CN103848825A - Preparation method and application of sulfonium sugar natural product with inhibition activity on alpha-glucosidase and derivatives thereof - Google Patents

Preparation method and application of sulfonium sugar natural product with inhibition activity on alpha-glucosidase and derivatives thereof Download PDF

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CN103848825A
CN103848825A CN201210505804.8A CN201210505804A CN103848825A CN 103848825 A CN103848825 A CN 103848825A CN 201210505804 A CN201210505804 A CN 201210505804A CN 103848825 A CN103848825 A CN 103848825A
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isosorbide
alcohol
bis
deoxidation
chlorination
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CN103848825B (en
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谢唯佳
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

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Abstract

The invention relates to the fields of organic synthesis and pharmaceutical chemistry, and specifically relates to a sulfonium sugar natural product with inhibition activity on alpha-glucosidase and derivatives thereof, the structure is shown in the general formula A. The invention also discloses a preparation method of the alpha-glucosidase inhibitors and application thereof to treat diabetes. The general formula A is shown in the specification.

Description

There is alpha-glucosidase and suppress active sulfonium carbohydrate natural product and the Preparation method and use of derivative thereof
Technical field
The present invention relates to organic synthesis and pharmaceutical chemistry field, be specifically related to a class and there is alpha-glucosidase and suppress active sulfonium carbohydrate natural product and derivative thereof, the invention also discloses the preparation method of these alpha-glucosidase inhibitors and the purposes aspect treatment diabetes thereof.
Background technology
Diabetes have become the disease of the third-largest harm humans life and health that is only second to cardiovascular and cerebrovascular diseases and cancer at present.And exceed 90% diabetic subject, to belong to type ii diabetes be non insulin dependent diabetes.For such patient, the metabolism of the generation of prevention or delay glucose and acceleration glucose is all effective treatment meanss.As the main source of glucose in blood of human body, starch (polysaccharide) and maltose, sucrose (disaccharides) finally become monose (as glucose, fructose) through multistage or single-stage hydrolysis under the effect of alpha-glucosidase, after small intestine epimere epithelial cell absorbs, enter circulation of blood.Therefore by the activity of Inhibiting α-glucosidase, can effectively reduce postprandial blood sugar concentration.At present successfully going on the market and be widely used in such clinical medicine has: acarbose, voglibose and miglitol.(Asano，N.，Glycobiology，2003，13，93.)
We study discovery, extract and separate the serial sulfonium saccharide compound obtaining to alpha-glucosidase inhibition active acarbose, voglibose higher than clinical application from Salacia prinoides (Willd.) DC. rhizome portion.For further carrying out structural modification, find to obtain alpha-glucosidase is suppressed to active higher novel cpd molecule; Further improve the research of this class bioactive natural product structure activity relationship; Progressively furtheing investigate the interactional mechanism of small molecules and alpha-glucosidase lays the first stone.
Summary of the invention
Easy to prepare for finding, and there is the new drug candidate compound of better hypoglycemic activity, the present invention has found the synthetic method of the advanced person's cheapness to natural product and analogue thereof, thereby a series of derivatives with general formula (A) structural performance are provided.
The technical problem to be solved in the present invention is to find the compound that alpha-glucosidase suppresses active and good hypoglycemic activity that has of new texture type, and the synthetic method of this compounds is further provided.Another object of the present invention be to provide above-mentioned medicinal compositions in preparation by the purposes aspect blocking-up alpha-glucosidase Other diseases or the illness medicine for the treatment of.
For solving the problems of the technologies described above, the invention provides following technical scheme:
Shown in general formula (A), there is alpha-glucosidase and suppress active sulfonium carbohydrate derivative:
Figure BSA00000815340700021
Wherein R 1be selected from H, CH 3, phenyl, substituted-phenyl, aromatic ring and contain heteroatomic aromatic ring and replace aromatic ring;
The compound or pharmaceutically acceptable salt thereof of general formula (A) is more preferably:
Wherein R 1be selected from H, CH 3,
Figure BSA00000815340700022
In aforementioned formula (A), ideal compound or pharmaceutically acceptable salt thereof is selected from:
Wherein R 1representative
Figure BSA00000815340700023
Part of compounds of the present invention is:
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-methylene radical amyl group] table sulfonium salt }-D-R alcohol (I)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-α-tolylene amyl group] table sulfonium salt }-D-R alcohol (IIa)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(2-oil of mirbane methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIb)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(2-chlorobenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIc)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(2-fluorobenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IId)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(2-anisole methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIe)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(2-methylbenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIf)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(2-trifluoromethyl α-tolylene) amyl group] table sulfonium salt }-D-R alcohol (IIg)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-oil of mirbane methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIh)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-chlorobenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIi)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-fluorobenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIj)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-anisole methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIk)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(2-methylbenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (II1)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-trifluoromethyl α-tolylene) amyl group] table sulfonium salt }-D-R alcohol (IIm)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(4-oil of mirbane methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIn)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(4-chlorobenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIo)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(4-fluorobenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIp)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(4-anisole methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIq)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(4-methylbenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIr)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(4-trifluoromethyl α-tolylene) amyl group] table sulfonium salt }-D-R alcohol (IIs)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-4-pyridine methylene amyl group] table sulfonium salt }-D-R alcohol (IIIa)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-4-(2-nitropyridine methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIb)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-4-(2-chloropyridine methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIc)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-4-(2-fluorine pyridine methylene) amyl group] table sulfonium salt }-D-R alcohol (IIId)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-4-(2-methoxypyridine methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIe)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-4-(2-picoline methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIf)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-35-O-4-(2-5-flumethiazine methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIg)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-nitropyridine methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIh)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-chloropyridine methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIi)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-fluorine pyridine methylene) amyl group] table sulfonium salt }-D-R alcohol (IIIj)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-Methoxy Pyridine methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIk)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(2-picoline methylene radical) amyl group] table sulfonium salt }-D-R alcohol (III1)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-5-flumethiazine methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIm)
The present invention includes one and be used for the treatment of Mammals, be used for the treatment of the pharmaceutical composition of human diseases or illness, compound and pharmaceutically acceptable carrier that it comprises treatment diabetes and treats the general formula (A) of the significant quantity of Other diseases or illness by blocking-up alpha-glucosidase.
The present invention also comprises that the compound of general formula (A) is in the application of preparing in the medicine for the treatment of diabetes and treating other illness by blocking-up alpha-glucosidase.
Compound synthetic preparation as follows in general formula A, first take D-R alcohol as starting raw material, obtain coupled reaction precursor compound triflate (6) through a series of selective protection and trifluoromethanesulfonic acid, afterwards again with protection thiosugar (7) (reference: Muraoka, O.; Yoshikai, K.; Takahashi, H.; Minematsu, T.; Lu, G.; Tanabe, G.; Wang, T.; Matsuda, H.; Yoshikawa; M.Synthesis and biological evaluation of deoxy salacinols; the role of polar substituentsin the side chain on the alpha-glucosidase inhibitory activity.Bioorg.Med.Chem.2006; 14; 500-509.) carry out coupled reaction, obtaining serial target product through deprotection reaction optionally.
Introduce the preparation method of triflate (6) below.With reference to reaction one, D-R alcohol (1), tosic acid, has different R 1substituent dimethylacetal Depressor response in DMF can obtain the intermediate 2 of selective protection for 24 hours; 2 again at dibutyl tin oxygen, and cesium fluoride (CsF) dewaters 2 hours in reflux in toluene; add again methoxy-benzyl chlorine, react and can obtain intermediate 3 in 3 hours.Two alcoholic extract hydroxyl groups of glycol (3) can be protected the intermediate (4) that obtains full guard by TBS silicon ether, and under the effect of ceric ammonium nitrate (CAN), the PMB protecting group of 1 can be sloughed and obtain primary alconol (5) by selectivity.5 at trifluoromethanesulfanhydride anhydride, 2, and under the condition that 6-lutidine exists, with methylene dichloride position solvent, low-temp reaction can obtain triflate 6.
Reaction one:
Figure BSA00000815340700051
Introduce the preparation method of target product (I, II, III) below.With reference to reaction two; the pentatomic sulphur sugar (7) of coupled reaction precursor 6 and TBS protection carries out coupled reaction slowly in anhydrous tetrahydro furan; obtain coupling product 8, under the condition existing at tetrabutyl ammonium fluoride, selectivity is sloughed silicon ether protective material and is obtained final product I, II, III.
Reaction two:
Figure BSA00000815340700052
The pharmacological experimental data of part of compounds of the present invention below.
(1). alpha-glucosidase suppresses (external) activity test method
According to literature method (Yoshikawa M.; Xu F.; Nakamura S.; Wang T.; Tanabe G.; Muraoka O..Heterocycles 2008,75,1397.) prepare mouse small intestine brush border membrane vesicle, the maleic acid ester damping fluid (pH=6.0) of this vesica and 0.1M is made into suspension liquid, as alpha-glucosidase (comprising maltin, sucrase and the isomaltase) solution of small intestine.Tested compound is dissolved in to DMSO, and gained solution is diluted to compound solution to be tested (concentration of DMSO is as 10%) take the maleic acid ester of 0.1M again.By the maleic acid ester buffered soln of substrate (maltose 74M, sucrose 74M, isomaltose 74M, each 50L), respectively with compound solution to be tested (25L), enzyme solution (25L) mixes, and 37 ℃ of hatchings 30 minutes.Then, by this mixed solution, rapidly by 2 minutes termination reactions of boiling water bath heating, gained solution is again with the dilution of 150L water, and its glucose concn is measured by conventional glucose carbohydrate oxidase method, IC 50value is calculated the log value curve tracing of test compounds concentration with suppressing per-cent.
Table1. part target compound alpha-glucosidase suppresses (external) active IC 50(μ M) data
Entry Compounds Maltase Sucrase Isomaltase
1 I 0.61 0.44 0.14
2 IIa 0.13 0.042 0.29
3 IIb 0.32 0.35 0.29
4 IIc 0.42 0.52 0.27
5 IId 0.39 0.19 0.33
6 IIe 0.22 0.41 0.25
7 IIf 0.32 0.32 0.55
8 IIg 0.31 0.18 0.36
9 IIh 0.41 0.22 0.46
10 IIi 0.33 0.48 0.28
11 IIj 0.29 0.84 0.35
12 IIk 0.47 0.51 0.36
13 II1 0.30 0.13 0.22
14 IIm 0.09 0.12 0.87
15 IIn 0.45 0.88 0.68
16 IIo 0.98 0.49 1.13
17 IIIa 0.54 0.45 0.20
18 IIIb 0.33 0.54 0.19
19 IIIc 0.47 0.82 0.66
20 IIId 0.65 0.48 0.32
21 IIIe 0.44 0.37 0.95
22 IIIf 0.52 0.63 0.18
[0062]?
23 IIIg 0.42 0.36 0.85
24 IIIh 0.66 0.69 0.19
25 IIIi 0.32 0.30 0.37
26 IIIj 0.45 0.09 0.48
27 IIIk 0.45 0.55 0.49
28 III1 0.98 0.63 0.62
29 IIIm 0.42 0.36 0.52
30 Acarbose 1.7 1.5 646
31 Voglibose 1.2 0.2 2.1
(2). hypoglycemic activity testing method in body
Choosing 8 male SD rats through 7 weeks sizes of SPF level laboratory rearing for every group tests.Raising temperature is 21-22 degree Celsius, and humidity is under 55-60%, to feed one week.The light and shade cycle is 12 hours.Freely intake.Before processing through gavage oral administration, every rat all keeps 16 hours on an empty stomach.After administration 5 minutes, the substrate of 1mL (2g/kg) (maltose, sucrose) solution injects in rat body.Do not pour into medicine injects same dose equally substrate as the rat of blank before.Every 30 minutes, rat blood sample extracted through tail vein, and carried out blood glucose levels (BGL) test by disposable glucose sensor immediately.All experiments all repeat 4 times and average.Experimental data adopts Dunnett ' s t-method of inspection in SPSS10.0 statistical software to carry out statistical procedures afterwards.
Table2. part embodiment is to injecting hypoglycemic activity (30-120min) in maltose rat body
? 30min?BGL(mg/dL) 60min?BGL(mg/dL) 120min?BGL(mg/dL)
Blank 183.6±3.5 179.8±6.1 115.2±5.7
Voglibose 121.5±6.5 112.6±3.8 107.5±5.3
Example I 125.3±5.8 118.5±3.3 109.4±4.7
Example II a 99.4±6.1 95.4±4.7 93.8±2.6
EXAMPLE III a 103.2±4.2 100.8±2.5 98.4±6.6
Dunnett’s?t-test(n＝8，P＜0.01)
Table3. part embodiment is to injecting hypoglycemic activity (30-120min) in sucrose rat body
? 30min?BGL(mg/dL) 60min?BGL(mg/dL) 120min?BGL(mg/dL)
Blank 164.1±4.8 144.8±4.2 113.2±5.1
Voglibose 132.5±6.0 109.6±5.5 103.9±4.8
Example I 148.3±2.5 120.7±6.7 106.5±4.5
Example II a 111.5±5.9 102.4±5.8 100.2±4.9
Example II a 126.3±4.4 105.1±5.3 101.8±5.0
Dunnett’s?t-test(n＝8，P＜0.01)
Embodiment
Below in conjunction with part of compounds specific examples, the present invention is further elaborated, but the present invention is not limited to these embodiment.
Embodiment 1
Synthesizing of 1,3-O-α-tolylene-D-R alcohol (2)
The D-R alcohol of 2.0mmol, the benzaldehyde dimethyl acetal of 2.1mmol, 10mg tosic acid is dissolved in 20mL DMF, in decompression, under 40 ℃ of conditions, react 8 hours, neutralize with triethylamine after completion of the reaction, the crude product that DMF obtains is gone out in underpressure distillation, with sherwood oil: ethyl acetate=3: 1 (V: V) column chromatography, obtain corresponding faint yellow product, productive rate is 82%.The collection of illustrative plates of product and document (Haskins, W.T.; Hann, Raymond M.; Hudson, C.S.J.Am.Chem.Soc.1943,65,1663-1667.) report in full accord.
Embodiment 2
5-O-is to methoxy-benzyl-1, the synthetic (R of 3-O-α-tolylene-D-R alcohol (3) 1=phenyl)
At the dibutyl tin oxygen that contains 1.15mmol, in toluene (20mL) solution of 1.25mmol CsF, add the compound 2 of 1.0mmol, mixing solutions dewaters 2 hours 120 ℃ of backflows.Add again methoxy-benzyl chlorine (1.15mmo1), continue to reflux 3 hours.Reaction stops rear underpressure distillation and removes toluene later with sherwood oil: ethyl acetate=5: 1 (V: V) column chromatography, obtain corresponding faint yellow oily product, and productive rate is 78%.There are all the other compound (R of similar structures with compound 3 1for aforementioned other group) synthetic method and aforesaid method similar, productive rate is 52%-81%.
MS(FAB)m/z：361.2[M+H] +.
IR(neat)：3383，1669，1418，1317，1204，1140，1074，1046，1030，843，802，723，666cm -1.
1HNMR(CDCl 3，300MHz)δ：3.57(br.1H，-CH-)，3.62-3.69(m，3H，-CH 2-×3)，3.75?(1H，dd，J＝9.8，4.2，-CH-)，3.86(1H，dd，J＝9.8，6.7，-CH-)，3.95(s，3H，-OCH 3)，4.35(m，1H，-CH 2-)，4.64(d，2H，J＝10.6，-CH 2-)，5.62(s，1H，Ph-CH)，7.21(2H，Ar-H)7.38-7.55(7H，Ar-H)。
Embodiment 3
5-O-is to methoxy-benzyl-1,3-O-α-tolylene-2,4-[bis-(tertiary butyl dimethyl-silicon) oxo]-D-R alcohol
(4) (R 1=phenyl) synthetic
The compound of 1.0mmol 3 is dissolved in DMF (25mL), in gained solution, adds TBSCl (1.2mmo1), imidazoles 3.5mmol.Gained solution at room temperature stirs 3.5 hours.Reaction is poured reaction solution in frozen water into after finishing, and with ether/sherwood oil (1: 1) mixed extractant solvent water layer, concentrated gained organic phase, with sherwood oil: ethyl acetate=20: 1 (V: V) column chromatography obtains white solid.Productive rate 75%.There are all the other compound (R of similar structures with compound 4 1for aforementioned other group) synthetic method and aforesaid method similar, productive rate is 62%-77%.
mp：165-167℃
MS(FAB)m/z：589.9[M+H] +.
IR(KBr)：1497，1454，1427，1397，1096，1090，1076，1043cm -1.
1HNMR(CDCl 3，300MHz)δ：0.067/0.70/0.074/0.76[each3H，s， tBu(CH 3) 2Si]，0.89/0.95[each9H，s，(CH 3) 3CMe 2Si]，3.59(b?r.1H，-CH-)，3.65-3.68(m，2H，-CH-)，3.70(1H，m，-CH-)，3.83(1H，m，-CH-)，3.91(s，3H，-OCH 3)，4.20(m，2H，-CH 2-)，4.64(d，2H，J＝10.6，-CH 2-)，5.60(s，1H，Ph-CH)，7.21(2H，Ar-H)，7.40-7.52(7H，Ar-H)。
Embodiment 4
1,3-O-α-tolylene-2,4-[bis-(tertiary butyl dimethyl-silicon) oxo]-D-R alcohol (5) (R 1=phenyl) synthetic
The compound of 1.0mmol 4 is dissolved in acetonitrile/water (1: 1,20mL), to the ceric ammonium nitrate (CAN) that adds 2.2mmol in gained solution.This mixing solutions at room temperature stirs raw material after 4 hours and disappears.Concentrated, with sherwood oil: ethyl acetate=20: 1 (V: V) column chromatography obtains faint yellow oily matter.Productive rate 80%.There are all the other compound (R of similar structures with compound 5 1for aforementioned other group) synthetic method and aforesaid method similar, productive rate is 75%-82%.
MS(FAB)m/z：469.1[M+H] +.
IR(neat)：1493，1448，1436，1392，1096，1094，1078，1038cm -1.
1HNMR(CDCl 3，300MHz)δ：0.068/0.71/0.074/0.76[each3H，s， tBu(CH 3) 2Si]，0.86/0.94[each9H，s，(CH 3) 3CMe 2Si]，3.56(b?r.1H，-CH-)，3.62(1H，m，-CH-)，3.69-3.73(m，2H，-CH-)，3.85(1H，m，-CH-)，4.25(m，2H，-CH 2-)，5.60(s，1H，Ph-CH)，7.44-7.63(5H，Ar-H)。
Embodiment 5
1,3-O-α-tolylene-2,4-[bis-(tertiary butyl dimethyl-silicon) oxo]-5-O-methylsulfonyl-D-R alcohol (5) (R 1=phenyl) synthetic
Under the condition of nitrogen protection; by 2.5mmo12; 6-lutidine adds in the methylene dichloride of 15mL; temperature is down to-20 ℃; add trifluoromethyl sulfonic acid anhydride (2.5mL), the dichloromethane solution (15mL) that contains 1.0mmol compound 5 toward gained mixed solution and dripping after 5 minutes.After 10 minutes, temperature of reaction is risen to room temperature and continue to stir 30 minutes.Gained mixing solutions is poured in frozen water, and with dichloromethane extraction, concentrated organic phase gained crude product obtains target product triflate 6 through column chromatography (sherwood oil: ethyl acetate=20: 1 (V: V)) rapidly, and productive rate is 78%.There are all the other compound (R of similar structures with compound 6 1for aforementioned other group) synthetic method and aforesaid method similar, productive rate is 65%-80%.
MS(FAB)m/z：601.8[M+H] +.
IR(neat)：1416，1385，1250，1211，1150，1119，1073，1015cm -1.
1HNMR(CDCl 3，300MHz)δ：0.067/0.71/0.075/0.78[each3H，s， tBu(CH 3) 2Si]，?0.86/0.92[each9H，s，(CH 3) 3CMe 2Si]，3.59(b?r.1H，-CH-)，3.64(1H，m，-CH-)，3.66-3.72(m，2H，-CH-)，3.85(1H，m，-CH-)，4.58(1H，dd，J＝10.5，7.2，-CH 2-)，4.64(1H，dd，J＝10.5，4.7，-CH 2-)，5.61(s，1H，Ph-CH)，7.42-7.63(5H，Ar-H)。
Embodiment 6
Chlorination-2,3,5-[tri-(tertiary butyl dimethyl-silicon) oxo]-1,4-dideoxy-1,4-{[(S)-1,3-O-α-tolylene-2,4-bis-(tertiary butyl dimethyl-silicon) oxo-5-deoxidation-D-5-arabopyranose] table sulfonium salt } synthetic (R of-D-R alcohol (7) 1=phenyl)
Rapid above-mentioned gained compound 6 (1.0mmol) and thiosugar (7,1.5mmo1) are added in 10 milliliters of tetrahydrofuran (THF)s, under the condition of 40 ℃, react 72 hours.After concentrated, again crude product is dissolved in 20mL methyl alcohol, adds 300mg chlorion exchange resin (IRA400J (C1 -form)) stir after 2 hours and concentrate, gained crude product obtains target product 7 through column chromatography (methylene dichloride: methyl alcohol=100: 1 (V: V)), and productive rate is 72%.There are all the other compound (R of similar structures with compound 7 1for aforementioned other group) synthetic method and aforesaid method similar, productive rate is 70%-78%.
MS(FAB)m/z：943.6[M+H] +.
IR(neat)：1454，1385，1262，1215，1157，1069，1030，1003cm -1.
1HNMR(CDCl 3，300MHz)δ：0.067-0.83[30H，s， tBu(CH 3) 2Si]，0.83-0.96[45H，s，(CH 3) 3CMe 2Si]，3.50(1H，dd，J＝13.2，6.0，-CH 2-)，3.62(1H，dd，J＝13.2，3.4，-CH 2-)，3.66(b?r.1H，-CH-)，3.72(1H，m，-CH-)，3.79(1H，dd，J＝13.0，4.0，-CH 2-)，3.83(1H，dd，J＝13.0，3.0，-CH 2-)，3.85(1H，m，-CH-)，3.86(1H，dd，J＝10.2，7.6，-CH 2-)，4.01(1H，dd，J＝10.2，7.4，-CH 2-)，4.14(1H，ddd，J＝8.2，5.0，2.6，-CH-)，4.36(1H，dd，J＝3.0，3.0，H-3)，4.66(1H，ddd，J＝4.0，3.0，3.0，H-2)，4.62(1H，dd，J＝11.2，6.8，-CH 2-)，4.65(1H，dd，J＝11.2，4.5，-CH 2-)，5.64(s，1H，Ph-CH)，7.40-7.66(5H，Ar-H)。
Embodiment 7
Synthetic (the R of chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-α-tolylene amyl group] table sulfonium salt }-D-R alcohol (IIa) 1=phenyl)
The tetrahydrofuran solution (5.2mL) of the tetrabutyl ammonium fluoride of above-mentioned gained compound 7 (1.0mmo1), 1.0mol/L is added in tetrahydrofuran (THF) (15mL), under the condition of 70 ℃, react 2 hours.By cooling gained solution, drop in frozen water, concentrated, obtaining target product IIa through column chromatography (methylene dichloride: methyl alcohol=40: 1 (V: V)) is white solid, productive rate is 85%.There are all the other compound (R of similar structures with Compound I Ia 1for aforementioned other group) synthetic method and aforesaid method similar, productive rate is 73%-85%.
mp：187-189℃
MS(FAB)m/z：373.4[M+H] +.
1HNMR(CD 3OD，300MHz)δ：3.46(1H，dd，J＝13.5，5.8，-CH 2-)，3.62(1H，dd，J＝13.5，2.0，-CH 2-)，3.64(m.1H，-CH-)，3.73(1H，m，-CH-)，3.77(1H，dd，J＝12.5，3.8，-CH 2-)，3.83(1H，dd，J＝12.5，2.6，-CH 2-)，3.83-3.86(3H，m，-CH-/-CH 2-)，4.08(1H，dd，J＝10.0，6.8，-CH 2-)，4.16(1H，m，-CH-)，4.38(1H，b?r.，-CH-)，4.66(1H，b?r.，-CH-)，4.60(1H，dd，J＝11.5，7.3，-CH 2-)，4.63(1H，dd，J＝11.5，4.2，-CH 2-)，5.65(s，1H，Ph-CH)，7.38-7.66(5H，Ar-H)。
Embodiment 8
Figure BSA00000815340700121
Get above-mentioned formula, be prepared into tablet by ordinary method.

Claims (4)

1. shown in general formula (A), there is alpha-glucosidase and suppress active sulfonium carbohydrate derivative:
Figure FSA00000815340600011
Wherein R 1be selected from H, CH 3, phenyl, substituted-phenyl, aromatic ring and contain heteroatomic aromatic ring and replace aromatic ring;
The compound or pharmaceutically acceptable salt thereof of general formula (A) is more preferably:
Wherein R 1be selected from H, CH 3,
Figure FSA00000815340600012
In aforementioned formula (A), ideal compound or pharmaceutically acceptable salt thereof is selected from:
Wherein R 1representative .
2. part of compounds of the present invention is:
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-methylene radical amyl group] table sulfonium salt }-D-R alcohol (I)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-α-tolylene amyl group] table sulfonium salt }-D-R alcohol (IIa)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(2-oil of mirbane methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIb)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(2-chlorobenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIc)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(2-fluorobenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IId)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(2-anisole methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIe)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(2-methylbenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIf)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(2-trifluoromethyl α-tolylene) amyl group] table sulfonium salt }-D-R alcohol (IIg)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-oil of mirbane methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIh)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-chlorobenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIi)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-fluorobenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIj)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-anisole methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIk)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(2-methylbenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (II1)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-trifluoromethyl α-tolylene) amyl group] table sulfonium salt }-D-R alcohol (IIm)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(4-oil of mirbane methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIn)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(4-chlorobenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIo)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(4-fluorobenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIp)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(4-anisole methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIq)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(4-methylbenzene methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIr)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(4-trifluoromethyl α-tolylene) amyl group] table sulfonium salt }-D-R alcohol (IIs)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-4-pyridine methylene amyl group] table sulfonium salt }-D-R alcohol (IIIa)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-4-(2-nitropyridine methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIb)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-4-(2-chloropyridine methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIc)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-4-(2-fluorine pyridine methylene) amyl group] table sulfonium salt }-D-R alcohol (IIId)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-4-(2-methoxypyridine methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIe)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-4-(2-picoline methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIf)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-4-(2-5-flumethiazine methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIg)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-nitropyridine methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIh)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-chloropyridine methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIi)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-fluorine pyridine methylene) amyl group] table sulfonium salt }-D-R alcohol (IIIj)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-Methoxy Pyridine methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIk)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(2-picoline methylene radical) amyl group] table sulfonium salt }-D-R alcohol (III1)
Chlorination-Isosorbide-5-Nitrae-bis-deoxidation-Isosorbide-5-Nitraes-{ (R)-[(2S, 3S, 4R)-2,4-dihydroxyl-3,5-O-(3-5-flumethiazine methylene radical) amyl group] table sulfonium salt }-D-R alcohol (IIIm).
3. the present invention includes one and be used for the treatment of Mammals, be used for the treatment of the pharmaceutical composition of human diseases or illness, compound and pharmaceutically acceptable carrier that it comprises treatment diabetes and treats the general formula (A) of the significant quantity of Other diseases or illness by blocking-up alpha-glucosidase.
4. the compound that the present invention also comprises general formula (A) is in the application of preparing in the medicine for the treatment of diabetes and treating other illness by blocking-up alpha-glucosidase.
CN201210505804.8A 2012-12-03 2012-12-03 Preparation method and application of sulfonium sugar natural product with inhibition activity on alpha-glucosidase and derivatives thereof Active CN103848825B (en)

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