JP6962572B2 - 2,4-Diaminophenol derivative and tau and / or amyloid β aggregation inhibitor - Google Patents

Description

The present invention comprises 2,4-diaminophenol derivatives and aggregates of tau aggregates that cause nerve loss and synaptic loss and / or amyloid β (hereinafter referred to as Aβ) that causes amyloid plaque and the like. With respect to aggregation inhibitors that inhibit the formation of.

Alzheimer's disease (AD) is a type of dementia whose main symptoms are cognitive decline and personality changes. Dementia is a common disease that affects about 25% of the Japanese population over the age of 85. According to an estimate issued by the Ministry of Health, Labor and Welfare in 2012, there are about 4.62 million elderly people with dementia in Japan, 70% of whom are AD. In addition, it is said that there are as many as 4 million reserve forces, and the number of patients will continue to increase as the population ages in the future. This is a serious problem especially in Japan, where the birthrate is declining and the population is aging.

Acetylcholinesterase inhibitors, which are currently the most effective for the prevention and treatment of AD, have only partial effects in mild to moderate patients, and negative views on their effectiveness in patients with advanced disease. There are many.

The neuropathological findings of AD patients are characterized by senile plaque consisting of Aβ and neurofibrillary tangles (NFT) formed by abnormal polymerization of tau protein.

In frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), mutations in the tau gene promote NFT formation and reduce cognitive function, and tau protein aggregates and accumulates in the brain. It has become clear that abnormalities occur in nerve cells just by doing so. Therefore, in recent years, much attention has been paid to the relationship between tau aggregation and the onset of AD.

Tau protein is abundant in central neurons and is an essential protein for the function of nerve axons that make up the neural network of the brain. It causes the death of nerve cells.

Patent Document 1 describes a drug containing a naphthoquinone-type compound as a main component for improving the symptoms of AD. This drug suppresses intracellular tau aggregation to some extent, and thus suppresses the formation of NFTs, thereby alleviating the symptoms of AD.

Amyloid plaque in the brains of AD patients is also an important pathological feature, formed mainly by the accumulation and aggregation of Aβ in the brain parenchyma. In AD patients, the brain metabolism of Aβ becomes abnormal for some reason, and it is said that amyloid fibers formed by the accumulation and aggregation of Aβ cause cell death of nerves. In recent years, Aβ oligomers formed during the Aβ aggregation process. Is attracting attention as showing neurotoxicity, and inhibition of the agglutination process of Aβ is expected to be effective as an AD treatment.

Japanese Patent Application Laid-Open No. 2004-534854 However, it cannot be said that the above-mentioned drug containing a naphthoquinone-type compound as a main component can accurately treat AD.

The present invention has been made in view of the above problems, and is a 2,4-diaminophenol derivative and a tau and / or Aβ aggregation inhibitor capable of sufficiently inhibiting intracellular tau and / or Aβ aggregation. The purpose is to provide.

The compound according to the present invention is a compound having the following formula (I) or a salt thereof.

here,
Q is (i) a hydrogen atom, (ii) a methyl group substituted at the 6-position, (iii) an N-methylpyrrole group, and (iv) a methoxymethyl group .
In formula (II) and (III),

(ここで、１若しく２個の置換基Ｘは-Ｒ₁₀-Ｙと表記され、Ｒ₁₀は化学結合、Ｏ、カルボニル、カルボキシル基、Ｃ１〜Ｃ６アルキル基で、Ｙは水素原子、炭素数１〜６の直鎖若しくは枝鎖のアルキル基、置換基を有しても良いフェニル基であり、環内に２個の置換基Ｘがある場合はそれら置換基Ｘは互いに結合して環を形成してもよい。)、

(ここで、Ｘは-Ｒ₁₀-Ｙと表記され、Ｒ₁₀は化学結合、Ｏ、カルボニル、カルボキシル基、Ｃ１〜Ｃ６アルキル基で、Ｙは水素原子、置換基を有しても良い炭素数１〜６の直鎖若しくは枝鎖のアルキル基、シクロアルキル基、置換基を有しても良いフェニル基、Ｎ、Ｏ又はＳ含有ヘテロ環、ＮＲ₁₁Ｒ₁₁’基（Ｒ₁₁及びＲ₁₁’はそれぞれ独立に、水素原子、置換若しくは未置換のアルキル基、置換若しくは未置換のアルケニル基、又は、置換若しくは未置換のアリール基を表わす。ここで、Ｒ₁₁とＲ₁₁’とが結合して環を形成しても良い。）である。)、

(ここで、Ｘはフェニル基、メチル基である。)、

(ここで、１若しく２個の置換基Ｘは-Ｒ₁₀-Ｙと表記され、Ｒ₁₀は化学結合、Ｃ１〜Ｃ６アルキル基で、Ｙは水素原子、炭素数１〜６の直鎖若しくは枝鎖のアルキル基であり、環内に２個の置換基Ｘがある場合はそれら置換基Ｘは互いに結合して環を形成してもよい。)、

、

又は

であり、
式(III)は、

、

、

、

、

(ここで、１若しく２個の置換基Ｘは、水素原子、メチル、ジメチル、フェニル、４-フェニルメチル基である。)、
又は

である。 Equation (II) is

(Here, one or two substituents X are _{written as -R 10-} Y, R ₁₀ is a chemical bond, O, carbonyl, carboxyl group, C1 to C6 alkyl group, and Y is a hydrogen atom and the number of carbon atoms. It is a phenyl group which may have a linear or branched alkyl group of 1 to 6 or a substituent, and when there are two substituents X in the ring, the substituents X are bonded to each other to form a ring. May be formed.),

(Here, X is _{written as -R 10-} Y, R ₁₀ is a chemical bond, O, carbonyl, carboxyl group, C1-C6 alkyl group, Y is a hydrogen atom, the number of carbon atoms which may have a substituent. 1-6 linear or alkyl group Edakusari, cycloalkyl group which may have a substituent phenyl group, N, O or S containing heterocycle, NR ₁₁ R ₁₁ 'group (R ₁₁ and R _11' They are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted aryl group. wherein, R ₁₁ and R ₁₁ 'are bonded to A ring may be formed.)),

(Here, X is a phenyl group and a methyl group.),

(Here, one or two substituents X are _{written as -R 10-} Y, R ₁₀ is a chemical bond, a C1 to C6 alkyl group, Y is a hydrogen atom, a linear or linear group having 1 to 6 carbon atoms. If it is an alkyl group of a branch chain and there are two substituents X in the ring, the substituents X may be bonded to each other to form a ring.),

,

Or

And
Equation (III) is

,

,

,

,

(Here, one or two substituents X are a hydrogen atom, methyl, dimethyl, phenyl, 4-phenylmethyl group.),
Or

Is.

However, the following compounds are excluded from the formula (I).

The tau aggregation inhibitor according to the present invention is a group consisting of treatment, diagnosis, symptom relief and prevention of amyloidosis caused by aggregation of tauopathy and / or Aβ, which contains a compound represented by the following formula (V) or a salt thereof. A tau and / or Aβ aggregation inhibitor used in at least one application selected from.

here,
R ₆ , R ₇ , R ₈ and R ₉ are (i) hydrogen atom, (ii) cyclohexyl group, (iii) isopentyl group, (iv) isopropyl group, (v) phenylethyl group, (v) phenylethyl group, (i) hydrogen atom, (ii) cyclohexyl group, (iii) isopentyl group, (iv) isopropyl group, (v) vi) If the methyl group and (vii) R ₆ and R ₇ are not hydrogen atoms, they are bonded via several atoms and R ₆ and R ₇ form a monocyclic or compound ring, ( viii) When both R ₈ and R ₉ are not hydrogen atoms, they are bonded via several atoms and R ₈ and R ₉ form a monocyclic or compound ring.

According to the present invention, intracellular tau aggregation can be sufficiently inhibited. Therefore, in the present age of aging society by relieving patients suffering from tauopathy such as AD for which there is no effective treatment, many societies are improving the lives of the elderly, reducing the burden of long-term care, and reducing medical expenses. Contribution is possible.

Of 2,4-bis (1-piperidyl) phenol dihydrochloride (KT-401) and 2,4-bis (7-azabicyclo [2.2.1] heptane-7-yl) phenol dihydrochloride (KT-417) It is a figure which shows the concentration dependence about the tau agglutination inhibitory activity.

Hereinafter, embodiments of the present invention will be specifically described with reference to the accompanying drawings, but the embodiments are for facilitating understanding of the principles of the present invention, and the scope of the present invention is as follows. The present invention is not limited to the embodiment, and other embodiments in which those skilled in the art appropriately replace the configurations of the following embodiments are also included in the scope of the present invention.

As a result of diligent research, the present inventors have found that the compound represented by the following formula (I) or a salt thereof has a tau aggregation inhibitory action and / or an Aβ aggregation inhibitory action, which is caused by the aggregation of tauopathy and / or Aβ. We have found a new finding that is beneficial for the prevention and treatment of amyloidosis, and completed the present invention based on this fact.

here,
Q is, (i) a hydrogen atom, (ii) N, O or an alkyl group which may have a heteroatom consisting of S, aryl group, aralkyl group, or an alkoxyalkyl group, and (iii) R ₅ -Y Notated,
R ₅ is (i) a chemical bond, (ii) a heteroatom consisting of O or S, (iii) a carbonyl or carboxyl group, (iv) a C1-6 alkyl group or a C2-6 alkenyl group, and
Y is (i) hydrogen, (ii) one or a plurality of independent substituents (the substituent of Y is a lower alkyl, a lower alkenyl, a lower alkynyl, to which one or more fluorine atoms may be bonded, An homocyclic or heterocycle which may have an alkoxy group, a carboxyl group, or an ester group to which a halogen atom, a hydroxyl group, or a plurality of fluorine atoms may be bonded, and (iii) a substituent (this substituent is , Alkyl group with 1 to 4 carbon atoms, alkoxy group, alkoxyalkyl group, ester group, ester alkyl group, or phenyl group, pyridyl group, amino group, hydroxyl group, thiol group, fluorine atom, chlorine atom) or hetero atoms which may have one or more, linear or alkyl group Edakusari 1 to 6 carbon atoms, independently (iv) NR ₁₁ R ₁₁ 'group (R ₁₁ and R _11' are each a hydrogen atom , substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted aryl group. wherein, R ₁₁ and R ₁₁ 'and may combine with each other to form a ring .) And
The following formulas (II) and (III) have a heteroatom, a double bond, a bridge, or one or two substituents X in each ring (the substituent X of the formula (II) and the formula). It may be the same as or different from the substituent X of (III), and if there are two substituents X in each ring of the formula (II) or the formula (III), the substituents X may be the same. It may be different, and if each ring of formula (II) or formula (III) has two substituents X, the substituents X may be bonded to each other to form a ring). It is also a good 5-10 member cyclic amine,

R ₁ and R ₂ are both hydrogen atoms, or if both R ₁ and R ₂ are not hydrogen atoms, they are bonded via several atoms and R ₁ and R ₂ are monocyclic or compound rings. Forming a ring of equations
R ₃ and R ₄ are both hydrogen atoms, or if both R ₃ and R ₄ are not hydrogen atoms, they are bonded via several atoms and R ₃ and R ₄ are monocyclic or compound rings. Forming a ring of equations
X is written as _{-R 10 -Y,}
R ₁₀ is (i) a chemical bond, (ii) a heteroatom composed of N, O or S, (iii) a carbonyl group or a carboxyl group, (iv) a C1-6 alkyl group or a C2-6 alkenyl group, (v). It is an alkylidene group of C1-4, and
Y is (i) hydrogen, (ii) one or a plurality of independent substituents (the substituent of Y is a lower alkyl, a lower alkenyl, a lower alkynyl, to which one or more fluorine atoms may be bonded, An homocyclic or heterocycle which may have an alkoxy group, a carboxyl group, or an ester group to which a halogen atom, a hydroxyl group, or a plurality of fluorine atoms may be bonded, and (iii) a substituent (this substituent is , Alkyl group with 1 to 4 carbon atoms, alkoxy group, alkoxyalkyl group, ester group, ester alkyl group, or phenyl group, pyridyl group, amino group, hydroxyl group, thiol group, fluorine atom, chlorine atom) or hetero atoms which may have one or more, linear or alkyl group Edakusari 1 to 6 carbon atoms, independently (iv) NR ₁₁ R ₁₁ 'group (R ₁₁ and R _11' are each a hydrogen atom , substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted aryl group. wherein, R ₁₁ and R ₁₁ 'and may combine with each other to form a ring .).

However, the following compounds are excluded from the formula (I).

The formula (II) or (III) is not particularly limited, but can be, for example, any of the following functional groups.

Further, the formula (II) or (III) can be, for example, any of the following functional groups.

Further, the formula (II) or (III) can be, for example, any of the following functional groups.

Further, the formula (II) or (III) can be, for example, any of the following functional groups.

Since compound (IV) is excluded from formula (I) as described above, it is excluded when both formulas (II) and (III) are piperazine rings.

Further, the formula (II) or (III) can be, for example, any of the following functional groups.

When there are two substituents X in the above formula (II) or (III), it is preferable that both of the two substituents X are present in the same atom. In this case, the substituents X can be the same. For example, the following formula shows the case where two methyl groups are present in the same atom of the piperidine ring.

Further, in the above formula (II) or (III), when two substituents X are present in the same atom, the substituents X can be different. For example, in the following formula, piperidine The case where a methyl group and an ethyl group are present in the same atom of the ring is shown.

Further, when there are two substituents X in the above formula (II) or (III), it is also possible that the substituents X are present in different atoms. For example, in the following formula, each atom has a different piperidine ring. The case where a methyl group is present is shown.

Next, the compound having the above formula (I) is specifically represented by the following formula.

The compound having the above formula (I) is specifically represented by the following formula.

The compound having the above formula (I) is specifically represented by the following formula.

The compound having the above formula (I) is specifically represented by the following formula.

The compound having the above formula (I) is specifically represented by the following formula.

The compound having the above formula (I) is specifically represented by the following formula.

The compound having the above formula (I) is specifically represented by the following formula.

The compound having the above formula (I) is specifically represented by the following formula.

The compound having the above formula (I) is specifically represented by the following formula.

The compound having the above formula (I) is specifically represented by the following formula.

The compound having the above formula (I) is specifically represented by the following formula.

The compound having the above formula (I) is specifically represented by the following formula.

The compound having the above formula (I) is specifically represented by the following formula.

The compound having the above formula (I) is specifically represented by the following formula.

The compound having the above formula (I) is specifically represented by the following formula.

The compound having the above formula (I) is specifically represented by the following formula.

The compound having the above formula (I) is specifically represented by the following formula.

The compound having the above formula (I) is specifically represented by the following formula.

KT-410, KT-409, KT-413, KT-417, KT-414, KT-415, and KT-416 can be synthesized as a substituent A derivative by, for example, the following reaction formula.
(Substituent A in the synthetic reaction formula indicates various cyclic amino groups.)

KT-426 and KT-427 can be synthesized as a substituent A derivative by, for example, the following reaction formula.

KT-419 can be synthesized by, for example, the following reaction formula.

KT-424 and KT-425 can be synthesized by, for example, the following reaction formula.

KT-431 and KT-434 can be synthesized as a substituent A derivative by, for example, the following reaction formula.

KT-430, KT-433, KT-436, KT-437, KT-429, KT-432, KT-435, and KT-438 can be synthesized as the substituent A derivative by, for example, the following reaction formula.

KT-441, KT-444, KT-446, KT-447, KT-449, KT-452, KT-454, KT-475, and KT-476 are synthesized as substituent A derivatives by, for example, the following reaction formula. be able to.

For KT-439, KT-440, KT-442, KT-445, KT-448, KT-450, KT-451, KT-453, KT-466, KT-470, KT-471, KT-472, As the substituent A derivative, for example, it can be synthesized by the following reaction formula.

KT-467, KT-468, and KT-469 can be synthesized as a substituent Q derivative by, for example, the following reaction formula. (However, the substituent Q in the synthetic reaction formula is distinguished from the substituent Q in the formula (I) described in claims and the like. The same shall apply hereinafter.)

KT-462 and KT-464 can be synthesized as a substituent A derivative by, for example, the following reaction formula.

For KT-456, KT-457, KT-458, KT-459, KT-460, KT-465, KT-473, KT-474, KT-477, KT-478, for example, the following reaction as a substituent Q derivative It can be synthesized by the formula.

KT-479, KT-480, KT-481, KT-482, KT-483, KT-484, and KT-485 can be synthesized as substituent Q derivatives by, for example, the following reaction formula.

KT-486 can be synthesized by, for example, the following reaction formula.

In addition, as a result of diligent research, the present inventors have found that the compound represented by the following formula (V) or a salt thereof has a tau aggregation inhibitory action and / or an Aβ aggregation inhibitory action, and tauopathy and / or Aβ aggregation. We have found new findings that are beneficial for at least one application selected from the group consisting of treatment, diagnosis, alleviation and prevention of amyloidosis caused by amyloidosis, and based on this fact, the present invention has been completed.

here,
R ₆ , R ₇ , R ₈ and R ₉ are (i) hydrogen atoms and (ii) substituents (these substituents are alkyl groups having 1 to 4 carbon atoms, alkoxy groups and alkoxyalkyl groups), either together or individually. , Esther group, ester alkyl group, or phenyl group, pyridyl group, amino group, hydroxyl group, thiol group, fluorine atom, chlorine atom) or may have one or more heteroatoms, having 1 to 1 carbon atoms. 6 linear or branched alkyl group, 3-8 carbon number cycloalkyl group, phenyl group, pyridyl group, (iii) _{If both R 6} and R ₇ are not hydrogen atoms, they are bonded via several atoms. Then, R ₆ and R ₇ form a monocyclic or compound ring, and (iv) _{if both R 8} and R ₉ are not hydrogen atoms, they are bonded via several atoms to form R ₈ and R. ₉ and 9 form a monocyclic or compound ring type ring.

The compound having the above formula (V) is specifically represented by the following formula.

The compound having the above formula (V) is specifically represented by the following formula.

The compound having the above formula (V) is specifically represented by the following formula.

The compound having the above formula (V) is specifically represented by the following formula.

KT-404, KT-396, KT-397, KT-398, KT-395, and KT-400 can be synthesized as a substituent A derivative by, for example, the following reaction formula.
(However, the substituent A in the synthetic reaction formula indicates an amino derivative.)

KT-402 can be synthesized by, for example, the following reaction formula.

KT-407 can be synthesized by, for example, the following reaction formula.

KT-383 can be synthesized as a substituent A derivative by, for example, the following reaction formula.

The salts of the above compounds also have a tau aggregation inhibitory effect. The salt is a pharmacologically acceptable salt, for example, a metal salt such as an alkali metal salt (for example, potassium salt, sodium salt, etc.), an alkaline earth metal salt (for example, magnesium salt, calcium salt, etc.), or an alkali carbonate. Metals (eg, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metals hydrogen carbonate (eg, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (eg, sodium hydroxide) , Potassium hydroxide, etc.); trialkylamine (eg, trimethylamine, triethylamine, etc.), pyridine, quinoline, piperidine, imidazole, picolin, dimethylaminopyridine, dimethylaniline, N-alkyl-morpholin, DBN, Salts of organic bases such as DBU; salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; formate, acetate, propionate, oxalic acid Salt, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, citrate, carbonate, picrate, methanesulfonate, benzenesulfon Salts of organic acids such as acids, p-toluenesulfonic acid and glutamate.

The tau and / or Aβ aggregation inhibitor according to the present embodiment can also contain at least one effective amount selected from the group consisting of the above compounds and salts thereof, together with a pharmaceutically acceptable carrier. .. As the carrier, a solid such as an excipient or a liquid such as a diluent is used. Specifically, for example, magnesium stearate, lactose, starch, gelatin, agar, talc, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, distilled water and the like.

Tauopathy is a neurodegenerative disease in which phosphorylated tau is accumulated in nerve cells and glial cells. Tauopathy can be, for example, AD, Down's disease, frontotemporal dementia, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), argyrophilic dementia, or neurofibrillary tangles. Dementia, etc., but is not limited to these. Amyloidosis caused by Aβ aggregation is a disease in which Aβ is deposited in the interstitial space and causes organ dysfunction. Amyloidosis caused by Aβ aggregation includes, but is not limited to, for example, AD, Down's syndrome, or cerebral amyloid angiopathy.

Treatment of tauopathy means blocking or ameliorating the progression of tauopathy disorder, diagnosis of tauopathy means determining the type and condition of tauopathy, and reduction of tauopathy symptoms means reducing the symptoms of tauopathy. Meaning to alleviate the degree, preventing the symptoms of tauopathy means preventing the development of tauopathy disorders. The above concepts of treatment, diagnosis, symptom relief, and symptom prevention are common not only for tauopathy but also for amyloidosis caused by Aβ aggregation.

The tau and / or Aβ aggregation inhibitor according to the present embodiment is one or more additives selected from pharmaceutically acceptable isotonic agents, buffers, solubilizers, preservatives, and pH adjusters. Can be appropriately blended.

As the tonicity agent, for example, potassium chloride, sodium chloride, boric acid, mannitol, glycerin, propylene glycol, polyethylene glycol, maltose, sucrose, sorbitol, glucose and the like can be used.

Examples of the buffer include organic acids such as amino acids and succinic acids, inorganic acids such as boric acid and phosphoric acid, and pharmaceutically acceptable salts thereof.

Examples of the solubilizing agent include polymers such as polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, and hydroxypropylmethylcellulose; surfactants such as polysorbate, polyoxyethylene hydrogenated castor oil, and polyoxyethylene polyoxypropylene; and propylene glycol and the like. Polyhydric alcohols; organic acids such as benzoic acid and sorbic acid; amino acids such as aspartic acid, histidine, glycine and lysine can be used.

Examples of preservatives include quaternary ammonium salts such as benzethonium, benzalkonium and benzododecinium, salts of cationic compounds such as chlorhexidine, and paraoxybenzoic acid esters such as methyl paraoxybenzoate and propyl paraoxybenzoate. , Alcohol compounds such as chlorobutanol and benzyl alcohol can be used.

As the pH adjuster, for example, sulfuric acid, hydrochloric acid, acetic acid, lactic acid, calcium hydroxide, potassium hydroxide, sodium hydroxide, magnesium hydroxide, monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine and the like are used. can do.

The dose of the tau and / or Aβ aggregation inhibitor according to the present embodiment is not particularly limited as long as an appropriate effect is produced, and the degree of symptoms, sex, age, etc. of the patient to be administered are taken into consideration. It will be decided as appropriate. For example, the amount of tau aggregation inhibitor can be 0.0001 to 1000 mg per adult per day. The daily dose may be administered once a day, but it is preferably administered in several divided doses a day.

The tau and / or Aβ aggregation inhibitor according to this embodiment can be prepared in a pharmaceutical form according to the administration mode. The oral administration form can be, for example, a solid preparation such as a granule, a pill, a tablet, a capsule, a powder, a liquid preparation, or a liquid preparation form. The parenteral administration form can be, for example, an injection form such as intravenous injection or intramuscular injection.

When tau is phosphorylated, it associates to form tau oligomers. When this tau oligomer grows and has a β-sheet structure, spherical granular tau aggregates are formed. Granular tau aggregates are thought to be composed of about 40 tau molecules. The granular tau aggregates connect to form tau fibers called paired helical filaments (PHFs) (NFT). In recent studies using mouse models, suppressing tau overexpression at the time when NFT was possible improved memory learning in mice, but NFT continued to form. This mainly suggests that neurological dysfunction occurs in the process of forming it rather than NFT. NFT itself is not toxic, and the agglutination process leading up to it is considered to be the main cause of neurotoxicity. The tau aggregation inhibitor according to the present embodiment not only inhibits tau aggregation in the process of connecting granular tau aggregates to form PHF, but also tau in the process of forming spherical granular tau aggregates. It also inhibits aggregation. In addition, degeneration of nerve cells in the brain occurs not only in the accumulation of mutant tau protein but also in the accumulation of normal tau protein, but the tau aggregation inhibitor of the present invention also inhibits the aggregation of normal tau protein. Therefore, it is possible to prevent or treat tauopathy symptoms such as AD.

In addition, the accumulation and aggregation of Aβ in the brain is considered to be located upstream of tau in the pathogenic mechanism of AD, and the Aβ aggregation inhibitor of the present invention suppresses cell death of brain nerves involved in Aβ and tau. Expected to be effective as a prophylactic or therapeutic drug for AD.

Hereinafter, the present invention will be described in more detail with reference to Examples and the like, but the present invention is not limited thereto, and many modifications may be made by a person having ordinary knowledge in the art within the technical idea of the present invention. Is possible.
[Example 1]
Compounds were synthesized as shown below. The following abbreviations may be used.

[Example 1-1] Synthesis of 2,4-bis (azepan-1-yl) phenol dihydrochloride (KT-410)
(Example 1-1-1) 1- [3- (Azepan-1-yl) -4-benzyloxy-phenyl] Synthetic azepan 1-benzyloxy-2,4 in a glass sealed tube under an argon gas stream -Add 1,4-dioxane 30.0 mL, azepane 1.48 mL, t-BuONa 1.05 g, rac-BINAP 437 mg and Pd ₂ (dba) ₃ 321 mg to 1.5 g of dibromobenzene, seal tightly, and stir at room temperature for 15 minutes. , Heated to 80 ° C and stirred for 70 hours. The reaction mixture was returned to room temperature and poured into a mixture of 70 mL each of AcOEt and water, and then the insoluble material was filtered off. The organic layer was separated from the obtained mother liquor, washed with brine, dried with DDL ₄ , and concentrated. The obtained residue was subjected to silica gel column chromatography purification (toluene) to obtain 244 mg (yield 15%) of the title compound.
(Example 1-1-2) Synthesis of 2,4-bis (azepan-1-yl) phenol dihydrochloride
1- [3- (Azepan-1-yl) -4-benzyloxy-phenyl] Azepane 200 mg was dissolved in methanol 6.0 mL, THF 2.0 mL, 4M-HCl / DOX 0.53 mL, and 10% Pd-C 100. mg was added. Hydrogen was added and catalytic reduction was carried out at room temperature for 4 hours under atmospheric pressure. The catalyst was filtered off and the mother liquor was concentrated. The obtained residue was _{pulverized with Et 2} O to give the title compound 161 mg (yield 84%).
[Example 1-2] Synthesis of 2,4-bis (1-pyrrolidinyl) phenol dihydrochloride (KT-409)
(Example 1-2-1) Synthesis of 1- (2-benzyloxy-5-pyrrolidin-1-yl-phenyl) pyrrolidine The title compound was obtained in the same manner as in Example 1-1-1 (Example 1-1-1). Yield 53%).
(Example 1-2-2) Synthesis of 2,4-bis (1-pyrrolidinyl) phenol dihydrochloride The title compound was obtained in the same manner as in Example 1-1-2 (yield 83%). ..
[Example 1-3] Synthesis of 2,4-dimorpholinophenol dihydrochloride (KT-413)
(Example 1-3-1) Synthesis of 4- (2-benzyloxy-5-morpholinophenyl) morpholine The title compound was obtained in the same manner as in Example 1-1-1 (yield 76%). ..
(Example 1-3-2) Synthesis of 2,4-dimorpholinophenol dihydrochloride The title compound was obtained in the same manner as in Example 1-1-2 (yield 93%).
[Example 1-4] Synthesis of 2,4-bis (7-azabicyclo [2.2.1] heptane-7-yl) phenol dihydrochloride (KT-417)
(Example 1-4-1) 7- [3- (7-Azabicyclo [2.2.1] heptane-7-yl) -4-benzyloxy-phenyl] -7-Azabicyclo [2.2.1] Synthesis of heptane Argon Under gas stream, 1.5 g of 1-benzyloxy-2,4-dibromobenzene, 40.0 mL of 1,4-dioxane, 1.76 g of 7-azabicyclo [2.2.1] heptane hydrochloride, 2.32 g of t-BuONa, rac-BINAP 437 After adding mg and Pd ₂ (dba) ₃ 321 mg and stirring at room temperature for 15 minutes under an argon gas atmosphere, the mixture was heated to 80 ° C. and stirred for 67 hours. The reaction mixture was returned to room temperature, poured into a mixture of 50 mL each of AcOEt and water, stirred, and then the insoluble material was filtered off. The organic layer was separated from the obtained mother liquor, washed with brine, dried with DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-AcOEt system). The column eluate was concentrated and the residue was pulverized with a small amount of methanol to give the title compound (594 mg, yield 36%).
(Example 1-4-2) Synthesis of 2,4-bis (7-azabicyclo [2.2.1] heptane-7-yl) phenol dihydrochloride
7- [3- (7-Azabicyclo [2.2.1] heptane-7-yl) -4-benzyloxy-phenyl] -7-Azabicyclo [2.2.1] 400 mg of heptane in methanol 12.0 mL, 4M-HCl / DOX It was dissolved in 0.80 mL and _{100 mg of 20% Pd (OH) 2-} C was added. Hydrogen was added and catalytic reduction was carried out at room temperature for 1 hour under atmospheric pressure. The catalyst was filtered off and the mother liquor was concentrated. The obtained residue was pulverized with AcOEt to give the title compound (359 mg, yield 94%).
[Example 1-5] Synthesis of 2,4-bis (4-phenyl-1-piperidyl) phenol dihydrochloride (KT-414)
(Example 1-5-1) Synthesis of 1- [2-benzyloxy-5- (4-phenyl-1-piperidyl) phenyl] -4-phenylpiperidine The title compound is the same as in Example 1-1-1. (Yield 32%).
(Example 1-5-2) Synthesis of 2,4-bis (4-phenyl-1-piperidyl) phenol dihydrochloride The title compound was obtained in the same manner as in Example 1-1-2 (yield). Rate 94%).
[Example 1-6] Synthesis of 2,4-bis (4-phenylpiperazine-1-yl) phenol tetrachloride (KT-415)
(Example 1-6-1) Synthesis of 1- [2-benzyloxy-5- (4-phenylpiperazine-1-yl) phenyl] -4-phenylpiperazine The title compound is Example 1-1-1. It was obtained in a similar manner (yield 32%).
(Example 1-6-2) Synthesis of 2,4-bis (4-phenylpiperazine-1-yl) phenol tetrachloride The title compound was obtained in the same manner as in Example 1-1-2 (Example 1-6-2). Yield 53%).
[Example 1-7] Synthesis of 2,4-bis (4-benzyl-1-piperidyl) phenol dihydrochloride (KT-416)
(Example 1-7-1) Synthesis of 4-benzyl-1- [2-benzyloxy-5- (4-benzyl-1-piperidyl) phenyl] piperidine The title compound is the same as in Example 1-1-1. (Yield 40%).
(Example 1-7-2) Synthesis of 2,4-bis (4-benzyl-1-piperidyl) phenol dihydrochloride The title compound was obtained in the same manner as in Example 1-1-2 (yield). Rate 92%).
[Example 1-8] Synthesis of 2- (7-azabicyclo [2.2.1] heptane-7-yl) -4- (1-piperidyl) phenol dihydrochloride (KT-426)
(Example 1-8-1) Synthesis of 1- (4-benzyloxy-3-bromophenyl) piperidine
To 8.0 g of 4-benzyloxy-3-bromoaniline, 120 mL of toluene, 5.84 mL of 1,5-dibromopentane, and 15.0 mL of DIPEA were added, and the mixture was heated to 100 ° C. and stirred for 24 hours. Toluene was distilled off, 60 mL of iPE and 90 mL of 1N hydrochloric acid were added to the residue, and the mixture was stirred at room temperature for 1 hour, and the precipitate was collected by filtration. Water was added to the obtained powder to adjust the _{pH to 8.5 at 20% K 2} CO ₃ aq., And the mixture was extracted with a mixture of AcOEt and THF. The extract was washed with brine, dried over DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-AcOEt system) to obtain 8.33 g (yield 84%) of the title compound.
(Example 1-8-2) Synthesis of 7- [2-benzyloxy-5- (1-piperidyl) phenyl] -7-azabicyclo [2.2.1] heptane Under an argon gas stream, 1- (4-benzyloxy) -3-Bromophenyl) Piperidine 1.0 g, 1,4-dioxane 15.0 mL, 7-azabicyclo [2.2.1] heptane hydrochloride 0.58 g, t-BuONa 0.75 g, rac-BINAP 288 mg and Pd ₂ (dba) ₃ 212 mg was added, and the mixture was stirred at room temperature for 15 minutes under an argon gas atmosphere, then heated to 80 ° C. and stirred for 70 hours. The reaction mixture was returned to room temperature, poured into a mixture of 20 mL each of AcOEt and water, stirred, and then the insoluble material was filtered off. The organic layer was separated from the obtained mother liquor, washed with brine, dried with DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-AcOEt system) to give the title compound (490 mg, yield 47%).
(Example 1-8-3) Synthesis of 2- (7-azabicyclo [2.2.1] heptane-7-yl) -4- (1-piperidyl) phenol dihydrochloride The title compound is Example 1-4- It was obtained in the same manner as in 2 (yield 97%).
[Example 1-9] Synthesis of 4- (7-azabicyclo [2.2.1] heptane-7-yl) -2- (1-piperidyl) phenol dihydrochloride (KT-427)
(Example 1-9-1) Synthesis of 1- (2-benzyloxy-5-bromophenyl) piperidine The title compound was obtained in the same manner as in Example 1-8-1 (yield 55%). ..
(Example 1-9-2) Synthesis of 7- [4-benzyloxy-3- (1-piperidyl) phenyl] -7-azabicyclo [2.2.1] heptane The title compound is Example 1-8-2. It was obtained in a similar manner (yield 39%).
(Example 1-9-3) Synthesis of 4- (7-azabicyclo [2.2.1] heptane-7-yl) -2- (1-piperidyl) phenol dihydrochloride The title compound is Example 1-4- It was obtained in the same manner as in 2 (yield 95%).
[Example 1-10] Synthesis of 2-methyl-4,6-bis (1-piperidyl) phenol dihydrochloride (KT-419)
(Example 1-10-1) Synthesis of 1,5-dibromo-2- (methoxymethoxy) -3-methylbenzene
_{Add 200 mL of CH 2} Cl ₂ and 13.1 mL of DIPEA to 10.0 g of 2,4-dibromo-6-methylphenol, add 3.38 mL of chloromethyl methyl ether 3.38 mL of CH ₂ Cl ₂ 10.0 mL solution under ice-cooled stirring, and then add dropwise. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was poured into 200 mL of ice water and adjusted to pH 6 with a 10% aqueous citric acid solution. CH ₂ Cl ₂ layers were separated, washed with water, dried with DDL ₄ , and concentrated. The residue was purified by silica gel column chromatography (CHCl ₃ -hexane) to give 10.57 g (yield 91%) of the title compound.
(Example 1-10-2) Synthesis of 1- [2- (methoxymethoxy) -3-methyl-5- (1-piperidyl) phenyl] piperidine Under an argon gas stream, 1,5-dibromo-2- (methoxy) To 2.0 g of methoxy) -3-methylbenzene, add 1,4-dioxane 40.0 mL, piperidine 1.91 mL, t-BuONa 1.55 g, rac-BINAP 643 mg and Pd ₂ (dba) ₃ 473 mg to room temperature in an argon gas atmosphere. After stirring for 15 minutes, the mixture was heated to 80 ° C. and stirred for 70 hours. The reaction mixture was returned to room temperature, poured into a mixture of 60 mL each of AcOEt and water, stirred, and then the insoluble material was filtered off. The organic layer was separated from the obtained mother liquor, washed with brine, dried with DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-AcOEt system) to obtain 0.80 g (yield 39%) of the title compound.
(Example 1-10-3) Synthesis of 2-methyl-4,6-bis (1-piperidyl) phenol dihydrochloride
480 mg of 1- [2- (methoxymethoxy) -3-methyl-5- (1-piperidyl) phenyl] piperidine was dissolved in 4.8 mL of iPA, and 3.8 mL of 4M-HCl / DOX was added. After stirring at room temperature for 4 hours, 10 mL of AcOEt was added and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration to give the title compound (495 mg, yield 95%).
[Example 1-11] Synthesis of 2,4-bis (1-piperidyl) -6- (pyrrolidin-1-ylmethyl) phenol trihydrochloride (KT-424)
(Example 1-11-1) Synthesis of 1-[[3,5-dibromo-2- (methoxymethoxy) phenyl] methyl] pyrrolidine
4.0 g of 3,5-dibromo-2- (methoxymethoxy) benzaldehyde _{was dissolved in CH 2} Cl ₂ 80.0 mL, 1.13 mL of pyrrolidine was added, and the mixture was stirred at room temperature for 0.5 hours. The reaction solution was added ice-cold NaBH (OAc) ₃ 3.66g, was stirred at room temperature for 14 hours. The reaction mixture was washed with sat. LVDS ₃ aq., Washed with water, dried with DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (CHCl _3- AcOEt system) to obtain 4.29 g (yield 92%) of the title compound.
(Example 1-11-2) Synthesis of 1- [2- (methoxymethoxy) -5- (1-piperidyl) -3- (pyrrolidin-1-ylmethyl) phenyl] piperidine The title compound is Example 1-10. Obtained in the same manner as -2 (yield 59%).
(Example 1-11-3) Synthesis of 2,4-bis (1-piperidyl) -6- (pyrrolidin-1-ylmethyl) phenol trihydrochloride The title compound is the same method as in Example 1-10-3. (Yield 42%).

[Example 1-12] Synthesis of 2- (methoxymethyl) -4,6-bis (1-piperidyl) phenol dihydrochloride (KT-425)
(Example 1-12-1) Synthesis of 1,5-dibromo-2- (methoxymethoxy) -3- (methoxymethyl) benzene
[3,5-Dibromo-2- (methoxymethoxy) phenyl] 2.5 g of methanol was dissolved in THF 25.0 mL, and under ice-cooled stirring, 0.46 g of 60% NaH was added, and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was cooled to 20 ° C. or lower, and a solution of 0.72 mL of iodomethane in THF (2.5 mL) was added dropwise at 10 to 20 ° C., and the mixture was stirred at room temperature for 15 hours. The reaction mixture was added to ice water and extracted with _{Et 2 O.} The obtained extract was washed with brine, dried over DDL ₄ , and concentrated. The residue was purified by silica gel column chromatography (hexane-AcOEt system) to give 2.42 g (yield 93%) of the title compound.
(Example 1-12-2) Synthesis of 1- [2- (methoxymethoxy) -3- (methoxymethyl) -5- (1-piperidyl) phenyl] piperidine The title compound is Example 1-10-2. Obtained in a similar manner (yield 40%).
(Example 1-12-3) Synthesis of 2- (methoxymethyl) -4,6-bis (1-piperidyl) phenol dihydrochloride The title compound was obtained in the same manner as in Example 1-10-3. (Yield 91%).
[Example 1-13] Synthesis of 2,4-bis (4-methyl-1-piperidyl) phenol dihydrochloride (KT-431)
(Example 1-13-1) Synthesis of 1- [2-benzyloxy-5- (4-methyl-1-piperidyl) phenyl] -4-methylpiperidine The title compound is the same as in Example 1-1-1. (Yield 39%).
(Example 1-13-2) Synthesis of 2,4-bis (4-methyl-1-piperidyl) phenol dihydrochloride The title compound was obtained in the same manner as in Example 1-4-2 (yield). Rate 91%).
[Example 1-14] Synthesis of 2,4-bis (3,5-dimethyl-1-piperidyl) phenol dihydrochloride (KT-434)
(Example 1-14-1) Synthesis of 1- [2-benzyloxy-5- (3,5-dimethyl-1-piperidyl) phenyl] -3,5-dimethylpiperidine The title compound is Example 1-1. It was obtained in the same manner as -1 (yield 28%).
(Example 1-14-2) Synthesis of 2,4-bis (3,5-dimethyl-1-piperidyl) phenol dihydrochloride The title compound was obtained in the same manner as in Example 1-4-2. (Yield 88%).
[Example 1-15] Synthesis of 4- (azepan-1-yl) -2- (1-piperidyl) phenol dihydrochloride (KT-432)
(Example 1-15-1) Synthesis of 1- [4-benzyloxy-3- (1-piperidyl) phenyl] azepane 1.0 g of 1- (2-benzyloxy-5-bromophenyl) piperidine under an argon gas stream. in 1,4-dioxane 15.0 mL, azepane 0.486 mL, t-BuONa 444 mg , rac-BINAP 288 mg and Pd ₂ (dba) ₃ 212 mg was added under an argon atmosphere and stirred for 15 minutes at room temperature, 80 The mixture was heated to ° C. and stirred for 70 hours. The reaction solution was returned to room temperature, _{poured into a mixture of Et 2} O and water, stirred, and then the insoluble matter was filtered off. The organic layer was separated from the obtained mother liquor, washed with brine, dried with DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-AcOEt system) to give the title compound 261 mg (yield 25%).
Synthesis of (Example 1-15-2)
4- (Azepan-1-yl) -2- (1-piperidyl) phenol dihydrochloride The title compound was obtained in the same manner as in Example 1-4-2 (yield 94%).
[Example 1-16] Synthesis of 2- (1-piperidyl) -4- (pyrrolidin-1-yl) phenol dihydrochloride (KT-435)
(Example 1-16-1) Synthesis of 1- (2-benzyloxy-5-pyrrolidin-1-ylphenyl) piperidine The title compound was obtained in the same manner as in Example 1-15-1 (yield). Rate 70%).
(Example 1-16-2) Synthesis of 2- (1-piperidyl) -4- (pyrrolidin-1-yl) phenol dihydrochloride The title compound was obtained in the same manner as in Example 1-4-2. (Yield 95%).
[Example 1-17] Synthesis of 4- (4-phenylpiperazine-1-yl) -2- (1-piperidyl) phenol trihydrochloride (KT-429)
(Example 1-17-1) Synthesis of 1- [4-benzyloxy-3- (1-piperidyl) phenyl] -4-phenylpiperazine The title compound was obtained in the same manner as in Example 1-15-1. (Yield 86%).
(Example 1-17-2) Synthesis of 4- (4-phenylpiperazine-1-yl) -2- (1-piperidyl) phenol trihydrochloride The title compound is the same method as in Example 1-4-2. Obtained in (yield 79%).
[Example 1-18] Synthesis of 2- (azepan-1-yl) -4- (pyrrolidin-1-yl) phenol dihydrochloride (KT-439)
(Example 1-18-1) Synthesis of 1- (4-benzyloxy-3-bromophenyl) pyrrolidine
To 8.0 g of 4-benzyloxy-3-bromoaniline, 120 mL of toluene, 5.1 mL of 1,4-dibromobutane, and 15.0 mL of DIPEA were added, and the mixture was heated to 100 ° C. and stirred for 25 hours. The reaction mixture was returned to room temperature, washed with water, dried by DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-CHCl ₃ system) to obtain 7.68 g (yield 80%) of the title compound.
(Example 1-18-2) Synthesis of 1- (2-benzyloxy-5-pyrrolidin-1-ylphenyl) azepane 1.0 g of 1- (4-benzyloxy-3-bromophenyl) pyrrolidine under an argon gas stream. Add 1,4-dioxane 15.0 mL, azepane 0.507 mL, t-BuONa 463 mg, rac-BINAP 300 mg and Pd ₂ (dba) ₃ 221 mg to the mixture, stir in an argon gas atmosphere for 15 minutes at room temperature, and then 80. The mixture was heated to ° C. and stirred for 70 hours. The reaction solution was returned to room temperature, _{poured into a mixture of Et 2} O and water, stirred, and then the insoluble matter was filtered off. The organic layer was separated from the obtained mother liquor, washed with brine, dried with DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-AcOEt system) and further purified by silica gel column chromatography (CH ₂ Cl _2- AcOEt system) to obtain 270 mg (yield 26%) of the title compound.
(Example 1-18-3) Synthesis of 2- (azepan-1-yl) -4- (pyrrolidin-1-yl) phenol dihydrochloride The title compound is prepared in the same manner as in Example 1-4-2. Obtained (yield 93%).
[Example 1-19] Synthesis of 2-morpholino-4- (pyrrolidin-1-yl) phenol dihydrochloride (KT-445)
(Example 1-19-1) Synthesis of 4- (2-benzyloxy-5-pyrrolidin-1-yl-phenyl) morpholine The title compound was obtained in the same manner as in Example 1-18-2 (Example 1-19-1). Yield 48%).
(Example 1-19-2) Synthesis of 2-morpholino-4- (pyrrolidin-1-yl) phenol dihydrochloride The title compound was obtained in the same manner as in Example 1-4-2 (yield). 85%).
[Example 1-20] Synthesis of 2- (4,4-dimethyl-1-piperidyl) -4- (pyrrolidin-1-yl) phenol dihydrochloride (KT-450)
(Example 1-20-1) Synthesis of 1- (2-benzyloxy-5-pyrrolidin-1-yl-phenyl) -4,4-dimethylpiperidine The title compound is the same as in Example 1-8-2. Obtained by the method (yield 29%).
(Example 1-20-2) Synthesis of 2- (4,4-dimethyl-1-piperidyl) -4- (pyrrolidin-1-yl) phenol dihydrochloride The title compound is Example 1-4-2. Obtained in a similar manner (yield 75%).
[Example 1-21] Synthesis of 2- (3,5-dimethyl-1-piperidyl) -4- (pyrrolidin-1-yl) phenol dihydrochloride (KT-453)
(Example 1-21-1) Synthesis of 1- (2-benzyloxy-5-pyrrolidin-1-ylphenyl) -3,5-dimethylpiperidine The title compound is the same method as in Example 1-18-2. (Yield 33%).
(Example 1-21-2) Synthesis of 2- (3,5-dimethyl-1-piperidyl) -4- (pyrrolidin-1-yl) phenol dihydrochloride The title compound is Example 1-4-2. It was obtained in a similar manner (yield 84%).
[Example 1-22] Synthesis of 2- (7-azabicyclo [2.2.1] heptane-7-yl) -4- (pyrrolidin-1-yl) phenol dihydrochloride (KT-466)
(Example 1-22-1) Synthesis of 7- (2-benzyloxy-5-pyrrolidin-1-ylphenyl) -7-azabicyclo [2.2.1] heptane The title compound is Example 1-8-2. Obtained in a similar manner (yield 16%).
(Example 1-22-2) Synthesis of 2- (7-azabicyclo [2.2.1] heptane-7-yl) -4- (pyrrolidin-1-yl) phenol dihydrochloride The title compound is Example 1- It was obtained in the same manner as in 4-2 (yield 93%).
[Example 1-23] Synthesis of 2- (4-phenyl-1-piperidyl) -4- (pyrrolidin-1-yl) phenol dihydrochloride (KT-471)
(Example 1-23-1) Synthesis of 1- [2-benzyloxy- (5-pyrrolidin-1-yl) phenyl] -4-phenylpiperidine The title compound is the same method as in Example 1-18-2. Obtained in (yield 54%).
(Example 1-23-2) Synthesis of 2- (4-phenyl-1-piperidyl) -4- (pyrrolidin-1-yl) phenol dihydrochloride The title compound is the same as in Example 1-4-2. Obtained by the method (yield 90%).
[Example 1-24] Synthesis of 2- (4-benzyl-1-piperidyl) -4- (pyrrolidin-1-yl) phenol dihydrochloride (KT-472)
(Example 1-24-1) Synthesis of 4-benzyl-1- [2-benzyloxy- (5-pyrrolidine-1-yl) phenyl] piperidine The title compound is the same method as in Example 1-18-2. Obtained in (yield 49%).
(Example 1-24-2) Synthesis of 2- (4-benzyl-1-piperidyl) -4- (pyrrolidin-1-yl) phenol dihydrochloride The title compound is the same as in Example 1-4-2. Obtained by the method (yield 94%).
[Example 1-25] Synthesis of 2- [4- (4-fluorobenzoyl) -1-piperidyl] -4- (pyrrolidin-1-yl) phenol dihydrochloride (KT-470)
(Example 1-25-1) Synthesis of 4- (2-benzyloxy-5-pyrrolidin-1-ylphenyl) -1- (4-fluorobenzoyl) piperazine The title compound is Example 1-8-2. Obtained in a similar manner (yield 80%).
(Example 1-25-2) Synthesis of 2- [4- (4-fluorobenzoyl) -1-piperidyl] -4- (pyrrolidin-1-yl) phenol dihydrochloride The title compound is Example 1-4. It was obtained in the same way as -2 (yield 74%).
[Example 1-26] Synthesis of 2- (4-isopropylpiperazin-1-yl) -4- (pyrrolidin-1-yl) phenol trihydrochloride (KT-442)
(Example 1-26-1) Synthesis of 1- [2-benzyloxy-5- (pyrrolidin-1-yl) phenyl] -4-isopropylpiperazine The title compound is the same method as in Example 1-18-2. Obtained in (yield 39%).
(Example 1-26-2) Synthesis of 2- (4-isopropylpiperazin-1-yl) -4- (pyrrolidin-1-yl) phenol trihydrochloride The title compound is the same as in Example 1-4-2. (Yield 78%).
[Example 1-27] Synthesis of 2- (4-tert-butylpiperazin-1-yl) -4- (pyrrolidin-1-yl) phenol trihydrochloride (KT-451)
(Example 1-27-1) Synthesis of 1- (2-benzyloxy-5-pyrrolidin-1-ylphenyl) -4-tert-butylpiperazine The title compound is the same method as in Example 1-18-2. Obtained in (yield 50%).
(Example 1-27-2) Synthesis of 2- (4-tert-butylpiperazin-1-yl) -4- (pyrrolidin-1-yl) phenol trihydrochloride The title compound is Example 1-4-2. It was obtained in the same manner as (yield 93%).
[Example 1-28] Synthesis of 2- (4-phenylpiperazine-1-yl) -4- (pyrrolidin-1-yl) phenol trihydrochloride (KT-440)
(Example 1-28-1) Synthesis of 1- [2-benzyloxy-5- (pyrrolidin-1-yl) phenyl] -4-phenylpiperazine The title compound is the same method as in Example 1-18-2. Obtained in (yield 68%).
(Example 1-28-2) Synthesis of 2- (4-phenylpiperazine-1-yl) -4- (pyrrolidin-1-yl) phenol trihydrochloride The title compound is the same as in Example 1-4-2. (Yield 92%).
[Example 1-29] Synthesis of 2- (4-phenyl-1,4-diazepan-1-yl) -4- (pyrrolidin-1-yl) phenol trihydrochloride (KT-448)
(Example 1-29-1) Synthesis of 1- (2-benzyloxy-5-pyrrolidin-1-yl-phenyl) -4-phenyl-1,4-diazepan The title compound is Example 1-18-2. It was obtained in the same manner as (yield 26%).
(Example 1-29-2) Synthesis of 2- (4-phenyl-1,4-diazepan-1-yl) -4- (pyrrolidin-1-yl) phenol trihydrochloride The title compound is Example 1-. It was obtained in the same manner as in 4-2 (yield 81%).
[Example 1-30] Synthesis of 2- (4-acetylpiperazin-1-yl) -4- (pyrrolidin-1-yl) phenol dihydrochloride (KT-467)
(Example 1-30-1) Synthesis of 4- (2-benzyloxy-5-pyrrolidin-1-ylphenyl) -1-tert-butoxycarbonylpiperazine Under an argon gas stream, 1- (4-benzyloxy-3) -Bromophenyl) Pyrrolidine 5.0 g plus 1,4-dioxane 100.0 mL, 1- (tert-butoxycarbonyl) piperazine 4.2 g, t-BuONa 2.31 g, rac-BINAP 937 mg and Pd ₂ (dba) ₃ 689 mg After stirring at room temperature for 15 minutes under an argon gas atmosphere, the mixture was heated to 80 ° C. for 70 hours. The reaction mixture was returned to room temperature, _{poured into a mixture of Et 2} O and water, stirred, and then the insoluble matter was filtered off. The organic layer was separated from the obtained mother liquor, washed with brine, dried with DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-AcOEt system), and the concentrated residue was pulverized with methanol to obtain 4.07 g (yield 62%) of the title compound.
(Example 1-30-2) Synthesis of 1- (2-benzyloxy-5-pyrrolidin-1-ylphenyl) piperazine
Dissolve 4.0 g of 4- (2-benzyloxy-5-pyrrolidin-1-ylphenyl) -1-tert-butoxycarbonylpiperazine in a mixture of 20 mL THF and 12 mL methanol to add 22.9 mL of 4M-HCl / DOX. Added. The reaction mixture was stirred at room temperature for 20 hours _{, 40 mL of Et 2} O and 60 mL of iPE were added, and the mixture was stirred at room temperature for 1 hour. 30 mL of water was added to the collected precipitate to adjust the pH to 10 with 2N-NaOH, and then the mixture was extracted with _{CHCl 3.} The obtained extract was dried over DDL ₄ and concentrated to give 3.04 g (yield 99%) of the title compound.

(Example 1-30-3) Synthesis of 1-acetyl-4- (2-benzyloxy-5-pyrrolidin-1-ylphenyl) piperazine Ice-cooled 1- (2-benzyloxy-5-pyrrolidin-1-) yl) piperazine _{400 mg, CH 2 Cl 2 6.0} mL, was added acetyl chloride 101 [mu] l in a mixture of DIPEA 248 [mu] l, was stirred for 3 hours at room temperature. The reaction mixture was washed with sat. LVDS ₃ aq., Washed with water, dried with DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (eluent AcOEt) to give the title compound 303 mg (yield 67%).
(Example 1-30-4) Synthesis of 2- (4-acetylpiperazin-1-yl) -4- (pyrrolidin-1-yl) phenol dihydrochloride The title compound is the same as in Example 1-4-2. (Yield 87%).
[Example 1-31] Synthesis of 2- (4-benzoylpiperazin-1-yl) -4- (pyrrolidin-1-yl) phenol dihydrochloride (KT-468)
(Example 1-31-1) Synthesis of 1-benzoyl-4- (2-benzyloxy-5-pyrrolidin-1-ylphenyl) piperazine The title compound was obtained in the same manner as in Example 1-30-3. (Yield 82%).
(Example 1-31-2) Synthesis of 2- (4-benzoylpiperazin-1-yl) -4- (pyrrolidin-1-yl) phenol dihydrochloride The title compound is the same as in Example 1-4-2. (Yield 87%).
[Example 1-32] Synthesis of 2- [4- (4-fluorobenzoyl) piperazine-1-yl] -4- (pyrrolidin-1-yl) phenol dihydrochloride (KT-469)
(Example 1-32-1) Synthesis of 4- (2-benzyloxy-5-pyrrolidin-1-ylphenyl) -1- (4-fluorobenzoyl) piperazine The title compound is Example 1-30-3. Obtained in a similar manner (yield 50%).
(Example 1-32-2) Synthesis of 2- [4- (4-fluorobenzoyl) piperazine-1-yl] -4- (pyrrolidin-1-yl) phenol dihydrochloride The title compound is Example 1- It was obtained in the same manner as in 4-2 (yield 92%).
[Example 1-33] Synthesis of 2- (4-methyl-1-piperidyl) -4- (1-piperidyl) phenol dihydrochloride (KT-436)
(Example 1-33-1) Synthesis of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] -4-methylpiperidine The title compound was obtained in the same manner as in Example 1-18-2. (Yield 59%).
(Example 1-33-2) Synthesis of 2- (4-methyl-1-piperidyl) -4- (1-piperidyl) phenol dihydrochloride The title compound is prepared in the same manner as in Example 1-4-2. Obtained (yield 93%).
[Example 1-34] Synthesis of 2- (4,4-dimethyl-1-piperidyl) -4- (1-piperidyl) phenol dihydrochloride (KT-449)
(Example 1-34-1) Synthesis of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] -4,4-dimethylpiperidine The title compound is the same method as in Example 1-8-2. Obtained in (yield 36%).
(Example 1-34-2) Synthesis of 2- (4,4-dimethyl-1-piperidyl) -4- (1-piperidyl) phenol dihydrochloride The title compound is the same as in Example 1-4-2. Obtained by the method (yield 63%).
[Example 1-35] Synthesis of 2- (3,5-dimethyl-1-piperidyl) -4- (1-piperidyl) phenol dihydrochloride (KT-454)
(Example 1-35-1) Synthesis of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] -3,5-dimethylpiperidine The title compound is the same method as in Example 1-18-2. Obtained in (yield 35%).
(Example 1-35-2) Synthesis of 2- (3,5-dimethyl-1-piperidyl) -4- (1-piperidyl) phenol dihydrochloride The title compound is the same as in Example 1-4-2. Obtained by the method (yield 77%).
[Example 1-36] Synthesis of 2- (4-methoxy-1-piperidyl) -4- (1-piperidyl) phenol dihydrochloride (KT-446)
(Example 1-36-1) Synthesis of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] -4-methoxypiperidine The title compound was obtained in the same manner as in Example 1-18-2. (Yield 71%).
(Example 1-36-2) Synthesis of 2- (4-methoxy-1-piperidyl) -4- (1-piperidyl) phenol dihydrochloride The title compound is prepared in the same manner as in Example 1-4-2. Obtained (yield 91%).
[Example 1-37] Synthesis of 2- (4-phenyl-1-piperidyl) -4- (1-piperidyl) phenol dihydrochloride (KT-437)
(Example 1-37-1) Synthesis of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] -4-phenylpiperidine The title compound was obtained in the same manner as in Example 1-18-2. (Yield 68%).
(Example 1-37-2) Synthesis of 2- (4-phenyl-1-piperidyl) -4- (1-piperidyl) phenol dihydrochloride The title compound is prepared in the same manner as in Example 1-4-2. Obtained (yield 88%).
[Example 1-38] Synthesis of 2- (4-benzyl-1-piperidyl) -4- (1-piperidyl) phenol dihydrochloride (KT-438)
(Example 1-38-1) Synthesis of 4-benzyl-1- [2-benzyloxy-5- (1-piperidyl) phenyl] piperidine The title compound was obtained in the same manner as in Example 1-18-2. (Yield 69%).
(Example 1-38-2) Synthesis of 2- (4-benzyl-1-piperidyl) -4- (1-piperidyl) phenol dihydrochloride The title compound is prepared in the same manner as in Example 1-4-2. Obtained (yield 88%).
[Example 1-39] Synthesis of 2- [4- (4-fluorobenzoyl) -1-piperidyl] -4- (1-piperidyl) phenol dihydrochloride (KT-475)
(Example 1-39-1) Synthesis of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] -4- (4-fluorobenzoyl) piperidine The title compound is as shown in Example 1-18-2. It was obtained in a similar manner (yield 74%).
(Example 1-39-2) Synthesis of 2- [4- (4-fluorobenzoyl) -1-piperidyl] -4- (1-piperidyl) phenol dihydrochloride The title compound is Example 1-4-2. It was obtained in the same manner as (yield 88%).
[Example 1-40] Synthesis of 4- (1-piperidyl) -2- [4- (2-pyridyl) piperazin-1-yl] phenol (KT-462)
(Example 1-40-1) Synthesis of 1- [2-methoxy-5- (1-piperidyl) phenyl] -4- (2-pyridyl) piperazine The title compound is the same as in Example 1-18-2. Obtained by the method (yield 67%).
(Example 1-40-2) Synthesis of 4- (1-piperidyl) -2- [4- (2-pyridyl) piperazine-1-yl] phenol Under an argon gas stream, 1M-BBr ₃ / CH ₂ Cl ₂ 4.96 mL of 1- [2-methoxy-5- (1-piperidyl) phenyl] -4- (2-pyridyl) piperazine was added _{dropwise to a solution of 0.35 g of CH 2} Cl ₂ 10.5 mL at 6 ° C or lower. .. The reaction mixture was stirred at room temperature for 3 hours _{, added to ice-cooled sat. LVDS 3} aq., And extracted with a mixture of AcOEt and THF. After the obtained extract to a pH 1 with hydrochloric acid added to water for 18 hours at room temperature stirring, and sat.NaHCO ₃ aq. PH 7.5 at the organic layer was separated. This organic layer was separated, washed with brine, dried with DDL ₄ , and concentrated. The obtained residue was _{pulverized with Et 2} O to give the title compound (136 mg, yield 41%).
[Example 1-41] Synthesis of 4- (1-piperidyl) -2- (4-pyrimidine-2-ylpiperazin-1-yl) phenol (KT-464)
(Example 1-41-1) Synthesis of 2- [4- [2-methoxy-5- (1-piperidyl) phenyl] piperazine-1-yl] pyrimidine The title compound is the same as in Example 1-18-2. (Yield 68%).
(Example 1-41-2) Synthesis of 4- (1-piperidyl) -2- (4-pyrimidine-2-ylpiperazin-1-yl) phenol The title compound is the same as in Example 1-40-2. Obtained by the method (yield 74%).
[Example 1-42] Synthesis of 2- (azepan-1-yl) -4- (1-piperidyl) phenol dihydrochloride (KT-433)
(Example 1-42-1) Synthesis of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] azepane The title compound was obtained in the same manner as in Example 1-18-2 (yield). Rate 24%).
(Example 1-42-2) Synthesis of 2- (azepan-1-yl) -4- (1-piperidyl) phenol dihydrochloride The title compound was obtained in the same manner as in Example 1-4-2. (Yield 92%).
[Example 1-43] Synthesis of 2- (4-methyl-1,4-diazepan-1-yl) -4- (1-piperidyl) phenol trihydrochloride (KT-444)
(Example 1-43-1) Synthesis of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] -4-methyl-1,4-diazepan The title compound is Example 1-18-2. It was obtained in a similar manner (yield 34%).
(Example 1-43-2) Synthesis of 2- (4-methyl-1,4-diazepan-1-yl) -4- (1-piperidyl) phenol trihydrochloride The title compound is Example 1-4-. It was obtained in the same manner as in 2 (yield 82%).
[Example 1-44] Synthesis of 2- (4-phenyl-1,4-diazepan-1-yl) -4- (1-piperidyl) phenol trihydrochloride (KT-447)
(Example 1-44-1) Synthesis of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] -4-phenyl-1,4-diazepan The title compound is Example 1-18-2. It was obtained in a similar manner (yield 29%).
(Example 1-44-2) Synthesis of 2- (4-phenyl-1,4-diazepan-1-yl) -4- (1-piperidyl) phenol trihydrochloride The title compound is Example 1-4-. It was obtained in the same manner as in 2 (yield 91%).
[Example 1-45] Synthesis of 2- (4-isopropylpiperazin-1-yl) -4- (1-piperidyl) phenol trihydrochloride (KT-441)
(Example 1-45-1) Synthesis of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] -4-isopropylpiperazine The title compound was obtained in the same manner as in Example 1-18-2. (Yield 38%).
(Example 1-45-2) Synthesis of 2- (4-isopropylpiperazin-1-yl) -4- (1-piperidyl) phenol trihydrochloride The title compound is the same method as in Example 1-4-2. Obtained in (yield 95%).
[Example 1-46] Synthesis of 2- (4-tert-butylpiperazin-1-yl) -4- (1-piperidyl) phenol trihydrochloride (KT-452)
(Example 1-46-1) Synthesis of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] -4-tert-butylpiperazine The title compound is the same method as in Example 1-18-2. Obtained in (yield 81%).
(Example 1-46-2) Synthesis of 2- (4-tert-butylpiperazin-1-yl) -4- (1-piperidyl) phenol trihydrochloride The title compound is the same as in Example 1-4-2. (Yield 64%).
[Example 1-47] Synthesis of 2- (4-phenylpiperazine-1-yl) -4- (1-piperidyl) phenol trihydrochloride (KT-430)
(Example 1-47-1) Synthesis of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] -4-phenylpiperazine The title compound was obtained in the same manner as in Example 1-18-2. (Yield 80%).
(Example 1-47-2) Synthesis of 2- (4-phenylpiperazine-1-yl) -4- (1-piperidyl) phenol trihydrochloride The title compound is the same method as in Example 1-4-2. (Yield 87%).
[Example 1-48] Synthesis of 2- [4- (isopropylcarbamoyl) piperazine-1-yl] -4- (1-piperidyl) phenol dihydrochloride (KT-457)
(Example 1-48-1) Synthesis of 4- [2-benzyloxy-5- (1-piperidyl) phenyl] -1- (tert-butoxycarbonyl) piperazine The title compounds are as shown in Examples 1-30-1. It was obtained in a similar manner (yield 73%).
(Example 1-48-2) Synthesis of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] piperazine The title compound was obtained in the same manner as in Example 1-30-2 (yield). Rate 99%).
(Example 1-48-3) Synthesis of 4- [2-benzyloxy-5- (1-piperidyl) phenyl] -1- (isopropylcarbamoyl) piperazine
After dissolving 0.3 g of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] piperazine in _{4.5 mL of CH 2} Cl ₂ and adding 0.1 mL of isopropyl isocyanate under ice-cooled stirring, 15 hours at room temperature. Stirred. The reaction mixture was washed with water, dried over DDL ₄ , and concentrated. The residue was crystallized from a mixture of AcOEt-hexane to give the title compound 278 mg (yield 75%).

(Example 1-48-4) Synthesis of 2- [4- (isopropylcarbamoyl) piperazine-1-yl] -4- (1-piperidyl) phenol dihydrochloride The title compound is Example 1-4-2. It was obtained in a similar manner (yield 86%).
[Example 1-49] Synthesis of 2- (4-ethoxycarbonylpiperazine-1-yl) -4- (1-piperidyl) phenol dihydrochloride (KT-458)
(Example 1-49-1) Synthesis of 4- [2-benzyloxy-5- (1-piperidyl) phenyl] -1-ethoxycarbonylpiperazine
After dissolving 0.3 g of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] piperazine in CH ₂ Cl ₂ 4.5 mL and adding DIPEA 178 μL and ethyl chlorostate 98 μL under ice-cooled stirring, The mixture was stirred at room temperature for 15 hours. The reaction mixture was _{washed with sat. LVDS 3} aq. _{, DD 4 was} dried, and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane-AcOEt system) to give the title compound (316 mg, yield 87%).
(Example 1-49-2) Synthesis of 2- (4-ethoxycarbonylpiperazine-1-yl) -4- (1-piperidyl) phenol dihydrochloride The title compound is the same as in Example 1-4-2. Obtained by the method (yield 88%).
[Example 1-50] Synthesis of 2- [4- (dimethylcarbamoyl) piperazine-1-yl] -4- (1-piperidyl) phenol dihydrochloride (KT-456)
(Example 1-50-1) Synthesis of 4- [2-benzyloxy-5- (1-piperidyl) phenyl] -1- (dimethylcarbamoyl) piperazine
Dissolve 0.3 g of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] piperazine in CH ₂ Cl ₂ 4.5 mL, add 178 μL of DIPEA and 94 μL of dimethylcarbamoyl chloride under ice-cooled stirring, and then room temperature. Was stirred for 15 hours. The reaction mixture was _{washed with sat. LVDS 3} aq. _{, DD 4 was} dried, and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane-AcOEt system) to give the title compound (328 mg, yield 91%).
(Example 1-50-2) Synthesis of 2- [4- (dimethylcarbamoyl) piperazine-1-yl] -4- (1-piperidyl) phenol dihydrochloride The title compound is Example 1-4-2. Obtained in a similar manner (yield 90%).
[Example 1-51] Synthesis of 2- (4-cyclopentyl piperazine-1-yl) -4- (1-piperidyl) phenol trihydrochloride (KT-465)
(Example 1-51-1) Synthesis of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] -4-cyclopentyl piperazine
0.5 g of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] piperazine _{was dissolved in 2 9.0 mL of CH 2} Cl, 0.20 mL of cyclopentanone was added, and the mixture was stirred at room temperature for 1 hour.
The reaction mixture was ice-cooled, ₃ 362 mg of NaBH (OAc) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with sat. LVDS ₃ aq., Washed with water, dried with DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography purification (CHCl ₃ -methanol type) to give the title compound 461 mg (yield 77%).
(Example 1-51-2) Synthesis of 2- (4-cyclopentylpiperazin-1-yl) -4- (1-piperidyl) phenol trihydrochloride The title compound is the same method as in Example 1-4-2. Obtained in (yield 75%).
[Example 1-52] Synthesis of 2- [4- (2-phenylethyl) piperazine-1-yl] -4- (1-piperidyl) phenol dihydrochloride (KT-460)
(Example 1-52-1) Synthesis of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] -4- (2-phenylethyl) piperazine The title compound is Example 1-51-1. It was obtained in a similar manner (yield 85%).
(Example 1-52-2) Synthesis of 2- [4- (2-phenylethyl) piperazine-1-yl] -4- (1-piperidyl) phenol dihydrochloride The title compound is Example 1-4-. It was obtained in the same manner as in 2 (yield 88%).
[Example 1-53] Synthesis of 2- (4-acetylpiperazin-1-yl) -4- (1-piperidyl) phenol dihydrochloride (KT-473)
(Example 1-53-1) Synthesis of 1-acetyl-4- [2-benzyloxy-5- (1-piperidyl) phenyl] piperazine The title compound is obtained in the same manner as in Example 1-30-3. (Yield 97%).
(Example 1-53-2) Synthesis of 2- (4-acetylpiperazin-1-yl) -4- (1-piperidyl) phenol dihydrochloride The title compound is the same method as in Example 1-4-2. (Yield 71%).
[Example 1-54] Synthesis of 2- (4-benzoylpiperazin-1-yl) -4- (1-piperidyl) phenol dihydrochloride (KT-459)
(Example 1-54-1) Synthesis of 1-benzoyl-4- [2-benzyloxy-5- (1-piperidyl) phenyl] piperazine The title compound was obtained in the same manner as in Example 1-30-3. (Yield 77%).
(Example 1-54-2) Synthesis of 2- (4-benzoylpiperazin-1-yl) -4- (1-piperidyl) phenol dihydrochloride The title compound is the same method as in Example 1-4-2. (Yield 89%).
[Example 1-55] Synthesis of 2- [4- (4-fluorobenzoyl) piperazine-1-yl] -4- (1-piperidyl) phenol dihydrochloride (KT-474)
(Example 1-55-1) Synthesis of 4- [2-benzyloxy-5- (1-piperidyl) phenyl] -1- (4-fluorobenzoyl) piperazine The title compound is Example 1-30-3. It was obtained in a similar manner (yield 93%).
(Example 1-55-2) Synthesis of 2- [4- (4-fluorobenzoyl) piperazine-1-yl] -4- (1-piperidyl) phenol dihydrochloride The title compound is Example 1-4-. It was obtained in the same manner as in 2 (yield 81%).
[Example 1-56] Synthesis of 2- [4- (furan-2-carbonyl) piperazine-1-yl] -4- (1-piperidyl) phenol dihydrochloride (KT-477)
(Example 1-56-1) Synthesis of 4- [2-benzyloxy-5- (1-piperidyl) phenyl] -1- (fran-2-carbonyl) piperazine
1- [2-Benzyloxy-5- (1-piperidyl) phenyl] Piperazine 0.35 g, 2-furancarboxylic acid 134 mg, 1-hydroxybenzotriazole monohydrate 183 mg CH ₂ Cl ₂ 7.0 mL mixture To 229 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added under ice-cooling stirring, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was washed with sat. LVDS ₃ aq., Washed with water, dried with DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (AcOEt-hexane system) to give the title compound (384 mg (yield 87%)).
(Example 1-56-2) Synthesis of 2- [4- (furan-2-carbonyl) piperazine-1-yl] -4- (1-piperidyl) phenol dihydrochloride The title compound is Example 1-4. It was obtained in the same way as -2 (yield 83%).
Synthesis of [Example 1-57] (KT-478)
(Example 1-57-1) Synthesis of 4- [2-benzyloxy-5- (1-piperidyl) phenyl] -1- (3-phenylpropanoyl) piperazine The title compound is Example 1-56-1. It was obtained in the same manner as (yield 84%).
(Example 1-57-2) Synthesis of 2- [4- (3-phenylpropanoid) piperazine-1-yl] -4- (1-piperidyl) phenol dihydrochloride The title compound is Example 1-4. Obtained in the same manner as -2 (yield 85%).
[Example 1-58] Synthesis of 2- (6,6-dimethyl-3-azabicyclo [3.1.0] hexane-3-yl) -4- (1-piperidyl) phenol dihydrochloride (KT-476)
(Example 1-58-1) Synthesis of 3- [2-benzyloxy-5- (1-piperidyl) phenyl] -6,6-dimethyl-3-azabicyclo [3.1.0] hexane The title compound is Example. It was obtained in the same manner as 1-8-2 (yield 26%).
(Example 1-58-2) Synthesis of 2- (6,6-dimethyl-3-azabicyclo [3.1.0] hexane-3-yl) -4- (1-piperidyl) phenol dihydrochloride The title compound is It was obtained in the same manner as in Example 1-4-2 (yield 93%).
[Example 1-59] Synthesis of 2- (4-benzyloxycarbonylpiperazin-1-yl) -4- (1-piperidyl) phenol dihydrochloride (KT-479)
(Example 1-59-1) Synthesis of 1- (3-bromo-4-tert-butoxyphenyl) piperidine The title compound was obtained in the same manner as in Example 1-8-1 (yield 82%). ).
(Example 1-59-2) Synthesis of 1-benzyloxycarbonyl-4- [2-tert-butoxy-5- (1-piperidyl) phenyl] piperazine Under an argon gas stream, 1- (3-bromo-4-) To 5.0 g of tert-butoxyphenyl) piperidine, add 100.0 mL of 1,4-dioxane, 5.29 g of 1-carbobenzoxiperazine, 2.46 g of t-BuONa, 997 mg of rac-BINAP and _{3 733 mg of Pd 2} (dba), and argon. After stirring at room temperature for 15 minutes in a gas atmosphere, the mixture was heated to 80 ° C. for 70 hours. The reaction mixture was returned to room temperature, _{poured into a mixture of Et 2} O and water, stirred, and then the insoluble matter was filtered off. The organic layer was separated from the obtained mother liquor, washed with brine, dried with DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-AcOEt system) to obtain 4.13 g (yield 57%) of the title compound.
(Example 1-59-3) Synthesis of 2- (4-benzyloxycarbonylpiperazin-1-yl) -4- (1-piperidyl) phenol dihydrochloride
To 0.17 g of 1-benzyloxycarbonyl-4- [2-tert-butoxy-5- (1-piperidyl) phenyl] piperazine, 0.85 mL of methanol and 1.88 mL of 4M-HCl / DOX were added, and the mixture was stirred at room temperature for 18 hours. The mixture was stirred at 40 ° C. for 3 hours. The reaction mixture was concentrated, and the obtained residue was pulverized with AcOEt to give the title compound (145 mg, yield 82%).
[Example 1-60] Synthesis of 2- [4- (2-chlorobenzoyl) piperazine-1-yl] -4- (1-piperidyl) phenol dihydrochloride (KT-480)
(Example 1-60-1) Synthesis of 1- [2-tert-butoxy-5- (1-piperidyl) phenyl] piperazine
3.5 g of 1-benzyloxycarbonyl-4- [2-tert-butoxy-5- (1-piperidyl) phenyl] piperazine was dissolved in 35.0 mL of methanol and 15.0 mL of THF, and 0.5 g of 10% Pd-C was added. Hydrogen gas was added and catalytic reduction was carried out at room temperature for 1.5 hours under atmospheric pressure. By filtering the catalyst and concentrating the mother liquor, 2.46 g (yield 100%) of the title compound was obtained.
(Example 1-60-2) Synthesis of 4- [2-tert-butoxy-5- (1-piperidyl) phenyl] -1- (2-chlorobenzoyl) piperazine Ice-cooled 1- [2-tert-butoxy -5- (1-Piperidyl) Phenyl] Piperazine 0.4 g,
2-Chlorobenzoyl chloride 0.192 mL was added to a mixture of CH ₂ Cl ₂ 6.0 mL and DIPEA 263 mL, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with sat. LVDS ₃ aq., Washed with water, dried with DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-AcOEt system) to give the title compound 208 mg (yield 36%).
(Example 1-60-3) Synthesis of 2- [4- (2-chlorobenzoyl) piperazine-1-yl] -4- (1-piperidyl) phenol dihydrochloride
To 0.19 g of 4- [2-tert-butoxy-5- (1-piperidyl) phenyl] -1- (2-chlorobenzoyl) piperazine, 0.95 mL of methanol and 1.04 mL of 4M-HCl / DOX are added and sealed at 40 ° C. Was warmed to and stirred for 5.5 hours. After adding 10 mL of AcOEt to the reaction mixture and stirring at room temperature, the precipitate was collected by filtration to give 178 mg (yield 90%) of the title compound.
[Example 1-61] Synthesis of 2- [4- (4-chlorobenzoyl) piperazine-1-yl] -4- (1-piperidyl) phenol dihydrochloride (KT-481)
(Example 1-61-1) Synthesis of 4- [2-tert-butoxy-5- (1-piperidyl) phenyl] -1- (4-chlorobenzoyl) piperazine The title compound is Example 1-60-2. It was obtained in the same manner as (yield 75%).
(Example 1-61-2) Synthesis of 2- [4- (4-chlorobenzoyl) piperazine-1-yl] -4- (1-piperidyl) phenol dihydrochloride The title compound is Example 1-60- It was obtained in the same manner as in 3 (yield 63%).
[Example 1-62] Synthesis of 2- [4- (2-chloro-4-fluorobenzoyl) piperazine-1-yl] -4- (1-piperidyl) phenol dihydrochloride (KT-482)
(Example 1-62-1) Synthesis of 4- [2-tert-butoxy-5- (1-piperidyl) phenyl] -1- (2-chloro-4-fluorobenzoyl) piperazine The title compound is Example 1. It was obtained in the same manner as -60-2 (yield 42%).
(Example 1-62-2) Synthesis of 2- [4- (2-chloro-4-fluorobenzoyl) piperazine-1-yl] -4- (1-piperidyl) phenol dihydrochloride The title compound is Example. It was obtained in the same manner as 1-60-3 (yield 62%).
[Example 1-63] Synthesis of 4- (1-piperidyl) -2- [4- (2-thienylmethyl) piperazin-1-yl] phenol trihydrochloride (KT-483)
(Example 1-63-1) Synthesis of 1- [2-tert-butoxy-5- (1-piperidyl) phenyl] -4- (2-thienylmethyl) piperazine
0.4 g of 1- [2-tert-butoxy-5- (1-piperidyl) phenyl] piperazine _{was dissolved in 12.0 mL of CH 2} Cl ₂ , 283 mg of 2-thiophenecarboxyaldehyde was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was ice-cooled, _{0.534 g of NaBH (OAc) 3} was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with sat. LVDS ₃ aq., Washed with water, dried with DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-AcOEt system) to give 0.407 g (yield 78%) of the title compound.
(Example 1-63-2) Synthesis of 4- (1-piperidyl) -2- [4- (2-thienylmethyl) piperazin-1-yl] phenol trihydrochloride
To 0.38 g of 1- [2-tert-butoxy-5- (1-piperidyl) phenyl] -4- (2-thienylmethyl) piperazine, add 1.9 mL of methanol and 2.3 mL of 4M-HCl / DOX to 40 ° C in a sealed state. Was warmed to and stirred for 45 minutes. The reaction mixture was concentrated, 10 mL of AcOEt was added to the residue, the mixture was stirred at room temperature, and the precipitate was collected by filtration to give the title compound (361 mg (yield 84%)).
[Example 1-64] Synthesis of 4- (1-piperidyl) -2- [4- (p-tolylmethyl) piperazin-1-yl] phenol trihydrochloride (KT-484)
(Example 1-64-1) Synthesis of 1- [2-tert-butoxy-5- (1-piperidyl) phenyl] -4- (p-tolylmethyl) piperazine The title compound is Example 1-63-1. It was obtained in a similar manner (yield 89%).
(Example 1-64-2) Synthesis of 4- (1-piperidyl) -2- [4- (p-tolylmethyl) piperazin-1-yl] phenol trihydrochloride The title compound is Example 1-63-2. It was obtained in the same manner as (yield 93%).
[Example 1-65] Synthesis of 2- [4-[(4-fluorophenyl) methyl] piperazine-1-yl] -4- (1-piperidyl) phenol trihydrochloride (KT-485)
(Example 1-65-1) Synthesis of 1- [2-tert-butoxy-5- (1-piperidyl) phenyl] -4-[(4-fluorophenyl) methyl] piperazine The title compound is Example 1- It was obtained in the same manner as 63-1 (yield 90%).
(Example 1-65-2) Synthesis of 2- [4-[(4-fluorophenyl) methyl] piperazine-1-yl] -4- (1-piperidyl) phenol trihydrochloride The title compound is Example 1. It was obtained in the same manner as -63-2 (yield 97%).
[Example 1-66] Synthesis of 2- (4-benzylidene-1-piperidyl) -4- (1-piperidyl) phenol dihydrochloride (KT-486)
(Example 1-66-1) 4-Bendylidene-1- [2-tert-butoxy-5- (1-piperidyl) phenyl] Synthesis of piperidine Under an argon gas stream, 1- (3-bromo-4-tert-) Add 1,4-dioxane 26.0 mL, 4-benziliden piperidine hydrochloride 1.31 g, t-BuONa 1.04 g, rac-BINAP 259 mg and Pd ₂ (dba) ₃ 191 mg to 1.3 g of butoxyphenyl) piperidine, and create an argon gas atmosphere. After stirring at room temperature for 15 minutes, the mixture was heated to 80 ° C. and stirred for 70 hours. The reaction mixture was returned to room temperature, _{poured into a mixture of Et 2} O and water, stirred, and then the insoluble matter was filtered off. The organic layer was separated from the obtained mother liquor, washed with brine, dried with DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-CH ₂ Cl _2- AcOEt system) to obtain 0.86 g (yield 51%) of the title compound.

(Example 1-66-2) Synthesis of 2- (4-benzylidene-1-piperidyl) -4- (1-piperidyl) phenol dihydrochloride
4-Benzylidene-1- [2-tert-butoxy-5- (1-piperidyl) phenyl] Piperidine 0.65 g, 3.3 mL of methanol and 4.0 mL of 4M-HCl / DOX were added and heated to 40 ° C in a sealed state 6 Stirred for hours. 2.0 mL of 4M-HCl / DOX was added to the reaction mixture, and the mixture was further stirred under the same conditions for 4 hours. The reaction mixture was concentrated and the residue was pulverized with a mixture of ethanol and AcOEt to give the title compound (552 mg, yield 82%).

The structural formulas and analytical data for each of the compounds obtained in Synthesis Examples 1-1 to 1-66 are shown in the table below.
Ex .: Example number; St .: Chemical structure; Dat .: Analytical data

[Example 2]
Next, compounds were synthesized as shown below.
[Example 2-1] Synthesis of 2-amino-4- (cyclohexylamino) phenol dihydrochloride (KT-404)
(Example 2-1-1) Synthesis of 4- (cyclohexylamino) -2-nitrophenol
_{CH 2} Cl ₂ 20.0 mL and cyclohexanone 0.81 mL were added to 1.0 g of 4-amino-2-nitrophenol, and the suspension was stirred at room temperature for 1 hour. The suspension was ice-cooled, NaBH (OAc) ₃ 1.93 g was added, and then room temperature. Returned to and stirred for 16 hours. The reaction mixture was added to sat. LVDS ₃ aq. And extracted with AcOEt. The obtained extract was washed with brine, dried over DDL ₄ , and concentrated. The residue was purified by silica gel column chromatography (hexane-AcOEt system) to obtain 1.24 g (yield 81%) of the title compound.
(Example 2-1-2) Synthesis of 2-amino-4- (cyclohexylamino) phenol dihydrochloride
300 mg of 4- (cyclohexylamino) -2-nitrophenol was dissolved in 9.0 mL of methanol and 0.95 mL of 4M-HCl / DOX, and _{100 mg of 20% Pd (OH) 2-} C was added. Hydrogen was added and catalytic reduction was carried out at room temperature for 3 hours under atmospheric pressure. The catalyst was filtered off and the mother liquor was concentrated. The obtained residue was pulverized with AcOEt to give the title compound (345 mg, yield 97%).
[Example 2-2] Synthesis of 2-amino-4- (isopentylamino) phenol dihydrochloride (KT-396)
(Example 2-2-1) Synthesis of 4- (isopentylamino) -2-nitrophenol The title compound was obtained in the same manner as in Example 2-1-1 (yield 59%).
(Example 2-2-2) Synthesis of 2-amino-4- (isopentylamino) phenol dihydrochloride
450 mg of 4- (isopentylamino) -2-nitrophenol was dissolved in 13.5 mL of methanol and 1.5 mL of 4M-HCl / DOX, and 300 mg of 10% Pd-C was added. Hydrogen was added and catalytic reduction was carried out at room temperature for 3 hours under atmospheric pressure. The catalyst was filtered off and the mother liquor was concentrated. The obtained residue was pulverized with a mixture of 10 mL of ethanol and _{40 mL of Et 2} O to obtain 440 mg (yield 82%) of the title compound.
[Example 2-3] Synthesis of 4-amino-2- (isopropylamino) phenol dihydrochloride (KT-397)
(Example 2-3-1) Synthesis of 2- (isopropylamino) -4-nitrophenol The title compound was obtained in the same manner as in Example 2-1-1 (yield 91%).
(Example 2-3-2) Synthesis of 4-amino-2- (isopropylamino) phenol dihydrochloride The title compound was obtained in the same manner as in Example 2-2-2 (yield 98%). ..
[Example 2-4] Synthesis of 4-amino-2- (cyclohexylamino) phenol dihydrochloride (KT-398)
(Example 2-4-1) Synthesis of 2- (cyclohexylamino) -4-nitrophenol The title compound was obtained in the same manner as in Example 2-1-1 (yield 96%).
(Example 2-4-2) Synthesis of 4-amino-2- (cyclohexylamino) phenol dihydrochloride The title compound was obtained in the same manner as in Example 2-2-2 (yield 97%). ..
[Example 2-5] Synthesis of 4-amino-2- (isopentylamino) phenol dihydrochloride (KT-395)
(Example 2-5-1) Synthesis of 2- (isopentylamino) -4-nitrophenol The title compound was obtained in the same manner as in Example 2-1-1 (yield 73%).
(Example 2-5-2) Synthesis of 4-amino-2- (isopentylamino) phenol dihydrochloride The title compound was obtained in the same manner as in Example 2-2-2 (yield 49%). ).
[Example 2-6] Synthesis of 4-amino-2- (2-phenylethylamino) phenol dihydrochloride (KT-400)
(Example 2-6-1) Synthesis of 4-nitro-2- (2-phenylethylamino) phenol The title compound was obtained in the same manner as in Example 2-1-1 (yield 16%). ..
(Example 2-6-2) Synthesis of 4-amino-2- (2-phenylethylamino) phenol dihydrochloride The title compound was obtained in the same manner as in Example 2-2-2 (yield). 90%).
[Example 2-7] Synthesis of 2,4-bis (1-piperidyl) phenol dihydrochloride (KT-401)
(Example 2-7-1) Synthesis of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] piperidine Under an argon gas stream, 1 to 2.0 g of 1-benzyloxy-2,4-dibromobenzene is 1, 4-Dioxane 40.0 mL, piperidine 1.73 mL, t-BuONa 1.4 g, rac-BINAP 583 mg and Pd ₂ (dba) ₃ 428 mg were added, and the mixture was stirred at room temperature for 15 minutes under an argon gas atmosphere and then heated to 90 ° C. The mixture was stirred for 20 hours. The reaction solution was returned to room temperature, _{poured into a mixture of 100 mL each of Et 2} O and water, stirred, and then the insoluble matter was filtered off. The organic layer was separated from the obtained mother liquor, washed with brine, dried with DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (CHCl ₃ ). _{CH 2} Cl ₂ 20 mL and 1N hydrochloric acid 40 mL were added to the obtained oily substance, and the mixture was stirred and then the aqueous layer was separated. The obtained aqueous layer was adjusted to pH 7.5 with sodium hydrogen carbonate and extracted with AcOEt. The extract was washed with brine, dried over DDL ₄ , and concentrated to give 720 mg (yield 35%) of the title compound.
(Example 2-7-2) Synthesis of 2,4-bis (1-piperidyl) phenol
1.5 g of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] piperidine was dissolved in 15 mL of methanol and 7.5 mL of THF, and _{0.5 g of 20% Pd (OH) 2-} C was added. Hydrogen was added and catalytic reduction was carried out at room temperature for 3 hours under atmospheric pressure. The catalyst was filtered off and the mother liquor was concentrated. The obtained residue was purified by silica gel column chromatography (hexane-AcOEt system) to obtain 1.05 g (yield 94%) of the title compound.
(Example 2-7-3) Synthesis of 2,4-bis (1-piperidyl) phenol dihydrochloride
100 mg of 2,4-bis (1-piperidyl) phenol was dissolved in 4.0 mL of AcOEt, and 0.25 mL of 4M-HCl / AcOEt was added with stirring at room temperature. The mixture was stirred at room temperature for 2 hours, and the precipitate was collected by filtration to give 115 mg (yield 90%) of the title compound.
[Example 2-8] Synthesis of 4-amino-2- (1-piperidyl) phenol dihydrochloride (KT-402)
(Example 2-8-1) Synthesis of 1- (2-benzyloxy-5-nitrophenyl) piperidine 1,4-dioxane in 1.0 g of 1-benzyloxy-2-bromo-4-nitrobenzene under an argon gas stream Add 10.0 mL, piperidine 0.40 mL, cesium carbonate 1.48 g, rac-BINAP 323 mg and Pd ₂ (dba) ₃ 238 mg, stir for 15 minutes at room temperature under an argon gas atmosphere, then heat to 90 ° C and stir for 20 hours. bottom. The reaction solution was returned to room temperature, poured into a mixture of AcOEt and water, stirred, and then the insoluble matter was filtered off. The organic layer was separated from the obtained mother liquor, washed with brine, dried with DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-CHCl ₃ system) to give the title compound 260 mg (yield 26%).
(Example 2-8-2) Synthesis of 4-amino-2- (1-piperidyl) phenol dihydrochloride The title compound was obtained in the same manner as in Example 2-2-2 (yield 85%). ).
[Example 2-9] Synthesis of 2- (dimethylamino) -4- (isopropylamino) phenol dihydrochloride (KT-407)
(Example 2-9-1) Synthesis of 2- (methoxymethoxy) -N, N-dimethyl-5-nitroaniline
_{Add 50 mL of CH 2} Cl ₂ and 4.78 mL of DIPEA to 2.5 g of 2- (dimethylamino) -4-nitrophenol, and add 1.13 mL of chloromethyl methyl ether 1.13 mL of CH ₂ Cl ₂ 2.5 mL solution under ice-cooled stirring. , Stirred at the same temperature for 15 minutes. The reaction solution was poured into 100 mL of ice water and adjusted to pH 7 with a 10% aqueous citric acid solution. The CH ₂ Cl ₂ layer was separated, washed with water, dried with DDL ₄ , and then concentrated to obtain 3.07 g (yield 99%) of the title compound.
(Example 2-9-2) Synthesis of 4- (methoxymethoxy) -N ³ , N ³ -dimethyl-benzene-1,3-diamine
3.0 g of 2- (methoxymethoxy) -N, N-dimethyl-5-nitroaniline was dissolved in 45 mL of methanol and 7.5 mL of THF, and 0.6 g of 10% Pd-C was added. Hydrogen was added and catalytic reduction was carried out at room temperature for 2.5 hours under atmospheric pressure. The catalyst was filtered off and the mother liquor was concentrated to give 2.55 g (yield 98%) of the title compound.
(Example 2-9-3) ^{Synthesis of N 1} -isopropyl-4- (methoxymethoxy) -N ³ , N ³ -dimethylbenzene-1,3-diamine The title compound is the same as in Example 2-1-1. (Yield 69%).
(Example 2-9-4) Synthesis of 2- (dimethylamino) -4- (isopropylamino) phenol dihydrochloride
400 mg of N ¹ -isopropyl-4- (methoxymethoxy) -N ³ , N ³ -dimethylbenzene-1,3-diamine was dissolved in 4.0 mL of iPA, and 4.2 mL of 4M-HCl / DOX was added. After stirring at room temperature for 5 hours, AcOEt and Et ₂ O were added, and the precipitate was collected by filtration to obtain 388 mg (yield 87%) of the title compound.
[Example 2-10] Synthesis of 4-amino-2- (3,4-dihydro-1H-isoquinoline-2-yl) phenol dihydrochloride (KT-383)
(Example 2-10-1) Synthesis of 3- (3,4-dihydro-1H-isoquinoline-2-yl) -4- (methoxymethoxy) aniline Under an argon gas stream, 2-bromo-1- (methoxymethoxy) ) -4-To nitrobenzene 2.0 g, add 1,4-dioxane 20.0 mL, 1,2,3,4-tetrahydroisoquinoline 1.21 mL, cesium carbonate 3.48 g, rac-BINAP 713 mg and Pd ₂ (dba) ₃ 559 mg. After stirring at room temperature for 15 minutes under an atmosphere of argon gas, the mixture was heated to 80-85 ° C and stirred for 20 hours. The reaction solution was returned to room temperature, poured into a mixture of AcOEt and water, stirred, and then the insoluble matter was filtered off. The organic layer was separated from the obtained mother liquor, washed with brine, dried with DDL ₄ , and concentrated. The obtained residue was purified by silica gel column chromatography (toluene) to 1.72 g of 2- [2- (methoxymethoxy) -5-nitrophenyl] -3,4-dihydro-1H-isoquinoline (intermediate, yield 72%). ) Was obtained. To 320 mg of the obtained intermediate, 3.2 mL of ethanol, 3.2 mL of water, 6.4 mL of methanol, 218 mg of ammonium chloride, and 227 mg of iron powder were added, and the mixture was stirred at 70 ° C. for 2.5 hours. The reaction mixture was concentrated, 20 mL of AcOEt, 10 mL of THF, and 20 mL of water were added to the residue, and the mixture was stirred and the insoluble material was filtered off. The organic layer was separated from the mother liquor, washed with brine, dried over DDL ₄ , and concentrated. The residue was purified by silica gel column chromatography (hexane-AcOEt system) to obtain 170 mg of the title compound (yield 59% from the intermediate).
(Example 2-10-2) Synthesis of 4-amino-2- (3,4-dihydro-1H-isoquinoline-2-yl) phenol dihydrochloride The title compound is the same as in Example 2-9-4. Obtained by the method (yield 66%).

The structural formulas and analytical data for each of the compounds obtained in Synthesis Examples 2-1 to 2-10 are shown in the table below.
Ex .: Example number; St .: Chemical structure; Dat .: Analytical data

[Example 3]
The tau agglutination inhibitory activity was measured as shown below. First, a plasmid expressing human tau 0N4R isoform (383 amino acids) was introduced into Escherichia coli BL21 (DE3) strain to purify recombinant tau. The purification method was modified from the method of Taniguchi et al. (Taniguchi et al, 2008, JBC, 280, 7614). A soluble fraction was prepared from Escherichia coli after inducing tau expression with isopropyl-β-thiogalactopyranoside, and fractionation was performed by a phosphocellulose column (Whatman, P11 column). Fractions eluted at a concentration of 0.1 to 0.3 M of NaCl were collected and precipitated and concentrated with ammonium sulfate. The resulting precipitate was dissolved in 0.5 M NaCl, 2% 2? Mercaptoethanol-containing buffer and heated at 100 ° C. for 5 minutes. The supernatant after centrifugation at 15,000 xg for 15 minutes was collected and concentrated by precipitation with ammonium sulfate. The obtained precipitate was dissolved in 20% acetonitrile and 0.1% formic acid solution, and purified by reverse phase HPLC (Nacalai Tesque, Cosmosil protein-R column). Fractions containing the full-length recombinant tau were mixed and dried in a lyophilizer to obtain a dry-purified recombinant tau standard. The yield and concentration of the obtained tau were analyzed by electrophoresis with 10% polyacrylamide gel and then by Coomassie Brilliant Blue (CBB) staining.

The dry and purified recombinant tau standard was dissolved in purified water at a concentration of 0.9 mg / ml. The final concentration of 10 μM thioflavin T (hereinafter also referred to as Th-T), 0.1 M NaCl, 0.45 mg / ml recombinant tau, 10 mM HEPES pH 7.4, and various compounds were diluted to the desired concentration. The fluorescence value (excitation light 360 nm / fluorescence 465 nm) was measured with a fluorescence plate reader (TECAN, infinit F200). Then, heparin was added to a concentration of 60 μg / ml, and the mixture was incubated in a moisturizing box at 37 ° C., and the change in fluorescence value with time was measured.

The tau aggregation inhibitory effect of various 2,4-diaminophenol derivatives and isoproterenol at a concentration of 1 μM was derived by the following formula 1 based on the Th-T fluorescence value during the 72-hour incubation when each compound was added. .. The higher the tau agglutination inhibitory effect, the higher the tau agglutination inhibitory rate.

Equation 1

The results are shown in Table 4 below. Various 2,4-diaminophenol derivatives have been shown to be compounds that significantly inhibit tau aggregation over isoproterenol.

Next, the concentration dependence of the tau aggregation inhibitory activity was investigated. FIG. 1 shows the concentration dependence of tau aggregation inhibitory activity of KT-401 and KT-417. As shown in FIG. 1, the IC ₅₀ values of each compound were 10.16 μM for Iso (isoproterenol), 0.77 μM for KT-401, and 0.43 μM for KT-417. As described above, it was shown that both KT-401 and KT-417 are compounds having a tau aggregation inhibitory effect at a lower concentration than isoproterenol.
[Example 4]
The agglutination inhibitory activity of Aβ was measured as shown below. Aβ1-42 (Peptide Institute) was dissolved in 0.1% aqueous ammonia to a concentration of 0.5 mM, and then diluted to 20 μM in phosphate buffered saline (pH 7.4) (hereinafter, also referred to as PBS). As the test compound, a PBS solution containing 2% methanol dissolved at twice the final concentration was prepared. Equal amounts of these test compound solutions and Aβ1-42 solutions were mixed and allowed to stand at 37 ° C. for 24 hours. After that, an equal amount of Th-T solution prepared to 6 μM with 100 mM Tris-glycine buffer (pH 8.5) was added, and the fluorescence intensity was measured with a fluorescence plate reader (excitation wavelength 440 nm, fluorescence wavelength 486 nm).

The final concentrations of each compound at the time of measurement were 0.1, 0.3, 1, 3, and 10 μM. As a negative control, the fluorescence intensity measured without the test compound was defined as 0% inhibitory action, and the 50% inhibitory concentration (IC ₅₀ ) of each compound was calculated. This evaluated the Aβ inhibitory effect of each compound.

The results are shown in Table 5 below. Various 2,4-diaminophenol derivatives have been shown to be compounds that inhibit Aβ aggregation.

[Example 5]
Plasma and brain homogenate obtained from mice orally administered with the compound of [Example 2-7] are deproteinized with methanol, centrifuged, and the supernatant is quantified using LC-MS / MS to obtain plasma. And the plasma concentration was determined. As a result, the brain concentration / plasma concentration ratio of this compound was 0.35.

This showed that the compound of [Example 2-7] was excellent in translocation into plasma and brain.

It is beneficial in the treatment of amyloidosis caused by tauopathy and / or Aβ aggregation.

Claims (4)

The following formula (I)

(here,
Q is (i) a hydrogen atom, (ii) a methyl group substituted at the 6-position, (iii) an N-methylpyrrole group, and (iv) a methoxymethyl group.
In the following formulas (II) and (III)

Equation (II) is

(Here, one or two substituents X are _{written as -R 10-} Y, R ₁₀ is a chemical bond, O, carbonyl, carboxyl group, C1 to C6 alkyl group, and Y is a hydrogen atom and the number of carbon atoms. It is a phenyl group which may have a linear or branched alkyl group of 1 to 6 or a substituent, and when there are two substituents X in the ring, the substituents X are bonded to each other to form a ring. May be formed.),

(Here, X is _{written as -R 10-} Y, R ₁₀ is a chemical bond, O, carbonyl, carboxyl group, C1-C6 alkyl group, Y is a hydrogen atom, the number of carbon atoms which may have a substituent. 1-6 linear or alkyl group Edakusari, cycloalkyl group which may have a substituent phenyl group, N, O or S containing heterocycle, NR ₁₁ R ₁₁ 'group (R ₁₁ and R _11' They are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted aryl group. wherein, R ₁₁ and R ₁₁ 'are bonded to A ring may be formed.)),

(Here, X is a phenyl group and a methyl group.),

(Here, one or two substituents X are _{written as -R 10-} Y, R ₁₀ is a chemical bond, a C1 to C6 alkyl group, Y is a hydrogen atom, a linear or linear group having 1 to 6 carbon atoms. If it is an alkyl group of a branch chain and there are two substituents X in the ring, the substituents X may be bonded to each other to form a ring.),

,

Or

And
Equation (III) is

,

,

,

,

(Here, one or two substituents X are a hydrogen atom, methyl, dimethyl, phenyl, 4-phenylmethyl group.),
Or

And
However, the following compounds are excluded from the formula (I).

) Or a salt thereof. The following formula (V)

(here,
R ₆ , R ₇ , R ₈ and R ₉ are (i) hydrogen atom, (ii) cyclohexyl group, (iii) isopentyl group, (iv) isopropyl group, (v) phenylethyl group, (v) phenylethyl group, (i) hydrogen atom, (ii) cyclohexyl group, (iii) isopentyl group, (iv) isopropyl group, (v) vi) If the methyl group and (vii) R ₆ and R ₇ are not hydrogen atoms, they are bonded via several atoms and R ₆ and R ₇ form a monocyclic or compound ring, ( viii) When _{both R 8} and R ₉ are not hydrogen atoms, they are bonded via several atoms and R ₈ and R ₉ form a monocyclic or compound ring. ) And / or tau used in at least one application selected from the group consisting of treatment, diagnosis, symptom relief and prevention of amyloidosis caused by aggregation of tauopathy and / or Aβ, which comprises a compound consisting of or a salt thereof. Or an Aβ aggregation inhibitor. The tau and / or Aβ agglutination inhibitor according to claim 2, wherein the compound composed of the formula (V) is a compound represented by the following formula (IV).

Treatment of AD, Down's disease, frontotemporal dementia, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), argyrophilic dementia, or neurofibrillary tangle dementia, The tau and / or Aβ aggregation inhibitor according to claim 2 or 3, which is used for at least one application selected from the group consisting of diagnosis, relief and prevention of symptoms.

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