Synthesis and structure-activity relationship of fluoro analogues of 8-{2-[4-(4-methoxyphenyl)piperazin-1yl]ethyl}-8-azaspiro[4.5]decane-7,9-dione as selective α1d-adrenergic receptor antagonists

Article abstract of DOI:10.1021/jm0491391

We have discovered high-affinity antagonists (exemplified by 11 and 12) that are the most selective for α_1d-adrenergic receptors (α_1d-AR) reported to date. In cloned receptor assay systems, 12 displays at least 95-fold selectivity fo

Full text of DOI:10.1021/jm0491391

3076
J. Med. Chem. 2005, 48, 3076-3079
Brief Articles
Synthesis and Structure-Activity Relationship of Fluoro Analogues of
8-{2-[4-(4-Methoxyphenyl)piperazin-1yl]ethyl}-8-azaspiro[4.5]decane-7,9-dione as
Selective r1d-Adrenergic Receptor Antagonists
Michael J. Konkel,* John M. Wetzel, Marie Cahir,† Douglas A. Craig, Stewart A. Noble,‡ and
Charles Gluchowski§
Lundbeck Research USA, Inc., 215 College Road, Paramus, New Jersey 07652
Received October 26, 2004
We have discovered high-affinity antagonists (exemplified by 11 and 12) that are the most
selective for R1d-adrenergic receptors (R1d-AR) reported to date. In cloned receptor assay systems,
12 displays at least 95-fold selectivity for the R1d-AR over all other G-protein-coupled receptors
tested, and the subtype selectivity of 11 was confirmed in pharmacologically defined isolated
tissue preparations.
Chart 1
R-Adrenergic receptors (R-ARs) modulate intercellular
biochemical processes in response to changes in extra-
cellular concentrations of the neurotransmitter norepi-
nephrine and the circulating hormone epinephrine,
leading to widespread physiological actions that make
them attractive targets for drug discovery.1 Antagonists
that are highly selective for the R1a-AR are well-known,1c
and recent reports have described compounds with
modest selectivity for the R1b-AR.2 Saussy et al. have
reported that 5 (Chart 1)3 is selective for the R1d-AR,4
and this has been confirmed in our assay systems (Table
1). However, 5 (pKi ) 8.8 at R1d) also has comparable
or higher affinity for several other G-protein-coupled
receptors (GPCRs),4 including the serotonin 5-HT1A
receptor and the dopamine D2 and D3 receptors (Table
1). Cystazosin5 has also been reported to be selective
for the R1D -AR and devoid of cross-reactivity to 5-HT1A
and dopamine receptors. Its subtype selectivity, how-
ever, is only about 10-fold. Recently, A-315456 has been
reported6 to be selective for the R1D-AR with low cross
reactivity to 5-HT1A and D2. Also, recently a report by
a group from Recordati on analogues of 5 with low cross-
reactivity has appeared.7 The report did not mention
whether the Recordati compounds had significant cross-
reactivity to dopamine receptors, a known cross-reactiv-
ity of 5.6
Scheme 1. Synthesis of Compounds 6-13a
We describe herein the synthesis and SAR of fluoro
analogues of 5 and novel trifluoro analogues that show
decreased affinity for 5-HT1A, D2, and D3 receptors while
maintaining high affinity and subtype selectivity for the
R1d-AR.8,9
a Reagents and conditions: (a) 2-ethanolamine or 2-aminopro-
panol; (b) SOCl2, 45% from 1; (c) substituted N-phenylpiperazine,
22-50%.
* To whom correspondence should be addressed. Phone: 201-350-
0355. Fax: 201-261-0623. E-mail: miko@lundbeck.com.
† Present address: Department of Mental Health, Queen’s Univer-
sity Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast, BT9
7BL, N. Ireland.
Synthesis
Compounds 6-13 were synthesized as outlined in
Scheme 1. 3,3-Tetramethyleneglutaric anhydride (1)
was allowed to react with ethanolamine, giving a
mixture of imide 2 and amide 3a. The crude mixture of
imide 2 and amide 3a was treated with thionyl chloride,
‡ Present address: Kalypsys, Inc., 11099 North Torrey Pines Road,
La Jolla, CA 92037.
§ Present address: Life Science Solutions, 154 Coolspring Ct.,
Danville, CA 94506.
10.1021/jm0491391 CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/30/2005

Brief Articles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 8 3077
Table 1. Binding Affinities at Cloned R-Adrenoceptors, 5-HT1A
,
for the 5-HT1A and D2 receptors (16- and 13-fold,
respectively) but essentially unchanged affinity for the
and Dopamine Receptors
R1d and D3 receptors (Table 1). The 4-fluoro-substituted
7 displays a 18-fold decrease in R1d-AR affinity and a
decrease in the selectivity for R1d versus 5-HT1A com-
pared to the 2-fluoro-substituted 6. For difluoro substi-
tution, the substitution pattern of the fluorine atoms
on the phenyl ring is critical for maximizing the affinity
and selectivity for the R1d-AR. For instance, it was found
that the affinity for R1d for 2,5-difluoro-substituted 10
is equivalent to the 2-fluoro-substituted 6 while affinity
for the 5-HT1A and R1a receptors is decreased. Compared
to 2,5-difluoro substitution (10), the binding affinity and
selectivity for the R1d-AR decreased with 2,4-difluoro
substitution (8) or 3,4-difluoro substitution (9). The
trifluorophenyl-substituted 11 exhibits R1d-AR affinity
approximately equal to that of 5 while displaying
significantly decreased affinity for R1a, 5-HT1a, and D2
receptors (Table 1). The affinity of 11 for the D3 receptor
was reduced relative to 5 (6-fold) but was still signifi-
cantly high (Ki ) 23 nM).
Ki (nM)a
compd
R1
R2 R3 R4 R1d
R1b
R1a 5-HT1A D2
D3
5
6
H
H
H
H
H
H
H
OMe
F
H
H
F
F
F
H
F
F
F
H
H
H
H
F
1.6
191 290
0.46
7.5
54
14
3.1
0.83 67
630
140 5.2
2200 91
7
H
14
255 620
8
F
5.6
7.9
1100 3800 24
1400 4100 55
NTb NTb
2200 160
120 8.1
700 23
9
H
F
F
10
11
12
13
F
0.95 54
1000 25
F
1.9
1.3
380 4400 360
165 14000 300
(R)-Me F
(S)-Me
F
F
580 120
F
>124 NTb NTb
NTb
NTb NTb
a R1d, R1b, R1a, 5-HT1A, and D2 are cloned human receptors. D3
is a cloned rat receptor. Ki determinations are an average of two
or more (four to six for key compounds) independent determina-
tions. The margin of error is within 5% of the mean for all data
shown. b NT: not tested.
Placement of a methyl group on the linker (12)
resulted in decreased binding affinity at the D3 receptor
(Ki ) 123 nM) while maintaining high affinity for the
R1d-AR (Ki ) 1.3 nM) and greater than 100-fold selectiv-
ity over other GPCRs including R1a, R1b, R2c, R2a, R2b,
D2, and 5-HT1A. The (R)-configuration of the methyl
group is important because the (S)-isomer was found
to have significantly lower binding affinity for the R1d-
AR (Ki g 124 nM).12
In conclusion, we have discovered high-affinity an-
tagonists (exemplified by 11 and 12) that are the most
selective for the R1d-AR reported to date. In cloned
receptor assay systems, 12 displays at least 95-fold
selectivity for the R1d-AR over all other GPCRs tested,
and the subtype selectivity of 11 was confirmed in
pharmacologically defined isolated tissue preparations.
These compounds display the highest selectivity for the
R1d-AR thus far reported and should prove useful for
further functional characterization of R1-ARs in in vivo
models. The information gained through such studies
will aid in the understanding of the physiological
importance of the individual R1-AR subtypes and po-
tentially lead to the discovery of therapies that benefit
from selective modulation of R1-ARs.
resulting in condensation of the amide to the imide and
substitution of the hydroxyl group with chloride. The
resulting intermediates 4 were treated with the ap-
propriately substituted N-arylpiperazines, giving the
desired compounds 6-13. The N-arylpiperazines were
commercially available or synthesized by a previously
described procedure.10 For 12 (and its enantiomer 13),
tetramethyleneglutaric anhydride (1) was allowed to
react with optically pure (R)-2-aminopropanol (or (S)-
2-aminopropanol), giving imide 3b that was converted
to 4b by thionyl chloride treatment.
Pharmacology
Radioligand binding experiments were performed on
membranes prepared from cells transiently transfected
with DNA for the cloned human R-AR (R1a, R1b, and R1d)
and 5-HT1A, as described previously.11 Membranes for
dopamine human D2 and rat D3 receptors were pur-
chased from New England Nuclear Corporation. The
binding affinities (Ki) were determined by displacement
of the following radioligands: [3H]prazosin (0.3 nM, R1-
ARs), [3H]-8-hydroxy-2-(di-n-propylamino)tetralin (8-
OH-DPAT, 0.3 nM, 5-HT1A), or [3H]spiperone (1 nM, D2,
D3). The results are presented in Table 1.
The KB of 11 at native R1-ARs was determined by
measuring antagonism of phenylephrine-evoked con-
tractions in three pharmacologically defined isolated rat
tissue preparations: vas deferens (R1A), spleen (R1B), and
thoracic aorta (R1D). In each of the preparations 11
behaved as a competitive antagonist. The KB determined
for each tissue (R1A, 5.4; R1B, 6.7; R1D, 8.8) correlates well
with the corresponding Ki derived from binding experi-
ments.
Experimental Section
General Methods. Substituted N-phenylpiperazines were
synthesized according to the procedure described by Martin.10
The syntheses of 4 were carried out as described previously
by Y. H. Wu.3 (R)-2-Aminopropanol and (S)-2-aminopropanol
were purchased from Aldrich and both are listed as 97% ee.
The actual ee purity for the batch of (R)-2-aminopropanol used
in the syntheses described herein was 99.9% (GLC) as com-
municated to us by Aldrich. Enantiomeric purities of 12 and
13 were determined by chiral HPLC, using a Chiralcel OD,
0.46 cm × 25 cm column (Daicel Chemical Industries, LTD),
Structure-Activity Relationships
1 mL/min (5% EtOH/95% hexane with 0.1% TEA). 1H and 13
C
We hypothesized that the selectivity of 5 for the R1d-
AR over the R1a- and R1b-ARs could be largely attributed
to the imide moiety because many examples were known
of 1-substituted 4-(methoxyphenyl)piperazines that were
not R1d-selective.1c Therefore, we focused our initial
studies on modification of the piperazine moiety.
It was found that the methoxyl group of 5 could be
replaced with fluorine (6), resulting in decreased affinity
NMR spectra were obtained at 300 and 75 MHz, respectively,
with CDCl3 as solvent and referenced to TMS as an internal
standard. Coupling constants (J) are reported in Hz.
8-[(1R)-2-Chloro-1-methylethyl]-8-azaspiro[4.5]decane-
7,9-dione (4b). A mixture of 3,3-tetramethyleneglutaric an-
hydride (1.12 g, 6.66 mmol) and (R)-(-)-2-amino-1-propanol
(Aldrich, 1.00 g, 13.3 mmol) in pyridine (15 mL) was heated
at reflux for 3 h. The solvent was removed, and the residue
was partioned between 1 N HCl (10 mL) and ethyl acetate

3078 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 8
Brief Articles
(10 mL). The aqueous layer was extracted with ethyl acetate
(2 × 10 mL). The combined ethyl acetate fractions were dried
over sodium sulfate and then the solvent was removed, leaving
a clear oil (1.92 g). A portion of this oil (0.70 g) in benzene (9
mL) and pyridine (0.40 mL) was cooled to 0 °C. Thionyl
chloride (0.40 mL) was added dropwise to the mixture, and
then the solution was heated at 60 °C for 90 min. The solution
was cooled to room temperature, and water (10 mL) was added.
The layers were separated, and the aqueous layer was
extracted with ethyl acetate (2 × 10 mL). The solvent was
removed from the combined organic fractions, and the residue
was purified by flash chromatography over silica gel, eluting
with hexane/ethyl acetate (3:1). The Rf ) 0.3 fraction was
concentrated, giving the title compound as a pale-yellow oil
(294 mg). 1H NMR δ 5.09-5.04 (m, 1H), 4.17 (t, 1H, J ) 10.5),
3.66 (dd, 1H, J ) 11.1, 5.7), 2.61 (s, 4H), 1.76-1.69 (m, 4H),
1.56-1.51 (m, 4H), 1.40 (d, 3H, J ) 6.9). The (S)-enantiomer
was synthesized in an identical manner.
45.5 (2C), 40.2, 38.1 (2C), 37.0, 24.8 (2C); ESI-MS m/z 374
(MH+). The title compound was dissolved in ether and pre-
cipitated by addition of 1 N HCl in ether, giving a white solid
(mp 238-229.5 °C).
8-{2-[4-(3,4-Difluorophenyl)piperazin-1yl]ethyl}-8-aza-
spiro[4.5]decane-7,9-dione (9). A mixture of 1-(3,4-difluo-
rophenyl)piperazine (100 mg, 0.51 mmol) and 8-(2-chloroethyl)-
8-azaspiro[4.5]decane-7,9-dione (100 mg, 0.44 mmol) was
heated with stirring at 160 °C for 7 h. The residue was
dissolved in methanol, transferred to a preparative thin layer
chromatographic plate (silica gel), and eluted with ethyl
acetate/hexane (1:1). A band at Rf ) 0.3 was removed and
rinsed with chloroform/methanol (4:1). The solvent was re-
moved, giving the title compound as a pale-yellow oil (69.8 mg,
1
0.18 mmol, 41%). H NMR δ 7.17 (q, 1H, J ) 9.3), 6.65 (ddd,
1H, J ) 13.5, 6.9, 3.0), 6.59-6.54 (m, 1H), 3.97 (t, 2H, J )
6.5), 3.07 (t, 4H, J ) 4.8), 2.68 (t, 4 H, J ) 5.0), 2.60 (s, 4H),
2.58 (t, 2H, J ) 6.3), 1.72-1.68 (m, 4H), 1.54-1.50 (m, 4H);
ESI-MS m/z 392 (MH+). The title compound was dissolved in
ether and precipitated by addition of 1 N HCl in ether, giving
white flakes (mp 227-228 °C).
8-{2-[4-(2-Fluorophenyl)piperazin-1yl]ethyl}-8-azaspiro-
[4.5]decane-7,9-dione (6). A mixture of 1-(2-fluorophenyl)-
piperazine (100 mg, 0.56 mmol) and 8-(2-chloroethyl)-8-azaspiro-
[4.5]decane-7,9-dione (100 mg, 0.44 mmol) was heated with
stirring at 160 °C for 5 h. The residue was dissolved in
methanol, transferred to a preparative thin layer chromato-
graphic plate (silica gel), and eluted with ethyl acetate/hexane
(1:1). A band at Rf ) 0.3 was removed and rinsed with
chloroform/methanol (4:1). The solvent was removed, giving
the title compound as pale-yellow oil (81.7 mg, 0.22 mmol,
8-{2-[4-(2,5-Difluorophenyl)piperazin-1yl]ethyl}-8-aza-
spiro[4.5]decane-7,9-dione (10). A mixture of 1-(2,5-difluo-
rophenyl)piperazine (100 mg, 0.51 mmol) and 8-(2-chloroethyl)-
8-azaspiro[4.5]decane-7,9-dione (100 mg, 0.44 mmol) was
heated with stirring at 160 °C for 5 h. The residue was
dissolved in methanol, transferred to a preparative thin layer
chromatographic plate (silica gel), and eluted with ethyl
acetate/hexane (1:1). A band at Rf ) 0.7 was removed and
rinsed with chloroform/methanol (4:1). The solvent was re-
moved, giving the title compound as a pale-yellow oil. 1H NMR
δ 6.99-6.89 (11-line m, 1H), 6.65-6.52 (m, 2H), 3.95 (t, 2H, J
) 6.5), 3.03 (t, 4H, J ) 4.7), 2.66 (t, 4 H, J ) 4.7), 2.60 (s, 4H),
2.54 (t, 2H, J ) 6.6), 1.74-1.69 (m, 4H), 1.55-1.51 (m, 4H);
ESI-MS m/z 392 (MH+). The title compound was dissolved in
ether and precipitated by addition of 1 N HCl in ether, giving
a white solid (64.9 mg, 0.15 mmol, 35%) (mp 237-239 °C).
1
50%). H NMR δ 7.04 (td, 1H, J ) 9.3, 1.5), 7.01 (t, 1H, J )
6.9), 6.97-6.87 (m, 2H), 3.96 (t, 2H, J ) 6.6), 3.05 (t, 4H, J )
4.8), 2.67 (t, 4 H, J ) 4.7), 2.59 (s, 4H), 2.54 (t, 2H, J ) 6.6),
1.73-1.68 (m, 4H), 1.55-1.50 (m, 4H); 13C NMR δ 172.8, 156.3
(d, J ) 244.4), 140.8 (d, J ) 8.5), 125.0 (d, J ) 3.4), 122.8 (d,
J ) 8.0), 119.5 (d, J ) 2.9), 116.7 (d, J ) 20.7), 56.1, 53.9 (2C),
51.2 (d, 2C, J ) 3.1), 45.5 (2C), 40.2, 38.1 (2C), 37.1, 24.8 (2C);
ESI-MS m/z 374 (MH+). The title compound was dissolved in
ether and precipitated by addition of 1 N HCl in ether, giving
a white solid (mp 212-214 °C).
8-{2-[4-(2,4,5-Trifluorophenyl)piperazin-1yl]ethyl}-8-
azaspiro[4.5]decane-7,9-dione (11). A mixture of 1-(2,4,5-
trifluorophenyl)piperazine (0.94 g, 4.35 mmol) and 8-(2-
chloroethyl)-8-azaspiro[4.5]decane-7,9-dione (1.00 g, 4.35 mmol)
was heated with stirring at 160 °C for 7 h. The residue was
partitioned between ethyl acetate (40 mL) and saturated
aqueous sodium carbonate (40 mL). The aqueous layer was
extracted with ethyl acetate (2 × 40 mL), and the combined
ethyl acetate fractions dried over sodium sulfate. The solvent
was removed, and the residue was purified by flash chroma-
tography over silica gel, eluting with a gradient of hexane to
hexane/ethyl acetate (1:1). The solvent was removed from the
desired product [Rf ) 0.7, hexane/ethyl acetate (1:1)], leaving
a pale-tan oil that slowly solidified (0.652 g, 1.60 mmol, 37%,
mp 230-234 °C). 1H NMR δ 6.89 (ddd, 1H, J ) 11.7, 10.2,
7.5), 6.74 (dt, 1H, J ) 12.0, 8.1), 3.95 (t, 2H, J ) 6.6), 2.97 (t,
4H, J ) 4.7), 2.65 (t, 4 H, J ) 4.7), 2.60 (s, 4H), 2.54 (t, 2H, J
) 6.5), 1.74-1.70 (m, 4H), 1.55-1.51 (m, 4H); 13C NMR δ
172.7, 151.0 (ddd, J ) 243.8, 8.5, 1.7), 146.9 (ddd, J ) 241.6,
12.2, 3.2), 144.7 (ddd, J ) 242.3, 13.9, 12.4), 137.4 (ddd, J )
9.6, 6.1, 2.9), 107.9 (dd, J ) 20.7, 4.1), 106.4 (dd, J ) 26.6,
21.5), 55.9, 53.6 (2C), 51.3 (d, 2C, J ) 3.0), 45.4 (2C), 40.1,
38.0 (2C), 36.9, 24.7 (2C); ESI-MS m/z 410 (MH+). The title
compound was dissolved in ether and precipitated by addition
of 1 N HCl in ether, giving a white solid. The solid was
recrystallized from hot methanol/chloroform (4:1) (with hexane
added to cloudiness), giving white flakes (0.43 g, 0.96 mmol,
22%) (mp 234-236.5 °C).
8-{2-[4-(4-Fluorophenyl)piperazin-1-yl]ethyl}-8-aza-
spiro[4.5]decane-7,9-dione (7). A mixture of 1-(4-fluorophen-
yl)piperazine (100 mg, 0.56 mmol) and 8-(2-chloroethyl)-8-
azaspiro[4.5]decane-7,9-dione (100 mg, 0.44 mmol) was heated
with stirring at 160 °C for 7 h. The residue was dissolved in
methanol, transferred to a preparative thin layer chromato-
graphic plate (silica gel), and eluted with ethyl acetate/hexane
(1:1). A band at Rf ) 0.3 was removed and rinsed with
chloroform/methanol (4:1). The solvent was removed, giving
the title compound as pale-yellow oil (77.3 mg, 0.21 mmol,
48%). 1H NMR δ 6.95 (dd, 2H, J ) 9.3, 8.1), 6.85 (dd, 2H, J )
9.3, 4.8), 3.96 (t, 2H, J ) 6.6), 3.05 (t, 4H, J ) 5.0), 2.65 (t, 4
H, J ) 4.8), 2.59 (s, 4H), 2.54 (t, 2H, J ) 6.5), 1.72-1.67 (m,
4H), 1.54-1.49 (m, 4H); 13C NMR δ 172.9, 157.6 (d, J ) 237.1),
148.6, 118.2 (d, 2C, J ) 7.6), 116.0 (d, 2C, J ) 21.9), 56.0, 53.8
(2C), 50.8 (2C), 45.5 (2C), 40.2, 38.1 (2C), 37.1, 24.8 (2C); ESI-
MS m/z 374 (MH+). The title compound was dissolved in ether
and precipitated by addition of 1 N HCl in ether, giving a white
solid (mp 223-224 °C).
8-{2-[4-(3-Fluorophenyl)piperazin-1yl]ethyl}-8-azaspiro-
[4.5]decane-7,9-dione (8). A mixture of 1-(4-fluorophenyl)-
piperazine (100 mg, 0.56 mmol) and 8-(2-chloroethyl)-8-azaspiro-
[4.5]decane-7,9-dione (100 mg, 0.44 mmol) was heated with
stirring at 160 °C for 7 h. The residue was dissolved in
methanol, transferred to a preparative thin layer chromato-
graphic plate (silica gel), and eluted with ethyl acetate/hexane
(1:1). A band at Rf ) 0.3 was removed and rinsed with
chloroform/methanol (4:1). The solvent was removed, giving
the title compound as a pale-yellow oil (63.0 mg, 0.17 mmol,
8-{(1R)-2-[4-(2,4,5-Trifluorophenyl)piperazin-1-yl]-1-
methylethyl}-8-azaspiro[4.5]decane-7,9-dione (12). A mix-
ture of 1-(2,4,5-trifluorophenyl)piperazine (105 mg, 0.49 mmol)
and (R)-8-(2-chloro-1-methylethyl)-8-azaspiro[4.5]decane-7,9-
dione (105 mg, 0.43 mmol) was heated with stirring at 160 °C
for 5 h. The residue was dissolved in methanol, transferred to
a preparative thin layer chromatographic plate (silica gel), and
eluted with ethyl acetate/hexane (1:1). A band at Rf ) 0.8 was
removed and rinsed with chloroform/methanol (4:1). The
1
39%). H NMR δ 7.17 (q, 1H, J ) 8.1), 6.65 (dd, 1H, J ) 8.4,
2.1), 6.57 (dt, 1H, J ) 12.3, 2.3), 6.51 (td, 1H, J ) 8.1, 2.1),
3.96 (t, 2H, J ) 6.5), 3.13 (t, 4H, J ) 5.0), 2.63 (t, 4 H, J )
5.0), 2.59 (s, 4H), 2.53 (t, 2H, J ) 6.6), 1.74-1.64 (m, 4H),
1.52-1.48 (m, 4H); 13C NMR δ 172.9, 164.4 (d, J ) 241.6),
153.6 (d, J ) 9.2), 130.6 (d, J ) 9.8), 111.6 (d, J ) 2.2), 106.2
(d, J ) 21.4), 103.1 (d, J ) 24.8), 56.0, 53.6 (2C), 49.3 (2C),

Brief Articles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 8 3079
Forray, C.; Bock M. G. 4-Amino-2-[4-[1-(benzyloxycarbonyl)-2(S)-
[[(1,1-dimethylethyl)amino]carbonyl]-piperazinyl]-6,7-dimethox-
yquinazoline (L-765,314): A Potent and Selective R1b Adrenergic
Receptor Antagonist. J. Med. Chem., 1998, 41, 1205-1208.
(3) (a) Wu, Y. H. Azaspirodecanediones and Azaspiroundecanedi-
ones. U.S. Patent 3,398,151, 1968. (b) Wu, Y. H.; Smith, K. R.;
Rayburn, J. W. Psychosedative Agents. N-(4-Phenyl-1-piper-
azinylalkyl)-Substituted Cyclic Imides. J. Med. Chem. 1969, 12,
876-881.
solvent was removed, giving the title compound as a pale-
yellow oil (86.2 mg, 0.20 mmol, 47%, 100% ee). 1H NMR δ 6.89
(ddd, 1H, J ) 11.7, 10.2, 7.5), 6.71 (dt, 1H, J ) 12.0, 8.1), 5.08-
4.96 (m, 1H), 3.14 (dd, 1H, J ) 12.6, 10.5), 2.92 (t, 4H, J )
4.7), 2.73-2.66 (m, 2H), 2.58 (s, 4H), 2.51-2.44 (m, 2H), 2.36
(dd, 1H, J ) 12.6, 5.4), 1.75-1.68 (m, 4H), 1.57-1.50 (m, 4H),
1.34 (d, 3H, J ) 6.9); ESI-MS m/z 424 (MH+). The title
compound was dissolved in ether and precipitated by addition
of 1 N HCl in ether, giving a white solid (mp 231-235 °C).
8-{(1S)-2-[4-(2,4,5-Trifluorophenyl)piperazin-1-yl]-1-
methylethyl}-8-azaspiro[4.5]decane-7,9-dione (13). 13 was
prepared in a manner analogous to that described above for
11, giving the title compound as a pale-yellow oil (18.1 mg,
0.043 mmol, 52%, 98% ee). 1H NMR δ 6.89 (ddd, 1H, J ) 11.7,
10.2, 7.5), 6.71 (dt, 1H, J ) 12.0, 8.1), 5.08-4.96 (m, 1H), 3.14
(dd, 1H, J ) 12.6, 10.5), 2.92 (t, 4H, J ) 4.7), 2.73-2.66 (m,
2H), 2.58 (s, 4H), 2.51-2.44 (m, 2H), 2.36 (dd, 1H, J ) 12.6,
5.4), 1.75-1.68 (m, 4H), 1.57-1.50 (m, 4H), 1.34 (d, 3H, J )
6.9); ESI-MS m/z 424 (MH+). The title compound was dissolved
in ether and precipitated by addition of 1 N HCl in ether,
giving a white solid (mp 231-235 °C).
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King, H. K.; Lutz, M. W.; Rimele, T. J. Structure Activity
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Adrenoceptors: Further Evidence That Rat Aorta Alpha-1
Adrenoceptors Are of the Alpha-1D-Subtype. J. Pharmacol. Exp.
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Acknowledgment. We are indebted to the following
people for their support of this research: Y. Z. Zheng
for cell culture and membrane preparation; Thelma
Thompson, Dipa Deshpande, and Michelle Iacolina for
radioligand displacement assays; Faye Hsieh and Usha
Yeramilli for mass spectroscopic analysis; Qingping Han
for enantiomeric purity assessments. We are also in-
debted to the National Institutes of Health for financial
support of this project (SBIR Grant 1 R44 NS33418-
02).
(7) Leonardo, A.; Barlocco, D.; Montesano, F.; Cignarella, G.; Motta,
G.; Testa, R.; Poggesi, E.; Seeber, M.; De Benedetti, P. G.;
Fanelli, F. Synthesis, Screening, and Molecular Modeling of New
Potent and Selective Antagonists at the R1d-Adrenergic Receptor.
J. Med. Chem. 2004, 47, 1900-1918.
(8) A part of this work was disclosed at an ACS meeting: Konkel,
M. J.; Wetzel, J. M.; Cahir, M.; Craig, D.; Noble, S.; Gluchowski,
C. Discovery of Antagonists Selective for the Alpha-1D-Adreno-
ceptor. Presented at the 216th National Meeting of the American
Chemical Society, Boston, MA, August 23-27, 1998; Abstract
Medi 129.
(9) Two compounds described in this paper have been cited in
reviews: (a) Bremner, J. B.; Griffith, R.; Coban, B. Ligand
Design for Alpha(1) Adrenoceptors. Curr. Med. Chem. 2001, 8,
607-620. (b) Romeo, G.; Materia, L.; Salerno, L.; Russo, F.;
Minneman, K. P. Novel Antagonists for R1-Adrenoceptor Sub-
types. Expert Opin. Ther. Pat. 2004, 14, 619-636.
Supporting Information Available: Results from el-
emental analysis. This material is available free of charge via
the Internet at http://pubs.acs.org.
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Kesslick, J. M.; Baldy, W. J.; Shank, R. P.; DiStefano, D. L.;
Fedde, C. L.; Scott, M. K. Activity of Aromatic Substituted
Phenylpiperazines Lacking Affinity for Dopamine Sites in a
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Tang, R.; Lepor, H.; Hartig, P. R.; Weinshank, R. L.; Branchek,
T. A.; Gluchowski, C. The R1-Adrenergic Receptor That Mediates
Smooth Muscle Contraction in Human Prostate Has the Phar-
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