CN102731411B - Preparation of 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thioketone and application of same as antidepressant drug - Google Patents

Abstract

The present invention relates to the application of 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thione shown in the chemical structural formula I and its pharmaceutically acceptable salt as the preparation of antidepressants: Among them, R ¹ is selected from: C ₁ ~ C ₂ alkyl, C ₃ ~ C ₄ straight chain alkyl or branched chain alkyl; R ² is selected from: H, COCH ₃ , CO ₂ CH ₃ , CO ₂ C ₂ H _5. CO ₂ CH ₂ CH ₂ OCH ₃ ; X ₁ is selected from: methyl, ethyl, chlorine, fluorine, hydroxyl, methoxy, ethoxy, nitro; X ₂ , X ₃ , X ₄ are selected from: Methyl, ethyl, chlorine, bromine, fluorine, hydroxyl, methoxy, ethoxy, nitro, sulfonate, methylsulfonylamino, sulfamoyl, trifluoromethyl, acetoxy.

Description

Preparation of 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thione and its application as antidepressant

technical field

The invention relates to a class of novel compounds and their application in medicine, in particular to the application of 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thione as an antidepressant.

Background technique

The Chinese patent describes the preparation of pyrimidine thione compounds from aromatic aldehydes, β-diketones or β-ketoesters and substituted thioureas under the catalysis of magnesium trifluoromethanesulfonate [CN 1803777A, published on July 19, 2006]; China The patent describes the synthesis of thiazolo[3,2-a]pyrimidines and their application as Bcl-2 family protein antagonists [CN 101348495A, published on January 21, 2009]; the Chinese patent describes aromatic aldehydes, β- Dicarbonyl compound and urea or thiourea were catalyzed by citric acid, formic acid, acetic acid, oxalic acid, etc., and reacted without solvent at room temperature to obtain 3,4-dihydropyrimidin-2-one compounds [CN 101367767A, February 18, 2009 Open]; Chinese patent describes the synthesis of 3-carbonyl-6-carboethoxy-thiazolopyrimidines and its application as an inhibitor of staphylococcal signal transduction system YyCG histidine kinase protein [CN 101613362A, 2009 December 30]; Chinese patent describes the precursor compound 4-( ³ -hydroxy-4-nitrophenyl)-5-ethoxycarbonyl-6-methyl-3,4 -The preparation method and application of dihydropyrimidine-2-thione [CN 101781259A, published on July 21, 2010]; the Chinese patent describes aromatic aldehydes, β-dicarbonyl compounds and urea or thiourea in small organic molecules Synthesis of 3,4-dihydropyrimidin-2-(thio)one under the catalytic action of (R)-tetrahydrothiazole-2-thione-4-carboxylic acid [CN 102225912A, published on October 26, 2011]; China The patent describes the preparation of tofu glucoside derivatives of 3,4-dihydropyrimidinone/thione and its application in improving central nervous system functions [CN 101475616A, published on July 8, 2009]; the world patent describes Synthesis of dihydropyrimidine derivatives and their application in anticancer [WO 2006097617A, published on September 21, 2006]. European patents describe the synthesis of 5-carboxy-1,4-dihydropyrimidine derivatives and their cardiovascular activity [EP 0202654A2(1), published Nov. 26, 1986]; world patents describe dihydropyrimidines Synthesis of the compound and its application as an anticancer drug [WO 2006097617A2, published on September 21, 2006]; the world patent describes aliphatic or aromatic aldehydes, (thio)urea and β-dicarbonyl compounds in tin chloride pentahydrate Synthesis of 4,5,6-trisubstituted-3,4-dihydropyrimidin-2-(thio)one under the catalysis of [WO 2007105233A2, published on September 20, 2007].

The 5-HT transporter (SERT) is an important target related to 5-HT reuptake. Almost all the existing first-line antidepressants are SERT inhibitors; in the rapid antidepressant drug research, some scholars believe that sleep deprivation and gland Glycoside receptors may be of great significance for the regulation of 5-HT reuptake, and it is possible to find new compounds with rapid antidepressant effects. The experiment of the present invention seeks to directly act on SERT by establishing a high-throughput screening method for fluorescent substance ASP. Or a compound that produces a 5-HT reuptake inhibitory effect via an adenosine receptor.

Contents of the invention

The object of the present invention is to provide 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thione shown in chemical structural formula I and its pharmaceutically acceptable salt as the application of antidepressant preparation:

Among them, R ¹ is selected from: C ₁ ~ C ₂ alkyl, C ₃ ~ C ₄ straight chain alkyl or branched chain alkyl; R ² is selected from: H, COCH ₃ , CO ₂ CH ₃ , CO ₂ C ₂ H _5. CO ₂ CH ₂ CH ₂ OCH ₃ ; X ₁ is selected from: methyl, ethyl, chlorine, fluorine, hydroxyl, methoxy, ethoxy, nitro; X ₂ is selected from: methyl, ethyl, Chlorine, bromine, fluorine, hydroxyl, methoxy, ethoxy, nitro, sulfonic acid, methylsulfonylamino, sulfamoyl, trifluoromethyl, acetoxy; _X3 is selected from: methyl, ethyl Base, chlorine, bromine, fluorine, hydroxyl, methoxy, ethoxy, nitro, sulfonate, methylsulfonylamino, sulfamoyl, trifluoromethyl, acetoxy; _X4 is selected from: methyl , ethyl, chlorine, bromine, fluorine, hydroxyl, methoxy, ethoxy, nitro, sulfonate, methylsulfonylamino, sulfamoyl, trifluoromethyl, acetoxy.

The object of the present invention is to provide the preparation method of 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thione: it is characterized in that its preparation reaction is as follows:

Compared with the prior art, the present invention has the following advantages:

The present invention finds for the first time that 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thione has antidepressant activity and can be used to prepare antidepressant drugs.

Detailed ways

The following examples are intended to illustrate the present invention without further limiting the invention.

Example 1

Preparation of 6-tert-butyl-4-(2,4-dichlorophenyl)-3,4-dihydropyrimidine-2-thione

4,4-Dimethyl-1-(2,4-dichlorophenyl)-1-ene-3-pentanone, thiourea and 10% NaOH solution, 20 mL ethanol, reflux reaction, TLC detection reaction, reaction After completion, the white product was obtained by rotary evaporation, and recrystallized from ethanol to obtain 6-tert-butyl-4-(2,4-dichlorophenyl)-3,4-dihydropyrimidine-2-thione with a yield of 74.5%. mp170～172℃. ¹ H 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 ₆ H ₃ 2-H ), 7.54 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H, C ₆ H ₃ 3-H), 7.60 (d, J = 2.0 Hz, 1H, C ₆ H ₃ 5-H), 8.85 (s, 1H, NH), 9.33 (s, 1H, NH).

Example 2

Preparation of 6-tert-butyl-4-(4-methoxyphenyl)-3,4-dihydropyrimidine-2-thione

4,4-Dimethyl-1-(4-methoxyphenyl)-1-ene-3-pentanone, thiourea and 10% NaOH solution, 20 mL ethanol, reflux reaction, TLC detection reaction, the reaction is complete Finally, the white product was obtained by rotary evaporation, and recrystallized from ethanol to obtain 6-tert-butyl-4-(4-methoxyphenyl)-3,4-dihydropyrimidine-2-thione, the yield was 68.1%, mp177～ 179°C. ¹ H 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, C6H43 _{, 5} -H), 7.12(s , 1H, NH). 7.21 ₍ m, 2H, _C6H42,6 -H).

Example 3

Preparation of 6-tert-butyl-4-(2-methoxyphenyl)-3,4-dihydropyrimidine-2-thione

4,4-Dimethyl-1-(2-methoxyphenyl)-1-ene-3-pentanone, thiourea and 10% NaOH solution, 20 mL ethanol, reflux reaction, TLC detection reaction, the reaction is complete Finally, the white product was obtained by rotary evaporation, and recrystallized from ethanol to obtain 6-tert-butyl-4-(2-methoxyphenyl)-3,4-dihydropyrimidine-2-thione, the yield was 68.1%, mp177～ 179°C. ¹ H 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, C6H43 _{, 5} -H), 7.12(s , 1H, NH). 7.21 ₍ m, 2H, _C6H42,6 -H).

Example 4

Preparation of 6-tert-butyl-4-(3,4-dimethoxyphenyl)-3,4-dihydropyrimidine-2-thione

According to the method of Example 3, 6-tert-butyl-4-(3,4-dimethoxyphenyl)-3,4-dihydropyrimidine-2-thione was obtained, with a melting point of 172-175 °C. ¹ H 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 ₆ H ₃ ). ¹³ C NMR (100MHz, DMSO-d ₆ ), δ: 27.81 (3C, 3×CH ₃ ), 33.41 (1C, tertiary carbon), 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, benzene ring 2, 5, 6-C), 137.25 (1C, benzene ring 1-C), 143.09, 148.48, 148.94 (3C, pyrimidine ring 4-C, benzene ring 3,4-C), 174.6 (1C, C=S).

Example 5

Preparation of 6-tert-butyl-4-(2-ethoxyphenyl)-3,4-dihydropyrimidine-2-thione

4,4-Dimethyl-1-(2-ethoxyphenyl)-1-ene-3-pentanone, thiourea and 10% NaOH solution, 20mL ethanol, reflux reaction, TLC detection reaction, after the reaction, The white product was obtained by rotary evaporation, and recrystallized from ethanol to obtain 6-tert-butyl-4-(4-ethoxyphenyl)-3,4-dihydropyrimidine-2-thione, yield 43.1%, mp 172～175 ℃ . ¹ H 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 = 2.4Hz, 2H, pyrimidine ring 5-H ), 4.85 (q, J = 4.4 Hz, J = 2.4Hz, 2H, pyrimidine ring 4- H), 6.90 (d, J = 8.4 Hz, 2H, C ₆ H ₄ 2,6-H), 7.14 (d, J = 8.4 Hz, 2H, C ₆ H ₄ 3,5-H), 8.81 (s , 1H, NH), 9.07 (s, 1H, NH).

Example 6

Preparation of 6-methyl-4-(4-chlorophenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione

20 mmol p-chlorobenzaldehyde, 25 mmol thiourea, 15 mL ethanol and 0.5 mL concentrated sulfuric acid were stirred and refluxed, 16.6 mmol ethyl acetoacetate was added dropwise, and the reaction process was monitored by TLC. After 24 h of reaction, the reaction solution was cooled, and a white solid was precipitated. Filter, wash with a small amount of ethanol, and dry to obtain -methyl-4-(4-chlorophenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione, yield 23.7%, m.p. 193～195 ℃.

Example 7

Preparation of 6-methyl-4-(4-fluorophenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione

40 mmol p-fluorobenzaldehyde, 50 mmol thiourea, 30 mL ethanol and 1.0 mL concentrated sulfuric acid were stirred and refluxed, 33.3 mmol ethyl acetoacetate was added dropwise, the reaction process was monitored by TLC, the reaction was reacted for 18 h, the reaction solution was cooled, and a beige solid was precipitated , filtered, washed with a small amount of ethanol, dried to obtain 6-methyl-4-(4-fluorophenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione, yield 45.1%, m.p. 191 ~192°C.

Example 8

Preparation of 6-methyl-4-(4-methoxyphenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione

20 mmol p-methoxybenzaldehyde, 25 mmol thiourea, 15 mL ethanol and 0.5 mL concentrated sulfuric acid, stirred and refluxed, 16.6 mmol ethyl acetoacetate was added dropwise, TLC monitored the reaction process, reacted for 15.5 h, cooled the reaction solution, and precipitated pink color solid, filtered, washed with a small amount of ethanol, and dried to obtain 6-methyl-4-(4-methoxyphenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione, yield 19.6 %, m.p. 154～156℃.

Example 9

Preparation of 6-methyl-4-(4-methylphenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione

20 mmol p-tolualdehyde, 25 mmol thiourea, 20 mL ethanol and 0.5 mL concentrated sulfuric acid were stirred and refluxed, 16.6 mmol ethyl acetoacetate was added dropwise, the reaction process was monitored by TLC, the reaction was reacted for 7.5 h, the reaction solution was cooled, and a light yellow color was precipitated The solid was filtered, washed with a small amount of ethanol, and dried to obtain 6-methyl-4-(4-methylphenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione with a yield of 49.0%. m.p.189～192℃.

Example 10

Preparation of 6-methyl-4-phenyl-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione

20 mmol benzaldehyde, 25 mmol thiourea, 20 mL ethanol and 0.5 mL concentrated sulfuric acid were stirred and refluxed, 16.6 mmol ethyl acetoacetate was added dropwise, and the reaction process was monitored by TLC. The reaction was cooled for 20.5 hours, and a white solid was precipitated, filtered, Wash with a small amount of ethanol and dry to obtain 6-methyl-4-phenyl-5-ethoxycarbonyl 3,4-dihydropyrimidine-2-thione, yield 36.5%, m.p. 208～210℃.

Example 11

Preparation of 6-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione

20 mmol m-nitrobenzaldehyde, 25 mmol thiourea, 20 mL ethanol and 0.5 mL concentrated sulfuric acid were stirred and refluxed, 16.6 mmol ethyl acetoacetate was added dropwise, the reaction process was monitored by TLC, the reaction was reacted for 19.5 h, the reaction solution was cooled, and a light yellow color was precipitated The solid was filtered, washed with a small amount of ethanol, and dried to obtain 6-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione with a yield of 10.9%. m.p.206～209℃.

Example 12

Preparation of 6-methyl-4-(4-nitrophenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione

20 mmol p-nitrobenzaldehyde, 25 mmol thiourea, 15 mL ethanol and 0.5 mL concentrated sulfuric acid were stirred and refluxed, 16.6 mmol ethyl acetoacetate was added dropwise, the reaction process was monitored by TLC, the reaction was carried out for 21 h, and the solvent was rotary evaporated to obtain a thick solid, add a small amount of petroleum ether and ethyl acetate mixture, stir and place in ice water to cool, a yellow solid precipitates, filter, wash with a small amount of ethanol, and dry to obtain 6-methyl-4-(4-nitrophenyl)- 5-Ethoxycarbonyl-3,4-dihydropyrimidine-2-thione, yield 21.8%, m.p. 190～193℃.

Example 13

Preparation of 6-methyl-4-(2-methoxyphenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione

20 mmol o-methoxybenzaldehyde, 25 mmol thiourea, 20 mL ethanol and 0.5 mL concentrated sulfuric acid were stirred and refluxed, 16.6 mmol ethyl acetoacetate was added dropwise, the reaction process was monitored by TLC, the reaction was reacted for 7 h, the reaction solution was cooled, and a solid was precipitated , filtered, washed with a small amount of ethanol, and dried to obtain 6-methyl-4-(2-methoxyphenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione, yield 44.1%, m.p.184～187℃.

Example 14

Preparation of 6-methyl-4-(3-methoxy-4-hydroxyphenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione

20 mmol 3-methoxy 4-hydroxybenzaldehyde, 25 mmol thiourea, 15 mL ethanol and 0.5 mL concentrated sulfuric acid, stirred and refluxed, 16.6 mmol ethyl acetoacetate was added dropwise, TLC monitored the reaction process, reacted for 16.5 h, cooled the reaction liquid, a white solid precipitated, filtered, washed with a small amount of ethanol, and dried to obtain 6-methyl-4-(3-methoxy-4-hydroxyphenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2 - Thione, yield 24.2%, m.p. 222～224 ℃.

Example 15

Determination of the antidepressant (SERT inhibitory activity) activity of 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thiones

1. Principle of SERT inhibitory activity assay

Fluorescent dye ASP ⁺ is a neurotoxic compound that can bind to monoamine transporters and enter cells and emit yellow fluorescence (the order of binding strength is dopamine transporter > adrenaline transporter > 5-HT transporter body). When there are other compounds that can bind to the transporter and compete with ASP, the number of ASP entering the cell decreases, and the yellow fluorescence weakens. The reuptake inhibitors acting on the 5-HT transporter are screened by comparing the changes in fluorescence intensity.

RBL-2H3 cells are a cell line that can secrete histamine and 5-HT. The cells are immortalized mast cells that can quantum release the aforementioned transmitters; and have SERT that can reuptake 5-HT.

CACO-2 cells are adenocarcinoma cell lines derived from the human small intestine. In the study, it was found that the cells that have been cultured and differentiated for a period of time can express a variety of transporters and receptors, including SERT, adenosine receptors, etc., through the establishment of cell culture The standardization process enables cells to achieve good differentiation after 6-7 days of culture. By pre-adding the test product to be screened for a period of time, adding a fluorescent dye at a certain concentration, washing away the dye that has not entered the cells, and comparing different samples Between the fluorescence intensity of ASP, you can find samples that directly inhibit SERT activity, or indirectly affect transporter activity through activation/inhibition of adenosine receptors.

2. Experimental equipment

Cells: RBL-2H3, CACO-2 cell lines, from the National Center for Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences.

Reagents: (1) cell culture medium; (2) fluorescent dye ASP.

Instrument: continuous spectrum enzyme label tester (spectramaxM5) produced by moleculardevices company.

3. Operating procedures

3.1 Cell culture

RBL cell lines were purchased from China Center for Type Culture Collection. The cell line was cultured in EMEM containing 1.5g/L sodium bicarbonate, 0.1mM non-essential amino acids, 1.0mM sodium pyruvate, 2mML-glutamine and Earle'sBSS, 85%; heat-inactivated FBS15%. nourish. The cells need to change the medium every other day, and the cells need to be subcultured when the cell proliferation reaches 80%, the ratio is 1:3.

Cell culture: Strict aseptic operation, cell culture with MEMα complete medium containing 15% fetal bovine serum, experiment when the cells reach the logarithmic growth phase, wash twice with D-hanks solution, add 0.125% pancreatic Digest the cells with enzymes and place them at 37°C for 5 minutes to open the intercellular connections and distribute the cells individually. Add an equal volume of complete medium to stop the digestion, gently pipette the cells, place the suspension in a centrifuge tube at 800 rpm, centrifuge for 3 minutes, and discard. Remove the supernatant, resuspend the cells with complete medium, count, and dilute the cells to 6×10 ⁵ cells/ml for later use.

Cell plating and dosing, adding fluorescent dyes: 4×10 ⁵ cells/ml cell suspension at 0.1ml/well, add to 96-well plate, wait for the cells to adhere to the wall and grow for more than 10 hours, when the growth is good, the fluorescent high-throughput screening experiment can be carried out , read at the excitation wavelength of 475nm and the emission wavelength of 605nm, and perform statistics on the results.

The CACO-2 cell line was preserved in the laboratory of the National Center for Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences. The cell line was cultured in EMEM containing 1.5g/L sodium bicarbonate, 0.1mM non-essential amino acids, 1.0mM sodium pyruvate, 2mML-glutamine and Earle'sBSS, 80%; heat-inactivated FBS 20%. nourish. The cells need to change the medium every other day, and the cells need to be subcultured when the cell proliferation reaches 80%, the ratio is 1:3.

3.2 Cell plating and differentiation

Add cells at 1×10 ⁵ /ml, 100ul per well into a 96-well black-bottomed transparent culture plate, change the medium every other day when the cells are not full, and change the medium every day when the cells grow rapidly and cover the bottom, and wait for their differentiation After 6 to 7 days of growth, cells can be seen with unclear cell boundaries and microvilli growth. Fluorescence high-throughput screening experiments can be carried out. Read at the excitation wavelength of 475nm and emission wavelength of 605nm for statistical results.

4. Data processing

Calculate the fluorescence intensity inhibition rate:

5. Test samples

4-Alkyl-6-aryl-3,4-dihydropyrimidine-2-thiones were all screened by the SERT transporter inhibitor screening model established in RBL-2H3 cells.

6. Evaluation of results

When the concentration was 10.0mg/L, the inhibition rate of 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thione to SERT was screened, and the excellent compound was 6-methyl-4-(4 -chlorophenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione. When the concentration was 10.0mg/L, the inhibition rate of the excellent compound 6-methyl-4-(4-chlorophenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione to SERT was 59.2%; when the concentration is 0.0293mmol/L, the inhibition rate of 6-methyl-4-(4-chlorophenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione to SERT 61.0%; the inhibitory activity of 6-methyl-4-(4-chlorophenyl)-5-ethoxycarbonyl-3,4-dihydropyrimidine-2-thione on SERT, _IC50 is 0.00697mmol/L .

The 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thione has good inhibitory activity on SERT and can be used as an antidepressant preparation.

Claims (2)

1. 4-alkyl-6-aryl-3 shown in chemical structural formula I, 4-dihydro-pyrimidin-2-thioketones and pharmaceutically acceptable salt are in the application of preparing in antidepressant drug:

Wherein, R ¹be selected from: C ₁～C ₂alkyl, C ₃～C ₄straight chained alkyl or branched-chain alkyl; R is selected from: CH ₃or C ₂h ₅; X ₁be selected from: methyl, ethyl, methoxy or ethoxy; X ₂be selected from: methyl, ethyl, methoxyl group, oxyethyl group or nitro; X ₃be selected from: methyl, ethyl, chlorine, bromine, fluorine, hydroxyl, methoxyl group, oxyethyl group or nitro; X ₄be selected from: methyl, ethyl, methoxyl group, oxyethyl group or nitro.

2. application as claimed in claim 1,4-alkyl-6-aryl-3 shown in its Chinese style I, 4-dihydro-pyrimidin-2-thioketones is selected from following compounds: