CN101307056A - Linear furocoumarin derivates, preparation method and application thereof, pharmaceutical compositions containing the derivates - Google Patents
Linear furocoumarin derivates, preparation method and application thereof, pharmaceutical compositions containing the derivates Download PDFInfo
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Abstract
The invention provides a linear furocoumarin derivate with a structure expressed by formula 1, a method for preparing the same, an application of the linear furocoumarin derivate and a drug composition containing the linear furocoumarin derivate. The linear furocoumarin derivate has an activating function to GLUT4 membrane transfer and protein expression, and can be used as drugs for treating diabetes mellitus and complicating diseases of the diabetes mellitus.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, particularly, the present invention relates to a class new linear furocoumarins derivative, Preparation Method And The Use, and the pharmaceutical composition that comprises this derivative.The GLUT4 film is shifted described linear furocoumarins derivative and protein expression has agonism, can be used as the medicine of treatment diabetes and complication thereof.
Background technology
Diabetes (diabetes mellitus) are one group of clinical syndromes that is caused by the h and E factor interaction, absolute or relative deficiency and target tissue cell reduce insulin sensitivity because of insulin secretion, cause a series of metabolism disorders such as sugar, albumen, fat, power and water Xie Zhi.Clinical is main common sign with the hyperglycemia, and prolonged illness can cause a plurality of system damages, be in a bad way and stress the time acute metabolism disorder such as ketoacidosis etc. can take place.The ratio of severe complications such as coronary heart disease, iron deficiency or hemorrhagic cerebrovascular disease, blind, acromelic gangrene takes place all apparently higher than non-diabetic people in the diabetics.
Generally diabetes are divided into two classes at present, type i diabetes (insulin-dependent diabetes mellitus, IDDM) with type ii diabetes (non insulin dependent diabetes, NIDDM).It in the diabetes type ii diabetes.WHO estimates that by 2025, diabetic subject's number will rise to 300,000,000 by 1.35 hundred million of nineteen ninety-five.The type i diabetes people is owing to the HLA-D gene cluster on the 6th pair of the short arm of a chromosome has determined genetic predisposition, to environmental factors, particularly the abnormal reaction of virus infection or chemical toxicity material incentive directly or indirectly passes through autoimmune response, cause that B cell destroys, so that insufficient insulin.The characteristics of type ii diabetes are the opposings to insulin action of insulin sensitivity tissue such as skeletal muscle, liver, fatty tissue.Though its concrete mechanism it be unclear that, insulin signaling weakening even blocking in its conduction path must be direct factor.
(Glucose Transporter 4 is an albumen of striding film for eight times GLUT4) to glucose transporter 4, and it belongs to glucose transporter family.GLUT4 is mainly at tissue expressions such as muscle, fat, hearts.In above-mentioned tissue, GLUT4 albumen response insulin stimulating is transferred on the cytolemma fast, and glucose transport is advanced cell and then lowering blood glucose level.GLUT4 albumen normal glucose level in keeping body plays crucial effects, though after the whole GLUT4 gene knockout, mouse only shows the decline of slight metabolism disorder and glucose tolerance, but after the GLUT4 albumen in muscle or the fatty tissue optionally knocked out, mouse showed the severe insulin resistance symptom.And overexpression GLUT4 albumen can be alleviated the insulin resistant symptom significantly in db/db diabetic mice body, improves its glucose tolerance.Therefore, GLUT4 is a key protein keeping glucose eubolism in the body.
Under general condition, GLUT4 mainly is distributed in more cytoplasmic special film bubble structures, and the stimulation of Regular Insulin can make this film bubble structure transfer on the cytolemma fast.GLUT4 is the rate-limiting step that cell absorbs glucose, and in the type ii diabetes symptom, because insulin resistant, GLUT4 is not subjected to the glucose in the Regular Insulin regulation and control transhipment blood to enter cell, causes glucose level high.Therefore, this albumen and regulate and control the field that signal path that this protein film shifts becomes the antidiabetic medicine exploitation.
Imbalance under proteic regulation and control of GLUT4 and the pathological state also involves this proteic expression not only in its film transfer process.Improve diabetics's the proteic expression level of GLUT4, symptom that also can diabetes-alleviating.
Summary of the invention
The inventor utilizes glucose transporter 4 (Glucose Transporter 4, GLUT4) the transcriptional activity cell screening model of film transfer and GLUT4 promotor, to its natural compounds storehouse screening, find that a class linear furocoumarins derivative has the activity that very strong promotion GLUT4 film shifts and GLUT4 expresses.With the linear furocoumarins is synthetic and structure and the active relation research that lead compound has further launched analogue, a series of linear furocoumarins derivatives have been prepared, can be used as the GLUT4 film and shift agonist and GLUT4 protein expression agonist, and then can be used for treating diabetes and complication thereof.
Therefore, the purpose of this invention is to provide a class and have treatment diabetes and the active linear furocoumarins derivative of complication thereof.
A further object of the present invention provides the method for the above-mentioned linear furocoumarins derivative of preparation.
Another purpose of the present invention provides the pharmaceutical composition that comprises above-mentioned linear furocoumarins derivative.
An also purpose of the present invention provides above-mentioned linear furocoumarins derivative and comprises the purposes of pharmaceutical composition in the medicine of preparation treatment diabetes and complication thereof of this derivative.
According to technical scheme of the present invention, a class linear furocoumarins derivative provided by the invention, it has as shown in the formula the structure shown in 1,
Wherein,
R
1, R
2, R
3, R
4, R
5And R
6Can be identical or inequality, and,
R
1, R
2, R
5And R
6Each represents hydrogen atom, alkyl, thiazolinyl or phenyl;
R
3And R
4Each represents hydrogen atom, alkyl, thiazolinyl, phenyl, hydroxyl or alkoxyl group;
For the group of above-mentioned definition, described alkyl can be the alkyl of replacement or non-replacement.Wherein, the alkyl of non-replacement, for example methyl, ethyl, propyl group etc.; The alkyl that replaces can be the alkyl of hydroxyl, halogen, alkoxyl group, acyloxy or alkenyl substituted, for example alkyl of hydroxyl, fluorine, methoxyl group, acetoxyl group or vinyl substituted.
For R
1, R
2, R
3, R
4, R
5And R
6, R
1Be preferably hydrogen atom or 2-vinyl sec.-propyl; R
2Be preferably alkyl, trifluoromethyl or the phenyl of hydrogen atom, methoxymethyl, C1-C4; R
3And R
4Respectively be preferably hydrogen atom, hydroxyl or C1-C4 alkoxyl group; R
5Be preferably hydrogen atom, hydroxypropyl or acetoxyl group propyl group; R
6Be preferably the alkyl or phenyl of hydrogen atom, C1-C4.
More preferably, linear furocoumarins derivative according to the present invention has with the structure shown in one of in the following formula 2～17:
The present invention also provides the method for preparing above-mentioned linear furocoumarins derivative, and described method comprises:
1) with 2, the 4-Dihydroxy benzaldehyde is a raw material, prolongs carbochain through the methyl triphenyl phosphine, and hydroboration oxidation and the water ring of sloughing a part close and obtain intermediate A hydroxyl dihydrobenzene azoles furans,
Intermediate A hydroxyl dihydrobenzene azoles furans makes 2 ', 3 ' of formula 1-two hydrogen line type furocoumarin(e) derivative G with 'beta '-ketoester or propiolate reaction again:
Perhaps
2) with 2, the 4-Dihydroxy benzaldehyde is a raw material, prolongs carbochain after cyclization obtains intermediate B hydroxybenzene azoles furans through Nitromethane 99Min.,
Intermediate B hydroxybenzene azoles furans makes the linear furocoumarins derivative F of formula 1 again with 'beta '-ketoester or propiolate reaction:
Perhaps
3) be that the reaction of raw material and 'beta '-ketoester or propiolate obtains intermediate C with the Resorcinol, obtain intermediate D with Mono Chloro acetone or chloroacetophenone reaction again, intermediate D cyclization again forms 4 and 3 ' disubstituted linear furocoumarins derivative E:
R wherein
2And R
6Definition as mentioned above;
Perhaps
4) with by method 2) the 8-hydroxyl linear furocoumarins that makes is that raw material obtains 5 by oxidation, 8-dioxo linear furocoumarins, reduce then 5, the linear furocoumarins derivative that the two hydroxyls of 8-replace, react by the alkoxide of hydroxyl then, obtain 5, the furocoumarin(e) derivative that the 8-bis-alkoxy replaces:
R wherein
3And R
4Be alkoxyl group;
Perhaps
5) with 6, the 7-dihydroxycoumarin is a raw material, and 7 obtain 6 carboxaldehyde radicals by the catalytic metal linked reaction of palladium carbon then by chloromethyl methyl ether reaction protection earlier, again with
Reaction, cyclization generate 2 ' linear furocoumarins H that replaces:
Further then, intermediate H reacts in cupric bromide and aluminum oxide, generates the coumarin derivatives of 3 bromos, generates 3 and 2 ' disubstituted linear furocoumarins derivative I with the alcohol reaction again under acidic conditions:
Particularly, the method according to this invention, for method 1) and 2), with 2, the 4-Dihydroxy benzaldehyde is a raw material, prolongs carbochain through the methyl triphenyl phosphine, hydroboration oxidation and the water ring of sloughing a part close and obtain intermediate A, or with 2, the 4-Dihydroxy benzaldehyde is a raw material, prolongs carbochain after cyclization obtains intermediate B through Nitromethane 99Min.; Intermediate A or B further make the linear furocoumarins derivative with 'beta '-ketoester or propiolate reaction.Usually come the assaying reaction performance level with TLC, reaction finishes, and the back is general to extract with ethyl acetate, methylene dichloride (DCM) or chloroform equal solvent, with saturated sodium bicarbonate aqueous solution, water, saturated common salt washing, behind anhydrous magnesium sulfate or anhydrous sodium sulfate drying, low-temperature reduced-pressure removes and desolvates successively.Intermediate and final product detect proof with nucleus magnetic resonance or mass spectrum.
2, the 4-Dihydroxy benzaldehyde is as follows to the synthetic route of intermediate A:
2, the 4-Dihydroxy benzaldehyde is through benzyl bromine protection phenolic hydroxyl group, and the methyl triphenyl phosphine prolongs carbochain, the borine hydroxylation, and palladium carbon deprotection and the water ring of sloughing a part close and obtain intermediate A.
2, the 4-Dihydroxy benzaldehyde to the synthetic route of intermediate B (with reference to Bang-Le ZHANG, Fang-Dao WANG, Jian-Min YUE Synlett 2006,4,567-570) as follows:
Chemical reagent and reaction conditions:
(i) CH
3NO
2, AcOH-NH
4OAC, 120 ℃, 45min; (ii) NaBH
4, i-PrOH-THF (1:4), r.t., 40min; (iii) Nef reaction.(with reference to Hwu, J.R.; Gilbert, B.A.J.Am.Chem.Soc.1991,113,5917)
2,4-Dihydroxy benzaldehyde and Nitromethane 99Min. reaction prolong carbochain, and the two keys of sodium borohydride reduction obtain intermediate B by Nef reaction cyclization again.
It is as follows that intermediate A or B further react the synthetic route that makes the linear furocoumarins derivative:
Method one: slowly add excessive methylsulfonic acid in intermediate A or B and the corresponding 'beta '-ketoester mixture (its part by weight 1: 1.2), stirred 30 minutes at 0 ℃ then, at room temperature continue to be stirred to react completely (thin layer detection) again.After reacting completely with in the reaction solution impouring frozen water, stirring at room 1 hour, ethyl acetate extraction merges organic layer, uses the saturated common salt water washing, anhydrous sodium sulfate drying, evaporated under reduced pressure.The residue silica gel column chromatography gets corresponding linear furocoumarins derivative.
Method two: with zinc dichloride, the mixture of ethyl propiolate and intermediate B is heated to 90 ℃ and stirred 3 hours under nitrogen protection.Reduce to room temperature then, in reaction solution, add 5% hydrochloric acid.Ethyl acetate extraction merges organic layer, uses the saturated common salt water washing, anhydrous sodium sulfate drying, evaporated under reduced pressure.The residue silica gel column chromatography gets 3 does not have the linear furocoumarins derivative that replaces.
For method 3), it is as follows that intermediate C further reacts the synthetic route that makes the linear furocoumarins derivative:
Intermediate C is heated to boiling back and keeps this temperature to stir 6 hours containing salt of wormwood anhydrous propanone solution and Mono Chloro acetone or chloroacetophenone, after reaction finishes with in the reaction solution impouring frozen water.Hcl acidifying, and spend the night 4 ℃ of stirrings.The precipitation that filtration obtains, recrystallization gets intermediate D in the methyl alcohol; Be suspended in intermediate D in the 1N potassium hydroxide solution then and be heated to backflow, nitrogen protection was stirred 24 hours down, after reaction finishes with in the reaction solution impouring frozen water.Hcl acidifying, and spend the night 4 ℃ of stirrings.The precipitation that filtration obtains, recrystallization obtains 4 and 3 ' disubstituted compd E as implied above in the methyl alcohol.
The present invention also provides above-mentioned linear furocoumarins derivative to be used for the treatment of application in the medicine of diabetes in preparation.
The present invention also provides a kind of pharmaceutical composition that comprises the above-mentioned linear furocoumarins derivative of one or more dose therapeutically effectives.
Above-mentioned pharmaceutical composition further can also contain pharmaceutically acceptable carrier and vehicle.
The present invention also provides aforementioned pharmaceutical compositions to be used for the treatment of application in the medicine of diabetes and complication thereof in preparation.
The linear furocoumarins derivative that design of the present invention and synthetic one class are novel can be used for the preparation of transfer of GLUT4 film and protein expression agonist.The compounds of this invention is synthetic simple, is easy to preparation, and synthesis material is abundant.
Description of drawings
Accompanying drawing 1 increases the transcriptional activity of glucose transporter (GLUT4) promotor in 293T (Figure 1A) and two clones of HepG2 (Figure 1B) for compound 17.
Accompanying drawing 2 is the 3T3-L1 adipocyte glucose absorption activity that compound 17 strengthens insulin stimulating.
Embodiment
The present invention is further elaborated below in conjunction with specific embodiment, but do not limit the present invention.
In the following preparation example,
1H-NMR Varian Mercury AMX300 type Instrument measuring.MS uses VG ZAB-HS or VG-7070 type and Esquire 3000 plus-01005 to measure.All through distillation again, employed anhydrous solvent all is to obtain by the standard method drying treatment to all solvents before use.Except that explanation, it all is to carry out under argon shield and follow the tracks of with TLC that institute responds, during aftertreatment all through saturated common salt washing and anhydrous magnesium sulfate drying process.The purge process of product is all used silica gel (200-300 order) column chromatography purifying except that explanation, employed silica gel comprises 200-300 order, GF
254, be Haiyang Chemical Plant, Qingdao or the production of the rich silica gel company of Yantai edge.
The preparation of preparation embodiment 1 compound 2
(1) preparation of 6-hydroxyl-7-escoparone (2a)
For convenience, the M in the following structural formula represents Me, i.e. methyl.
With methoxychlor methane (0.443mL, 5.84mmol) the adding Vitamin C2 (520.5mg of unit, 2.92mmol) and salt of wormwood (605mg, 4.38mmol) N, in dinethylformamide (14.6mL) solution, and under-20 ℃ of conditions, stirred 13 hours, reaction solution drips 1 normal hydrochloric acid to solution at 0 ℃ then and becomes colorless from yellow with the dilution of 10mL water.(2 * 10mL), the merging organic layer is used saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure to water layer with ethyl acetate extraction.Residue silica gel column chromatography (sherwood oil: ethyl acetate=9: 2 wash-outs), get yellow solid compound 2a.
(2) preparation of 7-dimethoxy-6-trifluoromethanesulfonic acid basic note legumin (2b)
With diisopropyl ethyl amine (0.261mL, 1.5mmol) the ice-cold compound 2a (114.4mg of adding, 0.497mmol) dichloromethane solution in (5mL), and 0 ℃ of stirring 10 minutes, make the temperature of reaction solution reduce to gradually then-30 ℃, dropwise add trifluoromethanesulfanhydride anhydride (0.126mL, 0.75mmol).Dropwise afterreaction liquid and continue to stir 2 hours at 0 ℃, add the 10mL saturated sodium bicarbonate aqueous solution then in reaction solution, (2 * 10mL) extract water layer with methylene dichloride.Merge organic layer, with saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure.Residue silica gel column chromatography (sherwood oil: ethyl acetate=8: 1 wash-outs), get white solid compound 2b.
(3) preparation of 6-carboxaldehyde radicals-7-escoparone (2c)
With compound 2b (70.8mg, 0.2mmol), palladium (4.5mg, 0.02mmol), pairs of 2-phenyl-phosphine oxide (12.4mg, 0.03mmol) and triethyl silicane (0.096mL 0.6mmol) adds N, in the dinethylformamide (2mL), and in 60 ℃ and 15 atmospheric CO (carbon monoxide converter) gas, stirred 5 hours.Reaction solution dilutes with 10 ml waters, drips 1 normal hydrochloric acid to solution at 0 ℃ then and becomes colorless from yellow.(2 * 10mL), the merging organic layer is used saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure to water layer with ethyl acetate extraction.Residue silica gel column chromatography (sherwood oil: ethyl acetate=5: 1 wash-outs), get white solid compound 2c.
(4) 7-dimethoxy-6-[(E)-3-oxo-1-butyl] preparation of tonka bean camphor (2d)
With compound 2c (106.4mg, 0.454mmol) and 1-triphenylphosphine ylide 2-acetone (180.8mg, 0.568mmol) add in the tetrahydrofuran (THF) of 4.5mL, and under 60 ℃ of conditions, stirred 50 hours, make temperature of reaction reduce to room temperature then, reaction solution dilutes with 10 ml waters, drips 1 normal hydrochloric acid to solution at 0 ℃ then and becomes colorless from yellow.(2 * 10mL), the merging organic layer is used saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure to water layer with ethyl acetate extraction.Residue silica gel column chromatography (sherwood oil: ethyl acetate=2.5: 1 wash-outs), get yellow solid compound 2d (9.2mg, 81%).
(5) 6-[(1R, 2S)-1,2-epoxy-3-oxo butyl]-preparation of 7-escoparone (2e)
Three isopropoxy lanthanums (0.125mL, 0.025mmol, 0.2M tetrahydrofuran solution) are added (R)-1,1 '-binaphthol (7.2mg, 0.025mmol), the triphenylarsine oxide compound (8.1mg, 0.025mmol) and
(3.4mL) also stirred 1 hour at ambient temperature in the exsiccant tetrahydrofuran solution of molecular sieve (250mg), add t-butyl peroxy (TBHP) (0.1mL then, 0.5mmol), restir adds compound 2d (68.5mg after 30 minutes, 0.25mmol), and continue at room temperature to stir 5 hours.Reaction finish the back with 2.5% aqueous citric acid solution (5mL) 0 ℃ of cancellation.Ethyl acetate extraction (3 * 10mL), merge organic layer, with saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure.Residue silica gel column chromatography (sherwood oil: ethyl acetate=4: 1) obtain white solid compound 2e (65.0mg).
(6) 3-dihydroxyl-3-methyl butyl 6-[(2S)-2 ,]-preparation of 7-(trifluoromethanesulfonic acid base) tonka bean camphor (2f)
Methyl-magnesium-bromide (0.267mmol) tetrahydrofuran solution is splashed into 2e (70.5mg under-78 ℃ of conditions, 0.267mmol) tetrahydrofuran solution in, behind the reaction 2h, temperature rises to 0 ℃, in reaction solution, drip the tetrahydrofuran (THF) mixing solutions of sodium borohydride (2eq) and borine (2.5eq) again, continue reaction 2h, the 2N hcl acidifying gets intermediate product.Then with trifluoromethanesulfanhydride anhydride (0.05mL, 0.297mmol) dropwise add ice-cold above-mentioned obtain intermediate product (61.5mg, 0.2mmol) and diisopropyl ethyl amine (0.116mL is in methylene dichloride 0.667mmol) (7.5mL) solution, at room temperature stirred then 10 minutes, after reaction finishes, receive the solution cancellation with 5mL unsaturated carbonate hydrogen, ethyl acetate extraction (3 * 10mL), merge organic layer, with saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure.Residue silica gel column chromatography (sherwood oil: ethyl acetate=1: 1), obtain white solid compound 2f (97.5mg, 92%).
(7) preparation of compound (+)-Marmesin (2)
With sodium tert-butoxide (0.415mL, 0.196mmol, 0.427M tetrahydrofuran solution) add compound 2f (51.7mg, 0.1305mmol), palladium (2.94mg, 0.0131mmol) and 1,1 '-two diphenylphosphine ferrocene (DPPF) (14.5mg, 0.0262mmol) toluene solution (3mL) in, 90 ℃ are stirred 1h, then with in the reaction solution impouring water (5mL), and water layer ethyl acetate extraction (2 * 10mL), merge organic layer, with saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure.Residue silica gel column chromatography (sherwood oil: ethyl acetate=2: 1), get white solid compound (+)-marmesin (2) (25.6mg, 80%).
1H?NMR(CDCl
3)δ：1.24(3H，s)，1.37(3H，s)，1.83(1H，s)，3.19(1H，dd，J＝9.5，15.9Hz)，3.25(1H，dd，J＝8.3，15.9Hz)，4.74(1H，dd，J＝8.3，9.5Hz)，6.21(1H，d，J＝9.5Hz)，6.73(1H，s)，7.22(1H，s)，7.59(1H，d，J＝9.5Hz)；
13C?NMR(CDCl
3)δ：24.3，26.1，29.5，71.6，91.1，97.9，112.2，112.7，123.4，125.1，143.7，155.6，161.4，163.1。MS(m/z)246[M
+]。
The preparation of preparation embodiment 2 compounds 3
(1) preparation of 4-methoxymethyl-umbelliferone (3a)
At Resorcinol (5.0g, 30mmol) and dropwise add methyl-4-methoxyl group methyl aceto acetate (4.4g in the mixing solutions of the vitriol oil (100mL), 30mmol), and spend the night 0 ℃ of stirring, after reacting completely with in the reaction solution impouring frozen water, stirring at room 1 hour, ethyl acetate extraction (2 * 100mL), merge organic layer, with saturated common salt water washing (100mL), anhydrous sodium sulfate drying, evaporated under reduced pressure.Residue silica gel column chromatography (sherwood oil: ethyl acetate=3: 1), get compound 3a (2.53g, 38%).
(2) preparation of 4-methoxymethyl-4 '-8-methylpsoralen (3)
(a) the anhydrous propanone solution (100mL) of 4-methoxymethyl-umbelliferone (20.0mmol) add 10 gram salt of wormwood and Mono Chloro acetone (1.8mL, 20.0mmol).Be heated to the boiling back and keep this temperature to stir 6 hours, in the frozen water with reaction solution impouring 300mL after reaction finishes.The 2N hcl acidifying, and spend the night 4 ℃ of stirrings.Filter out precipitation, recrystallization gets intermediate 3b (471mg, 90%) in the methyl alcohol.
(b) (262mg 10mmol) is suspended in the 1M potassium hydroxide solution (100mL) and be heated to backflow, and nitrogen protection was stirred 24 hours down, in the frozen water with reaction solution impouring 300mL after reaction finishes with 3b then.The 2N hcl acidifying, and spend the night 4 ℃ of stirrings.Filter out precipitation, recrystallization in the methyl alcohol gets 4-methoxymethyl-4 '-8-methylpsoralen (3) (127mg, 65%).
1H?NMR(300MHz，CDCl
3)δ：7.65(s，1H，5-H)，7.47(s，1H，5’-H)，7.43(s，1H，8-H)，6.51(s，1H，3-H)，4.72(s，2H，4-CH
2CH
3)，3.54(s，3H，4-CH
2-CH
3)，2.28(s，3H，4’-CH
3)；
13C?NMR(75MHz，CDCl
3)δ：161.1(C-2)，156.5(C-7)，151.8(C-8a)，151.6(C-4)，143.2(C-5’)，126.4(C-4’)，115.6(C-6)，113.9(C-5)，113.6(C-4a)，111.4(C-3)，99.9(C-8)，70.6(4-CH
2CH
3)，59.0(4-CH
2CH
3)，7.8(4’-CH
3)。
The preparation of preparation embodiment 3 compounds 4
According to the method for preparing embodiment 2, replace Mono Chloro acetone with chloroacetophenone, make compound 4, productive rate is 63%.
1H?NMR(300MHz，CDCl
3)δ：7.92(1H，s，5-H)，7.81(1H，s，5’-H)，7.63-7.41(6H，m，4’-C
6H
5?and?8-H)，6.53(1H，s，3-H)，4.69(2H，s，4-CH
2-CH
3)，3.53(3H，s，4-CH
2CH
3)；
13C NMR (75MHz, CDCl
3) δ: 130.9 (C-1 "), 129.2 (C-3 " and C-5 "), 128.0 (C-4 "), 127.4 (C-4 " and C-6 "), 123.9 (C-4 '), 122.2 (C-6).
The preparation of preparation embodiment 4 compounds 5
According to the method for preparing intermediate B; with Phloroglucinol (252mg; 2.0mmol) be prepared into compound 5a (150mg, 1.0mmol, 50%); then with zinc dichloride (210mg; 1.5mmol), ethyl propiolate (0.5mL, 5mmol); and 5a (150mg, mixture 1.0mmol) are heated to 90 ℃ and stirred 3 hours under nitrogen protection.Reduce to room temperature then, in reaction solution, add the hydrochloric acid of 25mL5%.Ethyl acetate extraction (2 * 10mL), merge organic layer, with saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure.Residue silica gel column chromatography (sherwood oil: ethyl acetate=3: 1 wash-outs) light yellow solid compound 5.
1H?NMR(300MHz，CDCl
3)δ：8.15(1H，d，J＝9.8Hz，)，7.63(1H，d，J＝2.2Hz)，7.41(1H，s)，6.93(1H，d，J＝2.2Hz)，6.29(1H，d，J＝9.8Hz)。
The preparation of preparation embodiment 5 compounds 6
(100mL) adding salt of wormwood (5g) and methyl-sulfate in the anhydrous propanone solution of 202mg (1.0mmol) compound 5 (1.0mL, 3.6mmol).Be heated to backflow under the nitrogen protection, react and also use hydrochloric acid (concentration) acidifying after 3 hours in the impouring 200mL frozen water, and ethyl acetate extraction after 24 hours (2 * 10mL), merge organic layer, with saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure.Residue silica gel column chromatography (sherwood oil: ethyl acetate=3: 1 wash-outs), get yellow solid compound 6 (149mg, 69%).
1H?NMR(300MHz，CDCl
3)δ：8.15(1H，d，J＝9.8Hz，)，7.63(1H，d，J＝2.2Hz)，7.41(1H，s)，6.93(1H，d，J＝2.2Hz)，6.29(1H，d，J＝9.8Hz)，3.82(3H，S)
The preparation of preparation embodiment 6 compounds 7
At 8-hydroxyl linear furocoumarins (5) (606mg, 3.0mmol) three excessive Cadmium oxide acetums of middle adding, stirring is spent the night and is obtained 5 oxidation products 5, the 8-dioxy replaces linear furocoumarins (500mg, 2.3mmol), again this product and 3g zinc powder are added in the mixing solutions of acetone (30mL) and water (100mL), then the 10mL concentrated hydrochloric acid is dropwise added.Leach zinc powder after 5 hours, filtrate is concentrated into half of original volume and spends the night 4 ℃ of reactions.Leach precipitation, recrystallization gets compound 7 (311mg, 62%) in water.
1H?NMR(300MHz，CDCl
3)δ：8.15(1H，d，J＝9.8Hz，)，7.63(1H，d，J＝2.2Hz)，6.93(1H，d，J＝2.2Hz)，6.29(1H，d，J＝9.8Hz)；
13C?NMR(75MHz，CDCl
3)δ：160.65(C-2)，150.41(C-7)，145.11(C-5’)，144.08(C-8a)，143.51(C-5)，139.65(C-4)，127(C-8)，115.55(C-6)，112.78(C-3)，108.27(C-4a)，105.16(C-4’)。
The preparation of preparation embodiment 7 compounds 8
(100mL) adding salt of wormwood (5g) and ethyl sulfate in the anhydrous propanone solution of 200mg (0.9mmol) compound 7 (1.0mL, 3.6mmo1).Be heated to backflow under the nitrogen protection, react and also use the 2N hcl acidifying after 3 hours in the impouring 200mL frozen water, and ethyl acetate extraction after 24 hours (2 * 10mL), merge organic layer, with saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure.Residue silica gel column chromatography (sherwood oil: ethyl acetate=3: 1 wash-outs), get yellow solid compound 8 (158mg, 64%).
1H?NMR(300MHz，CDCl
3)δ：8.13(1H，d，J＝9.8Hz，)，7.61(1H，d，J＝2.2Hz)，6.92(1H，d，J＝2.2Hz)，6.28(1H，d，J＝9.8Hz)，4.40(4H，q，J＝7.0Hz)，1.47(6H，t，J＝7.0Hz)；
13C NMR (75MHz, CDCl
3) δ: 160.65 (C-2), 150.41 (C-7), 145.11 (C-5 '), 144.08 (C-8a), 143.51 (C-5), 139.65 (C-4), 127 (C-8), 115.55 (C-6), 112.78 (C-3), 108.27 (C-4a), 105.16 (C-4 '), 69.95 and 69.43 (5-and 8-CH
2CH
3), 15.62 (5-and 8-CH
2CH
3).
The preparation of preparation embodiment 8 compounds 9
With ZnCl
2(210mg, 1.5mmo1), (0.5mL, 5mmo1) (134mg, mixture 1.0mmo1) are heated to 90 ℃ and stirred 3 hours ethyl propiolate under nitrogen protection with intermediate B hydroxybenzene azoles furans.Reduce to room temperature then, in reaction solution, add the hydrochloric acid of 25mL 5%.Ethyl acetate extraction (2 * 10mL), merge organic layer, with saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure.Residue silica gel column chromatography (sherwood oil: ethyl acetate=3: 1 wash-outs), get white solid compound 9 (productive rate 56%).
1H?NMR(400MHz，CDCl
3)δ：7.81(1H，d，J＝9.6Hz)，7.70(1H，d，J＝1.2Hz)，7.69(1H，s)，7.49(1H，s)，6.84(1H，d，J＝1.2Hz)，6.39(1H，d，J＝9.6Hz)。EI-MS(m/z)：186(M
+)，158，130，102。
The preparation of preparation embodiment 9 compounds 10
With intermediate B (134mg, 1.0mmo1) and methyl aceto acetate (161mg 1.2mmol) mix to stir at 0 ℃, slowly adds excessive methylsulfonic acid then, and stirs 30 minutes at 0 ℃, at room temperature continues to be stirred to react completely (thin layer detection) again.After reacting completely with in the reaction solution impouring frozen water, stirring at room 1 hour, ethyl acetate extraction (2 * 10mL), merge organic layer, with saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure.Residue silica gel column chromatography (sherwood oil: ethyl acetate=4: 1 wash-outs), get white solid compound 10 (productive rate 72%).
1H?NMR(400MHz，CDCl
3)δ：7.82(1H，s)，7.69(1H，d，J＝2.4Hz)，7.48(1H，d，J＝0.4Hz)，6.86(1H，dd，J＝2.4，0.4Hz)，6.27(1H，s)，2.51(3H，s)。EI-MS：(m/z)：200(M
+)，172，171，144，115。
The preparation of preparation embodiment 10 compounds 11
Make compound 11 by intermediate B by method one, productive rate: 70%.
1H?NMR(400MHz，CDCl
3)δ：7.86(1H，s)，7.69(1H，d，J＝2.4Hz)，7.49(1H，d，J＝0.8Hz)，6.84(1H，dd，J＝2.4，0.8Hz)，6.28(1H，t，J＝1.2Hz)，2.89(2H，dq，J＝7.2，1.2Hz)，1.38(3H，t，J＝7.2Hz)。EI-MS(m/z)：214(M
+)，185，171，115。
The preparation of preparation embodiment 11 compounds 12
Make compound 12 by intermediate B by method one, productive rate: 65%.
1H?NMR(300MHz，CDCl
3)δ：7.84(1H，s)，7.68(1H，d，J＝2.4Hz)，7.47(1H，s)，6.84(1H，d，J＝2.4Hz)，6.25(1H，s)，2.81(2H，t，J＝7.6Hz)，1.79(2H，m)，1.08(3H，t，J＝7.6Hz)。EI-MS(m/z)：228(M
+)，200，185，171，115。
The preparation of preparation embodiment 12 compounds 13
Make compound 13 by intermediate B by method one, productive rate: 67%.
1H?NMR(400MHz，CDCl
3)δ：7.97(1H，q，J＝1.9Hz)，7.75(1H，d，J＝2.2Hz)，7.56(1H，d，J＝0.5Hz)，6.90(1H，dd，J＝2.2，J＝0.8Hz)，6.79(1H，s)。EI-MS(m/z)：254(M
+)，226，198，169。
The preparation of preparation embodiment 13 compounds 14
Make compound 14 by intermediate B by method one, productive rate: 58%.
1H?NMR (300MHz，CDCl
3)δ：7.68(1H，s)，7.67(1H，brs)，7.57-7.47(6H，m)，6.76(1H，dd，J＝2.2，1.0Hz)，6.34(1H，s)。EI-MS(m/z)：262(M
+)，234，205，176，76。
The preparation of preparation embodiment 14 compounds 15
With 2,4-Dihydroxy benzaldehyde (1.38g, 10mmol) salt of wormwood with 5.5g is dissolved in the dimethyl sulfoxide solution of 25mL, slowly drips the benzyl chlorine of 2.75mL then, after dropwising, stirred at normal temperatures 10 hours, ethyl acetate extraction (2 * 10mL), merge organic layer, with saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure.Residue (1.59g with evaporate to dryness, 5mmol) potassium tert.-butoxide and the 3.5g trityl group phosphine with 2.0g is dissolved in the tetrahydrofuran solution of 25mL, stirring at normal temperature 2 hours, the hydrochloric acid of 2N is neutralized to neutrality, ethyl acetate extraction (2 * 10mL), merge organic layer, with saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure.Residue silica gel column chromatography (sherwood oil: ethyl acetate=3: 1 wash-outs), get white solid compd A 1 (productive rate 94%).
(790mg in tetrahydrofuran solution 2.5mmol), drips 1.2mL with 30mL intermediate A 1, the tetrahydrofuran solution of the borine of 1M at room temperature stirred 1 hour, dripped the water of 1mL then, then once add 0.4mL, the sodium hydroxide solution of 3M adds the 0.4mL hydrogen peroxide then fast, stirring at room 1 hour, ethyl acetate extraction (2 * 15mL), merge organic layer, with saturated common salt water washing (15mL), anhydrous sodium sulfate drying, evaporated under reduced pressure.The residue 500mg that gets evaporate to dryness adds in the round-bottomed flask with excessive palladium carbon, and nitrogen exchanges several times, and hydrogen exchanges several times, normal temperature stirs down and spends the night suction filtration, filtrate evaporate to dryness, residue 100mg adds the DIPD of 0.2mL, the triphenylphosphine of 250mg and the tetrahydrofuran solution of 20mL, stirring at normal temperature 2 hours, ethyl acetate extraction (2 * 10mL), merge organic layer, with saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure.Residue silica gel column chromatography (sherwood oil: ethyl acetate=15: 1 wash-outs), get white solid compd A (productive rate 70%).
(part by weight 1: 1.2 slowly adds excessive methylsulfonic acid in 100mg), stirs 30 minutes at 0 ℃ then, at room temperature continues to be stirred to react completely (thin layer detection) again at intermediate A hydroxyl dihydrobenzene azoles furans and corresponding 'beta '-ketoester mixture.After reacting completely with in the reaction solution impouring frozen water, stirring at room 1 hour, ethyl acetate extraction (2 * 10mL), merge organic layer, with saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure.Residue silica gel column chromatography (sherwood oil: ethyl acetate=4: 1 wash-outs) get white solid compound 15, productive rate 85%.
1H?NMR(400MHz，CDCl
3)：δ：7.38(1H，s)，6.73(1H，s)，6.10(1H，s)，4.69(1H，t，J＝9.0Hz)，3.27(1H，t，J＝9.0Hz)，2.38(3H，s。)。EI-MS(m/z)：202(M
+)。
The preparation of preparation embodiment 15 compounds 16
With compound 2 (246mg, 1.0mmol) join the excessive cupric bromide aqueous solution (2mol/L, 20mL) in, slowly add excessive aluminum oxide at ambient temperature, TLC detects to reacting completely, and then slowly add 2-methyl-3-butene-2-alcohol of 0.5mL, stirring at room 2 hours, ethyl acetate extraction (2 * 10mL), merge organic layer, with saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure.Residue silica gel column chromatography (sherwood oil: ethyl acetate=5: 1 wash-outs), get white solid compound 16, productive rate 65%.
1H?NMR(400MHz，CDCl
3)δ：7.45(1H，s)，7.17(1H，s)，6.69(1H，s)，6.15(1H，d，J＝18.0，10.2Hz)，5.10(1H，d，J＝18.0Hz)，5.04(1H，d，J＝10.2Hz)，4.70(1H，d，J＝9.0Hz)，3.20(1H，d，J＝9.0Hz)1.77(1H，s)，1.45(3H，s)，1.34(3H，s)，1.21(3H，s)。EI-MS(m/z)：314(M
+)。
The preparation of preparation embodiment 16 compounds 17
With compound 16 (314mg, 1.0mmol) add excessive aceticanhydride pyridine (1: 1,4mL) in the solution, stirred overnight at room temperature, ethyl acetate (40mL) and 2N hydrochloric acid (30mL) extraction merge organic phase, with saturated common salt water washing (10mL), anhydrous sodium sulfate drying, evaporated under reduced pressure.Residue silica gel column chromatography (sherwood oil: ethyl acetate=6: 1 wash-outs), get compound 17 (320mg, 90%).
1H?NMR(400MHz，CDCl
3)：δ：7.45(1H，s)，7.14(1H，s)，6.69(1H，s)，6.15(1H，dd，J＝18.0，10.2Hz，)，5.05(1H，d，J＝8.0Hz)，5.04(1H，d，J＝18.0Hz，，)，5.02(1H，d，J＝10.2Hz)，3.19(d，J＝8.0Hz，1H)1.96(3H，s)，1.53(3H，s)，1.48(3H，s)，1.44(3H，s)，
13C?NMR(100MHz，CDCl
3)δ：170.1(CO)，162.5(C-7)，160.6(CO)，154.9(C-9)，145.7(C-2’)，138.0(C-4)，97.1(C-8)，88.3(C-2”)，88.2(C-4”)，40.3(C-1’)，29.7(C-3”)，26.1(C-1’)，22.1(C-4”)，21.0(CH
3)。
EI-MS(m/z)：358(M
+)。
Experimental example
Experimental example 1: The compounds of this invention promotes glucose transporter (GLUT4) film shift experiment
Experimental principle
In plasmid pEGFPN1-rGLUT4-myc, first extracellular region of rat GLUT4 albumen is inserted one section c-myc epitope sequences, and form fusion rotein at carbon teminal and the coupling of EGFP green fluorescent protein.This plasmid stable transfection is gone into the CHO-K1 cell.When experimentizing, under the situation of penetrating cytolemma not, carry out indirect immunostaining with the anti-and red fluorescence two of anti-c-myc is anti-.Green fluorescence intensity is represented GLUT4 amount total in the cell, and red fluorescence intensity is represented the GLUT4 amount on the cytolemma, just can draw relative GLUT4 by the red fluorescence and the strength ratio of green fluorescence and go up the film ratio.
Experiment reagent
F12 substratum (F-12 Ham medium+10% foetal calf serum), the DMEM substratum (Delbecco ' s modified Eagle ' s medium+10% foetal calf serum+3.2mM vitamin H+16.8mM calcium pantothenate), identification c-myc label (Anti-c-myc) antibody ratio is 1: 1000, anti-mouse immuning ball protein (Anti-mouse IgG) the antibody final concentration of coupling Alexa Fluor 647 dyestuffs is 10 μ g/mL, all with DMEM substratum dilution configuration, the 0.1M sodium orthovanadate is (with 0.2M H for all antibody
2O
2With 0.2M Na
3VO
3Mixed at room temperature 20 minutes).
Experimental technique
The CHO-K1/GLUT4 stable cell line with the F12 culture medium culturing two days later, is changed to the DMEM substratum and continues to cultivate two days in black 96 orifice plates, and culture condition is 37 degree, 5%CO
2Compound dissolution is in the DMEM serum free medium, and concentration is 10 μ M.Compound is hatched and hungry cell after 8 hours simultaneously, and with 80nM insulin stimulating 5 minutes, formaldehyde (3.7%) stopped stimulating and fixed cell 15 minutes (room temperature).Formaldehyde is removed in suction, washes cell 3 times (100mL/ hole, 5 minutes/time) with PBS.Add identification Anti-c-myc one according to the 50mL/ hole and resist, 4 degree reactions are spent the night.Suction goes one to resist, and washes cell 3 times (100mL/ hole, 5 minutes/time) with PBS.Anti-mouse immuning ball protein (Anti-mouse IgG) the antibody room temperature reaction 1 hour that adds coupling Alexa Fluor 647 dyestuffs according to the 50mL/ hole.Suction goes two to resist, and washes cell 3 times (100mL/ hole, 5 minutes/time) with PBS.Utilize IN Cell Analyzer 1000 instruments to obtain green fluorescence photo (the 475nm exciting light of same field of view, 535nm launches light) and red fluorescence photo (575nm exciting light, 620nm launches light), obtain the relative proportion that GLUT4 goes up film by the ratio of statistics red fluorescence and green fluorescence.The cell that control experiment is adopted is the clone of stable transfection pEGFPN1 empty plasmid, carries out simultaneously according to above-mentioned experimental technique.Become different concns to experimentize diluted chemical compound to be detected, and measure EC
50Value the results are shown in Table 1.
Table 1 The compounds of this invention promotes glucose transporter (GLUT4) film transfer activity
Experimental example 2: compound 17 increases the transcriptional activity experiment of glucose transporter (GLUT4) promotor
Experimental principle
Promoter region (3225～+ 168) clone of mouse GLUT4 is advanced the pGL3-basic carrier.In the carrier pGL3-mpGLUT4 that builds, firefly luciferase gene transcribe the control that only is subjected to the GLUT4 promotor, therefore, the activity of Photinus pyralis LUC can characterize GLUT4 promoter transcription activity.PRL-SV40 expresses the Renilla luciferase under the control of SV40 strong promoter, this plasmid of corotation in experiment as confidential reference items, is eliminated the activity of Renilla luciferase because the errors that the transfection efficiency difference is brought.
Experimental technique
In HepG2 and two clones of 293T, two plasmids of corotation pGL3-mpGLUT4 and pRL-SV40 were treated plasmid expression after 24 hours, used the LX0278 incubated cell 24 hours of respective concentration again.Lose the back with the Lucifirase test kit lysing cell of Promega company and measure Photinus pyralis LUC and the activity of Renilla luciferase.Blank is not for adding the methyl-sulphoxide of sample.
Experimental result
As shown in Figure 1, in HepG2 cell and two clones of 293T, compound 17 all significantly strengthens the transcriptional activity of GLUT4 promotor, and this reinforced effects has concentration dependent.
Fig. 1 shows: in 293T (Figure 1A) and two clones of HepG2 (Figure 1B), compound 17 all can significantly strengthen the transcriptional activity of GLUT4 promotor.In 24 orifice plates, according to 400ng and the every hole of 30ng/ transfectional cell, after 24 hours, the compound that adds respective concentration is incubated cell 24 hours again with plasmid pGL3-mpGLUT4 and plasmid pRL-SV40.Detect the activity of two kinds of fluoresceins at last with the uciferase activity detection kit of Promega company.Just obtain standardized Photinus pyralis LUC activity after the Renilla uciferase activity of the activity of Photinus pyralis LUC and corresponding aperture is divided by.Relative GLUT4 promoter activity is obtained divided by the stdn Photinus pyralis LUC of control group is active by the stdn Photinus pyralis LUC activity of test group.
Experimental example 3: compound 17 can strengthen the 3T3-L1 adipocyte glucose absorption of insulin stimulating
Experimental principle
Glucose transporter (GLUT4) is mainly expressed in muscle and fatty tissue.Under the stimulation of Regular Insulin, GLUT4 transfers on the cytolemma fast from tenuigenin glucose transport is advanced cell.2-[
3H]-deoxyglucose, be that second hydrogen atom of glucose used
3The H isotropic substance replaces, like this, by isotropic substance in the quantitative cell just quantitatively cell absorb the amount of extraneous glucose.
Experiment reagent
The DMEM substratum (Delbecco ' s modified Eagle ' s medium+10% foetal calf serum+3.2mM vitamin H+16.8mM calcium pantothenate), Krebs damping fluid, scintillation solution.
Experimental technique
Breaking up completely, the 3T3-L1 adipocyte is grown in 24 orifice plates, hatch and after hungry 8 hours simultaneously with the compound 17 of respective concentration, use Regular Insulin (Regular Insulin is diluted in the Krebs damping fluid) irritation cell 30 minutes of 167nM again, stimulating last 5 minutes add 2-[in nutrient solution
3H]-deoxyglucose, glucose absorption is stopped by the PBS of frozen water precooling.Cell with after twice of the PBS rinse of precooling, is added 150 μ L, 0.1% Triton (Triton) lysing cell.100 μ L cell pyrolysis liquids are mixed back to isotropic substance calculating instrument to be counted with 400 μ L scintillation solutions.Get in addition and survey total protein concentration after 4 μ L cell pyrolysis liquids dilute 5 times, eliminate the deviation that cell quantity causes as confidential reference items.Add cytochalasin B in control wells, the glucose absorption of mensuration is deducted as non-specific absorption value.
Experimental result
As shown in Figure 2, compound 17 can significantly strengthen the glucose absorption of insulin stimulating, and this reinforced effects has concentration dependent form.The effect of the insulin sensitivity enhancing that compound 17 shows is better than positive compound C2.
[C2 is:
Remy I., Montmarquette A., Michnick S.W., PKB/Akt modulates TGF-beta signalingthrough a direct interaction with Smad3.Nat Cell Biol 2004,6,358-365.Buy from ChemBi ℃ of hem (Cat#539741).]
Fig. 2: in the 3T3-L1 adipocyte, compound 17 can significantly strengthen the 2-[of Regular Insulin excitement
3H]-absorption of deoxyglucose (after eight hours, with 167nM insulin stimulating 3T3-L1 adipocyte, at last five minutes, adds 2-[at the C2 of compound 17 of having hatched respective concentration and 10 μ M
3H]-deoxyglucose absorbs cell).
Experimental example 4: anti-diabetic activity experiment in compound 17 bodies
Experiment material
STZ (U-9889) is available from Sigma company, and blood glucose meter and test paper are Johson ﹠ Johnson's product.Kunming mouse is available from Shanghai Si Laike animal center.Medicine is a The compounds of this invention 17.
Experimental technique
Kunming mouse, male, after experimental one week of raising, overnight fast, abdominal injection STZ (150mg/kg).After three days, overnight fast detects blood sugar, is divided into four groups according to blood sugar: model group, medicine high dose group (40mg/kg), dosage group (20mg/kg) in the medicine, medicine low dose group (10mg/kg), 10 every group.Medicine is with tween-80 hydrotropy (content is 0.5%), and through intraperitoneal injection, once a day, the model group abdominal injection gives the physiological saline with the equal size tween-80.After two weeks, overnight fast detects blood sugar, the results are shown in Table 2.
Experimental result
The influence of 17 pairs of Kunming mouse blood sugar of table 2 compound
On STZ inductive insulin resistant mouse model, compound 17 has obvious hypoglycemic activity, and dose-dependence is arranged.
Claims (9)
1, the linear furocoumarins derivative that has structure shown in the following formula 1:
Wherein,
R
1, R
2, R
3, R
4, R
5And R
6Can be identical or inequality, and,
R
1, R
2, R
5And R
6Each represents hydrogen atom, alkyl, thiazolinyl or phenyl;
R
3And R
4Each represents hydrogen atom, alkyl, thiazolinyl, phenyl, hydroxyl or alkoxyl group.
2, linear furocoumarins derivative according to claim 1 is characterized in that, described alkyl is the alkyl of replacement or non-replacement, and wherein, the alkyl of replacement is the alkyl of hydroxyl, halogen, alkoxyl group, acyloxy or alkenyl substituted.
3, linear furocoumarins derivative according to claim 1 is characterized in that R
1Be hydrogen atom or 2-vinyl sec.-propyl; R
2Alkyl, trifluoromethyl or phenyl for hydrogen atom, methoxymethyl, C1-C4; R
3And R
4Respectively be hydrogen atom, hydroxyl or C1-C4 alkoxyl group; R
5Be hydrogen atom, hydroxypropyl or acetoxyl group propyl group; R
6Alkyl or phenyl for hydrogen atom, C1-C4.
According to the described linear furocoumarins derivative of one of claim 1-3, it is characterized in that 4, described derivative is the compound that has with the structure shown in one of in the following formula 2～17:
5, a kind of method for preparing the described linear furocoumarins derivative of one of claim 1-4 is characterized in that, described method comprises:
1) with 2, the 4-Dihydroxy benzaldehyde is a raw material, prolongs carbochain through the methyl triphenyl phosphine, and hydroboration oxidation and the water ring of sloughing a part close and obtain intermediate A hydroxyl dihydrobenzene azoles furans,
Intermediate A hydroxyl dihydrobenzene azoles furans makes 2 ', 3 ' of formula 1-two hydrogen line type furocoumarin(e) derivative G with 'beta '-ketoester or propiolate reaction again:
Perhaps
2) be raw material with hydroxybenzene azoles furans B,
React the linear furocoumarins derivative F that makes formula 1 with 'beta '-ketoester or propiolate:
Perhaps
3) be that the reaction of raw material and 'beta '-ketoester or propiolate obtains intermediate C with the Resorcinol, obtain intermediate D with Mono Chloro acetone or chloroacetophenone reaction again, intermediate D cyclization again forms 4 and 3 ' disubstituted linear furocoumarins derivative E:
R wherein
2And R
6Definition such as claim 1 described in;
Perhaps
4) with by method 2) the 8-hydroxyl linear furocoumarins that makes is that raw material obtains 5 by oxidation, 8-dioxo linear furocoumarins, reduce then 5, the linear furocoumarins derivative that the two hydroxyls of 8-replace, alkylated reaction by hydroxyl then, obtain 5, the furocoumarin(e) derivative that the 8-bis-alkoxy replaces:
R wherein
3And R
4Be alkoxyl group;
Perhaps
5) with 6, the 7-dihydroxycoumarin is a raw material, and 7 obtain 6 carboxaldehyde radicals by the catalytic metal linked reaction of palladium carbon then by chloromethyl methyl ether reaction protection earlier, again with
Reaction, cyclization generate 2 ' linear furocoumarins H that replaces:
Further then, intermediate H reacts in cupric bromide and aluminum oxide, generates the coumarin derivatives of 3 bromos, generates 3 and 2 ' disubstituted linear furocoumarins derivative I with the alcohol reaction again under acidic conditions:
6, a kind of pharmaceutical composition is characterized in that, the described linear furocoumarins derivative of one of claim 1-4 that comprises one or more dose therapeutically effectives.
7, the described linear furocoumarins derivative of one of claim 1-4 is used for the treatment of application in diabetes and the complication medicine thereof in preparation.
8, application as claimed in claim 7 is characterized in that, described linear furocoumarins derivative shifts agonist and GLUT4 protein expression agonist as the GLUT4 film.
9, the described pharmaceutical composition of claim 6 is used for the treatment of application in diabetes and the complication medicine thereof in preparation.
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