Aryl Sultam Derivatives with Quaternary Carbon for RORc Selectivity

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Solution Overview

Problem

There is a need for compounds that inhibit RORγ (RORc) to treat autoimmune diseases such as rheumatoid arthritis, osteoarthritis, psoriatic arthritis, irritable bowel disease, asthma, COPD, psoriasis, lupus, Sjogren's disease, idiopathic pulmonary fibrosis, and muscular sclerosis, as current treatments are inadequate in modulating RORc effectively.

Innovation Solution

Development of specific compounds of the formula I, which include a quaternary carbon substituent at group Z, providing improved selectivity for RORc over other receptor subtypes RORα and RORβ, and are used in pharmaceutical compositions for treating arthritis and other autoimmune diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If compounds without quaternary carbon substituent at group Z are used, then the compound structure is simpler, but the selectivity for RORc over other receptor subtypes is reduced

Engineering Contradiction:

Improveselectivity for RORcVSAvoidcompound structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies local quality by introducing a quaternary carbon substituent specifically at the group Z position of the compound structure. This localized structural modification enhances the selectivity for RORc receptor without requiring changes throughout the entire molecular structure, thus improving reliability while minimizing overall complexity

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by modifying the substituent at group Z to include a quaternary carbon with specific Rm groups. This parameter change in the molecular structure directly impacts the compound's binding affinity and selectivity for RORc, transforming the selectivity parameter from insufficient to enhanced

Inventive Principle:

Principle #35Parameter changes

2Reliability

If current treatments are used, then the treatment approach is simpler, but the modulation of RORc is inadequate

Engineering Contradiction:

Improvemodulation of RORcVSAvoidtreatment compound structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention introduces a specific local structural feature (quaternary carbon at group Z) that enhances RORc modulation capability. This localized modification allows the compound to achieve better therapeutic effect without requiring complete redesign of the entire treatment regimen

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent creates a composite molecular structure combining the base compound framework with an additional quaternary carbon substituent at group Z. This composite structure integrates the benefits of the original compound while adding enhanced RORc selectivity, resulting in superior modulation effectiveness

Inventive Principle:

Principle #40Composite materials

Data Source

PatentEP3092239B1Aryl sultam derivatives as rorc modulators

Publication Date: 2019.10.02 F HOFFMANN LA ROCHE & CO AG

AI summary

Compounds of the formula I: or pharmaceutically acceptable salts thereof, wherein in, n, p, q, r, X1, X2, X3, X4, Y, Z, A, R1, R2, R3, R4, R5 R6, R7, R8, R9, R10, R11, R12 and R13 are as defined herein.. Also disclosed are methods of making the compounds and using the compounds for treatment of inflammatory diseases such as arthritis, muscular sclerosis and psoriasis.