Selective androgen receptor modulators based on a series of 7H-[1,4]oxazino[3,2-g]quinolin-7-ones with improved in vivo activity

Article abstract of DOI:10.1016/j.bmcl.2008.03.062

Modification on a lead series of [1,4]oxazino[3,2-g]quinolin-7-ones at the 2-position led to selective androgen receptor modulators with improved in vivo activity. The most potent analog (-)-33a exhibited full maintenance of levator ani muscle at 3 mg/kg and reduced activity on ventral prostate weight in a 2-week orally-dosed and orchidectomized rat maintenance assay.

Full text of DOI:10.1016/j.bmcl.2008.03.062

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 2967–2971
Selective androgen receptor modulators based on a series of
7H-[1,4]oxazino[3,2-g]quinolin-7-ones with improved in vivo activity
Yun Oliver Long,* Robert I. Higuchi,* Thomas R. Caferro, Thomas L. S. Lau, Min Wu,
Marquis L. Cummings, Esther A. Martinborough, Keith B. Marschke, William Y. Chang,
´
Francisco J. Lopez, Donald S. Karanewsky and Lin Zhi
Discovery Research, Ligand Pharmaceuticals, 10275 Science Center Drive, San Diego, CA 92121, USA
Received 28 February 2008; revised 18 March 2008; accepted 20 March 2008
Available online 23 March 2008
Abstract—Modification on a lead series of [1,4]oxazino[3,2-g]quinolin-7-ones at the 2-position led to selective androgen receptor
modulators with improved in vivo activity. The most potent analog (À)-33a exhibited full maintenance of levator ani muscle at
3 mg/kg and reduced activity on ventral prostate weight in a 2-week orally-dosed and orchidectomized rat maintenance assay.
Ó 2008 Elsevier Ltd. All rights reserved.
The androgen receptor (AR) is a member of the super
CF3
N 2
CF3
CF3
family called nuclear receptors.1 Androgens, which in-
clude testosterone (T) and dihydrotestosterone (DHT,
Fig. 1), are the endogenous ligands that bind to AR.
Androgens, when bound to AR, control the develop-
ment, differentiation, and function of male reproductive
and accessory sex tissues (such as seminal vesicle, pros-
tate, and epididymis),2 which are called androgenic ef-
fects. Some other tissues and organs such as skeletal
muscle and bone are also under the influence of andro-
gens,2 which are anabolic effects. Other organs/tissues
that are affected by androgens are skin, hair follicles,
and brain.2 The main mechanism of androgen action
is to regulate gene expression through binding to the
androgen receptor, changing the levels of specific pro-
teins in cells, and controlling cell behavior.3 Androgens
can help both male and female patients with their frailty
and osteoporosis. However, hormone replacement ther-
apy (HRT) for prevention or treatment of osteoporosis
has caused concerns about the safety of HRT in long
term use, especially stimulation of the prostate for males
and virilization for females.2 Therefore, the concept of
non-steroidal selective androgen receptor modulators
(SARM) emerged as an attractive target for drug
discovery.4,5
CF3
N
CF3
1
10
5
N
R
8
3
2
6
3
O
O
O
N
H
6
4
1
H
1
2 (LGD2226)
1a, R = Me
R2
Me
CF3
O
CF3
N
N
R1
CF3
O
N
H
HO
O
N
H
4
3 (LGD2941)
OH
Me
4,5
Testosterone (T), Δ
Me
H
Dihydrotestosterone
(DHT), 4,5α-dihydro
H
H
O
Figure 1. AR Ligands.
SARMs are expected to be orally available, potent and
efficacious in anabolic effects while having reduced
androgenic activity. Research on SARMs aimed to alle-
viate androgen deficiency symptoms has been reported.6
The reported pharmacophores include tetrahydroquino-
line,7 hydantoin and hydantoin-derived compounds,8
bicalutamide derivatives,9 and our quinolinone deriva-
tives.10,11 More recently, we disclosed the discovery of
our LGD2226 (2, Fig. 1)12 series, LGD2941 (3),13
based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones14 and 1
based on 7H-[1,4]oxazino[3,2-g]quinolin-7-ones.15 With
Keywords: Androgen; SARM; Testosterone; Anabolic; Androgenic;
Benzoxazine; AR; Muscle; Oxazino[3,2-g]quinolin-7-one.
4
*
Corresponding author. Tel.: +1 619 218 2346; fax: +1 858 550
7249; e-mail: robert.higuchi@gmail.com
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.03.062

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Y. O. Long et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2967–2971
1a as the lead in this series, we performed additional
SAR studies on the C-2 position. This effort led to com-
pounds with tissue-selectivity, and significantly im-
proved in vivo potency, which we report in this letter.
rine with DAST, producing 14 after deprotection. Final-
ly, Moffatt–Swern oxidation of the primary hydroxyl
group in 7 formed an aldehyde intermediate that was
fluorinated in situ by DAST, leading to 15 after acidic
hydrolysis.
We previously15 examined the SAR study at N-1 and C-
3 position of 1, and the optimal substituents proved to
be 2,2,2-trifluoroethyl and hydrogen, respectively. This
current effort concentrated at the C-2 position with the
concept of introducing a broader array of functional
groups, since conceptually, this position was amenable
to the addition of a variety of different substituents. In
our previous work, we developed an enantiospecific syn-
thesis to prepare 2-alkyl-substituted analogs. However,
this method was not suitable to prepare our desired tar-
gets, so we utilized different methods of the synthesis.
Generally, racemates were prepared and selected com-
pounds were separated into their individual enantiomers
by chiral HPLC.16 The preparation of several of the tar-
get compounds required common intermediate 7, the
synthesis of which started from 517 (Scheme 1). Com-
pound 5 was treated with methyl bromoacetate, yielding
6, which under Tebbe reaction conditions, followed by
hydroboration, afforded 7. Compound 7 was alkylated
with an alkyl iodide and sodium hydride, followed by
deprotection under strong acidic conditions, leading to
targets 8–11. Alternatively, the hydroxyl group in 7
was mesylated, allowing for the nucleophilic replace-
ment by sodium thiomethoxide and sodium cyanide,
affording 12 and 13, respectively, after deprotection.
The hydroxyl group in 7 can directly be replaced by fluo-
Compounds 21a–23a were prepared (Scheme 2) in opti-
cally pure form starting from known compound 16.
Regioselective bromination and pyridone protection,
followed by demethylation afforded hydroxyquinoline
17. The hydroxyquinoline was alkylated by either the
replacement of the tosylate group (R@CH2CF3) under
basic conditions or utilizing Mitsunobu conditions
(R@CH2Ph and R@CH2CH2SCH3) to afford the Boc
protected aminoethers (20). The amine of 20 was un-
masked with TFA, cyclized under Buchwald amination
conditions,18 and subsequently deprotected under acidic
conditions to provide 21a–23a.
Scheme 3 shows the preparation of aryl-substituted
racemic analogs. Compound 25 was obtained by the
CF3
CF3
Br
a-c
O
N
OH
O
N
H
OMe
17
16
H
BocHN
TsO
H
BocHN
(d)
R
R
18
19
HO
CF3
CF3
CF3
Br
N
O
R
CF3
NH
CF3
e-h
CF3
N
CF3
N
NHBoc
N
O
O
O
N
O
O
N
H
a
H
R
O
OH
21a, R = CH2CF3
22a, R = Bn
O
20
5
6
23a, R = CH2CH2SMe
b
CF3
CF3
CF3
N
Scheme 2. Reagents and conditions: (a) NBS; (b) CsF, i-PrI (87%
overall); (c) PhSH, NaH, DMF, 110 °C; (d) 19, K2CO3, or 18,
diisopropylazodicarboxylate, PPh3, N-methylmorpholine; (e) TFA,
EtOAc, 60 °C; (f) Pd2dba3, KOt-Bu, BINAP, toluene, 90 °C; (g)
NaBH4, TFA, 50 °C; (h) HCl/HOAc, 85 °C.
CF3
N
c, d
N
OH
OR
O
O
O
N
H
O
7
8, R = H
9, R = Me
10, R = Et
11, R = Pr
e, d
f, d
CF3
CF3
N
H
N
NH2
OH
O
CF3
a
CF3
CF3
CF3
N
O
N
O
N
O
O
b
R
F
24
25
O
N
H
O
N
H
O
14
12, R = SMe
CF3
13, R = CN
CF3
H
OH
c, d
CF3
CHO
CF3
N
CF3
CF3
CF3
F
R
N
O
N
O
N
O
R
f, d
g
F
O
N
O
7
O
N
26
O
N
O
N
H
H
15
27, R = H
28, R = 3-Me
29, R = 4-Me
Scheme 1. Reagents and conditions: (a) methyl bromoacetate, K2CO3,
DMF, 110 °C, 86%; (b) Tebbe reagent, THF, then BH3, THF, H2O2,
NaOH; (c) NaH, R-I, THF, 0 °C to rt; (d) HOAc:concd. HCl (3:1), 60–
80 °C, 75–95%; (e) MsCl, NEt3, ether, then NaR, DMF, 80 °C; (f)
DAST, CH2Cl2; (g) Moffatt–Swern oxidation.
Scheme 3. Reagents and conditions: (a) Methyl bromoacetate, K2CO3,
DMF, rt, 52%; (b) ArBr, Mg, À78 to À45 °C; (c) NaBH3CN, TFA,
50 °C, 60–80%; (d) HCl/HOAc, 110 °C.

Y. O. Long et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2967–2971
2969
treatment of 2415 with methyl bromoacetate and
K2CO3, then was subjected to excess amount of an aryl
Grignard reagent, affording 26. The hydroxyl group was
reductively removed with sodium cyanoborohydride in
TFA, in which concomitant reductive alkylation of the
nitrogen with trifluoroethyl group took place. After
removal of the protecting isopropyl group, compounds
27–29 were obtained.
Scheme 4 describes the preparation of the racemic tri-
fluoromethyl analog 33. The treatment of aminophenol
30 with a reductive alkylation condition (NaBH4 in
TFA) selectively alkylated the amino group with a tri-
fluoroethyl and then treatment with a bromoacetone un-
der basic conditions selectively alkylated the phenolic
oxygen to give intermediate 31. Compound 31 was re-
duced by NaBH4 to form the benzoxazine ring that
was hydrogenated to provide aniline 32. A two step
Knorr cyclization reaction of aniline 32 afforded final
compound 33.
CF3
OH
NH2
OH
N
O
a, b
CF3
CF3
O2N
O2N
30
31
c, d
CF3
CF3
CF3
N
O
N
CF3
e, f
H2N
O
N
H
O
The compounds synthesized were evaluated in a tran-
scriptional activation assay with hAR in mammalian cell
background (CV-1).10 The results from this assay and a
competitive receptor binding assay15 are shown in Table
1. Consistent with the results of the analogs of structure
1,15 most of the AR agonist modulating activity and
32
33
Scheme 4. Reagents and conditions: (a) NaBH4,TFA, rt; (b)
BrCH2COCF3, K2CO3, DMF; (c) NaBH4, HOAc; (d) Pd/C, H2,
EtOAc; (e) CF3COCH2CO2Me, toluene, reflux; (f) conc. H2SO4,
95 °C.
Table 1. Cotransfection (hAR in CV-1 cells) and competitive binding data for the new analogs and reference compounds
CF3
CF3
R
N
O
N
H
O
Compound
R
CV-1 agonist
CV-1 antagonist
AR bindingd
Optical rotatione
Efficacyb (%)
Efficacyc (%)
IC50 (nM)
60
Kia (nM)
a
EC50 (nM)
a
(À)-(R)-8a
(+)-(S)-8b
(À)-(R)-9a
(+)-(S)-9b
( )-10
CH2OH
CH2OH
CH2OMe
CH2OMe
CH2OEt
CH2OPr
CH2SMe
CH2CN
CH2F
92 11
11
3
24 14
39 17
24
0
15
22
3
À62.9
+60.0
À43.8
+40.0
67
71
27
61
111
7
5
5
6.6 0.6
2.0 0.4
77 34
3.2
165 120
—
9.4
109
na
na
na
18
67 11
—
—
17
—
—
25
—
—
199
—
—
9
( )-11
( )-12
( )-13
4.2
66 30
106 24
125 14
83 11
127 19
28 12
30 18
3.8 2.0
35 12
1.3 0.2
23 18
31 31
(À)-(R)-14a
(+)-(S)-14b
( )-15
33
30
9
9
2.6 0.3
32
À67.2
CH2F
CHF2
4
+66.2
29 13
—
6.6 0.0
18
na
(À)-(R)-21a
(À)-(R)-22a
(À)-(R)-23a
(À)-(R)-27a
(+)-(S)-27b
(À)-(R)-28a
(+)-(S)-28b
(À)-(R)-29a
(+)-(S)-29b
( )-33
CH2CF3
CH2Ph
CH2CH2SMe
Ph
51
12
3
3
23
—
6
na
na
83
38
3
6
51 12
—
—
89 0.3
121 16
13
23 17
5.3 0.9
—
2.4 0.0
na
na
42 11
94
33 11
1.3
150
0
Ph
m-Tol
340
—
na
86 10
—
105
19
—
36
—
8
1.1 0.2
180
na
À38.7
+38.4
na
m-Tol
p-Tol
91
41
86
—
31
7
574 156
—
44
p-Tol
CF3
—
104
na
na
7
5.9 1.2
2.0 0.6
42 24
1.1 0.2
5.7 0.1
—
—
—
8.3 1.6
5.9 2.2
281 73
0.9 0.1
0.9 0.1
151 36
(À)-(R)-33a
(+)-(S)-33b
(À)-(R)-1a
DHT
CF3
CF3
87 10
23 13
6
À60.4
+62.7
À81.7
64 11
34 17
Me
82
5
28
—
89
7
70
—
6
100 0.0
—
Bicalutamide
9
162 99
a Values with standard errors represent the mean value of at least 2 separate experiments with triplicate determinations. ‘—’ indicates not active (an
efficacy of <20% and/or a potency of >10000 nM). ‘na’ means not available.
b Agonist efficacies were determined relative to DHT (100%).
c Antagonist efficacies (%) were determined as a function of maximal inhibition of DHT at the EC50 value.
d Competitive binding assay conducted as described in Ref. 15.
e All optical rotations were measured in ethanol at 589 nm with sodium arc lamps at 20 °C. The sample concentration ranges from 2.45 to 2.90 mg/ml.

2970
Y. O. Long et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2967–2971
binding affinity reside on the enantiomers with the R-
configuration at the C-2 position, although not all of
the pairs of enantiomers were prepared. The enantio-
mers with the S-configuration tend to have weaker ago-
nist activity or more AR antagonist activity in our
assays. As a result, the following SAR discussion by
using the data from both enantiomers and racemates
should not change the conclusions for the agonist
activities.
In order to evaluate the in vivo activity, compound 14a
and 33a were orally dosed to SD rats in a 2-week cas-
trated rat maintenance bioassay.12a,15 The ventral pros-
tate (VP) is an androgen-dependent male sexual
accessory organ, and is an endpoint to evaluate andro-
genic side effects of our non-steroidal SARMs. Over
stimulation of the prostate for an androgen is not de-
sired because of the risk of prostatic disease. The levator
ani muscle (LA) is a skeletal muscle that also demon-
strates androgen-dependent growth.19 The LA weight
is utilized as an endpoint to determine the anabolic ef-
fects. The eugonadal levels on both the androgenic side
effect (VP) and the anabolic (LA) endpoints were main-
tained when treated with 1.0 mg/kg testosterone propio-
nate (TP) (Fig. 2). Hence, testosterone is considered to
have no tissue selectivity in this model, as can be ob-
served by the overlap of the VP and LA dose-response
curves. In contrast, the VP dose response curves for
both 14a and 33a are right-shifted compared to the
LA. Compound 14a demonstrates full efficacy in LA
at 10 mg/kg, while 33a is fully efficacious at 3 mg/kg.
In comparison, compound 1a is less potent in this as-
say,15 maintaining the LA to the intact level at a dose
of 100 mg/kg. Hence, 33a is significantly more potent
than 1a, although the muscle-prostate selectivity profile
is similar, which indicates that the activity enhancement
may be the result of increased metabolic stability.
SAR study on C-2 position (Table 1) suggested that the
binding pocket in this region is rather large, tolerating a
variety of functional groups, which is different from the
paralleling bicyclic series exemplified by LGD2226. This
conclusion is supported by the following three observa-
tions. First, the compounds are still potent and effica-
cious AR agonist modulators when larger hydroxyl
(8a) and methoxyl (9a) groups are attached to the parent
compound 1a with R configuration at C-2 substitution.
Tests on the racemic mixtures with even larger ethoxyl
(10) and propoxyl (11) attached revealed that these com-
pounds were still potent and efficacious. Replacing this
C-2 side chain with sulfur containing chain structure
at approximately equivalent length (23a and 12, respec-
tively) led to about 10-fold reduction in agonist potency
relative to their oxygen containing analogs (10 and 9a).
The same potency reduction was observed in compari-
son of compound 13 and compound 9a. The second sup-
porting evidence for steric tolerance off C-2 site is that
when a large aromatic group was attached directly at
C-2 carbon (compounds 27a, 28a, and 29a), they still
exhibited very good agonist efficacy, potency, and recep-
tor binding affinity. However, the binding pocket ap-
peared to reach its limit in steric tolerance when one
methylene is placed between the newly introduced aro-
matic ring and the linear tricyclic structure (compound
22a). This compound turned into an antagonist that is
equally efficacious but more potent than bicalutamide,
which is a rather large change for a small structural
modification. When the same modification was made
to 33a, the resulting compound 21a showed significant
reduction in agonist efficacy, potency, and binding
activity.
These new SARMs demonstrate good steroid hormone
binding selectivity, just as most other SARMs in our
quinolinone series.12–15 Selected compounds were evalu-
ated in the progesterone, glucocorticoid, and mineralo-
corticoid receptor binding assays (PR, GR, and MR,
respectively)20 and no significant cross-reactivity was
observed.
In conclusion, we have discovered tissue and receptor
selective, and orally available SARMs with improved
in vivo potency based on 1-(2,2,2-trifluoroethyl)-7H-
[1,4]oxazino[3,2-g]quinolin-7-ones.
While the SAR of this linear tricyclic series was ongo-
ing, the studies on our LGD2226 series12 established
the importance of an additional halomethyl substituent
at the 6-amino position, especially 2,2,2-trifluoroethyl,
as being critical to increasing the in vivo activity of
our SARMs. This suggested that the trifluoromethyl
group on C-2 position would be an attractive target
to increase in vivo activity of the current series. Indeed,
the SAR results showed that the trifluoromethyl group
did lead to a compound (33a) that is equally potent
and efficacious in vitro as lead compound 1a. Changing
the number of fluorine atoms in this group (com-
pounds 14 and 15) appeared to increase the agonist
efficacy without affecting its potency and binding. To
our advantage, compound 33a demonstrated half life
of 100 min in rat liver microsomal study at 5 lM, while
that of 14a is only 34 min. The difference suggested
that additional fluorine atoms led to more metabolic
stability.
Figure 2. Effects of compounds 14a and 33a and testosterone
propionate treatment on levator ani muscle and ventral prostate
weights in a 2-week orchidectomized rat maintenance assay. 100%
identifies intact animals (sham), whereas 0% denotes levels for vehicle-
treated animals. Testosterone propionate was dosed subcutaneously
because it is rapidly metabolized when dosed orally.

Y. O. Long et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2967–2971
2971
11. Hamann, L. G.; Higuchi, R. I.; Zhi, L.; Edwards, J. P.;
Wang, X.-N.; Marschke, K. B.; Kong, J. W.; Farmer, L.
J.; Jones, T. K. J. Med. Chem. 1998, 41, 623.
Acknowledgments
We thank New Leads, DSD, and Pharmacology
Departments for performing in vitro and in vivo assays.
12. (a) Van Oeveren, A.; Motamedi, M.; Mani, N. S.;
Marschke, K. B.; Lopez, F. J.; Schrader, W. T.; Negro-
Vilar, A.; Zhi, L. J. Med. Chem. 2006, 49, 6143; (b)
Van Oeveren, A.; Motamedi, M.; Martinborough, E.
A.; Zhao, Z.; Shen, Y.; West, S. J.; Chang, W.; Kallel,
E. A.; Marschke, K. B.; Lopez, F. J.; Negro-Vilar, A.;
Zhi, L. Bioorg. Med. Chem. Lett. 2007, 17, 1527; (c)
Van Oeveren, A.; Pio, B. A.; Tegley, C. M.; Higuchi,
R. I.; Wu, M.; Jones, T. K.; Marschke, K. B.; Negro-
Vilar, A.; Zhi, L. Bioorg. Med. Chem. Lett. 2007, 17,
1523.
13. Martinborough, E. A.; Shen, Y.; Van Oeveren, A.; Long,
O.; Lau, T. L. S.; Marschke, K. B.; Chang, W. Y.; Lopez,
F. J.; Vajda, E. G.; Rix, P. J.; Viveros, O. H.; Zhi, L.
J. Med. Chem. 2007, 50, 5049.
14. Higuchi, R. I.; Thompson, A. W.; Chen, J.-H.; Cummings,
M. L.; Caferro, T. R.; Deckhut, C. P.; Adams, M. A.;
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16. The final compounds could be separated by Chiralcel OD,
Chiralcel AD, or Chiralpak AS columns using ethanol and
hexanes as eluents.
17. The preparation of this intermediate compound followed
the general conditions and procedures described in
Ref. 15. For details, please see the supporting material.
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