CN1326450A - Hydroxyflavone derivatives as tau protein kinase inhibitors - Google Patents
Hydroxyflavone derivatives as tau protein kinase inhibitors Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- 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
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- 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
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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
- C07D405/12—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
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 R<1> represents hydrogen atom or hydroxyl group; R<2> represents hydrogen atom or a C1-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
Technical field
The present invention relates to as active constituents of medicine to prevent and/or treat the disease that causes by tau protein kinases 1 hyperactivity (hyperactivty), for example the compound of Alzheimer etc.The invention still further relates to new Hydroxyflavone derivatives as the activeconstituents of said medicine.
Technical background
Alzheimer is progressive senile dementia, and the minimizing that wherein can be observed owing to neurocyte degeneration and neurocyte quantity causes tangible pallium atrophy.On pathology, at visible a large amount of senile plaque and the neurofibrillary tangleses of brain.Patient's quantity increases along with the increase of elderly population, and a series of social concern causes because of this disease.Although proposed a lot of theories, the cause of disease that should disease is not still illustrated.Make a clear distinction the cause of disease as early as possible still among expectation.
The appearance degree of two characteristic pathological changes of known Alzheimer and dysnoesia degree height correlation.Therefore, the research that discloses this sick cause of disease by component in early days from the eighties in 20th century at these two pathological changes of molecular level investigation.Senile plaque is assembled in the extracellular, and illustrated amyloid beta protein be its main component (this specification sheets hereafter is for " A β ": Biochem.Biophys.Res.Commun, 120,855 (1984); EMBO J., 4,2757 (1985); Proc.Natl.Acad.Sci.USA, 82,4245 (1985)).Another pathological change, promptly, in the neurofibrillary tangles, the duplex rope that is called pairing taenidium (this specification sheets hereafter is " PHF ") is assembled in cell, and have been found that τ-albumen (for the distinctive microtubule-associated protein of a kind of brain) is its main component (Proc.Natl.Acad.Sci.USA, 85,4506 (1988); Neuron, 1,827 (1988)).
In addition, on the basis of gene studies, find that presenilin genes (presenilins) 1 and 2 is Disease-causing gene (Nature, 375,754 (1995) of familial Alzheimer; Sience, 269,973 (1995); Nature, 376,775 (1995)), and the existence that has been found that presenilin genes 1 and 2 mutation can promote secretion (Neuron, 17,1005 (1996) of A β; Proc.Natl.Acad.Sci.USA, 94,2025 (1997)).According to these results, it is generally acknowledged that in Alzheimer, A β is unusual for some reason assembles and cohesion, causes the formation of PHF and then causes nerve cell death.General also think L-glutamic acid flow out the outer and glutamate receptor of born of the same parents this outflow is reacted and be activated may be the cerebrovascular ischemia accident cause nerve cell death commitment in important factor (Sai-shin Igaku[Latest Medicine], 49,1506 (1994)).
Reported the Helminal processing, it stimulates ampa receptor, a kind of glutamate receptor, can increase mRNA (the Society for Neuroscience Abstracts of amyloid precursor protein (this specification sheets abbreviates " APP " hereinafter as) as A β precursor, 17,1445 (1991)), but also promote APP metabolism (The Journal of Neuroscience, 10,2400 (1990)).Therefore, it is relevant with the A beta peptide aggregation that this obviously points out the necrocytosis due to the ischemic cerebrovascular disease.Having been found that A β is unusual assembles and other disease of cohesion comprises, for example, the cerebral hemorrhage that Down syndrome, cerebral amyloid angiopathy cause, Lewy body disease (Shin-kei Shipo[Nerve Advance], 34,343 (1990); Tanpaku-shitu Kaku-san Koso[Protein.Nucleic Acid, Enzyme], 41,1476 (1996.)) etc.In addition, the example of assembling the disease that shows neurofibrillary tangles owing to PHF comprises, shaking palsy after stein-leventhal syndrome, subacute sclerosing panencephalitis shaking palsy, the encephalitis, prizefight encephalitis, Guam shaking palsy-dementia, Lewy body disease or the like (Tanpakushitu Kakusan Koso[Protein.Nucleic Acid, Enzyme], 36,2 (1991); Igaku no Ayumi[Progress ofMedicine], 158,511 (1991); Tanpakushitu Kakusan Koso[Protein.Nucleic Acid, Enzyme], 41,1476 (1996)).
The related protein that tau protein is 48-65kDa by one group of molecular weight that forms several bands in the SDS-polyacrylamide gel electrophoresis is usually formed, and it promotes microtubule to form.Verified and common tau protein is compared in the brain of suffering from Alzheimer tau protein with the PHF bonded by unusual phosphorylation (J.Biochem., 99,1807 (1986); Proc.Natl.Acad.Sci.USA, 83,4913 (1986)).A kind of enzyme of this unusual phosphorylation of catalysis is separated.This protein is named as tau protein kinases 1 (abbreviating " TPK1 " at this specification sheets hereinafter as), and its physico-chemical property is illustrated (Seikagaku[Biochemistry], 64,308 (1992), J.Biol.Chem., 267,10897 (1992)).In addition, partial amino-acid series with TPK1 serves as that the cDNA of rat TPK1 has been cloned on the basis from rat cerebral cortex cDNA library, and has measured its nucleotide sequence and derived aminoacid sequence (open [Kokai] number 6-239893/1994 of Japanese patent unexamined).Consequently disclose the original texture consistent with the enzyme that is called rat GSSK-3 β (glycogen synthase kinase 3 β, FEBS Lett., 325,167 (1993)) of rat TPK1.
The main ingredient A β that has reported senile plaque has neurotoxicity (Science, 250,279 (1990)).Yet, how to cause necrocytosis that multiple theoretical the proposition arranged for A β, but still be established without any a kind of reliable theory.Discovery A β such as Takashima handle the former system of supporting that is commissioned to train of suckling mouse hippocampus and cause necrocytosis, and find that thus A β handles the activity increase of back TPK1 and the necrocytosis due to the A β is suppressed (Proc.Natl.Acad.Sci.USA by antisense TPK1,90,7789 (1993); Open [Kokai] number 6-329551/1994 of Japanese patent unexamined)).
In sum, suppress the active compound of TPK1 and may be able to suppress the neurotoxicity of A β and PHF and form and suppress necrocytosis in the Alzheimer, thereby stop or delay PD.These compounds also may be used as medicine and treat cerebral hemorrhage that ischemic cerebrovascular disease, Down syndrome, brain amyloid blood vessel disease, Lewy body disease cause etc. by the neurotoxicity that suppresses A β.In addition, these compounds also may be used as medicine and treat neurodegenerative disease such as stein-leventhal syndrome, subacute sclerosing panencephalitis shaking palsy, encephalitis after shaking palsy, prizefight encephalitis, Guam shaking palsy-chronic brain syndrome, Lewy body disease, Pick's disease, cortical degeneration and volume temporo dementia.
Of the present invention open
The purpose of this invention is to provide as the compound that prevents and/or treats as the active constituents of medicine of diseases such as Alzheimer.More particularly, the new compound that provides as active constituents of medicine is provided, TPK1 is active to suppress the neurotoxicity of A β and PHF forms and enable active prevention and/or treat disease as Alzheimer by suppressing nerve cell apoptosis by suppressing for it.Another object of the present invention provides the new compound as active constituents of medicine with above-mentioned characteristic.
For achieving the above object, the present inventor has screened has the active multiple compound of the TPK1 phosphorylation of inhibition.As a result, their compound of finding following structural (I) representative has required activity and useful as drug activeconstituents and prevents and/or treats above-mentioned disease.Of the present invention finishing based on these discoveries.
Therefore the invention provides and prevent and/or treat the disease that caused by tau protein kinases 1 hyperactivity or the medicine of neurodegenerative disease, its material as activeconstituents that comprises is selected from one group by the Hydroxyflavone derivatives of following formula (I) representative and material and their salt, solvate and the hydrate of solvate and hydrate thereof:
Wherein, R
1Represent hydrogen atom or hydroxyl; R
2Represent hydrogen atom or C
1-C
18Alkyl, it can contain a C
6-C
14Aryl; And the Ar representative can substituted C
6-C
14Aryl or can substituted aromatic heterocyclic group.
According to the preferred embodiments of the invention, this paper provides above-mentioned medicine, and wherein disease is selected from shaking palsy after cerebral hemorrhage due to Alzheimer, ischemic cerebral vascular accident, Down syndrome, the brain amyloid disease, stein-leventhal syndrome, subacute sclerosing panencephalitis shaking palsy, the encephalitis, boxing property encephalitis, Guam shaking palsy-chronic brain syndrome, Lewy body disease, Pick's disease, cortex substrate degeneration and volume temporo dementia.As preferred embodiment, also have the said medicine of medicinal compositions form, it contains as the above-mentioned substance of activeconstituents and one or more medicinal additive.The present invention further provides tau protein kinases 1 inhibitor, it is selected from the one group of material that comprises formula (I) Hydroxyflavone derivatives and salt, its solvate and its hydrate.
According to another aspect of the present invention, this paper provides the method that prevents and/or treats the disease that is caused by tau protein kinases 1 hyperactivity, its step comprise with the effective amount of preventing and/or treating be selected from one group comprise acceptable salt on formula (I) Hydroxyflavone derivatives and the physiology thereof, and the material of solvate and hydrate give the patient; And be selected from one group and comprise acceptable salt on formula (I) Hydroxyflavone derivatives and the physiology thereof, and the purposes of material in the preparation said medicine of solvate and hydrate.
According to a further aspect of the invention, this paper provides Hydroxyflavone derivatives or its salt, solvate or the hydrate of formula (I) representative:
Wherein, R
1Represent hydrogen atom or hydroxyl; R
2Represent hydrogen atom or C
1-C
18Alkyl, it can contain a C
6-C
14Aryl, and the Ar representative can substituted C
6-C
14Aryl or can substituted aromatic heterocyclic group.And its R
2During for hydrogen atom, Ar represents the group of formula (II) expression
R wherein
3, R
4, R
5, R
6And R
7Represent independently hydrogen atom, can substituted C
1-C
18Alkyl, can substituted C
1-C
18Alkoxyl group, hydroxyl, can substituted acyloxy, carboxyl, can substituted carbalkoxy, can substituted carbamyl, can substituted alkyl-carbonyl, can substituted amino, nitro or cyano group.
Condition is to work as R
3, R
4, R
5, R
6And R
7In any one representative formula (III) :-X-(CH
2)
m-R
8The group of expression, wherein R
8Expression can substituted amino or nitrogenous saturated heterocyclyl, and it can be substituted, and X represents singly-bound or Sauerstoffatom, and m is from 1 to 8 integer; And
Condition is R wherein
1Be hydrogen atom, R
2Be methyl, and Ar is a phenyl, 3,4-methylenedioxyphenyl, or those compounds of 3-pyridyl, wherein R
1Be hydrogen atom, R
2Be propyl group, and Ar is those compounds that contain the phenyl of carboxyl or ester group on 4, and R wherein
1Be hydroxyl, R
2Be methyl, and Ar is phenyl, 4-hydroxy phenyl, 4-p-methoxy-phenyl, or 3, those compounds of 4-Dimethoxyphenyl are left out.
The preferred embodiment above-mentioned according to the present invention provides:
Hydroxyflavone derivatives or its salt of formula (IV) representative, its solvate or its hydrate:
R wherein
1Represent hydrogen atom or hydroxyl; Z representative can substituted amino or nitrogen heterocycle, and it can be substituted; The integer of n representative from 1 to 8; R
5Represent hydrogen atom, C
1-C
15Alkoxyl group; And R
6Represent hydrogen atom or hydroxyl;
Hydroxyflavone derivatives or its salt of formula V representative, its solvate or its hydrate:
R wherein
2Represent hydrogen atom or C
1-C
18Alkyl, it can contain one or more C
6-C
14Aryl; R
4Representative can substituted C
1-C
18Alkyl, can substituted C
1-C
18Alkoxyl group, hydroxyl, can substituted acyloxy, carboxyl, can substituted carbalkoxy, can substituted carbamyl, can substituted alkyl-carbonyl, can substituted amino, nitro, or cyano group; And R
5Represent hydrogen atom, hydroxyl, methoxyl group, or nitro; And
Hydroxyflavone derivatives or its salt of formula (I) representative, its solvate or its hydrate:
Wherein, R
1Represent hydrogen atom or hydroxyl; R
2Represent hydrogen atom or C
1-C
18Alkyl, it can contain one or more C
6-C
14Aryl, and Ar represents aromatic heterocyclic group, it can be substituted, and condition is R wherein
1Be hydrogen atom, R
2Be methyl, and Ar is that those compounds of pyridyl are left out.
Indian J.Chem.Sect.B, Org.Chem.Incl.Med.Chem., 35B, 1253 (1996) disclose above-mentioned formula (I) compound, wherein R
1Be hydrogen atom, R
2Be allyl group, and Ar is phenyl, 4-tolyl, or the 4-chloro-phenyl-; Indian J.Chem.Sect.B, 30B, 93 (1991) disclose above-mentioned formula (I) compound, wherein R
1Be hydrogen atom, R
2Be 1-phenyl-2-propenyl, or 1-phenyl-1-propenyl, and Ar is a phenyl; IndianJ.Chem.Sect.B, 26B, 229 (1991) .J.Indian Chem.Soc., 60,411 (1983) and IndianJ.Indian Chem.Soc., 49,283 (1972) disclose above-mentioned formula (I) compound, wherein R
1Be hydrogen atom, R
2Be methyl, and Ar is a phenyl; IndianJ.Chem.Sect.B, 19B, 866 (1980) disclose above-mentioned formula (I) compound, wherein R
1Be hydrogen atom, R
2Be 1,2-dimethyl-2-propenyl, and Ar is a phenyl; And Ann.Pharm.France, 18,528 (1960) disclose above-mentioned formula (I) compound, wherein R
1Be hydrogen atom, R
2Be methyl, and Ar is 3, the 4-methylenedioxyphenyl.
Phytochemistry, 19,2179 (1980) disclose above-mentioned formula (I) compound, wherein R
1Be hydrogen atom, R
2Be 3-methyl-2-butene base, and Ar is the 4-hydroxy phenyl; IndianJ.Chem.Sect.B, 18B, 525 (1979) disclose above-mentioned formula (I) compound, wherein R
1Be hydrogen atom, R
2Be allyl group, and Ar is the phenyl that contains methoxyl group in 2-, 3-or 4-position; Indian J.Chem.Sect.B, 15B, 933 (1977) and Tetrahedron Lett., 1977,473 (1977) disclose above-mentioned formula (I) compound, wherein R
1Be hydrogen atom, R
2Allyl group, and Ar is a phenyl; And Bull.Soc.Chim.FR1960,95 (1960) disclose above-mentioned formula (I) compound, wherein R
1Be hydrogen atom, R
2Methyl, and Ar is the 3-pyridyl;
J.Indian Chem.Soc., 65,149 (1988) and Indian J.Chem.Sect.B, 20B, 624 (1981) disclose above-mentioned formula (I) compound, wherein R
1Be hydroxyl, R
2Be methyl, and Ar is 3, the 4-methylenedioxyphenyl; Tetrahedron, 31,265 (1975) disclose above-mentioned formula (I) compound, wherein R
1Be hydroxyl, R
2Be methyl, and Ar is a phenyl; Indian J.Chem., 4,481 (1966) disclose above-mentioned formula (I) compound, wherein R
1Be hydroxyl, R
2Be methyl, and Ar is the 4-p-methoxy-phenyl; And Phytochemistry, 22,2107 (1983) disclose above-mentioned formula (I) compound, wherein R
1Be hydroxyl, R
2Be methyl, and Ar is the 4-hydroxy phenyl;
In addition, U.S. Patent number 4042708 and German patent 2454670 disclose above-mentioned formula (I) compound that has the synthetic intermediate of anti-SRS active compound as preparation, wherein R
1Be hydroxyl, R
2Be propyl group, and Ar is the phenyl that contains 4-carboxyl or 4-ethoxy carbonyl; And do not examine disclosed Japanese patent publication [Kokai] number 8-225563/1996 and disclose above-mentioned formula (I) compound that is used for the treatment of chronic venous insufficiency, wherein R
1Be hydroxyl, R
2Be propyl group, and Ar is a 3-hydroxy-4-methyl phenyl.Yet unknown so far all these compounds have the activity that suppresses TPK1.Realize best mode of the present invention
" alkyl " used herein or the moieties that contains the functional group (for example, alkoxyl group) of moieties can be straight chain, ring-type or side chain.R
2The alkyl of representative can be, for example, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclobutyl, n-pentyl, isopentyl, neo-pentyl, 1,1-dimethyl propyl, cyclopentyl, n-hexyl, isohexyl, cyclohexyl, or straight or branched heptyl, octyl group, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, octadecyl or the like.
R
2Representative contain C
6-C
14The C of aryl
1-C
18The example of alkyl comprises, for example, and above-mentioned C
1-C
18Alkyl, it is by replacements such as phenyl, naphthyl, anthryls.More specifically, example comprises benzyl, 1-naphthyl methyl, 2-naphthyl methyl, 1-styroyl (Phenetyl), 2-styroyl, 3-hydrocinnamyl, 4-phenyl butyl etc.The C of Ar representative
6-C
14The example of aryl comprises, for example, and phenyl, 1-naphthyl, 2-naphthyl, anthryl or the like.
In this manual, when functional group was defined as " it can be substituted " or " the optional replacement ", its substituting group quantity and type and the position of substitution had no particular limits, and when two of existence or more substituting group, they can be identical or different.When the aryl of Ar representative had one or more substituting group, this aryl had one or more substituting group, and it is selected from by C
1-C
18Alkyl form as preamble to explaining R
2Those groups; C
1-C
8Alkoxyl group such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base and ring octyloxy; C
1-C
8Alkylthio such as methylthio group, ethylmercapto group, rosickyite base, iprotiazem base, butylthio, isobutyl sulfenyl, uncle's butylthio, penta sulfenyl; Methylene-dioxy; C
6-C
10Aryl such as phenyl, 1-naphthyl and 2-naphthyl; Fluorenyl; C
6-C
14Aryloxy such as phenoxy group and naphthyloxy; C
6-C
14Arylthio such as thiophenyl, naphthalene sulfenyl; C
1-C
5Alkyl sulphonyl such as methylsulfonyl, ethylsulfonyl, third alkylsulfonyl, fourth alkylsulfonyl and penta alkylsulfonyl; C
6-C
14Aryl sulfonyl such as benzenesulfonyl and naphthalene sulfonyl base; Halogen atom (term used herein " halogen atom " or " halogen " comprise any one in fluorine atom, chlorine atom, bromine atoms and the iodine atom); C
1-C
18Haloalkyl such as trifluoromethyl; Hydroxyl; Nitro; The oxygen base; Formyl radical; Cyano group; Carboxyl; C
2-C
6Carbalkoxy such as methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl and pentyloxy carbonyl; C
2-C
6Alkyl-carbonyl such as ethanoyl, propionyl, butyryl radicals and pentanoyl; C
2-C
6Alkyl carbonyl oxy such as acetoxyl group, propionyloxy, butyryl acyloxy and penta acyloxy; C
6-C
14Aryl-carbonyl oxygen such as benzoyloxy and naphthoyl oxygen base; Amino; C
1-C
5Alkyl monosubstituted amino such as methylamino, ethylamino, propyl group amino, sec.-propyl amino, butyl amino, isobutylamino, tertiary butyl amino, amyl group amino and isopentyl amino; C
2-C
10Dialkyl amido (two alkyl can be same to each other or different to each other) is as dimethylamino, ethylmethylamino, diethylamino, methyl-propyl amino and diisopropylaminoethyl; C
2-C
6Alkyl-carbonyl-amino such as kharophen, propionamido, different propionamido, butyrylamino and valeryl amino; Carbamyl; C
2-C
6Alkylcarbamoyl group such as methyl carbamyl, ethyl carbamyl, propyl group carbamyl, butyl carbamyl, tertiary butyl carbamyl and amyl group carbamyl; C
3-C
9Dialkyl amino formyl radical such as dimethylamino formyl radical, diethyl amino formyl radical, dipropyl carbamyl, di-isopropyl carbamyl and dibutylamine formyl radical; Contain 1-4 and be selected from Sauerstoffatom, the heteroatoms of sulphur atom and nitrogen-atoms, and amount on the ring and contain 5-10 heterocycle residue that becomes annular atoms, for example, furan nucleus, the dihydrofuran ring, the tetrahydrofuran (THF) ring, pyranoid ring, the dihydropyrane ring, amylene oxide ring, the cumarone ring, the isobenzofuran ring, the chromene ring, the chroman ring, the isochroman ring, thiphene ring, the thionaphthene ring, pyrrole ring, the pyrroline ring, pyrrolidine ring, imidazole ring, the tetrahydroglyoxaline ring, the imidazolidine ring, the pyrazoles ring, the pyrazoline ring, the pyrazolidine ring, triazole ring, tetrazole ring, pyridine ring, the pyridine oxide ring, piperidine ring, the pyrazine ring, piperazine ring, pyrimidine ring, the pyridazine ring, the indolizine ring, indole ring, the indoline ring, the isoindole ring, the isoindoline ring, the indazole ring, the benzoglyoxaline ring, purine skeleton, the quinolizine ring, the quinoline ring, the phthalazines ring, the naphtylidine ring, quinoxaline ring, the quinazoline ring, the cinnolines ring, the pyridine ring oxazole ring oxazolidine ring isoxazole ring isoxazole alkyl ring of talking endlessly, thiazole ring, the benzothiazole ring, the thiazolidine ring, the isothiazole ring, isothiazolidine ring diox ring, the dithiane ring, the morpholine ring, the thiomorpholine ring, phthalic imidine ring or the like (this group substituting group is called as " A organizes substituting group ").For A group substituting group, aryl and heterocyclic radical can further contain the one or more A of being selected from organizes substituent substituting group.
The example of the aromatic heterocyclic group that Ar represents comprises, for example, contain 1-4 heteroatoms that is selected from Sauerstoffatom, sulphur atom and nitrogen-atoms respectively, and ring is gone up the aromatic heterocycle residue that total contains 5-10 one-tenth annular atoms.These aromatic heterocyclic groups can the ring on any position Cheng Jian.More specifically, example comprises the residue of furan nucleus, cumarone ring, isobenzofuran ring, thiphene ring, thionaphthene ring, pyrrole ring, imidazole ring, pyrazoles ring, triazole ring, tetrazole ring, pyridine ring, pyrazine ring, pyrimidine ring, pyridazine ring, indole ring, isoindole ring, indazole ring, benzoglyoxaline ring, purine skeleton, quinoline ring, isoquinoline 99.9 ring, phthalazines Huan, oxazole ring, isoxazole ring, thiazole ring, benzothiazole ring, isothiazole ring etc.These aromatic heterocyclic groups can have the one or more A of being selected to organize substituent substituting group.
R
3To R
7The C of representative
1-C
18The example of alkyl comprises above-mentioned to R
2Those groups of explaining, and these alkyl can contain the one or more A of being selected from and organize substituent substituting group.R
3To R
7The example of alkoxyl group of representative comprises, for example, and C
1-C
18Alkoxyl group such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, ring propoxy-, n-butoxy, isobutoxy, tert.-butoxy, cyclobutoxy group, n-pentyloxy, isopentyloxy, cyclopentyloxy, positive hexyloxy, different hexyloxy, cyclohexyloxy, and straight chain, side chain or cyclic oxygen in heptan base, octyloxy, the ninth of the ten Heavenly Stems oxygen base, the last of the ten Heavenly stems oxygen base, undecane oxygen base, dodecyloxy, tridecane oxygen base, tetradecyloxyaniline, pentadecane oxygen base, n-Hexadecane oxygen base, heptadecane oxygen base, octadecane oxygen base etc.These alkoxyl groups can have the one or more A of being selected to organize substituent substituting group.
R
3To R
7The example of acyloxy of representative comprises, for example, and C
2-C
6Alkyl-carbonyl oxygen base such as acetoxyl group, propionyloxy, butyryl acyloxy and penta acyloxy; And C
6-C
14Aryl carbonyl oxygen base such as benzoyloxy and naphthoyl oxygen base.The aryl moiety of the moieties of alkyl-carbonyl oxygen base and aryl carbonyl oxygen base can have the one or more A of being selected to organize substituent substituting group.R
3To R
7The example of carbalkoxy of representative comprises, for example, and C
2-C
6Carbalkoxy such as methoxycarbonyl, ethoxycarbonyl, the positive third oxygen carbonyl, the different third oxygen carbonyl, positive butoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl and positive penta oxygen carbonyl.The moieties of carbalkoxy can have the one or more A of being selected to organize substituent substituting group.
Work as R
3To R
7When the carbamyl of representative had one or more substituting group, the example of carbamyl comprised, for example, and C
2-C
6Monoalkyl carbamyl such as methyl carbamyl, ethyl carbamyl, propyl group carbamyl, butyl carbamyl, tertiary butyl carbamyl and amyl group carbamyl; C
3-C
9Dialkyl amino formyl radical (two alkyl can be mutually the same or inequality) is as dimethylamino formyl radical, diethyl amino formyl radical, dipropyl carbamyl, di-isopropyl carbamyl and dibutylamine formyl radical etc.; The moieties of abovementioned alkyl carbamyl and dialkyl amino formyl radical can have the one or more A of being selected to organize substituent substituting group.
Work as R
3To R
7When the amino of representative had one or more substituting group, the example comprised C
1-C
5Monoalkyl amido such as methyl amido, ethylamino, propyl group amino, sec.-propyl amino, butyl amino, isobutylamino, tertiary butyl amino, amyl group acyl group, isopentyl carbamyl; C
2-C
10Dialkyl amino such as dimethylamino, ethylmethylamino, diethylamino, methyl-propyl amino and diisopropylaminoethyl; C
2-C
6Alkyl-carbonyl-amino such as kharophen, propionamido, different propionamido, butyrylamino and valeryl amino etc.The moieties of above-mentioned alkyl monosubstituted amino and dialkyl amido can have the one or more A of being selected to organize substituent substituting group.Work as R
8When the amino of representative has one or more substituting group, this group can be selected from above-mentioned to R
3To R
7Those substituted amino of explaining.
R
8Number of nitrogen atoms in the saturated nitrogen heterocyclic ring group of representative has no particular limits, and can contain one or more non-nitrogen heteroatom (for example Sauerstoffatom, sulphur atom etc.).This saturated nitrogen heterocyclic ring group can be substituted any position on ring.More particularly, example comprises the residue of pyrrolidine ring, piperidine ring, piperazine ring, high piperidines (homopiperidine) ring, high piperazine (homopiperazine) ring, morpholine ring, thiomorpholine ring etc.Saturated nitrogen heterocyclic ring group can be by the one or more substituent replacement that is selected from the A group.
When the amino of Z representative had one or more substituting group, this group can be to be selected from above-mentioned R
3To R
7Those substituted amino of explaining.The example of the saturated nitrogen heterocyclic ring group of Z representative comprises pyrrolidine ring, pyrazolidine ring, imidazolidine ring, thiazolidine ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring, rubane etc.
Except that the compound of above-mentioned formula (I) representative, acceptable salt can be as the activeconstituents of medicine of the present invention on their physiology.The example of these salt comprises, when having acidic-group, and an alkali metal salt and alkaline earth salt such as lithium, sodium, potassium, magnesium and calcium salt; Ammonium and amine salt such as methylamine, dimethylamine, Trimethylamine 99, dicyclohexyl amine, three (methylol) aminomethane, N, two (hydroxyethyl) piperazines of N-, 2-amino-2-methyl-1-propanol, thanomin, N-methylglucosamine and L-glycosamine; Or the salt that forms with basic aminoacids such as Methionin, δ-oxylysine and arginine.When having basic group, example comprises the salt that forms with mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid; The salt that forms with organic acid such as methylsulfonic acid, Phenylsulfonic acid, right-toluenesulphonic acids, acetate, propionic acid, tartrate, fumaric acid, toxilic acid, oxysuccinic acid, oxalic acid, succsinic acid, citric acid, phenylformic acid, amygdalic acid, styracin, lactic acid, oxyacetic acid, glucuronic acid, xitix, nicotinic acid and Whitfield's ointment; Or the salt that forms with acidic amino acid such as aspartic acid and L-glutamic acid.
Hydroxyflavone derivatives and the solvate of salt and the activeconstituents that hydrate also can be used as medicine of the present invention of above-mentioned formula (I) representative.And the Hydroxyflavone derivatives of above-mentioned formula (I) representative may have one or more unsymmetrical carbon.For the stereochemistry of these unsymmetrical carbons, they can be (R) or (S) configuration independently, and this Hydroxyflavone derivatives can be used as steric isomer such as optically active isomer, or diastereomer exists.The steric isomer of any respective pure form, any stereoisomer mixture, raceme or the like can be as the activeconstituentss of medicine of the present invention.In addition, can there be tautomer in the 4-ketone and the 4-oxy-compound of the Hydroxyflavone derivatives of above-mentioned formula (I) representative.The existence of these tautomers is conspicuous for those skilled in that art, and all these tautomers are also included within the scope of the present invention.
The example of preferred The compounds of this invention is as shown in the table.Yet scope of the present invention is not subjected to the restriction of following compounds.
Table 1
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 2
Table 2 (continuing)
Table 2 (continuing)
Table 2 (continuing)
Table 2 (continuing)
Table 2 (continuing)
Table 2 (continuing)
Table 2 (continuing)
Table 2 (continuing)
Table 2 (continuing)
Table 2 (continuing)
Table 2 (continuing)
Table 2 (continuing)
Table 3
Table 3 (continuing)
Table 3 (continuing)
Table 3 (continuing)
Table 3 (continuing)
Table 3 (continuing)
Table 3 (continuing)
Table 3 (continuing)
Table 3 (continuing)
Table 3 (continuing)
Table 3 (continuing)
Table 3 (continuing)
Table 3 (continuing)
Table 3 (continuing)
Table 3 (continuing)
Table 3 (continuing)
Table 3 (continuing)
Table 3 (continuing)
Table 3 (continuing)
Table 3 (continuing)
Table 4
Table 4 (continuing)
Table 4 (continuing)
Table 4 (continuing)
Table 4 (continuing)
Table 4 (continuing)
Table 4 (continuing)
Table 4 (continuing)
Table 4 (continuing)
Table 4 (continuing)
Table 4 (continuing)
Table 4 (continuing)
Table 4 (continuing)
Table 4 (continuing)
Table 4 (continuing)
Table 4 (continuing)
Table 4 (continuing)
Table 4 (continuing)
Table 4 (continuing)
Table 4 (continuing)
Table 5
Table 5 (continuing)
Table 5 (continuing)
Table 5 (continuing)
Table 5 (continuing)
Table 5 (continuing)
Table 5 (continuing)
Table 5 (continuing)
Table 6
Table 6 (continuing)
Table 6 (continuing)
Table 7 (continuing)
Table 7 (continuing)
Table 7 (continuing)
Table 7 (continuing)
Table 7 (continuing)
Table 8
Table 8 (continuing)
Table 8 (continuing)
| Compound number | ????X 1 | ????X 2 | ????X 3 | ????X 4 | ????X 5 |
| ?341 | ????OH | ????H | ????H | ????H | ????H |
| ?342 | ????H | ????OH | ????H | ????H | ????H |
| ?343 | ????H | ????H | ????OH | ????H | ????H |
| ?344 | ????H | ????OH | ????OH | ????H | ????H |
| ?345 | ????H | ????OH | ????H | ????OH | ????H |
| ?346 | ????OMe | ????H | ????H | ????H | ????H |
| ?347 | ????H | ????OMe | ????H | ????H | ????H |
| ?348 | ????H | ????H | ????OMe | ????H | ????H |
| ?349 | ????H | ????OMe | ????OMe | ????H | ????H |
| ?350 | ????H | ????OMe | ????H | ????OMe | ????H |
| ?351 | ????H | ????OH | ????OMe | ????H | ????H |
| ?352 | ????H | ????OMe | ????OH | ????Br | ????H |
| ?353 | ????O iPr | ????H | ????H | ????H | ????H |
| ?354 | ????COOH | ????H | ????H | ????H | ????H |
| ?355 | ????COOMe | ????H | ????H | ????H | ????H |
| ?356 | ????CONH 2 | ????H | ????H | ????H | ????H |
| ?357 | ????Me | ????H | ????H | ????H | ????H |
| ?358 | ????H | ????Me | ????H | ????H | ????H |
| ?359 | ????H | ????H | ????Me | ????H | ????H |
| Compound number | ????X 1 | ????X 2 | ????X 3 | ????X 4 | ????X 5 |
| ?360 | ????H | ????Me | ????H | ????Me | ????H |
| ?361 | ????H | ????Me | ????OH | ????H | ????H |
| ?362 | ????H | ????Me | ????OMe | ????H | ????H |
| ?363 | ????H | ????Pr | ????OH | ????H | ????H |
| ?364 | ????H | ????Pr | ????OMe | ????H | ????H |
| ?365 | ????F | ????H | ????H | ????H | ????H |
| ?366 | ????H | ????F | ????H | ????H | ????H |
| ?367 | ????H | ????H | ????F | ????H | ????H |
| ?368 | ????F | ????F | ????H | ????H | ????H |
| ?369 | ????Cl | ????H | ????H | ????H | ????H |
| ?370 | ????H | ????Cl | ????H | ????H | ????H |
| ?371 | ????H | ????H | ????Cl | ????H | ????H |
| ?372 | ????H | ????Cl | ????Cl | ????H | ????H |
| ?373 | ????Br | ????H | ????H | ????H | ????H |
| ?374 | ????H | ????Br | ????H | ????H | ????H |
| ?375 | ????H | ????H | ????Br | ????H | ????H |
| ?376 | ????H | ????Br | ????Br | ????H | ????H |
| ?377 | ????H | ????Br | ????OH | ????H | ????H |
| ?378 | ????NH 2 | ????H | ????H | ????H | ????H |
| Compound number | ????X 1 | ????X 2 | ????X 3 | ????X 4 | ????X 5 |
| ?379 | ????H | ????NH 2 | ????H | ????H | ????H |
| ?380 | ????H | ????H | ????NH 2 | ????H | ????H |
| ?381 | ????NH 2 | ????OMe | ????H | ????H | ????H |
| ?382 | ????H | ????MH 2 | ????OMe | ????H | ????H |
| ?383 | ????H | ????NH 2 | ????OH | ????H | ????H |
| ?384 | ????H | ????OMe | ????NH 2 | ????H | ????H |
| ?385 | ????H | ????OH | ????NH 2 | ????H | ????H |
| ?386 | ????NO 2 | ????H | ????H | ????H | ????H |
| ?387 | ????H | ????NO 2 | ????H | ????H | ????H |
| ?388 | ????H | ????H | ????NO 2 | ????H | ????H |
| ?389 | ????NO 2 | ????OMe | ????H | ????H | ????H |
| ?390 | ????NO 2 | ????OH | ????H | ????H | ????H |
| ?391 | ????NO 2 | ????Me | ????H | ????H | ????H |
| ?392 | ????NO 2 | ????H | ????OMe | ????OMe | ????H |
| ?393 | ????NO 2 | ????Cl | ????H | ????H | ????H |
| ?394 | ????H | ????NO 2 | ????OMe | ????H | ????H |
| ?395 | ????H | ????NO 2 | ????OH | ????H | ????H |
| ?396 | ????H | ????OMe | ????NO 2 | ????H | ????H |
| ?397 | ????H | ????OH | ????NO 2 | ????H | ????H |
| Compound number | ????X 1 | ????X 2 | ????X 3 | ????X 4 | ????X 5 |
| ?501 | ????OH | ????H | ????H | ????H | ????H |
| ?502 | ????H | ????OH | ????H | ????H | ????H |
| ?503 | ????H | ????H | ????OH | ????H | ????H |
| ?504 | ????H | ????OH | ????OH | ????H | ????H |
| ?505 | ????H | ????OH | ????H | ????OH | ????H |
| ?506 | ????OMe | ????H | ????H | ????H | ????H |
| ?507 | ????H | ????OMe | ????H | ????H | ????H |
| ?508 | ????H | ????H | ????OMe | ????H | ????H |
| ?509 | ????H | ????OMe | ????OMe | ????H | ????H |
| ?510 | ????H | ????OMe | ????H | ????OMe | ????H |
| ?511 | ????H | ????OH | ????OMe | ????H | ????H |
| ?512 | ????H | ????OMe | ????OH | ????Br | ????H |
| ?513 | ????O iPr | ????H | ????H | ????H | ????H |
| ?514 | ????COOH | ????H | ????H | ????H | ????H |
| ?515 | ????COOMe | ????H | ????H | ????H | ????H |
| ?516 | ????CONH 2 | ????H | ????H | ????H | ????H |
| ?517 | ????Me | ????H | ????H | ????H | ????H |
| ?518 | ????H | ????Me | ????H | ????H | ????H |
| ?519 | ????H | ????H | ????Me | ????H | ????H |
| Compound number | ????X 1 | ????X 2 | ????X 3 | ????X 4 | ????X 5 |
| ?520 | ????H | ????Me | ????H | ????Me | ????H |
| ?521 | ????H | ????Me | ????OH | ????H | ????H |
| ?522 | ????H | ????Me | ????OMe | ????H | ????H |
| ?523 | ????H | ????Pr | ????OH | ????H | ????H |
| ?524 | ????H | ????Pr | ????OMe | ????H | ????H |
| ?525 | ????F | ????H | ????H | ????H | ????H |
| ?526 | ????H | ????F | ????H | ????H | ????H |
| ?527 | ????H | ????H | ????F | ????H | ????H |
| ?528 | ????F | ????F | ????H | ????H | ????H |
| ?529 | ????Cl | ????H | ????H | ????H | ????H |
| ?530 | ????H | ????Cl | ????H | ????H | ????H |
| ?531 | ????H | ????H | ????Cl | ????H | ????H |
| ?532 | ????H | ????Cl | ????Cl | ????H | ????H |
| ?533 | ????Br | ????H | ????H | ????H | ????H |
| ?534 | ????H | ????Br | ????H | ????H | ????H |
| ?535 | ????H | ????H | ????Br | ????H | ????H |
| ?536 | ????H | ????Br | ????OH | ????H | ????H |
| ?537 | ????NH 2 | ????H | ????H | ????H | ????H |
| ?538 | ????H | ????NH 2 | ????H | ????H | ????H |
| Compound number | ????X 1 | ????X 2 | ????X 3 | ????X 4 | ????X 5 |
| ?539 | ????H | ????H | ????NH 2 | ????H | ????H |
| ?540 | ????NH 2 | ????OMe | ????H | ????H | ????H |
| ?541 | ????H | ????NH 2 | ????OMe | ????H | ????H |
| ?542 | ????H | ????NH 2 | ????OH | ????H | ????H |
| ?543 | ????H | ????OMe | ????NH 2 | ????H | ????H |
| ?544 | ????H | ????OH | ????NH 2 | ????H | ????H |
| ?545 | ????NO 2 | ????H | ????H | ????H | ????H |
| ?546 | ????H | ????NO 2 | ????H | ????H | ????H |
| ?547 | ????H | ????H | ????NO 2 | ????H | ????H |
| ?548 | ????NO 2 | ????OMe | ????H | ????H | ????H |
| ?549 | ????NO 2 | ????OH | ????H | ????H | ????H |
| ?550 | ????NO 2 | ????Me | ????H | ????H | ????H |
| ?551 | ????NO 2 | ????H | ????OMe | ????OMe | ????H |
| ?552 | ????NO 2 | ????Cl | ????H | ????H | ????H |
| ?553 | ????H | ????NO 2 | ????OMe | ????H | ????H |
| ?554 | ????H | ????NO 2 | ????OH | ????H | ????H |
| ?555 | ????H | ????OMe | ????NO 2 | ????H | ????H |
| ?556 | ????H | ????OH | ????NO 2 | ????H | ????H |
| ?557 | ????H | ????H | ????H | ????H | ????H |
| ?558 | ????H | ????O-Ph | ????H | ????H | ????H |
| Compound number | ????X 1 | ????X 2 | ????X 3 | ????X 4 | ????X 5 |
| ????591 | ????OH | ????H | ????H | ????H | ????H |
| ????592 | ????H | ????OH | ????H | ????H | ????H |
| ????593 | ????H | ????H | ????OH | ????H | ????H |
| ????594 | ????H | ????OH | ????OH | ????H | ????H |
| ????595 | ????H | ????OH | ????H | ????OH | ????H |
| ????596 | ????OMe | ????H | ????H | ????H | ????H |
| ????597 | ????H | ????OMe | ????H | ????H | ????H |
| ????598 | ????H | ????H | ????OMe | ????H | ????H |
| ????599 | ????H | ????OMe | ????OMe | ????H | ????H |
| ????600 | ????H | ????OMe | ????H | ????OMe | ????H |
| ????601 | ????H | ????OH | ????OMe | ????H | ????H |
| ????602 | ????H | ????OMe | ????OH | ????Br | ????H |
| ????603 | ????O iPr | ????H | ????H | ????H | ????H |
| ????604 | ????COOH | ????H | ????H | ????H | ????H |
| Compound number | ????X 1 | ????X 2 | ????X 3 | ????X 4 | ????X 5 |
| ?605 | ?COOMe | ????H | ????H | ????H | ????H |
| ?606 | ?CONH 2 | ????H | ????H | ????H | ????H |
| ?607 | ????Me | ????H | ????H | ????H | ????H |
| ?608 | ????H | ????Me | ????H | ????H | ????H |
| ?609 | ????H | ????H | ????Me | ????H | ????H |
| ?610 | ????H | ????Me | ????H | ????Me | ????H |
| ?611 | ????H | ????Me | ????OH | ????H | ????H |
| ?612 | ????H | ????Me | ????OMe | ????H | ????H |
| ?613 | ????H | ????Pr | ????OH | ????H | ????H |
| ?614 | ????H | ????Pr | ????OMe | ????H | ????H |
| ?615 | ????F | ????H | ????H | ????H | ????H |
| ?616 | ????H | ????F | ????H | ????H | ????H |
| ?617 | ????H | ????H | ????F | ????H | ????H |
| ?618 | ????F | ????F | ????H | ????H | ????H |
| ?619 | ????Cl | ????H | ????H | ????H | ????H |
| ?620 | ????H | ????Cl | ????H | ????H | ????H |
| ?621 | ????H | ????H | ????Cl | ????H | ????H |
| ?622 | ????H | ????Cl | ????Cl | ????H | ????H |
| ?623 | ????Br | ????H | ????H | ????H | ????H |
| ?624 | ????H | ????Br | ????H | ????H | ????H |
| Compound number | ????X 1 | ????X 2 | ????X 3 | ????X 4 | ????X 5 |
| ?625 | ????H | ????H | ????Br | ????H | ????H |
| ?626 | ????H | ????Br | ????Br | ????H | ????H |
| ?627 | ????H | ????Br | ????OH | ????H | ????H |
| ?628 | ????NH 2 | ????H | ????H | ????H | ????H |
| ?629 | ????H | ????NH 2 | ????H | ????H | ????H |
| ?630 | ????H | ????H | ????NH 2 | ????H | ????H |
| ?631 | ????NH 2 | ????OMe | ????H | ????H | ????H |
| ?632 | ????H | ????NH 2 | ????OMe | ????H | ????H |
| ?633 | ????H | ????NH 2 | ????OH | ????H | ????H |
| ?634 | ????H | ????OMe | ????NH 2 | ????H | ????H |
| ?635 | ????H | ????OH | ????NH 2 | ????H | ????H |
| ?636 | ????NO 2 | ????H | ????H | ????H | ????H |
| ?637 | ????H | ????NO 2 | ????H | ????H | ????H |
| ?638 | ????H | ????H | ????NO 2 | ????H | ????H |
| ?639 | ????NO 2 | ????OMe | ????H | ????H | ????H |
| ?640 | ????NO 2 | ????OH | ????H | ????H | ????H |
| ?641 | ????NO 2 | ????Me | ????H | ????H | ????H |
| ?642 | ????NO 2 | ????H | ????OMe | ????OMe | ????H |
| ?643 | ????NO 2 | ????Cl | ????H | ????H | ????H |
| ?644 | ????H | ????NO 2 | ????OMe | ????H | ????H |
| Compound number | ????X 1 | ????X 2 | ????X 3 | ????X 4 | ????X 5 |
| ????645 | ????H | ????NO 2 | ????OH | ????H | ????H |
| ????646 | ????H | ????OMe | ????NO 2 | ????H | ????H |
| ????647 | ????H | ????OH | ????NO 2 | ????H | ????H |
| ????648 | ????H | ????H | ????H | ????H | ????H |
| Compound number | ????X 1 | ????X 2 | ????X 3 | ????X 4 | ????X 5 |
| ????820 | ????H | ????H | ????H | ????H | ????H |
| ????821 | ????Me | ????H | ????H | ????H | ????H |
| ????822 | ????H | ????Me | ????H | ????H | ????H |
| ????823 | ????H | ????H | ????Me | ????H | ????H |
| ????824 | ????OMe | ????H | ????H | ????H | ????H |
| ????825 | ????H | ????OMe | ????H | ????H | ????H |
| ????826 | ????H | ????H | ????OMe | ????H | ????H |
| ????827 | ????OH | ????H | ????H | ????H | ????H |
| ????828 | ????H | ????OH | ????H | ????H | ????H |
| ????829 | ????H | ????H | ????OH | ????H | ????H |
| ????830 | ????H | ????OH | ????OH | ????H | ????H |
| ????831 | ????H | ????OH | ????OMe | ????H | ????H |
| ????832 | ????H | ????OMe | ????OH | ????H | ????H |
| ????833 | ????H | ????OEt | ????OH | ????H | ????H |
In the compound of formula (I) representative, comprise as the particularly preferred compound of the activeconstituents of medicine of the present invention:
(1) R wherein
1Be those compounds of hydrogen atom;
(2) R wherein
2Be hydrogen atom or C
1-C
18Those compounds of alkyl;
(3) R wherein
2Be C
1-C
18Those compounds of alkyl;
(4) R wherein
2Be C
2-C
18Those compounds of alkyl;
(5) wherein Ar be phenyl that replacement is arranged, can substituted C
10-C
14Aryl, or those compounds that can substituted aromatic heterocyclic group;
(6) wherein Ar is the C that replaces
6-C
14Aryl or those compounds that can substituted aromatic heterocyclic group;
(7) wherein Ar is the C that replaces
6-C
14Those compounds of aryl;
(8) wherein Ar is those compounds of the group of above-mentioned formula (II) representative;
(9) R wherein
2Be C
1-C
18Alkyl, it can have one or more C
6-C
14Aryl, and Ar is the C that can replace
6-C
14Aryl or those compounds that can substituted aromatic heterocyclic radical;
(10) R wherein
2Be C
1-C
18Alkyl, it can have one or more C
6-C
14Aryl, and Ar be the phenyl that replaces, can substituted C
10-C
14Aryl or those compounds that can substituted aromatic heterocyclic radical;
(11) R wherein
2Be C
1-C
18Alkyl, it can have one or more C
6-C
14Aryl, and Ar is the C that replaces
6-C
14Those compounds of aryl;
(12) compound in above-mentioned (9) to (11), R wherein
1It is hydrogen atom;
(13) compound in above-mentioned (9) to (12), Ar wherein are the groups of above-mentioned formula (II) representative;
(14) compound in above-mentioned (9) to (13), R wherein
2Be C
1-C
18Alkyl;
(15) compound in above-mentioned (9) to (13), R wherein
2Be C
2-C
18Alkyl; With
(16) compound in above-mentioned (9) to (12), R wherein
2Be C
4-C
18Alkyl.
In addition, particularly preferred compound also comprises:
(17) according to the Hydroxyflavone derivatives of formula (IV), wherein n is 2 or 3;
(18) according to the Hydroxyflavone derivatives of formula (IV), R wherein
5Be hydrogen atom or methoxyl group;
(19) according to the Hydroxyflavone derivatives of formula (IV), wherein Z be dimethylamino, can substituted piperazinyl or can substituted piperidyl;
(20) according to the Hydroxyflavone derivatives of formula V, R wherein
4Be can substituted C
1-C
18Alkyl, can substituted C
1-C
18Alkoxyl group, hydroxyl, nitro or cyano group;
(21) according to the Hydroxyflavone derivatives of formula (I), R wherein
1Represent hydrogen atom or hydroxyl; R
2Represent hydrogen atom or C
1-C
18Alkyl, it can contain one or more C
6-C
14Aryl; And Ar representative can substituted aromatic heterocyclic radical, and condition is R wherein
1It is hydrogen atom; R
2Be methyl, and Ar is that those compounds of pyridyl are left out.
Most preferred comprises:
7-hydroxyl-3 '-(3-(piperidino) propoxy-)-8-propyl group flavones.
4 ', 7-dihydroxyl-3 '-methoxyl group-8-propyl group flavones.
7-hydroxyl-8-methyl-3 '-(3-(piperidino) propoxy-) flavones.
7-hydroxyl-4 '-nitro-3 '-(3-(piperidino) propoxy-)-8-propyl group flavones.
4 ', 7-dihydroxyl-3 '-methoxyl group-8-methyl flavones and
7-hydroxyl-8-propyl group-2-(4-pyridyl) chromone.
Yet the activeconstituents of medicine of the present invention is not subjected to the restriction of above-mentioned these compounds of mentioning especially.
The Hydroxyflavone derivatives of above-mentioned formula (I) representative can be according to following graphic technique preparation.For example, they can be prepared as follows.＜step 1 〉
(those in symbol that flow process is used and the above-mentioned definition are equivalent in meaning.)
In the presence of solvent, make the compound of above-mentioned formula V representative and the activity derivatives reaction of alkali and above-mentioned formula (VI) representative can obtain the compound that above-mentioned formula (VII) is represented.The type of solvent is not particularly limited, as long as it does not influence reaction.For example, ether such as ether, tert-butyl methyl ether, tetrahydrofuran (THF), isopropyl ether He diox, aromatic hydrocarbon such as benzene, toluene and dimethylbenzene, halohydrocarbon such as methylene dichloride, chloroform and ethylene dichloride can be used as solvent.Can unite the solvent that uses two or more.The example of alkali comprises, for example, and lithium methide, butyllithium, hexamethyldisilazane base lithium, hexamethyldisilazane base sodium, di-isopropyl lithamide, sodium hydroxide, potassium hydroxide, sodium hydride or the like.Reactive derivative as formula (VI) representative can adopt symmetric anhydride, mixed acid anhydride, carboxylic acid halides, active amide, ester etc., and these compounds can be at an easy rate method by document description prepare by corresponding carboxylic acid.Temperature of reaction and reaction times are not particularly limited.Usually, reaction can be carried out under-78 ℃ to 250 ℃ 30 minutes to 48 hours.＜step 2 〉
(those in symbol that flow process is used and the above-mentioned definition are equivalent in meaning.)
Have or solvent-free in the presence of, the compound of formula (VII) representative that is obtained by step 1 can obtain the compound of formula (I) representative by dehydration reaction.Type of solvent is not particularly limited as long as it does not influence reaction.For example, ether such as ether, t-butyl methyl ether, tetrahydrofuran (THF), isopropyl ether He diox, aromatic hydrocarbon such as benzene, toluene and dimethylbenzene, halohydrocarbon such as methylene dichloride, chloroform and ethylene dichloride, nitrile such as acetonitrile and propionitrile, ester such as methyl acetate and ethyl acetate, pure as methyl alcohol and ethanol, organic acid such as acetate, acid anhydrides such as diacetyl oxide etc. can be used as solvent.Can unite this kind solvent that uses two or more.Above-mentioned dehydration reaction can be carried out in the presence of acid catalyst.The example of acid catalyst comprises, for example, and mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, and organic acid such as trifluoroacetic acid, right-toluenesulphonic acids, methylsulfonic acid and camphorsulfonic acid etc.Temperature of reaction and reaction times are not particularly limited.Usually, reaction can be carried out under 0 ℃ to 250 ℃ 30 minutes to 48 hours.In above steps, functional group needs protection sometimes and goes protection.Can select to be suitable for the blocking group of this functional group, and can protect and protective reaction according to any method of document description.
Medicine of the present invention has the activity that suppresses TPK1, and they suppress the activity of TPK1 in Alzheimer or the like disease, thereby suppresses the neurotoxicity of A β and formation and the inhibition nerve cell death of PHF.Correspondingly, be used as can active prevention and/or the medicine of treatment Alzheimer for medicine of the present invention.Medicine of the present invention in addition also is used to prevent and/or treat shaking palsy, boxing property encephalitis, Guam shaking palsy-chronic brain syndrome, Lewy body disease, Pick's disease after the shaking palsy, encephalitis of hematencephalon that cerebrovascular ischemia accident, Down syndrome, cerebral amyloid angiopathy cause, stein-leventhal syndrome, subacute sclerosing panencephalitis, cortex is degenerated and frontotemporal suture dementia or the like.
As for the active ingredient of medicine of the present invention, its material can adopt the one group of compound and the pharmacy acceptable salt thereof of the formula of being selected from (I) representative, and solvated compounds and hydrate.This material originally can be used as drug administration of the present invention on one's body, yet, to wish usually to give this medicine with the form of medicinal compositions, it comprises above-mentioned as the material of active ingredient and one or more medicinal additive.For the active ingredient of medicine of the present invention, can unite the above-mentioned substance that uses two or more.Above-mentioned medicinal compositions can replenish the medical active composition that other is used for the treatment of diseases such as Alzheimer.
The type of medicinal compositions is not particularly limited, and any said composition preparation that is fit to oral or parenteral admin can be provided.For example, the preparation of this medicinal compositions can be, for example, be fit to oral medicinal compositions formulation such as granule, fine granular, pulvis, hard capsule, soft capsule, syrup, emulsion, suspension, solution or the like, or the medicinal compositions formulation of suitable parenteral admin such as intravenous injection, intramuscular dose or subcutaneous injection agent, instillation, preparation capable of permeating skin, saturating film preparation, nasal drop, inhalation, suppository etc.Injection or instillation can be prepared into powder preparation such as freeze-dried, and can be dissolved in before use in the suitable water-bearing media such as physiological saline.Delay those of delivery formulations such as polymer coating can brain in directly administration.
Be used to make the medicinal additive kind of medicinal compositions, with respect to the content ratio of the medicinal additive of activeconstituents, and the preparation method of medicinal compositions can suitably be selected by those skilled in that art.Inorganic or organic substance, or solid or liquid substance all can be used as medicinal additive.Usually, based on activeconstituents weight, the weight ratio scope of the medicinal additive that mixes can from 1% to 90%.
The example that is used for the vehicle of solid pharmaceutical composition preparation comprises, for example, and lactose, sucrose, starch, talcum powder, Mierocrystalline cellulose, dextrin, kaolin, lime carbonate or the like.For the liquid oral compositions preparation, can adopt conventional inert diluent such as water or vegetables oil.Except that inert diluent, liquid composition can also contain auxiliary material such as wetting agent, suspending agent, sweeting agent, perfume compound, tinting material and sanitas.The capsule that this liquid composition can be packed into and be made by absorbable material such as gelatin.As the composite preparation of parenteral admin, for example, the example of the solution of injection, suppository or the medium of suspension comprises water, propylene glycol, polyoxyethylene glycol, phenylcarbinol, ethyl oleate, Yelkin TTS or the like.Comprise as the example of suppository base material, for example, theobroma oil, emulsification theobroma oil, laurel tallow, witepsol.
The dosage and the number of times of medicine of the present invention are not particularly limited, and they can suitably be selected as the purpose that prevents and/or treats, kinds of Diseases, patient's body weight and age, disease severity etc. according to the state of an illness.Usually, adult's oral dosage every day can be from 0.01 to 1000mg (weight of activeconstituents), and can be administered once every day or every day with the divided dose administration for several times, or a couple of days be administered once.When adopting the injection of medicine, for the adult can be preferably by the dosage of every day 0.001 to 100mg (weight of activeconstituents) continuously or administration discontinuously.
The Hydroxyflavone derivatives of above-mentioned formula (I) representative and its salt, with and solvate and its hydrate be new material and be the chemical substance that within the present invention, relates to, wherein R
1, R
2, and R identical with above-mentioned definition with Ar
2Be hydrogen atom, the Ar group of representing above-mentioned formula (II) expression (R wherein
3, R
4, R
5, R
6And R
7Identical with above-mentioned definition) time, condition is R
3, R
4, R
5, R
6And R
7The group of one of any above-mentioned formula of representative (III) expression, wherein R
8, X is identical with above-mentioned definition with m, and condition is R wherein
1Be hydrogen atom, R
2Be that methyl and Ar are phenyl, 3,4-methylenedioxyphenyl, or those compounds of 3-pyridyl, those are R wherein
1Be hydrogen atom, R
2Be that propyl group and Ar are phenyl and those R that the 4-position contains carboxyl or ester group
1Be hydroxyl, R
2Be that methyl and Ar are phenyl, 4-hydroxy phenyl, 4-p-methoxy-phenyl, or 3, those compounds of 4-Dimethoxyphenyl are excluded.
The purposes of these novel substances provided by the invention is not limited to medicine, and its all purposes all within the scope of the present invention.Can there be the enantiomer of steric isomer such as diastereomer in these materials, and the steric isomer of any respective pure form, any stereoisomer mixture, racemic modification are also within the scope of the invention.The example of these materials of salt form comprises acceptable salt on the physiology of above-mentioned explanation.
Embodiment
The present invention will be described in more detail by reference example.Yet scope of the present invention is not subjected to the restriction of the following example.Compound number among the embodiment is corresponding with above table.The preparation of embodiment 1:7-hydroxyl-3 '-(3-(piperidino) propoxy-)-8-propyl group flavones di-sulfate (compound 455)
Make 2,4-dihydroxyl-3-propylbenzene ethyl ketone (1.0g) is dissolved in the tetrahydrofuran (THF) of 30ml, and is dropwise adding 26ml hexamethyldisilazane lithium under-78 ℃ and stirred 2 hours in this solution.The tetrahydrofuran solution of 1.43g 3-piperidyl propoxy benzoic acid methyl esters is dropwise joined this reaction mixture, and reaction mixture was stirred 24 hours.This reaction mixture is poured in the icy water, with the concentrated hydrochloric acid neutralization, and with the ethyl acetate extracting.Organic phase is washed with water and saturated brine, dried over sodium sulfate, concentrating under reduced pressure and dry then.The gained residue adds the 0.2ml vitriol oil with the dissolving of 40ml acetate, and stirs 2 hours down at 100 ℃.Reaction mixture is cooled to room temperature, and the sedimentary solid of filtering separation obtains the required compound of 2.69g with the ethyl acetate washing again.Productive rate: 84%.Fusing point: 233 ℃.NMR(DMSO-d
6，δ)：0.98(t，J＝7.5Hz，3H)，1.41(m，1H)，1.63-1.69(m，5H)，1.85(m，2H)，2.19(m，2H)，2.85-2.96(m，4H)，3.22(m，2H)，3.51(m，2H)，4.19(t，J＝6.0Hz，2H)，6.95(s，1H)，7.01(d，J＝8.7Hz，1H)，7.18(d，J＝8.7Hz，1H)，7.50-7.56(m，2H)，7.66(d，J＝8.0Hz，1H)，7.77(d，J＝8.7Hz，1H)，8.99(br，1H)，10.60(br，1H)。The preparation of reference example 1:4-tert-butyl dimethyl-siloxy--3-methoxyl methyl benzoate
Vanillic acid (25.8g) is dissolved in 500ml methyl alcohol, with 1g right-toluenesulphonic acids joins in this solution and reflux 24 hours.This reaction mixture is cooled to room temperature, concentrating under reduced pressure, and with hexane/ethyl acetate=3/1 column purification acquisition 28.5g vanillic acid methyl esters (productive rate: 100%).Gained vanillic acid methyl esters (5.5g) is dissolved in 30mlN, dinethylformamide, under 0 ℃ with the 3.1g imidazoles with 5.5g tert-butyl dimethylchlorosilane joins in this solution and stirred 2 hours under room temperature.Pour into reaction mixture in the water and with the ethyl acetate extracting.The gained organic phase is with water and saturated brine washing, dried over sodium sulfate, concentrating under reduced pressure then.The gained residue obtains the required compound of 8.68g with column purification (hexane/ethyl acetate=15/1).(productive rate: 97%).NMR (CDCl
3, δ): 0.17 (s, 6H), 1.01 (s, 9H), 3.86 (s, 3H), 3.88 (s, 3H), 6.86 (d, J=8.7Hz, 1H), 7.51 (d, J=2.4Hz, 1H), 7.66 (dd, J=8.7Hz, 2.4Hz, 1H). and embodiment 2:4 ', the preparation of 7-dihydroxyl-3 '-methoxyl group-8-propyl group flavones (compound 682)
2,4-dihydroxyl-3-propylbenzene ethyl ketone (1.0g) is dissolved in the tetrahydrofuran (THF) of 30ml, and dropwise joins 26ml hexamethyldisilazane lithium in the solution under-78 ℃ and stirred 2 hours.The tetrahydrofuran solution that in reaction mixture, dropwise adds the 1.53g vanillic acid methyl esters that obtains in the reference example 1, and with reaction mixture stirring 24 hours.This reaction mixture is poured in the icy water, with the concentrated hydrochloric acid neutralization, then with the ethyl acetate extracting.Organic phase is with water and saturated brine washing, dried over sodium sulfate, concentrating under reduced pressure and drying then.The gained residue is with the dissolving of 40ml acetate, and the adding 0.2ml vitriol oil stirred 2 hours down in 100 ℃ again in this solution.In this reaction mixture, added 10ml water and restir 2 hours.Reaction mixture is cooled to room temperature, and the sedimentary solid of filtering separation obtains the required compound of 1.47g with the ethyl acetate washing again.Productive rate: 87%.Fusing point: 231-233 ℃.NMR(DMSO-d
6，δ)：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，1H)，6.94-6.99(m，2H)，7.51-7.55(m，2H)，10.53(br，1H)。
The compound of embodiment 3 to 73 prepares in the mode of similar reference example 1 and embodiment 1 and 2.The physical properties of these compounds is as follows.Embodiment 3:7-hydroxyl-3 '-(1-methyl-3-piperidyl) methoxy flavone (compound 42) fusing point: 134 ℃ (decomposition).NMR (DMSO-d
6, δ): 1.08 (m, 1H), 1.33 (m, 1H), 1.70 (m, 1H), 1.95 (m, 2H), 2.27 (br, 1H), 2.83 (s, 3H), 3.45 (m, 1H), 3.57 (m, 1H), 3.97 (m, 1H), 4.11 (m, 1H), and 6.94-6.97 (m, 2H), 7.01 (s, 1H), 7.17 (d, J=7.2Hz, 1H), 7.5 (m, 1H), 7.57 (s, 1H), 7.67 (d, J=7.5Hz, 1H), 7.89 (d, J=8.7HZ, 1H), 9.26 (br, 1H). fusing point: 238-239 ℃ of embodiment 4:7-hydroxyl-3 '-(2-dimethylamino ethoxy) flavones hydrochloride (compound 45).
Contain 100mM MES-sodium hydroxide (pH6.5), 1mM magnesium acetate, 0.5MmEGTA, 5mM beta-mercaptoethanol, 0.02% soil temperature 20,10% glycerine, 12 μ g/mlP-GSl, 41.7 μ M[γ-
32P] mixture (final mixture contains 1.7% DMSO; And it comes from the preparation liquid of test compound and has 10%DMSO) of compound shown in ATP (68kBq/ml); Calf brain TPK1 and the form is used as reactive system.Phosphorylation reaction starts by adding ATP; 25 ℃ of of of of 2 hours of and this is reflected at and carried out under; Then when ice bath cool off by adding 21% perchloric acid termination reaction.This reaction mixture under 12000rpm centrifugal 5 minutes and be adsorbed on the P81 paper (Whatmann); This paper is with 75mM phosphoric acid washing 4 times then; And water washing 3 times and washing with acetone are once.With this paper drying; And the radioactivity of employing liquid flashing counter measuring residue.The result is as shown in the table.Test compound significantly suppresses the catalytic P-GS1 phosphorylation of TPK1.This result obviously points out the activity of medicine inhibition TPK1 of the present invention; thereby suppresses neurotoxicity and the PHF formation of A β, and medicine of the present invention can effectively prevent and/or treat Alzheimer Ci Shi disease sick and that above explain.9 ( ) 10μM ( ％ ) 1 ( 455 ) 98.4 2 ( 682 ) 89.7 4 ( 45 ) 79.4 6 ( 55 ) 88.1 7 ( 58 ) 82.9 12 ( 148 ) 89.9 13 ( 158 ) 85.7 14 ( 161 ) 88.5 15 ( 162 ) 84.8 16 ( 264 ) 97.4 17 ( 310 ) 93.3 18 ( 342 ) 81.1 19 ( 343 ) 98.2 20 ( 347 ) 73.1 21 ( 351 ) 85.3 23 ( 365 ) 75.4 25 ( 386 ) 84.7 27 ( 389 ) 79.3 28 ( 391 ) 72.4 29 ( 392 ) 87.1 30 ( 393 ) 77.1 31 ( 491 ) 88.9 32 ( 502 ) 76.4 33 ( 503 ) 95.6 34 ( 504 ) 86.8 37 ( 512 ) 77.7 39 ( 521 ) 89.0 40 ( 523 ) 91.0 47 ( 554 ) 87.1 51 ( 560 ) 95.8 52 ( 561 ) 94.0 55 ( 593 ) 84.6 56 ( 680 ) 90.4 57 ( 681 ) 85.8 58 ( 684 ) 96.2 59 ( 690 ) 93.5 64 ( 785 ) 81.2 65 ( 786 ) 74.8 67 ( 788 ) 74.9 68 ( 794 ) 71.5 72 ( 815 ) 78.2 ( 1 )
Mix following ingredients and adopt the conventional equipment compressing tablet with ordinary method.
The compound 30mg of embodiment 2
Crystalline cellulose 60mg
W-Gum 100mg
Lactose 200mg
Magnesium Stearate 4mg (2) soft capsule
Mix following ingredients and fill soft capsule with ordinary method.
The compound 30mg of embodiment 2
Sweet oil 300mg
Yelkin TTS 20mg (3) parenteral formulation
Mix the injection that following ingredients is installed in preparation 1ml ampoule with ordinary method.The compound 0.1mg sodium-chlor 4mg distilled water for injection 1ml of embodiment 1
Commercial Application
Medicine of the present invention has and suppresses the active of TPK1 and be used for the treatment of and/or prevent owing to disease such as Alzheimer Ci Shi disease due to the TPK1 hyperactivity.
Claims (14)
1. prevent and/or treat the medicine of the disease that causes by tau protein kinases 1 hyperactivity or neurodegeneration, it comprises Hydroxyflavone derivatives and salt thereof as the formula that is selected from (I) representative of activeconstituents, and the material of their solvate and their hydrate:
Wherein, R
1Represent hydrogen atom or hydroxyl; R
2Represent hydrogen atom or C
1-C
18Alkyl, it can contain one or more C
6-C
14Aryl; And the Ar representative can substituted C
6-C
14Aryl or can substituted aromatic heterocyclic group.
2. prevent and/or treat the medicine of neurodegenerative disease, it comprises the Hydroxyflavone derivatives and the salt thereof that are selected from formula (I) representative according to claim 1 as activeconstituents, and the material of their solvate and their hydrate.
3. according to the medicine of claim 2, wherein disease is selected from shaking palsy, boxing property encephalitis, Guam shaking palsy-chronic brain syndrome, Lewy body disease, Pick's disease after the shaking palsy, encephalitis of cerebral hemorrhage that Alzheimer, cerebral blood vessel ischemia accident, Down syndrome, cerebral amyloid angiopathy cause, stein-leventhal syndrome, subacute sclerosing panencephalitis, cortex is degenerated and frontotemporal suture dementia or the like.
4. tau protein kinases 1 inhibitor, it is selected from the Hydroxyflavone derivatives and the salt thereof of formula (I) representative according to claim 1, and their solvate and hydrate.
5. Hydroxyflavone derivatives or its salt of formula (I) representative, or their solvate or their hydrate:
Wherein, R
1Represent hydrogen atom or hydroxyl; R
2Represent hydrogen atom or C
1-C
18Alkyl, it can contain one or more C
6-C
14Aryl, and the Ar representative can substituted C
6-C
14Aryl or can substituted aromatic heterocyclic group, and R wherein
2During for hydrogen atom, Ar represents the group of formula (II) expression
R wherein
3, R
4, R
5, R
6And R
7Represent independently hydrogen atom, can substituted C
1-C
18Alkyl, can substituted C
1-C
18Alkoxyl group, hydroxyl, can substituted acyloxy, carboxyl, can substituted carbalkoxy, can substituted carbamyl, can substituted alkyl-carbonyl, can substituted amino, nitro or cyano group,
Condition is R
3, R
4, R
5, R
6And R
7In any one representative formula (III) :-X-(CH
2)
m-R
8The group of expression, wherein R
8Expression can substituted amino or can substituted nitrogenous saturated heterocyclyl, and X represents singly-bound or Sauerstoffatom, and m is from 1 to 8 integer; And
Condition is R wherein
1Be hydrogen atom, R
2Be methyl, and Ar is phenyl, 3, the compound of 4-methylenedioxyphenyl base or 3-pyridyl, wherein R
1Be hydrogen atom, R
2Be propyl group, and Ar is the compound that contains the phenyl of carboxyl or ester group on 4, wherein R
1Be hydroxyl, R
2Be methyl, and Ar is phenyl, 4-hydroxy phenyl, 4-p-methoxy-phenyl, or 3, the compound of 4-Dimethoxyphenyl then is left out.
6. Hydroxyflavone derivatives or its salt of formula (IV) representative, or its solvate or its hydrate:
R wherein
1Represent hydrogen atom or hydroxyl; Z representative can substituted amino or can substituted nitrogenous saturated heterocyclic; The integer of n representative from 1 to 8; R
5Represent hydrogen atom, C
1-C
15Alkoxyl group; And R
6Represent hydrogen atom or hydroxyl.
7. according to Hydroxyflavone derivatives or its salt of claim 6, or its solvate or its hydrate, wherein n is 2 or 3.
8. according to Hydroxyflavone derivatives or its salt of claim 6, or its solvate or its hydrate, wherein R
5Be hydrogen atom or methoxyl group.
9. according to Hydroxyflavone derivatives or its salt of claim 6, or its solvate or its hydrate, wherein Z be dimethylamino, can substituted piperazinyl, or can substituted piperidyl.
10. Hydroxyflavone derivatives or its salt of formula V representative, or its solvate or its hydrate:
R wherein
2Represent hydrogen atom or C
1-C
18Alkyl, it can be by one or more C
6-C
14Aryl replaces; R
4Representative can substituted C
1-C
18Alkyl, can substituted C
1-C
18Alkoxyl group, can substituted acyloxy, carboxyl, can substituted carbalkoxy, can substituted carbamyl, can substituted alkyl-carbonyl, can substituted amino, nitro, or cyano group; And R
5Represent hydrogen atom, hydroxyl, methoxyl group or nitro.
11. according to Hydroxyflavone derivatives or its salt of claim 10, or its solvate or its hydrate, wherein R
4Be can substituted C
1-C
18Alkyl, can substituted C
1-C
18Alkoxyl group, hydroxyl, nitro or cyano group.
12. Hydroxyflavone derivatives or its salt of formula (I) representative, or its solvate or its hydrate:
Wherein, R
1Represent hydrogen atom or hydroxyl; R
2Represent hydrogen atom or C
1-C
18Alkyl, it can contain one or more C
6-C
14Aryl, and Ar representative can substituted aromatic heterocyclic group, condition are R wherein
1Be hydrogen atom, R
2Be methyl, and Ar is that those compounds of pyridyl are left out.
13. Hydroxyflavone derivatives or its salt, or its solvate or its hydrate, it is selected from:
7-hydroxyl-3 '-(3-(piperidino) propoxy-)-8-propyl group flavones,
4 ', 7-dihydroxyl-3 '-methoxyl group-8-propyl group flavones,
7-hydroxyl-8-methyl-3 '-(3-(piperidino) propoxy-) flavones,
7-hydroxyl-4 '-nitro-3 '-(3-(piperidino) propoxy-)-8-propyl group flavones,
4 ', 7-dihydroxyl-3 '-methoxyl group-8-methyl flavones and
7-hydroxyl-8-propyl group-2-(4-pyridyl) chromone.
14. it comprises medicine and being selected from according to claim 5 to one of any Hydroxyflavone derivatives of claim 13 and the material of salt and their solvate and hydrate thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27026298 | 1998-09-24 | ||
| JP270262/1998 | 1998-09-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1326450A true CN1326450A (en) | 2001-12-12 |
Family
ID=17483811
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99813534A Pending CN1326450A (en) | 1998-09-24 | 1999-09-24 | Hydroxyflavone derivatives as tau protein kinase inhibitors |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1115718A1 (en) |
| JP (1) | JP2002526488A (en) |
| KR (1) | KR20010079922A (en) |
| CN (1) | CN1326450A (en) |
| AU (1) | AU5759899A (en) |
| CA (1) | CA2345311A1 (en) |
| WO (1) | WO2000017184A1 (en) |
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| CN108299365A (en) * | 2018-01-31 | 2018-07-20 | 中南大学 | A kind of chromocor derivative and its application |
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| US20100216805A1 (en) | 2009-02-25 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
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| MX352614B (en) | 2009-04-22 | 2017-12-01 | Resverlogix Corp | Novel anti-inflammatory agents. |
| PT2773354T (en) | 2011-11-01 | 2019-07-17 | Resverlogix Corp | Oral immediate release formulations for substituted quinazolinones |
| ES2648154T3 (en) | 2012-01-26 | 2017-12-28 | Daiichi Sankyo Company, Limited | Chromone derivative that has an osteogenesis promoter effect |
| WO2014080291A2 (en) | 2012-11-21 | 2014-05-30 | Rvx Therapeutics Inc. | Biaryl derivatives as bromodomain inhibitors |
| US9073878B2 (en) | 2012-11-21 | 2015-07-07 | Zenith Epigenetics Corp. | Cyclic amines as bromodomain inhibitors |
| US9271978B2 (en) | 2012-12-21 | 2016-03-01 | Zenith Epigenetics Corp. | Heterocyclic compounds as bromodomain inhibitors |
| JP6468549B2 (en) * | 2015-01-30 | 2019-02-13 | 国立大学法人金沢大学 | Benzothiophene derivatives with anticancer activity |
| JO3789B1 (en) | 2015-03-13 | 2021-01-31 | Resverlogix Corp | Compositions and therapeutic methods for the treatment of complement -associated diseases |
| JP6416828B2 (en) * | 2016-06-23 | 2018-10-31 | 株式会社レーネ | Tau protein aggregation inhibitor |
| GB202104134D0 (en) * | 2021-03-24 | 2021-05-05 | Floratek Pharma Ag | Compounds and their use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1362782A (en) * | 1970-08-26 | 1974-08-07 | Fisons Ltd | Tetrazole derivatives |
| CA2116460A1 (en) * | 1993-03-02 | 1994-09-03 | Mitsubishi Chemical Corporation | Preventive or therapeutic agents for alzheimer's disease, a screening method of alzheimer's disease and tau-protein kinase i originated from human being |
| CA2182932A1 (en) * | 1995-08-10 | 1997-02-11 | Koju Watanabe | Chromone derivative, process for preparing same and pharmaceutical composition |
| JPH09301915A (en) * | 1996-05-08 | 1997-11-25 | Sankyo Co Ltd | Flavone and naphthalene derivative |
| FR2753969B1 (en) * | 1996-09-27 | 1998-10-30 | Adir | NOVEL FLAVON DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
-
1999
- 1999-09-24 KR KR1020017003819A patent/KR20010079922A/en not_active Application Discontinuation
- 1999-09-24 AU AU57598/99A patent/AU5759899A/en not_active Abandoned
- 1999-09-24 EP EP99944814A patent/EP1115718A1/en not_active Withdrawn
- 1999-09-24 JP JP2000574094A patent/JP2002526488A/en active Pending
- 1999-09-24 WO PCT/JP1999/005223 patent/WO2000017184A1/en not_active Application Discontinuation
- 1999-09-24 CA CA002345311A patent/CA2345311A1/en not_active Abandoned
- 1999-09-24 CN CN99813534A patent/CN1326450A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018233483A1 (en) * | 2017-06-23 | 2018-12-27 | 杭州百诚医药科技股份有限公司 | Preparation and use of phenylquinolinone and flavonoid derivatives |
| CN109111400A (en) * | 2017-06-23 | 2019-01-01 | 杭州百诚医药科技股份有限公司 | The preparation and application of phenylchinoline ketone and flavone derivative |
| CN108299365A (en) * | 2018-01-31 | 2018-07-20 | 中南大学 | A kind of chromocor derivative and its application |
| CN108299365B (en) * | 2018-01-31 | 2021-08-06 | 中南大学 | Flavone derivative and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2000017184A1 (en) | 2000-03-30 |
| JP2002526488A (en) | 2002-08-20 |
| CA2345311A1 (en) | 2000-03-30 |
| EP1115718A1 (en) | 2001-07-18 |
| AU5759899A (en) | 2000-04-10 |
| KR20010079922A (en) | 2001-08-22 |
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