Synthesis and SAR of novel hydantoin derivatives as selective androgen receptor modulators

Article abstract of DOI:10.1016/j.bmcl.2006.08.084

A novel series of hydantoin derivatives were identified by in vivo studies as tissue selective androgen receptor modulators. SAR around this series revealed that the function of the ligand could be altered by minor structural modification.

Full text of DOI:10.1016/j.bmcl.2006.08.084

Bioorganic & Medicinal Chemistry Letters 16 (2006) 5763–5766
Synthesis and SAR of novel hydantoin derivatives as selective
androgen receptor modulators
Xuqing Zhang,* George F. Allan, Tifanie Sbriscia, Olivia Linton,
Scott G. Lundeen and Zhihua Sui
Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, LLC, 665 Stockton Drive, Exton, PA 19341, USA
Received 5 June 2006; revised 18 August 2006; accepted 18 August 2006
Available online 7 September 2006
Abstract—A novel series of hydantoin derivatives were identified by in vivo studies as tissue selective androgen receptor modulators.
SAR around this series revealed that the function of the ligand could be altered by minor structural modification.
Ó 2006 Elsevier Ltd. All rights reserved.
The androgen receptor agonists and antagonists are use-
ful in the treatment of a variety of disorders and diseas-
es.1 Antagonists of the androgen receptor have shown
efficacy in the treatment of prostate cancer, benign pros-
tate hyperplasia, hirsutism in women, alopecia, anorexia
nervosa, breast cancer, and acne. Agonists of the andro-
gen receptor could be employed in male contraception,
male performance enhancement, as well as in the treat-
ment of cancer and AIDS cachexia. Recent success of
novel selective estrogen receptor modulators (SERMs)
has provided both preclinical and clinical proof-of-con-
cept that small molecules can be developed with a great
degree of tissue selectivity. These novel SERMs specifi-
cally target the estrogen receptor which prevents com-
mon side effects and maintains the positive protective
effects of selective transcriptional receptor activation.2
A new class of molecules targeting androgen receptors
called selective androgen receptor modulators (SARMs)
has been developed in response to the success of the
SERMs.3 An ideal SARM has antagonist or weak ago-
nist activity in the prostate (androgenic organ) while
presenting strong agonist activity in the muscle and
bone (anabolic organ). This profile would allow the mol-
ecules to treat muscle-wasting conditions, hypogonad-
ism, or age-related frailty while preventing potential
risks for nascent or undetected prostrate cancer. Typical
antiandrogens such as bicalutamide and nilutamide have
been modified leading to the discovery of novel SARMs
such as structure I, BMS-564929 and structure II
(Fig. 1), which behaved as partial agonists in the pros-
tate but full agonists in the levator ani. muscle as indi-
cated by the castrated rat model.4 These minor
structural differences are interesting to explore further
because they could greatly alter the nature of recep-
tor–ligand interactions while showing a promising in vi-
vo profile. In the present paper, we describe our design,
synthesis, and SAR studies on a novel series of bicyclic
structures containing hydantoin moiety as SARMs.
Our design approach was to mimic BMS 564929 by
incorporating a novel hydantoin moiety. First, replace-
ment of the angular H with a methyl group resulted in
structure 3 (Scheme 1). Second, introduction of another
heteroatom such as O or N into the B-ring of the bicyclic
structure afforded structure 6 or 8 (Scheme 2). Finally,
B-ring of the bicyclic structure was switched from pyrro-
lidinyl to dihydropyrazolinyl moiety to generate struc-
ture 13 (Scheme 3).
F
NC
O2N
F3C
O
O
F3C
N
H
S
N
O
OH
NH
O
O
Bicalutamide
Nilutamide
O
A
OH
NHAc
H
N
O2N
F3C
NC
O
O
H
N
NC
N
O
B
N
H
O
F3C
N
H
N
OH
Cl
Keywords: SARMs; Hydantoin.
*
CF3
I
II
BMS-564929
Corresponding author. Tel.: +1 908 704 5319; fax: +1 908 526
6469; e-mail: xzhang5@prdus.jnj.com
Figure 1.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.08.084

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X. Zhang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5763–5766
R1
R2
A
and reduction of the azides. Upon treatment with tri-
phosgene and TEA, the bicyclic structures 8 (where R3
is H) were obtained in good yields. The bicyclic struc-
tures 8 (where R3 is Me) could also be prepared from
alkylation of their amide precursors.
R1
R2
a, b, c
Me
COOH
N
N
O
(S)
+
N
H
(S)
N
C A
Me
1
2
3
Scheme 1. Reagents and conditions: (a) dioxane, 100 °C, 4–6 h; (b)
HCl, dioxane, 70 °C, 2 steps, 35–62%; (c) compounds 3c–3e, 3d–3f,
CuCN, NMP, 200 °C, 10 h, 43–55%.
The key step in the preparation of 13 consisted of an effi-
cient 1,3-dipolar cycloaddition between the a,b-unsatu-
rated
alkenes
11
and
the
hydrozones
(R3CH@NNHTs)7 in the presence of NaH to afford
12.4c The alkene precursors 11 were obtained by cou-
pling of methacryl chloride 10 with the corresponding
anilines 9. Compounds 13 were then prepared by intra-
molecular annulation of 12 with triphosgene, oxalyl
chloride, thionyl chloride or sulfuryl chloride in the
presence of TEA.
R1
R2
N C O
R1
R2
O
R1
R2
O
c
1
Me
N
a, b
Me
NH
+
N
O
OH
N
O
Me
NH2
O
O
O
HO
6
OH
5
4
Our early discovery of structure II (Fig. 1) showed that
it was active in both in vitro binding assay and in vivo
assay via oral administration. Here, we started to inves-
tigate the SAR of its structural derivatives (3, 6, 8, and
13).4c A modified Hershberger assay8 was utilized as
our primary guide for screening purposes to eliminate
the complexity of in vitro and ADME data analysis.
All compounds were tested in five-day immature
(approximately 50 g) castrated male Sprague–Dawley
rat (Charles River) agonist and antagonist assays. In
these studies, the weights of the ventral prostate and
seminal vesicle were used as the indicators of androgenic
activity, while the weight of levator ani muscle was used
as the indicator of anabolic activity. Thus, rationaliza-
tion of these results should combine a test compound’s
ADME properties and intrinsic efficacy. Initial studies
on structure 3 revealed that these hydantoin derivatives
acted like a pure antiandrogen. None of the compounds
listed in Table 1 showed any substantial agonist activity
on the ventral prostate or the levator ani muscle (data
not shown). The substitution pattern R1 and R2 on the
aniline portion of the molecule dictated the antiandro-
genic activity. Potent ventral prostate weight inhibition
activities were found in compound 3e and its sulfur ana-
log 3f where R1 = CN and R2 = CF3 on the phenyl
rings, which correlated to the SAR of known toluidide
antiandrogens such as hydroxyflutamide, nilutamide,
and bicalutamide. Electron-donating or neutral group
at either the R1 or R2 position of the phenyl group
diminished the antiandrogenic activity, as shown with
compounds 3a–3d. Table 2 illustrates the in vivo antian-
drogenic activities for compounds 6 and 8 containing
urea or oxazolidinone functionality in the B-ring of
the bicyclic hydantoin structures. Similar to compounds
3 in Table 1, compounds 6 and 8 demonstrated the AR
antagonist activities in the testosterone treated castrated
immature rats, while they did not present clear agonistic
potency. As the data indicated, both the substitutions at
R1 or R2 positions of the phenyl rings and the substitu-
tion at R3 position contributed to the overall activities
of this series of compounds. Strong prostate weight inhi-
bition was observed with oxazolidinone 6b (75% inhibi-
tion) and urea 8b (79% inhibition), 8e (87% inhibition).
Replacement of R1 from CN to Cl group significantly
reduced the potency (6a and 8a). Masking of R3 with
a methyl group seemed to improve the potency, as illus-
R1
R2
O
R1
R2
O
Me
N
c, g
d, e, f
Me
NH
N R3
N
5
NH2
N
O
O
O
7
8
Scheme 2. Reagents and conditions: (a) dioxane, 100 °C, 4–6 h; (b)
HCl, dioxane, 70 °C, 2 steps, 50–65%; (c) triphosgene, Et3N, 0 °C, rt,
2 h, 70–75%; (d) MsCl, Et3N, 0 °C, rt, 2 h, 82–85%; (e) KI (cat), NaN3,
DMF, 80 °C, 6 h, 85–90%; (f) Ph3P, H2O/THF, 80 °C, 1 h, 85–88%;
(g) NaH, MeI, 0 °C, rt, 2 h, 65–70%.
O
R1
R2
R1
R2
O
b
a
+
Cl
O
NH
NH2
9
10
11
R1
R2
R1
R2
O
H
N
c
NH
N
A
N
R3
N
N
R3
12
13
Scheme 3. Reagents and conditions: (a) Et3N, 0 °C, 0.5–2 h, 71–85%;
(b) R3CH@NNHTs, NaH, 0 °C, 30 min then 70 °C 4–6 h, 45–78%;
(c) CDI, triphosgene, (COCl)2, SOCl2 or SO2Cl2, Et3N, 0 °C, rt, 2 h,
55–80%.
The synthetic pathways utilized in the preparation of the
bicyclic hydantoins 3, 6, 8, and 13 are outlined in
Schemes 1–3. The desired bicyclic compounds 3 were
synthesized as described in the literature or with slight
modifications to known procedures (Scheme 1).5 Com-
pound 3e or 3f was obtained from 3c or 3d by treatment
with CuCN.
The synthesis of 6 or 8 was initiated through a manner
similar to 3 by condensations of isocyanates 16 with
the amino acid 4 followed by acid catalyzed cyclization
to afford 5 in reasonable yields (Scheme 2). Compounds
5 could easily fuse into the bicyclic structures 6 by treat-
ment with CDI or triphosgene in the presence of triethyl
amine (TEA). Compounds 5 were further transformed
into primary amines 7 through mesylation followed by
conversion of the mesylates to the corresponding azides

X. Zhang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5763–5766
Table 1. SAR at substitutions R1, R2 and A of structure 3a
5765
hydantoin structures as selective androgen receptor
modulators, as shown in Table 3. Unlike compounds
3, 6, and 8, compound 13d bearing a CF3 group at R3
position demonstrated the AR agonist activities in cas-
trated immature rats. In the agonist model, 13d prevent-
ed castration caused tissue weight loss and behaved as
partial agonist in the prostate (11% stimulation of the
prostate weight at 3 mg/d) but full agonist in the levator
ani muscle (75% stimulation of the levator ani muscle
weight at 2 mg/d). The activity observed on 13d was fur-
ther confirmed by a four-point dose-dependent study to
generate ED50 2.9 mg/d. On the other hand, it worked as
a weak AR antagonist in the prostate (26% inhibition of
the prostate weight at 2 mg/d) in the antagonist model.
Compound 13e, R-enantiomer of 13d,9 presented similar
dose-dependent response (ED50 > 3 mg/d) to the rat
prostate and levator ani muscle in the agonist model,
while the efficacy was substantially decreased, suggesting
13d acted as eutomer in the racemate. Any modification
of R3 group, including removal (13a), replacement with
hydrophilic (13b and 13g) or bulky group (13c), resulted
in total loss of agonistic activity. Several replacements of
the carbonyl linker at the A position of the bicyclic
structure were well tolerated for in vivo efficacies. As
illustrated in 13k and 13l, these compounds containing
sulfonyl or sulfinyl linker still maintained both agonistic
activity in the levator ani muscle and antagonistic activ-
ity in the ventral prostate.
Compound
R1 R2
A
Prostate Seminal vesicle
inhibition (%) inhibition (%)
Bicalutamideb
70
11
17
32
19
69
78
80
16
27
nac
na
na
95
3a
3b
3c
3d
3e
3f
Cl
Cl
Cl
Cl
Cl
Cl
O
S
CF3
CF3
O
S
CN CF3
CN CF3
O
S
a All compounds were administered via po (vehicle: 20% cyclodextrin)
once daily in the presence of 0.1 mg/d (approximately 1.3 mg/kg)
testosterone propionate (subcutaneous dosing; vehicle: sesame oil) at
a dose rate of 2 mg/day for 5 days. The data were normalized to
control group administered with vehicle (n = 3/group).
b Average value (n = 10).
c na, not active (<10% inhibition at a dose rated of 2 mg/day).
Table 2. SAR at substitutions R1, R2, and R3 of structures 6 and 8a
Compound
R1
R2
R3 Prostate
inhibition (%) inhibition (%)
Seminal vesicle
Bicalutamide
70
55
75
43
33
79
32
80
51
80
28
19
86
15
85
85
6a
6b
6c
8a
8b
8c
8d
8e
Cl
CF3
—
—
—
H
CN CF3
NO2 CF3
Cl
CF3
CN CF3
NO2 CF3
H
H
Cl CF3 Me 77
CN CF3 Me 87
In summary, we have shown that modification of hydan-
toin-based antiandrogens led to the discovery of a novel
series of bicyclic hydantoin derivatives as selective
androgen receptor modulators. The lead compound
13d, upon further optimization, has the opportunity to
be a novel therapeutic agent with potential application
in treatment of androgen-related disorders.
a All footnotes in Table 1 apply in this table.
trated in 8d. Overall, compounds 6 and 8 containing
urea or oxazolidinone moiety at the B-ring of the bicy-
clic hydantoin structure were well tolerated for antian-
drogenic activity compared with their carbon analogs
of compounds 3.
Acknowledgment
Interestingly, replacement of pyrrolidine with dihydro-
pyrazoline ring led to the discovery of a novel series of
We thank Miss Heather Rae Hufnagel for help in man-
uscript preparation.
Table 3. SAR at substitutions R1, R2, and R3 of structures 13a
Compound
R1
R2
R3
A
Prostate stimulation (%) Levator ani muscle stimulation (%) Prostate inhibition (%)
TPb
100
100
Bicalutamide
13a
13b
70
26
16
25
26
21
39
35
15
27
28
41
CN
CN
CN
CN
CN
CF3
CF3 CO2Et
H
CO
CO
na
na
na
11c
14c
51
na
na
13
75d
42c
73
13c
CF3 4-NHAc-Ph CO
13d (S)
13e (R)
13f
CF3 CF3
CF3 CF3
CO
CO
CO
CO
NO2 CF3 CF3
NO2 CF3 CO2Et
13g
13i
na
na
na
21
CN
CN
CN
CN
CF3 CO2Et
CF3 CF3
CF3 CF3
CF3 CF3
COCO na
COCO 12
13j (S)
13k (S)
13l (S)
SO2
SO
41
58
66
117
a All footnotes in Table 1 apply in this table.
b Testosterone propionate was administered subcutaneously by injection at the nape of the neck at 5 mg/kg, in a volume of 0.1 mL in sesame oil.
c 11% prostate weight stimulation at a dose rate of 3 mg/d.
d Compound 13d was further tested in a four-point dose-dependent study at doses from 0.1, 0.3, 1 to 3 mg/d to generate ED50 2.9 mg/d. Compound
13e in the similar test showed ED50 > 3.0 mg/d.

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X. Zhang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5763–5766
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set to 0 percent; (b) Agonist assay: Test compound
activity was determined as the percent stimulation of
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to zero percent and the testosterone alone-treated
control group set to 100%.
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