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6-membered aza-heterocyclic containing delta-opioid receptor modulating compounds, methods of using and making the same

A compound and heterocycle technology, applied in the field of delta opioid receptor modulating compounds containing six-membered aza heterocycles, their use and preparation, and can solve problems such as hindering the development of selective drugs

Active Publication Date: 2018-05-11
TREVENA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, some DOR agonists induce seizures in preclinical species, hampering the development of selective drugs targeting DOR

Method used

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  • 6-membered aza-heterocyclic containing delta-opioid receptor modulating compounds, methods of using and making the same
  • 6-membered aza-heterocyclic containing delta-opioid receptor modulating compounds, methods of using and making the same
  • 6-membered aza-heterocyclic containing delta-opioid receptor modulating compounds, methods of using and making the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0347] 1. A compound having formula I, I-1, I-a, I-a1 or I-b, Ib-1 or Ib-2

[0348]

[0349]

[0350]

[0351] or a pharmaceutically acceptable salt thereof, wherein:

[0352] BB is

[0353] Z is C, S, N, S(O) 2 or O;

[0354] R 35 is a protecting group, C(=O)OR 81b , H, optionally substituted aryl, optionally substituted C 1 -C 6 Haloalkyl, -R 63 R 64 , optionally substituted C 1 -C 6 Branched or unbranched alkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 Haloalkenyl-(CH 2 ) n R 65 , optionally substituted heterocycle, optionally substituted C 1 -C 6 Esters, optionally substituted cycloalkyl, optionally substituted C 1 -C 6 Alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, optionally substituted C 3 -C 6 Cyclic ether or optionally substituted piperidinyl;

[0355] R 36 is empty, H, halogen, optionally substituted C 1 -C 6 Haloalkyl, -SO 2 C 1 -C 6 Alkyl, -OCF 3 , optionally su...

Embodiment 1

[0711] Example 1:

[0712] General Procedure A1: Preparation of 3,4-Piperidine N-H Analogs

[0713] plan 1

[0714]

[0715] Scenario 2

[0716]

[0717] (+)-6-{[trans-4-(4-methoxyphenyl)piperidin-3-yl]methoxy}isoindolin-1-one[(+)B0515] and (- )-6-{[trans-4-(4-methoxyphenyl)piperidin-3-yl]methoxy}isoindolin-1-one[(-)B0523] (Scheme 1 )

[0718] 4-(Trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid 1-tert-butyl 3-ethyl ester (2)

[0719] Trifluoromethanesulfonic anhydride (33.3 mL, 203 mmol) was added portionwise to commercially available (+ / -) -4-oxopiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl ester ([+ / -]1, 50.0g, 184mmol] and N,N-diisopropylethylamine (48.3 mL, 277 mmol). The mixture was stirred at 0 °C for 2 h, then warmed to room temperature, and the solids were removed by filtration. The filtrate solvent was removed under reduced pressure to afford crude 2 as a brown oil, which was used in the next step without purification St...

Embodiment 2

[1190] Example 2: Compounds are effective as modulators of delta-opioid receptors

[1191] The compounds described herein were tested as modulators of delta-opioid receptors. These compounds were found to be modulators of receptor activity. Some compounds inhibit the β-arrestin pathway and the G protein-mediated pathway, while other compounds agonize or enhance the β-arrestin-mediated pathway or the G-protein-mediated pathway. Activity was measured according to the methods described herein. The compounds described herein were tested as modulators of mu and kappa-opioid receptors.

[1192] in vitro assay

[1193] Plasmids encoding the δ opioid receptor (accession number NP_000902), the μ opioid receptor (accession number NP_000905) and the kappa opioid receptor (accession number NP_000903) were generated in the pCMV-Prolink backbone and transfected into EA-arrestin parental human embryonic kidney (HEK-293) cell line. Clonal stable lines were subsequently selected under G41...

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PUM

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Abstract

The present embodiments are directed, in part, to compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for modulating the activity of delta opioid receptor,biased and / or unbiased, and / or methods for treating pain, migraines, headaches, depression, Parkinsons Disease, anxiety, and / or overactive bladder, and other disorders and conditions described hereinor any combination thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application No. 62 / 213,203, filed September 2, 2015, which is hereby incorporated by reference in its entirety. [0003] About government funding [0004] This invention was made with US Government funding (NIH Grant Nos. 5U01NS074480-02 and 1RC2MH090877-01), and thus the US Government may have certain rights in this invention. technical field [0005] Embodiments disclosed herein relate, in part, to compounds or pharmaceutically acceptable salts thereof for modulating delta opioid receptor activity and / or for use in the treatment of pain (e.g., neuropathic pain), migraine (e.g., episodic, chronic or acute), headache (eg, episodic, chronic, or acute), depression, Parkinson's disease, PTSD, anxiety, and / or overactive bladder, or any combination thereof. Background technique [0006] Opioid receptors (ORs) mediate the effects of morphine and morphine-like opioid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/445C07D211/00A61P25/00
CPCC07D401/12C07D401/14C07D211/22C07D405/14C07D471/08C07D211/24C07D211/20A61P25/04A61P25/06A61P25/22A61P25/24A61P13/10A61P9/10A61P29/00A61P19/02A61P15/06A61P25/32A61P25/30A61K31/445C07D403/12C07D241/04C07D451/02A61P25/00A61P25/16A61P43/00A61K2300/00A61K31/4035A61K31/454
Inventor 艾梅·科伦比·斯皮尔施内德丹尼斯·S·山下菲利普·迈克尔·皮蒂斯迈克尔·约翰·霍金斯刘国栋塔玛拉·安·米斯可斯基·多伯特凯瑟琳·C·K·袁罗伯特·勃波·卡格博罗伯特·杰森·赫尔唐纳·罗梅罗格雷戈里·J·帕科夫斯基
Owner TREVENA INC
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