Novel heterocycles as selective α1-adrenergic receptor antagonists

Article abstract of DOI:10.1016/S0960-894X(00)00472-8

A novel series of aryl piperazine substituted heterocycles has been synthesized and identified as antagonists of the α(1a)-adrenergic receptor (α(1a)-AR), which has been implicated in benign prostatic hyperplasia (BPH). These compounds selectively inhibit binding to the α(1a)-AR with K(i)s as low as 2.1 nM. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0960-894X(00)00472-8

Bioorganic & Medicinal Chemistry Letters 10 (2000) 2375±2377
Novel Heterocycles as Selective ꢀ1-Adrenergic Receptor
Antagonists
Xiaobing Li,a,* Kathleen A. McCoy,b William V. Murray,b Linda Jolli€eb and
Virginia Pulitob
aThe R. W. Johnson Pharmaceutical Research Institute, 3210 Merry®eld Row, San Diego, CA 92121, USA
bThe R. W. Johnson Pharmaceutical Research Institute, PO Box 300, Route 202, Raritan, NJ 08869, USA
Received 26 June 2000; accepted 16 August 2000
AbstractÐA novel series of aryl piperazine substituted heterocycles has been synthesized and identi®ed as antagonists of the a1a-
adrenergic receptor (a1a-AR), which has been implicated in benign prostatic hyperplasia (BPH). These compounds selectively
inhibit binding to the a1a-AR with Kis as low as 2.1 nM. # 2000 Elsevier Science Ltd. All rights reserved.
Benign prostatic hyperplasia (BPH), a nonmalignant
enlargement of the prostate, is the most common benign
tumor in men. There are two components of BPH, a
static and a dynamic component. The static component
is due to enlargement of the prostate gland, which may
result in compression of the urethra and obstruction to
the ¯ow of urine from the bladder. The dynamic com-
ponent is due to increased smooth muscle tone of the
bladder neck and the prostate itself (which interferes
with emptying of the bladder) and is regulated by a1-
adrenergic receptors (a1-ARs). The medical treatments
available for BPH address these components to varying
degrees, and therapeutic choices are expanding.
shown that the a1a-AR subtype comprises the majority
of a1-AR mRNAs and expressed protein in human pro-
static smooth muscle and mediates contraction in this
tissue.3 7 These ®ndings suggest that the development of
a subtype-selective a1a-AR antagonist might result in a
therapeutically e€ective agent with reduced side e€ects,
such as orthostatic hypotension, for the treatment of
BPH.8,9
Herein we report on a novel heterocyclic series of sub-
stituted arylpiperazines (Fig. 1) that selectively bind to
the a1a-AR receptor.
The compounds of Figure 1, when A is pyrazole or sub-
stituted pyrazole derivatives may be prepared according
to Scheme 1; Scheme 2 illustrates those compounds when
A is 2-aminopyrinidine, and Scheme 3 when A is iso-
xazole or isoxazoline.
The use of a1-AR antagonists in the treatment of BPH
is related to their ability to decrease the tone of prostatic
smooth muscle, leading to relief of the obstructive
symptoms. Adrenergic receptors are found throughout
the body and play a dominant role in the control of
blood pressure, nasal congestion, prostate function, and
other processes.1 There are a number of cloned a1-AR
receptor subtypes: a1a-, a1b-, and a1d-AR.2 It has been
We have previously reported the synthesis of dione 5,10
in which compound 1 reacts with chloroacetone at a
re¯ux temperature in the presence of potassium carbon-
Figure 1.
*Corresponding author. Tel.: +1-858-450-2061; fax: +1-858-450-2049; e-mail: xli@prius.jnj.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00472-8

2376
X. Li et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2375±2377
ate in acetonitrile a€ording compound 2, which is con-
densed with ester 4 using sodium hydride as base. A cata-
lytic amount of methanol is crucial in this condensation
reaction. Dione 5 is then treated with hydrazine or
methylhydrazine at room temperature to give the pyra-
zole 6 or the methyl pyrazoles 7a and 7b (Scheme 1).
The regiochemistry of 7a and 7b was con®rmed by NOE
studies.
Dione 5 may also be treated with guanidine hydrochloride
in the presence of a weak base, such as sodium acetate, in
ethanol at 50 ꢀC to give the 2-aminopyrimidine deriva-
tive 8 (Scheme 2).
Scheme 3 illustrates the preparation of both isoxazole 14
and isoxazoline derivative 15.11,12 The strategy involves
a 1,3-dipolar cycloaddition reaction of a nitrile oxide,
Scheme 1.
Scheme 2.
Scheme 3.

X. Li et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2375±2377
2377
Table 1.
6. Michel, M. C.; Grubbel, B.; Taguchi, K.; Verfurth, F.;
Otto, T.; Krop¯, D. J. Auton Pharmacol. 1996, 16, 21.
7. Price, D. T.; Schwinn, D. A.; Lomasney, J. W.; Allen, L.
F.; Caron, M. G.; Lefkowitz, R. J. J. Urol. 1993, 150, 546.
8. Brune, M. E.; Katwala, S. P.; Milicic, I.; Buckner, S. A.;
Ireland, L. M.; Kerwin, J. F., Jr.; Hancock, A. A. Pharmacol-
ogy 1996, 53, 356.
9. Kenny, B. A.; Miller, A. M.; Williamson, I. J. R.; O'Con-
nell, J.; Chalmers, D. H.; Naylor, A. M. Br. J. Pharmacol.
1996, 118, 871.
Compounds
Ki (nM)
Ratio
(1b/1a)
Ratio
(1d/1a)
a1a
a1b
a1d
177
52
44
>10,000
272
1517
6
2.1
3.7
9
79
3.8
89
3915
3080
2770
1864
832
308
>127
1172
>112
84
14
5
7a
7b
8
14
15
>10,000
4456
>10,000
>127
72
17
10. Li, X.; Murray, W. V.; Jolli€e, L.; Pulito, V. Bioorg. Med.
Chem. Lett. 2000, 10, 1093.
11. Gribble, A. D.; Dolle, R. E.; Shaw, A.; McNair, D.;
Novelli, R.; Novelli, C. E.; Slingsby, B. P.; Shah, V. P.; Tew,
D.; Saxty, B. A.; Allen, M.; Groot, P. H.; Pearce, N.; Yates, J.
J. Med. Chem. 1996, 39, 3569.
12. Curran, D. P. In Advances in Cycloaddition; Curran, D. P.,
Ed.; JAI: Greenwich, 1988; Vol. 1, pp 129±189.
13. Swern, D.; Mancuso, A. J.; Huang, S.-L. J. Org. Chem.
1978, 43, 2480.
14. Pulito, V. L.; Li, X.; Varga, S. S.; Mulcahy, L. S.; Clark,
K. S.; Pekow, C. A.; Halbert, S. A.; Reitz, A. B.; Murray,
W. V.; Jolli€e, L. K. J. Pharmacol. Exp. Ther. 2000, 294,
224.
generated in situ from the corresponding oxime 11, with
an alkyne or an alkene derivative. Treatment of compound
1 with bromoethanol and potassium carbonate at a re¯ux
temperature in acetonitrile gives the alcohol 9 in quan-
titative yield. The alcohol is oxidized under Swern oxi-
dation conditions a€ording the corresponding aldehyde
10.11,13 Subsequent treatment of 10 with hydroxylamine
hydrochloride in the presence of pyridine in ethanol at
room temperature gives the oxime 11 in good yield.
Reaction of oxime 11 with N-propargyl-d-valerolactam
12 or N-allyl-d-valerolactam 13, aqueous NaOCl and
triethylamine in dichloromethane at room temperature
gives the isoxazole 14 or isoxazoline 15 exclusively in
moderate yield.
15. 1H NMR and mass spectrum data for selected com-
pounds: Compound 2 (yield 98%) 1H NMR (300 MHz,
CDCl3) d 6.91 (m, 4H), 4.59 (m, 1H), 3.25 (s, 2H), 3.15 (bt,
4H), 2.67 (bt, 4H), 2.19 (s, 3H), 1.34 (d, 6H, J=6.03 Hz). MS
m/z 277 (MH+). 4 (yield 76%) 1H NMR (300 MHz, CDCl3) d
4.20 (q, 2H, J=7.22 Hz), 4.10 (s, 2H), 3.36 (m, 2H), 2.43 (m,
2H), 1.86 (m, 4H), 1.28 (t, 3H, J=7.25 Hz). 5 (yield 100%) 1H
NMR (300 MHz, CDCl3) d 6.91 (m, 4H), 4.59 (m, 1H), 4.26 &
4.18 (2s, 2H), 3.69 & 3.30 (2s, 2H), 3.35 (m, 2H), 3.20 (bs, 2H),
3.14 (bs, 4H), 2.69 (m, 4H), 2.46 (m, 2H), 1.86 (m, 4H), 1.34
The biological data14 of selected compounds15 can be
seen in Table 1. Ki data expressed in nanomolar con-
centration (nM) are determined by a radioligand binding
assay which tested the binding anity of these com-
pounds to COS cell membranes expressing the human
adrenergic receptor subtypes: a1a-, a1b-, and a1d-AR.14
1
(2d, 6H, J=6.06 Hz). MS m/z 416 (MH+). 6 (yield 62%) H
NMR (300 MHz, CDCl3) d 6.91 (m, 4H), 6.17 (s, 1H), 4.59 (m,
1H), 4.48 (s, 2H), 3.61 (s, 2H), 3.34 (m, 2H), 3.12 (bs, 4H),
2.67 (bs, 4H), 2.42 (m, 2H), 1.78 (m, 4H), 1.34 (d, 6H,
Radioligand binding studies showed that a number of the
compounds discussed have signi®cantly higher anity for
the a1a-AR subtype than for the a1b-AR or a1d-AR
subtype and displayed a higher level of receptor selec-
tivity than some of the comparators and currently mar-
keted tamsulosin (Flomax1). Some of these compounds
were more potent in inhibiting (Æ)-norepinephrine-
induced contractions of isolated rat prostate tissue than
those of isolated rat aorta tissue, whereas tamsulosin
had the reversed tissue selectivity.14 Pyrazole derivative
6 shows the best potency and selectivity among this
series of heterocyclic compounds. Expanded biological
pro®ling of key active compounds is underway.
1
J=6.10 Hz). MS m/z 412 (MH+). 7a (yield 40%) H NMR
(300 MHz, CDCl3) d 6.91 (m, 4H), 6.18 (s, 1H), 4.64 (s, 2H),
4.59 (m, 1H), 3.83 (s, 3H), 3.57 (s, 2H), 3.22 (m, 2H), 3.14 (bs,
4H), 2.69 (bs, 4H), 2.43 (m, 2H), 1.79 (m, 4H), 1.34 (d, 6H,
J=6.02 Hz). MS m/z 426 (MH+). 7b (yield 8%) 1H NMR
(300 MHz, CDCl3) d 6.91 (m, 4H), 6.11 (s, 1H), 4.59 (m, 1H),
4.53 (s, 2H), 3.87 (s, 3H), 3.50 (s, 2H), 3.30 (m, 2H), 3.08 (bs,
4H), 2.59 (bs, 4H), 2.42 (m, 2H), 1.77 (m, 4H), 1.34 (d, 6H,
J=6.00 Hz). MS m/z 426 (MH+). 8 (yield 20%) 1H NMR
(300 MHz, CDCl3) d 6.91 (m, 4H), 6.70 (s, 1H), 5.07 (bs, 2H),
4.59 (m, 1H), 4.50 (s, 2H), 3.48 (s, 2H), 3.34 (m, 2H), 3.14 (bs,
4H), 2.66 (bs, 4H), 2.49 (m, 2H), 1.85 (m, 4H), 1.34 (d, 6H,
J=6.06 Hz). MS m/z 439 (MH+). 9 (yield 92%) 1H NMR
(300 MHz, CDCl3) d 6.91 (m, 4H), 4.59 (m, 1H), 3.68 (t, 2H,
J=5.43 Hz), 3.27 (bs, 1H), 3.12 (bs, 4H), 2.68 (bs, 4H), 2.60 (t,
2H, J=5.40 Hz), 1.34 (d, 6H, J=6.03 Hz). MS m/z 265
(MH+). 11 (yield 86% from 9) 1H NMR (300 MHz, CDCl3) d
7.55 (t, 1H, J=6.06 Hz), 6.91 (m, 4H), 4.59 (m, 1H), 3.72 (dd,
1H, J=7.02 Hz), 3.23 (d, 1H, J=6.08 Hz), 3.15 (m, 6H), 2.73
(bs, 4H), 1.34 (d, 6H, J=6.08 Hz). MS m/z 278 (MH+). 14
References and Notes
1
1. Harrison, J. K.; Pearson, W. R.; Lynch, K. R. Trends
Pharmacol. Sci. 1991, 12, 62.
2. Goetz, A. S.; King, H. K.; Ward, S. D.; True, T. A.; Rimele,
T. J.; Saussy, D. L., Jr. Eur. J. Pharmacol. 1995, 272, R5.
3. Faure, C.; Pimoule, C.; Vallancien, G.; Langer, S. Z.; Gra-
ham, D. Life Sci. 1994, 54, 1595.
4. Schwinn, D. A.; Kwatra, M. M. Adv. Pharmacol. 1998, 42,
390.
5. Lepor, H.; Tang, R.; Kobayashi, S.; Sharpiro, E.; Forray,
C.; Wetzel, J. M.; Gluchowski, C. J. Urol. 1995, 154, 2096.
(yield 14%) H NMR (300 MHz, CDCl3) d 6.91 (m, 4H), 6.26
(s, 1H), 4.67 (s, 2H), 4.59 (m, 1H), 3.64 (s, 2H), 3.41 (t, 2H,
J=5.65 Hz), 3.12 (bs, 4H), 2.68 (bs, 4H), 2.43 (t, 2H, J=5.65),
1.83 (m, 4H), 1.34 (d, 6H, J=6.04 Hz). MS m/z 413 (MH+).
1
15 (yield 16%) H NMR (300 MHz, CDCl3) d 6.91 (m, 4H),
4.86 (m, 1H), 4.59 (m, 1H), 3.87 (dd, 1H, J=3.33 Hz), 3.57 (m,
1H), 3.41 (m, 1H), 3.30 (s, 2H), 3.17 (m, 2H), 3.11 (bs, 4H),
2.84 (dd, 1H, J=7.58 Hz), 2.63 (t, 4H, J=3.28 Hz), 2.40 (m,
2H), 1.79 (m, 4H), 1.34 (d, 6H, J=6.06 Hz). MS m/z 415
(MH+).