Analogues of prazosin that bear a benextramine-related polyamine backbone exhibit different antagonism toward α1-adrenoreceptor subtypes

Article abstract of DOI:10.1021/jm000995w

Hybrid tetraaamine disulfides 4-9 were synthesized by combining the structural features of prazosin (1), a competitive α₁-adrenoreceptor antagonist, and benextramine (2), an irreversible α₁/α₂-adrenoreceptor antagonist, and their biological profiles at α₁-adrenoreceptor subtypes were assessed by functional experiments in isolated rat vas deferens (α_1A), spleen (α_1B), and aorta (α_1D). To verify the role of the disulfide moiety on the interaction with α₁-adrenoreceptor subtypes, carbon analogues 10-15 were included in this study. All quinazolines lacking the disulfide bridge behaved, like 1, as competitive antagonists, whereas all polyamine disulfides displayed a nonhomogeneous mechanism of inhibition at the three subtypes since they were, like 2, noncompetitive antagonists at the α_1A and α_1B subtypes while being, unlike 2, competitive antagonists at the α_1D. In particular, the blocking effects were characterized by a decrease of the maximal response to noradrenaline that was affected only slightly by washings. Probably the α_1A and α_1B subtypes bear in the binding pocket a suitable thiol function that would suffer an interchange reaction with the disulfide moiety of the antagonist and which is missing, or not accessible, in the α_1D subtype. Polyamines 8, 9, and 14, among others, emerged as promising tools for the characterization of α₁-adrenoreceptors, owing to their receptor subtype selectivity. Finally, the effect of nonbasic substituents on the phenyl ring of prazosin arialogues 16-28 on potency and selectivity for the different subtypes can hardly be rationalized.

Full text of DOI:10.1021/jm000995w

362
J . Med. Chem. 2001, 44, 362-371
An a logu es of P r a zosin Th a t Bea r a Ben extr a m in e-Rela ted P olya m in e Ba ck bon e
Exh ibit Differ en t An ta gon ism tow a r d r1-Ad r en or ecep tor Su btyp es
Maria L. Bolognesi,† Gabriella Marucci,‡ Piero Angeli,‡ Michela Buccioni,‡ Anna Minarini,† Michela Rosini,†
Vincenzo Tumiatti,† and Carlo Melchiorre*,†
Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy, and Department of
Chemical Sciences, University of Camerino, Via S. Agostino 1, 62032 Camerino (MC), Italy
Received May 29, 2000
Hybrid tetraaamine disulfides 4-9 were synthesized by combining the structural features of
prazosin (1), a competitive R1-adrenoreceptor antagonist, and benextramine (2), an irreversible
R1/R2-adrenoreceptor antagonist, and their biological profiles at R1-adrenoreceptor subtypes
were assessed by functional experiments in isolated rat vas deferens (R1A), spleen (R1B), and
aorta (R1D). To verify the role of the disulfide moiety on the interaction with R1-adrenoreceptor
subtypes, carbon analogues 10-15 were included in this study. All quinazolines lacking the
disulfide bridge behaved, like 1, as competitive antagonists, whereas all polyamine disulfides
displayed a nonhomogeneous mechanism of inhibition at the three subtypes since they were,
like 2, noncompetitive antagonists at the R1A and R1B subtypes while being, unlike 2, competitive
antagonists at the R1D. In particular, the blocking effects were characterized by a decrease of
the maximal response to noradrenaline that was affected only slightly by washings. Probably
the R1A and R1B subtypes bear in the binding pocket a suitable thiol function that would suffer
an interchange reaction with the disulfide moiety of the antagonist and which is missing, or
not accessible, in the R1D subtype. Polyamines 8, 9, and 14, among others, emerged as promising
tools for the characterization of R1-adrenoreceptors, owing to their receptor subtype selectivity.
Finally, the effect of nonbasic substituents on the phenyl ring of prazosin analogues 16-28 on
potency and selectivity for the different subtypes can hardly be rationalized.
In tr od u ction
example, we have investigated antagonists structurally
related to prazosin (1),6-11 the prototype of quinazoline-
bearing compounds, which displays a competitive an-
tagonism, and antagonists structurally related to ben-
extramine (2),12 the prototype of tetraamine disulfides,
which inhibits R1-adrenoreceptors by an irreversible
(nonequilibrium in the kinetic sense) mechanism of
action.
Current evidence indicates that R1-adrenoreceptors
can be classified into at least three subtypes, that is,
R1A (R1a), R1B (R1b), and R1D (R1d), with upper and lower
case subscripts being used to designate native or
recombinant receptors, respectively.1-3 The existence of
an additional subtype (R1L) displaying a low affinity for
prazosin has also been claimed. Although this R1-
adrenoreceptor subtype has not been cloned yet, its
characterization may not be difficult since several
isolated tissue models have been shown to have R1L
characteristics.4
The observation that modifying both piperazine and
furan rings of 1 may afford antagonists10 that are able
to differentiate among R1-adrenoreceptor subtypes may
form the basis to further modify the structure of these
analogues, in an attempt to improve the selectivity. It
turned out that the piperazine ring of 1 is not essential
for activity and can be replaced by an R,ω-alkanedi-
amine.6,7 The most potent open analogue of 1 was the
one bearing a 1,6-disubstituted hexanediamine moiety,
and it was suggested that the hexane chain of this
compound might contribute to the binding by interact-
ing with a lipophilic site located between the sites where
quinazoline and furan rings interact.6 Since benextra-
mine (2)12 also has a 1,6-hexanediamine residue, sepa-
rating the inner from the outer nitrogens of the struc-
ture allowed us to speculate that this alkane chain
might interact with the same lipophilic pocket where
prazosin analogues bind. To test this hypothesis we
designed hybrid structures by combining the structural
features of both prazosin and benextramine.13 In these
compounds, the tetraamine backbone of benextramine
was kept constant owing to the observation that the four
amine functions have already been shown to be impor-
tant for R1-adrenoreceptor blocking activity, whereas the
The effort to design agents selective for each of the
three R1-adrenoreceptor subtypes has been an active
area of research. While R1A-adrenoreceptor antagonists
might be useful in the treatment of benign prostatic
hyperplasia,5 a potential therapeutic use for both R1B
-
and R1D-subtype antagonists remains to be established.
A vast array of structurally unrelated compounds
interacts with R1-adrenoreceptor subtypes, which makes
it difficult to determine the structural requirements
leading to receptor subtype selectivity.5 Our research
group has long been involved in designing new R1-
adrenoreceptor antagonists that display different an-
tagonism with the goal of developing high-affinity, site-
selective ligands for R1-adrenoreceptor subtypes. For
* To whom correspondence should be addressed: Department of
Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6,
40126 Bologna, Italy. Tel: +39 051 2099706. Fax: +39 051 2099734.
E-mail: camelch@kaiser.alma.unibo.it.
† University of Bologna.
‡ University of Camerino.
10.1021/jm000995w CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/16/2000

Prazosin Analogues with a Polyamine Backbone
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3 363
terminal benzyl groups of benextramine were replaced
with a quinazoline unit of prazosin because this func-
tionality is essential for high affinity toward R1-adreno-
receptors. Interestingly, all hybrid tetraamine disulfides
investigated, unlike benextramine, did not irreversibly
inhibit R1-adrenoreceptors, rather they competitively
antagonized agonist-induced responses such as pra-
zosin.13 This remarkable difference in the observed
antagonism of hybrid tetraamine disulfides compared
to benextramine stimulated our interest in designing
new structures in which the whole structure of both
benextramine and prazosin is almost retained.
The design strategy was based on the observation that
the replacement of the furan ring of 1 with a phenyl
moiety significantly increased the selectivity toward R1-
adrenoreceptors.10 This finding convinced us to design
prazosin analogues bearing a phenyl ring because it
offered the possibility to investigate the effect of sub-
stituents on both affinity and selectivity. It turned out
that the insertion of substituents on the benzene ring
affected, according to the type and the position of the
substituent, affinity and selectivity for R1-adrenorecep-
tor subtypes. Interestingly, the insertion of a 1,6-
hexanediamine moiety in the phenyl ring did not cause
a decrease in affinity, which allowed us to conclude that
the insertion of appropriate substituents in the phenyl
ring may form the basis of designing new selective
ligands for R1-adrenoreceptor subtypes. In addition, the
fact that a diamine function did not give rise to negative
interactions with the receptor clearly indicates that the
protonated amines recognize additional sites on the
receptor.10 Thus, the presence of a polyamine backbone
might increase the possibility to achieve receptor sub-
type selectivity.
F igu r e 1. Design strategy for the synthesis of hybrid struc-
tures 4-15 by inserting the structural features of prazosin
(1)-related compounds on the terminal nitrogens of the tetra-
amine backbone of benextramine (2) or of its carbon analogue
(3).
These observations taken together formed the basis
for the synthesis of hybrid tetraamine disulfides 4-9.
Furthermore, the corresponding carbon analogues 10-
15 were included in this study to verify the role, if any,
of the disulfide functionality on the interaction with R1-
adrenoreceptor subtypes.
Sch em e 1
Finally, the presence of a phenyl ring in place of the
furan ring of 1 in prazosin analogues afforded the
opportunity to further examine the effect of substituents
on both potency and selectivity toward R1-adrenorecep-
tor subtypes. In the present study, our aim was to
determine only whether electronic and/or lipophilic
properties of substituents in all positions of the phenyl
could exert any favorable effect on selectivity and
affinity for R1-adrenoreceptor subtypes, rather than
assess a quantitative relationship. It seemed this could
be determined with a few properly chosen substituents,
which were selected in such a way as to have σ and π
values in a positive or negative direction, in all combi-
nations.14 Comparison of the activity of these substi-
tuted derivatives with either the parent compound 1 or
the unsubstituted analogue 16 should reveal the im-
portance, if any, of one or both of these parameters. The
compounds used were the CF3 (+π, +σ), Me (+π, -σ),
CHO (-π, +σ), and OMe (-π, -σ) derivatives (17-28).
parison with prototypes prazosin (1), benextramine (2),
and its carbon analogue 3.
Ch em istr y
The design strategy for our compounds is shown in
Figure 1.
We describe here the synthesis and the pharmacologi-
cal profile of hybrid polyamines 4-15 and substituted
quinazolines 16-28 in functional experiments in com-
All the compounds were synthesized by standard
procedures (Schemes 1 and 2) and were characterized
by IR, H NMR, mass spectra, and elemental analysis.
1
Aldehydes 31 and 32 were synthesized by following
an adapted procedure described for 30.10 Thus, amida-

364 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3
Bolognesi et al.
Sch em e 2
the disulfide bridge behaved, like 1, as competitive
antagonists as they did not affect the maximal responses
induced by the agonist while causing a parallel shift to
the right of the concentration-response curves to the
agonist. By contrast, all polyamine disulfides 4-9
displayed a nonhomogeneous mechanism of receptor
inhibition at the three different R1-adrenoreceptor sub-
types, as they were, like 2, noncompetitive antagonists
at the R1A and R1B subtypes while being, unlike 2,
competitive antagonists at the R1D subtype. It is evident
that the presence of the disulfide functionality is neces-
sary, although not always sufficient, for a noncompeti-
tive mechanism of receptor inhibition.
Previously, it has been established that tetraamine
disulfide 2 inhibits R1-adrenoreceptors by way of a
disulfide bond formation through an interchange reac-
tion between the disulfide group of 2 and a thiol function
of the receptor.12,16 It is also clear that the disulfide
moiety is necessary for a covalent receptor inactivation
as revealed by the fact that the carbon analogue 3 of 2
behaved as a competitive antagonist at all R1-adreno-
receptors. To gain information about the mechanism of
inhibition, we compared the blocking effects of the
disulfide 8 with those of its corresponding carbon (two
methylenes for the disulfide bridge) analogue 14. It
turned out that the inhibition of 0.1 µM 14 against
noradrenaline in the prostatic portion of rat vas deferens
(R1A subtype) resulted in no decrease of the maximal
response with a parallel shift to the right of the
concentration-response curves and was recovered com-
pletely after 3 h washings, whereas the blocking effects
of 8, which were characterized by a decrease in the
maximal response, were affected only slightly by wash-
ings (Figure 2). Interestingly, the blocking effects of both
8 and 14 were recovered by the same extent following
washings of rat aorta (R1D subtype) (Figure 3), revealing
a similar competitive mechanism of receptor inhibition.
Taken together these results suggest that polyamine
disulfide 8, like tetraamine disulfide 2, may inhibit
irreversibly R1A- and R1B-adrenoreceptor subtypes. This
conclusion may apply also to the other polyamine
disulfides 4-7 and 9 since their blocking effects were
similar to those of 8.
tion of 2915 with 3-formyl- or 4-formyl-benzoyl chloride,
which were generated in situ by treating the corre-
sponding formylbenzoic acid with SOCl2, afforded 31
and 32, respectively. The condensation of aldehydes 30-
32 with tetraamine disulfide 3316 or its carbon analogue
3416 and subsequent reduction of the intermediate Schiff
bases afforded polyamine disulfides 7-9 and the cor-
responding carbon analogues 13-15 (Scheme 1).
Similarly, compounds 16-28 were obtained through
amidation of 3517 with an appropriate substituted
benzoyl chloride. Polyamine disulfides 4-6 and the
corresponding carbon analogues 10-12 were obtained
by condensation of aldehydes 17, 21, and 25 with 33 or
34 followed by the reduction of the intermediate Schiff
bases (Scheme 2).
Biology
The pharmacological profile of prazosin- and benex-
tramine-related compounds 4-28 was evaluated at R1-
adrenoreceptor subtypes on different isolated tissues
using prazosin (1) and benextramine (2) together with
the carbon analogue 3 of 2 as standard compounds. R1-
Adrenoreceptor subtype blocking activity was assessed
by antagonism of (-)-noradrenaline-induced contraction
If this assumption were correct, then R1A- and R1B
-
19
of prostatic vas deferens (R1A) )
18 or thoracic aorta (R1D
adrenoreceptors bear in the binding pocket for polyamine
disulfides a suitable thiol function that would suffer an
interchange reaction with the disulfide moiety of the
antagonist leading to receptor inactivation, which is
missing in the R1D subtype or that is not accessible to
the disulfide group of the antagonist.
and by antagonism of (-)-phenylephrine-induced con-
traction of spleen (R1B).20
The noncompetitive (irreversible) R1-antagonism was
determined after a 30 min incubation followed by 30 min
of washings. The decrease in maximum response was
expressed as a percentage of the control value and used
to estimate the IC50 values from graphical plots of
percent inhibition vs log molar concentration. The
potency of irreversible inhibitors was expressed as pIC50
values, whereas the potency of the competitive antago-
nists was expressed as pKb values.21
By taking as a starting point the tetraamine disulfide
2, it is possible to observe how affinity and selectivity
for R1-adrenoreceptor subtypes can be markedly affected
by replacing the 2-methoxy group by the structural
feature of 1 and related open analogues, leading to 4-9
as shown in Figure 1. As discussed above, 4-9 resulted
in noncompetitive antagonists at both R1A and R1B
subtypes and competitive antagonists at the R1D type.
All these disulfide-bearing compounds were more potent
than 2 at the R1A subtype while being more potent (4,
7-9) than or as potent as (5, 6) the prototype at the
R1B subtype. Interestingly, 8 was 355-fold more potent
than 2 at the R1A-adrenoreceptors and also displayed a
38-fold selectivity for the R1A subtype relative to the R1B
Resu lts a n d Discu ssion
The biological activity, expressed as pKb or pIC50
values, at R1-adrenoreceptor subtypes of compounds
used in the present study is shown in Table 1. To make
relevant considerations on structure-activity relation-
ships, prototypes 1 and 2 and the carbon analogue 3 of
2 were included for comparison. All quinazolines lacking

Prazosin Analogues with a Polyamine Backbone
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3 365
Ta ble 1. Antagonist Affinities, Expressed as pKb or pIC50 Values, of Polyamines 4-15 and Substituted Quinazolines 16-28 at
R1-Adrenoreceptors on Isolated Tissue from the Rat, Namely, Prostatic Vas Deferens (R1A), Spleen (R1B), and Thoracic Aorta (R1D), in
Comparison to Reference Compounds Prazosin (1), Benextramine (2), and Carbon Analogue (3)
a
pKb (pIC50
)
b
c
no.
position
X
R
R1A
R1B
R1D
1
2
3
4
5
6
7
8
8.99 ( 0.01
(4.79 ( 0.01)
5.32 ( 0.16
(5.30 ( 0.01)
(5.41 ( 0.02)
(5.70 ( 0.11)
(5.73 ( 0.01)
(7.34 ( 0.03)
(5.33 ( 0.03)
7.74 ( 0.18
7.29 ( 0.03
6.97 ( 0.04
8.17 ( 0.08
8.48 ( 0.13
8.53 ( 0.20
7.66 ( 0.23
6.94 ( 0.09
6.97 ( 0.13
7.34 ( 0.15
6.43 ( 0.11
7.79 ( 0.06
8.49 ( 0.14
7.87 ( 0.23
7.49 ( 0.10
7.59 ( 0.07
7.96 ( 0.11
8.46 ( 0.10
7.43 ( 0.14
8.74 ( 0.01
(4.17 ( 0.03)
6.01 ( 0.10
(5.29 ( 0.03)
(4.26 ( 0.05)
(4.38 ( 0.06)
(5.73 ( 0.05)
(5.76 ( 0.04)
(5.67 ( 0.01)
6.80 ( 0.12
6.50 ( 0.12
7.16 ( 0.21
7.22 ( 0.10
7.41 ( 0.15
7.56 ( 0.19
7.44 ( 0.11
6.50 ( 0.11
7.33 ( 0.13
6.77 ( 0.09
6.55 ( 0.16
6.92 ( 0.15
8.12 ( 0.15
7.84 ( 0.05
7.16 ( 0.21
6.95 ( 0.10
7.67 ( 0.02
7.74 ( 0.11
7.45 ( 0.21
9.71 ( 0.17
(5.30 ( 0.01)
6.21 ( 0.13
7.57 ( 0.06
7.09 ( 0.02
7.61 ( 0.14
8.05 ( 0.15
8.34 ( 0.09
8.50 ( 0.14
7.94 ( 0.22
7.43 ( 0.14
7.47 ( 0.13
8.47 ( 0.13
9.30 ( 0.21
7.90 ( 0.14
8.86 ( 0.02
7.56 ( 0.03
7.99 ( 0.12
7.76 ( 0.17
8.31 ( 0.04
8.07 ( 0.23
9.12 ( 0.12
7.46 ( 0.04
8.38 ( 0.13
8.38 ( 0.13
8.91 ( 0.19
8.98 ( 0.17
8.31 ( 0.06
2
3
4
2
3
4
2
3
4
2
3
4
S
S
S
S
S
S
CH2
CH2
CH2
CH2
CH2
CH2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
H
2-CHO
2-Me
2-OMe
2-CF3
3-CHO
3-Me
3-OMe
3-CF3
4-CHO
4-Me
4-OMe
4-CF3
a
Apparent pKb values ( SE were calculated according to Arunlakshana and Schild21 with the following equation: pKb ) -log Kb
)
log(DR - 1) - log [B]. The log(DR - 1) was calculated from two to three different antagonist concentrations, which were tested four
times. Dose-ratio (DR) values represent the ratio of the potency of the agonist (EC50) in the presence of the antagonist and in its absence.
pIC50 values ( SE, expressing noncompetitive (irreversible) blockade, are defined as the concentrations producing 50% inhibition of the
b
maximal response to agonist. It was reported that the rat vas deferens may also have R1L pharmacology.22 c The rat aorta appears to
have primarily R1D pharmacology. However, it may contain multiple R1-adrenoreceptors.23
type. This peculiarity emerging at R1A and R1B subtypes,
taken together with the competitive antagonism at R1D
subtypes, the only exception being that 9 was slightly
less potent than 6 at R1A-adrenoreceptors. Clearly, a
more flexible spacer between quinazoline and benzene
rings allows the open analogues to better interact with
their binding site. The same trend was observed for the
potency displayed by the carbon analogues 10-15. Open
analogues 13-15 were always more potent than the
corresponding piperazine analogues 10-12 at the three
R1-adrenoreceptor subtypes. Again, a comparison be-
tween the carbon analogue 3 of 2 and the prazosin-
related polyamines 10-15 reveals that replacing the
2-methoxy group of 3 with the quinazolinyl moiety of 1
resulted in a significant increase in potency at R1-
adrenoreceptor subtypes. Thus, these results confirm
-
adrenoreceptors, might have relevance. It is clear that
the competitive blocking effects at the latter receptor
subtype can be reversed by washings, which makes 8
an interesting tool for characterizing the R1A-adrenore-
ceptor subtype. Furthermore, 8 may also be important
for investigating R1D-adrenoreceptors owing to its higher
potency toward this subtype relative to both R1A and
R1B
.
A comparison between 4-6 and the corresponding
open analogues 7-9 reveals that replacing the pipera-
zine ring with a 1,6-diaminohexane moiety caused a
significant increase in potency at all R1-adrenoreceptor

366 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3
Bolognesi et al.
F igu r e 2. Effect of polyamine 8 (a) and 14 (b) on rat vas
deferens R1A-adrenoreceptors. Concentration-response curves
for noradrenaline were obtained before (9) and after exposure
to 0.1 µM 8 or 14 for 30 min (2), and after exposure to 0.1 µM
8 or 14 for 30 min followed by 30 (b), 60 (O), 120 (4), and 180
min (0) washings. Each point is the mean of at least four
independent observations. The SEMs were less than 10% and
are not shown.
F igu r e 3. Effect of polyamine 8 (a) and 14 (b) on rat aorta
R
1D-adrenoreceptors. Concentration-response curves for no-
radrenaline were obtained before (9) and after exposure to 0.1
µM 8 or 30 nM 14 for 30 min (2), and after exposure to 0.1
µM 8 or 30 nM 14 for 30 min followed by 60 (b), 120 (O), and
180 min (4) washings. Each point is the mean of at least four
independent observations. The SEMs were less than 10% and
are not shown.
and extend the view that the inclusion of a polyamine
backbone on the benzene ring of prazosin-related com-
pounds may not produce negative interactions with the
receptor and can lead to selectivity. In particular,
polyamine 14 showed an interesting selectivity profile,
being 7- and 78-fold more potent at R1D-adrenoreceptors
than at R1A- and R1B-adrenoreceptors, respectively.
However, concerning the selectivity toward R1D-adreno-
receptors, the most promising polyamine appears to be
9, which turned out to be more potent at this receptor
subtype than at both R1A and R1B subtypes.
A further analysis of the results shown in Table 1
reveals that high affinity for both R1A- and R1D-adreno-
receptors is observed when the polyamine chain is
inserted at position 3 of the benzene ring as in 8 and
14, suggesting that at these receptors the polyamine
chain can contribute to the binding. This reasoning finds
further support by comparing the results observed for
the unsubstituted analogue 16, which is less potent than
polyamine 14. The situation is less clear for the R1B
subtype since the inclusion of a polyamine chain at any
position of the benzene ring did not markedly affect
affinity.
To verify the effect of the nonbasic substituents on
the potency for R1-adrenoreceptor subtypes, we inves-
tigated derivatives 16-28. Clearly, the insertion of a
substituent on the benzene ring of 16 affected the
affinity and, as a consequence, the selectivity for R1-
adrenoreceptor subtypes differently, according to the
substituent type and position. Any substituent investi-
gated at position 2 (17-20) gave a decrease in potency
in comparison with 16 for all R1-adrenoreceptor sub-
types, revealing that a substituent in this position is
not tolerated by way of a possible steric hindrance with
the receptor. However, derivatives 17-20 retained a
selectivity profile similar to that of 16. In particular,
the 2-trifluoromethyl substituted derivative 20 was
markedly selective, being 76- and 58-fold more potent
at R1D-adrenoreceptors than at the R1A and R1B subtypes,
respectively. The insertion of the same substituents at
position 3 of the benzene ring of 16, affording 21-24,
produced different results. The selectivity profile was
similar, albeit different from a quantitative point of
view, to that displayed by 16, the only exception being
the 3-methoxy derivative 23 that turned out to be

Prazosin Analogues with a Polyamine Backbone
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3 367
compound was synthesized following an adapted procedure
described for the synthesis of the analogue 30.10 A solution of
3-formylbenzoic acid (0.15 g, 1 mmol) and SOCl2 (0.73 mL, 10
mmol) in toluene (10 mL) was refluxed for 1 h. Removal of
the solvent under reduced pressure afforded crude 3-formyl-
benzoyl chloride in a quantitative yield. A solution of this
chloride (0.168 g, 1 mmol) in dioxane (5 mL) was added
dropwise to a solution of 2915 (0.35 g, 1 mmol) and triethy-
lamine (0.14 mL, 1 mmol) in dioxane (10 mL). After the
mixture was stirred at room temperature for 24 h, the solvent
was removed under reduced pressure to give a residue that
was purified by chromatography. Eluting with methylene
chloride-petroleum ether-ethanol-aqueous 30% ammonia (8:
2:0.5:0.05) afforded 0.37 g (77% yield) of 31: mp (hydrochlo-
slightly more potent at both R1A- and R1B-adrenorecep-
tors than at R1D-adrenoreceptors. However, these com-
pounds were as active as or even more potent than 16
at R1A-adrenoreceptors, whereas the situation at the
other receptor subtypes was more complex. At the R1B
-
adrenoreceptors, 22 and 23 were more potent whereas
21 and 24 were less potent than 16, suggesting perhaps
that an electron-donating group might increase the
binding with the receptor. On the other hand, at R1D
-
adrenoreceptors all 3-substituted derivatives were sig-
nificantly less potent than 16, the only important
exception being the 3-methyl derivative 22, which
turned out to be more potent than not only prototype
16 but also 21, 23, and 24, pointing to a possible positive
effect of both electronic and lipophilic properties of a
methyl substituent. Compound 26 was slightly more
potent than 16 at the R1A and R1B subtypes but equi-
potent at the R1D subtype. Compound 27 was clearly
more potent than 16 at the R1A subtype, slightly more
potent at the R1B subtype, and practically equipotent
at the R1D subtype. This suggests that an electron-
releasing substituent at position 4 of the benzene ring
may not be detrimental to affinity. However, 25 and 28,
although bearing electron-attracting substituents, were
only slightly less potent than the unsubstituted proto-
type 16.
1
ride) 251 °C; H NMR (CDCl3) δ 1.10-1.82 (m, 8), 2.82-3.31
(m, 7), 3.45-3.78 (m, 3), 3.90 (s, 3), 3.95 (s, 3), 5.21 (br s, 2,
exchangeable with D2O), 6.81 (s, 1), 6.95-7.02 (m, 1), 7.51-
7.73 (m, 2), 7.89 (s, 2), 10.01 (s, 1).
N-{6-[(4-Am in o-6,7-d im eth oxyqu in a zolin -2-yl)m eth yl-
a m in o]h exyl}-4-for m yl-N-m eth ylben za m id e (32). It was
synthesized from 4-formylbenzoic acid and 2915 following the
procedure described for 31 and purified by chromatography.
Eluting with methylene chloride-methanol-aqueous 30%
ammonia (9.5:0.5:0.04) afforded 31: 71% yield; mp (hydro-
1
chloride) 221 °C; H NMR (CDCl3) δ 1.34-1.86 (m, 8), 2.89-
3.21 (m, 7), 3.51-3.70 (m, 3), 3.91 (s, 3), 3.97 (s, 3), 5.21 (br s,
2, exchangeable with D2O), 6.80 (s, 1), 6.85-7.01 (m, 1), 7.51
(d, 2), 7.90 (d, 2), 10.04 (s, 1).
[4-(4-Am in o-6,7-d im eth oxyqu in a zolin -2-yl)p ip er a zin o]-
(p h en yl)m eth a n on e Hyd r och lor id e (16). It was synthe-
sized from benzoyl chloride and 3517 following the procedure
described for 31 and purified by crystallization: 64% yield;
In conclusion, the effects of nonbasic substituents on
the phenyl ring of 16, affording 17-28, on potency, and
on selectivity for R1-adrenoreceptors can be hardly
rationalized on a firm basis with our series of com-
pounds. On the other hand, the inclusion of a tetraamine
backbone into prazosin-related compounds afforded a
series of polyamines that displayed an intriguing an-
tagonism, which was different, according to the type and
position of the tetraamine chain in the phenyl ring, for
R1-adrenoreceptor subtypes. In particular, polyamines
8, 9, and 14, among others, emerged as promising tools
for the characterization of R1-adrenoreceptor subtypes,
owing to their receptor subtype selectivity. Moreover,
several compounds, like 13, 14, and 21, may be proto-
types for the design of competitive R1A/R1D-antagonists,
a selectivity profile postulated to be of utility in benign
prostatic hyperplasia due to actions on both prostate
and bladder.5
1
mp 278 °C (from EtOH/Et2O); H NMR (free base; CDCl3) δ
3.41-3.70 (m, 4), 3.71-3.85 (m, 4), 3.92 (s, 3), 3.97 (s, 3), 5.23
(br s, 2, exchangeable with D2O), 6.83 (s, 1), 6.94 (s, 1), 7.31-
7.50 (m, 5). Anal. (C21H24ClN5O3) C, H, N.
[4-(4-Am in o-6,7-d im eth oxyqu in a zolin -2-yl)p ip er a zin o]-
(2-for m ylp h en yl)m eth a n on e Oxa la te (17). It was synthe-
sized from 2-formylbenzoic acid and 3517 following the proce-
dure described for 31 and purified by chromatography. Eluting
with methylene chloride-methanol-aqueous 30% ammonia
(9.5:0.5:0.04) afforded, in 64% yield, 17 as the free base, which
was transformed into the oxalate salt: mp 240 °C (from EtOH/
Et2O); 1H NMR (free base; CDCl3) δ 3.23 (t, 2), 3.71-3.79 (m,
2), 3.80-4.01 (m, 4), 3.88 (s, 3), 3.93 (s, 3), 5.42 (br s, 2,
exchangeable with D2O), 6.87 (s, 1), 6.89 (s, 1), 7.37-7.41 (m,
1), 7.45-7.71 (m, 2), 7.89-7.97 (m, 1), 10.05 (s, 1). Anal.
(C24H25N5O8) C, H, N.
[4-(4-Am in o-6,7-d im eth oxyqu in a zolin -2-yl)p ip er a zin o]-
(2-m eth ylp h en yl)m eth a n on e Hyd r och lor id e (18). It was
synthesized from 2-methylbenzoic acid and 3517 following the
procedure described for 31 and purified by chromatography.
Eluting with methylene chloride-methanol-aqueous 30%
ammonia (9.6:0.4:0.04) afforded, in 80% yield, 18 as the free
base, which was transformed into the hydrochloride salt: mp
Exp er im en ta l Section
Ch em istr y. Melting points were taken in glass capillary
tubes on a Bu¨chi SMP-20 apparatus and are uncorrected. IR,
MALDI-TOF-MS, and 1H NMR spectra were recorded on
Perkin-Elmer 297, Bruker Biflex III, and Varian VXR 300
instruments, respectively. Chemical shifts are reported in
parts per million (ppm) relative to tetramethylsilane (TMS),
and spin multiplicities are given as s (singlet), br s (broad
singlet), d (doublet), t (triplet), or m (multiplet). Although the
IR spectra data are not included (because of the lack of unusual
features), they were obtained for all compounds reported and
were consistent with the assigned structures. The elemental
compositions of the compounds agreed to within (0.4% of the
calculated value. When the elemental analysis is not included,
crude compounds were used in the next step without further
purification. Chromatographic separations were performed on
silica gel columns (Kieselgel 40, 0.040-0.063 mm, Merck) by
flash chromatography. Compounds were named following
IUPAC rules as applied by ACD/NAME, a PC integrated
software package for systematic naming in organic chemistry
(Advanced Chemistry Development Inc.).
1
290 °C (from EtOH/Et2O); H NMR (free base; CDCl3) δ 2.27
(s, 3), 3.22-3.38 (m, 2), 3.62-3.80 (m, 2), 3.81-4.02 (m, 4),
3.89 (s, 3), 3.93 (s, 3), 5.22 (br s, 2, exchangeable with D2O),
6.81 (s, 1), 6.91 (s, 1), 7.18-7.32 (m, 4). Anal. (C22H26ClN5O3)
C, H, N.
[4-(4-Am in o-6,7-d im eth oxyqu in a zolin -2-yl)p ip er a zin o]-
(2-m eth oxyp h en yl)m eth a n on e Hyd r och lor id e (19). It was
synthesized from 2-methoxybenzoic acid and 3517 following the
procedure described for 31 and purified by chromatography.
Eluting with methylene chloride-methanol-aqueous 30%
ammonia (9.6:0.4:0.04) afforded, in 78% yield, 19 as the free
base, which was transformed into the hydrochloride salt: mp
270 °C (from EtOH/Et2O); 1H NMR (free base; CDCl3) δ 3.22-
3.39 (m, 2), 3.78-3.99 (m, 6), 3.82 (s, 3), 3.92 (s, 3), 3.94 (s, 3),
5.22 (br s, 2, exchangeable with D2O), 6.82-7.05 (m, 4), 7.27-
7.42 (m, 2). Anal. (C22H26ClN5O4) C, H, N.
[4-(4-Am in o-6,7-d im eth oxyqu in a zolin -2-yl)p ip er a zin o]-
(2-tr iflu or om eth ylph en yl)m eth an on e Hydr och lor ide (20).
It was synthesized from 2-trifluoromethylbenzoic acid and 3517
N-{6-[(4-Am in o-6,7-d im eth oxyqu in a zolin -2-yl)m eth yl-
a m in o]h exyl}-3-for m yl-N-m et h ylb en za m id e (31). This

368 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3
Bolognesi et al.
1
following the procedure described for 31 and purified by
chromatography. Eluting with methylene chloride-methanol-
aqueous 30% ammonia (9.7:0.3:0.03) afforded in 71% yield 20
as the free base, which was transformed into the hydrochloride
salt: mp 280 °C (from EtOH/Et2O); 1H NMR (free base; CDCl3)
δ 3.23 (t, 2), 3.63-3.74 (m, 2), 3.80-4.01 (m, 4), 3.87 (s, 3),
3.93 (s, 3), 5.34 (br s, 2, exchangeable with D2O), 6.85 (s, 1),
6.89 (s, 1), 7.31-7.36 (m, 1), 7.57 (m, 2), 7.69-7.79 (m, 1). Anal.
(C22H23ClF3N5O3) C, H, N.
[4-(4-Am in o-6,7-d im eth oxyqu in a zolin -2-yl)p ip er a zin o]-
(3-for m ylp h en yl)m eth a n on e Hyd r och lor id e (21). It was
synthesized from 3-formylbenzoic acid and 3517 following the
procedure described for 31 and purified by chromatography.
Eluting with methylene chloride-petroleum ether-ethanol-
aqueous 30% ammonia (8:1.6:0.4:0.035) afforded in 60% yield
21 as the free base, which was transformed into the hydro-
chloride salt: the mp was indefinite, fusion started at 135 °C
but was not complete up to 300 °C: 1H NMR (D2O) δ 3.42-
3.82 (m, 8), 3.64 (s, 3), 3,72 (s, 3), 6.51 (s, 1), 6.86 (s, 1), 7.45-
7.99 (m, 4), 9.79 (s, 1). Anal. (C22H24ClN5O4) C, H, N.
280 °C (from EtOH/Et2O); H NMR (free base; CDCl3) δ 2.37
(s, 3), 3.42-3.64 (m, 2), 3.71-3.99 (m, 6), 3.83 (s, 3), 3.89 (s,
3), 5.32 (br s, 2, exchangeable with D2O), 6.83 (s, 1), 6.91 (s,
1), 7.28 (dd, 4). Anal. (C22H26ClN5O3) C, H, N.
[4-(4-Am in o-6,7-d im eth oxyqu in a zolin -2-yl)p ip er a zin o]-
(4-m eth oxyp h en yl)m eth a n on e Hyd r och lor id e (27). It was
synthesized from 4-methoxybenzoic acid and 3517 following the
procedure described for 31 and purified by chromatography.
Eluting with methylene chloride-methanol-aqueous 30%
ammonia (9.7:0.3:0.03) afforded, in 77% yield, 27 as the free
base, which was transformed into the hydrochloride salt: mp
230 °C (from EtOH/Et2O); 1H NMR (DMSO-d6) δ 3.23-3.45
(m, 4), 3.46-3.71 (m, 4), 3.77 (s, 3), 3.81 (s, 3), 3.86 (s, 3), 6.97-
7.10 (m, 2), 7.35-7.42 (m, 2), 7.43 (s, 1), 7.68 (s, 1), 8.63 (br s,
1, exchangeable with D2O), 8.62 (br s, 1, exchangeable with
D2O), 12. 10 (br s, 1, exchangeable with D2O). Anal. (C22H26
ClN5O4) C, H, N.
-
[4-(4-Am in o-6,7-d im eth oxyqu in a zolin -2-yl)p ip er a zin o]-
(4-tr iflu or om eth ylph en yl)m eth an on e Hydr och lor ide (28).
It was synthesized from 4-trifluoromethylbenzoic acid and 3517
following the procedure described for 31 and purified by
chromatography. Eluting with methylene chloride-methanol-
aqueous 30% ammonia (9.7:0.3:0.03) afforded, in 74% yield,
28 as the free base, which was transformed into the hydro-
chloride salt: mp 240 °C (from EtOH/Et2O); 1H NMR (DMSO-
d6) δ 3.40-3.61 (m, 2), 3.71-4.07 (m, 6), 3.81 (s, 3), 3.90 (s, 3),
7.42 (s, 1), 7.63-7.79 (m, 3), 7.80-7.91 (m, 2), 8.67 (br s, 1,
exchangeable with D2O), 8.90 (br s, 1, exchangeable with D2O),
12.20 (br s, 1, exchangeable with D2O). Anal. (C22H23ClF3N5O3)
C, H, N.
[4-(4-Am in o-6,7-d im eth oxyqu in a zolin -2-yl)p ip er a zin o]-
(3-m eth ylp h en yl)m eth a n on e Hyd r och lor id e (22). It was
synthesized from 3-methylbenzoic acid and 3517 following the
procedure described for 31 and purified by chromatography.
Eluting with methylene chloride-methanol-aqueous 30%
ammonia (9.6:0.4:0.04) afforded, in 71% yield, 22 as the free
base, which was transformed into the hydrochloride salt: mp
1
190-192 °C (from EtOH/Et2O); H NMR (free base; CDCl3) δ
2.32 (s, 3), 3.33-3.51 (m, 2), 3.62-3.82 (m, 6), 3.83 (s, 3), 3.87
(s, 3), 5.35 (br s, 2, exchangeable with D2O), 6.82 (s, 1), 6.84
(s, 1), 7.08-7.31 (m, 4). Anal. (C22H26ClN5O3) C, H, N.
[4-(4-Am in o-6,7-dim eth oxyqu in azolin -2-yl)piper azin o]-
{2-[({6-[(2-{[2-({6-[(2-{[4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-
p ip er a zin o]ca r bon yl}ben zyl)a m in o]h exyl}a m in o)eth yl]-
disulfanyl}ethyl)amino]hexyl}amino)methyl]phenyl}methanone
Hexa h yd r och lor id e (4). A solution of 17 (0.2 g, 0.42 mmol)
and 3316 (50 mg, 0.14 mmol) in toluene (10 mL) was refluxed
and the water formed continuously removed for 8 h. The cooled
mixture was filtered and the filtrate evaporated to give the
corresponding Schiff base that was dissolved in ethanol (15
mL) and treated with NaBH4 (11 mg, 0.30 mmol). After the
mixture was stirred at room temperature overnight, removal
of dried solvents gave an oil that was purified by chromatog-
raphy. Eluting with methylene chloride-methanol-30% am-
monia (8.5:1.5:0.15) afforded, in 38% yield, 4 as the free base
that was converted into the hexahydrochloride salt: mp 253
°C (from EtOH/Et2O); 1H NMR (free base; CDCl3) δ 1.17-1.49
(m, 16), 2.40 (br s, 4, exchangeable with D2O), 2.45-2.59 (m,
8), 2.71-2.82 (m, 4), 2.83-2.94 (m, 4), 3.2-3.39 (m, 4), 3.68-
3.98 (m, 12), 3.67 (s, 4), 3.86 (s, 6), 3.92 (s, 6), 5.42 (br s, 4,
exchangeable with D2O), 6.86 (s, 4), 7.15-7.41 (m, 8). MALDI-
MS calcd for C60H85N14O6S2 1161.62 (M + H)+, found 1161.75.
Anal. (C60H90Cl6N14O6S2) C, H, N.
[4-(4-Am in o-6,7-d im eth oxyqu in a zolin -2-yl)p ip er a zin o]-
(3-m eth oxyp h en yl)m eth a n on e Hyd r och lor id e (23). It was
synthesized from 3-methoxybenzoic acid and 3517 following the
procedure described for 31 and purified by chromatography.
Eluting with methylene chloride-methanol-aqueous 30%
ammonia (9.6:0.4:0.04) afforded, in 85% yield, 23 as the free
base, which was transformed into the hydrochloride salt: mp
250 °C (from EtOH/Et2O); 1H NMR (free base; CDCl3) δ 3.37-
3.63 (m, 2), 3.69-4.08 (m, 6), 3.69 (s, 3), 3.81 (s, 3), 3.91 (s, 3),
5.23 (br s, 2, exchangeable with D2O), 6.67-6.99 (m, 5), 7.19-
7.27 (m, 1). Anal. (C22H26ClN5O4) C, H, N.
[4-(4-Am in o-6,7-d im eth oxyqu in a zolin -2-yl)p ip er a zin o]-
(3-tr iflu or om eth ylph en yl)m eth an on e Hydr och lor ide (24).
It was synthesized from 3-trifluoromethylbenzoic acid and 3517
following the procedure described for 31 and purified by
chromatography. Eluting with methylene chloride-methanol-
aqueous 30% ammonia (9.7:0.3:0.03) afforded, in 56% yield,
24 as the free base, which was transformed into the hydro-
chloride salt: mp 275 °C (from EtOH/Et2O); 1H NMR (DMSO-
d6) δ 3.45-3.61 (m, 2), 3.68-4.01 (m, 6), 3.79 (s, 3), 3.85 (s, 3),
7.41 (s, 1), 7.63-7.90 (m, 5), 8.61 (br s, 1, exchangeable with
D2O), 8.82 (br s, 1, exchangeable with D2O), 12.10 (br s, 1,
exchangeable with D2O). Anal. (C22H23ClF3N5O3) C, H, N.
[4-(4-Am in o-6,7-d im eth oxyqu in a zolin -2-yl)p ip er a zin o]-
(4-for m ylp h en yl)m eth a n on e Hyd r och lor id e (25). It was
synthesized from 4-formylbenzoic acid and 3517 following the
procedure described for 31 and purified by chromatography.
Eluting with methylene chloride-methanol-aqueous 30%
ammonia (9.7:0.3:0.03) afforded, in 77% yield, 25 as the free
base, which was transformed into the hydrochloride salt: mp
250 °C (from EtOH/Et2O); 1H NMR (DMSO-d6) δ 3.40-3.61
(m, 2), 3.62-4.10 (m, 6), 3,79 (s, 3), 3.81 (s, 3), 7.45 (s, 3), 7.60-
7.78 (m, 2), 7.96-8.02 (m, 1), 8.33 (br s, 1, exchangeable with
D2O), 8.42 (br s, 1, exchangeable with D2O), 10.06 (s, 1), 12.15
(br s, 1, exchangeable with D2O). Anal. (C22H24ClN5O4) C, H,
N.
[4-(4-Am in o-6,7-d im eth oxyqu in a zolin -2-yl)p ip er a zin o]-
(4-m eth ylp h en yl)m eth a n on e Hyd r och lor id e (26). It was
synthesized from 4-methylbenzoic acid and 3517 following the
procedure described for 31 and purified by chromatography.
Eluting with methylene chloride-methanol-aqueous 30%
ammonia (9.7:0.3:0.03) afforded, in 74% yield, 26 as the free
base, which was transformed into the hydrochloride salt: mp
[4-(4-Am in o-6,7-dim eth oxyqu in azolin -2-yl)piper azin o]-
{3-[({6-[(2-{[2-({6-[(3-{[4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-
p ip er a zin o]ca r bon yl}ben zyl)a m in o]h exyl}a m in o)eth yl]-
disulfanyl}ethyl)amino]hexyl}amino)methyl]phenyl}methanone
Hexa h yd r och lor id e (5). It was synthesized from 21 and 3316
following the procedure described for 4 and purified by
chromatography. Eluting with methylene chloride-ethanol-
30% ammonia (8.5:1.5:0.15) afforded, in 32% yield, 5 as the
free base that was converted into the hexahydrochloride salt:
1
mp 252 °C (from EtOH/Et2O); H NMR (free base; CDCl3) δ
1.10-1.75 (m, 16), 2. 10 (br s, 4, exchangeable with D2O), 2.55-
2.69 (m, 8), 2.77-2.98 (m, 8), 3.41-3.62 (m, 4), 3.71-4.09 (m,
12), 3.82 (s, 4), 3.91 (s, 6), 3.96 (s, 6), 5.35 (br s, 4, exchangeable
with D2O), 6.85 (s, 2), 6.91 (s, 2) 7.23-7.50 (m, 8). MALDI-MS
calcd for C60H85N14O6S2 1161.62 (M + H)+, found 1161.64.
Anal. (C60H90Cl6N14O6S2) C, H, N.
[4-(4-Am in o-6,7-dim eth oxyqu in azolin -2-yl)piper azin o]-
{4-[({6-[(2-{[2-({6-[(4-{[4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-
p ip er a zin o]ca r bon yl}ben zyl)a m in o]h exyl}a m in o)eth yl]-
disulfanyl}ethyl) amino]hexyl}amino)methyl]phenyl}meth-
a n on e Hexa h yd r och lor id e (6). It was synthesized from 25
and 3316 following the procedure described for 4 and purified

Prazosin Analogues with a Polyamine Backbone
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3 369
by chromatography. Eluting with methylene chloride-etha-
nol-30% ammonia (8.5:1.5:0.15) afforded, in 31% yield, 6 as
the free base that was converted into the hexahydrochloride
salt: mp 250 °C (from EtOH/Et2O); 1H NMR (CD3OD) δ 2.01-
2.19 (m, 8), 2.31-2.58 (m, 8), 3.61-3.79 (m, 8), 3.82-4.09 (m,
8), 4.10-4.29 (m, 4), 4.46-4.71 (m, 4), 4.62 (s, 12), 4.64-4.81
(m, 8), 4.92 (s, 4), 8.22-8.38 (m, 4), 8.40-8.59 (m, 8), 9.41 (br
s, 2, exchangeable with D2O), 9.72 (br s, 2, exchangeable with
D2O), 10.05 (br s, 4, exchangeable with D2O), 10.20 (br s, 6,
exchangeable with D2O). MALDI-MS calcd for C60H85N14O6S2
1161.62 (M + H)+, found 1161.66. Anal. (C60H90Cl6N14O6S2)
C, H, N.
N1-{6-[(4-Am in o-6,7-dim eth oxyqu in azolin -2-yl)(m eth yl)-
a m in o]h e xyl}-N 1-m e t h yl-2-{[(6-{[6-({2-[(2-{[6-[(2-{[(6-
[(4-a m in o-6,7-d im eth oxyqu in a zolin -2-yl)(m eth yl)a m in o]-
h exyl}(m et h yl)a m in o]ca r b on yl}b en zyl)a m in o]h exyl}-
a m in o )e t h y l]d is u lfa n y l}e t h y l)a m in o ]h e x y l)a m in o )-
m et h yl}b en zen a m id e H exa h yd r och lor id e (7). It was
synthesized from 30 and 3316 following the procedure described
for 4 and purified by chromatography. Eluting with methylene
chloride-ethanol-30% ammonia (8.5:1.5:0.15) afforded 60 mg
(34% yield) of 7 as free base, which was converted into the
hexahydrochloride salt: mp 199-203 °C (from EtOH/Et2O);
1H NMR (free base; CDCl3) δ 1.01-1.81 (m, 32 + 4 exchange-
able with D2O), 2.41-2.70 (m, 8), 2.7-3.21 (m, 22), 3.49-3.80
(m, 10), 3.88 (s, 6), 3.93 (s, 6), 5.39 (br s, 2, exchangeable with
D2O), 5.55 (br s, 2, exchangeable with D2O), 6.81-7.01 (m, 4),
7.12-7.43 (m, 8). MALDI-MS calcd for C68H105N14O6S2 1277.78
(M + H)+, found 1277.94. Anal. (C68H110Cl6N14O6S2) C, H, N.
8), 3.21-3.39 (m, 4), 3.71-3.99 (m, 12), 3.74 (s, 4), 3.88 (s, 6),
3.92 (s, 6), 5.66 (br s, 4, exchangeable with D2O), 6.86 (s, 2),
6.98 (s, 2), 7.15-7.21 (m, 8). MALDI-MS calcd for C62H89N14O6
1125.71 (M + H)+, found 1125.83. Anal. (C62H94Cl6N14O6) C,
H, N.
[4-(4-Am in o-6,7-d im eth oxyqu in a zolin -2-yl)p ip er a zin o]-
(3-{[(6-{[6-({6-[(3-{[4-(4-a m in o-6,7-d im eth oxyqu in a zolin -
2-yl)p ip er a zin o]ca r b on yl}b en zyl)a m in o]h exyl}a m in o)-
h exyl]a m in o}h exyl) a m in o]m et h yl}p h en yl)m et h a n on e
Hexa h yd r och lor id e (11). It was synthesized from 21 and
3416 following the procedure described for 4 and purified by
chromatography. Eluting with chloroform-ethanol-30% am-
monia (7.5:2.5:0.25) afforded in 55% yield 11 as the free base
that was converted into the hexahydrochloride salt: mp > 300
°C (from EtOH/Et2O); 1H NMR (D2O) δ 1.15-1.26 (m, 12),
1.39-1.60 (m, 12), 2.78-2.85 (m, 8), 2.91 (t, 4), 3.43-3.81 (m,
16), 3.64 (s, 6), 3.71 (s, 6), 4.13 (s, 4), 6.55 (s, 2), 6.84 (s, 2),
7.39-7.55 (m, 8). MALDI-MS calcd for C62H89N14O6 1125.71
(M + H)+, found 1125.71. Anal. (C62H94Cl6N14O6) C, H, N.
[4-(4-Am in o-6,7-dim eth oxyqu in azolin -2-yl)piper azin o]-
(4-{[(6-{[6-({6-[(4-{[4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-
p ip er a zin o]ca r bon yl}ben zyl)a m in o]h exyl}a m in o)h exyl]-
amino}hexyl)amino]methyl}phenyl)methanone Hexahydro-
ch lor id e (12). It was synthesized from 25 and 3416 following
the procedure described for 4 and purified by chromatography.
Eluting with chloroform-methanol-30% ammonia (7.5:2.5:
0.25) afforded in 60% yield 12 as the free base that was
converted into the hexahydrochloride salt: mp > 300 °C (from
1
EtOH/Et2O); H NMR (free base; CDCl3) δ 1.12-1.62 (m, 24
+ 4 exchangeable with D2O) 2.51-2.69 (m, 12), 3.39-3.58 (m,
4), 3.69-3.99 (m, 12), 3.78 (s, 4), 3.87 (s, 6), 3.92 (s, 6), 5.42
(br s, 4, exchangeable with D2O) 6.82-6.93 (m, 4), 7.38 (s, 8).
MALDI-MS calcd for C62H89N14O6 1125.71 (M + H)+, found
1125.80. Anal. (C62H94Cl6N14O6) C, H, N.
N1-{6-[(4-Am in o-6,7-dim eth oxyqu in azolin -2-yl)(m eth yl)-
a m in o]h e xyl}-N 1-m e t h yl-3-{[(6-{[6-({2-[(3-{[6-[(2-{[(6-
[(4-a m in o-6,7-d im eth oxyqu in a zolin -2-yl)(m eth yl)a m in o]-
h exyl}(m et h yl)a m in o]ca r b on yl}b en zyl)a m in o]h exyl}-
a m in o )e t h y l]d is u lfa n y l}e t h y l)a m in o ]h e x y l)a m in o )-
m et h yl}b en zen a m id e H exa h yd r och lor id e (8). It was
synthesized from 31 and 3316 following the procedure described
for 4 and purified by chromatography. Eluting with chloroform-
methanol-30% ammonia (8.5:1.5:0.15) gave, in 31% yield, 8
as the free base that was converted into the hexahydrochloride
salt: mp 229 °C (from EtOH/Et2O); 1H NMR (free base; CDCl3)
δ 1.01-1.78 (m, 32), 2.08 (br s, 4, exchangeable with D2O),
2.24-2.41 (m, 8), 2.71-3.21 (m, 22), 3.41-3.70 (m, 6), 3.75 (s,
4), 3.84 (s, 6), 3.91 (s, 6), 5.41 (br s, 4, exchangeable with D2O),
6.81-6.95 (m, 4), 7.18-7.38 (m, 8). MALDI-MS calcd for
N1-{6-[(4-Am in o-6,7-dim eth oxyqu in azolin -2-yl)(m eth yl)-
a m i n o ]h e x y l}-N 1-m e t h y l-2-{[(6-{[6-({6-[(2-{[{6-[(4-
a m in o-6,7-d im et h oxyq u in a zolin -2-yl)(m et h yl)a m in o]-
h exyl}(m et h yl)a m in o]ca r b on yl}b en zyl)a m in o]h exyl}-
a m i n o )h e x y l]a m i n o }h e x y l)a m i n o ]m e t h y l}b e n z e n -
a m id e Hexa h yd r och lor id e (13). It was synthesized from 30
and 3416 following the procedure described for 4 and purified
by chromatography. Eluting with chloroform-ethanol-30%
ammonia (8:2:0.2) afforded, in 43% yield, 13 as the free base
that was converted into the hexahydrochloride salt: mp 250-
255 °C (from EtOH/Et2O); 1H NMR (free base; CDCl3) δ 1.10-
1.71 (m, 40), 2.07 (br s, 4, exchangeable with D2O), 2.40-2.61
(m, 12), 2.77 (s, 3), 2.90-3.18 (m, 11), 3.44-3.72 (m, 6), 3.69
(s, 4), 3.86 (s, 6), 3.93 (s, 6), 5.29 (br s, 2, exchangeable with
D2O), 5.43 (br s, 2, exchangeable with D2O), 6.83 (s, 2), 6.85-
6.92 (m, 2) 7.09-7.43 (m, 8). MALDI-MS calcd for C70H109N14O6
1241.87 (M + H)+, found 1241.88. Anal. (C70H114Cl6N14O6) C,
H, N.
N1-{6-[(4-Am in o-6,7-dim eth oxyqu in azolin -2-yl)(m eth yl)-
a m i n o ]h e x y l}-N 1-m e t h y l-3-{[(6-{[6-({6-[(3-{[{6-[(4-
a m in o-6,7-d im et h oxyq u in a zolin -2-yl)(m et h yl)a m in o]-
h exyl}(m et h yl)a m in o]ca r b on yl}b en zyl)a m in o]h exyl}-
a m i n o )h e x y l]a m i n o }h e x y l)a m i n o ]m e t h y l}b e n z e n -
a m id e Hexa h yd r och lor id e (14). It was synthesized from 31
and 3416 following the procedure described for 4 and purified
by chromatography. Eluting with chloroform-methanol-30%
ammonia (8:2:0.2) afforded, in 42% yield, 14 as the free base
that was converted into the hexahydrochloride salt: mp > 300
°C (from EtOH/Et2O); 1H NMR (free base; CDCl3) δ 1.10-1.71
(m, 40 + 4 exchangeable with D2O), 2.41-2.71 (m, 12), 2.80-
3.31 (m, 14), 3.41-3.72 (m, 6), 3.76 (s, 4), 3.87 (s, 6), 3.93 (s,
6), 5.41 (br s, 4, exchangeable with D2O), 6.88 (s, 4), 7.19-
7.41 (m, 8). MALDI-MS calcd for C70H109N14O6 1241.87 (M +
H)+, found 1242.02. Anal. (C70H114Cl6N14O6) C, H, N.
C
68H105N14O6S2 1277.78 (M + H)+, found 1277.82. Anal.
(C68H110Cl6N14O6S2) C, H, N.
N1-{6-[(4-Am in o-6,7-dim eth oxyqu in azolin -2-yl)(m eth yl)-
a m in o]h e xyl}-N 1-m e t h yl-4-{[(6-{[6-({2-[(4-{[6-[(2-{[(6-
[(4-a m in o-6,7-d im eth oxyqu in a zolin -2-yl)(m eth yl)a m in o]-
h exyl}(m et h yl)a m in o]ca r b on yl}b en zyl)a m in o]h exyl}-
a m in o )e t h y l]d is u lfa n y l}e t h y l)a m in o ]h e x y l)a m in o )-
m et h yl}b en zen a m id e H exa h yd r och lor id e (9). It was
synthesized from 32 and 3316 following the procedure described
for 4 and purified by chromatography. Eluting with chloroform-
ethanol-30% ammonia (8.5:1.5:0.15) gave, in 23% yield, 9 as
the free base that was converted into the hexahydrochloride
salt: mp 241 °C (from EtOH/Et2O); 1H NMR (free base; CDCl3)
δ 1.09-1.73 (m, 32), 2.03 (br s, 4, exchangeable with D2O),
2.50-2.61 (m, 8), 2.70-3.21 (m, 22), 3.41-3.71 (m, 6), 3.78 (s,
4), 3.88 (s, 6), 3.94 (s, 6), 5.36 (br s, 4, exchangeable with D2O),
6.83 (s, 2), 6.91 (s, 2), 7.32 (s, 8). MALDI-MS calcd for
C
68H105N14O6S2 1277.78 (M + H)+, found 1277.82. Anal.
(C68H110Cl6N14O6S2) C, H, N.
[4-(4-Am in o-6,7-d im eth oxyqu in a zolin -2-yl)p ip er a zin o]-
(2-{[(6-{[6-({6-[(2-{[4-(4-a m in o-6,7-d im eth oxyqu in a zolin -
2-yl)p ip er a zin o]ca r b on yl}b en zyl)a m in o]h exyl}a m in o)-
h exyl]a m in o}h exyl) a m in o]m et h yl}p h en yl)m et h a n on e
Hexa h yd r och lor id e (10). It was synthesized from 17 and
3416 following the procedure described for 4 and purified by
chromatography. Eluting with chloroform-ethanol-30% am-
monia (7.5:2.5:0.25) afforded, in 60% yield, 10 as the free base
that was converted into the hexahydrochloride salt: mp 259
°C (from EtOH/Et2O); 1H NMR (free base; CDCl3) δ 1.20-1.69
(m, 24 + 4 exchangeable with D2O), 2.54 (t, 4), 2.55-2.64 (m,
N1-{6-[(4-Am in o-6,7-dim eth oxyqu in azolin -2-yl)(m eth yl)-
a m i n o ]h e x y l}-N 1-m e t h y l-4-{[(6-{[6-({6-[(4-{[{6-[(4-
a m in o-6,7-d im et h oxyq u in a zolin -2-yl)(m et h yl)a m in o]-
h exyl}(m et h yl)a m in o]ca r b on yl}b en zyl)a m in o]h exyl}-
a m i n o )h e x y l]a m i n o }h e x y l)a m i n o ]m e t h y l}b e n z e n -
a m id e Hexa h yd r och lor id e (15). It was synthesized from 32

370 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3
Bolognesi et al.
and 3416 following the procedure described for 4 and purified
by chromatography. Eluting with chloroform-methanol-30%
ammonia (7.75:2.25:0.25) afforded, in 48% yield, 15 as the free
base that was converted into the hexahydrochloride salt: mp
220 °C (from EtOH/Et2O); 1H NMR (free base; CDCl3) δ 1.10-
1.79 (m, 40 + 4 exchangeable with D2O),2.45-2.79 (m, 12),
2.80-3.15 (m, 14), 3.21-3.76 (m, 6), 3.77 (s, 4), 3.88 (s, 6), 3.92
(s, 6), 5.58 (br s, 4, exchangeable with D2O), 6.91-7.02 (m, 4),
7.217.38 (m, 8). MALDI-MS calcd for C70H109N14O6 1241.87 (M
+ H)+, found 1241.97. Anal. (C70H114Cl6N14O6) C, H, N.
Biology. F u n ction a l An ta gon ism in Isola ted Tissu es.
Male Wistar rats (275-300 g) were killed by cervical disloca-
tion, and the organs required were isolated, freed from
adhering connective tissue, and set up rapidly under a suitable
resting tension in 20 mL organ baths containing physiological
salt solution kept at 37 °C and aerated with 5% CO2-95% O2
at pH 7.4. Concentration-response curves were constructed
by cumulative addition of agonist. The concentration of agonist
in the organ bath was increased approximately 3-fold at each
step, with each addition being made only after the response
to the previous addition had attained a maximal level and
remained steady. Contractions were recorded by means of a
force displacement transducer connected to the MacLab system
PowerLab/800 and to a poligraph channel recorder (Gemini).
In addition, parallel experiments in which tissues did not
receive any antagonist were run in order to check any variation
in sensitivity.
Va s Defer en s P r osta tic P or tion . This tissue was used
to assess the antagonism toward R1A-adrenoreceptors.18 Pro-
static portions of 2 cm length were mounted under 0.5 g
tension at 37 °C in Tyrode solution of the following composition
(mM): NaCl, 130; KCl, 2; CaCl2, 1.8; MgCl2, 0.89; NaH2PO4,
0.42; NaHCO3, 25; glucose, 5.6. Cocaine hydrochloride (0.1 µM)
was added to the Tyrode to prevent the neuronal uptake of
(-)-noradrenaline. The preparations were equilibrated for 60
min with washing every 15 min. After the equilibration period,
tissues were primed two times by addition of 10 µM norad-
renaline. After another washing and equilibration period of
60 min, a noradrenaline concentration-response curve was
constructed (basal response). When measuring the effect of
noncompetitive antagonism, the antagonist was allowed to
equilibrate with the tissue for 30 min followed by 30 min
washing; then a new concentration-response curve to the
agonist was obtained. In all other cases, the antagonist was
allowed to equilibrate with the tissue for 30 min before
constructing a new concentration-response curve to the
agonist. (-)-Noradrenaline solutions contained 0.05% Na2S2O5
to prevent oxidation.
noradrenaline and to block â-adrenoreceptors, respectively.
Two helicoidal strips (15 mm × 3 mm) were cut from each
aorta beginning from the end most proximal to the heart. The
endothelium was removed by rubbing with filter paper: the
absence of acetylcholine (100 µM)-induced relaxation to prepa-
rations contracted with (-)-noradrenaline (1 µM) was taken
as an indicator that the vessel was denuded successfully.
Vascular strips were then tied with surgical thread and
suspended in a jacketed tissue bath containing Tyrode solu-
tion. Strip contractions were measured isometrically. After at
least a 2 h equilibration period under an optimal tension of 1
g, cumulative (-)-noradrenaline concentration-response curves
were recorded at 1 h intervals, the first two being discarded
and the third one taken as control. The antagonist was allowed
to equilibrate with the tissue for 30 min before the generation
of the fourth cumulative concentration-response curve to (-)-
noradrenaline. (-)-Noradrenaline solutions contained 0.05%
K2EDTA in 0.9% NaCl to prevent oxidation.
Da ta An a lysis. The affinity constants (pKb values, Table
1) that were determined according to Arunlakshana and
Schild21 with the equation pKb ) -log Kb ) log(DR - 1) - log
[B], where DR represents the ratio of the potency of the agonist
(EC50) in the presence of the antagonist [B] and in its absence.
EC50 values were calculated at two or three different antago-
nist concentrations. Each concentration was tested at least four
times. The noncompetitive antagonist potency was expressed
by the negative logarithm of concentration that causes 50%
inhibition of agonist action (pIC50, Table 1). Data were
analyzed by pharmacological computer programs24 and are
presented as the mean ( SE of n experiments. Differences
between mean values were tested for significance by Student’s
t-test.
Ack n ow led gm en t. We thank Dr. C. Andalo` (De-
partment of Chemistry “G. Ciamician”, University of
Bologna) for mass spectra data. This research was
supported by grants from the University of Bologna and
MURST.
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J M000995W