KR20150090769A - Aryloxy azetidine compounds, and pharmaceutical composition comprising the same - Google Patents
Aryloxy azetidine compounds, and pharmaceutical composition comprising the same Download PDFInfo
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Abstract
An aryloxyacetidine compound, and a pharmaceutical composition comprising the same. The aryloxyacetidine compound can simultaneously inhibit reabsorption of neurotransmitters seretinin, noeepinephrine, and dopamine, and can prevent and / or prevent depression, other mental diseases, premature ejaculation, or neuropathic pain Can be used.
Description
An aryloxyacetidine compound, and a pharmaceutical composition comprising the same. The aryloxyacetidine compound can simultaneously inhibit reabsorption of neurotransmitters seretinin, noeepinephrine and dopamine, and can prevent and / or prevent mental diseases, premature ejaculation, and / or neuropathic pain, Or may be usefully used.
Depression, or depressive disorder, is defined as a condition in which depression and depression are the main symptoms, resulting in various cognitive and psychosomatic symptoms resulting in deterioration of daily function. Depressive disorder has a lifetime prevalence of 15%, especially 25% in women, and is a serious disease that causes changes in feelings, thoughts, physical condition, and behavior.
Depression is not caused by one cause. Rather, various types of gene interactions, epigenetic effects, embryologic causes, and environmental influences are combined to cause emotional disturbance by damaging emotions.
Typical drugs used to treat other major psychiatric or neurological diseases are efficacious through a variety of neuronal mechanisms distributed throughout much of the brain. Similarly, pharmacological, anatomical, and neuropsychological approaches to alleviate depression can not be made to show efficacy through any one mechanism.
Currently used antidepressant drugs include selective serotonin reuptake blockers, serotonin norepinephrine reuptake blockers, selective norepinephrine reuptake blockers, dopamine and norepinephrine reuptake blockers (DNRIs), naepinephrine and serotonin receptor antagonists (NaSSA), serotonin Receptor antagonists, serotonin reuptake inhibitors (SARIs), and selective serotonin reuptake enhancers (SSREs).
These antidepressant drugs have a low remission rate, and current medications do not provide sufficient therapeutic effect. In order to overcome this problem, it is necessary to develop a new therapeutic agent that overcomes the current low remission rate.
In addition, as depression is caused by various causes, it is necessary to administer several kinds of drugs together to suppress the reabsorption of various neurotransmitters. However, since the drug is unnecessarily consumed or administered, In addition to typical side effects such as weight gain, unexpected side effects are occurring.
Therefore, it is necessary to develop new drugs that can effectively suppress the reabsorption of various neurotransmitters, minimize such side effects, and exhibit high efficacy in the prevention or treatment of depression or other mental disorders.
One example provides a novel aryloxyacetidine compound or a pharmaceutically acceptable salt thereof.
Another example provides a pharmaceutical composition comprising the aryloxyazetidine compound or a pharmaceutically acceptable salt thereof as an active ingredient.
Another example provides a reuptake inhibitor of at least one neurotransmitter selected from the group consisting of serotonin, norepinephrine, and dopamine comprising the aryloxyazetidine compound or a pharmaceutically acceptable salt thereof as an active ingredient.
Another example provides a composition for preventing and / or treating a psychotic disorder, premature ejaculation, and / or neuropathic pain comprising the aryloxyacetidine compound or a pharmaceutically acceptable salt thereof as an active ingredient.
An example of the present invention provides an aryloxyacetidine compound of formula 1: < EMI ID = 2.1 > or a pharmaceutically acceptable salt thereof,
[Chemical Formula 1]
Wherein R 1 and R 2 are each independently selected from the group consisting of a substituted or unsubstituted aryl group having 6 to 10 carbon atoms, and wherein the substituted aryl group is a group selected from the group consisting of halogen (for example, F, Cl, etc.) , A linear or branched chain substituted or unsubstituted alkyl group having 1 to 10 carbon atoms (e.g., 1 to 3 carbon atoms), and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms (e.g., having 1 to 3 carbon atoms) And the substituted alkyl group or the substituted alkoxy group may be one in which one or more hydrogen atoms are each independently substituted with a substituent selected from the group consisting of halogen (for example, F, Cl, etc.). R1 and R2 may be the same or different from each other.
Specifically, R 1 and R 2 are each independently a phenyl group; Wherein at least one hydrogen is independently selected from the group consisting of a halogen (e.g., F, Cl, etc.), a straight or branched chain alkyl group having 1 to 10 carbon atoms, and a phenoxy group; Benzyl group; A benzyl group in which one or more of the hydrogens are each independently substituted with a functional group selected from the group consisting of halogen (e.g., F, Cl, etc.), a linear or branched chain alkyl group having 1 to 10 carbon atoms, and a phenoxy group; Naphthyl group; Or a naphthyl group substituted with a functional group selected from the group consisting of a halogen atom (e.g., F, Cl, etc.), a linear or branched chain alkyl group having 1 to 10 carbon atoms, and a phenoxy group, have.
In one embodiment, R1 is a phenyl group, a naphthyl group, or a phenyl group in which one or two hydrogens are each independently substituted with a substituent selected from the group consisting of halogen (for example, F, Cl, etc.) Or two hydrogens may each independently be a naphthyl group substituted with such a substituent. For example, R 1 may be a phenyl group, a naphthyl group, or a phenyl group substituted by a substituent selected from the group consisting of F and Cl, wherein one or two hydrogen atoms are each independently selected from the group consisting of F and Cl. R2 is a phenyl group or a phenyl group substituted with a substituent selected from the group consisting of halogen, a C1-C3 alkyl group, and a substituted or unsubstituted alkoxy group having 1 to 3 carbon atoms, The alkoxy group may be one in which one or more (e.g., one to three) hydrogen atoms are each independently substituted with a substituent selected from the group consisting of halogen. For example, R2 may be a phenyl group, or a phenyl group in which one or two hydrogens are each independently substituted with a substituent selected from the group consisting of F, Cl, methyl, and trifluoromethoxy.
In one embodiment, the aryloxyazetidine compound may be selected from the group consisting of the compounds listed in Table 1 below:
The pharmaceutically acceptable salt of the aryloxyacetidine compound of Formula 1 may be a salt of a pharmaceutically acceptable organic acid, and specifically includes oxalic acid, benzenesulfonic acid, camphorsulfonic acid, cinnamic acid, adipic acid, And salts of organic acids such as hydrochloric acid, methanesulfonic acid, bromic acid, acetic acid, fumaric acid, sulfuric acid, succinic acid, citric acid, phosphoric acid, maleic acid, nitric acid, tartaric acid, benzoic acid, trifluoroacetic acid or carbonic acid.
Another example of the present invention provides a pharmaceutical composition comprising the aryloxyacetidine compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
Another example is to provide a reuptake inhibitor for at least one neurotransmitter selected from the group consisting of serotonin, norepinephrine, and dopamine, which comprises the aryloxyacetidine compound of formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient do. The inhibitor of reuptake of the neurotransmitter may be one that simultaneously inhibits reabsorption of at least one, e.g., two or more, or all three selected from the group consisting of serotonin, norepinephrine, and dopamine.
Another example provides a composition for preventing and / or treating mental diseases, premature ejaculation, and / or neuropathic pain comprising an aryloxyacetidine compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The mental disorder may be at least one selected from the group consisting of depression, bipolar disorder, and other mental illnesses.
The present inventors synthesized a novel aryloxyacetidine compound having the structure of the above formula (1), and found that the aryloxyacetidine compound or a pharmaceutically acceptable salt thereof is effective to inhibit the release of certain neurotransmitters such as serotonin, norepinephrine, and / Or prevent the reabsorption of dopamine at high efficiency, and have high therapeutic and / or prophylactic effects against depression, bipolar disorder, other psychiatric disorders, premature ejaculation, and / or neuropathic pain.
Among serotonin reuptake inhibitors that have a therapeutic or prophylactic effect on depression, bipolar disorder, or other mental illnesses, compounds with short-acting properties are less effective in treating premature ejaculation (Moreland, A. J et al., Selective Serotonin Compounds capable of inhibiting the reuptake of serotonin and norepinephrine can be used as powerful neuropathic analgesics (Goldsteina, D, et al. J et al, Duloxetine vs. placebo in patients with painful diabetic neuropathy, Pain. 116, 109-118, 2005, etc.) are known.
This fact implies that a compound capable of inhibiting the reuptake of serotonin, norepinephrine, and / or dopamine, which is a synaptic neurotransmitter, or a pharmaceutical composition containing the compound as an active ingredient can be used not only for depression, manic depression, And may be applied to other diseases such as sexual dysfunction, sexual pain, premature ejaculation, etc., and there is a possibility of expanding the scope of application of antidepressant drugs through related studies.
Examples of such neurotransmitter re-uptake-related diseases include depression, bipolar disorder, other psychiatric disorders, premature ejaculation, and / or neuropathic pain as described above.
The aryloxyacetidine compound or a pharmaceutically acceptable salt thereof according to the present invention is excellent in the effect of inhibiting the re-absorption of serotonin, which is a neurotransmitter, and is effective for preventing depression, manic depression, other mental diseases, premature ejaculation, and / or neuropathic pain And / or treatment. The compounds or their pharmaceutically acceptable salts are also excellent in the effect of inhibiting re-absorption of norepinephrine and / or dopamine, which is another neurotransmitter, and can be used for the treatment of depression, manic depression, other psychiatric diseases, premature ejaculation, and / Can be used more effectively for the prevention and / or treatment of pain. In addition, the compound or a pharmaceutically acceptable salt thereof can very effectively inhibit the reabsorption of neurotransmitters such as serotonin, norepinephrine, and dopamine at the same time, thereby reducing adverse effects due to the combined use of drugs and the increase in the amount used.
Accordingly, the pharmaceutical composition may be useful for the treatment and / or prevention of diseases related to neurotransmitter reabsorption, selected from the group consisting of depression, manic depression, other psychiatric disorders, premature ejaculation, and neuropathic pain. The other mental illnesses may be selected from the group consisting of neuropathic pain, schizophrenia, mood disorders, sleep disorders, anxiety, attention deficit hyperactivity disorder (ADHD), eating disorders, and the like. The neuropathic pain refers to a pain caused by a primary lesion such as damage to the nervous system or a change in nervous function.
The pharmaceutical composition is characterized in that one or more neurotransmitters selected from the group consisting of dopamine, serotonin and naepinephrine are inhibited from being reabsorbed through the neurotransmitter transporter.
In one example, the pharmaceutical composition may further comprise other medicament, pharmacologically acceptable carrier or excipient. The pharmacologically acceptable carrier or excipient may be suitably adjusted according to the formulation to which the pharmaceutical composition is applied and is selected from the group consisting of depression, manic depression, other psychiatric disorders, premature ejaculation, and neuropathic pain, A carrier or an excipient known to be routinely usable in the prophylactic or therapeutic agent for a related disease can be used without any great limitation. Examples of the excipient include a common diluent, a filler, an extender, a wetting agent, a disintegrant, and / or a surfactant.
The content of the aryloxyacetidine compound of Formula 1 or a pharmaceutically acceptable salt thereof in the pharmaceutical composition may be appropriately adjusted depending on the method of use of the composition, the mode of use, the condition of the patient and the desired effect, for example, 0.1 To 99.9% by weight, from 0.5 to 95% by weight, from 1 to 95% by weight, or from 10 to 90% by weight.
According to another embodiment of the present invention, there is provided a method for preventing or treating neurotransmitter-related diseases selected from the group consisting of depression, bipolar disorder, other psychiatric disorders, premature ejaculation, and neuropathic pain comprising the above pharmaceutical composition A formulation may be provided.
As described above, when the composition containing the active ingredient of the aryloxyacetidine compound of Formula 1 or a pharmaceutically acceptable salt thereof is used, it is possible to prevent reabsorption of specific neurotransmitters at high efficiency, Premature ejaculation, or neuropathic pain, and can minimize adverse effects on the human body.
The method of administering the agent for preventing or treating depression, mental illness, premature ejaculation, or neuropathic pain can be either oral or parenteral, and the formulation can be variously determined depending on the method of use. For example, the formulations may be formulated with various excipients such as PLASTERS, GRANULES, LOTIONS, POWDERS, SYRUPS, LIQUIDS AND SOLUTIONS, AEROSOLS, OINTMENTS, ), Formulations in the form of FRUIDEXTRACTS, EMULSIONS, SUSTESIONS, INFUSIONS, TABLETS, INJECTIONS, CAPSULES or PILLS. Can be used.
An agent for the prevention or treatment of a neurotransmitter re-uptake-related disorder selected from the group consisting of depression, bipolar disorder, other psychiatric disorders, premature ejaculation, and neuropathic pain includes an agent for preventing or treating absorption of an active ingredient in the patient's age, sex, The dosage can be determined in consideration of the degree of inactivity and the drug to be used concomitantly, and preferably the daily dose is 0.1 mg / kg (body weight) to 4 mg / kg (body weight) based on the active ingredient, Can be 0.3 mg / kg (body weight) to 1.8 mg / kg (body weight).
According to another embodiment of the present invention, a food comprising the 3-aminomethylazetidine compound of Formula 1 may be provided.
The term " food " is intended to include not only conventional foods but also health supplements or food additives. Examples of the food, the health supplement food or the food additive are not limited to a specific one. Examples thereof include special nutrition foods (e.g., crude oil, spirits, infant foods, etc.), meat products, fish products, tofu, (Eg soy sauce), dairy products (eg fermented milk, cheese, etc.), other processed foods, kimchi, and other processed foods, (Such as a variety of kimchi, pickles, etc.), beverages (e.g., fruit, vegetable beverages, beverages, fermented beverages, etc.), natural seasonings (e.g., ramen soup, etc.).
In another example, a process for preparing the aryloxyacetidine compound of Formula 1 is provided.
The process may comprise preparing an aryloxyacetidine compound of formula (1) from a compound of formula (VIII) (step viii)
For example, when the compound of formula 8, that is, aryloxyacetidin hydrochloride or aryloxyacetidine trifluoroacetic acid salt is treated with saturated sodium bicarbonate, caustic soda, or triethylamine, the novel aryloxyacetate represented by Formula 1 Thiazine compound 1 can be obtained.
The preparation method further comprises a step of preparing a compound of the formula (8) from the compound of the following formula (6) before the step (viii) of producing the aryloxyazetidine compound of the formula (1) from the compound of the formula (Step vii) of Scheme 1:
The compound of formula (6) is an azetidine ether compound, and the protecting group, Boc group, is deprotected to obtain an aryloxyazetidine hydrochloride or aryloxyazetidine trifluoroacetate of formula (8). More specifically, when the azetidine ether compound 6 is dissolved in an organic solvent and stirred with an acid such as hydrochloric acid or trifluoroacetic acid at room temperature to 70 ° C, the Boc group is deprotected to obtain an aryloxyacetidine hydrochloride Or aryloxyazetidine trifluoroacetate can be obtained.
The preparation method may further comprise the step of preparing a compound of the formula (6) from the compound of the following formula (5) before the step of preparing the compound of the formula (8) from the compound of the formula (6)
The step of preparing the compound of formula (6) from the azetidine ether compound of formula (5) may be carried out by directly preparing the compound of formula (6) from the compound of formula (5) Can be carried out by preparing a compound of formula 7 (step v of scheme 1) followed by the preparation of a compound of formula 6 from the compound of formula 7 (step vi of scheme 1) (method B).
A method, the azetidine secondary alcohol compound of formula (5) is reacted in an ice cold bath with tetrahydrofuran (THF) in the presence of diisopropy azodicarboxylate (DIAD) and triphenylphosphine (PPh 3 ) Can be reacted with a phenol derivative (R < 2 > OH) to give a compound of formula (6). B method, the intermediate compound (Formula 7) obtained by substituting the alcohol group of the azetidine secondary alcohol compound of Formula 5 with methanesulfonyl group (OMs) is reacted with phenol derivative (Formula 7) at room temperature in the presence of sodium hydride (R < 2 > OH).
The preparation method may further comprise the step of preparing the compound of the formula (5) from the compound of the following formula (4) (step iii of the reaction formula 1) before the step of preparing the compound of the formula (6) from the compound of the formula have:
For example, the compound of formula (4) can be purified using silica gel and reacted at 78 ° C in a solution of Grignard reagent (R 1 MgBr) and tetrahydrofuran (THF) to obtain an azetidine secondary alcohol compound of formula .
The method comprises the step of preparing a compound of formula (4) from the compound of formula (3) below (step ii of scheme 1) before the step of preparing the compound of formula (5) from the compound of formula May further comprise: < RTI ID = 0.0 >
For example, compound 3 is dissolved in a methylene chloride solution, and the mixture is cooled to 78 ° C in acetone and dry ice bath in the presence of triethylamine (TEA), and reacted with oxalyl chloride and dimethylsulfoxide (DMSO) to obtain an azetidine aldehyde compound .
The method may further comprise the step of preparing a compound of formula (3) from the compound of formula (2) below, before the step of preparing the compound of formula (4) from the compound of formula :
For example, an azetidine methyl ester compound in which the nitrogen atom of the formula (2) is protected with a t-butyl oxycarbonyl is reduced with a reducing agent such as lithium aluminum hydride (LiAlH 4 ) or sodium borohydride (NaBH 4 ) An azetidine ethyl alcohol compound of formula (3), which is an intermediate, can be obtained. Compound 3 can be purified using silica gel, but can be used in the next step without purification.
In summary, the aryloxyacetidine compound of Formula 1 can be synthesized as shown in Reaction Scheme 1 below. However, the following Reaction Scheme 1 shows an example of a method of synthesizing the aryloxyacetidine compound of Formula 1, and the method of synthesizing the compound of Formula 1 is not limited thereto.
[Reaction Scheme 1]
Reaction reagent and reaction conditions: (i) Lithium aluminum hydride, THF, -78 ° C, (ii) oxalyl chloride, DMSO, TEA, MC, -78 ° C (iii) R 1 MgBr, THF, , PPh 3, THF, 0 ℃ , R 2 OH (v) MsCl, Et 3 N, CH 2 Cl 2, rt (vi) R 2 OH, NaH, THF, rt (vii) 1N HCl or CF 3 CO 2 H (viii) aq. NaHCO 3, aq. NaOH or TEA
The azetidinemethyl ester compound in which the nitrogen atom of the formula (2) is protected with a t-butyl oxycarbonyl group is reduced with a reducing agent such as lithium aluminum hydride (LiAlH 4 ) or sodium borohydride (NaBH 4 ) to give the corresponding intermediate To obtain thydine ethyl alcohol 3. Compound 3 can be purified using silica gel, but can be used in the next step without purification. Compound 3 is dissolved in methylene chloride solution, cooled to 78 ° C in acetone and dry ice bath in the presence of triethylamine (TEA), and reacted with oxalyl chloride and dimethylsulfoxide (DMSO) to obtain azetidine aldehyde 4. Compound 4 is purified using silica gel and reacted at 78 ° C in a solution of Grignard reagent (R 1 MgBr) and tetrahydrofuran (THF) to obtain intermediate azetidine secondary alcohol 5. The conversion of compound 5 to the azetidine ether compound 6 can be carried out in two ways (A and B). A method, azetidine secondary alcohol 5 is reacted with a phenol derivative (R 2 OH) at 0 ° C in an ice water cooled bath in a solution of diisopropy azodicarboxylate (DIAD) and triphenylphosphine (PPh 3 ) . B method, the intermediate compound 7 obtained by substituting the alcohol group of azetidine secondary alcohol 5 with methanesulfonyl group (OMs) is reacted with phenol derivative (R 2 OH) at room temperature in the presence of sodium hydride . The Boc group, which is a protecting group of the synthesized intermediate azetidine ether compound 6, is deprotected to obtain an aryloxyazetidine hydrochloride or an aryloxyazetidine trifluoroacetate salt of the compound 8. More specifically, when azetidine ether compound 6 dissolved in an organic solvent is stirred with hydrochloric acid or trifluoroacetic acid at room temperature to 70 ° C, the compound of the present invention represented by the general formula (8) Thiazine hydrochloride or aryloxyazetidine trifluoroacetate 8 is obtained. Treatment with saturated sodium bicarbonate, caustic soda, or triethylamine or the like without separation results in the novel aryloxyacetidine compound 1 represented by general formula 1. [
The compound usable as the acid is not particularly limited, and inorganic or organic acids such as acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid or para-toluenesulfonic acid can be used. Also, the organic solvent is not limited to the specific examples, and one kind selected from the group consisting of methylene chloride, chloroform, ethyl acetate, tetrahydrofuran, benzene, toluene, dimethylformamide (DMF), dimethylsulfoxide The above inert organic solvent may be used. The alcohols may be aliphatic linear or branched alcohols having 1 to 5 carbon atoms.
In the above Chemical Formulas 2 to 8 and Reaction Scheme 1, R 1 and R 2 denote the functional groups bonded to the respective compounds, and are as defined in Chemical Formula 1.
According to another embodiment of the present invention, there can be provided a pharmaceutical composition comprising the aryloxyacetidine compound of the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
As described above, the present inventors have newly synthesized an aryloxyacetidine compound of the above formula (1). Using such an aryloxyacetidine compound, highly efficient absorption of specific neurotransmitters can be prevented, It can be used as a therapeutic or preventive agent for re-absorption-related diseases.
According to the present invention, there is provided a pharmaceutical composition comprising a 3-aminomethylazetidine compound which can be used as a therapeutic or preventive agent for depression, psychiatric diseases, premature ejaculation, or neuropathic pain by preventing reabsorption of specific neurotransmitters with high efficiency, And a pharmaceutical composition capable of inhibiting the reabsorption of dopamine or no epinephrine and having a high therapeutic or prophylactic effect on depression, psychiatric disorders, premature ejaculation, or neuropathic pain, and an agent comprising the above pharmaceutical composition can be provided have.
Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.
[ Manufacturing example : Aryloxy Azetidine Synthesis of Compound]
The following Examples 1 to 49 were synthesized by the synthesis method according to the following Reaction Scheme 1, and specific examples will be described stepwise in Production Examples 1 to 8 below.
[Reaction Scheme 1]
Reaction reagent and reaction conditions: (i) Lithium aluminum hydride, THF, -78 ° C, (ii) oxalyl chloride, DMSO, TEA, MC, -78 ° C (iii) R 1 MgBr, THF, , PPh 3, THF, 0 ℃ , R 2 OH (v) MsCl, Et 3 N, CH 2 Cl 2, rt (vi) R 2 OH, NaH, THF, rt (vii) 1N HCl or CF 3 CO 2 H (viii) aq. NaHCO 3, aq. NaOH or TEA
[ Manufacturing example 1] Synthesis of Intermediate Compound 3 from Compound 2
tert- butyl azetidinecarboxylic acid methyl ester (2 g, 8.7 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL), lithium aluminum hydride (497 mg) was added thereto, and the mixture was stirred at 78 ° C for 3 hours. The temperature of the obtained reaction mixture was raised to room temperature, sodium sulfate (4 g) was added, and the mixture was stirred for one day. The resulting reaction mixture was dried over anhydrous magnesium sulfate, filtered and washed with methylene chloride. The solvent of the reaction mixture was removed by evaporation under reduced pressure to obtain Compound 3 in a liquid state. This product was identified as a single compound by TLC (n-hexane: ethyl acetate (1: 1, v / v)).
Yield 95%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 1.46 (s, 9H, Boc-H), 1.89 (q, 2H, J = 7.2 Hz, CH 2), 2.65-2.70 (m, 1H, CH), 3.60-4.08 (m, 6H, azetidin-H , CH 2)
[ Manufacturing example 2] Synthesis of Compound 4 from Compound 3
Oxalyl chloride (1.1 ml, 13 mmol) was added to dry methylene chloride (100 mL), cooled to 78 ° C., and dimethyl sulfoxide (0.92 mL, 13 mmol) was added thereto and stirred for 15 minutes. To the obtained reaction mixture was added the compound 3 (1.73 g, 8.6 mmol) obtained in Preparation Example 1 and stirred at the same temperature for 3 hours. Triethylamine (3.6 mL, 25 mmol) was added thereto and stirred at the same temperature for an additional 1 hour. The cooling bath was removed, the reaction mixture was extracted with methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the resulting pale yellow liquid was purified by flash chromatography (n-hexane: ethyl acetate (1: 1, v / v)) to obtain compound 4. The resulting compound 4 was identified as a single compound by TLC (n-hexane: ethyl acetate (1: 1, v / v)).
Yield 89%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 1.48 (s, 9H, Boc-H), 2.84 (d, 2H, J = 7.6 Hz, CH 2), 2.92-2.96 (m, 1H, CH), 3.56-4.16 (m, 4H, azetidine-H), 9.78 (s, 1H, Aldehyde-H)
[ Manufacturing example 3] Compound 4 to Intermediate Compound 5 ( R One = 3,4- di Cl ) Synthesis of
4-dichlorophenyl magnesium bromide (50 mL, 25 mmol) dissolved in 150 mL of dry tetrahydrofuran was cooled to 78 ° C. To the solution was then added the compound 4 (16.7 mL, 16.7 mmol) obtained in Preparation Example 2 Slowly added, and stirred for 3 hours. After removing the cooling water bath, a saturated aqueous ammonium chloride solution (15 mL) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with methylene chloride (3 x 100 mL), and the organic layer was washed once with saturated aqueous sodium chloride solution and once with distilled water and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the resulting yellow liquid was purified by flash chromatography (n-hexane: ethyl acetate (4: 1, v / v)) to give compound 5. The resulting compound 5 (R 1 = 3,4-di Cl) was identified as a single compound by TLC (n-hexane: ethyl acetate (4: 1, v / v)).
Yield 55%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 1.46 (s, 9H, Boc-H), 1.95 (d, 1H, J = 3.6 Hz, OH), 1.96-2.12 (m, 2H, CH 2), 2.66-2.70 (m, 1H, CH), 3.55-4.05 (m, 4H, azetidin-H), 4.68 (m, 1H, CH), 7.18 (dd, 1H, J = 2.0 Hz, J = 8.0 Hz, ArH), 7.44 -7.46 (m, 2H, ArH)
[ Manufacturing example 4] Intermediate compound 5 ( R One = Ph ) To compound 6 ( R One = R 2 = Ph ) (Reaction path A)
Compound (R 1 = Ph; obtained in the same manner as in Preparation Example 3, except that phenyl magnesium bromide (36 mL, 25 mmol) was used instead of 3,4-dichlorophenyl magnesium bromide) (300 mg, 1.08 mmol) And phenol (0.24 mL, 2.7 mmol) was added to a solution of triphenylphosphine (710 mg, 2.7 mmol) in dry tetrahydrofuran (50 mL). The mixture was cooled to 0 째 C under ice bath, diisopropyl azo carboxylate (0.53 mL, 2.7 mmol) Was slowly added thereto while maintaining the temperature at 0 ° C, and then stirred at room temperature for one day. The solvent of the reaction mixture was removed by evaporation under reduced pressure to obtain a yellow liquid, which was purified by flash chromatography (n-hexane: ethyl acetate (4: 1, v / v)) to obtain Compound 6. The resulting compound 6 (R 1 = R 2 = Ph) was identified as a single compound by TLC (n-hexane: ethyl acetate (4: 1, v / v)).
Yield 82%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 1.45 (s, 9H, Boc-H), 2.12-2.31 (m, 2H, CH 2), 2.74-2.78 (m, 1H, CH), 3.58-4.05 (m, 4H, azetidine-H), 5.09 (dd, 1H, J = 4.0 Hz, J = 8.0 Hz, CH), 6.79-7.34 (m, 10H, ArH)
[ Manufacturing example 5] Intermediate compound 5 ( R One = 3,4- di Cl ) from Compound 7 ( R One = 3,4- di Cl) (Reaction route B)
The compound obtained in Preparation Example 3 5 (R 1 = 3,4- di Cl) (125 mg, 0.3 mmol) of dry methylene chloride (30 mL) after dissolved in a solution of methanesulfonyl chloride (0.031 mL, 0.39 mmol ) and triethylamine ( 0.08 mL, 0.54 mmol) were added in this order, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with methylene chloride and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the resulting yellow liquid was purified by flash chromatography (n-hexane: ethyl acetate (2: 1, v / v)) to give compound 7. The obtained compound 7 (R 1 = 3,4-di Cl) was identified as a single compound by TLC (n-hexane: ethyl acetate (2: 1, v / v)).
Yield 71%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 1.43 (s, 9H, Boc-H), 2.05-2.38 (m, 2H, CH 2), 2.66-2.70 (m, 1H, CH), 2.83 (s, 3H, Ms-CH 3), 3.53-4.08 ( m, 4H, azetidin-H), 5.45 (dd, 1H, J = 4.0 Hz, J = 8.4 Hz, CH), 7.22 (dd, 1H, J = 2.0 Hz, J = 8.0 Hz, ArH), 7.47-7.51 (m, 3H, ArH)
[ Manufacturing example 6] Intermediate compound 7 ( R One = 3,4- di Cl ) To compound 6 ( R One = 3,4- di Cl, R 2 = Ph ) (Reaction route B)
Phenol (0.05 mL, 0.38 mmol) and sodium hydride (19 mg, 0.76 mmol) were dissolved in dry tetrahydrofuran (30 mL) and stirred at 80 ° C for 15 minutes. Compound 7 (R 1 = 3,4-di Cl) (108 mg, 0.25 mmol) was added to the reaction mixture and stirred at the same temperature for a further day. The reaction mixture was evaporated under reduced pressure to remove the solvent, the product was extracted with methylene chloride, and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting yellow liquid was purified by flash chromatography (n-hexane: ethyl acetate (2: 1, v / v)) to give compound 6 (R 1 = 2 = Ph). The resulting compound 6 was identified as a single compound by TLC (n-hexane: ethyl acetate (2: 1, v / v)).
Yield 80%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 1.48 (s, 9H, Boc-H), 2.06-2.29 (m, 2H, CH 2), 2.74-2.78 (m, 1H, CH), 3.64-4.10 (m, 4H, azetidine-H), 5.04 (dd, 1H, J = 4.0 Hz, J = 8.4 Hz, CH), 6.76-7.43
[ Manufacturing example 7] Compound 6 (R One = R 2 = Ph) Intermediate compound 8 ( R One = R 2 = Ph ) To give the compound 1 ( In hydrochloric acid water by Boc Group Deprotection )
Compound 6 (R 1 = R 2 = Ph) (246 mg, 0.7 mmol) obtained in Preparation Example 4 was dissolved in methanol (15 mL), and 1 N HCl (6 mL) was added thereto at 60 ° C. The reaction mixture was refluxed at the same temperature for one day, and the solvent was removed by evaporation under reduced pressure. Saturated aqueous sodium carbonate (10 mL) was added and the organics were dissolved in methylene chloride and extracted. After drying over anhydrous magnesium sulfate, the solvent was removed by evaporation under reduced pressure to obtain a yellow liquid. The yellow liquid was purified by flash chromatography (methylene chloride: methanol = 2: 1 (v / v)) to obtain Compound 1. The resulting compound 1 (R 1 = R 2 = Ph) was identified as a single compound by TLC (methylene chloride: methanol = 2: 1, (v / v)).
Yield 76%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.16-2.32 (m, 2H, CH 2), 2.98-3.02 (m, 1H, CH), 3.40-3.71 (m, 4H, azetidine H), 5.08 (dd, 1H , J = 8.0 Hz, J = 8.0Hz, CH), 6.81-6.91 (m, 3H, ArH), 7.18-7.35 (m, 7H, ArH)
[ Manufacturing example 8] compound 6 (R One = 3,4-diCl, R 2 = Ph) Intermediate compound 8 ( R One = 3,4- di Cl , R 2 = Ph) to synthesize Compound 1 ( To trifluoroacetic acid by Boc Group Deprotection )
Trifluoroacetic acid (0.5 mL, 6.5 mmol) was added to a solution of Compound 6 (R 1 = 3,4-diCl, R 2 = Ph) (0.25 g, 0.59 mmol) in methylene chloride After stirring for about 10 hours, saturated sodium bicarbonate (10.0 mL) was added. The reaction mixture was extracted with methylene chloride, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the resulting pale yellow liquid was purified by flash chromatography (methylene chloride: methanol (2: 1, v / v)) to obtain compound 1. The obtained compound 1 (R 1 = 3,4-diCl, R 2 = Ph) was identified as a single compound by TLC (methylene chloride: methanol (2: 1, v / v)).
Yield 45%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.08-2.89 (m, 2H, CH 2), 2.78 (br (s), 1H, NH), 2.94-3.00 (m, 1H, CH), 3.36-3.70 (m , 4H, azetidine H), 5.02 (dd, 1H, J = 7.6 Hz, J = 8.0 Hz, CH), 6.77-6.79 (d, 2H, J = 8.0 Hz, ArH), 6.92 (t, 1H, J = 7.2 Hz, ArH), 7.17-7.44 (m, 5H, ArH)
The novel aryloxyacetidine compound 1 was synthesized from the N-Boc-3-azetidine carboxylic acid methyl ester by the method of the above-mentioned Preparation Example according to the method shown in the reaction scheme 1, and the formula of the specific aryloxyacetidine compound Functional groups, and reaction paths are shown in Table 2 below. The yield, characteristics, and hydrogen nuclear magnetic resonance spectrum data thereof are shown in Examples 1 to 49 below.
[ Example : New Aryloxy Azetidine The yield, properties, and Hydrogen Nuclear Magnetic Resonance Spectrum data]
Example One
3- (2- (2- klorophenoxy ) -2- (3,4- dichlorophenyl ) ethyl ) azetidine
Yield 42%; oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.14-2.35 (m, 2H, CH 2), 2.94-3.01 (m, 1H, CH), 3.07 (br (s), 1H, NH), 3.40-3.71 (m , 4H, azetidine H), 5.10 (dd, 1H, J = 4.0 Hz, J = 7.2 Hz, CH), 6.63 (d, 1H, J = 8.0 Hz, ArH), 6.78 (t, 1H, J = 7.2 Hz , ArH), 6.78 (t, 1H, J = 7.2 Hz, ArH), 7.04 (t, 1H, J = 7.2 Hz, ArH), 7.18 (dd, 1H, J = 1.2 Hz, J = 1.6 Hz, ArH) , 7.35 (d, IH, J = 7.2 Hz, ArH), 7.40-7.44 (m, 2H, ArH)
Example 2
3- (2- (3,4- dichlorophenyl ) -2- (2- fluorophenoxy ) ethyl ) azetidine
Yield 38%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.06-2.36 (m, 2H, CH 2), 2.96-3.04 (m, 1H, CH), 3.35 (br (s), 1H, NH), 3.40-3.76 (m , 4H, azetidine H), 5.04 (dd, 1H, J = 8.0 Hz, J = 8.0 Hz, CH), 6.63-7.42
Example 3
3- (2- (3,4- dichlorophenyl )-2- phenoxyethyl ) azetidine
Yield 45%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.08-2.89 (m, 2H, CH 2), 2.78 (br (s), 1H, NH), 2.94-3.00 (m, 1H, CH), 3.36-3.70 (m , 4H, azetidine H), 5.02 (dd, 1H, J = 7.6 Hz, J = 8.0 Hz, CH), 6.77-6.79 (d, 2H, J = 8.0 Hz, ArH), 6.92 (t, 1H, J = 7.2 Hz, ArH), 7.17-7.44 (m, 5H, ArH)
Example 4
3- (2- (3,4- dichlorophenyl ) -2- (m- tolyloxy ) ethyl ) azetidine
Yield 43%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.07-2.25 (m, 2H, CH 2), 2.29 (s, 3H Cresol-CH 3), 2.94-3.00 (m, 1H, CH), 3.42-3.71 (m, 5H, azetidine H, NH), 5.02 (dd, 1H, J = 4.0 Hz, J = 8.0 Hz, CH), 6.54-6.56 (d, 1H, J = 8.0 Hz, ArH), 6.63 (s, 1H, ArH ), 6.74-6.76 (d, IH, J = 7.6 Hz), 7.08 (t, IH, J = 8.0 Hz, ArH), 7.17-7.19 (d, IH, J = 8.0 Hz, ArH), 7.37-7.44 m, 2H, ArH)
Example 5
3- (2- (3,4- dichlorophenyl ) -2- (o- tolyloxy ) ethyl ) azetidine
Yield 51%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.14-2.30 (m, 2H, CH 2), 2.32 (s, 3H Cresol-CH 3), 2.96-3.02 (m, 1H, CH), 3.30 (br (s) , 1H, NH), 3.30-3.73 ( m, 4H, azetidine H), 5.09 (dd, 1H, J = 4.8 Hz, J = 7.6 Hz, CH), 6.51-6.53 (d, 1H, J = 8.4 Hz, ArH), 6.83 (t, 1H, J = 7.6 Hz, ArH), 7.00 (t, 1H, J = 7.6 Hz, ArH) 7.15-7.17 (d, 2H, J = 8.0 Hz, ArH), 7.36-7.47 m, 2H, ArH)
Example 6
3- (2- (3- klorophenoxy ) -2- (3,4- dichlorophenyl ) ethyl ) azetidine
Yield 43%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.09-2.29 (m, 2H, CH 2), 2.73 (br (s), 1H, NH), 2.83-2.97 (m, 1H, CH), 3.36-3.70 (m , 4H, azetidine H), 5.01 (dd, 1H, J = 4.0 Hz, J = 8.0Hz, CH), 6.65 (d, 1H, J = 8.0 Hz, ArH), 6.80 (s, 1H, ArH), 6.90 (d, 1H, J = 8.0 Hz, ArH), 7.10-7.20 (m, 2H, ArH) 7.36-7.46
Example 7
3- (2- (3,4- dichlorophenyl ) -2- (p- tolyloxy ) ethyl ) azetidine
Yield 48%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.07-2.28 (m, 2H, CH 2), 2.25 (s, 3H Cresol-CH 3), 2.97-3.00 (m, 1H, CH), 3.34 (br (s) , 1H, NH), 3.43-3.72 ( m, 4H, azetidine H), 4.99 (dd, 1H, J = 4.0 Hz, J = 8.0 Hz, CH), 6.67-6.69 (d, 2H, J = 8.4 Hz, 2H, ArH), 7.01 (d, 2H, J = 8.4 Hz, ArH), 7.17 (d, 1H, J = 8.0 Hz, ArH) 7.40-7.44
Example 8
3- (2- (4- klorophenoxy ) -2- (3,4- dichlorophenyl ) ethyl ) azetidine
Yield 53%; Oil; 1 H NMR (400 MHz, CDCl 3 )? 2.07-2.28 (m, 2H, CH 2 ), 2.92-2.97 , 4H, azetidine H), 4.96 (dd, 1H, J = 4.0 Hz, J = 7.6 Hz, CH), 6.70 (d, 1H, J = 8.8 Hz, ArH), 7.14 (d, 3H, J = 8.4 Hz , ArH), 7.40-7.42 (m, 2H, ArH)
Example 9
3- (2- (3,4- dichlorophenyl ) -2- (3- fluorophenoxy ) ethyl ) azetidine
Yield 29%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.11-2.26 (m, 2H, CH 2), 2.74 (br (s), 1H, NH), 2.91-2.95 (m, 1H, CH), 3.35-3.69 (m , 4H, azetidine H), 4.99 (dd, 1H, J = 7.6 Hz, J = 8.0 Hz, CH), 6.48-6.64 (m, 3H, ArH), 7.13-7.17 7.43 (m, 2H, ArH)
Example 10
3- (2- (3,4- dichlorophenoxy ) -2- (3,4- dichlorophenyl ) ethyl ) azetidine
Yield 60%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.08-2.28 (m, 2H, CH 2), 2.90-2.94 (m, 1H, CH), 3.20 (br (s), 1H, NH), 3.36-3.70 (m , 4H, azetidine H), 4.97 (dd, 1H, J = 8.0 Hz, J = 8.0 Hz, CH), 6.62 (dd, 1H, J = 2.8 Hz, J = 12.0 Hz, ArH), 6.88 (d, 1H , J = 2.8 Hz, ArH) , 7.13 (dd, 1H, J = 2.0 Hz, J = 8.0 Hz, ArH), 7.23 (d, 1H, J = 8.8 Hz, ArH), 7.39-7.43 (m, 2H, ArH)
Example 11
3- (2- (3,4- dichlorophenyl ) -2- (3,4- difluorophenoxy ) ethyl ) azetidine
Yield 42%; Oil; 1 H NMR (400 MHz, CDCl 3 )? 2.06-2.28 (m, 2H, CH 2 ), 2.63 (br (s), 1H, NH), 2.90-2.93 , 4H, azetidine H), 4.92 (dd, 1H, J = 4.0 Hz, J = 7.6 Hz, CH), 6.46 (d, 1H, J = 9.2 Hz, ArH), 6.57-6.62 (m, 1H, ArH) , 6.97 (q, 1H, J = 9.2 Hz, ArH), 7.13 (dd, 1H, J = 2.0 Hz, J = 8.0 Hz, ArH), 7.23 (d, 1H, J = 8.8 Hz, ArH), 7.39- 7.43 (m, 2H, ArH)
Example 12
3- (2- (3,4- dichlorophenyl ) -2- (4- fluorophenoxy ) ethyl ) azetidine
Yield 38%; Oil; 1 H NMR (400 MHz, CDCl 3 )? 2.07-2.25 (m, 2H, CH 2 ), 2.93-2.97 2H, J = 8.8 Hz, ArH), 4H, azetidine H), 4.93 (dd, 1H, J = 4.0Hz, J = 7.6Hz, CH), 6.68-6.72 , 7.15 (dd, 1H, J = 1.6 Hz, J = 8.0 Hz, ArH), 7.39-7.41 (m, 2H, ArH)
Example 13
3- (2- (3,4- dichlorophenyl ) -2- (2- ( trifluoromethoxy ) phenoxy ) ethyl ) azetidine
Yield 28%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.17-2.33 (m, 2H, CH 2), 2.93-2.98 (m, 1H, CH), 3.41-3.73 (m, 5H, azetidine H, NH), 5.09 (dd , 1H, J = 4.0 Hz, J = 7.2 Hz, CH), 6.68 (d, 1H, J = 8.0 Hz, ArH) 6.68-6.72 (m, 2H, ArH), 6.88 (t, 2H, J = 8.8 Hz , ArH), 7.15 (dd, 1H, J = 1.6 Hz, J = 8.0 Hz, ArH), 7.39-7.41
Example 14
3- (2- (3,4- dichlorophenyl ) -2- (3- ( trifluoromethoxy ) phenoxy ) ethyl ) azetidine
Yield 35%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.10-2.29 (m, 2H, CH 2), 2.93-3.03 (m, 2H, CH, NH), 3.40-3.71 (m, 4H, azetidine H), 5.02 (dd , 1H, J = 4.0 Hz, J = 7.6 Hz, CH), 6.67-6.70 (m, 2H, ArH) 6.79 (d, 1H, J = 8.4 Hz, ArH), 7.15-7.44 (m, 4H, ArH)
Example 15
3- (2- (3,4- dichlorophenyl ) -2- (4- ( trifluoromethoxy ) phenoxy ) ethyl ) azetidine
Yield 41%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.10-2.31 (m, 2H, CH 2), 2.70 (s, 1H, NH), 2.91-2.98 (m, 1H, CH), 3.37-3.72 (m, 4H, 2H, ArH) 7.07 (d, 2H, J = 8.8 Hz, ArH), 7.15 (dd, 1H), 4.98 (dd, 1H, J = 7.6Hz, J = 8.0Hz, CH), 6.76-6.79 , 1H, J = 2.0Hz, J = 8.0Hz, ArH), 7.42-7.45 (m, 2H, ArH)
Example 16
3- (2- (4- chloro -3- fluorophenyl )-2- phenoxyethyl ) azetidine
Yield 46%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.09-2.30 (m, 2H, CH 2), 2.55 (s, 1H, NH), 2.93-3.00 (m, 1H, CH), 3.37-3.71 (m, 4H, 2H, J = 8.0 Hz, ArH) 6.92 (t, 1H, J = 7.2 Hz, ArH), 5.05 (dd, 1H, J = 4.0 Hz, J = 7.2 Hz, CH) 7.07 (d, 1H, J = 8.0 Hz, ArH), 7.15 (d, 1H, J = 9.6 Hz, ArH) 7.21 (t, 2H, J = 7.6 Hz, ArH), 7.37 (t, 1H, J = 8.0 Hz, ArH)
Example 17
3- (2- (4- chloro -3- fluorophenyl ) -2- (3- klorophenoxy ) ethyl ) azetidine
Yield 65%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.11-2.30 (m, 2H, CH 2), 2.94-2.98 (m, 1H, CH), 3.40-3.74 (m, 4H, azetidine H), 5.03 (dd, 1H , J = 7.6 Hz, J = 8.0Hz, CH), 6.67 (dd, 1H, J = 8.0 Hz, ArH) 6.80 (t, 1H, J = 2.4 Hz, ArH), 6.92 (dd, 1H, J = 1.2 Hz, J = 8.0 Hz, ArH), 7.05-7.41 (m, 4H, ArH)
Example 18
3- (2- (4- chloro -3- fluorophenyl ) -2- (4- klorophenoxy ) ethyl ) azetidine
Yield 64%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.08-2.29 (m, 2H, CH 2), 2.62 (s, 1H, NH), 2.89-2.96 (m, 1H, CH), 3.35-3.80 (m, 4H, azetidine H), 4.98 (dd, 1H, J = 4.0 Hz, J = 7.2 Hz, CH), 6.69-7.38 (m, 8H, ArH)
Example 19
3- (2- (4- chloro -3- fluorophenyl ) -2- (2- fluorophenoxy ) ethyl ) azetidine
Yield 57%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.13-2.38 (m, 2H, CH 2), 2.97-3.01 (m, 1H, CH), 3.40-3.74 (m, 4H, azetidine H), 5.07 (dd, 1H , J = 4.0 Hz, J = 8.0 Hz, CH), 6.70-7.10 (m, 5H, ArH), 7.18 (dd, 1H, J = 2.0 Hz, J = 4.0 Hz, ArH), 7.38 (t, 1H, J = 8.0 Hz, ArH)
Example 20
3- (2- (4- chloro -3- fluorophenyl ) -2- (3- fluorophenoxy ) ethyl ) azetidine
Yield 57%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.13-2.30 (m, 2H, CH 2), 2.99-3.05 (m, 1H, CH), 3.48-3.81 (m, 4H, azetidine H), 5.04 (dd, 1H , J = 4.0 Hz, J = 7.6 Hz, CH), 6.48-7.19 (m, 6H, ArH), 7.40 (t, 1H, J = 8.0 Hz, ArH)
Example 21
3- (2- (4- chloro -3- fluorophenyl ) -2- (4- fluorophenoxy ) ethyl ) azetidine
Yield 23%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.12-2.28 (m, 2H, CH 2), 2.95-2.98 (m, 1H, CH), 3.38-3.72 (m, 4H, azetidine H), 4.96 (dd, 1H , J = 4.0 Hz, J = 7.6 Hz, CH), 6.71-7.15 (m, 6H, ArH), 7.38 (t, 1H, J = 8.0 Hz, ArH)
Example 22
3- (2- (4- chloro -3- fluorophenyl ) -2- (2- klorophenoxy ) ethyl ) azetidine
Yield 35%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.20-2.35 (m, 2H, CH 2), 2.60 (s, 1H, NH), 2.97-3.01 (m, 1H, CH), 3.41-3.72 (m, 4H, azetidine H), 5.13 (dd, 1H, J = 4.0Hz, J = 7.2 Hz, CH), 6.64 (d, 1H, J = 8.0 Hz, ArH), 6.86 (t, 1H, J = 7.6 Hz, ArH) , 7.02-7.39 (m, 5H, ArH)
Example 23
3- (2- (4- chloro -3- fluorophenyl ) -2- (o- tolyloxy ) ethyl ) azetidine
Yield 42%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.16-2.29 (m, 2H, CH 2), 2.32 (s, 3H, Phenol-CH 3), 2.83 (s, 1H, NH), 2.96-2.99 (m, 1H , CH), 3.41-3.72 (m, 4H, azetidine H), 5.11 (dd, 1H, J = 4.0 Hz, J = 7.6 Hz, CH), 6.52 (d, 1H, J = 8.0 Hz, ArH), 6.83 (t, 1H, J = 7.2 Hz, ArH), 6.99 (t, 1H, J = 7.2 Hz, ArH), 7.05-7.39 (m, 4H, ArH)
Example 24
3- (2- (4- chloro -3- fluorophenyl ) -2- (m- tolyloxy ) ethyl ) azetidine
Yield 61%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.11-2.26 (m, 2H, CH 2), 2.28 (s, 3H, Phenol-CH 3), 2.97-3.01 (m, 1H, CH), 3.43-3.75 (m , 4H, azetidine H), 3.82 (s, 1H, NH), 5.05 (dd, 1H, J = 4.0 Hz, J = 8.0 Hz, CH), 6.56 (dd, 1H, J = 2.0 Hz, J = 8.0 Hz , ArH), 6.63 (s, 1H, ArH), 6.74 (d, 1H, J = 7.2 Hz, ArH), 7.06-7.16 (m, 3H, ArH), 7.36 (t, 1H, J = 8.0 Hz, ArH )
Example 25
3- (2- (4- chloro -3- fluorophenyl ) -2- (p- tolyloxy ) ethyl ) azetidine
Yield 50%; Oil; 1H NMR (400MHz, CDCl 3) δ 2.08-2.28 (m, 4H, CH 2, Phenol-CH 3), 2.96-3.02 (m, 1H, CH), 3.41-3.73 (m, 4H, azetidine H), 5.01 (dd, 1H, J = 7.6 Hz, J = 8.0 Hz, CH), 6.67 (d, 2H, J = 8.4 Hz, ArH), 7.00 (d, 1H, J = 8.4 Hz, ArH), 7.06 (d, 1H, J = 8.4 Hz, ArH ), 7.14 (dd, 1H, J = 1.6 Hz, J = 8.0 Hz, ArH), 7.36 (t, 1H, J = 7.6 Hz, ArH)
Example 26
3- (2- (4- chloro -3- fluorophenyl ) -2- (2- ( trifluoromethoxy ) phenoxy ) ethyl ) azetidine
Yield 40%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.20-2.34 (m, 2H, CH 2), 2.96-3.00 (m, 1H, CH), 3.44-3.74 (m, 4H, azetidine H), 5.11 (dd, 1H , J = 4.0 Hz, J = 7.6 Hz, CH), 6.68 (dd, 1H, J = 1.2 Hz, J = 8.0 Hz, ArH), 6.93 (td, 1H, J = 7.6 Hz, ArH), 7.06-7.26 (m, 4H, ArH), 7.39 (t, IH, J = 8.0 Hz, ArH)
Example 27
3- (2- (4- chloro -3- fluorophenyl ) -2- (3- ( trifluoromethoxy ) phenoxy ) ethyl ) azetidine
Yield 44%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.17-2.32 (m, 2H, CH 2), 2.93-2.99 (m, 1H, CH), 3.38-3.73 (m, 4H, azetidine H), 5.04 (dd, 1H , J = 4.0 Hz, J = 7.6 Hz, CH), 6.66-7.08 (m, 4H, ArH), 7.14 (dd, 1H, J = 2.0 Hz, J = 12.0 Hz, ArH), 7.21 (t, 1H, J = 8.0 Hz, J = 8.0 Hz, ArH)
Example 28
3- (2- (3,4- difluorophenyl )-2- phenoxyethyl ) azetidine
Yield 47%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.10-2.28 (m, 2H, CH 2), 2.93-3.01 (m, 1H, CH), 3.39-3.73 (m, 4H, azetidine H), 5.04 (dd, 1H , J = 4.0 Hz, J = 7.2 Hz, CH), 6.79 (d, 2H, J = 7.6 Hz, ArH), 6.92 (t, 1H, J = 7.2 Hz, ArH), 7.07-7.23 (m, 5H, ArH)
Example 29
3- (2- (2- klorophenoxy ) -2- (3,4- difluorophenyl ) ethyl ) azetidine
Yield 35%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.16-2.37 (m, 2H, CH 2), 2.24 (s, 1H, NH), 2.93-3.01 (m, 1H, CH), 3.38-3.71 (m, 4H, azetidine H), 5.12 (dd, 1H, J = 4.0 Hz, J = 7.6 Hz, CH), 6.67 (d, 1H, J = 8.4 Hz, ArH), 6.86 (t, 1H, J = 1.2 Hz, J = 8.0 Hz, ArH), 7.02-7.37 (m, 5H, ArH)
Example 30
3- (2- (3- klorophenoxy ) -2- (3,4- difluorophenyl ) ethyl ) azetidine
Yield 38%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.09-2.27 (m, 2H, CH 2), 2.91-2.95 (m, 1H, CH), 3.26 (s, 1H, NH), 3.37-3.71 (m, 4H, azetidine H), 5.01 (dd, 1H, J = 7.6 Hz, J = 8.0 Hz, CH), 6.66 (dd, 1H, J = 8.0 Hz, J = 8.4 Hz, ArH), 6.79 (t, 1H, J = 2.0 Hz, ArH), 6.88-7.17 (m, 5H, ArH)
Example 31
3- (2- (4- klorophenoxy ) -2- (3,4- difluorophenyl ) ethyl ) azetidine
Yield 31%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.07-2.27 (m, 2H, CH 2), 2.91-2.96 (m, 1H, CH), 3.35-3.68 (m, 4H, azetidine H), 4.98 (m, 1H , CH), 6.70-7.31 (m, 7H, ArH)
Example 32
3- (2- (3,4- difluorophenyl ) -2- (2- fluorophenoxy ) ethyl ) azetidine
Yield 41%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.15-2.37 (m, 2H, CH 2), 2.41 (s, 1H, NH), 2.95-2.99 (m, 1H, CH), 3.37-3.72 (m, 4H, azetidine H), 5.05 (dd, 1H, J = 4.0 Hz, J = 7.6 Hz, CH), 6.70-7.22 (m, 7H, ArH)
Example 33
3- (2- (3,4- difluorophenyl ) -2- (3- fluorophenoxy ) ethyl ) azetidine
Yield 36%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.10-2.27 (m, 2H, CH 2), 2.29 (s, 1H, NH), 2.89-2.96 (m, 1H, CH), 3.34-3.69 (m, 4H, azetidine H), 5.01 (dd, 1H, J = 4.0 Hz, J = 8.0 Hz, CH), 6.48-7.17 (m, 7H, ArH)
Example 34
3- (2- (3,4- difluorophenyl ) -2- (4- fluorophenoxy ) ethyl ) azetidine
Yield 54%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.08-2.27 (m, 2H, CH 2), 2.56 (s, 1H, NH), 2.92-2.96 (m, 1H, CH), 3.35-3.70 (m, 4H, azetidine H), 4.94 (dd, 1H, J = 4.0 Hz, J = 7.6 Hz, CH), 6.70-7.17 (m, 7H, ArH)
Example 35
3- (2- (3,4- difluorophenyl ) -2- (o- tolyloxy ) ethyl ) azetidine
Yield 29%; Oil; 1 H NMR (400MHz, CDCl3) δ 2.16-2.31 (m, 2H, CH 2), 2.32 (s, 3H, Phenol-CH 3), 2.56 (s, 1H, NH), 2.95-2.98 (m, 1H, (D, 1H, J = 8.0 Hz, ArH), 6.83 (t, 1H, J = 7.2 Hz), 3.40-3.71 (m, 4H, azetidine H), 5.08-5.10 , ArH), 6.97-7.16 (m, 5H, ArH)
Example 36
3- (2- (3,4- difluorophenyl ) -2- (m- tolyloxy ) ethyl ) azetidine
Yield 56%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.11-2.27 (m, 2H, CH 2), 2.29 (s, 3H, Phenol-CH3), 2.60 (s, 1H, NH), 2.94-2.98 (m, 1H, CH), 3.38-3.71 (m, 4H , azetidine H), 5.03 (dd, 1H, J = 4.0 Hz, J = 7.6 Hz, CH), 6.57 (d, 1H, J = 8.4 Hz, ArH), 6.64 ( (d, 1H, J = 7.6 Hz, ArH), 7.06-7.20 (m, 4H, ArH)
Example 37
3- (2- (3,4- difluorophenyl ) -2- (p- tolyloxy ) ethyl ) azetidine
Yield 53%; Oil; 1 H NMR (400 MHz, CDCl 3 )? 2.08-2.28 (m, 5H, CH 2 , Phenol-CH 3 ), 2.54 (s, 1H, NH), 2.93-2.97 (m, 4H, azetidine H), 4.99 (dd, 1H, J = 4.0 Hz, J = 7.2 Hz, CH), 6.69 (d, 1H, J = 8.0 Hz, ArH), 7.00-7.19 ArH)
Example 38
3- (2- (3,4- difluorophenyl ) -2- (2- ( trifluoromethoxy ) phenoxy ) ethyl ) azetidine
Yield 50%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.17-2.35 (m, 2H, CH 2), 2.94-3.02 (m, 1H, CH), 3.46-3.78 (m, 4H, azetidine H), 4.40 (s, 1H , NH), 5.10 (dd, 1H, J = 6.8 Hz, J = 8.0 Hz, CH), 6.69 (d, 1H, J = 8.4 Hz, ArH), 6.92 (t, 1H, J = 7.6 Hz, ArH) 7.06-7.25 (m, 5 H, ArH)
Example 39
3- (2- (3,4- difluorophenyl ) -2- (3- ( trifluoromethoxy ) phenoxy ) ethyl ) azetidine
Yield 54%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.10-2.28 (m, 2H, CH 2), 2.30 (s, 1H, NH), 2.90-2.97 (m, 1H, CH), 3.56-3.71 (m, 4H, azetidine H), 5.02 (dd, 1H, J = 4.0 Hz, J = 7.2 Hz, CH), 6.66 (s, 1H, ArH), 6.70 (dd, 1H, J = 2.0 Hz, J = 8.4 Hz, ArH) , 6.79 (d, 1H, J = 8.0 Hz, ArH) 7.04-7.23 (m, 4H, ArH)
Example 40
3- (2- (3,4- difluorophenyl ) -2- (4- ( trifluoromethoxy ) phenoxy ) ethyl ) azetidine
Yield 39%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.05-2.31 (m, 2H, CH 2), 2.93-2.97 (m, 1H, CH), 3.13 (s, 1H, NH), 3.83-3.71 (m, 4H, (d, 1H, J = 4.0 Hz, J = 7.6 Hz, CH), 7.12-7.19 (m, 7H, ArH)
Example 41
3- (2- (3,4- dichlorophenoxy ) -2- (3,4- difluorophenyl ) ethyl ) azetidine
Yield 41%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.06-2.30 (m, 2H, CH 2), 2.89-2.96 (m, 1H, CH), 3.16 (s, 1H, NH), 3.94-3.70 (m, 4H, azetidine H), 4.98 (dd, 1H, J = 7.2 Hz, J = 8.0 Hz, CH), 6.63 (dd, 1H, J = 2.4 Hz, J = 9.2 Hz, ArH), 6.89 (d, 1H, J = 2.8 Hz, ArH), 7.04-7.26 (m, 4H, ArH)
Example 42
3- (2- (3,4- difluorophenoxy ) -2- (3,4- difluorophenyl ) ethyl ) azetidine
Yield 46%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.08-2.30 (m, 2H, CH 2), 2.91-2.99 (m, 1H, CH), 3.40-3.74 (m, 4H, azetidine H), 3.66 (s, 1H , NH), 4.94 (dd, 1H, J = 4.0 Hz, J = 7.6 Hz, CH), 6.46-7.19 (m, 6H, ArH)
Example 43
3- (2- ( naphthalen -2- yl )-2- phenoxyethyl ) azetidine
Yield 54%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.20-2.40 (m, 2H, CH 2), 3.09-3.12 (m, 1H, CH), 3.62-3.80 (m, 4H, azetidine H), 3.87 (s, 1H , 7.48 (t, 2H, J = 7.6 Hz, ArH), 5.25 (dd, 1H, J = 4.0 Hz, J = 7.2 Hz, CH), 6.84-6.90 7.86 (m, 9H, ArH)
Example 44
3- (2- (2- klorophenoxy )-2-( naphthalen -2- yl ) ethyl ) azetidine
Yield 45%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.29-2.47 (m, 2H, CH 2), 3.07-3.10 (m, 1H, CH), 3.48 (s, 1H, NH), 3.50-3.78 (m, 4H, azetidine H), 5.33 (dd, 1H, J = 4.0 Hz, J = 8.0 Hz, CH), 6.73 (d, 1H, J = 8.4 Hz, ArH), 6.81 (t, 1H, J = 7.6 Hz, ArH) , 6.97 (t, 1H, J = 8.4 Hz, ArH), 7.35-7.86 (m, 8H, ArH)
Example 45
3- (2- ( naphthalen -2- yl ) -2- (o- tolyloxy ) ethyl ) azetidine
Yield 43%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.25-2.39 (m, 2H, CH 2), 2.40 (s, 3H, Phenol-CH 3), 3.08-3.12 (m, 1H, CH), 3.57-3.77 (m , 4H, azetidine H), 5.24 (s, 1H, NH), 5.32 (t, 1H, J = 5.2 Hz, CH), 6.65 (d, 1H, J = 8.0 Hz, ArH), 6.81 (t, 1H, J = 7.6 Hz, ArH), 6.96 (t, 1H, J = 7.6 Hz, ArH), 7.17 (d, 1H, J = 7.2 Hz, ArH), 7.46-7.89
Example 46
3- (2- phenoxy -2- 피닐 ) azetidine
Yield 65%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.16-2.32 (m, 2H, CH 2), 2.98-3.02 (m, 1H, CH), 3.40-3.71 (m, 4H, azetidine H), 5.08 (dd, 1H , J = 8.0 Hz, J = 8.0 Hz, CH), 6.81-6.91 (m, 3H, ArH), 7.18-7.35 (m, 7H, ArH)
Example 47
3- (2- (2- klorophenoxy )-2- 피닐 ) azetidine
Yield 34%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.17-2.35 (m, 2H, CH 2), 2.97-3.01 (m, 1H, CH), 3.40-3.68 (m, 4H, azetidine H), 5.13 (dd, 1H , J = 4.0 Hz, J = 7.6 Hz, CH), 6.65 (dd, 1H, J = 1.6 Hz, J = 8.4 Hz, ArH), 6.79 (dd, 1H, J = 1.2 Hz, J = 7.6 Hz, ArH ), 6.96-7.00 (m, 1H, ArH), 7.23-7.33 (m, 6H, ArH)
Example 48
3- (2- phenyl -2- (o- tolyloxy ) ethyl ) azetidine
Yield 54%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.16-2.35 (m, 2H, CH 2), 2.33 (s, 3H, Phenol-CH 3), 2.96-3.03 (m, 1H, CH), 3.41-3.70 (m , 4H, azetidine H), 5.14 (dd, 1H, J = 4.0 Hz, J = 7.2 Hz, CH), 6.58 (d, 1H, J = 8.0 Hz, ArH), 6.79 (t, 1H, J = 7.6 Hz , ArH), 6.97 (t, 1H, J = 7.2 Hz, ArH), 7.14 (d, 1H, J = 7.2 Hz, ArH), 7.25-7.40
Example 49
3- (2- (2- fluorophenoxy )-2- 피닐 ) azetidine
Yield 45%; Oil; 1 H NMR (400MHz, CDCl 3 ) δ 2.20-2.39 (m, 2H, CH 2), 3.02-3.06 (m, 1H, CH), 3.45-3.79 (m, 4H, azetidine H), 5.10 (t, 1H , J = 2.4 Hz, CH), 6.71-7.36 (m, 9H, ArH)
[ Experimental Example : Neurotransmitter Reabsorption Inhibition Essay ( Neurotransporter reuptake inhibitory assay )]
The reuptake inhibitory activity of the compounds synthesized in Examples 1 to 49 on the neurotransmitter transporter was tested in vitro. This activity means the ability of the compounds synthesized in the Examples to block the reabsorption of neurotransmitters through the transport of monovalent amine neurotransmitters via dopamine, serotonin and neoepinephrine transporters. A high-throughput screening system FDSS6000 (Functional Drug Screening System 6000), a real-time fluorescence analyzer, was used for cell-based screening of dopamine, serotonin and neophelin reuptake inhibitor candidates. In this experimental example, the HEK293 cell line (HEK-hDAT, HEK-hNET) expressing human dopamine, serotonin and neopinaphrin transporter was treated with a blocking agent and the change in intracellular monophosphate neurotransmitter was measured, Respectively.
(1) Cell culture and preparation
(HEK-hSERT, HEK-hDAT, HEK-hNET; provided by Professor Bryan Roth of North Carolina-Chapel Hill University) in which the human dopamine, serotonin and neoepinephrine transporter are stably expressed, respectively Respectively.
HEK293 cells stably expressing each transporter were cultured in the presence of 10% (v / v) fetal bovine serum, penicillin (100 U / ml), and streptomycin (100 μg / ml) Dulbecco's modified Eagle's medium (Welgene, Daegu, Korea) was used to culture the cells in an incubator at 37 ° C in a 5% CO 2 humidified condition and pass once every 3-4 days.
Geneticin G418 (Gibco, USA) for HEK-SERT cell line, Geneticin G418 (Gibco, USA) for HEK-hDAT cell line and Geneticin G418 (Gibco, USA) for HEK-hDAT cell line were used for screening cells expressing each transporter (Gibco, USA) supplemented with 200 / ml of Geneticin G418 (37 ° C, 5% carbon dioxide, humidified incubator). L-lysine (poly-L-lysine) was obtained 18-20 hours before the activity test for the monovalent amine reuptake inhibitor compound (Example 1-49) using FDSS6000 instrument (Hamamatsu Photonics, Hamamatsu, Japan) (NUNC, Rochester, NY, USA) coated at a density of 5 x 10 4 cells / well per well.
(2) High efficiency detector FDSS6000 Measurement and data analysis using
The reuptake inhibitory activity was measured using a Neurotransmitter Transporter Uptake Assay Kit (Molecular), which mimics DA (dopamine), 5-HT (serotonin) and NE (no epinephrine) Devices, Sunnyvale, Calif., USA) was used to treat intracellular reabsorption of the indicator with fluorescent signals after treatment with the blocking compounds (Examples 1-49). The indicator was included in the kit. In the assay kit, dopamine, serotonin, and naepinephrine were imitated and the indicator labeled with a fluorescent dye was included in powder form, which was dissolved in HEPES buffer and used in the experiment. The assay kit contained only one indicator and the same type of indicator was used for dopamine, serotonin, and neophelin reuptake experiments.
On the day of the experiment, the cells attached to the 96-well plate were washed with HEPES buffer (unit mM: 150 NaCl, 5 KCl, 2 CaCl 2, 1 MgCl 2) using a 96-well plate automatic washing machine ELx405 Select CW (BioTek Instruments, Winooski, , 10Glucose, 10HEPES, pH7.4), and the dye solution prepared according to the manufacturer's instructions was added thereto, and the fluorescence intensity was measured immediately. The reabsorption of the fluorescently labeled indicator was measured for 30 minutes by the change in fluorescence intensity according to the change of the intracellular indicator using an FDSS 6000 instrument (Hamamatsu Photonics, Hamamatsu, Japan).
Changes in intracellular fluorescence intensity were determined by the final fluorescence intensity (Endpoint) measured 30 minutes after starting measurement of fluorescence intensity. For detailed fluorescence imaging, a computer-controlled filter wheel was used to selectively expose cells to excitation wavelengths of 440 nm emitted from the four xenon lamp sources mounted on the FDSS 6000, followed by a 515 nm long- Pass filtered and cooled fluorescence CCD camera embedded in the instrument. The emitted fluorescence was measured by a digital fluorescence analyzer at 520 nm every 10 seconds.
In the experiment for measuring the inhibitory effect, the test drug containing the 3-aminomethylazetidine compound synthesized in Examples 1 to 49 was pre-treated in an incubator for 15 minutes at 37 ° C in a 5% carbon dioxide humidifying condition, Was added to the dye solution. More specifically, the test drug is prepared by making a 100 mM solution of DMSO in a 3-aminomethylazetidine compound and adding a solution of HEPES buffer (unit mM: 150 NaCl, 5 KCl, 2 CaCl 2, 1 MgCl 2, 10 Glucose, 10 HEPES , pH 7.4). After the addition of the dye solution to the cells, the fluorescence intensity was immediately measured and the change in intracellular fluorescence intensity was measured for 30 minutes to determine the final fluorescence intensity (Endpoint).
The percent inhibition (% of control) for the test material was calculated by taking the final fluorescence intensity (Endpoint) of the control group not treated with the test material as 100%, obtaining a dose-response curve and using GraphPad Prism4 , La Jolla, CA, USA). (dopamine inhibitor), Nisoxetine (no epinephrine inhibitor) and Fluoxetine (serotonin inhibitor) (supra, Tocris Bioscience, Ellisville, MO) as hNET (norepinephrine), hSERT (serotonin), and hDAT , USA), respectively. All image data and analysis were made using FDSS6000 dedicated program provided by Hamamatsu Photonics (Hamamatsu, Japan).
Test results of the obtained neurotransmitter re-absorption inhibitory activity are shown in Tables 3 to 5 below.
(%)
(%)
(%)
(%)
(%)
(%)
(%)
(%)
(%)
(%)
(%)
(%)
(All compounds tested in Table 3 above exhibited 100% or close inhibition at concentrations of 10 [mu] M and 1 [mu] M, and compounds 28-49 of Table 4 were also 100% or similar at concentrations of 10 [ Lt; / RTI > and 1 < RTI ID = 0.0 > uM) < / RTI >
As shown in Tables 3 and 4, the 3-aminomethylazetidine compounds synthesized in Examples 1 to 49 exhibited superior effects on serotonin inhibition than Fluoxetine, which is a selective serotonin inhibitor, Fluoxetine showed excellent inhibitory effect against no epinephrine or dopamine which showed almost no inhibitory effect. In addition, while Nisoxetine selectively inhibited the reuptake of norepinephrine, the 3-aminomethylazetidine compounds synthesized in Examples 1 to 49 inhibited the reuptake of norepinephrine as well as the reabsorption of serotonin and dopamine And showed excellent inhibitory effect. In addition, GBR12909 selectively exhibited a reuptake inhibitory effect on dopamine. However, the aryloxyacetidine compound synthesized in Examples 1 to 49 has an effect of inhibiting reabsorption of dopamine as well as an excellent inhibitory effect of serotonin and norepinephrine reuptake Respectively.
As a result, the aryloxyacetidine compounds of Examples 1 to 49 are expected to have a high therapeutic effect or preventive effect against premature or neuropathic pain as well as mental disorders such as depression and bipolar disorder, It is possible to effectively inhibit the reabsorption of neurotransmitters including seretonin, norepinephrine and dopamine as a compound at the same time, so that it is possible to remarkably reduce adverse effects caused by the combined use of medicines and the increase in the usage.
It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.
Claims (14)
[Chemical Formula 1]
Wherein R 1 and R 2 are each independently selected from the group consisting of substituted or unsubstituted aryl groups having 6 to 10 carbon atoms, wherein the substituted aryl group is substituted with at least one hydrogen atom, each independently selected from the group consisting of halogen, Substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and the substituted alkyl group or substituted alkoxy group is a group in which at least one hydrogen atom is independently substituted with halogen Substituted with a substituent selected from the group consisting of
A phenyl group;
A phenyl group in which at least one hydrogen is independently substituted with a functional group selected from the group consisting of halogen, a straight chain or branched chain alkyl group having 1 to 10 carbon atoms, and a phenoxy group;
Benzyl group;
A benzyl group in which at least one hydrogen is independently selected from the group consisting of halogen, straight or branched chain alkyl groups having 1 to 10 carbon atoms, and phenoxy groups;
Naphthyl group; or
Wherein at least one hydrogen is independently selected from the group consisting of halogen, a linear or branched chain alkyl group having 1 to 10 carbon atoms, and a naphthyl group substituted with a functional group selected from the group consisting of a phenoxy group
Aryloxyacetidine compound.
Wherein R1 is a phenyl group, a naphthyl group, or a phenyl group in which one or two hydrogens are each independently substituted with a substituent selected from the group consisting of halogen, or a naphthyl group in which one or two hydrogens are each independently substituted with the above substituent ,
R2 is a phenyl group or a phenyl group substituted with a substituent selected from the group consisting of halogen, a C1-C3 alkyl group, and a substituted or unsubstituted alkoxy group having 1 to 3 carbon atoms, Wherein the alkoxy group is optionally substituted with a substituent selected from the group consisting of halogen,
Aryloxyacetidine compound.
Wherein R1 is a phenyl group, a naphthyl group, or a phenyl group substituted by a substituent selected from the group consisting of F and Cl,
Wherein R2 is a phenyl group or a phenyl group substituted with a substituent selected from the group consisting of F, Cl, methyl, and trifluoromethoxy,
Aryloxyacetidine compound.
Wherein said composition inhibits the reabsorption of at least one neurotransmitter selected from the group consisting of dopamine, serotonin and naepinephrine to a neurotransmitter transporter.
Wherein the mental disease is depression, bipolar disorder, neuropathic pain, schizophrenia, mood disorders, sleep disorders, anxiety, attention deficit hyperactivity disorder (ADHD), or eating disorders.
Wherein R 1 and R 2 are each independently selected from the group consisting of a substituted or unsubstituted aryl group having 6 to 10 carbon atoms, wherein the substituted aryl group is a group selected from the group consisting of halogen, Substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and the substituted alkyl group or substituted alkoxy group is a group in which at least one hydrogen atom is independently substituted with halogen Substituted with a substituent selected from the group consisting of
In Formula 6, R 1 and R 2 are each independently selected from the group consisting of substituted or unsubstituted aryl groups having 6 to 10 carbon atoms, wherein the substituted aryl groups are each independently selected from the group consisting of halogen, Substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and the substituted alkyl group or substituted alkoxy group is a group in which at least one hydrogen atom is independently substituted with halogen Substituted with a substituent selected from the group consisting of
Wherein R1 is selected from the group consisting of substituted or unsubstituted aryl groups having 6 to 10 carbon atoms, wherein the substituted aryl group is a group selected from the group consisting of a halogen atom, a straight or branched chain alkyl group having 1 to 10 carbon atoms A substituted or unsubstituted alkyl group, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, wherein the substituted alkyl group or substituted alkoxy group is substituted with a substituent selected from the group consisting of halogen, .
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