CN104003983B - Containing the substituted bis-heterocyclic compounds of phenylseleno and preparation and application thereof - Google Patents

Containing the substituted bis-heterocyclic compounds of phenylseleno and preparation and application thereof Download PDF

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CN104003983B
CN104003983B CN201410234882.8A CN201410234882A CN104003983B CN 104003983 B CN104003983 B CN 104003983B CN 201410234882 A CN201410234882 A CN 201410234882A CN 104003983 B CN104003983 B CN 104003983B
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phenylseleno
heterocyclic compounds
substituted bis
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CN104003983A (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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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic 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
    • C07D417/14Heterocyclic 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 kind of containing the substituted bis-heterocyclic compounds of phenylseleno and preparation and application thereof, shown in described structure such as formula (VI 1) containing the substituted bis-heterocyclic compounds of phenylseleno or formula (VI 2), its synthetic route is as follows.The described substituted bis-heterocyclic compounds containing phenylseleno has good monoamine oxidase inhibitory activity, can be used for preparing MAOI.

Description

Containing the substituted bis-heterocyclic compounds of phenylseleno and preparation and application thereof
1, technical field
The present invention relates to a kind of containing the substituted bis-heterocyclic compounds of phenylseleno and preparation and application thereof, especially its application in preparation MAOI.
2, background technology
The complete entitled monoamine oxidoreducing enzyme of monoamine oxidase (monoamine oxidase, MAO, EC1.4.3.4), was found by Balschko in the 1830's, was a kind of enzyme playing an important role neurotransmitter metabolism.It is catalyzed the amine that some organisms produce in brain and peripheral nerve tissue, and oxidative deamination produces hydrogen peroxide.Nineteen sixty-eight, Johnston is divided into two subclass of A and B according to monoamine oxidase to the susceptibility of its irreversible inhibitor clorgyline (clorgiline), and MAOA is sensitive to clorgyline, and MAO-B is insensitive.Further study showed that MAOA has high-affinity to substrate thrombocytin (5-HT), norepinephrine (NE), dopamine (DA) and inhibitor clorgyline;MAO-B then has high-affinity (Kuwahara T, etc., Agric.Biol.Chem., 1990,54,253-257.) to phenethyl amine (PEA), benzene methanamine and inhibitor deprenyl (selegiline).
Research shows that monoamine oxidase, during metabolism dopamine, supervenes the endogenous material such as free radical and hydrogen peroxide, and the exception of its expression and Parkinson's, depression and aggression have extremely close relationship.Along with the gradually quickening of people's rhythm of life, stress is continuously increased, and the incidence of disease of depression rises the most rapidly, it is contemplated that to the year two thousand twenty, will become the second largest disease being only second to coronary heart disease in the world.The initiation of this disease may be relevant with the exception of monoamine oxidase (MAO), and the medicine of MAOI (MAOI) to be a class specifically suppress internal MAO activity, once the fifties first being used to treat depression.Its mechanism is that in minimizing central nervous system, the degraded of monoamine neurotransmitter, increases the concentration of maincenter monoamine transmitters relatively, improves mood, produces antidepressant effect by suppression MAO.Clinical used monoamine oxidase inhibitor has the nardil (Phenelzine) of hydrazine, isoniazid (Isonicotinyl hydrazide), iproniazid (Iproniazid), Nialamide (Nialamide,) etc., non-hydrazine with parnitene (Tranylcypromine) as representative (Kalgutkar, A.S.Chem.Res.Toxicol., 2001,14 (9), 1139-1162.).Owing to these medicine major part toxic and side effects are relatively big and single to the action effect of monoamine oxidase, so seeking low toxicity, respond well MAOI becomes the fresh target of current research.
Nitrogen-containing heterocycle compound all shows the goodst monoamine oxidase inhibitory activity, particularly Mazouz, F. the 1 of report different substituents is waited, 3,4-diazolones compounds derivatives have monoamine oxidase inhibitory activity (Mazouz, F. etc., J Med Chem., 1993,36,6394-63981157-1167).Isoxazole compounds is present in numerous natural products skeletons, is that a class has good biologically active or the material of potential source biomolecule activity, the most gradually becomes important medicine intermediate and lead compound.Such as, isoxazole compounds have the most antibacterial, anti-inflammatory, the BA 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 such as, the compound Isocarboxazid having isoxazole and hydrazides both active groups concurrently is first generation MAOI;Liu Bingni report containing the compound of isoxazole ring show certain monoamine oxidase inhibitory activity (Liu Bingni etc., synthesis chemistry., 2011,19 (6), 734-736.).Isoxazole ring or triazole ring are incorporated into diazole ring by the present invention, have synthesized series of new substituted bis-heterocyclic compounds Han phenylseleno, and they have good monoamine oxidase inhibitory activity, are that a good monoamine oxidase of class presses down agent (MAOIs).
3, summary of the invention
First purpose of the present invention be to provide a kind of have good monoamine oxidase inhibitory activity containing the substituted bis-heterocyclic compounds of phenylseleno.
Second object of the present invention is to provide a kind of method described in preparation containing the substituted heterocyclic compound of phenylseleno.
Third object of the present invention is to provide the described application containing the substituted bis-heterocyclic compounds of phenylseleno in preparation MAOI.
Below the technical scheme used for realizing the object of the invention is illustrated.
The invention provides a kind of substituted bis-heterocyclic compounds Han phenylseleno, shown in its structure such as formula (VI):
Wherein, R is selected from the group shown in formula (VIII) or formula (Ⅸ):
In formula (VIII), R1For aryl;
In formula (Ⅸ), R2Selected from one of following groups:
Aryl, benzyl;
Described aryl is unsubstituted or is replaced by one or more in following groups: the alkyl of C1-C3, halogen, the alkoxyl of C1-C3, trifluoromethyl;
R3、R4、R5、R6It is each independently selected from the alkyl of C1-C6.
Concrete, the substituted bis-heterocyclic compounds containing phenylseleno of the present invention can be divided into two categories below:
Further, R1For unsubstituted or by following groups one or more replace phenyl: the alkyl of C1-C3, halogen, the alkoxyl of C1-C3, trifluoromethyl.
Further, R2Selected from one of following groups:
Phenyl, the phenyl of halogen substiuted, benzyl.
Further, R3、R4、R5、R6It is each independently selected from the alkyl of C1-C4.
Further, R2Selected from one of following groups:
Phenyl, the phenyl of halogen substiuted, benzyl.
Further, described halogen is F, Cl or Br.
The most further, the described substituted bis-heterocyclic compounds containing phenylseleno is one of following:
Present invention also offers a kind of method containing the substituted bis-heterocyclic compounds of phenylseleno shown in formula (VI-1), described method includes:
(1) preparation of the intermediate product containing phenylseleno shown in formula (III):
The positive propionic aldehyde of α-phenylseleno shown in organic solvent B, formula (II) and the para hydroxybenzene hydrazine shown in formula (VII) is added in reaction vessel; acetic acid is added after being allowed to be completely dissolved; back flow reaction 1-3 hour the most under nitrogen protection, obtains the intermediate product containing phenylseleno shown in formula (III) through isolated and purified after reaction completely;
(2) preparation of the diazoles compound containing phenylseleno shown in formula (IV):
Adding the intermediate product containing phenylseleno shown in formula (III) and acetic anhydride in reaction vessel, the most separated purifying obtains the diazoles compound containing phenylseleno shown in formula (IV);
(3) preparation of the diazoles compound containing terminal triple link shown in formula (V):
The diazoles compound containing phenylseleno shown in organic solvent C, formula (IV), potassium carbonate is added in reaction vessel; it is slowly added to propargyl bromide under stirring; back flow reaction 3~5 hours under nitrogen protection, the most separated purifying obtains the diazoles compound containing terminal triple link shown in formula (V);
(4) preparation containing the substituted bis-heterocyclic compounds of phenylseleno shown in formula (VI-1):
Make the oxime compound shown in formula (X) and N-chlorosuccinimide (NCS) room temperature reaction 4-5 hour in organic solvent D, be subsequently adding the diazoles compound containing terminal triple link shown in formula (V) and triethylamine to react 5~8 hours, after reaction completely through isolated and purified obtain shown in formula (VI-1) containing the substituted bis-heterocyclic compounds of phenylseleno;
In formula (X), R1The same formula of definition (VI-1).
Further, in step (1), organic solvent B is selected from one of following: ethanol, oxolane, acetonitrile.
Further, in step (1), the molar ratio to hydroxyl hydrazides, acetic acid shown in the positive propionic aldehyde of α-phenylseleno, formula (VII) is 1:1:10~15.
Further, in step (2), the addition volume of acetic anhydride is calculated as (4~6) mL/mmol with the molal quantity of the intermediate product containing phenylseleno shown in formula (III).
Further, in step (2), the reaction time was at 3~4 hours.
Further, in step (3), organic solvent C is selected from one of following: acetone, DMF.
Further, in step (3), the diazoles compound containing phenylseleno shown in formula (IV) is 1:1~1.3:1.2~1.5 with potassium carbonate, the molar ratio of propargyl bromide.
Further, in step (4), organic solvent D is selected from one of following: dichloromethane, chloroform, oxolane.
Further, in step (4), the oxime compound shown in the diazoles compound containing terminal triple link shown in formula (V), formula (X), N-chlorosuccinimide, the molar ratio of triethylamine are 1:1.5~2:1.5~2:2~3.
Present invention also offers a kind of method containing the substituted bis-heterocyclic compounds of phenylseleno shown in formula (VI-2), described method includes:
The preparation of the intermediate product containing phenylseleno shown in (a) formula (III):
The positive propionic aldehyde of α-phenylseleno shown in organic solvent B, formula (II) and the para hydroxybenzene hydrazine shown in formula (VII) is added in reaction vessel; acetic acid is added after being allowed to be completely dissolved; back flow reaction 1-3 hour the most under nitrogen protection, obtains the intermediate product containing phenylseleno shown in formula (III) through isolated and purified after reaction completely;
The preparation of the diazoles compound containing phenylseleno shown in (b) formula (IV):
Adding the intermediate product containing phenylseleno shown in formula (III) and acetic anhydride in reaction vessel, the most separated purifying obtains the diazoles compound containing phenylseleno shown in formula (IV);
The preparation of the diazoles compound containing terminal triple link shown in (c) formula (V):
The diazoles compound containing phenylseleno shown in organic solvent C, formula (IV), potassium carbonate is added in reaction vessel; it is slowly added to propargyl bromide under stirring; back flow reaction 3~5 hours under nitrogen protection, the most separated purifying obtains the diazoles compound containing terminal triple link shown in formula (V);
The preparation containing the substituted bis-heterocyclic compounds of phenylseleno shown in (d) formula (VI-2):
The diazoles compound containing terminal triple link shown in formula (V) is made to be dissolved in solvent E, it is sequentially added into cupric sulfate pentahydrate and ascorbic acid, the azido compound shown in formula (XI) is added after stirring and dissolving, reaction 6-8 hour is stirred at room temperature, after reaction completely through isolated and purified obtain shown in formula (VI-2) containing the substituted bis-heterocyclic compounds of phenylseleno;
In formula (XI), R2The same formula of definition (VI-2).
Step (a)-step (c) is above-mentioned steps (1)-step (3), and it is prepared details and does not repeats them here.
In step (d), solvent E is selected from one of following: THF and the mixed solvent of water, dimethyl sulfoxide.
In step (d), the diazoles compound containing terminal triple link shown in formula (V), cupric sulfate pentahydrate, ascorbic acid, the molar ratio of azido compound are 1:0.05~0.1:0.15~0.25:1.3~1.6.
The positive propionic aldehyde of α-phenylseleno shown in raw material formula (II) that the present invention uses can be prepared by following equation according to the method that existing document is reported:
The substituted bis-heterocyclic compounds containing phenylseleno of the present invention has good monoamine oxidase inhibitory activity, especially MAO-B inhibitory activity, therefore can be used for preparing monoamine oxidase (especially MAO-B) inhibitor.
The beneficial effects of the present invention is provide a class new have good monoamine oxidase inhibitory activity containing the substituted bis-heterocyclic compounds of phenylseleno.
4, detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited to that:
The synthesis of the embodiment 1 diazoles compound derivatives VI-1-1. containing isoxazole
1) by the α of equivalent-phenylseleno propionic aldehyde (0.213g; 1mmol) adding in the round-bottomed flask containing 20ml ethanol with para hydroxybenzene hydrazine (1mmol, 0.152g), stirring is allowed to be completely dissolved; add 800 μ L acetic acid, back flow reaction 3h under nitrogen protection.After TLC detection reaction completely, drain ethanol, add 20mLCH2Cl2, use saturated Na2CO3Solution (3 × 20mL) solution washing, anhydrous Na2SO4It is dried, concentrates, obtain intermediate product (III) crude product containing phenylseleno.
2) being joined by the product (III) (1mmol) obtained in the acetic anhydride of 5mL, heating reflux reaction 3h under nitrogen protection, solution colour becomes salmon pink and has suspension to generate.After TLC detection reaction completely, drain acetic anhydride, add 20mLCH2Cl2, use saturated Na2CO3Solution (3 × 20mL) solution washing removes the acetic anhydride do not drained, then uses anhydrous Na2SO4It is dried, concentrates, through thin plate chromatography isolated product (IV), productivity 75%.
3) 1mmol (0.390g) compounds Ⅳ is dissolved in 20mL acetone; add (1.5mmol, 0.207g) potassium carbonate, under stirring, be slowly added to (1.2mmol; 0.143g) propargyl bromide, under nitrogen protection back flow reaction 3h.After TLC detection reaction completely, drain acetone, add 20mLCH2Cl2, use saturated Na2CO3Solution (3 × 20mL) solution washing, anhydrous Na2SO4It is dried, concentrates, after thin plate chromatographs, obtain compound V.
4) first the NCS (2mmol, 0.268g) of methylbenzene oxime (2mmol, 0.272g) Yu equivalent will be dissolved in 20mLCH2Cl2At room temperature react 4h, add compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) and react 6 hours, after TLC detection major part reaction completely, add saturated sodium-chloride layering, organic phase saturated sodium-chloride washing (30mL × 3), organic phase anhydrous magnesium sulfate is dried, and concentrates, thin plate chromatographs to obtain VI-1-1., productivity 82.5%.Characterization of The Products method:1H NMR by Bruker Avance nmr determination,13C NMR, by Bruker Avance nmr determination, uses CDCl3Making solvent, TMS makees internal standard.FT-IR is used KBr pressed disc method by Bruker Tensor27 type determination of infrared spectroscopy, solid, and liquid uses liquid-film method.Result is as follows:
1H NMR(400MHz,CDCl31H NMR(400MHz,CDCl3) δ 7.70 (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) .IR νmax(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)+.
The synthesis of the embodiment 2 diazoles compound derivatives VI-1-2. containing isoxazole
1) operation is such as embodiment 1 step 1
2) operation is such as embodiment 1 step 2
3) operation is such as embodiment 1 step 3
4) first the NCS (2mmol, 0.268g) of methoxybenzene oxime (2mmol, 0.288g) Yu equivalent will be dissolved in 20mLCH2Cl2At room temperature react 3h, add compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) react 6 hours, after TLC detection major part reaction completely, subsequent treatment such as embodiment 1 step 4, VI-1-2., productivity 85% is chromatographed to obtain through thin plate.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 7.75-7.72 (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);IRνmax(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)+.
The synthesis of the embodiment 3 diazoles compound derivatives VI-1-3. containing isoxazole
1) operation is such as embodiment 1 step 1
2) operation is such as embodiment 1 step 2
3) operation is such as embodiment 1 step 3
4) first the NCS (2mmol, 0.268g) of chlorobenzene oxime (2mmol, 0.313g) Yu equivalent will be dissolved in 20mLCH2Cl2At room temperature react 3h, add compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) react 6 hours, after TLC detection major part reaction completely, subsequent treatment such as embodiment 1 step 4, VI-1-3., productivity 71% is chromatographed to obtain through thin plate.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 7.68-7.60 (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);IRνmax(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)+.
The synthesis of the embodiment 4 diazoles compound derivatives VI-1-4. containing isoxazole
1) operation is such as embodiment 1 step 1
2) operation is such as embodiment 1 step 2
3) operation is such as embodiment 1 step 3
4) first the NCS (2mmol, 0.268g) of fluorobenzene oxime (2mmol, 0.280g) Yu equivalent will be dissolved in 20mLCH2Cl2At room temperature react 3h, add compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) react 6 hours, after TLC detection major part reaction completely, subsequent treatment such as embodiment 1 step 4, VI-1-4., productivity 78% is chromatographed to obtain through thin plate.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 7.75 (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);IRνmax(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)+.
The synthesis of the embodiment 5 diazoles compound derivatives VI-1-5. containing isoxazole
1) operation is such as embodiment 1 step 1
2) operation is such as embodiment 1 step 2
3) operation is such as embodiment 1 step 3
4) first the NCS (2mmol, 0.268g) of trifluoromethylbenzene oxime (2mmol, 0.380g) Yu equivalent will be dissolved in 20mLCH2Cl2At room temperature react 3h, add compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) react 6 hours, after TLC detection major part reaction completely, subsequent treatment such as embodiment 1 step 4, VI-1-5., productivity 72% is chromatographed to obtain through thin plate.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 7.75-7.56 (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);IRνmax(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)+.
The synthesis of the embodiment 6 diazoles compound derivatives VI-1-6. containing isoxazole
1) operation is such as embodiment 1 step 1
2) operation is such as embodiment 1 step 2
3) operation is such 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 20mLCH2Cl2At room temperature react 3h, add compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) react 6 hours, after TLC detection major part reaction completely, subsequent treatment such as embodiment 1 step 4, VI-1-6., productivity 76% is chromatographed to obtain through thin plate.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 7.99-7.93 (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);IRνmax(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: the preparation of the diazoles compound VI-2-1 containing triazole ring
1) operation is such as embodiment 1 step 1
2) operation is such as embodiment 1 step 2
3) operation is such as embodiment 1 step 3
4) compound V (1mmol) is dissolved in 10mL THF:H2In O=1:1 (volume ratio), it is sequentially added into CuSO4.5H2O (0.05mmol) and ascorbic acid (Vc, 0.15mmol), add 1-azido ethyl propionate (1.5mmol) after stirring and dissolving, stirring at normal temperature reaction 6h, course of reaction TLC detection is followed the trail of, and reacts concentrated solvent after complete cooling, uses CH2Cl2Extraction (3 × 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO4It is dried, 30 DEG C of evaporation and concentration, after thin-layer chromatography is isolated and purified, obtains the diazole compounds VI-2-1. containing triazole ring, productivity 86%.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 7.81-7.58 (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);IRνmax(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: the preparation of the diazoles compound VI-2-2 containing triazole ring
1) operation is such as embodiment 1 step 1;
2) operation is such as embodiment 1 step 2;
3) operation is such as embodiment 1 step 3;
4) compound V (1mmol) is dissolved in 10mL THF:H2In O=1:1 (volume ratio), it is sequentially added into CuSO4.5H2O (0.10mmol) and ascorbic acid (Vc, 0.25mmol), add 4-triazoacetic acid methyl esters (1.6mmol) after stirring and dissolving, stirring at normal temperature reaction 7h, course of reaction TLC detection is followed the trail of, and reacts concentrated solvent after complete cooling, uses CH2Cl2Extraction (3 × 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO4It is dried, 30 DEG C of evaporation and concentration, after thin-layer chromatography is isolated and purified, obtains the diazole compounds VI-2-2. containing triazole ring, productivity 82.5%.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 7.96-7.74 (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);IRνmax(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: the preparation of the diazoles compound VI-2-3 containing triazole ring
Operation is such as embodiment 1 step 1;
1) operation is such as embodiment 1 step 2;
2) operation is such as embodiment 1 step 3;
4) compound V (1mmol) is dissolved in 10mL THF:H2In O=1:1 (volume ratio), it is sequentially added into CuSO4.5H2O (0.05mmol) and ascorbic acid (Vc, 0.15mmol), add 4-azido methyl propionate (1.5mmol) after stirring and dissolving, stirring at normal temperature reaction 8h, course of reaction TLC detection is followed the trail of, and reacts concentrated solvent after complete cooling, uses CH2Cl2Extraction (3 × 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO4It is dried, 30 DEG C of evaporation and concentration, after thin-layer chromatography is isolated and purified, obtains the diazole compounds VI-2-3 containing triazole ring, productivity 81.8%.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 8.22 (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);IRνmax(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: the preparation of the diazoles compound VI-2-4 containing triazole ring
1) operation is such as embodiment 1 step 1;
2) operation is such as embodiment 1 step 2;
3) operation is such as embodiment 1 step 3;
4) compound V (1mmol) is dissolved in 10mL THF:H2In O=1:1 (volume ratio), it is sequentially added into CuSO4.5H2O (0.05mmol) and ascorbic acid (Vc, 0.15mmol), add triazobenzene (1.5mmol), stirring at normal temperature reaction 8h after stirring and dissolving, course of reaction TLC detection is followed the trail of, and reacts concentrated solvent after complete cooling, uses CH2Cl2Extraction (3 × 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO4It is dried, 30 DEG C of evaporation and concentration, after thin-layer chromatography is isolated and purified, obtains the diazole compounds VI-2-4. containing triazole ring, productivity 86.9%.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 8.22-7.93 (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);IRνmax(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: the preparation of the diazoles compound VI-2-5 containing triazole ring
1) operation is such as embodiment 1 step 1;
2) operation is such as embodiment 1 step 2;
3) operation is such as embodiment 1 step 3;
4) compound V (1mmol) is dissolved in 10mL THF:H2In O=1:1 (volume ratio), it is sequentially added into CuSO4.5H2O (0.05mmol) and ascorbic acid (Vc, 0.15mmol), add 4-azido chlorobenzene (1.5mmol) after stirring and dissolving, stirring at normal temperature reaction 8h, course of reaction TLC detection is followed the trail of, and reacts concentrated solvent after complete cooling, uses CH2Cl2Extraction (3 × 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO4It is dried, 30 DEG C of evaporation and concentration, after thin-layer chromatography is isolated and purified, obtains the diazole compounds VI-2-5. containing triazole ring, productivity 87%.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 8.12 (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);IRνmax(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: the preparation of the diazoles compound VI-2-6 containing triazole ring
1) operation is such as embodiment 1 step 1;
2) operation is such as embodiment 1 step 2;
3) operation is such as embodiment 1 step 3;
4) compound V (1mmol) is dissolved in 10mL THF:H2In O=1:1 (volume ratio), it is sequentially added into CuSO4.5H2O (0.10mmol) and ascorbic acid (Vc, 0.25mmol), add nitrine toluene (1.5mmol), stirring at normal temperature reaction 8h after stirring and dissolving, course of reaction TLC detection is followed the trail of, and reacts concentrated solvent after complete cooling, uses CH2Cl2Extraction (3 × 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO4It is dried, 30 DEG C of evaporation and concentration, after thin-layer chromatography is isolated and purified, obtains the diazole compounds VI-2-6 containing triazole ring, productivity 86.1%.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 8.24 (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);IRνmax(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
The compound (VI-1)~(VI-12) that embodiment 1~12 are prepared are dissolved in dimethyl sulfoxide (DMSO) (DMSO), be made into 10 respectively, 50,75,100, the sample liquid of 150mmol/L concentration gradient, be designated as sample 1~12.
(2) the substituted bis-heterocyclic compounds Han phenylseleno (VI) is to monoamine oxidase-A inhibitory activity detection method
The sample 1~12 that 10 μ L (concentration 5mg/mL) monoamine oxidase-A (MAO-A) and 4 μ L step (1) prepare is added respectively in 12 parts of EP pipes equipped with 381 μ L borate buffer (pH=8.4), mixing, mixture is reacted in 38 DEG C of water-baths 3h again, state the most again up and 12 parts of EP pipes add probe 7-(3-aminopropan the epoxide)-4-methylcoumarin (20mmol/ml) shown in 2.5 μ L formula (XII) and the bovine serum albumin (BSA of 2.5 μ L, concentration 60mg/mL), and EP pipe is placed in 38 DEG C of water-baths continuation reaction 3h.The enzyme detecting the enzyme of unchecked dose is simultaneously needed to live, in the EP pipe equipped with 385 μ L borate buffer (pH=8.4), i.e. add 10 μ L monoamine oxidase-A (MAO-A), reacting 3h in 38 DEG C of water-baths, the BSA adding 2.5 μ L probe (20mmol/ml) and 2.5 μ L the most also reacts 3h in 38 DEG C of water-baths.
In each EP pipe (microcentrifugal tube), finally take out 100 μ L add in 96 orifice plates and detect sample with global function sepectrophotofluorometer (λ ex/ λ em=365/460nm) (spectraMax M, molecule instrument company of the U.S.).The IC of sample 1~12 is calculated according to the fluorescent value surveyed50, compound (VI-1)~(VI-12) are shown in Table 1 to monoamine oxidase-A activity suppression test result.
The inhibition of compound half-inhibition concentration (IC50) represent.IC50Referring to the concentration of inhibitor when " reaction " is suppressed half, compound rejection ability is the strongest, and this numerical value is the lowest.
IC50Can calculate using the following method:
1) detect and calculate the most enzyme-added and probe buffer solution average fluorescent strength (FM);
2) average fluorescent strength (wanting background correction value) of each component enzymes containing variable concentrations gradient inhibitor is calculated;
3) do the linear regression of relation between the concentration (C) of inhibitor and fluorescence intensity (F) according to the fluorescence intensity of each component enzymes of variable concentrations gradient inhibitor, set up and obtain equation: F=aC+b (determine equation coefficient a by regression straight line and cut the b that crouches);
4) according to equation, F=1/2F is soughtMUnder corresponding inhibitor concentration, can obtain inhibiting rate is inhibitor concentration when 50%, is IC50
(3) monoamine oxidase-B inhibitory activity is tested by the substituted bis-heterocyclic compounds Han phenylseleno (VI)
Changing MAO-A into MAO-B, other operate same step (2), the results are shown in Table 1.
The substituted bis-heterocyclic compounds containing phenylseleno (VI) of table 1 embodiment 1~12 preparation is to MAOA and the inhibitory activity of B
A: inhibitory activity IC50Representing, each sample does 3 parallel group, takes 5 concentration gradients;
B: the selectivity SI of enzyme is represented, SI:selectivity index=IC50(MAO-A)/IC50(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) have inhibitory activity to MAOA, and wherein compound (VI-1-1)~(VI-1-5) have stronger inhibitory activity;Compound (VI-1-1)~(VI-1-6) and (VI-2-1)~(VI-2-6) have inhibitory activity to MAO-B, wherein compound (VI-1-1)~(VI-1-6) and (VI-2-2)~(VI-2-6) have stronger inhibitory activity, particularly compound (VI-1-1)~(VI-1-5) to have extremely strong inhibitory activity.

Claims (8)

1. a substituted bis-heterocyclic compounds Han phenylseleno, shown in its structure such as formula (VI):
Wherein, R is selected from the group shown in formula (VII) or formula (VIII):
In formula (VII), R1For phenyl that is unsubstituted or that replaced by one or more in following groups: C1-C3 Alkyl, halogen, the alkoxyl of C1-C3, trifluoromethyl;
In formula (VIII), R2Selected from one of following groups:
Phenyl, the phenyl of halogen substiuted, benzyl;
R3、R4、R5、R6It is each independently selected from the alkyl of C1-C6.
2. the substituted bis-heterocyclic compounds Han phenylseleno as claimed in claim 1, it is characterised in that: R3、 R4、R5、R6It is each independently selected from the alkyl of C1-C4.
3. the substituted bis-heterocyclic compounds Han phenylseleno as claimed in claim 1, it is characterised in that: described Halogen be F, Cl or Br.
4. the substituted bis-heterocyclic compounds Han phenylseleno as claimed in claim 1, it is characterised in that: described The substituted bis-heterocyclic compounds containing phenylseleno be one of following:
5. prepare the method as claimed in claim 1 containing the substituted bis-heterocyclic compounds of phenylseleno, described Shown in structure such as formula (VI-1) containing the substituted bis-heterocyclic compounds of phenylseleno, in formula (VI-1), R1Definition Same formula (VI), described method includes:
(1) preparation of the intermediate product containing phenylseleno shown in formula (III):
The positive propionic aldehyde of α-phenylseleno shown in organic solvent B, formula (II) and formula (VII) is added in reaction vessel Shown para hydroxybenzene hydrazine, adds acetic acid, the most under nitrogen protection back flow reaction 1-3 after being allowed to be completely dissolved Hour, obtain the intermediate product containing phenylseleno shown in formula (III) through isolated and purified after reaction completely;Described Organic solvent B is selected from one of following: ethanol, oxolane, acetonitrile;
(2) preparation of the diazoles compound containing phenylseleno shown in formula (IV):
In reaction vessel, add the intermediate product containing phenylseleno shown in formula (III) and acetic anhydride, reacted Through the isolated and purified diazoles compound containing phenylseleno obtained shown in formula (IV) after Biing;
(3) preparation of the diazoles compound containing terminal triple link shown in formula (V):
Reaction vessel adds the diazoles compound containing phenylseleno shown in organic solvent C, formula (IV), Potassium carbonate, is slowly added to propargyl bromide under stirring, under nitrogen protection back flow reaction 3~5 hours, has reacted Through the isolated and purified diazoles compound containing terminal triple link obtained shown in formula (V) after Biing;Described organic molten Agent C is selected from one of following: acetone, N,N-dimethylformamide;
(4) preparation containing the substituted bis-heterocyclic compounds of phenylseleno shown in formula (VI-1):
Make the oxime compound shown in formula (X) and N-chlorosuccinimide room temperature in organic solvent D anti- Answer 4-5 hour, be subsequently adding the diazoles compound containing terminal triple link shown in formula (V) and triethylamine is anti- Answer 5~8 hours, after reaction completely through isolated and purified obtain shown in formula (VI-1) substituted double containing phenylseleno Heterocyclic compound;Described organic solvent D is selected from one of following: dichloromethane, chloroform, oxolane;
In formula (X), R1The same formula of definition (VI-1).
6. prepare the method as claimed in claim 1 containing the substituted bis-heterocyclic compounds of phenylseleno, described Shown in structure such as formula (VI-2) containing the substituted bis-heterocyclic compounds of phenylseleno, in formula (VI-2), R2Definition Same formula (VI), described method includes:
The preparation of the intermediate product containing phenylseleno shown in (a) formula (III):
The positive propionic aldehyde of α-phenylseleno shown in organic solvent B, formula (II) and formula (VII) is added in reaction vessel Shown para hydroxybenzene hydrazine, adds acetic acid, the most under nitrogen protection back flow reaction 1-3 after being allowed to be completely dissolved Hour, obtain the intermediate product containing phenylseleno shown in formula (III) through isolated and purified after reaction completely;Described Organic solvent B is selected from one of following: ethanol, oxolane, acetonitrile;
The preparation of the diazoles compound containing phenylseleno shown in (b) formula (IV):
In reaction vessel, add the intermediate product containing phenylseleno shown in formula (III) and acetic anhydride, reacted Through the isolated and purified diazoles compound containing phenylseleno obtained shown in formula (IV) after Biing;
The preparation of the diazoles compound containing terminal triple link shown in (c) formula (V):
Reaction vessel adds the diazoles compound containing phenylseleno shown in organic solvent C, formula (IV), Potassium carbonate, is slowly added to propargyl bromide under stirring, under nitrogen protection back flow reaction 3~5 hours, has reacted Through the isolated and purified diazoles compound containing terminal triple link obtained shown in formula (V) after Biing;Described organic molten Agent C is selected from one of following: acetone, N,N-dimethylformamide;
The preparation containing the substituted bis-heterocyclic compounds of phenylseleno shown in (d) formula (VI-2):
Make the diazoles compound containing terminal triple link shown in formula (V) be dissolved in solvent E, be sequentially added into five Brochanite and ascorbic acid, add the azido compound shown in formula (XI), be stirred at room temperature after stirring and dissolving React 6-8 hour, after reaction completely through isolated and purified obtain shown in formula (VI-2) substituted double containing phenylseleno Heterocyclic compound;Described solvent E is selected from one of following: THF and the mixed solvent of water, dimethyl sulfoxide;
In formula (XI), R2The same formula of definition (VI-2).
7. as claimed in claim 1 press down preparing monoamine oxidase containing the substituted bis-heterocyclic compounds of phenylseleno Application in preparation.
Apply the most as claimed in claim 7, it is characterised in that: described MAOI is MAO-B inhibitor.
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