CN1990478B

CN1990478B - 6-aryl-3-substituted methylene pyranone compounds, preparation process and use thereof

Info

Publication number: CN1990478B
Application number: CN2005101325073A
Authority: CN
Inventors: 赵昱; 白骅; 蒋翔锐; 李水盛
Original assignee: Zhejiang Hisun Pharmaceutical Co Ltd
Current assignee: Zhejiang Hisun Pharmaceutical Co Ltd
Priority date: 2005-12-26
Filing date: 2005-12-26
Publication date: 2011-08-31
Anticipated expiration: 2025-12-26
Also published as: CN1990478A

Abstract

The present invention relates to 6-aryl 3-substituent methylene pyranones, a preparation method and an application thereof. The compound possesses strong activity for inhibiting acetylcholinesterase through pharmacological activity test, and weak inhibiting action for butyryl cholinesterase and good selective inhibiting action for acetylcholinesterase (ache). Acute toxicity and abnormal phenomena are not discovered in mice test so that the compound of the present invention can be expected to be used as medicine preventing senile dementia.

Description

6-aryl-3-substituted methylene pyranone compounds and its production and use

Invention field

The invention belongs to organic chemistry, pharmaceutical chemistry and area of pharmacology, particularly, the present invention relates to have 6-aryl 3-substituted methylene-pyranone derivatives of preventing and treating the senile dementia effect and its production and use.Test through pharmacologically active, this compounds has the activity of potent acetylcholine esterase inhibition, and to the butyrylcholine esterase restraining effect extremely a little less than, this compounds of in vivo test there is no toxicity to ICR mouse stomach administration 2.0g/kg and intraperitoneal injection 0.5g/kg, can expect as preventing and treating the senile dementia pharmaceutical use.

Background technology

Along with the world enters aging society, the senile dementia sickness rate rises year by year.At present AD has become the reason of the 4th death that is only second to heart trouble, malignant tumour and apoplexy in elderly population.The old man of China more than 60 years old reached 1.2 hundred million, nearly 5,000,000 senile dementia patients at present.Research prompting both at home and abroad, with advancing age, the sickness rate of senile dementia will progressively increase, and elderly dementia's sickness rate can reach 80% more than 80 years old.Therefore, research control medicine for senile dementia is the urgent problem of current the world of medicine.Because doctor Alois Alzheimer has found the unusual of presenile dementia patient brain tissue first, people are called for short AD with the called after Alzheimer ' sdisease of this disease.The cause of disease of senile dementia is with heredity, to increase factors such as age, immunologic dysfunction, infection, poisoning, environment relevant.Its pathogenesis is also not fully aware of at present, and what studies show that AD in a large number is various cause of disease results of interaction, has various pathogenic hypothesis, in the recent period prevailing 4 amyloid hypothesis and the cholinergic hypothesis of mainly containing.

As far back as nineteen sixties, it has been found that cholinergic plays crucial effect in the formation of remembering with in safeguarding.Davies in 1976 and Maloney report AD patient's cholinergic neuron selectivity loss becomes the AD investigator who finds that at first the specificity neurochemistry changes.The damaged research of the cholinergic eighties concentrates on the basal forebrain Mai Neite of cortex neural distribution center (Meynert) nuclear, and finds the structure of its proximity such as the influence that grey albumen is not subjected to progressive degeneration.In addition, the modification cell that is implanted into synthesis of acetyl choline (ACh) can reverse memory and the cognition dysfunction that the basalis nuclear damage causes, shows that there are substantial connection in cholinergic system and AD clinical symptom.The cholinergic hypothesis of memory function disorder is proposed nineteen eighty-two Bartus and co-worker thereof.In cholinergic synapse, acetylcholine transferase choline and acetyl-CoA reaction generate vagusstoff, are stored in the utricule of teleneuron; When neural depolarize, vagusstoff is discharged into from utricule in the gap of cynapse; Arrive the opposite side in gap by diffusion initiatively, the acceptor of bonding nicotine or muscarine, activated receptor and produce the signal conduction; Be bonded in acetylcholinesterase (AChE) the hydrolysis vagusstoff on neurone surface, the regeneration choline.In the cholinergic model of AD, main damaged synthetic and excretory disorder for vagusstoff, the vagusstoff katabolism that decomposes neurotransmitter does not have influencedly in addition, causes the reduction greatly of cholinergic synapse gap vagusstoff concentration, weakens to the signal of pallium district conduction thereupon.This hypothesis obtains the confirmation of clinical in a large number and data.

Based on AD pathogenetic " cholinergic hypothesis ", if clinical application at present and be in anti-AD drug main in the clinical study in order to improve the ACh level in the cranial nerve, recover the ACh nerve conduction, improve patient's memory, cognition and capacity, delay the development of the state of an illness.Wherein a class medicine is the cholinomimetic thing, mainly contains AChE inhibitor and M1 receptor stimulant.Another kind of medicine is the medicine that promotes that ACh discharges in the cranial nerve, mainly comprises M2 receptor antagonist, n receptor agonist, throtropin releasing hormone (TRH) analogue, adenosine (A1) receptor antagonist, 5-HT3 receptor antagonist and potassium, agents of calcium ion channel modulators etc.

Acetylcholinesterase is called true property or specificity Pseudocholinesterase again, is positioned at neurocyte, skeletal muscle, unstriated muscle, various body of gland and erythrocyte.Vagusstoff is kept certain level the human body memory function is played an important role in brain.The physiological action of AChE in brain is to make acetylcholine hydrolyzation and inactivation rapidly.So acetylcholine esterase inhibition is one of also successful method commonly used of treatment senile dementia.

Though it is more to be in the various kinds of drug of research or clinical evaluation at present, the senile dementia vaccine is also in development and be hopeful to make a breakthrough, but at present the most successful medicine is still acetylcholinesterase depressant, and four medicines of the treatment AD that successively passes through as FDA (FDA) are the AChE inhibitor.Tacrine (Tacrine, chemical name 9-amino 1,2,3,4-tetrahydrochysene-bifurcation pyridine) is first medicine that is used for the treatment of degenerative brain disorder by the special approval of FDA in 1993.E2020 (doepezil, trade(brand)name Acriept, chemical name 2,3-dihydro-5,6-dimethoxy-2-(1-phenylmethylene piperidin-4-yl) methylene radical-1H-1-ketone) be second medicine being used for the treatment of A Ercaimo disease of U.S. FDA in November, 1996 approval.Go on the market in the U.S. in January, 1997, and go on the market in China in October, 1999, uses in more than 50 countries at present.E2020 is a kind of efficient, highly selective, long lasting AChE inhibitor.The E2020 clinical efficacy is similar to tacrine, but it has that dosage is little, toxicity is low, easy administration, advantage such as cheap.

Rivastigmine (rivestigmine, sharp this bright) is the 3rd an AChE inhibitor that is used for anti-senile dementia disease of FDA approval.It is a vagusstoff selective depressant in a kind of novel false irreversible brain.Untoward reaction to liver will be lower than the above two, and better tolerance, no periphery anticholinesterase activity.The AChE inhibitor of lycoremine (Galanthamine) another treatment AD that to be calendar year 2001 ratified by FDA, its long action time, reversible, the maincenter selectivity is strong, is used for the treatment of light, moderate AD.

Butyrylcholine esterase Butylcholinesterase (being called for short BuChE) belongs to pseudocholinesterase, and is mainly synthetic at liver, is present in all kinds of neurogliocyte or satellite cell.In the neurone composition of maincenter and peripheral nervous system, only there is trace, mainly has blood plasma and liver.Report is arranged, and the hepatotoxicity that the AChE inhibitor causes may be relevant with suppressing BuChE.As his Kelin is exactly because its that BuChE is suppressed activity is too strong, so its liver toxicity is just very obvious when using clinically, the problem that patient's toxic side effects is big is unavoidable, has influenced its using dosage and use range and sales volume.The medicine of outstanding clinically treatment senile dementia requires that AChE is had potent restraining effect and many to butyrylcholine esterase BuChE unrestraint effect or a little less than suppressing the effect of active AChE relatively.

The inventor finds, 6-aryl 3-substituted methylene-pyranone derivatives that the present invention prepares has the potent acetylcholine esterase inhibition of selectivity and butyrylcholine esterase BuChE is not had obvious inhibiting activity, and the mouse in vivo test does not find that acute toxicity and abnormal response phenomenon occur, thereby can expect as preventing and treating the senile dementia pharmaceutical use; Finished the present invention thus.

Summary of the invention

The object of the present invention is to provide and a kind ofly have the potent acetylcholine esterase inhibition AChE of selectivity and butyrylcholine esterase BuChE is not had obviously inhibiting active compound.Particularly, the invention provides a kind of have the 6-aryl-3-replacement-pyranone derivatives shown in the formula (1) and pharmacologically acceptable salt or its solvate:

Wherein X can be oxygen or nitrogen (imines) atom; Substituent R ₁Can be identical or different, can be respectively halogen, hydrogen atom, or contain the alkoxyl group of 1～5 carbon or two or more R ₁Base also can close to form and replace or unsubstituted ring compound with phenyl ring a pair of horses going side by side; Substituent R ₂Can be hydrogen atom, carbonyl, thiocarbonyl group, hydroxyl; N is 0～10 integer; Substituent R ₂It can be hydrogen atom, perhaps replace or unsubstituted saturated five～octatomic ring, perhaps replace or unsubstituted saturated five～eight yuan of alicyclic heterocyclics, perhaps replace or unsubstituted five～eight yuan of aromatic nucleus, or replacement or unsubstituted five～eight membered aromatic heterocycles, or the group that is connected to form by methylene radical or carbonyl or nitrogen-atoms or Sauerstoffatom between a plurality of ring.

R ₃Group preferably has replacement or unsubstituted saturated five yuan or six-ring, have and replace or unsubstituted saturated five yuan or hexa-atomic alicyclic heterocyclic, perhaps replace or unsubstituted five yuan or hexa-atomic aromatic nucleus, or replacement or unsubstituted five yuan or hexa-atomic aromatic heterocycle, 2～5 replace or unsubstituted alicyclic ring or alicyclic heterocyclic and replacement or unsubstituted aromatic ring or fragrant heterocycle between the group that is connected to form by methylene radical or carbonyl.

R ₃Group more preferably replaces or unsubstituted six-ring alkyl, have and replace or unsubstituted saturated five yuan or hexa-atomic alicyclic heterocyclic, replace or unsubstituted phenyl ring, replace or unsubstituted aromatic heterocycle, 2～3 replace or unsubstituted alicyclic ring or alicyclic heterocyclic and replacement or unsubstituted aromatic ring or fragrant heterocycle between the group that is connected to form by methylene radical or carbonyl.

Wherein, be selected from halogen as the substituting group that replaces, amino, nitro, sulfydryl contains the alkyl of 1-8 carbon, the alkoxyl group of 1-8 carbon, the acyl group of 1-8 carbon, phenyl, or aryl.

Another object of the present invention has provided the preparation method of preparation formula (1) compound.

Another object of the present invention has provided formula (1) compound and has been used to prepare the purposes of preventing and treating senile dementia and control tumor disease medicine.

The invention provides a kind of have the 6-aryl-3-substituted methylene-pyranone derivatives shown in the formula (1) and pharmacologically acceptable salt or its solvate:

Wherein X can be oxygen or nitrogen (imines) or halogen atom; Substituent R ₁Can be identical or different, can be respectively halogen, hydrogen atom, or contain the alkoxyl group of 1～5 carbon or two or more R ₁Base also can close to form and replace or unsubstituted ring compound with phenyl ring a pair of horses going side by side; Substituent R ₂Can be hydrogen atom, carbonyl, thiocarbonyl group; N is 0～10 integer; Substituent R ₃It can be hydrogen atom, perhaps replace or unsubstituted saturated five～octatomic ring, perhaps replace or unsubstituted saturated five～eight yuan of alicyclic heterocyclics, perhaps replace or unsubstituted five～eight yuan of aromatic nucleus, or replacement or unsubstituted five～eight membered aromatic heterocycles, or the group that is connected to form by methylene radical or carbonyl or nitrogen-atoms or Sauerstoffatom between a plurality of ring;

R ₃Group preferably has replacement or unsubstituted saturated five yuan or six-ring, have and replace or unsubstituted saturated five yuan or hexa-atomic alicyclic heterocyclic, perhaps replace or unsubstituted five yuan or hexa-atomic aromatic nucleus, or replacement or unsubstituted five yuan or hexa-atomic aromatic heterocycle, 2～5 replace or unsubstituted alicyclic ring or alicyclic heterocyclic and replacement or unsubstituted aromatic ring or fragrant heterocycle between the group that is connected to form by methylene radical or carbonyl;

R ₃Group more preferably replaces or unsubstituted six-ring alkyl, have and replace or unsubstituted saturated five yuan or hexa-atomic alicyclic heterocyclic, replace or unsubstituted phenyl ring, replace or unsubstituted aromatic heterocycle, 2～3 replace or unsubstituted alicyclic ring or alicyclic heterocyclic and replacement or unsubstituted aromatic ring or fragrant heterocycle between the group that is connected to form by methylene radical or carbonyl;

The further embodiment of the present invention is: X is a Sauerstoffatom in formula (1), and dotted line does not exist, R ₂Be hydrogen atom, during n=0, be called formula (compound shown in the Ia～Ig):

I-a.6-(2-bromo-4,5-Dimethoxyphenyl)-3-(3-oxo-tetrahydrobenzene-1-thiazolinyl oxygen ylmethyl)-2H-pyrone;

I-b.6-(2-bromo-4,5-Dimethoxyphenyl)-3-(2-methyl-5-oxo-cyclopentenes-1-enol ylmethyl)-2H-pyrone;

I-c.6-(2-bromo-4,5-Dimethoxyphenyl)-3-((2-methyl pyrans-4-ketone)-3-base oxygen base) methyl-2H-pyrone;

I-d.6-(2-bromo-4,5-Dimethoxyphenyl)-3-((6-methyl-2-oxo-2H-pyrans)-4-base-oxygen ylmethyl)-2H-pyrone;

I-e.5-(6-(2-bromo-4,5-Dimethoxyphenyl)-2-oxo-2H-pyrans-3-ylmethoxy)-6-hydroxyl-5-tetrahydrobenzene-1,2,3, the 4-tetraketone;

I-f.6-(2-bromo-3,4,5-trimethoxyphenyl)-3-((6-methyl-2-oxo-2H-pyrans)-4-base-oxygen ylmethyl)-2H-pyrone;

I-g.6-(benzo [1,3] dioxolane-5-yl)-3-((6-methyl-2-oxo-2H-pyrans)-4-base-oxygen ylmethyl)-2H-pyrone.

X in formula (1) is a nitrogen-atoms, when dotted line does not exist, is called the compound shown in the formula (II):

Substituent R wherein ₁, R ₂, R ₃Identical with in the definition of n and the formula (1).

The preferred formula of the present invention (II) compound comprises:

II-a.6-(2-bromo-4,5-Dimethoxyphenyl)-3-((2-morpholine-4-base-ethylamino)-methyl)-2H-pyrone;

II-b.6-(2-bromo-4,5-Dimethoxyphenyl)-3-((2-(5-nitro-pyridine-2-base is amino)-ethylamino)-methyl)-2H-pyrone;

II-c.6-(2-bromo-4,5-Dimethoxyphenyl)-3-((tetrahydrofuran (THF)-2-base-methylamino) methyl)-2H-pyrone;

II-d.4-((6-(2-bromo-4,5-Dimethoxyphenyl)-2-oxo-2H-pyrans-3-ylmethyl)-amino)-piperidines-1-ethyl formate;

II-e.6-(2-bromo-4,5-Dimethoxyphenyl)-3-((2-piperazine-1-base-ethylamino)-methyl)-2H-pyrone;

II-f.N-2-((6-(2-bromo-4,5-Dimethoxyphenyl)-2-oxo-2H-pyrans-3-ylmethyl amino)-ethyl)-benzamide;

II-g.6-(2-bromo-4,5-Dimethoxyphenyl)-3-((4-fluoro-benzylamino)-methyl)-2H-pyrone;

II-h.3-((1-benzyl-piperidin-4-yl amino)-methyl)-6-(2-bromo-4,5-Dimethoxyphenyl)-2H-pyrone;

II-i.6-(2-bromo-4,5-Dimethoxyphenyl)-3-(2-(4-(4-fluoro-benzyl)-piperidines-1-yl)-ethylamino)-methyl-2H-pyrone;

II-j.3-(benzylamino-methyl)-6-(2-bromo-4,5-Dimethoxyphenyl)-2H-pyrone;

II-k.3-(4-(2-((6-(2-bromo-4,5-Dimethoxyphenyl)-2-oxo-2H-pyrans-3-ylmethyl)-amino)-ethyl)-piperazine-1-ylmethyl)-benzyl cyanide;

II-l.6-(benzo [1,3] dioxolane-5-yl)-3-((2-(5-nitro-pyridine-2-base is amino)-ethylamino)-methyl)-2H-pyrone;

II-m.3-((1-benzyl-piperidin-4-yl amino)-methyl)-6-(benzo [1,3] dioxolane-5-yl)-2H-pyrone;

II-n.6-(3, the 4-Dimethoxyphenyl)-2-oxo-2H-pyrans-3-formic acid (2-morpholine-4-base-ethyl) amine;

II-o.6-(2-bromo-4,5-Dimethoxyphenyl)-2-oxo-2H-pyrans-3-formic acid (1-benzyl-piperidin-4-yl) amine.

X is a nitrogen-atoms in formula (1), R ₂Be H, when there is to become two key in dotted line, be called the compound shown in the formula (III):

The substituent R of formula (III) compound ₁Identical with in the definition of n and the formula (1); R ₂Definition and the R in the formula (1) ₃Identical.

The preferred formula of the present invention (III) compound comprises:

III-a. suitable-3-((1-benzyl-piperidin-4-yl-imino-)-methyl)-6-(3, the 4-Dimethoxyphenyl)-2H-pyrone;

III-b. anti-3-((1-benzyl-piperidin-4-yl-imino-)-methyl)-6-(3, the 4-Dimethoxyphenyl)-2H-pyrone;

III-c. suitable-3-((1-benzyl-piperidin-4-yl-imino-)-methyl)-6-(benzo [1,3] dioxolane-5-yl)-2H-pyrone;

II-d. instead-3-((1-benzyl-piperidin-4-yl-imino-)-methyl)-6-(benzo [1,3] dioxolane-5-yl)-2H-pyrone.

The present invention also provides a kind of formula (I), the preparation method of formula (II) and formula (III) compound, the operational path feature of this synthetic route is: be starting raw material with the methyl aceto acetate, generate the 2-methyl-acetoacetic ester with iodomethane reaction under alkaline condition, again with identical or different R ₁The aryl aldehyde that replaces is condensed into pure I-1 under alkaline condition, become glycol I-2 through sodium borohydride reduction I-1; Under alkaline condition dehydration close encircle tetrahydropyrans ketone compounds I-3; Get pyrrolin ketone compounds I-4 through dehydration reaction again; Compound I-4 makes corresponding bromide I-5 at 6 brominations and 6,5 dehydrobrominations of reaching tetrahydro pyrone on the phenyl ring, on the methyl, the aldehyde I-7 of I-6 and no bromine through bromo-succinimide (NBS) step; The hydroxyl of bromide I-5 and different replacements carries out generating corresponding formula (I) compound after the substitution reaction, and is generated the corresponding formula (compound of IIa～IIk) after the different organic amine substitution reactions that replace; Bromide I-5 becomes the aldehyde I-7 that the benzene bromine in ring replaces after the silver peroxide oxidation, bromide I-6 replaces aldehyde I-7 through also can be generated the benzene bromine in ring by methyl-sulphoxide (DMSO) oxidation under alkaline condition, and the benzene bromine in ring replaces aldehyde I-7 and generates the corresponding formula (compound of IIn～IIo) with different organic amine reactions then through the NBS bromination earlier; The primary amine that the aldehyde I-7 that is not replaced by bromine on the phenyl ring is direct with different carries out condensation reaction and generates the corresponding formula (compound of IIIa～IIIb).

Formula (1) compound and formula (2) compound and preparation intermediate thereof have important biological, in vitro tests shows that this type of new compound with 6-aryl-3-substituted methylene-pyranone structure has restraining effect to acetylcholinesterase (AChE), but to butyrylcholine esterase (BuChE) restraining effect a little less than, and in the ICR acute toxicity test in mice, demonstrate good security, might develop into new anti-senile dementia disease medication.

Its preparation intermediate of formula of the present invention (1) compound or its pharmacologically acceptable salt or its solvate can combine with auxiliary material or carrier pharmaceutically commonly used, have the pharmaceutical composition that inhibiting activity of acetylcholinesterase, can be used to prevent and treat senile dementia thereby prepare.Above-mentioned various kinds of drug composition can adopt the pharmaceutical dosage form of different way of administration such as injection, tablet or capsule.Also can adopt known theory and technology that its preparation intermediate or its pharmacologically acceptable salt of formula (1) compound or its solvate are prepared into controlled release, slow release formulation and nanometer formulation etc.

Further specify the present invention below by preparation example and embodiment, OMe representation methoxy wherein, OEt represents oxyethyl group.Embodiment has provided synthetic and the dependency structure appraising datum and the part activity data of representative new compound.Mandatory declaration, following preparation example and embodiment are used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.

Preparation row 1: the preparation of Compound I-0 (2-methyl-acetoacetic ester):

In 300 milliliter ethanol, add 13.8 gram sodium Metal 99.5s (600mmol), fully after the dissolving, drip methyl aceto acetate 80ml (600mmol), heated up and reflux 1 hour, drip methyl iodide 50ml (660mmol), refluxed two hours, be cooled to room temperature, rotary evaporation is removed ethanol, adds entry extracted with diethyl ether (5 * 50ml), merge organic phase, anhydrous sodium sulfate drying, suction filtration, rotary evaporation is removed ether, underpressure distillation, collect 78-80 ℃ of (13mmHg) cut, obtain colourless transparent liquid 87.63 grams, separation yield Y=50.71%.

Preparation example 2: the preparation of Compound I-1 [with (2-methyl-3-oxygen-5-hydroxyl-5-(3 ', 4 ', 5 '-trimethoxyphenyl)-Valeric acid ethylester) be example]:

Bathe under the cooling conditions in cryosel, in the tetrahydrofuran (THF) suspension liquid (140ml) of 2.3 gram sodium hydrides (95.8mmol), drip 2-methyl-acetoacetic ester 5.78 grams (37.5 mmol), drip the hexane solution 28ml (70.2mmol) of 2.5M n-Butyl Lithium then, drip 3 after ten minutes, 4, the tetrahydrofuran solution (10ml) of 5-TMB 5.88 grams (30mmol), continue reaction 15 minutes, in reaction system, add saturated aqueous ammonium chloride (30ml), (3 * 50ml) extractions merge organic phase, with saturated common salt water washing (3 * 20ml) with ether, anhydrous sodium sulfate drying, suction filtration, silica gel column chromatography (petrol ether/ethyl acetate: 2/1) obtain yellow oily liquid 7.572 grams, separation yield Y=72.11%.

Rf (ethyl acetate/petroleum ether: 1/1): 0.59.

Preparation example 3: the preparation of Compound I-2 [with (2-methyl-3-hydroxyl-5-hydroxyl-5-(3 ', 4 ', 5 '-trimethoxy)-Valeric acid ethylester) be example]:

In ice-water bath, 3.06 gram (9mmol) intermediate I-1 are dissolved in tetrahydrofuran (THF) (67.5ml) and the methyl alcohol (27ml), slowly add sodium borohydride 1.04 grams (27mmol), reacted 30 minutes.Add saturated aqueous ammonium chloride 30ml, and extracted with diethyl ether (3 * 40ml), merge organic phase, the saturated common salt water washing, anhydrous sodium sulfate drying, rotary evaporation is removed ether, gets crude product 3.22 grams, directly carries out next step reaction.

Rf (ethyl acetate/petroleum ether: 1/1): 0.35.

Preparation example 4: the preparation of Compound I-3 [with (3-methyl-4-hydroxyl-6-(3 ', 4 ', 5 '-trimethoxyphenyl)-tetrahydropyrans-2-ketone) be example]:

3.08 gram (9mmol) I-2 is dissolved in 95% ethanol (72ml), adds 1M lithium hydroxide (10ml), reacts one hour in batches.Rotary evaporation is removed ethanol, adds water, the ethyl acetate washing.Water layer drips 1N hydrochloric acid 15ml, with ethyl acetate (7 * 30ml) extractions merge organic phase, anhydrous sodium sulfate drying, suction filtration, rotary evaporation is removed ethyl acetate, adds tetrahydrofuran (THF) (45ml), adds tosic acid 0.31 gram (1.8mmol), reaction is spent the night.Add the ether dilution, saturated sodium bicarbonate (2 * 5ml) washings, anhydrous sodium sulfate drying.Silica gel column chromatography (petrol ether/ethyl acetate: 2/1) get yellow jelly 0.837 gram.Embodiment 3,4 two step overall yield of reaction 31.42%.

Rf (ethyl acetate/petroleum ether: 1/1): 0.34.

Preparation example 5: Compound I-4 (3-methyl-6-(3 ', 4 ', 5 '-p-methoxy-phenyl)-5,6-dihydropyrane-2-ketone) preparation

0.837 gram (2.8mmol) I-3 is dissolved in methylene dichloride (435ml), splashes into three second by 1.67ml (11.9mmol) under the ice-water bath condition, slowly drips methylsulfonyl chloride 0.872mml (112mmol) then.Reacted 30 minutes.The adding water washing (2 * 5ml), and the saturated common salt water washing (2 * 5ml), anhydrous sodium sulfate drying.Rotary evaporation removes the continuation the next step of desolvating;

3-methyl-4-mesyloxy-6-(3 ', 4 ', 5 '-trimethoxyphenyl)-pyran-2-one 1.047 gram (2.8mmol) is dissolved in toluene (45ml), stirs under the room temperature, slowly adds DBU 2.24 grams (14.7mmol), and reaction is spent the night.Wash with water (2 * 10ml), and the saturated common salt water washing (2 * 5ml), anhydrous sodium sulfate drying.Silica gel column chromatography (petrol ether/ethyl acetate: 2/1) get 0.326 gram white needle-like crystals, separation yield Y=42%.M.p.115-116 ℃ (re-crystallizing in ethyl acetate).

Rf (ethyl acetate/petroleum ether: 1/1): 0.51.

Preparation example 6: the preparation of Compound I-5 [with (3-brooethyl-6-(2 '-bromo-3 ', 4 ', 5 '-trimethoxyphenyl)-pyran-2-one) be example]:

The mixture of 500mg Compound I-4 (2mmol), 13 gram N-bromo-succinimides (6.4mmol), 330mg Diisopropyl azodicarboxylate (2mmol), 100ml tetracol phenixin is stirred, temperature reaction was cooled to room temperature after 1.5 hours, add 30ml water, separatory takes off layer, water layer is washed twice with the 50ml chloroform, merge organic phase once with the saturated common salt washing, anhydrous sodium sulfate drying, suction filtration, rotary evaporation removes and desolvates, silica gel column chromatography (chloroform/sherwood oil: 1/1) get yellow solid, m.p.93～95 ℃ (chloroform recrystallization).Separation yield Y=43.8%.

Rf (ethyl acetate/petroleum ether: 1/3): 0.33

¹H-NMR(400MHz，CDCl ₃，δppm)：3.90(s，3H，4′-OMe)，3.91(s，3H，5′-OMe)，3.92(s，3H，3′-OMe)，4.40(s，2H，H-7)，6.70(d，J＝6.8Hz，H-5)，6.96(s，1H，H-6′)，7.57(d，J＝6.8Hz，1H，H-4)。

MS (ESI), m/e (relative abundance): 427 (M+23) ⁺(100).

Embodiment 1: the preparation of Compound I-6 [with (3-two brooethyls-6-(2 '-bromo-3 ', 4 ', 5 '-trimethoxyphenyl)-pyran-2-one) be example]:

The mixture of 500mg Compound I-4 (2mmol), 1.3 gram N-bromo-succinimides (12mmol), 330mg Diisopropyl azodicarboxylate (2mmol), 100ml tetracol phenixin is stirred, temperature reaction was cooled to room temperature after 1.5 hours, add 30ml water, separatory takes off layer, water layer is washed twice with the 5ml chloroform, merge organic phase once with the saturated common salt washing, anhydrous sodium sulfate drying, suction filtration, rotary evaporation removes and desolvates, silica gel column chromatography (chloroform/sherwood oil 1/1) gets yellow solid, m.p.83～84 ℃ (chloroform recrystallization).Separation yield Y=50.2%.

Rf (ethyl acetate/petroleum ether: 1/3): 0.42

¹H-NMR(400MHz，CDCl ₃，δppm)：3.90(s，3H，4′-OMe)，3.91(s，3H，5′-OMe)，3.92(s，3H，3′-OMe)，6.76(s，1H，H-7)，6.83(d，J＝6.0Hz，H-5)，6.96(s，1H，H-6′)，8.02(d，J＝6.0Hz，1H，H-4)。

MS (ESI), m/e (relative abundance): 513 (M) ⁺(6).

Embodiment 2: general structure be I-7 no bromine aldehyde preparation [with (3-formyl radical-6-(3 ', 4 ', 5 '-trimethoxyphenyl)-pyran-2-one) be example]:

The mixture of 500mg Compound I-4 (2mmol), 1.3 gram N-bromo-succinimides (12mmol), 330mg Diisopropyl azodicarboxylate (2mmol), 100ml tetracol phenixin is stirred, temperature reaction was cooled to room temperature after 1.5 hours, add 30ml water, separatory takes off layer, and water layer washes twice with the 50ml chloroform, merges organic phase with the saturated common salt washing once, anhydrous sodium sulfate drying, suction filtration, rotary evaporation removes and desolvates, silica gel column chromatography (chloroform/sherwood oil: 1/1) get yellow jelly.Separation yield Y=11.3%.

Rf (ethyl acetate/petroleum ether: 1/3): 0.15

¹H-NMR(400MHz，CDCl ₃，δppm)：3.93(s，3H，4′-OMe)，3.95(s，6H，3′-OMe，5′-OMe)，6.84(d，J＝7.2Hz，H-5)，7.13(s，2H，H-2′，H-6′)，8.16(d，J＝7.2Hz，1H，H-4)，10.15(s，1H，H-7)。

MS (ESI), m/e (relative abundance): 290 (M) ⁺(100).

Embodiment 3: general structure be bromated aldehyde on the phenyl ring of I-7 preparation [with (3-formyl radical-6-(2 '-bromo-3 ', 4 ', 5 '-trimethoxyphenyl)-pyran-2-one) be example]:

Method one: the mixture of 430mg Compound I-5 (1mmol), sodium bicarbonate (15mmol), 50ml methyl-sulphoxide is stirred, room temperature, methyl-sulphoxide is removed in decompression after 2 hours, add 10ml water, water layer washes twice with the 20ml ethyl acetate, merges organic phase, use anhydrous sodium sulfate drying, suction filtration, removal of solvent under reduced pressure, silica gel column chromatography (chloroform/sherwood oil: 1/1) get yellow jelly.Separation yield Y=42.5%.

Method two: 500mg Compound I-6 (1mmol), 17mg Silver Nitrate (0.1mmol), 100ml alcoholic acid mixture are stirred, temperature reaction was cooled to room temperature after 1.5 hours, remove by filter precipitation, filter residue is washed twice with ethanol, obtain filtrate, rotary evaporation removes and desolvates, and silica gel column chromatography (chloroform/sherwood oil 1/1) gets yellow jelly.Separation yield Y=48.6%.

Rf (ethyl acetate/petroleum ether: 1/3): 0.21

¹H-NMR(400MHz，CDCl ₃，δppm)：3.91(s，3H，4′-OMe)，3.92(s，3H，5′-OMe)，3.97(s，3H，3′-OMe)，6.96(d，J＝7.2Hz，H-5)，7.01(s，1H，H-6′)，8.17(d，J＝6.8Hz，1H，H-4)，10.18(s，1H，H-7)。MS (ESI), m/e (relative abundance): 369 (M) ⁺(60).

Embodiment 4: Compound I-c, the preparation of 6-(2-bromo-3,4-Dimethoxyphenyl)-3-((2-methyl pyrans-4-ketone)-3-base-oxygen base) methylene radical-2H-pyrone

10mg Compound I-5 (0.025mmol) is dissolved in the 2ml acetonitrile, add salt of wormwood 52mg (0.38mmol), stirring at room 12 hours, rotary evaporation removes and desolvates, and adds entry, wash twice with ethyl acetate, anhydrous sodium sulfate drying, suction filtration, removal of solvent under reduced pressure, silica gel column chromatography (ethyl acetate/petroleum ether: 1/4) get light yellow gluey thing 6mg, m.p.129-131 ℃ (re-crystallizing in ethyl acetate).Separation yield Y=52.0%.

Rf (ethyl acetate/petroleum ether: 1/1): 0.33.

¹H-NMR(400MHz，CDCl ₃，δppm)：2.38(s，2H，2″-Me)，3.94(s，3H，4′-OMe)，3.95(s，3H，5′-OMe)，4.99(d，2H，J＝0.8Hz，H-7)，6.40(d，1H，J＝5.6Hz，H-5″)，6.95(d，1H，J＝8.8Hz，H-5)，7.37(d，1H，J＝2.4Hz，H-6′)，7.54(dd，1H，J＝8.8，2.4Hz，H-4)，7.66(d，1H，J＝5.6Hz，H-6″)，7.55(s，1H，H-3′)。

MS (ESI), m/e (relative abundance): 471 (M+Na) ⁺(95%)

Prepare following table one illustrated embodiment 5-10 compound according to similar approach with one of above preparation example 1-6 and embodiment 4:

Table one:

What list below is the physicochemical data of each compound in the table one:

I-a: colourless jelly, Rf (ethyl acetate/petroleum ether: 1/3) 0.25; ¹H-NMR (400MHz, CDCl ₃, δ ppm): 2.04 (m, 2H, H-5 "), 2.39 (m, 2H; H-6 "), 2.52 (m, 2H, H-4 "), 3.94 (m, 2H; 4 '-OMe), 3.96 (s, 3H, 5 '-OMe), 4.78 (s, 2H; H-7), 5.47 (s, 1H, H-2 "), 6.95 (d, 1H, J=8.0Hz, H-5), 7.36 (m, 1H, H-6 '), 7.54 (m, 2H, H-4), 7.58 (s, 1H, H-3 '); ESI-MS (m/z): 435 (M) ⁺(15%).

I-b: colourless jelly, Rf (ethyl acetate/petroleum ether: 1/2) 0.20; ¹H-NMR (400MHz, CDCl ₃, δ ppm): 2.01 (s, 2H, 2 " Me), 2.39 (m, 2H; H-4 "), 2.49 (m, 2H, H-3 "), 3.93 (s, 3H; 4 '-OMe), 3.94 (s, 3H, 5 '-OMe), 5.05 (d, 2H; J=1.2Hz, H-7), 6.94 (d, 1H, J=8.8Hz, H-5); 7.36 (d, 1H, J=2.0Hz, H-6 '), 7.53 (dd, 1H; J=8.8,2.0Hz, H-4), 7.69 (s, 1H, H-3 '); ESI-MS (m/z): 457 (M+Na) ⁺(100%).

I-d: colourless jelly, Rf (ethyl acetate/petroleum ether: 1/1) 0.53; ¹H-NMR (400MHz, CDCl ₃, δ ppm):

2.19(s，2H，6″-Me)，3.56(s，2H，H-7)，3.91(s，3H，4′-OMe)，3.94(s，3H，5′-OMe)，5.89(s，1H，H-5″)，6.93(d，1H，J＝8.8Hz，H-5)，7.32(d，1H，J＝2.0Hz，H-6′)，7.48(dd，1H，J＝8.8，2.0Hz，H-4)，7.90(s，1H，H-3′)，9.94(s，1H，H-3″)；ESI-MS(m/z)：449(M) ⁺(98％)。

I-e: colourless jelly, Rf (ethyl acetate/petroleum ether: 1/2) 0.13; ¹H-NMR (400MHz, CDCl ₃, δ ppm): 3.93 (s, 3H, 4 '-OMe), 3.95 (s, 3H, 5 '-OMe), 4.57 (d, 2H, J=0.8Hz, H-7), 6.93 (d, 1H, J=8.4Hz, H-5), 7.35 (d, 1H, J=2.0Hz, H-6 '), 7.50 (dd, 1H, J=8.4,2.0Hz, H-4), 7.56 (s, 1H, H-3 '); ESI-MS (m/z): 515 (M+Na) ⁺(37%).

I-f: colourless jelly, Rf (ethyl acetate/petroleum ether: 1/1) 0.32; ¹H-NMR (400MHz, CDCl ₃, δ ppm): 2.12 (s, 2H, 6 " Me), 3.46 (s, 2H; H-7), 3.91 (s, 3H, 4 '-OMe), 3.92 (s, 3H; 3 '-OMe), 3.94 (s, 3H, 5 '-OMe), 5.89 (s, 1H; H-5 "), 6.70 (d, 1H, J=6.8Hz, H-5), (6.96 s, 1H, H-6 '), 7.57 (d, 1H, J=6.8Hz, H-4), 9.90 (s, 1H, H-3 "); ESI-MS (m/z): 479 (M) ⁺(100%).

I-g: colourless jelly, Rf (ethyl acetate/petroleum ether: 1/3) 0.33; ¹H-NMR (400MHz, CDCl ₃, δ ppm): 2.15 (s, 2H, 6 " Me), 3.52 (s, 2H; H-7), 5.89 (s, 1H, H-5 "), 6.05 (s, 2H, H-2 '), 6.54 (d, 1H, J=7.2Hz, H-5), 6.88 (d, 1H, J=8.4Hz, H-7 '), 7.27 (s, 1H, H-4 '), (7.41 d, 1H, J=8.4Hz, H-6 '), 7.53 (dd, 1H, J=7.2Hz, H-4), 9.94 (s, 1H, H-3 "); ESI-MS (m/z): 354 (M) ⁺(100%).

Embodiment 11: Compound I I-a, and the preparation of 6-(2-bromo-4,5-Dimethoxyphenyl)-3-((2-morpholine-4-base-ethylamino)-methyl)-2H-pyrone:

20mg Compound I-5 (0.05mmol) is dissolved in the 2ml acetonitrile, add amino-ethyl morpholine 20mg (0.15mmol), stirring at room 24 hours, removal of solvent under reduced pressure, silica gel column chromatography (ethyl acetate/petroleum ether: 1/4) get colourless jelly 20mg, separation yield Y=8.83%.

Rf (methyl alcohol/chloroform: 10/1) 0.61;

¹H-NMR(400MHz，CDCl ₃，δppm)：2.53(brs，4H，H-3″，H-5″)，2.63(brs，2H，H-10)，2.84(brs，2H，H-9)，3.75(bs，6H，H-2″，6″，7)，3.94(s，3H，4′-OMe)，3.95(s，3H，5′-OMe)，6.95(d，1H，J＝8.4Hz，H-5)，7.36(d，1H，J＝2.0Hz，H-6′)，7.51(dd，1H，J＝8.4，2.0Hz，H-4)，?7.63(s，1H，H-3′)。

MS (ESI), m/e (relative abundance): 453 (M) ⁺, (100%); 455 (M+2) ⁺, (98%)

According to preparing following table two illustrated embodiment 12-23 compounds with above preparation example 1-6, embodiment 11 similar methods:

Table two:

What list below is the physicochemical data of each compound in the table two:

II-b: colourless jelly, Rf (ethyl acetate/petroleum ether: 1/3) 0.20; ¹H-NMR:(400MHz, CDCl ₃, δ ppm) 2.87 (brs, 2H, H-9), 3.57 (brs, 2H, H-10), 3.75 (s, 2H, H-7), 3.89 (s, 3H, 4 '-OMe), 3.94 (s, 3H, 5 '-OMe), 6.57 (d, 1H, J=9.2Hz, H-3 "), 6.88 (d, 1H, J=8.4Hz; H-5), 7.30 (d, 1H, J=2.0Hz, H-6 '), 7.45 (dd, 1H; J=804,2.0Hz, H-4), 7.52 (s, 1H, H-4, H-3 '); 8.05 (d, 1H, J=9.2Hz, H-4 "), 9.00 (s, 1H, H-6 ").

II-c: colourless jelly, Rf (ethyl acetate/petroleum ether: 1/1) 0.22; ¹HNMR (400MHz, CDCl ₃, δ ppm): 1.59 (m, 2H, H-4 "), 1.91 (m, 2H, H-3 "), 2.74 (m, 2H, H-9), 3.74 (s, 2H, H-7), 3.77 (m, 1H, H-5 " b); 3.89 (m, 1H, H-5 " a), 3.93 (s, 3H, 4 '-OMe), 3.94 (s, 3H, 5 '-OMe), 4.08 (m, 1H, H-2 "), 6.92 (d, 1H; J=8.4Hz, H-5), 7.35 (d, J=2.0Hz, 1H, H-6 '), 7.50 (dd; 1H, J=8.0,2.0Hz, H-4), 7.60 (s, 1H, H-3 ').

II-d: colourless jelly, Rf (ethyl acetate/petroleum ether: 1/1) 0.15; ¹H-NMR (400MHz, CDCl ₃, δ ppm): 1.26 (t, 3H, J=7.2Hz, OCH ₂CH ₃), 1.41 (brs, 4H, H-2 ", H-6 "), 1.93 (m, 2H, H-3 " a, 5 " be 2.76 (m a),, 2H, H-4 "), 2.88 (m, 2H, H-3 " b, 5 " b), 3.75 (s, 2H, H-7), 3.94 (s; 3H, 4 '-OMe), 3.95 (s, 3H, 5 '-OMe), 4.19 (q, 2H, J=7.2Hz, OCH ₂CH ₃), 6.92 (d, 1H, J=8.8Hz, H-5), 7.35 (d, 1H, J=2.0Hz, H-6 '), 7.51 (dd, 1H, J=8.8,2.0Hz, H-4), 7.62 (s, 1H, H-3 ').

II-e: colourless jelly, Rf (chloroform/methanol: 2/1) 0.45; ¹H-NMR (400MHz, CDCl ₃, δ ppm): 2.60 (m, 8H, H-2 ", H-3 ", H-5 "; H-6 "), 3.46 (m, 4H, H-8, H-9), 3.69 (s, 2H, H-7), 3.93 (s, 3H, 4 '-OMe), 3.95 (s, 3H, 5 '-OMe), 6.93 (d, 1H, J=8.8Hz, H-5), (7.35 d, 1H, J=2.0Hz, H-6 '), 7.52 (dd, 1H, J=8.8,2.0Hz, H-4), 7.55 (s, 1H, H-3 ').

II-f: colourless jelly, Rf (ethyl acetate/petroleum ether: 1/3) 0.22; ¹H-NMR (400MHz, CDCl ₃, δ ppm): 3.49 (dd, 2H, J=4.8,12.6Hz, H-9), 3.75 (dd, 2H, J=2.0,12.0Hz, H-10), 3.94 (s, 3H, 4 '-OMe), 3.96 (s, 3H, 5 '-OMe), 4.57 (s, 1H, H-8), 4.92 (s, 2H, H-7), 5.28 (s, 1H, H-11), 6.92 (d, 1H, J=8.0Hz, H-5), 6.98 (d, 2H, J=10.8Hz, H-3 ", H-5 "), (7.35 m, 1H, H-6 '), 7.54 (m, 2H, H-2 ", H-6 "), 7.62 (s, 1H, H-3 '), 7.77 (d, 1H, J=8.0Hz, H-4).

II-g: colourless jelly, Rf (ethyl acetate/petroleum ether: 1/1) 0.15; ¹H-NMR (400MHz, CDCl ₃, δ ppm): 2.62 (brs, 4H, H-2 ", H-6 "), 2.68 (brs, 2H, H-10), 3.62 (m, 2H, H-9), 3.74 (brs, 4H, H-3 ", 5 "), 3.96 (s, 3H, 4 '-OMe), 3.97 (s, 3H, 5 '-OMe), 6.84 (d, 1H, J=7.6Hz, H-5), 6.97 (d, 1H, J=8.8Hz, H-5 '), 7.38 (d, 1H, J=2.4Hz, H-2 '), 7.54 (dd, 1H, J=8.8,2.0Hz, H-6 '), 7.57 (d, 1H, J=7.6Hz, H-4), 9.03 (s, 1H, H-8).

II-h: colourless jelly, Rf (chloroform/methanol: 5/1) 0.35; ¹H-NMR (400MHz, CDCl ₃, δ ppm): 1.46 (m, 2H, H-3 " b, 5 " b), 1.92 (m, 2H, H-3 " a, 5 " a), 2.08 (m, 2H, 2.52 H-2 " b, 6 " b), (m, 1H, H-4 "); 2.89 (m, 2H, H-2 " a, 6 " a), 3.53 (brs; 2H, H-7), 3.67 (d, 1H, J=0.8Hz; H-7 '), 3.92 (s, 3H, 4 '-OMe), 3.93 (s; 3H, 5 '-OMe), 6.93 (d, 1H, J=8.4Hz; H-5), 7.31 (m, 5H, Ph-H), 7.34 (s, 1H, H-6 '), 7.48 (dd, 1H, J=8.4,2.0Hz, H-4), 7.54 (brs, 1H, H-3 ').

II-i: colourless jelly, Rf (chloroform/methanol: 5/1) 0.30; ¹H-NMR (400MHz, CDCl ₃, δ ppm): 2.40 (brs, 2H, H-9), 2.47 (brs, 4H, H-2 ", H-6 "), 2.69 (brs, 2H, H-8), 2.83 (brs, 4H, H-3 ", H-5 "), 3.52 (s, 2H, H-7 "), 3.74 (s, 2H, H-7); 3.87 (s, 3H, 4 '-OMe), 3.89 (s, 3H; 5 '-OMe), 7.07 (m, 3H, H-5, H-2 , H-6

), 7.45 (m, 4H, H-4, H-6 ', H-3

, H-5

), 7.81 (s, 1H, H-3 ').

II-j: colourless jelly, Rf (ethyl acetate/petroleum ether: 1/3) 0.25; ¹H-NMR (400MHz, CDCl ₃, δ ppm): 1.77 (bs, 2H, H-2 " b, 6 " b), 2.02 (brs, 2H, H-3 "; 5 " b), 2.36 (brs, 2H, H-2 " a, 6 " a), 2.94 (brs, 2H, H-3 " a; 5 " a), 3.67 (s, 1H, H-7 "), 3.95 (s, 3H, 4 '-OMe), 3.96 (s; 3H, 5 '-OMe), 4.01 (m, 1H, H-1 "), 6.96 (d, 1H, J=8.4Hz, H-5), 7.32 (m, 5H, Ph-H), 7.44 (d, 1H, J=2.0Hz, H-6 '), 7.64 (dd, 1H, J=8.4,2.0Hz, H-4), 8.63 (s, 1H, H-3 ').

II-k: colourless jelly, Rf (ethyl acetate/petroleum ether: 1/1) 0.15; ¹H-NMR (400MHz, CDCl ₃, δ ppm): 2.46 (brs, 6H, H-2 ", H-6 ", H-9), 2.55 (brs, 4H, H-3 ", H-5 "), 2.66 (brs, 2H, H-8), 3.50 (s, 2H, H-7 "), 3.72 (s, 2H; H-7), 3.89 (s, 3H, 4 '-OMe), 3.91 (s, 3H; 5 '-OMe), 6.91 (d, 1H, J=8.4Hz, H-5), 7.30 (brs; 1H, H-6 '), 7.39 (d, 1H, J=7.6Hz, H-6

), 7.45 (dd, 1H, J=8.4,2.0Hz, H-4), 7.51 (m, 2H, H-3 ', H-5

), 7.62 (d, 1H, J=7.6Hz, H-4

), 7.67 (s, 1H, H-2

).

II-1: colourless jelly, Rf (ethyl acetate/petroleum ether: 1/1) 0.31; ¹H-NMR (400MHz, CDCl ₃, δ ppm): 2.87 (brs, 2H, H-9), 3.57 (brs, 2H, H-10), 3.75 (s, 2H, H-7), 6.05 (s, 2H, H-2 '), 6.54 (d, 1H, J=7.2Hz, H-5), 6.57 (d, 1H, J=9.2Hz, H-3 "), 6.81 (d; 1H, J=8.4Hz, H-7 '), 6.88 (d, 1H; J=8.4Hz, H-5), 7.27 (s, 1H, H-4 '); 7.30 (d, 1H, J=2.0Hz, H-6 '), 7.45 (dd; 1H, J=8.4,2.0Hz, H-4), 7.52 (s; 1H, H-4, H-3 '), 8.05 (d, 1H, J=9.2Hz, H-4 "), 9.00 (s, 1H, H-6 ").

II-m: colourless jelly, Rf (chloroform/methanol: 5/1) 0.35; ¹H-NMR (400MHz, CDCl ₃, δ ppm): 1.46 (m, 2H, H-3 " b, 5 " b), 1.92 (m, 2H, H-3 " a, 5 " a), 2.08 (m, 2H, H-2 " b; 6 " b), 2.52 (m, 1H, H-4 "), 2.89 (m, 2H; H-2 " a, 6 " a), 3.53 (brs, 2H, H-7), 3.67 (d; 1H, J=0.8Hz, H-7 "), 6.05 (s, 2H, H-2 '), 6.54 (d, 1H, J=7.2Hz, H-5), 6.88 (d, 1H, J=8.4Hz, H-7 '), 7.27 (s, 1H, H-4 '), 7.31 (m, 5H, Ph-H), 7.41 (d, 1H, J=8.4Hz, H-6 '), 7.53 (dd, 1H, J=7.2Hz, H-4), 9.94 (s, 1H, H-2 ").

Embodiment 24: Compound I I-n, and the preparation of 6-(3, the 4-Dimethoxyphenyl)-2-oxo-2H-pyrans-3-formic acid (2-morpholine-4-base-ethyl) ammonia:

26mg is dissolved in the mixed solvent of 2ml tetracol phenixin and methylene dichloride by the Compound I-7 (0.05mmol) that the I-5 preparation comes, add 27mg NBS (0.075mmol), illumination 3 hours, be cooled to room temperature, ice-water bath adds amino-ethyl morpholine 20mg (0.075mmol), stirring at room 24 hours, removal of solvent under reduced pressure, silica gel column chromatography (ethyl acetate/petroleum ether: 1/4) get colourless jelly 4mg, separation yield Y=17.3%.

Rf (ethyl acetate/petroleum ether: 1/1) 0.15;

¹H-NMR(400MHz，CDCl ₃，δppm)：2.62(brs，4H，H-3″，H-5″)，2.68(brs，2H，H-10)，3.62(m，2H，H-9)，3.74(brs，4H，H-2″，6″)，3.96(s，3H，4′-OMe)，3.97(s，3H，5′-OMe)，6.84(d，1H，J＝7.6Hz，H-5)，6.97(d，1H，J＝8.8Hz，H-5′)，7.38(d，1H，J＝2.4Hz，H-2′)，7.54(dd，1H，J＝8.8，2.0Hz，H-6′)，7.57(d，1H，J＝7.6Hz，H-4)，9.03(s，1H，H-8)。

MS (ESI), m/e (relative abundance): 490 (M+Na) ⁺, (100%)

Embodiment 25: Compound I I-o, and the preparation of 6-(2-bromo-4,5-Dimethoxyphenyl)-2-oxo-2H-pyrans-3-formic acid (1-benzyl-piperidin-4-yl) ammonia:

The Compound I-7 (0.05mmol) that 18mg Compound I-4 is got is dissolved in the mixed solvent of 3ml tetracol phenixin and methylene dichloride, add 15mg NBS (0.075mmol), illumination 3 hours, be cooled to room temperature, ice-water bath adds 4-amino-1-benzyl piepridine 20mg (0.11mmol), stirring at room 24 hours, removal of solvent under reduced pressure, silica gel column chromatography (ethyl acetate/petroleum ether: 1/4) get colourless jelly 6mg, separation yield Y=23.1%.

Rf (ethyl acetate/petroleum ether: 1/3) 0.25;

¹H-NMR(400MHz，CDCl ₃，δppm)：1.77(brs，2H，H-3″b，5″b)，2.02(brs，2H，H-2″b，6″b)，2.36(brs，2H，H-3″，5″a)，2.94(brs，2H，H-2″a，6″a)，3.67(s，1H，H-7′)，3.95(s，3H，4′-OMe)，3.96(s，3H，5′-OMe)，4.01(m，1H，H-1″)，6.96(d，1H，J＝8.4Hz，H-5)，7.32(m，5H，Ph-H)，7.44(d，1H，J＝2.0Hz，H-6′)，7.64(dd，1H，J＝8.4，2.0Hz，H-4)，8.63(s，1H，H-3′)。MS (ESI), m/e (relative abundance): 527 (M+1) ⁺, (100%).

Embodiment 26,27: compound III-a and III-b, suitable-3-((1-benzyl-piperidin-4-yl-imino-)-methyl)-6-(3, the 4-Dimethoxyphenyl)-preparation of 2H-pyrone and anti-3-((1-benzyl-piperidin-4-yl-imino-)-methyl)-6-(3, the 4-Dimethoxyphenyl)-2H-pyrone

15mg (0.06mmol) intermediate I-7 is dissolved in the 3ml methyl alcohol, stirring at room, add 16mg 4-amino-1-benzyl piepridine (0.09mmol), reacted three hours, removal of solvent under reduced pressure, column chromatography (petrol ether/ethyl acetate: 2/1) colourless jelly III-a and colourless jelly III-b, be respectively 9mg and the 5mg separation yield is respectively Y _a=34.7%, Y _b=19.3%.

II-a. colourless jelly, Rf (ethyl acetate/chloroform: 1/1) 0.35;

¹H-NMR(400MHz，CDCl ₃，δppm)：1.78(brs，2H，H-3″b，5″b)，1.98(brs，2H，H-2″b，6″b)，2.23(brs，2H，H-3″a，5″a)，2.93(brs，2H，H-2″a，6″a)，3.29(m，1H，H-4″)，3.60(s，1H，H-7″)，3.95(s，3H，3′-OMe)，3.96(s，3H，4′-OMe)，6.90(d，1H，J＝8.4Hz，H-5′)，7.28(m，5H，Ph-?H)，733(s，1H，H-2′)，7.41(d，1H，J＝14.0Hz，H-5)，7.56(d，1H，J＝16.4Hz，H-4)，7.62(d，1H，J＝8.4Hz，H-6′)，9.06(brs，1H，H-7)。

MS (ESI), m/e (relative abundance): 432 (M) ⁺, (100%).

III-b. colourless jelly, Rf (ethyl acetate/chloroform: 1/1) 0.30;

¹H-NMR(400MHz，CDCl ₃，δppm)：1.93(m，2H，H-3″b，5″b)，1.96(m，2H，H-2″b，6″b)，2.87(m，2H，H-3″a，5″a)，2.91(m，2H，H-2″a，6″a)，3.23(m，1H，H-4″)，3.49(s，1H，H-7″)，3.95(s，3H，3′-OMe)，3.96(s，3H，4′-OMe)，6.83(d，1H，J＝15.2Hz，H-5)，6.91(d，1H，J＝8.4Hz，H-5′)，7.28(m，5H，Ph-H)，7.33(s，1H，H-2′)，7.53(d，1H，J＝8.4Hz，H-6′)，7.59(d，1H，J＝15.2Hz，H-4)，9.48(brs，1H，H-7)。

MS (ESI), m/e (relative abundance): 432 (M) ⁺, (100%).

Embodiment 28,29: according to preparing compound III-c with above preparation example 1-6, embodiment 26 and 27 similar methods, III-d, be respectively suitable-3-((1-benzyl-piperidin-4-yl-imino-)-methyl)-6-(3, the 4-Dimethoxyphenyl)-2H-pyrone and anti-3-((1-benzyl-piperidin-4-yl-imino-)-methyl)-6-(3, the 4-Dimethoxyphenyl)-and the 2H-pyrone, the materialization data are as follows:

III-c. colourless jelly, Rf (ethyl acetate/chloroform: 1/1) 0.43; ¹H-NMR (400MHz, CDCl ₃, δ ppm): 1.78 (brs, 2H, H-3 " b, 5 " b), 1.98 (brs, 2H, H-2 " b, 6 " b), 2.23 (brs, 2H, H-3 " a; 5 " a), 2.93 (brs, 2H, H-2 " a, 6 " a), 3.29 (m, 1H, H-4 "), 3.60 (s, 1H; H-7 "), 6.05 (s, 2H, H-2 '), 6.88 (d, 1H, J=8.4Hz, H-7 '), 7.28 (m, 6H, Ph-H, H-4 '), 7.33 (s, 1H, H-2 '), 7.41 (d, 1H, J=14.0Hz, H-5), 7.56 (d, 1H, J=16.4Hz, H-4), 7.61 (d, 1H, J=8.4Hz, H-6 '), 9.06 (brs, 1H, H-7).

MS (ESI), m/e (relative abundance): 416 (M) ⁺, (100%).

III-d. colourless jelly, Rf (ethyl acetate/chloroform: 1/1) 0.28; ¹H-NMR (400MHz, CDCl ₃, δ ppm): 1.93 (m, 2H, H-3 " b, 5 " b), 1.96 (m, 2H, H-2 " b, 6 " b), 2.87 (m, 2H, H-3 " a; 5 " a), 2.91 (m, 2H, H-2 " a, 6 " be 3.23 (m a),, 1H, H-4 "), 3.49 (s, 1H, H-7 "), 6.05 (s, 2H, H-2 '), 6.83 (d, 1H, J=15.2Hz, H-5), (6.88 d, 1H, J=8.4Hz, H-7 '), 6.91 (d, 1H, J=8.4Hz, H-5 '), 7.28 (m, 5H, Ph-H), 7.33 (s, 1H, H-4 '), 7.53 (d, 1H, J=8.4Hz, H-6 '), 7.59 (d, 1H, J=15.2Hz, H-4), 9.48 (brs, 1H, H-7).

MS (ESI), m/e (relative abundance): 416 (M) ⁺, (100%).

In order to understand essence of the present invention better, the form of using pharmacology embodiment below respectively is to Compound I I-d, Compound I I-h, and the The pharmacological results of Compound I I-l and Compound I I-m is an example, and its new purposes in pharmacy field is described.Embodiment has provided the part activity data of representative compounds.Same mandatory declaration, the listed herein pharmacology of the present invention relevant embodiment be used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.

Embodiment 30: Compound I I-d is to acetylcholinesterase (acetylcholinesterase is called for short AChE) and active inhibition experiment of butyrylcholine esterase (BuChE) and result.

1:Ellman etc. have invented the sensitive testing method of measuring acetylcholine esterase active: with the male Wistar rat sacrificed by decapitation, tell brain rapidly, separate striatum and also weigh, add 0.05mol/L phosphoric acid buffer (pH7.2, the approximately homogenizer homogenate of 7mg albumen/mL) of 19 times of volumes.Get the trial drug II-d that suspension 25 μ L add 1mL solvent or 0.4mg/mL, in 37 ℃ of water-baths, incubated in advance 10 minutes.Add 10mM two sulphur-two nitrobenzoic acids (DTNB) 10 μ L, 405nm wavelength place colorimetric.(with the positive contrast of isocyatic selagine solution).

2: the restraining effect of butyrylcholine esterase (BuChE) is measured the ELISA method that adopts.With methyl-sulphoxide dissolved compound II-d, dilute with phosphoric acid buffer, making its final concentration is 0.04mg/mL, add substrate sulfo-BuCh (S-BCh, 4.4mg/mL) water-bath 30min in 37 ℃, add developer dithio dinitrobenzene formic acid (DTNB, 4mg/mL, 10 μ L), colorimetric estimation under the 405nm wavelength.Phosphoric acid buffer with equal volume in the blank well replaces substrate.Add and the isocyatic methyl-sulphoxide of compound in the solvent control hole.The compound inhibiting rate is calculated for blank and contrast OD value by sample OD value.

Compound I I-d that measures thus and positive control selagine are to the restraining effect of AChE and BuChE as shown in Table 3.

Table three Compound I I-d and selagine when 0.4mg/mL to the restraining effect of AChE and BuChE

Compound	To AChE inhibiting rate (%)	To BuChE inhibiting rate (%)
			II-d	65.8±6.2	5.5±1.4
Selagine	81.7±5.7	3.6±1.2

According to shown in the table three, Compound I I-d has higher inhibition activity to acetylcholinesterase, and it is extremely low that butyrylcholine esterase is suppressed activity.Therefore be hopeful to develop into the acetylcholinesterase selective depressant.

According to the method for embodiment 30, the inhibition test that we have carried out above-mentioned AChE and BuChE to the compound that synthesizes and intermediate.Representative active compounds II-h, the ratio tabulation of the percent inhibition of II-l and II-m relatively sees Table four.

Representative formula 1 compound of table four and selagine when 0.4mg/mL to the restraining effect of AChE and BuChE

Embodiment number	Compound	To AChE inhibiting rate (%)	To BuChE inhibiting rate (%)
				Embodiment 31	II-h	89.6±6.8	12.5±3.1

Embodiment 32	II-l	21.9±3.3	3.8±1.2
				Embodiment 33	II-m	87.8±8.4	8.5±2.2
?	Selagine	81.7±5.7	3.6±1.2

According to shown in the table four, some compounds that synthesized have very high inhibition activity to acetylcholinesterase, inhibition strength even surpassed selagine, and that butyrylcholine esterase is suppressed activity is extremely low for these compounds simultaneously.Therefore be hopeful to develop into the acetylcholinesterase selective depressant.

Embodiment 34: Compound I I-d is to the acute toxicity effect experiment of ICR mouse

1, purpose: Compound I I-d is carried out acute toxicity test, tentatively understand the acute toxicity situation of compound.

2, experimental animal and sample: 40 of animal ICR mouse, purchase medicine inspecting institute in Zhejiang Province, complete male.(laboratory animal credit number: SCXK (Zhejiang) 2004-0012, No. 0013); Solvent: 10% gumwater (self-control); Sample II-d is 99% above person for this prepared in laboratory purity.

3, grouping and dosage: laboratory animal is divided into following four groups by different route of administration and dosage, II-d A group: II-d 1.0g/kg gastric infusion; 3.2 II-dB group: II-d2.0g/kg gastric infusion; II-dC group: II-d 0.5g/kg intraperitoneal injection; 3.3 II-dD group: II-d 0.2g/kg intraperitoneal injection;

4, test methods and procedures: mouse fasting 12 hours, according to the sample gumwater of test design dosage preparation 10% according to two kinds of administering mode administrations.Observe the mouse response situation after the administration immediately, comprise animal appearance behavioral activity, the mental status, appetite, stool and urine color, had or not abnormal secretion thing and death condition by hair, the colour of skin, nose, eye, oral cavity, observed 14 days continuously, detail record is animal toxicity response situation and dead distribute (seeing table five for details) day by day.Dissect not dead mouse after the off-test and observe internal organs variation in the body.

The observed situation of acute toxicity test behind table five, sample II-d mouse stomach and the abdominal injection

?

Administering mode

Dosage (g/kg)

Size of animal

The dead animal number

Abnormal conditions

Dissect internal organs in the back

?

The same day

1-14 days

?

The II-dA group

Irritate stomach

1.0

10

0

No abnormal

The II-dB group

Irritate stomach

2.0

10

0

No abnormal

The II-dC group

Abdominal injection

0.5?

10?

0?

No abnormal

The II-dD group

Abdominal injection

0.2?

10?

0?

No abnormal

In the experiment, 40 mouse well-growns are movable normal.Dissect the no abnormality seen phenomenon after 14 days, this interpret sample II-d toxicity is less, and oral maximum tolerated dose is greater than 2.0g/kg.

Claims

1. one kind has 6-aryl-3-replacement-pyranone derivatives or its pharmacologically acceptable salt shown in the formula (1):

Formula (1)

Wherein X is oxygen or NH or imido grpup; Substituent R ₁Identical or different, be respectively halogen, hydrogen atom, or contain the alkoxyl group of 1～5 carbon; Substituent R ₂Be hydrogen atom, oxo; N is 0～10 integer; Substituent R ₃It is hydrogen atom, perhaps replace or unsubstituted saturated five～octatomic ring, perhaps replace or unsubstituted five～eight yuan of aromatic nucleus, or 2～3 replace or unsubstituted alicyclic ring or alicyclic heterocyclic and replacement or unsubstituted aromatic ring or fragrant heterocycle between the group that is connected to form by methylene radical or carbonyl;

Wherein, be selected from halogen as the substituting group that replaces, amino, nitro, sulfydryl, contain 1-8 carbon alkyl, the alkoxyl group of 1-8 carbon, the acyl group of 1-8 carbon or phenyl.

2. according to formula (1) compound of claim 1, substituent R wherein ₃Be replacement or unsubstituted saturated five～eight yuan of alicyclic heterocyclics, or replacement or unsubstituted five～eight membered aromatic heterocycles.

3. according to formula (1) compound of claim 2, substituent R wherein ₃For replacing or unsubstituted saturated five yuan or hexa-atomic alicyclic heterocyclic, perhaps replace or unsubstituted five yuan or hexa-atomic aromatic heterocycle.

4. according to formula (1) compound of claim 1, substituent R wherein ₃For replacing or unsubstituted phenyl.

5. one kind for compound, and it is selected from:

I-a.6-(2-bromo-4,5-Dimethoxyphenyl)-3-(3-oxo-hexamethylene-1-thiazolinyl oxygen ylmethyl)-2H-pyrone;

I-b.6-(2-bromo-4,5-Dimethoxyphenyl)-3-(2-methyl-5-oxo-ring penta-1-enol ylmethyl)-2H-pyrone;

According to formula (1) compound of claim 1 wherein X be NH, when dotted line does not exist, be structure shown in the formula (II):

Formula (II)

Substituent R wherein ₁, R ₂, R ₃, identical in the definition of n and the formula (1).

7. according to formula (II) compound of claim 6, they are:

II-j.3-(benzylamino-methyl)-6-(2-bromo-4,5-Dimethoxyphenyl)-2H-pyrone;

8. one kind for compound, and it is selected from:

II-m.3-((1-benzyl-piperidin-4-yl amino)-methyl)-6-(benzo [1,3] dioxolane-5-yl)-2H-pyrone.

9. be nitrogen-atoms according to X in formula (1) compound of claim 1, R ₂Be H, when there is to become two key in dotted line, be the compound shown in the formula (III):

Formula (III)

The substituent R of formula (III) compound ₁Identical with in the definition of n and the formula (1); R ₃Definition and the R in the formula (1) ₃Identical.

10. according to formula (III) compound of claim 9, they are:

III-b. instead-3-((1-benzyl-piperidin-4-yl-imino-)-methyl)-6-(3, the 4-Dimethoxyphenyl)-2H-pyrone.

11. a compound is selected from:

III-d. instead-3-((1-benzyl-piperidin-4-yl-imino-)-methyl)-6-(benzo [1,3] dioxolane-5-yl)-2H-pyrone.

12. according to the formula I-a～I-g compound of claim 5 or according to the preparation method of the compound of claim 7 or 8, be included under the alkaline condition key intermediate formula (I-5) compound and different organic alcohol or phenols reactions, perhaps prepare formula I-a～I-g or II-a～II-m compound respectively with the organic amine reaction:

Formula (I-5) compound substituent R ₁Definition and corresponding formula I-a～I-g or formula II-a～II-m compound in definition identical.

13. according to the preparation method of claim 7 Chinese style (II-n) or formula (II-o) compound, comprise, obtain formula (II-n) or formula (II-o) compound with the organic amine prepared in reaction again with formula (I-7) compound and bromide reagent generation bromination reaction:

Formula (I-7) compound substituent R ₁Definition and formula (II-n) or formula (II-o) in identical.

14., comprise formula (I-5) compound is prepared formula (I-7) compound with oxygenant generation oxidizing reaction under alkaline condition according to the preparation method of claim 13 Chinese style (I-7) compound:

15., comprise with formula (I-7) compound and the organic amine formula of preparing (III) compound that reacts according to the preparation method of claim 9 Chinese style (III) compound:

16. compound or their mixture according to one of claim 1-11 are used to prepare the purposes of preventing and treating senile dementia, vascular dementia and hypoxic ischemic encephalopathy, preventing and treating the medicine of cerebral apoplexy sequela.

17. one kind is used to the pharmaceutical composition preventing and treating senile dementia, vascular dementia and hypoxic ischemic encephalopathy, prevent and treat the cerebral apoplexy sequela, it contains compound or their mixture and the pharmaceutically acceptable auxiliaries according to one of claim 1-11 as activeconstituents for the treatment of significant quantity.