6-7 Substituted Morphinan Analogs for Peripheral Opioid Modulation

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Solution Overview

Problem

Current analgesics for pain management often have undesirable side effects and fail to effectively target peripheral opioid receptors, leading to a need for analgesics that can modulate μ, δ, κ, and ORL-1 opioid receptors both centrally and peripherally without significant central side effects.

Innovation Solution

Development of novel 6-substituted and 7-substituted morphinan analog compounds that act as modulators of opioid receptors, including μ, δ, κ, and ORL-1, to provide analgesia while minimizing central side effects by targeting both central and peripheral receptors.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If centrally penetrating κ agonists are used to produce antinociceptive effects, then pain relief is achieved, but sedative and psychotomimetic side effects occur

Engineering Contradiction:

Improveantinociceptive effectsVSAvoidsedative and psychotomimetic effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention segments the distribution of the compound by designing a peripherally restricted agonist that selectively targets peripheral opioid receptors while preventing central nervous system penetration, thereby separating the therapeutic effect from the side effects

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The compound is designed to have different distribution characteristics in different parts of the body - it acts locally at peripheral opioid receptors (in muscles, joints, and peripheral nerves) without reaching central receptors in the brain, achieving localized therapeutic action

Inventive Principle:

Principle #3Local quality

2Adaptability or versatility

If non-selective ligands with high affinity for μ, δ and κ receptors are used, then broad opioid receptor coverage is achieved, but affinity for ORL-1 receptor increases leading to potential side effects

Engineering Contradiction:

Improveopioid receptor coverageVSAvoidORL-1 receptor affinity

Core Design Contradiction:

Adaptability or versatilityVSObject-affected harmful factors

Solution Approach 1:

The compound exhibits selective affinity characteristics - it has high affinity for κ-opioid receptors while showing low or negligible affinity for ORL-1 receptors, creating a differentiated receptor profile that targets desired receptors while avoiding harmful ones

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention changes the affinity parameters of the ligand by modifying the morphinan structure to achieve selective binding - the compound maintains high affinity for κ receptors while reducing affinity for ORL-1 receptor through specific structural modifications at positions 6 and 7 of the morphinan core

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS10550088B26-substituted and 7-substituted morphinan analogs and the use thereof

Publication Date: 2020.02.04 PURDUE PHARMA LP

AI summary

The application is directed to compounds of Formula I or II: and pharmaceutically acceptable salts and solvates thereof, wherein R′, R″, R′″ R1, R2, R3, R4, R4a, and R20 are defined as set forth in the specification. The invention is also directed to use of compounds of Formula I or II and the pharmaceutically acceptable salts and solvates thereof to treat disorders responsive to the modulation of one or more opioid receptors. Certain compounds of the invention are especially useful for treating pain.