RU2004130295A - Малые молекулы-ингибиторы проникновения - Google Patents

Малые молекулы-ингибиторы проникновения Download PDF

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RU2004130295A
RU2004130295A RU2004130295/04A RU2004130295A RU2004130295A RU 2004130295 A RU2004130295 A RU 2004130295A RU 2004130295/04 A RU2004130295/04 A RU 2004130295/04A RU 2004130295 A RU2004130295 A RU 2004130295A RU 2004130295 A RU2004130295 A RU 2004130295A
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alkanediyl
alkyl
compound according
cycloalkyl
amino
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RU2004130295/04A
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RU2395491C2 (ru
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БЕТЮН Мари-Пьер Т. М. М. Дж. ДЕ (BE)
Бетюн Мари-Пьер Т. М. М. Дж. Де
МЕЙЕР Сандра ДЕ (BE)
Мейер Сандра Де
Курт ХЕРТОГС (BE)
Курт Хертогс
Жун Цз нь ЛУ (US)
Жун Цзянь ЛУ
Ливе Эмма Ян МИХИЛС (BE)
Ливе Эмма Ян МИХИЛС
Абделла ТАХРИ (BE)
Абделла Тахри
Донг КСИЕ (US)
Донг КСИЕ
Майкл АЙСЕНСТАТ (US)
Майкл АЙСЕНСТАТ
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Тиботек Фармасьютикалз Лтд. (Ie)
Тиботек Фармасьютикалз Лтд.
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Claims (25)

1. Соединение, имеющее формулу (I)
Figure 00000001
его N-оксидная форма, стереохимический изомер, рацемическая смесь, соль, пролекарство, сложный эфир или метаболит,
в котором А представляет собой арил, гетероарил или гетероциклоалкил;
R1 представляет собой водород, галоген, гидрокси, амино, нитро, алкил, алкилокси или радикал формулы (II)
Figure 00000002
R2 представляет собой алкил, алкенил, алкинил, гидрокси, галоген, нитро, циано, амино, галогеналкил, циклоалкил, арил, гетероарил, гетероциклоалкил, R8-O-, R8-S-, R8-S(=O)2-, R8-C(=O)-, R8-C(=S)-, R8-C(=NH)-, R8-C(=NCN)-, R8-NH-, (R8)2-N-, HO-C(=O)-, NH2-C(=O)-, NH2-S(=O)2-, NH2-C(=S)-, NH2-C(=NH)-, NH2-C(=NCN)-, R8-NR4-C(=O)-, R8-NR4-S(=O)2-, R8-O-C(=O)-, R8-C(=O)-NR4-, R8-S(=O)2-NR4-, R8-C(=O)-O-, R8-S-CH2- или R8-O-CH2-C(=O)-;
R3 представляет собой гидрокси, амино, алкилокси, циклоалкилокси или моно- или дизамещенный амино, для которого заместители выбирают из алкила и циклоалкила;
R4 - представляет собой водород, алкил или циклоалкил;
R6 - представляет собой водород, амино, R7-C(=O)-, R8-S(=O)2-NH-, R8-C(=O)-NH-, R8-C(=S)-NH-, R8-C(=NH)-NH-, R8-C(=NCN)-NH-, R8-O-C(=O)-NH-, R8-O-алкандиил-C(=O)-NH-, R8-алкандиил-S(=O)2-NH-, арил-алкандиил-C(=O)-NH-, арил-алкендиил-C(=O)-NH-, гетероарил-алкандиил-C(=O)-NH-, циклоалкил-алкандиил-C(=O)-NH-, гетероциклоалкил-алкандиил-C(=O)-NH- или замещенный алкил, для которого заместители выбирают из амино, R7-C(=O)-, R8-S(=O)2-NH-, R8-C(=O)-NH-, R8-C(=S)-NH-, R8-C(=NH)-NH-, R8-C(=NCN)-NH-, R8-O-C(=O)-NH-, R8-O-алкандиил-C(=O)-NH-, R8-алкандиил-S(=O)2-NH-, арил-алкандиил-C(=O)-NH-, гетероарил-алкандиил-C(=O)-NH-, циклоалкил-алкандиил-C(=O)-NH- и гетероциклоалкил-алкандиил-C(=O)-NH-;
R7 представляет собой гидрокси, амино, алкилокси, циклоалкилокси или моно- или дизамещенный амино, где заместители могут быть выбраны из алкила и циклоалкила;
R8 представляет собой алкил, галогеналкил, циклоалкил, арил, гетероарил или гетероциклоалкил;
Y представляет собой алкандиил, -C(=O)-, -C(=S)-, -C(=NH)-, -C(=NCN)-, -S(=O)-, -S(=O)2-, -C(=O)-CH2-O-, -C(=O)-O-, -C(=O)-(CH2)p-, -C(=O)-NH-, или алкендиил-C(=O)-;
X означает прямую связь, -O-, -S-, -S(=O)2-, -O-S(=O)2-,
-S(=O)2-O-, -NH-S(=O)2-, -S(=O)2-NH-, -C(=O)-, -C(=S)-, -C(=NH)-, -C(=NCN)-, -O-C(=O)-, -C(=O)-O-, -NH-C(=O)-, -C(=O)-NH- или алкандиил;
m и n, каждый независимо, означает нуль, единицу или два;
p равно целому числу от 1 до 4;
2. Соединение формулы (III)
Figure 00000003
его N-оксидная форма, стереохимический изомер, рацемическая смесь, соль, пролекарство, сложный эфир или метаболит, в которых
R1 представляет собой галоген, водород или радикал формулы (II)
Figure 00000002
R2 представляет собой алкил, алкенил, алкинил, гидрокси, галоген, нитро, циано, амино, галогеналкил, циклоалкил, арил, гетероарил, гетероциклоалкил, R8-O-, R8-S-, R8-S(=O)2-, R8-C(=O)-, R8-C(=S)-, R8-C(=NH)-, R8-C(=NCN)-, R8-NH-, (R8)2-N-, HO-C(=O)-, NH2-C(=O)-, NH2-S(=O)2-, NH2-C(=S)-, NH2-C(=NH)-, NH2-C(=NCN)-, R8-NR4-C(=O)-, R8-NR4-S(=O)2-, R8-O-C(=O)-, R8-C(=O)-NR4-, R8-S(=O)2-NR4- или R8-C(=O)-O-;
R3 представляет собой гидрокси, амино, алкилокси, циклоалкилокси или моно- или дизамещенный амино, где заместители могут быть выбраны из алкила и циклоалкила;
R4 - представляет собой водород, алкил или циклоалкил;
R6 - представляет собой водород, амино, R7-C(=O)-, R8-S(=O)2-NH-, R8-C(=O)-NH-, R8-C(=S)-NH-, R8-C(=NH)-NH-, R8-C(=NCN)-NH-, R8-O-C(=O)-NH-, R8-O-алкандиил-C(=O)-NH-, R8-алкандиил-S(=O)2-NH-, арил-алкандиил-C(=O)-NH-, гетероарил-алкандиил-C(=O)-NH-, циклоалкил-алкандиил-C(=O)-NH-, гетероциклоалкил-алкандиил-C(=O)-NH- или замещенный алкил, где заместители могут быть выбраны из амино, R7-C(=O)-, R8-S(=O)2-NH-, R8-C(=O)-NH-, R8-C(=S)-NH-, R8-C(=NH)-NH-, R8-C(=NCN)-NH-, R8-O-C(=O)-NH-, R8-O-алкандиил-C(=O)-NH-, R8-алкандиил-S(=O)2-NH-, арил-алкандиил-C(=O)-NH-, гетероарил-алкандиил-C(=O)-NH-, циклоалкил-алкандиил-C(=O)-NH- и гетероциклоалкил-алкандиил-C(=O)-NH-;
R7 представляет собой гидрокси, амино, алкилокси, циклоалкилокси или моно- или дизамещенный амино, где заместители могут быть выбраны из алкила и циклоалкила;
R8 представляет собой алкил, циклоалкил, арил, гетероарил или гетероциклоалкил;
Y представляет собой алкандиил, -C(=O)-, -C(=S)-, -C(=NH)-, -C(=NCN)-, -S(=O)-, -S(=O)2-, -C(=O)-CH2-O-, -C(=O)-O-, -C(=O)-(CH2)p-;
X означает прямую связь, -O-, -S-, -S(=O)2-, -O-S(=O)2-, -S(=O)2-O-, -NH-S(=O)2-, -S(=O)2-NH-, -C(=O)-, -C(=S)-, -C(=NH)-, -C(=NCN)-, -O-C(=O)-, -C(=O)-O-, -NH-C(=O)-, -C(=O)-NH- или алкандиил;
m и n, каждый независимо, означает нуль, единицу или два;
p равно целому числу от 1 до 4.
3. Соединение по п.1, где Y представляет собой -C(=O)-, -S(=O)2-.
4. Соединение по п.2, где Y представляет собой -C(=O)-, -S(=O)2-.
5. Соединение по п.1, где Х представляет собой -NH-S(=O)2, -S(=O)2-NH-, -NH-C(=O), -C(=O)-NH-.
6. Соединение по п.2, где Х представляет собой -NH-S(=O)2, -S(=O)2-NH-, -NH-C(=O), -C(=O)-NH-.
7. Соединение по п.1, где R2 представляет собой галоген, бром, хлор, алкил, алкилокси, галогеналкил, алкенил, алкинил, где указанные заместители находятся в мета- и пара- положении; и n равно 1.
8. Соединение по п.2, где R2 представляет собой галоген, бром, хлор, алкил, алкилокси, галогеналкил, алкенил, алкинил, где указанные заместители находятся в мета- и пара- положении; и n равно 1.
9. Соединение по п.1, где R1 является формулой (II)
Figure 00000002
R6 представляет собой R7-C(=O)-, R8-S(=O)2-NH-, R8-C(=O)-NH-, где указанные заместители R6 являются соседними; в мета- и пара-положении или в орто- и мета- положении;
m равно 2,
R7 представляет собой гидрокси, алкокси;
R8 представляет собой арил, замещенный одним галогеном, бромом, хлором, алкилом, алкилокси, галогеналкилом, алкенилом, алкинилом, где указанные заместители находятся в мета- или пара-положении.
10. Соединение по п.2, где R1 является формулой (II)
Figure 00000002
R6 представляет собой R7-С(=O)-, R8-S(=O)2-NH-, R8-C(=O)-NH-, где указанные заместители R6 являются соседними; в мета- и пара-положении или в орто- и мета- положении;
m равно 2;
R7 представляет собой гидрокси, алкокси;
R8 представляет собой арил, замещенный одним галогеном, бромом, хлором, алкилом, алкилокси, галогеналкилом, алкенилом, алкинилом, где указанные заместители находятся в мета- или пара-положении.
11. Соединение по п.1, где соединение является мономером.
12. Соединение по п.9, где соединение является мономером.
13. Соединение по п.10, где соединение является мономером.
14. Соединение по п.1, где соединение является димером.
15. Соединение по п.9, где соединение является димером.
16. Соединение по п.10, где соединение является димером.
17. Соединение по п.1 для применения в виде лекарственного средства.
18. Соединение по п.15 для применения в виде лекарственного средства.
19. Соединение по п.16 для применения в виде лекарственного средства.
20. Применение соединения по п.1 для производства лекарственного средства, способного ингибировать процесс проникновения вируса ВИЧ в клетки млекопитающего-хозяина.
21. Применение соединения по п.15 для производства лекарственного средства, способного ингибировать процесс проникновения вируса ВИЧ в клетки млекопитающего-хозяина.
22. Применение соединения по п.16 для производства лекарственного средства, способного ингибировать процесс проникновения вируса ВИЧ в клетки млекопитающего-хозяина.
23. Фармацевтическая композиция, содержащая терапевтически эффективное количество активного ингредиента по п.1 и один или более фармацевтически приемлемых носителей.
24. Фармацевтическая композиция, содержащая терапевтически эффективное количество активного ингредиента по п.15 и один или более фармацевтически приемлемых носителей.
25. Фармацевтическая композиция, содержащая терапевтически эффективное количество активного ингредиента по п.16 и один или более фармацевтически приемлемых носителей.
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