Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole α(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH)

1586

J . Med. Chem. 2000, 43, 1586-1603

Str u ctu r e-Activity Stu d ies for a Novel Ser ies of Tr icyclic Su bstitu ted

Hexa h yd r oben z[e]isoin d ole r_1AAd 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 (BP H)

Michael D. Meyer,* Robert J . Altenbach, Fatima Z. Basha, William A. Carroll, Stephen Condon,

Steven W. Elmore, J ames F. Kerwin, J r., Kevin B. Sippy, Karin Tietje, Michael D. Wendt, Arthur A. Hancock,

Michael E. Brune, Steven A. Buckner, and Irene Drizin*

Neurological & Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road,

Abbott Park, Illinois 60064

Received November 15, 1999

In search of a uroselective agent that exhibits a high level of selectivity for the R_1Areceptor, a

novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric

model was developed requiring the presence of a basic amine core and a fused heterocyclic

side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R

stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were

optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and

linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with

retention of potency and selectivity. In vitro functional assays for the R₁adrenoceptor subtypes

were used to further characterize these compounds, and in vivo models of vascular vs prostatic

tone were used to assess uroselectivity.

In tr od u ction

nist blockade of norepinephrine- or phenylephrine-

induced contractions of human prostate tissue has been

found to correlate with affinity for the R_1asubtype.¹⁰In

vitro binding selectivity for R_1aover R_1bhas also been

shown to correspond with selectivity in vivo for blockade

of agonist-induced increases in intraurethral versus

arterial pressure.¹¹Additional evidence in support of a

prominent role for the R_1Breceptor in the regulation of

blood pressure derives from a recent study where R_1b

knockout mice¹²displayed a substantially reduced

responsiveness to phenylephrine-induced increases in

blood pressure. The potential role of the R_1dreceptor in

the design of a “uroselective” R₁antagonist is less clear

since the relative contribution of this subtype to the

maintenance of prostatic and vascular tone is not well

defined. Interestingly, R_1dmRNA has been shown to be

the dominant R₁subtype present in the human bladder

detrusor.¹³Additional recent evidence suggests that R_1D

receptor blockade may ameliorate the irritative symp-

toms of BPH that result from involuntary contractions

of the bladder smooth muscle.¹⁴Thus, a strong scientific

rationale exists for the utility of R₁antagonists selective

for R_1aover R_1b, with activity at R_1dpotentially providing

some additional therapeutic benefit.

Benign prostatic hyperplasia (BPH) is a common

disease that afflicts middle-aged and elderly males, with

the percent incidence of pathological evidence of the

disease approximately equal to the man’s age.¹This

condition is characterized by a collection of urological

symptoms including hesitancy, nocturia, poor urine flow,

frequency of urination, and sensations of urgency. While

the term BPH suggests that the observed symptoms are

due to an increase in organ size causing an obstruction

to flow, an important dynamic component to symptom-

atic BPH has been demonstrated²that is mediated

primarily through prostatic R₁adrenoceptors.³Clinical

efficacy in ameliorating the symptoms of BPH has been

shown with several R₁antagonists, including terazosin,⁴

doxazosin,⁵tamsulosin,⁶and alfuzosin.⁷(Chart 1). How-

ever, these agents are suboptimal due to the appearance

of dose limiting side effects: hypotension, dizziness,

muscle fatigue. These side effects are believed to be

mediated by the blockade of R₁receptors in the vascu-

lature and the central nervous system. A highly “uro-

selective” R₁adrenoceptor antagonist would therefore

represent a major advance in pharmacotherapy for the

treatment of BPH.

The known nonselective R₁antagonist 1¹⁵served as

a template for the design of this series. It was reasoned

that 9-methoxybenz[e]isoindole could serve as a rigidi-

fied replacement for the o-methoxyphenylpiperazine

core of 1, with the additional conformational restraint

possibly resulting improved subtype selectivity (Chart

2). Unfortunately, the initial 9-methoxybenz[e]isoindole

target 26 exhibited only moderate affinity for the R_1A

binding site and was nonselective for R_1Avs R_1b.

However, relocation of the OMe substituent from the

9- to the 6-position resulted in compound 18, posessing

both enhanced affinity and improved selectivity for the

Within the past decade, the heterogeneity of the R₁

receptor has been realized both on a molecular and

pharmacological level.⁸At the molecular level, three

subtypes of the human R₁receptor have been identified

and cloned: R_1a, R_1b, and R_1d. These receptors correlate

with the pharmacologically defined receptors: R_1A, R_1B

,

and R_1D. In the human prostate, mRNA for all three

subtypes has been found⁹with that for the R_1asubtype

present in greatest abundance. In addition, the antago-

* To whom correspondence should be addressed. Tel: 847-937-7832.

Fax: 847-937-9195. E-mail: irene.drizin@abbott.com.

Published on Web 03/28/2000

Tricyclic Hexahydrobenz[e]isoindoles

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8 1587

Ch a r t 1

Ch a r t 2

R

_1Asubtype. Encouraged by these results, an extensive

SAR study was initiated based on the 6-methoxybenz-

synthesis of the benzothienopyrimidinediones 18-20.

In method A, the aminoesters 16 were reacted with

2-chloroethyl isocyanate¹⁵to yield the haloalkyl ureas

17 that were in turn reacted with the benz[e]isoindoles

6 (see Scheme 2) to yield the final products. In method

B, the heterocycle was prepared for coupling by reaction

of the aminoester 16 with triphosgene to yield the

isocyanate, which was in turn reacted with the amino-

ethylbenz[e]isoindole 7 to yield an intermediate urea.

This urea cyclized either spontaneously or upon treat-

ment with base (KOtBu in THF) to produce the pyrim-

idinedione final product.

[e]isoindole core.

Ch em istr y

SAR studies of the parent structure involved inves-

tigation of variously substituted benz[e]isoindoles, iden-

tification of the optimal stereochemistry of the ring

junction, optimization of the tether length, and studies

of the various replacements of the tricyclic heterocyclic

attachment of the molecule (Figure 1). Target com-

pounds were synthesized by one of two general methods

(Scheme 1), and the two methods are exemplified by the

The starting racemic cis-benz[e]isoindoles 6 were

prepared from the corresponding dihydronaphthalene-

1-carbonitriles 2¹⁶in several steps (Scheme 2). Addition

of LiCN to nitriles 2 afforded a mixture of cis 3 and trans

4 dinitriles. The mixture could be easily separated by

column chromatography on silica gel eluting with hex-

ane:ethyl acetate. Cyclization of the dinitrile intermedi-

ates 3 to the cyclic imides 5 by the action of HBr,

followed by reduction with diborane in THF, yielded the

desired racemic cis benz[e]isoindoles 6. When trans

dinitrile 4 was subjected to similar HBr treatment, the

F igu r e 1. SAR of compound 18.

1588 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8

Meyer et al.

Sch em e 1^a

a

Conditions and reagents: (a) 2-chloroethyl isocyanate; (b) DMSO, diisopropylethylamine; (c) phosgene, Et₃N; (d) (i) CH₂Cl₂, rt, (ii)

KOtBu.

Sch em e 2^a

a

Conditions and reagents: (a) LiCN/DMF, separate by flash chromatography; (b) HBr/DMF; (c) BH₃/THF; (d) (i) ClCH₂CN,

ethyldiisopropylamine, (ii) LiAlH₄; (e) H₂/Raney Ni, NH₄OH.

reaction proceeded sluggishly and the resulting product

was cis benz[e]isoindole 6. Consequently the conversion

of dinitriles to cis benz[e]isoindoles 6 can be done

without prior separation of diastereomers. The synthesis

of trans benz[e]isoindoles 8 was achieved by the catalytic

hydrogenation of the dinitriles 4 with Raney Ni in the

presence of methanolic ammonia. These conditions

facilitated the predominant formation of trans benz[e]-

isoindoles (10:1). Interestingly, treatment of the cis

dinitriles 3 under these hydrogenation conditions also

provided the predominant formation of the trans benz-

[e]isoindoles(10:1).³⁵cis- 9-Methoxybenz[e]isoindole 6d

was prepared from 5-bromo-8-methoxydihydronaphtha-

lene carbonitrile.¹⁷

The preparation of single enantiomers of cis 6-meth-

oxybenz[e]isoindole is shown in Scheme 3. Base pro-

moted condensation of the ester 10¹⁹with diethyl

oxalate yielded the keto diester 11, which was converted

to 12 by cyclization with sulfuric acid and subsequent

catalytic hydrogenation. Dehydrative condensation of

the anhydride with (S)-R-methylbenzylamine yielded a

diastereomeric mixture of imides. The (3aR,9bR) imide

13 was separated by crystallization and reduced with

diborane to give the N-benzyl substituted pyrrolidine.

Catalytic hydrogenation afforded the resolved (3aR,9bR)-

6-methoxy-benz[e] isoindole 14. Alkylation with chloro-

acetonitrile and reduction with LiAlH₄gave the primary

amine 15. The (3aS,9bS) imide 13a was obtained from

the filtrate of the aforementioned crystallization and

treated similarly to yield the primary amine 15a .

Aminoalkylbenz[e]isoindoles 7 and 9 (Scheme 2) were

synthesized via alkylation of the benz[e]isoindoles 6 and

8 with chloroacetonitrile followed by reduction of the

nitrile with either lithium aluminum hydride or alane.

Lengthening of the tether was accomplished when

3-chloropropionitrile was used instead of chloroaceto-

nitrile in the synthesis of primary amines. For the four-

carbon chain an alternative method was utilized. 5-Meth-

oxy-1,2,3,4-tetrahydronaphthalene-cis-1,2-dicarboxylic

acid diethyl ester¹⁸was reduced with lithium aluminum

hydride to the corresponding diol, which in turn was

converted to the corresponding bis-mesylate. The de-

sired 4-aminobutylbenz[e]isoindole was synthesized by

the reaction of the mesylate with 1,4-diaminobutane.

Pyrazinothiophenes used in this study were prepared

from the corresponding chloropyrazinonitriles and eth-

ylthioglycolate (Scheme 4). In order to obtain chloro and

methoxy-substituted pyrazinothiophene derivatives, chlo-

ropyrazinonitriles were first oxidized to the correspond-

ing N-oxides. X-ray studies established the position of

oxidation. The obtained pyrazine N-oxides were con-

verted to pyrazinothiophenes by treatment with ethyl-

thioglycolate in the presence of base and then subjected

to chlorination with phosphorus oxychloride. The vari-

ous substituted benzothiophenes were synthesized by

the same methodology from the corresponding chlo-

Tricyclic Hexahydrobenz[e]isoindoles

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8 1589

Sch em e 3^a

a

Conditions and reagents: (a) KOtBu, diethyl oxalate; (b) (i) H₂SO₄, (ii) H₂, Pd; (c) (S)-R-methylbenzylamine; (d) (i) BH₃‚THF, (ii) H₂,

Pd; (e) (i) ClCH₂CN, ethyldiisopropylamine, (ii) LiAlH₄.

Sch em e 4^a

a

Conditions and reagents: (a) POCl₃/Et₃N; (b) ethylthioglycolate, Na₂CO₃; (c) K₂S₂O₈/H₂SO₄; (d) ethylthioglycolate, Na₂CO₃; (e) POCl₃.

robenzonitriles or nitrobenzonitriles.²⁰The synthesis of

pyridothiophenes from the corresponding chloropyri-

donitriles and methylthioglycolate was described by

Dunn.²¹

substitution appears to most closely mimic the o-

methoxyphenylpiperazine substructure, this substitu-

tion was not optimal for the benz[e]isoindole. The

9-methoxybenz[e]isoindole analogue 26 did not display

selectivity for the R₁receptors and exhibited only

moderate affinity for the R_1Asubtype. The 6-methoxy

analogue 18 exhibited improved selectivity and in-

creased affinity for the R_1Areceptor and was the optimal

position for substitution on this ring system. Methoxy

substitution in the 7- and 8-positions was deleterious

to affinity. Exploration of the relative and absolute

stereochemistry of the benz[e]isoindole ring fusion

revealed that the relative stereochemistry (cis vs trans)

did not have a significant impact on either selectivity

or potency for the R₁subtypes. However, the 3aR,9bR

cis-enantiomer 22 was 20-fold more active than the

antipode 23, indicating a clear preference for the R,R

absolute stereochemistry. Table 2 examines the effect

of the spacer chain length on the activity. Among a

Resu lts a n d Discu ssion

Target compounds were evaluated for their affinity

at the R_1A, R_1b, and R_1dreceptors. The structural features

evaluated in the study are summarized in Chart 1, and

include: (i) optimization of the aromatic substitution

and stereochemistry of the ring fusion of the benz[e]-

isoindole portion of the molecule, (ii) length of the tether,

(iii) heteroatom substitutions in the center ring of the

pyrimidinedione substructure, and (iv) introduction of

heteroatoms into the aromatic ring of the pyrimidinedi-

one substructure.

Two aspects of the SAR of the benz[e]isoindole nucleus

were explored: aromatic substitution with OMe, and

ring fusion stereochemistry (Table 1). Although 9-OMe

1590 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8

Meyer et al.

Ta ble 1. Effect of Benz[e]isoindole Stereochemistry and Substitution on Selectivity

radioligand binding K_i(nM)

selectivity

ratio^b

a

no.

R

stereochemistry

R_1A

R_1b

R_1d

terazosin

0.82

(0.60, 1.12)

0.03

0.69

(0.59, 0.80)

0.20

1.01

(0.06, 0.07)

0.07

0.84

7.0

tamsulosin

(0.025, 0.032)

0.64

(0.56, 0.73)

1.08

(0.91,1.29)

0.47

(0.38, 0.58)

9.03

(8.70, 9.21)

38.1

(30.6, 47.4)

12.8

(11.6, 14.2)

5.27

(0.18, 0.23)

2.57

(2.07, 3.19)

3.43

(3.19, 3.69)

2.62

(2.35, 2.93)

14.01

(13.11, 14.97)

119

(104, 138)

37.9

(32.5, 44.3)

7.82

(0.068, 0.073)

0.37

(0.32, 0.43)

0.63

(0.55, 0.74)

0.94

(0.62, 1.44)

6.28

(5.43, 7.21)

47

(47, 37)

5.76

(4.15, 7.98)

8.67

18

21

22

23

24

25

26

6-OMe

7-OMe

8-OMe

9-OMe

rac (cis)

rac (trans)

R,R

4.0

3.17

5.57

1.55

3.12

2.95

1.48

S,S

rac (cis)

(4.48, 6.2)

(6.77, 9.04)

(5.29, 14.21)

a

b

Number of determinations g 3.Values in parentheses are the upper and lower limits derived as a result of the SEM. Selectivity

ratio ) K_i(R_1b)/K_i(R_1A).

Ta ble 2. Effects of Tether Length on Selectivity

radioligand binding K_i(nM)

selectivity

ratio^b

a

no.

n

stereochemistry

R_1A

R_1b

R_1d

18

1

rac (cis)

0.64

(0.56, 0.73)

17.1

2.57

(2.1, 3.2)

14.5

0.37

(0.32, 0.43)

7.7

4.01

0.85

27

28

2

3

rac (cis)

(15.1, 19.2)

(13.7, 15.2)

(5.4, 11.1)

7.43^c

9.95^c

4.77^c

1.33

a

b

Number of determinations g 3. Values in parentheses are the upper and lower limits derived as a result of the SEM. Selectivity

ratio ) K_i(R_1b)/K_i(R_1A). ^cNumber of determinations ) 1.

series of 6-OMe substituted benz[e]isoindole analogues,

the two-carbon linker was clearly preferred.

significantly greater potency and selectivity than the

parent compound 18, with the exception of compounds

29 and 37 that showed >10-fold selectivity. Certain

substitutions were, however, poorly tolerated. Introduc-

tion of substituents in the 6-position as in 43 and 44

was clearly detrimental for affinity.

Whereas phenyl ring substitution was not a particu-

larly useful approach, replacement of the phenyl ring

with various nitrogen-containing heterocycles resulted

in numerous compounds exhibiting significantly im-

proved R_1Aselectivity. Table 5 summarizes the results

On the basis of these preliminary findings, an exten-

sive SAR study of the attached heterocycle was initiated.

Although only minor differences were observed upon

alteration of the center ring heterocycle (see Table 3),

the thiophene substructure was selected for the remain-

der of the SAR study based principally on ease of

synthesis. Substitution on the phenyl ring of the benzo-

thiophene substructure was studied extensively (Table

4) but, in most cases, failed to produce compounds of

Tricyclic Hexahydrobenz[e]isoindoles

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8 1591

Ta ble 3. Effect of the Heteroatom Replacement

radioligand binding K_i(nM)

selectivity

a

no.

X

stereochemistry

R_1A

R_1b

R_1d

ratio^b

4.01

18

S

rac (cis)

0.64

(0.56, 0.73)

2.17

(1.81, 2.60)

0.79

2.57

(2.1, 3.2)

5.39

(4.98, 5.84)

2.25

0.37

(0.32, 0.43)

0.68

(0.61, 0.76)

0.74

19

20

O

rac (cis)

2.48

2.52

NH

(0.57, 1.11)

(2.11, 2.41)

(0.57, 0.96)

a

b

Number of determinations g 3. Values in parentheses are the upper and lower limits derived as a result of the SEM. Selectivity

ratio ) K_i(R_1b)/K_i(R_1A).

Ta ble 4. Effect of Phenyl Ring Substitution

radioligand binding K_i(nM)

selectivity

ratio^d

a

no.

R₁

R_1A

R_1b

R_1d

18

0.64

(0.56, 0.73)

0.40

(0.26, 0.61)

0.29

2.57

(2.1, 3.2)

6.20

(5.39, 7.14)

0.86

0.37

(0.32, 0.43)

0.74

(0.57, 0.96)

0.27

4.01

15.5

2.9

29

30

7-CN

7-CONH₂

(0.20, 0.43)

(0.56, 1.30)

(0.20, 0.37)

31

32

7-CF3

8-CN

9.27^c

23.8^c

6.84^c

2.56

8.7

1.64

14.3

0.59

(1.14, 2.36)

(11.2, 18.2)

(0.40, 0.88)

33

34

35

8-COOMe

8-CON(Me)₂

8-NO₂

4.75^c

14.3^c

2.84^c

3.01

6.07

6.64

0.28^c

1.7^c

0.63^c

1.28^b

8.49^b

1.31^b

(1.21, 1.37)

(8.29, 8.70)

(0.90, 1.91)

36

37

8-Me

8-CONH₂

2.16^c

4.26^c

1.04^c

1.97

12.2

0.52

6.34

0.51

(0.46, 0.60)

(4.62, 8.7)

(0.42, 0.62)

38

8-Cl

0.44^b

1.91^b

0.31^b

4.34

(0.45, 0.45)

0.51^c

(1.61, 2.27)

3.15^c

(0.24, 0.38)

1.32^c

39

40

41

42

43

9-Cl

6.17

4.0

10.8

5.38

12.3

9-OMe

9-CN

9-Me

6-Cl

0.77^c

3.1^c

1.07^c

3.3^c

35.8^c

6.6^c

1.29^c

6.95^c

0.88^c

98.9^b

1220^b

25^b

(49.4, 198)

(148.8, 10000)

(14.1, 44.5)

44

6-CN

6.35^c

26.9^c

2.08^c

4.24

a

b

Number of determinations g 3. Values in parentheses are the upper and lower limits derived as a result of the SEM. Number of

determinations ) 2. ^cNumber of determinations ) 1. Selectivity ratio ) K_i(R_1b)/K_i(R_1A).

d

of the phenyl ring replacement with various hetero-

cycles. The four isomeric pyridine analogues 45-48

showed an incremental improvement in selectivity for

the R_1Areceptor. The pyrimidine analogue 49 and the

pyrazine analogue 51 displayed a further enhancement

in selectivity with retention of sub-nanomolar affinity

for the R_1Abinding site. Further SAR studies explored

the effect of substituents on the heterocyclic ring (Table

6). The greatest selectivity (R_1Avs R_1b) was achieved

with the substituted pyrazine analogues (57, 58, and

1592 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8

Ta ble 5. Effect of Heterocycle Replacement

Meyer et al.

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 assesed in the (SHR) model using

an ascending iv dosing paradigm and measuring the

decrease in blood pressure averaged over a 60 min

period. From the area under the curve (T₆₀AUC) an

ED₅₀value 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 imput on variable pharmacokinetics between

compounds. Pseudo pA2 values from the IUP model and

pED₅₀values from the SHR model are reported in Table

8. Although the absolute selectivity ratios determined

in vivo are an order of magnitude greater than the in

vitro selectivity ratios, the rank order selectivity across

this series of R₁antagonists is nearly identical (terazosin

≈ doxazosin ≈ alfuzosin < tamsulosin < 22 ≈ 45 ≈ 48

< 60). The high correlation between receptor affinity

to subtypes of the R₁receptor, functional response in

target tissues, and the in vivo response to relax prostatic

smooth muscle vs blood pressure control adds further

evidence to support the hypothesis that the R_1Asubtype

differentially mediates prostatic tone and the R_1Bsub-

type mediates vascular tone.

Con clu sion

A structurally novel series of R₁-antagonists, possess-

ing a benz[e]isoindole unit attached to a pyrimidinedione

heterocycle via an alkyl chain, was described. 6-Methoxy

substitution on the benz[e]isoindole portion, R,R ster-

eochemistry, and a two-carbon linker were found to be

optimal for R₁activity. A variety of heterocyclic attach-

ments to this core were found that display high affinity

for the R_1Aadrenoceptor and >10-fold selectivity over

the R_1bsubtype. Compound 60 showed the highest

degree of selectivity in the radioligand binding assays

(50-fold), in the in vitro functional assays (40-fold), and

for in vivo prostate selectivity (3200-fold). This correla-

tion is further evidence that prostatic smooth muscle

tone is primarily mediated by the R_1Asubtype. A

number of the compounds in this study with >10-fold

selectivity for R_1Aover R_1balso possess appreciable

affinity for the R_1dsubtype. Given the possible influence

of the R_1Dreceptor on the irritative symptoms of BPH,

this is an extremely attractive profile for a clinical agent.

Thus, compounds such as 60 have the potential to not

only improve the objective symptoms of BPH such as

a

Number of determinations g 3. Values in parentheses are the

b

upper and lower limits derived as a result of the SEM. Number

of determinations ) 2. ^cSelectivity ratio ) K_i(R_1b)/K_i(R_1A).

60). Although a phenyl ring is relatively well tolerated

in the R₂-position (58), introduction of a phenyl group

in the R₁-position (59) led to a dramatic loss of receptor

binding affinity.

Functional assays for pharmacologically defined R₁

adrenoceptors were used to further characterize the

most selective compounds. Receptors were classified

using phenylephrine (PE) challenge in dog prostate

(R_1A),²²rat vas deferens (R_1A),²³and rat spleen (R_1B).²³

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 7). With the exception of

tamsulosin, functional antagonist selectivity was highly

correlated to receptor subtype binding affinity. Nonse-

lective R₁antagonists such as terazosin (as defined by

receptor binding affinity) also failed to demonstrate

functional antagonist selectivity, whereas the most

selective compounds from this study (i.e., 60) based on

receptor binding affinity also exhibited the greatest

selectivity in in vitro functional models.

urinary flow rate through selectivity for R_1Aover R_1B

,

but to also alleviate the subjective symptoms by an-

tagonism of the R_1Dreceptor at the level of the bladder

smooth muscle.

This same set of the most R_1Aselective compounds

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 measure of hypotensive liability. The IUP

model used aged male anesthesized dogs, in which a

pressure transducer was inserted through the urethra

to the region of prostate. Phenylephrine caused a dose

related increase in intraurethral pressure which was

blockable by R_1Aantagonists. Dose-response curves

Exp er im en ta l Section

Biology. Ra d ioliga n d Bin d in g Assa ys. The compounds

were evaluated for R₁adrenoceptor binding affinity in vitro

using [³H]-prazosin as the radioligand, two cloned R₁adreno-

ceptors expressed in LTK cell: (R_1b(hamster), and R_1d(rat))

and the pharmacologically defined R_1Aadrenoceptor (rat

submaxillary gland). Radioligand binding assays were per-

formed as described previously by Knepper et al.²⁴Briefly,

recombinant R₁-adrenoceptors were stably expressed in mouse

fibroblast cells (LTK^-) grown in roller bottle cultures to provide

Tricyclic Hexahydrobenz[e]isoindoles

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8 1593

Ta ble 6. SAR of Pyrazine and Pyridine Substitution

radioligand binding K_i(nM)

selectivity

a

no.

X

Y

N

R1

H

R2

Cl

R_1A

R_1b

R_1d

ratio^c

11

52

CH

0.38

(0.30, 0.48)

0.66

(0.50, 0.88)

3.13

(2.37, 4.14)

0.79

(0.73, 0.87)

0.49

(0.42, 0.58)

0.39

(0.38, 0.40)

3.91

4.15

(3.03, 5.67)

3.0

(1.99, 4.50)

61.6

(42.5, 89.3)

6.69

(5.54, 8.08)

13.5

(11.4, 15.9)

13.9

(13.7, 14.1)

120

0.61

(0.46, 0.79)

1.1

(0.7, 1.7)

4.16

(3.4, 5.1)

1.41

(1.16, 1.72)

2.31

(1.97, 2.7)

3.28

(2.73, 3.92)

19.8

53

54

55

56

57

58

59

60

61

CH

N

H

OMe

H

4.5

19.7

8.45

27.5

35.6

30.7

12

C-Cl

H

C-OMe

H

N

Me

H

Me

Ph

H

(3.14, 4.87)

(90, 160)

(17.7, 22.1)

Ph

H

153^b

1853^b

160^b

(125, 187)

0.69

(0.50, 0.98)

0.35

(343, 10000)

35.1

(24.5, 50.3)

3.73

(125, 205)

3.83

(3.11, 4.71)

1.10

Cl

50.9

10.6

H

OMe

(0.35, 0.37)

(3.41, 4.07)

(0.99, 1.21)

a

b

Number of determinations g 3. Values in parentheses are the upper and lower limits derived as a result of the SEM. Number of

determinations ) 2. ^cSelectivity ratio ) K_i(R_1b)/K_i(R_1A).

Ta ble 7. In Vitro Profile of Benz[e]isoindole Antagonists in

Ta ble 8. Comparison of Antagonists in the IUP and SHR

Comparison with Other Adrenergic Antagonists

Models.

pA2^arat

antagonist vas deferens

pA2^arat

spleen

pA2^adog

prostate

selectivity

ratio^b

IUP

SHR

(pseudo pED₅₀

((SEM)

a

(pseudo pA2)^a

(95% C. L.)

)

selectivity

ratio^b

antagonist

terazosin

doxazosin

alfuzosin

8.04 ( 0.45 8.6 ( 0.46 7.44 ( 0.24

8.69 ( 0.70 9.51 ( 0.41 7.59 ( 0.20

7.61 ( 0.13 8.31 ( 0.12 6.66 ( 0.10

0.27

0.15

0.20

0.60

13

7.4

10.9

41

terazosin

doxazosin

alfuzosin

tamsulosin

22

45

48

60

7.02 (6.36-7.69)

7.12 (6.54-7.70)

6.87 (6.46-7.28)

8.87 (8.41-9.33)

7.73 (7.33-8.13)

8.25 (7.80-8.45)

8.17 (7.60-8.74)

8.28 (7.84-8.72)

6.64 ( 0.76

6.50 ( 0.63

6.58 ( 0.62

7.33 ( 0.30

5.0 ( 0.17

5.35 ( 0.11

5.33 ( 0.74

4.77 ( 0.19

2.4

4.2

1.9

tamsulosin 9.47 ( 0.21 9.69 ( 0.44 9.54 ( 90.17

22

45

48

60

8.71 ( 0.45 7.59 ( 0.12 8.63 ( 0.34

8.65 ( 0.15 7.79 ( 0.15 8.78 ( 0.32

8.93 ( 0.18 7.89 ( 0.22 9.11 ( 0.15

8.96 ( 1.06 7.35 ( 0.64 9.35 ( 0.82

35

537

589

690

3236

a

Data expressed as pA₂( SEM; slopes are not different from

b

a

b

unity. Number of determinations g 3. Selectivity ratio )

Number of determinations g 3. Selectivity ratio ) anti-

log(pA2-pED₅₀).

antilog[pA2(rat v.d./pA₂(rat.s.)].

cell membranes for subsequent receptor binding characteriza-

tion 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 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 of 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 Whatman GF/B filters. Data were analyzed

as previously described.²⁴

15 mg/kg iv and then 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

with 1 mL of room air and the catheter 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 computerized data

acquisition system (Modular Instruments, Inc) for the mea-

surement of IUP. Dogs were then treated with propranolol (100

µg/kg iv) to block the â-adrenoceptor agonist effect of epineph-

rine. Dose-response curves of the intraurethral 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.²⁵

Sp on ta n eou sly Hyp er ten sive Ra t (SHR) Mod el. Male

spontaneously hypertensive rats (300-325 g) were briefly

anesthetized with Penthrane and the left femoral artery and

In Vivo Mod els. Deter m in a tion of In tr a u r eth r a l P r es-

su 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 thiophenal sodium

1594 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8

Meyer et al.

vein 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 online 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(T₆₀AUC)

was determined using a trapezoidal rule integration of the

percent change from the control arterial pressure data set. The

antagonist T₆₀AUC was compared to that of a hypothetical

antagonist producing complete normalization of blood pressure

for 60 min. The ED₅₀value was determined as the dose

required to produce a T₆₀AUC equivalent to a 50% change to

normotensive.

HCl was added dropwise. The mixture was stirred at reflux

for 0.5 h, then solvents were evaporated, and water was added.

The water solution was extracted with CH₂Cl₂(2×), and the

extracts were set aside. The water layer was basified with 1

M KOH solution and extracted with CH₂Cl₂(2×). The com-

bined basic extracts were washed with water and brine, dried

(MgSO₄), and evaporated to yield a yellow oil (0.69 g, 79%).

The free base was converted to the HCl salt 6a , mp 217-18

1

°C. H NMR (CDCl₃) (free base) δ 1.51 (m, 1H), 1.80 (m, 1H),

1.90 (s, 1H), 2.50 (m, 2H), 2.78 (m, 3H), 3.21 (q, 1H), 3.32 (dd,

1H, J ) 8,11 Hz), 3.42 (dd, 1H, J ) 7,11 Hz), 3.81 (s, 3H),

6.70 (d, 1H, J ) 8 Hz), 6.78 (d, 1H, J ) 8 Hz), 7.12 (t, 1H, J )

8 Hz). MS (DCI/NH₃) m/e 204 (M + H)⁺, 221 (M + NH₄)⁺. Anal.

(C₁₃H₁₈ClNO) C, H, N.

tr a n s-6-Met h oxy-2,3,3a ,4,5,9b -h exa h yd r o-1H-b en z[e]-

isoin d ole Hyd r och lor id e (8a ). The dinitrile 4a (1.00 g)was

dissolved in 24 mL MeOH and 2 mL anhydrous NH₃. Raney

Ni (#28, 3.0 g) was added, and the reaction was shaken under

4 atm of H₂pressure at 25 °C for 48 h. The reaction was then

filtered and evaporated to dryness, and the resulting product

was purified by column chromatography (95:4:1 CH₂Cl₂:

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.

tr a n s a n d cis-5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a -

len e-1,2-d in itr ile (3a a n d 4a ). Acetic acid (1.80 mL, 31.5

mmol) was added to a 0.5 M solution of LiCN in DMF (72 mL,

36 mmol). The solution was cooled to 5 °C, and 5-methoxy-

3,4-dihydronaphthalene-1-carbonitrile 2¹⁶was added (5.55 g,

30 mmol). The cooling bath was removed, and the reaction was

allowed to stir at room temperature for 15 min. The reaction

was quenched by the addition of H₂O (200 mL) and extracted

with Et₂O (2 × 150 mL). The combined organic extracts were

washed with H₂O (2 × 150 mL), 5% NaHCO₃(150 mL), and

brine (150 mL), dried (MgSO₄), and evaporated in vacuo to

yield 6.17 g (97%) of a mixture of 3a and 4a . The isomers were

separated by chromatography on silica gel (3:1 hexane: EtOAc)

to yield 2.35 g (37%) of the trans isomer 4a , mp 122-3 °C, as

the less polar diastereomer. ¹H NMR (CDCl₃) δ 2.2 (m, 1H),

2.4 (m, 1H), 2.9 (m, 2H), 3.3 (ddd, 1H, J ) 4, 7, and 8 Hz), 3.8

(s, 3H), 4.2 (d, 1H, J ) 7 Hz), 6.8 (d, 1H, J ) 8 Hz), 7.0 (d, 1H,

J ) 8 Hz), 7.3 (t, 1H, J ) 8 Hz). MS (DCI/NH₃) m/e 230 (M +

H)⁺. Anal. (C₁₃H₁₂N₂O) C, H, N.

Further elution yielded 3.11 g (49%) of the cis isomer 3a as

the more polar diastereomer, mp 110-12 °C. ¹H NMR (CDCl₃)

δ 2.3 (m, 2H), 2.7 (m, 1H), 3.0 (m, 1H), 3.2 (ddd, 1H, J ) 4, 5,

and 9 Hz), 3.8 (s, 3H), 4.8 (d, 1H, J ) 5 Hz), 6.8 (d, 1H, J ) 8

Hz), 7.0 (d, 1H, J ) 8 Hz), 7.3 (t, 1H, J ) 8 Hz). MS (DCI/

NH₃) m/e 230 (M + H)⁺. Anal. (C₁₃H₁₂N₂O) C, H, N.

cis-6-Met h oxy-3a ,4,5,9b -t et r a h yd r o-1H -b en z[e]isoin -

d ole 1,3-(2H)-d ion e (5a ). A solution of the dinitrile 3a (5.13

g, 22.3 mmol) in CH₂Cl₂was cooled to 0 °C as HBr (gas) was

bubbled through for 2 h. The solution was stirred at 0 °C for

an additional hour. The solvent was removed in vacuo to yield

an orange glass which was dried briefly (in vacuo), then a N₂

purged solution of 50 mL of water/25 mL of DMF was added.

The black solution was heated on the steam bath for 2 h and

was allowed to stand overnight at room temperature. The

precipitate was filtered, washed with cold water/EtOH (75 mL/

25 mL), then dried to yield 5a (2.89 g, 55%).¹H NMR (DMSO-

d₆) 1.62 (m, 1H), 2.08 (m, 2H), 2.82 (m, 1H), 3.3 (m, 1H), 3.78

(s, 3H), 4.09 (d, 1H), 6.86 (d, 1H), 7.04 (d, 1H), 7.19 (t, 1H),

11.25 (bs, 1H). MS (DCI/NH₃) m/e 232 (M + H)⁺.

1

methanol:Et₂NH) to yield 8a , mp >260 °C. H NMR (CDCl₃)

(free base) δ 1.58 (m, 1H), 1.86 (m, 1H), 2.18 (m, 3H), 2.72 (m,

2H), 2.87 (t, 1H), 2.97 (dd, 1H), 3.24 (dd, 1H, J ) 7, 9 Hz),

3.60 (dd, 1H, J ) 8, 9 Hz), 3.82 (s, 3H), 6.63 (d, 1H, J ) 8 Hz),

6.72 (d, 1H, J ) 8 Hz), 7.11 (t, 1H, J ) 8 Hz). MS (DCI/NH₃)

m/e 204 (M + H)⁺, m/e 221 (M + NH₄)⁺. Anal. (C₁₃H₁₈ClNO)

C, H, N.

cis-7-Meth oxy-2,3,3a,4,5,9b-h exah ydr o-1H-ben z[e]isoin -

d ole Hyd r och lor id e (6b). 6-Methoxy-3,4-dihydronaphtha-

lene-1-carbonitrile 2b¹⁶was treated following the procedure

1

described for 6a to yield 6b, mp 149-52 °C. H NMR (CDCl₃)

(free base) δ 1.6 (m, 1H), 1.8 (m, 1H), 2.5 (m, 1H), 2.7 (m, 3H),

2.8 (dd, 1H, J ) 4.5, 12), 3.2 (q, 1H, J ) 9), 3.4 (dd, 1H, J )

7, 11), 3.5 (dd, 1H, J ) 8, 11), 3.8 (s, 3H), 6.6 (d, 1H, J ) 2),

6.7 (dd, 1H, J ) 2, 9 Hz), 7.0 (d, 1H, J ) 9 Hz). MS (DCI/

NH₃), m/e 204 (M + H)⁺. Anal. (C₁₃H₁₈ClNO) C, H, N.

cis-8-Meth oxy-2,3,3a,4,5,9b-h exah ydr o-1H-ben z[e]isoin -

d ole Hyd r och lor id e (6c). 7-Methoxy-3,4-dihydronaphtha-

lene-1-carbonitrile 2b¹⁶was treated following the procedure

described for 6a to yield 6c, mp 231-233 °C. ¹H NMR (CDCl₃)

(free base) δ 1.58 (m, 1H), 1.75 (m, 1H), 2.5-2.7 (m, 3H), 2.88

(m, 1H), 3.05 (m, 1H), 3.42 (m, 3H), 3.72 (s, 3H), 6.73 (dd, 1H),

6.8 (d, 1H), 7.04 (d, 1H). MS (DCI/NH₃) m/e 204 (M + H)⁺.

Anal. (C₁₃H₁₈ClNO) C, H, N.

Eth yl (2-Meth oxyph en yl)-2-oxo-3-car boeth oxypen tan o-

a te (11). Potassium tert-butoxide (179 g, 1.51 mol) and Et₂O

(600 mL) were cooled to 10 °C. Diethyl oxalate (257 mL, 1.89

mol, 1.5 equiv) and ethyl 2-methoxyphenyl butyrate (10) (280

g, 1.26 mol) were dissolved in Et₂O (600 mL) and added to the

cold KOtBu slurry at such a rate as to maintain the reaction

temperature below 25 °C. The ice bath was removed, and the

reaction was allowed to stir at room temperature for 19 h. The

reaction was quenched onto 1 kg of ice and extracted with Et₂O

(2×). The combined organic extracts were washed with 1 N

NaOH (2×), and the aqueous layers were combined. The

aqueous layer was acidified with concentrated HCl to pH 1

and extracted with Et₂O. The Et₂O extract was washed with

brine, dried (MgSO₄), and concentrated to yield 384 g (95%)

of crude product, which was used in the next step without

purification. ¹H NMR (CDCl₃) δ 1.23 (t, 3H), 1.37 (t, 3H), 2.10-

2.35 (m, 2H), 2.6-2.8 (m, 2H), 3.81 (s, 3H), 4.0 (dd, 1H), 4.18

(q, 2H), 4.32 (q, 2H), 6.80-6.92 (m, 2H), 7.10-7.22 (m, 2H).

5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len e-1,2-ca r box-

ylic An h yd r id e (12). The keto diester 11 (384 g, 1.20 mol)

was added to an ice cold solution of 80% H₂SO₄(3.1 L). The

ice bath was removed, and the reaction was stirred at ambient

temperature for 6 h. The reaction was then poured onto 3 kg

of ice with vigorous stirring, and the resulting yellow solid was

collected by filtration, washed with 1.5 L of H₂O, and dried.

The product was recrystallized from 1:1 EtOAc:MeCN to yield

140 g (51%) of the intermediate dihydronaphthalene which was

dissolved in EtOAc (1500 mL) and hydrogenated with 10%

Pd/C (14 g) at 4 atm H₂for 20 h. The reaction mixture was

cis-6-Meth oxy-2,3,3a,4,5,9b-h exah ydr o-1H-ben z[e]isoin -

d ole Hyd r och lor id e (6a ). To a solution of the imide 5a (0.89

g, 3.8 mmol) in THF (10 mL), cooled to 0 °C, was added 1 M

BH₃in THF (30.4 mL). The reaction mixture was stirred at

reflux for 2 h and then was cooled to 0 °C. Excess methanolic

Tricyclic Hexahydrobenz[e]isoindoles

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8 1595

filtered and the solvent evaporated. Recrystallization from

EtOAc yielded 135 g (49%) of 12, mp 138-140 °C. ¹H NMR

(CDCl₃) δ 1.97 (m, 1H), 2.28 (m, 1H), 2.47 (m, 1H), 2.95 (m,

1H), 3.55 (m, 1H), 3.83 (s, 3H), 4.32 (d, 1H), 6.83 (d, 1H), 7.17

(d, 1H), 7.27 (t, 1H).

(3a R,9bR)-2-Am in oeth yl-6-m eth oxy-2,3,3a ,4,5,9b-[1H]-

h exa h yd r oben z[e]isoin d ole (15). To the free base isolated

from 14 (2.39 g, 10.0 mmol), dissolved in MeCN (10 mL) and

diisopropylethylamine (5 mL) was added 0.67 mL (10.6 mmol)

of chloroacetonitrile. The reaction was heated at 70 °C for 1

h, quenched in 5% NaHCO₃, and extracted with EtOAc (2×).

The organic extracts were washed with water (2×) and brine

(1×), dried (Na₂SO₄), and evaporated to yield 2.20 g of the

intermediate nitrile as an off-white solid (90.5%). ¹H NMR

(CDCl₃) δ 1.60 (m, 2H), 1.80 (m, 1H), 2.58 (m, 3H), 2.77 (m,

1H), 3.23 (m, 2H), 3.48 (q, 1H), 3.64 (s, 2H), 3.81 (s, 3H), 6.70

(d, 1H), 6.74 (d, 1H), 7.12 (t, 1H).

To LiAlH₄(0.82 g, 21.5 mmol) suspended in THF (30 mL)

at 0 °C was added dropwise a solution of nitrile (0.80 g, 3.30

mmol) dissolved in THF (5 mL). The reaction was then stirred

at room temperature for 1.5 h, quenched by addition of H₂O

(0.8 mL), 15% NaOH (0.8 mL), and H₂O (2.4 mL), filtered

through Celite, and washed with several hot portions of THF,

and the solvent was evaporated to yield 15 (0.75 g, 93%) as a

colorless oil. ¹H NMR (CDCl₃) δ 1.50 (m, 3H), 1.72 (m, 1H),

2.19 (m, 2H), 2.52 (m, 3H), 2.70 (m, 1H), 2.80 (t, 1H), 3.21 (dd,

1H), 3.28 (t, 1H), 3.40 (m, 1H), 3.80 (s, 3H), 6.67 (d, 1H), 6.75

(d, 1H), 7.11 (t, 1H).

(3aR,9bR)-6-Meth oxy-((S)-r-m eth ylben zyl)-2,3,3a,4,5,9b-

[1H ]-h exa h yd r ob en z[e]isoin d ole-1,3-d ion e (13) a n d

(3a S,9b S)-6-Met h oxy-(S)-r-m et h ylb en zyl)-2,3,3a ,4,5,9b -

[1H]-h exa h yd r oben z[e]isoin d ole-1,3-d ion e (13a ). The an-

hydride 12 (48.8 g, 210 mmol) was combined with (S)-(-)-R-

methylbenzylamine (28.1 g, 0.230 mmol) in xylene (200 mL),

and the reaction was heated to reflux with water removal

(Dean Stark trap) until the theoretical amount of water was

removed. The reaction was then cooled and diluted with EtOAc

(300 mL). The resulting solution was washed with 5% aqueous

HCl, 5% aqueous NaHCO₃, and brine, dried (MgSO₄), and

evaporated to dryness. The resulting oily solid was triturated

with Et₂O, and the resulting crystalline (3aR,9bR) product 13

was collected (28.14 g, 40%), mp 148-150 °C. The diastereo-

meric purity of the imide was determined by HPLC (Chiracel

OD column; 95:5 hexane:2-propanol; 1.0 mL/min) ¹H NMR

(CDCl₃) δ 1.75 (d, 3H), 1.80 (m, 1H), 2.20 (m, 2H), 2.89 (m,

1H), 3.20 (m, 1H),3.80 (s, 3H), 3.95 (d, 1H), 5.49 (q, 1H), 6.79

(d, 1H), 7.17-7.45 (m, 7H). From the mother liquor, on cooling,

a second crop was collected (16.8 g, 48%) and shown to be the

(3aS,9bS) product 13a , mp 101-103 °C. ¹H NMR (CDCl₃) δ

1.78 (d, 3H), 1.85 (m, 1H), 2.20 (m, 2H), 2.88 (m, 1H), 3.17 (m,

1H), 3.81 (s, 3H), 3.98 (d, 1H), 5.48 (q, 1H), 6.78 (d, 1H), 7.17-

7.42 (m, 7H).

cis-6-Me t h oxy-(2-(2-a m in oe t h yl))-2,3,3a ,4,5,9b -[1H ]-

h exa h yd r oben z[e]isoin d ole (7a ). From the free base of 6a

(4.5 g, 22.16 mmol), following the procedure for 15, was

1

isolated 7a (4.3 g, 79%) as a colorless oil. H NMR (CDCl₃) δ

1.50 (m, 3H), 1.72 (m, 1H), 2.19 (m, 2H), 2.52 (m, 3H), 2.70

(m, 1H), 2.80 (t, 1H), 3.21 (dd, 1H), 3.28 (t, 1H, 3.40 (m, 1H),

3.80 (s, 3H), 6.67 (d, 1H), 6.75 (d, 1H), 7.11 (t, 1H).

tr a n s-6-Meth oxy-(2-(2-a m in oeth yl))-2,3,3a ,4,5,9b-[1H]-

h exa h yd r oben z[e]isoin d ole (9a ). From the free base of 8a

(1.5 g, 7.4 mmol) following the procedure for 15, was isolated

8a (1.19 g, 65%) as a colorless oil.

(3aR,9bR)-6-Meth oxy-2,3,3a,4,5,9b-[1H]-h exah ydr oben z-

[e]isoin d ole Hyd r och lor id e (14). The imide 13 (28.0 g, 83.5

mmol) was dissolved in THF (100 mL) and added over 5 min

to a 1.0 M solution of BH₃in THF (417.5 mL). The reaction

mixture was heated at reflux for 2 h, cooled to 25 °C, and

treated cautiously with MeOH (100 mL). After the evolution

of H₂ceased, the solvent was evaporated at reduced pressure.

The resulting oil was dissolved in 2:1 MeOH:IPA saturated

with HCl(g), and the resulting solution was heated at reflux

for 3 h. The solvent was removed in vacuo, the resulting solid

was triturated with 1:1 EtOH:Et₂O, and the amine hydrochlo-

ride (25.8 g, 90%) was collected by filtration, mp 229-231 °C.

The diastereomeric purity of the amine was determined by

HPLC (Chiracel OD column; 99:1 hexane:2-propanol, 0.1%

diethylamine; 0.5 mL/min). Absolute stereochemistry was

determined by single-crystal X-ray of the amine hydrochloride

Meth od A. Method A is exemplified by the following

procedure for 18.

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][1]ben zoth ien o[3,2-d ]p yr im id in e-

2,4(1H,3H)-d ion e Hyd r och lor id e (18). N-(2-Chloroethyl)-

N′-[3-[(2-methoxycarbonyl)benzothienyl]]-urea 17a ¹⁵(0.625 g,

2.00 mmol), 6a (0.503 g, 2.1 mmol), and diisopropylethylamine

(0.35 mL, 2.0 mmol) were combined in DMSO (1 mL) and

heated at 100 °C for 3 h. The reaction was cooled, and EtOH

(3 mL) was added. The crystalline product was collected and

converted to its HCl salt to yield 18 (0.312 g) as a white solid,

1

mp >255 °C (MeOH). H NMR (DMSO-d₆) (free base) δ 1.45

1

salt. H NMR (CDCl₃) (free base) δ 1.38 (d, 3H), 1.49 (m, 1H),

(m, 1H), 1.53 (m, 1H), 2.10-2.80 (m, 6H), 3.10-3.45 (m, 4H),

3.74 (s, 3H), 4.04 (t, 2H), 6.73 (d, 2H), 7.07 (t, 1H), 7.55 (t,

1H), 7.63 (t, 1H), 8.10 (d, 1H), 8.39 (d, 1H), 12.50 (s, 1H). MS

(DCI/NH₃) m/e 448 (M + H)⁺. Anal. (C₂₅H₂₅N₃O₃S‚HCl‚

0.75H₂O) C, H, N.

1.57 (m, 1H), 2.07 (dd, 1H), 2.15 (m, 1H), 2.40-2.72 (m, 3H),

2.97 (dd, 1H), 3.21 (q, 1H), 3.49 (m, 2H), 3.81 (s, 3H), 6.68 (d,

1H), 6.77 (d, 1H), 7.11 (t, 1H), 7.19-7.38 (m, 5H).

The intermediate N-benzylamine hydrochloride (25.7 g, 74.7

mmol) was dissolved in MeOH (700 mL), and 10% Pd/C (5.9

g) was added. The reaction was hydrogenated at 4 atm of H₂

at room temperature for 24 h to yield 15.9 g of 14 (89%) as a

white solid, mp 223-225 °C. ¹H NMR (CD₃OD) δ 1.60 (m, 1H),

1.93 (m, 1H), 2.54 (m, 1H), 2.67 (m, 1H), 2.93 (m, 1H), 3.09

(dd, 1H), 3.13 (dd, 1H), 3.53 (m, 1H), 3.58 (dd, 1H), 3.67 (dd,

3-[2-(tr a n s-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]-[1]ben zoth 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 (21). The chloroethyl

urea 17a (0.40 g, 1.22 mmol)¹⁵and 8a (0.24 g, 1.2 mmol) were

treated by method A to yield 21 as a white solid (0.064 g, 11%),

1

mp >250 °C (MeOH-DMF/Et₂O). H NMR (DMSO-d₆) δ 1.61

20

1H), 3.80 (s, 3H), 6.78 (d, 1H), 6.81 (d, 1H), 7.16 (t, 1H). [R]_D

) -22.0° (c ) 1.39, MeOH, free base).

(m, 1H), 1.93 (m, 1H), 2.16 (m, 2H), 2.67 (m, 2H), 2.88 (m,

1H), 3.70 (m, 2H), 3.78 (s, 3H), 3.93 (m, 1H), 4.03 (m, 1H),

4.32 (m, 3H), 6.66 (m, 1H), 6.88 (d, 1H, J ) 8,4 Hz), 7.17 (t,

1H, J ) 7.9 Hz), 7.62 (m, 2H), 8.13 (d, 1H, J ) 8.1 Hz), 8.43

(d, 1H, J ) 8.1 Hz), 10.27 (br. s, 1H), 12.67 (br s, 1H). MS

(DCI/NH₃) m/e 448 (M + H)⁺. Anal. (C₂₅H₂₅N₃O₃S‚HCl‚

0.25H₂O) C, H, N.

(3aS,9bS)-6-Meth oxy-2,3,3a,4,5,9b-[1H]-h exah ydr oben z-

[e]isoin d ole Hyd r och lor id e (14a ). The imide 13a (8.0 g, 23.8

mmol) was treated as described for compound 14 to yield the

1

intermediate tertiary amine (7.2 g, 88%) as a white solid. H

NMR (CDCl₃) (free base) δ 1.38 (d, 3H), 1.52 (m, 1H), 1.72 (m,

1H), 2.02 (t, 1H), 2.18 (dd, 1H), 2.50-2.72 (m, 3H), 2.99 (t,

1H), 3.18 (q, 1H), 3.30-3.48 (m, 2H), 3.80 (s, 3H), 6.62 (d, 1H),

6.65 (d, 1H), 7.04 (t, 1H), 7.20-7.35 (m, 5H).

Meth od B. Method B is exemplified by the following

procedure for 22.

3-[2-((3a R,9bR)-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]-[1]ben zoth ien o[3,2-d ]p y-

r im id in e-2,4(1H,3H)-d ion e Hyd r och lor id e (22). 3-Amino-

2-carbomethoxy-benzothiophene¹⁵(2.21 g, 10 mmol) and

triphosgene (0.99 g, 3.33 mmol) were combined in toluene (40

mL) and heated at reflux for 3 h. The solvent was then

evaporated to yield the intermediate isocyanate (2.45 g) as a

white solid. The amine 15 (0.24 g, 1.0 mmol) and the obtained

The tertiary amine (5.7 g, 16.6 mmol) was treated as

described for the compound 14 to yield the title compound 14a

(3.10 g, 78%) as a white solid, mp 222-225 °C. ¹H NMR (CD₃-

OD) δ 1.60 (m, 1H), 1.93 (m, 1H), 2.54 (m, 1H), 2.67 (m, 1H),

2.93 (m, 1H), 3.09 (dd, 1H), 3.13 (dd, 1H), 3.53 (m, 1H), 3.58

(dd, 1H), 3.67 (dd, 1H), 3.80 (s, 3H), 6.78 (d, 1H), 6.81 (d, 1H),

25

7.16 (t, 1H). [R]_D) 22.2 (c ) 1.265, MeOH, free base).

1596 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8

Meyer et al.

isocyanate (0.260 g, 1.1 mmol) were combined in toluene (10

mL) and heated at reflux for 3 h. The product was then

partitioned between 5% NaHCO₃and hot EtOAc, and the

organic phase was dried (K₂CO₃), filtered, and evaporated. The

resulting product was converted to its HCl salt and recrystal-

lized from EtOH-Et₂O to yield 0.28 g of 22 as a white solid,

mp >250 °C (dec). ¹H NMR (CD₃OD) δ 1.62-1.71 (m, 1H),

1.89-1.97 (m, 1H), 2.54-2.62 (m, 1H), 2.76-2.88 (m, 1H),

3.13-3.51 (m, 2H), 3.60 (t, 2H), 3.63-3.71 (m, 1H), 3.80 (s,

3H), 3.84-4.19 (m, 2H), 4.42 (dt, 2H), 6.80 (t, 2H), 7.16 (t, 1H),

7.53 (t, 1H), 7.63 (t, 1H), 7.98 (d, 1H), 8.18 (d, 1H). MS (DCI/

NH₃) m/e 448 (M + H)⁺. Anal. (C₂₅H₂₅N₃O₃S‚HCl‚H₂O) C, H,

N.

3-[2-(cis-9-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]-[1]ben zoth ien o[3,2-d ]p yr im id in e-

2,4(1H,3H)-d ion e Hyd r och lor id e (26). The chloroethyl urea

17a ¹⁵(0.41 g, 1.25 mmol) and cis-9-methoxy-2,3,3a,4,5,9b-

hexahydro-[1H]-benz[e]isoindole 18 (0.33 g, 1.37 mmol) were

reacted by method A to yield 0.17 g of 26 as a white solid, mp

214-16 °C. ¹H NMR (CD₃OD) δ 1.73 (m, 1H), 1.91 (m, 1H),

2.78 (m, 4H), 3.00-4.40 (m, 4H), 3.62 (t, 2H), 3.83 (s, 3H), 4.43

(t, 2H), 6.76 (d, 1H), 6.81 (d, 1H), 7.16 (t, 1H), 7.55 (t, 1H),

7.66 (t, 1H), 8.00 (d, 1H), 8.19 (d, 1H). MS (DCI/NH₃) m/e 448

(M + H)⁺. Anal. (C₂₅H₂₅N₃O₃S‚HCl‚0.5H₂O) C, H, N.

3-[3-(cis-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-[1H]-ben z-

[e]isoin dol-2-yl)pr opyl]-[1]ben zoth ien o[3,2-d]pyr im idin e-

2,4(1H,3H)-d ion e Hyd r och lor id e (27). N-(3-Chloropropyl)-

N′-[3-[(2-methoxycarbonyl)benzothienyl]urea (0.613 g, 1.80

mmol) prepared by the method of Romeo,¹⁵substituting for

3-chloropropylisocyanate, and compound 6a (0.369 g, 1.82

mmol) were reacted by method A to yield 0.10 g of 27 as a

3-[2-((3a S,9bS)-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]-[1]ben zoth ien o[3,2-d ]p y-

r im id in e-2,4(1H,3H)-d ion e Hyd r och lor id e (23). The chlo-

roethyl urea 17a (1.50 g, 4.57 mmol) and the free base of 14a

(0.450 g, 1.85 mmol) were treated by method A to yield 23 as

a white solid, mp >250 °C. ¹H NMR (CD₃OD) δ 1.60-1.77 (m,

1H), 1.88-2.02 (m, 1H), 2.52-2.67 (m, 1H), 2.74-2.92 (m, 2H),

3.27-3.50 (m, 2H), 3.58-3.73 (m, 3H), 3.81 (s, 3H), 3.93-4.19

(m, 2H), 4.43 (t, 2H), 6.81 (t, 2H), 7.18 (t, 1H), 7.54 (t, 1H),

7.64 (t, 1H), 7.99 (d, 1H), 8.19 (d, 1H). MS (DCI/NH₃) m/e 448

(M + H)⁺. Anal. (C₂₅H₂₅N₃O₃S‚HCl) C, H, N.

1

white solid, mp 183-6 °C. H NMR (CD₃OD) δ 1.65 (m, 1H),

1.92 (m, 1H), 2.18 (m, 2H), 2.57 (m, 1H), 2.70-3.40 (m, 6H),

3.55-4.10 (m, 3H), 3.80 (s, 3H), 4.18 (t, 2H), 6.78 (d, 1H), 7.02

(d, 1H), 7.16 (t, 1H), 7.53 (t, 1H), 7.63 (t, 1H), 7.98 (d, 1H),

8.18 (d, 1H). MS (DCI/NH₃) m/e 462 (M + H)⁺. Anal.

(C₂₆H₂₇N₃O₃S‚HCl‚0.25H₂O) C, H, N.

3-[4-(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)bu tyl]-[1]ben zoth ien o[3,2-d ]p yr im id in e-

2,4(1H,3H)-d ion e Hyd r och lor id e (28). 5-Methoxy-1,2,3,4-

tetrahydronaphthalene-cis-1,2-dicarboxylic acid diethyl ester

(37.0 g, 129 mmol)¹⁷was dissolved in THF (100 mL) and added

over 15 min to a suspension of LiAlH₄(9.20 g, 241 mmol) in

THF (400 mL). The reaction was stirred at 25 °C for 18 h and

then quenched by sequential addition of 9.2 mL of H₂O, 9.2

mL of 15% aqueous KOH solution, and 29 mL of H₂O. The

reaction was filtered and the solvent evaporated at reduced

pressure to yield cis-5-methoxy-1,2- bis(hydroxymethyl)-1,2,3,4-

tetrahydronaphthalene (22.15 g, 82%) as a white solid. ¹H

NMR (CDCl₃) δ 1.70 (m, 2H), 2.04 (m, 1H), 2.53 (br s, 1H),

2.85 (m, 2H), 3.02 (br s, 1H), 3.48 (m, 1H), 3.65-3.85 (m, 4H),

3.86 (s, 3H), 6.70 (d, 1H), 6.73 (d, 1H), 7.12 (t, 1H).

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)et h yl]b en zofu r o[3,2-d ]p yr im id in e-2,4-

(1H,3H)-d ion e Hyd r och lor id e (19). The chloroethyl urea

16b¹⁵(0.390 g, 1.65 mmol) and 6a (0.497 g, 1.60 mmol) were

treated by method A to yield 19 (0.291 g) as a white solid, mp

252 °C. ¹H NMR (CD₃OD) δ 1.65 (m, 1H), 1.95 (m, 1H), 2.50-

3.15 (m, 6H), 3.40-3.75 (m, 3H), 3.60 (t, 2H), 3.81 (s, 3H), 4.42

(t, 2H), 6.80 (d, 1H), 6.83 (d, 1H), 7.17 (t, 1H), 7.45 (m, 1H),

7.69 (m, 2H), 7.94 (d, 1H). MS (DCI/NH₃) m/e 432 (M + H)⁺.

Anal. (C₂₅H₂₅N₃O₄‚HCl‚0.5H₂O) C, H, N.

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)e t h yl]-1H -p yr im id o[5,4-b]in d ole -2,4-

(3H,5H)-d ion e Hyd r och lor id e (20). 2-Carboethoxy-3-amino-

indole¹⁵(0.18 g, 0.85 mmol) and the amine 7a (0.19 g, 0.77

mmol) were treated by method B. The resulting product was

collected by filtration and dissolved in 15 mL of EtOH and 5

mL of THF. To this solution was added 0.58 mL of 1.0 M

KOtBu in THF, and the mixture was heated at reflux for 45

min. After cooling, the product was collected by filtration and

converted to its HCl salt to yield 20 (0.12 g, 61%), mp >250

cis-5-Methoxy-1,2-bis(hydroxymethyl)-1,2,3,4-tetrahydronaph-

thalene (22.2 g, 100 mmol), triethylamine (84 mL, 600 mmol),

and CH₂Cl₂(500 mL) were combined and cooled to 0 °C.

Methanesulfonyl chloride (23.3 mL, 300 mmol) was added over

15 min, and the reaction was stirred an additional 1.5 h. The

reaction was quenched in 5% aqueous NaHCO₃, the organic

phase washed with one additional portion of 5% aqueous

NaHCO₃and brine, then dried (MgSO₄), and filtered, and

solvent evaporated. The crude product was triturated with cold

Et₂O and then collected by filtration to yield cis-5-methoxy-

1,2(bishydroxymethyl)-1,2,3,4-tetrahydronaphthalene-1,2-bis-

mesylate (33.5 g, 94%) as a white solid. ¹H NMR (CDCl₃) δ

1.65-1.95 (m, 2H), 2.33 (m, 1H), 2.88 (m, 1H), 2.97 (s, 3H),

3.09 (s, 3H), 3.12 (m, 1H), 3.70 (m, 1H), 3.88 (s, 3H), 4.40 (m,

4H), 6.72 (d, 1H), 6.76 (d, 1H), 7.18 (t, 1H).

1

°C (dec). H NMR (DMSO-d₆) δ 1.52-1.66 (m, 1H), 1.74-1.84

(m, 1H), 2.36-2.52 (m, 1H), 2.62-2.82 (m, 2H), 2.97-3.08 (m,

1H), 3.42-3.57 (m, 3H), 3.64-3.86 (m, 1H), 3.77 (s 3H), 4.02-

4.34 (m, 4H), 6.72-6.86 (m, 2H), 7.09-7.19 (m, 2H), 7.36-

7.45 (m, 2H), 7.96 (t, 1H), 9.91 and 10.27 (bs and bs, 1H), 11.81

and 12.10 (d and d, 2H). MS (DCI/NH₃) m/e 431 (M + H)⁺.

Anal. (C₂₅H₂₆N₄O₃‚HCl‚0.5H₂O) C, H, N.

3-[2-(cis-7-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]-[1]ben zoth ien o[3,2-d ]p yr im id in e-

2,4(1H,3H)-d ion e Hyd r och lor id e (24). The chloroethyl urea

17a (1.21 g, 3.7 mmol)¹⁵and 6b (1.0 g, 4.17 mmol) were reacted

by method A to yield 24 as a white solid, mp 241-2 °C. ¹H

NMR (DMSO-d₆) (free base) δ 1.48 (m, 1H), 1.63 (m, 1H), 2.08

(m, 1H), 2.21 (m, 1H), 2.5-2.7 (m, 4H), 3.10-3.4 (m, 4H), 3.68

(s, 3H), 4.04 (t, 2H), 6.68 (m, 2H), 7.01 (d, 1H), 7.52 (t, 1H),

7.61 (t, 1H), 8.11 (d, 1H), 8.39 (d, 1H), 12.50 (s, 1H). MS (DCI/

NH₃) m/e 448 (M + H)⁺. Anal. (C₂₅H₂₅N₃O₃S‚HCl) C, H, N.

3-[2-(cis-8-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]-[1]ben zoth ien o[3,2-d ]p yr im id in e-

2,4(1H,3H)-d ion e Hyd r och lor id e (25). The chloroethyl urea

17a 15 (0.5 g, 1.53 mmol) and 6c (0.3 g, 1.47 mmol) were

reacted by method A to yield 25 as a white solid, mp > 250

°C. ¹H NMR (DMSO-d₆) (free base) δ 1.48 (m, 1H), 1.63 (m,

1H), 2.15 (m, 1 H), 2.22 (m, 1H), 2.41-2.74 (4 H), 3.16-3.36

(m, 4H), 3.69 (s, 3H), 4.05 (t, 2H), 6.64 (m, 2H), 6.90 (d, 1H),

7.55 (t, 1H), 7.63 (t, 1H), 8.11 (d, 1H), 8.39 (d, 1H), 12.53 (s,

1H). MS (DCI/NH₃) m/e 448 (M + H)⁺. Anal. (C₂₅H₂₅N₃O₃S‚

HCl) C, H, N.

The bis-mesylate intermediate (1.89 g, 5.0 mmol) was

dissolved in 1,4-diaminobutane (15 mL), and the reaction was

heated at 65 °C for 3 h. The reaction was quenched in 5%

aqueous NaOH and extracted with CH₂Cl₂. The organic

extracts were washed with brine, dried (K₂CO₃), filtered, and

evaporated to yield cis-6-methoxy-2-(4-aminobutyl)-2,3,3a,4,5,9b-

[1H]-hexahydrobenz[e]isoindole as a colorless oil (1.20 g, 85%).

¹H NMR (CDCl₃) δ 1.40-1.85 (m, 6H), 2.12 (m, 2H), 2.40-

2.68 (m, 5H), 2.71 (t, 2H), 3.23-3.5 (m, 4H), 3.70 (m, 1H), 3.82

(s, 3H), 6.68 (d, 1H), 6.75 (d, 1H), 7.11 (t, 1H).

The intermediate primary amine (0.24 g, 0.87 mmol) and

the benzothiophene 16 were treated by method B to yield 28

(0.28 g, 67%) as a white solid, mp 173-175 °C. ¹H NMR

(DMSO-d₆) (free base) δ 1.36-1.52 (m, 3H), 1.57-1.69 (m, 3H),

2.05 (t, 1H), 2.11 (dd, 1H), 2.34-2.62 (m, 5H), 3.06 (t, 1H),

3.15 (t, 1H), 3.26 (q, 1H), 3.74 (s, 3H), 3.92 (t, 2H), 6.71 (t,

2H), 7.05 (t, 1H), 7.55 (t, 1H), 7.63 (dt, 1H), 8.10 (d, 1H), 8.38

(d, 1H). MS (DCI/NH₃) m/e 476 (M + H)⁺. Anal. (C₂₇H₂₉N₃O₃S‚

HCl‚H₂O) C, H, N.

Tricyclic Hexahydrobenz[e]isoindoles

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8 1597

3-[2-((3a R,9bR)-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-cya n o[1]ben zoth ien o-

[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Hyd r och lor id e (29).

Nitroterephthalonitrile (5.0 g, 28.9 mmol)²⁶was refluxed in

MeOH with methyl thioglycolate (3.06 g, 28.9 mmol) and Na₂-

CO₃(3.06 g, 28.9 mmol) for 3 h. The reaction mixture was

cooled to room temperature, quenched with water, and con-

centrated. The residue was chromatographed on silica gel,

eluting with 4:1, then 1:1 hexane:EtOAc to yield 3-amino-2-

carbomethoxy-6-cyano-benzothiophene (5.50 g, 82%). ¹H NMR

(DMSO-d₆) δ 8.50 (s, 1H), 8.32 (d, 1H), 7.80 (dd, 1H), 7.29 (br

s, 2H), 3.81 (s, 3H). MS (DCI/NH₃) m/e 250 (M + NH₄)⁺.

3-Amino-2-carbomethoxy-6-cyano-benzothiophene (0.465 g,

2.0 mmol) and the amine 15 (0.39 g, 1.6 mmol) were reacted

by method B. The crude product was purified by chromatog-

raphy on silica gel, eluting with EtOAc:HCOOH:H₂O (18:1:1)

and converted to the HCl salt to yield 29 (0.28 g, 34%). ¹H

NMR (DMSO-d₆) δ 12.87 (d, 1H), 10.82 (s, 1H), 8.78 (s, 1H),

8.56 (d, 1H), 7.97 (d, 1H), 7.17 (t, 1H), 6.71-6.86 (m, 2H), 4.29

(m, 2H), 4.15 (m, 1H), 4.01 (m, 1H), 3.78 (s, 3H), 3.51 (m, 2H),

3.02 (m, 1H), 2.58-2.82 (m, 3H), 1.79 (m, 2H), 1.61 (m, 2H).

MS (DCI/NH₃) m/e 473 (M + H)⁺. Anal. (C₂₆H₂₄N₄O₃S‚2HCl‚

0.5H₂O) C, H, N.

3-[2-((3a R,9bR)-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-ca r boxa m id o[1]ben zo-

t h ien o[3,2-d ]p yr im id in e-2,4(1H ,3H )-d ion e H yd r och lo-

r id e (30). 3-Amino-2-carbomethoxy-6-cyano-benzothiophene

(2.46 g, 10.6 mmol) and ground KOH (7.12 g, 127 mmol) were

taken up in tert-butyl alcohol (80 mL) to form a slurry, which

was refluxed for 24 h. The mixture was cooled, poured into

water, and the solution adjusted to pH 3 with 37% HCl. The

resulting mixture was filtered, and the crude amido acid was

dissolved in DMSO (125 mL) and MeOH (75 mL) and stirred

at room temperature. A 2.0 M solution of trimethylsilyldiazo-

methane (TMSCHN₂) in hexanes (8 mL) was added slowly.

The reaction was stirred an additional 10 min and condensed

in vacuo. The crude product was chromatographed on silica

gel eluting with EtOAc, and the residue was recrystallized

from MeOH/EtOAc to yield 0.90 g (34%) of 3-amino-2-car-

bomethoxy-6-carboxamido-benzothiophene. ¹H NMR (DMSO-

d₆) δ 8.32 (d, 1H), 8.21 (d, 1H), 8.11 (br s, 1H), 7.88 (dd, 1H),

7.52 (br s, 1H), 7.22 (br s, 2H), 3.81 (s, 3H). MS (DCI/NH₃)

m/e 268 (M + NH₄)⁺.

The obtained benzothiophene (0.45 g, 1.7 mmol) and the

amine 15 (0.369 g, 1.5 mmol) were treated by method B to

yield the free base, which was taken up in 4.0 M HCl in

dioxane, and triturated with EtOH to give 31 (0.191 g, 24%),

mp >270 °C. ¹H NMR (DMSO-d₆) δ 12.88 (d, 1H), 10.48 (s,

1H), 8.60 (s, 1H), 8.46 (dd, 1H), 8.20 (s, 1H), 8.02 (dd, 1H),

7.62 (s, 1H), 7.17 (t, 1H), 6.72-6.87 (m, 2H), 4.29 (m, 2H), 4.16

(m, 1H), 4.02 (m, 1H), 3.78 (s, 3H), 3.51 (m, 2H), 3.02 (m, 1H),

2.60-2.85 (m, 3H), 1.79 (m, 2H), 1.61 (m, 2H). MS (DCI/NH₃)

m/e 491 (M + H)⁺. Anal. (C₂₆H₂₆N₄O₄S‚2HCl‚0.75H₂O) C, H,

N.

4-Chloroisophthalonitrile (5.69 g, 35 mmol), prepared by the

method of Markley²⁷was treated with methyl thioglycolate

(3.95 g, 35 mmol) and Na₂CO₃(3.7 g, 35 mmol) in MeOH by

the procedure described for 29 to yield 3-amino-2-carbomethoxy-

5-cyano-benzothiophene (3.00 g, 37%), mp 248 °C. ¹H NMR

(DMSO-d₆) δ 8.71 (s, 1H), 8.09 (d, 1H), 7.86 (dd, 1H), 7.30 (br

s, 2H), 3.81 (s, 3H). MS (DCI/NH₃) m/e 250 (M + NH₄)⁺.

The obtained benzothiophene (0.46 g, 2.0 mmol) and the

amine 15 (0.39 g, 1.6 mmol) were treated by method B to yield

1

32 (0.68 g, 83%). H NMR (DMSO-d₆) δ 1.61 (m, 2H), 1.79 (m,

2H), 2.59-2.83 (m, 3H), 3.02 (m, 1H), 3.52 (m, 2H), 3.78 (s,

3H), 4.01 (m, 1H), 4.14 (m, 1H), 4.29 (m, 2H), 6.71-6.86 (m,

2H), 7.17 (t, 1H), 8.02 (d, 1H), 8.39 (d, 1H), 8.90 (d, 1H), 10.69

(s, 1H), 12.82 (d, 1H). MS (DCI/NH₃) m/e 473 (M + H)⁺. Anal.

(C₂₆H₂₄N₄O₃S‚2HCl‚0.25H₂O) C, H, N.

3-[2-((3a R,9bR)-cis-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-

[1H]-ben z[e]isoin dol-2-yl)eth yl]-8-car bom eth oxy[1]ben zo-

t h ien o[3,2-d ]p yr im id in e-2,4(1H ,3H )-d ion e H yd r och lo-

r id e (33). 3-Amino-4-chlorobenzoic acid (18.72 g, 109.1 mmol)

was added to a mixture of H₂O (200 mL) and 37% HCl (35

mL), and the resulting slurry was cooled to 5 °C. A solution of

NaNO₂(8.65 g, 125 mmol) in H₂O (70 mL) was added dropwise,

and the solution was stirred at 5 °C for 30 min. The solution

was then added to a slurry consisting of H₂O (400 mL), CuCN

(9.85 g, 109 mmol), and KCN (12.06 g, 185 mmol), while

maintaining the temperature at 5-10 °C. The mixture was

stirred at 10 °C for another 30 min and then heated to 80 °C

for 1 h. The reaction was cooled, and the pH adjusted to ∼1

by addition of concentrated HCl. The solution was extracted

with CHCl₃(5×), and the combined extracts were rinsed with

1 M HCl, brine, and dried (MgSO₄). The solvent was removed

in vacuo, and the crude product was recrystallized from CHCl₃/

EtOAc to yield 15.9 g (80%) of 3-cyano-4-chloro-benzoic acid,

1

mp 180 °C. H NMR (CDCl₃) δ 10.55 (br s, 1H), 8.42 (d, 1H),

8.26 (dd, 1H), 7.68 (d, 1H). MS (DCI/NH₃) m/e 213 (M + NH₄)⁺.

3-Cyano-4-chloro-benzoic acid (4.83 g, 26.6 mmol) was

dissolved in 1:1 EtOAc/MeOH (150 mL) then treated slowly

with a 2.0 M solution of trimethylsilyldiazomethane (TM-

SCHN₂) in hexanes (25 mL) at room temperature. The reaction

mixture was stirred an additional 10 min, and concentrated

in vacuo. The residue was recrystallized from hexane/EtOAc

to yield 3.19 g (61%) of methyl-3-cyano-4-chloro-benzoate, mp

193 °C. ¹H NMR (CDCl₃) δ 8.34 (d, 1H), 8.19 (dd, 1H), 7.52 (d,

1H), 3.97 (s, 3H). MS (DCI/NH₃) m/e 199 (M + NH₄)⁺.

Methyl-3-cyano-4-chloro-benzoate (3.19 g, 16.3 mmol) was

treated with methyl thioglycolate (1.73 g, 16.3 mmol) and Na₂-

CO₃(1.72 g, 16.3 mmol) in MeOH by the procedure described

for 29 to yield 3-amino-2,5-carbomethoxy-benzo[b]thiophene

1

(2.78 g, 64%), mp 193 °C. H NMR (300 MHz, DMSO) δ 8.88

(d, 1H), 8.03 (dd, 1H), 7.97 (d, 1H), 7.39 (br s, 2H), 3.91 (s,

3H), 3.80 (s, 3H). MS (DCI/NH₃) m/e 283 (M + NH₄)⁺. This

intermediate (0.58 g, 2.0 mmol) and the amine 15 (0.30 g, 1.2

mmol) were treated by method B to yield 33 (0.44 g, 68%), mp

1

>250 °C. H NMR (DMSO-d₆) δ 12.83 (d, 1H), 10.50 (s, 1H),

3-[2-((3a R,9bR)-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]-7-t r iflu or om e t h yl[1]-

ben zoth ien o[2,3-d ]p yr im id in e-2,4(1H,3H)-d ion e Hyd r o-

ch lor id e (31). 6-Trifluoromethyl-3-amino-2-ethoxycarbonyl-

benzothiophene (0.556 g, 1.49 mmol), prepared by the method

of J . R. Beck²⁰from 4-trifluoromethyl-2-nitrobenzonitrile and

ethylthioglycolate, was converted to the corresponding isocy-

anate by method B. The resulting isocynate was reacted with

the amine 15 (1.24 mmol) in the presence of Et₃N (1.2 equiv,

0.21 mL) in toluene (10 mL) at reflux for 18 h to yield 30 (0.292

g, 43%), mp >270 °C. [R]_D) +30.6° (c ) 0.54, EtOH). ¹H NMR

(DMSO-d₆) δ 12.82 (br s, 1H), 8.70 (s, 1H), 8.63 (d, 1H), 7.93

(d, 1H), 7.17 (t, 1H), 6.84 (br d, 1H), 6.75 (br d, 1H), 4.29 (m,

2H), 4.17 (m, 1H), 4.04 (m, 1H), 3.77 (s, 3H), 3.52 (m, 3H),

3.04 (m, 2H), 2.70 (m, 2H), 2.43 (m, 1H), 1.78 (m, 1H), 1.59

(m, 1H). MS (DCI/NH₃) m/e 516 (M + H)⁺. Anal. (C₂₆H₂₄F₃N₃-

O₃S‚HCl‚0.5H₂O) C, H, N.

9.19 (d, 1H), 8.28 (d, 1H), 8.14 (d, 1H), 7.17 (t, 1H), 6.72-6.86

(m, 2H), 4.29 (m, 2H), 4.15 (m, 1H), 4.02 (m, 1H), 3.78 (s, 3H),

3.52 (m, 2H), 3.02 (m, 1H), 2.58-2.84 (m, 3H), 1.80 (m, 2H),

1.61 (m, 2H). MS (DCI/NH₃) m/e 506 (M + H)⁺. Anal.

(C₂₇H₂₇N₃O₅S‚HCl‚1.5H₂O) C, H, N.

3-[2-((3a R,9bR)-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]-8-N,N-d im eth ylca r box-

a m id o[1]b en zot h ien o[3,2-d ]p yr im id in e-2,4(1H ,3H )-d i-

on e Hyd r och lor id e (34). 3-Cyano-4-chlorobenzoic acid (5.55

g, 30.5 mol) in toluene (100 mL) was treated with oxalyl

chloride (2.93 mL, 33.6 mmol) and pyridine (0.1 mL), and the

solution was heated to reflux until HCl evolution ceased (6

h). The reaction was cooled and concentrated in vacuo. The

resulting solution was poured into a stirred mixture of 40%

aqueous dimethylamine (150 mL) and EtOAc (150 mL), and

the reaction stirred for 10 min. The layers were separated,

the aqueous layer was extracted with EtOAc (2×), and the

combined organic layers were rinsed with 1 M HCl (2×) and

brine and dried (MgSO₄). The solution was evaporated, and

the residue was recrystallized from EtOAc to yield 4.91 g (77%)

3-[2-((3a R,9bR)-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]-8-cya n o[1]ben zoth ien o-

[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Hyd r och lor id e (32).

1598 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8

Meyer et al.

of 3-cyano-4-chloro-N,N-dimethylbenzamide, mp 193 °C. ¹H

NMR (CDCl₃) δ 8.28 (d, 1H), 7.61 (dd, 1H), 7.58 (d, 1H), 3.12

(br s, 2H), 3.00 (br s, 3H). MS (DCI/NH₃) m/e 226 (M + NH₄)⁺.

3-Cyano-4-chloro-N,N-dimethylbenzamide (3.00 g, 14.4 mmol)

was treated with methyl thioglycolate (1.53 g, 14.4 mmol) and

Na₂CO₃(1.52 g, 14.4 mmol) in MeOH by the procedure

described in 29 to yield 3-amino-2-carbomethoxy-5-N,N-di-

methylcarboxamido-benzo[b]thiophene (1.55 g, 39%), mp 218-

220 °C. ¹H NMR (DMSO-d₆) δ 8.28 (d, 1H), 7.90 (dd, 1H), 7.54

(d, 1H), 7.23 (br s, 2H), 3.80 (s, 3H), 3.02 (br s, 3H), 2.98 (br s,

3H). MS (DCI/NH₃) m/e 296 (M + NH₄)⁺.

give 37 (0.117 g, 22%), mp >250 °C. ¹H NMR (DMSO-d₆) δ

12.72 (d, 1H), 11.20 (s, 1H), 9.08 (d, 1H), 8.19 (d, 1H), 8.10 (s,

1H), 8.08 (d, 1H), 7.56 (s, 1H), 7.17 (t, 1H), 6.72-6.87 (m, 2H),

4.29 (m, 2H), 4.14 (m, 1H), 4.01 (m, 1H), 3.78 (s, 3H), 3.51 (m,

2H), 3.01 (m, 1H), 2.58-2.85 (m, 3H), 1.79 (m, 2H), 1.62 (m,

2H). MS (DCI/NH₃) m/e 491 (M + H)⁺. Anal. (C₂₆H₂₆N₄O₄S‚

HCl‚0.75H₂O) C, H, N.

3-[2-((3a R,9bR)-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]- 8-ch lor o[1]ben zoth ien o-

[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Hyd r och lor id e (38).

5-Chloro-3-amino-2-carboethoxybenzothiophene³⁴(0.52 g, 2.03

mmol) and the amine 15 (0.417 g, 1.69 mmol) were treated by

method B to yield 38 (0.273 g, 32%) as a white solid, mp >210

°C. ¹H NMR (DMSO-d₆) δ 12.65 (m, 1H), 8.54 (m, 1H), 8.19

(m, 1H), 7.70 (m, 1H), 7.17 (m, 1H), 6.84 (m, 1H), 6.76 (m,

1H), 4.28 (m, 2H), 4.18 (m, 1H), 4.03 (m, 1H), 3.78 (s, 3H),

3.52 (m, 3H), 3.03 (m, 2H), 2.74 (m, 2H), 2.45 (m, 1H), 1.80

(m, 1H), 1.62 (m, 1H). MS (DCI/NH₃) m/e 482 (M + H)⁺. Anal.

(C₂₅H₂₅Cl₂N₃O₃S‚HCl‚2H₂O) C, H, N.

The intermediate benzo[b]thiophene (0.556 g, 2.0 mmol) and

the amine 15 (0.35 g, 1.42 mmol) were treated by method B to

1

yield 34 (0.183 g, 23%), mp 216-219 °C. H NMR (DMSO-d₆)

δ 12.79 (d, 1H), 10.66 (s, 1H), 8.53 (d, 1H), 8.20 (d, 1H), 7.69

(d, 1H), 7.17 (t, 1H), 6.72-6.87 (m, 2H), 4.29 (m, 2H), 4.15 (m,

1H), 4.02 (m, 1H), 3.78 (s, 3H), 3.55 (m, 2H), 3.04 (s, 3H), 3.02

(m, 1H), 2.92 (s, 3H), 2.60-2.85 (m, 3H), 1.80 (m, 2H), 1.62

(m, 2H). MS (DCI/NH₃) m/e 519 (M + H)⁺. Anal. (C₂₈H₃₀N₄O₄S‚

2HCl‚H₂O) C, H, N.

3-[2-((3a R,9bR)-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]-9-ch lor o[1]ben zoth ien o-

[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Hyd r och lor id e (39).

4-Chloro-3-amino-2-carboethoxybenzothiophene was prepared

as described by De Angelis²⁸from 2,6-dichlorobenzonitrile and

ethyl thioglycolate. The resulting benzothiophene (1.0 g, 4.17

mmol) and the amine 15 (1.65 mmol) were treated by method

B to yield 39 (0.273 g, 32%) as a white solid, mp >270 °C; [R]_D

+25.7° (c ) 0.51 in MeOH). ¹H NMR (DMSO-d₆) δ 8.16 (m,

1H), 7.64 (m, 2H), 7.17 (m, 1H), 6.84 (m, 1H), 6.77 (m, 1H),

4.29 (m, 2H), 4.15 (m, 1H), 4.03 (m, 1H), 3.77 (s, 3H), 3.52 (m,

3H), 3.04 (m, 2H), 2.78 (m, 1H), 2.70 (m, 2H), 1.81 (m, 1H),

3-[2-((3a R,9bR)-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]]-8-n itr o[1]ben zoth ien o-

[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Hyd r och lor id e (35).

2-Chloro-5-nitrobenzonitrile (25.0 g, 136.9 mmol) was treated

with ethyl thioglycolate (16.45, 136.9 mmol) and K₂CO₃(19 g,

136.9) in EtOH according to the method of example 29 to yield

3-amino-2-carbomethoxy-5-nitro-benzothiophene (19.68 g, 54%),

1

mp 208-210 °C. H NMR (DMSO-d₆) δ 9.23 (d, 1H), 8.29 (d,

1H), 8.11 (dd, 1H), 7.45 (br s, 2H), 4.29 (q, 2H), 1.31 (t, 3H).

MS (DCI/NH₃) m/e 284 (M + NH₄)⁺.

The intermediate benzo[b]thiophene (0.532 g, 1.9 mmol) and

the amine 15 (0.418 g, 1.7 mmol) were treated by method B to

1.61 (m, 1H). MS (DCI/NH₃) m/e 482(M + H)⁺. Anal. (C₂₅H₂₅

ClN₃O₃S‚HCl‚0.5H₂O) C, H, N.

-

1

yield 35 (0.329 g, 37%), mp 298-305 °C. H NMR (DMSO-d₆)

δ 12.93 (d, 1H), 10.37 (s, 1H), 9.48 (d, 1H), 8.42 (s, 2H), 7.17

(t, 1H), 6.72-6.86 (m, 2H), 4.29 (m, 2H), 4.15 (m, 1H), 4.02

(m, 1H), 3.78 (s, 3H), 3.52 (m, 2H), 3.02 (m, 1H), 2.59-2.86

(m, 3H), 1.79 (m, 2H), 1.61 (m, 2H). MS (DCI/NH₃) m/e 493

(M + H)⁺. Anal. (C₂₅H₂₄N₄O₅S‚HCl) C, H, N.

3-[2-((3a R,9bR)-cis-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-

[1H]-ben z[e]isoin dol-2-yl)eth yl]-9-m eth oxy[1]ben zoth ien o-

[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Hyd r och lor id e (40).

4-Methoxy-3-amino-2-carboethoxybenzothiophene²⁹(0.80 g,

3.18 mmol), prepared from 2-methoxy-6-chlorobenzonitrile and

ethyl thioglycolate, was reacted with the amine 15 (0.71 g, 2.88

mmol) according to method B to yield 40 (0.13 g, 10%) as a

white solid, mp 193-195 °C; [R]_D+31.4° (c ) 0.56, MeOH).

¹H NMR (MeOD) δ 1.65 (m, 2H), 2.02 (m, 2H), 2.60 (m, 2H),

2.92 (m, 2H), 3.18 (m, 1H), 3.62 (m, 3H), 3.85 (s, 3H), 4.15 (s,

3H), 4.45 (m, 2H), 6.80 (m, 2H), 7.08 (m, 1H), 7.20 (m, 1H),

3-[2-((3a R,9bR)-cis-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-

[1H]-ben z[e]isoin dol-2-yl)eth yl]- 8-m eth yl[1]ben zoth ien o-

[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Hyd r och lor id e (36).

5-Methyl-3-amino-2-caroboethoxybenzothiophene²⁸(1.0 g, 4.26

mmol) and the amine 15 (0.350 g, 1.45 mmol) were treated by

method B to yield 36 (0.340 g, 52%) as a white solid, mp 196-

198 °C; [R]_D+27.8° (c ) 0.66, MeOH). ¹H NMR (MeOD) δ 1.20

(m, 1H), 1.40 (m, 2H), 2.1.(m, 1H), 2.50 (s, 3H), 2.65 (m, 2H),

3.10 (m, 2H), 3.58 (m, 2H), 3.74 (s, 3H), 3.84 (m, 2H), 4.12 (m,

2H), 6.75 (q, 2H), 7.02 (t, 1H), 7.40 (m, 1H), 7.75 (m, 1H), 7.90

7.60 (m, 2H). MS (DCI/NH₃) m/e 478 (M + H)⁺. Anal. (C₂₆H₂₈

ClN₃O₄S‚HCl‚1.5H₂O) C, H, N.

-

3-[2-((3a R,9bR)-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]-9-cya n o[1]ben zoth ien o-

[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Hyd r och lor id e (41).

2,3-Dicyanonitrobenzene (2.6 g, 15 mmol) was treated with

methyl thioglycolate (1.59 g, 15 mmol) and Na₂CO₃(1.59 g,

15 mmol) in MeOH as described in 29 to yield 1.63 g of

3-amino-2-carbomethoxy-4-cyanobenzothiophene (47%), mp

169-170 °C. ¹H NMR (DMSO-d₆) δ 3.83 (s, 3H), 6.66 (bs, 2H),

7.68 (t, J ) 8 Hz, 1H), 7.97 (d, J ) 8 Hz, 1H), 8.30 (d, J ) 8

Hz, 1H). MS (DCI/NH₃) m/e 250 (M + NH₄)⁺.

3-amino-2-carbomethoxy-4-cyanobenzothiophene (0.35 g, 1.5

mmol) and the amine 15 (0.37 g, 1.6 mmol) were treated by

method B to yield 41 (0.360 g, 47%), mp 306-308 °C. ¹H NMR

(DMSO-d₆) δ 1.52-1.68 (m, 1H), 1.70-1.85 (m, 1H), 2.33-2.58

(m, 1H), 2.62-2.92 (m, 3H), 2.95-3.08 (m, 1H), 3.44-3.60 (m,

3H), 3.77 (s, 3H), 3.94-4.17 (m, 2H), 4.19-4.35 (m, 2H), 6.73

(d, 1H), 6.84 (d, 1H), 7.17 (t, 1H), 7.82 (t, 1H), 8.18 (d, 1H),

8.55 (d 1H). MS (DCI/NH₃) m/e 473 (M + H)⁺. Anal.

(C₂₆H₂₄N₄O₃S‚HCl‚0.25 H₂O) C, H, N.

(d, 1H). MS (DCI/NH₃) m/e 462 (M + H)⁺. Anal. (C₂₆H₂₈

ClN₃O₃S‚HCl‚0.25H₂O) C, H, N.

-

3-[2-((3a R,9bR)-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]-8-ca r boxa m id o[1]ben zo-

t h ien o[3,2-d ]p yr im id in e-2,4(1H ,3H )-d ion e H yd r och lo-

r id e (37). 3-Cyano-4-chlorobenzoic acid (5.55 g, 30.5 mmol)

was treated with oxalyl chloride (2.93 mL, 33.6 mmol) by the

procedure described for example 34. The resulting acid chloride

was poured into a stirred mixture of saturated aqueous NH₄-

OH (150 mL) and EtOAc (150 mL), and the reaction was

stirred for 10 min. The layers were separated, the aqueous

layer was extracted with EtOAc (2×), and the combined

organic layers were rinsed with 1 M HCl (2×) and brine and

dried (MgSO₄). The solution was condensed, and the residue

was recrystallized from EtOAc to yield 3.35 g (61%) of 3-cyano-

4-chloro-benzamide, mp 193 °C. ¹H NMR (CDCl₃) δ 8.12 (d,

1H), 7.98 (dd, 1H), 7.63 (d, 1H), 5.50-6.20 (br s, 2H). MS (DCI/

NH₃) m/e 198 (M + NH₄)⁺.

3-[2-((3a R,9bR)-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]-9-m eth yl[1]ben zoth ien o-

[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Hyd r och lor id e (42).

4-Methyl-3-amino-2-caroboethoxybenzothiophene was pre-

pared by the method of Beck²⁰from 6-nitro-o-tolunitrile and

ethyl thioglycolate. The resulting benzothiophene (0.505 g, 2.15

mmol) and the amine 15 (0.45 g, 1.65 mmol) were treated by

method B to yield 42 (0.525 g, 64%) as a white solid, mp >270

The intermediate benzamide (3.30 g, 18.3 mmol) was

converted by the procedure described for example 29 to

3-amino-2-carbomethoxy-5-carboxamido-benzo[b]thiophene (1.08

1

g, 30%), mp 248 °C. H NMR (DMSO-d₆) δ 9.31 (d, 1H), 7.98

(dd, 1H), 7.96 (br s, 1H), 7.91 (d, 1H), 7.48 (br s, 1H), 7.21 (br

s, 2H), 3.80 (s, 3H). MS (DCI/NH₃) m/e 268 (M + NH₄)⁺.

The intermediate benzo[b]thiophene (0.25 g, 1.0 mmol) and

the amine 15 (0.246 g, 1.0 mmol) were treated by method B to

1

°C. H NMR (DMSO-d₆) δ 7.94 (d, 1H, J ) 8.1 Hz), 7.51 (dd,

Tricyclic Hexahydrobenz[e]isoindoles

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8 1599

1H, J ) 8.1, 7.4 Hz), 7.30 (d, 1H, J ) 0.0 Hz), 7.17 (dd, 1H, J

) 8.1, 7.7 Hz), 6.84 (d, 1H, J ) 8.5 Hz), 6.77 (m, 1H), 4.27 (m,

2H), 4.18 (m, 1H), 4.05 (m, 1H), 3.77 (s, 3H), 3.52 (m, 3H),

3.08 (m, 2H), 2.87 (s, 3H), 2.72 (m, 2H), 2.42 (m, 1H), 1.83 (m,

1H), 1.59 (m, 1H). MS (DCI/NH₃) m/e 462 (M + H)⁺. Anal.

(C₂₆H₂₈ClN₃O₃S‚HCl‚0.5H₂O) C, H, N.

3-[2-((3a R,9bR)-cis-6-Meth 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]-p yr id o[4′,3′:4,5]t h ien o-

[3,2-d]pyr im idin e-2,4(1H,3H)-dion e Dih ydr och lor ide (46).

A solution of 3-amino-2-carbomethoxythieno[2,3-c]pyridine²¹

(0.61 g, 2.9 mmol) and Et₃N (0.88 mL, 6.3 mmol) in anhydrous

CH₂Cl₂under N₂at -78 °C was treated with phosgene (1.5

mL of a 1.93 M solution in toluene, 2.9 mmol), and the reaction

stirred at -78 °C for 45 min and room temperature for 1.5 h.

Then the amine 15 (0.60 g, 2.4 mmol) in CH₂Cl₂was added,

and the reaction mixture was stirred at room temperature for

2 h. The reaction mixture was partitioned between 1 M NaOH

and CH₂Cl₂. The organic layer was dried (MgSO₄), filtered,

and concentrated in vacuo. The residue obtained was taken

up in THF and treated with 3.6 mL of 1 M KOtBu in THF.

The reaction mixture was stirred at room temperature for 1

h, then concentrated under reduced pressure. The residue was

chromatographed on silica gel, eluting with 10% EtOH in CH₂-

Cl₂saturated with NH₃to provide after conversion to the HCl

salt, 46 (1.01 g, 92%) (EtOH-Et₂O), mp 226-229 °C. ¹H NMR

(CDCl₃) (free base) δ 1.48-1.62 (m, 1H), 1.70-1.83 (m, 1H),

2.45 (d, 3H), 2.52-2.75 (m, 3H), 2.88-2.99 (m, 1H), 3.03-3.13

(m, 1H), 3.40-3.63 (m, 3H), 3.78 (s, 3H), 4.31-4.47 (m, 2H),

6.64 (d, 1H), 6.69 (d, 1H), 7.03 (t, 1H), 8.01 (d, 1H), 8.60 (d,

1H), 9.19 (s, 1H). MS (DCI/NH₃) m/e 449 (M + H)⁺. Anal.

(C₂₄H₂₄N₄O₃S‚2HCl‚0.5H₂O) C, H, N.

3-[2-((3a R,9bR)-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]-6-ch lor o[1]ben zoth ien o-

[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Hyd r och lor id e (43).

A solution of 2,3-dichlorobenzoic acid (10.0 g, 52.4 mmol) and

oxalyl chloride (7.0 g, 55 mmol) in 100 mL of toluene was

heated to reflux for 4 h, cooled, and concentrated. The resulting

acid chloride was added to a mix of EtOAc and 12 N am-

monium hydroxide and stirred vigorously. The layers were

separated and the EtOAc layer was washed with 1 M HCl and

brine, dried (MgSO₄), and concentrated to give 9.4 g of 2,3-

1

dichlorobenzamide. H NMR (CDCl₃) δ 6.06 (bs, 2H), 7.28 (t,

J ) 8 Hz, 1H), 7.54-7.62 (m, 2H). MS (DCI/NH₃) m/e 207 (M

+ NH₄)⁺.

2,3-Dichlorobenzamide (9.4 g, 50 mmol) in POCl₃(150 mL)

was heated for 2 h at 95 °C. The solution was cooled and

concentrated. The residue was partitioned between EtOAc and

10% aqueous K₂CO₃. The layers were separated, the EtOAc

layer was washed with water (2 × 50 mL) and brine, dried

(MgSO₄), and concentrated to yield 8.2 g of 2,3-dichloroben-

1

3-[2-((3a R,9bR)-cis-6-Meth 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]-p yr id o[2′,3′:4,5]t h ien o-

[3,2-d]pyr im idin e-2,4(1H,3H)-dion e Dih ydr och lor ide (47).

Following the procedure described for example 46, 3-amino-

2-carbomethoxythieno[3,2-b]pyridine²¹(0.51 g, 2.4 mmol), Et₃N

(0.74 mL, 5.3 mmol), phosgene (1.3 mL of 1.93 M solution in

toluene, 2.4 mmol), and the amine 15 (0.50 g, 2.0 mmol) yielded

0.68 g (75%) of 47 which was converted to the HCl salt, mp

zonitrile, mp 60-61 °C. H NMR (CDCl₃) δ 7.34 (t, J ) 8 Hz,

1H), 7.62 (dd, J ) 8.1 Hz, 1H), 7.71 (dd, J ) 8.1 Hz, 1H).

2,3-Dichlorobenzonitrile (1.7 g, 10 mmol) was treated with

methyl thioglycolate and sodium carbonate in MeOH as

described for example 29 to give, after chromatography (4:1

hexane/EtOAc), 0.29 g (12%) of 3-amino-2-carbomethoxy-7-

1

chloro-benzothiophene. H NMR (CDCl₃) δ 3.81 (s, 3H), 5.90

(bs, 2H), 7.34 (t, J ) 8 Hz, 1H), 7.48 (dd, J ) 8.1 Hz, 1H), 7.56

(dd, J ) 8,1 Hz, 1H). MS (DCI/NH₃) m/e 259 (M + NH₄)⁺.

3-Amino-2-carbomethoxy-7-chloro-benzothiophene (0.30 g,

1.25 mmol) and the amine 15 (0.27 g, 1.1 mmol)) were treated

by method B to yield 43 as a white solid (0.32 g, 55%), mp

1

256-257 °C. H NMR (DMSO-d₆) δ 1.53-1.68 (m, 1H), 1.73-

1.86 (m, 1H), 2.60-3.10 (m, 4H), 3.64-3.83 (m, 4H), 3.77 (s,

3H), 3.83-4.35 (m, 4H), 6.73-6.87 (m, 2H), 7.17 (t, 1H), 7.65-

7.71 (m, 1H), 8.66-8.70 (m, 1H), 8.84-8.88 (m, 1H), 10.30 and

10.64 (bs and bs, 1H), 12.79 (s, 1H). MS (DCI/NH₃) m/e 449

(M + H)⁺. Anal. (C₂₄H₂₄N₄O₃S‚2HCl) C, H, N.

1

250-253 °C. H NMR (DMSO-d₆) δ 1.52-1.68 (m, 1H), 1.70-

1.85 (m, 1H), 2.33-2.58 (m, 1H), 2.62-2.86 (m, 3H), 2.95-

3.08 (m, 1H), 3.44-3.60 (m, 3H), 3.77 (s, 3H), 3.94-4.20 (m,

2H), 4.20-4.35 (m, 2H), 6.73 (d, 1H), 6.84 (d, 1H), 7.17 (t, 1H),

7.63 (t, 1H), 7.81 (d, 1H), 8.42 (d, 1H), 10.82 (s, 1H), 12.81 (s,

1H). MS (DCI/NH₃) m/e 482 (M + H)⁺. Anal. (C₂₅H₂₄ClN₃O₃S‚

HCl‚0.75 H₂O) C, H, N.

3-[2-((3a R,9bR)-cis-6-Meth 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]-p yr id o[3′,4′:4,5]t h ien o-

[3,2-d]pyr im idin e-2,4(1H,3H)-dion e Dih ydr och lor ide (48).

Following the procedure described for example 46 and using

THF in place of CH₂Cl₂as the solvent, 3-amino-2-carbomethoxy-

thieno[3,2-c]pyridine²¹(0.51 g, 2.4 mmol), Et₃N (0.74 mL, 5.3

mmol), phosgene (1.3 mL of 1.93 M solution in toluene, 2.4

mmol), and the amine 15 (0.50 g, 2.0 mmol) provided 0.68 g

(75%) of 48, mp 261-262 °C. ¹H NMR (CDCl₃) (free base) δ

1.48-1.63 (m, 1H), 1.70-1.83 (m, 1H), 2.44-2.76 (m, 5H),

2.93-3.05 (m, 1H), 3.09-3.21 (m, 1H), 3.41-3.55 (m, 1H),

3.59-3.71 (m, 2H), 3.79 (s, 3H), 4.29-4.45 (m, 2H), 6.62 (d,

1H), 6.70 (d, 1H), 7.01 (t, 1H), 7.76 (d, 1H), 8.62 (d, 1H), 9.45

(s, 1H). MS (DCI/NH₃) m/e 449 (M + H)⁺. Anal. (C₂₄H₂₄N₄O₃S‚

2HCl) C, H, N.

3-[2-((3aR,9bR)- 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[2,3-d :4,5-d ]d ip y-

r im id in e-2,4(1H,3H)-d ion e (49). A solution of 2-chloro-3-

cyanopyrimidine (5.60 g, 40.1 mmol)³⁰in DMF (75 mL) was

treated with ethyl thioglycolate (5.30 g, 44.2 mmol) and sodium

ethoxide (3.00 g, 44.2 mmol) at room temperature. After 4 h

the reaction mixture was diluted with water and extracted

several times with CHCl₃. The combined organic layers were

washed with water and brine, dried (Na₂SO₄), and evaporated

to dryness. The residual red-brown oil was purified by column

chromatography on silica gel eluting first with 2:1 hexane:

EtOAc then with 1:1 hexane:EtOAc to yield 4.26 g (48%) of

ethyl 3-aminothieno[2,3-d]pyrimidine-2-carboxylate as a yellow

solid, mp 138-140 °C. ¹H NMR (CDCl₃) δ 1.42 (t, 3H), 4.39

(q, 2H), 6.08 (br s, 2H), 9.05 (s, 1H), 9.17 (s, 1H). MS (DCI/

NH₃) m/e 224 (M + H)⁺, 241 (M + NH₄)⁺.

3-[2-((3a R,9bR)-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]-6-cya n o[1]ben zoth ien o-

[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Hyd r och lor id e (44).

2-Chloro-1,3-dicyanobenzene (0.972 g, 6.0 mmol) was treated

with methyl thioglycolate and Na₂CO₃in MeOH as described

for example 29 to give 3-amino-2-carbomethoxy-7-cyano-ben-

zothiophene (65%). ¹H NMR (DMSO-d₆) δ 3.83 (s, 3H), 7.38

(bs, 2H), 7.62 (t, J ) 8 Hz, 1H), 8.10 (d, J ) 8 Hz, 1H), 8.50 (d,

J ) 8 Hz, 1H). MS (DCI/NH₃) m/e 250 (M + NH₄)⁺.

The intermediate benzothiophene (0.35 g, 1.5 mmol) and the

amine 15 (0.37 g, 1.5 mmol) were treated using method B to

yield 44 (0.54 g, 68%), mp 265-269 °C. ¹H NMR (DMSO-d₆) δ

1.52-1.68 (m, 1H), 1.70-1.85 (m, 1H), 2.33-2.58 (m, 1H),

2.62-2.92 (m, 3H), 2.95-3.08 (m, 1H), 3.44-3.60 (m, 3H), 3.77

(s, 3H), 3.94-4.20 (m, 2H), 4.20-4.35 (m, 2H), 6.73 (d, 1H),

6.84 (d, 1H), 7.17 (t, 1H), 7.82 (t, 1H), 8.27 (d, 1H), 8.74 (d 1H)

10.55 (bs, 1H), 12.95 (s, 1H). MS (DCI/NH₃) m/e 473 (M + H)⁺.

Anal. (C₂₆H₂₄N₄O₃S‚HCl‚H₂O) C, H, N.

3-[2-((3a R,9bR)-cis-6-Meth 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]-p yr id o[3′,2′:4,5]t h ien o-

[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Hyd r och lor id e (45).

3-Amino-2-carbomethoxythieno[2,3-b]pyridine²¹(1.01 g, 3.6

mmol) and the amine 15 (0.75 g, 3.0 mmol) were treated by

method B to yield 45 (0.68 g, 47%) as a white solid, mp 231 °C

1

(dec). H NMR (DMSO-d₆) δ 12.83 (m, 1H), 10.46 (br s, 1H),

8.82 (m, 2H), 7.67 (m, 1H), 7.17 (t, 1H, J ) 7.9 Hz), 6.80 (m,

2H), 4.29 (m, 3H), 4.16 (m, 1H), 4.03 (m, 1H), 3.78 (s, 3H),

3.53 (m, 2H), 3.04 (m, 2H), 2.70 (m, 2H), 2.44 (m, 1H), 1.80

(m, 1H), 1.63 (m, 1H). MS (DCI/NH₃) m/e 449 (M + H)⁺. Anal.

(C₂₄H₂₄N₄O₃S‚HCl‚0.5H₂O) C, H, N.

Ethyl 3-aminothieno[2,3-d]pyrimidine-2-carboxylate (0.40 g,

1.79 mmol), the amine 15 (0.42 g, 1.70 mmol), and Et₃N (0.54

g, 5.37 mmol) were reacted by method B. Chromatography on

silica gel, eluting with EtOAc:HCOOH:H₂O (9:1:1) yielded

1600 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8

Meyer et al.

0.360 g (43%) of 49 as its formic acid salt. It was converted to

carbomethoxy-7-chlorothieno[3,2-b]pyridine. ¹H NMR (CDCl₃(5-

chloro)) δ 3.92 (s, 3H), 6.15 (bs, 2H), 7.37 (d, 1H), 7.99 (d, 1H).

the HCl salt by treatment with an excess of methanolic HCl,

mp 243-246 °C. H NMR (DMSO-d₆) δ 1.45 (m, 1H), 1.63 (m,

MS (DCI/NH₃) m/e 243 (M + H)⁺. H NMR (CDCl₃(7-chloro))

1

1H), 2.10-2.34 (m, 2H), 2.36-2.78 (m, 5H), 3.12-3.38 (m, 3H),

3.74 (s, 3H), 4.03 (t, 2H), 6.73 (d, 1H), 7.08 (t, 1H), 9.24 (s,

1H), 9.52 (s, 1H). MS (DCI/NH₃) m/e 450 (M + H)⁺. Anal.

(C₂₃H₂₃N₅OS‚2HCl‚H₂O) C, H, N.

δ 3.93 (s, 3H), 6.20 (bs, 2H), 7.41 (d, 1H), 8.54 (db, 1H), MS

(DCI/NH₃) m/e 243 (M + H)⁺.

3-Amino-2-carbomethoxy-5-chlorothieno[3,2-b]pyridine (540

mg, 2.2 mmol), prepared as described above, Et₃N (0.74 mL,

5.3 mmol), phosgene (1.2 mL of 1.93 M solution in toluene),

and the amine 15 (0.50 g, 2.0 mmol) were reacted as described

in 46 to provide 0.61 g (62%) of 52 which was converted to the

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)et h yl]-t h ien o[3,2-d :4,5-d ]d ip yr im id in e-

2,4(1H,3H)-d ion e (50). 5-Bromo-4-cyanopyrimidine (2.10 g,

11.4 mmol)³¹was treated with ethyl thioglycolate (1.38 g, 11.5

mmol) and Na₂CO₃(1.21 g, 11.4 mmol) in EtOH (36 mL) as

described for example 49 to yield 1.10 g (43%) of ethyl

3-aminothieno[3,2-d]pyrimidine-2-carboxylate, mp 139-141

°C. ¹H NMR (CDCl₃) δ 1.42 (t, 3H), 4.41 (q, 2H), 6.17 (br s,

2H), 9.19 (s, 1H), 9.20 (s, 1H). MS (DCI/NH₃) m/e 224 (M +

H)⁺, 241 (M + NH₄)⁺.

1

HCl salt, mp 129-131°. H NMR (CDCl₃) (free base) δ 1.59-

1.74 (m, 1H), 1.89-2.01 (m, 1H), 2.52-2.65 (m, 1H), 2.73-

2.91 (m, 3H), 2.91-3.05 (m, 1H), 3.32-3.53 (m, 1H), 3.73-

3.88 (m, 1H), 3.82 (s, 3H), 3.88-4.13 (m, 1H), 4.26-4.39 (m,

1H), 4.51-4.66 (m, 1H), 4.66-4.86 (m, 2H), 6.69 (d, 1H), 6.78

(d, 1H), 7.10 (t, 1H), 7.36 (d, 1H), 7.87 (d, 1H). MS (DCI/NH₃)

m/e 483 (M + H)⁺. Anal. (C₂₄H₂₃ClN₄O₃S‚HCl‚0.25H₂O) C, H,

N.

Ethyl 3-aminothieno[3,2-d]pyrimidine-2-carboxylate (0.400

g, 1.79 mmol), the amine 15 (0.384 g, 1.56 mmol), and Et₃N

(0.332 g, 3.28 mmol) were treated by method B. Chromatog-

raphy on silica gel, eluting with EtOAc:HCOOH:H₂O (9:1:1)

yielded 50 (0.399 g, 52%) as its formic acid salt. It was

converted to the HCl salt by treatment with an excess of

3-[2-((3a R,9bR)-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]-8-m eth oxy-p yr id o[2′,3′:

4,5]th ien o[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Dih yd r o-

ch lor id e (53). A solution of 3-amino-2-carbomethoxy-5-

chlorothieno[3,2-b]pyridine, prepared as described in 52 (5 g,

21 mmol), and sodium methoxide (4.5 g, 82 mmol) in MeOH

(150 mL) was heated to reflux for 18 h. The reaction was

concentrated and partitioned between EtOAc and NaHCO₃

solution. The EtOAc layer was dried (MgSO₄), filtered, con-

centrated, and chromatographed on silica gel (5:1 hex:EtOAc)

to yield 2.5 g of the 3-amino-2-carbomethoxy-5-methoxythieno-

1

methanolic HCl to give a tan solid, mp 230-235 °C. H NMR

(DMSO-d₆) δ 1.64 (m, 1H), 1.80 (m, 1H), 2.25-2.90 (m, 3H),

3.02 (m, 1H), 3.26-3.60 (m, 3H), 3.61-4.19 (m, 3H), 3.77 (s,

3H), 4.30 (m, 2H), 6.74 (d, 1H), 6.84 (d, 1H), 7.18 (t, 1H), 9.40

(s, 1H), 9.78 (s, 1H), 12.93 (s, 1H). MS (FAB/high resolution)

calcd m/e for (M + H)⁺C₂₃H₂₄N₅O₃S, 450.1600; obsd m/e,

450.1599. Anal. (C₂₃H₂₄N₅O₃S‚3HCl‚1H₂O) C, H, N.

1

[3,2-b]pyridine. H NMR (CDCl₃) δ 3.80 (s, 3H), 4.02 (s, 3H),

6.05 (bs, 2H), 6.89 (d, 1H), 7.88 (d, 1H). MS (DCI/NH₃) m/e

3-[2-((3aR,9bR)-cis- 6-Meth oxy-2,3,3a ,4,5,9b-h exa h ydr o-

[1H]-ben z[e]isoin d ol-2-yl)eth yl]-p yr a zin o[2′,3′:4,5]th ien o-

[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e (51). Ethyl 3-amino-

thieno[2,3-b]pyrazine-2-carboxylate (1.56 g, 6.99 mmol),²⁹the

amine 15 (1.71 g, 6.94 mmol), and Et₃N (1.48 g, 14.58 mmol)

were treated by method B. Chromatography on silica gel,

eluting with EtOAc: HCOOH: H₂O (9:1:1) yielded 2.51 g (73%)

of 51 as the formic acid salt. It was converted to the HCl salt

by treatment with an excess of methanolic HCl to give a tan

solid, mp 293-295 °C. ¹H NMR (DMSO-d₆) δ 1.62 (m, 1H),

1.80 (m, 1H), 2.30-2.87 (m, 3H), 3.02 (m, 1H), 3.30-3.90 (m,

4H), 3.78 (s, 3H), 4.02 (m, 1H), 4.14 (m, 1H), 4.30 (m, 2H),

6.74 (d, 1H), 6.85 (d, 1H), 7.17 (t, 1H), 8.91 (d, 1H), 8.99 (d,

1H), 13.01 (s, 1H). MS (DCI/NH₃) m/e 450 (M + H)⁺. Anal.

(C₂₃H₂₅N₅O₃S‚2HCl) C, H, N.

3-[2-((3a R,9bR)-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]-8-ch lor o-p yr id o[2′,3′:4,5]-

th ien o[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Dih yd r och lo-

r id e (52). To a solution of 3-chloro-2-cyanopyridine (40 g, 0.29

mol) in acetic acid (500 mL) was added dropwise 30% hydrogen

peroxide (52 g, 0.45 mol). After being stirred at 90 °C for 18 h,

the reaction was cooled to 25 °C and a solution of Na₂SO₃(57

g, 0.45 mol) in H₂O was added dropwise. The reaction was

concentrated in vacuo to remove the bulk of the acetic acid,

and the residue was partitioned between 1 M NaOH and CH₂-

Cl₂. The CH₂Cl₂layer was dried (MgSO₄), filtered, concen-

trated, and recrystallized from EtOAc to yield 23 g (51%) of

3-chloro-2-cyanopyridine-N-oxide. To the solution of the result-

ing pyridine N-oxide (12.2 g, 79 mmol) in DMF (160 mL) at 0

°C was added methyl thioglycolate (7.1 mL, 79 mmol), followed

by the portionwise addition of sodium methoxide (8.5 g, 160

mmol). The reaction mixture was stirred at room temperature

for 1 h and then it was poured onto ice, and the resulting solid

was collected by filtration, washed with water, dissolved in

CH₂Cl₂, dried (MgSO₄), filtered, concentrated, and recrystal-

lized from EtOAc to yield 10.6 g (60%) of 3-amino-2-car-

bomethoxythieno[3,2-b]pyridine-4-oxide. The resulting thieno-

pyridine-N-oxide (10.6 g, 47 mmol) was mixed with POCl₃(100

mL). The reaction mixture was heated to 80 °C for 30 min,

then concentrated and partitioned between CH₂Cl₂and NaH-

CO₃solution. The CH₂Cl₂layer was dried (MgSO₄), filtered,

concentrated, and chromatographed on silica gel (5:1 hexane:

EtOAc) to yield 8.3 g (73%) of 3-amino-2-carbomethoxy-5-

chlorothieno[3,2-b]pyridine and 2.0 g (18%) of the 3-amino-2-

239 (M + H)⁺.

Following the procedure described for example 46, 3-amino-

2-carbomethoxy-5-methoxythieno[3,2-b]pyridine (530 mg, 2.2

mmol), Et₃N (0.71 mL, 5.1 mmol), phosgene (1.2 mL of 1.93 M

solution in toluene), and the amine 15 (0.50 g, 2.0 mmol)

provided 0.91 g (94%) of 53 which was converted to the HCl

1

salt, mp 128-130°. H NMR (CDCl₃(free base)) δ 1.46-1.59

(m, 1H), 1.69-1.81 (m, 1H), 2.24-2.34 (m, 2H), 2.48-2.60 (m,

2H), 2.64-2.94 (m, 3H), 3.36-3.52 (m, 3H), 3.80 (s, 3H), 4.04

(s, 3H), 4.26 (t, 2H), 6.67 (d, 1H), 6.75 (d, 1H), 6.98 (d, 1H),

7.09 (t, 1H), 8.02 (d, 1H). MS (DCI/NH₃) m/e 479 (M + H)⁺.

Anal. (C₂₅H₂₆N₄O₄S‚HCl) C, H, N.

3-[2-((3a R,9bR)-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]-6-ch lor o-p yr id o[2′,3′:4,5]-

th ien o[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Dih yd r och lo-

r id e (54). From 3-amino-2-carbomethoxy-7-chlorothieno[3,2-

b]pyridine, prepared as described for example 52 (0.540 g, 2.2

mmol), Et₃N (0.71 mL, 5.1 mmol), phosgene (1.2 mL of 1.93 M

solution in toluene), and the amine 15 (0.50 g, 2.0 mmol) were

reacted by the method described for example 46 to provide 0.46

g (43%) of 54, mp >255 °C. ¹H NMR (CDCl₃) (free base) δ 1.54-

1.70 (m, 1H), 1.84-1.96 (m, 1H), 2.48-2.61 (m, 1H), 2.65-

2.92 (m, 4H), 3.35-3.50 (m, 1H), 3.70-3.87 (m, 2H), 3.80 (s,

3H), 4.31-4.42 (m, 1H), 4.45-4.63 (m, 3H), 6.68 (d, 1H), 6.77

(d, 1H), 7.10 (t, 1H), 7.42 (d, 1H), 8.58 (bd, 1H). MS (DCI/NH₃)

m/e 483 (M + H)⁺. Anal. (C₂₄H₂₃ClN₄O₃S‚HCl) C, H, N.

3-[2-((3a R,9bR)-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]-6-m eth oxy-p yr id o[2′,3′:

4,5]th ien o[3,2-d ]p yr im id in e-2,4(1H,3H)-d ion e Dih yd r o-

ch lor id e (55). Following the procedure described for 53,

3-amino-2-carbomethoxy-7-chlorothieno[3,2-b]pyridine (2.0 g,

8.2 mmol) provided 1.1 g (56%) of 3-amino-2-carbomethoxy-

7-methoxythieno[3,2-b]pyridine. ¹H NMR (CDCl₃) δ 3.92 (s,

3H), 4.05 (s, 3H), 6.18 (bs, 2H), 6.81 (d, 2H), 8.52 (d, 2H). MS

(DCI/NH₃) m/e 239 (M + H)⁺.

3-Amino-2-carbomethoxy-7-methoxythieno[3,2-b]pyridine

(0.530 g, 2.2 mmol), Et₃N (0.71 mL, 5.1 mmol), phosgene (1.2

mL of 1.93 M solution in toluene), and the amine 15 (0.50 g,

2.0 mmol) were reacted for example 46 to yield 0.82 g (85%)

1

of 55, mp 235-237°. H NMR (CDCl₃)(free base) δ 1.48-1.62

(m, 1H), 1.75-1.87 (m, 1H), 2.31-2.41 (m, 2H), 2.47-2.59 (m,

1H), 2.66-2.79 (m, 2H), 3.07-3.19 (m, 2H), 3.34-3.45 (m, 1H),

3.66 (q, 1H), 3.80 (s, 3H), 4.07 (s, 3H), 4.13 (q, 2H), 4.26-4.45

Tricyclic Hexahydrobenz[e]isoindoles

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8 1601

(m, 2H), 6.66 (d, 1H), 6.77 (d, 1H), 6.84 (d, 1H), 7.08 (t, 1H),

8.59 (d, 1H). MS (DCI/NH₃) m/e 479 (M + H)⁺. Anal.

(C₂₅H₂₆N₄O₄S‚HCl‚0.5H₂O) C, H, N.

2H (minor)), 9.0 (s, 1H (major)), 9.05 (s, 1H (minor)). MS (DCI/

NH₃) m/e 215 (M + H)⁺.

The obtained mixture of 5- and 6-phenylpyrazines (1.55 g,

7.16 mmol) was treated with methyl thioglycolate (0.708 mL,

7.88 mmol) and NaOCH₃(0.386 g, 7.16 mmol) in anhydrous

DMF (2 mL) at room temperature for 1 h. The reaction mixture

was partitioned between saturated NH₄Cl/CH₂Cl₂. The organic

layer was dried (MgSO₄) and concentrated in vacuo. The

residue was chromatographed on silica gel, eluting with CH₂-

Cl₂to yield methyl 3-amino-5-phenylthieno[2,3-b]pyrazine-2-

carboxylate (0.43 g, 21%) as a yellow solid. ¹H NMR (CDCl₃) δ

3.94 (s, 3H), 6.26 (bs, 2H), 7.53 (m, 3H), 8.09 (d, H) 2H), 9.09

(s, 1H). MS (DCI/NH₃) m/e 286 (M + H)⁺. Further eluting

yielded the isomeric methyl-3-amino-6-phenyl-thieno[2,3-b]-

pyrazine-2-carboxylate (0.35 g, 17%) as a yellow-green solid.

¹H NMR (CDCl₃) δ 3.95 (s, 3H), 6.11 (br s, 2H), 7.55 (m, 3H),

8.12 (m, 2H), 9.03 (s, 1H). MS (DCI/NH₃) m/e 286 (M + H)⁺.

3-[2-(cis-(3a R,9bR)-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 yl-p yr a zin o[2′,3′:

4,5]th ien o[3,2-d]pyr im idin e-2,4(1H,3H)-dion e Hydr och lo-

r id e (56). 3-Carboxamido-2-hydroxy-6-methylpyrazine³²(4.09

g, 26.70 mmol), was suspended in Et₃N (5.41 g, 53.41 mmol),

cooled to 0° and reacted with 70 mL POCl₃. The mixture was

heated to reflux for 3 h and concentrated in vacuo. The

resulting black oil was extracted with ether (5 × 100 mL), and

the combined extracts were treated with 10% Na₂CO₃(250

mL). The organic layers were separated, washed with water

and brine, dried (Na₂SO₄), and concentrated to yield 3-cyano-

2-chloro-6-methyl-pyrazine (3.16 g, 77%) as a fluffy yellow

1

solid, mp 63-65 °C. H NMR (CDCl₃) δ 2.70 (s, 3H), 8.50 (s,

1H). MS (DCI/NH₃) m/e 171 (M + NH₄)⁺.

Methyl 3-amino-5-phenylthieno[2,3-b]pyrazine-2-carboxy-

late (0.461 g, 1.62 mmol), the amine 15 and Et₃N (0.048 g,

3.40 mmol) were treated by method B to give 0.208 g (24%) of

3-Cyano-2-chloro-6-methylpyrazine (1.00 g, 6.51 mmol) was

treated as described for example 49 with ethyl thioglycolate

(0.782 g, 6.51 mmol) and Na₂CO₃(0.69 g, 6.51 mmol) to yield

ethyl-3-amino-6-methyl-thieno[2,3-b]pyrazine-2-carboxylate (1.12

g, 72%) as a bright yellow solid, mp 121-123 °C (EtOH/H₂O).

¹H NMR (CDCl₃) δ 1.41 (t, 3H), 2.71 (s, 3H), 4.38 (q, 2H), 6.15

(br s, 2H), 8.45 (s, 1H). MS (DCI/NH₃) m/e 238 (M + H)⁺, 255

(M + NH₄)⁺. Anal. calcd for C₁₀H₁₁N₃O₂S: C, 50.62; H, 4.67;

N, 17.71; Found: C, 50.75; H, 4.45; N, 17.70.

1

58 as a green-yellow solid, mp 296-298 °C. H NMR (DMSO-

d₆) δ 1.6 (m, 1H), 1.8 (m, 1H), 2.65 (m, 2H), 3.02 (m, 1H), 3.52

(m, 3H), 3.78 (s, 3H), 4.02 (m, 2H), 4.3 (m, 2H), 6.72-6.86 (m,

2H), 7.27 (dd, 1H), 7.6 (m, 3H), 8.48 (d, 2H), 9.55 (s, 1H). MS

(DCI/NH₃) m/e 526 (M + H)⁺. Anal. (C₂₉H₂₈N₅SO₃‚HCl‚0.5H₂O)

C, H, N.

3-[2-(cis-(3a R,9bR)-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 yl-p yr a zin o[2′,3′:

4,5]th ien o[3,2-d]pyr im idin e-2,4(1H,3H)-dion e Hydr och lo-

r id e (59). Methyl-3-amino-6-phenyl-thieno[2,3-b]pyrazine-2-

carboxylate (0.675 g, 2.37 mmol) Et₃N (0.48 g, 4.74 mmol) and

the amine 15 (0.550 g, 2.25 mmol) were treated by method B

to yield 0.435 g (33%) of 59 as a yellow-green solid, mp 310-

311 °C. ¹H NMR (DMSO-d₆) δ 1.63 (m, 1H), 1.80 (m, 1H), 2.35-

2.90 (m, 3H), 3.04 (m, 1H), 3.44-3.65 (m, 4H), 3.78 (s, 3H),

4.03 (m, 1H), 4.15 (m, 1H), 4.30 (m, 2H), 6.75 (d, 1H), 6.84 (d,

1H), 7.17 (t, 1H), 7.61 (m, 3H), 8.33 (m, 2H), 9.59 (s, 1H), 13.03

(br s, 1H). MS (DCI/NH₃) m/e 526 (M + H)⁺. Anal. (C₂₉H₂₇N₅-

O₃S‚HCl) C, H, N.

The intermediate ethyl-3-amino-6-methyl-thieno[2,3-b]pyra-

zine-2-carboxylate (0.275 g, 1.16 mmol), Et₃N (0.23 g, 2.28

mmol), and the amine 15 (0.280 g, 1.14 mmol) were treated

by method B. Chromatography of the crude concentrate on

silica gel, eluting with EtOAc:HCOOH:H₂O (18:1:1), provided

the formate salt of the product. Conversion to the HCl salt

1

afforded 56 (0.281 g, 49%) as a tan solid, mp 264-265 °C. H

NMR (DMSO-d₆) δ 1.61 (m,1H), 1.80 (m, 1H), 2.37-2.83 (m,

3H), 2.73 (s, 3H), 3.03 (m, 1H), 3.44-3.63 (m, 4H), 3.77 (s, 3H),

4.02 (m, 1H), 4.13 (m, 1H), 4.28 (m, 2H), 6.74 (d, 1H), 6.84 (d,

1H), 7.17 (t, 1H), 8.88 (s, 1H), 12.95 (s, 1H). MS (DCI/NH₃)

m/e 464 (M + H)⁺. Anal. (C₂₄H₂₅N₅O₃S‚HCl‚1.50H₂O) C, H,

N.

3-[2-(cis-(3a R,9bR)-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]-8-ch lor o-p yr a zin o[2′,3′:

4,5]th ien o[3,2-d]pyr im idin e-2,4(1H,3H)-dion e Hydr och lo-

r id e (60). To a solution of 2-chloro-3-cyanopyrazine (5.00 g,

35.94 mmol) in concentrated H₂SO₄(35 mL) that was cooled

to 0 °C was added K₂S₂O₈(11.65 g, 43.95 mmol) portionwise.

The flask was fitted with a CaCl₂drying tube, the reaction

mixture was allowed to warm to room temperature and stirred

for 24 h. After partitioning between CHCl₃and ice water, the

separated aqueous phase was extracted with CHCl₃. The

combined organic layers were washed with water, saturated

NaHCO₃, and brine, and dried (MgSO₄). Concentration gave

2.01 g (36%) of 2-chloro-3-cyano-pyrazino-4-oxide as an off-

3-[2-(cis-(3a R,9bR)-6-Meth 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 ylp yr a zin o-

[2′,3′:4,5]th 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 (57). 5,6-Dimethyl-2-hydroxy-3-carboximido-

pyrazine³³(4.4 g, 26.3 mmol) was treated with POCl₃(70 mL),

and Et₃N (7.3 mL, 52.3 mmol) as described for example 56 to

give 3.3 g (75%) of 2-chloro-3-cyano-5,6-dimethylpyrazine as

a yellow solid, mp 83-85 °C. ¹H NMR (DMSO-d₆) δ 2.54 (s,

3H), 2.59 (s, 3H). MS (DCI/NH₃) m/e 185 (M + H)⁺.

The intermediate dimethylpyrazine (1.5 g, 8.95 mmol), ethyl

thioglycolate (1.08 mL, 9.85 mmol), and Na₂CO₃(0.949 g, 8.95

mmol) were treated as described for example 49 to afford 1.3

g (58%) of ethyl 3-amino-5,6-dimethylthieno[2,3-b]pyrazine-

1

white solid. H NMR (CDCl₃) δ 8.12 (d, 1H), 8.38 (d, 1H). MS

1

(DCI/NH₃) m/e 173 (M + NH₄)⁺.

2-carboxylate, mp 136-139 °C. H NMR (CDCl₃) δ1.4 (t, 3H),

2.64 (s, 3H), 2.68 (s, 3H), 4.39 (q, 2H), 6.12 (br s 2H). MS (DCI/

2-Chloro-3-cyano-pyrazino-4-oxide (2.90 g, 18.64 mmol) was

dissolved in DMF (100 mL) under nitrogen and treated with

ethyl thioglycolate (2.24 g, 18.64 mmol). After cooling the

solution to 0 °C, it was treated with solid NaOEt (2.54 g, 37.29

mmol), allowed to warm to room temperature, and then stirred

for 13 h. The reaction mixture was partitioned between EtOAc

and brine, and the layers were separated. After extracting the

aqueous phase with EtOAc, the combined organic layers were

washed with water and brine and dried (MgSO₄). Concentra-

tion gave a yellow solid that was purified by column chroma-

tography on silica gel eluting with 2:1 then 1:1 hexane:EtOAc

to yield ethyl-3-aminothieno[2,3-b]pyrazine-2-carboxylate-4-

oxide (3.50 g, 78%) as a yellow solid, mp 126-127. ¹H NMR

(CDCl₃) δ 1.40 (t, 3H), 4.38 (q, 2H), 7.25 (br s, 2H), 8.02 (d,

1H), 8.41 (d, 1H). MS (DCI/NH₃) m/e 240 (M + H)⁺, 257 (M +

NH₄)⁺. Anal. (C₉H₉N₃O₃S) C, H, N.

NH₃) m/e 252 (M + H)⁺.

The intermediate thienopyrazine (0.269 g, 1.07 mmol), the

amine 15, and Et₃N (0.313 mL, 2.25 mmol) were treated by

method B to yield 0.236 g of 57 as a tan solid, mp 308-310

1

°C. H NMR (DMSO-d₆) δ 1.61 (s, 1H), 1.79 (m, 1H), 2.69 (s,

3H), 2.6-2.79 (m, 4H), 3.01 (m, 1H), 3.32 (s, 3H), 3.52 (m, 2H),

3.78 (s, 3H), 3.09-4.81 (sev m, 4H), 6.71-6.86 (m, 3H), 7.18

(m, 1H), 12.86 (m, 1H). HRMS calcd for C₂₅H₂₈N₅SO₃, 478.1913;

found, 478.1913. Anal. (C₂₅H₂₇N₅SO₃‚HCl‚H₂O) C, H, N.

3-[2-(cis-(3a R,9bR)-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-

[1H ]-ben z[e]isoin d ol-2-yl)et h yl]-8-p h en ylp yr a zin o[2′,3′:

4,5]th ien o[3,2-d]pyr im idin e-2,4(1H,3H)-dion e Hydr och lo-

r id e (58). A mixture of 5- and 6-phenyl regioisomers of

2-hydroxy-3-carboxamidopyrazines 33 (7.2 g, 33.5 mmol) was

treated with POCl₃(56 mL, 586 mmol) and Et₃N (9.3 mL, 67

mmol) as in example 56 to give a white solid as a 40:60 mixture

of the 2-chloro-3-cyano-5-phenylpyrazine and 2-chloro-3-cyano-

6-phenylpyrazine, mp (mixture) 121-125 °C. ¹H NMR (CDCl₃)

δ 7.52 (m, 5H major and minor), 8.02 (d, 2H (major)), 8.11 (d,

The intermediate thienopyrazine N-oxide (0.88 g, 3.68

mmol) was dissolved in POCl₃(50 mL) under nitrogen and

heated to 95 °C for 3 h. The reaction mixture was concentrated

and partitioned between EtOAc and water. After the aqueous

1602 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8

Meyer et al.

(8) 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. Recommenda-

tion for Nomenclature of R₁-Adrenoceptors: Consensus Update.

Pharmacol. Rev. 1995, 47, 267-70.

(9) 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, 546-51.

(10) Marshall, I.; Burt, R. P.; Chapple, C. R. Noradrenaline Contrac-

tions of Human Prostate Mediated by R_1A-(R_1c) Adrenoceptor

Subtype. Br. J . Pharmacol. 1995, 115, 781-86. Forray, C.; Bard,

J . A.; Wetzel, J . M.; Chiu, G.; Shapiro, E.; Tang, R.; Lepor, H.;

Hartig, P. R.; Weinshank, R. L.; Branchek, T. A.; Gluchowski,

C. The R₁-Adrenergic Receptor that Mediates Smooth Muscle

Contraction in Human Prostate Has the Pharmacological Prop-

erties of the Cloned Human R_1cSubtype. Mol. Pharmacol. 1994,

45, 703-08.

(11) Brune, M. E.; Katwala, S. P.; Milicic, I.; Buckner, S. A.; Ireland,

L. M.; Kerwin, J . F., J r.; Hancock, A. A. Effects of Selective and

Nonselective Alpha-1-Adrenoceptor Antagonists on Intraurethral

and Arterial Pressure. Pharmacology 1996, 53, 356-68. Tak-

enaka, T.; Fujikura, T.; Honda, K.; Asano, M.; Nigata, K.

Discovery and Development of Tamsulosin Hydrochloride, a New

R₁-Adrenoceptor Antagonist. Yakugaku Zasshi 1995, 115, 773-

789. Testa, R.; Sironi, G.; Colombo, D.; Greto, L.; Leonardi, A.

Rec 15/2739, a New R₁-Antagonist Selective for Lower Urinary

Tract: In Vivo Studies. Neuourol. Urodyn. 1994, 13, 471-472.

(12) 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 R_1b-Adrenergic Receptor. Proc. Natl. Acad. Sci.

U.S.A. 1997, 94, 11589-11594.

phase was extracted with EtOAc, the combined organic layers

were washed with water, saturated NaHCO₃, and brine and

dried over Na₂SO₄. Concentration gave a two component

mixture that was separated by column chromatography on

silica gel using a gradient elution from 10:1 to 1:1 hexanes:

EtOAc to give ethyl-3-amino-5-chloro-thieno[2,3-b]pyrazine-

2-carboxylate (0.56 g, 59%) and unreacted starting material

(0.30 g, 34%). ¹H NMR (CDCl₃) δ 1.41 (t, 3H), 4.40 (q, 2H),

6.11 (br s, 2H), 8.60 (s, 1H). MS (DCI/NH₃) m/e 258 (M + H)⁺,

275 (M + NH₄)⁺.

Ethyl-3-amino-5-chloro-thieno[2,3-b]pyrazine-2-carboxyl-

ate (0.420 g, 1.63 mmol) was treated by method B with Et₃N

(0.32 g, 3.20 mmol) and the amine 15 (0.394 g, 1.60 mmol) to

yield 60 (0.394 g, 47%) as a yellow solid, mp 262-265 °C

(EtOH). ¹H NMR (DMSO-d₆) δ 1.61 (m, 1H), 1.79 (m, 1H),

2.35-2.90 (m, 3H), 3.02 (m, 1H), 3.41-3.65 (m, 4H), 3.77 (s,

3H), 4.01 (m, 1H), 4.12 (m, 1H), 4.39 (m, 2H), 6.75 (d, 1H),

6.84 (d, 1H), 7.17 (t, 1H), 9.04 (s, 1H), 13.03 (br s, 1H). MS

(DCI/NH₃) m/e 484 (M + H)⁺. Anal. (C₂₃H₂₂ClN₅O₃S‚HCl‚

0.75H₂O) C, H, N.

3-[2-(cis-(3a R,9bR)-6-Meth oxy-2,3,3a ,4,5,9b-h exa h yd r o-

[1H]-ben z[e]isoin dol-2-yl)eth yl]-8-m eth oxy-pyr azin o[2′,3′:

4,5]th ien o[3,2-d]pyr im idin e-2,4(1H,3H)-dion e Hydr och lo-

r id e (61). Ethyl-3-amino-5-chloro-thieno[2,3-b]pyrazine-2-

carboxylate (0.700 g, 2.72 mmol) was dissolved in 75 mL of

MeOH and treated with solid NaOMe (1.47 g, 27.2 mmol), and

the resulting solution was refluxed for 12 h. The reaction

mixture was partitioned between saturated NH₄Cl and CHCl₃.

After the aqueous phase with CHCl₃, the combined organics

were washed with water then brine and dried (Na₂SO₄).

Concentration gave 0.50 g (77%) pure ethyl-3-amino-5-meth-

oxy-thieno[2,3-b]pyrazine-2-carboxylate as a yellow solid, mp

181-182 °C. ¹H NMR (CDCl₃) δ 3.92 (s, 3H), 4.05 (s, 3H), 6.02

(br s, 2H), 8.30 (s, 1H). MS (DCI/NH₃) m/e 240 (M + H)⁺, 257

(M + NH₄)⁺. Anal. (C₉H₉N₃O₃S) C, H, N.

(13) Malloy, B. J .; Price, D. T.; Price, R. R.; Bienstock, A. M.; Dole,

M. K.; Funk, B. L.; Donatucci, C. F.; Schwinn, D. A. R₁-

Adrenoceptor Subtypes in Human Bladder Detrusor. J . Urol.

1998, 159, 329.

(14) Broten, T.; Scott, A.; Siegl, P. K. S.; Forray, C.; Lagu, B.;

Nagarathnam, W. C.; Marzabadi, W. M.; Murali Dhar, T. G.;

Gluckowski, C. Alpha-1 Adrenoceptor Blockade Inhibits Detru-

sor Instability in Rats With Bladder Outlet Obstruction. FASEB

J . Abst. 1998, 12, A445.

(15) Romeo, G.; Ambrosini, G.; Gucione, S.; DeBlasi, A.; Russo, F.

Pyrimido[5,4-b]benzofuran and Pyrimido[5,4-b]benzothiophene

Derivatives. Ligands for R₁and 5HT_A-Receptors. Eur. J . Med.

Chem. 1993, 28, 499-504.

Ethyl-3-amino-5-methoxy-thieno[2,3-b]pyrazine-2-carboxy-

late (0.400 g, 1.67 mmol) was treated by method B with Et₃N

(0.25 g, 2.50 mmol) and the amine 15 (0.411 g, 1.67 mmol) to

yield 0.457 g (56%) of 61 as a tan solid, mp 243-245 °C (EtOH).

¹H NMR (DMSO-d₆) δ 1.63 (m, 1H), 1.80 (m, 1H), 2.42 (m,

1H), 2.58-2.86 (m, 2H), 3.02 (m, 1H), 3.37-3.91 (m, 4H), 3.79

(s, 3H), 3.91-4.20 (m, 2H), 4.10 (s, 3H), 4.30 (m, 2H), 6.75 (d,

1H), 6.84 (d, 1H), 7.17 (t, 1H), 8.56 (s, 1H), 12.77 (s, 1H).

HRFAB calcd for C₂₄H₂₆N₅O₄, 480.1706; found, 480.1710. Anal.

(C₂₄H₂₅N₅O₄S‚HCl‚0.5H₂O) C, H, N.

(16) Meyer, M. D.; Hancock, A. A.; Tietje, K.; Sippy, K. B.; Prasad,

R.; Stout, D. M.; Arendsen, D. J .; Donner, B. G.; Carroll, W. A.

Structure-Activity Studies for a Novel Series of N-(arylethyl)-

N-(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamines Pos-

sessing Dual 5-HT Uptake Inhibiting and R₂-Antagonistic

Activities. J . Med. Chem. 1997, 40, 1049.

(17) DeBernardis, J . F.; Meyer, D.M.; Sippy, K. B. Preparation of

Alkoxyhexahydrobenzindoles, -Indenopyrroles and -Indenopyr-

idines as Selective 5-HT Receptor Agents. U.S. Patent No.

5,049,564, 1991.

(18) DeBernardis, J . F.; Meyer, D. M.; Sippy, K. B. 5-HT Selective

Agents. U.S. Patent 5,244,888, 1993.

(19) Winstein, S.; Heck, R. F. Aryl Participation in the Solvolysis of

some gem-Dimethyl-Substituted 4-Aryl-alkyl p-Bromobenzene-

sulfonates. J . Org. Chem. 1972, 37, 825-836.

Refer en ces

(1) 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, 237-46.

(2) Caine, M.; Pfau, A.; Perlberg, S. The Use of Alpha Adrenergic

Blockers in Benign Prostatic Obstruction. Br. J . Urol. 1976, 48,

255-63.

(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, 375-86. 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.

(20) Beck, J . R. A Direct Synthesis of Benzo[b]thiophene-2-carboxy-

late Esters Involving Nitro Displacement J . Org. Chem. 1972,

37, 3224.

(21) Dunn, A. D.; Norrie, R. Nucleophilic Displacements in Pyridine

Rings. J . Heterocycl. Chem. 1987, 24, 85.

(22) Hieble, J . P.; Boyce, A. J .; Caine, M. Comparison of the

a1-Adrenoceptor Characteristics in Human and Canine Prostate.

Fed. Proc. 1986, 45 (11), 2609-2614.

(23) Burt, R.; Chapple, C. R.; Marshall, J . Evidence for a Functional

R

_1A-R_1cAdrenoceptor Mediating Contraction of the Rat epidymal

(6) Kawabe, K.; Ueno, A.; Takimoto, Y.; Aso, Y.; Kato, H. Use of an

R₁-Blocker, YM617, in the Treatment of Benign Prostatic Hy-

pertrophy. J . Urol. 1990, 154, 908-912.

(7) J ardin, A.; Bensadoun, H.; Delauche-Cavallier, M. C.; Stalla-

Bourdillon, A.; Attali, P. Long-term Treatment of Benign Pro-

static Hyperplasia with Alfuzosin: a 24-30 month Survey. Br.

J . Urol. 1984, 74, 579-584.

vas deferens and an R_1b-Adrenoceptor Mediating Contraction of

the Rat Spleen. Br. J . Pharmacol. 1995, 115, 467-475.

(24) Knepper, S. M.; Buckner, S. A.; Brune, M. E.; DeBernardis, J .

F.; Meyer, M. D.; Hancock, A. A. A-61603,

Adrenergic Receptor Agonist, Selective for the R_1AReceptor

Subtype. J . Pharmacol. Exp. Ther. 1995, 274, 97-103.

A Potent R₁-

Tricyclic Hexahydrobenz[e]isoindoles

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8 1603

(25) 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.

(26) Gorvin, J . H. Pharmaceutical Composition Containing Acridone

and Xanthone Compounds. U.S. Patent No. 4,250,182, 1981.

(27) Markley L. D.; Tong, J . C.; Dulworth, J . K.; Steward, D. L.;

Goralski, C. T.; J ohnston, H.; Wood, S. G.; Vinogradoff, A. P.;

Bargar, T. M. Antipicornavirus Activity of Substituted Phenoxy-

benzenes and Phenoxypyridines. J . Med. Chem. 1986, 29, 427.

(28) De Angelis, G. G.; Hess, H. J . E. Benzothieno- and Benzofuro-

[3,2-d]pyrimidine Inhibitors of Platelet Aggregation. U.S. Patent

3,706,747, 1972.

(29) Schneller, S. W.; Clough, F. W.; Hardee, L. E. A Simple Synthesis

of Thieno[2,3-b]pyrazine and Thieno[2,3-b]pyridine. J . Hetero-

cycl. Chem. 1975, 12, 513.

(30) Brederick, H.; Simchen, G.; Traut, H. Zur Pyrimidin-Synthese

aus Tris-formamino-methan and CH-aciden Verbindungen. Chem.

Ber. 1965, 98, 3883.

(31) Yamanaka, H.; Sakamoto, T.; Nishimura, S.; Sagi, M. Studies

on Pyrimidine Derivatives. XXXIX. Site-Selectivity in the Reac-

tion of 5-Substituted and 4,5-Disubstituted Pyrimidine N-Oxides

with Trimethylsilyl Cyanide. Chem. Pharm. Bull. 1987, 35, 3119.

(32) Dick, G. P. G.; Wood, H. C. S. Pteridine Derivatives. Part I. A

New Synthesis of 2-Amino-4-Hydroxypteridines. J . Chem. Soc.

1955, 1379.

(33) J ones, R. G. Pyrazines and Related Compounds I. A New

Synthesis of Hydroxypyrazines. J . Am. Chem. Soc. 1949, 71, 78.

(34) Beck, J . R.; Yahner, J . A. Synthesis of [1]Benzothieno[3,2-d]-

pyrimidine Derivatives. J . Org. Chem. 1973, 38, 2450.

(35) Dinitriles epimerize under the reaction conditions. It seems likely

that the trans dinitrile is converted to trans benzoisoindole at a

greater rate than the cis dinitrile, leading to predominant

formation of trans benzoisoindole in accordance with Curtin-

Hammett principle.

J M990567U

Article Doi

Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole α(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH)

DOI: 10.1021/jm990567u

Source and publish data:

Authors:

Article abstract of DOI:10.1021/jm990567u

Full text of DOI:10.1021/jm990567u

Products guided by the article

R&D Labs maybe for 195874-28-3

Relevant to this article

Hot Product