Estrogen Receptor Antagonist Salts and Solid Forms for Stable Handling

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Solution Overview

Problem

There is a need for anti-estrogen agents that can completely inhibit estrogen receptors, including those with activating mutations, to effectively treat cancers and other ER-mediated disorders.

Innovation Solution

Development of salts, solid forms, and compositions of the compound (1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, including solvates, hydrates, and crystalline forms, to provide complete estrogen receptor antagonism.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If Compound 1 is used as a free base, then complete estrogen receptor antagonism is achieved, but stability and handling properties are insufficient

Engineering Contradiction:

ImprovestabilityVSAvoidhandling properties

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent applies parameter changes by converting Compound 1 from its free base form into various salt forms (sulfonate salts, carboxylate salts, phosphate salts, etc.) and solid forms (crystalline, amorphous, solvates, hydrates). This chemical form transformation improves stability and handling properties while preserving the complete estrogen receptor antagonism activity, directly resolving the contradiction between reliability and ease of manufacture.

Inventive Principle:

Principle #35Parameter changes

2Stability of the object's composition

If salt forms of Compound 1 are developed, then stability and flow properties are improved, but formulation complexity increases

Engineering Contradiction:

ImprovestabilityVSAvoidformulation complexity

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The patent segments the formulation development by categorizing salts into distinct chemical families (sulfonate salts, carboxylate salts, phosphate salts, etc.) with specific counterions. This systematic segmentation allows for methodical evaluation and selection of optimal salt forms, managing formulation complexity while achieving improved stability and flow properties.

Inventive Principle:

Principle #1Segmentation

3Reliability

If complete estrogen receptor antagonism is achieved, then treatment effectiveness for mutant ER is improved, but selectivity challenges arise

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidselectivity challenges

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by developing salt forms with specific chemical characteristics (acidic, basic, neutral properties) that are optimized for different biological environments and delivery requirements. This allows the active compound to maintain complete ER antagonism activity while the salt form provides localized optimization for stability, solubility, and tissue distribution, addressing selectivity challenges in different biological contexts.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS20250214996A1Salts and solid forms of an estrogen receptor antagonist

Publication Date: 2025.07.03 OLEMA PHARMACEUTICALS INC

AI summary

The present disclosure provides solid and salt forms of an estrogen receptor (ER) inhibitor, compositions thereof and N methods of treating a ER-mediated disorder.