Arylpiperazine substituted heterocycles as selective alpha(1a) adrenergic antagonists.

Article abstract of DOI:10.1016/S0960-894X(02)00436-5

Antagonists of the alpha(1)-adrenergic receptors (alpha(1)-ARs) are useful for the treatment of benign prostatic hyperplasia. A series of potent and subtype-selective alpha(1a)-AR antagonists has been synthesized, displaying in vitro binding affinity in the low the nanomolar range.

Full text of DOI:10.1016/S0960-894X(02)00436-5

Bioorganic & Medicinal Chemistry Letters 12 (2002) 2443–2446
Arylpiperazine Substituted Heterocycles as Selective ꢀ1a
Adrenergic Antagonists
Haripada Khatuya, Richard H. Hutchings,y Gee-Hong Kuo, Virginia L. Pulito,
Linda K. Jolliffe, Xiaobing Li and WilliamV. Murray*
Drug Discovery Research, Johnson & Johnson Pharmaceutical Research and Development LLC, 1000 Route 202, PO Box300,
Raritan, NJ 08869, USA
Received 10 December 2001; accepted 13 May 2002
Abstract—Antagonists of the a1-adrenergic receptors (a1-ARs) are useful for the treatment of benign prostatic hyperplasia. A series
of potent and subtype-selective a1a-AR antagonists has been synthesized, displaying in vitro binding affinity in the low the nano-
molar range. # 2002 Elsevier Science Ltd. All rights reserved.
Benign prostatic hyperplasia (BPH) is characterized by
nonmalignant enlargement of the prostate.1 A number
of urological symptoms are associated with it, including
poor urine flow fromthe bladder, increased frequency
in urination, nocturia and hesitancy or delay in starting
urine flow. These symptoms of BPH result from a com-
bination of two components. The mechanical constric-
tion of the urethra is due to the increased prostatic
mass. The dynamic component of BPH is regulated by
a1 adrenergic receptors (a1-ARs), which cause increased
smooth muscle tone in the bladder neck and prostate.
azosin, have been approved for the treatment of BPH.
These agents work by relaxing the smooth muscle of the
prostate and other urinary tract tissues.6 These non-
subtype selective a1-antagonists have shown a greater
incidence of side effects than those agents with
improved a1a-AR selectivity.7,8 Substantial efforts at
designing a1a-AR antagonists have been shown.9 In this
report we wish to present a new series of potent and
selective a1a-AR antagonists.
a1-ARs belong to the superfamily of membrane-bound
G-protein coupled receptors (GPCRs), and stimulate
predominantly phospholipase C-b, resulting in mobili-
zation of Ca2+ fromintracellular stores, and ultimately,
smooth muscle contraction.2 a1-ARs are involved in the
regulation of cardiovascular and central nervous sys-
tems (CNS).3 The three native a1-AR subtypes (a1a, a1b,
and a1d) have been cloned froma number of species,
including human.4 The use of selective a1-AR blockers
is a potential therapeutic choice for the treatment of
BPH.1,5
In a previous study,10 we have shown that compound 1
(where R=OiPr, X=S, Y=Z=CH, and n=2) is a
potent and selective a1a-AR antagonist. We observed
that the 1-(2-alkoxyaryl)piperazinyl unit was required
for its binding affinity and selectivity, and 1-(2-iso-
propoxyphenyl)-piperazinyl moiety was optimal. We
also decided to modify the thiophene ring to other five-
membered heteroaromatic ring systems. (Formula 1
where X=O, S; Y=N, CH; Z=CH, N).
Several non-subtype selective a1-AR antagonists of the
quinazoline class, such as prazosin, terazosin and dox-
In order to evaluate the effects of differing amide groups
on a1-activity, we initially explored the isoxazole analo-
gues (Scheme 1). Isoxazole 611 was prepared by reaction
of 1-(2-isopropoxyphenyl)-piperazine (2) with propargyl
bromide to afford acetylene 4 which was submitted to
*Corresponding author. Tel.: +1-908-704-4375; fax: +1-908-722-
3420; e-mail: wmurray@prdus.jnj.com
yCurrent address: Ann Arbor Laboratories, Pfizer Inc., 2800 Plymouth
Road, Ann Arbor, MI 48105, USA
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00436-5

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H. Khatuya et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2443–2446
[3+2]-dipolar cyclo-addition conditions followed by
aqueous HCl treatment. Compound 6 was then reacted
sequentially with excess SOCl2 to generate the corre-
sponding chloro derivative in the formof its HCl salt
and lactamanions to furnish the N-alkylated products
(10a and 10b). Oxazoles 11a–c was prepared from1-(2-
phenoxyphenyl)-piperazine12 (3) in a similar fashion.
cell membranes expressing the human adrenergic recep-
tor subtypes (a1a-AR, a1b-AR, and a1d-AR), were
evaluated (Table 1).
The binding affinities of the derivatives 10a and 10b
against the a1a subtype remained comparable. This
indicated that the lactamring size was not critical but
favored a five-membered ring. The selectivity among the
subtypes a1b and a1d were excellent, >500-fold and
>50-fold, respectively. Upon changing the isopropyl
group to the phenyl at the aryl-piperazine moiety (see
11a–c), the binding affinity and selectivity decreased
dramatically. Nonetheless, the selectivity pattern
remained. The activity was lost when the lactam moiety
was omitted (see 7). The compounds having isopropyl
(10a and 10b) substituents were more potent than the
corresponding phenoxy analogues (11a–c). Therefore,
we decided to maintain the 1-(2-isopropoxyphenyl)-
piperazine moiety constant and modify other parts of
the lead molecule.
The oxazole 1213 was converted to the ester 14 as
depicted in Scheme 2. The ester functionality was
reduced to the alcohol 15. Compound 15 was allowed to
react with excess SOCl2 to produce, upon workup, the
corresponding chloro derivative in 57% yield in two
steps The chloride was subsequently displaced with a
number of lactams and cyclic imides to generate com-
pounds 16a–e in moderate yields.
The thiazole analogues were prepared in the same man-
ner as the oxazole derivatives (Scheme 3). Thiazole 1714
was brominated and the product (18) was heated with
piperazine 2 in 1-methyl-2-pyrrolidinone (NMP). The
resulting ester 19 was converted to the lactamderiva-
tives 21a and 21b employing the previous protocol.15,16
Oxazole derivatives were subsequently examined. It was
clear that the oxazole moiety is not well tolerated, and
resulted in a substantial decrease in binding affinity. We
did find that the introduction of a thiazole was well tol-
erated. The binding affinities of the thiazole compounds
(21a and 21b) towards the a1a subtype was in the 1.0 nM
range, comparable to the isoxazole analogues.
Binding data (Ki)17 were determined utilizing a 125I-
HEAT [(ꢀ)-(b-(([125I] 3-iodo-4-hydroxyphenyl)-ethyl)-
aminomethyl)-tetralone] radioligand binding assay. In
this assay the binding affinities of compounds to COS
Scheme 1. Synthesis of 3,5-disubstituted isoxazole tethered lactams.
Scheme 2. Preparation of 2,4-disubstituted oxazole tethered lactams and cyclic imides.
Scheme 3. Synthesis of 2,4-disubstituted thiazole tethered lactams.

H. Khatuya et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2443–2446
2445
Table 1. Binding affinitiesa to the human a1-ARs
Ki (nM)
Mulcahy, L. S.; Clark, K. S.; Jalbert, S. A.; Reitz, A. B.;
Murray, W. V.; Jolliffe, L. K. J. Pharmacol. Exp. Ther. 2000,
294, 224.
Ki ratio
10. Khatuya, H.; Murray, W. V.; Pulito, V. L.; Jolliffe, L. K.
2002, 12, 2145.
Compd
a1a
a1b
a1d
a
1b/a1a
2.5
a
1d/a1a
7
1502
3719
2992
>5000
>5000
2205
>5000
>5000
>5000
>5000
>5000
>5000
4251
3064
2
60
11. Scott, M. K.; Baxter, E. W.; Bennett, D. J.; Boyd, R. E.;
Blum, P. S.; Codd, E. E.; Kukla, M. J.; Malloy, E.; Maryan-
off, B. E.; Maryanoff, C. A.; Ortegon, M. E.; Rasmussen,
C. R.; Reitz, A. B.; Renzi, M. J.; Schwender, C. F.; Shank,
R. P.; Sherrill, R. G.; Vaught, J. L.; Villani, F. J.; Yim, N. J.
Med. Chem. 1995, 38, 4198.
12. We thank Mr. George Robinson for providing us with the
1-(2-phenoxyphenyl)-piperazine in gramquantities.
13. It was prepared by adapting the literature dehydrogena-
tion procedure: Williams, D. R.; Lowder, P. D.; Gu, Y.-G.;
Brooks, D. A. Tetrahedron Lett. 1997, 38, 331.
10a
10b
11a
11b
11c
16a
16b
16c
16d
16e
21a
21b
1.1
8.4
28
15
86
1298
2321
3466
297
82
65.5
1435
34.5
170
285
>5000
>5000
>5000
1107
4142
105
2720
>595
>170
147
174
1.2
11.3
3.3
>58
>3.8
>3.8
>2.2
>1.4
3.7
>2.2
>1.4
>16.8
>61
4522
1446
50
0.9
1.2
112
33
1735
39.5
14. Mashraqui, S. H.; Keehn, P. M. J. Am. Chem. Soc. 1982,
104, 4461.
aValues are means of three experiments, there was ꢂ5% standard
15. General procedure A. A mixture of propargyl bromide
(3.98 g, 3.5 mmol), piperazine 3 (7.09 g, 27.9 mmol) and
K2CO3 (5.01 g, 36.3 mmol) in CH3CN (50 mL) was heated at
60 ꢁC for 18 h. Then, the reaction was allowed to cool to rt
and worked up with EtOAc. The crude was chromatographed
(SiO2, 5–10% EtOAc/hexane) to produce 5 (3.70 g, 45%). To
a solution of acetylene 5 (3.60 g, 12.3 mmol) in toluene (200
mL) were added 2-(2-nitroethoxy)-tetrahydropyran (4.32 g,
24.6 mmol), PhNCO (6.61 g, 55.5 mmol) and Et3N (0.34 mL,
2.46 mmol) in that order, and heated at 62 ꢁC for 24 h. Stan-
dard workup and silica gel chromatography yielded a THP-
protected derivative (2.26 g, 41%). The latter (4.91 g) was
taken in Et2O (25 mL) and treated with 1 N HCl (aq, 25 mL)
at rt overnight to furnish isoxazole 7 in 71% (2.85 g) yield.
The alcohol 7 (0.25 g, 0.68 mmol) was stirred with SOCl2 (1
mmol, 13.5 mmol) in CH2Cl2 (2 mL) at rt for 6 h. The volatile
materials then were removed in vacuo to obtain a yellowish
foam. The latter was used immediately. 2-Pyrrolidinone (0.11
g, 1.3 mmol) was added to a suspension of NaH (0.062 g, 2.6
mmol) in DMF (2 mL) and stirred for 0.5 h. Then a solution
of the above chloro compound (DMF, 2 mL) was added, fol-
lowed by addition of KI (0.02 g, 0.13 mmol), and stirred for 24
h. Upon aqueous work up with EtOAc and chromatography
(SiO2, 10–40% EtOAc in hexane), pure 11a (0.13 g, 46%) was
obtained.
General procedure B. A mixture of piperazine 2 (1.87 g, 8.50
mmol), bromide 18 (1.94 g, 7.76 mmol) and Et3N (1.57 g,
15.52 mmol) in 1-methyl-2-pyrrolidinone (15 mL) was stirred
at 85 ꢁC for 21 h. The reaction was quenched with water,
extracted with Et2O and dried (Na2SO4) and concentrated in
vacuo. The product 19 was purified by column chromato-
graphy on silica gel (EtOAc/haxane) to obtain as red oil (2.27
g, 69%). A mixture of compound 19 and NaBH4 was stirred in
EtOH at 78 ꢁC for 5 h. Water was added and the mixture was
acidified to pH 7.0 with 1 N HCl (aq). The n extracted several
times with Et2O and the dried (Na2SO4) and concentrated.
The residue was purified by on silica gel (CH2Cl2/acetone) to
give compound 20 (1.64 g, 81%) as yellow oil. A mixture of
compound 20 (1.0 g, 2.9 mmol) and SO2Cl2 (1,7 g, 14.3 mmol)
in CH2Cl2 (5 mL) was stirred at rt for 20 h. Ice was added and
the mixture was basified to a pH of 7–8 by adding NaHCO3
(aq). Extracted with CH2Cl2 then dried (Na2SO4) and con-
centrated in vacuo to the crude chloride as dark-red oil. 2-
Pyrrolidinone (0.03 g, 0.36 mmol) was dissolved in THF (10
mL) ans treated with n-BuLi (0.23 mL, 1.6 M, 0.36 mmol) at rt
for 15 min. A solution of the crude chloride (0.087 g, 0.24
mmol) in DMF (1 mL) was added and the resulting mixture
was stirred at 80 ꢁC for 3 h. The reaction mixture was quen-
ched with water and extracted with Et2O. The organic layer
was dried and concentrated. Purification (SiO2, EtOAc/hex-
ane) afforded compound 21a (0.018 g, 18%).
error.
In summary, a novel series of ‘1,3-disubstuted’ iso-
xazole-, oxazole-, and thiazole- compounds were pre-
pared. The study of the SAR of these series has led to
the discovery of a family of potent and selective a1a-AR
inhibitors.
Acknowledgements
We wish to thank Drs. Peter Connolly and Allen Reitz
for their helpful comments.
References and Notes
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H. Khatuya et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2443–2446
16. 1H NMR [(300 MHz, CDCl3), d (ppm)] and mass spectral
data for selected compounds: Compound 11a: 6.90–7.31 (m,
9H), 6.13 (s, 1H), 4.50 (s, 2H), 3.61 (s, 2H), 3.37 (t, J=7.0 Hz,
2H), 3.12 (br s, 4H), 2.49 (br s, 4H), 2.42 (t, J=8.1 Hz, 2H),
2.03 (quintet, J=7.5 Hz, 2H). MS (ES): m/z 433 [M+H]+,
865 [2M+H]+. Compound 16b: 7.40 (s, 1H), 6.85–6.93 (m,
2H), 6.75–6.80 (m, 2H), 4.41 (s, 2H), 4.32 (septet, J=6.0 Hz,
1H), 3.50 (s, 2H), 3.05 (br m, 6H), 2.60 (br m, 4H), 2.15 (br m,
2H), 1.14–1.34 (m, 4H), 1.12 (d, J=6.0 Hz, 6H). LCMS (CI):
m/z 413 [M+H]+. Compound 21a: 7.54 (s, 1H), 6.92 (m, 4H),
4.62 (s, 2H), 4.59 (m, 1H), 3.87 (s, 2H), 3.36 (t, J=6.9 Hz,
2H), 3.14 (br s, 4H), 2.77 (m, 4H), 2.42 (t, J=8.0 Hz, 2H), 2.02
(m, 2H), 1.33 (d, J=6.0 Hz, 6H); MS (ES): m/z 415 [M+H]+.
Compound 21b: 7.55 (s, 1H), 6.90 (m, 4H), 4.68 (s, 2H), 4.59
(m, 1H), 3.87 (s, 2H), 3.30 (br s, 2H), 3.14 (br s, 4H), 2.75 (br
s, 4H), 2.42 (br s, 2H), 1.79 (m, 4H), 1.33 (d, J=6.0 Hz, 6H);
MS (ES): m/z 429 [M+H]+.
17. The Ki values were calculated according to the equation
Ki=[IC50]/(1+[radioligand]/Kd) Cheng, Y.-C.; Prusoff, W. H.
Biochem. Pharmacol. 1973, 22, 3099.