RU2014139599A - ATP-BINDING CASSETTE CARRIER MODULATORS - Google Patents

ATP-BINDING CASSETTE CARRIER MODULATORS Download PDF

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RU2014139599A
RU2014139599A RU2014139599A RU2014139599A RU2014139599A RU 2014139599 A RU2014139599 A RU 2014139599A RU 2014139599 A RU2014139599 A RU 2014139599A RU 2014139599 A RU2014139599 A RU 2014139599A RU 2014139599 A RU2014139599 A RU 2014139599A
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acceptable salt
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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:II,или 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 OH или -CHOCHCH(OH)CHOH, при условии, что соединение не являетсяСоединением 234Соединением 302Соединением 322.2. 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 формулы IIa:IIa,или его фармацевтически приемлемая соль,где Rпредставляет собой H, -CHCH(OH)CHOH, -CHCHN(CH)или -CHCHOH; иRпредставляет собой OH или -CHOCHCH(OH)CHOH.6. Соединение по п. 5, где Rпредставляет собой (S)-CHCH(OH)CHOH, -CHCHN(CH)или -CHCHOH.7.Соединение, выбранное изСоединения 307Соединения 308Соединения 309Соединения 311Соединения 312Соединения 313Соединения 314Соединения 315Соединения 316Соединения 318Соединения 320 иСоединения 321,или его фармацевтически приемлемой соли.8. Фармацевтическая композиция в качестве модулятора активности ABC-переносчиков, содержащая(i) соединение по любому из пп. 1-7; и(ii) фармацевтически приемлемый носитель.9. Способ увеличения числа функциональных ABC-переносчиков в мембране клетки, при условии, что клетка не присутствует в человеческом теле, включающий стадию приведения в контакт указанной клетки с соединением формулы II:II,или его фармацевтически приемлемой солью, 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 с1. 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-C1-6 alkyls; R represents H or F; R represents H or CN; R represents H, —CHCH (OH) CHOH, —CHCHN (CH) or —CHCHOH; and R is OH or —CHOCHCH (OH) CHOH, provided that the compound is not Compound 234 Compound 302 Compound 322.2. A compound according to claim 1, wherein two R together form —OCFO—, R is H, and R is F.3. The compound of claim 1, wherein the two R together form —OCFO—, R is H, R is F, and R is H.4. A compound according to claim 1, wherein two R together form —OCFO—, R is H, R is F, R is H, and R is —CHCH (OH) CHOH. 5. The compound of 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 OH or —CHOCHCH (OH) CHOH. 6. A compound according to claim 5, wherein R is (S) —CHCH (OH) CHOH, —CHCHN (CH) or —CHCHOH. 7. A compound selected from Compound 307 Compounds 308 Compounds 309 Compounds 311 Compounds 312 Compounds 318 or 318 Compounds 316 or 318 pharmaceutically acceptable salt. 8. A pharmaceutical composition as a modulator of ABC carrier activity, comprising (i) a compound according to any one of claims. 1-7; and (ii) a pharmaceutically acceptable carrier. A method of increasing the number of functional ABC transporters in a cell membrane, provided that the cell is not present in the human body, comprising the step of bringing said cell into contact with a compound of formula II: II, or a pharmaceutically acceptable salt thereof, where, for each case, independently, R represents H, OH, OCH, or two R together form -CHCHCH-, -OCHO- or -OCFO-; R represents H or up to two C-Calkyls; R represents with

Claims (40)

1. Соединение формулы II:1. The compound of formula II:
Figure 00000001
Figure 00000001
 II,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 OH или -CH2OCH2CH(OH)CH2OH, при условии, что соединение не являетсяR 5 represents OH or —CH 2 OCH 2 CH (OH) CH 2 OH, provided that the compound is not
Figure 00000002
Соединением 234
Figure 00000002
Compound 234
Figure 00000003
Соединением 302
Figure 00000003
Compound 302
Figure 00000004
Соединением 322.
Figure 00000004
Compound 322. 2. Соединение по п. 1, где две R образуют вместе -OCF2O-, R1 представляет собой H, и R2 представляет собой F.2. The compound of claim 1, wherein the two R together form —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 of claim 1, wherein the two R together form —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 of claim 1, wherein the two R together form —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 формулы IIa:5. The compound according to claim 1 of formula IIa:
Figure 00000005
Figure 00000005
 IIa,IIa или его фармацевтически приемлемая соль,or a pharmaceutically acceptable salt thereof, где R4 представляет собой H, -CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH; иwhere R 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 OH или -CH2OCH2CH(OH)CH2OH.R 5 represents OH or —CH 2 OCH 2 CH (OH) CH 2 OH. 6. Соединение по п. 5, где R4 представляет собой (S)-CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH.6. The compound of claim 5, wherein R 4 is (S) —CH 2 CH (OH) CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3, or —CH 2 CH 2 OH. 7.Соединение, выбранное из7.Connection selected from
Figure 00000006
Соединения 307
Figure 00000006
Compounds 307
Figure 00000007
Соединения 308
Figure 00000007
Compounds 308
Figure 00000008
Соединения 309
Figure 00000008
Compounds 309
Figure 00000009
Соединения 311
Figure 00000009
Compounds 311
Figure 00000010
Соединения 312
Figure 00000010
Compounds 312
Figure 00000011
Соединения 313
Figure 00000011
Compounds 313
Figure 00000012
Соединения 314
Figure 00000012
Compounds 314
Figure 00000013
Соединения 315
Figure 00000013
Compounds 315
Figure 00000014
Соединения 316
Figure 00000014
Compounds 316
Figure 00000015
Соединения 318
Figure 00000015
Compounds 318
Figure 00000016
Соединения 320 и
Figure 00000016
Compounds 320 and
Figure 00000017
Соединения 321,
Figure 00000017
Compounds 321, или его фармацевтически приемлемой соли.or a pharmaceutically acceptable salt thereof. 8. Фармацевтическая композиция в качестве модулятора активности ABC-переносчиков, содержащая8. A pharmaceutical composition as a modulator of ABC carrier activity, comprising (i) соединение по любому из пп. 1-7; и(i) a compound according to any one of paragraphs. 1-7; and (ii) фармацевтически приемлемый носитель.(ii) a pharmaceutically acceptable carrier. 9. Способ увеличения числа функциональных ABC-переносчиков в мембране клетки, при условии, что клетка не присутствует в человеческом теле, включающий стадию приведения в контакт указанной клетки с соединением формулы II:9. A method of increasing the number of functional ABC transporters in a cell membrane, provided that the cell is not present in the human body, comprising the step of bringing said cell into contact with a compound of formula II:
Figure 00000018
Figure 00000018
 II,II или его фармацевтически приемлемой солью, 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 R 4 represents H, —CH 2 CH (OH) CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 or -CH2CH2OH; и-CH 2 CH 2 OH; and R5 представляет собой OH или -CH2OCH2CH(OH)CH2OH,R 5 represents OH or —CH 2 OCH 2 CH (OH) CH 2 OH, при условии, что соединение не являетсяprovided that the compound is not
Figure 00000002
Соединением 234
Figure 00000002
Compound 234
Figure 00000003
Соединением 302 или
Figure 00000003
Compound 302 or
Figure 00000004
Соединением 322.
Figure 00000004
Compound 322. 10. Способ по п. 9, где две R образуют вместе -OCF2O-, R1 представляет собой H, и R2 представляет собой F.10. The method according to p. 9, where two R form together -OCF 2 O-, R 1 represents H, and R 2 represents F. 11. Способ по п. 9, где две R образуют вместе -OCF2O-, R1 представляет собой H, R2 представляет собой F, и R3 представляет собой H.11. The method according to claim 9, where two R form together -OCF 2 O-, R 1 represents H, R 2 represents F, and R 3 represents H. 12. Способ по п. 9, 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.12. The method of claim 9, wherein the two R together form —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. 13. Способ по п. 9, где соединение представлено формулой IIa:13. The method according to p. 9, where the compound is represented by formula IIa:
Figure 00000005
Figure 00000005
 IIa,IIa или его фармацевтически приемлемой солью,or a pharmaceutically acceptable salt thereof, где R4 представляет собой H, -CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH; иwhere R 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 OH или -CH2OCH2CH(OH)CH2OH.R 5 represents OH or —CH 2 OCH 2 CH (OH) CH 2 OH. 14. Способ по п. 13, где R4 представляет собой (S)-CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH.14. The method of claim 13, wherein R 4 is (S) —CH 2 CH (OH) CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3, or —CH 2 CH 2 OH. 15. Способ увеличения числа функциональных ABC-переносчиков в мембране клетки, включающий стадию приведения в контакт указанной клетки с соединением, выбранным из15. 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 selected from
Figure 00000006
Соединения 307
Figure 00000006
Compounds 307
Figure 00000007
Соединения 308
Figure 00000007
Compounds 308
Figure 00000008
Соединения 309
Figure 00000008
Compounds 309
Figure 00000009
Соединения 311
Figure 00000009
Compounds 311
Figure 00000010
Соединения 312
Figure 00000010
Compounds 312
Figure 00000011
Соединения 313
Figure 00000011
Compounds 313
Figure 00000012
Соединения 314
Figure 00000012
Compounds 314
Figure 00000013
Соединения 315
Figure 00000013
Compounds 315
Figure 00000014
Соединения 316
Figure 00000014
Compounds 316
Figure 00000015
Соединения 318
Figure 00000015
Compounds 318
Figure 00000016
Соединения 320 и
Figure 00000016
Compounds 320 and
Figure 00000017
Соединения 321,
Figure 00000017
Compounds 321, или его фармацевтически приемлемой соли. or a pharmaceutically acceptable salt thereof. 16. Способ по любому из п.п. 9-15, где ABC-переносчик представляет собой CFTR.16. The method according to any one of paragraphs. 9-15, where the ABC carrier is a CFTR. 17. Применение соединения формулы II:17. The use of the compounds of formula II:
Figure 00000019
Figure 00000019
 II,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 OH или -CH2OCH2CH(OH)CH2OH,R 5 represents OH or —CH 2 OCH 2 CH (OH) CH 2 OH, при условии, что соединение не являетсяprovided that the compound is not
Figure 00000002
Соединением 234
Figure 00000002
Compound 234
Figure 00000003
Соединением 302 или
Figure 00000003
Compound 302 or
Figure 00000004
Соединением 322,
Figure 00000004
Compound 322, для получения лекарственного средства для лечения у пациента состояния, заболевания или нарушения с участием активности ABC-переносчика.for the manufacture of a medicament for treating a patient with a condition, disease, or disorder involving the activity of an ABC carrier. 18. Применение по п. 17, где две R образуют вместе -OCF2O-, R1 представляет собой H, и R2 представляет собой F.18. The application of claim 17, wherein the two R together form —OCF 2 O—, R 1 represents H, and R 2 represents F. 19. Применение по п. 17, где две R образуют вместе -OCF2O-, R1 представляет собой H, R2 представляет собой F, и R3 представляет собой H.19. The use of claim 17, wherein the two R together form —OCF 2 O—, R 1 represents H, R 2 represents F, and R 3 represents H. 20. Применение по п. 17, 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.20. The use of claim 17, wherein the two R together form —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. 21. Применение по п. 17, где соединение представлено формулой IIa:21. The use of claim 17, wherein the compound is represented by formula IIa:
Figure 00000005
Figure 00000005
 IIa,IIa или его фармацевтически приемлемой солью,or a pharmaceutically acceptable salt thereof, где R4 представляет собой H, -CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH; иwhere R 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 OH или -CH2CH(OH)CH2OH.R 5 represents OH or —CH 2 CH (OH) CH 2 OH. 22. Применение по п. 21, где R4 представляет собой (S)-CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH.22. The use of claim 21, wherein R 4 is (S) —CH 2 CH (OH) CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3, or —CH 2 CH 2 OH. 23. Применение соединения, выбранного из23. The use of compounds selected from
Figure 00000006
Соединения 307
Figure 00000006
Compounds 307
Figure 00000007
Соединения 308
Figure 00000007
Compounds 308
Figure 00000008
Соединения 309
Figure 00000008
Compounds 309
Figure 00000009
Соединения 311
Figure 00000009
Compounds 311
Figure 00000010
Соединения 312
Figure 00000010
Compounds 312
Figure 00000011
Соединения 313
Figure 00000011
Compounds 313
Figure 00000012
Соединения 314
Figure 00000012
Compounds 314
Figure 00000013
Соединения 315
Figure 00000013
Compounds 315
Figure 00000014
Соединения 316
Figure 00000014
Compounds 316
Figure 00000015
Соединения 318
Figure 00000015
Compounds 318
Figure 00000016
Соединения 320 и
Figure 00000016
Compounds 320 and
Figure 00000017
Соединения 321,
Figure 00000017
Compounds 321, или его фармацевтически приемлемой соли,  or a pharmaceutically acceptable salt thereof, для получения лекарственного средства для лечения у пациента состояния, заболевания или нарушения с участием активности ABC-переносчика.for the manufacture of a medicament for treating a patient with a condition, disease, or disorder involving the activity of an ABC carrier. 24. Применение по пп. 17-23, где заболевание представляет собой муковисцедоз, наследственную эмфизему, ХОБЛ или болезнь сухих глаз.24. The use of PP. 17-23, where the disease is cystic fibrosis, hereditary emphysema, COPD, or dry eye disease. 25. Применение по п. 24, где заболевание представляет собой муковисцедоз. 25. The use of claim 24, wherein the disease is cystic fibrosis. 26. Набор для измерения активности ABC-переносчика или его фрагмента в биологическом образце in vitro или in vivo, включающий:26. 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 00000019
Figure 00000019
 II,II или его фармацевтически приемлемую 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 OH или -CH2OCH2CH(OH)CH2OH, R 5 represents OH or —CH 2 OCH 2 CH (OH) CH 2 OH, при условии, что соединение не являетсяprovided that the compound is not
Figure 00000002
Соединением 234
Figure 00000002
Compound 234
Figure 00000003
Соединением 302 или
Figure 00000003
Compound 302 or
Figure 00000004
Соединением 322,
Figure 00000004
Compound 322, и (ii) инструкции для:and (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. 27. Набор по п. 27, где соединение представлено формулой IIa:27. The kit of claim 27, wherein the compound is represented by formula IIa:
Figure 00000005
Figure 00000005
 IIa,IIa или его фармацевтически приемлемой солью,or a pharmaceutically acceptable salt thereof, где R4 представляет собой H, -CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH; иwhere R 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 OH или -CH2OCH2CH(OH)CH2OH.R 5 represents OH or —CH 2 OCH 2 CH (OH) CH 2 OH. 28. Набор по п. 26, где R4 представляет собой (S)-CH2CH(OH)CH2OH, -CH2CH2N+(CH3)3 или -CH2CH2OH.28. The kit of claim 26, wherein R 4 is (S) —CH 2 CH (OH) CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3, or —CH 2 CH 2 OH. 29. Набор для измерения активности ABC-переносчика или его фрагмента в биологическом образце in vitro или in vivo, включающий:29. 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, выбранное из(i) a first composition comprising a compound selected from
Figure 00000006
Соединения 307
Figure 00000006
Compounds 307
Figure 00000007
Соединения 308
Figure 00000007
Compounds 308
Figure 00000008
Соединения 309
Figure 00000008
Compounds 309
Figure 00000009
Соединения 311
Figure 00000009
Compounds 311
Figure 00000010
Соединения 312
Figure 00000010
Compounds 312
Figure 00000011
Соединения 313
Figure 00000011
Compounds 313
Figure 00000012
Соединения 314
Figure 00000012
Compounds 314
Figure 00000013
Соединения 315
Figure 00000013
Compounds 315
Figure 00000014
Соединения 316
Figure 00000014
Compounds 316
Figure 00000015
Соединения 318
Figure 00000015
Compounds 318
Figure 00000016
Соединения 320 и
Figure 00000016
Compounds 320 and
Figure 00000017
Соединения 321,
Figure 00000017
Compounds 321, или его фармацевтически приемлемой соли; и or a pharmaceutically acceptable salt thereof; 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. 30. Набор по любому из пп. 26-29, где набор используют для измерения плотности CFTR.30. Set according to any one of paragraphs. 26-29, where the kit is used to measure CFTR density. 31. Соединение формулы II:31. The compound of formula II:
Figure 00000019
Figure 00000019
 II,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 OH или -CH2OCH2CH(OH)CH2OH,R 5 represents OH or —CH 2 OCH 2 CH (OH) CH 2 OH, при условии, что соединение не являетсяprovided that the compound is not
Figure 00000002
Соединением 234
Figure 00000002
Compound 234
Figure 00000003
Соединением 302 или
Figure 00000003
Compound 302 or
Figure 00000004
Соединением 322,
Figure 00000004
Compound 322, для лечения у пациента состояния, заболевания или нарушения с участием активности ABC-переносчика.for treating a patient with a condition, disease, or disorder involving the activity of an ABC carrier. 32. Соединение для лечения у пациента состояния, заболевания или нарушения с участием активности ABC-переносчика, где соединение выбирают из32. A compound for treating a patient with a condition, disease or disorder involving ABC carrier activity, wherein the compound is selected from
Figure 00000006
Соединения 307
Figure 00000006
Compounds 307
Figure 00000007
Соединения 308
Figure 00000007
Compounds 308
Figure 00000008
Соединения 309
Figure 00000008
Compounds 309
Figure 00000009
Соединения 311
Figure 00000009
Compounds 311
Figure 00000010
Соединения 312
Figure 00000010
Compounds 312
Figure 00000011
Соединения 313
Figure 00000011
Compounds 313
Figure 00000012
Соединения 314
Figure 00000012
Compounds 314
Figure 00000013
Соединения 315
Figure 00000013
Compounds 315
Figure 00000014
Соединения 316
Figure 00000014
Compounds 316
Figure 00000015
Соединения 318
Figure 00000015
Compounds 318
Figure 00000016
Соединения 320 и
Figure 00000016
Compounds 320 and
Figure 00000017
Соединения 321,
Figure 00000017
Compounds 321, или его фармацевтически приемлемой соли.or a pharmaceutically acceptable salt thereof. 33. Соединение по п. 31 или 32, где заболевание представляет собой муковисцедоз, наследственную эмфизему, ХОБЛ или болезнь сухих глаз.33. The compound of claim 31 or 32, wherein the disease is cystic fibrosis, hereditary emphysema, COPD, or dry eye disease. 34. Применение по п. 33, где заболевание представляет собой муковисцедоз. 34. The use of claim 33, wherein the disease is cystic fibrosis. 35. Соединение формулы II:35. The compound of formula II:
Figure 00000019
Figure 00000019
 II,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 OH или -CH2OCH2CH(OH)CH2OH,R 5 represents OH or —CH 2 OCH 2 CH (OH) CH 2 OH, при условии, что соединение не являетсяprovided that the compound is not
Figure 00000002
Соединением 234
Figure 00000002
Compound 234
Figure 00000003
Соединением 302 или
Figure 00000003
Compound 302 or
Figure 00000004
Соединением 322,
Figure 00000004
Compound 322, для применения в качестве лекарственного средства, в качестве модулятора активности ABC-переносчиков.for use as a medicine, as a modulator of the activity of ABC carriers. 36. Соединение для применения в качестве лекарственного средства, в качестве модулятора активности ABC-переносчиков, где соединение выбирают из36. The compound for use as a medicine, as a modulator of the activity of ABC carriers, where the compound is selected from
Figure 00000006
Соединения 307
Figure 00000006
Compounds 307
Figure 00000007
Соединения 308
Figure 00000007
Compounds 308 Соединение 309 Compound 309
Figure 00000009
Соединения 311
Figure 00000009
Compounds 311
Figure 00000010
Соединения 312
Figure 00000010
Compounds 312
Figure 00000011
Соединения 313
Figure 00000011
Compounds 313
Figure 00000012
Соединения 314
Figure 00000012
Compounds 314
Figure 00000013
Соединения 315
Figure 00000013
Compounds 315
Figure 00000014
Соединения 316
Figure 00000014
Compounds 316
Figure 00000015
Соединения 318
Figure 00000015
Compounds 318
Figure 00000016
Соединения 320 и
Figure 00000016
Compounds 320 and
Figure 00000017
Соединения 321,
Figure 00000017
Compounds 321, или его фармацевтически приемлемой соли. or a pharmaceutically acceptable salt thereof. 37. Соединение, представляющее собой: 37. The compound is:
Figure 00000014
.
Figure 00000014
. 38. Фармацевтическая композиция в качестве модулятора активности ABC-переносчиков, содержащая38. A pharmaceutical composition as a modulator of ABC carrier activity, comprising (i) соединение по п. 37; и(i) the compound of claim 37; and (ii) фармацевтически приемлемый носитель.(ii) a pharmaceutically acceptable carrier. 39. Фармацевтическая композиция, дополнительно содержащая CFTR усилитель.39. A pharmaceutical composition further comprising a CFTR enhancer. 40. Фармацевтическая композиция по п. 39, где CFTR усилитель представляет собой N-(5-гидрокси-2,4-ди-трет-бутилфенил)-4-оксо-1H-хинолин-3-карбоксамид. 40. The pharmaceutical composition of claim 39, wherein the CFTR enhancer is N- (5-hydroxy-2,4-di-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide.
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