
(DMSO): 6.74 (m, 1H), 6.79 (s, 2H), 7.17 (m, 1H), 7.47 (d, J )
6.9 Hz, 1H), 7.61 (d, J ) 6.9 Hz, 1H) 10.0 (br s, 1H). 13C NMR

(Arylamino)imidazoles as R2-Adrenergic Agonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1 23
(2) Hieble, J . P.; Ruffolo, R. R., J r. In Progress in Basic and Clinical
Pharmacology: R-Adrenoceptors: Molecular Biology, Biochem-
istry, and Pharmacology; Ruffolo, R. R., J r., Ed.; S. Karger AG:
Basel, 1991; Vol. 8, pp 180-220.
(3) Shields, M. B. Textbook of Glaucoma, 3rd ed.;Williams and
Wilkins: Baltimore, 1992.
(4) Makabe, R. Ophthalmologische Untersuchungen mit Dichlo-
rophenylaminoimidazolin. Dtsch. Med. Wochenschr. 1966, 91,
1686-1688.
(5) Chacko, D. M.; Camras, C. B. The Potential of R2-Adrenergic
Agonists in the Medical Treatment of Glaucoma. Curr. Opin.
Ophthalmol. 1994, 5, 76-84.
(DMSO): 111.0, 116.4, 119.3 (br), 121.7, 128.5, 132.6, 139.6,
143.8. Anal. Calcd (C9H8BrN3) C, H, N.
2-[(2,6-Dich lor op h en yl)a m in o]im id a zole (18). 1H NMR
(CDCl3): 6.40-6.80 (br s, 2H), 6.69 (s, 2H), 6.99 (t, J ) 8.1
Hz, 1H), 7.30 (d, J ) 8.1 Hz, 2H). 13C NMR (CDCl3): 118.7,
125.4, 129.0, 129.6, 135.7, 144.9. Anal. Calcd (C9H7Cl2N3) C,
H, N.
2-[(5-Meth ylqu in oxa lin -6-yl)a m in o]im id a zole (19). 1H
NMR (DMSO): 2.62 (s, 3H), 6.70-6.90 (br s, 2H), 7.81 (d, J )
9.3 Hz, 1H), 8.30 (s, 1H), 8.44 (d, J ) 9.3 Hz, 1H), 8.66 (d, J
) 1.8 Hz, 1H), 8.80 (d, J ) 1.8 Hz, 1H), 11.0 (br s, 1H). 13C
NMR (DMSO): 10.5, 118.1, 118.4, 122.0, 126.7, 138.2, 141.4,
141.8, 141.9, 144.1, 144.3. Anal. Calcd (C12H10N5) C, H, N.
2-(Qu in oxa lin -6-yla m in o)im id a zole (20). 1H NMR
(DMSO): 6.74 (br s, 1H), 6.85 (br s, 1H), 7.70 (dd, J ) 9.3, 2.5
Hz, 1H), 7.89 (d, J ) 9.3 Hz, 1H), 8.22 (d, J ) 2.5 Hz, 1H),
8.61 (d, J ) 1.9 Hz, 1H), 8.73 (d, J ) 1.9 Hz, 1H), 9.41 (br s,
1H), 11.05 (br s, 1H). 13C NMR (DMSO): 108.4, 122.5, 129.3,
137.7, 141.5, 143.5, 143.9, 144.2, 145.4. Anal. Calcd (C11H9N5)
C, H, N.
(6) Robinson, C. P. Apraclonidine Hydrochloride. Drugs Future
1988, 13, 507-510 and references cited therein.
(7) Munk, S. A.; Harcourt, D.; Ambrus, G.; Denys, L.; Gluchowski,
C.; Burke, J . A.; Kharlamb, A. B.; Manlapaz, C. A.; Padillo, E.
U.; Runde, E.; Wheeler, L. A.; Garst, M. E. Synthesis and
Evaluation of 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazo-
line: a Potent, Peripherally Acting R2 Adrenoceptor Agonist. J .
Med. Chem. 1996, 39, 3533-3538.
(8) Bylund, D. B.; Blaxall, H. S.; Iversen, L. J .; Caron, M. G.;
Lefkowitz, R. J .; Lomasney, J . W. Pharmacological Character-
istics of R2-Adrenergic Receptors: Comparison of Pharmacologi-
cally Defined Subtypes with Subtypes Identified by Molecular
Cloning. Mol. Pharmacol. 1992, 42, 1-5.
(9) Munk, S. A.; Harcourt, D.; Wong, H.; Acheampong, A.; Breau,
A.; Tang-Liu, D.; Burke, J .; Lai, R.; Nguyen, H.; Wheeler, L.;
Garst M. Synthesis and Characterization of Degradation Prod-
ucts and Metabolites of Brimonidine - A Potent R2 Adrenergic
Agonist. 211th American Chemical Society National Meeting,
New Orleans, LA, March 1996; MEDI 21.
(10) Murray, R. E.; Zweifel, G. Preparation of Phenyl Cyanate and
its Utilization for the Synthesis of R,â-Unsaturated Nitriles.
Synthesis 1980, 150-151.
(11) Lawson, A. The Reaction of Cyanamide with R-Amino-acetals
and R-Amino-Aldehydes. J . Chem. Soc. 1956, 307-310.
(12) Czarnik, A. W.; Leonard, N. J . Unequivocal Assignment of the
Skeletal Structure of the Guanine-Glyoxal Adduct. J . Org. Chem.
1980, 45, 3514-3517.
(13) Edwards, J . D., J r.; McGuire, S. E.; Hignite, C. Friedel-Crafts
Acylation. Positional Selectivity and Reactivity of Acylating
Agents. J . Org. Chem. 1964, 29, 3028-3032.
(14) Borchardt, R. T.; Bhatia, P. Catechol O-Methyltransferase. 12.
Affinity Labeling the Active Site with the Oxidation Products
of 5,6-Dihydroxyindole. J . Med. Chem. 1982, 25, 263-271.
(15) J essup, P. J .; Petty, C. B.; Roos, J .; Overman, L. E. 1-N-
Acylamino-1,3-dienes from 2,4-Pentadienoic Acids by the Curtius
Rearrangement: Benzyl trans-1,3-Butadiene-1-Carbamate. In
Organic Syntheses; Noland, W. E., Ed.; J ohn Wiley: New York,
1988; Collect. Vol. VI, pp 95-101.
2-[(2-Meth yl-4-m eth oxyp h en yl)a m in o]im id a zole (21).
1H NMR (DMSO): 2.18 (s, 3H), 3.68 (s, 3H), 6.62 (s, 1H), 6.65-
6.74 (m, 2H), 7.45 (s, 1H), 7.68 (d, J ) 8.7 Hz, 1H), 10.47 (s,
1H). 13C NMR (DMSO): 19.4, 56.6, 112.6, 117.3, 119.8, 128.3,
135.7, 147.8, 154.6. Anal. Calcd (C11H13N3O) C, H, N.
2-[(2-Met h yl-3,4-d im et h oxyp h en yl)a m in o]im id a zole
(22). 1H NMR (DMSO): 2.08 (s, 3H), 3.66 (s, 3H), 3.72 (s, 3H),
6.63 (s, 2H), 6.77 (d, J ) 8.9 Hz, 1H), 7.42 (d, J ) 8.9 Hz, 1H).
13C NMR (DMSO): 10.4, 56.0, 59.9, 110.5, 112.8, 120.2, 135.1,
146.4, 146.7, 147.1. Anal. Calcd (C12H15N3O2) C, H, N.
2-[(2,6-Dim eth yl-3-m eth oxy-4-ter t-bu tylph en yl)am in o]-
im id a zole (23). 1H NMR: 1.39 (s, 9H), 2.19 (s, 3H), 2.21 (s,
3H), 3.73 (s, 3H), 6.05 (br s, 2H), 6.62 (s, 2H), 7.06 (s, 1H). 13
C
NMR: 12.7, 18.1, 30.9, 34.8, 60.9, 126.7, 126.8, 129.1, 129.7,
135.9, 141.0, 148.7, 157.4. Anal. Calcd (C16H22N3O‚0.25H2O)
C, H, N.
2-[(2-Meth yl-4-m eth oxy-5-ter t-bu tylp h en yl)a m in o]im i-
d a zole (24). 1H NMR (DMSO) 1.28 (s, 9H), 2.15 (s, 3H), 3.74
(s, 3H), 6.50-6.69 (m, 2H), 6.76 (s, 1H), 7.38 (s, 1H), 7.62 (s,
1H). 13C NMR (DMSO) 18.9, 31.2, 35.6, 57.0, 116.0, 118.5,
126.0, 134.9, 136.4, 148.2, 153.7, 156.5. Anal. Calcd (C15H21
-
N3O‚0.5H2O) C, H, N.
2-[(5-Meth ylben zoxa zin -6-yl)a m in o]im id a zole (25). 1H
NMR (acetone): 2.00 (s, 3H), 3.41 (m, 2H), 4.08 (t, J ) 4.4 Hz,
2H), 4.60 (br s, 1H), 6.48 (d, J ) 8.6 Hz, 1H), 6.58 (s, 2H), 6.77
(d, J ) 8.6 Hz, 1H), 6.98 (br s, 1H), 9.5 (br s, 1H). 13C NMR
(acetone): 11.3, 41.9, 65.2, 112.1, 114.6, 116.5, 118.3, 133.7,
134.5, 141.0, 149.5. MS (low res): obsd m/ z at 230 (EI+); (high
res) mass calcd for C12H14N4O (M•+) ) 230.1168; obsd m/ z at
230.1196, deviation from theoretical ) 1.8 mmu. Anal. Calcd
for C12H15ClN4O: C, 54.03; H, 5.67; N, 21.01. Found: C, 53.94;
H, 5.52; N, 20.23.
(16) Weinshank, R. L.; Hartig, P. R. DNA Encoding an R2B-Adrenergic
Receptor. U.S. Patent No. 5,053,337, Oct. 1, 1991.
(17) McConnell, H. M.; Owicki, J . C.; Parce, J . W.; Miller, D. L.;
Baxter, G. T.; Wada, H. G.; Pitchford, S. The Cytosensor Micro-
physiometer: Biological Applications of Silicon Technology.
Science 1992, 257, 1906-1912.
(18) Neve, K. A.; Kozlowski, M. R.; Rosser, M. P. Dopamine D2
Receptor Stimulation of Na+/H+ Exchange Assessed by Quan-
tification of Extracellular Acidification. J . Biol. Chem. 1992, 287,
25748-25753.
(19) J eon, Y. T.; Luo, C.; Forray, C.; Vaysse, P. J .-J .; Branchek, T.
A.; Gluchowski, C. Pharmacological Evaluation of UK-14,304
Analogs at Cloned Human R Adrenergic Receptors. BioMed.
Chem. Lett. 1995, 5, 2255-2258.
2-(Ben zim id a zol-5-yla m in o)im id a zole (26). 1H NMR
(DMSO): 6.68 (s, 2H), 7.0 (d, 1H), 7.01 (dd, J ) 8.7, 2.0 Hz,
1H), 7.41 (d, J ) 8.7 Hz, 1H), 7.89 (d, J ) 2.0 Hz, 1H), 7.99 (s,
1H), 8.56 (s, 1H), 11.5 (br s, 2H). 13C NMR (DMSO): 99.2 (br),
112.5, 117.1 (br), 118.0 (br), 138.1, 140.7, 145.6. Anal. Calcd
(C11H10N4‚0.2H2O) C, H, N.
(20) Still, W. C.; Kahn, M.; Mitra, A. Rapid Chromatographic
Technique for Preparative Separations with Moderate Resolu-
tion. J . Org. Chem. 1978, 43, 2923-2925.
Refer en ces
(1) Maze, M.; Tranquilli, W. Alpha-2 Adrenoceptor Agonists: Defin-
ing the Role in Clinical Anesthesia. Anesthesiology 1991, 74,
581-605.
J M9605142