Diarylhydantoin compounds

US007709517B2
(12) Unlted States Patent
(10) Patent N0.2
Sawyers et al.
(54)
(45) Date of Patent:
DIARYLHYDANTOIN COMPOUNDS
4,859,228 A
Inventors: Charles L. Sawyers, NeW York, NY
10/1989 Coussediere et al.
4,938,949 A
7/1990 Borch et a1~
(Us); Michael E_ Jung, Los Angeless
4,944,791 A
7/1990 Sch-roder et a1.
CA (Us); Charlie D- Chen’ Los
An eles CA (US) Samedy Ouk Costa
4,992,478 A
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12/1991 Evans etal.
Northndge, CA (Us); Chrls Tran, New
York, NY (US); John wongvipat,
Nanuet, NY (US); Dongwon Y00, Los
Angeles, CA (US)
5,166,358
5,411,981
5,434,176
5,556,983
11/1992
5/1995
7/1995
9/1996
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A
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5,589,497 A
(73)
Assignee: The Regents of the University of
California’ Oakland, CA (Us)
(*)
Notice:
Subject to any disclaimer, the term of this
patent is extended or adjusted under 35
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5,646,172 A
7/1997 Claussner et al.
5’656’65 l A
8/1997 Sovak et 31'
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aussner et al.
11/1998 Gaillard-Kelly et al.
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3/1997 Liao et a1~
5/1997 Gaillard-Kelly et al.
This patent 1s subject to a termmal d1sAPP1- NO-I 11/433329
Prior Publication Data
9/1999
7/2000 Claussner et al.
8/2000 Bouchet et al.
6,235,910 B1
5/2001 Bellef et al.
6,242,611 B1
6/2001
(52)
10/2001 French et al.
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10/2002 Sovak et a1.
11/2002 Weisman et a1.
Jan. 4, 2007
6,489,163 B1
6,506,607 B1
12/2002 R0?“ a1~
l/2003 ShyJan
Related US‘ Application Data
6,828,471 B2
12/2004 Sawyers et al.
Provisional application No. 60/ 680,835, ?led on May
13, 2005, provisional application No. 60/750,351,
?led on Dec. 15, 2005, provisional application No.
60/756,552, ?led on Jan. 6, 2006, provisional applica-
2002/0133833
2004/0009969
2004/0116417
2005/0153968
tion NO_ 60/786,837, ?led on Man 29, 2006'
2007/0249697 A1
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9/2007 Tachibana et al.
9/2002
l/2004
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7/2005
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Cleve et al.
Boubia et a1.
Bi et a1~
10/2007 Tachibana et a1.
FOREIGN PATENT DOCUMENTS
A61K 31/4166
(2006.01)
C07D 233/02
(2006.01)
AU
us. Cl. ............... .. 514/392; 548/3001; 548/3164;
548/317 1- 548/321 1- 514/385- 514/386
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US 7,709,517 B2
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Primary ExamineriGolam M Shameem
(74) Attorney, Agent, or FirmiVenable LLP; Michael A.
Gollin; Lars H. Genieser
(57)
ABSTRACT
The present invention relates to diarylhydantoin compounds,
including diarylthiohydantoins, and methods for synthesiz
ing them and using them in the treatment of hormone refrac
tory prostate cancer.
13 Claims, 29 Drawing Sheets
US 7,709,517 B2
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FOREIGN PATENT DOCUMENTS
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WO 2003/057220
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US. Patent
May 4, 2010
Sheet 1 0129
US 7,709,517 B2
Bicalutamide DISPLAYS AGONISTIC EFFECT AN LNCaP-AR
mg25wé:aE2
El 0.1 micM
0
B1 micM
El 10 micM
Bicalutamide
DMSO
FIG. 1
US. Patent
May 4, 2010
Sheet 2 0f 29
US 7,709,517 B2
ANTAGONIST ASSAY OF Bicalulamide ON LNCaP-AR
Z10 micM
mwhmyaécyzowpa o,‘
E1 1 micM
E13 micM
E19 micM
.7_/ / A
DMSO
Bicalulamide
FIG. 2
US. Patent
May 4, 2010
Sheet 4 0f 29
US 7,709,517 B2
EFFECT OF COMPOUNDS ON LNCaP-AR
Al 20
12125 0M
[3250 0M
0500 nM
-
$<2g
555 K
n 1000 nM
32. . 1.7 .H
0mg
FIG. 4
52Z...‘
.
wmEmm.”
US. Patent
May 4, 2010
Sheet 5 0f 29
US 7,709,517 B2
INHIBITION EFFECT ON LNCaP-AR
0 100 nM
E1200 nM
(UMRENFLTAIOLSVDE)
|
E1 500 M
E! 1000 nM
j
- ._
DMSO Bic'alutimde
US. Patent
May 4, 2010
Sheet 6 0f 29
US 7,709,517 B2
HORMONE REFRACTORY CELLS
D 0.3 micM
a 0.6 mjcM
B 1.2 MM
E! 2.5 micM
DMSO
Bicalulamide
EXAMPLE 5-3b EXAMPLE 700
FIG. 6
US. Patent
May 4, 2010
Sheet 7 0f 29
US 7,709,517 B2
Bic & EXAMPLE 7-3b ON LN/AR GROWTH (n=8)
g‘ 10' +804
3 8_ +EXAMPLE 7-301
% 6
9
g
4‘
E
E
2~
0
.
0
10
20
30
40
DAYS
EXAMPLE 7-30 ON LN/AR GROWTH (n=8)
12'
g
§ 8_
%
é
%
4
5
0
+VEH
+0.1 mpk
—¢—1mpk
50
US. Patent
May 4, 2010
Sheet 8 0f 29
US 7,709,517 B2
TISSUE PSA LNIAR (n=4)
450 -
400 -
350-
I
CA) C) CD
PSA(ng/ml)
—'
250 -
T
200 q
150 -
T
100 s0 -
Veh
‘0.1mpk I
1mpk
FIG. 8
I 10mpk
US. Patent
May 4, 2010
Sheet 9 0f 29
US 7,709,517 B2
LAPC4-HR GROWTH (n=4)
24
+ VEH
—I— Bic-1
18 -
1£[email protected] 5
+ EXAMPLE 7-3b-1
Al
062
q
FIG. 9A
LAPC4-HR PSA (DAY 17, n=4)
400 -
T
<2m2E2am;
Veh
Bic-1
FIG. 9B
' EXAMPLE 7-301 '
US. Patent
May 4, 2010
Sheet 10 0f 29
US 7,709,517 B2
HORMONE SENSITIVE CELLS
0 n6.
0
u
E!
l3
121
0.3 micM
0.6 micM
1 2m:cM
2.5 micM
c
n
1Q
1.“250
DMSO
' Bicalutamide 'EXAMPLES-3DIEXAMPLEY-3b'
FIG. 10
US. Patent
May 4, 2010
Sheet 11 0129
US 7,709,517 B2
ARRgPB-Luc
+ Vehicle
_|-_ BicaI.-10
----- -- Bical.-50
_._-RD162-10
- -o- -- RD162-50
T (d)
FIG. 11
US. Patent
May 4, 2010
c 5%52>
Sheet 12 0129
US 7,709,517 B2
0m?.GE
E
f
1 _.
5E0i:m2am aw?.QE
am
PW
A2
.
on
a
.an
,
%
%8+a§~\w 5gE0?
1
W.
a W
gig1.
10w,
we?.7 4
5k
..”.\
01.
. vain
AV
,1a;
v.»
70
gm§,,,
“¢
20351,‘£
a0
haw
#
w
a W
.m
a m
1
_\
g
ga,me\
g
.L2%;
$51
, E1
a;
.\vEEom
,J/1‘,
US. Patent
May 4, 2010
Sheet 13 0f 29
US 7,709,517 B2
PK OF RD162I INTRAVENOUS AND ORAL ADMINISTRATION
5E2 8
3245.105
0
FIG. 13
US. Patent
May 4, 2010
Sheet 14 0f 29
US 7,709,517 B2
LN-AR(HR)
m100nM
E1200 nM
D500nM
131000 nM
2RU..41|
u
I
a3<2$2582
0?u
I
—
DMSO
Bical
FIG. 14
RD162
US. Patent
May 4, 2010
Sheet 15 0129
US 7,709,517 B2
CHARACTERISTICS OF Bicalu1imide, RD37, RD131 AND RD162
NAME STRUCTURE
B10.
NC
RD37
0
QF
Css,10mpk Css,25mpk 033501101
[11M]
[NM]
11111]
2.91
10.0
11.4
11.9
124
4.20
NA
NA
NA
3 00%
F'igmimo 92
0%
HN\
34
.4
0.39
0.43
0.40
3.20
9.9
10.7
10.2
NWO?)
Ncjiliijcm
FC
RD131
LogP
1000
F30
I;
1050
["M]
F 0
RD162
i @AH/ 122
H
FIG. 15A
25
PK OF Bicalutamide, R0162, R0131 AND R037
_
_
+ Blcalutamlde
_
+RD162
5 20 ~
+RD131
5
+RD37
'-
15 -
‘2’ 10 -
8
E
E
5 ~
%
0 ‘H
0
x
5
.—t
10
T (HOURS)
FIG. 15B
15
20
US. Patent
May 4, 2010
Sheet 16 0129
US 7,709,517 B2
NON ~TRPNSGEN|C ANMALS
000.
uAVG PROSTATE
02 5
2%>>
§
0 0. 5
0
H
029m H
02 m
I
o6 @NO 80
2.5 m 8.351
73.52
FIG. 16
@2
5.2 :
2 %)