(12) United States Patent
`US 7,709,517 B2
`(10) Patent N0.:
`
` Sawyers et al. (45) Date of Patent: *May 4, 2010
`
`
`USOO7709517B2
`
`(54) DIARYLHYDANTOIN COMPOUNDS
`
`(75)
`
`Inventors: Charles L. Sawyers, New York, NY
`(Us); Michael E_ Junga L05 Angclcsa
`CA (Us); Charlie D_ Chen, LOS
`An eles, CA (US); Samedy Ouk, Costa
`g
`,
`,
`Mesav CA (Us); Derek WeISble:
`Northfidgea CA (US); Chris Tran: New
`York, NY (US); John Wongvipat,
`Nanuet, NY (US); Dongwon Yoo, Los
`Angelesa CA (US)
`
`.
`~
`,,
`( ‘l’ ) Notlce.
`
`(73) Assignee: The Regents of the University of
`California, Oakland, CA (Us)
`~
`~
`~
`~
`Subject. to any d1scla1mer, the term ofth1s
`patent 1s extended or adjusted under 35
`U-SC- 1540’) by 592 days~
`.
`.
`.
`.
`.
`Th1s patent 1s subject to a termmal d1s-
`claimer-
`
`(21) APP1~ N0: 11/4333329
`.
`Flledi
`
`May15s 2006
`
`(22)
`
`(65)
`
`Prior Publication Data
`Us 2007/0004753 A1
`Jan. 4, 2007
`
`4,859,228 A
`4,873,256 A
`4,938,949 A
`4,944,791 A
`4,992,478 A
`5’010’182 A
`5,069,711 A
`5,071,773 A
`5,166,358 A
`5,411,981 A
`5,434,176 A
`5,556,983 A
`5,589,497 A
`
`5,614,620 A
`5,627,201 A
`5,646,172 A
`5,656,651 A
`5,705,654 A
`5 750 553 A
`RE35:956 E
`5,958,936 A
`5,985,868 A
`6,087,509 A
`6,107,488 A
`6,235,910 B1
`6,242,611 B1
`6,307,030 B1
`6,472,415 B1
`6,479,063 B2
`6,439,163 Bl
`6,506,607 B1
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`filed on Dec. 15, 2005, provisional application No.
`60/756,552, filed on Jan. 6, 2006, provisional applica-
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`
`6’8E8’471 B2
`7,2/1,188 B2
`2002/0133833 A1
`2004/0009969 A1
`2004/0116417 A1
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`2007/0249697 A1
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`
`Int. Cl.
`(2006.01)
`A61K 31/4166
`(2006.01)
`C07D 233/02
`(52) US. Cl.
`............... .. 514/392, 548/3001, 548/3164,
`548/3171-548/321 1 514/385 514/386
`_
`‘
`r
`‘
`5
`5
`of Classification Search ............ ..
`548/3164, 317.1, 321.1, 514/385, 386, 392,
`
`544/358, 359, 370, 546/184, 192, 207, 210
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`
`AU
`DE
`EP
`EP
`EP
`
`217893
`2102605
`0017976 A2
`0017976 A3
`0017976 B1
`
`64958
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`
`Primary ExamineriGolam M Shameem
`(74) Attorney, Agent, or FirmiVenable LLP; Michael A.
`Lars
`Genieser
`
`(57)
`
`ABSTRACT
`
`The present invention relates to diarylhydantoin compounds,
`.
`.
`.
`.
`.
`.
`1nclud1ng d1arylth1ohydanto1ns, and methods for synthes1z-
`mg them and us1ng them 1n the treatment of hormone refrac-
`my Prostate cam“
`
`13 Claims, 29 Drawing Sheets
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 1
`
`

`

`US 7,709,517 132
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`Page 2
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`FOREIGN PATENT DOCUMENTS
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`0 002 259 B1
`EP
`033123 A2
`EP
`362179
`EP
`0 494 819 A1
`EP
`0 578 516 A1
`EP
`0 580 459 A1
`EP
`0572191 A1
`EP
`0 580 459 B1
`EP
`0 494 819 B1
`EP
`0 721944 B1
`EP
`1 790 640 A
`EP
`2 693 461 A1
`FR
`2 715 402 A1
`FR
`2 845 348 A1
`FR
`2019363 A
`JP
`W0 90/13646
`W0
`WO 97/00071
`W0
`WO 97/19064
`W0
`WO 97/19931
`W0
`WO 00/17163
`W0
`W0 02/053155 A1
`W0
`W0 02/081453 A1
`W0
`W0 03/029245 A1
`W0
`WO 2003/057220 A1
`W0
`W0 03/093243 A1
`W0
`W0 03/096980
`W0
`WO 2004/031160 A2
`W0
`WO 2004/070050 A2
`W0
`WO 2005/059109
`W0
`WO 2005/060661
`W0
`W0 05/089752
`W0
`WO 2005/099693
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`W0 06/010642
`W0
`WO 2006/028226 A1
`W0
`WO 2006/124118 A1
`W0
`WO 2007/126765
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`WO 2008/119015 A2
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`(BMS-354825), on Human Prostate Cancer Cells”. Cancer Res.,
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`Receptor cDNA Expression. Molecular and Cellular Endocrinology.
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`Breast Cancer MCF7 Cells Transfected with Androgen Receptor.
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`Scientific Retreat, Scottsdale, Arizona, Sept. 29 — Oct. 1, 2005.
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 4
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 1 of 29
`
`US 7,709,517 B2
`
`
`
`RELATIVELUCIFERASEACTIVITY(%)
`
`
`
`
`
`Bicalutamide DISPLAYS AGONISTIC EFFECT AN LNCaP-AR
`
`900
`800
`
`600
`
`500
`
`400
`
`300
`
`200
`
`100
`
`<3
`
`
`
`-—"-—7A 5'51"}:5-13
`
`DMSO
`
`Bicalutamide
`
`U 0.1 micM
`D I mICM
`El 10 micM
`
`FIG. 1
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 5
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 2 of 29
`
`US 7,709,517 B2
`
`ANTAGONIST ASSAY OF BicaIuIamide ON LNCaP-AR
`
`
`
`
`
`RELATIVELUCIFERASEACTIVITY(%)
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 6
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 3 of 29
`
`US 7,709,517 B2
`
`
`
`D 125 nM
`n 250 nM
`
`
`
`
`
`
`D 500 nM
`
`E11000nM
`
`
`EFFECT OF COMPOUNDS ON LNCaP-AR
`
`(%)
`
`
`RELATIVELUCIFERASEACTIVITY
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 7
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 4 of 29
`
`US 7,709,517 B2
`
`EFFECT OF COMPOUNDS ON LNCaP-AR
`
`EE5«3madam
`
`FIG. 4
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 8
`
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 5 of 29
`
`US 7,709,517 B2
`
`00003:Es22:55
`
`INHIBITION EFFECT ON LNCaP-AR
`
`i!!!
`
`
`
`Ii“:
`
`..........E£5285
`
`FIG. 5
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 9
`
`
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 6 of 29
`
`Us 7,709,517 B2
`
`HORMONE REFRACTORY CELLS
`
`
`D 0.3 micM
`a 0.6 micM
`
`
`B 1.2 micM
`
`
`
`‘.h.
`
`
`-3b
`
`FIG. 6
`
`0.18
`
`0.15
`
`0.12
`
`0.09
`
`0.06
`
`0.03
`
`RELATIVEMTSUNITS
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 10
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 7 of 29
`
`US 7,709,517 B2
`
`Bic & EXAMPLE T-3b ON LN/AR GROWTH (n=8)
`
`
`
`+VEH
`—-—Bic.-1
`+EXAMPLE7-3b-1
`
`
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`DAYS
`
`FIG. 7A
`
`EXAMPLE T-3b ON LN/AR GROWTH (n=8)
`
`12
`
`g 10
`g 8
`é a
`
`4
`
`2 0
`
`12
`
`2 n
`
`ot
`
`E E
`
`oo
`
`(FOLDS)
`
`TUMORVOLUME
`
`.5
`
`DAYS
`
`FIG. 7B
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 11
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 8 of 29
`
`US 7,709,517 B2
`
`TISSUE PSA LNIAR (n=4)
`
`PSA(nglml)
`
`450
`
`400
`
`350
`
`CA)(:3O
`
`250
`
`200
`
`150
`
`100
`
`50
`
`0
`
`Veh
`
`0.1 mpk
`
`1 mpk
`
`10 mpk
`
`FIG. 8
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 12
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 9 of 29
`
`US 7,709,517 B2
`
`LAPC4-HR GROWTH ((1:4)
`
`M4;
`
`+ VEH
`
`—I— Bic-1
`
`_x CD
`
`—A- EXAMPLE 7-3b-1
`
`12
`
`CHANGE)
`TUMORVOLUME(FOLD
`
`
`
`0
`
`5
`
`10
`
`15
`
`20
`
`LAPC4-HR PSA (DAY 1?, n=4)
`
`TISSUEPSA(ng/ml)
`
`400
`
`300
`
`200
`
`1 00
`
`0
`
`Veh
`
`Bic-1
`
`EXAMPLE mm
`
`FIG. QB
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 13
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 10 of 29
`
`US 7,709,517 B2
`
`HORMONE SENSITIVE CELLS
`
`0.3
`
`0.25
`
`0.2
`
`RELATIVEMTSUNIT
`
`0.15
`
`0.1
`
`0.05
`
`FIG. 10
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 14
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 11 0f 29
`
`US 7,709,517 B2
`
`
`—.— Vehicle
`
`—-—— Bical.-10
`
`
`
`ARRgPB-Luc
`
`TV(cubicmm)
`
`
`
`..... -- Bical.-50
`
`_._RD162-10
`
`
`
`
`
`w.— -- RD162-50
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 15
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 12 0f 29
`
`US 7,709,517 B2
`
`on_8_m
`
`2
`
`:85
`
`202%
`
`ON?
`.OE
`
`om
`
`oNm(\l
`
`o111OT.
`
`(m3) 'OBS/SNOiOHd
`
`OC’)
`
`(10a) 'OES/SNOiOHd
`
`8NoEx
`
`2Noam
`
`22;;
`
`om?
`.OE
`
`823%:
`
`0:58
`
`
`
`mm?.OE
`
`gaging:
`
`858532
`
`Eggnog
`
`mag):
`
`
`
`on,,.x,mm,7,
`
`ow.g9§§n§
`A,y,
`
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`
`
`
`
`
`mfmmgomuxsd(my?“.38u=._.mn_umm<
`
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`
`535033
`
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`
`«$1382
`
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`
`
`
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`
`8372:m._8_m
`
`0:58,1,
`
`82%“:
`
`£393is3
`
`<8.6:
`
`35%
`
`wowom_g
`‘.1k:5:
`
`
`
`2;93
`
`
`
`$22BEE/3_g83:23~3K
`
`
`
`25;§~
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 16
`
`
`
`
`
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 13 of 29
`
`US 7,709,517 B2
`
`PK OF RD162: INTRAVENOUS AND ORAL ADMINISTRATION
`
`[uM]
`CONCENTRATION
`
`TIME (h)
`
`FIG. 13
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 17
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 14 of 29
`
`US 7,709,517 B2
`
`LN-AR(HR)
`
`
`
`PSAABSORBANCE(FOLD)
`
`B100 nM
`E1200 mm
`0500 nM
`
`
`
`131000 nM
`
`
`
`
`
`m\
`
`
`
`DMSO
`
`Bical
`
`R0131
`
`RD162
`
`FIG. 14
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 18
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 15 of 29
`
`US 7,709,517 B2
`
`CHARACTERISTICS OF Bicalutimide, RD37, RD131 AND RD162
`
`STRUCTURE
`
`NAME
`
`
`
`1cm
`[nM]
`
`LogP
`
`CSS,10mpk
`[11M]
`
`083,25mpk
`[NM]
`
`CSS,50mpk
`[NM]
`
`F
`0
`NC
`BIC. D Q 1000
`
`I F3“
`
`133%
`
`2.91
`
`10.0
`
`11.4
`
`11.9
`
`I
`
`
`
`
`
`
`
`
`F3C
`
`0
`
`RD131
`
`NC
`
`3
`
`D
`
`O
`
`0
`
`92
`
`3.44
`
`0.39
`
`0.43
`
`0.40
`
`l 110% I
`
`
`
`PK OF Bicalutamide, RD162, RD131 AND RD37
`
`_
`.
`+ Blcalutamlde
`
`
`
`+ RD162
`+ RD131
`—x— R037
`
`5
`
`10
`
`15
`
`20
`
`T (HOURS)
`FIG. 158
`
`25
`
`_
`E 20
`S
`5 15
`
`E “
`
`z’ 10
`82
`g 5
`
`0
`
`0
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 19
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 16 of 29
`
`US 7,709,517 B2
`
`NON -TRPNSGEN|C ANMALS
`
`DAVG PROSTATE
`
`WEIGHT(9)
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 20
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 17 of 29
`
`US 7,709,517 B2
`
`LN-AR (HR)
`
`
`
`TISSUEPSA/OD
`
`250
`
`200
`
`150
`
`100
`
`50
`
`0
`
`Vehicle
`
`BicaI-10
`
`Bical-50
`
`RD162-10 RD162—50
`
`II I
`
`FIG. 17
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 21
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 18 of 29
`
`US 7,709,517 B2
`
`+ Vehicle
`
`
`
`_._ RD162-0.1
`.0.— RD162-1
`+RD162-10
`
`LN-AR (HR)
`
`4
`
`3
`
`‘é‘
`E 2
`E
`
`1
`
`0
`
`0
`
`6
`
`11
`
`17
`
`T(DAYS)
`
`FIG. 18
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 22
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 19 of 29
`
`US 7,709,517 B2
`
`DAY 0
`
`
`Veh.
`
`RD162
`
`DAY 17
`
`
`Veh.
`
`RD162
`
`25
`
`20
`
`10 FIG. 19
`
`15 g
`
`E
`
`DDAYO
`nDAY17
`
`vé
`
`' 2-10
`
`FIG. 190
`
`3‘5
`g 3
`g 2.5
`8 2
`
`Q g
`
`1.5
`E 1
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 23
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 20 of 29
`
`US 7,709,517 B2
`
`6
`
`LN -AR (HR)
`
`5
`g 4
`g 3
`I?
`
`2 1 0
`
`—<>—Vehic|e
`
`
`
`05101520253035
`
`T(DAYS)
`FIG. 20A
`
`Vehicle
`
`RD162-10
`
`a Vehicle
`
`0 RD162-10
`
`__n
`
`
`
`PHOTONSISEC.(FOLD)
`
`.m L ....
`
`DAY 0
`
`DAY 17
`
`DAY 31
`
`FIG. 20C
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 24
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 21 of 29
`
`US 7,709,517 B2
`
`1.8
`
`1.6
`
`1.4
`
`1.2
`
`1
`
`0.4
`
`PSA(ABSORBANCE)
`
`§\_\\\,\\\\.\\\15-_‘
`
`Vehicle
`
`RD162'
`
`U 100 nM
`E1200nM
`c1500nM
`
`U1000nM
`
`FIG. 21A
`
`PSA(ABSORBANCE)
`
`FIG. 21B
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 25
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 22 of 29
`
`US 7,709,517 B2
`
`_>. N
`
`LNCap (HS model)
`
`U 100 nM
`
`E1200 nM
`
` PSAUNITS
`(ABSORBANCE)
`
`O
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 26
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 23 of 29
`
`US 7,709,517 B2
`
`LUCIFERASE TRANSGENIC ANIMALS
`
`INTACT
`
`|NTACT+T
`
`TICAST
`
`BIC+TICASTRD162+TICAST
`
`I C
`
`AST
`
`FIG. 23A
`
`LUCIFERASE TRANSGENIC ANIMALS
`
`600
`
`3 500
`
`AVERAGEUGWEIGHT(m
`
`400
`
`300
`
`200
`
`100
`
`0
`
`
`
`ROI(PHOTON/SEC.)
`
`1.20E+08
`
`8.00E+07
`
`4.00E+07
`
`0.00E+00
`
`WT
`
`CAST
`
`INTACT
`
`|NTACT+T
`
`T/CAST
`
`BIC+TICAST RD162+TICAST
`
`FIG. 238
`
`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 27
`
`

`

`US. Patent
`
`May 4, 2010
`
`Sheet 24 of 29
`
`US 7,709,517 B2
`
`EQLGH
`
`L“‘
`
`
`
`““““““
`
` LQLGH
`
`m
`
`MARREPORTER
`L‘“ FIG.24
`
`L .".'_"... '."_‘. ‘...'..‘,‘.4,
`
`m
`
`zsma
`
`
`
`,. 5mg
`
`m
`
`9mm
`
`nn“‘“
`
`m‘““
`
`
`
` : may
`'.,'I'._‘.
`. -.,'
`.
`'.. '._"'.'
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`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 28
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`US. Patent
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`May 4, 2010
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`Sheet 25 of 29
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`MYLAN PHARMS. INC. EXHIBIT 1130 PAGE 29
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`May 4, 2010
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`Sheet 26 of 29
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`US 7,709,517 B2
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