CN102731411A - Preparation of 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thioketone and application of same as antidepressant drug - Google Patents
Preparation of 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thioketone and application of same as antidepressant drug Download PDFInfo
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- CN102731411A CN102731411A CN2012101987577A CN201210198757A CN102731411A CN 102731411 A CN102731411 A CN 102731411A CN 2012101987577 A CN2012101987577 A CN 2012101987577A CN 201210198757 A CN201210198757 A CN 201210198757A CN 102731411 A CN102731411 A CN 102731411A
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- pyrimidin
- dihydro
- thioketones
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- alkyl
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- 0 CCOC(C(C(c1c(*)cccc1)N1)=C(C)NC1=S)=O Chemical compound CCOC(C(C(c1c(*)cccc1)N1)=C(C)NC1=S)=O 0.000 description 3
- PXLULCMFZZNMDQ-UHFFFAOYSA-N CCOC(C(C(c(cc1)cc(OC)c1O)N1)=C(C)NC1=S)=O Chemical compound CCOC(C(C(c(cc1)cc(OC)c1O)N1)=C(C)NC1=S)=O PXLULCMFZZNMDQ-UHFFFAOYSA-N 0.000 description 1
- YZSCTNNFIRCYLX-UHFFFAOYSA-N CCOC(C(C(c(cc1)ccc1OC)N1)=C(C)NC1=S)=O Chemical compound CCOC(C(C(c(cc1)ccc1OC)N1)=C(C)NC1=S)=O YZSCTNNFIRCYLX-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to application of 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thioketone as represented by structural formula I and pharmaceutically acceptable salts thereof as antidepressant drugs. In the structural formula I as described in the specification, R1 is selected from the group consisting of C1-C2 alkyl groups and C3-C4 linear-chain alkyl groups and branched-chain alkyl groups, R2 is selected from the group consisting of H, COCH3, CO2CH3, CO2C2H5 and CO2CH2CH2OCH3, X1 is selected from the group consisting of methyl groups, ethyl groups, chlorine, fluorine, hydroxyl groups, methoxy groups, ethoxy groups and nitro groups, and X2, X3 and X4 are selected from the group consisting of methyl groups, ethyl groups, chlorine, bromine, fluorine, hydroxyl groups, methoxy groups, ethoxy groups, nitro groups, sulfonic groups, methanesulfonyl-amino groups, sulfamoyl groups, trifluoromethyl groups and acetyl groups.
Description
Technical field
The present invention relates to one type of new compound and in pharmaceutically purposes, specifically be 4-alkyl-6-aryl-3,4-dihydro-pyrimidin-2-thioketones is as the application of preparation antidepressant drug.
Background technology
Chinese patent has described aromatic aldehyde, beta-diketon or beta-ketoester and substituting thioureido prepares pyrimidine mercapto ketone compounds [CN 1803777A, on July 19th, 2006 is open] under the catalysis of trifluoromethanesulfonic acid magnesium; Chinese patent has been described also [3,2-a] pyrimidines synthetic and as the application [CN 101348495A, January 21 in 2009 is open] of Bcl-2 family protein antagonist of thiazole; Chinese patent has been described aromatic aldehyde, beta-dicarbonyl compound and urea or thiocarbamide under the catalysis of Hydrocerol A, formic acid, acetate, oxalic acid etc.; The room temperature solvent-free reaction obtains 3; 4-dihydropyrimidine-2-keto compounds [CN 101367767A, on February 18th, 2009 is open]; Chinese patent has been described the synthetic of 3-carbonyl-6-ethoxycarbonyl-thiazole miazines compound and as the application [CN 101613362A, on December 30th, 2009] of staphylococcus epidermidis signal transduction system YyCG histidine kinase protein inhibitor; Chinese patent has been described
18Precursor compound 4-(3-hydroxyl-4-nitrophenyl)-5-ethoxycarbonyl-6-methyl-3 of F sign tumor inhibitor Monastrol, the preparation method and its usage of 4-dihydro-pyrimidin-2-thioketones [CN 101781259A, on July 21st, 2010 is open]; Chinese patent has described aromatic aldehyde, beta-dicarbonyl compounds and urea or thiocarbamide synthesizes 3 under the katalysis of organic molecule (R)-thiazolidinethion-2-4-carboxylic acid; 4-dihydro-pyrimidin-2-(sulphur) ketone [CN 102225912A, on October 26th, 2011 is open]; Chinese patent has described 3, the preparation of the helicidum verivate of 4-dihydropyrimidinonesand/thioketones and in the application [CN 101475616A, on July 8th, 2009 is open] that improves aspect the central nervous system function; World patent has been described the synthetic of dihydropyrimidine derivatives and in the application [WO 2006097617A, on September 21st, 2006 is open] of anticancer aspect.European patent has been described 5-carboxyl-1,4-dihydropyrimidine derivatives synthetic and the activity [EP 0202654A2 (1), on November 26th, 1986 is open] aspect cardiovascular thereof; World patent has been described the synthetic of Dihydropyrimidines and as the application [WO 2006097617A2, on September 21st, 2006 is open] of cancer therapy drug; It is synthetic 4,5 under the catalysis of five water tin chlorides etc. that world patent has been described alkanoic or aromatic aldehyde, (sulphur) urea and beta-dicarbonyl compound, and 6-three replaces-3,4-dihydro-pyrimidin-2-(sulphur) ketone [WO 2007105233A2, on September 20th, 2007 is open].
5-HT transporter (SERT) is the relevant important target spot of 5-HT reuptake, and an existing line antidepressant drug almost is the SERT suppressor factor; In quick antidepressant drug research; There is the scholar to think that sleep deprivation and Adenosine Receptors maybe be significant for the regulating effect of 5-HT reuptake; And possibly therefrom find the new compound with quick antidepressant effect, experiment of the present invention is sought through the high flux screening means of setting up fluorescent substance ASP and is directly acted on SERT or produce the compound that the 5-HT reuptake suppresses effect through Adenosine Receptors.
Summary of the invention
The object of the present invention is to provide 4-alkyl-6-aryl-3 shown in the chemical structural formula I, 4-dihydro-pyrimidin-2-thioketones and pharmacy acceptable salt as the preparation antidepressant drug application:
Wherein, R
1Be selected from: C
1~ C
2Alkyl, C
3~ C
4Straight chained alkyl or branched-chain alkyl; R
2Be selected from: H, COCH
3, CO
2CH
3, CO
2C
2H
5, CO
2CH
2CH
2OCH
3X
1Be selected from: methyl, ethyl, chlorine, fluorine, hydroxyl, methoxyl group, oxyethyl group, nitro; X
2Be selected from: methyl, ethyl, chlorine, bromine, fluorine, hydroxyl, methoxyl group, oxyethyl group, nitro, sulfonic group, methanesulfonamido, sulfamyl, trifluoromethyl, acetoxyl group; X
3Be selected from: methyl, ethyl, chlorine, bromine, fluorine, hydroxyl, methoxyl group, oxyethyl group, nitro, sulfonic group, methanesulfonamido, sulfamyl, trifluoromethyl, acetoxyl group; X
4Be selected from: methyl, ethyl, chlorine, bromine, fluorine, hydroxyl, methoxyl group, oxyethyl group, nitro, sulfonic group, methanesulfonamido, sulfamyl, trifluoromethyl, acetoxyl group.
The object of the present invention is to provide 4-alkyl-6-aryl-3, the preparation method of 4-dihydro-pyrimidin-2-thioketones: the preparation feedback that it is characterized in that it is following:
The present invention compared with prior art has following advantage:
The present invention finds 4-alkyl-6-aryl-3 first, and 4-dihydro-pyrimidin-2-thioketones has antidepressant activity, can be used for preparing antidepressant drug.
Embodiment
Following examples are intended to explain the present invention rather than to further qualification of the present invention.
Embodiment 1
The 6-tertiary butyl-4-(2,4 dichloro benzene base)-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
4,4-dimethyl--1-(2,4 dichloro benzene base)-1-alkene-propione, thiocarbamide and 10%NaOH solution, 20 mL ethanol; Back flow reaction, the TLC detection reaction is after reaction finishes; Revolve steam white product, ethyl alcohol recrystallization gets the 6-tertiary butyl-4-(2,4 dichloro benzene base)-3; 4-dihydro-pyrimidin-2-thioketones, yield 74.5%, m.p.170～172 ℃.
1H NMR (400 MHz, CDCl
3), δ: 1.06 (s, 9H, 3 * CH
3); (4.77 d, 1H, J=2.4 Hz, pyrimidine ring 4-H), 5.27 (d, 1H, J=2.4 Hz, pyrimidine ring 5-H), 7.27 (d, 1H, J=8.0 Hz, C
6H
32-H), 7.54 (dd, J=8.0 Hz, J=2.0 Hz, 1H, C
6H
33-H), 7.60 (d, J=2.0 Hz, 1H, C
6H
35-H), 8.85 (s, 1H, NH), 9.33 (s, 1H, NH).
Embodiment 2
The 6-tertiary butyl-4-(4-p-methoxy-phenyl)-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
4,4-dimethyl--1-(4-p-methoxy-phenyl)-1-alkene-propione, thiocarbamide and 10%NaOH solution, 20 mL ethanol; Back flow reaction, the TLC detection reaction is after reaction finishes; Revolve steam white product, ethyl alcohol recrystallization gets the 6-tertiary butyl-4-(4-p-methoxy-phenyl)-3,4-dihydro-pyrimidin-2-thioketones; Yield 68.1%, m.p.177～179 ℃.
1H NMR (400 MHz, CDCl
3), δ: 1.19 (s, 9H, 3 * CH
3), 3.82 (s, 3H, OCH
3), 4.72 (d, J=3.6 Hz, 1H, pyrimidine ring 5-H), 5.07 (d, J=3.6 Hz, 1H, pyrimidine ring 4-H), 6.45 (s, 1H, NH), 6.91 (m, 2H, C
6H
43,5-H), 7.12 (s, 1H, NH).7.21(m，2H，C
6H
4?2,6-H)。
Embodiment 3
The 6-tertiary butyl-4-(2-p-methoxy-phenyl)-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
4,4-dimethyl--1-(2-p-methoxy-phenyl)-1-alkene-propione, thiocarbamide and 10%NaOH solution, 20 mL ethanol; Back flow reaction, the TLC detection reaction is after reaction finishes; Revolve steam white product, ethyl alcohol recrystallization gets the 6-tertiary butyl-4-(2-p-methoxy-phenyl)-3,4-dihydro-pyrimidin-2-thioketones; Yield 68.1%, m.p.177～179 ℃.
1H NMR (400 MHz, CDCl
3), δ: 1.19 (s, 9H, 3 * CH
3), 3.82 (s, 3H, OCH
3), 4.72 (d, J=3.6 Hz, 1H, pyrimidine ring 5-H), 5.07 (d, J=3.6 Hz, 1H, pyrimidine ring 4-H), 6.45 (s, 1H, NH), 6.91 (m, 2H, C
6H
43,5-H), 7.12 (s, 1H, NH).7.21(m，2H，C
6H
4?2,6-H)。
Embodiment 4
The 6-tertiary butyl-4-(3, the 4-Dimethoxyphenyl)-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
Method operation by embodiment 3 makes the 6-tertiary butyl-4-(3, the 4-Dimethoxyphenyl)-3,4-dihydro-pyrimidin-2-thioketones, 172～175 ℃ of fusing points.
1H NMR (400 MHz, CDCl
3), δ: 1.16 (s, 9H, 3 * CH
3), 3.84 (s, 6H, 2 * OCH
3), 4.73 (m, 1H, pyrimidine ring 5-H), 5.06 (m, 1H, pyrimidine ring 4-H), 6.12 (s, 1H, NH), 6.87 (s, 1H, NH), 6.79-5.84 (m, 3H, C
6H
3).
13C NMR (100MHz, DMSO-d
6), δ: 27.81 (3C, 3 * CH
3), 33.41 (1C, tertiary carbons), 54.16 (1C, pyrimidine ring 6-C), 55.64,55.88 (2C, 2 * OCH
3), 96.34 (1C, pyrimidine ring 5-C), 110.69,112.12,118.77 (3C, phenyl ring 2,5,6-C), 137.25 (1C, phenyl ring 1-C), 143.09,148.48,148.94 (3C, pyrimidine ring 4-C, phenyl ring 3,4-C), 174.6 (1C, C=S).
Embodiment 5
The 6-tertiary butyl-4-(2-phenelyl)-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
4,4-dimethyl--1-(2-phenelyl)-1-alkene-propione, thiocarbamide and 10%NaOH solution, 20 mL ethanol; Back flow reaction, the TLC detection reaction is after reaction finishes; Revolve steam white product, ethyl alcohol recrystallization gets the 6-tertiary butyl-4-(4-phenelyl)-3,4-dihydro-pyrimidin-2-thioketones; Yield 43.1%, 172～175 ℃ of m.p..
1H NMR (400 MHz, DMSO-d
6), δ: 1.11 (s, 9H, 3 * CH
3), 1.31 (t, J=7.2 Hz, 3H, CH
3), 4.00 (q, J=7.2 Hz, 2H, OCH
2), 4.73 (q, J=4.4 Hz, J=2.4 Hz, 2H, pyrimidine ring 5-H), 4.85 (q, J=4.4 Hz, J=2.4 Hz, 2H, pyrimidine ring 4-H), 6.90 (d, J=8.4 Hz, 2H, C
6H
42,6-H), 7.14 (d, J=8.4 Hz, 2H, C
6H
43,5-H), 8.81 (s, 1H, NH), 9.07 (s, 1H, NH).
Embodiment 6
6-methyl-4-(4-chloro-phenyl-)-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
20 mmol 4-chloro-benzaldehydes, 25 mmol thiocarbamides, 15 mL ethanol and the 0.5 mL vitriol oil, stirring and refluxing drips 16.6 mmol methyl aceto acetates, the TLC monitoring reaction course; React 24 h, cooling reaction liquid is separated out white solid; Filter, small amount of ethanol is washed, and drying obtains-methyl-4-(4-chloro-phenyl-)-5-ethoxycarbonyl-3; 4-dihydro-pyrimidin-2-thioketones, yield 23.7%, 193～195 ℃ of m.p..
Embodiment 7
6-methyl-4-(4-fluorophenyl)-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
40 mmol p-Fluorobenzenecarboxaldehydes, 50 mmol thiocarbamides, 30 mL ethanol and the 1.0 mL vitriol oils, stirring and refluxing drips 33.3 mmol methyl aceto acetates, the TLC monitoring reaction course; React 18 h, cooling reaction liquid is separated out the beige solid; Filter, small amount of ethanol is washed, and drying obtains 6-methyl-4-(4-fluorophenyl)-5-ethoxycarbonyl-3; 4-dihydro-pyrimidin-2-thioketones, yield 45.1%, 191～192 ℃ of m.p..
Embodiment 8
6-methyl-4-(4-p-methoxy-phenyl)-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
20 mmol aubepine, 25 mmol thiocarbamides, 15 mL ethanol and the 0.5 mL vitriol oil, stirring and refluxing drips 16.6 mmol methyl aceto acetates, the TLC monitoring reaction course; React 15.5 h, cooling reaction liquid is separated out pink solid; Filter, small amount of ethanol is washed, and drying obtains 6-methyl-4-(4-p-methoxy-phenyl)-5-ethoxycarbonyl-3; 4-dihydro-pyrimidin-2-thioketones, yield 19.6%, 154～156 ℃ of m.p..
Embodiment 9
6-methyl-4-(4-aminomethyl phenyl)-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
20 mmol p-tolyl aldehydes, 25 mmol thiocarbamides, 20 mL ethanol and the 0.5 mL vitriol oil, stirring and refluxing drips 16.6 mmol methyl aceto acetates, the TLC monitoring reaction course; React 7.5 h, cooling reaction liquid is separated out light yellow solid; Filter, small amount of ethanol is washed, and drying obtains 6-methyl-4-(4-aminomethyl phenyl)-5-ethoxycarbonyl-3; 4-dihydro-pyrimidin-2-thioketones, yield 49.0%, 189～192 ℃ of m.p..
Embodiment 10
6-methyl-4-phenyl-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
20 mmol phenyl aldehydes, 25 mmol thiocarbamides, 20 mL ethanol and the 0.5 mL vitriol oil, stirring and refluxing drips 16.6 mmol methyl aceto acetates, the TLC monitoring reaction course; React 20.5 h, cooling reaction liquid is separated out white solid; Filter, small amount of ethanol is washed, and drying obtains 6-methyl-4-phenyl-5-ethoxycarbonyl 3; 4-dihydro-pyrimidin-2-thioketones, yield 36.5%, 208～210 ℃ of m.p..
Embodiment 11
6-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
20 mmol m-nitrobenzaldehydes, 25 mmol thiocarbamides, 20 mL ethanol and the 0.5 mL vitriol oil, stirring and refluxing drips 16.6 mmol methyl aceto acetates, the TLC monitoring reaction course; React 19.5 h, cooling reaction liquid is separated out light yellow solid; Filter, small amount of ethanol is washed, and drying obtains 6-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-3; 4-dihydro-pyrimidin-2-thioketones, yield 10.9%, 206～209 ℃ of m.p..
Embodiment 12
6-methyl-4-(4-nitrophenyl)-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
20 mmol paranitrobenzaldehydes, 25 mmol thiocarbamides, 15 mL ethanol and the 0.5 mL vitriol oil, stirring and refluxing drips 16.6 mmol methyl aceto acetates, the TLC monitoring reaction course; React 21 h, revolve the steaming solvent, get thick shape solid; The mixed solution that adds a small amount of sherwood oil and ETHYLE ACETATE stirs and to place that frozen water is cold to be put, and separates out yellow solid; Filter, small amount of ethanol is washed, and drying obtains 6-methyl-4-(4-nitrophenyl)-5-ethoxycarbonyl-3; 4-dihydro-pyrimidin-2-thioketones, yield 21.8%, 190～193 ℃ of m.p..
Embodiment 13
6-methyl-4-(2-p-methoxy-phenyl)-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
20 mmol O-methoxy phenyl aldehydes, 25 mmol thiocarbamides, 20 mL ethanol and the 0.5 mL vitriol oil, stirring and refluxing drips 16.6 mmol methyl aceto acetates, the TLC monitoring reaction course; React 7 h, cooling reaction liquid is separated out solid; Filter, small amount of ethanol is washed, and drying obtains 6-methyl-4-(2-p-methoxy-phenyl)-5-ethoxycarbonyl-3; 4-dihydro-pyrimidin-2-thioketones, yield 44.1%, 184～187 ℃ of m.p..
Embodiment 14
6-methyl-4-(3-methoxyl group-4-hydroxy phenyl)-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
20 mmol 3-methoxyl group 4-hydroxy benzaldehydes, 25 mmol thiocarbamides, 15 mL ethanol and the 0.5 mL vitriol oil, stirring and refluxing drips 16.6 mmol methyl aceto acetates, the TLC monitoring reaction course; React 16.5 h, cooling reaction liquid is separated out white solid; Filter, small amount of ethanol is washed, and drying obtains 6-methyl-4-(3-methoxyl group-4-hydroxy phenyl)-5-ethoxycarbonyl-3; 4-dihydro-pyrimidin-2-thioketones, yield 24.2%, 222～224 ℃ of m.p..
Embodiment 15
4-alkyl-6-aryl-3, the active mensuration of the antidepressant of 4-dihydro-pyrimidin-2-thioketones (it is active that SERT suppresses)
1. SERT suppresses the determination of activity principle
Optical dye ASP
+Be a kind of neurovirulent compound that has, can combine with the transporter of monoamine to get in the cell, and (the strong and weak order of bonded is DAT to send yellow fluorescence; Suprarenin Zhuan Yunti>The 5-HT transporter).When exist other can with the transporter binding compounds, when being at war with, getting into intracellular ASP quantity and reduce with ASP, yellow fluorescence weakens, and acts on the reuptake inhibitor of 5-HT transporter through the variation screening of fluorescence intensity relatively.
The RBL-2H3 cell is a kind of cell strain that can secrete histamine and 5-HT, and this cell is the mastocyte of immortalization, can discharge aforesaid mediator by quantum; And have SERT and can carry out the 5-HT reuptake.
The CACO-2 cell is the adenocarcinoma cell strain that derives from people's small intestine, finds under study for action can express multiple transporter and acceptor through this cell of Culture and Differentiation for some time, comprises SERT; Adenosine Receptors etc.; Through setting up the standardisation process of cell cultures, make cell after cultivating 6 ~ 7 days, can realize well differentiated, through adding trial-product for some time to be screened in advance; Adding optical dye according to finite concentration; Through will not getting into the dyestuff flush away of cell, the fluorescence intensity of ASP between the more different samples can find active, or the active sample of effect remote effect transporter through activation/inhibition Adenosine Receptors of direct inhibition SERT.
2. experiment equipment
Cell: RBL-2H3, CACO-2 clone are from institute of Materia Medica,Chinese Academy of Medical Sciences national drug screening center.
Reagent: (1) cell culture medium; (2) optical dye ASP.
Instrument: continuous spectrum enzyme mark tester (spectramaxM5) moleculardevices company produces.
3. schedule of operation
3.1 cell cultures
The RBL cell strain is available from China typical culture collection center.This cell strain uses and contains the 1.5g/L sodium hydrogencarbonate, 0.1mM non-essential amino acid, 1.0mM Sodium.alpha.-ketopropionate, the EMEM of 2mML-Stimulina and Earle'sBSS, 85%; The substratum of hot deactivation FBS15% carries out cell cultures.Cell changes liquid 1 time next day of the need, and cell proliferation reaches at 80% o'clock need go down to posterity, and ratio is 1: 3.
Cell cultures: Strict aseptic operation, carry out cell cultures with the MEM α perfect medium that contains 15% foetal calf serum, treat that cell reaches logarithmic phase and experimentizes when in good condition; Wash twice with D-hanks liquid, add 0.125% trypsin digestion cell, place 5min at 37 ℃; Make iuntercellular connect and open that the single distribution of cell adds the equal-volume perfect medium and stops digestion; Blow and beat cell gently and place centrifuge tube with 800 commentaries on classics/min suspension, centrifugal 3min, supernatant discarded; With the perfect medium re-suspended cell, to count, diluting cells reaches 6 * 10
5Individual/ml is subsequent use.
Cell bed board and dosing, add optical dye: 4 * 10
5Individual/ml cell suspension adds 96 orifice plates according to the 0.1ml/ hole, treats can carry out the experiment of fluorescence high flux screening during well-grown more than the cell attachment growth 10h, and at excitation wavelength 475nm, emission wavelength 605nm place reading carries out result's statistics.
CACO-2 cell strain institute of Materia Medica,Chinese Academy of Medical Sciences national drug screening centralab preserves.This cell strain uses and contains the 1.5g/L sodium hydrogencarbonate, 0.1mM non-essential amino acid, 1.0mM Sodium.alpha.-ketopropionate, the EMEM of 2mML-Stimulina and Earle'sBSS, 80%; The substratum of hot deactivation FBS20% carries out cell cultures.Cell changes liquid 1 time next day of the need, and cell proliferation reaches at 80% o'clock need go down to posterity, and ratio is 1: 3.
3.2 cell bed board and differentiation
Cell is according to 1 * 10
5/ ml, every hole 100ul add at the bottom of the 96 hole black in the transparent culture plate, change liquid next day of when cell does not cover with once, treat the cell growth rapidly; Cover with the bottom, need to change liquid every day, treat its differentiation; The visible cell cell boundary on the 6th ~ 7 of growing is unclear, and the growth microvillus can be carried out the experiment of fluorescence high flux screening; At excitation wavelength 475nm, emission wavelength 605nm place reading carries out result's statistics.
4. data processing
Calculate the fluorescence intensity inhibiting rate:
5. test sample
4-alkyl-6-aryl-3,4-dihydro-pyrimidin-2-thioketones, the SERT transporter inhibitors screening model screening of all setting up through the RBL-2H3 cell.
6. evaluation of result
When concentration is 10.0mg/L, screening 4-alkyl-6-aryl-3,4-dihydro-pyrimidin-2-thioketones is to the inhibiting rate of SERT, and outstanding compound is 6-methyl-4-(4-chloro-phenyl-)-5-ethoxycarbonyl-3,4-dihydro-pyrimidin-2-thioketones.When concentration is 10.0mg/L, outstanding compound 6-methyl-4-(4-chloro-phenyl-)-5-ethoxycarbonyl-3,4-dihydro-pyrimidin-2-thioketones is 59.2% to the inhibiting rate of SERT; When concentration is 0.0293mmol/L, 6-methyl-4-(4-chloro-phenyl-)-5-ethoxycarbonyl-3,4-dihydro-pyrimidin-2-thioketones is 61.0% to the inhibiting rate of SERT; 6-methyl-4-(4-chloro-phenyl-)-5-ethoxycarbonyl-3,4-dihydro-pyrimidin-2-thioketones is active to the inhibition of SERT, IC
50Be 0.00697mmol/L.
4-alkyl-6-aryl-3,4-dihydro-pyrimidin-2-thioketones has better inhibited activity to SERT, can be used as the application of preparation antidepressant drug.
Claims (10)
1. 4-alkyl-6-aryl-3 shown in the chemical structural formula I, 4-dihydro-pyrimidin-2-thioketones and in the application of pharmacy acceptable salt as the preparation antidepressant drug:
Wherein, R
1Be selected from: C
1~ C
2Alkyl, C
3~ C
4Straight chained alkyl or branched-chain alkyl; R
2Be selected from: H, COCH
3, CO
2CH
3, CO
2C
2H
5, CO
2CH
2CH
2OCH
3X
1Be selected from: methyl, ethyl, chlorine, fluorine, hydroxyl, methoxyl group, oxyethyl group, nitro; X
2Be selected from: methyl, ethyl, chlorine, bromine, fluorine, hydroxyl, methoxyl group, oxyethyl group, nitro, sulfonic group, methanesulfonamido, sulfamyl, trifluoromethyl, acetoxyl group; X
3Be selected from: methyl, ethyl, chlorine, bromine, fluorine, hydroxyl, methoxyl group, oxyethyl group, nitro, sulfonic group, methanesulfonamido, sulfamyl, trifluoromethyl, acetoxyl group; X
4Be selected from: methyl, ethyl, chlorine, bromine, fluorine, hydroxyl, methoxyl group, oxyethyl group, nitro, sulfonic group, methanesulfonamido, sulfamyl, trifluoromethyl, acetoxyl group.
2. the described 4-alkyl-6-aryl-3 of claim 1, the preparation method of 4-dihydro-pyrimidin-2-thioketones: the preparation feedback that it is characterized in that it is following:
R
1, R
2, X
1, X
2, X
3, X
4Definition according to claim 1.
3. the described 4-alkyl-6-aryl-3 of claim 1; 4-dihydro-pyrimidin-2-thioketones is 6-methyl-4-(4-chloro-phenyl-)-5-ethoxycarbonyl-3; 4-dihydro-pyrimidin-2-thioketones or 6-methyl-4-(4-fluorophenyl)-5-ethoxycarbonyl-3,4-dihydro-pyrimidin-2-thioketones is as the application of preparation antidepressant drug.
4. the described 4-alkyl-6-aryl-3 of claim 1; 4-dihydro-pyrimidin-2-thioketones is 6-methyl-4-(2-p-methoxy-phenyl)-5-ethoxycarbonyl-3; 4-dihydro-pyrimidin-2-thioketones or 6-methyl-4-(4-p-methoxy-phenyl)-5-ethoxycarbonyl-3; 4-dihydro-pyrimidin-2-thioketones or 6-methyl-4-(3-methoxyl group-4-hydroxy phenyl)-5-ethoxycarbonyl-3,4-dihydro-pyrimidin-2-thioketones is as the application of preparation antidepressant drug.
5. the described 4-alkyl-6-aryl-3 of claim 1; 4-dihydro-pyrimidin-2-thioketones is 6-methyl-4-phenyl-5-ethoxycarbonyl-3; 4-dihydro-pyrimidin-2-thioketones or 6-methyl-4-(4-aminomethyl phenyl)-5-ethoxycarbonyl-3,4-dihydro-pyrimidin-2-thioketones is as the application of preparation antidepressant drug.
6. the described 4-alkyl-6-aryl-3 of claim 1; 4-dihydro-pyrimidin-2-thioketones is 6-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-3; 4-dihydro-pyrimidin-2-thioketones or 6-methyl-4-(4-nitrophenyl)-5-ethoxycarbonyl-3,4-dihydro-pyrimidin-2-thioketones is as the application of preparation antidepressant drug.
7. the described 4-alkyl-6-aryl-3 of claim 1,4-dihydro-pyrimidin-2-thioketones is the 6-tertiary butyl-4-(2,4 dichloro benzene base)-3,4-dihydro-pyrimidin-2-thioketones is as the application of preparation antidepressant drug.
8. the described 4-alkyl-6-aryl-3 of claim 1; 4-dihydro-pyrimidin-2-thioketones is the 6-tertiary butyl-4-(2-p-methoxy-phenyl)-3; 4-dihydro-pyrimidin-2-thioketones or the 6-tertiary butyl-4-(4-p-methoxy-phenyl)-3,4-dihydro-pyrimidin-2-thioketones is as the application of preparation antidepressant drug.
9. the described 4-alkyl-6-aryl-3 of claim 1,4-dihydro-pyrimidin-2-thioketones is the 6-tertiary butyl-4-(3, the 4-Dimethoxyphenyl)-3,4-dihydro-pyrimidin-2-thioketones is as the application of preparation antidepressant drug.
10. the described 4-alkyl-6-aryl-3 of claim 1,4-dihydro-pyrimidin-2-thioketones is the 6-tertiary butyl-4-(2-phenelyl)-3,4-dihydro-pyrimidin-2-thioketones is as the application of preparation antidepressant drug.
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| CN87103225A (en) * | 1986-04-29 | 1987-11-11 | 美国辉瑞有限公司 | Antidepressant calcium independent cyclic amp (CAMP) phosphodiesterase inhibitor |
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| CN87103225A (en) * | 1986-04-29 | 1987-11-11 | 美国辉瑞有限公司 | Antidepressant calcium independent cyclic amp (CAMP) phosphodiesterase inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| SHAIFALI VERMA ET AL: "《Three-component condensation. Synthesis and characterization of bioactive 4-substituted aryl pyrimidinones and pyrimidinethiones》", 《ORIENTAL JOURNAL OF CHEMISTRY》, vol. 27, no. 3, 31 December 2011 (2011-12-31), pages 1094 * |
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