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RU2011122646A - ATP-BINDING CASSETTE CARRIER MODULATORS - Google Patents

ATP-BINDING CASSETTE CARRIER MODULATORS Download PDF

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RU2011122646A
RU2011122646A RU2011122646/04A RU2011122646A RU2011122646A RU 2011122646 A RU2011122646 A RU 2011122646A RU 2011122646/04 A RU2011122646/04 A RU 2011122646/04A RU 2011122646 A RU2011122646 A RU 2011122646A RU 2011122646 A RU2011122646 A RU 2011122646A
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compound
ocf
together form
disease
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Сара С. Хадида РУА
Петер Д. Й. Гротенхейс
Марк Т. МИЛЛЕР
Джейсон МАККАРТНИ
Гур Фредрик Ван
Мехди Мишель Джамель Нума
Цзинлань ЧЖОУ
Брайан БЕАР
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Вертекс Фармасьютикалз Инкорпорейтед
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Abstract

1. Соединение формулы II:IIили его фармацевтически приемлемая соль, где независимо для каждого случая:R представляет собой H, OH, OCH, или две R образуют вместе -CHCHCH-, -OCHO- или -OCFO-;Rпредставляет собой H или до двух C-Cалкилов;Rпредставляет собой H или F;Rпредставляет собой H или CN;Rпредставляет собой H, -CHCH(OH)CHOH, -CHCHN(CH)или -CHCHOH; иRпредставляет собой H, OH, -CHOCHCH(OH)CHOH, -CHOH, или Rи Rобразуют вместе конденсированное пирролидиновое кольцо.2. Соединение по п.1, где две R образуют вместе -OCFO-, Rпредставляет собой H, и Rпредставляет собой F.3. Соединение по п.1, где две R образуют вместе -OCFO-, Rпредставляет собой H, Rпредставляет собой F, и Rпредставляет собой H.4. Соединение по п.1, где две R образуют вместе -OCFO-, Rпредставляет собой H, Rпредставляет собой F, Rпредставляет собой H, и Rпредставляет собой -CHCH(OH)CHOH.5. Соединение по п.1, где две R образуют вместе -OCFO-, Rпредставляет собой H, Rпредставляет собой F, Rпредставляет собой H, и Rпредставляет собой ()-CHCH(OH)CHOH.6. Соединение по п.1 формулы IIa:IIaили его фармацевтически приемлемая соль, где:Rпредставляет собой H, -CHCH(OH)CHOH, -CHCHN(CH)или -CHCHOH; иRпредставляет собой H, OH, -CHOCHCH(OH)CHOH, -CHOH, или Rи Rобразуют вместе конденсированное пирролидиновое кольцо.7. Соединение по п.6, где Rпредставляет собой ()-CHCH(OH)CHOH, ()-CHCH(OH)CHOH, -CHCHN(CH)или -CHCHOH.8. Соединение по п. 6, где Rпредставляет собой OH, -CHOCHCH(OH)CHOH или -CHOH.9. Соединение по п.6, где Rпредставляет собой ()-CHCH(OH)CHOH, ()-CHCH(OH)CHOH, -CHCHN(CH)или -CHCHOH; и Rпредставляет собой OH, -CHOCHCH(OH)CHOH или -CHOH.10. Соединение, выбранное из Таблицы 1.11. Фармацевтическая композиция, содержащая(i) соединение по п.1; и(ii) фармацевтически приемлемый носитель.12. Композиция по п.11, дополнительно содержащая добавочный агент, выбранный из муколитического средства, бронход1. The compound of formula II: II or a pharmaceutically acceptable salt thereof, wherein, independently for each case: R is H, OH, OCH, or two R together form —CHCHCH—, —OCHO— or —OCFO—; R is H or up to two C-Calkyl; R is H or F; R is H or CN; R is H, -CHCH (OH) CHOH, -CHCHN (CH) or -CHCHOH; and R is H, OH, —CHOCHCH (OH) CHOH, —CHOH, or R and R together form a fused pyrrolidine ring. 2. The compound of claim 1, wherein the two R together form —OCFO—, R is H, and R is F.3. A compound according to claim 1, wherein the two R together form —OCFO—, R is H, R is F, and R is H. A compound according to claim 1, wherein the two R together form —OCFO—, R is H, R is F, R is H, and R is —CHCH (OH) CHOH. 5. A compound according to claim 1, wherein the two R together form —OCFO—, R represents H, R represents F, R represents H, and R represents () -CHCH (OH) CHOH. 6. The compound according to claim 1 of formula IIa: IIa or a pharmaceutically acceptable salt thereof, wherein: R is H, —CHCH (OH) CHOH, —CHCHN (CH), or —CHCHOH; and R is H, OH, —CHOCHCH (OH) CHOH, —CHOH, or R and R together form a fused pyrrolidine ring. The compound according to claim 6, where R is () -CHCH (OH) CHOH, () -CHCH (OH) CHOH, -CHCHN (CH) or -CHCHOH. A compound according to claim 6, wherein R is OH, —CHOCHCH (OH) CHOH or —CHOH. The compound according to claim 6, where R is () -CHCH (OH) CHOH, () -CHCH (OH) CHOH, -CHCHN (CH) or -CHCHOH; and R is OH, —CHOCHCH (OH) CHOH or —CHOH. 10. A compound selected from Table 1.11. A pharmaceutical composition comprising (i) a compound according to claim 1; and (ii) a pharmaceutically acceptable carrier. 12. The composition according to claim 11, additionally containing an additional agent selected from a mucolytic agent, bronchus

Claims (42)

1. Соединение формулы II:1. The compound of formula II:
Figure 00000001
II
Figure 00000001
II или его фармацевтически приемлемая соль, где независимо для каждого случая:or its pharmaceutically acceptable salt, where independently for each case: R представляет собой H, OH, OCH3, или две R образуют вместе -CH2CH2CH2-, -OCH2O- или -OCF2O-;R represents H, OH, OCH 3 , or two R together form —CH 2 CH 2 CH 2 -, —OCH 2 O— or —OCF 2 O—; R1 представляет собой H или до двух C1-C6алкилов;R 1 represents H or up to two C 1 -C 6 alkyls; R2 представляет собой H или F;R 2 represents H or F; R3 представляет собой H или CN;R 3 represents H or CN; R4 представляет собой H, -CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH; иR 4 represents H, —CH 2 CH (OH) CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 or —CH 2 CH 2 OH; and R5 представляет собой H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, или R4 и R5 образуют вместе конденсированное пирролидиновое кольцо.R 5 represents H, OH, —CH 2 OCH 2 CH (OH) CH 2 OH, —CH 2 OH, or R 4 and R 5 together form a fused pyrrolidine ring. 2. Соединение по п.1, где две R образуют вместе -OCF2O-, R1 представляет собой H, и R2 представляет собой F.2. The compound according to claim 1, where two R form together -OCF 2 O-, R 1 represents H, and R 2 represents F. 3. Соединение по п.1, где две R образуют вместе -OCF2O-, R1 представляет собой H, R2 представляет собой F, и R3 представляет собой H.3. The compound according to claim 1, where two R form together -OCF 2 O-, R 1 represents H, R 2 represents F, and R 3 represents H. 4. Соединение по п.1, где две R образуют вместе -OCF2O-, R1 представляет собой H, R2 представляет собой F, R3 представляет собой H, и R4 представляет собой -CH2CH(OH)CH2OH.4. The compound according to claim 1, where two R form together -OCF 2 O-, R 1 represents H, R 2 represents F, R 3 represents H, and R 4 represents -CH 2 CH (OH) CH 2 OH. 5. Соединение по п.1, где две R образуют вместе -OCF2O-, R1 представляет собой H, R2 представляет собой F, R3 представляет собой H, и R4 представляет собой (R)-CH2CH(OH)CH2OH.5. The compound according to claim 1, where two R form together -OCF 2 O-, R 1 represents H, R 2 represents F, R 3 represents H, and R 4 represents ( R ) -CH 2 CH ( OH) CH 2 OH. 6. Соединение по п.1 формулы IIa:6. The compound according to claim 1 of formula IIa:
Figure 00000002
IIa
Figure 00000002
IIa или его фармацевтически приемлемая соль, где:or its pharmaceutically acceptable salt, where: R4 представляет собой H, -CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH; иR 4 represents H, —CH 2 CH (OH) CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 or —CH 2 CH 2 OH; and R5 представляет собой H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, или R4 и R5 образуют вместе конденсированное пирролидиновое кольцо.R 5 represents H, OH, —CH 2 OCH 2 CH (OH) CH 2 OH, —CH 2 OH, or R 4 and R 5 together form a fused pyrrolidine ring. 7. Соединение по п.6, где R4 представляет собой (R)-CH2CH(OH)CH2OH, (S)-CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH.7. The compound according to claim 6, where R 4 represents ( R ) -CH 2 CH (OH) CH 2 OH, ( S ) -CH 2 CH (OH) CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 or -CH 2 CH 2 OH. 8. Соединение по п. 6, где R5 представляет собой OH, -CH2OCH2CH(OH)CH2OH или -CH2OH.8. The compound of claim 6, wherein R 5 is OH, —CH 2 OCH 2 CH (OH) CH 2 OH, or —CH 2 OH. 9. Соединение по п.6, где R4 представляет собой (R)-CH2CH(OH)CH2OH, (S)-CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH; и R5 представляет собой OH, -CH2OCH2CH(OH)CH2OH или -CH2OH.9. The compound according to claim 6, where R 4 represents ( R ) -CH 2 CH (OH) CH 2 OH, ( S ) -CH 2 CH (OH) CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 or -CH 2 CH 2 OH; and R 5 is OH, —CH 2 OCH 2 CH (OH) CH 2 OH, or —CH 2 OH. 10. Соединение, выбранное из Таблицы 1.10. The compound selected from Table 1. 11. Фармацевтическая композиция, содержащая11. A pharmaceutical composition comprising (i) соединение по п.1; и(i) the compound according to claim 1; and (ii) фармацевтически приемлемый носитель.(ii) a pharmaceutically acceptable carrier. 12. Композиция по п.11, дополнительно содержащая добавочный агент, выбранный из муколитического средства, бронходилататора, антибиотика, противоинфекционного средства, противовоспалительного средства, корректора CFTR, потенциирующего CFTR средства или питательного вещества.12. The composition according to claim 11, additionally containing an additional agent selected from a mucolytic agent, bronchodilator, antibiotic, anti-infective agent, anti-inflammatory agent, CFTR corrector, potentiating CFTR agent or nutrient. 13. Способ увеличения числа функциональных ABC-переносчиков в мембране клетки, включающий стадию приведения в контакт указанной клетки с соединением формулы II:13. A method of increasing the number of functional ABC transporters in a cell membrane, comprising the step of bringing said cell into contact with a compound of formula II:
Figure 00000001
II
Figure 00000001
II где независимо для каждого случая:where independently for each case: R представляет собой H, OH, OCH3, или две R образуют вместе -CH2CH2CH2-, -OCH2O- или -OCF2O-;R represents H, OH, OCH 3 , or two R together form —CH 2 CH 2 CH 2 -, —OCH 2 O— or —OCF 2 O—; R1 представляет собой H или до двух C1-C6алкилов;R 1 represents H or up to two C 1 -C 6 alkyls; R2 представляет собой H или F;R 2 represents H or F; R3 представляет собой H или CN;R 3 represents H or CN; R4 представляет собой H, -CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH; иR 4 represents H, —CH 2 CH (OH) CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 or —CH 2 CH 2 OH; and R5 представляет собой H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, или R4 и R5 образуют вместе конденсированное пирролидиновое кольцо.R 5 represents H, OH, —CH 2 OCH 2 CH (OH) CH 2 OH, —CH 2 OH, or R 4 and R 5 together form a fused pyrrolidine ring. 14. Способ по п.13, где ABC-переносчик представляет собой CFTR.14. The method of claim 13, wherein the ABC carrier is a CFTR. 15. Способ по п.13, где две R образуют вместе -OCF2O-, R1 представляет собой H, и R2 представляет собой F.15. The method according to item 13, where two R form together -OCF 2 O-, R 1 represents H, and R 2 represents F. 16. Способ по п.13, где две R образуют вместе -OCF2O-, R1 представляет собой H, R2 представляет собой F, и R3 представляет собой H.16. The method according to item 13, where two R form together -OCF 2 O-, R 1 represents H, R 2 represents F, and R 3 represents H. 17. Способ по п.13, где две R образуют вместе -OCF2O-, R1 представляет собой H, R2 представляет собой F, R3 представляет собой H, и R4 представляет собой -CH2CH(OH)CH2OH.17. The method according to item 13, where two R form together -OCF 2 O-, R 1 represents H, R 2 represents F, R 3 represents H, and R 4 represents -CH 2 CH (OH) CH 2 OH. 18. Способ по п.13, где две R образуют вместе -OCF2O-, R1 представляет собой H, R2 представляет собой F, R3 представляет собой H, и R4 представляет собой (R)-CH2CH(OH)CH2OH.18. The method according to item 13, where two R form together -OCF 2 O-, R 1 represents H, R 2 represents F, R 3 represents H, and R 4 represents ( R ) -CH 2 CH ( OH) CH 2 OH. 19. Способ по п.13, где соединение представлено формулой IIa:19. The method according to item 13, where the compound is represented by formula IIa:
Figure 00000003
IIa
Figure 00000003
IIa или его фармацевтически приемлемой солью, где:or its pharmaceutically acceptable salt, where: R4 представляет собой H, -CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH; иR 4 represents H, —CH 2 CH (OH) CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 or —CH 2 CH 2 OH; and R5 представляет собой H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, или R4 и R5 образуют вместе конденсированное пирролидиновое кольцо.R 5 represents H, OH, —CH 2 OCH 2 CH (OH) CH 2 OH, —CH 2 OH, or R 4 and R 5 together form a fused pyrrolidine ring. 20. Способ по п.19, где R4 представляет собой (R)-CH2CH(OH)CH2OH, (S)-CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH.20. The method according to claim 19, where R 4 represents ( R ) -CH 2 CH (OH) CH 2 OH, ( S ) -CH 2 CH (OH) CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 or -CH 2 CH 2 OH. 21. Способ по п.19, где R5 представляет собой OH, -CH2OCH2CH(OH)CH2OH или -CH2OH.21. The method according to claim 19, where R 5 represents OH, -CH 2 OCH 2 CH (OH) CH 2 OH or -CH 2 OH. 22. Способ по п.19, где R4 представляет собой (R)-CH2CH(OH)CH2OH, (S)-CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH; и R5 представляет собой OH, -CH2OCH2CH(OH)CH2OH или -CH2OH.22. The method according to claim 19, where R 4 represents ( R ) -CH 2 CH (OH) CH 2 OH, ( S ) -CH 2 CH (OH) CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 or -CH 2 CH 2 OH; and R 5 is OH, —CH 2 OCH 2 CH (OH) CH 2 OH, or —CH 2 OH. 23. Способ по п.13, где соединение выбирают из Таблицы 1.23. The method according to item 13, where the compound is selected from Table 1. 24. Способ лечения у пациента состояния, заболевания или нарушения с участием активности ABC-переносчика, включающий стадию введения упомянутому пациенту соединения формулы II:24. A method of treating a patient with a condition, disease or disorder involving ABC carrier activity, comprising the step of administering to said patient a compound of formula II:
Figure 00000001
II
Figure 00000001
II или его фармацевтически приемлемой соли, где независимо для каждого случая:or its pharmaceutically acceptable salt, where independently for each case: R представляет собой H, OH, OCH3, или две R образуют вместе -CH2CH2CH2-, -OCH2O- или -OCF2O-;R represents H, OH, OCH 3 , or two R together form —CH 2 CH 2 CH 2 -, —OCH 2 O— or —OCF 2 O—; R1 представляет собой H или до двух C1-C6алкилов;R 1 represents H or up to two C 1 -C 6 alkyls; R2 представляет собой H или F;R 2 represents H or F; R3 представляет собой H или CN;R 3 represents H or CN; R4 представляет собой H, -CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH; иR 4 represents H, —CH 2 CH (OH) CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 or —CH 2 CH 2 OH; and R5 представляет собой H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, или R4 и R5 образуют вместе конденсированное пирролидиновое кольцо.R 5 represents H, OH, —CH 2 OCH 2 CH (OH) CH 2 OH, —CH 2 OH, or R 4 and R 5 together form a fused pyrrolidine ring. 25. Способ по п.24, где две R образуют вместе -OCF2O-, R1 представляет собой H, и R2 представляет собой F.25. The method according to paragraph 24, where two R form together -OCF 2 O-, R 1 represents H, and R 2 represents F. 26. Способ по п.24, где две R образуют вместе -OCF2O-, R1 представляет собой H, R2 представляет собой F, и R3 представляет собой H.26. The method according to paragraph 24, where two R form together -OCF 2 O-, R 1 represents H, R 2 represents F, and R 3 represents H. 27. Способ по п.24, где две R образуют вместе -OCF2O-, R1 представляет собой H, R2 представляет собой F, R3 представляет собой H, и R4 представляет собой -CH2CH(OH)CH2OH.27. The method according to paragraph 24, where two R form together -OCF 2 O-, R 1 represents H, R 2 represents F, R 3 represents H, and R 4 represents -CH 2 CH (OH) CH 2 OH. 28. Способ по п.24, где две R образуют вместе -OCF2O-, R1 представляет собой H, R2 представляет собой F, R3 представляет собой H, и R4 представляет собой (R)-CH2CH(OH)CH2OH.28. The method according to paragraph 24, where two R form together -OCF 2 O-, R 1 represents H, R 2 represents F, R 3 represents H, and R 4 represents ( R ) -CH 2 CH ( OH) CH 2 OH. 29. Способ по п.24, где соединение представлено формулой IIa:29. The method according to paragraph 24, where the compound is represented by formula IIa:
Figure 00000004
IIa
Figure 00000004
IIa или его фармацевтически приемлемой солью, где:or its pharmaceutically acceptable salt, where: R4 представляет собой H, -CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH; иR 4 represents H, —CH 2 CH (OH) CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 or —CH 2 CH 2 OH; and R5 представляет собой H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, или R4 и R5 образуют вместе конденсированное пирролидиновое кольцо.R 5 represents H, OH, —CH 2 OCH 2 CH (OH) CH 2 OH, —CH 2 OH, or R 4 and R 5 together form a fused pyrrolidine ring. 30. Способ по п.29, где R4 представляет собой (R)-CH2CH(OH)CH2OH, (S)-CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH.30. The method according to clause 29, where R 4 represents ( R ) -CH 2 CH (OH) CH 2 OH, ( S ) -CH 2 CH (OH) CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 or -CH 2 CH 2 OH. 31. Способ по п.29, где R5 представляет собой OH, -CH2OCH2CH(OH)CH2OH или -CH2OH.31. The method according to clause 29, where R 5 represents OH, -CH 2 OCH 2 CH (OH) CH 2 OH or -CH 2 OH. 32. Способ по п.29, где R4 представляет собой (R)-CH2CH(OH)CH2OH, (S)-CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH; и R5 представляет собой OH, -CH2OCH2CH(OH)CH2OH или -CH2OH.32. The method according to clause 29, where R 4 represents ( R ) -CH 2 CH (OH) CH 2 OH, ( S ) -CH 2 CH (OH) CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 or -CH 2 CH 2 OH; and R 5 is OH, —CH 2 OCH 2 CH (OH) CH 2 OH, or —CH 2 OH. 33. Способ по п.24, где соединение выбрано из Таблицы 1.33. The method according to paragraph 24, where the compound is selected from Table 1. 34. Способ по п.24, где упомянутое состояние, заболевание или нарушение выбрано из муковисцидоза, первичной эмфиземы, наследственного гемохроматоза, дефектов системы коагуляции/фибринолиза, таких как дефицит протеина С, наследственный ангионевротический отек типа 1, дефектов процессинга липидов, таких как семейная гиперхолестеринемия, хиломикронемия типа I, абеталипопротеинемия, лизосомальных болезней накопления, таких как болезнь I-клеток/псевдо-Гурлер, мукополисахаридозы, болезнь Сандхоффа/Тея-Сакса, синдром Криглера-Найяра типа II, полиэндокринопатия/гиперинсулинемия, сахарный диабет, карликовость Ларона, недостаточность миелопероксидазы, первичный гипопаратиреоз, меланома, гликаноз CDG типа 1, первичная эмфизема, врожденный гипертиреоз, несовершенный остеогенез, врожденная гипофибриногенемия, дефицит ACT, несахарный диабет (DI), нейрогенный DI, нефрогенный DI, синдром Шарко-Мари-Тута, болезнь Перлицеуса-Мерцбахера, нейродегенеративных заболеваний, такие как болезнь Альцгеймера, болезнь Паркинсона, амиотрофический боковой склероз, прогрессирующий надъядерный паралич, болезнь Пика, некоторых полиглутаминовых неврологических нарушений, таких как болезнь Гентингтона, спиноцеребеллярная атаксия тип I, спинально-бульбарная мышечная атрофия, дентаторубро-паллидолюисова атрофия и миотоническая дистрофия, а также губчатых энцефалопатий, таких как наследственная болезнь Крейтцфельда-Якоба, болезнь Фабри и синдром Штреусслера-Шейнкера, ХОБЛ, синдрома «сухого глаза» и болезни Шегрена.34. The method according to paragraph 24, where the aforementioned condition, disease or disorder is selected from cystic fibrosis, primary emphysema, hereditary hemochromatosis, defects in the coagulation / fibrinolysis system, such as protein C deficiency, hereditary angioneurotic edema type 1, defects in lipid processing, such as familial hypercholesterolemia, type I chylomicronemia, abetalipoproteinemia, lysosomal storage diseases such as I-cell disease / pseudo-Hurler, mucopolysaccharidoses, Sandhoff / Tay-Sachs disease, Krigler-Nayyar type II syndrome, poly endocrinopathy / hyperinsulinemia, diabetes mellitus, Laron's dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, type 1 CDG glycanosis, primary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, congenital hypofibrinogenemia, nephrogenic deficiency D, non-deficient I, D neurogen, I D, non-deficient I, D neurogen, I, D neurogen, D neurogen, D neurogen, I, D Charcot-Marie-Tooth syndrome, Perliceus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, pain Peak's illness, certain polyglutamine neurological disorders, such as Huntington's disease, type I spinocerebellar ataxia, spinal-bulbar muscular atrophy, dentatorubro-pallidoluyis atrophy and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Strädzreitz and Frederize’s disease -Sheinker, COPD, dry eye syndrome and Sjögren’s disease. 35. Набор для измерения активности ABC-переносчика или его фрагмента в биологическом образце in vitro или in vivo, включающий:35. A kit for measuring the activity of an ABC carrier or fragment thereof in an in vitro or in vivo biological sample, comprising: (i) первую композицию, содержащую соединение формулы II:(i) a first composition comprising a compound of formula II:
Figure 00000001
II
Figure 00000001
II где независимо для каждого случая:where independently for each case: R представляет собой H, OH, OCH3, или две R образуют вместе -CH2CH2CH2-, -OCH2O- или -OCF2O-;R represents H, OH, OCH 3 , or two R together form —CH 2 CH 2 CH 2 -, —OCH 2 O— or —OCF 2 O—; R1 представляет собой H или до двух C1-C6алкилов;R 1 represents H or up to two C 1 -C 6 alkyls; R2 представляет собой H или F;R 2 represents H or F; R3 представляет собой H или CN;R 3 represents H or CN; R4 представляет собой H, -CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH; иR 4 represents H, —CH 2 CH (OH) CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 or —CH 2 CH 2 OH; and R5 представляет собой H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, или R4 и R5 образуют вместе конденсированное пирролидиновое кольцо; иR 5 represents H, OH, —CH 2 OCH 2 CH (OH) CH 2 OH, —CH 2 OH, or R 4 and R 5 together form a fused pyrrolidine ring; and (ii) инструкции для:(ii) instructions for: a) приведения композиции в контакт с биологическим образцом;a) bringing the composition into contact with a biological sample; b) измерения активности упомянутого ABC-переносчика или его фрагмента.b) measuring the activity of said ABC carrier or fragment thereof. 36. Набор по п.35, дополнительно содержащий инструкции для:36. The kit of claim 35, further comprising instructions for: a) приведения дополнительной композиции в контакт с биологическим образцом;a) bringing the additional composition into contact with a biological sample; b) измерения активности упомянутого ABC-переносчика или его фрагмента в присутствии упомянутого дополнительного соединения, иb) measuring the activity of said ABC carrier or fragment thereof in the presence of said additional compound, and c) сравнения активности ABC-переносчика в присутствии дополнительного соединения с плотностью ABC-переносчика в присутствие упомянутой первой композиции.c) comparing the activity of the ABC carrier in the presence of an additional compound with the density of the ABC carrier in the presence of said first composition. 37. Набор по п.35, где набор используют для измерения плотности CFTR.37. The kit of claim 35, wherein the kit is used to measure CFTR density. 38. Набор по п.35, где соединение представлено формулой IIa:38. The kit according to clause 35, where the compound is represented by formula IIa:
Figure 00000005
IIa
Figure 00000005
IIa или его фармацевтически приемлемой солью, где:or its pharmaceutically acceptable salt, where: R4 представляет собой H, -CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH; иR 4 represents H, —CH 2 CH (OH) CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 or —CH 2 CH 2 OH; and R5 представляет собой H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, или R4 и R5 образуют вместе конденсированное пирролидиновое кольцо.R 5 represents H, OH, —CH 2 OCH 2 CH (OH) CH 2 OH, —CH 2 OH, or R 4 and R 5 together form a fused pyrrolidine ring. 39. Набор по п.38, где R4 представляет собой (R)-CH2CH(OH)CH2OH, (S)-CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH.39. The kit of claim 38, wherein R 4 is ( R ) —CH 2 CH (OH) CH 2 OH, ( S ) —CH 2 CH (OH) CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 or -CH 2 CH 2 OH. 40. Набор по п.38, где R5 представляет собой OH, -CH2OCH2CH(OH)CH2OH или -CH2OH.40. The kit of claim 38, wherein R 5 is OH, —CH 2 OCH 2 CH (OH) CH 2 OH, or —CH 2 OH. 41. Набор по п.38, где R4 представляет собой (R)-CH2CH(OH)CH2OH, (S)-CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH; и R5 представляет собой OH, -CH2OCH2CH(OH)CH2OH или -CH2OH.41. The kit of claim 38, wherein R 4 is ( R ) —CH 2 CH (OH) CH 2 OH, ( S ) —CH 2 CH (OH) CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 or -CH 2 CH 2 OH; and R 5 is OH, —CH 2 OCH 2 CH (OH) CH 2 OH, or —CH 2 OH. 42. Набор по п.35, где соединение выбрано из Таблицы 1. 42. The kit of claim 35, wherein the compound is selected from Table 1.
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