Cyclic imides as potent and selective α-1A adrenergic receptor antagonists

Article abstract of DOI:10.1016/S0960-894X(01)00320-1

We disclose a new compound class of potent and selective α-1A adrenergic receptor antagonists exemplified by the geminally, disubstituted cyclic imide 7. The optimization of lead compounds resulting in the cyclic imide motif is highlighted. The results of in vitro and in vivo studies of selected compounds are presented.

Full text of DOI:10.1016/S0960-894X(01)00320-1

Bioorganic & Medicinal Chemistry Letters 11 (2001) 1959–1962
Cyclic Imides as Potent and Selective ꢀ-1A Adrenergic
Receptor Antagonists
Robert M. DiPardo,a Michael A. Patane,a Randall C. Newton,a RoseAnn Price,a
Theodore P. Broten,b Raymond S. L. Chang,c Richard W. Ransom,c Jerry Di Salvo,d
Roger M. Freidingera and Mark G. Bocka,*
aDepartment of Medicinal Chemistry, Merck & Co., Inc., West Point, PA 19486, USA
bDepartment of Cardiovascular Pharmacology, Merck & Co., Inc., West Point, PA 19486, USA
cDepartment of New Lead Pharmacology, Merck & Co., Inc., West Point, PA 19486, USA
dDepartment of Biochemistry and Physiology, Merck & Co., Inc., Rahway, NJ 07065, USA
Received 7 February 2001; accepted 10 May 2001
Abstract—We disclose a new compound class of potent and selective a-1A adrenergic receptor antagonists exemplified by the
geminally, disubstituted cyclic imide 7. The optimization of lead compounds resulting in the cyclic imide motif is highlighted. The
results of in vitro and in vivo studies of selected compounds are presented. # 2001 Elsevier Science Ltd. All rights reserved.
Benign prostatic hyperplasia (BPH) is a pathological
disorder in men that develops in response to the action
of dihydrotestosterone on the aging prostate gland.1 It
is a disease that causes voiding difficulties and impacts
the quality of life. One contributory component to the
origin of symptoms is the contraction of smooth mus-
cles under a-1 adrenergic receptor-mediated sympa-
thetic stimulation.2 Among the three a-1 receptor
subtypes (a-1A, a-1B, and a-1D), it is the a-1A receptor
that is chiefly responsible for the contractile tone of the
prostatic urethra.3À6 This has led to an intensive effort
to develop uroselective a-1A adrenergic receptor
antagonists with the expectation that such agents would
have the potential to offer an improved side-effect
profile compared to currently available drugs.7,8
and also imparted more rigidity. The concept was to
modify previously identified regions of the phenyl acet-
amides that had the highest potential to impact a-1A
receptor binding potency and metabolic stability. Our
findings are disclosed herein.
The requisite 4-aryl piperidines were synthesized
employing a bis-alkylation reaction between benzylni-
trile 11 and N-Boc-bis-chloroethylamine 12 (Scheme 1).10
Deprotection, alkylation, and a subsequent deprotec-
tion completed the assembly of intermediate 13. The
corresponding 4-carboxymethyl piperidines were
obtained by hydrolyzing the initial 4-cyanopiperidine
alkylation product, followed by esterification of the
resulting carboxylic acid. The condensation of amine 13
with the diphenylacetic acid 14 was carried out in the
standard way utilizing a soluble carbodiimide reagent.
The conversion of 5 to 6 was effected with p-nitrophenyl
chloroformate and sodium hydride; thus, acylation at
ambient temperature was followed by ring forma-
tion, which was induced by heating the mixture of
intermediates.
The starting point for this investigation was the phenyl
acetamide 1, which we had previously shown to be a
useful structural motif for designing potent and selec-
tive, low molecular weight a-1A adrenergic receptor
antagonists.9 We supposed that the physicochemical
properties of 1 and its congeners, as well as their phar-
macokinetic (PK) properties, might be improved by
incorporating structural features that altered their log P
The cyclic imides were prepared according to the gen-
eral route outlined in Scheme 2. Ditolylacetic acid was
converted to the half-acid ester 15 in the following
three-step operation: (1) esterification, (2) a-alkylation,
and (3) debenzylation via catalytic hydrogenation.
*Corresponding author. Fax: +1-215-652-3971; e-mail: mark_bock@
merck.com
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00320-1

1960
R. M. DiPardo et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1959–1962
Reaction of 3-bromopropylamine with 15 yielded the
intermediate amide-ester, which spontaneously cyclized
to give imide 16. Standard N-alkylation of 4-(2-methyl-
phenyl)-4-cyanopiperidine 17 or its 2-chloro analogue
18 with bromide 16 delivered 7 and 8, respectively. The
latter compound was transformed to the thioimide 10
with Lawesson’s reagent. The half-acid ester 15 was
converted to the amide-ester and heated to provide
the corresponding imide. This material was reacted
with epichlorohydrin to give the epoxide, which served
as substrate for the alkylation with 17 to provide
compound 9.
diphenylacetamide analogues displayed improved bind-
ing affinities for all a-1 receptor subtypes (cf. 2). Func-
tional group manipulation of 2 to give 3 led to further
potency gains. While this trend was encouraging, repre-
sentative compounds in this structural series showed
poor pharmacokinetic (PK) properties (rat and dog: F
<10%; t1=2 <1 h; Cmax <100 nM). We reasoned that
one plausible explanation for these properties was facile
metabolism and the rapid clearance of these com-
pounds. A probable locus of metabolism in the diphe-
nylacetamide structure is the benzylic position.11 This
prompted the preparation of 4 and the more potent
homologue 5. Although the a-1a receptor binding affi-
nity of the latter compound was improved relative to its
precursors, its PK properties remained poor (Table 2).
Our next strategy was to reduce the number of hydro-
gen bond donating groups in 5 and to simultaneously
bias the conformation of the diphenylacetamide frag-
ment by forming an oxazolidinedione ring. This led to 6
and a reduction in a-1a receptor binding affinity. How-
ever, the exchange of oxygen in the oxazolidine ring
The binding affinity of synthetic compounds to human
a-1 receptors was measured utilizing cloned receptor
binding assays (Table 1).4 These data are provided in
Table 1.
We have previously shown that phenylacetamides,
exemplified by compound 1, are potent and selective a-
1A receptor antagonists.9 It was further determined that
Scheme 1. (a) NaH, DMF, 60 ꢀC or Cs2CO3, DMSO; (b) HCl (g), EtOAc, 0 ꢀC; (c) Br(CH2)3NHBOC, DMF, NEt3, 23 ꢀC; (d) HCl (g), EtOAc, 0 ꢀC;
(e) EDC, HOBt, DIEA, DMF, 23 ꢀC; (f) 4-nitrophenylchloroformate, NaH, THF, 65 ꢀC.
Scheme 2. (a) BnBr, K2CO3, DMF, 23 ꢀC; (b) LHMDS, BrCH2CO2Et; (c) H2, 10% Pd/C, EtOH; (d) Br(CH2)3NH2, EDC, HBT, NaHCO3, DMF.

R. M. DiPardo et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1959–1962
1961
Table 1.
Table 2.
Ki (nM)a
a-1b
Rata
Dogb
a-1a
a-1d
F
t1=2 (h)
F
t1=2 (h)
5
7
8
<1
18
19
1.3
2.5
0.66
ND
8
11
ND
1.3
1.7
1
74
>3000
3400
ND, not determined.
aMale Sprague–Dawley rats (0.2–0.25) kg were dosed with 1–3 mg/kg
iv and 3–10 mg/kg po (3–4 animals). Plasma samples were analyzed
from 0.08 to 24 h using LC–MS/MS quantification.
bMale beagle dogs (ca. 8 kg) were dosed with 1–3 mg/kg iv and 3–10
mg/kg po (2–3 animals). Plasma samples were analyzed by LC–MS/
MS; computation of pharmacokinetic parameters was performed with
the aid of TOPFIT software.
2
17
170
>2000
1800
975
1400
4800
1500
with methylene led to a dramatic change in the receptor
binding profile. The resulting imide, 7, showed excellent
affinity for the a-1a receptor subtype with greater than
1000- and 880-fold selectivity for the a-1b and a-1d
receptors, respectively. Additional a-1a receptor binding
potency was gained by modifying the ortho-substituent
on the 4-aryl ring of piperidine 8 (cf. 7 and 8). Other
structural modifications connected with the propyl
chain linking unit [e.g., incorporation of OH for solu-
bility, (9)] and the imide carbonyl groups (10) proved
detrimental to a-1a receptor binding affinity relative to 7
and 8.
3
7.3
5.7
2.0
77
4
Three key compounds, 5, 7, and 8, were dosed in rats (1
mg/kg, iv and 3 mg/kg, po) and dogs (3 mg/kg, iv and
10 mg/kg, po). Plasma levels were measured by LC–MS
from 0.3 to 6 h in rats and from 1 to 24 h in dogs.
Selected PK data are collated in Table 2, from which it
is evident that the pharmacokinetic profiles of these
analogues were modestly improved compared to the
precursor phenylacetamides (vide supra).
5
570
6
>2000 >5000
We successfully designed a series of potent, cyclic imide
a-1A receptor antagonists exemplified by compounds 7
and 8. Analogue 7 shows greater than 1100- and 880-
fold selectivity versus the a-1b and a-1d receptor sub-
types. This compound also displayed >100-fold selec-
tivity against other G-protein coupled receptors (a-2a,
a-2b, a-2c, dopamine-1, -2, -3, -5, H-1, H-2, and 5HT-
1a) tested. Inroads were made in improving the phar-
macokinetic properties of the prototype phenyl-
acetamide a-1A antagonists by incorporating this
structural motif in a cyclic imide scaffold.
7
1.7
1900
1500
8
0.48
98
220
9
9.7
1500
4100
References and Notes
1. Steers, W. D.; Zorn, B. Disease-a-Month 1995, 41, 437.
2. Eri, L. M.; Tveter, K. J. J. Urol. 1995, 154, 923.
3. a-1A, a-1B, and a-1D refer to pharmacologically char-
acterized receptors; a-1a, a-1b, and a-1d refer to cloned
receptors.
10
220
>2000 >5000
4. Price, D. T.; Schwinn, D. A.; Lomasney, J. W.; Allen, L. F.;
Caron, M. G.; Lefkowitz, R. J. J. Urol. 1993, 150, 546.
5. Forray, C.; Bard, J. A.; Wetzel, J. M.; Chiu, G.; Shapiro,
E.; Tang, R.; Lepor, H.; Hartig, P. R.; Weinshank, R. L.;
aAll Ki values are calculated for competition binding assays (I
125-HEAT) utilizing cloned human a-1 receptors and are the geometric
mean of at least two experiments.

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