CN101293864A - Compound having affinity with brain A beta plaque, preparation method and application thereof - Google Patents

Compound having affinity with brain A beta plaque, preparation method and application thereof Download PDF

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CN101293864A
CN101293864A CNA2008101159861A CN200810115986A CN101293864A CN 101293864 A CN101293864 A CN 101293864A CN A2008101159861 A CNA2008101159861 A CN A2008101159861A CN 200810115986 A CN200810115986 A CN 200810115986A CN 101293864 A CN101293864 A CN 101293864A
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dmf
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brain
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段新红
刘伯里
崔孟超
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Beijing Normal University
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Abstract

The invention provides a compound having affinity with beta-amyloid in brain, with the molecular structure shown in Figure, wherein A represents CH or N; Z represents CH or N; X represent NH, O or S; Y represents NHPh; R1 represents H, F, Cl, Br, I, OH, OCH3, CH3, NH2, NH(CH3) or N(CH3)2; and R2 represents H or CH3. The invention also provides a preparation method of the compound and an application thereof in diagnosis of brain with Alzheimer's disease.

Description

A kind of have compound of avidity and its production and application with brain A beta plaque
Technical field
The present invention relates to a kind of compound, relate in particular to the compound that a kind of and brain A beta plaque have avidity, and preparation method thereof and the application aspect the degenerative brain disorder diagnosis.
Background technology
Degenerative brain disorder (Alzheimer ' s disease is to cause thinking ability to be lost gradually by the brain cell degeneration finally to cause dead disease AD).By beta amyloid peptide (β-amyloid, A β) assemble and the old patch that forms (Senile Plaque, SP) a large amount of depositions in the cranial nerve zone are to cause the main pathological characters of AD (Selkoe, JAMA 2000,283:1615-1617).Ubiquitous in the world aging problem makes the AD morbidity be rapid ascendant trend, especially China is nearly 1.27 hundred million as far back as the aged more than 60 years old in 2000, has embodied this and has a strong impact on the internationalization difficult problem of human health and about 5,000,000 AD patient and the huge family that produces and social economy's burden are outstanding at present thereupon.Therefore, obtained the great attention of domestic and international scientific circles at the diagnosis of AD and treatment research.Yet, because the irreversibility of AD makes all possible treatment measures all be faced with great challenge.So the AD early diagnosis that occurs prior to nervosa regression symptom just becomes particularly important.
Utilize patch molecule developer, on molecular level, do not have the SPECT and the PET video picture of wound live body brain patch, just can realize the early diagnosis of AD.This outstanding diagnosis advantage makes the development research of molecule video picture probe become the advanced subject of AD circle in the world.The prerequisite most important condition of molecule that is used for the video picture of A beta plaque is the inside and outside avidity (Ki＜40nM) that SPs is had height, just because of Congo red (CR) and thioflavin (ThT) SPs there is external binding ability highly, the investigator carried out a series of modifications as parent respectively in recent years, the A beta plaque video picture of having derived a large amount of (Mathis et al., Curr.pharm.Design 2004; 10:1469-1492).At present, the representative patch developer of Congo red analog derivative has: X-34, SB-13, I-Fluorene and I-Biphen etc.; The representative patch developer of thioflavin analog derivative has PIB, IBOX, IMPY and I-Benzofuran etc.Wherein, [ 11C] PIB (Klunk et al., Ann.Neurol.2004; 55:306-319), [ 11C] SB-13 (Ono et al., Nucl.Med.Biol.2003; 30:565-571) and [ 123I] IMPY (Newberg et al., J.Nucl.Med.2006; 47:748-754) clinical PET of carrying out and SPECT video picture have been used for.
When having obtained breakthrough with the A beta plaque developer of CR and ThT development, explore the core texture of novel patch particular combination, the research of Development of New Generation patch developer is also carried out.At present, comparatively successful example is that (Curcumin Cur) carries out the design studies work of patch developer for core texture with small molecules A beta inhibitor flavones (flavone) and turmeric yellow.Wherein, the Ki=15.6 ± 2.4nM of 6-iodo-the 4 '-dimethylamino flavones that designs for core texture with flavones shows that it has high affinity (Ono etal., J.Med.Chem.2005 to A β; 48:7253-7260); The Cur warp 18Its Ki=0.07 ± 0.01nM of the derivative of F mark (Ryu et al., J.Med.Chem.2006; 49:6111-6119).These two examples provide possibility for the A beta plaque developer of further development of new core texture.
The present invention endeavours to research and develop a kind of novel cpd on the prior art basis, make it have very high A beta plaque avidity, is applied to the early diagnosis of AD in the hope of preparation A beta plaque developer.
Summary of the invention
The objective of the invention is to: propose a kind of compound, make it have good avidity, can effectively be applied to the diagnosis of AD the A beta plaque.
Above-mentioned purpose of the present invention is achieved through the following technical solutions;
A kind of compound that has avidity with brain A beta plaque is provided, and its general structure is as follows:
Figure A20081011598600051
Wherein,
A gets CH or N;
Z gets CH or N;
X gets NH, O or S;
Y gets H or NHPh;
R 1Get H, F, Cl, Br, I, OH, OCH 3, CH 3, NH 2, NH (CH 3) or N (CH 3) 2
R 2Get H or CH 3
In the described compound, the structure of preferred compound is:
When described Y got NHPh, A, Z all got CH, and X gets NH, R 1Get H, R 2Get CH 3
When perhaps described Y got H, A, Z all got CH, and X gets NH, R 1Get H, Br, I, OCH 3Or CH 3, R 2Get CH 3
The present invention also provides the preparation method of described compound.
Y in described structure gets NHPh, and A and Z all get CH, X and get NH, R 1Get H and R 2Get CH 3The time, the preparation method of described compound is:
With molecular structure be Compound and CH 3I by 1: 3 weight ratio in the presence of Anhydrous potassium carbonate in room temperature reaction 6 hours, obtain structure behind the purifying and be The yellow needle-like crystal of described compound.
Above-mentioned preparation method's concrete steps can be:
Taking by weighing the 6.6mg molecular structure is Compound be dissolved among the 15ml DMF, add the 1g Anhydrous potassium carbonate and stir, slowly drip and be dissolved with 20mg 11CH 3The DMF solution 5ml of I, reaction is 6 hours under the room temperature, suction filtration then, pressure reducing and steaming DMF; Use ethyl acetate again: the separator column of sherwood oil=1: 4 (v/v) separates, and obtains the yellow needle-like crystal 5.9mg of described compound, productive rate: 85.8%. 1H NMR(500MHz，CDCl 3)δppm：7.64(1H，s)，7.37(2H，t，J＝7.7Hz)，7.07(3H，s)，5.89(1H，b)，3.14(1.5H，s)。ESI-MS：m/z calcd for C 21H 17N 3O 2(MH +)344.1，found 344.3。Anal.C 21H 17N 3O 2。
When Y got H in the described molecular structure, the preparation method of described compound was:
With general structure be Compound and general structure be
Figure A20081011598600063
Compound be dissolved in the DMF solution according to 1: 1.2～1.9 weight ratio and add Anhydrous potassium carbonate, 130 ℃ of following stirring reactions 6～8 hours, obtain general formula of molecular structure through separation and purification then and be Described compound;
The present invention also provides the described application of compound in the diagnosis of degenerative brain disorder that has avidity with brain A beta plaque.
Described application is after passing through the ordinary method mark by the compound that of the present invention and brain A beta plaque is had avidity with radionuclide, to be prepared into A beta plaque developer, is applied to the diagnosis of degenerative brain disorder.
Studies have shown that by experiment compound of the present invention has very high avidity to the A beta plaque in the cerebral tissue, through being used for the diagnosis of AD brain behind the radio-labeling effectively, concrete effect will be elaborated in an embodiment.
Description of drawings
Fig. 1 has shown saturated measurement result in conjunction with experiment among the embodiment 7.
Embodiment
Mode with embodiment elaborates technical scheme of the present invention and effect below, but technical scheme of the present invention is not limited to following examples.
Below used starting compound all can select the commercially available prod, or take method of the prior art to prepare.
(1) preparation embodiment
(in its molecular structure, Y gets NHPh to embodiment 1. preparation The compounds of this invention 1, and A, Z all get CH, and X gets NH, R 1Get H, R 2Get CH 3)
Taking by weighing the commercially available molecular structure of 6.6mg is
Figure A20081011598600071
Compound be dissolved among the 15ml DMF, add the 1g Anhydrous potassium carbonate and stir.Slowly drip the DMF solution 5ml that is dissolved with the 20mg methyl iodide, reaction is 6 hours under the room temperature.Suction filtration, pressure reducing and steaming DMF.Use ethyl acetate: the separator column of sherwood oil=1: 4 (v/v) separates, and obtains the yellow needle-like crystal of 5.9mg compound 1, and molecular structure is:
Figure A20081011598600072
Productive rate: 85.8%. 1H NMR(500MHz，CDCl 3)δppm：7.64(1H，s)，7.37(2H，t，J＝7.7Hz)，7.07(3H，s)，5.89(1H，b)，3.14(1.5H，s)。ESI-MS：m/z calcd for C 21H 17N 3O 2(MH +)344.1，found 344.3。Anal.C 21H 17N 3O 2。
Can be with the above-mentioned compound that obtains 1 according to ordinary method mark of the prior art 11C is prepared into structure and is
Figure A20081011598600073
A beta plaque developer, be used for the early diagnosis of AD brain.
(in its molecular structure, Y gets H to embodiment 2. preparation The compounds of this invention 2, and A, Z all get CH, and X gets NH, R 1Get I, R 2Get CH 3)
Taking by weighing commercially available molecular structure is
Figure A20081011598600074
Compound 176mg and 330mg paradiiodobenzene be dissolved among the 15ml DMF, add 100mg copper powder and 138mg Anhydrous potassium carbonate, 130 ℃ of following stirring reactions 6 hours.Suction filtration, pressure reducing and steaming DMF, use ethyl acetate: the separator column of sherwood oil=1: 4 (v/v) separates, and obtains the orange/yellow solid of 96.5mg compound 2, and molecular structure is:
Figure A20081011598600075
Productive rate: 25.5%, m.p.212～213 ℃. 1H NMR(500MHz，CDCl 3)δppm：7.70(1H，d，J＝7.9Hz)，7.69(2H，d，J＝8.3Hz)，7.38(1H，s)，7.15(1H，d，J＝8.1Hz)，6.98(2H，d，J＝8.4Hz)，6.21(1H，b)，3.17(3H，s)。
Can be with the above-mentioned compound that obtains 2 according to ordinary method mark of the prior art 125I is prepared into structure and is
Figure A20081011598600081
A beta plaque developer; Perhaps can be according to ordinary method with its mark 11C is prepared into structure and is
Figure A20081011598600082
A beta plaque developer be used for the early diagnosis of AD brain.
(in its molecular structure, Y gets H to embodiment 3. preparation The compounds of this invention 3, and A, Z all get CH, and X gets NH, R 1Get OCH 3, R 2Get CH 3)
Taking by weighing commercially available molecular structure is
Figure A20081011598600083
Compound 176mg and 234mg the methoxyl group iodobenzene is dissolved among the 20ml DMF, add 100mg copper powder and 138mg Anhydrous potassium carbonate, 130 ℃ of following stirring reactions 8 hours.Suction filtration, pressure reducing and steaming DMF, use ethyl acetate: the separator column of sherwood oil=1: 4 (v/v) separates, and obtains the yellow needle-like crystal of 21.6mg compound 3 behind the sherwood oil recrystallization, and its molecular structure is:
Productive rate: 7.8%, m.p.173～174 ℃ 1H NMR (500MHz, CDCl 3) δ ppm:7.63 (1H, d, J=8.2Hz), 7.20 (1H, s), 7.17 (2H, d, J=8.6Hz), 6.95 (3H, d, J=8.6Hz), 3.86 (3H, s).
(in its molecular structure, Y gets H to embodiment 4. preparation The compounds of this invention 4, and A, Z all get CH, and X gets NH, R 1, R 2All get CH 3)
Taking by weighing commercially available molecular structure is
Figure A20081011598600085
Compound 176mg and 218mg the methyl iodobenzene is dissolved among the 20ml DMF, add 100mg copper powder and 138mg Anhydrous potassium carbonate, 130 ℃ of following stirring reactions 6 hours.Suction filtration, pressure reducing and steaming DMF, use ethyl acetate: the separator column of sherwood oil=1: 4 (v/v) separates, and the sherwood oil recrystallization obtains the yellowish needle-like crystal of 45.7mg compound 4, and its molecular structure is:
Figure A20081011598600091
Productive rate: 17.2%, m.p.:195～196 ℃ 1H NMR (500MHz, CDCl 3) δ ppm:7.65 (1H, d, J=8.2Hz), 7.31 (1H, s), 7.21 (2H, d, J=8.0Hz), 7.12 (2H, d, J=7.6Hz), 7.06 (1H, d, J=7.6Hz), 3.15 (3H, s), 2.37 (3H, s).
(in its molecular structure, Y gets H to embodiment 5. preparation The compounds of this invention 5, and A, Z all get CH, and X gets NH, R 1Get Br, R 2Get CH 3)
Taking by weighing commercially available molecular structure is
Figure A20081011598600092
Compound 176mg and 283mg 1-bromo-4-iodobenzene be dissolved among the 15ml DMF, add 100mg copper powder and 138mg Anhydrous potassium carbonate, 130 ℃ of following stirring reactions 6 hours.Suction filtration, pressure reducing and steaming DMF, use ethyl acetate: the separator column of sherwood oil=1: 4 (v/v) separates, and obtains the faint yellow solid of 91.3mg compound 5, and its molecular structure is:
Figure A20081011598600093
Productive rate: 27.8%, m.p.:204～205 ℃. 1H NMR(500MHz，CDCl 3)δppm：7.69(1H，d，J＝8.1Hz)，7.50(2H，d，J＝8.3Hz)，7.37(1H，s)，7.13(1H，d，J＝8.3Hz)，7.10(2H，d，J＝8.4Hz)，6.21(1H，b)，3.17(3H，s)。
(in its molecular structure, Y gets H to embodiment 6. preparation The compounds of this invention 6, and A, Z all get CH, and X gets NH, R 1Get H, R 2Get CH 3)
Taking by weighing commercially available molecular structure is Compound 325mg and 408mg iodobenzene be dissolved among the 25ml DMF, add 130mg copper powder and 276mg Anhydrous potassium carbonate, 130 ℃ of following stirring reactions 8 hours.Suction filtration, pressure reducing and steaming DMF, use ethyl acetate: the separator column of sherwood oil=1: 4 (v/v) separates, and obtains the golden yellow tabular crystal of 34.3mg compound 6, and its molecular structure is:
Figure A20081011598600095
Productive rate: 13.6%, m.p.:171～172 ℃. 1H NMR(500MHz，CDCl 3)δppm：7.68(1H，d，J＝8.2Hz)，7.42(1H，s)，7.39(2H，d，J＝7.8Hz)，7.22(2H，d，J＝7.7Hz)，7.17(1H，t，J＝7.4Hz)，7.13(1H，d，J＝8.2Hz)，6.27(1H，b)，3.16(3H，s)。
Above compound 3～6 also all can reference compound 1 marking method mark radionuclide, make corresponding A beta plaque developer, be used for the early diagnosis of AD brain.
(2) Application Example
Embodiment 7.
Below in conjunction with experiment compound of the present invention is carried out biological assessment in conjunction with experiment and competition by saturated, fully verify the high-affinity of they and A beta plaque.
1. experimental program:
At first carry out saturated in conjunction with experiment (K dMeasure): the marker ligand base standard substance of certain density dementia people brain homogenate and different concns (are used 125The compound 2 of I mark) play association reaction, the separated free aglucon obtains mixture, calculates aglucon and protein binding amount, i.e. total binding TB by measuring its radiocounting.Add the excessive non-aglucon of putting and suppress its specificity in conjunction with obtaining non-specific binding NSB.
Be at war with then in conjunction with experiment (K iMeasure): certain density dementia people brain homogenate and certain density marker ligand base standard substance (are used 125The compound 2 of I mark) play association reaction, add the compound reaction in the cold embodiment of the invention of different concns in the reactive system simultaneously, isolated complex is surveyed radioactivity after the balance.
2. experimental procedure:
2.1 the mark of standard substance
(1) takes by weighing 115mg above-claimed cpd 5 and 580.1mg tributyl tin and be dissolved in the 15ml toluene, add the 1.16g triphenylphosphine palladium, 110 ℃ of following back flow reaction 30 hours.Suction filtration, pressure reducing and steaming toluene, ethyl acetate: sherwood oil=post separated in 1: 4, obtained faint yellow solid 47.6mg.Productive rate: 8.8%. 1H NMR(500MHz，CDCl 3)δppm：7.67(1H，d，J＝8.2Hz)，7.48(2H，d，J＝8.2Hz)，7.41(1H，s)，7.18(2H，d，J＝8.1Hz)，7.15(1H，d，J＝8.2Hz)，6.22(1H，b)，3.16(3H，s)，1.58(6H，m)，1.37(6H，m)，1.09(6H，m)，0.93(9H，m)。
(2) take by weighing the compound that 1mg above-mentioned steps (1) obtains, 100 μ L dissolve with ethanol.The H that adds 50 μ L3% respectively 2O 2, 50 μ L activity be 0.2mCi [ 125I] NaI solution (specific activity: 2200Ci/mmol) and the hydrochloric acid 100 μ L of 1mol/L.Shake up, confined reaction 10 minutes adds NaHSO 3Cancellation reaction, saturated sodium carbonate solution are regulated pH to neutral.Ethyl acetate extraction.The HPLC post separates (Cl8,10 μ m, 3.9 * 30mm.Moving phase: ethanol/water=6/4v/v) obtains 400 μ Ci radiochemicsl purities greater than 98% standard substance compound.
2.2. carry out saturated in conjunction with test:
A. being equipped with the PBS damping fluid of 4L 0.1M, pH=7.2～7.4 and the standard substance concentration of about 0.1 μ Ci/100 μ L is 10 -3To 10 -9A series of ethanolic solns of mol/L are standby.Take out and to freeze brain homogenate (H provides by America NI for 1mL, prefrontal cortex) deeply and thaw, add 1ml PBS dilution and also change in the 15mlGlas-Col pipe.With 4mLPBS drip washing Glas-Col pipe, obtain 6mL and contain albumen and organize about 320 μ g solution.
B. the solution, the PBS damping fluid of different volumes, standard substance and the 50 μ L brain homogenate solution of 10～600 μ L of compound 2 that in 12 * 75mm test tube, adds the embodiment 2 of 50 μ L respectively, vortex.
C. in 37 ℃ of water-baths, shake and hatched 3 hours.
D. collect on cell harvestor with Whatman GF/B filter paper.
E. the Y counter tube of packing into is surveyed counting.
The combination experiment 2.3. be at war with: other operation is with saturated identical in conjunction with test, and difference is:
B. in 12 * 75mm test tube, add 10 μ L 10 respectively -3To 10 -9Solution, the 840 μ L PBS damping fluids of the compound 1～6 of the embodiment of the invention preparation of mol/L.Add 100 μ L standard substance and 50 μ L brain homogenate solution, vortex.
3. experimental result:
A. the dissociation constant (Kd) that draws A beta plaque in compound 2 and the AD brain by saturated combination experiment is the 0.2nM (see figure 1).
B. partly suppress constant (IC by competition in conjunction with what experiment obtained 50) and the inhibition constant that further calculates according to formula see the following form 1:
The competition of table 1. The compounds of this invention is in conjunction with experimental result
Test used compound of the present invention Partly suppress constant/nM Suppress constant/nM
Compound 1 10.46 6.008
Compound 2 2.72 1.565
Compound 3 0.0087 0.005
Compound 4 0.024 0.014
Compound 5 0.04 0.022
The above results shows that each compound of the present invention and AD people's brain homogenate have high affinity, suppress constant (Ki) and reach nmole (nM) level, under the same experimental conditions, it is higher that compound of the present invention and existing internationally recognized classical molecule (seeing Table 2) are compared avidity, particularly the Ki=0.005 of above-claimed cpd 3 ± 0.0x nM.Therefore, the compound utmost point of the present invention is hopeful to carry out the A beta plaque video picture of SPECT or PET live body AD, realizes early diagnosis and estimates degenerative brain disorder.
Internationally recognized classical molecule competition is in conjunction with experimental data in table 2. prior art
Classical molecule of the prior art SB-13 IMPY PIB Curcumin FDDNP
Suppress constant/nM 2.0 15 2.8 0.07 0.12

Claims (10)

1. compound that has avidity with brain A beta plaque, its general structure is as follows:
Figure A2008101159860002C1
Wherein,
A gets CH or N;
Z gets CH or N;
X gets NH, O or S;
Y gets H or NHPh;
R 1Get H, F, Cl, Br, I, OH, OCH 3, CH 3, NH 2, NH (CH 3) or N (CH 3) 2
R 2Get H or CH 3
2. the described compound of claim 1, it is characterized in that: when described Y got NHPh, A, Z all got CH, and X gets NH, R 1Get H, R 2Get CH 3
3. the described compound of claim 1, it is characterized in that: when described Y got H, A, Z all got CH, and X gets NH, R 1Get H, Br, I, OCH 3Or CH 3, R 2Get CH 3
4. the preparation method of the described compound of claim 2 may further comprise the steps:
With molecular structure be
Figure A2008101159860002C2
Compound and CH 3I by 1: 3 weight ratio in the presence of Anhydrous potassium carbonate in room temperature reaction 6 hours, obtain structure behind the purifying and be
Figure A2008101159860002C3
Described compound.
5. the preparation method of the described compound of claim 3 may further comprise the steps:
With general structure be Compound and general structure be
Figure A2008101159860002C5
Compound be dissolved in the DMF solution according to 1: 1.2～1.9 weight ratio and add Anhydrous potassium carbonate, 130 ℃ of following stirring reactions 6～8 hours, obtain molecular structure through separation and purification then and be
Figure A2008101159860002C6
Described compound.
6. the preparation method of the described compound of claim 5 is characterized in that, as described R 1When getting I, step is as follows:
Taking by weighing the 176mg molecular structure is
Figure A2008101159860003C1
Compound and 330mg paradiiodobenzene be dissolved among the 15ml DMF, add 100mg copper powder and 138mg Anhydrous potassium carbonate, 130 ℃ of following stirring reactions 6 hours, suction filtration, pressure reducing and steaming DMF, use ethyl acetate: the volume ratio of sherwood oil is that 1: 4 separator column separates, and obtains the described compound of 96.5mg.
7. the preparation method of the described compound of claim 5 is as described R 1Get OCH 3The time, step is as follows:
Taking by weighing the 176mg molecular structure is Compound and 234mg the methoxyl group iodobenzene is dissolved among the 20ml DMF, add 100mg copper powder and 138mg Anhydrous potassium carbonate, 130 ℃ of following stirring reactions 8 hours, suction filtration, pressure reducing and steaming DMF, use ethyl acetate: the volume ratio of sherwood oil is that 1: 4 separator column separates, and the sherwood oil recrystallization obtains the described compound of 21.6mg then.
8. the preparation method of the described compound of claim 5 is as described R 1When getting Br, step is as follows:
Taking by weighing the 176mg molecular structure is Compound and 283mg 1-bromo-4-iodobenzene be dissolved among the 15ml DMF, add 100mg copper powder and 138mg Anhydrous potassium carbonate, 130 ℃ of following stirring reactions 6 hours, suction filtration, pressure reducing and steaming DMF, use ethyl acetate: the volume ratio of sherwood oil is that 1: 4 separator column separates, and obtains the described compound of 91.3mg.
9. the described application of compound in the diagnosis of degenerative brain disorder that has avidity with brain A beta plaque of claim 1.
10. the described application of claim 9 is characterized in that: with radionuclide the compound that described and brain A beta plaque have avidity is carried out mark, be prepared into the diagnosis that corresponding A beta plaque developer is applied to degenerative brain disorder.
CN2008101159861A 2008-07-01 2008-07-01 Compound having affinity with brain A beta plaque, preparation method and application thereof Expired - Fee Related CN101293864B (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102786532A (en) * 2012-08-31 2012-11-21 北京林业大学 Sulfur heterocyclic compound and preparation process thereof
CN104447496A (en) * 2014-11-28 2015-03-25 山东大学 Isoindole-1,3-diketone compound as well as preparation method and application thereof
CN106220552A (en) * 2016-08-04 2016-12-14 温州大学 A kind of preparation method of 2 replacement iso-indoles 1,3 derovatives
CN106278992A (en) * 2016-08-05 2017-01-04 温州大学 A kind of synthetic method of 2 replacement iso-indoles 1,3 derovatives

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102786532A (en) * 2012-08-31 2012-11-21 北京林业大学 Sulfur heterocyclic compound and preparation process thereof
CN102786532B (en) * 2012-08-31 2015-06-03 北京林业大学 Sulfur heterocyclic compound and preparation process thereof
CN104447496A (en) * 2014-11-28 2015-03-25 山东大学 Isoindole-1,3-diketone compound as well as preparation method and application thereof
CN104447496B (en) * 2014-11-28 2017-04-19 山东大学 Isoindole-1,3-diketone compound as well as preparation method and application thereof
CN106220552A (en) * 2016-08-04 2016-12-14 温州大学 A kind of preparation method of 2 replacement iso-indoles 1,3 derovatives
CN106220552B (en) * 2016-08-04 2019-02-15 温州大学 A kind of preparation method of 2- substitution-iso-indoles -1,3- derovatives
CN106278992A (en) * 2016-08-05 2017-01-04 温州大学 A kind of synthetic method of 2 replacement iso-indoles 1,3 derovatives
CN106278992B (en) * 2016-08-05 2018-12-11 温州大学 A kind of synthetic method of 2- substitution-iso-indoles -1,3- derovatives

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