RU2004100109A - Химерные аналоги соматостатина-дофамина - Google Patents

Химерные аналоги соматостатина-дофамина Download PDF

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RU2004100109A
RU2004100109A RU2004100109/04A RU2004100109A RU2004100109A RU 2004100109 A RU2004100109 A RU 2004100109A RU 2004100109/04 A RU2004100109/04 A RU 2004100109/04A RU 2004100109 A RU2004100109 A RU 2004100109A RU 2004100109 A RU2004100109 A RU 2004100109A
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pharmaceutically acceptable
acceptable salt
compound
alkyl
subject
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RU2004100109/04A
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RU2277539C2 (ru
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Майкл Д. КАЛЛЕР (US)
Майкл Д. КАЛЛЕР
Женг Ксин ДОНГ (US)
Женг Ксин Донг
Сун Х. КИМ (US)
Сун Х. Ким
Жак-Пьер МОРО (US)
Жак-Пьер МОРО
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Сосьете Де Консей Де Решерш Э Д`Аппликасьон Сьентифик С.А.С. (Fr)
Сосьете Де Консей Де Решерш Э Д`Аппликасьон Сьентифик С.А.С.
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Claims (17)

1. Соединение формулы (I)
Figure 00000001
где Х представляет собой H, Cl, Br, I, F, -CN или C1-5алкил;
R1 представляет собой H, C1-4алкил, аллил, алкенил или –CN;
R2 и R3 оба независимо представляют собой H или отсутствуют, причем если R2 и R3 отсутствуют, между атомами углерода, к которым они присоединены, присутствует двойная связь;
R4 представляет собой H или –CH3;
Y представляет собой -O-, -C(O)-, -S-, -S-(CH2)s-C(O)-, -S(O)-, -S(O)2-, -SC(O)-, -OC(O)-, -N(R5)-C(O)- или -N(R6)-;
R5, R6, R7 и R8 каждый независимо представляет собой H или C1-5алкил;
R6 представляет собой H или C1-5алкил;
m представляет собой 0 или 1;
n представляет собой 0-10;
L представляет собой -(CH2)p-C(O)-, когда Y представляет собой -S-, -S(O)-, -S(O)2-, -O- или -N(R6)-;
L представляет собой -C(O)-(CR7R8)q-C(O)-, когда Y представляет собой -N(R6)-, -O- или -S-;
L представляет собой -(Doc)t-, когда Y представляет собой -C(O)-, SC(O)-, -OC(O)-, -S-(CH2)s-C(O)- или -N(R5)-C(O)-;
p представляет собой 1-10;
q представляет собой 2-4;
s представляет собой 1-10;
t представляет собой 1-10;и
Z представляет собой аналог соматостатина или группу, включающую –H, -OH, (C1-C6)алкокси, арилалкокси, -NH2 или -NR9R10, где R9 и R10 независимо представляют собой H или C1-5алкил,
или его фармацевтически приемлемая соль.
2. Соединение формулы (II)
Figure 00000002
где X представляет собой H, Cl, Br, I, F,-CN или C1-5алкил;
R1 представляет собой C1-4алкил, H, аллил, алкенил или -CN;
R2 и R3 оба независимо представляют собой H или отсутствуют, причем если R2 и R3 отсутствуют, между атомами углерода, к которым они присоединены, присутствует двойная связь;
R4 представляет собой H или –CH3;
R5 представляет собой C1-5алкильную группу или группу формулы -(CH2)rN(CH3)q;
Y представляет собой -O-, -C(O)-, -S-, -SC(O)-, -OC(O)-, -N(R6)-C(O)-, -N(R7)- или -N(R8)-(CH2)s-C(O)-;
R6, R7, R8, R9 и R10, каждый независимо представляет собой H или C1-5алкил;
L представляет собой -(CH2)p-C(O)-, когда Y представляет собой -S-, -O- или -N(R7)-;
L представляет собой -C(O)-(CR9R10)q-C(O)-, когда Y представляет собой -N(R7)-, -O- или -S-;
L представляет собой -(Doc)t-, когда Y представляет собой -C(O)-, SC(O)-, -OC(O)-, -N(R8)-(CH2)s-C(O)- или -N(R6)-C(O)-;
m представляет собой 0 или 1;
n представляет собой 2-10;
r представляет собой 1-8;
q представляет собой 2-4;
p представляет собой 1-10;
s представляет собой 1-10;
t представляет собой 1-10; и
Z представляет собой аналог соматостатина или группу, включающую –H, -OH, (C1-C6)алкокси, арилалкокси, -NH2 или -NR9R10,
или его фармацевтически приемлемая соль.
3. Соединение формулы
Figure 00000003
Figure 00000004
Figure 00000005
Figure 00000006
Figure 00000007
Figure 00000008
Figure 00000009
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Figure 00000015
Figure 00000016
Figure 00000017
Figure 00000018
Figure 00000019
Figure 00000020
Figure 00000021
Figure 00000022
Caeg=N-(2-аминоэтил)-N-(2-цитозинил-1-оксоэтил)глицин
Figure 00000023
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Figure 00000027
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Figure 00000099
Figure 00000100
Figure 00000101
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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
Figure 00000183
Figure 00000184
Figure 00000185
Figure 00000186
Figure 00000187
Figure 00000188
Figure 00000189
Figure 00000190
Figure 00000191
Figure 00000192
Figure 00000193
Figure 00000194
Figure 00000195
Figure 00000196
Figure 00000197
Figure 00000198
Figure 00000199
Figure 00000200
Figure 00000201
Figure 00000202
Figure 00000203
Figure 00000204
Figure 00000205
Figure 00000206
Figure 00000207
Figure 00000208
Figure 00000209
Figure 00000210
Figure 00000211
Figure 00000212
Figure 00000213
Figure 00000214
Figure 00000215
Figure 00000216
Figure 00000217
Figure 00000218
Figure 00000219
Figure 00000220
Figure 00000221
Figure 00000222
Figure 00000223
Figure 00000224
Figure 00000225
Figure 00000226
Figure 00000227
Figure 00000228
Figure 00000229
Figure 00000230
Figure 00000231
Figure 00000232
Figure 00000233
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
AEPA=4-(2-аминоэтил)-1-карбоксиметилпиперазин
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
Figure 00000316
Figure 00000317
Figure 00000318
Figure 00000319
Figure 00000320
Figure 00000321
Figure 00000322
Figure 00000323
Figure 00000324
Figure 00000325
Figure 00000326
или
Figure 00000327
или его фармацевтически приемлемая соль.
4. Соединение формулы
Figure 00000328
Figure 00000329
Figure 00000330
Figure 00000331
Figure 00000332
Figure 00000333
Figure 00000334
Figure 00000335
Figure 00000336
Figure 00000337
Figure 00000338
Figure 00000339
Figure 00000340
Figure 00000341
Figure 00000342
Figure 00000343
Figure 00000344
Figure 00000345
Figure 00000346
Figure 00000347
Figure 00000348
Figure 00000349
Figure 00000350
Figure 00000351
Figure 00000352
Figure 00000353
Figure 00000354
Figure 00000355
Figure 00000356
Figure 00000357
Figure 00000358
Figure 00000359
Figure 00000360
Figure 00000361
Figure 00000362
Figure 00000363
Figure 00000364
Figure 00000365
Figure 00000366
Figure 00000367
Figure 00000368
Figure 00000369
Figure 00000370
Figure 00000371
Figure 00000372
Figure 00000373
Figure 00000374
Figure 00000375
Figure 00000376
Figure 00000377
Figure 00000378
Figure 00000379
Figure 00000380
Figure 00000381
Figure 00000382
Figure 00000383
Figure 00000384
Figure 00000385
Figure 00000386
Figure 00000387
Figure 00000388
Figure 00000389
Figure 00000390
Figure 00000391
Figure 00000392
Figure 00000393
Figure 00000394
Figure 00000395
Figure 00000396
Figure 00000397
Figure 00000398
Figure 00000399
Figure 00000400
Figure 00000401
Figure 00000402
Figure 00000403
Figure 00000404
Figure 00000405
Figure 00000406
Figure 00000407
Figure 00000408
Figure 00000409
Figure 00000410
Figure 00000411
Figure 00000412
Figure 00000413
Figure 00000414
Figure 00000415
Figure 00000416
Figure 00000417
Figure 00000418
Figure 00000419
Figure 00000420
Figure 00000421
Figure 00000422
Figure 00000423
Figure 00000424
Figure 00000425
Figure 00000426
Figure 00000427
Figure 00000428
Figure 00000429
Figure 00000430
Figure 00000431
Figure 00000432
Figure 00000433
Figure 00000434
Figure 00000435
Figure 00000436
Figure 00000437
Figure 00000438
Figure 00000439
Figure 00000440
Figure 00000441
Figure 00000442
Figure 00000443
Figure 00000444
Figure 00000445
Figure 00000446
Figure 00000447
Figure 00000448
Figure 00000449
Figure 00000450
Figure 00000451
Figure 00000452
Figure 00000453
Figure 00000454
Figure 00000455
Figure 00000456
Figure 00000457
Figure 00000458
Figure 00000459
Figure 00000460
Figure 00000461
Figure 00000462
или
Figure 00000463
или его фармацевтически приемлемую соль.
5. Соединение формулы
Figure 00000464
Figure 00000465
Figure 00000466
Figure 00000467
Figure 00000468
Этил[6-метил-8β-эрголинилметил]тиоацетат;
6-метил-8β-эрголинилметилтиоацетил-D-Phe-цикло(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH2;
Этил(6-н-пропил-8β-эрголинил)метилтиоацетат;
6-н-пропил-8β-эрголинилметилтиоацетил-D-Phe-цикло(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH2;
6-D-метил-8β-эрголинилметилтиоаминосукциноил-D-Phe-цикло(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH2;
Figure 00000469
Figure 00000470
Figure 00000471
Figure 00000472
Figure 00000473
Figure 00000474
Figure 00000475
Figure 00000476
Figure 00000477
Figure 00000478
Figure 00000479
или
Figure 00000480
или его фармацевтически приемлемая соль.
6. Соединение формулы
Figure 00000481
или
Figure 00000482
или его фармацевтически приемлемая соль.
7. Способ индукции эффекта агониста дофаминового рецептора у нуждающегося в этом субъекта, где указанный способ включает введение указанному субъекту эффективного количества соединения по любому из пп.1-6 или его фармацевтически приемлемой соли.
8. Способ индукции эффекта агониста соматостатинового рецептора у нуждающегося в этом субъекта, где указанный способ включает введение указанному субъекту эффективного количества соединения по любому из пп.1-6 или его фармацевтически приемлемой соли.
9. Способ одновременной индукции эффекта агониста дофаминового рецептора и эффекта агониста соматостатинового рецептора у нуждающегося в этом субъекта, где указанный способ включает введение указанному субъекту эффективного количества соединения по любому из пп.1-6 или его фармацевтически приемлемой соли.
10. Фармацевтическая композиция, содержащая эффективное количество соединения по любому из пп.1-6 или его фармацевтически приемлемой соли и фармацевтически приемлемый носитель.
11. Способ лечения у субъекта заболевания, включающий введение указанному субъекту терапевтически эффективного количества соединения по любому из пп.1-6, где указанное заболевание выбрано из перечня, состоящего из рака легких, глиомы, анорексии, гипотиреоза, гиперальдостеронизма, пролиферации H. pylori, акромегалии, рестеноза, болезни Крона, системного склероза, внешних и внутренних панкреатических псевдоцист и асцитов, випомы, гиперплазии островковых клеток поджелудочной железы, гиперинсулинизма, гастриномы, синдрома Золлингера-Эллисона, диарреи, связанной со СПИД диарреи, связанной с химиотерапией диарреи, склеродермы, синдрома раздраженной толстой кишки, панкреатита, обструкции тонкого кишечника, желудочно-пищеводного рефлюкса, дуоденогастрального рефлюкса, синдрома Кушинга, гонадотропиномы, гиперпаратиреоидизма, базедовой болезни, диабетической невропатии, болезни Педжета, поликистоза яичника, рака щитовидной железы, гепатомы, лейкоза, менингиомы, кахексии при злокачественной опухоли, ортостатической гипотензии, послеобеденной гипотензии, острого тревожного состояния с реакцией паники, секретирующих GH аденом, акромегалии, секретирующих TSH аденом, секретирующих пролактин аденом, инсулиномы, глюкагономы, сахарного диабета, гиперлипидемии, нечувствительности к инсулину, синдрома Тернера, ангиопатии, пролиферативной ретинопатии, феномена “восходящего солнца”, нефропатии, гиперсекреции кислоты желудка, пептических язв, кишечного свища, панкреатического свища, демпинг-синдрома, синдром водянистой диареи, панкреатита, секретирующей гастроинтестинальный гормон опухоли, ангиогенеза, артрита, отторжения аллотрансплантата, кровотечения из сосудов трансплантата, портальной гипертезии, желудочно-кишечного кровотечения, ожирения и передозировки опиоидов.
12. Способ по п.11, где указанное заболевание или состояние представляет собой акромегалию.
13. Способ по любому из пп.7-9, 11 или 12, где указанное соединение представляет собой
Figure 00000483
или его фармацевтически приемлемую соль.
14. Фармацевтическая композиция по п.10, где указанное соединение представляет собой
Figure 00000484
или его фармацевтически приемлемую соль.
15. Соединение по п.1 или 2, где z представляет собой группу, включающую –H, -OH, (C1-C6)алкокси, арилалкокси, -NH2 или –NR9R10; или его фармацевтически приемлемая соль.
16. Соединение по п.15, где z представляет собой группу, включающую –H, -OH, (C1-C6)алкокси или бензил; или его фармацевтически приемлемая соль.
17. Соединение по п.15, где указанное соединение соответствует формуле
Figure 00000485
Figure 00000486
или его фармацевтически приемлемая соль.
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