RU2220950C2 - N-алканоилфенилаланиновые производные - Google Patents

N-алканоилфенилаланиновые производные Download PDF

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RU2220950C2
RU2220950C2 RU2000106434/04A RU2000106434A RU2220950C2 RU 2220950 C2 RU2220950 C2 RU 2220950C2 RU 2000106434/04 A RU2000106434/04 A RU 2000106434/04A RU 2000106434 A RU2000106434 A RU 2000106434A RU 2220950 C2 RU2220950 C2 RU 2220950C2
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RU2000106434A (ru
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Ли ЧЕНЬ (US)
Ли ЧЕНЬ
Роберт Уилль м ГАТРИ (US)
Роберт Уилльям ГАТРИ
Тайнан ХУАН (US)
Тайнан ХУАН
Кеннет Г. ХАЛЛ (US)
Кеннет Г. ХАЛЛ
Акитарао СИДДУРИ (US)
Акитарао СИДДУРИ
Джефферсон Райт ТИЛЛИ (US)
Джефферсон Райт ТИЛЛИ
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Ф.Хоффманн-Ля Рош Аг
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Abstract

Изобретение относится к N-алканоилфенилаланиновым производным формулы (I), значения радикалов X, X', Y, Z определены в формуле изобретения, к их фармацевтически приемлемым солям и сложным эфирам. Соединения по изобретению обладают высокой антагонистической активностью в отношении VLA-4 и могут использоваться для лечения ревматоидного артрита, рассеянного склероза, астмы и воспалительного заболевания кишечника. 3 с. и 47 з.п. ф-лы, 16 табл.

Description

Текст описания в факсимильном виде (см. графический материал)

Claims (49)

1. N-алканоилфенилаланиновые производные формулы
Figure 00000134
где один из X и X' обозначает водород, галоген или (низш.)алкил, а другой обозначает группу формулы
Figure 00000135
где R1 обозначает водород или (низш.)алкил;
R15 обозначает водород, галоген, нитро, циано, (низш.)алкил, ОН, (низш.)алкокси, перфтор(низш.)алкил или (низш.)алканоил;
R16 обозначает водород, галоген, нитро, циано, (низш.)алкил, ОН или перфтор (низш.) алкил,
а равно 0 или 1, либо один из Х и X' обозначает группу формулы
Figure 00000136
где Het обозначает 5- или 6-членное гетероароматическое кольцо, содержащее 1, 2 или 3 гетероатома, выбранных из группы, включающей N, О или S, или Het обозначает 9- или 10-членное бициклическое гетероароматическое кольцо, содержащее 1, 2, 3 или 4 гетероатома, выбранных из группы, включающей О, S или N, a, R1, R15 и R16 имеют указанные выше значения и R30 обозначает водород или (низш.)алкил либо отсутствует, либо один из Х и X' обозначает группу формулы
Figure 00000137
где R18 обозначает водород, (низш.)алкил, арил или арилалкил,
R19 обозначает (низш.)алкил, который является незамещенным или может быть замещен одним или несколькими заместителями, выбранными из группы, включающей арил или гетероарил;
R20 обозначает (низш.)алкил или (низш.)алканоил, или R19 и R20 вместе обозначают тетраметилен, и Y обозначает группу формулы
Figure 00000138
где R22 и R23 независимо обозначают водород, (низш.)алкил, (низш.)алкокси, (низш.)алкиламино, арил, арилалкил, нитро, (низш.)алкилтио, (низш.)алкилсульфинил, (низш.)алкилсульфонил, (низш.)алканоил, галоген или перфторалкил и по крайней мере один из радикалов R22 и R23 не обозначает водород и
R24 обозначает водород, гидрокси, (низш.)алкил, (низш.)алкокси, нитро, (низш.)алкилсульфонил, галоген или группу формулы
Figure 00000139
Figure 00000140
или
Figure 00000141
где R25 обозначает водород, (низш.)алкил или арил,
а R26 обозначает водород или (низш.)алкил, или R22 и R24 вместе обозначают конденсированное бензольное кольцо, либо Y обозначает группу Y-2, которая представляет собой 5- или 6-членную моноциклическую гетероароматическую группу, содержащую 1, 2 или 3 гетероатома, выбранных из группы, включающей N, О или S, или 9- или 10-членную бициклическую гетероароматическую группу, содержащую 1, 2, 3 или 4 гетероатома, выбранных из группы, включающей О, S или N, где гетероароматическая группа связана через атом углерода с карбониламидом и один или два атома углерода гетероароматической группы замещены (низш.)алкилом, галогеном, перфторалкилом или арилом и по крайней мере один из этих замещенных атомов углерода представляет собой атом, соседний с атомом углерода, связанным с карбониламидом, и Z обозначает водород или (низш.)алкил,
и его фармацевтически приемлемые соли и сложные эфиры.
2. Соединение по п.1, где Z обозначает водород.
3. Соединение по п.1 или 2, где X' обозначает водород.
4. Соединение по любому из пп.1-3, где R22 и R23 независимо друг от друга обозначают водород, (низш.)алкил, нитро, (низш.)алкилтио, (низш.)алкокси, (низш.)алкиламино, (низш.)алкилсульфинил, (низш.)алкилсульфонил, (низш.)алканоил, галоген или перфторалкил, причем по крайней мере один из радикалов R22 и R23 не обозначает водород, a R24 обозначает водород, гидрокси, (низш.)алкил, (низш.)алкокси, (низш.)алкилсульфонил, нитро, галоген или группу формулы
Figure 00000142
Figure 00000143
или
Figure 00000144
где R25 обозначает (низш.)алкил и R26 обозначает водород или (низш.)алкил, или R22 и R24 вместе обозначают конденсированное бензольное кольцо.
5. Соединение по п.4, где R22 обозначает водород (если R23 не обозначает водород), (низш.)алкил или галоген.
6. Соединение по п.4 или 5, где R24 обозначает водород, гидрокси, (низш.)алкилсульфонил, (низш.)алкил, галоген, нитро или (низш.)алкокси, или группу формулы
Figure 00000145
Figure 00000146
или
Figure 00000147
где R25 обозначает (низш.)алкил, a R26 обозначает водород или R22 и R24 вместе обозначают конденсированное фенильное кольцо.
7. Соединение по п.6, где R24 обозначает водород, гидрокси, метил, хлор, бром, нитро, -ОСН3, -SО2СН3, R26 обозначает Н.
8. Соединение по любому из пп.4-7, где R23 обозначает водород (если R22 не обозначает водород), (низш.)алкил, (низш.)алкиламино, галоген, нитро(низш.)алкилтио перфтор(низш.)алкил, (низш.)алкокси, (низш.)алканоил, (низш.)алкилсульфинил или (низш.)алкилсульфонил.
9. Соединение по п.8, где R23 обозначает метил, этил, изопропил, трет-бутил, трифторметил, хлор, бром, фтор, нитро, -СОСН3, -SOCH3, -SO2СH3, - SСН3, -NНСН3 или -ОСН3.
10. Соединение по любому из пп.4-9, где Y-1 выбирают из группы, включающей
Figure 00000148
Figure 00000149
Figure 00000150
Figure 00000151
Figure 00000152
Figure 00000153
Figure 00000154
Figure 00000155
Figure 00000156
Figure 00000157
Figure 00000158
Figure 00000159
Figure 00000160
Figure 00000161
Figure 00000162
Figure 00000163
Figure 00000164
Figure 00000165
Figure 00000166
Figure 00000167
Figure 00000168
Figure 00000169
Figure 00000170
Figure 00000171
Figure 00000172
Figure 00000173
Figure 00000174
Figure 00000175
Figure 00000176
Figure 00000177
Figure 00000178
Figure 00000179
Figure 00000180
Figure 00000181
Figure 00000182
или
Figure 00000183
11. Соединение по любому из пп.1-3, где моноциклическую гетероароматическую или 9- или 10-членную бициклическую гетероароматическую группу в Y-2 выбирают из группы, включающей
Figure 00000184
Figure 00000185
Figure 00000186
Figure 00000187
Figure 00000188
или
Figure 00000189
12. Соединение по п.11, где группы Y-2 представляют собой группы формул
Figure 00000190
Figure 00000191
Figure 00000192
Figure 00000193
Figure 00000194
Figure 00000195
Figure 00000196
или
Figure 00000197
13. Соединение по любому из пп.1-3, где группы R15 и R16 в Х-6 обозначают независимо друг от друга водород, (низш.)алкил, нитро, галоген, перфтор(низш.)алкил, циано.
14. Соединение по п.13, где R15 или R16 обозначают Н, метил, нитро, хлор, фтор, трифторметил, циано.
15. Соединение по п.13 или 14, где группа Х-6 представляет собой группу формулы
Figure 00000198
Figure 00000199
Figure 00000200
Figure 00000201
Figure 00000202
Figure 00000203
или
Figure 00000204
16. Соединение по любому из пп.1-3, где Het в Х-7 обозначает 5- или 6-членное моноциклическое гетероароматическое кольцо, содержащее 1, 2 или 3 атома азота, или атом азота и атом серы, или атом азота и атом кислорода.
17. Соединение по п.16, где гетероароматическое кольцо представляет собой
Figure 00000205
Figure 00000206
Figure 00000207
Figure 00000208
или
Figure 00000209
18. Соединение по любому из пп.1-3, где Het в Х-7 обозначает бициклическое гетероароматическое кольцо, содержащее в качестве гетероатомов от 1 до 3 атомов азота.
19. Соединение по п.18, где бициклическое гетероароматическое кольцо представляет собой 4-хинолинил, 1-изохинолинил или
Figure 00000210
20. Соединение по любому из пп.1-3, где R15 в Х-7 обозначает водород, нитро, (низш.)алкилсульфонил, циано, (низш.)алкил, (низш.)алкокси, перфтор(низш.)алкил, (низш.)алканоил.
21. Соединение по п.20, где R15 обозначает изопропил, метил.
22. Соединение по любому из пп.1-3, где R16 в Х-7 обозначает водород, галоген, нитро, циано, (низш.)алкил или перфтор(низш.)алкил.
23. Соединение по п.22, где R16 обозначает метил или трифторметил.
24. Соединение по любому из пп.1-3, где R30 в Х-7 обозначает водород или (низш.)алкил.
25. Соединение по любому из пп.1-3, где группами Х-7 являются группы формул
Figure 00000211
Figure 00000212
Figure 00000213
Figure 00000214
Figure 00000215
Figure 00000216
Figure 00000217
Figure 00000218
Figure 00000219
и
Figure 00000220
Соединение по любому из пп.1-3, где R1 в Х-6 или в Х-7 обозначает водород.
27. Соединение по любому из пп.1-3, где а равно 0 в Х-6 или в Х-7.
28. Соединение по любому из пп.1-3, где R18 в Х-10 обозначает (низш.)алкил или фенил, причем фенильное кольцо является незамещенным или монозамещенным галогеном, или фенил (низш.)алкил.
29. Соединение по п.28, где R18 обозначает трет-бутил, фенил, хлорфенил или фенилэтил.
30. Соединение по любому из пп.1-3, где R19 в Х-10 обозначает (низш.)алкил, который является незамещенным или может быть замещен пиридилом или фенилом, причем фенильное кольцо является незамещенным или имеет один заместитель, выбранный из (низш.)алкокси и галогена.
31. Соединение по п.30, где R19 обозначает метил, изобутил, бензил, 4-хлорбензил, 4-метоксибензил или 2-пиридилметил.
32. Соединение по любому из пп.1-3, где R20 в Х-10 обозначает (низш.)алканоил.
33. Соединение по п.32, где R20 в Х-10 обозначает ацетил.
34. Соединение по любому из пп.1-3, где группами Х-10 являются группы формул
Figure 00000221
Figure 00000222
Figure 00000223
Figure 00000224
Figure 00000225
Figure 00000226
Figure 00000227
Figure 00000228
Figure 00000229
Figure 00000230
Figure 00000231
Figure 00000232
и
Figure 00000233
35. Соединение, по п.1 выбранное из следующей группы:
Figure 00000234
Figure 00000235
Figure 00000236
Figure 00000237
Figure 00000238
Figure 00000239
Figure 00000240
Figure 00000241
Figure 00000242
Figure 00000243
Figure 00000244
Figure 00000245
Figure 00000246
Figure 00000247
Figure 00000248
Figure 00000249
Figure 00000250
Figure 00000251
Figure 00000252
Figure 00000253
Figure 00000254
Figure 00000255
Figure 00000256
Figure 00000257
Figure 00000258
Figure 00000259
Figure 00000260
Figure 00000261
Figure 00000262
Figure 00000263
Figure 00000264
Figure 00000265
Figure 00000266
Figure 00000267
Figure 00000268
Figure 00000269
Figure 00000270
Figure 00000271
Figure 00000272
Figure 00000273
Figure 00000274
Figure 00000275
Figure 00000276
Figure 00000277
Figure 00000278
Figure 00000279
Figure 00000280
Figure 00000281
Figure 00000282
Figure 00000283
Figure 00000284
Figure 00000285
Figure 00000286
Figure 00000287
Figure 00000288
Figure 00000289
Figure 00000290
Figure 00000291
Figure 00000292
Figure 00000293
Figure 00000294
Figure 00000295
Figure 00000296
Figure 00000297
Figure 00000298
Figure 00000299
Figure 00000300
Figure 00000301
Figure 00000302
Figure 00000303
Figure 00000304
Figure 00000305
Figure 00000306
Figure 00000307
Figure 00000308
Figure 00000309
Figure 00000310
Figure 00000311
Figure 00000312
Figure 00000313
Figure 00000314
Figure 00000315
и
Figure 00000316
36. Соединение по п.1, представляющее собой N-(2-хлор-6-метилбензоил)-4- [(2,6-дихлорфенил)карбонил]амино-L-фенилаланин или натриевую соль N-(2-хлор-6-метилбензоил)-4-[(2,6-дихлорфенил)карбонил] амино-L-фенилаланина.
37. Соединение по п.1 общей формулы
Figure 00000317
где X, X', Z и Y имеют значения, приведенные в п.1, R31 обозначает низший алкил; или R31 обозначает группу формулы Р-1
Figure 00000318
где R32 обозначает водород или низший алкил;
R33 обозначает водород или низший алкил или арил;
R34 обозначает водород или низший алкил;
h обозначает целое число от 0 до 2;
g обозначает целое число от 0 до 2;
сумма от h до g составляет от 1 до 3;
или R31 обозначает группу формулы Р-2
Figure 00000319
где R32, g и h имеют вышеприведенные значения для Р-1, Т обозначает О, S, (СН2)i, связь (когда j=0) или группу формулы N-R35, R35 обозначает водород, низший алкил, низший алканоил, низший алкоксикарбонил и j равен 0, 1 или 2.
38. Соединение по п.37, где R31 обозначает низший алкил.
39. Соединение по п.38, где R31 обозначает метил, этил, бутил, 1-метилэтил, 2-метилпропил.
40. Соединение по п.39, выбранное из группы
Метиловый эфир N-(2-хлор-6-метилбензоил)-4-[[(2,6-дихлорфенил)карбонил]амино]-L-фенилаланина,
Этиловый эфир N-(2-хлор-6-метилбензоил)-4-[[(2,6-дихлорфенил) карбонил]амино]-L-фенилаланина,
Бутиловый эфир N-(2-хлор-6-метилбензоил)-4-[[(2,6-дихлорфенил) карбонил]амино]-L-фенилаланина,
1-Метилэтиловый эфир N-(2-хлор-6-метилбензоил)-4-[[(2,6-дихлорфенил)карбонил]амино]-L-фенилаланина,
2-Метилпропиловый эфир N-(2-хлор-6-метилбензоил)-4-[[(2,6-дихлорфенил)карбонил]амино]-L-фенилаланина.
41. Соединение по п.1, представляющее собой 2-метоксиэтиловый эфир N-(2-хлор-6-метилбензоил)-4-[[(2,6-дихлорфенил)карбонил]амино]-L-фенилаланина.
42. Соединение по п.1, представляющее собой 2-гидроксиэтиловый эфир N-(2-хлор-6-метилбензоил)-4-[[(2,6-дихлорфенил)карбонил]амино]-L-фенилаланина.
43. Соединение по п.37, где R31 означает Р-1 или Р-2.
44. Соединение по п.43, где R31 означает диэтиламиноэтил, 2-(4-морфолинил)этил, 1-метил-2-(4-морфолинил) этил, 1-метил-4-пиперидинил, 2-(1-пиперазинил)этил или 2-(4-метил-1-пиперазинил)этил.
45. Соединение по п.44, выбранное из группы
2-(4-Морфолинил)этиловый эфир N-(2-хлор-6-метилбензоил)-4-[[(2,6-дихлорфенил)карбонил]амино]-L-фенилаланина,
1-Метил-2-(4-морфолинил) этиловый эфир N-(2-хлор-6-метилбензоил)-4-[[(2,6-дихлорфенил)карбонил]амино]-L-фенилапанина,
1-Метил-4-пиперидиниловый эфир N-(2-хлор-6-метилбензоил)-4-[[(2,6-дихлорфенил)карбонил]амино]-L-фенилаланина,
2-(1-Пиперазинил)этиловый эфир N-(2-хлор-6-метилбензоил)-4-[[(2,6-дихлорфенил)карбонил]амино]-L-фенилаланина, и
2-(4-метил-1-пиперазинил) этиловый эфир N-(2-хлор-6-метилбензоил)-4-[[(2,6-дихлорфенил)карбонил]амино]-L-фенилаланина.
46. Соединение по п.44 общей формулы
Figure 00000320
представляющее собой 2-диэтиламиноэтиловый эфир N-(2-хлор-6-метилбензоил)-4-[[(2,6-дихлорфенил)карбонил]амино]-L-фенилаланина.
47. Соединения по любому из пп.1-46, обладающие антагонистической активностью в отношении VLA-4.
48. Соединения по любому из пп.1-46, предназначенные для применения в качестве лекарственного средства при лечении ревматоидного артрита, рассеянного склероза, воспалительного заболевания кишечника или астмы.
49. Лекарственное средство, обладающее антагонистической активностью в отношении VLA-4, содержащее соединение по любому из пп.1-46 и терапевтически инертный носитель.
50. Лекарственное средство, предназначенное для лечения ревматоидного артрита, рассеянного склероза, воспалительного заболевания кишечника или астмы и содержащее соединение по любому из пп.1-46 и терапевтически инертный носитель.
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RU2624732C2 (ru) * 2012-01-27 2017-07-06 Ф.Хоффманн-Ля Рош Аг Конъюгаты антагонистов интегрина для нацеленной доставки к клеткам, экспрессирующим lfa-1

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CA2301377A1 (en) 1999-03-04
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NZ502813A (en) 2002-10-25
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ZA987604B (en) 1999-07-28
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