Chromane substituted benzimidazole derivatives
This invention relates to compounds of the formula (I): or a pharmaceutically acceptable salt thereof, wherein: A, B, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each as described herein or a pharmaceutically acceptable salt, and compositions containing such compounds and the use of such compounds in the treatment of a condition mediated by acid pump antagonistic activity such as, but not limited to, as gastrointestinal disease, gastroesophageal disease, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcers, gastritis, infection of Helicobacter pylori , dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral pain, heartburn, nausea, esophagitis, dysphagia, hypersalivation, airway disorders or asthma.
1. A compound of the formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
-A-B— represents —O—CH 2 —, —S—CH 2 —, —CH 2 —O— or —CH2—S—;
X represents an oxygen atom or NH;
R 1 represents a C 1 -C 6 alkyl group being unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of a hydroxy group and a alkoxy group;
R 2 and R 3 independently represent a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 7 cycloalkyl group or a heteroaryl group selected from 2-thienyl, 2-thiazolyl, 4-thiazolyl, 2-furyl, 2-oxazolyl, 1-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl and 2-pyrimidinyl, said C 1 -C 6 alkyl group, said C 3 -C 7 cycloalkyl group and said heteroaryl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a C 1 -C 6 alkoxy group, a C 3 -C 7 cycloalkyl group, an amino group, a C 1 -C 6 alkylamino group, and a di(C 1 -C 6 alkyl)amino group;
or R 2 and R 3 taken together with the nitrogen atom to which they are attached form a 4 to 6 membered heterocyclic group being unsubstituted or substituted with 1 to 2 substituents selected from the group consisting of a hydroxy group, a C 1 -C 6 alkyl group, a C 1 -C 6 acyl group and a hydroxy-C 1 -C 6 alkyl group;
R 4 , R 5 , R 6 and R 7 independently represent a hydrogen atom, a halogen atom, a hydroxy group, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group; and
R 8 represents a hydrogen atom, a hydroxy group or a C 1 -C 6 alkoxy group.
2. The compound or the pharmaceutical acceptable salt thereof of claim 1 , wherein:
X is an oxygen atom;
R 2 and R 3 are independently a C 1 -C 6 alkyl group or a C 3 -C 7 cycloalkyl group, said C 1 -C 6 alkyl group and said C 3 -C 7 cycloalkyl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a C 1 -C 6 alkoxy group, a C 3 -C 7 cycloalkyl group and a di(C 1 -C 6 alkyl)amino group;
or R 2 and R 3 taken together with the nitrogen atom to which they are attached form an azetidinyl group, a pyrrolidinyl group, a piperazinyl group or a morpholino group, said azetidinyl group, said pyrrolidinyl group, said piperazinyl group and said morpholino group being unsubstituted or substituted with a substituent selected from the group consisting of a hydroxy group, a C 1 -C 6 alkyl group, a C 1 -C 6 acyl group and a hydroxy-C 1 -C 6 alkyl group;
R 4 , R 5 , R 6 and R 7 are independently a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group; and
R 8 is a hydrogen atom.
3. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of claim 2 , and at least one pharmaceutically acceptable carrier.
4. The compound or the pharmaceutical acceptable salt thereof of claim 1 , wherein:
-A-B— is —O—CH 2 — or —CH 2 —O—;
X is an oxygen atom;
R 1 is a C 1 -C 6 alkyl group;
R 2 and R 3 are independently a C 1 -C 6 alkyl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a hydroxy group and a C 1 -C 6 alkoxy group and;
or R 2 and R 3 taken together with the nitrogen atom to which they are attached form a pyrrolidinyl group being unsubstituted or substituted with a substituent selected from the group consisting of a hydroxy group, a C 1 -C 6 alkyl group and a hydroxy-C 1 -C 6 alkyl group;
R 4 , R 5 , R 6 and R 7 are independently a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group; and
R 8 is a hydrogen atom.
5. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of claim 4 , and at least one pharmaceutically acceptable carrier.
6. A compound selected from:
4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxyl]-N,N,2-trimethyl-1H-benzimidazole -6-carboxamide;
4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxyl]-2-methhyl-6-(pyrrolidin-1-ylcarbonyl)-1H-benzimidazole;
4-[(5-fluoro-3,4-dihydro-2H-chromen-4-yl)oxyl]-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide;
or a pharmaceutically acceptable salt thereof.
7. A compound selected from:
(−)-4-[((4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxyl]-N,N,2-trimethyl-1H -benzimidazole-6-carboxamide;
(−)-4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-2-methyl-6-(pyrrolidin- 1-ylcarbonyl)-1H-benzimidazole;
(−)-4-[(5-fluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N2-trrimethyl-1H-benzimdiazole -6-carboxamide;
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of claim 7 , and at least one pharmaceutically acceptable carrier.