KR20160039817A - Alpha-aminoamide derivatives and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention relates to an alpha-aminoamide derivative compound and a pharmaceutical composition comprising the same. According to various embodiments of the present invention, the pharmaceutical composition can overcome shortcomings of a conventional drug used as a MAO-B inhibitor. More particularly, the pharmaceutical composition reversibly suppresses MAO-B through a non-covalent bond, and thus can alleviate or remove side effects of a conventional drug which exhibits treatment efficacy by irreversibly acting with MAO-B through a covalent bond. Particularly, the novel compound of the present invention has remarkable stability and efficacy in comparison to a conventional reversible MAO-B inhibitor. The alpha-aminoamide derivative compound is represented by chemical formula 1.

Description

[0001] Alpha-aminoamide derivatives and pharmaceutical compositions comprising same [0002]

The present invention relates to alpha-aminoamide derivative compounds and pharmaceutical compositions containing them.

Parkinson's disease is the second most common form of degenerative neurological disease, with an estimated incidence of 6.3 million people worldwide, with an estimated one out of every 1,000 people suffering from Parkinson's disease. It is common in older people, but it also affects young people. Parkinson's disease is characterized by gradual onset of symptoms, which are difficult to distinguish from other diseases and are difficult to detect in the early stages. Clinical features include trembling, stiffness, stiffness, posture instability, stiff posture, gait freezing, depression, There are abnormal symptoms accompanying the back.

Parkinson 's disease is not known to be the cause of the disease, but neurons that secrete neurotransmitters called dopamine in the brain are destroyed, and it is known that the disease is caused by lack of dopamine. Levodopa therapy, which is a method of administering levodopa, which is converted into dopamine in the body, is generally performed as the most developed and used drug. Although levodopa is the most effective remedy for Parkinson's disease, there are cases in which the drug-related effects and various motor disorders occur during the treatment process. Other drugs include COMT inhibitors and MAO-B inhibitors that inhibit dopamine metabolism and maintain the concentration of dopamine in the brain.

MAO-B plays an important role in the metabolism of dopamine in the brain and is known to inhibit neuronal cell damage. Although there is no clear evidence that MAO-B inhibitors actually slow Parkinson's progression, inhibition of MAO-B inhibits the degeneration or death of dopamine neurons by playing an important role in the pathogenesis of Parkinson's disease by MPTP or similar environmental toxins Is known to act. In addition, MAO-B inhibitors are presented as evidence for animal and clinical studies that they have a protective effect against the brain, unlike other drugs.

The most approved MAO-B inhibitor is selegiline, which is prescribed as a treatment for Parkinson's disease. However, it is metabolized to amphetamine in the body when taken, resulting in liver toxicity, and is associated with various side effects as an irreversible inhibitor. Since it was first marketed in Israel in 2005, Azurekt has been launched with rasagiline, which has recently been introduced in more than 50 countries, including Europe and the United States. Azuret has no amphetamine side effects in the body when taken and is more potent than other dopamine drugs. However, rasagiline is an irreversible MAO-B inhibitor as well as selenazine, so it has an excellent MAO-B inhibitory effect, but it has safety drawbacks. Thus, recently, a drug capable of reversibly inhibiting the activity while being effective has been developed as an alternative to compensate for such disadvantages, but a remarkable reversible inhibitor has not been prescribed to date.

It is an object of the present invention to overcome the disadvantages of existing drugs used as MAO-B inhibitors. And to develop a therapeutic agent that reversibly inhibits MAO-B through non-covalent bonding in order to alleviate or eliminate side effects of existing drugs that are irreversibly acting through covalent bonding with MAO-B. Also, it is intended to provide a compound having stability and efficacy superior to the conventional reversible MAO-B inhibitor, a composition containing the same, and a method for producing the same.

One aspect of the present invention relates to an alpha-aminoamide derivative having a structure represented by the following formula (1).

Wherein R and X are the same as defined in the present invention.

Another aspect of the present invention relates to a monoamine oxidase B (MAO-B) inhibitor comprising an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof according to various embodiments of the present invention.

Another aspect of the present invention relates to a pharmaceutical composition for the treatment or prevention of degenerative neurological diseases, comprising an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof according to various embodiments of the present invention.

Another aspect of the present invention relates to the use of an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof according to various embodiments of the present invention for the manufacture of a medicament for the treatment or prevention of degenerative neurological diseases.

Another aspect of the present invention is a method for treating or ameliorating a degenerative neurological disease by administering to a mammal an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, according to various embodiments of the present invention ≪ / RTI >

Another aspect of the present invention relates to a method for preparing an alpha-aminoamide derivative having the structure of Formula 1 below.

According to various embodiments of the present invention, it is possible to overcome the disadvantages of existing drugs used as MAO-B inhibitors, and more specifically to prevent adverse effects of existing drugs which are irreversibly acting through covalent bonding with MAO- B can be reversibly inhibited by non-covalent coupling so as to alleviate or eliminate MAO-B. Especially new compounds with greater stability and efficacy than conventional reversible MAO-B inhibitors.

Figure 1 shows a flow chart of the reversibility verification experiment.
Figure 2a shows the dopamine neuronal cell protection effect (Pre-treatment) of compound 9 in black and striatum.
Figure 2b shows the dopamine neuronal protective effect of Compound 9 on the black and striatum.
Figure 2c shows the 30-day pre-treatment of dopamine neurons in black and striatum.
Figure 3a shows the spike probability according to stimulus intensity in APP / PS1 mice (Jo et al., Nature Medicine, 2014).
FIG. 3B shows the spike probability according to stimulus intensity in APP / PS1 mouse of Compound 9.
FIG. 4 shows the results of excitability verification in DGGCs (dentate gyrus granule cells) of Compound 9.
Figure 5 shows the binding mode prediction results of sapinamide and compound 9.

Hereinafter, various aspects and various embodiments of the present invention will be described in more detail.

One aspect of the present invention relates to an alpha-aminoamide derivative having a structure represented by the following formula (1).

[Chemical Formula 1]

R is hydrogen or an alkyl group; X is selected from the group consisting of hydrogen, a halogen group, an alkyl group, a halogenated alkyl group, an alkoxy group, and a halogenated alkoxy group.

According to one embodiment, wherein R is selected from hydrogen, C ₁ -C ₇ alkyl group; Wherein X is selected from the group consisting of hydrogen, a halogen group, a C ₁ -C ₇ alkyl group, a halogenated C ₁ -C ₇ alkyl group, a C ₁ -C ₇ alkoxy group, and a halogenated C ₁ -C ₇ alkoxy group.

According to another embodiment, R is selected from among hydrogen, a methyl group, an ethyl group, an n -propyl group, an isopropyl group, a cyclopropyl group, an n -butyl group, an isobutyl group, a sec -butyl group and a tert -butyl group; X is selected from a halogen group, a halogenated methyl group, a halogenated ethyl group, a halogenated methoxy group, a halogenated ethoxy group, a methoxy group and an ethoxy group. In particular, when R and X are the same as above, it is confirmed that the effect of alleviating antibody-dependent cytotoxicity is additionally observed, unlike the case of not.

According to another embodiment, R is selected from among hydrogen, a methyl group, an isopropyl group, and an isobutyl group; X is selected from a fluoro group, a chloro group, a trifluoromethyl group, a trifluoromethoxy group, and a methoxy group. In particular, when R and X are the same as above, the channel inhibition effect is almost zero, unlike the case where the channel inhibition effect is low, and the channel inhibitory effect is remarkably lower than that of the existing product, sapinamide, There are advantages.

According to another embodiment, R is selected from among hydrogen, a methyl group, an isopropyl group, and an isobutyl group; Wherein X is a p-trifluoromethyl group, p-trifluoromethoxy Messenger time, m-tree as a methyl group, m-fluoro-trifluoromethoxy Messenger time, p-chloro group, m-chloro group, p-methoxy, m- A methoxy group, a p -fluoro group, and an m -fluoro group.

According to another embodiment, R is selected from among hydrogen, a methyl group, an isopropyl group, and an isobutyl group; Wherein X is a p-trifluoromethyl group, p-trifluoromethoxy Messenger time, m-tree as a methyl group, m-fluoro-trifluoromethoxy Messenger time, p-chloro group, m-chloro group, p-methoxy, m- Methoxy group. According to another embodiment, R is hydrogen or a methyl group; Wherein X is a p-trifluoromethyl group, p-trifluoromethoxy Messenger time, m-tree as a methyl group, m-fluoro-trifluoromethoxy Messenger time, p-chloro group, m-chloro group, p-methoxy, m- Methoxy group.

According to another embodiment, R is hydrogen or a methyl group; Wherein X is p-it is selected from trifluoromethoxy Messenger group-trifluoromethyl group, p-trifluoromethoxy Messenger time, m-tree methyl group, m fluoro. In particular, it has been confirmed that, in the case where R and X are the same as above, the effect of completely blocking the antibody-dependent cytotoxicity is additionally observed, unlike the case of not.

According to another embodiment, R is hydrogen or a methyl group; Wherein X is a p -trifluoromethyl group or p -trifluoromethoxy.

According to another embodiment, R is a methyl group; Wherein X is a p -trifluoromethyl group or p -trifluoromethoxy.

According to another embodiment, R is a methyl group; Wherein X is a p -trifluoromethyl group.

According to another embodiment, the alpha-aminoamide derivative is selected from the following compounds.

(S) -2 - (((2'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,

(S) -2 - (((3'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,

(S) -2 - (((4'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,

(S) -2 - (((2'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,

(S) -2 - (((3'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,

(S) -2 - ((4'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,

(S) -2 - (((2'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,

(S) -2 - (((3'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,

(S) -2 - (((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,

(S) -2 - (((3'-trifluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,

(S) -2 - (((4'-trifluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,

(S) -2 - (((3'-methoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,

(S) -2 - (((4'-methoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,

(R) -2 - ((3'-fluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,

(R) -2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,

(R) -2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) acetamide methanesulfonate,

(R) -3-methyl-2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) butanamide methanesulfonate,

(R) -4-methyl-2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) pentanamide methanesulfonate

According to another embodiment, the alpha-aminoamide derivatives according to various embodiments of the present invention are (S) -isomers.

Another aspect of the present invention relates to a monoamine oxidase B (MAO-B) inhibitor comprising an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof according to various embodiments of the present invention.

Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate or sulfate, and organic acid salts such as carboxylate or sulfonate. Examples of the carboxylic acid salt include, but are not limited to, acetate, maleate, fumarate, malate, citrate, tartrate, lactate or benzoate. Examples of the sulfonic acid salt include, but are not limited to, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate or naphthalenedisulfonate.

Another aspect of the present invention relates to a pharmaceutical composition for the treatment or prevention of degenerative neurological diseases, comprising an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof according to various embodiments of the present invention.

Examples of degenerative neurological diseases in the present invention include, but are not limited to, Parkinson's disease, Alzheimer's disease, and the like.

Another aspect of the present invention relates to the use of an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof according to various embodiments of the present invention for the manufacture of a medicament for the treatment or prevention of degenerative neurological diseases.

Another aspect of the present invention is a method for treating or ameliorating a degenerative neurological disease by administering to a mammal an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, according to various embodiments of the present invention ≪ / RTI >

Another aspect of the present invention is a process for preparing a compound of formula (I), comprising: (A) reacting a compound of formula (I) (B) reacting the compound of Formula 1c with a compound of Formula 1d to synthesize a compound of Formula 1e; (C) converting the compound of formula (1e) into an alpha-aminoamide derivative of formula (1).

[Formula 1a]

[Chemical Formula 1b]

[Chemical Formula 1c]

;

;

≪ RTI ID = 0.0 &

[Formula 1e]

Wherein R and X are as defined above.

Hereinafter, the present invention will be described in more detail, but the scope of the present invention is not limited thereto.

In order to achieve the above object, a compound of the present invention was designed by introducing a biphenyl group into the benzyloxyphenyl group position of safinamide, which is a conventional reversible MAO-B inhibitor.

Sapinamide is a compound that is known to have excellent antioxidant and potency in animals, but also as a calcium channel and sodium channel inhibitor, and has limitations as a selective Mao inhibitor. Therefore, in the present invention, the compounds of the present invention having improved stability and efficacy in animal models of degenerative brain diseases were synthesized through the development of selective and improved Mao inhibitors, and the specific method thereof is as shown in the following Scheme 1.

[Reaction Scheme 1]

Since the compound has optical activity by the carbon marked with an asterisk (*), the R-type compound and the S-type compound are separately synthesized through the following respective synthesis steps.

(1) Step 1

As shown in Scheme 1a below, 4-bromobenzaldehyde, boronic acid and palladium catalyst were used as limiting reactants through the Suzuki cross coupling reaction. Specifically, 4-bromobenzaldehyde (3 g, 16.21 mmol), boronic acid compound (1.28 equivalents), tetrakis (triphenylphosphine) palladium (0) (4-8 mol%), sodium carbonate Add to distilled water (150 mL / 21.6 mL) and heat to reflux for 18 hours. The reaction mixture is filtered through celite. Wash the filtrate twice with ethyl acetate (200 mL) and water (200 mL). The organic layer is dried with sodium sulfate and concentrated in vacuo. And then separated and purified by silica column chromatography.

[Reaction Scheme 1a]

(2) Step 2 and Step 3

L-alaninamide hydrochloride or D-Alaninamide hydrochloride is used to conduct reductive amination reaction with the compound of step (a) to obtain an imine compound, followed by reduction with sodium cyanoborohydride to obtain an amine compound.

Add 1.2 equivalents of Glycinamide hydrochloride or L-Alaninamide hydrochloride or D-Alaninamide hydrochloride or L-Valinamide hydrochloride or L-Leucinamide hydrochloride to methanol at a concentration of 0.92 mol, and add 1.5 equivalents of triethylamine. When the solution becomes transparent, 1.0 equivalent of the aldehyde synthesized in step (a) is added. After two hours, wash with ethyl acetate and distilled water. The organic layer is dried with sodium sulfate and concentrated in vacuo. After dissolving the reaction solution in anhydrous methanol at a concentration of 1.0 mole, 4.0 equivalents of sodium cyanoborohydride is added at 0 ° C. The reaction is then allowed to proceed at room temperature for 18 hours. The reaction mixture is washed with ethyl acetate and distilled water. The organic layer is dried with sodium sulfate and concentrated in vacuo. And then separated and purified by silica column chromatography.

[Reaction Scheme 1b]

[Reaction Scheme 1c]

(3) Step 4

Step 4 is an optional and optional step that may or may not be performed as needed. In order to improve the solubility of the amine compound synthesized above, salt form compounds are synthesized using methanesulfonic acid. Ethyl acetate is heated to 50-55 째 C to dissolve 1.0 equivalent of the compound of step (b), followed by 1.25 equivalents of methanesulfonic acid. After 1 hour, the reaction mixture was cooled to room temperature, filtered using a vacuum, and washed with ethyl acetate. Dry the filtrate thoroughly without further purification.

[Reaction Scheme 1d]

Hereinafter, the present invention will be described in more detail with reference to Examples and the like, but the scope and content of the present invention can not be construed to be limited or limited by the following Examples. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit and scope of the present invention as set forth in the following claims. It is natural that it belongs to the claims.

Although there are differences in the structure and physical properties of the substituents depending on the kind of the substituent, the reaction principle and conditions of the examples may be applied to the substituent-containing compounds not described in the examples of this specification, Therefore, it is obvious to those skilled in the art that these substituent-containing compounds can be easily carried out based on the disclosure of the examples and common sense in the art.

Example

Example 1: Synthesis of (S) -2 - ((2'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate

White solid; Yield: 90%; ^{1 H NMR (300 MHz, DMSO-} d 6) δ 9.17 (br s, 2H), 7.94 (br s, 1H), 7.30-7.94 (m, 9H), 4.16 (m, 2H), 3.80 (q, J = 6.54 Hz, 1 H), 2.30 (s, 3 H), 1.45 (d, J = 6.93 Hz, 3 H); ^{13 C NMR (75 MHz, DMSO-} d 6) δ 170.9 (C (O)), 161.2, 157.9, 136.2, 131.7, 131.2, 131.1, 130.8, 130.5, 130.3, 129.5, 129.4, 128.1, 127.9, 125.5, 125.4 , 116.8, 116.5 (Ar C ), 55.1 (C (O) C H ⁺ NH ₂ ), 48.7 ( ⁺ NH ₂ C H ₂ Ph), 16.4 ( C H ₃ ). S C H ₃ signal overlaps DMSO signal.

Example 2: Synthesis of (S) -2 - ((3'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate

White solid; Yield: 97%; ^{1 H NMR (300 MHz, DMSO-} d 6) δ 9.15 (br s, 2H), 7.92 (br s, 1H), 7.81 (d, J = 8.25 Hz, 2ArH), 7.68 (br s, 1H), 7.49 -7.60 (m, 5ArH), 7.20-7.27 (m, 1ArH), 4.15 (s, 2H), 3.76 (q, J = 9.24 Hz, 1H), 2.30 (s, 3H), 1.44 (d, J = 9.28 Hz, 3H); ^{13 C NMR (75 MHz, DMSO-} d 6) δ 171.0 (C (O)), 164.9, 161.8, 161.6, 142.4, 142.3, 139.8, 132.0, 131.5, 131.4, 131.2, 127.5, 123.3, 115.2, 114.9, 114.1 , 113.8 (Ar C ), 55.0 (C (O) C H ⁺ NH ₂ ), 48.6 ( ⁺ NH ₂ C H ₂ Ph), 16.4 ( C H ₃ ). S C H ₃ signal overlaps DMSO signal.

Example 3: Synthesis of (S) -2 - ((4'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate

White solid; Yield: 88%; ¹ H NMR (300 MHz, DMSO- d ₆ ) ? 9.18 (br s, 2H), 7.95 (br s, 1H), 7.72-7.77 J = 8.16 Hz, 2ArH), 7.28-7.34 (m, 2ArH), 4.12-4.15 (m, 2H), 3.78-3.84 (m, 1H), 2.37 (s, 3H), 1.45 (d, J = 6.93 Hz , 3H); ^{13 C NMR (75 MHz, DMSO-} d 6) δ 171.0 (C (O)), 164.9, 161.8, 161.6, 142.4, 142.3, 139.8, 132.0, 131.5, 131.4, 131.2, 127.5, 123.3, 115.2, 114.9, 114.1 , 113.8 (Ar C ), 55.0 (C (O) C H ⁺ NH ₂ ), 48.6 ( ⁺ NH ₂ C H ₂ Ph), 16.4 ( C H ₃ ). S C H ₃ signal overlaps DMSO signal.

Example 4: Synthesis of (S) -2 - ((2'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate

White solid; Yield: 62%; ^{1 H NMR (300 MHz, DMSO-} d 6) δ 9.18 (br s, + N H 2), 7.96 (br s, 1C (O) N H H '), 7.67 (br s, 1C (O) NH H '), 7.59 (d, J = 8.1 Hz, 3Ar H), 7.52 (d, J = 8.2 Hz, 2Ar H), 7.39-7.47 (m, 3Ar H), 4.09-4.28 (m, 2 H), 3.86 -3.90 (m, 1H ), 2.30 (s, 3H ), 1.47 (d, J = 6.9 Hz, 3H ); ^{13 C NMR (75 MHz, DMSO-} d 6) δ 170.9 (C (O)), 139.8, 139.6, 131.9, 131.8, 131.7, 130.4, 130.0, 128.1, 55.2 (C (O) C H + NH 2), 48.7 ( ⁺ NH ₂ C H ₂ Ph), 16.4 ( C H ₃ ), S C H ₃ signal overlaps DMSO signal. The remaining peaks are not detected or are assumed to overlap with other signals.

Example 5: Synthesis of (S) -2 - ((3'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate

White solid; Yield: 90%; ^{1 H NMR (400 MHz, DMSO-} d 6) δ 9.16 (br s, 2H), 7.92 (br s, 1H), 7.81 (d, J = 8.14 Hz, 2ArH), 7.77 (br s, 1H), 7.67 J = 8.18 Hz, 1 ArH), 7.52 (t, J = 7.88 Hz, 1 ArH), 7.46 (d, J = 8.1 Hz, 2H), 3.78 (d, J = 6.7 Hz, 1H), 2.30 (s, 3H), 1.45 (d, J = 6.7 Hz, 3H); ^{13 C NMR (75 MHz, DMSO-} d 6) δ 170.9 (C (O)), 141.9, 139.5, 134.3, 132.0, 131.3, 131.2, 128.7, 127.5, 126.9, 125.9 (Ar C), 55.1 (C (O ) C H ⁺ NH ₂ ), 48.6 ( ⁺ NH ₂ C H ₂ Ph), 16.4 ( C H ₃ ). S C H ₃ signal overlaps DMSO signal.

Example 6: Synthesis of (S) -2 - ((4'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate

White solid; Yield: 84%; ¹ H NMR (300 MHz, DMSO- d ₆ ) ? 9.17 (br s, 1 H), 7.94 (br s, 1 H), 7.73-7.78 m, 4ArH), 4.10-4.20 (m, 2H), 3.76-3.82 (m, 1H), 2.32 (s, 3H), 1.45 (d, J = 6.93 Hz, 3H); ^{13 C NMR (100 MHz, DMSO-} d 6) δ 170.9 (C (O)), 139.9, 138.6, 133.2, 131.7, 131.2, 129.5, 129.4, 129.0, 127.3 (Ar C), 54.9, (C (O) C H ⁺ NH ₂ ), 48.5 ( ⁺ NH ₂ C H ₂ Ph), 16.3 ( C H ₃ ). S C H ₃ signal overlaps DMSO signal.

Example 7: Synthesis of (S) -2 - ((2'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate

White solid; Yield: 87%; ^{1 H NMR (300 MHz, DMSO-} d 6) δ 9.20 (br s, + N H 2), 7.94 (br s, 1C (O) N H H '), 7.85 (d, J = 7.8 Hz, 1Ar H ), 7.75 (t, J = 7.4 Hz, 1Ar H), 7.61-7.67 (m, 2Ar H), 7.57 (d, J = 7.2 Hz, 1Ar H), 7.39-7.41 (m, 2Ar H, 1C (O ) NH H '), 4.11-4.22 ( m, 2 H), 3.86-3.88 (m, 1 H), 2.32 (s, 3 H), 1.47 (d, J = 6.7 Hz, 3 H); ^{13 C NMR (75 MHz, DMSO-} d 6) δ 170.9 (C (O)), 140.5, 140.4, 132.8, 132.5, 131.9, 130.1, 129.4, 128.7, 127.3 (q, J C- F = 29.2 Hz), _{126.5 (q, J CF = 5.2} Hz), 124.6 (q, J CF = 270.5 Hz), 55.4 (C (O) C H + NH 2), 48.8 (+ NH 2 C H 2 Ph), 40.2 ( S C H ₃ ), 16.4 ( C H ₃ ).

Example 8: Synthesis of (S) -2 - ((3'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate

White solid; Yield: 92%; ^{1 H NMR (400 MHz, DMSO-} d 6) δ 9.16 (br s, 2H), 7.988.02 (m, 2ArH), 7.90 (br s, 1H), 7.84 (d, J = 8.10 Hz, 2ArH), 7.69-7.76 (m, 2ArH), 7.65 (br s, 1H), 7.59 (d, J = 8.10 Hz, 2ArH), 4.14 (m, 2H), 3.76 (d, J = 5.36 Hz, 1H), 2.27 ( S, 3H), 1.43 (d, J = 6.88 Hz, 3H); ^{13 C NMR (100 MHz, DMSO-} d 6) δ 170.9 (C (O)), 140.9, 139.5, 132.2, 131.3, 131.2, 130.7, 130.5, 130.2, 129.9, 128.7, 127.7, 126.0, 124.8, 123.6, 123.3 (Ar 2 C ), 55.0 (C (O) C H ⁺ NH ₂ ), 48.5 ( ⁺ NH ₂ C H ₂ Ph), 16.4 ( C H ₃ ). S C H ₃ signal overlaps DMSO signal.

Example 9: Synthesis of (S) -2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate

White solid; Yield: 82%; ^{1 H NMR (300 MHz, DMSO-} d 6) δ 9.17 (br s, 2H), 7.93-7.96 (m, 3H), 7.84 (d, J = 7.65 Hz, 4H), 7.63-7.66 (m, 3H) , 4.12-4.23 (m, 2H), 3.78-3.83 (m, IH), 2.32 (s, 3H), 1.46 (d, J = 6.93 Hz, 3H); ^{13 C NMR (75 MHz, DMSO-} d 6) δ 170.9 (C (O)), 143.8, 139.6, 132.4, 131.3, 128.8, 128.4, 128.0, 127.8, 126.6, 126.3, 126.2, 123.0 (Ar C), 54.9 (C (O) C H ⁺ NH ₂ ), 48.5 ( ⁺ NH ₂ C H ₂ Ph), 16.4 ( C H ₃ ). S C H ₃ signal overlaps DMSO signal.

Example 10: (S) -2 - (((3'-Trifluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate

White solid; Yield: 90%; ^{1 H NMR (300 MHz, DMSO-} d 6) δ 9.16 (br s, 2H), 7.92 (br s, 1H), 7.83 (d, J = 8.22 Hz, 2ArH), 7.77 (d, J = 8.22 Hz, 2H), 3.77 (q, J = 7.08 Hz, 1H), 2.30 (s, 3H), 1.44 (d, 1H), 7.59-7.69 (m, 5H), 7.39-7.42 , ≪ / RTI > J = 6.99 Hz, 3H); ^{13 C NMR (100 MHz, DMSO-} d 6) δ 170.9 (C (O)), 149.5, 142.2, 139.4, 132.2, 131.5, 131.3, 131.2, 127.6, 126.3, 124.4, 121.9, 120.5, 119.8, 119.7, 119.3 (Ar 2 C ), 55.0, (C (O) C H ⁺ NH ₂ ), 48.5 ( ⁺ NH ₂ C H ₂ Ph), 16.4 ( C H ₃ ). S C H ₃ signal overlaps DMSO signal.

Example 11: Synthesis of (S) -2 - ((4'-trifluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate

White solid; Yield: 92%; ^{1 H NMR (400 MHz, DMSO-} d 6) δ 9.17 (br s, 2H), 7.92 (br s, 1H), 7.83 (d, J = 8.68 Hz, 2ArH), 7.78 (d, J = 8.16 Hz, 2ArH), 7.67 (br s, 1H), 7.59 (d, J = 8.12 Hz, 2ArH), 7.48 (d, J = 8.20 Hz, 2ArH), 4.16 (s, 2H), 3.78 (s, 1H), 2.30 (s, 3H), 1.44 (d, J = 6.96 Hz, 3H); ^{13 C NMR (100 MHz, DMSO-} d 6) δ 170.9 (C (O)), 148.5, 139.7, 139., 131.8, 131.3, 131.2, 129.2, 129.1, 127.6, 127.5, 124.4, 122.1, 121.9, 121.8, 119.8, 116.7 (Ar C ), 55.3, 55.1, 54.9, 54.7 (C (O) C H ⁺ NH ₂ ), 48.6 ( ⁺ NH ₂ C H ₂ Ph), 16.4 ( C H ₃ ). S C H ₃ signal overlaps DMSO signal.

Example 12: Synthesis of (S) -2 - ((3'-methoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate

White solid; Yield: 91%; ^{1 H NMR (400 MHz, DMSO-} d 6) δ 9.14 (br s, 2H), 7.91 (br s, 1H), 7.76 (d, J = 8.16 Hz, 2ArH), 7.66 (br s, 1H), 7.66 (br s, 1 H), 7.40 (t, J = 7.92 Hz, 3 ArH), 7.26 (d, J = 7.76 Hz, 1 ArH), 7.21 2H), 3.83 (s, 3H), 3.77 (q, J = 6.96 Hz, 1H), 2.30 (s, 3H), 1.44 (d, J = 6.96 Hz, 3H); ^{13 C NMR (75 MHz, DMSO-} d 6) δ 170.9 (C (O)), 160.3, 141.3, 141.1, 131.4, 131.1, 130.6, 127.4, 119.5, 113.8, 112.7 (Ar C), 55.6, 54.9 (C (O) C H ⁺ NH ₂ ), 48.6 ( ⁺ NH ₂ C H ₂ Ph), 16.4 ( C H ₃ ). S C H ₃ signal overlaps DMSO signal.

Example 13: Synthesis of (S) -2 - ((4'-methoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate

White solid; Yield: 84%; ^{1 H NMR (300 MHz, DMSO-} d 6) δ 9.14 (br s, 2H), 7.92 (br s, 1H), 7.64-7.72 (m, 5H), 7.54 (d, J = 8.25 Hz, 2H), 7.04 (d, J = 8.79 Hz, 2ArH), 4.13 (s, 2H), 3.72-3.89 (m, 4H), 2.31 (s, 3H), 1.44 (d, J = 6.96 Hz, 3H); ^{13 C NMR (75 MHz, DMSO-} d 6) δ 170.9 (C (O)), 159.6, 140.9, 132.1, 131.0, 128.4, 128.2, 126.8, 115.2, 115.0, 114.8, 114.6 (Ar C), 55.8, 55.6 , 54.9, 54.8 (C (O) C H ⁺ NH ₂ ), 48.7 ( ⁺ NH ₂ C H ₂ Ph), 16.4 ( C H ₃ ). S C H ₃ signal overlaps DMSO signal.

Example 14: Synthesis of (R) -2 - ((3'-fluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate

White solid; Yield: 87%; ^{1 H NMR (300 MHz, DMSO-} d 6) δ 9.16 (br s, 2H), 7.93 (br s, 1H), 7.81 (d, J = 8.07 Hz, 2H), 7.67 (br s, 1H), 7.49 (M, 2H), 3.79 (q, J = 6.93 Hz, 1H), 2.30 (s, 3H), 1.44 (d, J = 6.90 Hz, 3H); ^{13 C NMR (75 MHz, DMSO-} d 6) δ 170.9, (C (O)), 164.8, 161.6, 142.3, 142.2, 139.7, 139.6, 132.0, 131.5, 131.4, 131.2, 127.5, 123.3, 123.2, 115.1, 114.8, 114.0, 113.7 (Ar C ), 55.0 (C (O) C H ⁺ NH ₂ ), 48.6 ( ⁺ NH ₂ C H ₂ Ph), 16.4 ( C H ₃ ). S C H ₃ signal overlaps DMSO signal.

Example 15: Synthesis of (R) -2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate

White solid; Yield: 87%; ^{1 H NMR (300 MHz, DMSO-} d 6) δ 9.18 (br s, 2H), 7.93-7.95 (m, 3H), 7.84 (d, J = 7.89 Hz, 4H), 7.62-7.66 (m, 3H) , 4.12-4.22 (m, 2H), 3.80 (q, J = 6.27 Hz, 1H), 2.31 (s, 3H), 1.45 (d, J = 6.78 Hz, 3H); ^{13 C NMR (75 MHz, DMSO-} d 6) δ 170.9 (C (O)), 143.8, 139.5, 132.4, 131.3, 130.2, 129.2, 128.8, 128.4, 128.0, 127.7, 126.6, 126.3, 126.2, 123.0, 119.4 (Ar 2 C ), 55.1 (C (O) C H ⁺ NH ₂ ), 48.6 ( ⁺ NH ₂ C H ₂ Ph), 16.4 ( C H ₃ ). S C H ₃ signal overlaps DMSO signal.

Example 16: Synthesis of (R) -2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) acetamide methanesulfonate

White solid; Yield: 90%; ¹ H NMR (300 MHz, DMSO- d ₆ ) ? 9.26 (br s, ⁺ NH ₂ ), 7.91-7.93 (m, 2ArH, 1C (O) NHH '), 7.79-7.82 (d, J = 7.2 Hz, 2ArH), 7.58 (br s, C (O) NHH '), 4.25 (s, 2H), 3.71 (s, 2H), 2.40 ^{13 C NMR (75 MHz, DMSO-} d 6) δ 167.3 (C (O)), 143.8, 139.6, 132.3, 131.4, 128.6 (q, J CF = 31.7 Hz), 128.0, 127.7, 126.3 (q, J CF = 3.7 Hz), 124.8 (q, J _CF = 270.2 Hz) (ArC), 49.9 (C (O) CH ⁺ NH ₂ ), 47.3 ( ⁺ NH ₂ CH ₂ Ph), 40.1 (SCH ₃ ).

Example 17: Synthesis of (R) -3-methyl-2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) butanamide methanesulfonate

White solid; Yield: 74%; ^{1 H NMR (300 MHz, DMSO-} d 6) δ 9.20 (br s, + N H H '), 8.95 (br s, + NH H'), 7.78-7.96 (m, 6Ar H, C (O) N _{H 2), 7.60-7.65 (m,} 2Ar H), 4.02-4.18 (m, 2 H), 3.47-3.69 (m, 1 H), 2.30 (s, 3 H), 2.16-2.22 (m, 1 H ), 0.92-1.00 (m, 6 H ); ^{13 C NMR (75 MHz, DMSO-} d 6) δ 168.4 (C (O)), 143.8, 139.6, 131.8, 131.7, 128.6 (q, J CF = 31.8 Hz), 126.3 (q, J CF = 3.7 Hz) _{, 124.8 (q, J CF =} 270.2 Hz), 64.1 (C (O) C H + NH 2), 49.7 (+ NH 2 C H 2 Ph), 40.2 (S C H 3), 29.3 (CH C H 2 _{), 19.1 (C H 3)} , 18.1 (C H 3).

Example 18: Synthesis of (R) -4-methyl-2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) pentanamide methanesulfonate

White solid; Yield: 77%; ^{1 H NMR (300 MHz, DMSO-} d 6) δ 9.30 (br s, + N H H '), 9.16 (br s, + NH H'), 8.13 (br s, C (O) N H H ') , 7.94 (d, J = 7.85 Hz, 2Ar H), 7.84 (d, J = 7.80 Hz, 4Ar H), 7.79 (br s, C (O) NH H '), 7.63 (d, J = 7.85 Hz, 2Ar H), 4.05-4.25 (m, 2 H), 3.70-3.83 (m, 1 H), 2.35 (s, 3 H), 1.59-1.79 (m, 1C H, 2CHC H 2), 0.80-1.03 ( m, 6 H ); ^{13 C NMR (75 MHz, DMSO-} d 6) δ 169.9 (C (O)), 143.8, 139.6, 132.2, 131.4, 128.6 (q, J CF = 31.9 Hz), 128.4, 127.7, 126.3 (q, J CF = 3.7 Hz), 124.8 (q , J C -F = 270.3 Hz), 58.4 (C (O) C H + NH 2), 49.0 (+ NH 2 C H 2 Ph), 40.2 (S C H 3), 24.4, 23.5, 22.3. The remaining peaks are not detected or are assumed to overlap with other signals.

Test Example 1: Inhibitory effect of monoamine oxidase B activity (MAO-B assay)

10 mM compound was diluted 10 times and prepared at 5 concentrations, 1 mM, 0.1 mM, 0.01 mM, 0.001 mM and 0.0001 mM. 0.05 M sodium phosphate (pH 7.4) buffer and diluted 1/200 with monoamine oxidase B type human-derived enzyme at a concentration of 5 mg / mL, mixed with 2 μL of 5 concentrations of compound solution, and a total of 100 μL enzyme buffer 96 plate and reacted for 1 hour. Working buffer (200 μL) containing 20 mM Amplex red (200 μL), 100 mM benzylamine substrate (200 μL) and 200 U / mL horseradish peroxidase (100 μL) were added to 0.05 M sodium phosphate buffer And incubated for 2 hours with 1: 1 enzyme buffer (100 μL), followed by measurement with absorbance (570 nm).

The activity of the compounds of the present invention was verified using safinamide, which is well known as a reversible Mao inhibitor, as a control. As a result, as shown in Table 1 below, introduction of various functional groups at the X position of the biphenyl resulted in excellent activity when the functional group was introduced into the para position rather than the ortho and meta position. When -CF ₃ and -OCF ₃ were introduced, excellent inhibitory effect was confirmed. Compound 9 exhibited the best activity and showed more than two times better activity than sapinamide. Compound 15, which is a stereoisomer of Compound 9, showed excellent activity, but tended to decrease slightly compared to Compound 9. An alkyl group such as hydrogen, isopropyl, or isobutyl group was introduced instead of the methyl group at the R position. Compound 16 incorporating a hydrogen group showed a slight decrease in activity, while a decrease in activity was observed when isopropyl and isobutyl groups larger in size than the methyl group were introduced.

Compound Stereo R X MAO-B
(IC ₅₀ , uM) MAO-A
(IC ₅₀ , uM) One S CH ₃ 2'-F > 10 > 100 2 S CH ₃ 3'-F > 10 > 100 3 S CH ₃ 4'-F > 10 > 100 4 S CH ₃ 2'-Cl > 10 > 100 5 S CH ₃ 3'-Cl 0.442 > 100 6 S CH ₃ 4'-Cl 0.416 > 100 7 S CH ₃ 2'-CF ₃ > 10 > 100 8 S CH ₃ 3'-CF ₃ 0.316 > 100 9 S CH ₃ 4'-CF ₃ 0.042 > 500 10 S CH ₃ 3'-OCF ₃ 0.216 > 100 11 S CH ₃ 4'-OCF ₃ 0.098 > 100 12 S CH ₃ 3'-OCH ₃ 3.33 > 100 13 S CH ₃ 4'-OCH ₃ 1.06 > 100 14 R CH ₃ 3'-F > 10 > 100 15 R CH ₃ 4'-CF ₃ 0.082 > 100 16 S H 4'-CF ₃ 0.126 > 100 17 S CH (CH _{3) 2} 4'-CF ₃ 4.073 > 100 18 S CH ₂ CH (CH ₃ ) ₂ 4'-CF ₃ 5.302 > 100 (S) -safinamide 0.112 > 100 selegiline 0.009 ~ 1

Hereinafter, a test example in which only the 9th compound among the above compounds is typically used is verified, and in the case of other compounds, the test can be easily conducted and the effect can be confirmed by the same method based on the disclosure contents of the present invention It is clear that.

Test Example 2: Reversible inhibition effect test

And proceeded in the same manner as shown in Fig. 0.05 M sodium phosphate (pH 7.4) buffer was prepared and monoamine oxidase B type human-derived enzyme at a concentration of 5 mg / mL was diluted 1/40 with buffer and reacted with each 0.1 mM compound for 2 hours. The reaction mixture was transferred to a 96-well plate and centrifuged at 14,000 g for 20 minutes using a centrifuge (B). After centrifugation at 14,000 g for 20 minutes, 0.05 M sodium phosphate buffer (pH 7.4) was added to the centrifugal filter. The monoamine oxidase B type human-derived enzyme remaining in the centrifugal filtration filter was diluted with a 0.05 M sodium phosphate (pH 7.4) buffer to a centrifugal filter and transferred to a 96-well plate. Then add 20 μL Amplex red (200 μL), 100 μM benzylamine substrate (200 μL) and 200 U / mL horseradish peroxidase (100 μL) to 0.05 M sodium phosphate (pH 7.4) buffer The working buffer (100 μL) was mixed with the reacted enzyme buffer (1: 1) and incubated for 2 hours.

In addition, the reversibility of the compounds of the present invention was confirmed using selegiline, which is well known as an irreversible Mao inhibitor, as a result. As shown in Table 2 below, when 1 μM of both compounds was treated 80% inhibition effect. When the Mao Biogen activity was verified again after three washes of the buffer with the buffer, the selenizin which remained irreversibly retained its inhibitory effect as it was. However, the compound of the present invention was washed out during the washing process, . It was confirmed that the compound of the present invention was a reversible inhibitor on the basis that the inhibitory compound was removed by washing and the Maobienzyme activity was restored.

Compound (1 [mu] M) A. Mao inhibitory efficacy B. Mao inhibitory efficacy Recovered maoi activity Reversibility Selegiline > 90% > 90% 0% Irreversible Compound 9 82% <15%  > 85% Reversible

Test Example 3: Efficacy of Compound 9 in MPTP mouse model of Parkinson's disease model

Compound 9 was compared with efficacy of sapinamide (safinamide), a conventional maio inhibitor, in MPTP mouse model of Parkinson's disease model. To induce Parkinson's disease, 20 mg / kg of MPTP was intraperitoneally injected, and 10 mg / kg of various Mao inhibitors including Compound 9 were orally administered. To evaluate the effect of MAO inhibitor for three days before the injection of MPTP, TH (tyrosine hydroxylase) used as a marker of dopaminergic neurons was quantitatively analyzed by immunohistochemistry. The brain region for analysis was selected from black and streaks of dopaminergic neurons, and it is well known that the expression of TH in these regions is significantly reduced when Parkinson 's disease is present. In the experiments below, compound 9 was found to inhibit dopamine neurons, which are destroyed by MPTP by inhibiting Mao.

(1) First, the compound 9 was pretreated in advance, and the efficacy in the MPTP mouse model treated with MPTP was verified.

As a result, as shown in FIG. 2A, in the model treated with MPTP alone, the expression of TH was markedly decreased in tyrosine hydroxylase staining compared to the control (saline), indicating that the number of dopaminergic neurons was remarkably decreased . However, dopaminergic neurons were found to be alive in the model treated with saponamide and compound 9, a Mao inhibitor, similar to the control group.

(2) Next, the MPTP mice were first treated with MPTP, and after 3 days, compounds were treated to confirm that the dopaminergic neurons in the Parkinson's disease model were restored through Mao inhibition.

As a result, as shown in FIG. 2B, it can be confirmed that neurons are killed in the MPTP treatment group as in the pre-treatment experiment, but in the model treated with saponamide and 9, And it was confirmed that it significantly reduced the death. In particular, it was confirmed that compound 9 recovered dopaminergic neurons in a similar level to the control group not treated with MPTP.

(3) Next, based on the long-term use of the drug in clinical trials, a Mao inhibitor was administered for 30 days to confirm the effect of the MPTP Parkinson's model on neuronal cell protection. In the striatum, both irreversible inhibitors selenazine and compound 9 protected dopaminergic neurons to a similar level as controls without MPTP. Sapinamide showed slightly lower efficacy. On the other hand, the effect of the irreversible inhibitor, selegiline, on the other hand, decreased in number, and the number of nerve cells was not significantly recovered as compared with the MPTP group. However, Compound 9, a reversible inhibitor, protected nerve cells in a similar manner to the control. It was confirmed that celecoxib inhibits Mao inhibitory effect by the irreversible inhibition of selenoglyphine by long - term administration of celecoxib, which is a reason why it does not have any effect on the treatment of Parkinson 's disease. That is, as shown in FIG. 2C, in the above three MPTP Parkinsonian mouse model efficacy experiments, Compound 9 was found to be superior to selegiline and sapaminamide.

Test Example 4: Effectiveness of Compound 9 in APP / PS1 mouse model of Alzheimer's disease model

The present inventors recently revealed new possibilities for the treatment of Alzheimer's disease through Mao inhibition (Jo et al., Nature Medicine 2014). In the above study, as shown in Fig. 3, the irreversible Mao inhibitor, selenazine, initially exhibited excellent efficacy in the Alzheimer's disease model, but when treated for 2 weeks, the effect was remarkably decreased. When treated for 4 weeks, , Whereas sapinamide, a reversible Mao inhibitor, has been shown to maintain excellent efficacy in the two-week treatment group.

In Experimental Example 4, the above experiment was conducted using Compound 9 to confirm the efficacy of the reversible Mao inhibitor in APP / PS1 mice. First, compound 9 was mixed with water to which APP / PS1 mice were given and allowed to take a dose of 10 mg / kg / day for 2 weeks. After 2 weeks of administration, brain tissue sections were prepared and the electrodes were connected to the granule cells of the dentate gyrus by a patch-clamp technique. This electrode can detect the change of cell membrane potential difference and ignition of granule neurons. The spike probability was calculated by counting the number of stimulation of granulocyte cells by applying electric stimulation 10 times to the teeth. As a result of measuring the firing probability according to the stimulation while changing the intensity of the electric stimulus after treating the compound 9 for 2 weeks, the efficacy was excellent as shown in FIG. 3B, and the efficacy was higher than that of the safinamide.

Test Example 5: Differential and superiority test of Compound 9 compared to sapinamide

Sapinamide, a conventional reversible Mao inhibitor, is known to be an inhibitor of sodium and calcium channels, as well as a Mao inhibitor. Such channel inhibition is minimized, and selective treatment of Parkinson's disease and Alzheimer's disease through inhibition of Mao can secure stability as a therapeutic agent for brain diseases. In order to verify this channel inhibition effect, we used electrophysiology experiments to determine how to inhibit channel excitability by using hippocampal DGGCs (dentate gyrus granule cells).

As can be seen from FIG. 4, sapinamide showed an excitability inhibitory effect of about 40% at 10 μM, while compound 9 was hardly inhibited. Compared with sapinamide, compound 9 exhibited a lower inhibitory effect than that of sapinamide even at a high concentration of 50 [mu] M, indicating that the hippocampal DGGCs had significantly less excitability inhibition than sapinamide. This result shows that Compound 9 has a stability as a selective Mao inhibitor through a significantly lower channel inhibitory effect than sapinamide.

Test Example 6: Molecular modeling of compound 9 and saponamide against Mao

Binding mode was predicted by docking experiment of compound 9 against maobee. First, the binding mode of sapinamide, a reversible inhibitor, was predicted using the MaoBi X-ray crystal structure, and as shown in FIG. 5, the binding strength was excellent in the pocket known as MaoBi's active site (SP score: 10.862 kcal / mol). In the same manner, compound 9 was found to bind to active sites such as sapinamide, and binding force was predicted better than sapinamide (SP score: -11.795 kcal / mol).

Claims (20)

An alpha-aminoamide derivative having the structure of Formula 1:
[Chemical Formula 1]

R is hydrogen or an alkyl group;
Wherein X is selected from the group consisting of hydrogen, a halogen group, an alkyl group, a halogenated alkyl group, an alkoxy group, and a halogenated alkoxy group. 2. The method of claim 1, wherein R is selected from hydrogen, C ₁ -C ₇ alkyl group;
Wherein X is selected from the group consisting of hydrogen, a halogen group, a C ₁ -C ₇ alkyl group, a halogenated C ₁ -C ₇ alkyl group, a C ₁ -C ₇ alkoxy group and a halogenated C ₁ -C ₇ alkoxy group. derivative. The method according to claim 1, wherein R is selected from the group consisting of hydrogen, methyl, ethyl, n -propyl, isopropyl, cyclopropyl, n -butyl, isobutyl, sec -butyl and tert -butyl;
Wherein X is selected from the group consisting of a halogen group, a halogenated methyl group, a halogenated ethyl group, a halogenated methoxy group, a halogenated ethoxy group, a methoxy group and an ethoxy group. The compound according to claim 1, wherein R is selected from among hydrogen, a methyl group, an isopropyl group, and an isobutyl group;
Wherein X is selected from the group consisting of a fluoro group, a chloro group, a trichloromethyl group, a trichloromethoxy group, and a methoxy group. The compound according to claim 1, wherein R is selected from among hydrogen, a methyl group, an isopropyl group, and an isobutyl group;
Wherein X is p - methyl trichlorosilane, p - trichloro Romero Messenger time, m - methyl trichlorosilane, m - trichloro Romero Messenger time, p - chloro group, m - chloro group, p - methoxy group, m - methoxy group, p - fluoro group, and m -fluoro group. The compound according to claim 1, wherein R is selected from among hydrogen, a methyl group, an isopropyl group, and an isobutyl group;
Wherein X is p-methyl trichlorosilane, p-trichloro Romero Messenger time, m-methyl trichlorosilane, m-trichloro Romero Messenger time, p-chloro group, m-chloro group, p-selected from methoxy-methoxy, m Amino-amide derivative. The alpha-aminoamide derivative according to claim 1, wherein R is hydrogen or a methyl group. The compound according to claim 1, wherein R is hydrogen or a methyl group;
Wherein X is p-methyl trichlorosilane, p-trichloro Romero Messenger time, m-methyl trichlorosilane, m-trichloro Romero Messenger time, p-chloro group, m-chloro group, p-selected from methoxy-methoxy, m Amino-amide derivative. The compound according to claim 1, wherein R is hydrogen or a methyl group;
Wherein X is p-methyl trichlorosilane, p-trichloro Romero Messenger time, m-methyl trichlorosilane, m-amino derivative-trichloro Romero Messenger alpha, characterized in that is selected from the group. The compound according to claim 1, wherein R is hydrogen or a methyl group;
Wherein X is a p -trichloromethyl group or p -trichloromethoxy. The compound according to claim 1, wherein R is a methyl group;
Wherein X is a p -trichloromethyl group or p -trichloromethoxy. The compound according to claim 1, wherein R is a methyl group;
Wherein X is a p -trichloromethyl group. The alpha-aminoamide derivative according to claim 1, wherein the alpha-aminoamide derivative is selected from the following compounds:
(S) -2 - (((2'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((3'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((4'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((2'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((3'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - ((4'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((2'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((3'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((3'-trifluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((4'-trifluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((3'-methoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((4'-methoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(R) -2 - ((3'-fluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(R) -2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(R) -2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) acetamide methanesulfonate,
(R) -3-methyl-2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) butanamide methanesulfonate,
(R) -4-methyl-2 - (((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) pentanamide methanesulfonate. The alpha -aminoamide derivative according to any one of claims 1 to 12, wherein the alpha-aminoamide derivative is (S) -isomer. 14. A monoamine oxidase B (MAO-B) inhibitor comprising an alpha-aminoamide derivative according to any one of claims 1 to 13 or a pharmaceutically acceptable salt or solvate thereof. 14. A pharmaceutical composition for treating or preventing degenerative neurological diseases, comprising an alpha-aminoamide derivative according to any one of claims 1 to 13 or a pharmaceutically acceptable salt or solvate thereof. The pharmaceutical composition according to claim 16, wherein the degenerative neurological disease is selected from Parkinson's disease, Alzheimer's disease, epilepsy, and depression. 14. A pharmaceutical composition for treating or preventing degenerative neurological diseases, comprising an alpha-aminoamide derivative according to claim 14 or a pharmaceutically acceptable salt or solvate thereof. The pharmaceutical composition for treating or preventing a neurodegenerative disease according to claim 18, wherein the degenerative neurological disease is selected from Parkinson's disease and Alzheimer's disease. (A) reacting a compound represented by the following formula (1a) with a compound represented by the following formula (1b) to synthesize a compound represented by the following formula (1c):
[Formula 1a]

[Chemical Formula 1b]

[Chemical Formula 1c]

;
(B) reacting the compound of Formula 1c with a compound of Formula 1d to synthesize a compound of Formula 1e:
&Lt; RTI ID = 0.0 &

[Formula 1e]

(C) converting the compound of formula (1e) into an alpha-aminoamide derivative of formula (1): &lt; EMI ID =
[Chemical Formula 1]

Wherein R is selected from among hydrogen, a methyl group, an ethyl group, an n -propyl group, an isopropyl group, a cyclopropyl group, an n -butyl group, an isobutyl group, a sec -butyl group and a tert -butyl group;
X is selected from a halogen group, a halogenated methyl group, a halogenated ethyl group, a halogenated methoxy group, a halogenated ethoxy group, a methoxy group and an ethoxy group.

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