Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02562526 2006-10-11
WO 2005/100343 PCT/EP2005/003741
86999pct
Selected CGRP antagonists, method for producing the same
and the use thereof as drugs
s The present invention relates to the CGRP antagonists of general formula
A
O R2
I
N X N~Ra
1
R , (I)
the tautomers, the diastereomers, the enantiomers, the hydrates thereof, the
mixtures thereof and the salts thereof as well as the hydrates of the salts,
particularly
the physiologically acceptable salts thereof with inorganic or organic acids
or bases,
pharmaceutical compositions containing these compounds, the use thereof and
processes for the preparation thereof.
15 In the above general formula (I)
A denotes a group of formula
F3 F3 F3 F3
\ NHz \ NHZ \ OH \ NHz
/ CI ~ / CF3 ~ / CI ~ / Br
> > > ,
CH
CH3 CH3 ~ ~ F3 H
NHZ ~ \ NH2 ~ \ NHZ ~ \ N~CH3
20 / CI / CI / CI / CI
> >
F3 F3
CI ~ \ Br
/ /
or ,
X denotes an oxygen atom, a methylene or NH group,
s ,
CA 02562526 2006-10-11
-2
R' denotes a group of formula
/ I N~ \ I N~
H ~ Or H ~ and
-NR2R3 denotes a group of formula
-N~N~ -~-N~ ~N-CH3 -~-N_
~/ , ,
~N-CH3 ~- ~N~N-H -~N N-CH3
> >
CH3
~N N N-H ~N~N -~-N~NCH
CH3 3
, , ,
-N~N~ -~- ~ ~ ~N ~N~N\~N-CH3
> > >
-~-N N N-CH3 ~' ~ --~~<~ ~N~N
~~//N
> > >
-~-N N
N~ -~-N N ~-N N
CH3 U
,
H3 H.,C .CH3
~N~N N-CH3 -~-N~N~N-CH3
H3 H C 'CH3 ~N~ ~N~
> >
-N~N N -~-N N N ~N\~
N
CH3
, ,
CH3
/~ H ~N
-~- ~N~N-CH3 -~-N_ r-' \CH3 -~-N N-H
CA 02562526 2006-10-11
-3-
N
\ ~ w
~N N ~N I /
w
or
Particularly preferred compounds of the above general formula (I) are as
follows, for
example:
N _ a //
F N
F \ / a / \
~J'~ O N~--~ 2 ~f~'~ N~-- N
\ / ~~~0~~ ~ N~N~O~~ _
N O ~ /
c1 N F N a
~/ \
Y FF
3 ~ ' 4 _ N' _ ~1
I / N~ ~N O~N~ \ / ~~~O~N~ ~N~
O N
O
CI N //
F N
/ \ / \
O FF 6 a
I / N~ ~N~O N \ N
O ~ N~
CI N F N a
/ \ F
F F \ /
Q F g F
I i ~ ~N~O~N~~O \ / J~~~~N~
N O O N
a N //
N
/ \
9 o FF 10
I j N~~NJ~O N N-~~ N_
~''O
CI N //
/ \ N
/ \
11 ~ ;, F F 12
I / N~ O ~ _ N~N~N~~ N-
O
CA 02562526 2006-10-11
-4-
G N F I/
/ \ N~ \
13 o FF 14
I w N~N~O~-N~-N
\ N~O N~ i/ UN_
N O O ~N~ 1 / N o
CI N N CI
F
/ \ \ /
15 ~ ;, F F 16 ~
N~ ~N O U N~ \ / r~~N~ ~
O N
CI N N CI
/ \ F
F ' \ /
17 ~ ;, F 18 ~ _ ~,
I ~ ~~ O~N~ N \ / ~~0~~/N~
N 0 0O
N O
CI N II
F
\ / \
19 ~ , F F ~ 20 a ' ,
N N
I ~ N~~N O N N ~ o0
O o
CI F I/
/ \ N
/ \
21 o FF _ 22
O N
I , N~ ~N~O N ~N-a \ N-~ N
O
CI N F N G
\ ~_ \ /
23 w N N~ ~ F F 24 r~N
I ~ N~~ O N ~ / ~~ O
O N O
CI N II
/ \ F N
/ \
25 ~ ;, F F ~ 26 a '
I ~ N~~N O N - ~ N_
-~~O o
CI N N CI
/ \ F
_ ~ \ /
27 ~ ;, F F 28 ~ _
I \ N O N~N~ / N N
O -(,
O O
CA 02562526 2006-10-11
-5-
F F F II
29 ~ I _ 30 G
~N O N N --/N \ / N 00
N O ,
N
F F F N CI
G
I
31 / I N ~O ~N N 32 ~N~O~ ~N N
O ~ N~ ~~' ,N''0
N G N G
F
F F \ /
33 = 34 ,,~
N N
N N- ~N'~0~~ ~/
\ / ~~ O O _
N O \ / N~O
F
N / \
F G
35 F F ~ / 36 =
N~ ~~N ~ N~O~ UN N_
\ / ~~ O O
N / \
O
F F
N /
F G
37 F F \ / 38
~~~N~ -/( o~N~ ~-
N o I
F N
F F
F G
39 F 40 ~ ~ ~ ~~N~
N / \ ~ 00
N
Br
N
F
F \
41 F = ~ 42 ~N~O~.~N~N
/ NCO ~ / N O
O G N '
F
F \ /
F -~ ~
43 0 = ~ 44 ~( ~ .~N N
~~O~N~ JN - N~N 00~~ ~J U
N~O \ / N~O
CA 02562526 2006-10-11
-6-
o _G N
F / \
F \ ~ G
45 F = 46 =
~N~ ~N- N~N~N~ ~N N-
/N~ O '/ ~JO
N~o /
N N
G / \
CI
47 : 48
N.J~N~N~o~~N N-/~ N N
/ \
O G N
F , \
F \ ~ G
49 F : 50
~~~-~N-~- N~O ~N~~~
00
N / \
O
o G N a
F
F \
51 F ~ : ~ 52 0 .
~N~N~- N~N~GO~o -ni ?-( N
N o \ / NkC
-N G N
F
F \ ~ CI
F
53 ~o~ VN 54 N~ ~~N-~ ~N~N
\ / N~~ O 1 ~ N \J O O
O
~N G N
F ' / \
F \ ~ G
55 = _ 56 0
.! ~--r~-- NJ( ~~ N N
\ ~ ~~ 00
N / \
O
N G ,N G
F F \ I F F \ I
57 0~ ~ 58 - o-
\ / N~~~O O ~N \ ~ N~ ~~O O
O O
G N CI
N
F
F
F
59 ~ ~ N N 60 N~o-~NxN
~, ~- ~- ~''- _ N-G
N~ \ / N'~C
CA 02562526 2006-10-11
-7-
0 G N
F / \
F \ / CI
61 F ~ 62
_ o _ //
\ / N~~~O~~N 1 ~ N~N~N~O~N~
O
N CI
N
/ \ \ l
CI
63 N~o N~ ~~N~ 64 ~N~--~~N~N
N~ O
/ O \ / Nko
G
N
F \
FI \ l
65 F ~ = 66
/~ ~N
~('~ -~N~N O
\ / N \J O O \~/ ~! _
N-~O
\ / N O
~N G N
F ' ~ \
F \ / CI
67 ; _ 68
~~ ~N~ ~JN N-~ ~O~N~N-
\ / N 00
N-~o i
N G N
F ~ \
F \ / CI
69 F = ~ ~- 70 /~
~~~N N N-t ~N~ UN~N-
\ I N-~ ~ O O ~J ~ O
N'~O ~ \
N G N
F / \
F \ / CI
71 F = _ 72 /~ =
N~N~ ~JN-
OO
\
N O
O G N
F ~ \
F \ / G
73 \ / ~~o~~~N- 74 ~~~~N,
~I~J' / \\
0
~N G N CI
F F \ / \ /
O ~ O \-/N N
\ / ~ boo \
N~ N~O
CA 02562526 2006-10-11
_ $ _
~N G N
F F \ / p CI
77 F ~ ~N~ 7v ~ N N
\ / J~-~' oo \ / N o0
N~ N~O
N G N G
F F \ / F F \ /
79 ; 80
~-. ~. ~N ~ N~-N
\ / ~~~p~N~ 1 ~ ~~N~O~~~
N O " '" OO
O G
F
F \ /
81 F ; ~ 82 ~-ty~, N
NON N- r,N "O
\ _
O ~ / N.~Q
O _G N
F / \
F \ / CI
F
83 84 N~ N~N~N
\ / N~ O ~ N-C O O
~O
N N
/ \ G / \
CI
85 : 86 p
NJ~O N N~ N~N~_
I / N~ 00 / \
,N G N CI
F F \ / \ I
F
87 \ / ~,, 0 88 \ / -~'~- ~J-
- ' N N N
0 0
~N G N
F.F \ / CI
F
89 \ / ~ 90 \ / ~~o N N
N '
N G ~N G
F F \ / F F \ I
91 ~ 92 ~--~
N~ N O
CA 02562526 2006-10-11
_g_
~N CI N CI
F F \ I' \ I
93 ~ ~ 94
~~N N-~N ~ N
J~ ~- 00 ~/ \ ~ N 00
N~ N~O
-N _G N
F F \ ~ CI
95 F ~ ~ 96 /~-~
/ N~ N NVN \ / ~~N~~N N
N~O-~ ~ N ~/O
N G N CI
F F \ ~
97 = _ 98
\ ~ r~ t~ ~ ~-(~~N~N
N~ ~ / N~O
N G N CI
F F \ ~
99 ~ ~ 100 p
N N N- ~~~. N~- N N
N O 1 / N~ ~O
O G
F N
F \ ~ CI / \
101 F ; 102 .
_ ~ O ~ r-.
\ / ~ ~ n~~N- N~~~N~N_
N O ~ / \\
~N G
F N
F \ ~ CI / \
103 F = 104 .
- N J( ~~ N ~N-
\ ~, ~.' 0
N / \
O
.N G N CI
F F \
105 ~'~ 106
N ~N N
~-~r~ ~ , ~N-~~~'l~
N~ ~ / N~O
N G N G
F F \ ~
107 ~ 108
N ~ -~--
N ~ UN
\ ~ 00 ~~ 00
N O / N O
CA 02562526 2006-10-11
-10-
N II N II
CI \
109 a 110
p p~- ~N~N-
_ N~~N~O~ VN~ ~ ~N~ '/O
I / / \
N ~~ N //
CI \
111 G / \ 112
N //N O N N ~ ~N~~N VN-
I / / \\
II N CI
N
/ \ ~ \ /
113 a ' 114 0
N~~~~ ~~N_(O~h~N
JN-~ ~ ~/O
I / ~ / N O
~N CI
F N
F \ / a / \
115 F ~ _ _ 116 -,
\ / N~~O O NL../N \ /N \ NJ~N~N~~N~N~
N-L~p \.~ I /
~N CI /I
F N
F \ / CI / \
117 F N ~ ~ _ 118 p .
/ N~~O~NUN \ / ~N~~~ N-
N~Ov / \.J
,N CI N G
F F \ / ~ \ /
119 = ~ _ 120
/ ~ NVN \ ~ N~N
N~ ' / N~O
N F F N II
121 F F \ / 122
N O 0 N~ I ~ NJ~N~~ N
~~O
N r N CI
F
F \ / ~ \ /
123 F p = ~ 124
~~O~N~~ ~N~N
N~ \\JJ 1 / N~O
CA 02562526 2006-10-11
-11-
N Br N CI
F F \ / ~ \ /
125 = 126
~~~~O~N~~ ~ UN
\ / 0 ~ N O
N O 1 ~ N~O
//
c1 N / \
127 ~ -~N~N~ 128 0
~N 00 ~Nv ~ ~~ ~N-
tJ~l~1 ~\
\ / N~0
N _Br //
F N
F \ / CI / \
129 F = 130 -
\ / ~ ~ N ~ ~~~N~N-
N O / \\
//
N
/ \
131 N-~ N~ 132 p1
00 ~N ~ ~~N VN_
N~f~N~0 0
\ / N'~0
0 G N Ci
F
F \ /
0 '
133 F ~ 134 ~
_ ~~~ O ~ ~~0~ ~N \ iN
\ I N~~O O N\-/N N~~I\\//I O
N~0 ~J .L
\ / N O
0 CI N CI
F F \ / ~ \ /
135 ~ _ 136
~~ ~N~N~ NxN
\ / 00
N-~
//
/ N
/\
137 /~ ~ ~ 138 _ .
N~N~N~~Nv ~O N~~N
N
N~ O O
\ / N~O
N N //
\ /\
139 G ~ 140
N-~ -~ ~ ~N ~ ~~N~N-
% N 00
CA 02562526 2006-10-11
-12-
N CI
N
\ /
N
141 G : 142
N~ ~ N N ~ \
N~ 00 _
I / \ / N'~°
N N G
CI / \ \ /
143 \ N~o N~o~ ~N~ 144 ~N-!~-"L/N v ,N
N~ _
I / \ / N~°
N G
GN~~ ~ \ /
145 : _ 146 = _
~~N~ ~~ ~ ~N \ /N
\ / 00 ~ N O O
N O I / N~O
O G N CI
F F \ / ~ \ /
147 ~ _ 148 = _ _
\ / ~~0~ ~N~ \ ~~N~O~~N \ /N
N--((~~0~ I / N O
O G N CI
F F \ / ~ \ /
149 N = ~ 150 ~ ~ _
~.(O~N~N N ~~N \ /N
\ / N-~ ~ O U ~ N O
N~O I / N~O
N G N G
F
F \ /
151 F ~ ~N N 152 ~N-~o~ ~N-~N
N
\ / N~~ O O ~ \ I ~ O
O N O
N G N G
F
F \ /
153 F = _ 154 0 ' /--.
_ ~ ~j-N~ ~ ~N~O~N~N~N
\ / N~~ O O \ ~ ~ (~I'J~N
O N 'O
0 G N
F ~ \
F \ / G
155 F = 156
~N~.IO~~N -~ ~~O~~N~N-
\ ~ /\
N 0
CA 02562526 2006-10-11
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O G N
F I \
F \ / G
157 F = ~ 158 ~~~~
~~ ~-N~"'N~ ~ ~N~ ~~N N-
\ / N 0 O ~ 00
N~O / \
N O G
F
G I~ F \
159 ~ 160 F ~ ~N '
N~N~-C~O ~N \ / ~ 0 O
I / N'D
O
N N
I \ G / \
161 ~I ~ : 162 : _
/'O N
N'\ N~ ~~N N N-/~N~N_(O~N~N-~N
N~ 00
N N a
/ \
CI~ \ /
163 p : ~ /~ 164 N~N N~N
~~N N~ ~N'~00 LJ
~N N 0 O ~--~ ~ ~ ~ N
N a
N
G I % \ l
165 N : ~ 166 ~N N N
_ ~~N~ ~N.GOO ~ ~/
\ I N-~-~OO ~/ ~ ~ ~~~JJ,N
O \ N 'O
N G N
F I \
F \ / G
167 F ~ 168
/ ~~(O~--t~N-~N ~N O N-
N
O
N G N
F I \
F \ / G
169 F ~~~ 170
/ ~~~r~ ' -r(p N-t~~r-~ "-
N
O
p G N CI
F
F \ /
171 F N = 172 ~ -~. N
/ ~~O~~~N ~N 00
N~ /~N ~ ~ N'N~'1~IO
CA 02562526 2006-10-11
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o G N a
F \ /
F \ I
173 F N = 174 ~ ~
_ ~~ ~N~N N ?-( N
\ I N~ 0 0 ~ ~ ~.J ~--~N
O \ N 'O
~N G N
F F \ I a I \
175 F p = 176 ° °
~~ ~N~N N~ ~~O~N~N
\ I N OO ~ ~ O
N~O / \\
N G N
F I \
F \ I G
177 F = 178
~~N~~O~N~ ~ ~~O~~N-
\ I \
N~O
N G O G
F F \ I F F \ I
179 ~ 180
~~O~N~N ~/ ~~o~N~~
\ I N O \ I N O
N~O N~O
O G N G
F F \ I F F \ I
181 ~ 182
~~-N N-~ ~ ~ ~-N
\ IN~ 00 ~ \ I ~~ 00
O N O
G
F /
F \I
183 _ I F ~~ ~N 184 .c ~,--~J- ~
N
N~N O
fJ~l~I\
N O \ / Nk0
N G
N
\ \ /
185 m ~ ~ 186 ~ N
N~ N~JN N~O
% N'~ 00
O
N N
/ \ G
187 p c~ - , 188 ° ~ ~N~ ,~-
N~ ~--N~N~N- N~ ~N O O
N-'~ 00 / \\
CA 02562526 2006-10-11
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N N
\ \
CI / G
189 : 190 p
//0 ~
N~ ~N~NV ~N N N
N O
N N d
G / \ \ /
191 : _ 192
_ N~~N ~N 00 NON N
\ /N~~-X00 \ I NN
O n -O
N CI N G
\ /
193 ~ ~~N~ 194 ~~ VN
w N \J O O ~N~ i O
N~O
~N G N
F / \
F \ / G
195 F ~ 196 ~~ ~ ~' _
/ N~~O~N~"'N~ ~N~N~~
-JV[J // v N
/ \
O
N G N
F / \
F \ / G
197 F = 198 O ~--~ N N-
/ ~'lO~N\~ ~N N 00
/ \
N O
N G N G
F F \ I F F \ /
19g = 200
'~ ~N~N ~ ~'~ ~N~~
\ /~r~ 00 \ / ~ 00
p N O
N G O G
F F \ I F F \ I
201 = ~ 202 =
/
/ ~ NU ~ / ~~ N
N N O
G N CI
N
F
F \ /
203 F ~ /-~ ~ 204 N N
~N~N N N
\ / ~~ 00
N O \ / N O
CA 02562526 2006-10-11
-16-
o G N a
F
F \ /
205 F ,-~~ ~ /~ 206 /~
~J~~N~N ~N~N~N
\ / N \.J O O ~ I N
N~O \ N~O
0 G N
F F \ / a / \
207 F ; 208
-~N~'N~ N~ ~N~N~N
\ / N OO ~ O
N~O /
N G N
/ G
209 ~~~N~ 210 ~~N_
o ~N~ ~',~~ 00
\
N O
~N G N G
F F \ / ~ \ /
211 = 212 = _
_ o
~~N~"N~ ~ ~,(O~N~N~N
I /N~~~[~1~O O/r \ / N O
N~O N~O
N G N G
F F \ / ~ \ /
213 = 214
N~N ~ ~ N~ UN
\ / /N-~ O O \ / J~~ O O
N~O N-QO
N G N G
/ i \ /
215 = 216
N
N N
~ ~~~ ~N\ \ / N~~~O~N
~~O O
II N G
aN ~ \ ~ \ /
217 '. ~ 218 N~~~
_ N~N~~~~N \ / ~-~~O 0 ''l~N
N-tp
II N CI
N
G / \ ~ \ /
219 '~ 220 ~--~
O ,( ~~N~
N-.~~~ N N N ~ l~/-
~N~ O 0
00
I N O
CA 02562526 2006-10-11
-17-
II N G
N
d / \
221 ' . _ 222
o- _ o
~N~ ~~ ~N N
\ / ~N-~O~ \ ~ ~ O O
O N O
II N I~
N
/ \ a / \
223 a ' . ~ 224
\ N-~0~~~~N -~O ~~~N~N~
/ / \
N CI
N / \I i
225 G ' 226
\ NJ~N~~ N N
/
II N G
aN/ \
227 ' . _ 228 /~\ ~
/ N-~ \JN ~ ~ ~~~(O~h~N
N ~--~ '--'O
O G II
F N
F \ ~ / \
229 F o~ ~ _ 230 0
\ ~ N~~O O ~N \ / ~ ~~~N N
/\\
II N G
N
d / \
231 ' ~ 232
_ _ ~,,--~~~ N ~~J.!
N~N~~~N \ I ~~~~N~
1/ N
O
II N G
N
/ \
233 G ' _ 234 ~--~
N~ ~~~N_ ~ ~~N~N
~ N~-~(~00 \ ,\~/N
/ O
II N a
N /
/ \
235 G ' : 236 O~ r-,
N/~ ~~N~- NVN \ /N
N~~N~ 0 O
\ / 00 ~ I N
O ~O
CA 02562526 2006-10-11
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O G N G
F F \ I ~ \ I
237 = _ 238
~~ ~-N N \ , N
\ I N O O ~--/ ~ N-~N O p
N~O , ~ N~O
N CI N G
F F \ I ~ \ I
239 = _ _ 240
~~ ~~ ~ N N \ , N
\ I N 00 ~/ \ I 00
N O N O
N _G II
F N
F \ I l \
241 F ~ ; _ _ 242
UN \ /N ~ ~~N N
/ \\
O
O G N d
F
F \ I \ l
243 F = _ 244 N
N N ~N~O~N~j \ ~N
\ IN~ 00 ~ \ / ~ I N O
O \ ~O
F N d
F F
N
F - \ I
245 F F \ / . 246
_ O N UN \ /N
\ / N~~O O ~ ~ N~O
N G N G
F F \ I ~ \ I
247 ~ _ 248 = _
~~N N \ , ~~~~ ~N N \ /
I 00 ~/ \ I 00 U
N O N O
N G
N
F \
249 F F \ / 250 N _
\ / ~O O L.J N \ I N~~~~ \ /N
N-~ N~O
N G
N F
F \
251 F F \ / 252 _
H~-N~-N ~~-N N \ /N
\ /N~ O \ IN~ 00
CA 02562526 2006-10-11
-19-
N N G
/ \ \ /
G
253 : 254
0 0 ,--~ p
I N~ ~N~ ~-N N N- ~ ~.I ~-N N-~N
N O O ~/ \ / ,,, O O ~/
/ ~~O
N N G
/ \ \ /
G
255 : _ 256
N~N~N~p~N~ ~JN \ / ~~0~~
I / N
O
N CI N G
\ / \ /
257 = ~ 258 = _
w ~~0~~ ~N~ \ I ~~~~ UN~
I / N~O N O
N a N G
\ / \ /
259 ~-\' ~ 260 /~
N~N~~N~ ~Nv ~~~N~NUN
i I \ / ~ 00
~O N O
N a
N _
a / \ \ /
261 : 262 p '
O / '~ p N N
N~N N O~-f~N-~N- N O
I ' N~O
N N G
G / \ \ /
263 : 264
_ o
N~N N UN \ / ~~~0~~
I / N~'O
N CI N
\/ a
/ \.
265 = ~ ~ 266 ~
N ~ ~N\ NJC N O ~'N
~/O
I / N~O / \\
a a
N\ / N\ /
267 N~N~N~N~ ~ 2 N~N~O~-N
' ~ N'~p ~J - ' ~ N'~ /-o
CA 02562526 2006-10-11
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N N G
/ \ \ /
CI
269 : 270 ~ /~
I N~ ~N~ ~N~N- ~~ ~~ ~N~N
~N-~V, O O/r \ I N 0 0
/ N O
N N
G / \
G
271 : 272
O N
N-~ ~N_( ~N~N- NFL ~N-~O O N
N 00 / \
N G
a _
273 : 274
N N N- ~N N
N"/~ N O ~ \ ~ N~ O O ~J
I / N-C~
O
N N G
G
275 : 276 ~--~
// ~N N N- ~N~N N
N~ N O ~ ~J \ I N~ O O V
I / N~O
N CI N CI
\ /. \ /.
277 - ~ 278
N~~~ ~Nw I ~ ~~N~~N~
~~O ~ O
a a
N\ / N\ /
279 1~_'~ ~ 280
N N~N~ ~,N~ N N
I N'~p \ ~ N'~O
N CI N G
\ ~ \ /
281 = ~ 282
N N ~N
N 00 U \ I N 00
I / N~O N~O
N N
G / \
283 = 284 p
N~O ~N~ ~N~N N -~ N
N 00
CA 02562526 2006-10-11
-21 -
N a N a
\ / ~ \ /
285 0 ' N,--~ 286
O ~N ~ ~~ ~N~N
i O \ / /N 00
w ~ ~O N~O
N a
N
G I \ i \ l
287 : 288
N N ~ ~~ ~-N~N
\ / N-O 00 \ I N~ 0 0
O O
N N G
a / ~ \
289 p p ~ ,~ 290 p = ~ _
'l~N~'-~p~t~N~ \ I ~~0~/-HEN \
/ \
N O
O G N a
F F \ / ~ \ /
291 = 292
\ I ~~O~N~N~ \ I N~~~~N
N~p O
N N a
/ \ \ /
G
293 : 294 = _ _
N~N~N~N~/N- ~ / N~-~ ~/N \ /N
I / O
N G N a
\ / \ /.
295 [~/ : 296 ~ _
~~~N N-~N~ ~N N \ /N
N O O U \ I ~ O O \_/
I / N~O N
N a
N
I \ \ /
297 p ci - , 298 N.eo~,-~-~t
N~N N~N~N- ~ O
I / \ / N 0
N a N a
\/ \/
299 ~~~N~ 300 ~N.eo~--N'~-rl
N r~~
/ Nk0
CA 02562526 2006-10-11
-22-
N G
N
/ \
G
301 : 302
N ~N DO N N
\ / ~ 00 _
N p \ / N~~
GN/ \ GN/ \
303 o N ~ ,~ 304 p o
/ \-(~N~~(O~p --~N~' / \-/~ ~N-lO~~N
O G N
F / \
F \ ~ G
305 F ; 306 '
p N
N N~ ~N'~0~~
\ / \
N O
N G N
F / \
F \ ~ G
307 F = 308 // ~~~---(~~
N
~(O~-N~'N~ N~ ~N~~
O ~ O
N / \
O
N G N CI
309 = 310 =
~~N N~ ~N~ ~~~
N 00 ~ ~ N 00
I / N~O I / N~O
N G
CI / \
311 : 312
/r ~\~. N N ~~~ ~,-.N~N
N~N~ I ~ N
~~ ~O
N d N G
\ / ~ \ /
313 ~~ ' ,--, ~ 314
I N~N~~N
~N'~O I / N~O
N
/ \ / \
315 N~ N_ 316
\ I N~ 00 ~~ '~ 00
N~p
CA 02562526 2006-10-11
-23-
GN/ \ aNl~
317 p ° ~ 318 p = ,
// N ~ N~-N
r \~N~ / N-~N~N
N ~I N
I \
a / \ G
319 ~ 320 /~
P N-'t N
_ N~~N~~~N N / \ ~ 00
N'~~
II
N N
\ / \
321 a 322
N~~N~p~~ V p ~~p~~N
O
N _G II
N
a / \
323 p ; ~ 324 p N
\ r N~~O~N~ ~N~ N-~ ~N-~'p~N~~
/ \\
O
N G II
F N
F \ r CI / \
325 F = 326
~N~~O~N~ -~ ~N~N~N
\
N /
O
O G N
F I\
F \ r G
327 F ; ~~ 328
r\
O
it
N/ \ G I \
329 a ~ . 330 ,'
N~O~~O N N N_ \~O ~N~O~~
N''"
F F
N F
331 332 G
N~-N~N'JN~
00
N O
CA 02562526 2006-10-11
-24-
F F F F
N F HO F
333 ci ~ \ 334 ci ~ \
~1 ~N~N~ ~ I ~N~N~N
N 00 / N 00
~~O ~~O
the tautomers, the diastereomers, the enantiomers, the hydrates thereof, the
mixtures thereof and the salts thereof as well as the hydrates of the salts,
while the
compounds
(1) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-[4-(2-piperidin-
1-yl-
ethyl)-piperidin-1-yl]-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-
3-
yl)-piperidine-1-carboxylate,
(2) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-aza-
bicyclo[2.2.2]oct-
3-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahyd ro-
benzo[d][1,3]diazepin-3-yl)-piperidine-1-carboxylate,
(3) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(5-methyl-2,5-diaza-
bicyclo[2.2.1]hept-2-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-
tetrahydro-
benzo[d](1,3]diazepin-3-yl)-piperidine-1-carboxylate,
(4) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-(5-dimethylamino-
pentylcarbamoyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzo[dJ[1,3]diazepin-3-yl)-
2o piperidine-1-carboxylate,
(5) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-[4-((3R,5S)-
3,4,5-
trimethyl-piperazin-1-yl)-piperidin-1-yl]-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
benzo[d][1,3]diazepin-3-yl)-piperidine-1-carboxylate,
(6) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-[4-(3,3,4,5,5-
pentamethyl-piperazin-1-yl)-piperidin-1-yl]-ethyl 4-(2-oxo-1,2,4, 5-tetrahydro-
benzo[d][1,3]diazepin-3-yl)-piperidine-1-carboxylate,
CA 02562526 2006-10-11
-25-
(7) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-cyclopropyl-
piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
benzo[d][1,3]diazepin-3-yl)-piperidine-1-carboxylate,
(8) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-
4-yl)-
[1,4]diazepan-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
benzo[d][1,3]diazepin-3-yl)-piperidine-1-carboxylate,
(9) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(7-dimethylaminomethyl-
1,2,4,5-tetrahydro-benzo[dJazepin-3-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
tetrahydro-benzo[dj[1,3]diazepin-3-yl)-piperidine-1-carboxylate,
(10) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(cyclopropyl-
methyl-
~5 amino)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-
benzo[d][1,3]diazepin-3-yl)-piperidine-1-carboxylate,
(11) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(hexahydro-
pyrrolo[1,2-
a]pyrazin-2-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
2o benzo[d][1,3]diazepin-3-yl)-piperidine-1-carboxylate,
(12) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-ethyl-piperidin-
4-yl)-
piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzo[dj[1,3]diazepin-
3-
yl)-piperidine-1-carboxylate,
(13) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(8-methyl-8-aza-
bicyclo[3.2.1 ]oct-3-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
tetrahydro-
benzo[c~[1,3]diazepin-3-yl)-piperidine-1-carboxylate,
(14) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-
[1,4]diazepan-
1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
benzo[d][1,3]diazepin-3-yl)-piperidine-1-carboxylate,
CA 02562526 2006-10-11
-26-
(15) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(4-cyclopropylmethyl-
piperazin-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-
3-yl)-piperidine-1-carboxylate,
(16) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(4-azepan-1-yl-
piperidin-1-
yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzo[dj[1,3]diazepin-3-yl)-
piperidine-1-carboxylate,
(17) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(4-morpholin-4-yl-
piperidin-
1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahyd ro-benzo[dj[1,3]d iazepin-3-yl)-
piperidine-1-carboxylate,
(18) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(4-imidazol-1-yl-
piperidin-
1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4, 5-tetrahyd ro-benzo[d][1,3]diazepin-3-yl)-
~5 piperidine-1-carboxylate,
(19) 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidine-1-
carboxylic
acid-{(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-cyclopropyl-
piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide,
(20) (R)-1-(4-chloro-3-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-
piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-
3-
yl)-piperid ine-1-carboxylate,
2s (21 ) (R)-1-(4-chloro-3-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-4-
yl)-
piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzo[dj[1,3]diazepin-
3-
yl)-piperidine-1-carboxylate,
(22) 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidine-1-
carboxylic
3o acid-[(R)-1-(4-amino-3-chloro-5-methyl-benzyl)-2-(4-cyclopropyl-piperazin-
1-yl)-2-oxo-ethyl]-amide,
CA 02562526 2006-10-11
-27-
(23) 4-(2-oxo-1,2,4,5-tetrahydro-benzo[dJ[1,3]diazepin-3-yl)-piperidine-1-
carboxylic
acid-[(R)-1-(4-amino-3-chloro-5-methyl-benzyl)-2-(4-isopropyl-piperazin-1-yl)-
2-oxo-ethyl]-amide,
(24) 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidine-1-
carboxylic
acid-{(R)-1-(4-amino-3-chloro-5-ethynyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-
piperidin-1-yl]-2-oxo-ethyl}-amide,
(25) 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidine-1-
carboxylic
acid-{(R)-1-(4-amino-3-chloro-5-ethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-
piperidin-1-yl]-2-oxo-ethyl}-amide,
(26) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-cyclopropyl-
piperazin-
1-yl)-piperid in-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]d iazepin-3-
yl)-
~5 piperidin-1-yl]-butane-1,4-dione,
(27) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(cyclopropyl-
methyl-
amino)-piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-
yl)-piperidin-1-yl]-butan-1,4-dione,
(28) (S)-2-(3-chloro-4-hydroxy-5-trifluoromethyl-benzyl)-1-(4-morpholin-4-yl-
piperid in-1-yl)-4-[4-(2-oxo-1,2,4,5-tetrahyd ro-benzo[d][1,3]diazepin-3-yl)-
piperidin-1-yl]-butane-1,4-dione,
2s the tautomers, the diastereomers, the enantiomers, the hydrates thereof,
the
mixtures thereof and the salts thereof as well as the hydrates of the salts
are of
exceptional importance.
The compounds of general formula (I) are prepared by methods known in
principle.
3o The following methods have proved particularly useful for preparing the
compounds
of general formula (I) according to the invention:
(a) In order to prepare compounds of general formula
CA 02562526 2006-10-11
-28-
A
O R2
I
N X N~Rs
1
R , (I)
wherein X denotes the oxygen atom or the NH group and A and R1 to R3 are as
hereinbefore defined:
reacting a piperidine of general formula
R1
NH , (III)
wherein R1 is as hereinbefore defined,
(i) with a carbonic acid derivative of general formula
O
G- _G
, (IV)
wherein G denotes a nucleofugic group which may be identical or different,
preferably the phenoxy, 1 H-imidazol-1-yl, 1 H-1,2,4-triazol-1-yl,
trichloromethoxy or 2,5-dioxopyrrolidin-1-yloxy group, with the proviso that X
2o denotes the NH group, or
(ii) with a carbonic acid derivative of general formula
O
G- _G
(IV)
CA 02562526 2006-10-11
-29-
wherein G denotes a nucleofugic group which may be identical or different,
preferably the chlorine atom, the p-nitrophenoxy or trichloromethoxy group,
with the proviso that X denotes the oxygen atom,
and with a compound of general formula
A R2
I
HwX N~Rs
(V)
wherein X denotes the oxygen atom or a -NH- group and A, RZ and R3 are as
hereinbefore defined, with the proviso that R2 and R3 do not contain any other
free,
unprotected, primary or secondary aliphatic amino function.
Any primary or secondary amino function additionally present in the group -
NR2R3 is
in each case provided with a suitable protective group.
~ 5 The reactions which are theoretically two-step reactions are usually
carried out as
one-pot processes, preferably by reacting one of the two components (III) or
(V) with
equimolar quantities of the carbonic acid derivative of general formula (IV)
in a
suitable solvent at lower temperature in the first stage, then adding at least
equimolar
amounts of the other component (III) or (V) and finishing the reaction at
elevated
2o temperature. The reactions with bis-(trichloromethyl)-carbonate are
preferably carried
out in the presence of at least 2 equivalents (based on bis-(trichloromethyl)-
carbonate) of a tertiary base, e.g. triethylamine, N-ethyl-diisopropylamine,
pyridine,
1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane or 1,8-
diazabicyclo[5.4.0]undec-7-ene. Examples of solvents, which should be
anhydrous,
25 include tetrahydrofuran, dioxane, dimethyl formamide, dimethylacetamide, N-
methyl-
2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or acetonitrile; if bis-
(trichloromethyl)-
carbonate is used as the carbonyl component anhydrous chlorohydrocarbons such
as dichloromethane, 1,2-dichloroethane or trichloroethylene are preferred. The
reaction temperatures for the first reaction step are between -30 and
+25°C,
3o preferably -5 and +10°C, for the second reaction step they are
between +15°C and
CA 02562526 2006-10-11
-30-
the boiling temperature of the solvent used, preferably between +20°C
and +70°C (cf.
also: H. A. Staab and W. Rohr, "Synthesen mit heterocyclischen Amiden
(Azoliden)",
Neuere Methoden der Praparativen Organischen Chemie, Vol. V, p. 53 - 93,
Verlag
Chemie, Weinheim/Bergstr., 1967; P. Majer and R.S. Randad, J. Org. Chem. 59,
s 1937 - 1938 (1994); K. Takeda, Y. Akagi, A. Saiki, T. Sukahara and H. Ogura,
Tetrahedron Letters 24 (42), 4569 - 4572 (1983); S.R. Sandier and W. Karo in
"Organic Functional Group Preparations", Vol. II, p. 223-245, Academis Press,
New
York 1971 ).
(b) In order to prepare compounds of general formula
A
O R2
I
N X N~R3
O
R , (I)
wherein X denotes the methylene group and A and R' to R3 are as hereinbefore
~5 defined, with the proviso that no other free unprotected primary or
secondary
aliphatic amino functions are present:
coupling a carboxylic acid of general formula
O A R2
I
HO N~R3
2o O , (VI)
wherein A, RZ and R3 are as hereinbefore defined, with a piperidine of general
formula
R'
2s NH , (III)
CA 02562526 2006-10-11
-31 -
wherein R~ is as hereinbefore defined.
The coupling is preferably carried out using methods known from peptide
chemistry
(cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for
example
using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl
carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide,
O-(1 H-benzotriazol-1-yl)- N,N-N;N'-tetramethyluronium hexafluorophosphate
(HBTU)
or tetrafluoroborate (TBTU) or 1 H-benzotriazol-1-yl-oxy-
tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). By adding
1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-
benzotriazine
(HOObt) the reaction speed can be increased. The couplings are normally
carried out
with equimolar amounts of the coupling components as well as the coupling
reagent
in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl
formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or
mixtures thereof and at temperatures between -30 and +30°C, preferably -
20 and
+25°C. If necessary, N-ethyl-diisopropylamine (Hunig base) is
preferably used as an
additional auxiliary base.
The so-called anhydride process is used as a further coupling method for
synthesising compounds of general formula (I) (cf. also: M. Bodanszky,
"Peptide
Chemistry", Springer-Verlag 1988, p. 58-59; M. Bodanszky, "Principles of
Peptide
Synthesis", Springer-Verlag 1984, p. 21-27). The Vaughan variant of the mixed
anhydride process is preferred (J.R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547
(1951 )), in which the mixed anhydride of the carboxylic acid of general
formula (VI)
which is to be coupled and monoisobutyl carbonate is obtained, using isobutyl
chlorocarbonate in the presence of bases such as 4-methylmorpholine or
4-ethylmorpholine. The preparation of this mixed anhydride and the coupling
with
3o amines are carried out in a one-pot process, using the above-mentioned
solvents
and at temperatures between -20 and +25°C, preferably 0°C and
+25°C.
(c) In order to prepare compounds of general formula
CA 02562526 2006-10-11
-32-
A
O R2
I
N X N~Rs
O
R , (I)
wherein X denotes the methylene group and A and R' to R3 are as hereinbefore
defined, with the proviso that diese groups do not contain any free
unprotected
primary or secondary amine:
coupling a compound of general formula
A
O R2
I
Nu N~R3
O , (VII)
wherein A, R2 and R3 are as hereinbefore defined, with the proviso that R2 and
R3 do
not contain any free unprotected primary or secondary amine, and Nu denotes a
leaving group, for example a halogen atom, such as the chlorine, bromine or
iodine
atom, an alkylsulphonyloxy group with 1 to 10 carbon atoms in the alkyl
moiety, a
phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or
trisubstituted by chlorine or bromine atoms or by methyl or nitro groups,
while the
substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-
yl
optionally substituted by one or two methyl groups in the carbon skeleton, a
1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, a
vinyl, propargyl,
p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl,
pentafluorophenyl, pyranyl or pyridinyl, a dimethylaminyloxy, 2(11-oxopyridin-
1-yl-
oxy, 2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1H-benzo-triazol-1-yloxy or
azide
group,
with a piperidine of general formula
CA 02562526 2006-10-11
-33-
R1
NH , (III)
wherein R1 is as hereinbefore defined.
The reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e.
the
components are reacted in the presence of at least one equivalent of an
auxiliary
base at temperatures between -50°C and +120°C, preferably -
10°C and +30°C, and
optionally in the presence of solvents. The auxiliary bases used are
preferably alkali
metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium
hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate,
potassium carbonate or caesium carbonate, alkali metal acetates, e.g. sodium
or
potassium acetate, as well as tertiary amines, e.g. pyridine, 2,4,6-
trimethylpyridine,
quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine,
~5 1,4-diazabicyclo[2.2.2]octane or 1,8-diazabicyclo[5.4.0]undec-7-ene, the
solvents
used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane,
acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or
mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali
metal
carbonates or acetates are used as the auxiliary bases, water may also be
added to
2o the reaction mixture as cosolvent.
(d) In order to prepare compounds of general formula
A
O R2
I
N X N~Rs
1
R , (I)
wherein A, X and R1 to R3 are as hereinbefore defined:
coupling a carboxylic acid of general formula
CA 02562526 2006-10-11
-34-
A
O
~ OH
N- _X
1
R , (VIII)
wherein A, X and R1 are as hereinbefore defined, with an amine of general
formula
HNR2R3, wherein R2 and R3 are as hereinbefore defined, with the proviso that
they
do not contain any other free unprotected primary or secondary aliphatic amino
function.
The coupling is preferably carried out using methods known from peptide
chemistry
(cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for
example
using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl
carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide,
O-(1 H-benzotriazol-1-yl)- N,N-N;N'-tetramethyluronium hexafluorophosphate
(HBTU)
or tetrafluoroborate (TBTU) or 1 H-benzotriazol-1-yl-oxy-
~5 tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). By adding
1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-
benzotriazine
(HOObt) the reaction speed can be increased. The couplings are normally
carried out
with equimolar amounts of the coupling components as well as the coupling
reagent
in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl
2o formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or
mixtures thereof and at temperatures between -30 and +30°C, preferably -
20 and
+25°C. If necessary, N-ethyl-diisopropylamine (Hianig base) is
preferably used as an
additional auxiliary base.
25 The so-called anhydride process is used as a further coupling method for
synthesising compounds of general formula (I) (cf. also: M. Bodanszky,
"Peptide
Chemistry", Springer-Verlag 1988, p. 58-59; M. Bodanszky, "Principles of
Peptide
Synthesis", Springer-Verlag 1984, p. 21-27). The Vaughan variant of the mixed
anhydride process is preferred (J.R. Vaughan Jr., J. Amer. Chem.Soc. 73, 3547
CA 02562526 2006-10-11
-35-
(1951 )), in which the mixed anhydride is obtained from the carboxylic acid of
general
formula (VIII) which is to be coupled and monoisobutyl carbonate, using
isobutyl
chlorocarbonate in the presence of bases such as 4-methylmorpholine or
4-ethylmorpholine. The preparation of this mixed anhydride and the coupling
with the
amines of general formula HNR2R3 are carried out in a one-pot process, using
the
above-mentioned solvents and at temperatures between -20 and +25°C,
preferably
0°C and +25°C.
(e) In order to prepare compounds of general formula
A
O R2
I
N X N~R3
1
R , (I)
wherein A, X and R1 to R3 are as hereinbefore defined, with the proviso that
no free
unprotected primary or secondary amine is present:
coupling a compound of general formula
A
O
~ Nu
N- _X
1 O
R , (IX)
2o wherein A, X and R1 are as hereinbefore defined and Nu denotes a leaving
group, for
example a halogen atom, such as the chlorine, bromine or iodine atom, an alkyl-
sulphonyloxy group with 1 to 10 carbon atoms in the alkyl moiety, a
phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or
trisubstituted by chlorine or bromine atoms or by methyl or nitro groups,
while the
substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-
yl
optionally substituted by one or two methyl groups in the carbon skeleton, a
CA 02562526 2006-10-11
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1 H-1,2,4-triazol-1-yl, 1 H-1,2,3-triazol-1-yl, 1 H-1,2,3,4-tetrazol-1-yl, a
vinyl, propargyl,
p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl,
pentafluorophenyl, pyranyl or pyridinyl, a dimethylaminyloxy, 2(11-n-
oxopyridin-1-yl-
oxy, 2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1H-benzo-triazol-1-yloxy or
azide
group,
with an amine of general formula HNR2R3, wherein R2 and R3 are as hereinbefore
defined, with the proviso that no other free unprotected primary or secondary
aliphatic amino function is present.
The reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e.
the
components are reacted in the presence of at least one equivalent of an
auxiliary
base at temperatures between -50°C and +120°C, preferably -
10°C and +30°C, and
optionally in the presence of solvents. The auxiliary bases used are
preferably alkali
metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium
hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate,
potassium carbonate or caesium carbonate, alkali metal acetates, e.g. sodium
or
potassium acetate, as well as tertiary amines, e.g. pyridine, 2,4,6-
trimethylpyridine,
quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine,
1,4-diazabicyclo[2.2.2]octane or 1,8-diazabicyclo[5.4.0]undec-7-ene, the
solvents
used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane,
acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or
mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali
metal
carbonates or acetates are used as the auxiliary bases, water may also be
added to
the reaction mixture as cosolvent.
The new compounds of general formula (I) according to the invention contain
one or
more chiral centres. If for example there are two chiral centres the compounds
may
occur in the form of two pairs of diastereomeric antipodes. The invention
covers the
3o individual isomers as well as the mixtures thereof.
The diastereomers may be separated on the basis of their different physico-
chemical
properties, e.g. by fractional crystallisation from suitable solvents, by high
pressure
CA 02562526 2006-10-11
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liquid or column chromatography, using chiral or preferably non-chiral
stationary
phases.
Racemates covered by general formula (I) may be separated for example by HPLC
on suitable chiral stationary phases (e.g. Chiral AGP, Chiralpak AD).
Racemates
which contain a basic function can also be separated via the diastereomeric,
optically
active salts which are produced on reacting with an optically active acid, for
example
(+) or (-)-tartaric acid, (+) or (-)-diacetyl tartaric acid, (+) or (-)-
monomethyl tartrate or
(+)-camphorsulphonic acid.
According to a conventional method of separating isomers, the racemate of a
compound of general formula (I) is reacted with one of the above-mentioned
optically
active acids or bases in equimolar amounts in a solvent and the resulting
crystalline,
diastereomeric, optically active salts thereof are separated using their
different
solubilities. This reaction may be carried out in any type of solvent provided
that it is
sufficiently different in terms of the solubility of the salts. Preferably,
methanol,
ethanol or mixtures thereof, for example in a ratio by volume of 50:50, are
used.
Then each of the optically active salts is dissolved in water, carefully
neutralised with
a base such as sodium carbonate or potassium carbonate, or with a suitable
acid,
2o e.g. dilute hydrochloric acid or aqueous methanesulphonic acid, and in this
way the
corresponding free compound is obtained in the (+) or (-) form.
The (R) or (S) enantiomer alone or a mixture of two optically active
diastereomeric
compounds covered by general formula I may also be obtained by performing the
syntheses described above with a suitable reaction component in the (R) or (S)
configuration.
The starting compounds of general formula (III), if they are not known from
the
literature or commercially available, are obtained using the processes
described in
3o International Patent Application WO 98/11128 and DE 199 52 146. The
starting
compounds of general formula (IV) are commercially available. Compounds of
general formula (V) may be obtained by methods familiar to the peptide chemist
from
protected phenylalanines and amines of general formula HNR2R3.
CA 02562526 2006-10-11
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The phenyalanine derivatives needed to prepare the optically pure compounds of
general formula (V) may be prepared from the compounds of general formula
A
HEN OR
I
H ~ ~(X)
wherein A is as hereinbefore defined and R denotes an unbranched alkyl group,
preferably the methyl or ethyl group, by racemate cleaving.
This racemate cleaving may be carried out using enzymatic methods, while only
one
enantiomer of the racemate is transformed and the resulting mixture is then
separated using physicochemical methods, preferably using chromatographic
methods. A suitable enzyme system for this step is the enzyme alkalase 2.4 L
FG
(Novozymes A/S; DK 2880 Bagsvaerd). The compounds of general formula (X) can
then be converted into the enantiomerically pure compounds of general formula
(V)
using methods familiar to the peptide chemist.
If the group X in compounds of general formula (V) denotes the oxygen atom,
the
hydroxycarboxylic acids of general formula
A
H~O OH
2o O , (XI)
wherein A is as hereinbefore defined which are needed for the synthesis may be
obtained from compounds of general formula (X), with the proviso that R
denotes the
hydrogen atom.
With the proviso that the group A does not contain the amino or methylamino
group,
by diazotising compounds of general formula (X) with a suitable diazotising
reagent,
CA 02562526 2006-10-11
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preferably sodium nitrite in an acid medium, it is possible to obtain the
compounds of
general formula (XI). If enantiomerically pure compounds are used the
corresponding
enantiomerically pure hydroxycarboxylic acid compounds are obtained, the
configuration being retained as the reaction proceeds.
Another method of obtaining compounds of general formula (XI) wherein the
groups
A are as hereinbefore defined comprises alkylating the compound
O O
I O~N O
U
(X11)
with correspondingly substituted benzylchlorides, benzylbromides or
benzyliodides of
general formula
A
X , (X111)
wherein A is as hereinbefore defined and X denotes a chlorine, bromine or
iodine
atom, analogously to methods known from the literature (Michael T. Crimmins,
Kyle
A. Emmitte and Jason D. Katz, Org. Lett. 2, 2165-2167 (2000]).
2o The diastereomeric products formed may then be separated using
physicochemical
methods, preferably chromatographic methods. The hydrolytic cleaving of the
chiral
auxiliary, coupling with amines of general formula HNR2R3 and cleaving of the
benzyl
protective group also provides a way of obtaining enantiomerically pure
hydroxycarboxylic acid compounds of general formula (V).
CA 02562526 2006-10-11
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Compounds of general formula (XI) wherein the groups A are as hereinbefore
defined may also be obtained by boiling down 2-acetylamino-3-phenyl-acrylic
acids
of formula
A
O
~ OH
H C- _ N
H
O ,(XIV)
using strong acids and subsequently reducing the 2-hydroxy-3-phenyl-acrylic
acids
formed.
The starting compounds of general formula (VI) are obtained for example by
reacting
amines of general formula HNR2R3 with 2-(alkoxycarbonylmethyl)-3-aryl-
propanoic
acids and subsequently hydrolytically cleaving the alkyl group. The
2-(alkoxycarbonylmethyl)-3-aryl-propanoic acids needed may be prepared
analogously to methods known from the literature (David A. Evans, Leester D.
Wu,
John J. M. Wiener, Jeffrey S. Johnson, David H. B. Ripin and Jason S. Tedrow,
J.
Org.Chem 64, 6411-6417 [1999]; Saul G. Cohen and Aleksander Milovanovic, J.
Am.
Chem. Soc. 90, 3495-3502 (1968]; Hiroyuki Kawano, Youichi Ishii, Takao
Ikariya,
Masahiko Saburi, Sadao Yoshikawa, Yasuzo Uchida and Hidenori Kumobayashi,
Tetrahedron Letters 28, 1905-1908 [1987]). Carboxylic acids of general formula
(VIII) may be prepared by the methods recited in WO 98/11128 from generally
available starting materials.
The compounds of general formula I obtained may, if they contain suitable
basic
functions, be converted, particularly for pharmaceutical use, into their
physiologically
2s acceptable salts with inorganic or organic acids. Suitable acids include
for example
hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric
acid,
methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid,
p-toluenesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic
acid, mandelic
acid, malic acid, citric acid, tartaric acid or malefic acid.
CA 02562526 2006-10-11
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The present invention relates to racemates if the compounds of general formula
(I)
have only one chiral element. However, the application also includes the
individual
diastereomeric pairs of antipodes or mixtures thereof which are obtained if
there is
more than one chiral element in the compounds of general formula (I), as well
as the
s individual optically active enantiomers of which the above-mentioned
racemates are
made up.
Also included in the subject matter of this invention are the compounds
according to
the invention, including the salts thereof, in which one or more hydrogen
atoms, for
example one, two, three, four or five hydrogen atoms, are replaced by
deuterium.
The new compounds of general formula (I) and the physiologically acceptable
salts
thereof have valuable pharmacological properties, based on their selective
CGRP-
antagonistic properties. The invention further relates to pharmaceutical
compositions
~5 containing these compounds, their use and the preparation thereof.
The new compounds mentioned above and the physiologically acceptable salts
thereof have CGRP-antagonistic properties and exhibit good affinities in CGRP
receptor binding studies. The compounds display CGRP-antagonistic properties
in
2o the pharmacological test systems described hereinafter.
The following experiments were carried out to demonstrate the affinity of the
above-
mentioned compounds for human CGRP-receptors and their antagonistic
properties:
2s A. Binding studies with SK-N-MC cells (expressing the human CGRP receptor)
SK-N-MC cells are cultivated in "Dulbecco's modified Eagle medium". The medium
is
removed from confluent cultures. The cells are washed twice with PBS buffer
(Gibco
041-04190 M), detached by the addition of PBS buffer mixed with 0.02% EDTA,
and
3o isolated by centrifuging. After resuspension in 20 ml of "Balanced Salts
Solution"
[BSS (in mM): NaCI 120, KCI 5.4, NaHC03 16.2, MgS04 0.8, NaHP04 1.0, CaCl2
1.8,
D-glucose 5.5, HEPES 30, pH 7.40] the cells are centrifuged twice at 100 x g
and
resuspended in BSS. After the number of cells has been determined, the cells
are
CA 02562526 2006-10-11
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homogenised using an Ultra-Turrax and centrifuged for 10 minutes at 3000 x g.
The
supernatant is discarded and the pellet is recentrifuged in Tris buffer (10 mM
Tris, 50
mM NaCI, 5 mM MgCl2, 1 mM EDTA, pH 7.40) enriched with 1 % bovine serum
albumin and 0.1 % bacitracin, and resuspended (1 ml / 1000000 cells). The
homogenised product is frozen at -80°C. The membrane preparations are
stable for
more than 6 weeks under these conditions.
After thawing, the homogenised product is diluted 1:10 with assay buffer (50
mM
Tris, 150 mM NaCI, 5 mM MgCl2, 1 mM EDTA, pH 7.40) and homogenised for 30
seconds with an Ultra-Turrax. 230 NI of the homogenised product are incubated
for
180 minutes at ambient temperature with 50 pM X251-iodotyrosyl-Calcitonin-Gene
Related Peptide (Amersham) and increasing concentrations of the test
substances in
a total volume of 250 NI. The incubation is ended by rapid filtration through
GF/B-
glass fibre filters treated with polyethyleneimine (0.1 %) using a cell
harvester. The
~5 protein-bound radioactivity is measured using a gamma counter. Non-specific
binding
is defined as the bound radioactivity in the presence of 1 uM human CGRP-alpha
during incubation.
The concentration binding curves are analysed using computer-aided non-linear
2o curve matching.
The compounds mentioned hereinbefore show ICSO values <_ 10000 nM in the test
described.
2s B. CGRP Antagonism in SK-N-MC cells
SK-N-MC cells (1 million cells) are washed twice with 250 NI incubation buffer
(Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1 % BSA, pH 7.4) and pre-
incubated at 37°C for 15 minutes. After the addition of CGRP (10 NI) as
agonist in
3o increasing concentrations (10-~~ to 10-6 M), or additionally the substance
in 3 to 4
different concentrations, the mixture is incubated for another 15 minutes.
CA 02562526 2006-10-11
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Intracellular cAMP is then extracted by the addition of 20 NI of 1 M HCI and
centrifugation (2000 x g, 4°C, for 15 minutes). The supernatants are
frozen in liquid
nitrogen and stored at -20°C.
The cAMP contents of the samples are determined by radioimmunoassay (Messrs.
Amersham) and the pA2 values of antagonistically acting substances are
determined
graphically.
The compounds of general formula I exhibit CGRP-antagonistic properties in the
in
vitro test model described, in a dosage range between 10-'2 and 10-5 M.
In view of their pharmacological properties the compounds of general formula I
and
the salts thereof with physiologically acceptable acids are thus suitable for
the acute
and prophylactic treatment of headaches, particularly migraine or cluster
headaches.
Moreover, the compounds of general formula I also have a positive effect on
the
following diseases: non-insulin-dependent diabetes mellitus ("NIDDM"), complex
regional pain syndrome (CRPS1 ), cardiovascular diseases, morphine tolerance,
diarrhoea caused by clostridium toxin, skin diseases, particularly thermal and
radiation-induced skin damage including sunburn, inflammatory diseases, e.g.
2o inflammatory diseases of the joints (arthritis), neurogenic inflammation of
the oral
mucosa, inflammatory lung diseases, allergic rhinitis, asthma, diseases
accompanied
by excessive vasodilatation and resultant reduced blood supply to the tissues,
e.g.
shock and sepsis. In addition, the compounds according to the invention have a
general pain-relieving effect.
The symptoms of menopausal hot flushes caused by vasodilatation and increased
blood flow in oestrogen-deficient women and hormone-treated patients with
prostate
carcinoma are favourably affected by the CGRP-antagonists of the present
application in a preventive and acute-therapeutic capacity, this therapeutic
approach
3o being distinguished from hormone replacement by the absence of side
effects.
The dosage required to achieve a corresponding effect is conveniently 0.01 to
3
mg/kg of body weight, preferably 0.01 to 1 mg/kg of body weight, when
administered
CA 02562526 2006-10-11
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intravenously or subcutaneously and 0.01 to 20 mg/kg of body weight,
preferably 0.1
to 10 mg/kg of body weight when administered orally, and 0.01 to 10 mg/kg of
body
weight, preferably 0.1 to 10 mg/kg of body weight when administered nasally or
by
inhalation, 1 to 3 x a day in each case.
If the treatment with CGRP antagonists and/or CGRP release inhibitors is given
as a
supplement to conventional hormone replacement, it is advisable to reduce the
doses specified above, in which case the dosage may be from 1/5 of the lower
limits
mentioned above up to 1/1 of the upper limits specified.
The compounds prepared according to the invention may be administered either
on
their own or optionally in combination with other active substances for the
treatment
of migraine by intravenous, subcutaneous, intramuscular, intrarectal,
intranasal route,
by inhalation, transdermally or orally, while aerosol formulations are
particularly
suitable for inhalation. The combinations may be administered either
simultaneously
or sequentially.
Categories of active substance which may be used in the combination include
e.g.
angiotensin II receptor antagonists, a-agonists and a-antagonists, 5-HT~B,~p
2o agonists, AMPA antagonists, mild analgesics, antidepressants, antiemetics,
anti-
convulsants, antimuscarinics, ~i-blockers, calcium antagonists,
corticosteroids, ergot
alkaloids, histamine-H1 receptor antagonists, neurokinine antagonists,
neuroleptics,
non-steroidal antiinflammatories, NO-synthase inhibitors, prokinetics,
selective
serotonin reuptake inhibitors or other anti-migraine agents, which may be
formulated
together with one or more inert conventional carriers and/or diluents, e.g.
with corn
starch, lactose, glucose, microcrystalline cellulose, magnesium stearate,
polyvinyl
pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol,
water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl
alcohol,
carboxymethylcellulose or fatty substances such as hard fat or suitable
mixtures
3o thereof, into conventional galenic preparations such as plain or coated
tablets,
capsules, powders, suspensions, solutions, metered dose aerosols or
suppositories.
Thus other active substances which may be used for the combinations mentioned
CA 02562526 2006-10-11
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above include for example the non-steroidal antiinflammatories aceclofenac,
acemetacin, acetylsalicylic acid, azathioprine, diclofenac, diflunisal,
fenbufen,
fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, leflunomide,
lornoxicam,
mefenamic acid, naproxen, phenylbutazone, piroxicam, sulphasalazine,
tenoxicam,
zomepirac or the pharmaceutically acceptable salts thereof as well as
meloxicam and
other selective COX2-inhibitors, such as for example rofecoxib and celecoxib.
It is also possible to use candesartan, eprosartan, irbesartan, losartan,
olmesartan,
tasosartan, telmisartan, valsartan, duloxetine, ergotamine, dihydroergotamine,
metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine,
chlorpromazine, vigabatrin, timolol, isometheptene, pizotifen, botox,
gabapentin,
topiramate, riboflavin, montelukast, lisinopril, prochloroperazine,
dexamethasone,
flunarizine, dextropropoxyphene, meperidine, metoprolol, propranolol, nadolol,
atenolol, clonidine, indoramin, carbamazepine, phenytoin, valproate,
amitryptiline,
15 lidocaine or diltiazem and other 5-HT~B,~p-agonists such as, for example,
almotriptan,
avitriptan, donitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan,
sumatriptan and
zolmitriptan and the physiologically acceptable salts thereof.
The dosage of these active substances is expediently 1/5 of the lowest
2o recommended dose to 1/1 of the normally recommended dose, i.e. for example
20 to
100 mg of sumatriptan.
The invention further relates to the use of the compounds according to the
invention
as valuable adjuvants for the production and purification (by affinity
chromatography)
2s of antibodies as well as in RIA and ELISA assays, after suitable
radioactive labelling,
for example by tritiation of suitable precursors, for example by catalytic
hydrogenation with tritium or replacing halogen atoms with tritium, and as a
diagnostic or analytical adjuvant in neurotransmitter research.
CA 02562526 2006-10-11
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Experimental section
As a rule, IR, ~H-NMR and/or mass spectra have been obtained for the compounds
prepared.
Unless otherwise stated, Rf values are obtained using ready-made silica gel
TLC
plates 60 F254 (E. Merck, Darmstadt, Item no. 1.05714) without chamber
saturation.
The Rf values obtained under the name Alox were determined using ready-made
aluminium oxide TLC plates 60 F254 (E. Merck, Darmstadt, Item no. 1.05713)
without chamber saturation
The ratios given for the eluants relate to units by volume of the solvent in
question.
The units by volume specified for NH3 refer to a concentrated solution of NH3
in
water.
Unless otherwise stated, the acid, base and salt solutions used for working up
the
reaction solutions are aqueous systems of the concentrations specified.
~ 5 For chromatographic purification, silica gel made by Millipore (MATREXTM,
35-70 Vim)
is used. For chromatographic purification, Alox (E. Merck, Darmstadt,
standardised
aluminium oxide 90, 63-200 Nm, Item no. 1.01097.9050) is used.
The HPLC data provided are measured using the parameters specified below:
Analytical column: Zorbax column (Agilent Technologies), SB (Stable Bond) C18;
3.5
Nm; 4.6 x 75 mm; column temperature: 30°C; flow: 0.8 mL / min;
injection volume: 5
pL; detection at 254 nm
CA 02562526 2006-10-11
-47-
Method A:
time percent by volume of percent by volume of acetonitrile
(min) water (with 0.1 % formic acid)
(with 0.1 % formic acid)
0 90 10
9 10 90
10 90
11 90 10
In preparative HPLC purifications as a rule the same gradients are used as
were
used to collect the analytical HPLC data.
5 The products are collected under mass control and the fractions containing
the
product are combined and freeze-dried.
If no detailed information is given as to the configuration, it is not clear
whether it is a
pure enantiomer or whether partial or even complete racemisation has occurred.
The following abbreviations are used in the description of the experiments:
abs. absolute
Boc tert.-butoxycarbonyl
CDI N,N'-carbonyldiimidazole
~5 CDT 1,1'-carbonyldi-(1,2,4-triazol)
cyc cyclohexane
DCM dichloromethane
DMAP 4-dimethylaminopyridine
DMF N,N-dimethylformamide
2o EtOAc ethyl acetate
EtOH ethanol
semiconc. semiconcentrated
HCI hydrochloric acid
HOAc acetic acid
25 HOBt 1-hydroxybenzotriazole-hydrate
CA 02562526 2006-10-11
-48-
i. vac. under vacuum (in vacuo)
KOH potassium hydroxide
conc. concentrated
MeOH methanol
NaCI sodium chloride
NaOH sodium hydroxide
NMP N-methylpyrrolidone
org. organic
PE petroleum ether
1o RT ambient temperature
TBME tert.-butyl-methylether
TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate
TFA trifluoroacetic acid
THF tetrahydrofuran
Example 1
(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-[4-(2-piperidin-1-yl-
ethyl)-
piperidin-1-yl]-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-
2o piperidine-1-carboxylate
F F
j NHZ
I CI
N~O~-N
N~ ~~----~~ ~~O
~ N~p
H
(1 a) (~-2-acetylamino-3- 4-amino-3-chloro-5-trifluoromethyl-phen rLl)-ac~rlic
acid
A mixture of 50.0 g (224 mmol) 4-amino-3-chloro-5-trifluoromethyl-
benzaldehyde,
39.3 g (335 mmol) N-acetylglycine, 27.5 g (335 mmol) sodium acetate and 200 ml
acetic anhydride was stirred for 2 hours in an oil bath at an oil bath
temperature of
128°C. After cooling to an oil bath temperature of 90°C 100 ml
of water were added
dropwise and the resulting suspension was added to a mixture of 1000 ml of
water
CA 02562526 2006-10-11
-49-
and 500 ml of toluene. The precipitate formed was suction filtered, washed
with 300
ml of toluene and 500 ml of water and dried overnight at 60°C in the
circulating air
d rye r.
Yield: 51.0 g (71 % of theory)
ESI-MS: (M+H)+ = 323 / 325 (CI)
(1 b) (~-3- 4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-hydroxy-acrylic acid
51.0 g (158 mmol) (~-2-acetylamino-3-(4-amino-3-chloro-5-trifluoromethyl-
phenyl)-
acrylic acid, dissolved in 408 ml NMP, were combined with 612 ml aqueous 4-
molar
hydrochloric acid solution and stirred for 3 hours at a bath temperature of
130°C
stirred. The reaction mixture was cooled and poured onto 2000 ml of water with
stirring. The precipitate formed was suction filtered, washed with 400 ml of
water,
dried overnight at 60°C and recrystallised from 1000 ml boiling
toluene.
Yield: 24.2 g (54% of theory)
~5 MS: (M)+ = 281 / 283 (CI)
(1c) (R)-3-,4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-h d~~ roxy=propionic
acid
33,5 g (104.3 mmol) (-DIP-chloride dissolved in 195 ml THF was added unter
protective nitrogen gas to a mixture of 24.5 g (86.9 mmol) (~-3-(4-amino-3-
chloro-5-
2o trifluoromethyl-phenyl)-2-hydroxy-acrylic acid, 12.1 ml (86.9 mmol)
triethylamine and
98 ml THF cooled to -20°C. The reaction mixture was stirred for 1.5
hours at -20°C,
brought to ambient temperature and evaporated down under reduced pressure. The
residue was combined with 200 ml aqueous 1-molar sodium hydroxide solution and
150 ml TBME and stirred thoroughly. The aqueous phase was separated off,
25 acidified with 2-molar hydrochloric acid solution with stirring and
extracted twice with
250 ml TBME. The combined organic phases were filtered through activated
charcoal
and evaporated down under reduced pressure. The residue was heated to boiling
with 500 ml of water and the hot solution was filtered clear through Celite.
The
precipitate formed at ambient temperature was suction filtered and dried at
65°C in
3o the circulating air dryer.
Yield: 14.3 g (58% of theory)
MS: (M+H)+ = 284 / 286 (CI)
CA 02562526 2006-10-11
-50-
(1d) eth~il (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-hydroxy-
propionate
A mixture of 14.3 g (50.0 mmol) (R)-3-(4-amino-3-chloro-5-trifluoromethyl-
phenyl)-2-
hydroxy-propionic acid and 100 ml of ethanol was combined with 100 ml of an
approx. 12-molar ethanolic hydrochloric acid solution and stirred overnight.
The
reaction mixture was evaporated down under reduced pressure.
Yield: 15.7 g (100% of theory)
MS: (M+H)+ = 312 / 314 (CI)
(1e) (,R)-2-(4-amino-3-chloro-5-trifluoromethyl-pheny)-1-ethoxycarbonyl-eth
1~4-(2-
oxo-1.2,4.5-tetrahydro-benzo[dlf 1,3ldiazepin-3-yl)-pJ~eridine-1-carbox I~r
ate
5.2 g (25.6 mmol) 4-nitrophenyl chloroformate were added under protective
nitrogen
gas to a mixture of 3.1 g (25.6 mmol) DMAP and 70 ml of pyridine and stirred
for 1.5
hours at ambient temperature. Then 8.0 g (25.7 mmol) ethyl (R)-3-(4-amino-3-
chloro-
5-trifluoromethyl-phenyl)-2-hydroxy-propionate, dissolved in 30 ml of
pyridine, were
~5 slowly added dropwise at ambient temperature, the reaction mixture was
stirred for 2
hours at ambient temperature, 6.3 g (25.6 mmol) 3-piperidin-4-yl-1,3,4,5-
tetrahydro-
1,3-benzdiazepin-2-one were added as a solid substance and the mixture was
stirred
overnight at ambient temperature. The reaction mixture was evaporated down
under
reduced pressure and distributed between 200 ml of ethyl acetate and 200 ml
2o aqueous 10% citric acid solution. The organic phase was washed twice with
200 ml
10% citric acid solution and five times with 150 ml 15% aqueous potassium
carbonate solution, dried over sodium sulphate and evaporated down under
reduced
pressure. The residue was purified by column chromatography.
Yield: 5.0 g (33% of theory)
25 MS: (M+H)+ = 583 / 585 (CI)
(1f) (R)-2-(4-amino-3-chloro-5-trifluoromethy~henyl)-1-carboxyethyl4-(2-oxo-
1.2.4.5-tetrahvd ro-benzofdlf 1.3ldiazepin-3-vl)-piperid ine-1-carboxylate
A solution of 804 mg (33.5 mmol) lithium hydroxide dissolved in 80 ml of water
was
3o added dropwise to a mixture of 13.0 g (22.3 mmol) (R)-2-(4-amino-3-chloro-5-
trifluoromethyl-phenyl)-1-ethoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
benzo[d]-
[1,3]diazepin-3-yl)-piperidine-1-carboxylate and 120 ml THF. The mixture was
stirred
for 3 hours at ambient temperature, freed from THF under reduced pressure,
r
CA 02562526 2006-10-11
-51 -
combined with 150 ml of water, and acidified by the addition of aqueous 4-
molar
hydrochloric acid solution. Then the aqueous phase was extracted with 300 ml
of
ethyl acetate, the organic phase was dried and evaporated down under reduced
pressure. The residue was recrystallised from 50 ml isopropanol.
Yield: 5.3 g (43% of theory)
(1g) (R)-1- 4-amino-3-chloro-5-trifluoromethyl-benz~)-2-oxo-2-f4-(2-piperidin-
1-yl-
ethyl)-piperidin-1-yll-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzo(dlf
1,3ldiazepin-3-
yl)-piperidine-1-carbox, 1y ate
A mixture of 100 mg (0.18 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-
phenyl)-1-
carboxyethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzo[dJ[1,3]diazepin-3-yl)-
piperidine-1-
carboxylate, 35.3 mg (0.18 mmol) 4-(2-piperidin-1-yl-ethyl)-piperidine, 64.2
mg (0.20
mmol) TBTU, 0.028 ml (0.20 mmol) triethylamine and 2.0 ml DMF was stirred for
12
hours at ambient temperature. The reaction mixture was purified by column
~5 chromatography.
Yield: 84 mg (64% of theory)
MS: (M+H)+ = 733 / 735 (CI)
retention time HPLC: 6.5 min (method A)
2o The following compounds were prepared analogously from in each case 100 mg
(R)-
2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-
tetra-
hydro-benzo[d][1,3]diazepin-3-yl)-piperidine-1-carboxylate and the
corresponding
amount of amine:
CA 02562526 2006-10-11
-52-
Example R Yield (%) Mass retention time
spectrum HPLC
(method)
1.1 15
732/734
6.0
min
N (M+H]+
(A)
(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(
1-aza-bicyclo[2.2.2]oct-3-
yl)-piperazin-1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-
yl)-piperidine-1-carboxylate
1.2 N~
74 732/734
5.5
min
N [M+H]
(A)
N
(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(5-methyl-2,5-diaza-
bicyclo-
[2.2.1
]hept-2-yl)-piperid
in-1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,
5-tetrahydro-
benzo[d][1,3]diazepin-3-yl)-piperidine-1-carboxylate
1.3 I 92 667/669 5.9 min
N~N~ (M+H]+ (A)
(R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-(5-dimethylamino-
pentylcarba-
moyl)-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-benzo[d](1,3]diazepin-3-yl)-piperidine-1-
carboxylate
1.4 65
748/750
5.5
min
[M+H]+
(A)
'N
r~N
(R)-1-(4-am
i no-3-chlo
ro-5-trifl
uoromethyl-benzyl
)-2-oxo-2-[4-((3R,
5S)-3,4,
5-
trimethyl-piperazin-1-yl)-piperidin-1-yl]-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-
benzo[d][1,3]diazepin-3-yl)-piperidine-1-carboxylate
1.5 61
776/778
6.3
min
[M+H]+
(A)
'N
r~N
(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-[4-(3,3,4,5,5-
pentamethyl-piperazin-1-yl)-piperid
in-1-yl]-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-
CA 02562526 2006-10-11
-53-
Example R Yield (%) Mass retention time
spectrum HPLC
(method)
benzo[dJ[1,3]diazepin-3-yl)-piperidine-1-carboxylate
1.6 ~ 54 746/748 5.3 min
[M+H]+ (A)
N
( R)-1-( 4-a m i no-3-c h to ro-5-trifl uo ro m ethyl-be nzyl )-2-[4-( 4-cyclo
p ro pyl-p i pe razi n-1-
yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-
benzo[d][1,3]diazepin-3-
yl)-piperidine-1-carboxylate
1.7 N~ 82 734/736 5.3 min
N [M+H]+ (A)
N
(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl )-2-[4-( 1-methyl-pi perid in-
4-yl)-
[1,4]d iazepan-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4, 5-tetrahyd ro-benzo[dj[1,3]d
iazepin-
3-yl)-piperidine-1-carboxylate
1.8 ~ 61 741/743 6.7 min
N
~N~ [M+H]+ (A)
(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(7-dimethylaminomethyl-
1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-
tetrahydro-
benzo[dJ[1,3]diazepin-3-yl)-piperidine-1-carboxylate
1.9 45 691/693 6.3 min
N~ [M+H]+ (A)
N
(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(cyclopropyl-methyl-
amino)-
piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-
3-yl)-
piperidine-1-carboxylate
1.10 ~~ 62 746/748 5.9 min
N [M+Fi]+ (A)
N
CA 02562526 2006-10-11
-54-
Example R Yield (%) Mass retention time
spectrum HPLC
(method)
(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(hexahydro-pyrrolo[1,2-
a]-
pyrazin-2-yl)-piperidin-1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-
benzo[d][1,3]diazepin-3-yl)-piperidine-1-carboxylate
1.11
N~ 37
734/736
5.3
min
N [M+H]
(A)
J
(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(
1-ethyl-piperidin-4-yl)-
piperazin-1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]d
iazepin-3-yl)-
piperidine-1-carboxylate
1.12
N~ 22
746/748
5.4
min
~'N [M+H]
NJ
(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(8-methyl-8-aza-
bicyclo[3.2.1
]oct-3-yl)-piperazin-1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-
benzo[d][1,3]diazepin-3-yl)-piperidine-1-carboxylate
16 734/736
5.4
min
1.13
~
-
N~ [
N
(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-[1,4]diazepan-
1-
yl)-piperid
in-1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,
5-tetrahydro-benzo[d][1,3]diazepin-3-
yl)-piperidine-1-carboxylate
1.14
~N~
88 677/679
5.4
min
NJ [M+H]
(A)
(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(4-cyclopropylmethyl-
piperazin-1-yl)-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-
piperidine-1-carboxylate
1.15 53 719/721 6.5 min
N~ [
N
r
CA 02562526 2006-10-11
-55-
Example R Yield (%) Mass retention time
spectrum HPLC
(method)
(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(4-azepan-1-yl-piperidin-1-
yl)-
2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidine-
1-
carboxylate
1.16 ~0 68 707/709 6.0 min
NJ [M+H]+ (A)
N
(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(4-morpholin-4-yl-
piperidin-1-
yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-
piperidine-
1-carboxylate
1.17 rN 33 688/690 6.2 min
NJ
N Inn+f-I]+ (A)
(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(4-imidazol-1-yl-piperid
in-1-yl)-
2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahyd ro-benzo[d][1,3]d iazepin-3-yl)-
piperidine-1-
carboxylate
Example 2
4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidine-1-
carboxylic acid-
{(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-cyclopropyl-
piperazin-1-yl)-
piperidin-1-yl]-2-oxo-ethyl}-am ide
(2a) ethy~R)-2-amino-3-(4-amino-3-chloro-5-trifluorometh I-~_phen~)-propionate
A solution of 3.5 g (10.97 mmol) (R)-2-amino-3-(4-amino-3-chloro-5-
trifluoromethyl-
CA 02562526 2006-10-11
-56-
phenyl)-propionic acid in 100 mL EtOH and 70 mL ethanolic hydrochloric acid
solution (11.5 M) was stirred overnight at RT. The mixture was evaporated down
i.
vac., the residue was taken up in 150 mL water, combined with 30 mL 15% K2C03
solution, extracted with 150 mL EtOAc, the organic phase was separated off and
dried over Na2S04. After the desiccant and solvent had been eliminated the
desired
product was obtained.
Yield: 3.5 g (92% of theory)
ESI-MS: (M+H)+ = 311/313 (CI)
(2b) ethy~R)-3- 4-amino-3-chloro-5-trifluoromethyl-phen~ -L{f4-(2-oxo-1.2.4.5-
tetrahvdro-1.3-benzdiazepin-3-vl)-piper7dine-1-carbonvll-amino)-propionate
1.8 g (11.0 mmol) CDT were added to a solution of 3.2 g (10.2 mmol) ethyl (R)-
2-
amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionate and 1.8 mL
(10.3
mmol) ethyldiisopropylamine in 150 mL THF cooled to 0°C and the
reaction mixture
was stirred for 45 min at this temperature and after removal of the ice bath
stirred for
a further 30 min. Then 2.5 g (10.2 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-
1,3-
benzdiazepin-2-one, suspended in 50 mL THF was added. 40 mL DMF were added
to the reaction solution and this was stirred for 2 h at 80°C. The
mixture was
evaporated down i. vac., combined with 200 mL EtOAc and 200 mL 10% citric acid
2o solution, the organic phase was separated off, extracted with 150 mL NaHC03
solution and dried over Na2S04. After the desiccant and solvent had been
eliminated
the desired product was obtained.
Yield: 5.9 g (100% of theory)
ESI-MS: (M+H)+ = 582/584 (CI)
Rf : 0.4 (silica gel, EtOAc)
(2c) (R)-3- 4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-(f4-(2-oxo-1.2.4,5-
tetrahvdro-1.3-benzdiazepin-3-vl)-piperidine-1-carbonvll-amino)-propionic acid
A solution of 0.64 g (15 mmol) lithium hydroxide hydrate in 100 mL water was
added
3o to a suspension of 6.0 g (10.31 mmol) ethyl (R)-3-(4-amino-3-chloro-5-
trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)-
piperidine-1-carbonyl]-amino}-propionate in 50 mL THF. In each case 100 mL
water
and THF were again added to this suspension, and a solution formed after 5
min.
CA 02562526 2006-10-11
-57-
This was stirred for 1 hour at RT, the THF was eliminated i.vac., the
remainder was
diluted with 100 mL water and 1 M aqueous hydrochloric acid solution was added
dropwise while cooling with ice until an acid reaction was obtained. The
precipitated
substance was filtered, washed with water and dried in the air.
Yield: 5.5 g (96% of theory)
ESI-MS: (M+H)+ = 554/556 (CI)
(2d) 4-(2-oxo-1,2,4,5-tetrahydro-benzofdlf 1,3ldiazepin-3-yl~piperidine-1-
carboxylic
acid- jR)-1- 4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-f4-(4-cycloprop~
~perazin-1-Lrl)-piperidin-1-yll-2-oxo-eth~ -amide
321 mg (1.0 mmol) TBTU, 0.28 mL (2.0 mmol) triethylamine and 200 mg (0.9 mmol)
1-cyclopropyl-4-piperidin-4-yl-piperazine were added to a solution of 500 mg
(0.90
mmol) (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino)-propionic
acid in
~5 100 mL THF and the reaction mixture was stirred overnight at RT. The
reaction
solution was evaporated down under reduced pressure, the residue was
distributed
between 150 ml of ethyl acetate and 150 ml of 15% aqueous potassium carbonate
solution, the organic phase was separated off, dried over sodium sulphate and
evaporated down under reduced pressure. The residue was then purified by
column
2o chromatography (silica gel, gradient from methylene
chloride/methanol/ammonia
from 100/0/0 to 0/90/10 within 60 minutes). The corresponding fractions were
evaporated down under reduced pressure, the residue was triturated with 50 ml
diisopropylether, suction filtered and dried.
Yield: 440 mg (65% of theory)
25 ESI-MS: (M+H)+ = 746/748 (CI)
Rf: 0.55 (methylene chloride/methanol/ammonia = 90/10/1 )
Example 3
30 (R)-1-(4-chloro-3-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-
piperidin-1-yl]-
2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidine-
1-
carboxylate
CA 02562526 2006-10-11
_58_
F F
F CI
I
N~O~-N~-t~N-
N~ O
NRO
H
(3a) (E7-2-acetylamino-3- 4-chloro-3-trifluoromethyl-phenyl~-acrylic acid
Prepared analogously to Example 1 a.
Yield: 75% of theory
ESI-MS: (M+H)+ = 308 / 310 (CI)
(3b) (E7-3-(4-chloro-3-trifluorometh I-~~)-2-hydroxy-acrylic acid
Prepared analogously to Example 1 b.
Yield: 55% of theory
MS: (M-H)- = 265 / 267 (CI)
(3c) (R)-3- 4-chloro-3-trifluoromethyl-phenyl)-2-hydroxy propionic acid
Prepared analogously to Example 1 c.
~ 5 Yield: 64% of theory
ESI-MS: (M-H)- = 267 /269 (CI)
(3d) meth I (Y R)-3-(4-chloro-3-trifluoromethylphe~l~l-2-hydroxy-propionate
Prepared analogously to Example 1 d.
2o Yield: 78% of theory
ESI-MS: (M)+ = 282 /284 (CI)
(3e) ~R~4-chloro-3-trifluoromethyl-phenyl)-1-methoxycarbon~l-ethyl4-(2-oxo-
1.2.4 5-tetrahydro-benzofd]~f 1,3ldiazepin-3 yl'~ piperidine-1-carboxylate
25 Prepared analogously to Example 1 e.
Yield: 22% of theory
ESI-MS: (M+H)+ = 554 /556 (CI)
CA 02562526 2006-10-11
_59_
(3f) (R)2-(4-chloro-3-trifluoromethyl-phenyl)-1-carboxyeth I 4- 2-oxo-1,2,4,5-
tetrahydro-benzofdlf 1,3ldiazepin-3-yl'~ piperidine-1-carboxylate
Prepared analogously to Example 1f.
Yield: 77% of theory
ESI-MS: (M+H)+ = 540 /542 (CI)
(3g) (R)-1- 4-chloro-3-trifluoromethyl-benzyl)-2-f4-(4-methyl-piperazin-1-yl)-
piperidin-1-yll-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzofdlf1,3ldiazepin-
3-
~rl~piperidine-1-carboxylate
Prepared an analogously to Example 1g.
Yield: 40% of theory
ESI-MS: (M+H)+ = 705 /707 (CI)
Rf: 0.4 (methylene chloride/cyclohexane/methanol/ammonia = 70/15/15/2)
~ 5 Example 3.1
(R)-1-(4-chloro-3-trifluoromethyl-benzyl)-2-[4-( 1-methyl-piperidin-4-yl)-
piperazin-1-yl]-
2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidine-
1-
carboxylate
F F
F CI
N~O~-N -CN-
N~ O
N~O
H
Prepared analogously to Example 3g.
Yield: 26% of theory
ESI-MS: (M+H)+ = 705 /707 (CI)
Rf: 0.4 (methylene chloride/cyclohexane/methanol/ammonia = 70/15/15/2)
CA 02562526 2006-10-11
-60-
Example 4
4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidine-1-
carboxylic acid-
[(R)-1-(4-amino-3-chloro-5-methyl-benzyl)-2-(4-cyclopropyl-piperazin-1-yl)-2-
oxo-
ethyl]-amide
/ NHZ
_I CI
N~H~ ~J
N~ O
N~O
H
(4a) methyl (E1-2-acetylamino-3- 4-amino-3-chloro-5-methyl-phenyl)-acrylate
Under protective nitrogen gas 2.02 g (9.0 mmol) palladium(II)acetate and 2.82
g (9.0
mmol) tri-o-tolylphosphine were added to a mixture of 25.0 g (113 mmol) 4-
bromo-2-
chloro-6-methyl-aniline, 19.9 g (136 mmol) methyl 2-acetamidoacrylate, 350 ml
triethylamine and 150 ml acetonitrile at ambient temperature. The reaction
mixture
was stirred for 18 hours at 80°C, evaporated down under reduced
pressure, the
~5 residue was combined with 600 ml dichloromethane and water and filtered off
from
the insoluble precipitate. The organic phase was dried over sodium sulphate,
evaporated down under reduced pressure and then combined with 200 ml of ethyl
acetate/cyclohexane (3/1 ). The insoluble fraction was suction filtered and
the mother
liquor was purified by column chromatography through silica gel. The
corresponding
2o fractions were evaporated down under reduced pressure and combined with the
insolublen fraction suction filtered previously.
Yield: 20.7 g (64% of theory)
MS: (M-H)- = 281 /283 (CI)
25 (4b) meth~rl2-acetylamino-3-(4-amino-3-chloro-5-methyl-phenyl~propionate
20.6 g (73.0 mmol) methyl (~-2-acetylamino-3-(4-amino-3-chloro-5-methyl-
phenyl)-
acrylate, 0.445 g (0.90 mmol) bis(1,5-cyclooctadiene)-di-rhodium(I)-
dichloride, 0.744
g (1.8 mmol) 1,3-bis(diphenylphosphino)-propane were dissolved in 400 ml
degassed
methanol and 12 ml degassed triethylamine and then hydrogenated at ambient
CA 02562526 2006-10-11
-61 -
temperature under 3 bar hydrogen pressure. The reaction mixture was evaporated
down under reduced pressure and taken up in ethyl acetate. The insoluble
precipitate
was removed by suction filtering and the filtrate was evaporated down under
reduced
pressure. The residue was purified by column chromatography.
Yield: 21.1 g (quantitative)
MS: (M+H)+ = 285 /287 (CI)
(4c) methy~R)-2-acetylamino-3-(4-amino-3-chloro-5-methyl-phenyl)-propionate
22 mL Alcalase 2.4 L FG (Novozymes A/S; DK 2880 Bagsvaerd) were added to a
solution of 27.3 g (178 mmol) disodium hydrogen phosphate dehydrate in 1000 mL
water at 37°C and the pH was adjusted to 7.5 by the addition of sodium
dihydrogen
phosphate dehydrate. Then 21.1 g (74 mmol) methyl 2-acetylamino-3-(4-amino-3-
chloro-5-methyl-phenyl)-propionate dissolved in 210 mL acetone was added
dropwise with stirring at 37°C. The pH of the reaction mixture was kept
constantly in
the range from pH 7.4 to pH 7.6 by the addition of 1 M NaOH. After the
addition had
ended the mixture was stirred for 3 h at 37 °C. The reaction mixture
was combined
with 500 ml 15% potassium carbonate solution and extracted twice with 250 ml
dichloromethane. The combined organic extracts were dried over sodium
sulphate,
evaporated down under reduced pressure and purified by column chromatography
over silica gel.
Yield: 2.57 g (12% of theory)
ESI-MS: (M+H)+ = 285 / 287 (CI)
(4d) eth~yR)-2-amino-3-(4-amino-3-chloro-5-methyl-phenyl)-propionate
A mixture of 2.6 g (9.0 mmol) methyl (R)-2-acetylamino-3-(4-amino-3-chloro-5
methyl-phenyl)-propionate and 15 ml 4-molar hydrochloric acid solution was
refluxed
for 6 hours gekocht, the reaction mixture was evaporated down under reduced
pressure and stirred for 3 days at ambient temperature with 15 ml of 12 molar
ethanolic hydrochloric acid solution. The reaction mixture was evaporated to
dryness,
3o the residue was taken up with 50 ml of water and extracted with 50 ml of
ethyl
acetate. The aqueous phase was made alkaline by the addition of potassium
carbonate and repeatedly extracted with ethyl acetate. The combined ethyl
acetate
CA 02562526 2006-10-11
-62-
extracts were dried over sodium sulphate and evaporated down under reduced
pressure.
Yield: 2.09 g (90% of theory)
ESI-MS: (M+H)+ = 257 / 259 (CI)
(4e) ethy~R)-3-(4-amino-3-chloro-5-methyl-phenyl)-2-~f4-(2-oxo-1,2.4.5-tetrah
benzofdlf 1.3ldiazepin-3-~)-piperidine-1-carbons]-amino-propionate
An ice-cooled mixture of 2.09 g (8.1 mmol) ethyl (R)-2-amino-3-(4-amino-3-
chloro-5-
methyl-phenyl)-propionate and 100 ml DMF was combined with 1.6 g (9.7 mmol)
1o CDT and stirred for 30 minutes while cooling with ice. Then while cooling
with ice 2.0
g (8.1 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one,
dissolved in 80 ml DMF, was added dropwise and the mixture was stirred for 12
hours at ambient temperature. The reaction mixture was poured onto 300 ml ice
water, the precipitate was suction filtered and dried in the circulating air
dryer at
30°C.
Yield: 4.1 g (95% of theory)
ESI-MS: (M+H)+ = 528 / 530 (CI)
(4f) {R)-3- 4-amino-3-chloro-5-methyl-phenyl)-2-~f4-(2-oxo-1,2,4,5-tetrahydro-
2o benzofd]f1 3ldiazepin-3-yl)-piperidine-1-carbonyll-amino-propionic acid
The mixture of 4.1 g (7.8 mmol) ethyl (R)-3-(4-amino-3-chloro-5-methyl-phenyl)-
2-{[4-
(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidine-1-carbonyl]-
amino}-
propionate, 60 ml of methanol and 60 ml THF was combined with a solution of
1.5 g
(36.8 mmol) lithium hydroxide in 30 ml of water and stirred for 20 hours at
40°C. The
reaction mixture was evaporated down under reduced pressure, the residue was
taken up in 50 ml of water and acidified by the addition of 2-molar
hydrochloric acid
solution. The resulting precipitate was suction filtered and dried at
35°C in the
circulating air dryer.
Yield: 3.6 g (94% of theory)
3o ESI-MS: (M+H)+ = 500 / 502 (CI)
CA 02562526 2006-10-11
-63-
(4g) 4-(2-oxo-1,2,4,5-tetrahydro-benzo[dl[1.3ldiazepin-3-yl)-piperidine-1-
carboxylic
acid-f(R)-1-(4-amino-3-chloro-5-methyl-benzyl)-2-(4-cyclo~ropyl-p~erazin-
1-yl )-2-oxo-ethyll-amide
0.1 ml diisopropylethylamine, 64.2 mg (0.20 mmol) TBTU and 27.0 mg (0.20 mmol)
HOBt was added to a mixture of 100 mg (0.20 mm01) (R)-3-(4-amino-3-chloro-5-
methyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-benzo[dj[1,3]diazepin-3-yl)-
piperidine-
1-carbonyl]-amino}-propionic acid, 10 ml THF and 1 ml DMF, the mixture was
stirred
for 15 hours at ambient temperature and then combined with 80 mg (0.60 mmol) 1-
cyclopropyl-piperazine. The reaction mixture was stirred for 3 hours at
ambient
temperature, combined with 20 ml semisaturated sodium hydrogen carbonate
solution and extracted twice with 20 ml of ethyl acetate. The combined organic
phases were washed once with 20 ml saturated saline solution, dried over
sodium
sulphate and evaporated down under reduced pressure. The residue was purified
by
column chromatography through silica gel.
~ 5 Yield: 89.5 mg (74% of theory)
ESI-MS: (M+H)+ = 608 / 610 (CI)
Example 4.1
20 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidine-1-
carboxylic acid-
[(R)-1-(4-amino-3-chloro-5-methyl-benzyl)-2-(4-isopropyl-piperazin-1-yl)-2-oxo-
ethyl]-
amide
NH2
_I CI
N~H~ U
N~ O
N~p
H
Prepared analogously to Example 4g.
Yield: 65% of theory)
ESI-MS: (M+H)+ = 610 / 612 (CI)
' CA 02562526 2006-10-11
' ~ -64-
Example 5
4-(2-oxo-1,2,4,5-tetrahydro-benzo[dJ[1,3]diazepin-3-yl)-piperidine-1-
carboxylic acid-
{(R)-1-(4-amino-3-chloro-5-ethynyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-
piperidin-1-
s yl]-2-oxo-ethyl}-amide
()
NHZ
I CI
~ ~ n
N~H~-N~I~N-
N~ v v0
N~O
H
(5a) meth rLl (E~-2-acetylamino-3-(4-amino-3-chloro-phenyl)-acr IYate
Prepared analogously to Example 4a.
Yield: 56% of theory
MS: (M+H)+ = 2691271 (CI)
(5b) methyl 2-acetylamino-3-(4-amino-3-chloro-phenyll propionate
~5 Prepared analogously to Example 4b.
Yield: 100% of theory
(5c) methyl jR)-2-acetylamino-3-(4-amino-3-chloro-phenyl)-propionate
Prepared analogously to Example 4c.
2o Yield: 39% of theory
MS: (M+H)+ = 271 /273 (CI)
(5d) ethyl (R)-2-amino-3-(4-amino-3-chloro-phenyl)-propionate
Prepared analogously to Example 4d.
25 Yield: 80% of theory
MS: (M+H)+ = 243 /245 (CI)
(5e) ethi~R)-2-amino-3-(4-amino-3-chloro-5-iodo-phenyl)-propionate
CA 02562526 2006-10-11
-65-
A solution of 1.85 g (7.6 mmol) (R)-2-amino-3-(4-amino-3-chloro-phenyl)-
propionate
ethyl was added dropwise to a mixture of 1.95 g (7.7 mmol) iodine, 2.4 g (7.7
mmol)
silver sulphate and 70 ml of ethanol. The reaction mixture was stirred for 4
days at
ambient temperature, again combined with a solution of 195 mg (0.77 mmol)
iodine
and 240 mg (0.77 mmol) silver sulphate in 10 ml of ethanol and stirred for a
further 3
days. The reaction mixture was filtered, the filtrate was evaporated down
under
reduced pressure, combined with 100 ml 15% potassium carbonate solution and
extracted twice with 100 ml of ethyl acetate. The combined organic phases were
dried over sodium sulphate, evaporated down and purified by chromatography
over
silica gel .
Yield: 1.5 g (54% of theory)
MS: (M+H)+ = 369 /371 (CI)
(5f) ethy~R)-2-amino-3-(4-amino-3-chloro-5-trimethylsilanylethynyl-phenyl)-
propionate
Under protective argon gas a mixture of 235 mg (0.64 mmol) ethyl (R)-2-amino-3-
(4-
amino-3-chloro-5-iodo-phenyl)-propionate, 45.9 mg (0.064 mmol) bis-
(triphenylphosphine~palladium(II)-dichloride, 6.0 mg (0.032 mmol) copper(I)-
iodide
and 15 ml triethylamine was combined with 0.19 ml (1.32 mmol)
2o trimethylsilylacetylene and stirred for 3 hours at ambient temperature. The
reaction
mixture was combined with 30 ml of water and extracted with 40 ml of ethyl
acetate.
The organic phase was dried over sodium sulphate, evaporated down under
reduced
pressure and the residue was purified by column chromatography through silica
gel.
Yield: 168 mg (78% of theory)
MS: (M+H)+ = 339 /341 (CI)
(5g) ethyl (R)-3- 4-amino-3-chloro-5-trimethylsilanyleth~yl-phenylL{~'~2-oxo-
1 2 4 5-tetrahydro-benzo[d1f1,31diazepin-3-yl)-piperidine-1-carbon-amino)-
propionate
3o Prepared analogously to Example 4e.
Yield: 89% of theory
ESI-MS: (M+H)+ = 610 / 612 (CI)
CA 02562526 2006-10-11
-66-
(5h) f R)3-(4-amino-3-chloro-5-ethynyl-phenyl-2-{f4-(2-oxo-1,2,4,5-tetrahydro-
benzof dIf 1,31d iazepin-3- rLl)-piperidine-1-carbonyll-amino}-propionic acid
Prepared analogously to Example 4f.
Yield: 91 % of theory
ESI-MS: (M+H)+ = 510 / 512 (CI)
(5i) ~2-oxo-1,2,4,5-tetrahydro-benzofdlf1,31diazepin-3-yl)-piperidine-1-
carboxylic
acid-,;~R~1-(4-amino-3-chloro-5-ether I-~yl)-2-f4-(4-methyl-piperazin-1-yl)-
piperidin-1-yll-2-oxo-ethyl)-amide
Prepared analogously to Example 4g.
Yield: 75% of theory
ESI-MS: (M+H)+ = 675 / 677 (CI)
retention time (HPLC): 5.4 min (method A)
Example 6
4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidine-1-
carboxylic acid-
{(R)-1-(4-amino-3-chloro-5-ethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-
piperid in-1-yl]-
2-oxo-ethyl}-amide
/ NHZ
CI
N~H~-N~-t~N-
N~ O
NRO
H
54 mg (73.0 mmol) 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-
piperidine-
1-carboxylic acid-{(R)-1-(4-amino-3-chloro-5-ethynyl-benzyl)-2-[4-(4-methyl-
piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl)-amide, 10 mg (0.02 mmol) of
bis(1,5-
cyclooctadiene)-di-rhodium(I)-dichloride, 16.5 mg (0.04 mmol) 1,3-
bis(diphenylphosphino)-propane were dissolved in 10 ml degassed methanol and
0.1
ml degassed triethylamine and then hydrogenated for 2 hours at ambient
temperature and 3 bar hydrogen pressure. The reaction mixture was evaporated
CA 02562526 2006-10-11
-67-
down under reduced pressure and taken up in ethyl acetate. The insoluble
precipitate
was removed by suction filtering and the filtrate was evaporated down under
reduced
pressure. The residue was purified by column chromatography.
Yield: 23.3 mg (43% of theory)
MS: (M+H)+ = 679 /681 (CI)
retention time (HPLC): 5.4 min (method A)
Exam~~le 7
(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-cyclopropyl-
piperazin-1-yl)-
piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-
piperidin-1-
yl]-butane-1,4-dione
F F
F
/ NHZ
I CI _
N~N~ V
N~ ~---~O
~ N~O
H
(7a) 1-benzyl-4-cyclopropyl-piperazine
A mixture of 1.946 ml (10.5 mmol) benzylpiperidone, 3.0 g (10.4 mmol) 1-
cyclopropyl-piperazine and 300 ml DCM, stirred and cooled in the ice bath, was
2o combined batchwise with 5.58 g (25.0 mmol) sodiumacetoxyborohydride and
stirred
overnight at RT. The reaction mixture was then combined with 60 ml 1-molar
sodium
hydroxide solution, the organic phase was separated off and evaporated down
under
reduced pressure. The residue was purified by column chromatography through
Alox
(eluant: petroleum ether / ethyl acetate = 4 / 1 ).
Yield: 1.50 g (48% of theory)
MS: (M)+ = 300
Rf: 0.75 (PE / EtOAc = 1 /1 )
(7b) 1-cyclopropyl-4-piperidin-4-yl-piperazine
CA 02562526 2006-10-11
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1.5 g (5.0 mmol) 1-benzyl-4-cyclopropyl-piperazine in 50 ml of methanol was
hydrogenated for 7 hours at RT under 5 bars pressure with the addition of 250
mg
palladium on charcoal (10%). The catalyst was filtered off, the mother liquor
was
evaporated down under reduced pressure.
Yield: 1.05g (100% of theory)
MS: (M)+ = 210
(7c) ~S)-2- 4-amino-3-chloro-5-trifluoromethyl-Benz r~l -1-f4- 4-cyclopropyl-
piperazin-
1-yl)-piperidin-1-yll-4-f 4-(2-oxo-1,2,4,5-tetrahydro-benzojdl[1,3ldiazepin-3-
yl)-
piperidin-1-yll-butane-1,4-dione
A mixture of 499 mg (0.90 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-
benzyl)-4-
oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidin-1-yl]-
butanoic
acid, 199 mg (0.95 mmol) 1-cyclopropyl-4-piperidin-4-yl-piperazine, 321 mg
(1.00
mmol) TBTU, 0.277 ml triethylamine and 100 ml THF was stirred overnight at
~5 ambient temperature. The reaction mixture was evaporated down under reduced
pressure and the residue was distributed between 150 ml of ethyl acetate and
150 ml
15% potassium carbonate solution. The organic phase was separated off, dried
and
evaporated down under reduced pressure. The residue was purified by column
chromatography through silica gel.
2o Yield: 360.0 mg (54% of theory)
MS: (M+H)+ = 744 / 746 (CI)
Rf: 0.55 (DCM/MeOH/aqu. ammonia = 90/10/1 )
Example 8
(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(cyclopropyl-methyl-
amino)-
piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-
piperidin-1-
yl]-butan-1,4-dione
CA 02562526 2006-10-11
-69-
F F
F
NHZ
CI
N~-N
N~ v 'O
N~p
H
A mixture of 500 mg (0.90 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-
benzyl)-4-
oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidin-1-yl]-
butanoic
acid, 207 mg (0.91 mmol) cyclopropyl-methyl-piperidin-4-yl-amine
dihydrochloride,
385 mg (1.20 mmol) TBTU, 0,695 ml triethylamine, 50 ml DMF and 50 ml THF was
stirred overnight at ambient temperature. The reaction mixture was freed from
THF
under reduced pressure and stirred into 200 ml of 15% potassium carbonate
solution.
The resulting solid precipitate was suction filtered, dried and then purified
by column
1o chromatography through silica gel.
Yield: 450.0 mg (72% of theory)
MS: (M+H)+ = 689 / 691 (CI)
Rf: 0.55 (DCM/MeOH/aqu. ammonia = 85/15/1.5)
Example 9
(S)-2-(3-chloro-4-hydroxy-5-trifluoromethyl-benzyl)-1-(4-morpholin-4-yl-
piperidin-1-yl)-
4-[4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidin-1-yl]-
butane-1,4-
dione
n
-Iy .0
(9a) 4-hydroxy-3-trifluoromethyl-benzoic acid
CA 02562526 2006-10-11
-70-
A mixture of 10.0 g (45.4 mmol) 4-methoxy-3-trifluoromethyl-benzoic acid and
75 g
(649 mmol) pyridine hydrochloride was stirred for 5 hours at 180°C
under nitrogen
gas. The reaction mixture was then poured onto 1 L of 10% citric acid
solution,
extracted with 500 ml EtOAc, the organic phase was washed with 1 L water,
dried
s and evaporated down under reduced pressure.
Yield: 11.7 g crude product
ESI-MS: (M+H)- = 205
retention time HPLC: 6.1 min (method A)
(9b) 3-chloro-4-hydroxy-5-trifluoromethyl-benzoic acid
A mixture of 11.7 g (57 mmol) 4-hydroxy-3-trifluoromethyl-benzoic acid and 40
ml
acetic acid was combined dropwise with 5.15 ml (63 mmol) sulphurylchloride,
with
stirring at a bath temperature of 40°C, and stirred for 2 hours at
40°C. Then another
2.5 ml (31 mmol) sulphurylchloride were added and the mixture was stirred for
4
15 hours at 60°C. The reaction mixture was poured onto 300 ml of water
and extracted
with 200 ml EtOAc. The organic phase was washed twice with 500 ml of water,
dried
and evaporated down under reduced pressure. The residue was stirred with 80 ml
petroleum ether, the precipitate was suction filtered, washed with 20 ml
petroleum
ether and dried.
2o Yield: 7.7 g (56% of theory)
ESI-MS: (M+H)+ = 239 / 241 (CI)
retention time HPLC: 6.5 min (method A)
(9c) 2-chloro-4-hydroxymethyl-6-trifluorometh~phenol
2s 7.7 g ( 32 mmol) 3-chloro-4-hydroxy-5-trifluoromethyl-benzoic acid
dissolved in 100
ml THF were combined with 5.76 g (36 mmol) carbonyldiimidazole and stirred for
1
hour at 40°C. Then the mixture was cooled to ambient temperature and
slowly added
under a nitrogen atmosphere to a stirred solution of 3.78 g (100 mmol) sodium
borohydride in 40 ml of water and stirred for a further 2 hours at ambient
3o temperature. The reaction mixture was diluted with 200 ml of water,
acidified with 50
ml semiconcentrated hydrochloric acid and extracted twice with EtOAc. The
combined organic phases were dried over sodium sulphate, filtered and
evaporated
down under reduced pressure.
CA 02562526 2006-10-11
-71 -
Yield: 5.9 g (81 % of theory)
ESI-MS: (M+H)+ = 225 / 227 (CI)
Rf: 0.85 (EtOAc)
(9d) 3-chloro-4-hydroxy-5-trifluoromethyl- benzaldehyde
30.0 g (345 mmol) manganese dioxide was added batchwise, with stirring, to a
mixture of 5.90 g (26 mmol) 2-chloro-4-hydroxymethyl-6-trifluoromethyl-phenol
and
100 ml dichloromethane and stirred for 2 hours at ambient temperature. The
reaction
mixture was suction filtered to remove the solid, the solution was evaporated
down
under reduced pressure and further reacted as the crude product.
(9e) 1-methyl2-f1-(3-chloro-4-hydroxy-5-trifluoromethyl-phenyl)-meth-(Z)-
ylidenel-
succinate
A mixture of 3.0 g (14.4 mmol) 3-chloro-4-hydroxy-5-trifluoromethyl-
benzaldehyde
~5 and 100 ml THF was combined with 10.48 g (26.7 mmol) monomethyl 3-
(triphenyl-
~5-phosphanylidene)-dipentanoate and stirred for 6 days at 42°C. The
reaction
mixture was evaporated down under reduced pressure, the residue was taken up
in
water and EtOAc. The organic phase was separated off, washed with water and
extracted three times with 15% potassium carbonate solution. The combined
2o aqueous extracts were washed with EtOAc, combined with 200 ml EtOAc and
acidified with stirring by the addition of cone. hydrochloric acid. The
organic phase
was separated off, dried over sodium sulphate, filtered and evaporated down
under
reduced pressure. The residue was purified by column chromatography through
silica
gel (eluant: PE/EtOAc = 1 /1 ).
25 Yield: 2.5 g (55% of theory)
ESI-MS: (M+H)+ = 337 / 339 (CI)
Rf: 0.75 (EtOAc)
(9f) 1-methyl (S)-2-(3-chloro-4-hydroxy-5-trifluoromethyl-benzyl)-succinate
30 2.3 g (6.7 mmol) 1-methyl 2-[1-(3-chloro-4-hydroxy-5-trifluoromethyl-
phenyl)-meth-
(Z)-ylidene]-succinate was dissolved in a degassed solution of 30 ml of
methanol
and 2.5 ml triethylamine and combined with 100 mg (-)-1,2-bis-((2R,5R)-2,5-
diethyl-
phospholano)benzene-(cyclooctadiene)-rhodium-(I) tetrafluoroborate. The
reaction
CA 02562526 2006-10-11
-72-
solution was hydrogenated for 8 hours at RT under 50 bar hydrogen. The
reaction
mixture was evaporated down under reduced pressure, the residue was dissolved
in
100 ml EtOAc and washed twice with 70 ml of 2-molar hydrochloric acid. The
organic
phase was then extracted three times with 15% potassium carbonate solution,
the
combined aqueous phases were acidified with conc. hydrochloric acid and
extracted
twice with EtOAc. The combined organic phases were dried over sodium sulphate,
filtered and evaporated down under reduced pressure.
Yield: 1.7 g (74% of theory)
ESI-MS: (M+H)+ = 341 / 343 (CI)
retention time HPLC: 7.1 min (method A)
(9g) methy~S)-2-(3-chloro-4-hydroxy-5-trifluoromethyl-benzyl)-4-oxo-4-f4-(2-
oxo
1,2,4,5-tetrahydro-benzofdlf 1,3]diazepin-3-yl)-piperidin-1-yl]-butanoate
A mixture of 1.19 g (4.9 mmol) 1-methyl (S)-2-(3-chloro-4-hydroxy-5-
trifluoromethyl-
~5 benzyl)-succinate, 1.56 g (4.9 mmol) TBTU, 0.73 ml (5.0 mmol)
triethylamine, 1.65 g
(4.8 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3Jdiazepin-2-one and
30 ml
DMF was stirred for 12 hours at RT. The reaction mixture was evaporated down
under reduced pressure, the residue was taken up in 200 ml EtOAc and washed
with
200 ml 10% citric acid solution and 50 ml saturated aqueous sodium hydrogen
2o carbonate solution. The organic phase was dried and evaporated down under
reduced pressure.
Yield: 1.8 g (65% of theory)
ESI-MS: (M+H)+ = 568 / 570 (CI)
retention time HPLC: 8.1 min (method A)
(9h) (S)-2- 3-chloro-4-hydroxLr-5-trifluorometh I-~~)-4-oxo-4-f4-(2-oxo-
1,2,4,5-
tetrahydro-benzofdlf1,31diazepin-3-~)-piperidin-1-yll-butanoic acid
1.8 g methyl (S)-2-(3-chloro-4-hydroxy-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-
oxo
1,2,4,5-tetrahydro-benzo[dJ[1,3Jdiazepin-3-yl)-piperidin-1-yIJ-butanoate
dissolved in
50 ml THF was combined with a solution of 115.2 mg (4.8 mmol) lithium
hydroxide in
50 ml of water and stirred overnight at RT. The reaction mixture was
evaporated
down under reduced pressure, combined with 150 ml of water and washed with 150
ml EtOAc. The aqueous phase was acidified with conc. hydrochloric acid and
' CA 02562526 2006-10-11
-73-
extracted with 150 ml EtOAc. The organic phase was separated off, dried and
evaporated down under reduced pressure.
Yield: 1.5 g (85% of theory)
ESI-MS: (M+H)+ = 554 / 556 (CI)
s retention time HPLC: 7.2 min (method A)
(9i) f S)-2-(3-chloro-4-hydroxy-5-trifluoromethyl-benzyl)-1-(4-morpholin-4-
iLl-
piperidin-1-~~4-[~2-oxo-1,2,4,5-tetrahydro-benzofdll1,3ldiazepin-3-yl)-
piperidin-1-yll-butan-1.4-dione
Prepared analogously to Example (1 g) from 70 mg (0.126 mmol) (S)-2-(3-chloro-
4-
hydroxy-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-
benzo[dJ[1,3]diazepin-3-yl)-piperidin-1-yl]-butanoic acid and 22 mg (0.130
mmol) 4-
piperidin-4-yl-morpholine.
Yield: 47 mg (53% of theory)
15 ESI-MS: (M+H)+ = 706 / 708 (CI)
retention time HPLC: 6.0 min (method A)
The following Examples describe the preparation of pharmaceutical formulations
which contain as active substance any desired compound of general formula (I):
Example I
Capsules for powder inhalation containing 1 ma of active ingredient
Composition:
1 capsule for powder inhalation contains:
active ingredient 1.0 mg
lactose 20.0 mg
hard gelatine capsules 50.0 mg
71.0 mg
' CA 02562526 2006-10-11
-74-
Method of preparation:
The active ingredient is ground to the particle size required for inhaled
substances.
The ground active ingredient is homogeneously mixed with the lactose. The
mixture
is transferred into hard gelatine capsules.
Example II
Inhalable solution for Respimat~ containing 1 mct of active ingredient
Composition:
1 puff contains:
active ingredient 1.0 mg
benzalkonium chloride 0.002 mg
disodium edetate 0.0075 mg
~ 5 purified water ad 15.0 NI
Method of preparation:
The active ingredient and benzalkonium chloride are dissolved in water and
transferred into Respimat~ cartridges.
Example III
Inhalable solution for nebulisers containing 1 ma of active ingredient
Composition:
1 vial contains:
active ingredient 0.1 g
sodium chloride 0.18 g
benzalkonium chloride 0.002 g
3o purified water ad 20.0 ml
°
CA 02562526 2006-10-11
' ~ -75-
Method of preparation:
The active ingredient, sodium chloride and benzalkonium chloride are dissolved
in
wate r.
Example IV
Propellant ctas-operated meterinct aerosol containing 1 mg of active
ingredient
Composition:
1 puff contains:
active ingredient 1.0 mg
lecithin 0.1
propellant gas ad 50.0 NI
Method of preparation:
The micronised active ingredient is homogeneously suspended in the mixture of
lecithin and propellant gas. The suspension is transferred into a pressurised
container with a metering valve.
Example V
Nasal spray containinct 1 mgi of active ingredient
Composition:
active ingredient 1.0 mg
sodium chloride 0.9 mg
benzalkonium chloride 0.025 mg
disodium edetate 0.05 mg
so purified water ad 0.1 ml
CA 02562526 2006-10-11
-76-
Method of preparation:
The active ingredient and the excipients are dissolved in water and
transferred into a
suitable container.
Example VI
Iniectable solution containing 5 mg of active substance per 5 ml
Composition:
1o active substance 5 mg
glucose 250 mg
human serum albumin 10 mg
glycofurol 250 mg
water for injections ad 5 ml
Preparation:
Glycofurol and glucose are dissolved in water for injections (Wfl); human
serum
albumin is added; active ingredient is dissolved with heating; made up to
specified
2o volume with Wfl; transferred into ampoules under nitrogen gas.
Example VII
Inlectable solution containing 100 mg of active substance per 20 ml
Composition:
active substance 100 mg
monopotassium dihydrogen phosphate = KH2P04 12 mg
disodium hydrogen phosphate = Na2HP04~2H20 2 mg
3o sodium chloride 180 mg
human serum albumin 50 mg
Polysorbate 80 20 mg
water for injections ad 20 ml
~
' CA 02562526 2006-10-11
-77-
Preparation:
Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and
disodium hydrogen phosphate are dissolved in water for injections (Wfl); human
serum albumin is added; active ingredient is dissolved with heating; made up
to
specified volume with Wfl; transferred into ampoules.
Example VIII
Lyophilisate containing 10 ma of active substance
Composition:
Active substance 10 mg
Mannitol 300 mg
~5 human serum albumin 20 mg
Preparation:
Mannitol is dissolved in water for injections (Wfl); human serum albumin is
added;
active ingredient is dissolved with heating; made up to specified volume with
Wfl;
2o transferred into vials; freeze-dried.
Solvent for lyophilisate:
Polysorbate 80 = Tween 80 20 mg
mannitol 200 mg
25 water for injections ad 10 ml
Preparation:
Polysorbate 80 and mannitol are dissolved in water for injections (Wfl);
transferred
into ampoules.
' CA 02562526 2006-10-11
_78_
Example IX
Tablets containinc~20 mg of active substance
Composition:
active substance 20 mg
lactose 120 mg
maize starch 40 mg
magnesium stearate 2 mg
Povidone K 25 18 mg
Preparation:
Active substance, lactose and maize starch are homogeneously mixed; granulated
with an aqueous solution of Povidone; mixed with magnesium stearate;
compressed
in a tablet press; weight of tablet 200 mg.
Example X
Capsules containing 20 mg active substance
Composition:
active substance 20 mg
maize starch 80 mg
highly dispersed silica 5 mg
magnesium stearate 2.5 mg
Preparation:
Active substance, maize starch and silica are homogeneously mixed; mixed with
magnesium stearate; the mixture is packed into size for 3 hard gelatine
capsules in a
3o capsule filling machine.
- CA 02562526 2006-10-11
_79_
Example XI
Suppositories containinct 50 mp of active substance
Composition:
active substance 50 mg
hard fat (Adeps solidus) q.s. ad 1700 mg
Preparation:
1o Hard fat is melted at about 38°C; ground active substance is
homogeneously
dispersed in the molten hard fat; after cooling to about 35°C it is
poured into chilled
moulds.
Example XII
Iniectable solution containing 10 ma of active substance per 1 ml
Composition:
active substance 10 mg
2o mannitol 50 mg
human serum albumin 10 mg
water for injections ad 1 ml
Preparation:
Mannitol is dissolved in water for injections (Wfl); human serum albumin is
added;
active ingredient is dissolved with heating; made up to specified volume with
Wfl;
transferred into ampoules under nitrogen gas.
