RU2017139564A - 5-ароматическое алкинилзамещенное бензамидное соединение и способ его получения, фармацевтическая композиция и их применение - Google Patents

5-ароматическое алкинилзамещенное бензамидное соединение и способ его получения, фармацевтическая композиция и их применение Download PDF

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RU2017139564A
RU2017139564A RU2017139564A RU2017139564A RU2017139564A RU 2017139564 A RU2017139564 A RU 2017139564A RU 2017139564 A RU2017139564 A RU 2017139564A RU 2017139564 A RU2017139564 A RU 2017139564A RU 2017139564 A RU2017139564 A RU 2017139564A
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substituted
group
unsubstituted
halogen
alkyl
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RU2017139564A
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RU2695371C2 (ru
RU2017139564A3 (ru
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Хун Лю
Юй ЧЖОУ
Дон ЧЖАН
Цзянь ЛИ
Хуалян Цзян
Кайсянь ЧЭНЬ
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Шанхай Инститьют Оф Матириа Медика, Чайниз Экэдеми Оф Сайэнсиз
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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Claims (30)

1. 5-ароматическое алкинилзамещенное бензамидное соединение, включающее структуру, представленную общей формулой I, и рацемат, R-изомер, S-изомер, фармацевтически приемлемую соль, или их смесь:
Figure 00000001
X - это СН или N;
R1 выбран из следующей группы: водород, галоген, С1-С6-алкил, галогензамещенный С1-С6-алкил, циано;
R2 и R3 каждый независимо выбран из группы, включающей водород, замещенный или незамещенный фенил, замещенный или незамещенный 3-7-членный гетероарил, замещенный или незамещенный 5-7-членный арилметилен, 3-7-членный гетероциклилметилен, при этом каждый гетероциклил независимо содержит от 1 до 4 гетероатомов, выбранных из кислорода, серы и азота; и R2 и R3 не являются одновременно водородом; либо R2 и R3 вместе с присоединенным атомом азота образуют группу, выбранную из группы, состоящей из замещенного либо незамещенного 5-20-членного гетеро-спироциклического кольца или замещенного либо незамещенного 4-20-членного конденсированного гетероциклического кольца; где замещенное означает один или несколько атомов водорода в группе, замещенные заместителями, выбранными из группы, включающей галоген, С1-С6-алкил, галогензамещенный С1-С6-алкил, С1-С6-алкокси, С1-С6-алкоксикарбонил, галогензамещенный С1-С6-алкокси, С2-С6-алкенил, С2-С6-алкинил, С3-С8-циклоалкил, циано, нитро, амино, гидрокси, гидроксиметил, карбокси, меркапто, сульфонил, С6-С10-арил и 3-12-членный гетероциклил; где гетероспироциклическое кольцо, конденсированное гетероциклическое кольцо или гетероциклил, каждый независимо, содержит от 1 до 4 гетероатомов, выбранных из кислорода, серы и азота;
Figure 00000002
кольцо выбрано из группы, состоящей из замещенного или незамещенного 5-6-членного ароматического гетероцикла, замещенного или незамещенного 6-20-членного гетероароматического конденсированного кольца, где заместитель представляет собой 1, 2, 3 или 4 заместителя, выбранных из группы, состоящей из галогена, С1-С6-алкил, галогензамещенный С1-С6-алкил, С1-С6-алкокси, галогензамещенный С1-С6-алкокси, С3-С8-циклоалкил, С3-С8-галогенированный циклоалкил, циано, нитро, амино (-NH2), амино (предпочтительно С1-С6-амино), гидрокси, гидроксиметил, карбокси, меркапто, сульфонил, С6-С10-арил и 3-12-членный гетероциклил, где ароматический гетероцикл, гетероароматическое конденсированное кольцо или гетероциклил, каждый независимо, содержит от 1 до 4 гетероатомов, выбранных из кислорода, серы и азота;
при этом, когда R1 является Н,
Figure 00000003
кольцо представляет собой замещенное или незамещенное 5-членное ароматическое гетероциклическое кольцо;
галоген представляет собой F, Cl, Br или I.
2. Соединение по п. 1, отличающееся тем, что R2 и R3 каждый независимо выбран из группы, состоящей из водорода, замещенного или незамещенного фенила, замещенного или незамещенного 3-7-членного гетероарила, замещенного или незамещенного 5-7-членного арилметилена, 3-7-членного гетероциклил-метилена, тогда как каждый гетероциклил независимо содержит от 1 до 4 гетероатомов, выбранных из кислорода, серы и азота; R2 и R3 представляют собой водород не одновременно;
либо R2 и R3 вместе с присоединенным атомом азота образуют группу, выбранную из группы, состоящей из замещенного или незамещенного гетеро-спироциклического кольца, замещенного или незамещенного конденсированного гетероциклического кольца; где замещенное означает один или несколько атомов водорода в группе, замещенные заместителями, выбранными из группы, состоящей из галогена, С1-С6 алкила, С1-С6 алкокси, галогензамещенного С1-С6 алкокси, циано, нитро, амино, гидрокси, гидроксиметил, карбокси, меркапто, сульфонила или трифторметила.
3. Соединение по п. 1, отличающееся тем, что
Figure 00000004
кольцо выбрано из группы, состоящей из
Figure 00000005
,
Figure 00000006
,
Figure 00000007
Figure 00000008
,
Figure 00000009
,
Figure 00000010
где R4, R5, R6, R7 и R8 каждый представляет 1-4 заместитель в гетерогруппе, и каждый заместитель независимо выбран из группы, состоящей из галогена, С1-С6-алкила, галогензамещенного С1-С6-алкила, С1-С6-алкокси, циано, нитро, амино, гидрокси.
4. Соединение по п. 1, отличающееся тем, что R2 выбран из группы, состоящей из замещенного или незамещенного фенила, замещенного или незамещенного пиридила, замещенного или незамещенного пиразинила; где указанное замещенное означает, что атом(ы) водорода замещен(ы) заместителем (заместителями), выбранным(ы) из группы, состоящей из галогена, С1-С6-алкила, галогензамещенного С1-С6-алкила, С1-С6-алкокси, циано, нитро, амино, гидрокси;
R3 является Н;
либо R2 и R3 вместе с присоединенным N-атомом образуют замещенную или незамещенную группу, выбранную из группы, состоящей из
Figure 00000011
Figure 00000012
,
Figure 00000013
,
Figure 00000014
,
где R9, R10, R11, R12 и R13 каждый представляет собой 1-4 заместителя при любом прообразе кольца, и каждый заместитель независимо выбран из группы, состоящей из галогена, С1-С6-алкила, галогензамещенного С1-С6-алкила, С1-С6 алкокси, циано, нитро, амино, гидрокси.
5. Соединение по п. 1, отличающееся тем, что
Figure 00000015
выбран из группы, состоящей из замещенного или незамещенного пиридила, замещенного или незамещенного тиазолила, замещенного или незамещенного изоксазолила, замещенного или незамещенного пиримидинила или замещенного или незамещенного индазолила; где заместитель выбран из группы, состоящей из галогена, С1-С6-алкила, галогензамещенного С1-С6-алкила, С1-С6-алкокси, циано, нитро, амино, гидрокси.
6. Соединение по п. 1, отличающееся тем, что соединение выбрано из следующей группы:
Figure 00000016
Figure 00000017
Figure 00000018
Figure 00000019
Figure 00000020
Figure 00000021
Figure 00000022
7. Фармацевтическая композиция, включающая:
(а) терапевтически эффективное количество 5-ароматического алкинилзамещенного бензамидного соединения формулы I или его фармацевтически приемлемую соль, рацемат, R-изомер, S-изомер или их комбинацию; и (ii) фармацевтически приемлемый носитель.
8. Отрицательный аллостерический модулятор mGluR5, содержащий компонент, выбранный из 5-ароматического алкинилзамещенного бензамидного соединения общей формулы I по п. 1, его фармацевтически приемлемой соли, рацемата, R-изомера, S-изомера или их комбинации.
9. Отрицательный аллостерический модулятор по п. 8, отличающийся тем, что отрицательный аллостерический модулятор mGluR5 избирательно ингибирует mGluR5.
10. Применение соединения по п. 1 формулы I или его фармацевтически приемлемой соли, рацемата, R-изомера, S-изомера или их смеси для приготовления лекарственного средства для лечения заболевания, связанного с mGluR5 (метаботропный глутаматный рецептор, подтип 5).
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RU2695371C2 (ru) 2019-07-23
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EP3284738B1 (en) 2020-11-25
JP2018514524A (ja) 2018-06-07
EA039234B1 (ru) 2021-12-21
US20180194767A1 (en) 2018-07-12
EA201700504A1 (ru) 2018-10-31
EP3284738A1 (en) 2018-02-21
KR102117453B1 (ko) 2020-06-01
US10618900B2 (en) 2020-04-14
EP3284738A4 (en) 2018-09-12
CA2988861A1 (en) 2016-10-20
RU2017139564A3 (ru) 2019-05-15
WO2016165658A1 (zh) 2016-10-20
CN106146391A (zh) 2016-11-23
KR20170137197A (ko) 2017-12-12
JP6795517B2 (ja) 2020-12-02
ES2864800T3 (es) 2021-10-14
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CA2988861C (en) 2021-09-28
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