Novel Compounds Modulating Dopamine D3 Receptor Affinity
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Solution Overview
Problem
Current compounds disclosed in previous patent applications do not cover the scope of novel compounds with affinity for dopamine receptors, specifically the dopamine D3 receptor, which are beneficial for treating conditions requiring modulation of these receptors.
Innovation Solution
Development of novel compounds of formula (I) or their pharmaceutically acceptable salts, featuring specific substituents and configurations, which exhibit affinity for dopamine D3 receptors, including stereochemical isomers enriched in certain configurations, to modulate receptor activity effectively.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing compounds are used, then current patent coverage is maintained, but affinity for dopamine D3 receptors and therapeutic efficacy are insufficient
Solution Approach 1:
The patent applies parameter changes by systematically varying substituents at multiple positions (R1-R6, G, p) of the core bicyclic structure. This includes changing atomic composition (halogen, hydroxy, cyano, alkyl, alkoxy, alkanoyl groups), molecular weight, and spatial configuration (stereoisomers). These parameter variations generate a comprehensive series of compounds with optimized D3 receptor affinity while maintaining broad patent coverage.
Solution Approach 2:
The patent employs composite molecular structures by combining a core 3-azabicyclo[3.1.0]hexane framework with diverse substituent groups including heterocyclic moieties (isoxazolyl, thienyl, thiazolyl, pyridyl), aromatic systems (phenyl, pyridyl), and various functional groups. This composite approach creates molecules with tailored properties that achieve both high D3 affinity and broad therapeutic applicability.
2Reliability
If specific stereochemical configurations are specified, then biological activity is enhanced, but synthesis complexity increases
Solution Approach 1:
The patent applies preliminary action by establishing the correct stereochemical configuration early in the synthesis process through chiral pool synthesis or asymmetric synthesis methods. By pre-establishing the desired chirality at the bicyclic core and substituent positions, the patent ensures optimal biological activity from the outset, avoiding the need for complex resolution steps later in the synthesis.
Solution Approach 2:
The patent uses chiral intermediates and auxiliaries as mediators during synthesis to control stereochemistry. These intermediary chiral agents facilitate the formation of specific enantiomers and diastereomers, enabling precise control over the three-dimensional configuration required for high D3 receptor affinity while simplifying the overall synthetic pathway.
Data Source
AI summary
The present invention relates to novel compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein G is selected from a group consisting of: phenyl, pyridyl, benzothiazolyl, indazolyl; p is an integer ranging from 0 to 5; R1 is independently selected from a group consisting of: halogen, hydroxy, cyano, C1-4alkyl, halo C1-4alkyl, C1-4alkoxy, halo C1-4alkoxy, C1-4alkanoyl and SF5; or corresponds to a group R5; R2 is hydrogen or C1-4alkyl; R3 is C1-4alkyl; R4 is hydrogen, C1-4alkyl or C1-6cycloalkyl optionally substituted by 1or 2 substituents selected from the group consisting of: halogen, cyano, C1-4alkyl, halo C1-4alkyl, C1-4alkoxy, C1-4alkanoyl; R5 is a moiety selected from the group consisting of: isoxazolyl, -CH2-N-pyrrolyl, 1,1-dioxido-2-isothiazolidinyl, thienyl, thiazolyl, pyridyl, 2-pyrrolidinonyl, and such a group is optionally substituted by one or two substituents selected from: halogen, cyano, C1-4alkyl, halo C1-4alkyl, C1-4alkoxy, C1-4alkanoyl; processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, as modulators of dopamine D3 receptors, e.g. to treat drug dependency, or as antipsychotic agents, or to treat obsessive compulsive spectrum disorders or premature ejaculation.