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RU2500673C2 - Гетероциклические ингибиторы мек и способы их применения - Google Patents

Гетероциклические ингибиторы мек и способы их применения Download PDF

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RU2500673C2
RU2500673C2 RU2009118281/04A RU2009118281A RU2500673C2 RU 2500673 C2 RU2500673 C2 RU 2500673C2 RU 2009118281/04 A RU2009118281/04 A RU 2009118281/04A RU 2009118281 A RU2009118281 A RU 2009118281A RU 2500673 C2 RU2500673 C2 RU 2500673C2
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Russia
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carboxamide
oxo
fluoro
dihydropyridazin
dimethyl
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RU2009118281/04A
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RU2009118281A (ru
Inventor
Эллисон Л. МАРЛОУ
Эли УОЛЛЭС
Джеонгбеоб СЕО
Джозеф П. ЛИССИКАТОС
Хонг Вун ЯНГ
Джим БЛЕЙК
Ричард Энтони СТОРИ
Ребекка Джейн БУТ
Джон Дэвид ПИТТАМ
Джон ЛЕОНАРД
Марк Ричард ФИЛДИНГ
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Астразенека Аб
Эррэй Биофарма Инк.
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Application filed by Астразенека Аб, Эррэй Биофарма Инк. filed Critical Астразенека Аб
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Abstract

Изобретение раскрывает соединение, имеющее формулу I
Figure 00000157
или его фармацевтически приемлемую соль, где:
R1 представляет собой Cl или F; R3 представляет собой Н, Me, Et, ОН, МеО-, EtO-, HOCH2CH2O-, НОСН2С(Ме)2O-, (S)-MeCH(OH)CH2O-, (R)-НОСН2СН(ОН)CH2O-, циклопропил-CH2O-, НОСН2СН2-,
Figure 00000158
,
Figure 00000159
,
Figure 00000160
,
Figure 00000175
,
Figure 00000162
или
Figure 00000163
; R7 представляет собой циклопропил-СН2- или С1-С4алкил, где указанный алкил возможно замещен одним или более чем одним F; R8 представляет собой Br, I или SMe; и R9 представляет собой СН3, CH2F, CHF2, CF3, F или Cl. Также изобретение раскрывает применение указанного выше соединения в изготовлении лекарственного средства для лечения гиперпролиферативного расстройства или воспалительного состояния, а также фармацевтическую композицию, которая ингибирует МЕК. Технический результат: получены и описаны новые соединения, которые являются ингибиторами МЕК и которые могут быть полезны в лечении гиперпролиферативных заболеваний, таких как рак и воспаление, у млекопитающих и воспалительных состояний. 6 н. и 7 з.п. ф-лы, 25 пр., 8 табл., 15 ил.

Description

Текст описания приведен в факсимильном виде
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Figure 00000108
Figure 00000109
Figure 00000110
Figure 00000111
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Figure 00000114
Figure 00000115
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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
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Figure 00000151
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Figure 00000153
Figure 00000154
Figure 00000155
Figure 00000156

Claims (13)

1. Соединение, имеющее формулу I
Figure 00000157

или его фармацевтически приемлемая соль,
где R1 представляет собой Cl или F;
R3 представляет собой Н, Me, Et, ОН, МеО-, EtO-, HOCH2CH2O-, HOCH2C(Me)2O-, (S)-MeCH(OH)CH2O-, (R)-HOCH2CH(OH)CH2O-, циклопропил-СН2О-, НОСН2СН2-,
Figure 00000158
,
Figure 00000159
,
Figure 00000160
,
Figure 00000161
,
Figure 00000162
или
Figure 00000163
;
R7 представляет собой циклопропил-СН2- или С1-С4алкил, где указанный алкил возможно замещен одним или более чем одним F;
R8 представляет собой Br, I или SMe; и
R9 представляет собой СН3, CH2F, CHF2, CF3, F или Cl.
2. Соединение, имеющее формулу IA:
Figure 00000164

или его фармацевтически приемлемая соль,
где R1 представляет собой Cl или F;
R3 представляет собой Н, Me, ОН, МеО, EtO, HOCH2CH2O, MeOCH2CH2O, НОСН2СН2СН2,
Figure 00000165
,
Figure 00000166
,
Figure 00000167
,
Figure 00000168
,
Figure 00000169
,
Figure 00000170
или
Figure 00000171
;
R7 представляет собой циклопропил-СН2- или С1-С4алкил, где указанный алкил возможно замещен одним или более чем одним F;
R8 представляет собой Br, I или SMe; и
R9 представляет собой СН3, CH2F, CHF2, CF3, F или Cl.
3. Соединение по п.1 или 2, где R7 представляет собой циклопропил-СН2-или Me.
4. Соединение по п.1 или 2, где R9 представляет собой СН3, F или Cl.
5. Соединение, имеющее формулу II:
Figure 00000172

или его фармацевтически приемлемая соль, где:
R3 представляет собой Н, МеО, НОСН2СН2О, МеОСН2СН2О, HOCH2CH2CH2,
Figure 00000173
,
Figure 00000165
или
Figure 00000170
; и
R9 представляет собой Н, СН3, F или Cl.
6. Соединение по п.5 или его фармацевтически приемлемая соль, где соединение выбрано из:
4-(2-фтор-4-(метилтио)фениламино)-N-(2-гидроксиэтокси)-1-метил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
4-(2-фтор-4-(метилтио)фениламино)-N-(2-гидроксиэтокси)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
N-(циклопропилметокси)-4-(2-фтор-4-(метилтио)фениламино)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
4-(2-фтор-4-(метилтио)фениламино)-N-(2-метоксиэтокси)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
4-(2-фтор-4-(метилтио)фениламино)-N-метокси-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
(S)-4-(2-фтор-4-(метилтио)фениламино)-N-(2-гидроксипропокси)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
4-(2-фтор-4-(метилтио)фениламино)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
5-фтор-4-(2-фтор-4-(метилтио)фениламино)-N-(2-гидроксиэтокси)-1-метил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
(S)-5-фтор-4-(2-фтор-4-(метилтио)фениламино)-N-(2-гидроксипропокси)-1-метил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
5-хлор-4-(2-фтор-4-(метилтио)фениламино)-N-(2-гидроксиэтокси)-1-метил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
(S)-5-хлор-4-(2-фтор-4-(метилтио)фениламино)-N-(2-гидроксипропокси)-1-метил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
4-(2-фтор-4-(метилтио)фениламино)-N-(3-гидроксипропил)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида; и
(S)-N-(2,3-дигидроксипропил)-4-(2-фтор-4-(метилтио)фениламино)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида.
7. Соединение, имеющее формулу III:
Figure 00000174

или его фармацевтически приемлемая соль, где:
R1 представляет собой Cl или F;
R3 представляет собой Н, Me, MeO, НОСН2СН2О, HOCH2CH2CH2, НОСН2СН2,
Figure 00000165
,
Figure 00000166
,
Figure 00000167
,
Figure 00000168
,
Figure 00000169
,
Figure 00000170
или
Figure 00000171
;
R8 представляет собой Br или I; и R9 представляет собой СН3, F, Cl или Br.
8. Соединение по п.7, или его фармацевтически приемлемая соль, выбранное из:
5-бром-4-(4-бром-2-фторфениламино)-N-(циклопропилметокси)-1-метил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
4-(2-фтор-4-йодфениламино)-N-(2-гидроксиэтокси)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
(R)-N-(2,3-дигидроксипропокси)-4-(2-фтор-4-йодфениламино)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
4-(2-фтор-4-йодфениламино)-N-метокси-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
N-(циклопропилметокси)-4-(2-фтор-4-йодфениламино)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
(S)-4-(2-фтор-4-йодфениламино)-N-(2-гидроксипропокси)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
4-(2-хлор-4-йодфениламино)-N-(2-гидроксиэтокси)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
(S)-4-(2-хлор-4-йодфениламино)-N-(2-гидроксипропокси)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
4-(4-бром-2-хлорфениламино)-N-(2-гидроксиэтокси)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
(S)-4-(4-бром-2-хлорфениламино)-N-(2-гидроксипропокси)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
4-(4-бром-2-фторфениламино)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
(R)-4-(4-бром-2-фторфениламино)-N-(2,3-дигидроксипропокси)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
4-(4-бром-2-фторфениламино)-N-(1-гидрокси-2-метилпропан-2-илокси)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
4-(2-фтор-4-йодфениламино)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
4-(4-бром-2-фторфениламино)-5-фтор-N-(2-гидроксиэтокси)-1-метил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
4-(2-фтор-4-йодфениламино)-N,1,5-триметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
N-(циклопропилметил)-4-(2-фтор-4-йодфениламино)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
4-(2-фтор-4-йодфениламино)-N-(3-гидроксипропил)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
5-фтор-4-(2-фтор-4-йодфениламино)-N-(2-гидроксиэтокси)-1-метил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
4-(2-фтор-4-йодфениламино)-N-(2-гидроксиэтил)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
N-(2,3-дигидроксипропил)-4-(2-фтор-4-йодфениламино)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
5-хлор-4-(2-фтор-4-йодфениламино)-N-(2-гидроксиэтокси)-1-метил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
(S)-5-хлор-4-(2-фтор-4-йодфениламино)-N-(2-гидроксипропокси)-1-метил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
5-хлор-4-(2-фтор-4-йодфениламино)-1-метил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
5-хлор-N-(2,3-дигидроксипропил)-4-(2-фтор-4-йодфениламино)-1-метил-6-оксо-1,6-дигидропиридазин-3-карбоксамида;
(S)-N-(2,3-дигидроксипропил)-4-(2-фтор-4-йодфениламино)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида; и
(S)-5-хлор-N-(2,3-дигидроксипропил)-4-(2-фтор-4-йодфениламино)-1-метил-6-оксо-1,6-дигидропиридазин-3-карбоксамида.
9. Соединение по п.1 или 7 или его фармацевтически приемлемая соль,
где соединение выбрано из:
4-(4-бром-2-фторфениламино)-N-(2-гидроксиэтокси)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида; и
(S)-4-(4-бром-2-фторфениламино)-N-(2-гидроксипропокси)-1,5-диметил-6-оксо-1,6-дигидропиридазин-3-карбоксамида.
10. Соединение по любому из пп.1, 2, 5, 7 и 9 для применения в качестве лекарственного средства.
11. Соединение по любому из пп.1, 2, 5, 7 и 9 для применения в качестве лекарственного средства для лечения гиперпролиферативного расстройства или воспалительного состояния.
12. Применение соединения по любому из пп.1, 2, 5, 7 и 9 в изготовлении лекарственного средства для лечения гиперпролиферативного расстройства или воспалительного состояния.
13. Фармацевтическая композиция, которая ингибирует МЕК (киназа митоген-активируемых ERK (киназ, регулируемых внеклеточными сигналами)), содержащая соединение по любому из пп.1, 2, 5, 7 и 9 вместе с фармацевтически приемлемым носителем.
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KR20110074772A (ko) 2011-07-01
ATE447559T1 (de) 2009-11-15
AU2006299902B2 (en) 2012-11-01
UA100007C2 (ru) 2012-11-12
EP2361905B1 (en) 2013-03-06
TWI506020B (zh) 2015-11-01
CY1112297T1 (el) 2015-12-09
KR20110074908A (ko) 2011-07-04
ZA201203844B (en) 2014-02-26
ECSP078013A (es) 2008-04-28
DE602006010243D1 (de) 2009-12-17
WO2007044084A3 (en) 2009-04-16
MY149957A (en) 2013-11-15
IL187353A (en) 2013-02-28
EP2364973B1 (en) 2014-07-09
JP2013028637A (ja) 2013-02-07

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