KR20170001936A - Novel 2-substituted tetrahydropyran or 2-substituted tetrahydrofuran derivatives, method for preparing the same, and use thereof - Google Patents

Abstract

The present invention relates to a novel 2-substituted tetrahydropyran or a 2-substituted tetrahydrofuran derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, a process for producing the same, and prevention of a neurological disease Or a pharmaceutical composition for therapeutic use. The compound exhibits an inhibitory function against activation of microglial cells induced by toxic substances and can be used as a pharmaceutical composition for the prevention and treatment of neurological diseases.

Description

Novel 2-substituted tetrahydropyran or 2-substituted tetrahydrofuran derivatives, a method for preparing same, and use thereof, and a process for preparing the same,

The present invention relates to novel 2-substituted tetrahydropyran or 2-substituted tetrahydrofuran derivative compounds, processes for their preparation and their uses, in particular to novel 2-substituted tetrahydropyran or 2-substituted tetrahydrofuran derivatives, A furan derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for preventing or treating a neurological disorder containing the same as an active ingredient.

In the natural world, there are many aliphatic ring compounds containing oxygen. Among them, there exist organic and inorganic substances which constitute living bodies or exhibit physiological activity. The most representative oxygen-containing aliphatic ring compound is sugar. For example, nucleoside triphosphates and nucleotides such as ATP and GTP in vivo contain 5-membered oxygen-containing rings. The glycation of lipids and proteins has been reported to play a key role in regulating the ecological pathology associated with the expression of diseases such as infection, metastasis, inflammation, differentiation, and regulation of vital signs, which confer specificity of in vivo cognition (Hang et al ...., Acc Chem Res , 2001, 34 (9):... 727-736; Wong, Acc Chem Res, 1999, 32 (4): 376-385). The use of the oxygen-containing aliphatic ring compound is not limited to the carbohydrate or glycoprotein, the saccharide lipid and the sugar constituting the nucleotide. Among the natural products or existing medicines or known physiologically active compounds made by the biosynthetic pathway, there are substances other than sugar including tetrahydropyran or tetrahydrofuran. One example is Amprenavir, an antiviral agent comprising Tacrolimus (FK-506 or fujimycin), an immunosuppressant with a tetrahydropyran core and Tetrahydrofuran, and Amprenavir, an antiviral agent comprising tetrahydrofuran. In addition, there are antiviral agents and anticancer agents that are artificially modified forms of sugar present in nature (Ghosh et al. , Future Med. Chem., 2011, 3 (9): 1181-1197).

A synthetic method for introducing a substituent into an oxygen-containing aliphatic cyclic compound has been studied. The introduction of the substituent has been mainly focused on the chemoselective ligation which selectively connects the parent compound of the ring compound to another structure. In the case of the sugar peptide, the reaction site connecting the sugar and the peptide is an anomeric position (Hang et al, Acc Chem Res 2001 Sep; 34 (9): 727-36). That is, a synthesis method of introducing a substituent at an anomeric position by a compound extension method has been developed. In order to increase the protein affinity of a drug derived from the sugar chain, it is common to introduce a hydrophobic group or a charged substituent, and various synthetic methods have been tried for this purpose (Trejbalova et al. , Nucleic Acids Res., 2011, 39 ): 8728-8739).

However, it has been required to develop a new synthetic method because of the limited or inefficient method of synthesizing 2-aminotetrahydropyran and 2-aminotetrahydrofuran derivatives in which two aromatic substituents are present in the previously reported method.

Under these circumstances, the object of the present invention is to provide a novel tetrahydropyran or tetrahydrofuran derivative having a tertiary amine introduced at an anomeric position, and as a result, it has been found that an aromatic 3 It has been found that a 2-substituted tetrahydropyran or a 2-substituted tetrahydrofuran derivative can be efficiently synthesized, which has not been reported by existing methods, and that the synthesized compound (LPS) -induced " microglial activation "inhibition and 6-OHDA (6-hydroxydopamine) -mediated cell death inhibition effects as an example of industrial availability, And have utility in the prevention or treatment of diseases. Thus, the present invention has been completed.

One object of the present invention is to provide a novel 2-substituted tetrahydropyran or a 2-substituted tetrahydrofuran derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for preparing the 2-substituted tetrahydropyran or the 2-substituted tetrahydrofuran derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

It is still another object of the present invention to provide a method for preventing or treating a neurological disease comprising the 2-substituted tetrahydropyran or 2-substituted tetrahydrofuran derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient And to provide a pharmaceutical composition.

It is still another object of the present invention to provide a method for preventing or treating a neurological disease in an individual, comprising administering the pharmaceutical composition to a subject in need thereof.

In order to achieve the above object, the present invention provides, in one embodiment, a compound represented by the following formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In this formula,

n is 0 or 1;

R ¹ and R ² are the same or different, each independently represent a C ₅ -C ₁₄ aryl or C ₅ -C ₁₄ heteroaryl, wherein aryl or heteroaryl are halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy, and -NR ⁷ R ⁸ , or R ¹ and R ² may be connected to each other to form a 5- to 8-membered ring containing a nitrogen atom to which they are bonded, Said heterocyclic ring being fused to another C ₅ -C ₁₄ aryl or unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or C ₁ -C ₆ alkyl;

R ³ and R ^{3 'are} the same or different, each independently represent hydrogen, hydroxy, halogen, C _5-14 aryl -C _1-6 alkoxy, hydroxy C ₁ -C ₆ alkyl, or tri (C ₁ -C _6-alkyl) - silyloxy -C ₁ -C ₆ alkyl (wherein, tri (C ₁ -C ₆ alkyl) are all the same or may be configured as two or more different from each other (C ₁ -C ₆ alkyl)), and;

R ⁴ and R ^{4 'are} the same or different, each independently represent hydrogen, hydroxy, halogen, C ₅ -C ₁₄ aryl, or C _5-14 aryl -C _1-6 alkoxy;

R ⁵ and R ^{5 '} are the same or different and each independently is hydrogen, hydroxy, halogen, or C _5-14 aryl-C _1-6 alkoxy;

R ⁶ and R ^{6 '} are the same or different and each independently hydrogen or C ₁ -C ₆ alkyl,

R ⁷ and R ⁸ are the same or different and each independently represents hydrogen or C ₁ -C ₆ alkyl.

Specifically, in Formula 1, R ¹ and R ² are the same or different and each independently represents phenyl or pyridinyl, and R ¹ and R ² are each independently selected from the group consisting of fluoro, methoxy, dimethylamino, methyl, and bromo substituted with one or more substituents selected from the group, or may not be substituted, or R ¹ and R ² are connected to each other is formed, methyl, iodo, or both represents the indolinyl substituted with both;

R ³ and R ^{3 '} are the same or different and each independently is hydrogen, hydroxy, fluoro, benzyloxy, hydroxymethyl, or tert-butyldimethylsilyloxymethyl;

R ⁴ and R ^{4 '} are the same or different and each independently hydrogen, hydroxy, fluoro, phenyl, or benzyloxy;

R ⁵ and R ^{5 '} are the same or different and each independently hydrogen, hydroxy, fluoro, or benzyloxy;

R ⁶ and R ^{6 '} are the same or different and each independently hydrogen or methyl.

More specifically, R ¹ and R ² are phenyl, unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, methoxy, dimethylamino, methyl, and bromo, or pyridinyl; Or methyl and iodo-substituted indolinyl formed by connecting R ¹ and R ² to each other.

More specifically, R ¹ may be phenyl, methoxyphenyl, dimethylaminophenyl, fluoromethylphenyl, methylphenyl or bromophenyl and R ² may be phenyl, methoxyphenyl, fluorophenyl, pyridinyl or dimethylaminophenyl . Alternatively, R ¹ and R ² may be connected to each other to form 2-iodo-2-methylindolinyl.

In another aspect, the present invention provides a compound represented by the following formula (1-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1-1]

In this formula,

R ¹ and R ² are the same or different, each independently represent a C ₅ -C ₁₄ aryl or C ₅ -C ₁₄ heteroaryl, wherein aryl or heteroaryl are halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy, and -NR ⁷ R ⁸ , or R ¹ and R ² may be connected to each other to form a 5- to 8-membered ring containing a nitrogen atom to which they are bonded, Said heterocyclic ring being fused to another C ₅ -C ₁₄ aryl or unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or C ₁ -C ₆ alkyl;

R ³ and R ^{3 'are} the same or different, each independently represent hydrogen, hydroxy, halogen, C _5-14 aryl -C _1-6 alkoxy, hydroxy C ₁ -C ₆ alkyl, or tri (C ₁ -C _6-alkyl) - silyloxy -C ₁ -C ₆ alkyl (wherein, tri (C ₁ -C ₆ alkyl) are all the same or may be configured as two or more different from each other (C ₁ -C ₆ alkyl)), and;

R ⁴ and R ^{4 'are} the same or different, each independently represent hydrogen, hydroxy, halogen, C ₅ -C ₁₄ aryl, or C _5-14 aryl -C _1-6 alkoxy;

R ⁵ and R ^{5 '} are the same or different and each independently is hydrogen, hydroxy, halogen, or C _5-14 aryl-C _1-6 alkoxy;

R ⁶ and R ^{6 '} are the same or different and each independently hydrogen or C ₁ -C ₆ alkyl,

R ⁷ and R ⁸ are the same or different and each independently represents hydrogen or C ₁ -C ₆ alkyl.

Specifically, in Formula 1-1, R ¹ and R ² are the same or different and each independently represents phenyl or pyridinyl, and R ¹ and R ² are fluoro, methoxy, dimethylamino, methyl, and Bromo, or indolinyl substituted by methyl, iodo, or both, wherein R < ¹ > and R < ² > are linked to each other;

R ³ and R ^{3 '} are the same or different and each independently is hydrogen, hydroxy, fluoro, benzyloxy, hydroxymethyl, or tert-butyldimethylsilyloxymethyl;

R ⁴ and R ^{4 '} are the same or different and each independently hydrogen, hydroxy, fluoro, phenyl, or benzyloxy;

R ⁵ and R ^{5 '} are the same or different and each independently hydrogen, hydroxy, fluoro, or benzyloxy;

R ⁶ and R ^{6 '} are the same or different and each independently hydrogen or methyl.

More specifically, R ¹ and R ² are phenyl, unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, methoxy, dimethylamino, methyl, and bromo, or pyridinyl; Or methyl and iodo-substituted indolinyl formed by connecting R ¹ and R ² to each other.

More specifically, R ¹ can be phenyl, methoxyphenyl, dimethylaminophenyl, fluoromethylphenyl, methylphenyl or bromophenyl, and R ² can be phenyl, methoxyphenyl, fluorophenyl, pyridinyl or dimethylaminophenyl . Alternatively, R ¹ and R ² may be connected to each other to form 2-iodo-2-methylindolinyl.

In another aspect, the present invention provides a compound represented by the following general formula (1-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1-2]

In this formula,

R ¹ and R ² are the same or different and are each independently C ₅ -C ₁₄ aryl which is unsubstituted or substituted by one or more C ₁ -C ₆ alkoxy.

Specifically, in Formula 1-2, R ¹ and R ² may be the same or different and each independently phenyl substituted with at least one C ₁ -C ₆ alkoxy.

More specifically, R ¹ and R ² may be phenyl substituted with one or more methoxy groups.

More specifically, the compound represented by Formula 1 may be a compound selected from the group consisting of the following compounds:

One) N, N-bis (4-methoxyphenyl) tetrahydrofuran-2-amine]

2) N, N-diphenyltetrahydrofuran-2-amine], N, N-diphenyltetrahydrofuran-

3) N, N-bis (4-methoxyphenyl) tetrahydro-2H-pyran-2-amine]

4) N, N-bis (4-methoxyphenyl) -4-phenyltetrahydro-2H-pyran-2-amine] ,

5) 3,3,4,4,5,5-hexafluoro-N, N-bis (4-methoxyphenyl) tetrahydro-2H-pyran-2-amine [ -hexafluoro-N, N-bis (4-methoxyphenyl) tetrahydro-2H-pyran-2-amine]

6) (3S) -3- ((2R, 3S) -3 - ((tert- butyldimethylsilyloxy) methyl) -N, N-bis (4- methoxyphenyl) tetrahydro- (tert-butyldimethylsilyloxy) methyl) -N, N-bis (4-methoxyphenyl) tetrahydro-2H- pyran-

7) (3S) -2- (bis (4-methoxyphenyl) amino) tetrahydro-2H-pyran- -2H-pyran-3-yl) methanol],

8) (2R, 3R, 3S, 5S) -3,4,5-tris (benzyloxy) -N, N-bis (4- methoxyphenyl) tetrahydro- 4S, 5S) -3,4,5-tris (benzyloxy) -N, N-bis (4- methoxyphenyl) tetrahydro-2H- pyran-

9) N1- (4- (dimethylamino) phenyl) -N4, N4-dimethyl-N1- (tetrahydro-2H-pyran- -N4, N4-dimethyl-N1- (tetrahydro-2H-pyran-2-yl) benzene- 1,4-diamine]

10) N- (4-methoxyphenyl) -N- (tetrahydro-2H-pyran-2-yl) ) pyridin-3-amine],

11) Phenyl-tetrahydro-2H-pyran-2-amine], and N- (4-fluorophenyl) -N-phenyltetrahydro-

12) 2-fluoro-5-methylphenyl) -N-phenyltetrahydro-2H-pyran-2-amine ],

13) N-phenyl-Nm-tolyltetrahydro-2H-pyran-2-amine [N-phenyl-Nm-tolyltetrahydro-2H-

14) (4-bromophenyl) -N-phenyltetrahydro-2H-pyran-2-amine], and N- (4-bromophenyl) -N-phenyltetrahydro-

15) 2H-pyran-2-amine], which is a compound represented by the following general formula (1): ???????? N- (4-methoxyphenyl) -N-p- tolyltetrahydro-

16) N-di-p-tolyltetrahydro-2H-pyran-2-amine [N, N-dip-tolyltetrahydro-2H-

17) N, N-bis (4-methoxyphenyl) -6-methyltetrahydro-2H-pyran-2-amine] ,

18) 2-iodo-2-methyl-1- (tetrahydro-2H-pyran-2-yl) indoline], 2-iodo-2- And

19) (2S, 3S, 3R, 5R) -3,4,5-tris (benzyloxy) -N, N-bis (4- methoxyphenyl) tetrahydro- 4R, 5R) -3,4,5-tris (benzyloxy) -N, N-bis (4-methoxyphenyl) tetrahydro-2H-pyran-2-amine].

In the specific examples of the present invention, the above-mentioned 19 compounds were synthesized.

The compounds of the present invention may exist in the form of a salt, particularly a pharmaceutically acceptable salt. Salts include, without limitation, salts commonly used in the art, such as acid addition salts formed by pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" of the present invention means a concentration that has a relatively non-toxic and harmless effective action in a patient, wherein the adverse effect due to the salt is an adverse effect of the compound &Quot; means all organic or inorganic addition salts.

The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration.

As the free acid, organic acids and inorganic acids can be used. As the inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. Examples of the organic acids include methanesulfonic acid, p- toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like can be used , But are not limited to these.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal salt or the alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the non-soluble salt salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically acceptable to produce sodium, potassium, or calcium salt, but not limited thereto. The corresponding silver salt can also be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

Pharmaceutically acceptable salts of the compounds of this invention include, unless otherwise indicated, salts of acidic or basic groups that may be present in the compounds of formula (I). For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of hydroxy groups, and the other pharmaceutically acceptable salts of amino groups include hydrobromides, sulphates, sulphates, phosphates, hydrogen phosphates (Hydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts and the like, ≪ / RTI >

The pharmaceutically acceptable salts of the 2-substituted tetrahydropyran or the 2-substituted tetrahydrofuran derivative of the present invention include 2-substituted tetrahydropyran or 2-substituted tetrahydrofuran derivative compounds, Of the compound of the present invention can be used without limitation.

In addition, the compound represented by Formula 1 according to the present invention includes not only pharmaceutically acceptable salts thereof but also solvates such as possible hydrates which can be prepared therefrom. The solvate of the compound represented by the formula (1) can be prepared from the compound represented by the formula (1) using methods known in the art.

In addition, the compound represented by Formula 1 according to the present invention may be prepared in crystalline form or amorphous form, and may be optionally hydrated or solvated when prepared in crystalline form. In the present invention, compounds containing various amounts of water as well as stoichiometric hydrates of the compound represented by the formula (1) may be included. Solvates of the compounds of formula (I) according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.

In another aspect, the present invention provides a process for producing a compound represented by the general formula (1-1), which comprises a step of converting a compound represented by the following general formula (2) into a compound represented by the general formula (1-1) by an oxidative cyclization reaction :

[Formula 1-1]

(2)

In this formula,

R ¹ and R ² are the same or different, each independently represent a C ₅ -C ₁₄ aryl or C ₅ -C ₁₄ heteroaryl, wherein aryl or heteroaryl are halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy, and -NR ⁷ R ⁸ , or R ¹ and R ² may be connected to each other to form a 5- to 8-membered ring containing a nitrogen atom to which they are bonded, Said heterocyclic ring being fused to another C ₅ -C ₁₄ aryl or unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or C ₁ -C ₆ alkyl;

R ³ and R ^{3 'are} the same or different, each independently represent hydrogen, hydroxy, halogen, C _5-14 aryl -C _1-6 alkoxy, hydroxy C ₁ -C ₆ alkyl, or tri (C ₁ -C _6-alkyl) - silyloxy -C ₁ -C ₆ alkyl (wherein, tri (C ₁ -C ₆ alkyl) are all the same or may be configured as two or more different from each other (C ₁ -C ₆ alkyl)), and;

R ⁴ and R ^{4 'are} the same or different, each independently represent hydrogen, hydroxy, halogen, C ₅ -C ₁₄ aryl, or C _5-14 aryl -C _1-6 alkoxy;

R ⁵ and R ^{5 '} are the same or different and each independently is hydrogen, hydroxy, halogen, or C _5-14 aryl-C _1-6 alkoxy;

R ⁶ and R ^{6 '} are the same or different and each independently hydrogen or C ₁ -C ₆ alkyl,

R ⁷ and R ⁸ are the same or different and each independently represents hydrogen or C ₁ -C ₆ alkyl.

The reaction can be represented by the following reaction formula (1).

[Reaction Scheme 1]

  (2)

In this method, the oxidative cyclization reaction can be carried out using iodine or a hypervalent iodine oxidant in the presence of a catalytic amount of a radical as a reaction to form the tetrahydropyran ring.

The radical used as a catalytic amount in the cyclization reaction may be TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl) oxidanyl) or a derivative thereof. The radical of the catalytic amount is not limited to the TEMPO derivative, and as an example thereof, tris-4-bromophenyl ammonium hexachloroantimonate (TBPA) is used.

As the iodide oxidant, preferably BAIB (bis (acetoxy) iodobenzene) or PIFA (phenyliodine bis (trifluoroacetate)) may be used.

As the solvent, chloroform may be used, but it is not limited thereto.

The compound of formula (2) can be obtained by a method in which a substituted or unsubstituted glutaric acid monoester is commercially purchased or a glutaric acid monoester obtained by using sodium methoxide from glutaric anhydride is reacted with N, N-substituted Acyl-substituted amine derivative to obtain a glutaric amide ester and reducing it with a reducing agent such as LAH to obtain an N, N-substituted-1,5-amino alcohol.

Alternatively, the compound of formula 2 may be prepared from 2-hydroxytetrahydropyran and N, N-substituted amine derivatives of reduced amide according to the literature (Org. Lett., 2006, 8 (15): 3307-3310) Can be prepared by obtaining an N, N-substituted-1,5-amino alcohol from a stereoselective 2-alkylmalonamide ester synthesized via a reductive amination reaction.

As another alternative, when the compound having the substituent is affected by the reduction reaction, the compound of the formula 2 may be O-silyl (2-ethylhexyl) silane synthesized according to J. Am. Chem. Soc., 2015, 137: 6120-6123 N-substituted < RTI ID = 0.0 > 1, 5-amino < / RTI > alcohol from the reaction to remove the silyl protecting group after the substitution reaction of the substituted 5-iodopentan- have.

Preferably, the production process of the present invention may further include filtration, drying, washing, refining, or a combination thereof. The filtration, drying, washing, and purification steps may be carried out using any method known in the art without limitation.

In another aspect, the present invention provides a process for preparing a compound represented by the general formula (1-2), which comprises the step of converting the compound represented by the general formula (3) into the compound represented by the general formula (1-2) by an oxidative cyclization reaction:

[Formula 1-2]

(3)

In this formula,

R ¹ and R ² are the same or different and are each independently C ₅ -C ₁₄ aryl which is unsubstituted or substituted by one or more C ₁ -C ₆ alkoxy.

The reaction can be represented by the following reaction formula (2).

[Reaction Scheme 2]

  (3)

In this method, the oxidative cyclization reaction can be carried out using iodine or a hypervalent iodine oxidant in the presence of a catalytic amount of a radical as a reaction for forming a tetrahydrofuran ring.

The radical used as a catalytic amount in the cyclization reaction may be TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl) oxidanyl) or a derivative thereof, but is not limited thereto.

As the iodide oxidizing agent, BAIB (bis (acetoxy) iodobenzene) or PIFA (phenyliodine bis (trifluoroacetate)) may be preferably used.

As the solvent, chloroform may be used, but it is not limited thereto.

The compound of Formula 3 may be prepared by reacting an N, N-substituted amine derivative with a succinyl halide alkly ester such as ethyl 4-chloro-4-oxobutanoate ) To obtain a succinamide ester, which is then reduced with a reducing agent such as LAH to obtain an N, N-substituted-1,4-amino alcohol.

Preferably, the production process of the present invention may further include filtration, drying, washing, refining, or a combination thereof. The filtration, drying, washing, and purification steps may be carried out using any method known in the art without limitation.

In another aspect, the present invention provides a process for preparing a compound represented by the general formula (1-3), which comprises the step of converting the compound represented by the general formula (4) into the compound represented by the general formula (1-3) by an oxidative cyclization reaction:

[Formula 1-3]

[Chemical Formula 4]

In this formula,

R ¹ and R ² are the same or different, each independently represent a C ₅ -C ₁₄ aryl or C ₅ -C ₁₄ heteroaryl, wherein aryl or heteroaryl are halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy, and -NR ⁷ R ⁸ , or R ¹ and R ² may be connected to each other to form a 5- to 8-membered ring containing a nitrogen atom to which they are bonded, Said heterocyclic ring being fused to another C ₅ -C ₁₄ aryl or unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or C ₁ -C ₆ alkyl;

R ⁵ is hydrogen, hydroxy, halogen, or C _5-14 aryl-C _1-6 alkoxy;

R ⁷ and R ⁸ are the same or different and each independently represents hydrogen or C ₁ -C ₆ alkyl;

PG represents a protecting group.

The reaction can be represented by the following reaction formula (3).

[Reaction Scheme 3]

  (4)

In this method, the oxidative cyclization reaction can be carried out using iodine or a hypervalent iodine oxidant in the presence of a catalytic amount of a radical as a reaction to form the tetrahydropyran ring.

The radical used as a catalytic amount in the cyclization reaction may be TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl) oxidanyl) or a derivative thereof, but is not limited thereto.

As the iodide oxidizing agent, BAIB (bis (acetoxy) iodobenzene) or PIFA (phenyliodine bis (trifluoroacetate)) may be preferably used.

As the solvent, chloroform may be used, but it is not limited thereto.

In Formula 1-3 and Formula 4, PG is a protecting group and may be, but not limited to, tert-butyldimethylsilyloxymethyl.

The compound of formula 4 can be prepared by reducing the stereoselective malonamide ester obtained according to the literature (Chem. Comm., 2009, 782; Org. Lett., 2010, 12: 2826) 2S) -alkyl-1,3-aminoalcohols were synthesized and the N, N-substituted-4-alkyl-1, 5-aminoalcohol was reacted with hydrogen peroxide by the introduction of O- substituent into the hydroxyl group and the hyrdoboration. . ≪ / RTI >

Preferably, a compound of formula 1-6 can be obtained from the compound of formula 1-3, further comprising a deprotection step in the process:

[Chemical Formula 1-6]

In this formula,

R ¹ and R ² are the same or different, each independently represent a C ₅ -C ₁₄ aryl or C ₅ -C ₁₄ heteroaryl, wherein aryl or heteroaryl are halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy, and -NR ⁷ R ⁸ , or R ¹ and R ² may be connected to each other to form a 5- to 8-membered ring containing a nitrogen atom to which they are bonded, Said heterocyclic ring being fused to another C ₅ -C ₁₄ aryl or unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or C ₁ -C ₆ alkyl;

R ⁵ is hydrogen, hydroxy, halogen, or C _5-14 aryl-C _1-6 alkoxy;

R ⁷ and R ⁸ are the same or different and each independently represents hydrogen or C ₁ -C ₆ alkyl.

On the other hand, the deprotection reaction of a hydroxy group can be carried out by selecting a suitable method according to a protecting group among known methods (see Protective Groups in Organic Synthesis, 4th Ed.).

Preferably, the production process of the present invention may further include filtration, drying, washing, refining, or a combination thereof. The filtration, drying, washing, and purification steps may be carried out using any method known in the art without limitation.

In another aspect, the present invention provides a process for preparing a compound represented by formula (1-4), comprising the step of converting a compound represented by formula (5) into an compound represented by formula (1-4) by an oxidative cyclization reaction:

[Formula 1-4]

[Chemical Formula 5]

In this formula,

R ¹ and R ² are the same or different, each independently represent a C ₅ -C ₁₄ aryl or C ₅ -C ₁₄ heteroaryl, wherein aryl or heteroaryl are halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy, and -NR ⁷ R ⁸ , or R ¹ and R ² may be connected to each other to form a 5- to 8-membered ring containing a nitrogen atom to which they are bonded, Said heterocyclic ring being fused to another C ₅ -C ₁₄ aryl or unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or C ₁ -C ₆ alkyl;

R ⁷ and R ⁸ are the same or different and each independently represent hydrogen or C ₁ -C ₆ alkyl;

PG means a protecting group.

The reaction can be represented by the following reaction formula (4).

[Reaction Scheme 4]

  (5)

In this method, the oxidative cyclization reaction can be carried out using iodine or a hypervalent iodine oxidant in the presence of a catalytic amount of a radical as a reaction to form the tetrahydropyran ring.

The radical used as a catalytic amount in the cyclization reaction may be TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl) oxidanyl) or a derivative thereof, but is not limited thereto.

As the iodide oxidizing agent, BAIB (bis (acetoxy) iodobenzene) or PIFA (phenyliodine bis (trifluoroacetate)) may be preferably used.

As the solvent, chloroform may be used, but it is not limited thereto.

In the general formulas 1-4 and 5, PG is a protecting group and may be tert-butyldimethylsilyloxymethyl, but is not limited thereto.

The compound of Formula 5 can be obtained by selectively introducing an O-substituent and iodinating 2-alkyl-1,3-dialcohols obtained according to the European Journal of Organic Chemistry, 2012, (29): 5818-5827 Iodide is obtained and N, N-substituted-1,3-aminoalcohol is synthesized through substitution reaction with N, N-substituted amine derivative. Then, after the hyrdoboration, hydrogenation treatment with N, N -Substituted-4-alkyl-l, 5-aminoalcohols.

Preferably, the compound of formula 1-7 can be obtained from the compound of formula 1-4, further comprising a deprotection step in the process:

[Chemical Formula 1-7]

In this formula,

R ¹ and R ² are the same or different, each independently represent a C ₅ -C ₁₄ aryl or C ₅ -C ₁₄ heteroaryl, wherein aryl or heteroaryl are halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy, and -NR ⁷ R ⁸ , or R ¹ and R ² may be connected to each other to form a 5- to 8-membered ring containing a nitrogen atom to which they are bonded, Said heterocyclic ring being fused to another C ₅ -C ₁₄ aryl or unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or C ₁ -C ₆ alkyl;

R ⁷ and R ⁸ are the same or different and each independently represents hydrogen or C ₁ -C ₆ alkyl.

On the other hand, the deprotection reaction of a hydroxy group can be carried out by selecting a suitable method according to a protecting group among known methods (cf. Protective Groups in Organic Synthesis, 4th Ed.).

Preferably, the production process of the present invention may further include filtration, drying, washing, refining, or a combination thereof. The filtration, drying, washing, and purification steps may be carried out using any method known in the art without limitation.

The compound represented by the formula (1) according to the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof can be used as an example of industrial applicability of synthesized compounds as a microglial cell activated by LPS (lipid polysaccharide) (6-hydroxydopamine) and dopaminergic cell death (6-OHDA) in the prevention and treatment of neurological diseases.

According to another embodiment of the present invention, there is provided a pharmaceutical composition for the prevention and treatment of neurological diseases, comprising the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The neurological disease may be a neurological disease requiring treatment for inhibiting microglial cell activation. In addition, the nervous system diseases may include cerebral nervous system and central nervous system diseases.

More specifically, the nervous system disease is a neurological disease that requires treatment to inhibit microglial cell activation, more preferably to inhibit the activation of microglial cells by acting on a dopamine receptor. Examples thereof include ischemic brain diseases , Degenerative brain diseases, Alzheimer's disease, Parkinson's disease, Huntington's disease, and the like, but the present invention is not limited thereto.

In the substantia nigra, which is distributed in the middle of the brain, microglial cells are distributed at a high concentration and D1 or D2 subtype of dopamine receptor is known to exist in microglial cells. It is also known that dopamine binds to the D1 receptor and regulates the amount of NO produced by regulating the activity of microglial cells. Overactivation of microglia leads to destruction of dopaminergic neurons. The novel 2-substituted tetrahydropyran of the present invention has an effect of inhibiting the expression of NO which is an inhibitory index of "microglia activation" induced by LPS (lipid polysaccharide), and the effect of inhibiting dopamine cell death by 6-OHDA This mechanism is useful for treating neurological diseases. However, the effect of the compound of the present invention is not necessarily limited to the above mechanism.

The compound of formula (I) according to the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt, hydrate or solvate thereof has cytoprotective activity per se. However, the compound is absorbed into the body, It does not exclude the possibility that the product or the like may exhibit a pharmacological action as an agonist.

Accordingly, the pharmaceutical dosage form of the compound of formula (I) according to the present invention, its stereoisomer or pharmaceutically acceptable salt, hydrate or solvate thereof may be used in the form of a pharmaceutically acceptable salt or solvate thereof .

As used herein, the term "prophylactic " may refer to any action that inhibits or delays the onset of a neurological disease by administering the pharmaceutical composition of the present invention to a subject.

The term "treatment" as used in the present invention means all actions for improving or alleviating symptoms of neurological diseases by administering the pharmaceutical composition according to the present invention to a subject.

The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, excipient or diluent.

As used herein, the term "pharmaceutically acceptable carrier" may mean a carrier or diluent that does not disturb the biological activity and properties of the compound being injected, without irritating the organism. The type of the carrier that can be used in the present invention is not particularly limited, and any carrier conventionally used in the art and pharmaceutically acceptable may be used. Non-limiting examples of the carrier include saline, sterilized water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol and the like. These may be used alone or in combination of two or more. If necessary, other conventional additives such as an antioxidant, a buffer and / or a bacteriostatic agent may be added and used.

The pharmaceutical composition may be in the form of tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations and suppositories May have one formulation, and may be various forms of oral or parenteral administration. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may contain one or more excipients such as starch, calcium carbonate, sucrose or lactose lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions and syrups. Common diluents such as water and liquid paraffin are used in addition to various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like. . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used as the non-aqueous solvent and suspension agent. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.

The pharmaceutical composition of the present invention can also be used as a single preparation. In addition, one or more kinds of therapeutic agents for other neurological diseases may be additionally contained and used as a combined preparation.

In another aspect, the present invention provides a method for preventing or treating a neurological disease, comprising the step of administering the pharmaceutical composition to an individual in an effective amount. The pharmaceutical composition refers to a pharmaceutical composition for preventing or treating a neurological disease, comprising the compound of the above-mentioned formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

As used herein, the term "administering" means introducing the pharmaceutical composition of the present invention to a subject in an appropriate manner, and the administration route of the pharmaceutical composition of the present invention is not limited to any general route ≪ / RTI > Intraperitoneal, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrapulmonary, rectal, intrauterine or intracerbroventricular injections, , But is not limited thereto.

As used herein, the term "individual" refers to all animals, including humans, who have developed or are capable of developing neurological diseases. The pharmaceutical composition of the present invention can be administered to an individual to effectively prevent or treat a neurological disease.

The term "effective amount" means an amount that is sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and does not cause side effects, in a pharmaceutically effective amount, And other factors including drugs used in combination or at the same time, such as age, body weight, health status, type of disease, severity, activity of the drug, sensitivity to the drug, administration method, administration time, administration route, Can be readily determined by those skilled in the art according to factors well known in the medical arts. Generally, the active ingredient may be administered at a dose of about 0.01 mg / kg / day to 1000 mg / kg / day. When administered orally, a dose of 50 to 500 mg / kg may be appropriate, and may be administered at least once a day.

The novel 2-substituted tetrahydropyran or 2-substituted tetrahydrofuran derivative compounds, stereoisomers, or pharmaceutically acceptable salts thereof according to the present invention are useful as an example of industrial applicability by LPS (lipid polysaccharide) Can be effectively used as a pharmaceutical composition for the prevention or treatment of neurological diseases through inhibition of induced "microglial activation" and inhibition of cell death by 6-OHDA (6-hydroxydopamine) . Further, the production process according to the present invention has the effect of efficiently synthesizing a 2-substituted tetrahydropyran or a 2-substituted tetrahydrofuran derivative.

Figure 1 shows the production of nitrite in the neurotoxicant (LPS) -treated murine microglial BV-2 cells of Examples 6 and 7 of the invention and Comparative Example 6-shogaol. FIG.
FIG. 2 is a graph showing the effect of compounds of the present invention on cell survival in LPS-reduced murine microglial BV-2 cells. FIG.
3 is a graph showing an increase in the survival rate of a cell line (SH-SY5Y) treated with a compound 6 of Example of the present invention and 6-hydroxy-dopamine by a comparative example "Ropinirole" compound.

While the invention is susceptible to various modifications and alternative forms, specific embodiments thereof are shown by way of example in the drawings and will herein be described in detail. It should be understood, however, that the invention is not intended to be limited to the particular forms disclosed, but includes all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.

Hereinafter, the present invention will be described in detail.

Example  One: N, N - Bis (4-methoxyphenyl) tetrahydrofuran -2- Amine  synthesis

Step 1) Ethyl 4- Bis -4- Methoxyphenylamino -4- Oxobutanoate ( ethyl 4-bis (4-methoxyphenyl) amino-4-oxobutanoate: 3a )

3 g of N, N'-dimethoxydiphenylamine 2a was dissolved in 48 mL of methylene chloride (CH ₂ Cl ₂ ), and the mixture was stirred in an ice-water bath. Then, ethyl 4- 2.56 mL of ethyl 4-chloro-4-oxobutanoate ( 1 ) was slowly added dropwise. After confirming that the product no longer increases on TLC, the reaction mixture was diluted with methylene chloride by adding distilled water to the ice bath, and washed with water and a saturated aqueous solution of sodium chloride. The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using a mobile phase of Acetone: Hex (1: 5) to give 4.9 g of ethyl 4-bis-4-methoxyphenylamino- Ethyl 4-bis (4-methoxyphenyl) amino-4-oxobutanoate: 3a was obtained.

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.15 ~ 7.24 (m, 4H), 6.80 ~ 6.91 (m, 4H), 4.09 ~ 4.13 (m, 2H), 3.79 (s, 3H), 3.73 (s, 3H), 2.57-2.61 (m, 2H), 2.48-2.50 (m, 2H), 1.21-1.23 (m, 3H);

¹³ C-NMR (600 MHz, CDCl ₃ ) δ 176.9, 173.1, 172.1 159.0, 157.5, 135.9, 135.7, 129.6, 127.4, 115.0, 114.1, 60.5, 55.5, 55.4, 30.0, 29.0, 14.2 ppm.

Step 2) 4- Bis -4- Methoxyphenyl - Amino butanol ( 4-bis-4- 메틸oxyphenyl -aminobutan-1-ol: < / RTI > 4a )

Anhydrous butyl ether was added dropwise to lithium aluminum hydride (LiAlH ₄ ) in an anhydrous vacuum state, and the mixture was refluxed at 140 캜 under an argon stream, heated and stirred. A solution of 2 g of ethyl 4-bis-4-methoxyphenylamino-4-oxobutanoate ( 3a ) in anhydrous butyl ether was transferred to a cannula at 140 ° C and stirred at the same temperature for 30 minutes. The reaction solution was cooled in an ice water bath, and the reaction was completed by adding 23 mL of diethyl ether and distilled water (1.7 mL). After completion of the reaction, 1.7 mL of 15% sodium hydroxide and 5.1 mL of water were added in this order and the mixture was stirred. , Dried, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a mobile phase of EtOAc: Hex (1: 1) to give 4-bis-4-methoxyphenyl-aminobutan-1 -ol: 4a ).

^{1 H-NMR (600 MHz,} CDCl 3) δ 6.88 ~ 6.89 (m, 4H), 6.81 ~ 6.87 (m, 4H), 3.78 (s, 6H), 3.63 ~ 3.65 (m, 2H), 3.59 ~ 3.61 ( m, 2H), 1.67-1.72 (m, 2H), 1.60-1.65 (m, 2H);

¹³ C-NMR (600 MHz, CDCl ₃ )? 154.3, 142.50, 122.2, 114.6, 62.7, 55.61, 52.72, 30.38, 24.08 ppm.

Step 3) 4- Bis -4- Methoxyphenyl -Tetrahydrofuran-2- Amine ( N, N - bis (4-methoxyphenyl) tetrahydrofuran-2-amine < / RTI >

200 mg of 4-bis-4-methoxyphenyl-aminobutanol ( 4a ) was dissolved in 6 mL of chloroform, stirred in an ice water bath, and 2 mL of a saturated aqueous sodium bicarbonate solution was added dropwise. 200 mg of iodine and TEMPO (2,2,6,6-Tetramethylpiperidin-1-yl) oxyl were added and stirred. When no further increase in product was observed in the reaction solution, the reaction mixture was diluted with diethyl ether, diluted with water and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium bisulfite solution, And washed. The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was _{Acetone: Hex: NH 4 OH (} aq) (1:10: 0.1) carried 90 mg of purified by column chromatography on silica gel using the mobile phase of the example compounds, 4-bis-4-methoxy Phenyl-tetrahydrofuran-2-amine (N, N-bis (4-methoxyphenyl) tetrahydrofuran-2-amine).

^{1 H-NMR (600 MHz,} CDCl 3) δ 1.29 ~ 1.44 (m, 3H), 1.87 ~ 1.91 (m, 1H), 3.29 (s, 6H), 3.76 ~ 3.79 (m, 1H), 3.82 ~ 3.86 ( m, 1 H), 4.69-4.71 (m, 1 H), 6.74-6.81 (m, 4H), 7.29-7.31 (m, 4H);

¹³ C-NMR (600 MHz, CDCl ₃ ) 隆 17.21, 33.97, 54.61, 66.06, 87.46, 95.47, 114.28, 125.89, 141.35, 156.04 ppm;

HRMS (ESI): calcd for C 18 H 21 NO 3 [M]: 299.1521, found: 299.1521.

Example  2: N, N - Diphenyltetrahydrofuran -2- Amine  synthesis

The procedure of Example 1 was repeated except that diphenylamine was used instead of N, N'-dimethoxydiphenylamine in Step 1 of Example 1.

^{1 H-NMR (600 MHz,} CDCl 3) δ 6.8 ~ 7.3 (m, 10H), 4.63 ~ 4.65 (m, 1H), 3.68 ~ 3.80 (m, 2H), 2.04 ~ 2.05 (m, 2H), 1.76 ~ 1.85 (m, 2H) ppm

Example  3: N, N - Bis (4-methoxyphenyl) tetrahydro -2H-pyran-2- Amine  synthesis

Step 1) methyl  5- Bis -4- Methoxyphenylamino -5- Oxopentanoate (methyl 5- (bis (4-methoxyphenyl) amino) -5-oxopentanoate: 3c )

5 g of N, N'-dimethoxydiphenylamine ( 2a ) and 530 mg of dimethyl amino pyridine were dissolved in 50 mL of anhydrous methylene chloride and stirred. The reaction solution was stirred in an ice water bath, and 5.5 mL of 5-methoxy-5-oxopentanoic acid was added dropwise thereto, followed by sufficient stirring at the same temperature. 8.4 g of EDC (1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide) was slowly added dropwise to the stirred reaction solution (portionwise addition). After confirming that the product no longer increases on the TLC, the reaction mixture was diluted with methylene chloride by adding distilled water to the ice bath, and then washed with water and a saturated aqueous solution of sodium chloride. The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a mobile phase of EtOAc: Hex (1: 1) to give 3.1 g of methyl 5-bis-4-methoxyphenylamino-5-oxopentanoate - (bis (4-methoxyphenyl) amino) -5-oxopentanoate.

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.16 ~ 7.17 (m, 4H), 6.82 ~ 6.90 (m, 4H), 3.79 (s, 3H), 3.74 (s, 3H), 3.6 (s, 3H) , 2.34 ~ 2.36 (m, 2H), 2.27 ~ 2.39 (m, 2H), 1.93 ~ 1.97 (m, 2H) ppm.

Step 2) and Step 3) N, N - Bis (4-methoxyphenyl) tetrahydro -2H-pyran-2- Amine  Produce

The same procedure as in the step 2) and the step 3) of Example 1 was carried out except that methyl 5-bis-4-methoxyphenylamino-5-oxopentanoate obtained in the above step 1) The title compound N, N-bis (4-methoxyphenyl) tetrahydro-2H-pyran-2-amine was synthesized in 70% yield.

^{1 H-NMR (600 MHz,} CDCl 3) δ 1.20 ~ 1.30 (m, 2H), 1.34 ~ 1.41 (m, 2H), 1.52 ~ 1.54 (m, 2H), 3.30 ~ 3.36 (m, 7H), 3.91 ~ 3.93 (m, 1H), 4.88-4.90 (m, 1H), 6.83-6.85 (m, 4H), 7.15-7.18 (m, 4H);

¹³ C-NMR (600 MHz, CDCl ₃ )? 24.03, 25.42, 31.44, 54.68, 66.66, 87.63, 114.23, 125.33, 140.80, 155.87 ppm.

Alternatively, instead of steps 1 and 2 described above, synthesis was carried out through the following route.

The compound of Formula 2 can be prepared by reacting an O-silyl substituted 5-iodopentan-1-ol synthesized according to the literature (J. Am. Chem. Soc., 2015, 137: 6120-6123) N-substituted-1, 5-aminoalcohols from the reaction of removing the silyl protecting group after the substitution reaction of the substituted amine derivative.

Example  4: N, N - Bis (4- Methoxyphenyl )-4- Phenyltetrahydro -2H-pyran-2- Amine  synthesis

In the same manner as in Example 3 except that 3-phenyl-5-methoxy-5-oxopentanoic acid was used instead of 5-methoxy-5-oxopentanoic acid in the step 1), the title compound N, 4-methoxyphenyl) -4-phenyltetrahydro-2H-pyran-2-amine was synthesized in 89% yield.

^{1 H-NMR (600 MHz,} CDCl 3) δ 1.30 ~ 1.34 (m, 1H), 1.44 ~ 1.51 (m, 1H), 1.59 ~ 1.65 (m, 1H), 1.87 ~ 1.90 (m, 1H), 2.54 ~ (M, 1H), 3.97 (m, 1H), 3.31 (s, 6H), 3.34 6.93 ~ 6.95 (m, 2H), 7.00 ~ 7.03 (m, 1H), 7.07 ~ 7.09 (m, 2H), 7.14 ~ 7.16 (m, 4H);

¹³ C-NMR (600 MHz, CDCl ₃ ) 隆 32.87, 39.15, 54.64, 65.99, 87.73, 114.27, 125.45, 126.25, 127.84, 127.97, 128.46, 140.79, 145.25, 155.96 ppm.

Example  5: 3,3,4,4,5,5- Hexafluoro - N, N - Bis (4-methoxyphenyl) tetrahydro -2H-pyran-2-amine < / RTI &

Step 1) methyl  5- Bis -4- Methoxyphenylamino -2,2,3,3,4,4- Hexafluoro -5- Oxopentanoate (methyl 5- ( bis (4-methoxyphenyl) amino ) -2,2,3,3,4,4- hexafluoro -5-oxopentanoate: 3e )

1.67 g of N, N ' -dimethoxydiphenylamine ( 2a ) and 178 mg of dimethylaminopyridine were mixed with 5 mL of tetrahydrofuran, and the mixture was stirred in an ice water bath. To the cooled reaction solution was added 3,3,4,4,5,5-hexafluorodihydro-2H-pyran-2,6 (H) -dione (3,3,4,4,5,5-hexafluorodihydro-2H -pyran-2,6 (3H) -dione) was added drop-wise. The temperature of the mixture was then raised to about 10 DEG C and the mixture was stirred at the same temperature for 1 hour. 1.4 g of compound EDC (1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide) and 1 mL of methanol were added to the obtained reaction product, and the mixture was stirred at room temperature for 3 hours. After confirming that the product no longer increased on TLC, the obtained solution was allowed to stand, and ethyl acetate was sufficiently added thereto, followed by dropwise addition of a 5% aqueous hydrogen chloride solution, followed by separation, and the organic layer was recovered. The resulting organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a mobile phase of EtOAc: Hex (1: 1) to give 1 g of methyl 5-bis-4-methoxyphenylamino- 4-methoxyphenylamino) -2,2,3,3,4,4-hexafluoro-5-oxopentanoate: 3e ) was obtained.

Step 2) and Step 3) 3,3,4,4,5,5- Hexafluoro - N, N - Bis (4-methoxyphenyl) tetrahydro -2H-pyran-2-amine < / RTI &

Except that methyl 5-bis-4-methoxyphenylamino-2,2,3,3,4,4-hexafluoro-5-oxopentanoate obtained in the above step 1) was used as a reactant In the same manner as in step 2) and step 3) of Example 1, the title compound 3,3,4,4,5,5-hexafluoro-N, N-bis (4-methoxyphenyl) tetrahydro-2H-pyran-2-amine was synthesized in 45% yield.

¹ H-NMR (600 MHz, C ₆ D ₆ )? 7.10 -7.13 (m, 4H), 6.69-6.72 (m, 4H), 5.10-5.14 3.25 (s, 6H), 2.89 - 2.97 (m, 1H);

¹³ C-NMR (150 MHz, C ₆ D ₆ )? 157.7, 140.3 114.9, 88.0, 78.0, 70.7, 65.2, 63.6, 55.2, 34.4, 32.7, 29.7, 25.5, 23.5, 14.7 ppm;

^{HRMS (ESI +): calcd for} C 19 H 23 NO 3 + [M + H] +: 422.1191, found: 422.1195.

Example  6: ( 2R, 3S ) -3 - (( tert - Butyldimethylsilyloxy ) methyl ) - N, N - Bis (4-methoxyphenyl) tetrahydro -2H-pyran-2-amine < / RTI &

Step 1) Synthesis of (2S) -N-tert- Butyl dimethylsilyloxymethyl  4-methoxyphenyl aniline ((S) -N- (2 - ((tert-butyldimethylsilyl) oxy) methyl) pent- 1-yl) -4-methoxy-N- (4-methoxyphenyl) aniline: 3f )

(2S) -bis-4-methoxyphenylaminomethylpent-4-methoxyphenylaminomethylpent-4-ene-1-ol was prepared by the method described in the literature (Chem. Comm., 2009, 4-en-1-ol) was synthesized and mixed with 460 mg of tert-butyldimethylsilyl chloride and 400 mg of imidazole, and anhydrous tetrahydropyran was added dropwise. After stirring at room temperature, 1 mL of diisopropylethylamine was slowly added dropwise and the mixture was stirred. After confirming that the product no longer increases on TLC, the reaction solution was diluted with EtOAc and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using a mobile phase of EtOAc: Hex (3: 1) to give 1 g of (2S) -N-tert- butyldimethylsilyloxymethylphen-4- 4-methoxyphenyl aniline ((S) -N- (2 - ((tert-butyldimethylsilyl) oxy) methyl) pent- methoxy-N- (4-methoxyphenyl) aniline: 3f ).

^{1 H-NMR (600 MHz,} CDCl 3) δ 6.93 ~ 6.94 (m, 4H), 6.79 ~ 6.80 (m, 4H), 5.71 ~ 5.78 (m, 1H), 4.98 ~ 5.01 (m, 2H), 3.77 ( 1H, s, 6H), 3.67-3.73 (m, 2H), 3.47-3.53 (m, 2H), 2.13-2.15 6H);

³ C-NMR (600 MHz, CDCl ₃ ) δ 154.4, 143.2, 137.0, 122.5, 116.5, 114.7, 62.5, 55.7, 54.3, 39.1, 33.9, 26.1, 18.4, -5.3, -5.4 ppm.

Step 2) methyl  ( 2S ) -5- Bis -4- Methoxyphenylamino -4- tert - Butyl dimethylsilyloxymethyl  Pentan-1-ol (( S ) -5- bis (4-methoxyphenyl) amino -4- tert -butyldimethylsilyloxymethylpentan-1-ol: < / RTI > 4f )

After 590 mg of the vacuum-treated 9-BBN was dissolved in anhydrous tetrahydropyran, the butyldimethylsilyloxymethylphen-4-en-1-yl-4-methoxy-N- ( 3f ) was slowly and carefully added at room temperature, followed by stirring for one day. 20 mL of methanol, 2.0 mL of a 30% aqueous hydrogen peroxide solution and 3.0 mL of a 3 molar aqueous sodium hydroxide solution were carefully added dropwise to the reaction solution at 0 째 C, and the mixture was stirred sufficiently. The reaction solution was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The crude product was purified by column chromatography on silica gel using a mobile phase of EtOAc: Hex (1: 1) to give 560 mg of methyl ( 2S ) -5-bis-4-methoxyphenylamino- ( S ) -5-bis (4-methoxyphenyl) amino-4-tert-butyldimethylsilyloxymethylpentan-1-ol: 4f ).

^{1 H-NMR (600 MHz,} CDCl 3) δ 6.91 ~ 6.92 (m, 4H), 6.79 ~ 6.81 (m, 4H), 3.77 (s, 6H), 3.70 ~ 3.74 (m, 2H), 3.58 ~ 3.60 ( 1H, shielding with water peaks, 1.41-1.44 (m, 2H), 3.54-3.56 (m, 1H), 3.44-3.47 2H), 0.90 (s, 9H), 0.03 (s, 6H);

¹³ C-NMR (600 MHz, CDCl ₃ )? 154.3, 143.3, 122.5, 114.7, 63.4, 62.7, 55.8, 54.8, 39.1, 30.4, 26.1, 25.3, 18.4, -5.3, -5.4 ppm.

Step 3) ( 2R, 3S ) -3 - (( tert - Butyldimethylsilyloxy ) methyl ) - N, N - Bis (4-methoxyphenyl) tetrahydro -2H-pyran-2-amine < / RTI &

The title compound was prepared by the same procedure as described in step 1 of Example 1, except that methyl (2S) -5-bis-4-methoxyphenylamino-4-tert- butyldimethylsilyloxymethylpentan- 3, but it was possible to obtain not only iodine as an oxidizing agent but also bisacetoxy-iodobenzene or bistrifluoroacetoxy-iodobenzene with an oxidizing agent. Further, in place of the saturated aqueous solution of sodium bicarbonate, a solution of the title compound (3R) -3-tert-butyldimethylsilyloxymethyl-N, N-bis-4-methoxyphenyltetrahydro -2H-pyran-2-amine ((3R) -3-tert-butyldimethylsilyloxymethyl-N, N-bis (4-methoxyphenyl) tetrahydro-2H- pyran-2-amine) was obtained in a yield of 60%.

¹ H-NMR (400 MHz, C ₆ D ₆ )? 7.35-7.37 (m, 4H), 6.80-6.83 (m, 4H), 5.10 (d, J = 10 Hz, 1H) 1H), 3.79-3.83 (m, 1H), 3.49-3.52 (m, 1H), 3.31 (s, 6H), 3.18-3.25 (m, 1H), 1.54-1.65 (m, 1H), 1.42-1.47 (m, 1H), 1.21-1.24 3H);

¹³ C-NMR (600 MHz, C ₆ D ₆ ) δ 155.9, 126.0, 114.2, 91.0, 67.3, 63.7, 54.6, 39.9, 27.0, 26.0, 18.2, -5.6, -5.7 ppm.

Example  7: (( 2R, 3S )-2-( Bis (4-methoxyphenyl) amino ) Tetrahydro -2H-pyran-3-yl) methanol Synthesis of

20 mg of the title compound of Example 6 was dissolved in 1 mL of anhydrous tetrahydrofuran and 20 uL of a 1.0 M tetrabutylammonium fluoride tetrahydrofuran solution was added dropwise. The disappearance of all of the substrates on the TLC was observed, and water was added to the reaction solution to terminate the reaction. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient mobile phase gradient from EtOAc: Hex (2: 1) to EtOAc to give 5 mg of the title compound (3R) -2-Bis-4-methoxyphenyltetrahydro -2H-2-pyran-3-yl) methanol ((3R) -2-bis (4-methoxyphenyl) tetrahydro-2H- pyran-3-yl) methanol.

^{1 H-NMR (400 MHz,} C 6 D 6) δ 7.31 ~ 7.33 (m, 4H), 6.78 ~ 6.80 (m, 4H), 4.99 (d, J = 9.6 Hz, 1H), 3.84 ~ 3.86 (m, 1H), 3.53-3.55 (m, 1H), 3.39-3.42 (m, 1H), 3.31 (s, 6H), 3.10-3.14 m, 1H), 1.35-1.38 (m, 1H), 1.25-1.28 (m, 1H), 1.15-1.20 (m, 1H);

¹³ C-NMR (600 MHz, C ₆ D ₆ )? 156.4, 126.5, 114.6, 92.5, 67.5, 64.4, 55.0, 39.8, 27.0, 26.0 ppm.

Example  8: ( 2R, 3R, 4S, 5S ) -3,4,5- Tris ( Benzyloxy ) - N, N - Bis (4-methoxyphenyl) tetrahydro -2H-pyran-2-amine < / RTI &

Step 1) Synthesis of (2S, 3R, 4S) -2,3,4-tris (benzyloxy) -5- (bis (4- methoxyphenyl) amino) pentan- -2,3,4-tris (benzyloxy) -5- (bis (4-methoxyphenyl) amino) pentan- 4g )

420 mg of 2,3,4-tris-O- (phenylmethyl) -α-L-arabinose (N, N'- 230 mg of 4,4-dimethoxydiphenylamine ( 2a ) were mixed, and 10 mL of ethyl acetate was added dropwise. The reaction solution was stirred at room temperature, 0.15 mL of trifluoroacetic acid was added dropwise, and 320 mg of tetramethylammonium triacetoxyborohydride was fractionated and slowly added. The mixture was heated and stirred at 40 ° C. for 30 minutes, , And the mixture was stirred at room temperature. After confirming that the product no longer increased on TLC, the reaction mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using a mobile phase of EtOAc: Hex (2: 1) to give 230 mg of (2S, 3R, 4S) -2,3,4-tris (benzyloxy) -5 ((2S, 3R, 4S) -2,3,4-tris (benzyloxy) -5- (bis (4-methoxyphenyl) amino) pentane -1-ol: 4g ).

^{1 H-NMR (600 MHz,} CDCl 3) δ 3.65 ~ 3.70 (m, 1H), 3.73 ~ 3.83 (m, 3H), 3.78 (s, 6H), 3.84 ~ 3.90 (m, 1H), 3.94 ~ 4.04 ( (m, 2H), 4.33-4.44 (m, 1H), 4.43-4.45 (m, 1H), 4.49-4.52 6.76 ~ 6.78 (m, 4H), 6.92 ~ 6.95 (m, 4H), 7.13 ~ 7.35 (m, 15H);

¹³ C-NMR (600 MHz, CDCl ₃ )? 154.3, 142.5, 138.2, 128.3, 127.82, 122.37, 114.6, 79.40, 78.8, 76.14, 74.19, 73.40, 71.66, 60.85, 55.60, 54.38 ppm.

Step 2) ( 2R, 3R, 4S, 5S ) -3,4,5- Tris ( Benzyloxy ) - N, N - Bis (4-methoxyphenyl) tetrahydro -2H-pyran-2-amine < / RTI &

Except that (2R, 3R, 4S, 5S) -3,4,5-trisbenzyloxy-5-bis-4-aminopentan-1-ol obtained in the above step 1) 1, step 3), the titled compound (3R, 4S, 5S) -3,4,5-tris (benzyloxy) -N, N-bis (4-methoxyphenyl) tetrahydro- 2H- pyran-2-amine was synthesized in a yield of 80% .

^{1 H-NMR (600 MHz,} CDCl 3) δ 3.20 ~ 3.22 (m, 1H), 3.60 ~ 3.63 (m, 1H), 3.70 ~ 3.78 (m, 1H), 3.76 (s, 6H), 4.28 ~ 4.31 ( (m, 2H), 6.67 (s, 2H), 4.65-4.74 (m, 1H) 6.78 (m, 4H), 7.16-7.22 (m, 4H), 7.26-7.47 (m, 15H);

¹³ C-NMR (600 MHz, CDCl ₃ ) 隆 55.30, 138.36, 128.10, 127.62, 125.21, 114.2, 93.57, 82.92, 75.16, 72.08, 70.76, 63.94, 55.46 ppm;

[?] _D ²⁰ = +0.17 (c 0.90, CHCl ₃ ); 97.5% ee [chiral HPLC analysis DAICEL ChiralPak AD-H, hexane: 2-propanol = 70:30, flow rate = 1.0 mL / min, 23 째 C, λ = 254 nm, retention time, major 3.31 min, minor 4.62 min] .

Example  9: N ^One - (4- (dimethylamino) phenyl) - N ⁴ , N ⁴ - dimethyl-N ^One - ( Tetrahydro -2H-pyran-2-yl) benzene-1,4-diamine

N, N'- di instead methoxydiphenylsilyl amine N, N '- (dimethylamino) in the same manner as in Example 3, except for using diphenylamine title compound N ¹ - (4- (dimethylamino) phenyl) -N ⁴ , N ⁴ -dimethyl-N ¹ - (tetrahydro-2H-pyran-2-yl) benzene-1,4-diamine.

^{1 H-NMR (600 MHz,} C 6 D 6) δ 6.69 ~ 7.2 (m, 8H), 4.98 ~ 5.2 (m, 1H), 3.95 ~ 3.98 (m, 1H), 3.37 ~ 3.34 (m, 1H), 2.53 ~ 2.56 (s, 12H), 1.04 ~ 1.64 (m, 6H).

Example  10: N- (4- Methoxyphenyl ) -N- ( Tetrahydro -2H-pyran-2-yl) pyridine-3- Amine  synthesis

N-4-methoxyphenyl-N'-methoxyphenyl-N'-dimethoxydiphenylamine was prepared in the same manner as in Example 3, except that N-4-methoxyphenyl- - (tetrahydro-2H-pyran-2-yl) pyridin-3-amine.

^{1 H-NMR (600 MHz,} CDCl 3) δ 1.21 ~ 1.27 (m, 1H, sheided water), 1.43 ~ 1.49 (m, 2H), 1.56 ~ 1.63 (m, 2H), 1.83 ~ 1.86 (m, 1H) (M, 2H), 6.95-6. 98 (m, 1H), 3.60-3.67 (m, 1H), 7.04-7.06 (m, 2H), 7.11-7.13 (m, 2H), 8.04-8.05 (m, 1H), 8.11 (d, J = 2.4 Hz, 1H) ppm.

Example  11: N- (4- Fluorophenyl ) -N- Phenyltetrahydro -2H-pyran-2- Amine  synthesis

N'-dimethoxydiphenylamine was used instead of N, N'-dimethoxydiphenylamine to obtain the title compound N- (4-fluorophenyl) -N -Phenyltetrahydro-2H-pyran-2-amine was synthesized in 99% yield.

^{1 H-NMR (600 MHz,} C 6 D 6) δ 6.7 ~ 7.2 (m, 9H), 4.77 ~ 4.79 (dd, 1H), 3.2 ~ 3.8 (m, 2H), 0.9 ~ 1.45 (m, 6H);

¹³ C-NMR (600 MHz, CDCl ₃ ) δ 160, 147.8, 141.48, 129, 121.47, 120.92, 115.4, 86.70, 66.69, 29.86, 25.21, 23.85 ppm.

Example  12: N- (2- Fluoro -5- Methylphenyl ) -N- Phenyltetrahydro -2H-pyran-2- Amine  synthesis

(2-fluoro-5-methylphenyl) -N-phenylamine was used in place of N, N'-dimethoxydiphenylamine in place of N- Methylphenyl) -N-phenyltetrahydro-2H-pyran-2-amine was synthesized in 84% yield.

^{1 H-NMR (600 MHz,} C 6 D 6) δ 7.29 ~ 7.31 (m, 1H), 7.17 ~ 7.18 (m, 1H), 7.00 ~ 7.02 (m, 2H), 6.80 ~ 6.87 (m, 3H), 3H), 1.70-1.72 (d, 1H, m), 6.30 (m, IH) ), 1.31-1.44 (m, 3H), 1.13-1.21 (m, 2H);

^{13 C-NMR (600 MHz,} C 6 D 6) δ 157.2 (d, J = 241.5 Hz), 148.8, 134.2, 131.3, 129.0, 120.0, 119.0, 117.2, 115.8, 88.0, 66.9, 30.3, 25.5, 24.0, 20.3 ppm.

Example  13: N-phenyl-N-m- Tolyltetrahydro -2H-pyran-2- Amine  synthesis

Phenyl-Nm-tolyltetrahydro-2H-pyran-2-ylmethylamide was prepared in the same manner as in Example 3, except for using N-phenyl-Nm-tolylamine instead of N, Amine was synthesized with a yield of 95%.

^{1 H-NMR (600 MHz,} C 6 D 6) δ 7.14 ~ 7.86 (m, 2H), 7.02 ~ 7.13 (m, 5H), 6.90 ~ 6.93 (m, 1H), 6.80 ~ 6.82 (m, 1H), (M, 1H), 3.25-3.29 (m, 1H), 2.06 (s, 3H), 1.16-1.26 (m, 6H);

¹³ C-NMR (150 MHz, C ₆ D ₆ )? 147.6, 146.6, 138.8, 129.5, 129.1, 126.3, 124.6, 123.3, 122.7, 122.5, 118.1, 87.1, 67, 31.6, 25.5, 24.2, 24.1 ppm.

Example  14: N- (4- Bromophenyl ) -N- Phenyltetrahydro -2H-pyran-2- Amine  synthesis

(4-bromophenyl) -N-phenylamine was obtained in the same manner as in Example 3, except that N- (4-bromophenyl) -N-phenylamine was used in place of N, N'-dimethoxydiphenylamine. N-tetrahydro-2H-pyran-2-amine was synthesized in a yield of 86%.

^{1 H-NMR (600 MHz,} C 6 D 6) δ 7.22 ~ 7.25 (m, 2H), 7.12 ~ 7.16 (m, 2H), 7.05 ~ 7.07 (m, 2H), 6.93 ~ 6.96 (m, 1H), (M, 1H), 1.39-1.42 (m, 1H), 1.29-1.31 (m, 2H), 4.72-4.73 , 1H), 1.06-1.18 (m, 3H), 0.94-0.96 (m, 1H);

¹³ C-NMR (150 MHz, C ₆ D ₆ ) δ 146.6, 145.8, 132.1, 129.3, 126, 124.3, 124.7, 115, 86.8, 67, 31.3, 25.4, 24 ppm.

Example  15: N- (4- Methoxyphenyl ) -N-p- Tolyltetrahydro -2H-pyran-2- Amine  synthesis

(4-methoxyphenyl) -N- (p-tolyl) amine was used in place of N, N'-dimethoxydiphenylamine, Methoxyphenyl) -N- (p-tolyl) tetrahydro-2H-pyran-2-amine was synthesized in 80% yield.

^{1 H-NMR (600 MHz,} C 6 D 6) δ 7.20 ~ 7.23 (m, 2H), 7.03 (s, 4H), 6.77 ~ 6.79 (m, 2H), 4.90 ~ 4.92 (m, 1H), 3.88 ~ 2H), 1.15-1.35 (m, 3H), 2.16 (s, 3H), 1.47-1.51 (m, 1.00 to 1.02 (m, 1H), 0.94 to 0.96 (m, 1H);

¹³ C-NMR (150 MHz, C ₆ D ₆ ) δ 157.6, 146.9, 138.6, 130, 129.8, 129.6, 121.5, 120, 114.9, 87.4, 66.9, 54.8, 53.2, 31.6, 25.7, 24.3, 20.6 ppm.

Example  16: N, N - D p - Tolyltetrahydro -2H-pyran-2- Amine  synthesis

N, N-di-p-tolyltetrahydro-2H-pyran-2-one was obtained in the same manner as in Example 3, except that N, N-dipitolamine was used instead of N, 2-amine was synthesized in 85% yield.

^{1 H-NMR (600 MHz,} C 6 D 6) δ 7.11 ~ 7.13 (m, 4H), 7.00 ~ 7.01 (m, 4H), 4.92 ~ 4.94 (m, 1H), 3.86 ~ 3.88 (m, 1H), (M, 2H), 1.14-1.67 (m, 2H), 1.98-1.00 (m, 1H) );

¹³ C-NMR (150 MHz, C ₆ D ₆ )? 144.9, 132.1, 129.8, 124.4, 87.3, 67, 53.3, 31.6, 25.6, 24.3, 20.7 ppm.

Example  17: N, N - Bis (4- Methoxyphenyl ) -6- Methyltetrahydro -2H-pyran-2- Amine  synthesis

Step 1) 6- ( Bis (4-methoxyphenyl) amino ) Hexane -2-one

500 mg of N, N'-dimethoxydiphenylamine 2a was dissolved in 7 mL of anhydrous acetonitrile together with 0.9 g of potassium carbonate and 0.4 g of potassium iodide and stirred. After 6-chlorohexanone was added, the reaction mixture was warmed to reflux and stirred. After confirming that the product was no longer increased by TLC, ethyl acetate was added to dilute the reaction solution. The inorganic solid was removed by filtration, and the solvent was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a gradient mobile phase of EtOAc: Hex (1: 5-> 1:10) to give 114 mg of 6- (bis (4-methoxyphenyl) amino) 2-one (6- (bis (4-methoxyphenyl) amino) hexan-2-one.

^{1 H-NMR (600 MHz,} CDCl 3) δ 6.84 ~ 6.86 (m, 4H), 6.80 ~ 6.81 (m, 4H), 3.77 (s, 6H), 3.55 ~ 3.57 (m, 2H), 2.41 ~ 2.43 ( m, 2H), 2.10 (s, 3H), 1.59 ~ 1.64 (m, 4H);

¹³ C-NMR (150 MHz, CDCl ₃ )? 154.2, 142.4, 122, 114.6, 97.2, 61.3, 59.4, 55.5, 52.3, 43.5, 35.8, 29.8, 27.2, 21.2 ppm;

IR (FT-IR) 3840, 3725, 2916, 2850, 1507, 1240, 1219, 772, 649 cm ^-1 ;

^{HRMS (ESI +): calcd for} C 20 H 25 NO 3 + [M + H] +: 328.1913, found: 328.1913

Step 2) 6- ( Bis (4-methoxyphenyl) amino ) Hexane -2-ol

100 mg of 6- (bis (4-methoxyphenyl) amino) hexan-2-one obtained in the above step 1) was dissolved in 2 ml of methanol, and 36 mg of sodium borohydride (NaBH ₄ ) And the mixture was stirred. When the reaction no longer proceeds, the solvent was concentrated. The crude product was purified by column chromatography on silica gel using a gradient mobile phase of EtOAc: Hex (1: 5> 1: 2) to give 45 mg of 6- (bis (4- methoxyphenyl) amino) 6- (bis (4-methoxyphenyl) amino) hexan-2-ol.

^{1 H-NMR (600 MHz,} CDCl 3) δ 6.8 ~ 6.86 (m, 8 H), 3.77 (s, 6H), 3.56 ~ 3.65 (m, 3 H), 1.59 ~ 1.66 (m, 2H), 1.34 ~ 1.47 (m, 4H), 1.16-1.17 (d, 3H);

¹³ C-NMR (150 MHz, CDCl ₃ )? 154.2, 142.5, 122.1, 14.6, 67.9, 55.6, 52.7, 39.0, 32.5, 23.3 ppm.

Step 3) N, N - Bis (4- Methoxyphenyl ) -6- Methyltetrahydron -2H-pyran-2- Amine  Produce

The title compound N, N-bis (4-methoxyphenyl) amino) hexanoic acid was obtained in the same manner as in step 3 of Example 3, using 6- (bis (4- methoxyphenyl) amino) N-bis (4-methoxyphenyl) -6-methyltetrahydro-2H-pyran-2-amine) was synthesized in a yield of 80% .

^{1 H-NMR (600 MHz,} C 6 D 6) δ 7.12 ~ 7.14 (m, 4 H), 6.80 ~ 6.81 (m, 4 H), 4.93 ~ 4.95 (m, 1 H), 3.37 ~ 3.40 (m, 1 H), 3.33 (s, 6H), 1.45-1.56 (m, 2H), 1.26-1.37 (m, 4H), 1.18-1.25 (d, 3H);

¹³ C-NMR (150 MHz, C ₆ D ₆ )? 155.8, 140.8, 119.5, 114.6, 114.2, 87.4, 72.3, 54.8, 32.6, 30.6, 23.8, 21.9 ppm.

Example  18: 2- Iodo -2- methyl -One-( Tetrahydro -2H-pyran-2-yl) Indolin  synthesis

2-methyl-1-tetrahydro-2H-pyran-2-one was obtained in the same manner as in Example 3, except that 2-methylindoline was used in place of N, N'-dimethoxydiphenylamine. - yl) indolin was synthesized in 69% yield.

¹ H-NMR (600 MHz, C ₆ D ₆ )? 7.63-7.66 (m, 1H), 7.63-7.65 2H), 3.16-3.16 (m, 2H), 2.06 (s, 3H), 1.13-1.33 (m, 2H) ), 1.08-1.13 (m, 2H), 0.93-0.98 (m, 2H);

¹³ C-NMR (600 MHz, C ₆ D ₆ ) 隆 137.1, 137.0, 130.8, 128.2, 122.1, 121.0, 120.6, 109.5, 77.6, 62.1, 58.6, 53.2, 44.1, 42.9, 33.4, 30, 13.0 ppm;

^{HRMS (ESI +): calcd for} C 14 H 18 INO + [M + H] +: 344.0506, found: 344.0515.

Example  19: ( 2S, 3S, 4R, 5R ) -3,4,5- Tris ( Benzyloxy ) - N, N - Bis (4-methoxyphenyl) tetrahydro -2H-pyran-2-amine < / RTI &

(3R, 4S, 5S) -3,4,5-trisbenzyloxytetrahydro-2H-pyran-2-ol ((3R, ((3S, 4R, 5R) -3, 4, 5-trisbenzyloxytetrahydro-2H-pyran- (2S, 3S, 4R, 5R) -3, 5-tris (benzyloxy) tetrahydro-2H- pyran- , (4,5-tris (benzyloxy) -N, N-bis (4-methoxyphenyl) tetrahydro- bis-4-methoxyphenyl-tetrahydro-2H-pyran-2-amine) was synthesized in 40% yield.

Experimental Example 1. Measurement of cell-based nerve cell line protective activity

1-1) Method for measuring cell-based activity

1) Cell culture

Human neuroblastoma SH-SY5Y cells (American Type Culture Collection, USA) and mouse microglia BV2 cells were cultured in a humidified 95%, 5% CO ₂ incubator with 10% heat- were incubated at 37 ° C in Dulbecco's modified Eagle's medium (DMEM; Hyclone) supplemented with inactivated fetal bovine serum (Hyclone, USA). "LPS (lipid polysaccahride)" and "6-hydroxy dopamine" were used as toxic substances to induce cell damaging reaction. That is, 'LPS' was used as a stimulant for inducing overactivation of BV2 cells and '6-hydroxy dopamine' was used as a toxic substance for inducing cytotoxic response in SH-SY5Y cells. '6-shogaol' was used to confirm inactivation in BV2 cells, and 'Ropinirole' was used as a positive control in SH-SY5Y cells to determine cytoprotective activity. After confluence of cells from 70% to 80% of area, the compound and the comparative compound were treated at each treatment concentration under serum-free conditions and 30 minutes after stimulation and toxicity treatment. All treatment chemicals were dissolved in dimethyl sulfoxide (DMSO) and the final concentration of DMSO was 0.2%. After 24 hours, nitric oxide and MTT were measured in BV2 cells, and MTT measurement was performed in SH-SY5Y cells after 48 hours.

2) LPS  Treated Nerve cell line  Production quantitation of nitrite

The inflammatory response in the central nervous system is known to play an important role in degenerative brain diseases. Activation of microglial cells is an in vivo protective mechanism, but inflammation mediated by hyperactivity of microglial cells induces the death of neuronal cells . Thus inhibiting the activation of microglial cells may be a pharmacological target for the treatment of degenerative brain diseases. In addition, the relationship between Parkinson 's disease and Alzheimer' s and microglia activation is activated by the activation of microglial cells and secretion of nitric oxide (NO) by the expression of iNOS. The amount of nitric oxide secreted can be quantified by the amount of nitrite. Quantitative nitrite inhibits the activation of microglial cells to determine the protective effect of nerve cells. 100 mg / ml of LPS was treated with BV-2 neuronal cell line and treated with BV-2 cell lines at the concentrations of 0.01, 0.1, 1, 10 and 20 μM of Example Compounds 6 and 7, The amount of production was compared with the control, and a significant difference was confirmed as p <0.001 (***). In addition, 100 mg / after the ml LPS in the process in BV-2 neural cell lines, in Examples 1 to were treated for 10 compounds of the BV-2 cell line, as compared to each concentration amount of nitrite to the control IC ₅₀ (μM ). At this time, cell viability was measured in the remaining cells after removing the supernatant.

3) Inhibition of neurotoxicity of 6-hydroxy dopamine-induced neuronal cell line

The cells were treated with 25 μM 6-hydroxy dopamine to induce neurotoxicity against human neuroblastoma cells (SH-SY5Y), and were treated with 0.001, 0.01, 0.1, 1, 5, 10, a was treated 48 hours in SH-SY5Y cell line, for each concentration statistical significance measure the control and compared to cell viability (%), and, through analysis of variance (one-way ANOVA followed by Tukey 's multiple comparison test) * p <0.05 and ** p <0.01 .

1-2) Experimental results

Compounds 6 and 7 of the present invention showed significant inhibition of nitrite production in LPS treated murine microglial BV-2 cells (FIG. 1).

Example 3, Example 5, Example 9 and Example 10 significantly inhibited the production of nitrite in LPS-treated murine microglial BV-2 cells at the concentration of μM (Table 1 below).

sample IC ₅₀ (μg / ml) Example 1 > 500 Example 2 > 500 Example 3 75.66 Example 4 > 500 Example 5 162.49 Example 8 > 500 Example 9 12.57 Example 10 20.21 Example 11 > 500 6-Shogaol 5.59

Among the compounds of Examples 1 to 19 of the present invention, compounds other than the compounds of Examples 1, 4 and 8 were found to increase the cell survival rate in murine microglial BV-2 cells reduced by LPS 1 and 2).

In addition, it was confirmed that the compound of Example 6 of the present invention significantly inhibited the neurotoxicity of 6-hydroxy dopamine-induced neuroblastoma cells (SH-SY5Y) in a concentration-dependent manner (FIG. 3).

Claims (19)

Claims 1. A compound represented by the following formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In this formula,
n is 0 or 1;
R ¹ and R ² are the same or different, each independently represent a C ₅ -C ₁₄ aryl or C ₅ -C ₁₄ heteroaryl, wherein aryl or heteroaryl are halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy, and -NR ⁷ R ⁸ , or R ¹ and R ² may be connected to each other to form a 5- to 8-membered ring containing a nitrogen atom to which they are bonded, Said heterocyclic ring being fused to another C ₅ -C ₁₄ aryl or unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or C ₁ -C ₆ alkyl;
R ³ and R ^{3 'are} the same or different, each independently represent hydrogen, hydroxy, halogen, C _5-14 aryl -C _1-6 alkoxy, hydroxy C ₁ -C ₆ alkyl, or tri (C ₁ -C _6-alkyl) - silyloxy -C ₁ -C ₆ alkyl (wherein, tri (C ₁ -C ₆ alkyl) are all the same or may be configured as two or more different from each other (C ₁ -C ₆ alkyl)), and;
R ⁴ and R ^{4 'are} the same or different, each independently represent hydrogen, hydroxy, halogen, C ₅ -C ₁₄ aryl, or C _5-14 aryl -C _1-6 alkoxy;
R ⁵ and R ^{5 '} are the same or different and each independently is hydrogen, hydroxy, halogen, or C _5-14 aryl-C _1-6 alkoxy;
R ⁶ and R ^{6 '} are the same or different and each independently hydrogen or C ₁ -C ₆ alkyl,
R ⁷ and R ⁸ are the same or different and each independently represents hydrogen or C ₁ -C ₆ alkyl.
The method according to claim 1,
R ¹ and R ² are the same or different and each independently represent phenyl or pyridinyl, and R ¹ and R ² are each independently selected from the group consisting of fluoro, methoxy, dimethylamino, methyl, and bromo Or indolinyl substituted with methyl, iodo, or both, formed by R ¹ and R ² linked to each other;
R ³ and R ^{3 '} are the same or different and each independently is hydrogen, hydroxy, fluoro, benzyloxy, hydroxymethyl, or tert-butyldimethylsilyloxymethyl;
R ⁴ and R ^{4 '} are the same or different and each independently hydrogen, hydroxy, fluoro, phenyl, or benzyloxy;
R ⁵ and R ^{5 '} are the same or different and each independently hydrogen, hydroxy, fluoro, or benzyloxy;
R ⁵ and R ^{5 '} are the same or different and each independently is hydrogen or methyl, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
3. The method of claim 2,
R ¹ and R ² are phenyl or pyridinyl, unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, methoxy, dimethylamino, methyl, and bromo; Or R &lt; ¹ &gt; and R &lt; ² &gt; are bonded to each other to form a methyl and an iodo-substituted indolinyl, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
A compound represented by the following formula (1-1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
[Formula 1-1]

In this formula,
R ¹ and R ² are the same or different, each independently represent a C ₅ -C ₁₄ aryl or C ₅ -C ₁₄ heteroaryl, wherein aryl or heteroaryl are halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy, and -NR ⁷ R ⁸ , or R ¹ and R ² may be connected to each other to form a 5- to 8-membered ring containing a nitrogen atom to which they are bonded, Said heterocyclic ring being fused to another C ₅ -C ₁₄ aryl or unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or C ₁ -C ₆ alkyl;
R ³ and R ^{3 'are} the same or different, each independently represent hydrogen, hydroxy, halogen, C _5-14 aryl -C _1-6 alkoxy, hydroxy C ₁ -C ₆ alkyl, or tri (C ₁ -C _6-alkyl) - silyloxy -C ₁ -C ₆ alkyl (wherein, tri (C ₁ -C ₆ alkyl) are all the same or may be configured as two or more different from each other (C ₁ -C ₆ alkyl)), and;
R ⁴ and R ^{4 'are} the same or different, each independently represent hydrogen, hydroxy, halogen, C ₅ -C ₁₄ aryl, or C _5-14 aryl -C _1-6 alkoxy;
R ⁵ and R ^{5 '} are the same or different and each independently is hydrogen, hydroxy, halogen, or C _5-14 aryl-C _1-6 alkoxy;
R ⁶ and R ^{6 '} are the same or different and each independently hydrogen or C ₁ -C ₆ alkyl,
R ⁷ and R ⁸ are the same or different and each independently represents hydrogen or C ₁ -C ₆ alkyl.
5. The method of claim 4,
R ¹ and R ² are the same or different and each independently represent phenyl or pyridinyl, and R ¹ and R ² are each independently selected from the group consisting of fluoro, methoxy, dimethylamino, methyl, and bromo Or indolinyl substituted with methyl, iodo, or both, formed by R ¹ and R ² linked to each other;
R ³ and R ^{3 '} are the same or different and each independently is hydrogen, hydroxy, fluoro, benzyloxy, hydroxymethyl, or tert-butyldimethylsilyloxymethyl;
R ⁴ and R ^{4 '} are the same or different and each independently hydrogen, hydroxy, fluoro, phenyl, or benzyloxy;
R ⁵ and R ^{5 '} are the same or different and each independently hydrogen, hydroxy, fluoro, or benzyloxy;
R ⁵ and R ^{5 '} are the same or different and each independently is hydrogen or methyl, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
6. The method of claim 5,
R ¹ and R ² are phenyl or pyridinyl, unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, methoxy, dimethylamino, methyl, and bromo; Or R &lt; ¹ &gt; and R &lt; ² &gt; are bonded to each other to form a methyl and an iodo-substituted indolinyl, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
A compound represented by the following formula (1-2), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
[Formula 1-2]

In this formula,
R ¹ and R ² are the same or different and are each independently C ₅ -C ₁₄ aryl which is unsubstituted or substituted by one or more C ₁ -C ₆ alkoxy.
8. The method of claim 7,
R ¹ and R ² are the same or different and each independently is phenyl optionally substituted by one or more C ₁ -C ₆ alkoxy, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
8. The method of claim 7,
R ¹ and R ² are phenyl optionally substituted with one or more methoxy groups, stereoisomers thereof, or pharmaceutically acceptable salts thereof.
2. The compound according to claim 1, wherein the compound represented by the formula (1) is selected from the group consisting of the following compounds, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
1) N, N-bis (4-methoxyphenyl) tetrahydrofuran-2-amine [N, N-bis
2) N, N-diphenyltetrahydrofuran-2-amine [N, N-diphenyltetrahydrofuran-
3) N, N-bis (4-methoxyphenyl) tetrahydro-2H-pyran-
4) Synthesis of N, N-bis (4-methoxyphenyl) -4-phenyltetrahydro-2H-pyran- amine],
5) Synthesis of 3,3,4,4,5,5-hexafluoro-N, N-bis (4-methoxyphenyl) tetrahydro-2H-pyran- , 5-hexafluoro-N, N-bis (4-methoxyphenyl) tetrahydro-2H-pyran-
6) Synthesis of (2S, 3S) -3 - ((tert-butyldimethylsilyloxy) methyl) -N, N-bis (4- methoxyphenyl) tetrahydro- - ((tert-butyldimethylsilyloxy) methyl) -N, N-bis (4-methoxyphenyl) tetrahydro-2H- pyran-
7) Synthesis of ((2R, 3S) -2- (bis (4-methoxyphenyl) amino) tetrahydro-2H- ) amino) tetrahydro-2H-pyran-3-yl) methanol],
8) Synthesis of (2R, 3R, 4S, 5S) -3,4,5-tris (benzyloxy) -N, N-bis (4- methoxyphenyl) tetrahydro- 3R, 4S, 5S) -3,4,5-tris (benzyloxy) -N, N-bis (4- methoxyphenyl) tetrahydro-
9) Synthesis of N1- (4- (dimethylamino) phenyl) -N4, N4-dimethyl-N1- (tetrahydro- phenyl) -N4, N4-dimethyl-N1- (tetrahydro-2H-pyran-2-yl) benzene- 1,4-diamine]
10) Preparation of N- (4-methoxyphenyl) -N- (tetrahydro-2H-pyran-2 -yl) pyridin-3-amine],
11) Synthesis of N- (4-fluorophenyl) -N-phenyltetrahydro-2H-pyran-2-amine], N- (4-fluorophenyl) -N-phenyltetrahydro-
12) Preparation of N- (2-fluoro-5-methylphenyl) -N-phenyltetrahydro-2H-pyran-2 -amine],
13) N-phenyl-Nm-tolyltetrahydro-2H-pyran-2-amine [N-phenyl-Nm-tolyltetrahydro-2H-
14) Synthesis of N- (4-bromophenyl) -N-phenyltetrahydro-2H-pyran-2-amine], N-
15) Synthesis of N- (4-methoxyphenyl) -Np-tolyltetrahydro-2H-pyran-2-amine], N- (4-methoxyphenyl) -Np-tolyltetrahydro-
16) N, N-di-p-tolyltetrahydro-2H-pyran-2-amine [N, N-dip-tolyltetrahydro-2H-
17) Synthesis of N, N-bis (4-methoxyphenyl) -6-methyltetrahydro-2H-pyran- amine],
18) Preparation of 2-iodo-2-methyl-1- (tetrahydro-2H-pyran-2-yl) indoline 2-iodo-2- ], And
19) Synthesis of (2S, 3S, 4R, 5R) -3,4,5-tris (benzyloxy) -N, N-bis (4- methoxyphenyl) tetrahydro- 3S, 4R, 5R) -3,4,5-tris (benzyloxy) -N, N-bis (4-methoxyphenyl) tetrahydro-2H-pyran-2-amine].
10. A pharmaceutical composition for preventing or treating a neurological disorder, comprising the compound of any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
12. The method of claim 11,
Wherein the nervous system disease is a cerebral nerve or central nervous system disease.
12. The method of claim 11,
Wherein the neurological disease is selected from the group consisting of ischemic brain disease, degenerative brain disease, Alzheimer's disease, Parkinson's disease, and Huntington's disease.
12. The method of claim 11,
And inhibiting hyperactivation of microglial cells to prevent or treat said neurological diseases.
12. The method of claim 11,
LPS or 6-OHDA, thereby preventing and treating the neurological diseases.
A process for producing a compound represented by the general formula (1-1) according to claim 4, which comprises a step of converting a compound represented by the formula (2) into an compound represented by the formula (1-1) by an oxidative cyclization reaction:
[Formula 1-1]

(2)

In this formula,
R ¹ , R ² , R ³ , R ^{3 '} , R ⁴ , R ^4' , R ⁵ , R ^{5 '} , R ⁶ and R ^6' are as defined in claim 4.
A process for producing a compound represented by the general formula (1-2) of claim 7 comprising the step of converting a compound represented by the formula (3) into an compound represented by the formula (1-2) by an oxidative cyclization reaction:
[Formula 1-2]

(3)

In this formula,
R ¹ and R ² are as defined in claim 7.
The method of claim 16 or 17, wherein the oxidative cyclization reaction is carried out using iodine or a hypervalent iodine oxidant in the presence of TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl) oxidanyl) &Lt; / RTI &gt;
19. The method of claim 18, wherein the periodate is BAIB (bis (acetoxy) iodobenzene) or PIFA (phenyliodine bis (trifluoroacetate)).

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