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Recent Esophagitis News and Articles

• New Pediatric Gastroenterology and Nutrition Study Findings Recently Were Published by Researchers at Northwestern University
• Study Results from J. Chai and Colleagues Broaden Understanding of Esophageal Cancer
• Studies in the Area of Esophageal Cancer Reported from University of Chicago
• Data on Physiology and Pharmacology Described by Researchers at Chung Ang University
• Agency Reviews Patent Application Approval Request for \"Use of Antifungal Compositions to Treat Upper Gastrointestinal Conditions\"
• New Candidiasis Research Has Been Reported by Scientists at Dongguk University
• Recent Studies from University of California Add New Data to Adenocarcinomas
• Researchers from Department of Gastroenterology and Hepatology Detail Findings in Neurogastroenterology
• Data on Acid Reflux Disease Published by Researchers at Kyoto Pharmaceutical University

Agency Reviews Patent Application Approval Request for "5-Ht4 Receptor Agonists for the Treatment of Dementia"

The patent's inventors are Ohshiro, Hiroyuki (Aichi, JP); Fujiuchi, Akiyoshi (Aichi, JP); Take, Yukinori (Aichi, JP).

This patent application was filed on February 14, 2011 and was cleared for further review on December 27, 2012.

From the background information supplied by the inventors, news correspondents obtained the following quote: "In general, 5-HT4 receptor agonists are found to be useful for the treatment of a variety of diseases such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease (AD), cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders such as cardiac failure and heart arrhythmia, and apnea syndrome (See NPL 1; NPL 2; NPL 3; NPL 4; NPL 5; NPL 6; and NPL 7).

"Alzheimer's disease is the most prevalent form of dementia. Its diagnosis is described in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., published by the American Psychiatric Association (DSM-IV). It is a neurodegenerative disorder, clinically characterized by progressive loss of memory and general cognitive function, and pathologically characterized by the deposition of extracellular proteinaceous plaques in the cortical and associative brain regions of sufferers. In the past, cholinergic hypothesis, Abeta hypothesis and tau hypothesis has been advocated and tremendous amount of researches are undertaken in each story to identify the causative mechanisms of AD.

"Over the 20 years since the origins of the cholinergic hypothesis, data from numerous studies have challenged its veracity as an explanation for the syndrome of dementia in Alzheimer's disease (NPL 8). These studies, together with the emerging role of acetylcholine (ACh) in learning and memory, led to the 'cholinergic hypothesis of Alzheimer's disease'. Thus it was proposed that degeneration of cholinergic neurons in the basal forebrain and the associated loss of cholinergic neurotransmission in the cerebral cortex and other areas contributed significantly to the deterioration in cognitive function seen in patients with AD. Based on this mechanism of action, acetylcholine esterase inhibitors which suppress the degradation of acetylcholine in brain synapses are in the market as the therapeutic medicines for AD.

"Abeta is formed from amyloid precursor protein (APP) via separate intracellular proteolytic events involving the enzymes beta-secretase and gamma-secretase. Variability in the site of the proteolysis mediated by gamma-secretase results in Abeta of varying chain length, e.g. Abeta(1-38), Abeta(1-40) and Abeta(1-42). After secretion into the extracellular medium, Abeta forms initially-soluble aggregates which are widely believed to be the key neurotoxic agents in AD (see NPL 9), and which ultimately result in the insoluble deposits and dense neuritic plaques which are the pathological characteristics of AD (NPL 10). Several candidates of AD therapeutics based on this hypothesis, are presently in the clinical trials and some efficacy in AD patients were reported (NPL 11, NPL 12).

"Above two mechanisms, 1) the induction of acetylcholine levels in the brain, and 2) the suppression of Abeta production following deposition of amyloid plaques in the cortical and associative brain regions are the promising mechanisms for AD therapy proofed in human. The mechanism 1) is exemplified by acetylcholine esterase inhibitors such as donepezil, galantamine, and rivastigmine, in the market, and the mechanism 2) is exemplified by the drugs such as Abeta antibody and secretase inhibitors, and their efficacy has been reported in clinical studies of AD.

"These two mechanisms are expected to show different efficacy on the AD therapy. The mechanism 1) restores the memory and cognitive functions in patients while it is a symptomatic therapy. In the other hand, the mechanism 2) by the suppression of Abeta production should have neuro-protective function which brings a disease-modifying therapy in AD patients. Therefore, a medicine which has both mechanisms of action will be an attractive medicine for AD therapy. As far as we know, this invention is the first example of the compound which has been demonstrated both mechanisms 1) and 2) clearly in animals.

"Particularly in AD, it is discussed in the literatures that 5-HT4 agonism provides both the proposed mechanisms of treatment mentioned above. Then some 5-HT4 agonists have been synthesized and the non-clinical and clinical studies have been commenced by using the agonists. However, no effective working examples in animal Abeta reducing study have been identified. For example, PRX-03140, which is developed in clinical stage, has showed Abeta reducing tendency while those efficacies were not significant suppressions in animal models (NPL 13). RS67333 has been tested for the inhibition of Abeta secretion using cell culture but has not been tested in animals (NPL 14). Therefore, this invention is the first example of the compound which has been demonstrated both above two mechanisms clearly in animals."

Supplementing the background information on this patent application, NewsRx reporters also obtained the inventors' summary information for this patent: "Technical Problem

"An object of the present invention is to provide compounds for use in therapeutic treatment of the human body. In particular, an object of the present invention is to provide compounds with selective 5-HT4 receptor agonism which are useful for treating dementia, or preventing or delaying the onset or the progression of dementia that is associated with the augmentation of Abeta in the brain, and/or associated with a depletion of ACh levels in the brain synapses.

"In addition, an object of the present invention is to provide a pharmaceutical composition for the treatment of dementia which comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a method for the treatment of dementia in an animal subject including a mammalian subject, which comprises administering to the animal subject including a mammalian subject a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and a method for the treatment of dementia in an animal subject including a mammalian subject, which comprises administering to the animal subject including a mammalian subject in need a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.

"Solution to Problem

"The gist of the present invention is as follows:

"[1] Use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of dementia in an animal subject including a mammalian subject:

"##STR00002##

"wherein

"Het represents a heterocyclic group having one nitrogen atom and from 4 to 7 carbon atoms, to which B binds directly, said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of substituents alpha.sup.1;

"said substituents alpha.sup.1 are independently selected from a hydroxy group, a halogen atom and an amino group;

"A represents an alkylene group having from 1 to 4 carbon atoms;

"B represents a covalent bond or an alkylene group having from 1 to 5 carbon atoms;

"Ar represents aryl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of

"hydrogen, halogen, C.sub.1-C.sub.4 alkyl, C.sub.4-C.sub.6 cycloalkyl, --O--C.sub.1-C.sub.4 alkyl, --O-heterocyclyl and --O--CH.sub.2--R.sup.2; wherein said C.sub.4-C.sub.6 cycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of hydroxy, oxo and C.sub.1-C.sub.4 alkoxy;

"R.sup.2 is selected from the group consisting of trifluoromethyl, isopropyl and C.sub.4-C.sub.6 cycloalkyl; wherein said C.sub.4-C.sub.6 cycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of hydroxy, oxo, C.sub.1-C.sub.4 alkoxy and hydroxy-C.sub.1-C.sub.4 alkyl;

"X represents --O--, --S--, --NH--, or --CH.sub.2--

"n represents 0 or 1;

"m represents 0 or 1;

"R independently represents

"(i) an oxo group, a hydroxy group, an amino group, an alkylamino group, a carboxyl group or a tetrazole group;

"(ii) a cycloalkyl group having from 3 to 8 carbon atoms, said cycloalkyl group being substituted by 1 to 5 substituents independently selected from the group consisting of substituents alpha.sup.2, or

"(iii) a heterocyclic group having from 3 to 8 atoms, said heterocyclic group being unsubstituted or substituted by 1 to 5 substituents independently selected from the group consisting of substituents beta,

"said substituents alpha.sup.2 are independently selected from a hydroxy group, an amino group, a hydroxy-substituted alkyl group having from 1 to 4 carbon atoms, a carboxyl group, an alkoxy group having from 1 to 4 carbon atoms, and a tetrazole group;

"said substituents beta are independently selected from a hydroxy group, a hydroxy-substituted alkyl group having from 1 to 4 carbon atoms, a carboxyl group, an amino group, an alkyl group having from 1 to 4 carbon atoms, an amino-substituted alkyl group having from 1 to 4 carbon atoms, a carbamoyl group, and a tetrazole group; and

"p represents 1, 2 or 3;

"[2] The use of [1], wherein

"Het represents a heterocyclic group selected from

"##STR00003##

"said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of substituents alpha.sup.1;

"said substituents alpha.sup.1 are independently selected from a hydroxy group, and a halogen atom;

"A represents an alkylene group having from 1 to 2 carbon atoms;

"B represents an alkylene group having from 1 to 5 carbon atoms;

"Ar represents,

"##STR00004##

"R.sup.1a represents an isopropyl group, an n-propyl group or a cyclopentyl group,

"R.sup.2a represents a methyl group, a fluorine atom or a chlorine atom;

"##STR00005##

"R.sup.1b represents an alkyl group having from 1 to 4 carbon atoms or a halogen atom,

"R.sup.2b represents an alkyl group having from 1 to 4 carbon atoms;

"##STR00006##

"R.sup.1c is selected from the group consisting of C.sub.4-C.sub.6 cycloalkyl, heterocyclyl and --CH.sub.2--R.sup.2c; wherein said C.sub.4-C.sub.6 cycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of hydroxy, oxo and C.sub.1-C.sub.4 alkoxy;

"R.sup.2c is selected from the group consisting of trifluoromethyl, isopropyl and C.sub.4-C.sub.6 cycloalkyl; wherein said C.sub.4-C.sub.6 cycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of hydroxy, oxo, C.sub.1-C.sub.4 alkoxy and hydroxy-C.sub.1-C.sub.4 alkyl;

"##STR00007##

"R.sup.1d is a hydrogen atom, a halogen atom or a C.sub.1-C.sub.6 alkyl group;

"R.sup.2d is a C.sub.1-C.sub.6 alkyl group or a C.sub.3-C.sub.6 cycloalkyl group;

"##STR00008##

"R.sup.1e represents an isopropyl group or a cyclopentyl group;

"R.sup.2e independently represents a halogen atom or an alkyl group having from 1 to 4 carbon atoms; q is 0, 1, 2, 3 or 4;

"##STR00009##

"R.sup.1f represents a hydrogen atom, a halogen atom or a C.sub.1-C.sub.4 alkyl group;

"R.sup.2f and R.sup.3f represent independently a methyl or ethyl group, or R.sup.2f and R.sup.3f may together form a C.sub.2-C.sub.4 alkylene bridge to yield a 3 to 5 membered ring;

"##STR00010##

"R.sup.1g represents a C.sub.1-C.sub.4 alkyl group, a --CH.sub.2--C.sub.3-C.sub.6-cycloalkyl group or C.sub.3-C.sub.6-cycloalkyl group;

"R.sup.2g represents a hydrogen atom or a halogen atom;

"##STR00011##

"R.sup.1h represents a C.sub.1-C.sub.4 alkyl group;

"R.sup.2h represents a hydrogen atom or a halogen atom;

"q represents 1 or 2;

"##STR00012##

"R.sup.1i represents a C.sub.1-C.sub.4 alkyl group;

"R.sup.2i represents a hydrogen atom or a halogen atom;

"r represents 1 or 2;

"##STR00013##

"R.sup.1j represents a C.sub.1-C.sub.4 alkyl group;

"R.sup.2j represents a hydrogen atom or a halogen atom; or

"##STR00014##

"X represents --O-- when Ar represents

"##STR00015##

"n represents 1 when Ar represents

"##STR00016##

"m represents 0 or 1;

"R independently represents

"(i) a hydroxy group, an amino group, an alkylamino group, or a carboxyl group;

"(ii) a cycloalkyl group having from 4 to 7 carbon atoms, said cycloalkyl group being substituted by 1 to 3 substituents independently selected from the group consisting of substituents alpha.sup.2, or

"(iii) a heterocyclic group having from 5 to 7 atoms, said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of substituents beta,

"said substituents alpha.sup.2 are independently selected from a hydroxy group, a carboxyl group, an alkoxy group having from 1 to 4 carbon atoms and a tetrazole group;

"said substituents beta are independently selected from a hydroxy group, a carboxyl group, an alkyl group having from 1 to 4 carbon atoms, a carbamoyl group, and a tetrazole group;

"p represents 1;

"[3] The use of [2], wherein

"Het represents a group of formula

"##STR00017##

"and this group is unsubstituted or substituted by one substituent selected from the group consisting of substituents alpha.sup.1;

"said substituents alpha.sup.1 are independently selected from a hydroxy group;

"A represents a methylene group;

"B represents a methylene group;

"m represents 0 when Ar represents

"##STR00018##

"R independently represents

"(i) a hydroxy group;

"(ii) a cycloalkyl group having from 4 to 6 carbon atoms, said cycloalkyl group being substituted by 1 to 2 substituents independently selected from the group consisting of substituents alpha.sup.2, or

"(iii) a heterocyclic group having from 5 to 6 atoms, said heterocyclic group being unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of substituents beta,

"said substituents alpha.sup.2 are independently selected from a hydroxy group, a carboxyl group, and a tetrazole group;

"said substituents beta are selected from a hydroxy group, a carboxyl group, an alkyl group having from 1 to 4 carbon atoms, and a tetrazole group;

"p represents 1;

"[4] The use of [3], wherein

"R independently represents a 1,4-dihydroxycyclohexyl group, a hydroxycyclopentyl group, a hydroxytetrahydropyranyl group, a tetrazolyltetrahydropyranyl group, a tetrazolylcyclopentyl group, a piperidinyl group or a morpholinyl group;

"[5] The use of [1], wherein the compound of formula (I) is selected from: N-((1-((1-(2H-Tetrazol-5-yl)cyclopentyl)methyl)piperidin-4-yl)methyl)-3-i- sopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxamide; 3-isopropyl-N-((1-(2-Methyl-2-(2H-tetrazol-5-yl)propyl)piperidin-4-yl)met- hyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxamide; N-((1-((1-(2H-Tetrazol-5-yl)cyclopentyl)methyl)piperidin-4-yl)methyl)-2'-- oxospiro[cyclopentane-1,3'-indoline]-1'-carboxamide; N-((1-(((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)methyl)-- 3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxamide; 5-Fluoro-N-((1-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)- methyl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; 5-Chloro-N-((1-(((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl- )methyl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; N-((1-(((4-Hydroxytetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)methyl)-- 1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; N-((1-((trans-1,4-Dihydroxycyclohexyl)methyl)piperidin-4-yl)methyl)-1-iso- propyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; N-((1-((cis-1,4-Dihydroxycyclohexyl)methyl)piperidin-4-yl)methyl)-1-isopr- opyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; 5-Bromo-N-((1-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)m- ethyl)-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide oxalate; 5-Chloro-N-((1-((trans-1,4-dihydroxy-4-methylcyclohexyl)methyl)piperidin-- 4-yl)methyl)-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-Chloro-N-((1-((trans-1-hydroxy-4-methoxycyclohexyl)methyl)piperi- din-4-yl)methyl)-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxam- ide; 5-Chloro-N-((1-((cis-1-hydroxy-4-methoxycyclohexyl)methyl)piperidin-4-yl)- methyl)-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-Chloro-N-((1-((1-hydroxycyclohexyl)methyl)piperidin-4-yl)methyl)- -1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-Chloro-N-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)-1-isopropyl-6-met- hyl-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-Fluoro-N-((1-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)- methyl)-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-Bromo-N-((1-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)piperidin- -4-yl)methyl)-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide- ; N-((1-(((4-Hydroxytetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)- methyl)-1-isopropyl-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-Chloro-N-((1-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)piperidi- n-4-yl)methyl)-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamid- e; 4-((4-(((4-((trans-4-Hydroxycyclohexyl)oxy)benzo[d]isoxazol-3-yl- )oxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol; 4-((4-(((4-(((1S,2R)-2-Hydroxycyclohexyl)oxy)benzo[d]isoxazol-3-yl)oxy)me- thyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol; 4-((4-(((4-(((1R,3R)-3-Hydroxycyclopentyl)oxy)benzo[d]isoxazol-3-yl)oxy)m- ethyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol; 4-((4-(((4-(((1S,2R)-2-Methoxycyclopentyl)oxy)benzo[d]isoxazol-3-yl)oxy)m- ethyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol; 4-((4-(((4-(((1S,2R)-2-Hydroxycyclopentyl)oxy)benzo[d]isoxazol-3-yl)oxy)m- ethyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol; 4-((4-(((4-(((1R,2R)-2-Methoxycyclopentyl)oxy)benzo[d]isoxazol-3-yl)oxy)m- ethyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol; 4-((4-(((4-(((1R,2R)-2-Hydroxycyclopentyl)oxy)benzo[d]isoxazol-3-yl)oxy)m- ethyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol; 4-((4-(((4-((1-Hydroxycyclopentyl)methoxy)benzo[d] isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol; 4-((4-(((4-(Tetrahydro-2H-pyran-4-yl)oxy)benzo[d] isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol; 4-((4-(((4-Isobutoxybenzo[d] isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol; N-(cis-6-(((4-Hydroxytetrahydro-2H-pyran-4-yl)methyl)piperidin-3-y- l)-1-isopropyl-1H-indazole-3-carboxamide; N-(cis-6-(2-Hydroxy-2-methylpropyl)piperidin-3-yl)-1-isopropyl-1H-indazol- e-3-carboxamide; 1-Cyclobutyl-N-(cis-6-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidi- n-3-yl)-1 H-indazole-3-carboxamide; N-((3S,5S)-5-(2-Hydroxy-2-methylpropyl)pyrrolidin-3-yl)-1-isopropyl-1H-in- dazole-3-carboxamide; 5-Fluoro-N-((3S,5S)-5-(2-hydroxy-2-methylpropyl)pyrrolidin-3-yl)-1-isopro- pyl-1H-indazole-3-carboxamide; N-((3S,5S)-5-[(1-Hydroxycyclohexyl)methyl]pyrrolidin-3-yl)-1-isopropyl-1H- -indazole-3-carboxamide; 4-Amino-5-chloro-N-((1-((1,4-dihydroxycyclohexyl)methyl)piperidin-4-yl)me- thyl)-2,3-dihydrobenzofuran-7-carboxamide; 4-Amino-5-chloro-N-((1-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)piperid- in-4-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide; 4-Amino-5-chloro-N-((1-((1,4-dihydroxycyclohexyl)methyl)piperidin-4-yl)me- thyl)-2-ethoxybenzamide; 4-Amino-5-chloro-2-ethoxy-N-((1-((4-hydroxytetrahydro-2H-pyran-4-yl)methy- l)piperidin-4-yl)methyl)benzamide; 4-Amino-5-chloro-N-((1-((1,4-dihydroxycyclohexyl)methyl)piperidin-4-yl)me- thyl)-2-methoxybenzamide; 4-Amino-5-chloro-N-((1-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)piperid- in-4-yl)methyl)-2-methoxybenzamide; 5-Amino-6-bromo-N-((1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)me- thyl)chroman-8-carboxamide; 4-Amino-5-chloro-N-((1-((tetrahydrofuran-2-yl)methyl)piperidin-4-yl)methy- l)benzofuran-7-carboxamide; 8-Amino-7-chloro-N-((1-((tetrahydrofuran-2-yl)methyl)piperidin-4-yl)methy- l)-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide; (S)-5-Amino-6-chloro-N-((1-((tetrahydrofuran-2-yl)methyl)piperidin-4-yl)m- ethyl)chroman-8-carboxamide; (S)-4-Amino-5-chloro-2-methoxy-N-((1-((tetrahydrofuran-2-yl)methyl)piperi- din-4-yl)methyl)benzamide; ®-4-Amino-5-chloro-2-methoxy-N-((1-((tetrahydrofuran-2-yl)methyl)piperi- din-4-yl)methyl)benzamide; (S)-4-Amino-5-chloro-N-((1-((tetrahydrofuran-2-yl)methyl)piperidin-4-yl)m- ethyl)benzofuran-7-carboxamide; ®-4-Amino-5-chloro-N-((1-((tetrahydrofuran-2-yl)methyl)piperidin-4-yl)m- ethyl)benzofuran-7-carboxamide; (S)-5-Amino-6-chloro-N-((1-((tetrahydrofuran-3-yl)methyl)piperidin-4-yl)m- ethyl)chroman-8-carboxamide; ®-5-Amino-6-chloro-N-((1-((tetrahydrofuran-3-yl)methyl)piperidin-4-yl)m- ethyl)chroman-8-carboxamide; (S)-8-Amino-7-chloro-N-((1-((tetrahydrofuran-2-yl)methyl)piperidin-4-yl)m- ethyl)-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide; ®-8-Amino-7-chloro-N-((1-((tetrahydrofuran-2-yl)methyl)piperidin-4-yl)m- ethyl)-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide; and 4-Amino-5-chloro-N-((1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)m- ethyl)benzofuran-7-carboxamide, or a pharmaceutically acceptable salt thereof;

"[6] The use of [1], wherein the compound of the formula (I) or the pharmaceutically acceptable salt is used in combination with one or more additional compounds known to be useful in the treatment or prevention of dementia or the symptoms thereof;

"[7] A pharmaceutical composition for the treatment of dementia which comprises a therapeutically effective amount of a compound of the formula (I) in claim 1 or a pharmaceutically acceptable salt thereof;

"[8] The pharmaceutical composition of [7], which further comprises a therapeutically effective amount of one or more additional compounds known to be useful in the treatment or prevention of dementia or the symptoms thereof;

"[9] A method for the treatment of dementia in an animal subject including a mammalian subject, which comprises administering to the animal subject including a mammalian subject a compound of the formula (I) in [1] or a pharmaceutically acceptable salt thereof;

"[10] The method of [9], which further comprises administering a therapeutically effective amount of one or more additional compounds known to be useful in the treatment or prevention of dementia;

"[11] A method for the treatment of dementia, which comprises administering to an animal subject including a mammalian subject in need a therapeutically effective amount of a compound of the formula (I) in [1] or a pharmaceutically acceptable salt thereof;

"[12] The method of [11], which further comprises administering a therapeutically effective amount of one or more additional compounds known to be useful in the treatment or prevention of dementia; and

"[13] A compound of the formula (I) in [1] or a pharmaceutically acceptable salt thereof for use in the treatment of dementia in an animal subject including a mammalian subject.

"Advantageous Effects of Invention

"It has now surprisingly been found that compounds of this invention which have a strong affinity to 5-HT4 receptor are useful for the treatment of dementia.

"Namely, inventors confirmed that above compounds of this invention have the desirable property for the treatment of AD using the rat Novel Object Recognition Test and rat scopolamine-induced spontaneous alteration model, based on the mechanism 1) mentioned above. Compounds of this invention have also been confirmed to have the desirable property for the treatment of AD using quantitating Abeta-peptides in the Tg2576 mice, based on the mechanism 2) mentioned above.

"Therefore the compounds of this invention are useful for the treatment of dementia."

For the URL and additional information on this patent application, see: Ohshiro, Hiroyuki; Fujiuchi, Akiyoshi; Take, Yukinori. 5-Ht4 Receptor Agonists for the Treatment of Dementia. U.S. Patent Serial Number 578127, filed February 14, 2011, and posted December 27, 2012. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser'Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1786&p=36&f=G&l=50&d=PG01&S1=20121220.PD.&OS=PD/20121220&RS=PD/20121220

Keywords for this news article include: Gases, Dementia, Elements, Hydrogen, Dyspepsia, Imidazole, Benzamides, Tauopathies, Therapeutics, Acetylcholine, Benzoic Acids, Brain Diseases, Biogenic Amines, Gastroenterology, Alzheimer Disease, Inorganic Chemicals, Rqualia Phamra Inc., Neurodegenerative Diseases, Central Nervous System Diseases.

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