Dual H1 and 5-HT2A Receptor Modulators for Sleep Fragmentation
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Solution Overview
Problem
Current pharmacological options are limited for treating sleep fragmentation, a common sleep disorder that affects a significant portion of the population, leading to various health and economic implications.
Innovation Solution
Development of piperazine substituted azapine derivatives with dual H1 inverse agonist and 5-HT2A antagonist activity, which can be used to modulate H1/5-HT2A receptors, thereby addressing sleep fragmentation by promoting better sleep quality.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If existing pharmacological options are used for treating sleep fragmentation, then some sleep disorder symptoms may be addressed, but the treatment options remain limited and insufficient for effective management of sleep fragmentation
Solution Approach 1:
The patent combines two distinct pharmacological activities (H1 inverse agonist and 5-HT2A antagonist) into a single compound molecule. This dual-action approach merges the benefits of both receptor modulations to effectively treat sleep fragmentation, addressing the limitation of existing single-action pharmacological options.
Solution Approach 2:
The compound of Formula (I) is designed to perform multiple functions simultaneously by modulating both H1 and 5-HT2A receptors. This multi-functionality allows a single agent to address multiple aspects of sleep fragmentation pathology, expanding the versatility of pharmacological treatment options.
2Reliability
If new compounds with dual H1/5-HT2A activity are developed, then treatment effectiveness for sleep fragmentation is improved, but the complexity of compound design and synthesis increases
Solution Approach 1:
The compound design is segmented into distinct functional components: a core azepine/oxazepine/thiazepine/diazepine structure (providing 5-HT2A antagonist activity) and a piperazine substituent with carboxylic acid side chain (providing H1 inverse agonist activity). This segmentation allows systematic optimization of each component's contribution to overall efficacy.
Solution Approach 2:
The patent systematically varies structural parameters of the compound including different azepine ring substitutions (R1-R6), side chain length (R7-R9), and functional group configurations to optimize the balance between H1 and 5-HT2A receptor affinity, thereby managing complexity through controlled parameter variation.
Data Source
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AI summary
The present disclosure relates to 3-(4-(llH-dibenzo[b,e][l,4]azepin-6- yl)piperazin-l-yl)-, 3-(4-(dibenzo[b,f][l,4]oxazepin-ll-yl)piperazin-l- yl)-, 3-(4-(dibenzo[b,f][l,4]thiazepin-ll-yl)piperazin-l-yl)- and 3- (4-(dibenzo[b,f][l,4]diazepin-ll-yl)piperazin-l-yl)-propanoic acid derivatives of the formulae (I), (II1) and (II): wherein X is CR7R8, O, S or NR7, and to their pharmaceutically acceptable salts, pharmaceutical compositions, methods for their preparation, as well as to the compounds for use in methods of medical treatment. The compounds disclosed herein are useful for modulating HI and 5- HT2Areceptors and are to be used in the treatment of sleep disorders such as sleep fragmentation, disturbed sleep/arousals, and arousal threshold. The present description discloses the synthesis and characterisation of exemplary compounds as well as pharmacological data thereof (e.g. pages 143 to 224; examples 1 to 33; compounds 1 to 39; tables A to R). An exemplary compound is e.g. 3-(4-(7-chloro-3-methyldibenzo[b,f] [l,4]oxazepin-ll-yl)piperazin-l-yl)-2, 2-dimethyl propanoic acid (example 1, compound 1):