Substituted hexahydrobenzo[f]thieno[c]quinolines as dopamine D1- selective agonists: Synthesis and biological evaluation in vitro and in vivo

Article abstract of DOI:10.1021/jm970038v

A series of substituted 9,10- dihydroxyhexahydrobenzo[f]thieno[c]quinolines (TB[f]Q), varying with respect to the position of the thiophene relative to the benzo[f]quinoline core and the nature and position of the substituent on the thiophene, were prepared and evaluated for their affinity and selectivity for the dopamine D1-like receptor. The thieno[3,2-c]B[f]Q regioisomers bearing a small alkyl (C1-C3) substituent at the 2 position were potent (K(i) < 20 nM) and selective (D2/D1 > 50) D1 agonists with close to full agonist activity (IA > 85%). The compounds were resolved and found to exhibit a high level of enantiospecificity in their interaction with the D1 receptor. Selected compounds were tested in vivo in the 6-OHDA rodent model of Parkinson's disease and for their liability to produce seizure-like activities in mice. (5aR)-trans-2-Propyl-4,5,5a,6,7,11b-hexahydro-3-thia-5-azacyclopent-1- ena[c]phenanthrene-9,10-diol (5) emerged as the compound with the best overall in vivo profile in terms of potency (ED₅₀ = 0.04 μmol/kg) and safety.

Full text of DOI:10.1021/jm970038v

J . Med. Chem. 1997, 40, 1585-1599
1585
Su bstitu ted Hexa h yd r oben zo[f]th ien o[c]qu in olin es a s Dop a m in e D1-Selective
Agon ists: Syn th esis a n d Biologica l Eva lu a tion in Vitr o a n d in Vivo
Michael R. Michaelides,* Yufeng Hong, Stanley DiDomenico, J r., Erol K. Bayburt, Karen E. Asin,
Donald R. Britton, Chun Wel Lin, and Kazumi Shiosaki
Neuroscience Research, Pharmaceutical Discovery, Abbott Laboratories, 100 Abbott Park Road,
Abbott Park, Illinois 60064-3500
Received J anuary 17, 1997X
A series of substituted 9,10-dihydroxyhexahydrobenzo[f]thieno[c]quinolines (TB[f]Q), varying
with respect to the position of the thiophene relative to the benzo[f]quinoline core and the
nature and position of the substituent on the thiophene, were prepared and evaluated for their
affinity and selectivity for the dopamine D1-like receptor. The thieno[3,2-c]B[f]Q regioisomers
bearing a small alkyl (C1-C3) substituent at the 2 position were potent (Ki < 20 nM) and
selective (D2/D1 > 50) D1 agonists with close to full agonist activity (IA > 85%). The compounds
were resolved and found to exhibit a high level of enantiospecificity in their interaction with
the D1 receptor. Selected compounds were tested in vivo in the 6-OHDA rodent model of
Parkinson’s disease and for their liability to produce seizure-like activities in mice. (5aR)-
trans-2-Propyl-4,5,5a,6,7,11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene-9,10-
diol (5) emerged as the compound with the best overall in vivo profile in terms of potency
(ED50 ) 0.04 µmol/kg) and safety.
Ch a r t 1. Dopamine D1-Selective Agonists
In tr od u ction
Dopamine receptors can be divided into either the D1-
like or the D2-like family of subtypes based on their
pharmacological profiles and coupling with the enzyme
adenylate cyclase.1 Molecular cloning techniques have
shown that the D1-like family is further divided into
the D1 and D5 receptors, both of which activate ade-
nylate cyclase, and the D2-like family is divided into
the D2, D3, and D4 receptors, which either inhibit cyclic
adenosine monophosphate (cAMP) production or are not
coupled to adenylate cyclase.2
Parkinson’s disease (PD) is characterized by the
degeneration of dopamine-secreting neurons in the
nigrostriatal pathway.3 Dopamine agonist replacement
therapy with L-Dopa, which is endogenously converted
to dopamine and thereby stimulates both the D1 and
the D2 families of receptors, remains the cornerstone
of PD therapy.4 Long-term treatment with L-Dopa,
however, is associated with the induction of drug-related
side effects such as dyskinesia and on-off phenomena
(motor fluctuations). Direct-acting D2-selective agonists
such as bromocriptine, lisuride, and pergolide are also
prescribed, although their use is primarily as add-on
therapy to L-Dopa since they demonstrate limited ef-
ficacy as monotherapy.5
agonist, was efficacious in MPTP-lesioned primates and
produced a weak, albeit significant, improvement in PD
patients.8
The recent identification of novel structural classes
of D1-selective full DA agonists has led to renewed
interest in the potential utility of D1 agonists for the
treatment of PD. Isochromans, typified by A-77636 (1c),
are potent and selective full agonists at the D1-recep-
tor.9 Isochroman 1c was shown to be effective in both
primate and rodent models of PD;9b however, its devel-
opment was precluded because of the rapid behavioral
desensitization observed after repeated administra-
tion.10
The therapeutic benefit of D1-selective agonists in
treating PD has not yet been fully explored. Initial
results with the prototypical D1 agonist SKF-38393 (1a )
showed lack of efficacy in both an MPTP-lesioned
primate model of PD and clinical trials.6 The lack of
efficacy of SKF-38393 has been attributed to its low
intrinsic activity in vitro (ca. 10-40% relative to DA)
in both primate and human caudate tissues and to its
questionable levels of brain penetration.7 The benzer-
goline CY208-243 (1b), another D1-selective partial
Dihydrexidine (2), a benzophenanthridine that func-
tions as a D1 full agonist, was also shown to be effective
in a primate model of PD and is reported to be in clinical
development.11 We have investigated the structurally
related series of substituted hexahydrothieno[c]benzo-
[f]quinolines 3 (TB[f]Q), in which the phenyl ring in
dihydrexidine is replaced with its thiophene bioisostere.
It is noteworthy that these compounds were originally
* Corresponding author address: Dept. 47J , Bldg. AP10, Abbott
Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064-3500.
X Abstract published in Advance ACS Abstracts, May 1, 1997.
S0022-2623(97)00038-1 CCC: $14.00 © 1997 American Chemical Society

1586 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Michaelides et al.
Ch a r t 2
Sch em e 1a
designed as conformationally restricted analogs of the
fully efficacious D1 agonists 4a ,b.12
We have previously reported compound 5 (A-86929:
(5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-
azacyclopent-1-ena[c]phenanthrene-9,10-diol) to be a
potent and selective full agonist at the D1 receptor that
is efficacious in rodent and primate models of PD after
both acute and long-term (30 days) administration.13
The diacetyl prodrug (5a ) of 5 imparts greater long-term
solid-state stability, is readily converted to the parent
compound (5) under physiological conditions, and is
currently under clinical development. We now wish to
report on the synthesis of substituted regioisomeric
hexahydrothieno[c]benzo[f]quinolines 3 and the results
of subsequent structure-activity studies that led to the
selection of 5 as a clinical candidate.
a
Reagents: (a) C(NO2)4, pyridine; (b) (1) n-BuLi, 8, THF, (2)
Et3N, CH3CN; (c) Zn, 6 M HCl; (d) (1) HCHO, K2CO3, (2) TFA; (e)
BBr3, CH2Cl2.
Sch em e 2a
Ch em istr y
Synthetic schemes 1-8 were used to prepare the
compounds described in this report. The compounds
vary with respect to the positioning of the thiophene
ring relative to the benzo[f]quinoline nucleus and the
type and site of substitution on the thiophene. The
compounds were first prepared in racemic form, in a
convergent manner through the addition of an ap-
propriately substituted thiophene to either the nitroole-
fin 7 (Schemes 1-6) or the nitroolefin 41 (Scheme 7).
Selected compounds were then resolved into their
respective enantiomers using chiral HPLC (Scheme 8).
The hexahydrothieno[3,2-c]benzo[f]quinolines 12a -i
were prepared by lithiation and subsequent Michael
addition of a 2-substituted thiophene (8) to the nitroole-
fin 7 (Scheme 1). Compound 7 was synthesized from
the dihydronaphthalene 6 via nitration with tetrani-
tromethane in pyridine.14 The thiophenes employed
were either commercially available or prepared via one
of the following literature methods: (i) alkylation of
2-lithiothiophene with either alkyl halides or trialky-
lboranes15 or (ii) Friedel-Crafts acylation followed by
Wolff-Kishner deoxygenation.16 Lithiation of 8 with
n-BuLi and subsequent Michael addition to the ni-
troolefin 7 gave adduct 9 as a ca. 3:1 cis:trans mixture
of diastereomers. Equilibration of this crude mixture
under thermodynamic conditions, with triethylamine,
typically afforded a 4-5:1 mixture of diastereomers in
favor of the trans product 9. Chromatographic separa-
a
Reagents: (a) t-BuBr, AlCl3; (b) HOCH2CH2OH, TsOH; (c) (1)
n-BuLi, 7, (2) Et3N; (d) Zn, HCl; (e) BBr3, CH2Cl2.
tion followed by reduction of the trans product to the
amine 10 with zinc in acetic acid proceeded in high yield
with retention of stereochemistry. The tetracycle 11
was then constructed via a modified Pictet-Spengler
cyclization.17 Thus, the amine 10 was reacted first with
paraformaldehyde in methanol in the presence of K2-
CO3 to form an intermediate N,O-acetal or imine, which
was then treated with TFA in CH2Cl2 to effect cycliza-
tion in 25-40% yield. Standard Pictet-Spengler condi-
tions (formalin, HCl) gave very poor yields (<5%) of 11.
Deprotection of the methyl ethers with BBr3 gave the
catecholamines 12a -i in high yields.
An alternative preparation of the thieno[3,2-c]B[f]Q
series is outlined in Scheme 2. This method was applied
to the synthesis of the tert-butyl derivative 12j. Thus,
Friedel-Crafts alkylation (t-BuBr, AlCl3) of 3-thiophene
carboxaldehyde followed by protection of the aldehyde
produced the acetal 15. Lithiation of 15 with n-BuLi
followed by addition to the nitroolefin 7, equilibration

TB[f]Q as Dopamine D1-Selective Agonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1587
Sch em e 3a
of the resulting diastereomeric mixture, and chromato-
graphic separation gave the trans nitro compound 16
in low yield (14%). The low yield can be partly at-
tributed to competing lithiation at the acetal carbon.
Lithiation of 15 with 1 equiv of n-BuLi followed by a
D2O quench gave a 1:1 mixture of compounds resulting
from deuterium incorporation at either C2 or the acetal
carbon, indicating a competitive rate of lithiation at C2
versus the acetal methine. Treatment of 16 with Zn in
aqueous HCl afforded directly the tetracycle 11j in
moderate yield (20-30%). Apparently deprotection of
the acetal led to an intermediate amino aldehyde that
condensed to the imine, which was then reduced to give
11j. BBr3-mediated deprotection of the methyl ethers
gave 12j.
The isomeric cis thieno[3,2-c]B[f]Q 17 was obtained
in quantitative yield via treatment of 11a with refluxing
HBr in AcOH (eq 1). The reaction presumably proceeds
a
via the trans catechol 12a , which undergoes epimeriza-
tion to the cis compound under the reaction conditions.
We had initially observed that BBr3 deprotection of 11a
was accompanied by epimerization leading to varying
amounts of the cis isomer depending on the reaction
time. Deprotection of 11a at 0 °C for only 10 min
produced exclusively the trans isomer 12a , whereas
longer reaction times (3-4 h) led to mixtures containing
>75% of the cis isomer 17, suggesting epimerization of
12a to 17. It is interesting to note that no epimerization
was observed when compounds bearing a substituent
at the 2 position (11b-i) were deprotected under similar
conditions (BBr3, 0 °C, 2-3 h).
Reagents: (a) (1) n-BuLi, THF, (2) Et3N; (b) Zn, HCl; (c) TsOH,
toluene, reflux; (d) BH3‚THF; (e) BBr3.
Sch em e 4a
The synthesis of the 2-substituted thieno[3,2-c]B[f]Q
analogs 23a -n is outlined in Scheme 3. Lithiation of
thiophene 18 and subsequent Michael addition to the
nitroolefin 7 followed by Et3N-mediated equilibration
yielded the nitro adduct 19 with a trans:cis isomer ratio
of greater than 15:1. The carboxamide group of 18
serves to both direct lithiation at the 3 position and to
participate in the formation of the tetracycle. Thus, the
nitro compound 19 was reduced to the amino amide 20,
which, after treatment of 20 with TsOH in refluxing
toluene, afforded the lactam 21.18 Borane reduction and
subsequent deprotection afforded the catechols 23a -
n .
The requisite 5-substituted 2-thiophene carboxamides
18a -n used in Scheme 3 were prepared using one of
three methods (Scheme 4). In method A, 2-substituted
thiophene 8 was lithiated with n-BuLi and then reacted
with tert-butyl isocyanate to directly afford 18. In
method B (used for 18g,h ), thiophene-2-carboxylic acid
(24) underwent Friedel-Crafts alkylation to give a
5-alkylthiophene-2-carboxylic acid. The resulting acid
was converted to the acid chloride, which was then
reacted with tert-butyl amine to give 18. Method C was
applied to the aryl-substituted compounds 18l,m and
involved palladium-catalyzed coupling of arylboronic
acids with 2-bromo-5-thiophenecarboxaldehyde (25).19
The 2-aryl-5-thiophenecarboxaldehyde obtained was
a
Reagents: (a) (1) n-BuLi, (2) t-BuNCO; (b) RCl, AlCl3; (c) (1)
SOCl2, (2) t-BuNH2; (d) (1) ArB(OH)2, Pd(PPh3)4, (2) AgNO3, KOH.
oxidized to the acid and then converted to the corre-
sponding tert-butylamide 18, as in method B.
The synthesis of the 2-thia regioisomer 31 is shown
in Scheme 5. The requisite 4-lithio-3-carboxamide
thiophene was obtained by initially blocking the C2
position of commercially available 26 with a trimeth-
ylsilyl group. Exclusive 4-lithiation of the TMS-
thiophene 27 and its subsequent addition to the olefin
7 and equilibration gave the trans adduct 28. Reduction
of the nitro group followed by removal of the TMS group
gave the corresponding aminoamide, which underwent
Me3Al-mediated cyclization to afford the lactam 29. The
lactam was then reduced with borane to give 30. BBr3-
mediated deprotection of the methyl ethers was ac-
companied by epimerization to give the catechol 31 as
a 3:1 trans:cis mixture.
The synthesis of the 2-thia-3-alkyl regioisomer 39 is
depicted in Scheme 6. Lithiation of 3,4-dibromothiophene
(32) with LDA followed by reaction with n-propyl iodide
gave 33. Halogen-metal exchange and subsequent
reaction with DMF afforded a 1:1 mixture of regioiso-

1588 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Michaelides et al.
Sch em e 5a
Sch em e 7a
a
Reagents: (a) (1) n-BuLi, CH3CH2CON(MeO)Me, (2) KOH,
NH2NH2; (b) (1) LDA, 41, (2) Et3N; (c) (1) Zn, HCl, (2) H2, Pd/C;
(d) (1) (HCHO)n, K2CO3, (2) TFA; (e) BCl3.
a
Reagents: (a) s-BuLi, TMEDA, TMSCl; (b) (1) s-BuLi, TMEDA,
7, (2) Et3N; (c) (1) Zn, 6 M HCl, (2) Me3Al, toluene, reflux; (d)
BH3‚THF; (e) BBr3.
Sch em e 8a
Sch em e 6a
c
a
Reagents: (a) chiral HPLC separation; (b) BBr3.
deprotection of 38, we used an alternative catechol
protecting group that could be cleaved under milder
conditions for the preparation of the 3-propylthieno[3,2-
c]B[f]Q derivative 45 (Scheme 7). Halogen-metal ex-
change of 32 followed by acylation and Wolff-Kishner
deoxygenation gave thiophene 40. Lithiation of 40 with
LDA occurred regiospecifically to give the corresponding
2-lithiothiophene which was allowed to react with the
methylenedioxy-protected nitroolefin 41 to yield the
adduct 42. Reduction and dehalogenation of 42 followed
by Pictet-Spengler cyclization gave 44. Deprotection
with BCl3 gave 45, as a 5:1 mixture of trans:cis isomers.
Racemic mixtures of selected compounds were re-
solved into their respective enantiomers using chiral
HPLC (Scheme 8). Thus, the racemic amines 22b-d ,g
were separated on a preparative Chiracel OD column
to obtain the enantiomers in >98% ee as determined
by analytical HPLC.20 Deprotection of the methyl
ethers gave the corresponding catechols 5, 46a -c, and
47a -d in >98% ee.
a
Reagents: (a) LDA, n-PrI; (b) n-BuLi, DMF; (c) (1) NaBH4,
(2) MOM-Cl; (d) (1) n-BuLi, 7, (2) Et3N; (e) (1) Zn, HCl, (2) HCl,
THF, H2O; (f) K2CO3, t-BuOH; (g) BBr3.
meric aldehydes. The desired aldehyde 34 was chro-
matographically separated and reduced to the alcohol
that was protected as a MOM ether (35). Halogen-
metal exchange followed by Michael addition to the
nitroolefin 7 gave the adduct 36 in 57% yield. Reduction
of the nitro group and treatment with aqueous HCl gave
the amino chloride 37, which underwent base-mediated
cyclization to afford the tetracycle 38 (62% overall yield).
Deprotection under the usual conditions with BBr3 (0
°C, 2 h) was accompanied by significant epimerization
to yield a ca. 1:1 mixture of cis:trans isomers. The trans
isomer 39 was purified from the cis isomer using
reverse-phase HPLC.
In view of the epimerization encountered in the

TB[f]Q as Dopamine D1-Selective Agonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1589
Ta ble 1. In Vitro Pharmacology: SAR of 2-Alkylthieno[3,2-c]benzo[f]quinolinesa
binding affinity, Kib
binding selectivity
functional activity, D1
compd
R
D1-like (nM)
D2-like (nM)
R2 (nM)
D2/D1
5
R2/D1
EC50 (nM)
IAc (%)
12a
H
70 ( 15
(8)
340 ( 10
(8)
84 ( 15
(3)
1
39 ( 5.8
(3)
120 ( 3
(3)
12b
12c
12d
12e
12f
12g
12h
12i
12j
17
Me
Et
18 ( 8.1
205 ( 15
100 ( 15
11
17
11
20
1
5
26
47 ( 11
85 ( 12
(3)
(3)
(3)
(3)
(3)
8.5 ( 2.4
(3)
13 ( 3
(4)
22 ( 3.9
(4)
690 ( 350
(3)
165 ( 26
(4)
280 ( 115
(4)
4.3 ( 0.6
(3)
78 ( 19
(5)
145 ( 25
(3)
150 ( 52
(3)
450 ( 130
(3)
540 ( 115
(3)
1530 ( 14
(3)
560 ( 72
(4)
145 ( 58
(3)
910 ( 205
(6)
255 ( 67
(3)
400 ( 110
(3)
980 ( 78
(3)
50 ( 18
(3)
28 ( 9.5
(3)
44 ( 25
(3)
140 ( 35
(3)
79 ( 28
(4)
125 ( 70
(3)
43 ( 5.9
(3)
28 ( 5.1
(3)
100 ( 12
(3)
93 ( 2
(3)
79 ( 4
(3)
76 ( 9
(3)
87 ( 15
(4)
63 ( 5
(3)
97 ( 4
(3)
74 ( 10
(3)
n-Pr
n-Bu
30
44
n-hexyl
>10000
>10
54
(2)
cyclohexyl
CH2cycloC5
Cl
8900 ( 200
9
(5)
7200 ( 1050
(2)
595 ( 140
(2)
2450 ( 800
(3)
nd
2
25
33
12
1
140
31
tert-butyl
H
(cis)
3800 ( 250
(5)
2800 ( 460
(4)
nd
3200 ( 630
(4)
48 ( 2
(4)
Reference Compounds
1a
1c
2
SKF-38393
A-77636
DHX
35 ( 8.6
(23)
30 ( 5.4
(68)
100 ( 34
(17)
2900 ( 510
3050 ( 680
83
60
14
85
43
30
950 ( 400
(11)
8.2 ( 1.1
(29)
88 ( 20
(8)
58 ( 3
(11)
102 ( 4
(29)
130 ( 7
(8)
(21)
(3)
1800 ( 135
(69)
1400 ( 450
(18)
1300 ( 240
(17)
3000 ( 450
(8)
a
b
Values represent the mean ( SEM, with the number of experiments in parentheses. Binding ligands were as follows: D1, [125I]SCH
23982; D2, [3H]spiperone; R2, [3H]rauwalsine. The tissues used were as follows: D1, D2, rat caudate membrane; R2, rat cortical membrane.
c IA ) intrinsic activity relative to dopamine.
P h a r m a cology
away from (contralateral to) the lesioned side. The ED50
value (dose of a test compound at which one-half of the
animals in the test group exhibit at least 50 net
contralateral rotations in a 30-min period) and duration
of action at the ED50 were determined.
Selected compounds were also tested for their ability
to induce seizures in mice. Drug-induced seizures were
scored by placing animals in cages, allowing them to
habituate for 1 h, and then injecting them with drug.
The animals were observed for the presence of behav-
ioral seizure-like activity consisting of forelimb clonus
with or without arching of the back and loss of balance.
The ED50 is defined as the dose at which one-half of the
test group animals displayed any of these behaviors
during the observation period.
In Vitr o P h a r m a cology. The binding affinities (Ki)
were determined in dopamine D1 and D2 receptor
assays as well as in the adrenergic R2 receptor assay.
It is important to note that the affinity determined for
the D1 receptor in this series of experiments indicates
affinity for the D1 family of receptors (D1 and D5), while
the affinity determined for the D2 receptor indicates
affinity for the D2 family of receptors (D2, D3, and D4).
Rat caudate membrane was used as the tissue source
for the D1 and D2 receptors, while rat cortical mem-
brane was used as the source for the R2 receptor. [125I]-
SCH 23982, [3H]spiperone, and [3H]rauwalsine were
used as the radioligands for the D1, D2, and R2 assays,
respectively. The ability of a compound to stimulate the
D1 receptor was assayed by measuring cAMP produc-
tion in cell-free homogenates of goldfish retinal tissue.
An EC50 value and intrinsic activity (IA, the magnitude
of the response expressed as a percent relative to
dopamine) were determined from this assay.
In Vivo P h a r m a cology. Selected compounds were
tested in the rat rotation model of PD.21 This model is
produced by discrete unilateral 6-hydroxydopamine
injections into the brain that destroy a certain set of
ascending dopamine-secreting neurons. As a result of
the loss of dopaminergic input, DA receptors on the
lesioned side become supersensitive, and administration
of direct-acting DA agonists causes the animal to rotate
Resu lts a n d Discu ssion
The compounds examined in this study can be divided
into three structural classes depending on the position-
ing of the thiophene ring relative to the benzo[f]-
quinoline nucleus and the site of the substituent on the
thiophene ring: (a) 2-substituted 1-thia, (b) 2-substi-
tuted 3-thia, and (c) 3-substituted 1- or 2-thia. The in
vitro pharmacological data for the 2-substituted 1-thia
derivatives are presented in Table 1. The unsubstituted
parent compound 12a showed high affinity (Ki ) 70 nM)
and potent, full agonist activity (EC50 ) 39 nM, IA )
120%) at the D1-like receptor. However, it suffers from

1590 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Ch a r t 3. Superimposition of 1c and 12a (Bold)
Michaelides et al.
ity. Nichols has reported that the cis isomer of dihy-
drexidine binds very weakly at the D1 receptor (binding
IC50 > 5 µM).24 Consistent with these previous reports,
the cis isomer 17 is much weaker than the trans isomer
12a in both its binding affinity (50-fold) and functional
activity (80-fold) at the D1 receptor.
The data for the 2-substituted 3-thia series are shown
in Table 2. The unsubstituted parent compound 23a
had high affinity (Ki ) 73 nM) and functional potency
for the D1-like receptor with good selectivity (18-fold)
over the D2-like receptor but poor selectivity (2-fold)
over the R2 receptor. A comparison of 23a and 12a
reveals that changing the relative position of the
thiophene sulfur atom from the 1 to the 3 position
resulted in a 3-4-fold weaker affinity for the D2
receptor, whereas D1 receptor affinity was unaffected.
In order to boost potency and selectivity for the D1
receptor in this particular series, we investigated the
effect of substitution at the C2 position in an attempt
to replicate the success previously observed upon sub-
stitution in the 1-thia series.
poor selectivity (5-fold) over the D2-like receptor. As
dopaminergic compounds are known to bind to other
biogenic amine receptors, 12a was screened for its
binding affinity to adrenergic and serotonergic recep-
tors. The compound had weak affinity (Ki > 5000 nM)
for the adrenergic R1, 5HT1a, 5HT1c, and 5HT2 recep-
tors but had significant affinity for the adrenergic R2
receptor (Ki ) 84 nM) that was comparable to that for
the D1 receptor. Therefore, we routinely screened all
compounds for adrenergic R2 activity.22
Introduction of substituents at the C2 position re-
sulted in pronounced effects on D1 and R2 binding,
whereas the effects on D2 were more moderate. Affinity
for the R2 receptor decreased with increasing steric size
of the C2 substituents. As observed with the 1-thia
series, substitution with small alkyl groups (23b-d ,h ,
Me, Et, n-propyl, isopropyl) led to increased affinity for
the D1 receptor (Ki < 20 nM) and a concomitant
decrease in affinity for the D2 and R2 receptors resulting
in high levels of selectivity (D2/D1 Kis > 50). These
compounds were potent D1 agonists (EC50 ) 29-87 nM)
stimulating adenylate cyclase with high intrinsic activ-
ity (IA ) 82-99%). Introduction of a tert-butyl group
(23g) resulted in maintenance of high D1 affinity and
further decrease in D2 and R2 affinity. However,
introduction of extended groups such as n-pentyl or
isopentyl (23f,j) and phenyl (23l) resulted in a signifi-
cant loss (4-15-fold) in D1 binding affinity. Further
substitution of the pendant phenyl with a methyl group
(23m ) led to a dramatic decrease (>100-fold) in binding
affinity.
Extensive evaluation of the structure-activity rela-
tionship inherent in the previously described isochro-
man series as well as modeling of the D1 and D2
receptors revealed that the D1 receptor differs from the
D2 receptor in that the former posseses a putative
lipophilic binding pocket that can accommodate a range
of sterically demanding substituents.23 The binding
pocket can be accessed by substituting appropriate
groups at the 3 position of the isochromans, e.g, the
adamantyl group in isochroman 1c. Interaction with
this pocket by a compound is expected to confer selectiv-
ity and potency for the D1 receptor. Superimposing the
structures of 1c with 12a suggested that the auxiliary
lipophilic binding pocket is only partially filled by the
thiophene ring of 12a (Chart 3). Thus, we subsequently
examined whether substituents on the thiophene ring
could increase favorable interactions with the lipophilic
binding pocket and thereby lead to increased selectivity
and potency for the D1 receptor. Introduction of short
(C1-C4) unbranched alkyl groups at the 2 position
(12b-e) resulted in a consistent 3-8-fold increased
affinity for the D1 receptor, whereas the effect on D2
receptor binding was variable and less pronounced. A
decrease in affinity for the adrenergic R2 receptor was
also observed. The 2-chloro compound 12i showed both
enhanced potency and selectivity for the D1 receptor.
Compounds 12a -e,j potently stimulated adenylate cy-
clase (EC50 ) 28-50 nM) and possessed high intrinsic
activity relative to dopamine. Although substitution
with the bulky tert-butyl group (12j) was tolerated,
introduction of extended alkyl groups (e.g., n-hexyl,
cyclohexyl) (12f-h ) resulted in decreased affinity for
both dopaminergic and R2 receptors relative to the
parent compound 12a .
The addition of substituents on the thiophene did not
have a pronounced effect on the ability of the compound
to stimulate adenylate cyclase. In general, there is good
agreement between binding and cyclase values (see
Table 2). However, as we have previously reported with
the isochroman class of compounds, certain compounds
(e.g., 23l,n ) can show a significant discrepancy between
binding and cyclase values.23 The reasons for this
discrepancy remain unclear, although it could be partly
attributed to the fact that different tissues from differ-
ent species were used in the binding and functional
assays. Additionally, these assays are only simple
biochemical models of the complex signal transduction
processes.
Compounds 12a , 23a , and dihydrexidine have com-
parable affinities for the D1-like receptor, whereas 12a
and 23a have significantly higher affinity for the
adrenergic receptor. However, as discussed above,
introduction of small alkyl groups at the 2 position of
either the 1-thia or the 3-thia series led to increased
potency and selectivity for the D1 receptor. The same
observation was reported on dihydrexidine upon sub-
stitution of small alkyl groups at either the 2 or the 3
position.25 The results from the present thieno[c]benzo-
As previously noted with other benzo[f]quinolines
such as the benzergoline 1b and dihydrexidine (2), the
trans ring juncture is essential for dopaminergic activ-

TB[f]Q as Dopamine D1-Selective Agonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1591
Ta ble 2. In Vitro Pharmacology: SAR of 2-Alkylthieno[2,3-c]benzo[f]quinolinesa
binding affinity, Kib
binding selectivity
functional assay, D1
compd
R
D1-like (nM)
D2-like (nM)
R2 (nM)
D2/D1
17
R2/D1
EC50 (nM)
IAc (%)
23a
H
73 ( 25
(7)
1290 ( 330
(7)
185 ( 65
(3)
2
47 ( 3.9
(3)
98 ( 15
(3)
23b
23c
23d
23e
23f
23g
23h
23i
Me
Et
18 ( 3.4
980 ( 290
730 ( 205
54
98
78
10
4
40
145
123
30
87 ( 20
82 ( 4
(7)
(7)
(9)
(7)
(7)
6.5 ( 1.0
(3)
18 ( 4.5
(5)
125 ( 17
(6)
520 ( 140
(3)
51 ( 11
(5)
20 ( 5.2
(4)
52 ( 8.6
(3)
440 ( 100
(3)
640 ( 96
(3)
940 ( 58
(3)
31 ( 7.8
(3)
52 ( 18
(3)
77 ( 26
(3)
170 ( 22
(3)
69 ( 15
(4)
29 ( 4.3
(3)
88 ( 11
(3)
470 ( 270
(3)
95 ( 12
(3)
99 ( 14
(3)
78 ( 3
(3)
80 ( 11
(3)
97 ( 5
(4)
87 ( 15
(3)
84 ( 5
(3)
67 ( 5
(3)
n-Pr
n-Bu
1400 ( 475
2220 ( 185
(3)
(3)
1320 ( 560
(6)
3800 ( 1360
(2)
n-pentyl
tert-butyl
i-Pr
2090 ( 140
>10000
>19
138
150
152
>20
>130
5
(3)
(2)
3260 ( 1030
(4)
7060 ( 1650
64
86
49
4
(5)
1720 ( 280
3000 ( 650
(3)
7940 ( 2300
(4)
CH2-i-Pr
CH2CH2-i-Pr
cyclohexyl
phenyl
2560 ( 490
(5)
(3)
>10000
(2)
23j
1760 ( 530
(3)
23k
23l
150 ( 24
(3)
3110 ( 260
(3)
>20000
20
2
94 ( 47
(3)
80 ( 16
(7)
71 ( 7
(3)
88 ( 11
(7)
(2)
1130 ( 220
2590 ( 650
6420 ( 890
(7)
(4)
(3)
23m
23n
m-Me-phenyl
Cl
>7500
(6)
>10000
(6)
>20000
(2)
2795
(1)
640 ( 430
(4)
170 ( 60
(4)
70 ( 18
(4)
91 ( 9
(4)
12 ( 2.4
(9)
300 ( 98
(7)
25
232
a
b
Values represent the mean ( SEM, with the number of experiments in parentheses. Binding ligands were as follows: D1, [125I]SCH
23982; D2, [3H]spiperone; R2, [3H]rauwalsine. The tissues used were as follows: D1, D2, rat caudate membrane; R2, rat cortical membrane.
c IA ) intrinsic activity relative to dopamine.
Ta ble 3. In Vitro Pharmacology: SAR of 3-Alkylthienobenzo[f]quinolinesa
binding affinity, Kib
binding selectivity
functional activity, D1
compd
X1
X2
R
D1-like (nM)
D2-like (nM)
R2 (nM)
D2/D1
22
R2/D1
EC50 (nM)
IAc (%)
31d
CH
S
H
45 ( 8
(3)
1030 ( 375
(4)
575 ( 140
(3)
12
240 ( 80
(4)
77 ( 7
(4)
39
CH
S
S
n-Pr
n-Pr
125 ( 92
100 ( 11
515 ( 58
1
1
4
82 ( 33
71 ( 3
(6)
(6)
(3)
(4)
(4)
45e
CH
58 ( 19
(3)
51 ( 13
(3)
ndf
nd
160 ( 58
(3)
98 ( 12
(3)
a
b
Values represent the mean ( SEM, with the number of experiments in parentheses. Binding ligands were as follows: D1, [125I]SCH
23982; D2, [3H]spiperone; R2, [3H]rauwalsine. The tissues used were as follows: D1, D2, rat caudate membrane; R2, rat cortical membrane.
c IA ) intrinsic activity relative to dopamine. Compound tested as a 3:1 trans:cis mixture of diastereomers. e Compound tested as a 5:1
d
trans:cis mixture. f Not determined.
[f]quinolines along with those from the dihydrexidine
derivatives and the 3-substituted isochromans should
provide additional insights in mapping the length and
breadth of the putative lipophilic binding pocket of the
D1 receptor.
The in vitro biological data for the 3-substituted
compounds are shown in Table 3. The 2-thia compound
31 bound to the D1 receptor with comparable affinity
as the regioisomeric 12a and 23a , although the former
exhibited weaker potency in the functional assay.
Introduction of a n-propyl group at the 3 position (39)
resulted in a 2-fold decrease in D1 affinity and a 10-
fold increase in D2 affinity relative to the parent 31,
providing a nonselective dopaminergic compound. Simi-
larly, introduction of a n-propyl substituent at the 3
position of 12a (compound 45) resulted in a nonselective
compound (D2/D1 Ki ) 1). The increased affinity for
the D2 receptor relative to D1 upon substitution at the
3 position of the thieno[c]benzo[f]quinolines was similar

1592 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Michaelides et al.
Ta ble 4. In Vitro Pharmacology: SAR of Homochiral 2-Alkylthieno[3,2-c]benzo[f]quinolinesa
binding affinity, Kib
binding selectivity
functional activity, D1
compd
R
D1-like (nM)
D2-like (nM)
R2 (nM)
D2/D1
57
R2/D1
EC50 (nM)
IAc (%)
5
(-)-n-Pr
14 ( 1.7
(30)
800 ( 190
(36)
4020 ( 850
(8)
290
24 ( 2.6
(19)
85 ( 3
(19)
47d
46a
47a
46b
47b
46c
47c
(+)-n-Pr
(-)-Me
(+)-Me
(-)-Et
640 ( 130
5400 ( 1060
1410 ( 29
8
42
3
2
150
1
2700 ( 800
28 ( 5
(4)
(3)
(2)
(3)
(3)
5.7 ( 0.9
(4)
240 ( 70
(4)
870 ( 400
(3)
33 ( 6.8
(3)
>10000
87 ( 12
(3)
0%
(3)
104 ( 4
(4)
0%
(3)
90 ( 11
(9)
25 ( 3
(3)
1520 ( 130
4790 ( 1670
2370 ( 1100
(3)
(3)
(2)
(3)
22 ( 5.3
(4)
2.3 ( 0.3
(6)
790 ( 190
(6)
6.6 ( 0.8
(7)
810 ( 150
(3)
345 ( 58
(5)
970 ( 360
(5)
150
7
420
1.7
(+)-Et
5450 ( 790
1360 ( 500
>10000
(6)
(3)
(3)
24 ( 4.2
(9)
(-)-t-Bu
(+)-t-Bu
1380 ( 140
(9)
6410 ( 1050
(6)
210
5
970
>10
4490 ( 260
>10000
1750 ( 50
(3)
(2)
(3)
a
b
Values represent the mean ( SEM, with the number of experiments in parentheses. Binding ligands were as follows: D1, [125I]SCH
23982; D2, [3H]spiperone; R2, [3H]rauwalsine. The tissues used were as follows: D1, D2, rat caudate membrane; R2, rat cortical membrane.
c IA ) intrinsic activity relative to dopamine.
Ta ble 5. In Vivo Pharmacology
to that observed upon substitution at the C4 position
of dihydrexidine.25
ED50
rotation
compd (sc, µmol/kg)a at the ED50 (sc, µmol/kg)b ED50(rotation)
,
duration
ED50, seizures ED50(seizures)/
An analysis of the above in vitro data in Tables 1-3
revealed that the C2-alkyl (C1-C3)-substituted thieno-
[3,2-c] series represented the most promising compounds
in terms of potency and selectivity for the D1 receptor.
Since these compounds were initially tested as racemic
mixtures, we obtained the enantiomerically pure iso-
mers for 23b-d ,g. The data shown in Table 4 reflect
the high degree of enantioselectivity displayed by the
D1 receptor for these compounds; the (+) enantiomers
47a -d are 45-350-fold weaker in both binding and
functional activity than the respective (-) enanti-
omers.26 All the (-) enantiomers (5, 46a -c) studied had
similar in vitro profiles, exhibiting high affinity (Ki <
14 nM) and selectivity (D2/D1 > 50) for the D1 receptor
while potently stimulating adenylate cyclase with high
intrinsic activity (ranging from 85% to 104%) relative
to dopamine.
(()-23a
(()-23e
(()-23i
(-)-5
0.06
(0.03-0.13)
0.55
(0.31-0.95)
2.0
(0.6-7.1)
0.04
(0.02-0.1)
0.05
(0.04-0.05)
0.5
1.5
1
15.5
260
(9.9-24.1)
88.6
160
(57.8-135.8)
ndc
1.5
1-1.5
2
7.55
(6.3-9.4)
1.02
190
20
(-)-46a
(0.6-1.6)
1.25
(-)-46b 0.04
(0.01-0.1)
0.04
(0.025-0.06)
30
(0.8-1.9)
3.4
(-)-46c
2.5
85
(2.4-4.7)
a
Dose at which one-half of the test group animals (rats) exhibit
at least 50 net contralateral rotations in a 30 min period; 95%
b
confidence limits shown in parentheses. Dose at which one-half
of the test group animals (mice) display seizure-like behaviors.
c Not determined.
The 6-OHDA rodent model of PD has been extensively
used to characterize the central actions of dopaminergic
compounds. DA agonists that are used clinically for the
treatment of PD, including L-Dopa and D2-selective
agonists, produce robust contralateral rotation in this
model. Selected compounds from the thieno[3,2-c] series
were tested in this model (Table 5). The enantiomeri-
cally pure compounds 5 and 46a -c were potent in
eliciting robust contralateral rotation after subcutane-
ous administration with ED50 values ranging from 0.04
to 0.05 µmol/kg. The racemic unsubstituted compound
23a was also quite potent (0.06 µmol/kg). The n-butyl
and isobutyl compounds (23e,i), despite their compa-
rable in vitro profile relative to the parent (23a ), were
significantly weaker (0.5 and 2 µmol/kg, respectively)
than 23a in producing contralateral rotation in the
lesioned rats.
compounds were tested for their ability to induce
seizure-like activity in mice (Table 5). All the com-
pounds tested induced seizure activity once a threshold
dose was achieved. A comparison of the enantiomeri-
cally pure compounds 5 and 46a -c shows that 5 has
the greatest separation (>150-fold) between the doses
required to elicit rotation (ED50 ) 0.04 µmol/kg) versus
those that produced seizure-like activity (ED50 ) 7.55
µmol/kg). Compound 5 was further evaluated for its
seizuregenic liability in rats. The doses required to
induce seizures were substantially higher in rats than
in mice (ED50 ) 34.2 (rats) versus 7.5 (mice) µmol/kg,
sc).
Con clu sion
Dopamine D1-selective agonists including A-77636
have been reported to produce a seizure-like response
in nonlesioned rats and mice at high doses.27 Selected
As part of a program at Abbott to develop potent and
selective dopamine D1-like full agonists as a potential
treatment for PD, a series of substituted thienobenzo-

TB[f]Q as Dopamine D1-Selective Agonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1593
was then quenched with 200 mL of 1 M aqueous KOH, and
the mixture was stirred at 0 °C for 20 min resulting in a thick
yellow precipitate. The precipitate was filtered off, washed
with water, and dried in a vacuum oven overnight to afford
27.5 g (74%) of 7 as a yellow solid: mp 90.5-1.0 °C; 1H NMR
(CDCl3) δ 7.82 (s, 1H), 6.82 (s, 1H), 6.75 (s, 1H), 3.94 (s, 3H),
3.90 (s, 3H), 2.98 (m, 4H).
Ca u tion : Tetranitromethane has been reported to be
explosive in the presence of impurities; thus all the appropriate
precautions should be taken.
[f]quinolines were prepared and tested for affinity to
dopaminergic receptors, affinity to the adrenergic R2
receptor, and functional activity at the D1-like receptor.
The position of the thiophene relative to the benzo[f]-
quinoline core and the nature and position of the
substituent on the thiophene were found to be important
in optimizing the affinity and selectivity of these
compounds for the D1 receptor. Introduction of small
alkyl groups (C1-C4) at the 2 position of the 3-thia
series was found to be optimal for potency and selectiv-
ity for the D1 receptor. This optimization was likely
due to the ability of these compounds to better accom-
modate the putative lipophilic binding pocket that exists
in the D1 receptor. The compounds also exhibited a
high level of enantiospecificity in their interaction with
the D1 receptor as the (+) enantiomers were 45-300-
fold weaker in both binding and functional activity.
The compounds with the most promising in vitro
profile were tested in the 6-OHDA rodent model of PD.
Those compounds that were the most potent in eliciting
contralateral rotation were further tested for their
liability to produce seizure-like activities in mice. From
this series of evaluations compound 5 emerged as the
compound with the best overall in vivo profile in terms
of potency and safety.
The preparation of 12b is outlined in the following experi-
ments and is representative for the synthesis of compounds
12a -i.
tr a n s-1,2,3,4-Tetr a h yd r o-6,7-d im eth oxy-1-(5-m eth yl-2-
th iop h en eyl)-2-n itr on a p h th a len e (9b) (R ) Me). A solu-
tion of 2-methylthiophene (8b) (0.97 mL, 10 mmol) in 10 mL
of dry THF was cooled to -78 °C, treated with n-BuLi (4 mL,
2.5 M solution in hexanes, 10 mmol), and then stirred at -78
°C for 10 min and at 0 °C for 2.5 h. The solution was again
cooled to -78 °C, and a solution of 2.30 g (10 mmol) of 7 in
THF (10 mL) was added dropwise via cannula. Stirring was
continued as the solution was allowed to warm to room
temperature, and the reaction was then quenched with 100
mL of saturated NH4Cl solution. The mixture was then
extracted with CH2Cl2, which was dried over Na2SO4 and
concentrated in vacuo to afford 3.04 g of crude product. This
material was dissolved in 30 mL of acetonitrile treated with
0.75 mL (7 mmol) of triethylamine and stirred at room
temperature for 16 h. The solution was concentrated, and the
residue was purified by flash chromatography on silica gel,
eluting with 15% ethyl acetate in hexanes, to afford 1.72 g
(52% yield) of 9b: 1H NMR (CDCl3) δ 6.74 (d, 1H, J ) 3 Hz),
6.58 (s, 1H), 6.56 (dd, 1H, J ) 1, 3 Hz), 6.52 (s, 1H), 4.95-
4.84 (m, 2H), 3.87 (s, 3H), 3.72 (s, 3H), 3.0-2.85 (m, 2H), 2.5-
2.4 (m, 2H), 2.42 (s, 3H).
tr a n s-1,2,3,4-Tetr a h yd r o-6,7-d im eth oxy-1-(5-m eth yl-2-
th iop h en eyl)-2-n a p h th a len a m in e (10b). To a suspension
of 9b (1.52 g, 4.5 mmol) in 40 mL of 95% ethanol and 12 mL
of 6 N HCl was added 2.97 g (45 mmol) of Zn dust, added in
four portions. The mixture was stirred at room temperature
for 30 min and filtered and the filtrate concentrated to one-
half the original volume and then partitioned between CH2-
Cl2 and aqueous NaHCO3. The organic extract was dried over
Na2SO4 and concentrated to yield 1.35 g (99%) of 10b: MS
304 (M + H)+; 1H NMR (CDCl3) δ 6.70 (d, 1H, J ) 3 Hz), 6.60
(bs, 2H), 6.46 (s, 1H), 3.88 (d, 1H, J ) 8 Hz), 3.85 (s, 3H), 3.69
(s, 3H), 3.18 (m, 1H), 2.92-2.78 (m, 2H), 2.43 (s, 3H), 2.12-
2.04 (m, 1H), 1.78-1.64 (m, 1H).
tr a n s-9,10-Dim eth oxy-2-m eth yl-4,5,5a ,6,7,11b-h exa h y-
d r o-1-th ia -5-a za cyclop en t-2-en a [c]p h en a n th r en e (11b).
To a solution of 1.34 g of 10b (44 mmol) in 45 mL of methanol
was added 2.8 g (20.2 mmol) of K2CO3. The mixture was
stirred for 15 min, then 396 mg (13.2 mmol) of paraformalde-
hyde was added, and the suspension was stirred at room
temperature for 18 h. The reaction mixture was filtered, and
the filtrate was concentrated in vacuo. The residue was
dissolved in 100 g of trifluoroacetic acid, and the solution was
stirred for 3 h, then concentrated to about 10 mL, and adjusted
to a basic pH with aqueous NaHCO3 solution. The mixture
was extracted twice with CH2Cl2, and the combined extracts
were washed with brine, then dried (Na2SO4), and concen-
trated. The residue was purified by flash chromatography,
eluting with 4% MeOH:CH2Cl2, to afford 0.35 g (25% yield) of
11b: MS 316 (M + H)+; 1H NMR (CDCl3) δ 7.40 (s, 3H), 6.64
(s, 1H), 6.48 (s, 1H), 4.12-4.05 (m, 3H), 3.93 (s, 3H), 3.86 (s,
3H), 3.1-2.88 (m, 3H), 2.47 (s, 3H), 2.28 (m, 1H), 1.90 (m, 1H).
tr a n s-2-Meth yl-4,5,5a ,6,7,11b-h exa h yd r o-1-th ia -5-a za -
cyclop en t -2-en a [c]p h en a n t h r en e-9,10-d iol H yd r ob r o-
m id e (12b). BBr3 (3.3 mL, 1 M solution in CH2Cl2, 3.3 mmol)
was added dropwise to a -78 °C solution of 260 mg (0.83 mmol)
of 11b in CH2Cl2 (5 mL). The reaction mixture was allowed
to warm to 0 °C over a 2 h period and then stirred at that
temperature for 2 h. The mixture was then cooled to -78 °C,
and the reaction was quenched by the slow addition of MeOH
(5 mL). The solution was then stirred at room temperature
for 20 min and at reflux for 30 min and concentrated. The
product was collected by triturating with CH2Cl2, filtering, and
Compound 5 has been further characterized in vitro
in human cloned dopamine receptors and in vivo in both
rodent and primate models of PD and was found to be
efficacious after both acute and long-term (30 days)
administration.13b The diacetyl prodrug derivative of
5, ABT-431 (5a ), is currently in early clinical trials as
a potential treatment for Parkinson’s disease.
Exp er im en ta l Section
Gen er a l. Melting points were determined with a Thomas-
Hoover melting point apparatus and are uncorrected. All
spectral and analytical data were obtained through the Abbott
analytical Department. All reactions were conducted in oven-
dried or flame-dried glassware under a nitrogen atmosphere.
Anhydrous solvents were purchased from Aldrich Chemical
Co. Analytical thin-layer chromatography was performed by
using 2.5 cm × 10 cm plates coated with a 0.25 mm thickness
of silica gel containing PF 254 indicator (Analtech). Flash
chromatography was performed using silica gel 60 (E. Merck
9285, 230-400 mesh). Elemental microanalysis gave results
for the elements stated within (0.4% of the theoretical values.
1,2-Dih yd r o-6,7-d im eth oxyn a p h th a len e (6). To a cloudy
solution of 6,7-dimethoxy-1-tetralone (60 g, 0.29 mol) in 600
mL of ethanol was added NaBH4 (13.2 g, 0.35 mol) in portions
over 0.5 h, and the mixture was stirred for 14 h at room
temperature. Most of the solvent was removed by evaporation,
and to the residue was added 100 mL of water. The resulting
suspension was heated to 45 °C for 45 min, cooled to room
temperature, and then extracted twice with CH2Cl2. The
combined organic extracts were washed with brine, dried
(MgSO4), and concentrated to leave an oily residue. The crude
intermediate alcohol was dissolved in 600 mL of toluene heated
to reflux and then treated with 0.55 g (2.9 mmol) of p-
toluenesulfonic acid (added carefully so as to avoid boiling
over), and the solution was heated at reflux for 30 min. The
reaction mixture was cooled to room temperature, poured into
water, basified with aqueous NaHCO3, and extracted with
EtOAc. The organic extract was washed with brine, dried
(MgSO4), and concentrated to afford 55 g (99% yield) of 6: 1H
NMR (CDCl3) δ 6.67 (s, 1H), 6.60 (s, 1H), 6.38 (d, 1H, J ) 10
Hz), 5.94 (dt, 1H, J ) 4, 10 Hz), 3.88 (s, 3H), 3.86 (s, 3H), 2.73
(t, 2H, J ) 8 Hz), 2.32-2.24 (m, 2H).
1,2-Dih ydr o-6,7-dim eth oxy-3-n itr on aph th alen e (7). Tet-
ranitromethane (34 g, 0.17 mol) was added slowly (streamwise
addition over 5-10 min) to a 0 °C solution of 6 (30 g, 0.16
mol) and pyridine (15 mL, 0.19 mol) in 200 mL of acetone,
and the reaction mixture was stirred for 5 min. The reaction

1594 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Michaelides et al.
drying to afford 274 mg of the title product (90% yield): mp
195-8 °C; MS 288 (M + H)+; 1H NMR (CD3OD) δ 1.9 (m, 1H),
2.30 (m, 1H), 2.49 (s, 3H), 2.90 (m, 2H), 3.42 (m, 1H), 4.28 (d,
1H, J ) 11 Hz), 4.35 (s, 2H), 6.62 (s, 1H), 6.68 (s, 1H), 7.30 (s,
1H). Anal. (C16H18BrNO2S‚0.3HBr) C,H,N.
The following compounds 12a ,c-i were prepared from
8a ,c-i using the same methodology as that described for 12b.
tr a n s-4,5,5a ,6,7,11b-Hexa h yd r o-1-th ia -5-a za cyclop en t-
2-en a [c]p h en a n th r en e-9,10-d iol h yd r obr om id e (12a ): MS
274 (M + H)+; 1H NMR (CD3OD) δ 1.9-2.05 (m, 1H), 2.3-2.4
(m, 1H), 2.88-2.97 (m, 2H), 3.4-3.5 (m, 1H), 4.36 (d, 1H, J )
10 Hz), 4.46 (s, 2H), 6.62 (s, 1H), 7.02 (d, 1H, J ) 6 Hz), 7.34
(s, 1H), 7.49 (d, 1H, J ) 6 Hz). Anal. (C15H16BrNO2S‚0.2H2O)
C,H,N.
of 14 as an oil: 1H NMR (CD3OD) δ 1.41 (s, 9H), 7.26 (d, 1H,
J ) 1 Hz), 8.2 (d, 1H, J ) 1 Hz), 9.78 (s, 1H).
5-(1,1-Dim eth yleth yl)-3-th ioph en ecar boxaldeh yde Eth -
ylen e Glycol Aceta l (15). A flask fitted with a Dean-Stark
trap was charged with a solution of 2.23 g (13.3 mmol) of 14,
1.65 g (26.5 mmol) of ethylene glycol, and 25 mg of p-
toluenesulfonic acid in 50 mL of cyclohexane (50 mL) and then
heated at reflux for 12 h. The reaction mixture was cooled to
room temperature and partitioned between saturated aqueous
NaHCO3 and ether. The ether layer was washed with water,
dried over MgSO4, and concentrated to afford 2.31 g (82% yield)
of 15: MS 213 (M + H)+; 1H NMR (CDCl3) δ 1.37 (s, 9H), 4.86
(s, 4H), 5.72 (s, 1H), 6.87 (d, 1H, J ) 1 Hz), 7.23 (d, 1H, J )
1 Hz).
2-(1,2,3,4-Tetr a h yd r o-6,7-d im eth oxy-2-n itr on a p h th yl)-
5-(1,1-d im eth yleth yl)-3-th iop h en eca r boxa ld eh yd e Eth -
ylen e Glycol Aceta l (16). To a -78 °C solution of 1.49 g
(7.0 mmol) of 15 in 10 mL of THF was added n-BuLi (2.8 mL,
2.5 M in hexane, 7.0 mmol), and the reaction mixture was
stirred at -78 °C for 10 min and at 0 °C for 50 min. The
solution was again cooled to -78 °C, and a solution of 1.50 g
(6.4 mmol) of 7 in 15 mL of THF was added. The solution
was stirred at -78 °C for 2 h and at -20 °C for 1 h. The
reaction was quenched by the addition of saturated NH4Cl
solution, and then the mixture was partitioned between CH2-
Cl2 and water. The organic extract was washed with water,
dried over MgSO4, and concentrated. The crude product was
dissolved in acetonitrile, treated with a catalytic amount of
triethylamine, stirred for 16 h, and concentrated. The residue
was chromatogaphed on silica gel to afford 369 mg (14% yield)
of 16: MS 448 (M + H)+; 1H NMR (CDCl3) δ 1.30 (s, 9H), 2.4-
2.5 (m, 2H), 2.8-3.0 (m, 2H), 3.73 (s, 3H), 3.87 (s, 3H), 3.95-
4.05 (s, 2H), 4.1-4.2 (m, 2H), 5.05-5.1 (m, 1H), 5.35 (d, 1H, J
) 6 Hz), 5.72 (s, 1H), 6.54 (s, 1H), 6.57 (s, 1H), 6.79 (s, 1H).
tr a n s-9,10-Dim eth oxy-2-(1,1-d im eth yleth yl)-4,5,5a ,6,7,-
11b -h exa h yd r o-1-t h ia -5-a za cyclop en t -2-en a [c]p h en a n -
th r en e (11j). To a solution of 390 mg (0.87 mmol) of 16 in 10
mL of a 3:1 mixture of acetic acid:water was added 570 mg of
Zn dust, and the suspension was stirred at 60 °C for 15 min.
The mixture was diluted with CH2Cl2 and water, made basic
by the addition of saturated NaHCO3 solution, and extracted
with CH2Cl2. The organic extract was washed with brine,
dried over MgSO4, and concentrated. The residue was chro-
matographed on silica gel, eluting with 85:5 CH2Cl2:methanol,
to afford 63 mg (20% yield) of 11j: MS 358 (M + H)+; 1H NMR
(CD3OD) δ 1.39 (s, 9H), 1.78-1.9 (m, 1H), 2.16-2.26 (m, 1H),
2.85-3.02 (m, 3H), 3.85 (s, 3H), 3.94 (s, 3H), 3.97 (d, 1H, J )
11 Hz), 4.06 (s, 2H), 6.54 (s, 1H), 6.64 (s, 1H), 7.47 (s, 1H).
tr a n s-2-(1,1-Dim eth yleth yl)-4,5,5a ,6,7,11b-h exa h yd r o-
1-th ia-5-azacyclopen t-2-en a[c]ph en an th r en e-9,10-diol Hy-
d r obr om id e (12j). Following the deprotection procedure
described for the conversion of 11b to 12b, the title compound
was prepared from 11j: mp 202-4 °C dec; MS (M + H)+ 330;
1H NMR (CD3OD) δ 1.41 (s, 9H), 1.9-2.0 (m, 1H), 2.26-2.4
(m, 1H), 2.85-2.95 (m, 2H), 3.35-3.48 (m, 1H), 4.28 (d, 1H, J
) 11 Hz), 4.35 (s, 2H), 6.62 (s, 1H), 6.76 (s, 1H), 7.35 (s, 1H).
Anal. (C19H24BrNO2S‚0.1HBr‚0.1H2O) C,H,N.
tr a n s-2-Eth yl-4,5,5a ,6,7,11b-h exa h yd r o-1-th ia -5-a za cy-
clop en t-2-en a [c]p h en a n th r en e-9,10-d iol h yd r obr om id e
1
(12c): mp 154-5 °C; MS 302 (M + H)+; H NMR (CD3OD) δ
1.32 (t, 3H, J ) 7 Hz), 1.88-2.02 (m, 1H), 2.3-2.4 (m, 1H),
2.75-3.0 (m, 4H), 3.42 (dt, 1H, J ) 5, 11 Hz), 4.29 (d, 1H, J )
11 Hz), 4.37 (s, 2H), 6.63 (s, 1H), 6.71 (s, 1H), 7.32 (s, 1H).
Anal. (C17H20BrNO2S) C,H,N.
tr a n s-2-P r op yl-4,5,5a ,6,7,11b-h exa h yd r o-1-th ia -5-a za -
cyclopen t-2-en a[c]ph en an th r en e-9,10-diol h ydr obr om ide
1
(12d ): mp 183-6 °C; MS 316 (M + H)+; H NMR (CD3OD) δ
1.0 (t, 3H, J ) 7 Hz), 1.72 (sx, 2H, J ) 7 Hz), 1.88-2.02 (m,
1H), 2.26-2.4 (m, 1H), 2.82 (t, 2H, J ) 7 Hz), 2.92 (t, 2H, J )
6 Hz), 3.36-3.5 (m, 1H), 4.30 (d, 1H, J ) 11 Hz), 4.36 (s, 2H),
6.62 (s, 1H), 6.71 (s, 1H), 7.32 (s, 1H); high-resolution MS calcd
316.1371, found 316.1384.
tr a n s-2-Bu tyl-4,5,5a ,6,7,11b-h exa h yd r o-1-th ia -5-a za cy-
clop en t-2-en a [c]p h en a n th r en e-9,10-d iol h yd r obr om id e
1
(12e): mp 111-2 °C; MS 330 (M + H)+; H NMR (CD3OD) δ
0.96 (t, 3H, J ) 7 Hz), 1.35-1.45 (m, 2H), 1.58-1.76 (m, 2H),
1.9-2.0 (m, 1H), 2.05-2.2 (m, 1H), 2.7-3.0 (m, 4H), 3.41 (dt,
1H, J ) 6 Hz), 4.28 (d, 1H, J ) 11 Hz), 4.38 (s, 2H), 6.62 (s,
1H), 6.70 (s, 1H), 7.33 (s, 1H). Anal. (C19H24BrNO2S‚0.2H2O).
tr a n s-2-Hexyl-4,5,5a ,6,7,11b-h exa h yd r o-1-th ia -5-a za cy-
clop en t-2-en a [c]p h en a n th r en e-9,10-d iol h yd r obr om id e
(12f): mp 165-70 °C; MS 358 (M + H)+; 1H NMR (CD3OD) δ
7.32 (s, 1H), 6.7 (s, 1H), 6.61 (s, 1H), 4.37 (s, 2H), 4.31 (d, J )
11 Hz, 1H), 3.42 (ddd, J ) 6, 11, 11 Hz, 1H), 3.0-2.9 (m, 2H),
2.82 (t, J ) 7 Hz, 2H), 2.4-2.3 (m, 1H), 2.05-1.9 (m, 1H),
1.72-1.6 (m, 2H), 1.4-1.2 (m, 6H), 0.94 (m, 3H).
tr a n s-2-Cycloh exyl-4,5,5a ,6,7,11b-h exa h yd r o-1-th ia -5-
a za cyclop en t-2-en a [c]p h en a n th r en e-9,10-d iol h yd r obr o-
m id e (12g): mp 195-6 °C; MS 356 (M + H)+; high-resolution
MS calcd for C21H26NO2S 356.1693, found 356.1684; 1H NMR
(CD3OD) δ 1.35-1.50 (m, 6H), 1.7-2.1 (m, 5H), 2.26-2.4 (m,
1H), 2.91 (t, 2H, J ) 6 Hz), 3.4 (dt, 1H, J ) 4, 11 Hz), 4.38 (d,
1H, J ) 11 Hz), 4.46 (s, 2H), 6.61 (s, 1H), 6.71 (s, 1H), 7.34 (s,
1H).
tr a n s-2-(1-Cyclopen tylm eth yl)-4,5,5a,6,7,11b-h exah ydr o-
1-th ia-5-azacyclopen t-2-en a[c]ph en an th r en e-9,10-diol h y-
d r obr om id e (12h ): mp 180-5 °C; MS 356 (M + H)+; 1H NMR
(CD3OD) δ 7.34 (s, 1H), 6.71 (s, 1H), 6.64 (s, 1H), 4.38 (s, 2H),
4.29 (d, J ) 11 Hz, 1H), 3.42 (ddd, J ) 6, 11, 11 Hz, 1H), 3.0-
2.8 (m, 2H), 2.83 (d, J ) 8 Hz, 2H), 2.4-2.26 (m, 1H), 2.22-
2.1 (m, 1H), 2.0-1.55 (m, 7H), 1.35-1.2 (m, 2H). Anal.
(C22H26BrClNO2S‚0.15HBr‚0.15EtOH) C,H,N.
cis-4,5,5a ,6,7,11b-Hexa h yd r o-1-th ia -5-a za cyclop en t-2-
en a [c]p h en a n t h r en e-9,10-d iol H yd r ob r om id e (17).
A
solution of 11a (72 mg, 0.24 mmol) in AcOH (3 mL) and 48%
HBr (3 mL) was stirred at reflux for 2 h, then cooled to ambient
temperature, and concentrated. Residual acetic acid was
removed by azeotroping with heptane. The residue was dried
overnight to give 83 mg (98%) of 17 as a tan solid: mp 193-4
tr a n s-2-Ch lor o-4,5,5a ,6,7,11b-h exa h yd r o-1-th ia -5-a za -
cyclopen t-2-en a[c]ph en an th r en e-9,10-diol h ydr obr om ide
1
(12i): mp 261-3 °C; MS 308 (M + H)+; H NMR (CD3OD) δ
7.18 (s, 1H), 6.95 (s, 1H), 6.52 (s, 1H), 4.39 (s, 2H), 4.33 (d, J
) 11 Hz, 1H), 3.46 (ddd, J ) 5, 11, 1 Hz, 1H), 2.95-2.88 (m,
1
°C dec; MS (M + H)+ 274; H NMR (CD3OD) δ 7.37 (d, J ) 6
2H), 2.4-2.27 (m, 1H), 2.05-1.85 (m, 1H). Anal. (C15H15
BrClNO2S‚0.1H2O) C,H,N.
-
Hz, 1H), 6.92 (d, J ) 6 Hz, 1H), 6.89 (s, 1H), 6.57 (s, 1H), 4.42
(d, J ) 6 Hz, 1H), 4.38 (d, J ) 16 Hz, 1H), 4.29 (d, J ) 16 Hz,
1H), 4.1 (m, 1H), 2.9-2.7 (m, 2H), 2.15-1.9 (m, 2H). Anal.
(C15H16BrNO2S‚0.2HBr) C,H,N.
5-(1,1-Dim eth yleth yl)-3-th ioph en ecar boxaldeh yde (14).
To a 0 °C solution of 13 (3.63 g, 32.4 mmol) in 60 mL of CH2-
Cl2 were added 9.17 g (80.9 mmol) of AlCl3 and 2-methyl-2-
bromopropane (4.66 g, 34 mmol). The solution was stirred at
room temperature for 16 h and at reflux for 4 h, then cooled
to room temperature, and poured into water. The mixture was
made basic with aqueous NaHCO3 and extracted with ether.
The ethereal extract was washed with water, dried over
MgSO4, concentrated, and chromatographed on silica gel,
eluting with 15:1 hexane:ethyl acetate, to afford 2.23 g (41%)
R ep r esen t a t ive E xa m p les of t h e P r ep a r a t ion of
Th iop h en es 18a -n . Met h od A: 5-(3-Met h ylb u t yl)-2-
th iop h en eca r boxylic Acid , N-ter t-Bu tyla m id e (18j). Iso-
pentyl bromide (8 g, 53 mmol) was added to 53 mL of an ice-
cooled solution of lithiothiophene (1.0 M in THF, 53 mmol).
The reaction mixture was stirred at 0 °C for 2 h and at room
temperature for 16 h, then poured into water, and extracted
with hexane. The organic layer was dried and concentrated,

TB[f]Q as Dopamine D1-Selective Agonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1595
and the residue was purified by column chromatography on
silica gel, eluting with hexane, to give 7.2 g (88% yield) of 2-(3-
methyl butyl)thiophene: 1H NMR (CDCl3) δ 7.10 (dd, J ) 1, 6
Hz, 1H), 6.90 (dd, J ) 4, 6 Hz, 1H), 6.78 (dd, J ) 1, 4 Hz, 1H),
2.84 (t, J ) 8 Hz, 2H), 1.7-1.5 (m, 3H), 0.94 (d, J ) 6 Hz, 6H).
1H, J ) 5 Hz), 7.5-7.4 (m, 2H), 7.35-7.10 (m, 3H), 2.4 (s, 3H).
This compound was converted to 18m following the procedures
described for the preparation of 18g.
The general procedure for preparing compounds 23a -n is
illustrated below for the synthesis of 23j.
3-(6,7-Dim eth oxy-2-n itr o-1,2,3,4-tetr ah ydr o-1-n aph th yl)-
5-(3-m eth ylbu tyl)-2-th iop h en eca r boxylic Acid , N-ter t-
Bu tyla m id e (19j). A 0 °C solution of 18j (2.3 g, 9.1 mmol) in
THF (20 mL) was treated with n-BuLi (7.3 mL, 2.5 M in
hexane, 18.2 mmol), stirred at 0 °C for 1 h, then cooled to -78
°C, and treated with a precooled (-78 °C) solution of 7 (2.1 g,
9.1 mmol) in THF (20 mL). The reaction mixture was stirred
at -78 °C for 1.5 h and then at 0 °C for 45 min and then the
reaction quenched with saturated NH4Cl. The mixture was
extracted twice with CH2Cl2, and the combined extracts were
dried over MgSO4 and concentrated. The residue was dis-
solved in acetonitrile (50 mL), treated with Et3N (0.3 mL), and
stirred overnight. The reaction mixture was concentrated and
purified via column chromatography eluting with 8:1 hexane:
ethyl acetate to give 2.7 g (61%) of 19j: MS 489 (M + H)+; 1H
NMR (CDCl3) δ 6.58 (s, 1H), 6.36 (s, 1H), 6.30 (s, 1H), 5.71
(bs, 1H), 5.47 (d, J ) 9 Hz, 1H), 5.05 (m, 1H), 3.85 (s, 3H),
3.68 (s, 3H), 3.05-2.85 (m, 2H), 2.68 (t, J ) 9 Hz, 2H), 2.5-
2.35 (m, 2H), 1.6-1.45 (m, 3H), 1.42 (s, 9H), 0.91 (d, J ) 6
Hz, 3H), 0.90 (s, J ) 6 Hz, 3H).
3-(2-Am in o-6,7-d im et h oxy-1,2,3,4-t et r a h yd r o-1-n a p h -
th yl)-5-(3-m eth ylbu tyl)-2-th iop h en eca r boxylic Acid , N-
ter t-Bu tyla m id e (20j). Following the procedure described for
the reduction of 9b to 10b, 19j (2.7 g, 5.5 mmol) was converted
to 20j (1.88 g, 75% yield): MS 459 (M + H)+; 1H NMR (CDCl3)
δ 6.60 (s, 1H), 6.30 (s, 1H), 6.20 (s, 1H), 4.51 (d, J ) 10 Hz,
1H), 3.86 (s, 3H), 3.64 (s, 3H), 3.36-3.25 (m, 1H), 3.1-2.8 (m,
2H), 2.70 (t, J ) 9 Hz, 2H), 2.3-2.2 (m, 1H), 2.0-1.85 (m, 1H),
1.7-1.5 (m, 3H), 1.42 (s, 9H), 0.89 (d, J ) 6 Hz, 3H), 0.88 (d,
J ) 6 Hz, 3H).
n-BuLi (13 mL, 2.5 M in hexanes, 32.4 mmol) was added to
an ice cold solution of 2-(3-methylbutyl)thiophene (5 g, 32.4
mmol) in THF (50 mL), and the resulting solution was stirred
at 0 °C for 1 h, then cooled to -78 °C, and treated with tert-
butyl isocyanate (3.5 g, 35.6 mmol). The reaction mixture was
allowed to warm up to 0 °C over 2 h; then the reaction was
quenched with water and extracted with EtOAc. The extract
was dried, concentrated, and purified via silica gel column
chromatography eluting with 3:1 hexane:ethyl acetate to afford
6.4 g of 18j as a white solid: MS 254 (M + H)+, 271 (M +
NH4)+; 1H NMR (CDCl3) δ 7.24 (d, J ) 4 Hz, 1H), 6.72 (d, J )
4 Hz, 1H), 5.7 (bs, 1H), 2.82 (t, J ) 8 Hz, 2H), 1.7-1.5 (m,
3H), 1.44 (s, 9H), 0.93 (d, J ) 6 Hz, 6H).
Meth od B: 5-(1,1-Dim eth yleth yl)-2-th iop h en eca r boxy-
lic Acid , N-ter t-Bu tyla m id e (18g). To a 0 °C solution of 5.0
g (39.02 mmol) of 24 in 100 mL of CH2Cl2 were added 11 g
(82.5 mmol) of AlCl3 and 5.8 g (43.0 mmol) of tert-butyl
bromide. The solution was stirred at room temperature for
18 h and then poured into 100 mL of ice water, and the mixture
was extracted with ether. The extracts were washed with
brine, dried over MgSO4, and then concentrated to give 3.33 g
(46%) of 5-tert-butyl-2-thiophenecarboxylic acid: MS (M + H)+
1
202; H NMR (CDCl3) δ: 1.42 (s, 9H), 6.89 (d, 1H, J ) 4 Hz),
7.72 (d, 1H, J ) 4 Hz).
A solution of this compound (3.1 g, 16.8 mmol) in CHCl3
(60 mL) was treated with SOCl2 (3.7 mL, 50.5 mmol), stirred
at reflux for 4 h, and then concentrated. The residue was
dissolved in CHCl3 (60 mL), then treated with tert-butylamine
(5.3 mL, 50.5 mmol), and stirred at reflux overnight. The
reaction mixture was partitioned between CH2Cl2 and water,
and the extract was washed with water and brine, dried,
concentrated, and then purified via silica gel chromatography
to yield 2.92 g (73%) of 18g: MS 240 (M + H)+; 1H NMR
(CDCl3) δ 7.25 (d, J ) 4 Hz, 1H), 6.78 (d, J ) 4 Hz, 1H), 5.70
(bs, 1H), 1.45 (s, 9H), 1.39 (s, 9H).
Meth od C: 5-(3-Meth ylp h en yl)-2-th iop h en eca r boxylic
Acid , N-ter t-Bu t yla m id e (18m ). A -78 °C solution of
3-bromotoluene (5.8 g, 34 mmol) in THF (50 mL) was treated
with n-BuLi (15 mL, 2.5 M in hexanes, 37 mmol), stirred at
-78 °C for 30 min, and then treated with B(OMe)3 (10.6 g,
102 mol). The reaction mixture was allowed to warm up to
room temperature, stirred overnight, and then cooled in ice
water and the reaction quenched with 2 N HCl. The mixture
was extracted with CH2Cl2, washed with brine, dried, and
concentrated to give 4.24 g (92% yield) of 3-methylphenylbo-
ronic acid.
A suspension of 907 mg (0.78 mmol) of Pd(PPh3)4 and 25
(5.09 g, 26.2 mmol) in 50 mL of DME was stirred at room
temperature for 15 min and then treated with a solution of
freshly prepared 3-methylphenylboronic acid (4.24 g, 31.2
mmol) in 10 mL of ethanol and 26 mL of 2 M aqueous Na2-
CO3. The reaction mixture was stirred at reflux for 24 h, then
cooled to room temperature, diluted, and extracted with ether.
The organic extract was washed with water and brine, dried
over MgSO4, and concentrated. The residue was purified by
flash chromatography on silica gel, eluting with 5% ethyl
acetate in hexane, to give 4.75 g (90% yield) of 5-(3-methyl-
phenyl)-2-thiophenecarboxaldehyde: MS 203 (M + H)+, 220
(M + NH4)+; 1H NMR (CDCl3) δ 9.89 (s, 1H), 7.74 (d, 1H, J )
5 Hz), 7.55-7.20 (m, 5H), 2.42 (s, 3H).
A solution of this compound (4.7 g, 23.3 mmol) was dissolved
in 100 mL of ethanol and sequentially treated with a solution
of AgNO3 (7.9 g, 116.5 mmol) in 15 mL of water and a solution
of KOH (6.5 g, 116.5 mmol) in 100 mL of water. The
suspension was stirred at room temperature for 1 h and then
filtered, and the filter cake was washed with water and ether.
The filtrate was separated, and the aqueous layer was acidified
with concentrated HCl to pH 4 and extracted twice with ether.
The ethereal extract was dried over MgSO4 and concentrated
to give 4.6 g (96% yield) of 5-(3-methylphenyl)-2-thiophenecar-
boxylic acid: MS 236 (M + NH4)+; 1H NMR (CDCl3) δ 7.86 (d,
tr a n s-2-(3-Meth ylbu tyl)-4,5,5a,6,7,11b-h exah ydr o-3-th ia-
4-oxo-5-a za -9,10-d im et h oxycyclop en t -1-en a [c]p h en a n -
th r en e (21j). To a solution of 1.87 g (4.1 mmol) of 20j in 100
mL of toluene was added p-TsOH‚H2O (1.55 g, 8.2 mmol), and
the reaction mixture was stirred at reflux for 48 h. The
reaction mixture was cooled to room temperature, diluted with
ethyl acetate, washed with aqueous NaHCO3, H2O, and brine,
then dried over Na2SO4, and concentrated under vacuum. The
crude product was crystallized from ethanol to give 0.91 g (60%
yield) of 21j as a white solid: MS 386 (M + H)+, 403 (M +
1
NH4)+; H NMR (CDCl3) δ 7.14 (s, 1H), 7.13 (s, 1H), 6.67 (s,
1H), 5.95 (s, 1H), 4.14 (d, J ) 12 Hz, 1H), 3.94 (s, 3H), 3.88 (s,
3H), 3.75 (ddd, J ) 3, 12, 12 Hz, 1H), 3.0-2.76 (m, 4H), 2.1-
1.9 (m, 2H), 1.7-1.55 (m, 3H), 0.95 (d, J ) 6 Hz, 6H).
tr a n s-2-(3-Meth ylbu tyl)-4,5,5a,6,7,11b-h exah ydr o-3-th ia-
5-a za -9,10-d im et h oxycyclop en t -1-en a [c]p h en a n t h r en e
(22j). A suspension of 21j (0.91 g, 2.3 mmol) in THF (12 mL)
was treated with BH3‚THF (12 mL, 1 M solution in THF, 12
mmol) resulting in a clear solution which was then stirred at
reflux for 14 h. The reaction mixture was cooled in an ice bath
and then the reaction quenched with 10 mL of a ca. 1 M
solution of anhydrous HCl in MeOH. After being stirred at
reflux for 4 h, the reaction mixture was poured into aqueous
NaHCO3 and extracted with CH2Cl2 twice. The combined
organic extracts were washed with water and brine, dried, and
concentrated. The residue was purified via silica gel chroma-
tography to afford 0.85 g (97%) of 22j as a white solid: mp
1
110-2 °C; MS 372 (M + H)+; H NMR (CDCl3) δ 7.0 (s, 1H),
6.89 (s, 1H), 6.72 (s, 1H), 4.05 (s, 2H), 3.88 (s, 3H), 3.82 (s,
3H), 3.56 (d, J ) 11 Hz, 1H), 3.0-2.6 (m, 5H), 2.3-2.15 (m,
1H), 1.8-1.5 (m, 4H), 0.95 (d, J ) 6 Hz, 6H). Anal. (C22H29
NO2S) C,H,N.
-
tr a n s-2-(3-Meth ylbu tyl)-4,5,5a,6,7,11b-h exah ydr o-3-th ia-
5-a za cyclop en t-1-en a [c]p h en a n th r en e-9,10-d iol Hyd r o-
br om id e (23j). Following the procedure described for the
preparation of 12b, 22j (484 mg, 1.3 mmol) was deprotected
with BBr3 (5.2 mL, 1 M solution in CH2Cl2) to afford 426 mg
of 23j: mp 73-5 °C; MS 344 (M + H)+; 1H NMR (CDCl3) δ
7.01 (s, 1H), 6.98 (s, 1H), 6.67 (s, 1H), 4.45 (s, 2H), 4.0 (d, J )
11 Hz, 1H), 3.28-3.15 (m, 1H), 3.0-2.8 (m, 4H), 2.4-2.25 (m,
1H), 2.0-1.8 (m, 2H), 1.7-1.58 (n, 2H), 0.98 (d, J ) 6 Hz, 6H).
Anal. (C20H26BrNO2S‚0.5H2O) C,H,N.

1596 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Michaelides et al.
The following compounds 23a-n were prepared from 18a-n
following the procedures described for 23j.
tr a n s-2-P h en yl-4,5,5a ,6,7,11b-Hexa h yd r o-3-th ia -5-a za -
cyclopen t-1-en a[c]ph en an th r en e-9,10-diol h ydr obr om ide
1
(23l): mp 204-5 °C; MS 350 (M + H)+; H NMR (CD3OD) δ
tr a n s-4,5,5a ,6,7,11b-h exa h yd r o-3-th ia -5-a za cyclop en t-
1-en a [c] p h en a n th r en e-9,10-d iol h yd r obr om id e (23a ):
mp 185 °C; MS 274 (M + H)+; 1H NMR (CD3OD) δ 7.59 (d,
1H, J ) 3 Hz), 7.32 (d, 1H, J ) 3 Hz), 6.88 (s, 1H), 4.58 (d,
1H, J ) 8 Hz), 4.52 (d, 1H, J ) 8 Hz), 4.10 (d, 1H, J ) 6 Hz),
3.25 (m, 1H), 2.98 (m, 1H), 2.84 (m, 1H), 2.37 (m, 1H), 1.96
(m, 1H). Anal. (C15H16BrNO2S‚0.2HBr) C,H,N.
1.9-2.05 (m, 1H), 2.32-2.44 (m, 1H), 2.8-3.06 (m, 2H), 3.2-
3.3 (m, 1H), 4.12 (d, 1H, J ) 11 Hz), 4.52 (d, 1H, J ) 15 Hz),
4.60 (d, 1H, J ) 15 Hz), 6.68 (s, 1H), 6.97 (s, 1H), 7.3-7.5 (m,
3H), 7.58 (s, 1H), 7.66-7.75 (m, 2H). Anal. (C21H20
BrNO2S‚0.2HBr) C,H,N.
-
2-(3-Meth ylp h en yl)-4,5,5a ,6,7,11b-h exa h yd r o-3-th ia -5-
a za cyclop en t-1-en a [c]p h en a n th r en e-9,10-d iol h yd r obr o-
m id e (23m ): mp 214-5 °C; MS 364 (M + H)+; 1H NMR
(CD3OD) δ 7.6-7.4 (m, 2H), 7.32 (t, 1H, J ) 7 Hz), 7.16 (d,
1H, J ) 7 Hz), 6.97 (s, 1H), 6.68 (s, 1H), 4.56 (m, 2H), 4.10 (d,
1H, J ) 11 Hz), 3.3-3.2 (m, 1H), 3.1-2.8 (m, 2H), 2.40 (s, 3H),
tr a n s-2-Meth yl-4,5,5a ,6,7,11b-h exa h yd r o-3-th ia -5-a za -
cyclopen t-1-en a[c]ph en an th r en e-9,10-diol h ydr obr om ide
1
(23b): mp 223-5 °C; MS 288 (M + H)+; H NMR (CD3OD) δ
7.0 (s, 1H), 6.89 (s, 1H), 6.68 (s, 1H), 4.4 (s, 2H), 4.01 (d, 1H,
J ) 11 Hz), 3.20 (m, 1H), 3.02-2.80 (m, 2H), 2.35 (s, 3H), 2.45-
2.20 (m, 1H), 2.0-1.85 (m, 1H). Anal. (C16H18BrNO2S‚0.2HBr)
C,H,N.
2.4-2.2 (m, 1H), 2.05-1.9 (m, 1H). Anal. (C22H22
BrNO2S‚0.2HBr) C,H,N.
-
tr a n s-2-Ch lor o-4,5,5a ,6,7,11b-h exa h yd r o-3-th ia -5-a za -
cyclopen t-2-en a[c]ph en an th r en e-9,10-diol h ydr obr om ide
tr a n s-2-Eth yl-4,5,5a ,6,7,11b-h exa h yd r o-3-th ia -5-a za cy-
clop en t-1-en a [c]p h en a n th r en e-9,10-d iol h yd r obr om id e
1
1
(23n ): mp 255-7 °C; MS 308 (M + H)+; H NMR (CD3OD) δ
(23c): mp 235-6 °C; MS 302 (M + H)+; H NMR (CD3OD) δ
7.24 (s, 1H), 6.81 (s, 1H), 6.67 (s, 1H), 4.52-4.40 (m, 2H), 4.04
(d, J ) 11 Hz, 1H), 3.30-3.18 (m, 1H), 3.02-2.77 (m, 2H),
7.20 (s, 1H), 6.90 (s, 1H), 6.67 (s, 1H), 4.46 (s, 2H), 4.02 (d,
1H, J ) 11 Hz), 3.2 (m, 1H), 3.0-2.8 (m, 4H), 2.40-2.28 (m,
2.40-2.28 (m, 1H), 2.00-1.85 (m, 1H). Anal. (C15H15
BrClNO2S) C,H,N.
-
1H), 2.20-1.86 (m, 1H), 1.36 (t, 3H, J ) 7 Hz). Anal. (C17H20
BrNO2S‚0.10HBr) C,H,N.
-
3-Th iop h en eca r boxylic Acid , N,N-Dieth yla m id e (26).
A solution of 3-thiophenecarboxylic acid (5.0 g, 39 mmol) in
CHCl3 (20 mL) was treated with 10 mL (134 mmol) of SOCl2.
After being stirred at reflux for 3 h, the reaction mixture was
concentrated, redissolved in 15 mL of CH2Cl2, cooled in an ice
bath, and then treated with Et2N (13 mL, 126 mmol). The
reaction mixture was stirred at room temperature for 1 h.
Water was added, and the mixture was extracted with CH2-
Cl2, which was washed with aqueous NaHCO3 solution, water,
and brine, concentrated, and purified by flash chromatography
on silica gel, eluting with 6:1 hexane:ethyl acetate, to afford
6.34 g (89%) of 26: 1H NMR (CDCl3) δ 7.48 (dd, 1H, J ) 1, 3
Hz), 7.32 (dd, 1H, J ) 3, 6 Hz), 7.20 (dd, 1H, J ) 1, 6 Hz),
3.60-3.30 (bs, 4H), 1.20 (bm, 6H).
2-(Tr im eth ylsilyl)-3-th iop h en eca r boxylic Acid , N,N-
Dieth yla m id e (27). To a -78 °C solution of 3 g (16.4 mmol)
of 26 in 20 mL of THF was added 1.68 g (2.1 mL, 16.4 mmol)
of TMEDA followed by 12.6 mL of a 1.3 M solution of s-BuLi
in cyclohexane (16.4 mmol), and the reaction mixture was
stirred for 1 h. Chlorotrimethylsilane (2.1 mL, 16.4 mmol) was
added, and the solution was stirred for 45 min and then poured
into 100 mL of water. The mixture was extracted three times
with CH2Cl2, and the solvent was washed with brine, dried
over MgSO4, concentrated, and purified by flash chromatog-
raphy, eluting with 3:1 hexane:ethyl acetate, to afford 1.4 g
(38% yield) of 27: MS 256 (M + H)+; 1H NMR (CDCl3) δ 7.51
(d, 1H, J ) 5 Hz), 7.10 (d, 1H, J ) 5 Hz), 3.60-3.50 (bm, 2H),
3.3-3.10 (bm, 2H), 1.30-1.20 (bm, 3H), 1.15-1.05 (bm, 3H),
0.34 (s, 9H).
tr a n s-4-(1,2,3,4-Tetr ah ydr o-6,7-dim eth oxy-2-n itr on aph -
th alen -1-yl)-2-(tr im eth ylsilyl)-3-th ioph en ecar boxylic Acid,
N,N-Dieth yla m id e (28). To a -78 °C solution of 27 (1.4 g,
5.49 mmol) in 15 mL of THF was added TMEDA (0.7 mL, 5.5
mmol) followed by s-BuLi (4.2 mL, 1.3 M in cyclohexane, 5.5
mmol), and the reaction mixture was stirred for 40 min. To
this solution was added a solution of 1.30 g of 7 (5.49 mmol)
in 20 mL of THF, and the reaction mixture was stirred at -78
°C for 1 h and at -20 °C for 1.5 h; then the reaction was
quenched by the addition of saturated NH4Cl. The mixture
was diluted with water and extracted with CH2Cl2. The
solvent layer was washed with brine, dried over MgSO4, and
concentrated. The residue was dissolved in 50 mL of aceto-
nitrile, 1 mL of triethylamine was added, and the reaction
mixture was stirred for 16 h. The solvent and amine were
removed by evaporation, and the residue was purified by flash
chromatography over silica gel to afford 554 mg (20%) of 28.
tr a n s-9,10-Dim eth oxy-4,5,5a ,6,7,11b-h exa h yd r o-4-oxo-
2-th ia -5-a za cyclop en t-3-en a [c]p h en a n th r en e (29). To a
solution of 554 mg (1.13 mmol) of 28 in 8 mL of ethanol and 3
mL of 6 N HCl was added 700 mg of Zn dust, and the mixture
was stirred for 15 min. The mixture was diluted with 20 mL
of CH2Cl2 and then filtered. The organic layer of the filtrate
was separated. The aqueous layer was adjusted to pH 10 and
extracted with CH2Cl2. The extract was dried over Na2SO4,
tr a n s-2-P r op yl-4,5,5a ,6,7,11b-h exa h yd r o-3-th ia -5-a za -
cyclopen t-1-en a[c]ph en an th r en e-9,10-diol h ydr obr om ide
1
(23d ): mp 133-4 °C; MS 316 (M + H)+; H NMR (CD3OD) δ
1.03 (t, 3H, J ) 8 Hz), 1.75 (sx, 2H, J ) 8 Hz), 1.9-2.0 (m,
1H), 2.28-2.41 (m, 1H), 2.87 (t, 2H, J ) 8 Hz), 2.88-3.05 (m,
2H), 3.15-3.27 (m, 1H), 4.02 (d, 1H, J ) 11 Hz), 4.46 (s, 2H),
6.67 (s, 1H), 6.90 (s, 1H), 7.02 (s, 1H). Anal. (C18H22
-
BrNO2S‚0.3H2O) C,H,N.
tr a n s-2-Bu tyl-4,5,5a ,6,7,11b-h exa h yd r o-3-th ia -5-a za cy-
clop en t-1-en a [c]p h en a n th r en e-9,10-d iol h yd r obr om id e
1
(23e): mp 152-3 °C; MS 330 (M + H)+; H NMR (CD3OD) δ
0.98 (t, 3H, J ) 7 Hz), 1.35-1.5 (m, 2H), 1.6-1.8 (m, 2H),
1.85-2.0 (m, 1H), 2.26-2.4 (m, 1H), 2.76-3.05 (m, 4H), 3.16-
3.26 (m, 1H), 4.01 (d, 1H, J ) 11 Hz), 4.46 (s, 2H), 6.67 (s,
1H), 6.89 (s, 1H), 7.02 (s, 1H). Anal. (C19H24BrNO2S‚0.6H2O)
C,H,N.
tr a n s-2-P en t yl-4,5,5a ,6,7,11b -h exa h yd r o-3-t h ia -5-a za -
cyclopen t-1-en a[c]ph en an th r en e-9,10-diol h ydr obr om ide
1
(23f): mp 78-80 °C; MS 344 (M + H)+; H NMR (CD3OD) δ
7.01 (s, 1H), 6.89 (s, 1H), 6.66 (s, 1H), 4.46 (bs, 2H), 4.02 (d, J
) 11 Hz, 1H), 3.3-3.15 (m, 1H), 3.05-2.8 (m, 4H), 2.4-2.3
(m, 1H), 2.0-1.9 (m, 1H), 1.8-1.65 (m, 2H), 1.5-1.3 (m, 4H),
0.94 (t, J ) 6 Hz, 3H). Anal. (C20H26BrNO2S‚0.8H2O‚0.1HBr)
C,H,N.
tr a n s-2-(1,1-Dim eth yleth yl)-4,5,5a ,6,7,11b-h exa h yd r o-
3-th ia-5-azacyclopen t-1-en a[c]ph en an th r en e-9,10-diol h y-
d r obr om id e (23g): mp 197-8 °C; MS 330 (M + H)+; 1H NMR
(CD3OD) δ 1.46 (s, 9H), 1.86-2.02 (m, 1H), 2.29-2.43 (m, 1H),
2.78-3.04 (m, 2H), 3.16-3.28 (m, 1H), 4.02 (d, 1H, J ) 11 Hz),
4.46 (s, 2H), 6.68 (s, 1H), 6.88 (s, 1H), 7.03 (s, 1H). Anal.
(C19H24BrNO2S‚0.6H2O) C,H,N.
tr a n s-2-(2-P r op yl)-4,5,5a ,6,7,11b -h exa h yd r o-3-t h ia -5-
a za cyclop en t-1-en a [c]p h en a n th r en e-9,10-d iol h yd r obr o-
m id e (23h ): mp 186-7 °C; MS 316 (M + H)+; 1H NMR
(CD3OD) δ 1.39 (d, 6H, J ) 7 Hz), 1.87-2.02 (m, 1H), 2.28-
2.43 (m, 1H), 2.8-3.28 (m, 4H), 4.03 (d, 1H, J ) 11 Hz), 4.47
(s, 2H), 6.68 (s, 1H), 6.89 (s, 1H), 7.03 (s, 1H). Anal. (C18H22
-
BrNO2S‚0.4H2O) C,H,N.
tr a n s-2-(2-Met h ylp r op yl)-4,5,5a ,6,7,11b -h exa h yd r o-3-
th ia -5-a za cyclop en t-1-en a [c]p h en a n th r en e-9,10-d iol h y-
d r obr om id e (23i): mp 164-5 °C; MS 330 (M + H)+; 1H NMR
(CD3OD) δ 0.98 (d, 3H, J ) 7 Hz), 1.01 (d, 3H, J ) 7 Hz), 1.01
(d, 3H, J ) 7 Hz), 1.85-2.0 (m, 2H), 2.27-2.4 (m, 1H), 2.75
(d, 2H, J ) 7 Hz), 2.8-3.05 (m, 2H), 3.15-3.28 (m, 1H), 4.02
(d, 1H, J ) 11 Hz), 4.48 (s, 2H), 6.67 (s, 1H), 6.89 (s, 1H), 7.00
(s, 1H). Anal. (C19H24BrNO2S‚0.1HBr) C,H,N.
tr a n s-2-Cycloh exyl-4,5,5a ,6,7,11b-h exa h yd r o-3-th ia -5-
a za cyclop en t-1-en a [c]p h en a n th r en e-9,10-d iol h yd r obr o-
m id e (23k ): mp 191-2 °C; MS 356 (M + H)+; 1H NMR
(CD3OD) δ 1.2-1.5 (m, 6H), 1.7-2.2 (m, 5H), 2.28-2.4 (m, 1H),
2.8-3.04 (m, 2H), 3.15-3.3 (m, 1H), 4.02 (d, 1H, J ) 11 Hz),
4.46 (s, 2H), 6.67 (s, 1H), 6.89 (s, 1H), 7.02 (s, 1H). Anal.
(C21H26BrNO2S‚0.1H2O‚0.2HBr) C,H,N.

TB[f]Q as Dopamine D1-Selective Agonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1597
filtered, and concentrated. The residue was dissolved in 7 mL
of methanol, 3 mL of 6 N HCl was added, and the solution
was stirred for 4 h. The methanol was evaporated off, and
the residue was dissolved in 6 mL of water, which was then
extracted with ether. The aqueous layer was adjusted to pH
10 and extracted with ethyl acetate. Removal of the solvent
gave 256 mg (66%) of trans-4-(2-amino-1,2,3,4-tetrahydro-6,7-
dimethoxynaphthalen-1-yl)-3-thiophenecarboxylic acid, N,N-
diethylamide.
of 35: 1H NMR (CDCl3) δ 7.09 (s, 1H), 4.69 (s, 2H), 4.52 (s,
2H), 3.44 (s, 3H), 2.88-2.82 (m, 2H), 1.75-1.62 (m, 2H), 0.99
(t, J ) 7 Hz, 3H).
4-(6,7-Dim et h oxy-2-n it r o-1,2,3,4-t et r a h yd r on a p h t h -1-
yl)-3-[(m eth oxym eth oxy)m eth yl]-2-pr op ylth iop h en e (36).
A -78 °C solution of 35 (0.75 g, 2.7 mmol) in ether (20 mL)
was treated with n-BuLi (1.07 mL, 2.5 M in hexane, 2.7 mmol),
stirred at -78 °C for 0.5 h, and then treated with a precooled
solution of 7 (0.63 g, 2.7 mmol) in THF (10 mL). The reaction
mixture was stirred at -78 °C for 1 h, gradually turning into
a suspension, and at 0 °C for 0.5 h, after which the reaction
was quenched with saturated NH4Cl and extracted with CH2-
Cl2. The extract was dried and concentrated. The residue was
dissolved in CH3CN, treated with Et3N, stirred overnight,
concentrated, and purified via silica gel column chromatogra-
To a solution of 240 mg (0.6 mmol) of this compound in 10
mL of toluene was added 2 mL of trimethylaluminum, and
the solution was heated at reflux for 2 h. The solution was
cooled to room temperature, and the reaction was quenched
by addition of Na2SO4‚10H2O followed by addition of K2CO3
and stirring for 20 min. The mixture was filtered, and the
filtrate was evaporated. The residue was dissolved in ethyl
acetate and washed with saturated Na2CO3 and brine. The
solvent was removed, and the material was purified by flash
chromatography on silica gel, eluting with 100:5:0.5 CH2Cl2:
EtOH:NH4OH, to afford 170 mg (90%) of 29: MS 316 (M +
1
phy to afford 0.67 g (57%) of 36: MS 453 (M + H)+; H NMR
(CDCl3) δ 6.59 (s, 1H), 6.56 (s, 1H), 6.39 (s, 1H), 5.2-5.15 (m,
1H), 4.91 (d, J ) 6 Hz, 1H), 4.63 (d, J ) 6 Hz, 1H), 4.58 (d, J
) 6 Hz, 1H), 4.48 (d, J ) 11 Hz, 1H), 4.35 (d, J ) 11 Hz, 1H),
3.86 (s, 3H), 3.68 (s, 3H), 3.37 (s, 3H), 2.95-2.85 (m, 2H), 2.81
(t, J ) 7 Hz, 2H), 2.5-2.3 (m, 2H), 1.68 (sx, J ) 7 Hz, 2H),
0.97 (t, J ) 7 Hz, 3H).
1
H)+; H NMR (CDCl3) δ 7.53 (d, 1H, J ) 6 Hz), 7.36 (s, 1H),
7.17 (d, 1H, J ) 6 Hz), 6.65 (s, 1H), 5.75 (bs, 1H), 4.49 (d, 1H,
J ) 12 Hz), 3.98 (s, 3H), 3.88 (s, 3H), 3.80 (dd, 1H, J ) 4, 12
Hz), 3.15-2.80 (m, 2H), 2.10-1.95 (m, 2H).
9,10-Dim et h oxy-3-p r op yl-4,5,5a ,6,7,11b -h exa h yd r o-2-
th ia -5-a za cyclop en t-3-en a [c]p h en a n th r en e (38). To a
solution of 36 (0.38 g, 0.9 mmol) in 6 mL of EtOH and 1 mL of
6 M HCl was added Zn (0.6 g, 9 mmol). After being stirred at
room temperature, the reaction mixture was filtered, and the
filtrate was concentrated and partitioned between aqueous
NaHCO3 and CH2Cl2. The organic layer was dried, concen-
trated, and then dissolved in 10 mL of THF, 0.5 mL of 12 N
HCl was added, and the mixture was stirred at reflux for 1.5
h. Removal of the solvent gave the intermediate chloro
compound 37, which was immediately dissolved in tert-butyl
alcohol, treated with Na2CO3 (1.0 g, 7.1 mmol), and stirred at
reflux for 30 min. The mixture was cooled to room tempera-
ture, poured into water, and extracted with CH2Cl2. The
solvent was dried and removed by evaporation. The residue
was purified by silica gel chromatography, eluting with CH2-
Cl2:methanol 97:3, to afford 184 mg (62% overall) of 38: MS
tr a n s-9,10-Dim eth oxy-4,5,5a ,6,7,11b-h exa h yd r o-2-th ia -
5-a za cyclop en t-3-en a [c]p h en a n th r en e (30). A sample (170
mg, 0.54 mmol) of 29 was reduced to 30 (74 mg, 46%) following
the procedure described for the conversion of 21j to 22j: MS
1
302 (M + H)+; H NMR (CDCl3) δ 7.48 (s, 1H), 7.20 (d, 1H, J
) 6 Hz), 6.84 (d, 1H, J ) 6 Hz), 6.67 (s, 1H), 4.14 (s, 2H), 3.98
(d, 1H, J ) 9 Hz), 3.95 (s, 3H), 3.88 (s, 3H), 3.0-2.8 (m, 3H),
2.22-2.14 (m, 1H), 1.9-1.78 (m, 1H).
tr a n s-4,5,5a ,6,7,11b-Hexa h yd r o-2-th ia -5-a za cyclop en t-
3-en a [c]p h en a n th r en e-9,10-d iol Hyd r obr om id e (31). Fol-
lowing the procedure described for the deprotection of 11b to
12b, 30 (74 mg, 0.24 mmol) was converted to 81 mg (90%) of
31: MS 274 (M + H)+; 1H NMR (CD3OD) δ 7.38 (d, 1H, J ) 6
Hz), 6.92 (d, 1H, J ) 6 Hz), 6.90 (s, 1H), 6.58 (s, 1H), 4.45-
4.20 (m, 3H), 4.10 (m, 1H), 3.0-2.8 (m, 2H), 2.2-1.95 (m, 2H).
Anal. (C15H16BrNO2S‚0.30HBr) C,H,N.
1
344 (M + H)+; H NMR (CDCl3) δ 7.23 (s, 1H), 7.10 (d, J ) 1
Hz, 1H), 6.80 (s, 1H), 4.13 (d, J ) 15 Hz, 1H), 3.95 (d, J ) 15
Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.71 (d, J ) 11 Hz, 1H),
3.60-3.52 (m, 1H), 2.88 (t, J ) 7 Hz, 2H), 2.75-2.65 (m, 2H),
2.22-2.10 (m, 1H), 1.9-1.6 (m, 3H), 1.0 (t, J ) 7 Hz, 3H).
3-P r op yl-4,5,5a ,6,7,11b -h exa h yd r o-2-t h ia -5-a za cyclo-
pen t-3-en a[c]ph en an th r en e-9,10-diol Tr iflu or oacetate Salt
(39). Following the procedures described for the preparation
of 12b, 38 was reacted with BBr3 to give 39 as a 1:1 mixture
of cis:trans isomers. The mixture was purified by reverse
phase HPLC, eluting with 1:1 methanol:0.1% TFA to give the
trans isomer: mp 114-6 °C; MS 316 (M + H)+; 1H NMR (CD3-
OD) δ 7.27 (d, J ) 1 Hz, 1H), 7.11 (s, 1H), 6.64 (s, 1H), 4.43
(d, J ) 14 Hz, 1H), 4.34 (d, J ) 14 Hz, 1H), 4.10 (d, J ) 11 Hz,
1H), 3.14 (td, J ) 11, 6 Hz, 1H), 2.9-2.75 (m, 4H), 2.35-2.24
(m, 1H), 2.0-1.85 (m, 1H), 1.71 (sx, J ) 7 Hz, 2H), 1.02 (t, J
) 7 Hz, 3H); high-resolution MS calcd for C18H22NO2S (M +
H)+ 316.1371, found 316.1374.
3-Br om o-4-p r op ylth iop h en e (40). A solution of 3,4-
dibromothiophene (32) (15.3 g, 63.3 mmol) in 50 mL of ether
was cooled to -78 °C and treated with n-BuLi (25.3 mL, 2.5
M solution in hexanes, 66.5 mmol). While holding the tem-
perature at -78 °C, the reaction mixture was stirred for 15
min, then 7.8 g (66.5 mmol) of N-methyl-N-methoxypropiona-
mide was added to the resulting suspension, and the reaction
mixture was stirred for 1 h. The reaction was quenched with
saturated NH4Cl, and the mixture was diluted with ether. The
ether layer was separated, washed with water and brine, dried
over MgSO4, and concentrated. The residue was recrystallized
4-Br om o-2-pr opyl-3-th ioph en ecar boxaldeh yde (34). To
a solution of diisopropylamine (2.7 mL, 19.4 mmol) in 50 mL
of THF cooled to -78 °C was added 7.8 mL (2.5 M in hexane,
19.4 mmol) of n-butyllithium, and the reaction mixture was
stirred for 0.5 h. To the solution was added 4.7 g (19.4 mmol)
of 3,4-dibromothiophene (32); then the reaction mixture was
stirred for 1 h at -78 °C. Iodopropane (2.8 mL, 29.1 mmol)
was then added; the reaction mixture was stirred for 10 min
at -78 °C and then stirred for 2 h at room temperature. The
reaction was quenched with aqueous saturated NH4Cl, ex-
tracted with ether, washed with H2O and brine, and concen-
trated to give 5.27 g of crude 33. This compound (5.25 g, 18.5
mmol) was dissolved in 80 mL of ether and cooled to -78 °C.
n-BuLi (7.4 mL, 18.5 mmol) was added dropwise via syringe,
and the resulting mixture was stirred at -78 °C for 20 min.
DMF was added (1.86 mL, 24.03 mmol), and the reaction
mixture was stirred at -78 °C for 1 h, then poured into water,
and extracted with ether. The extract was washed with water,
dried over MgSO4, and concentrated in vacuo. Silica gel
column chromatography afforded 0.63 g (15%) of 34: 1H NMR
(CDCl3) δ 10.07 (s, 1H), 7.09 (s, 1H), 3.20 (t, J ) 7 Hz, 2H),
1.74 (m, 2H), 1.02 (t, J ) 7 Hz, 3H).
4-Br om o-3-[(m e t h oxym e t h oxy)m e t h yl]-2-p r op ylt h -
iop h en e (35). A solution of 34 (850 mg, 3.6 mmol) in 20 mL
of EtOH was treated with 206 mg (5.4 mmol) of NaBH4. The
mixture was stirred at room temperature for 1 h; then the
reaction was quenched with water and extracted with ether.
The extract was washed with water, dried over MgSO4, and
concentrated in vacuo to give 950 mg of an oil which was
dissolved in 20 mL of CH2Cl2 and then treated with 1.4 mL
(8.1 mmol) of diisopropylethylamine and 0.46 mL (6 mmol) of
chloromethyl methyl ether. The reaction mixture was stirred
at room temperature for 16 h, diluted with ether, washed with
water and brine, then dried over MgSO4, and concentrated.
The residue was purified by chromatography on silica gel,
eluting with 20:1 hexane:ethyl acetate, to afford 754 mg (75%)
from hexanes to give 7.7
g
(53%) of 3-bromo-4-(1-
oxopropyl)thiophene: MS 236, 238 (M + NH4)+; 1H NMR
(CDCl3) δ 7.99 (d, J ) 3 Hz, 1H), 7.32 (d, J ) 3 Hz, 1H), 2.98
(q, J ) 7 Hz, 2H), 1.21 (t, J ) 7 Hz, 3H).
This compound was dissolved in diethylene glycol (100 mL),
treated with KOH (5.9 g, 0.1 mol) and hydrazine (4.4 g, 2.7
mmol), stirred at reflux for 16 h, and then partitioned between
3 M HCl and pentane. The extract was washed with brine,
dried, and concentrated to afford 4.75 g (66%) of 40: 1H NMR

1598 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Michaelides et al.
(CDCl3) δ 7.22 (d, J ) 3 Hz, 1H), 6.95 (d, J ) 3 Hz, 1H), 2.56
(t, J ) 7.5 Hz, 2H), 1.65 (sextet, J ) 7.5 Hz, 2H). 0.98 (t, J )
7.5 Hz, 3H).
The following compounds were prepared from 22b-d in the
same way as described for 5 and 47d .
(-)-tr a n s-2-Eth yl-4,5,5a,6,7,11b-h exah ydr o-3-th ia-5-aza-
cyclopen t-1-en a[c]ph en an th r en e-9,10-diol h ydr obr om ide
(46b): mp 174-5 °C; [R]25D ) -192.2° (c ) 1.01, MeOH). Anal.
(C17H20BrNO2S‚0.60H2O) C,H,N.
1-(3-Br om o-4-p r op yl-2-th iop h en eyl)-1,2,3,4-tetr a h yd r o-
6,7-(m eth ylen ed ioxy)-2-n itr on a p h th a len e (42). A solution
of 40 (2.0 g, 9.1 mmol) in THF (5 mL) was added to a -78 °C
solution of freshly prepared LDA (prepared be reacting n-BuLi
(3.9 mL, 2.5 M in hexanes, 9.8 mmol) with diisopropylamine
(0.99 g, 9.8 mmol) for 0.5 h at -78 °C). The reaction mixture
was stirred at -78 °C for 1 h, then treated with a solution of
41 (2.24 g, 9.8 mmol) in THF (12 mL), and stirred for an
additional 1.5 h, after which the reaction was quenched with
saturated aqueous NH4Cl. After being extracted with ether,
washed with brine, dried, and concentrated, the residue was
dissolved in CH3CN treated with Et3N (ca. 2 mL), stirred
overnight, concentrated, and directly purified via column
chromatography to afford 0.72 g (20%) of 42: 1H NMR (CDCl3)
δ 6.93 (s, 1H), 6.58 (s, 1H), 6.38 (s, 1H), 5.91 (s, 2H), 5.18 (d,
J ) 7 Hz, 1H), 5.05-4.95 (m, 1H), 3.0-2.8 (m, 2H), 2.6-2.4
(m, 4H), 1.7-1.55 (m, 2H), 1.0 (t, J ) 8 Hz, 3H).
(+)-tr a n s-2-Eth yl-4,5,5a,6,7,11b-h exah ydr o-3-th ia-5-aza-
cyclopen t-1-en a[c]ph en an th r en e-9,10-diol h ydr obr om ide
(47b): [R]25 ) +197° (c ) 1.02, MeOH). Anal. (C17H20
-
D
BrNO2S‚0.60H2O) C,H,N.
(-)-tr a n s-2-Met h yl-4,5,5a ,6,7,11b -h exa h yd r o-3-t h ia -5-
a za cyclop en t-1-en a [c]p h en a n th r en e-9,10-d iol h yd r obr o-
m id e (46a ): [R]25 ) -162° (c ) 1.03, MeOH); mp 201-2 °C.
D
Anal. (C16H18BrNO2S‚0.2HBr) C,H,N.
(+)-tr a n s-2-Met h yl-4,5,5a ,6,7,11b -h exa h yd r o-3-t h ia -5-
a za cyclop en t-1-en a [c]p h en a n th r en e-9,10-d iol h yd r obr o-
m id e (47a ): [R]25 ) +176° (c ) 1.0, MeOH). Anal. (C16H18
-
D
BrNO2S‚0.4HBr) C,H,N.
(-)-tr a n s-2-(1,1-Dim eth yleth yl)-4,5,5a ,6,7,11b-h exa h y-
d r o-3-t h ia -5-a za cyclop en t -1-en a [c]p h en a n t h r en e-9,10-
d iol h yd r obr om id e (46c): [R]25D ) -193° (c ) 1.04, MeOH);
mp 167-8 °C. Anal. (C19H24BrNO2S‚0.2HBr‚0.2H2O) C,H,N.
(+)-tr a n s-2-(1,1-Dim eth yleth yl)-4,5,5a ,6,7,11b-h exa h y-
d r o-3-t h ia -5-a za cyclop en t -1-en a [c]p h en a n t h r en e-9,10-
d iol h yd r obr om id e (47c): [R]25D ) +188° (c ) 1.01, MeOH).
Anal. (C19H24BrNO2S‚0.5H2O) C,H,N.
1-(4-P r op yl-2-th iop h en eyl)-1,2,3,4-tetr a h yd r o-6,7-(m e-
th ylen ed ioxy)-2-n a p h th yla m in e (43). Following the pro-
cedure described for the reduction of 9b to 10b, compound 42
(1.25 g, 2.95 mmol) was converted to 0.91
g (84%) of
1-(3-bromo-4-propyl-2-thiopheneyl)-1,2,3,4-tetrahydro-6,7-(me-
thylenedioxy)-2-naphthylamine: MS 394, 396 (M + H)+; 1H
NMR (CDCl3) δ 6.92 (s, 1H), 6.57 (s, 1H), 6.28 (s, 1H), 5.87 (s,
2H), 4.22 (d, J ) 9 Hz, 1H), 3.33-3.23 (m, 1H), 3.0-2.8 (m,
2H), 2.62-2.55 (m, 2H), 2.15-2.05 (m, 1H), 1.82-1.6 (m, 3H),
1.02 (t, J ) 7 Hz, 3H).
A solution (0.78 g, 2.0 mmol) of this compound in ethanol
was hydrogenated at 4 atm of H2 with 0.3 g of 10% Pd/C
catalyst. The catalyst was removed by filtration, and the
filtrate was concentrated to give 0.63 g (100%) of 43: 1H NMR
(CDCl3) δ 6.81 (s, 1H), 6.77 (s, 1H), 6.56 (s, 1H), 6.41 (s, 1H),
5.87 (s, 2H), 3.90 (d, J ) 8 Hz, 1H), 3.25-3.15 (m, 1H), 2.92-
2.78 (m, 2H), 2.54 (t, J ) 7 Hz, 2H), 2.13-2.05 (m, 1H), 1.8-
1.6 (m, 3H), 0.96 (t, J ) 7 Hz, 3H).
Biologica l Meth od s. Gen er a l. Rat striatal membranes
were obtained from Analytical Biological Services (ABS)
(Wilmington, DE). The radioligands [3H]SCH 23390, [3H]-
spiperone, and [3H]rauwalsine were obtained from DuPont
NEN (Boston, MA).
[
125I]SCH 23982 was obtained from
Amersham (Arlington Heights, IL). For the binding assays,
the Ki values were determined from the IC50 values as
described by Cheng and Prussof.28
Ra d ioliga n d Bin d in g Stu d ies: Ra t Str ia tu m . Assays
were conducted in 96-well microtiter plates using 1 mL
minitubes and assay volumes of 250 µL. Rat striatal mem-
branes were resuspended in 50 mM Tris-HCl, 5 mM MgCl2,
pH 7.4, at 4 °C. For the D1 binding assay, 10 µg of membrane
tr a n s-3-P r op yl-4,5,5a ,6,7,11b-h exa h yd r o-1-th ia -5-a za -
cyclop en t -2-en a [c]p h en a n t h r en e-9,10-d iol H yd r och lo-
r id e (45). Following the procedures described for the prepa-
ration of 11b from 10b, 45 (0.85 g, 2.7 mmol) was converted
to 0.4 g (45%) of a 1.5:1 mixture of cis:trans 44. Pure trans
isomer (0.07 g, 0.21 mmol; isolated via silica gel column
chromatography) was dissolved in CH2Cl2 (5 mL), cooled to 0
°C, and then treated with BCl3 (2 mL, 1 M in CH2Cl2, 2 mmol).
After being stirred for 2 h at 0 °C, the reaction was quenched
with MeOH, stirred at room temperature for 2 h, concentrated,
and triturated with ether. The precipitate was collected and
dried to give 0.08 g (99%) of 45: mp > 170 °C dec; HRMS calcd
protein was incubated with [125I]SCH 23982 (0.02 nM, Kd
)
1.7 nM), with or without competitor, for 30 min at room
temperature. SCH 23390 (1 µM) was used to define nonspe-
cific binding. For the D2 binding assay, 20 µg of membrane
protein was incubated with [3H]spiperone (0.5 nM, Kd ) 0.08
nM), with or without competitor, at 37 °C for 20 min. (+)-
Butaclamol (100 µM) was used to define nonspecific binding.
For R2 binding, [3H]rauwaulscine (0.7 nM, Kd ) 0.6 nM) was
incubated with rat cortical membranes (50 µg of tissue/assay)
at room temperature for 60 min. Nonspecific binding was
defined with 10 µM phentolamine.
1
for C18H22NO2S 316.1371, found 316.1365; H NMR (CD3OD)
Ad en yla te Cycla se Activity: F ish Retin a . The method
for determining cAMP accumulation in fish retina has been
described previously.29 Common Comets, approximately 2-3
in. long, were obtained from Grassy Fork Fisheries (Martin-
sville, In). Fish were dark-adapted for at least 1 h before
sacrificing. Each retina was homogenized in 1.5 mL of ice cold
50 mM Tris-HCl with 0.4 mM EDTA, pH 7.4, at 4 °C.
Homogenization procedure, assay buffer, and incubation vol-
ume were identical to those described for the rat striatum
adenylate cyclase assay. Each retina was used in 100 assay
tubes. The incubation was conducted for 10.5 min at 37 °C.
Beh a vior a l P h a r m a cology. The rat rotation experiments
were performed using male Sprague-Dawley rats that were
given unilateral lesions of the ascending medial forebrain
bundle with 6-OHDA, as described previously.13b
The evaluation of the seizuregenic liability of the compounds
was carried out using male CD-1 mice (Charles River, Portage,
MI) weighing approximately 13-22 g. Clear plastic shoebox
cages (28 × 17.5 × 13 cm) containing animal bedding and wire
cage lids served as the observation apparatus. Mice were
injected subcutaneously with varying doses of test compound
or vehicle and immediately placed in the observation cage.
Each cage held up to four mice. The animals were observed
for behavioral signs of seizure activity that included buccal
movements (rhythmic opening and closing of the mouth),
forelimb clonus (repetitive rhythmic clawing motion by one or
both of the forepaws and may progress to animals adopting
δ 7.35 (s, 1H), 7.13 (s, 1H), 6.63 (s, 1H), 4.36 (s, 2H), 4.33 (d,
J ) 11 Hz, 1H), 3.50-3.35 (m, 1H), 3.0-2.85 (m, 2H), 2.52 (t,
J ) 7 Hz, 2H), 2.40-2.28 (m, 1H), 2.04-1.90 (m, 1H), 1.67
(sextet, J ) 7 Hz, 2H), 0.99 (t, J ) 7 Hz, 3H).
Ch ir a l Sep a r a tion of tr a n s-2-P r op yl-9,10-d im eth oxy-
4,5,5a ,6,7,11b-h exa h yd r o-3-th ia -5-a za cyclop en t-1-en a [c]-
p h en a n th r en e (22d ). Racemic 22d was separated on a
preparative (50 mm × 500 mm) Chiracel OD column, eluting
with a 5% mixture of 2-propanol in hexanes at a flow rate of
50 mL/min, monitoring at 254 nm. Good separation was
obtained with samples weighing up to 300 mg. The (-) and
(+) enantiomers eluted at 62 and 85 min, respectively (80-
85% recovery). (-)-22d : [R]25D ) -343° (c ) 0.52, methanol);
mp 86-87 °C. (+)-22d : [R]D ) +335° (c ) 1.05, methanol);
mp 86-87 °C.
(-)-tr a n s-2-P r op yl-4,5,5a ,6,7,11b -h exa h yd r o-3-t h ia -5-
a za cyclop en t-1-en a [c]p h en a n th r en e-9,10-d iol Hyd r obr o-
m id e (5). The title compound was prepared from (-)-22d
following the procedure described for 12b: mp 155-62 °C dec;
[R]25 ) -167° (c ) 1.03, MeOH). Anal. (C18H22BrNO2S‚
D
0.7H2O) C,H,N.
(+)-tr a n s-2-P r op yl-4,5,5a ,6,7,11b -h exa h yd r o-3-t h ia -5-
a za cyclop en t-1-en a [c]p h en a n th r en e-9,10-d iol Hyd r obr o-
m id e (47d ). The title compound was prepared from (+)-22d
following the procedure described for 12b: [R]25 ) +165° (c
D
) 0.35, ethanol). Anal. (C18H22BrNO2S‚0.1HBr) C,H,N.

TB[f]Q as Dopamine D1-Selective Agonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1599
Hodges, L.; Hong, Y.; Mahan, L.; Mikusa, J .; Miller, T.; Nikkel,
A.; Stashko, M.; Witte, D.; Williams, M. ABT-431: The Diacetoxy
an upright position with arched back and tilted head), clonic
seizure, tonic seizure, and death. Bouts of running typically
preceded these seizure-like events. From these data, the dose
at which at least one-half of the test group animals exhibited
seizure-like behaviors (ED50) was calculated.
Prodrug of A-86929,
a Potent and Selective Dopamine D1
Receptor Agonist: In Vitro Characterization and Effects in
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Miller, Arthur Nikkel, Michael Stashko, Ellen Roberts,
and David Witte for expert technical assistance and Dr.
Charles Hutchins for providing Chart 3.
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