Application of substituted cinnamamide derivatives in preparation of anti-anxiety medication

Abstract

Disclosed is an application of substituted cinnamamide derivatives in the preparation of anti-anxiety medications, the substituted cinnammide derivatives are compounds having the structure of formula (I) or pharmaceutically acceptable salts thereof, wherein, R.sub.1 is H, OH, F, Cl, Br, I, OCH.sub.3, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.3, CH.sub.3CH.sub.2, CF.sub.3CH.sub.2, CN, NO.sub.2, NH.sub.2 or COOR.sub.5; R.sub.2 is H, C.sub.1-C.sub.10 linear alkyl, C.sub.3-C.sub.10 branched alkyl, C.sub.3-C.sub.10 cyclic alkyl, C.sub.1-C.sub.10 hydroxyalkyl or a N-substituted piperazine-derived group; or R.sub.2 is a group forming with adjacent Y a tetrahydropyrrolyl group, a piperidyl group or a cyclohexanimido group. ##STR00001##

Claims

1. A method of ameliorating a disorder, comprising administering a pharmaceutical composition comprising a substituted cinnamamide derivative to a subject in need thereof, wherein the disorder is an anxiety disorder, and, wherein the substituted cinnamamide is a compound selected from the group consisting of 5-iodine-3,4-methylenedioxy cinnamic acid isobutylamide (II-3), ##STR00026## 5-chlorine-3,4-methylenedioxy cinnamic acid isobutylamide (II-4), ##STR00027## 5-trifluoromethyl-3,4-methylenedioxy cinnamic acid isobutylamide (II-5), ##STR00028## 5-trifluoromethyl-3,4-methylenedioxy cinnamic acid piperidylamide (II-10), ##STR00029## 3-(5-trifluoromethyl-3,4-methylenedioxy phenyl)-propionic acid isobutylamide (II-11), and ##STR00030## 5-trifluoromethyl-3,4-methylenedioxy benzoic acid isobutylamide (II-12) ##STR00031##

2. The method of claim 1, wherein the anxiety disorder is chronic anxiety or acute anxiety.

3. The method of claim 1, wherein the pharmaceutical formulation consists of a dosage form selected from the group consisting of a tablet, capsule, granule, pill, pulvis, cream, pellet, powder, solution, injection, suppository, spray, drop, and patch.

4. The method of claim 1, wherein the pharmaceutical formulation further comprises polyethylene glycol and paraffin and consists of a pill.

5. The method of claim 1, wherein the pharmaceutical formulation further comprises sodium thiosulfate and distilled water and consists of a solution for injection.

6. The method of claim 1, wherein the pharmaceutical formulation is administered 1-5 times per day.

7. The method of claim 1, wherein the anxiety disorder displays as emotional symptoms selected from the group consisting of jitters, scariness, terror, fear and apprehensiveness.

8. The method of claim 1, wherein the anxiety disorder displays as vegetative nervous symptoms selected from the group consisting of dizziness, chest distress, palpitation, tachypnea, dry mouth, frequent urination, urgent urination, sweating and tremor.

9. The method of claim 1, wherein the anxiety disorder displays as psychomotor anxiety selected from the group consisting of restlessness, uneasiness, irritability, and difficulties in staying calm.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The present invention is further illustrated below in combination with embodiments.

(2) Please refer to Chinese patent CN201210123842.7 (publication number: CN102850317A) for compounds II-3, II-4, II-5, II-10, II-11 and II-12 and preparation methods thereof;

(3) please refer to Chinese patent CN201410504555.X (publication number: CN104513172A) for compounds III-2, III-4, III-7, III-9, III-10, III-11 and III-13 and preparation methods thereof;

(4) please refer to Embodiments 1-4 for preparation methods of compounds II-13, II-14, II-15 and II-16.

Embodiment 1: (E)-N-(4-Methylpiperazinyl)-5-(5-Trifluoromethyl-3,4-Methylenedioxy Phenyl)-1-Pentene Amide Hydrochloride (II-13)

(5) ##STR00022##

(6) Step 1: Compound 1 (1.53 g, 4.0 mmol) was placed in a single-necked flask of 100 ml, and 15 ml of chloroform was added for dissolving; then, compound 2 (1 g, 4.0 mmol) was added into the reaction system, stirring and reacting at room temperature for 14 hours; TLC (developing solvents PE:EA=5:1) showed that the reaction was completed, then the reactants were directly concentrated to obtain a crude product compound 3; after being purified by silica gel column chromatography (PE:EA=5:1), 1.1 g of white solid compound 3 was obtained, with a yield of 78.87%.

(7) Step 2: the compound 3 (0.3 g, 0.87 mmol) was dissolved in 5 ml of dichloromethane, and the temperature was lowered to 0; trifluoroacetic acid (1 ml) was added dropwise into the reaction system; then, the reaction system was warmed up to room temperature for reaction; 1 hour later, after TLC showed that raw materials were completely reacted, the reaction system was directly concentrated to obtain 0.21 g of white solid compound 4 (84%).

(8) Step 3: the compound 4 (0.48 g, 1.66 mmol), N-methylpiperazine (0.5 g, 5 mmol) and DIPEA (0.43 g, 3.34 mmol) were added into dichloromethane, and nitrogen replacement was conducted for three times; then, HATU (0.95 g, 2.5 mmol) was added and stirred at room temperature for 6 hours; the reaction system was washed with water; an organic phase was dried and concentrated to obtain a crude product; then, this crude product was purified by silica gel column chromatography to obtain 400 mg of colorless oily matter; then dissolved using 2 ml of dioxane, and 4 ml of hydrochloric acid solution of dioxane was added and stirred at room temperature for 30 minutes, concentrated and dried to obtain 43 mg of compound II-13 (65%).

(9) .sup.1H NMR (DMSO, 400 MHz): 11.28-11.27.00 (1H, NH, br), 7.11 (1H, s), 6.94 (1H, s), 6.70 (1H, d, J=15.2 Hz), 6.50 (1H, d, J=15.2 Hz), 6.17 (2H, s), 4.33 (2H, br), 3.42-3.20 (6H, br), 2.75 (4H, s), 2.51 (3H, s);

(10) ESI-MS: 371.1 [M+H].sup.+

Embodiment 2: (2E,4E)-N-Isobutyl-7-(5-Trifluoromethyl-3,4-Methylenedioxy phenyl)-2,4-Heptadiene Amide (II-14)

(11) ##STR00023##

(12) Step 1: compound 5 (650 mg, 2.6 mmol), 20 ml of anhydrous tetrahydrofuran and lithium hydroxide (326 mg, 7.8 mmol) were added into a three-necked flask of 50 ml; heated to 70 C. and reacted for 1 hours under the protection of N.sub.2. The compound 1 (0.76 g, 2.0 mmol) was dissolved in 10 ml of anhydrous tetrahydrofuran, and then added dropwise into a reaction flask within half an hour. The reaction liquid was subjected to reaction at 70 C. for 10 hours. Detected by thin-layer chromatography, and heating was stopped after the reaction was completed. The reaction liquid was subjected to rotary evaporation concentration until it was dried, and then, 20 ml of distilled water was added to dissolve the solid. 2N hydrochloric acid was added dropwise slowly into the above solution until its pH value became to 2.0; continued to stir for 1 hour, and a light yellow solid was separated out; decompression and suction filtration were conducted to collect the solid, dried in vacuum to obtain a compound 6 (400 mg, 65%).

(13) Step 2: the material 6 (400 mg, 1.4 mmol), EDCI (410 mg, 2.14 mmol) and isobutylamine (310 mg, 4.2 mmol) were dissolved into 20 ml of dichloromethane; TLC showed that the raw materials were reacted completely after being stirred and reacted at room temperature for 6 hours, the reaction system was directly concentrated to be dried; after the crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), 270 mg of white solid II-14 (52%) was obtained.

(14) .sup.1H NMR (DMSO, 400 MHz): 7.18 (1H, dd, J.sub.1=10.8 Hz, J.sub.2=4.4 Hz), 6.80 (1H, d, J=5.6 Hz), 6.11 (2H, m), 6.06 (2H, s), 5.76 (1H, d, J=15.2 Hz), 5.46 (1H, s), 3.17 (2H, t, J=6.0 Hz), 2.68 (2H, t, J=7.6 Hz), 2.44 (2H, m), 1.80 (1H, m), 0.94 (3H, s), 0.92 (3H, s);

(15) ESI-MS: 370.1 [M+H].sup.+

Embodiment 3: (2E,4E)-N-(4-Methylpiperazinyl)-7-(5-Trifluoromethyl-3,4-Methylenedioxy phenyl)-2,4-heptadiene amide hydrochloride (II-15)

(16) ##STR00024##

(17) The compound 6 (0.52 g, 1.66 mmol), N-methylpiperazine (0.5 g, 5 mmol) and DIPEA (0.43 g, 3.34 mmol) were added into dichloromethane; then, HATU (0.95 g, 2.5 mmol) was added and stirred at room temperature for 6 hours; the reaction system was washed with water; the organic phase was dried and concentrated to obtain a crude product; 350 mg of colorless oily matter was obtained after being purified by silica gel column chromatography; then, dissolved with 2 ml of dioxane, and 4 ml of hydrochloric acid solution of dioxane was added; stirred at room temperature for 30 minutes, and concentrated and dried to obtain 370 mg of compound II-15 (53%).

(18) .sup.1H NMR (MeOD, 400 MHz): 7.25 (1H, dd, J.sub.1=10.8 Hz, J.sub.2=4.4 Hz), 6.96 (1H, s), 6.87 (1H, s), 6.48 (1H, d, J=14.8 Hz), 6.31 (1H, dd, J.sub.1=10.8 Hz, J.sub.2=4.4 Hz), 6.21 (1H, m), 6.10 (2H, s), 4.87 (2H, br), 3.77-3.50 (3H, br), 3.40-3.10 (3H, br), 3.15 (3H, s), 2.76 (2H, t, J=7.2 Hz), 2.50 (2H, t, J=7.2 Hz);

(19) ESI-MS: 397.1 [M+1].sup.+

Embodiment 4: N-Methyl-(5-Trifluoromethyl-3,4-Methylenedioxy)-Amphetamine Hydrochloride (II-16)

(20) ##STR00025##

(21) The compound 1 (650 mg, 2.6 mmol) and methylamine solution (0.4 ml, 5.1 mmol) were added into a three-necked flask of 50 ml, sodium cyanoborohydride (430 mg, 5.2 mmol) was added into 20 ml of anhydrous methanol; reacted at room temperature for 6 hours. 50 ml of water was added into the reaction liquid, organic phase was concentrated to obtain a crude product after being extracted with ethyl acetate (50 ml2); the crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain 320 mg of oily matter; then, dissolved with 2 ml of dioxane, and 4 ml of hydrochloric acid solution of dioxane was added; stirred at room temperature for 30 minutes, concentrated and dried to obtain 340 mg of compound II-16 (47%).

(22) .sup.1H NMR (D.sub.2O, 400 MHz): 6.93 (1H, s), 6.92 (1H, s), 6.01 (2H, s), 2.93 (2H, t, J=8.0 Hz), 2.62 (2H, t, J=8.0 Hz), 2.61 (3H, s), 1.90 (2H, m);

(23) ESI-MS: 263.2 [M+H].sup.+

Embodiment 5: Preparation of Drop Pills

(24) 0.5 g of compound II-3, II-4, II-5, II-10, II-11, II-12, II-13, II-14, II-15, II-16, III-2, II-4, III-7, III-9, III-10, III-11 or III-13 was taken, and mixed evenly with 10.5 g of polyethylene glycol-6000, heated for fusion; the materials were moved into a drop tank for drop pills after being melted, the pharmaceutical liquid was dropped to liquid paraffin of 6-8 C., oil was removed to obtain 500 granules of drop pills.

Embodiment 6: Injections

(25) 0.5 g of compound II-3, II-4, II-5, II-10, II-11, II-12, II-13, II-14, II-15, II-16, III-2, III-4, III-7, III-9, III-10, III-11 or III-13, 4.5 g of glucose, 0.9 g of sodium thiosulfate and 1 ml of distilled water were taken; after being evenly mixed, freeze-dried and sub-packaged to obtain 500 injections.

(26) The beneficial effects of the present invention are illustrated below by means of experimental data.

Experimental Example 1: Elevated Plus-Maze Test for Mice

(27) (I) Experimental Materials

(28) 1. Samples to be Tested

(29) Substituted cinnamamide derivatives such as compounds II-3, II-4, II-5, II-10, II-11, II-12, II-13, II-14, II-15, II-16, III-2, II-4, III-7, III-9, III-10, III-11 and III-13, were provided by the Traditional Chinese Medicine Department of the Institute of TASLY Holding Group Co., Ltd.

(30) Sample Processing: compounds II-3, II-4, II-5, II-10, II-11, II-12, II-13, II-14, II-15, II-16, III-2, III-4, III-7, III-9, III-10, III-11 and III-13 were added into Tween 80 aqueous solution (2 wt %) to respectively formulate the above compounds into solutions with concentration of 0.5 mg/ml.

(31) Diazepam, manufactured by: Beijing Yimin Pharmaceuticals Co., Ltd., specification: 2.5 mg/tablet, SFDA Approval Number: H11020898, formulated into a solution containing 0.075 mg/ml drug with Tween 80 aqueous solution (2 wt %) before use.

(32) 2. Experimental Animals

(33) SPF-grade ICR male mice, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., Production Certificate for Laboratory Animals: SCXK (JING) 2012-0001.

(34) Raising Conditions: raised in sheltered animal houses with a temperature of 20-25 C. and a relative humidity of 40%-60%, 12 mice in each cage, free diet, feeds were sterilized complete feeds dedicated to mice, which were offered by Beijing FMK Bioscience Co., Inc.; bedding was replaced daily.

(35) 3. Experimental Instrument

(36) Elevated plus-maze: Beijing Xintiandi Science and Technology Co., Ltd.

(37) (II) Experimental Method

(38) 247 ICR male mice aged 6-8 weeks with the weight of 18-22 g were taken and fed adaptively for 1 week. Then, these mice were evenly divided, at random, into 19 groups based on their weights. Intragastric administration was conducted once a day according to the drugs and dosages listed in Table 1, which lasted for 7 consecutive days. 20 minutes after administration on the 7th day, the elevated plus-maze test was conducted.

(39) The elevated plus-maze (EPM) for mice were composed of two opposite open arms (50 cm10 cm) and two opposite enclosed arms (50 cm10 cm40 cm), wherein upper portions of the enclosed arms were not capped, an open portion of 10 cm10 cm was located in the middle of the maze, and the maze was 50 cm away from the ground. The test was conducted in a quite environment at a time period ranging from 13:00 to 18:00.

(40) Each administration group was administered continuously for 7 days, the elevated plus-maze tests were conducted with test substances 20 minutes after the final administration and positive drug diazepam 60 minutes after the final administration, each of the mice was placed in a plastic case of 60 cm60 cm35 cm, then placed in the center of the maze after it acquainted itself with the environment for 5 minutes. The open-arms entries (OE) and enclosed-arms entries, as well as the residence time in two arms, of the mice, within 5 minutes, were recorded respectively, and the percentage of the open-arms entries (OE %) and that of the open-arms time (OT %) for each group of mice with respect to the total entries into the two arms and the total residence time in the two arms therein were calculated respectively.

(41) (III) Experimental Statistics

(42) Analysis was conducted using SPSS 11.5 software, and data were represented by xS, the significance of differences between groups was compared using the analysis of variance, differences were significant while P was less than 0.05.

(43) (IV) Experimental Results

(44) In the present experiment, the effects of the 17 compounds of the present invention on the open-arms entries and the open-arms time of the mice during the elevated plus-maze test were evaluated.

(45) TABLE-US-00001 TABLE 1 Effects of Various Compounds on the Open-arms Entries and the Open-arms Time of Mice Groups Dosages OE % OT % Solvent control groups 0.53 0.04 0.43 0.06 Diazepam 1.5 mg/kg 0.61 0.06 0.62 0.06** II-3 10 mg/kg 0.66 0.04* 0.66 0.06** II-4 10 mg/kg 0.64 0.04* 0.68 0.04** II-5 10 mg/kg 0.65 0.04* 0.69 0.04** II-10 10 mg/kg 0.66 0.04* 0.68 0.02** II-11 10 mg/kg 0.65 0.05* 0.65 0.04** II-12 10 mg/kg 0.64 0.02* 0.63 0.05** II-13 10 mg/kg 0.60 0.04 0.58 0.04* II-14 10 mg/kg 0.64 0.03* 0.58 0.02* II-15 10 mg/kg 0.67 0.02* 0.68 0.02** II-16 10 mg/kg 0.63 0.02* 0.64 0.03** III-2 10 mg/kg 0.61 0.05 0.58 0.05* III-4 10 mg/kg 0.61 0.03 0.62 0.06** III-7 10 mg/kg 0.63 0.02* 0.60 0.04* III-9 10 mg/kg 0.61 0.04 0.59 0.05* III-10 10 mg/kg 0.64 0.03* 0.61 0.04* III-11 10 mg/kg 0.62 0.05 0.61 0.05* III-13 10 mg/kg 0.66 0.06* 0.62 0.05** Notes: compared with the solvent control groups, *p < 0.05, and **p < 0.01.

(46) As shown by the experimental results of Table 1, compared with the solvent control groups, after intragastric administration with the compounds II-3, II-4, II-5, II-10, II-11, II-12, II-13, II-14, II-15, II-16, III-2, III-4, III-7, III-9, III-10, III-11 and III-13 of the present invention for 1 week in a dosage of 10 mg/kg, they all could increase the open-arms entries of the mice, and prolong their open-arms time, the above results had significant differences in statistics (p<0.05, and p<0.01).

(47) Experimental Conclusion: In the elevated plus-maze test, after the 17 compounds described in the present invention were administered for 7 days in a dosage of 10 mg/kg, they could, in varying degrees, increase the open-arms entries of the mice and prolong their open-arms time during the elevated plus-maze test.

(48) It could be proved by the experimental results that, the 17 compounds described in the present invention had significant anti-anxiety activities.

Experimental Example 2: Drinking Conflict Experiment for Rats

(49) (I) Experimental Materials

(50) 1. Samples to be Tested

(51) Substituted cinnamamide derivatives such as compounds II-3, II-4, II-5, II-10, II-11, II-12, II-13, II-14, II-15, II-16, III-2, III-4, III-7, III-9, III-10, III-11 and III-13, were provided by the Traditional Chinese Medicine Department of the Institute of TASLY Holding Group Co., Ltd.

(52) Sample Processing: compounds II-3, II-4, II-5, II-10, II-11, II-12, II-13, II-14, II-15, II-16, III-2, III-4, III-7, III-9, III-10, III-11 and III-13 were added into Tween 80 aqueous solution (2 wt %) to respectively formulate the above compounds into solutions with concentration of 0.5 mg/ml.

(53) Diazepam, manufactured by: Beijing Yimin Pharmaceuticals Co., Ltd., specification: 2.5 mg/tablet, SFDA Approval Number: H11020898, formulated into a solution containing 0.01 mg/ml drug with Tween 80 aqueous solution (2 wt %) before use.

(54) 2. Experimental Animals

(55) SPF-grade male SD rats, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., Production Certificate for Laboratory Animals: SCXK (JING) 2012-0001.

(56) Raising Conditions: raised in sheltered animal houses with a temperature of 20-25 C. and a relative humidity of 40%-60%, 6 rats in each cage, free diet, feeds were sterilized complete feeds dedicated to rats, which were offered by Beijing HFK Bioscience Co., Inc.; bedding was replaced daily.

(57) 3. Experimental Instrument

(58) Vogel test anxiety testing system, model: LE100-25, produced by Harvard Apparatus of the U.S.A.

(59) (II) Experimental Method

(60) 230 SD male rats with the weight of 180-220 g were taken and fed adaptively for 1 week. Then, these rats were divided, at random, into 19 groups based on their weights, 12-13 rats in each group. Intragastric administration was conducted one a day according to the drugs and dosages listed in Table 2, which lasted for 10 consecutive days. Water deprivation 48 hours before the final administration, and non-punitive drinking training was conducted on the 9th day; on the 10th day, half an hour after the final intragastric administration of all the groups, the punitive experimental test was conducted.

(61) On the first stage (non-punitive drinking training): after water deprivation for 24 hours, the rats were placed in operation boxes individually to explore thoroughly, until they found bottle mouths and began to lick water, water licks of the rats within 3 minutes under the conditions of no electric shock (the condition was set as follows: the strength of electric shock was 0 mA) were automatically recorded by counters, and rats whose water licks were less than 300 were eliminated. On the second stage (punitive experiment): the above rats which were not eliminated were placed in the operation boxes after continuing the water deprivation for 24 hours (48 hours in total). The rats could find the bottle mouths rapidly and begin to lick water, the instruments began to time automatically and imparted one electric shock (the ratio of licks to the number of electric shocks was 20:1) while the water licks reached to 20, wherein the strength of electric shocks was 0.3 mA, lasting for 2 seconds, but these rats may control the length of the time for which they were electrically shocked by keeping away from the bottle mouths. Water licks of the rats during the punished session (3 minutes) were recorded.

(62) Observational indexes of the Vogel drinking conflict model: water licks of the rats during the punished session.

(63) (III) Experimental Statistics

(64) Analysis was conducted using SPSS 11.5 software, and data were represented by xS, the significance of differences between groups was compared using the analysis of variance, differences were significant while P was less than 0.05.

(65) (IV) Experimental Results

(66) In the present experiment, the effects of the 17 compounds of the present invention on the water licks of the rats during the punished session of the drinking conflict experiment were evaluated.

(67) TABLE-US-00002 TABLE 2 Effects of Various Compounds on Water Licks of Rats During Punished Session Groups Dosages Number of rats Water licks Solvent control groups 8 310.75 45.14 Diazepam 1 mg/kg 9 510.22 48.43** II-3 5 mg/kg 8 483.75 59.05** II-4 5 mg/kg 10 477.22 66.66** II-5 5 mg/kg 9 469.11 50.51** II-10 5 mg/kg 8 459.75 59.23** II-11 5 mg/kg 8 426.25 37.29** II-12 5 mg/kg 10 402.67 50.35** II-13 5 mg/kg 9 393.44 48.99** II-14 5 mg/kg 9 368.00 47.38* II-15 5 mg/kg 8 412.25 42.90** II-16 5 mg/kg 9 406.56 65.38** III-2 5 mg/kg 9 368.00 39.59* III-4 5 mg/kg 10 394.22 50.29** III-7 5 mg/kg 10 378.33 54.97* III-9 5 mg/kg 9 363.56 39.70* III-10 5 mg/kg 8 369.00 44.83* III-11 5 mg/kg 8 361.13 38.38* III-13 5 mg/kg 9 375.67 58.13* Notes: When compared with the solvent control groups, *p < 0.05, and **p < 0.01.

(68) As shown by the experimental results of Table 2, compared with the solvent control groups, after intragastric administration with the compounds II-3, II-4, II-5, II-10, II-11, II-12, II-13, II-14, II-15, II-16, III-2, III-4, III-7, III-9, III-10, III-11 and III-13 of the present invention for 10 days in a dosage of 5 mg/kg, they all could increase water licks of the rats during the punished session, and the above results had significant differences in statistics (p<0.05, and p<0.01).

(69) Experimental Conclusion: In the drinking conflict experiment for rats, after the 17 compounds described in the present invention were administered for 10 days in a dosage of 5 mg/kg, they all could, in varying degrees, increase water licks of the rats during the punished session.

(70) It could be proved by the experimental results that, the 17 compounds described in the present invention had anti-anxiety activities.