RU2003132706A - Диариловые соединения в качестве ингибиторов сериновых протеаз - Google Patents

Диариловые соединения в качестве ингибиторов сериновых протеаз Download PDF

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RU2003132706A
RU2003132706A RU2003132706/04A RU2003132706A RU2003132706A RU 2003132706 A RU2003132706 A RU 2003132706A RU 2003132706/04 A RU2003132706/04 A RU 2003132706/04A RU 2003132706 A RU2003132706 A RU 2003132706A RU 2003132706 A RU2003132706 A RU 2003132706A
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compound
compound according
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well
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RU2003132706/04A
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Ярлагадда С. БАБУ (US)
Ярлагадда С. Бабу
Скотт Р. РОУЛАНД (US)
Скотт Р. РОУЛАНД
Пуран ЧАНД (US)
Пуран ЧАНД
Правин Л. КОТИАН (US)
Правин Л. КОТИАН
Ях ЭЛЬ-КАТТАН (US)
Яхя ЭЛЬ-КАТТАН
Шри НИВАС (US)
Шри Нивас
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Байокрист Фармасьютикалз, Инк. (Us)
Байокрист Фармасьютикалз, Инк.
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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    • A61K31/425—Thiazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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Claims (54)

1. Соединение, имеющее структурную формулу (I), показанную ниже
Figure 00000001
его фармацевтические допустимые соли, а также пролекарства,
где каждое из Е1 и L отдельно представляет собой насыщенное или ненасыщенное углеродное ядро с 5-7 членами, насыщенное или ненасыщенное гетероциклическое ядро с 5-7 членами, бициклическое насыщенное или ненасыщенное углеродное ядро, бициклическое насыщенное или ненасыщенное гетероциклическое ядро или углеводородную цепь с 1-8 членами, которая может быть замещенной одной или несколькими гетерогруппами, выбранными из N, О, S, S(O) и S(O2), и которая может быть насыщенной или ненасыщенной;
R представляет собой -CH=CH-R2, -C=C-R2, -C(R2)=СН2, -C(R2)=C(R3), -CH=NR2, -C(R2)=N-R3, систему с насыщенным или ненасыщенным углеродным ядром, содержащим 4-7 членов, с замещением или без замещения, систему с насыщенным или ненасыщенным гетероциклическим ядром, содержащим 4-7 членов, с замещением или без замещения, или цепь из 2-8 атомов углерода, имеющих от 1 до 5 двойных или тройных связей, с замещениями, выбранными из R1, R2 или R3, эти R, R1, R2 или R3 предпочтительно не включают -(С2-4алкенил)-CO2-C1-8алкил, -(С2-4алкенил)-CO2-C1-8алкил-фенил и -(C2-4алкенил)-CO2-C1-8алкил-O-C1-4алкил;
R1 представляет собой Н, -R, -NO2, -CN, -гало, -N3, -C1-8алкил, -(CH2)nCO2R2, -C2-8алкенил-CO2R2, -O(CH2)nCO2R2, -C(O)NR2R3, -P(O)(OR2)2, алкил-замещенный тетразол-5-ил, -(СН2)nО(СН2)nарил, -NR2R3, -(CH2)nOR2, -(CH2)nSR2, -N(R2)C(O)R3, -S(O2)NR2R3, -N(R2)S(O2)R3, -(CHR2)n NR2R3, -C(O)R3, (CH2)n N(R3)C(O)R3, -N(R2)CR2R3, замещенный или незамещенный (СН2)n-циклоаклил, замещенный или незамещенный (СН2)n-фенил или замещенный или незамещенный (CH2)n-гетероцикл, который может быть насыщенным или ненасыщенным;
m=1 за исключением тех случаев, когда Е1 представляет собой циклическое ядро, содержащее более 5 атомов, тогда m=1 или более, в зависимости от размера ядра;
R2 представляет собой Н, -гало, -алкил, -галоалкил, -(СН2)n -фенил, -(СН2)1-3-бифенил, -(СН2)1-4-Ph-N(SO2-C1-2-алкил)2, -CO(CHR1)n-OR1, -(CHR1)n-гетороцикл, -(CHR1)n-NH-CO-R1, -(CHRl)n-NH-SO2Rl, -(CHRl)n-Ph-N(SO2-C1-2-алкил)2, -(CHR1)n,-C(O)(CHR1)-NHR1, -(CHRl)n-C(S)(CHRl)-NHRl, -(СН2)nО(СН2)nСН3, -CF3, -C2-5ацил, -(CHR1)nOH, -(CHRl)nCO2Rl, -(CHR1)n-O-алкил, -(CHR1)n-O-(CH2)n-O-алкил, -(CHR1)n-S-алкил, -(CHRl)n-S(O)-алкил, -(CHR1)n-S(O2)-алкил, -(CHR1)n-S(O2)-NHR3, -(CHR3)n-N3, -(CHR3)nNHR4, алкеновую цепь, содержащую от 2 до 8 атомов углерода, с 1 до 5 двойных связей, алкиновую цепь, содержащую от 2 до 8 атомов углерода, с 1 до 5 тройных связей, замещенный или незамещенный (CHR3)n-гетероцикл или замещенный или незамещенный (CHR3)n-циклоалкил, который может быть насыщенным или ненасыщенным;
Если n>1, заместители R1 и R3 могут быть одинаковыми или различными;
R3 представляет собой Н, -OH, -CN, замещенный алкил, -C2-8алкенил, замещенный или незамещенный циклоалкил, -N(R1)R2, или насыщенное замещенное или незамещенное гетероциклическое ядро с 5-6 членами;
-NR2R3 может образовывать систему ядер, содержащую от 4 до 7 атомов, или может быть бициклическим ядром. Система ядер может содержать углерод или гетероциклические атомы и, кроме того, может быть насыщенной или ненасыщенной, а также - замещенной или незамещенной;
W представляет собой прямую связь, -CHR2-, -CH=CR2-, -CR2=CH-, -CR2=CR2-, -C=С-, -O-CHR2-, -CHR2-O-, -N(R2)-C(O)-, -C(O)-N(R2)-, -N(R2)-CH-(R3)-, -CH2-N(R2)-, -CH(R1)-N(R2)-, -S-CHR2-, -CHR2-S-, -S(O2)-N(R2)-, -C(O)N(R2)-(CHR2)n-, -C(R1R2)n-NR2-, -N(R2)-S(O2)-, -R2C(O)NR2-, -R2NC(O)NR2-, -CONR2CO-, -C(=NR2)NR2-, -NR2C(=NR2)NR2-, -NR2O-, -N=NCHR2- или -C(O)NR2SO2-;
E2 - насыщенное или ненасыщенное углеродное ядро, содержащее 5-7 членов, насыщенное или ненасыщенное гетероциклическое ядро, содержащее 5-7 членов, бициклическая система ядер, C1-8алкил, C2-8алкенил, C2-8 алкинил, алкиларил, аралкил, аралкенил, аралкинил, алкокси, алкилтио, или алкиламино;
каждый Х отдельно представляет собой прямую связь, замещенную или незамещенную С1-4-метиленовую цепь, одну или две незамещенные или замещенные C1-4-метиленовые цепи, содержащие О, S, NR2, S(O), S(O2), или N(O), X в различных позициях могут быть одинаковыми или различными;
В представляет собой Н, -гало, -CN, -NH2, -(CH2)n-C(=NR4)NHR5, -(CH2)n-NHR4, -(CH2)nNHC(=NR4)NR5, -(CH2)n-OR4, C1-8 замещенный или незамещенный алкил, замещенную или незамещенную систему ядер, содержащую 4-7 атомов углерода, которые могут быть насыщенными или ненасыщенными;
В1 выбирают из В, В1 и В могут быть одинаковыми или различными;
если Е2 представляет собой циклическую систему, содержащую более 5 атомов, в Е2 могут присутствовать несколько аналогичных или различных групп R2, p=1 за исключением тех случаев, когда Е2 - циклическое ядро, содержащее более 5 атомов, p=1 или более в зависимости от размера ядра;
n равно 0-4;
А выбирают из R1;
о=1 за исключением тех случаев, когда L - циклическое ядро, содержащее более 5 атомов, при этом в зависимости от размера ядра о≥1;
каждое из V и V1 отдельно выбирают из R1 и N-алкил замещенного карбоксиамидила (-CONHR), где алкильная группа может быть прямой, разветвленной, циклической или бициклической, N,N-двухзамещенного карбоксамидила (-CONR1R2 где R1 и R2 могут быть замещенным или незамещенным алкилом или арилом и могут быть одинаковыми или различными), одно- или двузамещенных сульфонамидов (SO2NHR или –SO2NR1R2), а также их расширенных вариантов с метиленовой или полиметиленовой цепью;
каждое R4 и R5 отдельно представляет собой Н, -(CH2)nОН, -C(O)OR6, -C(O)SR6, -(CH2)nC(O)NR7R8, -O-C(O)-O-R7, аминокислоту или дипептид;
каждое R6 представляет собой Н, R7, -C(R7)(R8)-(CH2)n-O-C(O)-R9, -(СН2)n-C(R7)(R8)-O-C(O)R9, -(CH2)n-C(R7)(R8)-O-C(O)-O-R9, или -C(R7)(R8)-(CH2)n-O-C(O)-O-R9 и каждое R7, R8 и R9 отдельно представляет собой Н, алкил, замещенный алкил, арил, замещенный арил, алкенил, замещенный алкенил, алкинил, замещенный алкинил, гетероцикл, замещенный гетероцикл, алкиларил, замещенный алкиларил, циклоалкил, замещенный циклоалкил или СН2CO2алкил.
2. Соединение по п.1, которое представлено структурой
Figure 00000002
где R выбирают из группы, состоящей из
-OH, -OSO2CF3, и
Figure 00000003
и R’ выбирают из группы, состоящей из
Figure 00000004
,
Figure 00000005
,
Figure 00000006
,
Figure 00000007
,
Figure 00000008
,
Figure 00000009
,
Figure 00000010
,
Figure 00000011
,
Figure 00000012
, -CO2MEM,
Figure 00000013
,
Figure 00000014
,
Figure 00000015
,
Figure 00000016
,
Figure 00000017
,
Figure 00000018
, и –CH2NH2,
а также фармацевтически допустимые соли и пролекарства этого соединения.
3. Соединение по п.1, которое представлено структурой
Figure 00000019
где R выбирают из группы, состоящей из
-Obn, -OH, -OSO2CF3,
Figure 00000020
,
Figure 00000021
,
Figure 00000022
,
Figure 00000023
,
Figure 00000024
,
Figure 00000025
,
Figure 00000026
,
Figure 00000027
,
Figure 00000028
,
Figure 00000029
,
Figure 00000030
,
Figure 00000031
,
Figure 00000032
, и -OCH3
и R’ выбирают из группы, состоящей из -CHO, -CO2Н, и -CO2МЕМ а также фармацевтически допустимые соли и пролекарства этого соединения.
4. Соединение по п.1, которое представлено структурой
Figure 00000033
где R представляет собой –OSO2CF3 и R’ выбирают из группы, состоящей из –CHO, -CO2H,
Figure 00000034
а также фармацевтически допустимые соли и пролекарства этого соединения.
5. Соединение по п.1, которое представлено структурой
Figure 00000035
где R выбирают из группы, состоящей из
-OBn, -OH, -OSO2CF3,
Figure 00000036
,
Figure 00000037
,
Figure 00000038
,
Figure 00000039
,
Figure 00000040
,
Figure 00000041
,
Figure 00000042
,
Figure 00000043
,
Figure 00000044
,
Figure 00000045
,
Figure 00000046
,
Figure 00000047
,
Figure 00000048
,
Figure 00000049
,
Figure 00000050
,
Figure 00000051
,
Figure 00000052
,
Figure 00000053
,
Figure 00000054
,
Figure 00000055
,
Figure 00000056
,
Figure 00000057
,
Figure 00000058
,
Figure 00000059
,
Figure 00000060
,
Figure 00000061
,
Figure 00000062
,
Figure 00000063
,
Figure 00000064
,
Figure 00000065
,
Figure 00000066
,
Figure 00000067
,
Figure 00000068
,
Figure 00000069
,
Figure 00000070
,
Figure 00000071
,
Figure 00000072
,
Figure 00000073
,
Figure 00000074
,
Figure 00000075
,
Figure 00000076
, и
Figure 00000077
и R’ выбирают из группы, состоящей из -CHO, -CO2H, и –CO2MEM, а также фармацевтически допустимые соли и пролекарства этого соединения.
6. Соединение по п.1, которое представлено структурой
Figure 00000078
где R выбирают из группы, состоящей из
Figure 00000079
,
Figure 00000080
,
Figure 00000081
,
Figure 00000082
,
Figure 00000083
,
Figure 00000084
,
Figure 00000085
, ,
Figure 00000087
,
Figure 00000088
,
Figure 00000089
,
Figure 00000090
,
Figure 00000091
,
Figure 00000092
,
Figure 00000093
,
Figure 00000094
,
Figure 00000095
,
Figure 00000096
,
Figure 00000097
,
Figure 00000098
,
Figure 00000099
,
Figure 00000100
,
Figure 00000101
,
Figure 00000102
,
Figure 00000103
,
Figure 00000104
,
Figure 00000105
,
Figure 00000106
,
Figure 00000107
,
Figure 00000108
,
Figure 00000109
,
Figure 00000110
,
Figure 00000111
,
Figure 00000112
, и
Figure 00000113
,
а также фармацевтически допустимые соли и пролекарства этого соединения.
7. Соединение по п.1, которое представлено структурой
Figure 00000114
где R выбирают из группы, состоящей из
Figure 00000115
,
Figure 00000116
,
Figure 00000117
,
Figure 00000118
,
Figure 00000119
,
Figure 00000120
,
Figure 00000121
,
Figure 00000122
,
Figure 00000123
,
Figure 00000124
,
Figure 00000125
,
Figure 00000126
,
Figure 00000127
,
Figure 00000128
,
Figure 00000129
,
Figure 00000130
,
Figure 00000131
,
Figure 00000132
,
Figure 00000133
,
Figure 00000134
,
Figure 00000135
,
Figure 00000136
,
Figure 00000137
,
Figure 00000138
,
Figure 00000139
,
Figure 00000140
,
Figure 00000141
,
Figure 00000142
,
Figure 00000143
,
Figure 00000144
,
Figure 00000145
,
Figure 00000146
,
Figure 00000147
,
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
,и
и R’ выбирают из группы, состоящей из
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
и
Figure 00000193
,
а также фармацевтически допустимые соли и пролекарства этого соединения.
8. Соединение по п.1, которое представлено структурой
Figure 00000194
где R выбирают из группы, состоящей из
Figure 00000195
,
Figure 00000196
,
Figure 00000197
,
Figure 00000198
,
Figure 00000199
,
Figure 00000200
,
Figure 00000201
,
Figure 00000202
,
Figure 00000203
,
Figure 00000204
, -OBn, -OCH3 и
Figure 00000205
а также фармацевтически допустимые соли и пролекарства этого соединения.
9. Соединение по п.1, которое представлено структурой
Figure 00000206
где R выбирают из группы, состоящей из
-OSO2CF3,
Figure 00000207
и
Figure 00000208
и R’ представляет собой -Н или
Figure 00000209
,
а также фармацевтически допустимые соли и пролекарства этого соединения.
10. Соединение по п.1, которое представлено структурой
Figure 00000210
где R выбирают из группы, состоящей из
-Obn, -OH, -OSO2CF3,
Figure 00000211
,
Figure 00000212
, -CH=CH2 и –H;
R’ выбирают из группы, состоящей из -CHO, -CO2Н, и –CO2МЕМ;
и R” выбирают из группы, состоящей из
-CO2MEM,
Figure 00000213
,
Figure 00000214
,
Figure 00000215
,
Figure 00000216
,
Figure 00000217
,
Figure 00000218
,
Figure 00000219
и CO2H,
а также фармацевтически допустимые соли и пролекарства этого соединения.
11. Соединение по п.1, которое представлено структурой
Figure 00000220
где R выбирают из группы, состоящей из
-OBn, -OH, -OSO2CF3,
Figure 00000221
, -CH=CH2;
R’ представляет собой -Н или -Boc; и R” представляет собой –СО2МЕМ или -CO2Н, а также фармацевтически допустимые соли и пролекарства этого соединения.
12. Соединение по п.1, которое представлено структурой
Figure 00000222
где R представляет собой –СН3 и R’ выбирают из группы, состоящей из
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
и
Figure 00000252
или
Figure 00000253
или
Figure 00000254
;
а также фармацевтически допустимые соли и пролекарства этого соединения.
13. Соединение по п.1, которое представлено структурой
Figure 00000255
где R представляет собой
Figure 00000256
и R’ выбирают из группы, состоящей из
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
,
а также фармацевтически допустимые соли и пролекарства этого соединения.
14. Соединение по п.1, которое представлено структурой
Figure 00000289
где R представляет собой
Figure 00000290
и -CH=СН2, и R’ выбирают из группы, состоящей из
Figure 00000291
,
Figure 00000292
,
Figure 00000293
и
Figure 00000294
а также фармацевтически допустимые соли и пролекарства этого соединения.
15. Соединение по п.1, которое представлено структурой
Figure 00000295
где R представляет собой –СН3, и R’ выбирают из группы, состоящей из
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
,
а также фармацевтически допустимые соли и пролекарства этого соединения.
16. Соединение по п.1, которое представлено структурой
Figure 00000320
где по меньшей мере R выбирают из группы, состоящей из
-OCH3, -OH, -OSO2CF3, -CH=СН2, -OCH2CO2С2Н5, -OCH2CONH2,
Figure 00000321
Figure 00000322
,
Figure 00000323
,
Figure 00000324
,
Figure 00000325
,
Figure 00000326
Figure 00000327
-OBn, -OH, -OSO2CF3,
Figure 00000328
-OCH3, -OBn, -H, -OBn, и –CH=CH2;
R’ выбирают из группы, состоящей из
-CHO, -CO2H, -CO2MEM,
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
и
Figure 00000342
,
и R” выбирают из группы, состоящей из -Н, -CH3 и -Bn,
а также фармацевтически допустимые соли и пролекарства этого соединения.
17. Соединение по п.1, которое представлено структурой
Figure 00000343
где, по меньшей мере, один из R выбирают из группы, состоящей из -CH=СН2, -OSO2CF3, -OCH2CO2С2Н5, -OCH2CONH2,
Figure 00000344
,
Figure 00000345
, -OCH3,
Figure 00000346
,
Figure 00000347
,
Figure 00000348
, -O-CH2-CH2-OAc, -OH, -OCH2CO2H, -O-CH2-CH2-OH, -CH(OH)CH2OH, -CH2OH, -CO2H,
Figure 00000349
, -OBn, -OH, -OCH3, -OBn, -OH, -OC2H5, -OBn, -OCH3, и -CH(ОН)СН3;
и R’ выбирают из группы, состоящей из –СН3, -CH2С6Н5, -Bn, -Н,
а также фармацевтически допустимые соли и пролекарства этого соединения.
18. Соединение по п.1, которое представлено структурой
Figure 00000350
где, по меньшей мере, один из R выбирают из группы, состоящей из -CH=СН2, -CH(ОН)СН2OH, -CH=O, -CH2OH, -CO2Н, -OCH3, -CH=СН2, а также фармацевтически допустимые соли и пролекарства этого соединения.
19. Соединение по п.1, которое представлено структурой
Figure 00000351
где R выбран из группы, состоящей из галогена и -В(ОН)2;
R1 выбран из группы, состоящей из -Н, -OCH3, -OBn;
R2 выбран из группы, состоящей из
-Н, -OCH3, -OC2Н5, -OCH(СН3)2, и
Figure 00000352
R3 выбран из группы, состоящей из -Н, -OH, -OBn; и
R4 представляет собой -OBn или -Н,
а также фармацевтически допустимые соли и пролекарства этого соединения.
20. Соединение по п.1, которое представлено структурой
Figure 00000353
а также фармацевтически допустимые соли и пролекарства этого соединения.
21. Соединение по п.1, которое представлено структурой
Figure 00000354
где R выбран из группы, состоящей из
-CH3,-C2Н5,-CH(СН3)2,
Figure 00000355
R’ выбран из группы, состоящей из -OBn, -OH, -OSO2CF3, и -CH=СН2;
R” выбран из группы, состоящей из –СО2Н, -CO2МЕМ, или -CHO;
и R′′′ выбран из группы, состоящей из
Figure 00000356
,
Figure 00000357
,
Figure 00000358
,
Figure 00000359
,
Figure 00000360
,
Figure 00000361
,
Figure 00000362
,
Figure 00000363
,
Figure 00000364
,
Figure 00000365
, и
Figure 00000366
,
а также фармацевтически допустимые соли и пролекарства этого соединения.
22. Соединение по п.1, которое представлено структурой
Figure 00000367
где R выбран из группы, состоящей из
-CH3,-C2Н5,-CH(СН3)2,
Figure 00000368
и -Н;
R’ представляет собой -Н или алкил, и R” выбирают из группы, состоящей из
Figure 00000369
,
Figure 00000370
,
Figure 00000371
,
Figure 00000372
,
Figure 00000373
,
Figure 00000374
,
Figure 00000375
,
Figure 00000376
,
Figure 00000377
,
Figure 00000378
и
Figure 00000379
,
а также фармацевтически допустимые соли и пролекарства этого соединения.
23. Соединение по п.1, которое представлено структурой
Figure 00000380
где R выбран из группы, состоящей из
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
, и
Figure 00000423
;
R’ представляет собой -Н, -CH=СН2, и R” представляет собой -Н или алкил, а также фармацевтически допустимые соли и пролекарства этого соединения.
24. Соединение по п.1, которое представлено структурой
Figure 00000424
где R выбран из группы, состоящей из
Figure 00000425
,
Figure 00000426
, -CH=CH2, и –H;
R’ представляет собой -Н или алкил;
а R” выбран из группы, состоящей из
Figure 00000427
,
Figure 00000428
,
Figure 00000429
и
Figure 00000430
,
а также фармацевтически допустимые соли и пролекарства этого соединения.
25. Соединение по п.1, которое представлено структурой
Figure 00000431
где N расположен в позициях 3 или 4 фенольного кольца;
R выбирают из группы, состоящей из -CHO, -CO2Н и
Figure 00000432
и R’ представляет собой -Н или алкил,
а также фармацевтически допустимые соли и пролекарства этого соединения.
26. Соединение по п.1, которое представлено структурой
Figure 00000433
где R выбирают из группы, состоящей из
-CH3, -C2Н5, -CH2С6Н5, -C(СН3)3, -CH2-CCl3,
Figure 00000434
,
Figure 00000435
,
Figure 00000436
,
Figure 00000437
и
Figure 00000438
;
и R’ представляет собой -Н или алкил,
а также фармацевтически допустимые соли и пролекарства этого соединения.
27. Соединение по п.1, которое представлено структурой
Figure 00000439
где R выбирают из группы, состоящей из
-CHO, -CO2Н, и
Figure 00000440
, и R’ представляет собой -Н или алкил,
а также фармацевтически допустимые соли и пролекарства этого соединения.
28. Соединение по п.1, которое представлено структурой
Figure 00000441
где по меньшей мере один R выбран из группы, состоящей из -CH=СН2, -OCH3, -OBn, -OH, и -Н;
R’ представляет собой
Figure 00000442
или
Figure 00000443
;
R” выбирают из группы, состоящей из
Figure 00000444
,
Figure 00000445
и
Figure 00000446
; и
R′′′ представляет собой -Н,
а также фармацевтически допустимые соли и пролекарства этого соединения.
29. Соединение по п.1, которое представлено структурой
Figure 00000447
где R представляет собой –СН2ОН или
Figure 00000448
;
и R’ представляет собой -Boc или -Н,
а также фармацевтически допустимые соли и пролекарства этого соединения.
30. Соединение по п.1, которое представлено структурой
Figure 00000449
где R представляет собой –ОСН3, -OH, -OSO2CF3, -C(=NH)NH2, и -Н;
R’ представляет собой
Figure 00000450
или –NH2;
и R” представляет собой галоген, -CH=СН2, -CO2СН3 и
Figure 00000451
,
а также фармацевтически допустимые соли или пролекарства этого соединения.
31. Соединение по п.19 или 37, где указанный галоген представляет собой -Br.
32. Соединение по п.1, которое представлено структурой
Figure 00000452
где R выбирают из группы, состоящей из -CHO, -CO2Н, -CO2МЕМ,
Figure 00000453
,
Figure 00000454
;
R’ выбирают из группы, состоящей из -OBn, -OH, -OSO2CF3, и -CH=СН2;
и R” представляет собой -Н или алкил,
а также фармацевтически допустимые соли и пролекарства этого соединения.
33. Соединение по п.1, которое представлено структурой
Figure 00000455
где R представляет собой –СО2СН3,
а также фармацевтически допустимые соли и пролекарства этого соединения.
34. Соединение по п.1, которое представлено структурой
Figure 00000456
где R представляет собой -Н или -CO2Н;
R’ выбирают из группы, состоящей из -CHO, -CO2Н и
Figure 00000457
;
R” представляет собой -Н или алкил,
а также фармацевтически допустимые соли и пролекарства этого соединения.
35. Соединение по п.1, которое представлено структурой
Figure 00000458
где R выбирают из группы, состоящей из -CH(ОН)-CH2OH, -CHO, и -CH(ОН)-CH=СН2;
R’ представляет собой -Boc или -Н; и
R” представляет собой -Н или алкил,
а также фармацевтически допустимые соли и пролекарства этого соединения.
36. Соединение по любому из пп.22-27, 32, 34, 35, где указанный алкил представляет собой –СН3.
37. Соединение по п.1, которое представлено структурой
Figure 00000459
где R представляет собой
Figure 00000460
или
Figure 00000461
а также фармацевтически допустимые соли и пролекарства этого соединения.
38. Фармацевтический состав, который содержит по меньшей мере одно соединение по п.1.
39. Способ ингибирования сериновой протеазы у пациента, который включает назначение пациенту по меньшей мере одного соединения по п.1 в количестве, эффективном для ингибирования сериновой протеазы.
40. Способ ингибирования каскада свертывания крови и предотвращения или ограничения свертываемости, который включает назначение пациенту эффективного количества по меньшей мере одного соединения по п.1.
41. Способ ингибирования образования эмболов и тромбов в кровеносных сосудах, который включает назначение пациенту эффективного количества по меньшей мере одного соединения по п.1.
42. Способ лечения по меньшей мере одного (болезненного) состояния, которое выбирают из группы, включающей тромболимфангит, тромбосинусит, тромбоэндокардит, тромобоангит и тромбоартерит, который включает назначение пациенту эффективного количества по меньшей мере одного соединения по п.1.
43. Способ ингибирования образования тромбов после пластической операции на сосудах, который включает назначение пациенту эффективного количества по меньшей мере одного соединения по п.1.
44. Способ предотвращения закупорки артерий как следствия тромболитической терапии, который включает назначение пациенту в эффективном количестве по меньшей мере одного соединения по п.1 совместно с эффективным количеством по меньшей мере одного другого противотромболитического агента.
45. Способ по п.44, где указанный другой противотромболитический агент выбирают из группы, которая включает тканевые активаторы плазминогена, стрептокиназу и урокиназу и их функциональные производные.
46. Способ лечения метастатических заболеваний, который включает назначение пациенту эффективного количества по меньшей мере одного соединения по п.1.
47. Способ по п.40 который дополнительно включает назначение другого антикоагулирующего агента указанному пациенту.
48. Способ по п.47, где указанный дополнительный антикоагулирующий агент выбирают из группы, включающей гепарин, аспирин и варфарин.
49. Способ лечения пациента, нуждающегося в назначении противовоспалительного агента, который включает назначение пациенту эффективного количества по меньшей мере одного соединения по п.1.
50. Способ ингибирования свертывания крови in vitro, который включает введение в контакт указанной крови и по меньшей мере одного соединения по п.1.
51. Способ по п.50, в котором ингибируют свертывание крови в пробирке.
52. Экстраарпереальное устройство, которое имеет внутри себя покрытие, содержащее соединение по п.1.
53. Способ определения предполагаемого присутствия сериновой протеазы, который включает введение в контакт образца и соединения по п.1.
54. Соединение по п.1, которое представлено структурой
Figure 00000462
где R представляет собой алкил, a R’ выбирают из группы, состоящей из
Figure 00000463
,
Figure 00000464
,
Figure 00000465
,
Figure 00000466
,
Figure 00000467
,
Figure 00000468
,
Figure 00000469
,
Figure 00000470
,
Figure 00000471
,
Figure 00000472
,
Figure 00000473
,
Figure 00000474
,
Figure 00000475
,
Figure 00000476
,
Figure 00000477
,
Figure 00000478
,
Figure 00000479
,
Figure 00000480
,
Figure 00000481
,
Figure 00000482
,
Figure 00000483
,
Figure 00000484
,
Figure 00000485
,
Figure 00000486
,
Figure 00000487
,
Figure 00000488
, ,
Figure 00000490
,
Figure 00000491
, и
Figure 00000492
; или
Figure 00000493
или
Figure 00000494
,
а также фармацевтически допустимые соли и пролекарства этого соединения.
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US6699994B1 (en) 2004-03-02
JP2004523481A (ja) 2004-08-05
IL155202A (en) 2013-05-30
IL222773B (en) 2018-02-28
EP1383731A4 (en) 2005-09-28
US20040162281A1 (en) 2004-08-19
IL222773A0 (en) 2012-12-31
EP1383731A1 (en) 2004-01-28
US6936719B2 (en) 2005-08-30
CY1110527T1 (el) 2015-04-29
PT1383731E (pt) 2009-11-03
DE60139510D1 (de) 2009-09-17
ATE438615T1 (de) 2009-08-15

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