CN111518012A - Compound containing phenylene sulfide structure or its pharmaceutically acceptable salt, preparation method and use - Google Patents

Abstract

The present invention discloses a compound containing a phenylene sulfide structure having the structure of general formula (I) or a pharmaceutically acceptable salt thereof, a preparation method and use thereof. The compound containing a phenylene sulfide structure of the present invention or a pharmaceutically acceptable salt thereof can be used for preparing an antidepressant drug.

Description

Compound containing phenylene sulfide structure or pharmaceutically acceptable salt thereof, preparation method and use

technical field

The present invention relates to the field of medicinal chemistry, in particular to a compound containing a phenylene sulfide structure or a pharmaceutically acceptable salt thereof, a preparation method and use thereof.

Background technique

Depression, as a common mental illness, has the characteristics of high recurrence rate, high suicide rate, and high disability rate. Depression is listed by the World Health Organization as the second highest disability rate disease after cardiovascular disease. Among people with depression, 60% have suicidal thoughts, and about 15% eventually commit suicide. Because the clinical treatment of major depressive disorder has the characteristics of long course of treatment and poor medication compliance of patients, conventional antidepressant drugs have little effect.

The pathogenesis of depression is complex, and the currently accepted mechanism is the hypothesis of dysfunction of monoamine neurotransmitters in the brain. The monoamine neurotransmitter hypothesis believes that the lack or functional decline of monoamine neurotransmitters such as 5-HT and norepinephrine in the brain of patients leads to the occurrence of depression.

Serotonin transporter (SERT) is a transmembrane transporter with high affinity for 5-HT, which can re-uptake serotonin in the synaptic cleft to regulate nerve signal transduction. Therefore, inhibiting the serotonin transporter to increase the concentration of 5-HT in the synaptic cleft and the selectivity of drug action has become an important strategy for the treatment of depression. Selective serotonin reuptake inhibitors (Selective Serotonin Reuptake Inhibitors, SSRIs) can improve the symptoms of depression in patients by inhibiting the serotonin transporter to achieve the purpose of treatment. Representative drugs of SSRIs include Fluoxetine, Fluvoxamine, Paroxetine, Citalopram and Sertraline. Among them, escitalopram, the S-enantiomer of citalopram, was approved by the FDA in 2012 for the treatment of major depressive disorder. However, most SSRIs have the disadvantages of low response rate, low cure rate, sexual dysfunction, and easy recurrence. In 2011, the FDA approved vilazodone for the treatment of major depressive disorder in adults, and vilazodone was the first SSRI and 5-HT _1A receptor partial agonist to be marketed in the United States. Compared with existing SSRIs, vilazodone has a unique mechanism of action, clear clinical efficacy, fewer sexual side effects, and is effective in depression of varying symptoms and severity.

Vortioxetine as 5-HT _3A , 5-HT ₇ receptor antagonist, 5-HT _1B receptor partial agonist, 5-HT _1A receptor agonist and highly potent 5-HT transporter inhibitor, It has high affinity for 5-HT _1A , 5-HT _1B , 5-HT _3A , 5-HT ₇ receptors, noradrenergic receptor β1 and 5-HT transporter, and has a good effect on depression. Although compared with vilazodone, efficacy was not significantly improved. However, vortioxetine is well tolerated, with fewer adverse reactions such as sexual dysfunction and weight gain, and can significantly improve the response rate and cure rate. Therefore, by combining the 5-HT transporter pharmacophore in the vilazodone structure with the vortioxetine pharmacophore and optimizing the structure, it is possible to obtain strong antidepressant effect, short onset time and good tolerance Newer antidepressants.

SUMMARY OF THE INVENTION

Object of the invention: The object of the present invention is to provide a compound containing a phenylene sulfide structure or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a preparation method of the compound containing a phenylene sulfide structure or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide the use of the compound containing a phenylene sulfide structure or a pharmaceutically acceptable salt thereof.

Technical scheme: The present invention provides a compound of general formula (I) containing a phenylene sulfide structure or a pharmaceutically acceptable salt thereof,

Wherein, R represents CN, F, Cl, Br, I or CF ₃ ; n represents 1-5.

Further, the R represents CN.

Further, the R represents CN.

Further, the described compound with general formula (I) structure containing phenylene sulfide structure or its pharmaceutically acceptable salt is any of the following:

3-(4-(4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazinyl)butyl)-5-cyanoindole (I-1);

3-(4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazinyl)propyl)-5-cyanoindole (I-2);

3-(5-(4-(2-((2,4-Dimethylphenyl)thio)phenyl)piperazinyl)pentyl)-5-cyanoindole (I-3).

Further, the salt is hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p- A salt of addition of toluenesulfonic acid or ferulic acid to an indole structure-containing compound having the structure of general formula (I).

The described preparation method of the compound containing the phenylene sulfide structure or its pharmaceutically acceptable salt with the structure of general formula (I), the synthesis technique is as follows:

Compound (II) and compound (III) are reacted under the condition of a base and an organic solvent to obtain compound (IV), and compound (IV) is reacted under the condition of a base and an organic solvent to obtain compound (I),

The definitions of R and n are the same as in claim 1, and X=Cl, Br or I.

The preparation method of compound II is as follows:

The definitions of R, n and X are the same as before.

Compound V, aqueous sodium hydroxide solution, tetrabutylammonium bromide and toluene are mixed, and the toluene solution of p-toluenesulfonyl chloride is added dropwise with stirring. After completion of the reaction, compound VI is obtained by post-treatment.

Aluminium trichloride and dichloromethane are mixed, and under stirring, the corresponding halogenated acid chloride dissolved in dichloromethane and compound VI are sequentially added dropwise. After the reaction is completed, compound VII is obtained by post-treatment.

At low temperature, trifluoroacetic acid and sodium borohydride are mixed, and after stirring uniformly, the dichloromethane solution of compound VII is added, and after completion of the reaction, compound II is obtained by post-treatment.

The preparation method of compound III is as follows:

3-Amino-2-nitro-4-bromopyridine (VIII) and piperazine were placed in a pressure-resistant bottle, and the temperature was raised to 120°C for reaction. After the reaction is completed, 3-amino-4-(piperazin-1-yl)-2-nitropyridine (IX) is obtained by post-treatment.

3-Amino-4-(piperazin-1-yl)-2-nitropyridine (IX) was dissolved in absolute ethanol, hydrazine hydrate and Pd/C were added, and the reaction was allowed to stand at room temperature. After completion of the reaction, 2,3-diamino-4-(piperazin-1-yl)pyridine (X) is obtained by post-treatment.

2,3-Diamino-4-(piperazin-1-yl)-pyridine (X) was dissolved in absolute ethanol, triethyl orthoformate was added, and the reaction was heated. After the completion of the reaction, 7-(piperazin-1yl)-3H-imidazo[5,4-b]pyridine (III) was obtained by post-treatment.

Further, compound (IV) is prepared by reacting compound (II) and (III), the base used is triethylamine, potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide, and the reaction solvent is ethyl acetate, toluene, Glycol dimethyl ether, dioxane, N,N-dimethylformamide or dimethylsulfoxide.

Further, to prepare compound (I) from compound (IV), the base used is sodium hydroxide or potassium hydroxide, and the solvent used is methanol, ethanol, water or a mixed solvent of any two.

A pharmaceutical composition, which contains the compound having the structure of general formula (I) containing a phenylene sulfide structure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or auxiliary material. The compound can be added with a pharmaceutically acceptable carrier to make common pharmaceutical preparations, such as tablets, capsules, syrups, suspensions, injections, and commonly used flavors, sweeteners, liquid or solid fillers or diluents can be added. medical supplements.

The use of the compound containing a phenylene sulfide structure having the structure of general formula (I) or a pharmaceutically acceptable salt thereof in the preparation of an antidepressant drug.

Beneficial effects: The compound containing phenylene sulfide structure or the pharmaceutically acceptable salt thereof of the present invention can be used to prepare antidepressant drugs.

Detailed ways

Example 1

Preparation of 3-(4-(4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazinyl)butyl)-5-cyanoindole (I-1)

1-p-Tosyl-5-cyanoindole (VI)

5-Cyanoindole (V) (10.0 g, 0.07 mol) was added to toluene (300 mL) and heated until the sample dissolved. The reaction solution was cooled to room temperature, 15% NaOH aqueous solution (300 mL) and tetrabutylammonium bromide (2.3 g) were added, and a solution of p-toluenesulfonyl chloride (14.8 g, 0.074 mol) in toluene (100 mL) was added dropwise at room temperature, followed by stirring. React for 1 hour. It was extracted with ethyl acetate (3×125 mL), and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, and the filtrate was evaporated to dryness under reduced pressure to obtain 20.5 g of pale red crude product. It was recrystallized with absolute ethanol (120 mL) to obtain 20.4 g of white crystals, yield 98.0%, mp 116-118°C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.07 (d, 1H, J=8.7 Hz, 7-ArH), 7.87 (d, 1H, J=1.4 Hz, 4-ArH), 7.78 (d , 2H, J=8.3Hz, 1'-ArH), 7.70 (d, 1H, J=3.7Hz, ₂ -ArH), 7.55 (dd, 1H, J1 ₌ 8.7Hz, J2=1.4Hz, 6- ArH), 7.26 (d, 2H, J=8.3 Hz, 2'-ArH), 6.72 (d, 1H, J=3.7 Hz, 3-ArH), 2.36 (s, 3H, _-CH3 ).

1-p-Tosyl-3-(4-chlorobutyryl)-5-cyanoindole (VII-1)

AlCl ₃ (18.7 g, 0.14 mol) and dichloromethane (400 mL) were added to a 1 L three-neck flask. A solution of 4-chlorobutyryl chloride (11.4 g, 0.081 moL) in dichloromethane (40 mL) was added dropwise with stirring at room temperature, and stirred until most of the AlCl ₃ was dissolved. A solution of compound VI (20.0 g, 0.067 moL) in dichloromethane (200 mL) was added dropwise, the dropping was completed, and the reaction was continued for 8 hours. The reaction solution was slowly added to ice water (600 mL), extracted with dichloromethane (3×250 mL), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was evaporated to dryness under reduced pressure to obtain 25.7 g of crude product. Recrystallization from n-propanol (600 mL) gave 24.3 g of white solid, yield 89.8%, mp 154-156°C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.71 (s, 1H, 4-ArH), 8.36 (s, 1H, 2-ArH), 8.03 (d, 1H, J=8.7 Hz, 7- ArH), 7.86 (d, 2H, J=8.3Hz, 1'-ArH), 7.62 (dd, 1H, J1 ₌ 8.7Hz, J2=1.4Hz, ₆ -ArH), 7.34 (d, 2H, J =8.3Hz, _2' -ArH), 3.69 (t, 2H, J=6.3Hz, _-CH2CH2Cl ), 3.13 (t, 2H, J=6.3Hz, _{-COCH2CH2- )} , 2.40 (s, 3H, _-CH3 ), 2.26 (q, 2H, J=6.3 Hz, _-CH2CH2Cl- ); HRMS (ESI): m/z [ _M +H]+ _calcd . for C20H _18ClN2O3S : _401.0721 ; found: _401.0722 .

1-p-Tosyl-3-(4-chlorobutyl)-5-cyanoindole (II-1)

Trifluoroacetic acid (375mL) was added to a 1L three-neck flask and cooled to about -10°C. Sodium borohydride (25.4g, 0.6732mol) was slowly added in batches. After the addition, compound VII-1 (15.0g, 37.4g) was added. mmol) in dichloromethane (281 mL) and stirred at room temperature for 6 hours. The reaction solution was poured into ice water, extracted with dichloromethane (3×250 mL), the organic layers were combined, washed three times with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, and the filtrate was evaporated to dryness under reduced pressure to obtain 13.5 g of crude product, which was recrystallized from anhydrous methanol (450 mL) to obtain 12.5 g of white solid, yield 86.4%, mp 110-112°C. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 8.06 (d, 1H, J=8.6 Hz, 7-ArH), 7.81 (s, 1H, 4-ArH), 7.75 (d, 2H, J=8.3Hz, 1'-ArH), 7.56(d, 1H, J=8.6Hz, 6-ArH), 7.46(s, 1H, 2-ArH), 7.25(d, 2H, J=8.3Hz, 2 '-ArH), 3.57 (m, 2H, _-CH2Cl ), 2.70 (m, 2H, _-CH2 ( _{CH2 ) 2CH2Cl} ), 2.36 (s, 3H, _-CH3 ), 1.76-1.92 (m, 4H, - ( _{CH2 ) 2CH2Cl} ). MS (ESI, 70V): m/z = 385 [MH] ^- .HRMS (ESI): m/z [M+Na]+calcd.for _{C20H19ClN2NaO2S : 409.0748} ; found: _409.0744 .

1-p-Tosyl-3-(4-(4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazinyl)butyl)-5-cyanoindole (IV-1)

Compound II-1 (0.3 g, 0.775 mmol), vortioxetine (III) (0.25 g, 0.838 mmol), triethylamine (1 mL), appropriate amount of potassium iodide and DMF (20 mL) were added to a 100 mL eggplant flask, 80 -85°C for 12 hours. After cooling, the reaction solution was added to ice water (100 mL), extracted with ethyl acetate (3×100 mL), the organic layers were combined, washed with saturated brine (3×150 mL), and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was separated by column chromatography (eluent: dichloromethane-methanol=60:1) to obtain 0.27 g of a brown solid, yield 52.5%, mp 64-66°C. ¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 8.08 (d, J=8.4 Hz, 1H, ArH), 7.85 (s, 1H, ArH), 7.78 (d, J=7.9 Hz, 2H, ArH) ), 7.57(d, J=8.7Hz, 1H, ArH), 7.48(s, 1H, ArH), 7.40(d, J=7.7Hz, 1H, Ar'H), 7.28(d, J=8.0Hz, 2H, ArH), 7.17 (s, 1H, Ar'H), 7.11 (m, 2H, Ar'H), 7.05 (d, J=8.0Hz, 1H, Ar'H), 6.88 (m, 1H, Ar''H), 6.52 (d, J=8.1 Hz, 1H, Ar'H), 3.17 (s, 4H, 2CH ₂ ), 2.72 (m, 4H, CH ₂ CH ₂ N<&Ar-CH ₂ -CH ₂ ), 2.38 (s, 4H, 2CH ₂ ), 2.33 (s, 3H, -CH ₃ ), 1.74 (m, 2H, Ar-(CH ₂ ) ₂ -CH ₂ ), 1.58 (s, 3H, Ar ' _-CH3 ), 1.28 (s, 3H, Ar'- _CH3 ), 0.90 (m, 2H, Ar- _CH2 - _CH2 ); MS (ESI(+) 70eV) m/z: 649.3 [M +H] ⁺ .

3-(4-(4-(2-((2,4-Dimethylphenyl)thio)phenyl)piperazinyl)butyl)-5-cyanoindole (I-1)

IV-1 (0.5 g, 0.77 mmol), sodium hydroxide (0.5 g, 12.5 mmol) and methanol (25 mL) were added to a 50 mL eggplant flask, and the reaction was carried out under reflux for 4 hours. After cooling, the reaction solution was evaporated to dryness under reduced pressure, 50 mL of ice water was added, extracted with ethyl acetate (3×40 mL), the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was separated by column chromatography (eluent: dichloromethane-methanol=100:1+TEA) to obtain 0.15 g of off-white solid, yield 39.5%, mp 58-60°C. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 11.28 (s, 1H, >NH), 7.98 (s, 1H, ArH), 7.39 (d, J=8.4 Hz, 1H, ArH), 7.29(d, J=8.4Hz, 1H, ArH), 7.22(d, J=7.8Hz, 2H, Ar'H), 7.12(s, 1H, ArH), 7.00(d, J=3.0Hz, 2H, Ar'H), 6.97(s, 1H, Ar'H), 6.77(t, J=7.4Hz, 1H, Ar'H), 6.25(d, J=8.0Hz, 1H, Ar'H), 2.86( s, 4H, _2CH2 ), 2.63 (t, J=7.3Hz, _2H , _CH2CH2N <), 2.27 (t, J=7.1Hz, 2H, Ar- _CH2 - _CH2 ), 2.21 (s, 4H, 2CH ₂ ), 2.12 (m, 2H, CH ₂ CH ₂ N<), 1.57 (s, 3H, Ar'-CH ₃ ), 1.41 (s, 3H, Ar'-CH ₃ ), 1.12 (m, 2H, Ar-CH ₂ -CH ₂ ). ¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 20.09, 20.68, 24.27, 26.13, 27.47, 51.02 (2C), 53.16 (2C) ，58.02，101.56，111.48，114.50，117.00，119.33，120.49，122.91，123.84，124.21，124.97，125.60，126.94，127.29，127.49，131.17，134.05，135.74，137.54，138.70，141.97，148.66.HRMS(ESI)： m/z[M+H] ⁺ calcd for C ₃₁ H ₃₅ N ₄ S: 495.2577; found: 495.2578.

Example 2

Preparation of 3-(4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazinyl)propyl)-5-cyanoindole (I-2)

1-p-Tosyl-3-(3-chloropropionyl)-5-cyanoindole (VII-2)

Using compound VI (8.0 g, 0.027 mol) as raw material, 3-chloropropionyl chloride as acylating agent, and operating the same as compound VII-1, 8.5 g of white solid was obtained, yield 81.4%, mp 102-104°C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.72 (s, 1H, 2-ArH), 8.33 (s, 1H, 4-ArH), 8.03 (d, 1H, J=8.7 Hz, 7- ArH), 7.84 (d, 2H, J=8.3Hz, 1'-ArH), 7.63 (dd, 1H, J1 ₌ 8.7Hz, J2=1.4Hz, ₆ -ArH), 7.34 (d, 2H, J =8.2Hz, 2'-ArH), 3.94 (t, 2H, J=6.5Hz, _-CH2Cl ), 3.72 (t, 2H, J=6.5Hz, _-COCH2- ), 2.41 (s, 3H, -CH ₃ ).

1-p-Tosyl-3-(3-chloropropyl)-5-cyanoindole (II-2)

Using compound VII-2 (3.1 g, 8.01 mmol) as raw material, the same operation as compound II-1 was used to obtain 2.35 g of white solid, yield 78.1%, mp 106-108°C. ¹ H-NMR (300 MHz, CDCl ₃ ), δ (ppm): 8.07 (d, 1H, J=8.6 Hz, 7-ArH), 7.83 (s, 1H, 4-ArH), 7.76 (d, 2H, J =8.3Hz, 1'-ArH), 7.56(d, 1H, J=8.6Hz, 6-ArH), 7.43(s, 1H, 2-ArH), 7.25(d, 2H, J=8.3Hz, 2 '-ArH), 3.53 (t, 2H, J=6.6Hz, _-CH2Cl ), 2.87 (t, 2H, J=6.6Hz, _ArCH2- ), 2.36 (s, 3H, _-CH3 ), 2.09 ~2.20 ₍ m, 2H, _{-CH2CH2CH2Cl )} .

1-p-Tosyl-3-(3-(4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazinyl)propyl)-5-cyanoindole (IV-2)

Using compound II-2 (0.8 g, 2.16 mmol) and compound III (0.77 g, 2.58 mmol) as raw materials, the same operation as compound IV-1 was used to obtain 0.76 g of an orange-yellow solid, yield 55.5%, mp 86-88°C. ¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 8.09 (d, J=8.5 Hz, 1H, ArH), 7.89 (s, 1H, ArH), 7.77 (d, J=8.1 Hz, 2H, ArH) ), 7.58(d, J=8.5Hz, 1H, ArH), 7.49(s, 1H, ArH), 7.39(d, J=7.7Hz, 1H, Ar'H), 7.28(d, J=8.0Hz, 2H, ArH), 7.16 (s, 1H, Ar'H), 7.10 (m, 2H, Ar'H), 7.04 (d, J=7.7Hz, 1H, Ar'H), 6.88 (m, 1H, Ar''H), 6.52 (d, J=8.0Hz, 1H, Ar'H), 3.17 (s, 4H, 2CH ₂ ), 2.76 (m, 2H, CH ₂ CH ₂ N<), 2.38 (s, 7H , 2CH ₂ &-CH ₃ ), 2.34 (s, 2H, Ar-CH ₂ -CH ₂ ), 1.97 (s, 3H, Ar'-CH ₃ ), 1.28 (s, 3H, Ar'-CH ₃ ) , 0.90 (m, 2H, Ar-CH ₂ -CH ₂ ). MS (ESI(+) 70eV) m/z: 635.2 [M+H] ⁺

3-(3-(4-(2-((2,4-Dimethylphenyl)thio)phenyl)piperazinyl)propyl)-5-cyanoindole (I-2)

Using compound IV-2 (0.5g, 0.79mmol) and sodium hydroxide (0.5g, 12.5mmol) as raw materials, the same operation as compound I-1 was used to obtain 0.21g of light yellow solid, yield 55.3%, mp 76-78°C. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ (ppm): 11.37 (s, 1H, >NH), 8.11 (s, 1H, ArH), 7.50 (d, J=8.4 Hz, 1H, ArH), 7.40(d, J=8.4Hz, 1H, ArH), 7.35(s, 1H, ArH), 7.32(d, J=7.8Hz, 1H, Ar'H), 7.22(s, 1H, Ar'H), 7.13(t, J=8.6Hz, 1H, Ar'H), 7.08(d, J=7.6Hz, 2H, Ar'H), 6.89(t, J=7.4Hz, 1H, Ar'H), 6.39( d, J=7.8Hz, 1H, Ar'H), 3.01 (s, 4H, _2CH2 ), 2.76 (t, J=7.2Hz, _2H , _CH2CH2N <), 2.54 (m, 4H, 2CH ₂ ), 2.39 (m, 2H, Ar-CH ₂ -CH ₂ ), 2.32 (s, 3H, Ar'-CH ₃ ), 2.23 (s, 3H, Ar'-CH ₃ ), 1.87-1.78 ( m, 2H, Ar-CH ₂ -CH ₂ ). ¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 20.11, 20.70, 22.12, 26.79, 51.12 (2C), 53.18 (2C), 57.64, 101.57 ，111.48，114.50，116.85，119.33，120.49，122.92，123.86，124.28，125.00，125.61，127.03，127.31，127.47，131.19，134.05，135.77，137.49，138.74，141.99，148.68.HRMS(ESI)：m/z[ M+H] ⁺ calcd for C ₃₀ H ₃₃ N ₄ S: 481.2420; found: 481.2420.

Example 3

Preparation of 3-(5-(4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazinyl)pentyl)-5-cyanoindole (I-3)

1-p-Tosyl-3-(5-bromovaleryl)-5-cyanoindole (VII-3)

Using compound VI (8.0 g, 0.027 mol) as raw material, 5-bromovaleryl chloride as acylating agent, and operating the same as compound VII-1, 10.4 g of white solid was obtained, yield 83.8%, mp 120-122°C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.73 (s, 1H, 2-ArH), 8.31 (s, 1H, 4-ArH), 8.02 (d, 1H, J=8.7 Hz, 7- ArH), 7.84 (d, 2H, J=8.3Hz, 1'-ArH), 7.62 (d, 1H, J=8.7Hz, 6-ArH), 7.33 (d, 2H, J=8.3Hz, 2'- ArH), 3.46(t, 2H, J=6.3Hz, -CH2Br), 2.95(t, 2H, J=6.3Hz, _{-COCH2- )} , 2.40(s, 3H, _-CH3 ), 1.88～ _2.10 (m, 4H, -COCH2( _{CH2 ) 2CH2Br} ).

1-p-Tosyl-3-(5-bromopentyl)-5-cyanoindole (II-3)

Using compound VII-3 (3.0 g, 6.53 mmol) as raw material, the operation was the same as II-1 to obtain 2.65 g of white solid, yield 91.1%, mp 99-100°C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.06 (d, 1H, J=8.6 Hz, 7-ArH), 7.80 (s, 1H, 4-ArH), 7.75 (d, 2H, J= 8.3Hz, 1'-ArH), 7.55(d, 1H, J=8.6Hz, 6-ArH), 7.44(s, 1H, 2-ArH), 7.25(d, 2H, J=8.3Hz, 2'- ArH), 3.41 (t, 2H, J=6.6 Hz, -CH ₂ Cl), 2.68 (t, 2H, J=6.6 Hz, ArCH ₂ -), 2.36 (s, 3H, -CH ₃ ), 1.48-1.98 (m, 6H, -CH ₂ (CH ₂ ) ₃ CH ₂ Br).

1-p-Tosyl-3-(5-(4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazinyl)pentyl)-5-cyanoindole (IV-3)

Using compound II-3 (0.8 g, 1.80 mmol) and compound III (0.64 g, 2.16 mmol) as raw materials, the same operation as compound IV-1 was used to obtain about 0.63 g of an orange-yellow solid, yield 52.5%, mp 66-68°C. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ (ppm): 8.20 (s, 1H, ArH), 8.08 (d, J=8.5 Hz, 1H, ArH), 7.88 (d, J=8.2 Hz, 2H) , ArH), 7.77(s, 1H, ArH), 7.73(d, J=8.3Hz, 1H, ArH), 7.38(d, J=8.0Hz, 2H, ArH), 7.32(d, J=7.7Hz, 1H, Ar'H), 7.22 (s, 1H, Ar'H), 7.09 (m, 3H, Ar'H), 6.89 (dd, J1 ₌ 9.3Hz, J2=4.2Hz, 1H, _Ar'H ), 6.38(d, J=7.7Hz, 1H, Ar'H), 2.95(s, 4H, _2CH2 ), 2.69(t, J=7.2Hz, _2H , _CH2CH2N <), 2.31( s, 7H, 2CH ₂ &-CH ₃ ), 2.23 (s, 2H, Ar-CH ₂ -CH ₂ ), 1.66 (s, 3H, Ar'-CH ₃ ), 1.48 (s, 3H, Ar'- CH ₃ ), 1.32-1.09 (m, 6H, Ar-CH ₂ -(CH ₂ ) ₃ - ); MS (ESI(+) 70eV) m/z: 663.3 [M+H] ⁺ .

3-(5-(4-(2-((2,4-Dimethylphenyl)thio)phenyl)piperazinyl)pentyl)-5-cyanoindole (I-3)

Using compound IV-3 (0.5 g, 0.75 mmol) and sodium hydroxide (0.5 g, 12.5 mmol) as raw materials, the same operation as compound I-1 was used to obtain 0.2 g of orange-yellow solid, yield 52.6%, mp 118-120°C. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ (ppm): 11.36 (s, 1H, >NH), 8.06 (s, 1H, ArH), 7.49 (d, J=8.3 Hz, 1H, ArH), 7.39 (d, J=7.8Hz, 1H, ArH), 7.32 (d, J=7.1Hz, 2H, Ar'H), 7.22 (s, 1H, ArH), 7.10 (m, 3H, Ar'H), 6.88 (s, 1H, Ar'H), 6.38 (d, J=7.6Hz, 1H, Ar'H), 2.96 (s, 4H, _2CH2 ), 2.72 (t, J=7.0Hz, 2H, _CH2 CH2N<), 2.32 (s, _4H , _2CH2 ), 2.23 (m, 2H, Ar- _CH2 - _CH2 ), 1.68 (s, 3H, Ar'- _CH3 ), 1.51 (s, 3H, Ar'-CH ₃ ), 1.36-1.23 (m, 6H, Ar-CH ₂ -(CH ₂ ) ₃ - ); ¹³ C-NMR (75MHz, DMSO-d ₆ )δ(ppm): 20.10, 20.69，24.30，26.20，26.99，29.21，29.51，51.05(2C)，53.15(2C)，58.24，101.61，111.42，117.34，119.31，120.47，122.74，123.82，124.25，124.96，125.61，127.00，127.29，127.50， 128.25, 131.17, 134.06, 135.75, 137.49, 138.70, 141.97, 148.69; HRMS (ESI): m/z[M+H] ⁺ calcd for C ₃₂ H ₃₇ N ₄ S: 509.2733; found: 509.2729.

Example 4

Pharmacological experiments and results of some compounds of the present invention are as follows:

1) Antidepressant activity test

Experimental principle: The mouse forced swimming experimental model was used to observe the effect of compounds on immobility time of mice, and to investigate the antidepressant activity of these compounds.

Experimental drugs: Compounds I-1 to I-3, assisted by 1% DMSO.

Experimental grouping: 40 ICR male mice were randomly divided into 4 groups according to body weight, 10 mice in each group. They were blank control group (physiological saline containing 1% DMSO) and three test drug groups (10 mg/kg), and the administration volume was 0.2 mL/10 g. Experimental method: After the mice were purchased and delivered, they were adapted to the environment and raised for 7 days, so that the body weight reached about 22g and can be administered.

The mice were administered by intragastric administration for 7 consecutive days, once a day, and pre-swimming was performed 1 hour after intragastric administration on the 6th day. Pre-swimming was 24 hours before the formal forced swimming experiment. In a 2000mL container with a water depth of 10em and a water temperature of 25°C, swim for 15 minutes, and fast for 12 hours before the formal experiment. On the 7th day, the formal forced swimming experiment was started 1 hour after the last intragastric administration. The mice were placed in the same environment as the pre-swimming, and observed for 6 minutes. After recording, the accumulated immobility time (stop struggling or floating, Only minor limb movements to keep the head afloat).

Experimental results: The statistical results using one-way analysis of variance are shown in Table 1:

Table 1 Results of forced swimming experiment of mice (10 mice/group)

sample name Immobility time (s) Improvement rate (%) blank 184.4±35.4 - I-1 153.2±28.6^＊＊ 16.9 I-2 170.2±33.3^* 7.7 I-3 153.9±23.2^＊＊ 16.5

Note: ^* p<0.05; ^** p<0.01, the drug is compared with the blank group

As can be seen from Table 1, in the forced swimming experiment of mice, the intragastric administration of compound I-1 (16.9%, p<0.01) and I-3 (16.5%, p<0.01) had certain antidepressant activity.

On the basis of the above results, compound I-1 with better activity was selected, and high and low doses (10mg/kg and 20mg/kg) of antidepressant activity experiments were carried out using the same mouse model and method. The experimental results are shown in Table 2:

Table 2 Results of forced swimming experiment of high and low dose mice (10 mice/group)

Note: ^* p<0.05; ^** p<0.01, the drug is compared with the blank group

As can be seen from Table 2, Compound I-1 showed good antidepressant activity at the dosage of 10 mg/kg (22.2%, p<0.01) and 20 mg/kg (22.4%, p<0.01), and There is a certain dose dependence.

Claims (10)

1. A compound containing a phenyl sulfide structure with a structure shown in a general formula (I) or a pharmaceutically acceptable salt thereof,

wherein R represents CN, F, Cl, Br, I or CF₃(ii) a n represents 1 to 5.

2. The compound containing phenylsulfide structure having the structure of general formula (I) or its pharmaceutically acceptable salt according to claim 1, characterized in that: and R represents CN.

3. The compound containing phenylsulfide structure having the structure of general formula (I) or its pharmaceutically acceptable salt according to claim 1, characterized in that: and n is 1-3.

4. The compound containing phenylsulfide structure having the structure of general formula (I) or pharmaceutically acceptable salt thereof according to claim 1, is any one of the following:

3- (4- (4- (2- ((2, 4-dimethylphenyl) thio) phenyl) piperazinyl) butyl) -5-cyanoindole (I-1);

3- (4- (2- ((2, 4-dimethylphenyl) thio) phenyl) piperazinyl) propyl) -5-cyanoindole (I-2);

3- (5- (4- (2- ((2, 4-dimethylphenyl) thio) phenyl) piperazinyl) pentyl) -5-cyanoindole (I-3).

5. The compound containing phenylsulfide structure having the structure of general formula (I) or its pharmaceutically acceptable salt according to claim 1, characterized in that: the salt is the addition salt of hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid and a compound containing an indole structure and having a structure in a general formula (I).

6. The method for preparing a compound containing a phenylsulfide structure having the structure of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: the synthesis process comprises the following steps:

reacting a compound (II) with a compound (III) under the conditions of alkali and an organic solvent to obtain a compound (IV), reacting the compound (IV) under the conditions of alkali and an organic solvent to obtain a compound (I),

wherein R and n are as defined in claim 1 and X is Cl, Br or I.

7. The method for preparing the compound containing a phenylsulfide structure with the structure of the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 6, characterized in that: the compound (IV) is prepared by the reaction of the compounds (II) and (III), the used alkali is triethylamine, potassium carbonate, sodium hydroxide or potassium hydroxide, and the reaction solvent is ethyl acetate, toluene, ethylene glycol dimethyl ether, dioxane, N-dimethylformamide or dimethyl sulfoxide.

8. The method for preparing the compound containing a phenylsulfide structure with the structure of the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 6, characterized in that: the compound (I) is prepared from the compound (IV), the alkali is sodium hydroxide or potassium hydroxide, and the solvent is methanol, ethanol, water or a mixed solvent of any two.

9. A pharmaceutical composition, which comprises the compound containing phenylsulfide structure with general formula (I) or its pharmaceutically acceptable salt according to any one of claims 1-5, and pharmaceutically acceptable carrier or adjuvant.

10. Use of the compound containing a phenylsulfide structure with the structure of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of an antidepressant medicament.