Indian Patents. 272138:AMINE COMPOUNDS AND MEDICAL USES THEREOF

Title of Invention	AMINE COMPOUNDS AND MEDICAL USES THEREOF
Abstract	The present invention relates to a new amine compound or a pharmaceutically acceptable salt thereof, wherein the definitions of X, R1, R2 and n are given in the description, to a pharmaceutical composition containing the compound as active ingredient, and to use of the amine compound or its pharmaceutically acceptable salt for the manufacture of an anti-depressent drug.

Full Text	Technical field The present invention relates to new amine compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds as an active ingredient, and uses of such amine compounds or pharmaceutically acceptable salts thereof for manufacture of antidepressant drugs. Background Depression is the most common nerval and mental disorder that seriously affects physical and psychological health of people. With the acceleration of living tempo and the elevation of social pressure, the incidence of depression increases significantly. Treatments with drugs are main means for treatment of depression. Principal theraputical drugs include: tricyclic antidepressant drugs such as imipramine, amitriptyline, etc.; monoamine oxidase inhibitors such as moclobemide, etc.; selective serotonin reuptake inhibitors such as fluoxetine, sertraline, etc.; selective noradrenaline reuptake inhibitors such as reboxetine, etc.; dual noradrenergic/serotonergic inhibitors such as mirtazapine, etc.; dual serotonin/noradrenaline reuptake inhibitors such as venlafaxine, Duloxetine, etc. Currently, these commonly used drugs usually have drawbacks of slow onset, low efficiency and significant toxic and side effects and the like. US Patent USP4018895 discloses antidepressant drugs including fluoxetine, which have the following formula: wherein Ar is naphthalene ring or substituted benzene ring, and ri and R2 independently are H or CH3. Chinese Patent CN1019113 discloses antidepressant drugs including Duloxetine, which have the following formula: wherein Ar is naphthalene ring or substituted benezene ring, Ar' is cycloalkyl, thienyl, furyl or thiazolyl, ri and R2 independently are H or CH3. Contents of the Invention The present invention provides an amine compound represented by Formula I or a pharmaceutically acceptable salt thereof: wherein, X represents S or O; ri and R2 independently represent H or C1-4alkyl, or ri and R2 together with N atom to which they are attached can form a 5- or 6-membered heterocyclic ring; and n is 1 or 2. In the second aspect, the present invention relates to a method for preparing a compound of Formula I or a pharmaceutically acceptable salt thereof. In the third aspect, the present invention relates to a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as well as one or more pharmaceutically acceptable carriers or excipients. In the fourth aspect, the present invention relates to use of a compound of Formula I or a pharmaceutically acceptable salt thereof for manufacturing an antidepressant drug. Therefore, according to one embodiment of the present invention, the present invention provides an amine compound represented by the Formula I or a pharmaceutically acceptable salt thereof: wherein, X represents S or O; R1 and R2 independently represent H or a C1-4alkyl, or ri and R2 together with N atom to which they are attached can form a 5- or 6-membered heterocyclic ring; and n is 1 or 2. According to the present invention, the term "5- or 6-membered heterocyclic ring" includes but is not limited to pyrrole ring, piperidine ring, etc. Accroding to another embodiment of the present invention, the present invention provides an amine compound of the Formula I or a pharmaceutically acceptable salt thereof: wherein, X represents S or O; R1 and R2 independently represent H or a C1-4alkyl; and n is 1 or 2. According to one preferred embodiment of the present invention, the present invention provides an amine compound of the Formula I or a pharmaceutically acceptable salt thereof: wherein, X represents S or O; R1 and R2 independently represent H, methyl or ethyl; and n is 1 or 2. The present more preferably provides the following compounds: N,N-dimethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-(thiophen-2-yl)-propylami ne-oxalate; N-methyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-(thiophen-2-yl)-propylamineo xalate; N,N-diethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-(thiophen-2-yl)-propylamine oxalate; 1-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(thiophen-2-yl)-propyl]-pyrrolidineoxal ate; 1-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(thiophen-2-yl)-propyl]-piperidineoxal ate; N,N-dimethyl-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(furan-2-yl)]-propylamine- oxalate; N-methyl-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(furan-2-yl)]-propylamineoxal ate; N,N-dimethyl-3-[(benzo[1,4]dioxan-5-yl-oxy)-3-(thiophen-2-yl)-propylamine] oxalate; N-methyl-3-[(benzo[1,4]dioxan-5-yl-oxy)-3-(thiophen-2-yl)-propylamine]ox alate; and N,N-dimethyl-3-[(benzo[1,4]dioxan-5-yl-oxy)-3-(furan-2-yl)propylamine]oxa late. The amine compounds of the present invention can be prepared according to a method shown in following scheme: Specifically, acetyl thiophene or acetyl furan and a dialkyl amine as well as paraformaldehyde are dissolved in anhydrous ethanol. The mixture is adjusted to a pH value of 3-4 with concentrated hydrochloric acid, heated to reflux for 6-1 Oh to obtain 3-dialkylamino-1-(thiophen/furan-2-yl)-1 -acetone hydrochloride. The free base is obtained by alkalisation, and reacts with LiAIH4 to obtain a hydroxyl derivative in which the reaction solvent is anhydrous tetrahydrofuran, the reaction temperature is -5°C to room temperature and the reaction time is 1-5h; the hydroxyl derivative reacts with 4-hydroxyl-benzo[1,3]dioxolane or 5-hydroxyl-benzo[1,4]dioxane in the presence of triphenylphosphine and diethyl azodicarboxylate to obtain a target compound with a dialkyl substituted on the nitrogen atom, in which the reaction solvent is anhydrous tetrahydrofuran, the reaction temperature is -5°C to room temperature and the reaction time is 12-36h; the target compound with a dialkyl substituted on the nitrogen atom is subjected to the action of phenyl chloroformate to remove one substituent thereon to obtain a target compound with a monoalkyl substituted on the nitrogen atom. Similarly, tetrahydropyrrole or piperidine can be used to replace dialkylamine to carry out the above reaction to obtain a target compound in which R1 and R2 together with the N atom to which they are attached form a 5- or 6-membered heterocyclic ring. The free base of the target compound reacts with a corresponding acid to obtain a salt of the target compound. The present invention further provides pharmaceutically acceptable salts of the amine compounds of the Formula I, in which these salts can be formed by reacting the amino group of the amine compounds of the Formula I with various inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid or phosphoric acid, or formed by reacting the amino group of an amine compounds of the Formula I with various organic acids such as oxalic acid, maleic acid, benzoic acid, fumaric acid, etc. Oxalate is preferred. The present invention further provides a pharmaceutical composition comprising an amine compound of the Formula I or a pharmaceutically acceptable salt thereof as an active ingredient as well as a suitable carrier or excipient. The carrier or excipient includes but is not limited to ion exchanger, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycerol, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, bee wax, lanoline, etc. The pharmaceutical composition of the present invention can be formulated to the form of solution, tablet, capsule or injection by conventional methods known by the person skilled in the art. The amine compounds of Formula I or pharmaceutically acceptable salts thereof as well as a pharmaceutical composition thereof according to the present invention can be used for the antidepressive treatment. The amine compounds of Formula I or pharmaceutically acceptable salts thereof or a pharmaceutical composition thereof according to the present invention can be adimisttrated by oral, parenteral such as subcutaneous, intravenous, intramuscular or intraperitoneal route, or via an externally explanted reservoir. Oral or injection administration is preferred. In addition, it is noted that the dosage and method of use of the present compounds depend on many factors including age, body weight, gender, physical health condition, nutritional state, strength of compound, duration of administration, metabolic rate, severity of the conditions to be treated and the subjective judgment of the medician. The preferred dosage of administration is 0.01 - 100 mg/kg body weight/day, and the most preferred dosage of administration is 0.1 -10 mg/kg body weight/day. Concrete Modes for Carrying Out the Invention The following examples further illustrate the present invention but are not intended to limit the scope of the present invention. The skilled in the art would understand that the present invention can be varied and modified without departing from the scope of spirit of the present invention. 1.1: Preparation of 3-dimethylamino-1-(thiophen-2-yl)-1- acetonehydrochloride 2-Acetylthiophene (20.0g, 0.16mol), dimethylamine hydrochloride (16.8g, 0.21 mol), paraformaldehyde (9.5g, 0.32mol) and 50mL anhydrous ethanol were placed into a 150mL three-necked bottle, The mixture was added with concentrated hydrochloric acid to reach a pH of 3-4, and heated to reflux for 8h. The reaction was stopped, and the reacton mixture was cooled to room temperature, frozen overnight, and filtrated in vacumm. The filter cake was washed with cold anhydrous ethanol to be white to obtain 31 2g of white crystal with a yield of 89.6%. MS (m/e): 184.3 (M+1+). 1.2: Preparation of 3-dimethylamino-1-(thiophen-2-yl)-1-propanol 3-Dimethylamino-1-(2-thienyl)-1 -acetone hydrochloride (30.8g, 0.14mol) was dissolved in 150 ml distilled water. The mixture was added dropwise with 2.5 M sodium hydroxide aqueous solution to reach a pH of about 10, extracted with ethyl acetate (100 mlx3). The organic phases were combined and washed with saturated sodium chloride anqueous solution twice, dried over anhydrous sodium sulfate, and distilled under a reduced pressure to remove ethyl acetate, thereby obtaining a yellow oily liquid. The liquid was dissolved in 30ml anhydrous tetrahydrofuran, the mixture was slowly added dropwise to the solution of LiAIH4 (7.8g, 0.21 mol) in 100 ml anhydrous tetrahydrofuran, and the reaction temperature was controlled at 0-5°C in an ice bath. The ice bath was removed, and the reaction was performed at room temperature for 2h and stopped. The reaction liquid was added dropwise with anhydrous ethanol slowly, and the solids were removed by filtration under vacumm after the residual LiAIH4 was completed. Tetrahydrofuran was distilled out under a reduced pressure and the residue was extracted with dichloromethane (50 mlx3). The organic phases were combined, washed with saturated sodium chloride aqueous solution twice, dried over anhydrous sodium sulfate, and distilled to remove dichloromethane, to obtain 22.9g of 3-dimethylamino-1-(thiophen-2-yl)-1-propanol as a white solid in a yield of 88.3%. 1H-NMR δ (ppm, CD3COCD3-d6): 7.28-7.30(dd,1H,Ar-H); 6.92-6.96(m,2H,Ar-H); 5.06-5.09(t,1H,CHOH); 2.87(s,1H,OH); 2.55-2.62(m,1H,CH2N); 2.40-2.47 (m,1H, CH2N); 2.23(s,6H,N(CH3)2); 1.86-1.91(m,2H,CH2CH2N). 1.3: Preparation of N,N-dimethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3- (thiophen-2-yl)-propylamineoxalate (Compound l1) 3-Dimethylamino-1-(thiophen-2-yl)-1-propanol (1.85g, 0.01 mol), 4-hydroxyl-benzo[1,3]dioxolane (1.38g, 0.01mol) and triphenylphosphine (3.93g, 0.015mol) were dissolved in 80ml of anhydrous tetrahydrofuran. The mixture was slowly added dropwise with the solution of diethyl azodicarboxylate (2.61g, 0.015mol) in 20ml anhydrous tetrahydrofuran, the reaction temperature was controlled to be lower than -5°C in an ice-salt bath. After compeletion of the addition, the ice-salt bath was removed, and the reaction was performed at room temperature for 24h. After the end of reaction, tetrahydrofuran was distilled out under a reduced pressure, the resultant oily liquid was dissolved in 100ml of ethyl acetate, washed with diluted sodium hydroxide aqueous solution and saturated sodium chloride aqueous solution separately once, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain 1.07g of N,N-dimethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3- (thiophen-2-yl)-propylamine as a pale yellow oily liquid, which was dissolved in 30ml of ethyl acetate, added with oxalic acid (0.32g, 0.035mol) to generate a pale yellow solid. The mixtyure was heated to reflux, cooled to room temperature, frozen for 2h and filtrated. The filter cake was washed with cold ethyl acetate to obtain 1.31g of the target compound as a pale yellow powdery solid in a yield of 33.2% and a melting point of 85-88X. MS (m/e): 306.5 (M+1+); 1H-NMR δ (ppm, DMSO-d6): 7.46-7.48(d,1H,5'-H); 7.11-7.12 (d,1H,3'-H); 6.95-6.97(dd,1H,4'-H); 6:66-6.70(t,lH,6-H); 6.53-6.59(dd,2H,5,7-H); 5.97-5.98(d, 2H.2-H); 5.71-5.75(t,1H,CHO); 2.27-2.30(t,2H,CH2N); 2.19-2.21(m,1H,CH2 CH2N); 2.11(s,6H,N(CH3)2); 2.06-2.08(m,1H, CH2CH2N). Example 2: Preparation of N-methvl-3-[(benzo[1,-3]dioxolan-4-yl)-oxy]-3- (thiophen-2-vl)-propylamineoxalate (compound I2) N,N-dimethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-(thiophen-2-yl)-propylami ne (1.26g, 4.14mmol) was dissolved in 50ml of anhydrous toluene. The mixture was heated to reflux, added dropwise over 0.5h with the solution of phenyl chloroformate (0.78g, 4.97mmol) in 10ml anhydrous toluene. After compeletion of the addition, the refluxing was maintained for 1h, and then the reaction was terminated, and cooled to room temperature. The organic phase was washed with 2.5M sodium hydroxide aqueous solution (20mLx3), the organic phase was washed with distilled water to neutral, then with 1.0M hydrochloric acid aqueous solution (20ml_x3), with distilled water to neutral, with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and distilled under a reduced pressure to remove toluene to obtain a pale yellow oil. 40mL of 1,2-propylene glycol was added to the above oil, sodium hydroxide (1.65g, 4.14mmol) was dissolved in 10ml_ of distilled water and added to the above 1,2-propylene glycol solution. The mixture was heated to reflux for 3h, the reaction was then terminated, cooled to room temperature, added with diluted hydrochloric acid aqueous solution to adjust the pH of about 3, stirred at room temperature for 1h, extracted with n-hexane (30mLx3), added with sodium hydroxide aqueous solution to adjust a pH of about 10, extracted with ethyl acetate (30ml_x3). The organic phase was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and distilled under a reduced pressure to remove solvent to a residue of about 20ml_. The residue was then added with 0.37g (4.14mmol) of oxalic acid to generate a white precipitate. The mixture was heated to reflux for 0.5h, cooled to room temperature, frozen for 4h. After filtration under vacumm, the filter cake was washed with cold ethyl acetate to obtain 0.34g of the target compound as a white powdery solid in a yield of 21.6% and a melting point of 120-123°C. MS (m/e): 292.2 (M+H+), 314.3(M+Na+). 1H-NMR δ (ppm, DMSO-d6): 7.46-7.48(d,1H,5'-H); 7.11-7.12 (d,1H,3'-H); 6.95-6.97(dd,1H,4'-H); 6.66-6.70(t,1H,6-H); 6.58-6.60(d,2H,7-H); 6.53-6.55 (d,1H, 5-H); 5.96-5.98(dd,1H,2-H); 5.76-5.79(t,1H,CHO); 2.50-2.52(t,2H,CH2N); 2.24(s, 6H,N(CH3)2); 2.11-2.19 (m,1H,CH2CH2N); 1.90 -1.98(m,1H, CH2CH2N). Example 3: Preparation of N.N-diethvl-3-[(penzo[1-3]dioxolan-4-vl)-oxvl-3- (thiophen-2-vl)-propvlamineoxalate (compound l3) 3.1: Prepation of 3-diethylamino-1-(thiophen-2-yl)-1-acetone- hydrochloride 2-Acetylthiophene (20.0g, 0.16mol), diethylamine hydrochloride (15.3g, 0.21 mol), paraformaldehyde (9.5g, 0.32mol) and 50mL anhydrous ethanol were placed in a 150ml_ three-necked bottle. The mixture was added dropwise with concentrated hydrochloric acid to reach a pH of 3-4 and heated to reflux for 8h. The reaction was stopped, cooled to room temperature, frozen overnight, and filtrated under vacumm. The filter cake was washed with cold anhydrous ethanol to white to obtain 31.1g of 3-diethylamino-1-(thiophen-2-yl)-1- acetonehydrochloride as a pale yellow crystal in a yield of 78.6%. MS (m/e): 212.3 (M+1+). 3.2: Preparation of 3-diethylamino-1-(thiophen-2-yl)-1-propanol 3-Diethylamino-1-(thiophen-2-yl)-1-acetonehydrochloride (7.92g, 0.032mol) was dissolved in 50mL of distilled water. The mixture was added dropwise with 2.5M NaOH aqueous solution to reach a pH of about 10, and extracted with ethyl acetate (20mlx3). The organic phases were combined, washed with saturated sodium chloride aqueous solution twice, dried over anhydrous sodium sulfate, and distilled to remove ethyl acetate. The resultant yellow oily liquid was dissolved in 20ml of anhydrous tetrahydrofuran, and then added dropwise slowly into the solution of LiAIH4 (1.78g, 0.048mol) in 50ml anhydrous tetrahydrofuran, in which an ice bath was used to control the reaction temperature. After the addition, the ice bath was removed, and the reaction was performed for 2h and then stopped. Anhydrous ethanol was slowly added dropwise into the reaction liquid. After complete reaction of the residual LiAim, solids were removed by filtration under vacumm, tetrahydrofuran was distilled out under a reduced pressure, and the residue was extracted with dichloromethane (20mlx3). The organic phases were combined, washed with saturated sodium chloride aqueous solution twice, dried over anhydrous sodium sulfate, and distilled to remove dichloromethane to obtain 5.93g of 3-diethylamino-1-(thiophen-2-yl)-1-propanol as a deep yellow oily liquid in a yield of 87.0%. 1H-NMR δ (ppm, DMSO-d6): 7.347.35 (dd,1H,Ar-H); 6.93-6.95 (dd,H,Ar-H); 6.91-6.92 (dd,H,Ar-H); 5.95 (s,1H,OH); 4.86-4.89(t,1H,CHOH); 2.56-2.37 (m,6H,. CH2N(CH2CH3); 1.76-1.81 (m,2H,CH2CH2N); 0.92-0.95 (m,6H,N(CH2CH3)2); 3.3: Preparation of N,N-diethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3- (thiophen-2-yl)-propylamineoxalate (compound I3) 3-Diethylamino-1-(thiophen-2-yl)-1-propanol (2.11g, 0.01 mol), 5-hydroxyl-benzo[1,3]dioxolane (1.38g, 0.01 mol) and triphenylphosphine (3.93g, 0.015mol) were dissolved in 80ml of anhydrous tetrahydrofuran. The mixture was slowly added dropwise with the solution of diethyl azodicarboxylate (2.61g, 0.015mol) in 20ml anhydrous tetrahydrofuran, and an ice-salt bath was used to control the reaction temperature below -5°C. After compeletion of the addition, the ice-salt bath was removed, and the reaction was performed at room temperature for 24h. After the end of the reaction, tetrahydrofuran was distilled out under a reduced pressure, and the obtained oily liquid was dissolved in 100ml of ethyl acetate. The mixture washed with diluted sodium hydroxide aqueous solution and saturated sodium chloride aqueous solution respectively, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain 1.06g of the target compound as a pale yellow oily liquid in a yield of 31.8%. MS (m/e): 334.2(M+1+). 1H-NMR δ (ppm, DMSO-d6): 7.25-7.26(dd,1H,5'-H); 6.97-6.98 (d,1H,3'-H); 6.81-6.83(dd,1H,4'-H); 6.52-6.56 (t,1H,6-H); 6.42-6.44(d,1H,7-H); 6.34-6.36(d,1H, 5-H); 5.81-5.82(d,2H,2-H); 5.68-5.71(t,1H,CHO); 2.34-2.54(m,6H, CH2N(CH2CH3)2); 2.06-2.12(m, 1H, CH2CH2N); 1.86-1.92(m,1H,CH2CH2N); 0.80-0.84(t,6H, N(CH2CH3)2).. Example 4: Preparation of 1-f3-(benzof1.3ldioxolan-4-vl-oxv)-3-(thiophen- 2-vl)-propvl1-pyrrolidineoxalate (compound l4) 4.1: Preparation of 3-(tetrahydropyrrol-1-yl)-1-(thiophen-2-yl)-1- acetonehydrochloride 2-Acetylthiophene (8.82g, 0.070mol), tetrahydropyrrole (6.15g, 0.087mol), paraformaldehyde (3.90g, 0.13mol) and 30mL of anhydrous ethanol were placed in a 100 mL three-necked bottle. The mixture was added dropwise with concentrated hydrochloric acid to reach a pH of 3-4, and heated to reflux for 8h. The reaction was stopped, cooled to room temperature, frozen overnight, and filtered. The titer cake was washed with cold anhydrous ethanol to white to obtain 13.3g of 3-(tetrahydropyrrol-1-yl)-1-(thiophen-2-yl)-1-acetone hydrochloride as a pale yellow crystal in a yield of 77.6%. MS (m/e): 210.4 (M+1+). 4.2: Preparation of 3-(tetrahydropyrrol-1-yl)-1-(thiophen-2-yl)-1-propanol 3-(tetrahydropyrrol-1-yl)-1-(thiophen-2-yl)-1-acetone hydrochloride (12.3g, 0.050mol) was dissolved in 50 mL of distilled water. The mixture was added dropwise with 2.5M sodium hydroxide aqueous solution to reach a pH of about 10, and extracted with ethyl acetate (20 mLx3). The organic phases were combined, washed with saturated sodium chloride aqueous solution twice, dried over anhydrous sodium sulfate, and distilled to remove ethyl acetate. The obtained yellow oily liquid was dissolved in 15ml anhydrous tetrahydrofuran, added dropwise slowly into the solution of LiAIH4 (2.78g, 0.075mol) in 50 mL anhydrous tetrahydrofuran, and an ice bath was used to control the reaction temperature. After dropping, the ice bath was removed, and the reaction was performed at room temperature for 2h and then stopped. Into the reaction liquid, anhydrous ethanol was slowly added dropwise. After complete reaction of the residual LiAIH4, solids were removed by filtration under vacumm, tetrahydrofuran was distilled out under a reduced pressure, and the residue was extracted with dichloromethane (20 ml_x3). The organic phases were combined, washed with saturated sodium chloride aqueous solution twice, dried over anhydrous sodium sulfate, and distilled to remove dichloromethane to obtain 8.92g of a deep yellow oily liquid in a yield of 84.6%. 1H-NMR δ (ppm, DMSO-d6): 7.35-7.36(dd,1H,Ar-H); 6.93-6.95(m,H,Ar-H); 6.91-6.92(m,H,Ar-H); 5.81(s,1H, OH); 4.86-4.89(t,1H,CHO); 2.40-2.53(m,6H, CH2N(CH2CH3)2); 1.78-1.85(m,2H, HOCHCH2CH2N); 1.62-1.70(m,4H,CH2CH2 CH2CH2). 4.3: Preparation of 1-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(thiophen-2-yl)- propyl]-pyrrolidineoxalate (compound l4) 3-(tetrahydropyrrol-1-yl)-1-(thiophen-2-yl)-1-propanol (2.11g, 0.0Imol), 5-hydroxylbenzo[1,4]dioxolane (1.38g, 0.0Imol) and triphenylphosphine (3.93g, 0.015mol) were dissolved in 80 mL anhydrous tetrahydrofuran. The mixture was slowly added dropwise with the solution of diethyl azodicarboxylate (2.61g, 0.015mol) in 20 mL anhydrous tetrahydrofuran, in which the reaction temperature was controlled with an ice-salt bath to be below -5°C. After addition, the ice-salt bath was removed, and the reaction was performed at room temperature for 24h. After the end of the reaction, tetrahydrofuran was distilled out under a reduced pressure, and the obtained oily liquid was dissolved in 100 mL ethyl acetate. The mixture was washed with diluted sodium hydroxide aqueous solution and saturated sodium chloride aqueous solution respectively, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain 1.12g of a pale yellow oily liquid. The oily liquid was dissolved in 30 mL ethyl acetate, added with 0.30g (0.034mol) oxalic acid to generate a white solid. The mixture was heated to reflux, cooled to room temperature, frozen for 2h, and filtrated under vacumm. The filter cake was washed with cooled ethyl acetate to obtain 1.18g of target compound as a white powdery solid in a yield of 28.2% and a melting point of 105-108°C. MS (m/e): 332.5(M+H+). 1H-NMR δ (ppm, DMSO-d6): 7.47-7.48(dd,1H,5,-H); 7.11-7.12 (d,1H,3'-H); 6.95-6.97(dd,1H,4'-H); 6.66-6.70 (t,1H,6-H); 6.57-6.59(d,1H,7-H); 6.53-6.55(d,1H, 5-H); 5.97-5.98(d,2H,2-H); 5.72-5.75(t,1H,CHO); 2.40-2.50(m,6H, CH2N(CH2CH3)2); 2.16-2.25(m, 1H,HOCHCH2CH2N); 1.94-2.03(m,1H, HOCHCH2CH2N; 1.67(s, 4H, CH2CH2CH2CH2). Example 5: Preparation of 1-[3-(benzof1,31dioxolan-4-vl-oxy)-3-(thiophen- 5.1: Preparation 3-(piperidin-1-yl)-1-(thiophen-2-yl)-1- acetonehydrochloride 2-Acetylthiophene (8.82g, 0.070mol), piperidine (7.37g, 0.087mol), paraformaldehyde (3.90g, 0.13mol) and 30 mL anhydrous ethanol were placed in a 100 ml_ three-necked bottle. The mixture was added dropwise with concentrated hydrochloric acid to reach a pH of 3-4 and heated to reflux for 8h. The reaction was terminated, cooled to room temperature, frozen overnight, and filtrated under vacumm. The filter cake was washed with cold anhydrous ethanol to white to obtain 13.3g of a pale yellow crystal in a yield of 74.6%. MS (m/e): 224.3 (M+1+). 5.2: Preparation of 3-(piperidin-1-yl)-1-(thiophen-2-yl)-1-propanol 3-(Piperidin-1-yl)-1-(thiophen-2-yl)-1-acetone hydrochloride (13.0g, 0.050mol) was dissolved in 50 mL distilled water. The mixture was added dropwise with 2.5M sodium hydroxide aqueous solution to reach a pH of 10, and extracted with ethyl acetate (20 mLx3). The organic phases were combined, washed with saturated sodium chloride aqueous solution twice, dried over anhydrous sodium sulfate, and distilled to remove ethyl acetate. The obtained yellow oily liquid was dissolved in 15ml anhydrous tetrahydrofuran, added dropwise slowly into the solution of LiAlhU (2.78g, 0.075mol) in 50 mL anhydrous tetrahydrofuran, and the reaction temperature was controlled with an ice bath. After the addition, the ice bath was removed. The reaction was performed at room temperature for 2h and then stopped. Into the reaction liquid, anhydrous ethanol was slowly added dropwise. After complete reaction of the residual LiAIH4, solids were removed by filtration under vacumm, tetrahydrofuran was distilled out under a reduced pressure, and the residue was extracted with dichloromethane (20 mLx3). The organic phases were combined, washed with saturated sodium chloride aqueous solution twice, dried over anhydrous sodium sulfate, and distilled to remove dichloromethane to obtain 9.26g of a deep yellow oily liquid in a yield of 82.3%. 1H-NMR δ (ppm, DMSO-d6): 7.33-7.34(dd,1H,Ar-H); 6.93-6.95(dd,1H, Ar-H); 6.91-6.92(m,1H,Ar-H); 5.93(s,1H,OH); 4.86-4.89(t,1H,CHOH); 2.29-2.50 (m,6H, CH2NCH2CH2)2); 1.79-1.86(m,2H,HOCHCH2CH2N); 1.45-1.51 (m,4H,N(CH2CH2)2CH2); 1.38-1.42 (m, 2H, (CH2CH2)2CH2). 5.3: Preparation of 1-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(thiophen-2-yl)- propyl]-piperidineoxalate (compound l5) 3-(Piperidin-1-yl)-1-(thiophen-2-yl)-1-propanol (2.25g, 0.01 mol), 5-hydroxyl-benzo[1,4]dioxolane (1.38g, 0.01 mol) and triphenylphosphine (3.93g, 0.015mol) were dissolved in 80 mL anhydrous tetrahydrofuran. The mixture was slowly added dropwise with the solution of diethyl azodicarboxylate (2.61 g, 0.015mol) in 20 mL anhydrous tetrahydrofuran, and the reaction temperature was controlled by an ice-salt bath to be below -5°C. After compeletion of the addition, the ice-salt bath was removed. The reaction was performed at room temperature for 24h. After the end of reaction, tetrahydrofuran was distilled out under a reduced pressure, and the obtained oily liquid was dissolved in 100 mL ethyl acetate. The mixture was washed with diluted sodium hydroxide aqueous solution and saturated sodium chloride aqueous solution respectively, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain 1.45g of a pale yellow oily liquid. The oily liquid was dissolved in 30 mL of ethyl acetate, added with oxalic acid (0.38g, 0.042mol) to generate a white solid. The mixture was heated to reflux, cooled to room temperature, frozen for 2h, and filtrated under vacumm. The filter cake was washed with cooled ethyl acetate to obtain 1.53g of the target compound as a white powdery solid in a yield of 35.2% and a melting point of 118-120°C. MS (m/e): 346.4(M+H+). 1H-NMR δ (ppm, DMSO-d6): 7.47-7.48(d,1H,5'-H); 7.10-7.11(d,1H,3'-H); 6.95-6.97(dd,1H,4'-H); 6.67-6.71 (t,1H,6-H); 6.58-6.60(d,1H,7-H); 6.53-6.55(d,1H, 5-H); 5.97-5.98(d,2H, 2-H); 5.71-5.74(t,1H,CHO); 2.30-2.32(m,6H, CH2N(CH2CH2)2); 2.13-2.05(m,1H, HOCHCH2CH2N); 1.93-2.01(m,1H, HOCHCH2CH2N); 1.45-1.49{m,4H, N(CH2CH2)2CH2)); 1.35-1.37(m,2H, (CH2CH2)2CI±>). Example 6: Preparation of N.N-dimethvl-[3-(benzoM.31dioxolan-4-yl-oxy)- 3-(furan-2-yl)]-propvlamineoxalate (compound l6) 6.1: Preparation of 3-dimethylamino-1-(furan-2-yl)-1-acetonehydrochloride 2-acetylfuran (17.6g, 0.16mol), dimethylamine hydrochloride (16.8g, 0.21 mol), paraformaldehyde (9.5g, 0.32mol) and 50 ml_ anhydrous ethanol were placed in a 150 mL three-necked bottle. The mixture was added dropwise with concentrated hydrochloric acid to reach a pH of 3-4 and heated to reflux for 8h. The reaction was terminated, cooled to room temperature, frozen overnight, and filtrated under vacumm. The filter cake was washed with cold anhydrous ethanol to obtain 28.1g of 3-dimethylamino-1-(furan-2-yl)-1 -acetone hydrochloride as a pale yellow crystal in a yield of 86.4%. MS (m/e): 168.3 (M+1+). 6.2: Preparation of 3-dimethylamino-1-(furan-2-yl)-1-propanol 3-Dimethylamino-1 -(furan-2-yl)-1 -acetonehydrochloride (24.4g, 0.12mol) was dissolved in 120 mL distilled water. The mixture was added dropwise with 2.5M sodium hydroxide aqueous solution to reach a pH of 10, and extracted with ethyl acetate (80 ml_x3). The organic phases were combined, washed with saturated sodium chloride aqueous solution twice, dried over anhydrous sodium sulfate, and distilled under a reduced pressure to remove ethyl acetate. The obtained yellow oily liquid was dissolved in 30 mL anhydrous tetrahydrofuran, added dropwise slowly into LiAlH4 (6.7g, 0.18mol) in 100 mL anhydrous tetrahydrofuran solution, and the reaction temperature was controlled in an ice bath. After the addition, the ice bath was removed. The reaction was performed at room temperature for 2h and then stopped. Into the reaction liquid, anhydrous ethanol was slowly added dropwise. After complete reaction of the residual LiAIH4, solids were removed by filtration under vacumm, tetrahydrofuran was distilled out under a reduced pressure, and the residue was extracted with dichloromethane (50 mLx3). The organic phases were combined, washed with saturated sodium chloride aqueous solution twice, dried over anhydrous sodium sulfate, and distilled to remove dichloromethane to obtain 16.8g of 3-dimethylamino-1-(furan-2-yl)-1-propanol as a yellow oily liquid in a yield of 82.6%. 1H-NMR δ (ppm, DMSO-d6): 7.55(s,1H,Ar-H); 6.36-6.37(m,1H,Ar-H); 6.22-6.23(d,1H, Ar-H); 5.45(s,1H,OH); 4.56-4.59(t,1H,CHOH); 2.24-2.50(m,2H, CH2N); 2.11(s,6H, N(CH3)2); 1.76-1.83(m,2H,CH2CH2N). 6.3: Preparation of N,N-dimethyl[3-(benzo[1,3]dioxolan-4-yl-oxy)-3- (furan-2-yl)]-propylamineoxalate (compound l6) 3-Dimethylamino-1-(furan-2-yl)-1-propanol (169g, 0.0Imol), 4-hydroxyl-benzo[1,3]dioxolane (1.38g, 0.0Imol) and triphenylphosphine (3.93g, 0.015mol) were dissolved in 80 mL anhydrous tetrahydrofuran. The mixture was slowly added drop wise with the solution of diethyl azodicarboxylate (2.61g, 0.015mol) in 20 mL anhydrous tetrahydrofuran, and the reaction temperature was controlled by an ice-salt bath to be below -5°C. After compeletion of the addition, the ice-bath was removed. The reaction was performed at room temperature for 24h. After the end of reaction, tetrahydrofuran was distilled out under a reduced pressure, and the obtained oily liquid was dissolved in 100 mL ethyl acetate. The mixture was washed with diluted sodium hydroxide aqueous solution and saturated sodium chloride aqueous solution respectively, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain 0.75g of N,N-dimethyl-[3-(benzo[1,3]dioxolan- 4-yl-oxy)-3-(furan-2-yl)]-propylamine as a pale yellow oily liquid. The oily liquid was dissolved in 20 mL ethyl acetate, and the mixture was added with 0.23g (0.026mol) of oxalic acid to generate a pale yellow solid, heated to reflux, cooled to room temperature, frozen for 2h, and filtrated under vacumm. The filter cake was washed with cold ethyl acetate to obtain 0.88g of the target compound as a pale yellow powdery solid in a yield of 23.2% and a melting point of 97-101 °C. MS (m/e): 290.4 (M+1+), 312.5(M+Na+). 1H-NMR δ (ppm, DMSO-d6): 7.63-7.64(dd,1H,5'-H); 6.62-6.66(t,1H,6-H); 6.60-6.62(d,1H,5-H); 6.55-6.57 (d,1H,7-H); 6.46-6.47(d,1H, 3'-H); 6.39-6.41 (dd,1H, 4'-H); 5.95-5.97(dd,1H,2-H); 5.44-5.47(t,1H,CHO); 2.24-2.28(t,2H,CH2N); 1.99-2.19 (m,2H,CH2CH2N); 2.11(s,6H,N(CH3)2). Example 7: Preparation of N-methvl-[3-(benzo[1-3]dioxolan-4-yl-oxy)3- (furan-2-yl-propylamineoxalate (compound I7) N,N-dimethyl-3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(furan-2-ylpropylamine (0.59g, 2.03mmol) was dissolved in 30 mL anhydrous toluene. The mixture was heated to reflux, and added dropwise with phenyl chloroformate (0.38g, 2.44mmol) in 10 mL anhydrous toluene solution within 0.5h. After compeletion of the addition, the reflux was maintained for 1h, and the reaction was then terminated, and cooled to room temperature. The organic phase was washed with 2.5M sodium hydroxide aqueous solution (20 ml_x3), with distilled water to neutral, with 1.0M hydrochloric acid aqueous solution (20 mLx3), with distilled water to neutral, with saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and toluene was removed by distillation under a reduced pressure to obtain a yellow oil. 30 mL 1,2-propylene glycol was added to the above yellow oil, and 0.81 g (2.03mmol) sodium hydroxide dissolved in 8mL distilled water was added to the above 1,2-propylene glycol solution. The mixture was heated to reflux for 3h, cooled to room temperature after the end of reaction, added with diluted hydrochloric acid aqueous solution to reach a pH of about 3, stirred at room temperature to carry out the reaction for 1h, extracted with n-hexane (20 mLx3), then added with sodium hydroxide aqueous solution to reach a pH of about 10, and extracted with ethyl actate (20 ml_x3). The organic phase was washed with saturated saline aqueous solution, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was removed by distillation under vacumm to obtain a residue of about 15mL. The residue was then added with 0.18g (2.03mmol) oxalic acid to generate a white precipitate. The mixture was heated to reflux for 0.5h, cooled to room temperature, and frozen for 4h. After filtration, the filter cake was washed with cold ethyl acetate to obtain 0.13g of the target compound as a white powdery solid in a yield of 17.8% and a melting point of 130-133°C. MS (m/e): 276.1 (M+1+), 298.0(M+Na+). 1H-NMR δ (ppm, DMSO-d6): 7.63-7.64(dd,1H,5'-H); 6.69-6.73(t,1H,6-H); 6.62-6.64(d,1H,5-H); 6.55-6.57 (d,1H,7-H); 6.46-6.47(d,1H, 3'-H); 6.40-6.41 (dd,1H, 4'-H); 5.95-5.97(dd,1H,2-H); 5.49-5.52(t,1H,CHO); 2.50-2.53(t,2H,CH2N); 2.25(s, 6H,NCH3); 2.10-2.16 (m, H, CH2CH2N); 1.99-2.05 (m,H, CH2CH2N)., Example 8: Preparation of N.N-dimethvl-3-[(benzo[1.4]dioxan-5-vl-oxv)-3- (thiophen-2-yl)-propylamine1oxalate (compound l8) 3-Dimethylamino-1-(thiophen-2-yl)-1-propanol (1.85g, 0.01 mol), 5-hydroxyl-benzo[1,4]dioxane (1.52g, 0.01 mol) and triphenylphosphine (3.93g, 0.015mol) were dissolved in 80 mL mhydrous tetrahydrofuran. The mixture was slowly added dropwise with the 'solution of diethyl azodicarboxylate (2.61 g, 0.015mol) in 20 mL anhydrous telrahydrofuran, and the reaction temperature was controlled by an ice-salt bath to be below -5°C. After compeletion of the addition, the ice-salt bath was removed, and the reaction was performed at room temperature for 24h. After the reaction, tetrahydrofuran was distilled out under a reduced pressure, and the obtained oil liquid was dissolved in 100 mL ethyl acetate. The mixture was washed with diluted sodium hydroxide aqueous solution and saturated sodium chloride aqueous solution respectively, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain 1.56g of IM,N-dimethyl-3-[(benzo[1,4]dioxan- 5-yl-oxy)-3-(thiophen-2-yl)-propylamine] as a yellow oil. The yellow oil was dissolved in 50 mL ethyl acetate, the mixture was added with 0.41g (0.045mol) oxalic acid to generate a pale yellow precipitate, heated to reflux, cooled to room temperature, frozen for 2h, and filtrated under vacumm. The filter cake was washed with cold ethyl acetate to obtain 1.69g of the target compound as a pale yellow powdery solid in a yield of 39.1% and a melting point of 89-92X. MS (m/e): 320.5 (M+1+). 1H-NMR 5 (ppm, CDCI3-d3): 7.22-7.24(dd,1H,5'-H); 6.99-7.00 (d,1H,3'-H); 6.92-6.94(dd,1H,4'-H); 6.61-6.65(t,1H,7-H); 6.49-6.51 (d, 2H,6,8-H); 5.48-5.51 (t,1H, CHO); 4.23-4.31 (t,4H,2,3-H); 2.44-2.47(t,2H,CH2N); 2.35-2.42(m,1H,CH2CH2N); 2.25(s,6H,N(CH3)2); 2.08-2.13(m,1H, CH2CH2N). Example 9: Preparation of N-methyl-3-f(benzof1.41dioxan-5-vl-oxv)-3- (thiophen-2-vl)-propylaminel oxalate (compound la) N,N-dimethyl-3-[(benzo[1,4]dioxan-5-yl-oxy)-3-(thiophen-2-yl)-propylamine] (0.78g, 2.44mmol) was dissolved in 50 mL anhydrous toluene. The mixture was heated to reflux, and added dropwise with the solution of phenyl chloroformate (0.46g, 2.93mmol) in 10 mL anhydrous toluene over 0.5h. The reflux was maintained for 1h after compeletion of the addition, and then the reaction was terminated, and cooled to room temperature. The organic phase was washed with 2.5M sodium hydroxide aqueous solution (20 ml_x3), with distilled water to neutral, then with 1.0M hydrochloric acid aqueous solution (20 ml_x3), with distilled water to neutral, with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and toluene was distilled out under a reduced pressure to obtain a yellow oil. 30 ml_ of 1,2-propylene glycol was added to the above yellow oil, and sodium hydroxide (0.98g, 2.44mmol) dissolved in 8ml_ of distilled water was added into the above 1,2-propylene soludion. The mixture was heated to reflux for 3h, the reaction was terminated, cooled to room temperature, added with diluted hydrochloric acid aqueous solution to reach a pH of about 3, stirred to perform the reaction at room temperature for 1h, extracted with n-hexane (20 ml_x3), then added with sodium hydroxide aqueous solution to reach a pH of about 10, and extracted with ethyl acetate (20 mLx3). The organic phase was washed with saturated saline aqueous solution, dried over anhydrous sodium sulfate, filterated to remove the drying agent, distilled under vacumm to remove solvent and obtain a residue of about 15mL. The residue was added with 0.22g (2.44mmol) of oxalic acid to generate a white precipitate. The mixture was heated to reflux for 0.5h, cooled to room temperatre, and frozen for 4h. After filtration under vacumm, the filter cake was washed with cold ethyl acetate to obtain 0.30g of the target compound as a pale yellow powdery solid in a yield of 31.4% and a melting point of 128-131°C. MS (m/e): 306.4 (M+H+), 328.1 (M+Na+) 1H-NMR 6 (ppm, DMSO-d6): 7.45-7.46(dd,1H,5'-H); 7.09-7.10 (dd,1H,3'-H); 6.95-6.97(dd,1H,4'-H); 6.58-6.62(t,1H,7-H); 6.51-6.53(d,1H, 8-H); 6.41-6.43(d,1H, 6-H); 5.63-5.66(t,1H,CHO); 4.20-4.24(m,4H,2,3-H); 2.52-2.56(t,2H,Cli>N); 2.26 (s,3H,NCH3); 2.12-2.16 (m.lH.CHzCHzN); 1.95-1.99(m,1H,CH2CH2N). Example 10: Preparation of N.N-dimethyl-3-f(benzof1.41dioxan-5-vl-oxy)-3- (furan-2-vl)propvlaminel-oxalate (compound lin) 3-Dimethylamino-1-(furan-2-yl)-1-propanol (169g, 0.01 mol), 5-benzo[1,4]dioxane (1.52g, 0.01 mol) and triphenylphosphine (3.93g, 0.015mol) was dissolved in 80 ml_ anhydrous tetrahydrofuran. The mixture was slowly added dropwise with the solution of diethyl azodicarboxylate (2.61 g, 0.015mol) in 20 mL anhydrous tetrahydrofuran, and the reaction temperature was controlled by an ice-salt bath to be below -5°C. After compeletion of the addition, the ice-salt bath was removed, and the reaction was performed at room temperature for 24h. After the reaction, tetrahydrofuran was distilled out under a reduced pressure, and the obtained oily liquid was dissolved in 100 mL ethyl acetate. The mixture was washed with diluted sodium hydroxide aqueous solution and saturated sodium chloride aqueous solution respectively, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain 0.98g of N,N-dimethyl-3-[(benzo[1,4]dioxan- 5-yl-oxy)-3-(furan-2-yl)propylamine] as a yellow oil. The yellow oil was dissolved in 30 mL ethyl acetate, and added with oxalic acid (0.29g, 0.032mol) to generate a pale yellow precipitate. The mixture was heated to reflux, cooled to room temperature, frozen for 2h, and filtrated under vacumm. The filter cake was washed with cold ethyl acetate to obtain 0.75g of the target compound as a pale yellow powdery solid in a yield of 19.1% and a melting point of 101-103°C. MS (m/e): 304.3 (M+1+), 326.2(M+Na+). 1H-NMR 6 (ppm, DMSO-d6): 7.63(s,1H,5'-H); 6.62-6.66(t,1H,7-H); 6.54-6.56 (d,1H,6-H); 6.44-6.46 (d,1H,8-H); 6.39-6.40 (m,2H, 3',4'-H); 5.30-5.34(t,1H, CHO); 4.16-4.23(t,4H,2,3-H); 2.23-2.27(t,2H,CH2N); 1.99-2.23 (m,2H,CH2CH2N); 2.10 (s,6H, N(CH3)2). Example 11: Antidepressant effect of the target compounds as measured by tail suspension test in mice Male ICR mice (SPF grade) weighing 18-22g each was suspended by clampping separately at 1cm from the end of the tail with a clamp attached to a rope at the center of top plate of a 25x25x25 cm tail suspension box, and the head is away from the box bottom by 4-5 cm. The mice were administrated via intraperitoneal injection at 30 min before the test or via intragastric administration at 60min before the test with the compound to be tested and Duloxetine as the positive control. The tail was suspended for 6min, and the immobility time of mice during the last 4 min was accumulated. The results of antidepressant effects of the target compounds administrated via intraperitoneal injection as determined by the tail suspension test in mice are given in Table 1. In the tail-suspended model of mice, the antidepressant effect was evaluated by observing the immobility time of the tail-suspended mice, and the shorter the immobility time, the stronger the antidepressant effect. As seen from Table 1, the target compounds can significantly shorten the immobility time; under the same, dose, the target compounds have more significant antidepressant effect than Duloxetine; and with increasing of the dose, more significant effect on the immobility time was observed, indicating that their antidepressant effects are explicitly dose dependent. The antidepressant effect of compound I2 was evaluated via intragastric administration and the results thereof are shown in Table 2. Table 2 shows that compound l2 can significantly shorten the immobility time of the tail-suspended mice via intragastric administration; its at the dose of 5mg/kg is remarkably greater than that of duloxetine at the dose of 10mg/kg; and the higher the dose, the greater the effect on the immobility time, which indicates that its antidepressant effect is explicitly dose dependent. Example 12: The antidepressant effect of the target compounds as measured by forced swim test in mice Mail ICR mice (SPF grade) weighing 18-22g were placed in a glass jar (diameter 10cm, and height 20cm) with water 10cm in depth and a temperature of 25°C, observed for 6 min, and the accumulated immobility time of mice (i.e., the time that the animal has no motion or a slight motion in its hind limbs, but maintains body floated without motion) during the last 4min was recorded. The mice were administrated with the compound to be tested and Duloxetine as the positive control drug via intraperitoneal injection at 30min before the test or via intragastric administration at 60min before the test. The effects of the target compounds on the immobility time of the forced swim mice via intraperitoneal injection are given in Table 3. In the forced swim model of mice, the antidepressant effect was evaluated by observing the immobility time of the forced swim mice, and the shorter the immobility time, the stronger the antidepressant effect. As seen from Table 3, the target compounds can significantly shorten the immobility time; at the same dose, the antidepressant effects of the target compounds are significantly greater than that of the Duloxetine; and the higher the dose, the greater the effect on the immobility time, which indicates that their antidepressant effects are explicitly dose dependent. The antidepressant effect of compound I2 was further evaluated via intragastric administration, and the results thereof are shown in Table 4. Table 4: Effect of the target compound on the immobility time of the forced swim mice via intragastric administration Table 4 shows that compound b can significantly shorten the immobility time via intragastric administration; its antidepressant effect at the dose of 20 mg/kg is comparable to that of Duloxetine at the dose of 40 mg/kg; and the higher the dose, the greater the effect on the immobility time, which indicates that its antidepressant effect is explicitly dose dependent. We claim: 1. An amine compound represented by Formula I: wherein, X represents S or O; R1 and R2 independently represent H or C1-4alkyl, or R1 and R2 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring; and n is 1 or 2, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein, X represents S or O; R1 and R2 independently represent H or C1-4alkyl; and n is 1 or 2. 3. The compound of claim 1, wherein, X represents S or O; R1 and R2 independently represent H, methyl or ethyl; and n is 1 or 2. 4. The compound of claim 1, wherein, X represents S or O; R1 and R2 together with the nitrogen atom to which they are attached form pyrrole ring or piperidine ring; and n is 1 or 2. 5. The compound of any one of claims 1-4, wherein the pharmaceutically acceptable salt is oxalate. 6. The compound of claim 1, which is selected from the group consisting of: N,N-dimethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-(thiophen-2-yl)-propylam ineoxalate; N-methyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-(thiophen-2-yl)-propylamine • oxalate; N,N-diethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-(thiophen-2-yl)-propylamin eoxalate; 1-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(thiophen-2-yl)-propyl]-pyrrolidineox a late; 1-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(thiophen-2-yl)-propyl]-piperidineoxa late; N,N-dimethyl-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(furan-2-yl)]-propylamine •oxalate; N-methyl-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(furan-2-yl)]-propylamineoxal ate; N,N-dimethyl-3-[(benzo[1,4]dioxan-5-yl-oxy)-3-(thiophen-2-yl)-propylamin e]- oxalate; N-methyl-3-[(benzo[1,4]dioxan-5-yl-oxy)-3-(thiophen-2-yl)-propylamine]ox alate; and N,N-dimethyl-3-[(benzo[1,4]dioxan-5-yl-oxy)-3-(furan-2-yl)propylamine]ox alate. 7. A pharmaceutical composition comprising a compound of Formula I of claims 1 to 6 or a pharmaceutically acceptable salt thereof, together with one , or more pharmaceutically acceptable carriers or excipients. 8. Use of a compound of Formula I of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of an anti-depressent medicament. The present invention relates to a new amine compound or a pharmaceutically acceptable salt thereof, wherein the definitions of X, R1, R2 and n are given in the description, to a pharmaceutical composition containing the compound as active ingredient, and to use of the amine compound or its pharmaceutically acceptable salt for the manufacture of an anti-depressent drug.

Full Text

Technical field
The present invention relates to new amine compounds or pharmaceutically
acceptable salts thereof, pharmaceutical compositions containing such
compounds as an active ingredient, and uses of such amine compounds or
pharmaceutically acceptable salts thereof for manufacture of antidepressant
drugs.
Background
Depression is the most common nerval and mental disorder that seriously
affects physical and psychological health of people. With the acceleration of
living tempo and the elevation of social pressure, the incidence of depression
increases significantly.
Treatments with drugs are main means for treatment of depression.
Principal theraputical drugs include: tricyclic antidepressant drugs such as
imipramine, amitriptyline, etc.; monoamine oxidase inhibitors such as
moclobemide, etc.; selective serotonin reuptake inhibitors such as fluoxetine,
sertraline, etc.; selective noradrenaline reuptake inhibitors such as reboxetine,
etc.; dual noradrenergic/serotonergic inhibitors such as mirtazapine, etc.; dual
serotonin/noradrenaline reuptake inhibitors such as venlafaxine, Duloxetine, etc.
Currently, these commonly used drugs usually have drawbacks of slow onset,
low efficiency and significant toxic and side effects and the like.
US Patent USP4018895 discloses antidepressant drugs including
fluoxetine, which have the following formula:

wherein Ar is naphthalene ring or substituted benzene ring, and ri and R2
independently are H or CH3.

Chinese Patent CN1019113 discloses antidepressant drugs including
Duloxetine, which have the following formula:
wherein Ar is naphthalene ring or substituted benezene ring, Ar' is
cycloalkyl, thienyl, furyl or thiazolyl, ri and R2 independently are H or CH3.
Contents of the Invention
The present invention provides an amine compound represented by
Formula I or a pharmaceutically acceptable salt thereof:
wherein,
X represents S or O;
ri and R2 independently represent H or C1-4alkyl, or ri and R2 together with
N atom to which they are attached can form a 5- or 6-membered heterocyclic
ring; and
n is 1 or 2.
In the second aspect, the present invention relates to a method for
preparing a compound of Formula I or a pharmaceutically acceptable salt
thereof.
In the third aspect, the present invention relates to a pharmaceutical
composition comprising a compound of Formula I or a pharmaceutically
acceptable salt thereof as well as one or more pharmaceutically acceptable
carriers or excipients.
In the fourth aspect, the present invention relates to use of a compound of

Formula I or a pharmaceutically acceptable salt thereof for manufacturing an
antidepressant drug.
Therefore, according to one embodiment of the present invention, the
present invention provides an amine compound represented by the Formula I or
a pharmaceutically acceptable salt thereof:
wherein,
X represents S or O;
R1 and R2 independently represent H or a C1-4alkyl, or ri and R2 together
with N atom to which they are attached can form a 5- or 6-membered
heterocyclic ring; and
n is 1 or 2.
According to the present invention, the term "5- or 6-membered
heterocyclic ring" includes but is not limited to pyrrole ring, piperidine ring, etc.
Accroding to another embodiment of the present invention, the present
invention provides an amine compound of the Formula I or a pharmaceutically
acceptable salt thereof:
wherein,
X represents S or O;

R1 and R2 independently represent H or a C1-4alkyl; and
n is 1 or 2.
According to one preferred embodiment of the present invention, the present
invention provides an amine compound of the Formula I or a pharmaceutically
acceptable salt thereof:

wherein,
X represents S or O;
R1 and R2 independently represent H, methyl or ethyl; and
n is 1 or 2.
The present more preferably provides the following compounds:
N,N-dimethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-(thiophen-2-yl)-propylami
ne-oxalate;
N-methyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-(thiophen-2-yl)-propylamineo
xalate;
N,N-diethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-(thiophen-2-yl)-propylamine
oxalate;
1-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(thiophen-2-yl)-propyl]-pyrrolidineoxal
ate;
1-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(thiophen-2-yl)-propyl]-piperidineoxal
ate;
N,N-dimethyl-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(furan-2-yl)]-propylamine-
oxalate;
N-methyl-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(furan-2-yl)]-propylamineoxal
ate;
N,N-dimethyl-3-[(benzo[1,4]dioxan-5-yl-oxy)-3-(thiophen-2-yl)-propylamine]

oxalate;
N-methyl-3-[(benzo[1,4]dioxan-5-yl-oxy)-3-(thiophen-2-yl)-propylamine]ox
alate; and
N,N-dimethyl-3-[(benzo[1,4]dioxan-5-yl-oxy)-3-(furan-2-yl)propylamine]oxa
late.
The amine compounds of the present invention can be prepared according
to a method shown in following scheme:

Specifically, acetyl thiophene or acetyl furan and a dialkyl amine as well as
paraformaldehyde are dissolved in anhydrous ethanol. The mixture is adjusted
to a pH value of 3-4 with concentrated hydrochloric acid, heated to reflux for
6-1 Oh to obtain 3-dialkylamino-1-(thiophen/furan-2-yl)-1 -acetone hydrochloride.
The free base is obtained by alkalisation, and reacts with LiAIH4 to obtain a
hydroxyl derivative in which the reaction solvent is anhydrous tetrahydrofuran,
the reaction temperature is -5°C to room temperature and the reaction time is
1-5h; the hydroxyl derivative reacts with 4-hydroxyl-benzo[1,3]dioxolane or
5-hydroxyl-benzo[1,4]dioxane in the presence of triphenylphosphine and diethyl
azodicarboxylate to obtain a target compound with a dialkyl substituted on the
nitrogen atom, in which the reaction solvent is anhydrous tetrahydrofuran, the
reaction temperature is -5°C to room temperature and the reaction time is

12-36h; the target compound with a dialkyl substituted on the nitrogen atom is
subjected to the action of phenyl chloroformate to remove one substituent
thereon to obtain a target compound with a monoalkyl substituted on the
nitrogen atom.
Similarly, tetrahydropyrrole or piperidine can be used to replace
dialkylamine to carry out the above reaction to obtain a target compound in
which R1 and R2 together with the N atom to which they are attached form a 5-
or 6-membered heterocyclic ring.
The free base of the target compound reacts with a corresponding acid to
obtain a salt of the target compound.
The present invention further provides pharmaceutically acceptable salts of
the amine compounds of the Formula I, in which these salts can be formed by
reacting the amino group of the amine compounds of the Formula I with various
inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid or
phosphoric acid, or formed by reacting the amino group of an amine compounds
of the Formula I with various organic acids such as oxalic acid, maleic acid,
benzoic acid, fumaric acid, etc. Oxalate is preferred.
The present invention further provides a pharmaceutical composition
comprising an amine compound of the Formula I or a pharmaceutically
acceptable salt thereof as an active ingredient as well as a suitable carrier or
excipient. The carrier or excipient includes but is not limited to ion exchanger,
alumina, aluminum stearate, lecithin, serum proteins such as human serum
albumin, buffer substances such as phosphate, glycerol, sorbic acid, potassium
sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt
or electrolyte, such as protamine sulfate, disodium hydrogen phosphate,
potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silicon
dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, bee wax,
lanoline, etc. The pharmaceutical composition of the present invention can be
formulated to the form of solution, tablet, capsule or injection by conventional
methods known by the person skilled in the art.

The amine compounds of Formula I or pharmaceutically acceptable salts
thereof as well as a pharmaceutical composition thereof according to the
present invention can be used for the antidepressive treatment.
The amine compounds of Formula I or pharmaceutically acceptable salts
thereof or a pharmaceutical composition thereof according to the present
invention can be adimisttrated by oral, parenteral such as subcutaneous,
intravenous, intramuscular or intraperitoneal route, or via an externally
explanted reservoir. Oral or injection administration is preferred.
In addition, it is noted that the dosage and method of use of the present
compounds depend on many factors including age, body weight, gender,
physical health condition, nutritional state, strength of compound, duration of
administration, metabolic rate, severity of the conditions to be treated and the
subjective judgment of the medician. The preferred dosage of administration is
0.01 - 100 mg/kg body weight/day, and the most preferred dosage of
administration is 0.1 -10 mg/kg body weight/day.
Concrete Modes for Carrying Out the Invention
The following examples further illustrate the present invention but are not
intended to limit the scope of the present invention. The skilled in the art would
understand that the present invention can be varied and modified without
departing from the scope of spirit of the present invention.

1.1: Preparation of 3-dimethylamino-1-(thiophen-2-yl)-1-

acetonehydrochloride
2-Acetylthiophene (20.0g, 0.16mol), dimethylamine hydrochloride (16.8g,
0.21 mol), paraformaldehyde (9.5g, 0.32mol) and 50mL anhydrous ethanol were
placed into a 150mL three-necked bottle, The mixture was added with
concentrated hydrochloric acid to reach a pH of 3-4, and heated to reflux for 8h.
The reaction was stopped, and the reacton mixture was cooled to room
temperature, frozen overnight, and filtrated in vacumm. The filter cake was
washed with cold anhydrous ethanol to be white to obtain 31 2g of white crystal
with a yield of 89.6%. MS (m/e): 184.3 (M+1+).
1.2: Preparation of 3-dimethylamino-1-(thiophen-2-yl)-1-propanol
3-Dimethylamino-1-(2-thienyl)-1 -acetone hydrochloride (30.8g, 0.14mol)
was dissolved in 150 ml distilled water. The mixture was added dropwise with
2.5 M sodium hydroxide aqueous solution to reach a pH of about 10, extracted
with ethyl acetate (100 mlx3). The organic phases were combined and washed
with saturated sodium chloride anqueous solution twice, dried over anhydrous
sodium sulfate, and distilled under a reduced pressure to remove ethyl acetate,
thereby obtaining a yellow oily liquid. The liquid was dissolved in 30ml
anhydrous tetrahydrofuran, the mixture was slowly added dropwise to the
solution of LiAIH4 (7.8g, 0.21 mol) in 100 ml anhydrous tetrahydrofuran, and the
reaction temperature was controlled at 0-5°C in an ice bath. The ice bath was
removed, and the reaction was performed at room temperature for 2h and
stopped. The reaction liquid was added dropwise with anhydrous ethanol slowly,
and the solids were removed by filtration under vacumm after the residual LiAIH4
was completed. Tetrahydrofuran was distilled out under a reduced pressure and
the residue was extracted with dichloromethane (50 mlx3). The organic phases
were combined, washed with saturated sodium chloride aqueous solution twice,
dried over anhydrous sodium sulfate, and distilled to remove dichloromethane,
to obtain 22.9g of 3-dimethylamino-1-(thiophen-2-yl)-1-propanol as a white solid
in a yield of 88.3%. 1H-NMR δ (ppm, CD3COCD3-d6): 7.28-7.30(dd,1H,Ar-H);
6.92-6.96(m,2H,Ar-H); 5.06-5.09(t,1H,CHOH); 2.87(s,1H,OH);

2.55-2.62(m,1H,CH2N); 2.40-2.47 (m,1H, CH2N); 2.23(s,6H,N(CH3)2);
1.86-1.91(m,2H,CH2CH2N).
1.3: Preparation of N,N-dimethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-
(thiophen-2-yl)-propylamineoxalate (Compound l1)
3-Dimethylamino-1-(thiophen-2-yl)-1-propanol (1.85g, 0.01 mol),
4-hydroxyl-benzo[1,3]dioxolane (1.38g, 0.01mol) and triphenylphosphine (3.93g,
0.015mol) were dissolved in 80ml of anhydrous tetrahydrofuran. The mixture
was slowly added dropwise with the solution of diethyl azodicarboxylate (2.61g,
0.015mol) in 20ml anhydrous tetrahydrofuran, the reaction temperature was
controlled to be lower than -5°C in an ice-salt bath. After compeletion of the
addition, the ice-salt bath was removed, and the reaction was performed at
room temperature for 24h. After the end of reaction, tetrahydrofuran was
distilled out under a reduced pressure, the resultant oily liquid was dissolved in
100ml of ethyl acetate, washed with diluted sodium hydroxide aqueous solution
and saturated sodium chloride aqueous solution separately once, dried over
anhydrous sodium sulfate, and separated by silica gel column chromatography
to obtain 1.07g of N,N-dimethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-
(thiophen-2-yl)-propylamine as a pale yellow oily liquid, which was dissolved in
30ml of ethyl acetate, added with oxalic acid (0.32g, 0.035mol) to generate a
pale yellow solid. The mixtyure was heated to reflux, cooled to room
temperature, frozen for 2h and filtrated. The filter cake was washed with cold
ethyl acetate to obtain 1.31g of the target compound as a pale yellow powdery
solid in a yield of 33.2% and a melting point of 85-88X. MS (m/e): 306.5 (M+1+);
1H-NMR δ (ppm, DMSO-d6): 7.46-7.48(d,1H,5'-H); 7.11-7.12 (d,1H,3'-H);
6.95-6.97(dd,1H,4'-H); 6:66-6.70(t,lH,6-H); 6.53-6.59(dd,2H,5,7-H);
5.97-5.98(d, 2H.2-H); 5.71-5.75(t,1H,CHO); 2.27-2.30(t,2H,CH2N);
2.19-2.21(m,1H,CH2 CH2N); 2.11(s,6H,N(CH3)2); 2.06-2.08(m,1H, CH2CH2N).
Example 2: Preparation of N-methvl-3-[(benzo[1,-3]dioxolan-4-yl)-oxy]-3-
(thiophen-2-vl)-propylamineoxalate (compound I2)

N,N-dimethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-(thiophen-2-yl)-propylami
ne (1.26g, 4.14mmol) was dissolved in 50ml of anhydrous toluene. The mixture
was heated to reflux, added dropwise over 0.5h with the solution of phenyl
chloroformate (0.78g, 4.97mmol) in 10ml anhydrous toluene. After compeletion
of the addition, the refluxing was maintained for 1h, and then the reaction was
terminated, and cooled to room temperature. The organic phase was washed
with 2.5M sodium hydroxide aqueous solution (20mLx3), the organic phase was
washed with distilled water to neutral, then with 1.0M hydrochloric acid aqueous
solution (20ml_x3), with distilled water to neutral, with saturated sodium chloride
aqueous solution, dried over anhydrous sodium sulfate, filtered to remove the
drying agent, and distilled under a reduced pressure to remove toluene to obtain
a pale yellow oil.
40mL of 1,2-propylene glycol was added to the above oil, sodium hydroxide
(1.65g, 4.14mmol) was dissolved in 10ml_ of distilled water and added to the
above 1,2-propylene glycol solution. The mixture was heated to reflux for 3h, the
reaction was then terminated, cooled to room temperature, added with diluted
hydrochloric acid aqueous solution to adjust the pH of about 3, stirred at room
temperature for 1h, extracted with n-hexane (30mLx3), added with sodium
hydroxide aqueous solution to adjust a pH of about 10, extracted with ethyl
acetate (30ml_x3). The organic phase was washed with saturated saline solution,
dried over anhydrous sodium sulfate, filtered to remove the drying agent, and
distilled under a reduced pressure to remove solvent to a residue of about 20ml_.
The residue was then added with 0.37g (4.14mmol) of oxalic acid to generate a
white precipitate. The mixture was heated to reflux for 0.5h, cooled to room
temperature, frozen for 4h. After filtration under vacumm, the filter cake was

washed with cold ethyl acetate to obtain 0.34g of the target compound as a
white powdery solid in a yield of 21.6% and a melting point of 120-123°C. MS
(m/e): 292.2 (M+H+), 314.3(M+Na+). 1H-NMR δ (ppm, DMSO-d6):
7.46-7.48(d,1H,5'-H); 7.11-7.12 (d,1H,3'-H); 6.95-6.97(dd,1H,4'-H);
6.66-6.70(t,1H,6-H); 6.58-6.60(d,2H,7-H); 6.53-6.55 (d,1H, 5-H);
5.96-5.98(dd,1H,2-H); 5.76-5.79(t,1H,CHO); 2.50-2.52(t,2H,CH2N); 2.24(s,
6H,N(CH3)2); 2.11-2.19 (m,1H,CH2CH2N); 1.90 -1.98(m,1H, CH2CH2N).
Example 3: Preparation of N.N-diethvl-3-[(penzo[1-3]dioxolan-4-vl)-oxvl-3-
(thiophen-2-vl)-propvlamineoxalate (compound l3)

3.1: Prepation of 3-diethylamino-1-(thiophen-2-yl)-1-acetone- hydrochloride
2-Acetylthiophene (20.0g, 0.16mol), diethylamine hydrochloride (15.3g,
0.21 mol), paraformaldehyde (9.5g, 0.32mol) and 50mL anhydrous ethanol were
placed in a 150ml_ three-necked bottle. The mixture was added dropwise with
concentrated hydrochloric acid to reach a pH of 3-4 and heated to reflux for 8h.
The reaction was stopped, cooled to room temperature, frozen overnight, and
filtrated under vacumm. The filter cake was washed with cold anhydrous ethanol
to white to obtain 31.1g of 3-diethylamino-1-(thiophen-2-yl)-1-
acetonehydrochloride as a pale yellow crystal in a yield of 78.6%. MS (m/e):
212.3 (M+1+).
3.2: Preparation of 3-diethylamino-1-(thiophen-2-yl)-1-propanol
3-Diethylamino-1-(thiophen-2-yl)-1-acetonehydrochloride (7.92g, 0.032mol)
was dissolved in 50mL of distilled water. The mixture was added dropwise with

2.5M NaOH aqueous solution to reach a pH of about 10, and extracted with
ethyl acetate (20mlx3). The organic phases were combined, washed with
saturated sodium chloride aqueous solution twice, dried over anhydrous sodium
sulfate, and distilled to remove ethyl acetate. The resultant yellow oily liquid was
dissolved in 20ml of anhydrous tetrahydrofuran, and then added dropwise
slowly into the solution of LiAIH4 (1.78g, 0.048mol) in 50ml anhydrous
tetrahydrofuran, in which an ice bath was used to control the reaction
temperature. After the addition, the ice bath was removed, and the reaction was
performed for 2h and then stopped. Anhydrous ethanol was slowly added
dropwise into the reaction liquid. After complete reaction of the residual LiAim,
solids were removed by filtration under vacumm, tetrahydrofuran was distilled
out under a reduced pressure, and the residue was extracted with
dichloromethane (20mlx3). The organic phases were combined, washed with
saturated sodium chloride aqueous solution twice, dried over anhydrous sodium
sulfate, and distilled to remove dichloromethane to obtain 5.93g of
3-diethylamino-1-(thiophen-2-yl)-1-propanol as a deep yellow oily liquid in a
yield of 87.0%. 1H-NMR δ (ppm, DMSO-d6): 7.347.35 (dd,1H,Ar-H); 6.93-6.95
(dd,H,Ar-H); 6.91-6.92 (dd,H,Ar-H); 5.95 (s,1H,OH); 4.86-4.89(t,1H,CHOH);
2.56-2.37 (m,6H,. CH2N(CH2CH3); 1.76-1.81 (m,2H,CH2CH2N); 0.92-0.95
(m,6H,N(CH2CH3)2);
3.3: Preparation of N,N-diethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-
(thiophen-2-yl)-propylamineoxalate (compound I3)
3-Diethylamino-1-(thiophen-2-yl)-1-propanol (2.11g, 0.01 mol),
5-hydroxyl-benzo[1,3]dioxolane (1.38g, 0.01 mol) and triphenylphosphine (3.93g,
0.015mol) were dissolved in 80ml of anhydrous tetrahydrofuran. The mixture
was slowly added dropwise with the solution of diethyl azodicarboxylate (2.61g,
0.015mol) in 20ml anhydrous tetrahydrofuran, and an ice-salt bath was used to
control the reaction temperature below -5°C. After compeletion of the addition,
the ice-salt bath was removed, and the reaction was performed at room
temperature for 24h. After the end of the reaction, tetrahydrofuran was distilled

out under a reduced pressure, and the obtained oily liquid was dissolved in
100ml of ethyl acetate. The mixture washed with diluted sodium hydroxide
aqueous solution and saturated sodium chloride aqueous solution respectively,
dried over anhydrous sodium sulfate, and separated by silica gel column
chromatography to obtain 1.06g of the target compound as a pale yellow oily
liquid in a yield of 31.8%. MS (m/e): 334.2(M+1+). 1H-NMR δ (ppm, DMSO-d6):
7.25-7.26(dd,1H,5'-H); 6.97-6.98 (d,1H,3'-H); 6.81-6.83(dd,1H,4'-H); 6.52-6.56
(t,1H,6-H); 6.42-6.44(d,1H,7-H); 6.34-6.36(d,1H, 5-H); 5.81-5.82(d,2H,2-H);
5.68-5.71(t,1H,CHO); 2.34-2.54(m,6H, CH2N(CH2CH3)2); 2.06-2.12(m, 1H,
CH2CH2N); 1.86-1.92(m,1H,CH2CH2N); 0.80-0.84(t,6H, N(CH2CH3)2)..
Example 4: Preparation of 1-f3-(benzof1.3ldioxolan-4-vl-oxv)-3-(thiophen-
2-vl)-propvl1-pyrrolidineoxalate (compound l4)

4.1: Preparation of 3-(tetrahydropyrrol-1-yl)-1-(thiophen-2-yl)-1-
acetonehydrochloride
2-Acetylthiophene (8.82g, 0.070mol), tetrahydropyrrole (6.15g, 0.087mol),
paraformaldehyde (3.90g, 0.13mol) and 30mL of anhydrous ethanol were
placed in a 100 mL three-necked bottle. The mixture was added dropwise with
concentrated hydrochloric acid to reach a pH of 3-4, and heated to reflux for 8h.
The reaction was stopped, cooled to room temperature, frozen overnight, and
filtered. The titer cake was washed with cold anhydrous ethanol to white to
obtain 13.3g of 3-(tetrahydropyrrol-1-yl)-1-(thiophen-2-yl)-1-acetone
hydrochloride as a pale yellow crystal in a yield of 77.6%. MS (m/e): 210.4
(M+1+).

4.2: Preparation of 3-(tetrahydropyrrol-1-yl)-1-(thiophen-2-yl)-1-propanol
3-(tetrahydropyrrol-1-yl)-1-(thiophen-2-yl)-1-acetone hydrochloride (12.3g,
0.050mol) was dissolved in 50 mL of distilled water. The mixture was added
dropwise with 2.5M sodium hydroxide aqueous solution to reach a pH of about
10, and extracted with ethyl acetate (20 mLx3). The organic phases were
combined, washed with saturated sodium chloride aqueous solution twice, dried
over anhydrous sodium sulfate, and distilled to remove ethyl acetate. The
obtained yellow oily liquid was dissolved in 15ml anhydrous tetrahydrofuran,
added dropwise slowly into the solution of LiAIH4 (2.78g, 0.075mol) in 50 mL
anhydrous tetrahydrofuran, and an ice bath was used to control the reaction
temperature. After dropping, the ice bath was removed, and the reaction was
performed at room temperature for 2h and then stopped. Into the reaction liquid,
anhydrous ethanol was slowly added dropwise. After complete reaction of the
residual LiAIH4, solids were removed by filtration under vacumm,
tetrahydrofuran was distilled out under a reduced pressure, and the residue was
extracted with dichloromethane (20 ml_x3). The organic phases were combined,
washed with saturated sodium chloride aqueous solution twice, dried over
anhydrous sodium sulfate, and distilled to remove dichloromethane to obtain
8.92g of a deep yellow oily liquid in a yield of 84.6%. 1H-NMR δ (ppm, DMSO-d6):
7.35-7.36(dd,1H,Ar-H); 6.93-6.95(m,H,Ar-H); 6.91-6.92(m,H,Ar-H); 5.81(s,1H,
OH); 4.86-4.89(t,1H,CHO); 2.40-2.53(m,6H, CH2N(CH2CH3)2); 1.78-1.85(m,2H,
HOCHCH2CH2N); 1.62-1.70(m,4H,CH2CH2 CH2CH2).
4.3: Preparation of 1-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(thiophen-2-yl)-
propyl]-pyrrolidineoxalate (compound l4)
3-(tetrahydropyrrol-1-yl)-1-(thiophen-2-yl)-1-propanol (2.11g, 0.0Imol),
5-hydroxylbenzo[1,4]dioxolane (1.38g, 0.0Imol) and triphenylphosphine (3.93g,
0.015mol) were dissolved in 80 mL anhydrous tetrahydrofuran. The mixture was
slowly added dropwise with the solution of diethyl azodicarboxylate (2.61g,
0.015mol) in 20 mL anhydrous tetrahydrofuran, in which the reaction

temperature was controlled with an ice-salt bath to be below -5°C. After addition,
the ice-salt bath was removed, and the reaction was performed at room
temperature for 24h. After the end of the reaction, tetrahydrofuran was distilled
out under a reduced pressure, and the obtained oily liquid was dissolved in 100
mL ethyl acetate. The mixture was washed with diluted sodium hydroxide
aqueous solution and saturated sodium chloride aqueous solution respectively,
dried over anhydrous sodium sulfate, and separated by silica gel column
chromatography to obtain 1.12g of a pale yellow oily liquid. The oily liquid was
dissolved in 30 mL ethyl acetate, added with 0.30g (0.034mol) oxalic acid to
generate a white solid. The mixture was heated to reflux, cooled to room
temperature, frozen for 2h, and filtrated under vacumm. The filter cake was
washed with cooled ethyl acetate to obtain 1.18g of target compound as a white
powdery solid in a yield of 28.2% and a melting point of 105-108°C. MS (m/e):
332.5(M+H+). 1H-NMR δ (ppm, DMSO-d6): 7.47-7.48(dd,1H,5,-H); 7.11-7.12
(d,1H,3'-H); 6.95-6.97(dd,1H,4'-H); 6.66-6.70 (t,1H,6-H); 6.57-6.59(d,1H,7-H);
6.53-6.55(d,1H, 5-H); 5.97-5.98(d,2H,2-H); 5.72-5.75(t,1H,CHO);
2.40-2.50(m,6H, CH2N(CH2CH3)2); 2.16-2.25(m, 1H,HOCHCH2CH2N);
1.94-2.03(m,1H, HOCHCH2CH2N; 1.67(s, 4H, CH2CH2CH2CH2).
Example 5: Preparation of 1-[3-(benzof1,31dioxolan-4-vl-oxy)-3-(thiophen-

5.1: Preparation 3-(piperidin-1-yl)-1-(thiophen-2-yl)-1-
acetonehydrochloride
2-Acetylthiophene (8.82g, 0.070mol), piperidine (7.37g, 0.087mol),
paraformaldehyde (3.90g, 0.13mol) and 30 mL anhydrous ethanol were placed

in a 100 ml_ three-necked bottle. The mixture was added dropwise with
concentrated hydrochloric acid to reach a pH of 3-4 and heated to reflux for 8h.
The reaction was terminated, cooled to room temperature, frozen overnight, and
filtrated under vacumm. The filter cake was washed with cold anhydrous ethanol
to white to obtain 13.3g of a pale yellow crystal in a yield of 74.6%. MS (m/e):
224.3 (M+1+).
5.2: Preparation of 3-(piperidin-1-yl)-1-(thiophen-2-yl)-1-propanol
3-(Piperidin-1-yl)-1-(thiophen-2-yl)-1-acetone hydrochloride (13.0g,
0.050mol) was dissolved in 50 mL distilled water. The mixture was added
dropwise with 2.5M sodium hydroxide aqueous solution to reach a pH of 10, and
extracted with ethyl acetate (20 mLx3). The organic phases were combined,
washed with saturated sodium chloride aqueous solution twice, dried over
anhydrous sodium sulfate, and distilled to remove ethyl acetate. The obtained
yellow oily liquid was dissolved in 15ml anhydrous tetrahydrofuran, added
dropwise slowly into the solution of LiAlhU (2.78g, 0.075mol) in 50 mL
anhydrous tetrahydrofuran, and the reaction temperature was controlled with an
ice bath. After the addition, the ice bath was removed. The reaction was
performed at room temperature for 2h and then stopped. Into the reaction liquid,
anhydrous ethanol was slowly added dropwise. After complete reaction of the
residual LiAIH4, solids were removed by filtration under vacumm,
tetrahydrofuran was distilled out under a reduced pressure, and the residue was
extracted with dichloromethane (20 mLx3). The organic phases were combined,
washed with saturated sodium chloride aqueous solution twice, dried over
anhydrous sodium sulfate, and distilled to remove dichloromethane to obtain
9.26g of a deep yellow oily liquid in a yield of 82.3%. 1H-NMR δ (ppm, DMSO-d6):
7.33-7.34(dd,1H,Ar-H); 6.93-6.95(dd,1H, Ar-H); 6.91-6.92(m,1H,Ar-H);
5.93(s,1H,OH); 4.86-4.89(t,1H,CHOH); 2.29-2.50 (m,6H, CH2NCH2CH2)2);
1.79-1.86(m,2H,HOCHCH2CH2N); 1.45-1.51 (m,4H,N(CH2CH2)2CH2); 1.38-1.42
(m, 2H, (CH2CH2)2CH2).

5.3: Preparation of 1-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(thiophen-2-yl)-
propyl]-piperidineoxalate (compound l5)
3-(Piperidin-1-yl)-1-(thiophen-2-yl)-1-propanol (2.25g, 0.01 mol),
5-hydroxyl-benzo[1,4]dioxolane (1.38g, 0.01 mol) and triphenylphosphine (3.93g,
0.015mol) were dissolved in 80 mL anhydrous tetrahydrofuran. The mixture was
slowly added dropwise with the solution of diethyl azodicarboxylate (2.61 g,
0.015mol) in 20 mL anhydrous tetrahydrofuran, and the reaction temperature
was controlled by an ice-salt bath to be below -5°C. After compeletion of the
addition, the ice-salt bath was removed. The reaction was performed at room
temperature for 24h. After the end of reaction, tetrahydrofuran was distilled out
under a reduced pressure, and the obtained oily liquid was dissolved in 100 mL
ethyl acetate. The mixture was washed with diluted sodium hydroxide aqueous
solution and saturated sodium chloride aqueous solution respectively, dried
over anhydrous sodium sulfate, and separated by silica gel column
chromatography to obtain 1.45g of a pale yellow oily liquid. The oily liquid was
dissolved in 30 mL of ethyl acetate, added with oxalic acid (0.38g, 0.042mol) to
generate a white solid. The mixture was heated to reflux, cooled to room
temperature, frozen for 2h, and filtrated under vacumm. The filter cake was
washed with cooled ethyl acetate to obtain 1.53g of the target compound as a
white powdery solid in a yield of 35.2% and a melting point of 118-120°C. MS
(m/e): 346.4(M+H+). 1H-NMR δ (ppm, DMSO-d6): 7.47-7.48(d,1H,5'-H);
7.10-7.11(d,1H,3'-H); 6.95-6.97(dd,1H,4'-H); 6.67-6.71 (t,1H,6-H);
6.58-6.60(d,1H,7-H); 6.53-6.55(d,1H, 5-H); 5.97-5.98(d,2H, 2-H);
5.71-5.74(t,1H,CHO); 2.30-2.32(m,6H, CH2N(CH2CH2)2); 2.13-2.05(m,1H,
HOCHCH2CH2N); 1.93-2.01(m,1H, HOCHCH2CH2N); 1.45-1.49{m,4H,
N(CH2CH2)2CH2)); 1.35-1.37(m,2H, (CH2CH2)2CI±>).
Example 6: Preparation of N.N-dimethvl-[3-(benzoM.31dioxolan-4-yl-oxy)-
3-(furan-2-yl)]-propvlamineoxalate (compound l6)

6.1: Preparation of 3-dimethylamino-1-(furan-2-yl)-1-acetonehydrochloride
2-acetylfuran (17.6g, 0.16mol), dimethylamine hydrochloride (16.8g,
0.21 mol), paraformaldehyde (9.5g, 0.32mol) and 50 ml_ anhydrous ethanol were
placed in a 150 mL three-necked bottle. The mixture was added dropwise with
concentrated hydrochloric acid to reach a pH of 3-4 and heated to reflux for 8h.
The reaction was terminated, cooled to room temperature, frozen overnight, and
filtrated under vacumm. The filter cake was washed with cold anhydrous ethanol
to obtain 28.1g of 3-dimethylamino-1-(furan-2-yl)-1 -acetone hydrochloride as a
pale yellow crystal in a yield of 86.4%. MS (m/e): 168.3 (M+1+).
6.2: Preparation of 3-dimethylamino-1-(furan-2-yl)-1-propanol
3-Dimethylamino-1 -(furan-2-yl)-1 -acetonehydrochloride (24.4g, 0.12mol)
was dissolved in 120 mL distilled water. The mixture was added dropwise with
2.5M sodium hydroxide aqueous solution to reach a pH of 10, and extracted with
ethyl acetate (80 ml_x3). The organic phases were combined, washed with
saturated sodium chloride aqueous solution twice, dried over anhydrous sodium
sulfate, and distilled under a reduced pressure to remove ethyl acetate. The
obtained yellow oily liquid was dissolved in 30 mL anhydrous tetrahydrofuran,
added dropwise slowly into LiAlH4 (6.7g, 0.18mol) in 100 mL anhydrous
tetrahydrofuran solution, and the reaction temperature was controlled in an ice
bath. After the addition, the ice bath was removed. The reaction was performed
at room temperature for 2h and then stopped. Into the reaction liquid, anhydrous
ethanol was slowly added dropwise. After complete reaction of the residual
LiAIH4, solids were removed by filtration under vacumm, tetrahydrofuran was
distilled out under a reduced pressure, and the residue was extracted with

dichloromethane (50 mLx3). The organic phases were combined, washed with
saturated sodium chloride aqueous solution twice, dried over anhydrous sodium
sulfate, and distilled to remove dichloromethane to obtain 16.8g of
3-dimethylamino-1-(furan-2-yl)-1-propanol as a yellow oily liquid in a yield of
82.6%. 1H-NMR δ (ppm, DMSO-d6): 7.55(s,1H,Ar-H); 6.36-6.37(m,1H,Ar-H);
6.22-6.23(d,1H, Ar-H); 5.45(s,1H,OH); 4.56-4.59(t,1H,CHOH); 2.24-2.50(m,2H,
CH2N); 2.11(s,6H, N(CH3)2); 1.76-1.83(m,2H,CH2CH2N).
6.3: Preparation of N,N-dimethyl[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-
(furan-2-yl)]-propylamineoxalate (compound l6)
3-Dimethylamino-1-(furan-2-yl)-1-propanol (169g, 0.0Imol),
4-hydroxyl-benzo[1,3]dioxolane (1.38g, 0.0Imol) and triphenylphosphine (3.93g,
0.015mol) were dissolved in 80 mL anhydrous tetrahydrofuran. The mixture was
slowly added drop wise with the solution of diethyl azodicarboxylate (2.61g,
0.015mol) in 20 mL anhydrous tetrahydrofuran, and the reaction temperature
was controlled by an ice-salt bath to be below -5°C. After compeletion of the
addition, the ice-bath was removed. The reaction was performed at room
temperature for 24h. After the end of reaction, tetrahydrofuran was distilled out
under a reduced pressure, and the obtained oily liquid was dissolved in 100 mL
ethyl acetate. The mixture was washed with diluted sodium hydroxide aqueous
solution and saturated sodium chloride aqueous solution respectively, dried
over anhydrous sodium sulfate, and separated by silica gel column
chromatography to obtain 0.75g of N,N-dimethyl-[3-(benzo[1,3]dioxolan-
4-yl-oxy)-3-(furan-2-yl)]-propylamine as a pale yellow oily liquid. The oily liquid
was dissolved in 20 mL ethyl acetate, and the mixture was added with 0.23g
(0.026mol) of oxalic acid to generate a pale yellow solid, heated to reflux, cooled
to room temperature, frozen for 2h, and filtrated under vacumm. The filter cake
was washed with cold ethyl acetate to obtain 0.88g of the target compound as a
pale yellow powdery solid in a yield of 23.2% and a melting point of 97-101 °C.
MS (m/e): 290.4 (M+1+), 312.5(M+Na+). 1H-NMR δ (ppm, DMSO-d6):
7.63-7.64(dd,1H,5'-H); 6.62-6.66(t,1H,6-H); 6.60-6.62(d,1H,5-H); 6.55-6.57

(d,1H,7-H); 6.46-6.47(d,1H, 3'-H); 6.39-6.41 (dd,1H, 4'-H); 5.95-5.97(dd,1H,2-H);
5.44-5.47(t,1H,CHO); 2.24-2.28(t,2H,CH2N); 1.99-2.19 (m,2H,CH2CH2N);
2.11(s,6H,N(CH3)2).
Example 7: Preparation of N-methvl-[3-(benzo[1-3]dioxolan-4-yl-oxy)3-
(furan-2-yl-propylamineoxalate (compound I7)

N,N-dimethyl-3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(furan-2-ylpropylamine
(0.59g, 2.03mmol) was dissolved in 30 mL anhydrous toluene. The mixture was
heated to reflux, and added dropwise with phenyl chloroformate (0.38g,
2.44mmol) in 10 mL anhydrous toluene solution within 0.5h. After compeletion
of the addition, the reflux was maintained for 1h, and the reaction was then
terminated, and cooled to room temperature. The organic phase was washed
with 2.5M sodium hydroxide aqueous solution (20 ml_x3), with distilled water to
neutral, with 1.0M hydrochloric acid aqueous solution (20 mLx3), with distilled
water to neutral, with saturated sodium chloride aqueous solution, and then
dried over anhydrous sodium sulfate. The drying agent was removed by filtration,
and toluene was removed by distillation under a reduced pressure to obtain a
yellow oil.
30 mL 1,2-propylene glycol was added to the above yellow oil, and 0.81 g
(2.03mmol) sodium hydroxide dissolved in 8mL distilled water was added to the
above 1,2-propylene glycol solution. The mixture was heated to reflux for 3h,
cooled to room temperature after the end of reaction, added with diluted
hydrochloric acid aqueous solution to reach a pH of about 3, stirred at room
temperature to carry out the reaction for 1h, extracted with n-hexane (20 mLx3),

then added with sodium hydroxide aqueous solution to reach a pH of about 10,
and extracted with ethyl actate (20 ml_x3). The organic phase was washed with
saturated saline aqueous solution, and dried over anhydrous sodium sulfate.
The drying agent was removed by filtration, and the solvent was removed by
distillation under vacumm to obtain a residue of about 15mL. The residue was
then added with 0.18g (2.03mmol) oxalic acid to generate a white precipitate.
The mixture was heated to reflux for 0.5h, cooled to room temperature, and
frozen for 4h. After filtration, the filter cake was washed with cold ethyl acetate
to obtain 0.13g of the target compound as a white powdery solid in a yield of
17.8% and a melting point of 130-133°C. MS (m/e): 276.1 (M+1+), 298.0(M+Na+).
1H-NMR δ (ppm, DMSO-d6): 7.63-7.64(dd,1H,5'-H); 6.69-6.73(t,1H,6-H);
6.62-6.64(d,1H,5-H); 6.55-6.57 (d,1H,7-H); 6.46-6.47(d,1H, 3'-H);
6.40-6.41 (dd,1H, 4'-H); 5.95-5.97(dd,1H,2-H); 5.49-5.52(t,1H,CHO);
2.50-2.53(t,2H,CH2N); 2.25(s, 6H,NCH3); 2.10-2.16 (m, H, CH2CH2N); 1.99-2.05
(m,H, CH2CH2N).,
Example 8: Preparation of N.N-dimethvl-3-[(benzo[1.4]dioxan-5-vl-oxv)-3-
(thiophen-2-yl)-propylamine1oxalate (compound l8)

3-Dimethylamino-1-(thiophen-2-yl)-1-propanol (1.85g, 0.01 mol),
5-hydroxyl-benzo[1,4]dioxane (1.52g, 0.01 mol) and triphenylphosphine (3.93g,
0.015mol) were dissolved in 80 mL mhydrous tetrahydrofuran. The mixture was
slowly added dropwise with the 'solution of diethyl azodicarboxylate (2.61 g,
0.015mol) in 20 mL anhydrous telrahydrofuran, and the reaction temperature
was controlled by an ice-salt bath to be below -5°C. After compeletion of the

addition, the ice-salt bath was removed, and the reaction was performed at
room temperature for 24h. After the reaction, tetrahydrofuran was distilled out
under a reduced pressure, and the obtained oil liquid was dissolved in 100 mL
ethyl acetate. The mixture was washed with diluted sodium hydroxide aqueous
solution and saturated sodium chloride aqueous solution respectively, dried
over anhydrous sodium sulfate, and separated by silica gel column
chromatography to obtain 1.56g of IM,N-dimethyl-3-[(benzo[1,4]dioxan-
5-yl-oxy)-3-(thiophen-2-yl)-propylamine] as a yellow oil. The yellow oil was
dissolved in 50 mL ethyl acetate, the mixture was added with 0.41g (0.045mol)
oxalic acid to generate a pale yellow precipitate, heated to reflux, cooled to
room temperature, frozen for 2h, and filtrated under vacumm. The filter cake
was washed with cold ethyl acetate to obtain 1.69g of the target compound as a
pale yellow powdery solid in a yield of 39.1% and a melting point of 89-92X. MS
(m/e): 320.5 (M+1+). 1H-NMR 5 (ppm, CDCI3-d3): 7.22-7.24(dd,1H,5'-H);
6.99-7.00 (d,1H,3'-H); 6.92-6.94(dd,1H,4'-H); 6.61-6.65(t,1H,7-H); 6.49-6.51 (d,
2H,6,8-H); 5.48-5.51 (t,1H, CHO); 4.23-4.31 (t,4H,2,3-H); 2.44-2.47(t,2H,CH2N);
2.35-2.42(m,1H,CH2CH2N); 2.25(s,6H,N(CH3)2); 2.08-2.13(m,1H, CH2CH2N).
Example 9: Preparation of N-methyl-3-f(benzof1.41dioxan-5-vl-oxv)-3-
(thiophen-2-vl)-propylaminel oxalate (compound la)

N,N-dimethyl-3-[(benzo[1,4]dioxan-5-yl-oxy)-3-(thiophen-2-yl)-propylamine]
(0.78g, 2.44mmol) was dissolved in 50 mL anhydrous toluene. The mixture was
heated to reflux, and added dropwise with the solution of phenyl chloroformate
(0.46g, 2.93mmol) in 10 mL anhydrous toluene over 0.5h. The reflux was

maintained for 1h after compeletion of the addition, and then the reaction was
terminated, and cooled to room temperature. The organic phase was washed
with 2.5M sodium hydroxide aqueous solution (20 ml_x3), with distilled water to
neutral, then with 1.0M hydrochloric acid aqueous solution (20 ml_x3), with
distilled water to neutral, with saturated sodium chloride aqueous solution, and
dried over anhydrous sodium sulfate. The drying agent was removed by filtration,
and toluene was distilled out under a reduced pressure to obtain a yellow oil.
30 ml_ of 1,2-propylene glycol was added to the above yellow oil, and
sodium hydroxide (0.98g, 2.44mmol) dissolved in 8ml_ of distilled water was
added into the above 1,2-propylene soludion. The mixture was heated to reflux
for 3h, the reaction was terminated, cooled to room temperature, added with
diluted hydrochloric acid aqueous solution to reach a pH of about 3, stirred to
perform the reaction at room temperature for 1h, extracted with n-hexane (20
ml_x3), then added with sodium hydroxide aqueous solution to reach a pH of
about 10, and extracted with ethyl acetate (20 mLx3). The organic phase was
washed with saturated saline aqueous solution, dried over anhydrous sodium
sulfate, filterated to remove the drying agent, distilled under vacumm to remove
solvent and obtain a residue of about 15mL. The residue was added with 0.22g
(2.44mmol) of oxalic acid to generate a white precipitate. The mixture was
heated to reflux for 0.5h, cooled to room temperatre, and frozen for 4h. After
filtration under vacumm, the filter cake was washed with cold ethyl acetate to
obtain 0.30g of the target compound as a pale yellow powdery solid in a yield of
31.4% and a melting point of 128-131°C. MS (m/e): 306.4 (M+H+), 328.1 (M+Na+)
1H-NMR 6 (ppm, DMSO-d6): 7.45-7.46(dd,1H,5'-H); 7.09-7.10 (dd,1H,3'-H);
6.95-6.97(dd,1H,4'-H); 6.58-6.62(t,1H,7-H); 6.51-6.53(d,1H, 8-H);
6.41-6.43(d,1H, 6-H); 5.63-5.66(t,1H,CHO); 4.20-4.24(m,4H,2,3-H);
2.52-2.56(t,2H,Cli>N); 2.26 (s,3H,NCH3); 2.12-2.16 (m.lH.CHzCHzN);
1.95-1.99(m,1H,CH2CH2N).
Example 10: Preparation of N.N-dimethyl-3-f(benzof1.41dioxan-5-vl-oxy)-3-
(furan-2-vl)propvlaminel-oxalate (compound lin)

3-Dimethylamino-1-(furan-2-yl)-1-propanol (169g, 0.01 mol),
5-benzo[1,4]dioxane (1.52g, 0.01 mol) and triphenylphosphine (3.93g, 0.015mol)
was dissolved in 80 ml_ anhydrous tetrahydrofuran. The mixture was slowly
added dropwise with the solution of diethyl azodicarboxylate (2.61 g, 0.015mol)
in 20 mL anhydrous tetrahydrofuran, and the reaction temperature was
controlled by an ice-salt bath to be below -5°C. After compeletion of the addition,
the ice-salt bath was removed, and the reaction was performed at room
temperature for 24h. After the reaction, tetrahydrofuran was distilled out under a
reduced pressure, and the obtained oily liquid was dissolved in 100 mL ethyl
acetate. The mixture was washed with diluted sodium hydroxide aqueous
solution and saturated sodium chloride aqueous solution respectively, dried
over anhydrous sodium sulfate, and separated by silica gel column
chromatography to obtain 0.98g of N,N-dimethyl-3-[(benzo[1,4]dioxan-
5-yl-oxy)-3-(furan-2-yl)propylamine] as a yellow oil. The yellow oil was dissolved
in 30 mL ethyl acetate, and added with oxalic acid (0.29g, 0.032mol) to generate
a pale yellow precipitate. The mixture was heated to reflux, cooled to room
temperature, frozen for 2h, and filtrated under vacumm. The filter cake was
washed with cold ethyl acetate to obtain 0.75g of the target compound as a pale
yellow powdery solid in a yield of 19.1% and a melting point of 101-103°C. MS
(m/e): 304.3 (M+1+), 326.2(M+Na+). 1H-NMR 6 (ppm, DMSO-d6):
7.63(s,1H,5'-H); 6.62-6.66(t,1H,7-H); 6.54-6.56 (d,1H,6-H); 6.44-6.46
(d,1H,8-H); 6.39-6.40 (m,2H, 3',4'-H); 5.30-5.34(t,1H, CHO);
4.16-4.23(t,4H,2,3-H); 2.23-2.27(t,2H,CH2N); 1.99-2.23 (m,2H,CH2CH2N); 2.10
(s,6H, N(CH3)2).

Example 11: Antidepressant effect of the target compounds
as measured by tail suspension test in mice
Male ICR mice (SPF grade) weighing 18-22g each was suspended by
clampping separately at 1cm from the end of the tail with a clamp attached to a
rope at the center of top plate of a 25x25x25 cm tail suspension box, and the
head is away from the box bottom by 4-5 cm. The mice were administrated via
intraperitoneal injection at 30 min before the test or via intragastric
administration at 60min before the test with the compound to be tested and
Duloxetine as the positive control. The tail was suspended for 6min, and the
immobility time of mice during the last 4 min was accumulated. The results of
antidepressant effects of the target compounds administrated via intraperitoneal
injection as determined by the tail suspension test in mice are given in Table 1.

In the tail-suspended model of mice, the antidepressant effect was
evaluated by observing the immobility time of the tail-suspended mice, and the
shorter the immobility time, the stronger the antidepressant effect. As seen from
Table 1, the target compounds can significantly shorten the immobility time;
under the same, dose, the target compounds have more significant
antidepressant effect than Duloxetine; and with increasing of the dose, more

significant effect on the immobility time was observed, indicating that their
antidepressant effects are explicitly dose dependent.
The antidepressant effect of compound I2 was evaluated via intragastric
administration and the results thereof are shown in Table 2.

Table 2 shows that compound l2 can significantly shorten the immobility
time of the tail-suspended mice via intragastric administration; its at the dose of
5mg/kg is remarkably greater than that of duloxetine at the dose of 10mg/kg;
and the higher the dose, the greater the effect on the immobility time, which
indicates that its antidepressant effect is explicitly dose dependent.
Example 12: The antidepressant effect of the target compounds
as measured by forced swim test in mice
Mail ICR mice (SPF grade) weighing 18-22g were placed in a glass jar
(diameter 10cm, and height 20cm) with water 10cm in depth and a temperature
of 25°C, observed for 6 min, and the accumulated immobility time of mice (i.e.,
the time that the animal has no motion or a slight motion in its hind limbs, but
maintains body floated without motion) during the last 4min was recorded. The
mice were administrated with the compound to be tested and Duloxetine as the
positive control drug via intraperitoneal injection at 30min before the test or via

intragastric administration at 60min before the test. The effects of the target
compounds on the immobility time of the forced swim mice via intraperitoneal
injection are given in Table 3.

In the forced swim model of mice, the antidepressant effect was evaluated
by observing the immobility time of the forced swim mice, and the shorter the
immobility time, the stronger the antidepressant effect. As seen from Table 3,
the target compounds can significantly shorten the immobility time; at the same
dose, the antidepressant effects of the target compounds are significantly
greater than that of the Duloxetine; and the higher the dose, the greater the
effect on the immobility time, which indicates that their antidepressant effects
are explicitly dose dependent.
The antidepressant effect of compound I2 was further evaluated via
intragastric administration, and the results thereof are shown in Table 4.
Table 4: Effect of the target compound on the immobility time of the
forced swim mice via intragastric administration

Table 4 shows that compound b can significantly shorten the immobility
time via intragastric administration; its antidepressant effect at the dose of 20
mg/kg is comparable to that of Duloxetine at the dose of 40 mg/kg; and the
higher the dose, the greater the effect on the immobility time, which indicates
that its antidepressant effect is explicitly dose dependent.

We claim:
1. An amine compound represented by Formula I:

wherein,
X represents S or O;
R1 and R2 independently represent H or C1-4alkyl, or R1 and R2 together
with the nitrogen atom to which they are attached form a 5- or 6-membered
heterocyclic ring; and
n is 1 or 2,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein,
X represents S or O;
R1 and R2 independently represent H or C1-4alkyl; and
n is 1 or 2.
3. The compound of claim 1, wherein,
X represents S or O;
R1 and R2 independently represent H, methyl or ethyl; and
n is 1 or 2.
4. The compound of claim 1, wherein,

X represents S or O;
R1 and R2 together with the nitrogen atom to which they are attached form
pyrrole ring or piperidine ring; and
n is 1 or 2.
5. The compound of any one of claims 1-4, wherein the pharmaceutically
acceptable salt is oxalate.
6. The compound of claim 1, which is selected from the group consisting of:
N,N-dimethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-(thiophen-2-yl)-propylam
ineoxalate;
N-methyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-(thiophen-2-yl)-propylamine •
oxalate;
N,N-diethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-(thiophen-2-yl)-propylamin
eoxalate;
1-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(thiophen-2-yl)-propyl]-pyrrolidineox
a late;
1-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(thiophen-2-yl)-propyl]-piperidineoxa
late;
N,N-dimethyl-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(furan-2-yl)]-propylamine
•oxalate;
N-methyl-[3-(benzo[1,3]dioxolan-4-yl-oxy)-3-(furan-2-yl)]-propylamineoxal
ate;
N,N-dimethyl-3-[(benzo[1,4]dioxan-5-yl-oxy)-3-(thiophen-2-yl)-propylamin
e]- oxalate;
N-methyl-3-[(benzo[1,4]dioxan-5-yl-oxy)-3-(thiophen-2-yl)-propylamine]ox
alate; and
N,N-dimethyl-3-[(benzo[1,4]dioxan-5-yl-oxy)-3-(furan-2-yl)propylamine]ox
alate.

7. A pharmaceutical composition comprising a compound of Formula I of
claims 1 to 6 or a pharmaceutically acceptable salt thereof, together with one
, or more pharmaceutically acceptable carriers or excipients.
8. Use of a compound of Formula I of claims 1 to 6 or a pharmaceutically
acceptable salt thereof for the manufacture of an anti-depressent medicament.

The present invention relates to a new amine compound or a
pharmaceutically acceptable salt thereof, wherein the definitions of X, R1, R2 and
n are given in the description, to a pharmaceutical composition containing the
compound as active ingredient, and to use of the amine compound or its
pharmaceutically acceptable salt for the manufacture of an anti-depressent drug.

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=v0m7hsh2Khzk5ydRATDadg==&loc=wDBSZCsAt7zoiVrqcFJsRw==

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Patent Number

272138

Indian Patent Application Number

324/KOLNP/2011

PG Journal Number

13/2016

Publication Date

25-Mar-2016

Grant Date

18-Mar-2016

Date of Filing

20-Jan-2011

Name of Patentee

INSTITUTE OF PHARMACOLOGY AND TOXICOLOGY ACADEMY OF MILITARY MEDICAL SCIENCES P.L.A. CHINA

Applicant Address

NO. 27, TAIPING ROAD, HAIDIAN DISTRICT, BEIJING 100850 CHINA

Inventors:

#	Inventor's Name	Inventor's Address
1	ZHONG, BOHUA	NO. 27, TAIPING ROAD, HAIDIAN DISTRICT, BEIJING 100850 CHINA
2	ZHANG, YOUZHI	NO. 27, TAIPING ROAD, HAIDIAN DISTRICT, BEIJING 100850 CHINA
3	ZHANG, YANPING	NO. 27, TAIPING ROAD, HAIDIAN DISTRICT, BEIJING 100850 CHINA
4	XUE, RUI	NO. 27, TAIPING ROAD, HAIDIAN DISTRICT, BEIJING 100850 CHINA
5	HE, XINHUA	NO. 27, TAIPING ROAD, HAIDIAN DISTRICT, BEIJING 100850 CHINA
6	LI, YUNFENG	NO. 27, TAIPING ROAD, HAIDIAN DISTRICT, BEIJING 100850 CHINA
7	CHEN, HONGXIA	NO. 27, TAIPING ROAD, HAIDIAN DISTRICT, BEIJING 100850 CHINA
8	ZHAO, NAN	NO. 27, TAIPING ROAD, HAIDIAN DISTRICT, BEIJING 100850 CHINA
9	LI, MEIYING	NO. 27, TAIPING ROAD, HAIDIAN DISTRICT, BEIJING 100850 CHINA

PCT International Classification Number

C07D 407/12,A61K 31/36

PCT International Application Number

PCT/CN2009/000697

PCT International Filing date

2009-06-23

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	200810127171.5	2008-06-23	China