WO2000017184A1 - Hydroxyflavone derivatives as tau protein kinase 1 inhibitors - Google Patents

Hydroxyflavone derivatives as tau protein kinase 1 inhibitors

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Publication number
WO2000017184A1
WO2000017184A1 PCT/JP1999/005223 JP9905223W WO0017184A1 WO 2000017184 A1 WO2000017184 A1 WO 2000017184A1 JP 9905223 W JP9905223 W JP 9905223W WO 0017184 A1 WO0017184 A1 WO 0017184A1
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Prior art keywords
group
substituted
hydrogen atom
solvate
hydrate
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PCT/JP1999/005223
Other languages
French (fr)
Inventor
Aya Shoda
Kazutoshi Watanabe
Keiichi Aritomo
Tetsuo Jikihara
Ryoichi Ando
Ken-Ichi Saito
Toshiyuki Honda
Rie Kawamoto
Original Assignee
Mitsubishi Chemical Corporation
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Application filed by Mitsubishi Chemical Corporation filed Critical Mitsubishi Chemical Corporation
Priority to KR1020017003819A priority Critical patent/KR20010079922A/en
Priority to JP2000574094A priority patent/JP2002526488A/en
Priority to AU57598/99A priority patent/AU5759899A/en
Priority to CA002345311A priority patent/CA2345311A1/en
Priority to EP99944814A priority patent/EP1115718A1/en
Publication of WO2000017184A1 publication Critical patent/WO2000017184A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Examples of the CrCis alkyl group having a C ⁇ -Ci4 aryl group represented by R 2 include, for example, the aforementioned CrCis alkyl groups which are substituted with phenyl group, naphthyl group, anthryl group or the like. More specifically, examples include benzyl group, 1-naphtylmethyl group, 2-naphtylmethyl group, 1-phenetyl group, 2-phenetyl group, 3-phenylpropyl group, 4-phenylbutyl group and the like.
  • Examples of the C ⁇ -Ci4 aryl group represented by Ar include, for example, phenyl group, 1 -naphthyl group, 2-naphthyl group, anthryl group and the like.
  • the number of nitrogen atoms contained in the nitrogen-containing saturated heterocyclic group represented by R 8 is not particularly limited, and the group may contain one or more heteroatom s other than nitrogen (e.g. , oxygen atom, sulfur atom etc.).
  • the nitrogen-containing saturated heterocyclic group may be substituted at any position on the ring. More specifically, examples include residues of pyrrolidine ring, piperidine ring, piperazine ring, homopiperidine ring, homopiperazine ring, morpholine ring, thiomorpholine ring and the like.
  • the nitrogen-containing saturated heterocyclic group may be substituted with one or more substituents selected from the substituent group A.
  • R 2 is hydrogen atom or a Ci - Ci ⁇ alkyl group
  • hydroxyflavone derivatives represented by the aforementioned formula (I) can be prepared by a method described in the literature. For example, they can be prepared as follows.
  • the organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated and dried under reduced pressure .
  • the resulting re sidue was dissolved in 40 ml of acetic acid, and the solution was added with 0.2 ml of concentrated sulfuric acid and stirred at 100°C for 2 hours.
  • the reaction mixture was added with 10 ml of water and further stirred for 2 hours.
  • the reaction mixture was cooled to room temperature, and the deposited solid was separated by filtration and washed with ethyl acetate to obtain 1.47 g of the desired compound. Yield: 87%.
  • Example 14 5.7-Dihydroxy-3'-(3-(l-piperidyl)propyloxy)flavone l/2sulfate (Compound 161) Melting point: 184-186°C.
  • Example 53 3' Butoxy4',7-dihydroxy8-propylflavone (Compound 563) Melting point: 215-217°C .
  • Example 57 4',7-Dihydroxy8-ethyl-3'-methoxyflavone (Compound 681) Melting point: 255"257°C.
  • Example 58 8 Butyl-4',7-dihydroxy 3'-methoxyflavone (Compound 684) Melting point: 228-231°C.
  • Example 59 4 ⁇ 7-Dihydroxy8-isopentyl-3'-methoxyflavone (Compound 690) Melting point: 225-227°C.
  • the phosphorylation was started by adding ATP, and the reaction was conducted at 25°C for 2 hours, and then stopped by adding 21% perchloric acid on ice cooling.
  • the reaction mixture was centrifuged at 12.000 rpm for 5 minutes and adsorbed on P81 paper (Whatmann), and then the paper was washed four times with 75 mM phosphoric acid, three times with water and once with acetone .
  • the paper wa s dried, and the residual radioactivity was measured using a liquid scintillation counter. The results are shown in the table below.
  • the test compound markedly inhibited the P-GSl phosphorylation by TPKl .

Abstract

A medicament for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity or a neurodegenerative disease which comprises as an active ingredient a substance selected from the group consisting of a hydroxyflavone derivative represented by formula (I) and a salt thereof, and a solvate thereof and a hydrate thereof, wherein R1 represents hydrogen atom or hydroxyl group; R2 represents hydrogen atom or a C¿1?-C18 alkyl group which may have one or more C6-C14 aryl groups; and Ar represents a C6-C14 aryl group which may be substituted or an aromatic heterocyclic group which may be substituted.

Description

SPECIFICATION
HYDROXYFLAVONE DERIVATIVES AS TAU PROTEIN KINASE 1 INHIBITORS
Technical Field
The present invention relates to compounds that are useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of diseases caused by tau protein kinase 1 hyperactivity, such as Alzheimer disease and the like. The present invention also relates to novel hydroxyflavone derivatives useful as an active ingredient of the aforementioned medicament.
Background Art
Alzheimer disease is progressive senile dementia, in which marked cerebral cortical atrophy is observed due to degeneration of nerve cells and decrease of nerve cell number. Pathologically, numerous senile plaques and neurofibrillary tangles are observed in brain. The number of patients has been increased with the increment of aged population, and the disease arises a serious social problem. Although various theories have been proposed, a cause of the disease has not yet been elucidated. Early resolution of the cause has been desired.
It has been known that the degree of appearance of two characteristic pathological changes of Alzheimer disease well correlates to the degree of intellectual dysfunction. Therefore, researches have been conducted from early 1980 s to reveal the cause of the disease through molecular level investigations of components of the two pathological changes. Senile plaques accumulate extracellularly. and amyloid β protein has been elucidated as their main component (abbreviated a s "A ? " hereinafter in the specification : Biochem. Biophys. Res. Commun.. 120, 855 (1984) ; EMBO J., 4, 2757 ( 1985) ; Proc . Natl. Acad. Sci. USA, 82. 4245 ( 1985)). In the other pathological change, i.e ., the neurofibrillary tangles, a double-helical filamentous substance called paired helical filament (abbreviated as "PHF" hereinafter in the specification) accumulate intracellularly, and tau protein, which is a kind of microtubule-associated protein specific for brain, has been revealed as its main component (Proc. Natl. Acad. Sci. USA, 85, 4506 (1988) ; Neuron, 1, 827 (1988)).
Furthermore, on the basis of genetic investigations, presenilins 1 and 2 were found a s causative genes of familial Alzheimer disease (Nature , 375, 754 (1995); Science, 269, 973 ( 1995) ; Nature. 376, 775 (1995)), and it has been revealed that presence of mutants of presenilins 1 and 2 promotes the secretion of A 3 (Neuron, 17, 1005 (1996); Proc. Natl. Acad. Sci. USA, 94, 2025 (1997)) . From these results, it is considered that, in Alzheimer disease, A 3 abnormally accumulates and agglomerates due to a certain reason, which engages with the formation of PHF to cause death of nerve cells. It is also expected that extracellular outflow of glutamic acid and activation of glutamate receptor responding to the outflow may possibly be important factors in an early process of the nerve cell death caused by ischemic cerebrovascular accidents (Sai- shin Igaku [Latest Medicine] , 49, 1506 (1994)).
It has been reported that kainic acid treatment that stimulates the AMPA receptor, one of glutamate receptor, increase s mRNA of the amyloid precursor protein (abbreviated a s "APP" hereinafter in the specification) as a precursor of A/3 (Society for Neuroscience Abstracts. 17, 1445 ( 1991)), and also promotes metabolism of APP (The Journal of Neuroscience, 10, 2400 (1990)) Therefore it has been strongly suggested that the accumulation of A 3 is involved in cellular death due to ischemic cerebrovascular disorders Other diseases in which abnormal accumulation and agglomeration of A 3 are observed include, for example, Down syndrome cerebral bleeding due to cerebral amyloid angiopathy Lewy body disease (Shin-kei Shinpo [Nerve Advance], 34 343 (1990). Tanpaku-shitu Kaku-san Koso [Protein Nucleic Acid, Enzyme] , 41, 1476 (1996)) and the like Furthermore, as diseases showing neurofibrillary tangles due to the PHF accumulation, examples include progressive supranuclear palsy, subacute sclerosing panencephahtic parkmsomsm, postencepha tic parkinsomsm, pugilistic encephalitis, Guam parkinsomsm-dementia complex, Lewy body disease and the like (Tanpakushitu Kakusan Koso [Protein, Nucleic Acid Enzyme], 36 2 (1991), Igaku no Ayumi [Progress of Medicine], 158, 511 (1991), Tanpakushitu Kakusan Koso [Protein, Nucleic Acid, Enzyme], 41, 1476 (1996))
The tau protein is generally composed of a group of related proteins that forms several bands at molecular weights of 48*65 kDa in SDS-polyacrylamide gel electrophoresis, and it promotes the formation of microtubules It has been verified that tau protein incorporated in the PHF in the brain suffering from Alzheimer disease is abnormally phosphorylated compared with usual tau protein (J Biochem , 99, 1807 (1986), Proc Natl Acad Sci USA, 83, 4913 (1986)) An enzyme catalyzing the abnormal phosphorylation has been isolated The protein was named as tau protein kinase 1 (abbreviated as "TPK1" hereinafter in the specification), and its physicochemical properties have been elucidated (Seikagaku [Biochemistry], 64, 308 (1992), J Biol Chem 267, 10897 (1992)) Moreover, cDNA of rat TPKl was cloned from a rat cerebral cortex cDNA library based on a partial ammo acid sequence of TPKl and its nucleotide sequence was determined and an amino acid sequence was deduced (Japanese Patent Un-examined Publication [Kokai] No. 6 239893/1994). As a result, it has been revealed that the primary structure of the rat TPKl corresponds to that of the enzyme known as rat GSK-3 β (glycogen synthase kinase 3 /3 , FEBS Lett., 325, 167 (1993)).
It has been reported that A/3 , the main component of senile plaques, is neurotoxic (Science, 250. 279 (1990)). However, various theories have been proposed as for the reason why A/3 causes the cell death, and any authentic theory has not yet been established. Takashima et al. observed that the cell death was caused by A/3 treatment of fetal rat hippocampus primary culture system, and then found that the TPKl activity was increased by A /3 treatment and the cell death by A /3 was inhibited by antisense of TPKl (Proc. Natl. Acad. Sci. USA, 90, 7789 (1993); Japanese Patent Un-examined Publication [Kokai] No. 6-329551/1994).
In view of the foregoing, compounds, which inhibit the TPKl activity may possibly suppress the neurotoxicity of A/3 and the formation of PHF and inhibit the nerve cell death in the Alzheimer disease, thereby cease or defer the progress of the disease. The compounds may also be possibly used as a medicament for therapeutic treatment of ischemic cerebrovascular disorder, Down syndrome, cerebral amyloid angiopathy, cerebral bleeding due to Lewy body disease and the like by suppressing the cytotoxicity of A/3 . Furthermore, the compounds may possibly be used as a medicament for therapeutic treatment of neurodegenerative diseases such as progressive supranuclear palsy, subacute sclerosing panencephahtic parkinsonism, postencephahtic parkinsonism, pugilistic encephalitis, Guam parkinsonism-dementia complex, Lewy body disease, Pick's disease, corticobasal degeneration and frontotemporal dementia. Disclosure of the Invention
An object of the present invention is to provide compounds useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of diseases such as Alzheimer disease and the like. More specifically, the object is to provide novel compounds useful as an active ingredient of a medicament that enables radical prevention and/or treatment of the diseases such as Alzheimer disease by inhibiting the TPKl activity to suppress the neurotoxicity of A /3 and the formation of the PHF and by inhibiting the drop of nerve cells. Another object of the present invention is to provide novel compounds useful as an active ingredient of the medicament haveing the aforementioned features.
In order to achieve the foregoing object, the inventors of the present invention conducted screenings of various compounds having inhibitory activity against the phosphorylation of TPKl . As a result, they found that compounds represented by the following formula (I) had the desired activity and were useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of the aforementioned diseases. The present invention was achieved on the basis of these findings.
The present invention thus provides a medicament for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity or a neurodegenerative disease which comprises as an active ingredient a substance selected from the group consisting of a hydroxyflavone derivative represented by formula (I):
Figure imgf000008_0001
wherein R1 represents hydrogen atom or hydroxyl group, R2 represents hydrogen atom or a CrCiβ alkyl group which may have a Cβ Ci4 aryl group, and Ar represents a Cβ'Cu aryl group which may be substituted or an aromatic heterocyclic group which may be substituted and a salt thereof, and a solvate thereof and a hydrate thereof
According to a preferred embodiment of the present invention, there is provided the aforementioned medicament wherein the diseases are selected from the group consisting of Alzheimer disease ischemic cerebrovascular accidents, Down syndrome, cerebral bleeding due to cerebral amyloid angiopathy, progressive supranuclear palsy, subacute sclerosing panencephahtic parkinsonism, postencephahtic parkinsonism, pugilistic encephalitis, Guam parkmsonism-dementia complex, Lewy body disease, Pick's disease corticobasal degeneration and frontotemporal dementia. Also as a preferred embodiment, the aforementioned medicament in the form of pharmaceutical composition containing the above substance as an active ingredient together with one or more pharmaceutical additives The present invention further provides an inhibitor of tau protein kinase 1 selected from the group of the hydroxyflavone derivatives of formula (I) and the salts thereof and the solvates thereof and the hydrates thereof
According to further aspects of the present invention, there are provided a method for preventive and/or therapeutic treatment of diseases caused by tau protein kinase 1 hyperactivity which comprises the step of administering to a patient a preventively and/or therapeutically effective amount of a substance selected from the group consisting of the hydroxyflavone derivatives of formula (I) and the physiologically acceptable salts thereof, and the solvates thereof and the hydrates thereof; and a use of a substance selected from the group consisting of the hydroxyflavone derivatives of formula (I) and the physiologically acceptable salts thereof, and the solvates thereof and the hydrates thereof for the manufacture of the aforementioned medicament.
According to still further aspect of the preset invention, there is provided a hydroxyflavone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof:
Figure imgf000009_0001
wherein R1 represents hydrogen atom or hydroxyl group; R2 represents hydrogen atom or a CrCiβ alkyl group which may have a Ce-Ci . aryl group; and Ar represents a C6- C14 aryl group which may be substituted or an aromatic heterocyclic group which may be substituted, and where R2 is hydrogen atom, Ar represents a group represented by formula (II)
Figure imgf000009_0002
wherein R3, R4, R5, R6, and R7, independently represent hydrogen atom, a CrCiβ alkyl group which may be substituted, a CrCiβ alkoxyl group which may be substituted, hydroxyl group, an acyloxy group which may be substituted, carboxyl 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, nitro group, or a cyano group, provided that any one of R3, R4, R5, R6, and R7 represents a group represented by formula (III): -X-(CH2)m R8 wherein R8 represents an amino group which may be substituted or a nitrogen-containing saturated heterocyclic group which may be substituted, X represents single bond or oxygen atom, and m is an integer of from 1 to 8; and provided that those wherein R1 is hydrogen atom, R2 is methyl group, and Ar is phenyl group, a 3,4-methylenedioxyphenyl group, or a 3-pyridyl group, those wherein R1 is hydrogen atom, R2 is propyl group, and Ar is phenyl group having a carboxyl group or an ester group in the 4-position, and those wherein R1 is hydroxyl group, R2 is methyl group, and Ar is phenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, or 3, 4-dimethoxyphenyl group are excluded.
According to preferred embodiments of the aforementioned invention, there are provided: a hydroxyflavone derivative represented by formula (IV) or a salt thereof, or a solvate thereof or a hydrate thereof:
Figure imgf000011_0001
wherein R1 repre sents hydrogen atom or hydroxyl group; Z represents an amino group which may be substituted or a nitrogen-containing saturated heterocyclic group which may be substituted; n represents an integer of from 1 to 8; R5 repre sents hydrogen atom, a C1 -C15 alkoxyl group; and R6 represents hydrogen atom or hydroxyl group; a hydroxyflavone derivative represented by formula (V) or a salt thereof, or a solvate thereof or a hydrate thereof:
Figure imgf000011_0002
wherein R2 represents hydrogen atom or a CrCis alkyl group which may have one or more Cβ- C aryl groups; R4 represents a CrCis alkyl group which may be substituted, a CrCis alkoxyl group which may be substituted, hydroxyl group, an acyloxy group which may be substituted, carboxyl 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, nitro group, or a cyano group; and R5 represents hydrogen atom , hydroxyl group, methoxy group , or nitro group ; and a hydroxyflavone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof:
Figure imgf000012_0001
wherein R1 represents hydrogen atom or hydroxyl group; R2 represents hydrogen atom or a CrCis alkyl group which may have one or more CΘ- C aryl groups; and Ar represents an aromatic heterocyclic group which may be substituted, provided that those wherein R1 is hydrogen atom; R2 is methyl group, and Ar is a pyridyl group are excluded.
Indian J. Chem. Sect. B, Org. Chem. Incl. Med. Chem., 35B, 1253 (1996) discloses compounds of the aforementioned formula (I) wherein R1 is hydrogen atom, R2 is allyl group, and Ar is phenyl group, 4-tolyl group, or 4-chlorophenyl group; Indian J. Chem. Sect. B. 30B. 93 (1991) discloses compounds of the aforementioned formula (I) wherein R1 is hydrogen atom, R2 is l phenyl-2-propenyl group, or I phenyM-propenyl group, and Ar is phenyl group; Indian J. Chem. Sect. B, 26B, 229 (1991), J. Indian Chem. Soc, 60, 411 (1983), and Indian J. Indian Chem. Soc, 49, 283 (1972) disclose compounds of the aforementioned formula (I) wherein R1 is hydrogen atom, R2 is methyl group, and Ar is phenyl group; Indian J. Chem. Sect. B, 19B, 866 (1980) discloses compounds of the aforementioned formula (I) wherein R1 is hydrogen atom, R2 is l, 2-dimethyl-2-propenyl group, and Ar is phenyl group; and Ann. Pharm. France, 18, 528 (i960), discloses compounds of the aforementioned formula (I) wherein R1 is hydrogen atom, R2 is methyl group, and Ar is 3,4-methylenedioxyphenyl group.
Phytochemistry, 19. 2179 (1980) discloses compounds of the aforementioned formula (I) wherein R1 is hydrogen atom, R2 is 3-methyl-2-butenyl group, and Ar is 4-hydroxyphenyl group; Indian J. Chem. Sect. B, 18B, 525 (1979) discloses compounds of the aforementioned formula (I) wherein R1 is hydrogen atom, R2 is allyl group, and Ar is a phenyl group having methoxy group at 2-, 3- or 4-position; Indian J. Chem. Sect. B, 15B, 933 (1977) and Tetrahedron Lett., 1977, 473 (1977) disclose compounds of the aforementioned formula (I) wherein R1 is hydrogen atom, R2 is allyl group, and Ar is phenyl group; and Bull. Soc. Chim. FR1960. 95(1960) discloses compounds of the aforementioned formula (I) wherein R1 is hydrogen atom, R2 is methyl group, and Ar is 3-pyridyl group.
J. Indian Chem. Soc, 65, 149 (1988) and Indian J. Chem. Sect. B, 20B, 624 (1981) disclose compounds of the aforementioned formula (I) wherein R1 is hydroxyl group, R2 is methyl group, and Ar is 3,4-methylenedioxyphenyl group; Tetrahedron, 31, 265 (1975) discloses compounds of the aforementioned formula (I) wherein R1 is hydroxyl group, R2 is methyl group, and Ar is phenyl group; Indian J. Chem., 4, 481 (1966) discloses compounds of the aforementioned formula (I) wherein R1 is hydroxyl group, R2 is methyl group, and Ar is 4-methoxyphenyl group; and Phytochemistry, 22, 2107 (1983) discloses compounds of the aforementioned formula (I) wherein R1 is hydroxyl group, R2 is methyl group, and Ar is 4-hydroxyphenyl group.
Furthermore, U.S. Patent No. 4,042, 708 and German Patent No. 2,454,670 disclose compounds of the aforementioned formula (I) wherein R1 is hydroxyl group, R2 is propyl group, and Ar is a phenyl group having 4-carboxyl group or 4-ethoxycarbonyl group as synthetic intermediates for preparation of compounds having anti-SRS activity, and Japanese Patent Un-examined Publication [Kokai] No. 8-225563/1996) discloses that compounds of the aforementioned formula (I) wherein R1 is hydroxyl group, R2 is propyl group, and Ar is 3-hydroxy4-methylphenyl group are useful for treatment of chronic venous insufficiency. However, it has not hitherto been known at all that these compounds have inhibitory activity against TPKl.
Best Mode for Carrying Out the Invention
The "alkyl group" or an alkyl portion of a functional group containing the alkyl portion (alkoxyl group, for example) used herein may be either linear, cyclic or branched. The alkyl group represented by R2 may be, for example, methyl group, 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 a linear or branched heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, octadecyl group or the like.
Examples of the CrCis alkyl group having a Cβ-Ci4 aryl group represented by R2 include, for example, the aforementioned CrCis alkyl groups which are substituted with phenyl group, naphthyl group, anthryl group or the like. More specifically, examples include benzyl group, 1-naphtylmethyl group, 2-naphtylmethyl group, 1-phenetyl group, 2-phenetyl group, 3-phenylpropyl group, 4-phenylbutyl group and the like. Examples of the Cβ-Ci4 aryl group represented by Ar include, for example, phenyl group, 1 -naphthyl group, 2-naphthyl group, anthryl group and the like.
In the specification, when a functional group is defined as "which may be substituted" or "optionally substituted", the number of substituents as well as their types and substituting positions are not particularly limited, and 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 may have one or more substituents selected form the group consisting of a CrCis alkyl group such as those explained above as for R2; a CrCs alkoxyl group such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group , isobutoxy group, tert-butoxy group , n-pentyloxy group, isopentyloxy group, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, and cyclooctyloxy group; a Ci -Cβ alkylthio group such as methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, tert-butylthio group, pentylthio group; methylenedioxy group; a Cβ-Cio aryl group such as phenyl group, 1 -naphthyl group, and 2-naphthyl group ; fluorenyl group ; a Cθ-Ci4 aryloxy group such as phenoxy group, and naphthoxy group; a Cβ-Ci4 arylthio group such as phenylthio group, and naphthylthio group ! a C1 C5 alkylsulfonyl group such as methanesulfonyl group , ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group ; a Cβ-C arylsulfonyl group such as phenylsulfonyl group, and naphthylsulfonyl group ; a halogen atom (the term "halogen atom" or "halogen" used herein encompasses any one of fluorine atom, chlorine atom, bromine atom, and iodine atom); a CrCis halogenated alkyl group such as trifluoromethyl group ; hydroxyl group ; nitro group ; oxo group; formyl group ; cyano group ; carboxyl group; a C2-C6 alkyloxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, and pentyloxycarbonyl group; a C2-C6 alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group ; a C2-C6 alkylcarbonyloxy group such as acetoxy group, propionyloxy group, butyryloxy group , and valeryloxy group ; a Cβ- C arylcarbonyloxy group such as benzoyloxy group, and naphthoyloxy group ; amino group; a CrCs monoalkylamino group such as methylamino group, ethylamino group, propylamino group , isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and isopentylamino group! a C2-C10 dialkylamino group (two alkyl groups may be the same or different from each other) such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C2-C6 alkylcarbonylamino group such as acetylamino group, propionylamino group, isopropionylamino group, butyrylamino group, and valerylamino group; carbamoyl group; a C2-C6 alkylcarbamoyl group such as methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, butylcarbamoyl group , tert-butylcarbamoyl group, and pentylcarbamoyl group ; a C3- C9 dialkylcarbamoyl group such as dimethylcarbamoyl group, diethylcarbamoyl group, dipropylcarbamoyl group, diisopropylcarbamoyl group, and dibutylcarbamoyl group; and a residue of heterocyclic ring having 1-4 heteroatoms selected from oxygen atom, sulfur atom, and nitrogen atom, and having total ring-constituting atoms of 5- 10, for example, furan ring, dihydrofuran ring, tetrahydrofuran ring, pyran ring, dihydropyran ring, tetrahydropyran ring, benzofuran ring, isobenzofuran ring, chromene ring, chroman 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, quinolizine ring, quinoline ring, phthalazine ring, naphtylidine ring, quinoxaline ring, quinazoline ring, cinnoline ring, pteridine ring, oxazole ring, oxazolidine ring, isoxazole ring, isoxazolidine ring, thiazole ring, benzothiazole ring, thiazylidine ring, isothiazole ring, isothiazolidine ring, dioxane ring, dithian ring, morpholine ring, thiomorpholine ring, phthalimide ring and the like (the group of these substituents is referred to as "substituent group A"). As for 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, residues of aromatic heterocyclic rings each having 1-4 heteroatoms selected from oxygen atom, sulfur atom, and nitrogen atom, and having total ring-constituting atoms of 5- 10. These aromatic heterocyclic groups may be bound at any position on the rings. More specifically, examples include residues of 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, isoxazole ring, thiazole ring, benzothiazole ring, isothiazole ring and the like. The aromatic heterocyclic group may have one or more substituents selected from the substituent group A.
Example of the CrCis alkyl group represented by R3 through R7 include those explained above as for R2, and the alkyl group may have one or more substituents selected from the substituent group A. Example of the alkoxyl group represented by R3 through R7 include, for example, CrCis alkoxyl group such as methoxy group , ethoxy group, n-propoxy group, 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 group, as well as linear, branched, or cyclic heptyloxy group, octyloxy group, nonyloxy group, decyloxy group, undecyloxy group, dodecyloxy group, tridecyloxy group, tetradecyloxy group, pentadecyloxy group, hexadecyloxy group , heptadecyloxy group, octadecyloxy group and the like. The alkoxyl group may have one or more substituents selected from the substituent group A.
Example of the acyloxy group represented by R3 to R7 include, for example, a C2-C6 alkylcarbonyloxy group such as acetoxy group, propionyloxy group, butyryloxy group, and valeryloxy group; and a Cβ-C arylcarbonyloxy group such as benzoyloxy group and 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 the substituent group A. Example of the alkoxycarbonyl group repre sented by R3 through R7 include, for example, a C2- C6 alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl 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 the substituent group A.
When the carbamoyl group represented by R3 through R7 has one or more substituents, examples of the carbamoyl group include, for example, a C2-C6 monoalkylcarbamoyl group such as methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, butylcarbamoyl group, tert-butylcarbamoyl group, and pentylcarbamoyl group; a C3-C9 dialkylcarbamoyl group (two alkyl groups may be the same or different from each other) such as dimethylcarbamoyl group , diethylcarbamoyl group, dipropylcarbamoyl group, diisopropylcarbamoyl group, and dibutylcarbamoyl group and the like . The alkyl portions of the aforementioned alkylcarbamoyl group and the dialkylcarbamoyl group may have one or more substituents selected from the substituent group A.
Where the amino group represented by R3 through R7 has one or more substituents, examples include a CrCs monoalkylamino group such as methylamino group , ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and isopentylamino group ; a C2-C10 dialkylamino group such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C2-C6 alkylcarbonylamino group such as acetylamino group, propionylamino group, isopropionylamino group, butyrylamino group, and valerylamino group and the like. The alkyl portions of the aforementioned monoalkylamino group and the dialkylamino group may have one or more substituents selected from the substituent group A. When the amino group represented by R8 has one or more substituents, the group may be a substituted amino group selected from those explained above as for R3 through R7.
The number of nitrogen atoms contained in the nitrogen-containing saturated heterocyclic group represented by R8 is not particularly limited, and the group may contain one or more heteroatom s other than nitrogen (e.g. , oxygen atom, sulfur atom etc.). The nitrogen-containing saturated heterocyclic group may be substituted at any position on the ring. More specifically, examples include residues of pyrrolidine ring, piperidine ring, piperazine ring, homopiperidine ring, homopiperazine ring, morpholine ring, thiomorpholine ring and the like. The nitrogen-containing saturated heterocyclic group may be substituted with one or more substituents selected from the substituent group A.
When the amino group represented by Z has one or more substituents, the group may be a substituted amino group selected from those explained above as for R3 through R7. Examples of the nitrogen-containing saturated heterocyclic group represented by Z include pyrrolidine ring, pyrazolidine ring, imidazolidine ring, thiazolidine ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring, quinuclidine ring and the like.
In addition to the compounds represented by the aforementioned formula (I), physiologically acceptable salts thereof may be used as the active ingredient of the medicament of the present invention. Examples of the salt include, when an acidic group exists, salts of alkali metals and alkaline earth metals such as lithium, sodium, potassium, magnesium, and calcium; salts of ammonia and amines such as methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris(hydroxyme thy Daminome thane, N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyM-propanol, ethanolamine, N-methylglucamine, and L-glucamine; or salts with basic amino acids such as lysine, δ -hydroxylysine, and arginine. When a basic group exists, examples include salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; salts with organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionic 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; or salts with acidic amino acids such as aspartic acid, and glutamic acid.
Solvates and hydrates of the hydroxyflavone derivatives represented by the aforementioned formula (I) and salts thereof may also be used as the active ingredient of the medicament of the present invention. Furthermore, the hydroxyflavone derivatives represented by the aforementioned formula (I) may have one or more asymmetric carbon atoms. As for the stereochemistry of such asymmetric carbon atoms, they may independently be in either (R) or (S) configuration, and the hydroxyflavone derivatives may exist as stereoisomers such as optical isomers, or diastereoisomers. Any stereoisomers of pure form, any mixtures of stereoisomers, racemates and the like may be used as the active ingredient of the medicament of the present invention. Furthermore, 4-keto and 4-hydroxy compounds of the hydroxyflavone derivatives represented by the aforementioned formula (I) may exist as tautomers. The existence of the tautomers is readily apparent to those skilled in the art. and any of the tautomers also fall within the scope of the present invention.
Examples of preferred compounds of the present invention are shown in the tables below. However, the scope of the present invention is not limited by the following compounds.
Figure imgf000022_0001
Figure imgf000022_0002
Table-1 (continued)
Figure imgf000023_0001
Table-1 (continued)
Figure imgf000024_0001
Tab! e-1 (continued)
Figure imgf000025_0001
Table-1( continued)
Figure imgf000026_0001
Tabl e-1 (continued)
Figure imgf000027_0001
Tab! e-1 (continued)
Figure imgf000028_0001
Table-1 (continued)
Figure imgf000029_0001
Tabl e-1 (continued)
Figure imgf000030_0001
Figure imgf000031_0001
Tabl e-1 (continued)
Figure imgf000032_0001
Tab!e-1(continued)
Figure imgf000033_0001
Tabl e-1 (continued)
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000035_0002
Tabl e-2( continued)
Figure imgf000036_0001
Tabl e-2( continued)
Figure imgf000037_0001
Tabl e-2( continued)
Figure imgf000038_0001
Tab! e-2( continued)
Figure imgf000039_0001
Tabl e-2( continued)
Figure imgf000040_0001
Tab! e-2( continued)
Figure imgf000041_0001
Tab! e-2( continued)
Figure imgf000042_0001
Table-2(continued)
Figure imgf000043_0001
Tab! e-2( continued)
Figure imgf000044_0001
Tab! e-2( continued)
Figure imgf000045_0001
Tab! e-2( continued)
Figure imgf000046_0001
Tabl e-2( continued)
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000048_0002
Tabl e-3( continued)
Figure imgf000049_0001
Tabl e-3( continued)
Figure imgf000050_0001
Tabl e-3( continued)
Figure imgf000051_0001
Table-3(continued)
Figure imgf000052_0001
Tabl e-3( continued)
Figure imgf000053_0001
Tabl e-3( continued)
Figure imgf000054_0001
Tabl e-3( continued)
Figure imgf000055_0001
Tabl e-3( continued)
Figure imgf000056_0001
Tabl e-3( continued)
Figure imgf000057_0001
Tabl e-3( continued)
Figure imgf000058_0001
Tabl e-3( continued)
Figure imgf000059_0001
Tabl e-3( continued)
Figure imgf000060_0001
Table-3(continued)
Figure imgf000061_0001
Tab! e-3( continued)
Figure imgf000062_0001
Tab! e-3( continued)
Figure imgf000063_0001
Tab! e-3( continued)
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000068_0002
Tabl e-4( continued)
Figure imgf000069_0001
Tabl e-4( continued)
Figure imgf000070_0001
Table-4(continued)
Figure imgf000071_0001
Table-4(continued)
Figure imgf000072_0001
Tabl e-4( continued)
Figure imgf000073_0001
Table-4(continued)
Figure imgf000074_0001
Table-4(continued)
Figure imgf000075_0001
Tabl e-4( continued)
Figure imgf000076_0001
Table-4(continued)
Figure imgf000077_0001
Tab1e-4(continued)
Figure imgf000078_0001
Table-4(continued)
Figure imgf000079_0001
Tab! e-4( continued)
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Table-4(continued)
Figure imgf000084_0001
Tab! e-4( continued)
Figure imgf000085_0001
Tabl e-4 ( cont i nued )
Figure imgf000086_0001
Table-4(continued)
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000088_0002
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Table-5(continued)
Figure imgf000092_0001
Tabl e-5 (continued)
Figure imgf000093_0001
Tab! e-5 (continued)
Figure imgf000094_0001
Tabl e-5 (continued)
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000096_0002
Tabl e-6 (continued)
Figure imgf000097_0001
Tab! e-6 (continued)
Figure imgf000098_0001
Figure imgf000099_0001
Tabl e-7
Figure imgf000099_0002
Tabl e-7 (continued)
Figure imgf000100_0001
Tabl e-7 (continued)
Figure imgf000101_0001
Tabl e-7 (continued)
Figure imgf000102_0001
Figure imgf000103_0001
Tabl e-7 (continued)
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000105_0002
Figure imgf000106_0001
Tabl e-8( continued)
Figure imgf000107_0001
Among the compounds represented by the formula (I), particularly preferred compounds as the active ingredient of the medicament of the present invention include^
(1) those wherein R1 is hydrogen atom;
(2) those wherein R2 is hydrogen atom or a Ci - Ciβ alkyl group;
(3) those wherein R2 is a Ci - Ciβ alkyl group;
(4) those wherein R2 is a C2-C18 alkyl group;
(5) those wherein Ar is a substituted phenyl group , a C10- C 14 aryl group which may be substituted, or an aromatic heterocyclic group which may be substituted;
(6) those wherein Ar is a substituted Ce-Ci4 aryl group or an aromatic heterocyclic group which may be substituted;
(7) those wherein Ar is a substituted Cβ- C aryl group;
(8) those wherein Ar is a group represented by the aforementioned formula
(II);
(9) those wherein R2 is a Ci Cis alkyl group which may have one or more Cβ-C aryl groups, and Ar is a Cβ- Ci4 aryl group which may be substituted, or an aromatic heterocyclic group which may be substituted;
(10) those wherein R2 is a CrCiβ alkyl group which may have one or more C6-C14 aryl group s, and Ar is a substituted phenyl group, a C10-C14 aryl group which may be substituted, or an aromatic heterocyclic group which may be substituted;
(11) those wherein R2 is a CrCis alkyl group which may have one or more C6-C14 aryl groups, and Ar is a substituted Ce- Ci4 aryl group;
(12) the compounds of the above (9) to (11) wherein R1 is hydrogen atom;
(13) the compounds of the above (9) to ( 12) wherein Ar is a group represented by the aforementioned formula (II); (14) the compounds of the above (9) to (13) wherein R2 is a Ci-Ciβ alkyl group;
(15) the compounds of the above (9) to (13) wherein R2 is a C2-C18 alkyl group; and
(16) the compounds of the above (9) to (12) wherein R2 is a C4-C18 alkyl group.
In addition, particularly preferred compounds also include:
(17) the hydroxyflavone derivatives according to formula (IV) wherein n is 2 or 3;
(18) the hydroxyflavone derivative according to formula (IV) wherein RB is hydrogen atom or methoxy group;
(19) the hydroxyflavone derivative according to formula (IV) wherein Z is dimethylamino group, piperazinyl group which may be substituted, or piperidinyl group which may be substituted;
(20) the hydroxyflavone derivative according to formula (V) wherein R4 is a CrCis alkyl group which may be substituted, a Ci Ciβ alkoxyl group which may be substituted, hydroxyl group, nitro group, or a cyano group;
(21) the hydroxyflavone derivative according to formula (I) wherein R1 represents hydrogen atom or hydroxyl group; R2 represents hydrogen atom or a CrCis alkyl group which may have one or more Cβ-Ci4 aryl groups! and Ar represents an aromatic heterocyclic group which may be substituted, provided that those wherein R1 is hydrogen atom; R2 is methyl group, and Ar is a pyridyl group are excluded.
Most preferred compound include: 7-hydroxy-3'-(3-(l-piperidyl)propyloxy)-8-propylflavone. 4',7-dihydroxy-3'-methoxy-8 propylflavone, 7-hydroxy-8-methyl-3'-(3-(l-piperidyl)propyloxy)flavone. 7-hydroxy-4'-nιtro-3'-(3-(l-pιpeπdyl)propyloxy)-8-propylflavone 4',7-dιhydroxy-3'-methoxy-8-methylflavone, and 7-hydroxy-8-propyl-2-(4-pyrιdyl)chromone.
However the active ingredient of the medicament of the present invention is not limited to the compounds specifically mentioned above.
The hydroxyflavone derivatives represented by the aforementioned formula (I) can be prepared by a method described in the literature. For example, they can be prepared as follows.
<Step 1>
Figure imgf000110_0001
(The symbols used in the scheme have the same meanings as those defined above.)
A compound represented by the aforementioned formula (VII) can be obtained by allowing a compound represented by the aforementioned formula (V) to react with a base and a reactive derivative represented by the aforementioned formula (VI) in the presence of a solvent. The type of the solvent is not particularly limited so 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, halogenated hydrocarbons such as dichloromethane chloroform, and dichloroethane can be used as a solvent. Two or more of the solvents may be used in combination. 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, and these compounds can be readily prepared from corresponding carboxylic acids by a method described in the literature. Reaction temperature and reaction time are not particularly limited. Normally, the reaction can be performed at a temperature of from -78°C to 250°C for 30 minutes to 48 hours.
Figure imgf000111_0001
(The symbols used in the scheme have the same meanings as those defined above.)
The compound represented by the formula (VII) obtained in Step 1 can be subjected to dehydration reaction in the presence or absence of a solvent to obtain a compound represented by the formula (I) . The type of the solvent is not particularly limited so 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, halogenated hydrocarbons such as dichloromethane chloroform and dichloroethane mtriles such as acetonitrile and propionitπle, esters such as methyl acetate and ethyl acetate, alcohols such as methanol and ethanol organic acids such as acetic acid, acid anhydrides such as acetic anhydride and the like can be used Two or more of these solvents may be used in combination The aforementioned dehydration reaction can be performed in the presence of 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 tπfluoroacetic acid, p-toluenesulfonic acid, methanesulfomc acid and camphorsulfonic acid and the like Reaction temperature and reaction time are not particularly limited Normally the reaction can usually be performed at a temperature of from 0°C to 250°C for 30 minutes to 48 hours In each of the aforementioned steps, protection of functional groups and deprotection may sometimes be required Protective groups can be chosen so as to be suitable for such functional groups, and protection and deprotection can be performed in accordance with any methods described in the literature
The medicament of the present invention have inhibitory activity against TPKl, and they inhibit TPKl activity in Alzheimer disease and the like, thereby suppress the neurotoxicity of A/3 and the formation of PHF and inhibit the nerve cell death Accordingly, the medicament of the present invention are useful as a medicament which radically enables preventive and/or therapeutic treatment of Alzheimer disease In addition, the medicament of the present invention are also useful for preventive and/or therapeutic treatment of ischemic cerebrovascular accidents, Down syndrome, cerebral bleeding due to cerebral amyloid angiopathy, progressive supranuclear palsy, subacute sclerosing panencepha tic parkinsonism, postencephahtic parkinsonism, pugilistic encephalitis. Guam parkinsonism-dementia complex. Lewy body disease, Pick's disease, corticobasal degeneration frontotemporal dementia and the like.
As the active ingredient of the medicament of the present invention, a substance may be used which is selected from the group consisting of the compound represented by the aforementioned formula (I) and pharmacologically acceptable salts thereof, and solvates thereof and hydrates thereof. The substance, per se, may be administered as the medicament of the present invention, however, it is generally desirable to administer the medicament in a form of a pharmaceutical composition which comprises the aforementioned substance as an active ingredient and one or more of pharmaceutical additives. As the active ingredient of the medicament of the present invention, two or more of the aforementioned substance may be used in combination. The above pharmaceutical composition may be supplemented with an active ingredient of other medicament for the treatment of Alzheimer disease and the like.
A type of the pharmaceutical composition is not particularly limited, and the composition may be provided as any formulation for oral or parenteral administration. For example, the pharmaceutical composition may be formulated, for example, in the form of pharmaceutical compositions for oral administration such as granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions and the like, or in the form of pharmaceutical compositions for parenteral administrations such as injections for intravenous, intramuscular, or subcutaneous administration, drip infusions, transdermal preparations, transmucosal preparations, nasal drops, inhalants, suppositories and the like. Injections or drip infusions may be prepared as powdery preparations such as in the form of lyophilized preparations, and may be used by dissolving just before use in an appropriate aqueous medium such as physiological saline. Sustained-release preparations such as those coated with a polymer may be directly administered intracerebrally.
Types of pharmaceutical additives used for the manufacture of the pharmaceutical composition, content rations of the pharmaceutical additives relative to the active ingredient, and methods for preparing the pharmaceutical composition may be appropriately chosen by those skilled in the art. Inorganic or organic substances, or solid or liquid substances may be used as pharmaceutical additives. Generally, the pharmaceutical additives may be incorporated in a ratio ranging from 1% by weight to 90% by weight based on the weight of an active ingredient.
Examples of excipients used for the preparation of solid pharmaceutical compositions include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like. For the preparation of liquid compositions for oral administration, a conventional inert diluent such as water or a vegetable oil may be used. The liquid composition may contain, in addition to the inert diluent, auxiliaries such as moistening agents, suspension aids, sweeteners, aromatics, colorants, and preservatives. The liquid composition may be filled in capsules made of an absorbable material such as gelatin. Examples of solvents or suspension mediums used for the preparation of compositions for parenteral administration, e .g. injections, suppositories, include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. Examples of base materials used for suppositories include, for example, cacao butter, emulsified cacao butter, lauric lipid, witepsol.
Dose and frequency of administration of the medicament of the present invention are not particularly limited and they may be appropriately chosen depending on conditions such as a purpose of preventive and/or therapeutic treatment, a type of a disease the body weight or age of a patient severity of a disease and the like Generally, a daily dose for oral administration to an adult may be 0.01 to 1,000 mg (the weight of an active ingredient), and the dose may be administered once a day or several times a day as divided portions, or once in several days. When the medicament is used as an injection, administrations may preferably be performed continuously or intermittently in a daily dose of 0.001 to 100 mg (the weight of an active ingredient) to an adult.
The hydroxyflavone derivatives represented by the aforementioned formula (I) and salts thereof, and solvates thereof and hydrates thereof are novel substance and fall withm the scope of the present invention relating to chemical substances, wherein R1, R2, and Ar are the same as those defined above and where R2 is hydrogen atom, Ar represents a group represented by the aforementioned formula (II) wherein R3, R4, R5, R6, and R7 are the same as those defined above, provided that any one of R3, R4, R5, R6, and R7 represents a group represented by the aforementioned formula (III) wherein R8, X, and m are those defined above, provided that those wherein R1 is hydrogen atom, R2 is methyl group, and Ar is phenyl group, a 3,4-methylenedioxyphenyl group, or a 3-pyrιdyl group, those wherein R1 is hydrogen atom, R2 is propyl group, and Ar is phenyl group having a carboxyl group or an ester group in the 4-posιtιon, and those wherein R1 is hydroxyl group, R2 is methyl group, and Ar is phenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, or 3 4-dιmethoxyphenyl group are excluded.
Utilities of the novel substances provided by the present invention are not limited to medicaments, and any utilities fall withm the scope of the present invention The substances may exist as stereoisomers such as enantiomers of diastereomers any pure form of a stereoisomers, any mixture of stereoisomers racemates also fall within the scope of the present invention Examples of the substances in the form of salts include physiologically acceptable salts explained above
Examples
The present invention will be explained more specifically with reference to examples However, the scope of the present invention is not limited to the following examples The compound number in the examples corresponds to that in the table above
Example 1 Preparation of
7-hydroxy-3'-(3 ( l-pιpeπdyl)propyloxy) -8-propylflavone disulfate (Compound 455)
2,4-Dιhydroxy- 3-propylacetophenone (l 0 g) was dissolved in 30 ml of tetrahydrofuran and the solution was added dropwise with 26 ml of lithium hexamethyldisilazane at - 78°C and stirred for 2 hours A tetrahydrofuran solution of 1 43 g of methyl 3 pipeπdylpropyloxybenzoate was added dropwise to the reaction mixture, and the mixture was stirred for 24 hours The reaction mixture was poured into ice-cold water neutralized with concentrated hydrochloric acid, and extracted with ethyl acetate The organic layer was washed with water and saturated brine dried over sodium sulfate, and then concentrated and dried under reduced pressure The resulting residue was dissolved in 40 ml of acetic acid added with 0.2 ml of concentrated sulfuric acid and stirred at 100°C for 2 hours The reaction mixture was cooled to room temperature and the deposited 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-dβ. ό* ) : 0.98 (t, J=7.5Hz, 3H), 1.41 (m. IH), 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=6.0Hz, 2H), 6.95 (s, IH), 7.01 (d, J=8.7Hz, IH), 7. 18 (d. J=8.7Hz,
IH), 7.50- 7.56 (m. 2H), 7.66 (d, J=8.0Hz, IH), 7.77 (d, J=8.7Hz, IH), 8.99 (br,
IH), 10.60 (br, IH).
Reference Example l: Preparation of methyl 4-tert-butyldimethyl- siloxy-3-methoxybenzoate
Vanillic acid (25.8 g) was dissolved in 500 ml of methanol, and the solution was added with 1 g of p - toluenesulfonic acid and heated under reflux for 24 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure , and purified on a column with hexane/ethyl acetate = 3/1 to obtain 28.5 g of methyl vanillate (Yield: 100%) . The resulting methyl vanillate (5.5 g) was dissolved in 30ml of N,N-dimethylformamide , and the solution was added with 3. 1 g of imidazole and 5.5 g of tert-butyldimethylchlorosilane at 0°C and then stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate . The resulting organic layer was washed with water and saturated brine, dried over sodium sulfate. and then concentrated under reduced pressure. The resulting residue was purified on a column with hexane/ethyl acetate = 15/1 to obtain 8.68 g of the desired compound (Yield: 97%).
NMR (CDCls. ό* ): 0. 17 (s, 6H), 1.01 (s, 9H) , 3.86 (s, 3H) . 3.88 (s, 3H) , 6.86 (d, J=8.7Hz, IH), 7.51 (d, J=2.4Hz, IH), 7.66 (dd, J=8.7Hz, 2.4Hz. IH). Example 2: Preparation of 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 the solution wa s added dropwise with 26 ml of lithium hexamethyldisilazane at - 78 °C and then stirred for 2 hours. A tetrahydrofuran solution of 1.53 g of methyl vanillate obtained in Reference Example 1 was added dropwise to the reaction mixture, and the mixture was stirred for 24 hours. The reaction mixture was poured into ice-cold water, neutralized with concentrated hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated and dried under reduced pressure . The resulting re sidue was dissolved in 40 ml of acetic acid, and the solution was added with 0.2 ml of concentrated sulfuric acid and stirred at 100°C for 2 hours. The reaction mixture was added with 10 ml of water and further stirred for 2 hours. The reaction mixture was cooled to room temperature, and the deposited 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- d6, (5 ) : 0.98 (t, J=7.2Hz. 3H), 1.65 (m, 2H), 2.88 (t, J=6.9Hz, 2H), 3.90 (s, 3H), 6.82 (s, IH), 6.94-6.99 (m, 2H), 7.51- 7.55 (m, 2H), 10.53 (br. lH).
Compounds of Example 3 to 73 were prepared in similar manners to those in Reference Example 1 and Examples 1 and 2. Physical properties of the compounds are shown below. Example 3: 7-Hydroxy-3' (l-methyl-3-piperidyl)methoxyflavone (Compound
42)
Melting point: 134°C (decomposition).
NMR (DMSO-dβ.c5): 1.08 (m. IH), 1.33 (m, IH). 1.70 (m, IH), 1.95 (m, 2H),
2.27 (br. IH), 2.83 (s, 3H), 3.45 (m, IH), 3.57 (m. IH), 3.97 (m, IH).4.11 (m,
IH), 6.94-6.97 (m, 2H), 7.01 (s, IH), 7.17 (d, J=7.2Hz, IH), 7.5 (m. IH), 7.57
(s, IH), 7.67 (d, J=7.5Hz, IH).7.89 (d, J=8.7Hz. IH), 9.26 (br, IH).
Example 4- 7-Hydroxy-3' (2-dimethylaminoethoxy)flavone hydrochloride
(Compound 45)
Melting point: 238-239°C.
NMR (DMSO-de, δ )■ 2.87 (s, 3H), 2.89 (s, 3H), 4.48 (t, J=5.lHz, 2H),
6.93-6.98 (m, 2H), 7.03 (d, J=2.lHz, IH), 7.23 (dd, J=2.1Hz, 8.1Hz, IH), 7.53
(t, J=8.lHz, IH), 7.65 (d, J=2.lHz, IH), 7.71 (d, J=8.1Hz, IH), 7.89 (d,
J=8.7Hz, IH), 10.10 (br, IH), 10.90 (br, IH).
Example 5: 7-Hydroxy-3'-(2-(l-piperidyl)ethoxy)flavone hydrochloride
(Compound 48)
Melting point: 120-121°C.
NMR (DMSO-de, δ)- 1.68-1.83 (m, 4H), 3.03 (m, 2H), 3.51-3.63 (m, 4H), 3.62
(m, 2H), 4.55 (m, 2H), 6.96-6.98 (m, 2H), 7.06 (s, IH), 7.23 (d, J=8.lHz, IH),
7.52 (m. IH), 7.64 (s, IH), 7.70 (d, J=7.8Hz, IH), 7.89 (d, J=8.71H), 10.58 (br,
IH).
Example 6: 7 Hydroxy-3'-(3-dimethylaminopropyloxy)flavone hydrochloride (Compound 55) Melting point: 244-245°C.
NMR (DMSO-de, δ)- 2.18 (m, 2H), 2.80 (s, 3H). 2.81 (s. 3H), 3.25 (m, 2H), 4,19 (t, J=6.0Hz, 2H), 6.93-6.97 (m, 2H), 7.04 (s, IH). 7.17 (m, IH), 7.50 (m. IH), 7.58 (s, IH), 7.66 (d, J=7.8Hz, IH), 7.89 (d. J=8.7Hz. IH), 10.17 (br. IH), 10.83 (br, IH).
Example 1'- 7-Hydroxy-3'-(3-(l-piperidyl)propyloxy)flavone l/2sulfate
(Compound 58)
Melting point: 205°C (decomposition).
NMR(DMSO-de,c5"): 1.42 (m. IH), 1.59-1.80 (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, IH), 6.95 (dd,
J=2.1Hz, 9.0Hz, IH), 7.10 (d, J=2.1Hz, IH), 7.17 (dd. J=2.lHz, 8.4Hz, IH),
7.51 (m, IH), 7.57 (d, J=2.lHz, IH), 7.67 (d, J=8.lHz. IH), 7.90 (d, J=9.0Hz,
IH), 8.97 (br, IH), 10.80 (br, IH).
Example 8: 7-Hydroxy-3'-(3-(4-phenyl- l-piperazyl)propyloxy)flavone dihydrochloride (Compound 62)
Melting point: 245°C (decomposition).
NMR (DMSO-de, δ)- 2.29 (m, 2H), 3.14-3.22 (m, 4H). 3.36 (m, 2H), 3.64 (m,
2H), 3.84 (m, 2H), 6.87 (m, IH), 6.93-7.05 (m.5H), 7.18-7.39 (m, 3H), 7.53 (m,
IH), 7.59 (s, IH), 7.66 (d, J=8.1Hz, IH), 7.89 (d, J=8.6Hz. IH), 10.74 (br,
IH).
Example 9: 7-Hydroxy-4'-(3-(l-piperidyl)propyloxy)flavone l/2sulfate
(Compound 89)
Melting point: 210°C.
NMR (DMSO-de, δ)- 1.41 (m, IH), 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. IH), 6.92 (dd, J=2.1Hz, 9.0Hz. IH), 6.99 (d, J=2.1Hz, IH), 7.12 (d, J=8.7Hz, IH), 7.88 (d, J=8.7Hz, IH).8.04 (d, J=9.0Hz, IH), 9.52 (br, IH), 9.70 (br, IH). 10.76 (s, IH).
Example 10: 7- Hydroxy- 4' -methoxy 3' (3 (l-piperidyl)propyloxy)flavone l/2sulfate (Compound 96)
Melting point: 210°C (decomposition).
NMR (DMSO-de, (5): 1.42 (m, IH), 1.58-1.69 (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, IH), 6.92 (d, J=8.7Hz, IH), 7.01 (s, IH), 7.17 (d, J=8.7Hz, IH),
7.59 (s, IH), 7.70 (d, J=8.7Hz, IH), 7.87 (d, J=8.7Hz, IH), 8.87 (br, IH).
Example 11: 3',7-Dihydroxy-5'-(3-(l-piperidyl)propyloxy)flavone l/2sulfate
(Compound 98)
Melting point: 180°C.
NMR (DMSO-de, δ)- 1.40 (m, IH), 1.62-1.68 (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=6.0Hz.2H), 6.55 (s,
IH), 6.80 (s, IH), 6.91-6.96 (m, 2H), 7.03 (s, 2H), 7.88 (d, J=8.4Hz, IH), 8.95
(br, IH).
Example 12: 5,7-Dihydroxy-3'-(2-dimethylaminoethoxy)flavone (Compound
148)
Melting point: 175-177°C.
NMR (DMSO-de, δ)- 2.24 (s, 6H), 2.66 (t, J=5.7Hz, 2H), 4.17 (t, J=5.7Hz, 2H),
6.22 (d, J=2.lHz, IH), 6.54 (d, J=2.lHz, IH), 7.02 (s, IH), 7.19 (d, J=8.Hz,
IH), 7.48 (t, J=8.lHz, IH), 7.59 (s, IH), 7.64 (d, J=8.1Hz, IH). 12.82 (s, IH). Example 13: 5,7-Dihydroxy-3'-(3-dimethylaminopropyloxy)flavone l/2sulfate
(Compound 158)
Melting point: 220-223°C.
NMR (DMSO-de, 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.lHz. IH), 6.53 (d, J=2.lHz, IH), 7.01 (s, IH), 7.20
(d, J=7.8Hz, IH), 7.51 (t, J=7.8Hz, IH), 7,58 (s, IH), 7.68 (d, J=7.8Hz. IH),
12.80 (s. IH).
Example 14 : 5.7-Dihydroxy-3'-(3-(l-piperidyl)propyloxy)flavone l/2sulfate (Compound 161) Melting point: 184-186°C.
NMR (DMSO-de, δ)- 1.40 (m. IH), 1.60-1.80 (m, 3H), 1.81-1.93 (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, IH), 6.53 (d, J=2.lHz, IH), 7.01 (s, IH), 7.19 (d, J=8.1Hz, IH), 7.51 (d, J=8.lHz, IH), 7.57 (s, IH). 7.68 (d, J=8.lHz, IH), 10.93 (s, IH), 12.80 (s, IH).
Example 15: 5,7-Dihydroxy-3'-(3-(4-morpholinyl)propyloxy)flavone l/2sulfate
(Compound 162)
Melting point: 210-212°C.
NMR (DMSO-de, 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.lHz, IH), 6.53 (d, J=2.1Hz,
IH), 7.01 (s, IH), 7.20 (dd. J=2.lHz, 8.1Hz, IH), 7.52 (m, IH), 7.58 (s, IH),
7.68 (d, J=7.5Hz, IH), 9.58 (br, IH), 10.92 (s, IH), 12.80 (s, IH).
Example 16: 7-Hydroxy-8-methyl-3'-(3 (l-piperidyl)propyloxy)flavone l/2sulfate (Compound 264)
Melting point: 226°C (decomposition).
NMR (DMSO-de, (ϊ): 1.32-1.90 (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, IH), 7.00 (d. J=8.8Hz,
IH), 7.17 (d, J=7.8Hz, IH). 7.50-7.57 (m, 2H), 7.69 (d. J=7.8Hz, IH), 7.76 (d,
J=8.8Hz, IH).
Example 17: 4'.7-Dihydroxy-3'-ethoxy-8-methylflavone (Compound 310) Melting point: 152-1560C.
NMR (DMSO-de, (5"): 1.37 (t, J=6.9Hz, 3H), 2.83 (s, 3H), 4.15 (q, J=6.9Hz, 2H), 6.79 (s, IH), 6.95 (d, J=8.8Hz, 2H), 7.52-7.54 (m.2H), 7.70 (d, J=8.8Hz, IH).
Example 18: 3',7-Dihydroxy-8-methylflavone (Compound 342)
Melting point: 230-231°C.
NMR (DMSO-de, δ)- 2.36 (s, 3H), 6.78 (s, IH), 6.97-7.00 (m, 2H), 7.37 (t,
J=7.8Hz, IH), 7.41-7.51 (m, 2H), 10.61 (s, IH).
Example 19: 4',7-Dihydroxy-8-methylflavone (Compound 343)
Melting point: >300°C.
NMR (DMSO-de, δ)- 2.30 (s, 3H), 6.67 (s, IH), 6.88-6.93 (m, 4H), 7.68 (s,
J=7.8Hz, IH), 7.88 (d, J=8.7Hz, IH).
Example 20: 7-Hydroxy-3'-methoxy-8-methylflavone (Compound 347) Melting point: 233-236°C.
NMR (DMSO-de, (5): 2.36 (s, 3H), 3.87 (s, 3H), 6.95 (s, IH), 7.00 (d, J=8.7Hz, IH), 7.17 (ss. J=2.lHz, 7.8Hz, IH), 7.50 (t, J=7.8Hz, IH). 7.57 (s, IH), 7.66 (d, J=7.8Hz, IH), 7.76 (d, J=8.7Hz, IH), 10.63 (br. IH). Example 21 : 3', 7-Dihydroxy-4' methoxy-8-methylflavone (Compound 351) Melting point: 263°C (decomposition).
NMR (DMSO-de, £ ) : 2.35 (s, 3H), 3.86 (s, 3H), 6.69 (s. IH), 6.97 (d. J=8.7Hz, IH), 7.09 (d. J=7.8Hz, IH) . 7.48 (d. J=2.4Hz, IH), 7.53 (dd, J=2.4Hz, 8.7Hz. IH), 7.73 (d, J=8.7Hz, IH), 10.59 (br, IH).
Example 22: 2'- Carboxy-7-hydroxy8-methylflavone (Compound 354) Melting point: >300°C .
NMR (DMSO- de, δ ) ■ 2.16 (s, 3H), 6.50 (s, IH), 7.00 (d, J=8.7Hz, IH), 7.65-7.88 (m, 5H), 10.65 (s. IH), 13.03 (br, IH).
Example 23: 2' Fluoro-7-hydroxy8-methylflavone (Compound 365)
Melting point: 230-231°C .
NMR (DMSO-de, δ )■ 2.30 (s, 3H), 6.68 (s, IH), 7.01 (d, J=8.7Hz, IH),
7.42- 7.49 (m, 2H), 7.65 (m, IH), 7.77 (d, J=8.7Hz, IH), 8.02 (m, IH), 10.68
(br, IH).
Example 24: 2', 3'-Difluoro-7-hydroxy 8-methylflavone (Compound 368) Melting point: 229°C .
NMR (DMSO -de, δ )■ 2.29 (s, 3H), 6.71 (s, IH), 7.02 (d, J=8.4Hz, IH), 7.45 (m, IH), 7.60-7.90 (m. 3H), 10.70 (br, IH).
Example 25: 7-Hydroxy8-methyl-2' -nitroflavone (Compound 386)
Melting point: 271 -272°C .
NMR (DMSO -de, δ )■ 2.01 (s, 3H), 6.72 (s, IH), 7.02 (s. J=8.7Hz. IH),
7.76-8.00 (m, 4H), 8.15 (d, J=7.5Hz, IH), 10.75 (br, IH). Example 26: 7-Hydroxy8-methyl-3' -nitroflavone (Compound 387)
Melting point: 250°C (decomposition).
NMR (DMSO-de. δ ) - 2.83 (s. 3H), 7.02 (d, J=8.7Hz, IH), 7. 13 (s, IH) , 7.78 (d,
J=8.7Hz, IH), 7.88 (m, IH) . 8.42 (d, J=7.8Hz, IH), 8.53 (d. J=8. 1Hz, IH).
8.80 (s, IH), 10.70 (br, IH) .
Example 27: 7-Hydroxy3'-methoxy8-methyl-2' nitroflavone (Compound 389) Melting point: 227-229°C .
NMR (DMSO-de, δ )- 2.11 (s. 3H), 3.87 (s, 3H), 6.67 (s, IH), 7.01 (d. J=8.7Hz, IH), 7.54 (d, J=7.8Hz, IH) , 7.61 (d, J=8.7Hz. IH), 7.72- 7.79 (m, 2H), 10.74 (br, IH).
Example 28: 3',8-Dimethyl-7-hydroxy2'-nitroflavone (Compound 391) Melting point: 230°C (decomposition).
NMR (DMSO-de, δ ) - 2.10 (s, 3H), 2.40 (s, 3H), 6.67 (s, IH), 7.01 (d, J=8.7Hz, IH), 7.71-7.82 (m, 4H), 10.78 (br, IH).
Example 29: 3' , 4' -Dimethoxy7-hydroxy8-methyl-2' -nitroflavone (Compound
392)
Melting point: 284-285°C .
NMR (DMSO-de, δ ) - 2.05 (s, 3H), 3.95 (s, 3H), 3.98 (s, 3H), 6.71 (s, IH), 7.00
(d, J=8.7Hz, IH), 7.42 (s. IH), 7.73 (s, IH), 7.78 (d, J=8.7Hz, IH), 10.69
(s, lH).
Example 30: 3'-Chloro-7-hydroxy8-methyl-2'-nitroflavone (Compound 393) Melting point: 242-243°C . NMR (DMSO-de, δ ) - 2. 12 (s. 3H), 6.78 (s, IH). 7.03 (d. J=8.7Hz, IH), 7.78 (d, J=8.7Hz, IH), 7.85 (t, J=8.1Hz, IH), 8.99-8.06 (m, 2H), 10.78 (br, IH).
Example 31: 7-Hydroxy4"-nitro- 3'-(3- (l-piperidyl)propyloxy)-8-propylflavone l/2sulfate (Compound 491)
Melting point: 214-217°C .
NMR (DMSO-de, ) : 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, IH),
7.20 (s, IH), 7.79 (d, J=9.0Hz, 2H), 7.90 (s, IH), 8. 14 (d, J=9.0Hz, IH), 8.95
(br, IH), 10.69 (br, IH).
Example 32: 3', 7-Dihydroxy8-propylflavone (Compound 502)
Melting point: 281 -282°C .
NMR (DMSO-de, δ ) - 0.97 (t, J=7.5Hz, 3H), 1.64 (m, 2H), 2.88 (t, J=7.5Hz,
2H), 6.78 (s, IH), 6.99 (d, J=8.7Hz, IH), 7.38 (t. J=7.8Hz, IH), 7.40 (s, IH),
7.48 (d, J=7.8Hz, IH), 7.76 (s, J=8.7Hz, IH), 9.88 (s, IH), 10.59 (s, IH).
Example 33: 4', 7-Dihydroxy8-propylflavone (Compound 503)
Melting point: >300°C .
NMR (DMSO- de, δ ) - 0.92 (t, J=7.5Hz, 3H), 1.59 (m, 2H), 2.83 (t, J=7.5Hz,
2H), 6.68 (s, IH). 6.89-6.94 (m, 3H), 7.69 (d, J=8.7Hz, IH) , 7.85 (d, J=8.7Hz,
2H), 10.20 (br, IH), 10.45 (br. IH).
Example 34: 8-Propyl-3',4', 7-trihydroxyflavone (Compound 504)
Melting point: 293-294°C .
NMR (DMSO-de, (J ) : 0.97 (t, J=7.2Hz, 3H), 1.63 (m, 2H), 2.87 (t, J=6.9Hz,
2H), 6.62 (s, IH), 6.90 (d, J=8, lHz, IH), 6.96 (d, J=9.0Hz, IH), 7.37- 7.41 (m, 2H), 7.73 (d, J=9.0Hz. IH), 9.87 (br, 2H), 10.56 (br. IH).
Example 35: 7-Hydroxy3'-methoxy8-propylflavone (Compound 507) Melting point: 232-234°C.
NMR (DMSO-de, 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, IH), 7.00 (d, J=8.7Hz, IH), 7.17 (dd, J=1.5Hz, 8.4Hz, IH), 7.48-7.55 (m, 2H), 7.66 (d, J=7.8Hz, IH), 7.77 (d, J=8.7Hz, IH), 10.60 (br, IH).
Example 36: 3',7-Dihydroxy-4' methoxy8-propylflavone (Compound 511) Melting point: 271-272°C.
NMR (DMSO-de, δ)- 0.97 (t, J=7.5Hz, 3H), 1.64 (m, 2H), 2.88 (t, J=7.5Hz, 2H), 6.70 (s, IH), 6.96 (d, J=8.7Hz, IH), 7.12 (d, J=8.4Hz, IH), 7.44 (d, J=2.1Hz, IH), 7.52 (dd, J=2.lHz, 8.4Hz, IH), 7.74 (d, J=8.7Hz, IH), 9.50 (br, IH), 10.47 (br, IH).
Example 37: 3'-Bromo-4',7 dihydroxy 5'-methoxy8-propylflavone (Compound
512)
Melting point: 250-255°C.
NMR (DMSO-de, δ)- 0.77 (t, J=7.5Hz, 3H), 1.40 (m, 2H), 2.62 (t, J=6.9Hz,
2H), 3.72 (s, 3H), 6.72-6.76 (m, 2H), 7.35 (d, J=1.8Hz. IH), 7.50 (d, J=9.0Hz,
IH), 7.56 (d, J=1.8Hz, IH), 10.17 (br, IH), 10.39 (brs, IH).
Example 38: 7-Hydroxy2'-isopropoxy8-propylflavone (Compound 513) Melting point: 199-200°C.
NMR (DMSO-de, δ )■ 0.93 (t, J=7.5Hz, 3H), 1.33 (d, J=6.0Hz, 6H), 1.60 (m, 2H), 2.82 (t, J=7.5Hz, 2H), 4.81 (m, IH), 6.84 (s, IH), 7.00 (d, J=8.7Hz, IH), 7.14 (t, J=7.8Hz, IH). 7.26 (d, J=8.lHz, IH), 7.53 (m. IH), 7.75 (d. J=8.7Hz. IH), 7.84 (dd, J=1.5Hz, 7.8Hz. IH), 10.58 (br, IH).
Example 39: 4',7 Dihydroxy3'-methyl-8-propylflavone (Compound 521) Melting point: 191-192°C.
NMR (DMSO-de, (5" ): 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, IH), 6.96 (d, J=8.7Hz, 2H), 7.73 (d, J=8.7Hz, 2H), 7.79 (s, IH), 10.23 (s, IH), 10.55 (s, IH).
Example 40: 4',7-Dihydroxy3',8-dipropylflavone (Compound 523)
Melting point: 228-230°C.
NMR (DMSO-de, ): 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=8.4Hz, 2H), 6.73 (s, IH), 6.94-7.99 (m,
2H), 7.71-7.77 (m, 3H), 10.12 (br, IH), 10.54 (br, IH).
Example 41: 2'-Fluoro-7-hydroxy8-propylflavone (Compound 525)
Melting point: 204-207°C.
NMR (DMSO-de, δ)- 0.94 (t, J=7.5Hz, 3H), 1.61 (m.2H). 2.82 (t, J=7.5Hz,
2H), .68 (s, IH), 7.02 (d, J=8.7Hz, IH), 7.43-7.50 (m. 2H), 7.5 (m, IH), 7.78
(d, J=8.4Hz, IH), 7.97 (m, IH), 10.65 (br.lH).
Example 42: 4'-Fluoro-7-hydroxy8-propylflavone (Compound 527)
Melting point: 243°C.
NMR (DMSO-de, δ)- 0.95 (t, J=7.5Hz, 4H), 1.64 (m. 2H), 2.87 (t, J=6.9Hz,
2H), 6.99 (d, J=8.7Hz, IH), 7.44 (t, J=8.7Hz, 2H), 7.75 (d, J=8.7Hz, IH), 8.10
(dd, J=2.1Hz, 8.7Hz, IH), 10.59 (s, IH). Example 43: 3'-Bromo-4',7-dihydroxy8-propylflavone (Compound 536) Melting point: 267-270°C.
NMR (DMSO-de, d): 1.00 (t, J=7.5Hz, 3H), 1.64 (m, 2H), 2.89 (t. J=7.5Hz, 2H), 6.81 (s, IH). 6.99 (d, J=8.7Hz, IH), 7.18 (d, J=8.7Hz, IH), 7.74 (d, J=8.7Hz, IH), 7.91 (d, J=8.7Hz, IH), 8.15 (s, IH), 10.56 (s, IH), 11.17 (s.lH).
Example 44: 7-Hydroxy2'-nitro-8-propylflavone (Compound 545)
Melting point: 117-118°C.
NMR (DMSO-de, δ)- 0.87 (t, J=7.5Hz, 3H), 1.43 (m, 2H), 2.51 (t, J=7.2Hz,
2H), 6.97 (s,lH), 7.01 (d, J=8.7Hz, IH), 7.78-7.95 (m, 4H), 8.16 (dd, J=1.5Hz,
7.8Hz. IH), 10.68 (s, IH).
Example 45: 7 Hydroxy3'-methoxy2'-nitro-8-propylflavone (Compound 548) Melting point: 236°C.
NMR (DMSO-de, 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, IH), 7.01 (d, J=8.7Hz, IH), 7.52 (d, J=7.5Hz, IH), 7.61 (d, J=8.7Hz, IH), 7.73-7.80 (m, 2H), 10.68 (br, IH).
Example 46: 7-Hydroxy4'-methoxy3'-nitro-8-propylflavone (Compound 553) Melting point: 273°C (decomposition).
NMR (DMSO-de, d): 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. IH), 7.59 (d, J=8.7Hz, IH), 7.76 (d, J=9.0Hz, IH), 8.33 (dd, J=2.4Hz, 9.0Hz, IH), 8.53 (s, J=2.4Hz. IH), 10.62 (s,lH).
Example 47: 4',7-Dihydroxy3'-nitro-8-propylflavone (Compound 554)
Melting point: 263-264°C.
NMR (DMSO-de, δ). 1.01 (t, J=7.8Hz, 3H), 1.64 (m. 2H), 2.87 (t, J=7.8Hz, 2H), 6.90 (s, IH). 6.99 (s, J=8.7Hz, IH), 7.29 (s, J=9.0Hz, IH). 7.75 (d, J=8.7Hz, IH), 8.20 (dd, J=1.8Hz, 9.0Hz, IH), 8.53 (d, J=1.8Hz, IH). 10.63 (s, IH).
Example 48: 7-Hydroxy3'-methoxy4'-nitro-8-propylflavone (Compound 555) Melting point'- 244-245°C.
NMR (DMSO-de, δ)- 0.97 (t. J=7.5Hz, 3H), 1.65 (m, 2H), 2.89 (t, J=7.5Hz, 2H), 4.07 (s, 3H), 7.02 (d. J=9.0Hz, IH), 7.19 (s, IH), 7.75-7.80 (m.2H), 8.19 (d. J=8.7Hz, IH), 10.67 (br, IH).
Example 49: 7-Hydroxy8-propylflavone (Compound 557)
Melting point: 224-226°C.
NMR (DMSO-de, δ)- 0.97 (t, J=7.2Hz, 3H), 1.65 (m, 2H), 2.89 (t, J=6.9Hz,
2H), 6.93 (s, IH), 7.00 (d, J=8.7Hz, IH), 7.59-7.62 (m, 3H), 7.77 (s, J=8.7Hz,
IH), 8.04-8.07 (m, 2H), 10.65 (s, IH).
Example 50: 7-Hydroxy3'-phenoxy8-propylflavone (Compound 558) Melting point: 198-201°C.
NMR (DMSO-de, tf): 0.78 (t, J=7.5Hz, 3H), 1.50 (m, 2H), 2.71 (t, J=7.2Hz, 2H), 6.94 (s, IH), 6.98 (d, J=8.7Hz, IH), 7.14 (d, J=7.5Hz, 2H), 7.22-7.26 (m, 2H), 7.43-7.49 (m, 2H), 7.57-7.63 (m, 2H), 7.75 (d, J=8.4Hz, IH), 7.83 (d, J=8.7Hz, IH), 10.64 (br, IH).
Example 51: 4',7-Dihydroxy3'-propoxy8-propylflavone (Compound 560) Melting point: 220-222°C.
NMR (DMSO-de, δ)- 0.95-1.03 (m, 6H), 1.62 (m. 2H), 1.78 (m, 2H), 2.85 (t, J=7.2Hz. 2H), 4.04 (t, J=6.6Hz, 2H), 6.79 (s, IH), 6.95 (d, J=8.7Hz, 2H), 7.49-7.52 (m, 2H), 7.72 (d, J=8.7Hz, IH), 9.75 (brs, IH). 10.51 (s, IH).
Example 52: 3'-Isopropoxy4', 7-dihydroxy8-propylflavone (Compound 561)
Melting point: 260-261°C .
NMR (DMSO -de, δ ) : 1.25 (t, J=7.2Hz, 3H), 1.38 (d, J=6.6Hz, 6H), 1.64- 1.73
(m, 4H), 4.69 (m, IH), 6.69 (s, IH), 6.94 (d, J=8.4Hz. IH), 7.06 (d. J=8.4Hz.
IH), 7.40 (d, J=1.8Hz, IH), 7.51 (dd, J= 1.8Hz, 8.4Hz, IH), 7.98 (d, J=8.4Hz,
IH).
Example 53: 3' Butoxy4',7-dihydroxy8-propylflavone (Compound 563) Melting point: 215-217°C .
NMR (DMSO-de, (5 ): 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, IH) , 6.94 (d, J=8.5Hz, 2H), 7.48-7.52 (m, 2H), 7.72 (d, J=8.5Hz, IH).
Example 54: 3'-Decanyloxy4', 7-dihydroxy8-propylflavone (Compound 582) ff$tK : Syrup.
NMR (DMSO-de, 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, IH), 6.95-6.98 (m, 2H), 7.50- 7.54 (m, 2H), 7.74 (d, J=8.7Hz, IH), 9.81 (s, IH), 10.57 (s, IH).
Example 55: 8-Butyl-4', 7-dihydroxyflavone (Compound 593)
Melting point: 233-236°C .
NMR (DMSO-de, (5 ) : 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, IH), 6.93-6.98 (m, 2H), 7.73 (d, J=8.7Hz, IH) , 7.89 (d,
J=9.0Hz, IH). Example 56: 4',7 Dihydroxy3'-methoxy8-methylflavone (Compound 680) Melting point: 170°C.
NMR (DMSO-de, δ): 2.35 (s, 3H), 3.89 (s, 3H), 6.83 (s, IH), 6.94-7.00 (m, 2H). 7.55-7.57 (m, 2H), 7.73 (d, J=8.4Hz, IH), 10.57 (s, IH).
Example 57: 4',7-Dihydroxy8-ethyl-3'-methoxyflavone (Compound 681) Melting point: 255"257°C.
NMR (DMSO-de, δ): 1.22 (t, J=7.5Hz, 3H), 5.81 ( , J=7.5Hz, 2H), 6.85 (s, IH), 6.95-6.99 (m, 2H), 7.52-7.55 (m, 2H), 7.73 (d, J=8.4Hz, IH), 9.90 (s, IH), 10.59 (s, IH).
Example 58: 8 Butyl-4',7-dihydroxy 3'-methoxyflavone (Compound 684) Melting point: 228-231°C.
NMR (DMSO-de, δ): 0.93 (t, J=7.2Hz, 3H), 1.39 (m, 2H), 1.60 (m, 2H), 2.89 (t, J=7.5Hz, 2H), 3.89 (s, 3H), 6.82 (s, IH), 6.93-6.98 (m, 2H), 7.51-7.54 (m, 2H), 7.73 (s, J=8.4Hz, IH), 9.85 (s, IH), 10.51 (s, IH).
Example 59: 4\7-Dihydroxy8-isopentyl-3'-methoxyflavone (Compound 690) Melting point: 225-227°C.
NMR (DMSO-de, δ): 0.96 (d, J=6.6Hz, 6H), 1.47 (m, 2H), 1.65 (m, IH), 2.89 (t, J=7,5Hz, 2H), 3.89 (s, 3H), 6.82 (s, IH), 6.92-6.98 (m, 2H), 7.51-7.54 (m, 2H), 7.73 (d, J=8.7Hz, IH), 9.86 (s, IH), 10.52 (s, IH).
Example 60: 8-Benzyl-4',7"dihydroxy 3'-methoxyflavone (Compound 712)
Melting point: 281-282°C.
NMR (DMSO-de, (J): 3.78 (s, 3H), 4.26 (s, 2H), 6.83 (s, IH), 6.90 (d, J=8.lHz, IH), 7.04 (d, J=8.7Hz. IH), 7.14 (m, IH), 7.20-7.26 (m, 4H), 7.41-7.46 (m, 2H), 7.81 (d, J=8.7Hz, IH).9.88 (br. IH), 10.82 (br, IH).
Example 61: 7-Hydroxy8-methyl-2-(l-naphthyl)chromone (Compound 764) Melting point: 250-253"C.
NMR (DMSO-de, δ )■ 1.87 (s, 3H), 6.52 (s, IH), 7.00 (d, J=8.7Hz, IH), 7,58-7.66 (m, 3H). 7.80 (d. J=8.7Hz, IH), 7.85 (dd, J=1.2Hz, 7.5Hz, IH), 8.03-8.15 (m, 3H), 10.68 (br. IH).
Example 62: 7-Hydroxy 2 (2-hydroxyl-naphthyl)-8-methylchromone
(Compound 766)
NMR (DMSO-de, d ): 2.10 (s. 3H), 6.60 (d, J=8.7Hz, IH), 7.11 (s, IH), 7.60-7.69 (m, 3H), 7.73-7.81 (m, 2H), 8.09 (d, J=8.lHz, IH), 8.31 (d, J=9.3Hz, IH), 9.97 (s, IH), 9.99 (s,lH).
Example 63: 7-Hydroxy 2- (3 -hydroxy 2-naphthyl) -8- me thylchromone
(Compound 767)
Melting point: >300°C .
NMR (DMSO-de, δ )■ 2.38 (s, 3H), 7.00 (d, J=8.7Hz, IH), 7.07 (s, IH),
7.33-7.39 (m, 2H), 7.51 (m. IH), 7.75-7.79 (m, 2H), 7.98 (d, J=8.1Hz, IH),
8.47 (s, IH), 10.62 (s,
Example 64: 7-Hydroxy8-propyl-2-(2-pyridyl)chromone l/2sulfate
(Compound 785)
Melting point: 213-217°C.
NMR (DMSO-de, 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, IH), 7.10 (s, IH), 7.63 (m, IH), 7.80 (d, J=8.7Hz, IH), 8.09-8.14 (m.2H), 8.78 (d, J=4.8Hz, IH), 10.70 (s. IH).
Example 65: 7-Hydroxy8-propyl-2-(3-pyridyl)chromone methanesulfonate
(Compound 786)
Melting point: 278-279°C.
NMR (DMSO-de, (5): 0.97 (t, J=7.5Hz, 3H), 1.64 (m, 2H), 2.89 (t. J=8.1Hz,
2H), 6.98-7.06 (m, 2H), 7.65 (m, IH), 7.78 (d. J=9.0Hz, IH), 8.42 (m, IH),
8.77 (m, IH), 9.23 (d. J=2.1Hz, IH), 10.68 (br, IH).
Example 66: 7-Hydroxy2-(2-methoxy5-pyridyl)-8-propylchromone l/2sulfate
(Compound 787)
Melting point: 173-176°C.
NMR (DMSO-de, 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, IH), 6.91-7.06 (m, 2H), 7.76 (d, J=8.7Hz, IH), 8.32
(dd, J=2.4Hz, 8.7Hz, IH), 8.86 (d, J=2.4Hz, IH).10.63 (br, IH).
Example 67: 7-Hydroxy8-propyl-2-(4-pyridyl)chromone methanesulfonate
(Compound 788)
Melting point: 230-233°C.
NMR (DMSO-de, δ)- 0.98 (t, J=7.2Hz, 3H), 1.65 (m, 2H), 2.35 (t, J=7.2Hz,
2H), 2.91 (s, 3H), 7.05 (s, IH), 7.30 (d, J=8.7Hz, IH), 7.80 (d, J=8.7Hz, IH),
8.24 (dd, J=1.2Hz, 6.3Hz, 2H), 8.97 (dd, J=1.2Hz.6.6Hz, 2H), 10.81 (br, IH).
Example 68: 2-(2,4-dimethyl-5-pyrimidyl)-7-hydroxy8-propylchromone
(Compound 794)
Melting point: 179-182°C.
NMR (DMSO-de, (5): 0.91 (t, J=7.5Hz, 3H), 1.54 (m, 2H), 2.65 (s, 3H), 2.68 (s, 3H), 2.74 (t, J=7.2Hz, 2H). 6.62 (s, IH), 7.02 (d, J=8.7Hz. IH), 7.81 (d. J=8.7Hz, IH), 8.87 (s, IH), 10.70 (s, IH).
Example 69: 7-Hydroxy8-propyl-2-(2-pyrazyl)chromone methanesulfonate
(Compound 795)
Melting point: 275-278°C .
NMR (DMSO- de, δ ) - 0.98 (t, J=7.5Hz, 3H), 1.67 (m, 2H), 2.92 (t, J=7.2Hz,
2H), 7.04 (d, J=8.7Hz, IH), 7. 10 (s, IH), 7.80 (d, J=8.4Hz, IH), 8.86-8.89 (m,
2H), 9.29 (d, J=1.2Hz, IH), 10.75 (br, IH).
Example 70: 7-Hydroxy8-propyl-2-(2- quinolyl)chromone l/2sulfate
(Compound 802)
Melting point: 242-245°C .
NMR (DMSO-de, δ )- 1.02 (t, J=7.2Hz, 3H), 1.71 (m, 2H), 2.97 (m, 2H), 7.05 (d,
J=8.7Hz. IH), 7.32 (s, IH), 7.74 (m, IH), 7.83 (d, J=8.7Hz, IH), 7.89 (m, IH),
8.10-8. 17 (m, 2H), 8.40 (d, J=9.0Hz, IH), 8.70 (d, J=8.7Hz, IH), 10.73 (br,
IH).
Example 71 : 7-Hydroxy 8-propyl-2- (l -propyl-2-pyridone- 5-yl)chromone
(Compound 814)
Melting point: >300°C .
NMR (DMSO- de, 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=7.2Hz. 2H), 4.42 (t, J=7.2Hz, 2H), 6.57 (d,
J=9.6Hz, IH), 6.74 (s, IH), 6.97 (d, J=8.7Hz, IH) , 7.73 (d. J=8.7Hz, IH) , 7.99
(dd, J=2.4Hz, 9.6Hz, IH), 8.46 (d, J=2.4Hz, IH).
Example 72: 2- (l -Dimethylaminopropyl-2-pyridone- 5-yl)- 7-hydroxy8- propylchromone (Compound 815)
Melting point: 290-293βC .
NMR (DMSO-de, δ ) - 0.98 (t, J=7.5Hz, 3H) , 1.61 (m, 2H), 1.84 (m, 2H) , 2.13 (s,
6H), 2.22 (t, J=6.6Hz, 2H), 2.86 (t, J=7.8Hz, 2H), 4.05 (t, J=6.9Hz. 2H), 6.56
(d, J=9.3Hz, IH), 6.73 (s, IH). 6.97 (d, J=8.4Hz, IH), 7.73 (d, J=8.4Hz, IH),
8.01 (dd, J=2.4Hz, 9.3Hz, IH). 8.45 (d, J=2.4Hz, IH), 10.61 (br, IH).
Example 73: 3'-Methoxy8-propyl4', 5, 7-trihydroxyflavone (Compound 832) NMR (DMSO- de, 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, IH) , 6.88-6.95 (m, 2H), 7.54- 7.57 (m, 2H), 10.00 (br, 2H), 12.90 (s, IH) .
Test Example: Inhibitory activity of the medicament of the present invention against P-GS l phosphorylation by bovine cerebral TPKl :
A mixture containing 100 mM MES-sodium hydroxide (pH 6.5), 1 mM magnesium acetate , 0.5 mM E GTA, 5 mM β mercaptoethanol, 0.02% Tween 20, 10% glycerol, 12 μg/ml P- GS l , 41.7 μM [ γ -32P] ATP (68 kBq/ml) , bovine cerebral TPKl and a compound shown in Table (a final mixture contained 1.7% DMSO deriving from a solution of a test compound prepared in the presence of 10% DMSO) was used as a reaction system. The phosphorylation was started by adding ATP, and the reaction was conducted at 25°C for 2 hours, and then stopped by adding 21% perchloric acid on ice cooling. The reaction mixture was centrifuged at 12.000 rpm for 5 minutes and adsorbed on P81 paper (Whatmann), and then the paper was washed four times with 75 mM phosphoric acid, three times with water and once with acetone . The paper wa s dried, and the residual radioactivity was measured using a liquid scintillation counter. The results are shown in the table below. The test compound markedly inhibited the P-GSl phosphorylation by TPKl . The results strongly suggest that the medicaments of the present invention inhibit the TPKl activity, thereby suppress the A β neurotoxicity and the PHF formation, and that the medicaments of the present invention are effective for preventive and/or therapeutic treatment of Alzheimer disease and the above-mentioned diseases.
Table 9
Example (Compound No.) Inhibitory rate at 10 j M(%)
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 (365) 75.4
(386) 84.7
(389) 79.3
(391) 72.4
(392) 87.1
(393) 77.1
(491) 88.9
(502) 76.4
(503) 95.6
(504) 86.8
(512) 77.7
(521) 89.0
(523) 91.0
(554) 87.1
(560) 95.8
(561) 94.0
(593) 84.6
(680) 90.4
(681) 85.8
(684) 96.2
(690) 93.5
(785) 81.2
(786) 74.8
(788) 74.9
(794) 71.5
(815) 78.2 Formulation Example
(1) Tablets
The ingredients below were mixed by an ordinary method and compressed by 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 capsules
The ingredients below were mixed by an ordinary method and filled in soft capsules.
Compound of Example 2 30 mg
Olive oil 300 mg
Lecithin 20 mg
(3) Parenteral preparations
The ingredients below were mixed by an ordinary method to prepare injections contained in a 1 ml ample . Compound of Example 1 0.1 mg
Sodium chloride 4 mg
Distilled water for infection 1 ml
Industrial Applicability
The medicaments of the present invention have TPKl inhibitory activity and are useful for preventive and/or therapeutic treatment of diseases caused by TPKl hyperactivity such as Alzheimer disease.

Claims

ClcLi. ms
1. A medicament for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity or a neurodegenerative disease which comprises as an active ingredient a substance selected from the group consisting of a hydroxyflavone derivative represented by formula (I) and a salt thereof, and a solvate thereof and a hydrate thereof:
Figure imgf000140_0001
wherein R1 represents hydrogen atom or hydroxyl group; R2 represents hydrogen atom or a Ci-Ci╬▓ alkyl group which may have one or more C6-C14 aryl groups; and Ar represents a C╬▓-C aryl group which may be substituted or an aromatic heterocyclic group which may be substituted.
2. A medicament for preventive and/or therapeutic treatment of a neurodegenerative disease which comprises as an active ingredient a substance selected from the group consisting of a hydroxyflavone derivative represented by formula (I) according to claim 1 and a salt thereof, and a solvate thereof and a hydrate thereof.
3. The medicament according to claim 2, wherein the disease is selected from the group consisting of Alzheimer disease, ischemic cerebrovascular accidents, Down syndrome, cerebral bleeding due to cerebral amyloid angiopathy, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephahtic parkinsonism, pugilistic encephalitis, Guam parkinsonism-dementia complex. Lewy body disease, Pick's disease, corticobasal degeneration, and frontotemporal dementia.
4. A tau protein kinase 1 inhibitor selected from the group of a hydroxyflavone derivative represented by formula (I) according to claim 1 and a salts thereof, and a solvate thereof and a hydrate thereof.
5. A hydroxyflavone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof:
Figure imgf000141_0001
wherein R1 represents hydrogen atom or hydroxyl group; R2 represents hydrogen atom or a Ci-Cis alkyl group which may have one or more C╬▓-C aryl groups; and Ar represents a C╬▓-Ci4 aryl group which may be substituted or an aromatic heterocyclic group which may be substituted, and where R2 is hydrogen atom, Ar represents a group represented by formula (II)
Figure imgf000141_0002
wherein R3, R4, R5, R6, and R7, independently represent hydrogen atom, a CrCis alkyl group which may be substituted, a CrCis alkoxyl group which may be substituted, hydroxyl group, an acyloxy group which may be substituted, carboxyl 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, nitro group, or a cyano group, provided that any one of R3, R4, R5, R6, and R7 represents a group represented by formula (III): -X-(CH2)m-R8 wherein R8 represents an amino group which may be substituted or a nitrogen-containing saturated heterocyclic group which may be substituted, X represents single bond or oxygen atom, and m is an integer of from 1 to 8; and provided that those wherein R1 is hydrogen atom, R2 is methyl group, and Ar is phenyl group, a 3,4-methylenedioxyphenyl group, or a 3-pyridyl group, those wherein R1 is hydrogen atom, R2 is propyl group, and Ar is phenyl group having a carboxyl group or an ester group in the 4-position, and those wherein R1 is hydroxyl group, R2 is methyl group, and Ar is phenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, or 3,4-dimethoxyphenyl group are excluded.
6. A hydroxyflavone derivative represented by formula (IV) or a salt thereof, or a solvate thereof or a hydrate thereof:
Figure imgf000142_0001
wherein R1 represents hydrogen atom or hydroxyl group ; Z represents an amino group which may be substituted or a nitrogen-containing saturated heterocyclic group which may be substituted; n represents an integer of from 1 to 8; R5 represents hydrogen atom, a CrCis alkoxyl group; and R6 represents hydrogen atom or hydroxyl group.
7. The hydroxyflavone derivative according to claim 6 or a salt thereof, or a solvate thereof or a hydrate thereof, wherein n is 2 or 3.
8. The hydroxyflavone derivative according to claim 6 or a salt thereof, or a solvate thereof or a hydrate thereof, wherein R5 is hydrogen atom or methoxy group.
9. The hydroxyflavone derivative according to claim 6 or a salt thereof, or a solvate thereof or a hydrate thereof, wherein Z is dimethylamino group, piperazinyl group which may be substituted, or piperidinyl group which may be substituted.
10. A hydroxyflavone derivative represented by formula (V) or a salt thereof, or a solvate thereof or a hydrate thereof:
Figure imgf000143_0001
wherein R2 represents hydrogen atom or a Ci-Ci╬▓ alkyl group which may have one or more C╬▓-C aryl groups; R4 represents a CrCis alkyl group which may be substituted, a Ci-Ci╬▓ alkoxyl group which may be substituted, hydroxyl group, an acyloxy group which may be substituted, carboxyl 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, nitro group, or a cyano group; and R5 represents hydrogen atom, hydroxyl group, methoxy group, or nitro group.
11. The hydroxyflavone derivative according to claim 10 or a salt thereof, or a solvate thereof or a hydrate thereof, wherein R4 is a CrCis alkyl group which may be substituted, a CrCis alkoxyl group which may be substituted, hydroxyl group, nitro group, or a cyano group.
12. A hydroxyflavone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof:
Figure imgf000144_0001
wherein R1 represents hydrogen atom or hydroxyl group; R2 represents hydrogen atom or a CrCis alkyl group which may have one or more C╬▓-Cu aryl groups; and Ar represents an aromatic heterocyclic group which may be substituted, provided that those wherein R1 is hydrogen atom; R2 is methyl group, and Ar is a pyridyl group are excluded.
13. A hydroxyflavone derivative or a salt thereof, or a solvate thereof or a hydrate thereof which is selected from the group consisting of: 7-hydroxy3'-(3-(l-piperidyl)propyloxy)-8-propylflavone, 4l,7-dihydroxy3'-methoxy8-propylflavone, 7-hydroxy8-methyl-3'-(3-(l-piperidyl)propyloxy)flavone, 7-hydroxy4'-nitro-3'-(3-(l-piperidyl)propyloxy)-8-propylflavone. 4',7-dihydroxy3'-methoxy8-methylflavone, and 7-hydroxy8-propyl-2-(4-pyridyl)chromone.
14. A medicament comprising a substance selected from the group consisting of a hydroxyflavone derivative according to any one of claims 5 to 13 and a salt thereof, and a solvate thereof and a hydrate thereof.
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