LONG-ACTING LOW-ADDICTION HNK DERIVATIVE AND PREPARATION METHOD THEREFOR
20230303481 · 2023-09-28
Inventors
Cpc classification
A61P25/28
HUMAN NECESSITIES
C07C227/18
CHEMISTRY; METALLURGY
International classification
C07C229/60
CHEMISTRY; METALLURGY
C07C227/18
CHEMISTRY; METALLURGY
Abstract
The present application relates to a compound having the effects of being an antidepressant, anesthetizing, alleviating pain, improving cognitive functions, protecting lungs, preventing or treating amyotrophic lateral sclerosis or preventing or treating complex regional pain syndrome. Compared with existing known HNK compounds, the compound provided in the present application has a longer drug efficacy period. Moreover the compound provided in the present application basically does not produce addiction.
Claims
11. A compound represented by Formula I, or a salt, stereoisomer or tautomer thereof: ##STR00016## wherein, m is an integer from 0 to 3, and n is an integer from 0 to 4; R.sub.1 and R.sub.2 are each independently one or more selected from a group consisting of H, halogen, hydroxyl, amino, cyano, substituted or unsubstituted C.sub.1-C.sub.6 alkyl group, substituted or unsubstituted C.sub.2-C.sub.6 alkenyl group, substituted or unsubstituted C.sub.2-C.sub.6 alkynyl group, substituted or unsubstituted C.sub.3-C.sub.10 cycloalkyl group, substituted or unsubstituted C.sub.2-C.sub.10 heterocyclic group, substituted or unsubstituted C.sub.1-C.sub.6 alkoxy group, substituted or unsubstituted mono- and di- C.sub.1-C.sub.6 alkylamino group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group; R.sub.3 is halogen; R.sub.4 is selected from a group consisting of H, substituted or unsubstituted C.sub.1-C.sub.6 alkyl group, substituted or unsubstituted C.sub.1-C.sub.8 acyl group, substituted or unsubstituted arylacyl group, and substituted or unsubstituted heteroarylacyl group; R.sub.5 is selected from a group consisting of substituted or unsubstituted C.sub.3-C.sub.10 cycloalkylene group, substituted or unsubstituted C.sub.2-C.sub.10 heterocyclylene group, substituted or unsubstituted arylene group, and substituted or unsubstituted heteroarylene group; R.sub.6 and R.sub.7 are independently selected from a group consisting of H, substituted or unsubstituted C.sub.1-C.sub.6 alkyl group, substituted or unsubstituted C.sub.2-C.sub.6 alkenyl group, substituted or unsubstituted C.sub.2-C.sub.6 alkynyl group, substituted or unsubstituted C.sub.3-C.sub.10 cycloalkyl group, substituted or unsubstituted C.sub.2-C.sub.10 heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted C.sub.1-C.sub.8 acyl group, substituted or unsubstituted arylacyl group, and substituted or unsubstituted heteroaryl acyl, or R.sub.6 and R.sub.7, together with N atom to which R.sub.6 and R.sub.7 are connected, form a substituted or unsubstituted 3 to 10-membered monocyclic or bicyclic structure, wherein a group is substituted means that the group is substituted by a substituent selected from OH; NH.sub.2; C.sub.1-C.sub.10 alkyl, alkenyl or alkynyl group; C.sub.1-C.sub.10 alkylamine group; sulfhydryl group; C.sub.1-C.sub.10 alkylsulfhydryl group; C.sub.1-C.sub.20 alkoxy group; C.sub.1-C.sub.10 carbonyl group; C.sub.3-C.sub.10 cycloalkyl group; 3 to 10-membered heterocyclic group with one or more heteroatoms selected from N, S, O and P; C.sub.6-C.sub.20 aryl group; C.sub.2-C.sub.20 heteroaryl group; nitrocyano; and halogen.
12. The compound, stereoisomer or tautomer thereof according to claim 11, wherein the compound is represented by Formula II: ##STR00017## .
13. The compound, stereoisomer or tautomer thereof according to claim 11, wherein the compound is represented by Formula III: ##STR00018## .
14. The compound, or a salt, stereoisomer or tautomer thereof according to claim 11, wherein the compound is represented by Formula IV: ##STR00019## .
15. The compound, or a salt, stereoisomer or tautomer thereof according to claim 11, wherein the compound is shown below: ##STR00020## .
16. The compound, or a salt, stereoisomer or tautomer thereof according to claim 11, wherein the compound is shown below: ##STR00021## .
17. A compound, or a salt, stereoisomer or tautomer thereof, wherein the compound is shown below: ##STR00022## wherein R .sub.8 is H or a protecting group.
18. The compound, or a salt, stereoisomer or tautomer thereof according to claim 17, wherein the compound is shown below: ##STR00023## .
19. The compound, or a salt, stereoisomer or tautomer thereof according to claim 17, wherein the compound is shown below: ##STR00024## ##STR00025## .
20. A pharmaceutical composition, comprising the compound, or a salt, stereoisomer or tautomer thereof according to claim 11, and optionally a pharmaceutically acceptable carrier.
21. A pharmaceutical composition, comprising the compound, or a salt, stereoisomer or tautomer thereof according to claim 17, and optionally a pharmaceutically acceptable carrier.
22. A preparation method of a compound, wherein: ##STR00026## .
23. A method for anesthesia, alleviating pain, improving cognitive function, lung protection, anti-depression, mitigating anxiety and post-traumatic stress syndrome, or preventing or treating amyotrophic lateral sclerosis or complex regional pain syndrome of a subject, comprising administrating therapeutic effective amount of the compound, or a salt, stereoisomer or tautomer thereof according to claim 11 to the subject.
24. The method of claim 23, wherein the pain comprises chronic pain or neuropathic pain; the depression comprises bipolar depression or major depressive disorder; and improving of cognitive function comprises preventing or treating Alzheimer’s dementia or Parkinson’s disease.
25. A method for anesthesia, alleviating pain, improving cognitive function, lung protection, anti-depression, mitigating anxiety and post-traumatic stress syndrome, or preventing or treating amyotrophic lateral sclerosis or complex regional pain syndrome of a subject, comprising administrating therapeutic effective amount of the compound, or a salt, stereoisomer or tautomer thereof according to claim 17 to the subject.
26. The method of claim 25, wherein the pain comprises chronic pain or neuropathic pain; the depression comprises bipolar depression or major depressive disorder; and improving of cognitive function comprises preventing or treating Alzheimer’s dementia or Parkinson’s disease.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION
Example 1: Synthesis of (2R,6R)-6-Hydroxynorketamine (HNK)
[0065] ##STR00012##
Step 1: To a two-neck flask or a three-neck flask, added were 50 g of magnesium powder, and dropwise a mixed solution of tetrahydrofuran (THF) and 119.2 g of bromocyclopentane slowly after initiation. When the dropwise addition was completed, the system was refluxed for 2-4 h to obtain 1.6 mol/L cyclopentyl Grignard reagent. Into a mixed solution of THF and o-chlorobenzonitrile (50.0 g), 840 mg CuBr was added, and cyclopentyl Grignard reagent (1.6 mol/L, 280 mL) was added dropwise under ice bath condition. After the dropwise addition, the system was refluxed for 1 h, and then cooled to room temperature, in which 100 ml of water, and then 200 ml of 15% dilute sulfuric acid were added. The system was stirred overnight. THF was rotary dried. The resultant was extracted with ethyl acetate (EA), dried and purified by passing through a silica gel column to obtain 60 g of Compound A, 2-chlorophenyl cyclopentyl ketone, with a yield of 80%.
[0066] Step 2: According to the reported method (Bioorganic & Medicinal Chemistry 2013, 12, 5098), 20 g (96 mmol) of Compound A was dissolved in 400 ml of EA. After Compound A was dissolved, copper bromide (54 g, 242 mmol) was added therein, the system was heated to refluxe for 3 h, and then cooled to room temperature. The solid insolubles were filtered with diatomite. The filter residue was washed with dichloromethane (DCM). The washed solution was combined with the filtrate and then concentrated to obtain yellow oily compound B, 2- chlorophenyl (1- bromocyclopentyl) ketone. After passing through a silica gel column, 22 g of pure compound B was obtained with a yield of 80%.
[0067] Step 3: Ammonia gas was bubbled into 200 ml of ammonia water until saturation. Compound B (10 g) was added therein, and the solution was stirred for 24 h. Compound C was precipitated out, filtered and dried to obtain a brown solid of Compound C (7 g) with a yield of 70%, which was used directly in the next step.
[0068] Step 4: Compound C (5 g) was dissolved in dry THF, HCl gas was introduced therein until the pH value of the solution reached 1, and then the solution was rotary dried to obtain solid hydrochloride. To a single-neck flask, added was the solid hydrochloride salt. The system was placed in an oil bath at 190° C. under nitrogen protection for about 20 min, and then cooled to room temperature, neutralized with saturated sodium bicarbonate solution, extracted with DCM, concentrated and crystallized to obtain 2.9 g of compound D, a racemate of norketamine HNK, with a yield of 75%. .sup.1H NMR (400 MHz, CDCl.sub.3): δ7.67 (dd, J = 7.8, 1.5 Hz, 1H), 7.37-7.32 (m, 2H), 7.25 (m, 1H), 2.78-2.71 (m, 1H), 2.61 (m, 1H), 2.51-2.43 (m, 1H), 2.08-2.0 (m, 1H), 1.88-1.63 (m, 4H).
[0069] Step 5: Compound D (1.11 g, 5 mmol) was dissolved in 2 ml methanol, L-tartaric acid (2.5 mmol) was added therein, and the solution was stirred for 1 h. The solution was dripped into 10 mL of acetone, and stood for crystallization. Then, the system was filtered to obtain L-tartrate crystals. The obtained L-tartrate crystals were recrystallized for 3 times. The obtained crystals were added into sodium bicarbonate solution to be neutralized, and then extracted with EA to obtain 165 mg of optically pure compound, E(R)-norketamine. The optical purity detected by chiral HPLC was 98.3%ee%, and the yield was 15%.
[0070] The chiral HPLC detection was performed with the following steps. In 1 ml of ethanol, 1 mg of compound E and 1 mg of control racemic compound D were dissolved, respectively, and were analyzed with Agilent 1260-A high performance liquid chromatography for normal phase uniformity. Chromatography column: Chiralcel-AD-H (4.6 mm × 250 mm), mobile phase A: (n-hexane +0.1% diethylamine), mobile phase B: (ethanol +0.1% diethylamine), A: B=40: 60, and flow rate: 1 mL/min. For Compound E, the retention time of the isomer of R configuration is 6.8 min, and the corresponding retention time of the isomer of S configuration is 5.3 min.
[0071] Step 6: Compound E (2.23 g, 10 mmol) was added to 60 ml of THF, and triethylamine (2.7 mL, 20 mmol) and Boc.sub.2O (3.3 g, 15 mmol) were added. The system was refluxed for 6 h, then cooled, and rotary dried. The resultant was passed through a silica gel column to obtain 2.92 g of Compound F with a yeild of 90%. .sup.1H NMR (400 MHz, CDCl.sub.3): δ7.81 (d,J = 8.1 Hz, 1H), 7.40-7.28 (m, 2H), 7.24-7.12 (m, 1H), 6.57 (s, 1H), 3.82 (d,J=14.4 Hz, 1H), 2.45-2.36 (m, 1H), 2.28 (m, 1H), 2.04 (m, 1H), 1.89-1.56 (m, 4H), 1.27 (s, 9H). .sup.13C NMR (100 MHz,CDCl.sub.3): δ207.9, 152.3, 134.5, 132.6, 130.3, 130.0, 128.3, 125.2, 78.0, 66.1, 38.5, 37.4, 29.7, 27.2, 20.9.
[0072] Step 7: Compound F (2.91 g, 9 mmol) was added to 60 mL of dry THF. The solution was cooled to -78° C. under argon protection, and 5 mL of HMPA was added, and then 2 M of LDA in THF solution (12 mL, 24 mmol) was slowly added dropwise. The system was stirred for 30-40 min, then slowly heated to -30° C. and stirred for 1 h. Then the system was cooled to -78° C. again and trimethylchlorosilane (TMSCl, 2.6 g, 24 mmol) was added. The system was slowly heated to -50° C., stirred for 3 h, saturated ammonium chloride solution was poured in and then the temperature of the system was elevated to room temperature. The system was concentrated by removing the solvent THF, and EA was added for extraction. The organic phase was dried over anhydrous Na.sub.2SO.sub.4. The solvent was rotary dried and the resultant was vacuum-dried to obtain an oily substance. The obtained oily substance was dissolved by adding 100 mL of anhydrous DCM. The solution was cooled to -15° C., and mCPBA (2.5 g, 11 mmol) was added under protection of argon gas. The obtained solution was stirred for 1 h, and then 50 mL of DCM was added and further stirred for 1 h. Then saturated solution of sodium thiosulfate and sodium bicarbonate (1:1) was poured in, and the system was extracted with DCM. The solvent was rotary dried and the resultant was vacuum dried to obtain an oily substance. The obtained oily substance was dissolved in 100 mL THF, and then cooled to -5° C., and tetrabutyl ammonium fluoride (3 g, 11.4 mmol) was added in the solution. The system was stirred for 30 min, and saturated solution of NaHCO.sub.3 was added therein. The system was extracted with EA, the solvent was rotary dried and the resultant was vacuum-dried. The obtained substance was then passed through a silica gel column to obtain 1.92 g of compound G with a yield of 65%. .sup.1H NMR (400 MHz, CDCl.sub.3):δ7.81 (d,J = 7.8 Hz, 1H), 7.34 (m, 2H), 7.24 (m, 1H), 6.60 (s, 1H), 4.12 (dd,J = 11.7, 6.8 Hz, 1H), 3.87 (d,J = 14.4 Hz, 1H), 3.38 (m, 1H), 2.36 (m, 1H), 1.74 (m, 2H), 1.68-1.57 (m, 1H), 1.55-1.40 (m, 1H), 1.30 (s, 9H). .sup.13C NMR (100 MHz, CDCl.sub.3): 209.8, 153.2, 134.1, 133.6, 131.3, 130.8, 129.5, 126.2, 79.3, 72.2, 66.5, 40.3, 38.7, 28.1, 19.4.
[0073] Step 8: Compound G (680 mg) was dissolved in 5 ml of dry THF. Gaseous HCl was introduced into the solution at room temperature until saturated. The system was stirred for 4 h, 20 mL dry ether was added, and crystals were precipitated followed by filtration, and 520 mg hydrochloride salt of compound H, (2R,6R)-6-hydroxydemethylketamine (HNK) was obtained with a yield of 95%. .sup.1H NMR (400 MHz, CD.sub.3OD): δ 7.85 (m, 1H), 7.65-7.51 (m, 3H), 4.28 (m, 1H), 3.19 (m, 1H), 2.30 (m, 1H), 1.81-1.72 (m, 2H), 1.64-1.51 (m, 2H).
Example 2: Synthesis of Compound I5
[0074] Compound G (170 mg, 0.5 mmol) was dissolved in 3 mL of dry THF, followed by addition of dry triethylamine (0.28 mL, 2 mmol). Then benzoyl chloride (117 .Math.L, 1 mmol) was added under ice bath condition, then the temperature of the system was slowly raised to room temperature over 1 hour, and the system was stirred overnight. Sodium bicarbonate solution was added in the system, and the system was extracted with EA. The solvent was rotary dried and the resultant was dried in vacuum. The obtained substance was passed through a silica gel column to obtain 184 mg of Compound H.sub.4, N-Boc-(2R,6R)-6- benzoyloxydemethylketamine, with a yield of 85%. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.22-8.19 (m, 2H), 7.91 (m, 1H), 7.69-7.64 (m, 1H), 7.56-7.45 (m, 4H), 6.75 (br, 1H), 5.54-5.50 (m, 1H), 4.00 (m, 1H), 2.54-2.52 (m, 1H), 2.14-1.93 (m, 3H), 1.86 (m, 1H), 1.41 (m, 9H). .sup.13C NMR (100 MHz, CDCl.sub.3): δ 202.2, 164.9, 153.3, 133.2, 131.4, 131.1, 129.9, 129.7, 129.5, 128.3, 128.0, 126.1, 79.2, 73.8, 67.2, 36.6, 34.8, 28.2, 19.0.
[0075] Compound H.sub.4 (180 mg) was dissolved in 3 mL of dry THF, gaseous HCl was introduced into the solution at room temperature until saturated and the system was stirred for 4 h. 15-20 mL of dry ether was added, crystals were precipitated, and the system was vacuum filtered to obtain 124 mg of Compound I.sub.4, (2R,6R)-6-benzoyloxydemethylketamine hydrochloride salt, with a yield of 83%. .sup.1H NMR (400 MHz, CD.sub.3OD): δ 9.25-9.20 (brs, 3H), 8.21-8.19 (m, 2H), 7.90 (m, 1H), 7.66-7.52 (m, 6H), 5.57 (m, 1H), 3.66 (m, 1H), 2.58-2.43 (m, 2H), 2.08-1.97 (m, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD): δ 200.1, 164.8, 134.6, 133.4, 131.9, 131.0, 129.9, 129.2, 129.1, 128.4, 127.9, 73.9, 68.1, 36.6, 34.9, 19.0.
##STR00013##
[0076] Compound H (339 mg, 1 mmol) was dissolved in 8 mL of dry THF, followed by addition of dry triethylamine (0.56 ml, 4 mmol), and then p-dimethylaminobenzoyl chloride (275 mg, 1.5 mmol). The mixture was refluxed overnight. The solvent was rotary dried, sodium bicarbonate solution was added into the mixture, and the mixture was extracted with EA. The solvent of the organic phase was rotary dried and the mixture was dried in vacuum. The mixture passed through a silica gel column to obtain compound H.sub.5 N-Boc-(2R, 6R)-6-p-dimethylaminobenzoyloxydemethylketamine 292 mg with a yield of 60%. Compound H.sub.5 (292 mg) was dissolved in 6 mL dry THF, gaseous HCl was introduced at room temperature until saturated. The mixture was stirred for 4 h. Dry ether of 15-20 mL was added, crystals were precipitated, which was vacuum filtered to obtain compound I.sub.5 (2R, 6R)-6-p-dimethylaminobenzoyloxydemethylketamine dihydrochloride 148 mg, with a yield of 54%. .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.00 (br, 2H), 7.79 (m, 1H), 7.44-7.15 (m, 5H), 5.45 (m, 1H), 3.59-3.56 (m, 6H), 3.01-2.92 (m, 6H), 2.38-2.35 (m, 1H), 2.19-2.16 (m, 1H) 1.96-1.93 (m, 3H)..sup.13C NMR (100 MHz, CD3OD): δ 200.8, 164.5, 150.6, 134.4, 132.4, 132.1, 131.0, 129.4, 128.5, 115.8, 74.1, 67.8, 43.7, 37.0, 35.3, 19.2.
Example 3: Synthesis of Compounds C and D
[0077] ##STR00014##
##STR00015##
Compounds C and D were prepared and obtained by the following preparation method.
Example 4: Activity Tests
1. Forced Swimming Test
[0078] One hour before the forced swimming test (FST), the mice were transferred to the laboratory. The test was conducted under normal light condition and monitored by a digital camera. During the test, the mice were individually placed in transparent glass cylinders (28.5 cm in height, 14 cm in diameter) filled with 20 cm height of water (23±1° C.). On the first day, the mice were trained for 6 minutes and then removed from the cylinder. On the second day, the mice were administered saline, HNK, Compound I5, Compound C, and Compound D, and after different time periods, their immobility time was tested. During the last 4 minutes of the entire 6-minute swimming test, the static time was recorded through EthoVision XT (Noldus, Netherlands) of Noldus system. The static time was defined as passive floating, that is there was no other movement except the movements necessary to keep the animal’s head above the water. After every two to three tests, the water in the cylinders was replaced. After the swimming test, the mice were removed from the water and dried under an infrared lamp.
[0079] The mice were given 1 mg (A), 10 mg (B) and 30 mg (C) of HNK and Compund I5 by intragastric administration, respectively, and their immobility time was measured after 1 hour and 7 days. The percentage of immobility time is expressed as mean ± SEM. *p<0.05, **p<0.01, compared to base test. Mice of each group was N=8. Saline: saline group; I5: Compound I5 treatment group; HNK: 2R,6R-hydroxynorketamine treatment group.
2. Addiction Research
Materials and Methods
[0080] Animals: Male C57BL/6J mice of 8-12 weeks old were randomly divided into groups, 10 mice in each group, with body weight of 18-22 g, fed at room temperature (22±1° C.), under humidity of (50±10)%, illumination time from 8:00 to20:00. The mice had free access to food and water, and adapted to the experimental environment for at least 2-3 days before the experiments. All experiments were conducted from 8:00 to 16:00.
Behavioral Sensitization Experiment
[0081] 1.1 Small animal spontaneous activity measurement: An animal spontaneous activity infrared analysis system consists of a spontaneous activity box, an infrared probe device and a data acquisition system. The size of the spontaneous activity box is 40 cm × 40 cm × 65 cm, with sound isolation and light isolation, and mounted with a ventilation device. The activity statuses of the animals were recorded by the infrared probe, and the numbers of spontaneous activities of the animals were calculated. In order to test the effect of drugs on spontaneous activities of mice, the mice were randomly divided into 4 groups with 10 mice in each group. The Groups included: vehicle, I5, C, D (5.0, 10.0, 30.0 mg/kg), mor (10 mg/kg). The mice were administrated intragastrically once a day in the morning for 7 consecutive days; after that, the drugs withdrew for 7 days (without any treatment). On the 15.sup.th day, mice in each group were given Veh and the drugs (5.0, 10.0, 30.0 mg/kg) by intragastric administration to stimulate. Spontaneous activity of the mice within 1 hour was measured immediately after administration at d1, d7 and d15.
[0082] 1.2 CPP experiment: A three-room CPP system includes black and white boxes (25 cm × 25 cm × 30 cm) at left and right sides, separated by a middle box (10 cm × 25 cm × 30 cm). During the experiment, mice were put into the middle box and could freely move to the black and white boxes. A door with the size of 5 cm × 5 cm was arranged between the middle box and each of the black and white boxes. The experiment adopted a biased procedure, which had three stages of pre-test, training, and test stages. During the whole experiment, the environmental conditions such as light, color and smell in the boxes were guaranteed to be consistent.
[0083] Pre-test stage: On days 1-3, the spacer plates between the boxes were removed, and all mice were put into the middle box after being injected with saline subcutaneously, allowing them to move freely in the boxes for 15 min, once a day for 3 consecutive days. The residence time of the mice in the black and white boxes was respectively recorded to determine the natural preference of the mice. The mice were trained with the non-natural preference box as the companion medicine box.
[0084] Training stage: On days 4-9, the doors were closed, the mice were randomly divided into groups of Veh, mor, I5, C, D (5.0, 10.0, 30.0 mg/kg), and mor (10 mg/kg), 10 mice in each group. In the morning of each odd number of days, all mice were given saline by intragastric administration and immediately put into non-companion medicine box (black box) for 45 min. In the afternoon of each odd number of days, groups of Veh, mor, I5, C and D (5.0, 10.0, 30.0 mg/kg) were administered with the drugs by intragastric administration, and then immediately put into the companion medicine box (white box) for 45 min. In each even number of days, the training order was reversed. The interval between morning and afternoon trainings was more than 6 hours, and the training time was fixed every day, with 10 mice in each group for 6 days.
[0085] Test stage: on day 10, the spacer plates were removed, and the mice were put into the middle box allowing to move freely. At the same time, the residence time of the mice in the white box within 15 min were recorded.
[0086] Statistical analysis: Experimental data were expressed as X±SEM. Graphpad software was used for statistical analysis, and t-test was used for comparison between two groups. One-way ANOVA analysis was used for comparison among multiple groups, and then LSD method was used for pairwise comparison.
3. Position Preference Experiment
[0087] Position preference was tested by a three-room system. Mice were trained with the non-natural preference box as the companion medicine box. During the training stage, the mice were given saline (Veh), morphine (mor, 10 mg/kg), Compounds I5, C and D (5.0, 10.0, 30.0 mg/kg), respectively. After continuous training for 6 days, the test was carried out, and the residence times of the mice within 15 min in the white box were recorded. Compared with Veh group, * p < 0.05 (n=10).
Example 5: Experimental Results
1. Depression-Like Behavior Test Results of the Mice
[0088] 1 mg of HNK or I5 had no antidepressant effect. Both 10 mg of HNK and I5 had antidepressant effect, in which I5 has a long-acting effect, where the efficacy thereof substantially did not decrease within 7 days, while the efficacy of HNK decreased rapidly within 7 days, and substantially had no effect on the 7.sup.th day. Both 30 mg HNK and I5 had antidepressant effect, in which I5 had a long-acting effect, and the efficacy thereof substantially did not decrease within 7 days, while the efficacy of HNK decayed rapidly within 7 days, and substantially had no effect on the 7.sup.th day.
[0089] Compounds C and D had no antidepressant effect with the dose of 30 mg.
[0090] Compared with the HNK-treated group, the I5-treated group had a significant antidepressant effect even at the 7.sup.th day after administration, as manifested by a reduction in the animals’ immobility time during forced swimming. The I5 group had less immobility time. There was no significant difference between the 10 mg and 30 mg treatment groups, although the 30 mg treated group showed a stronger decreasing trend. Compounds C and D had no antidepressant effect.
2. Addiction Experiment
[0091] Different doses (5 mg, 10 mg, 30 mg) of I5 had no behavioral sensitization effect on mice.
[0092] Different doses (5 mg, 10 mg, 30 mg) of C and D had behavioral sensitizing effect on mice.
3. Position Preference Experiment
[0093] Different doses (5 mg, 10 mg, 30 mg) of I5 had no position preference effect on mice.
[0094] Different doses (5 mg, 10 mg, 30 mg) of C and D induced position preference on mice.
[0095] The technical features of the above-mentioned embodiments can be combined arbitrarily. For the sake of brevity, all possible combinations of the technical features in the above-described embodiments are not described. However, as long as there is no contradiction between the combinations of these technical features, they should be regarded as within the scope described in this specification.
[0096] The above-mentioned embodiments only represent several embodiments of the disclosure, and the descriptions thereof are relatively specific and detailed, but should not be construed as a limitation on the scope of the patent application. It should be noted that a number of modifications and improvements may be made by those skilled in the art, without departing from the concept of the disclosure, which all belong to the protection scope of the application. Therefore, the protection scope of the patent application shall be subject to the appended claims.