CN104016938A - Benzeneselenenyl-containing oxadiazole compounds, preparation and application thereof - Google Patents
Benzeneselenenyl-containing oxadiazole compounds, preparation and application thereof Download PDFInfo
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- CN104016938A CN104016938A CN201410231726.6A CN201410231726A CN104016938A CN 104016938 A CN104016938 A CN 104016938A CN 201410231726 A CN201410231726 A CN 201410231726A CN 104016938 A CN104016938 A CN 104016938A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract
The invention discloses benzeneselenenyl-containing oxadiazole compounds, preparation and application thereof. The structural formula of the selenium-containing oxadiazole compounds is shown as a formula (IV), and R is selected from one of the following groups: alkyl, substituted alkyl, aryl, substituted pyrazolyl, benzopyronyl, substituted quinolyl and substituted isoxazolyl. The synthetic route of the benzeneselenenyl-containing oxadiazole compounds is shown in the specification. The benzeneselenenyl-containing oxadiazole compounds have good monoamine-oxidase inhibiting activity and are applicable to prepare monoamine-oxidase inhibitors.
Description
1, technical field
The present invention relates to a kind of preparation and application containing phenylseleno oxadiazole compounds, especially the application in preparation oxidase inhibitor.
2, background technology
Monoamine oxidase (monoamine oxidase, MAO) is a chondrioid membrane bound enzyme, and it is the aminated compounds in catalysis biological body in brain and peripheral nerve tissue, and oxidative deamination generates corresponding aldehyde.Research shows that monoamine oxidase is in the process of metabolism Dopamine HCL, supervene the endogenous material such as free radical and hydrogen peroxide, abnormal and dysthymia disorders, anxiety disorder, Parkinson's disease, Alzheimer and some tumours of its expression amount have extremely close relationship (Kalgutkar, A.S.Chem.Res.Toxicol., 2001,14 (9), 1139-1162.).The inhibitor of some monoamine oxidase has been applied in the middle of the treatment of these diseases at present, for example, Phenelzine, U-10387, Iproniazid, tranylcypromine, moclobemide etc. have been used for the treatment of dysthymia disorders, and Si Lijilan has been used for the treatment of Parkinson's disease, procarbazine has been used for the treatment of tumour, etc.It should be noted that some Chinese medicine also has monoamine oxidase restraining effect, as isatin, pilose antler, hawthorn, Tuber Fleeceflower Root etc.Therefore, the development research of oxidase inhibitor has been become the focus of domestic and international Related Research Domain.
1,3,4-oxadiazole class heterocyclic compounds is present in numerous natural product skeletons, has biological activity very widely, and they are in medical science, material, and the various fields such as agricultural chemicals all have good application prospect.This structure is introduced on different compound skeletons, by structural modification, can generate a series of medicine intermediate (Chimenti that have broad-spectrum biological activity, F etc., J.Med.Chem., 2004, 47, 2071 – 2074.), 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), therefore, 1, 3, 4-oxadiazole rings is that a good monoamine oxidase suppresses parent, the present invention passes through 1, 3, on 4-oxadiazole rings precursor structure, introduce organoselenium, synthetic a series of containing 1 of bioactive molecules selenium, 3, 4-oxadiazole compounds, from this compounds, filter out potential MAO inhibitor.
3, summary of the invention
First object of the present invention be to provide a kind of have good monoamine oxidase inhibitory activity containing phenylseleno oxadiazole compounds.
Second object of the present invention is to provide a kind of described method containing phenylseleno oxadiazole compounds of preparing.
The 3rd object of the present invention is to provide the described application as oxidase inhibitor containing phenylseleno oxadiazole compounds.
The technical scheme that below the present invention adopted for achieving the above object illustrates.
The invention provides a kind of phenylseleno oxadiazole compounds that contains, its structure is suc as formula shown in (IV):
Wherein, R is selected from one of following groups: the pyrazolyl of alkyl, substituted alkyl, aryl, replacement, chromene ketone group, the quinolyl of replacement, the isoxazolyl of replacement; The carbon atom number of described alkyl is 1～12, and described substituted alkyl is by the C1-C12 alkyl of the one or more replacements in following groups: halogen, hydroxyl; Described aryl is not substituted or by the one or more replacements in following groups: the-oxyl of halogen, trifluoromethyl, hydroxyl, C1-C6; The pyrazolyl of described replacement, the quinolyl of replacement or the substituting group replacing in isoxazolyl are that one or more, described substituting groups is independently selected from one of following groups: C1-C6 alkyl, halogen, hydroxyl, be not substituted or the furyl that replaced by halogen, be not substituted or the pyridyl being replaced by halogen, the imidazolyl that is not substituted or is replaced by halogen.Described chromene ketone group is on the pyranoid ring of benzopyrone, to slough the group that a H forms.
Further, described aryl is not preferably substituted or by the phenyl of the one or more replacements in following groups: halogen, trifluoromethyl, hydroxyl.
Further, the carbon atom number of described alkyl is preferably 1～6.
Further, described substituted alkyl is preferably by the C1-C6 alkyl of the one or more replacements in following groups: halogen, hydroxyl.
Further, the preferred Cl of described halogen or Br.
Further, the pyrazolyl of described replacement is preferably replaced or is replaced by C1-C6 alkyl and imidazolyl by the pyridyl of halogen and halogen replacement; The quinolyl of described replacement is preferably replaced by C1-C6 alkyl and hydroxyl; Described replacement isoxazolyl is preferably replaced by furyl.
Further, the-oxyl of described C1-C6 preferably contains alkynyl, and the carbon atom number of the-oxyl that contains alkynyl is 3-6.
Further, one of preferred following groups of R: C1-C6 alkyl; The C1-C6 alkyl being replaced by hydroxyl; Phenyl; The phenyl being replaced by the-oxyl of trifluoromethyl or hydroxyl or the C3-C6 that contains alkynyl; By the pyrazolyl that pyridyl replaced of halogen and halogen replacement; By the pyrazolyl of C1-C6 alkyl and imidazolyl replacement; By furyl, replaced isoxazolyl; By the quinolyl of C1-C6 alkyl and hydroxyl replacement.
Again further, described is one of following containing phenylseleno oxadiazole compounds:
The present invention also provides a kind of described method containing phenylseleno oxadiazole compounds of preparing, and in formula (IV), R is not contained the aryl that the-oxyl of the C3-C6 of alkynyl replaces, and described method comprises:
(1) preparation of the intermediate product containing phenylseleno shown in formula III:
In reaction vessel, add the hydrazides shown in the positive propionic aldehyde of α-phenylseleno shown in organic solvent, formula (II) and formula (V), 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, heating reflux reaction 2-3h under nitrogen protection, after completion of the reaction through separation and purification obtain shown in formula IV containing phenylseleno oxadiazole compounds;
The definition cotype (IV) of R in its Chinese style (V), formula (III).
Further, in step (1), it is one of following that organic solvent is selected from: ethanol, tetrahydrofuran (THF), acetonitrile.
Further, in step (1), the molar ratio of the hydrazides shown in the positive propionic aldehyde of α-phenylseleno, formula (V), acetic acid is 1:1:10～15.
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).
When containing in phenylseleno oxadiazole compounds shown in formula (IV), during aryl that the-oxyl of the C1-C6 that R is contained alkynyl replaces, its preparation method normally first prepares the compound that R is the aryl of hydroxyl replacement, and the alkyl compound that then this compound replaces with halogen again reacts and obtains corresponding target compound.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:
Of the present invention have good monoamine oxidase inhibitory activity containing phenylseleno oxadiazole compounds, especially has good MAO-B and suppress active, therefore can be used for preparing monoamine oxidase (especially MAO-B) inhibitor.
Compared with prior art, beneficial effect of the present invention be to provide a class new have good monoamine oxidase inhibitory activity containing phenylseleno oxadiazole compounds.
4, embodiment
For further understanding the present invention, the following example has been set forth more detailed details.
Embodiment 1 is synthetic containing phenylseleno oxadiazole compounds IV-1
1) by α-phenylseleno propionic aldehyde (0.213g of equivalent; 1mmol) add in the round-bottomed flask that contains 20mL ethanol with acethydrazide V-1 (1mmol, 0.073g), stir and make it to dissolve completely; add again 800 μ L (14mmol) acetic acid, back flow reaction 2h 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 the intermediate product (III-1) containing phenylseleno, productive rate 98%.
2) (III-1) that obtains (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-1).Characterization of The Products method:
1h NMR is by Bruker Avance400MHz nmr determination,
13c NMR, by Bruker Avance100MHz 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.Structural characterization is as follows:
1H?NMR(400MHz,CDCl
3)δ7.54(dd,J＝6.4,2.9Hz,2H),7.25(dd,J＝6.6,3.9Hz,3H),6.07(s,1H),4.04-3.97(m,1H),2.09(s,3H),1.79(s,3H),1.52(d,J＝7.5Hz,3H)；IRν
max(cm
-1):3413,3052,2964,2927,2344,1660,1476,1439,1378,1332,1242,1170,947,958,892,866,739,691,607,588,552,509,467,421.
Embodiment 2 is synthetic containing phenylseleno oxadiazole compounds IV-2
1) α-phenylseleno propionic aldehyde (0.213g of equivalent; 1mmol) add in the round-bottomed flask that contains 20mL ethanol with benzoyl hydrazine V-2 (1mmol, 0.136g), 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, subsequent disposal, as embodiment 1 step 1, obtains the intermediate product (III-2) containing phenylseleno.
2) product obtaining (III-2) (1mmol) joins in the acetic anhydride of 6mL, and subsequent operations and treatment step, as embodiment 1 step 2, obtain product (IV-2), productive rate 82% through thin plate chromatographic separation.Structural characterization is as follows:
1H?NMR(400MHz,CDCl
3)δ7.79-7.77(m,2H),7.69-7.67(m,2H),7.50-7.45(m,1H),7.44-7.32(m,2H),7.30-7.32(m,3H),6.54(s,1H),3.97(d,J＝7.1Hz,1H),2.34(s,3H),1.36(d,J＝7.2Hz,3H)；
13C?NMR(125MHz,CDCl3):δ168.17,156.18,134.59,131.69,129.16,128.88,128.65,127.79,126.97,124.12,94.75,38.65,21.40,13.34；IRν
max(cm
-1):3418,3067,2964,2925,2869,1663,1439,1416,1330,1291,1024,1006,971,920,833,770,740,691,671,597,579,470,422.MS(ESI)m/z375.0(M+H)
+.
Embodiment 3 is synthetic containing phenylseleno oxadiazole compounds IV-3
1) by α-phenylseleno propionic aldehyde (0.213g of equivalent; 1mmol) add in the round-bottomed flask that contains 20mL ethanol with hydrazides V-3 (1mmol, 0.112g), 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, subsequent disposal, as embodiment 1 step 1, obtains the intermediate product (III-3) containing phenylseleno.
2) product obtaining (III-3) (1mmol) joins in the acetic anhydride of 5mL, and subsequent operations and treatment step, as embodiment 1 step 2, obtain product (IV-3), productive rate 79% through thin plate chromatographic separation.Structural characterization is as follows:
1H?NMR(400MHz,CDCl
3)δ7.62-7.60(m,2H),7.28-7.27(m,3H),6.29(d,1H),4.88(s,1H),3.93-3.81(m,1H),2.30-2.26(m,2H),2.20(s,3H),1.64(dd,J＝14.9,5.8Hz,2H),1.30(d,J＝7.2Hz,3H),0.98(t,J＝7.4Hz,3H)；IRν
max(cm
-1):3417,?3055,2966,2931,2874,1661,1453,1419,1364,1338,1247,1171,957,903,850,804,740,692,649,585,472,446,428,406.
Embodiment 4 is synthetic containing phenylseleno oxadiazole compounds IV-4
1) by α-phenylseleno propionic aldehyde (0.213g of equivalent; 1mmol) add in the round-bottomed flask that contains 20mL ethanol with hydrazides V-4 (1mmol, 0.112g), 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, subsequent disposal, as embodiment 1 step 1, obtains the intermediate product (III-4) containing phenylseleno.
2) product obtaining (III-4) (1mmol) is joined in the acetic anhydride of 5mL, subsequent operations and treatment step, as embodiment 1 step 2, obtain product (IV-4), productive rate 79% through thin plate chromatographic separation.Structural characterization is as follows:
1H?NMR(400MHz,CDCl
3)δ7.61-7.58(m,2H),7.32-7.24(m,3H),6.29(s,1H),3.91-3.83(m,1H),2.29(t,J＝7.6Hz,2H),2.20(s,3H),1.60(dd,J＝14.3,6.8Hz,2H),1.32(d,J＝3.5Hz,3H),1.30(s,1H),1.28(s,2H),0.89(t,J＝6.8Hz,3H).IRν
max(cm
-1):3442,3216,3057,295,2957,2929,2870,1662,1598,1453,1419,1368,1334,1244,1101,1072,1022,977,897,739,692,669,585,468.
Embodiment 5 is synthetic containing phenylseleno oxadiazole compounds IV-5
1) by α-phenylseleno propionic aldehyde (0.213g of equivalent; 1mmol) add in the round-bottomed flask that contains 20mL ethanol with para-bromophenyl-hydrazine V-5 (1mmol, 0.215g), stir and make it to dissolve completely; add again 700 μ L acetic acid, back flow reaction 2h under nitrogen protection.After TLC detection reaction is complete, subsequent disposal, as embodiment 1 step 1, obtains the intermediate product (III-5) containing phenylseleno.
2) product obtaining (III-5) (1mmol) is joined in the acetic anhydride of 4mL, subsequent operations and treatment step, as embodiment 1 step 2, obtain product (IV-5), productive rate 83% through thin plate chromatographic separation.Structural characterization is as follows:
1H?NMR(400MHz,CDCl
3)δ7.99-7.93(m,2H),7.75-7.68(m,2H),7.60-7.56(m,2H),7.32-7.31(m,3H),6.58(s,1H),3.97-3.92(m,1H),2.34(s,3H),1.36(d,J＝7.1Hz,3H)；IRν
max(cm
-1):3414,3055,2968,2925,2869,1665,1630,1438,1398,1360,1329,1268,1174,1104,1071,1036,1008,970,893,831,740,715,692,665,596,494.
Embodiment 6 is synthetic containing phenylseleno oxadiazole compounds IV-6
1) by α-phenylseleno propionic aldehyde (0.213g of equivalent; 1mmol) Yu to trifluoromethyl phenyl hydrazine V-6 (1mmol, 0.167g) add in the round-bottomed flask that contains 20mL ethanol, stir and make it to dissolve completely; add again 800 μ L acetic acid, back flow reaction 2h under nitrogen protection.After TLC detection reaction is complete, subsequent disposal, as embodiment 1 step 1, obtains the intermediate product (III-6) containing phenylseleno.
2) product obtaining (III-6) (1mmol) joins in the acetic anhydride of 5mL, and subsequent operations and treatment step, as embodiment 1 step 2, obtain product (IV-6), productive rate 78% through thin plate chromatographic separation.Structural characterization is as follows:
1H?NMR(400MHz,CDCl
3)δ7.66-7.61(m,4H),7.56-7.54(m,2H),7.32-7.30(m,3H),6.53(s,1H),3.93(dd,J＝13.8,6.8Hz,1H),2.32(s,3H),1.34(d,J＝7.1Hz,3H)；IRν
max(cm
-1):3857,3436,3072,2927,2869,1668,1634,1436,1416,1366,1329,1262,1171,1131,1103,1071,1035,1007,971,894,806,741,713,693,653,600,528,471.MS(ESI)m/z443.0(M+H)
+.
Embodiment 7 is synthetic containing phenylseleno oxadiazole compounds IV-7
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 V-7 (1mmol, 0.152g), stir and make it to dissolve completely; add again 1000 μ L acetic acid, back flow reaction 3h under nitrogen protection.After TLC detection reaction is complete, subsequent disposal, as embodiment 1 step 1, obtains the intermediate product (III-7) containing phenylseleno.
2) product obtaining (III-7) (1mmol) joins in the acetic anhydride of 6mL, and subsequent operations and treatment step, as embodiment 1 step 2, obtain product (IV-7), productive rate 75% through thin plate chromatographic separation.Structural characterization is as follows:
1H?NMR(400MHz,CDCl
3)δ7.87-7.77(m,3H),7.68-7.63(m,2H),7.51-7.49?(m,1H),7.29-7.31(m,3H),6.52(s,1H),3.93(dd,J＝13.6,6.9Hz,1H),2.33(s,3H),1.33(d,J＝7.1Hz,3H)；IRν
max(cm
-1):3857,3436,3072,2927,2869,1668,1634,1436,1416,1366,1329,1262,1171,1131,1103,1071,1035,1007,971,894,806,741,713,693,653,600,528,471.MS(ESI)m/z391.0(M+H)
+.
Embodiment 8 is synthetic containing phenylseleno oxadiazole compounds IV-8
1) by α-phenylseleno propionic aldehyde (0.213g of equivalent; 1mmol) add in the round-bottomed flask that contains 20mL ethanol with hydrazides V-8 (1mmol, 0.318g), 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, subsequent disposal, as embodiment 1 step 1, obtains the intermediate product (III-8) containing phenylseleno.
2) product obtaining (III-8) (1mmol) joins in the acetic anhydride of 5mL, and subsequent operations and treatment step, as embodiment 1 step 2, obtain product (IV-8), productive rate 79% through thin plate chromatographic separation.Structural characterization is as follows:
1H?NMR(400MHz,CDCl
3)δ7.68-7.60(m,3H),7.38-7.26(m,4H),6.99(d,J＝7.0Hz,1H),6.47(s,1H),5.77(t,J＝7.0Hz,1H),4.21-4.16(m,1H),2.30(s,3H),1.30(d,J＝7.3Hz,3H)；IRν
max(cm
-1):3414,3055,2968,2925,2869,1665,1630,1438,1398,1360,1329,1268,1174,1104,1071,1036,1008,970,893,831,740,715,692,665,596,494.MS(ESI)m/z553.9(M+H)
+.
Embodiment 9 is synthetic containing phenylseleno oxadiazole compounds IV-9
1) by α-phenylseleno propionic aldehyde (0.213g of equivalent; 1mmol) add in the round-bottomed flask that contains 20mL ethanol with hydrazides V-9 (1mmol, 0.196g), 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, subsequent disposal, as embodiment 1 step 1, obtains the intermediate product (III-9) containing phenylseleno.
2) product obtaining (III-9) (1mmol) joins in the acetic anhydride of 5mL, and subsequent operations and treatment step, as embodiment 1 step 2, obtain product (IV-9), productive rate 83% through thin plate chromatographic separation.Structural characterization is as follows:
1H?NMR(400MHz,CDCl
3)δ8.77(s,1H),8.69(s,1H),8.09-8.07(m,1H),7.53-7.49(m,1H),7.42-7.33(m,3H),7.26(s,1H),7.18(d,J＝8.7Hz,1H),7.04(d,J＝8.2Hz,1H),6.98-6.95(m,1H),3.98(dd,J＝19.8,7.4Hz,1H),2.42(s,3H),1.59(s,3H)；
13C?NMR(125MHz,CDCl
3)δ169.14,165.49,164.70,159.87,157.23,150.30,133.43,132.49,128.71,126.32,125.89,123.17,119.65,117.56,116.98,89.78,33.82.23.40,21.05；IRν
max(cm
-1):3054,1723,1708,1683,1600,1568,1558,1530,1467,1429,1349,1341,1220,1197,1114,1065,1054,1009,985,830,774,765,716,712,673,653,440.MS(ESI)m/z443(M+H)
+.
Embodiment 10 is synthetic containing phenylseleno oxadiazole compounds IV-10
1) by α-phenylseleno propionic aldehyde (0.213g of equivalent; 1mmol) with 4-hydroxyl-8-toluquinoline-3-acethydrazide V-10 (1mmol; 0.216g) add in the round-bottomed flask that contains 20mL ethanol; stirring makes it to dissolve completely; add again 800 μ L acetic acid, back flow reaction 3h under nitrogen protection.After TLC detection reaction is complete, subsequent disposal, as embodiment 1 step 1, obtains the intermediate product (III-10) containing phenylseleno.
2) product obtaining (III-10) (1mmol) joins in the acetic anhydride of 5mL, and subsequent operations and treatment step, as embodiment 1 step 2, obtain product (IV-10), productive rate 75% through thin plate chromatographic separation.Structural characterization is as follows:
1H?NMR(400MHz,CDCl3)δ9.64(s,1H),7.50-7.48(m,3H),7.34-7.19(m,4H),7.13(d,J＝6.5Hz,1H),6.07(s,1H),3.94-3.91(m,1H),1.98(s,3H),1.51(d,J＝7.6Hz,3H),1.43(s,3H)；IRν
max(cm
-1):3554,3051,2937,1723,1714,1683,1603,1578,1558,1530,1480,1468,1374,1341,1220,1197,1114,1073,1065,1054,1009,985,819,787,750,716,712,673,498.MS(ESI)m/z456(M+H)
+.
Embodiment 11 is synthetic containing phenylseleno oxadiazole compounds IV-11
1) by α-phenylseleno propionic aldehyde (0.213g of equivalent; 1mmol) add in the round-bottomed flask that contains 20mL ethanol with hydrazides V-11 (1mmol, 0.193g), stir and make it to dissolve completely; add again 800 μ L acetic acid, back flow reaction 2h under nitrogen protection.After TLC detection reaction is complete, subsequent disposal, as embodiment 1 step 1, obtains the intermediate product (III-11) containing phenylseleno.
2) product obtaining (III-11) (1mmol) joins in the acetic anhydride of 4mL, and subsequent operations and treatment step, as embodiment 1 step 2, obtain product (IV-11), productive rate 72% through thin plate chromatographic separation.Structural characterization is as follows:
1H?NMR(400MHz,CDCl
3)δ7.48(s,1H),7.34-7.30(m,5H),6.47-6.43(m,3H),5.62(s,1H),4.09(dd,J＝16.8,7.1Hz,1H),2.02(s,3H),1.08(d,J＝7.3Hz,3H)；IRν
max(cm
-1):3414,3055,2955,2905,2862,1865,1785,1438,1410,1360,1309,1249,1174,1071,1049,1010,968,929,833,740,715,692,653,460.MS(ESI)m/z432(M+H)
+.
Embodiment 12 is synthetic containing phenylseleno oxadiazole compounds IV-12
1) by α-phenylseleno propionic aldehyde (0.213g of equivalent; 1mmol) add in the round-bottomed flask that contains 20mL ethanol with hydrazides V-12 (1mmol, 0.131g), 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, subsequent disposal, as embodiment 1 step 1, obtains the intermediate product (III-12) containing phenylseleno.
2) product obtaining (III-12) (1mmol) joins in the acetic anhydride of 5mL, and subsequent operations and treatment step, as embodiment 1 step 2, obtain product (IV-12), productive rate 94% through thin plate chromatographic separation.Structural characterization is as follows:
1H?NMR(400MHz,CDCl3)δ7.61-7.54(m,2H),7.33-7.22(m,3H),6.28-6.27(m,1H),5.17(dd,J＝12.7,6.4Hz,1H),3.88-3.87(m,1H),2.58(d,J＝1.9Hz,2H),2.19(d,J＝2.1Hz,3H),2.05(s,3H),2.00(d,J＝1.5Hz,2H),1.32(d,J＝6.3Hz,3H)；IRν
max(cm
-1):3055,2970,2889,1708,1568,1530,1472,1467,1429,1388,1349,1341,1114,1099,1065,1054,1010,992,830,726,712,673,658,438.
Embodiment 13 is synthetic containing phenylseleno oxadiazole compounds IV-13
1) by α-phenylseleno propionic aldehyde (0.213g of equivalent; 1mmol) add in the round-bottomed flask that contains 20mL ethanol with hydrazides V-13 (1mmol, 0.234g), stir and make it to dissolve completely; add again 800 μ L acetic acid, back flow reaction 2h under nitrogen protection.After TLC detection reaction is complete, subsequent disposal, as embodiment 1 step 1, obtains the intermediate product (III-13) containing phenylseleno.
2) product obtaining (III-13) (1mmol) joins in the acetic anhydride of 5mL, and subsequent operations and treatment step, as embodiment 1 step 2, obtain product (IV-13), productive rate 88% through thin plate chromatographic separation.Structural characterization is as follows:
1H?NMR(400MHz,CDCl
3)δ7.77(s,1H),7.65-7.63(m,2H),7.63-7.62(m,1H),7.28-7.26(m,4H),6.43(s,1H),3.92(dd,J＝14.2,7.1Hz,1H),3.53-3.50(m,1H),2.35(d,J＝6.6Hz,3H),1.38-1.35(m,3H),1.34(s,6H)；IRν
max(cm
-1):3204,3133,3107,2935,2879,2788,1584,1708,1583,1558,1528,1480,1403,1358,1291,1133,1065,1054,1010,985,787,748,716,712,690,440.MS(ESI)m/z473.1(M+H)
+.
Embodiment 14 is synthetic containing phenylseleno oxadiazole compounds IV-14
1mmol (0.390g) compounds Ⅳ-7 are dissolved in 20ml acetone, then add (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 compounds Ⅳ-14, productive rate 81%.Structural characterization is as follows:
1H?NMR(400MHz,CDCl
3)δ7.74(d,J＝8.9Hz,2H),7.67(d,J＝6.7Hz,2H),7.34-7.29(m,3H),7.03-7.01(m,2H),6.52(d,J＝10.7Hz,1H),4.76(d,J＝2.2Hz,2H),3.95(dd,J＝12.7,5.6Hz,1H),2.58(s,1H),2.32(s,3H),1.34(d,J＝7.2Hz,3H)；IRν
max(cm
-1):3059,2950,1790,1707,1618,1578,1551,1530,1493,1437,1403,1210,1114,1010,927,829,739,692,428.MS(ESI)m/z429.2(M+H)
+.
Embodiment 15 monoamine oxidase inhibitory activity tests
(1) sample preparation
Compound (IV-1)～(IV-14) of embodiment 1～13 preparation are dissolved in dimethyl sulfoxide (DMSO) (DMSO), are made into respectively 10,50,75,100, the sample liquid of 150mmol/L concentration gradient, be designated as sample 1～14.
(2) containing phenylseleno oxadiazole compounds (IV), monoamine oxidase-A is suppressed to activity test method
To 14 parts, the sample 1～14 that adds 10 μ L (concentration 4mg/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 formula VI 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 1～14
50, compound (IV-1)～(IV-14) suppress test result in Table 1 to monoamine oxidase-A activity.
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) the oxadiazole compounds (IV) containing phenylseleno changes MAO-A into MAO-B to monoamine oxidase-B inhibition active testing, and other operate same step (2), the results are shown in Table 1.
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 (IV-1), (IV-2), (IV-3), (IV-6), (IV-7), (IV-8), (IV-10), (IV-12), (IV-13) and (IV-14) monoamine oxidase A is had and suppresses active, wherein compound (IV-1), (IV-2), (IV-6), (IV-7), (IV-8), (IV-12) and (IV-13) have a stronger inhibition activity; Compound (IV-1)～(IV-14) monoamine oxidase-B is had and suppresses active, wherein compound (IV-1), (IV-2), (IV-6), (IV-7), (IV-8), (IV-10), (IV-11), (IV-12), (IV-13) and (IV-14) have stronger inhibition active, particularly compound (IV-2), (IV-8) and (IV-14) have an extremely strong inhibition activity.
Claims (10)
1. containing an oxadiazole compounds for phenylseleno, its structure is suc as formula shown in (IV):
Wherein, R is selected from one of following groups: the pyrazolyl of alkyl, substituted alkyl, aryl, replacement, chromene ketone group, the quinolyl of replacement, the isoxazolyl of replacement; The carbon atom number of described alkyl is 1～12, and described substituted alkyl is by the C1-C12 alkyl of the one or more replacements in following groups: halogen, hydroxyl; Described aryl is not substituted or by the one or more replacements in following groups: the-oxyl of halogen, trifluoromethyl, hydroxyl, C1-C6; The pyrazolyl of described replacement, the quinolyl of replacement or the substituting group replacing in isoxazolyl are that one or more, described substituting groups is independently selected from one of following groups: C1-C6 alkyl, halogen, hydroxyl, be not substituted or the furyl being replaced by halogen, the pyridyl that is not substituted or is replaced by halogen.
2. as claimed in claim 1 containing phenylseleno oxadiazole compounds, it is characterized in that: described aryl is not to be substituted or by the phenyl of the one or more replacements in following groups: halogen, trifluoromethyl, hydroxyl.
3. as claimed in claim 1 or 2 containing phenylseleno oxadiazole compounds, it is characterized in that: the pyrazolyl of described replacement is replaced or replaced by C1-C6 alkyl and imidazolyl by the pyridyl of halogen and halogen replacement; The quinolyl of described replacement is replaced by C1-C6 alkyl and hydroxyl; Described replacement isoxazolyl is replaced by furyl.
4. as claimed in claim 1 or 2 containing phenylseleno oxadiazole compounds, it is characterized in that: the-oxyl of described C1-C6 is the C3-C6-oxyl that contains alkynyl.
5. as claimed in claim 1 containing phenylseleno oxadiazole compounds, it is characterized in that: R is selected from one of following groups: C1-C6 alkyl; The C1-C6 alkyl being replaced by hydroxyl; Phenyl; The phenyl being replaced by the-oxyl of trifluoromethyl or hydroxyl or the C3-C6 that contains alkynyl; By the pyrazolyl that pyridyl replaced of halogen and halogen replacement; By the pyrazolyl of C1-C6 alkyl and imidazolyl replacement; By furyl, replaced isoxazolyl; By the quinolyl of C1-C6 alkyl and hydroxyl replacement.
As described in claim 1 or 5 containing phenylseleno oxadiazole compounds, it is characterized in that: described halogen is Cl or Br.
7. as claimed in claim 6 containing phenylseleno oxadiazole compounds, it is characterized in that: described is one of following containing phenylseleno oxadiazole compounds:
8. a method of preparing the oxadiazole compounds containing phenylseleno as claimed in claim 1, in formula (IV), R is not contained the aryl that the-oxyl of the C3-C6 of alkynyl replaces, and described method comprises:
(1) preparation of the intermediate product containing phenylseleno shown in formula III:
In reaction vessel, add the hydrazides shown in the positive propionic aldehyde of α-phenylseleno shown in organic solvent, formula (II) and formula (V), 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, heating reflux reaction 2-3h under nitrogen protection, after completion of the reaction through separation and purification obtain shown in formula IV containing phenylseleno oxadiazole compounds;
The definition cotype (IV) of R in its Chinese style (V), formula (III).
9. the application in preparation oxidase inhibitor containing phenylseleno oxadiazole compounds as claimed in claim 1.
10. application as claimed in claim 9, is characterized in that: described oxidase inhibitor is MAO-B inhibitor.
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