Novel thiophene derivatives for the treatment of benign prostatic hyperplasia

Article abstract of DOI:10.1016/S0960-894X(02)00347-5

The syntheses and biological activities of a novel series of 2,4- and 2,5-disubstituted thiophenes are reported. These analogues have shown excellent affinity and selectivity against α₁-adrenoreceptor subtypes.

Full text of DOI:10.1016/S0960-894X(02)00347-5

Bioorganic & Medicinal Chemistry Letters 12 (2002) 2145–2148
Novel Thiophene Derivatives for the Treatment of Benign
Prostatic Hyperplasia
Haripada Khatuya, Virginia L. Pulito, Linda K. Jolliffe, Xiaobing Li
and William V. Murray*
Johnson & Johnson Pharmaceutical Research and Development LLC, Drug Discovery Research, 1000 Route 202, PO Box300,
Raritan, NJ 08869, USA
Received 26 October 2001; accepted 3 May 2002
Abstract—The syntheses and biological activities of a novel series of 2,4- and 2,5-disubstituted thiophenes are reported. These
analogues have shown excellent affinity and selectivity against a1-adrenoreceptor subtypes. # 2002 Elsevier Science Ltd. All rights
reserved.
Benign prostatic hyperplasia is the most common clin-
ical disorder observed in men above age 60. The condi-
tion causes a variety of urological symptoms, including
poor urine flow from the bladder, increased frequency
in urination, nocturia and hesitancy or delay in starting
the urine flow. There are two components to BPH. The
static component is characterized by a nonmalignant
enlargement of prostatic tissue; resulting in obstruction
of urethra.1 The dynamic component, regulated by a1-
adrenergic receptors (a1-ARs), is due to the increased
smooth muscle tone in the bladder neck and prostate.
muscle and other urinary tract tissues by blocking the
adrenergic receptors.6 These compounds exhibit various
side effects, due in part to their nonselective binding with
other a1-AR subtypes.7 Tamsulosin, a non-quinazoline,
also suffers from side effects, despite its modest a1a-AR
selectivity.8 Substantial efforts at designing a1a-AR
antagonists have been shown.9 Herein, we will describe 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+ from intracellular 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 from a number of species,
including human.4 It is believed that the use of a selec-
tive a1a-AR antagonist would be valuable for the
treatment of BPH.1,5
Initial effort in screening our corporate chemical library
against a1-ARs in a radioligand binding assay had led
to the discovery of 13a. We quickly established that 1-
(2-alkoxyaryl)piperazine moiety was necessary for its
potency and selectivity. At that point, we decided to
modify the alkoxy group, thiophene substitutions and/
or the lactam ring according to the general formula 1.
In order to evaluate the effects of differing amide groups
on a1a-selectivity, we initially explored the analogues
prepared in Scheme 1. Aldehyde 4 smoothly underwent
reductive amination9 with piperazine 3 affording thio-
phene 6. The latter was converted to the aldehyde 8
upon metal halogen exchange with tBuLi and sub-
sequent quenching with DMF. The aldehyde 8 was
reduced to the alcohol 10. When 10 was treated with
excess SOCl2, salt 12 was obtained as white foam after
removal of the volatile materials. Salt 12 reacted with
lactam anions to furnish N-alkylated products (13b–d).
Several non-subtype selective a1-AR antagonists of the
quinazoline class (i.e., prazosin, tetrazosin and dox-
azosin) have been approved for the treatment of BPH.
These agents cause relaxation of the prostate smooth
*Corresponding author. Tel.: +1-908-704-4375; fax: +1-908-722-
3420; e-mail: wmurray@prdus.jnj.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00347-5

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H. Khatuya et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2145–2148
Scheme 1. Synthesis of 2,5-disubstituted thiophene tethered lactams.
Figure 1. 2,5-Disubstituted analogues differing in substitution at the 5-position.
Scheme 2. Synthesis of 2,4-disubstituted thiophene tethered lactams.
Having demonstrated the alcohol 10 as a key inter-
mediate for the coupling with lactams, the isopropoxy
analogue 13a10 was prepared in the same fashion, start-
ing from the same aldehyde (4) as shown in Scheme 1.
methyl)-tetralone] radioligand binding assay, in which
the binding affinity of the compounds to COS cell
membranes, expressing the human adrenergic
receptor subtypes (a1a-AR, a1b-AR, and a1d-AR), were
evaluated.9d,16
The reductive amination11 of aldehyde 8 was carried out
with 2o-amines in the presence of NaBH(OAc)3 to give
3o-amines, 14a and 14 b (Fig. 1), in good yields.
The 2-methoxyphenyl substituted compounds (13b–d)
were not as potent as the lead 13a (Table 1). Also, the
potency of the analogues 13b–d remained in the same
order while the size of the lactam ring varied from five
to seven. In this series of compounds, almost no selec-
tivity was observed between a1a and a1d. Though, the
selectivity between the subtypes a1a and a1b was good
(>125-fold). From Table 1, it is clear that the affinity of
the derivatives 6–10, lacking the lactam portion, against
the a1a subtype was poor (>128 nM). When the lactam
portion in 13b was replaced with a pyrrolidinyl group
(14a), potency remained more or less the same. How-
ever, upon modification of the 2-piperidinone (viz., 13c)
to a piperidinyl moiety (14b) potency dropped dramati-
cally by 30-fold. Thus, a carbonyl group may be
required for potency as well as selectivity.
3-Thiophenemethanol (15) was protected with tert-butyl
diphenylsilyl chloride, the latter was formylated under
strong basic conditions (tBuLi; DMF). The 1HNMR
data12 of the crude material showed the presence of a
single regiomer and was assigned as 16.13 Reductive
amination of the aldehyde 16 with piperazine 2, fol-
lowed by deprotection of the silyl group with TBAF
furnished alcohol 17. The alcohol 17 then was converted
to the chloro-derivative and alkylated with various lac-
tams to afford compounds 18a–c (Scheme 2).12,14
The binding data15 was measured using [125I]-HEAT
[(Æ) - (b - (([125I]3 - iodo -4-hydroxyphenyl)ethyl)amino -

H. Khatuya et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2145–2148
2147
Table 1. Binding affinitiesa to the human a1-Ars
4. (a) Hieble, J. P.; Bylund, D. B.; Clarke, D. E.; Eikenberg,
D. C.; Langer, S. Z.; Lefkowitz, R. J.; Minneman, K. P.;
Ruffalo, R. R., Jr. Pharmacol. Rev. 1995, 47, 267. (b) Forray,
C.; Bard, J. A.; Wetzel, J. M.; Chiu, G.; Shapiro, E.; Tang, R.;
Lepor, H.; Hartig, P. R.; Weinshank, R. L.; Brancheck, T. A.;
Gluchowski, C. Mol. Pharmacol. 1994, 45, 703.
5. (a) Kumar, V. L.; Dewan, S. Int. Urol. Nephrol. 2000, 32,
67. (b) Lowe, F. C.; McDaniel, R. L.; Chmiel, J. J.; Hillman,
A. L. Urology 1995, 46, 477.
6. Monda, J. M.; Osterling, J. E. J. Mayo Clinic Proceed.
1993, 68, 670.
7. (a) Lepor, H. J. Androl 1991, 12, 389. (b) Lepor, H. Urol-
ogy 1995, 45, 406.
Compd
Ki (nM)
Ki ratio
1b/a1a
a1a
a1b
a1d
a
a
1d/a1a
6
8
10
128
578
202
0.3
40
14
18
12
419
331
0.2
0.5
1.8
757
1878
1063
413
>5000
>5000
>5000
592
92
262
138
18
23
12
13
15
130
339
25
6
3.2
5.3
0.7
0.4
0.7
54
0.6
0.9
0.7
1.3
0.3
1
13a
13b
13c
13d
14a
14b
17
18a
18b
18c
1251
>125
>357
>278
49
2569
>5000
259
6.1
8. (a) Lowe, F. C. Prostate Cancer Prostatic Dis. 1999, 2, 110.
(b) Schulman, C. C.; Cortvriend, J.; Jonas, U.; Lock,
T. M. T. W.; Vaage, S.; Speakman, M. J. Eur. Urol. 1996, 29,
145.
>15
1523
768
147
184
26
384
615
92
47
342
9. (a) Bock, M. G.; Patane, M. A. Ann. Rep. Med. Chem.
2000, 35, 221. (b) Li, X.; Murray, W. V.; Jolliffe, L.; Pulito, V.
Bioorg. Med. Chem. Lett. 2000, 10, 1093. (c) Li, X.; McCoy,
K. A.; Murray, W. V.; Jolliffe, L.; Pulito, V. Bioorg. Med.
Chem. Lett. 2000, 10, 2375. (d) Pulito, V.; Li, X.; Varga, S. S.;
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.
aValues are means of three experiments; there was ꢁ5% standard
error.
Since the lead compound 13a, having an isopropyl sub-
stituent, was more potent than the corresponding
methoxy analogues (13b–d), we decided to conduct
additional SAR studies holding the isopropyl constant.
10. Abdel-Majid, A. F.; Carson, K. G.; Harris, B. D.; Mar-
yanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
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.
The affinity of the 2,4-disubstituted thiophenes (18a–c)
was in the sub-nanomolar range. In the same vein,
selectivity against a1d increased to around 150-fold (18a
and 18b); better than that of 13a. It should be noted
that, by changing the substitution pattern from a 2,5-
disubstituted thiophene (para-bioisoster) to its 2,4-
derivative (meta-), the affinity was retained and selec-
tivity was enhanced. Compounds 18a–c, are highly
potent against a1a-AR and very selective against the
other subtypes, a1b-AR and a 1d-AR.
t
12. General procedure A: BuLi (1.7 M; 7.9 mL, 13.4 mmol)
was added to a solution of 6 (4.1 g, 11.2 mmol) in THF at
À78 ꢀC. After 1 h, DMF (2.0 mL, 25.8 mmol) was added and
stirred for another 6 h. It was allowed to warm to 0 ꢀC, and
satd NH4Cl was added, followed by extraction with EtOAc.
The organic extracts were washed with brine, dried (Na2SO4),
and concentrated. The material was flushed through a short
silica gel plug eluting with EtOAc, affording the aldehyde 8 in
86% yield.
General procedure B: SOCl2 (3.0 mL, excess) was added to
the alcohol 10 (0.182 g, 0.57 mmol) in CH2Cl2 (5.0 mL) at rt.
After 6 h, the volatile materials were removed in a rotary eva-
porator and dried in vacuo to obtain the chloro derivative as
foam. In a separate flask, 2-pyrrolidinone (0.098 g, 1.16 mmol)
was added slowly to a suspension of NaH (0.055 g, 2.3 mmol)
in DMF (1 mL). After 0.5 h, a solution (1.0 mL, DMF) of the
above chloro derivative was injected slowly. Stirred for 18 h,
then satd NH4Cl was added and extracted with EtOAc. The
combined extracts were washed with water, brine, then dried
(Na2SO4), and concentrated. Silica gel chromatography (10–
25% EtOAc/hexanes) afforded product 13b in 57% yield.
13. After completion of this work, there appeared a paper on
the synthesis of similar compounds on solid support. Li, Z.;
Ganesan, A. Synlett 1998, 405.
In summary, a convenient synthesis of 2,4-disubstitued
thiophenes from a 3-substituted thiophene and general
route for the introduction of lactam moieties at the 4-
and 5-thiophenemethyl center were illustrated. The
SAR studies of these series have shown the importance
of the isopropyl group and the need for a carbonyl
group in the thiophene substituent and led to the dis-
covery of a family of very potent and selective a1a-AR
inhibitors.
Acknowledgements
We wish to thank Drs. Richard H. Hutchings, Gee-
Hong Kuo, Peter J. Connolly, Allen B. Reitz, Linda Mul-
cahy, and James P. Edwards for their valuable suggestions.
14. 1H NMR [(300 MHz, CDCl3), (ppm)] and mass spectral
data of selected compounds: Compound 8: 9.85 (s, 1H), 7.64
(d, J=3.7 Hz, 1H), 7.06 (d, J=3.7 Hz, 1H), 6.84–7.01 (m,
4H), 3.85 (s, 3H), 3.81 (s, 2H), 3.11 (br s, 4H), 2.73 (t, J=4.5
Hz, 4H). MS (ES): m/z 317 [M+H]+. Compound 13b: 6.77–
7.00 (m, 6H), 4.57 (s, 2H), 3.85 (s, 3H), 3.74 (s, 2H), 3.37 (t,
J=7.0 Hz, 2H), 3.10 (br s, 4H), 2.69 (br s, 4H), 2.42 (t, J=8.1
Hz, 2H), 2.01 (quintet, J=7.5 Hz, 2H). MS (ES): m/z 386
[M+H]+. Compound 14a: 6.78–7.02 (m, 4H), 6.76 (d, J=3.4
Hz, 1H), 6.74 (d, J=3.4 Hz, 1H), 4.03 (d, J=14.0 Hz, 1H),
3.86 (d, J=14.0 Hz, 1H), 3.85 (s, 3H), 3.74 (s, 2H), 3.70 (s,
3H), 3.33 (dd, J=5.8 Hz, 8.7 Hz, 1H), 3.10 (m, 5H), 2.70 (br s,
References and Notes
1. Geller, J.; Kirschenbaun, A.; Lepor, H.; Levine, A. C. J.
Clin. Endocrinol. Metab. 1995, 80, 745.
2. Schwinn, D. A.; Price, R. R. Eur. Urol. 1999, 36, 7.
3. (a) Bylund, D. B.; Eikenberg, D. C.; Hieble, J. P.; Langer,
S. Z.; Lefkowitz, R. J.; Minneman, K. P.; Molinoff, P. B.;
Ruffalo, R. R., Jr.; Trendelenburg, U. Pharmacol. Rev. 1994,
46, 121. (b) Harrison, J. K.; Pearson, W. R.; Lynch, K. R.
Trends Pharmacol. Sci. 1991, 12, 62.

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H. Khatuya et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2145–2148
4H), 2.55 (dd, J=6.5 Hz, 8.0 Hz, 1H), 1.61–2.18 (m, 4H). MS
(ES): m/z 430 [M+H]+. Compound 16: 9.87 (s, 1H), 7.67 (dd,
J=1.4 Hz, 6.0 Hz, 4H), 7.61 (d, J=0.8 Hz, 1H) 7.55 (br s,
1H), 7.36–7.44 (m, 6H), 4.74 (s, 2H), 1.09 (s, 9H). MS (ES): m/z
381 [M+H]+. Compound 18a: 7.02 (br s, 1H), 6.84–6.91 (m,
4H), 6.84 (br s, 1H), 4.59 (septet, J=6.0 Hz, 1H), 4.39 (s, 2H),
3.72 (s, 2H), 3.31 (t, J=7.0 Hz, 2H), 3.12 (br s, 4H), 2.65 (br s,
4H), 2.43 (t, J=8.0 Hz, 2H), 2.00 (quintet, J=7.5 Hz, 2H),
1.34 (d, J=6.0 Hz, 6H). MS (ES): m/z 414 [M+H]+.
16. Antagonist activity of the lead compound (13a) was
assessed by the inhibition of (Æ)-norepinephrine-induced
contractions in isolated rat prostate (predominantly express
a1a) and aorta tissues (predominantly express a1d). Either rat
aorta or rat prostate tissue are bathed in buffer or buffer plus
test compound. The effects of increasing concentrations of
norepinphrine upon tissue tension are measured. The pA2
value is the negative log of the molar concentration of the test
compound that would produce a 2-fold shift in the con-
centration–response curve of the agonist (NE). For compound
13c, the pA2 values for prostate and aorta are 8.311 and 6.898,
respectively.
15. The Ki values were calculated according to the equation
Ki=[IC50]/(1+[radioligand]/Kd) Cheng, Y.-C.; Prusofff, W. H.
Biochem. Pharmacol. 1973, 22, 3099.