KR100373485B1 - Novel isoxazole piperazine derivatives and preparation thereof - Google Patents

Abstract

The present invention relates to a novel isoxazole piperazine derivative and a method for preparing the same, wherein the isoxazole piperazine derivative acts as an antagonist of the dopamine-1 receptor associated with various central nervous system disorders, and its structure is represented by Chemical Formula 1 Same as

R ₁ -R ₅ in Formula 1 are each independently hydrogen, alkyl, alkoxy, halogen, hydroxy, hydroxymethyl, aryl, heteroaryl, amino, alkylamino, alkenyl, carbonyl, cycloalkyl, heterocyclic group R ₆ is hydrogen, alkyl, alkoxy, halogen, aryl, pyridyl group, heterocyclic group or pyrimidyl group, X is nitrogen or carbon, n is 1-4; Q is isoxazole (A) or 4,5-dihydroisoxazole (B) derivative, n has 1-4.

The production method is a condensation reaction between amine and aldehyde, and is the same as in Scheme 1.

Description

Novel isoxazole piperazine derivatives and preparation method thereof {NOVEL ISOXAZOLE PIPERAZINE DERIVATIVES AND PREPARATION THEREOF}

The present invention relates to an isoxazole piperazine-based compound having a physiological activity with respect to the dopamine receptor and a method for producing the same.

Haloperidol (Psychopharmacologia. 1971. 22 (1) .P 31-44) or Trifluperidol (Chem. Biol), a piperidine and piperazine ring system involved in the treatment of schizophrenia in the 1950s 1 nteract 1972 4 (6) P427-39) has been reported as a selective antagonist of receptors with antipsychotic activity. The tertiary amino group attached to the fourth carbon of the butyrophenones skeleton structure was essential for the activity, and this site maintains antipsychotic effects and is a modifiable part. When three carbons next to the ketone group were lengthened, shortened, or attached to side chains, the activity was lowered. In addition, side effects due to hypersensitivity reactions due to long-term blockade of central dopamine receptors have been reported in long-term treatment.

It is therefore an object of the present invention to provide novel analogs and methods for their preparation by introducing isoxazole derivatives in place of restrictive ketone groups and benzene ring fluorine substituents while modifying tertiary amino groups.

Ixoxazole piperazine-based compound of the present invention has the following formula (1).

[Formula 1]

R ₁ -R ₅ in Formula 1 are each independently hydrogen, alkyl, alkoxy, halogen, hydroxy, hydroxymethyl, aryl, heteroaryl, amino, alkylamino, alkenyl, carbonyl, cycloalkyl, heterocyclic group R ₆ is hydrogen, alkyl, alkoxy, halogen, aryl, pyridyl group, heterocyclic group or pyrimidyl group, X is nitrogen or carbon, n is 1-4; Q is isoxazole (A) or 4,5-dihydroisoxazole (B) derivative, n has 1-4.

Acceptable salts of compounds of formula 1 include nontoxic inorganic acids, nontoxic salts formed from organic acids, or quaternary ammonium salts. Examples of inorganic acids include hydrogen chloride, hydrogen bromide, sulfonic acid, amido sulfuric acid, phosphoric acid and nitric acid. Organic acids include propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid, methanesulfonic acid and Same things are possible.

Acceptable salts of the present invention are the steps used for the purpose of purification in the development of the manufacturing process, and are synthesized by chemical methods from the compound of the formula (1) containing a base. In general, the salts can be formed in a mixed solvent of organic solvents such as methanol, chloroform, methylene chloride, ether, and these solvents, and by reaction with free amines using an excess of an organic acid or an equivalent of an organic acid. Can be generated.

The compounds of the present invention may have a chiral center and racemic forms, individual isomers, or all possible isomers may be produced.

Alkyl of R ₁ -R ₆ denotes an alkyl having 1-6 carbon atoms or a cycloalkyl group having 5-7 carbon atoms. Examples of preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. Examples of preferred cycloalkyl groups include cyclopentyl and cyclohexyl. Alkoxy refers to an alkyl group of carbon linked to oxygen. Alkylamino group refers to an alkyl group to which carbon atoms are connected through a nitrogen atom. Aryl refers to an aromatic ring. Aryl is one ring having at least six atoms, two rings having 10 atoms, or a state that is resonance-stabilized by a double bond to adjacent carbon atoms. Examples of the aryl group include phenyl and naphthyl, and may have substituents such as alkyl, halogen, alkoxy and phenoxy. Heteroaryl refers to a single ring aromatic group having 5-6 ring atoms, a bicyclic aromatic group having 8-10 atoms, and includes at least one hetero atom such as N, O, S, or the like. Examples of this form include pyrrole, pyridine, oxazole, thiazole, oxazine and the like. Heterocycle refers to a heterocycle consisting of 5-7 atoms that are stable, regardless of saturation or unsaturation, and consists of 1-3 heteroatoms and carbon atoms consisting of N, O, and S. Examples of such heterocycles are pyridine, pyrazine, pyrimidine, pyridazine, triazine, imidazole, triazole, quinoline, isoquinoline, quinazoline, quinoxaline, phthalazine, oxazole, isoxazole, thia N-oxide derivatives of basic nitrogen with sol, isothiazole, thiadiazole, oxadiazole, pyrrole, furan, thiophene, and hydrogenated derivatives such as piperidine, pyrrolidine, azetidine, tetrahydrofuran It includes, and may have a substituent such as alkyl, amine, alkylamino, halogen (F, Cl, Br, I).

In summary, the method for preparing the compound of the present invention is to synthesize the compound of Formula 1 by reacting the compounds of Formulas 2 and 3 in the presence of a base and a reducing agent, as shown in Scheme 1 below.

Scheme 1

In more detail, the preparation method is a synthetic step of synthesizing the compound of Chemical Formula 1 by reacting the compounds of Chemical Formulas 2 and 3, followed by extraction with an organic solvent and separating the desired product by hydrogen chloride therefrom. It consists of a series of purification processes and can be divided into two stages.

The first step is to prepare an alkylamine by reacting the starting amine secondary amine of formula 2 with the aldehyde of formula 3 in the presence of a reducing agent. All reactions were performed at room temperature under a nitrogen atmosphere. During the reaction, molecular sieves (molecular s1eve, 4A, beads, 4-8 mesh) were used. When the reactivity of the starting material was low, 1-3 equivalents of glacial acetic acid was added as an additive during the reaction. Reducing agents that can be used in the reaction may be NaBH (OAc) ₃ , NaBH ₃ CN, NaBH ₄ and the like, in this manufacturing process is a reducing agent for reducing the imine produced by the condensation reaction of amine and aldehyde NaBH (OAc ) ₂ to 3 equivalents. The equivalents that can be used vary from 2-10 equivalents depending on the reactivity. Tetrahydrofuran, 1,2-dichloroethane, acetonitrile and methylene chloride may be used as the reaction solvent, and methylene chloride was used in this manufacturing process. The reaction time is about 3-24 hours, preferably 12-14 hours. The progress of the reaction was tracked using Thin-layer Chromatography. After the reaction was completed, saturated NaHCO ₃ aqueous solution was added and the reaction was extracted with a suitable organic solvent. Ether, methylene chloride or ethyl acetate can be used as the organic solvent for extraction, and the most suitable organic solvent for extraction is methylene chloride.

The second step is to separate the target compound purely from the extracted organic solvent layer in the form of a salt without any purification. The extracted solvent is dried, evaporated, the residue is dissolved in a small amount of ether, and about 1-10 equivalents of an ether solution of hydrogen chloride is added to produce the hydrochloride of the desired target compound in the form of a white solid. As the organic solvent that can be used to prepare the hydrogen chloride solution, chloroform, methylene chloride, ether, methanol, ethyl acetate or a mixed solvent thereof can be used, preferably ether is useful. At this time, the product obtained in the form of a white solid can be separated using a centrifuge or a solvent removal device using a simple cotton. The solid is washed 2-3 ml of ether over 2-3 times and dried well to obtain a high purity target compound as a white solid.

The following examples show in more detail the preparation of compounds having formula (1).

Example 1

1- (5-{[4- (2H-benzo [3,4-d] 1,3-dioxoren-5-yl-methyl) piperazinyl} isoxazol-3-yl) -3-phenoxy Synthesis of Cybenzene Hydrochloride

3- (3-phenoxyphenyl) isoxazole-5-carbaldehyde (13.0 mg, 0.05 mmol) was dissolved in 3 ml of well dried methylene chloride. To this was added about 5 grains of molecular sieve, 1-piperonylpiperazine (10 mg, 0.05 mmol), NaBH (OAc) ₃ (20 mg, 0.10 mmol). The reaction was carried out at room temperature for about 12 hours. After the reaction was completed, the mixture was stopped with concentrated NaHCO ₃ and extracted twice with about 10 ml of methylene chloride. The organic layer was dried over magnesium sulfate and then the solvent was removed. After 1 ml of ether was added, hydrogen chloride saturated in ether (Ethereal HCl) was slowly dropped. The resulting solid was well filtered using ether, washed twice with 2 ml of ether again and dried well. 25.9 mg (96.5%) of product were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.50 (br s, 4H), 2.59 (br s, 4H), 3.42 (s, 2H), 3.72 (s, 2H), 5.93 (s, 2H), 6.44 ( s, 1H), 6.73 (s, 2H), 6.84 (s, 1H), 7.03-7.15 (m, 4H), 7.26-7.41 (m, 4H), 7.53 (d, 1H)

Example 2

Synthesis of 5-{[4- (4-nitrophenyl) piperazinyl] methyl} -3- (2-phenylvinyl) isoxazole hydrochloride

3- (2-phenylvinyl) isoxazole-5-carbaldehyde (11.6 mg, 0.06 mmol), 1- (4-nitrophenyl) piperazine (12.0 mg, 0.06 mmol), molecular sieve (5 granules) , NaBH (OAc) ₃ (24.7 mg, 0.12 mmol) was reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 25.0 mg (92.9%) of product was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.71 (br t, 4H), 3.47 (br s, 4H), 3.78 (s, 2H), 6.47 (s, 1H), 6.83 (d, 2H, J = 9.48 Hz), 7.15 (d, 2H), 7.39 (m, 5H), 7.52 (d, 2H, J = 6.87 Hz), 8.13 (d, 2H, J = 9.33 Hz)

Example 3

Synthesis of 1- (5-{[4- (diphenylmethyl) piperazinyl] methyl} isoxazol-3-yl) -3-phenoxy benzene hydrochloride

3- (3-phenoxyphenyl) isoxazole-5-carbaldehyde (15.3 mg, 0.06 mmol), 1-diphenylmethylpiperazine (14.5 mg, 0.06 mmol), molecular sieve (5 granules), NaBH (OAc) ₃ (24.0 mg, 0.12 mmol) was reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 33.2 mg (96.5%) of product was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.47 (br s, 4H), 2.61 (br s, 4H), 3.75 (s, 2H), 4.25 (s, 1H), 6.44 (s, 1H), 7.04- 7.64 (overlap m, 19H)

Example 4

Synthesis of 4- (4-chlorophenyl) -1-{[3- (2-phenylvinyl) isoxazol-5-yl] methyl} piperidin-4-ol hydrochloride

3- (2-phenylvinyl) isoxazole-5-carbaldehyde (13.8 mg, 0.07 mmol), 4- (4-chlorophenyl) -4-hydroxypiperidine (14.7 mg, 0.07 mmol), min The self (5 granules), NaBH (OAc) ₃ (29.4 mg, 0.14 mmol) was reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 32.3 mg (99.7%) of product were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.76 (d, 2H), 2.20 (t, 2H), 2.67 (t, 2H), 2.87 (d, 2H), 3.80 (s, 2H), 6.50 (s , 1H), 7.14 (d, 2H, J = 4.11 Hz), 7.28-7.59 (overlap m, 9H)

Example 5

Synthesis of 3-methyl-5-[(4-{[2- (trifluoromethyl) phenyl] methyl} piperazinyl) methyl] isoxazole hydrochloride

3-methylisoxazole-5-carbaldehyde (13.4 mg, 0.12 mmol), 1- [2- (trifluoromethyl) benzyl] piperazine (25.0 μl, 0.12 mmol), molecular sieve (5 granules), NaBH (OAc) ₃ (76.6 mg, 0.36 mmol) and glacial acetic acid (13.7 μl, 0.24 mmol) were reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. Product obtained 40.0 mg (98.2%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.28 (s, 3H), 2.54 (br s, 8H), 3.64 (overlap s, 4H), 6.01 (s, 1H), 7.32 (d, 1H), 7.49 ( t, 1H, J = 7.35 Hz), 7.60 (d, 1H, J = 7.77 Hz), 7.75 (d, 1H, J = 7.68 Hz)

Example 6

Synthesis of 4- (5-{[4- (diphenylmethyl) piperazinylmethyl} isoxazol-3-yl) -1,2-dimethoxybenzene hydrochloride

3- (3,4-dimethoxyphenyl) isoxazole-5-carbaldehyde (10.7 mg, 0.05 mmol), 1-diphenylmethylpiperazine (11.6 mg, 0.05 mmol), molecular sieve (5 granules) , NaBH (OAc) ₃ (19.5 mg, 0.09 mmol) was reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 23.5 mg (94.4%) of product were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.46 (br s, 4H), 2.61 (br s, 4H), 3.74 (s, 2H), 3.92 (s, 3H), 3.94 (s, 3H), 4.24 ( s, 1H), 6.44 (s, 1H), 6.91 (d, 1H, J = 8.31 Hz), 7.18 (d, 1H, J = 7.20 Hz), 7.26-7.41 (overlap m. 11H)

Example 7

Synthesis of 1,2-dimethoxy-4- (5-[{4- (2-methylphenyl) piperazinyl] methyl} isoxazol-3-yl) benzene hydrochloride

3- (3,4-dimethoxyphenyl) isoxazole-5-carbaldehyde (10.0 mg, 0.04 mmol), 1- (o-tolyl) piperazine hydrochloride (9.12 mg, 0.04 mmol), molecular sieve (5 Granules), NaBH (OAc) ₃ (27.3 mg, 0.12 mmol) and diisopropylethylamine (7.47 μl, 0.04 mmol) were reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 15.2 mg (76.0%) of product were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.29 (s, 3H), 2.75 (br s, 4H), 2.99 (br t, 4H), 3.82 (s, 2H), 3.93 (s, 3H), 3.96 ( s, 3H), 6.51 (s, 1H), 6.92-7.05 (oeverlap m, 3H), 7.19 (t, 2H), 7.33 (d, 1H), 7.44 (d, 1H)

Example 8

Synthesis of 4- (4-chlorophenyl) -1-[(3-methylisoxazol-5-yl) methyl] piperidin-4-ol hydrochloride

3-methylisoxazole-5-carbaldehyde (11.8 mg, 0.11 mmol), 4- (4-chlorophenyl) -4-hydroxy-piperidine (22.5 mg, 0.11 mmol), molecular sieve (5 granules) ), NaBH (OAc) ₃ (67.5 mg, 0.32 mmol) and glacial acetic acid (12.2 μl, 0.21 mmol) were reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 29.3 mg (90.0%) of product were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.72 (d, 2H), 2.13 (m, 2H), 2.29 (s, 3H), 2.59 (t, 2H), 2.81 (br d, 2H), 3.71 (s , 2H), 6.04 (s, 1H), 7.31 (d, 2H, J = 8.49 Hz), 7.43 (d, 2H, J = 8.31 Hz)

Example 9

Synthesis of [(3-methoxyisoxazol-5-yl) methyl] (2-phenylethyl) amine hydrochloride

3-methoxyisoxazole-5-carbaldehyde (11.0 mg, 0.09 mmol), phenylethylamine (10.9 μl, 0.09 mmol), molecular sieve (5 granules), NaBH (OAc) ₃ (55.3 mg, 0.26 mmol ) And glacial acetic acid (9.97 μl, 0.17 mmol) were reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 21.8 mg (80.5%) of product were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.81 (m, 2H), 2.92 (m, 2H), 3.81 (s, 2H), 3.96 (s, 3H), 5.73 (s, 1H), 7.18-7.31 ( m, 5H)

Example 10

Synthesis of 5-{[4- (diphenylmethyl) piperazinyl] methyl} -3-methoxyisoxazole hydrochloride

3-methoxyisoxazole-5-carbaldehyde (12.6 mg, 0.10 mmol), 1-diphenylmethylpiperazine (25.0 mg, 0.10 mmol), molecular sieve (5 granules), NaBH (OAc) ₃ (42.0 mg, 0.20 mmol) was reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 32.6 mg (82.3%) of product were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.45 (br s, 4H), 2.56 (br s, 4H), 2.56 (br s, 4H), 3.58 (s, 2H), 3.96 (s, 3H), 4.24 (s, 1H), 5.79 (s, 1H), 7.19 (m, 2H), 7.26 (m, 4H), 7.41 (d, 4H)

Example 11

Synthesis of 5-{[4- (2-fluoro-4-nitrophenyl) piperazinyl] methyl} -3-methoxyisoxazole hydrochloride

3-methoxyisoxazole-5-carbaldehyde (16.4 mg, 0.13 mmol), 1-[(1-fluoro-4-nitro) phenyl] piperazine hydrochloride (33.8 mg, 0.13 mmol), molecular sieve (5 Granules), NaBH (OAc) ₃ (54.7 mg, 0.12 mmol) and diisopropylethylamine (22.5 μl, 0.13 mmol) were reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 52.0 mg (98.5%) of product was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.69 (br t, 4H), 3.32 (br t, 4H), 3.64 (s, 2H), 3.95 (s, 3H), 5.83 (s, 1H), 6.89 ( t, 1H, J = 8.52 Hz), 7.90 (dd, 1H), 7.97 (dd, 1H)

Example 12

Synthesis of 3-methoxy-5-{[4-benzylpiperazinyl] methyl} isoxazole hydrochloride

3-methoxyisoxazole-5-carbaldehyde (11.4 mg, 0.09 mmol), 1-benzylpiperazine (18.6 μl, 0.09 mmol), molecular sieve (5 granules), NaBH (OAc) ₃ (38.0 mg, 0.18 mmol) was reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 19.7 mg (60.9%) were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.50 (br s, 4H), 2.56 (br s, 4H), 3.51 (s, 2H), 3.57 (s, 2H), 3.95 (s, 3H), 5.79 ( s, 1H), 7.22-7.31 (m, 5H)

Example 13

Synthesis of 2- (5-{[4- (2-fluoro-4-nitrophenyl) piperazinyl] methyl} isoxazol-3-yl) thiophene hydrochloride

3- (2-thienyl) isoxazole-5-carbaldehyde (16.6 mg, 0.10 mmol), 1-[(1-fluoro-4-nitro) phenyl] piperazine hydrochloride (24.2 mg, 0.10 mmol) Molecular sieve (5 granules), NaBH (OAc) ₃ (39.3 mg, 0.19 mmol) and diisopropylethylamine (16.1 μl, 0.10 mmol) were reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 20.0 mg (46.8%) of product was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.74 (br t, 4H), 3,34 (br t, 4H), 3.80 (s, 2H), 6.46 (s, 1H), 6.90 (t, 1H), 7.11 (dd, 1H), 7.42 (d, 1H, J = 5.1 Hz), 7.45 (d, 1H, J = 3.09 Hz), 7.88 (dd, 1H), 7.97 (dd, 1H)

Example 14

Synthesis of 4- (5-{[4- (4-chlorophenyl) -4-hydropiperidyl] methyl} isoxazol-3-yl) benzenecarbonitrile hydrochloride

4- (5-formylisoxazol-3-yl) benzenecarbonitrile (13.9 mg, 0.07 mmol), 4- (4-chlorophenyl) -4-hydroxy-piperidine (14.7 mg, 0.07 mmol), min The self (5 pellets), NaBH (OAc) ₃ (30.0 mg, 0.14 mmol) was reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 24.1 mg (74.2%) of product were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.76 (d, 2H), 2.12 (m, 2H), 2.66 (br t, 2H), 2.86 (br d, 2H), 3.02 (s, 2H), 6.58 ( s, 1H), 7.31 (d, 2H, J = 8.58 Hz), 7.43 (d, 2H, J = 8.73 Hz), 7.75 (d, 2H, J = 8.28 Hz), 7.92 (d, 2H, J = 8.28 Hz)

Example 15

Synthesis of 2- {5-[(4-{[2- (trifluoromethyl) phenyl] piperazinyl) methyl] isoxazol-3-yl} thiophene hydrochloride

3- (2-thienyl) isoxazole-5-carbaldehyde (18.5 mg, 0.10 mmol), 1- [2- (trifluoromethyl) benzyl] piperazine (21.5 μl, 0.10 mmol), molecular sieve (5 granules) and NaBH (OAc) ₃ (43.7 mg, 0.21 mmol) were reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 42.0 mg (100%) of product were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.56 (br s, 4H), 2.61 (br s, 4H), 3.67 (s, 2H), 3.73 (s, 2H), 6.44 (s, 1H), 7.11 ( t, 1H), 7.27 (d, 1H, J = 9.33 Hz), 7.33 (d, 1H, J = 7.5 Hz), 7.42 (t, 1H, J = 7.41 Hz), 7.61 (d, 1H, J = 7.68 Hz), 7.77 (d, 1H, J = 7.68 Hz)

Example 16

Synthesis of 5-{[4- (2-fluoro-4-nitrophenyl) piperazinyl] methyl} -3- (3-nitrophenyl) isoxazole hydrochloride

3- (3-nitrophenyl) isoxazole-5-carbaldehyde (11.5 mg, 0.05 mmol), 1-[(1-fluoro-4-nitro) phenyl] piperazine hydrochloride (13.8 mg, 0.05 mmol) , Molecular sieves (5 granules), NaBH (OAc) ₃ (22.3 mg, 0.10 mmol) and diisopropylethylamine (9.2 μl, 0.05 mmol) were reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 21.0 mg (79.8%) of product was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.78 (br t, 4H), 3.36 (br t, 4H), 3.86 (s, 2H), 6.67 (s, 1H), 6.91 (t, 1H, J = 8.79 Hz), 7.67 (t, 1H), 7.90 (dd, 1H), 7.96 (dd, 1H), 8.20 (d, 1H, J = 7.92 Hz), 8.30 (d, 1H), 8.62 (s, 1H)

Example 17

Synthesis of 4- (5-{[4- (diphenylmethyl) piperazinyl] methyl} isoxazol-3-yl) benzenecarbonitrile Hydrochloride

4- (5-formylisoxazol-3-yl) benzenecarbonitrile (12.4 mg, 0.06 mmol), 1-diphenylmethyl piperazine (15.8 mg, 0.06 mmol), molecular sieve (5 granules), NaBH (OAc ) ₃ (26.5 mg, 0.13 mmol) was reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 30.0 mg (94.6%) of product was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.47 (br, s, 4H), 2.61 (br s, 4H), 3.77 (s, 2H), 4.25 (s, 1H), 6.52 (s, 1H), 7.18 (d, 2H), 7.26 (t, 4H), 7.41 (d, 4H), 7.74 (d, 2H, J = 8.46 Hz), 7.91 (d, 2H, J = 8.31 Hz)

Example 18

Synthesis of 5-{[4- (diphenylmethyl) piperazinyl] methyl} -3- (2-pyridyl) isoxazole hydrochloride

3- (2-pyridyl) isoxazole-5-carbaldehyde (10.4 mg, 0.06 mmol), 1-diphenylmethyl piperazine (15.1 mg, 0.06 mmol), molecular sieve (5 granules), NaBH ( OAc) ₃ (25.3 mg, 0.12 mmol) is added in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 27.5 mg (95.3%) of product was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.46 (br s, 4H), 2.61 (br s, 4H), 3.79 (s, 2H), 4.23 (s, 1H), 6.82 (s, 1H), 7.14- 7.41 (overlap m, 11H), 7.79 (t, 1H), 8.07 (dd, 1H), 8.67 (dd, 1H)

Example 19

Synthesis of 5-{[4- (diphenylmethyl) piperazinyl] methyl} -3- (4-methylphenyl) isoxazole hydrochloride

3- (4-methylphenyl) isoxazole-5-carbaldehyde (13.8 mg, 0.07 mmol), 1-diphenylmethyl piperazine (18.6 mg, 0.07 mmol), molecular sieve (5 granules), NaBH (OAc ) ₃ (31.2 mg, 0.15 mmol) was reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 35.1 mg (95.9%) of product were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.46 (s, 3H), 2.45 (br s, 4H), 2.61 (br s, 4H), 3.75 (s, 2H), 4.24 (s, 1H), 6.45 ( s, 1H), 7.17-7.29 (overlap, 8H), 7.40 (d, 4H), 7.69 (d, 2H, J = 7.95 Hz)

Example 20

Synthesis of 3- (4-methylphenyl) -5-{[4-benzylpiperazinyl] methyl} isoxazole hydrochloride

3- (4-methylphenyl) isoxazole-5-carbaldehyde (11.1 mg, 0.06 mmol), 1-benzylpiperazine (10.3 μl, 0.06 mmol), molecular sieve (5 granules), NaBH (OAc) ₃ (25.1 mg 0.12 mmol) was reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 18.1 mg (63.1%) of product were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.40 (s, 3H), 2.54 (br s, 4H), 2.62 (br s, 4H), 3.54 (s, 3H), 3.79 (s, 2H), 6.46 ( s, 1H), 7.27 (m, 7H), 7.68 (d, 2H, J = 8.19 Hz)

Example 21

Synthesis of 5-{[4- (diphenylmethyl) piperazinyl] methyl} -3- (4-fluorophenyl) isoxazole hydrochloride

3- (4-fluorophenyl) isoxazole-5-carbaldehyde (16.6 mg, 0.09 mmol), 1-diphenylmethylpiperazine (21.9 mg, 0.09 mmol), molecular sieve (5 granules), NaBH (OAc) ₃ (36.8 mg, 0.17 mmol) was reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 42.9 mg (98.7%) of product were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.48 (br s, 4H), 2.62 (br s, 4H), 3.76 (s, 2H), 4.25 (s, 1H), 6.45 (s, 1H), 7.11- 7.29 (m, 8H), 7.41 (d, 4H), 7.79 (m, 2H)

Example 22

Synthesis of 3- {4- [4- (diphenylmethyl) piperazinyl] butyl} -5- (2-pyridyl) -4,5-dihydroisoxazole hydrochloride

4- (5- (2-pyridyl) -4,5-dihydroisoxazol-3-yl) butanal (14.1 mg, 0.06 mmol), 1-diphenylmethyl piperazine (16.0 mg, 0.06 mmol), Molecular sieves (5 granules) and NaBH (OAc) ₃ (27.0 mg, 0.12 mmol) were reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 30.0 mg (88.4%) of product was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.52 (d, 1H, J = 4.8z), 7.67 (t, J = 7.8z), 7.41 (m, 4H), 7.25 (m, 8H), 5.62 (dd , 1H, J = 10.8 Hz, 6.4 Hz), 4.21 (s, 1H), 3.39 (dd, 1H, J = 17.0, 10.9 Hz), 3.22 (dd, 1H, J = 17.0, 6.6 Hz), 2.40 (br m, 12H), 1.50 (br m, 4H)

Example 23

Synthesis of 3- {4- [4- (diphenylmethyl) piperazinyl] butyl} -5- (4-pyridyl) -4,5-dihydroisoxazole hydrochloride

4- (5- (4-pyridyl) -4,5-dihydroisoxazol-3-yl) butanal (11.0 mg, 0.05 mmol), 1-diphenylmethyl piperazine (12.7 mg, 0.05 mmol), Molecular sieves (5 granules) and NaBH (OAc) ₃ (21.0 mg, 0.10 mmol) were reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 19.6 mg (74.0%) of product was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.57 (d, 2H, J = 6.1 Hz), 7.40 (d, 4H, J = 7.1 Hz), 7.25 (m, 8H), 5.50 (dd, 1H, J = 7.1, 11.0 Hz), 4.21 (s, 1H), 3.40 (dd, J = 17.0, 11.2 Hz), 2.80 (dd, 1H, J = 17.0, 7.1 Hz), 2.35 (br m, 12H), 1.52 (br m, 4H)

Example 24

Synthesis of 5- (2-pyridyl) -3- [4- (4-{[2- (trifluoromethyl) phenyl} piperazinyl) butyl] -4,5-dihydroisoxazole hydrochloride

4- (5- (2-pyridyl) -4,5-dihydroisoxazol-3-yl) butanal (11.8 mg, 0.05 mmol), 1- [2- (trifluoromethyl) benzyl] piperazine (11.2 μl, 0.05 mmol), molecular sieves (5 granules), and NaBH (OAc) ₃ (23.0 mg, 0.10 mmol) were reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 25.0 mg (89.4%) of product was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.54 (d, 1H, J = 4.8 Hz), 7.75 (d, 1H, J = 7.7 Hz), 7.67 (t, 1H, J = 7.7 Hz), 7.59 (d , 1H, 7.7 Hz, 7.48 (m, 2H), 7.30 (t, 1H, J = 7.6 Hz), 7.17 (m, 1H), 5.62 (dd, 1H, J = 11.0, 6.8 Hz), 3.64 (s , 2H), 3.40 (dd, 1H, J = 17.0, 11.0 Hz), 3.23 (dd, 1H, J = 17.0, 6.6 Hz), 2.40 (br m, 12H), 1.52 (br m, 4H)

Example 25

Synthesis of 5- (2-pyridyl) -3- [4- (4-{[2- (trifluoromethyl) phenyl} piperazinyl) butyl] -4,5-dihydroisoxazole hydrochloride

4- (5- (4-pyridyl) -4,5-dihydroisoxazol-3-yl) butanal (11.4 mg, 0.05 mmol), 1- [2- (trifluoromethyl) benzyl] piperazine (10.8 μl, 0.05 mmol), molecular sieves (5 granules), and NaBH (OAc) ₃ (22.0 mg, 0.10 mmol) were reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 25.6 mg (94.8%) of the product were obtained.

¹ H NMR (300 MHz, CDC1 ₃ ,) δ 8.57 (d, 2H, J = 6.0 Hz), 7.76 (d, 1H, J = 7.7 Hz), 7.60 (d, 1H, J = 7.9 Hz), 7.49 ( t, 1H, J = 7.4 HZ), 7.30 (t, 1H, J = 7.4 Hz), 7.24 (d, 2H, J = 6.1 Hz), 5.52 (dd, 1H, J = 11.0, 7.1 Hz), 3.64 ( s, 2H), 3.43 (dd, 1H, J = 17.0, 11.0 Hz), 2.83 (dd, 1H, J = 17.0, 7.1 Hz), 2.39 (br m, 12H), 1.56 (br m, 4H)

Example 26

Synthesis of 3- (2-furyl) -5-({4- [2- (trifluoromethyl) phenyl] piperazinyl} methyl) isoxazole hydrochloride

3- (2-furyl) isoxazole-5-carbaldehyde (12.5 mg, 0.08 mmol), 1 (α, α, α-trifluoro-O-tolyl) piperazine (14.5 μl, 0.08 mmol), Molecular sieves (5 granules) and NaBH (OAc) ₃ (32.5 mg, 0.15 mmol) were reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 27.2 mg (78.4%) of product was obtained.

¹ H NMR (300 MHz, CDC1 ₃ ,) δ 2.78 (br t, 4H), 3.29 (br t 4H), 3.82 (s, 2H), 6.52 (overlap, 2H), 6.9 (t, 1H), 7.07 ( overlap m, 3H), 7.32 (t, 1H), 7.55 (s, 1H)

Example 27

Synthesis of 1- (1-{[3- (2,4-dimethoxyphenyl) isoxazol-5-yl] methyl} -4-piperidyl) -3-hydrobenzimidazol-2-one hydrochloride

3- (2,4-dimethoxyphenyl) isoxazole-5-carbaldehyde (11.5 mg, 0.05 mmol), 4- (2-keto-1-benzimidazolinyl) piperidine (10.7 mg, 0.05 mmol), molecular sieves (5 granules), and NaBH (OAc) ₃ (20.9 mg, 0.10 mmol) were reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 10.0 mg (40.0%) of product was obtained.

¹ H NMR (300 MHz, CDC1 ₃ ,) δ 1.85 (br t, 2H), 2.41 (m, 2H), 2.58 (m, 2H), 3.15 (br d, 2H), 3.81 (s, 3H), 3.92 (s, 3H), 3.96 (s, 3H), 4.37 (m, 1H), 6.53 (s, 1H), 6.92-7.44 (overlap m, 7H), 9.72 (br s, 1H)

Example 28

Synthesis of 1- (1-{[3-(2-phenylvinyl) isoxazol-5-yl] methyl} 4-piperidyl) -3-hydrobenzimidazol-2-one hydrochloride

3- (2-phenylvinyl) isoxazole-5-carbaldehyde (13.5 mg, 0.07 mmol), 4- (2- (keto-1-benzimidazolinyl) piperidine (14.7 mg, 0.07 mmol ), Molecular sieves (5 granules), NaBH (OAc) ₃ (28.7 mg, 0.13 mmol) and glacial acetic acid (7.7 μl, 0.13 mmol) were reacted in 3 ml of methylene chloride for about 12 hours. It carried out by the same method as Example 1. 32.0 mg (99.8%) of the product were obtained.

¹ H NMR (300 MHz, CDCl ₃ ,) δ 1.86 (br d, 2H), 2.30 (br t, 2H), 2.6 (m, 2H), 3.18 (br d, 2H), 3.80 (s, 2H), 4.39 (m, 1H), 6.50 (s, 1H), 7.03-7.59 (overlap m, 9H), 9.89 (s, 1H)

Example 29

Synthesis of 1- (1-{[3- (4-chlorophenyl) isoxazol-5-yl] methyl} -4-piperidyl-3-hydrobenzimidazol-2-one hydrochloride

3- (4-chlorophenyl) isoxazole-5-carbaldehyde (10.2 mg, 0.05 mmol), 4- (2-keto-1-benzimidazolinyl) piperidine (10.7 mg, 0.05 mmol) , Molecular sieves (5 granules), NaBH (OAc) ₃ (31.2 mg, 0.15 mmol) and glacial acetic acid (5.6 μl, 0.10 mmol) were reacted in 3 ml of methylene chloride for about 12 hours. The following reaction procedure was carried out in the same manner as in Example 1. 22.5 mg (95.4%) of product was obtained.

¹ H NMR (300 MHz, CDC1 ₃ ) δ 1.85 (br d, 2H), 2.37 (br t, 2H), 2.55 (m, 2H), 3.15 (br d, 2H), 3.84 (s, 2H), 4.39 (m, 1H), 6.53 (s, 1H), 7.01-7.17 (m, 3H), 7.29 (m, 1H), 7.42 (d, 2H), 7.79 (d, 2H)

The effect of the present invention will be better explained by the following affinity test for the dopamine D ₁ receptor and the results.

Affinity Test with Radioisotopes

In order to study the effect of each drug on the dopamine receptor type 1 and the receptor-ligand interaction, the ligand is reacted with a radioisotope attached ligand and then filtered through a glass wool filter. After removing the ligand, the amount of isotope remaining in the washed filter plate was measured to quantify the binding reaction of the ligand to the receptor, and used to determine the effect of the drug.

The receptor for this study used cell fractions expressed in sf9 cells that dopamine receptors to exclude interactions with different types of drugs. Cell fractions containing a large amount of these receptors were stored frozen and diluted to an optimal concentration, and the reaction between the receptor and the ligand was optimal under these conditions.

In the experimental method, the receptor fractions stored frozen at -70 ° C were suspended in buffer for each experiment, the protein content was confirmed by the Bio-Rad DC Protein Assay Kit, and then adjusted to the optimal concentration for each receptor. At this time, the setting of the protein concentration represented by the content of the receptor was determined through the basic experiment, and then dispensed by appropriate volume, and stored frozen at -70 ℃. Samples of all experiments were tested in duplicate, and the buffers required for the experiments were used for each buffer to which each receptor could bind in optimal conditions. The final volume of the reaction was 0.25 ml, which included 50 μl of Hot-ligand and 10 μl of test drug. The start of the reaction was allowed to react at 27 ° C. for 30-60 minutes by adding 100 μl of receptor suspension. In the first stage drug screening, the affinity of the drug for receptors was measured for concentrations (10 μM). The standard drug used to search for affinity for the dopamine receptor was 1 μM of haloperidol.

After incubation for 1 hour, the reaction was terminated by filtration with cold Tris buffer using an Inotech cell harvester system using a Wallac glass fiber filtermat GF / C. After the isotope bound to the receptor was separated and washed, the amount of isotope remaining in the filtermat was measured with a liquid scintillation counter.

Substituent information for the compounds of the present invention and affinity for the dopamine D ₁ receptor are shown in Table 1. In Table 1, the substituent information of Formula 1 is as follows. The following is for the substituent R ₁ .

R ₂ , R ₃ , R ₄ and R ₅ are all hydrogen.

The following is for the substituent R ₆ .

TABLE 1

Affinity to Dopamine (D ₁ ) Receptors and Substituent Information of Formula 1

Table 1 continued

Table 1 continued

Claims (5)

Ioxoxazole piperazine derivatives having Formula 1 [Formula 1] In Formula 1, n = 1-4; R ₁ is a by more than one selected from the group consisting of alkoxy groups, halogen, trifluoromethyl, -NO _2, C ₁ -C ₃ alkyl and C ₁ -C ₃ substituted in the ortho, meta or para-position phenyl , C ₁ -C ₃ alkyl, hydroxy, 4- (2-keto-1-benzimidazolinyl), 1- [2- (trifluoromethyl) benzyl, 4- (4-chlorophenyl)- 4-hydroxy, 1- (2-pyrimidyl), 1-benzyl; R ₂ -R ₅ is hydrogen; R ₆ is ortho, meta or at least one selected from the group consisting of halogen, trifluoromethyl, -CN, -NO ₂ , C ₁ -C ₃ alkyl, phenoxy and C ₁ -C ₃ alkoxy groups; Phenyl substituted in the para position; Unsaturated 5 or 6 ring heterocyclic groups comprising C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, thiophenyl, (2-phenyl) vinyl, pyridyl and oxygen, sulfur or nitrogen atoms. A pharmaceutical composition for treating mental disorders using the dopamine D1 receptor antagonism of the isoxazole piperazine derivative according to claim 1. A process for preparing the compound according to claim 1 by reacting an amine having the formula (2) with an aldehyde having the formula (3) in the presence of a reducing agent. [Formula 2] [Formula 3] The method according to claim 3, wherein NaBH (OAc) ₃ , NaBH ₃ CN, NaBH ₄ are used as reducing agents. The process according to claim 3 or 4, wherein the product is purified using an acid.