KR20010079922A - Hydroxyflavone Derivatives - Google Patents

Abstract

A disease or nerve caused by tau protein kinase 1 hyperactivity, comprising a substance selected from the group consisting of hydroxyflavone derivatives, salts, solvates, and hydrates thereof disclosed in Formula (I) Medications for the prevention and / or treatment of degenerative diseases:

Where

R ¹ is hydrogen or a hydroxy group;

R ² is hydrogen or C ₁ -C ₁₈ which may have one or more C ₆ -C ₁₄ aryl groups

An alkyl group; And,

Ar is a C ₆ -C ₁₄ aryl group which may be substituted or an aromatic heterocycle which may be substituted

Clicker.

Description

Hydroxyflavone Derivatives

Alzheimer's disease is a progressive senile dementia in which cerebral cortical atrophy is observed due to neuronal degeneration and reduction. Pathologically, numerous senile plaques and neurofibrillary tangles have been observed in the brain. The number of patients continued to increase in older people, and Alzheimer's disease became a serious social problem. Although many theories have been proposed, the cause of Alzheimer's disease is still unknown. Initial resolution of the cause was required.

Two characteristic pathological changes in Alzheimer's disease are known to be associated with the degree of perceptual dysfunction. Therefore, from the early 1980's, research was carried out to identify two pathological changes at the molecular biological level. The senile plaques accumulate extracellularly, and amyloid βprotein has been found to be a major component (abbreviated herein as "Aβ": Biochem. Biophys. Res. Commun., 120, 855 (1984); EMBO J., 4, 2757 (1985); Proc. Natl. Acad. Sci., USA., 82, 4245 (1985)). In other pathological changes, neurofibrillary tangles, double base filament materials, referred to herein as paired helical filaments (abbreviated herein as "PHF"), have accumulated in cells and are associated with brain-specific microtubule related proteins. One type of tau protein has been found to be a major component (Proc. Natl. Sci., USA., 95, 4506 (1988); Neuron, 1, 827 (1988)).

Furthermore, in genetic studies, presenilins 1 and 2 were found to be family-specific Alzheimer's disease genes (Nature, 375, 754 (1995); Science, 269, 973 (1995); Nature; , 376, 775 (1995)), and mutations of presenilin 1 and 2 have been shown to promote the secretion of Aβ (Neuron, 17, 1005 (1996); Proc. Natl. Acad. Sci., USA., 94, 2025 (1997). From the previous results, Aβ accumulates abnormally and agglomerates due to the formation of PHF, which causes neuronal death in Alzheimer's disease. In addition, the activation of glutamate receptors in response to the extracellular and outflow of glutamic acid is an important factor in the early process of neuronal death caused by ischemic cerebrovascular accidents. Sai-shin Igaku [ Lastet Medicine, 49, 1506 (1994).

Treatment with kainic acid promotes AMPA receptors, one of the glutamic acid receptors, increasing the mRNA of the amyloid precursor protein (hereinafter abbreviated herein as "APP"), the precursor of Aβ (Society for Neuroscience). Abstracts, 17, 1445 (1991)), have been reported to improve metabolism of APP (The Journal of Neuroscience, 10, 2400 (1990)). It has been strongly suggested that the accumulation of Αβ is involved in cell death due to ischemic cerebrovascular disease. Diseases in which abnormal accumulation and mass of Αβ are observed include Down syndrome, cerebral hemorrhage caused by cerebral amyloid angiopathy, and Lewy body disease (Shin-kei Shinpo [Nerve Advance], 34, 343). (1990); Tanpaku-shitu Kaku-san Koso [Protein, Nucleic Acid, Enzyme], 41, 1476 (1996)). Furthermore, diseases that show neurofibrillary tangles caused by the accumulation of PHF include: supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, and boxer Encephalitis (pulgilistic encephalitis), Guam parkinsonism-dementia complex, Lewy body disease, and others (see Tanpaku-shitu Kaku-san Koso [Protein, Nucleic Acid, Enzyme]). 36, 2 (1991); Igaku no Ayumi [Progress of Medicine], 158, 511 (1991); Tanpaku-shitu Kaku-san Koso [Protein, Nucleic Acid, Enzyme], 41, 1476 (1996)).

Tau proteins generally consist of proteins that form several bands with a molecular weight of 48 to 65 kDa in SDS-PAGE electrophoresis and promote microtubule formation. In brains with Alzheimer's disease, tau protein mixed with PHF has been demonstrated to be abnormally phosphorylated compared to normal tau protein (J. Biochem., 99, 1807 (1996); Proc. Natl. Acad. Sci. , USA., 83, 4913 (1986). Enzymes that promote abnormal phosphorylation were isolated. The electroenzyme was named tau protein kinase 1 (abbreviated herein as "TPK1") and its physicochemical properties were revealed (Seikagaku [Biochemistry], 64, 308 (1992). J. Biol. Chem., 267, 10897 (1992). The cDNA of murine TPK1 was cloned from a murine cerebral cortical cDNA library based on the partial amino acid sequence of TPK1, its nucleotide sequence was determined and the amino acid sequence was inferred. See Japanese Patent Un-examined Publication [Kokai] No. 6-239893 / 1994). As a result, the primary structure of the mouse TPK1 corresponding to the primary structure of the enzyme known as mouse GSK-3β (glycogen synthase kinase 3β) (FEBS Lett., 325, 167 (1993)) was revealed.

Aβ, a major component of senile plaques, has been reported to cause neurotoxicity (Science, 250, 279 (1990)). However, while various theories have suggested why Aβ causes apoptosis, no clear theory has been published. Takashima et al. Observed that Aβ treatment resulted in cell death when the rats were treated with a fetal rat hippocampus primary culture system. TPK1 activity was increased by Aβ treatment, and cell death by Aβ was antisense of TPK1. Was inhibited by Proc. Natl. Acad. Sci., USA., 90, 7789 (1993); Japanese Patent Un-examined Publication [Kokai] No. 6-329551 / 1994.

In view of the foregoing, compounds that inhibit the activity of TPK1 prevent neurotoxicity of PH and formation of PHF and inhibit neuronal cell death in Alzheimer's disease to stop or delay the progression of Alzheimer's disease. In addition, the compound may be used as a therapeutic agent for ischemic cerebrovascular disease, Down Syndrome, cerebral amyloid angiopathy, and cerebral hemorrhage caused by Roy body disease by inhibiting cytotoxicity of Aβ. Furthermore, supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pulgilistic encephalitis, Guam Parkin's disease-dementia complications It can be used to treat neurodegenerative diseases such as Guam parkinsonism-dementia complex, Lewy body disease, Pick's disease, corticobasal degeneration, and frontotemporal dementia.

Summary of the Invention

The main object of the present invention is to provide a compound useful as an active ingredient of a medicament for the prevention and / or treatment of diseases such as Alzheimer's disease. More specifically, an object of the present invention is to inhibit the activity of TPK1 to inhibit neurotoxicity of PH and formation of PHF, and to prevent and / or treat diseases such as Alzheimer's disease by inhibiting neuronal degeneration. It is to provide a new compound as an active ingredient of. Another object of the present invention is to provide a new compound useful as an active ingredient of a medicament having electrical properties.

To accomplish the above purpose, the inventors of the present invention examined several compounds having inhibitory activity on phosphorylation of TPK1. As a result, the compound disclosed in general formula (I) was found as an effective ingredient useful for the prevention and / or treatment of electrical diseases. The present invention focused on this finding.

The present invention provides for the prevention and / or treatment of diseases or neurodegenerative diseases caused by the overactivity of tau protein kinase 1 constituting a substance selected from the group consisting of hydroxyflavone derivatives disclosed in general formula (I) as an active ingredient. Provides medication for:

Where

R ¹ is hydrogen or a hydroxy group;

R ² is hydrogen or C ₁ -C ₁₈ which may have one or more C ₆ -C ₁₄ aryl groups

An alkyl group; And,

Ar is a C ₆ -C ₁₄ aryl group which may be substituted or an aromatic heterocycle which may be substituted

Click groups and salts, solvates, and hydrates thereof.

According to a preferred embodiment of the present invention, Alzheimer's disease, ischemic cerebrovascular disease, Down's syndrome, cerebral hemorrhage caused by cerebral amyloid angiopathy, supranuclear palsy, and subacute sclerosing panencephalitic parkinsonism , Postencephalitic parkinsonism, pulgilistic encephalitis, Guam parkinsonism-dementia complex, Lewy body disease, Pick's disease, cerebral To provide electrical medicine for diseases selected from the group consisting of corticobasal degeneration, frontotemporal dementia. Furthermore, in a preferred embodiment, a medicament in the form of a medicinal composition comprising an electrical material as an active ingredient with one or more pharmaceutical additives. The present invention provides an hydroxyflavone derivative of formula (I) and an inhibitor of tau protein kinase 1 selected from salts, solvates, and hydrates thereof.

According to another aspect of the invention, the method comprises administering to a patient an effective amount of a substance selected from the group consisting of a hydroxyflavone derivative of formula (I) and a physiologically acceptable salt, solvate, and hydrate thereof Providing a method for the prevention and / or treatment of a disease caused by tau protein kinase 1 overactivity; There is provided the use of a substance selected from the group consisting of hydroxyflavone derivatives of formula (I) and their physiologically acceptable salts, solvates, hydrates for the manufacture of an electric medicament.

According to another aspect of the present invention there is provided a hydroxyflavone derivative, a salt, a solvate, or a hydrate thereof disclosed in Formula (I):

Where

R ¹ is hydrogen or a hydroxy group;

R ² is hydrogen or C ₁ -C ₁₈ which may have one or more C ₆ -C ₁₄ aryl groups

An alkyl group; And,

Ar is a C ₆ -C ₁₄ aryl group which may be substituted, or an aromatic hetero yarn which may be substituted

Is an cyclic group, provided that when R ² is hydrogen, Ar is represented by the following general formula (II)

To be

{

Where

R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are each hydrogen, a substituted C ₁ -C ₁₈ alkyl group, a substituted C ₁ -C ₁₈ alkoxy group, a hydroxyl group, a substituted group An acyloxy group, a carboxy group, an alkoxycarbonyl group which may be substituted, a carbamoyl group which may be substituted, an alkylcarbonyl group which may be substituted, an amino group which may be substituted, a nitro group, or a cyano group, provided that R ³ , One of R ⁴ , R ⁵ , R ⁶ , and R ⁷ is represented by the general formula (III): -X- (CH ₂ ) _m -R ⁸ (wherein R ⁸ comprises an amino group which may be substituted, or nitrogen; A saturated heterocyclic group which may be substituted, X is a single bond or oxygen, m is an integer from 1 to 8), and

A compound in which R ¹ is hydrogen, R ² is a methyl group, and Ar is a phenyl group, 3,4-methylenedioxyphenyl group, or 3-pyridyl group; R ¹ is hydrogen, R ² is a propyl group, and Ar is a phenyl group having a carboxy group or ester group at position 4; And compounds in which R ¹ is a hydroxy group, R ² is a methyl group and Ar is a phenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, or 3,4-dimethoxyphenyl group] are excluded.

According to a preferred embodiment of the invention,

Provided are the hydroxyflavone derivatives, salts, solvates, or hydrates thereof disclosed in Formula (IV):

Where

R ¹ is hydrogen or a hydroxy group;

Z contains an amino group which may be substituted, or nitrogen, and is saturated

Heterocyclic group;

n is an integer from 1 to 8;

R ⁵ is hydrogen or a C ₁ -C ₁₅ alkoxy group; And,

R ⁶ is hydrogen or a hydroxy group;

Provided are the hydroxyflavone derivatives, salts, solvates, or hydrates thereof disclosed in Formula (V):

Where

R ² is hydrogen or a C ₁ -C ₁₈ alkyl group having at least one C ₆ -C ₁₄ aryl group;

R ⁴ is a C ₁ -C ₁₈ alkyl group which may be substituted, a C ₁ -C ₁₈ alkoxy group which may be substituted,

Doxy group, acyloxy group which may be substituted, carboxy group, which may be substituted

Alkoxycarbonyl Group, Substituted Carbamoyl Group, Substituted Al

A chelcarbonyl group, a substituted amino group, a nitro group, or a cyano group

; And,

R ⁵ is hydrogen, a hydroxy group, a methoxy group, or a nitro group;

Provided are the hydroxyflavone derivatives, salts, solvates, or hydrates thereof disclosed in Formula (I):

Where

R ¹ is hydrogen or a hydroxy group;

R ² is hydrogen or C ₁ -C ₁₈ which may have one or more C ₆ -C ₁₄ aryl groups

An alkyl group; And,

Ar is a C ₆ -C ₁₄ aryl group which may be substituted, or an aromatic hetero yarn which may be substituted

(Except for compounds in which R ¹ is hydrogen, R ² is a methyl group, and Ar is a pyridyl group).

Indian J. Chem. Sect. B, Org. Chem. Incl. Med. Chem., 35B, 1253 (1996) discloses compounds of the general formula (I) wherein R ¹ is hydrogen, R ² is an allyl group, Ar is a phenyl group, 4-tolyl group, or 4-chlorophenyl group; ; Indian J. Chem. Sect. In B, 30B, 93 (1991), R ¹ is hydrogen, R ² is a 1-phenyl- ² -propenyl group, or a 1-phenyl-1-propenyl group, and Ar is a phenyl group. Is disclosed; Indian J. Chem. Sect. B, 26B, 229 (1991), J. Indian Chem. Soc., 60, 411 (1983), Indian J. Indian Chem. Soc., 49, 283 (1972) disclose compounds of the general formula (I) wherein R ¹ is hydrogen, R ² is a methyl group, and Ar is a phenyl group; Indian J. Chem. Sect. B, 19B, 866 (1980) disclose compounds of the general formula (I) wherein R ¹ is hydrogen, R ² is a 1,2-dimethyl- ² -propenyl group and Ar is a phenyl group; Ann. Pharm. France, 18, 528 (1960) discloses compounds of the general formula (I) wherein R ¹ is hydrogen, R ² is a methyl group, and Ar is a 3, 4-methylenedioxyphenyl group.

Phytochemistry, 19, 2179 (1980) discloses compounds of the general formula (I) wherein R ¹ is hydrogen, R ² is a 3-methyl- ² -butenyl group, and Ar is a 4-hydroxyphenyl group; Indian J. Chem. Sect. B, 18B, 525 (1979) disclose compounds of the general formula (I) wherein R ¹ is hydrogen, R ² is an allyl group and Ar is a phenyl group having a methoxy group at the 2, 3 or 4 position; Indian J. Chem. Sect. B, 15B, 933 (1977) and Tetrahedron Lett., 1977, 473 (1977) disclose compounds of the general formula (I) wherein R ¹ is hydrogen, R ² is an allyl group, and Ar is a phenyl group; Bull. Soc. Chim. FR1960, 95 (1960) disclose compounds of the general formula (I) wherein R ¹ is hydrogen, R ² is a methyl group, and Ar is a 3-pyridyl group.

J. Indian Chem. Soc., 65, 149 (1988), and Indian J. Chem. Sect. B, 20B, 624 (1981) discloses compounds of the general formula (I) wherein R ¹ is a hydroxy group, R ² is a methyl group, and Ar is a 3,4-methylenedioxyphenyl group; Tetrahedron, 31, 265 (1975) discloses compounds of the general formula (I) wherein R ¹ is a hydroxy group, R ² is a methyl group and Ar is a phenyl group; Indian J. Chem., 4, 481 (1966) discloses compounds of the general formula (I) wherein R ¹ is a hydroxy group, R ² is a methyl group and Ar is a 4-methoxyphenyl group; And Phytochemistry, 22, 2107 (1983) disclose compounds of the general formula (I) wherein R ¹ is a hydroxy group, R ² is a methyl group, and Ar is a 4-hydroxyphenyl group.

Furthermore, US Patent No. 4,042,708 and German Patent No. In 2,454,670, R ¹ is a hydroxy group, R ² is a propyl group, and Ar is a phenyl group having a 4-carboxyl group or 4-ethoxycarbonyl group as a synthetic intermediate for preparing a compound having anti-SRS activity. The compound of (I) has been disclosed, and the Japanese Patent Un-examined Publication [Kokai] No. 8-225563 / 1996 discloses compounds of the general formula (I) wherein R ¹ is a hydroxy group, R ² is a propyl group and Ar is a 3-hydroxy-4-methylphenyl group useful for the treatment of chronic venous insufficiency. It is. However, such components having inhibitory activity against TPK1 are not known until now.

Best Mode for Carrying Out the Invention

The alkyl moiety of the functional group, including the "alkyl group" or alkyl moiety (eg, alkoxy group) used herein, may be linear, cyclic, or branched. For example, the alkyl group represented by R ² is methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclobutyl group, n-pen Tyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group, cyclopentyl group, n-hexyl group, isohexyl group, cyclohexyl group, linear or branched heptyl group, octyl group, nonyl group, de It is a real group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, an octadecyl group.

For example, examples of the C ₁ -C ₁₈ alkyl group having a C ₆ -C ₁₄ aryl group represented by R ² include an electric C ₁ -C ₁₈ alkyl group which may be substituted with a phenyl group, a naphthyl group, an anthryl group, or the like. Specifically, examples include benzyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, 1-phenethyl group, 2-phenethyl group, 3-phenylpropyl group, 4-phenylbutyl group, and the like. For example, examples of the C ₆ -C ₁₄ aryl group represented by Ar include a phenyl group, 1-naphthyl group, 2-naphthyl group, anthryl group and the like.

In the present specification, when the functional group is defined as “which may be substituted” or “optionally substituted”, the number of substituents, the kind, and the substitution position are not particularly limited, and When more than one substituent is present, they may be the same or different. If the aryl group represented by Ar has one or more substituents, the aryl group may have one or more substituents selected from the group constituting the C ₁ -C ₁₈ alkyl group previously represented by R ² ; Methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group, cyclopropyloxy group, cyclobutyl jade such as time, tilok cyclopentenyl group, and a cyclohexyloxy group C ₁ -C ₁₈ alkoxy group; C ₁ -C ₈ alkylthio groups such as methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, tert-butylthio group, pentylthio group and methylenedioxy group; C ₆ -C ₁₀ aryl groups such as phenyl group, 1-naphthyl group, and 2-naphthyl group; Fluorenyl group; C ₆ -C ₁₄ aryloxy groups such as phenoxy group and naphthoxy group; C ₆ -C ₁₄ arylthio groups such as phenylthio group and naphthylthio group; C ₁ -C ₅ alkylsulfonyl groups such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; C ₆ -C ₁₄ arylsulfonyl groups such as phenylsulfonyl group and naphthylsulfonyl group, and naphthylsulfonyl group; Halogen element (the term "halogen element" or "halogen" as used herein includes any one of fluorine, chlorine, bromine, and iodine); C ₁ -C ₁₈ activating alkyl groups such as trifluoromethyl group; Hydroxyl group, nitro group; Oxo group; Formyl group; Cyano group; Carboxy group; C ₂ -C ₆ such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxy carbonyl group, tert-butoxycarbonyl group, and pentyloxycarbonyl group Alkyloxycarbonyl group; C ₂ -C ₆ alkylcarbonyl groups such as an acetyl group, propionyl group, butyryl group, and valeryl group; C ₂ -C ₆ alkylcarbonyloxy groups such as acetoxy group, propionyloxy group, butyryloxy group, and valeryloxy group; C ₆ -C ₁₄ arylcarbonyloxy groups such as a benzoyloxy group and a naphtolyloxy group; Amino group; C ₁ -C ₅ monoalkylamino groups such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and isopentylamino group; C ₂ -C ₁₀ dialkylamino groups such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group (the two alkyl groups may be the same or different); C ₂ -C ₆ alkylcarbonylamino groups such as acetylamino group, propionylamino group, isopropionylamino group, butyrylamino group, and valerylamino group; Carbamoyl group; C ₂ -C ₆ alkyl carbamoyl groups such as methyl carbamoyl group, tert-butyl carbamoyl group and pentyl carbamoyl group; C ₃ -C ₉ dialkyl carbamoyl groups such as dimethyl carbamoyl group, diethyl carbamoyl group, dipropyl carbamoyl group, diisopropyl carbamoyl group, and dibutyl carbamoyl group; And 1-4 heteroelements selected from an oxygen element, a sulfur element, and a nitrogen element, for example, 5-10 furan ring, dihydrofuran ring, tetrahydrofuran ring, pyran ring, dihydropyran ring, tetra Hydropyran ring, benzofuran ring, isobenzofuran ring, chrome ring, chroman ring, isochroman ring, thiophene ring, benzothiophene ring, pyrrole ring, pyrroline ring, imidazole 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, indole Lysine ring, indole ring, indolin ring, isoindole ring, isoindolin ring, indazole ring, benzimidazole ring, purine ring, quinolizine ring, quinoline ring, phthalazine ring, naphthyridine ring, quinox Saline ring, quinazoline ring, cynoline ring, putridine ring, olsazole ring, oxazolidine ring, two Zazole ring, isozozolidine ring, thiazole ring, benzothiazole ring, thiaziridine ring, isothiazole ring, isothiazolidine ring, dioxan ring, dithiane ring, morpholine ring, thiomorpholine ring , Phthalimide ring, and the like (the group of such substituents are represented by "substituent A"). In substituent A, the aryl group and heterocyclic group may have one or more substituents selected from substituent A.

For example, the aromatic heterocyclic group represented by Ar includes residues of an aromatic heterocyclic ring having a total ring constituting 1-10 hetero elements and 5-10 elements selected from oxygen, sulfur, and nitrogen. Such aromatic heterocyclic groups may be bonded at any position in the ring. Specifically, examples include 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, isoindole ring, indazole ring, benzimidazole ring, purine ring, quinoline ring, isoquinoline ring, phthalazine ring, oxazole ring, isoazole ring, thiazole Ring, benzothiazole ring, isothiazole ring and the like. The aromatic heterocyclic group may have one or more substituents selected from substituents A.

Examples of C ₁ -C ₁₈ alkyl groups represented by R ³ to R ⁷ include R ² described above, and the alkyl group may have one or more substituents selected from substituents A. For example, examples of the disclosed C ₁ -C ₁₈ alkoxy group represented by R ³ to R ⁷ are methoxy group, ethoxy group, n-propoxy group, isopropoxy group, cyclopropyloxy group, n-butoxy group, Isobutoxy, tert-butoxy, cyclobutoxy, n-pentyloxy, isopentyloxy, cyclopentyloxy, n-hexyloxy, isolexyloxy, cyclohexyloxy and linear, branched, cyclic Heptyloxy group, octyloxy group, nonyloxy group, decyloxy group, undecyloxy group, dodecyloxy group, tridecyloxy group, tetradecyloxy group, pentadecyloxy group, hexadecyloxy group, heptadecyloxy group, octadecyl include a C ₁ -C ₁₈ alkoxy, such as -1,3 time. The alkoxy group may have one or more substituents selected from substituents A.

For example, examples of the alkyloxy group represented by R ⁷ in R ³ is an acetoxy group, propionyl oxy group, butynyl rilok time, and ballet rilok group C ₂ -C ₆ alkylcarbonyl group optionally the same; C ₆ -C ₁₄ arylcarbonyloxy groups such as a benzoyloxy group and a naphthoyloxy group. The alkyl portion of the alkylcarbonyloxy group and the aryl portion of the arylcarbonyloxy group may have one or more substituents selected from substituents A. For example, examples of the C ₂ -C ₆ alkoxycarbonyl group disclosed in R ³ to R ⁷ are methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbon C ₂ -C ₆ alkoxycarbonyl groups such as a silyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, and n-pentyloxycarbonyl group. The alkyl portion of the alkoxycarbonyl group may have one or more substituents selected from substituents A.

When the disclosed carbamoyl group represented by R ⁷ at R ³ has one or more substituents selected from substituents A, for example, examples of carbamoyl groups include methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, butyl C ₂ -C ₆ monoalkylcarbamoyl groups such as carbamoyl group, tert-butyl carbamoyl group, and pentyl carbamoyl group; C ₃ -C ₉ dialkylcarbamoyl groups such as dimethyl carbamoyl group, diethyl carbamoyl group, dipropyl carbamoyl group, diisopropyl carbamoyl group, and dibutyl carbamoyl group (both alkyl groups may be the same or different). It is included). The alkyl moiety of the foregoing alkylcarbamoyl group and dialkylcarbamoyl group may have one or more substituents selected from substituents A.

Amino group in R ³ to R ⁷ shown may have one or more substituents, for example, methylamino group, ethylamino group, propylamino group, isopropyl group, butyl group, isobutyl group, tert- butyl group, a pentyl group, and C ₁ -C ₅ monoalkylamino groups such as isopentylamino group; C ₂ -C ₁₀ dialkylamino groups such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; And C ₂ -C ₆ alkylcarbonylamino groups such as acetylamino group, propionylamino group, isopropionylamino group, butyrylamino group, and valerylamino group. The alkyl portion of the foregoing monoalkylamino group and the dialkylamino group may have one or more substituents selected from substituents A. The amino group represented by R ⁸ may have one or more substituents, which group is a substitutable amino group selected from R ⁷ in R ³ described above.

The number of nitrogens including the disclosed nitrogen represented by R ⁸ and contained in the saturated heterocyclic group is not particularly limited and may include one or more heteroelements and nitrogen (eg, oxygen, sulfur, etc.). Saturated heterocyclic groups, including nitrogen, may be substituted at the position of the ring. In particular, for example, pyrrolidine ring, piperidine ring, piperazine ring, homopiperidine ring, homopiperazine ring, morpholine ring, thiomorpholine ring and the like. The heterocyclic group containing nitrogen and saturated may have one or more substituents selected from substituents A.

If the amino group represented by Z has one or more substituents, it may be a substituted amino group selected from R ⁷ to R ³ described above. Examples of saturated heterocyclic groups containing nitrogen represented by Z include pyrrolidine ring, pyrazolidine ring, imidazolidine ring, thiazolidine ring, piperidine ring, piperazine ring, morpholin ring, Thiomorpholine ring, quinuclidin ring, and the like.

In addition to the compounds disclosed in the general formula (I), physiologically acceptable salts may be used as the active ingredient of the medicament of the present invention. When the acidic group is present, examples of the salts include salts of alkali metals and alkaline earth metals such as lithium, sodium, potassium, magnesium, and calcium; Methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanol Salts of amines and ammonia, such as amines, N-methylglucamine, and L-glucamine; Or salts of basic amino acids such as lysine, δ-hydroxylysine, and arginine. When a basic group is present, for example, salts of mineral acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, and phosphoric acid; Methanesulfoninic acid, benzenesulfoninic acid, p-toluenesulfoninic acid, acetic acid, propionic acid, tartaric acid, fumarin acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, manderinic acid Salts of organic acids such as cinnamic acid, lactic acid, glycolic acid, glucuronine acid, ascorbic acid, nicotinic acid, and salicylic acid; Salts of acidic amino acids such as aspartic acid and glutamic acid.

Solvates, hydrates and salts thereof of the hydroxyflavone derivatives disclosed in the general formula (I) can be used as the active ingredient of the medicament of the present invention. Moreover, the hydroxyflavone derivatives disclosed in the general formula (I) may have one or more asymmetric carbon elements. In the stereochemistry of asymmetric carbon elements, they can be independently in the (R) or (S) form, and the hydroxyflavone derivatives exist as stereoisomers such as optical isomers or diastereomers. Stereoisomers such as pure forms, mixtures of stereoisomers, racemates and the like can be used as active ingredients in the pharmaceutical of the present invention. Furthermore, the 4-keto and 4-hydroxy components of the hydroxyflavone derivatives disclosed in the general formula (I) may exist as tautomers. The presence of tautomers is apparent to those skilled in the art, and is also within the scope of the present invention.

Examples of preferred compounds of the invention are set forth in the table below. However, the scope of the present invention is not limited by the following compound.

Among the compounds disclosed in formula (I), particularly preferred compounds as active ingredients of the medicaments of the invention are as follows:

(1) a compound in which R ¹ is hydrogen;

(2) a compound in which R ² is hydrogen or a C ₁ -C ₁₈ alkyl group;

(3) a compound in which R ² is a C ₁ -C ₁₈ alkyl group;

(4) a compound in which R ² is a C ₂ -C ₁₈ alkyl group;

(5) a compound in which Ar is a substituted phenyl group, a substituted C ₁₀ -C ₁₄ aryl group, or a substituted heterocyclic group;

(6) a compound in which Ar is a substituted C ₆ -C ₁₄ aryl group or a substituted aromatic heterocyclic group;

(7) a compound in which Ar is a substituted C ₆ -C ₁₄ aryl group;

(8) a compound in which Ar is a group disclosed in the general formula (II);

(9) a compound in which R ² is a C ₁ -C ₁₈ alkyl group having one or more C ₆ -C ₁₄ aryl groups, Ar is a substituted C ₆ -C ₁₄ aryl group, or a substituted aromatic heterocyclic group;

(10) a C ₁ -C ₁₈ alkyl group wherein R ² has at least one C ₆ -C ₁₄ aryl group, Ar is a substituted phenyl group, a substituted C ₁₀ -C ₁₄ aryl group, or a substituted aromatic heterocyclic Attributable compounds;

(11) a compound in which R ² is a C ₁ -C ₁₈ alkyl group having at least one C ₆ -C ₁₄ aryl group, Ar is a substituted C ₆ -C ₁₄ aryl group;

(12) the compound of (9) to (11), wherein R ¹ is hydrogen;

(13) Ar is a compound of Claims (9) to (12) which is a group disclosed in the general formula (II);

(14) the compound of (9) to (13), wherein R ² is a C ₁ -C ₁₈ alkyl group;

(15) The compound of (9) to (14), wherein R ² is a C ₂ -C ₁₈ alkyl group; And,

(16) The compound of (9) to (12), wherein R ² is a C ₄ -C ₁₈ alkyl group.

In addition, particularly preferred compounds are as follows:

(17) a hydroxyflavone derivative disclosed in Formula (IV) wherein n is 2 or 3;

(18) R ⁵ is a hydroxyflavone derivative disclosed in formula (IV) wherein hydrogen or a methoxy group;

(19) Z is a hydroxyflavone derivative disclosed in formula (IV) wherein dimethylamino group, substituted piperazinyl group, or substituted piperidyl group;

(20) R ⁴ is a hydroxyflavone derivative disclosed in formula (V), which may be a substituted C ₁ -C ₁₈ alkyl group, a substituted C ₁ -C ₁₈ alkoxy group, a nitro group, or a cyano group;

(21) R ₁ is hydrogen or a hydroxy group; R ² is hydrogen or a C ₁ -C ₁₈ alkyl group having at least one C ₆ -C ₁₄ aryl group; And hydroxyflavone derivatives disclosed in Formula (I) wherein Ar is an aromatic heterocyclic group which may be substituted, provided that R ¹ is hydrogen; R ² is a methyl group; and wherein Ar is a pyridyl group. ).

In addition, the most preferred compounds are as follows:

7-hydroxy-3 '(3- (1-piperidyl) propyloxy) -8-propylflavone,

4 ', 7-dihydroxy-3'-methoxy-8-propylflavone,

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) chrome.

However, the active ingredient of the medicament of the present invention is not limited to the compound exemplified above.

The hydroxyflavone derivatives disclosed in the general formula (I) can be prepared by methods known in the literature. For example, it can be manufactured by the following procedure.

<1st process>

(Indications used in the scheme are as described above.)

The compounds disclosed in Formula (VII) can be obtained by reacting the compounds disclosed in Formula (V) in the presence of a base and a reactive derivative of Formula (VI) with a solvent. The kind of solvent is not particularly limited as long as it does not affect the reaction. Ethers such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, isopropyl ether and dioxane; Aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbon compounds such as dichloromethane, chloroform, and dichloroethane may be used as the solvent. Two or more solvents may be used in combination. For example, examples of the base include methyllithium, butyllithium, lithium hexamethyldisilazane, sodium hexamethyldisilazane, lithium diisopropylamide, sodium hydroxide, potassium hydroxide, sodium hydride and the like. As reactive derivatives of general formula (VI), symmetric acid anhydrides, mixed acid anhydrides, acid halogen compounds, active amides, esters and the like can be used, and these compounds are easily prepared from the corresponding carboxylic acids by the methods disclosed in the literature. can do. The reaction temperature and time are not particularly limited. In general, the reaction is carried out for 30 minutes to 48 hours at a temperature of -78 ℃ to 250 ℃.

<Second process>

(Indications used in the scheme are as described above.)

The compound disclosed in formula (VII) obtained in the first step is prepared as a compound of formula (I) by dehydration reaction with or without solvent. The kind of solvent is not particularly limited as long as it does not affect the reaction. For example, ethers such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, isopropyl ether and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, chloroform, and dichloroethane Acid anhydrides such as halogenated hydrocarbons, nitriles such as acetonitrile and propionitrile, esters such as methyl acetate and ethyl acetate, alcohols such as methanol and ethanol, organic solvents acetic anhydrides such as acetic acid, etc. are used. Can be used. The electro dehydration reaction can be carried out in the presence of an acid catalyst. For example, examples of the acid catalyst include inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, and phosphoric acid, organic acids such as trifluoroacetic acid, p-toluenesulphonic acid, methanesulphonic acid, and camphorsulphonic acid. Can be. The reaction temperature and time are not particularly limited, but are generally carried out for 30 minutes to 48 hours at a temperature of 0 ℃ to 250 ℃. In each of the foregoing processes, protection and deprotection of functional groups are sometimes required. The protecting group can be appropriately selected depending on the functional group, and the protection and deprotection can be carried out by the methods described in the literature.

The medicine of the present invention has an inhibitory activity against TPK1, inhibits TPK1 activity in Alzheimer's disease and the like, and inhibits neurotoxicity of Aβ, inhibition of PHF formation and neuronal cell death. Therefore, the medicament of the present invention is useful as a medicament capable of preventing and / or treating Alzheimer's disease. In addition, the medicament of the present invention is ischemic cerebrovascular disease, Down syndrome, cerebral hemorrhage caused by cerebral amyloid angiopathy, gradual supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, encephalitis Parkins Disease (postencephalitic parkinsonism), pulgilistic encephalitis, Guam parkinsonism-dementia complex, Lewy body disease, Pick's disease, cortical degeneration ), And can be used as a prophylactic and / or therapeutic agent for frontotemporal dementia.

As an active ingredient of the medicament of the present invention, it may be selected from the group consisting of a compound disclosed in the general formula (I), a pharmaceutically acceptable salt, and a solvate and a hydrate. The above-mentioned compounds may be administered by themselves as a medicament of the present invention, but it is generally preferable to administer them in the form of a pharmaceutical composition containing the foregoing compound and one or more adjuvants as an active ingredient. As an active ingredient of the medicament of the present invention, two or more electrical compounds may be used in combination. The pharmaceutical composition may be supplemented with an active ingredient of another medicine for the treatment of Alzheimer's disease and the like.

The kind of the pharmaceutical composition is not particularly limited, and the composition may be provided by oral or parenteral administration. For example, the pharmaceutical composition may be oral or intravenous, intramuscular, or subcutaneous injection, drip infusion, such as granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions, etc. It may be formulated in the form of parenteral administration such as transdermal medicine, mucosal medicine, nasal drops, inhalants, suppositories, and the like. Injectables or drips can be prepared in powder form in a lyophilized form, and can be used by dissolving using a suitable liquid solution such as physiological saline. Sustained release formulations coated with a polymer may be administered directly into the brain.

The type of the pharmaceutical adjuvant used in the pharmaceutical composition, the quantification of the pharmaceutical adjuvant with respect to the active ingredient, and the method for producing the pharmaceutical composition may be appropriately selected by those skilled in the art. Inorganic or organic compounds, or solid or liquid components, can be used as medicinal aids. Generally, medicinal auxiliaries are incorporated in the range of 1 to 90% of the weight of the active ingredient.

For example, examples of excipients used in the preparation of solid pharmaceutical compositions include lactose, sucrose, starch, talc, cellulose, deckscreen, kaolin, calcium carbonate and the like. For the preparation of liquid compositions for oral administration, water or vegetable oils can be used as conventional inert diluents. In addition to the inert diluent, the liquid formulation may include adjuvants such as wetting agents, suspension aids, sweeteners, flavorings, colorants, and preservatives. The liquid composition may be filled in a capsule made of an absorbent material such as gelatin. For example, solvents or suspensions used in compositions for parenteral administration such as injections, suppositories, and the like include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. For example, examples of base materials used in suppositories include cacao butter, emulsified cacao butter, lauric lipids, witepsol.

The dosage and frequency of administration of the medicine of the present invention are not particularly limited and are appropriately selected depending on conditions such as the use of prophylaxis and / or treatment, the type of disease, the weight or age of the patient, and the severity of the disease. In general, the daily dose of oral administration of an adult is 0.01 to 1,000 mg (weight of active ingredient), and can be administered once or several times a day or once every several days. If a medicament is used as an injection, it is preferable to administer to adults in a continuous or hepatic way in an amount of 0.001 to 100 mg (weight of the active ingredient) per day.

The hydroxyflavone derivatives and salts, solvates, and hydrates thereof disclosed in the above general formula (I) are novel compounds and fall within the scope of the present invention with respect to chemicals, wherein R ¹ , R ² , and Ar are Is the same as defined above, wherein R ² is hydrogen and Ar is a group as defined in the above general formula (II), wherein R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are as defined above; The same, provided that one of R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is a group as disclosed in Formula (III), wherein R ⁸ , X, and m are as defined above , R ¹ is hydrogen, R ² is methyl group, and Ar is phenyl group, 3,4-methylenedioxyphenyl group, or 3-pyridine group, R ¹ is hydrogen, R ² is propyl group, Ar is at position 4 A compound which is a phenyl group having a carboxy group or ester group, R ¹ is a hydroxy group, R ² is a methyl group, and Ar is a phenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, or 3,4-dimethok Compounds which are cyphenyl groups are excluded]}.

The use of the novel compounds provided by the present invention is not limited to medicaments, and any use falls within the scope of the present invention. Compounds exist as stereoisomers such as enantiomers of diastereomers, and pure forms of stereoisomers, mixtures of stereoisomers, and racemates are within the scope of the present invention. Examples of compounds in salt form include the physiologically acceptable salts described above.

The present invention relates to a compound useful as an active ingredient of a medicament for the prevention and / or treatment of diseases caused by tau protein kinase 1 hyperactivity such as Alzheimer's disease.

The present invention also relates to novel hydroxyflavone derivatives useful as active ingredients in electrical medicine.

The present invention will be described in more detail with reference to examples. However, the scope of the present invention is not limited in the following examples. In the Examples the compound numbers correspond to the numbers in the preceding table.

Example 1 7-hydroxy-3 '(3- (1-piperidyl) propyloxy) -8-propylflavone disulfate (Compound 455)

2,4-Dihydroxy-3-propylacetophenone (1.0 g) was dissolved in 30 ml of tetrahydrofuran and 26 ml of lithium hexamethyldisilazane was added and stirred at -78 ° C for 2 hours. 1.43 g of tetrahydrofuran of methyl 3-piperidylpropyloxybenzoic acid was added dropwise to the reaction mixture, and the mixture was stirred for 24 hours. The reaction mixture was poured into iced water, neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and hydrated brine, dried over sodium sulfate and then concentrated under reduced pressure. The residue was dissolved in 40 ml of acetic acid, 0.2 ml of concentrated sulfuric acid was added and stirred at 100 ° C. for 2 hours. The reaction was cooled at room temperature and washed with ethyl acetate to give 2.69 g of the desired compound.

Yield: 84%

Melting Point: 233 ℃

NMR (DMSO · d ₆ , δ): 0.98 (t, J = 7.5Hz, 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 = 8.7 Hz, 1H), 7.50 · 7.56 (m.2H), 7.06 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H) , 8.99 (br, 1 H), 10.60 (br, 1 H).

Reference Example 1 Preparation of Methyl 4-tert-Butyldimethyl-siloxy-3-methoxybenzoic Acid

Vanillic acid (25.8 g) was dissolved in 500 ml of methanol, 1 g of p-toluenesulphonic acid was added and heated under reflux for 24 hours. The reaction was cooled to room temperature, concentrated under reduced pressure and purified by eluting with hexane and ethyl acetate (3: 1) using a column to give 28.5 g of methyl vanillate (yield: 100%). Methyl vanylate (5.5 g) was dissolved in 30 ml of N, N-dimethylformamide, and 3.1 g of imidazole and 5.5 g of tert-butyldimethylchlorosilane were added to the solution at 0 ° C, followed by 2 hours at room temperature. Was stirred. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with water and hydrated brine, dried over sodium sulfate and concentrated under reduced pressure. By eluting with hexane: ethyl acetate (15: 1) using a column, the product was purified to yield 8.68 g of the desired component (yield: 97%).

NMR (CDCl ₃ δ): 0.17 (s, 9H), 1.01 (s, 9H), 3.86 (s, 3H), 3.88 (s, 3H), 6.66 (d, J = 8.7 Hz, 1H), 7.51 ( d, J = 2.4Hz, 1H), 7.66 (dd, J = 8.7Hz, 2.4Hz, 1H)

Example 2 : 4 ', 7-dihydroxy-3'-methoxy-8-propylflavone (Compound 682)

2,4-Dihydroxy-3-propylacetophenone (1.0 g) was dissolved in 30 ml of tetrahydrofuran, and 26 ml of lithium hexamethyldisilazane was added dropwise and stirred at -78 ° C for 2 hours. Tetrahydrofuran solution of 1.53 g of methyl vanillin acid obtained in Reference Example 1 was added to the reaction mixture, and the mixture was stirred for 24 hours. The reaction mixture was poured into iced water, neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and hydrated brine, dried over sodium sulfate, then concentrated under reduced pressure and dried. The residue was dissolved in 40 ml of acetic acid, 0.2 ml of concentrated sulfuric acid was added and stirred at 100 ° C. for 2 hours. The reaction was cooled indoors and washed with ethyl acetate to give 1.47 g of the desired compound.

Yield: 87%

Melting Point: 233-233 ℃

NMR (DMSOd 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, 3H), 6.82 ( s, 1H), 6.94 · 6.99 (m.2H), 7.51 · 7.55 (m, 2H), 10.53 (br, 1H).

The compounds disclosed in Examples 3 to 73 were prepared in a similar manner to Reference Example 1 and Examples 1 and 2. Physical properties of the compound are as follows.

Example 3 : 7-hydroxy-3 '-(1-methyl-3'-piperidyl) methoxyflavone (Compound 42)

Melting point: 134 ° C. (decomposition).

NMR (DMSO and _{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 = 7.2Hz, 1H), 7.5 (m, 1H), 7.57 (s, 1H), 7,67 (d, J = 7.5Hz, 1H), 7.89 (d, J = 8.7Hz, 1H), 9.26 ( br, 1H).

Example 4 : 7-hydroxy-3 '-(2-dimethylaminoethoxy) flavone hydrochloride (Compound 45)

Melting point: 238-239 ° C. (decomposition).

NMR (DMSO and _{d 6, δ): 2.87 (} s, 3H), 2.89 (s, 3H), 4.48 (t, J = 5.1Hz, 2H), 6.93 and 6.98 (m, 2H), 7.03 (d, J = 2.1 Hz, 1H), 7.23 (dd, J = 2.1Hz, 8.1Hz, 1H), 7.53 (t, J = 8.1Hz, 1H), 7.65 (d, J = 2.1Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 10.10 (br, 1H), 10.10 (br, 1H), 10.90 (br, 1H).

Example 5 7-Hydroxy-3 '-(2- (1-piperidyl) ethoxy) flavone hydrochloride (Compound 48)

Melting point: 120-121 ° C.

NMR (DMSO and d _6, δ): 1.68 and 1.83 (m, 4H), 3.03 (m, 2H), 3.51 and 3.63 (m, 4H), 3.62 (m, 2H), 4.55 (m, 2H), 4.55 (m, 2H), 6.96 · 6.98 (m, 2H), 7.06 (s, 1H), 7.23 (d, J = 8.1Hz, 1H), 7.52 (m, 1H), 7.64 (s, 1H), 7.70 ( d, J = 7.8Hz, 1H), 7.89 (d, J = 8.71Hz, 1H), 10.58 (br, 1H)

Example 6 : 7-hydroxy-3 '-(3-dimethylaminopropyloxy) flavone hydrochloride (Compound 55)

Melting point: 244-245 ° C.

NMR (DMSO and d _6, δ): 1.68 and 1.83 (m, 4H), 3.03 (m, 2H), 3.51 and 3.63 (m, 4H), 3.62 (m, 2H), 4.55 (m, 2H), 4.55 (m, 2H), 6.96 · 6.98 (m, 2H), 7.06 (s, 1H), 7.23 (d, J = 8.1Hz, 1H), 7.52 (m, 1H), 7.64 (s, 1H), 7.70 ( d, J = 7.8Hz, 1H), 7.89 (d, J = 8.71Hz, 1H), 10.58 (br, 1H)

Example 7 : 7-hydroxy-3 '-(3- (1-piperidyl) propyloxy) flavone 1/2 sulfate (compound 58)

Melting point: 205 ° C. (decomposition).

NMR (DMSO and _{d 6, δ): 1.42 (} m, 1H), 1.59 and 1.80 (m, 3H), 1.85 (m, 2H), 2.16 (m, 2H), 2.93 (m, 2H), 3.56 (m , 2H), 4.19 (t, J = 5.7Hz, 2H), 6.94 (s, 1H), 6.95 (dd, J = 2.1Hz, 9.0Hz, 1H), 7.10 (d, J = 2.1Hz, 8.4Hz, 1H), 7.51 (m, 1H), 7.57 (d, J = 2.1Hz, 1H), 7.67 (d, J = 8.1Hz, 1H), 7.90 (d, J = 9.0Hz, 1H), 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 and _{d 6, δ): 2.29 (} m, 2H), 3.14 and 3.22 (m, 4H), 3.36 (m, 2H), 3.64 (m, 2H), 3.84 (m, 2H), 6.87 (m , 1H), 6.93.7.05 (m, 5), 7.18.7.39 (m, 3H), 7.53 (m, 1H), 7.59 (s, 1H), 7.66 (d, J = 8.1Hz, 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)

Melting point: 210 ° C.

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 · 3.40 (m, 4H), 3.48 (m, 2H), 4.17 (t, J = 6.0Hz, 2H), 6.81 (s, 1H), 6.92 (dd, J = 2.1Hz, 9.0Hz, 1H), 6.99 (d, J = 2.1Hz, 1H ), 7.12 (d, J = 8.7Hz, 1H), 7.88 (d, J = 8.7Hz, 1H), 8.04 (d, J = 9.0Hz, 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 and _{d 6, δ): 1.42 (} m, 1H), 1.58 and 1.69 (m, 3H), 1.85 (m, 2H), 2.17 (m, 2H), 2.93 (m, 2H), 3.23 (m , 2H), 3.52 (m, 2H), 3.87 (s, 3H), 4.20 (t, J = 6.0Hz, 2H), 6.89 (s, 1H), 6.92 (d, J = 8.7Hz, 1H), 7.01 (s, 1H), 7.17 (d, J = 8.7Hz, 1H), 7.59 (s, 1H), 7.70 (d, J = 8.7Hz, 1H), 7.87 (d, J = 8.7Hz, 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 and _{d 6, δ): 1.40 (} m, 1H), 1.62 and 1.68 (m, 3H), 1.92 (m, 2H), 2.13 (m, 2H), 2.90 (m, 2H), 3.22 (m , 2H), 2.49 (m, 2H), 4.12 (t, J = 6.0 Hz, 2H), 6.65 (s, 1H), 6.80 (s, 1H), 6.91 · 6.96 (m, 2H), 7.03 (s, 2H), 7.88 (d, J = 8.7 Hz, 1H), 8.85 (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 = 5,7Hz, 2H), 4.17 (t, J = 5.7Hz, 2H), 6.22 (d, J = 2.1Hz , 1H), 6.54 (d, J = 2.1Hz, 1H), 7.02 (s, 1H), 7.19 (d, J = 8Hz, 1H), 7.48 (t, J = 8.1Hz, 1H), 7.59 (s, 1H), 7.74 (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 and _{d 6, δ): 2.12 (} m, 2H), 2.81 (s, 6H), 3.22 (t, J = 8.1Hz, 2H), 4.17 (t, J = 6.0Hz, 2H), 6.24 ( d, J = 2.1Hz, 1H), 6.53 (d, J = 2.1Hz, 1H), 7.01 (s, 1H), 7.20 (d, J = 7.8Hz, 1H), 7.58 (s, 1H), 7.68 ( d, J = 7.8Hz, 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 and _{d 6, δ): 1.40 (} m, 1H), 1.60 and 1.82 (m, 3H), 1.81 and 1.93 (m, 2H), 2.49 (m, 2H), 2.94 (m, 2H), 3.46 (m, 2H), 4.18 (t, J = 5.7Hz, 2H), 6.24 (d, J = 2.1Hz, 1H), 6.53 (d, J = 2.1Hz, 1H), 7.01 (s, 1H), 7.19 (d, J = 8.1Hz, 1H), 7.51 (d, J = 8.1Hz, 1H), 7.57 (s, 1H), 7.68 (d, J = 8.1Hz, 1H), 10.93 (s, 1H), 12.80 (s, 1 H).

Example 15 5,7-Dihydroxy-3 '-(3- (4-morpholinyl) propyloxy) flavone 1/2 sulfate (Compound 162)

Melting point: 210-212 ° C.

NMR (DMSO and _{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 = 6.0Hz, 2H), 6.24 (d, J = 2.1Hz, 1H), 6.53 (d, J = 2.1Hz, 1H), 7.01 (s, 1H), 7.20 (dd, J = 2.1Hz, 8.1Hz, 1H), 7.52 (m, 1H), 7.58 (s, 1H), 7.08 (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 and d _6, δ): 1.32 and 1.90 (m, 6H), 2.18 (m, 2H), 2.36 (s, 3H), 2.95 (m, 2H), 3.24 (m, 2H), 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 and _{d 6, δ): 1.37 (} t, J = 6.9Hz, 3H), 2.83 (s, 3H), 4.15 (q, J = 6.9Hz, 2H), 6.79 (s, 1H), 6.95 ( d, J = 8.9 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 and _{d 6, δ): 2.36 (} s, 3H), 6.78 (s, 1H), 6.97 and 7.00 (m, 2H), 7.37 (t, J = 7.8Hz, 1H), 7.41 and 7.51 (m , 2H), 10.61 (s, 1H).

Example 19 : 4'-7-dihydroxy-8-methylflavone (Compound 343)

Melting Point:> 300 ℃.

NMR (DMSO and _{d 6, δ): 2.30 (} s, 3H), 6.67 (s, 1H), 6.88 and 6.93 (m, 4H), 7.68 (s, J = 7.8Hz, 1H), 7.88 (d, J = 8.7 Hz, 1 H).

Example 20 7-hydroxy-3'-methoxy-8-methylflavone (Compound 347)

Melting point: 233-236 ° C.

NMR (DMSO-d ₆ , δ): 2.36 (s, 3H), 3.87 (s, 3H), 6.95 (s, 1H), 7.00 (d, J = 8.7Hz, 1H), 7.17 (ss, J = 2.1 Hz, 7.8Hz, 1H), 7.50 (t, J = 8.7Hz, 1H), 7.57 (s, 1H), 7.66 (d, J = 7.8Hz, 1H), 7.76 (d, J = 8.7Hz, 1H) , 10.63 (br, 1H)

Example 21 3'-7-dihydroxy-4'-methoxy-8-methylflavone (Compound 351)

Melting point: 263 ° C. (decomposition).

NMR (DMSO and _{d 6, δ): 2.35 (} s, 3H), 3.86 (s, 3H), 6.69 (s, 1H), 6.97 (d, J = 8.7Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 2.4Hz, 1H), 7.53 (dd, J = 2.4Hz, 8.7Hz, 1H), 7.73 (d, J = 8.7Hz, 1H), 10.59 (br, 1H) .

Example 22 2'-Carboxy-7-hydroxy-8-methylflavones (Compound 354)

Melting Point:> 300 ℃.

NMR (DMSO and _{d 6, δ): 2.16 (} s, 3H), 6.50 (s, 1H), 7.00 (d, J = 8.7Hz, 1H), 7.65 and 7.88 (m, 5H), 10.65 (s, 1H ), 13.03 (br, 1 H).

Example 23 2'-Fluoro-7-hydroxy-8-methylflavone (Compound 365)

Melting point: 230-231 ° C.

NMR (DMSO and _{d 6, δ): 2.30 (} s, 3H), 6.68 (s, 1H), 7.01 (d, J = 8.7Hz, 1H), 7.42 and 7.49 (m, 5H), 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)

Melting point: 229 ° C.

NMR (DMSO and _{d 6, δ): 2.29 (} s, 3H), 6.71 (s, 1H), 7.02 (d, J = 8.4Hz, 1H), 7.45 (m, 1H), 7.60 and 7.90 (m, 3H ), 10.70 (br, 1 H).

Example 25 7-hydroxy-8-methyl-2'-nitroflavone (compound 386)

Melting point: 271-272 ° C.

NMR (DMSO and _{d 6, δ): 2.01 (} s, 3H), 6.72 (s, 1H), 7.02 (s, J = 8.7Hz, 1H), 7.76 and 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 387)

Melting point: 250 ° C. (decomposition).

NMR (DMSO · d ₆ , δ): 2.83 (s, 3H), 7.02 (d, J = 8.7Hz, 1H), 7.13 (s, 1H), 7.78 (d, J = 8.7Hz, 1H), 7.88 ( m, 1H), 8.42 (d, J = 7.8 Hz, 1H), 8.53 (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. (decomposition).

NMR (DMSO and _{d 6, δ): 2.11 (} s, 3H), 3.87 (s, 3H), 6.67 (s, 1H), 7.01 (d, J = 8.7Hz, 1H), 7.54 (d, 7.8Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.72.7.79 (m, 2H), 10.74 (br, 1H).

Example 28 3 ', 8-dimethyl-7-hydroxy-2'-nitroflavone (Compound 391)

Melting point: 230 ° C. (decomposition).

NMR (DMSO and _{d 6, δ): 2.10 (} s, 3H), 2.40 (s, 3H), 6.67 (s, 1H), 7.01 (d, J = 8.7Hz, 1H), 7.71 and 7.82 (m, 4H ), 10.78 (br, 1 H).

Example 29 3 ', 4'-dimethoxy-7-hydroxy-8-methyl-2'-nitroflavone (Compound 392)

Melting point: 284-285 ° C. (decomposition).

NMR (DMSO-d ₆ , δ): 2.05 (s, 3H), 3.95 (s, 3H), 3.98 (s, 3H), 6.71 (s, 1H), 7.00 (d, J = 8.7Hz, 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: 242-243 ° C.

NMR (DMSO · d ₆ , δ): 2.12 (s, 3H), 6.78 (s, 1H), 7.03 (d, J = 8.7Hz, 1H), 7.78 (d, J = 8.7Hz, 1H), 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) propyloxy) -8-propylflavone 1/2 sulfate (component 491)

Melting point: 214-217 ° C.

NMR (DMSO and _{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 = 8.7Hz, 1H), 7.20 (s, 1H), 7.79 (d, J = 9.0Hz, 2H), 7.90 (s , 1H), 8.14 (d, J = 9.0 Hz, 1H), 8.85 (br, 1H), 10.69 (br, 1H).

Example 32 : 3 ', 7-dihydroxy-8-propylflavone (Compound 502)

Melting point: 281-282 ° C.

NMR (DMSO and _{d 6, δ): 0.97 (} t, J = 7.5Hz, 3H), 1.64 (m, 2H), 2.88 (t, J = 7.5Hz, 2H), 6.78 (s, 1H), 6.99 ( d, J = 8.7Hz, 1H), 7.38 (t, J = 7.8Hz, 1H), 7.40 (s, 1H), 7.48 (d, J = 7.8Hz, 1H), 7.76 (s, J = 8.7Hz, 1H), 9.88 (s, 1H), 10.59 (s, 1H).

Example 33 : 4 ', 7-dihydroxy-8-propylflavone (Compound 503)

Melting Point:> 300 ℃.

NMR (DMSO and _{d 6, δ): 0.92 (} t, J = 7.5Hz, 3H), 1.59 (m, 2H), 2.83 (t, J = 7.5Hz, 2H), 6.68 (s, 1H), 6.89 and 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-trihydroxy-flavone (Compound 504)

Melting point: 293-294 ° C.

NMR (DMSO and _{d 6, δ): 0.97 (} t, J = 7.2Hz, 3H), 1.63 (m, 2H), 2.87 (t, J = 6.9Hz, 2H), 6.62 (s, 1H), 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), 9.07 (br, 2H), 10.56 (br, 1 H).

Example 35 7-hydroxy-3'-methoxy-8-propylflavone (Compound 507)

Melting point: 232-234 ° C.

NMR (DMSO and _{d 6, δ): 0.97 (} t, J = 7.5Hz, 3H), 1.67 (m, 2H), 2.88 (t, J = 7.5Hz, 2H), 3.87 (s, 3H), 6.95 ( s, 1H), 7.00 (d, J = 8.7Hz, 1H), 7.17 (dd, J = 1.5Hz, 8.4Hz, 1H), 7.48 · 7.55 (m, 2H), 7.66 (d, J = 7.8Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 10.60 (br, 1H).

Example 36 7-hydroxy-3'-methoxy-8-propylflavone (Compound 507)

Melting point: 232-234 ° C.

NMR (DMSO and _{d 6, δ): 0.97 (} t, J = 7.5Hz, 3H), 1.64 (m, 2H), 2.88 (t, J = 7.5Hz, 2H), 6.70 (s, 1H), 6.96 ( d, J = 8.7Hz, 1H), 7.12 (d, J = 8.4Hz, 1H), 7.44 (d, J = 2.1Hz, 1H), 7.52 (dd, J = 2.1Hz, 8.4Hz, 1H), 7.74 Hz (d, J = 8.7 Hz, 1H), 9.50 (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 and _{d 6, δ): 0.77 (} t, J = 7.5Hz, 3H), 1.40 (m, 2H), 2.62 (t, J = 6.9Hz, 2H), 3.72 (s, 3H), 6.72 and 6.76 (m, 2H), 7.35 (d, J = 1.8Hz, 1H), 7.50 (d, J = 9.0Hz, 1H), 7.56 (d, J = 1.8Hz, 1H), 10.17 (br, 1H), 10.39 (br, 1 H).

Example 38 7-hydroxy-2'-isopropoxy-8-propylflavone (Compound 513)

Melting Point: 199-200 ° C.

NMR (DMSO · d ₆ , δ): 0.93 (t, J = 7.5Hz, 3H), 1.33 (d, J = 6.0Hz, 6H), 1.60 (m, 2H), 2.82 (t, 7.5Hz, 2H) , 4.81 (m, 1H), 6.84 (s, 1H), 7.00 (d, J = 8.7Hz, 1H), 7.14 (t, J = 7.8Hz, 1H), 7.26 (d, J = 8.1Hz, 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)

Melting point: 191-192 ° C.

NMR (DMSO and _{d 6, δ): 0.99 (} t, J = 7.5Hz, 3H), 1.64 (m, 2H), 2.21 (s, 3H), 2.87 (t, J = 7.5Hz, 2H), 6.72 ( s, 1H), 6.96 (d, J = 8.7 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 7.79 (s, 1H), 10.23 (s, 1H), 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 = 7.2Hz, 3H), 0.99 (t, J = 7.2Hz, 3H), 1.63 (m, 4H), 2.59 (t, J = 7.5Hz, 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 and _{d 6, δ): 0.94 (} t, J = 7.5Hz, 3H), 1.61 (m, 2H), 2.82 (t, J = 7.5Hz, 2H), 0.68 (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, 1H), 10.59 (s, 1H).

Example 43 3'-Bromo-4 ', 7-dihydroxy-8-propylflavone (Compound 536)

Melting point: 267-270 ° C.

NMR (DMSO and _{d 6, δ): 1.00 (} t, J = 7.5Hz, 3H), 1.64 (m, 2H), 2.89 (t, J = 7.5Hz, 2H), 6.81 (s, 1H), 6.99 ( d, J = 8.7Hz, 1H), 7.18 (d, J = 8.7Hz, 1H), 7.74 (d, J = 8.7Hz, 1H), 7.91 (d, J = 8.7Hz, 1H), 8.15 (s, 1H), 11.17 (s, 1H).

Example 44 7-hydroxy-2'-nitro-8-propylflavone bromo-4 ', 7-dihydroxy-8-propylflavone (Compound 536)

Melting point: 267-270 ° C.

NMR (DMSO and _{d 6, δ): 0.87 (} t, J = 7.5Hz, 3H), 1.43 (m, 2H), 2.51 (t, J = 7.2Hz, 2H), 6.97 (s, 1H), 7.01 ( d, J = 8.7 Hz, 1H), 7.78 占 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 = 7.5Hz, 3H), 1.48 (m, 2H), 2.60 (t, J = 6.9Hz, 2H), 3.98 (s, 3H), 6.66 ( s, 1H), 7.01 (d, J = 8.7Hz, 1H), 7.52 (d, J = 7.5Hz, 1H), 7.61 (d, J = 8.7Hz, 1H), 7.73.7.80 (m, 2H), 10.68 (br, 1 H).

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 = 7.5Hz, 3H), 1.64 (m, 2H), 2.87 (t, J = 7.2Hz, 2H), 4.04 (d, 3H), 7.00 ( s, 1H), 7.59 (d, J = 8.7Hz, 1H), 7.76 (d, J = 9.0Hz, 1H), 8.33 (dd, J = 2.4Hz, 9.0Hz, 1H), 8.53 (s, J = 2.4 Hz, 1 H), 10.62 (s, 1 H).

Example 47 4 ', 7-dihydroxy-3'-nitro-8-propylflavone (Compound 554)

Melting point: 263-264 ° C. (decomposition).

NMR (DMSO · d ₆ , δ): 1.01 (t, J = 7.8Hz, 3H), 1.64 (m, 2H), 2.87 (t, J = 7.8Hz, 2H), 6.90 (s, 1H), 6.99 ( s, J = 8.7Hz, 1H), 7.29 (s, J = 9.0Hz, 1H), 7.75 (d, J = 8.7Hz, 1H), 8.20 (dd, J = 1.8Hz, 9.0Hz, 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 = 7.5Hz, 3H), 1.64 (m, 2H), 2.89 (t, J = 7.5Hz, 2H), 4.07 (s, 3H), 7.02 ( s, J = 9.0 Hz, 1H), 7.19 (s, 1H), 7.75 7.80 (m, 2H), 8.19 (d, J = 8.7 Hz, 1H), 10.67 (br, 1H).

Example 49 7-hydroxy-8-propylflavones (Compound 557)

Melting point: 224-226 ° C.

NMR (DMSO and _{d 6, δ): 0.97 (} t, J = 7.2Hz, 3H), 1.65 (m, 2H), 2.89 (t, J = 6.9Hz, 2H), 6.93 (s, 1H), 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 = 7.5 Hz, 3H), 1.50 (m, 2H), 2.71 (t, J = 7.2 Hz, 2H), 6.14 (s, 1H), 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 = 7.2Hz, 3H), 1.38 (d, J = 6.6Hz, 6H), 1.64 · 1.73 (m, 4H), 4.69 (m, 1H), 6.69 (s, 1H), 6.94 (d, J = 8.4Hz, 1H), 7.06 (d, J = 8.4Hz, 1H), 7.40 (d, J = 1.8Hz, 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 = 8.0Hz, 2H ), 4.07 (t, J = 6.6Hz, 2H), 6.79 (s, 1H), 6.94 (d, J = 8.5Hz, 2H), 7.48 ・ 7.52 (m, 2H), 7.72 (d, J = 8.5Hz , 1H).

Example 54 3'-decanyloxy-4 ', 7-dihydroxy-8-propylflavone (Compound 582)

Shape: Syrup

NMR (DMSO · d ₆ , δ): 0.85 (t, J = 6.9Hz, 3H), 0.98 (t, J = 7.2Hz, 3H), 1.24 · 1.35 (m, 14H), 1.64 (m, 2H), 75 (m, 2H), 2.86 (m, 2H), 4.08 (t, J = 6.6Hz, 2H), 6.83 (s, 1H), 6.95 · 6.98 (m, 2H), 7.507.54 (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 = 7.2Hz, 3H), 1.39 (m, 2H), 1.58 (m, 2H), 2.89 (t, J = 7.2Hz, 2H), 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)

Melting point: 170 ° C.

NMR (DMSO and _{d 6, δ): 2.35 (} s, 3H), 3.89 (s, 3H), 6.83 (s, 1H), 6.94 and 7.00 (m, 2H), 7.55 and 7.57 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 10.57 (s, 1H).

Example 57 4 ', 7-dihydroxy-8-ethyl-3'-methoxyflavone (Compound 681)

Melting point: 255-257 ° C.

NMR (DMSO and ₆ d, δ): 1.22 (t, J = 7.5Hz, 3H), 5.81 (, J = 7.5Hz, 2H), 6.85 (s, 1H), 6.95 and 6.99 (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 (DMSOd 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, 2H), 3.89 ( s, 3H), 6.82 (s, 1H), 6.93 · 6.98 (m, 2H), 7.51 · 7.54 (m, 2H), 7.73 (s, J = 8.4Hz, 1H), 9.85 (s, 1H), 10.51 (s, 1 H).

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 = 6.6Hz, 6H), 1.47 (m, 2H), 1.65 (m, 1H), 2.89 (t, J = 7.5Hz, 2H), 3.89 ( s, 3H), 6.82 (s, 1H), 6.92 · 6.98 (m, 2H), 7.51 · 7.54 (m, 2H), 7.73 (d, J = 8.7Hz, 1H), 9.86 (s, 1H), 10.52 (s, 1 H).

Example 60 8-benzyl-4 ', 7-dihydroxy-3'-methoxyflavone (Compound 712)

Melting point: 281-282 ° C.

NMR (DMSO and _{d 6, δ): 3.78 (} s, 3H), 4.26 (s, 2H), 6.83 (s, 1H), 6.90 (d, J = 8.1Hz, 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) chrome (Compound 764)

Melting point: 250-253 ° C.

NMR (DMSO and _{d 6, δ): 1.87 (} s, 3H), 6.52 (s, 1H), 7.00 (d, J = 8.7Hz, 1H), 7.58 and 7.66 (m, 3H), 7.80 (d, J = 8.7 Hz, 1H), 7.85 (dd, J = 1.2 Hz, 7.5 Hz, 1H), 8.03.8.15 (m, 3H), 10.68 (br, 1H).

Example 62 7-hydroxy-2- (2-hydroxy-1-naphthyl) -8-methylchrome (Compound 766)

Melting point: 250-253 ° C.

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).

Example 63 7-hydroxy-2- (3-hydroxy-2-naphthyl) -8-methylchrome (Compound 767)

Melting Point:> 300 ℃.

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,

Example 64 7-hydroxy-8-propyl-2- (2-pyridyl) chrome 1/2 sulfate (Compound 785)

Melting point: 213-217 ° C.

NMR (DMSO · d ₆ , δ): 0.98 (t, J = 7.5Hz, 3H), 1.66 (m, 2H), 2.92 (t, J = 7.5Hz, 2H), 7.02 (d, J = 8.7Hz, 1H), 7.10 (s, 1H), 7.63 (m, 1H), 7.80 (d, J = 8.7 Hz, 1H), 8.09, 8.14 (m, 2H), 8.78 (d, J = 4.8 Hz, 1H), 10.70 (s, 1 H).

Example 65 7-hydroxy-8-propyl-2- (3-pyridyl) chrome methanesulfonate (Compound 786)

Melting point: 278-279 ° C.

NMR (DMSO and _{d 6, δ): 0.97 (} t, J = 7.5Hz, 3H), 1.64 (m, 2H), 2.89 (t, J = 8.1Hz, 2H), 6.98 and 7.06 (m, 2H), 7.65 (m, 1H), 7.78 (d, J = 9.0Hz, 1H), 8.42 (m, 1H), 8.77 (m, 1H), 9.23 (d, J = 2.1Hz, 1H), 10.68 (br, 1H ).

Example 66 7-hydroxy-2- (2-methoxy-5-pyridyl) -8-propylchrome 1/2 sulfate (Compound 787)

Melting point: 173-176 ° C.

NMR (DMSO and _{d 6, δ): 0.96 (} t, J = 7.5Hz, 3H), 1.63 (m, 2H), 2.87 (t, J = 7.2Hz, 2H), 3.96 (s, 3H), 6.72 ( s, 1H), 6.91.7.06 (m, 2H), 7.76 (d, J = 8.7Hz, 1H), 8.32 (dd, J = 2.4Hz, 8.7Hz, 1H), 8.86 (d, J = 2.4Hz, 1H), 10.63 (br, 1H).

Example 67 7-hydroxy-8-propyl-2- (4-pyridyl) chrome-methanesulfonate (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, 3H), 7.05 ( s, 1H), 7.30 (d, J = 8.7Hz, 1H), 7.80 (d, J = 8.7Hz, 1H), 8.24 (dd, J = 1.2Hz, 6.3Hz, 2H), 8.97 (dd, J = 1.2 Hz, 6.6 Hz, 2H), 10.81 (br, 1H).

Example 68 : 2- (2-, 4-dimethyl-5-pyrimidyl) -7-hydroxy-8-propylchrome (Compound 794)

Melting point: 179-182 ° C.

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, 1H), 7.81 (d, J = 8.7 Hz, 1H), 8.87 (s, 1H), 10.70 (s, 1H).

Example 69 7-hydroxy-8-propyl-2- (2-pyrazyl) chrome methanesulfonate (Compound 795)

Melting point: 275-278 ° C.

NMR (DMSOd ₆ , δ): 0.98 (t, J = 7.5 Hz, 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-quinoyl) chrome 1/2 sulfate (Compound 802)

Melting point: 242-245 ° C.

NMR (DMSO · d ₆ , δ): 1.02 (t, J = 7.2Hz, 3H), 1.71 (m, 2H), 2.97 (m, 2H), 7.05 (d, J = 8.7Hz, 1H), 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 = 9.0Hz, 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) chrome (Compound 814)

Melting Point:> 300 ℃.

NMR (DMSO and _{d 6, δ): 0.91 (} t, J = 7.5Hz, 3H), 0.96 (t, J = 7.2Hz, 3H), 1.60 (m, 2H), 1.72 (m, 2H), 2.86 ( t, J = 7.2 Hz, 2H), 4.42 (t, J = 7.2Hz, 2H), 6.57 (d, J = 9.6Hz, 1H), 6.74 (s, 1H), 6.97 (d, J = 8.7Hz, 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-propylchrome (Compound 815)

Melting point: 290-293 ° C.

NMR (DMSO-d ₆ , δ): 0.98 (t, J = 7.5Hz, 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 = 7.8Hz, 2H), 4.05 (t, J = 6.9Hz, 2H), 6.56 (d, J = 9.3Hz, 1H), 6.73 (s, 1H), 6.97 ( d, J = 8.4Hz, 1H), 7.73 (d, J = 8.4Hz, 1H), 8.01 (dd, J = 2.4Hz, 9.3Hz, 1H), 8.45 (d, J = 2.4Hz, 1H), 10.61 (br, 1H).

Example 73 : 3'-methoxy-8-propyl-4 ', 5,7-trihydroxyflavone (component 832)

NMR (DMSO and _{d 6, δ): 0.95 (} t, J = 7.2Hz, 3H), 1.58 (m, 2H), 2.75 (t, J = 6.9Hz, 2H), 3.89 (s, 3H), 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 Activity of the Medicine of the Present Invention on P-GS1 Phosphorylation by Cerebellum TPK1

100 mM MES-Sodium Hydroxide (pH 6.5), 1 mM Magnesium Acetate, 0.5 mM EGTA, 5 mM β-mercaptoethanol, 0.02% Tween 20, 10% Glycerol, 12 μg / ml P-GS1, 41.7 μM [γ 32 P Use as a reaction system a compound containing ATP (68 kBq / ml), cerebellar TPK1 and a compound listed in the table (final mixture containing 1.7% DMSO liberated from a solution of test compound prepared in the presence of 10% DMSO) It became. Phosphorylation was initiated by the addition of ATP and the reaction was carried out at 25 ° C. for 2 hours and then stopped by adding 21% perchloric acid on an ice refrigerant. The reaction mixture was centrifuged at 12,000 rpm for 5 minutes, absorbed into P81 paper (Whatman), the paper washed four times with 75 mM phosphoric acid, three times with water, and once with acetone. Once the paper dries, the residual radioactivity is measured using a liquid scintillation counter and the results are shown in the table below. The test compound significantly inhibited P-GS1 phosphorylation by TPK1. These results strongly suggest that the medicament of the present invention inhibits TPK1 activity, inhibits Aβ neurotoxicity and PHF formation, and is effective as a prophylactic and / or therapeutic agent for Alzheimer's disease and electrical disease.

Table 9

Example (Compound No.) Inhibition Rate at 10 μM (%)

1 (455) 98.4

2 (682) 89.7

4 (45) 79.4

6 (55) 88.1

7 (58) 82.9

12 (148) 89.9

13 (158) 85.7

14 (161) 88.5

15 (162) 84.8

16 (264) 97.4

17 (310) 93.3

18 (342) 81.1

19 (343) 98.2

20 (347) 73.1

21 (351) 85.3

23 (365) 75.4

25 (386) 84.7

27 (389) 79.3

28 (391) 72.4

29 (392) 87.1

30 (393) 77.1

31 (491) 88.9

32 (502) 76.4

33 (503) 95.6

34 (504) 86.8

37 (512) 77.7

39 (521) 89.0

40 (523) 91.0

47 (554) 87.1

51 (560) 95.8

52 (561) 94.0

55 (593) 84.6

56 (680) 90.4

57 (681) 85.8

58 (684) 96.2

59 (690) 93.5

64 (785) 81.2

65 (786) 74.8

67 (788) 74.9

68 (794) 71.5

72 (815) 78.2

Formulation Example

(1) tablets

The following components were mixed in a conventional manner and compressed by conventional means.

30 mg of the compound of Example 2

Crystalline cellulose 60 mg

Corn starch 100 mg

Lactose 200 mg

Magnesium Stearate 4 mg

(2) soft capsule

The following ingredients were mixed in a conventional manner and filled into soft capsules.

30 mg of the compound of Example 2

300 mg olive oil

Lecithin 20 mg

(3) parenteral manufacture

The following components were mixed in a conventional manner to prepare injections contained in 1 ml of ampoules.

0.1 mg of compound of Example 1

Sodium chloride 4 mg

1 ml of distilled water for injection

Industrial availability

The medicine of the present invention has a TPK1 inhibitory activity and is useful as a prophylactic and / or therapeutic agent for diseases caused by TPK1 overactivity such as Alzheimer's disease.

Claims (14)

A disease or nerve caused by tau protein kinase 1 hyperactivity, comprising a substance selected from the group consisting of hydroxyflavone derivatives, salts, solvates, and hydrates thereof disclosed in Formula (I) Medications for the prevention and / or treatment of degenerative diseases: Where R ¹ is hydrogen or a hydroxy group; R ² is hydrogen or C ₁ -C ₁₈ which may have one or more C ₆ -C ₁₄ aryl groups An alkyl group; And, Ar is a C ₆ -C ₁₄ aryl group which may be substituted or an aromatic heterocycle which may be substituted Clicker. A medicament for the prevention and / or treatment of neurodegenerative diseases, comprising as an active ingredient a substance selected from the group consisting of a hydroxyflavone derivative of formula (I), a salt, a solvate, and a hydrate of claim 1. The method of claim 2, Diseases include Alzheimer's disease, ischemic cerebrovascular disease, Down's syndrome, brain amyloid blood vessels Cerebral hemorrhage caused by pathology, progressive pronuclear paralysis palsy), subacute encephalitis encephalitis Parkin's disease panencephalitic parkinsonism, postencephalitic parkinsonism, pulgilistic encephalitis, Guam Parkin's disease Guam parkinsonism-dementia complex, Louis body Lewy body disease, Pick's disease, cerebral cortex Corticobasal degeneration, frontotemporal dementia) selected from the group consisting of medicine. A tau protein kinase 1 inhibitor selected from the group consisting of hydroxy flavone derivatives of formula (I) as described in claim 1, salts, solvates, and hydrates thereof. Hydroxy flavone derivatives, salts, solvates, or hydrates thereof disclosed in Formula (I) Where R ¹ is hydrogen or a hydroxy group; R ² is hydrogen or C ₁ -C ₁₈ which may have one or more C ₆ -C ₁₄ aryl groups An alkyl group; And, Ar is a C ₆ -C ₁₄ aryl group which may be substituted, or an aromatic hetero yarn which may be substituted Is an cyclic group, provided that when R ² is hydrogen, Ar is represented by the following general formula (II) To be { Where R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are each hydrogen, a substituted C ₁ -C ₁₈ alkyl group, a substituted C ₁ -C ₁₈ alkoxy group, a hydroxyl group, a substituted group An acyloxy group, a carboxy group, an alkoxycarbonyl group which may be substituted, a carbamoyl group which may be substituted, an alkylcarbonyl group which may be substituted, an amino group which may be substituted, a nitro group, or a cyano group, provided that R ³ , One of R ⁴ , R ⁵ , R ⁶ , and R ⁷ is represented by the general formula (III): -X- (CH ₂ ) _m -R ⁸ (wherein R ⁸ comprises an amino group which may be substituted, or nitrogen; A saturated heterocyclic group which may be substituted, X is a single bond or oxygen, m is an integer from 1 to 8), and A compound in which R ¹ is hydrogen, R ² is a methyl group, and Ar is a phenyl group, 3,4-methylenedioxyphenyl group, or 3-pyridyl group; R ¹ is hydrogen, R ² is a propyl group, and Ar is a phenyl group having a carboxy group or ester group at position 4; And compounds in which R ¹ is a hydroxy group, R ² is a methyl group and Ar is a phenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, or 3,4-dimethoxyphenyl group] are excluded. Hydroxyflavone derivatives, salts, solvates, or hydrates thereof disclosed in Formula IV below: Where R ¹ is hydrogen or a hydroxy group; Z contains an amino group which may be substituted, or nitrogen, and is saturated Heterocyclic group; n is an integer from 1 to 8; R ⁵ is hydrogen or a C ₁ -C ₁₅ alkoxy group; And, R ⁶ is hydrogen or a hydroxy group. The method of claim 6, n is 2 or 3 Hydroxyflavone derivatives, salts, solvates or hydrates thereof. The method of claim 6, R ⁵ is hydrogen or a methoxy group Hydroxyflavone derivatives, salts, solvates, or hydrates thereof. The method of claim 6, Z is a dimethylamino group, a piperazinyl group which may be substituted, or may be substituted Characterized by the piperidinyl group Hydroxyflavone derivatives, salts, solvates, or hydrates thereof. Hydroxy flavone derivatives, salts, solvates, or hydrates thereof disclosed in Formula (V): Where R ² is hydrogen or a C ₁ -C ₁₈ alkyl group having at least one C ₆ -C ₁₄ aryl group; R ⁴ is a C ₁ -C ₁₈ alkyl group which may be substituted, a C ₁ -C ₁₈ alkoxy group which may be substituted, Doxy group, acyloxy group which may be substituted, carboxy group, which may be substituted Alkoxycarbonyl Group, Substituted Carbamoyl Group, Substituted Al A chelcarbonyl group, a substituted amino group, a nitro group, or a cyano group ; And, R ⁵ is hydrogen, a hydroxy group, a methoxy group, or a nitro group. The method of claim 10, R ⁴ is a C ₁ -C ₁₈ alkyl group which may be substituted, a C ₁ -C ₁₈ alkoxy group which may be substituted, a hydroxyl group, a nitro group, or a cyano group, characterized in that Hydroxyflavone derivatives, salts, solvates, or hydrates thereof. Hydroxyflavone derivatives or salts, solvates or hydrates thereof disclosed in general formula (I) Where R ¹ is hydrogen or a hydroxy group; R ² is hydrogen or a C ₁ -C ₁₈ alkyl group having at least one C ₆ -C ₁₄ aryl group; And, Ar is an aromatic heterocyclic group which may be substituted (However, compounds in which R ¹ is hydrogen, R ² is methyl group and Ar is pyridyl group are excluded). 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 Hydroxyflavone derivatives selected from the group consisting of 7-hydroxy-8-propyl-2- (4-pyridyl) chrome, salts, solvates, or hydrates thereof. A medicament comprising a substance selected from the group consisting of the hydroxyflavone derivatives described in any one of claims 5 to 13, salts, solvates and hydrates thereof.