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Piperidine derivatives as orexin receptor antagonists

A compound, selected technology, applied in the direction of drug combination, active ingredient of heterocyclic compounds, organic chemistry, etc., can solve problems such as solubility and pharmacokinetic half-life effect to be improved

Active Publication Date: 2017-12-08
SHANGHAI HAIYAN PHARMA TECH +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Its activity, solubility, pharmacokinetics, half-life and other aspects need to be improved

Method used

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  • Piperidine derivatives as orexin receptor antagonists
  • Piperidine derivatives as orexin receptor antagonists
  • Piperidine derivatives as orexin receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1，2

[0121]

[0122] A wavy bond indicates that the bond may face up or down and is not affected by other groups (the same below).

[0123] The first step (synthesis of 1-3)

[0124] Compound 1-1 (10.0 g, 44.4 mmol) was dissolved in 55 mL of tetrahydrofuran, LDA (24.4 mL, 0.0488 mol) was slowly added dropwise at -78°C, and stirred for 1 hour at -78°C. The temperature was kept at -78°C, and compound 1-2 was added dropwise to the reaction. After the addition, the temperature was slowly raised to room temperature, and the reaction was stirred overnight at room temperature. The reaction solution was poured into an aqueous ammonium chloride solution (50 mL), and concentrated under reduced pressure to obtain a crude product. Add 50mL saturated aqueous sodium chloride solution to it, extract with ethyl acetate (100mL×3), combine the organic phases, wash with water (100mL×2), saturated sodium chloride solution (100mL×2) successively, wash with anhydrous sodium sulfate Drying, filtrati...

Embodiment 3，4

[0151]

[0152]

[0153] The first step (synthesis of 3-1)

[0154] Compound 1-12 (100 mg) was dissolved in 4 mL of ethyl acetate, ethyl hydrogen chloride acetate (4 mL, 4M) was added dropwise under ice-bath conditions, stirred for 2 hours, and concentrated under reduced pressure to obtain product 3-1 (hydrochloride salt form) , the product was directly carried out to the next reaction without purification.

[0155] The second step (synthesis of 3-2)

[0156]Compound 3-1 (100mg, 0.26mmol), Compound 1-14 (58mg, 0.28mmol), HATU (150mg, 0.39mmol) and DIEA (124mg, 0.96mmol) were dissolved in 5mL of DMF and stirred at room temperature for 3 hours , the reaction solution was poured into saline solution and extracted with ethyl acetate (10mL×3), the organic phases were combined, washed with water (10mL×2) and saturated sodium chloride solution (10mL×2) successively, dried, filtered and concentrated to obtain Crude. The crude product was separated by preparative HPLC to obtai...

Embodiment 5，6

[0162]

[0163]

[0164] The first step (synthesis of 5-2)

[0165] Compound 1-12 (120mg, 0.32mmol), Compound 5-1 (77mg, 0.38mmol), HATU (182mg, 0.48mmol) and DIEA (124mg, 0.96mmol) were dissolved in 5mL of DMF and stirred at room temperature for 3 hours , the reaction solution was poured into saline solution and extracted with ethyl acetate (10mL×3), the organic phases were combined, washed with water (10mL×2) and saturated sodium chloride solution (10mL×2) successively, dried over anhydrous sodium sulfate, After filtration, the crude product was purified by preparative HPLC to obtain product 5-2 (24 mg, white solid, yield: 14%).

[0166] 1 H NMR (400MHz, METHANOL-d 4 )=8.83(br.s., 2H), 8.17-8.01(m, 2H), 7.49-7.33(m, 3H), 6.86(dd, J=3.5, 9.0Hz, 1H), 6.41(br.s. , 1H), 4.63 (br.s., 1H), 4.43 (br.s., 1H), 4.11 (br.s, 1H), 3.79 (br.s., 1H), 2.52-2.48 (m, 2H ), 2.35-2.11(m, 1H), 2.01-1.95(m, 3H), 1.90-1.67(m, 3H), 1.63-1.43(m, 1H), 1.29-1.20(m, 2H)

[0167] The second s...

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Abstract

The invention discloses a series of piperidine derivatives as orexin receptor antagonists and their compositions, and relates to their use in the preparation and treatment of insomnia, chronic obstructive pulmonary disease, obstructive sleep apnea, drowsiness, anxiety, compulsion, panic, Drug use in nicotine dependence or disordered eating disorders.

Description

technical field [0001] The present invention relates to piperidine derivatives and compositions thereof as orexin receptor antagonists, and to their use in the preparation and treatment of insomnia, chronic obstructive pulmonary disease, obstructive sleep apnea, drowsiness, anxiety, obsession, panic, nicotine dependence or Use of Drugs in Eating Disorders. Background technique [0002] Orexin (orexin) includes two neuropeptides produced in the hypothalamus: orexin A (OX-A) (33 amino acid peptide) and orexin B (OX-B) (28 amino acid peptide) ( Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins were found to stimulate food consumption in rats, suggesting that these peptides have a physiological role as mediators in the central feedback mechanism regulating feeding behavior (Sakurai T. et al., Cell, 1998, 92, 573- 585). Orexin regulates the state of sleep and insomnia, potentially suggesting a new approach to treating patients with narcolepsy or insomnia (Chemelli R.M. et a...

Claims

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Application Information

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IPC IPC(8): C07D451/02C07D487/08A61K31/46A61P25/20A61P11/00A61P25/22A61P25/34A61P25/30
CPCC07D451/02A61P11/00A61P11/08A61P25/20A61P25/22A61P25/30A61P25/34A61P3/04A61P43/00A61K31/46C07D401/14
Inventor 贺海鹰吴松亮张杨马彪陈远王玉贺陈曙辉吕强兰炯刘星
Owner SHANGHAI HAIYAN PHARMA TECH
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