Phenylpiperazine derivative, use method and uses thereof

Abstract

The present invention discloses a phenylpiperazine derivative, a use method and uses thereof, and particularly relates to a class of novel (2-(heteroaryloxo)phenyl)piperazine derivatives and a pharmaceutical composition containing the compound, wherein the derivatives and the composition can be used for inhibiting 5-hydroxytryptamine reuptake. The present invention further relates to a method for preparing the compounds and the pharmaceutical composition, and uses of the compounds and the pharmaceutical composition in treatment of central nervous system dysfunction, particularly affective disorders.

Description

technical field

[0001] The invention belongs to the technical field of medicines, and in particular relates to compounds and compositions for treating central nervous system dysfunction, especially affective disorders, as well as methods and uses thereof. In particular, described herein are phenylpiperazine derivatives that are useful as serotonin reuptake inhibitors. Background technique

[0002] 5-HT (serotonin), a neurotransmitter that transmits signals in the brain and nervous system, plays a role in central nervous system (CNS) dysfunction, especially anxiety, depression, aggression and impulsive mood. play an important role. The five-serotonin transporter (5-HTtransporter, 5-HTT / serotonintransporter, SERT) is a transmembrane transporter with high affinity for 5-HT, which reuptakes five-serotonin from the synaptic gap into the presynaptic neuron, directly Affects the concentration of serotonin in the synaptic cleft.

[0003] Historically, pharmacological treatment of...

Examples

Embodiment 1

[0195] Example 12-(2-(piperazin-1-yl)phenoxy)nicotinamide

[0196]

[0197] Step 1) Synthesis of 4-(2-((3-carbamoylpyridin-2-yl)oxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0198] 4-(2-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (0.42g, 1.51mmol), 2-chloronicotinamide (0.25g, 1.58mmol) and potassium carbonate (0.42g, 3.02mmol) were sequentially It was added into DMSO (10 mL), and then the reaction solution was heated to 110° C. for 20 hours. After the reaction, the reaction solution was cooled to room temperature, washed with water (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether / ethyl acetate (v / v)=2 / 1) to obtain the title compound as a pale yellow solid (0.42 g, 69.9%).

[0199] MS(ESI,pos.ion)m / z:399.1[M+H] + ;

[0200] 1 HNMR (CD...

Embodiment 2

[0205] Example 21-(2-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)piperazine

[0206]

[0207] Step 1) Synthesis of 4-(2-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0208] The title compound of this step can be prepared by referring to the method described in step 1 of Example 1, that is, tert-butyl 4-(2-hydroxyphenyl)piperazine-1-carboxylate (0.42g, 1.51mmol), 2-chloro-4 -(trifluoromethyl)pyridine (0.29g, 1.58mmol) and potassium carbonate (0.42g, 3.02mmol) were reacted in DMSO (10mL) to prepare the crude product, which was purified by silica gel column (petroleum ether / ethyl acetate (v / v) = 2 / 1) to obtain the title compound as a pale yellow solid (0.25 g, 39.1%).

[0209] MS(ESI,pos.ion)m / z:424.1[M+H] + ;

[0210] 1 HNMR (CDCl 3 ,400MHz)δ(ppm):8.33(d,J=5.2Hz,1H),7.24-7.22(m,1H),7.19-7.16(m,2H),7.14-7.12(m,1H),7.07-7.04 (m,1H),6.95(m,1H),3.20-3.17(m,4H),2.93-2.91(m,4H),1.43(s,9H).

[0211] Step 2) Synthesis of 1-...

Embodiment 3

[0215] Example 31-(2-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)piperazine

[0216]

[0217] Step 1) Synthesis of tert-butyl 4-(2-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)piperazine-1-carboxylate

[0218] The title compound of this step can be prepared by referring to the method described in step 1 of Example 1, that is, tert-butyl 4-(2-hydroxyphenyl)piperazine-1-carboxylate (0.42g, 1.51mmol), 2-chloro-5 -(trifluoromethyl)pyridine (0.29g, 1.58mmol) and potassium carbonate (0.42g, 3.02mmol) were reacted in DMSO (10mL) to prepare the crude product, which was purified by silica gel column (petroleum ether / ethyl acetate (v / v)=2 / 1) the title compound was obtained as a white solid (0.35 g, 54.8%).

[0219] MS(ESI,pos.ion)m / z:424.1[M+H] + ;

[0220] 1 HNMR (CDCl 3 ,400MHz)δ(ppm):8.24(s,1H),7.85(dd,J=8.4,2.4Hz,1H),7.26-7.21(m,1H),7.15(dd,J=7.6,1.6Hz,1H ), 7.12(dd, J=7.2, 1.2Hz, 1H), 7.07-7.05(m, 1H), 6.87(d, J=8.8Hz, 1H), 3.25-3.23(m, 4H), 2.95-2.92( m,4H),1.44(s,9...

technical field

[0001] The invention belongs to the technical field of medicines, and in particular relates to compounds and compositions for treating central nervous system dysfunction, especially affective disorders, as well as methods and uses thereof. In particular, described herein are phenylpiperazine derivatives that are useful as serotonin reuptake inhibitors. Background technique

[0002] 5-HT (serotonin), a neurotransmitter that transmits signals in the brain and nervous system, plays a role in central nervous system (CNS) dysfunction, especially anxiety, depression, aggression and impulsive mood. play an important role. The five-serotonin transporter (5-HTtransporter, 5-HTT / serotonintransporter, SERT) is a transmembrane transporter with high affinity for 5-HT, which reuptakes five-serotonin from the synaptic gap into the presynaptic neuron, directly Affects the concentration of serotonin in the synaptic cleft.

[0003] Historically, pharmacological treatment of...

Examples

Embodiment 1

[0195] Example 12-(2-(piperazin-1-yl)phenoxy)nicotinamide

[0196]

[0197] Step 1) Synthesis of 4-(2-((3-carbamoylpyridin-2-yl)oxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0198] 4-(2-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (0.42g, 1.51mmol), 2-chloronicotinamide (0.25g, 1.58mmol) and potassium carbonate (0.42g, 3.02mmol) were sequentially It was added into DMSO (10 mL), and then the reaction solution was heated to 110° C. for 20 hours. After the reaction, the reaction solution was cooled to room temperature, washed with water (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether / ethyl acetate (v / v)=2 / 1) to obtain the title compound as a pale yellow solid (0.42 g, 69.9%).

[0199] MS(ESI,pos.ion)m / z:399.1[M+H] + ;

[0200] 1 HNMR (CD...

Embodiment 2

[0205] Example 21-(2-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)piperazine

[0206]

[0207] Step 1) Synthesis of 4-(2-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0208] The title compound of this step can be prepared by referring to the method described in step 1 of Example 1, that is, tert-butyl 4-(2-hydroxyphenyl)piperazine-1-carboxylate (0.42g, 1.51mmol), 2-chloro-4 -(trifluoromethyl)pyridine (0.29g, 1.58mmol) and potassium carbonate (0.42g, 3.02mmol) were reacted in DMSO (10mL) to prepare the crude product, which was purified by silica gel column (petroleum ether / ethyl acetate (v / v) = 2 / 1) to obtain the title compound as a pale yellow solid (0.25 g, 39.1%).

[0209] MS(ESI,pos.ion)m / z:424.1[M+H] + ;

[0210] 1 HNMR (CDCl 3 ,400MHz)δ(ppm):8.33(d,J=5.2Hz,1H),7.24-7.22(m,1H),7.19-7.16(m,2H),7.14-7.12(m,1H),7.07-7.04 (m,1H),6.95(m,1H),3.20-3.17(m,4H),2.93-2.91(m,4H),1.43(s,9H).

[0211] Step 2) Synthesis of 1-...

Embodiment 3

[0215] Example 31-(2-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)piperazine

[0216]

[0217] Step 1) Synthesis of tert-butyl 4-(2-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)piperazine-1-carboxylate

[0218] The title compound of this step can be prepared by referring to the method described in step 1 of Example 1, that is, tert-butyl 4-(2-hydroxyphenyl)piperazine-1-carboxylate (0.42g, 1.51mmol), 2-chloro-5 -(trifluoromethyl)pyridine (0.29g, 1.58mmol) and potassium carbonate (0.42g, 3.02mmol) were reacted in DMSO (10mL) to prepare the crude product, which was purified by silica gel column (petroleum ether / ethyl acetate (v / v)=2 / 1) the title compound was obtained as a white solid (0.35 g, 54.8%).

[0219] MS(ESI,pos.ion)m / z:424.1[M+H] + ;

[0220] 1 HNMR (CDCl 3 ,400MHz)δ(ppm):8.24(s,1H),7.85(dd,J=8.4,2.4Hz,1H),7.26-7.21(m,1H),7.15(dd,J=7.6,1.6Hz,1H ), 7.12(dd, J=7.2, 1.2Hz, 1H), 7.07-7.05(m, 1H), 6.87(d, J=8.8Hz, 1H), 3.25-3.23(m, 4H), 2.95-2.92( m,4H),1.44(s,9...

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