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RU2012114846A - Соединение глицина - Google Patents

Соединение глицина Download PDF

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Publication number
RU2012114846A
RU2012114846A RU2012114846/04A RU2012114846A RU2012114846A RU 2012114846 A RU2012114846 A RU 2012114846A RU 2012114846/04 A RU2012114846/04 A RU 2012114846/04A RU 2012114846 A RU2012114846 A RU 2012114846A RU 2012114846 A RU2012114846 A RU 2012114846A
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RU
Russia
Prior art keywords
substituted
lower alkyl
compound
pyrimidin
represent
Prior art date
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RU2012114846/04A
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English (en)
Inventor
Коусеи ЙОСИХАРА
Дайсуке СУЗУКИ
Сусуму ЯМАКИ
Юдзи КОГА
Норио СЕКИ
Дзиро ФУДЗИЯСУ
Масахиро НЕЯ
Original Assignee
Астеллас Фарма Инк.
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Application filed by Астеллас Фарма Инк. filed Critical Астеллас Фарма Инк.
Publication of RU2012114846A publication Critical patent/RU2012114846A/ru

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    • C07C237/40Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
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Abstract

1. Соединение, представленное формулой (I), или его соль:[Хим. 1](гдеRпредставляет собой H или низший алкил, который может быть замещен,Rпредставляет собой галоген,Rи Rявляются одинаковыми или отличаются друг от друга и представляют собой H или галоген,m равен 0, 1, 2, 3 или 4,Yи Yявляются одинаковыми или отличаются друг от друга и представляют собой N или CR,Rпредставляет собой H или галоген,X представляет собой H, галоген, Z-(CRR)-, RRN-SO- или низший алкенил, который может быть замещен,n равен 0 или 1,Rи Rявляются одинаковыми или отличаются друг от друга и представляют собой H, или Rи Rобъединены вместе с образованием оксо (=O),Rи Rявляются одинаковыми или отличаются друг от друга и представляют собой H или низший алкил,Z представляет собой RRN-, RO- или[Хим. 2]Rи Rявляются одинаковыми или отличаются друг от друга и представляют собой H, -C(=O)-R, -C(=O)-O-R, -C(=O)-NH, -C(=O)-NHR, -C(=O)-N(R), -SO-(низший алкил, который может быть замещен), -SO-(арил, который может быть замещен), низший алкил, который может быть замещен, или гетероциклическую группу, которая может быть замещена,Rявляются одинаковыми или отличаются друг от друга и представляют собой низший алкил, который может быть замещен, циклоалкил, который может быть замещен, или гетероциклическую группу, которая может быть замещена,Rпредставляет собой низший алкил, который может быть замещен, или гетероциклическую группу, которая может быть замещена,p равен 0, 1 или 2,q равен 1 или 2,E представляет собой CH или N,G представляет собой CRR, NR, O или SO,Rи Rявляются одинаковыми или отличаются друг от друга и представляют собой H, OH, NH, -C(=O)-R, -C(=O)-O-R, -C(=O)-NHR, -C(=O)-N(R), -SO-R, амино, который может быть замещен, или низший алкил, который может быть замещен, цикл

Claims (25)

1. Соединение, представленное формулой (I), или его соль:
[Хим. 1]
Figure 00000001
(где
R1 представляет собой H или низший алкил, который может быть замещен,
R2 представляет собой галоген,
R3 и R4 являются одинаковыми или отличаются друг от друга и представляют собой H или галоген,
m равен 0, 1, 2, 3 или 4,
Y1 и Y2 являются одинаковыми или отличаются друг от друга и представляют собой N или CRY,
RY представляет собой H или галоген,
X представляет собой H, галоген, Z-(CR11R12)n-, R13R14N-SO2- или низший алкенил, который может быть замещен,
n равен 0 или 1,
R11 и R12 являются одинаковыми или отличаются друг от друга и представляют собой H, или R11 и R12 объединены вместе с образованием оксо (=O),
R13 и R14 являются одинаковыми или отличаются друг от друга и представляют собой H или низший алкил,
Z представляет собой RZ1RZ2N-, RZ3O- или
[Хим. 2]
Figure 00000002
RZ1 и RZ2 являются одинаковыми или отличаются друг от друга и представляют собой H, -C(=O)-RZ11, -C(=O)-O-RZ11, -C(=O)-NH2, -C(=O)-NHRZ11, -C(=O)-N(RZ11)2, -SO2-(низший алкил, который может быть замещен), -SO2-(арил, который может быть замещен), низший алкил, который может быть замещен, или гетероциклическую группу, которая может быть замещена,
RZ11 являются одинаковыми или отличаются друг от друга и представляют собой низший алкил, который может быть замещен, циклоалкил, который может быть замещен, или гетероциклическую группу, которая может быть замещена,
RZ3 представляет собой низший алкил, который может быть замещен, или гетероциклическую группу, которая может быть замещена,
p равен 0, 1 или 2,
q равен 1 или 2,
E представляет собой CH или N,
G представляет собой CRG1RG2, NRG3, O или SO2,
RG1 и RG2 являются одинаковыми или отличаются друг от друга и представляют собой H, OH, NH2, -C(=O)-RG31, -C(=O)-O-RG31, -C(=O)-NHRG31, -C(=O)-N(RG31)2, -SO2-RG31, амино, который может быть замещен, или низший алкил, который может быть замещен, циклоалкил, который может быть замещен, арил, который может быть замещен, или гетероциклическую группу, которая может быть замещена,
RG3 представляет собой H, NH2, -C(=O)-RG31, -C(=O)-O-RG31, -C(=O)-NHRG31, -C(=O)-N(RG31)2, -SO2-RG31 или низший алкил, который может быть замещен, циклоалкил, который может быть замещен, арил, который может быть замещен, или гетероциклическую группу, которая может быть замещена,
RG31 являются одинаковыми или отличаются друг от друга и представляют собой низший алкил, который может быть замещен, циклоалкил, который может быть замещен, арил, который может быть замещен, или гетероциклическую группу, которая может быть замещена, и
R21, R22, R23, R24, R25 и R26 являются одинаковыми или отличаются друг от друга и представляют собой H, OH, галоген, NH2, амино, который может быть замещен, или низший алкил, который может быть замещен,
в котором RG1 или RG2 могут быть объединены либо с R21, либо с R22 с образованием новой связи, или
RG1, RG2, R21 и R22 могут быть объединены вместе с образованием азотсодержащей гетероциклической группы, которая может быть замещена, и
RG3, R21 и R22 могут быть объединены вместе с образованием азотсодержащей гетероциклической группы, которая может быть замещена).
2. Соединение или его соль по п.1, где Y1 и Y2 оба представляют собой CRY, и оба RY представляют собой H.
3. Соединение или его соль по п.1, где Y1 и Y2 оба представляют собой N.
4. Соединение или его соль по п.1, где Y1 представляет собой N, Y2 представляет собой CRY, и RY представляет собой H.
5. Соединение или его соль по п.1, где X представляет собой Z-(CR11R12)n-, n равен 0, и Z представляет собой
[Хим. 3]
Figure 00000003
6. Соединение или его соль по п.5, где E представляет собой N, G представляет собой CRG1RG2, O или SO2, p равен 1, и q равен 1 или 2.
7. Соединение или его соль по п.1, где X представляет собой Z-(CR11R12)n-, n равен 0, Z представляет собой
[Хим. 4]
Figure 00000004
G представляет собой O или SO2, и R21, R22, R23, R24, R25 и R26 являются одинаковыми или отличаются друг от друга и представляют собой H или низший алкил, который может быть замещен.
8. Соединение или его соль по п.7, где G представляет собой O или SO2, и R21, R22, R23, R24, R25 и R26 являются одинаковыми или отличаются друг от друга и представляют собой H, метил или гидроксиметил.
9. Соединение или его соль по п.1, где X представляет собой Z-(CR11R12)n-, n равен 0, и Z представляет собой
[Хим. 5]
Figure 00000005
10. Соединение или его соль по п.9, где RG1 и RG2 являются одинаковыми или отличаются друг от друга и представляют собой H, OH или гетероциклическую группу, которая может быть замещена,
R21, R22, R23, R24, R25 и R26 представляют собой H, или
RG1, RG2, R21 и R22 могут быть объединены вместе с образованием азотсодержащей гетероциклической группы, которая может быть замещена, и
RG1 или RG2 могут быть объединены либо с R21, либо с R22 с образованием новой связи.
11. Соединение или его соль по п.9, где RG1 и RG2 являются одинаковыми или отличаются друг от друга и представляют собой H, OH или пиридин или морфолин, которые могут быть замещены,
R21, R22, R23, R24, R25 и R26 представляют собой H или F, или
RG1, RG2, R21 и R22 могут быть объединены вместе с образованием пиридина или тиазола, которые могут быть замещены, и
RG1 или RG2 могут быть объединены либо с R21, либо с R22 с образованием новой связи.
12. Соединение или его соль по п.9, где RG1 и RG2 являются одинаковыми или отличаются друг от друга и представляют собой H, OH или пиридин-3-ил или морфолин-4-ил, или RG1, RG2, R21 и R22 объединены с атомами углерода, к которым они присоединены, с образованием
[Хим. 6]
Figure 00000006
или
R21, R22, R23, R24, R25 и R26 представляют собой H или F.
13. Соединение или его соль по п.5, где E представляет собой N, G представляет собой NRG3, p равен 1, и q равен 2.
14. Соединение или его соль по п.5, где Z представляет собой
[Хим. 7]
Figure 00000007
R21, R22, R23, R24, R25 и R26 представляют собой H, Y4 представляет собой N или CRY41, Y5 представляет собой N или CRY51, RY41, RY51 и RG32 представляют собой H, галоген, -OH, -O-низший алкил (в котором низший алкил может быть замещен 1-3 заместителями, представляющими собой OH, галоген, -O-низший алкил (в котором низший алкил может быть замещен одной или несколькими -COOH группами), или арильные группы), -CHO, -CO-низший алкил (в котором низший алкил может быть замещен 1-3 атомами галогена), -CO-циклоалкил (в котором циклоалкил может быть замещен одной или несколькими -O-низшими алкильными группами), -CO-арил, -CO-моноциклическая насыщенная гетероциклическая кольцевая группа, циано, -COOH, -COO-низший алкил (в котором низший алкил может быть замещен 1-3 атомами галогена), -NH2, NH(низший алкил), N(низший алкил)2 или низший алкил, который может быть замещен -COOH или -O-низшим алкилом (в котором низший алкил может быть замещен одной или несколькими -COOH группами), или низший алкенил, который может быть замещен -COOH или -O-низшим алкилом (в котором низший алкил может быть замещен одной или несколькими -COOH группами), и s равен 0, 1, 2 или 3.
15. Соединение или его соль по п.5, где Z представляет собой
[Хим. 8]
Figure 00000008
R21, R22, R23, R24, R25 и R26 представляют собой H, и
[Хим. 9]
Figure 00000009
представляет собой фенил, 4-аминофенил, 4-диметиламинофенил, 4-карбоксифенил, 4-карбокси-6-хлор-фенил, 4-метилфенил, 4-фторфенил, 4-хлорфенил, 2-фторфенил, 2-метилфенил, 2,4-дифторфенил, 2-метоксифенил, 3-метилпиридин-2-ил, 3-трифторметилпиридин-2-ил, 3-циано-6-метилпиридин-2-ил, 5-[(E)-2-карбоксивинил]-3-метилпиридин-2-ил, 5-карбокси-3-хлорпиридин-2-ил, 5-[(E)-2-карбоксивинил]-3-хлорпиридин-2-ил, 3-карбоксиметоксиметилпиридин-2-ил, 5-(2-карбоксиэтил)-3-метилпиридин-2-ил, 5-карбоксипиридин-2-ил, пиридин-2-ил, 5-этоксикарбонилпиридин-2-ил, 5-цианопиридин-2-ил, 3-цианопиридин-2-ил, 3-хлорпиридин-2-ил, 5-трифторметилпиридин-2-ил, 3-фторпиридин-2-ил, 5-фторпиридин-2-ил, 5-хлорпиридин-2-ил, 5-бромпиридин-2-ил, 3-метоксипиридин-2-ил, 3-гидроксиметилпиридин-2-ил, 5-метилпиридин-2-ил, 4-метилпиридин-2-ил, 5-карбокси-3-метилпиридин-2-ил, 6-метилпиридин-2-ил, 5-(2-карбоксиэтил)-3-гидроксиметилпиридин-2-ил, 5-[(E)-2-карбоксивинил]-3-гидроксиметилпиридин-2-ил, 5-[(E)-2-карбоксивинил]пиридин-2-ил, 5-(2-карбоксиэтил)пиридин-2-ил, 6-хлорпиридин-3-ил, 4-метилпиридин-3-ил, 5-этоксикарбонилпиридин-3-ил, 5-метилпиридин-3-ил, 2-метилпиридин-3-ил, пиридин-3-ил, 6-аминопиридин-3-ил, 5-хлорпиридин-3-ил, 5-карбоксипиридин-3-ил или 6-цианопиридин-3-ил, 6-хлорпиримидин-3-ил или пиримидин-3-ил.
16. Соединение или его соль по п.5, где R1 представляет собой низший алкил, который может быть замещен.
17. Соединение или его соль по п.1, где R3 и R4 представляют собой H.
18. Соединение или его соль по п.1, где m равен 0.
19. Соединение или его соль по п.1, которое представляет собой:
N-метил-N-[3-(2-морфолин-4-илпиримидин-5-ил)бензил]глицинамид,
N-метил-N-[3-(2-пирролидин-1-илпиримидин-5-ил)бензил]глицинамид,
N-(3-{2-[(2R,6S)-2,6-диметилморфолин-4-ил]пиримидин-5-ил}бензил)-N-метилглицинамид,
N-(3-{2-[2-(гидроксиметил)морфолин-4-ил]пиримидин-5-ил}бензил)-N-метилглицинамид,
N-(3-{6-[(2R,6S)-2,6-диметилморфолин-4-ил]пиридин-3-ил}бензил)-N-метилглицинамид,
N-{3-[2-(4-гидроксипиперидин-1-ил)пиримидин-5-ил]бензил}-N-метилглицинамид,
N-{3-[2-(1,1-диоксидотиоморфолин-4-ил)пиримидин-5-ил]бензил}-N-метилглицинамид,
N-метил-N-{3-[2-(4-морфолин-4-илпиперидин-1-ил)пиримидин-5-ил]бензил}глицинамид,
N-{3-[2-(3',6'-дигидро-3,4'-бипиридин-1'(2'H)-ил)пиримидин-5-ил]бензил}-N-метилглицинамид,
N-метил-N-{3-[2-(4-пиридин-3-илпиперидин-1-ил)пиримидин-5-ил]бензил}глицинамид,
N-метил-N-(3-{2-[4-(3-метилпиридин-2-ил)пиперазин-1-ил]пиримидин-5-ил}бензил)глицинамид,
(2E)-3-(6-{4-[5-(3-{[глицил(метил)амино]метил}фенил)пиримидин-2-ил]пиперазин-1-ил}-5-метилпиридин-3-ил)акриловую кислоту,
3-(6-{4-[5-(3-{[глицил(метил)амино]метил}фенил)пиримидин-2-ил]пиперазин-1-ил}-5-метилпиридин-3-ил)пропионовую кислоту,
5-хлор-6-{4-[5-(3-{глицил(метил)амино]метил}фенил)пиримидин-2-ил]пиперазин-1-ил}никотиновую кислоту,
(2E)-3-(5-хлор-6-{4-[5-(3-{[глицил(метил)амино]метил}фенил)пиримидин-2-ил]пиперазин-1-ил}пиридин-3-ил)акриловую кислоту,
3-хлор-4-{4-[5-(3-{[глицил(метил)амино]метил}фенил)пиримидин-2-ил]пиперазин-1-ил}бензойную кислоту,
N-(3-{2-[4-(6-цианопиридин-3-ил)пиперидин-1-ил]пиримидин-5-ил}бензил)-N-метилглицинамид,
N-метил-N-(3-{2-[4-(2-метилпиридин-3-ил)пиперидин-1-ил]пиримидин-5-ил}бензил)глицинамид,
N-(3-{2-[4-(3-хлорпиридин-2-ил)пиперазин-1-ил]пиримидин-5-ил}бензил)-N-метилглицинамид,
N-метил-N-{3-[2-(2-метил-6,7-дигидро[1,3]триазоло[5,4-c]пиридин-5(4H)-ил)пиримидин-5-ил]бензил}глицинамид,
N-{3-[2-(5,7-дигидро-6H-пирроло[3,4-b]пиридин-6-ил)пиримидин-5-ил]бензил}-N-метилглицинамид или
N-(3-{2-[(3S)-3-фторпирролидин-1-ил]пиримидин-5-ил}бензил)-N-метилглицинамид.
20. Фармацевтическая композиция, содержащая соединение или его соль по п.1 и фармацевтически приемлемый инертный наполнитель.
21. Фармацевтическая композиция для профилактики и/или лечения связанных с VAP-1 заболеваний, содержащая соединение или его соль по п.1.
22. Применение соединения или его соли по п.1 для получения фармацевтической композиции для профилактики и/или лечения связанных с VAP-1 заболеваний.
23. Применение соединения или его соли по п.1 для профилактики и/или лечения связанных с VAP-1 заболеваний.
24. Способ профилактики и/или лечения связанных с VAP-1 заболеваний, включающий введение пациенту эффективного количества соединения или его соли по п.1.
25. Соединение или его соль по п.1 для профилактики и/или лечения связанных с VAP-1 заболеваний.
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