KR101426408B1 - 4-membered cyclic nitrogen compounds, pharmaceutical composition for treatment or prevention of depression, mental disease, premature ejaculation, or neuropathic pain comprising the same, and medicine comprising the same - Google Patents

Abstract

The present invention relates to a 4-membered cyclic nitrogen compound which can be used as a therapeutic agent or a preventive agent for depression, mental disease, premature ejaculation, or neuropathic pain by preventing re-uptake of certain neurotransmitters with high efficiency; a pharmaceutical composition which can inhibit serotonin and dopamine or norepinephrine re-uptake and has a high therapeutic or prophylactic effect against depression, mental disease, premature ejaculation, or neuropathic pain; and a pharmaceutical formulation comprising the same.

Description

(4-MEMBERED CYCLIC NITROGEN COMPOUNDS, PHARMACEUTICAL COMPOSITION FOR TREATMENT OR), and a pharmaceutical composition for the prevention or treatment of depression, mental illness, premature ejaculation, or neuropathic pain, PREVENTION OF DEPRESSION, MENTAL DISEASE, PREMATURE EJACULATION, OR NEUROPATHIC PAIN COMPRISING THE SAME, AND MEDICINE COMPRISING THE SAME}

The present invention relates to a quaternary ring nitrogen compound, a pharmaceutical composition containing the same, and a preparation containing the pharmaceutical composition. More particularly, the present invention relates to a pharmaceutical composition containing the quaternary ring nitrogen compound, A novel quadruplet ring nitrogen compound which can be used as a therapeutic or prophylactic agent for mental illness, premature ejaculation, or neuropathic pain, a high therapeutic effect or prevention against depression, certain mental disorders, premature ejaculation, or neuropathic pain And to pharmaceutical preparations comprising such pharmaceutical compositions.

Depression, or depressive disorder, is defined as a condition in which depression and depression are the main symptoms, resulting in various cognitive and psychosomatic symptoms resulting in deterioration of daily function. Depressive disorder has a lifetime prevalence of 15%, especially 25% in women, and is a serious disease that causes changes in feelings, thoughts, physical condition, and behavior.

Major depression does not occur as a cause. Rather, various types of gene interactions, epigenetic effects, embryologic causes, and environmental influences compromise emotions and cause emotional disturbances.

Typical drugs used to treat other major psychiatric or neurological diseases are efficacious through a variety of neuronal mechanisms distributed throughout much of the brain. Similarly, pharmacological, anatomical, and neuropsychological approaches to alleviate depression can not be made to show efficacy through any one mechanism.

The development of modern antidepressants has been active since the proven efficacy of iproniazide as a monoamine oxidase inhibitor (MAOIs), an anti-depressant drug developed by the TB drug. The antipsychotic drug, chlorpromazine, was developed as a 1950s antihistamine and proved effective in the treatment of schizophrenia. Similarly, in 1955, Geigy Drug Co., Switzerland, activated imipramine, an antihistamine drug. This finding has led to the development of tricyclic antidepressants (TCAs) and many additional TCAs such as nortriptyline, doxepin, and clomipramine have begun to be used in addition to amitriptyline or desipramine, which has modified the trichome structure.

Since then, second- and third-generation antidepressants have been developed. In the early 1980s, tetracyclic compounds such as maprotiline and amoxapine, which are similar in structure and efficacy, have been marketed and are sometimes referred to as heterocyclics.

In the 1980s, prozac, a selective serotonin reuptake inhibitors (SSRIs), has been developed and used as a good therapeutic agent. However, anticholinergic actions such as gonorrhea, constipation, dysuria, visual disturbance, , It has been reported that the effect on blood pressure, pulse, and cardiac conduction, and orthostatic hypotension due to blocking of 1-adrenergic receptor, and sedation by antihistamine effect are reported.

Currently used antidepressant drugs include selective serotonin reuptake blockers, serotonin norepinephrine reuptake blockers, selective norepinephrine reuptake blockers, dopamine and norepinephrine reuptake blockers (DNRIs), naepinephrine and serotonin receptor antagonists (NaSSA), serotonin Receptor antagonists, serotonin reuptake inhibitors (SARIs), and selective serotonin reuptake enhancers (SSREs).

The currently used antidepressant drug has a low remission rate, and thus the present drug can not obtain a sufficient therapeutic effect and it is expected that the depressant market will be reduced in the future. In order to overcome this problem, it is necessary to develop a new therapeutic agent that overcomes the current low remission rate.

In addition, as depression is caused by various causes, it is necessary to administer several kinds of drugs together to suppress the reabsorption of various neurotransmitters. However, since the drug is unnecessarily consumed or administered, In addition to typical side effects such as weight gain, unexpected side effects are occurring.

Therefore, it is necessary to develop new antidepressants that can effectively suppress the reabsorption of various neurotransmitters, minimize such side effects, and exhibit high efficacy in the prevention or treatment of depression or mental disorders.

On the other hand, among the serotonin reuptake inhibitors which have a therapeutic or preventive effect on depression or mental disorders, the compounds having the characteristic of acting for a short period of time are effective for treating premature ejaculation, and the compounds capable of inhibiting the reuptake of serotonin and norepinephrine are strong It can be used as a neuropathic analgesic agent, and it is known that the analgesic effect is greater and the side effect is less than that of the tricyclic compound.

That is, the compounds capable of inhibiting the reuptake of serotonin and norepinephrine or dopamine, which are synaptic neurotransmitters, and the pharmaceutical compositions containing the same, are useful not only for depression, bipolar disorder and mental disorders, but also for other diseases such as neuropathic pain, It is possible to expand the market for antidepressants by research and development through related research.

The present invention provides a quaternary ring nitrogen compound that can be used as a therapeutic or preventive agent for depression, certain psychiatric disorders, premature ejaculation, or neuropathic pain by preventing the reabsorption of certain neurotransmitters with high efficiency .

The present invention also provides a pharmaceutical composition capable of effectively inhibiting the reabsorption of neurotransmitters such as serotonin, which has a high therapeutic effect or preventive effect on depression, certain psychiatric disorders, premature ejaculation, or neuropathic pain will be.

The present invention also provides a pharmaceutical composition comprising the above pharmaceutical composition.

The present invention provides novel quaternary ring nitrogen compounds of the general formula (1).

[Chemical Formula 1]

Wherein R ₁ is a straight or branched chain alkyl having 1 to 10 carbon atoms; Cycloalkyl having 3 to 10 carbon atoms; An aryl group having 6 to 20 carbon atoms in which at least one functional group selected from the group consisting of a halogen, an alkoxy group and an alkyl group having 1 to 5 carbon atoms is substituted or unsubstituted; An arylalkyl group having 7 to 20 carbon atoms; And an aromatic heterocycle having 6 to 20 carbon atoms and containing at least one element selected from the group consisting of nitrogen, oxygen and sulfur, R ₂ is a halogen, an alkoxy group, An aryl group having 6 to 20 carbon atoms in which at least one functional group selected from the group consisting of an alkyl group having 1 to 20 carbon atoms is substituted or unsubstituted; And n is an integer of 1 to 5. [

The present invention also provides a pharmaceutical composition comprising the tetravalent nitrogen compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides an agent for the prevention or treatment of depression, mental illness, premature ejaculation, or neuropathic pain comprising the above pharmaceutical composition.

The present invention will now be described in more detail with reference to a pharmaceutical composition for quadricepsin nitrogen compound according to a specific embodiment of the present invention and an agent for the prevention or treatment of depression, mental illness, premature ejaculation, or neuropathic pain.

According to one embodiment of the present invention, tetrahedral ring nitrogen compounds of the above formula (1) may be provided.

The present inventors have newly synthesized quaternary ring nitrogen compounds having the above specific structure. These quaternary ring nitrogen compounds effectively prevent the reabsorption of specific neurotransmitters at high efficiency, and are useful as agents for preventing depression, mental diseases, premature ejaculation, The present inventors have confirmed through experimentation that the compound can be used as a therapeutic or prophylactic agent for sexual pain and have a high therapeutic or preventive effect on depression, mental disease, premature ejaculation, or neuropathic pain.

In particular, the quaternary nitrogen compound of formula (1) is superior in the effect of suppressing re-absorption of serotonin, which is a neurotransmitter, and can exert a high effect in preventing or treating depression, mental illness, premature ejaculation, or neuropathic pain. In addition, the compound additionally exhibits an effect of inhibiting re-absorption of dopamine or neophenephrine, which is another neurotransmitter, to be more effective in preventing or treating depression, mental disorders, premature ejaculation, or neuropathic pain, And the side effects caused by an increase in the usage amount can be reduced.

In the formula 1, wherein R ₁ is alkyl of straight or branched chain having 1 to 10 carbon atoms; Cycloalkyl having 3 to 10 carbon atoms; An aryl group having 6 to 20 carbon atoms in which at least one functional group selected from the group consisting of a halogen, an alkoxy group and an alkyl group having 1 to 5 carbon atoms is substituted or unsubstituted; An arylalkyl group having 7 to 20 carbon atoms; Or an aromatic heterocycle having 6 to 20 carbon atoms and containing at least one element selected from the group consisting of nitrogen, oxygen and sulfur, and R ₂ is a group selected from the group consisting of a halogen, an alkoxy group and an alkyl group having 1 to 5 carbon atoms An aryl group having 6 to 20 carbon atoms in which at least one functional group is substituted or unsubstituted; And n may be an integer of 1 to 5.

The alkoxy group means a monovalent functional group derived from an alkyl group bonded with oxygen, and specific examples thereof include a methoxy group, an ethoxy group, and a phenoxy group, and the aryl group is a monovalent functional group derived from arene . Also, the arylalkyl group means an alkyl group substituted with an aryl group.

Preferably, the alkoxy group may be a phenoxy group, and the arylalkyl group may be a benzyl group. The aryl group may be a phenyl group or a naphthyl group, and the aromatic heterocycle having 6 to 20 carbon atoms and containing at least one element selected from the group consisting of nitrogen, oxygen and sulfur may be benzothiazole.

R < ₁ > is cycloalkyl having 3 to 10 carbon atoms; Phenyl substituted with one or more functional groups selected from the group consisting of halogen, a straight or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group; Benzyl, which is substituted or unsubstituted with at least one functional group selected from the group consisting of halogen, a straight or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group; Naphthyl which is substituted or unsubstituted by at least one functional group selected from the group consisting of halogen, a straight or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group; Benzothiazole in which at least one functional group selected from the group consisting of halogen, a straight or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group is substituted or unsubstituted; Lt; / RTI > Specific examples of the halogen include F, Cl, Br, I and the like.

And R ₂ is phenyl, which is substituted with one or more functional groups selected from the group consisting of halogen, a straight or branched alkyl group having 1 to 10 carbon atoms, and an alkoxy group having 1 to 10 carbon atoms; Or naphthyl substituted with one or more functional groups selected from the group consisting of halogen, a straight or branched alkyl group having 1 to 10 carbon atoms, and an alkoxy group having 1 to 10 carbon atoms; Lt; / RTI > Specific examples of the halogen include F, Cl, Br and I.

R2 is a naphthyl group; Or phenyl substituted with halogen, a straight or branched alkyl group having 1 to 10 carbon atoms, or an alkoxy group having 1 to 10 carbon atoms, is preferable because it can prevent the reabsorption of a specific neurotransmitter with high efficiency, And more preferably a phenyl group or a naphthyl group substituted with a halogen when it is a benzyl group.

Meanwhile, the tetravalent ring nitrogen compound of Formula 1 can be synthesized through the process as shown in Reaction Scheme 1 below. However, the following Reaction Scheme 1 shows an example of a method for synthesizing tetrahedral ring nitrogen compounds of Formula 1, and the method for synthesizing the tetra-ring nitrogen compounds of one embodiment of the present invention is not limited thereto.

[Reaction Scheme 1]

As shown in Reaction Scheme 1, the compound of Formula 3 can be obtained by reductive amination of the primary amine (R ₁ NH ₂ ) to N-Boc-3-azetidinone of Formula 2 . The reductive amination can be carried out according to the method (i) or (ii) described later. According to the method (i), a primary amine (R ₁ NH ₂ ) and sodium triacetoxyborohydride are added to N-Boc-3-azetidinone of formula (2) , The N-Boc-3-azetidinone of formula ( ₂ ) and the primary amine (R ₁ NH ₂ ) are heated in an organic solvent, and the reaction mixture is distilled under reduced pressure to remove the solvent and the generated water. lt; RTI ID = 0.0 > borohydride. < / RTI >

The compound of formula (4) can be synthesized from the compound of formula (3) prepared by the above method (i) or (ii) by the following two reaction routes. According to the reaction path A, an intermediate of formula (3) and R ₂ CH ₂ X (wherein X is a halogen, a mesyl, a silyl group, A leaving group such as an aldehyde group) can be reacted to obtain a compound of the formula (4). According to reaction path B, the compound of formula (IV) can be obtained by reductive amination of the intermediate compound of formula (3) and R ₂ CHO. That is, in an organic solvent, the intermediate compound of formula (3) can be reacted with R ₂ CHO, sodium triacetoxyborohydride, and an acid to obtain a compound of formula (4).

In the formula (4) synthesized by the reaction pathway A or B, a novel quaternary ring nitrogen compound derivative represented by the general formula (1) can be obtained by deblocking the protecting group Boc. More specifically, the compound of formula (IV) dissolved in an organic solvent is stirred at room temperature in the presence of an acid to produce a quaternary ring nitrogen compound derivative of formula (I). At this time, when a salt of a tetrahedral ring nitrogen compound derivative of the formula (1) is produced, it can be treated with saturated sodium bicarbonate or caustic soda water to obtain a tetrahedral ring nitrogen compound derivative of the formula (1).

The compound usable as the acid is not particularly limited, and inorganic or organic acids such as acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid or para-toluenesulfonic acid can be used. In addition, specific examples of the organic solvent are not limited, and inert organic solvents such as methylene chloride, chloroform, ethyl acetate, tetrahydrofuran, benzene, toluene, DMF and DMSO can be used. As the alcohols, aliphatic alcohols having 1 to 5 carbon atoms can be used.

In the above Reaction Scheme 1, R ₁ to R ₃ denote the functional groups bonded to the respective compounds, and may be different from those defined in Formula 1.

According to another embodiment of the present invention, there can be provided a pharmaceutical composition comprising, as an active ingredient, a quaternary ring nitrogen compound of the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof.

As described above, the present inventors newly synthesized quaternary ring nitrogen compounds of the above formula (1). Using these quaternary nitrogen compounds can prevent the reabsorption of specific neurotransmitters with high efficiency, It can be used as a therapeutic or prophylactic agent for dyspareunia, premature ejaculation, neuropathic pain, and can provide a pharmaceutical composition.

The pharmaceutical composition may contain a quaternary ring nitrogen compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. Such a pharmaceutically acceptable salt thereof includes salts of pharmaceutically acceptable organic acids, and specifically includes salts of organic acids such as oxalic acid, benzenesulfonic acid, camphorsulfonic acid, cinnamic acid, adipic acid, cyclamic acid, hydrochloric acid, methanesulfonic acid, bromine And salts of organic acids such as acetic acid, acetic acid, fumaric acid, sulfuric acid, succinic acid, citric acid, phosphoric acid, maleic acid, nitric acid, tartaric acid, benzoic acid or carbonic acid.

In particular, the quaternary ring nitrogen compound of formula (1) or its pharmaceutically acceptable salt is excellent in the effect of suppressing re-absorption of serotonin, which is a neurotransmitter, and the pharmaceutical composition containing it as an active ingredient is useful as a therapeutic agent for depression, Can be highly effective in preventing or treating neuropathic pain. In addition, since the compound further exhibits an effect of inhibiting re-absorption of dopamine or neophenephrine, which is another neurotransmitter, the pharmaceutical composition comprising the compound of Formula 1 as an active ingredient has a side effect And can more effectively prevent or treat depression or mental illness.

As described above, the pharmaceutical composition can be used for the prevention or treatment of depression, mental illness, premature ejaculation, or neuropathic pain. The mental disorder may be a neuropathic pain, a bipolar disorder, a schizophrenia, a mood disorder, a sleep disorder, an anxiety disorder, an ADHD or an eating disorder, Or pain caused by a primary lesion or a change in nerve function.

Meanwhile, the pharmaceutical composition may further comprise other medicines, a pharmacologically acceptable carrier or excipient. The pharmacologically acceptable carrier or excipient may be suitably adjusted according to the formulation to which the pharmaceutical composition is applied and may be a carrier or a carrier known to be routinely usable in the prophylactic or therapeutic agent for depression, mental illness, premature ejaculation, The excipient can be used without any limit. Examples of the excipient include a common diluent, a filler, an extender, a wetting agent, a disintegrant, and / or a surfactant.

The content of the tetravalent nitrogen compound of Formula 1 or the pharmaceutically acceptable salt thereof in the pharmaceutical composition may be appropriately adjusted according to the method of use of the composition, the mode of use, the condition of the patient, and the desired effect, To 99% by weight, preferably 50 to 95% by weight.

According to another embodiment of the present invention, there is provided an agent for the prevention or treatment of depression or mental disorder comprising the above pharmaceutical composition.

As described above, by using the quaternary ring nitrogen compound of Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient, it is possible to prevent the reabsorption of specific neurotransmitters at high efficiency and to prevent depression, Premature ejaculation, or neuropathic pain, and can minimize adverse effects on the human body.

The method of administering the agent for preventing or treating depression, mental illness, premature ejaculation, or neuropathic pain can be either oral or parenteral, and the formulation can be variously determined depending on the method of use. For example, the formulations may be formulated with various excipients such as PLASTERS, GRANULES, LOTIONS, POWDERS, SYRUPS, LIQUIDS AND SOLUTIONS, AEROSOLS, OINTMENTS, ), Formulations in the form of FRUIDEXTRACTS, EMULSIONS, SUSTESIONS, INFUSIONS, TABLETS, INJECTIONS, CAPSULES or PILLS. Can be used.

The agent for the prevention or treatment of depression, psychiatric diseases, premature ejaculation, or neuropathic pain is determined in consideration of the age, sex, condition of the patient, the degree of absorption of the active ingredient, the rate of inactivation, (Body weight) to 4 mg / kg (body weight), more preferably 0.3 mg / kg (body weight) to 1.8 mg / kg (body weight) per day based on the active ingredient, Can be.

According to another embodiment of the present invention, a food comprising the quaternary ring nitrogen compound of Formula 1 may be provided.

The term " food " is intended to include not only conventional foods but also health supplements or food additives. Examples of the food, the health supplement food or the food additive are not limited to a specific one. Examples thereof include special nutrition foods (e.g., crude oil, spirits, infant foods, etc.), meat products, fish products, tofu, (Eg soy sauce), dairy products (eg fermented milk, cheese, etc.), other processed foods, kimchi, and other processed foods, (Such as a variety of kimchi, pickles, etc.), beverages (e.g., fruit, vegetable beverages, beverages, fermented beverages, etc.), natural seasonings (e.g., ramen soup, etc.).

According to the present invention, there is provided a pharmaceutical composition comprising a quaternary ring nitrogen compound which can prevent a specific neurotransmitter from being highly efficiently reabsorbed and can be used as a therapeutic or preventive agent for depression, mental illness, premature ejaculation or neuropathic pain, Or a norepinephrine reuptake inhibitor, and which has a high therapeutic or prophylactic effect on depression, mental illness, premature ejaculation, or neuropathic pain, and a pharmaceutical composition containing the pharmaceutical composition.

The invention will be described in more detail in the following examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

[ Manufacturing example : New  4 Synthesis of each ring nitrogen compound]

The following Examples 1 to 72 were synthesized by the synthesis method according to the following Reaction Scheme 1, and specific examples will be described stepwise in Production Examples 1 to 5 below.

[ Scheme 1 ]

[ Manufacturing example  1] from compound 2 via method (i) Compound 3  synthesis

: tert - Butyl  3- ( naphthalen -2- ylamino ) azetidine -One- carboxylate

2-naphthylamine (2.0 g, 14 mmol), sodium triacetoxyborohydride (8.9 g, 42 mmol) and acetic acid (0.080 mL) were added to a solution of N- Boc-3-azetidinone (3.6 g, 21 mmol) , 1.4 mmol), and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added 1 N aqueous NaOH solution (30 mL) and stirred for 30 minutes. The reaction mixture was extracted with methylene chloride, dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure to obtain a light brown precipitate. The resulting solid was filtered and dried at room temperature for 12 hours to obtain tert- butyl 3- (naphthalen-2-ylamino) azetidine-1-carboxylate (3.8 g, yield 92%) as a light brown solid.

[Yield 92%; Melting point 103 ° C; _{^{1 H NMR (600MHz, CDCl 3}} ) δ 1.46 (s, 9H, tert -butyl H), 3.77-3.79 (m, 2H, azetidine H), 4.13 (d, 1H, J = 6.0Hz, NH), 4.30- 4.37 (m, 3H, N CH , azetidine H), 6.61-7.67 (m, 7H, ArH)]

 [ Manufacturing example  2] method ( ii ) ≪ / RTI > Compound 3  synthesis

: tert - Butyl  3- ( cyclohexylamino ) azetidine -One- carboxylate

Cyclohexylamine (3.4 mL, 29 mmol) was added to a toluene (25 mL) solution of N-Boc-3-azetidinone (5.0 g, 29 mmol) and heated for 1 hour. The reaction mixture was evaporated under reduced pressure. 50 mL), and sodium borohydride (5.5 g, 150 mmol) was added thereto. After the reaction mixture was stirred at room temperature for 3 hours, 1N aqueous NaOH solution (20 mL) was added and stirred for an additional 1 hour. The reaction mixture was extracted with methylene chloride (3 x 50 mL portions) and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure to obtain a yellow oil-like liquid, which was purified by flash chromatography to obtain tert- butyl 3- (cyclohexylamino) azetidine-1-carboxylate (5.5 g, yield 74%) as a colorless transparent oil phase liquid .

[Yield: 74%; oil; ¹ H NMR (600 MHz, CDCl ₃ )? 1.00-1.77 (m, 10H, cyclohexyl methylene H), 1.40 (s, 9H, tert -butyl H), 2.40 (m, 1H, cyclohexyl methine H), 3.56-3.58 4.30-4.37 (2m, 4H, azetidinyl methylene H), 3.64 (m, 1H, azetidinyl methylene H)]

 [ Manufacturing example  3] Intermediate From compound 3  Synthesis of intermediate compound 4 (reaction path A)

: tert - Butyl  3- ( benzyl ( naphthalen -2- yl ) amino) azetidine -One- carboxylate

Potassium carbonate (0.41 g, 3.0 mmol) and benzyl bromide (0.18 mL, 1.5 mmol) were added to a dimethylformamide (6 mL) solution of tert- butyl 3- (naphthalen-2-ylamino) azetidine-1-carboxylate ), And the mixture was heated under reflux for 3 hours. The solvent was removed by evaporation under reduced pressure, dissolved in ethyl acetate, washed once with saturated aqueous sodium bicarbonate and once with distilled water, and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting brown oil was purified by flash chromatography to give tert- butyl 3- (benzyl (naphthalen-2-yl) amino) azetidine-1-carboxylate (0.23 g, yield 58%).

[Yield 58%; oil; ¹ H NMR (400 MHz, CDCl ₃ )? 1.42 (s, 9H, tert -butyl H), 3.92-3.95 and 4.17-4.20 (2m, 4H, azetidinyl methylene H) 4.60 (s, 2H, benzylic H), 6.80-7.68 (m, 12H, ArH)]

 [ Manufacturing example  4] Intermediate From compound 3  Synthesis of Intermediate Compound 4 (Reaction Route B)

: tert - Butyl  3- ( phenethyl ( phenyl ) amino) azetidine -One- carboxylate

phenylacetaldehyde (0.18 g, 1.6 mmol) and sodium triacetoxyborohydride (0.51 g, 2.4 mmol) were added to a solution of tert- butyl 3- (phenylamino) azetidine-1-carboxylate acetic acid (4.6, 0.08 mmol) was added thereto, followed by stirring at room temperature for 6 hours. To the reaction mixture was added 1 N aqueous NaOH solution (30 mL) and further stirred for 30 minutes. The reaction mixture was extracted with methylene chloride and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure to give a pale yellow oil which was purified by flash chromatography to give tert- butyl 3- (phenethyl (phenyl) amino) azetidine-1-carboxylate (0.24 g, yield 86 %).

[Yield 86%; oil; _{^{1 H NMR (600MHz, CDCl 3}} ) δ 1.41 (s, 9H, tert -butyl H), 2.73 (t, 2H, J = 7.8Hz, CH 2), 3.51 (t, 2H, J = 7.8Hz, CH 2 , 3.80 and 4.05 (m, 4H, azetidinyl methylene H), 4.20 (m, 1H, azetidinyl methine H), 6.73-7.28

 [ Manufacturing example  5] < / RTI > From intermediate compound 4 (1)  Synthesis of each ring nitrogen compound

: tert - butyl  3- ( benzyl ( naphthalen -2- yl ) amino) azetidine -One- carboxylate

To a solution of tert- Butyl 3- (benzyl (naphthalen-2-yl) amino) azetidine-1-carboxylate After stirring for 10 hours, 1 N aqueous NaOH solution (2.0 mL) was added and stirred for an additional 30 minutes. The reaction mixture was extracted with methylene chloride and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting brown oil was purified by flash chromatography to give tert- butyl 3- (benzyl (naphthalen-2-yl) amino) azetidine-1-carboxylate (80 mg, Yield: 54%).

[Yield 54%; oil; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 3.75-3.85 (m, 4H, azetidinyl methylene H), 4.06 (s, 1H, NH), 4.54 (s, 2H, benzylic H), 4.63 (m, 1H, methine H ), 7.03-7.66 (m, 12H, ArH)]

A novel quadrivalent nitrogen compound 1 was synthesized from N-Boc-3-azetidinone through intermediate compounds 3 and 4 according to the above-mentioned preparation example. The formula and the functional group of the quaternary nitrogen compound, Table 1 shows the results. The yield, characteristics, and hydrogen nuclear magnetic resonance spectrum data thereof are shown in Examples 1 to 72 below.

number R ₁ R ₂ n Reaction path One cyclohexyl C ₆ H ₄ (4-OCH ₃ ) One A 2 cyclohexyl C ₆ H ₄ (4-Cl) One A 3 cyclohexyl C ₆ H ₄ (4-CH ₃ ) One A 4 cyclohexyl C ₁₀ H ₇ One A 5 C ₆ H ₅ C ₆ H ₄ (4-OCH ₃ ) One A 6 C ₆ H ₅ C ₁₀ H ₇ One A 7 C ₆ H ₅ C ₆ H ₄ (4-Cl) One A 8 cyclohexyl C ₆ H ₅ One A 9 cyclohexyl C ₆ H ₅ 2 B 10 cyclohexyl C ₆ H ₅ 3 B 11 C ₆ H ₅ C ₆ H ₅ One A 12 C ₆ H ₅ C ₆ H ₅ 2 B 13 C ₆ H ₅ C ₆ H ₅ 3 B 14 C ₁₀ H ₇ C ₆ H ₅ One A 15 C ₁₀ H ₇ C ₆ H ₅ 2 B 16 C ₁₀ H ₇ C ₆ H ₅ 3 B 17 C ₆ H ₃ (3,4-di Cl) C ₆ H ₅ 2 B 18 C ₆ H ₃ (3,4-di Cl) C ₆ H ₅ 3 B 19 C ₆ H ₄ (4-OPh) C ₆ H ₅ 2 B 20 C ₆ H ₄ (4-OPh) C ₆ H ₅ 3 B 21 C ₁₀ H ₇ C ₁₀ H ₇ One A 22 C ₁₀ H ₇ C ₆ H ₄ (4-Cl) One A 23 C ₆ H ₃ (3,4-di Cl) C ₆ H ₅ One A 24 C ₆ H ₃ (3,4-di Cl) C ₁₀ H ₇ One A 25 C ₆ H ₃ (3,4-di Cl) C ₆ H ₄ (4-Cl) One A 26 C ₆ H ₄ (4-CH ₃ ) C ₆ H ₅ One A 27 C ₆ H ₄ (4-CH ₃ ) C ₁₀ H ₇ One A 28 C ₆ H ₄ (4-CH ₃ ) C ₆ H ₄ (4-Cl) One A 29 C ₆ H ₃ (2,4-di CH ₃ ) C ₆ H ₅ One A 30 C ₆ H ₃ (2,4-di CH ₃ ) C ₁₀ H ₇ One A 31 C ₆ H ₃ (2,4-di CH ₃ ) C ₆ H ₄ (4-Cl) One A 32 C ₆ H ₄ (4-OPh) C ₆ H ₅ One A 33 C ₆ H ₄ (4-OPh) C ₁₀ H ₇ One A 34 C ₆ H ₄ (4-OPh) C ₆ H ₄ (4-Cl) One A 35 CH ₂ C ₆ H ₅ C ₁₀ H ₇ One A 36 CH ₂ C ₆ H ₅ C ₆ H ₄ (4-Cl) One A 37 CH ₂ C ₆ H ₅ C ₆ H ₄ (2-Cl) One A 38 CH ₂ C ₆ H ₅ C ₆ H ₄ (2-F) One A 39 CH ₂ C ₆ H ₅ C ₆ H ₄ (3-Cl) One A 40 C ₆ H ₄ (4- i- Pr) C ₆ H ₅ One A 41 C ₆ H ₄ (4- i- Pr) C ₁₀ H ₇ One A 42 C ₆ H ₄ (4- i- Pr) C ₆ H ₄ (4-Cl) One A 43 C ₆ H ₄ (4- i- Pr) C ₆ H ₄ (2-Cl) One A 44 C ₆ H ₄ (4- i- Pr) C ₆ H ₄ (2-F) One A 45 C ₆ H ₄ (4- i- Pr) C ₆ H ₄ (3-Cl) One A 46 cyclopropyl C ₁₀ H ₇ One A 47 cyclopropyl C ₆ H ₄ (4-F) One A 48 cyclopropyl C ₆ H ₄ (3-CH ₃ ) One A 49 cyclopropyl C ₆ H ₄ (4- i- Pr) One A 50 cyclopentyl C ₁₀ H ₇ One A 51 cyclopentyl C ₆ H ₄ (2-CH ₃ ) One A 52 cyclopentyl C ₆ H ₄ (2-F) One A 53 cyclopentyl C ₆ H ₄ (3-Cl) One A 54 C ₆ H ₃ (2-CH ₃ , 3-Cl) C ₁₀ H ₇ One A 55 C ₆ H ₃ (2-CH ₃ , 3-Cl) C ₆ H ₄ (4-Cl) One A 56 C ₆ H ₄ (2-F) C ₁₀ H ₇ One A 57 C ₆ H ₄ (2-F) C ₆ H ₄ (4-Cl) One A 58 C ₆ H ₄ (3-Cl) C ₁₀ H ₇ One A 59 C ₆ H ₄ (3-Cl) C ₆ H ₄ (4-Cl) One A 60 benzothiazole C ₁₀ H ₇ One A 61 C ₆ H ₅ C ₆ H ₃ (3,4-di Cl) One A 62 C ₁₀ H ₇ C ₆ H ₃ (3,4-di Cl) One A 63 C ₆ H ₄ (4-CH ₃ ) C ₆ H ₃ (3,4-di Cl) One A 64 C ₆ H ₃ (2,4-di CH ₃ ) C ₆ H ₃ (3,4-di Cl) One A 65 C ₆ H ₄ (3-Cl) C ₆ H ₃ (3,4-di Cl) One A 66 C ₆ H ₄ (4-OPh) C ₆ H ₃ (3,4-di Cl) One A 67 C ₆ H ₄ (2-F) C ₆ H ₃ (3,4-di Cl) One A 68 C ₆ H ₄ (4- i- Pr) C ₆ H ₃ (3,4-di Cl) One A 69 C ₆ H ₃ (2-CH ₃ , 3-Cl) C ₆ H ₃ (3,4-di Cl) One A 70 CH ₂ C ₆ H ₅ C ₆ H ₃ (3,4-di Cl) One A 71 cyclopropyl C ₆ H ₃ (3,4-di Cl) One A 72 cyclopentyl C ₆ H ₃ (3,4-di Cl) One A

[Example: yield, properties, and hydrogen nuclear magnetic resonance spectrum data of a novel tetrahedral ring nitrogen compound]

Example 1: Synthesis of N-cyclohexyl-N- (4-methoxybenzyl) azetidin-3-amine

[Yield 57%; oil; 1H, cyclohexyl C1H), 3.43 (m, 2H, azetidine H), 3.59 (m, 2H, azetidine H) 2H, J = 7.8 (d, 2H, NCH2), 3.75 (s, 3H, OCH3), 3.93 Hz, ArH)]

Example 2: Preparation of N- (4-chlorobenzyl) -N-cyclohexylazetidin-3-amine

[Yield 57%; oil; 2H, NCH2 (d, 2H), 3.30 (m, 1H, cyclohexylC1H), 3.28-3.58 ), 3.99 (m, 1 H, NCH), 7.17-7.23 (m, 4H, ArH)

Example 3: N-cyclohexyl-N- (4-methylbenzyl) azetidin-3-amine

[Yield 40%; oil; 1H, cyclohexyl C1H), 3.41 (m, 2H, azetidine H), 2.29 (s, 3H, CH3) 2H, J = 7.8 Hz, ArH), 7.18 (d, 2H, J = 8.4 Hz, 7.2 Hz, ArH)]

Example 4:

N-cyclohexyl-N- (naphthalen-2-ylmethyl) azetidin-3-amine

[Yield 61%; 1 H, cyclohexyl H), 2.41 (m, 1H, cyclohexylC1H), 2.51 (br (s), 1H, NH), 3.40 (m 2H, azetidine H), 3.55 (m, 2H, azetidine H), 3.82 (s, 2H, NCH2), 3.99 (m, 1H, NCH), 7.39-7.79

Example 5: Preparation of N- (4-methoxybenzyl) -N-phenylazetidin-3-amine

[Yield 49%; oil; (M, 2H, azetidine H), 3.66-3.75 (m, 5H, NCH2, OCH3), 3.99 (m, 2H, azetidine H), 4.36 , 6.44-7.17 (m, 9H, ArH)]

Example 6: Preparation of N- (naphthalen-2-ylmethyl) -N-phenylazetidin-3-amine

[Yield 90%; oil; 4H, azetidine H), 4.68 (m, 3H, NCH2, NCH), 6.69-7.83 (m, 12H, ArH )]

Example 7: Preparation of N- (4-chlorobenzyl) -N-phenylazetidin-3-amine

[Yield 91%; 2H, NCH2), 4.60 (m, 1H, NCH2), 3.68-3.79 (m, 4H, azetidine H) , 6.60-7.25 (m, 9H, ArH)]

Example 8: Synthesis of N-benzyl-N-cyclohexylazetidin-3-amine

[Yield 28%; oil; 2H, NCH2), 3.67-3.58 (m, 4H, azetidine H), 3.67 (s, 2H, NCH2) , 3.96 (m, 1H, NCH), 7.16-7.31 (m, 5H, ArH)]

Example 9: Synthesis of N-cyclohexyl-N-phenethylazetidin-3-amine

[Yield: 73%; oil; 2H, J = 7.2 Hz, CH2), 2.74 (t, 2H, cyclohexyl H), 2.45 (m, 1H, NCH), 7.16-7.27 (m, 5H, ArH)], 3.45-3.59 (m, 4H, azetidine H)

Example 10: Synthesis of N-cyclohexyl-N- (3-phenylpropyl) azetidin-3-amine

[Yield 82%; oil; 2H), 2.58 (t, 2H, J = 7.2 Hz, CH 2), 2.58 (t, (M, 4H, azetidine H), 3.82 (m, 1H, NCH), 7.13-7.25 (m, 5H, ArH)]

Example 11: Preparation of N-benzyl-N-phenylazetidin-3-amine

[Yield 59%; oil; (S, 2H, NCH2), 4.60 (m, 1H, NCH2), 3.70-3.77 (m, 4H, azetidine H), 4.51 , 6.62-7.30 (m, 10H, ArH)]

Example  12: N- phenethyl -N- phenylazetidine -3- amine

[Yield 75%; oil; (T, 2H, J = 7.8 Hz, CH 2), 3.64 (t, 2H, J = 7.8 Hz, (M, 4H, azetidine H), 4.37 (m, 1H, NCH), 6.73-7.29

Example  13: N- phenyl -N- (3- phenylpropyl ) azetidine -3- amine

[Yield 63%; oil; 2H, J = 7.8 Hz, CH2), 3.25 (t, 2H, CH2), 2.12 (br (M, 4H, azetidine H), 4.38 (m, 1H, NCH), 6.62-7.26

Example  14: N- benzyl -N- ( naphthalen -2- yl ) azetidine -3- amine

[Yield 54%; 2H), 4.63 (s, 2H, NCH2), 4.63 (m, 4H, azetidine H), 4.06 , NCH), 7.03-7.66 (m, 12H, ArH)]

Example  15: N- ( naphthalen -2- yl ) -N- phenethylazetidine -3- amine

[Yield 36%; oil; (T, 2H, J = 7.8 Hz, CH 2), 3.65 (t, 2H, J = 7.8 Hz, (M, 4H, azetidine H), 4.47 (m, 1H, NCH), 6.85-7.75

Example  16:

N- ( naphthalen -2- yl ) -N- (3- phenylpropyl ) azetidine -3- amine

[Yield 63%; oil; 2H, J = 7.2 Hz, CH2), 3.35 (t, 2H, J = 7.8 Hz, CH2), 3.70-3.88 (m, 2H, CH2), 2.59 (m, 5H, azetidine H, NH), 4.53 (m, 1H, NCH), 6.81-7.71

Example  17: N- (3,4- dichlorophenyl ) -N- phenethylazetidine -3- amine

[Yield 30%; oil; 2H, J = 7.2 Hz, CH2), 3.50 (t, 2H, J = 7.2 Hz, CH2), 3.58 (M, 4H, azetidine H), 4.28 (m, 1H, NCH), 6.52-7.30

Example  18:

N- (3,4- dichlorophenyl ) -N- (3- phenylpropyl ) azetidine -3- amine

[Yield 75%; oil; (M, 2H, CH2), 2.58 (t, 2H, J = 7.2 Hz, CH2), 3.21-3.66 (m, 6H, CH2, azetidine H), 4.15 1H, NCH), 6.40-7.29 (m, 8H, ArH)]

Example  19: N- phenethyl -N- (4- 펜oxyphenyl ) azetidine -3- amine

[Yield 64%; oil; 2H, J = 7.2 Hz, CH2), 3.69-3.78 (m, 4H, azetidine H), 4.38 (t, 2H) m, 1 H, NCH), 6.77-7.34 (m, 14H, ArH)]

Example  20:

N- (4- 펜oxyphenyl ) -N- (3- phenylpropyl ) azetidine -3- amine

[Yield 87%; oil; 2H, J = 7.2 Hz, CH2), 3.20 (t, 2H, J = 7.2 Hz, CH2), 3.70-3.78 (m, 2H, , 4H, azetidine H), 3.97 (br (s), IH, NH), 4.37 (m, IH, NCH), 6.70-7.33

Example  21:

N- ( naphthalen -2- yl ) -N- ( naphthalen -2- ylmethyl ) azetidine -3- amine

[Yield 42%; (M, 2H, azetidine H), 4.76 (m, 1H, NCH), 4.84 (s, 2H, NCH2 ), 6.88-7.84 (m, 14H, ArH)]

Example  22:

N- (4- chlorobenzyl ) -N- ( naphthalen -2- yl ) azetidine -3- amine

[Yield 54%; (M, 2H, azetidine H), 4.22 (m, 2H, azetidine H), 4.57 (s, 2H, NCH2), 4.77 6.81-7.78 (m, 11 H, ArH)]

Example  23: N- benzyl -N- (3,4- dichlorophenyl ) azetidine -3- amine

[Yield 87%; 2H, azetidine H), 4.70 (s, 2H, NCH2), 4.82 (m, 1H, NCH ), 6.65-7.39 (m, 11H, ArH), 8.61 (br (s), 1H, NH)

Example  24:

N- (3,4- dichlorophenyl ) -N- ( naphthalen -2- ylmethyl ) azetidine -3- amine

[Yield 81%; 2H, azetidine H), 4.66 (s, 2H, NCH2), 4.79 (m, 1H, NCH ), 6.45-7.72 (m, 10H, ArH)]

Example  25:

N- (4- chlorobenzyl ) -N- (3,4- dichlorophenyl ) azetidine -3- amine

[Yield 89%; 2H, azetidine H), 4.66 (s, 2H, NCH2), 4.79 (m, 1H, NCH ), 6.45-7.72 (m, 10H, ArH)]

Example  26: N- benzyl -N- (p- tolyl ) azetidine -3- amine

[Yield 81%; (M, 3H, CH3), 3.85 (m, 2H, azetidine H), 4.14 (m, 2H, azetidine H), 4.52-4.58 (D, 2H, J = 8.4 Hz, ArH), 7.18-7.34 (m, 5H, ArH)

Example  27: N- ( naphthalen -2- ylmethyl ) -N- ( p - tolyl ) azetidine -3- amine

[Yield 84%; 2H), 4.21 (m, 2H, azetidine H), 4.62-4.68 (m, 3H, CH) (D, 2H, J = 8.4 Hz, ArH), 7.35-7.91 (m, 7H, ArH), 8.70 , NH)]

Example  28: N- (4- chlorobenzyl ) -N- (p- tolyl ) azetidine -3- amine

[Yield 68%; 2H, azetidine H), 4.50-4.58 (m, 3H, CH3), 3.88 (m, 2H, (D, 2H, J = 8.4 Hz, ArH), 7.32 (d, 2H, J = 8.4 Hz, ArH) d, 2H, J = 8.4 Hz, ArH), 8.73 (s, 1H, NH)

Example 29: Synthesis was carried out in the same manner as in N- benzyl- N- (2,4- dimethylphenyl ) azetidin- 3- amine .

[Yield 69%; 3H, CH3), 3.57 (m, 2H, azetidine H), 3.83 (m, 2H, azetidine 1H), 4.00 (s, 2H, NCH2), 4.17 (m, 1H, NCH), 6.81-7.31 (m, 8H, ArH), 8.57

Example  30:

N- (2,4- dimethylphenyl ) -N- ( naphthalen -2- ylmethyl ) azetidine -3- amine

[Yield 48%; 2H), 3.81 (m, 2H, azetidine H), 3.62 (s, 3H, CH3) ), 4.19-4.25 (m, 3H, NCH2, NCH), 6.88-7.87 (m, 10H, ArH)

Example  31:

N- (4- chlorobenzyl ) -N- (2,4- dimethylphenyl ) azetidine -3- amine

[Yield 58%; oil; (S, 3H, CH3), 3.62 (m, 2H, azetidine H), 3.83 (m, 2H, azetidine H), 4.02 (s, 2H, NCH2), 4.16 (m, 1H, NCH), 6.82-7.33

Example  32: N- benzyl -N- (4- 펜oxyphenyl ) azetidine -3- amine

[Yield 84%; 2H, azetidine H), 3.95 (m, 2H, azetidine H), 4.53-4.57 (m, 3H, NCH2, NCH), 6.68-7.36 (m, 14H, ArH)]

Example  33:

N- ( naphthalen -2- ylmethyl ) -N- (4- 펜oxyphenyl ) azetidine -3- amine

[Yield 96%; oil; 2H, NCH2), 4.66 (m, 1H, NCH), 6.72-7.86 (m, 16H, ArH)].

Example  34:

N- (4- chlorobenzyl ) -N- (4- 펜oxyphenyl ) azetidine -3- amine

[Yield 85%; oil; (M, 2H, azetidine H), 3.90 (m, 2H, azetidine H), 4.49-4.52 (m, 3H, NCH2, NCH), 6.68-7.41 , ArH)]

Example  35: N- benzyl -N- ( naphthalen -2- ylmethyl ) azetidine -3- amine

[Yield 62%; 2H, NCH2), 3.74 (m, 2H, azetidine H), 3.50-3.61 (m, 4H, azetidine H, NCH2) , NCH), 7.27-7.86 (m, 12H, ArH)]

Example  36: N- benzyl -N- (4- chlorobenzyl ) azetidine -3- amine

[Yield 43%; oil; (S, 2H, NCH2), 3.54 (m, 2H, NH), 3.42-3.47 (m, 4H, azetidine H, NCH2), 3.49 , 3.66 (m, 1H, NCH3), 7.26-7.35 (m, 9H, ArH)

Example  37: N- benzyl -N- (2- chlorobenzyl ) azetidine -3- amine

[Yield 36%; oil; (M, 2H, azetidine H), 3.54-3.61 (m, 4H, azetidine H, NCH2), 3.65 (s, 2H, NCH2), 3.77 , 7.17-7.58 (m, 9H, ArH)]

Example  38: N- benzyl -N- (2- fluorobenzyl ) azetidine -3- amine

[Yield 50%; oil; (M, 2H, azetidine H), 3.54-3.59 (m, 6H, azetidine H, NCH2, NCH2), 3.71 (m, 2H, , 1H, NCH), 7.00-7.41 (m, 9H, ArH)].

Example  39: N- benzyl -N- (3- chlorobenzyl ) azetidine -3- amine

[Yield 42%; oil; (M, 2H, azetidine H), 3.74 (m, 1H, NCH), 7.18-7. 36 (m, 6H, azetidine H, NCH2, NCH2) 9H, ArH)]

Example  40: N- benzyl -N- (4- isopropylphenyl ) azetidine -3- amine

[Yield 72%; CH (CH3) 2), 2.86 (m, 1H, CH (CH3) 2), 3.94-4.01 (m, 4H , azetidine H), 4.48 (s, 2H, NCH2), 4.71 (m, 1H, NCH), 6.65-7.33

Example  41: N- (4- isopropylphenyl ) -N- ( naphthalen -2- ylmethyl ) azetidine -3- amine

[Yield 89%; oil; CH (CH3) 2), 2.86 (m, 1H, CH (CH3) 2), 3.91-4.01 (m, 4H, azetidine H) (D, 2H, J = 8.4 Hz, ArH), 7.38-7.83 (m, 2H, NCH2) (m, 7H, ArH)]

Example  42:

N- (4- chlorobenzyl ) -N- (4- isopropylphenyl ) azetidine -3- amine

[Yield 76%; oil; (M, 4H, azetidine H (CH3) 2), 2.85 (m, 1H, CH (D, 2H, J = 8.4 Hz, ArH), 4.45 (s, 2H, NCH2), 4.67 d, 2H, J = 8.4 Hz, ArH), 7.31 (d, 2H, J = 8.4 Hz, ArH)

Example  43: N- (2- chlorobenzyl ) -N- (4- isopropylphenyl ) azetidine -3- amine

[Yield 62%; oil; (M, 2H, azetidine H), 2.82 (m, 1H, CH (CH3) 2), 3.82 2H, J = 8.4 Hz, ArH), 7.10 (d, 2H, J = 8.4 Hz, ArH), 7.22-7.42 (m, 4H, ArH)]

Example  44: N- (2- fluorobenzyl ) -N- (4- isopropylphenyl ) azetidine -3- amine

[Yield 39%; oil; (M, 2H, azetidine H), 4.02 (d, 6H, J = 6.8 Hz, CH (CH3) 2), 2.83 (d, 2H, J = 8.4 Hz, ArH), 7.04-7.29 (m, 6H, ArH )]

Example  45: N- (3- chlorobenzyl ) -N- (4- isopropylphenyl ) azetidine -3- amine

[Yield 40%; 1H NMR (400MHz, CDCl3)? 1.24 (d, 6H, J = 6.8Hz, CH (CH3) 2), 2.85 , 4.00 (m, 2H, azetidine H), 4.47 (s, 2H, NCH2), 4.69 (m, 1H, NCH), 6.63 (d, 2H, J = 8.4 Hz, ArH) = 8.4 Hz, ArH), 7.16-7.29 (m, 4H, ArH)]

Example  46: N- cyclopropyl -N- ( naphthalen -2- ylmethyl ) azetidine -3- amine

[Yield 87%; oil; 1H, NMR (400MHz, CDCl3)? 0.44-0.57 (m, 4H, cyclopropyl H), 1.78 , NCH2, NCH), 7.39-7.85 (m, 7H, ArH)].

Example  47: N- cyclopropyl -N- (4- fluorobenzyl ) azetidine -3- amine

[Yield: 73%; oil; 1H, NMR (400MHz, CDCl3) 灌 0.38-0.50 (m, 4H, cyclopropyl H), 1.65 (m, 1H, cyclopropylC1H), 3.46 3.66-3.73 (m, 3H, azetidine H, NCH), 6.98-7.25 (m, 4H, ArH)

Example  48: N- cyclopropyl -N- (3- 메틸benzyl ) azetidine -3- amine

[Yield 61%; oil; 1H, NMR (400MHz, CDCl3) 灌 0.43-0.52 (m, 4H, cyclopropyl H), 1.70 (m, 1H, cyclopropylC1H) 3.62 (s, 2H, NCH2), 3.76-3.77 (m, 3H, azetidine H,

Example  49: N- cyclopropyl -N- (4- isopropylbenzyl ) azetidine -3- amine

[Yield 67%; oil; 1H NMR (400MHz, CDCl3)? 0.44-0.53 (m, 4H, cyclopropyl H), 1.27 (d, 6H, J = 6.8Hz, CH (CH3) 2H), 3.67 (s, 2H, NCH2), 3.75-3.80 (m, 3H, azetidine H, NCH), 7.16-7.17 (m, , 4H, ArH)]

Example  50: N- cyclopentyl -N- ( naphthalen -2- ylmethyl ) azetidine -3- amine

[Yield 89%; oil; 1H, cyclopentylC1H), 3.47 (m, 2H, azetidine H), 3.63 (m, 2H, azetidine H) 2H), 3.91 (m, 1H, NCH), 7.44-7.85 (m, 7H, ArH)

Example  51: N- cyclopentyl -N- (2- 메틸benzyl ) azetidine -3- amine

[Yield 67%; oil; 2H), 3.58 (s, 3H, CH3), 3.10 (m, 1H, cyclopentylC1H), 3.43 (m, 2H, azetidine H) 2H), 3.64 (s, 2H, NCH2), 3.90 (m, 1H, NCH), 7.11-7.51 (m,

Example  52: N- cyclopentyl -N- (2- fluorobenzyl ) azetidine -3- amine

[Yield 56%; oil; 1H), 3.51 (m, 2H, azetidine H), 3.53 (m, 2H, azetidine H), 3.10 (m, 1H, cyclopentylC1H) , 3.73 (s, 2H, NCH2), 3.91 (m, IH, NCH), 6.98-7.55 (m, 4H, ArH)

Example  53: N- (3- chlorobenzyl ) -N- cyclopentylazetidine -3- amine

[Yield 78%; oil; (M, 2H, azetidine H), 3.42 (m, 2H, azetidine H), 3.60 (m, 1H, cyclopentyl H) , 3.66 (s, 2H, NCH2), 3.86 (m, 1H, NCH), 7.21-7.39

Example  54:

N- (3- chloro -2- 메틸 피닐 ) -N- ( naphthalen -2- ylmethyl ) azetidine -3- amine

[Yield 34%; oil; (M, 2H, azetidine H), 4.07 (s, 2H, NCH 2), 4.26 (m, 2H, 8H, ArH), 7.01 (t, 1H, J = 8.0 Hz, ArH), 7.19-7.82 (m, 8H, ArH)

Example  55: N- (3- chloro -2- 메틸 피닐 ) -N- (4- chlorobenzyl ) azetidine -3- amine

[Yield 63%; oil; 2H, azetidine H), 3.93 (s, 2H, NCH2), 4.20 (m, 2H, azetidine H) (M, 6H, ArH)), 6.62 (d, 1H, J = 7.6Hz, ArH), 6.99-7.25

Example  56: N- (2- fluorophenyl ) -N- ( naphthalen -2- ylmethyl ) azetidine -3- amine

[Yield 40%; oil; 2H, NCH2), 4.47 (m, 1H, NCH), 6.78-7.83 (m, 11H, ArH)].

Example  57: N- (4- chlorobenzyl ) -N- (2- fluorophenyl ) azetidine -3- amine

[Yield 52%; oil; (M, 2H, azetidine H), 4.21 (s, 2H, NCH2), 4.46 (m, , 1H, J = 7.6 Hz, ArH), 7.00-7.29 (m, 7H, ArH)

Example  58: N- (3- klorophenyl ) -N- ( naphthalen -2- ylmethyl ) azetidine -3- amine

[Yield 80%; oil; (M, 2H, azetidine H), 4.73 (s, 2H, NCH2), 4.79 (m, 1H, NCH), 6.57 (D, 1H, J = 8.0Hz, J = 1.2Hz, ArH), 7.14 ArH), 7.35 (dd, 1H, J = 8.4 Hz, J = 2.0 Hz, ArH), 7.47-7.85 (m, 6H, ArH)

Example  59: N- (4- chlorobenzyl ) -N- (3- klorophenyl ) azetidine -3- amine

[Yield 78%; (M, 2H, azetidine H), 4.02 (m, 2H, azetidine H), 4.54 (s, 2H, NCH2), 4.72 (Dd, 1H, J = 8.0 Hz, J = 2.0 Hz, ArH), 6.52 ArH), < / RTI > 7.13-7.34 (m, 5H, ArH)

Example  60:

N- ( azetidine -3- yl ) -N- ( naphthalen -2- ylmethyl ) benzo [d] thiazole -2- amine

[Yield 35%; (M, 2H, azetidine H), 4.08 (m, 2H, azetidine H), 5.10-5.13 (m, 3H, NCH2, NCH), 7.09 , 7.48-7.94 (m, 9H, ArH)], 7.31 (t, 1H, J = 7.6Hz, ArH)

Example  61: N- (3,4- dichlorobenzyl ) -N- phenylazetidine -3- amine

[Yield 80%; oil; (M, 2H, azetidine H), 4.50 (s, 2H, NCH2), 4.65 (m, 1H, NCH), 6.64 2H, J = 7.6 Hz, ArH), 6.84 (t, 1H, J = 7.2 Hz, ArH), 7.11-7.42 (m,

Example  62: N- (3,4- dichlorobenzyl ) -N- ( naphthalen -2- yl ) azetidine -3- amine

[Yield 87%; Melting point 187 ° C; (M, 2H, azetidine H), 4.59 (s, 2H, NCH2), 4.72 (m, 1H, NCH), 6.81-7.78 m, 10H, ArH)]

Example  63: N- (3,4- dichlorobenzyl ) -N- (p- tolyl ) azetidine -3- amine

[Yield 87%; Melting point 162 캜; (M, 2H, azetidine H), 4.84 (s, 2H, NCH2), 4.58 (m, 2H, ArH), 7.02 (d, 2H, J = 8.0 Hz, ArH), 7.10-7.41 (m, 4H, ArH)], 6.56 (d, 2H, J = 8.4 Hz,

Example  64: N- (3,4- dichlorobenzyl ) -N- (2,4- dimethylphenyl ) azetidine -3- amine

[Yield 26%; oil; (S, 3H, CH3), 3.45-3.46 (m, 4H, azetidine H), 3.92 (s, 2H, NCH2), 4.12 , 6.30-7.32 (m, 5H, ArH)], 6.71 (d,

Example  65: N- (3- klorophenyl ) -N- (3,4- dichlorobenzyl ) azetidine -3- amine

[Yield 78%; Melting point 187 ° C; 2H), 4.22 (m, 2H, azetidine H), 4.70 (s, 2H, NCH2), 4.82 (m, 1H, NCH), 6.61 7.63 (m, 7H, ArH), 8.80 (br (s) 1H, NH)

Example  66: N- (3,4- dichlorobenzyl ) -N- (4- 펜oxyphenyl ) azetidine -3- amine

[Yield 62%; Melting point 185 ° C; 2H, azetidine H), 4.52 (s, 2H, NCH2), 4.59 (m, 1H, NCH), 6.75 (m, 7.63 (m, 12H, ArH), 8.86 (br (s) 1H, NH)

Example  67: N- (3,4- dichlorobenzyl ) -N- (2- fluorophenyl ) azetidine -3- amine

[Yield 53%; oil; (M, 2H, azetidine H), 3.70 (m, 2H, azetidine H), 4.23 (s, 2H, NCH2), 4.31 (m, 1H, NCH), 6.69-7.35 m, 7H, ArH)]

Example  68: N- (3,4- dichlorobenzyl ) -N- (4- isopropylphenyl ) azetidine -3- amine

[Yield: 73%; oil; (M, 2H, azetidine H), 3.88 (m, 2H, CH (CH3) 2) (d, 2H, J = 8.8 Hz, ArH), 7.07-7.42 (m, 5H, ArH )]

Example  69:

N- (3- chloro -2- 메틸 피닐 ) -N- (3,4- dichlorobenzyl ) azetidine -3- amine

[Yield 45%; oil; (M, 2H, azetidine H), 3.61 (s, 2H, NCH 2), 4.16 (m, 1H, NCH), 6.65 (d, 1H, J = 7.6 Hz, ArH), 6.88-7.35 (m, 5H, ArH)

Example  70: N- benzyl -N- (3,4- dichlorobenzyl ) azetidine -3- amine

[Yield 44%; oil; (M, 6H, NCH2), 3.57 (m, 2H, azetidine H), 3.67 (m, 1H, NCH), 7.16-7.44 , ArH)]

Example  71: N- cyclopropyl -N- (3,4- dichlorobenzyl ) azetidine -3- amine

[Yield 64%; oil; 2H), 3.63 (s, 2H, NCH2), 3.65 (m, 1H, cyclopropylC1H) -3.69 (m, 3H, azetidine H, NCH), 7.10-7.39 (m, 3H, ArH)

Example  72: N- cyclopentyl -N- (3,4- dichlorobenzyl ) azetidine -3- amine

[Yield 45%; oil; (M, 2H, azetidine H), 3.04 (m, 1H, cyclopentylC1H), 3.49 (m, 2H, azetidine H), 3.6359 3.63 (s, 2H, NCH2), 3.85 (m, 1H, NCH), 7.19-7.50

[Experimental Example: Neurotransporter reuptake inhibitory assay]

The reuptake inhibitory activity of the synthesized compound on the neurotransmitter transporter was tested in vitro . This activity means the ability of the compounds synthesized in the Examples to block the reabsorption of neurotransmitters through the transport of monovalent amine neurotransmitters via dopamine, serotonin and neoepinephrine transporters. A high-throughput screening system FDSS6000 (Functional Drug Screening System 6000), a real-time fluorescence analyzer, was used for cell-based retrieval of dopamine, serotonin and norepinephrine reuptake inhibitor candidates. In this experiment, blocking agents were treated with HEK293 cell line (HEK-hDAT, HEK-hNET) expressing human dopamine, serotonin and neopinaphrin transporter, and IC ₅₀ values were measured by measuring changes in intracellular monophosphate neurotransmitter Respectively.

(1) Cell culture and preparation

(HEK-hDAT, HEK-hNET; provided by Professor Bryan Roth of Chapel Hill University, North Carolina), in which the human dopamine, serotonin and neoepinephrine transporter were stably expressed, respectively.

HEK293 cells stably expressing each transporter were cultured in the presence of 10% (v / v) fetal bovine serum, penicillin (100 U / ml), and streptomycin (100 μg / ml) Dulbecco's modified Eagle's medium (Welgene, Daegu, Korea) was used to culture the cells in an incubator at 37 ° C in a 5% CO 2 humidified condition and pass once every 3-4 days.

In order to screen cells expressing each transporter, 350 mg / ml of HEK-hDAT cell line and 200 mg / ml of Geneticin G418 (Gibco, USA) were added to the HEK-hNET cell line (37 ° C, 5% L-lysine (0.05 mg / ml) was added 18-20 hours prior to the detection of monovalent amine reuptake inhibitor compound activity using an FDSS 6000 instrument (Hamamatsu Photonics, Hamamatsu, Japan) to the coated 96-well plates (NUNC, Rochester, NY, USA ) it was dispensed at a density of 5 x 10 ⁴ cells per well one.

(2) Measurement and data analysis using high efficiency detector FDSS6000

The reuptake inhibitory activity was measured using a Neurotransmitter Transporter Uptake Assay Kit (Molecular), which mimics DA (dopamine), 5-HT (serotonin) and NE (no epinephrine) Devices, Sunnyvale, Calif., USA), and the intracellular reabsorption of the indicator was measured by fluorescence signal. The indicator was included in the kit. In the assay kit, dopamine, serotonin, and naepinephrine were imitated and the indicator labeled with a fluorescent dye was included in powder form, which was dissolved in HEPES buffer and used in the experiment. The assay kit contained only one indicator and the same type of indicator was used for dopamine, serotonin, and neophelin reuptake experiments.

On the day of the experiment, the cells attached to the 96-well plate were washed with HEPES buffer (unit mM: 150 NaCl, 5 KCl, 2 CaCl ₂ , 5 mM) using a 96-well plate automatic washing machine ELx405 Select CW (BioTek Instruments, Winooski, 1MgCl ₂ , 10Glucose, 10HEPES, pH 7.4), and the fluorescence intensity was measured immediately after adding the dye solution prepared according to the manufacturer's instructions. The reabsorption of the fluorescently labeled indicator was measured for 30 minutes by the change in fluorescence intensity according to the change of the intracellular indicator using an FDSS 6000 instrument (Hamamatsu Photonics, Hamamatsu, Japan).

Changes in intracellular fluorescence intensity were determined by the final fluorescence intensity (Endpoint) measured 30 minutes after starting measurement of fluorescence intensity. For detailed fluorescence imaging, a computer-controlled filter wheel was used to selectively expose cells to excitation wavelengths of 440 nm emitted from the four xenon lamp sources mounted on the FDSS 6000, followed by a 515 nm long- Pass filtered and cooled fluorescence CCD camera embedded in the instrument. The emitted fluorescence was measured by a digital fluorescence analyzer at 520 nm every 10 seconds.

In the experiment for measuring the inhibitory effect, the test drug containing the quadruple ring nitrogen compound synthesized in the examples was pretreated in an incubator for 15 minutes at 37 ° C in a 5% carbon dioxide humidifying condition, and then the dye prepared in accordance with the manufacturer's instructions Solution. More specifically, the test drug was prepared by making a 100 mM solution of DMSO in a tetra-ring nitrogen compound and adding HEPES buffer (unit mM: 150 NaCl, 5 KCl, 2 CaCl ₂ , 1 MgCl ₂ , 10 Glucose, 10 HEPES , pH 7.4). After the addition of the dye solution to the cells, the fluorescence intensity was immediately measured, and the intensity of intracellular fluorescence intensity was measured for 30 minutes to determine the final fluorescence intensity (Endpoint).

The percent inhibition (% of control) for the test material was calculated by taking the final fluorescence intensity (Endpoint) of the control group not treated with the test material as 100%, obtaining a dose-response curve and using GraphPad Prism4 by fitting the Hill equation La Jolla, CA, USA) program, IC ₅₀ values were calculated. GBR12909, Nisoxetine and Fluoxetine (Tocris Bioscience, Ellisville, MO, USA) were used as reference drugs for hNET, hSERT and hDAT, respectively. All image data and analysis were made using FDSS6000 dedicated program provided by Hamamatsu Photonics (Hamamatsu, Japan).

Experimental result of inhibition of neurotransmitter reabsorption Example No. % reuptake inhibition, at 10 % reuptake inhibition, at 1.0 hSERT hNET hDAT hSERT hNET hDAT Fluoxetine 89 56 31 84 78 5 Nisoxetine 85 - 73 43 92 42 GBR12909 69 85 89 6 20 86 One 98 37 48 89 6 5 2 97 91 88 93 61 66 3 96 86 80 76 36 29 4 99 97 90 98 82 71 6 98 95 90 97 73 69 7 96 94 88 90 75 72 10 97 40 81 83 10 33 11 96 95 80 64 67 40 12 90 83 80 51 39 46 13 95 71 78 89 20 31 14 96 94 90 93 93 78 15 97 93 79 86 70 21 16 97 95 85 68 71 30 17 98 96 83 77 74 27 18 100 100 89 73 81 30 20 90 85 32 62 4 One 21 86 100 95 61 61 21 22 87 100 100 87 100 45 23 100 100 100 96 100 40 24 84 100 96 59 56 22 25 91 100 100 72 88 25 26 84 100 90 45 93 29 27 100 100 100 100 77 51 28 92 100 99 86 83 44 29 91 100 51 89 99 11 30 100 100 97 100 27 22 31 100 100 81 100 48 19 32 85 100 63 38 17 7 33 98 76 40 77 5 3 35 100 100 100 100 100 73 36 92 100 99 88 94 54 37 90 100 95 67 78 32 38 76 100 93 29 58 41 39 100 100 87 61 99 29 40 100 100 68 60 49 6 41 100 96 97 100 9 17 42 100 95 94 69 10 14 43 100 100 76 75 87 8 44 100 100 82 52 65 10 45 100 100 84 66 70 7 46 100 96 98 100 39 68 50 100 100 100 100 78 87 51 97 100 49 4 66 9 53 100 100 95 68 76 56 54 100 100 100 100 23 42 55 100 98 98 100 34 19 56 100 100 100 100 100 75 57 100 100 100 100 100 63 58 100 100 100 100 73 70 59 100 100. 100 91 79 66 60 100 99 67 85 21 11 61 100 100 100 100 100 100 62 100 100 100 54 77 58 63 100 100 100 100 100 100 64 100 100 100 100 42 44 65 100 100 100 83 100 85 66 100 100 85 31 30 8 67 100 100 100 100 100 76 68 100 100 100 63 58 35 69 100 100 100 95 43 22 70 100 100 100 99 100 89 71 100 100 100 100 100 100 72 100 100 100 99 100 80

Experimental results of inhibition of neurotransmitter reabsorption Example No. Reuptake assay (IC ₅₀ , nM) hSERT hNET hDAT Fluoxetine 150 4410 18400 23 83.7 16.8 1202 27 23.0 597 696 31 20.2 130 406 35 20.2 130 406 46 12.1 1794 544 50 12.8 526 257 54 35.9 807 746 55 44.9 1008 1032 56 12.2 119 338 57 67.4 179 415 58 99.9 531.1 394

As shown in the above Tables 2 and 3, the tetrahedral ring nitrogen compounds synthesized in the Examples show superior effects to the serotonin inhibition than Fluoxetine, which is a conventional serotonin inhibitor. In addition, Fluoxetine shows almost no inhibitory effect It was also confirmed that the compound showed excellent inhibitory effect against no epinephrine or dopamine.

Accordingly, the quaternary nitrogen compound of the above-mentioned examples is expected to have a high therapeutic effect or preventive effect against not only depression or mental diseases but also premature or neuropathic pain, It is possible to effectively suppress the reabsorption of various neurotransmitters and thus to significantly reduce the adverse effects caused by the combined use of the drug and the increase in the amount of the drug.

Claims (8)

A tetrahedral ring nitrogen compound represented by the following formula:
[Chemical Formula 1]

In Formula 1,
R ₁ is cycloalkyl having 3 to 10 carbon atoms; Phenyl substituted with one or more functional groups selected from the group consisting of halogen, a straight or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group; Benzyl, which is substituted or unsubstituted with at least one functional group selected from the group consisting of halogen, a straight or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group; Naphthyl which is substituted or unsubstituted by at least one functional group selected from the group consisting of halogen, a straight or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group; Or a benzothiazole in which at least one functional group selected from the group consisting of halogen, a straight chain or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group is substituted or unsubstituted,
R ₂ is phenyl, which is substituted with one or more functional groups selected from the group consisting of halogen, a straight or branched alkyl group having 1 to 10 carbon atoms, and an alkoxy group having 1 to 10 carbon atoms; Or naphthyl which is substituted or unsubstituted by at least one functional group selected from the group consisting of halogen, a straight or branched alkyl group having 1 to 10 carbon atoms, and an alkoxy group having 1 to 10 carbon atoms,
n is an integer of 1 to 5;
delete delete (ADHD), depression, neuropathic pain, bipolar disorder, schizophrenia, mood disorder, sleep disorder, anxiety disorder, attention deficit hyperactivity disorder (ADHD) disorder, A pharmaceutical composition for preventing or treating eating disorder, premature ejaculation, or neuropathic pain.
delete delete For the prevention or treatment of depression, neuropathic pain, bipolar disorder, schizophrenia, mood disorders, sleep disorders, anxiety, attention deficit hyperactivity disorder (ADHD), eating disorders, premature ejaculation, or neuropathic pain comprising the pharmaceutical composition of claim 4. Formulation.
8. The method of claim 7,
Depression, neuropathic pain, bipolar disorder, schizophrenia, mood disorders, sleep disorders, anxiety, attention deficit hyperactivity disorder (ADHD), eating disorders with a daily dose of 0.1 mg / kg (body weight) to 4 mg / , Premature ejaculation, or neuropathic pain.