Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole α1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia

Article abstract of DOI:10.1021/jm000541z

In search of a uroselective α_1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,¹ this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the α_1A/α_1B selectivity of these compounds were identified. In vitro functional assays for the α₁ adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).

Full text of DOI:10.1021/jm000541z

J . Med. Chem. 2001, 44, 1971-1985
1971
Str u ctu r e-Activity Stu d ies for a Novel Ser ies of Bicyclic Su bstitu ted
Hexa h yd r oben z[e]isoin d ole r1A Ad r en ocep tor An ta gon ists a s P oten tia l Agen ts
for th e Sym p tom a tic Tr ea tm en t of Ben ign P r osta tic Hyp er p la sia
Michael D. Meyer, Robert J . Altenbach, Hao Bai, Fatima Z. Basha, William A. Carroll, J ames F. Kerwin, J r.,
Suzanne A. Lebold, Edmund Lee, J ohn K. Pratt, Kevin B. Sippy, Karin Tietje, Michael D. Wendt,
Michael E. Brune, Steven A. Buckner, Arthur A. Hancock, and Irene Drizin*
Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories,
100 Abbott Park Road, Abbott Park, Illinois 60064
Received December 18, 2000
In search of a uroselective R1A subtype selective antagonist, a novel series of 6-OMe
hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker
was synthesized. It was found that in contrast to the previously described series of tricyclic
heterocycles,1 this bicyclic series has very specific requirements for the heterocyclic attachments.
The most important structural features contributing to the R1A/R1B selectivity of these
compounds were identified. In vitro functional assays for the R1 adrenoceptor subtypes were
used to further characterize the most selective compounds, and in vivo models of vascular vs
prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of
selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold),
and for in vivo prostate selectivity (960-fold).
Ch a r t 1
In tr od u ction
Benign prostatic hyperplasia (BPH) is a highly preva-
lent condition, with the percentage incidence approxi-
mately equaling a man’s age.2 This condition is char-
acterized by a collection of urological symptoms including
hesitancy, nocturia, poor urine flow, frequency of urina-
tion, and sensations of urgency. It was demonstrated
that the dynamic component of BPH is mediated
primarily through prostatic R1 adrenoceptors.3 First-
generation drugs used to treat BPH (i.e., terazosin,4
doxazosin,5 and alfuzosin6), although effective in im-
proving symptoms of BPH, were found to be suboptimal
because of the dose-limiting side effects. These included
hypotension, dizziness, and muscle fatigue and were
believed to be mediated by the blockade of R1 receptors
in the vasculature and the central nervous system.
Within the past decade the heterogeneity of the R1
receptor was realized on both a molecular level and a
pharmacological level.7 It was shown that even though
all three subtypes of the human R1 receptor were
present in the prostate, the R1A receptor was the most
prevalent.8 There was also scientific evidence of a
prominent role of R1B receptor in the regulation of blood
pressure.9 This stimulated interest in finding a “urose-
lective” R1A/R1B selective agent that would have a better
side effect profile. The therapeutic relevance of these
findings has been proven in the clinical setting where
tamsulosin, the second-generation drug for the treat-
ment of BPH (20-fold selective for R1A over R1B recep-
tors),10 demonstrated a more favorable side effect pro-
file.11
a “uroselective “ drug. It was suggested that blockade
of this receptor could ameliorate the irritative symptoms
of BPH that result from the involuntary contractions
of the bladder smooth muscle.12 Thus, agents with
improved selectivity for R1A/R1B receptor with activity
at R1D receptor could demonstrate further improvement
in the side effect profile.
A number of R1A subtype selective antagonists rep-
resenting different structural classes of compounds such
as SNAP 5089 (dihydropyridine),13 GG818 (oxazole),14
dihydropyrimidinones,15,16 and SNAP 7915 (oxazolidi-
none)17 were disclosed recently. A review18 on the
development of R1A antagonists outlined the progress
made in this field within the past decade.
In our earlier publication1 we described structure-
activity (SAR) studies on a series of hexahydrobenz[e]-
isoindoles attached to a tricyclic heterocycle, as in
compound 1 (Chart 1). This compound exhibited a 50-
fold selectivity for the R1A/R1D receptors versus R1B
receptor. Although the requirements for the left-hand
portion of the molecule were found to be very specific
(6-methoxybenz[e]isoindole with (R,R) stereochemistry
of the ring junction, and a two-carbon chain linker) a
There has also been considerable interest in further
understanding the role of R1D receptor in the design of
* To whom correspondence should be addressed. For I. Drizin:
phone, 847-937-7832; fax, 847 -937-9195; E-mail, irene.drizin@
abbott.com.
10.1021/jm000541z CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/11/2001

1972 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 12
Meyer et al.
Ch a r t 2
The majority of monosubstituted anthranilic acids
used in this study were obtained from commercial
sources. Disubstituted anthranilic acids that were not
available commercially were most conveniently pre-
pared via oxidative cleavage of substituted isatins.21
Aminocarboethoxythiophenes were obtained from com-
mercial sources or synthesized via known methods. 22,23
Aminocarboethoxypyridines used in this study were
prepared in accordance with literature procedures.24,25
Synthesis of 1-methyl-substituted quinazolinedione
46 is outlined in Scheme 2. Methyl 2-amino-4,5-
dimethoxybenzoate was converted to the intermediate
methyl 4,5-dimethoxy-2-(methylamino)benzoate 44 by
the two-step sequence.26 Compound 44 was reacted with
chloroethylisocyanate to yield the intermediate chloro-
ethylquinazolinedione 45 that was in turn reacted with
the benz[e]isoindole 5 to form the desired N-methyl-
substituted derivative 46.
The route to 4-quinazolinone compounds is depicted
in Scheme 3. Ethyl 6-amino-3,4-dimethoxybenzoate was
converted to the intermediate formamidine 47 that was
coupled with 6 in the presence of p-toluenesulfonic acid
to yield the 4-quinazolinone 48. Dihydroquinazolinone
49 was obtained by the hydrogenation of compound 48.
Scheme 4 illustrates the synthesis of tetrahydro-
quinazoline 52 and 2-quinazoline derivative 53. The
starting dimethoxynitrobenzaldehyde was coupled with
the amine 6 to result in the intermediate nitro deriva-
tive 50 that was hydrogenated over Pd/C to yield the
amine 51. Reaction of formaldehyde with 51 produced
compound 52, whereas action of carbonyldiimidazole on
51 resulted in 53. Scheme 5 outlines the synthesis of
isoquinoline derivatives 55 and 56. The starting benz-
[e]isoindole 5 was reacted with 1-bromo-2-chloroethane
to result in chloroethyl derivative 54 that was coupled
with the corresponding isoquinolines to yield 55 and 56.
Compound 57 was synthesized by the coupling of the
2-amino-4,5-dimethoxybenzoic acid with the amine 6.
wide variety of tricyclic heterocyclic attachments were
tolerated in the right-hand portion of the molecule with
the retention of potency and selectivity. We were
interested in finding out if the replacement of tricyclic
heterocycles with the bicyclic units would result in
improved selectivity and potency. Additional impetus
to the bicyclic heterocyclic replacements was provided
by the fact that there were known R1 adrenergic
antagonists 2 and 3 (Chart 2) with such structural
elements.19
The initial attempt at appending a bicyclic heterocycle
to the 6-OMe-benz[e]isoindole resulted in compound 4
(Chart 3). Unfortunately, although this compound re-
tained R1 potency, it was not subtype-selective. Previ-
ously, we found that introduction of substituents, as well
as other heteroatoms, augmented potency and selectiv-
ity. Consequently, we initiated further study of this class
of compounds.
Ch em istr y
SAR studies of the parent structure focused on
identification of the optimal bicyclic heterocyclic attach-
ment. The synthesis of target structures was accom-
plished via two different methods. In method A (Scheme
1) quinazolinediones 10 were formed by the coupling of
isocyanate intermediates 8 with the primary amines 61
followed by cyclization accomplished thermally or as-
sisted by potassium tert-butoxide. The isocyanates 8
were obtained from the corresponding aminoesters 7 by
treatment with triphosgene in toluene at reflux. In
certain cases the isocyanates were not isolated but
formed in situ using phosgene solution in toluene in the
presence of triethylamine and then reacted directly with
the primary amines 6. The primary amines 6 or 6a were
derived from the benz[e]isoindoles 5 or 5a 1 via alkyla-
tion with chloroacetonitrile followed by reduction of the
resulting nitriles with lithium aluminum hydride. Method
B (Scheme 1) entailed the reaction of 2-chloroethyl
isocyanate20 with the starting aminoesters 7 to give the
haloalkyl ureas 9 that were in turn reacted with the
benz[e]isoindoles 5.
Resu lts a n d Discu ssion
Compounds were assayed for their affinity at the R1
receptor subtypes. The SAR study reported herein was
broken into the following parts: (i) variation of the
bicyclic heterocycles; (ii) effects of the substituents on
the quinazolinedione portion of the molecule; (iii) modi-
fication of the pyrimidinedione ring.
The first objective of our studies was to investigate
compounds that could be viewed as the truncated
version of the tricyclic lead compound 1. The results of
this effort are summarized in Table 1. As is evident,
Ch a r t 3

Agents for Treatment of BPH
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 12 1973
Sch em e 1a
a
Conditions and reagents: (a) phosgene, Et3N; (b) 2-chloroethyl isocyanate; (c) (i) CH2Cl2, room temperature, (ii) KOtBu; (d) toluene,
reflux; (e) DMSO, diisopropylethylamine.
Sch em e 2a
a
Conditions and reagents: (a) (i) HCO2H, acetic anhydride, THF, (ii) BH3(CH3)2S, THF; (b) 2-chloroethylisocyanate, toluene; (c)
diisopropylethylamine, CH3CN.
with the exception of 15, thieno[3,2-d]pyrimidinediones
were generally not selective for the R1A receptor. It is of
interest to note the different effects of substituents on
the thiophene ring. The 6-phenyl group, as in 14,
significantly lowered the potency, whereas the introduc-
tion of the phenyl group in the 7-position as in 13
resulted in increased affinity at the R1A receptor but no
improvement in selectivity. The smaller OMe group, as
in compound 15, increased both the potency and the
selectivity. The combination of methoxy and alkyl group
substitution as in 17 and 18 resulted in somewhat
diminished selectivity by comparison with 15.
Further explorations of the effect of different hetero-
cyclic isosteres on the selectivity and potency of bicyclic
analogues are summarized in Table 2. It is evident that
all these analogues lacked the desired level of selectiv-
ity. Of all the replacements, one of the more potent
examples was the quinazolinedione 27. The more de-
tailed SAR study of the substituted quinazolinediones
was made possible by the abundance of commercially

1974 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 12
Meyer et al.
Sch em e 3a
a
Conditions and reagents: (a) (Me)2NCH(OMe)2, DMF; (b) p-toluenesulfonic acid, dioxane, reflux; (c) H2, Pd/C.
Sch em e 4a
a
Conditions and reagents: (a) NaBH4, MeOH; (b) H2, Pd/C, MeOH; (c) 37% HCHO, HCl, EtOH; (d) CDI, CH3CN.
available anthranilic acids. The results of this SAR
analysis are presented in Table 3. It is of interest to
note that the 8-OMe-substituted derivative 28 mani-
fested only marginal selectivity whereas 7-substituted
derivatives, in particular 7-CN and 7-OCH3 (30 and 31)
showed somewhat improved selectivity and affinity for
the R1A receptor. It is noted that similar selectivities
were observed in compounds 15 and 31, wherein the
thiophene ring was replaced by phenyl. The moderate
selectivity of compound 31 was lost when the substit-
uents were moved to the 5-position of the ring (36 and
37). The disubstituted derivatives, like the 6,7-dimethoxy
(40), the 7,8-dimethyl (42), and the 7,8-dimethoxy (43),
were generally more selective than their monosubsti-
tuted analogues.
Since compound 40 represented the most selective
compound so far, we explored pyrimidine ring modifica-
tions in the quinazolinedione series with 6,7-dimethoxy
substitution (Table 4). Introduction of the methyl group
as in compound 46 attenuated the selectivity. The
removal of the 2-carbonyl group on the other hand
improved the (R1A vs R1B) selectivity and resulted in the
most selective compound in the series, compound 48.
Saturation of the double bond of 48 resulted in com-

Agents for Treatment of BPH
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 12 1975
Sch em e 5a
a
Conditions and reagents: (a) 1-bromo-2-chloroethane, K2CO3, DMF; (b) K2CO3, DMF; (c) NaH, DMF.
Ta ble 1. SAR of Thieno[3,2-d] Pyrimidindiones
radioligand binding Ki f (nM)
selectivity ratioe
b
b
b
compound
R1
R2
R1A
R1B
R1D
11a
12a
13a
14a
15
16
17
18
H
H
H
Ph
OMe
COOMe
OMe
H
Me
Ph
H
H
H
1.39 (1.21, 1.6)
0.85 (0.73, 0.98)
0.33c (0.30, 0.35)
7.73d
1.63 (1.43, 1.85)
1.28 (1.04, 1.57)
0.33c (0.25, 0.42)
11.3d
0.92 (0.89, 0.91)
0.71 (0.68, 0.71)
0.66c (0.60, 0.72)
4.40d
0.24 (0.20, 0.24)
1.38 (1.06, 1.79)
1.45d
1.17
1.50
1.0
1.5
18
2.3
6.5
5.6
0.04 (0.02, 0.08)
1.48 (1.06, 1.48)
1.09d
0.74 (0.64, 0.86)
3.37 (2.65, 4.29)
7.14d
Me
i-propyl
OMe
0.41d
2.31d
1.5
a
b
d
Racemic. Number of determinations: g3. c Number of determinations: 2. Number of determinations: 1. e Selectivity ratio: Ki(R1B
/
R
1A). f Values in parentheses are the upper and lower limits derived as a result of the SEM.
pound 49 with a drastically lowered potency. Elimina-
using phenylephrine (PE) challenge in dog prostate
tion of both carbonyl groups as in 52 and 55 produced
a further loss of affinity. It was also shown that the
4-carbonyl group was absolutely essential for the affinity
at the receptors. Its removal as in 53 led to a dramatic
loss of the potency.
It is of interest to note that compounds with the
modified pyrimidine ring (e.g., 48) manifested the
greatest level of selectivity (R1A vs R1B) and had very
weak affinity for the R1D receptor subtype. This finding
distinguishes these analogues from the pyrimidinedione
analogues (40, 43, and 30) and previously described
tricyclic substituted benz[e]isoindoles like 1. Comparison
of compounds 1 and 48 could be useful tools in estab-
lishing the role of the R1D receptor in treatment of BPH.
Functional assays for pharmacologically defined R1
adrenoceptors were used to further characterize the
most selective compounds. Receptors were classified
(R1A),27 rat vas deferens (R1A),28 and rat spleen (R1B).28
For each of these models, agonist dose response curves
were repeated against increasing concentrations of test
antagonist and Schild plot analysis was used to deter-
mine the pA2 value (Table 5). With the exception of
tamsulosin, functional antagonist selectivity was highly
correlated to receptor subtype binding affinity. Nonse-
lective R1 antagonists such as terazosin (as defined by
receptor binding affinity) also failed to demonstrate
functional antagonist selectivity, whereas the most
selective compounds from this study (e.g., 48) based on
receptor binding affinity also exhibited the greatest
selectivity in in vitro functional models.
The most R1A selective compound 48 was further
evaluated in two in vivo models: an intraurethral
pressure (IUP) model as a measure of efficacy and the
spontaneously hypertensive rat (SHR) model as a

1976 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 12
Ta ble 2. SAR of Heterocyclic Substituents
Meyer et al.
a
b
d
* Racemic. Number of determinations: g3. Number of determinations: 2. c Number of determinations: 1. Selectivity ratio ) Ki(R1B
/
R
1A). e Values in parentheses are the upper and lower limits derived as a result of the SEM.
measure of hypotensive liability. The IUP model used
aged male anesthetized dogs, in which a pressure
transducer was inserted through the urethra to the
region of the prostate. Phenylephrine caused a dose-

Agents for Treatment of BPH
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 12 1977
Ta ble 3. SAR of Mono- and Disubstituted Quinazolinediones
f
radioligand binding Ki (nM)
b
b
b
compound
substituent
R1A
R1B
R1D
selectivity ratioe
27
0.67d
1.16d
0.62d
1.73
2.67
4.75
17.3
7.3
3.65
1.95
6.07
3.68
1.31
0.90
4.9
2.94
26.9
5.96
14.6
16.5
28a
29a
30
8-OMe
7-Cla
7-CN
7-OMe
7-NO2
7-NHCOCH3
7-COOMe
6-OMe
5-Cl
0.85 (0.75, 0.96)
0.57 (0.50, 0.64)
0.09 (0.05, 0.15)
0.09 (0.05, 0.17)
0.91d
2.27 (2.10, 2.45)
2.71 (1.90, 3.86)
1.56 (1.16, 2.11)
0.66 (0.63, 0.68)
3.33d
1.15 (1.08, 1.23)
0.58 (0.50, 0.69)
0.77 (0.61, 0.99)
0.21 (0.14, 0.32)
1.20d
31
32
33
34
0.43d
0.84d
0.41d
0.27d
1.64c (1.07, 2.54)
3.76 (3.26, 4.33)
0.92 (0.82, 1.04)
1.04 (0.92, 1.17)
9.27 (7.64, 11.2)
4.07d
0.77c (0.61, 0.98)
1.13 (1.11, 1.15)
0.69 (0.62, 0.76)
1.13 (0.81, 1.58)
2.71 (2.15, 3.43)
0.73d
35a
36a
37a
38
1.02 (0.88, 1.21)
0.71 (0.57, 0.88)
1.15 (1.65, 2.17)
1.89 (1.53, 2.35)
1.38d
0.24 (0.21, 0.28)
2.73c (2.66, 2.80)
0.09 (0.05, 0.15)
0.04 (0.03, 0.05)
5-Me
6-Cl,7-OMe
6,7-Me
6,7-OMe
6,8-Me
7,8-Me
7,8-OMe
39
40
6.46 (6.03, 6.91)
16.28c (13.3, 19.9)
1.32 ((1.15, 1.50)
0.66 (0.62, 0.71)
1.40 (1.36, 1.44)
2.86c (2.72, 3.02)
0.89 (0.68, 1.17)
0.68 (0.63, 0.73)
41a
42
43
a
b
d
Racemic. Number of determinations: g3. c Number of determinations: 2. Number of determinations: 1. e Selectivity ratio ) Ki(R1B
/
R
1A). f Values in parentheses are the upper and lower limits derived as a result of the SEM.
related increase in intraurethral pressure, which was
manifested only with specifically substituted quinazo-
blockable by R1A antagonists. Dose response curves were
generated at varying antagonist doses. From these data
a pseudo-pA2 value could be generated to calculate the
dose required to produce a 2-fold rightward shift of the
agonist dose response curve. Hypotensive activity of test
compounds was assessed in the SHR model using an
ascending iv dosing paradigm and measuring the de-
crease in blood pressure averaged over a 60-minute
period. From the area under the curve (T60 AUC) an
ED50 value was calculated as the dose required to
produce a decrease in mean arterial pressure equivalent
to 50% of normotensive. Measuring the blood pressure
over only a 60 min period was chosen to minimize the
potential impact of variable pharmacokinetics between
compounds. Pseudo-pA2 values from the IUP model and
pED50 values from the SHR model are reported in Table
6. As was found previously,1 the absolute selectivity
ratio determined in vivo is an order of magnitude
greater than the in vitro selectivity ratio. The high
correlation among receptor affinity, functional response
in target tissues, and in vivo response to relax prostatic
smooth muscle vs blood pressure control adds further
evidence to support the hypothesis that the R1A subtype
differentially mediates prostatic tone and that the R1B
subtype plays a prominent role in control of vascular
tone.
linediones, where 6,7-dimethoxy compounds were the
best. Further modification of the pyrimidine portion of
the molecule resulted in the development of the more
potent and selective pyrimidinone analogue 48. Com-
pound 48 showed the highest degree of selectivity in
radioligand binding assays (57-fold), in vitro functional
assays (80-fold), and in vivo prostate selectivity (almost
1000-fold). This correlation is further evidence that
prostatic smooth muscle tone is primarily mediated by
the R1A subtype.
Exp er im en ta l Section
1. Biology. 1.1. Ra d ioliga n d Bin d in g Assa ys. The com-
pounds were evaluated for R1 adrenoceptor binding affinity in
vitro using the cloned R1B (hamster) and for R1D (rat) adreno-
ceptors expressed in LTK cells as well as for the pharmacologi-
cally defined R1A adrenoceptor (rat submaxillary gland). Ra-
dioligand binding assays were performed as described previously
by Knepper et al.29 Briefly, recombinant R1 adrenoceptors were
stably expressed in mouse fibroblast cells (LTK-) grown in
roller bottle cultures to provide cell membranes for subsequent
receptor binding characterization studies. Membranes were
prepared from confluent cells, and aliquots of the pooled
homogenates were frozen in N2(l) and stored at -70 °C until
the time of assay. Radioligand binding was performed as
follows. Tubes containing 0.05 mL of water (total binding), 0.05
mL of 10-5 M final concentration of phentolamine (nonspecific
binding) or 0.05 mL of the compound of interest, 0.45 mL of
[3H]-prazosin, approximately 200 pM, and 0.5 mL of receptor
preparation (generally 0.83 mg wet weight or approximately
0.1 mg protein per assay tube) in 50 mM Tris-HCl (pH ) 7.4)
and samples were incubated for 60 min at 25 °C. All assays
were terminated by filtration under vacuum through What-
man GF/B filters. Data were analyzed as previously de-
scribed.29
Con clu sion
A structurally novel series of R1 antagonists, possess-
ing a 6-methoxybenz[e]isoindole unit attached to a
variety of bicyclic heterocycles via a two-carbon alkyl
chain, was described. It was found that selectivity was

1978 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 12
Ta ble 4. SAR of Pyrimidine Ring Modification
Meyer et al.
a
b
d
*Racemic. Number of determinations: g3. Number of determinations: 2. c Number of determinations: 1. Selectivity ratio ) Ki(R1B
/
R
1A). e Values in parentheses are the upper and lower limits derived as a result of the SEM.
1.2. In Vivo Mod els. Deter m in a tion of In tr a u r eth r a l
with 1 mL of room air, and the catheter was slowly withdrawn
just past the first resistance that is felt at the bladder neck.
The balloon port of the catheter was connected to a Gould
Statham P23Dd pressure transducer interfaced to a computer-
ized data acquisition system (Modular Instruments, Inc.) for
the measurement of IUP. Dogs were then treated with pro-
pranolol (100 µg/kg iv) to block the â adrenoceptor agonist
effect of epinephrine. Dose response curves of the intraurethral
P r essu r e (IUP ) in Dogs. Beagle dogs (Marshall Farms,
North Rose, NY) greater than 2 years of age and weighing
between 12 and 15 kg were preanesthetized with thiopental
sodium, 15 mg/kg iv, and anesthetized using isoflurane. A 7F
balloon catheter (Multiflex list no. 41224-01, Abbott) was
inserted into the urethral orifice until the balloon tip was
placed well inside the bladder. The balloon was then inflated

Agents for Treatment of BPH
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 12 1979
Ta ble 5. In Vitro Profile of Benz[e]isoindole Antagonists in
Comparison with Other Adrenergic Antagonists
mmol) were heated at reflux in toluene (25 mL) for 3 h. The
reaction mixture was concentrated in vacuo to yield crude
methyl 3-isocyanato-2-thiophenecarboxylate as a white crys-
talline compound. This isocyanate (0.21 g, 1.15 mmol) was
reacted with the amine 6 (0.24 g, 1.0 mmol) in toluene (40 mL)
at reflux for 3 h. The reaction mixture was then partitioned
between 5% NaHCO3 and hot EtOAc, and the organic phase
was dried (K2CO3) and evaporated. The resulting product was
converted to its HCl salt and recrystallized to yield 11 (0.12
g, 28%) as a white solid, mp 190-192 °C. 1H NMR (CDCl3)
(free base): δ 1.55-1.68 (m, 1H), 1.85-1.98 (m, 1H), 2.53-
2.65 (m, 1H), 2.70-2.83 (m, 2H), 2.83-2.96 (m, 2H), 3.39-
3.50 (m, 2H), 3.67 (q, 1H), 3.82 (s, 3H), 4.08-4.30 (m, 2H),
4.37 (t, 2H), 6.74 (t, 2H), 6.84 (d, 1H), 7.15 (t, 1H), 7.62 (d,
1H), 8.17 (bs, 1H). MS (DCI/NH3): m/e 398 (M + H)+. Anal.
(C21H23N3O3S‚HCl‚0.75H2O) C, H, N.
a
a
a
pA2 rat
pA2
pA2
selectivity
ratioc
antagonist vas deferens rat spleen dog prostate
terazosin
doxazosin
alfuzosin
8.04 ( 0.45 8.6 ( 0.46
7.44 ( 0.24
0.27
0.15
0.20
0.60
10.23
5.62
8.69 ( 0.70 9.51 ( 0.41 7.59 ( 0.20
7.61 ( 0.13 8.31 ( 0.12 6.66 ( 0.10
tamsulosin 9.47 ( 0.21 9.69 ( 0.44 9.54 ( 0.17
40
43
48
30
8.53 ( 0.08b 7.52 ( 0.03b 9.01 ( 0.10b
8.9 ( 0.12b 8.15 ( 0.01b 9.45 ( 0.09b
8.97 ( 0.49b 7.07 ( 0.16b 9.23 ( 0.16b
8.83 ( 0.07b 7.73 ( 0.04b 9.83 ( 0.15b
79.43
12.59
a
Data expressed as a pA2 ( SEM. Slopes are not different from
b
unity. Number of determinations: g3. Number of determina-
tions: 2. c Selectivity ratio: antilog[pA2(rat vas deferens)/pA2(rat
spleen)].
2.1.2. 3-[2-(cis-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-[1H]-
ben z[e]isoin d ol-2-yl)eth yl]-7-m eth ylth ien o[3,2-d ]p yr im i-
d in e-2,4(1H,3H)-d ion e Hyd r och lor id e (12). The amine 6
(0.24 g, 1.0 mmol) and methyl 3-isocyanate-4-methyl-2-
thiophenecarboxylate (0.22 g, 1.1 mmol) were treated by
method A to yield 0.12 g of 12 as a white solid, mp 255-257
°C. 1H NMR (CDCl3) (free base): δ 1.52 (m, 1H), 1.75 (m, 1H),
2.25 (m, 2H), 2.28 (s, 3H), 2.55 (m, 2H), 2.64-2.90 (m, 3H),
3.36-3.50 (m, 3H), 3.81 (s, 3H), 4.21 (t, 2H), 6.67 (d, 1H), 6.74
(d, 1H), 7.10 (t, 1H), 7.31 (d, 1H), 10.5 (bs, 1H). MS (DCI/
NH3): m/e 412 (M + H)+. Anal. (C22H25N3O3S‚HCl‚0.5H2O) C,
H, N.
Ta ble 6. Comparison of Antagonists in the IUP and SHR
Models
IUP,
pseudo-pA2
(95% CL)
SHR,
pseudo-pED50
( SEM
a
a
selectivity
ratiob
antagonist
terazosin
doxazosin
alfuzosin
tamsulosin
48
7.02 (6.36-7.69)
7.12 (6.54-7.70)
6.87 (6.46-7.28)
8.87 (8.41-9.33)
8.30c (8.09-8.51)
6.64 ( 0.76
6.50 ( 0.63
6.58 ( 0.62
7.33 ( 0.30
5.32 ( 0.32c
2.4
4.2
1.9
35
959
a
Number of determinations: g3. b Selectivity ratio: antilog(pA2
2.1.3. 3-[2-(cis-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-[1H]-
ben z[e]isoin d ol-2-yl)eth yl]-7-p h en ylth ien o[3,2-d ]p yr im i-
d in e-2,4(1H,3H)-d ion e Meth a n esu lfon a te (13). The amine
6 (0.55 g, 2.2 mmol) and the isocyanate (0.90 g, 3.3 mmol)
prepared from 2-carboethoxy-3-amino-4-phenylthiophene23 were
treated by method A to yield the free base (0.39 g, 38%) of 13,
which was converted to the methanesulfonic acid salt, mp
- pED50). c Number of determinations: 2.
pressor effect of epinephrine were obtained before and after
each dose of a test antagonist. The estimated antagonist
dissociation constant (in vivo pseudo-pA2) was determined by
Schild analysis.30
1
268-271 °C. H NMR (DMSO-d6): δ 1.6 (m, 1H), 1.8 (m, 1H),
1.3. Sp on t a n eou sly H yp er t en sive R a t (SH R ) Mod el.
Male spontaneously hypertensive rats (300-325 g) were briefly
anesthetized with Penthrane, and the left femoral artery and
vein were catheterized for the measurement of mean arterial
pressure (MAP) and drug administration, respectively. After
a 2.5 h recovery period, the arterial catheter was connected
to a Gould Statham p23ID transducer and the pressure
waveform was recorded. Mean arterial pressure (MAP, mmHg)
and heart rate (HR, beats/min) were determined on line using
a BUXCO cardiovascular analyzer. After a 30 min predose
control period each rat was given one dose of a test antagonist
iv and the MAP and HR were measured over a 60 min period.
The area under the hypotensive dose response curve (T60 AUC)
was determined using a trapezoidal rule integration of the
percent change from the control arterial pressure data set. The
antagonist T60 AUC was compared to that of a hypothetical
antagonist producing complete normalization of blood pressure
for 60 min. The ED50 value was determined as the dose
required to produce a T60 AUC equivalent to a 50% change to
normotensive.
2. Ch em istr y. Proton NMR spectra were obtained on a
General Electric QE 300 or QZ 300 MHz instrument with
chemical shifts (δ) reported relative to tetramethylsilane as
internal standard. Melting points were determined on a
Thomas-Hoover capillary melting point apparatus and are
uncorrected. Elemental analyses were performed by Robertson
Microlit Laboratories. Column chromatography was carried
out on silica gel 60 (230-400 mesh). Thin layer chromatog-
raphy (TLC) was performed using 250 mm silica gel 60 glass-
backed plates with F254 as indicator. Optical rotations were
measured with a Perkin-Elmer 541 polarimeter. All physical
data and yields for final compounds correspond to the indicated
salt form unless otherwise noted.
2.42 (m, 2H), 2.65 (m, 2H), 3.03 (m, 3H), 3.55 (m, 3H), 3.75 (s,
3H), 4.25 (m, 2H), 6.75 (m, 1H), 6.85 (m, 1H), 7.18 (t, 1H), 7.3
(d, 1H), 7. 5 (m, 3H), 7.8 (m, 2H), 10.35 (bs, 1H). MS (DCI/
NH3): m/e 474 (M + H)+. Anal. (C28H31N3O6S2‚0.25H2O) C, H,
N.
2.1.4. 3-[2-(cis-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-[1H]-
ben z[e]isoin d ol-2-yl)eth yl]-7-p h en ylth ien o[3,2-d ]p yr im i-
d in e-2,4(1H,3H)-d ion e Hyd r och lor id e (14). The amine 6
(0.40 g, 1.6 mmol) and the isocyanate (0.54 g, 2.1 mmol)
derived from 2-carboethoxy-3-amino-5-phenylthiophene22 were
treated by method A to yield 14 (0.39 g, 38%) as a white solid,
1
mp 229-231 °C. H NMR (DMSO-d6): δ 1.6 (m, 1H), 1.8 (m,
1H), 2.45 (m, 2H), 2.72 (m, 2H), 3.05 (m, 3H), 3.55 (m, 3H),
3.75 (s, 3H), 4.25 (m, 2H), 6.8 (m, 2H), 7.18 (t, 1H), 7.5 (m,
5H), 8.1 (m, 1H), 10.35 (s, 1H). MS (DCI/NH3): m/e 474 (M +
H)+. Anal. (C27H27N3O3S‚HCl‚0.5H2O) C, H, N.
2.1.5. 3-[2-((3aR,9bR)-cis-6-Meth oxy-2,3,3a,4,5,9b-h exah y-
d r o-[1H ]-b en z[e]isoin d ol-2-yl)et h yl]-6-m et h oxyt h ien o-
[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e F u m a r a te (15). A 2.5
M n-BuLi (4.0 mL, 10 mmol) sample was added to MeOH (404
mL, 10 mmol) in THF (10 mL) at 0 °C under nitrogen. After
the mixture was stirred for 20 min, CS2 (600 mL, 10 mmol)
was added and stirring was continued for 4 h. The reaction
was then cooled to 0 °C followed by the addition of MeI (620
mL, 10 mmol), whereupon the reaction mixture was stirred
for 4 h at 0 °C and then at ambient temperature overnight. In
a separate flask the anion of acetonitrile was prepared by the
dropwise addition of MeCN (520 mL, 10 mmol) to a solution
of LDA (10 mmol) in THF at -78 °C followed by stirring for
30 min at that temperature. The solution of the xanthate
prepared above was added to the acetonitrile anion. The
reaction mixture was stirred for 1 h at -78 °C, then 1 h at 0
°C. The reaction mixture was then cooled to -78 °C, treated
with ethyl bromoacetate (1.1 mL, 10 mmol), warmed to room
temperature, treated with 1.0 M lithium bistrimethylsilyla-
mide (1 mL), and heated at reflux for 1.5 h. After cooling, the
reaction mixture was partitioned between saturated NaHCO3
solution and CH2Cl2. The organic layer was dried with sodium
2.1. Meth od A. Method A is exemplified by the following
procedure for 11.
2.1.1. 3-[2-(cis-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-[1H]-
ben z[e]isoin d ol-2-yl)eth yl]-th ien o[3,2-d ]-p yr im id in e-2,4-
(1H,3H)-d ion e Hyd r och lor id e (11). 3-Amino-2-carboethoxy-
thiophene (0.20 g, 1.15 mmol) and triphosgene (0.11 g, 0.38

1980 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 12
Meyer et al.
sulfate, filtered, concentrated in vacuo, and chromatographed
on silica gel eluting with 4:1 hexanes/EtOAc to give 0.343 g
(17%) of 5-amino-4-carboethoxy-2-methoxythiophene. 5-Amino-
4-carboethoxy-2-methoxythiophene (0.3 g, 1.51 mmol) in CH2-
Cl2 was cooled to -78 °C and treated with 1.93 M solution of
phosgene in toluene (0.082 mL, 1.55 mmol) in the presence of
triethylamine (0.045 mL). After 1 h at -78 °C the solution of
the amine 6a (0.375 g, 1.52 mmol) in CH2Cl2 was added to
the reaction mixture. After being stirred for 1 h, the reaction
mixture was quenched into NaHCO3 solution and extracted
with CH2Cl2. The combined organic extracts were dried
(MgSO4) and evaporated to yield the corresponding urea. This
was dissolved in THF, and 1.7 mL of 1.0 M potassium tert-
butoxide was added to the solution. After 1 h at 60 °C the
reaction mixture was neutralized with 1 N HCl and extracted
with EtOAc (3×). The combined organic layers were dried (Na2-
SO4) and evaporated to give the crude product that was
chromatographed on silica gel eluting with 3% Et3N/3% MeOH/
EtOAc to yield 15 (0.24 g, 38%) as a free base that was
2.2.1. 3-[2-((3aR,9bR)-cis-6-Meth oxy-2,3,3a,4,5,9b-h exah y-
d r o-[1H]-ben z[e]isoin d ol-2-yl)eth yl]-th ien o[2,3-d ]p yr im i-
d in e-2,4(1H,3H)-d ion e Hyd r och lor id e (19). 2-Amino-3-
carboethoxythiophene, prepared by the method of Gewald,31
was treated with 2-chloroethylisocyanate.20 The resulting urea
(1.65 g, 6.0 mmol), the benz[e]isoindole 5a (1.10 g, 5.4 mmol),
and diisopropylethylamine (1 mL) in DMSO (2 mL) were
heated at 100 °C for 2 h. The reaction mixture was quenched
in water and extracted with EtOAc. The combined organic
extracts were dried and concentrated in vacuo, resulting in
the urea ester intermediate, which was treated with 1.0 M
KOtBu (0.6 mL) in EtOH (6 mL) at reflux for 0.5 h. The
reaction mixture was evaporated, and the residue was chro-
matographed on silica gel, eluting with EtOAc/EtOH (95:5) to
yield 19 (0.91 g (39%) as a free base that was converted to the
1
HCl salt, mp 179-182 °C (dec). H NMR (free base) (CDCl3):
δ 1.52-1.66 (m, 1H), 1.80-1.92 (m, 1H), 2.49-2.65 (m, 3H),
2.69-2.83 (m, 2H), 3.18-3.38 (m, 2H), 3.59-3.70 (m, 1H), 3.82
(s, 3H), 3.96-4.10 (m, 2H), 4.30 (bt, 2H), 6.49 (d, 1H), 6.70 (d,
1H), 6.79 (d, 1H), 6.93 (d, 1H), 7.13 (t, 1H). MS (DCI/NH3):
m/e 398 (M + H)+. Anal. (C21H23N3O3S‚HCl‚1.5H2O) C, H, N.
1
converted to the fumarate salt, mp 217 °C. H NMR (DMSO-
d6): δ 1.45 (1H, m), 1.65 (1H, m), 2.23 (1H, m), 2.32 (1H, m),
2.44 (2H, m), 2.58 (1H, m), 2.66 (2H, m), 3.30 (3H, m), 3.75
(3H, s), 3.95 (2H, t), 3.99 (3H, s), 6.10 (1H, s), 6.59 (2H, s),
6.72 (1H, d), 6.75 (1H, d), 7.09 (1H, t), 11.76 (1H, br s). Anal.
(C26H29N3O8S) C, H, N.
2.2.2. 3-[2-(cis-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-[1H]-
ben z[e]isoin d ol-2-yl)eth yl]-th ien o[3,4-d ]p yr im id in e-2,4-
(1H,3H)-d ion e Hyd r och lor id e (20). The amine 6 (0.30 g, 1.2
mmol) and the isocyanate derived from 3-amino-4-carboethoxy-
thiophene32 were treated by method A to yield 20 (0.15 g, 45%)
as a white solid, mp 205-210 °C. 1H NMR (CDCl3) (free
base): δ 1.54-1.88 (m, 1H), 1.82-1.94 (m, 1H), 2.52-2.65 (m,
1H), 2.71-2.86 (m, 4H), 3.25-3.38 (m, 2H), 3.66-3.79 (m, 1H),
3.83 (s, 3H), 3.98-4.18 (m, 2H), 4.29 (t, 2H), 6.55 (d, 1H), 6.71
(d, 1H), 6.77 (d, 1H), 7.13 (t, 1H), 8.10 (d, 1H), 10.2 (bs, 1H).
MS (DCI/NH3): m/e 398 (M + H)+. Anal. (C21H23N3O3S‚HCl‚
1.5H2O) C, H, N.
2.1..6.
3-[2-((3a R ,9b R )-cis-6-Met h oxy-2,3,3a ,4,5,9b -
h e x a h y d r o -[1H ]-b e n z [e]i s o i n d o l-2-y l)e t h y l]-6-c a r -
bom eth oxyth ien o[3,2-d ]pyr im idin e-2,4(1H,3H)-dion e Hy-
d r och lor id e (16). To a slurry of compound 11 (0.39 g, 1 mmol)
in THF cooled to -5 °C was slowly added 2.1 equiv of LDA
solution. After the mixture was stirred at this temperature
for 1 h, methylformate (0.08 mL, 1 mmol) was added. The
reaction mixture was stirred for another hour at 0 °C, then it
was quenched into saturated NaHCO3 solution and extracted
with CH2Cl2 (3×). The combined organic extracts were dried
(Na2SO4) and evaporated. The residue was chromatographed
on silica gel, eluting with 18:1:1 EtOAc/H2O/HCOOH to yield
16 (0.11 g, 24%) as its formic acid salt. It was converted to
HCl salt and triturated with EtOH/toluene to form an amor-
2.2.3. 3-[2-(cis-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-[1H]-
ben z[e]isoin d ol-2-yl)eth yl]-1H-p yr r olo[2,3-d ]p yr im id in e-
2,4(3H,7H)-d ion e F u m a r a te (21). 2-Amino-3,4-bis(ethoxy-
carbonyl)pyrrole33 was reacted with 2-chloroethylisocyanate by
method B. The intermediate urea (0.60 g, 2.1 mmol) was
reacted with the benz[e]isoindole 5 (0.41, 2 mmol) as in 19.
The urea ester intermediate was treated with 5% KOH (50
mL) and heated at 110 °C for 1 h. After the mixture was cooled
to room temperature, the pH of the reaction mixture was
adjusted to 12 by the addition of concentrated HCl, resulting
in the precipitation of the product. The product was extracted
with CH2Cl2, and the organic layer was dried and evaporated
to give 0.19 g of 21 as a free base that was converted to the
1
phous solid. H NMR (CDCl3) (free base): δ 1.55 (m, 1H), 1.8
(m, 1H), 2.38 (m, 2H), 2.5-2.75 (m, 3H), 3.02 (m, 1H), 3.12
(m, 1H), 3.48 (m, 1H), 3.73 (m, 2H), 3.8 (s, 3H), 3.95 (s, 3H),
4.25 (m, 2H), 6.65 d, 1H), 6.76 (d, 1H), 7.09 (t, 1H), 7.15 (s,
1H). MS (DCI/NH3): m/e 456 (M + H)+. Anal. (C23H25N3O5S‚
HCl) C, H, N.
2.1..7. 3-[2-((3aR,9bR)-cis-6-Meth oxy2,3,3a,4,5,9b-h exah y-
d r o-[1H]-ben z[e]isoin d ol-2-yl)eth yl]-6-m eth oxy-7-m eth -
ylth ien o[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Hyd r och lo-
r ide (17). 4-Amino-5-carboethoxy-2-methoxy-3-methylthiophene
(0.46 g, 1.93 mmol) prepared by the method described for 15,
substituting propionitrile for MeCN, and the amine 6a (0.49
g, 2 mmol) were reacted as described in the procedure for 15
to yield the free base of 17 (0.42 g), which was converted to
1
fumaric acid salt. H NMR (CD3OD): δ 1.62 (m, 1H), 1.90 (m,
1H), 2.58 (m, 1H), 2.78 (m, 1H), 2.82 (dt, 1H), 3.18 (m, 2H),
3.40 (t, 2H), 3.62 (dd, 1H), 3.81 (s, 3H), 3.86 (dd, 1H), 4.01
(dd, 1H), 4.33 (t, 2H), 6.42 (d, 1H), 6.64 (d, 1H), 6.65 (s, 2H),
6.77 (d, 1H), 6.81 (d, 1H), 7.15 (t, 1H). MS (DCI/NH3): m/e
381 (M + H)+. Anal. (C25H28N4O7‚0.75H2O) C, H, N.
2.2.4. 3-[2-(cis-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-[1H]-
ben z[e]isoin d ol-2-yl)eth yl]-p yr id o[2,3-d ]p yr im id in e-2,4-
(1H,3H)-d ion e Hyd r och lor id e (22). 2-Amino-3-ethoxycar-
bonylpyridine (0.46 g, 2.8 mmol), prepared from 2-aminonicotinic
acid by the procedure described for 3-aminopicolinic acid,24 was
converted to the isocyanate in situ as described for 15 and
reacted with the amine 6 (2.8 mmol) by method A to yield 22,
mp 234-236 °C. 1H NMR (CDCl3) (free base): δ 1.47-1.61
(m, 1H), 1.72-1.86 (m, 1H), 2.27 (q, 2H), 2.49-2.61 (m, 1H),
2.64-2.77 (m, 2H), 2.84-2.95 (m, 1H), 3.05-3.16 (m, 1H), 3.53
(q, 1H), 3.76 (t, 2H), 3.80 (s, 3H), 4.17-4.35 (m, 2H), 6.67 (d,
1H), 6.77 (d, 1H), 6.90-6.96 (m, 1H), 7.09 (t, 1H), 8.05 (dt,
1H), 8.48 (dd, 1H). MS (DCI/NH3): m/e 393 (M + H)+. Anal.
(C22H24N4O3‚HCl‚0.75H2O) C, H, N.
2.2.5. 3-[2-(cis-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-[1H]-
ben z[e]isoin d ol-2-yl)eth yl]-p yr id o[3,4-d ]p yr im id in e-2,4-
(1H,3H)-d ion e Dih yd r och lor id e (23). 3-Amino-4-ethoxy-
carbonylpyridine (0.58 g, 3,5 mmol), prepared from 3,4-
pyridinedicarboxyimide by the literature procedure,24 and the
benz[e]isoindole 5a (0.60 g, 2.4 mmol) were reacted as de-
scribed for 15 to yield 0.68 g (71%) of 23, which was converted
to its HCl salt, mp 228-230 °C. 1H NMR (CD3OD) (free base):
1
HCl salt, mp 205 °C (dec). H NMR (DMSO-d6): δ 1.45 (1H,
m), 1.65 (1H, m), 2.0(s, 3H), 2.1-2.32 (2H, m), 2.44 (2H, m),
2.6 (2H, m), 3.30 (3H, m), 3.75 (3H, s), 3.95 (2H, m), 3.99 (3H,
s), 6.72 (1H, d), 6.75 (2H, m), 7.09 (1H, t). MS (DCI/NH3): m/e
442 (M + H).+ Anal. (C23H27N3O4S ‚HCl‚0.25H2O) C, H, N.
2.1..8.
3-[2-((3a R ,9b R )-cis-6-Met h oxy-2,3,3a ,4,5,9b -
h exa h yd r o-[1H]-ben z[e]isoin d ol-2-yl)eth yl]-7-isop r op yl-
6-m eth oxyth ien o[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Hy-
d r och lor id e (18). 4-Amino-3-isopropyl-5-carboethoxy-2-
methoxythiophene (0.33 g, 1.36 mmol), prepared by the method
described for 15, substituting isovaleronitrile for acetonitrile,
and the amine 6a were reacted as described in the procedure
for 15 to yield the free base of 18 (0.22 g, 34%), which was
converted to HCl salt. 1H NMR (CDCl3) (free base): δ 1.29 (s,-
3H), 1.31 (s, 3H), 1.55 (m, 1H), 1.75 (m, 1H), 2.28 (m, 2H),
2.55 (m, 2H), 2.62-2.85 (m, 3H), 3.05 (m, 1H), 3.41 (m, 3H),
3.8 (s, H), 4.0 (s, 3H), 4.18 (t, 2H), 6.68 (d, 1H), 6.72 (d, 1H),
6.95 (t, 1H). MS (DCI/NH3): m/e 470(M + H)+. Anal.
(C25H31N3O4S‚HCl) C, H, N.
2.2. Meth od B. Method B is exemplified by the following
procedure for 19.

Agents for Treatment of BPH
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 12 1981
δ 1.45-1.49 (m, 1H), 1.66-1.78 (m, 1H), 2.22 (t, 1H), 2.33 (dt,
1H), 2.50-2.68 (m, 3H), 2.77-2.86 (m, 2H), 3.24-3.51 (m, 3H),
3.77 (s, 3H), 4.20 (t, 2H), 6.71 (dd, 2H), 7.07 (t, 1H), 7.91 (d,
1H), 8.39 (d, 1H), 8.55 (s, 1H). MS (DCI/NH3): m/e 393 (M +
H)+. Anal. (C22H24N4O3‚2 HCl) C, H, N.
2.2.6. 3-[2-(cis-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-[1H]-
ben z[e]isoin d ol-2-yl)eth yl]-p yr id o[4,3-d ]p yr im id in e-2,4-
(1H,3H)-d ion e Dih yd r och lor id e (24). 4-Amino-3-ethoxy-
carbonylpyridine25 (0.57 g, 3.4 mmol) and the amine 6 (0.60 g,
2.4 mmol) were reacted as described for 15 to yield 0.69 g (72%)
of 24, which was converted to its HCl salt, mp 229-233 °C.
1H NMR (CDCl3) (free base): δ 1.49-1.62 (m, 1H), 1.75-1.87
(m, 1H), 2.38 (t, 2H), 2.50-2.77 (m, 3H), 2.88-2.98 (m, 1H),
3.09-3.20 (m, 1H), 3.47 (q, 1H), 3.69 (bt, 2H), 3.80 (s, 3H),
4.15-4.37 (m, 2H), 6.63 (d, 1H), 6.67 (d, 1H), 6.78 (d, 1H), 7.10
(t, 1H), 8.47 (d, 1H), 8.98 (s, 1H). MS (DCI/NH3): m/e 393 (M
+ H)+. Anal. (C22H24N4O3‚2 HCl‚1.5H2O) C, H, N.
7.28 (m, 2H), 7.95 (m, 1H). MS (DCI/NH3): m/e 426 (M + H)+.
Anal. (C23H24N3O3Cl‚HCl‚0.25H2O) C, H, N.
2.2.12.
3-[2-((3a R ,9b R )-cis-6-Met h oxy-2,3,3a ,4,5,9b -
h e xa h yd r o-[1H ]-b e n z[e]isoin d ol-2-yl)e t h yl]-7-cya n o-
qu in a zolin e-2,4(1H,3H)-d ion e Hyd r och lor id e (30). The
amine 6a (0.41 g, 1.7 mmol) and the isocyanate (0.36 g, 1.8
mmol), prepared from the 2-carboethoxy-5-cyanoaniline,34 were
reacted by method A and chromatographed on silica gel (18:
1:1 EtOAc/H2O/HCOOH) to yield the formic acid salt of 30 that
was converted to HCl salt (0.24 g, 35%), mp >250 °C. 1H NMR
(DMSO-d6): δ 1.54-1.68 (m, 1H), 1.70-1.85 (m, 1H), 2.43-
2.53 (m, 1H), 2.55-2.82 (m, 2H), 2.93-3.10 (m, 1H), 3.40-
3.55 (m, 4H), 3.77 (s, 3H), 3.97-4.30 (m, 4H), 6.73-6.90 (m,
2H), 7.17 (t, J ) 8 Hz, 1H), 7.58-7.65 (m, 2H), 8.10 (d, J ) 8
Hz, 1H), 10.40 (bs, 1H), 11.92 (s, 1H). MS (DCI/NH3): m/e 417
(M + H)+. Anal. (C24H24N4O3‚HCl‚0.35H2O) C, H, N.
2.2.13.
3-[2-((3a R,9bR)-cis-6-Meth oxy-2,3,3a ,4,5,9b-
2.2.7. 3-[2-(cis-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-[1H]-
ben z[e]isoin d ol-2-yl)eth yl]-p yr id o[3,2-d ]p yr im id in e-2,4-
(1H,3H)-d ion e Hyd r och lor id e (25). 3-Amino-2-ethoxycar-
bonylpyridine24 (0.30 g, 1.8 mmol) and the amine 6 (0.40 g,
1.6 mmol) were reacted as described for 15 to yield 0.51 g (80%)
of 25, which was converted to its HCl salt, mp 195-198 °C.
1H NMR (CDCl3) (free base): δ 1.47-1.62 (m, 1H), 1.74-1.87
(m, 1H), 2.47 (t, 2H), 2.50-2.76 (m, 3H), 2.97-3.07 (m, 1H),
3.13-3.25 (m, 1H), 3.46 (q, 1H), 3.70-3.83 (m, 2H), 3.78 (s,
3H), 4.24-4.43 (m, 2H), 6.65 (d, 1H), 6.77 (d, 1H), 7.07 (d, 1H),
7.12 (d, 1H), 7.31 (dd, 1H), 8.25 (d, 1H). MS (DCI/NH3): m/e
393 (M + H)+. Anal. (C22H24N4O3‚HCl‚1.25H2O) C, H, N.
2.2.8. 3-[2-((3aR,9bR)-cis-6-Meth oxy-2,3,3a,4,5,9b-h exah y-
d r o-[1H ]-b en z[e]isoin d ol-2-yl)et h yl]-2,4-p t er id in ed ion e
Hyd r och lor id e (26). Methyl 3-amino-2-pyrazinecarboxylate
(10 g, 65.2 mmol) was treated with 2-chloroethylisocyanate20
(5.6 mL, 65.2 mmol) to yield 1.1 g of chloroethyl urea. The urea
(0.264 g, 1.02 mmol) and 5a (0.2, 1.0 mmol) were reacted by
method B as in 19 and chromatographed on silica gel, eluting
with EtOAc/HCOOH/H2O (8:1:1) to yield the formic acid salt
of 26 that was converted to HCl salt, mp 310-312 °C.
1H NMR (DMSO-d6): δ 1.47 (m, 1H), 1.62 (m, 1H), 2.11-
2.28 (m, 2H), 2.4-2.68 (m, 1H), 3.18-3.31 (m, 3H), 3.78 (s,
3H), 4.0 (t, 2H), 6.78 (m, 1H), 6.82 (d, 2H), 7.09 (t, 1H), 7.85
(m, 1H), 8.36 (d, 1H), 8.65 (d, 1H). Anal. (C21H23N5O3‚HCl‚
1.25H2O) C, H, N.
h e x a h y d r o -[ 1 H ] -b e n z [ e ] i s o i n d o l -2 -y l ) e t h y l ] -7 -
m eth oxyqu in azolin e-2,4(1H,3H)-dion e Hydr och lor ide (31).
The amine 6a (0.42 g, 1.7 mmol) and the isocyanate (0.37 g,
1.8 mmol), prepared from 2-carboethoxy-5-methoxyaniline,35
were reacted by method A to yield 31 (0.32 g, 45%) as a tan
1
solid, mp 226-230 °C. H NMR (DMSO-d6): δ 1.70-1.85 (m,
1H), 1.54-1.68 (m, 1H), 2.43-2.53 (m, 1H), 2.55-2.82 (m, 2H),
2.93-3.10 (m, 1H), 3.40-3.55 (m, 4H), 3.77 (s, 3H), 3.85 (s,
3H), 3.97-4.30 (m, 4H), 6.73-6.90 (m, 4H), 7.17 (t, J ) 8 Hz,
1H), 7.88 (d, J ) 8 Hz, 1H), 10.25 (bs, 1H), 11.50 (s, 1H). MS
(DCI/NH3): m/e 422 (M + H)+. Anal. (C24H27N3O4‚HCl‚0.3H2O)
C, H, N.
2.2.14.
3-[2-((3a R ,9b R )-cis-6-Met h oxy-2,3,3a ,4,5,9b -
h e x a h y d r o -[1H ]-b e n z[e]is o in d o l-2-y l)e t h y l]-7-n it r o -
qu in a zolin e-2,4(1H,3H)-d ion e Hyd r och lor id e (32). 2-Car-
boethoxy-5-nitroaniline (4.74 g, 22.6 mmol), prepared from
2-amino-4-nitrobenzoic acid, and 2-chloroethylisocyanate (2.5
mL, 29.4 mmol) in toluene (50 mL) were heated at reflux for
16 h. Solvent was evaporated, and the remaining residue was
triturated with ethyl acetate to provide a crystalline urea (1.3
g). The benz[e]isoindole 5 (0.66 g, 3.25 mmol) and the inter-
mediate urea (1.23 g, 3.9 mmol) were reacted by method B to
yield, after chromatography on silica gel (18:1:1 EtOAc/H2O/
HCOOH), 32 (0.4 g, 29%) as its formic acid salt, which was
converted to the HCl salt. 1H NMR (CDCl3) (free base): δ
1.52-1.68 (m, 1H), 1.7-1.86 (m, 1H), 2.45 (m, 2H), 2.52-2.78
(m, 3H), 3.05 (m, 2H), 3.5 (m, 1H), 3.68 (m, 2H), 3.78 (s, 3H),
4.3 (m, 2H), 6.68 (d, 1H), 6.78 (d, 1H), 7.09 (t, 1H), 7.7 (s, 1H),
7.78 (d, 1H), 7.95 (d, 1H). MS (DCI/NH3): m/e 437 (M + H)+.
Anal. (C23H24N4O5‚HCl‚0.5H2O) C, H, N.
2.2.9. 3-[2-(cis-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-[1H]-
b e n z[e]isoin d ol-2-yl)e t h yl]q u in a zolin e -2,4(1H ,3H )-d i-
on e Hyd r och lor id e (27). 2-Carboethoxyphenylisocyanate
(0.20 g, 1.0 mmol) and the amine 6 (0.24 g, 1.0 mmol) were
1
reacted by method A to yield 0.12 g of 27 as a white solid. H
2.2.15.
3-[2-((3a R ,9b R )-cis-6-Met h oxy-2,3,3a ,4,5,9b -
NMR (DMSO-d6): δ 1.37-1.5 (m, 1H), 1.57-1.68 (m, 1H), 2.1-
2.3 (m, 2H), 2.38-2.48 (m, 2H), 2.52-2.65 (m, 3H), 3.12-3.3
(m, 3H), 3.73 (s, 3H), 4.02 (t, 2H), 6.72 (dd, 2H), 7.08 (t, 1H),
7.12-7.27 (m, 2H), 7.65 (t, 1H), 7.92 (d, 1H). Anal. (C23H25N3O3‚
HCl‚H2O) C, H, N.
2.2.10. 3-[2-(cis-6-Meth oxy-2,3,3a,4,5,9b-h exah ydr o-[1H]-
b en z[e]isoin d ol-2-yl)et h yl]-8-m et h oxyq u in a zolin e-2,4-
(1H,3H)-d ion e Hyd r och lor id e (28). The amine 6 (0.25 g, 1.0
mmol) and the isocyanate (0.30 g, 1.1 mmol) prepared from
2-methoxy-6-carboethoxyaniline were reacted by method A to
yield 28 (0.15 g, 33%) as a white solid, mp 233-235 °C. 1H
NMR (CDCl3) (free base): δ 1.52-1.68 (m, 1H), 1.88-1.98 (m,
1H), 2.51-2.63 (m, 1H), 2.7-2.98 (m, 4H), 3.41 (m, 2H), 3.68
(q, 1H), 3.82 (s, 3H), 3.98 (s, 3H), 4.1-4.28 (m, 2H), 4.42 (m,
2H), 6.75 (t, 2H), 7.08-7.2 (m, 3H), 7.68 (dd, 1H). MS (DCI/
NH3): m/e 422 (M + H)+. Anal. (C24H27N3O4‚HCl‚1.25H2O) C,
H, N.
h exa h yd r o-[1H ]-b en z[e]isoin d ol-2-yl)et h yl]-7-a cet a m i-
doqu in azolin e-2,4(1H,3H)-dion e Hydr och lor ide (33). Com-
pound 32 (0.3 g, 0.68 mmol) in MeOH was hydrogenated at 4
atm over 10% Pd/C catalyst to yield 0.18 g of an intermediate
aniline. The aniline (0.15 g, 0.37 mmol) was stirred at room
temperature for 24 h in CH2Cl2 with pyridine (0.045 mL) and
acetic anhydride (0.049 mL). Solvents were removed in vacuo,
and the residue was chromatographed on silica gel (18:1:1
EtOAc/H2O/HCOOH) to yield 33 (0.66 g, 66%), which was
converted to the HCl salt, mp 255-257 °C (dec). 1H NMR
(DMSO-d6): δ 1.6 (m, 1H), 1.8 (m, 1H), 2.1 (s, 3H), 2.3-2.5
(m, 5H), 3.05 (m, 2H), 3.5 (m, 3H), 3.78 (s, 3H), 4.2 (m, 2H),
6.75 (m, 1H), 6.85 (m, 1H), 7.18 (t, 1H), 7.3 (d, 1H), 7.78 (d,
1H), 7.88 (t, 1H). MS (DCI/NH3): m/e 449 (M + H)+. Anal.
(C25H28N4O4‚HCl‚H2O) C, H, N
2.2.16.
3-[2-((3a R ,9b R )-cis-6-Met h oxy-2,3,3a ,4,5,9b -
h e x a h y d r o -[1H ]-b e n z [e]i s o i n d o l-2-y l)e t h y l]-7-c a r -
bom eth oxy-2,4(1H,3H)-d ion e Hyd r och lor id e (34). The
amine 6a (1.35 g, 5.5 mmol) and the isocyanate (1.41 g, 6
mmol) prepared from dimethylaminoterephthalate were re-
acted by method A to yield 34 (1.4, 57%) as a white solid, mp
228-230 °C. 1H NMR (CDCl3) (free base): δ 1.52-1.68 (m,
1H), 1.7-1.86 (m, 1H), 2.32 (m, 2H), 2.52-2.75 (m, 3H), 2.92-
3.1 (m, 2H), 3.5 (m, 1H), 3.66 (m, 2H), 3.8 (s, 3H), 3.98 (s, 3H),
4.28 (t, 2H), 6.66 (d, 1H), 6.78 (d, 1H), 7.1 (t, 1H), 7.5 (s, 1H),
2.2.11. 3-[2-(cis-6-Meth oxy-2,3,3a,4,5,9b-h exah ydr o-[1H]-
ben z[e]isoin d ol-2-yl)eth yl]-7-ch lor oqu in a zolin e-2,4(1H,-
3H)-d ion e Hyd r och lor id e (29). The amine 6 (0.25 g, 1.0
mmol) and the isocyanate (0.26 g, 1.25 mmol) prepared from
2-carboethoxy-5-chloroaniline were reacted by method A to
1
yield 29 (0.12 g, 25%) as a white solid, mp >250 °C (dec). H
NMR (DMSO-d6): δ 1.52-1.68 (m, 1H), 1.7-1.86 (m, 1H), 2.6-
2.85 (m, 2H), 2.92-3.1 (m, 2H), 3.42-3.58 (m, 4H), 3.78 (s,
3H), 3.95-4.3 (m, 4H), 6.75 (m, 1H), 6.84 (m, 1H), 7.18 (t, 1H),

1982 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 12
Meyer et al.
7.6 (d, 1H), 7.82 (d, 1H). MS (DCI/NH3): m/e 450 (M + H)+.
Anal. (C25H27N3O5‚HCl‚0.25H2O) C, H, N.
2.2.23. 3-[2-(cis-6-Meth oxy-2,3,3a,4,5,9b-h exah ydr o-[1H]-
ben z[e]isoin d ol-2-yl)eth yl]-6,8-d im eth ylqu in a zolin e-2,4-
(1H,3H)-d ion e Hyd r och lor id e (41). The amine 6 (0.46 g, 1.6
mmol) and the isocyanate (0.45 g, 2.1 mmol) prepared from
2-carboethoxy-4,6-dimethylaniline21 were treated by method
A to yield 41 (0.22 g, 30%) as a white solid, mp 273-4 °C (dec).
1H NMR (DMSO-d6): δ 1.48-1.68 (m, 1H), 1.72-1.85 (m, 1H),
2.3 (s, 3H), 2.33 (s, 3H), 2.6-2.83 (m, 2H), 2.88-3.1 (m, 2H),
3.4-3.58 (m, 4H), 3.8 (s, 1H), 3.8-4.1 (m, 1H), 4.08-4.2 (m,
1H), 4.2-4.3 (m, 2H), 6.7-6.9 (m, 2H), 7.18 (t, 1H), 7.39 (s,
1H), 7.62 (s, 1H). MS (DCI/NH3): m/e 420 (M + H)+. Anal.
(C25H29N3O3‚HCl) C,H,N.
2.2.17. 3-[2-(cis-6-Meth oxy-2,3,3a,4,5,9b-h exah ydr o-[1H]-
b en z[e]isoin d ol-2-yl)et h yl]-6-m et h oxyq u in a zolin e-2,4-
(1H,3H)-d ion e Hyd r och lor id e (35). The amine 6 (0.32 g, 1.3
mmol) and the isocyanate (0.33 g, 1.5 mmol), prepared from
2-carboethoxy-4-methoxyaniline, were reacted by method A to
1
yield 35 (0.129 g, 25%) as a white solid, mp 159-161 °C. H
NMR (DMSO-d6): δ 1.55-1.68 (m, 1H), 1.7-1.9 (m, 1H), 2.6-
2.85 (m, 2H), 2.95-3.1 (m, 2H), 3.4-3.6 (m, 4H), 3.6-3.8 (m,
1H), 3.78 (s, 3H), 3.8 (s, 3H), 3.98-4.18 (m, 3H), 6.7-6.88 (m,
2H), 7.18 (m, 2H), 7.35 (m, 2H). MS (DCI/NH3): m/e 422 (M +
H)+. Anal. (C24H27N3O4‚HCl‚H2O) C, H, N.
2.2.24.
3-[2-((3a R ,9b R )-cis-6-Met h oxy-2,3,3a ,4,5,9b -
h exa h yd r o-[1H]-b en z[e]isoin d ol-2-yl)et h yl]-7,8-d im et h -
ylqu in a zolin e-2,4(1H,3H)-d ion e Hyd r och lor id e (42). The
amine 6a (0.5 g, 2 mmol) and the isocyanate (0.53 g, 2.1 mmol)
prepared from 2,3-dimethyl-6-carboethoxyaniline21 were treated
by method A to yield 42 (0. 6 g, 70%), which was converted to
2.2.18. 3-[2-(cis-6-Meth oxy-2,3,3a,4,5,9b-h exah ydr o-[1H]-
ben z[e]isoin d ol-2-yl)eth yl]-5-ch lor oqu in a zolin e-2,4(1H,-
3H)-d ion e Hyd r och lor id e (36). The amine 6 (0.40 g, 1.6
mmol) and the isocyanate (0.44 g, 2.1 mmol) prepared from
2-carboethoxy-3-chloroaniline were reacted by method A to
1
the HCl salt, mp 210-12 °C (EtOH/EtOAc). H NMR (CDCl3)
1
yield 36 (0.12 g, 18%) as a white solid, mp >250 °C (dec). H
(free base): δ 1.45-1.59 (m, 1H), 1.69-1.8 (m, 1H), 2.28 (s,
3H), 2.39 (s, 3H), 2.48-2.6 (m, 2H), 2.6-2.88 (m, 3H), 2.7-
3.15 (m, 2H), 3.42 (m, 3H), 3.83 (s, 3H), 4.22 (t, 2H), 6.68 (d,
1H), 6.75 (d, 1H), 7.05 (d, 1H), 7.11 (t, 1H), 7.69 (s, 1H), 8.5 (s,
1H). MS (DCI/NH3): m/e 420 (M + H)+. Anal. (C25H29N3O3‚
HCl‚H2O) C, H, N.
NMR (CDCl3) (free base): δ 1.55-1.7 (m, 1H), 1.87-1.98 (m,
1H), 2.52-2.65 (m, 1H), 2.7-2.84 (m, 2H), 2.87-3.0 (m, 2H),
3.4-3.57 (m, 2H), 3.68 (q, 1H), 3.82 (s, 3H), 4.1-4.42 (m, 4H),
6.73 (dd, 2H), 7.0 (d, 2H), 7.18 (m, 2H), 7.35 (m, 2H). MS (DCI/
NH3): m/e 426 (M + H)+. Anal. (C23H24N3O3Cl‚HCl‚2H2O) C,
H, N.
2.2.25.
3-[2-((3a R,9bR)-cis-6-Meth oxy-2,3,3a ,4,5,9b-
2.2.19. 3-[2-(cis-6-Meth oxy-2,3,3a,4,5,9b-h exah ydr o-[1H]-
ben z[e]isoin d ol-2-yl)eth yl]-5-m eth ylqu in a zolin e-2,4(1H,-
3H)-d ion e Hyd r och lor id e (37). The amine 6 (0.28 g, 1.1
mmol) and the isocyanate (0.28 g, 1.4 mmol) prepared from
2-carbomethoxy-3-methylaniline were reacted by method A to
yield 37 (0.16 g, 28%) as a white solid, mp 178-180 °C. 1H
NMR (CDCl3) (free base): δ 1.53-1.7 (m, 1H), 1.87-2.0 (m,
1H), 2.51-2.65 (m, 1H), 2.73 (s, 3H), 2.7-2.85 (m, 2H), 2.93-
3.06 (m, 2H), 3.4-3.58 (m, 2H), 3.68 (q, 1H), 3.82 (s,3H), 4.1
(m, 2H), 4.2 (t, 2H), 6.72 (dd, 2H), 6.92 (dd, 2H), 7.17 (t, 1H),
7.38 (t, 1H). MS (DCI/NH3): m/e 406 (M + H)+. Anal.
(C24H27N3O3‚HCl‚H2O) C, H, N.
h e x a h y d r o -[1H ]-b e n z[e]is o in d o l-2-y l)e t h y l]-7,8-d i-
m eth oxyqu in azolin e-2,4(1H,3H)-dion e Hydr och lor ide (43).
The amine 6a (0.5 g, 2 mmol) and the isocyanate (0.56 g, 2.1
mmol) prepared from 2,3-dimethoxy-6-carboethoxyaniline39
were treated by method A to yield 43 (0. 5 g, 55%), which was
converted to HCl salt, mp 174-176 °C (EtOH/Et2O). 1H NMR
(CDCl3) (free base): δ 1.45-1.59 (m, 1H), 1.69-1.8 (m, 1H),
2.21-2.32 (m, 2H), 2.48-2.62 (m, 2H), 2.62-2.85 (m, 3H),
2.62-2.85 (m, 3H), 3.81 (s, 3H), 3.92 (s, 3H), 3.98 (s, 3H), 4.2
(t, 2H), 6.68 (d, 1H), 6.75 (d, 1H), 6.7 (d, 1H), 7.1 (t, 1H), 7.82
(d, 1H), 8.22 (s, 1H). MS (DCI/NH3): m/e 452 (M + H)+. Anal.
(C25H29N3O3‚HCl‚H2O) C, H, N.
2.2.26. Met h yl 4,5-Dim et h oxy-2-(m et h yla m in o)-b en -
zoa te (44). A sample of 96% HCOOH (1.22 mL) was added to
the cooled to 0 °C acetic anhydride (2.7 g, 26 mmol), and the
reaction mixture was heated at 50 °C for 2 h, cooled to room
temperature, and diluted with THF.26 A solution of methyl
2-amino-4,5-dimethoxybenzoate (2.1 g, 10 mmol) in THF (30
mL) was added to that reagent, and the reaction mixture was
stirred at room temperature for 1 h and then concentrated to
1/2 of the volume. The resulting methyl 2-(formylamino)-4,5-
dimethoxybenzoate (0.95 g) was filtered off as a white solid.
1H NMR (CDCl3): δ 3.89 (s, 3H), 3.91 (s, 3H), 3.98 (s, 3H),
7.48 (s, 1H), 8.42 (s, 1H), 8.49 (d, 1H), 11.06 (s, 1H).
A solution of 10 M BH3‚(CH3)2S (1 mL) was added to a
suspension of methyl 2-(formylamino)-4,5-dimethoxybenzoate
(0.95 g, 4 mmol) in THF (20 mL). The reaction mixture was
stirred at room temperature for 2 h, diluted with THF (30 mL),
and treated with TMEDA (4 mL). After the mixture was
stirred at room temperature for 2 h, the reaction mixture was
partitioned between dilute NaHCO3 and EtOAc. The organic
layer was washed with H2O and then with brine, dried
(MgSO4), and evaporated. The obtained residue was chromato-
graphed on silica gel, eluting with 30% EtOAc/hexane to yield
0.5 g of 44 as a white crystalline substance. 1H NMR (CDCl3):
δ 2.93 (d, 3H), 3.82 (s, 6H), 3.92 (s, 3H), 6.1 (s, 1H), 7. 38 (s,
1H), 7.6 (bs, 1H).
2.2.20.
3-[2-((3a R ,9b R )-cis-6-Met h oxy-2,3,3a ,4,5,9b -
h exa h yd r o-[1H ]-b en z[e]isoin d ol-2-yl)et h yl]-6-ch lor o-7-
m eth oxyqu in azolin e-2,4(1H,3H)-dion e Hydr och lor ide (38).
The amine 6a (0.42 g, 1.7 mmol) and the isocyanate (0.43 g,
1.8 mmol) prepared from 2-carbomethoxy-4-chloro-3-meth-
35
oxyaniline
were reacted by method A to yield 38 (0.44 g,
1
57%) as a white solid, mp 218-220 °C. H NMR (DMSO-d6):
δ 1.54-1.68 (m, 1H), 1.70-1.85 (m, 1H), 2.43-2.53 (m, 1H),
2.55-2.82 (m, 2H), 2.93-3.10 (m, 1H), 3.40-3.55 (m, 4H), 3.77
(s, 3H), 3.94 (s, 3H), 3.97-4.30 (m, 4H), 6.73-6.90 (m, 3H),
7.17 (t, J ) 8 Hz, 1H), 7.88 (d, J ) 8 Hz, 1H), 10.40 (bs, 1H),
11.75 (s, 1H). MS (DCI/NH3): m/e 456 (M + H)+. Anal.
(C24H26N3O4Cl‚HCl‚0.3H2O) C, H, N.
2.2.21.
3-[2-((3a R ,9b R )-cis-6-Met h oxy-2,3,3a ,4,5,9b -
h exa h yd r o-[1H]-b en z[e]isoin d ol-2-yl)et h yl]-6,7-d im et h -
ylqu in a zolin e-2,4(1H,3H)-d ion e Hyd r och lor id e (39). The
amine 6a (0.5 g, 2 mmol) and the isocyanate (0.7 g, 2.1 mmol)
prepared from 2-carboethoxy-4,5-dimethylaniline21 were re-
acted by method A to yield 39 (0. 3 g, 54%), mp 185-188 °C.
1H NMR (CDCl3) (free base): δ 1.52-1.68 (m, 1H), 1.73-1.88
(m, 1H), 2.22 (s, 3H), 2.28 (s, 3H), 2.28-2.38 (m, 2H), 2.5-
2.75 (m, 2H), 2.7-3.15 (m, 2H), 3.42 (m, 2H), 3.63 (m, 2H),
3.83 (s, 3H), 4.25 (t, 2H), 6.65 (d, 1H), 6.68 (s, 1H), 6.76 (d,
1H), 7.11 (t, 1H), 7.66 (s, 1H). MS (DCI/NH3): m/e 420 (M +
H
)+. Anal. (C25H29N3O3‚HCl‚0.75H2O) C, H, N.
2.2.22. 3-[2-((3a R,9bR)-cis-6-Meth oxy-2,3,3a ,4,5,9b-
2.2.27.1-Meth yl-3-(2-ch lor oeth yl)-6,7-dim eth oxyqu in azo-
lin e-2,4-d ion e (45). Methyl 4,5-dimethoxy-2-(methylamino)-
benzoate 44 (0.47 g, 2 mmol) and 2-chloroethylisocyanate (0.21
mL, 2.4 mmol) were heated to reflux for 48 h in toluene (50
h e x a h y d r o -[1H ]-b e n z[e]is o in d o l-2-y l)e t h y l]-6,7-d i-
m eth oxyqu in azolin e-2,4(1H,3H)-dion e Hydr och lor ide (40).
The amine 6a (0.6 g, 2.44 mmol) and the isocyanate (0.7 g,
2.46 mmol) derived from 2-carboethoxy-4,5-dimethoxyaniline
were treated by method A to yield 40 (0.6 g, 54%). 1H NMR
(DMSO-d6): δ 1.52-1.68 (m, 1H), 1.73-1.88 (m, 1H), 2.6-2.85
(m, 2H), 2.92-3.6 (m, 2H), 3.42 (m, 3H), 3.65 (m, 1H), 3.8 (s,
3H), 3.84 (s, 3H), 3.88 (s, 3H), 3.9-4.1 (m, 1H), 4.2-4.32 (m,
3H), 6.75 (d, 1H), 6.81 (s, 1H), 6.85 (d, 1H), 7.18 (t, 1H), 7.36
(s, 1H). Anal. (C25H29N3O5‚HCl‚H2O) C, H, N.
1
mL) to yield 0.33 g of 45. H NMR (CDCl3): δ (3.6 (s, 3H), 3.8
(t, 2H), 3.92 (s, 3H), 4.02 (s, 3H), 4.48 (t, 2H), 6.6 (s, 1H), 7.6
(s, 1H).
2.2.28. 3-[2-[(3a R ,9b R )-cis-2,3,3a ,4,5,9b -H exa h yd r o-6-
m eth oxy-[1H]-ben z[e]isoin d ol-2-yl]eth yl]-6,7-d im eth oxy-
1-m eth ylqu in a zolin e-2,4(1H,3H)-d ion e, Mon oh yd r och lo-
r id e (46). The benz[e]isoindole 5a (0.2 g, 1 mmol), compound

Agents for Treatment of BPH
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 12 1983
45 (0.3 g, 1.05 mmol), and diisopropylethylamine (0.8 mL) were
combined in acetonitrile (3 mL) and heated at reflux for 18 h.
Solvents were removed in vacuo, and the residue was chro-
matographed on silica gel (18:1:1 EtOAc/H2O/HCOOH) to yield
0.23 g (64%) of 46 as its formic acid salt that was converted to
the HCl salt, mp 188-190 °C. 1H NMR (free base): δ 1.52 (m,
1H), 1.75 (m, 1H), 2.28 (m, 2H), 2.48-2.87 (m, 5H), 3.42 (m,
3H), 3.6 (s, 3H), 3.81 (s, 3H), 3.95 (s, 3H), 4.02 (s, 3H), 4.25 (t,
2H), 6.58 (s, 1H), 6.66 (d, 1H), 6.78 (d, 1H), 7.1 (t, 1H), 7.61 (s,
1H). MS (DCI/NH3): m/e 466 (M + H)+. Anal. (C25H29N3O5‚
HCl‚H2O) C, H, N.
2.2.29. E t h yl 2-(N,N-d im et h yl-N′-for m a m id in yl)-4,5-
d im eth oxyben zoa te (47). Ethyl 6-amino-3,4-dimethoxyben-
zoate (5.2 g, 23.1 mmol) and N,N-dimethylformamide dime-
thylacetal (6.87 g, 57.7 mmol) were treated by the method of
Gupton36 to yield 6.7 g of 47. 1H NMR (CDCl3): δ 1.32 (t, 3H),
3.1 (s, 6H), 3.9 (s, 6H), 4.28 (q, 2H), 6.4 (s, 1H), 7.26 (s, 1H), 7.
36 (s, 1H).
tion of the compound 51 (0.3 g, 0.73 mmol) in EtOH (10 mL)
was added 37% formaldehyde (0.4 mL) and concentrated HCl
(0.4 mL). The reaction mixture was stirred at room tempera-
ture overnight. The solvents were evaporated, and the obtained
residue was chromatographed on silica gel, eluting with 89:
9:1 CH2Cl2/MeOH/NH4OH to yield 0.33 g of 52 as a free base,
which was converted to the HCl salt, mp 152-154 °C. 1H NMR
(CD3OD): δ 1.74 (m, 1H), 1.92 (m, 1H), 2.72 (m, 6H), 2.85 (m,
2H), 3.42 (m, 1H), 3.7 (m, 3H), 3.78 (s, 3H), 3.8 (s, 3H), 3.82
(s, 3H), 4.32 (s, 2H), 4.6 (bs, 2H), 6.62 (s, 1H), 6.78 (m, 3H),
7.1 (d, 1H). MS (DCI/NH3): m/e 424 (M + H)+. Anal.
(C25H33N3O3‚2HCl‚2.25H2O) C, H, N.
2.2.35. 3-[2-cis-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-[1H]-
b e n z [ e ] i s o i n d o l -2 -y l ) e t h y l ] -3 ,4 -d i h y d r o -6 ,7 -d i -
m eth oxyqu in azolin -2(1H)-on e, Dih ydr och lor ide (53). Com-
pound 51 (0.3 g, 0.73 mmol) in CH3CN (10 mL) was treated
with 1,1′-carbonyldiimidazole (0.15 g, 0.82 mmol) for 3 h at
room temperature by the method of Takai37 to yield 53 (0.25
g) after removal of the solvent and conversion to HCl salt, mp
175-177 °C (MeOH/Et2O). 1H NMR (CD3OD): δ 1.58 (m, 1H),
1.76 (m, 1H), 2.38-2.7 (m, 6H), 2.9 (m, 2H), 3.42 (m, 1H), 3.58
(m, 3H), 3.72 (s, 3H), 3.75 (s, 3H), 3.79 (s, 3H), 4.43 (s, 2H),
6.42 (s, 1H), 6.68 (m, 3H), 7.0 (d, 1H). MS (DCI/NH3): m/e 438
(M + H)+. Anal. (C25H31N3O4‚2 HCl‚0.75H2O) C, H, N.
2.2.36. 2-(2-Ch lor oeth yl)-2,3,3a,4,5,9b-h exah ydr o-6-m eth -
oxy-1H-ben z[e]isoin d ole (54). To a solution of the hydro-
chloride salt of benz[e]isoindole 5 (1.0 g, 4.17 mmol) and
1-bromo-2-chloroethane (0.72 g, 5.0 mmol) in DMF (25 mL)
was added potassium carbonate (1.27 g, 9.7 mmol), and the
reaction mixture was stirred at room temperature overnight.
The precipitate was filtered off, and the filtrate was acidified.
Upon addition of ether a precipitate was formed that was
filtered off and crystallyzed from EtOH/ether to yield 1.3 g of
54 as an off-white precipitate. 1H NMR (CDCl3): δ 1.52 (m,
1H), 1.75 (m, 1H), 1.8 (m, 1H), 2.21 (m, 1H), 2.4-2.8 (m, 4H),
2.82 (m, 1H), 3.4 (m, 3H), 3.7 (m, 1H), 3.8 (s, 3H), 3.9 (m, 1H),
4.3 (m, 1H), 6.72 (m, 2H), 7.12 (m, 1H).
2.2.37. 2-[2-[(3a R ,9b R )-cis-2,3,3a ,4,5,9b -H exa h yd r o-6-
m eth oxy-[1H]-ben z[e]isoin d ol-2-yl)eth yl]-1,2,3,4-tetr a h y-
d r o-6,7-d im et h oxyisoq u in olin e, Dih yd r och lor id e (55).
Potassium carbonate (0.12 g, 0.87 mmol) was added to a
solution of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.1
g, 0.44 mmol) and compound 55 (0.11 g, 0.36 mmol) in DMF
(5 mL), and the reaction mixture was stirred at room temper-
ature overnight. Solids were filtered off, the filtrate was
evaporated, and the residue was partitioned in EtOAc/
NaHCO3. The organic layer was washed with H2O and then
brine, dried (Na2SO4), and evaporated. The obtained residue
was chromatographed, eluting with 2% MeOH/CH2Cl2 to give
0.13 g of 55 as a free base, which was converted to the HCl
salt, mp >200 °C. 1H NMR (CDCl3) (free base): δ 1.65 (m, 1H),
1.9 (m, 1H), 2.6 (m, 1H), 2.9 (m, 3H), 3.13 (m, 2H), 3.6 (m,
3H), 3.75 (s, 3H), 3.8 (s, 6H), 6.76 (s, 1H), 6.8 (m, 2H), 6.82 (s,
1H), 7.18 (t, 1H). MS (DCI/NH3): m/e 452 (M + H)+. Anal.
(C26H34N2O3‚2HCl‚0.2H2O) C, H, N.
2.2.30. 3-[2-[(3a R,9bR)-cis-2,3,3a ,4,5,9b-Hexa h yd r o-6-
m e t h o x y -[1 H ]-b e n z [e ]i s o i n d o l -2 -y l ]e t h y l ]-6 ,7 -d i -
m eth oxyqu in a zolin -4(3H)-on e, Dih yd r och lor id e (48). The
compound 47 (2.5 g, 8.9 mmol) and the amine 6a (0.57 g, 2.3
mmol) were refluxed in 1,4-dioxane (30 mL) with p-toluene-
sulfonic acid monohydrate (0.15 g, 0.8 mmol) for 4 h. The
reaction mixture was concentrated to a crude oil, which was
crystallized from MeOH to give 48 as the free base. The free
base was converted to the HCl salt (0.67 g, 57%), mp 181-
1
185 °C (EtOH/Et2O). H NMR (D2O): δ 1.65 (m, 1H), 1.94 (m,
1H), 2.55 (m, 1H), 2.85 (m, 3H), 3.7 (m, 3H), 3.84 (s, 3H), 3.96
(s, 3H), 3.99 (s, 3H), 4.45 (t, 2H), 4.72 (m, 3H), 6.87 (d, 1H),
6.94 (d, 1H), 7.14 (s, 1H), 7.25 (t, 1H), 7.5 (s, 1H), 8.26 (s, 1H).
MS (DCI/NH3): m/e 436 (M + H)+. [R]D +27.4° (c 0.53, CH3-
OH). Anal. (C25H29N3O4‚2HCl‚1.5H2O) C, H, N.
2.2.31. 3-[2-[(3a R ,9b R )-cis-2,3,3a ,4,5,9b -H exa h yd r o-6-
m et h oxy-[1H ]-b en z[e]isoin d ol-2-yl)et h yl]-2,3-d ih yd r o-
6,7-dim eth oxyqu in azolin -4(1H)-on e, Dih ydr och lor ide (49).
Compound 48 (0.15 g, 0.3 mmol) in MeOH (25 mL) was
hydrogenated at 4 atm of H2 at room temperature over 10%
Pd/C catalyst (dry, 0.02 g) for 17 h. The catalyst was removed
by filtration, and the filtrate was concentrated. The obtained
residue was basified with K2CO3 to pH 13 and extracted with
EtOAc. The combined organic extracts were dried (Na2SO4)
and concentrated to give, after chromatography on silica gel
(10% EtOAc/EtOH), the formic acid salt of 49 (0.06 g), which
was converted to the HCl salt, mp 191-193 °C. 1H NMR (CD3-
OD): δ 1.65 (m,1H), 1.95 (m, 1H), 2.6 (m, 1H), 2.8 (m, 2H),
2.95 (m, 1H), 3.05 (m, 2H), 3.4 (m, 2H), 3.65 (m, 1H), 3.8 (s,
3H), 4.05 (s, 3H), 4.12 (m, 2H), 4.2 (s, 3H), 4.6 (m, 2H), 6.8 (m,
2H), 7.08 (d, 1H), 7.18 (s, 1H), 7.8 (s, 1H). MS (DCI/NH3): m/e
438 (M + H)+. Anal. (C25H31N3O4‚2 HCl‚2.25H2O) C, H, N.
2.2.32. N-[(4,5-Dim eth oxy-2-n itr op h en yl)m eth yl]-2,3,-
3a ,4,5,9b -h exa h yd r o-6-m et h oxy-1H -b en z[e]isoin d ole-2-
eth a n ea m in e (50). 4,5-Dimethoxy-2-nitrobenzaldehyde (0.68
g, 3.25 mmol) and the amine 6 (0.8 g, 3.25 mmol) in MeOH
(100 mL) were treated with NaBH4 (0.16 g, 4.23 mmol) at room
temperature for 2 h by the method of Takai37 to yield, after
2.2.38. 2-[2-[(3a R ,9b R )-cis-2,3,3a ,4,5,9b -H exa h yd r o-6-
m et h oxy-[1H ]-b en z[e]isoin d ol-2-yl)et h yl]-3,4-d ih yd r o-
6,7-d im et h oxyisoq u in olin -1(2H )-on e, Mon oh yd r och lo-
r id e (56). The isocyanate (2.7 g, 13.1 mmol) obtained from
3,4-dimethoxyphenethylamine was treated with POCl3 and
SnCl4 by the method of Y. Tsuda38 to yield 1.36 g of the
intermediate 6,7-dimethoxy-3,4-dihydroisoquinoline-1-one. 1H
NMR (CDCl3): δ 2.9 (m, 2H), 3.55 (m, 2H), 3.9 (s, 6H), (m,
6.68 (s, 1H), 6.8 (s, 1H), 6.82 (s, 1H), 7.58 (s, 1H).
6,7-Dimethoxy-3,4-dihydroisoquinoline-1-one (0.5 g, 2.42
mmol) was dissolved in DMF, and NaH (0.11 g, 4.84 mmol)
was added to the solution. After the mixture was stirred for
30 min at room temperature, compound 54 (0.77 g, 2.89 mmol)
was added to the solution. The reaction mixture was heated
at 40 °C overnight, then diluted with H2O and extracted with
Et2O (2×). The organic layer was washed with NaHCO3, H2O,
and brine, dried (Na2SO4), and evaporated to yield, after
chromatography on silica gel, 56 as a free base, which was
converted to the HCl salt, mp >200 °C. 1H NMR (CDCl3) (free
1
standard workup, 1.62 g of 43. H NMR (CDCl3): δ 1.52 (m,-
1H), 1.72 (m, 1H), 2.28 (t, 2H), 2.55 (m, 3H), 2.65 (m, 2H),
2.69 (m, 2H), 3.26 (m, 2H), 3.4 (m, 1H), 3.8 (s, 3H), 3.95 (s,
3H), 3.99 (s, 3H), 4.08 (s, 2H), 6.7 (m, 2H), 7.1 (t, 1H), 7.15 (s,
1H), 7.52 (s, 1H). MS (DCI/NH3): m/e 442 (M + H)+.
2.2.33. N-[(2-Am in o-4,5-d im eth oxyp h en yl)m eth yl]-2,3,-
3a ,4,5,9b -h exa h yd r o-6-m et h oxy-1H -b en z[e]isoin d ole-2-
eth a n ea m in e (51). Compound 50 (1.62 g, 3.8 mmol) in MeOH
(200 mL) was hydrogenated at 4 atm of H2 over 0.7 g of Pd/C
at room temperature for 4 h. The catalyst was filtered off and
1
the filtrate evaporated to yield 1.2 g of 51. H NMR (CDCl3):
δ 1.55 (m, 1H), 1.73 (m, 1H), 2.2 (m, 2H), 2.6 (m, 5H), 2.76 (m,
2H), 3.27 (m, 2H), 3.4 (m, 1H), 3.73 (s, 2H), 3.74 (s, 3H), 3.81
(s, 3H), 3.83 (s, 3H), 6.28 (s, 1H), 6.67 (m, 2H), 7.02 (d, 1H),
7.27 (s, 1H).
2.2.34. 3-[2-cis-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-[1H]-
b e n z [e]i s o i n d o l-2-y l)e t h y l]-1,2,3,4-t e t r a h y d r o -6,7-
d im eth oxyqu in a zolin e, Dih yd r och lor id e (52). To a solu-

1984 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 12
Meyer et al.
(11) De Mey, C.; Michel, M. C.; McEwen, J .; Moreland, T. A Double
Blind Comparison of Terazosin and Tamsulosin on Their Dif-
ferential Effects on Ambulatory Blood Pressure and Nocturnal
Orthostatic Stress Testing. Eur. Urol. 1998, 33, 481-488.
(12) Broten, T.; Scott, A.; Siegl, P. K. S.; Forray, C.; Lagu, B.;
Nagarathnam, D.; Wong, W. C.; Marzabadi, M. R.; Murali Dhar,
T. G.; Gluckowski, C. Alpha-1 Adrenoceptor Blockade Inhibits
Detrusor Instability in Rats With Bladder Outlet Obstruction.
FASEB J . 1998, 12, A445.
(13) Wetzel, J . M.; Miao, S. W.; Forray, C.; Borden, L. A.; Branchek,
T. A.; Gluchovski, C. Discovery of a1a-Adrenergic Receptor
Antagonists Based on the L-Type Ca2+ Channel Antagonist
Niguldipine. J . Med. Chem. 1995, 38, 1579-1581.
(14) Adkison, K. K.; Halm, K. A.; Shaffer, J . E.; Drewry, D.;
Sinhababu, A. K.; Bermann, J . Discovery of a Potent and
Selective a1a Antagonist. Utilization of a Rapid Screening Method
To Obtain Pharmacokinetic Parameters. In Integration of Phar-
maceutical Discovery and Development: Case Studies; Borchardt
et al., Eds.; Plenum Press: New York, 1988; pp 423-443.
(15) Nagarathnam, D.; Miao, S. W.; Lagu, B.; Chiu, G.; Fang, J .;
Murali Dhar, T. G.; Zhang, J .; Tyagarajan, S.; Marzabadi, M.
R.; Zhang, F.; Wong, W. C.; Sun, W.; Tian, D.; Wetzel, J . M.;
Forray, C.; Chang, R. S. L.; Broten, T. P.; Schorn, T. W.; Chen,
T. B.; O’Malley, S.; Ransom, R. W.; Schneck, K.; Bendesky, R.;
Harrell, C. M.; Gluchowski, C. Novel R1a Adrenoceptor Selective
Antagonists: Structure-Activity Relationships of Dihydropyri-
midinones. J . Med. Chem. 1999, 42, 4764-4777.
(16) Murali-Dhar, T. G.; Nagarathnam, D.; Marzabadi, M. R.; Lagu,
B.; Wong, W. C.; Chiu, G.; Tyagarajan, S.; Miao, S. W.; Zhang,
F.; Sun, W.; Tian, D.; Shen, Q.; Wetzel, J . M.; Forray, C.; Chang,
R. S. L.; Broten, T. P.; Schorn, T. W.; Chen, T. B.; O’Malley, S.;
Ransom, R. W.; Schneck, K.; Bendesky, R.; Harrell, C. M.; Vyas,
K.; Zhang, K.; Gilbert, J .; Pettibone, D. J .; Kling, P.; Patane, M.
A.; Bock, M. G.; Freidinger, R. M.; Gluchovski, D. C. Design and
Synthesis of Novel R1a Adrenoceptor Selective Antagonists:
Approaches To Eliminate Opioid Agonist Metabolites via Modi-
fication of Linker and 4-Methoxycarbonyl-4-piperidine Moiety.
J . Med. Chem, 1999, 42, 4778-4793.
(17) Lagu, B.; Tian, D.; J eon, Y.; Li, C.; Wetzel, J . M.; Nagarathnam,
D.; Shen, Q.; Forray, C.; Chang, R. S. L.; Broten, T. P.; Ransom,
R. W.; Chan, T. B.; O’Malley, S. S.; Schorn, T. W.; Rodrigues, A.
D.; Kassahun, K.; Pettibone, D. J .; Freidinger, R.; Gluchowski,
C. De Novo Design of a Novel Oxazolidinone Analogue as a
Potent and Selective R1a Adrenergic Receptor Antagonist with
High Oral Bioavailability. J . Med. Chem. 2000, 43, 2775-2778.
(18) Bock, M. G.; Patane, M. A. Toward the Development of R1a
Adrenergic Receptor Antagonists. Annu. Rep. Med. Chem. 2000,
35, 221-230.
(19) Russell, R. K.; Press, J . B.; Rampulla, R. A.; McNally, J . J .;
Falotico, R.; Keiser, J . A.; Bright, D. A.; Tobia, A. Thiophene
Systems. 9. Thienopyrimidinedione Derivatives as Potential
Antihypertensive Agents. J . Med. Chem. 1988, 31, 1786-1793.
(20) Romeo, G.; Ambrosini, G.; Guccione, S.; DeBlasi, A.; Russo, F.
Pyrimido[5,4-b]benzofuran and Pyrimido[5,4-b]benzothiopene
Derivatives. Ligands for R1 and 5HTA-Receptors. Eur. J . Med.
Chem. 1993, 28, 499-504.
(21) Rewcastle, G. W.; Atwell, G. J .; Zhuang, L.; Baguley, B. C.;
Denny, W. A. Potential Antitumor Agents. 61. Structure-
Activity Relationships for in Vivo Colon 38 Activity among
Disubstituted 9-Oxo-9H-xanthine-4-acetic acids. J . Med.Chem.
1991, 34 (1), 217-222.
(22) Hartmann, H. A Simple Method for the Synthesis of 5-Aryl-3-
amino-2-alkoxycarbonylthiophenes. Synthesis 1984, 275.
(23) Kirsch, G.; Cagniant, D.; Cagniant, P. Synthesis of Amino-3-
thiophenes from Aryl and Heteroaryl MeCNs. J . Heterocycl.
Chem. 1982, 19, 443.
base): δ 1.54 (m, 1H), 1.75 (m, 3H), 2.35 (m, 2H), 2.57 (m,
1H), 2.72 (m, 8H), 2.88 (m, 3H), 3.6 (s, 2H), 3.82 (s, 3H), 3.84
(s, 3H), 3.86 (s, 3H), 6.5 (s, 1H), 6.59 (s, 1H), 6.69 (d, 1H), 6.75
(d, 1H), 7.1 (t, 1H), 7.58 (s, 1H). MS (DCI/NH3): m/e 437 (M +
H)+. Anal. (C26H32N2O4‚HCl‚1.5H2O) C, H, N.
2.2.39. 2-Am in o-N-[2-[(3aR,9bR)-cis-2,3,3a,4,5,9b-h exah y-
d r o -6-m e t h o x y -[1H ]-b e n z[e]is o in d o l-2-y l]e t h y l]-4,5-
d im eth oxyben za m id e, Dih yd r och lor id e (57). To a solution
of the amine 6 (0.25 g, 1.01 mmol), 2-amino-4,5-dimethoxy-
benzoic acid (0.22 g, 1.12 mmol), diisopropylethylamine (0.3
mL), and HOBT (0.21 g, 1.53 mmol) in a 1:1 mixture of CH2-
Cl2 and DMF was added EDCI (0.29 g, 1.53 mmol). The
reaction mixture was stirred at room temperature overnight
and after standard workup yielded 57, mp 193-195 °C. 1H
NMR (CD3OD): δ 1.7 (m, 1H), 1.93 (m, 1H), 2.6 (m, 2H), 2.85
(m, 4H), 3.08 (m, 2H), 3.5 (m, 2H), 3.78 (m, 2H), 3.82 (s, 3H),
3.92 (s, 3H), 3.94 (s, 3H), 6.8 (d, 1H), 6.82 (d, 1H), 6.9 (s, 1H),
7.18 (t, 1H), 7.5 (s, 1H). MS (DCI/NH3): m/e 426 (M + H)+.
Anal. (C24H31N3O4‚2HCl‚0.5H2O) C, H, N.
Refer en ces
(1) Meyer, M. D.; Altenbach, R. J .; Basha, F. Z.; Carroll, W. A.;
Elmore, S. W.; Condon, S.; Kerwin, J . F.; Sippy, K. B.; Tietje,
K.; Wendt, M. D.; Hancock, A. A.; Brune, M. E.; Buckner, S. A.;
Drizin, I. Structure Activities Studies for a Novel Series of
Tricyclic Substituted Hexahydrobenz[e]isoindole R1A Adreno-
ceptor Agonists as Potential Agents for the Symptomatic Treat-
ment of Benign Prostatic Hyperplasia (BPH). J . Med.Chem,
2000, 43, 1586-1603.
(2) Shapiro, E.; Lepor, H. Pathophysiology of Clinical Benign
Prostatic Hyperplasia. Urol. Clin. N. Am. 1995, 22, 285-290.
Lee, C.; Kozlowski, J . M.; Grayhack, J . T. Etiology of Benign
Prostatic Hyperplasia. Urol. Clin. N. Am. 1995, 22, 237-246.
(3) Kenny, B.; Ballard, S.; Blagg, J .; Fox, D. Pharmacological
Options in the Treatment of Benign Prostatic Hyperplasia. J .
Med. Chem. 1997, 40, 1293-1315. Lepor, H. Alpha Blockade for
the Treatment of Benign Prostatic Hyperplasia. Urol. Clin. N.
Am. 1995, 22, 375-386. Chapple, C. R. R-Adrenergic Blocking
Drugs in Bladder Outflow Obstruction: What Potential Has R1-
Adrenoceptor Selectivity? Br. J . Urol. 1995, 76 (Suppl. 1), 47-
55.
(4) Lepor, H.; Henry, D.; Laddu, A. R. The Efficacy and Safety of
Terazosin in the Treatment of BPH. Prostate 1991, 18, 345-
355.
(5) Holme, J . B.; Christensen, M. M.; Rasmussen, P. C.; J acobsen,
F.; Nielsen, J .; Norgaard, J . P.; Olesen, S.; Noer, L.; Wolf, H.;
Husted, S. E. 29-Week Doxazosin Treatment in Patients with
Symptomatic Benign Prostatic Hyperplasia. Scand. J . Urol.
1994, 28, 77-82.
(6) J ardin, A.; Bensadoun, H.; Delauche-Cavallier, M. C.; Stalla-
Bourdillon, A.; Attali, P. Long-Term Treatment of Benign
Prostatic Hyperplasia with Alfuzosin: A 24-30 Month Survey.
Br. J . Urol. 1984, 74, 579-584.
(7) Hancock, A. A. R1-Adrenoceptor Subtypes: A Synopsis of Their
Pharmacology and Molecular Biology. Drug. Dev. Res. 1996, 39,
54-107. Hieble, J . P.; Bylund, D. B.; Clarke, D. E.; Eikenburg,
D. C.; Langer, S. Z.; Lefkowitz, R. J .; Minneman, K. P.; Ruffolo,
R. R., J r. International Union of Pharmacology. X. Recom-
mendation for Nomenclature of R1-Adrenoceptors: Consensus
Update. Pharmacol. Rev. 1995, 47, 267-270.
(8) Nasu, K.; Moriyama, N.; Kawabe, K.; Tsujimoto, G.; Murai, M.;
Tanaka, T.; Yano, J . Quantification and Distribution of R1-
Adrenoceptor Subtype mRNAs in Human Prostate: Comparison
of Benign Hypertrophied Tissue and Non-Hypertrophied Tissue.
Br. J . Pharmacol. 1996, 119, 797-803. Price, D. T.; Scwhinn,
D. A.; Lomasney, J . W.; Allen, L. F.; Caron, M. G.; Lefkowitz, R.
J . Identification, Quantitation, and Localization of mRNA for
Three Distinct Alpha1 Adrenergic Subtypes in Human Prostate.
J . Urol. 1993, 150, 546-551.
(9) Cavalli, A.; Lattion, A.-L.; Hummler, E.; Nenniger, M.; Pe-
drazzini, T.; Aubert, J .-F.; Michel, M. C.; Yang, M.; Lembo, G.;
Vecchione, C.; Mostardini, M.; Schmidt, A.; Beermann, F.;
Cotecchia, S. Decreased Blood Pressure Response in Mice
Deficient of the R1B-Adrenergic Receptor. Proc. Natl. Acad. Sci.
U.S.A. 1997, 94, 11589-11594.
(24) Oakes, V.; Pascoe, R.; Rydon, H. N. Polyazanaphthalenes. Part
III. Some Derivatives of 1:3:5 and 1:3:8-Triazanaphthalene. J .
Chem. Soc. 1956, 1045.
(25) Bachman, G. B.; Barker, R. S. Derivatives of the Pyridoquino-
lines. J . Org. Chem. 1949, 15, 97.
(26) Krishnamurthy, S. A Highly Efficient and General N-Monom-
ethylation of Functionalized Primary Amines via Formylation-
Borane-Methyl Sulfide Reduction. Tetrahedron 1982, 28, 3315-
3318.
(27) Hieble, J . P.; Boyce, A. J .; Caine, M. Comparison of the
R1-Adrenoceptor Characteristics in Human and Canine Prostate.
Fed. Proc., Fed. Am. Soc. Exp. Biol. 1986, 45 (11), 2609-2614.
(28) Burt, R.; Chapple, C. R.; Marshall, J . Evidence for a Functional
(10) Hancock, A. A.; Buckner, S. A.; Brune, M. E.; Katwala, S.; Milicic,
I.; Ireland, L. M.; Morse, P. A.; Knepper, S. M.; Meyer, M. D.;
Chapple, C. R.; Chess-Williams, R.; Noble, A. J .; Williams, M.;
Kerwin, J . F., J r. Pharmacological Characterization of A-131701,
a Novel R1-Adrenoceptor Antagonist Selective for R1a and R1D
Compared to R1B Adrenoceptors. Drug Dev. Res. 1998, 44, 140-
162.
R
1A-R1c Adrenoceptor Mediating Contraction of the Rat Epidy-
mal Vas Deferens and an R1B-Adrenoceptor Mediating Con-
traction of the Rat Spleen. Br. J . Pharmacol. 1995, 115, 467-
475.

Agents for Treatment of BPH
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 12 1985
(29) Knepper, S. M.; Buckner, S. A.; Brune, M. E.; DeBernardis, J .
(36) Gupton, J . T.; Miller, J . F.; Bryant, R. D.; Maloney, P. R.; Foster,
B. S. The Preparation of Aromatic Amidino Esters and Their
Reaction with Primary Amines. Tetrahedron 1987, 43 (8), 1747-
1752.
F.; Meyer, M. D.; Hancock, A. A. A-61603,
A Potent R1-
Adrenergic Receptor Agonist Selective for the R1A Receptor
Subtype. J . Pharmacol. Exp. Ther. 1995, 274, 97-103.
(30) Brune, M. E.; Buckner, S. A.; Polakowski, J .; Kerwin, J . F.;
Hancock, A. A. Pharmacological Antagonism of Alpha-Adrener-
gic Agonist Induced Increases in Canine Intraurethral Pressure
In Vivo. Drug Dev. Res. 1995, 34, 267-275.
(37) Takai, H.; Obase, H.; Nakamizo, N.; Teranishi, M.; Kubo, K.;
Shuto, K.; Kasuya, Y.; Shigenobu, K.; Hashikami, M.; Karash-
ima, N. Synthesis of 1- and 3-(1-Substituted 4-Piperidinyl)-
1,2,3,4-Tetrahydro-2-Oxoquinazolines as Potential Antihyper-
tensive Agents. Chem. Pharm. Bull. 1985, 33 (3), 1116-1128.
(38) (a) Tsuda, Y.; Isobe, K.; Toda, J .; Taga, J . A New Modification
of Bishler-Napieralski Reaction for â-Arylethylisocyanates and
â-Arylethylisocyanates. Heterocycles 1976, 5, 157-162. (b) Tsu-
da, Y.; Sono, T.; Taga, Y.; Isobe, K.; Toda, J .; Irie, H.; Tamaka,
H.; Takagi, S.; Yamaki, M. Synthesis of the Amarylidacea
Alkaloid Lycorine. J . Chem. Soc., Chem. Commun. 1975, 933-
934.
(31) Gewald, K. 2-Aminothiophene from R-Oxomercaptans and Me-
thylene-Activated Nitriles. Chem. Ber. 1965, 98, 3571.
(32) Baker, B. R.; J oseph, J . P.; Shaub, R. E.; McEvoy, F. J .; Williams,
J . H. An Antimalarial Alkaloid from Hydrangea XIX. Thiophene
Isosteres. J . Org. Chem. 1953, 18, 138.
(33) Poehlmann, H.; Heyne, S.; Kraft, R.; Pfeifer, S. Biotransforma-
tion and Pharmacokinetics of Drugs. Part 24. Analysis and
Biochemistry of the Azaanalogs of Methaqualone. Part 6.
Synthesis of 2-Methyl-3-[4′-chlorophenyl]-4-oxo-3,4-dihydropy-
rrolo[2,3-d]pyrimidine. Pharmazie 1976, 31 (1), 28-29.
(34) Chan, R. L.; Bruice, T. C. The Chemistry of an Electron-Deficient
5-Deazaflavin. 8-Cyano-10-methyl-5-deazaisoalloxazine. J . Am.
Chem. Soc, 1977, 99 (20), 6721-6730.
(39) Pschorr, R.; Simuleanu, C. About o-Nitrovanilin. Chem. Ber.
1899, 32, 3405.
(35) Hess, H.-J .; Bindra, J . S.; Shah, P. K. Alkoxysubstituted 6-Chlo-
roquinazoline-2,4-diones. U.S. Patent 4,287,341, 1981.
J M000541Z