(12) United States Patent
`Van Wagenen et al.
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US006211244Bl
`US 6,211,244 Bl
`*Apr. 3, 2001
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) CALCIUM RECEPTOR-ACTIVE
`COMPOUNDS
`
`(75)
`
`Inventors: Bradford C. Van Wagenen; Scott T.
`Moe, both of Salt Lake City; Manuel
`F. Balandrin, Sandy; Eric G. DelMar;
`Edward F. Nemeth, both of Salt Lake
`City, all of UT (US)
`
`(73) Assignee: NPS Pharmaceuticals, Inc., Salt Lake
`City, UT (US)
`
`( *) Notice:
`
`This patent issued on a continued pros(cid:173)
`ecution application filed under 37 CFR
`1.53( d), and is subject to the twenty year
`patent term provisions of 35 U.S.C.
`154(a)(2).
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 08/546,998
`
`(22) Filed:
`
`Oct. 23, 1995
`
`(51)
`
`Int. Cl.7 ........................ A61K 31/135; AOlN 33/02;
`C07C 209/48
`(52) U.S. Cl. .......................... 514/649; 564/182; 564/271;
`564/374; 536/23.5
`(58) Field of Search ..................................... 564/374, 182,
`564/271; 514/649; 536/23.5
`
`(56)
`
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`Primary Examiner-Gary Geist
`Assistant Examiner-Sreeni Padmanabhan
`
`(57)
`
`ABSTRACT
`
`The present invention features compounds able to modulate
`one or more activities of an inorganic ion receptor and
`methods for treating diseases or disorders by modulating
`inorganic ion receptor activity. Preferably, the compound
`can mimic or block the effect of extracellular Ca2
`+ on a
`calcium receptor.
`
`46 Claims, 104 Drawing Sheets
`
`1
`
`EX 1003
`IPR of U.S. Pat. No. 7,829,595
`
`

`
`US 6,211,244 Bl
`Page 2
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`
`5
`
`

`
`U.S. Patent
`
`Apr. 3, 2001
`
`Sheet 1 of 104
`
`US 6,211,244 Bl
`
`~~yOOCH
`
`CHJ
`
`3
`NPS 467
`
`~ H r')
`~N~OCH:i
`CH3
`NPS R-467
`
`~ H~
`~N~OCH:i
`NPS S-467
`
`~ HRCI
`~N:::...I
`1H
`
`H~ ~N~
`Y
`
`1S
`
`°o~~
`°o~
`
`N H (ij
`~~N~.
`
`H
`
`1V
`
`NC,,...__N
`
`H~ :::... I
`1W Hyql
`
`EtO~N :::...
`Q
`1X
`
`~ ()
`~l~y
`HO
`
`Hyql
`"'" Q ) 2A
`
`'"""
`
`N
`
`M
`H
`
`H~l
`H
`~ ~N ~
`28
`
`038 .
`
`N
`H
`
`.....
`
`H
`N
`
`H~I
`OS--&
`N
`:::...
`2C
`
`N
`H
`
`~ H riJ
`~N~OCH:i
`
`Cl
`
`CH3
`
`NPS R-568
`
`~~~OCH
`
`:
`
`3
`NPS S-568
`
`Cl
`
`H~I
`~N..,.,
`V
`1C
`
`FIG. la.
`
`6
`
`

`
`U.S. Patent
`
`Apr. 3, 2001
`
`Sheet 2 of 104
`
`US 6,211,244 Bl
`
`7;-"f?
`~HfQ °&"P
`°Q"Y9
`°Q"ti
`°Q"P
`°cH}O
`°2)HP
`
`N
`
`"'"
`F
`3A
`
`"'-"'
`
`._,.N
`
`"' I F
`
`38
`
`N
`
`30
`
`""'
`CF 3
`
`~l
`
`,._ " CF3
`JE
`
`I
`
`I
`
`I
`
`°QHf~(J
`
`N
`
`::...
`
`.
`
`I
`
`3F
`
`I
`
`Q.~,-~,fJ
`f
`3G
`~H;q N
`"" I
`3H
`
`°QH-P
`
`N
`Me
`
`"'-
`
`I CN
`
`3K
`
`~N <I 2P
`
`Hy:J
`
`H
`
`""N
`
`-
`
`20
`
`,._ I
`
`.~H~
`2R
`
`N
`
`&
`
`N
`
`,._ I 2S
`OCH3
`
`I
`
`N
`
`I
`
`"" I
`Ci
`2X
`
`N
`
`"'
`
`I
`
`Cl
`
`2Y
`
`N...._,):.N.
`
`H 2E
`
`I
`
`:;,.,
`
`N
`
`,,._;J
`2F
`
`I
`
`N
`
`,._ 2~
`
`°6" '1
`°6\,C
`°c"~
`°6~Yo
`?H
`-
`"" °cH
`°cHyCrCN
`°cH
`
`Ny?
`
`• I
`
`I
`
`""
`
`N
`
`"" .
`2J
`
`I
`
`N02K
`
`v
`
`N
`
`~H-0
`N
`N
`,._ I
`I
`2L
`I"" H~
`~ 2M
`°6H~ N
`
`"' I 2N
`COzH
`
`I
`
`D
`
`I H~
`
`N
`
`""20
`
`FIG. lb.
`
`7
`
`

`
`U.S. Patent
`
`Apr. 3, 2001
`
`Sheet 3 of 104
`
`US 6,211,244 Bl
`
`H r7)
`Ny-'"Y
`Me Me
`3L
`
`ropOCH3
`
`3X
`
`wpOCH3
`3Y
`
`HyOOI"'
`
`h
`~N "'--<
`Me
`30
`
`I 0
`
`H r7) NyY
`Me ~H
`3P
`
`~~yOOH
`6 Me
`
`30
`
`~~OCH3
`
`~ 3T
`
`'
`•
`
`3
`
`3Z
`
`w~OCH
`~~~A
`ca~~
`co-yq
`
`Hh
`["'YY1'J~
`40
`~ j
`
`n_~
`U" I
`41
`
`FIG. le.
`
`F
`
`rA Hn
`~N~OMe
`CH3
`40
`
`F~Hp.
`I
`I'
`"' . OMe
`"'
`N
`4P
`F~ H Fil
`~N~or·ile
`40
`
`H ( )
`CIY)
`~N~OMe
`Me
`4R
`
`~~PocH1
`
`CF3
`
`4V
`
`F1C~~POCH3
`
`WJ
`
`8
`
`

`
`U.S. Patent
`
`Apr. 3, 2001
`
`Sheet 4 of 104
`
`US 6,211,244 Bl
`
`F3C~ HRI
`
`OCH3
`
`~N """
`4X
`H ('n
`(Ii
`~N~OCH3
`Cl
`4Y
`
`I
`
`~ ~()
`Cl~I 1~0CH3
`SA
`Cl'Y")~ HI
`~ """
`OCH3
`'
`58
`Cl~H ~
`N~OCH3
`"'-I
`I SC
`~~Pso
`HyOI
`
`N
`
`,.,
`
`SE
`
`r7')
`HO~ H
`~NJ0
`I
`SP
`HD~~ (']
`l~
`U -~y9,lOCH3
`u
`SU
`H r9')
`N~OCH3
`. sv
`
`H ( )
`~N~OCH3
`VV
`SW
`
`n.H {)
`u TN~OCH3
`C'IOyW,ocH,
`~~ ()OCH3 ~
`~~~OCH3
`Cl Tu
`~~-nl
`
`'
`
`6H
`
`61
`
`H (Ii
`~·N~OCH3
`VV
`SY
`
`H~
`~ .. N~OCH3
`vv . sz
`
`~~ ,J?
`Cl ~
`H n
`r9'IJ
`~Nn6M
`Cl
`OCH3
`
`6L
`
`H rll
`N~
`CF3;:,. 60
`
`FIG. Id.
`
`9
`
`

`
`U.S. Patent
`
`Apr. 3, 2001
`
`Sheet 5 of 104
`
`US 6,211,244 Bl
`
`~~PoEt
`~~PoEt
`~~OEt
`~LQOEt
`
`5R
`
`'
`
`65
`
`.
`
`6T
`
`Cl
`
`Cl
`
`.
`
`6U
`
`Cl'?')
`H ( )
`~N~OMe
`5V
`H Fjl
`CIY)
`~N~OMe
`.
`6W
`
`Cl~~P.'OMe
`
`6X
`
`Cl~LQOMe
`
`5Y
`
`OCHJ
`
`~~H0
`~7E
`
`Cl
`
`OCHJ
`
`~~H0
`1~7F
`
`Cl
`
`~~-~nOCH3
`u7~
`OCHJ
`
`Cl
`
`~~~0_
`tr,,
`
`Cl
`
`r7iJ
`7M
`r9'(0H
`H
`~~OCH··
`Cl
`
`0
`
`yo~ OH
`
`I
`~ OCH3
`
`7N
`
`Cl
`
`0 HA
`
`HO~N _,._1
`7PP
`
`FIG. le.
`
`10
`
`

`
`U.S. Patent
`
`Apr. 3, 2001
`
`Sheet 6 of 104
`
`US 6,211,244 Bl
`
`~ H
`~N'r--()
`(.)--ff 9J
`~ H
`~N-0
`(.}--ff 9K
`
`H
`N
`
`-
`~ /i
`
`tfJ9L
`
`N
`
`""
`I
`CH3
`
`""
`
`HRIJ
`U.H ur·i .. cD 9H
`U.H uN'd) 91
`
`9G
`I .
`
`~ r1"ji
`~NJVgx
`
`FIG. -lf.
`
`11
`
`

`
`U.S. Patent
`
`Apr. 3, 2001
`
`Sheet 7 of 104
`
`6 211244 Bl
`us '
`'
`
`H&I
`CH3 ""'
`mH ~
`~UN~ gz
`
`N
`
`""'
`
`I gy
`
`10N
`
`I
`
`H~ ~ I
`N
`CH3
`
`""'
`
`& H
`'/" I N-n, 100
`tH3TJ
`
`'/" I
`H
`N ~
`
`H3&
`
`10S
`
`~ Hr)
`~N~CH3
`NH
`11F
`
`H&I
`~
`N
`10V
`~CH3~/
`v
`~ H£~1 10W
`VV ,,,N
`
`I
`
`CH3 "'
`
`AG lq
`
`12
`
`

`
`U.S. Patent
`
`Apr. 3, 2001
`
`Sheet 8 of 104
`
`US 6,211,244 Bl
`
`µ_p.,_
`
`Cl
`
`CH,
`
`11K
`
`H,C~ Hroj
`
`~N:,..
`:,.. I
`CH,
`
`Q~P~
`
`CH,
`
`12K
`
`Q~_n
`l,\J
`
`11z
`
`12A
`
`12B
`
`120
`
`12E
`
`I
`
`OCH,
`
`I
`
`H
`6 -# N:,..
`CH,
`
`H,C~CH, p
`n 12F
`A:
`~~~OCH,
`
`CH,
`
`12G
`
`12N
`
`120
`
`N
`
`" ' I
`
`12P
`
`H&
`CH, "' I
`~ H ~~
`
`~NyV
`CH,
`120
`
`~ H ~~
`~NyV
`
`Cl
`
`CH3
`
`~2R
`
`H,C~~POCH,
`
`CH3
`
`12V
`
`H
`~0 N
`
`121 Q{O
`
`I
`
`,d-
`
`CH,'>- I
`
`v
`
`l?J
`
`FIG. 1 h.
`
`~~o
`x_~ 11S
`H,C
`CH,
`
`llW
`
`13
`
`

`
`U.S. Patent
`
`Apr. 3, 2001
`
`Sheet 9 of 104
`
`US 6,211,244 Bl
`
`~,~ Hl61
`0,N~ H&j
`
`~N ::,._
`::,._ I
`
`CH,
`
`1JV
`
`~N"'
`""' I
`
`CH,
`
`1JW
`
`~~ H ~
`~NyV
`
`CH:J
`
`lt8
`
`H,CYYCH'
`
`H h
`~N~OCH,
`
`CH,
`
`CH,
`
`12X
`
`12Z
`
`13A
`
`,,,. I
`::,._
`
`~~s:"'-1
`~~0)
`6 138
`~~
`
`::,._
`
`13C
`
`Q,~~~
`
`130
`
`~N ::,._
`
`Cl-\,
`
`::,._
`
`130
`
`I
`
`13P
`
`~N ::,._
`
`::,._