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Combinations of opioid receptor ligands and cytochrome p450 inhibitors

A technology of inhibitors and compositions, which can be used in drug combinations, medical preparations containing active ingredients, anti-inflammatory agents, etc., and can solve problems such as vomiting.

Inactive Publication Date: 2018-09-28
TREVENA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition to experiencing pain relief, some patients experience euphoria
However, when morphine is given to pain-free individuals at selected pain-relieving doses, the experience is not always pleasant; nausea is common, and vomiting may also occur

Method used

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  • Combinations of opioid receptor ligands and cytochrome p450 inhibitors
  • Combinations of opioid receptor ligands and cytochrome p450 inhibitors
  • Combinations of opioid receptor ligands and cytochrome p450 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0278] Example 1: Intermediate 1 : Methyl 2-cyano-2-(oxan-4-ylidene)acetate

[0279] To a 50 ml round bottom flask equipped with a Dean-Stark distillation apparatus and condenser was added tetrahydro-4H-pyran-4-one (4.61 ml, 50 mmol), methyl cyanoacetate (5.3 ml, 60 mmol), ammonium acetate (1 g, 13 mmol), acetic acid (0.57 ml, 10 mmol) and benzene (30 ml). The mixture was refluxed until no more water collected in the Dean-Stark (2 hours), cooled, benzene (30ml) added and the organic layer washed with water (50ml). use CH 2 Cl 2 (3 x 50ml) to extract the aqueous layer. The combined organic phases were washed with saturated NaHCO 3 (100ml), washed with brine (100ml), dried (MgSO 4 ), filtered and concentrated. Via normal phase SiO 2 Purification by chromatography (10 to 60% EtOAc / hexanes) gave methyl 2-cyano-2-(oxan-4-ylidene)acetate (6.30 g, 70%, m / z:181.1[M+H] + measured value).

[0280] Intermediate 2 : 2-cyano-2-[4-(4-fluorophenyl)oxan-4-yl)methyl acetate

[...

Embodiment 2

[0286] Example 2: Benzyl({2-[4-(4-fluorophenyl)oxan-4-yl]ethyl})amine (Compound 8)

[0287] 2-[4-(4-Fluorophenyl)oxan-4-yl]ethan-1-amine (250mg, 1.12mmol) and NA 2 SO 4 (159mg, 1.12mmol) in anhydrous CH 2 Cl 2 To a solution in (5ml) 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 h. The solution was then treated with H 2 O (10ml) quenched with CH 2 Cl 2 (3×20ml), washed with brine (10ml) and washed with Na 2 SO 4 dry. Via normal phase SiO 2 Chromatography (0 to 10% MeOH / CH 2 Cl 2 ) to give benzyl({2-[4-(4-fluorophenyl)oxan-4-yl]ethyl})amine (200 mg, 60%, m / z : 314.2[M+H] + measured value).

[0288] Intermediate 5: 2,2-Dimethyl-4-(4-methylphenyl)oxan-4-ol

[0289] in N 2 n-BuLi (26.3ml, 1.6M in hexane, 42mmol) was added dropwise to ...

Embodiment 3

[0297] Example 3: {2-[2,2-Dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(3-methylphenyl)methyl]amine (compound 32)

[0298] 2-[2,2-Dimethyl-4-(4-methylphenyl)oxan-4-yl]acetaldehyde (61.6mg, 0.25mmol), 3-methylbenzylamine (63μl , 0.5mmol) and acetic acid (50μl, 8.6mmol) of CH 2 Cl 2 (3ml) The solution was stirred at room temperature for 1h, then sodium triacetoxyborohydride (106mg, 0.50mmol) was added. The resulting mixture was stirred at room temperature for 18 h. The mixture was concentrated and dissolved in MeOH and purified by HPLC to afford {2-[2,2-Dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[ (3-Methylphenyl)methyl]amine as a white solid (35 mg, 40%, m / z: 352.3 [M+H] + measured value).

[0299] Intermediate 8 : Methyl 2-cyano-2-[(9Z)-6-oxaspiro[4.5]decane-9-ylidene]acetate

[0300] Add 6-oxaspiro[4.5]decane-9-one (6g, 39mmol, which was obtained by Hanschke, E.Chem.Ber.1955,88 , prepared in 1053), methyl cyanoacetate (4.1ml, 46.7mmol), ammonium acetate (780mg, 10....

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Abstract

This application described compounds that can act as opioid receptor ligands, and compositions comprising the compounds and cytochrome P450 inhibitors, which can be used in the treatment of, for example, pain and pain related disorders.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application No. 62 / 268,874, filed December 17, 2015, the entire disclosure of which is incorporated herein by reference. This application is also related to U.S. Nonprovisional Application No. 13 / 428,849, filed March 23, 2012, Provisional Application No. 61 / 596,808, filed February 9, 2012, and U.S. Provisional Application No. 61 / 596,808, filed March 23, 2011 Serial No. 61 / 466,809, the entire contents of each of which are incorporated herein by reference. technical field [0003] The present disclosure generally relates to combinations of families of compounds useful as opioid receptor ligands and families of compounds useful as cytochrome p450 inhibitors for, but not limited to, the treatment of pain, depression and other disorders or conditions. Background technique [0004] Opioid receptors (ORs) mediate the effects of morphine and morphine-like opioids, including m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/439A61K31/444A61K31/165
CPCA61K31/444A61K45/06A61K31/436A61K31/352A61K31/381A61K31/427A61K31/4433A61K31/4436A61K31/4525A61K31/472A61K31/4725A61K31/496A61K31/7048A61P25/04A61K31/138A61P29/00A61K2300/00A61P25/00
Inventor 乔纳森·D·维奥林大卫·G·泽格尔
Owner TREVENA INC
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