WO2007041936A1

WO2007041936A1 - Alkyl alcohol piperazine derivative optical isomers and their salts and applications thereof

Info

Publication number: WO2007041936A1
Application number: PCT/CN2006/002571
Authority: WO
Inventors: Jianqi Li; Zhijie Weng; Wenxin Dong; Liying Huang; Hua Jin; Shaojing Zhang; Fenghua Gu
Original assignee: Shanghai Institute Of Pharmaceutical Industry
Priority date: 2005-10-10
Filing date: 2006-09-29
Publication date: 2007-04-19
Also published as: CN100415728C; CN1948297A

Abstract

The present application has disclosed preparation methods of aralkyl alcohol piperazine derivative optical isomers of the following general formula (I) and their salts and applications thereof. The activity of antidepression of the present optical isomers are better than present clinical antidepression agents of single inhibiting effect such as desipramine,fluoxetine or antidepression agents of double inhibiting effect such as Venlafaxine, Dutoxetine as they may have wider indications and smaller nerve side effect.

Description

Alkanol piperazine derivative optical isomer or salt thereof and application thereof

The present invention relates to a sterol piperazine derivative optical isomer or a salt thereof, in particular, to N ¹ -benzyl-N ⁴ -[l-methyl-2-(5,-chloro-6,-methoxy Synthesis of optical isomers of -2,-naphthyl)hydroxyethyl]piperazine or a salt thereof (hereinafter referred to as SIPIyy24, the same hereinafter) and its use in the preparation of an antidepressant drug. Background technique

Depression is a common disease in humans and is the most common mental illness that currently jeopardizes human health. The main symptoms of depression are: low mood, reduced activity, altered appetite or weight, changes in sleep (insomnia or lethargy), fatigue, difficulty concentrating, hesitancy, and even suicide. The incidence of depression worldwide is about 3.1%. Currently, there are about 340 million people with depression worldwide, and about one in every 20 people has suffered from depression. In 2005, the incidence of depression will reach 10% of the total population. Currently, the disease ranks fourth in the world's most common diseases and will rise to the second most common disease in the world in the next 20 years. There are about 36 million people with depression in China, and as the pace of life increases, life pressure increases, people's psychological load generally increases, and the incidence of depression will continue to grow.

According to the hypothesis of the pathogenesis of depression, antidepressants mainly act on neurotransmitters such as 5-hydroxytryptamine (5-HT) and norepinephrine (NE). Mainly include monoamine oxidase inhibitor (MAOI), tricyclic antidepressant (TCA), tetracyclic antidepressant, selective serotonin reuptake inhibitor (SSRI), norepinephrine reuptake inhibitor (NRI) , 5-HT, NE dual reuptake inhibitor (SNRI), etc.

Fifty years ago, people began to use MAOI to treat depression, which was replaced by TCA because of its more serious adverse reactions. However, TCA has a significant effect on a variety of neurotransmitters, with anticholinergic and adverse effects on the cardiovascular system. Excessive appendages can even serve as a tool for suicide. From the late 1950s to the late 1980s, MAOI and TCA continued to be the mainstay of drug therapy for depression for 30 years until the emergence of selective serotonin reuptake inhibitors.

The emergence of selective serotonin reuptake inhibitors is a milestone in the treatment of depression, because it can selectively act on the 5-HT system, and is equivalent to tricyclic antidepressants, but the adverse reactions are significantly reduced. Easy to take, good treatment compliance. Fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram are currently widely used clinically.

Following the selective serotonin reuptake inhibitor, a 5-HT, NE dual reuptake inhibitor appeared, representing the drug venlafaxine. Venlafaxine is superior to TCA and SSRI in the treatment of depression. It has obvious curative effect on severe depression and refractory depression, and it has a faster onset, about 1 week. Starting from venlafaxine, new antidepressants with fast acting effects and small side effects on the 5-HT and NA dual action pathways have become important development directions for research and development. Mildoxetine hydrochloride was marketed in 2004 and is a dual inhibitor of serotonin and norepinephrine reuptake. After the company’s anti-depressant drug fluoxetine lost patent protection, new information suggests that the company’s new antidepressant, duloxetine, could fill this gap at the American Psychiatric Association meeting in Philadelphia. The results of the report indicate that duloxetine is effective in treating the emotional and physical symptoms of depression, allowing it to gain a foothold in the antidepressant market.

The success of dual-acting drugs has prompted scientists to develop new antidepressant drugs that work on the triple pathways of 5-HT, NA, and DA systems.

The applicant disclosed in Chinese patent ZL02111934.1 an linalool piperazine derivative and its use in the preparation of a medicament for treating antidepressant, wherein the compound N ¹ -benzyl-N ⁴ -[l-methyl -2-(5,-Chloro-6,-methoxy-2,-naphthyl)hydroxyethyl]piperazine (SIHyy24) has a dual inhibitory effect on the reuptake of 5-HT and NA, with strong resistance Depressive biological activity. Further research found that its antidepressant effect is not ideal and the side effects are large.

The structure of the SIPIyy24 compound contains two chiral carbon atoms and has four optical isomers, of which two are erythro isomers and two are threo optical isomers, which may be biologically active, pharmacologically active. There are large differences and exploreability in activity and toxicity. The applicant's previous study found that the erythrosome of SIPIyy24 (a mixture of two erythro isomers) differs greatly from SIPIyy24 and threo racemate in terms of target and toxicity: erythrosome It has a high inhibitory activity on the reuptake of 5-HT, NA and DA, and is a compound acting on a triple-targeted target; the racemic racem only has a strong inhibitory effect on the reuptake of 5-HT and NA. It has no inhibitory effect on DA reuptake and is a compound that acts on two targets. The results of acute toxicity test showed that the LD _{5Q of the} erythrosome was 1.5 g/kg, while the LD _{5Q of the} racemic form was about 220 mg kg. The toxicity of the erythro race was much less than that of the Soviet racemate. Most antidepressants are currently on the market.

The SIPIyy24 erythrosome has significant antidepressant activity and safety, and has the development and research value as a novel multi-effect antidepressant. However, the two vertices still contain two optical isomers (1S, 2R) and (1R, 2S), and the two isomers may also have large differences in activity and safety; Although the overall toxicity is large, it is also possible that one of the optical isomers is more toxic and affects the overall toxicity. Therefore, it is necessary to conduct a comparative study on the biological activity and safety of the four optical isomers of SIPIyy24 to determine the low toxicity and high efficiency of candidate new drug structures for further preclinical development studies.

In addition, the dual inhibitors that inhibit both 5-HT and NA reuptake have the advantages of good antidepressant effect, small side effects and fast onset, but at the same time, triple acting compounds with inhibitory activity against DA reuptake are more effective. It still shows the anti-depressant effect and reflects the side effects. It is still a hot spot in the research of new monoamine antidepressants. The SIPIyy24 erythrosome has triple inhibitory activity on 5-HT, NA and DA reuptake, and the inhibition of DA by the two optical isomers may be significantly different from that of the erythrosome. Therefore, SIPIyy24 The results of the erythro isomers have theoretical value for understanding the relationship between multiple inhibition of monoamine transmitter reuptake and ideal antidepressant therapeutics.

In summary, the invention of SIPIyy24 optical isomer biology has helped to identify optical isomer compounds with the best efficacy, the fastest onset, and the least toxic side effects as candidate drugs to improve the success rate of new drug research. Reduce risk, shorten development cycle, and have more practical value. Disclosure of invention

One of the technical problems to be solved by the present invention is to disclose an optical isomer of a sterol piperazine derivative or a salt thereof and use thereof to overcome the above-mentioned drawbacks of the prior art to meet the needs of people for treating depression.

The second technical problem to be solved by the present invention is to disclose the use of the above optical isomers for the preparation of a medicament for treating an antidepressant.

The optical isomer of an alkyl alcohol piperazine derivative or a salt thereof according to the present invention, and the optical isomer of the sterol piperazine derivative has the following structural formula:

CI

Wherein: C^n C ₂ two chiral carbon atoms have the following configurations: (1S, 2R), (1S, 2S), (1R, 2S), (1R, 2R);

Said salt is a hydrochloride, a hydrobromide, a sulfate, a trifluoroacetate or a methanesulfonate;

A preferred salt is a hydrochloride or a hydrobromide salt, the salt of which may contain 0.5 to 4 molecules of water of crystallization.

Among them, (1S, 2R), (1R, 2S) are erythro isomers, (1S, 2S), (1R, 2R) are threo optical isomers.

Preferred is:

N ¹ -pyringyl-N ⁴ -[1S-methyl-2R-(5,-chloro-6,-methoxy-2,-naphthyl)light ethyl]piperazine,

N ¹ -benzyl-N ⁴ -[1S-methyl-2S-(5,-chloro-6,-methoxy-2,-naphthyl)hydroxyethyl]piperazine,

N ¹ -benzyl-N ⁴ -[1R-methyl-2S-(5,-chloro-6'-methoxy-2,-naphthyl)hydroxyethyl]piperazine or

N ¹ -Benzyl-N ⁴ -[1R-methyl-2R-(5,-chloro-6'-methoxy-2,-naphthyl)hydroxyethyl]piperazine.

The present invention synthesizes the compound N ¹ -benzyl-N ⁴ -[l-methyl-2-(5,-chloro-6,-methoxy-2'-naphthyl) by a prochiral method. The four optical isomers of hydroxyethyl]piperazine are (1S, 2R), (IS, 2S), (1R, 2S) and (1R, 2R) optical isomers, respectively. A mixture of (1S, 2R) isomer and (1S, 2S) isomer is synthesized from L-alanine; (1R, 2S) isomer is synthesized from D-alanine and A mixture of 1R, 2R) isomers was separated by column chromatography to give four single isomers. The purity of the four optical isomers was determined by capillary electrophoresis; the configuration was estimated by correlating with the configuration of the prochiral starting material and the coupling constant value of the nuclear magnetic resonance of the target product. The specific synthetic route is as follows:

The present invention carries out five monoamine transmitters of 5-HT, NA, and DA for four optical isomers by the method recommended in the literature (Br J Pharmacol, 1997, 122: 302-306, 1992, 105: 147-151). The reuptake inhibition assay showed that the (IS, 2R) isomer and the (1R, 2S) isomer have a triple action of inhibiting 5-HT, NA and DA reuptake, while the (1S, 2S) isomer and The (1R, 2R) isomer only inhibited the reuptake of 5-HT and NA, and did not inhibit the reuptake of DA.

The present invention measures the ED ₅ o values of four optical isomers by a method recommended by the "Modern Pharmacological Experimental Method" (edited by Zhang Juntian), a single oral administration of a mouse tail suspension test, and a mouse swimming test. The ED ₅ o value of the mouse tail suspension test was determined as follows: (1S, 2R) isomer 12.6 mg/kg; (1R, 2S) isomer 16.5 mg kg; (1S, 2S) isomer 27.9 mg kg; (1R, 2R) isomer 24.5 mg / kg; ED _5Q value of mouse swimming test: (1S, 2R) isomer 28.9 mg kg; (1R, 2S) isomer 49.2 mg / kg; No statistically significant difference was observed after administration of the 1S, 2S) isomer and the (1R, 2R) isomer. The invention adopts the method recommended by the "Modern Pharmacological Experimental Method" (edited by Zhang Juntian), and the minimum effective dose of four optical isomers is determined by tail suspension test, mouse swimming test and rat swimming test of oral administration for one week. . The results showed that the minimum effective doses of the four isomers were: (1S, 2R) isomer 15-20 mg kg; (1R, 2S) isomer 30-40 mg kg; (1S, 2S) isomer 30-40 mg/kg; (1R, 2R) isomer 30-40 mg/kg.

The invention adopts the method recommended by the "Modern Pharmacological Experimental Method" (edited by Zhang Juntian), and the LD _5Q value of four optical isomers is determined by oral administration of mice, and the results show that the LD ₅ o values of the four isomers are respectively For: ( IS, 2 ) isomer 1030-1202 mg/kg; (1R, 2S) isomer 1171-1259 mg kg; (1S, 2S) isomer 300-400 mg/kg; (1R, 2R ) Isomer 200-250 mg / kg. The toxicity is significantly lower than that of the racemate.

At the same time, its antidepressant activity and safety are superior to those of racemates, and it has value as a new type of antidepressant.

The optical isomer of the present invention can be administered to a patient in need of such treatment by oral administration, injection or the like in the form of a composition.

Said composition comprises a therapeutically effective amount of an alkanolpiperazine derivative optical isomer of the invention or a salt thereof and a pharmaceutically acceptable carrier;

The carrier is a conventional carrier in the pharmaceutical field, for example: a diluent, an excipient such as water, etc.; a binder such as a cellulose derivative, gelatin, polyvinylpyrrolidone or the like; a filler such as starch, etc.; a cracking agent such as carbonic acid Calcium, sodium bicarbonate; in addition, other adjuvants such as flavoring agents and sweeteners may also be added to the composition.

For oral administration, it can be prepared into a conventional solid preparation such as a tablet, a powder or a capsule; for injection, it can be prepared as an injection.

The various dosage forms of the compositions of the present invention can be prepared by conventional methods in the medical field, wherein the active ingredient is present in an amount of from 0.1% to 99.5 °/. (weight ratio).

The administration amount of the present invention may vary depending on the route of administration, the age and weight of the patient, the type and severity of the disease to be treated, and the like, and the daily dose is 5-30 mg/kg body weight (oral) or 1-10 mg/kg. Weight (injection). The optical isomer compounds of the present invention show an antagonistic effect on depression in animal tests.

The present inventors have found that the anti-depressant effect of the optical isomer of the present invention is lower than that of the currently used single-targeted antidepressant, such as diazepam, fluoxetine, and a dual-targeted antidepressant. Such as venlafaxine, duloxetine may have a wider indication and less neurotoxic side effects. BEST MODE FOR CARRYING OUT THE INVENTION General Method 1: Synthesis of (S)-N-ethoxycarbonylalanine (2)

The compound (S)-N-ethoxycarbonylalanine was synthesized by the method of J. Am. Chem. Soc. 10(20): 6157-6163. (R)-N-ethoxycarbonylalanine is prepared in the same manner as (S)-N-ethoxycarbonylalanine. General Method 2: Synthesis of (S)-2-[5-chloro-6-methoxy-2-naphthyl]-2-(ethoxycarbonyl)amino-1-propyl ketone (5).

Compound 8 16.1 g (Ol mol) in 0 ° C, dissolved in 300 ml of dichloromethane, protected with nitrogen. Add 0.5 ml DMF, 10 ml oxalyl chloride, stir the reaction at room temperature for 2 hours, add 150 ml of dichloromethane, add 19.3 g (0.1 mol) of compound 4, cool to -15 ° C in ice salt bath, and add Α 3⁄4 26.7 g ( 0.2 mol), continue to react at -15 ° C for 12 hours. Was added IN HCl (300 ml) to suspend the reaction, water was added to 200 ml, the organic layer was separated, washed with 1N HC1 wash (300 mlx2), water (300 mlxl), saturated NaHC0 ₃ wash (2x300 ml), the solvent was evaporated to give an oil, The crystals were recrystallized from the hexane, yielding a white solid, 16.6 g, yield 49.7%. MS: m/z 335(M+) (R)-2-[5-chloro-6-methoxy-2-naphthyl]-2-(ethoxycarbonyl)aminopropylpropyl ketone (S)-2-[5-Chloro-6-methoxy-2-naphthyl]-2-(ethoxycarbonyl)amino-1-propyl ketone. General Method 3: Synthesis of (1S)-N-ethoxycarbonyl-2-(5-chloro-6-methoxynaphthalene)-2-carbomethoxymethylethylamine (6).

Compound 5 10.07 g (0.03 mol) was dissolved in 100 ml of methanol, stirred (partially dissolved), and a total of 2.2 (0.06 mol) of sodium boron hydride was added in portions. The reaction was carried out for 1 hour, and TLC was detected (the product on the plate layer was two points). ), the reaction is complete.

The reaction was stopped, a little aqueous solution of citric acid was added to quench the reaction, and methanol was evaporated. Water and chloroform (100 ml×5) were evaporated. The mixture was combined and evaporated to give a white solid 9.9 g, yield 98%. MS: m/z 337 (M+) (1R) -N-ethoxycarbonyl-2-(5-chloro-6-methoxynaphthalene)-2-hydroxy-1-methylethylamine -N-ethoxycarbonyl-2-(5-chloro-6-methoxynaphthalene)-2-hydroxy-1-methylethylamine. General Method 4: Synthesis of (lS)-2-(5-chloro-6-methoxynaphthalene)-2-hydroxymethylethylamine (7)

Compound 6 7.8 g (0.023 mol), 78 ml of a 30% aqueous potassium hydroxide solution, 390 ml of methanol, and heated to reflux for 20 hours, and the reaction was completed by TLC.

After adding citric acid to adjust pH = 8 to 9, methanol was distilled off, and a white solid was precipitated. The solid was filtered, washed with water, and washed with a small amount of ethyl acetate to give a white solid (6.0 g, yield 98.8%). MS: m/z 265.5 (M+).

Preparation of ( 1R) -2- (5-chloro-6-methoxynaphthalene)-2-hydroxy-1-methylethylamine with ( 1S) -2- (5-chloro-6-methoxynaphthalene) )-2-Lightyl-1-methylethylamine. General Method 5: (lS)-N ¹ -pyringyl-N ⁴ -[l-methyl-2-hydroxy-2-(5,-chloro-6,-methoxy-2,)-naphthylethyl Preparation of piperazine hydrochloride (9).

Compound 7 3.7 g (0.014 mol), 50 ml of acetonitrile, 10 ml of triethylamine, compound 8 (prepared by US Pat. No. 4,748,726) 7.4 g (0.032 mol) was heated to reflux, refluxed for 20 hours, and detected by TLC. The acetonitrile was evaporated, chloroform (50 ml×3) was added, EtOAc (EtOAc) (EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Mixture (9). Column separation of the mixture, the eluent dichloromethane: methanol = 80:1, the (1S, 2R) isomer was obtained as a yellow oil 2 g (yield 34%), dissolved in 20 ml of methanol, Hydrochloric acid/ethanol was added to adjust pH = 2, and a white solid precipitated, which was filtered to yield white product (yield: 1.4 g). The (1S, 2S) isomer was obtained as a yellow oil 0.5 g (yield 8.5%), dissolved in 10 ml of methanol, and adjusted to pH=2 with hydrochloric acid/ethanol, and a pale yellow solid was precipitated. 0.3 grams.

(1R, 2S) and (1R, 2R)-N ¹ -benzyl-N ⁴ -[l-methyl-2-hydroxy-2-(5'-chloro-6,-methoxy-) were prepared in the same manner. 2,)-Naphthylethyl]piperazine hydrochloride.

Example 1 Referring to General Method 1 to 5 Synthesis (1S, 2R) - SIPIyy24 Optical Isomer

[a] _D ²⁵ = -8.05° (C= l, CH ₃ OH) ; mp: 242-243. C (dec) ; MS: m/z 425 (M+);

¹ H NMR (DMSO-d6): δ 1.05 (d, 3H, NCHCH ₃ ), 3.47-4.28 (m, 9H, NCHCH ₃ , piperazine-H), 3.99 (s, 3H, OCH ₃ ), 5.59 (d, lH, PhCHOH, J=3.2), 7.45-8.10 (m, 10H, ArH Elemental analysis: C ₂₅ 3⁄4 ₉ C1N ₂ 0 ₂ .2HC1.23⁄40 Theoretical value: C: 56.24%, H: 6.51%, N: 5.25% ; Measured value: C: 56.04%, H: 6.36%, N: 5.30%. Example 2 Refer to General Procedure 1 to 5 Synthesis (1R, 2S) - SIPIyy24 Optical Isomer

[a ] _D ²⁵ = 8.54° (C= l, CH ₃ OH); mp: 242-243°C (dec); MS: m/z 425 (M+);

¹ H NMR (DMSO-d6): 51.05 (d, 3H, NCHCH ₃ ), 3.33-4.33 (m, 9H, NCHCH ₃ , piperazine-H), 3.99 (s, 3H, OCH ₃ ), 5.64 (d, lH) , PhCHOH, J=3.2), 7.45-8.10 (m, 10H, ArH Elemental analysis: C2 ₅ H ₂₉ C1N ₂ 02'2HC1' 253⁄40 Theoretical value: C: 55.31%, H: 6.68%, N: 5.16% : C: 55.20%, H: 6.77%, N: 5.26% Example 3 Refer to General Method 1 to 5 Synthesis (1S, 2S) - SIPIyy24 Optical Isomer

[a ] _D ²⁵ = 50.60° (C= l, CH ₃ OH) ; mp: 242-243 ° C (dec) ; MS: m/z 425 (M+); iHNMRpMSO-cW): 61.07 (d, 3H, NCHCH ₃ ), 3.42-3.81 (m, 9H, NCHCH ₃ , piperazine-H), 4.41 (s, 3H, OC 3⁄4), 4.93 (d, 1 H, PhCHOH, J = 9.6), 7.54 - 8.21 (m, 1 ΟΗ, ΑτΗ). Elemental analysis: C ₂₅ H ₂₉ C1N ₂ 0 ₂ .2HC1*23⁄40 Theoretical value: C: 56.24%, H: 6.51%, N: 5.25% Found: C: 56.44%, H: 6.21%, N: 5.30% Example 4 Refer to General Method I~5 Synthesis (1R, 2R) - SIPIyy24 Optical Isomer

[a ] _D ²⁵ = -50.10° (C= l, CH ₃ OH) ; mp: 242-243°C (dec); MS: m/z 425 (M+);

¹ H NMR (DMSO-d6): 60.97 (d, 3H, NCHCH3), 3.49-3.71 (m, 9H, NCHC3⁄4, piperazine-H), 4.36 (s, 3H, OCH ₃ ), 4.82 (d, lH, PhCHOH) , J = 9.6), 7.48 - 8.21 (m, 10H, ArH). Elemental analysis: C ₂₅ H ₂₉ C1N ₂ 0 ₂ .2HC1.23⁄40 Theory: C: 56.24%, H: 6.51%, N: 5.25% Found: C: 56.15%, H: 6.28%, N: 5.26% Example 5 Inhibition of 5-HT, NA and DA by brain four-isomer re-uptake:

The research method of re-uptake of monoamine neurotransmitters by brain synaptosome is one of the most important methods for the study of central nervous system in the world. This method can be used not only to study the mechanism of action of drugs, but also to screen New drugs in this session. The present invention employs a method for reuptake of monoamine neurotransmitters 5-HT, NA and DA by brain synaptosomes, with an effective 5-HT reuptake inhibitor fluoxetine, a NA reuptake inhibitor, dipamamine. And the dual reuptake inhibitor venlafaxine as a positive control drug, the effects of the four optical isomers inhibited by brain inducing the reuptake of 5-HT, NA and DA by brain synaptosomes were investigated. Methods as below:

(1) Preparation of brain synaptosomes. The rats were decapitated and quickly removed from the brain. They were placed in physiological saline pre-cooled at 4 °C to remove the pia mater and vascular tissue. 3 g of the cerebral cortex was taken and placed in a 0.32 mol/L cold sucrose solution in 30 ml. The pulverizer is homogenized at low temperature, equilibrated at 4 °C (1500xg) for 10 _m in, then the supernatant is centrifuged (20000xg) for 30min, the supernatant is discarded, the precipitate is refined, and suspended in a small amount of artificial brain effusion. The protein content of the suspension was determined using a total protein assay kit.

(2) Reuptake of monoamine transmitters, which is appropriately modified according to the literature (Br J Pharmacol, 1997, 122: 302-306, 1992 105: 147-151). Add artificial brain effusion (pre-oxygenated for 15 min) to 1.0 ml, then add synaptic suspension 20 μΐ, then add 10 μΐ of the drug solution to be tested (all in 4 Ό environment), mix well, Warm bath in a 37 °C water bath for 5 min. Subsequent addition of substrate ( ³ H-5HT, ³ NA or ϋΑ) 10μ1, mixed hook, 37 Ό warm bath for 5 min, the test tube was placed in ice water to stop the reaction, and the cell was quickly filtered through a glass fiber membrane with a multi-head cell harvester, and then the tube and filter were rinsed with 3 ml of artificial brain effusion 2 Times. Remove the filter, dry at 60-70 ° C, put the filter into a scintillation vial, add toluene scintillation fluid, count in the β-liquid scintillation counter, and the net uptake of synaptosome is 37 μm cpm ( Active re-uptake) minus (cpm value of TC (non-specific aggregation).

(3) Results:

I. Inhibition of 5-HT uptake by brain synaptosomes (IC ₅₀ )

Fluoxetine - 0.04 μΜ

Venlafaxine: 0.35 μΜ

(IS, 2R) isomer: 0.012 μΜ

(1R, 2S) isomer: 0.548 μΜ

(IS, 2S) isomer - 0.825 μΜ

(1R, 2R) isomer: 0.375 μΜ

II. Inhibition of brain synaptophysin intake (IC ₅ o)

Diazepam: 0.8 μΜ

Venlafaxine: 1.4μΜ

(IS, 2R) isomer: 0.185 μΜ

(1R, 2S) isomer: 7.0 μΜ

(IS, 2S) isomer: 0.425 μΜ

(1R, 2R) isomer: 1.25 μΜ

III. Inhibition of DA uptake by brain synaptosomes (IC ₅₀ )

6-hydroxy DA: 0.4 μΜ

Venlafaxine: weak inhibition

(IS, 2R) isomer: 1.15μΜ

(1R, 2S) isomer: 10.0 μΜ

(1S, 2S) isomer: no inhibition

(1R, 2R) isomer: no inhibition

The (IS, 2R) isomer significantly inhibited the reuptake of 5-HT, NA, and DA, and the IC ₅ o values were smaller than the positive control drug and the other three optical isomers. , Example 6

In vivo test results of four optical isomers

Using the "acquired desperation experiment", the rat tail suspension experiment and the forced swimming "immobility" test, with venlafaxine as a positive control drug, the four optical isomers were studied for antidepressant effects in animals. The results are as follows:

1. The ED ₅ o values of the four optical isomers were determined by mouse tail suspension and swimming test. Table 1 (1S, 2R), effects of oral administration of (1R, 2S) isomers on tail suspension and swimming tests in mice (single dose)

(XtSD, n=10)

Group drug dose mouse tail suspension test mouse swimming experiment

No time (seconds) no time (seconds) blank control N.S 124.3±43.8

Venlafaxine 50 mg/kg 39.2±21.66** 46.5±25.14**

(1S, 2R) isomer 48 mg/kg 55.0±39.26** 90.1±26.02**

28.8 mg/kg 66.1±42.13** 92.1±23.11**

17.3 mg/kg 75.1±46.83* 105.4±33.11

10.4 mg/kg 92.3±57.95 107.9±37.19

(1R, 2S) isomer 48 mg/kg 57.4±25.61** 94.5±27.86*

28.8 mg/kg 60.4±44.33** 102.6±42.29

Η-

17.3 mg/kg 71.3±50.92* 106.2±39.2

10.4 mg/kg 95.6±51.09 129.8±25.47

P < 0.05 compared with the blank control group

P < 0.01 compared with the blank control group

ED _{5Q for} tail suspension test _: (IS, 2R) isomer: 12.6 mg/kg; (1R, 2S) isomer: 16.5 mg/kg. ED _{50 for} swimming test _: (IS, 2R) isomer: 28.9 mg/kg; (1R, 2S) isomer: 49.2 mg/kgo Table 2 (1S, 2S), (1R, 2R) isomer orally Effect of administration on tail suspension and swimming test in mice (single dose)

(X±SD, n=10)

Group drug dose mouse tail suspension test mouse swimming experiment

Immobility time (seconds) immobility time (seconds) blank control N.S 63.1±46.88 129.9±34.96

Venlafaxine 50 mg/kg 16.5±22.47* 35.6i28.99**

(1S, 2S) isomer 48 mg/kg 35.0±38.82 106.8±30.58

28.8 mg/kg 52.6±38.66 99.7±34.71

17.3 mg/kg 47.2±40.09 106.2±34.13

10.4 mg/kg 58.7±38.36 104.8±36.46 (1R, 2R) isomer 48 mg/kg 20.6±18.65* 119.2±32.87

28.8 mg/kg 26.6±19.73* 120.8±22.49

17.3 mg/kg 24.9±22.33* 109.1±44.25

10.4 mg/kg 52.0±37.43 109.5±36.25

* P < 0.05 compared with the blank control group

** P < 0.01 compared with the blank control group

ED ₅ o of the tail suspension test _: (IS, 2S) isomer: 27.9 mg/kg; (1R, 2S) isomer: 24.5 mg/kg. There were no statistically significant differences in the results of the swimming test.

2. Determination of the four optical isomers of the lowest effective agent by mouse tail suspension test, mouse swimming test and rat swimming test. Table 3 (1S, 2R), (1R, 2S) isomers were orally administered to mice. Effects of tail suspension and swimming tests (one-week administration)

(X Shi SD, n=10)

Group drug dose mouse tail suspension test mouse swimming experiment

No time (seconds) No time (seconds) Blank control N.S 139.7±71.53 145.0±25.67

Venlafaxine 30 mg/kg 71.6±47.79* 83.5±29.0**

(1S, 2R) isomer 48 mg/kg 72.6±35.03* 95.5±27.0**

28.8 mg/kg 71.4±45.01* 97.2±28.33**

17.3 mg kg 76.8±32.42* 102.9±37.94**

1.0.4 mg/kg 109.0±31.76 123.8±21.68

(1R, 2S) isomer 48 mg/kg 68.0±38.31* 119.3±28.1*

28.8 mg/kg 75.1±58.57* 118.4d=48.38

17.3mg/kg 91.8±70.6 126.3±40.02

10.4mg/kg 113.7±59.22 125.1±45.63

P < 0.05 compared with the blank control group

P < 0.01 compared with the blank control group

Table 4 (1S, 2S), Effects of oral administration of (1R, 2R) isomers on tail suspension and swimming tests in mice (one-week administration)

(X±SD, n=10)

Group drug dose mouse tail suspension test mouse swimming experiment

Immobility time (seconds) immobility time (seconds) blank control N.S 113.0±46.8 131.7±29.53

Venlafaxine 30 mg/kg 29.5i43.l l** 60.5±67.77**

(IS, 2S) isomer 48 mg/kg 76.3±60.47 98.7±31.36*

28.8 mg/kg 104.2±65.07 101.4±30.06*

17.3 mg/kg 84.7±46.6 138.8±29.85

10.4 mg/kg 100.5±43.36 109.0±56.99

(1R, 2R) isomer 48 mg/kg 46.9±53.91** 106.4±52.96

28.8 mg/kg 65.1±43.11* 119.0±40.88

17.3 mg/kg 65.5±45.24* 101.4±28.39*

10.4 mg/kg 106.0±53.16 153.1±37.77 * P < 0.05 compared with the blank control group

** P < 0.01 compared with the blank control group

Table 5 (1S, 2R), Effects of oral administration of (1R, 2S) isomers on rat swimming test (one-week administration) (X±SD, n=10)

~m\ drug dose rat swimming experiment

No time (seconds) ~~

Blank control RS 222.8 ± 27.3

Venlafaxine 30 mg/kg 152.2 ± 61.33**

(IS, 2R) isomer 20 mg/kg 145.8 ± 47.59**

10 mg/kg 169.2 ± 45.19**

5 mg/kg 204.7 ± 24.14

( 1R, 2S) isomer ~ 20 mg kg 196.4 ± 45.77

10 mg/kg 227.3 ± 28.69

5 mg/kg 233.1 ± 22.72

** P < 0.01 compared with the blank control group

The minimum effective doses of the four isomers obtained from the above results are: (1S, 2R) isomer 15-20 mg/kg; (1R, 2S) isomer 30-40 mg/kg; (1S, 2S ) Isomer 30-40 mg kg; (1R, 2R) isomer 30-40 mg / kg. The (1S, 2R) isomer has the lowest minimum effective dose value and is more active than the other three isomers.

Example 7

Acute toxicity of four optical isomers (LD ₅₍₎ ) _:

According to the Bliss method, the LD ₅ o values of the four optical isomers in a single administration were: (1S, 2R) isomer 1030-1202 mg/kg; (1R, 2S) isomer 1171- 1259 mg/kg; (1S, 2S) isomer 300-400 mg/kg; (1R, 2R) isomer 200-250 mg/kg.

The (IS, 2R) isomer and the (1R, 2S) isomer are significantly safer than the other two isomers.

Example 8

Tablets: Compounds of the invention 10 mg

Sucrose 150 mg

Corn Starch 38 mg

Calcium stearate 2 mg Preparation method: The active ingredient is mixed with sucrose and corn starch, moistened with water, stirred evenly, dried, pulverized and sieved, added with calcium stearate, mixed and hooked, and compressed. Each tablet weighs 200 mg and has an active ingredient content of 10 mg. Example 9

Injection: Compound of the invention 20 mg

Water for injection 80 mg

Preparation method: The active ingredient is dissolved in water for injection, uniformly mixed, filtered, and the obtained solution is dispensed in an ampoule under sterile conditions, 10 mg per bottle, and the active ingredient content is 2 mg/bottle.

Claims

Claim

An optical isomer of an alkanol piperazine derivative or a salt thereof, characterized in that the structural formula of the optical isomer of the alkanol piperazine derivative is as follows:

Cl

Where: and the configuration of the two chiral carbon atoms are: (1S, 2R), (1S, 2S), (1R, 2S), (1R,

2R).

The optical isomer of an alkanol piperazine derivative or a salt thereof according to claim 1, wherein the salt is a hydrochloride, a hydrobromide, a sulfate, a trifluoroacetate or Methanesulfonate.

The alkanolpiperazine derivative optical isomer or a salt thereof according to claim 2, wherein the salt is a hydrochloride or a hydrobromide.

The optical isomer of a sterol piperazine derivative or a salt thereof according to claim 2, wherein the salt thereof contains 0.5 to 4 molecules of water of crystallization.

The optical isomer of a sterol piperazine derivative or a salt thereof according to claim 1, wherein the optical isomer of the alkane piperazine derivative is:

N ¹ -benzyl-N ⁴ -[1S-methyl-2R-(5,-chloro-6,-methoxy-2,-naphthyl)hydroxyethyl]piperazine,

N ¹ -pyringyl-N ⁴ -[1R-methyl-2S-(5,-chloro-6,-methoxy-2,-naphthyl)hydroxyethyl]piperazine or

N ¹ -Benzyl-N ⁴ -[1R-methyl-2R-(5,-chloro-6,-methoxy-2,-naphthyl)hydroxyethyl]piperazine.

A pharmaceutical composition comprising a therapeutically effective amount of the optical isomer of an alkylol piperazine derivative according to any one of claims 1 to 5, or a salt thereof, and a pharmaceutically acceptable carrier.

The optical isomer of a sterol piperazine derivative according to any one of claims 1 to 5 or a salt thereof for use in the preparation of a medicament for treating an antidepressant.