Treatment
The invention provides a compound for use in treating or preventing a disease or condition selected from cystic fibrosis, chronic obstructive pulmonary disease (COPD), asthma, mild pulmonary disease, bronchitis, bronchiectasis, idiopathic bronchiectasis, allergic bronchopulmonary aspergillosis, sinusitis, rhinosinusitis, CFTR-related metabolic syndrome (CRMS), pancreatitis, idiopathic chronic pancreatitis and Sjörgren's syndrome, or for use in preventing male infertility caused by congenital absence of the vas deferens, in a patient by modulating CFTR activity, which compound is 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one or a pharmaceutically acceptable acid addition salt thereof. The invention also provides a composition comprising (i) 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one or a pharmaceutically acceptable acid addition salt thereof and (ii) a leukotriene receptor antagonist. The invention also provides a composition comprising (i) 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one or a pharmaceutically acceptable acid addition salt thereof and (ii) a CFTR potentiator or a CFTR corrector.
1. A composition comprising (a) 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one or a pharmaceutically acceptable acid addition salt thereof, and (b) a CFTR potentiator or a CFTR corrector.
2. A composition according to claim 1 , wherein:
the CFTR potentiator is Ivacaftor (VX770, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide), QBW251, NPPB (5-nitro-2-(3-phenylpropylamino)-benzoate), VRT532 (4-methyl-2-(5-phenyl-1H-pyrazol-3-yl)phenol), PG-01 (N-methyl-N-[2-[[4-(1-Methylethyl)phenyl]amino]-2-1H-indole-3-acetamide), or a pharmaceutically acceptable acid addition salt thereof; or
the CFTR corrector is VX809 (Lumacaftor, 3-{6-{[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino}-3-methylpyridin-2-yl}benzoic acid), VX661 (1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide), Corr-4a (N-{2-[(5-chloro-2-methoxyphenyl)amino]-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl}benzamide), VRT532 (4-methyl-2-(5-phenyl-1H-pyrazol-3-yl)phenol), or a pharmaceutically acceptable acid addition salt thereof.
3. A composition according to claim 1 , wherein the CFTR potentiator or CFTR corrector is N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Ivacaftor) or a pharmaceutically acceptable acid addition salt thereof.
4. A method for treating or preventing cystic fibrosis in a patient, the method comprising administering a composition to the patient, which composition comprises (i) 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one or a pharmaceutically acceptable acid addition salt thereof, and (ii) a CFTR potentiator or a CFTR corrector.
5. A method according to claim 4 , wherein the patient has a CFTR mutation.
6. A method according to claim 5 , wherein the CFTR mutation is a class III CFTR mutation or class IV CFTR mutation.
7. A method according to claim 5 , wherein the CFTR mutation is G551D, G178R, G551S, S549N, G1349D, R117H, R117C, R347P or R334W.
8. A method according to claim 5 , wherein the CFTR mutation is R117H.
9. A method according to claim 4 , wherein the patient is heterozygous with (i) one allele displaying a class III or class IV CFTR mutation and (ii) the other allele displaying a class II CFTR mutation.
10. A method according to claim 4 , wherein the patient is susceptible to, or suffering from, diarrhoea.
11. A method according to claim 10 , wherein the patient is suffering from ulcerative colitis, Crohn's disease, microscopic colitis, celiac disease, irritable bowel syndrome, bile acid malabsorption, or diverticulitis.
12. A product comprising (a) 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one or a pharmaceutically acceptable acid addition salt thereof, and (b) a CFTR potentiator or a CFTR corrector for simultaneous, separate or sequential use in treating or preventing cystic fibrosis in a patient.
13. A method for treating or preventing cystic fibrosis in a patient, the method comprising administering to the patient (a) 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one or a pharmaceutically acceptable acid addition salt thereof simultaneously, separately or sequentially in combination with (b) a CFTR potentiator or a CFTR corrector.
14. A method for treating or preventing cystic fibrosis in a patient, the method comprising administering to the patient (b) a CFTR potentiator or a CFTR corrector simultaneously, separately or sequentially in combination with (a) 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one or a pharmaceutically acceptable acid addition salt thereof.