HK1173374A

HK1173374A - 5-ht4 receptor agonists for the treatment of dementia

Info

Publication number: HK1173374A
Application number: HK13100646.3A
Authority: HK
Inventors: 博行大城; 章嘉藤内; 之令武
Original assignee: 拉夸里亚创药株式会社
Priority date: 2010-02-12
Filing date: 2011-02-14
Publication date: 2013-05-16

Description

5-HT4 receptor agonists for the treatment of dementia

Technical Field

The present invention relates to a compound for use in the treatment of the human body. In particular, the present invention relates to a compound having selective 5-HT4 receptor agonism useful in the treatment of dementia associated with increased beta-amyloid peptide (Abeta) in the brain and/or associated with depletion of ACh levels in brain synapses, or in the prevention or retardation of onset or development of said dementia.

The present invention also relates to a pharmaceutical composition for treating dementia, which comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present invention relates to a method for treating dementia in an animal subject including a mammalian subject, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to an animal subject including a mammalian subject. The present invention further relates to a method for treating dementia in an animal subject including a mammalian subject, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the animal subject including the mammalian subject in need of treatment.

Background

In general, 5-HT4 receptor agonists have been found to be useful in 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, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's Disease (AD), cognitive disorders, emesis, migraine, neurological disease, pain, cardiovascular disease (e.g., heart failure and arrhythmia), and apnea syndrome (see NPL1, NPL2, NPL3, NPL4, NPL5, NPL6, and NPL 7).

Alzheimer's disease is the most common form of dementia. The diagnosis is described in the Diagnostic and Statistical handbook for Mental Disorders, published by the American society of Psychiatric, 4th ed., published by the American Psychiatric Association (DSM-IV), 4th edition. It is a neurodegenerative disease characterized clinically by progressive loss of memory and general cognitive function, and pathologically by the deposition of extracellular protein plaques in the patient's cortex and related brain regions. The cholinergic hypothesis, as well as the Abeta hypothesis and the tau hypothesis, have been advocated in the past, and a great deal of research has been conducted on various hypotheses in order to confirm the etiology of AD.

Over a period of 20 years since the origin of the cholinergic hypothesis, the data of many studies challenge the authenticity of the cholinergic hypothesis as an explanation of dementia symptoms in alzheimer's disease (NPL 8). These studies, along with the novel role of acetylcholine (ACh) in learning and memory, led to the "cholinergic hypothesis of alzheimer's disease". It is proposed that degeneration of cholinergic neurons of the basal forebrain and the associated loss of cholinergic neurotransmission in the cerebral cortex and other areas are the major causes of the deterioration of cognitive function exhibited in AD patients. Acetylcholinesterase inhibitors that inhibit the degradation of acetylcholine in brain synapses based on this mechanism of action are commercially available as therapeutic agents for AD.

Abeta is formed from Amyloid Precursor Protein (APP) by separate intracellular proteolytic events involving the enzymes β -secretase and γ -secretase. Because of the variability of the proteolytic site mediated by gamma-secretase, Abeta is produced in a variety of chain lengths, e.g., Abeta (l-38), Abeta (l-40), and Abeta (l-42). Upon secretion into the extracellular medium, Abeta forms primary-soluble aggregates, which are widely regarded as the major nerve agent in AD (reference NPL 9). The result was the formation of insoluble deposits and dense senile plaques (NPL 10) which are pathological features of AD. Several candidate AD therapies based on this hypothesis are undergoing clinical trials and have reported partial efficacy in AD patients (NPL 11, NPL 12).

The two mechanisms described above, 1) induction of acetylcholine levels in the brain and 2) inhibition of Abeta production immediately following deposition of amyloid plaques in the cortex and associated brain regions, are potent mechanisms for proven AD treatment in humans. Mechanism 1) is exemplified by acetylcholinesterase inhibitors, such as commercially available donepezil, galantamine and rivastigmine. Mechanism 2) is exemplified by drugs such as Abeta antibodies and secretase inhibitors, the efficacy of which has been reported by clinical studies of AD.

These two mechanisms are expected to show different efficacy for AD treatment. Mechanism 1) restores memory and cognitive function in patients, however it is a symptomatic therapy. On the other hand, mechanism 2) based on inhibition of Abeta production should possess a neuro-protective function to produce a disease modifying therapy in AD patients. Therefore, drugs having two mechanisms of action will be attracting attention as drugs for the treatment of AD. The present invention is known to be the first case of compounds in animals that have clearly demonstrated two mechanisms 1) and 2).

In particular, 5-HT4 agonism in AD is discussed in the literature to provide the two mechanisms proposed in the above-mentioned treatments. Next, a partial 5-HT4 agonist was synthesized and non-clinical and clinical studies were initiated by using this agonist. However, no effective examples were identified in the animal Abeta reduction study. For example, although PRX-03140 developed at the clinical stage showed a propensity for Abeta reduction, this potency did not result in significant inhibition in animal models (NPL 13). Inhibition of Abeta secretion by RS67333 was tested by using cell culture, but not in animals (NPL 14). Thus, the present invention is the first case of compounds that clearly demonstrate both of the above mechanisms in animals.

Non-patent documents:

{NPL1}

Bockaert J.et al.，TiPs 13；141-45，1992

{NPL2}

Ford A.P et al.，Med.Res.Rev.13：633-62，1993

{NPL3}

Gullikson G.W.et al.，Drug Dev.Res.26；405-17，1992

{NPL4}

Richard M.Eglen et al.，TiPs 16；391-98，1995

{NPL5}

Bockaert J.et al.，CNS Drugs 1；6-15，1994

{NPL6}

Romanelli M.N.et al.，Arzheim Forsch./Drug Res.，43；913-18，1993

{NPL7}

Kaumann A.J.et al.，Naunyn-Schmiedebergs Arch Pharmacol.，344；150-59，1991

{NPL8}

Fracis P et al.，J Neurol Neurosurg Psychiatry 66；137-147，1999

{NPL9}

Gong Y et al.，PNAS 100；10417-22，2003

{NPL10}

Hardy J et al.，Science 297；353-356，2002

{NPL11}

Mount C et al.，Nature Medicine 12；780-784，2006

{NPL12}

Siemers ER et al.，Clinical Neuropharmacology 30；317-325，2007

{NPL13}

Shacham S et al.，10th ICAD O3-05-03，2006

{NPL14}

Cho，S et al.，Experimental Neurology 203；274-278，2007

disclosure of Invention

The object of the present invention is to provide a compound for use in the treatment of the human body. In particular, the present invention provides a compound having selective 5-HT4 receptor agonism useful in the treatment of dementia associated with increased Abeta in the brain or associated with depletion of ACh levels in brain synapses, or in the prevention or retardation of the onset or development of dementia.

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

The key points of the invention are as follows:

[1] use of a compound of 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:

{ chemical formula 1}

In the above-mentioned formula, the compound of formula,

het represents a heterocyclic group having 1 nitrogen atom and 4 to 7 carbon atoms to which B is directly bonded, said heterocyclic group being unsubstituted or 1 to 4 independently selected from the group consisting of substituents α¹Substituted with a substituent of the group;

the substituent alpha¹Independently selected from hydroxyl, halogen and amino;

a represents an alkylene group having 1 to 4 carbon atoms;

b represents a covalent bond or an alkylene group having 1 to 5 carbon atoms;

ar is optionally 1-5 independently selected from hydrogen, halogen, C₁-C₄Alkyl radical, C₄-C₆Cycloalkyl, -O-C₁-C₄Alkyl, -O-heterocyclyl and-O-CH₂-R²Aryl substituted with a substituent in the group; wherein, the C₄-C₆Cycloalkyl is unsubstituted or independently selected from 1 to 4 of hydroxy, oxo and C₁-C₄Substituted with a substituent of the group consisting of alkoxy;

R²selected from the group consisting of trifluoromethyl, isopropyl and C₄-C₆Cycloalkyl groups; wherein, the C₄-C₆Cycloalkyl is unsubstituted or independently selected from the group consisting of hydroxy, oxo, and C₁-C₄Alkoxy and hydroxy-C₁-C₄Alkyl groups;

x represents-O-, -S-, -NH-or-CH₂-；

n represents 0 or 1;

m represents 0 or 1;

r independently represents

(i) Oxo, hydroxy, amino, alkylamino, carboxy or tetrazolyl;

(ii) a cycloalkyl group having 3 to 8 carbon atoms, the cycloalkyl group being substituted with 1 to 5 substituents independently selected from the group consisting of substituents α 2, or

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

the substituent alpha²Independently selected from the group consisting of hydroxy, amino, hydroxy-substituted alkyl having 1 to 4 carbon atoms, carboxy, alkoxy having 1 to 4 carbon atoms, and tetrazolyl;

the substituent beta is independently selected from the group consisting of hydroxyl, hydroxyl-substituted alkyl having 1 to 4 carbon atoms, carboxyl, amino, alkyl having 1 to 4 carbon atoms, amino-substituted alkyl having 1 to 4 carbon atoms, carbamoyl, and tetrazolyl;

p represents 1, 2 or 3;

[2] [1] use of, wherein,

het represents selected from

{ chemical formula 2}

And

the heterocyclic group of (a) is unsubstituted or 1 to 4 of which are independently selected from the group consisting of¹Substituted with a substituent of the group;

the substituent alpha¹Independently selected from hydroxyl and halogen atoms;

a represents an alkylene group having 1 to 2 carbon atoms;

b represents an alkylene group having 1 to 5 carbon atoms;

ar represents

{ chemical formula 3}

R^1aRepresents an isopropyl group, an n-propyl group or a cyclopentyl group,

R^2arepresents a methyl group, a fluorine atom or a chlorine atom;

{ chemical formula 4}

R^1bRepresents an alkyl group having 1 to 4 carbon atoms or a halogen atom,

R^2brepresents an alkyl group having 1 to 4 carbon atoms;

{ chemical formula 5}

R^1cSelected from the group consisting of C₄-C₆Cycloalkyl, heterocyclyl and-CH₂-R^2cA group of; wherein, the C₄-C₆Cycloalkyl is unsubstituted or independently selected from 1 to 4 of hydroxy, oxo and C₁-C₄Substituted with a substituent of the group consisting of alkoxy;

R^2cselected from the group consisting of trifluoromethyl, isopropyl and C₄-C₆Cycloalkyl groups; wherein, the C₄-C₆Cycloalkyl is unsubstituted or independently selected from the group consisting of hydroxy, oxo, and C₁-C₄Alkoxy and hydroxy-C₁-C₄Alkyl groups;

{ chemical formula 6}

R^1dIs a hydrogen atom, a halogen atomSeed or C₁-C₆An alkyl group;

R^2dis C₁-C₆Alkyl or C₃-C₆A cycloalkyl group;

{ chemical formula 7}

R^1eRepresents isopropyl or cyclopentyl;

R^2eindependently represents a halogen atom or an alkyl group having 1 to 4 carbon atoms; q is 0, 1, 2, 3 or 4;

{ chemical formula 8}

R^1fRepresents a hydrogen atom, a halogen atom or C₁-C₄An alkyl group;

R^2fand R^3fIndependently represent methyl or ethyl, or R^2fAnd R^3fMay together form C₂-C₄Alkylene bridges to form 3-5 membered rings;

{ chemical formula 9}

R^1gIs represented by C₁-C₄Alkyl, -CH₂-C₃-C₆-cycloalkyl or C₃-C₆-a cycloalkyl group;

R^2grepresents a hydrogen atom or a halogen atom;

{ chemical formula 10}

R^1hIs represented by C₁-C₄An alkyl group;

R^2hrepresents a hydrogen atom or a halogen atom;

q represents 1 or 2;

{ chemical formula 11}

{ chemical formula 12}

R¹ⁱIs represented by C₁-C₄An alkyl group;

R²ⁱrepresents a hydrogen atom or a halogen atom;

r represents 1 or 2;

{ chemical formula 13}

R^1jIs represented by C₁-C₄An alkyl group;

R^2jrepresents a hydrogen atom or a halogen atom; or

{ chemical formula 14}

When Ar represents

{ chemical formula 15}

When, X represents-O-;

when Ar represents

{ chemical formula 16}

When n represents 1;

m represents 0 or 1;

r independently represents

(i) Hydroxy, amino, alkylamino, or carboxy;

(ii) a cycloalkyl group having 4 to 7 carbon atoms, the cycloalkyl group being substituted with 1 to 3 substituents independently selected from the group consisting of substituents α 2; or

(iii) A heterocyclic group having 5 to 7 atoms, said heterocyclic group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a substituent β;

the substituent group alpha 2 is independently selected from hydroxyl, carboxyl, alkoxy with 1-4 carbon atoms and tetrazolyl;

the substituent beta is independently selected from hydroxyl, carboxyl, alkyl with 1-4 carbon atoms, carbamoyl and tetrazolyl;

p represents 1;

[3] [2] use, wherein,

het represents the formula

{ chemical formula 17}

The group being unsubstituted or substituted by 1 substituent selected from the group consisting of¹Substituted with a substituent of the group;

the substituent alpha¹Independently selected from hydroxyl;

a represents a methylene group;

b represents a methylene group;

when Ar represents

{ chemical formula 18}

When m represents 0;

r independently represents

(i) A hydroxyl group;

(ii) cycloalkyl having 4 to 6 carbon atoms, said cycloalkyl being independently selected by 1 to 2 substituents α²Substituted by substituents of the group consisting of, or

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

the substituent alpha²Independently selected from hydroxy, carboxy and tetrazolyl;

the substituent beta is selected from hydroxyl, carboxyl, alkyl with 1-4 carbon atoms and tetrazolyl;

p represents 1;

[4] [3] use, wherein,

r independently represents 1, 4-dihydroxycyclohexyl, hydroxycyclopentyl, hydroxytetrahydropyranyl, tetrazolyltetrahydropyranyl, tetrazolylcyclopentyl, piperidinyl or morpholinyl;

[5] [1] use, wherein the compound of formula (I) is selected from the following:

n- ((1- ((1- (2H-tetrazol-5-yl) cyclopentyl) methyl) piperidin-4-yl) methyl) -3-isopropyl-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) methyl) -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-isopropyl-5-methyl-2-oxo-1, 2-dihydroquinoline-3-carboxamide;

n- ((1- ((cis-1, 4-dihydroxycyclohexyl) methyl) piperidin-4-yl) methyl) -1-isopropyl-5-methyl-2-oxo-1, 2-dihydroquinoline-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 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) piperidin-4-yl) methyl) -1-isopropyl-6-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide;

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-methyl-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) piperidin-4-yl) methyl) -1-isopropyl-6-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide;

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) methyl) piperidin-1-yl) methyl) tetrahydro-2H-pyran-4-ol;

4- ((4- (((4- (((1R, 3R) -3-hydroxycyclopentyl) oxy) benzo [ d ] isoxazol-3-yl) oxy) methyl) piperidin-1-yl) methyl) tetrahydro-2H-pyran-4-ol;

4- ((4- (((4- (((1S, 2R) -2-methoxycyclopentyl) oxy) benzo [ d ] isoxazol-3-yl) oxy) methyl) piperidin-1-yl) methyl) tetrahydro-2H-pyran-4-ol;

4- ((4- (((4- (((1S, 2R) -2-hydroxycyclopentyl) oxy) benzo [ d ] isoxazol-3-yl) oxy) methyl) piperidin-1-yl) methyl) tetrahydro-2H-pyran-4-ol;

4- ((4- (((4- (((1R, 2R) -2-methoxycyclopentyl) oxy) benzo [ d ] isoxazol-3-yl) oxy) methyl) piperidin-1-yl) methyl) tetrahydro-2H-pyran-4-ol;

4- ((4- (((4- (((1R, 2R) -2-hydroxycyclopentyl) oxy) benzo [ d ] isoxazol-3-yl) oxy) methyl) 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-yl) -1-isopropyl-1H-indazole-3-carboxamide;

n- (cis-6- (2-hydroxy-2-methylpropyl) piperidin-3-yl) -1-isopropyl-1H-indazole-3-carboxamide;

1-cyclobutyl-N- (cis-6- [ (4-hydroxytetrahydro-2H-pyran-4-yl) methyl ] piperidin-3-yl) -1H-indazole-3-carboxamide;

n- ((3S, 5S) -5- (2-hydroxy-2-methylpropyl) pyrrolidin-3-yl) -1-isopropyl-1H-indazole-3-carboxamide;

5-fluoro-N- ((3S, 5S) -5- (2-hydroxy-2-methylpropyl) pyrrolidin-3-yl) -1-isopropyl-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) methyl) -2, 3-dihydrobenzofuran-7-carboxamide;

4-amino-5-chloro-N- ((1- ((4-hydroxytetrahydro-2H-pyran-4-yl) methyl) piperidin-4-yl) methyl) -2, 3-dihydrobenzofuran-7-carboxamide;

4-amino-5-chloro-N- ((1- ((1, 4-dihydroxycyclohexyl) methyl) piperidin-4-yl) methyl) -2-ethoxybenzamide;

4-amino-5-chloro-2-ethoxy-N- ((1- ((4-hydroxytetrahydro-2H-pyran-4-yl) methyl) piperidin-4-yl) methyl) benzamide;

4-amino-5-chloro-N- ((1- ((1, 4-dihydroxycyclohexyl) methyl) piperidin-4-yl) methyl) -2-methoxybenzamide;

4-amino-5-chloro-N- ((1- ((4-hydroxytetrahydro-2H-pyran-4-yl) methyl) piperidin-4-yl) methyl) -2-methoxybenzamide;

5-amino-6-bromo-N- ((1- ((tetrahydro-2H-pyran-4-yl) methyl) piperidin-4-yl) methyl) chroman-8-carboxamide;

4-amino-5-chloro-N- ((1- ((tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methyl) benzofuran-7-carboxamide;

8-amino-7-chloro-N- ((1- ((tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methyl) -2, 3-dihydrobenzo [ b ] [1, 4] dioxine-5-carboxamide;

(S) -5-amino-6-chloro-N- ((1- ((tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methyl) chroman-8-carboxamide;

(S) -4-amino-5-chloro-2-methoxy-N- ((1- ((tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methyl) benzamide;

(R) -4-amino-5-chloro-2-methoxy-N- ((1- ((tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methyl) benzamide;

(S) -4-amino-5-chloro-N- ((1- ((tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methyl) benzofuran-7-carboxamide;

(R) -4-amino-5-chloro-N- ((1- ((tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methyl) benzofuran-7-carboxamide;

(S) -5-amino-6-chloro-N- ((1- ((tetrahydrofuran-3-yl) methyl) piperidin-4-yl) methyl) chroman-8-carboxamide;

(R) -5-amino-6-chloro-N- ((1- ((tetrahydrofuran-3-yl) methyl) piperidin-4-yl) methyl) chroman-8-carboxamide;

(S) -8-amino-7-chloro-N- ((1- ((tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methyl) -2, 3-dihydrobenzo [ b ] [1, 4] dioxine-5-carboxamide;

(R) -8-amino-7-chloro-N- ((1- ((tetrahydrofuran-2-yl) methyl) piperidin-4-yl) methyl) -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) methyl) benzofuran-7-carboxamide,

Or a pharmaceutically acceptable salt thereof;

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

[7] a pharmaceutical composition for treating dementia, comprising a therapeutically effective amount of a compound of formula (I) in [1], or a pharmaceutically acceptable salt thereof;

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

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

[10] [9] wherein the method further comprises administering a therapeutically effective amount of one or more other compounds known to be useful in the treatment or prevention of dementia;

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

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

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

Effects of the invention

It has now surprisingly been found that the compounds of the invention having a strong affinity for the 5-HT4 receptor are useful in the treatment of dementia.

That is, the present inventors confirmed that the above-mentioned compounds of the present invention have ideal properties as a drug for treating AD based on the above-mentioned mechanism 1) by a rat neosome recognition test and a rat tyramine-induced spontaneous change model. Furthermore, based on the above mechanism 2), it was confirmed that the compound of the present invention has desirable properties as a drug for treating AD in Tg2576 mice using a quantitative Abeta-peptide.

Thus, the compounds of the present invention are useful in the treatment of dementia.

Drawings

FIG. 1 is a graph showing the improvement in the discrimination index of a new object identification test.

Fig. 2 is a graph showing recovery of spontaneous change.

FIG. 3 is a graph showing the reduction of Abeta (Abeta 1-40 (left side) or 1-42 (right side)) in Tg2576 mice.

Fig. 4 is a graph showing the ACh concentration (N = 6) in rat hippocampus.

Detailed Description

The compounds of the present invention for the treatment of dementia are of the following formula (I) or a pharmaceutically acceptable salt thereof:

{ chemical formula 19}

In the above-mentioned formula, the compound of formula,

the substituent alpha¹Independently selected from hydroxyl, halogen and amino;

a represents an alkylene group having 1 to 4 carbon atoms;

b represents a covalent bond or an alkylene group having 1 to 5 carbon atoms;

R²selected from the group consisting of trifluoromethyl, isopropyl and C₄-C₆Cycloalkyl groups; wherein, the C₄-C₆Cycloalkyl is unsubstituted or independently selected from the group consisting of hydroxy, oxo, and C₁-C₄Alkoxy and hydroxy-C₁-C₄Alkyl radicalSubstituted with a substituent of the group;

x represents-O-, -S-, -NH-or-CH₂-；

n represents 0 or 1;

m represents 0 or 1;

r independently represents

(i) Oxo, hydroxy, amino, alkylamino, carboxy or tetrazolyl;

(ii) cycloalkyl having 3 to 8 carbon atoms, said cycloalkyl being independently selected from 1 to 5 substituents α²Substituted by substituents of the group consisting of, or

p represents 1, 2 or 3.

The compounds of the present invention include solvates, hydrates, complexes, polymorphs, prodrugs, isomers and isotopically labeled compounds.

Furthermore, the present invention provides a pharmaceutical composition for the treatment of dementia in an animal subject including a mammalian subject, said treatment comprising administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Further, the present invention relates to a pharmaceutical composition for treating dementia, comprising a therapeutically effective amount of the quinolone carboxylic acid compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Furthermore, the present invention provides a method for treating dementia in an animal subject including a mammalian subject, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject in need of treatment. Further, the present invention provides a method for treating dementia in an animal subject including a mammalian subject, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the animal subject including the mammalian subject. Furthermore, the present invention provides the use of a compound of 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.

The term "animal subject" as used herein includes mammalian subjects or non-mammalian subjects. Examples of suitable mammalian subjects may include, but are not limited to: humans, rodents, pets, livestock and primates. Suitable rodents may include, but are not limited to: mouse, rat, hamster, gerbil, and guinea pig. Suitable pets may include, but are not limited to: cats, dogs, rabbits, and ferrets. Suitable livestock may include, but are not limited to: horses, goats, sheep, pigs, cattle, llamas, and alpacas. Suitable primates can include, but are not limited to: chimpanzee, lemur, macaque, marmoset, spider ape, squirrel monkey and ape. Examples of suitable non-mammalian subjects may include, but are not limited to: birds, reptiles, amphibians, and fish. Non-limiting examples of birds include chickens, turkeys, ducks, and geese.

The term "dementia" includes: AD and other types of dementia associated with increased Abeta-peptide in the brain and/or depletion of ACh levels, such as vascular dementia, dementia associated with neurodegenerative diseases, dementia associated with parkinson's disease, frontotemporal dementia, pick syndrome, dementia associated with diffuse lewy bodies, dementia associated with traumatic brain injury or ischemic hypoxic injury, dementia associated with depression or schizophrenia, dementia associated with huntington, dementia associated with HIV. The term "dementia" also includes clinical symptoms associated with an increase in the Abeta-peptide in the brain and/or depletion of ACh levels in the above-mentioned diseases, such as cognitive dysfunction, memory loss and behavioral transitions.

The term "heterocyclyl" as used herein with "Het" refers to heterocyclyl groups having 1 nitrogen atom and 4 to 7 carbon atoms, e.g. is

{ chemical formula 20}

And

the term "alkylene" as used herein in "A" refers to a straight or branched chain saturated group having 1 to 4 carbon atoms, including, but not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, and the like. The "alkylene group" in "A" is preferably a methylene group, an ethylene group or a propylene group, more preferably a methylene group or an ethylene group, and most preferably a methylene group.

The term "alkylene" as used herein in "B" means a straight or branched chain saturated group having 1 to 5 carbon atoms, and includes methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, isopentylene, sec-pentylene, tert-pentylene, and the like, but is not limited thereto. The "alkylene group" in "B" is preferably an alkylene group having 1 to 4 carbon atoms, more preferably an alkylene group having 1 to 3 carbon atoms, further preferably a methylene group or an ethylene group, and further preferably a methylene group.

The term "alkyl" as used herein for "alkylamino" in "R"; "substituent group alpha²"a" hydroxy-substituted alkyl group "and" an "alkyl group" of an "alkoxy group having 1 to 4 carbon atoms"; the "alkyl group" in the "substituent β"; the "alkyl group" of the "hydroxy-substituted alkyl group" and the "amino-substituted alkyl group" in the "substituent β" means a straight-chain or branched saturated group having 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like, but is not limited thereto.

The term "cycloalkyl" as used herein in "R" refers to cycloalkyl groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The term "heterocyclyl" as used herein in "R" denotes a heterocyclic ring having 1 or more heteroatoms, preferably 2 to 6 carbon atoms and 1 to 3 heteroatoms, within the ring, and includes aziridinyl, azetidinyl, piperidinyl, morpholinyl (including morpholino), pyrrolidinyl, pyrazolidinyl, piperazinyl, tetrahydropyrazolyl, pyrazolinyl, tetrahydropyranyl and the like.

The term "treating" as used herein refers to reversing, alleviating, inhibiting or preventing the onset or development of a disease or disorder to which the term is applied or reversing, alleviating, inhibiting or preventing one or more symptoms of the disease or disorder. As defined above for treatment (treating), the term "treatment" as used herein refers to the act of treating (treating).

The substituent "R" may be bonded to the carbon atom connecting the "B group" and the "R group", for example, of the formula:

{ chemical formula 21}

Preferred, more preferred or most preferred compounds of formula (I) have the following respective substituents:

het is preferably selected from

{ chemical formula 22}

And

het is more preferably of the formula

{ chemical formula 23}

Said group being unsubstituted or substituted by 1 substituent independently selected from the group consisting of¹Substituted with a substituent of the group;

the substituent alpha¹Preferably independently selected from hydroxyl and halogen atoms; the substituent alpha¹More preferably independently selected from hydroxyl;

a represents an alkylene group having 1 to 2 carbon atoms; more preferably, a represents methylene;

b represents an alkylene group having 1 to 5 carbon atoms; b more preferably represents an alkylene group having 1 to 2 carbon atoms; b most preferably represents methylene;

ar is preferably

{ chemical formula 24}

R^1aRepresents an isopropyl group, an n-propyl group or a cyclopentyl group,

R^2arepresents a methyl group, a fluorine atom or a chlorine atom;

{ chemical formula 25}

R^1bRepresents an alkyl group having 1 to 4 carbon atoms or a halogen atom,

R^2brepresents an alkyl group having 1 to 4 carbon atoms;

{ chemical formula 26}

R^2cselected from the group consisting of trifluoromethyl, isopropyl and C₄-C₆Cycloalkyl groups; wherein, theC₄-C₆Cycloalkyl is unsubstituted or independently selected from the group consisting of hydroxy, oxo, and C₁-C₄Alkoxy and hydroxy-C₁-C₄Alkyl groups;

{ chemical formula 27}

R^1dIs a hydrogen atom, a halogen atom or C₁-C₆An alkyl group;

R^2dis C₁-C₆Alkyl or C₃-C₆A cycloalkyl group;

{ chemical formula 28}

R^1eRepresents isopropyl or cyclopentyl;

{ chemical formula 29}

R^1fRepresents a hydrogen atom, a halogen atom or C₁-C₄An alkyl group;

{ chemical formula 30}

R^2grepresents a hydrogen atom or a halogen atom;

{ chemical formula 31}

R^1hIs represented by C₁-C₄An alkyl group;

R^2hrepresents a hydrogen atom or a halogen atom;

q represents 1 or 2;

{ chemical formula 32}

{ chemical formula 33}

R¹ⁱIs represented by C₁-C₄An alkyl group;

R²ⁱrepresents a hydrogen atom or a halogen atom;

r represents 1 or 2;

{ chemical formula 34}

R^1jIs represented by C₁-C₄An alkyl group;

R^2jrepresents a hydrogen atom or a halogen atom; or

{ chemical formula 35}

When Ar represents

{ chemical formula 36}

When X preferably represents-O-;

when Ar represents

{ chemical formula 37}

When n represents 1;

m preferably represents 0 or 1; when Ar represents

{ chemical formula 38}

When m most preferably represents 0;

r preferably independently represents

(i) Hydroxy, amino, alkylamino, or carboxy;

(ii) a cycloalkyl group having 4 to 7 carbon atoms, the cycloalkyl group being substituted with 1 to 3 substituents independently selected from the group consisting of substituents α 2, or

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

the substituent alpha²Preferably independently selected from the group consisting of hydroxy, carboxy, alkoxy having 1 to 4 carbon atoms, and tetrazolyl; the substituent alpha²More preferably independently selected from hydroxy, carboxy and tetrazolyl;

the substituent beta is preferably independently selected from hydroxyl, carboxyl, alkyl with 1-4 carbon atoms, carbamoyl and tetrazolyl; the substituent beta is more preferably selected from the group consisting of a hydroxyl group, a carboxyl group, an alkyl group having 1 to 4 carbon atoms and a tetrazolyl group;

p preferably represents 1;

r more preferably independently represents

(i) A hydroxyl group;

(ii) cycloalkyl having 4 to 6 carbon atoms, said cycloalkyl being independently selected by 1 to 2 substituents α²Substituted with a substituent of the group; or

(iii) A heterocyclic group having 5 to 6 atoms, said heterocyclic group being unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of substituents β;

the substituent alpha²Independently selected from hydroxy, amino and tetrazolyl,

the substituent beta is independently selected from hydroxyl, alkyl with 1-4 carbon atoms and tetrazolyl;

p preferably represents 1;

most preferably, R independently represents 1, 4-dihydroxycyclohexyl, hydroxycyclopentyl, hydroxytetrahydropyranyl, tetrazolyltetrahydropyranyl, tetrazolylcyclopentyl, piperidinyl or morpholinyl.

The most preferred compounds are as follows:

Or a pharmaceutically acceptable salt thereof.

Several compounds of the invention have asymmetric centers. Thus, the compounds of the present invention can exist not only in isolated (+) -and (-) -optically active forms, but also in their racemic forms. All of these forms are included within the scope of the present invention. The individual isomers can be obtained by well-known methods, for example, separation by a photo-selective reaction or chromatography in the preparation of the final product or an intermediate thereof.

The present invention also includes isotopically-labeled compounds, which are identical to those recited in formula (I), except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as,²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸f and³⁶and (4) Cl. Compounds of the present invention, prodrugs thereof, pharmaceutically acceptable esters of said compounds, and pharmaceutically acceptable salts of said compounds, said esters, or said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are also within the scope of the present invention. The specific isotopically-labeled compounds of the present invention (e.g., incorporating, for example³H and¹⁴those of radioactive isotopes such as C) in pharmaceuticalsUseful in substance and/or substrate tissue distribution analysis. Tritiated hydrogen (i.e.,³H) isotopes and carbon-14 (i.e.,¹⁴C) isotopes are particularly preferred for their ease of presentation and detection. Further, the metal oxide is removed from the metal oxide layer with, for example, deuterium (i.e.,²H) such heavier isotopic substitutions may provide therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. Isotopically labeled compounds of formula (I) and prodrugs thereof of the present invention can generally be prepared by carrying out the procedures described in the reaction schemes described above and/or in the examples and preparations below and by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

The invention includes the salt forms of the compounds of formula (I) obtained.

Certain compounds of the present invention are capable of forming pharmaceutically acceptable, non-toxic cations. Pharmaceutically acceptable non-toxic cations of compounds of formula (I) can be prepared by conventional techniques, for example by contacting the compounds with stoichiometric amounts of the appropriate alkali or alkaline earth metal (sodium, potassium, calcium and magnesium) hydroxides or alkoxides in water or an appropriate organic solvent, i.e. ethanol, propanol, mixtures thereof and the like.

The bases of the pharmaceutically acceptable base addition salts useful for preparing the acidic compounds of formula (I) of the present invention are those salts which form non-toxic base addition salts, i.e., salts containing pharmaceutically acceptable cations, such as adenine, arginine, cytosine, lysine, benethamine (i.e., N-benzyl-2-phenylethylamine), benzathine (i.e., N-dibenzylethylenediamine), choline, diethanolamine (i.e., diethanolamine), ethylenediamine, glucosamine, glycine, guanidine, guanine, meglumine (i.e., N-methylglucamine), nicotinamide, alkylolamines (i.e., ethanolamine), ornithine, procaine, proline, pyridoxine, serine, tyrosine, valine, and tromethamine (i.e., tri or tri (hydroxymethyl) aminomethane). Base addition salts may be prepared by conventional procedures.

Only in the case of the specific compounds of the invention being basic compounds are various inorganic and organic acids and a wide variety of different salts formed.

The acids used for the preparation of the pharmaceutically acceptable acid addition salts of the basic compounds of the invention of formula (I) are those which form non-toxic acid addition salts, i.e. salts comprising pharmaceutically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, malate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, adipate, aspartate, d-camphorsulfonic acid, ethanedisulfonate (i.e. 1, 2-ethanedisulfonate), dodecylsulfate (estolate) (i.e. lauryl sulfate), glucoheptonate (gluceptate) (i.e., glucoheptonate (glucoheptonate)), gluconate, 3-hydroxy-2-naphthoate, xinonovoate (i.e., 1-hydroxy-2-naphthoate), isethionate (i.e., 2-hydroxyethanesulfonate), galactarate (mucate) (i.e., galactarate), 2-naphsylate (i.e., naphthalenesulfonate), stearate, cholate, glucuronate, glutamate, hippurate, lactobionate, lysine, maleate, mandelate, napadisylate, nicotinate, polygalacturonate, salicylate, sulfosalicylic acid, tannate, tryptophan, borate, carbonate, oleate, phthalate, and pamoate (i.e., 1.1' -methylene-bis- (2-hydroxy-3-naphthoate). Acid addition salts may be prepared by conventional procedures.

For a suitable salt reference [ Berge et al, j. pharm. sci., 66, 1-19, 1977 ].

Also included within the scope of the present invention are the biological precursors (also referred to as "prodrugs") of the compounds of formula (I). The biological precursors of the compounds of formula (I) are chemical derivatives thereof which are readily convertible in a biological system back to the parent compound of formula (I). In particular, the biological precursor of the compound of formula (I) changes back to the parent compound of formula (I) after the biological precursor has been administered to and absorbed by an animal subject (e.g., a human subject), including a mammalian subject. For example, a biological precursor of a compound of formula (I) containing a hydroxyl group can be prepared by preparing an ester of the hydroxyl group. When the compound of formula (I) contains 1 hydroxyl group, only a monoester can be prepared. When the compound of formula (I) contains 2 hydroxyl groups, monoesters and diesters (which may be the same or different) may be prepared. When the compound of formula (I) contains 1 or 2 carboxyl groups, monoesters and diesters (which may be the same or different) may be prepared. Typical esters are simple alkanoates such as acetates, propionates, butyrates, and the like. In addition, when the compound of formula (I) contains a hydroxyl group, the bioprecursor can be prepared by reacting with an acyl halide (e.g., pivaloyl chloride) to change the hydroxyl group to an acyloxy derivative (e.g., pivaloyloxy derivative).

Other typical prodrugs known to those skilled in the art include formulations of phosphates, amides, esters, thioesters, carbonates and carbamates. Further information on the use of prodrugs can be found in the literature [ Pro-drugs as Noveldelivery Systems, Vol.14, ACS Symposium Series (T Higuchi and W Stella) ] and in the literature [ Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed.E B Roche, American pharmaceutical Association) ].

When the compound of formula (I) of the present invention may form solvates such as hydrates, these solvates are included in the scope of the present invention.

For the treatment or prevention of dementia, suitable dosage levels of the compounds of the invention are from about 0.1 mg/day to 400 mg/day, preferably from about 0.5 mg/day to 40 mg/day, more preferably from about 1 mg/day to 10 mg/day of the active compound. The compounds may be administered on a regimen of 1 to 4 times per day. However, in some cases, dosages outside of these limits may also be used.

The compounds of the present invention may be administered by any of the previously described routes, alone or in combination with a pharmaceutically acceptable carrier or diluent, and such administration may be in a single dose or in multiple doses. More specifically, the novel therapeutic agents of the present invention can be administered in a wide variety of different dosage forms, i.e., the novel therapeutic agents of the present invention can be combined with various pharmaceutically acceptable inert carriers to form tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents and the like. Furthermore, oral pharmaceutical compositions may be suitably sweetened and/or flavored. In general, the therapeutically effective compounds of the present invention are present in these dosage forms at a concentration level of 5% to 70% by weight, preferably at a concentration level of 10% to 50% by weight.

For oral administration, tablets containing various excipients, such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium hydrogen phosphate and glycine, may be used with various disintegrants, such as starch (preferably corn, potato or tapioca starch), alginic acid and certain silicate complexes, and granulation binders, such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often very useful for tableting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules, preferred materials in this connection also including lactose or milk sugar, and high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, emulsifying and/or suspending agents, if desired, and diluents such as water, ethanol, propylene glycol, glycerin, and the like, and various like combinations thereof.

For parenteral administration, solutions of the compounds of the invention in sesame or peanut oil or in aqueous propylene glycol may be used. The aqueous solution should be suitably buffered (preferably pH > 8) if necessary, and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques known to those skilled in the art. Furthermore, the compounds of the present invention may also be administered topically when treating skin inflammation according to standard pharmaceutical practice and are preferably administered topically by way of creams, gels, pastes, ointments and the like.

These compounds as 5-HT4 receptor agonists are disclosed in WO2005049608, WO2005073222, WO2006090224, WO2007010390, WO2006/090279, WO2005021539, WO2007048623, WO2007068739 and WO 2007096352. However, no examples are disclosed in these documents for the treatment of dementia.

Further, the present invention provides a pharmaceutical composition for treating dementia in an animal subject including a mammalian subject, the treatment comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

The present invention also provides a method of treating dementia or preventing or delaying the onset or development of dementia associated with an increase in Abeta in the brain and/or with a depletion in ACh level by administering a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof as defined above to a patient in need of treatment or an animal subject including a mammalian subject.

In another aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for the treatment of dementia or the prevention or delay of onset or progression of dementia.

The use of some drugs is limited to a particular stage of AD. For example, memantine can only be used during the severe phase of AD, whereas the compounds of the invention can be used by patients during all phases of AD (mild, intermediate and severe).

The compounds of formula (I) may be administered in combination with one or more other compounds known to be useful in the treatment or prevention of AD or its symptoms. Thus, such other compounds include cognition enhancing drugs, such as acetylcholinesterase inhibitors (e.g., donepezil and galantamine), NMDA antagonists (e.g., memantine), antihistamines (e.g., dimebon, The Lancet, 372 (2008) 207-]) Or PDE4 inhibitors (e.g. Ariflo)^TMAnd the compounds disclosed in WO03/018579, WO01/46151, WO02/074726 and WO 02/098878). These other compounds also include cholesterol lowering agents such as statins, for example simvastatin. These other compounds also include compounds known to alter the production or processing of Abeta in the brain ("amyloid modifying genes"), such as compounds that inhibit Abeta secretion, including gamma-secretase inhibitors, beta-secretase inhibitors, and GSK-3 alpha inhibitors, compounds that inhibit Abeta aggregation, and antibodies that selectively bind to Abeta. These other compounds also include growth hormone secretagogues, as disclosed in WO 2004/11043.

{ example }

List of compounds:

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 (compound a);

4- ((4- (((4-butoxybenzo [ d ] isoxazol-3-yl) oxy) methyl) piperidin-1-yl) methyl) tetrahydro-2H-pyran-4-ol;

4-amino-5-chloro-N- ((1- ((tetrahydro-2H-pyran-4-yl) methyl) piperidin-4-yl) methyl) benzofuran-7-carboxamide.

Example 1: rat novel object recognition study (reference method: PNAS, 101 (2003)) 853-

Male IGS rats (9 weeks old, Charles River Laboratories Japan, Inc.) were used in this study. Compound a and donepezil hydrochloride (reference substance) were administered orally 60 minutes prior to the training test and 60 minutes prior to the memory test. The number of animals per group was 15. An open box (40 × 40 × 40 cm) with wood chips spread on the bottom was used for this study. For the training trial, the animals were allowed to probe 2 identical objects (a 1 and a 2) for 3 minutes. The object is plastic 'LEGO bricks (LEGO bricks)' with different shapes, colors and sizes. Animal behavior was monitored and recorded using an aerial camera and DVD recorder. After 24 hours after the training test, a memory test was performed. 1 replicate familiar object (A3) and a new object (B) were placed in the same position as the training trial and the animals were allowed to probe for the objects for 3 minutes. Animal behavior was monitored and recorded using an aerial camera and DVD recorder.

Object detection is defined as the nose facing the object at a distance < 1cm and/or touching the object with the nose. The DVD image was analyzed by an observer who had no knowledge of the processing conditions. To evaluate cognitive ability, the time required to detect familiar (TA 3) and novel (TB) objects and the discrimination index (DI; (TB-TA 3)/(TB + TA 3)) were analyzed. The pre-cognitive effect (Pro-cognitive effect) is specified as increased DI and increased TB and/or decreased TA 3. To evaluate the overall level of detection capability, the total time required to detect two objects is analyzed.

For compound a, the discrimination index was analyzed using the barteride assay followed by the dunnit multiple comparison assay. The differential index in the 0.1, 0.3, 1mg/kg compound a-treated group was statistically significant (. < |)0.05, p < 0.01). For donepezil, the discrimination index was analyzed using the F-test followed by student t-test. The discriminatory index in donepezil-treated group had statistical significance compared with the vehicle-treated group: (^#p < 0.05) (see FIG. 1).

In this new object recognition study in rats, compounds listed in the compound list were similarly treated. In all cases an improvement in the discrimination index was observed.

Example 2: spontaneous Change test in rats (reference method: Eur. J. Pharmacol., 236 (1993) 341-345)

Male IGS rats (6 weeks old, Charles River Laboratories Japan, Inc.) were used in this study. After 30 minutes following administration of the test substance or vehicle, a solution of ranolane or saline is administered intraperitoneally. After 30 minutes following injection, rats were placed on the end of one arm towards the end of the arm, and allowed to freely pass through the maze for 8 minutes during the test period. The arm-in sequence was manually recorded. The variation is specified as a continuous selection into all 3 arms. The rate of change (percent alteration) as an index of the spontaneous change ability was calculated as (number of changes/total number of arms moved-2) × 100.

The effect of compound a on the impairment of the ability of the ranolamine-induced spontaneous changes in rats was investigated. The values in the saline-and ranolane-treated groups were 75.2% and 53.9%, respectively, in the rate of change. The rate of change was significantly reduced by the injection of ranolamine (p < 0.01). Compound a at doses of 0.3 and 1mg/kg resulted in a significant increase in the rate of change (p < 0.01) when compared to the vehicle-treated group. Compound a at doses of 0.1 and 3mg/kg showed a tendency to improve without statistical significance (see figure 2).

In this spontaneous change test in rats, compounds described in the compound list were similarly treated. Recovery from spontaneous changes was observed in all cases.

Example 3: abeta reduction in Tg2576 mice (reference method: J. Neurosci 21 (2001) 372-381)

Expression of the protein with Swedish-type mutation (APP) purchased from Taconic farm (catalog # 001349-TF)_SWE) Female Tg2576 mouse of the human Amyloid Precursor Protein (APP) gene.

Tg2576 mice (31 weeks old early in the experiment) were dosed orally for 3 weeks with 2 times per day (BID) of 0.1, 1 or 10mg/kg of compound a in a medium consisting of 0.5% methylcellulose and 0.1% Tween 80. After 3 hours after the last dose, the mice were euthanized. Brain tissue was collected and homogenized in 5-volume of ice-cold TBS buffer (50 mM Tris-HCl) containing 1% CHAPS and protease inhibitor. The homogenate was centrifuged at 14,000 g and 4 ℃ for 10 minutes and the supernatant was collected as a soluble pool for Abeta. The pellet was dissolved in an initial volume of 5M guanidine in TBS buffer and the resulting homogenate was collected as an insoluble pool of Abeta. Abeta1-40 and Abeta1-42 were quantified using a commercially available ELISA kit according to the manufacturer's instructions. The measurement was performed 2 times. The final value of Abeta in the brain is expressed in nanograms per gram of wet brain weight. Total Abeta levels were obtained by adding the values for soluble and insoluble Abeta levels.

The results are summarized in fig. 3. By administering compound a at doses of 1 and 10mg/kg BID for 3 weeks, the total level of Abeta1-40 in the brain in Tg2576 mice was significantly reduced, and also dose-dependently and substantially reduced the total level of Abeta1-42 in the brain.

In Tg2576 mice, compounds described in the compound list were treated similarly in terms of this Abeta reduction. In all cases a decrease in Abeta was observed.

Example 4: increase in hippocampal ACh release in rats

The effect of compound a on ACh levels in the hippocampus (Hip) of rats was tested in male Wistar rats using microdialysis. One day prior to the start of the experiment, anesthetized rats had a guide cannula implanted in the dorsal Hip. After 1 day after the operation, the dialysis probe was inserted into the Hip via the guide cannula and perfusedContaining 148mM NaCl, 2.7mM KCl, 1.2mM CaCl₂、0.85mM MgCl₂And artificial cerebrospinal fluid (aCSF) of 100nM physostigmine. After a 1h equilibration period, sample collection was started. The effluent fractions were collected every 20 minutes. After collection of 6 stable baseline fractions, the perfusate was replaced with aCSF containing 100nM physostigmine and Compound A for 120 min, followed by a further aCSF containing 100nM physostigmine alone. Next, the dialysis fractions were analyzed by high performance liquid chromatography with an electrochemical detection system. Isopropyl homocholine (homocholine) was used as internal standard. The amount of ACh in each dialysate sample was calculated from the peak height ratio of ACh/IPHC. ACh content was expressed as a percentage of a reference value calculated from the average of 3 samples before drug infusion.

The results are summarized in fig. 4. ACh concentration was increased to 187% by direct injection of compound a into rat Hip.

This ACh microdialysis study was carried out analogously for the compounds described in the compound list. An increase in ACh levels was observed in all cases.

(the symbols in FIGS. 1 to 4 show)

(FIG. 1)

The discrimination index is defined as the difference in the detection time of the object divided by the total detection time.

A compound A: the differential index was analyzed using the bartlett test followed by the dunnit multiple comparison test (p < 0.05, p < 0.01 relative to the media).

For Donepezil (DPZ), the discrimination index was analyzed using the F-test, followed by student's t-test (relative to vehicle,^#p＜0.05）。

(FIG. 2)

N =15, mean ± s.e.m

⁺⁺p is less than 0.01; relative to normal control group (student)t-test)

P < 0.01; relative to a Canuoamine control group (Dennit test)

No significant change in total arm was observed between treatment groups.

(FIG. 3)

Medium, 1 and 10mg/kg arm (N = 10), 0.1mg/kg arm (N = 9), mean ± s.e.m

P < 0.05; one-way analysis of variance, followed by post-Dennit analysis

(FIG. 4)

ACh content was expressed as a percentage of the baseline value calculated from the average of 3 samples prior to drug infusion.

Industrial applicability

According to the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof is useful in the treatment of dementia.

The entire contents of each of all publications (including, but not limited to, issued patents, patent applications, and journal articles) cited in this application are hereby incorporated by reference. Although the present invention has been described with reference to the disclosed embodiments, it is understood by those skilled in the art that the specific experimental details are merely illustrative of the invention. It will be understood that various changes may be made without departing from the spirit of the invention. Accordingly, the invention is to be limited only by the following claims.

Claims

1. Use of a compound of 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:

in the above-mentioned formula, the compound of formula,

het represents a hetero atom having 1 nitrogen atom and 4 to 7 carbon atoms, to which B is directly bondedA cyclic group, said cyclic group being unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of¹Substituted with a substituent of the group;

the substituent alpha¹Independently selected from hydroxyl, halogen and amino;

a represents an alkylene group having 1 to 4 carbon atoms;

b represents a covalent bond or an alkylene group having 1 to 5 carbon atoms;

x represents-O-, -S-, -NH-or-CH₂-；

n represents 0 or 1;

m represents 0 or 1;

r independently represents

(i) Oxo, hydroxy, amino, alkylamino, carboxy or tetrazolyl;

the substituent alpha²Independently selected from hydroxy, amino,A hydroxy-substituted alkyl group having 1 to 4 carbon atoms, a carboxyl group, an alkoxy group having 1 to 4 carbon atoms, and a tetrazolyl group;

p represents 1, 2 or 3.

2. The use according to claim 1, wherein,

het represents selected from

And

the substituent alpha¹Independently selected from hydroxyl and halogen atoms;

a represents an alkylene group having 1 to 2 carbon atoms;

b represents an alkylene group having 1 to 5 carbon atoms;

ar represents

R^1aRepresents an isopropyl group, an n-propyl group or a cyclopentyl group,

R^2arepresents a methyl group, a fluorine atom or a chlorine atom;

R^1brepresents an alkyl group having 1 to 4 carbon atoms or a halogen atom,

R^2brepresents an alkyl group having 1 to 4 carbon atoms;

R^1dis a hydrogen atom, a halogen atom or C₁-C₆An alkyl group;

R^2dis C₁-C₆Alkyl or C₃-C₆A cycloalkyl group;

R^1erepresents isopropyl or cyclopentyl;

R^1frepresents a hydrogen atom, a halogen atom or C₁-C₄An alkyl group;

R^2grepresents a hydrogen atom or a halogen atom;

R^1his represented by C₁-C₄An alkyl group;

R^2hrepresents a hydrogen atom or a halogen atom;

q represents 1 or 2;

R¹ⁱis represented by C₁-C₄An alkyl group;

R²ⁱrepresents a hydrogen atom or a halogen atom;

r represents 1 or 2;

R^1jis represented by C₁-C₄An alkyl group;

R^2jrepresents a hydrogen atom or a halogen atom; or

When Ar represents

When, X represents-O-;

when Ar represents

When n represents 1;

m represents 0 or 1;

r independently represents

(i) Hydroxy, amino, alkylamino, or carboxy;

(ii) cycloalkyl having 4 to 7 carbon atoms, said cycloalkyl being independently selected from 1 to 3 substituents α²Substituted with a substituent of the group; or

the substituent alpha²Independently selected from the group consisting of hydroxy, carboxy, alkoxy having 1 to 4 carbon atoms, and tetrazolyl;

p represents 1.

3. The use according to claim 2, wherein,

het represents the formula

The group of (a) or (b),

said group being unsubstituted or substituted by 1 substituent selected from the group consisting of¹Substituted with a substituent of the group;

the substituent alpha¹Independently selected from hydroxyl;

a represents a methylene group;

b represents a methylene group;

when Ar represents

When m represents 0;

r independently represents

(i) A hydroxyl group;

p represents 1.

4. The use according to claim 3, wherein,

r independently represents 1, 4-dihydroxycyclohexyl, hydroxycyclopentyl, hydroxytetrahydropyranyl, tetrazolyltetrahydropyranyl, tetrazolylcyclopentyl, piperidinyl or morpholinyl.

5. Use according to claim 1, wherein the compound of formula (I) is selected from the following:

Or a pharmaceutically acceptable salt thereof.

6. The use according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with one or more other compounds known to be useful in the treatment or prevention of dementia or a symptom thereof.

7. A pharmaceutical composition for treating dementia, comprising a therapeutically effective amount of the compound of formula (I) of claim 1 or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition further comprises a therapeutically effective amount of one or more other compounds known to be useful in the treatment or prevention of dementia or a symptom thereof.

9. A method for treating dementia in an animal subject including a mammalian subject, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 to the animal subject including the mammalian subject.

10. The method of claim 9, wherein the method 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 treating dementia, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 to an animal subject including a mammalian subject in need of treatment.

12. The method of claim 11, wherein the method further comprises administering a therapeutically effective amount of one or more additional compounds known to be useful in the treatment or prevention of dementia.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 for use in the treatment of dementia in an animal subject, including a mammalian subject.