Tricyclic delta-opioid modulators

一种药物、化合物的技术，应用在三环δ阿片样物质调节剂领域

Inactive Publication Date: 2008-02-20
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when pain-free individuals are given pain-reducing doses of morphine, the experience is not always pleasant; nausea and possibly vomiting are common

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment A

[0340]

[0341] step 1

[0342] 4-bromo-2-phenoxy-benzonitrile, 1a

[0343] Sodium hydride (12 g, 300 mmol) (60% by weight) was weighed into the flask and washed with hexane several times to wash off the oil. The hexane was decanted and discarded, and DMF was added to the flask. A DMF solution of phenol (23.5 g, 250 mmol dissolved in 100 mL DMF) was added dropwise to the NaH mixture and stirred at room temperature. The 4-bromo-2-fluoro-benzonitrile solution (50 g, 250 mmol dissolved in 100 mL DMF) was added dropwise to the phenate. After the addition was complete, the reaction was refluxed for 20 hours. The reaction was cooled to room temperature and poured into cooled 1N NaOH. A fine yellow-brown precipitate formed and was collected by vacuum filtration to obtain 62.04 g (226 mmol) of 1a 4-bromo-2-phenoxybenzonitrile. MS m / z(MH + )277.

[0344] Step 2

[0345]4-bromo-2-phenoxy-benzoic acid, 2a

[0346] 4-Bromo-2-phenoxy-benzonitrile (35.3 g, 129 mmol) was added to 130 mL Et...

Embodiment B

[0390]

[0391] 4-bromo-2-(2-methoxy-phenoxy)-benzonitrile, 1b

[0392] Using a modification of the method described in step 1, replacing phenol with 2-methoxyphenol, the title compound 1b 4-bromo-2-(2-methoxy-phenoxy)-benzonitrile was prepared.

[0393] 4-bromo-2-(2-methoxy-phenoxy)-benzoic acid, 2b

[0394] Using the modification of the method described in step 2, substituting compound 1b for compound 1a, the title compound 2b 4-bromo-2-(2-methoxy-phenoxy)-benzoic acid was prepared.

[0395] 3-Bromo-5-methoxy-xanthene-9-one, 3b

[0396] Using the modification of the method described in step 3, replacing compound 2a with compound 2b, the title compound 3b 3-bromo-5-methoxy-xanthene-9-one was prepared.

[0397] 1-[4-(3-Bromo-5-methoxy-xanthene-9-ylidene)-piperidin-1-yl]-2,2,2-trifluoro-ethanone, 4b

[0398] Using the modification of the method described in step 7, replace compound 6a with compound 3b, and replace 3-oxo-8-aza- with 1-(2,2,2-trifluoroacetyl)-piperidin-4-one Bicycl...

Embodiment C

[0414]

[0415] 2-(2-Methoxy-phenoxy)-dimethyl terephthalate, 1c

[0416] Using the modification of the method described in step 1, using 2-methoxyphenol instead of phenol and potassium carbonate instead of sodium hydride, the title compound 1c 2-(2-methoxyphenoxy)-dimethyl terephthalate was prepared .

[0417] Step 12

[0418] 5-Methoxy-9-oxo-9H-xanthene-3-carboxylic acid methyl ester, 2c

[0419] A polyphosphoric acid (290 g) solution of 1c 2-(2-methoxyphenoxy)-dimethyl terephthalate (12.8 g, 40.5 mmol) was heated at 125°C while stirring with a mechanical stirrer. The mixture was poured into ice water and stirred overnight. The solid was separated by filtration, washed with water, and air dried. By silica gel flash column chromatography (MeOH / CH 2 Cl 2 The mixture was eluted) to obtain 6.48 g (56.3%) of 2c 5-methoxy-9-oxo-9H-xanthene-3-carboxylic acid methyl ester.

[0420] Step 13

[0421] 5-Methoxy-9-oxo-9H-xanthene-3-carboxylic acid, 3c

[0422] To a methanol (100 mL) s...

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Abstract

The invention is directed to delta opioid receptor modulators of formula (I). More specificially, the invention relates to tricyclic s-opioid modulators. Pharmaceutical and veterinary compositions for treating mild to severe pain and various diseases are also described.

Description

[0001] Cross-references to related applications [0002] This application claims the benefit of U.S. Patent Application 60 / 638,314 filed on December 22, 2004, which is incorporated herein by reference in its entirety. [0003] Statement on Federally Sponsored Research and Development [0004] The research and development of the invention described below is not under federal sponsorship. Background of the invention [0005] The term "opiate" is used to refer to pharmaceutically active alkaloids derived from opiates (e.g. morphine, codeine) and many semi-synthetic homologs of morphine. After isolating peptide compounds with morphine-like effects, the term opioid was introduced to collectively refer to all drugs with morphine-like effects. Opioids include various peptides with morphine-like activity (for example, endorphin, enkephalin, and dynorphin). However, some literature uses the term "opiate" in the general sense, and opiates and opioids are interchangeable at this time. In ad...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14C07D405/04C07D409/14C07D413/14A61K31/435A61P25/00
CPCC07D413/14C07D405/14C07D405/04C07D409/14A61P25/00A61P25/04A61K31/435
Inventor J·R·卡森S·L·达克斯B·德科尔特刘莉M·麦唐奈J·J·麦纳利
Owner JANSSEN PHARMA NV
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