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Небесная энциклопедия

Космические корабли и станции, автоматические КА и методы их проектирования, бортовые комплексы управления, системы и средства жизнеобеспечения, особенности технологии производства ракетно-космических систем

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Мониторинг СМИ

Мониторинг СМИ и социальных сетей. Сканирование интернета, новостных сайтов, специализированных контентных площадок на базе мессенджеров. Гибкие настройки фильтров и первоначальных источников.

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Поддерживает ввод нескольких поисковых фраз (по одной на строку). При поиске обеспечивает поддержку морфологии русского и английского языка
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05-01-2012 дата публикации

Modulators of atp-binding cassette transporters

Номер: US20120004216A1
Автор: Ashvani K. Singh, Lewis R. Makings, Mark T. Miller, Matthew Hamilton, Peter D.J. Grootenhuis, Sara S. Hadida Ruah, Thomas Cleveland
Принадлежит: Vertex Pharmaceuticals Inc

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including CF Transmembrane Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

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Номер записи: 1
09-02-2012 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20120035179A1
Автор: Grootenhuis Peter D.J., Hadida-Ruah Sara S., Hamilton Matthew, Miller Mark, Singh Ashvani
Принадлежит:

The present invention provides compounds of Formula I useful as modulators of ABC transporter activity, 144-. (canceled)46. (canceled)47. The method according to claim 45 , wherein said disease is selected from cystic fibrosis claim 45 , hereditary emphysema claim 45 , hereditary hemochromatosis claim 45 , coagulation-cibrinolysis deficiencies claim 45 , such as protein C deficiency claim 45 , Type 1 hereditary angioedema claim 45 , lipid processing deficiencies claim 45 , such as familial hypercholesterolemia claim 45 , Type 1 chylomicronemia claim 45 , abetalipoproteinemia claim 45 , lysosomal storage diseases claim 45 , such as I-cell disease/Pseudo-Hurler claim 45 , secretory diarrhea or polycystic kidney disease claim 45 , mucopolysaccharidoses claim 45 , Sandhof/Tay-Sachs claim 45 , Crigler-Najjar type II claim 45 , polyendocrinopathy/Hyperinsulemia claim 45 , Diabetes mellitus claim 45 , Laron dwarfism claim 45 , myleoperoxidase deficiency claim 45 , primary hypoparathyroidism claim 45 , melanoma claim 45 , glycanosis CDG type 1 claim 45 , hereditary emphysema claim 45 , congenital hyperthyroidism claim 45 , osteogenesis imperfecta claim 45 , hereditary hypofibrinogenemia claim 45 , ACT deficiency claim 45 , Diabetes insipidus (DI) claim 45 , neurophyseal DI claim 45 , Neprogenic DI claim 45 , Charcot-Marie Tooth syndrome claim 45 , Perlizaeus-Merzbacher disease claim 45 , neurodegenerative diseases such as Alzheimer's disease claim 45 , Parkinson's disease claim 45 , Amyotrophic lateral sclerosis claim 45 , progressive supranuclear plasy claim 45 , Pick's disease claim 45 , several polyglutamine neurological disorders such as Huntington claim 45 , Spinocerebullar ataxia type I claim 45 , spinal and bulbar muscular atrophy claim 45 , Dentatorubal pallidoluysian claim 45 , and Myotonic dystrophy claim 45 , as well as Spongiform encephalopathies claim 45 , such as Hereditary Creutzfeldt-Jakob disease (due to Prion protein processing defect) claim 45 , Fabry ...

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Номер записи: 2
22-03-2012 дата публикации

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Номер: US20120071504A1
Автор: Botfield Martyn Curtis, Grootenhuis Peter Diederik Jan, Ruah Sara Sabina Hadida, Van Goor Fredrick F., Yang Xiaoqing, Zlokarnik Gregor
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

This invention relates to a compound of Formula I: 2. A compound according to claim 1 , wherein R is CHOH.3. A compound according to claim 1 , wherein R is COOH.4. (canceled)5. (canceled)6. A pharmaceutical composition comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'a compound of Formula I, according to ; and'}a pharmaceutically acceptable carrier or adjuvant.9. The pharmaceutical composition of claim 6 , further comprising an additional agent selected from a mucolytic agent claim 6 , a bronchodilator claim 6 , an antibiotic claim 6 , an anti-invective agent claim 6 , an anti-inflammatory agent claim 6 , a CFTR modulator claim 6 , or a nutritional agent.10. A method of modulating CFTR activity in a biological sample comprising the step of contacting said biological sample with a compound of Formula I according to .13. A method of treating or lessening the severity of a disease in a patient comprising administering to said patient an effective amount of a compound of Formula I according to claim 1 , wherein said disease is selected from cystic fibrosis claim 1 , asthma claim 1 , smoke induced COPD claim 1 , chronic bronchitis claim 1 , rhinosinusitis claim 1 , constipation claim 1 , pancreatitis claim 1 , pancreatic insufficiency claim 1 , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) claim 1 , mild pulmonary disease claim 1 , idiopathic pancreatitis claim 1 , allergic bronchopulmonary aspergillosis (ABPA) claim 1 , liver disease claim 1 , hereditary emphysema claim 1 , hereditary hemochromatosis claim 1 , coagulation-fibrinolysis deficiencies claim 1 , such as protein C deficiency claim 1 , Type 1 hereditary angioedema claim 1 , lipid processing deficiencies claim 1 , such as familial hypercholesterolemia claim 1 , Type 1 chylomicronemia claim 1 , abetalipoproteinemia claim 1 , lysosomal storage diseases claim 1 , such as I-cell disease/pseudo-Hurler claim 1 , mucopolysaccharidoses claim 1 , Sandhof/Tay-Sachs claim ...

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Номер записи: 3
17-05-2012 дата публикации

PROCESS FOR MAKING MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Номер: US20120122921A1
Автор: Botfield Martyn Curtis, DeMattei John, Grootenhuis Peter Diederik Jan, Krueger Brian R., Looker Adam R., Neubert-Langille Bobbianna J., Roeper Stefanie, Ryan Michael P., Trudeau Martin, Van Goor Fredrick F., Yap Guerette Dahrika Milfred Lao, Zlokarnik Gregor
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The invention provides a process for the preparation of a compound of Formula 1, 2. The process of claim 1 , wherein Ris independently —OC(O)OR′ claim 1 , —OC(O)NHR′ claim 1 , or{'sub': '2', '—OC(O)N(R), wherein R′ is not hydrogen.'}3. The process of claim 2 , further comprising cleaving the —OC(O)OR′ claim 2 , —OC(O)NHR′ claim 2 , or —OC(O)N(R′)to form —OH.4. The process of claim 3 , wherein the cleavage is performed by treating a compound of Formula 1 with an alcoholic solvent in the presence of NaOH claim 3 , KOH or sodium methoxide.5. The process of claim 4 , wherein the alcoholic solvent is methanol.6. The process of claim 1 , wherein at least one of Ror Ris independently a Cstraight or branched alkyl which is substituted with —COOR′ or —CON(R′) claim 1 , wherein R′ is not hydrogen.7. The process of claim 6 , further comprising hydrolyzing each —COOR′ claim 6 , or —CON(R′)to form —COOH.8. The process of claim 7 , wherein the hydrolysis is performed by treating a compound of Formula 1 with an alcoholic solvent in the presence of NaOH claim 7 , KOH or sodium methoxide.9. The process of claim 8 , wherein the alcoholic solvent is methanol.10. The process of claim 6 , wherein Ris independently —OC(O)OR′ claim 6 , —OC(O)NHR′ claim 6 , or —OC(O)N(R′) claim 6 , wherein R′ is not hydrogen.11. The process of claim 10 , further comprising cleaving the —OC(O)OR′ claim 10 , —OC(O)NHR′ claim 10 , or —OC(O)N(R′)to form —OH.12. The process of claim 11 , wherein the cleavage is performed by treating a compound of Formula 1 with an alcoholic solvent in the presence of NaOH claim 11 , KOH or sodium methoxide.13. The process of claim 12 , wherein the alcoholic solvent is methanol.14. The process of claim 1 , wherein the coupling is performed in the presence of a base.15. The process of claim 14 , wherein the base is KCO claim 14 , EtN claim 14 , NMM claim 14 , pyridine or DIEA.16. The process of claim 1 , wherein the coupling is performed in the presence of a solvent.17. The ...

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Номер записи: 4
19-07-2012 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20120184583A1
Автор: Chambers, GONZALEZ, Grootenhuis Peter Diederik Jan, Hadida-Ruah Sara Sabina, III Fred, III Jesus E., Liu Yahua, Makings Lewis Ray, Miller Mark Thomas, Olson Eric R., Rader James Arvid, Singh Ashvani Kumar, Van Goor Frederick F.
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 2. The method according to claim 1 , wherein each of C and X is H.3. The method according to claim 2 , wherein A and B are independently optionally substituted aryl or heteroaryl.4. The method according to claim 3 , wherein A and B are independently selected from optionally substituted phenyl claim 3 , pyrazolyl claim 3 , pyridyl claim 3 , thiazolyl claim 3 , oxazolyl claim 3 , thiophenyl claim 3 , or furanyl.7. The method according to any one of claim 6 , wherein Ris selected from halo claim 6 , CF claim 6 , NH claim 6 , NH(C1-C6 alkyl) claim 6 , NHC(O)CH claim 6 , OH claim 6 , O(C1-C6 alkyl) claim 6 , OPh claim 6 , O-benzyl claim 6 , S—(C1-C6 alkyl) claim 6 , C1-C6 alkyl claim 6 , NO claim 6 , CN claim 6 , methylenedioxy claim 6 , ethylenedioxy claim 6 , SONH(C1-C6 alkyl) claim 6 , or SON(C1-C6 alkyl).8. The method according to claim 1 , wherein said compound is selected compounds IA-1 to IA-139 in Table 1 compound I-1 to I-21 in Table 2.10. The method according to claim 9 , wherein Cis H.11. The method according to claim 10 , wherein{'sub': 1', '2, 'Xis selected from (C1-C4)-aliphatic, or C(O)—NH.'}13. The method according to claim 12 , said compound has one or more of the features selected from the group:{'sub': 3', '3', '2, '(a) Xis halo, CF, or NO; and'}{'sub': 2', '3', '2, '(b) Xis halo, CF, methyl, ethyl, propyl, or CONH.'}16. The method according to claim 15 , wherein Xand Care H.17. The method according to claim 16 , wherein compounds of formula (IV) have one or more of the features selected from the group:{'sub': '2', 'claim-text': 5-(3′-trifluoromethylphenyl)-furan-2-yl;', '5-trifluoromethyl-2-methyl-furan-3-yl;', '5-t-butyl-2- ...

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Номер записи: 5
02-08-2012 дата публикации

PYRROLOPYRAZINE-SPIROCYCLIC PIPERIDINE AMIDES AS MODULATORS OF ION CHANNELS

Номер: US20120196869A1
Автор: Anderson Corey, Arumugam Vijayalaksmi, Grootenhuis Peter Diederik Jan, Hadida Ruah Sara Sabina, Jiang Licong, Kallel Edward Adam, McCartney Jason, Miller Mark Thomas
Принадлежит:

The invention relates to pyrrolopyrazine-spirocyclic piperidine amide compounds useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders. 2. The compound of claim 1 , wherein claim 1 , independently for each occurrence:{'sup': 1', '8', '8', '8', '8', '8', '8', '8', '8', '8', '8', '8', '9', '8', '1, 'sub': 2', '2', '2', '2', '2', '2', '3', '2', '2, 'Ris H, C1-C6 alkyl, C3-C8 cycloalkyl, halo, CN, NRSOR, SOR, SR, SOR, NRCOR, NRCOR, CON(R), SON(R), CF, heterocycloalkyl, or a straight chain, branched, or cyclic (C1-C8)-Rwherein up to two CHunits may be replaced with O, CO, S, SO, SOor NR, or two Rtaken together form an oxo group, or a 3 to 7 membered fused cycloalkyl ring, or a 3 to 7 membered spirocyclic ring;'}{'sup': 2', '8', '8', '8', '8', '8', '8', '9', '8, 'sub': 2', '2', '2', '2', '2', '3', '2', '2', '2', '2, 'Ris H, C1-C6 alkyl, C1-C6 haloalkyl, CN, OH, SOR, SR, SOR, COR, CON(R), SON(R), CF, CHF, or a straight chain, branched, or cyclic (C1-C8)-Rwherein up to two CHunits may be replaced with O, CO, S, SO, SO, CF, or NR;'}{'sup': 3', '8', 'S', '8', '9', '8, 'sub': 2', '2', '3', '2', '3', '2', '2', '2', '2, 'Ris H, C1-C6 alkyl, C3-C8 cycloalkyl, COR, COR, COH, CON(R), CF, CHCF, CHCHF, or a straight chain, branched, or cyclic (C1-C8)-Rwherein up to two CHunits may be replaced with O, CO, S, SO, SOor NR;'}{'sup': 4', '8', '4, 'sub': 2', '2, 'Ris H, C1-C6 alkyl, halo, C3-C8 cycloalkyl, wherein up to two CHunits may be replaced by O, CO, S, SO, SO, or NR, or 2 Rtaken together form a fused 3 to 7 membered cycloalkyl ring;'}{'sup': 8', '9', '8, 'sub': 3', '2', '2, 'Ris H, C1-C6 alkyl, CF, C3-C8 cycloalkyl, or a straight chain, branched, or cyclic (C1-C8)-Rwherein up to two CHunits may be replaced with O, CO, S, SO, SOor NR, or 2 Rtaken together with the atoms to which they are attached form a ring;'}{'sup ...

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Номер записи: 6
30-08-2012 дата публикации

Pharmaceutical composition and administrations thereof

Номер: US20120220625A1
Автор: Alfredo Grossi, Christopher R. Young, Fredrick F. Van Goor, Gregor Zlokarnik, Kirk Dinehart, Kirk Overhoff, Marinus Jacobus Verwijs, Martyn Botfield, Patricia Hurter, Peter D.J. Grootenhuis, William Rowe
Принадлежит: Vertex Pharmaceuticals Inc

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, methods of manufacturing pharmaceutical compositions of the present invention, and methods of administering pharmaceutical compositions of the present invention.

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Номер записи: 7
13-09-2012 дата публикации

Modulators of ATP-Binding Cassette Transporters

Номер: US20120232059A1
Автор: Bear Brian, Grootenhuis Peter D.J., Hadida-Ruah Sara, Hamilton Matthew, McCartney Jason, Miller Mark, van Goor Frederick, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 1. (canceled)3. (canceled)4. A method of treating or lessening the severity of cystic fibrosis in a patient comprising the administering to said patient an effective amount of a compound the composition according to .57-. (canceled) The present application claims the benefit under 35 U.S.C. §120 of U.S. application Ser. No. 11/594,431, filed Nov. 8, 2006, which claims the benefit under 35 U.S.C. §119 of U.S. Provisional Application No. 60/734,506, filed on Nov. 8, 2005, U.S. Provisional Application No. 60/754,086, filed on Dec. 27, 2005, and U.S. Provisional Application No. 60/802,458, filed on May 22, 2006, the entire contents of each of the above applications being incorporated herein by reference.The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.ABC transporters are a family of membrane transporter proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics, as well as anions. ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were discovered as multi-drug resistance proteins (like the MDR1-P glycoprotein, or the multi-drug resistance protein, MRP1), defending malignant cancer cells against chemotherapeutic agents. To date, ...

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Номер записи: 8
11-10-2012 дата публикации

Pharmaceutical Composition and Administrations Thereof

Номер: US20120258983A1
Автор: Botfield Martyn, Dinehart Kirk, Grootenhuis Peter D.J., Grossi Alfredo, Hurter Patricia, Overhoff Kirk, Rowe William, Van Goor Fredrick F., Verwijs Marinus Jacobus, Young Christopher R., Zlokarnik Gregor
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, methods of manufacturing pharmaceutical compositions of the present invention, and methods of administering pharmaceutical compositions of the present invention. 1. A method of treating or lessening the severity of Osteoporosis or Osteopenia in a patient comprising administering to said patient Compound 1 or a pharmaceutically acceptable salt thereof.2. The method of claim 1 , wherein Compound 1 is substantially amorphous Compound 1 or a pharmaceutically acceptable salt thereof.3. The method of claim 1 , wherein Compound 1 is amorphous Compound 1 or a pharmaceutically acceptable salt thereof.4. The method of claim 1 , wherein administering Compound 1 to said patient comprises administering a pharmaceutical composition claim 1 , in which the pharmaceutical composition comprises about 34.1 wt % of a solid dispersion by weight of the composition claim 1 , wherein the dispersion comprises about 80 wt % of substantially amorphous or amorphous Compound 1 by weight of the dispersion claim 1 , about 19.5 wt % of HPMCAS by weight of the dispersion claim 1 , and about 0.5 wt % SLS by weight of the dispersion; about 30.5 wt % of microcrystalline cellulose by weight of the composition; about 30.4 wt % of lactose by weight of the composition; about 3 wt % of sodium croscarmellose by weight of the composition; about 0.5 wt % of SLS by weight of the composition; about 0.5 wt % of colloidal silicon dioxide by weight of the composition; and about 1 wt % of magnesium stearate by weight of the composition.5. The method of claim 4 , wherein the pharmaceutical composition contains 150 mg of Compound 1.6. A method of providing bone healing and/or bone repair in a patient comprising administering to said patient Compound 1 or a pharmaceutically acceptable salt thereof.7. The method of claim 6 , wherein ...

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Номер записи: 9
25-10-2012 дата публикации

PYRIDYL DERIVATIVES AS CFTR MODULATORS

Номер: US20120270869A1
Автор: Bear Brian, Grootenhuis Peter, Hadida Ruah Sara, Miller Mark, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 5. The compound of claim 1 , wherein Ris selected from the group consisting of chloro claim 1 , methyl claim 1 , OH claim 1 , methoxy claim 1 , thiomethyl claim 1 , and trifluoromethoxy.7. The compound of claim 6 , wherein J is CH.8. The compound of claim 6 , wherein J is CF.9. The compound of claim 1 , wherein Ris H or alkyl.10. The compound of claim 1 , wherein W is a bond.11. The compound of claim 1 , wherein W is an optionally substituted (C1-C6) alkylidene chain.12. The compound of claim 1 , wherein W is selected from the group consisting of —CH— claim 1 , —NH— claim 1 , —O— claim 1 , —CO— claim 1 , and —OCH—.13. The compound of claim 1 , wherein Ris selected from the group consisting of H claim 1 , OH claim 1 , heterocyclic claim 1 , aryl claim 1 , phenyl claim 1 , heteroaryl claim 1 , pyridyl claim 1 , alkoxy claim 1 , cycloalkyl claim 1 , and cyclohexyl.14. The compound of claim 1 , wherein —W—Ris acyclic.15. The compound of claim 1 , wherein —W—Ris an aryl claim 1 , heteroaryl claim 1 , cycloaliphatic claim 1 , or heterocycloaliphatic ring.19. The compound of claim 18 , wherein J is CH.20. The compound of claim 18 , wherein J is CF.21. The compound of claim 18 , wherein —W—Ris acyclic.22. The compound of claim 18 , wherein —W—Ris an aryl claim 18 , heteroaryl claim 18 , cycloaliphatic claim 18 , or heterocycloaliphatic ring.33. The compound of claim 1 , wherein the compound is selected from Table 1.34. A pharmaceutical composition comprising{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, '(i) a compound of ; and'}(ii) a pharmaceutically acceptable carrier.35. The composition of claim 34 , further comprising an ...

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Номер записи: 10
06-12-2012 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20120309758A1
Автор: Binch Hayley, Botfield Martyn C., Fanning Lev T.D., Grootenhuis Peter Diederik Jan, Hadida Ruah Sara S., Hazlewood Anna R., Hurley Dennis James, Numa Mehdi, Sheth Urvi, Silina Alina, Vairagoundar Rajendran, Van Goor Fredrick F., Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 1. A compound selected from:6,7-difluoro-N-(2-fluoro-5-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide;5-hydroxy-N-[5-hydroxy-4-tert-butyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide;4-oxo-N-[3-(1-piperidyl)-5-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide;N-[4-(3,3-dimethylpyrrolidin-1-yl)-2-(trifluoromethyl)phenyl]-6-methyl-4-oxo-1H-quinoline-3-carboxamide;6-fluoro-N-(3-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide;N-(3-fluoro-4-tert-butyl-phenyl)-5-hydroxy-4-oxo-1H-quinoline-3-carboxamide;methyl 1-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-3-(trifluoromethyl)phenyl]piperidine-2-carboxylate;5-hydroxy-N-[4-[2-hydroxy-1-(hydroxymethyl)-1-methyl-ethyl]phenyl]-4-oxo-1H-quinoline-3-carboxamide;5-hydroxy-4-oxo-N-[5-(trifluoromethyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide;6-fluoro-4-oxo-N-[2-(trifluoromethyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide;N-(5-hydroxy-2,4-ditert-butyl-phenyl)-6-methoxy-4-oxo-1H-quinoline-3-carboxamide;N-[5-hydroxy-4-isopropyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide;N-[2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)-phenyl]-5-methyl-4-oxo-1H-quinoline-3-carboxamide;N-[2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)-phenyl]-7-methyl-4-oxo-1H-quinoline-3-carboxamide;5-hydroxy-4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide;N-[2-fluoro-5-hydroxy-4-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide;5-hydroxy-N-[3-methoxy-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide;6-methyl-N-[4-(2-methylpyrrolidin-1-yl)-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide;N-[4-(3,3-dimethylpyrrolidin-1-yl)-2-(trifluoromethyl) ...

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Номер записи: 11
20-12-2012 дата публикации

Modulators of ATP-Binding Cassette Transporters

Номер: US20120322798A1
Автор: Bear Brian, Grootenhuis Peter D.J., Hadida Ruah Sara S., Hamilton Matthew, McCartney Jason, Miller Mark, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTC”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 148-. (canceled)5052-. (canceled)53. The method according to claim 49 , wherein one Rthat is attached to 5- or 6-position of the pyridyl ring is aryl or heteroaryl claim 49 , each optionally substituted with 1 claim 49 , 2 claim 49 , or 3 of R; wherein Ris —ZR; wherein each Zis independently a bond or an optionally substituted branched or straight Caliphatic chain wherein up to two carbon units of Zare optionally and independently replaced by —CO— claim 49 , —CS— claim 49 , —CONR— claim 49 , —CONRNR— claim 49 , —CO— claim 49 , —COO— claim 49 , —NRCO— claim 49 , —O— claim 49 , —NRCONR— claim 49 , —OCONR— claim 49 , —NRNR— claim 49 , —NRCO— claim 49 , —S— claim 49 , —SO— claim 49 , —SO— claim 49 , —NR— claim 49 , —SONR— claim 49 , —NRSO— claim 49 , or —NRSONR—; each Ris independently R claim 49 , halo claim 49 , —OH claim 49 , —NH claim 49 , —NO claim 49 , —CN claim 49 , —CF claim 49 , or —OCF; and each Ris independently hydrogen claim 49 , an optionally substituted Caliphatic group claim 49 , an optionally substituted cycloaliphatic claim 49 , an optionally substituted heterocycloaliphatic claim 49 , an optionally substituted aryl claim 49 , or an optionally substituted heteroaryl.54. The method according to claim 53 , wherein the one Rattached to the 5- or 6-position of the pyridyl ring is phenyl optionally substituted with 1 claim 53 , 2 claim 53 , or 3 of R.55. The method according to claim 53 , wherein the one Rattached to the 5- or 6-position of the pyridyl ring is heteroaryl optionally substituted with 1 claim 53 , 2 claim 53 , or 3 of R.56. The method according to claim 53 , ...

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Номер записи: 12
10-01-2013 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20130011923A1
Автор: Grootenhuis Peter, Hazelwood Anna, Ruah Sara Hadida, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 3. The method according to claim 2 , wherein Ais an optionally substituted 6 membered aromatic ring having 0-4 heteroatoms claim 2 , wherein said heteroatom is nitrogen.4. The method according to claim 3 , wherein Ais an optionally substituted phenyl claim 3 , pyridyl claim 3 , pyrimidinyl claim 3 , pyrazinyl or triazinyl.5. The method according to claim 2 , wherein Ais an optionally substituted 5-membered aromatic ring having 0-3 heteroatoms independently selected from nitrogen claim 2 , oxygen claim 2 , or sulfur.6. The method according to claim 2 , wherein Ais an optionally substituted 5-6 membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen claim 2 , oxygen claim 2 , or sulfur.7. The method according to claim 6 , wherein Ais an optionally substituted 5-membered aromatic ring having 0-3 heteroatoms independently selected from nitrogen claim 6 , oxygen claim 6 , or sulfur.9. The method according to claim 1 , wherein W is a bond or is an optionally substituted Calkylidene chain wherein one or two non-adjacent methylene units are optionally and independently replaced by O claim 1 , NR′ claim 1 , S claim 1 , SO claim 1 , or COO claim 1 , or CO.10. The method according to claim 1 , wherein Ris R′ or halo.11. The method according to claim 1 , wherein each occurrence of WRis independently —Calkyl claim 1 , —Cperhaloroalkyl claim 1 , —O(Calkyl) claim 1 , —CF claim 1 , —OCF claim 1 , —CHF claim 1 , —OCHF claim 1 , —SCF claim 1 , —F claim 1 , —Cl claim 1 , —Br claim 1 , or —COOR′ claim 1 , —COR′ claim 1 , —O(CH)N(R′)(R′) claim 1 , —O(CH)N(R)(R′) claim 1 , —CON(R′)(R′) claim 1 , —(CH)OR′ claim 1 , —(CH)OR′ ...

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Номер записи: 13
17-01-2013 дата публикации

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Номер: US20130018070A1
Автор: Binch Hayley, Fanning Lev T.D., Grootenhuis Peter D.J., Hadida Ruah Sara S, Hazlewood Anna, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 132-. (canceled)34. A method of treating or lessening the severity of a disease in a patient claim 33 , wherein said disease is selected from cystic fibrosis claim 33 , hereditary emphysema claim 33 , hereditary hemochromatosis claim 33 , coagulation-fibrinolysis deficiencies claim 33 , such as protein C deficiency claim 33 , Type 1 hereditary angioedema claim 33 , lipid processing deficiencies claim 33 , such as familial hypercholesterolemia claim 33 , Type 1 chylomicronemia claim 33 , abetalipoproteinemia claim 33 , lysosomal storage diseases claim 33 , such as I-cell disease/pseudo-Hurler claim 33 , mucopolysaccharidoses claim 33 , Sandhof/Tay-Sachs claim 33 , Crigler-Najjar type II claim 33 , polyendocrinopathy/hyperinsulemia claim 33 , Diabetes mellitus claim 33 , Laron dwarfism claim 33 , myleoperoxidase deficiency claim 33 , primary hypoparathyroidism claim 33 , melanoma claim 33 , glycanosis CDG type 1 claim 33 , congenital hyperthyroidism claim 33 , osteogenesis imperfecta claim 33 , hereditary hypofibrinogenemia claim 33 , ACT deficiency claim 33 , Diabetes insipidus (DI) claim 33 , neurophyseal DI claim 33 , neprogenic DI claim 33 , Charcot-Marie Tooth syndrome claim 33 , Perlizaeus-Merzbacher disease claim 33 , neurodegenerative diseases such as Alzheimer's disease claim 33 , Parkinson's disease claim 33 , amyotrophic lateral sclerosis claim 33 , progressive supranuclear plasy claim 33 , Pick's disease claim 33 , several polyglutamine neurological disorders asuch as Huntington claim 33 , spinocerebullar ataxia type I claim 33 , spinal and bulbar muscular atrophy claim 33 , dentatorubal pallidoluysian claim 33 , and myotonic ...

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Номер записи: 14
07-02-2013 дата публикации

Modulators of ATP-Binding Cassette Transporters

Номер: US20130035327A1
Автор: Grootenhuis Peter, Hadida-Ruah Sara, Hazlewood Anna, McCartney Jason, Singh Ashvani, Van Goor Fredrick, Zhou Jinglan
Принадлежит:

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 3. The compound according to claim 2 , wherein Ais an optionally substituted 6 membered aromatic ring having 0-4 heteroatoms claim 2 , wherein said heteroatom is nitrogen.4. The compound according to claim 2 , wherein Ais an optionally substituted phenyl.5. The compound according to claim 2 , wherein Ais an optionally substituted 6 membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen claim 2 , oxygen claim 2 , or sulfur.6. The compound according to claim 2 , wherein Ais an optionally substituted 5-membered aromatic ring having 0-3 heteroatoms independently selected from nitrogen claim 2 , oxygen claim 2 , or sulfur.7. The compound according to claim 2 , wherein Ais a 5-membered aromatic ring having 1-2 nitrogen atoms.9. The compound according to claim 1 , wherein Rand Ris hydrogen.10. The compound according to claim 9 , wherein Rand Rare simultaneously hydrogen; Ris hydrogen or —OH; and Ris hydrogen or fluoro.11. The compound according to claim 10 , Ris hydrogen.12. The compound according to claim 1 , wherein each occurrence of WRis independently —C1-C3 alkyl claim 1 , C1-C3 perhaloalkyl claim 1 , —O(C1-C3 alkyl) claim 1 , —CF claim 1 , —OCF claim 1 , —SCF claim 1 , —F claim 1 , —Br claim 1 , or —COOR′ claim 1 , —COR′ claim 1 , —O(CH)N(R′)(R′) claim 1 , —O(CH)N(R′)(R′) claim 1 , —CON(R′)(R′) claim 1 , —(CH)OR′ claim 1 , —(CH)OR′ claim 1 , optionally substituted monocyclic or bicyclic aromatic ring claim 1 , optionally substituted arylsulfone claim 1 , optionally substituted 5-membered heteroaryl ring claim 1 , —N(R′)(R′) claim 1 , —(CH)N(R′)(R′) claim 1 , or —(CH)N(R′)(R′).13. The compound according to claim ...

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Номер записи: 15
14-02-2013 дата публикации

Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

Номер: US20130040986A1
Автор: Binch Hayley, Botfield Martyn, Fanning Lev T.D., Grootenhuis Peter D.J., Numa Mehdi Michel Djamel, Van Goor Fredrick
Принадлежит:

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR. 65. The compound according to any one of - claims 2 , wherein Ris —CF.75. The compound according to any one of - claims 2 , wherein Ris —CN.85. The compound according to any one of - claims 2 , wherein Ris —CH.98. The compound according to any one of - claims 6 , wherein Ris hydrogen.108. The compound according to any one of - claims 6 , wherein Ris —CH.118. The compound according to any one of - claims 6 , wherein Ris —CF.128. The compound according to any one of - claims 6 , Ris —OH.138. The compound according to any one of - claims 6 , wherein Ris —CHOH.1413. The compound according to any one of - claims 9 , wherein Ris hydrogen.1513. The compound according to any one of - claims 9 , wherein Ris —CH.1613. The compound according to any one of - claims 9 , wherein Ris —OCH.1712. The compound according to any one of - claims 9 , wherein Ris —CN.1817. The compound according to any one of - wherein X is nitrogen.1917. The compound according to any one of - wherein Y is nitrogen.2120. A pharmaceutical composition comprising a compound according to any one of - and a pharmaceutically acceptable carrier or adjuvant.22. The pharmaceutical composition according to claim 21 , further comprising an additional agent selected from a mucolytic agent claim 21 , a bronchodialator claim 21 , an antibiotic claim 21 , an anti-infective agent claim 21 , an anti-inflammatory agent claim 21 , a CFTR modulator other than a compound of formula (I) claim 21 , or a nutritional agent.23. The pharmaceutical composition according to claim 22 , wherein said additional agent is a CFTR modulator other than a compound of formula (I).2420. A method of treating or lessening the severity of a disease in a patient claims 1 , wherein said disease is selected ...

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Номер записи: 16
21-03-2013 дата публикации

Process for Making Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

Номер: US20130072522A1
Автор: Adam R. Looker, Bobbianna J. Neubert-Langille, Brian R. Krueger, Dahrika Milfred Yap GUERETTE, Fredrick F. Van Goor, Gregor Zlokarnik, John Demattei, Martin Trudeau, Martyn Curtis Botfield, Michael P. Ryan, Peter Diederik Jan Grootenhuis, Stefanie Roeper
Принадлежит: Vertex Pharmaceuticals Inc

The invention provides a process for the preparation of a compound of Formula 1, comprising coupling a carboxylic acid of Formula 2 with an aniline of Formula 3 in the presence of a coupling agent.

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Номер записи: 17
23-05-2013 дата публикации

PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATIONS THEREOF

Номер: US20130131107A1
Автор: Alargova Rossitza Gueorguieva, Alcacio Tim Edward, Arekar Sneha G., Binch Hayley Marie, Botfield Martyn Curtis, Fanning Lev Tyler Dewey, Grootenhuis Peter Diederik Jan, Hurley Dennis James, Johnston Steven C., Kadiyala Irina Nikolaevna, Kaushik Ritu Rohit, Keshavarz-Shokri Ali, Krawiec Mariusz, Lee Elaine Chungmin, Luisi Brian, Medek Ales, Mudunuri Praveen, Numa Mehdi, Sheth Urvi Jagdishbhai, Silina Alina, Sullivan Mark Jeffrey, Van Goor Fredrick F., Verwijs Marinus Jacobus, Yang Xiaoqing, Young Christopher Ryan, Zaman Noreen Tasneem, Zhang Beili, Zhang Yuegang, Zlokarnik Gregor
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to pharmaceutical compositions comprising a compound of Formulas I and II, optionally in combination with a Compound of Formula III and/or a Compound of Formula IV. The invention also relates to solid forms and to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis. 9. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component is any of the embodiments listed in Column C of Table I.10. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component is any of the embodiments listed in Column D of Table I.1128-. (canceled)29. A pharmaceutical composition comprising:a solid dispersion of Compound 1 or a pharmaceutically acceptable salt thereof; andCompound 3 or a pharmaceutically acceptable salt thereof.30. The pharmaceutical composition of claim 29 , wherein the solid dispersion of Compound 1 comprises about 80 wt % of substantially amorphous Compound 1 by weight of the dispersion claim 29 , about 19.5 wt % of HPMCAS by weight of the dispersion claim 29 , and about 0.5 wt % SLS by weight of the dispersion.31. The pharmaceutical composition of claim 30 , wherein the composition comprises about 34.1 wt % of the solid dispersion by weight of the composition; about 30.5 wt % of microcrystalline cellulose by weight of the composition; about 30.4 wt % of lactose by weight of the composition; about 3 wt % of sodium croscarmellose by weight of the composition; about 0.5 wt % of SLS by weight of the composition; about 0.5 wt % of colloidal silicon dioxide by weight of the composition; and about 1 wt % of magnesium stearate by weight of the composition.32. The pharmaceutical composition according to claim 31 , wherein the composition ...

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Номер записи: 18
20-06-2013 дата публикации

PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATIONS THEREOF

Номер: US20130158071A1
Автор: Alargova Rossitza Gueorguieva, Alcacio Tim Edward, Binch Hayley Marie, Botfield Martyn Curtis, Fanning Lev Tyler Dewey, Grootenhuis Peter Diederik Jan, Hurley Dennis James, Kadiyala Irina Nikolaevna, Kaushik Ritu Rohit, Keshavarz-Shokri Ali, Krawiec Mariusz, Lee Elaine Chungmin, Luisi Brian, Medek Ales, Numa Mehdi, Sheth Urvi Jagdishbhai, Silina Alina, Van Goor Fredrick F., Verwijs Marinus Jacobus, Yang Xiaoqing, Young Christopher Ryan, Zaman Noreen Tasneem, Zhang Beili, Zhang Yuegang, Zlokarnik Gregor
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to pharmaceutical compositions comprising a compound of Formula I in combination with one or both of a Compound of Formula II and/or a Compound of Formula III. The invention also relates to solid forms and to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis. 2. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and a Compound of Formula II.3. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and a Compound of Formula III.4. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I claim 1 , a Compound of Formula II and a Compound of Formula III.9. A method of treating a CFTR mediated disease in a human comprising administering to the human an effective amount of a pharmaceutical composition according to .10. The method of claim 9 , wherein the CFTR mediated disease is selected from cystic fibrosis claim 9 , asthma claim 9 , smoke induced COPD claim 9 , chronic bronchitis claim 9 , rhinosinusitis claim 9 , constipation claim 9 , pancreatitis claim 9 , pancreatic insufficiency claim 9 , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) claim 9 , mild pulmonary disease claim 9 , idiopathic pancreatitis claim 9 , allergic bronchopulmonary aspergillosis (ABPA) claim 9 , liver disease claim 9 , hereditary emphysema claim 9 , hereditary hemochromatosis claim 9 , coagulation-fibrinolysis deficiencies claim 9 , such as protein C deficiency claim 9 , Type 1 hereditary angioedema claim 9 , lipid processing deficiencies claim 9 , such as familial hypercholesterolemia claim 9 , Type 1 chylomicronemia claim 9 , abetalipoproteinemia claim 9 , lysosomal storage diseases claim 9 , such as I-cell disease/pseudo-Hurler claim 9 , mucopolysaccharidoses claim 9 , Sandhof/Tay-Sachs claim 9 , Crigler-Najjar type II claim 9 , polyendocrinopathy/ ...

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Номер записи: 19
27-06-2013 дата публикации

Modulators of ATP-Binding Cassette Transporters

Номер: US20130165442A1
Автор: Binch Hayley, Botfield Martyn, Fanning Lev T.D., Grootenhuis Peter D.J., Hadida Ruah Sara S., Hazlewood Anna, Hurley Dennis, Numa Mehdi Michael Djamel, Sheth Urvi, Silina Alina, Vairagoundar Rajendran, Van Goor Fredrick, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 2. A pharmaceutical composition comprising a compound according to and a pharmaceutically acceptable carrier or adjuvant.3. The pharmaceutical composition according to claim 2 , further comprising an additional agent selected from a mucolytic agent claim 2 , a bronchodialator claim 2 , an antibiotic claim 2 , an anti-infective agent claim 2 , an anti-inflammatory agent claim 2 , a CFTR modulator claim 2 , or a nutritional agent.4. The pharmaceutical composition according to claim 2 , wherein said additional agent is a CFTR modulator other than a compound according to .5. A method of treating or lessening the severity of a disease in a patient claim 1 , wherein said disease is selected from cystic fibrosis claim 1 , asthma claim 1 , smoke induced COPD claim 1 , chronic bronchitis claim 1 , rhinosinusitis claim 1 , constipation claim 1 , pancreatitis claim 1 , pancreatic insufficiency claim 1 , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) claim 1 , mild pulmonary disease claim 1 , idiopathic pancreatitis claim 1 , allergic bronchopulmonary aspergillosis (ABPA) claim 1 , liver disease claim 1 , hereditary emphysema claim 1 , hereditary hemochromatosis claim 1 , coagulation-fibrinolysis deficiencies claim 1 , such as protein C deficiency claim 1 , Type 1 hereditary angioedema claim 1 , lipid processing deficiencies claim 1 , such as familial hypercholesterolemia claim 1 , Type 1 chylomicronemia claim 1 , abetalipoproteinemia claim 1 , lysosomal storage diseases claim 1 , such as I-cell disease/pseudo-Hurler claim 1 , mucopolysaccharidoses claim 1 , Sandhof/Tay-Sachs claim 1 , Crigler-Najjar type II claim ...

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Номер записи: 20
11-07-2013 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20130178471A1
Автор: Bear Brian Richard, Grootenhuis Peter Diederik Jan, Mc Cartney Jason, Miller Mark Thomas, Numa Mehdi Michel Djamel, Ruah Sara Sabina Hadida, Van Goor Fredrick F., Zhou Jinglan
Принадлежит: Vextex Pharmaceuticals Incorporated

Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 2. The compound of claim 1 , wherein two R taken together form —OCFO— claim 1 , Ris H claim 1 , and Ris F.3. The compound of claim 1 , wherein two R taken together form —OCFO— claim 1 , Ris H claim 1 , Ris F claim 1 , and Ris H.4. The compound of claim 1 , wherein two R taken together form —OCFO— claim 1 , Ris H claim 1 , Ris F claim 1 , Ris H claim 1 , and Ris H.5. The compound of claim 1 , wherein two R taken together form —OCFO— claim 1 , Ris H claim 1 , Ris F claim 1 , Ris H claim 1 , and Ris —CHCHN(CH).6. The compound of claim 1 , wherein two R taken together form —OCFO— claim 1 , Ris H claim 1 , Ris F claim 1 , Ris H claim 1 , and Ris —CHCH(OH)CHOH.7. The compound of claim 1 , wherein two R taken together form —OCFO— claim 1 , Ris H claim 1 , Ris F claim 1 , Ris H claim 1 , and Ris (R)—CHCH(OH)CHOH.8. The compound of claim 1 , wherein two R taken together form —OCFO— claim 1 , Ris H claim 1 , Ris F claim 1 , Ris H claim 1 , and Ris (S)—CHCH(OH)CHOH9. The compound of claim 1 , wherein two R taken together form —OCFO— claim 1 , Ris H claim 1 , Ris F claim 1 , Ris H claim 1 , and Rand Rtaken together form a fused pyrrolidine ring.10. The compound of claim 1 , wherein two R taken together form —OCHO— claim 1 , Ris H claim 1 , and Ris F.11. The compound of claim 1 , wherein two R taken together form —OCHO— claim 1 , Ris H claim 1 , Ris F claim 1 , and Ris H.12. The compound of claim 1 , wherein two R taken together form —OCHO— claim 1 , Ris H claim 1 , Ris F claim 1 , Ris H claim 1 , and Ris —CHCH(OH)CHOH.13. The compound of claim 1 , wherein two R taken together form —OCHO— claim 1 , ...

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Номер записи: 21
11-07-2013 дата публикации

Modulators of cystic fibrosis transmembrane conductance regulator

Номер: US20130178496A1
Автор: Anna Hazlewood, Hayley Binch, Jinglan Zhou, Lev T.D. Fanning, Peter D.J. Grootenhuis, Sara S. Hadida Ruah
Принадлежит: Vertex Pharmaceuticals Inc

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

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Номер записи: 22
01-08-2013 дата публикации

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Номер: US20130196983A1
Автор: Binch Hayley, Botfield Martyn, Fanning Lev T.D., Grootenhuis Peter D.J., Hurley Dennis, VanGoor Fredrick
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using such CFTR modulators. 147-. (canceled)49. A method of treating or lessening the severity of a disease in a patient claim 48 , wherein said disease is selected from cystic fibrosis claim 48 , said method comprising the step of administering to said patient an effective amount of a compound according to .50. The method according to claim 49 , wherein said disease is cystic fibrosis.5155-. (canceled)56. A method of modulating CFTR activity in a biological sample comprising the step of contacting said CFTR with a compound according to .57. A kit for use in measuring the activity of CFTR or a fragment thereof in a biological sample in vitro or in vivo claim 48 , comprising:{'claim-ref': {'@idref': 'CLM-00048', 'claim 48'}, '(i) a composition comprising a compound of Formula I according to ;'} a) contacting the composition with the biological sample;', 'b) measuring activity of said CFTR or a fragment thereof., '(ii) instructions for58. The kit of claim 57 , further comprising instructions for:a) contacting an additional compound with the biological sample;b) measuring the activity of said CFTR or a fragment thereof in the presence of said additional compound, andc) comparing the activity of said CFTR or a fragment thereof in the presence of said additional compound with the activity of said CFTR or a fragment thereof in the presence of a composition of Formula I.5987-. (canceled)88. The kit according to claim 58 , wherein the step of comparing the activity of said CFTR or a fragment thereof provides a measure of the density of said CFTR or a fragment thereof.90. The method according to claim 89 , wherein Ais an optionally substituted 6 membered aromatic ring having 0-4 heteroatoms ...

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Номер записи: 23
05-09-2013 дата публикации

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Номер: US20130231364A1
Автор: Binch Hayley, Grootenhuis Peter D.J., Hadida Ruah Sara S., Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 3. The compound according to claim 2 , wherein Ais an optionally substituted 6 membered aromatic ring having 0-4 heteroatoms claim 2 , wherein said heteroatom is nitrogen.4. The compound according to claim 2 , wherein Ais an optionally substituted phenyl.5. The compound according to claim 2 , wherein Ais an optionally substituted 6 membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen claim 2 , oxygen claim 2 , or sulfur.6. The compound according to claim 2 , wherein Ais an optionally substituted 5-membered aromatic ring having 0-3 heteroatoms independently selected from nitrogen claim 2 , oxygen claim 2 , or sulfur.7. The compound according to claim 2 , wherein Ais a 5-membered aromatic ring having 1-2 nitrogen atoms.9. The compound according to claim 1 , wherein Rand Ris hydrogen.10. The compound according to claim 9 , wherein Ris hydrogen.13. The compound according to claim 12 , wherein each of X claim 12 , X claim 12 , X claim 12 , X claim 12 , and Xin formula IIIA′ is CH14. The compounds according to claim 12 , wherein X claim 12 , X claim 12 , X claim 12 , X claim 12 , and Xtaken together in compound of formula IIIA′ is an optionally substituted ring selected from pyridyl claim 12 , pyrazinyl claim 12 , or pyrimidinyl.17. The compound according to claim 16 , wherein ring Ais an optionally substituted claim 16 , saturated claim 16 , unsaturated claim 16 , or aromatic 5-7 membered ring with 0-3 heteroatoms selected from O claim 16 , S claim 16 , or N.22. The compound according to claim 21 , wherein WRis hydrogen claim 21 , C1-C6 aliphatic claim 21 , C(O)C1-C6 aliphatic claim 21 , or C(O)OC1-C6 aliphatic.23 ...

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Номер записи: 24
05-09-2013 дата публикации

Solid Forms of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluorormethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihyroquinoline-3-carboxamide

Номер: US20130231368A1
Автор: Botfield Martyn, Grootenhuis Peter D.J., Krawiec Mariusz, Van Goor Fredrick, Zhang Beili
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to solid state forms, for example, crystalline forms of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, pharmaceutical compositions thereof, and methods therewith. 126-. (canceled)27. A method of treating or lessening the severity of a disease in a patient , wherein said disease is selected from cystic fibrosis , asthma , smoke induced COPD , chronic bronchitis , rhinosinusitis , constipation , pancreatitis , pancreatic insufficiency , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) , mild pulmonary disease , idiopathic pancreatitis , allergic bronchopulmonary aspergillosis (ABPA) , liver disease , hereditary emphysema , hereditary hemochromatosis , coagulation-fibrinolysis deficiencies , such as protein C deficiency , Type 1 hereditary angioedema , lipid processing deficiencies , such as familial hypercholesterolemia , Type 1 chylomicronemia , abetalipoproteinemia , lysosomal storage diseases , such as I-cell disease/pseudo-Hurler , mucopolysaccharidoses , Sandhof/Tay-Sachs , Crigler-Najjar type II , polyendocrinopathy/hyperinsulemia , Diabetes mellitus , Laron dwarfism , myleoperoxidase deficiency , primary hypoparathyroidism , melanoma , glycanosis CDG type 1 , congenital hyperthyroidism , osteogenesis imperfecta , hereditary hypofibrinogenemia , ACT deficiency , Diabetes insipidus (DI) , neurophyseal DI , neprogenic DI , Charcot-Marie Tooth syndrome , Perlizaeus-Merzbacher disease , neurodegenerative diseases such as Alzheimer's disease , Parkinson's disease , amyotrophic lateral sclerosis , progressive supranuclear plasy , Pick's disease , several polyglutamine neurological disorders such as Huntington's , spinocerebullar ataxia type I , spinal and bulbar muscular atrophy , dentatorubal pallidoluysian , and myotonic dystrophy , as well as spongiform encephalopathies , such as hereditary Creutzfeldt-Jakob disease (due ...

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Номер записи: 25
12-09-2013 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20130237568A1
Автор: Bear Brian, Grootenhuis Peter D.J., Hadida Ruah Sara S., Hamilton Matthew, McCartney Jason, Miller Mark, Zhou Jinglan
Принадлежит:

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 165-. (canceled)6769-. (canceled)70. The method of claim 66 , wherein the patient has two copies of the defective gene.72. The method of claim 71 , wherein the patient has two copies of the defective gene.73. The method of or claim 71 , wherein the composition further comprises a mucolytic agent claim 71 , a bronchodilator claim 71 , an antibiotic claim 71 , an anti-infective agent claim 71 , an anti-inflammatory agent claim 71 , a CFTR modulator claim 71 , or a nutritional agent.74. The method of or claim 71 , wherein the composition further comprises a CFTR modulator.75. The method of or further comprising the additional step of administering to the patient a mucolytic agent claim 71 , a bronchodilator claim 71 , an antibiotic claim 71 , an anti-infective agent claim 71 , an anti-inflammatory agent claim 71 , a CFTR modulator claim 71 , or a nutritional agent.76. The method of or claim 71 , wherein the method comprises the additional step of administering to the patient a CFTR modulator.78. The method of claim 77 , wherein the compound is administered concurrently with the CFTR modulator.79. The method of claim 77 , wherein the compound is administered prior to the CFTR modulator. The present application is a continuing application of and claims the benefit of priority under 35 U.S.C. §120 of co-pending International Application Serial No. PCT/US06/043289, filed Nov. 8, 2006, which claims the benefit, under 35 U.S.C. §119, of U.S. provisional patent application Ser. Nos. 60/734,506, filed on Nov. 8, 2005; 60/754,086, filed on Dec. 27, 2005; and 60/802,458, filed on May 22, 2006, the ...

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Номер записи: 26
12-09-2013 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20130237569A1
Автор: Bear Brian, Grootenhuis Peter D.J., Hadida Ruah Sara S., Hamilton Matthew, McCartney Jason, Miller Mark, Zhou Jinglan
Принадлежит:

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTC”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 161-. (canceled)6369-. (canceled)70. The pharmaceutical composition of claim 62 , wherein the additional therapeutic agent is a CFTR modulator. The present application is a continuing application of and claims the benefit of priority under 35 U.S.C. §120 of co-pending International Application Serial No. PCT/US06/043289, filed Nov. 8, 2006, which claims the benefit, under 35 U.S.C. §119, of U.S. provisional patent application Ser. Nos. 60/734,506, filed on Nov. 8, 2005; 60/754,086, filed on Dec. 27, 2005; and 60/802,458, filed on May 22, 2006, the entire contents of each of above applications is incorporated herein by reference.The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.ABC transporters are a family of membrane transporter proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics, as well as anions. ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were discovered as multi-drug resistance proteins (like the MDR1-P glycoprotein, or the multi-drug resistance protein, MRP1), defending malignant cancer cells against chemotherapeutic agents. To date, 48 ABC Transporters have been identified and grouped into 7 families ...

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Номер записи: 27
19-09-2013 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20130245010A1
Автор: Bear Brian, Grootenhuis Peter D.J., Hadida Ruah Sara S., Hamilton Matthew, McCartney Jason, Miller Mark, Zhou Jinglan
Принадлежит:

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTC”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 261-. (canceled)62. A pharmaceutical composition comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, '(i) a compound according to ; and'}(ii) a pharmaceutically acceptable carrier.63. The composition according to claim 62 , optionally further comprising a mucolytic agent claim 62 , a bronchodialator claim 62 , an antibiotic claim 62 , an anti-infective agent claim 62 , an anti-inflammatory agent claim 62 , a CFTR modulator claim 62 , or a nutritional agent.6469-. (canceled)70. The composition of claim 62 , further comprising a CFTR modulator.72. The compound of claim 1 , wherein T is —CF—.73. The compound of claim 1 , wherein R′ is H claim 1 , methyl claim 1 , ethyl claim 1 , i-propyl claim 1 , t-butyl claim 1 , F claim 1 , Cl claim 1 , CF claim 1 , OCF claim 1 , CHF claim 1 , —OCH claim 1 , —OCHCH claim 1 , —O-(i-propyl) claim 1 , or —O-(t-butyl).74. The compound of claim 1 , wherein R′ is methyl.75. The compound of claim 1 , wherein R″ is H claim 1 , methyl claim 1 , ethyl claim 1 , i-propyl claim 1 , t-butyl claim 1 , F claim 1 , Cl claim 1 , CF claim 1 , OCF claim 1 , CHF claim 1 , —OCH claim 1 , —OCHCH claim 1 , —O-(i-propyl) claim 1 , or —O-(t-butyl).76. The compound of claim 1 , wherein R″ is H.77. The compound of claim 1 , wherein for R claim 1 , Zis an optionally substituted branched or straight Caliphatic chain wherein one carbon unit of Zis replaced by —CO— claim 1 , —SO— claim 1 , —SO— claim 1 , —OCO— claim 1 , —OCO— claim 1 , —CONR— claim 1 , —NRCO— claim 1 , NRCO— claim 1 , —O— claim 1 , —NRSO— claim 1 , or —SONR—.78. The compound of claim 1 , wherein in R claim ...

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Номер записи: 28
19-09-2013 дата публикации

Modulators of ATP-Binding Cassette Transporters

Номер: US20130245011A1
Автор: Bear Brian, Grootenhuis Peter D.J., Hadida Ruah Sara S., Hamilton Matthew, McCartney Jason, Miller Mark, Zhou Jinglan
Принадлежит:

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTC”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 2. The compound according to claim 1 , wherein one Rthat is attached to 5- or 6-position of the pyridyl ring is aryl or heteroaryl claim 1 , each optionally substituted with 1 claim 1 , 2 claim 1 , or 3 of R; wherein Ris —ZR; wherein each Zis independently a bond or an optionally substituted branched or straight Caliphatic chain wherein up to two carbon units of Zare optionally and independently replaced by —CO— claim 1 , —CS— claim 1 , —CONR— claim 1 , —CONRNR— claim 1 , —CO— claim 1 , —OCO— claim 1 , —NRCO— claim 1 , —O— claim 1 , —NRCONR— claim 1 , —OCONR— claim 1 , —NRNR— claim 1 , —NRCO— claim 1 , —S— claim 1 , —SO— claim 1 , —SO— claim 1 , —NR— claim 1 , —SONR— claim 1 , —NRSO— claim 1 , or —NRSONR—; each Ris independently R claim 1 , halo claim 1 , —OH claim 1 , —NH claim 1 , —NO claim 1 , —CN claim 1 , —CF claim 1 , or —OCF; and each Ris independently hydrogen claim 1 , an optionally substituted Caliphatic group claim 1 , an optionally substituted cycloaliphatic claim 1 , an optionally substituted heterocycloaliphatic claim 1 , an optionally substituted aryl claim 1 , or an optionally substituted heteroaryl.3. The compound according to claim 2 , wherein the one Rattached to the 5- or 6-position of the pyridyl ring is phenyl optionally substituted with 1 claim 2 , 2 claim 2 , or 3 of R.4. The compound according to claim 2 , wherein the one Rattached to the 5- or 6-position of the pyridyl ring is heteroaryl optionally substituted with 1 claim 2 , 2 claim 2 , or 3 of R.5. The compound according to claim 2 , wherein one Rattached to the 5- or 6-position of the pyridyl ring is a 5 ...

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Номер записи: 29
26-09-2013 дата публикации

Modulators of ATP-Binding Cassette Transporters

Номер: US20130252333A1
Автор: Cleveland Thomas, Grootenhuis Peter D.J., Hadida Ruah Sara S., Hamilton Matthew, Makings Lewis R., Miller Mark T., Singh Ashvani K.
Принадлежит:

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including CF Transmembrane Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 1230-. (canceled)232. The method according to claim 231 , wherein Xis CH claim 231 , CF claim 231 , or O.233. The method according to claim 231 , wherein Xis CH.234. The method according to claim 231 , wherein Ais selected from phenyl claim 231 , triazinyl claim 231 , pyrazinyl claim 231 , pyrimidinyl claim 231 , pyridazinyl claim 231 , pyridyl claim 231 , thiadiazolyl claim 231 , triazolyl claim 231 , oxadiazolyl claim 231 , isothiazolyl claim 231 , pyrazolyl claim 231 , imidazolyl claim 231 , thiazolyl claim 231 , oxazolyl claim 231 , pyrrolyl claim 231 , thienyl claim 231 , furanyl claim 231 , indolizinyl claim 231 , indolyl claim 231 , isoindolyl claim 231 , benzofuranyl claim 231 , benzo[b]thienyl claim 231 , 1H-indazolyl claim 231 , benzimidazolyl claim 231 , benzthiazolyl claim 231 , purinyl claim 231 , quinolinyl claim 231 , isoquinolinyl claim 231 , cinnolinyl claim 231 , phthazinyl claim 231 , quinazolinyl claim 231 , quinoxalinyl claim 231 , 1 claim 231 ,8-naphthyridinyl claim 231 , pteridinyl claim 231 , carbazolyl claim 231 , acridinyl claim 231 , phenazinyl claim 231 , phenothiazinyl claim 231 , phenoxazinyl claim 231 , indenyl claim 231 , naphthyl claim 231 , azulinyl claim 231 , or anthracenyl.235. The method according to claim 231 , wherein each Bis independently selected from optionally substituted C6-C10 aryl.236. The method according to claim 231 , wherein each Bis independently an optionally substituted phenyl or naphthyl.237. The method according to claim 231 , wherein each Bis an unsubstituted phenyl.238. The method according to claim 231 , wherein each Bis independently selected from optionally substituted C5-C12 heteroaryl.239. ...

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Номер записи: 30
07-11-2013 дата публикации

Modulators of ATP-Binding Cassette Transporters

Номер: US20130296306A1
Автор: Bear Brian, Grootenhuis Peter D.J., Hadida Ruah Sara S, McCartney Jason, Miller Mark T.
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 171-. (canceled)7375-. (canceled)76. The method of claim 72 , wherein the one Rattached to the 3- or 4-position of the phenyl ring is an aryl optionally substituted with 1 claim 72 , 2 claim 72 , or 3 of R claim 72 , wherein Ris —ZR; in which each Zis independently a bond or an optionally substituted branched or straight Caliphatic chain wherein up to two carbon units of Zare optionally and independently replaced by —CO— claim 72 , —CS— claim 72 , —CONR— claim 72 , —CONRNR— claim 72 , —CO— claim 72 , —OCO— claim 72 , —NRCO— claim 72 , —O— claim 72 , —NRCONR— claim 72 , —OCONR— claim 72 , —NRNR— claim 72 , —NRCO— claim 72 , —S— claim 72 , —SO— claim 72 , —SO— claim 72 , —NR— claim 72 , —SONR— claim 72 , —NRSO— claim 72 , or —NRSONR—; each Ris independently R claim 72 , halo claim 72 , —B(OH) claim 72 , —OH claim 72 , —NH claim 72 , —NO claim 72 , —CN claim 72 , or —OCF; and each Ris independently hydrogen claim 72 , an optionally substituted Caliphatic group claim 72 , an optionally substituted cycloaliphatic claim 72 , an optionally substituted heterocycloaliphatic claim 72 , an optionally substituted aryl claim 72 , or an optionally substituted heteroaryl.77. The method of claim 76 , wherein the one Rattached to the 3- or 4-position of the phenyl ring is a phenyl optionally substituted with 1 claim 76 , 2 claim 76 , or 3 of R.78. The method of claim 72 , wherein Ris hydrogen or methyl.79. The method of claim 72 , wherein ring A is an unsubstituted Ccycloaliphatic.80. The method of claim 79 , wherein ring A is an unsubstituted cyclopropyl claim 79 , an unsubstituted cyclopentyl claim 79 ...

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Номер записи: 31
07-11-2013 дата публикации

MODULATORS OF ATP-BINDING CASSETTE-TRANSPORTERS

Номер: US20130296364A1
Автор: Bear Brian, Grootenhuis Peter, Hadida Ruah Sara S., Miller Mark, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 145-. (canceled)4749-. (canceled)50. The method of claim 46 , wherein the patient has two copies of the defective gene.52. The method of claim 51 , wherein the patient has two copies of the defective gene.53. The method of or claim 51 , wherein the composition further comprises a mucolytic agent claim 51 , a bronchodialator claim 51 , an antibiotic claim 51 , an anti-infective agent claim 51 , an anti-inflammatory agent claim 51 , a CFTR modulator claim 51 , or a nutritional agent.54. The method of or claim 51 , wherein the composition further comprises a CFTR modulator. This application claims the benefit under 35 U.S.C. §119 to U.S. provisional patent application Ser. No. 60/988,559, filed Nov. 16, 2007, the entire contents of which are incorporated herein by reference.The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.ABC transporters are a family of membrane transporter proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics, as well as anions. ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were discovered as multi-drug resistance proteins (like the MDR1-P glycoprotein, or the multi-drug resistance protein, MRP1), ...

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Номер записи: 32
14-11-2013 дата публикации

Prodrugs of Modulators of ABC Transporters

Номер: US20130303484A1
Автор: Binch Hayley, Grootenhuis Peter D.J., Hadida Ruah Sara, Hazlewood Ann, Zhou Jinglan
Принадлежит:

The present invention relates to prodrugs of modulators of ABC transporters, particularly, CFTR modulators, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 2. The compound according to claim 1 , y is 0-2.3. The compound according to claim 2 , wherein y is 0.4. The compound according to claim 1 , wherein each of Rand Ris independently selected from hydrogen claim 1 , CN claim 1 , CF claim 1 , halo claim 1 , C1-C6 straight or branched alkyl claim 1 , 3-12 membered cycloaliphatic claim 1 , or phenyl claim 1 , wherein said Rand Ris independently and optionally substituted with up to three substituents selected from —OR′ claim 1 , —CF claim 1 , —OCF claim 1 , —SCF claim 1 , halo claim 1 , —COOR′ claim 1 , —OCOR′ claim 1 , —COR′ claim 1 , —O(CH)N(R′)(R′) claim 1 , —O(CH)N(R′)(R′) claim 1 , —CON(R′)(R′) claim 1 , —(CH)OR′ claim 1 , —(CH)OR′ claim 1 , optionally substituted phenyl claim 1 , —N(R′)(R′) claim 1 , —NC(O)OR′ claim 1 , —NC(O)R′ claim 1 , —(CH)N(R′)(R′) claim 1 , or —(CH)N(R′)(R′).5. The compound according to claim 5 , wherein Ris a phenyl ring optionally substituted with up to three substituents selected from —OR′ claim 5 , —CF claim 5 , —OCF claim 5 , SR′ claim 5 , S(O)R′ claim 5 , SOR′ claim 5 , —SCF claim 5 , halo claim 5 , CN claim 5 , —COOR′ claim 5 , —OCOR′ claim 5 , —COR′ claim 5 , —O(CH)N(R′)(R′) claim 5 , —O(CH)N(R′)(R′) claim 5 , —CON(R′)(R′) claim 5 , —(CH)OR′ claim 5 , —(CH)OR′ claim 5 , CHCN claim 5 , optionally substituted phenyl or phenoxy claim 5 , —N(R′)(R′) claim 5 , —NR′C(O)OR′ claim 5 , —NR′C(O)R′ claim 5 , —(CH)N(R′)(R′) claim 5 , or —(CH)N(R′)(R′); and Ris C1-C6 straight or branched alkyl.6. The compound according to claim 4 , wherein each of Rand Ris independently selected from CFor halo.7. The compound according to claim 4 , wherein each of Rand Ris independently selected from hydrogen or optionally substituted C1-C6 straight or ...

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Номер записи: 33
14-11-2013 дата публикации

Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

Номер: US20130303570A1
Автор: Binch Hayley, Botfield Martyn, Fanning Lev T.D., Grootenhuis Peter D.J., Hurley Dennis, Numa Mehdi Michel Djamel, Sheth Urvi, Silina Alina, Van Goor Fredrick, Yang Xiaoqing
Принадлежит:

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR. 65. The compound according to any one of - claims 2 , wherein Ris —CF.75. The compound according to any one of - claims 2 , wherein Ris —CN.85. The compound according to any one of - claims 2 , wherein Ris —C≡CCHN(CH).98. The compound according to any one of - claims 6 , wherein Ris hydrogen.108. The compound according to any one of - claims 6 , wherein Ris —CH.118. The compound according to any one of - claims 6 , wherein Ris —CF.128. The compound according to any one of - claims 6 , Ris —OH.138. The compound according to any one of - claims 6 , wherein Ris —CHOH.1413. The compound according to any one of - claims 10 , wherein Ris hydrogen.1513. The compound according to any one of - claims 9 , wherein Ris —CH.1613. The compound according to any one of - claims 9 , wherein Ris —OCH.1713. The compound according to any one of - claims 9 , wherein Ris —CN.1918. A pharmaceutical composition comprising a compound according to any one of - and a pharmaceutically acceptable carrier or adjuvant.20. The pharmaceutical composition according to claim 19 , further comprising an additional agent selected from a mucolytic agent claim 19 , a bronchodialator claim 19 , an antibiotic claim 19 , an anti-infective agent claim 19 , an anti-inflammatory agent claim 19 , a CFTR modulator other than a compound of Formula (I) claim 19 , or a nutritional agent.21. The pharmaceutical composition according to claim 20 , wherein said additional agent is a CFTR modulator other than a compound of Formula (I).2218. A method of treating or lessening the severity of a disease in a patient claims 1 , wherein said disease is selected from cystic fibrosis claims 1 , asthma claims 1 , smoke induced COPD claims 1 , chronic bronchitis claims 1 , rhinosinusitis ...

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Номер записи: 34
28-11-2013 дата публикации

Pyridyl Derivatives as CFTR Modulators

Номер: US20130317020A1
Автор: Brian Bear, Jinglan Zhou, Mark Miller, Peter Grootenhuis, Sara Hadida Ruah
Принадлежит: Vertex Pharmaceuticals Inc

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

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Номер записи: 35
12-12-2013 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20130331567A1
Автор: Grootenhuis Peter, Hadida-Ruah Sara, Hazelwood Anna, McCartney Jason, Singh Ashvani, Van Goor Fred, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 175-. (canceled)77. The compound claim 76 , or a pharmaceutically acceptable salt thereof claim 76 , according to claim 76 , wherein each occurrence of WRis independently —C-Calkyl claim 76 , —O(C1-Calkyl) claim 76 , —CF claim 76 , —OCF claim 76 , —SCF claim 76 , —F claim 76 , —Br claim 76 , —COOR′ claim 76 , —COR′ claim 76 , —O(CH)N(R′)(R′) claim 76 , —O(CH)N(R′)(R′) claim 76 , —CON(R′)(R′) claim 76 , —(CH)OR′ claim 76 , —(CH)OR′ claim 76 , an optionally substituted monocyclic or bicyclic aromatic ring claim 76 , an optionally substituted arylsulfone claim 76 , an optionally substituted 5-membered heteroaryl ring claim 76 , —N(R′)(R′) claim 76 , —(CH)N(R′)(R′) claim 76 , or —(CH)N(R′)(R′).78. The compound claim 76 , or a pharmaceutically acceptable salt thereof claim 76 , according to claim 76 , wherein each occurrence of WRis selected from halo claim 76 , cyano claim 76 , CF claim 76 , CHF claim 76 , OCHF claim 76 , Me claim 76 , Et claim 76 , CH(Me) claim 76 , CHMeEt claim 76 , n-propyl claim 76 , t-butyl claim 76 , OMe claim 76 , OEt claim 76 , OPh claim 76 , O-fluorophenyl claim 76 , O-difluorophenyl claim 76 , O-methoxyphenyl claim 76 , O-tolyl claim 76 , O-benzyl claim 76 , SMe claim 76 , SCF claim 76 , SCHF claim 76 , SEt claim 76 , CHCN claim 76 , NH claim 76 , NHMe claim 76 , N(Me) claim 76 , NHEt claim 76 , N(Et) claim 76 , C(O)CH claim 76 , C(O)Ph claim 76 , C(O)NH claim 76 , SPh claim 76 , SO-(amino-pyridyl) claim 76 , SONH claim 76 , SOPh claim 76 , SONHPh claim 76 , SO—N-morpholino claim 76 , SO—N-pyrrolidyl claim 76 , N-pyrrolyl claim 76 , N-morpholino claim 76 , 1-piperidyl claim 76 , phenyl claim 76 , benzyl claim 76 , ( ...

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Номер записи: 36
09-01-2014 дата публикации

PROCESS FOR MAKING MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Номер: US20140012003A1
Автор: Botfield Martyn C., DeMattei John, Grootenhuis Peter D.J., Guerette Dahrika Milfred Yap, Krueger Brian R., Looker Adam R., Neubert-Langille Bobbianna, Roeper Stefanie, Ryan Michael P., Trudeau Martin, Van Goor Fredrick F., Zlokarnik Gregor
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The invention provides a process for the preparation of a compound of Formula 1, 158-. (canceled)6058. The compound according to claim , wherein the compound is Compound 32.6158. The compound according to claim , wherein the compound is Compound 33. This application claims priority to three U.S. Provisional Applications having Ser. Nos. 61/162,148, filed on Mar. 20, 2009; 61/246,303, filed on Sep. 28, 2009; and 61/248,565, filed on Oct. 5, 2009. Each of the foregoing Provisional Applications are hereby incorporated by reference in their entirety.The present invention relates to a process for making modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”).Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 30,000 children and adults in the United States and approximately 30,000 children and adults in Europe. Despite progress in the treatment of CF, there is no cure.CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes an epithelial chloride ion channel responsible for aiding in the regulation of salt and water absorption and secretion in various tissues. Small molecule drugs, known as potentiators that increase the probability of CFTR channel opening represent one potential therapeutic strategy to treat CF.Specifically, CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are ...

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Номер записи: 37
20-02-2014 дата публикации

Modulators of atp-binding cassette transporters

Номер: US20140051724A1
Автор: Anna Hazlewood, Ashvani Singh, Fredrick Van Goor, Jason Mccartney, Jinglan Zhou, Peter Grootenhuis, Sara Hadida-Ruah
Принадлежит: Vertex Pharmaceuticals Inc

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

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Номер записи: 38
27-02-2014 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20140057906A1
Автор: Bear Brian, Grootenhuis Peter D.J., Hadida Ruah Sara S., McCartney Jason, Miller Mark T., Numa Mehdi Michel Jamel, Van Goor Fredrick, Yang Xiaoqing, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 2. The compound of claim 1 , wherein Ris —ZR claim 1 , e is a bond claim 1 , and Ris hydrogen.3. The compound of claim 1 , wherein Ris an optionally substituted branched or straight Caliphatic.4. The compound of claim 3 , wherein Ris a branched or straight Caliphatic chain that is optionally substituted with 1-3 of halo claim 3 , hydroxy claim 3 , cyano claim 3 , cycloaliphatic claim 3 , heterocycloaliphatic claim 3 , aryl claim 3 , heteroaryl claim 3 , or combinations thereof.5. The compound of claim 1 , wherein Ris an optionally substituted branched or straight Calkoxy.6. The compound of claim 1 , wherein Ris a Calkoxy that is optionally substituted with 1-3 of hydroxy claim 1 , aryl claim 1 , heteroaryl claim 1 , cycloaliphatic claim 1 , heterocycloaliphatic claim 1 , or combinations thereof.7. The compound of claim 1 , wherein Ris hydroxy claim 1 , halo claim 1 , or cyano.8. The compound of claim 1 , wherein Ris —ZR; Zis independently a bond or an optionally substituted branched or straight Caliphatic chain wherein up to two carbon units of Zare optionally and independently replaced by —C(O)— claim 1 , —O— claim 1 , —S— claim 1 , —S(O)— claim 1 , or —NH—; Ris R claim 1 , halo claim 1 , —OH claim 1 , —NH claim 1 , —NO claim 1 , —CN claim 1 , —CF claim 1 , or —OCF claim 1 , and Ris hydrogen or aryl.10. The compound of claim 9 , wherein two adjacent Rgroups together with the atoms to which they are attached form a 5-6 membered carbocycle that is optionally substituted with 1-3 of halo claim 9 , hydroxy claim 9 , cyano claim 9 , oxo claim 9 , cyano claim 9 , alkoxy claim 9 , alkyl claim ...

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Номер записи: 39
13-03-2014 дата публикации

Modulators of ATP-Binding Cassette Transporters

Номер: US20140072995A1
Автор: Cleveland Thomas, Grootenhuis Peter D.J., Hadida Ruah Sara S., Hamilton Matthew, Makings Lewis R., Miller Mark T., Singh Ashvani K.
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including CF Transmembrane Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 1228-. (canceled)230. (canceled)231. The method according to claim 229 , wherein Xis CH claim 229 , CF claim 229 , or O.232. The method according to claim 229 , wherein Xis CH.233. The method according to claim 229 , wherein Ais selected from phenyl claim 229 , triazinyl claim 229 , pyrazinyl claim 229 , pyrimidinyl claim 229 , pyridazinyl claim 229 , pyridyl claim 229 , thiadiazolyl claim 229 , triazolyl claim 229 , oxadiazolyl claim 229 , isothiazolyl claim 229 , pyrazolyl claim 229 , imidazolyl claim 229 , thiazolyl claim 229 , oxazolyl claim 229 , pyrrolyl claim 229 , thienyl claim 229 , furanyl claim 229 , indolizinyl claim 229 , indolyl claim 229 , isoindolyl claim 229 , benzofuranyl claim 229 , benzo[b]thienyl claim 229 , 1H-indazolyl claim 229 , benzimidazolyl claim 229 , benzthiazolyl claim 229 , purinyl claim 229 , quinolinyl claim 229 , isoquinolinyl claim 229 , cinnolinyl claim 229 , phthazinyl claim 229 , quinazolinyl claim 229 , quinoxalinyl claim 229 , 1 claim 229 ,8-naphthyridinyl claim 229 , pteridinyl claim 229 , carbazolyl claim 229 , acridinyl claim 229 , phenazinyl claim 229 , phenothiazinyl claim 229 , phenoxazinyl claim 229 , indenyl claim 229 , naphthyl claim 229 , azulinyl claim 229 , or anthracenyl.234. The method according to claim 229 , wherein each Bis independently selected from optionally substituted C6-C10 aryl.235. The method according to claim 229 , wherein each Bis independently an optionally substituted phenyl or naphthyl.236. The method according to claim 229 , wherein each Bis an unsubstituted phenyl.237. The method according to claim 229 , wherein each Bis independently selected from optionally substituted C5-C12 ...

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Номер записи: 40
13-03-2014 дата публикации

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Номер: US20140073653A1
Автор: Binch Hayley, Fanning Lev T.D., Grootenhuis Peter D.J., Pierce Albert
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to compounds of formula IVA, formula IVB, or formula IVC, useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using such CFTR modulators. 143-. (canceled)48. The method according to claim 44 , wherein said compound is selected from N-(2 claim 44 ,4-di-tert-butyl-5-hydroxyphenyl)-2-methyl-7-oxo-4 claim 44 ,7-dihydropyrazolo[1 claim 44 ,5-a]pyrimidine-6-carboxamide claim 44 , N-(4-(3 claim 44 ,3-dimethylpyrrolidin-1-yl)-2-(trifluoromethyl)phenyl)-7-methyl-4-oxo-1 claim 44 ,4-dihydropyrrolo[1 claim 44 ,2-a]pyrimidine-3-carboxamide claim 44 , N-(2 claim 44 ,4-di-tert-butyl-5-hydroxyphenyl)-7-oxo-4 claim 44 ,7-dihydropyrazolo[1 claim 44 ,5-a]pyrimidine-6-carboxamide claim 44 , 7-ethyl-N-(2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)phenyl)-4-oxo-1 claim 44 ,4-dihydropyrrolo[1 claim 44 ,2-a]pyrimidine-3-carboxamide claim 44 , 7-oxo-N-(4-(pyrrolidin-1-yl)-2-(trifluoromethyl)phenyl)-4 claim 44 ,7-dihydropyrazolo[1 claim 44 ,5-a]pyrimidine-6-carboxamide claim 44 , N-(2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)phenyl)-7-methyl-4-oxo-1 claim 44 ,4-dihydropyrrolo[1 claim 44 ,2-a]pyrimidine-3-carboxamide claim 44 , N-(4-cyclopentyl-5-hydroxy-2-(trifluoromethyl)phenyl)-7-methyl-4-oxo-1 claim 44 ,4-dihydropyrrolo[1 claim 44 ,2-a]pyrimidine-3-carboxamide claim 44 , N-(2 claim 44 ,4-di-tert-butyl-5-hydroxyphenyl)-7-ethyl-4-oxo-1 claim 44 ,4-dihydropyrrolo[1 claim 44 ,2-a]pyrimidine-3-carboxamide claim 44 , N-(4-cyclopentyl-5-hydroxy-2-methylphenyl)-7-methyl-4-oxo-1 claim 44 ,4-dihydropyrrolo[1 claim 44 ,2-a]pyrimidine-3-carboxamide or N-(2-cyano-4-cyclopentyl-5-hydroxyphenyl)-7-methyl-4-oxo-1 claim 44 ,4-dihydropyrrolo[1 claim 44 ,2-a]pyrimidine-3-carboxamide.52. The method according to claim 49 , wherein said compound is selected from N-(3-tert-butyl- ...

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Номер записи: 41
20-03-2014 дата публикации

Modulators of ATP-binding cassette transporters

Номер: US20140080825A1
Автор: Mark Thomas Miller, Matthew Hamilton, Peter Diederik Jan Grootenhuis, Sara Sabina Hadida-Ruah
Принадлежит: Vertex Pharmaceuticals Inc

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

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Номер записи: 42
20-03-2014 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20140080826A1
Автор: Bear Brian Richard, Grootenhuis Peter Diederik Jan, Mc Cartney Jason, Miller Mark Thomas, Numa Mehdi, Ruah Sara Sabina Hadida, Van Goor Frederick F., Yang Xiaoqing, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 2. The compound of claim 1 , wherein Ris H or C1-C6 aliphatic.3. The compound of claim 1 , wherein Ris H.4. The compound of claim 1 , wherein two adjacent Rtogether with the atoms to which they are attached form an optionally substituted carbocyclic or an optionally substituted heterocycle.5. The compound of claim 1 , wherein two adjacent Rtogether with the atoms to which they are attached form an optionally substituted heterocycle.11. The compound of claim 1 , wherein 1 Ris halo.12. The compound of claim 1 , wherein 1 Ris F.13. The compound of claim 1 , wherein R′and an adjacent Rtogether with the atoms to which they are attached form an optionally substituted heterocycle.14. The compound of claim 1 , wherein R′and an adjacent Rtogether with the atoms to which they are attached form an optionally substituted 3 to 7 membered heterocycle in which one or more of the ring atoms is N claim 1 , O claim 1 , S claim 1 , or combination thereof.15. The compound of claim 1 , wherein R′and an adjacent Rtogether with the atoms to which they are attached form an optionally substituted 7 membered heterocycle in which one or more of the ring atoms is N claim 1 , O claim 1 , S claim 1 , or combination thereof.16. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier or adjuvant.17. The composition of claim 16 , wherein the composition comprises an additional agent selected from a mucolytic agent claim 16 , bronchodialator claim 16 , an anti-biotic claim 16 , an anti-infective agent claim 16 , an anti-inflammatory agent claim 16 , CFTR modulator claim 16 , or a ...

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Номер записи: 43
27-03-2014 дата публикации

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Номер: US20140088141A1
Автор: Binch Hayley, Botfield Martyn, Fanning Lev T.D., Grootenhuis Peter D.J., Numa Mehdi Michel Djamel, Van Goor Fredrick
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR. 123-. (canceled)25. The method according to claim 24 , wherein said disease is cystic fibrosis.27. The method of claim 26 , wherein disease is cystic fibrosis claim 26 , chronic bronchitis claim 26 , recurrent bronchitis claim 26 , acute bronchitis claim 26 , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) claim 26 , female infertility caused by congenital absence of the uterus and vagina (CAUV) claim 26 , idiopathic chronic pancreatitis (ICP) claim 26 , idiopathic recurrent pancreatitis claim 26 , idiopathic acute pancreatitis claim 26 , chronic rhinosinusitis claim 26 , primary sclerosing cholangitis claim 26 , allergic bronchopulmonary aspergillosis claim 26 , diabetes claim 26 , dry eye claim 26 , constipation claim 26 , allergic bronchopulmonary aspergillosis (ABPA) claim 26 , bone diseases claim 26 , and asthma.29. The method of claim 28 , wherein disease is chronic obstructive pulmonary disease (COPD) claim 28 , chronic bronchitis claim 28 , recurrent bronchitis claim 28 , acute bronchitis claim 28 , rhinosinusitis claim 28 , constipation claim 28 , chronic pancreatitis claim 28 , recurrent pancreatitis claim 28 , and acute pancreatitis claim 28 , pancreatic insufficiency claim 28 , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) claim 28 , mild pulmonary disease claim 28 , idiopathic pancreatitis claim 28 , liver disease claim 28 , hereditary emphysema claim 28 , gallstones claim 28 , gasgtro-esophageal reflux disease claim 28 , gastrointestinal malignancies claim 28 , inflammatory bowel disease claim 28 , constipation claim 28 , diabetes claim 28 , arthritis claim 28 , osteoporosis claim 28 , and osteopenia.30. The method of claim 28 , wherein ...

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Номер записи: 44
27-03-2014 дата публикации

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Номер: US20140088142A1
Автор: Botfield Martyn Curtis, Grootenhuis Peter Diederik Jan, Hadida Ruah Sara Sabina, Van Goor Fredrick F., Yang Xiaoqing, Ziokamik Gregor
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

This invention relates to a compound of Formula I: 19-. (canceled)16. The method according to claim 13 , wherein said disease is cystic fibrosis.1721-. (canceled)22. The method according to claim 13 , wherein said disease is selected from cystic fibrosis claim 13 , COPD claim 13 , smoke induced COPD claim 13 , hereditary emphysema claim 13 , pancreatitis claim 13 , pancreatic insufficiency claim 13 , and dry-eye disease. This application is a continuation of PCT Application No. PCT/US2010/028062 filed Mar. 19, 2010, which claims the priority of U.S. Application No. 61/162,130 filed Mar. 20, 2009, which is incorporated by reference herein in its entirety.The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 30,000 children and adults in the United States and approximately 30,000 children and adults in Europe. Despite progress in the treatment of CF, there is no cure.CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes an epithelial chloride ion channel responsible for aiding in the regulation of salt and water absorption and secretion in various tissues. Small molecule drugs, known as potentiators that increase the probability of CFTR channel opening represent one potential therapeutic strategy to treat CF.Specifically, CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is ...

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Номер записи: 45
28-01-2016 дата публикации

Pharmaceutical Compositions and Administrations Thereof

Номер: US20160022664A2
Автор: Alargova Rossitza Gueorguieva, Alcacio Tim Edward, Binch Hayley Marie, Botfield Martyn Curtis, Fanning Lev Tyler Dewey, Grootenhuis Peter Diederik Jan, Hurley Dennis James, Kadiyala Irina Nikolaevna, Kaushik Ritu Rohit, Keshavarz-Shokri Ali, Krawiec Mariusz, Lee Elaine Chungmin, Luisi Brian, Medek Ales, Numa Mehdi, Sheth Urvi Jagdishbhai, Silina Alina, Van Goor Fredrick F., Verwijs Marinus Jacobus, Yang Xiaoqing, Young Christopher Ryan, Zaman Noreen Tasneem, Zhang Beili, Zhang Yuegang, Zlokarnik Gregor
Принадлежит:

The present invention relates to pharmaceutical compositions comprising a compound of Formula I in combination with one or both of a Compound of Formula II and/or a Compound of Formula III. The invention also relates to solid forms and to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis. 2. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and a Compound of Formula II.3. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and a Compound of Formula III.4. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I claim 1 , a Compound of Formula II and a Compound of Formula III.98. A method of treating a CFTR mediated disease in a human comprising administering to the human an effective amount of a pharmaceutical composition according to any one of -.10. The method of claim 9 , wherein the CFTR mediated disease is selected from cystic fibrosis claim 9 , asthma claim 9 , smoke induced COPD claim 9 , chronic bronchitis claim 9 , rhinosinusitis claim 9 , constipation claim 9 , pancreatitis claim 9 , pancreatic insufficiency claim 9 , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) claim 9 , mild pulmonary disease claim 9 , idiopathic pancreatitis claim 9 , allergic bronchopulmonary aspergillosis (ABPA) claim 9 , liver disease claim 9 , hereditary emphysema claim 9 , hereditary hemochromatosis claim 9 , coagulation-fibrinolysis deficiencies claim 9 , such as protein C deficiency claim 9 , Type 1 hereditary angioedema claim 9 , lipid processing deficiencies claim 9 , such as familial hypercholesterolemia claim 9 , Type 1 chylomicronemia claim 9 , abetalipoproteinemia claim 9 , lysosomal storage diseases claim 9 , such as I-cell disease/pseudo-Hurler claim 9 , mucopolysaccharidoses claim 9 , Sandhof/Tay-Sachs claim 9 , Crigler-Najjar type II claim 9 , ...

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Номер записи: 46
28-01-2016 дата публикации

Pharmaceutical Compositions and Administrations Thereof

Номер: US20160022665A2
Автор: Alargova Rossitza Gueorguieva, Alcacio Tim Edward, Arekar Sneha G., Binch Hayley Marie, Botfield Martyn Curtis, Fanning Lev Tyler Dewey, Grootenhuis Peter Diederik Jan, Hurley Dennis James, Johnston Steven C., Kadiyala Irina Nikolaevna, Kaushik Ritu Rohit, Keshavarz-Shokri Ali, Krawiec Mariusz, Lee Elaine Chungmin, Luisi Brian, Medek Ales, Mudunuri Praveen, Numa Mehdi, Sheth Urvi Jagdishbhai, Silina Alina, Sullivan Mark Jeffrey, Van Goor Fredrick F., Verwijs Marinus Jacobus, Yang Xiaoqing, Young Christopher Ryan, Zaman Noreen Tasneem, Zhang Beili, Zhang Yuegang, Zlokarnik Gregor
Принадлежит:

The present invention relates to pharmaceutical compositions comprising a compound of Formulas I and II, optionally in combination with a Compound of Formula III and/or a Compound of Formula IV. The invention also relates to solid forms and to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis. 2. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and Compound of Formula II.5. The pharmaceutical composition of claim 4 , comprising Compound 1 claim 4 , Compound 2 claim 4 , and Compound 3.6. The pharmaceutical composition of claim 1 , comprising Compound 1 claim 1 , Compound 2 claim 1 , and Compound 4.7. The pharmaceutical composition of claim 4 , comprising Compound 1 claim 4 , Compound 2 claim 4 , Compound 3 and Compound 4.9. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component is any of the embodiments listed in Column C of Table I.10. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component is any of the embodiments listed in Column D of Table I.11. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , the third component is any of the embodiments listed in Column C of Table I claim 8 , and the fourth Component is any of the embodiments listed in Column D of Table I.12. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component is Compound 3.13. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component ...

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Номер записи: 47
22-01-2015 дата публикации

MORPHOLINE-SPIROCYCLIC PIPERIDINE AMIDES AS MODULATORS OF ION CHANNELS

Номер: US20150025073A1
Автор: Arumugam Vijayalaksmi, Binch Hayley Marie, DeNinno Michael Paul, Fanning Lev Tyler Dewey, Frieman Bryan A., Grootenhuis Peter Diederik Jan, Hadida-Ruah Sara Sabina, Hilgraf Nicole, Hurley Dennis James, Joshi Pramod, Kallel Edward Adam, Miller Mark Thomas, PONTILLO Joseph, Sheth Urvi Jagdishbhai, Silina Alina
Принадлежит:

The invention relates to morpholine spirocyclic piperidine amide compounds useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders. 23-. (canceled)4: The compound of claim 1 , wherein Ris H claim 1 , C1-C6 alkyl claim 1 , C1-C6 fluoroalkyl claim 1 , CF claim 1 , cycloalkyl claim 1 , aryl claim 1 , heterocycloalkyl claim 1 , heteroaryl claim 1 , or a straight chain claim 1 , branched claim 1 , or cyclic (C1-C8)-Rwherein up to two CHunits may be replaced with O claim 1 , CO claim 1 , S claim 1 , SO claim 1 , SO claim 1 , N claim 1 , or NR.6: The compound of claim 1 , wherein n is 2 or 3.7: The compound of claim 1 , wherein n is 3.8. (canceled)9: The compound of claim 1 , wherein o is 0 or 1.10: The compound of claim 1 , wherein o is 0.12: The compound of claim 11 , wherein Ris H claim 11 , C1-C6 alkyl claim 11 , halo claim 11 , or OCHF.13: The compound of claim 11 , wherein Ris H claim 11 , F claim 11 , CH claim 11 , or OCHF.14: The compound of claim 11 , wherein Ris H claim 11 , C1-C6 alkyl claim 11 , C1-C6 alkoxy claim 11 , halo claim 11 , CF claim 11 , CN claim 11 , or a straight chain claim 11 , branched claim 11 , or cyclic (C1-C8)-Rwherein up to three CHunits may be replaced with O claim 11 , CO claim 11 , S claim 11 , SO claim 11 , SO claim 11 , N claim 11 , or NR.15: The compound of claim 11 , wherein Ris H claim 11 , CH claim 11 , OCH claim 11 , OCHCH claim 11 , OCH(CH) claim 11 , F claim 11 , Cl claim 11 , CF claim 11 , CN claim 11 , or CHOH.16: The compound of claim 11 , wherein Ris H claim 11 , C1-C6 alkyl claim 11 , C1-C6 alkoxy claim 11 , SOR claim 11 , SON(R) claim 11 , R claim 11 , or a straight chain claim 11 , branched claim 11 , or cyclic (C1-C8)-R claim 11 , wherein up to three CHunits may be replaced with O claim 11 , S claim 11 , SO claim 11 , SO claim 11 , N claim 11 , or NR.1974 ...

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Номер записи: 48
22-01-2015 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20150025076A1
Автор: Cleveland Thomas, Grootenhuis Peter D.J., Hadida Ruah Sara S., Hamilton Matthew, Makings Lewis R., Miller Mark T., Singh Ashvani K.
Принадлежит:

The present invention relates to modulator of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including CF Transmembrane Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 1226-. (canceled)228230-. (canceled)231. The pharmaceutical composition according to claim 227 , wherein Xis CH claim 227 , CF claim 227 , or O.232. The pharmaceutical composition according to claim 227 , wherein Xis CH.233. The pharmaceutical composition according to claim 227 , wherein Ais selected from phenyl claim 227 , triazinyl claim 227 , pyrazinyl claim 227 , pyrimidinyl claim 227 , pyridazinyl claim 227 , pyridyl claim 227 , thiadiazolyl claim 227 , triazolyl claim 227 , oxadiazolyl claim 227 , isothiazolyl claim 227 , pyrazolyl claim 227 , imidazolyl claim 227 , thiazolyl claim 227 , oxazolyl claim 227 , pyrrolyl claim 227 , thienyl claim 227 , furanyl claim 227 , indolizinyl claim 227 , indolyl claim 227 , isoindolyl claim 227 , benzofuranyl claim 227 , benzo[b]thienyl claim 227 , 1H-indazolyl claim 227 , benzimidazolyl claim 227 , benzthiazolyl claim 227 , purinyl claim 227 , quinolinyl claim 227 , isoquinolinyl claim 227 , cinnolinyl claim 227 , phthazinyl claim 227 , quinazolinyl claim 227 , quinoxalinyl claim 227 , 1 claim 227 ,8-naphthyridinyl claim 227 , pteridinyl claim 227 , carbazolyl claim 227 , acridinyl claim 227 , phenazinyl claim 227 , phenothiazinyl claim 227 , phenoxazinyl claim 227 , indenyl claim 227 , naphthyl claim 227 , azulinyl claim 227 , or anthracenyl.234. The pharmaceutical composition according to claim 227 , wherein each Bis independently selected from optionally substituted C6-C10 aryl.235. The pharmaceutical composition according to claim 227 , wherein each Bis independently an optionally substituted phenyl or naphthyl.236. The pharmaceutical composition according to claim 227 , wherein each Bis an unsubstituted ...

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Номер записи: 49
10-02-2022 дата публикации

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Номер: US20220041621A1
Автор: Bookser Brett C., Clemens Jeremy J., Cleveland Thomas, Coon Timothy R., Gallant Michel, Grootenhuis Peter Diederik Jan, Hadida Ruah Sara Sabina, Laterreur Julie, Melillo Vito, Miller Mark Thomas, Paraselli Prasuna, Ramtohul Yeeman K., Reddy Thumkunta Jagadeeswar, STURINO Claudio, Valdez Lino, Zhou Jinglan
Принадлежит:

This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing at least one such modulator, methods of treatment of cystic fibrosis using such modulators and pharmaceutical compositions, and processes for making such modulators. 2. The compound claim 1 , deuterated derivative claim 1 , or pharmaceutically acceptable salt according to claim 1 , wherein X is —O— claim 1 ,3. The compound claim 1 , deuterated derivative claim 1 , or pharmaceutically acceptable salt according to or claim 1 , wherein each Ris independently selected from hydrogen claim 1 , halogen claim 1 , C-Calkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q) claim 1 , C-Ccycloalkyl claim 1 , and —OR.4. The compound claim 1 , deuterated derivative claim 1 , or pharmaceutically acceptable salt according to any one of to claim 1 , wherein —ORis —OH.5. The compound claim 1 , deuterated derivative claim 1 , or pharmaceutically acceptable salt according to any one of to claim 1 , wherein each Q is independently selected from:{'sub': 3', '8, 'C-Ccycloalkyl,'}{'sub': 6', '10', '1', '6, 'b': 1', '3, 'C-Caryl optionally substituted with - groups independently selected from halogen and C-Calkyl.'}8. The compound claim 1 , deuterated derivative claim 1 , or pharmaceutically acceptable salt according to any one of to claim 1 , wherein Ring B is selected from C-Ccycloalkyl and phenyl optionally substituted with 1-3 groups independently selected from halogen.10. The compound claim 1 , deuterated derivative claim 1 , or pharmaceutically acceptable salt according to any one of to claim 1 , wherein n is selected from 4 claim 1 , 5 claim 1 , and 6.12. The compound claim 1 , deuterated derivative claim 1 , or pharmaceutically acceptable salt according to any one of to claim 1 , wherein each Ris independently selected from C-Calkyl (optionally substituted with 1-6 groups independently selected from halogen and ...

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Номер записи: 50
28-01-2021 дата публикации

PHARMACEUTICAL COMPOSITION AND ADMINISTRATIONS THEREOF

Номер: US20210023070A1
Автор: Botfield Martyn, Dinehart Kirk, Grootenhuis Peter D.J., Grossi Alfredo, Hurter Patricia, Overhoff Kirk, Rowe William, Verwijs Marinus Jacobus, Young Christopher
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, methods of manufacturing pharmaceutical compositions of the present invention, and methods of administering pharmaceutical compositions of the present invention. 1111-. (canceled)112. A method of treating or lessening the severity of cystic fibrosis in a patient in need thereof , comprising administering to the patient a pharmaceutical composition comprising a solid dispersion , wherein the solid dispersion comprises:a) 80% of amorphous or substantially amorphous N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) by weight of the dispersion, wherein substantially amorphous Compound 1 comprises less than 15% crystalline Compound 1,b) 19.5% of hydroxypropylmethylcellulose acetate succinate (HPMCAS) by weight of the dispersion, andc) 0.5% of sodium lauryl sulfate (SLS) by weight of the dispersion.113. The method of claim 112 , wherein the pharmaceutical composition further comprises 30.5% of microcrystalline cellulose by weight of the composition.114. The method of claim 112 , wherein the pharmaceutical composition further comprises 30.4% of lactose by weight of the composition.115. The method of claim 112 , wherein the pharmaceutical composition further comprises 3% of sodium croscarmellose by weight of the composition.116. The method of claim 112 , wherein the pharmaceutical composition further comprises 0.5% of SLS by weight of the composition.117. The method of claim 112 , wherein the pharmaceutical composition further comprises 0.5% of colloidal silicon dioxide by weight of the composition.118. The method of claim 112 , wherein the pharmaceutical composition further comprises 1.0% of magnesium stearate by weight of the composition.119. The method of claim 112 , wherein the pharmaceutical composition comprises 34.1% of the solid ...

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Номер записи: 51
28-01-2021 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20210024505A1
Автор: Grootenhuis Peter D.J., Hadida Ruah Sara S., HAMILTON Matthew M., Miller Mark
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 169.-. (canceled) The present application is a continuing application of and claims the benefit of priority under 35 U.S.C. § 120 of co-pending International Application Serial No. PCT/US06/043289, filed Nov. 8, 2006, which claims the benefit, under 35 U.S.C. § 119, of U.S. provisional patent application Ser. Nos. 60/734,506, filed on Nov. 8, 2005; 60/754,086, filed on Dec. 27, 2005; and 60/802,458, filed on May 22, 2006, the entire contents of each of above applications is incorporated herein by reference.The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.ABC transporters are a family of membrane transporter proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics, as well as anions. ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were discovered as multi-drug resistance proteins (like the MDR1-P glycoprotein, or the multi-drug resistance protein, MRP1), defending malignant cancer cells against chemotherapeutic agents. To date, 48 ABC Transporters have been identified and grouped into 7 families based on their sequence identity and function.ABC transporters regulate a variety of important physiological roles within the ...

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Номер записи: 52
24-04-2014 дата публикации

Pharmaceutical Composition and Administrations Thereof

Номер: US20140112988A1
Автор: Botfield Martyn, Dinehart Kirk, Grootenhuis Peter D.J., Grossi Alfredo, Hurter Patricia, Overhoff Kirk, Rowe William, Verwijs Marinus Jacobus, Young Christopher
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, methods of manufacturing pharmaceutical compositions of the present invention, and methods of administering pharmaceutical compositions of the present invention. 1. A pharmaceutical composition comprising:a. a solid dispersion comprising substantially amorphous Compound 1 and a polymer;b. a filler;c. a disintegrant;d. a surfactant;e. a binder;f. a glidant; andg. a lubricant.2. The pharmaceutical composition of claim 1 , wherein the solid dispersion comprises substantially amorphous Compound 1 and a polymer claim 1 , and the polymer comprises HPMC claim 1 , HPMCAS claim 1 , PVP/VA claim 1 , PVP claim 1 , methacrylic acid/methacrylate copolymer claim 1 , HPC claim 1 , or any combination thereof.3. The pharmaceutical composition of claim 2 , wherein the solid dispersion has a mean particle diameter of greater than about 5 μm.4. The pharmaceutical composition of claim 2 , wherein the solid dispersion has a bulk density of about 0.10 g/cc or greater.5. The pharmaceutical composition of claim 2 , wherein the solid dispersion comprises substantially amorphous Compound 1 claim 2 , and Compound 1 is present in a concentration of at least 20 wt % by weight of the solid dispersion.6. The pharmaceutical composition of claim 5 , wherein the solid dispersion comprises 80 wt % or less of HPMCAS or PVP/VA.7. The pharmaceutical composition of claim 5 , wherein the solid dispersion comprises a surfactant.8. The pharmaceutical composition of claim 7 , wherein the solid dispersion comprises less than 10 wt % of surfactant by weight of solid dispersion.9. The pharmaceutical composition of claim 8 , wherein the solid dispersion comprises a surfactant claim 8 , and the surfactant is SLS.10. The pharmaceutical composition of claim 9 , wherein the solid dispersion comprises amorphous Compound 1.11. The ...

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Номер записи: 53
24-04-2014 дата публикации

Solid Forms of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihyroquinoline-3-carboxamide

Номер: US20140113933A9
Автор: Botfield Martyn, Grootenhuis Peter D.J., Krawiec Mariusz, Van Goor Fredrick, Zhang Beili
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to solid state forms, for example, crystalline forms of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, pharmaceutical compositions thereof, and methods therewith. 126-. (canceled)27. A method of treating or lessening the severity of a disease in a patient , wherein said disease is selected from cystic fibrosis , asthma , smoke induced COPD , chronic bronchitis , rhinosinusitis , constipation , pancreatitis , pancreatic insufficiency , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) , mild pulmonary disease , idiopathic pancreatitis , allergic bronchopulmonary aspergillosis (ABPA) , liver disease , hereditary emphysema , hereditary hemochromatosis , coagulation-fibrinolysis deficiencies , such as protein C deficiency , Type 1 hereditary angioedema , lipid processing deficiencies , such as familial hypercholesterolemia , Type 1 chylomicronemia , abetalipoproteinemia , lysosomal storage diseases , such as I-cell disease/pseudo-Hurler , mucopolysaccharidoses , Sandhof/Tay-Sachs , Crigler-Najjar type II , polyendocrinopathy/hyperinsulemia , Diabetes mellitus , Laron dwarfism , myleoperoxidase deficiency , primary hypoparathyroidism , melanoma , glycanosis CDG type 1 , congenital hyperthyroidism , osteogenesis imperfecta , hereditary hypofibrinogenemia , ACT deficiency , Diabetes insipidus (DI) , neurophyseal DI , neprogenic DI , Charcot-Marie Tooth syndrome , Perlizaeus-Merzbacher disease , neurodegenerative diseases such as Alzheimer's disease , Parkinson's disease , amyotrophic lateral sclerosis , progressive supranuclear plasy , Pick's disease , several polyglutamine neurological disorders such as Huntington's , spinocerebullar ataxia type I , spinal and bulbar muscular atrophy , dentatorubal pallidoluysian , and myotonic dystrophy , as well as spongiform encephalopathies , such as hereditary Creutzfeldt-Jakob disease (due ...

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Номер записи: 54
29-01-2015 дата публикации

MODULATORS OF CFTR

Номер: US20150031708A1
Автор: Bear Brian, Grootenhuis Peter, Hadida-Ruah Sara, McCartney Jason, Miller Mark, Zhou Jinglan
Принадлежит:

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating CFTR mediated diseases using compounds of the present invention. 179-. (canceled)81. A pharmaceutical composition comprising:{'claim-ref': {'@idref': 'CLM-00080', 'claim 80'}, '(i) a compound according to ; and'}(ii) a pharmaceutically acceptable carrier.82. The composition according to claim 81 , further comprising a mucolytic agent claim 81 , a bronchodialator claim 81 , an antibiotic claim 81 , an anti-infective agent claim 81 , an anti-inflammatory agent claim 81 , a CFTR modulator claim 81 , or a nutritional agent.83. A method of modulating CFTR activity comprising the step of contacting said CFTR with a compound according to .84. A method of treating or lessening the severity of a disease in a patient claim 80 , wherein said disease is selected from cystic fibrosis claim 80 , hereditary emphysema claim 80 , COPD claim 80 , or dry-eye disease claim 80 , said method comprising the step of administering to said patient an effective amount of a compound according to .85. A kit for use in measuring the activity of CFTR or a fragment thereof in a biological sample in vitro or in vivo claim 80 , comprising:{'claim-ref': {'@idref': 'CLM-00080', 'claim 80'}, '(i) a composition comprising a compound according ; and'} a) contacting the composition with the biological sample; and', 'b) measuring activity of said CFTR or a fragment thereof., '(ii) instructions for86. The kit according to claim 85 , further comprising instructions fora) contacting an additional composition with the biological sample;b) measuring the activity of said CFTR or a fragment thereof in the presence of said additional compound, and{'claim-ref': {'@idref': 'CLM-00080', 'claim 80'}, 'c) ...

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Номер записи: 55
29-01-2015 дата публикации

Modulators of atp-binding cassette transporters

Номер: US20150031722A1
Автор: Anna Hazlewood, Ashvani Singh, Fredrick Van Goor, Jason Mccartney, Jinglan Zhou, Peter Grootenhuis, Sara Hadida-Ruah
Принадлежит: Vertex Pharmaceuticals Inc

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

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Номер записи: 56
17-02-2022 дата публикации

METHODS OF TREATMENT FOR CYSTIC FIBROSIS

Номер: US20220047564A1
Автор: ALTSHULER David M., Anderson Corey Don, Borek Bartlomiej, Chen Weichao George, Clemens Jeremy J., Cleveland Thomas, Coon Timothy Richard, Frieman Bryan, Grootenhuis Peter, Hadida Ruah Sara Sabina, HARE Brian J., KEWALRAMANI Reshma, McCartney Jason, Miller Mark Thomas, Paraselli Prasuna, Pierre Fabrice, ROBERTSON Sarah M., SOSNAY Patrick R., Swift Sara E., Van Goor Fredrick, YOUNG TIM, Zhou Jinglan
Принадлежит:

This application describes methods of treating cystic fibrosis or a CFTR mediated disease comprising administering Compound I or a pharmaceutically acceptable salt thereof. (I) The application also describes pharmaceutical compositions comprising Compound I or a pharmaceutically acceptable salt thereof and optionally comprising one or more additional CFTR modulating agents. 2. The method according to claim 1 , comprising administering to said patient:(a) at least one compound chosen from Compound I and pharmaceutically acceptable salts thereof;(b) at least one compound chosen from Compound II and pharmaceutically acceptable salts thereof; and(c) at least one compound chosen from (i) Compound III and pharmaceutically acceptable salts thereof, or (ii) Compound III-d and pharmaceutically acceptable salts thereof.3. (canceled)4. The method according to claim 1 , comprising administering to said patient:(a) at least one compound chosen from Compound I and pharmaceutically acceptable salts thereof;(b) at least one compound chosen from Compound II and pharmaceutically acceptable salts thereof; and(c) at least one compound chosen from Compound III-d and pharmaceutically acceptable salts thereof.5. The method according to claim 1 , wherein the at least one compound chosen from Compound I and pharmaceutically acceptable salts thereof claim 1 , is administered in a single composition with the at least one compound chosen from Compound II claim 1 , Compound III claim 1 , Compound III-d claim 1 , and pharmaceutically acceptable salts thereof.6. The method according to claim 1 , wherein the at least one compound chosen from Compound I and pharmaceutically acceptable salts thereof claim 1 , and the at least one compound chosen from Compound II claim 1 , Compound III claim 1 , Compound III-d claim 1 , and pharmaceutically acceptable salts thereof claim 1 , are administered in one or more separate compositions.7. (canceled)8. (canceled)9. The method according to claim 1 , wherein a ...

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Номер записи: 57
04-02-2021 дата публикации

Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator

Номер: US20210032272A1
Автор: Alexander Russell Abela, Fabrice Jean Denis PIERRE, Haripada Khatuya, Jason Mccartney, Jeremy J. Clemens, Jinglan Zhou, Joe Anh Tran, Mark Thomas Miller, Peter Diederik Jan Grootenhuis, Sara Sabina Hadida Ruah, Yoshihiro Ishihara
Принадлежит: Vertex Pharmaceuticals Inc

This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing at least one such modulator, methods of treatment of cystic fibrosis by administering such modulators and pharmaceutical compositions, and processes for making such modulators.

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Номер записи: 58
18-02-2021 дата публикации

MODULATOR OF THE CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR, PHARMACEUTICAL COMPOSITIONS, METHODS OF TREATMENT, AND PROCESS FOR MAKING THE MODULATOR

Номер: US20210047295A1
Автор: ABELA Alexander Russell, Alcacio Timothy, Anderson Corey, Angell Paul Timothy, Baek Minson, Clemens Jeremy J., Cleveland Thomas, Ferris Lori Ann, Grootenhuis Peter Diederik Jan, Gross Raymond Stanley, Gulevich Anton V., Hadida Ruah Sara Sabina, Hsia Clara Kuang-Ju, Hughes Robert M., Joshi Pramod Virupax, KANG Ping, Keshavarz-Shokri Ali, KHATUYA Haripada, Krenitsky Paul John, McCartney Jason, Miller Mark Thomas, Paraselli Prasuna, PIERRE Fabrice Jean Denis, Shi Yi, Shrestha Muna, Siesel David Andrew, Stavropoulos Kathy, Termin Andreas P., Uy Johnny, Van Goor Fredrick F., Young Timothy John, Zhou Jinglan
Принадлежит:

Compounds of Formula (I): 171.-. (canceled)73. Crystalline Form A according to in substantially pure form.74. Crystalline Form A according to claim 72 , characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 6.6±0.2 claim 72 , 7.6±0.2 claim 72 , 9.6±0.2 claim 72 , 12.4±0.2 claim 72 , 13.1±0.2 claim 72 , 15.2±0.2 claim 72 , 16.4±0.2 claim 72 , 18.2±0.2 claim 72 , and 18.6±0.2.75. Crystalline Form A according to claim 72 , characterized by an X-ray powder diffractograph having a signal at at least three two-theta values chosen from 6.6±0.2 claim 72 , 9.6±0.2 claim 72 , 13.1±0.2 claim 72 , 15.2±0.2 claim 72 , 18.2±0.2 claim 72 , and 18.6±0.2.76. Crystalline Form A according to claim 72 , characterized by an X-ray powder diffractograph having a signal at three two-theta values of 6.6±0.2 claim 72 , 13.1±0.2 claim 72 , 18.2±0.2.77. Crystalline Form A according to claim 72 , characterized by an X-ray powder diffractograph having a signal at six two-theta values of 6.6±0.2 claim 72 , 9.6±0.2 claim 72 , 13.1±0.2 claim 72 , 15.2±0.2 claim 72 , 18.2±0.2 claim 72 , and 18.6±0.2.78. Crystalline Form A according to claim 72 , characterized by an X-ray powder diffractogram substantially similar to that in .79115.-. (canceled)116. A pharmaceutical formulation comprising at least one crystalline form according to and a pharmaceutically acceptable carrier.117125.-. (canceled) Disclosed herein is a modulator of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing the modulator, methods of treatment of cystic fibrosis, and a process for making the modulator.Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 70,000 children and adults worldwide. Despite progress in the treatment of CF, there is no cure.In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelia lead to reduced apical anion secretion causing an imbalance in ion and ...

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Номер записи: 59
18-02-2021 дата публикации

CRYSTALLINE FORMS OF CFTR MODULATORS

Номер: US20210047323A1
Автор: Anderson Corey Don, Clemens Jeremy J., Cleveland Thomas, Coon Timothy Richard, Frieman Bryan, Gagnon Kevin J., Grootenhuis Peter, Hadida Ruah Sara Sabina, Li Jicong, Lu Jennifer, McCartney Jason, Medek Ales, Miller Mark Thomas, Paraselli Prasuna, Pierre Fabrice, Shi Yi, Shrestha Muna, Swift Sara E., Waldo Michael, Zhang Beili, Zhou Jinglan, Zwicker Carl L.
Принадлежит:

Crystalline forms of Compound I: 2. The substantially crystalline Compound I according to claim 1 , wherein less than 15% of Compound I is in amorphous form.3. The substantially crystalline Compound I according to claim 1 , wherein less than 10% of Compound I is in amorphous form.4. The substantially crystalline Compound I according to claim 1 , wherein less than 5% of Compound I is in amorphous form.5. The substantially crystalline Compound I according to claim 1 , wherein 100% of Compound I is crystalline.6. The substantially crystalline Compound I according to characterized by an X-ray powder diffractogram (XRPD).7. The substantially crystalline Compound I according to claim 1 , characterized by C solid state nuclear magnetic resonance (C ss NMR) spectrum.8. The substiantially crystalline Compound I according to claim 1 , characterized by crystal lattice parameters.9. A pharmaceutical composition comprising the substantially crystalline Compound I according to .10. The pharmaceutical composition according to claim 9 , further comprising one or more additional CFTR modulating compounds.11. The pharmaceutical composition according to claim 10 , wherein at least one additional CFTR modulating compound is a CFTR potentiator.12. The pharmaceutical composition according to claim 10 , wherein at least one additional CFTR modulating compound is a CFTR corrector.13. The pharmaceutical composition according to claim 10 , wherein the one or more additional CFTR modulating compounds are selected from (a) Compound II claim 10 , (b) Compound III or Compound III-d claim 10 , and (c) Compound IV.14. A method of treating cystic fibrosis comprising administering the substantially crystalline Compound I according to claim 1 , to a subject in need thereof.15. The method of treating cystic fibrosis according to claim 14 , wherein the substantially crystalline Compound I is administered with one or more additional CFTR modulating compounds.16. The method of treating cystic fibrosis ...

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Номер записи: 60
18-02-2021 дата публикации

PROCESS OF MAKING CFTR MODULATORS

Номер: US20210047345A1
Автор: Anderson Corey Don, Angell Paul, Clemens Jeremy J., Cleveland Thomas, Cochran John E., Coon Timothy Richard, Frieman Bryan, Grootenhuis Peter, Hadida Ruah Sara Sabina, Littler Benjamin J., McCartney Jason, Miller Mark Thomas, Paraselli Prasuna, Pierre Fabrice, Siesel David, Swift Sara E., Urbina Armando, Zhou Jinglan
Принадлежит:

The disclosure provides processes for synthesizing Compound I, and pharmaceutically acceptable salts thereof. This application claims priority from U.S. Provisional Application No. 62/886,660, filed Aug. 14, 2019, which is hereby incorporated by reference in its entirety.Disclosed herein are processes for making a modulator of cystic fibrosis transmembrane conductance regulator (“CFTR”).Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 70,000 children and adults worldwide. Despite progress in the treatment of CF, there is no cure.In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelia lead to reduced apical anion secretion, causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, result in death. In addition, the majority of males with CF are infertile, and fertility is reduced among females with CF.Sequence analysis of the CFTR gene has revealed a variety of disease-causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, greater than 2000 mutations in the CF gene have been identified; currently, the CFTR2 database contains information on 412 of these identified mutations, with sufficient evidence to define 346 mutations as disease-causing. The most prevalent disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence and is commonly referred to as the ΔF508 mutation. This mutation occurs in most of the cases of cystic fibrosis and is associated with severe disease.The ...

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Номер записи: 61
18-02-2021 дата публикации

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Номер: US20210047350A1
Автор: Anderson Corey Don, Clemens Jeremy J., Cleveland Thomas, Coon Timothy Richard, Frieman Bryan, Grootenhuis Peter, Hadida Ruah Sara Sabina, McCartney Jason, Miller Mark Thomas, Paraselli Prasuna, Pierre Fabrice, Swift Sara E., Zhou Jinglan
Принадлежит:

This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing at least one such modulator, methods of treatment of cystic fibrosis using such modulators and pharmaceutical compositions, and processes for making such modulators. 4. The compound of claim 1 , wherein at least one hydrogen is replaced by deuterium.5. The compound of claim 1 , wherein the compound is a pharmaceutically acceptable salt.9. The compound of claim 6 , wherein at least one hydrogen is replaced by deuterium.10. The compound of claim 6 , wherein the compound is a pharmaceutically acceptable salt.12. The compound of claim 11 , wherein at least one hydrogen is replaced by deuterium.13. The compound of claim 11 , wherein the compound is a pharmaceutically acceptable salt.15. The compound of claim 14 , wherein at least one hydrogen is replaced by deuterium.16. The compound of claim 14 , wherein the compound is a pharmaceutically acceptable salt.17. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier.18. The pharmaceutical composition of claim 17 , further comprising one or more additional therapeutic agent(s).19. The pharmaceutical composition of claim 18 , wherein the one or more additional therapeutic agent(s) comprise(s) a compound selected from Compound II claim 18 , Compound III claim 18 , Compound III-d claim 18 , and pharmaceutically acceptable salts thereof.20. The pharmaceutical composition of claim 19 , wherein the composition comprises Compound II and Compound III.21. The pharmaceutical composition of claim 19 , wherein the composition comprises Compound II and Compound III-d.23. A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound of .24. The method of claim 23 , further comprising administering to the patient one or more additional therapeutic agent(s) prior to claim 23 , concurrent with claim 23 , or subsequent to the ...

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Номер записи: 62
25-02-2021 дата публикации

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Номер: US20210052584A1
Автор: Anderson Corey, Arumugam Vijayalaksmi, Bear Brian Richard, Binch Hayley Marie, Clemens Jeremy J., Cleveland Thomas, Conroy Erica, Coon Timothy Richard, Frieman Bryan A., Grootenhuis Peter Diederik Jan, Gross Raymond Stanley, Hadida-Ruah Sara Sabina, Joshi Pramod Virupax, KHATUYA Haripada, Krenitsky Paul John, LIN Chun-Chieh, MARELIUS Gulin Erdogan, McCartney Jason, Melillo Vito, Miller Mark Thomas, Nicholls Georgia McGaughey, PIERRE Fabrice Jean Denis, Silina Alina, Termin Andreas P., Uy Johnny, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention features a compound of formula I: 155.-. (canceled)57. The compound claim 56 , salt claim 56 , or deuterated derivative of claim 56 , wherein ring B is phenyl claim 56 , pyridyl claim 56 , pyridine-2(1H)-one claim 56 , pyrazole claim 56 , indole claim 56 , thiophene claim 56 , dihydrobenzofuran claim 56 , pyrazine claim 56 , indazole claim 56 , thiazole claim 56 , pyridine-4(1H)-one claim 56 , pyrrolidinone claim 56 , or quinoline.59. The compound claim 56 , salt claim 56 , or deuterated derivative of claim 56 , wherein ring C is phenyl claim 56 , indole claim 56 , cycloalkyl claim 56 , pyridyl claim 56 , pyrrolidine claim 56 , naphthalene claim 56 , or dihydroindene.61. The compound claim 56 , salt claim 56 , or deuterated derivative of claim 56 , wherein Y is O.62. The compound claim 56 , salt claim 56 , or deuterated derivative of claim 56 , wherein Y is CH.63. The compound claim 56 , salt claim 56 , or deuterated derivative of claim 56 , wherein Y is CH(C1-C6 aliphatic).64. The compound claim 56 , salt claim 56 , or deuterated derivative of claim 56 , wherein Y is CH(CH).65. The compound claim 56 , salt claim 56 , or deuterated derivative of claim 56 , wherein Y is CH(CHCH).66. The compound claim 56 , salt claim 56 , or deuterated derivative of claim 56 , wherein Ris halo claim 56 , CN claim 56 , C1-C6 aliphatic claim 56 , C1-C6alkoxy claim 56 , C3-C8 cycloalkyl claim 56 , or a phenyl claim 56 , pyridyl claim 56 , pyrimidine claim 56 , indole claim 56 , aza-indole claim 56 , or thiophene ring claim 56 , wherein all rings may be substituted with halo claim 56 , C1-C6 aliphatic claim 56 , C1-C6 alkoxy claim 56 , C1-C6 fluoroaliphatic claim 56 , C1-C6 fluoroalkoxy claim 56 , OH claim 56 , CHOH claim 56 , CHOCH claim 56 , CN claim 56 , COH claim 56 , amino claim 56 , amido claim 56 , C3-C10 heteroaryl claim 56 , C3-C10 heterocycloalkyl claim 56 , or a (C1-C8 aliphatic)-Rwherein up to three CHunits may be replaced with O claim 56 , CO claim 56 , ...

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Номер записи: 63
21-02-2019 дата публикации

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Номер: US20190055220A1
Автор: Bear Brian, Clemens Jeremy, Cleveland Thomas, Coon Timothy Richard, Frieman Bryan A., Grootenhuis Peter Diederik Jan, Hadida Ruah Sara S., KHATUYA Haripada, Krenitsky Paul J., Miller Mark Thomas, Silina Alina, Uy Johnny, Zhou Jinglan
Принадлежит:

The present disclosure features a compound of formula I: or a pharmaceutically acceptable salt thereof, where R, R, W, X, Z, n, p, and Rings A and B are defined herein, for the treatment of CFTR mediated diseases, such as cystic fibrosis. The present disclosure also features pharmaceutical compositions, method of treating, and kits thereof. 1309.-. (canceled)311. The compound of or a pharmaceutically acceptable salt thereof claim 310 , wherein Ring A is pyridyl claim 310 , indole claim 310 , indoline claim 310 , isoindoline claim 310 , pyrazole claim 310 , pyrimidine claim 310 , 1 claim 310 ,2 claim 310 ,3 claim 310 ,4-tetrahydroquinoline claim 310 , quinoline claim 310 , 5 claim 310 ,6 claim 310 ,7 claim 310 ,8-tetrahydroquinoline claim 310 , 1 claim 310 ,2 claim 310 ,3 claim 310 ,4-tetrahydroisoquinoline claim 310 , pyrrolodine claim 310 , aza-indole claim 310 , pyrrole claim 310 , thiophene claim 310 , oxazole claim 310 , pyrazine claim 310 , triazole claim 310 , thiazole claim 310 , indazole claim 310 , 2 claim 310 ,3 claim 310 ,4 claim 310 ,5-tetrahydro-1H-benzo[d]azepine claim 310 , 1H-benzo[d]imidazole claim 310 , imidazo[1 claim 310 ,2-a]pyridine claim 310 , or imidazole ring.313. The compound of or a pharmaceutically acceptable salt thereof claim 310 , wherein Ring B is a pyridyl claim 310 , pyridine-2(1H)-one claim 310 , pyrazole claim 310 , indole claim 310 , pyrrole claim 310 , indoline claim 310 , thiophene claim 310 , dihydrobenzofuran claim 310 , tetrahydrofuran claim 310 , furan claim 310 , pyrazine claim 310 , indazole claim 310 , thiazole claim 310 , pyridine-4(1H)-one claim 310 , pyrrolidinone claim 310 , 3-azabicyclo[3.1.0]hexane claim 310 , (1R claim 310 ,4R)-2-oxa-5-azabicyclo[2.2.1]heptane claim 310 , pyrrolidine claim 310 , azetidine claim 310 , piperidine claim 310 , piperazine claim 310 , imidazo[1 claim 310 ,2-a]pyridine claim 310 , or quinoline.315. The compound of or a pharmaceutically acceptable salt thereof claim 310 , wherein Ris ...

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Номер записи: 64
05-03-2015 дата публикации

Modulators of atp-binding cassette transporters

Номер: US20150065487A1
Автор: Anna Hazlewood, Ashvani Singh, Fred Van Goor, Jason Mccartney, Jinglan Zhou, Peter Grootenhuis, Sara Hadida-Ruah
Принадлежит: Vertex Pharmaceuticals Inc

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

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Номер записи: 65
05-03-2015 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20150065497A1
Автор: Bear Brian, Grootenhuis Peter D.J., Hadida Ruah Sara S., McCartney Jason, Miller Mark T.
Принадлежит:

Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 21. The compound of claim Error! Reference source not found. , wherein the one Rattached to the 3-position of the phenyl ring is an aryl optionally substituted with 1 , 2 , or 3 of R , wherein Ris —ZR; in which each Zis independently a bond or an optionally substituted branched or straight Caliphatic chain wherein up to two carbon units of Zare optionally and independently replaced by —CO— , —CS— , —CONR— , —CONRNR— , —CO— , —OCO— , —NRCO— , —O— , —NRCONR— , —OCONR— , —NRNR— , —NRCO— , —S— , —SO— , —SO— , —NR— , —SONR— , —NRSO— , or —NRSONR—; each Ris independently R , halo , —B(OH) , —OH , —NH , —NO , —CN , or —OCF; and each Ris independently hydrogen , an optionally substituted Caliphatic group , an optionally substituted cycloaliphatic , an optionally substituted heterocycloaliphatic , an optionally substituted aryl , or an optionally substituted heteroaryl.3. The compound of claim 2 , wherein the one Rattached to the 3-position of the phenyl ring is a phenyl optionally substituted with 1 claim 2 , 2 claim 2 , or 3 of R.4. The compound of claim 3 , wherein the one Rattached to the 3-position of the phenyl ring is a phenyl substituted with one of R claim 3 , wherein Ris —ZR; each Zis independently a bond or an optionally substituted branched or straight Caliphatic chain wherein up to two carbon units of Zare optionally and independently replaced by —O— claim 3 , —NHC(O)— claim 3 , —C(O)NR— claim 3 , —SO— claim 3 , —NHSO— claim 3 , —NHC(O)— claim 3 , —SO— claim 3 , —NRSO— claim 3 , —SONH— claim 3 , —SONR— claim 3 , —NH— claim 3 , or —C(O)O—.5. The compound of claim 4 , wherein one ...

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Номер записи: 66
05-03-2015 дата публикации

Modulators of ATP-Binding Cassette Transporters

Номер: US20150065500A1
Автор: Bear Brian, Grootenhuis Peter D.J., Hadida-Ruah Sara, Hamilton Matthew, McCartney Jason, Miller Mark, van Goor Frederick, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 1. A compound selected from Table 1 , compounds 1-528.2. A pharmaceutical composition comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, '(i) a compound according to ; and'}(ii) a pharmaceutically acceptable carrier.3. The composition according to claim 2 , optionally further comprising a mucolytic agent claim 2 , a bronchodialator claim 2 , an antibiotic claim 2 , an anti-infective agent claim 2 , an anti-inflammatory agent claim 2 , a CFTR modulator claim 2 , or a nutritional agent.4. A method of treating or lessening the severity of a disease in a patient claim 1 , wherein said disease is selected from cystic fibrosis claim 1 , hereditary emphysema claim 1 , hereditary hemochromatosis claim 1 , coagulation-fibrinolysis deficiencies claim 1 , such as protein C deficiency claim 1 , Type 1 hereditary angioedema claim 1 , lipid processing deficiencies claim 1 , such as familial hypercholesterolemia claim 1 , Type 1 chylomicronemia claim 1 , abetalipoproteinemia claim 1 , lysosomal storage diseases claim 1 , such as I-cell disease/pseudo-Hurler claim 1 , mucopolysaccharidoses claim 1 , Sandhof/Tay-Sachs claim 1 , Crigler-Najjar type II claim 1 , polyendocrinopathy/hyperinsulemia claim 1 , Diabetes mellitus claim 1 , Laron dwarfism claim 1 , myleoperoxidase deficiency claim 1 , primary hypoparathyroidism claim 1 , melanoma claim 1 , glycanosis CDG type 1 claim 1 , congenital hyperthyroidism claim 1 , osteogenesis imperfecta claim 1 , hereditary hypofibrinogenemia claim 1 , ACT deficiency claim 1 , Diabetes insipidus (DI) claim 1 , neurophyseal DI claim 1 , neprogenic DI claim 1 ...

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Номер записи: 67
12-03-2015 дата публикации

PROCESS FOR MAKING MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Номер: US20150073015A2
Автор: Botfield Martyn C., DeMattei John, Grootenhuis Peter D.J., Guerette Dahrika Milfred Yap, Krueger Brian R., Looker Adam R., Neubert-Langille Bobbianna, Roeper Stefanie, Ryan Michael P., Trudeau Martin, Van Goor Fredrick F., Zlokarnik Gregor
Принадлежит:

The invention provides a process for the preparation of a compound of Formula 1, 2. The process of claim 1 , wherein Ris independently —OC(O)OR′ claim 1 , —OC(O)NHR′ claim 1 , or —OC(O)N(R′) claim 1 , wherein R′ is not hydrogen.3. The process of claim 2 , further comprising cleaving the —OC(O)OR′ claim 2 , —OC(O)NHR′ claim 2 , or —OC(O)N(R′)to form —OH.4. The process of claim 3 , wherein the cleavage is performed by treating a compound of Formula 1 with an alcoholic solvent in the presence of NaOH claim 3 , KOH or sodium methoxide.5. The process of claim 4 , wherein the alcoholic solvent is methanol.6. The process of claim 1 , wherein at least one of Ror Ris independently a Cstraight or branched alkyl which is substituted with —COOR′ or —CON(R′) claim 1 , wherein R′ is not hydrogen.7. The process of claim 6 , further comprising hydrolyzing each —COOR′ claim 6 , or —CON(R′)to form —COOH.8. The process of claim 7 , wherein the hydrolysis is performed by treating a compound of Formula 1 with an alcoholic solvent in the presence of NaOH claim 7 , KOH or sodium methoxide.9. The process of claim 8 , wherein the alcoholic solvent is methanol.10. The process of claim 6 , wherein Ris independently —OC(O)OR′ claim 6 , —OC(O)NHR′ claim 6 , or —OC(O)N(R′) claim 6 , wherein R′ is not hydrogen.11. The process of claim 10 , further comprising cleaving the —OC(O)OR′ claim 10 , —OC(O)NHR′ claim 10 , or —OC(O)N(R′)to form —OH.12. The process of claim 11 , wherein the cleavage is performed by treating a compound of Formula 1 with an alcoholic solvent in the presence of NaOH claim 11 , KOH or sodium methoxide.13. The process of claim 12 , wherein the alcoholic solvent is methanol.1413. The process of any of - claims 1 , wherein the coupling is performed in the presence of a base.15. The process of claim 14 , wherein the base is KCO claim 14 , EtN claim 14 , NMM claim 14 , pyridine or DIEA.1615. The process of any of - claims 1 , wherein the coupling is performed in the presence of a ...

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Номер записи: 68
05-06-2014 дата публикации

Modulators of atp-binding cassette transporters

Номер: US20140155431A1
Автор: Anna Hazlewood, Ashvani Singh, Fredrick Van Goor, Jason Mccartney, Jinglan Zhou, Peter Grootenhuis, Sara Hadida-Ruah
Принадлежит: Vertex Pharmaceuticals Inc

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

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Номер записи: 69
05-06-2014 дата публикации

Modulators of atp-binding cassette transporters

Номер: US20140155626A1
Автор: Anna Hazlewood, Jinglan Zhou, Peter Grootenhuis, Sara Hadida Ruah
Принадлежит: Vertex Pharmaceuticals Inc

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

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Номер записи: 70
14-03-2019 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20190076419A1
Автор: Bear Brian Richard, Grootenhuis Peter Diederik Jan, Hadida Ruah Sara Sabina, McCartney Jason, Miller Mark Thomas, Numa Mehdi Michel Djamel, Van Goor Fredrick F., Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 128-. (canceled) The present application claims the benefit under 35 U.S.C. § 120 of U.S. application Ser. No. 11/786,001, filed Apr. 9, 2007, which claims the benefit under 35 U.S.C. § 119 of U.S. Provisional Application No. 60/790,459, filed Apr. 7, 2006, the entire contents of both applications being incorporated herein by reference.The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.ABC transporters are a family of membrane transporter proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics, as well as anions. ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were discovered as multidrug resistance proteins (like the MDR1-P glycoprotein, or the multidrug resistance protein, MRP1), defending malignant cancer cells against chemotherapeutic agents. To date, 48 ABC Transporters have been identified and grouped into 7 families based on their sequence identity and function.ABC transporters regulate a variety of important physiological roles within the body and provide defense against harmful environmental compounds. Because of this, they represent important potential drug targets for the treatment of diseases associated with ...

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Номер записи: 71
12-06-2014 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20140163011A1
Автор: Grootenhuis Peter, Hadida-Ruah Sara, Hazlewood Anna, McCartney Jason, Singh Ashvani, Van Goor Fredrick, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 175-. (canceled)76. A pharmaceutical composition comprising:a. a pharmacological agent capable of inducing or augmenting CFTR activity;b. N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide; andc. a pharmaceutically acceptable carrier, adjuvant or vehicle.77. The composition according to claim 76 , wherein the pharmacological agent capable of inducing or augmenting CFTR activity increases the amount of CFTR present at the cell surface.78. The composition according to claim 76 , wherein the pharmacological agent induces a hitherto absent CFTR activity.79. The composition according to claim 76 , wherein the pharmacological agent augments an existing residual CFTR activity.80. A method of treating cystic fibrosis in a patient claim 76 , comprising the step of administering to said patient a composition according to .81. The method according to claim 80 , wherein the pharmacological agent capable of inducing or augmenting CFTR activity increases the amount of CFTR present at the cell surface.82. The method according to claim 80 , wherein the pharmacological agent induces a hitherto absent CFTR activity.83. The method according to claim 80 , wherein the pharmacological agent augments an existing residual CFTR activity.84. The method according to claim 80 , wherein N-(5-hydroxy-2 claim 80 ,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide is administered concurrently with claim 80 , prior to claim 80 , or subsequent to the pharmacological agent capable of inducing or augmenting CFTR activity.85. The method according to claim 84 , wherein N-(5-hydroxy-2 claim 84 ,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide is ...

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Номер записи: 72
30-03-2017 дата публикации

PHARMACEUTICAL COMPOSITION AND ADMINISTRATIONS THEREOF

Номер: US20170087144A1
Автор: Botfield Martyn, Dinehart Kirk, Grootenhuis Peter D.J., Grossi Alfredo, Hurter Patricia, Overhoff Kirk, Rowe William, Verwijs Marinus Jacobus, Young Christopher
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, methods of manufacturing pharmaceutical compositions of the present invention, and methods of administering pharmaceutical compositions of the present invention. 1111-. (canceled)112. A pharmaceutical tablet comprising 34.1% of a solid dispersion by weight of the tablet , wherein the solid dispersion comprises 80% of a mixture of amorphous N-[2 ,4-Bis(1 ,1-dimethylethyl)-5-hydroxyphenyl]-1 ,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) and less than 15% crystalline Compound 1 by weight of the dispersion , 19.5% of HPMCAS by weight of the dispersion , and 0.5% SLS by weight of the dispersion.113. The pharmaceutical tablet of claim 112 , wherein the tablet further comprises 30.5% of microcrystalline cellulose by weight of the tablet.114. The pharmaceutical tablet of claim 112 , wherein the tablet further comprises 30.4% of lactose by weight of the tablet.115. The pharmaceutical tablet of claim 112 , wherein the tablet further comprises 3% of sodium croscarmellose by weight of the tablet.116. The pharmaceutical tablet of claim 112 , wherein the tablet further comprises 0.5% of SLS by weight of the tablet.117. The pharmaceutical tablet of claim 112 , wherein the tablet further comprises 0.5% of colloidal silicon dioxide by weight of the tablet.118. The pharmaceutical tablet of claim 112 , wherein the tablet further comprises 1.0% of magnesium stearate by weight of the tablet.119. The pharmaceutical tablet of claim 112 , wherein the tablet further comprises a coating.120. The pharmaceutical tablet of claim 112 , wherein the tablet has a hardness of 98 N (10 kp)±20 percent.121. The pharmaceutical tablet of claim 112 , wherein the tablet contains 150 mg of Compound 1.122. The pharmaceutical tablet of claim 112 , wherein the tablet contains 100 mg of Compound 1.123. A method of treating ...

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Номер записи: 73
02-04-2015 дата публикации

Modulators of ATP-Binding Cassette Transporters

Номер: US20150094304A1
Автор: Bear Brian Richard, Grootenhuis Peter Diederik Jan, Mc Cartney Jason, Miller Mark Thomas, Numa Mehdi Michel Djamel, Ruah Sara Sabina Hadida, Van Goor Fredrick F., Zhou Jinglan
Принадлежит:

Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 2. The compound of claim 1 , wherein two R taken together form —OCFO— claim 1 , Ris H claim 1 , and Ris F.3. The compound of claim 1 , wherein two R taken together form —OCFO— claim 1 , Ris H claim 1 , Ris F claim 1 , and Ris H.4. The compound of claim 1 , wherein two R taken together form —OCFO— claim 1 , Ris H claim 1 , Ris F claim 1 , Ris H claim 1 , and Ris H.5. The compound of claim 1 , wherein two R taken together form —OCFO— claim 1 , Ris H claim 1 , Ris F claim 1 , Ris H claim 1 , and Ris —CHCHN(CH).6. The compound of claim 1 , wherein two R taken together form —OCFO— claim 1 , Ris H claim 1 , Ris F claim 1 , Ris H claim 1 , and Ris —CHCH(OH)CHOH.7. The compound of claim 1 , wherein two R taken together form —OCFO— claim 1 , Ris H claim 1 , Ris F claim 1 , Ris H claim 1 , and Ris (R)—CHCH(OH)CHOH.8. The compound of claim 1 , wherein two R taken together form —OCFO— claim 1 , Ris H claim 1 , Ris F claim 1 , Ris H claim 1 , and Ris (S)—CHCH(OH)CHOH9. The compound of claim 1 , wherein two R taken together form —OCFO— claim 1 , Ris H claim 1 , Ris F claim 1 , Ris H claim 1 , and Rand Rtaken together form a fused pyrrolidine ring.10. The compound of claim 1 , wherein two R taken together form —OCHO— claim 1 , Ris H claim 1 , and Ris F.11. The compound of claim 1 , wherein two R taken together form —OCHO— claim 1 , Ris H claim 1 , Ris F claim 1 , and Ris H.12. The compound of claim 1 , wherein two R taken together form —OCHO— claim 1 , Ris H claim 1 , Ris F claim 1 , Ris H claim 1 , and Ris —CHCH(OH)CHOH.13. The compound of claim 1 , wherein two R taken together form —OCHO— claim 1 , ...

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Номер записи: 74
19-06-2014 дата публикации

Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels

Номер: US20140171427A1
Автор: Anderson Corey, Arumugam Vijayalaksmi, Bear Brian Richard, Frieman Bryan A., Grootenhuis Peter Diederik Jan, Hadida-Ruah Sara Sabina, Hilgraf Nicole, Johnson, JR. Jason Philip, Kallel Edward Adam, McCartney Jason, Miller Mark Thomas, Numa Mehdi, PONTILLO Joseph
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The invention relates to heterocyclic chromene-spirocyclic piperidine amides useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders. 2. The compound of claim 1 , wherein all W's are CH.3. The compound of claim 1 , wherein one W is N.4. The compound of claim 1 , wherein Ris C1-C6 alkyl claim 1 , C1-C6 alkoxy claim 1 , halo claim 1 , CN claim 1 , CON(R) claim 1 , or (C1-C6)-Rwherein up to two CHunits may be replaced with O or NR.5. The compound of claim 1 , wherein Ris F claim 1 , Cl claim 1 , CH claim 1 , CN claim 1 , OCH claim 1 , CHOH claim 1 , CHN(CH) claim 1 , CHNH claim 1 , CONHCH claim 1 , CON(CH) claim 1 , CHOCH.6. The compound of claim 1 , wherein Ris C1-C6 alkyl claim 1 , C1-C6 haloalkyl claim 1 , halo claim 1 , CN claim 1 , CF claim 1 , CON(R) claim 1 , SOR claim 1 , or (C1-C6)-Rwherein up to two CHunits may be replaced with O claim 1 , CO claim 1 , S claim 1 , SO claim 1 , SO claim 1 , CF claim 1 , or NR.7. The compound of claim 1 , wherein Ris CH claim 1 , CF claim 1 , CHF claim 1 , CH claim 1 , CHOH claim 1 , F claim 1 , CN claim 1 , (CH)OCH claim 1 , SOCH claim 1 , SOCH claim 1 , CHCF claim 1 , CHNH claim 1 , CHNHCOCH claim 1 , CHNHCOH claim 1 , COCH claim 1 , or CONHCH.8. The compound of claim 1 , wherein Ris C1-C6 alkyl.9. The compound of claim 1 , wherein Ris methyl.10. The compound of claim 1 , wherein 2 occurrences of Rtaken together form a C3-C8 cycloalkyl group.12. The compound of claim 11 , wherein Ris H claim 11 , C1-C6 alkyl claim 11 , C1-C6 alkoxy claim 11 , halo claim 11 , CN claim 11 , OH claim 11 , OR claim 11 , CON(R) claim 11 , NRSOR claim 11 , SOR claim 11 , SOR claim 11 , SR claim 11 , COR claim 11 , NRCOR claim 11 , CHF claim 11 , CF claim 11 , OCF claim 11 , OCHF claim 11 , heteroaryl claim 11 , or a straight chain claim 11 , branched claim 11 , or cyclic (C1-C8)- ...

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Номер записи: 75
07-04-2016 дата публикации

Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

Номер: US20160095858A1
Автор: Alina Silina, Andreas P. Termin, Brian Richard Bear, Bryan A. Frieman, Chun-Chieh Lin, Corey Anderson, Erica Conroy, Fabrice Jean Denis PIERRE, Georgia Mcgaughey Nicholls, Gulin Erdgogan Marelius, Hayley Marie Binch, Jason Mccartney, Jeremy J. Clemens, Jinglan Zhou, Johnny Uy, KHATUYA Haripada, Mark Thomas Miller, Paul John Krenitsky, Peter Diederik Jan Grootenhuis, Pramod Virupax JOSHI, Raymond Stanley Gross, Sara Sabina Hadida-Ruah, Thomas Cleveland, Timothy Richard Coon, Vijayalaksmi Arumugam, Vito Melillo
Принадлежит: Vertex Pharmaceuticals Inc

The present invention features a compound of formula I: or a pharmaceutically acceptable salt thereof, where R 1 , R 2 , R 3 , W, X, Y, Z, n, o, p, and q are defined herein, for the treatment of CFTR mediated diseases, such as cystic fibrosis. The present invention also features pharmaceutical compositions, method of treating, and kits thereof.

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Номер записи: 76
05-04-2018 дата публикации

Modulator of Cystic Fibrosis Transmembrane Conductance Regulator, Pharmaceutical Compositions, Methods of Treatment, and Process for Making the Modulator

Номер: US20180093969A1
Автор: ABELA Alexander Russell, Alcacio Timothy, Anderson Corey, Baek Minson, Busch Brett Bradley, Cleveland Thomas, Frieman Bryan A., Grootenhuis Peter, Hadida Ruah Sara Sabina, Hughes Robert M., Joshi Pramod Virupax, Keshavarz-Shokri Ali, KHATUYA Haripada, Krenitsky Paul John, McAuley-Aoki Rachel, McCartney Jason, Melillo Vito, Miller Mark Thomas, Paraselli Prasuna, PIERRE Fabrice Jean Denis, Siesel David Andrew, Termin Andreas P., Uy Johnny, Van Goor Fredrick, Zhang Beili, Zhou Jinglan
Принадлежит:

Compounds of Formula I: 4. A compound according to claim 1 , a pharmaceutically acceptable salt thereof claim 1 , or a deuterated derivative of any of the foregoing claim 1 , wherein if Ris cyano claim 1 , then said Ris meta or para relative to the sulfur atom.5. A compound according to claim 1 , a pharmaceutically acceptable salt thereof claim 1 , or a deuterated derivative of any of the foregoing claim 1 , wherein:{'sub': 3', '1l', '1', '2', '1', '2, 'each Ring A is independently chosen from C-Ccycloalkyl groups optionally substituted with one or more substituents each independently chosen from C-Calkyl groups, halogenated C-Calkyl groups, and halogens, and'}each R is independently chosen from H and OH;{'sup': '2', 'sub': 1', '2', '1', '2, 'each Ris independently chosen from C-Calkyl groups, OH, C-Calkoxy groups, and halogens;'}{'sup': '4', 'Ris F;'}k is 0;p is 0, 1, or 2;q is 0, 1, 2, 3, or 4;r is 0; andwherein m and n are not 0 at the same time.6. A compound according to claim 5 , a pharmaceutically acceptable salt thereof claim 5 , or a deuterated derivative of any of the foregoing claim 5 , wherein:{'sup': '1', 'sub': 2', 'm, 'claim-text': {'sub': 3', '10', '1', '2', '1', '2, 'wherein Ring A is chosen from C-Ccycloalkyl groups groups optionally substituted with one or more substituents each independently chosen from C-Calkyl groups, halogenated C-Calkyl groups, and halogens, and'}, 'Ris chosen from —O—(CR)-Ring A groups,'}m is 1 or 2.7. A compound according to claim 6 , a pharmaceutically acceptable salt thereof claim 6 , or a deuterated derivative of any of the foregoing claim 6 , wherein each Ris a methyl group and q is 3 or 4.9. A compound according to claim 8 , wherein p is 0 or 1.10. A compound according to claim 8 , wherein p is 0.12. A compound according to claim 1 , a pharmaceutically acceptable salt thereof claim 1 , or a deuterated derivative of any of the foregoing claim 1 , wherein each Ris independently chosen from CH claim 1 , OH claim 1 , F ...

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Номер записи: 77
06-04-2017 дата публикации

PROCESS FOR MAKING MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Номер: US20170096396A1
Автор: Botfield Martyn C., DeMattei John, Grootenhuis Peter D.J., Guerette Dahrika Milfred Yap, Krueger Brian R., Looker Adam R., Neubert-Langille Bobbianna, Roeper Stefanie, Ryan Michael P., Trudeau Martin, Van Goor Fredrick F., Zlokarnik Gregor
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The invention provides a process for the preparation of a compound of Formula 1, 158-. (canceled)60. A compound of Formula 3 , or a pharmaceutically acceptable salt thereof.61. A compound of Formula 4 , or a pharmaceutically acceptable salt thereof. This application claims priority to three U.S. Provisional Applications having Ser. No. 61/162,148, filed on Mar. 20, 2009; 61/246,303, filed on Sep. 28, 2009; and 61/248,565, filed on Oct. 5, 2009. Each of the foregoing Provisional applications are hereby incorporated by reference in their entirety.The present invention relates to a process for making modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”).Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 30,000 children and adults in the United States and approximately 30,000 children and adults in Europe. Despite progress in the treatment of CF, there is no cure.CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes an epithelial chloride ion channel responsible for aiding in the regulation of salt and water absorption and secretion in various tissues. Small molecule drugs, known as potentiators that increase the probability of CFTR channel opening represent one potential therapeutic strategy to treat CF.Specifically, CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are ...

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Номер записи: 78
03-07-2014 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20140187770A9
Автор: Grootenhuis Peter, Hadida-Ruah Sara, Hazlewood Anna, McCartney Jason, Singh Ashvani, Van Goor Fred, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 175-. (canceled)77. The compound claim 76 , or a pharmaceutically acceptable salt thereof claim 76 , according to claim 76 , wherein each occurrence of WRis independently —C-Calkyl claim 76 , —O(C1-Calkyl) claim 76 , —CF claim 76 , —OCF claim 76 , —SCF claim 76 , —F claim 76 , —Cl claim 76 , —Br claim 76 , —COOR′ claim 76 , —COR′ claim 76 , —O(CH)N(R′)(R′) claim 76 , —O(CH)N(R′)(R′) claim 76 , —CON(R′)(R′) claim 76 , —(CH)OR′ claim 76 , —(CH)OR′ claim 76 , an optionally substituted monocyclic or bicyclic aromatic ring claim 76 , an optionally substituted arylsulfone claim 76 , an optionally substituted 5-membered heteroaryl ring claim 76 , —N(R′)(R′) claim 76 , —(CH)N(R′)(R′) claim 76 , or —(CH)N(R′)(R′).78. The compound claim 76 , or a pharmaceutically acceptable salt thereof claim 76 , according to claim 76 , wherein each occurrence of WRis selected from halo claim 76 , cyano claim 76 , CF claim 76 , CHF claim 76 , OCHF claim 76 , Me claim 76 , Et claim 76 , CH(Me) claim 76 , CHMeEt claim 76 , n-propyl claim 76 , t-butyl claim 76 , OMe claim 76 , OEt claim 76 , OPh claim 76 , O-fluorophenyl claim 76 , O-difluorophenyl claim 76 , O-methoxyphenyl claim 76 , O-tolyl claim 76 , O-benzyl claim 76 , SMe claim 76 , SCF claim 76 , SCHF claim 76 , SEt claim 76 , CHCN claim 76 , NH claim 76 , NHMe claim 76 , N(Me) claim 76 , NHEt claim 76 , N(Et) claim 76 , C(O)CH claim 76 , C(O)Ph claim 76 , C(O)NH claim 76 , SPh claim 76 , SO-(amino-pyridyl) claim 76 , SONH claim 76 , SOPh claim 76 , SONHPh claim 76 , SO—N-morpholino claim 76 , SO—N-pyrrolidyl claim 76 , N-pyrrolyl claim 76 , N-morpholino claim 76 , 1-piperidyl claim 76 , phenyl claim 76 , ...

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Номер записи: 79
20-04-2017 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20170107205A1
Автор: Bear Brian, Grootenhuis Peter D.J., Hadida Ruah Sara S., HAMILTON Matthew M., McCartney Jason, Miller Mark, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 169-. (canceled) The present application is a continuing application of and claims the benefit of priority under 35 U.S.C. §120 of co-pending International Application Serial No. PCT/US06/043289, filed Nov. 8, 2006, which claims the benefit, under 35 U.S.C. §119, of U.S. provisional patent application Ser. Nos. 60/734,506, filed on Nov. 8, 2005; 60/754,086, filed on Dec. 27, 2005; and 60/802,458, filed on May 22, 2006, the entire contents of each of above applications is incorporated herein by reference.The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.ABC transporters are a family of membrane transporter proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics, as well as anions. ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were discovered as multi-drug resistance proteins (like the MDR1-P glycoprotein, or the multi-drug resistance protein, MRP1), defending malignant cancer cells against chemotherapeutic agents. To date, 48 ABC Transporters have been identified and grouped into 7 families based on their sequence identity and function.ABC transporters regulate a variety of important physiological roles within the body ...

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Номер записи: 80
20-04-2017 дата публикации

Modulators of atp-binding cassette transporters

Номер: US20170107206A1
Автор: Brian Bear, Jason Mccartney, Jinglan Zhou, Mark Miller, Matthew Hamilton, Peter D.J. Grootenhuis, Sara S. Hadida Ruah
Принадлежит: Vertex Pharmaceuticals Inc

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.

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Номер записи: 81
30-04-2015 дата публикации

Modulators of ATP-Binding Cassette Transporters

Номер: US20150119441A1
Автор: Bear Brian, Grootenhuis Peter D.J., Hadida Ruah Sara S., McCartney Jason, Miller Mark T., Numa Mehdi Michel Jamel, Van Goor Fredrick, Yang Xiaoqing, Zhou Jinglan
Принадлежит:

Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 139-. (canceled)41. A pharmaceutical composition comprising the compound as described in and a pharmaceutically acceptable carrier.42. A kit for use in measuring the activity of an ABC transporter or a fragment thereof in a biological sample in vitro or in vivo claim 40 , comprising:{'claim-ref': {'@idref': 'CLM-00040', 'claim 40'}, '(i) a composition comprising the compound according to ; and'} a) contacting the composition with the biological sample; and', 'b) measuring activity of said ABC transporter or a fragment thereof., '(ii) instructions for43. The kit of claim 42 , further comprising instructions for:a) contacting an additional composition with the biological sample;b) measuring the activity of said ABC transporter or a fragment thereof in the presence of said additional compound; andc) comparing the activity of the ABC transporter in the presence of the additional compound with the density of the ABC transporter in the presence of a composition of formula (I).44. The kit of claim 42 , wherein the kit is used to measure the density of CFTR.46. The method of claim 45 , wherein the ABC transporter is CFTR.48. The method of claim 47 , wherein the disease is cystic fibrosis. The present patent application claims priority to U.S. provisional patent application Ser. No. 60/790,459, filed on Apr. 7, 2006, which is hereby incorporated by reference in its entirety.The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof and methods therewith ...

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Номер записи: 82
13-05-2021 дата публикации

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Номер: US20210139514A1
Автор: ABELA Alexander Russell, Clemens Jeremy J., Grootenhuis Peter Diederik Jan, Hadida Ruah Sara Sabina, ISHIHARA Yoshihiro, KHATUYA Haripada, McCartney Jason, Miller Mark Thomas, PIERRE Fabrice Jean Denis, TRAN Joe Anh, Zhou Jinglan
Принадлежит:

This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing at least one such modulator, methods of treatment of cystic fibrosis using such modulators and pharmaceutical compositions, and processes for making such modulators. 2. A compound according to embodiment 1 , a pharmaceutically acceptable salt thereof , or a deuterated derivative of any of the foregoing , wherein at least one of the carbon atoms at positions 3 and 8 of Formula (1) is replaced by a silicon atom.4. A compound according to claim 1 , a pharmaceutically acceptable salt thereof claim 1 , or a deuterated derivative of any of the foregoing claim 1 , wherein at least one of the methylene groups at positions 1 claim 1 , 2 claim 1 , 4 claim 1 , 5 claim 1 , 9 claim 1 , and 12 of Formula (1) is replaced by a group chosen from >Si(R)groups and >Si(R)(OR) groups.5. A compound according to claim 1 , a pharmaceutically acceptable salt thereof claim 1 , or a deuterated derivative of any of the foregoing claim 1 , wherein the methine group at position 11 of Formula (1) is replaced by a group chosen from ≡Si(R) groups and Si(OR) groups9. A compound according to claim 1 , a pharmaceutically acceptable salt thereof claim 1 , or a deuterated derivative of any of the foregoing claim 1 , wherein at least one hydrogen atom of at least one R group is replaced by a deuterium atom.10. A compound according to claim 1 , a pharmaceutically acceptable salt thereof claim 1 , or a deuterated derivative of any of the foregoing claim 1 , wherein each R is independently chosen from Calkyl groups and Calkyl groups.11. A compound according to claim 1 , a pharmaceutically acceptable salt thereof claim 1 , or a deuterated derivative of any of the foregoing claim 1 , wherein each R is independently —CHor —CD.12. A compound according to claim 1 , a pharmaceutically acceptable salt thereof claim 1 , or a deuterated derivative of any of the foregoing claim 1 , ...

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Номер записи: 83
16-04-2020 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20200115366A1
Автор: Bear Brian, Grootenhuis Peter D.J., Hadida Ruah Sara S., McCartney Jason, Miller Mark T., Numa Mehdi Michel Jamel, Van Goor Fredrick, Yang Xiaoqing, Zhou Jinglan
Принадлежит:

Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 140-. (canceled)44. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as described in claim 41 , and a pharmaceutically acceptable carrier claim 41 , adjuvant claim 41 , or vehicle.45. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as described in claim 42 , and a pharmaceutically acceptable carrier claim 42 , adjuvant claim 42 , or vehicle.46. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as described in claim 43 , and a pharmaceutically acceptable carrier claim 43 , adjuvant claim 43 , or vehicle.47. The pharmaceutical composition of claim 44 , wherein the pharmaceutical composition further comprises one or more additional therapeutic agents.48. The pharmaceutical composition of claim 45 , wherein the pharmaceutical composition further comprises one or more additional therapeutic agents.49. The pharmaceutical composition of claim 46 , wherein the pharmaceutical composition further comprises one or more additional therapeutic agents.50. A method of treating or lessening the severity of cystic fibrosis in a patient claim 41 , comprising the step of administering to a patient an effective amount of a compound or a pharmaceutically acceptable salt thereof according to .51. A method of treating or lessening the severity of cystic fibrosis in a patient claim 42 , comprising the step of administering to a patient an effective amount of a compound or a pharmaceutically acceptable salt thereof according to .52. A method of treating or lessening the ...

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Номер записи: 84
24-07-2014 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20140206689A1
Автор: Bear Brian, Grootenhuis Peter, Hadida Ruah Sara S., Miller Mark, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 2. The compound according to claim 1 , wherein the one Rattached to the 1-position of the isoquinoline ring is substituted with 1 claim 1 , 2 claim 1 , or 3 of —ZR; wherein each Zis independently a bond or an optionally substituted branched or straight Caliphatic chain wherein up to two carbon units of Zare optionally and independently replaced by —CO— claim 1 , —CONR— claim 1 , —CO— claim 1 , —O— claim 1 , —NRCO— claim 1 , —SO— claim 1 , —NR— claim 1 , —SONR— claim 1 , or —NRSO—; each Ris independently R claim 1 , —OH claim 1 , —NH claim 1 , —N(CH) claim 1 , or —N(CH); and each Ris independently hydrogen or an optionally substituted Caliphatic group.3. The compound according to claim 2 , wherein the one Rattached to the 1-position of the isoquinoline ring is phenyl optionally substituted with 1 or 2 of —ZR.4. The compound according to claim 2 , wherein the one Rattached to the 1-position of the isoquinoline ring is a heteroaryl optionally substituted with 1 —ZR.5. The compound according to claim 2 , wherein the one Rattached to the 1-position of the isoquinoline ring is a heterocycloaliphatic claim 2 , optionally substituted with 1 —ZR.7. The compound according to claim 1 , wherein Rand R′together with the carbon atom to which they are attached form a Ccycloaliphatic.8. The compound according to claim 1 , wherein Rand R′together with the carbon atom to which they are attached form a cyclopropyl ring.9. The compound according to claim 1 , wherein Ris an optionally substituted phenyl.13. The compound according to claim 12 , wherein T is selected from the group consisting of —CH— and —CF ...

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Номер записи: 85
26-05-2016 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20160143898A1
Автор: Bear Brian, Grootenhuis Peter D.J., Hadida Ruah Sara S., Hamilton Matthew, McCartney Jason, Miller Mark, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 169-. (canceled) The present application is a continuing application of and claims the benefit of priority under 35 U.S.C. §120 of co-pending International Application Serial No. PCT/US06/043289, filed Nov. 8, 2006, which claims the benefit, under 35 U.S.C. §119, of U.S. provisional patent application Ser. Nos. 60/734,506, filed on Nov. 8, 2005; 60/754,086, filed on Dec. 27, 2005; and 60/802,458, filed on May 22, 2006, the entire contents of each of above applications is incorporated herein by reference.The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.ABC transporters are a family of membrane transporter proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics, as well as anions. ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were discovered as multi-drug resistance proteins (like the MDR1-P glycoprotein, or the multi-drug resistance protein, MRP1), defending malignant cancer cells against chemotherapeutic agents. To date, 48 ABC Transporters have been identified and grouped into 7 families based on their sequence identity and function.ABC transporters regulate a variety of important physiological roles within the body ...

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Номер записи: 86
25-05-2017 дата публикации

Pyrrolopyrazine-Spirocyclic piperidine amides as modulators of ion channels

Номер: US20170145011A1
Автор: Anderson Corey, Arumugam Vijayalaksmi, Grootenhuis Peter Diederik Jan, Hadida Ruah Sara Sabina, Jiang Licong, Kallel Edward Adam, McCartney Jason, Miller Mark Thomas
Принадлежит:

The invention relates to pyrrolopyrazine-spirocyclic piperidine amide compounds useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders. 1. (canceled)4. The compound of claim 2 , wherein said pharmaceutically acceptable salt is selected from acid addition salts of suitable inorganic and organic acids.5. The compound of claim 4 , wherein said pharmaceutically acceptable salt is selected from the group consisting of adipate claim 4 , alginate claim 4 , ascorbate claim 4 , aspartate claim 4 , benzenesulfonate claim 4 , benzoate claim 4 , bisulfate claim 4 , borate claim 4 , butyrate claim 4 , camphorate claim 4 , camphorsulfonate claim 4 , citrate claim 4 , cyclopentanepropionate claim 4 , digluconate claim 4 , dodecylsulfate claim 4 , ethanesulfonate claim 4 , formate claim 4 , fumarate claim 4 , glucoheptonate claim 4 , glycerophosphate claim 4 , gluconate claim 4 , hemisulfate claim 4 , heptanoate claim 4 , hexanoate claim 4 , hydroiodide claim 4 , 2-hydroxy-ethanesulfonate claim 4 , lactobionate claim 4 , lactate claim 4 , laurate claim 4 , lauryl sulfate claim 4 , malate claim 4 , maleate claim 4 , malonate claim 4 , methanesulfonate claim 4 , 2-naphthalenesulfonate claim 4 , nicotinate claim 4 , nitrate claim 4 , oleate claim 4 , oxalate claim 4 , palmitate claim 4 , pamoate claim 4 , pectinate claim 4 , persulfate claim 4 , 3-phenylpropionate claim 4 , phosphate claim 4 , picrate claim 4 , pivalate claim 4 , propionate claim 4 , stearate claim 4 , succinate claim 4 , sulfate claim 4 , tartrate claim 4 , thiocyanate claim 4 , p-toluenesulfonate claim 4 , undecanoate claim 4 , valerate salts.6. The compound of claim 4 , wherein said pharmaceutically acceptable salt is selected from hydrochloride claim 4 , hydrobromide claim 4 , phosphate claim 4 , sulfate claim 4 , perchlorate claim 4 , acetate ...

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Номер записи: 87
14-08-2014 дата публикации

Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

Номер: US20140228399A2
Автор: Fredrick Van Goor, Hayley Binch, Lev T.D. Fanning, Martyn Botfield, Mehdi Michel Djamel Numa, Peter D.J. Grootenhuis
Принадлежит: Vertex Pharmaceuticals Inc

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.

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Номер записи: 88
14-08-2014 дата публикации

Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

Номер: US20140228400A2
Автор: Botfield Martyn Curtis, Grootenhuis Peter Diederik Jan, Hadida Ruah Sara Sabina, Van Goor Fredrick F., Yang Xiaoqing, Zlokarnik Gregor
Принадлежит:

This invention relates to a compound of Formula I: 19-. (canceled)16. The method according to claim 13 , wherein said disease is cystic fibrosis.1721-. (canceled)22. The method according to claim 13 , wherein said disease is selected from cystic fibrosis claim 13 , COPD claim 13 , smoke induced COPD claim 13 , hereditary emphysema claim 13 , pancreatitis claim 13 , pancreatic insufficiency claim 13 , and dry-eye disease. This application is a divisional application of U.S. Ser. No. 13/237,303, filed on Sep. 20, 2011, now U.S. Pat. No. 8,614,325, issued Dec. 24, 2013, which is a continuation of PCT Application No. PCT/US2010/028062 filed Mar. 19, 2010, which claims the priority of U.S. Application No. 61/162,130 filed Mar. 20, 2009. The entire contents of each of the aforementioned applications are incorporated herein by reference in their entirety.The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 30,000 children and adults in the United States and approximately 30,000 children and adults in Europe. Despite progress in the treatment of CF, there is no cure.CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes an epithelial chloride ion channel responsible for aiding in the regulation of salt and water absorption and secretion in various tissues. Small molecule drugs, known as potentiators that increase the probability of CFTR channel opening represent one potential therapeutic strategy to treat CF.Specifically, CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion ...

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Номер записи: 89
16-05-2019 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20190144450A1
Автор: Grootenhuis Peter, Hadida-Ruah Sara, Hazlewood Anna, McCartney Jason, Singh Ashvani, Van Goor Fredrick, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

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Номер записи: 90
21-08-2014 дата публикации

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

Номер: US20140235625A1
Автор: Binch Hayley, Botfield Martyn, Fanning Lev T.D., Grootenhuis Peter D.J., Hurley Dennis, Van Goor Fredrick
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using such CFTR modulators. 158-. (canceled)60. The compound according to claim 59 , wherein Ris halo claim 59 , CN claim 59 , CH claim 59 , CF claim 59 , OCF claim 59 , OCHor SOMe.61. The compound according to claim 59 , wherein Ris hydrogen.62. The compound according to claim 59 , wherein Ris methyl.63. The compound according to claim 59 , wherein Ris hydrogen.64. The compound according to claim 59 , wherein Rand Rare hydrogen.66. The compound according to wherein WRis a C-Cstraight or branched aliphatic claim 65 , or a 3-12 membered cycloaliphatic claim 65 , WRis —OH or OR′ and WRis —C≡CCHN(R′)(R′) claim 65 , —(CH)N(R′)(R′) claim 65 , —(CH)N(R′)(R′) claim 65 , —(CH)N(R′)(R′) or —N(R′)(R′).68. The compound according to wherein WRis a substituted C-Cstraight or branched aliphatic claim 67 , C-Cheterocyclic claim 67 , 3-12 membered cycloaliphatic claim 67 , or 3-12 membered bicyclic and WRis —C≡CCHN(R′)(R′) claim 67 , —(CH)N(R′)(R′) claim 67 , —(CH)N(R′)(R′) claim 67 , —(CH)N(R′)(R′) or —N(R′)(R′).70. The compound according to wherein WRis a substituted C-Cstraight or branched aliphatic claim 69 , C-Cheterocyclic claim 69 , 3-12 membered cycloaliphatic claim 69 , or 3-12 membered bicyclic and WRis —C≡CCHN(R′)(R′) claim 69 , —(CH)N(R′)(R′) claim 69 , —(CH)N(R′)(R′) claim 69 , —(CH)N(R′)(R′) or —N(R′)(R′).71. The compound according to any one of wherein Ris hydrogen.72. The compound according to any one of wherein wherein Ris hydrogen.73. The compound according to any one of wherein wherein Rand Ris hydrogen.75. A pharmaceutical composition comprising a compound of Formula IVD according to and a pharmaceutically acceptable carrier or adjuvant.76. The pharmaceutical composition according ...

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Номер записи: 91
21-08-2014 дата публикации

Modulators of cystic fibrosis transmembrane conductance regulator vpi

Номер: US20140235668A1
Автор: Hayley Binch, Jinglan Zhou, Peter D.J. Grootenhuis, Sara Hadida Ruah
Принадлежит: Vertex Pharmaceuticals Inc

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

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Номер записи: 92
09-06-2016 дата публикации

Fused Piperidine Amides as Modulators of Ion Channels

Номер: US20160159815A1
Автор: Anderson Corey, CONROY Erica Lynn, DeNinno Michael Paul, Frieman Bryan A., GROOTENHUIS Peter Drederik Jan, Hadida-Ruah Sara Sabina, Hurley Dennis James, PIERRE Fabrice Jean Denis, Silina Alina, Uy Johnny, Zhou Jinglan
Принадлежит:

The invention relates to fused piperidine amides useful as inhibitors of ion channels for the treatment of pain. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders. 2. The compound of claim 1 , wherein Ris C1-C6 alkyl claim 1 , halo claim 1 , or oxo.3. The compound of or claim 1 , wherein Ris CH claim 1 , F claim 1 , or oxo.4. The compound of any one of to claim 1 , wherein Ris C1-C6 alkyl claim 1 , C1-C6 alkoxy claim 1 , fluoro-C1-C6 alkyl claim 1 , halo claim 1 , CN claim 1 , or (C1-C8)-Rwherein up to two CHunits may be replaced with O claim 1 , CO claim 1 , CF claim 1 , or NR.5. The compound of any one of to claim 1 , wherein Ris CH claim 1 , OCH claim 1 , CF claim 1 , F claim 1 , Cl claim 1 , Br claim 1 , CN claim 1 , OCHCHOtBu claim 1 , OCHCH(CH).6. The compound of any one of to claim 1 , wherein Ris C1-C6 alkyl.7. The compound of any one of to claim 1 , wherein Ris CH.8. The compound of any one of to claim 1 , wherein ring A is a fused cycloalkyl ring.9. The compound of any one of to claim 1 , wherein ring A is a fused heterocycloalkyl ring.12. The compound of any one of to claim 1 , wherein ring B is an aryl ring.13. The compound of any one of to claim 1 , wherein ring B is a heteroaryl ring.14. The compound of claim 12 , wherein ring B is a phenyl ring.16. The compound of claim 13 , wherein ring B is a pyridyl claim 13 , thiazole claim 13 , pyrimidine claim 13 , pyrazole claim 13 , furan claim 13 , thiophene claim 13 , pyrrole claim 13 , oxazole claim 13 , imidazole claim 13 , isoxazole claim 13 , isothiazole claim 13 , pyridazine claim 13 , or pyrazine ring.18. The compound of any one of to claim 13 , wherein ring C is a substituted or unsubstituted aryl ring.20. The compound of claim 19 , wherein Ris H claim 19 , C1-C6 alkoxy claim 19 , or halo.21. The compound of or claim 19 , wherein Ris H claim 19 , OCH claim 19 , or F. ...

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Номер записи: 93
18-06-2015 дата публикации

Pharmaceutical Compositions and Administrations Thereof

Номер: US20150164881A1
Автор: Alargova Rossitza Gueorguieva, Alcacio Tim Edward, Binch Hayley Marie, Botfield Martyn Curtis, Fanning Lev Tyler Dewey, Grootenhuis Peter Diederik Jan, Hurley Dennis James, Kadiyala Irina Nikolaevna, Kaushik Ritu Rohit, Keshavarz-Shokri Ali, Krawiec Mariusz, Lee Elaine Chungmin, Luisi Brian, Medek Ales, Numa Mehdi, Sheth Urvi Jagdishbhai, Silina Alina, Van Goor Fredrick F., Verwijs Marinus Jacobus, Yang Xiaoqing, Young Christopher Ryan, Zaman Noreen Tasneem, Zhang Beili, Zhang Yuegang, Zlokarnik Gregor
Принадлежит:

The present invention relates to pharmaceutical compositions comprising a compound of Formula I in combination with one or both of a Compound of Formula II and/or a Compound of Formula III. The invention also relates to solid forms and to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis. 2. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and a Compound of Formula II.3. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and a Compound of Formula III.4. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I claim 1 , a Compound of Formula II and a Compound of Formula III.98. A method of treating a CFTR mediated disease in a human comprising administering to the human an effective amount of a pharmaceutical composition according to any one of -.10. The method of claim 9 , wherein the CFTR mediated disease is selected from cystic fibrosis claim 9 , asthma claim 9 , smoke induced COPD claim 9 , chronic bronchitis claim 9 , rhinosinusitis claim 9 , constipation claim 9 , pancreatitis claim 9 , pancreatic insufficiency claim 9 , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) claim 9 , mild pulmonary disease claim 9 , idiopathic pancreatitis claim 9 , allergic bronchopulmonary aspergillosis (ABPA) claim 9 , liver disease claim 9 , hereditary emphysema claim 9 , hereditary hemochromatosis claim 9 , coagulation-fibrinolysis deficiencies claim 9 , such as protein C deficiency claim 9 , Type 1 hereditary angioedema claim 9 , lipid processing deficiencies claim 9 , such as familial hypercholesterolemia claim 9 , Type 1 chylomicronemia claim 9 , abetalipoproteinemia claim 9 , lysosomal storage diseases claim 9 , such as I-cell disease/pseudo-Hurler claim 9 , mucopolysaccharidoses claim 9 , Sandhof/Tay-Sachs claim 9 , Crigler-Najjar type II claim 9 , ...

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Номер записи: 94
18-06-2015 дата публикации

PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATIONS THEREOF

Номер: US20150164883A1
Автор: Alargova Rossitza Gueorguieva, Alcacio Tim Edward, Arekar Sneha G., Binch Hayley Marie, Botfield Martyn Curtis, Fanning Lev Tyler Dewey, Grootenhuis Peter Diederik Jan, Hurley Dennis James, Johnston Steven C., Kadiyala Irina Nikolaevna, Kaushik Ritu Rohit, Keshavarz-Shokri Ali, Krawiec Mariusz, Lee Elaine Chungmin, Luisi Brian, Medek Ales, Mudunuri Praveen, Numa Mehdi, Sheth Urvi Jagdishbhai, Silina Alina, Sullivan Mark Jeffrey, Van Goor Fredrick F., Verwijs Marinus Jacobus, Yang Xiaoqing, Young Christopher Ryan, Zaman Noreen Tasneem, Zhang Beili, Zhang Yuegang, Zlokmik Gregor
Принадлежит:

The present invention relates to pharmaceutical compositions comprising a compound of Formulas I and II, optionally in combination with a Compound of Formula III and/or a Compound of Formula IV. The invention also relates to solid forms and to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis. 2. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and Compound of Formula II.5. The pharmaceutical composition of claim 4 , comprising Compound 1 claim 4 , Compound 2 claim 4 , and Compound 3.6. The pharmaceutical composition of claim 1 , comprising Compound 1 claim 1 , Compound 2 claim 1 , and Compound 4.7. The pharmaceutical composition of claim 4 , comprising Compound 1 claim 4 , Compound 2 claim 4 , Compound 3 and Compound 4.9. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component is any of the embodiments listed in Column C of Table I.10. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component is any of the embodiments listed in Column D of Table I.11. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , the third component is any of the embodiments listed in Column C of Table I claim 8 , and the fourth Component is any of the embodiments listed in Column D of Table I.12. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component is Compound 3.13. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component ...

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Номер записи: 95
18-06-2015 дата публикации

MODULATORS OF CFTR

Номер: US20150166516A1
Автор: Bear Brian, Grootenhuis Peter, Hadida-Ruah Sara, McCartney Jason, Miller Mark, Zhou Jinglan
Принадлежит:

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating CFTR mediated diseases using compounds of the present invention. 240-. (canceled)4248-. (canceled)5054-. (canceled)5660-. (canceled)7173-. (canceled)7577-. (canceled)79. (canceled)80. (canceled)81. A pharmaceutical composition comprising:{'claim-ref': [{'@idref': 'CLM-00001', 'claim 1'}, {'@idref': 'CLM-00070', '70'}], '(i) a compound according to or ; and'}(ii) a pharmaceutically acceptable carrier.82. (canceled)83. A method according to modulating CFTR activity comprising the step of contacting said CFTR with a compound according to or .84. A method of treating or lessening the severity of a disease in a patient , wherein said disease is selected from cystic fibrosis , hereditary emphysema , hereditary hemochromatosis , coagulation-fibrinolysis deficiencies , such as protein C deficiency , Type 1 hereditary angioedema , lipid processing deficiencies , such as familial hypercholesterolemia , Type 1 chylomicronemia , abetalipoproteinemia , lysosomal storage diseases , such as I-cell disease/pseudo-Hurler , mucopolysaccharidoses , Sandhof/Tay-Sachs , Crigler-Najjar type II , polyendocrinopathy/hyperinsulemia , Diabetes mellitus , Laron dwarfism , myleoperoxidase deficiency , primary hypoparathyroidism , melanoma , glycanosis CDG type 1 , congenital hyperthyroidism , osteogenesis imperfecta , hereditary hypofibrinogenemia , ACT deficiency , Diabetes insipidus (DI) , neurophyseal DI , neprogenic DI , Charcot-Marie Tooth syndrome , Perlizaeus-Merzbacher disease , neurodegenerative diseases such as Alzheimer's disease , Parkinson's disease , amyotrophic lateral sclerosis , progressive supranuclear plasy , Pick's disease , several polyglutamine neurological ...

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Номер записи: 96
28-08-2014 дата публикации

PRODRUGS OF MODULATORS OF ABC TRANSPORTERS

Номер: US20140243289A1
Автор: Binch Hayley, Grootenhuis Peter D.J., Hadida Ruah Sara, Hazlewood Anna, Zhou Jinglan
Принадлежит: VERTEX PHARMACEUTICALS INCORPORATED

The present invention relates to prodrugs of modulators of ABC transporters, particularly, CFTR modulators, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. 2. The compound according to claim 1 , y is 0-2.3. The compound according to claim 2 , wherein y is 0.4. The compound according to claim 1 , wherein each of Rand Ris independently selected from hydrogen claim 1 , CN claim 1 , CF claim 1 , halo claim 1 , C1-C6 straight or branched alkyl claim 1 , 3-12 membered cycloaliphatic claim 1 , or phenyl claim 1 , wherein said Rand Ris independently and optionally substituted with up to three substituents selected from —OR′ claim 1 , —CF claim 1 , —OCF claim 1 , —SCF claim 1 , halo claim 1 , —COOR′ claim 1 , —OCOR′ claim 1 , —COR′ claim 1 , —O(CH)N(R′)(R′) claim 1 , —O(CH)N(R′)(R′) claim 1 , —CON(R′)(R′) claim 1 , —(CH)OR′ claim 1 , —(CH)OR′ claim 1 , optionally substituted phenyl claim 1 , —N(R′)(R′) claim 1 , —NC(O)OR′ claim 1 , —NC(O)R′ claim 1 , —(CH)N(R′)(R′) claim 1 , or —(CH)N(R′)(R′).5. The compound according to claim 5 , wherein Ris a phenyl ring optionally substituted with up to three substituents selected from —OR′ claim 5 , —CF claim 5 , —OCF claim 5 , SR′ claim 5 , S(O)R′ claim 5 , SOR′ claim 5 , —SCF claim 5 , halo claim 5 , CN claim 5 , —COOR′ claim 5 , —OCOR′ claim 5 , —COR′ claim 5 , —O(CH)N(R′)(R′) claim 5 , —O(CH)N(R′)(R′) claim 5 , —CON(R′)(R′) claim 5 , —(CH)OR′ claim 5 , —(CH)OR′ claim 5 , CHCN claim 5 , optionally substituted phenyl or phenoxy claim 5 , —N(R′)(R′) claim 5 , —NR′C(O)OR′ claim 5 , —NR′C(O)R′ claim 5 , —(CH)N(R′)(R′) claim 5 , or —(CH)N(R′)(R′); and Ris C1-C6 straight or branched alkyl.6. The compound according to claim 4 , wherein each of Rand Ris independently selected from CFor halo.7. The compound according to claim 4 , wherein each of Rand Ris independently selected from hydrogen or optionally substituted C1-C6 straight or ...

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Номер записи: 97
14-06-2018 дата публикации

Modulator of the Cystic Fibrosis Transmembrane Conductance Regulator, Pharmaceutical Compositions, Methods of Treatment, and Process for Making the Modulator

Номер: US20180162839A1
Автор: Alexander Russell Abela, Ali Keshavarz-Shokri, Andreas P. Termin, Anton V. Gulevich, Clara Kuang-Ju Hsia, Corey Anderson, David Andrew Siesel, Fabrice Jean Denis PIERRE, Fredrick F. Van Goor, Haripada Khatuya, Jason Mccartney, Jeremy J. Clemens, Jinglan Zhou, Johnny Uy, Kathy Stavropoulos, Lori Ann Ferris, Mark Thomas Miller, Minson BAEK, Muna Shrestha, Paul John Krenitsky, Paul Timothy Angell, Peter Diederik Jan Grootenhuis, PING Kang, Pramod Virupax JOSHI, Prasuna PARASELLI, Raymond Stanley Gross, Robert M. HUGHES, Sara Sabina Hadida Ruah, Thomas Cleveland, Timothy ALCACIO, Timothy John Young, Yi Shi
Принадлежит: Vertex Pharmaceuticals Inc, Vertex Pharmaceuticals San Diego LLC

Compounds of Formula (I): pharmaceutically acceptable salts thereof, deuterated derivatives of any of the foregoing, and metabolites of any of the foregoing are disclosed. Pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods for making the same are also disclosed. Also disclosed are solid state forms of Compound 1 and salts and solvates thereof.

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Номер записи: 98
14-06-2018 дата публикации

Modulators of atp-binding cassette transporters

Номер: US20180162842A1
Автор: Brian Bear, Fredrick Van Goor, Jason Mccartney, Jinglan Zhou, Mark T. Miller, Mehdi Michel Jamel Numa, Peter D.J. Grootenhuis, Sara S. Hadida Ruah, Xiaoqing Yang
Принадлежит: Vertex Pharmaceuticals Inc

Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.

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Номер записи: 99
25-06-2015 дата публикации

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Номер: US20150174098A1
Автор: Bear Brian Richard, Grootenhuis Peter Diederik Jan, McCartney Jason, Miller Mark Thomas, Numa Mehdi, Ruah Sara Sabina Hadida, Van Goor Fredrick F., Yang Xiaoqing, Zhou Jinglan
Принадлежит:

Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention. 128-. (canceled)30. The method of claim 29 , wherein the condition claim 29 , disease claim 29 , or disorder is cystic fibrosis claim 29 , hereditary emphysema claim 29 , or COPD.31. The method of claim 30 , wherein the condition claim 30 , disease claim 30 , or disorder is cystic fibrosis. The present application claims the benefit under 35 U.S.C. §120 of U.S. application Ser. No. 11/786,001, filed Apr. 9, 2007, which claims the benefit under 35 U.S.C. §119 of U.S. Provisional Application No. 60/790,459, filed Apr. 7, 2006, the entire contents of both applications being incorporated herein by reference.The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.ABC transporters are a family of membrane transporter proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics, as well as anions. ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were discovered as multidrug resistance proteins (like the MDR1-P glycoprotein, or the multidrug resistance protein, MRP1), defending malignant cancer cells against chemotherapeutic agents. To date, 48 ABC Transporters have been identified and grouped into 7 families based on their sequence identity ...

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Номер записи: 100