Acid pump antagonist for the treatment of diseases involved in abnormal gastrointestinal motility
The present invention relates to a use of a compound having an acid pump antagonistic activity, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the manufacture of a medicament for prevention or treatment of diseases in which abnormal gastrointestinal motility is involved. In addition, the present invention relates to the method of prevention or treatment including administering to a human or animal. The compound, the pharmaceutically acceptable salt thereof, or pharmaceutical compositions containing them, may be used in combination with one or more second active agent. Further, the present invention relates to pharmaceutical compositions and kits comprising a compound having an acid pump antagonistic activity or a pharmaceutically acceptable salt thereof for the prevention or treatment of said diseases.
1. A method for adjusting a gastrointestinal function or activating a gastrointestinal motility in a disease in which abnormal gastrointestinal motility is involved, in a human or an animal, which comprises administering to the human or the animal in need a therapeutically effective amount of a compound having an acid pump antagonistic activity or a pharmaceutically acceptable salt thereof.
2. The method according to claim 1 , wherein the compound or salt having the acid pump antagonistic activity is selected from the group consisting of:
(1) (S)-(+4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide;
(2) (S)-(+4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-2-methyl-6-(pyrrolidin-1-ylcarbonyl)-1H-benzimidazole;
(3) (S)-(−)-4-[(5-fluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide;
(4) (−)-1-(2-methoxyethyl)-N,N,2-trimethyl-8-phenyl-1,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide;
(5) (+8-(4-fluorophenyl)-1-(2-methoxyethyl)-N,N,2-trimethyl-1,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide;
(6) 8-(4-fluorophenyl)-1-(3-hydroxypropyl)-N,N,2-trimethyl-1,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide;
(7) 8-(4-fluorophenyl)-1-(isoxazol-3-ylmethyl)-N,N,2-trimethyl-1,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide;
(8) 8-(4-fluorophenyl)-N-(2-hydroxyethyl)-1-(2-methoxyethyl)-N,2-dimethyl-1,6,7,8-tetrahydrochromeno[8,7-d]imidazole-5-carboxamide;
(9) (8-(4-fluorophenyl)-1-(2-methoxyethyl)-2-methyl-1,6,7,8-tetrahydrochromeno[8,7-d]imidazol-5-yl)(morpholino)methanone;
(10) 1-{5-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine;
(11) 1-[4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine;
(12) N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamine;
(13) 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine;
(14) N-methyl-1-[5-(2-methylphenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamine;
(15) 8-[{2,6-dimethylbenzyl}amino]-N-[2-hydroxyethyl]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide;
(16) (7R,8R,9R)-7-(2-methoxyethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-8-ol;
(17) 5,6-dimethyl-2-(4-fluoro-phenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine;
(18) (S)—N,N,2,3-tetramethyl-8-O-tolyl-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide; and
(19) 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine.
3. The method according to claim 1 , wherein the compound or salt having the acid pump antagonistic activity is selected from the group consisting of:
(1) (S)-(−)-4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide;
(4) (−)-1-(2-methoxyethyl)-N,N,2-trimethyl-8-phenyl-1,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide;
(13) 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine;
(15) 8-[{2,6-dimethylbenzyl} amino]-N-[2-hydroxyethyl]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide; and
(17) 5,6-dimethyl-2-(4-fluoro-phenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine.
4. The method according to claim 1 , wherein the disease involves a loss of a motor function of a stomach or an intestine of the human or the animal.
5. The method according to claim 1 , further comprising administering the compound having the acid pump antagonistic activity or the pharmaceutically acceptable salt thereof in combination with one or two additional active agent(s).
6. The method according to claim 5 , wherein the additional active agent is selected from the group consisting of:
piperacillin, lenampicillin, tetracycline, metronidazole, bithmuth citrate and bithmuth subsalicylate.
7. The method according to claim 1 , wherein the gastrointestinal motility involves duodenal motility.