KR101380181B1 - (1S,3aR,9bS)-1-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole derivatives and 3,4-diarylpyrrolidin-2-one derivatives having inhibition of monoamine reuptake - Google Patents

Abstract

The present invention provides (1S, 3aR, 9bS) -1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole derivative with 3,4 showing monovalent amine reuptake inhibitory activity. -Diarylpyrrolidin-2-one derivatives, methods for preparing these compounds, and pharmaceutical compositions containing these compounds as active ingredients.

Description

(1S, 3AR, 9WS) -1-phenyl-2,3,3a, 4,5,9'-hexahydro-1H-benzo [e] indole derivative and 3,4-diaryl pi exhibiting monovalent amine reuptake inhibitory activity Rollidin-2-one derivatives {(1S, 3aR, 9bS) -1-Phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole derivatives and 3,4-diarylpyrrolidin-2 -one derivatives having inhibition of monoamine reuptake}

The present invention provides (1S, 3aR, 9bS) -1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole derivative with 3,4 showing monovalent amine reuptake inhibitory activity. -Diarylpyrrolidin-2-one derivatives, methods for preparing these compounds, and pharmaceutical compositions containing these compounds as active ingredients.

Depression, one of the most common diseases in modern people, is not caused by a momentary depression or personal weakness, but by a person's will. Depression is a lifelong prevalence of 15% of the population, and in the United States and Europe, it is reported to be the second most disturbing disease after heart disease. In addition, depression does not occur only in a certain age group, regardless of age or gender, and affects not only mental pain such as depression or loss of helplessness, but also physical health such as headache, digestive disorder, and insomnia. These depressions are short-lived but often chronic. In addition, depression is a very easy disease that relapses within 50% of patients with depression within 5 years, and more than 90% of cases with three history of depression.

Although the cause of depression is not known in detail, it has been accepted that it is due to the post-synaptic monovalent amine receptor rather than abnormal concentration of monovalent amine, a neurotransmitter in the brain. Recently, endocrine and immune systems have also been reported to be involved in the pathology of depression. Neurotransmitters contained in the synaptic vesicles of nerve cells are signaling materials secreted by nerve cells. When stimuli are delivered to nerve cells, calcium ion channels are opened before neuronal synapses, and calcium is introduced into the neurons, thereby synaptic vesicles It serves to move to the cell membrane, and also to increase or decrease the potential of adjacent nerve cells through synapses. As neurotransmitters, acetylcholine, amino acids, monoamines, peptides, purines and the like are known.

Dangaamine, one of the neurotransmitters, is divided into serotonin, norepinephrine, and dopamine. Serotonin is involved in mood, appetite, and temperature in the brain, and lack of serotonin causes anorexia, depression, and insomnia. Norepinephrine is released from activated neurons from noradrenaline and affects adrenergic regulators of neuronal cells in the brain. Finally, dopamine is found in the central nervous system of various animals and affects behaviors and roles that involve many functions of the brain. Excessive release of dopamine can lead to mood swings or schizophrenia, lack of depression, and damage to dopamine-producing neurons can lead to Parkinson's disease. As such, neurotransmitters are closely related to depression.

These depressions are divided into major depression, dysthymia, depressive personality disorder, mood swings, and adaptation disorders. The main symptoms of depression are depression and depression. Major depression causes not only mental symptoms such as anxiety and lethargy, but also physical symptoms such as headaches and insomnia.

Most antidepressants are monovalent amine enzyme inhibitors and monovalent amine transfer inhibitors as modulators of monoaminergic neurotransmitters. Monovalent amine transfer inhibitors have been developed as antihistamines, and tricyclic antidepressants have been developed, starting with the development of imipramine, which has been shown to be effective in treating schizophrenia. Tricyclic antidepressants and monoaminetase inhibitors, however, have been reported to have side effects that result in a deficiency of histamine, acetylcholine and alpha-adrenergic receptor resistance.

Subsequently, the antidepressant drugs developed include selective serotonin reuptake blockers (SSRI), serotonin norepinephrine reuptake blockers (SNRI), and selective norepinephrine reuptake blockers (Selective NRI). It has little antagonism against histamine and alpha-adrenergic receptors, which are side effects of tricyclic antidepressants. Selective serotonin reuptake blockers are typically fluoxetine. Selective serotonin reuptake blockers block the selective absorption of the neurotransmitter serotonin at the synapse, with fewer side effects of the tricyclic antidepressants mentioned above and less or no affinity for other proteins. However, these drugs have different side effects according to the individual differences of patients, and have side effects such as weight gain or loss, skin rash, and decreased libido. Serotonin norepinephrine reuptake blockers include venlafaxine. Serotonin norepinephrine reuptake blockers inhibit serotonin reuptake at low concentrations, and norepinephrine and dopamine reuptake at high concentrations, and act faster than selective serotonin reuptake blockers and are effective in patients with severe depression. It is not related to weight gain or sedation, and no drug interaction occurs. Selective norepinephrine reuptake blockers do not inhibit serotonin reuptake and do not block 1-adrenergic receptors, thus preventing nausea, diarrhea, hypotension and the like.

However, the currently used antidepressant drugs, such as selective serotonin reuptake blockers, serotonin norepinephrine reuptake blockers, and selective norepinephrine reuptake blockers were effective 2-4 weeks after drug administration. Only showed effect. In order to remedy this problem, researches on triple reuptake inhibitors that block all reuptake of anti-depressant drugs, such as serotonin, norepinephrine, and dopamine, which are absorbed from synapses, are being conducted. [1] Beer et al, J. Clinical Pharmacology (2004) 44: 1360-1367; 2) Skolnick et al, Eur J Pharmacol. (2003) Feb 14; 461 (2-3): 99-104; 3) International Publication Nos. WO 2010/000198 and WO 2010/040315]

Accordingly, the present inventors have tried for many years to develop a triple reuptake inhibitor that blocks reuptake of all monoamine-based neurotransmitters of serotonin, norepinephrine, and dopamine. As a result, a tricyclic amine compound derivative and a diaryl delta lactam-type compound derivative were newly designed. In addition, the present invention was completed by confirming that the tricyclic amine compound derivative and the diaryl delta lactam compound derivative having a novel structure have an activity of inhibiting triple reuptake.

It is an object of the present invention to provide novel (1S, 3aR, 9bS) -1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole derivatives or pharmaceutically acceptable salts thereof. To provide.

It is also another object of the present invention to provide novel 3,4-diarylpyrrolidin-2-one derivatives or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a method for preparing the novel compound.

Another object of the present invention is to provide a pharmaceutical composition for the treatment and prevention of depression, which is based on a triple reuptake inhibitor containing the novel compound as an active ingredient.

In order to achieve the above object, the present invention is (1S, 3aR, 9bS) -1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] represented by the following formula (1) It is characterized by indole derivatives or pharmaceutically acceptable salts thereof.

[Chemical Formula 1]

(In Formula 1, R ₁ represents a halogen atom, n represents an integer of 1 to 4)

The present invention is characterized by a 3,4-diarylpyrrolidin-2-one derivative represented by the following formula (2) or a pharmaceutically acceptable salt thereof.

(2)

(In Formula 2, R ₂ represents a substituted or unsubstituted phenyl group or naphthyl group of 1 to 5 halogen atoms, R ₃ represents a halogen atom, m represents an integer of 1 to 5)

In another aspect, the present invention is (1S, 3aR, 9bS) -1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole derivative represented by Formula 1 and the formula It provides a method for producing the 3,4-diarylpyrrolidin-2-one derivative.

Furthermore, the present invention provides (1S, 3aR, 9bS) -1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole derivative represented by Chemical Formula 1 and Chemical Formula 2 Provided is a pharmaceutical composition for treating and preventing depression based on a triple reuptake inhibitor of a 3,4-diarylpyrrolidin-2-one derivative represented by the present invention.

The novel compounds according to the present invention have the effect of inhibiting triple reuptake that blocks all neurotransmitters of neurotransmitters serotonin, noepinenetrin and dopamine.

Therefore, the pharmaceutical composition containing the novel compound according to the present invention as an active ingredient is useful for treating depression by pharmacological mechanisms that inhibit triple reuptake.

In the compound represented by Chemical Formula 1 according to the present invention, preferably, R ₁ is chloride and n is 1 to 3 in the case of a compound. More preferably, (R ₁ ) _n is a case where the compound is 2-chloro, 3-chloro, 4-chloro, 3,4-dichloro.

Specific examples of the compound represented by Chemical Formula 1 are as follows.

1) (1S, 3aR, 9bS) -9-chloro-1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole;

2) (1S, 3aR, 9bS) -8-chloro-1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole;

3) (1S, 3aR, 9bS) -7-chloro-1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole;

4) (1S, 3aR, 9bS) -7,8-dichloro-1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole; Or a pharmaceutically acceptable salt thereof.

In the compound represented by Formula 2 according to the present invention, preferably, R ₂ is a phenyl group, a phenyl group substituted with 1 to 3 chlorides, a naphthyl group, or a naphthyl group substituted with 1 to 3 chlorides; R ₃ is chloride and m is for compounds of 1 to 3. More preferably, R ₂ is a phenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3,4-dichlorophenyl group, or naphthyl group; (R ₃ ) _m is the case of a compound that is 2-chloro, 3-chloro, 4-chloro, 3,4-dichloro.

Specific examples of the compound represented by Formula 2 are as follows.

5) 4- (2-chlorophenyl) -3-phenylpyrrolidin-2-one;

6) 4- (3-chlorophenyl) -3-phenylpyrrolidin-2-one;

7) 4- (4-chlorophenyl) -3-phenylpyrrolidin-2-one;

8) 4- (3,4-dichlorophenyl) -3-phenylpyrrolidin-2-one;

9) 3,4-bis (2-chlorophenyl) pyrrolidin-2-one;

10) 3- (2-chlorophenyl) -4- (3-chlorophenyl) pyrrolidin-2-one;

11) 3- (2-chlorophenyl) -4- (4-chlorophenyl) pyrrolidin-2-one;

12) 3- (2-chlorophenyl) -4- (3,4-dichlorophenyl) pyrrolidin-2-one;

13) 4- (2-chlorophenyl) -3- (3-chlorophenyl) pyrrolidin-2-one;

14) 3,4-bis (3-chlorophenyl) pyrrolidin-2-one;

15) 3- (3-chlorophenyl) -4- (4-chlorophenyl) pyrrolidin-2-one;

16) 4- (2-chlorophenyl) -3- (4-chlorophenyl) pyrrolidin-2-one;

17) 4- (3-chlorophenyl) -3- (4-chlorophenyl) pyrrolidin-2-one;

18) 3,4-bis (4-chlorophenyl) pyrrolidin-2-one;

19) 4- (2-chlorophenyl) -3- (3,4-dichlorophenyl) pyrrolidin-2-one;

20) 4- (3-chlorophenyl) -3- (3,4-dichlorophenyl) pyrrolidin-2-one;

21) 4- (4-chlorophenyl) -3- (3,4-dichlorophenyl) pyrrolidin-2-one;

22) 3,4-bis (3,4-dichlorophenyl) pyrrolidin-2-one;

23) 4- (2-chlorophenyl) -3- (naphthalen-2-yl) pyrrolidin-2-one;

24) 4- (3-chlorophenyl) -3- (naphthalen-2-yl) pyrrolidin-2-one;

25) 4- (4-chlorophenyl) -3- (naphthalen-2-yl) pyrrolidin-2-one;

26) 4- (3,4-dichlorophenyl) -3- (naphthalen-2-yl) pyrrolidin-2-one; Or a pharmaceutically acceptable salt thereof.

The derivative represented by Formula 1 or 2 according to the present invention may form a pharmaceutically acceptable salt by a conventional method in the art. For example, a non-toxic inorganic acid such as hydrochloric acid, hydrobromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid, or nitric acid, or an acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, para toluenesulfonic acid, Together with non-toxic organic acids such as acids, to form salts with pharmaceutically acceptable acids.

On the other hand, the present invention provides a method for producing a derivative represented by the formula (1) or (2).

[Manufacturing Method 1]

The compound represented by Chemical Formula 1 according to the present invention may be prepared by performing the preparation step shown in Scheme 1 below. Specifically, the step of preparing a compound represented by the following formula (4) by cyclizing a phenylacetic acid derivative, which is a compound represented by the following formula (3) as a starting material (step 1); Preparing a compound represented by the following Chemical Formula 6 by esterifying 2-bromo-2-phenylacetic acid which is a compound represented by the following Chemical Formula 5 (step 2); Preparing a compound represented by Chemical Formula 7 by reacting the compound represented by Chemical Formula 4 prepared above with the compound represented by Chemical Formula 6 (step 3); A ketone compound represented by the formula (7) is reacted with an amine hydroxide compound to prepare an oxime compound represented by the formula (8) (step 4); Preparing an compound represented by the following Chemical Formula 9 by reducing and cyclizing the oxime compound represented by the following Chemical Formula 8 (step 5); And reacting the compound represented by Chemical Formula 9 in the presence of a base to prepare a compound represented by Chemical Formula 1 (step 6); It provides a (1S, 3aR, 9bS) -1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole derivative comprising a.

[Reaction Scheme 1]

(In Scheme 1, R ₁ and n are as defined in Formula 1).

Hereinafter, the preparation method 1 shown in Scheme 1 will be described in more detail as follows.

Step 1

Step 1 is a step of preparing a compound represented by Chemical Formula 4 by cyclization reaction of a phenylacetic acid derivative which is a compound represented by Chemical Formula 3. In the cyclization reaction, the carbonyl acid is substituted with chloride using thionyl chloride, and then the cyclization reaction is performed using Lewis acid and ethylene gas. In addition, the compound represented by the formula (3) used in the step 1 was used to purchase a commercial product as a known compound.

Step 2

Step 2 is a step of preparing a compound represented by Chemical Formula 6 by esterification of 2-bromo-2-phenylacetic acid, which is a compound represented by Chemical Formula 5. The esterification reaction is commonly known in the field of organic chemistry, and reaction conditions such as a reaction solvent, a reaction temperature, and a reaction time may be appropriately selected in consideration of reactants, products, and the like. Although the embodiment of the present invention uses methanol as a reaction solvent and illustrates a process of stirring at room temperature using thionyl chloride as a reaction material, the present invention is not limited thereto. In addition, the compound represented by the formula (5) used in the step 2 was used to purchase a commercial product as a known compound.

Step 3

Step 3 is a step of preparing a compound represented by Chemical Formula 7 by reacting the compound represented by Chemical Formula 4 prepared in Step 1 and Step 2 with the compound represented by Chemical Formula 6.

Step 3 is carried out in the presence of a base. In this case, an alkali metal salt compound may be used as the base, and specifically, an alkali metal hydroxide, an alkali metal C _1-10 alkoxide, an alkali metal C _1-10 alkylamide, or the like may be used. As the reaction solvent, organic polar solvents such as C _1-10 alcohol, tetrahydrofuran (THF) and dimethylformamide (DMF) can be used. The present invention proposes two methods as the manufacturing method of step 3. The first method uses sodium hydride as the base, ethylene glycol as the solvent, and the second method uses lithium diisopropylamide as the base and tetrahydrofuran as the solvent.

Step 4

Step 4 is a step of preparing an oxime compound represented by Chemical Formula 8 by reacting the ketone compound represented by Chemical Formula 7 with an amine hydroxide compound.

The reaction is carried out by heating to reflux with a pyridine base and a C _1-10 alcohol solvent. In this case, alcohol, methanol, ethanol, propanol, isopropanol and the like can be used.

Step 5

Step 5 is a step of preparing a compound represented by Chemical Formula 9 by reducing and simultaneously cyclizing the oxime compound represented by Chemical Formula 8.

The reaction proceeds to a one-pot reaction. Specifically, the oxime compound represented by Chemical Formula 8 is mixed with an Adams catalyst and 1 N hydrochloric acid in an ethanol solvent, followed by stirring under a hydrogen atmosphere. Proceed.

Step 6

Step 6 is a step of preparing a compound represented by Chemical Formula 1, which is an amine by using a base to make one stereoisomer that is thermodynamically stable using a base and reducing lactam. Specifically, the compound of Formula 9 is stirred in the presence of a base, and then proceeds to the step of stirring in the presence of Lewis acid and lithium aluminum hydride. The base used at this time may be an alkali metal hydroxide, carbonate, hydrogen carbonate, sulfate, hydrogen sulfate, etc., and the reaction solvent is organic such as C _1-10 alcohol, tetrahydrofuran (THF), dimethylformamide (DMF) Polar solvents can be used. In an embodiment of the present invention, after the compound represented by the formula (9) and potassium carbonate are stirred under methanol, the Lewis acid of aluminum chloride and lithium aluminum hydride are stirred under a tetrahydrofuran solvent at a low temperature of −90 ° C. to −40 ° C. Although illustrated, the present invention is not limited thereto.

[Manufacturing Method 2]

In addition, the compound represented by Formula 2 according to the present invention can be prepared by performing the preparation step shown in Scheme 2. Specifically, preparing a compound represented by the following formula (11) using nitromethane to the benzaldehyde derivative represented by the following formula (10) as a starting material (step 6); Preparing a compound represented by the following Chemical Formula 13 by esterifying the compound represented by the following Chemical Formula 12 (step 7); Preparing a compound represented by Chemical Formula 14 by reacting the compound represented by Chemical Formula 11 prepared above with the compound represented by Chemical Formula 13 (step 8); Preparing a compound represented by the following Chemical Formula 2 by reducing and cyclizing the compound represented by the following Chemical Formula 14 under a base (step 9); It provides a method for producing a 3,4-diarylpyrrolidin-2-one derivative comprising a.

[Reaction Scheme 2]

(In Scheme 2, R ₂ , R ₃ and m are as defined in Formula 2).

The preparation method 2 shown in Scheme 2 will be described in more detail step by step.

Step 6

Step 6 is a step of preparing a compound represented by the formula (11) using nitromethane to the benzaldehyde derivative represented by the formula (10). Specifically, a benzaldehyde derivative represented by Chemical Formula 10, nitromethane, and ammonium acetate are reacted under acidic conditions to prepare a compound represented by Chemical Formula 11, which is in the form of nitrostyrene. The compound represented by Chemical Formula 10 used in Step 6 was purchased from a commercial product as a known compound.

Step 7

Step 7 is an esterification reaction of the acetic acid compound represented by Formula 12 to prepare an ester compound represented by Formula 13. The esterification reaction is carried out using thionyl chloride and methanol. In addition, the compound represented by Chemical Formula 12 used in Step 7 was purchased from a commercial product as a known compound.

Step 8

Step 8 is a step of preparing the compound represented by Chemical Formula 14 by reacting the compound represented by Chemical Formula 11 and the compound represented by Chemical Formula 13 prepared above. The reaction is carried out in the presence of a base, an alkali metal salt compound may be used as the base, specifically, an alkali metal hydroxide, an alkali metal C _1-10 alkoxide, an alkali metal C _1-10 alkylamide, or the like may be used. As the reaction solvent, organic polar solvents such as C _1-10 alcohol, tetrahydrofuran (THF) and dimethylformamide (DMF) can be used. The compound represented by Chemical Formula 13 of the present invention was stirred with lithium diisopropyl amide at a temperature of -20 ° C to 10 ° C, and then the compound represented by Formula 11 was added dropwise at a low temperature of -90 ° C to -40 ° C Although the method of stirring is illustrated, this invention is not limited to this.

Step 9

Step 9 is a step of preparing a compound represented by Chemical Formula 2 by reducing the nitro compound represented by Chemical Formula 14 and converting it to an amine compound, followed by cyclization under a base.

The reduction is a reaction for converting the nitro group to an amine group, which is carried out in a hydrogen atmosphere under a Raney Ni catalyst. The cyclization reaction is carried out by heating to reflux using sodium hydride as the base.

On the other hand, the present invention includes a pharmaceutical composition comprising a compound represented by Formula 1 or 2 or a pharmaceutically acceptable salt thereof as a therapeutically effective ingredient.

The pharmaceutical composition of the present invention may be formulated in a conventional formulation method including oral administration or parenteral administration, including other conventional carriers, adjuvants or diluents, together with the compound represented by Formula 1 or 2 or a pharmaceutically acceptable salt thereof. It may be prepared in a form suitable for. In the case of oral administration, it can be prepared in the form of tablets, capsules, solutions, syrups, suspensions, etc. In the case of parenteral administration, it can be prepared in the form of injections for peritoneal, subcutaneous, muscular and transdermal administration.

As a triple reuptake inhibitor of the pharmaceutical composition of the present invention, the effective daily dose is 0.01 to 1000 mg / day based on an adult, but the dosage is depending on the patient's age, weight, sex, dosage form, health condition and degree of disease. It may vary, and may be divided once or several times a day at regular time intervals according to the judgment of a doctor or a pharmacist.

Accordingly, the present invention provides a pharmaceutical use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same for the purpose of treating and preventing a disease.

That is, the present invention is active as a triple reuptake inhibitor, and therefore includes a medicinal use used for the purpose of treating and preventing depression.

The present invention as described above will be described in more detail through the following Examples and Experimental Examples, but the present invention is not limited to these Examples and Experimental Examples.

The following example is an example of preparing a compound represented by Formula 1 or 2 according to the present invention.

Example Synthesis of Compound

Example 3 Preparation of (1S, 3aR, 9bS) -7-chloro-1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole

Step 1: Preparation of 6-chloro-3,4-dihydronaphthalene-2 (1H) -one

4-chlorophenylacetic acid (3 g, 17.58 mmol) was dissolved in ethylene glycol (12 mL), and thionyl chloride (3.85 mL, 52.75 mmol) was slowly added dropwise at room temperature, and the mixed solution was heated to reflux at 90 ° C. After the reaction was completed, the mixture was distilled under reduced pressure to remove thionyl chloride and ethylene glycol. The residue was taken up in dichloromethane (20 mL) and slowly added dropwise aluminum chloride (5.39 g, 40.39 mmol) at 0 ° C. and stirred under ethylene gas atmosphere for 3 hours. After completion of the reaction, an aqueous sodium carbonate solution was slowly added dropwise at 0 ° C. The reaction was filtered under reduced pressure, extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The residue was purified by column chromatography (dichloromethane). The resulting compound was isolated and purified to yield 1.56 g of the title compound in a yield of 49.21%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.55 (2H, t, J = 6.66 Hz, CH ₂ ), 3.04 (2H, t, J = 6.66 Hz, CH ₂ ), 3.55 (2H, s, CH ₂ ) , 7.05 (1H, d, J = 8.06 Hz, CH), 7.20 (1H, d, J = 8.06 Hz, CH), 7.24 (1H, s, CH)

Step 2: Preparation of 2-bromo-2-phenylacetic acid methyl ester

2-bromo-2-phenylacetic acid (2 g, 9.30 mmol) was dissolved in anhydrous methanol (10 mL) and then thionyl chloride (3.32 g, 27.90 mmol) was slowly added dropwise at low temperature for 10 minutes. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the pH was adjusted to 8-9 using sodium hydrogen carbonate (5 mL). The mixed solution was extracted with ethyl acetate, the organic layer was dried over sodium sulfate, filtered under reduced pressure and concentrated under reduced pressure to obtain 2.05 g of the target compound in a yield of 96.24%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.79 (3H, s, OMe), 5.36 (1H, s, CHBr), 7.35-7.37 (3H, m, 3CH (Ph)), 7.54 (2H, d, J = 7.88 Hz, 2CH (Ph))

Step 3: Preparation of Methyl 2- (6-chloro-2-oxo-1,2,3,4-tetrahydronaphthalen-1-yl) -2-phenylacetate

To a solution of sodium hydride (28.7 mg, 1.196 mmol) in ethylene glycol (2 mL), slowly add dropwise solution of 6-chloro-β-tetralone (200 mg, 1.107 mmol) in ethylene glycol (3 mL). It was then heated to reflux. After 1 hour, the solution was cooled to room temperature and methyl bromophenyl acetate was added dropwise, followed by stirring at room temperature. After completion of the reaction, water was added to the cooled solution and extracted with diethyl ether. The extracted solution was dried over sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane / normal hexane = 2/1) to give 1.20 g of the target compound in a yield of 63.44%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.36-2.52 (2H, m, CH ₂ ), 3.70 (3H, s, OMe), 4.24 (1H, d, J = 6.68 Hz, CH), 4.50 (1H, d, J = 6.68 Hz, CH), 6.83-6.90 (1H, m, CH), 7.06-7.17 (5H, m, Ph), 7.21-7.24 (1H, m, CH), 7.38 (1H, m, CH) )

Step 4: Preparation of (E) -methyl 2- (6-chloro-2- (hydroxyamino) -1,2,3,4-tetrahydronaphthalen-yl) -2-phenylacetate

Methyl 2- (6-chloro-2-oxo-1,2,3,4-tetrahydronaphthalen-1-yl) -2-phenylacetate (150 mg, 0.456 mmol) was dissolved in anhydrous methanol (2 mL). In addition, a solution of hydroxylamine hydrochloride (40.5 mg, 0.585 mmol) and pyridine (0.18 mL, 2.28 mmol) in anhydrous methanol (2 mL) was slowly added dropwise, followed by heating to reflux. After completion of the reaction, the solvent was removed by distillation under reduced pressure, dissolved in water and diethyl ether and extracted with diethyl ether. The extracted solvent was dried over sodium sulfate, filtered under reduced pressure and concentrated under reduced pressure. The residue was chromatographed (ethyl acetate / normal hexane). = 1/4) to give 63 mg of the target compound in 40.18% yield.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.65-2.72 (1H, m, CH _a ), 2.85-2.90 (1H, m, CH _b ), 2.95-3.02 (m, 2H, CH ₂ ), 3.70 (3H , s, OMe), 3.87 (1H, d, J = 11.08 Hz, CH), 4.19 (1H, d, J = 11.08 Hz, CH), 6.38 (1H, d, J = 8.18 Hz, 4-ClPh)

Step 5: Preparation of (3aR, 9bS) -7-chloro-1-phenyl-3,3a, 4,5-tetrahydro-1H-benzo [e] indole-2 (9bH) -one

1 N hydrochloric acid (0.3 mL), Adams catalyst (9.2 mg), and (E) -methyl 2- (6-chloro-2- (hydroxyamino) -1,2,3,4-tetrahydronaphthalen-yl)- 2-phenylacetate (63 mg, 0.183 mmol) was dissolved in anhydrous methanol (3 mL) and stirred under hydrogen atmosphere. After completion of the reaction, the resultant was filtered under reduced pressure using diatomaceous earth and concentrated under reduced pressure to obtain 50 mg of the target compound in 91.64% yield.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.02-2.06 (2H, m, CH ₂ ), 2.72-2.86 (2H, m, CH ₂ ), 3.50 (1H, d, J = 9.77 Hz, CH), 3.73 (1H, t, J = 9.60 Hz, CH), 4.01-4.05 (1H, m, CH), 6.53 (1H, d, J = 8.31 Hz, Ph), 6.80 (1H, s, Ph), 6.98 (1H , dd, J ₁ = 8.31 Hz, J ₂ = 2.18 Hz, Ph), 7.14 (1H, d, J = 2.38 Hz, Ph), 7.22-7.24 (1H, m, Ph), 7.33-7.35 (1H, m , Ph), 7.40-7.42 (2H, m, Ph)

Step 6: Preparation of (1S, 3aR, 9bS) -7-chloro-1-phenyl-3,3a, 4,5-tetrahydro-1H-benzo [e] indol-2 (9bH) -one

(3aR, 9bS) -7-chloro-1-phenyl-3,3a, 4,5-tetrahydro-1H-benzo [e] indol-2 (9bH) -one (50 mg, 0.168 mmol) was dissolved in anhydrous methanol ( 2 mL), and potassium carbonate (69.6 mg, 0.504 mmol) was added dropwise and stirred at room temperature. After completion of the reaction, the mixture was dissolved in an aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered under reduced pressure, and concentrated under reduced pressure. The residue was taken up in tetrahydrofuran (3 mL) and slowly added dropwise aluminum chloride (11.19 mg, 0.084 mmol) followed by lithium aluminum hydride (12.9 mg, 0.336 mmol) at -78 ° C. After completion of the reaction, 1 N water, 1 N aqueous sodium hydroxide solution and 3 N water were slowly added dropwise, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate, filtered under reduced pressure and concentrated under reduced pressure.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.70-1.88 (1H, m, CH _2a ), 2.58-2.78 (2H, m, CH ₂ ), 2.87-3.07 (1H, m, CH _2b ), 3.32-3.52 (2H, m, 2CH), 3.59-3.36 (2H, m, CH ₂ ), 3.93-4.03 (1H, m, CH), 6.89-6.91 (1H, m, Ph), 7.03-7.06 (1H, m, Ph), 7.14-7.34 (5H, m, Ph)

The compound represented by Chemical Formula 1 was prepared by the preparation method according to Example 3, and the physicochemical data of the prepared compound was summarized in Table 1 below.

Example 1

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.56-1.60 (1H, m, CH), 2.14-2.18 (1H, m, CH), 2.54-2.60 (1H, m, CH), 2.84-2.89 (2H, m, CH ₂ ), 3.06-3.12 (1H, m, CH), 3.45-3.53 (2H, m, CH ₂ ), 3.57-3.61 (1H, m, CH), 6.89-6.91 (2H, m, Ph) , 7.11-7.22 (5H, m, Ph), 7.34-7.36 (1H, m, Ph)

Example 2

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.62-1.71 (1H, m, CH), 2.30-2.35 (1H, m, CH), 2.42-2.48 (1H, m, CH), 2.82-2.87 (2H, m, CH ₂ ), 2.99-3.06 (1H, m, CH), 3.40-3.48 (2H, m, CH ₂ ), 3.57-3.61 (1H, m, CH), 6.56 (1H, s, Ph), 7.7 .04-7.10 (2H, m, Ph), 7.27-7.39 (5H, m, Ph)

Example 3

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.70-1.88 (1H, m, CH _2a ), 2.58-2.78 (2H, m, CH ₂ ), 2.87-3.07 (1H, m, CH _2b ), 3.32-3.52 (2H, m, 2CH), 3.59-3.36 (2H, m, CH ₂ ), 3.93-4.03 (1H, m, CH), 6.89-6.91 (1H, m, Ph), 7.03-7.06 (1H, m, Ph), 7.14-7.34 (5H, m, Ph)

Example 4

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.53-5.56 (2H, m, CH ₂ ), 2.78-2.83 (1H, m, CH ₂ ), 2.98-3.04 (1H, m, CH _a ), 3.20-3.24 (1H, m, CH), 3.31-3.35 (1H, m, CH _b ) 3.57-3.62 (2H, m, CH ₂ ), 3.73-3.76 (1H, m, CH), 6.51 (1H, s, Ph) , 6.61 (1H, s, Ph), 7.26-7.33 (5H, m, Ph)

Example 10 Preparation of 3,4-Dichlorophenylpyrrolidin-2-one Derivatives

Step 1: Preparation of (E) -1-chloro-4- (2-nitrovinyl) benzene

4-chlorobenzaldehyde derivative (8 g, 0.57 mol), nitromethane (9.3 mL, 0.171 mol) and ammonium acetate (11 g, 0.142 mol) were dissolved in acetic acid (100 mL) and then heated to reflux. After completion of the reaction, the reaction was added with water. The mixture was extracted with dichloromethane and then the organic layer was extracted again with saturated aqueous sodium chloride solution. The extracted organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was separated using column chromatography (ethyl acetate / normal-hexane: 1/30) to obtain 8.02 g of the title compound in a yield of 76.76%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42-7.50 (4H, m, Ph), 7.56 (1H, d, J = 13.69 Hz, CH [vinyl]), 7.96 (1H, J = 13.69 Hz, CH [ vinyl])

Step 2: Preparation of Methyl 2- (3,4-Dichlorophenyl) Acetate

Dissolve 3,4-dichlorophenylacetic acid (1 g, 4.88 mmol) in anhydrous methanol (10 mL), then slowly add dropwise thionyl chloride (1.06 mL, 14.63 mmol) at 0 ° C., and then add the reaction at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove thionyl chloride, and the residue was dissolved in ethyl acetate and water. The mixture was extracted with ethyl acetate, and the extracted organic layer was extracted with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate, filtered under reduced pressure and concentrated under reduced pressure to obtain 1.05 g of the target compound in a yield of 98.58%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.58 (2H, s, CH ₂ Ph), 3.70 (3H, s, OMe), 7.11 (1H, dd, J ₁ = 8.16 Hz, J ₂ = 1.98 Hz, Ph ), 7.38 (1H, s, Ph), 7.39 (1H, d, J = 6.8 Hz)

Step 3: Preparation of Methyl 3- (4-chlorophenyl) -2- (3,4-dichlorophenyl) -4-nitrobutanoate

Diisopropylamine (1.7 mL, 11.88 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) and n-butyllithium (2.5M hexane solution, 4.8 mL, 11.88 mmol) was slowly added dropwise at -78 ° C for 1 hour. It stirred at 0 degreeC. The solution was cooled to −78 ° C. and methyl 2- (3,4-dichlorophenyl) acetate (1.3 g, 5.94 mmol) dissolved in anhydrous tetrahydrofuran (30 mL) was slowly added dropwise. After stirring for 30 minutes while maintaining the same temperature, (E) -1-chloro-4- (2-nitrovinyl) benzene (1.2 g, 6.54 mmol) dissolved in anhydrous tetrahydrofuran (3 mL) was slowly added dropwise. The mixture was stirred while maintaining the temperature for 3 hours. After completion of the reaction, the mixture was neutralized with an aqueous ammonium chloride solution and extracted with ethyl acetate. The extracted organic layer was dried over sodium sulfate, filtered under reduced pressure and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate). / Normal-hexane = 1/10) to give 885.4 mg of the title compound as a pale yellow solid in a yield of 37.04%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.46 (3H, s, OMe), 3.94 (1H, d, J = 11.58 Hz, CH), 4.09-4.17 (1H, m, CH), 4.30-4.34 (1H , dd, J ₁ = 12.82 Hz, J ₂ = 4.39 Hz, CH _a ), 4.39-4.45 (1H, dd, J ₁ = 12.82 Hz, J ₂ = 9.80 Hz, CH _b ), 7.23 (2H, t, J = 8.66 Hz, Ph), 7.31-7.34 (3H, m, Ph), 7.50 (1H, d, J = 8.27 Hz, Ph), 7.56 (1H, d, J = 2.04 Hz, Ph)

Step 4: Preparation of 4- (4-chlorophenyl) -3- (3,4-dichlorophenyl) pyrrolidin-2-one

Methyl 3- (4-chlorophenyl) -2- (3,4-dichlorophenyl) -4-nitrobutanoate (880 mg, 2.19 mmol) in diethylether and ethanol (1: 1) solution (5 mL After dissolving in), Raney nickel was added and stirred at room temperature for 20 hours under 8 bar of hydrogen gas. After completion of the reaction, the resultant was filtered under reduced pressure using diatomaceous earth and concentrated under reduced pressure. The residue was taken up in toluene (5 mL) and then sodium hydride (175 mg, 4.37 mmol) was added dropwise and heated to reflux for 6 hours. After completion of the reaction, an aqueous ammonium chloride solution was slowly added dropwise to terminate the reaction, followed by extraction with ethyl acetate. The extracted organic layer was dried over sodium sulfide, filtered under reduced pressure, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / ethyl acetate = 10). / 1) to separate and obtain 401.7 mg of the title compound as a pale yellow solid in a yield of 53.96%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.50 (1H, t, J = 9.02 Hz, CH), 3.61-3.68 (2H, m, CH ₂ ), 3.77 (1H, t, J = 9.54 Hz, CH) , 6.64 (1H, brs, NH), 6.96 (1H, dd, J ₁ = 8.26 Hz, J ₂ = 2.11 Hz, Ph), 7.12 (2H, d, J = 8.46 Hz, Ph), 7.26 (1H, d , J = 2.11 Hz, Ph), 7.31 (2H, d, J = 8.46 Hz, Ph), 7.37 (1H, d, J = 8.26 Hz, Ph)

The compound represented by Chemical Formula 2 was prepared by the preparation method according to Example 10, and the physical and chemical data of the prepared compound were summarized in Table 2 below.

Example 5

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.40 (1H, t, J = 8.23 Hz, CH), 3.58-3.67 (2H, m, CH), 3.75 (1H, t, J = 11.05 Hz, CH), 7.04-7.07 (2H, m, Ph), 7.10-7.15 (1H, td, J ₁ = 2.24 Hz, J ₂ = 7.68 Hz, Ph), 7.16 (1H, d, J = 3.34 Hz, Ph), 7.18- 7.23 (2H, m, Ph), 7.35-7.38 (1H, m, Ph)

Example 6

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.51 (1H, t, J = 9.06 Hz, CH), 3.59-3.69 (2H, m, CH ₂ ), 3.74-3.78 (1H, m, CH), 6.42 ( 1H, s, NH), 7.07 (2H, d, J = 8.45 Hz, Ph), 7.11 (2H, d, J = 8.45 Hz, Ph), 7.27 (2H, d, J = 3.51 Hz, Ph), 7.29 (2H, d, J = 3.51 Hz, Ph)

Example 7

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.52 (1H, t, J = 9.2 Hz, CH), 3.58-3.71 (2H, m, CH ₂ ), 3.78 (1H, t, J = 8.42 Hz, CH) , 6.28 (1H, s, NH), 6.98 (1H, dd, J ₁ = 8.18 Hz, J ₂ = 1.89 Hz, Ph), 7.05-7.07 (1H, m, Ph), 7.20 (1H, s, Ph) , 7.26-7.29 (4H, m, Ph), 7.38 (1H, d, J = 8.25 Hz, Ph)

Example 8

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.43 (1H, t, J = 8.94 Hz, CH), 3.85-3.91 (2H, m, CH), 4.20-4.26 (1H, m, CH), 7.17 (2H , d, J = 6.64 Hz, Ph), 7.19-7.23 (1H, td, J ₁ = 1.63 Hz, J ₂ = 7.78 Hz, Ph), 7.28 (3H, d, J = 8.24 Hz, Ph), 7.35- 7.41 (2H, m, Ph)

Example 9

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.54 (1H, t, J = 10.16 Hz, CH), 3.61-3.72 (2H, m, CH ₂ ), 3.90-3.95 (1H, m, CH), 6.27 ( 1H, brs, NH), 6.70 (1H, dd, J ₁ = 8.32 Hz, J ₂ = 1.93 Hz, Ph), 6.87 (1H, dd, J ₁ = 8.26 Hz, J ₂ = 2.03 Hz, Ph), 7.02 (1H, d, J = 1.93 Hz, Ph), 7.15 (1H, d, J = 2.03 Hz, Ph), 7.23 (1H, d, J = 8.32 Hz, Ph), 7.27 (1H, d, J = 8.26 Hz, Ph)

Example 10

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.50 (1H, t, J = 9.02 Hz, CH), 3.61-3.68 (2H, m, CH ₂ ), 3.77 (1H, t, J = 9.54 Hz, CH) , 6.64 (1H, brs, NH), 6.96 (1H, dd, J ₁ = 8.26 Hz, J ₂ = 2.11 Hz, Ph), 7.12 (2H, d, J = 8.46 Hz, Ph), 7.26 (1H, d , J = 2.11 Hz, Ph), 7.31 (2H, d, J = 8.46 Hz, Ph), 7.37 (1H, d, J = 8.26 Hz, Ph)

Example 11

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.52 (1H, t, J = 9.22 Hz, CH), 3.59-3.72 (2H, m, CH ₂ ), 3.78 (1H, t, J = 7.97 Hz, CH) , 5.91 (1H, brs, NH), 7.09 (1H, d, J = 8.36 Hz, Ph), 7.20-7.22 (2H, m, Ph), 7.28 (1H, s, Ph), 7.30 (2H, d, J = 3.27 Hz, Ph)

Example 12

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.45 (1H, t, J = 8.88 Hz, CH), 3.85-3.90 (2H, m, CH ₂ ), 4.19-4.26 (1H, m, CH), 6.43 ( 1 H, brs, NH), 7.07 (1 H, dd, J ₁ = 8.28 Hz, J ₂ = 2.11 Hz, Ph), 7.20-7.31 (2H, m, Ph), 7.34 (1H, d, J = 2.11 Hz, Ph), 7.38 (3H, d, J = 8.26 Hz, Ph)

Example 13

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.53 (1H, t, J = 8.85 Hz, CH), 3.71-3.84 (2H, m, CH ₂ ), 4.18 (1H, d, J = 9.86 Hz, CH) , 6.01 (1H, brs, NH), 7.07 (1H, doublet of doublets, J ₁ = 8.26 Hz, J ₂ = 2.14 Hz, Ph), 7.17-7.19 (1H, m, Ph), 7.22 (1H, d, J = 2.14 Hz, Ph), 7.23-7.24 (1H, m, Ph), 7.33 (1H, d, J = 2.14 Hz, Ph), 7.35 (1H, d, J = 1.7 Hz, Ph), 7.38 (1H, d , J = 8.26 Hz, Ph)

Example 14

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.54 (1H, t, J = 8.21 Hz, CH), 3.74-3.83 (2H, m, CH ₂ ), 4.20 (1H, d, J = 9.71 Hz, CH) , 6.33 (1 H, brs, NH), 7.16 (1 H, d, J = 8.50 Hz, Ph), 7.18-7.23 (3 H, m, Ph), 7.27 (1 H, d, J = 8.50 Hz, Ph), 7.33 -7.35 (1H, m, Ph)

Example 15

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.55 (1H, t, J = 8.53 Hz, CH), 3.73-3.84 (2H, m, CH ₂ ), 4.23 (1H, d, J = 9.71 Hz, CH) , 6.55 (1H, brs, NH), 7.09-7.12 (1H, m, Ph), 7.18-7.25 (6H, m, Ph), 7.34-7.36 (1H, m, Ph)

Example 16

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.48 (1H, t, J = 8.51 Hz, CH), 3.87-3.91 (1H, m, CH _a ), 4.35-4.39 (1H, m, CH _b ), 4.45 (1H, d, J = 10.21 Hz, CH), 6.31 (1H, brs, NH), 7.17-7.34 (7H, m, Ph), 7.47-7.49 (1H, m, Ph)

Example 17

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.49 (1H, t, J = 8.40 Hz, CH), 3.62-3.66 (2H, m, CH ₂ ), 3.79 (1H, t, J = 7.72 Hz, CH) , 6.30 (1H, brs, NH), 7.00-7.04 (2H, m, Ph), 7.17 (1H, brs, Ph), 7.25-7.26 (2H, m, Ph), 7.30 (1H, d, J = 2.08 Hz, Ph), 7.40 (1H, d, J = 8.28 Hz, Ph)

Example 18

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.50 (1H, t, J = 8.91 Hz, CH), 3.63-3.70 (1H, m, CH ₂ ), 3.75-3.79 (1H, m, CH), 6.81 ( 1H, brs, NH), 7.00-7.02 (1H, m, Ph), 7.12 (2H, d, J = 8.46 Hz, Ph), 7.17 (1H, s, Ph), 7.23-7.24 (1H, m, Ph ), 7.29 (2H, d, J = 8.46 Hz, Ph)

Example 19

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.52 (1H, t, J = 8.89 Hz, CH), 3.64-3.72 (2H, m, CH ₂ ), 3.79 (1H, d, J = 9.46 Hz, CH) , 6.41 (1H, brs, NH), 7.02-7.08 (2H, m, Ph), 7.18 (1H, s, Ph), 7.20 (1H, s, Ph), 7.23-7.26 (4H, m, Ph)

Example 20

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.74 (1H, t, J = 7.53 Hz, CH), 3.90 (1H, d, J = 8.21 Hz, Ph), 4.03-4.06 (1H, m, CH _a ) , 4.12-4.16 (1H, m, CH _b ), 6.49 (1H, brs, NH), 7.06-7.38 (8H, m, Ph)

Example 21

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.48 (1H, m, CH), 3.64-3.69 (2H, m, CH ₂ ), 3.74-3.81 (1H, m, CH), 6.23 (1H, s, NH ), 7.03 (1H, dd, J ₁ = 8.29 Hz, J ₂ = 2.16 Hz, Ph), 7.14-7.24 (3H, m, Ph), 7.27-7.34 (m, 3H, Ph), 7.38 (1H, d) , J = 8.29 Hz, Ph)

Example 22

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.49-3.52 (1H, m, CH), 3.66-3.69 (2H, m, CH ₂ ), 3.77-3.78 (1H, m, CH), 6.19 (1H, s , NH), 7.12-7.15 (4H, m, Ph), 7.25-7.33 (5H, m, Ph)

Meanwhile, the novel compounds represented by Formula 1 according to the present invention can be formulated into various forms according to the purpose. The following is a description of some formulations containing the compound of Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

[Formulation Example]

Formulation 1: Tablets (direct pressurization)

After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.

Formulation 2: Tablet (wet assembly)

After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressurized to make tablets.

Formulation 3: Powder and Capsule

5.0 mg of the active ingredient was sieved and mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. 5 gelatin capsules.

Formulation 4: Injection

100 mg as an active ingredient, 180 mg of mannitol, 26 mg of Na ₂ HPO _{4 12} H ₂ O and 2974 mg of distilled water were added to prepare an injection.

On the other hand, for the novel compound represented by the formula (1) according to the present invention was confirmed the activity as a triple reuptake inhibitor by the method as shown in the following experimental example.

[Experimental Example]

In order to evaluate the activity of the compound represented by Formula 1 according to the present invention as a triple reuptake inhibitor, binding affinity experiments were performed for serotonin, norepinephrine, and dopamine membrane transporters as amine transporters.

Makjeon was cotransporter as the use of the over-expressing human recombinant makjeon cotransporter, Isotopes in the ^[3 H] imipramine, ^[3 H] Niso paroxetine, ^[3 H] Innotech Harvey of was used such Win35428, 96-well format harvesters Radiation dose was measured using Innotech harvester and MicroBeta Plus. The binding affinity test method for each membrane transporter is as follows.

(1) Binding Affinity for Serotonin Membrane Transporter (5-HT Transporter)

This experiment was performed using human recombinant serotonin transporter membrane (PerkinElmer Life and Analytical Sciences, USA) and radioisotope [ ³ H] Imipramine (PerkinElmer) expressed in HEK293 cells. That is, the final volume was added to the test compound, [ ³ H] impramine 2 nM, serotonin transporter membrane (9 ug / well), 50 mM Tris-HCl buffer (pH 7.4) containing 120 mM NaCl and 5 mM KCl, and the like. 0.25 mL of reaction mixture was prepared and incubated at 27 ° C. for 30 min. After incubation, the reaction was terminated by rapid filtration through a glass fiber filter (Filtermat A) pre-soaked with 0.5% PEI using an Inotech harvester (Inotech) and a cold washing buffer (50 mM Tris-HCl, pH 7.4). , 154 mM NaCl), the filter was covered with MeltiLex, sealed in a sample bag and dried in an oven, and the radiation dose was counted with MicroBeta Plus (Wallac). Nonspecific binding was measured in the presence of 200 uM imipramine. IC ₅₀ values of the test compounds were obtained by calculating the non-linear regression analysis (GraphPad Prism Program, San Diego, USA) of the respective% inhibition values obtained from the drug at 7 to 8 levels of concentration. Fluoxetine (Sigma) and imipramine (Sigma) were used as standard compounds.

Experimental results showed that the binding affinity (IC ₅₀ ) of the standard compound to serotonin membrane transporter was fluoxetine 7.2 nM and imipramine 6.8 nM. The binding affinity for the serotonin membrane transporter of the compound represented by Formula 1 according to the present invention is summarized in Table 3 below.

(2) Binding Affinity to Norepinephrine Transporter

This experiment was performed using human recombinant recombinant norepinephrine membrane transporter (PerkinElmer Life and Analytical Sciences, USA) and radioisotope [ ³ H] Nisoxetine (PerkinElmer) expressed in MDCK cells. That is, the final volume was added by adding a test compound, [ ³ H] nicecetin 6 nM, a norepinephrine transporter membrane (11 ug / well), 50 mM Tris-HCl buffer (pH 7.4) containing 120 mM NaCl and 5 mM KCl, and the like. 0.25 mL of reaction mixture was prepared and incubated at 4 ° C. for 60 min. After incubation, the reaction was terminated by rapid filtration through a glass fiber filter (Filtermat A) pre-soaked in 0.5% PEI using an Inotech harvester (Inotech) and a cold washing buffer (50 mM Tris-HCl, pH 7.4). , 0.9% NaCl), the filter was covered with MeltiLex, sealed in a sample bag and dried in an oven, and the radiation dose was counted with MicroBeta Plus (Wallac). Nonspecific binding was measured in the presence of 1 uM desipramine. IC ₅₀ values of the test compounds were obtained by calculating the non-linear regression analysis (GraphPad Prism Program, San Diego, USA) of the respective% inhibition values obtained from the drug at 7 to 8 levels of concentration. As standard compounds, desipramine (desipramine, Sigma) and clomipramine (Sigma) were used.

Experimental results showed that the binding affinity (IC ₅₀ ) of the standard compound to norepinephrine membrane transporter was desipramine 1.5 nM and clomipramine 64.6 nM. The binding affinity for the norepinephrine membrane transporter of the compound represented by Formula 1 according to the present invention is summarized in Table 3 below.

(3) binding affinity for dopamine transporter

In this experiment, human recombinant recombinant dopamine membrane transporter (PerkinElmer Life and Analytical Sciences, USA) and radioisotope [ ³ H] WIN35428 (PerkinElmer) expressed in CHO-K1 cells were used. That is, a final volume of 0.25 was added by adding a test compound, [ ³ H] WIN35428 (8 nM), dopamine transporter membrane (23 ug / well), 50 mM Tris-HCl buffer containing NaCl (100 mM), pH 7.4, and the like. mL reaction mixture was prepared and incubated at 4 ° C. for 60 min. After incubation, the reaction was terminated by rapid filtration through a glass fiber filter (Filtermat A) pre-soaked in 0.5% PEI using an Inotech harvester (Inotech) and a cold washing buffer (50 mM Tris-HCl, pH 7.4). , 0.9% NaCl), the filter was covered with MeltiLex, sealed in a sample bag and dried in an oven, and the radiation dose was counted with MicroBeta Plus (Wallac). Nonspecific binding was measured in the presence of 10 uM GBR-12909. IC ₅₀ values of the test compounds were obtained by calculating the non-linear regression analysis (GraphPad Prism Program, San Diego, USA) of the respective% inhibition values obtained from the drug at 7 to 8 levels of concentration. GBR-12909 (Sigma) and clomipramine (Sigma) were used as standard compounds.

As a result, the binding affinity of the standard compound to the dopamine membrane transporter (IC ₅₀ ) was GBR-12909 14 nM and clomipramine 2777 nM. The binding affinity for the dopamine membrane transporter of the compound represented by Formula 1 according to the present invention is summarized in Table 3 below.

Test compound STM NET DAT % Inhibition rate IC ₅₀ (nM) % Inhibition rate IC ₅₀ (nM) % Inhibition rate IC ₅₀ (nM) Example 1 20 23 8 Example 2 9 26 5 Example 3 10 10 54 Example 4 61 6157 69 4831 41 Example 5 90 85.6 83 2033 76 99.6 Example 6 84 99.2 75 5176 99 179.3 Example 7 49 87 1662 95 33.1 Example 8 26 60 7619 51 Example 9 42 90 990.3 85 284.7 Example 10 57 92 1900 96 280.6 Example 11 71 3757 78 2745 99 171.9 Example 12 26 90 2521 87 1731 Example 13 52 99 509.5 100 8.14 Example 14 49 74 3570 97 81.5 Example 15 39 41 96 17.3 Example 16 20 33 45 Example 17 57 93 384.2 87 41.7 Example 18 22 72 3825 99 36.3 Example 19 26 59 98 38.7 Example 20 Example 21 49 87 865.7 83 36.6 Example 22 20 50 99 32.7

Claims (7)

From (1S, 3aR, 9bS) -1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole derivative represented by Formula 1 below and a pharmaceutically acceptable salt thereof Selected compound.
[Chemical Formula 1]

(In Formula 1, R ₁ represents a halogen atom, n represents an integer of 1 to 4)
The method according to claim 1,
(1S, 3aR, 9bS) -9-chloro-1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole;
(1S, 3aR, 9bS) -8-chloro-1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole;
(1S, 3aR, 9bS) -7-Chloro-1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole;
(1S, 3aR, 9bS) -7,8-dichloro-1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole; And
Compounds selected from pharmaceutically acceptable salts thereof.
delete delete A pharmaceutical composition for treating and preventing depression containing the compound of claim 1 or 2 as an active ingredient.
Preparing a compound represented by the following Chemical Formula 4 by cyclizing a phenylacetic acid derivative which is a compound represented by the following Chemical Formula 3 (Step 1);
Preparing a compound represented by the following Chemical Formula 6 by esterifying 2-bromo-2-phenylacetic acid, which is a compound represented by the following Chemical Formula 5 (step 2);
Preparing a compound represented by Chemical Formula 7 by reacting the compound represented by Chemical Formula 4 prepared above with the compound represented by Chemical Formula 6 (step 3);
Reacting a ketone compound represented by Formula 7 with an amine hydroxide compound to prepare an oxime compound represented by Formula 8 (step 4);
Preparing an compound represented by the following Chemical Formula 9 by reducing and cyclizing the oxime compound represented by the following Chemical Formula 8 (step 5); And
Preparing a compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 9 in the presence of a base (step 6);
Method for producing (1S, 3aR, 9bS) -1-phenyl-2,3,3a, 4,5,9b-hexahydro-1H-benzo [e] indole derivative comprising a.

(In the above scheme, R ₁ represents a halogen atom, n represents an integer of 1 to 4)
Preparing a compound represented by the following Chemical Formula 11 using nitromethane to a benzaldehyde derivative represented by the following Chemical Formula 10 (step 6);
Preparing a compound represented by the following Chemical Formula 13 by esterifying the compound represented by the following Chemical Formula 12 (step 7);
Preparing a compound represented by Chemical Formula 14 by reacting the compound represented by Chemical Formula 11 prepared above with the compound represented by Chemical Formula 13 (step 8);
Preparing a compound represented by the following Chemical Formula 2 by reducing and cyclizing the compound represented by the following Chemical Formula 14 under a base (step 9);
Method for producing a 3,4-diarylpyrrolidin-2-one derivative comprising a.

(In the above scheme, R ₂ represents a substituted or unsubstituted phenyl group or naphthyl group having 1 to 5 halogen atoms, R ₃ represents a halogen atom, and m represents an integer of 1 to 5).