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2-Substituted-oxy-5-methylsulfonyl aryl piperazine acidamide analogue and preparation method and application thereof

A technology of aryl piperazine amides and analogues, applied in the field of 2-substituted oxy-5-thiamphenicol aryl piperazine amides and their preparation, capable of solving negative symptoms and no improvement in cognitive symptoms, etc. question

Active Publication Date: 2016-06-29
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs did not improve negative and cognitive symptoms (Sharma, T.; 1999, Br. J. Psychiatry, 1999, 174, 44-51)

Method used

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  • 2-Substituted-oxy-5-methylsulfonyl aryl piperazine acidamide analogue and preparation method and application thereof
  • 2-Substituted-oxy-5-methylsulfonyl aryl piperazine acidamide analogue and preparation method and application thereof
  • 2-Substituted-oxy-5-methylsulfonyl aryl piperazine acidamide analogue and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] Example 1: (S)-5-(4-(5-(methylsulfonyl)-2-((1,1,1-trifluoropropan-2-yl)oxo)nicotinyl)piperazine-1 Preparation of -yl)-2,3-dihydro-1H-inden-1-one

[0107] Step 1: Preparation of (S)-5-(methylsulfonyl)-2-((1,1,1-trifluoropropan-2-yl)oxo)nicotine acid

[0108]

[0109] Sodium hydride (500mg, 12.5mmoL) was dissolved in 5mL of DMF, (S)-trifluoroisopropanol (1.2g) was added, stirred at room temperature for 30 minutes, and then 2-chloro-5-bromonicotinic acid (900mg) After adding to the system, stirring at 110°C for 16 hours, spin off DMF, dissolve the residue in 10ml DMSO, add sodium proline (274mg, 2.0mmoL), sodium methanesulfinate (1.0g, 10mmoL) and sulfite Copper (761.8mg, 4.0mmoL), heated to 110°C under nitrogen atmosphere and stirred for 4 hours, separated and purified directly by reverse phase column chromatography to obtain 5-(methylsulfonyl)-2-((1,1,1-tri Fluoropropan-2-yl)oxo)nicotinic acid (150 mg).

[0110] The second step: the preparation of 5-(piperazin-1-yl...

Embodiment 2

[0119] Example 2: (S)-(4-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)piperazin-1-yl)(5-(methylsulfonyl)-2 Preparation of -((1,1,1-trifluoropropan-2-yl)oxo)phenyl)methanone

[0120] Step 1: Preparation of tert-butyl 4-(4-acetyl-2,5-difluorophenyl)piperazine-1-carboxylate

[0121]

[0122] Dissolve 2,4,5-trifluoroacetophenone (522mg, 3.0mmol) in 10mL of acetonitrile, then add N-tert-butoxycarbonylpiperazine (671mg, 3.6mmol) and potassium carbonate (829mg, 6.0mmol), Heat to reflux overnight. Separation by reverse-phase column chromatography gave compound 4-(4-acetyl-2,5-difluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (670 mg, 66%). LC-MS:t R =3.12min, [M+H] + 341.2.

[0123] The second step: Preparation of tert-butyl 4-(2,5-difluoro-4-(1-(oximino)ethyl)phenyl)piperazine-1-carboxylate

[0124]

[0125] 4-(4-acetyl-2,5-difluorophenyl)piperazine-1-carboxylate tert-butyl ester (670mg, 1.97mmol), hydroxylamine hydrochloride (205mg, 2.95mmol) and sodium acetate tri...

Embodiment 3

[0137] Example 3: (S)-(4-(7-fluoroquinolin-6-yl)piperazin-1-yl)(5-(methylsulfonyl)-2-((1,1,1-trifluoro Preparation of propan-2-yl)oxo)pyridin-3-yl)methanone

[0138] The first step: the preparation of 7-fluoro-6-(piperazin-1-yl)quinoline

[0139]

[0140] Weigh 6-bromo-7-fluoroquinoline (226mg, 1.00mmol) and piperazine (129mg, 1.50mmol) and dissolve them in 5mL of 1,4-dioxane, add bis(tri-tert-butylphosphine)palladium under nitrogen protection (51 mg, 0.10 mmol) and sodium tert-butoxide (192 mg, 2.00 mmol). Microwave at 120°C for 1 hour. Add ethyl acetate to extract, wash with saturated NaCl aqueous solution, anhydrous NaCl 2 SO 4 dry. Filtration and concentration gave tan viscous liquid (210 mg, 91%), and the crude product was directly used in the next reaction.

[0141] The second step: (S)-(4-(7-fluoroquinolin-6-yl)piperazin-1-yl)(5-(methylsulfonyl)-2-((1,1,1-trifluoro Preparation of propan-2-yl)oxo)pyridin-3-yl)methanone

[0142]

[0143] Weigh the above crud...

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Abstract

The invention discloses 2-substituted-oxy-5-methylsulfonyl aryl piperazine acidamide analogue and a preparation method and application thereof, and particularly, relates to 2-substituted-oxy-5-methylsulfonyl aryl piperazine acidamide analogue with a formula (I) compound and a preparation method and application thereof, wherein substitutions in the formula (I) compound are defined as in the description. This serial compound can inhibit the activity of glycine transport protein-1 (GlyT1), is useful in treating related diseases in central nerve and psychological fields, for example, schizophrenia (including positive symptoms, negative symptoms and cognitive symptoms), senile dementia, Parkinson's disease and other related psychological diseases, is widely applicable to the drugs for preventing and treating central nerve and psychological diseases, and is expected to be developed into new-generation GlyT1 inhibitors.

Description

technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to a 2-substituted oxy-5-thiamphenicol aryl piperazine amides and a preparation method and application thereof. Background technique [0002] Schizophrenia is a progressive and destructive mental illness. According to symptoms, schizophrenia is usually divided into three types of symptoms in the world: positive symptoms, negative symptoms and cognitive symptoms. Yang and sexual symptoms are manifested as delusions, hallucinations, strange behaviors, and thinking disorders; negative symptoms are manifested as flat emotions, loss of interest, decreased willpower, and reduced speech; cognitive symptoms are manifested as long-term memory, operational memory, and abstraction. and planning, as well as speech comprehension and creativity (Lewis, D.A.; LiebermanJ.A. Neuron, 2000, 28, 325-33). For decades, the scientific community has focused on the "dopamine hypothesis" that schizophr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/20C07D413/12C07D417/12C07D275/04C07D231/56C07D401/06C07D295/192C07D405/12C07D307/88C07D401/12C07D215/38C07D217/02C07D217/24A61K31/496A61P25/18A61P25/28A61P25/16
CPCC07D215/38C07D217/02C07D217/24C07D231/56C07D261/20C07D275/04C07D295/192C07D307/88C07D401/06C07D401/12C07D405/12C07D413/12C07D417/12
Inventor 危明松孙兴义张秀春杨飞王少宝廖建春仝朝龙李成海包如迪喻红平徐耀昌
Owner SHANGHAI HANSOH BIOMEDICAL
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