RU2447060C2 - Ингибиторы сфингозинкиназы - Google Patents

Ингибиторы сфингозинкиназы Download PDF

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RU2447060C2
RU2447060C2 RU2008100606/04A RU2008100606A RU2447060C2 RU 2447060 C2 RU2447060 C2 RU 2447060C2 RU 2008100606/04 A RU2008100606/04 A RU 2008100606/04A RU 2008100606 A RU2008100606 A RU 2008100606A RU 2447060 C2 RU2447060 C2 RU 2447060C2
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chlorophenyl
carboxylic acid
adamantane
ethyl
adamantan
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RU2008100606/04A
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RU2008100606A (ru
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Чарльз Д. СМИТ (US)
Чарльз Д. СМИТ
Кевин Дж. ФРЕНЧ (US)
Кевин Дж. ФРЕНЧ
Ян ЖУАНГ (US)
Ян ЖУАНГ
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Эпоуджи Биотекнолоджи Корпорейшн
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Abstract

Настоящее изобретение к новым соединениям формулы I или их фармацевтически приемлемым солям, обладающим способностью ингибировать сфингозинкиназу, к фармацевтической композиции на их основе, к способу ингибирования сфингозинкиназы и к способу лечения заболеваний, выбранных из рака молочной железы, диабетической ретинопатии, артрита и колита.
Figure 00000108
,
где X представляет собой -C(R3,R4)N(R5)-, -C(O)N(R4)-; R1 представляет собой фенил, незамещенный или замещенный 1 или 2 галогенами. Значения заместителей R2, R3, R4, R5 такие, как указаны в формуле изобретения. 4 н. и 13 з.п. ф-лы, 9 табл., 18 ил., 26 пр.

Description

Текст описания приведен в факсимильном виде.
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Claims (17)

1. Соединение формулы I
Figure 00000108

или его фармацевтически приемлемая соль, где
X представляет собой -C(R3,R4)N(R5)-, -C(O)N(R4)-;
R1 представляет собой фенил, незамещенный или замещенный 1 или 2 галогенами;
R2 представляет собой (С3-С6)циклоалкил, фенил, (С1-С6)алкилфенил, (С2-С6)алкенилфенил, (С2-С6)алкенилнафтил, гетероарил, выбранный из бензооксазолила, бензотиазолила, индолила, тетразолила, карбазолила и пуринила, (С1-С6)алкилгетероарила, где гетероарил выбран из бензодиоксолила, пиридила, имидазолила, карбазолила и тиенила, 6-членный гетероциклоалкил, содержащий 1 или 2 атома азота в качестве гетероатомов, (С1-С6)алкилгетероциклоалкил, где гетероциклоалкил представляет собой 5-членный гетероциклоалкил, содержащий 1 атом азота, в качестве гетероатома, который необязательно замещен оксогруппой, или 6-членный гетероциклоалкил, содержащий 2 гетероатома, выбранных из азота и кислорода, -моно(С1-С6)алкиламино(С1-С6)алкил, -(С1-С6)алкил-S-(С1-С6)алкил, -тиазолилфенил, -тиенилфенил, (С2-С6)алкенилгетероарил, где гетероарил выбран из пиридила, имидазолила и карбазолила, или (С2-С6)алкенилтиенилфенил;
R3 представляет собой Н или (С1-С6)алкил;
где алкил и кольцевая часть каждой из указанных выше R2 групп является необязательно замещенной вплоть до 5 группами, которые независимо представляют собой (С1-С6)алкил, галоген, галоген(С1-С6)алкил, -ОС(O)(С1-С6алкил), -С(O)O(С1-С6алкил), -CF3, -OCF3, -ОН, (С1-С6)алкокси, гидрокси(С1-С6)алкил, -CN, -S-(С1-С6)алкил, -SO2R′ или NR′R″, и где каждая алкильная часть заместителя является дополнительно необязательно замещенной 1, 2 или 3 группами, независимо выбранными из CN, ОН, NH2; и
R4 и R5 независимо представляют собой Н или (С1-С6)алкил,
где R′ и R″ независимо представляют собой Н или (С1-С6)алкил,
2. Соединение по п.1, где R2 представляет собой (С2-С6)алкенилфенил, (С2-С6)алкенилнафтил, (С2-С6)алкенилгетероарил, где гетероарил выбран из пиридила, имидазолила и карбазолила, или -(С2-С6)алкенилтиенилфенил.
3. Соединение по п.1, где R2 представляет собой (С2-С6)алкенилфенил или (С2-С6)алкенилнафтил.
4. Соединение по п.3, где арильная часть (С2-С6)алкенилфенила или (С2-С6)алкенилнафтила необязательно замещена 1 или 2 галогенами, циано или гидрокси.
5. Соединение по п.1, где R2 представляет собой (С3-С6)циклоалкил, фенил, (С1-С6)алкилфенил, гетероарил, выбранный из бензооксазолила, бензотиазолила, индолила, тетразолила, карбазолила и пуринила, (С1-С6)алкилгетероарил, где гетероарил выбран из бензодиоксолила, пиридила, имидазолила, карбазолила и тиенила.
6. Соединение по п.1, где R2 представляет собой фенил или (С1-С6)алкилфенил.
7. Соединение по п.1, где R2 представляет собой гетероарил или (С1-С6)алкилгетероарил.
8. Соединение по п.6 или 7, где арил или гетероарил возможно замещены 1, 2, 3, 4 или 5 группами, независимо выбранными из галогена, гидрокси, алкила, цианоалкила, аминоалкила, трифторметила и алкокси.
9. Соединение по любому из пп.1-8, где X представляет собой -C(R3,R4)N(R5)-.
10. Соединение по п.9, где R3 представляет собой метил и R4 представляет собой Н.
11. Соединение по п.9, где R5 представляет собой Н.
12. Соединение по любому из пп.1-8, где X представляет собой -C(O)N(R4)-.
13. Соединение по п.9, где R4 представляет собой Н.
14. Соединение по п.1, которое представляет собой:
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты циклопропиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (2-этилсульфанилэтил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты фениламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (4-гидроксифенил)-амид;
Уксусной кислоты 4-{[3-(4-хлорфенил)-адамантан-1-карбонил]-амино}-фениловый эфир;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (2,4-дигидроксифенил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (3-гидроксиметил-фенил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (4-цианометил-фенил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты бензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 4-трет-бутилбензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 4-метилсульфанилбензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 3-трифторметилбензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 4-трифторметилбензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 3,5-бис-трифторметилбензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 3-фтор-5-трифторметилбензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 2-фтор-4-трифторметилбензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 3,5-дифторбензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 3,4-дифторбензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 3,4,5-трифторбензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 3-хлор-4-фторбензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 4-фтор-3-трифторметилбензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 2-хлор-4-фторбензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 4-хлор-3-трифторметилбензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 3-аминометил-2,4,5,6-тетрахлорбензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты [1-(4-хлорфенил)-этил]-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты [1-(4-бромфенил)-этил]-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 4-метансульфонилбензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 4-диметиламинобензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 4-трифторметоксибензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 3-трифторметоксибензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты 3,4-дигидроксибензиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты фенэтиламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты [2-(4-фторфенил)-этил]-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты [2-(4-бромфенил)-этил]-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты [2-(4-гидроксифенил)-этил]-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты [2-(4-метоксифенил)-этил]-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты [2-(3-бром-4-метоксифенил)-этил]-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты [2-(3,4-дигидроксифенил)-этил]-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (2-бензо[1,3]диоксол-5-илэтил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (3-фенилпропил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (1-метилпиперидин-4-ил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (4-метилпиперазин-1-ил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (3-трет-бутиламинопропил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (3-пирролидин-1-илпропил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты [3-(2-оксопирролидин-1-ил)-пропил]-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты [2-(1-метилпирролидин-2-ил)-этил]-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (2-морфолин-4-илэтил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (2-пиперазин-1-илэтил)-амид;
3-(4-Фторфенил)-адамантан-1-карбоновой кислоты (пиридин-4-илметил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (пиридин-4-илметил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (2-пиридин-4-илэтил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (3-имидазол-1-илпропил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (2-метил-1Н-индол-5-ил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (1Н-тетразол-5-ил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (9-этил-9Н-карбазол-3-ил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты [4-(4-хлорфенил)-тиазол-2-ил]-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты бензотиазол-2-иламид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (5-хлор-бензооксазол-2-ил)-амид;
3-(4-Хлорфенил)-адамантан-1-карбоновой кислоты (9Н-пурин-6-ил)-амид;
4-{[3-(4-Хлорфенил)-адамантан-1-илметил]-амино}-фенол;
[3-(4-Хлорфенил)-адамантан-1-илметил]-(4-трифторметилбензил)-амин;
[3-(4-Хлорфенил)-адамантан-1-илметил]-(2-фтор-4-трифторметилбензил)-амин;
[3-(4-Хлорфенил)-адамантан-1-илметил]-(4-фтор-3-трифторметилбензил)-амин;
[3-(4-Хлорфенил)-адамантан-1-илметил]-(4-трифторметоксибензил)-амин;
[3-(4-Хлорфенил)-адамантан-1-илметил]-(1-метилпиперидин-4-ил)-амин;
[3-(4-Хлорфенил)-адамантан-1-илметил]-(4-метилпиперазин-1-ил)-амин;
N-трет-Бутил-N′-[3-(4-хлорфенил)-адамантан-1-илметил]-пропан-1,3-диамин;
[3-(4-Хлорфенил)-адамантан-1-илметил]-(3-пирролидин-1-илпропил)-амин;
[3-(4-Хлорфенил)-адамантан-1-илметил]-[2-(1-метилпирролидин-2-ил)-этил]-амин;
[3-(4-Хлорфенил)-адамантан-1-илметил]-(2-морфолин-4-илэтил)-амин;
[3-(4-Хлорфенил)-адамантан-1-илметил]-пиридин-4-илметиламин;
[3-(4-Хлорфенил)-адамантан-1-илметил]-(9-этил-9Н-карбазол-3-ил)-амин;
[3-(4-Хлорфенил)-адамантан-1-илметил]-[5-(4-хлорфенил)-тиазол-2-ил]-амин;
Фенил-[1-(3-фениладамантан-1-ил)-этил]-амин;
{1-[3-(4-Фторфенил)-адамантан-1-ил]-этил}-фениламин;
{1-[3-(4-Хлорфенил)-адамантан-1-ил]-этил}-фениламин;
Бензил-{1-(3-фениладамантан-1-ил)-этил}-амин;
Бензил-{1-[3-(4-фторфенил)-адамантан-1-ил]-этил}-амин;
Бензил-{1-[3-(4-хлорфенил)-адамантан-1-ил]-этил}-амин;
(4-трет-Бутилбензил)-{1-[3-(4-хлорфенил)-адамантан-1-ил]-этил}-амин;
[1-(4-Бромфенил)-этил]-{1-[3-(4-хлорфенил)-адамантан-1-ил]-этил}-амин;
[2-(4-Бромфенил)-этил]-{1-[3-(4-хлорфенил)-адамантан-1-ил]-этил}-амин;
(1-Метилпиперидин-4-ил)-[1-(3-фениладамантан-1-ил)-этил]-амин;
{1-[3-(4-Фторфенил)-адамантан-1-ил]-этил}-(1-метилпиперидин-4-ил)-амин;
{1-[3-(4-Хлорфенил)-адамантан-1-ил]-этил}-(1-метилпиперидин-4-ил)-амин;
{1-[3-(4-Хлорфенил)-адамантан-1-ил]-этил}-(4-метилпиперазин-1-ил)-амин;
{1-[3-(Фенил)-адамантан-1-ил]-этил}-пиридин-4-илметиламин;
{1-[3-(4-Хлорфенил)-адамантан-1-ил]-этил}-(6-хлорпиридин-3-илметил)-амин;
{1-[3-(4-Хлорфенил)-адамантан-1-ил]-этил}-(2-пиридин-4-илэтил)-амин;
{1-[3-(4-Хлорфенил)-адамантан-1-ил]-этил}-(3Н-имидазол-4-илметил)-амин;
{1-[3-(4-Хлорфенил)-адамантан-1-ил]-этил}-(2-метил-1Н-индол-5-ил)-амин;
{1-[3-(4-Хлорфенил)-адамантан-1-ил]-этил}-(9-этил-9Н-карбазол-3-ил)-амин;
{1-[3-(4-Хлорфенил)-адамантан-1-ил]-этил}-(9-этил-9Н-карбазол-3-илметил)-амин;
(4-Бромтиофен-2-илметил)-{1-[3-(4-хлорфенил)-адамантан-1-ил]-этил}-амин;
или их фармацевтически приемлемые соли.
15. Фармацевтическая композиция, обладающая способностью ингибировать сфингозинкиназу, содержащая эффективное количество соединения по любому из п.1-14 или его фармацевтически приемлемой соли в комбинации с фармацевтически приемлемым носителем, средой или вспомогательным агентом.
16. Способ ингибирования сфингозинкиназы, включающий введение эффективного количества соединения по любому из пп.1-14 или его фармацевтически приемлемой соли или композиции по п.15.
17. Способ лечения заболевания, выбранного из рака молочной железы, диабетической ретинопатии, артрита и колита, включающий введение терапевтически эффективного количества соединения или соли по любому из пп.1-14 или композиции по п.15.
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