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RU2003127731A - Ингибиторы металлопротеиназ - Google Patents

Ингибиторы металлопротеиназ Download PDF

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RU2003127731A
RU2003127731A RU2003127731/04A RU2003127731A RU2003127731A RU 2003127731 A RU2003127731 A RU 2003127731A RU 2003127731/04 A RU2003127731/04 A RU 2003127731/04A RU 2003127731 A RU2003127731 A RU 2003127731A RU 2003127731 A RU2003127731 A RU 2003127731A
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alkyl
pharmaceutically acceptable
aryl
heteroaryl
acceptable salt
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Матти ЛЕПИСТЕ (SE)
Матти ЛЕПИСТЕ
АФ РОЗЕНСКЕЛЬД Магнус МУНК (SE)
АФ РОЗЕНСКЕЛЬД Магнус МУНК
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Астразенека Аб (Se)
Астразенека Аб
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Claims (12)

1. Соединение формулы I или его фармацевтически приемлемая соль или in vivo гидролизуемый эфир
Figure 00000001
где X выбран из NR1, О, S;
Y1 и Y2 независимо выбраны из О, S;
Z выбран из NR2, О, S;
m равно 0 или 1;
А выбран из прямой связи, (С1-6)алкила, (С1-6)алкенила, (С1-6)галогеноалкила или (С1-6)гетероалкила, содержащего гетерогруппу, выбранную из N, О, S, SO, SO2, или содержащего две гетерогруппы, выбранные из N, О, S, SO, SO2 и разделенные по меньшей мере двумя атомами углерода;
R1 выбран из Н, алкила, галогеноалкила;
R2 выбран из Н, алкила, галогеноалкила;
R3 и R6 независимо выбраны из Н, галогена (предпочтительно F), алкила, галогеноалкила, алкоксиалкила, гетероалкила, циклоалкила, арила, алкиларила, гетероалкил-арила, гетероарила, алкилгетероарила, гетероалкил-гетероарила, арилалкила, арил-гетероалкила, гетероарил-алкила, гетероарил-гетероалкила, бисарила, арил-гетероарила, гетероарил-арила, бисгетероарила, циклоалкила или гетероциклоалкила, содержащих от 3 до 7 кольцевых атомов, где алкильный, гетероалкильный, арильный, гетероарильный, циклоалкильный или гетероциклоалкильный радикалы могут быть возможно замещены одной или более чем одной группой, независимо выбранной из гидрокси, алкила, гетероалкила, циклоалкила, арила, гетероарила, галогено, галогеноалкила, гидроксиалкила, алкокси, алкоксиалкила, галогеноалкокси, галогеноалкоксиалкила, карбокси, карбоксиалкила, алкилкарбокси, амино, N-алкиламино, N,N-диалкиламино, алкиламино, алкил(N-алкил)амино, алкил(N,N-диалкил)амино, амидо, N-алкиламидо, N,N-диалкиламидо, алкиламидо, алкил(N-алкил)амидо, алкил(N,N-диалкил)амидо, тиола, сульфона, сульфонамино, алкилсульфонамино, арилсульфонамино, сульфонамидо, галогеноалкилсульфона, алкилтио, арилтио, алкилсульфона, арилсульфона, аминосульфона, N-алкиламиносульфона, N,N-диалкиламиносульфона, алкиламиносульфона, ариламиносульфона, циано, алкилциано, гуанидино, N-циано-гуанидино, тиогуанидино, амидино, N-аминосульфон-амидино, нитро, алкилнитро, 2-нитро-этен-1,1-диамина;
R4 выбран из Н, алкила, гидроксиалкила, галогеноалкила, алкоксиалкила, галогеноалкокси, аминоалкила, амидоалкила, тиоалкила;
R5 представляет собой моноциклическую группу, содержащую от 3 до 7 кольцевых атомов, независимо выбранную из циклоалкила, арила, гетероциклоалкила или гетероарила, возможно замещенную одним или более чем одним заместителем, независимо выбранным из галогена, гидрокси, галогеноалкокси, амино, N-алкиламино, N,N-диалкиламино, циано, нитро, алкила, алкокси, алкилсульфона, галогеноалкилсульфона, карбонила, карбокси, где любой алкильный радикал в пределах любого заместителя сам может быть возможно замещен одной или более чем одной группой, независимо выбранной из галогена, гидрокси, амино, N-алкиламино, N,N-диалкиламино, алкилсульфонамино, алкилкарбоксиамино, циано, нитро, тиола, алкилтиола, алкилсульфоно, алкиламиносульфоно, алкилкарбоксилата, амидо, N-алкиламидо, N,N-диалкиламидо, алкокси, галогеноалкокси, карбонила, карбокси;
при условии, что:
когда X представляет собой NR1, R1 представляет собой Н, Y1 представляет собой О, Y2 представляет собой О, Z представляет собой О, m равно О, А представляет собой прямую связь, R3 представляет собой Н, R4 представляет собой Н, и R6 представляет собой Н, тогда R5 не представляет собой фенил, нитрофенил, гидроксифенил, алкоксифенил или пиридин;
когда X представляет собой NR1, R1 представляет собой Н или метил, Y1 представляет собой О, Y2 представляет собой О, Z представляет собой О, m равно О, А представляет собой прямую связь, R3 представляет собой Н, R4 представляет собой Н, и R6 представляет собой фенил, тогда R5 не представляет собой фенил,
когда X представляет собой NR1, R1 представляет собой Н, Y1 представляет собой О, Y2 представляет собой О, Z представляет собой О, m равно О, А представляет собой прямую связь, R3 представляет собой фенил, R4 представляет собой Н, и R6 представляет собой Н, тогда R5 не представляет собой фенил;
когда X представляет собой S, по меньшей мере один из Y1 и Y2 представляет собой О, m равно О, А представляет собой прямую связь, R3 представляет собой Н или метил, R6 представляет собой Н или метил, тогда R5 не представляет собой фенил, пиридин, пиррол, тиофен или фуран;
когда X представляет собой О, Y1 представляет собой О, Y2 представляет собой О, Z представляет собой О, m равно О, А представляет собой прямую связь, R3 представляет собой метилхлорид, R4 представляет собой Н, и R6 представляет собой Н, тогда R5 не представляет собой фенил.
2. Соединение формулы I по п.1 или его фармацевтически приемлемая соль или in vivo гидролизуемый эфир, где X представляет собой NR1, R1 представляет собой Н или (С1-3)алкил, по меньшей мере один из Y1 и Y2 представляет собой О, Z представляет собой О; m равно 0, и А представляет собой прямую связь.
3. Соединение по п.1 или 2 или его фармацевтически приемлемая соль или in vivo гидролизуемый эфир, где R3 представляет собой Н, алкил или галогеноалкил, R4 представляет собой Н, алкил или галогеноалкил.
4. Соединение по любому из пп.1-3 или его фармацевтически приемлемая соль или in vivo гидролизуемый эфир, где R5 представляет собой возможно замещенное 5- или 6-членное кольцо, независимо выбранное из циклоалкила, арила, гетероциклоалкила или гетероарила.
5. Соединение по любому из пп.1-4 или его фармацевтически приемлемая соль или in vivo гидролизуемый эфир, где R6 представляет собой Н, алкил, гидроксиалкил, аминоалкил, циклоалкил-алкил, алкил-циклоалкил, арилалкил, алкиларил, гетероалкил, гетероциклоалкил-алкил, алкил-гетероциклоалкил, гетероарил-алкил или гетероалкил-арил.
6. Соединение формулы II или его фармацевтически приемлемая соль или in vivo гидролизуемый эфир,
Figure 00000002
где Ar представляет собой 5- или 6-членную арильную или гетероарильную группу, возможно замещенную одним или двумя заместителями, выбранными из галогена, амино, нитро, (С1-6)алкила, (С1-6)алкокси или (С1-6)галогеноалкокси;
R6 выбран из Н, арила или (С1-6)алкила, и R6 возможно замещен группой, выбранной из гидрокси, тиоалкила, фенила, галогенофенила, пиридила или карбамата.
7. Соединение формулы II по п.6 или его фармацевтически приемлемая соль или in vivo гидролизуемый эфир, где Ar представляет собой фенил или замещенный фенил, либо Ar представляет собой 5-членное гетероарильное кольцо, содержащее два гетероатома, независимо выбранных из О и N.
8. Соединение формулы II по п.6 или 7 или его фармацевтически приемлемая соль или in vivo гидролизуемый эфир, где R6 представляет собой фенил, фенил, замещенный галогеном, метиленпиридин или (С1-3)алкил, возможно замещенный гидрокси, тиометилом или бензилкарбаматом.
9. Фармацевтическая композиция, содержащая соединение формулы I по п.1 или его фармацевтически приемлемую соль или in vivo гидролизуемый эфир и фармацевтически приемлемый носитель.
10. Фармацевтическая композиция, содержащая соединение формулы II по п.6 или его фармацевтически приемлемую соль или in vivo гидролизуемый эфир и фармацевтически приемлемый носитель.
11. Способ лечения опосредованного металлопротеиназой заболевания или состояния, при котором теплокровному животному вводят терапевтически эффективное количество соединения формулы I или формулы II или его фармацевтически приемлемой соли или in vivo гидролизуемого эфира.
12. Применение соединения формулы I или формулы II или его фармацевтически приемлемой соли или in vivo гидролизуемого предшественника в изготовлении лекарства для применения при лечении заболевания или состояния, опосредованного одним или более чем одним ферментом металлопротеиназой.
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WO2002074749A1 (en) 2002-09-26
RU2293730C2 (ru) 2007-02-20
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US20040116486A1 (en) 2004-06-17
NZ528141A (en) 2005-05-27
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JP2004523582A (ja) 2004-08-05

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