Formula I Heterocyclic Ethers for CNS Disorders

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Solution Overview

Problem

Current treatments for depression, such as selective serotonin reuptake inhibitors (SSRIs), have limitations including delayed onset of antidepressant activity, limited efficacy, and significant side effects, and do not effectively address patients who poorly respond to these drugs.

Innovation Solution

Development of compounds of Formula I that inhibit neurokinin-1 (NK-1) receptors or serotonin reuptake, or both, to treat CNS disorders related to tachykinins or serotonin levels, offering an alternative approach for depression and other conditions like anxiety and obsessive-compulsive disorder.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If selective serotonin reuptake inhibitors (SSRIs) are used to treat depression, then antidepressant activity is achieved, but onset is delayed and side effects are significant

Engineering Contradiction:

Improveantidepressant efficacyVSAvoidonset delay

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The patent combines SSRI activity with NK-1 receptor antagonism in a single compound structure (Formula I), merging two separate mechanisms of action into one therapeutic agent. This allows simultaneous serotonin reuptake inhibition and neurokinin-1 blocking, achieving faster and more comprehensive antidepressant effect without the delays and side effects of SSRI monotherapy

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The compounds of Formula I exhibit multi-functionality by simultaneously acting as serotonin reuptake inhibitors and NK-1 receptor antagonists. This universal approach addresses multiple pathophysiological mechanisms of depression (serotonin deficiency and tachykinin excess) through a single agent, improving both speed of onset and overall efficacy

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Reliability

If selective serotonin reuptake inhibitors (SSRIs) are used to treat depression, then antidepressant activity is achieved, but efficacy is limited in poorly responding patients

Engineering Contradiction:

Improveantidepressant efficacyVSAvoidresponse variability

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

By merging SSRI and NK-1 antagonist activities into one compound, the patent creates a therapeutic agent that addresses multiple depression pathophysiological mechanisms simultaneously. This combined approach increases adaptability to different patient subgroups, particularly those who do not respond to SSRI monotherapy, by targeting both serotonin and tachykinin systems

Inventive Principle:

Principle #5Merging (Combining)

3Adaptability or versatility

If NK-1 antagonists are used to treat depression, then alternative approach is provided, but combination with SSRIs may be needed for optimal effect

Engineering Contradiction:

Improvetherapeutic approach flexibilityVSAvoidcombination therapy complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent merges SSRI and NK-1 antagonist activities into a single integrated compound structure (Formula I), eliminating the need for separate combination therapy. This single-agent approach provides the flexibility of combined mechanism action while avoiding the complexity of managing multiple medications, dosing schedules, and potential drug-drug interactions

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentUS8026257B2Substituted heterocyclic ethers and their use in CNS disorders

Publication Date: 2011.09.27 BRISTOL MYERS SQUIBB CO

AI summary

The invention encompasses compounds of Formula I, including pharmaceutically acceptable salts, their pharmaceutical compositions, and their use in treating CNS disorders.