RU2014113973A - Фармацевтические соединения - Google Patents

Фармацевтические соединения Download PDF

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RU2014113973A
RU2014113973A RU2014113973/04A RU2014113973A RU2014113973A RU 2014113973 A RU2014113973 A RU 2014113973A RU 2014113973/04 A RU2014113973/04 A RU 2014113973/04A RU 2014113973 A RU2014113973 A RU 2014113973A RU 2014113973 A RU2014113973 A RU 2014113973A
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Russia
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group
compound
alkyl
formula
amino
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RU2014113973/04A
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Эндрю Джеймс ВУДХЕД
Кристофер Чарльз Фредерик Гамлетт ГАМЛЕТТ
Гилберт Ибэй БЕСОНГ
Джанни ЧЕССАРИ
Мария Грация КАРР
Алессия МИЛЛЕМАДЖИ
Дэвид Нортон
Сьюзан Мария СААЛАУ-БЕТЕЛЛ
Хендрика Мария Герарда УИЛЛЕМС
Нейл Томас ТОМПСОН
Стивен Дуглас Хискок
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Астекс Терапьютикс Лимитед
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Priority claimed from GBGB1118875.2A external-priority patent/GB201118875D0/en
Priority claimed from GB201118874A external-priority patent/GB201118874D0/en
Application filed by Астекс Терапьютикс Лимитед filed Critical Астекс Терапьютикс Лимитед
Publication of RU2014113973A publication Critical patent/RU2014113973A/ru

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/73—Unsubstituted amino or imino radicals
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
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    • C07C237/30—Carboxylic 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 hydrogen atoms or to acyclic carbon atoms
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Abstract

1. Соединение формулы (1):или соль, N-оксид, таутомер или стереоизомер указанного соединения, где:А представляет собой СН или азот;Е представляет собой СН или азот;Rвыбран из следующего:- ациклическая Cуглеводородная группа, возможно содержащая один или два заместителя R, причем один атом углерода в ациклической Cуглеводородной группе может быть необязательно заменен гетероатомом или группой, выбранными из О, S, NR, S(O) и SO, или два соседних атома углерода в ациклической d.углеводородной группе могут быть необязательно заменены группой, выбранной из CONR, NRCO, NRSOи SONR, при условии, что в каждом случае в ациклической Cуглеводородной группе сохраняется по меньшей мере один атом углерода; и- моноциклическая карбоциклическая или гетероциклическая группа, содержащая от 3 до 7 членов кольца, из которых 0, 1, 2, 3 или 4 членов кольца являются гетероатомами, выбранными из О, N и S, причем указанная карбоциклическая или гетероциклическая группа возможно содержит один или два заместителя R;Rвыбран из водорода и группы X-R;X представляет собой Cалкандиил, причем один атом углерода Салкандиила может быть необязательно связан с группой-СН-СН- с образованием циклопропан-1,1-диила, или два соседних атома углерода Cалкандиила могут быть необязательно связаны с группой -(СН), где n равен от 1 до 5, с образованием С-циклоалкан-1,2-диила;Rпредставляет собой 3-10-членное моноциклическое или бициклическое карбоциклическое или гетероциклическое кольцо, содержащее 0, 1, 2 или 3 гетероатома в кольце, выбранные из N, О и S, и возможно содержащее один или более заместителей R;Rвыбран из водорода и заместителя R;Rвыбран из следующего: галоген; циано; Салкил, возможно содержащи

Claims (20)

1. Соединение формулы (1):
Figure 00000001
или соль, N-оксид, таутомер или стереоизомер указанного соединения, где:
А представляет собой СН или азот;
Е представляет собой СН или азот;
R1 выбран из следующего:
- ациклическая C1-8 углеводородная группа, возможно содержащая один или два заместителя R6, причем один атом углерода в ациклической C1-8 углеводородной группе может быть необязательно заменен гетероатомом или группой, выбранными из О, S, NRc, S(O) и SO2, или два соседних атома углерода в ациклической d.8 углеводородной группе могут быть необязательно заменены группой, выбранной из CONRc, NRcCO, NRcSO2 и SO2NRc, при условии, что в каждом случае в ациклической C1-8 углеводородной группе сохраняется по меньшей мере один атом углерода; и
- моноциклическая карбоциклическая или гетероциклическая группа, содержащая от 3 до 7 членов кольца, из которых 0, 1, 2, 3 или 4 членов кольца являются гетероатомами, выбранными из О, N и S, причем указанная карбоциклическая или гетероциклическая группа возможно содержит один или два заместителя R7a;
R2 выбран из водорода и группы X-R8;
X представляет собой C1-8 алкандиил, причем один атом углерода С1-8 алкандиила может быть необязательно связан с группой-СН2-СН2- с образованием циклопропан-1,1-диила, или два соседних атома углерода C1-8 алкандиила могут быть необязательно связаны с группой -(СН2)n, где n равен от 1 до 5, с образованием С3-7-циклоалкан-1,2-диила;
R3 представляет собой 3-10-членное моноциклическое или бициклическое карбоциклическое или гетероциклическое кольцо, содержащее 0, 1, 2 или 3 гетероатома в кольце, выбранные из N, О и S, и возможно содержащее один или более заместителей R13;
R4 выбран из водорода и заместителя R4a;
R4a выбран из следующего: галоген; циано; С1-4алкил, возможно содержащий в качестве заместителей один или более атомов фтора; С1-4алкокси, возможно содержащий в качестве заместителей один или более атомов фтора; гидрокси-С1-4 алкил; и С1-2алкокси-С1-4алкил;
R5 выбран из водорода и заместителя R5a;
R5a выбран из следующего: C1-2алкил, возможно содержащий в качестве заместителей один или более атомов фтора; С1-3алкокси, возможно содержащий в качестве заместителей один или более атомов фтора; галоген; циклопропил; и циано;
R6 выбран из следующего: гидрокси; фтор; карбамоил; моно- или ди-С1-4 алкилкарбамоил; нитро; амино; моно- или ди-С1-4алкиламино; моноциклическая карбоциклическая или гетероциклическая группа, содержащая от 3 до 7 членов кольца, из которых 0, 1 или 2 гетероатома кольца выбраны из О, N и S, где указанная карбоциклическая или гетероциклическая группа возможно содержит один или два заместителя R7b;
R7a и R7b каждый независимо выбран из следующего: (=O); (=S); амино; галоген; циано; гидрокси; С1-4алкил; гидрокси-С1-4алкил; амино-С1-4 алкил; моно- и ди-С1-4алкиламино-С1-4алкил;
R8 выбран из следующего: гидрокси-группы и C(=O)NR10R11; при условии, что если R8 представляет собой гидрокси, между гидрокси-группой и атомом азота, к которому присоединен X, располагаются по меньшей мере три атома углерода подряд;
R10 выбран из водорода и C1-4алкила;
R11 выбран из следующего: водород; амино-С2-4 алкил и гидрокси-С2-4 алкил;
R13 выбран из следующего: галоген; циано; (=O); (=S); нитро; CH=NOH; и группа Ra-Rb;
Ra представляет собой связь, О, СО, Х1С(Х2), С(Х2)Х1, Х1С(Х2)Х1, S, SO, SO2, NRC, SO2NRc или NRcSO2;
Rb представляет собой водород, циклическую группу Rd; или ациклическую C1-8 углеводородную группу, возможно содержащую один или более заместителей, выбранных из гидрокси, оксо, галогена, циано, нитро, карбокси, амино, моно- или ди-C1-4 алкиламино и циклической группы Rd; причем один или два, но не все атомы углерода в ациклической C1-8 углеводородной группе могут быть необязательно заменены на О, S, SO, SO2, NRc, Х1С(Х2), С(Х2)Х1 или Х1С(Х2)Х1; SO2NRc или NRcSO2;
циклическая группа Rd представляет собой моноциклическую карбоциклическую или гетероциклическую группу, содержащую от 3 до 7 членов кольца, из которых 0, 1, 2 или 3 гетероатома кольца выбраны из О, N и S и их окисленных форм, причем карбоциклическая или гетероциклическая группа возможно содержит один или более заместителей, выбранных из R14;
R14 выбран из оксо; галогена; циано; и Ra-Re;
Re представляет собой водород или ациклическая C1-8 углеводородную группу, возможно содержащую один или более заместителей, выбранных из следующих: фенил; гидрокси; оксо; галоген; циано; карбокси; амино; моно- или ди-С1-4алкиламино; причем один или два, но не все атомы углерода в ациклической C1-8 углеводородной группе могут быть необязательно заменены на О, S, SO, SO2, NRc, Х1С(Х2), С(Х2)Х1 или Х1С(Х2)Х1; SO2NRc или NRcSO2;
X1 представляет собой О или NRc;
X2 представляет собой =O или =NRc; и
Rc представляет собой водород или алкил;
но за исключением соединений 1-(3-бензоилфенил)-этиламин и 1-(3-фуран-2-илкарбонилфенил)-этиламин.
2. Соединение по п. 1, отличающееся тем, что А представляет собой СН, и Е представляет собой СН.
3. Соединение по п. 1 или 2, где R2 представляет собой X-R8.
4. Соединение по п. 1 или 2, где R2 представляет собой водород.
5. Соединение по п. 3, где X представляет собой группу АА:
Figure 00000002
где "b" представляет собой точку присоединения к R8, и "а" представляет собой точку присоединения к атому азота бензила.
6. Соединение по п. 1, где R8 представляет собой C(=O)NH2.
7. Соединение по п. 1, где R1 представляет собой этил или циклопропил.
8. Соединение по п. 1, где R3 выбран из фенила и пиридила, каждый из которых содержит один или более заместителей R13.
9. Соединение по п. 1, где R13 представляет собой амино.
10. Соединение по п. 1, имеющее изомерную форму (1а):
Figure 00000003
или соль, N-оксил или таутомер указанного соединения, где:
А представляет собой СН;
Е представляет собой СН;
R1 представляет собой этил или циклопропил;
R2 представляет собой X-R8; где X представляет собой -*СН(СН3)СН2-, и звездочка обозначает хиральный центр, который находится в S-конфигурации;
R8 представляет собой C(=O)NR10R11 где R10 и R11 оба являются водород;
R4 представляет собой фтор;
R5 представляет собой хлор; и
R3 представляет собой пиридил, сожержащий один заместитель, который представляет собой группу NH2.
11. Соединение по п. 1, имеющее формулу (7):
Figure 00000004
или соль, N-оксид, таутомер или стереоизомер указанного соединения, где:
R1b выбран из следующего: С1-4алкил, аллил и циклопропил;
R2b выбран из водорода и группы Xb-R8b;
Xb представляет собой С1-5 алкандиил, где один атом углерода С1-4алкандиила может быть необязательно связан с группой -СН2-СН2- с образованием циклопропан-1,1-диила, или два соседних атома углерода С1-4алкандиила могут быть необязательно связаны с группой -СН2-СН2-СН2- с образованием циклопентан-1,2-диила;
R3b представляет собой карбоциклическое или гетероциклическое кольцо, выбранное из следующих: фенил, пиридил, 1-оксипиридил, пиридонил, пиразинил, пиримидинил, пиразинил, пиразолил, изотиазолил, тиазолил, изоксазолил, пиридооксазинонил и дигидробензоксазинил, каждый из которых возможно содержит один или более заместителей R13b;
R4b представляет собой галоген;
R5b выбран из следующего: галоген; гидрокси; С1-2алкил; С1-2алкокси; дифторметокси; трифторметокси;
R8b выбран из гидрокси и C(=O)NHR11b; при условии, что если R8b представляет собой гидрокси, то между гидрокси-группой и атомом азота, к которому присоединен Хb, располагаются по меньшей мере два атома углерода подряд;
R11b выбран из водорода и амино-С2-4алкил; и
R13b выбран из следующего: галоген, циано; гидрокси, C1-4 алкил, оксо, C1-4алкокси, гидрокси-С1-4 алкил, С1-4ацилокси-С1-4 алкил, С1-4 алкилсульфанил, амино, моно-C1-4 алкиламино, ди-С1-4 алкиламино, пиразолил, С1-4 алкоксикарбонилпиразолил, гидрокси-С1-4 алкил-пиразолил, карбокси и карбамоил.
12. Соединение по п. 1, имеющее формулу (8):
Figure 00000005
или соль, N-оксид, таутомер или стереоизомер указанного соединения,
где R11 выбран из водорода, амино-С2-4алкила и гидрокси-С2-4алкила;
X выбран из следующего: -(СН2)Р-, (CH2)q-CH(Alk)-(CH2)r, -CH(Alk)-W-, -(CH2)rC(CH3)2-(СН2)t- и -(CH2)t-W-(CH2)u-, где W представляет собой циклопропан-1,1-диил или циклопентан-1,2-диил; каждый Alk независимо выбран из метила, этила и изопропила; p равен 1, 2 или 3; q равен 0 или 1; r равен 0 или 1; t равен 0 или 1, и u равен 0 или 1; при условии, что общее число атомов углерода, содержащихся в X, за исключением атомомв углерода в любой присутствующей циклопропан-1,1-диильной группе или циклопентан-1,2-диильной группе, не превосходит 8;
R1 выбран из следующего: этил, пропил, циклопропил, циклопропилметил проп-2-ен-1-ил;
R5a выбран из следующего: фтор, хлор, метил и метокси;
R3 выбран из следующего: фенил, пиридил, пиразинил, пиримидинил, изоксазолил, изотиазолил, пиразолил, 3,4-дигидро-пиридооксазин и 3,4-дигидробензоксазин, каждый из которых является незамещенным или содержит один или два заместителя R13; и
R13 выбран из следующего: галоген, циано, гидрокси, С1-4алкокси, С1-4 алкил, гидрокси-С1-4 алкил, амино, моно-C1-4 алкиламино, ди-С1-4 алкиламино, оксо, оксидо, пиразолил, гидрокси-С1-4 алкил-пиразолил, карбокси и карбамоил.
13. Соединение по п. 1, имеющее формулу (9):
Figure 00000006
или соль, N-оксид, таутомер или стереоизомер указанного соединения,
где R17 выбран из этила и циклопропила; R18 выбран из следующего: амино и гидроксиметил; Е представляет собой N или C-R19; и R19 выбран из водорода, метила и хлора.
14. Соединение по п. 1, которое выбрано из
(3S)-3-{[(1R)-1-(3-бензоил-4-хлор-2-фторфенил)пропил]амино}бутанамида;
(3S)-3-{[(1R)-1-{3-[(6-аминопиридин-3-ил)карбонил]-4-хлор-2-фторфенил}пропил]-амино}бутанамида;
(3S)-3-{[(R)-{3-[(6-aминoпиpидин-3-ил)кapбoнил]-4-xлop-2-фтopфeнил}(циклoпpoпил)-метил]амино}бутанамида;
(3S)-3-{[(R)-{3-[(4-амино-3-хлорфенил)карбонил]-4-хлор-2-фторфенил}-(циклопропил)метил]-амино}бутанамида; и
(3S)-3-{[(R)-{3-[(4-амино-3-метилфенил)карбонил]-4-хлор-2-фторфенил}-(циклопропил)метил]-амино}бутанамида; и их солей.
15. Фармацевтическая композиция, содержащая соединение согласно любому из пп. 1-14 и фармацевтически приемлемое вспомогательное вещество.
16. Применение соединения по любому из пп. 1-14 в медицине; например, для применения в профилактике или лечении инфекции, вызванной вирусом гепатита С (HCV, ВГС).
17. Комбинация соединения по любому из пп. 1-14 и дополнительного агента против вируса гепатита С.
18. Комбинация соединения по любому из пп. 1-14 с по меньшей мере одним (например, 1, 2, 3 или 4, или более предпочтительно 1, 2 или 3, и наиболее предпочтительно от 2 до 3) другимтерапевтическим агентом, выбранным из (а) интерферонов; (b) рибавирина и его аналогов; (с) других ингибиторов протеазы NS3 ВГС; (d) ингибитора альфа-глюкозидазы 1; (е) гепатопротекторов; (f) нуклеозидных или нуклеотидных ингибиторов полимеразы NS5B ВГС; (g) ненуклеозидных ингибиторов полимеразы NS5B ВГС; (h) ингибиторов NS5A ВГС; (i) агонистов TLR-7; (j) ингибиторов циклофиллина; (k) ингибиторов IRES ВГС; (I) средств. улучшающих фармакокинетические свойства; (m) имменоглобулинов; (n) иммуномодуляторов; (о) противовоспалительных агентов; (p) антибиотиков; (q) ингибиторов геликазы NS3 ВГС; (r) антагонистов NS4a ВГС; (s) связывающих ингибиторов NS4b ВГС; (t) ингибиторов p7 ВГС; (u) ингибиторов кора ВГС; и (v) ингибиторов проникновения ВГС в клетку; (w) ингибиторов диацилглицеринацилтрансферазы 1 типа(DGAT-1).
19. Комбинация соединения по любому из пп. 1-14 с противораковым лекарственным средством, эффективая для лечения гепатоцеллюлярной карциномы.
20. Способ получения соединения формулы (1), определенного в любом из пп. 1-14, который включает:
(a) в случае, если необходимо получить соединение формулы (1), где R2 представляет собой водород, реакцию соединения формулы (10):
Figure 00000007
где PG представляет собой защитную группу, такую как группа трет-бутилоксикарбонил (Воc), с основным реагентом, таким как алкиллитий (например, бутиллитий), с последующей реакцией с соединением формулы R3-C(=O)-LG, где LG представляет собой уходящую группу, такую как метокси- или этоксигруппа, или хлорид (т.е. хлорангидрид кислоты), с получением а соединения формулы: (11):
Figure 00000008
с последующим удалением защитной группы PG; или
(b) в случае, если необходимо получить соединение формулы (1), где R2 представляет собой водород, окисление соединения формулы (30):
Figure 00000009
с использованием подходящего окисляющего агента, такого как диоксид магния или периодинан Десса-Мартина, с последующим удалением защитной группы PG; или
(c) в случае, если необходимо получить соединение формулы (1), где R3 представляет собой аминопиридин или аминопиразин, реакцию соединения формулы (31), (32), (33), (34) или (35):
Figure 00000010
Figure 00000011
Figure 00000012
Figure 00000013
Figure 00000014
где R° представляет собой водород, и R13 представляет собой бром или хлор, с аммиаком с получением соответствующего соединения, где R13 представляет собой амино; или
(d) в случае, если необходимо получить соединение формулы (1), где R2 представляет собой X-R8, реакцию соединения формулы (1), где R2 представляет собой водород с алкилирующим агентом формулы LG1-X-R8, где LG1 представляет собой уходящую группу, обычно в присутствии основания; или
(e) в случае, если необходимо получить соединение формулы (1), где R2 представляет собой X-R8, реакцию соединения формулы (1), где R2 представляет собой водород с альдегидом или кетоном X"-C(=0)-X'-R8, где X" и X' представляют собой остатки группы X; в присутствии восстанавливающего агента; или
(f) в случае, если необходимо получить соединение формулы (1), где R8 представляет собой C(=O)NR10R11, реакцию соединения формулы (1), где R2 представляет собой водород, с соединением X'"-C(=O)NR10R11 или Х"'-С(=0)Ма, где Ма представляет собой маскированную аминогруппу или предшественник аминогруппы, и X'" содержит двойную смесь, сопряженную с карбонильной группой фрагмента C(=O)NR10R11; или
(g) в случае, если необходимо получить соединение формулы (1), где R2 представляет собой X-R8, и R8 представляет собой C(=O)NR10R11, реакцию соединения-предшественника, содержащего группу X-R8prec, где R8prec представляет сбой группу-предшественника группы C(=O)NR10R11 (такую как группа карбоновой кислоты, или циано-группа или сложноэфирная группа) с реагентом, подходящим для превращения R8prec в группу C(=O)NR10R11; с последующим удалением всех еще присутствующих групп PG; и
(h) возможно превращение одного соединения формулы (1) в другое соединение формулы (1).
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AU2012331190A1 (en) 2014-04-10
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CN104039766A (zh) 2014-09-10
SG11201400872YA (en) 2014-08-28
US9145354B2 (en) 2015-09-29
ZA201403832B (en) 2016-02-24
WO2013064543A1 (en) 2013-05-10
US20150051199A1 (en) 2015-02-19
JP2015501316A (ja) 2015-01-15
IL232392A0 (en) 2014-06-30
EP2773615A1 (en) 2014-09-10
TW201329025A (zh) 2013-07-16
MX2014005228A (es) 2015-07-06
HK1201534A1 (en) 2015-09-04
CA2853008A1 (en) 2013-05-10
BR112014009319A2 (pt) 2017-05-30

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