7,8-dihydrobenzo[e]pyrido[3,4-c]azocine-2,5(3H,6H)-dione derivatives as Factor XIa inhibitors
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Solution Overview
Problem
Current anticoagulants for thromboembolic disorders have limitations such as a narrow therapeutic index, bleeding risks, and interactions with diet and other drugs, necessitating the development of safer and more effective oral anticoagulants.
Innovation Solution
Development of 7,8-dihydrobenzo[e]pyrido[3,4-c]azocine-2,5(3H,6H)-dione derivatives and their stereoisomers, isotopologues, and pharmaceutically acceptable salts for use in treating and preventing thromboembolic disorders and inflammatory conditions by targeting plasma kallikrein activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If warfarin is used as an oral anticoagulant, then it is effective in preventing venous and arterial thrombosis, but it has a narrow therapeutic index with respect to bleeding safety and requires monitoring and dose adjustment
Solution Approach 1:
The patent employs fixed-dose oral anticoagulant tablets that are designed to be used without monitoring or adjustment, similar to disposable items with predetermined parameters. The compounds provide a set-and-forget solution where the dosage is optimized during development and remains fixed in the final product, eliminating the need for patient monitoring and dose adjustments required by warfarin.
2Reliability
If warfarin is used as an oral anticoagulant, then it is effective in preventing thrombosis, but it has numerous dietary and drug-drug interactions
Solution Approach 1:
The patent extracts the anticoagulant activity specifically from the factor XIa pathway while leaving other coagulation pathways intact. This selective inhibition approach isolates the therapeutic effect from the broad systemic effects that cause dietary and drug interactions, allowing the medication to work effectively without interfering with normal hemostasis or interacting with common substances.
3Object-affected harmful factors
If novel oral anticoagulants directly targeting thrombin or factor Xa are used, then bleeding risk is reduced compared to warfarin, but bleeding risk is not completely eliminated and remains as high as 2-3% per year in patients with atrial fibrillation
Solution Approach 1:
The patent segments the coagulation cascade into distinct pathways and selectively targets only the factor XIa segment. By dividing the anticoagulant approach into pathway-specific inhibition rather than broad inhibition of thrombin or factor Xa, the treatment achieves sufficient anticoagulation to prevent thrombosis while preserving other protective hemostatic mechanisms, thereby further reducing bleeding risk.
Data Source
AI summary
The present invention is directed to 7,8-dihydrobenzo[e]pyrido[3,4-c]azocine-2,5(3H,6H)-dione derivatives, stereoisomers, isotopologues, isotopomers and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing said compounds and the use of said compounds in the treatment and/or prophylaxis of thromboembolic disorders, inflammatory disorders and diseases or conditions in which plasma kallikrein activity is implicated.