WO2014129744A1 - Four-membered cyclic nitrogen compound, pharmaceutical composition for preventing or treating depression, mental disorders, premature ejaculation or neuropathic pain, containing same, and preparation containing pharmaceutical composition - Google Patents

Four-membered cyclic nitrogen compound, pharmaceutical composition for preventing or treating depression, mental disorders, premature ejaculation or neuropathic pain, containing same, and preparation containing pharmaceutical composition Download PDF

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WO2014129744A1
WO2014129744A1 PCT/KR2014/000260 KR2014000260W WO2014129744A1 WO 2014129744 A1 WO2014129744 A1 WO 2014129744A1 KR 2014000260 W KR2014000260 W KR 2014000260W WO 2014129744 A1 WO2014129744 A1 WO 2014129744A1
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group
carbon atoms
azetidine
arh
pharmaceutical composition
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PCT/KR2014/000260
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French (fr)
Korean (ko)
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한호규
노은주
송치만
한민수
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한국과학기술연구원
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Publication of WO2014129744A1 publication Critical patent/WO2014129744A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Quaternary cyclic nitrogen compounds for the prevention or treatment of depression, mental disorders, hepatic diarrhea, or neuropathic pain comprising the same, and preparations comprising the pharmaceutical compositions
  • the present invention relates to a tetracyclic nitrogen compound, a pharmaceutical composition comprising the same, and an agent containing the pharmaceutical composition, and more particularly, it can suppress reuptake of a specific neurotransmitter, such as serotonin, which can lead to depression, High therapeutic effect or prevention against novel tetragonal nitrogen compounds, depression, certain mental disorders, premature ejaculation, or neuropathic pain that can be used as a therapeutic or prophylactic agent for mental illness, premature ejaculation, or neuropathic pain It relates to a pharmaceutical composition having an effect, and to a formulation comprising said pharmaceutical composition.
  • a specific neurotransmitter such as serotonin
  • Depression refers to a disease that causes various cognitive and psychosomatic symptoms due to decreased motivation and depression as main symptoms, leading to deterioration of daily function.
  • Depressive disorder is a lifelong prevalence of 15%, especially 25% in women, and is a serious disease that causes changes in emotions, thoughts, physical condition, and behavior.
  • Major depression does not occur for one reason. Rather, the interaction of various genes, epigenetic influences, embryological causes, and environmental influences can cause emotional disturbances.
  • Typical drugs used in the treatment of other major psychological and neurological diseases show efficacy through a variety of neurological mechanisms distributed over many parts of the brain. Similarly, pharmacology to relieve depression Anatomical and neuropsychological approaches also cannot be made effective through any one mechanism.
  • TCAs tricyclic antidepressants
  • additional TCAs such as nortriptyline, doxe in, clomipramine, etc.
  • amitriptyline and desipramine with modified tricyclic structures began to be used.
  • prozac a selective serotonin reuptake inhibitors (SSRIs)
  • SSRIs serotonin reuptake inhibitors
  • Current antidepressants include selective serotonin reuptake blockers, serotonin norepinephrine reuptake blockers, selective noepinephrine reuptake blockers, dopamine and noepinephrine reuptake blockers (DNRIs), noepinephrine and serotonin receptor antagonists (NaSSA), serotonin Receptor antagonists, serotonin reuptake blockers (SARI), selective serotonin reuptake accelerators (SSRE), and the like.
  • DNRIs dopamine and noepinephrine reuptake blockers
  • NaSSA noepinephrine and serotonin receptor antagonists
  • SARI serotonin Reuptake blockers
  • SSRE selective serotonin reuptake accelerators
  • the antidepressants used in these current treatments have a low remisssion rate, which makes them difficult to treat. Not only that, but it is expected that this will reduce the market for depression. To overcome this, it is necessary to develop a new concept of treatment that overcomes the current low remission rate.
  • serotonin reuptake inhibitors that have a therapeutic or prophylactic effect on depression or mental disorders
  • compounds having a short period of time are effective in treating premature ejaculation, and those that can inhibit reuptake of serotonin and norepinephrine are potent. It can be used as a neuropathic analgesic and it is known that the analgesic effect is larger than the tricyclic compound and the side effects are few.
  • a compound capable of inhibiting reabsorption of serotonin and norepinephrine or dopamine, which are neurotransmitters on synapses, and a pharmaceutical composition comprising the same are used for depression, mood swings, and mental disorders, as well as other diseases such as neuropathic pain and premature ejaculation.
  • a pharmaceutical composition comprising the same
  • the present invention provides a tetracyclic nitrogen compound that can be used as a therapeutic or prophylactic agent for depression, certain mental disorders, premature ejaculation, or neuropathic pain by preventing reabsorption of certain neurotransmitters with high efficiency. It is for.
  • the present invention has a high therapeutic or preventive effect on depression, certain mental disorders, premature ejaculation, or neuropathic pain, such as serotonin It is to provide a pharmaceutical composition that can effectively inhibit the reuptake of neurotransmitter.
  • the present invention is to provide a formulation comprising the pharmaceutical composition.
  • the present invention provides novel tetracyclic nitrogen compounds of the following general formula (1).
  • 3 ⁇ 4 is linear or branched alkyl having 1 to 10 carbon atoms; Cycloalkyl having 3 to 10 carbon atoms; An aryl group having 6 to 2 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 at least one; Arylalkyl groups having 7 to 20 carbon atoms; And an aromatic hetero ring having 6 to 20 carbon atoms containing at least one element selected from the group consisting of nitrogen, oxygen, and sulfur; a monovalent functional group selected from the group consisting of 3 ⁇ 4 is halogen, alkoxy group, and 1 to 5 carbon atoms.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a tetracyclic cyclic nitrogen compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a preparation for the prevention or treatment of depression mental illness, premature ejaculation, or neuropathic pain comprising the pharmaceutical composition.
  • a tetracyclic nitrogen compound, a pharmaceutical composition, and an agent for preventing or treating depression, mental illness, premature ejaculation, or neuropathic pain will be described in detail.
  • the tetracyclic nitrogen compound of Formula 1 may be provided.
  • the present inventors have synthesized a tetracyclic nitrogen compound having the specific structure, and the tetracyclic nitrogen compound prevents reabsorption of specific neurotransmitters with high efficiency so that it can cause depression, mental illness, premature ejaculation, or neuropathy. It can be used as a therapeutic or prophylactic agent for sexual pain, has been confirmed through experiments to have a high therapeutic or prophylactic effect on depression mental illness, premature ejaculation, or neuropathic pain and completed the invention.
  • the tetracyclic nitrogen compound of Formula 1 is excellent in the reuptake inhibitory effect of the serotonin, a neurotransmitter, can exhibit a high effect in the prevention or treatment of depression, mental illness, premature ejaculation, or neuropathic pain.
  • the compound further exhibits a reuptake inhibitory effect on another neurotransmitter, dopamine or noepinephrine, which is more effective in the prevention or treatment of depression, mental illness, premature ejaculation, or neuropathic pain, and combined use of drugs. You can also reduce the side effects caused by increased usage.
  • 3 ⁇ 4 is linear or branched 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 at least one; Arylalkyl groups having 7 to 20 carbon atoms; Or an aromatic hetero ring having 6 to 20 carbon atoms containing at least one element selected from the group consisting of nitrogen, oxygen, and sulfur, wherein is a halogen alkoxy group, and one selected from the group consisting of alkyl groups 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; N may be an integer of 1 to 5.
  • the alkoxy group refers to a monovalent functional group derived from an alkyl group bonded to oxygen, and specific examples thereof include methoxy group, ethoxy group, phenoxy group, and the like.
  • Aryl group means a monovalent functional group derived from arene.
  • an arylalkyl group means the alkyl group which the aryl group substituted.
  • the alkoxy group may be a phenoxy group
  • the arylalkyl group may be a benzyl group.
  • the aryl group may be a phenyl group or a naphthyl group, and an aromatic hetero ring having 6 to 20 carbon atoms including at least one element selected from the group consisting of nitrogen, oxygen, and sulfur may be benzothiazole.
  • Ri is cycloalkyl having 3 to 10 carbon atoms; Phenyl in which one or more functional groups selected from the group consisting of halogen, a linear or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group are substituted or unsubstituted; Benzyl in which at least one functional group selected from the group consisting of halogen, a linear or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group is substituted or unsubstituted; Naphthyl having one or more substituted or unsubstituted functional groups selected from the group consisting of halogen, a linear or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group; Or ban3 ⁇ 4 thiazole in which at least one functional group selected from the group consisting of halogen, a linear or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group is
  • R 2 is phenyl unsubstituted or substituted with one or more functional groups selected from the group consisting of halogen, a linear or branched alkyl group of 1 to 10 carbon atoms, and an alkoxy group of 1 to 10 carbon atoms; Or naphthyl having one or more substituted or unsubstituted functional groups selected from the group consisting of halogen, linear or branched alkyl groups having 1 to 10 carbon atoms, and alkoxy groups having 1 to 10 carbon atoms; Can be.
  • Specific examples of the halogen include F, CI, Br, I all.
  • 3 ⁇ 4 is a naphthyl group; Or halogen, phenyl substituted with a straight or branched chain alkyl group having 1 to 10 carbon atoms, or an alkoxy group having 1 to 10 carbon atoms; and it is preferable because it can prevent reabsorption of a specific neurotransmitter with high efficiency.
  • the benzyl group is more preferably a phenyl group or a naphthyl group substituted with a halogen.
  • the tetracyclic nitrogen compound of Formula 1 can be synthesized through the same process as in the following reaction. However, the following reaction formula 1 shows an example of the method for synthesizing the tetracyclic cyclic nitrogen compound of Chemical Formula 1, but the synthesis method of the tetracyclic nitrogen compound of the embodiment of the present invention is not limited thereto.
  • N-Boc-3-azetidinone and primary amine 0 ⁇ ⁇ 3 ⁇ 4 were heated in an organic solvent, and the reaction mixture was distilled under reduced pressure to remove the solvent and water, and alcohol and sodium borohydride were added to the residue. I can folkize.
  • the compound of formula (4) can be synthesized by two semi-routing paths to be described later from the compound of the intermediate formula (3) prepared by the method (i) or ( ⁇ ).
  • an organic solvent containing an inorganic or organic base such as potassium carbonate, sodium carbonate, triethylamine or pyridine
  • the compound of Intermediate Formula 3 and R 2 C3 ⁇ 4X (where X is halogen, mesyl, Leaving groups such as tosyl groups) can be reacted to obtain a compound of formula (4).
  • the compound of formula (4) can be obtained by the reductive amination of the compound of intermediate formula (3) and R 2 CH0. That is, under the organic solvent, the compound of formula 4 may be obtained by reacting the intermediate compound of formula 3 with 3 ⁇ 4CH0, sodium triacetoxyborohydride and an acid.
  • the general formula (4) synthesized by the semi-routing route A or B may deprotect the Boc group as a protecting group to obtain a novel tetracyclic nitrogen compound derivative represented by the general formula (1). More specifically, when the compound of Formula 4 dissolved in the organic solvent is stirred at room temperature in the presence of an acid, a tetracyclic nitrogen compound derivative of Formula 1 may be produced. In this case, when the salt of the tetracyclic nitrogen compound derivative of Formula 1 is produced, it is treated with saturated sodium bicarbonate water or caustic soda water to obtain the tetracyclic nitrogen compound derivative of 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 paraluenesulfonic acid may be used.
  • 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 DMS0 may be used.
  • the alcohol aliphatic alcohols having 1 to 5 carbon atoms may be used.
  • 3 ⁇ 4 to represent a functional group bonded to each compound it may be different from that defined in the formula (1).
  • a pharmaceutical composition comprising as an active ingredient a tetracyclic nitrogen compound of Formula 1 or a pharmaceutically acceptable salt thereof as described above.
  • the present inventors newly synthesized tetracyclic nitrogen compounds of Formula 1, and using these tetracyclic nitrogen compounds prevents reabsorption of specific neurotransmitters with high efficiency, resulting in depression and mental retardation.
  • it can be used as a therapeutic or prophylactic agent for diseases, premature ejaculation, or neuropathic pain and can provide a pharmaceutical composition.
  • the pharmaceutical composition may include, as an active ingredient, a tetracyclic cyclic nitrogen compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • Such pharmaceutically acceptable salts thereof include salts of pharmaceutically acceptable organic acids, and in particular oxalic acid, benzenesulfonic acid, camposulfonic acid, cinnamic acid, adipic acid, cycric acid, hydrochloric acid, methanesulfonic acid, bromine Salts of organic acids such as acid, acetic acid, fumaric acid, sulfuric acid, succinic acid, citric acid, phosphoric acid, maleic acid, nitric acid, tartaric acid, benzoic acid or carbonic acid.
  • the tetracyclic nitrogen compound of Formula 1 or a pharmaceutically acceptable salt thereof is excellent in inhibiting the reuptake of the neurotransmitter serotonin
  • the pharmaceutical composition comprising the active ingredient is depression, mental illness, premature ejaculation, or It can have a high effect on the prevention or treatment of neuropathic pain.
  • the compound additionally exhibits a reuptake inhibitory effect on another neurotransmitter, dopamine or noepinephrine, and thus the pharmaceutical composition comprising the compound of Formula 1 as an active ingredient has side effects due to complex use of the drug or an increase in the amount used. Can significantly reduce and more effectively prevent or treat depression or mental illness.
  • the pharmaceutical composition may be used for the prevention or treatment of depression, mental illness, premature ejaculation, or neuropathic pain.
  • the mental disorders may be diseases such as neuropathic pain, mood swings, schizophrenia, mood disorders, sleep disorders, anxiety, attention deficit hyperactivity disorder (ADHD) or eating disorders, and the neuropathic pain is a nervous system Refers to pain caused by primary lesions or neurological changes such as impairment.
  • the pharmaceutical composition may further comprise other pharmaceutical, pharmacologically acceptable carrier or excipient.
  • the pharmacologically acceptable carrier or excipient may be appropriately adjusted according to the formulation to which the pharmaceutical composition is applied, and is known to be commonly used in the prophylactic or therapeutic agent of depression, mental illness, premature ejaculation, or neuropathic pain. Big excipient Can be used without limitation.
  • the excipients include conventional diluents, layering agents, extenders, wetting agents, disintegrating agents and / or surfactants.
  • the content of the tetracyclic 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, the form of use, the condition of the patient and the desired effect, for example 0.1 To 99% by weight, preferably 50 to 95% by weight.
  • an agent for preventing or treating depression or mental disease including the pharmaceutical composition may be provided.
  • compositions comprising an active ingredient in the tetracyclic nitrogen compound of Formula 1 or a pharmaceutically acceptable salt thereof may prevent reabsorption of specific neurotransmitters with high efficiency, thereby reducing depression, mental illness, It can treat or prevent premature ejaculation or neuropathic pain, and minimize side effects on the human body.
  • the method of administering the agent for preventing or treating depression, mental disorders, premature ejaculation, or neuropathic pain can be all oral or parenteral routes, and the dosage form can be variously determined according to the method of use.
  • the formulations include PLASTERS, GRANULES, LOTIONS, POWDERS, SYRUPS, LIQUIDS AND SOLUTIONS, AEROSOLS, OINTMENTS ), FRUIDEXTRACTS, Emulsion (EMULSIONS), Suspension (SUSTESI0NS), Acupuncture (INFUSIONS), Tablets (TABLETS), INJECTIONS, Capsules (CAPSULES) or Pills (PILLS) Can be used.
  • the preparation for the prevention or treatment of depression, mental illness, premature ejaculation, or neuropathic pain may be determined in consideration of the age, sex, condition, hop count of the active ingredient, inactivation rate and the drug used in the body.
  • a food comprising a tetracyclic nitrogen compound of Formula 1 may be provided.
  • the food is meant to include not only conventional foods, but also health supplements or food additives.
  • the food, health supplements or food additives are not limited to, for example, special nutritional products (e.g., delicatessen, young, baby food, etc.), processed meat products, fish products, tofu, jelly, noodles (e.g. ramen, Noodles, breads, functional foods, seasoned foods (e.g., soy sauce, miso, red pepper paste, mixed soy sauce), sauces, confectionery (e.g. snacks), dairy products (e.g. fermented milk, cheese, etc.), other processed foods, kimchi, Pickled foods (various kimchi pickles, etc.), beverages (e.g. fruits, vegetable drinks, soy milk, fermented beverages, etc.), natural seasonings (e.g. ramen soup, etc.).
  • special nutritional products e.g., delicatessen, young, baby food, etc.
  • processed meat products e.g., fish products, tofu, jelly, noodles (e.
  • quaternary cyclic nitrogen compounds which can be used as a therapeutic or prophylactic agent for depression, mental illness, premature ejaculation, or neuropathic pain by preventing specific neurotransmitters with high efficiency of resorption, serotonin and dopamine Or a pharmaceutical composition capable of inhibiting reuptake of noepinephrine and having a high therapeutic or prophylactic effect on depression, mental illness, premature ejaculation, or neuropathic pain, and a formulation comprising the pharmaceutical composition.
  • 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 give ier -butyl 3- (naphthalen-2-ylamino) azetidine-l-carboxylate (3.8g, yield 92%) as a light brown solid.
  • the reaction mixture was extracted with methylene chloride (3 ⁇ 50 mL) and dried over anhydrous magnesium sulfate.
  • the yellow oily liquid obtained by evaporation of the solvent under reduced pressure was purified by flash chromatography.
  • the colorless and transparent oily liquid er -butyl 3- eye 1 ohexy 1 am i no) aze tidi ne- 1-carboxylate (5.5 g, yield 74%).
  • the brown oily liquid obtained by evaporation of the solvent under reduced pressure was purified by flash chromatography.
  • the light yellow oily liquid ieri-butyl 3- (benzy 1 (napht ha 1 en-2-y 1) am i no) aze tidi ne 1-car boxy late (0.23 g, yield 58%) was obtained.
  • the reaction mixture was extracted with methylene chloride and dried over anhydrous magnesium sulfate.
  • the pale yellow oily liquid obtained by evaporation of the solvent under reduced pressure was purified by flash chromatography.
  • An oily liquid, tert-butyl 3- (phenethyl (phenyl) amino) azet idine-1-carboxylate (0.24 g, yield 86%) was obtained.
  • 9UIUIB_g_Uipi 9ZBlAU9l [(I-N- (l q3 ⁇ 49UI ⁇ A-2-U9iBl [qclBU)- ⁇ : 9 [tp [y ⁇
  • Example 29 Synthesis was carried out by the same method as N-benzyl-N- (2,4-dimethylphenyl) azet idin-3-amine.
  • Example 62 N- (3, 4-di chl orobenzyl) -N to (naphthal en-2-yl) azet i din-3-amine
  • reuptake inhibitory activity was tested in vitro. This activity refers to the ability of the compound synthesized in the Examples to block the number of hops of the neurotransmitter via the monovalent amine neurotransmitter transporter dopamine, serotonin and noepinephrine transporter.
  • a high-throughput screening system FDSS6000 Full-throughput Screening System 6000 was used.
  • HEK293 cell lines (HEK-hDAT, HEK-hNET; North Carolina-Chapel) stably expressing human dopamine, serotonin and noepinephrine transporters, respectively (Provided by Professor Bryan Roth, Hill University), the activity of the synthesized compounds was tested.
  • HEX293 cells stably expressing each transporter were added with 10% (v / v) fetal bovine serum, penicillin (penicillin, 100 U / ml), and streptomycin (100 yg / ml).
  • Dulbecco's modified Eagle's medium (Deubecco's medium, Wei gene, Daegu, Korea) was incubated in an incubator at 37 ° C 5% carbon dioxide humidification conditions and passaged once every 3-4 days.
  • HEK-hDAT cell line 350 mg / ml of HEK-hDAT cell line and 200 mg / ml of HEK-hNET cell line were added and cultured (37 ° C 5%). Carbon dioxide, humidifier incubator).
  • the reuptake inhibitory activity mimics DA (dopamine), 5-HT (serotonin) and NE (noepinephrine) and includes a neurotransmitter transporter uptake assay kit, Molecular Devices, Sunnyvale, CA, USA), after treatment with the blocking agent, the intracellular resorption of the indicator was measured by a fluorescence signal.
  • the indicator used was included in the kit.
  • the assay kit mimics dopamine, serotonin, and noepinephrine, and contains a fluorescent dye-labeled indicator in powder form, which was dissolved in HEPES buffer and used in the experiment. Only one type of indicator was included in the assay kit, and the same type of indicator was used for all dopamine, serotonin, and noepinephrine reuptake experiments.
  • the cells attached to the 96-well plate were placed in a 96-well plate auto washer ELx405 Select CW (BioTek Instruments, Winooski, VT, USA). After washing for 3 dilution with HEPES buffer (unit mM: 150 NaCI, 5 KC1, 2 CaCl 2 , lMgCl 2) 10Glucose, 10HEPES, pH7.4 ) , add the dye solution prepared according to the manufacturer's instructions and immediately fluoresce Intensity was measured. Resorption of the fluorescently labeled indicator was measured for 30 minutes using a FDSS6000 instrument (Hamamatsu Photonics, Hamamatsu, Japan) as a change in fluorescence intensity according to the concentration of the intracellular indicator.
  • HEPES buffer unit mM: 150 NaCI, 5 KC1, 2 CaCl 2 , lMgCl 2
  • 10Glucose 10HEPES, pH7.4
  • the change in intracellular fluorescence intensity was determined by the final fluorescence intensity (Endpoint) measured 30 minutes after the start of fluorescence intensity measurement.
  • Detailed fluorescence imaging techniques include the use of a computer-controlled filter wheel to selectively expose cells with an excitation wavelength of 440 nm from the four xenon lamp light sources mounted on the FDSS6000 to the cells, and then to 515 nm long- The past emission fluorescence was measured every 10 seconds at 520 nm with a cold CCD camera built into the instrument through a pass filter.
  • test drug containing the tetracyclic nitrogen compounds synthesized in the examples in an incubator at 37 ° C 5% carbon dioxide humidification conditions for 15 minutes.
  • Dye solution was added. More specifically, the test drug is a solution of HEPES (unit mM: 150 NaCI, 5 C1, 2 CaCl 2> lMgCl 2) lOGlucose, lOHEPES to make DMS0 100 mM solution of tetracyclic nitrogen compounds and the final test drug concentration is 10 ⁇ . , pH7.4) was added. Immediately after the dye solution was added to the cells, the fluorescence intensity was measured and the final fluorescence intensity (Endpoint) was obtained by measuring the fluorescence intensity change in the cell for 30 minutes.
  • HEPES unit mM: 150 NaCI, 5 C1, 2 CaCl 2> lMgCl 2
  • lOGlucose lOHEPES to make DMS0 100 mM solution of tetracyclic nitrogen compounds and the final test drug
  • the tetracyclic nitrogen compound synthesized in the Example showed a superior effect on serotonin inhibition than Fluoxetine, a conventional serotonin inhibitor, and Fluoxetine almost showed an inhibitory effect. It was also confirmed that excellent inhibitory effects were observed for no-epinephrine and dopamine.
  • the tetracyclic nitrogen compounds of the above embodiments are expected to have a high therapeutic or prophylactic effect on depression, or mental disorders, as well as premature ejaculation or neuropathic pain, and include a serotonin as a single compound. Since the reuptake of various neurotransmitters can be effectively suppressed, it is possible to significantly reduce the side effects caused by the combined use of the drug or the increase in the amount used.

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Abstract

The present invention relates to: a novel four-membered cyclic nitrogen compound capable of being used as an agent for treating or preventing depression, mental disorders, premature ejaculation or neuropathic pain by highly preventing the reabsorption of a specific neurotransmitter; a pharmaceutical composition capable of inhibiting the reabsorption of seretonin and dopamine or norepinephrine and having a high effect of treating or preventing depression, mental disorders, premature ejaculation or neuropathic pain; and a preparation containing the pharmaceutical composition.

Description

【명세서】  【Specification】
【발명의 명칭】  [Name of invention]
4 각 고리 질소 화합물, 이를 포함하는 우을증, 정신 질환, 조투증, 또는 신경병증성 통증의 예방 또는 치료용 약학 조성물， 및 상기 약학 조성물을 포함하는 제제  Quaternary cyclic nitrogen compounds, pharmaceutical compositions for the prevention or treatment of depression, mental disorders, hepatic diarrhea, or neuropathic pain comprising the same, and preparations comprising the pharmaceutical compositions
[기술분야】 [Technical Field]
본 발명은 4 각 고리 질소 화합물， 이를 포함하는 약학 조성물， 및 상기 약학 조성물올 포함하는 제제에 관한 것으로서， 보다 상세하게는 특정 신경 전달 물질인 세레토닌 등의 재흡수를 억제할 수 있어 우울증, 정신 질환， 조루증， 또는 신경병증성 통증 (neuropathic pain)의 치료제 또는 예방제로 사용될 수 있는 신규한 4각 고리 질소 화합물， 우울증， 특정 정신 질환, 조루증， 또는 신경병증성 통증에 대하여 높은 치료 효과 또는 예방 효과를 가지는 약학 조성물, 및 상기 약학 조성물올 포함하는 제제에 관한 것이다.  The present invention relates to a tetracyclic nitrogen compound, a pharmaceutical composition comprising the same, and an agent containing the pharmaceutical composition, and more particularly, it can suppress reuptake of a specific neurotransmitter, such as serotonin, which can lead to depression, High therapeutic effect or prevention against novel tetragonal nitrogen compounds, depression, certain mental disorders, premature ejaculation, or neuropathic pain that can be used as a therapeutic or prophylactic agent for mental illness, premature ejaculation, or neuropathic pain It relates to a pharmaceutical composition having an effect, and to a formulation comprising said pharmaceutical composition.
【발명의 배경이 되는 기술】 [Technique to become background of invention]
우울증， 즉 우울장애는 의욕 저하와 우울감을 주요 증상으로 하여 다양한 인지 및 정신 신체적 증상을 일으켜 일상 기능의 저하를 가져오는 질환을 의미한다. 우울장애는 평생 유병율이 15%, 특히 여자에서는 25% 정도에 이르며, 감정， 생각, 신체 상태， 그리고 행동 등에 변화를 일으키는 심각한 질환이다.  Depression, or depressive disorder, refers to a disease that causes various cognitive and psychosomatic symptoms due to decreased motivation and depression as main symptoms, leading to deterioration of daily function. Depressive disorder is a lifelong prevalence of 15%, especially 25% in women, and is a serious disease that causes changes in emotions, thoughts, physical condition, and behavior.
주요 우울증은 한 가지의 원인으로 발생하지 않는다. 오히려 다양한 종류의 유전자의 상호작용， 후성학적인 영향, 발생학적 원인， 그리고 환경적 영향 등이 복합적으로 감정을 손상시켜서 정서 장애를 일으키게 된다.  Major depression does not occur for one reason. Rather, the interaction of various genes, epigenetic influences, embryological causes, and environmental influences can cause emotional disturbances.
다른 주요 정신병이나 신경학적인 질병들의 치료에 쓰이는 전형적인 약물들은 뇌의 많은 부분에 걸쳐서 분포되어 있는 다양한 신경 기전을 통하여 효능을 나타낸다. 유사하게， 우울증을 경감시키기 위한 약리학적， 해부학적， 그리고 신경정신학적 접근 또한 어떤 한 가지의 기전을 통해서만 효능을 나타내도록 이루어질 수는 없다. Typical drugs used in the treatment of other major psychological and neurological diseases show efficacy through a variety of neurological mechanisms distributed over many parts of the brain. Similarly, pharmacology to relieve depression Anatomical and neuropsychological approaches also cannot be made effective through any one mechanism.
현대적인 항우울제의 개발은 결핵약으로 개발된 iproniazid 가 단가아민효소 억제제 (monoamine oxidase inhibitors: MAOIs)로서 항우울효과가 있다는 것이 입증된 이후부터 활발해 졌다. 항정신병약물인 ch lor promazine 이 1950 초 항히스타민제로 개발되고 정신분열병 치료에 효과가 있음이 증명되고， 이와 유사하게 1955 년 스위스의 Geigy Drug Co.에서 항히스타민제로 개발된 imipramine을 합성되면서부터 활성화되었다. 이 발견을 통하여 삼환계 항우울제 (tricyclic antidepressants; TCA)의 발전을 가져왔고, 삼환 구조를 변형한 amitriptyline이나 desipramine 외에 nortriptyline, doxe in, clomipramine 등의 많은 부가적인 TCA 들이 사용되기 시작하였다.  The development of modern antidepressants has been active since it has been demonstrated that iproniazid, a tuberculosis drug, has antidepressant effects as monoamine oxidase inhibitors (MAOIs). Chlor lor promazine, an antipsychotic drug, was developed as an antihistamine in the early 1950s and proved effective in treating schizophrenia.Similarly, it was activated by the synthesis of imipramine, an antihistamine developed by Geigy Drug Co., Switzerland, in 1955. This discovery led to the development of tricyclic antidepressants (TCAs), and many additional TCAs such as nortriptyline, doxe in, clomipramine, etc., in addition to amitriptyline and desipramine with modified tricyclic structures, began to be used.
이후 2 세대와 3 세대 항우울제가 개발되었는데， 1980 년대 초 구조 및 효능이 비슷한 maproti 1 ine 과 amoxa ine 같은 }환계 합성물 (tetracyclic compounds)이 판매되었고， heterocyclics 라 불리기도 한다.  Later, second and third generation antidepressants were developed. In the early 1980s, tetracyclic compounds, such as maproti 1 ine and amoxa ine, which were similar in structure and potency, were sold, also called heterocyclics.
1980 년대 선택적 세로토닌 재흡수 억제제 (selective serotonin reuptake inhibitors; SSRIs)인 prozac 이 개발되어 좋은 치료제로 사용되고 있으나, 그 부작용으로 항콜린 작용인 구갈， 변비, 배뇨곤란， 시력장애， 발기 부전 등이 나타나고， 심혈관계에 대한 작용으로 혈압， 맥박， 심장전도 (cardiac conduction) 등에 상당한 영향을 미치며， 1-adrenergic 수용체의 차단으로 인한 기립성 저혈압이 나타나고, 항히스타민 효과로 진정작용이 나타남이 보고되었다.  In the 1980s, prozac, a selective serotonin reuptake inhibitors (SSRIs), was developed and used as a good treatment, but its side effects include anticholinergic action such as dry mouth, constipation, difficulty in urination, vision impairment, and erectile dysfunction. It has been reported to have a significant effect on blood pressure, pulse rate, cardiac conduction, and orthostatic hypotension due to the blocking of 1-adrenergic receptors, and sedation by antihistamine effects.
현재 사용되는 우울증 치료제로서, 선택적인 세로토닌 재흡수 차단제， 세로토닌 노에피네프린 재흡수 차단제， 선택적 노에피네프린 재흡수 차단제, 도파민과 노에피네프린 재흡수 차단제 (DNRI), 노에피네프린과 세로토닌 수용체 길항제 (NaSSA), 세로토닌수용체 길항과 세로토닌 재흡수 차단제 (SARI), 선택적 세로토닌 재흡수 촉진제 (SSRE) 등이 있다.  Current antidepressants include selective serotonin reuptake blockers, serotonin norepinephrine reuptake blockers, selective noepinephrine reuptake blockers, dopamine and noepinephrine reuptake blockers (DNRIs), noepinephrine and serotonin receptor antagonists (NaSSA), serotonin Receptor antagonists, serotonin reuptake blockers (SARI), selective serotonin reuptake accelerators (SSRE), and the like.
이러한 현재 치료에 사용되고 있는 우울증 치료제는 낮은 관해율 (remisssion rate)을 보이고 있어, 현재의 약물로는 층분한 치료효과를 얻을 수 없을 뿐 아니라, 이로 인하여 향후 우울제 시장이 축소될 것이 전망되고 있다. 이의 극복올 위해서는 현재의 낮은 관해율을 극복하는 새로운 개념의 치료제 개발이 필요하다. The antidepressants used in these current treatments have a low remisssion rate, which makes them difficult to treat. Not only that, but it is expected that this will reduce the market for depression. To overcome this, it is necessary to develop a new concept of treatment that overcomes the current low remission rate.
또한， 우울증은 여러 가지 원인으로 인해 발병하는 만큼， 여러 신경전달물질의 재흡수를 억제하기 위하여 수 종의 약물을 함께 투여하여야 하였으나， 이로 인해 약물을 필요 이상으로 섭취 또는 투여 하게 되어, 성기능 장애와 체중 증가 등과 같은 대표적인 부작용 이외， 예상치 못한 부작용들이 나타나고 있다.  In addition, as depression occurs due to various causes, several drugs must be administered together to suppress reabsorption of various neurotransmitters. However, the drug is ingested or administered more than necessary, resulting in sexual dysfunction and In addition to the typical side effects such as weight gain, unexpected side effects are appearing.
따라서 여러 신경 전달 물질의 재흡수를 효과적으로 억제 할 수 있어 이러한 부작용을 최소화하고, 우을증 또는 정신 질환의 예방 또는 치료에 높은 효과를 나타낼 수 있는 새로운 항우울제의 개발이 필요하다.  Therefore, there is a need for the development of new antidepressants that can effectively suppress the reuptake of several neurotransmitters, thereby minimizing these side effects and exhibiting high effects in the prevention or treatment of depression or mental illness.
한편， 우울증 또는 정신질환에 대하여 치료 또는 예방효과를 가지는 세로토닌 재흡수 억제제 중에서 짧은 시간 동안 작용하는 특징을 가진 화합물은 조루증 치료에 효과적이며， 세로토닌과 노르에피네프린의 재흡수를 억제할 수 있는 화합물은 강력한 신경병증성 진통제로 사용될 수 있으며 삼환계 화합물보다 진통효과가 크고 부작용은 적음이 알려져 있다. 즉， 시냅스 상의 신경전달물질인 세로토닌 및 노르에피네프린 또는 도파민의 재흡수를 억제할 수 있는 화합물과 이를 포함하는 약학 조성물은 우울증, 조울증, 및 정신질환뿐만 아니라, 신경병증성 통증， 조루증 등 다른 질환에도 적용될 수 있어서， 관련 연구를 통한 연구 개발로 항우울제의 시장의 외연올 확장할 수 있는 가능성이 있다.  On the other hand, among the serotonin reuptake inhibitors that have a therapeutic or prophylactic effect on depression or mental disorders, compounds having a short period of time are effective in treating premature ejaculation, and those that can inhibit reuptake of serotonin and norepinephrine are potent. It can be used as a neuropathic analgesic and it is known that the analgesic effect is larger than the tricyclic compound and the side effects are few. That is, a compound capable of inhibiting reabsorption of serotonin and norepinephrine or dopamine, which are neurotransmitters on synapses, and a pharmaceutical composition comprising the same, are used for depression, mood swings, and mental disorders, as well as other diseases such as neuropathic pain and premature ejaculation. As a result, research and development through related research have the potential to expand the market of antidepressants.
【발명의 내용] [Contents of the Invention]
【해결하고자 하는 과제】  Problem to be solved
본 발명은， 특정 신경 전달 물질들의 재흡수를 높은 효율로 방지하여 우울증， 특정 정신 질환， 조루증， 또는 신경병증성 통증 (neuropathic pain)의 치료제 또는 예방제로 사용될 수 있는 4 각 고리 질소 화합물을 제공하기 위한 것이다.  The present invention provides a tetracyclic nitrogen compound that can be used as a therapeutic or prophylactic agent for depression, certain mental disorders, premature ejaculation, or neuropathic pain by preventing reabsorption of certain neurotransmitters with high efficiency. It is for.
또한， 본 발명은 우울증， 특정 정신 질환， 조루증， 또는 신경병증성 통증에 대하여 높은 치료 효과 또는 예방 효과를 가지며， 세로토닌 등의 신경 전달 물질의 재흡수를 효과적으로 억제할 수 있는 약학 조성물을 제공하기 위한 것이다. In addition, the present invention has a high therapeutic or preventive effect on depression, certain mental disorders, premature ejaculation, or neuropathic pain, such as serotonin It is to provide a pharmaceutical composition that can effectively inhibit the reuptake of neurotransmitter.
또한， 본 발명은 상기 약학 조성물을 포함하는 제제를 제공하기 위한 것이다. 【과제의 해결 수단】  In addition, the present invention is to provide a formulation comprising the pharmaceutical composition. [Measures of problem]
본 발명은 신규한 하기 화학식 1 의 4 각 고리 질소 화합물을 제공한다.  The present invention provides novel tetracyclic nitrogen compounds of the following general formula (1).
Figure imgf000005_0001
Figure imgf000005_0001
상기 화학식 1 에서, ¾은 탄소수 1 내지 10 의 직쇄 또는 분지쇄의 알킬; 탄소수 3 내지 10 의 사이클로 알킬; 할로겐， 알콕시기 및 탄소수 1 내지 5 의 알킬기로 이루어진 군에서 선택된 1 종 이상의 작용기가 1 이상 치환되거나 비치환된 탄소수 6 내지 2이 의 아릴기; 탄소수 7 내지 20 의 아릴알킬기; 및 질소， 산소 및 황으로 이루어진 군에서 선택된 1 종 이상의 원소를 포함하는 탄소수 6 내지 20 의 방향족 헤테로 고리;로 이루어진 군에서 선택된 1 가 작용기이고， ¾는 할로겐， 알콕시기, 및 탄소수 1 내지 5 의 알킬기로 이루어진 군에서 선택된 1 종 이상의 작용기가 1 이상 치환되거나 비치환된 탄소수 6 내지 20의 아릴기 ; 인 1가 작용기이고， n은 1 내지 5의 정수이다.  In Chemical Formula 1, ¾ is linear or branched alkyl having 1 to 10 carbon atoms; Cycloalkyl having 3 to 10 carbon atoms; An aryl group having 6 to 2 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 at least one; Arylalkyl groups having 7 to 20 carbon atoms; And an aromatic hetero ring having 6 to 20 carbon atoms containing at least one element selected from the group consisting of nitrogen, oxygen, and sulfur; a monovalent functional group selected from the group consisting of ¾ is halogen, alkoxy group, and 1 to 5 carbon atoms. An aryl group having 6 to 20 carbon atoms in which one or more functional groups selected from the group consisting of alkyl groups are substituted or unsubstituted; Phosphorous monovalent functional group, n is an integer of 1-5.
또한， 본 발명은 상기 화학식 1 의 4각 고리 질소 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 약학 조성물을 제공한다.  In addition, the present invention provides a pharmaceutical composition comprising a tetracyclic cyclic nitrogen compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
또한， 본 발명은 상기 약학 조성물을 포함하는 우울증 정신 질환， 조루증， 또는 신경병증성 통증의 예방또는 치료용 제제를 제공한다. 이하 발명의 구체적인 구현예에 따른 4 각 고리 질소 화합물, 약학 조성물， 및 우울증, 정신 질환， 조루증， 또는 신경병증성 통증의 예방 또는 치료용 제제에 관하여 보다 상세하게 설명하기로 한다. 발명의 일 구현예에 따르면， 상기 화학식 1 의 4 각 고리 질소 화합물이 제공될 수 있다. In addition, the present invention provides a preparation for the prevention or treatment of depression mental illness, premature ejaculation, or neuropathic pain comprising the pharmaceutical composition. Hereinafter, a tetracyclic nitrogen compound, a pharmaceutical composition, and an agent for preventing or treating depression, mental illness, premature ejaculation, or neuropathic pain according to specific embodiments of the present invention will be described in detail. According to one embodiment of the invention, the tetracyclic nitrogen compound of Formula 1 may be provided.
본 발명자들은, 상기 특정 구조를 갖는 4 각 고리 질소 화합물을 새로이 합성해냈으며, 이러한 4 각 고리 질소 화합물이 특정 신경 전달 물질들의 재흡수를 높은 효율로 방지하여 우을증， 정신 질환， 조루증, 또는 신경병증성 통증의 치료제 또는 예방제로 사용될 수 있으며， 우울증 정신 질환, 조루증, 또는 신경병증성 통증에 대하여 높은 치료 효과 또는 예방 효과를 가지는 것을 실험을 통하여 확인하고 발명을 완성하였다.  The present inventors have synthesized a tetracyclic nitrogen compound having the specific structure, and the tetracyclic nitrogen compound prevents reabsorption of specific neurotransmitters with high efficiency so that it can cause depression, mental illness, premature ejaculation, or neuropathy. It can be used as a therapeutic or prophylactic agent for sexual pain, has been confirmed through experiments to have a high therapeutic or prophylactic effect on depression mental illness, premature ejaculation, or neuropathic pain and completed the invention.
특히， 상기 화학식 1 의 4 각 고리 질소 화합물은 신경 전달 물질인 세로토닌의 재흡수 억제 효과가 뛰어나， 우울증, 정신 질환, 조루증, 또는 신경병증성 통증의 예방 또는 치료에 높은 효과를 나타낼 수 있다. 또한， 상기 화합물은 또 다른 신경 전달 물질인 도파민 또는 노에피네프린에 대한 재흡수 억제 효과를 추가적으로 나타냄으로써 우울증， 정신 질환, 조루증， 또는 신경병증성 통증의 예방 또는 치료에 보다 효과적이고， 약물의 복합 사용이나 사용량 증가 등에 따라 나타나는 부작용을 감소시킬 수 있다.  In particular, the tetracyclic nitrogen compound of Formula 1 is excellent in the reuptake inhibitory effect of the serotonin, a neurotransmitter, can exhibit a high effect in the prevention or treatment of depression, mental illness, premature ejaculation, or neuropathic pain. In addition, the compound further exhibits a reuptake inhibitory effect on another neurotransmitter, dopamine or noepinephrine, which is more effective in the prevention or treatment of depression, mental illness, premature ejaculation, or neuropathic pain, and combined use of drugs. You can also reduce the side effects caused by increased usage.
상기 화학식 1 에서， 상기 ¾ 은 탄소수 1 내지 10 의 직쇄 또는 분지쇄의 알킬; 탄소수 3 내지 10 의 사이클로 알킬; 할로겐， 알콕시기 및 탄소수 1 내지 5 의 알킬기로 이루어진 군에서 선택된 1 종 이상의 작용기가 1 이상 치환되거나 비치환된 탄소수 6 내지 20 의 아릴기; 탄소수 7 내지 20 의 아릴알킬기; 또는 질소， 산소 및 황으로 이루어진 군에서 선택된 1 종 이상의 원소를 포함하는 탄소수 6 내지 20 의 방향족 헤테로 고리일 수 있으며, 상기 는 할로겐 알콕시기， 및 탄소수 1 내지 5 의 알킬기로 이루어진 군에서 선택된 1 종 이상의 작용기가 1 이상 치환되거나 비치환된 탄소수 6 내지 20의 아릴기 ; 일 수 있고， n은 1 내지 5의 정수일 수 있다. 상기 알콕시기는 산소와 결합된 알킬기로부터 유래한 1 가 작용기를 의미하며 구체적인 예로는 메톡시기, 에특시기, 페녹시기 등을 들 수 있고， 아릴기 (aryl)는 아렌 (arene)으로부터 유래한 1 가 작용기를 의미한다. 또한 아릴알킬기는 아릴기가 치환된 알킬기를 의미한다. In Chemical Formula 1, ¾ is linear or branched 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 at least one; Arylalkyl groups having 7 to 20 carbon atoms; Or an aromatic hetero ring having 6 to 20 carbon atoms containing at least one element selected from the group consisting of nitrogen, oxygen, and sulfur, wherein is a halogen alkoxy group, and one selected from the group consisting of alkyl groups 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; N may be an integer of 1 to 5. The alkoxy group refers to a monovalent functional group derived from an alkyl group bonded to oxygen, and specific examples thereof include methoxy group, ethoxy group, phenoxy group, and the like. Aryl group means a monovalent functional group derived from arene. In addition, an arylalkyl group means the alkyl group which the aryl group substituted.
바람직하게는 상기 알콕시기는 페녹시기 일 수 있고， 상기 아릴알킬기는 벤질기 일 수 있다. 또한 상기 아릴기는 페닐기， 또는 나프틸기 일 수 있고, 질소， 산소 및 황으로 이루어진 군에서 선택된 1 종 이상의 원소를 포함하는 탄소수 6 내지 20 의 방향족 헤테로 고리는 벤조티아졸 일 수 있다.  Preferably, the alkoxy group may be a phenoxy group, and the arylalkyl group may be a benzyl group. In addition, the aryl group may be a phenyl group or a naphthyl group, and an aromatic hetero ring having 6 to 20 carbon atoms including at least one element selected from the group consisting of nitrogen, oxygen, and sulfur may be benzothiazole.
또한， 상기 Ri 은 탄소수 3 내지 10 의 사이클로 알킬; 할로겐， 탄소수 1 내지 10 의 직쇄 또는 분지쇄의 알킬기, 및 페녹시기로 이루어진 군에서 선택되는 작용기가 1 이상 치환되거나 비치환된 페닐; 할로겐, 탄소수 1 내지 10 의 직쇄 또는 분지쇄의 알킬기， 및 페녹시기로 이루어진 군에서 선택되는 작용기가 1 이상 치환되거나 비치환된 벤질; 할로겐， 탄소수 1 내지 10 의 직쇄 또는 분지쇄의 알킬기， 및 페녹시기로 이루어진 군에서 선택되는 작용기가 1 이상 치환되거나 비치환된 나프틸; 또는 할로겐， 탄소수 1 내지 10 의 직쇄 또는 분지쇄의 알킬기, 및 페녹시기로 이-루어진 군에서 선택되는 작용기가 1 이상 치환되거나 비치환된 밴¾티아졸; 일 수 있다. 상기 할로겐의 구체적인 예로는 F, CI, Br, I 등을 들 수 있다.  In addition, Ri is cycloalkyl having 3 to 10 carbon atoms; Phenyl in which one or more functional groups selected from the group consisting of halogen, a linear or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group are substituted or unsubstituted; Benzyl in which at least one functional group selected from the group consisting of halogen, a linear or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group is substituted or unsubstituted; Naphthyl having one or more substituted or unsubstituted functional groups selected from the group consisting of halogen, a linear or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group; Or ban¾ thiazole in which at least one functional group selected from the group consisting of halogen, a linear or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group is substituted or unsubstituted; Can be. Specific examples of the halogen include F, CI, Br, I and the like.
그리고, 상기 R2는 할로겐, 탄소수 1 내지 10의 직쇄 또는 분지쇄의 알킬기, 및 탄소수 1 내지 10 의 알콕시기로 이루어진 군에서 선택되는 작용기가 1 이상 치환되거나 비치환된 페닐; 또는 할로겐， 탄소수 1 내지 10 의 직쇄 또는 분지쇄의 알킬기， 및 탄소수 1 내지 10 의 알콕시기로 이루어진 군에서 선택되는 작용기가 1 이상 치환되거나 비치환된 나프틸; 일 수 있다. 상기 할로겐의 구체적인 예로는 F, CI, Br, I 올 들 수 있다. And, R 2 is phenyl unsubstituted or substituted with one or more functional groups selected from the group consisting of halogen, a linear or branched alkyl group of 1 to 10 carbon atoms, and an alkoxy group of 1 to 10 carbon atoms; Or naphthyl having one or more substituted or unsubstituted functional groups selected from the group consisting of halogen, linear or branched alkyl groups having 1 to 10 carbon atoms, and alkoxy groups having 1 to 10 carbon atoms; Can be. Specific examples of the halogen include F, CI, Br, I all.
상기 ¾는 나프틸기; 또는 할로겐， 탄소수 1 내지 10 의 직쇄 또는 분지쇄의 알킬기， 또는 탄소수 1 내지 10 의 알콕시기로 치환된 페닐;인 것이 특정 신경전달물질의 재흡수를 높은 효율로 방지할 수 있어 바람직하며, 특히 R1 이 벤질기인 경우 할로겐으로 치환된 페닐기 또는 나프틸기인 것이 더욱 바람직하다. 한편, 상기 화학식 1 의 4 각 고리 질소 화합물은 하기 반웅식 1 과 같은 과정을 통하여 합성할 수 있다. 다만 하기 반웅식 1 은 상기화학식 1의 4각 고리 질소 화합물의 합성 방법의 일 예를 나타난 것으로세 상기 발명의 일 구현예의 4 각 고리 질소 화합물의 합성 방법이 이에 한정되는 것은 아니다. ¾ is a naphthyl group; Or halogen, phenyl substituted with a straight or branched chain alkyl group having 1 to 10 carbon atoms, or an alkoxy group having 1 to 10 carbon atoms; and it is preferable because it can prevent reabsorption of a specific neurotransmitter with high efficiency. The benzyl group is more preferably a phenyl group or a naphthyl group substituted with a halogen. On the other hand, the tetracyclic nitrogen compound of Formula 1 can be synthesized through the same process as in the following reaction. However, the following reaction formula 1 shows an example of the method for synthesizing the tetracyclic cyclic nitrogen compound of Chemical Formula 1, but the synthesis method of the tetracyclic nitrogen compound of the embodiment of the present invention is not limited thereto.
[반응식 1]  Scheme 1
Figure imgf000008_0001
반응조건 반응조건
Figure imgf000008_0001
Reaction conditions reaction conditions
(a) K2C03, D F, 150°C (a) K 2 C0 3 , DF, 150 ° C
방법 (i) NaBH(OAc)3, AcOH, CH2CI2, r.t. Method (i) NaBH (OAc) 3 , AcOH, CH 2 CI 2 , rt
(b) NaBH(OAc)3, AcOH, CH2Cl2, r.t. (b) NaBH (OAc) 3 , AcOH, CH 2 Cl 2 , rt
방법 (ii) toluene, 110°C, NaBH4, MeOH. r.t. Method (ii) toluene, 110 ° C., NaBH 4 , MeOH. rt
(c) TFA, CH2CI2,r.t. 상기 [반응식 1]에 나타난 바와 같이, 화학식 2 의 N-Boc-3- azetidinone 에 1 차 아민 (RiN¾)의 환원적 아민화 (reductive amination)에 의해서 중간체 화학식 3 의 화합물올 얻을 수 있다. 상기 환원적 아민화는 후술할 방법 (i) 또는 (ii)에 의하여 수행 할 수 있다. 방법 G)에 의하면, 화학식 2 의 N-Boc-3-azetidinone 에 1 차 아민 ¾Ν¾)과 sodium triacetoxyborohydride, 산을 가하여 상온에서 교반하여 환원적 아민화 할 수 있고 방법 (ii)에 의하면, 화학식 2 의 N-Boc-3-azetidinone 과 1 차 아민 0^Ν¾)을 유기 용매에서 가열한 후 반웅 흔합물을 감압증류하여 용매와 생성된 물을 제거하고 잔류물에 알코올과 sodium borohydride 를 첨가하여 환원적 아민화 할 수 있다. (c) TFA, CH 2 CI 2 , rt As shown in [Scheme 1], an intermediate by reductive amination of primary amine (RiN¾) in N-Boc-3-azetidinone of formula (2) The compound of formula (3) can be obtained. The reductive amination may be carried out by the method (i) or (ii) described later. According to method G), primary amine ¾Ν¾), sodium triacetoxyborohydride and an acid can be added to N-Boc-3-azetidinone of formula (2) and stirred at room temperature for reductive amination. According to method (ii), N-Boc-3-azetidinone and primary amine 0 ^ Ν¾) were heated in an organic solvent, and the reaction mixture was distilled under reduced pressure to remove the solvent and water, and alcohol and sodium borohydride were added to the residue. I can folkize.
그리고 상기 방법 (i) 또는 (Π)에 의하여 제조된 중간체 화학식 3 의 화합물로부터 후술할 2 가지 반웅경로에 의하여 화학식 4 의 화합물을 합성 할 수 있다. 반응경로 A 에 의하면, potassium carbonate, sodium carbonate, 트리에틸아민 또는 피리딘 등의 무기 또는 유기염기를 포함하는 유기용매에， 중간체 화학식 3의 화합물과 R2C¾X(여기서 X는 할로겐， 메실, 토실기 등의 이탈기)를 반웅시켜 화학식 4 의 화합물을 얻을 수 있다. 그리고， 반응경로 B 에 의하면， 중간체 화학식 3 의 화합물과 R2CH0 의 환원적 아민화에 의해서 화학식 4 의 화합물을 얻을 수 있다. 즉， 유기용매 하에서， 화학식 3 의 증간체 화합물을 ¾CH0, sodium triacetoxyborohydride 및 산과 반응시켜 화학식 4의 화합물을 얻을 수 있다, And the compound of formula (4) can be synthesized by two semi-routing paths to be described later from the compound of the intermediate formula (3) prepared by the method (i) or (Π). According to Reaction Path A, an organic solvent containing an inorganic or organic base such as potassium carbonate, sodium carbonate, triethylamine or pyridine, the compound of Intermediate Formula 3 and R 2 C¾X (where X is halogen, mesyl, Leaving groups such as tosyl groups) can be reacted to obtain a compound of formula (4). And, according to the reaction route B, the compound of formula (4) can be obtained by the reductive amination of the compound of intermediate formula (3) and R 2 CH0. That is, under the organic solvent, the compound of formula 4 may be obtained by reacting the intermediate compound of formula 3 with ¾CH0, sodium triacetoxyborohydride and an acid.
그리고， 상기 반웅경로 A또는 B로 합성된 화학식 4는 보호기인 Boc 기를 탈보호화하여 일반식 1 로 표시되는 신규한 4 각 고리 질소 화합물 유도체를 얻을 수 있다. 보다 상세하게는， 유기용매에 용해되어 있는 화학식 4의 화합물을 산의 존재 하에서 상온에서 교반하면 화학식 1의 4각 고리 질소 화합물 유도체가 생성될 수 있다. 이때, 화학식 1 의 4 각 고리 질소 화합물 유도체의 염이 생성 되는 경우 이를 포화중탄산소다수 또는 가성소다수로 처리하여 화학식 1의 4각 고리 질소 화합물 유도체를 얻을 수 있다.  In addition, the general formula (4) synthesized by the semi-routing route A or B may deprotect the Boc group as a protecting group to obtain a novel tetracyclic nitrogen compound derivative represented by the general formula (1). More specifically, when the compound of Formula 4 dissolved in the organic solvent is stirred at room temperature in the presence of an acid, a tetracyclic nitrogen compound derivative of Formula 1 may be produced. In this case, when the salt of the tetracyclic nitrogen compound derivative of Formula 1 is produced, it is treated with saturated sodium bicarbonate water or caustic soda water to obtain the tetracyclic nitrogen compound derivative of Formula 1.
상기 산으로 사용 가능한 화합물은 크게 제한되는 것은 아니며， 아세트산, 삼불화아세트산, 염산， 황산 또는 파라를루엔술폰산 등의 무기 또는 유기산을 사용할 수 있다. 또한， 상기 유기 용매의 구체적인 예도 한정되는 것은 아니며, 메틸렌클로라이드， 클로로포름， 에틸아세테이트， 테트라하이드로퓨란， 벤젠， 를루엔, DMF, DMS0 등의 비활성 유기 용매를 사용할 수 있다. 또한， 상기 알코을로는 탄수소 1 내지 5 의 지방족 알코을을 사용할 수 있다.  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 paraluenesulfonic acid may 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 DMS0 may be used. In addition, as the alcohol, aliphatic alcohols having 1 to 5 carbon atoms may be used.
상기 반웅식 1 에서， 내지 ¾는 각각의 화합물에 결합된 작용기를 표시한 것으로서, 상기 화학식 1에서 정의한 바와 다를 수 있다. 한편， 발명의 다른 구현예에 따르면, 상술한 화학식 1 의 4 각 고리 질소 화합물 또는 이의 약학적으로 허용 가능한 염을 유효 성분으로 포함하는 약학 조성물이 제공될 수 있다.  In the formula 1, ¾ to represent a functional group bonded to each compound, it may be different from that defined in the formula (1). Meanwhile, according to another embodiment of the present invention, there may be provided a pharmaceutical composition comprising as an active ingredient a tetracyclic nitrogen compound of Formula 1 or a pharmaceutically acceptable salt thereof as described above.
상술한 바와 같이， 본 발명자들은 상기 화학식 1 의 4 각 고리 질소 화합물을 새로이 합성해냈으며， 이러한 4 각 고리 질소 화합물을 사용하면 특정 신경 전달 물질들의 재흡수를 높은 효율로 방지하여 우을증， 정신 질환, 조루증， 또는 신경병증성 통증의 치료제 또는 예방제로 사용될 수 있으며， 약학 조성물을 제공할 수 있음을 실험을 통하여 확인하였다. As described above, the present inventors newly synthesized tetracyclic nitrogen compounds of Formula 1, and using these tetracyclic nitrogen compounds prevents reabsorption of specific neurotransmitters with high efficiency, resulting in depression and mental retardation. Experiments have shown that it can be used as a therapeutic or prophylactic agent for diseases, premature ejaculation, or neuropathic pain and can provide a pharmaceutical composition.
상기 약학 조성물은 상술한 화학식 1 의 4각 고리 질소 화합물 또는 이의 약학적으로 허용 가능한 염을 유효 성분으로 포함할 수 있다. 이러한 이의 약학적으로 허용 가능한 염은 약학적으로 허용되는 유기산의 염을 포함하고， 구체적으로 옥살산， 벤젠설폰산， 캠포설폰산, 신남산， 아디프산， 사이크라민산， 염산， 메탄술폰산， 브롬산， 초산, 퓨마린산, 황산， 숙신산， 시트르산， 인산， 말레인산， 질산, 타르타르산， 벤조산 또는 카본산 등의 유기산의 염을 포함할 수 있다.  The pharmaceutical composition may include, as an active ingredient, a tetracyclic cyclic nitrogen compound of Formula 1 or a pharmaceutically acceptable salt thereof. Such pharmaceutically acceptable salts thereof include salts of pharmaceutically acceptable organic acids, and in particular oxalic acid, benzenesulfonic acid, camposulfonic acid, cinnamic acid, adipic acid, cycric acid, hydrochloric acid, methanesulfonic acid, bromine Salts of organic acids such as acid, acetic acid, fumaric acid, sulfuric acid, succinic acid, citric acid, phosphoric acid, maleic acid, nitric acid, tartaric acid, benzoic acid or carbonic acid.
특히 , 상기 화학식 1의 4각 고리 질소 화합물 또는 이의 약학적으로 허용 가능한 염은 신경 전달 물질인 세로토닌의 재흡수 억제 효과가 뛰어나， 이를 유효 성분으로 포함하는 약학 조성물은 우울증， 정신 질환， 조루증, 또는 신경병증성 통증의 예방 또는 치료에 높은 효과를 나타낼 수 있다. 또한, 상기 화합물은 또 다른 신경 전달 물질인 도파민 또는 노에피네프린에 대한 재흡수 억제 효과를 추가적으로 나타냄으로써 상기 화학식 1 의 화합물을 유효 성분으로 포함하는 약학 조성물은 약물의 복합 사용이나 사용량 증가 등에 따라 나타나는 부작용을 현저하게 감소 시킬 수 있으며, 보다 효과적으로 우울증 또는 정신 질환올 예방 또는 치료할 수 있다.  In particular, the tetracyclic nitrogen compound of Formula 1 or a pharmaceutically acceptable salt thereof is excellent in inhibiting the reuptake of the neurotransmitter serotonin, the pharmaceutical composition comprising the active ingredient is depression, mental illness, premature ejaculation, or It can have a high effect on the prevention or treatment of neuropathic pain. In addition, the compound additionally exhibits a reuptake inhibitory effect on another neurotransmitter, dopamine or noepinephrine, and thus the pharmaceutical composition comprising the compound of Formula 1 as an active ingredient has side effects due to complex use of the drug or an increase in the amount used. Can significantly reduce and more effectively prevent or treat depression or mental illness.
상술한 바와 같이， 상기 약학 조성물은 우울증， 정신 질환， 조루증， 또는 신경병증성 통증의 예방 또는 치료용으로 사용될 수 있다. 상기 정신 질환은 신경성 통증, 조울증， 정신분열증， 기분장애， 수면장애， 불안증， 주의력결핍 과다행동장애 (ADHD) 또는 섭식장애 등의 질환일 수 있고, 상기 신경병증성 통증 (neuropathic pain)은 신경계통의 손상 등의 1 차적인 병변 또는 신경기능 변화에 의해 나타나는 통증을 의미한다.  As described above, the pharmaceutical composition may be used for the prevention or treatment of depression, mental illness, premature ejaculation, or neuropathic pain. The mental disorders may be diseases such as neuropathic pain, mood swings, schizophrenia, mood disorders, sleep disorders, anxiety, attention deficit hyperactivity disorder (ADHD) or eating disorders, and the neuropathic pain is a nervous system Refers to pain caused by primary lesions or neurological changes such as impairment.
한편, 상기 약학 조성물은 다른 약제， 약리학적으로 허용 가능한 담체 또는 부형제를 더 포함할 수 있다. 상기 약리적으로 허용 가능한 담체 또는 부형제는 상기 약학 조성물이 적용되는 제형에 따라 적절히 조절될 수 있으며， 우울증， 정신 질환， 조루증， 또는 신경병증성 통증의 예방제 또는 치료제에 통상적으로 사용될 수 있는 것으로 알려진 담체 또는 부형제를 큰 제한없이 사용할 수 있다. 예를 들어 상기 부형제로는 통상의 희석제， 층진제， 증량제, 습윤제， 붕해제 및 /또는 계면활성제 등을 들 수 있다. On the other hand, the pharmaceutical composition may further comprise other pharmaceutical, pharmacologically acceptable carrier or excipient. The pharmacologically acceptable carrier or excipient may be appropriately adjusted according to the formulation to which the pharmaceutical composition is applied, and is known to be commonly used in the prophylactic or therapeutic agent of depression, mental illness, premature ejaculation, or neuropathic pain. Big excipient Can be used without limitation. For example, the excipients include conventional diluents, layering agents, extenders, wetting agents, disintegrating agents and / or surfactants.
상기 화학식 1 의 4 각 고리 질소 화합물 또는 이의 약학적으로 허용 가능한 염의 상기 약학 조성물 중 함량은， 조성물의 사용방법， 사용 형태， 환자의 상태 및 목적하는 효과 등에 따라 적절히 조절할 수 있으며, 예를 들어 0.1 내지 99 중량 %， 바람직하게는 50 내지 95 중량 %일 수 있다. 한편， 발명의 또 다른 구현예에 따르면， 상기 약학 조성물을 포함하는 우울증 또는 정신 질환의 예방 또는 치료용 제제가 제공될 수 있다.  The content of the tetracyclic 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, the form of use, the condition of the patient and the desired effect, for example 0.1 To 99% by weight, preferably 50 to 95% by weight. Meanwhile, according to another embodiment of the present invention, an agent for preventing or treating depression or mental disease including the pharmaceutical composition may be provided.
상술한 바와 같이， 상기 화학식 1 의 4 각 고리 질소 화합물 또는 이의 약학적으로 허용 가능한 염을 유효 성분을 포함하는 조성물을 사용하면 특정 신경 전달 물질들의 재흡수를 높은 효율로 방지하여 우울증， 정신 질환， 조루증， 또는 신경병증성 통증을 치료 또는 예방할 수 있으며 , 인체에 대한 부작용을 최소화할 수 있다.  As described above, the use of a composition comprising an active ingredient in the tetracyclic nitrogen compound of Formula 1 or a pharmaceutically acceptable salt thereof may prevent reabsorption of specific neurotransmitters with high efficiency, thereby reducing depression, mental illness, It can treat or prevent premature ejaculation or neuropathic pain, and minimize side effects on the human body.
상기 우을증, 정신 질환， 조루증， 또는 신경병증성 통증의 예방 또는 치료용 제제의 투여 방법은 경구 또는 비경구 경로가 모두 가능하고， 제형은 사용방법에 따라 다양하게 결정될 수 있다. 예를 들어， 상기 제제는 경고제 (PLASTERS), 과립제 (GRANULES), 로션제 (LOTIONS) , 산제 (POWDERS), 시럽제 (SYRUPS), 액제 (LIQUIDS AND SOLUTIONS) , 에어로솔제 (AEROSOLS), 연고제 (OINTMENTS), 유동액스제 (FRUIDEXTRACTS), 유제 (EMULSIONS)， 현탁제 (SUSTESI0NS)， 침제 ( INFUSIONS) , 정제 (TABLETS)， 주사제 ( INJECTIONS)， 캅셀제 (CAPSULES) 또는 환제 (PILLS) 등의 형태로 제형화하여 사용할 수 있다.  The method of administering the agent for preventing or treating depression, mental disorders, premature ejaculation, or neuropathic pain can be all oral or parenteral routes, and the dosage form can be variously determined according to the method of use. For example, the formulations include PLASTERS, GRANULES, LOTIONS, POWDERS, SYRUPS, LIQUIDS AND SOLUTIONS, AEROSOLS, OINTMENTS ), FRUIDEXTRACTS, Emulsion (EMULSIONS), Suspension (SUSTESI0NS), Acupuncture (INFUSIONS), Tablets (TABLETS), INJECTIONS, Capsules (CAPSULES) or Pills (PILLS) Can be used.
상기 우울증， 정신 질환， 조루증， 또는 신경병증성 통증의 예방 또는 치료용 제제는 환자의 연령， 성별, 상태， 체내에서활성 성분의 홉수도， 불활성률 및 병용되는 약물을 고려하여 그 투여량이 결정 될 수 있으며， 바람직하게는 유효성분을 기준으로 1 일 투여량이 0.1 rag/kg (체중) 내지 4 rag/kg (체중)， 보다 바람직하게는 0.3 mg/kg (체중) 내지 1.8 mg/kg (체중)일수 있다. 한편， 발명의 또 다른 하나의 구현예에 따르면， 상기 화학식 1 의 4각 고리 질소 화합물을 포함하는 식품이 제공될 수 있다. The preparation for the prevention or treatment of depression, mental illness, premature ejaculation, or neuropathic pain may be determined in consideration of the age, sex, condition, hop count of the active ingredient, inactivation rate and the drug used in the body. Preferably, a daily dosage of 0.1 rag / kg (body weight) to 4 rag / kg (body weight), more preferably 0.3 mg / kg (body weight) to 1.8 mg / kg body weight, based on the active ingredient. Can be. On the other hand, according to another embodiment of the invention, a food comprising a tetracyclic nitrogen compound of Formula 1 may be provided.
상기 식품은 통상적인 식품뿐만 아니라， 건강보조식품 또는 식품 첨가제를 모두 포함하는 의미이다. 상기 식품, 건강보조식품 또는 식품첨가제의 예가 크게 한정되는 것은 아니며, 예컨대， 특수영양식품 (예， 조제유류， 영，유아식 등)， 식육가공품, 어육제품， 두부류， 묵류， 면류 (예， 라면류， 국수류 둥)， 빵류, 기능성 식품, 조미식품 (예， 간장, 된장， 고추장, 흔합장 등)， 소스류， 과자류 (예， 스넥류)， 유가공품 (예， 발효유, 치즈 등)， 기타 가공식품， 김치， 절임식품 (각종 김치류 장아찌 등), 음료 (예， 과실, 채소류 음료， 두유류， 발효음료류 등), 천연조미료 (예， 라면 스프 등)등 일 수 있다.  The food is meant to include not only conventional foods, but also health supplements or food additives. Examples of the food, health supplements or food additives are not limited to, for example, special nutritional products (e.g., delicatessen, young, baby food, etc.), processed meat products, fish products, tofu, jelly, noodles (e.g. ramen, Noodles, breads, functional foods, seasoned foods (e.g., soy sauce, miso, red pepper paste, mixed soy sauce), sauces, confectionery (e.g. snacks), dairy products (e.g. fermented milk, cheese, etc.), other processed foods, kimchi, Pickled foods (various kimchi pickles, etc.), beverages (e.g. fruits, vegetable drinks, soy milk, fermented beverages, etc.), natural seasonings (e.g. ramen soup, etc.).
【발명의 효과】 【Effects of the Invention】
본 발명에 따르면， 특정 신경 전달 물질들을 재흡수를 높은 효율로 방지하여 우울증, 정신 질환， 조루증， 또는 신경병증성 통증의 치료제 또는 예방제로 사용될 수 있는 4 각 고리 질소 화합물과， 세레토닌 및 도파민 또는 노에피네프린의 재흡수를 억제할 수 있고 우울증, 정신 질환， 조루증， 또는 신경병증성 통증에 대하여 높은 치료 효과 또는 예방 효과를 갖는 약학 조성물과， 상기 약학 조성물을 포함하는 제제가 제공될 수 있다.  According to the present invention, quaternary cyclic nitrogen compounds which can be used as a therapeutic or prophylactic agent for depression, mental illness, premature ejaculation, or neuropathic pain by preventing specific neurotransmitters with high efficiency of resorption, serotonin and dopamine Or a pharmaceutical composition capable of inhibiting reuptake of noepinephrine and having a high therapeutic or prophylactic effect on depression, mental illness, premature ejaculation, or neuropathic pain, and a formulation comprising the pharmaceutical composition.
【발명을 실시하기 위한 구체적인 내용】 [Specific contents to carry out invention]
발명을 하기의 실시예에서 보다 상세하게 설명한다. 단， 하기의 실시예는 본 발명을 예시하는 것일 뿐 본 발명의 내용이 하기의 실시예에 의하여 한정되는 것은 아니다.  The invention is explained in more detail in the following examples. However, the following examples are merely to illustrate the present invention is not limited to the contents of the present invention.
[제조예 : 신규한 4각 고리 질소 화합물의 합성 ] Preparation Example: Synthesis of Novel Quadrivalent Nitrogen Compounds
하기 반웅식 1 에 따른 합성방법으로 하기 실시예 1 내지 72 를 합성하였으며， 구체적인 예를 하기 제조예 1 내지 5에서 단계별로 설명한다. [반웅식 1]The following Examples 1 to 72 were synthesized by the synthesis method according to Banung Formula 1 below, and specific examples will be described step by step in Preparation Examples 1 to 5 below. [Banungsik 1]
Figure imgf000013_0001
Figure imgf000013_0001
n=1 -3 반응조건 반응조건  n = 1 -3 reaction condition reaction condition
(a) K2C03,D F, 150°C (a) K 2 C0 3 , DF, 150 ° C
방법 (i) NaBH(OAc)3, AcOH, CH2CI2, r.t. Method (i) NaBH (OAc) 3 , AcOH, CH 2 CI 2 , rt
(b) NaBH(OAch, AcOH, CH2CI2, r.t. (b) NaBH (OAch, AcOH, CH 2 CI 2 , rt
방법 (ii) toluene, 110'C, NaBH4, MeOH. r.t Method (ii) toluene, 110'C, NaBH 4 , MeOH. rt
(c) TFA, CH2CI2, r.t. (c) TFA, CH 2 CI 2 , rt
[제조예 1] 방법 (i)을통한화합물 2로부터 중간체 화합물 3의 합성 -Yeri-Butyl 3- (naphtha 1 en-2-y 1 am i no ) aze t i d i ne- l~car boxy 1 at e Preparation Example 1 Synthesis of Intermediate Compound 3 from Compound 2 via Method (i) -Yeri-Butyl 3- (naphtha 1 en-2-y 1 am i no) aze tidi ne-l to car boxy 1 at e
Figure imgf000013_0002
Figure imgf000013_0002
A^Boc— 3ᅳ azetidinone (3.6 g, 21 腿 ol)의 methylene chloride (100 mL) 용액에 2-naphthyl amine (2.0 g, 14 醒 ol), sodium t r i acet oxybor ohydr i de (8.9 g, 42 誦 ol), 및 acetic acid (0.080 mL, 1.4 隱 ol)을 가하고, 18시간 동안 상온에서 교반 하였다. 반웅흔합물에 l Na0H 수용액 (30 mL)을 가하고， 30 분 동안 교반하였다. 반웅흔합물을 methylene chloride 로 추출한 후， 무수황산마그네슴으로 건조하고 용매를 감압증발로 제거하여 연갈색 침전물을 얻었다. 생성된 고체를 여과하고 12 시간 동안 상온에서 건조하여 연갈색의 고체인 ier -butyl 3-(naphthalen-2- ylamino)azetidine-l-carboxylate (3.8g, 수율 92%)를 얻었다.  A ^ Boc— 2-naphthyl amine (2.0 g, 14 醒 ol), sodium tri acet oxybor ohydr i de (8.9 g, 42 誦) in a solution of 3 chloride azetidinone (3.6 g, 21 腿 ol) in methylene chloride (100 mL) ol), and acetic acid (0.080 mL, 1.4 μl ol) were added and stirred at room temperature for 18 hours. 1 Na0H aqueous solution (30 mL) was added to the reaction mixture, and the mixture was 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 give ier -butyl 3- (naphthalen-2-ylamino) azetidine-l-carboxylate (3.8g, yield 92%) as a light brown solid.
[수율 92%; 녹는점 103°C; ¾ NMR (600MHz, CDC13) δ 1.46 (s, 9H, ί erf-butyl H) , 3.77-3.79 (m, 2H, azetidine H) , 4.13 (d, 1H, J = 6.0Hz, NH), 4.30-4.37 (m, 3H, NCH, azetidine H), 6.61-7.67 (m, 7H, ArH)] [제조예 2] 방법 (ii)를 통한 화합물 2 로부터 중간체 화합물 3 의 tert-Quty 1 3ᅳ ( eye 1 ohexy 1 amino) azet i d i ne-l-carboxy 1 at e
Figure imgf000014_0001
[92% yield; Melting point 103 ° C; ¾ NMR (600 MHz, CDC1 3 ) δ 1.46 (s, 9H, ί erf-butyl H), 3.77-3.79 (m, 2H, azetidine H), 4.13 (d, 1H, J = 6.0 Hz, NH), 4.30- 4.37 (m, 3H, NCH, azetidine H), 6.61-7.67 (m, 7H, ArH)] Preparation Example 2 tert-Quty 1 3 (eye 1 ohexy 1 amino) azet idi ne-l-carboxy 1 at e of intermediate compound 3 from compound 2 through method (ii)
Figure imgf000014_0001
N-Boc-3-azetidinone (5.0 g, 29 薩 ol)의 toluene (25 mL) 용액에 eye 1 ohexy 1 amine (3.4 mL, 29 mmol)을 가하고 1 시간동안 가열한 다음 반웅흔합물을 감압증발하고 잔유물을 실온에서 methanol (50 mL)에 녹인 후， sodium borohydride (5.5 g, 150 mmol)을 가하였다. 반웅 흔합물을 3 시간 동안 상온에서 교반 한 뒤, IN NaOH 수용액 (20 mL)을 가하고， 1 시간 더 교반하였다. 반응 흔합물을 methylene chloride (50 mL 씩 3회)을 이용하여 추출한 후， 무수황산마그네슘으로 건조하였다. 용매를 감압증발로 제거하여 얻은 노란색 기름상의 액체를 속성 크로마토그래피로 정제하여 무색, 투명의 기름상의 액체인 er -butyl 3- ( eye 1 ohexy 1 am i no ) aze t i d i ne- 1- carboxylate (5.5 g, 수율 74%)를 얻었다. To the solution of toluene (25 mL) of N-Boc-3-azetidinone (5.0 g, 29 mL ol), add eye 1 ohexy 1 amine (3.4 mL, 29 mmol), heat for 1 hour, and then evaporate the semi-mixture under reduced pressure. The residue was taken up in methanol (50 mL) at room temperature and then sodium borohydride (5.5 g, 150 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, then an IN NaOH aqueous solution (20 mL) was added, and the mixture was further stirred for 1 hour. The reaction mixture was extracted with methylene chloride (3 × 50 mL) and dried over anhydrous magnesium sulfate. The yellow oily liquid obtained by evaporation of the solvent under reduced pressure was purified by flash chromatography. The colorless and transparent oily liquid er -butyl 3- (eye 1 ohexy 1 am i no) aze tidi ne- 1-carboxylate (5.5 g, yield 74%).
[수율 74%; oil; ¾ NMR (600腿 z, CDC13) δ 1.00-1.77 (m, 10H, eye 1 ohexy 1 methylene H) , 1.40 (s, 9H, ferf-butyl H)， 2.40 (m, 1H, eye 1 ohexy 1 methine H) , 3.56-3.58 및 4.30-4.37(2m, 4H, azetidinyl methylene H) , 3.64 (m, 1H, azetidinyl methine H)] [74% yield; oil; ¾ NMR (600 腿 z, CDC1 3 ) δ 1.00-1.77 (m, 10H, eye 1 ohexy 1 methylene H), 1.40 (s, 9H, ferf-butyl H) ， 2.40 (m, 1H, eye 1 ohexy 1 methine H), 3.56-3.58 and 4.30-4.37 (2m, 4H, azetidinyl methylene H), 3.64 (m, 1H, azetidinyl methine H)]
[제조예 3] 중간체 화합물 3 으로부터 중간체 화합물 4 의 합성 (반웅경로 A) Preparation Example 3 Synthesis of Intermediate Compound 4 from Intermediate Compound 3 (Reaction Path A)
•Yeri-Butyl 3- (benzyl (naphthalen-2-yl )amino)azetidine-l- carboxylate  Yeri-Butyl 3- (benzyl (naphthalen-2-yl) amino) azetidine-l-carboxylate
Figure imgf000014_0002
feri-Butyl 3- (napht ha 1 en-2-y 1 am i no ) aze t i d i ne- 1-car boxy late (0.30 g, 1.0 mmol)의 dimethyl formamide (6 mL) 용액에 potassium carbonate (0.41 g, 3.0 麵 ol)와 benzyl bromide (0.18 mL, 1.5 讓 ol)을 가하고， 3 시간 동안 가열 환류 하였다. 용매를 감압 증발로 제거하고, ethyl acetate 에 녹인 다음, 포화 중탄산나트륨 수용액과 증류수 각각 1 회씩 씻고, 무수황산마그네슴으로 건조하였다. 용매를 감압증발로 제거하여 얻은 갈색 기름상의 액체를 속성 크로마토그래피로 정제하여 연노란 기름상의 액체인 ieri-butyl 3- ( benzy 1 ( napht ha 1 en-2-y 1 ) am i no ) aze t i d i ne- 1- car boxy late (0.23 g, 수율 58%)를 얻었다.
Figure imgf000014_0002
feri-Butyl 3- (napht ha 1 en-2-y 1 am i no) aze tidi ne- 1-car boxy late (0.30 g, 1.0 mmol) in dimethyl formamide (6 mL) solution of potassium carbonate (0.41 g, 3.0 麵 ol) and benzyl bromide (0.18 mL, 1.5 讓 ol) were added and heated to reflux for 3 hours. The solvent was removed by evaporation under reduced pressure, dissolved in ethyl acetate, washed once with each saturated aqueous sodium bicarbonate solution and distilled water, and dried over anhydrous magnesium sulfate. The brown oily liquid obtained by evaporation of the solvent under reduced pressure was purified by flash chromatography. The light yellow oily liquid ieri-butyl 3- (benzy 1 (napht ha 1 en-2-y 1) am i no) aze tidi ne 1-car boxy late (0.23 g, yield 58%) was obtained.
[수율 58%; oil; ¾ 醒 R (400腿 z, CDC13) δ 1.42 (s, 9Η, tert- butyl H), 3.92-3.95 및 4.17—4.20 (2m, 4H, azetidinyl methylene H) , 4.45 (m, 1H, azetidinyl methine H), 4.60 (s, 2H, benzyl ic H) , 6.80- 7.68 (m, 12H, ArH)] [Yield 58%; oil; ¾ 醒 R (400 腿 z, CDC1 3 ) δ 1.42 (s, 9Η, tert-butyl H), 3.92-3.95 and 4.17—4.20 (2 m, 4H, azetidinyl methylene H), 4.45 (m, 1H, azetidinyl methine H ), 4.60 (s, 2H, benzyl ic H), 6.80-7.68 (m, 12H, ArH)]
[제조예 4] 중간체 화합물 3 으로부터 증간체 화합물 4 의 합성 (반웅경로 B) Preparation Example 4 Synthesis of Intermediate Compound 4 from Intermediate Compound 3
•'ie i-Butyl 3-(phenethyl (phenyl ) am i no ) azet i d i ne- 1-c ar boxy late  'Ie i-Butyl 3- (phenethyl (phenyl) am i no) azet i d i ne- 1-c ar boxy late
Figure imgf000015_0001
Figure imgf000015_0001
feri-Butyl 3-(phenyl ami no) azet idine-l-carboxy late (0.20 g, 0.8 匪 ol)의 methylene chloride (15 mL) 용액에 2-pheny 1 acet a 1 dehyde (0.18 g, 1.6 mmol), sodium t r i acet oxybor ohydr i de (0.51 g, 2.4 mmol ) 그리고 acetic acid (4.6 uL, 0.08 瞧 ol)을 가하고， 6 시간 동안 상온에서 교반하였다. 반응흔합물에 lvVNaOH 수용액 (30 mL)를 가하고, 30분 동안 더 교반하였다. 반웅흔합물을 methylene chloride 로 추출한 후， 무수황산마그네슘으로 건조하였다. 용매를 감압증발로 제거하여 얻은 연노란색 기름상의 액체를 속성 크로마토그래피로 정제하여 무색 투명의 기름상 액체인 tert-butyl 3-(phenethyl (phenyl )amino)azet idine-1- carboxylate(0.24 g, 수율 86%) 를 얻었다. feri-Butyl 3- (phenyl ami no) azet idine-l-carboxy late (0.20 g, 0.8 匪 ol) in a solution of methylene chloride (15 mL) 2-pheny 1 acet a 1 dehyde (0.18 g, 1.6 mmol), Sodium tri acet oxybor ohydride (0.51 g, 2.4 mmol) and acetic acid (4.6 uL, 0.08 dl ol) were added and stirred at room temperature for 6 hours. LvVNaOH aqueous solution (30 mL) was added to the reaction mixture, and the mixture was further stirred for 30 minutes. The reaction mixture was extracted with methylene chloride and dried over anhydrous magnesium sulfate. The pale yellow oily liquid obtained by evaporation of the solvent under reduced pressure was purified by flash chromatography. An oily liquid, tert-butyl 3- (phenethyl (phenyl) amino) azet idine-1-carboxylate (0.24 g, yield 86%) was obtained.
[수율 86%; oil; ¾ MR (600MHz, CDC13) δ 1.41 (s, 9H, tert- butyl H), 2.73 (t, 2H, J = 7.8Hz, CH2) , 3.51 (t, 2H, J = 7.8Hz, CH2) , 3.80 및 4.05 (m, 4H, azetidinyl methylene H), 4.20 (m, 1H, azetidinyl methine H), 6.73-7.28 (m, 10H, ArH)] [Yield 86%; oil; ¾ MR (600MHz, CDC1 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 (m, 10H, ArH)]
[제조예 5] 중간체 화합물 4 로부터 화학식 1 의 4 각 고리 질소 화합물의 합성 Preparation Example 5 Synthesis of Tetracyclic Nitrogen Compound of Formula 1 from Intermediate Compound 4
•Yeri-butyl 3-(benzyl (naphtha len-2-yl )amino)azet idine-l- carboxylate  Yeri-butyl 3- (benzyl (naphtha len-2-yl) amino) azet idine-l-carboxylate
Figure imgf000016_0001
Figure imgf000016_0001
f erf-Butyl 3- ( benzy 1 ( napht ha 1 en-2-y 1 ) am i no ) azet i d i ne- 1- carboxylate (0.2 g, 0.51 誦 ol)를 methylene chloride (10 mL)어 1 녹이고 trifluoroacetic acid (0.5 mL, 6.5 讓 ol)를 가하고 상온에서 10 시간 동안 교반 시킨 후， N NaOH 수용액 (2.0 mL)를 가하고， 30 분 동안 더 교반하였다. 반웅 흔합물을 methylene chloride 로 추출한 후， 무수황산마그네슘으로 건조하였다. 용매를 감압증발로 제거하여 얻은 갈색 기름상의 액체를 속성 크로마토그래피로 정제하여 노란색의 기름상 액체인 feri-butyl 3-(benzyl (naphthalen-2-yl )amino)azet idine-l-carboxylate (80 mg, 수율 54%)를 얻었다.  f erf-Butyl 3- (benzy 1 (napht ha 1 en-2-y 1) am i no) azet idi ne- 1-carboxylate (0.2 g, 0.51 誦 ol) dissolved in methylene chloride (10 mL) and trifluoroacetic acid (0.5 mL, 6.5 讓 ol) was added thereto, stirred at room temperature for 10 hours, an aqueous N NaOH solution (2.0 mL) was added, and further stirred for 30 minutes. The reaction mixture was extracted with methylene chloride and dried over anhydrous magnesium sulfate. The brown oily liquid obtained by evaporation of the solvent under reduced pressure was purified by flash chromatography. The yellow oily liquid feri-butyl 3- (benzyl (naphthalen-2-yl) amino) azet idine-l-carboxylate (80 mg , Yield 54%) was obtained.
[수율 54%; oil; ¾ NMR (400MHz, CDCI3) δ 3.75-3.85 (m, 4Η, azetidinyl methylene H), 4.06 (s, 1H, NH), 4.54 (s, 2H, benzyl ic H) ' 4.63 (m, 1H, methine H), 7.03-7.66 (m, 12H, ArH)] 상기와 같은 제조예의 방법에 의해서 N-Boc-3-azet idi none 으로부터 중간체 화합물 3， 4 를 통하여 신규의 4 각 고리 질소 화합물 1 을 합성하였으며， 상기 구체적인 4 각 고리 질소 화합물의 화학식 및 작용기， 반응경로는 하기 표 1 과 같다. 그리고， 이들의 수율 성상， 및 수소핵자기공명스펙트럼 데이터는 하기 실시예 1 내지 72에 나타내었다. [54% yield; oil; ¾ NMR (400 MHz, CDCI 3 ) δ 3.75-3.85 (m, 4Η, azetidinyl methylene H), 4.06 (s, 1H, NH), 4.54 (s, 2H, benzyl ic H) '4.63 (m, 1H, methine H ), 7.03-7.66 (m, 12H, ArH)] A novel quaternary cyclic nitrogen compound 1 was obtained from N-Boc-3-azet idi none through intermediate compounds 3 and 4 by the method of Preparation Example as described above. It was synthesized, the chemical formula, functional group, and reaction path of the specific tetracyclic nitrogen compound are shown in Table 1 below. In addition, these yield characteristics and hydrogen nuclear magnetic resonance spectrum data are shown in Examples 1 to 72 below.
Figure imgf000017_0001
Figure imgf000017_0001
Figure imgf000017_0002
OAV//:> 09soois2Mld7
Figure imgf000017_0002
OAV // : > 09 soo i s2Mld 7
Figure imgf000018_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000019_0001
[실시예: 신규한 4 각 고리 질소 화합물의 수율, 성상, 및 수소핵자기공명스펙트럼 데이테 EXAMPLES Yield, Properties, and Hydrogen Nuclear Magnetic Resonance Spectrum
실시예 1： N-cyc 1 ohexy 1 -N- ( 4-methoxybenzy Dazetidi n一 3一 am i ne  Example 1 N-cyc 1 ohexy 1 -N- (4-methoxybenzy Dazetidi n 一 3 一 am i ne
[수율 57%; oil； IH NMR (600MHz, CDC13) δ 1.00-1.70 (m, 10H, cyclohexyl H), 2.33 (m, IH, cyclohexyl CIH), 3.43 (m, 2H, azetidine H), 3.59 (m, 2H, azetidine H), 3.63 (s, 2H, NCH2), 3.75 (s, 3H, 0CH3), 3.93 (m, IH, NCH), 6.77 (d, 2H, J = 8.4Hz, ArH) , 7.19 (d, 2H, J = 7.8Hz, ArH)] 실시예 2： N-(4-chlorobenzyl )-N-cyclohexylazet idin-3-amine  [Yield 57%; oil; IH NMR (600 MHz, CDC13) δ 1.00-1.70 (m, 10H, cyclohexyl H), 2.33 (m, IH, cyclohexyl CIH), 3.43 (m, 2H, azetidine H), 3.59 (m, 2H, azetidine H ), 3.63 (s, 2H, NCH2), 3.75 (s, 3H, 0CH3), 3.93 (m, IH, NCH), 6.77 (d, 2H, J = 8.4 Hz, ArH), 7.19 (d, 2H, J = 7.8 Hz, ArH)] Example 2 N- (4-chlorobenzyl) -N-cyclohexylazet idin-3-amine
[수율 57%; oil; IH NMR (600顧 z, CDC13) δ 0.98-1.79 (m, 10H, cyclohexyl H), 2.30 (m, IH, cyclohexyl CIH), 3.28-3.58 (m, 4H, azetidine H), 3.66 (s, 2H, NCH2), 3.99 (m, IH, NCH), 7.17-7.23 (m, 4H, ArH)] 실시예 3: N-cyclohexyl-N-(4-methylbenzyl )azet idin-3-amine
Figure imgf000020_0001
[Yield 57%; oil; IH NMR (600 Hz z, CDC13) δ 0.98-1.79 (m, 10H, cyclohexyl H), 2.30 (m, IH, cyclohexyl CIH), 3.28-3.58 (m, 4H, azetidine H), 3.66 (s, 2H, NCH2), 3.99 (m, IH, NCH), 7.17-7.23 ( m, 4H, ArH)] Example 3: N-cyclohexyl-N- (4-methylbenzyl) azet idin-3-amine
Figure imgf000020_0001
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' {ΖΙ <U1) C8"
Figure imgf000020_0002
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Figure imgf000020_0002
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Figure imgf000020_0003
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Figure imgf000020_0004
[(H J V 'ΗΛ' «6 · -6ε · Λ '(HON' HI '" 0 66 , ε' (2H0N Ή2 's) Ζ2 ' '(Η 3UiPil3zs' HS '"55 " C' (Η smp sze
Figure imgf000020_0003
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Figure imgf000020_0004
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Figure imgf000021_0001
Figure imgf000021_0001
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= r 'HZ ' 1 'Z '(HID l 9qo AD Ήΐ 'ω) I ' 7， '(2Η3 Ή μ)«ψ)ρΑ3 = r 'HZ' 1 ' Z' (HID l 9qo AD Ήΐ 'ω) I ' 7 ， '(2Η3 Ή μ ) «ψ ) ρΑ3
'ΕΖΙ '"0 ^Z'T-OO"! 9 (εΐ (Ό 'ζ丽 009) 讓 Ηΐ ： Ι?ο ζ% 룡^] 'ΕΖΙ'"0 ^ Z ' T-OO " ! 9 (εΐ (Ό ' ζ丽 009) 讓 Ηΐ ： Ι? Ο ζ% dragon ^]
3UIUiB-g-UT I19ZB(\A(lOJ(I AU9t[(I-g)-^-iA 9l[O A0-N:0I [γ^ 3 UIUiB-g-UT I19ZB (\ A (lOJ (I AU9t [ ( Ig)-^-iA 9l [O A0-N: 0I [γ ^
[ V 'HS '" LZ'L-^Y L '(HON 'HI '"0 88'S Οΐ '(H sujpi zB 'Ηί7 'ui) 69- - V£ ' {ZD 'ZHZ'Z = Γ 'HZ Ί) U'Z ' {ZVO [V 'HS'"LZ' L- ^ YL' (HON 'HI'" 0 88 ' S Οΐ' (H sujpi zB ' Ηί7 ' ui) 69 --V £ '{ZD' ZHZ ' Z = Γ' HZ ' ) U ''Z''(ZVO
'ΖΗΖ·Λ = f 'W, 99'2 '(HIO lA aqo Ao Ήχ 'ui) j '(H lA aqo Ao' Ζ ΗΖ · Λ = f' W, 99'2 '(HIO lA aqo Ao Ήχ' ui) j '(H lA aqo Ao
'HOT '" wi-wi (ειοαο 'z面 oo9) 藤 HI ： no :%ε 룡^] 'HOT' "wi-wi (ειοαο 'z 面 oo9) 藤 HI ： no:% ε Dragon ^]
9U I IBB-^-U I p I Ϊ9ΖΒ { 9U9qd-]^- \ XdV01 OAO-^l :6 [{p y^  9U I IBB-^-U I p I Ϊ9ΖΒ {9U9qd-] ^-\ XdV01 OAO- ^ l: 6 [{p y ^
5  5
'HS 'ω) ΐε· -9Ι' '(HON 'HI '«0 96 'S '(ZH3N 'HS 's) 9"S '(H 3"ΐ μ3ΖΒ 'HS ' ω) ΐε · -9Ι '' (HON 'HI' «0 96 ' S' (ZH3N 'HS' s ) 9 " S '(H 3 "ΐ μ3ΖΒ
<UI) 85"S-S^'C '(HID \^Ψ\οΑο Ήΐ 'u]) gg-g '(H \A ^O\ O 'HOT '"0 0Ζ·Τ-66'0 9 (eiOQO '2服009) 翻 HI ： 11° :¾8S 룡 < UI ) 85 " SS ^ ' C' (HID \ ^ Ψ \ οΑο Ήΐ 'u ] ) gg-g' (H \ A ^ O \ O 'HOT'" 0 0Ζ · Τ-66 ' 0 9 (eiOQO' 2 服 009) 翻 HI ： 11 °: ¾8S Dragon
09Ζ000/Μ0ΖΗΜ/Χ3<1 CH2), 3.61-3.69 (m, 4H, azetidine H), 4.38 (m, IH, NCH), 6.62-7.26 (m 5H, ArH)] 실시예 14： N-benzyl-N-(naphthalen-2-yl )azet idin-3-amine 09Ζ000 / Μ0ΖΗΜ / Χ3 <1 CH 2), 3.61-3.69 (m, 4H, azetidine H), 4.38 (m, IH, NCH), 6.62-7.26 (m 5H, ArH)] Example 14 N-benzyl-N- (naphthalen-2-yl azet idin-3-amine
[수율 54%; 녹는점 204°C IH NMR (400MHz, CDC13) δ 3.75-4.06 (m,[54% yield; Melting point 204 ° C IH NMR (400 MHz, CDC13) δ 3.75-4.06 (m,
4H, azetidine H), 4.06 (br(s), IH, NH)， 4.54 (s, 2H, NCH2) , 4.63 (m, IH, NCH), 7.03-7.66 (m, 12Hᅳ ArH)] 실시예 15 ： N-(naphthalen-2-yl )-N-phenethylazet idin-3-amine 4H, azetidine H), 4.06 (br (s), IH, NH), 4.54 (s, 2H, NCH2), 4.63 (m, IH, NCH), 7.03-7.66 (m, 12H ᅳ ArH)] Example 15 ： N- (naphthalen-2-yl) -N-phenethylazet idin-3-amine
[수율 36%; oil; IH NMR (600MHz, CDC13) 52.16 (br(s), IH, NH) , [Yield 36%; oil; IH NMR (600 MHz, CDC13) 52.16 (br (s), IH, NH),
2,75 (t, 2H, J = 7.8Hz, CH2), 3.61 (t, 2H, J = 7:8Hz, CH2), 3.65-3.79 (m, 4H, azetidine H) , 4.47 (m, IH, NCH), 6.85-7.75 (m, 12H, ArH)] 실시예 16: 2,75 (t, 2H, J = 7.8 Hz, CH2), 3.61 (t, 2H, J = 7: 8 Hz, CH2), 3.65-3.79 (m, 4H, azetidine H), 4.47 (m, IH, NCH ), 6.85-7.75 (m, 12H, ArH)] Example 16:
N- ( napht ha 1 en~2-y 1 )-N-(3-phenylpropyl )azet idin-3-amine  N- (napht ha 1 en ~ 2-y 1) -N- (3-phenylpropyl) azet idin-3-amine
[수율 63%; oil; IH NMR (600MHz, CDC13) 51.81 (m, 2H, CH2), 2.59 (t, 2H, J = 7.2Hz, CH2), 3.35 (t, 2H, J = 7.8Hz, CH2) , 3.70-3.88 (m, 5H, azetidine H, NH) , 4.53 On, IH, NCH), 6.81-7.71 (m, 12H, ArH)] 실시예 17： N- ( 3 , 4-d i ch 1 or opheny 1 ) -N-phene t hy 1 aze t i d i η-3-am i ne [Yield 63%; oil; IH NMR (600 MHz, CDC13) 51.81 (m, 2H, CH2), 2.59 (t, 2H, J = 7.2 Hz, CH2), 3.35 (t, 2H, J = 7.8 Hz, CH2), 3.70-3.88 (m, 5H, azetidine H, NH), 4.53 On, IH, NCH), 6.81-7.71 (m, 12H, ArH)] Example 17 N- (3, 4-di ch 1 or opheny 1) -N-phene t hy 1 aze tidi η-3-am i ne
[수율 30%; oil; IH NMR (600MHz, CDC13) 52.52 (br(s), IH, NH) , 2.74 (t, 2H, J = 7.2Hz, CH2) , 3.50 (t, 2H, J = 7.2Hz, CH2) , 3.58-3.70 (m, 4H, azetidine H), 4.28 (m, IH, NCH), 6.52-7.30 (m, 8H, ArH)] 실시예 18: [Yield 30%; oil; IH NMR (600 MHz, CDC13) 52.52 (br (s), IH, NH), 2.74 (t, 2H, J = 7.2 Hz, CH2), 3.50 (t, 2H, J = 7.2 Hz, CH2), 3.58-3.70 (m, 4H, azetidine H), 4.28 (m, IH, NCH), 6.52-7.30 (m, 8H, ArH)] Example 18:
N-(3 , 4-di chlorophenyl )-N-(3~phenylpropy 1 )azet idin-3-amine N- (3, 4-di chlorophenyl) -N- (3 ~ phenylpropy 1) azet idin-3-amine
[수율 75%; oil; IH MR (60( Hz, CDC13) δ 1.79 (m, 2H, CH2), 2.58 2H, J = 7.2Hz, CH2), 3.21-3.66 (m, 6H, CH2, azetidine H), 4.15 (m, NCH), 6.40-7.29 (m, 8H, ArH)] 실시예 19: N-p enethyl-N-(4-phenoxyphenyl )azet idin-3-amine [Yield 75%; oil; IH MR (60 (Hz, CDC13) δ 1.79 (m, 2H, CH2), 2.58 2H, J = 7.2 Hz, CH2), 3.21-3.66 (m, 6H, CH2, azetidine H), 4.15 (m, NCH) , 6.40-7.29 (m, 8H, ArH)] Example 19 Np enethyl-N- (4-phenoxyphenyl) azet idin-3-amine
[수율 64%; oil; IH NMR (400MHz, CDC13) δ 2.76 (t, 2H, J =7.2Hz, CH2), 3.47 (t, 2H, J = 7.2Hz, CH2), 3.69-3.78 (m, 4H, azetidine H), 4.38 (m, IH, NCH), 6.77-7.34 (m, 14H, ArH)] 실시예 20:  [Yield 64%; oil; IH NMR (400 MHz, CDC13) δ 2.76 (t, 2H, J = 7.2 Hz, CH 2), 3.47 (t, 2H, J = 7.2 Hz, CH 2), 3.69-3.78 (m, 4H, azetidine H), 4.38 ( m, IH, NCH), 6.77-7.34 (m, 14H, ArH)] Example 20:
N-(4-phenoxyphenyl )-N-(3-phenylpropyl )azet idin-3-amine  N- (4-phenoxyphenyl) -N- (3-phenylpropyl) azet idin-3-amine
[수율 87%; oil; IH 匪 R (400MHz, CDC13) δ 1.81 (m, 2H, CH2), 2.62 (t, 2H, J= 7.2Hz, CH2), 3.20 (t, 2H, J = 7.2Hz, CH2), 3.70-3.78 (m, 4H, azetidine H)， 3.97 (br(s), IH, NH), 4.37 (m, IH, NCH), 6.70- 7.33 (m, 14H, ArH)] 실시예 21:  [Yield 87%; oil; IH 匪 R (400 MHz, CDC13) δ 1.81 (m, 2H, CH2), 2.62 (t, 2H, J = 7.2 Hz, CH2), 3.20 (t, 2H, J = 7.2 Hz, CH2), 3.70-3.78 ( m, 4H, azetidine H), 3.97 (br (s), IH, NH), 4.37 (m, IH, NCH), 6.70-7.33 (m, 14H, ArH)] Example 21:
N— (naphtha 1 en一 2—yl )-N-(naphtha 1 en~2-y lmethy 1 )azet idinᅳ 3— amine [수율 42%; 녹는점 183°C IH NMR (600丽 z, DMS0-d6) δ 3.96 (m, 2H, azetidine H) , 4.25 (m, 2H, aze idine H) , 4.76 (m, IH, NCH), 4.84 (s, 2H, NCH2), 6.88-7.84 (m, 14H, ArH)] 실시예 22: N— (naphtha 1 en1 2—yl) -N- (naphtha 1 en to 2-y lmethy 1) azet idin ᅳ 3— amine [yield 42%; Melting point 183 ° C IH NMR (600 d z, DMS0-d6) δ 3.96 (m, 2H, azetidine H), 4.25 (m, 2H, aze idine H), 4.76 (m, IH, NCH), 4.84 (s , 2H, NCH 2), 6.88-7.84 (m, 14H, ArH)] Example 22:
N-(4-chlorobenzyl)-N-(naphthalen-2-yl)azetidin-3-amine  N- (4-chlorobenzyl) -N- (naphthalen-2-yl) azetidin-3-amine
[수율 54%; 녹는점 20rc IH NMR (400MHz, CDC13) δ 4.07 (m, 2H, azetidine H), 4.22 (m, 2H, azetidine H) , 4.57 (s, 2H, NCH2), 4.77 (m, IHᅳ NCH), 6.81-7.78 Cm, 11H, ArH)] 실시예 23： N-benzyl-N-(3 ,4-dichlorophenyl )azet idin-3-amine  [54% yield; Melting point 20rc IH NMR (400 MHz, CDC13) δ 4.07 (m, 2H, azetidine H), 4.22 (m, 2H, azetidine H), 4.57 (s, 2H, NCH2), 4.77 (m, IH ᅳ NCH), 6.81 -7.78 Cm, 11H, ArH)] Example 23 N-benzyl-N- (3,4-dichlorophenyl) azet idin-3-amine
[수율 87%; 녹는점 200°C IH NMR (400顧 z, DMS0-d6) δ 3.93 (m, 2H, azetidine H), 4.19 (m, 2H, azetidine H) , 4.70 (s, 2H, NCH2), 4.82 (m, IH, NCH), 6.65-7.39 (m, 11H, ArH), 8.61 (br(s), IH, NH)] 실시예 24: οε [Yield 87%; Melting point 200 ° C IH NMR (400 顧 z, DMS0-d6) δ 3.93 (m, 2H, azetidine H), 4.19 (m, 2H, azetidine H), 4.70 (s, 2H, NCH2), 4.82 (m, IH, NCH), 6.65-7.39 (m, 11H, ArH), 8.61 (br (s), IH, NH)] Example 24: οε
[(HN Ήι 's) 'αμν [(HN Ήι's) 'αμν
= Γ 'Η2 'Ρ) 8CZ '(fPV 'zW8 = Γ 'HZ 'Ρ) T2' '(iPV 'ΖΗ^"8 = f 'Ρ) ZO'L '(HJV 'ζΗί^8 = Γ Ήδ 'Ρ) 29"9 '(HON 'ΏΌΝ Ήδ '" 8S -0S '(Η suip szB 'ui) 61 ^ '(Η ^ϊΡί^ζ^ 'HZ 'ω) 88·ε '(8Η3 'HS 's) 6Γ2 9 (9P-0Sia 'ζΗ«00ΐ 顧 Ηΐ a 091 89룡^] 32 = Γ 'Η2' Ρ) 8CZ '(fPV' zW8 = Γ 'HZ' Ρ) T2 ' ' (iPV ' Ζ Η ^ " 8 = f ' Ρ) ZO ' L' (H J V ' ζ Ηί ^ 8 = Γ Ήδ 'Ρ) 29 " 9' (HON ' ΏΌΝ Ήδ'" 8S -0S '(Η suip szB' ui) 61 ^ '(Η ^ ϊΡί ^ ζ ^' HZ ' ω ) 88 · ε' (8Η3 'HS 's) 6Γ2 9 (9P-0Sia ' ζ Η «00ΐ ΗΗΐ a 091 89
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Figure imgf000024_0001
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Figure imgf000024_0001
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Figure imgf000024_0002
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Figure imgf000024_0002
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Figure imgf000024_0003
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Figure imgf000024_0004
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Figure imgf000024_0003
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Figure imgf000024_0004
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Figure imgf000024_0005
Figure imgf000024_0005
09Ζ000/Μ0ΖΗΜ/Χ3<1 실시예 29: N-benzyl-N-(2,4-dimethylphenyl )azet idin-3-amine 과 동일한 방법을 수행하여 합성하였다. 09Ζ000 / Μ0ΖΗΜ / Χ3 <1 Example 29: Synthesis was carried out by the same method as N-benzyl-N- (2,4-dimethylphenyl) azet idin-3-amine.
[수율 69%; 녹는점 115°C 1H NMR (400MHz, DMS0_d6) 52.22 (s, 3H,[Yield 69%; Melting Point 115 ° C 1H NMR (400MHz, DMS0_d6) 52.22 (s, 3H,
CH3), 2.26 (s, 3H, CH3) , 3.57 (m, 2H, azetidine H), 3.83 (m, 2H, azetidine H) , 4.00 (s, 2H, NCH2) , 4.17 (m, 1H, NCH), 6.81-7.31 (m, 8H, ArH), 8.57 (s, 1H, NH)] 실시예 30: CH3), 2.26 (s, 3H, CH3), 3.57 (m, 2H, azetidine H), 3.83 (m, 2H, azetidine H), 4.00 (s, 2H, NCH2), 4.17 (m, 1H, NCH), 6.81-7.31 (m, 8H, ArH), 8.57 (s, 1H, NH)] Example 30:
N一 (2 ,4—di methyl phenyl )-N-(naphthalen-2-ylmethyl )azetidin-3-amine [수율 48%; 녹는점 143°C 1H NMR (400MHz, DMS0-d6) δ 2.20 (s, 3H,Ni (2,4—di methyl phenyl) -N- (naphthalen-2-ylmethyl) azetidin-3-amine [yield 48%; Melting point 143 ° C 1H NMR (400MHz, DMS0-d6) δ 2.20 (s, 3H,
CH3), 2.30 (s, 3H, CH3), 3.62 (m, 2H, azetidine H), 3.81 (m, 2H, azetidine H), 4.19-4.25 (m, 3H, NCH2, NCH), 6.88-7.87 (m, 10H, ArH)] 실시예 31: CH3), 2.30 (s, 3H, CH3), 3.62 (m, 2H, azetidine H), 3.81 (m, 2H, azetidine H), 4.19-4.25 (m, 3H, NCH2, NCH), 6.88-7.87 (m , 10H, ArH)] Example 31:
N一 (4-chl orobenzy 1 ) -N- (2,4-dimethyl heny Dazetidi η-3-am i ne  N 一 (4-chl orobenzy 1) -N- (2,4-dimethyl heny Dazetidi η-3-am i ne
[수율 58%; oil; 1H 画 R (400MHz, DMS0-d6) 52.21 (s, 3H, CH3) , 2.23 (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 (m, 7H, ArH)] 실시예 32： N-benzyl-N-(4-p enoxyphenyl )azet idin-3-amine  [Yield 58%; oil; 1H 画 R (400MHz, DMS0-d6) 52.21 (s, 3H, CH3), 2.23 (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 (m, 7H, ArH)] Example 32 N-benzyl-N- (4-p enoxyphenyl) azet idin-3-amine
[수율 84%; 녹는점 106 °C 1H NMR (400MHz, DMS0-d6) δ 3.75 (m, 2H, azetidine H), 3.95 (m, 2H, azetidine H) , 4.53-4.57 (m, 3H, NCH2, NCH), 6.68-7.36 (m, 14H, ArH)] 실시예 33: [84% yield; Melting point 106 ° C 1H NMR (400MHz, DMS0-d6) δ 3.75 (m, 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- ( -phenoxypheny 1 )aze idin-3-amine  N- (naphthalen-2-ylmethyl) -N- (-phenoxypheny 1) aze idin-3-amine
[수율 96%; oil; 1H NMR (400顧 z, CDC13) 53.86-3.95 (m, 4H, azetidine H)ᅳ 4.60 (s, 2H, NCH2) , 4.66 (m, 1H, NCH), 6.72-7.86 (m, 16H, ArH)] 실시예 34: [96% yield; oil; 1 H NMR (400 顧 z, CDC13) 53.86-3.95 (m, 4H, azetidine H) ᅳ 4.60 (s, 2H, NCH2), 4.66 (m, 1H, NCH), 6.72-7.86 (m, 16H, ArH)] Example 34:
N- ( 4-ch 1 or obenzy 1 )-N-(4-phenoxyphenyl )azet idin-3~amine  N- (4-ch 1 or obenzy 1) -N- (4-phenoxyphenyl) azet idin-3 ~ amine
[수율 85%; oil; 1H MR (400MHz, DMS0-d6) δ 3.69 (m, 2H, azetidine H), 3.90 (m, 2H, azetidine H), 4.49-4.52 (m, 3H, NCH2, NCH), 6.68-7.41 (tn, 13H, ArH)] 실시예 35： N-benzyl-N-(naphthalen-2-ylmethyl )azet idin-3-amine [Yield 85%; oil; 1 H MR (400 MHz, DMS0-d6) δ 3.69 (m, 2H, azetidine H), 3.90 (m, 2H, azetidine H), 4.49-4.52 (m, 3H, NCH2, NCH), 6.68-7.41 (tn, 13H , ArH)] Example 35 N-benzyl-N- (naphthalen-2-ylmethyl) azet idin-3-amine
[수율 62%; 녹는점 U8°C 1H NMR (400MHz, CDC13) δ 3.45 (m, 2H, azetidine H), 3.50-3.61 (m, 4H, azetidine H, NCH2), 3.66 (s, 2H, NCH2) 3.74 (m, 1H, NCH), 7.27-7.86 (m, 12H, ArH)] 실시예 36: N-benzyl-N-(4-chlorobenzyl )azet idin-3-amine [Yield 62%; Melting point U8 ° C 1H NMR (400 MHz, CDC13) δ 3.45 (m, 2H, azetidine H), 3.50-3.61 (m, 4H, azetidine H, NCH2), 3.66 (s, 2H, NCH2) 3.74 (m, 1H , NCH), 7.27-7.86 (m, 12H, ArH)] Example 36: N-benzyl-N- (4-chlorobenzyl) azet idin-3-amine
[수율 43%; oil; 1H NMR (400MHz , CDC 13) 62.42 (br(s), 1H, H) , 3.42-3.47 (m, 4H, azetidine H, NCH2), 3.49 (s, 2H, NCH2) , 3.54 (m, 2H, azetidine H), 3.66 (m, 1H, NCH), 7.26-7.35 (m, 9H, ArH)] 실시예 37: N-benzyl-N-(2-ch lor obenzy 1 )azet idin-3-amine  [Yield 43%; oil; 1 H NMR (400 MHz, CDC 13) 62.42 (br (s), 1H, H), 3.42-3.47 (m, 4H, azetidine H, NCH2), 3.49 (s, 2H, NCH2), 3.54 (m, 2H, azetidine H), 3.66 (m, 1H, NCH), 7.26-7.35 (m, 9H, ArH)] Example 37: N-benzyl-N- (2-chlor obenzy 1) azet idin-3-amine
[수율 36%; oil; 1H NMR (400MHz, CDC13) 53.45 (m, 2H, azetidine H), 3.54-3.61 (m, 4H, azetidine H, NCH2), 3.65 (s, 2H, NCH2) , 3.77 (m, 1H, NCH), 7.17-7.58 (m, 9H, ArH)] 실시예 38: N-benzyl-N-(2-f luorobenzyl )azet idin-3-amine  [Yield 36%; oil; 1 H NMR (400 MHz, CDC13) 53.45 (m, 2H, azetidine H), 3.54-3.61 (m, 4H, azetidine H, NCH2), 3.65 (s, 2H, NCH2), 3.77 (m, 1H, NCH), 7.17 -7.58 (m, 9H, ArH)] Example 38 N-benzyl-N- (2-f luorobenzyl) azet idin-3-amine
[수율 50%; oil; 1H NMR (400MHz , CDC13) 62.39 (br(s), 1H, NH), 3.45 (m, 2H, azetidine H), 3.54-3.59 (m, 6H, azetidine H, NCH2, NCH2), 3.71 (m, 1H, NCH), 7.00-7.41 (m, 9H, ArH)] 실入 1예 39: N-benzyl-N-(3-chlorobenzyl )azet idin-3-amine  [50% yield; oil; 1 H NMR (400 MHz, CDC13) 62.39 (br (s), 1H, NH), 3.45 (m, 2H, azetidine H), 3.54-3.59 (m, 6H, azetidine H, NCH2, NCH2), 3.71 (m, 1H , NCH), 7.00-7.41 (m, 9H, ArH)] Example 1 39: N-benzyl-N- (3-chlorobenzyl) azet idin-3-amine
[수율 42%; oil; 1H NMR (400MHz, CDC13) 63.35-3.56 (m, 6H, azetidine H, NCH2, NCH2), 3.67 (m, 2H, azetidine H), 3.74 (m, 1H, NCH) 7.18-7.36 (m, 9H, ArH)] 실시예 40: N-benzyl-N-(4-isopropyl henyl )azet idin~3-amine [Yield 42%; oil; 1 H NMR (400 MHz, CDC13) 63.35-3.56 (m, 6H, azetidine H, NCH2, NCH2), 3.67 (m, 2H, azetidine H), 3.74 (m, 1H, NCH) 7.18-7.36 (m, 9H, ArH )] Example 40 N-benzyl-N- (4-isopropyl henyl) azet idin - 3-amine
[수율 Ί2 녹는점 98°C IH NMR (400MHz, CDC13) δ 1.24 (d, 6H, J = 6.8Hz, CH(CH3)2), 2.86 (m, IH, CH(CH3)2), 3.94-4.01 (m, 4H, azetidine H), 4.48 (s, 2H, NCH2), 4.71 (m, IH, NCH), 6.65-7.33 (m, 9H, ArH)] 실시예 41： N-(4-i sopropylpheny 1 ) -N- (napht ha 1 en-2- ylmethyl)azetidin-3-amine [Yield Ί2 Melting Point 98 ° C IH NMR (400 MHz, CDC13) δ 1.24 (d, 6H, J = 6.8 Hz, CH (CH3) 2), 2.86 (m, IH, CH (CH3) 2), 3.94-4.01 (m, 4H, azetidine H), 4.48 (s, 2H, NCH2), 4.71 (m, IH, NCH), 6.65-7.33 (m, 9H, ArH)] Example 41: N- (4-i sopropylpheny 1 ) -N- (napht ha 1 en-2-ylmethyl) azetidin-3-amine
[수율 89%; oil; IH NMR (400MHz, CDC13) δ 1.24 (d, 6H, J = 6.8Hz, [89% yield; oil; IH NMR (400 MHz, CDC13) δ 1.24 (d, 6H, J = 6.8 Hz,
CH(CH3)2), 2.86 (m, IH, CH(CH3)2), 3.91-4.01 (m, 4H, azetidine H), 4.62 (s, 2H, NCH2), 4.76 (m, IH, NCH), 6.67 (d, 2H, J = 8.4Hz, ArH), 7.11 (d, 2H, J = 8.4Hz, ArH), 7.38-7.83 (m, 7H, ArH)] 실시예 42: CH (CH3) 2), 2.86 (m, IH, CH (CH3) 2), 3.91-4.01 (m, 4H, azetidine H), 4.62 (s, 2H, NCH2), 4.76 (m, IH, NCH), 6.67 (d, 2H, J = 8.4 Hz, ArH), 7.11 (d, 2H, J = 8.4 Hz, ArH), 7.38-7.83 (m, 7H, ArH)] Example 42:
N- ( 4-ch 1 or obenzy 1 )-N-(4-i sopropylpheny 1 )azetidin-3-amine  N- (4-ch 1 or obenzy 1) -N- (4-i sopropylpheny 1) azetidin-3-amine
[수율 76%; oil; IH NMR (400MHz, CDC13) δ 1.24 (d, 6H, J = 6.8Hz, CH(CH3)2), 2.85 (m, IH, CH(CH3)2), 3.86-4.01 (m, 4H, azetidine H) , 4.45 (s, 2H, NCH2), 4.67 (m, IH, NCH), 6.62 (d, 2H, J = 8.4Hz, ArH), 7.12 (d, 2H, J = 8.4Hz, ArH), 7.20 (d, 2H, J = 8.4Hz, ArH), 7.31 (d, 2H, J = 8.4Hz, ArH)] 실시예 43 :N-(2-chlorobenzyl )-N-(4-isopropylphenyl )azet idin-3- amine  [76% yield; oil; IH NMR (400 MHz, CDC13) δ 1.24 (d, 6H, J = 6.8 Hz, CH (CH3) 2), 2.85 (m, IH, CH (CH3) 2), 3.86-4.01 (m, 4H, azetidine H) , 4.45 (s, 2H, NCH2), 4.67 (m, IH, NCH), 6.62 (d, 2H, J = 8.4 Hz, ArH), 7.12 (d, 2H, J = 8.4 Hz, ArH), 7.20 (d , 2H, J = 8.4 Hz, ArH), 7.31 (d, 2H, J = 8.4 Hz, ArH)] Example 43 N- (2-chlorobenzyl) -N- (4-isopropylphenyl) azet idin-3-amine
[수율 62%; oil; IH蘭 R (400MHz, CDC13) δ 1.23 (d, 6H, J = 6.8Hz, [Yield 62%; oil; IH 蘭 R (400 MHz, CDC13) δ 1.23 (d, 6H, J = 6.8 Hz,
CH(CH3)2) , 2.82 (m, IH, CH(CH3)2) , 3.82 (m, 2H, azetidine H) , 3.93 (m, 2H, azetidine H), 4.54 (s, 2H, NCH2), 4.76 On, IH, NCH), 6.57 (d, 2H, J = 8.4Hz, ArH), 7.10 (d, 2H, J = 8.4Hz, ArH), 7.22-7.42 On, 4H, ArH)] 실시예 44 :N-( 2- f luorobenzyl )-N-(4-i sopropylphenyl )azet idin-3- amine CH (CH3) 2), 2.82 (m, IH, CH (CH3) 2), 3.82 (m, 2H, azetidine H), 3.93 (m, 2H, azetidine H), 4.54 (s, 2H, NCH2), 4.76 On, IH, NCH), 6.57 (d, 2H, J = 8.4 Hz, ArH), 7.10 (d, 2H, J = 8.4 Hz, ArH), 7.22-7.42 On, 4H, ArH)] Example 44 N- (2-f luorobenzyl) -N- (4-i sopropylphenyl) azet idin-3-amine
[수율 39%; oil; IH NMR (400MHz, CDC13) δ 1.22 (d, 6H, J = 6.8Hz CH(CH3)2), 2.83 (m, IH, CH(CH3)2), 3.89 (m, 2H, azetidine H), 4.02 (m, 2H, azetidine H), 4.47 (s, 2H, NCH2) , 4.60 (m, IH, NCH), 6.65 (d, 2H, J = 8.4Hz, ArH), 7.04-7.29 (m, 6H, ArH)] 실시예 45： - (3-ch 1 or obenzy 1 )-N-(4-i sopropylphenyl )azetidin-3- amine  [Yield 39%; oil; IH NMR (400 MHz, CDC13) δ 1.22 (d, 6H, J = 6.8 Hz CH (CH3) 2), 2.83 (m, IH, CH (CH3) 2), 3.89 (m, 2H, azetidine H), 4.02 ( m, 2H, azetidine H), 4.47 (s, 2H, NCH2), 4.60 (m, IH, NCH), 6.65 (d, 2H, J = 8.4 Hz, ArH), 7.04-7.29 (m, 6H, ArH) Example 45 ：-(3-ch 1 or obenzy 1) -N- (4-i sopropylphenyl) azetidin-3-amine
[수율 40%; oil IH丽 R (400腿 z, CDC13) δ 1.24 (d, 6H, J = 6.8Hz, [Yield 40%; oil IHlli R (400 腿 z, CDC13) δ 1.24 (d, 6H, J = 6.8 Hz,
GH(CH3)2), 2.85 (m, IH, CH(CH3)2), 3.89 (m, 2H, azetidine H)， 4.00 (m, 2H, azetidine H)， 4.47 (s, 2H, NCH2) , 4.69 (m, IH, NCH), 6.63 (d, 2H, J = 8.4Hz, ArH), 7.12 (dᅳ 2H, J = 8.4Hz, ArH), 7.16-7.29 (m, 4H, ArH)] 실시예 46： N-cyc 1 opropyl-N-(naphthalen-2-ylmethyl )azet idin-3-amineGH (CH3) 2), 2.85 (m, IH, CH (CH3) 2), 3.89 (m, 2H, azetidine H), 4.00 (m, 2H, azetidine H), 4.47 (s, 2H, NCH2), 4.69 (m, IH, NCH), 6.63 (d, 2H, J = 8.4 Hz, ArH), 7.12 (d ᅳ 2H, J = 8.4 Hz, ArH), 7.16-7.29 (m, 4H, ArH)] Example 46 ： N-cyc 1 opropyl-N- (naphthalen-2-ylmethyl) azet idin-3-amine
[수율 87%; oil; IH 蘭 R (400MHz, CDC13) δ 0.44-0.57 (m, 4H, cyclopropyl H) , 1.78 (m, IH, cyclopropyl CIH), 3.45-3.62 (m, 4H, azetidine H), 3.82-3.84 (m, 3H, NCH2, NCH), 7.39-7.85 (m, 7H, ArH)] 실시예 47 ： N-cyclopropyl-N-(4-f luorobenzyl )azet idin-3-amine [Yield 87%; oil; IH 蘭 R (400 MHz, CDC13) δ 0.44-0.57 (m, 4H, cyclopropyl H), 1.78 (m, IH, cyclopropyl CIH), 3.45-3.62 (m, 4H, azetidine H), 3.82-3.84 (m, 3H , NCH2, NCH), 7.39-7.85 (m, 7H, ArH)] Example 47 N-cyclopropyl-N- (4-f luorobenzyl) azet idin-3-amine
[수율 73%; oil; IH NMR (400MHz, CDC13) 60.38-0.50 (m, 4H, cyclopropyl H), 1.65 (m, IH, cyclopropyl CIH) , 3.46 (m, 2H, azet i dine H), 3.62 (s, 2H, NCH2), 3.66-3.73 (m, 3H, azetidine H, NCH), 6.98-7.25 (m, 4H, ArH)] 실시예 48 ： N-cy c 1 opr opy 1 -M- ( 3-me t hy 1 benzy 1 ) azet i d i η-3-am i ne  [Yield 73%; oil; IH NMR (400 MHz, CDC13) 60.38-0.50 (m, 4H, cyclopropyl H), 1.65 (m, IH, cyclopropyl CIH), 3.46 (m, 2H, azet i dine H), 3.62 (s, 2H, NCH2), 3.66-3.73 (m, 3H, azetidine H, NCH), 6.98-7.25 (m, 4H, ArH)] Example 48 N-cy c 1 opr opy 1 -M- (3-me t hy 1 benzy 1) azet idi η-3-am i ne
[수율 61%; oil; IH 丽 R (400MHz, CDC13) δ 0.43-0.52 (m, 4H, cyclopropyl H) , 1.70 (m, IH, cyclopropyl CIH), 2.35 (s, 3H, CH3), 3.52 (m, 2H, azetidine H), 3.62 (s, 2H, NCH2) , 3.76-3.77 (m, 3H, azetidine H, NCH), 7.05-7.22 (m, 4H, ArH)] 실시예 49： N-cyc 1 opr opy 1 -N-(4- i sopr opy Ibenzy 1 ) azet i di η-3-ami ne[Yield 61%; oil; IH δ R (400MHz, CDC13) δ 0.43-0.52 (m, 4H, cyclopropyl H), 1.70 (m, IH, cyclopropyl CIH), 2.35 (s, 3H, CH3), 3.52 (m, 2H, azetidine H), 3.62 (s, 2H, NCH 2), 3.76-3.77 (m, 3H, azetidine H, NCH), 7.05-7.22 (m, 4H, ArH)] Example 49: N-cyc 1 opr opy 1 -N- (4-i sopr opy Ibenzy 1) azet i di η-3-ami ne
[수율 67%; oil; IH NMR (400MHz, CDC13) δ 0.44-0.53 (m, 4H, cyclopropyl H) , 1.27 (d, 6H, J = 6.8Hz, CH(CH3)2), 1.70 (m, IH, cyclopropyl CIH), 2.91 (m, IH, CH(CH3)2), 3.53 (m, 2H, azetidine H)， 3.67 (s, 2H, NCH2), 3.75-3.80 (m, 3H, azetidine H, NCH), 7.16-7.17 (m, 4H, ArH)] 실시예 5Q:N-cyclopentyl-N-(naphthalen-2-ylmethyl )azet idin-3-amine [수율 89%; oil; IH NMR (400MHz, CDC 13) δ 1.41-1.74 (m, 8H, cyclopentyl H) , 3.11 (m, IH, cyclopentyl CIH), 3.47 (m, 2H, azetidine H), 3.63 0n' 2H, azetidine H), 3.83 (s, 2H, NCH2) , 3.91 (m, IH, NCH), 7.44-7.85 (m, 7H, ArH)] 실시예 51： N-cyclopentyl-N-(2-methylbenzyl )azet idin~3-amine [Yield 67%; oil; IH NMR (400 MHz, CDC13) δ 0.44-0.53 (m, 4H, cyclopropyl H), 1.27 (d, 6H, J = 6.8 Hz, CH (CH3) 2), 1.70 (m, IH, cyclopropyl CIH), 2.91 ( m, IH, CH (CH 3) 2), 3.53 (m, 2H, azetidine H), 3.67 (s, 2H, NCH 2), 3.75-3.80 (m, 3H, azetidine H, NCH), 7.16-7.17 (m, 4H, ArH)] Example 5Q: N-cyclopentyl-N- (naphthalen-2-ylmethyl) azet idin-3-amine [Yield 89%; oil; IH NMR (400 MHz, CDC 13) δ 1.41-1.74 (m, 8H, cyclopentyl H), 3.11 (m, IH, cyclopentyl CIH), 3.47 (m, 2H, azetidine H), 3.63 0n '2H, azetidine H), 3.83 (s, 2H, NCH 2), 3.91 (m, IH, NCH), 7.44-7.85 (m, 7H, ArH)] Example 51: N-cyclopentyl-N- (2-methylbenzyl) azet idin ~ 3-amine
[수율 67%; oil; IH 匪 R (400MHz, CDC13) δ 1.41-1.68 (m, 8H, cyclopentyl H) , 2.37 (s, 3H, CH3) , 3.10 (m, IH, cyclopentyl CIH), 3.43 (m, 2H, azetidine H) , 3.58 (m, 2H, azetidine H), 3.64 (s, 2H, NCH2), 3.90 (m, IH, NCH), 7.11-7.51 Cm, 4H, ArH)] 실시예 52: N-cyc 1 openty 1 -N-( 2-f 1 uor obenzy 1 ) azet i di n~3-ami ne  [Yield 67%; oil; IH 匪 R (400 MHz, CDC13) δ 1.41-1.68 (m, 8H, cyclopentyl H), 2.37 (s, 3H, CH3), 3.10 (m, IH, cyclopentyl CIH), 3.43 (m, 2H, azetidine H), 3.58 (m, 2H, azetidine H), 3.64 (s, 2H, NCH 2), 3.90 (m, IH, NCH), 7.11-7.51 Cm, 4H, ArH)] Example 52: N-cyc 1 openty 1 -N -(2-f 1 uor obenzy 1) azet i di n ~ 3-ami ne
[수율 56%; oil; IH MR (400MHz, CDC 13) δ 1.41-1.68 (m, 8H, cyclopentyl H) , 3.10 (m, IH, cyclopentyl CIH), 3.51 (m, 2H, azetidine H), 3.53 (m, 2H, azetidine H) , 3.73 (s, 2H, NCH2) , 3.91 (m, IH, NCH), 6.98-7.55 (m, 4H, ArH)] 실시예 53: N-(3-chlorobenzyl )-N-cyclopentylazet idin-3-amine  [Yield 56%; oil; IH MR (400 MHz, CDC 13) δ 1.41-1.68 (m, 8H, cyclopentyl H), 3.10 (m, IH, cyclopentyl CIH), 3.51 (m, 2H, azetidine H), 3.53 (m, 2H, azetidine H) , 3.73 (s, 2H, NCH 2), 3.91 (m, IH, NCH), 6.98-7.55 (m, 4H, ArH)] Example 53: N- (3-chlorobenzyl) -N-cyclopentylazet idin-3-amine
[수율 78%; oil; IH 丽 R (400MHz, CDC13) δ 1.40-1.70 (m, 8H, cyclopentyl H), 3.05 (m, IH, cyclopentyl CIH), 3.42 (m, 2H, azetidine H), 3.60 (m, 2H, azetidine H), 3.66 (s, 2H, NCH2), 3.86 (m, IH, NCH), 7.21-7.39 (m, 4H, ArH)] 실시예 54: [Yield 78%; oil; IH δ R (400MHz, CDC13) δ 1.40-1.70 (m, 8H, cyclopentyl H), 3.05 (m, IH, cyclopentyl CIH), 3.42 (m, 2H, azetidine H), 3.60 (m, 2H, azetidine H), 3.66 (s, 2H, NCH2), 3.86 (m, IH, NCH), 7.21-7.39 (m, 4H, ArH)] Example 54:
N-(3-chloro-2-methylphenyl )-N-(naphthalen-2-ylmethyl )azet idin—3— amine  N- (3-chloro-2-methylphenyl) -N- (naphthalen-2-ylmethyl) azet idin—3— amine
[수율 34%; oil; IH NMR (400MHz, CDC13) 52.55 (s, 3H, CH3) , 3.58 (m, 2H, azetidine H), 3.65 (m, 2H, azetidine H), 4.07 (s, 2H, NCH2), 4.26 (m, IH, NCH), 6.63 (d, IH, J = 7.6Hz, ArH), 7.01 (t, IH, J = 8.0Hz, ArH), 7.19-7.82 (m, 8H, ArH)] 실시예 55： N- ( 3-ch 1 or ο-2-met hy 1 pheny 1 ) -N-(4~ch lor obenzy 1 )azet idi n- 3-amine [Yield 34%; oil; IH NMR (400 MHz, CDC13) 52.55 (s, 3H, CH3), 3.58 (m, 2H, azetidine H), 3.65 (m, 2H, azetidine H), 4.07 (s, 2H, NCH2), 4.26 (m, IH , NCH), 6.63 (d, IH, J = 7.6 Hz, ArH), 7.01 (t, IH, J = 8.0 Hz, ArH), 7.19-7.82 (m, 8H, ArH)] Example 55: N- ( 3-ch 1 or ο-2-met hy 1 pheny 1) -N- (4 ~ ch lor obenzy 1) azet idi n- 3-amine
[수율 63%； oil; IH NMR (400MHz, CDC13) 52.46 (s, 3H, CH3), 3.57 (m, 2H, azetidine H), 3.66 (m, 2H, azetidine H)， 3.93 (s, 2H, NCH2) , 4.20 (m, IH, NCH), 6.62 (d, IH, J = 7.6Hz, ArH), 6.99-7.25 (m, 6H, ArH)] 실시예 56 :N-(2-f luorophenyl ) -N- (napht ha len-2-yl methyl )azet idin-3- amine  [Yield 63%; oil; IH NMR (400 MHz, CDC13) 52.46 (s, 3H, CH3), 3.57 (m, 2H, azetidine H), 3.66 (m, 2H, azetidine H), 3.93 (s, 2H, NCH2), 4.20 (m, IH , NCH), 6.62 (d, IH, J = 7.6 Hz, ArH), 6.99-7.25 (m, 6H, ArH)] Example 56: N- (2-f luorophenyl) -N- (napht ha len-2) -yl methyl) azet idin-3-amine
[수율 40%; oil; IH NMR (400MHz, CDC13) δ 3.75-3.85 (ra, 4H, azetidine H) , 4.39 (s, 2H, NCH2) , 4.47 (m, IH, NCH), 6.78-7.83 (m, 11H, ArH)] 실시예 57 : N— ( 4_ch 1 or obenzy l)~N-(2-f 1 uoropheny l)azetidin-3-amine [Yield 40%; oil; IH NMR (400 MHz, CDC13) δ 3.75-3.85 (ra, 4H, azetidine H), 4.39 (s, 2H, NCH2), 4.47 (m, IH, NCH), 6.78-7.83 (m, 11H, ArH)] Example 57: N— (4_ch 1 or obenzy l) ~ N- (2-f 1 uoropheny l) azetidin-3-amine
[수율 52%; oil; IH NMR (400MHz, CDC13) 53.84 (m, 2H, azetidine H), 3.93 (m, 2H, azetidine H) , 4.21 (s, 2H, NCH2), 4.46 (m, IH, NCH), 6.78 (dd, IH, J = 7.6Hz, ArH), 7.00-7.29 (m, 7H, ArH)] 실시예 58:N-(3-chlorophenyl )~N-(naphthal en-2-ylmethy 1 )azetidin-3~ amine [Yield 52%; oil; IH NMR (400 MHz, CDC13) 53.84 (m, 2H, azetidine H), 3.93 (m, 2H, azetidine H), 4.21 (s, 2H, NCH2), 4.46 (m, IH, NCH), 6.78 (dd, IH , J = 7.6 Hz, ArH), 7.00-7.29 (m, 7H, ArH)] Example 58: N- (3-chlorophenyl) ~ N- (naphthal en-2-ylmethy 1) azetidin-3 ~ amine
[수율 80%; oil; IH NMR (400MHz, CDC13) 53.95 (m, 2H, azetidine H), 4.01 (m, 2H, azetidine H) , 4.73 (s, 2H, NCH2), 4.79 (m, IH, NCH), 6.57 (dd, IH, J = 8.0Hz, J = 2.0Hz, ArH), 6.68 (t, IH, J = 2.0Hz, ArH) 6.85 (dd, IH, J = 8.0Hz, J = 1.2Hz, ArH), 7.14 (t, IH, J = 8.4Hz, ArH) 7.35 (dd, IH, J = 8.4Hz, J = 2.0Hz, ArH), 7.47-7.85 (m, 6H, ArH)] 실시예 59:N-(4-chlorobenzyl)-N-(3-chlorophenyl )azet idin一 3_amine [수율 78%; 녹는점 168°C IH NMR (400MHz, CDC13) 63.90 (m, 2H, azetidine H)， 4.02 (m, 2H, azetidine H) , 4.54 (s, 2H, NCH2), 4.72 (m, IH, NCH), 6.52 (dd, IH, J = 8.0Hz, J = 2.0Hz, ArH), 6.63 (t, IH, J = 2.0Hz, ArH), 6.84 (dd, IH, J = 8.0Hz, J - 1.2Hz, ArH), 7.13-7.34 (m, 5H, ArH)] 실시예 60: [Yield 80%; oil; IH NMR (400 MHz, CDC13) 53.95 (m, 2H, azetidine H), 4.01 (m, 2H, azetidine H), 4.73 (s, 2H, NCH2), 4.79 (m, IH, NCH), 6.57 (dd, IH , J = 8.0 Hz, J = 2.0 Hz, ArH), 6.68 (t, IH, J = 2.0 Hz, ArH) 6.85 (dd, IH, J = 8.0 Hz, J = 1.2 Hz, ArH), 7.14 (t, IH, J = 8.4 Hz, ArH) 7.35 (dd, IH, J = 8.4 Hz, J = 2.0 Hz, ArH), 7.47-7.85 (m, 6H, ArH)] Example 59: N- (4-chlorobenzyl) -N- (3-chlorophenyl) azet idin 一 3_amine [yield 78%; Melting point 168 ° C IH NMR (400 MHz, CDC13) 63.90 (m, 2H, azetidine H), 4.02 (m, 2H, azetidine H), 4.54 (s, 2H, NCH2), 4.72 (m, IH, NCH), 6.52 (dd, IH, J = 8.0 Hz, J = 2.0 Hz, ArH), 6.63 (t, IH, J = 2.0 Hz, ArH), 6.84 (dd, IH, J = 8.0 Hz, J-1.2 Hz, ArH , 7.13-7.34 (m, 5H, ArH)] Example 60:
N-(azetidi η-3-y 1 ) ~N- ( napht ha 1 en一 2一 y Imethyl ) benzo [d]thiazol-2- amine  N- (azetidi η-3-y 1) to N- (napht ha 1 en 一 2 一 y Imethyl) benzo [d] thiazol-2-amine
[수율 35%; 녹는점 80°C IH 應 R (400MHz, DMS0~d6) δ 3.95 (m, 2H, azetidine H), 4.08 (m, 2H, azetidine H)， 5.10-5.13 (m, 3H, NCH2, NCH), 7.09 (t, IH, J = 7.6Hz, ArH), 7.31 (t , IH, J = 7.6Hz, ArH), 7.46-7.94 (m, 9H, ArH)] 실시예 61: N-(3 , 4-di chl orobenzy 1 )-N-phenylazet idin-3-amine [수율 80%; oil; IH NMR (400MHz, CDC13) δ 3.71 (m, 2H, azetidine[Yield 35%; Melting point 80 ° C IH 應 R (400 MHz, DMS0 to d6) δ 3.95 (m, 2H, azetidine H), 4.08 (m, 2H, azetidine H), 5.10-5.13 (m, 3H, NCH2, NCH), 7.09 (t, IH, J = 7.6 Hz, ArH), 7.31 (t, IH, J = 7.6 Hz, ArH), 7.46-7.94 (m, 9H, ArH)] Example 61: N- (3, 4-di chl orobenzy 1) -N-phenylazet idin-3-amine [yield 80%; oil; IH NMR (400 MHz, CDC13) δ 3.71 (m, 2H, azetidine
H), 3.85 (m, 2H, azetidine H) , 4.50 (s, 2H, NCH2) , 4.65 (m, IH, NCH), 6.64 (d, 2H, J = 7.6Hz, ArH), 6.84 (t, IHᅳ J = 7.2Hz, ArH), 7.11-7.42 (m, 5H, ArH)] 실시예 62: N-(3 , 4-di chl orobenzyl )-N~(naphthal en-2-yl )azet i din-3- amine H), 3.85 (m, 2H, azetidine H), 4.50 (s, 2H, NCH2), 4.65 (m, IH, NCH), 6.64 (d, 2H, J = 7.6 Hz, ArH), 6.84 (t, IH ᅳ J = 7.2 Hz, ArH), 7.11-7.42 (m, 5H, ArH)] Example 62: N- (3, 4-di chl orobenzyl) -N to (naphthal en-2-yl) azet i din-3-amine
[수율 87%; 녹는점 187°C; 1H NMR (400MHz, CDC13) δ 3.80 (m, 2H, azetidine H), 3.97 (m, 2H, azetidine H), 4.59 (s, 2H, NCH2), 4.72 (m, 1H, NCH), 6.81-7.78 (m, 10H, ArH)] 실시예 63: N-(3 , 4-di chlorobenzyl )-N-(p-tolyl )azet i din-3-amine[Yield 87%; Melting point 187 ° C; 1 H NMR (400 MHz, CDC13) δ 3.80 (m, 2H, azetidine H), 3.97 (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-di chlorobenzyl) -N- (p-tolyl) azet i din-3-amine
[수율 87%; 녹는점 162°C; 1H NMR (400MHz, CDC13) δ 2.28 (s, 3H, CH3), 3.71 (in, 2H, azetidine H) , 3.84 (m, 2H, azetidine H) , 4.42 (s, 2H, NCH2), 4.58 (m, 1H, NCH), 6.56 (d, 2H, J = 8.4Hz, ArH), 7,02 (d, 2H, J = 8.0Hz, ArH), 7.10-7.41 (m, 4H, ArH)] 실시예 64： N- ( 3 , 4-d i ch 1 orobenzy 1 ) -N- ( 2 , 4-d i me t hy 1 pheny 1 ) aze t i d i n- 3ᅳ amine [Yield 87%; Melting point 162 ° C; 1 H NMR (400 MHz, CDC13) δ 2.28 (s, 3H, CH 3), 3.71 (in, 2H, azetidine H), 3.84 (m, 2H, azetidine H), 4.42 (s, 2H, NCH 2), 4.58 (m, 1H, NCH), 6.56 (d, 2H, J = 8.4 Hz, ArH), 7,02 (d, 2H, J = 8.0 Hz, ArH), 7.10-7.41 (m, 4H, ArH)] Example 64: N- (3, 4-di ch 1 orobenzy 1) -N- (2, 4-di me t hy 1 pheny 1) aze tidi n- 3 ᅳ amine
[수율 26%; oil; 1H NMR (400MHz, CDC13) δ 2.29 (s, 3H, CH3), [Yield 26%; oil; 1 H NMR (400 MHz, CDC13) δ 2.29 (s, 3H, CH 3),
2.32 (s, 3H, CH3), 3.45-3.46 (m, 4H, azetidine H), 3.92 (sᅳ 2H, NCH2), 4.12 (m, 1H, NCH), 6.71 (d, 1H, J = 8.0Hz, ArH), 6.91-7.32 (m, 5H, ArH)] 실시예 65:N-(3-chlorophenyl )-N-(3, 4-di chl orobenzyl )azet idin-3- amine 2.32 (s, 3H, CH3), 3.45-3.46 (m, 4H, azetidine H), 3.92 (s ᅳ 2H, NCH2), 4.12 (m, 1H, NCH), 6.71 (d, 1H, J = 8.0 Hz, ArH), 6.91-7.32 (m, 5H, ArH)] Example 65: N- (3-chlorophenyl) -N- (3, 4-di chl orobenzyl) azet idin-3-amine
[수율 78%; 녹는점 187°C; 1H NMR (400MHz, DMS0-d6) δ 3.92 (m, 2H, azetidine H) , 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)] 실시예 66: N-(3 , -di chlorobenzyl )-N-(4-phenoxyphenyl )azet idin- 3ᅳ amine [Yield 78%; Melting point 187 ° C; 1 H NMR (400 MHz, DMS0-d6) δ 3.92 (m, 2H, azetidine H), 4.22 (m, 2H, azetidine H), 4.70 (s, 2H, NCH 2), 4.82 (m, 1H, NCH), 6.61- 7.63 (m, 7H, ArH), 8.80 (br (s) 1H, NH)] Example 66: N- (3, -di chlorobenzyl) -N- (4-phenoxyphenyl) azet idin-3 ′ amine
[수율 62%; 녹는점 185°C; 1H NMR (400丽 z, DMS0~d6) δ 3.89 (m, 2H, azetidine H), 4.20 (m, 2H, azetidine H) , 4.52 (s, 2H, NCH2), 4.59 (m, 1H, NCH), 6.75-7.63 (m, 12H, ArH), 8.86 (br(s) 1H, NH)] 실시예 67： N-(3 , 4-di chl orobenzyl )-N-(2-f 1 uoropheny 1 )azet idin-3- amine [Yield 62%; Melting point 185 ° C; 1 H NMR (400 d z, DMS0 to d6) δ 3.89 (m, 2H, azetidine H), 4.20 (m, 2H, azetidine H), 4.52 (s, 2H, NCH2), 4.59 (m, 1H, NCH), 6.75-7.63 (m, 12H, ArH), 8.86 (br (s) 1H, NH)] Example 67 ： N- (3, 4-di chl orobenzyl) -N- (2-f 1 uoropheny 1) azet idin-3-amine
[수율 53%; oil; 1H NMR (400丽 z, CDC13) δ 3.64 (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)] 실시예 68 : N— (3 , -di ch 1 orobenzy 1 ) -N-(4- i sopropy 1 pheny 1 ) azet idin-3- amine  [Yield 53%; oil; 1 H NMR (400 z, CDC13) δ 3.64 (m, 2H, azetidine H), 3.70 (m, 2H, azetidine H), 4.23 (s, 2H, NCH 2), 4.31 (m, 1H, NCH), 6.69- 7.35 (m, 7H, ArH)] Example 68: N— (3, -di ch 1 orobenzy 1) -N- (4- i sopropy 1 pheny 1) azet idin-3-amine
[수율 ᅳ、 oil; 1H NMR (400丽 z, CDCI3) 6 1.23 (d, 6H, J = 6.8Hz, [Yield ᅳ, oil; 1 H NMR (400 liza, CDCI3) 6 1.23 (d, 6H, J = 6.8 Hz,
CH(CH3)2), 2.85 (m, 1H, CH(CH3)2), 3.75 (m, 2H, azetidine H), 3.88 (m, 2H, azetidine H)， 4.43 (s, 2H, NCH2) , 4.63 (m, 1H, NCH), 6.58 (d, 2H, J = 8.8Hz, ArH), 7.07-7.42 (m, 5H, ArH)] 실시예 69: CH (CH3) 2), 2.85 (m, 1H, CH (CH3) 2), 3.75 (m, 2H, azetidine H), 3.88 (m, 2H, azetidine H), 4.43 (s, 2H, NCH2), 4.63 (m, 1H, NCH), 6.58 (d, 2H, J = 8.8 Hz, ArH), 7.07-7.42 (m, 5H, ArH)] Example 69:
N- ( 3-ch 1 or o— 2~me thy】 phenyl )—N_ ( 3 , 4-di ch 1 orobenzy Dazetidi n-3- amine  N- (3-ch 1 or o— 2 ~ me thy] phenyl) —N_ (3, 4-di ch 1 orobenzy Dazetidi n-3- amine
[수율 45%; oil; 1H 證 (400MHz, CDC13) δ 2.46 (s, 3H, CH3), 3.55 (m, 2H, azetidine H) , 3.61 (m, 2H, azetidine H) , 3.95 (s, 2H, NCH2) , 4.16 (m, 1H, NCH), 6.65 (d, 1H, J = 7.6Hz, ArH), 6.88-7.35 (m, 5H, ArH)] 실시예 70: N-benzy 1 -N- ( 3 , 4-d i ch 1 or obenzy 1 ) aze t i d i η-3-am i ne  [Yield 45%; oil; 1 H 證 (400 MHz, CDC13) δ 2.46 (s, 3H, CH3), 3.55 (m, 2H, azetidine H), 3.61 (m, 2H, azetidine H), 3.95 (s, 2H, NCH2), 4.16 (m, 1H, NCH), 6.65 (d, 1H, J = 7.6 Hz, ArH), 6.88-7.35 (m, 5H, ArH)] Example 70: N-benzy 1 -N- (3, 4-di ch 1 or obenzy 1) aze tidi η-3-am i ne
[수율 44%; oil; 1H NMR (400MHz, CDC13) δ 3.41-3.51 (m, 6H, azetidine H, NCH2, NCH2), 3.57 (m, 2H, azetidine H)， 3.67 (m, 1H, NCH), 7.16-7.44 (m, 8H, ArH)] 실시예 71： N-cyc 1 opropy l-N-(3 , 4-di chl orobenzy 1 )azet i din-3- amine [수율 64%; oil; 1H NMR (400MHz, CDC13) δ 0.38-0.50 (m, 4H, cyclopropyl H) , 1.68 (m, 1H, cyclopropyl ClH) , 3.49 (m, 2H, azetidine H), 3.63 (s, 2H, NCH2) , 3.65-3.69 (m, 3H, azetidine H, NCH)， 7.10-7.39 (m, 3H, ArH)] 실시예 72： N-cyc 1 openty 1 -N-(3 , 4-di chl orobenzy 1 )azet i din-3- amine [Yield 44%; oil; 1 H NMR (400 MHz, CDC13) δ 3.41-3.51 (m, 6H, azetidine H, NCH2, NCH2), 3.57 (m, 2H, azetidine H), 3.67 (m, 1H, NCH), 7.16-7.44 (m, 8H , ArH)] Example 71 N-cyc 1 opropy lN- (3, 4-di chl orobenzy 1) azet i din-3-amine [Yield 64%; oil; 1 H NMR (400 MHz, CDC13) δ 0.38-0.50 (m, 4H, cyclopropyl H), 1.68 (m, 1H, cyclopropyl ClH), 3.49 (m, 2H, azetidine H), 3.63 (s, 2H, NCH2), 3.65 -3.69 (m, 3H, azetidine H, NCH), 7.10-7.39 (m, 3H, ArH)] Example 72: N-cyc 1 openty 1 -N- (3, 4-di chl orobenzy 1) azet i din -3-amine
[수율 45%; oil; 1H NMR (400丽 z, CDC13) δ 1.41-1.73 (m, 8H, eye 1 openty 1 H)， 3.04 (m, 1H, eye 1 openty 1 ClH), 3.49 (m, 2H, azetidine H), 3.6359 (m, 2H, azetidine H) , 3.63 (s, 2H, NCH2) , 3.85 (m, 1H, NCH) 7.19-7.50 (m, 3H, ArH)]  [Yield 45%; oil; 1 H NMR (400 δ z, CDC13) δ 1.41-1.73 (m, 8H, eye 1 openty 1 H), 3.04 (m, 1H, eye 1 openty 1 ClH), 3.49 (m, 2H, azetidine H), 3.6359 ( m, 2H, azetidine H), 3.63 (s, 2H, NCH2), 3.85 (m, 1H, NCH) 7.19-7.50 (m, 3H, ArH)]
[실험예: 신경전달물질 재흡수 저해 에세이 (Neurotransporter reuptake inhibitory assay)] Experimental Example: Neurotransporter reuptake inhibitory assay
합성한 화합물의 신경전달물질 수송체에 대한 재흡수 저해 활성 Reuptake Inhibitory Activity of Synthesized Compounds on Neurotransmitter Transporters
(reuptake inhibitory activity)을 in vitro 에서 시험하였다. 이 활성은 실시예에서 합성된 화합물이 단가아민 신경전달물질 수송체인 도파민, 세로토닌 및 노에피네프린 수송체를 통한 신경전달물질의 재홉수를 차단하는 능력을 의미한다. 도파민， 세로토닌 및 노에피네프린 재흡수 차단제 후보 물질에 대한 세포기반 검색을 위해， 실시간 형광분석 기기인 고효율 검색기 (high-throughput screening system) FDSS6000 (Functional Drug Screening System 6000)올 이용하였다. 본 실험 예에서는 인간 도파민 세로토닌 및 노에피네프린 수송체가 각각 발현된 HEK293 세포주 (HEK-hDAT, HEK-hNET)에 차단제를 처리한 후， 세포 내 단가아민 신경전달물질의 변화를 측정하여 IC50값을 구하였다. (reuptake inhibitory activity) was tested in vitro. This activity refers to the ability of the compound synthesized in the Examples to block the number of hops of the neurotransmitter via the monovalent amine neurotransmitter transporter dopamine, serotonin and noepinephrine transporter. For cell-based screening of dopamine, serotonin, and norepinephrine reuptake blocker candidates, a high-throughput screening system FDSS6000 (Functional Drug Screening System 6000) was used. In this experiment, we treated the HEK293 cell lines (HEK-hDAT, HEK-hNET) expressing human dopamine serotonin and noepinephrine transporters, respectively, and measured the change in the monovalent amine neurotransmitter in the cell to determine the IC 50 value. It was.
(1) 세포 배양과 준비 (1) Cell Culture and Preparation
인간 도파민， 세로토닌 및 노에피네프린 수송체가 각각 안정적으로 발현되어 있는 HEK293 세포주 (HEK-hDAT, HEK-hNET; North Carolina-Chapel Hill 대학교 Bryan Roth 교수 제공)를 사용하여 합성된 화합물의 활성 검사를 진행하였다. HEK293 cell lines (HEK-hDAT, HEK-hNET; North Carolina-Chapel) stably expressing human dopamine, serotonin and noepinephrine transporters, respectively (Provided by Professor Bryan Roth, Hill University), the activity of the synthesized compounds was tested.
각 수송체가 안정적으로 발현된 HEX293 세포는 10%(v/v) 소태아 혈청 (fetal bovine serum), 페니실린 (penicillin, 100 U/ml), 및 스트렙토마이신 (streptomycin, 100 yg/ml)이 첨가된 둘베코 이글 배양액 (Dulbecco's modified Eagle's medium, Wei gene, Daegu, Korea)을 사용하여 37 °C 5% 이산화탄소 가습 조건의 배양기에서 배양하였고, 3-4 일에 한 번씩 계대하였다. HEX293 cells stably expressing each transporter were added with 10% (v / v) fetal bovine serum, penicillin (penicillin, 100 U / ml), and streptomycin (100 yg / ml). Dulbecco's modified Eagle's medium (Deubecco's medium, Wei gene, Daegu, Korea) was incubated in an incubator at 37 ° C 5% carbon dioxide humidification conditions and passaged once every 3-4 days.
각 수송체를 발현하는 세포를 선별하기 위하여 , HEK-hDAT세포주에는 350 mg/ml , HEK-hNET 세포주에는 200 mg/ml 의 Geneticin G418 (Gibco, USA)을 첨가하여 배양하였다 (37°C 5% 이산화탄소, 가습 조건의 배양기). FDSS6000 기기 (Hamamatsu Photonics, Hamamatsu, Japan)를 이용한 단가아민 재흡수 차단제 화합물 활성 검색 18-20 시간 전에, 폴리 -L-라이신 (poly-L-lysine, 0.05 mg/ml)으로 코팅된 96-웰 플레이트 (NUNC, Rochester, NY, USA)에 한 웰당 5 x 104세포의 밀도로 분주하였다. In order to select cells expressing each transporter, 350 mg / ml of HEK-hDAT cell line and 200 mg / ml of HEK-hNET cell line were added and cultured (37 ° C 5%). Carbon dioxide, humidifier incubator). 96-well plate coated with poly-L-lysine (0.05 mg / ml) 18-20 hours prior to detection of monovalent amine reuptake blocker compound activity using FDSS6000 instrument (Hamamatsu Photonics, Hamamatsu, Japan) (NUNC, Rochester, NY, USA) were dispensed at a density of 5 × 10 4 cells per well.
(2) 고효율 검색기 FDSS6000을 이용한측정과 데이터 분석 (2) Measurement and data analysis using high efficiency browser FDSS6000
재흡수 저해 활성은 DA (도파민)， 5-HT (세로토닌) 및 NE (노에피네프린)를 모방하고 형광염료로 표지된 지시약이 포함된 신경전달물질 수송체 흡수 에세이 키트 (Neurotransmitter Transporter Uptake Assay Kit , Molecular Devices, Sunnyvale, CA, USA)를 사용하여 차단제를 처리한 후， 지시약의 세포 내 재흡수를 형광신호로 측정하였다. 상기 지시약은 키트 내에 포함되어 있는 것을 사용하였다. 에세이 키트 내에는 도파민, 세로토닌， 및 노에피네프린을 모방하고 형광염료로 표지된 지시약이 가루형태로 포함되어 있으며， 이 지시약을 HEPES 버퍼로 녹여서 실험에 사용하였다. 에세이 키트 내에는 한 종류의 지시약만 포함되어 있고, 도파민， 세로토닌 및 노에피네프린 재흡수 실험에 모두 동일한 종류의 지시약을사용하였다.  The reuptake inhibitory activity mimics DA (dopamine), 5-HT (serotonin) and NE (noepinephrine) and includes a neurotransmitter transporter uptake assay kit, Molecular Devices, Sunnyvale, CA, USA), after treatment with the blocking agent, the intracellular resorption of the indicator was measured by a fluorescence signal. The indicator used was included in the kit. The assay kit mimics dopamine, serotonin, and noepinephrine, and contains a fluorescent dye-labeled indicator in powder form, which was dissolved in HEPES buffer and used in the experiment. Only one type of indicator was included in the assay kit, and the same type of indicator was used for all dopamine, serotonin, and noepinephrine reuptake experiments.
실험 당일 96-웰 플레이트에 부착된 세포를 96-웰 플레이트 자동 세척기 ELx405 Select CW (BioTek Instruments, Winooski , VT, USA)를 이용하여 HEPES 완충용액 (단위 mM: 150 NaCI, 5 KC1 , 2 CaCl2, lMgCl2) 10Glucose,10HEPES,pH7.4)으로 3 희 세척한 후， 제조회사의 지침에 따라 만든 염료 용액을 넣고 바로 형광세기를 측정하였다. 형광으로 표지된 지시약의 재흡수는 FDSS6000 기기 (Hamamatsu Photonics, Hamamatsu, Japan)를 이용하여 세포 내 지시약의 농도 변화에 따른 형광세기의 변화로 30분 동안 측정하였다. On the day of the experiment, the cells attached to the 96-well plate were placed in a 96-well plate auto washer ELx405 Select CW (BioTek Instruments, Winooski, VT, USA). After washing for 3 dilution with HEPES buffer (unit mM: 150 NaCI, 5 KC1, 2 CaCl 2 , lMgCl 2) 10Glucose, 10HEPES, pH7.4 ) , add the dye solution prepared according to the manufacturer's instructions and immediately fluoresce Intensity was measured. Resorption of the fluorescently labeled indicator was measured for 30 minutes using a FDSS6000 instrument (Hamamatsu Photonics, Hamamatsu, Japan) as a change in fluorescence intensity according to the concentration of the intracellular indicator.
세포 내 형광세기의 변화는， 형광세기의 측정을 시작한지 30 분 후 측정한 최종 형광세기 (Endpoint)로 구하였다. 자세한 형광 영상화 기술로는 컴퓨터로 제어 된 필터 휠 (filter wheel)을 이용하여 FDSS6000 에 장착된 네 개의 크세논 램프 광원에서 조사된 여기 파장 440 nm 의 빛을 세포에 선택적으로 노출시킨 후, 515 nm long-pass 필터를 통과하여 기기 안에 내장된 냉각 CCD 카메라를 지난 방출 형광을 디지털 형광 분석기로 520 nm에서 10초 마다 측정하였다.  The change in intracellular fluorescence intensity was determined by the final fluorescence intensity (Endpoint) measured 30 minutes after the start of fluorescence intensity measurement. Detailed fluorescence imaging techniques include the use of a computer-controlled filter wheel to selectively expose cells with an excitation wavelength of 440 nm from the four xenon lamp light sources mounted on the FDSS6000 to the cells, and then to 515 nm long- The past emission fluorescence was measured every 10 seconds at 520 nm with a cold CCD camera built into the instrument through a pass filter.
저해 효과를 측정하기 위한 실험에서는 세포에 실시예에서 합성된 4 각 고리 질소 화합물을 포함하는 시험 약물을 15 분 동안 37°C 5% 이산화탄소 가습 조건의 배양기에서 전처리 한 후 제조회사의 지침에 따라 만든 염료 용액을 첨가하였다. 보다 구체적으로, 시험약물은 4각 고리 질소 화합물의 DMS0 lOOmM 용액을 만들고 최종시험약물의 농도가 10μΜ 이 되도록 HEPES 완충용액 (단위 mM: 150 NaCI , 5 C1 , 2 CaCl2> lMgCl2) lOGlucose, lOHEPES, pH7.4)을 가하여 제조하였다. 세포에 염료 용액을 첨가한 후 바로 형광세기를 측정하기 시작하여 30 분 동안 세포 내 형광세기 변화를 측정하여 최종 형광세기 (Endpoint)를 구하였다. In experiments to determine the inhibitory effect, cells were tested according to the manufacturer's instructions after pre-treatment of the test drug containing the tetracyclic nitrogen compounds synthesized in the examples in an incubator at 37 ° C 5% carbon dioxide humidification conditions for 15 minutes. Dye solution was added. More specifically, the test drug is a solution of HEPES (unit mM: 150 NaCI, 5 C1, 2 CaCl 2> lMgCl 2) lOGlucose, lOHEPES to make DMS0 100 mM solution of tetracyclic nitrogen compounds and the final test drug concentration is 10 μΜ. , pH7.4) was added. Immediately after the dye solution was added to the cells, the fluorescence intensity was measured and the final fluorescence intensity (Endpoint) was obtained by measuring the fluorescence intensity change in the cell for 30 minutes.
시험 물질을 처리하지 않은 대조군의 최종 형광세기 (Endpoint)를 100%로 하였을 때 시험 물질에 대한 ¾ 억제율 (% of control)올 계산하여 용량 반웅 곡선 (dose-response curve)을 얻고 GraphPad Prism4 (GraphPad Software, La Jolla, CA, USA) 프로그램의 Hill 식으로 피팅하여 IC50값을 구하였다. hNET, hSERT 및 hDAT 를 위한 대조 약물로는 GBR12909, Nisoxetine 그리고 Fluoxetine (Tocris Bioscience, Ellisville, MO, USA)을 각각 사용하였다. 모든 영상 데이터와 분석은 하마마츠사 (Hamamatsu Photonics, Hamamatsu, Japan)에서 제공한 FDSS6000 전용 프로그램을 이용하였다. When the final fluorescence intensity of the untreated control group was 100%, a ¾ inhibition curve for the test substance was calculated to obtain a dose-response curve to obtain a GraphPad Prism4 (GraphPad Software). , La Jolla, CA, USA) program was used to calculate the IC 50 value by fitting the Hill equation. As controls for hNET, hSERT and hDAT, GBR12909, Nisoxetine and Fluoxetine (Tocris Bioscience, Ellisville, MO, USA) were used, respectively. All video data and analysis is Hamamatsu Photonics, Hamamatsu, Japan) was used for the FDSS6000 dedicated program.
[표 2] 신경전달물질 재흡수 저해 활성 실험 결과  Table 2 Results of Neurotransmitter Reuptake Inhibition Activity
Figure imgf000037_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000038_0001
Figure imgf000039_0001
[표 3] 신경전달물질 재흡수 저해 에세이 실험 결과 [Table 3] Results of neurotransmitter reuptake inhibition assay
Figure imgf000039_0002
상기 표 2 및 표 3 에 나타난 바와 같이， 실시예에서 합성된 4 각 고리 질소화합물은 기존의 세레토닌 저해제인 Fluoxetine 보다 세로토닌 저해에 우수한 효과를 보임은 물론이고, Fluoxetine 이 거의 저해 효과를 보이지 않는 노에피네프린이나 도파민에 대해서도 우수한 저해효과를 보이는 점이 확인되었다.
Figure imgf000039_0002
As shown in Table 2 and Table 3, the tetracyclic nitrogen compound synthesized in the Example showed a superior effect on serotonin inhibition than Fluoxetine, a conventional serotonin inhibitor, and Fluoxetine almost showed an inhibitory effect. It was also confirmed that excellent inhibitory effects were observed for no-epinephrine and dopamine.
이에 따라， 상기 실시예의 4 각 고리 질소화합물은 우울증, 또는 정신 질환 뿐만 아니라, 조루증 또는 신경병증성 통증에 대하여도 높은 치료 효과 또는 예방 효과를 가질 것으로 기대되며， 단일 화합물로서 세레토닌을 포함하는 여러 가지 신경전달물질의 재흡수를 효과적으로 억제할 수 있기 때문에 약물의 복합 사용이나 사용량 증가 등에 따라 나타나는 부작용을 현저하게 감소시킬 수 있을 것으로 보인다.  Accordingly, the tetracyclic nitrogen compounds of the above embodiments are expected to have a high therapeutic or prophylactic effect on depression, or mental disorders, as well as premature ejaculation or neuropathic pain, and include a serotonin as a single compound. Since the reuptake of various neurotransmitters can be effectively suppressed, it is possible to significantly reduce the side effects caused by the combined use of the drug or the increase in the amount used.

Claims

【특허청구범위】 【청구항 1】 하기 화학식 1의 4각 고리 질소 화합물: Claims [Claim 1] A tetracyclic cyclic nitrogen compound represented by the following general formula (1):
[화학식 1]  [Formula 1]
Figure imgf000041_0001
Figure imgf000041_0001
상기 화학식 1에서，  In Chemical Formula 1,
¾은 탄소수 1 내지 10 의 직쇄 또는 분지쇄의 알킬; 탄소수 3 내지 10 의 사이클로 알킬; 할로겐, 알콕시기 및 탄소수 1 내지 5 의 알킬기로 이루어진 군에서 선택된 1 종 이상의 작용기가 1 이상 치환되거나 비치환된 탄소수 6 내지 20 의 아릴기; 탄소수 7 내지 20 의 아릴알킬기 ; 및 질소, 산소 및 황으로 이루어진 군에서 선택된 1 종 이상의 원소를 포함하는 탄소수 6 내지 20 의 방향족 헤테로 고리;로 이루어진 군에서 선택된 1 가 작용기이고，  ¾ is straight or branched chain alkyl of 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 at least one; Arylalkyl group having 7 to 20 carbon atoms; It is a monovalent functional group selected from the group consisting of; aromatic hetero ring having 6 to 20 carbon atoms containing at least one element selected from the group consisting of nitrogen, oxygen and sulfur,
R2는 할로겐， 알콕시기， 및 탄소수 1 내지 5 의 알킬기로 이루어진 군에서 선택된 1 종 이상의 작용기가 1 이상 치환되거나 비치환된 탄소수 6 내지 20의 아릴기 ; 인 1가 작용기이고， R 2 is 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 unsubstituted or substituted at least one; Is a monovalent functional group ，
n은 1 내지 5의 정수이다.  n is an integer of 1-5.
【청구항 2】 [Claim 2]
제 1항에 있어서，  The method of claim 1,
상기 Ri은 탄소수 3 내지 10 의 사이클로 알킬; 할로겐, 탄소수 1 내지 10 의 직쇄 또는 분지쇄의 알킬기， 및 페녹시기로 이루어진 군에서 선택되는 작용기가 1 이상 치환되거나 비치환된 페닐; 할로겐, 탄소수 1 내지 10 의 직쇄 또는 분지쇄의 알킬기, 및 페녹시기로 이루어진 군에서 선택되는 작용기가 1 이상 치환되거나 비치환된 벤질; 할로겐， 탄소수 1 내지 10 의 직쇄 또는 분지쇄의 알킬기, 및 페녹시기로 이루어진 군에서 선택되는 작용기가 1 이상 치환되거나 비치환된 나프틸; 또는 할로겐， 탄소수 1 내지 10 의 직쇄 또는 분지쇄의 알킬기， 및 페녹시기로 이루어진 군에서 선택되는 작용기가 1 이상 치환되거나 비치환된 벤조티아졸; 인 4각 고리 질소 화합물. Ri is cycloalkyl having 3 to 10 carbon atoms; Phenyl in which one or more functional groups selected from the group consisting of halogen, a linear or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group are substituted or unsubstituted; Benzyl in which at least one functional group selected from the group consisting of halogen, a linear or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group is substituted or unsubstituted; In the group consisting of a halogen, a linear or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group Naphthyl with one or more substituted or unsubstituted functional groups selected; Or benzothiazole in which at least one functional group selected from the group consisting of halogen, a linear or branched alkyl group having 1 to 10 carbon atoms, and a phenoxy group is substituted or unsubstituted; Phosphorus tetracyclic nitrogen compound.
【청구항 3】 [Claim 3]
제 1항에 있어서，  The method of claim 1,
상기 ¾는 할로겐， 탄소수 1 내지 10 의 직쇄 또는 분지쇄의 알킬기， 및 탄소수 1 내지 10 의 알콕시기로 이루어진 군에서 선택되는 작용기가 1 이상 치환되거나 비치환된 페닐; 또는 할로겐， 탄소수 1 내지 10 의 직쇄 또는 분지쇄의 알킬기 및 탄소수 1 내지 10의 알콕시기로 이루어진 군에서 선택되는 작용기가 1 이상 치환되거나 비치환된 나프틸；인 4 각 고리 질소 화합물.  ¾ is phenyl in which one or more functional groups selected from the group consisting of halogen, a linear or branched alkyl group having 1 to 10 carbon atoms, and an alkoxy group having 1 to 10 carbon atoms are substituted or unsubstituted; Or naphthyl having one or more substituted or unsubstituted functional groups selected from the group consisting of halogen, a linear or branched alkyl group having 1 to 10 carbon atoms, and an alkoxy group having 1 to 10 carbon atoms;
【청구항 4】 [Claim 4]
제 1 항의 4 각 고리 질소 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는， 우을증， 정신 질환， 조루증， 또는 신경병증성 통증의 예방 또는 치료용 약학 조성물.  Claim 4 tetracyclic nitrogen compound or a pharmaceutically acceptable salt thereof as an active ingredient, depression, psychiatric disorders, premature ejaculation, or neuropathic pain pharmaceutical composition for the treatment.
【청구항 5】 [Claim 5]
제 4항에 있어서，  The method of claim 4,
약리학적으로 허용 가능한 약제， 담체 또는 부형제를 더 포함하는 약학 조성물.  A pharmaceutical composition further comprising a pharmaceutically acceptable agent, carrier or excipient.
【청구항 6】 [Claim 6]
제 4항에 있어서，  The method of claim 4,
상기 정신 질환은 신경성 통증， 조울증， 정신분열증, 기분장애， 수면장애, 불안증， 주의력결핍 과다행동장애 (ADHD), 또는 섭식장애를 포함하는 약학 조성물. The mental disorders include neurological pain, mood swings, schizophrenia, mood disorders, sleep disorders, anxiety, attention deficit hyperactivity disorder (ADHD), or eating disorders.
【청구항 7】 [Claim 7]
제 4 항의 약학 조성물을 포함하는 우을증， 정신 질환， 조루증， 또는 신경 병증성 통증의 예방 또는 치료용 제제 .  A preparation for the prevention or treatment of depression, mental illness, premature ejaculation, or neuropathic pain, comprising the pharmaceutical composition of claim 4.
【청구항 8】 [Claim 8]
제 7 항에 있어서 ,  The method of claim 7, wherein
1 일 투여량이 0. 1 rag/kg (체중) 내지 4 rag/kg (체중)인， 우울증， 정신 질환， 조루증， 또는 신경 병증성 통증의 예방 또는 치료용 제제 .  A formulation for the prophylaxis or treatment of depression, mental illness, premature ejaculation, or neuropathic pain, with a daily dosage of between 0.01 rag / kg body weight and 4 rag / kg body weight.
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