CN104003983A - Benzene-containing selenium group substituted diheterocyclic compound as well as preparation and application thereof - Google Patents

Benzene-containing selenium group substituted diheterocyclic compound as well as preparation and application thereof Download PDF

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CN104003983A
CN104003983A CN201410234882.8A CN201410234882A CN104003983A CN 104003983 A CN104003983 A CN 104003983A CN 201410234882 A CN201410234882 A CN 201410234882A CN 104003983 A CN104003983 A CN 104003983A
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phenylseleno
bis
add
heterocyclic compounds
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CN104003983B (en
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王宇光
吴中礼
朱冰春
李清思
张海梁
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Zhejiang University of Technology ZJUT
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Zhejiang University of Technology ZJUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The invention discloses a benzene-containing selenium group substituted diheterocyclic compound as well as preparation and application thereof. The structural formula of the benzene-containing selenium group substituted diheterocyclic compound is as shown in a formula (VI-1) or a formula (VI-2), and the synthesis route is as shown in the specification. The benzene-containing selenium group substituted diheterocyclic compound is good in monoamine oxidase inhibition activity and can be applied to preparation of a monoamine oxidase inhibitor. The formula (VI-1) and the formula (VI-2) are as shown in the specification.

Description

The bis-heterocyclic compounds and the preparation and application thereof that containing phenylseleno, replace
1, technical field
The present invention relates to a kind of bis-heterocyclic compounds and preparation and application thereof that replace containing phenylseleno, especially its application in preparation oxidase inhibitor.
2, background technology
Monoamine oxidase (monoamine oxidase, MAO, EC1.4.3.4) is monoamine oxydo-reductase by name entirely, in the 1830's, by Balschko, found, and be a kind of enzyme that neurotransmitter metabolism is played an important role.The amine of its some organisms generation of catalysis in brain and peripheral nerve tissue, oxidative deamination produces hydrogen peroxide.Nineteen sixty-eight, Johnston is divided into A and two subclass of B according to monoamine oxidase to the susceptibility of its irreversible inhibitor clorgyline (M B 9302), and monoamine oxidase A is responsive to clorgyline, and monoamine oxidase-B is insensitive.Further research shows that monoamine oxidase A has high-affinity to substrate thrombotonin (5-HT), norepinephrine (NE), Dopamine HCL (DA) and inhibitor clorgyline; Monoamine oxidase-B to styroyl amine (PEA), benzene methanamine and inhibitor deprenyl (selegiline) have high-affinity (Kuwahara T, etc., Agric.Biol.Chem., 1990,54,253-257.).
Research shows that monoamine oxidase, in the process of metabolism Dopamine HCL, supervenes the endogenous material such as free radical and hydrogen peroxide, the abnormal and Parkinson's disease of its expression amount, and dysthymia disorders and Aggression have extremely close relationship.Along with the quickening gradually of people's rhythm of life, stress constantly increases, and the sickness rate of dysthymia disorders is soaring just rapidly, estimates to the year two thousand twenty, will become the second largest disease that is only second in the world coronary heart disease.The initiation of this disease may be with monoamine oxidase (MAO) extremely relevant, and oxidase inhibitor (MAOI) is the medicine that a class specificity suppresses MAO activity in body, once at the first Cure of depression that the is used to fifties.Its mechanism is by suppressing MAO, reduce the degraded of monoamine neurotransmitter in central nervous system, relatively increase the concentration of maincenter monoamine transmitters, improve mood, producing antidepressant effect.The clinical monoamine oxidase inhibitor with crossing has Phenelzine (Phenelzine), vazadrine (Isonicotinyl hydrazide), iproniazid (Iproniazid), the nialamide (Nialamide of hydrazine class,) etc., non-hydrazine class be take Tranylcypromine (Tranylcypromine) as representative (Kalgutkar, A.S.Chem.Res.Toxicol., 2001,14 (9), 1139-1162.).Because the most of toxic side effect of these medicines is larger, and single to the action effect of monoamine oxidase, so seek low toxicity, respond well MAOI becomes the fresh target of current research.
Nitrogen-containing heterocycle compound all shows particularly good monoamine oxidase inhibitory activity, Mazouz particularly, F. wait 1 of report different substituents, 3,4-oxadiazole ketone compounds derivative has monoamine oxidase inhibitory activity (Mazouz, F. etc., J Med Chem., 1993,36,6394-63981157-1167).Isoxazole compounds is present in numerous natural product skeletons, is the material that a class has good biological activity or potential source biomolecule activity, gradually becomes important medicine intermediate and lead compound.Such as, isoxazole compounds have well antibacterial, anti-inflammatory, the biologic activity such as antitumor (He Hongwu etc. agricultural chemicals., 2000,39 (8), 4-7).Isoxazole compound is also in the news and has monoamine oxidase inhibitory activity, and for example, the compound Isocarboxazid that has these two kinds of active groups of isoxazole and hydrazides concurrently is first-generation oxidase inhibitor; The compound that Liu Bingni report contains isoxazole ring show certain monoamine oxidase inhibitory activity (Liu Bingni etc., synthetic chemistry., 2011,19 (6), 734-736.).Of the present invention Jiang isoxazole ring or triazole ring Yin Ru Dao oxadiazole rings, synthesized the bis-heterocyclic compounds that series of new replaces containing phenylseleno, they have good monoamine oxidase inhibitory activity, are that the good monoamine oxidase of a class presses down agent (MAOIs).
3, summary of the invention
First object of the present invention is to provide a kind of bis-heterocyclic compounds replacing containing phenylseleno with good monoamine oxidase inhibitory activity.
Second object of the present invention is to provide a kind of method of preparing the described heterogeneous ring compound replacing containing phenylseleno.
The 3rd object of the present invention is to provide the application of the described bis-heterocyclic compounds replacing containing phenylseleno in preparation oxidase inhibitor.
Below to illustrating for realizing the technical scheme that the object of the invention adopts.
The invention provides a kind of bis-heterocyclic compounds replacing containing phenylseleno, its structure is suc as formula shown in (VI):
Wherein, R is selected from the group shown in formula (VIII) or formula (IX):
In formula (VIII), R 1for aryl;
In formula (IX), R 2be selected from one of following groups:
aryl, benzyl;
Described aryl is not substituted or by one or more replacements in following groups: the alkoxyl group of the alkyl of C1-C3, halogen, C1-C3, trifluoromethyl;
R 3, R 4, R 5, R 6independently be selected from separately the alkyl of C1-C6.
Concrete, the bis-heterocyclic compounds replacing containing phenylseleno of the present invention can be divided into following two classes:
Further, R 1for not being substituted or by the alkoxyl group of the alkyl of the phenyl of one or more replacements in following groups: C1-C3, halogen, C1-C3, trifluoromethyl.
Further, R 2be selected from one of following groups:
phenyl, the phenyl that halogen replaces, benzyl.
Further, R 3, R 4, R 5, R 6independently be selected from separately the alkyl of C1-C4.
Further, R 2be selected from one of following groups:
phenyl, the phenyl that halogen replaces, benzyl.
Further, described halogen is F, Cl or Br.
Again further, the described bis-heterocyclic compounds replacing containing phenylseleno is one of following:
The present invention also provides the method for the bis-heterocyclic compounds replacing containing phenylseleno shown in a kind of preparation formula (VI-1), and described method comprises:
(1) preparation of the intermediate product containing phenylseleno shown in formula III:
In reaction vessel, add the para hydroxybenzene hydrazine shown in the positive propionic aldehyde of α-phenylseleno shown in organic solvent B, formula (II) and formula (VII), after making it to dissolve completely, add acetic acid, then back flow reaction 1-3 hour under nitrogen protection, reacts completely and obtains the intermediate product containing phenylseleno shown in formula (III) by separation and purification;
(2) preparation containing phenylseleno oxadiazole compounds shown in formula IV:
In reaction vessel, add shown in formula (III) containing intermediate product and the diacetyl oxide of phenylseleno, after completion of the reaction through separation and purification obtain shown in formula IV containing phenylseleno oxadiazole compounds;
(3) preparation containing terminal triple link oxadiazole compounds shown in formula (V):
In reaction vessel, add shown in organic solvent C, formula IV containing phenylseleno oxadiazole compounds, salt of wormwood, under stirring, slowly add propargyl bromide, under nitrogen protection, back flow reaction is 3～5 hours, obtains the oxadiazole compounds containing terminal triple link shown in formula (V) after completion of the reaction through separation and purification;
(4) preparation of the bis-heterocyclic compounds replacing containing phenylseleno shown in formula (VI-1):
Make the oxime compounds shown in formula (X) and N-chlorosuccinimide (NCS) room temperature reaction 4-5 hour in organic solvent D, then add reacting 5～8 hours containing terminal triple link oxadiazole compounds and triethylamine shown in formula (V), react completely and obtain the bis-heterocyclic compounds replacing containing phenylseleno shown in formula (VI-1) by separation and purification;
In formula (X), R 1definition cotype (VI-1).
Further, in step (1), it is one of following that organic solvent B is selected from: ethanol, tetrahydrofuran (THF), acetonitrile.
Further, in step (1), shown in the positive propionic aldehyde of α-phenylseleno, formula (VII) is 1:1:10～15 to the molar ratio of hydroxyl hydrazides, acetic acid.
Further, in step (2), the volume that adds of diacetyl oxide is counted (4～6) mL/mmol with the mole number of the intermediate product containing phenylseleno shown in formula (III).
Further, in step (2), the reaction times was at 3～4 hours.
Further, in step (3), it is one of following that organic solvent C is selected from: acetone, DMF.
Further, in step (3), the molar ratio containing phenylseleno oxadiazole compounds and salt of wormwood, propargyl bromide shown in formula IV is 1:1～1.3:1.2～1.5.
Further, in step (4), it is one of following that organic solvent D is selected from: methylene dichloride, trichloromethane, tetrahydrofuran (THF).
Further, in step (4), the molar ratio containing the oxime compounds shown in terminal triple link oxadiazole compounds, formula (X), N-chlorosuccinimide, triethylamine shown in formula (V) is 1:1.5～2:1.5～2:2～3.
The present invention also provides the method for the bis-heterocyclic compounds replacing containing phenylseleno shown in a kind of preparation formula (VI-2), and described method comprises:
(a) preparation of the intermediate product containing phenylseleno shown in formula III:
In reaction vessel, add the para hydroxybenzene hydrazine shown in the positive propionic aldehyde of α-phenylseleno shown in organic solvent B, formula (II) and formula (VII), after making it to dissolve completely, add acetic acid, then back flow reaction 1-3 hour under nitrogen protection, reacts completely and obtains the intermediate product containing phenylseleno shown in formula (III) by separation and purification;
(b) preparation containing phenylseleno oxadiazole compounds shown in formula IV:
In reaction vessel, add shown in formula (III) containing intermediate product and the diacetyl oxide of phenylseleno, after completion of the reaction through separation and purification obtain shown in formula IV containing phenylseleno oxadiazole compounds;
(c) preparation containing terminal triple link oxadiazole compounds shown in formula (V):
In reaction vessel, add shown in organic solvent C, formula IV containing phenylseleno oxadiazole compounds, salt of wormwood, under stirring, slowly add propargyl bromide, under nitrogen protection, back flow reaction is 3～5 hours, obtains the oxadiazole compounds containing terminal triple link shown in formula (V) after completion of the reaction through separation and purification;
(d) preparation of the bis-heterocyclic compounds replacing containing phenylseleno shown in formula (VI-2):
Make being dissolved in solvent E containing terminal triple link oxadiazole compounds shown in formula (V), add successively cupric sulfate pentahydrate and xitix, after stirring and dissolving, add the triazo-compound shown in formula (XI), stirring at room reaction 6-8 hour, reacts completely and obtains the bis-heterocyclic compounds replacing containing phenylseleno shown in formula (VI-2) by separation and purification;
In formula (XI), R 2definition cotype (VI-2).
Step (a)-step (c) is above-mentioned steps (1)-step (3), and it is prepared details and does not repeat them here.
In step (d), it is one of following that solvent E is selected from: the mixed solvent of THF and water, methyl-sulphoxide.
In step (d), the molar ratio containing terminal triple link oxadiazole compounds, cupric sulfate pentahydrate, xitix, triazo-compound shown in formula (V) is 1:0.05～0.1:0.15～0.25:1.3～1.6.
The positive propionic aldehyde of α-phenylseleno shown in the raw material formula (II) that the present invention uses can be prepared by following equation according to the method for existing bibliographical information:
The bis-heterocyclic compounds replacing containing phenylseleno of the present invention has good monoamine oxidase inhibitory activity, and especially MAO-B suppresses active, therefore can be used for preparing monoamine oxidase (especially MAO-B) inhibitor.
Beneficial effect of the present invention has been to provide the bis-heterocyclic compounds replacing containing phenylseleno with good monoamine oxidase inhibitory activity that a class is new.
4, embodiment
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this:
Embodiment 1 Han isoxazole oxadiazole compounds derivative VI-1-1.'s is synthetic
1) by α-phenylseleno propionic aldehyde (0.213g of equivalent; 1mmol) add in the round-bottomed flask that contains 20ml ethanol with para hydroxybenzene hydrazine (1mmol, 0.152g), stir and make it to dissolve completely; add again 800 μ L acetic acid, back flow reaction 3h under nitrogen protection.After TLC detection reaction is complete, drain ethanol, add 20mLCH 2cl 2, use saturated Na 2cO 3solution (3 * 20mL) solution washing, anhydrous Na 2sO 4dry, concentrated, obtain intermediate product (III) crude product containing phenylseleno.
2) product obtaining (III) (1mmol) is joined in the acetic anhydride of 5mL, heating reflux reaction 3h under nitrogen protection, solution colour becomes orange and has suspended substance to generate.After TLC detection reaction is complete, drain diacetyl oxide, add 20mLCH 2cl 2, use saturated Na 2cO 3solution (3 * 20mL) solution washing is removed the diacetyl oxide of not draining, then uses anhydrous Na 2sO 4dry, concentrated, through thin plate chromatographic separation, obtain product (IV), productive rate 75%.
3) 1mmol (0.390g) compounds Ⅳ is dissolved in 20mL acetone, then adds (1.5mmol, 0.207g) salt of wormwood, under stirring, slowly add (1.2mmol, 0.143g) propargyl bromide, back flow reaction 3h under nitrogen protection.After TLC detection reaction is complete, drain acetone, add 20mLCH 2cl 2, use saturated Na 2cO 3solution (3 * 20mL) solution washing, anhydrous Na 2sO 4dry, concentrated, after thin plate chromatography, obtain compound V.
4) first will be dissolved in 20mLCH with the NCS (2mmol, 0.268g) of equivalent to methylbenzene oxime (2mmol, 0.272g) 2cl 2at room temperature react 4h, add again compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) reaction 6 hours, after TLC detects major part and reacts completely, add saturated sodium-chloride layering, organic phase saturated sodium-chloride washing (30mL * 3), organic phase anhydrous magnesium sulfate drying, concentrated, thin plate chromatography obtains VI-1-1., productive rate 82.5%.Characterization of The Products method: 1h NMR is by Bruker Avance nmr determination, 13c NMR, by Bruker Avance nmr determination, uses CDCl 3make solvent, mark in TMS does.FT-IR is by Bruker Tensor27 type determination of infrared spectroscopy, and solid adopts KBr pressed disc method, and liquid adopts liquid-film method.Result is as follows:
1H?NMR(400MHz,CDCl 3)δ 1H?NMR(400MHz,CDCl 3)δ7.70(d,J＝7.9Hz,2H),7.62(d,J＝7.8Hz,2H),7.52-7.48(m,4H),7.37-7.17(m,5H),6.92(d,J＝8.5Hz,1H),6.35(s,1H),4.10(dd,J＝49.1,14.1Hz,1H),2.46(s,2H),2.40(s,3H),1.62(s,3H),1.25(d,J＝4.6Hz,3H).IRν max(cm -1):3375,2971,1767,1665,1599,1562,1508,1493,1432,1397,1210,1193,1122,1087,927,891,789,690,525,480.MS(ESI)m/z562.1(M+H) +.
Embodiment 2 Han isoxazole oxadiazole compounds derivative VI-1-2.'s is synthetic
1) operation is as embodiment 1 step 1
2) operation is as embodiment 1 step 2
3) operation is as embodiment 1 step 3
4) first will be dissolved in 20mLCH with the NCS (2mmol, 0.268g) of equivalent to anisole oxime (2mmol, 0.288g) 2cl 2at room temperature react 3h, then add compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) reaction is 6 hours, and after TLC detection major part reacts completely, subsequent disposal is as embodiment 1 step 4, through thin plate chromatography, obtain VI-1-2., productive rate 85%.Characterization of The Products result is as follows:
1H?NMR(400MHz,CDCl 3)δ7.75-7.72(m,4H),7.68-7.64(m,4H),7.30(d,J＝3.5Hz,2H),7.12-7.10(m,3H),6.99(d,J＝8.8Hz,1H),6.62(s,1H),5.24(s,2H),3.94-3.62(m,1H),3.85(s,3H),2.31(s,3H),1.34(d,J＝7.2Hz,3H)；IRν max(cm -1):3120,2976,2920,2820,1665,1607,1580,1562,1504,1455,1409,1234,1210,1167,1122,1098,1026,927,803,708,690,503,414,338.MS(ESI)m/z578.1(M+H) +.
Embodiment 3 Han isoxazole oxadiazole compounds derivative VI-1-3.'s is synthetic
1) operation is as embodiment 1 step 1
2) operation is as embodiment 1 step 2
3) operation is as embodiment 1 step 3
4) first will be dissolved in 20mLCH with the NCS (2mmol, 0.268g) of equivalent to chlorobenzene oxime (2mmol, 0.313g) 2cl 2at room temperature react 3h, then add compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) reaction is 6 hours, and after TLC detection major part reacts completely, subsequent disposal is as embodiment 1 step 4, through thin plate chromatography, obtain VI-1-3., productive rate 71%.Characterization of The Products result is as follows:
1H?NMR(400MHz,CDCl 3)δ7.68-7.60(m,4H),7.52(d,J＝8.5Hz,2H),7.37–7.17(m,7H),6.92(d,J＝8.5Hz,1H),6.35(s,1H),4.10(dd,J＝49.1,14.1Hz,1H),2.47(s,2H),2.40(s,3H),1.25(d,J＝4.6Hz,3H)；IRν max(cm -1):3031,2922,2867,1884,1760,1618,1578,1551,1487,1445,1398,1376,1206,1175,1109,1088,1038,1014,938,802,739,630,483,376.MS(ESI)m/z582.1(M+H) +,584.1(M+2+H) +.
Embodiment 4 Han isoxazole oxadiazole compounds derivative VI-1-4.'s is synthetic
1) operation is as embodiment 1 step 1
2) operation is as embodiment 1 step 2
3) operation is as embodiment 1 step 3
4) first will be dissolved in 20mLCH with the NCS (2mmol, 0.268g) of equivalent to fluorobenzene oxime (2mmol, 0.280g) 2cl 2at room temperature react 3h, then add compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) reaction is 6 hours, and after TLC detection major part reacts completely, subsequent disposal is as embodiment 1 step 4, through thin plate chromatography, obtain VI-1-4., productive rate 78%.Characterization of The Products result is as follows:
1H?NMR(400MHz,CDCl 3)δ7.75(d,J＝9.0Hz,2H),7.68-7.64(m,4H),7.33-7.28(m,4H),7.16(d,J＝1.7Hz,2H),7.13-7.10(m,1H),6.92(d,J＝8.7Hz,1H),6.63(s,1H),4.10(dd,J＝49.1,14.1Hz,1H),2.46(s,2H),2.32(s,3H),1.37-1.35(m,3H)；IRν max(cm -1):3042,2927,1708,1613,1601,1551,1507,1454,1409,1223,1158,1114,1026,1019,842,814,730,678,501,452,422..MS(ESI)m/z566.1(M+H) +.
Embodiment 5 Han isoxazole oxadiazole compounds derivative VI-1-5.'s is synthetic
1) operation is as embodiment 1 step 1
2) operation is as embodiment 1 step 2
3) operation is as embodiment 1 step 3
4) first will be dissolved in 20mLCH with the NCS (2mmol, 0.268g) of equivalent to trifluoromethylbenzene oxime (2mmol, 0.380g) 2cl 2at room temperature react 3h, then add compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) reaction is 6 hours, and after TLC detection major part reacts completely, subsequent disposal is as embodiment 1 step 4, through thin plate chromatography, obtain VI-1-5., productive rate 72%.Characterization of The Products result is as follows:
1H?NMR(400MHz,CDCl 3)δ7.75-7.56(m,4H),7.28-7.25(m,4H),7.16-7.13(m,2H),7.10-7.03(m,3H),6.69-6.68(m,1H),6.64(s,1H),5.27(s,2H),3.86(dd,J＝14.1,9.8Hz,1H),2.31(s,3H),1.34(d,J＝7.2Hz,3H)；IRν max(cm -1):3475,3390,?2971,1767,1665,1626,1551,1524,1444,1324,1210,1184,1157,1110,1063,1010,927,830,691,599,505,428.MS(ESI)m/z616.1(M+H) +.
Embodiment 6 Han isoxazole oxadiazole compounds derivative VI-1-6.'s is synthetic
1) operation is as embodiment 1 step 1
2) operation is as embodiment 1 step 2
3) operation is as embodiment 1 step 3
4) first will pair between the NCS (2mmol, 0.268g) of bromobenzene oxime (2mmol, 0.402g) and equivalent be dissolved in 20mLCH 2cl 2at room temperature react 3h, then add compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) reaction is 6 hours, and after TLC detection major part reacts completely, subsequent disposal is as embodiment 1 step 4, through thin plate chromatography, obtain VI-1-6., productive rate 76%.Characterization of The Products result is as follows:
1H?NMR(400MHz,CDCl 3)δ7.99-7.93(m,4H),7.75(d,J＝7.8Hz,2H),7.68(d,J＝4.6Hz,2H),7.36-7.32(m,2H),7.26-7.23(m,3H),6.87-6.82(m,1H),6.58(s,1H),5.21(s,2H),3.97-3.92(m,1H),2.34(s,3H),1.36(d,J＝8.6Hz,3H)；IRν max(cm -1):3058,2917,1708,1629,1601,1568,1587,1473,1411,1214,1162,1115,1073,997,870,834,772,679,664,452,426.MS(ESI)m/z626.0(M+H) +,628.0(M+2+H) +.
Embodiment 7: containing the preparation of triazole Huan oxadiazole compounds VI-2-1
1) operation is as embodiment 1 step 1
2) operation is as embodiment 1 step 2
3) operation is as embodiment 1 step 3
4) compound V (1mmol) is dissolved in to 10mL THF:H 2in O=1:1 (volume ratio), add successively CuSO 4.5H 2o (0.05mmol) and xitix (Vc, 0.15mmol), add 1-azido-ethyl propionate (1.5mmol) after stirring and dissolving, stirring at normal temperature reaction 6h, and reaction process detects and follows the trail of with TLC, reacts complete cooling rear concentrated solvent, uses CH 2cl 2extraction (3 * 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO 4dry, 30 ℃ of evaporation concentration obtain containing triazole Huan oxadiazole compound VI-2-1. productive rate 86% after thin-layer chromatography separation and purification.Characterization of The Products result is as follows:
1H?NMR(400MHz,CDCl 3)δ7.81-7.58(m,2H),7.61(t,J＝7.7Hz,1H),7.50-7.32(m,3H),7.34-7.21(m,3H),7.03(s,1H),6.49-6.48(m,1H),5.42-5.26(m,2H),5.16(dd,J＝20.4,2.4Hz,1H),4.31-4.21(m,4H),2.38-2.20(m,2H),1.94(s,3H),1.87(d,J＝11.5Hz,3H),0.94(t,J＝20.1Hz,3H)；IRν max(cm -1):3347,3155,2965,1708,1551,1530,1494,1454,1379,1309,1255,1132,1114,1082,970,896,788,764,724,660,452,440.MS(ESI)m/z572.1(M+H) +.
Embodiment 8: containing the preparation of triazole Huan oxadiazole compounds VI-2-2
1) operation is as embodiment 1 step 1;
2) operation is as embodiment 1 step 2;
3) operation is as embodiment 1 step 3;
4) compound V (1mmol) is dissolved in to 10mL THF:H 2in O=1:1 (volume ratio), add successively CuSO 4.5H 2o (0.10mmol) and xitix (Vc, 0.25mmol), add 4-triazoacetic acid methyl esters (1.6mmol) after stirring and dissolving, stirring at normal temperature reaction 7h, and reaction process detects and follows the trail of with TLC, reacts complete cooling rear concentrated solvent, uses CH 2cl 2extraction (3 * 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO 4dry, 30 ℃ of evaporation concentration obtain containing triazole Huan oxadiazole compound VI-2-2. productive rate 82.5% after thin-layer chromatography separation and purification.Characterization of The Products result is as follows:
1H?NMR(400MHz,CDCl 3)δ7.96-7.74(m,2H),7.76-7.60(m,2H),7.65-7.50(m,2H),7.52-7.29(m,3H),7.32-7.18(m,1H),6.59(d,J＝6.8Hz,1H),5.22(s,2H),4.82(dd,J＝10.8,5.3Hz,1H),2.07(s,3H),1.45-1.43(m,2H),1.76(d,J＝7.0Hz,3H),0.97(s,3H)；IRν max(cm -1):3639,3147,2922,1738,1511,1466,1436,1394,1364,1319,1252,1234,1123,1058,973,922,890,871,796,769,722,622,450,420.MS(ESI)m/z544.1(M+H) +.
Embodiment 9: containing the preparation of triazole Huan oxadiazole compounds VI-2-3
Operation is as embodiment 1 step 1;
1) operation is as embodiment 1 step 2;
2) operation is as embodiment 1 step 3;
4) compound V (1mmol) is dissolved in to 10mL THF:H 2in O=1:1 (volume ratio), add successively CuSO 4.5H 2o (0.05mmol) and xitix (Vc, 0.15mmol), add 4-azido-methyl propionate (1.5mmol) after stirring and dissolving, stirring at normal temperature reaction 8h, and reaction process detects and follows the trail of with TLC, reacts complete cooling rear concentrated solvent, uses CH 2cl 2extraction (3 * 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO 4dry, 30 ℃ of evaporation concentration obtain containing triazole Huan oxadiazole compound VI-2-3 productive rate 81.8% after thin-layer chromatography separation and purification.Characterization of The Products result is as follows:
1H?NMR(400MHz,CDCl 3)δ8.22(d,J＝1.9Hz,2H),7.94(d,J＝8.0Hz,2H),7.63-7.58(m,2H),7.58-7.53(m,3H),7.10-7.06(m,1H),6.52-6.50(m,1H),5.25-5.21(m,2H),5.65(s,2H),4.68(dd,J＝12.6,8.4Hz,1H),2.28(s,3H),1.76(s,2H),1.34-1.32(m,3H),1.01-0.98(m,3H)；IRν max(cm -1):3287,2981,1768,1741,1500,1455,1384,1316,1271,1250,1189,1144,1098,1055,1020,976,879,806,754,722,618,520,480.MS(ESI)m/z558.1(M+H) +.
Embodiment 10: containing the preparation of triazole Huan oxadiazole compounds VI-2-4
1) operation is as embodiment 1 step 1;
2) operation is as embodiment 1 step 2;
3) operation is as embodiment 1 step 3;
4) compound V (1mmol) is dissolved in to 10mL THF:H 2in O=1:1 (volume ratio), add successively CuSO 4.5H 2o (0.05mmol) and xitix (Vc, 0.15mmol), add triazobenzene (1.5mmol) after stirring and dissolving, stirring at normal temperature reaction 8h, and reaction process detects and follows the trail of with TLC, reacts complete cooling rear concentrated solvent, uses CH 2cl 2extraction (3 * 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO 4dry, 30 ℃ of evaporation concentration obtain containing triazole Huan oxadiazole compound VI-2-4. productive rate 86.9% after thin-layer chromatography separation and purification.Characterization of The Products result is as follows:
1H?NMR(400MHz,CDCl 3)δ8.22-7.93(m,4H),7.70-7.67(m,4H),7.58(d,J＝7.9Hz,2H),7.43-7.38(m,4H),7.09(s,1H),5.81-5.80(m,1H),5.43(s,2H),3.98(dd,J＝18.6,9.8Hz,1H),2.48(s,3H),1.48(d,J＝6.8Hz,3H)；IRν max(cm -1):3059,2953,2925,1787,1707,1552,1546,1493,1438,1405,1349,1210,1188,1012,987,865,745,695,626,525,420.MS(ESI)m/z548.1(M+H) +.
Embodiment 11: containing the preparation of triazole Huan oxadiazole compounds VI-2-5
1) operation is as embodiment 1 step 1;
2) operation is as embodiment 1 step 2;
3) operation is as embodiment 1 step 3;
4) compound V (1mmol) is dissolved in to 10mL THF:H 2in O=1:1 (volume ratio), add successively CuSO 4.5H 2o (0.05mmol) and xitix (Vc, 0.15mmol), add 4-azido-chlorobenzene (1.5mmol) after stirring and dissolving, stirring at normal temperature reaction 8h, and reaction process detects and follows the trail of with TLC, reacts complete cooling rear concentrated solvent, uses CH 2cl 2extraction (3 * 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO 4dry, 30 ℃ of evaporation concentration obtain containing triazole Huan oxadiazole compound VI-2-5. productive rate 87% after thin-layer chromatography separation and purification.Characterization of The Products result is as follows:
1H?NMR(400MHz,CDCl 3)δ8.12(s,1H),7.90(d,J＝8.5Hz,2H),7.49-7.35(m,5H),7.24(m,3H),7.07(d,J＝7.7Hz,2H),6.98(s,1H),5.71(d,J＝4.1Hz,1H),5.42(s,2H),4.38(dd,J＝16.2,8.6Hz,1H),2.82(s,3H),1.49-1.45(m,3H)；IRν max(cm -1):3061,2951,1738,1707,1566,1545,1492,1438,1409,1352,1218,1114,1070,937,862,737,693,674,525,468.MS(ESI)m/z582.1(M+H) +,584.1(M+H) +.
Embodiment 12: containing the preparation of triazole Huan oxadiazole compounds VI-2-6
1) operation is as embodiment 1 step 1;
2) operation is as embodiment 1 step 2;
3) operation is as embodiment 1 step 3;
4) compound V (1mmol) is dissolved in to 10mL THF:H 2in O=1:1 (volume ratio), add successively CuSO 4.5H 2o (0.10mmol) and xitix (Vc, 0.25mmol), add nitrine toluene (1.5mmol) after stirring and dissolving, stirring at normal temperature reaction 8h, and reaction process detects and follows the trail of with TLC, reacts complete cooling rear concentrated solvent, uses CH 2cl 2extraction (3 * 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO 4dry, 30 ℃ of evaporation concentration obtain containing triazole Huan oxadiazole compound VI-2-6 productive rate 86.1% after thin-layer chromatography separation and purification.Characterization of The Products result is as follows:
1H?NMR(400MHz,CDCl 3)δ8.24(d,J＝7.9Hz,1H),7.95(d,J＝8.3Hz,2H),7.73-7.68(m,1H),7.63(s,1H),7.59(d,J＝8.3Hz,2H),7.45-7.42(m,2H),7.32-7.38(m,5H),7.23-7.19(m,1H),5.64-5.62(m,1H),5.42(s,2H),4.99-4.96(m,2H),3.98(dd,J＝21.4,12.6Hz,1H),2.81(s,3H).1.28-1.21(m,3H)；IRν max(cm -1):3066,2950,2941,1787,1708,1551,1540,1444,1405,1349,1218,1116,1009,927,865,715,695,653,586,480.MS(ESI)m/z562.1(M+H) +.
Embodiment 13: monoamine oxidase inhibitory activity detects
(1) sample preparation
By the compound (VI-1) of embodiment 1～12 preparation～(VI-12) be dissolved in dimethyl sulfoxide (DMSO) (DMSO), be made into respectively 10,50,75,100, the sample liquid of 150mmol/L concentration gradient, be designated as sample 1～12.
(2) bis-heterocyclic compounds (VI) replacing containing phenylseleno suppresses activity test method to monoamine oxidase-A
To 12 parts, the sample 1～12 that adds 10 μ L (concentration 5mg/mL) monoamine oxidase-A (MAO-A) and 4 μ L steps (1) to prepare in the EP pipe of 381 μ L borate buffers (pH=8.4) is housed respectively, mix, again mixture is reacted to 3h in 38 ℃ of water-baths, then respectively again to the bovine serum albumin (BSA that adds (the amino propoxy-of the 3-)-4-methylcoumarin (20mmol/ml) of the probe 7-shown in 2.5 μ L formulas (XII) and 2.5 μ L in above-mentioned 12 parts of EP pipes, concentration 60mg/mL), and by EP pipe be placed on continuation reaction 3h in 38 ℃ of water-baths.Need to detect the not enzyme of the enzyme of inhibiting with it lives simultaneously, to being equipped with in the EP pipe of 385 μ L borate buffers (pH=8.4), add 10 μ L monoamine oxidase-A (MAO-A), in 38 ℃ of water-baths, react 3h, then add the BSA of 2.5 μ L probes (20mmol/ml) and 2.5 μ L equally also in 38 ℃ of water-baths, to react 3h.
Finally in each EP pipe (Eppendorf tube), taking-up 100 μ L also detect sample with global function spectrophotofluorometer (λ ex/ λ em=365/460nm) (spectraMax M, U.S. molecule instrument company) in adding 96 orifice plates.According to the IC of surveyed fluorescent value calculation sample 1～12 50, compound (VI-1)～(VI-12) monoamine oxidase-A activity is suppressed to test result in Table 1.
Half-inhibition concentration (the IC for inhibition of compound 50) represent.IC 50refer to the concentration of " reaction " suppressed half inhibitor, it is stronger that compound suppresses ability, and this numerical value is lower.
IC 50can calculate with following methods:
1) detect and calculate the only average fluorescent strength (F of enzyme-added and probe damping fluid m);
2) calculate the average fluorescent strength (wanting background correction value) of each component enzymes that contains different concns gradient inhibitor;
3) according to the fluorescence intensity of each component enzymes of different concns gradient inhibitor, do the straight-line regression of relation between the concentration (C) of inhibitor and fluorescence intensity (F), set up and obtain equation: F=aC+b (determine equation coefficient a and cut the b that crouches by regression straight line);
4), according to equation, ask F=1/2F munder corresponding inhibitor concentration, the inhibitor concentration in the time of can obtaining inhibiting rate and be 50%, is IC 50.
(3) bis-heterocyclic compounds (VI) replacing containing phenylseleno suppresses active testing to monoamine oxidase-B
Change MAO-A into MAO-B, other operate same step (2), the results are shown in Table 1.
The bis-heterocyclic compounds (VI) replacing containing phenylseleno of table 1 embodiment 1～12 preparation is active to the inhibition of monoamine oxidase A and B
A: suppress activity IC 50represent, each sample is done 3 parallel group, gets 5 concentration gradients;
B: the selectivity to enzyme represents with SI, SI:selectivity index=IC 50(MAO-A)/IC 50(MAO-B)
c:ND:too?large?that?were?not?detected(>1.0mM).
As can be seen from Table 1, compound (VI-1-1)～(VI-1-5) and (VI-2-1)～(VI-2-6) has and suppresses active monoamine oxidase A, and wherein compound (VI-1-1)～(VI-1-5) has stronger inhibition active; Compound (VI-1-1)～(VI-1-6) and (VI-2-1)～(VI-2-6) has and suppresses active monoamine oxidase-B, wherein compound (VI-1-1)～(VI-1-6) and (VI-2-2)～(VI-2-6) has stronger inhibition active, and particularly compound (VI-1-1)～(VI-1-5) has extremely strong inhibition active.

Claims (10)

1. the bis-heterocyclic compounds replacing containing phenylseleno, its structure is suc as formula shown in (VI):
Wherein, R is selected from the group shown in formula (VII) or formula (VIII):
In formula (VII), R 1for aryl;
In formula (VIII), R 2be selected from one of following groups:
aryl, benzyl;
Described aryl is not substituted or by one or more replacements in following groups: the alkoxyl group of the alkyl of C1-C3, halogen, C1-C3, trifluoromethyl;
R 3, R 4, R 5, R 6independently be selected from separately the alkyl of C1-C6.
2. the bis-heterocyclic compounds replacing containing phenylseleno as claimed in claim 1, is characterized in that: R 1for not being substituted or by the alkoxyl group of the alkyl of the phenyl of one or more replacements in following groups: C1-C3, halogen, C1-C3, trifluoromethyl.
3. the bis-heterocyclic compounds replacing containing phenylseleno as claimed in claim 1 or 2, is characterized in that: R 2be selected from one of following groups:
phenyl, the phenyl that halogen replaces, benzyl.
4. the bis-heterocyclic compounds replacing containing phenylseleno as claimed in claim 3, is characterized in that: R 3, R 4, R 5, R 6independently be selected from separately the alkyl of C1-C4.
5. the bis-heterocyclic compounds replacing containing phenylseleno as claimed in claim 3, is characterized in that: described halogen is F, Cl or Br.
6. the bis-heterocyclic compounds replacing containing phenylseleno as claimed in claim 1, is characterized in that: the described bis-heterocyclic compounds replacing containing phenylseleno is one of following:
7. a method of preparing the bis-heterocyclic compounds replacing containing phenylseleno as claimed in claim 1, the structure of the described bis-heterocyclic compounds replacing containing phenylseleno is suc as formula shown in (VI-1), and described method comprises:
(1) preparation of the intermediate product containing phenylseleno shown in formula III:
In reaction vessel, add the para hydroxybenzene hydrazine shown in the positive propionic aldehyde of α-phenylseleno shown in organic solvent B, formula (II) and formula (VII), after making it to dissolve completely, add acetic acid, then back flow reaction 1-3 hour under nitrogen protection, reacts completely and obtains the intermediate product containing phenylseleno shown in formula (III) by separation and purification;
(2) preparation containing phenylseleno oxadiazole compounds shown in formula IV:
In reaction vessel, add shown in formula (III) containing intermediate product and the diacetyl oxide of phenylseleno, after completion of the reaction through separation and purification obtain shown in formula IV containing phenylseleno oxadiazole compounds;
(3) preparation containing terminal triple link oxadiazole compounds shown in formula (V):
In reaction vessel, add shown in organic solvent C, formula IV containing phenylseleno oxadiazole compounds, salt of wormwood, under stirring, slowly add propargyl bromide, under nitrogen protection, back flow reaction is 3～5 hours, obtains the oxadiazole compounds containing terminal triple link shown in formula (V) after completion of the reaction through separation and purification;
(4) preparation of the bis-heterocyclic compounds replacing containing phenylseleno shown in formula (VI-1):
Make the oxime compounds shown in formula (X) and N-chlorosuccinimide (NCS) room temperature reaction 4-5 hour in organic solvent D, then add reacting 5～8 hours containing terminal triple link oxadiazole compounds and triethylamine shown in formula (V), react completely and obtain the bis-heterocyclic compounds replacing containing phenylseleno shown in formula (VI-1) by separation and purification;
In formula (X), R 1definition cotype (VI-1).
8. a method of preparing the bis-heterocyclic compounds replacing containing phenylseleno as claimed in claim 1, the structure of the described bis-heterocyclic compounds replacing containing phenylseleno is suc as formula shown in (VI-2), and described method comprises:
(a) preparation of the intermediate product containing phenylseleno shown in formula III:
In reaction vessel, add the para hydroxybenzene hydrazine shown in the positive propionic aldehyde of α-phenylseleno shown in organic solvent B, formula (II) and formula (VII), after making it to dissolve completely, add acetic acid, then back flow reaction 1-3 hour under nitrogen protection, reacts completely and obtains the intermediate product containing phenylseleno shown in formula (III) by separation and purification;
(b) preparation containing phenylseleno oxadiazole compounds shown in formula IV:
In reaction vessel, add shown in formula (III) containing intermediate product and the diacetyl oxide of phenylseleno, after completion of the reaction through separation and purification obtain shown in formula IV containing phenylseleno oxadiazole compounds;
(c) preparation containing terminal triple link oxadiazole compounds shown in formula (V):
In reaction vessel, add shown in organic solvent C, formula IV containing phenylseleno oxadiazole compounds, salt of wormwood, under stirring, slowly add propargyl bromide, under nitrogen protection, back flow reaction is 3～5 hours, obtains the oxadiazole compounds containing terminal triple link shown in formula (V) after completion of the reaction through separation and purification;
(d) preparation of the bis-heterocyclic compounds replacing containing phenylseleno shown in formula (VI-2):
Make being dissolved in solvent E containing terminal triple link oxadiazole compounds shown in formula (V), add successively cupric sulfate pentahydrate and xitix, after stirring and dissolving, add the triazo-compound shown in formula (XI), stirring at room reaction 6-8 hour, reacts completely and obtains the bis-heterocyclic compounds replacing containing phenylseleno shown in formula (VI-2) by separation and purification;
In formula (XI), R 2definition cotype (VI-2).
9. the application of the bis-heterocyclic compounds replacing containing phenylseleno as claimed in claim 1 in preparation oxidase inhibitor.
10. application as claimed in claim 9, is characterized in that: described oxidase inhibitor is MAO-B inhibitor.
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