JP2002145840A - N-arylhydrazing compound and its medicinal use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an effective treating agent and preventing agent for dementia, especially for Alzheimer type dementia by its amyloid β-coagulation- suppressing activity. SOLUTION: This N-arylhydrazide compound is compound expressed by the general formula (I) or its pharmaceutically permissible salt, and the dementia-treating and preventing agent containing the above compound are provided. As a concrete example of the general formula (I), the following compound (II) is cited.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to novel N-arylhydrazide compounds having an inhibitory effect on amyloid β protein, and pharmaceutical compositions containing these N-arylhydrazide compounds which are useful as anti-dementia drugs.

[0002]

2. Description of the Related Art In the old age, the brain degenerates and shrinks, so that intellectual functions such as judgment, understanding, memory and calculation are reduced. This is what is commonly called dementia. Dementia can be classified into “cerebrovascular dementia” and “Alzheimer-type dementia” based on its state. "Cerebrovascular dementia" is caused by cerebral arteriosclerosis or cerebral blood flow disorder, which makes it impossible to supply nutrients and oxygen to the brain tissue sufficiently, and may occur as a sequela of stroke. Many. On the other hand, “Alzheimer-type dementia” is caused by atrophy of nerve cells and loss of cell tissue in the cerebral cortex. There is also. At present, therapeutic agents for Alzheimer's dementia include tetrahydroaminoacridine hydrochloride (1, 1).
2,3,4-tetrahydro-9-acridinamine hydrochloride), donepezil hydrochloride (2-[(1-benzylpiperidin-4-yl) methyl] -5,6-dimethoxyindan-1-one hydrochloride) and the like. Drugs are known, and all have a main effect of activating the acetylcholine nervous system. Therefore, in the progressive disease seen in Alzheimer-type dementia, a therapeutic agent for a mechanism having a mechanism different from existing anti-dementia agents, for example, a therapeutic agent for suppressing nerve death is expected. Histologically, Alzheimer's dementia is
Characteristic features include loss of nerve cells, changes in neurofibrillary tangles, and senile plaques. This senile plaque is formed by deposition of amyloid protein in the brain. Amyloidosis is a process in which a specific amyloid protein is polymerized as an insoluble fiber in the extracellular space and deposits to cause structural and functional damage to organs and tissues. The main diseases caused by amyloid accumulation in the cerebral parenchyma and blood vessel wall include Alzheimer's disease (AD), Down's syndrome, dementia of sword fighters, cerebral amyloid vasculopathy and the like.

[0003] The types of amyloidosis are roughly classified into systemic amyloidosis and localized amyloidosis, and are also classified according to the amyloid that causes the amyloidosis. At present, at least 15 different types of amyloid proteins have been reported, and it is considered that their onset mechanisms and biochemical roles are also different. Among them, amyloid β is Alzheimer's dementia, Down syndrome, cerebrovascular amyloidosis,
Amyloid protein found in the brain of patients with hereditary amyloid cerebral hemorrhage (especially Dutch type) and is considered to be one of the causes of these diseases (Yamaguchiigaku, 44 (6), 319)
-327, 1995). In particular, the deposition of amyloid β in the brain is a pathological finding that is the earliest confirmed in the brain of Alzheimer-type dementia. As a mechanism of the onset of amyloidosis related to this amyloid β, the amyloid β precursor protein whose production has increased or which has increased due to the decrease in excretion / decomposition becomes amyloid β through processing or proteolysis,
It is believed that the amyloid β then aggregates or polymerizes. This is thought to cause extracellular amyloid fibrils to act toxic to nerve cells or cause deposition in the brain, resulting in cell dysfunction (Science, 2
50, 279-282, 1990; PNAS, 88, 7247-7251, 1991). It has also been suggested that amyloid β may induce neuronal death (NeuroReport, 4, 523, 1993). Therefore, it is considered that reducing the harmful effects of amyloid β on the human body, in particular, suppressing the aggregation of amyloid β is effective for treating and preventing diseases related to amyloid β.

It has also been reported that aggregated amyloid β protein generates radicals, and these radicals cause further damage and destruction of various nerve cells (Brain Research Bulletin, 50 (2), 133-141, 1999).
Excessive generation of reactive oxygen species, such as oxygen anion radicals, peroxide ions, and hydroxyl radicals, in vivo promotes the peroxidation of unsaturated fatty acids that form phospholipids in biological membranes, forming lipid peroxides. Can be This lipid peroxide also generates alkoxy radicals and hydroxyl radicals, damaging biological membranes and inactivating enzymes. Diseases caused by such excessive generation of radicals or accumulation of lipid peroxide in the body include brain diseases (eg, cerebrovascular, hippocampus), cardiovascular diseases (eg, arteries), and gastrointestinal diseases (eg, gastrointestinal tract, liver). , Pancreas), respiratory diseases (eg, lungs, bronchi), urinary diseases (eg, kidneys), skin diseases, eye diseases, ear diseases, neurological diseases, etc., and are found in various places in a living body. Specifically, ischemic brain disease, ischemic heart disease, ischemic liver disease, arteriosclerosis, hyperlipidemia, stroke, cerebral edema, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis Disease, seizures, central nervous injury after stroke, myocardial infarction, ventricular arrhythmia, rheumatoid arthritis, osteoarthritis, Behcet's syndrome, atopic dermatitis, burns, ultraviolet / radiation skin diseases, asthma, emphysema, adults Respiratory distress syndrome, inflammatory bowel disease, uveitis,
Autoimmune disease, infectious disease, retinopathy of prematurity, diabetic retinopathy, cataract, glaucoma, senile macular degeneration, cancer, peripheral neuronal degeneration, peripheral circulatory disorders, Meniere's disease, pain, itching,
It shows symptoms such as diseases due to hemolysis and platelet aggregation.

Therefore, a compound having an inhibitory effect on amyloid β aggregation and also having an antioxidant effect can be greatly expected as an excellent therapeutic agent for Alzheimer-type dementia or a therapeutic agent for various diseases caused by radicals. it can. An object of the present invention is to provide a novel compound having an excellent inhibitory action on amyloid β aggregation, a novel compound having an antioxidant action, or a novel compound having both actions, and another object is to provide such a compound. An object of the present invention is to provide an anti-dementia drug and a drug for treating amyloidosis, which have an excellent action, particularly a drug for treating Alzheimer-type dementia.

Some reports have already been made on the use of hydrazide compounds in medicine. For example, the following compound A, known as indapamide, has already been marketed as a diuretic antihypertensive. Further, Japanese Patent Application Laid-Open No. 7-118231 discloses the cytotoxicity-protecting action of indapamide and its derivatives, and it has been shown that the compound protects against cytotoxicity caused by reactive oxygen species. Hematologic brain diseases are mentioned.

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[0007] WO 91/01979 (Japanese Patent No. 2531304, US Pat. No. 5,250,528) shows an effect of enhancing the cholinergic activity of the following compound B and the like, and amnesia and dementia are mentioned as indications of the compound. ing. Further, WO99 / 01421 discloses the following compound C
And D and the like, and Alzheimer's disease is mentioned as an indication for these compounds.

Embedded image However, although these publications state that the hydrazide compound can be used for central nervous system diseases, none of the publications discloses the compound of the present invention, and does not disclose the action of amyloid protein through the amyloid protein like the compound of the present invention. No description or suggestion is made at all.

Further, Japanese Patent Application Laid-Open No. 58-124765 discloses that
The following compounds E and the like are shown, and hypertension is mentioned as an indication of those compounds. However, the publication does not disclose the compound of the present invention, and although there is a description that the hydrazide compound can be used as a medicament, there is no description about dementia and Alzheimer's disease.

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Further, US Pat. No. 2,808,416 discloses the following compound F and the like, and indicates that they are used as antioxidants for fats and oils. Further, in the chemical abstract (Record No. 97: 222814), the following compound G (CAS registration number 83807-17-4) is shown in the literature relating to the study of IR spectra.

Embedded image However, these publications do not disclose the compound of the present invention,
Furthermore, there is no description about use in medicine.

The following compound J, which has a chemical structure partially similar to the compound of the present invention, is known to have a strong antioxidant action, and is a compound which has been tried to be applied to medicine. However, it cannot be administered to humans due to its teratogenicity.

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[0011]

Means for Solving the Problems The present inventors have found a novel compound having an inhibitory action on amyloid β aggregation, especially a novel compound having both an inhibitory action on amyloid β aggregation and an antioxidant action, and have completed the present invention. The compound of the present invention is a novel compound having an excellent inhibitory action on amyloid β aggregation, particularly a novel compound having both an inhibitory action on amyloid β aggregation and an antioxidant action, and is provided by amyloid β protein such as Alzheimer's disease, Down's syndrome and cerebrovascular amyloidosis. It can be used for the manufacture of a medicament useful for suppressing or stopping the progress of a disease that occurs, particularly Alzheimer's dementia. In addition, the compound of the present invention having an antioxidant effect,
In addition to Alzheimer's dementia, it is useful as an agent for treating and preventing diseases caused by radicals as described above. In addition, some of the compounds of the present invention can cross the blood-brain barrier and are therefore particularly useful for adaptation to central nervous system diseases.
Further, the compound of the present invention having an antioxidant effect is used as a protective agent for stored matter such as blood and organs, a cosmetic for treating and preventing acne and spots, and an antioxidant for oils and fats contained in processed foods. Can also. More specifically, it is as shown in the following (1) to (13).

(1) N- represented by the following general formula [I]
An aryl hydrazide compound or a pharmaceutically acceptable salt thereof.

Embedded image 意味 In the above general formula, the meaning of each symbol is as follows. 1. R ^a , R ^a1 and R ^a2 are the same or different and are (1) a hydrogen atom, and (2) a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from the following group A. , (3) C _1-6 alkoxy group, (4) nitro group, (5)
Halogen atom, (6) amino group, (7) _C1-4 alkylamino group, (8) di ( _C1-4 alkyl) amino group, (9) cyclic amino group, (10) cyano group, (11) Carboxyl group, (12)
C _1-6 alkoxycarbonyl group, (13) aryl group, (1
4) hydroxyl group or (15) mercapto group, wherein group A is (1 ′) halogen atom, (2 ′) nitro group, (3 ′)
Amino group, (4 ′) cyano group, (5 ′) carboxyl group, (6 ′) C
_It means a group consisting of a _1-6 alkoxy group, a (7 ′) C _1-6 alkoxycarbonyl group and an (8 ′) aryl group. ) 2. R ¹ , R ² and R ³ are the same or different and are (1) a hydrogen atom, (2) a C _1-6 alkyl group, or
(3) R ¹ is taken together with ^Ra to form-(CH ₂ ) ₂ -,-(C
_{H 2) 3 -, - CH} = CH -, - CH 2 -CH = CH- or -CH = CH-CH ₂ - to form,

3. R ^b1 and R ^b2 are the same or different and are each (1) a hydrogen atom, (2) an arylalkyl group,
(3) an arylamino group or (4) an arylalkylamino group; R ^c1 and R ^c2 are the same or different,
(1) a hydrogen atom, (2) a C _1-6 alkyl group _optionally substituted with 1 to 3 substituents selected from the above group A,
(3) _{C 1-6} alkoxy group, (4) nitro group, (5) halogen atom, (6) amino, (7) _{C 1-4} alkylamino group, (8) di _{(C 1-4} alkyl) Amino group, (9) cyclic amino group, (10) cyano group, (11) carboxyl group, (12) C
_1-6 alkoxycarbonyl group, (13) aryl group, (14)
Hydroxyl group, or, (15) means mercapto group,

5. R ^c represents (1) a hydrogen atom, or (2)

Embedded image Where X is (1 ′)-NR ^{d1 -where} R
^d1 represents a hydrogen atom or a C _1-6 alkyl group.
^{(2 ') - NR d1 CO-} (R d1 is defined as.), (3') - CONR d1 - (R d1 is as defined above.), (4 ') - O -, ( 5 ')-S-, (6')-CO-,
(7 ′) — CH ₂ — or (8 ′) — (CH ₂ ) ₂ —, wherein ring A is substituted with 1 to 3 substituents selected from (1 ′) group B below. An aryl group selected from a phenyl group and a naphthyl group, (2 ′) a nitrogen atom which may be substituted with 1 to 3 substituents selected from the following group B,
Substituted with a 5- or 6-membered heteroaryl group containing 1 to 3 hetero atoms selected from an oxygen atom and a sulfur atom, or (3 ') 1 to 3 substituents selected from the following group B Means a C _3-7 cycloalkyl group which may be (Here, Group B is (1 '') Group A
Or (2 '') C which may be substituted with 1 to 3 substituents selected from the group A
_It means a group consisting of _1-6 alkyl groups. )｝

(2) The N-arylhydrazide compound or a pharmaceutically acceptable salt thereof according to (1), wherein R ¹ , R ² and R ³ are hydrogen atoms.

(3) R ¹ together with Ra ^is- (C
_{H 2) 2 -, - (} CH 2) 3 -, - CH = CH -, - CH 2 -C
H = CH— or —CH ＝ CH—CH ₂ — to form R ²
And the N-arylhydrazide compound or a pharmaceutically acceptable salt thereof according to (1), wherein R ³ is a hydrogen atom.

(4) R ¹ together with Ra ^is- (C
N _{2 according} to (3), which forms H ₂ ) ₂ — or —CH ＝ CH—
-An arylhydrazide compound or a pharmaceutically acceptable salt thereof.

(5) In the general formula [I]

Embedded image 中 In the formula, each symbol is as described in (1). The substitution position of｝ is
N in any of (1) to (4) above, which is meta or para to the position of hydrazide substitution on the benzene ring.
-An arylhydrazide compound or a pharmaceutically acceptable salt thereof.

(6) R ^c is

Embedded image 中 In the formula, each symbol is as described in (1). And the N-arylhydrazide compound according to any one of (1) to (5), wherein the substitution position of R ^c is a meta position or a para position with respect to the substitution position of —NR ³ — on the benzene ring. Or a pharmaceutically acceptable salt thereof.

(7) R ^b1 , R ^b2 , R ^c1 and R
The N-arylhydrazide compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (6), wherein ^c2 is a hydrogen atom.

(8) R ^a1 and R ^a2 are the same or different and are each a hydrogen atom, a C _1-6 alkyl group optionally substituted by a halogen atom, a C _1-6 alkoxy group or a nitro group. N) according to any one of (1) to (7),
-An arylhydrazide compound or a pharmaceutically acceptable salt thereof.

(9) R ^c is

Embedded image And X is —NR ^d1 —, R ^d1 is a hydrogen atom, and ring A is a group B of (1)
N is a phenyl group which may be substituted with 1 to 3 substituents selected from
-An arylhydrazide compound or a pharmaceutically acceptable salt thereof.

(10) 4- [4-{(4-methylphenyl) amino} phenylamino] benzoic acid 2- [4-
(Trifluoromethyl) phenyl] hydrazide (Example 1), N- (2,3-dihydro-5-methyl-1H-indol-1-yl) -4- [4-{(4-methylphenyl) amino} Phenylamino] benzamide (Example 2), N- [2,3-dihydro-5- (trifluoromethyl) -1H-indol-1-yl] -4- [4-
{(4-methylphenyl) amino} phenylamino] benzamide (Example 3), 4- (phenylamino) benzoic acid 2-phenylhydrazide (Example 4), 4- (phenylamino) benzoic acid 2- (2- Nitrophenyl)
Hydrazide (Example 5), 3- (phenylamino) benzoic acid 2- (2-nitrophenyl) hydrazide (Example 6), 2- (phenylamino) benzoic acid 2- (2-nitrophenyl) hydrazide (Example) 7), 4- (phenylamino) benzoic acid 2- (2-methoxyphenyl) hydrazide (Example 8), 4- (phenylamino) benzoic acid 2- [2- (trifluoromethyl) phenyl] hydrazide (Example) 9), 4- (phenylamino) benzoic acid 2- [4- (trifluoromethyl) phenyl] hydrazide (Example 10)

4- (phenylamino) -2- (3-phenylpropyl) benzoic acid 2-phenylhydrazide (Example 11), 4- (phenylamino) -2- (3-phenylpropyl) benzoic acid 2- ( 2-methoxyphenyl) hydrazide (Example 12), 4- (phenylamino) -2- (3-phenylpropyl) benzoic acid 2-
[2- (trifluoromethyl) phenyl] hydrazide (Example 13), 4- (phenylamino) -2- (3-
Phenylpropyl) benzoic acid 2- [4- (trifluoromethyl) phenyl] hydrazide (Example 14), N-
(2,3-dihydro-1H-indol-1-yl)-
4- (phenylamino) benzamide (Example 15),
4- (phenylamino) benzoic acid 2-methyl-2-phenylhydrazide (Example 16), 4- (phenylamino) benzoic acid 1-methyl-2-phenylhydrazide (Example 17), 4- [3- ( Phenylamino) phenylamino] benzoic acid 2-phenylhydrazide (Example 18), 4- [3- (phenylamino) phenylamino] benzoic acid 2- (2-methoxyphenyl) hydrazide (Example 19), 4- [ 3- (phenylamino) phenylamino] benzoic acid 2- [2- (trifluoromethyl) phenyl] hydrazide (Example 20)

4- [3- (phenylamino) phenylamino] benzoic acid 2- [4- (trifluoromethyl) phenyl] hydrazide (Example 21), 4- [4- (phenylamino) phenylamino] benzoic acid 2-phenylhydrazide (Example 22), 4- [4- (phenylamino) phenylamino] benzoic acid 2- (2-methoxyphenyl) hydrazide (Example 23), 4- [4- (phenylamino) phenylamino Benzoic acid 2- [2-
(Trifluoromethyl) phenyl] hydrazide (Example 24), 4- [4- (phenylamino) phenylamino] benzoic acid 2- [4- (trifluoromethyl) phenyl] hydrazide (Example 25), 4- [ 4- @ 4-
(Methoxy) phenylamino} phenylamino] benzoic acid 2- [4- (trifluoromethyl) phenyl] hydrazide (Example 26), 4- [4- {4- (methyl) phenylamino} phenylamino] benzoic acid 2 − (4-
Methylphenyl) hydrazide (Example 27), 4- [4
-(Phenylcarbamoyl) phenylamino] benzoic acid 2-phenylhydrazide (Example 28), 4- [4-
(Phenylcarbamoyl) phenylamino] benzoic acid
2- (2-methoxyphenyl) hydrazide (Example 2
9), 4- [4- (phenylcarbamoyl) phenylamino] benzoic acid 2- [2- (trifluoromethyl) phenyl] hydrazide (Example 30)

4- [4- (phenylcarbamoyl) phenylamino] benzoic acid 2- [4- (trifluoromethyl) phenyl] hydrazide (Example 31), 4- [3-
(Phenylcarbamoyl) phenylamino] benzoic acid
2-phenylhydrazide (Example 32), 4- [3-
(Phenylcarbamoyl) phenylamino] benzoic acid
2- (2-methoxyphenyl) hydrazide (Example 3
3), 4- [3- (phenylcarbamoyl) phenylamino] benzoic acid 2- [2- (trifluoromethyl) phenyl] hydrazide (Example 34), 4- [3- (phenylcarbamoyl) phenylamino] benzoic acid 2-
[4- (trifluoromethyl) phenyl] hydrazide (Example 35), 4- [4- (benzoylamino) phenylamino] benzoic acid 2-phenylhydrazide (Example 36), 4- [4- (benzoylamino) Phenylamino] benzoic acid 2- (2-methoxyphenyl) hydrazide (Example 37), 4- [4- (benzoylamino)
Phenylamino] benzoic acid 2- [2- (trifluoromethyl) phenyl] hydrazide (Example 38), 4-
[4- (Benzoylamino) phenylamino] benzoic acid 2- [4- (trifluoromethyl) phenyl] hydrazide (Example 39), 4- [3- (benzoylamino)
Phenylamino] benzoic acid 2-phenylhydrazide (Example 40), 4- [3- (benzoylamino) phenylamino] benzoic acid 2- (2-methoxyphenyl)
Hydrazide (Example 41), 4- [3- (benzoylamino) phenylamino] benzoic acid 2- [2- (trifluoromethyl) phenyl] hydrazide (Example 42),
4- [3- (Benzoylamino) phenylamino] benzoic acid 2- [4- (trifluoromethyl) phenyl] hydrazide (Example 43), N- (5-methylindol-1-yl) -4- [4 -{(4-methylphenyl) amino} phenylamino] benzamide (Example 44) and N- [5- (trifluoromethyl) indole-1-
Yl] -4- [4-{(4-methylphenyl) amino}
[Phenylamino] benzamide (Example 45). The N-arylhydrazide compound or a pharmaceutically acceptable salt thereof according to (1), which is selected from the group consisting of compounds.

(11) A pharmaceutical composition comprising the N-arylhydrazide compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(12) An amyloid β aggregation inhibitor comprising, as an active ingredient, the N-arylhydrazide compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof.

(13) Treatment and treatment of dementia and / or amnesia comprising the N-arylhydrazide compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof as an active ingredient. And / or a pharmaceutical composition for prevention.

The meanings of the terms used in the present specification are as follows. “Halogen atom” is a fluorine atom, chlorine atom, bromine atom or iodine atom, preferably a fluorine atom, chlorine atom or bromine atom, more preferably a fluorine atom.

The term "C _1-6 alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like. Group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, tert-pentyl group, hexyl group and the like. It is preferably an alkyl group having 1 to 4 carbon atoms, particularly preferably a methyl group or an ethyl group, and more preferably a methyl group. The “C _1-6 alkyl group” may be substituted with one to three substituents selected from Group A below. Here, the group A includes a halogen atom, a nitro group, an amino group, a cyano group, a carboxyl group, a C _1-6 alkoxy group,
_1-6 means a group consisting of an alkoxycarbonyl group and an aryl group. Specifically, chloromethyl group, dichloromethyl group, 2-chloroethyl group, 1,2-dichloroethyl group, trifluoromethyl group, nitromethyl group,
Examples include an aminomethyl group, a cyanomethyl group, a carboxymethyl group, a methoxymethyl group, and a methoxycarbonylmethyl group. The “C _1-6 alkyl group _optionally substituted with 1 to 3 substituents selected from group A” is preferably an unsubstituted “C _1-6 alkyl group” or may be substituted with a halogen atom. a "C _1-6 alkyl group", particularly preferably a methyl group or a trifluoromethyl group, more preferably a methyl group.

The "C _1-6 alkoxy group" is an alkyloxy group whose alkyl moiety is the above-defined "C _1-6 alkyl group", and specifically, a methoxy group, an ethoxy group, a propoxy group, Isopropyloxy group, butoxy group, isobutyloxy group, tert-butyloxy group,
Examples include a pentyloxy group and a hexyloxy group.
Preferably, the alkyl moiety is an alkoxy group having a linear or branched alkyl group having 1 to 4 carbon atoms, particularly preferably a methoxy group or an ethoxy group, and more preferably a methoxy group.

[0033] The "C _1-6 alkoxycarbonyl group", the alkoxy part is an alkyloxycarbonyl group is a "C _1-6 alkoxy group" defined above, specifically, methoxycarbonyl group, ethoxycarbonyl Groups, propoxycarbonyl, isopropyloxycarbonyl, butoxycarbonyl, isobutyloxycarbonyl, tert-butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and the like. Preferably, the alkoxy moiety is an alkoxycarbonyl group having a straight or branched chain alkoxy group having 1 to 4 carbon atoms, and particularly preferably, a methoxycarbonyl group.

The “C _1-4 alkylamino group” is a monoalkylamino group substituted with an alkyl group having 1 to 4 carbon atoms. Specifically, methylamino, ethylamino, propylamino, isopropylamino, te
and an rt-butylamino group. Preferably it is a methylamino group or an ethylamino group.

The “di (C _1-4 alkyl) amino group” is a di (alkyl) amino group disubstituted by an alkyl group having 1 to 4 carbon atoms. Specific examples include a dimethylamino group, a methylethylamino group, a diethylamino group, a diisopropylamino group, a di-tert-butylamino group, and the like. Preferably it is a dimethylamino group or a diethylamino group.

The "cyclic amino group" is a 5- or 6-membered cyclic group containing at least one nitrogen atom and substituted by the nitrogen atom. Further, it is a saturated or unsaturated cyclic group which may further contain a hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom in addition to one nitrogen atom. Specifically, 1-pyrrolidinyl group, 1-pyrrolinyl group, 1
-Pyrrolyl, 1-imidazolidinyl, 1-imidazolyl, piperidino, 1-piperazinyl, morpholino, thiomorpholino and the like. R ^a ,
Preferably as definitive ^{in R a1,} R a2, R ^c1 and ^{R c2} "cyclic amino group" is a 1-pyrrolidinyl group, piperidino group or morpholino group.

The "aryl group" means a phenyl group or a naphthyl group, and is preferably a phenyl group. The “aryl group” may be substituted with 1 to 3, preferably 1 substituent selected from the following group B. Here, the group B includes 1 to 3 halogen atoms, a nitro group, an amino group, a cyano group, a carboxyl group, a C _1-6 alkoxy group, a C _1-6 alkoxycarbonyl group, an aryl group, and one to three groups selected from the group A. It means a group of good C _{1 -6} alkyl group optionally substituted with a substituent. Specifically, 2-methylphenyl group, 4-methylphenyl group, 4-fluorophenyl group, 2,4,6
-Trichlorophenyl group, 2-nitrophenyl group, 4-
Nitrophenyl group, 3,5-diaminophenyl group, 4-
Cyanophenyl group, 4-carboxylphenyl group, 2-
Methoxyphenyl group, 4-methoxyphenyl group, 4-methoxycarbonylphenyl group, 4-biphenylyl group, 6
-Nitronaphthalen-2-yl group, 5-methoxynaphthyl group, 2-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 4- (aminomethyl) phenyl group, 4- (methoxymethyl) phenyl group, — (Methoxycarbonylmethyl) phenyl group and the like. Particularly preferred substituents are “C _1-6 alkyl group _optionally substituted by 1 to 3 substituents according to group A” as defined above.
Or " _C1-6 alkoxy group" as defined above. As the “aryl group optionally substituted with 1 to 3 substituents selected from group B”, a phenyl group, 4
A methylphenyl group or a 4-methoxyphenyl group, and more preferably a 4-methylphenyl group.

The “arylalkyl group” is an “alkyl group” substituted with an “aryl group”, wherein the “aryl group” has the same meaning as the above “aryl group”, and the “alkyl group” is the same as the above “aryl group”. it is synonymous with C _1-6 alkyl group ". Specific examples include a benzyl group, a naphthylmethyl group, a 2-phenylethyl, a 3-phenylpropyl group, and a 4-phenylbutyl group. Preferred are a benzyl group, a 2-phenylethyl group and a 3-phenylpropyl group, and particularly preferred is a 3-phenylpropyl group. “Aryl” in the “arylalkyl group” may be substituted with 1 to 3 substituents selected from the above group B, as in the case of the above “aryl group”. Specifically, 4-
Examples thereof include a trifluoromethylbenzyl group, a 2-trifluoromethylbenzyl group, a 2- (4-trifluoromethylphenyl) ethyl group, a 4-nitrobenzyl group, a 4-methoxybenzyl group, and a 4-tolylmethyl group.

The "arylamino group" is an "amino group" substituted with an "aryl group", wherein the "aryl group" has the same meaning as described above, and specifically, a phenylamino group, 2-naphthyl Amino and the like. Preferably,
It is a phenylamino group. The “aryl group” may be substituted with one to three substituents selected from the above group B. Specific examples include a 4-tolylamino group, a (4-trifluoromethylphenyl) amino group, and a (4-nitrophenyl) amino group.

The “arylalkylamino group” is an “amino group” substituted with an “arylalkyl group”,
Here, the “arylalkyl group” has the same meaning as described above, and specific examples include a benzylamino group and a phenethylamino group. Preferably, it is a benzylamino group. The “arylalkyl group” may be substituted with 1 to 3 substituents selected from the above group B, and specifically, a benzylamino group, a (4-tolylmethyl) amino group, a (4
-Trifluoromethylbenzyl) amino group, (4-nitrobenzyl) amino group and the like.

"A 5-membered or 6-membered atom containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom
Membered heteroaryl group "means a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a 1,2,4-triazinyl group, a 1,3,5-triazinyl group, a pyrrolyl group, a thienyl group, a furyl group, a pyrazolyl group , Imidazolyl group, 1,2,4-triazolyl group, 1,2,4,5-
It means a tetrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group or the like, and is preferably a pyridyl group. These heteroaryl groups are
It may be substituted with 1 to 3 substituents selected from the above group B, and specifically, 3-methyl-pyridine-2
-Yl group, 5-methyl-pyridin-2-yl group, 5-nitro-pyridin-2-yl group, 6-methyl-pyridine-
Examples include a 3-yl group and a 5-methyl-pyridin-3-yl group. The “heteroaryl group optionally substituted with 1 to 3 substituents selected from group B” is preferably a 5-methyl-pyridin-2-yl group or a 6-methyl-pyridin-3-yl group. .

"C _3-7 cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The "C
_{The “3-7} cycloalkyl group” may be substituted with 1 to 3 substituents selected from the above group B, specifically, 4-methylcyclohexyl group, 4-trifluoromethylcyclohexyl group, 4-nitrocyclohexyl And the like. The “C _3-7 cycloalkyl group _optionally substituted with one to three substituents selected from group B” is preferably a cyclopentyl group or a cyclohexyl group.

As R ^a , R ^a1 and R ^a2 , preferably a hydrogen atom or a halogen atom,
_1-6 alkyl group ", a" _{C 1-6} alkoxy group "or a nitro group. Particularly preferably, R ^a1 is a methyl group,
It is an ethyl group or a trifluoromethyl group, and more preferably a methyl group. ^Ra2 is particularly preferably a hydrogen atom. The substitution position of ^Ra is preferably an ortho position or a para position with respect to the hydrazine substitution position, and particularly preferably a para position. R ¹ is a hydrogen atom or a methyl group, or together with ^Ra is — (CH ₂ ) ₂
-Or -CH = CH- is preferable, and particularly preferably a hydrogen atom or together with Ra ^is- (CH
_{2) 2} - is when forming the, more preferably taken together with R ^a - it is time to form a - (CH _{2) 2.} R ² and R ³ are preferably a hydrogen atom or a methyl group, and particularly preferably a hydrogen atom. R ^b1 and R ^b2
Is preferably a hydrogen atom or a phenylalkyl group such as a benzyl group, a 2-phenylethyl group, a 3-phenylpropyl group, or a 4-phenylbutyl group, and particularly preferably a hydrogen atom or a 3-phenylpropyl group. Preferably it is a 3-phenylpropyl group. R ^c1 and R
^c2 is preferably a hydrogen atom. Preferably as R ^c ,

Embedded image And X is preferably -NR ^d1- , -N
R ^d1 CO— or —CONR ^d1 —, particularly preferably —NR ^d1 —, and R ^d1 is preferably a hydrogen atom. Further, ring A is preferably a phenyl group. The ring A may be substituted with a substituent selected from the group B. In this case, a preferable substituent is
"C _1-6 alkyl group", "C _1-6 alkoxy group", particularly preferably a methyl group or a methoxy group,
More preferably, it is a methyl group. The substitution position of the substituent on ring A is preferably para to -X-.

In the general formula [I], the following substituents

Embedded image (Wherein each symbol is as defined above), the substitution position is preferably a meta position or a para position with respect to the hydrazide substitution position, and particularly preferably a para position. Further, in the above substituent, the substitution position of R ^c is preferably -NR ^3-.
At the meta or para position with respect to the substitution position, and particularly preferably at the para position.

The term "amyloid β" refers to the entire protein formed from amyloid β precursor protein by processing or proteolysis, and mainly represents amyloid β _1-40 and amyloid β _1-42 .

The term “aggregation of amyloid β” refers to the formation of the above-described aggregate of amyloid β alone and the formation of the aggregate of proteins mainly composed of amyloid β. As a form of the set,
It is not limited to a bonding mode such as electrostatic interaction, ionic bonding, covalent bonding, or physical entanglement.

There are several definitions of "dementia" and "amnesia". Currently, the third edition of the American Psychiatric Association's revised diagnostic and statistical manual is widely used as a general diagnostic standard for dementia. ing. However, in general, a disease in which only memory impairment is observed is referred to as “amnesia”, and a symptom in which some cognitive impairment is observed in addition to memory impairment is referred to as “dementia”. The terms "symptoms" and "amnesia" also follow this general definition. As symptoms of dementia, basic symptoms include memorization and memory impairment, disorientation about date and place, impaired calculation,
Impairment of understanding and judgment, impairment of daily living ability, disability of putting on and taking off clothes, disturbance of food intake, disturbance of excretion (incontinence), disturbance of bathing, abnormal behavior and mental symptoms wandering, going out without permission, day and night Reversal / insomnia, solitude, pseudo-work, abuse,
Filthy acts (feeling stool), anorexia, hallucinations, excitement / delirium, depression,
Physical disorders include dysarthria, walking disorders and the like.

There are several definitions for "Alzheimer's dementia". Currently, the fourth edition of the American Psychiatric Association's Diagnostic and Statistical Manual is widely used as a diagnostic standard for Alzheimer's dementia. Manual 4
According to the version, Alzheimer's dementia has, in addition to memory impairment, one or more disorders of aphasia, apraxia, agnosia, and impairment of executive function. The disease is classified as other diseases because it causes significant disability and shows a remarkable decrease from the pre-sickness functional level, and that cognitive deficits are not due to any of the following.・ Other central nervous system diseases that cause progressive deficits in memory and cognition (cerebrovascular disease, Parkinson's disease, Huntington's disease, subdural hematoma, normal pressure hydrocephalus, brain tumors, etc.) Systemic diseases (hypothyroidism, vitamin B12 or folate deficiency, nicotinic acid deficiency, hypercalcemia, neurosyphilis, HIV infection, etc.), substance-induced diseases “Alzheimer's disease” as used herein The term "disease" encompasses diseases in which changes in neurofibrillary tangles and senile plaques are found in the patient's brain as pathological features, even for symptoms without significant memory impairment (eg, delusions, etc.). I do. "Alzheimer's disease" refers to the symptoms of the above-mentioned "dementia" in the "Alzheimer's disease", including Alzheimer's disease dementia diagnosed by various criteria.

The use of the “amyloid β aggregation inhibitor” used in the specification includes the above “dementia”,
Examples include “amnesia”, “Alzheimer's disease” and “Alzheimer's dementia”, and further include the amyloid β described above.
Diseases caused by the above. Specific examples of the disease caused by amyloid β include Alzheimer's dementia, Down's syndrome, cerebrovascular amyloidosis, and hereditary amyloid cerebral hemorrhage (particularly, Dutch type). Uses of the "antioxidant" include the above-mentioned "dementia", "amnesia",
"Alzheimer's disease" and "Alzheimer's disease"
And the disease caused by the above-mentioned radical. Specific examples of the disease caused by radicals include ischemic brain disease, ischemic heart disease, ischemic liver disease, arteriosclerosis, hyperlipidemia, stroke, cerebral edema, Parkinson's disease, Huntington's disease, and amyotrophic lateral cord Sclerosis, multiple sclerosis, seizures, central nervous injury after stroke, myocardial infarction, ventricular arrhythmia, rheumatoid arthritis, osteoarthritis, Behcet's syndrome, atopic dermatitis, burns, skin diseases caused by ultraviolet rays and radiation, Asthma, emphysema, adult respiratory distress syndrome, inflammatory bowel disease, uveitis, autoimmune disease, infection, retinopathy of prematurity, diabetic retinopathy, cataract, glaucoma, senile macular degeneration, cancer, peripheral nerves Examples include cell degeneration, peripheral circulatory disorders, Meniere's disease, pain, itching, hemolysis, and diseases caused by platelet aggregation.

The indication of the compound of the present invention is preferably
A symptom caused by amyloid β, specifically dementia and Alzheimer's disease, particularly Alzheimer-type dementia.

In the present invention, solvates, prodrugs and metabolites of each compound are also included. "Prodrug" has a group that can be chemically or metabolically degradable,
A derivative of the compound of the present invention, which is restored to the original compound after administration to a living body and exhibits an original medicinal effect, and includes a complex and a salt without covalent bond.

When the compound of the present invention is used as a pharmaceutical preparation, it is generally known as a pharmaceutically acceptable carrier, excipient, diluent, extender, disintegrant, stabilizer, preservative, buffer, emulsifier, fragrance, and the like. Agents, coloring agents, sweeteners, thickeners, flavoring agents, solubilizing agents, and other additives, specifically, water, vegetable oil, alcohols such as ethanol or benzyl alcohol, polyethylene glycol, glycerol triacetate, gelatin, lactose, starch Carbohydrates, etc.
Mixed with magnesium stearate, talc, lanolin, petrolatum, etc., tablets, pills, powders, granules,
Suppositories, injections, eye drops, liquids, capsules, troches, aerosols, elixirs, suspensions, emulsions, syrups, etc. can be used systemically or locally, orally or It can be administered parenterally. The dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, etc., but is usually 0.1 mg per adult per dose.
It is administered once to several times a day in the range of 1 to 1 g.

[0053]

Next, an example of a method for producing a compound used for carrying out the present invention will be described. However, the production method of the compound of the present invention is not limited to these. Although not described in the present production method, the production may be carried out efficiently by introducing a protecting group into a functional group as necessary and performing deprotection in a subsequent step, or changing the order of each production method and step. In each step, the post-reaction treatment may be performed by a commonly used method, including isolation and purification, crystallization, recrystallization, silica gel chromatography, and preparative HPLC.
And other commonly used methods may be appropriately selected and combined.

Production Method 1 This production method is a method for obtaining the carboxylic acid compound used in Production Method 3.

Embedded image (In the formula, Hal is a halogen atom such as a bromine atom and a chlorine atom, and other symbols are as described above.)

Step 1 The compound [1] obtained by a conventional method or commercially available is
Potassium carbonate, triethylamine, potassium in a solvent such as N, N-dimethylformamide (DMF), acetonitrile, tetrahydrofuran (THF), and toluene
-Compound [3] can be obtained by reacting with a commercially available or commercially available amine compound [2] at room temperature or under heating conditions in the presence of a base such as butoxide. Palladium catalysts such as tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, palladium acetate-triphenylphosphine, nickel chloride, [1,3-bis (diphenylphosphino) propane] nickel chloride A catalyst such as a nickel catalyst such as (II) may be used. Step 2 Compound [4] can be obtained by reducing the nitro group of compound [3] by a conventional method. For example, if the catalytic reduction is carried out at room temperature or under heating, under normal pressure to high pressure, in a solvent such as THF, DMF or toluene, in the presence of a hydrogenation catalyst such as palladium carbon, palladium hydroxide, palladium black, Raney nickel or platinum oxide, Good. Third step In the same manner as in the first step of Production method 1, compound [6] can be obtained by reacting compound [4] with a nitrile compound [5] obtained by a conventional method or commercially available.

[0056]

Embedded image (In the formula, each symbol is as described above.) Fourth step A nitrile compound [7] obtained in the same manner as in the third step of the conventional method or the production method 1 is mixed with potassium hydroxide and water in a solvent such as ethylene glycol and glycerin. Compound [8] can be obtained by reacting under heating conditions in the presence of a strong base such as sodium oxide or a strong acid such as concentrated sulfuric acid or concentrated hydrochloric acid.

Production Method 2 This production method is a method for obtaining the amine compound used in Production Method 3.

Embedded image (In the formula, n is 1 or 2, R ^P1 is an alkyl group such as a methyl group or an ethyl group, R ^P2 is an amine protecting group such as t-butoxycarbonyl, benzyloxycarbonyl, and other symbols are As described above.)

Step 1 Nitro compound [9] obtained by a conventional method or commercially available
In a solvent such as DMF, acetonitrile, THF, toluene, potassium carbonate, triethylamine, potassium t
Compound [11] can be obtained by dropwise addition of a halogen compound [10] little by little in the presence of a base such as butoxide at room temperature or under cooling conditions. Step 2 Compound [12] can be obtained by reducing the carbonyl site of compound [11] by a conventional method. For example, treatment with a reducing agent such as lithium aluminum hydride or lithium borohydride in a solvent such as THF or 1,4-dioxane, or dialkyl such as diisobutylaluminum hydride in a solvent such as dichloromethane or chloroform under cooling. What is necessary is just to process with aluminum hydride. Third Step The compound [13] can be obtained by reducing the nitro group of the compound [12] by a conventional method such as the second step of the production method 1. Fourth Step Compound [14] can be obtained by introducing a protecting group into the amino group of compound [13] by a conventional method. For example, when the protecting group is a t-butoxycarbonyl group, by treating with t-butoxycarbonyl chloride in THF at a low temperature, or by reacting di-t-butyl dicarbonate in THF in the presence of triethylamine. Protecting groups can be introduced. Fifth Step A compound [15] is obtained by treating the compound [14] with a dialkyl azodicarboxylate such as diethyl azodicarboxylate in a solvent such as DMF, acetonitrile or THF in the presence of a phosphine such as triphenylphosphine. be able to. Sixth Step The compound [16] can be obtained by removing the amine protecting group of the compound [15] by a conventional method. For example, when the protecting group is a t-butoxycarbonyl group,
Deprotection can be achieved by treating with 2N hydrochloric acid in HF or with trifluoroacetic acid in chloroform. Step 5 ′ Compound [16] can also be obtained by cyclizing compound [13] in the same manner as in Production Method 2, Step 5.

[0059]

Embedded image (In the formula, each symbol is as described above.) Step 6 ′ The compound [18] can be obtained by hydrogenating the compound [17] by a conventional method. For example, a method of treating with sodium cyanoborohydride in acetic acid or performing catalytic reduction in the same manner as in the second step of Production Method 1 may be used.

[0060]

Embedded image (In the formula, each symbol is as described above.) Step 7 The compound [1] obtained in Step 6 or Step 6 ′ of Production Method 2
6] (including compound [18]) is treated with sodium nitrite in the presence of concentrated hydrochloric acid under cooling conditions to obtain a nitroso compound, and then reduced by a conventional method to give compound [19]. Can be obtained. As the reduction method, for example, treatment with a reducing agent such as lithium aluminum hydride or lithium borohydride in a solvent such as diethyl ether, THF, 1,4-dioxane, or
A method such as treatment with zinc powder and acetic acid under cooling may be used.

Production Method 3 This production method is a method for obtaining an amide compound from an amine compound and a carboxylic acid compound, or a hydrazide compound from a hydrazine compound and a carboxylic acid compound. Manufacturing method 3-1

Embedded image (In the formula, each symbol is as described above.) Compound [2] obtained commercially or by a conventional method or Production Method 2
0] in a solvent such as DMF, acetonitrile, THF, chloroform, ethyl acetate, methylene chloride, and toluene;
Dicyclohexylcarbodiimide, 1-ethyl-3-
A condensing agent such as (3-dimethylaminopropyl) carbodiimide hydrochloride, diphenylphosphoryl azide and the like, and if necessary, N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like, are added, and the compound is condensed with a carboxylic acid compound [8]. [I] can be obtained. Further, an acid halide derived by reacting the carboxylic acid compound [8] with thionyl chloride, oxalyl chloride (oxalyl chloride), etc., or a mixed acid anhydride derived by reacting with chloroethyl carbonate, etc. To an activated ester of compound [8], and then chloroform, THF, DMF in the presence of a base such as triethylamine, potassium carbonate or pyridine.
Compound [I] can also be obtained by reacting in a solvent such as pyridine or an amine solvent such as pyridine. Also,
Compounds in [I], ^{R 1} and ^{R a} together -
When (CH ₂ ) ₂ — (indoline derivative), it can be converted to —CH ＝ CH— (indole derivative) by oxidation in a conventional manner.

Production Method 3-2 When a condensation reaction is carried out in Production Method 3-1, an amide compound or a hydrazide compound can also be obtained by introducing an amine protecting group, conducting a condensation reaction and then deprotecting.

Embedded image (In the formula, each symbol is as described above.)

Step 1 From compound [6 '], in the same manner as in Step 4 of Production Method 2,
Compound [21] can be obtained. Step 2 From compound [21], in the same manner as in Step 4 of Production Method 1,
Compound [22] can be obtained. Third Step From compound [22] and compound [20], compound [23] can be obtained in the same manner as in production method 3-1. Fourth step From compound [23], in the same manner as in the sixth step of Production method 2,
Compound [I '] can be obtained.

Next, the compound represented by the general formula [I] according to the present invention and the method for producing the same will be specifically described with reference to examples. However, the present invention is not limited by these examples.

Example 1 4- [4-{(4-methylphenyl) amino} phenylamino] benzoic acid 2- [4- (trifluoromethyl)
Preparation of [phenyl] hydrazide (1) Step: Preparation of 4'-methyl-4-nitrodiphenylamine In a solution of p-toluidine (25.0 g) in DMF (500 ml), 4-bromonitrobenzene (47.1 g), tetrakis (triphenyl) (Phosphine) palladium (13.5 g) and potassium carbonate (64.5 g) were added, and the mixture was stirred at 180 ° C. for 2 hours. Then
The mixture was cooled to room temperature and filtered. The filtrate was diluted with distilled water and extracted with ethyl acetate. The extract was washed with distilled water and brine, and concentrated. The residue was crystallized from ethyl acetate and hexane to give the title compound (25.0 g). (2) Step: Production of N- (4-tolyl) -1,4-phenylenediamine 10% palladium-carbon (3.0%) was added to a solution of 4′-methyl-4-nitrodiphenylamine (6.10 g) in tetrahydrofuran (THF, 100 ml). g) at room temperature under 1 atm of hydrogen.
Stirred for hours. Then, the mixture was filtered and concentrated to give the title compound (4.73 g). (3) Step: Production of 4- [4- (4-tolylamino) phenylamino] benzonitrile N- (4-tolyl) -1,4-phenylenediamine (4.
73g) in dimethylformamide (DMF, 100ml) solution
-Bromobenzonitrile (4.84 g), tetrakis (triphenylphosphine) palladium (1.38 g) and potassium carbonate (9.89 g) were added, and the mixture was stirred at 180 ° C for 2 hours. Then the mixture was cooled to room temperature and filtered. The filtrate was diluted with distilled water and extracted with ethyl acetate. The extract was washed with distilled water and brine, and concentrated. The residue was purified by chromatography to give the title compound (3.30 g).

Step (4): Production of 4- [4- (4-tolylamino) phenylamino] benzoic acid 4- [4- (4-tolylamino) phenylamino] benzonitrile (2.32 g) in ethylene glycol (12 ml) ) Potassium hydroxide (1.67 g) was added to the solution, and the mixture was stirred at 180 ° C for 2 hours. Then the mixture was cooled to room temperature and poured into distilled water. This was acidified to pH = 4 and extracted with ethyl acetate.
The extract was concentrated, and the residue was crystallized from ethyl acetate and hexane to give the title compound (2.22 g). (5) Step: Production of 4- [4-{(4-methylphenyl) amino} phenylamino] benzoic acid 2- [4- (trifluoromethyl) phenyl] hydrazide 4- (trifluoromethyl) phenylhydrazine (400 m
g) in DMF (20 ml) was added to 4- [4- (4-tolylamino) phenylamino] benzoic acid (694 mg), 1-hydroxybenzotriazole (307 mg) and 1-ethyl-3.
-(3-Dimethylaminopropyl) carbodiimide hydrochloride (435 mg) was added, and the mixture was stirred at room temperature for 12 hours. Then the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was concentrated, and the residue was purified by chromatography to obtain the title compound (Example 1, 522 mg). Table 1 shows the chemical structural formula and physical properties of this compound.

Example 2 N- (2,3-dihydro-5-methyl-1H-indol-1-yl) -4- [4-{(4-methylphenyl)
Preparation of amino {phenylamino] benzamide (1) Step: Preparation of 4- {benzyl [4- {benzyl (4-tolyl) amino} phenyl] amino} benzonitrile Obtained in step (3) of Example 1. 4- [4- (4-tolylamino) phenylamino] benzonitrile (3.0 g)
Sodium hydride (60% oil dispersion,
1.32 g) and stirred at 120 ° C. for 0.5 hour. Benzyl bromide (4.5 ml) was added and the mixture was stirred for another 0.5 hour at 120
Stirred at ° C. Then the mixture was cooled to room temperature, diluted with distilled water and extracted with ethyl acetate. The extract was washed with distilled water and brine, and concentrated. The residue was purified by chromatography to give the title compound (3.0 g). (2) Step: Production of 4- {benzyl [4- {benzyl (4-tolyl) amino} phenyl] amino} benzoic acid 4- {benzyl [4- {benzyl (4-tolyl) amino} phenyl] amino} benzo Potassium hydroxide (2.81) was added to a solution of nitrile (6.0 g) in ethylene glycol (36 ml).
g) was added and the mixture was stirred at 180 ° C. for 2 hours. Then the mixture was cooled to room temperature and poured into distilled water. This was acidified to pH = 4, extracted with ethyl acetate, and the extract was concentrated. The residue was crystallized from ethyl acetate and hexane to give the title compound (3.48 g). (3) Step: Production of 5-methylindoline A solution of 5-methylindole (2.0 g) in acetic acid (20 ml) was added to 15
Sodium cyanoborohydride (1.92 g) was added at
Stirred at C for 2 hours. Next, distilled water was added to the mixture, and the mixture was cooled in an ice bath, made strongly alkaline with sodium hydroxide, and extracted with diethyl ether. The extract was washed with distilled water and brine, and concentrated to give the title compound (2.0 g).

Step (4): Production of 1-amino-5-methylindoline hydrochloride To a solution of 5-methylindoline (1.89 g) in 6N hydrochloric acid (20 ml) was added an aqueous solution (10 ml) of sodium nitrite (979 mg). 1
The mixture was added dropwise at 0 ° C., and the mixture was further stirred for 0.5 hour. The mixture was extracted with diethyl ether, and the extract was washed with brine and dried. Lithium aluminum hydride (1.07 g) was added to the extract cooled to 0 ° C., and the mixture was stirred for 0.5 hour. The mixture was quenched sequentially with distilled water, 15% aqueous sodium hydroxide, and distilled water. Magnesium sulfate was added to the mixture, stirred for 12 hours, and then filtered. The filtrate was concentrated. The residue was purified by chromatography to obtain 1-amino-5-methylindoline. A solution of 1-amino-5-methylindoline in ethyl acetate was treated with 4M hydrogen chloride in ethyl acetate and concentrated to give the title compound (1.90 g). Step (5): N- (2,3-dihydro-5-methyl-1)
H-Indol-1-yl) -4- [benzyl (4-
{Benzyl (4-tolyl) amino} phenyl) amino]
Production of Benzamide To a solution of 4- {benzyl [4- {benzyl (4-tolyl) amino} phenyl] amino} benzoic acid (748 mg) obtained in the above step (2) in chloroform (15 ml) was added oxalic acid chloride (0.157 ml). ) Was added and stirred at room temperature for 0.5 hour. Then, the mixture was concentrated to obtain the acid chloride. The above (4)
In a chloroform (10 ml) solution of 1-amino-5-methylindoline hydrochloride (292 mg) obtained in the step, pyridine (1.21 ml) and chloroform (5 m
l) The solution was added and stirred at room temperature for 12 hours. The mixture was diluted with ethyl acetate, washed with 10% aqueous citric acid, distilled water and brine, and concentrated. The residue was purified by chromatography to give the title compound (536 mg). Step (6): N- (2,3-dihydro-5-methyl-1)
Preparation of H-indol-1-yl) -4- [4-{(4-methylphenyl) amino} phenylamino] benzamide N- (2,3-dihydro-5-methyl-1H-indol-1-yl) -4- [benzyl (4- {benzyl (4
-Tolyl) amino {phenyl) amino] benzamide (536 mg) in THF (5 ml) and methanol (5 ml).
% Palladium on carbon (134 mg) and under 1 atm of hydrogen,
Stirred at room temperature for 12 hours. The mixture was filtered and concentrated.
The residue was purified by chromatography to give the title compound (202 mg). Table 1 shows the chemical structural formula and physical properties of this compound.

Crystallization method of the compound of Example 2 (1) Example 2 after column purification Compound N- (2,3-dihydro-5-methyl-1H-indol-1-yl) -4-
[4-{(4-methylphenyl) amino} phenylamino] benzamide (1 mg) was dissolved in ethyl acetate (3 ml) under heating, and isopropyl ether (9 ml) was added.
The mixture was brought to room temperature and filtered to obtain crystals. Melting point: 149 ° C

Crystallization Method of Compound of Example 2 Part 2 N- (2,3-dihydro-5-
Methyl-1H-indol-1-yl) -4- [4-
The crude crystals of {(4-methylphenyl) amino} phenylamino] benzamide were treated with activated carbon in methanol and tetrahydrofuran. The obtained compound (1 mg) was suspended in ethyl acetate (4 ml), refluxed for 2 hours, brought to room temperature, and filtered to obtain a crystal. Melting point: 183 ° C

Example 3 N- [2,3-dihydro-5- (trifluoromethyl)
-1H-indol-1-yl] -4- [4-{(4-
Preparation of methylphenyl) amino {phenylamino] benzamide (1) Step: Preparation of ethyl [2-nitro-5- (trifluoromethyl) phenyl] acetic acid 4-nitrobenzotrifluoride (5 g) and ethyl chloroacetate (3.85) g) in THF (30 ml)
A solution of -butoxide (7.05 g) in THF (70 ml) was added in small portions at -78 ° C over 15 minutes, and the mixture was stirred at -50 ° C for 0.5 hour. The mixture was then quenched with 10% aqueous citric acid and extracted with ethyl acetate. The organic layer is washed with distilled water and saline,
Concentrated. The residue was purified by chromatography to give the title compound (6.30 g). (2) Step: Production of 2- [2-nitro-5- (trifluoromethyl) phenyl] ethanol A solution of ethyl [2-nitro-5- (trifluoromethyl) phenyl] acetic acid (6.30 g) in dichloromethane (60 ml). To the mixture was added diisobutylaluminum hydride (1.0 M THF solution, 67.5 ml) at -78 ° C, and the mixture was heated to 0 ° C and stirred.
Next, after the mixture was quenched with methanol, hydrochloric acid was added, the mixture was stirred, and extracted with ethyl acetate. The organic layer was washed with distilled water and brine, and concentrated. The residue was purified by chromatography to give the title compound (3.71 g). (3) Step: Preparation of 2- [2-amino-5- (trifluoromethyl) phenyl] ethanol THF of 2- [2-nitro-5- (trifluoromethyl) phenyl] ethanol (3.71 g) in THF (10 ml). To the solution was added 5% palladium-carbon (0.778 mg), and the mixture was heated at room temperature under 1 atm of hydrogen.
Stir for 2 hours. Then the mixture was filtered and concentrated.
The residue was purified by chromatography to give the title compound (3.24 g).

Step (4): Production of 2- [2- (t-butoxycarbonyl) amino-5- (trifluoromethyl) phenyl] ethanol 2- [2-amino-5- (trifluoromethyl) phenyl] ethanol (3.24 g) and triethylamine (10 ml)
To a THF (50 ml) solution of di-t-butyl dicarbonate (1
2.57 g) and refluxed for 6 hours. The mixture was concentrated and dissolved in THF (15 ml) -methanol (15 ml).
A 4N aqueous sodium hydroxide solution (30 ml) was added to the solution, and the mixture was stirred at room temperature for 12 hours. Then the mixture is 10%
Quenched with aqueous citric acid and extracted with ethyl acetate.
The organic layer was washed with distilled water and brine, and concentrated. The residue was purified by chromatography to give the title compound (3.
30 g). (5) Step: 1- (t-butoxycarbonyl) -5
Production of (trifluoromethyl) indoline 2- [2- (t-butoxycarbonyl) amino-5
(Trifluoromethyl) phenyl] ethanol (3.30
g) and triphenylphosphine (4.25 g) in THF (100 ml)
Diethyl azodicarboxylate (2.55 ml) was added to the solution.
C. and stirred at room temperature for 2 hours. Then the mixture was diluted with ethyl acetate, washed with brine and concentrated. The residue was purified by chromatography to give the title compound (2.45 g). (6) Step: Production of 5- (trifluoromethyl) indoline 1- (t-butoxycarbonyl) -5- (trifluoromethyl) indoline (2.45 g) in chloroform (20 ml)
To the mixture was added trifluoroacetic acid (20 ml) at 0 ° C., and the mixture was heated to room temperature and stirred for 1 hour. Then the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate.
The organic layer was washed with distilled water and brine, and concentrated. The residue was purified by chromatography to give the title compound (1.
56g).

Step (7): Preparation of 1-amino-5- (trifluoromethyl) indoline hydrochloride 6N of 5- (trifluoromethyl) indoline (1.18 g)
An aqueous solution (6 ml) of sodium nitrite (480 mg) was added dropwise to the hydrochloric acid (12 ml) solution at -10 ° C, and the mixture was stirred at -10 ° C for 1 hour. The mixture was extracted with diethyl ether. The extract was washed with brine and concentrated to give 1-nitroso-5-
(Trifluoromethyl) indoline was obtained. Zinc powder (1.
1-Nitroso-5- in a suspension of 24 g) of distilled water (18 ml).
A solution of (trifluoromethyl) indoline in acetic acid (12 ml) was added dropwise at 0 ° C, and the mixture was stirred at 0 ° C for 2 hours. Dichloromethane was added to the mixture and the mixture was filtered. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and brine,
Concentrated. The residue was purified by chromatography to obtain 1-amino-5- (trifluoromethyl) indoline. A solution of 1-amino-5- (trifluoromethyl) indoline in ethyl acetate was treated with 4M hydrogen chloride in ethyl acetate and concentrated to give the title compound (837m
g) was obtained. Step (8): N- [2,3-dihydro-5- (trifluoromethyl) -1H-indol-1-yl] -4-
Production of [benzyl (4- {benzyl (4-methylphenyl) amino} phenyl) amino] benzamide 4- {benzyl [4-] obtained in step (2) of Example 2
{Benzyl (4-tolyl) amino {phenyl] amino}
Oxalic acid chloride (0.105m) was added to a solution of benzoic acid (498mg) in chloroform (10ml), and the mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated to give the acid chloride. 1-amino-5- (trifluoromethyl) indoline hydrochloride (238m
g) in chloroform (5 ml) solution, pyridine (0.808m
l) was added, followed by the addition of a solution of the above acid chloride in chloroform (5 ml), followed by stirring at room temperature for 12 hours. The mixture was diluted with ethyl acetate, washed with a 10% aqueous citric acid solution, distilled water and brine, and concentrated. The residue was purified by chromatography to give the title compound (444 mg). Step (9): N- [2,3-dihydro-5- (trifluoromethyl) -1H-indol-1-yl] -4-
Preparation of [4-{(4-methylphenyl) amino} phenylamino] benzamide N- [2,3-dihydro-5- (trifluoromethyl)
-1H-indol-1-yl] -4- [benzyl (4
-{Benzyl (4-methylphenyl) amino} phenyl) amino] benzamide (444 mg) in a solution of THF (5 ml) and methanol (5 ml) in 5% palladium-carbon (444 m
g) was added and the mixture was stirred at room temperature under 1 atm of hydrogen for 12 hours.
The mixture was filtered and concentrated. The residue was purified by chromatography to give the title compound (171 mg). Table 1 shows the chemical structural formula and physical properties of this compound.

Example 4-43 The compounds of Examples 4 to 43 were obtained in the same manner as in Examples 1 to 3. Tables 1 to 11 show the chemical structural formulas and physical properties of this compound.

Example 44 N- (5-methylindol-1-yl) -4- [4-
Preparation of {(4-methylphenyl) amino} phenylamino] benzamide N- (2,3-dihydro-5 obtained according to Example 2
-Methyl-1H-indol-1-yl) -4- [4-
{(4-Methylphenyl) amino} phenylamino] benzamide (50 mg) in 1,4-dioxane (5 ml)
-Dichloro-5,6-dicyano-1,4-benzoquinone (25 mg) was added at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was filtered, and the filtrate was diluted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate solution and concentrated to obtain the title compound (34 mg). Table 12 shows the chemical structural formula and physical properties of this compound.

Example 45 In the same manner as in Example 44, the compound of Example 45 was obtained.
Table 12 shows the chemical structural formula and physical properties of this compound.

In the same manner as in Examples 1 to 45, compounds 1001 to 1351 shown in Tables 14 to 19 can be obtained.

[0078]

[Table 1]

[0079]

[Table 2]

[0080]

[Table 3]

[0081]

[Table 4]

[0082]

[Table 5]

[0083]

[Table 6]

[0084]

[Table 7]

[0085]

[Table 8]

[0086]

[Table 9]

[0087]

[Table 10]

[0088]

[Table 11]

[0089]

[Table 12]

Next, a method for evaluating the amyloid β inhibitory activity and the antioxidant activity of the compound of the present invention will be described. 1. Measurement of Amyloid β Aggregation Inhibitory Activity i. Method for Preparing Amyloid β 1-40 Peptide Seed Fiber Suspension Fiber as seed for amyloid β aggregation (seed fibril)
The following suspension was prepared. Synthetic amyloid β 1-4
0 peptide (manufactured by American peptide company or Peptide Research Institute, purity> 95%, hereinafter referred to as amyloid β) was dissolved in hexafluoroisopropanol to obtain a 0.5 mg / mL amyloid β solution. Then sonicate at room temperature (10mi
After complete dissolution according to n), and after lyophilization, it was stored at -20 to -80 ° C or lower. Deionized purified water was added to the lyophilized amyloid β, and the whole was completely dissolved by sonication (5 min) at room temperature to obtain a 0.5 mg / mL amyloid β solution. Next, the suspension was incubated at 37 ° C. for 18 hours in a thermostatic shaking incubator to prepare a suspension of the target amyloid β seed fiber. As confirmation of fiber formation, Congo-R by Congo-Red method (Note 1)
The ed binding concentration was measured. Note 1: Amyloid β fiber suspension (10 μL) was added to 25 μM Congo-Red-containing phosphate buffer (90 μL), allowed to stand at room temperature for 30 minutes, and the absorbance at 477 and 540 nm was measured. -Red binding concentration was determined. Congo-Red binding concentration calculation formula: (μM) = (OD540 × 39.
5)-(OD477 x 29.6)

Ii. Measurement of Amyloid β Aggregation Inhibitory Activity A suspension (50 μL / well) containing the 250 μg / mL amyloid β solution prepared from the lyophilized amyloid β and the 25 μg / mL amyloid β seed fiber suspension and the test Compound (1mM)
The contained DMSO solution (1 μL / well) was dispensed into a 96-well plate. After the plate was covered, it was humidified and sealed in a plastic bag, stirred with a plate mixer (10 min), and allowed to undergo a natural agglutination reaction (37 ° C., 150 rpm, 18 hours) in a thermostatic shaking incubator. Next, 3 μM Thioflavin-T / 50m was added to 51 μL of the reaction solution.
Add M sodium phosphate buffer (pH 6,200μl) and add Pl
After stirring with an ate mixer (10 min), a fluorescent plate reader (Tecan: Fluor-Star with BIORASE, excitation filter = 4)
The fluorescence intensity was measured using 50 nm, fluorescence Filter = 480 nm, Gain = 0-25, flash time = 10) (Thioflavin-T fluorescence colorimetric method). Amyloid β aggregation inhibitory activity of the compound of the present invention (IC
₅₀ ) is the fluorescence intensity when the test substance is added and 25 μg / mL
It was calculated from the fluorescence intensity when the amyloid β suspension (50 μL) was added. The results are shown in Table 13.

2. Measurement of Antioxidant Action As an evaluation of the antioxidant action of the compound of the present invention, the action of mouse compounds on lipid autoxidation was measured. i. Preparation of mouse brain homogenate supernatant fraction A male mouse (manufactured by CRJ: C57 / BL6N species, body weight: 18-22 g) was decapitated, the whole brain was removed, the cerebellum and medulla oblongata were removed, and the weight was measured. 9 volumes of ice-cold 20 mM Tris-HCl buffer (p
H.7.4) and homogenized (Teflon (registered trademark) Potter, 20 times), followed by centrifugation (3000 rpm, 10 minutes, 4 ° C).
Then, a brain homogenate supernatant fraction was obtained. The supernatant fraction was stored at -30 ° C until use. ii. Measurement of anti-lipid peroxide activity The above-mentioned brain homogenate supernatant was incubated in a constant temperature incubator at 37 ° C. for 0-120 minutes, and the amount of lipid peroxide produced was determined as N-methyl-2-phenyl as a malondialdehyde-like substance. The measurement was carried out using an indole color development kit (manufactured by BIOXYTECH: LPO 586 TM). Specifically, the above-mentioned frozen brain homogenate supernatant (0.20 mL) was added with various concentrations of a test substance DMSO solution (2 μL).
Was added and incubated in a constant temperature shaking incubator (37 ° C., 0-120 minutes). Add R1 Mix coloring solution (10.3m
MN-methyl-2-phenylindole / acetonitrile
25% methanol (0.65 ml) and 15.4 M methanesulfonic acid solution (0.15 mL) were added, heated (45 ° C, 40 min), and centrifuged (1000 rpm, 15 min).
0.3 mL) was transferred to a micro cuvette or a 96-well plate, and the absorbance at 586 nm was measured. DMSO as a positive control
(2.5 μL) and the reaction solution incubated at 37 ° C. and 4 ° C. for 30 minutes in an incubator for 30 minutes in the same manner as described above. Lipid peroxide calculated from the difference in the absorbance at 586 nm of the supernatant obtained by the same procedure. Assuming the amount to be 100% (inhibition rate 0%), the lipid autoxidation inhibition rate (IC ₅₀ ) was calculated from the absorbance when each compound was added. The results are shown in Table 13.

[0093]

[Table 13]

[0094]

[Table 14]

[0095]

[Table 15]

[0096]

[Table 16]

[0097]

[Table 17]

[0098]

[Table 18]

[0099]

[Table 19]

[0100]

[Table 20]

[0101]

[Table 21]

[0102]

[Table 22]

[0103]

[Table 23]

[0104]

[Table 24]

[0105]

[Table 25]

[0106]

[Table 26]

[0107]

[Table 27]

[0108]

[Table 28]

[0109]

[Table 29]

[0110]

[Table 30]

[0111]

[Table 31]

[0112]

[Table 32]

[0113]

[Table 33]

[0114]

[Table 34]

[0115]

[Table 35]

[0116]

[Table 36]

[0117]

[Table 37]

Examples of preparations are shown below, but it should not be construed that the invention is limited thereto. Formulation Examples (a) 10 g of the compound of Example 1 (b) lactose 50 g (c) corn starch 15 g (d) sodium carboxymethylcellulose 44 g (e) magnesium stearate 1 g (a), (b), the total amount of (c) and 30 g of (d) is kneaded with water, dried in vacuum, and then granulated. 14 at the end of this granulation
g (d) and 1 g (e) are mixed and made into tablets with a tableting machine to produce 1000 tablets each containing 10 mg of (a).

[0119]

As is apparent from the above results, the compounds of the present invention have an amyloid β aggregation-inhibiting action and also have an antioxidant action. Therefore, these compounds, as an inhibitor of amyloid β aggregation, and as a drug having both an aggregation inhibitory action and an antioxidant action of amyloid β, amnesia, dementia,
It can be an agent for treating and preventing Alzheimer's disease, particularly Alzheimer's dementia.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/28 A61P 25/28 39/06 39/06 43/00 111 43/00 111 C07D 209/08 C07D 209/08 // A61K 7/00 A61K 7/00 CD (72) Inventor Yoshinori Kosugi 1-1, Muramachi, Takatsuki-shi, Osaka F-term in Japan Tobacco Inc. Pharmaceutical Research Institute 4C083 AC641 AC851 CC01 CC02 EE01 EE09 EE12 EE14 FF01 4C086 AA01 AA02 AA03 BC13 MA01 MA04 NA14 ZA15 ZA16 ZA89 ZB01 ZC02 4C204 BB01 CB03 DB01 EB02 FB35 GB03 4C206 AA01 AA02 AA03 HA03 MA01 MA04 ZA01 ZA01 Z04A01

Claims (13)

[Claims] 1. An N-arylhydrazide compound represented by the following general formula [I] or a pharmaceutically acceptable salt thereof. Embedded image 意味 In the above general formula, the meaning of each symbol is as follows. 1. R ^a , R ^a1 and R ^a2 are the same or different and are each (1) a hydrogen atom, (2) a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from Group A below. , (3) _{C 1-6} alkoxy group, (4) nitro group, (5) halogen atom, (6) amino, (7) _{C 1-4} alkylamino group, (8) di _{(C 1-4} alkyl ) amino group, (9) a cyclic amino group, (10) cyano group, (11) carboxyl group, (12) C _1-6 alkoxycarbonyl group, (13) aryl group, (14) hydroxyl, or (15) (Here, group A is (1 ′) halogen atom, (2 ′) nitro group, (3 ′) amino group, (4 ′) cyano group, (5 ′) carboxyl group, (6 _{') C 1-6} alkoxy group, _(7' means a group _{of) C 1-6} alkoxycarbonyl group and (8 ') an aryl group.) 2. R ^{1, R 2} and ^{R 3} are the same or different and each is (1) hydrogen atom, (2) _{C 1-6} alkyl group, or, (3) ^{R 1} is taken together with ^{R a} - (CH ₂ ) ₂ -,-(C
_{H 2) 3 -, - CH} = CH -, - CH 2 -CH = CH- or -CH = CH-CH ₂ - to form 3. 3. R ^b1 and R ^b2 are the same or different and each means (1) a hydrogen atom, (2) an arylalkyl group, (3) an arylamino group, or (4) an arylalkylamino group; R ^c1 and R ^c2 are the same or different and are (1) a hydrogen atom, (2) a C _1-6 alkyl group _optionally substituted with 1 to 3 substituents selected from the above group A, (3 ) C _1-6 alkoxy, (4) nitro, (5) halogen, (6) amino, (7) C _1-4 alkylamino, (8) di (C _1-4 alkyl) amino , (9) a cyclic amino group, (10) cyano group, (11) carboxyl group, (12) C _1-6 alkoxycarbonyl group, (13) aryl group, (14) hydroxyl, or (15) a mercapto group Meaning, 5. R ^c is represented by (1) a hydrogen atom, or (2) Wherein X is (1 ′)-NR ^d1 − where R ^d1 represents a hydrogen atom or a C _1-6 alkyl group. ^{(2 ') - NR d1 CO-} (R d1 is as defined above.), (3') - CONR d1 - (R d1 is as defined above.), (4 ') - O-, ( 5 ′) — S—, (6 ′) — CO—, (7 ′) — CH ₂ —, or (8 ′) — (CH ₂ ) ₂ —, and ring A is (1 ′) An aryl group selected from a phenyl group or a naphthyl group which may be substituted with 1 to 3 substituents selected from Group B, (2 ′) an aryl group substituted with 1 to 3 substituents selected from Group B below A 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or (3 ′) 1 to 3 selected from the following group B Means a C _3-7 cycloalkyl group which may be substituted with a substituent of (Here, the group B is (1 ″) a substituent selected from the group A, and (2 ″) a C _1- which may be substituted with 1 to 3 substituents selected from the group A. _It means a group consisting of ₆ alkyl groups.) 2. The N-arylhydrazide compound according to claim ¹ , wherein R ¹ , R ² and R ³ are a hydrogen atom, or a pharmaceutically acceptable salt thereof. 3. R ¹ together with ^Ra is — (CH ₂ )
_{2 -, - (CH 2)} 3 -, - CH = CH -, - CH 2 -CH =
CH- or -CH = CH-CH ₂ - to form its ^{salt R 2} and ^{R 3} are allowed N- aryl hydrazide compound or a pharmaceutical according to claim 1, which is a hydrogen atom. 4. R ¹ together with ^Ra is — (CH ₂ ) ₂ —
Or the N-arylhydrazide compound or a pharmaceutically acceptable salt thereof according to claim 3, which forms -CH = CH-. 5. A compound of the formula [I] 5. The N-position according to claim 1, wherein the substitution position of (wherein each symbol is as defined in claim 1) is meta-position or para-position with respect to the substitution position of hydrazide on the benzene ring. -An arylhydrazide compound or a pharmaceutically acceptable salt thereof. 6. A method according to claim 1, wherein R ^c is (Wherein each symbol is as defined in claim 1), and R ^c
A salt thereof to substitution position of, that is meta or N- aryl hydrazide compound according to any one of claims 1 to 5 is para or a pharmaceutically acceptable ^- substitution positions, -NR 3 on the benzene ring of . 7. R ^b1 , R ^b2 , R ^c1 and R ^c2 are:
7. The N-arylhydrazide compound according to claim 1, which is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 8. The method according to claim 1, wherein R ^a1 and R ^a2 are the same or different and each is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a nitro group which may be substituted with a halogen atom. Or the pharmaceutically acceptable salt thereof. 9. When R ^c is: And X is —NR ^d1 —, R ^d1 is a hydrogen atom, and ring A is further substituted with 1 to 3 substituents selected from group B according to claim 1. 9. The N-arylhydrazide compound according to claim 1, which is a phenyl group, or a pharmaceutically acceptable salt thereof. 10. 4- [4-{(4-methylphenyl)
Amino [phenylamino] benzoic acid 2- [4- (trifluoromethyl) phenyl] hydrazide, N- (2,3
-Dihydro-5-methyl-1H-indol-1-yl) -4- [4-{(4-methylphenyl) amino} phenylamino] benzamide, N- [2,3-dihydro-5- (trifluoromethyl ) -1H-indole-1
-Yl] -4- [4-{(4-methylphenyl) amino} phenylamino] benzamide, 4- (phenylamino) benzoic acid 2-phenylhydrazide, 4- (phenylamino) benzoic acid 2- (2-nitro Phenyl) hydrazide, 3- (phenylamino) benzoic acid 2- (2
-(Nitrophenyl) hydrazide, 2- (phenylamino) benzoic acid 2- (2-nitrophenyl) hydrazide, 4- (phenylamino) benzoic acid 2- (2-methoxyphenyl) hydrazide, 4- (phenylamino) benzoic acid 2- [2- (trifluoromethyl) phenyl]
Hydrazide, 4- (phenylamino) benzoic acid 2-
[4- (trifluoromethyl) phenyl] hydrazide,
4- (phenylamino) -2- (3-phenylpropyl) benzoic acid 2-phenylhydrazide, 4- (phenylamino) -2- (3-phenylpropyl) benzoic acid
2- (2-methoxyphenyl) hydrazide, 4- (phenylamino) -2- (3-phenylpropyl) benzoic acid 2- [2- (trifluoromethyl) phenyl] hydrazide, 4- (phenylamino) -2- (3-phenylpropyl) benzoic acid 2- [4- (trifluoromethyl)
Phenyl] hydrazide, N- (2,3-dihydro-1H
-Indol-1-yl) -4- (phenylamino) benzamide, 4- (phenylamino) benzoic acid 2-methyl-2-phenylhydrazide, 4- (phenylamino) benzoic acid 1-methyl-2-phenylhydrazide,
4- [3- (phenylamino) phenylamino] benzoic acid 2-phenylhydrazide, 4- [3- (phenylamino) phenylamino] benzoic acid 2- (2-methoxyphenyl) hydrazide, 4- [3- (phenyl) amino)
Phenylamino] benzoic acid 2- [2- (trifluoromethyl) phenyl] hydrazide, 4- [3- (phenylamino) phenylamino] benzoic acid 2- [4- (trifluoromethyl) phenyl] hydrazide, 4- [ 4-
(Phenylamino) phenylamino] benzoic acid 2-phenylhydrazide, 4- [4- (phenylamino) phenylamino] benzoic acid 2- (2-methoxyphenyl)
Hydrazide, 4- [4- (phenylamino) phenylamino] benzoic acid 2- [2- (trifluoromethyl) phenyl] hydrazide, 4- [4- (phenylamino) phenylamino] benzoic acid 2- [4- ( Trifluoromethyl) phenyl] hydrazide, 4- [4- {4- (methoxy) phenylamino} phenylamino] benzoic acid 2
-[4- (trifluoromethyl) phenyl] hydrazide, 4- [4- {4- (methyl) phenylamino} phenylamino] benzoic acid 2- (4-methylphenyl) hydrazide, 4- [4- (phenylcarbamoyl) ) Phenylamino] benzoic acid 2-phenylhydrazide, 4-
[4- (phenylcarbamoyl) phenylamino] benzoic acid 2- (2-methoxyphenyl) hydrazide, 4-
[4- (Phenylcarbamoyl) phenylamino] benzoic acid 2- [2- (trifluoromethyl) phenyl] hydrazide, 4- [4- (phenylcarbamoyl) phenylamino] benzoic acid 2- [4- (trifluoromethyl) Phenyl] hydrazide, 4- [3- (phenylcarbamoyl) phenylamino] benzoic acid 2-phenylhydrazide, 4- [3- (phenylcarbamoyl) phenylamino] benzoic acid 2- (2-methoxyphenyl) hydrazide, 4- [ 3- (phenylcarbamoyl) phenylamino] benzoic acid 2- [2- (trifluoromethyl) phenyl] hydrazide, 4- [3- (phenylcarbamoyl) phenylamino] benzoic acid 2- [4- (trifluoromethyl) phenyl Hydrazide, 4- [4-
(Benzoylamino) phenylamino] benzoic acid 2-
Phenylhydrazide, 4- [4- (benzoylamino)
Phenylamino] benzoic acid 2- (2-methoxyphenyl) hydrazide, 4- [4- (benzoylamino) phenylamino] benzoic acid 2- [2- (trifluoromethyl) phenyl] hydrazide, 4- [4- (benzoyl) Amino) phenylamino] benzoic acid 2- [4- (trifluoromethyl) phenyl] hydrazide, 4- [3- (benzoylamino) phenylamino] benzoic acid 2-phenylhydrazide, 4- [3- (benzoylamino) phenyl Amino] benzoic acid 2- (2-methoxyphenyl)
Hydrazide, 4- [3- (benzoylamino) phenylamino] benzoic acid 2- [2- (trifluoromethyl)
Phenyl] hydrazide, 4- [3- (benzoylamino) phenylamino] benzoic acid 2- [4- (trifluoromethyl) phenyl] hydrazide, N- (5-methylindol-1-yl) -4- [4- {(4-methylphenyl) amino} phenylamino] benzamide and N
The N-aryl hydrazide according to claim 1, wherein the N-aryl hydrazide is selected from the group consisting of-[5- (trifluoromethyl) indol-1-yl] -4- [4-{(4-methylphenyl) amino} phenylamino] benzamide. A compound or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition comprising the N-arylhydrazide compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 12. An amyloid β aggregation inhibitor comprising the N-arylhydrazide compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 13. A therapeutic agent for dementia and / or amnesia comprising the N-arylhydrazide compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient. Prophylactic agent.