KR100420663B1 - Novel Quinoline derivatives, the process for the preparation thereof and pharmaceutical compositions containing them - Google Patents

Abstract

The present invention relates to a quinoline derivative that binds to a serotonin transporter (SERT), a method for preparing the same, and a pharmaceutical composition comprising the same, wherein the quinoline compound of the present invention represented by Formula 1 is one of neurotransmitters of the brain. It strongly blocks the binding of phosphorus serotonin and the serotonin transporter to prevent the reabsorption of serotonin into ganglion neurons and normalizes serotonin levels in ganglions, which is useful for the prevention and treatment of mental diseases caused by lack of serotonin levels in ganglions. Can be.

Wherein R ¹ , R ² , R ³ and R ⁴ are as described in the specification.

Description

Quinoline derivatives, preparation methods thereof, and pharmaceutical compositions containing them {Novel Quinoline derivatives, the process for the preparation of sweet and pharmaceutical compositions containing them}

The present invention relates to a quinoline derivative represented by the following formula (1), and more particularly, to a quinoline derivative represented by the formula (1) useful for the prevention and treatment of mental diseases caused by a lack of serotonin concentration in the ganglion and pharmaceutically acceptable A salt, a preparation method thereof, and a pharmaceutical composition comprising the compound as an active ingredient.

Formula 1

In Chemical Formula 1,

R ¹ is piperazinyl, 2-methylpiperazinyl, diazepanyl or N-methyl-N- (2-N'-methylamino) ethylamine group,

R ² is hydrogen, a halogen atom, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl group,

R ³ is hydrogen, a halogen atom, a vinyl or a furanyl group,

R ⁴ is a halogen atom or a nitro group.

Mental illness is an advanced national disease that is rapidly increasing as society develops and civilization is advanced, but there are inherent factors, but the weighted stress of modern man is pointed out as the cause of its great cause.

Like most mental illnesses, depression is difficult to pinpoint, so it is difficult to accurately diagnose and usually is discussed with a psychiatrist. Mental disability, worthlessness, repeated thoughts of death, and suicidal prayer symptoms, and physically complain of anorexia, digestive disorders, sleep disorders, weight loss, etc. It is most common in women, and the likelihood of lifelong depression is 10-25% in women and 5-12% in men. Currently, 5 to 9% of the female population and 2 to 3% of the male population are known to be depressed.

Mental activity is carried out through the neurotransmitters that are constantly in the human brain, and in order to develop normal thinking, these neurotransmitters must be maintained at a certain concentration in the brain. If the concentration of neurotransmitters changes, that is, increases or decreases in concentration, this results in mental disorders. Correlation between neurotransmitters and diseases caused by abnormalities is being studied continuously, and the constant stress on modern people is thought to cause changes in brain activity, but the cause and mechanism of action are still unknown. I'm not losing.

On the other hand, as one of the neurotransmitters that act in the brain, serotonin is known to be involved in various mental disorders, in particular directly affecting depression.

Serotonin's mechanism of action is similar to other neurotransmitters. Serotonin is biosynthesized in two steps from tryptophan, one of the amino acids by enzymes in neurons. Biosynthesized serotonin is encased in the endoplasmic reticulum and secreted at the nerve endings. The secreted serotonin binds to the serotonin receptors present in the neuronal cell membranes after ganglion and transmits a signal to the next neuron and then dissociates and is called a serotonin transporter (SERT). ) Moves into neuronal neurons. Depression is known to occur due to lack of serotonin levels in the ganglion. Therefore, the development of drugs that selectively block SERT may be expected to normalize serotonin levels in the ganglion.

In Korea, there is also a lack of awareness of the disease itself, so there is little interest in developing new antidepressants. However, in the United States, about 10 million people are reported receiving treatment for depression each year, resulting in over $ 40 billion in lost productivity, reduced incomes, and the estimated total cost of treatment and rehabilitation. Occupies. Antidepressant, Fluoxetine (trade name: Prozac), marketed by Lilly in the US, generates $ 1.7 billion in annual sales as a single item despite the side effects of vomiting, itching, and delayed drug action.

Selective SERT inhibitors that are classified as second-generation antidepressants are already commercialized, in addition to fluorocetin, peroxetine, setraline, fluorocetin (Ki = 16 nM), peroxetine (Ki = 0.24 nM), and setraline (Ki = 0.39 nM) and a compound that binds to SERT and has a stronger binding affinity (Ki) 6-nitro-2-piperazin-1-yl-quinoline (common name: 6-nitroquizazine) (Ki = 0.18 nM) is known. However, few studies have been reported on the chemical structure and activity thereof and the synthesis of derivatives.

Accordingly, the present inventors are developing a new SERT inhibitor having a higher binding affinity with SERT and a selective SERT inhibitor through changes in the basic structure and substituents of 6-nitro-2-piperazin-1-yl-quinoline. The present invention has been completed by discovering that quinoline derivatives have a similar or strong binding affinity to 6-nitro-2-piperazin-1-yl-quinoline.

It is an object of the present invention to provide candidates of third-generation antidepressants that make up for the shortcomings of second-generation antidepressants through the synthesis of more selective and binding compounds for SERT.

In order to achieve the above object, it provides a quinoline derivative represented by the following formula (1) and a pharmaceutically acceptable salt thereof.

Formula 1

In Chemical Formula 1,

R ¹ is piperazinyl, 2-methylpiperazinyl, diazepanyl or N-methyl-N- (2-N'-methylamino) ethylamine group,

R ² is hydrogen, a halogen atom, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl group,

R ³ is hydrogen, a halogen atom, a vinyl or a furanyl group,

R ⁴ is a halogen atom or a nitro group.

More preferably, in the compound of Formula 1

R ¹ is a 2-methylpiperazinyl, diazepanyl or N-methyl-N- (2-N'-methylamino) ethylamine group,

R ² is hydrogen, bromine, methyl, ethyl, propyl, chloropropyl or fluoropropyl group,

R ³ is hydrogen, chlorine, bromine, iodine, vinyl or 2-furanyl group,

R ⁴ is a chlorine, bromine, iodine or nitro group.

Particularly preferred compounds among the compounds of Formula 1 are shown in Table 1 below.

Example Compound name constitutional formula Example Compound name constitutional formula One 3-Methyl-6-nitro- 2-piperazin-1-yl-quinoline 10 4-Chloro-6-nitro-2-piperazin-1-yl-quinoline 2 3-ethyl-6-nitro- 2-piperazin-1-yl-quinoline 11 4-Bromo-6-nitro-2-piperazin-1-yl-quinoline 3 6-nitro-2-piperazin-1-yl-3-propylquinoline 12 4-iodo-6-nitro-2-piperazin-1-yl-quinoline 4 3- (3-Chloropropyl) -6-nitro-2-piperazin-1-yl-quinoline 13 6-nitro-2-piperazin-1-yl-4-vinylquinoline 5 3- (3-fluoropropyl) -6-nitro-2-piperazin-1-yl-quinoline 14 4- (2-furanyl) -6-nitro-2-piperazin-1-yl-quinoline 6 6-iodo-2-piperazin-1-yl-quinoline 15 2- (3-methylpiperazin-1-yl) -6-nitroquinoline 7 6-Bromo-2-piperazin-1-yl-quinoline 16 2- (N-methyl-N- (2-N'-methylamino) ethyl) amino-6-nitroquinoline 8 6-chloro-2-piperazin-1-yl-quinoline 17 2- [1,4] diazepane-1-yl-6-nitroquinoline 9 3-Bromo-6-nitro-2-piperazin-1-yl-quinoline

The present invention includes both the quinoline derivative represented by the formula (1) and pharmaceutically acceptable salts thereof, as well as possible solvates and hydrates that can be prepared therefrom.

The compound of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Organic acids and inorganic acids can be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid and nitric acid can be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid and maleic acid (maleic) can be used as the organic acid. acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutamic acid Tartaric acid (glutaric acid), glucuronic acid (glucuronic acid), aspartic acid, ascorbic acid, carboxylic acid, vanillic acid, iodic acid and the like can be used.

The acid addition salts according to the invention can be prepared by conventional methods, for example by dissolving a compound of formula 1 in an excess aqueous solution of an acid and using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.

Equivalent amounts of the compound of formula (1) and acid or alcohol (eg, glycol monomethyl ether) in water may be heated and then the mixture is dried or the precipitated salt is filtered off with suction.

In addition, the compound of formula 1 is dissolved using a possible organic solvent such as diethyl ether, tetrahydrofuran, dichloromethane, acetonitrile, and various inorganic and organic acids listed above are dissolved directly or in an organic solvent. It can also be prepared by precipitation of the resulting salt by precipitation and suction filtration.

The present invention provides a method for preparing a quinoline derivative represented by the formula (1).

Specifically, the present invention provides a method for preparing 2-piperazinyl-1-yl-quinoline, represented by Scheme 1 below.

In Scheme 1, R ² is hydrogen, bromine, methyl, ethyl, propyl, chloropropyl or fluoropropyl group, R ³ is hydrogen, chlorine or bromine atom, R ⁴ is chlorine, bromine, iodine or nitro group .

The 2-piperazin-1-yl-quinoline compound represented by the formula (3) is substituted with the quinoline compound represented by the formula (2) with 1-piperazincarboxaldehyde, or treated with an acid or substituted with piperazine to quinoline Obtained by introducing the piperazinyl group at the 2nd position of the compound.

The piperazine substitution reaction is preferably carried out at 20 to 140 ° C. When 1-piperazinecarboxaldehyde is used as the reaction reagent, after the substitution reaction, it is dissolved in an acid solution such as an aqueous sulfuric acid solution to remove an aldehyde group. Reaction is performed in -80 degreeC range.

Also provided is a method for preparing 4-iodo-6-nitro-2-piperazin-1-yl-quinoline, represented by Scheme 2 below.

Method for preparing 4-iodo-6-nitro-2-piperazin-1-yl-quinoline which is a compound of the present invention represented by the formula (5)

1) Reaction of 4-tributylstannyl-6-nitro-2- (4-formylpiperazin-1-yl) -quinoline compound of formula 4 with NaI, phosphoric acid, dichloroamine T Introducing an iodine group at position 4 (step 1); And

2) acid-treating the compound obtained in step 1 to prepare 4-iodo-6-nitro-2-piperazin-1-yl-quinoline (step 2).

Of 6-nitro-2-piperazin-1-yl-4-vinylquinoline and 4- (2-furanyl) -6-nitro-2-piperazin-1-yl-quinoline, also represented by Scheme 3 below. It provides a manufacturing method.

In Scheme 3, R ³ is a vinyl group or 2-furanyl group.

6-nitro-2-piperazin-1-yl-4-vinylquinoline and 4- (2-furanyl) -6-nitro-2-piperazinylquinoline of Scheme 3

1) 4-bromo-6-nitro-2- (4-formylpiperazin-1-yl) -quinoline under a palladium catalyst to tributyl (vinyl) tin or tributyl (2-furanyl) tin and steel ( stille) reacting to introduce a vinyl or furanyl group at position 4 of quinoline (step 1); And

2) acid-treating the compound obtained in step 1 to 6-nitro-2-piperazin-1-yl-4-vinylquinoline or 4- (2-furanyl) -6-nitro-2-piperazinylquinoline Manufacturing step (step 2).

The steel reaction using the palladium metal catalyst is preferably reacted at a temperature range of 90 to 120 ° C. under a nitrogen atmosphere, and an aryl group, heteroaryl group or allyl group may be introduced in addition to the vinyl group and furanyl group.

2- (3-methylpiperazin-1-yl) -6-nitroquinoline, 2- (N-methyl-N- (2-N'-methylamino) ethylamino-6-, also represented by Scheme 4 below Methods for preparing nitroquinoline and 2- [1,4] diazepane-1-yl-6-nitroquinoline are provided.

R ¹ in Scheme 4 is 2-methylpiperazinyl, N-methyl-N- (2-N'-methylamino) ethylamine or diazepanyl group.

Compound of the present invention represented by the formula (9) is a 2-chloro-6-nitroquinoline compound is reacted with 2-methylpiperazine, N-methyl-N- (2-N'-methylamino) ethylamine or diazefan Product 2- (3-methylpiperazin-1-yl) -6-nitroquinoline, 2- (N-methyl-N- (2-N'-methylamino) ethylamino-6-nitroquinoline or 2- [ 1,4] diazefan-1-yl-6-nitroquinoline.

In another aspect, the present invention provides a pharmaceutical composition for the treatment of antidepressants, antipsychotic diseases or preventive agents containing a quinoline derivative of Formula 1 and a pharmaceutically acceptable salt thereof as an active ingredient.

As a result of measuring the physiological activity of SERT at 11 different concentrations after quilling the quinoline derivatives of the present invention represented by the formula (1) and pulverizing the brain tissue of the rat, most of the compounds of the present invention are currently commercialized for SERT The binding affinity (Ki) was significantly higher than that of fluorocetin, and similar to that of paroxetine. In particular, 4-chloro-6-nitro-2-piperazin-1-yl-quinoline showed a binding affinity 10 times better than 6-nitro-2-piperazin-1-yl-quinoline.

The compound of formula 1 may be administered in various oral and parenteral dosage forms during clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are commonly used, may be used. It is prepared. Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which solid preparations contain at least one excipient such as starch, calcium carbonate Sucrose (Sucrose) or lactose (Lactose), gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solution solutions, emulsion syrups, and the like, and may include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

The dosage of the active ingredient according to the present invention is appropriately selected according to the absorption of the active ingredient in the body, the rate of water activation and excretion, the age, sex and condition of the patient, and the severity of the disease to be treated, but in general, one day for adults The compound of formula 1 per kg of body weight can be administered once to several times in an amount of 0.1 to 500 mg, preferably 1 to 20 mg.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are illustrative of the present invention and the contents of the present invention are not limited by the examples.

Preparation Example 1 Preparation of 2-Chloro-3-methyl-6-nitroquinoline

(Step 1) Preparation of 3-methylhydrocarbostyryl

Hydrocarbostyril (1.00 g, 6.79 mmol) was dissolved in anhydrous THF (15 mL), 2 M LDA (Lithium diisopropylamide) (7.47 mL, 14.94 mmol) was added at -78 ° C, and stirred for an hour. . The solution was again cooled to -78 ° C, methane iodide (0.44 mL, 7.13 mmole) was added slowly and stirred for an hour while gradually raising the reaction temperature to room temperature. The reaction mixture was separated by column chromatography to give the title compound.

(Step 2) Preparation of 3-methyl-6-nitro-hydrocarbostyryl

The compound obtained in step 1 (586 mg, 3.64 mmol) was dissolved in concentrated sulfuric acid (10 mL), then concentrated nitric acid (0.30 mL, 4.00 mmol) was added slowly and stirred for 5 minutes, and then carefully poured into ice water. The resulting precipitate was filtered under reduced pressure, dissolved in ethyl acetate solution again, and then subjected to column chromatography to obtain a target compound.

(Step 3) Preparation of 2-chloro-3-methyl-6-nitroquinoline

Compound (586 mg, 2.84 mmol) obtained in step 2 and 1.1 equivalent (724 mg, 3.13 mmol) of DDQ (2,3-dichloro-5,6-dicyanobenzoquinone), an oxidizing agent, were added to DMF (N, N'-dimethylformamide) (15 mL) and POCl ₃ (phosphorus oxychloride) (0.41 mL, 4.26 mmol), a chlorination reagent, was slowly added at room temperature and stirred at room temperature for 1 hour. The reaction mixture was carefully poured ice water to form a precipitate, and the resulting precipitate was filtered under reduced pressure and dissolved in ethyl acetate solution again to obtain the target compound through column chromatography.

<Manufacture example 2-5>

In accordance with the method of Preparation Example 1 using ethane iodide, 1-propane iodide, 1-chloro-3-iodopropane, 1-bromo-3-fluoropropane or hydrogen iodide as a starting material Chloro-3-ethyl-6-nitroquinoline, 2-chloro-6-nitro-3-propylquinoline, 2-chloro-3- (3-chloropropyl) -6-nitroquinoline and 2-chloro-3- (3 -Fluoropropyl) -6-nitroquinoline The compound was prepared.

Preparation Example 6 Preparation of 2-Chloro-6-iodoquinoline

(Step 1) Preparation of 6-iodocarbostyryl

Hydrocarbostyryl (1.00 g, 6.79 mmol) was dissolved in acetic acid (10 mL), and then 1.1 eq (0.40 mL) of ICl (iodine monochloride) was slowly added at room temperature, followed by stirring for 30 minutes. The reaction mixture was poured into iced water to form a precipitate. The resulting precipitate was filtered and dried under reduced pressure, dissolved in ethyl acetate solvent and separated by column chromatography to obtain the title compound.

(Step 2) Preparation of 2-chloro-6-iodoquinoline

Chlorination was carried out according to the preparation method of Step 3 in Preparation Example 1 to obtain the target compound.

Preparation Example 7 Preparation of 6-Bromo-2-chloroquinoline

(Step 1) Preparation of 6-bromohydrocarbostyryl

Hydrocarbostyryl (1.00 g, 6.79 mmol) was dissolved in a mixed solvent of acetic acid (40 mL) and bromic acid (10 mL), and then NaBrO ₃ (366 mg, 2.38 mmol) was dissolved in 2 mL of water at room temperature and added dropwise. After stirring for 30 minutes. The reaction mixture was poured into iced water to form a precipitate. The resulting precipitate was filtered and dried under reduced pressure, dissolved in ethyl acetate solvent, and separated by column chromatography to obtain the target compound.

(Step 2) Preparation of 6-bromo-2-chloroquinoline

Chlorination was carried out according to the preparation method of Step 3 in Preparation Example 1 to obtain the target compound.

Preparation Example 8 Preparation of 2,6-dichloroquinoline

Except for using aqueous solution of hydrochloric acid and NaClO ₃ instead of aqueous bromic acid and NaBrO ₃ in step 1, it was carried out according to the preparation method of Preparation Example 7 to obtain the target compound.

Preparation Example 9 Preparation of 3-Bromo-2-chloro-6-nitroquinoline

(Step 1) Preparation of 2-hydroxy-6-nitroquinoline

2-chloro-6-nitroquinoline (2.22 g, 10.65 mmol) was dissolved in acetic acid (90 mL) and then heated to reflux for 10 hours. The reaction mixture was cooled to room temperature, poured into iced water to form a precipitate, and the resulting precipitate was washed several times with water and dried to obtain the target compound.

(Step 2) Preparation of 3-bromo-2-hydroxy-6-nitroquinoline

The compound obtained in step 1 was dissolved in 48% bromic acid (50 mL), and an aqueous NaBrO ₃ (790 mg, 5.23 mmol) solution (10 mL) was added dropwise and stirred at 100 ° C. for 3 hours. The reaction mixture was poured into iced water to form a precipitate. The resulting precipitate was filtered and dried under reduced pressure, dissolved in ethyl acetate solvent, and separated by column chromatography to obtain the target compound.

(Step 3) Preparation of 3-bromo-2-chloro-6-nitroquinoline

The compound (619 mg, 2.30 mmol) obtained in Step 2 the following chlorination reagent is POCl ₃ 3 equivalents (0.66 mL) were dissolved in DMF (50 mL) was added slowly and stirred at room temperature for 1 hour. The reaction mixture was carefully poured into iced water to form a precipitate. The resulting precipitate was filtered under reduced pressure, dissolved in ethyl acetate solution, and separated through column chromatography to obtain a target compound.

Preparation Example 10 Preparation of 2,4-dichloro-6-nitroquinoline

(Step 1) Preparation of 4-nitroaniline-N-ethylmalonate

4-nitroaniline (10.00 g, 72.40 mmol) was added to diethylmalonate (44 mL, 289.60 mmol), and the mixture was condensed at 150 ° C for 6 hours. The reaction mixture was extracted with ethyl acetate, distilled under reduced pressure and separated by column chromatography to obtain the title compound.

(Step 2) Preparation of 2,4-dihydroxy-6-nitroquinoline

The compound obtained in step 1 was dissolved in PPA (polyphosphoric acid) (100 g) and reacted at about 110 ° C. for 1 hour. The reaction mixture was carefully poured into iced water to form a precipitate. The resulting precipitate was filtered under reduced pressure, dissolved in ethyl acetate solution, and separated through column chromatography to obtain a target compound.

(Step 3) Preparation of 2,4-dichloro-6-nitroquinoline

The compound obtained in step 2 (2.00 g, 9.70 mmol) was dissolved in chlorination reagent POCl ₃ (phosphorus oxychloride) (40 mL) without using another solvent and stirred at room temperature for 1 hour. The remaining POCl ₃ was removed under reduced pressure, water was added thereto, the organic compound was extracted with an ethyl acetate solution, and then separated by column chromatography to obtain a target compound.

Preparation Example 11 Preparation of 2,4-Dibromo-6-nitroquinoline

2,4-Dihydroxy-6-nitroquinoline (4.00 g, 19.40 mmol) obtained in step 2 of Preparation Example 10 was dissolved in 1,4-dioxane (80 mL), and then brominated reagent POBr ₃ (phosphorus oxybromide) (16.69 g, 58.21 mmol) was added slowly and heated to reflux for about 6 hours. Ice water was carefully added to the reaction mixture, which was extracted with ethyl acetate and separated by column chromatography to obtain the title compound.

Preparation Example 12 Preparation of 4-tributylstannyl-6-nitro-2- (4-formylpiperazin-1-yl) -quinoline

(Step 1) Preparation of 4-bromo-6-nitro-2- (4-formylpiperazin-1-yl) -quinoline

2,4-Dibromo-6-nitroquinoline (7.33 g, 22.08 mmol) was dissolved in DMF (100 mL) and 1-piperazinecarboxaldehyde (6.70 mL, 55.20 mmol) was added and stirred at room temperature for 1 hour. . The reaction mixture was carefully poured into iced water, and the resulting precipitate was filtered under reduced pressure to obtain the target compound.

(Step 2) Preparation of 4-tributylstannyl-6-nitro-2- (4-formylpiperazin-1-yl) -quinoline 4

Under nitrogen atmosphere, the compound (3 g, 8.22 mmol) and tetrakis (triphenylphosphine) palladium (0) (190 mg, 0.16 mmol) obtained in step 1 were dissolved in dioxane (60 mL), followed by bistributyl Tin (4.81 mL, 9.04 mmol) is added dropwise at room temperature and the reaction mixture is heated to reflux for 3 hours, then cooled to room temperature and filtered through celite. Water and ammonia water were added to the mother liquor, followed by extraction with dichloromethane to obtain the target compound through a column chromatograph.

Preparation Example 13 Preparation of 2-Chloro-6-nitroquinoline

(Step 1) Preparation of 6-nitrohydrocarbostyryl

Hydrocarbostyryl (1.00 g, 6.79 mmol) was dissolved in concentrated sulfuric acid (20 mL) and 1.1 equivalent (0.56 mL) of concentrated nitric acid was added, followed by stirring at room temperature for 10 minutes. The reaction mixture was carefully poured into iced water to form a precipitate. The resulting precipitate was filtered under reduced pressure, dissolved in ethyl acetate solution, and separated through column chromatography to obtain a target compound.

(Step 2) Preparation of 2-chloro-6-nitroquinoline

Chlorination was carried out according to the method of Step 3 in Preparation Example 1 to obtain a target compound.

Example 1 Preparation of 3-methyl-6-nitro-2-piperazin-1-yl-quinoline

(Step 1) Preparation of 3-methyl-6-nitro-2- (4-formylpiperazin-1-yl) -quinoline

2-chloro-3-methyl-6-nitroquinoline (609 mg, 2.74 mmol) obtained in Preparation Example 1 was dissolved in DMF (30 mL), and 1-piperazinecarboxaldehyde (1.00 mL, 8.21 mmol) was added dropwise at room temperature. After stirring for 3 hours at 100 ℃. After cooling the reaction solution, water was added, and the produced precipitate was filtered, washed with water (50 mL), and dried under reduced pressure for 1 hour to obtain a solid product.

(Step 2) Preparation of 3-methyl-6-nitro-2-piperazin-1-yl-quinoline

The solid obtained in step 1 was dissolved in 4 M aqueous sulfuric acid solution (30 mL) and stirred at 80 ° C. for 3 hours. After cooling the reaction solution, water (50 mL) was added, the pH was adjusted to 12 by the addition of 4 N aqueous sodium hydroxide solution, and the resulting precipitate was filtered, washed with water (50 mL), dried under reduced pressure for 1 hour, and yellow. Solid product 3-methyl-6-nitro-2-piperazinyl-1-yl-quinoline (402 mg, 1.51 mmol, 55%) was obtained.

mp 164-166 ° C; ¹ H NMR (200 MHz, CDCl ₃ ) δ 8.55 (d, J = 1.8 Hz, 1H), 8.29 (dd, J = 9.2, 1.8 Hz, 1H), 7.87 (s, 1H), 7.83 (d, J = 10.2 Hz, 1H), 3.40-3.44 (m, 4H), 3.04-3.09 (m, 4H), 2.46 (s, 3H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ 161.5, 147.3, 141.6, 137.6, 126.5, 125.0, 122.0, 121.5, 120.5, 48.8, 44.4, 18.0; MS (CI) m / z 273 (M ⁺⁺ 1), 257, 243 (100), 173.

<Examples 2-5>

3-alkyl-2-chloro-6-nitroquinoline obtained in Production Examples 2 to 5 was the same product as in <Example 1>, and 3-alkyl-6-nitro-2-piperazin-1-yl-quinoline was used as a product. Compounds were obtained and the results of NMR analysis of the compounds are shown in Table 2 below.

Example compound Constellation Yield Analysis 2 3-ethyl-6-nitro-2-piperazin-1-yl-quinoline Yellow solid 66% mp 130-131 ° C .; ¹ H NMR (200 MHz, CDCl ₃ ) δ 8.60 (d, J = 2.6 Hz, 1H), 8.30 (dd, J = 9.2, 2.2 Hz, 1H), 7.94 (s, 1H), 7.85 (d, J = 9.2 Hz, 1H), 3.35-3.40 (m, 4H), 3.04-3.09 (m, 4H), 2.80 (q, J = 7.2 Hz, 2H), 1.61 (br s, 1H), 1.37 (t, J = 7.4 Hz, 3 H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ 161.6, 147.0, 141.6, 135.4, 131.3, 126.6, 122.4, 121.8, 120.5, 49.5, 44.4, 22.8, 12.3; MS (CI) m / z 287 (M ⁺⁺ 1), 271, 257 (100), 187. 3 6-nitro-2-piperazin-1-yl-3-propylquinoline Yellow solid 54% mp 140-141 ° C; ¹ H NMR (200 MHz, CDCl ₃ ) δ 8.58 (d, J = 2.4 Hz, 1H), 8.30 (dd, J = 9.1, 2.5 Hz, 1H), 7.92 (s, 1H), 7.84 (d, J = 9.2 Hz, 1H), 3.35-3.39 (m, 4H), 3.04-3.09 (m, 4H), 2.72 (t, J = 7.7 Hz, 2H), 1.72-1.83 (m, 2H), 1.67 (br s, 1H), 1.01 (t, J = 7.3 Hz, 3H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ 161.8, 147.1, 141.8, 136.0, 126.7, 122.3, 121.8, 120.5, 49.6, 44.4, 32.1, 21.4, 12.4; MS (CI) m / z 301 (M ⁺ +1), 285, 271 (100), 201. 4 3- (3-Chloropropyl) -6-nitro-2-piperazin-1-yl-quinoline Yellow solid 42% mp 132-133 ° C; ¹ H NMR (200 MHz, CDCl ₃ ) δ 8.58 (d, J = 2.6 Hz, 1H), 8.30 (dd, J = 9.2, 2.6 Hz, 1H), 7.93 (s, 1H), 7.85 (d, J = 9.2 Hz, 1H), 3.59 (t, J = 6.3 Hz, 2H), 3.34-3.41 (m, 4H), 3.05-3.10 (m, 4H), 2.91-2.99 (m, 2H), 2.17-2.24 (m , 2H), 1.98 (br s, 1H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ 161.6, 147.2, 142.0, 136.6, 128.5, 126.9, 122.3, 121.8, 120.8, 49.6, 44.3, 42.7, 30.7, 27.6. 5 3- (3-fluoropropyl) -6-nitro-2-piperazin-1-yl-quinoline Yellow solid 53% mp 136-138 ° C; ¹ H NMR (200 MHz, CDCl ₃ ) δ 8.58 (d, J = 2.4 Hz, 1H), 8.31 (dd, J = 9.2, 2.6 Hz, 1H), 7.93 (s, 1H), 7.85 (d, J = 9.2 Hz, 1H), 4.52 (dt, J = 47.4, 5.7 Hz, 2H), 3.35-3.40 (m, 4H), 3.05-3.10 (m, 4H), 2.92 (t, J = 7.9 Hz, 2H), 2.32 (br s, 1 H), 2.13 (dm, J = 26.0 Hz, 2H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ 161.6, 147.2, 141.9, 136.4, 128.8, 126.8, 122.3, 121.8, 120.8, 81.5 (d, J = 165 Hz), 49.5, 44.2, 28.8 (d, J = 20 Hz), 26.1. HRMS (FAB) m / z C ₁₆ H ₁₉ FN ₄ O ₂ (MH ⁺ ) calcd: 319.1578; found: 319.1574.

Example 6 Preparation of 6-iodo-2-piperazin-1-yl-quinoline

(Step 1) Preparation of 6-iodo-2- (4-formylpiperazin-1-yl) -quinoline

2-Chloro-6-iodoquinoline (1.591 g, 5.28 mmol) obtained in Preparation Example 6 was dissolved in DMF (20 mL), and 1-piperazinecarboxaldehyde (1.922 mL, 15,84 mmol) was added dropwise at room temperature. Then stirred at 110 ° C. for 10 hours. After cooling to room temperature, water was added, and the resulting precipitate was filtered, washed with water (50 mL), and dried under reduced pressure for 1 hour to obtain a solid product.

(Step 2) Preparation of 6-iodo-2-piperazin-1-yl-quinoline

The solid obtained in step 1 was dissolved in 4 M aqueous sulfuric acid solution and stirred at 100 ° C. for 2 hours 30 minutes. After cooling the reaction solution, water (50 mL) was added, the pH was adjusted to 12 with 4 N aqueous sodium hydroxide solution, and the resulting precipitate was filtered, washed with water (50 mL), and dried under reduced pressure for 1 hour to yellow. 6-iodo-2-piperazin-1-yl-quinoline (975 mg, 2.87 mmol, 54%) was obtained as a solid product.

Hydrochloric acid salts; ¹ H NMR (D ₂ O) δ 8.15 (d, J = 10.0 Hz, 1H), 8.12 (d, J = 1.8 Hz, 1H), 7.92 (dd, J = 8.7, 1.9 Hz, 1H), 7.46 (d , J = 8.8 Hz, 1H), 7.28 (d, J = 9.6 Hz, 1H), 4.05 (t, J = 5.3 Hz, 4H), 3.40 (t, J = 5.3 Hz, 4H); ¹³ C NMR (D ₂ O) δ 149.9, 140.8, 139.0, 134.4, 133.0, 120.5, 117.1, 110.3, 87.6, 41.7, 40.3.

Example 7 Preparation of 6-Bromo-2-piperazin-1-yl-quinoline

(Step 1) Preparation of 6-bromo-2- (4-formylpiperazin-1-yl) -quinoline

6-Bromo-2-chloroquinoline (1.130 g, 4.66 mmol) obtained in Preparation Example 7 was dissolved in DMF (40 mL), and 1-piperazinecarboxaldehyde (1.696 mL, 13.98 mmol) was added dropwise at room temperature, and then 110 Stir at 5 ° C. for 5 hours. After cooling to room temperature, water was added, and the resulting precipitate was filtered, washed with water (50 mL), and dried under reduced pressure for 1 hour to obtain a solid product.

(Step 2) Preparation of 6-bromo-2-piperazin-1-yl-quinoline

The solid obtained in step 1 was dissolved in 4 M aqueous sulfuric acid solution (30 mL) and stirred at 100 ° C. for 5 hours. After cooling the reaction solution, water (50 mL) was added, the pH was adjusted to 12 by the addition of 4 N aqueous sodium hydroxide solution, and the resulting precipitate was filtered, washed with water (50 mL), dried under reduced pressure for 1 hour, and yellow. A solid product, 6-bromo-2-piperazin-1-yl-quinoline (431 mg, 1.48 mmol, 32%) was obtained.

Hydrochloric acid salts; ¹ H NMR (D ₂ O) δ 8.22 (d, J = 10.0 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.79 (dd, J = 9.0, 2.0 Hz, 1H), 7.64 (d , J = 8.8 Hz, 1H), 7.35 (d, J = 9.8 Hz, 1H), 4.11 (t, J = 5.1 Hz, 4H), 3.47 (t, J = 5.1 Hz, 3H); ¹³ C NMR (D ₂ O) d 150.0, 140.9, 133.6, 132.8, 128.3, 120.4, 117.5, 116.3, 110.4, 41.5, 40.3.

Example 8 Preparation of 6-Chloro-2-piperazin-1-yl-quinoline

(Step 1) Preparation of 6-chloro-2- (4-formylpiperazin-1-yl) -quinoline

2,6-dichloroquinoline (752 mg, 3.80 mmol) obtained in Preparation Example 8 was dissolved in DMF (20 mL), and 1-piperazinecarboxaldehyde (1.383 mL, 11.40 mmol) was added dropwise at room temperature, followed by 10 at 110 ° C. Stir for hours. After cooling to room temperature, water was added, and the resulting precipitate was filtered, washed with water (50 mL), and dried under reduced pressure for 1 hour to obtain a solid product.

(Step 2) Preparation of 6-chloro-2-piperazin-1-yl-quinoline

The solid obtained in step 1 was dissolved in 4 M aqueous sulfuric acid solution (30 mL) and stirred at 100 ° C. for 5 hours. After cooling the reaction solution, water (50 mL) was added, the pH was adjusted to 12 by the addition of 4 N aqueous sodium hydroxide solution, and the resulting precipitate was filtered, washed with water (50 mL), dried under reduced pressure for 1 hour, and yellow. 6-chloro-2-piperazin-1-yl-quinoline (395 mg, 1.60 mmol, 42%) was obtained as a solid product.

Hydrochloric acid salts; ¹ H NMR (D ₂ O) δ 8.05 (d, J = 9.6 Hz, 1H), 7.49-7.59 (m, 3H), 7.17 (d, J = 9.2 Hz, 1H), 3.89 (br s, 4H), 3.26 (br s, 4 H); ¹³ C NMR (D ₂ O) d 149.6, 140.9, 132.0, 130.7, 128.4, 124.9, 119.7, 116.9, 110.1, 41.2, 39.9.

Example 9 Preparation of 3-Bromo-6-nitro-2-piperazin-1-yl-quinoline

(Step 1) Preparation of 3-bromo-6-nitro-2- (4-formylpiperazin-1-yl) -quinoline

3-bromo-2-chloro-6-nitroquinoline (1.0 g, 3.48 mmol) obtained in Preparation Example 9 was dissolved in DMF (30 mL), and 1-piperazinecarboxaldehyde (1.266 mL, 10.44 mmol) was added at room temperature. It was added dropwise and stirred at 130 ° C. for 4 hours. After cooling to room temperature, water was added, and the resulting precipitate was filtered, washed with water (50 mL), and dried under reduced pressure for 1 hour to obtain a solid product.

(Step 2) Preparation of 3-bromo-6-nitro-2-piperazin-1-yl-quinoline

The solid obtained in step 1 was dissolved in 4 M aqueous sulfuric acid solution (30 mL) and stirred at 100 ° C. for 5 hours. After cooling the reaction solution, water (50 mL) was added, the pH was adjusted to 12 by the addition of 4 N aqueous sodium hydroxide solution, and the resulting precipitate was filtered, washed with water (50 mL), dried under reduced pressure for 1 hour, and yellow. Solid product 3-bromo-6-nitro-2-piperazin-1-yl-quinoline (686 mg, 2.12 mmol, 61%) was obtained.

Hydrochloric acid salts; ¹ H NMR (D ₂ O) δ 8.28 (s, 1H), 8.26 (s, 1H), 8.10 (d, J = 9.4 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 3.63 (br s, 4H), 3.37 (br s, 4H); ¹³ C NMR (D ₂ O) δ 156.3, 149.7, 145.2, 141.2, 125.7, 121.7, 121.2, 121.0, 110.8, 44.2, 41.5.

Example 10 Preparation of 4-Chloro-6-nitro-2-piperazin-1-yl-quinoline

(Step 1) Preparation of 4-chloro-6-nitro-2- (4-formylpiperazin-1-yl) -quinoline

2,4-Dichloro-6-nitroquinoline (263 mg, 1.08 mmol) obtained in Preparation Example 10 was dissolved in DMF (20 mL), and 1-piperazinecarboxaldehyde (0.392 mL, 3.23 mmol) was added dropwise at room temperature. After stirring for 1 hour at room temperature, water was added, and the resulting precipitate was filtered, washed with water (50 mL), dissolved in dichloromethane, and then purified by column chromatography (5% methanol / dichloromethane) as an intermediate, 4-chloro-6. Nitro-2- (4-formylpiperazin-1-yl) -quinoline (191 mg, 0.60 mmol, 55%) was obtained.

(Step 2) Preparation of 4-chloro-6-nitro-2-piperazin-1-yl-quinoline

The yellow solid obtained in step 1 was dissolved in 4 M aqueous sulfuric acid solution (10 mL) and stirred at 60 ° C. for 24 hours. After cooling the reaction solution, water (10 mL) was added and the pH was adjusted to 12 by adding 4 N aqueous sodium hydroxide solution. The resulting precipitate was filtered, washed with water (20 mL), dried under reduced pressure for 1 hour, and yellow. A solid product, 4-chloro-6-nitro-2-piperazinyl-1-yl-quinoline (158 mg, 0.54 mmol, 90%) was obtained.

mp 175.2-177.0 ° C; ¹ H NMR (CDCl ₃ ) δ 8.89 (d, J = 2.6 Hz, 1H), 8.31 (dd, J = 9.5, 2.5 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.14 (s, 1H), 3.79 (t, J = 5.2 Hz, 4H), 3.00 (t, J = 5.1 Hz, 4H); ¹³ C NMR (CDCl ₃ ) δ 156.5, 150.2, 142.8, 140.7, 125.9, 122.7, 119.7, 118.0, 108.9, 44.4, 44.3; MS (CI) m / z (relative intensity) 293 (M ⁺⁺ 1, 7), 265 (29), 263 (100).

Example 11 Preparation of 4-Bromo-6-nitro-2-piperazin-1-yl-quinoline

A solution of piperazine (1.266 mL, 10.44 mmol) dissolved in 2,4-dibromo-6-nitroquinoline (700 mg, 2.11 mmol) obtained in Preparation Example 11 in DMF (15 mL) and dissolved in DMF (15 mL) was prepared. It was added dropwise at room temperature and then stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the resulting precipitate was filtered, washed with water (50 mL), and dried under reduced pressure for 6 hours to give 4-bromo-6-nitro-2-piperazin-1-yl- as a yellow solid product. Quinoline (508 mg, 1.39 mmol, 66%) was obtained.

_{^{1 H NMR (DMSO- d 6)}} δ 8.63 (d, J = 2.6 Hz, 1H), 8.26 (dd, J = 9.2, 2.6 Hz, 1H), 7.81 (s, 1H), 7.58 (d, J = 9.4 Hz, 1H), 3.76 (t, J = 5.0 Hz, 4H), 2.82 (t, J = 5.0 Hz, 4H); _{^{13 C NMR (DMSO- d 6)}} δ 156.8, 150.2, 140.4, 133.6, 126.3, 123.2, 121.8, 119.0, 114.3, 44.8, 44.6.

Example 12 Preparation of 4-iodo-6-nitro-2-piperazin-1-yl-quinoline

(Step 1) Preparation of 4-iodo-6-nitro-2- (4-formylpiperazin-1-yl) -quinoline

4-tributylstannyl-6-nitro-2- (4-formylpiperazin-1-yl) -quinoline (140 mg, 0.243 mmol) obtained in Preparation Example 12 was dissolved in ethanol (10 mL) and NaI (0.487 mL, 0.487 mmol) in water, 1 M phosphoric acid (0.243 mL, 0.243 mmol) and dichloroamine T (TCI, 58 mg, 0.243 mmol) were added, followed by stirring at room temperature for 20 minutes to form a precipitate. The reaction solution was distilled under reduced pressure to obtain a solid product.

(Step 2) Preparation of 4-iodo-6-nitro-2-piperazin-1-yl-quinoline

4 M sulfuric acid aqueous solution (10 mL) was added to the solid obtained in step 1, followed by stirring at 80 ° C. for 1 hour. After cooling the reaction solution, 15 mL of water was added thereto to adjust the pH to 12 by adding 4 N aqueous sodium hydroxide solution, and the resulting precipitate was filtered, washed with 50 mL of water, and dried under reduced pressure for 3 hours to obtain a yellow solid product. 4-iodo-6-nitro-2-piperazin-1-yl-quinoline (86 mg, 93%) was obtained.

_{^{1 H NMR (DMSO- d 6)}} δ 8.55 (d, J = 2.2 Hz, 1H), 8.20 (dd, J = 9.2, 2.6 Hz, 1H), 7.96 (s, 1H), 7.51 (d, J = 9.2 Hz, 1H), 3.82 (t, J = 4.8 Hz, 4H), 2.77 (t, J = 4.6 Hz, 4H); _{^{13 C NMR (DMSO- d 6)}} δ 156.4, 149.0, 141.1, 126.9, 126.6, 123.2, 122.1, 121.6, 113.6, 42.1, 41.3.

Example 13 Preparation of 6-Nitro-2-piperazin-1-yl-4-vinylquinoline

Under a nitrogen atmosphere, 4-bromo-6-nitro-2- (4-formylpiperazin-1-yl) -quinoline (200 mg, 0.5477 mmol) and tetrakis (triphenyl) obtained in Step 1 of Preparation Example 12 were obtained. Phosphine) palladium (0) (15 mg, 13 mmol) was dissolved in dioxane (5 mL), then tributyl (vinyl) tin (0.181 mL, 0.6024 mmol) was added dropwise at room temperature and the reaction mixture was stirred at 100 ° C. After heating for 30 minutes, it is cooled to room temperature and filtered through celite. Water and ammonia water were added to the mother liquor, followed by extraction with dichloromethane. A yellow solid 6-nitro-2-piperazin-2-yl-4-vinylquinoline (130 mg, 84%) was obtained through a column chromatograph.

¹ H NMR (CDCl ₃ ) δ 8.77 (d, J = 2.2 Hz, 1H), 8.29 (dd, J = 9.1, 2.5 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.28 (dd, J = 17.2, 11.0 Hz, 1H), 7.06 (s, 1H), 5.91 (d, J = 17.2 Hz, 1H), 5.68 (d, J = 11.0 Hz, 1H), 3.84 (t, J = 4.9 Hz, 4H), 3.02 (t, J = 4.9 Hz, 4H); ¹³ C NMR (CDCl ₃ ) δ 157.0, 150.2, 144.9, 130.6, 125.9, 122.2, 121.9, 119.7, 119.3, 118.2, 105.4, 44.4, 44.2.

Example 14 Preparation of 4- (2-furanyl) -6-nitro-2-piperazin-1-yl-quinoline

(Step 1) Preparation of 4- (2-furanyl) -6-nitro-2- (4-formyl-piperazin-1-yl) -quinoline

Under a nitrogen atmosphere, 4-bromo-6-nitro-2- (4-formylpiperazin-1-yl) -quinoline (300 mg, 0.82 mmol) obtained in step 1 of Preparation Example 12, CuI (15 mg, 0.08 mmol) and tributyl (2-furanyl) tin (587 mg, 1.64 mmol) in a solution of dioxane (7 mL) containing tetrakis (triphenylphosphine) palladium (0) (19 mg, 0.02 mmol). After dropwise addition at room temperature, the mixture was heated to reflux for 24 hours and then cooled to room temperature. 1% aqueous KF solution (10 mL) was added thereto, stirred at room temperature for 10 hours, and the resulting precipitate was filtered. Water and (10 mL) were added to the mother liquor, and the organic material was extracted with ethyl acetate. Separation by column chromatography gave 4- (2-furanyl) -6-nitro-2- (4-formylpiperazin-1-yl) -quinoline.

(Step 2) Preparation of 4- (2-furanyl) -6-nitro-2-piperazin-1-yl-quinoline

To the 4- (2-furanyl) -6-nitro-2- (4-formylpiperazin-1-yl) -quinoline of step 1 was added 4 M sulfuric acid aqueous solution (10 mL) and stirred at 70 ° C. for 10 hours. After cooling to room temperature. 15 mL of water was added and the pH was adjusted to 12 by addition of 4 N aqueous sodium hydroxide solution. The resulting precipitate was filtered, washed with 50 mL of water, and dried under reduced pressure for 3 hours to give 4- (2-fura) as a yellow solid. Nil) -6-nitro-2-piperazin-1-yl-quinoline (206 mg, 77%) was obtained.

¹ H NMR (CDCl ₃ ) δ 9.15 (d, J = 2.6 Hz, 1H), 8.31 (dd, J = 9.1, 2.5 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.25 (s, 1H), 6.98 (d, J = 3.4 Hz, 1H), 6.65 (dd, J = 3.6, 1.6 Hz, 1H), 3.86 (t, J = 4.9 Hz, 4H), 3.03 (t, J = 5.1 Hz, 4H), 1.71 (br s, 1H); ¹³ C NMR (CDCl ₃ ) δ 155.9, 150.0, 147.8, 141.7, 140.0, 136.0, 125.3, 121.1, 120.2, 112.2, 109.8, 109.7, 105.4, 43.7, 43.5.

Example 15 Preparation of 2- (3-methylpiperazin-1-yl) -6-nitro-quinoline

2-Chloro-6-nitroquinoline (500 mg, 2.40 mmol) obtained in Preparation Example 13 was dissolved in DMF (10 mL), and 2-methylpiperazine (721 mg, 7.20 mmol) was added dropwise at room temperature, and then at 70 ° C. Stir for 3 hours and cool to room temperature. The precipitate formed when water was added was filtered, washed with water (50 mL) and dried under reduced pressure for 3 hours to give a yellow solid, 2- (3-methylpiperazin-1-yl) -6-nitroquinoline (556 mg , 2.04 mmol, 85%).

¹ H NMR (CDCl ₃ ) δ 8.42 (d, J = 2.6 Hz, 1H), 8.20 (dd, J = 9.3, 1.9 Hz, 1H), 7.86 (d, J = 9.4 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 6.99 (d, J = 9.4 Hz, 1H), 4.45 (d, J = 11.2 Hz, 1H), 2.63-3.14 (m, 5H), 1.75 (br s, 1H), 1.35 (d, J = 6.0 Hz, 3H); ¹³ C NMR (CDC _l3 ) δ 156.81, 149.9, 140.1, 136.9, 125.3, 122.6, 121.9, 119.3, 109.2, 50.2, 48.9, 44.1, 43.4, 17.9.

Example 16 Preparation of 2- (N-methyl-N- (2-N'-methylamino) ethyl) amino-6-nitroquinoline

2-chloro-6-nitroquinoline (500 mg, 2.40 mmol) was dissolved in DMF (10 mL) and N, N'-dimethylethane-1,2-diamine (635 mg, 7.20 mmol) was added dropwise at room temperature. Stir for 5 hours at 100 ℃ and cooled to room temperature. The precipitate formed when water was added was filtered, washed with water (50 mL) and dried under reduced pressure for 3 hours to give a yellow solid. 2- (N-methyl-N- (2-N'-methylamino) ethylamino-6-nitroquinoline (487 mg, 1.87 mmol, 78%) was obtained.

Hydrochloric acid salts; ¹ H NMR (D ₂ O) δ 8.66 (d, J = 2.4 Hz, 1H), 8.33-8.42 (m, 2H), 7.91 (d, J = 9.2 Hz, 1H), 7.34 (d, J = 8.0 Hz , 1H), 4.08 (t, J = 6.9 Hz, 2H), 3.24-3.38 (m, 5H), 2.68 (s, 3H). 13 C NMR (D ₂ O) δ 153.2, 143.5, 143.2, 139.5, 126.2, 124.3, 119.9, 118.6, 112.6, 47.9, 44.6, 38.1, 32.7.

Example 17 Preparation of 2- [1,4] diazepane-1-yl-6-nitroquinoline

2-chloro-6-nitroquinoline (500 mg, 2.40 mmol) was dissolved in DMF (10 mL) and diazepan (894 mg, 7.20 mmol) was added dropwise at room temperature, then stirred at 80 ° C. for 5 hours and cooled to room temperature. I was. The precipitate formed when water was added was filtered, washed with water (50 mL) and dried under reduced pressure for 3 hours to give 2- [1,4] diazepane-1-yl-6-nitroquinoline (602 mg) as a yellow solid. , 2.21 mmol, 92%).

¹ H NMR (CDCl ₃ ) δ 8.52 (d, J = 2.6 Hz, 1H), 8.27 (dd, J = 9.3, 2.7 Hz, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.62 (d, 9.4 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H), 3.87-3.93 (m, 4H), 3.11 (t, J = 5.3 Hz, 2H), 2.89 (t, J = 5.9 Hz, 2H) , 2.22 (br s, 1 H), 1.91-2.03 (m, 2 H); _{^{13 C NMR (DMSO- d 6)}} δ 157.1, 150.5, 139.4, 137.7, 125.4, 123.6, 122.2, 119.7, 46.92, 46.03, 45.41, 37.2, 27.5.

Preparation Example 1 Manufacturing Method of Syrup

A syrup containing the quinoline derivative of the present invention and a pharmaceutically acceptable salt thereof as an active ingredient of 2% (weight / volume) is prepared by the following method.

Acid addition salts, saccharin and sugars of the quinoline derivatives were dissolved in 80 g of warm water. After the solution was cooled, a solution consisting of glycerin, saccharin, spices, ethanol, sorbic acid and distilled water was prepared and mixed thereto. Water was added to this mixture to 100 mL. The addition salt can be replaced with other salts according to the examples.

The components of the syrup are as follows.

4-Chloro-6-nitro-2-piperazin-1-yl-quinolin hydrochloride 2 g

Saccharin 0.8 g

25.4 g of sugar

Glycerin ... 8.0 g

Spices ··················· 0.04 g

Ethanol 4.0 g

0.4 g of sorbic acid

Distilled water ·····················

Preparation Example 2 Preparation of Tablet

A tablet containing 15 mg of active ingredient is prepared by the following method.

250 g of 4-chloro-6-nitro-2-piperazin-1-yl-quinoline hydrochloride were mixed with 175.9 g of lactose, 180 g of potato starch, and 32 g of colloidal silicic acid. 10% gelatin solution was added to the mixture, which was then ground and passed through a 14 mesh sieve. It was dried and the mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into a tablet.

The components of the tablet are as follows.

4-Chloro-6-nitro-2-piperazin-1-yl-quinoline hydrochloride 250 g

Lactose ......... 175.9 g

Potato starch ··············· 180 g

Colloidal silicic acid 32 g

10% gelatin solution

Potato starch ... 160 g

Talc · 50 g

Magnesium stearate 5 g

Preparation Example 3 Manufacturing Method of Injection Solution

Injection solution containing 10 mg of the active ingredient was prepared by the following method.

4-Chloro-6-nitro-2-piperazin-1-yl-quinoline hydrochloride One g, 0.6 g sodium chloride and 0.1 g ascorbic acid were dissolved in distilled water to make 100 ml. The solution was bottled and sterilized by heating at 20 ° C. for 30 minutes.

The components of the injection solution are as follows.

4-chloro-6-nitro-2-piperazin-1-yl-quinoline hydrochloride ... 1 g

Sodium Chloride ... 0.6 g

Ascorbic acid ・ ・ ・ 0.1 g

Distilled water ······················

Preparation Example 1 Preparation of Synaptic Membrane

The male Sprague Dawley Rat (250-350 g) was guillotined (quillotine), carefully cut off the cerebral cortex on ice, weighed, and weighed about 0.32 M in 10-fold tissue weight. Cross was added and homogenized twice with Polytron twice every 15 seconds. After centrifugation at 1,000 g at 4 ° C for 10 minutes, the supernatant was taken and centrifuged again at 20,000 g for 20 minutes. The precipitate was separated and then resuspended by addition of deionized water, followed by an osmotic shock for 10 minutes, which was centrifuged at 8,000 g for 20 minutes at high speed. After resuspending the precipitate with 50 mM Tri-acetate buffer, the precipitate obtained by ultra-fast centrifugation at 48,000 g was taken out and dissolved immediately before binding assay. 48,000 g The precipitate was washed by ultrafast centrifugation for 20 minutes. The final synaptic membrane fragment was allowed to have a protein concentration of about 1.5 mg / mL.

Experimental Example 1 Measurement of Bioactivity

In order to measure the binding force of the quinoline compounds of the present invention to serotonin transporter (SERT), the following experiment was conducted.

The radioligand used in the binding assay was [ ³ H] citalopram (1 nM) and the final reaction volume was 0.6 mL in 50 mM Tris HCl buffer (pH 7.4 at 25 ° C). Ligand, a synaptic membrane prepared in Preparation Example 1, and the test drug were added by 200 μL per concentration. After incubation for 60 minutes at 25 ℃ shaken using a Brandel cell harvester (Brandel cell harvester) was filtered with Whatman GF / B filter pre-soaked in 0.05% polyethylenimine (polyethylenimine). Wash twice with 5 mL ice cold buffer, dry the filter, add 7 mL Ultima Gold scintillation cocktail, shake for 3-4 hours, and liquid scintillation counter ), Radioactivity was measured. 30 μM Fluoxetine was used to measure nonspecific binding, and the concentration of [ ³ H] citalopram was measured at 15 concentrations in the range of 0.01 to 30 nM to measure saturation binding. The experiment was conducted.

The binding affinity (Ki) of the compounds of the present invention with serotonin carriers was calculated from the following equation. Where [F] is the free radioligand concentration and K _d is the affinity of the radioligand for the serotonin transporter. The equilibrium-saturation experiment was measured by Scatchard analysis, and the K _d value of [ ³ H] citalopram was 1.12 nM. IC ₅₀ and Kd were calculated using a prism computer program, and the results are shown in Table 3 below.

Ki50d

Binding affinity for serotonin transporter (SERT) (K _i ) compound Ki (nM) Example 1 8.45 ± 0.62 Example 2 0.36 ± 0.02 Example 3 0.26 ± 0.01 Example 4 1.08 ± 0.17 Example 5 0.32 ± 0.01 Example 6 6.60 ± 0.52 Example 7 0.91 ± 0.07 Example 8 1.68 ± 0.13 Example 9 12.62 ± 1.14 Example 10 0.017 ± 0.05 Example 11 - Example 12 - Example 13 1.42 Example 14 6.4 Example 15 22.19 ± 1.70 Example 16 8.43 ± 0.45 Example 17 1.90 ± 0.15 Fluoxetine 22.13 ± 1.77 Paroxetine 0.53 ± 0.08 6-nitro-2-piperazin-1-yl-quinoline 0.17 ± 0.03

TABLE 3As shown in FIG. 3, most of the compounds obtained in the present invention showed a superior binding affinity (Ki) than the currently best-selling antidepressant, Fluoxetine (Prozac), and 3-ethyl-6-nitro-2-pipe. Razin-1-yl-quinoline (Example 2), 6-nitro-2-piperazin-1-yl-3-propylquinoline (Example 3), 3- (3-fluoropropyl) -6-nitro- The Ki value of 2-piperazin-1-yl-quinoline (Example 5) surpassed fluorocetin. Especially 4-chloro-6-nitro-2-piperazin-1-yl-quinoline In Example 10, the Ki value was 0.017 nM on average, and showed 10 times better bioactivity than 6-nitro-2-piperazin-1-yl-quinoline, which is one of the compounds acting on serotonin transporters known to date. It is the best thing.

Experimental Example 2 Parenteral Administration Acute Toxicity in Rats

On the other hand, the following experiment was carried out to determine the acute toxicity of the compound of Formula 1.

Acute toxicity test was performed using 6-week-old SPF SD rats. The compounds of Examples 2, 3, 5 and 10 were each suspended in 1 ml of saline solution and injected intramuscularly into the anterior tibialis of the two rats at a dose of 1 mg / kg. After administration of the test substance, mortality, clinical symptoms, and changes in body weight were observed. Hematological and hematological examinations were performed. Necropsy was performed to observe abdominal and thoracic organ abnormalities. As a result, there were no clinical symptoms or deaths in all animals treated with the test substance, and no toxicity change was observed in weight change, blood test, blood biochemistry test, autopsy findings, etc. As a result, the compound of Formula 1 did not show a toxic change in rats up to 1 mg / kg and the parenteral administration minimum dose (LD ₅₀ ) was determined to be a safe substance of 1 mg / kg or more.

As described in detail above, the quinoline derivatives of the present invention represented by the general formula (1) have an excellent binding affinity for serotonin transporters, and thus are very useful as a therapeutic and preventive agent for mental disorders related to serotonin, especially depression. In addition, the production method of the present invention has the advantage that can be easily prepared a novel quinoline derivative of formula (1).

Claims (5)

A quinoline derivative represented by the following formula (1) and a pharmaceutically acceptable salt thereof. Formula 1 In Chemical Formula 1, 1) R ¹ is piperazinyl, 2-methylpiperazinyl, diazepanyl or N-methyl-N- (2-N'-methylamino) ethylamine group, R ² is hydrogen, a halogen atom, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl group, R ³ is a halogen atom, vinyl or furanyl group, R ⁴ is a nitro group; 2) R ¹ is piperazinyl, 2-methylpiperazinyl, diazepanyl or N-methyl-N- (2-N'-methylamino) ethylamine group, R ² is hydrogen, a halogen atom, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl group, R ³ is hydrogen, a halogen atom, a vinyl or a furanyl group, R ⁴ is selected from the group consisting of halogen atoms. The compound of claim 1, wherein 1) R ¹ is 2-methylpiperazinyl, diazepanyl or N-methyl-N- (2-N'-methylamino) ethylamine group, R ² is hydrogen, bromine, methyl, ethyl, propyl, chloropropyl or fluoropropyl group, R ³ is a chlorine, bromine, iodine, vinyl or 2-furanyl group, R ⁴ is a nitro group; 2) R ¹ is a 2-methylpiperazinyl, diazepanyl or N-methyl-N- (2-N'-methylamino) ethylamine group, R ² is hydrogen, bromine, methyl, ethyl, propyl, chloropropyl or fluoropropyl group, R ³ is hydrogen, chlorine, bromine, iodine, vinyl or 2-furanyl group, R ⁴ is a quinoline derivative and a pharmaceutically acceptable salt thereof, wherein the quinoline derivative is selected from the group consisting of chlorine, bromine or iodine. According to claim 1, wherein the quinoline derivative represented by the formula (1) 6-iodo-2-piperazin-1-yl-quinoline, 6-bromo-2-piperazin-1-yl-quinoline, 6-chloro-2-piperazin-1-yl-quinoline, 4-chloro-6-nitro-2-piperazin-1-yl-quinoline, 4-bromo-6-nitro-2-piperazin-1-yl-quinoline, 4-iodo-6-nitro-2-piperazin-1-yl-quinoline, 6-nitro-2-piperazin-1-yl-4-vinylquinoline, 4- (2-furanyl) -6-nitro-2-piperazin-1-yl-quinoline, 2- (3-methylpiperazin-1-yl) -6-nitroquinoline, 2- (N-methyl-N- (2-N'-methylamino) ethyl) amino-6-nitroquinoline and A quinoline derivative and a pharmaceutically acceptable salt thereof, wherein the quinoline derivative is selected from the group consisting of 2- [1,4] diazepane-1-yl-6-nitroquinoline. A method for preparing a compound represented by the formula (3), wherein the quinoline compound represented by the formula (2) is substituted with piperazine to introduce a piperazinyl group at position 2 of the quinoline compound. Scheme 1 In Reaction Scheme 1, 1) R ² is hydrogen, bromine, methyl, ethyl, propyl, chloropropyl or fluoropropyl group, R ³ is chlorine or bromine atom, R ⁴ is nitro group; 2) R ² is a propyl, chloropropyl or fluoropropyl group, R ³ is a hydrogen, chlorine or bromine atom, and R ⁴ is a nitro group; And 3) R ² is hydrogen, bromine, methyl, ethyl, propyl, chloropropyl or fluoropropyl group, R ³ is hydrogen, chlorine or bromine atom, R ⁴ is selected from the group consisting of chlorine, bromine or iodine . A pharmaceutical composition for treating mental disorders and depression related to serotonin, comprising the quinoline derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.