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Opioid receptor ligands and methods of using and making same

A compound and free technology, applied in botany equipment and methods, pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve problems such as vomiting

Active Publication Date: 2014-04-02
特维娜SPV2有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when given the pain-relieving dose of morphine selected for pain-free individuals, the experience is not always pleasant; nausea is common and vomiting may also occur

Method used

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  • Opioid receptor ligands and methods of using and making same
  • Opioid receptor ligands and methods of using and making same
  • Opioid receptor ligands and methods of using and making same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0248] Intermediate 1: Methyl 2-cyano-2-(oxan-4-ylidene)acetate (2-cyano-2-(oxan-4-ylidene)methyl acetate) Fill tetrahydro-4H-pyran-4-one (4.61ml, 50mmol), methyl cyanoacetate (5.3ml, 60mmol), ammonium acetate (1g, 13mmol) in the 50ml round bottom flask of distillation apparatus and condenser, Acetic acid (0.57ml, 10mmol) and benzene (30ml). The mixture was refluxed until no more water was collected in the Dean-Stark (2 hours), cooled, benzene (30ml) added and the organic layer washed with water (50ml). use CH 2 Cl 2 (3x50ml) to extract the aqueous layer. The combined organic layers were washed with saturated NaHCO 3 (100ml), washed with brine (100ml), dried (MgSO 4 ), filtered and concentrated. Via normal phase SiO 2 Chromatographic (10 to 60% EtOAc / hexanes) purification to give methyl 2-cyano-2-(oxan-4-ylidene)acetate (6.30 g, 70%, found m / z: 181.1 [ M+H] + ), as a colorless oil.

[0249] Intermediate 2: Methyl 2-cyano-2-[4-(4-fluorophenyl)oxan-4-yl]acetate

...

Embodiment 2

[0255] Example 2: Benzyl({2-[4-(4-fluorophenyl)oxan-4-yl]ethyl})amine (compound 8)

[0256] At room temperature, to anhydrous CH 2 Cl 2 2-[4-(4-fluorophenyl)oxan-4-yl]ethan-1-amine (250mg, 1.12mmol) and Na in (5ml) 2 SO 4 (159mg, 1.12mmol) was added benzaldehyde (0.17ml, 1.68mmol). The reaction was stirred overnight. The reaction mixture was filtered and concentrated. The residue was dissolved in 5 ml MeOH at 0 °C and NaBH was added in one portion 4 (51 mg, 1.34 mmol). The reaction was stirred at 0 °C for 1 hour. The solution was then treated with H 2 O (10ml), quenched with CH 2 Cl 2 (3x20ml) was extracted, washed with brine (10ml) and dissolved in Na 2 SO 4 Dry on top. Via normal phase SiO 2 Chromatography (0 to 10% MeOH / CH 2 Cl 2 ) was purified to give benzyl({2-[4-(4-fluorophenyl)oxan-4-yl]ethyl})amine (200 mg, 60%, found m / z: 314.2 [M+ H] + ), as a colorless oil.

[0257] Intermediate 5: 2,2-Dimethyl-4-(4-methylphenyl)oxan-4-ol

[0258] in N 2 n-B...

Embodiment 3

[0265] Example 3:{2-[2,2-Dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(3-methylphenyl)methyl]amine (compound 32 )

[0266] will be in CH 2 Cl 2 2-[2,2-Dimethyl-4-(4-methylphenyl)oxan-4-yl]acetaldehyde (61.6 mg, 0.25 mmol), 3-methylbenzyl A mixture of amine (63 µl, 0.5 mmol) and acetic acid (50 µl, 8.6 mmol) was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (106 mg, 0.50 mmol) was added. The resulting mixture was stirred at room temperature for 18 hours. The mixture was concentrated and dissolved in MeOH, and purified by HPLC to give {2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[( 3-Methylphenyl)methyl]amine (35 mg, 40%, found m / z: 352.3 [M+H] + ), as a white solid.

[0267] Intermediate 8: Methyl 2-cyano-2-[(9Z)-6-oxaspiro[4.5]decane-9-ylidene]acetate

[0268] A 100ml round-bottomed flask equipped with a Dean-Stark distillation apparatus and a condenser was charged with 6-oxaspiro[4.5]decane-9-one (6g, 39mmol, according to Hanschke, ...

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Abstract

This application describes compounds that can act as opioid receptor ligands, which compounds can be used in the treatment of, for example, pain and pain related disorders.

Description

technical field [0001] This application relates to a family of compounds useful as opioid receptor ligands. Such compounds may provide therapeutic benefit in the treatment of pain. Background technique [0002] The opioid receptor (OR) mediates the effects of morphine and morphine-like opioids, including most clinical analgesics. Three molecularly and pharmacologically distinct opioid receptor types have been described: delta, kappa, and mu. Furthermore, each type is considered to have subtypes. All three of these opioid receptor types appear to share the same mechanism of action at the cellular level. For example, activation of opioid receptors causes inhibition of adenylyl cyclase and recruits β-arrestin. [0003] When a patient suffering from pain is given therapeutic amounts of morphine, the patient reports a decrease in pain intensity, less discomfort, or complete elimination. In addition to feeling pain relief, some patients experience euphoria. However, when pai...

Claims

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Application Information

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IPC IPC(8): A01N43/16A61K31/35
CPCC07D409/14A61K31/4433C07D409/12C07D311/96C07D405/12A61K45/06A61K31/35C07D405/14A61K31/444A61K31/4436C07D405/04A61P29/00A61K31/352A61K9/0019A61P1/04A61P1/10A61P1/12A61P13/00A61P15/00A61P25/00A61P25/04A61P25/30A61P37/02A61P43/00
Inventor 丹尼斯·山下迪米塔·戈奇夫菲利普·皮蒂斯陈小涛刘国栋凯瑟琳·C·K·袁
Owner 特维娜SPV2有限责任公司
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