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RU2020134082A - Модуляторы регулятора трансмембранной проводимости при муковисцидозе - Google Patents

Модуляторы регулятора трансмембранной проводимости при муковисцидозе Download PDF

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RU2020134082A
RU2020134082A RU2020134082A RU2020134082A RU2020134082A RU 2020134082 A RU2020134082 A RU 2020134082A RU 2020134082 A RU2020134082 A RU 2020134082A RU 2020134082 A RU2020134082 A RU 2020134082A RU 2020134082 A RU2020134082 A RU 2020134082A
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Russia
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ring
independently
compound
salt
deuterated derivative
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RU2020134082A
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RU2850782C2 (ru
RU2020134082A3 (ru
Inventor
Марк Томас Миллер
Кори Андерсон
Виджаялаксми Арумугам
Брайан Ричард БЕАР
Хэйли Мари БИНЧ
Джереми Дж. Клеменс
Томас Кливленд
Эрика КОНРОЙ
Тимоти Ричард Кун
Брайан А. Фриман
Петер Дидерик Ян Гротенхейс
Рэймонд Стэнли ГРОСС
Сара Сабина АДИДА-РУА
Харипада Кхатуя
Прамод Вирупакс Джоши
Пол Джон Кренитски
Чун-Чиех ЛИН
Гулин Эрдоган МАРЕЛИУС
Вито Мелилло
Джейсон Маккартни
Джорджия Макгохи НИКОЛЛЗ
Фабрис Жан Денис Пьер
Алина Силина
Андреас П. Термин
Джонни Ю
Цзинлань ЧЖОУ
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Вертекс Фармасьютикалз Инкорпорейтед
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    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
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    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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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
    • A61K31/403—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 carbocyclic rings, e.g. carbazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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Claims (102)

1. Соединение формулы Ia:
Figure 00000001
Ia
его фармацевтически приемлемая соль или дейтерированное производное любого из них, где независимо для каждого случая:
кольцо B представляет собой C6-C10 арильное кольцо или C3-C10 гетероарильное или гетероциклическое кольцо, где любые из от 1 до 4 кольцевых атомов независимо представляют собой О, S, N или NR;
кольцо С представляет собой C6-C10 арильное кольцо, C3-C14 гетероарильное или гетероциклическое кольцо, где любые из от 1 до 4 кольцевых атомов независимо представляют собой N, O или S, или C3-C10 циклоалкильное кольцо;
X представляет собой O или NR;
Y представляет собой CRR, CO, O, S, SO, SO2, S(O)NH или NR;
R1 представляет собой галоген; CN; F5S; SiR3; OH; NRR; C1-C6 алкил или фторалкил; C1-C6 алкокси или фторалкокси; C2-C6 алкенил; C2-C6 алкинил; (C1-C9 алкилен)-R4, где до четырех звеньев СН2 независимо заменены на O, CO, S, SO, SO2 или NR; C6-C10 арил; C3-C10 гетероарильное или гетероциклическое кольцо, где любые из от 1 до 4 кольцевых атомов независимо представляют собой О, S, N или NR; или C3-C10 циклоалкил;
R2 представляет собой галоген; OH; NRR; азид; CN; CO2R; C1-C6 алкил или фторалкил; C1-C6 алкокси или фторалкокси; C2-C6 алкенил; C2-C6 алкинил; C6-C10 арил; C3-C13 гетероарильное или гетероциклическое кольцо, где любые из от 1 до 4 кольцевых атомов независимо представляют собой О, S, N или NR; C3-C10 циклоалкил; или (C1-C9 алкилен)-R4, где до четырех звеньев СН2 независимо заменены на O, CO, S, SO, SO2 или NR;
или две группы R2, взятые вместе, могут образовывать группу =CH2 или =O;
R3 представляет собой галоген; CN; CO2R; C1-C6 алкил или фторалкил; C2-C6 алкенил; C2-C6 алкинил; C1-C6 алкокси или фторалкокси; или C6-C10 арил; C3-C10 гетероарильное или гетероциклическое кольцо, где любые из от 1 до 4 кольцевых атомов независимо представляют собой О, S, N или NR; C3-C10 циклоалкил; или (C1-C9 алкилен)-R4, где до четырех звеньев СН2 независимо заменены на O, CO, S, SO, SO2 или NR;
или две группы R3, взятые вместе, могут образовывать группу =CH2 или =O;
R4 представляет собой H; азид; CF3; CHF2; или; CCH; CO2R; OH; C6-C10 арил, C3-C10 гетероарил или гетероциклоалкил, где любые из от 1 до 4 кольцевых атомов независимо представляют собой О, S, N или NR; C3-C10 циклоалкил; NRR, NRCOR, CONRR, CN, галоген или SO2R;
R независимо представляет собой H; OH; CO2H; CO2C1-C6 алкил; C1-C6 алкил; C2-C6 алкенил; C2-C6 алкинил; C6-C10 арил; C3-C10 гетероарил или гетероциклоалкил, где любые из от 1 до 4 кольцевых атомов независимо представляют собой О, S, N или NR; или C3-C10 циклоалкил;
n равно 0, 1, или 2;
o равно 0, 1, 2, 3, 4 или 5;
p равно 0, 1, 2 или 3; и
q равно 0, 1, 2, 3, 4 или 5.
2. Соединение, соль или дейтерированное производное по п.1, где кольцо B представляет собой фенил, пиридил, пиридин-2(1H)-он, пиразол, индол, тиофен, дигидробензофуран, пиразин, индазол, тиазол, пиридин-4(1H)-он, пирролидинон или хинолин.
3. Соединение, соль или дейтерированное производное по п. 1 или 2, где кольцо B выбрано из
Figure 00000002
Figure 00000002
Figure 00000003
Figure 00000004
или
Figure 00000004
.
4. Соединение, соль или дейтерированное производное по любому из пп. 1-3, где кольцо C представляет собой фенил, индол, циклоалкил, пиридил, пирролидин, нафталин, пиперидин или дигидроинден.
5. Соединение, соль или дейтерированное производное по любому из пп. 1-4, где кольцо C представляет собой
Figure 00000005
Figure 00000006
Figure 00000007
Figure 00000008
или
Figure 00000008
.
6. Соединение, соль или дейтерированное производное по любому из пп. 1-5, где Y представляет собой O.
7. Соединение, соль или дейтерированное производное по любому из пп. 1-5, где Y представляет собой CH2.
8. Соединение, соль или дейтерированное производное по любому из пп. 1-5, где Y представляет собой CH(C1-C6 алифатическую группу).
9. Соединение, соль или дейтерированное производное по любому из пп. 1-5, где Y представляет собой CH(CH3).
10. Соединение, соль или дейтерированное производное по любому из пп. 1-5, где Y представляет собой CH(CH2CH3).
11. Соединение, соль или дейтерированное производное по любому из пп. 1-10, где R1 представляет собой галоген, CN, C1-C6 алифатическую группу, C1-C6 алкокси, C3-C8 циклоалкил, или фенил, пиридил, пиримидин, индол, аза-индол или тиофеновое кольцо, где все кольца могут быть заменены галогеном, C1-C6 алифатической группой, C1-C6 алкокси, C1-C6 фторалифатической группой, C1-C6 фторалкокси, OH, CH2OH, CH2OCH3, CN, CO2H, амино, амидо, C3-C10 гетероарилом, C3-C10 гетероциклоалкилом или (C1-C8 алифатическая группа)-R4, где до трех звеньев CH2 могут быть заменены на O, CO, S, SO, SO2 или NR.
12. Соединение, соль или дейтерированное производное по любому из пп. 1-11, где R1 выбран из CH3, Cl, F, CN, OCH3, CF3, CH2CH3, трет-Bu, CH(CH3)2,
Figure 00000009
Figure 00000009
Figure 00000010
Figure 00000010
Figure 00000010
Figure 00000011
Figure 00000011
Figure 00000012
или
Figure 00000012
.
13. Соединение, соль или дейтерированное производное по любому из пп. 1-12, где R2 выбран из галогена, OH, CN, азида, амино, C1-C6 алифатической группы или фторалифатической группы, C1-C6 алкокси или фторалкокси, C3-C10 моно- или бициклического гетероциклического кольца, где до 4 атомов углерода могут быть заменены на O, S, N или NR; или (C1-C8 алифатическая группа)-R4, где до трех звеньев CH2 могут быть заменены на O, CO, S, SO, SO2 или NR.
14. Соединение, соль или дейтерированное производное по любому из пп. 1-13, где R2 выбран из Cl, F, OH, CN, N3, NH2, NH(CH3), N(CH3)2, CH3, CH2OH, CH2CH3, CH(CH3)2, CHF2, OCH3, OCF3, OCHF2, OCH(CH3)2, C(O)CH3, CH2CH2OH, CH2NH2, NH(CH2)2OH, NH(CH2)2N(CH3)2, NH(CH2)2NH2, NH(CH2)3NH2, NH(CH2)2OCH3, NHCH(CH3)2,
Figure 00000013
или CO2H.
15. Соединение, соль или дейтерированное производное по любому из пп. 1-14, где R3 выбран из галогена, CN, C1-C6 алифатической группы или фторалифатической группы, C1-C6 алкокси или C3-C10 моно- или бициклического гетероарила, где до 4 атомов углерода могут быть заменены на O, S, N или NR.
16. Соединение, соль или дейтерированное производное по любому из пп. 1-15, где R3 выбран из Cl, F, CN, CH3, OCH3, CF3, CH2CH3, CH2CF3, CH2CH2CH3, OCH2CH3, CH2OCH3, CH(CH3)2, CCH, CO2CH3, трет-Bu, =CH2, =O,
Figure 00000014
Figure 00000015
Figure 00000016
или
Figure 00000017
.
17. Соединение, соль или дейтерированное производное по любому из пп. 1-16, где o равно 0.
18. Соединение, соль или дейтерированное производное по любому из пп. 1-16, где o равно 1.
19. Соединение, соль или дейтерированное производное по любому из пп. 1-18, где n равно 0.
20. Соединение, соль или дейтерированное производное по любому из пп. 1-18, где n равно 1.
21. Соединение, соль или дейтерированное производное по любому из пп. 1-18, где n равно 2.
22. Соединение, соль или дейтерированное производное по любому из пп. 1-21, где p равно 0.
23. Соединение, соль или дейтерированное производное по любому из пп. 1-21, где p равно 1.
24. Соединение, соль или дейтерированное производное по любому из пп. 1-21, где p равно 2.
25. Соединение, соль или дейтерированное производное по любому из пп. 1-24, где кольцо B представляет собой фенил.
26. Соединение, соль или дейтерированное производное по любому из пп. 1-25, где кольцо B и кольцо C независимо представляют собой фенил или пиридил.
27. Соединение формулы Ic:
Figure 00000018
Ic
его фармацевтически приемлемая соль или дейтерированное производное любого из них, где независимо для каждого случая:
кольцо B представляет собой C6-C10 арильное кольцо или C3-C10 гетероарильное или гетероциклическое кольцо, где любые из от 1 до 4 кольцевых атомов независимо представляют собой О, S, N или NR;
кольцо С представляет собой C6-C10 арильное кольцо, C3-C14гетероарильное или гетероциклическое кольцо, где любые из от 1 до 4 кольцевых атомов независимо представляют собой N, O или S, или C3-C10 циклоалкильное кольцо;
Y представляет собой CRR, CO, O, S, SO, SO2, S(O)NH или NR;
R1 представляет собой галоген; CN; F5S; SiR3; OH; NRR; C1-C6 алкил или фторалкил; C1-C6 алкокси или фторалкокси; C2-C6 алкенил; C2-C6 алкинил; (C1-C9 алкилен)-R4, где до четырех звеньев СН2 независимо заменены на O, CO, S, SO, SO2 или NR; C6-C10 арил; C3-C10 гетероарильное или гетероциклическое кольцо, где любые из от 1 до 4 кольцевых атомов независимо представляют собой О, S, N или NR; или C3-C10 циклоалкил;
R2 представляет собой галоген; OH; NRR; азид; CN; CO2R; C1-C6 алкил или фторалкил; C1-C6 алкокси или фторалкокси; C2-C6 алкенил; C2-C6 алкинил; C6-C10 арил; C3-C13 гетероарильное или гетероциклическое кольцо, где любые из от 1 до 4 кольцевых атомов независимо представляют собой О, S, N или NR; C3-C10 циклоалкил; или (C1-C9 алкилен)-R4, где до четырех звеньев СН2 независимо заменены на O, CO, S, SO, SO2 или NR;
или две группы R2, взятые вместе, могут образовывать группу =CH2 или =O;
R3 представляет собой галоген; CN; CO2R; C1-C6 алкил или фторалкил; C2-C6 алкенил; C2-C6 алкинил; C1-C6 алкокси или фторалкокси; или C6-C10 арил; C3-C10 гетероарильное или гетероциклическое кольцо, где любые из от 1 до 4 кольцевых атомов независимо представляют собой О, S, N или NR; C3-C10 циклоалкил; или (C1-C9 алкилен)-R4, где до четырех звеньев СН2 независимо заменены на O, CO, S, SO, SO2 или NR;
или две группы R3, взятые вместе, могут образовывать группу =CH2 или =O;
R4 представляет собой H; азид; CF3; CHF2; или; CCH; CO2R; OH; C6-C10 арил, C3-C10 гетероарил или гетероциклоалкил, где любые из от 1 до 4 кольцевых атомов независимо представляют собой О, S, N или NR; C3-C10 циклоалкил; NRR, NRCOR, CONRR, CN, галоген или SO2R;
R независимо представляет собой H; OH; CO2H; CO2C1-C6 алкил; C1-C6 алкил; C2-C6 алкенил; C2-C6 алкинил; C6-C10 арил; C3-C10 гетероарил или гетероциклоалкил, где любые из от 1 до 4 кольцевых атомов независимо представляют собой О, S, N или NR; или C3-C10 циклоалкил;
n равно 0, 1, 2 или 3;
o равно 0, 1, 2, 3, 4 или 5;
p равно 0, 1, 2 или 3; и
q равно 0, 1, 2, 3, 4 или 5.
28. Соединение формулы Id:
Figure 00000019
Id
его фармацевтически приемлемая соль или дейтерированное производное любого из них, где независимо для каждого случая:
кольцо B представляет собой C6-C10 арильное кольцо или C3-C10 гетероарильное или гетероциклическое кольцо, где любые из от 1 до 4 кольцевых атомов независимо представляют собой O, S, N или NR;
кольцо С представляет собой C6-C10 арильное кольцо, C3-C14 гетероарильное или гетероциклическое кольцо, где любые из от 1 до 4 кольцевых атомов независимо представляют собой N, O или S, или C3-C10 циклоалкильное кольцо;
Y представляет собой CRR, CO, O, S, SO, SO2, S(O)NH или NR;
R1 представляет собой галоген; CN; F5S; SiR3; OH; NRR; C1-C6 алкил или фторалкил; C1-C6 алкокси или фторалкокси; C2-C6 алкенил; C2-C6 алкинил; (C1-C9 алкилен)-R4, где до четырех звеньев СН2 независимо заменены на O, CO, S, SO, SO2 или NR; C6-C10 арил; C3-C10 гетероарильное или гетероциклическое кольцо, где любые из от 1 до 4 кольцевых атомов независимо представляют собой О, S, N или NR; или C3-C10 циклоалкил;
R2 представляет собой галоген; OH; NRR; азид; CN; CO2R; C1-C6 алкил или фторалкил; C1-C6 алкокси или фторалкокси; C2-C6 алкенил; C2-C6 алкинил; C6-C10 арил; C3-C13 гетероарильное или гетероциклическое кольцо, где любые из от 1 до 4 кольцевых атомов независимо представляют собой О, S, N или NR; C3-C10 циклоалкил; или (C1-C9 алкилен)-R4, где до четырех звеньев СН2 независимо заменены на O, CO, S, SO, SO2 или NR;
или две группы R2, взятые вместе, могут образовывать группу =CH2 или =O;
R3 представляет собой галоген; CN; CO2R; C1-C6 алкил или фторалкил; C2-C6 алкенил; C2-C6 алкинил; C1-C6 алкокси или фторалкокси; или C6-C10 арил; C3-C10 гетероарильное или гетероциклическое кольцо, где любые из от 1 до 4 кольцевых атомов независимо представляют собой О, S, N или NR; C3-C10 циклоалкил; или (C1-C9 алкилен)-R4, где до четырех звеньев СН2 независимо заменены на O, CO, S, SO, SO2 или NR;
или две группы R3, взятые вместе, могут образовывать группу =CH2 или =O;
R4 представляет собой H; азид; CF3; CHF2; или; CCH; CO2R; OH; C6-C10 арил, C3-C10 гетероарил или гетероциклоалкил, где любые из от 1 до 4 кольцевых атомов независимо представляют собой О, S, N или NR; C3-C10 циклоалкил; NRR, NRCOR, CONRR, CN, галоген или SO2R;
R независимо представляет собой H; OH; CO2H; CO2C1-C6 алкил; C1-C6 алкил; C2-C6 алкенил; C2-C6 алкинил; C6-C10 арил; C3-C10 гетероарил или гетероциклоалкил, где любые из от 1 до 4 кольцевых атомов независимо представляют собой О, S, N или NR; или C3-C10 циклоалкил;
n равно 0, 1, 2 или 3;
o равно 0, 1, 2, 3, 4 или 5;
p равно 0, 1, 2 или 3; и
q равно 0, 1, 2, 3, 4 или 5.
29. Соединение, соль или дейтерированное производное любого из них по любому из пп. 1-28, выбранное из таблицы 1.
30. Фармацевтическая композиция, содержащая соединение, соль или дейтерированное производное по любому из пп. 1-29 и фармацевтически приемлемый носитель.
31. Фармацевтическая композиция по п.30, дополнительно содержащая один или несколько дополнительных терапевтических агентов.
32. Фармацевтическая композиция по п.31, где один или несколько дополнительных терапевтических агентов включают модулятор CFTR.
33. Фармацевтическая композиция по п.32, где один или несколько дополнительных терапевтических агентов включают
Figure 00000020
или его фармацевтически приемлемую соль.
34. Фармацевтическая композиция по п.32, где один или несколько дополнительных терапевтических агентов включают
Figure 00000021
или его фармацевтически приемлемую соль.
35. Способ лечения кистозного фиброза у пациента, включающий введение пациенту эффективного количества соединения по любому из пп. 1-29 или фармацевтической композиции по любому из пп. 30-34.
36. Способ по п.35, дополнительно включающий введение пациенту одного или нескольких дополнительных терапевтических агентов до, одновременно с или после введения соединения по любому из пп. 1-29 или фармацевтической композиции по любому из пп. 30-34.
37. Способ по п.36, где одного или несколько дополнительных терапевтических агентов включают модулятор CFTR.
38. Способ по п.37, где один или несколько дополнительных терапевтических агентов включают
Figure 00000022
или его фармацевтически приемлемую соль.
39. Способ по п.37, где один или несколько дополнительных терапевтических агентов включают
Figure 00000023
или его фармацевтически приемлемую соль.
40. Способ по п.35, где пациент является гомозиготным по F508del мутации.
41. Способ по п.35, где пациент является гетерозиготным по F508del мутации.
RU2020134082A 2014-10-06 2015-10-06 Модуляторы регулятора трансмембранной проводимости при муковисцидозе RU2850782C2 (ru)

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