JP2002526488A - Hydroxyflavone derivative - Google Patents

Abstract

(57) Abstract: Tau protein kinase 1 comprising, as an active ingredient, a hydroxyflavone derivative represented by the formula (I) and a salt thereof, and a substance selected from the group consisting of solvates and hydrates thereof. For preventing and / or treating a disease or a neurodegenerative disease caused by hyperactivity of the following: (Wherein R ¹ represents a hydrogen atom or a hydroxyl group; R ² represents a hydrogen atom or a C ₁ -C ₁₈ which may have one or more C ₆ -C ₁₄ aryl groups) Ar represents an alkyl group; Ar represents an optionally substituted C ₆ -C ₁₄ aryl group or an optionally substituted aromatic heterocyclic group).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

【Technical field】

The present invention relates to a compound useful as an active ingredient of a medicament for preventing and / or treating a disease such as Alzheimer's disease caused by hyperactivity of tau protein kinase 1. Further, the present invention relates to a novel hydroxyflavone derivative useful as an active ingredient of the above-mentioned medicine.

[0002]

[Background Art]

Alzheimer's disease is progressive senile dementia in which degeneration of nerve cells and atrophy of the cerebral cortex due to a decrease in the number of nerve cells are remarkably observed. Pathologically, there are numerous senile plaques and neurofibrillary tangles in the brain. The number of patients increases with an increasing elderly population, and the disease has become a serious social problem. However, although there are various theories about the cause of this disease, it is still unknown, and early elucidation of the cause is desired.

It is known that the degree of appearance of two pathological changes characteristic of Alzheimer's disease correlates well with the degree of intellectual dysfunction. Therefore, 198 studies have been conducted to investigate the components of these two pathological changes at the molecular level and to clarify the etiology of this disease.
It has been done since the early 0s. Senile plaques accumulate extracellularly, and its main component has been elucidated to be amyloid β protein (hereinafter abbreviated as “Aβ”) (Biochem. Biophys. Res. Commun., 120, 855 (1984); EMBO J.,
4, 2757 (1985); Proc. Natl. Acad. Sci. USA, 82, 4245 (1985)). In addition, another pathological change, a fibril concentrate of neurofibrillary tangles, is a double helical fibrous substance called a paired helical filament (hereinafter abbreviated as “PHF”). It has been shown that it accumulates in cells and its main component is tau protein, a kind of brain-specific microtubule-associated protein (Proc. Natl. Acad. Sci. USA , 85, 4506 (1988); Neuron, 1,
827 (1988)).

Further, from genetic studies, presenilin 1 and 2 were found as causative genes of familial Alzheimer's disease (Nature, 375, 754 (1995); Science, 269, 973 (1995);
Nature. 376, 775 (1995)), it was revealed that the presence of mutants of presenilin 1 and 2 promotes Aβ secretion (Neuron, 17, 1005 (1996); Proc. Natl. Acad.
Sci. USA, 94, 2025 (1997)). From these results, it is considered that Aβ abnormally accumulates and aggregates for some reason in Alzheimer's disease, which leads to neuronal cell death in conjunction with PHF formation. In the initial stage of neuronal cell death caused by ischemic cerebrovascular disease, extracellular glutamate efflux and activation of the glutamate receptor in response thereto are considered to be important factors (Latest Medicine, 49
, 1506 (1994)).

Amyloid precursor protein (hereinafter referred to as “AP”, which is a precursor of Aβ by kainic acid treatment to stimulate AMPA receptor which is a kind of glutamate receptor
P ") (Society for Neuroscience Abstracts, 17,
1445 (1991)) that the metabolism of APP is enhanced (The Journal of Neuroscience, 10, 24
00 (1990)), strongly suggesting that Aβ accumulation is involved in cell death due to ischemic cerebrovascular disease. Other diseases in which abnormal accumulation and aggregation of Aβ are observed include, for example, Down's syndrome, cerebral hemorrhage due to cerebral amyloid angiopathy, and Lewy body disease (Nerve Progress, 34, 343 (1990); proteins and nucleic acids)・
Enzyme, 41, 1476 (1996)). Examples of diseases in which fibril concentrates of neurofibrillary fibers due to PHF accumulation appear include progressive supranuclear palsy, subacute sclerosing panencephalitis parkinsonism, post-encephalitis parkinsonism, fighter encephalopathy, and guam-parkinson dementia complex. Disease and Lewy body disease (Protein, nucleic acid, enzyme, 36, 2 (1991);
History of Medicine, 158, 511 (1991); Proteins, nucleic acids and enzymes, 41, 1476 (1996)).

[0006] Tau proteins are usually composed of a group of closely related proteins that form several bands with a molecular weight of 48-65 KDa by SDS-polyacrylamide gel electrophoresis, and promote the formation of microtubules. It has been demonstrated that tau protein incorporated into PHF of Alzheimer's disease brain is abnormally phosphorylated compared to normal tau protein (J. Biochem., 9).
9, 1807 (1986); Proc. Natl. Acad. Sci. USA, 83, 4913 (1986)). Enzymes that catalyze this abnormal phosphorylation have been isolated. This protein is named tau protein kinase 1 (hereinafter abbreviated as "TPK1"), and its physicochemical properties have been elucidated (Biochemistry, 64, 308 (1992); J. Biol. Chem). ., 267, 1089
7 (1992)). Furthermore, a rat TPK1 cDNA was cloned from a rat cerebral cortex cDNA library based on a partial amino acid of TPK1, its base sequence was determined, and its amino acid sequence was deduced (JP-A-6-239893 (1994)). . As a result, it has been confirmed that the primary structure of this rat TPK1 matches the primary structure of an enzyme known as rat GSK-3β (glycogen synthase kinase 3β) (FEBS Lett., 325, 167 (1993)). .

It has been reported that Aβ, the main component of senile plaques, has neurotoxicity (Sc
ience, 250, 279 (1990)). However, there are various theories as to why Aβ causes cell death, and a unified theory has not been established. Takashima et al. Confirmed that Aβ treatment of rat fetal hippocampal primary cultures resulted in neuronal cell death, and that Aβ treatment increased TPK1 activity and that Aβ cell death was inhibited by TPK1 antisense. (Proc. Natl. Acad. Sci. USA, 90,
7789 (1993); JP-A-6-329551 (1994)).

[0008] Based on the above, compounds that inhibit TPK1 activity are considered to be Aβ neurotoxic and PH
It may suppress the formation of F, cause neuronal loss in Alzheimer's disease, and prevent or slow the progress of the disease. In addition, by suppressing the cytotoxicity of Aβ,
It may be used as a therapeutic agent for ischemic cerebrovascular disease, Down syndrome, cerebral amyloid angiopathy, cerebral hemorrhage due to Lewy body disease, and the like. In addition, this compound
Progressive supranuclear palsy, subacute sclerosing panencephalitis Parkinson's syndrome, post-encephalitis Parkinson's syndrome, fighter encephalopathy, Guam-Parkinson dementia complex, Lewy body disease, Pick's disease, cortical basal degeneration, frontotemporal dementia Etc. may be used as therapeutic agents for neurodegenerative diseases.

[0009]

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a compound useful as an active ingredient of a medicament for preventing and / or treating a disease such as Alzheimer's disease. More specifically, TP
As an active ingredient of a medicament capable of fundamentally preventing and / or treating diseases such as Alzheimer's disease by inhibiting the neurotoxicity of Aβ and the formation of PHF by inhibiting K1 activity and preventing neuronal loss. It is to provide a useful new compound. Another object of the present invention is to provide a novel compound useful as an active ingredient of a medicine having the above characteristics.

[0010] In order to achieve the above object, the present inventors screened various compounds having an inhibitory activity on TPK1 phosphorylation. As a result, they have found that a compound represented by the following formula (I) has a desired activity and is useful as an active ingredient of a medicament for preventing and / or treating the above-mentioned diseases. The present invention has been completed based on these findings.

That is, the present invention provides a compound represented by the formula (I):

Embedded image(Where R¹Represents a hydrogen atom or a hydroxyl group;^TwoIs a hydrogen atom or C₆~ C_{1 Four} C optionally having an aryl group₁~ C₁₈Ar represents a substituted alkyl group;
C that may be₆~ C₁₄An aryl group or an optionally substituted aromatic heterocycle
A hydroxyflavone derivative represented by the formula
Including as an active ingredient a substance selected from the group consisting of solvates and hydrates thereof,
Prevention of diseases caused by hyperactivity of tau protein kinase 1 or neurodegenerative diseases
And / or a medicament for treatment.

According to a preferred embodiment of the present invention, the disease is Alzheimer's disease, ischemic cerebrovascular disease, Down syndrome, cerebral hemorrhage due to cerebral amyloid angiopathy, progressive supranuclear palsy, subacute sclerosing panencephalitis parkinsonism, The above drug is provided which is selected from the group consisting of post-encephalitis Parkinson's syndrome, fighter encephalopathy, Guam-Parkinson dementia complex, Lewy body disease, Pick's disease, cortical basal degeneration, and frontotemporal dementia. In a preferred embodiment, the medicament is provided in the form of a pharmaceutical composition containing the above substance as an active ingredient together with one or more pharmaceutical additives. Further, the present invention provides a tau protein kinase 1 inhibitor selected from the group consisting of hydroxyflavone derivatives of the formula (I) and salts thereof, and solvates and hydrates thereof.

Another aspect of the present invention is a method for preventing and / or treating a disease caused by hyperactivity of tau protein kinase 1, comprising a hydroxyflavone derivative of formula (I) and a physiologically acceptable derivative thereof. A method comprising administering to a patient a prophylactically and / or therapeutically effective amount of a substance selected from the group consisting of salts, and their solvates and hydrates thereof; Provided is the use of a substance selected from the group consisting of the hydroxyflavone derivative (I) and physiologically acceptable salts thereof, and solvates and hydrates thereof.

In still another aspect of the present invention, there is provided a compound of formula (I):

Embedded image[Wherein, R¹Represents a hydrogen atom or a hydroxyl group;^TwoIs a hydrogen atom or C₆~ C_{1 Four} C optionally having an aryl group₁~ C₁₈Ar represents a substituted alkyl group;
C that may be₆~ C₁₄An aryl group or an optionally substituted aromatic heterocycle
Represents a group; R^TwoIs a hydrogen atom, Ar is a group represented by the formula (II):

Embedded image ^{Wherein, R 3, R 4, R} 5, R 6, and R ⁷ are each independently a hydrogen atom, an alkyl group substituted C ₁ optionally -C _18, optionally substituted C ₁ to A C ₁₈ alkoxy group, a hydroxyl group, an optionally substituted acyloxy group, a carboxyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, an optionally substituted alkylcarbonyl group, Represents an amino group, a nitro group, or a cyano group which may be substituted, provided that R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷
Is one of the formula (III): -X- (CH ₂ ) _m -R ⁸ (wherein R ⁸ is an optionally substituted amino group or an optionally substituted nitrogen-containing saturated heterocyclic group X represents a single bond or an oxygen atom; m represents an integer from 1 to 8), wherein R ¹ is a hydrogen atom, When R ² is a methyl group and Ar is a phenyl group, a 3,4-methylenedioxyphenyl group or a 3-pyridyl group, R ¹ is a hydrogen atom, R ² is a propyl group, and Ar Is 4
Is a phenyl group having a carboxyl group or an ester group at the position, and R ¹ is a hydroxyl group, R ² is a methyl group, and Ar is a phenyl group, a 4-hydroxyphenyl group, a 4-methoxyphenyl group or A hydroxyflavone derivative or a salt thereof, or a solvate or hydrate thereof, represented by the following formula:

According to a preferred embodiment of the above invention, the compound of formula (IV):

Embedded image (Wherein, R ¹ represents a hydrogen atom or a hydroxyl group; Z represents an optionally substituted amino group, or an optionally substituted nitrogen-containing saturated heterocyclic group; n represents 1 to 8
R ⁵ represents a hydrogen atom or a C ₁ -C ₁₅ alkoxy group; R ⁶ represents a hydrogen atom or a hydroxyl group) or a salt thereof, or a solvate thereof. Or a hydrate thereof; Formula (V):

Embedded image (Wherein, R ² represents a hydrogen atom or one or more alkyl groups of C ₆ -C ₁₄ C ₁ may have an aryl group -C _18; R ⁴ is optionally substituted Good C ₁
Alkyl -C _18, optionally substituted C ₁ -C ₁₈ alkoxy group, a hydroxyl group, an optionally substituted acyloxy group, a carboxyl group, an optionally substituted alkoxycarbonyl group, optionally substituted An optionally substituted carbamoyl group, an optionally substituted alkylcarbonyl group, an optionally substituted amino group, a nitro group, or a cyano group; R ⁵ represents a hydrogen atom, a hydroxyl group, a methoxy group,
Or a nitro group), a hydroxyflavone derivative or a salt thereof, or a solvate or hydrate thereof; and a formula (I):

Embedded image (Wherein R ¹ represents a hydrogen atom or a hydroxyl group; R ² represents a hydrogen atom or a C ₁ -C ₁₈ alkyl optionally having one or more C ₆ -C ₁₄ aryl groups) Ar represents an optionally substituted aromatic heterocyclic group; provided that R ¹ is a hydrogen atom, R ² is a methyl group, and Ar is a pyridyl group) Provided is a hydroxyflavone derivative or a salt thereof, or a solvate or a hydrate thereof.

[0016] Indian J. Chem. Sect. B, Org. Chem. Incl. Med. Chem., 35B, 1253 (1996).
Discloses a compound in which R ¹ is a hydrogen atom, R ² is an allyl group, and Ar is a phenyl group, a 4-tolyl group, or a 4-chlorophenyl group in the above formula (I), In Indian J. Chem. Sect. B, 30B, 93 (1991), R ¹ in the above formula (I) is a hydrogen atom, and R ² is a 1-phenyl-2-propenyl group or 1-phenyl-1- A compound having a propenyl group and Ar being a phenyl group is disclosed, and is disclosed in Indian J. Chem. Sect. B, 26B, 229 (1991), J. Indian Chem. Soc.,
60, 411 (1983) and Indian J. Indian Chem. Soc., 49, 283 (1972) show that in the above formula (I), R ¹ is a hydrogen atom, R ² is a methyl group, and Ar Is a phenyl group, and is disclosed in Indian J. Chem. Sect. B, 19B, 866 (19
80) discloses a compound in which R ¹ is a hydrogen atom, R ² is a 1,2-dimethyl-2-propenyl group and Ar is a phenyl group in the above formula (I), Pharm. France, 18, 528 (1960) states that in the above formula (I), R ¹ is a hydrogen atom, R ² is a methyl group, and Ar is a 3,4-methylenedioxyphenyl group. Compounds are disclosed.

Phytochemistry, 19, 2179 (1980) states that in the above formula (I), R ¹ is a hydrogen atom, R ² is a 3-methyl-2-butenyl group, and Ar is a 4-hydroxyphenyl group. Are disclosed, Indian J. Chem. Sect. B, 18B, 52
5 (1979) shows that in the above formula (I), R ¹ is a hydrogen atom, R ² is an allyl group, and Ar is a phenyl group having a methoxy group at the 2-, 3- or 4-position. Are disclosed in Indian J. Chem. Sect. B, 15B, 933 (1977) and Tetrahedr.
on Lett., 1977, 473 (1977) states that in the above formula (I), R ¹ is a hydrogen atom,
A compound in which R ² is an allyl group and Ar is a phenyl group is disclosed.
Soc. Chim. FR1960, 95 (1960) discloses a compound in which R ¹ is a hydrogen atom, R ² is a methyl group, and Ar is a 3-pyridyl group in the above formula (I). ing.

[0018] J. Indian Chem. Soc., 65, 149 (1988) and Indian J. Chem. Sect. B, 20B,
624 (1981) discloses a compound in which R ¹ is a hydroxyl group, R ² is a methyl group, and Ar is a 3,4-methylenedioxyphenyl group in the above formula (I), Tetrahedron, 31, 265 (1975) discloses a compound in which R ¹ is a hydroxyl group, R ² is a methyl group and Ar is a phenyl group in the above formula (I). Chem., 4, 481 (1966) discloses a compound in which R ¹ is a hydroxyl group, R ² is a methyl group, and Ar is a 4-methoxyphenyl group in the above formula (I). , Phytochemistry, 22, 2107 (19
83) discloses a compound in which R ¹ is a hydroxyl group, R ² is a methyl group, and Ar is a 4-hydroxyphenyl group in the above formula (I).

In addition, US Pat. No. 4,042,708 and German Patent No. 2,454,670 describe in US Pat.
Is a synthetic intermediate for the production of a compound having anti-SRS activity,
At R¹Is a hydroxyl group, and R^TwoIs a propyl group, and Ar is 4-
Compound which is a phenyl group having a carboxyl group or a 4-ethoxycarbonyl group
And JP-A-8-225563 (1996) discloses that R in the above formula (I) ¹ Is a hydroxyl group, and R^TwoIs a propyl group, and Ar is 3-hydroxy
The compound that is a 4-methylphenyl group is useful for treating chronic venous insufficiency.
Is disclosed. However, these compounds have an inhibitory activity on TPK1.
Has never been known before.

[0020]

BEST MODE FOR CARRYING OUT THE INVENTION

As used herein, the alkyl portion of an “alkyl group” or a functional group containing an alkyl portion (eg, an alkoxy group) may be linear, cyclic, or branched. The alkyl group represented by R ² is, for example, a methyl group, an ethyl group, n
-Propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclobutyl group, n-pentyl group, isopentyl group,
Neopentyl group, 1,1-dimethylpropyl group, cyclopentyl group, n-hexyl group, isohexyl group, cyclohexyl group, or linear or branched heptyl group, octyl group, nonyl group, decyl group, undecyl group, It may be a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, an octadecyl group, or the like.

R^TwoC indicated by₆~ C₁₄Having an aryl group of₁~ C₁₈Examples of alkyl groups of
For example, the above C substituted with a phenyl group, a naphthyl group, an anthryl group, etc.₁
~ C₁₈Alkyl group. More specifically, a benzyl group, 1-naphthyl
Methyl group, 2-naphthylmethyl group, 1-phenethyl group, 2-phenethyl group, 3-
Examples include a phenylpropyl group and a 4-phenylbutyl group. C represented by Ar ₆ ~ C₁₄Examples of the aryl group include, for example, a phenyl group, a 1-naphthyl group,
-A naphthyl group, an anthryl group and the like.

In the present specification, when a certain functional group is defined as “optionally substituted” or “optionally substituted”, the number, type and substitution position of the substituent are not particularly limited. However, when two or more substituents are present, they may be the same or different. When the aryl group represented by Ar has one or more substituents, the aryl group is a C ₁ -C ₁₈ alkyl group as described above for R ² ;
Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyl C ₁ -C ₈ alkoxy groups such as oxy group, cyclohexyloxy group, cycloheptyloxy group, cyclooctyloxy group; methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, tert-
A C ₁ -C ₈ alkylthio group such as a butylthio group and a pentylthio group; a methylenedioxy group; a C ₆ -C ₁₀ aryl group such as a phenyl group, a 1-naphthyl group and a 2-naphthyl group; a fluorenyl group; A C ₆ -C ₁₄ aryloxy group such as a naphthoxy group; a C ₆ -C ₁₄ arylthio group such as a phenylthio group and a naphthylthio group; a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a butanesulfonyl group, a pentanesulfonyl group, and the like A C ₁ -C ₅ alkylsulfonyl group; a C ₆ -C ₁₄ arylsulfonyl group such as a phenylsulfonyl group and a naphthylsulfonyl group;
Halogen atom ("halogen atom" or "halogen" as used herein)
The term is fluorine atom, chlorine atom, bromine atom, and) includes any iodine atom; hydroxyl group; a nitro group; oxo group halogenated alkyl group of C ₁ -C ₁₈ such as a trifluoromethyl group; Formyl group; cyano group; carboxyl group;
Methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group,
tert- butoxycarbonyl group, an alkyloxycarbonyl group having C ₂ -C ₆ such as a pentyloxy group; an acetyl group, a propionyl group, a butyryl group, an alkylcarbonyl group having C ₂ -C ₆ such as a valeryl group; acetoxy group, propionyl A C ₂ -C ₆ alkylcarbonyloxy group such as an oxy group, a butyryloxy group, a valeryloxy group; a C ₆ -C ₁₄ arylcarbonyloxy group such as a benzoyloxy group or a naphthoyloxy group; an amino group; a methylamino group; Amino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, ter
t- butylamino group, pentylamino group, monoalkylamino group of C ₁ -C _5, such as isopentyl amino group; a dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino groups, C such diisopropylamino group ₂ -C ₁₀ dialkylamino group (two alkyl groups may be the same or different from each other);
A carbamoyl group; an acetylamino group, propionylamino group, isopropionyl group, butyrylamino group, alkylcarbonylamino group of C ₂ -C ₆ such as a valerylamino group methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, butylcarbamoyl group, tert- butylcarbamoyl group, an alkylcarbamoyl group of C ₂ -C ₆ such as a pentylcarbamoyl group; dimethylcarbamoyl group, diethylcarbamoyl group, dipropylcarbamoyl group, diisopropylcarbamoyl group, dialkyl C ₃ -C _9, such as dibutyl carbamoyl group Carbamoyl group; for example, furan ring, dihydrofuran ring, tetrahydrofuran ring, pyran ring, dihydropyran ring, tetrahydropyran ring, benzofuran ring, isobenzofuran ring, chromene ring, Roman ring, isochroman ring, thiophene ring, benzothiophene ring, pyrrole ring, pyrroline ring, pyrrolidine ring, imidazole ring, imidazoline ring, imidazolidine ring, pyrazole ring, pyrazoline ring, pyrazolidine ring, triazole ring, tetrazole ring, pyridine ring, Pyridine oxide ring, piperidine ring, pyrazine ring, piperazine ring, pyrimidine ring, pyridazine ring, indolizine ring, indole ring, indoline ring, isoindole ring, isoindoline ring, indazole ring, benzimidazole ring, purine ring, quinolidine ring, Quinoline ring, phthalazine ring, naphthyridine ring, quinoxaline ring, quinazoline ring, cinnoline ring, pteridine ring, oxazole ring, oxazolidine ring, isoxazole ring, isoxazolidine ring, thiazole ring, benzothiazo Ring, thiazolidine ring, isothiazole ring, isothiazolidine ring, dioxane ring, dithiane ring, morpholine ring, thiomorpholine ring, phthalimide ring, etc., from 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen atoms May have one or two or more substituents selected from the group consisting of heterocyclic residues having 5 to 10 total atoms constituting the ring (these substituents The group is referred to as “substituent group A”.) Regarding the substituent group A, the aryl group and the heterocyclic group may further have one or more substituents selected from the substituent group A.

Examples of the aromatic heterocyclic group represented by Ar include, for example, an oxygen atom, a sulfur atom,
And a residue of an aromatic heterocyclic compound having 1 to 4 heteroatoms selected from nitrogen atoms and having a total number of 5 to 10 atoms constituting a ring. These aromatic heterocyclic groups can be bonded to any position on the ring. More specifically, as examples, furan ring, benzofuran ring, isobenzofuran ring, thiophene ring, benzothiophene ring, pyrrole ring, imidazole ring, pyrazole ring, triazole ring, tetrazole ring, pyridine ring, pyrazine ring, pyrimidine ring, Pyridazine ring, indole ring,
Examples thereof include residues such as an isoindole ring, an indazole ring, a benzimidazole ring, a purine ring, a quinoline ring, an isoquinoline ring, a phthalazine ring, an oxazole ring, an isoxazole ring, a thiazole ring, a benzothiazole ring, and an isothiazole ring.
The aromatic heterocyclic group may have one or more substituents selected from substituent group A.

Examples of the C _{1 to} C ₁₈ alkyl groups represented by R ^{3 to} R ⁷ include those described above for R ² , wherein the alkyl group is one or more selected from substituent group A. It may have two or more substituents. Examples of the alkoxy group represented by R ^{3 to} R ⁷ include, for example, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group,
Cyclopropyloxy group, n-butoxy group, isobutoxy group, tert-butoxy group, cyclobutoxy group, n-pentyloxy group, isopentyloxy group, cyclopentyloxy group, n-hexyloxy group, isohexyloxy group, cyclohexyloxy Other than a group, a linear, branched, or cyclic heptyloxy group,
C such as octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, etc. ₁ to _C18 alkoxy groups are exemplified. The alkoxy group may have one or more substituents selected from substituent group A.

R^Three~ R⁷Examples of the acyloxy group represented by are, for example, an acetoxy group,
C such as ropionyloxy, butyryloxy, valeryloxy, etc._Two~ C₆Al
C such as a carbonyloxy group, a benzoyloxy group and a naphthoyloxy group ₆ ~ C₁₄Arylcarbonyloxy group. Alkylcarbonyloxy
The alkyl part of the thio group and the aryl part of the arylcarbonyloxy group are
It may have one or more substituents selected from group A. R^Three~ R⁷Indicated by
Examples of the alkoxycarbonyl group are, for example, a methoxycarbonyl group,
Ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl
Group, n-butoxycarbonyl group, isobutoxycarbonyl group, tert-but
C such as xycarbonyl group and n-pentyloxycarbonyl group_Two~ C₆The alkoxy of
And a carbonyl group. The alkyl moiety of the alkoxycarbonyl group is substituted
It may have one or more substituents selected from group A.

When the carbamoyl group represented by R ^{3 to} R ⁷ has one or more substituents, examples of the carbamoyl group include, for example, a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, and a butyric group. carbamoyl group, tert- butylcarbamoyl group, a mono-alkylcarbamoyl group of C ₂ -C ₆ such as a pentylcarbamoyl group; dimethylcarbamoyl group, diethylcarbamoyl group, dipropylcarbamoyl group, diisopropylcarbamoyl group, C _3, such as dibutyl carbamoyl group
Dialkylcarbamoyl groups -C ₉ (2 one alkyl group may be the same or different), and the like. The alkyl portion of the alkylcarbamoyl group and the dialkylcarbamoyl group may have one or more substituents selected from the substituent group A.

When the amino group represented by R ^{3 to} R ⁷ has one or more substituents, examples thereof include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group and a butylamino group. , isobutylamino group, tert- butylamino group, pentylamino group, monoalkylamino group of C ₁ -C _5, such as isopentyl amino group;
Dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, a dialkylamino group of C ₂ -C _10, such as a diisopropylamino group; an acetylamino group, propionylamino group, isopropionyl group, butyrylamino group, valerylamino group alkylcarbonylamino group Nadoa of C ₂ -C ₆ the like. The alkyl portion of the above monoalkylamino group and dialkylamino group may have one or more substituents selected from substituent group A.
When the amino group represented by R ⁸ has one or more substituents, the amino group may be a substituted amino group selected from those described above for R ^{3 to} R ⁷ .

The number of nitrogen atoms contained in the nitrogen-containing saturated heterocyclic group represented by R ⁸ is not particularly limited, and the heterocyclic group may contain one heteroatom (eg, oxygen atom, sulfur atom, etc.) other than nitrogen atom. Or two or more of them. The nitrogen-containing saturated heterocyclic group may be substituted at any position on the ring. More specifically, for example, a pyrrolidine ring, a piperidine ring, a piperazine ring, a homopiperidine ring, a homopiperazine ring, a morpholine ring,
And a residue such as a thiomorpholine ring. The nitrogen-containing saturated heterocyclic group may be substituted with one or more substituents selected from substituent group A.

When the amino group represented by Z has one or more substituents, the amino group may be a substituted amino group selected from those described above for R ^{3 to} R ⁷ . Examples of the nitrogen-containing saturated heterocyclic group represented by Z include a pyrrolidine ring, a pyrazolidine ring, an imidazolidine ring, a thiazolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, a thiomorpholine ring, and a quinuclidine ring.

As the active ingredient of the medicament of the present invention, in addition to the compound represented by the above formula (I),
Physiologically acceptable salts thereof may be used. Examples of salts include, when an acidic group is present, salts of alkali metals and alkaline earth metals such as lithium, sodium, potassium, magnesium, and calcium; ammonia, and methylamine, dimethylamine, trimethylamine, dicyclohexylamine, Tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, L-
Salts of amines such as glucamine; and salts with basic amino acids such as lysine, δ-hydroxylysine and arginine. When a basic group is present, examples thereof include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, and propion. Organic acids such as acid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid and salicylic acid A salt with an acid; or a salt with an acidic amino acid such as aspartic acid and glutamic acid.

As the active ingredient of the medicament of the present invention, solvates and hydrates of the hydroxyflavone derivative represented by the above formula (I) and a salt thereof may be used. Further, the hydroxyflavone derivative represented by the above formula (I) may have one or more asymmetric carbon atoms. Regarding the stereochemistry of such asymmetric carbon atoms, each of the asymmetric carbon atoms may independently be either the (R) -form or the (S) -form, and the hydroxyflavone derivative may be an optical isomer or It may exist as stereoisomers such as diastereoisomers. As the active ingredient of the medicament of the present invention, any stereoisomer in a pure form, any mixture of stereoisomers, a racemate, and the like can be used. Further, the 4-keto form and the 4-hydroxy form of the hydroxyflavone derivative represented by the above formula (I) may exist as tautomers. The existence of the tautomers will be obvious to those skilled in the art, and any tautomers are included in the scope of the present invention.

Examples of preferred compounds of the present invention are shown in the following table. However, the scope of the present invention is not limited by the following compounds.

[0033]

[Table 1]

[0034]

[Table 2]

[0035]

[Table 3]

[0036]

[Table 4]

[0037]

[Table 5]

[0038]

[Table 6]

[0039]

[Table 7]

[0040]

[Table 8]

[0041]

[Table 9]

[0042]

[Table 10]

[0043]

[Table 11]

[0044]

[Table 12]

[0045]

[Table 13]

[0046]

[Table 14]

[0047]

[Table 15]

[0048]

[Table 16]

[0049]

[Table 17]

[0050]

[Table 18]

[0051]

[Table 19]

[0052]

[Table 20]

[0053]

[Table 21]

[0054]

[Table 22]

[0055]

[Table 23]

[0056]

[Table 24]

[0057]

[Table 25]

[0058]

[Table 26]

[0059]

[Table 27]

[0060]

[Table 28]

[0061]

[Table 29]

[0062]

[Table 30]

[0063]

[Table 31]

[0064]

[Table 32]

[0065]

[Table 33]

[0066]

[Table 34]

[0067]

[Table 35]

[0068]

[Table 36]

[0069]

[Table 37]

[0070]

[Table 38]

[0071]

[Table 39]

[0072]

[Table 40]

[0073]

[Table 41]

[0074]

[Table 42]

[0075]

[Table 43]

[0076]

[Table 44]

[0077]

[Table 45]

[0078]

[Table 46]

[0079]

[Table 47]

[0080]

[Table 48]

[0081]

[Table 49]

[0082]

[Table 50]

[0083]

[Table 51]

[0084]

[Table 52]

[0085]

[Table 53]

[0086]

[Table 54]

[0087]

[Table 55]

[0088]

[Table 56]

[0089]

[Table 57]

[0090]

[Table 58]

[0091]

[Table 59]

[0092]

[Table 60]

[0093]

[Table 61]

[0094]

[Table 62]

[0095]

[Table 63]

[0096]

[Table 64]

[0097]

[Table 65]

[0098]

[Table 66]

[0099]

[Table 67]

[0100]

[Table 68]

[0101]

[Table 69]

[0102]

[Table 70]

[0103]

[Table 71]

[0104]

[Table 72]

[0105]

[Table 73]

[0106]

[Table 74]

[0107]

[Table 75]

[0108]

[Table 76]

[0109]

[Table 77]

[0110]

[Table 78]

[0111]

[Table 79]

[0112]

[Table 80]

[0113]

[Table 81]

[0114]

[Table 82]

[0115]

[Table 83]

[0116]

[Table 84]

[0117]

[Table 85]

[0118]

[Table 86]

Among the compounds represented by the formula (I), compounds particularly suitable for the active ingredient of the medicament of the present invention.
As an object, (1) R¹Is a hydrogen atom; (2) R^TwoIs a hydrogen atom or C₁~ C₁₈A compound which is an alkyl group of (3) R^TwoIs C₁~ C₁₈A compound which is an alkyl group of (4) R^TwoIs C_Two~ C₁₈(5) Ar is a substituted phenyl group, an optionally substituted C_Ten~ C₁₄Aryl group of
Or a compound which is an optionally substituted aromatic heterocyclic group; (6) Ar-substituted C₆~ C₁₄Aryl group or optionally substituted fragrance
A compound which is an aromatic heterocyclic group; (7) Ar-substituted C₆~ C₁₄(8) a compound wherein Ar is a group represented by the above formula (II); (9) R^TwoIs one or more C₆~ C₁₄C optionally having an aryl group₁ ~ C₁₈Wherein Ar is optionally substituted C₆~ C₁₄Allies
A compound which is a group or an aromatic heterocyclic group which may be substituted; (10) R^TwoIs one or more C₆~ C₁₄C optionally having an aryl group ₁ ~ C₁₈Wherein Ar is a substituted phenyl group, optionally substituted C_{1 0} ~ C₁₄Is an aryl group or an aromatic heterocyclic group which may be substituted
(11) R^TwoIs one or more C₆~ C₁₄C optionally having an aryl group ₁ ~ C₁₈Wherein Ar is substituted C₆~ C₁₄Is an aryl group of
(12) R in the compounds of the above (9) to (11)¹Is a hydrogen atom
(13) In the above compounds (9) to (12), Ar is represented by the above formula (II).
(14) In the compounds of the above (9) to (13), R^TwoIs C₁~ C₁₈Archi
(15) In the compounds of the above (9) to (13), R^TwoIs C_Two~ C₁₈Archi
And (16) the compound of the above (9) to (12)^TwoIs C_TwoOr C_Four~ C₁₈
A compound which is an alkyl group of

In addition, as particularly preferred compounds, (17) a hydroxyflavone derivative according to the formula (IV), wherein n is 2 or 3; (18) a hydroxyflavone derivative according to the formula (IV), wherein R ⁵ is hydrogen (19) In the hydroxyflavone derivative according to the formula (IV), Z is a dimethylamino group, an optionally substituted piperazinyl group, or an optionally substituted piperidinyl group; 20) In the hydroxyflavone derivative according to the formula (V), R ⁴ may be a substituted C ₁ -C ₁₈ alkyl group, an optionally substituted C ₁ -C ₁₈ alkoxy group, a hydroxyl group, a nitro group, or derivative is a cyano group; in hydroxyflavone derivative by (21) the formula (I), R ¹ is a hydrogen atom or a hydroxymethyl It indicates Le group, R ² is a hydrogen atom, or one or two or more C ₆ -C ₁₄ ants - represents an optionally have a Le group C ₁ -C ₁₈ alkyl group, and Ar is substituted (Wherein R ¹ is a hydrogen atom, R ² is a methyl group, and Ar is a pyridyl group);

The most preferred compounds include 7-hydroxy-3 ′-(3- (1-piperidyl) propyloxy) -8-propylflavone, 4 ′, 7-dihydroxy-3′-methoxy-8-propylflavone, 7-hydroxy-8-methyl-3 '-(3- (1-piperidyl) propyloxy) flavone, 7-hydroxy-4'-nitro-3'-(3- (1-piperidyl) propyloxy) -8- Propylflavone, 4 ', 7-dihydroxy-3'-methoxy-8-methylflavone, and 7-hydroxy-8-propyl-2- (4-pyridyl) chromone. However, the active ingredients of the medicament of the present invention are not limited to the compounds specifically mentioned above.

The hydroxyflavone derivative represented by the above formula (I) can be produced by a method described in the literature, and can be produced, for example, as follows.

Embedded image (The symbols used in the scheme are as defined above.)

By reacting a compound represented by the above formula (V) with a base and a reactive derivative represented by the above formula (VI) in the presence of a solvent, the compound represented by the above formula (VII) Can be obtained. The type of the solvent is not particularly limited as long as it does not affect the reaction. For example, as solvents, ethers such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, isopropyl ether, dioxane,
Aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane can be used. Two or more solvents may be used as a mixture. Examples of the base include, for example, methyllithium, butyllithium, lithium hexamethyldisilazane, sodium hexamethyldisilazane, lithium diisopropylamide, sodium hydroxide, potassium hydroxide, sodium hydride and the like. As the reactive derivative represented by the formula (VI), symmetric acid anhydrides, mixed acid anhydrides, acid halides, active amides, esters and the like can be used. It can be easily manufactured by the method. The reaction temperature and reaction time are not particularly limited, but the reaction can be usually carried out at a temperature of -78 ° C to 250 ° C for 30 minutes to 48 hours.

Embedded image (The symbols used in the scheme are as defined above.)

By subjecting the compound represented by the formula (VII) obtained in the step 1 to a dehydration reaction in the presence or absence of a solvent, the compound represented by the formula (I) can be obtained. it can. The type of the solvent is not particularly limited as long as it does not affect the reaction. For example, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, isopropyl ether, ethers such as dioxane, benzene, toluene, aromatic hydrocarbons such as xylene, dichloromethane, chloroform, halogenated hydrocarbons such as dichloroethane, acetonitrile, Nitriles such as propionitrile, esters such as methyl acetate and ethyl acetate, alcohols such as methanol and ethanol,
Organic acids such as acetic acid and acid anhydrides such as acetic anhydride can be used. Two or more of these solvents may be used as a mixture. The dehydration reaction can be performed in the presence of an acid catalyst. Examples of the acid catalyst include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, and camphorsulfonic acid. . The reaction temperature and reaction time are not particularly limited, but the reaction can be usually carried out at a temperature of 0 ° C to 250 ° C for 30 minutes to 48 hours. In each of the above steps, protection and deprotection of a functional group may be required. The protecting group can be selected to be suitable for such a functional group, and protection and deprotection can be performed according to any method described in the literature.

The medicament of the present invention has an inhibitory activity on TPK1, and inhibits Aβ neurotoxicity and PHF formation by inhibiting TPK1 activity in Alzheimer's disease and the like,
Prevent nerve cell death. Therefore, the medicament of the present invention is useful as a medicament capable of fundamentally preventing and / or treating Alzheimer's disease. Also, the medicament of the present invention ischemic cerebrovascular disease, Down syndrome, cerebral hemorrhage due to cerebral amyloid angiopathy, progressive supranuclear palsy, subacute sclerosing panencephalitis Parkinson syndrome, post-encephalitis Parkinson syndrome, fighter encephalopathy, Guam -It is useful for prevention and / or treatment of Parkinson's dementia complex disease, Lewy body disease, Pick's disease, cortical basal degeneration, frontotemporal dementia and the like.

The active ingredient of the medicament of the present invention is selected from the group consisting of the compound represented by the above formula (I) and physiologically acceptable salts thereof, and solvates and hydrates thereof. Substances can be used. As the medicament of the present invention, the above-mentioned substance itself may be administered, but generally, the form of a pharmaceutical composition containing the above-mentioned substance as an active ingredient and one or more kinds of pharmaceutical additives is used. It is desirable to administer at As the active ingredient of the medicament of the present invention, two or more of the above substances may be used in combination. It is also possible to mix the above-mentioned pharmaceutical composition with an active ingredient of another medicament for treating Alzheimer's disease and the like.

[0127] The type of the pharmaceutical composition is not particularly limited, and may be provided as any formulation for oral administration or parenteral administration. For example, the pharmaceutical composition may be in the form of a pharmaceutical composition for oral administration such as granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions or solutions, or for intravenous administration. , Prepared in the form of pharmaceutical compositions for parenteral administration such as injections, drops, transdermal absorbers, transmucosal absorbers, nasal drops, inhalants and suppositories for intramuscular or subcutaneous administration. be able to. Injections and drops can be prepared as a powdery preparation such as a lyophilized preparation, and dissolved in a suitable aqueous medium such as physiological saline before use. It is also possible to directly administer a sustained-release preparation such as a preparation coated with a polymer into the brain.

A person skilled in the art can appropriately select the kind of the pharmaceutical additive used in the production of the pharmaceutical composition, the content ratio of the pharmaceutical additive to the active ingredient, and the method of producing the pharmaceutical composition. Inorganic or organic substances, or solid or liquid substances can be used as pharmaceutical additives. In general, the pharmaceutical additives can be blended in a ratio ranging from 1% by weight to 90% by weight based on the weight of the active ingredient.

Examples of excipients used in the production of solid pharmaceutical compositions include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like. For preparing liquid compositions for oral administration, conventional inert diluents such as water or vegetable oils can be used. The liquid compositions may contain, in addition to the inert diluent, auxiliary agents such as wetting agents, suspending agents, sweetening agents, flavoring agents, coloring agents, preservatives, and the like. Liquid compositions may be filled in capsules made of an absorbable substance such as gelatin. Examples of compositions for parenteral administration, for example, solvents or suspensions used in the production of injections, suppositories and the like include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. . Examples of bases used for suppositories include cocoa butter, emulsified cocoa butter, laurin butter, and witepsol.

The dose and frequency of administration of the medicament of the present invention are not particularly limited, and may be appropriately determined depending on the purpose of prevention and / or treatment, the type of disease, the weight and age of the patient, the severity of the disease, and the like. It is possible to choose. In general, the daily dose for an adult in oral administration can be from 0.01 to 1000 mg (weight of the active ingredient), and is administered once or several times a day or every few days be able to. When the medicament is used as an injection, the daily dose for an adult is 0.001 to 100 mg (weight of the active ingredient).
Is preferably administered continuously or intermittently.

In the above formula (I), wherein R ¹ , R ² and Ar are as defined above, and when R ² is a hydrogen atom, Ar is the above formula (II) [wherein R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are the same as defined above, provided that one of R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ is represented by the above formula ( III) (wherein, R ⁸ , X, and m are the same as defined above)] wherein R ¹ is a hydrogen atom, and R ² is When a methyl group, and Ar is a phenyl group, a 3,4-methylenedioxyphenyl group or a 3-pyridyl group, R ¹ is a hydrogen atom, R ² is a propyl group,
And Ar is a phenyl group having a carboxyl group or an ester group at the 4-position, and R ¹ is a hydroxyl group, R ² is a methyl group, and Ar is a phenyl group, a 4-hydroxyphenyl group, -Methoxyphenyl group or 3,4-dimethoxyphenyl group), and its salts, solvates and hydrates thereof are novel substances, This is included in the scope of the present invention.

The use of the novel substance provided by the present invention is not limited to medicine, and any use is included in the scope of the present invention. These substances may exist as stereoisomers such as diastereoisomeric enantiomers, but stereoisomers in any pure form, arbitrary mixtures of the stereoisomers, and racemates are also included in the scope of the present invention. Is done. Examples of substances in salt form include the physiologically acceptable salts described above.

[0133]

【Example】

Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. The compound numbers in the examples correspond to the compound numbers in the above table.

Example 1 7-Hydroxy-3 ′-(3- (1-piperidyl) propyloxy)
Preparation of -8-propylflavone disulfate (compound 455) 1.0 g of 2,4-dihydroxy-3-propylacetophenone was dissolved in 30 ml of tetrahydrofuran, and lithium hexamethyldisilazane 26m was added at -78 ° C.
1 was added dropwise and stirred for 2 hours. A tetrahydrofuran solution of 1.43 g of methyl 3-piperidylpropyloxybenzoate was added dropwise to the reaction solution, and the mixture was stirred for 24 hours. The reaction solution was poured into ice water, neutralized with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over sodium sulfate, concentrated under reduced pressure, and dried under reduced pressure. The obtained residue was dissolved in 40 ml of acetic acid, 0.2 ml of concentrated sulfuric acid was added, and the mixture was stirred at 100 ° C. for 2 hours. After cooling the reaction solution to room temperature, the precipitated solid was separated by filtration and washed with ethyl acetate to obtain 2.69 g of the desired compound. Yield: 84% Melting point: 233 ° C. NMR (DMSO-d ₆ , δ): 0.98 (t, J = 7.5 Hz, 3H), 1.
41 (m, 1H), 1.63-1.69 (m, 5H), 1.85 (m, 2H),
2.19 (m, 2H), 2.85-2.96 (m, 4H), 3.22 (m, 2H)
), 3.51 (m, 2H), 4.19 (t, J = 6.0 Hz, 2H), 6.95.
(S, 1H), 7.01 (d, J = 8.7 Hz, 1H), 7.18 (d, J = 8
. 7Hz, 1H), 7.50-7.56 (m, 2H), 7.66 (d, J = 8.
0 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 8.99 (br, 1
H), 10.60 (br, 1H).

Reference Example 1: Production of methyl 4-tert-butyldimethylsiloxy-3-methoxybenzoate 25.8 g of vanillic acid was dissolved in 500 ml of methanol, 1 g of p-toluenesulfonic acid was added, and the mixture was heated under reflux for 24 hours. did. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column with hexane / ethyl acetate = 3/1 to give methyl vanillate 2
8.5 g (100% yield) was obtained. 5.5 g of the obtained methyl vanillate is 30 m
of N, N-dimethylformamide, 3.1 g of imidazole and 5.5 g of tert-butyldimethylchlorosilane were added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column with hexane / ethyl acetate = 15/1 to give 8.68 g of the desired compound (yield 97%).
) Got. NMR (CDCl ₃ , δ): 0.17 (s, 6H), 1.01 (s, 9H), 3
. 86 (s, 3H), 3.88 (s, 3H), 6.86 (d, J = 8.7 Hz,
1H), 7.51 (d, J = 2.4 Hz, 1H), 7.66 (dd, J = 8.7)
Hz, 2.4 Hz, 1H).

Example 2: 4 ', 7-dihydroxy-3'-methoxy-8-propylflavone (
Preparation of Compound 682) 1.0 g of 2,4-dihydroxy-3-propylacetophenone was dissolved in 30 ml of tetrahydrofuran, and lithium hexamethyldisilazane 26m was added at -78 ° C.
1 was added dropwise and stirred for 2 hours. The methyl vanillate 1 obtained in Reference Example 1 was added to the reaction solution.
. A solution of 53 g of tetrahydrofuran was added dropwise and stirred for 24 hours. The reaction solution was poured into ice water, neutralized with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over sodium sulfate, concentrated under reduced pressure, and dried under reduced pressure. The residue obtained is 4
It was dissolved in 0 ml of acetic acid, 0.2 ml of concentrated sulfuric acid was added, and the mixture was stirred at 100 ° C for 2 hours. 10 ml of water was added to the reaction solution, and the mixture was stirred for 2 hours. After cooling the reaction solution to room temperature, the precipitated solid was separated by filtration and washed with ethyl acetate to obtain 1.47 g of the desired compound. Yield: 87% Melting point: 231-233 ° C. NMR (DMSO-d ₆ , δ): 0.98 (t, J = 7.2 Hz, 3H), 1.
65 (m, 2H), 2.88 (t, J = 6.9 Hz, 2H), 3.90 (s, 3
H), 6.82 (s, 1H), 6.94-6.99 (m, 2H), 7.51-7
. 55 (m, 2H), 10.53 (br, 1H).

In the same manner as in Reference Example 1, Example 1, and Example 2, the compounds of Example 3 to Example 73 were produced. The physical properties are described below.

Example 3: 7-Hydroxy-3 ′-(1-methyl-3-piperidyl) methoxyflavone (compound 42) Melting point: 134 ° C. (decomposition) NMR (DMSO-d ₆ , δ): 1.08 ( m, 1H), 1.33 (m, 1H)
, 1.70 (m, 1H), 1.95 (m, 2H), 2.27 (br, 1H), 2
. 83 (s, 3H), 3.45 (m, 1H), 3.57 (m, 1H), 3.97
(M, 1H), 4.11 (m, 1H), 6.94-6.97 (m, 2H), 7.
01 (s, 1H), 7.17 (d, J = 7.2 Hz, 1H), 7.5 (m, 1H)
), 7.57 (s, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.89
(D, J = 8.7 Hz, 1H), 9.26 (br, 1H).

Example 4: 7-Hydroxy-3 '-(2-dimethylaminoethoxy) flavone
Hydrochloride (compound 45) Melting point: 238-239 ° C NMR (DMSO-d ₆ , δ): 2.87 (s, 3H), 2.89 (s, 3H)
, 4.48 (t, J = 5.1 Hz, 2H), 6.93-6.98 (m, 2H),
7.03 (d, J = 2.1 Hz, 1H), 7.23 (dd, J = 2.1 Hz, 8
. 1Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.65 (d, J
= 2.1 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.89 (d
, J = 8.7 Hz, 1H), 10.10 (br, 1H), 10.90 (br, 1
H).

Example 5: 7-Hydroxy-3 ′-(2- (1-piperidyl) ethoxy) flavone hydrochloride (Compound 48) Melting point: 120-121 ° C. NMR (DMSO-d ₆ , δ): 1.68 -1.83 (m, 4H), 3.03 (
m, 2H), 3.51-3.63 (m, 4H), 3.62 (m, 2H), 4.5.
5 (m, 2H), 6.96-6.98 (m, 2H), 7.06 (s, 1H), 7
. 23 (d, J = 8.1 Hz, 1H), 7.52 (m, 1H), 7.64 (s,
1H), 7.70 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 8.71)
H), 10.58 (br, 1H).

Example 6: 7-Hydroxy-3 ′-(3-dimethylaminopropyloxy) flavone hydrochloride (Compound 55) Melting point: 244-245 ° C. NMR (DMSO-d ₆ , δ): 2.18 (m , 2H), 2.80 (s, 3H)
, 2.81 (s, 3H), 3.25 (m, 2H), 4,19 (t, J = 6.0H)
z, 2H), 6.93-6.97 (m, 2H), 7.04 (s, 1H), 7.1
7 (m, 1H), 7.50 (m, 1H), 7.58 (s, 1H), 7.66 (d
, J = 7.8 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 10.1
7 (br, 1H), 10.83 (br, 1H).

Example 7: 7-Hydroxy-3 ′-(3- (1-piperidyl) propyloxy)
Flavone 1/2 sulfate (Compound 58) Melting point: 205 ° C (decomposition) NMR (DMSO-d ₆ , δ): 1.42 (m, 1H), 1.59-1.80 (
m, 3H), 1.85 (m, 2H), 2.16 (m, 2H), 2.93 (m, 2
H), 3.56 (m, 2H), 4.19 (t, J = 5.7 Hz, 2H), 6.9
4. (s, 1H), 6.95 (dd, J = 2.1 Hz, 9.0 Hz, 1H), 7.
10 (d, J = 2.1 Hz, 1H), 7.17 (dd, J = 2.1 Hz, 8.4
Hz, 1H), 7.51 (m, 1H), 7.57 (d, J = 2.1 Hz, 1H)
, 7.67 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H)
H), 8.97 (br, 1H), 10.80 (br, 1H).

Example 8: 7-Hydroxy-3 ′-(3- (4-phenyl-1-piperazyl) propyloxy) flavone dihydrochloride (Compound 62) Melting point: 245 ° C. (decomposition) NMR (DMSO-d ₆ , Δ): 2.29 (m, 2H), 3.14-3.22 (
m, 4H), 3.36 (m, 2H), 3.64 (m, 2H), 3.84 (m, 2
H), 6.87 (m, 1H), 6.93-7.05 (m, 5H), 7.18-7
. 39 (m, 3H), 7.53 (m, 1H), 7.59 (s, 1H), 7.66
(D, J = 8.1 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 10
. 74 (br, 1H).

Example 9: 7-hydroxy-4 ′-(3- (1-piperidyl) propyloxy)
Flavone 1/2 sulfate (Compound 89) mp: 210 ℃ NMR (DMSO-d 6, δ): 1.41 (m, 1H), 1.58-1.96 (
m, 5H), 2.16 (m, 2H), 2.92 (m, 2H), 3.10-3.4.
0 (m, 4H), 3.48 (m, 2H), 4.17 (t, J = 6.0 Hz, 2H
), 6.81 (s, 1H), 6.92 (dd, J = 2.1 Hz, 9.0 Hz, 1
H), 6.99 (d, J = 2.1 Hz, 1H), 7.12 (d, J = 8.7 Hz)
, 1H), 7.88 (d, J = 8.7 Hz, 1H), 8.04 (d, J = 9.0
Hz, 1H), 9.52 (br, 1H), 9.70 (br, 1H), 10.76
(S, 1H).

Example 10: 7-Hydroxy-4′-methoxy-3 ′-(3- (1-piperidyl) propyloxy) flavone 1/2 sulfate (Compound 96) Melting point: 210 ° C. (decomposition) NMR (DMSO −d ₆ , δ): 1.42 (m, 1H), 1.58-1.69 (
m, 3H), 1.85 (m, 2H), 2.17 (m, 2H), 2.93 (m, 2
H), 3.23 (m, 2H), 3.52 (m, 2H), 3.87 (s, 3H),
4.20 (t, J = 6.0 Hz, 2H), 6.89 (s, 1H), 6.92 (d
, J = 8.7 Hz, 1H), 7.01 (s, 1H), 7.17 (d, J = 8.7)
Hz, 1H), 7.59 (s, 1H), 7.70 (d, J = 8.7 Hz, 1H)
, 7.87 (d, J = 8.7 Hz, 1H), 8.87 (br, 1H).

Example 11: 3 ′, 7-dihydroxy-5 ′-(3- (1-piperidyl) propyloxy) flavone 1/2 sulfate (Compound 98) Melting point: 180 ° C. NMR (DMSO-d ₆ , δ) ): 1.40 (m, 1H), 1.62-1.68 (
m, 3H), 1.92 (m, 2H), 2.13 (m, 2H), 2.90 (m, 2
H), 3.22 (m, 2H), 2.49 (m, 2H), 4.12 (t, J = 6.
0 Hz, 2H), 6.55 (s, 1H), 6.80 (s, 1H), 6.91-6
. 96 (m, 2H), 7.03 (s, 2H), 7.88 (d, J = 8.4 Hz,
1H), 8.95 (br, 1H).

Example 12: 5,7-Dihydroxy-3 ′-(2-dimethylaminoethoxy) flavone (Compound 148) Melting point: 175-177 ° C. NMR (DMSO-d ₆ , δ): 2.24 (s, 6H), 2.66 (t, J = 5
. 7 Hz, 2H), 4.17 (t, J = 5.7 Hz, 2H), 6.22 (d, J
= 2.1 Hz, 1H), 6.54 (d, J = 2.1 Hz, 1H), 7.02 (s
, 1H), 7.19 (d, J = 8. Hz, 1H), 7.48 (t, J = 8.1H)
z, 1H), 7.59 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H),
12.82 (s, 1H).

Example 13: 5,7-dihydroxy-3 ′-(3-dimethylaminopropyloxy) flavone 1/2 sulfate (Compound 158) Melting point: 220-223 ° C. NMR (DMSO-d ₆ , δ): 2.12 (m, 2H), 2.81 (s, 6H)
, 3.22 (t, J = 8.1 Hz, 2H), 4.17 (t, J = 6.0 Hz, 2H)
H), 6.24 (d, J = 2.1 Hz, 1H), 6.53 (d, J = 2.1 Hz)
, 1H), 7.01 (s, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7
. 51 (t, J = 7.8 Hz, 1H), 7, 58 (s, 1H), 7.68 (d,
J = 7.8 Hz, 1H), 12.80 (s, 1H).

Example 14: 5,7-dihydroxy-3 ′-(3- (1-piperidyl) propyloxy) flavone 1/2 sulfate (Compound 161) Melting point: 184-186 ° C. NMR (DMSO-d ₆ , δ): 1.40 (m, 1H), 1.60-1.80 (
m, 3H), 1.81-1.93 (m, 2H), 2.49 (m, 2H), 2.9
4 (m, 2H), 3.46 (m, 2H), 4.18 (t, J = 5.7 Hz, 2H
), 6.24 (d, J = 2.1 Hz, 1H), 6.53 (d, J = 2.1 Hz,
1H), 7.01 (s, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.
51 (d, J = 8.1 Hz, 1H), 7.57 (s, 1H), 7.68 (d, J
= 8.1 Hz, 1H), 10.93 (s, 1H), 12.80 (s, 1H).

Example 15: 5,7-dihydroxy-3 ′-(3- (4-morpholinyl) propyloxy) flavone 1/2 sulfate (Compound 162) Melting point: 210-212 ° C. NMR (DMSO-d ₆ , δ): 2.18 (m, 2H), 3.14 (m, 2H)
, 3.37 (m, 2H), 3.70 (m, 2H), 4.10 (m, 2H), 4.
20 (t, J = 6.0 Hz, 2H), 6, 24 (d, J = 2.1 Hz, 1H),
6.53 (d, J = 2.1 Hz, 1H), 7.01 (s, 1H), 7.20 (d
d, J = 2.1 Hz, 8.1 Hz, 1H), 7.52 (m, 1H), 7.58 (
s, 1H), 7.68 (d, J = 7.5 Hz, 1H), 9.58 (br, 1H)
, 10.92 (s, 1H), 12.80 (s, 1H).

Example 16: 7-Hydroxy-8-methyl-3 ′-(3- (1-piperidyl) propyloxy) flavone 1/2 sulfate (Compound 264) Melting point: 226 ° C. (decomposition) NMR (DMSO— d ₆ , δ): 1.32-1.90 (m, 6H), 2.18 (
m, 2H), 2.36 (s, 3H), 2.95 (m, 2H), 3.24 (m, 2
H), 3.51 (m, 2H), 4.17 (m, 2H), 6.95 (s, 1H),
7.00 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H)
), 7.50-7.57 (m, 2H), 7.69 (d, J = 7.8 Hz, 1H)
, 7.76 (d, J = 8.8 Hz, 1H).

Example 17: 4 ′, 7-dihydroxy-3′-ethoxy-8-methylflavone (
Compound 310) Melting point: 152-156 ° C NMR (DMSO-d ₆ , δ): 1.37 (t, J = 6.9 Hz, 3H), 2.
83 (s, 3H), 4.15 (q, J = 6.9 Hz, 2H), 6.79 (s, 1
H), 6.95 (d, J = 8.8 Hz, 2H), 7.52-7.54 (m, 2H
), 7.70 (d, J = 8.8 Hz, 1H).

Example 18: 3 ′, 7-dihydroxy-8-methylflavone (compound 342) Melting point: 230-231 ° C. NMR (DMSO-d ₆ , δ): 2.36 (s, 3H), 6.78 (S, 1H)
, 6.97-7.00 (m, 2H), 7.37 (t, J = 7.8 Hz, 1H),
7.41-7.51 (m, 2H), 10.61 (s, 1H).

Example 19: 4 ′, 7-dihydroxy-8-methylflavone (compound 343) Melting point:> 300 ° C. NMR (DMSO-d ₆ , δ): 2.30 (s, 3H), 6.67 ( s, 1H)
, 6.88-6.93 (m, 4H), 7.68 (s, J = 7.8 Hz, 1H),
7.88 (d, J = 8.7 Hz, 1H).

Example 20: 7-Hydroxy-3′-methoxy-8-methylflavone (Compound 3
47) Melting point: 233-236 ℃ NMR (DMSO-d 6, δ): 2.36 (s, 3H), 3.87 (s, 3H)
, 6.95 (s, 1H), 7.00 (d, J = 8.7 Hz, 1H), 7.17 (
ss, J = 2.1 Hz, 7.8 Hz, 1H), 7.50 (t, J = 7.8 Hz,
1H), 7.57 (s, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.
76 (d, J = 8.7 Hz, 1H), 10.63 (br, 1H).

Example 21: 3 ′, 7-dihydroxy-4′-methoxy-8-methylflavone (
Compound 351) Melting point: 263 ° C. (decomposition) NMR (DMSO-d ₆ , δ): 2.35 (s, 3H), 3.86 (s, 3H)
, 6.69 (s, 1H), 6.97 (d, J = 8.7 Hz, 1H), 7.09 (
d, J = 7.8 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.5
3 (dd, J = 2.4 Hz, 8.7 Hz, 1 H), 7.73 (d, J = 8.7 H
z, 1H), 10.59 (br, 1H).

Example 22: 2′-carboxy-7-hydroxy-8-methylflavone (compound 354) Melting point:> 300 ° C. NMR (DMSO-d ₆ , δ): 2.16 (s, 3H), 6. 50 (s, 1H)
, 7.00 (d, J = 8.7 Hz, 1H), 7.65-7.88 (m, 5H),
10.65 (s, 1H), 13.03 (br, 1H).

Example 23: 2′-Fluoro-7-hydroxy-8-methylflavone (Compound 3
65) Melting point: 230-231 ° C NMR (DMSO-d ₆ , δ): 2.30 (s, 3H), 6.68 (s, 1H)
, 7.01 (d, J = 8.7 Hz, 1H), 7.42-7.49 (m, 2H),
7.65 (m, 1H), 7.77 (d, J = 8.7 Hz, 1H), 8.02 (m
, 1H), 10.68 (br, 1H).

Example 24: 2 ′, 3′-Difluoro-7-hydroxy-8-methylflavone (
Compound 368) mp: 229 ℃ NMR (DMSO-d 6, δ): 2.29 (s, 3H), 6.71 (s, 1H)
, 7.02 (d, J = 8.4 Hz, 1H), 7.45 (m, 1H), 7.60 −
7.90 (m, 3H), 10.70 (br, 1H).

Example 25: 7-Hydroxy-8-methyl-2'-nitroflavone (Compound 38
6) Melting point: 271-272 ° C. NMR (DMSO-d ₆ , δ): 2.01 (s, 3H), 6.72 (s, 1H)
, 7.02 (s, J = 8.7 Hz, 1H), 7.76-8.00 (m, 4H),
8.15 (d, J = 7.5 Hz, 1H), 10.75 (br, 1H).

Example 26: 7-Hydroxy-8-methyl-3′-nitroflavone (Compound 38
7) Melting point: 250 ° C. (decomposition) NMR (DMSO-d ₆ , δ): 2.83 (s, 3H), 7.02 (d, J = 8)
. 7 Hz, 1H), 7.13 (s, 1H), 7.78 (d, J = 8.7 Hz, 1
H), 7.88 (m, 1H), 8.42 (d, J = 7.8 Hz, 1H), 8.5
3 (d, J = 8.1 Hz, 1H), 8.80 (s, 1H), 10.70 (br,
1H).

Example 27: 7-hydroxy-3′-methoxy-8-methyl-2′-nitroflavone (compound 389) Melting point: 227-229 ° C. NMR (DMSO-d ₆ , δ): 2.11 (s) , 3H), 3.87 (s, 3H)
, 6.67 (s, 1H), 7.01 (d, J = 8.7 Hz, 1H), 7.54 (
d, J = 7.8 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.7
2-7.79 (m, 2H), 10.74 (br, 1H).

Example 28: 3 ′, 8-Dimethyl-7-hydroxy-2′-nitroflavone (Compound 391) Melting point: 230 ° C. (decomposition) NMR (DMSO-d ₆ , δ): 2.10 (s, 3H), 2.40 (s, 3H)
, 6.67 (s, 1H), 7.01 (d, J = 8.7 Hz, 1H), 7.71-
7.82 (m, 4H), 10.78 (br, 1H).

Example 29: 3 ′, 4′-Dimethoxy-7-hydroxy-8-methyl-2′-nitroflavone (compound 392) Melting point: 284-285 ° C. NMR (DMSO-d ₆ , δ): 05 (s, 3H), 3.95 (s, 3H)
, 3.98 (s, 3H), 6.71 (s, 1H), 7.00 (d, J = 8.7H)
z, 1H), 7.42 (s, 1H), 7.73 (s, 1H), 7.78 (d, J
= 8.7 Hz, 1H), 10.69 (s, 1H).

Example 30: 3′-chloro-7-hydroxy-8-methyl-2′-nitroflavone (compound 393) Melting point: 242 to 243 ° C. NMR (DMSO-d ₆ , δ): 2.12 (s) , 3H), 6.78 (s, 1H).
, 7.03 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H)
H), 7.85 (t, J = 8.1 Hz, 1H), 8.99-8.06 (m, 2H
), 10.78 (br, 1H).

Example 31: 7-hydroxy-4′-nitro-3 ′-(3- (1-piperidyl)
Propyl) -8- propyl flavone 1/2 sulfate (Compound 491) mp: 214-217 ℃ NMR (DMSO-d 6, δ): 1.97 (t, 3H), 1.65 (m, 6H)
, 1.84 (m, 2H), 2.21 (m, 2H), 2.91 (m, 4H), 3.
21 (m, 2H), 3.48 (m, 2H), 4.43 (m, 2H), 7.03 (
d, J = 8.7 Hz, 1H), 7.20 (s, 1H), 7.79 (d, J = 9.
0 Hz, 2H), 7.90 (s, 1H), 8.14 (d, J = 9.0 Hz, 1H
), 8.95 (br, 1H), 10.69 (br, 1H).

Example 32: 3 ′, 7-Dihydroxy-8-propylflavone (Compound 502)
Melting point: 281-282 ° C. NMR (DMSO-d ₆ , δ): 0.97 (t, J = 7.5 Hz, 3H), 1.
64 (m, 2H), 2.88 (t, J = 7.5 Hz, 2H), 6.78 (s, 1
H), 6.99 (d, J = 8.7 Hz, 1H), 7.38 (t.J = 7.8H)
z, 1H), 7.40 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H),
7.76 (s, J = 8.7 Hz, 1H), 9.88 (s, 1H), 10.59 (
s, 1H).

Example 33: 4 ′, 7-Dihydroxy-8-propylflavone (Compound 503)
Melting point:> 300 ° C. NMR (DMSO-d ₆ , δ): 0.92 (t, J = 7.5 Hz, 3H), 1.
59 (m, 2H), 2.83 (t, J = 7.5 Hz, 2H), 6.68 (s, 1
H), 6.89-6.94 (m, 3H), 7.69 (d, J = 8.7 Hz, 1H
), 7.85 (d, J = 8.7 Hz, 2H), 10.20 (br, 1H), 10
. 45 (br, 1H).

Example 34: 8-propyl-3 ′, 4 ′, 7-trihydroxyflavone (compound 504) Melting point: 293-294 ° C. NMR (DMSO-d ₆ , δ): 0.97 (t, J = 7.2Hz, 3H), 1.
63 (m, 2H), 2.87 (t, J = 6.9 Hz, 2H), 6.62 (s, 1
H), 6.90 (d, J = 8, 1 Hz, 1H), 6.96 (d, J = 9.0 Hz)
, 1H), 7.37-7.41 (m, 2H), 7.73 (d, J = 9.0 Hz,
1H), 9.87 (br, 2H), 10.56 (br, 1H).

Example 35: 7-Hydroxy-3′-methoxy-8-propylflavone (Compound 507) Melting point: 232-234 ° C. NMR (DMSO-d ₆ , δ): 0.97 (t, J = 7. 5Hz, 3H), 1.
67 (m, 2H), 2.88 (t, J = 7.5 Hz, 2H), 3.87 (s, 3
H), 6.95 (s, 1H), 7.00 (d, J = 8.7 Hz, 1H), 7.1
7 (dd, J = 1.5 Hz, 8.4 Hz, 1H), 7.48-7.55 (m, 2
H), 7.66 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 8.7 Hz)
, 1H), 10.60 (br, 1H).

Example 36: 3 ′, 7-dihydroxy-4′-methoxy-8-propylflavone (Compound 511) Melting point: 271-272 ° C. NMR (DMSO-d ₆ , δ): 0.97 (t, J) = 7.5 Hz, 3H), 1.
64 (m, 2H), 2.88 (t, J = 7.5 Hz, 2H), 6.70 (s, 1
H), 6.96 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 8.4 Hz)
, 1H), 7.44 (d, J = 2.1 Hz, 1H), 7.52 (dd, J = 2.
1 Hz, 8.4 Hz, 1 H), 7.74 (d, J = 8.7 Hz, 1 H), 9.5
0 (br, 1H), 10.47 (br, 1H).

Example 37: 3′-bromo-4 ′, 7-dihydroxy-5′-methoxy-8-propylflavone (Compound 512) Melting point: 250-255 ° C. NMR (DMSO-d ₆ , δ): 0. 77 (t, J = 7.5 Hz, 3H);
40 (m, 2H), 2.62 (t, J = 6.9 Hz, 2H), 3.72 (s, 3
H), 6.72-6.76 (m, 2H), 7.35 (d, J = 1.8 Hz, 1H
), 7.50 (d, J = 9.0 Hz, 1H), 7.56 (d, J = 1.8 Hz,
1H), 10.17 (br, 1H), 10.39 (brs, 1H).

Example 38: 7-Hydroxy-2′-isopropoxy-8-propylflavone (
Compound 513) Melting point: 199-200 ° C NMR (DMSO-d ₆ , δ): 0.93 (t, J = 7.5 Hz, 3H), 1.
33 (d, J = 6.0 Hz, 6H), 1.60 (m, 2H), 2.82 (t, J
= 7.5 Hz, 2H), 4.81 (m, 1H), 6.84 (s, 1H), 7.0
0 (d, J = 8.7 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 7
. 26 (d, J = 8.1 Hz, 1H), 7.53 (m, 1H), 7.75 (d,
J = 8.7 Hz, 1H), 7.84 (dd, J = 1.5 Hz, 7.8 Hz, 1H)
), 10.58 (br, 1H).

Example 39: 4 ′, 7-dihydroxy-3′-methyl-8-propylflavone (
Compound 521) mp: 191-192 ℃ NMR (DMSO-d 6, δ): 0.99 (t, J = 7.5Hz, 3H), 1.
64 (m, 2H), 2.21 (s, 3H), 2.87 (t, J = 7.5 Hz, 2
H), 6.72 (s, 1H), 6.96 (d, J = 8.7 Hz, 2H), 7.7
3 (d, J = 8.7 Hz, 2H), 7.79 (s, 1H), 10.23 (s, 1
H), 10.55 (s, 1H).

Example 40: 4 ′, 7-dihydroxy-3 ′, 8-dipropylflavone (compound 523) Melting point: 228-230 ° C. NMR (DMSO-d ₆ , δ): 0.94 (t, J = 7.2 Hz, 3H), 0.
99 (t, J = 7.2 Hz, 3H), 1.63 (m, 4H), 2.59 (t, J
= 7.5 Hz, 2H), 2.87 (t, J = 8.4 Hz, 2H), 6.73 (s
, 1H), 6.94-7.99 (m, 2H), 7.71-7.77 (m, 3H).
, 10.12 (br, 1H), 10.54 (br, 1H).

Example 41: 2′-fluoro-7-hydroxy-8-propylflavone (compound 525) Melting point: 204-207 ° C. NMR (DMSO-d ₆ , δ): 0.94 (t, J = 7. 5Hz, 3H), 1.
61 (m, 2H), 2.82 (t, J = 7.5 Hz, 2H),. 68 (s, 1H
), 7.02 (d, J = 8.7 Hz, 1H), 7.43-7.50 (m, 2H)
, 7.5 (m, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.97 (m
, 1H), 10.65 (br, 1H).

Example 42: 4′-fluoro-7-hydroxy-8-propylflavone (compound 527) Melting point: 243 ° C. NMR (DMSO-d ₆ , δ): 0.95 (t, J = 7.5 Hz, 4H), 1.
64 (m, 2H), 2.87 (t, J = 6.9 Hz, 2H), 6.99 (d, J
= 8.7 Hz, 1H), 7.44 (t, J = 8.7 Hz, 2H), 7.75 (d
, J = 8.7 Hz, 1H), 8.10 (dd, J = 2.1 Hz, 8.7 Hz, 1
H), 10.59 (s, 1H).

Example 43: 3′-bromo-4 ′, 7-dihydroxy-8-propylflavone (
Compound 536) Melting point: 267-270 ° C. NMR (DMSO-d ₆ , δ): 1.00 (t, J = 7.5 Hz, 3H), 1.
64 (m, 2H), 2.89 (t, J = 7.5 Hz, 2H), 6.81 (s, 1
H), 6.99 (d, J = 8.7 Hz, 1H), 7.18 (d, J = 8.7 Hz)
, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 8.7)
Hz, 1H), 8.15 (s, 1H), 10.56 (s, 1H), 11.17 (
s, 1H).

Example 44: 7-Hydroxy-2′-nitro-8-propylflavone (Compound 5
45) Melting point: 117-118 ℃ NMR (DMSO-d 6, δ): 0.87 (t, J = 7.5Hz, 3H), 1.
43 (m, 2H), 2.51 (t, J = 7.2 Hz, 2H), 6.97 (s, 1
H), 7.01 (d, J = 8.7 Hz, 1H), 7.78-7.95 (m, 4H
), 8.16 (dd, J = 1.5 Hz, 7.8 Hz, 1H), 10.68 (s,
1H).

Example 45: 7-hydroxy-3′-methoxy-2′-nitro-8-propylflavone (compound 548) Melting point: 236 ° C. NMR (DMSO-d ₆ , δ): 0.93 (t, J) = 7.5 Hz, 3H), 1.
48 (m, 2H), 2.60 (t, J = 6.9 Hz, 2H), 3.98 (s, 3
H), 6.66 (s, 1H), 7.01 (d, J = 8.7 Hz, 1H), 7.5
2 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7
. 73-7.80 (m, 2H), 10.68 (br, 1H).

Example 46: 7-hydroxy-4′-methoxy-3′-nitro-8-propylflavone (compound 553) Melting point: 273 ° C. (decomposition) NMR (DMSO-d ₆ , δ): 1.00 ( t, J = 7.5 Hz, 3H), 1.
64 (m, 2H), 2.87 (t, J = 7.2 Hz, 2H), 4.04 (d, 3
H), 7.00 (s, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.7
6 (d, J = 9.0 Hz, 1H), 8.33 (dd, J = 2.4 Hz, 9.0H)
z, 1H), 8.53 (s, J = 2.4 Hz, 1H), 10.62 (s, 1H)
.

Example 47: 4 ′, 7-Dihydroxy-3′-nitro-8-propylflavone (
Compound 554) Melting point: 263-264 ° C. NMR (DMSO-d ₆ , δ): 1.01 (t, J = 7.8 Hz, 3H), 1.
64 (m, 2H), 2.87 (t, J = 7.8 Hz, 2H), 6.90 (s, 1
H), 6.99 (s, J = 8.7 Hz, 1H), 7.29 (s, J = 9.0 Hz)
, 1H), 7.75 (d, J = 8.7 Hz, 1H), 8.20 (dd, J = 1.
8 Hz, 9.0 Hz, 1H), 8.53 (d, J = 1.8 Hz, 1H), 10.
63 (s, 1H).

Example 48: 7-Hydroxy-3′-methoxy-4′-nitro-8-propylflavone (compound 555) Melting point: 244-245 ° C. NMR (DMSO-d ₆ , δ): 0.97 (t) , J = 7.5 Hz, 3H), 1.
65 (m, 2H), 2.89 (t, J = 7.5 Hz, 2H), 4.07 (s, 3
H), 7.02 (d. J = 9.0 Hz, 1H), 7.19 (s, 1H), 7.0.
75-7.80 (m, 2H), 8.19 (d. J = 8.7 Hz, 1H), 10
. 67 (br, 1H).

Example 49: 7-hydroxy-8-propylflavone (compound 557) Melting point: 224 ° -226 ° C. NMR (DMSO-d ₆ , δ): 0.97 (t, J = 7.2 Hz, 3H), 1.
65 (m, 2H), 2.89 (t, J = 6.9 Hz, 2H), 6.93 (s, 1
H), 7.00 (d, J = 8.7 Hz, 1H), 7.59-7.62 (m, 3H
), 7.77 (s, J = 8.7 Hz, 1H), 8.04-8.07 (m, 2H)
, 10.65 (s, 1H).

Example 50: 7-hydroxy-3′-phenoxy-8-propylflavone (compound 558) Melting point: 198-201 ° C. NMR (DMSO-d ₆ , δ): 0.78 (t, J = 7. 5Hz, 3H), 1.
50 (m, 2H), 2.71 (t, J = 7.2 Hz, 2H), 6.94 (s, 1
H), 6.98 (d, J = 8.7 Hz, 1H), 7.14 (d, J = 7.5 Hz)
, 2H), 7.22-7.26 (m, 2H), 7.43-7.49 (m, 2H).
, 7.57-7.63 (m, 2H), 7.75 (d, J = 8.4 Hz, 1H),
7.83 (d, J = 8.7 Hz, 1H), 10.64 (br, 1H).

Example 51: 4 ′, 7-dihydroxy-3′-propoxy-8-propylflavone (Compound 560) Melting point: 220-222 ° C. NMR (DMSO-d ₆ , δ): 0.95-1.03 (M, 6H), 1.62 (
m, 2H), 1.78 (m, 2H), 2.85 (t, J = 7.2 Hz, 2H),
4.04 (t, J = 6.6 Hz, 2H), 6.79 (s, 1H), 6.95 (d
, J = 8.7 Hz, 2H), 7.49-7.52 (m, 2H), 7.72 (d,
J = 8.7 Hz, 1H), 9.75 (brs, 1H), 10.51 (s, 1H)
.

Example 52: 3′-Isopropoxy-4 ′, 7-dihydroxy-8-propylflavone (Compound 561) Melting point: 260-261 ° C. NMR (DMSO-d ₆ , δ): 1.25 (t, J = 7.2 Hz, 3H);
38 (d, J = 6.6 Hz, 6H), 1.64-1.73 (m, 4H), 4.6
9 (m, 1H), 6.69 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H
), 7.06 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 1.8 Hz,
1H), 7.51 (dd, J = 1.8 Hz, 8.4 Hz, 1H), 7.98 (d
, J = 8.4 Hz, 1H).

Example 53: 3′-butoxy-4 ′, 7-dihydroxy-8-propylflavone (compound 563) Melting point: 215-217 ° C. NMR (DMSO-d ₆ , δ): 0.92-0.99 (M, 6H), 1.45 (
m, 2H), 1.61 (m, 2H), 1.72 (m, 2H), 2.85 (t, J
= 8.0 Hz, 2H), 4.07 (t, J = 6.6 Hz, 2H), 6.79 (s
, 1H), 6.94 (d, J = 8.5 Hz, 2H), 7.48-7.52 (m,
2H), 7.72 (d, J = 8.5 Hz, 1H).

Example 54: 3′-Decanyloxy-4 ′, 7-dihydroxy-8-propylflavone (Compound 582) Form: Syrup NMR (DMSO-d ₆ , δ): 0.85 (t, J = 6. 9 Hz, 3H), 0.
98 (t, J = 7.2 Hz, 3H), 1.24-1.35 (m, 14H), 1.
64 (m, 2H), 75 (m, 2H), 2.86 (m, 2H), 4.08 (t,
J = 6.6 Hz, 2H), 6.83 (s, 1H), 6.95-6.98 (m, 2
H), 7.50-7.54 (m, 2H), 7.74 (d, J = 8.7 Hz, 1H
), 9.81 (s, 1H), 10.57 (s, 1H).

Example 55: 8-butyl-4 ′, 7-dihydroxyflavone (compound 593) Melting point: 233-236 ° C. NMR (DMSO-d ₆ , δ): 0.93 (t, J = 7.2 Hz, 3H), 1.
39 (m, 2H), 1.58 (m, 2H), 2.89 (t, J = 7.2 Hz, 2
H), 6.72 (s, 1H), 6.93-6.98 (m, 2H), 7.73 (d
, J = 8.7 Hz, 1H), 7.89 (d, J = 9.0 Hz, 1H).

Example 56: 4 ′, 7-Dihydroxy-3′-methoxy-8-methylflavone (
Compound 680) mp: 170 ℃ NMR (DMSO-d 6, δ): 2.35 (s, 3H), 3.89 (s, 3H)
, 6.83 (s, 1H), 6.94-7.00 (m, 2H), 7.55-7.5.
7 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 10.57 (s, 1
H).

Example 57: 4 ′, 7-Dihydroxy-8-ethyl-3′-methoxyflavone (
Compound 681) Melting point: 255-257 ° C. NMR (DMSO-d ₆ , δ): 1.22 (t, J = 7.5 Hz, 3H), 5.
81 (, J = 7.5 Hz, 2H), 6.85 (s, 1H), 6.95-6.9
9 (m, 2H), 7.52-7.55 (m, 2H), 7.73 (d, J = 8.4)
Hz, 1H), 9.90 (s, 1H), 10.59 (s, 1H).

Example 58: 8-Butyl-4 ′, 7-dihydroxy-3′-methoxyflavone (
Compound 684) Melting point: 228-231 ° C. NMR (DMSO-d ₆ , δ): 0.93 (t, J = 7.2 Hz, 3H), 1.
39 (m, 2H), 1.60 (m, 2H), 2.89 (t, J = 7.5 Hz, 2
H), 3.89 (s, 3H), 6.82 (s, 1H), 6.93-6.98 (m
, 2H), 7.51-7.54 (m, 2H), 7.73 (s, J = 8.4 Hz,
1H), 9.85 (s, 1H), 10.51 (s, 1H).

Example 59: 4 ′, 7-Dihydroxy-8-isopentyl-3′-methoxyflavone (Compound 690) Melting point: 225-227 ° C. NMR (DMSO-d ₆ , δ): 0.96 (d, J) = 6.6 Hz, 6H), 1.
47 (m, 2H), 1.65 (m, 1H), 2.89 (t, J = 7.5 Hz, 2
H), 3.89 (s, 3H), 6.82 (s, 1H), 6.92-6.98 (m
, 2H), 7.51-7.54 (m, 2H), 7.73 (d, J = 8.7 Hz,
1H), 9.86 (s, 1H), 10.52 (s, 1H).

Example 60: 8-benzyl-4 ′, 7-dihydroxy-3′-methoxyflavone (compound 712) Melting point: 281-282 ° C. NMR (DMSO-d ₆ , δ): 3.78 (s, 3H) ), 4.26 (s, 2H)
, 6.83 (s, 1H), 6.90 (d, J = 8.1 Hz, 1H), 7.04 (
d, J = 8.7 Hz, 1H), 7.14 (m, 1H), 7.20-7.26 (m
, 4H), 7.41-7.46 (m, 2H), 7.81 (d, J = 8.7 Hz,
1H), 9.88 (br, 1H), 10.82 (br, 1H).

Example 61: 7-hydroxy-8-methyl-2- (1-naphthyl) chromone (compound 764) Melting point: 250-253 ° C NMR (DMSO-d ₆ , δ): 1.87 (s, 3H) ), 6.52 (s, 1H)
, 7.00 (d, J = 8.7 Hz, 1H), 7, 58-7.66 (m, 3H),
7.80 (d, J = 8.7 Hz, 1H), 7.85 (dd, J = 1.2 Hz, 7
. 5Hz, 1H), 8.03-8.15 (m, 3H), 10.68 (br, 1H)
).

Example 62: 7-hydroxy-2- (2-hydroxy-1-naphthyl) -8-methylchromone (compound 766) NMR (DMSO-d ₆ , δ): 2.10 (s, 3H), 6.60 (d, J = 8
. 7Hz, 1H), 7.11 (s, 1H), 7.60-7.69 (m, 3H),
7.73-7.81 (m, 2H), 8.09 (d, J = 8.1 Hz, 1H), 8
. 31 (d, J = 9.3 Hz, 1H), 9.97 (s, 1H), 9.99 (s, 1H)
1H).

Example 63: 7-Hydroxy-2- (3-hydroxy-2-naphthyl) -8-methylchromone (Compound 767) Melting point:> 300 ° C. NMR (DMSO-d ₆ , δ): 2.38 (s, 3H), 7.00 (d, J = 8)
. 7Hz, 1H), 7.07 (s, 1H), 7.33-7.39 (m, 2H),
7.51 (m, 1H), 7.75-7.79 (m, 2H), 7.98 (d, J =
8.1 Hz, 1H), 8.47 (s, 1H), 10.62 (s, 1H), 10.
71 (s, 1H).

Example 64: 7-Hydroxy-8-propyl-2- (2-pyridyl) chromone
1/2 sulfate (compound 785) Melting point: 213-217 ° C NMR (DMSO-d ₆ , δ): 0.98 (t, J = 7.5 Hz, 3H), 1.
66 (m, 2H), 2.92 (t, J = 7.5 Hz, 2H), 7.02 (d, J
= 8.7 Hz, 1H), 7.10 (s, 1H), 7.63 (m, 1H), 7.8
0 (d, J = 8.7 Hz, 1H), 8.09-8.14 (m, 2H), 8.78
(D, J = 4.8 Hz, 1H), 10.70 (s, 1H).

Example 65: 7-Hydroxy-8-propyl-2- (3-pyridyl) chromone
Methanesulfonate (Compound 786) mp: 278-279 ℃ NMR (DMSO-d 6, δ): 0.97 (t, J = 7.5Hz, 3H), 1.
64 (m, 2H), 2.89 (t, J = 8.1 Hz, 2H), 6.98-7.0
6 (m, 2H), 7.65 (m, 1H), 7.78 (d, J = 9.0 Hz, 1H
), 8.42 (m, 1H), 8.77 (m, 1H), 9.23 (d, J = 2.1)
Hz, 1H), 10.68 (br, 1H).

Example 66: 7-hydroxy-2- (2-methoxy-5-pyridyl) -8-propylchromone 1/2 sulfate (Compound 787) Melting point: 173-176 ° C NMR (DMSO-d ₆ , δ) ): 0.96 (t, J = 7.5 Hz, 3H), 1.
63 (m, 2H), 2.87 (t, J = 7.2 Hz, 2H), 3.96 (s, 3
H), 6.72 (s, 1H), 6.91-7.06 (m, 2H), 7.76 (d
, J = 8.7 Hz, 1H), 8.32 (dd, J = 2.4 Hz, 8.7 Hz, 1
H), 8.86 (d, J = 2.4 Hz, 1H), 10.63 (br, 1H).

Example 67: 7-Hydroxy-8-propyl-2- (4-pyridyl) chromone
Methanesulfonic acid salt (Compound 788) Melting point: 230-233 ° C NMR (DMSO-d ₆ , δ): 0.98 (t, J = 7.2 Hz, 3H), 1.
65 (m, 2H), 2.35 (t, J = 7.2 Hz, 2H), 2.91 (s, 3
H), 7.05 (s, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.8
0 (d, J = 8.7 Hz, 1H), 8.24 (dd, J = 1.2 Hz, 6.3H
z, 2H), 8.97 (dd, J = 1.2 Hz, 6.6 Hz, 2H), 10.8
1 (br, 1H).

Example 68: 2- (2,4-Dimethyl-5-pyrimidyl) -7-hydroxy-8
- propyl chromone (Compound 794) mp: 179-182 ℃ NMR (DMSO-d 6, δ): 0.91 (t, J = 7.5Hz, 3H), 1.
54 (m, 2H), 2.65 (s, 3H), 2.68 (s, 3H), 2.74 (
t, J = 7.2 Hz, 2H), 6.62 (s, 1H), 7.02 (d, J = 8.
7 Hz, 1 H), 7.81 (d, J = 8.7 Hz, 1 H), 8.87 (s, 1 H)
), 10.70 (s, 1H).

Example 69: 7-Hydroxy-8-propyl-2- (2-pyrazyl) chromone
Methanesulfonate (Compound 795) mp: 275-278 ℃ NMR (DMSO-d 6, δ): 0.98 (t, J = 7.5Hz, 3H), 1.
67 (m, 2H), 2.92 (t, J = 7.2 Hz, 2H), 7.04 (d, J
= 8.7 Hz, 1H), 7.10 (s, 1H), 7.80 (d, J = 8.4 Hz)
, 1H), 8.86-8.89 (m, 2H), 9.29 (d, J = 1.2 Hz,
1H), 10.75 (br, 1H).

Example 70: 7-Hydroxy-8-propyl-2- (2-quinolyl) chromone
1/2 sulfate (compound 802) Melting point: 242-245 ° C. NMR (DMSO-d ₆ , δ): 1.02 (t, J = 7.2 Hz, 3H), 1.
71 (m, 2H), 2.97 (m, 2H), 7.05 (d, J = 8.7 Hz, 1
H), 7.32 (s, 1H), 7.74 (m, 1H), 7.83 (d, J = 8.
7Hz, 1H), 7.89 (m, 1H), 8.10-8.17 (m, 2H), 8
. 40 (d, J = 9.0 Hz, 1H), 8.70 (d, J = 8.7 Hz, 1H)
, 10.73 (br, 1H).

Example 71: 7-Hydroxy-8-propyl-2- (1-propyl-2-pyridone-5-yl) chromone (compound 814) Melting point:> 300 ° C NMR (DMSO-d ₆ , δ): 0.91 (t, J = 7.5 Hz, 3H), 0.
96 (t, J = 7.2 Hz, 3H), 1.60 (m, 2H), 1.72 (m, 2
H), 2.86 (t, J = 7.2 Hz, 2H), 4.42 (t, J = 7.2 Hz)
, 2H), 6.57 (d, J = 9.6 Hz, 1H), 6.74 (s, 1H), 6
. 97 (d, J = 8.7 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H)
, 7.99 (dd, J = 2.4 Hz, 9.6 Hz, 1H), 8.46 (d, J =
2.4 Hz, 1H).

Example 72: 2- (1-Dimethylaminopropyl-2-pyridone-5-yl)-
7-Hydroxy-8-propylchromone (Compound 815) Melting point: 290-293 ° C NMR (DMSO-d ₆ , δ): 0.98 (t, J = 7.5 Hz, 3H), 1.
61 (m, 2H), 1.84 (m, 2H), 2.13 (s, 6H), 2.22 (
t, J = 6.6 Hz, 2H), 2.86 (t, J = 7.8 Hz, 2H), 4.0
5 (t, J = 6.9 Hz, 2H), 6.56 (d, J = 9.3 Hz, 1H), 6
. 73 (s, 1H), 6.97 (d, J = 8.4 Hz, 1H), 7.73 (d,
J = 8.4 Hz, 1H), 8.01 (dd, J = 2.4 Hz, 9.3 Hz, 1H)
), 8.45 (d, J = 2.4 Hz, 1H), 10.61 (br, 1H).

Example 73: 3′-Methoxy-8-propyl-4 ′, 5,7-trihydroxyflavone (Compound 832) NMR (DMSO-d ₆ , δ): 0.95 (t, J = 7.2 Hz) , 3H), 1.
58 (m, 2H), 2.75 (t, J = 6.9 Hz, 2H), 3.89 (s, 3
H), 6.29 (s, 1H), 6.88-6.95 (m, 2H), 7.54-7.
. 57 (m, 2H), 10.00 (br, 2H), 12.90 (s, 1H).

Test Example: Inhibitory Effect of Pharmaceutical of the Invention on P-GS1 Phosphorylation by Bovine Brain TPK1 As a reaction system, 100 mM MES-sodium hydroxide (pH 6.5), 1 m
M magnesium acetate, 0.5 mM EGTA, 5 mM β-mercaptoethanol, 0.02% twin 20, 10% glycerol, 12 μg / ml P-GS1
, 41.7 μM [γ- ³² P] ATP (68 kBq / ml), bovine brain TPK1, and the compounds listed in the table (the final mixture was prepared by preparing solutions of test compounds in the presence of 10% DMSO). Contains 1.7% DMSO).
The phosphorylation reaction was started by adding ATP, and the reaction was allowed to proceed at 25 ° C. for 2 hours. Then, the reaction was stopped by adding 21% perchloric acid on ice. After the reaction solution was centrifuged at 12,000 rpm for 5 minutes, it was adsorbed on P81 paper (Whatmann) and washed four times with 75 mM phosphoric acid, three times with water, and once with acetone. The paper was dried and the residual radioactivity was measured in a liquid scintillation counter. The results are shown in the table below.
The test compound significantly inhibited P-GS1 phosphorylation by TPK1. This result indicates that the medicaments of the present invention inhibit TPK1 activity and thus Aβ neurotoxicity and PH.
It strongly suggests that the formation of F is suppressed and that the medicament of the present invention is effective for preventing and / or treating Alzheimer's disease and the above-mentioned diseases.

[0210]

[Table 87]

Formulation Examples (1) Tablets The following components were mixed by a conventional method, and tableted using a conventional apparatus. Compound of Example 2 30 mg Crystalline cellulose 60 mg Corn starch 100 mg Lactose 200 mg Magnesium stearate 4 mg (2) Soft capsule The following components were mixed by a conventional method and filled in a soft capsule. Compound of Example 2 30 mg Olive oil 300 mg Lecithin 20 mg (3) Parenteral preparation The following ingredients were mixed by a conventional method to prepare an injection in a 1 ml ampoule. Compound of Example 1 0.1 mg Sodium chloride 4 mg Distilled water for injection 1 ml

[0212]

[Industrial applicability]

The medicament of the present invention has TPK1 inhibitory activity and is useful for the prevention and / or treatment of diseases such as Alzheimer's disease caused by TPK1 hyperactivity.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4035 A61K 31/4035 31/41 31/41 31/4155 31/4155 31/4178 31/4178 31 / 422 31/422 31/4433 31/4433 31/453 31/453 31/496 31/496 31/501 31/501 31/506 31/506 31/5375 31/5375 A61P 7/02 A61P 7/02 9 / 00 9/00 25/16 25/16 25/28 25/28 43/00 111 43/00 111 C07D 405/04 C07D 405/04 405/12 405/12 407/04 407/04 409/04 409 / 04 413/04 413/04 417/04 417/04 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC , NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH , GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM , HR, HU, ID, IL, IN, IS, JP, KE, KG, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Tetsuo Naohara 1000 Kamoshita-cho, Aoba-ku, Yokohama-shi, Kanagawa Prefecture Mitsubishi Chemical Corporation Yokohama total Within the joint research institute (72) Inventor Ryoichi Ando 1000, Kamoshita-cho, Aoba-ku, Yokohama-shi, Kanagawa Prefecture Mitsubishi Chemical Corporation Yokohama Research Laboratory (72) Inventor Kenichi Saito 1000, Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa Mitsubishi Chemical Corporation Yokohama Inside the Research Institute (72) Inventor Toshiyuki Honda 1000 Kamoshita-cho, Aoba-ku, Yokohama-shi, Kanagawa Prefecture Mitsubishi Chemical Corporation Inside Yokohama Research Institute (72) Inventor Rie Kawamoto 1000 Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa Mitsubishi Chemical Corporation F-term in Yokohama Research Institute (reference) 4C062 EE56 EE59 4C063 AA01 BB01 CC79 CC92 CC94 DD04 DD06 DD07 DD10 DD12 DD14 DD22 DD25 DD26 DD28 DD29 DD31 DD34 DD42 DD47 DD51 DD52 DD61 DD62 DD75 DD76 DD79 EE01 4C086 AA01 BA0802 BC03 BC36 BC38 BC41 BC42 BC48 BC50 BC60 BC62 BC67 BC69 BC73 BC79 BC82 GA02 GA04 GA07 GA08 GA09 GA10 GA12 MA01 MA04 ZA02 ZA16 ZA36 ZA54 ZC20

Claims (14)

[Claims] 1. Function of tau protein kinase 1 containing, as an active ingredient, a hydroxyflavone derivative represented by the formula (I) and a salt thereof, and a solvate and a hydrate thereof as an active ingredient. Pharmaceutical for preventing and / or treating a disease caused by hyperactivity or a neurodegenerative disease: (Wherein R ¹ represents a hydrogen atom or a hydroxyl group; R ² represents a hydrogen atom or a C ₁ -C ₁₈ which may have one or more C ₆ -C ₁₄ aryl groups) Ar represents an alkyl group; Ar represents an optionally substituted C ₆ -C ₁₄ aryl group or an optionally substituted aromatic heterocyclic group). 2. An active ingredient comprising a substance selected from the group consisting of the hydroxyflavone derivative represented by the formula (I) according to claim 1 and salts thereof, and solvates and hydrates thereof. And a medicament for preventing and / or treating a neurodegenerative disease. 3. The disease includes Alzheimer's disease, ischemic cerebrovascular disease, Down's syndrome, cerebral hemorrhage due to cerebral amyloid angiopathy, progressive supranuclear palsy, subacute sclerosing panencephalitis Parkinson's syndrome, post-encephalitis Parkinson's syndrome, fist fighting Cerebral encephalopathy, Guam
3. The medicament according to claim 2, wherein the medicament is selected from the group consisting of Parkinson's dementia complex, Lewy body disease, Pick's disease, cortical basal degeneration, and frontotemporal dementia. 4. Inhibition of tau protein kinase 1 selected from the group consisting of the hydroxyflavone derivative represented by the formula (I) according to claim 1 and salts thereof, and solvates and hydrates thereof. Agent. 5. A hydroxyflavone derivative represented by the formula (I) or a salt thereof:
Or their solvates or their hydrates: [In the formula, R ¹ represents a hydrogen atom or a hydroxyl group; R ² represents a hydrogen atom or a C ₁ -C ₁₈ which may have one or more C ₆ -C ₁₄ aryl groups. An alkyl group; Ar represents an optionally substituted C ₆ -C ₁₄ aryl group or an optionally substituted aromatic heterocyclic group, and when R ² is a hydrogen atom, Ar represents Formula (II): ^{Wherein, R 3, R 4, R} 5, R 6, and R ⁷ are each independently a hydrogen atom, an alkyl group substituted C ₁ optionally -C _18, optionally substituted C ₁ to A C ₁₈ alkoxy group, a hydroxyl group, an optionally substituted acyloxy group, a carboxyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, an optionally substituted alkylcarbonyl group, Represents an amino group, a nitro group, or a cyano group which may be substituted, provided that any one of R ³ , R ⁴ , R ⁵ , R ⁶ , and R ^{7 is} a group represented by the formula (III): -X- ( CH ₂ ) _m -R ⁸ (wherein, R ⁸ represents an optionally substituted amino group or an optionally substituted nitrogen-containing saturated heterocyclic group; X represents a single bond or an oxygen atom; Which represents an integer from 1 to 8) Represents a group represented by However, R ¹ is a hydrogen atom, R ² is a methyl group, and Ar is a phenyl group, 3,4-
When a methylenedioxyphenyl group or a 3-pyridyl group, R ¹ is a hydrogen atom, R ² is a propyl group, and Ar is a phenyl group having a carboxyl group or an ester group at the 4-position, And R ¹ is a hydroxyl group, R ² is a methyl group, and Ar is a phenyl group,
Excluding the case of a hydroxyphenyl group, a 4-methoxyphenyl group or a 3,4-dimethoxyphenyl group. ]. 6. A hydroxyflavone derivative represented by the formula (IV) or a salt thereof:
Or their solvates or their hydrates: (Wherein, R ¹ represents a hydrogen atom or a hydroxyl group; Z represents an optionally substituted amino group or an optionally substituted nitrogen-containing saturated heterocyclic group; n represents an integer of 1 to 8) It is shown; R ⁵ represents an alkoxy group of a hydrogen atom or a C ₁ ~C _15; R ⁶ is a hydrogen atom or a hydroxyl group).. 7. The hydroxyflavone derivative or salt thereof according to claim 6, wherein n is 2 or 3, or a solvate or hydrate thereof. 8. The hydroxyflavone derivative or salt thereof according to claim 6, wherein R ⁵ is a hydrogen atom or a methoxy group, or a solvate or hydrate thereof. 9. Z is a dimethylamino group, an optionally substituted piperazinyl group,
Or the hydroxyflavone derivative or a salt thereof, or a solvate or a hydrate thereof, according to claim 6, which is a piperidinyl group which may be substituted. 10. A hydroxyflavone derivative represented by the formula (V) or a salt thereof:
Or a solvate thereof or a hydrate thereof:(Where R^TwoIs a hydrogen atom, or one or more C₆~ C₁₄The aryl group of
C that you may have₁~ C₁₈R represents an alkyl group of^FourIs optionally substituted C ₁ ~ C₁₈An alkyl group of an optionally substituted C₁~ C₁₈An alkoxy group, hydro
A xyl group, an optionally substituted acyloxy group, a carboxyl group,
An optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group,
An alkylcarbonyl group which may be substituted, an amino group which may be substituted,
R represents a toro group or a cyano group;^FiveRepresents a hydrogen atom, a hydroxyl group, a methoxy group,
Or a nitro group. ). Alkyl group 11. R ⁴ is optionally substituted C ₁ -C _18, substituted C ₁ optionally -C ₁₈ alkoxy group, a hydroxyl group, a nitro group, or a cyano group, The hydroxyflavone derivative or a salt thereof according to claim 10, or a solvate or a hydrate thereof. 12. A hydroxyflavone derivative represented by the formula (I) or a salt thereof, or a solvate or a hydrate thereof: (Wherein R ¹ represents a hydrogen atom or a hydroxyl group; R ² represents a hydrogen atom or a C ₁ -C ₁₈ alkyl optionally having one or more C ₆ -C ₁₄ aryl groups) Ar represents an optionally substituted aromatic heterocyclic group, provided that R ¹ is a hydrogen atom, R ² is a methyl group, and Ar is pyridyl). 13. 13-Hydroxy-3 '-(3- (1-piperidyl) propyloxy) -8-propylflavone, 4', 7-dihydroxy-3'-methoxy-8-propylflavone, 7-hydroxy- 8-methyl-3 '-(3- (1-piperidyl) propyloxy) flavone, 7-hydroxy-4'-nitro-3'-(3- (1-piperidyl) propyloxy) -8-propylflavone, 4 A hydroxyflavone derivative or a salt thereof, or a salt thereof, selected from the group consisting of ', 7-dihydroxy-3'-methoxy-8-methylflavone, and 7-hydroxy-8-propyl-2- (4-pyridyl) chromone; Solvates or hydrates thereof. 14. A medicament comprising a substance selected from the group consisting of the hydroxyflavone derivatives and salts thereof according to any one of claims 5 to 13, and solvates and hydrates thereof.