Pyrimidine Derivative Oral Absorbability for GnRH Antagonists
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Solution Overview
Problem
Current GnRH antagonists, particularly peptidic ones, have poor oral absorbability and require subcutaneous or intramuscular administration, and existing non-peptidic GnRH antagonists with a pyrimidine ring fused with a 5-membered hetero ring lack sufficient oral absorbability and detailed blood kinetics data.
Innovation Solution
Development of a pyrimidine derivative fused with a 5-membered hetero ring, specifically represented by the general formula (I), which exhibits excellent GnRH antagonistic activity and improved blood kinetics upon oral administration, allowing for flexible dosing and reduced local reactivity at injection sites.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptidic GnRH antagonists are used, then GnRH receptor blocking activity is achieved, but oral absorbability is poor requiring subcutaneous or intramuscular administration
Solution Approach 1:
The patent changes the chemical structure from peptidic to non-peptidic compounds, specifically incorporating pyrimidine rings fused with 5-membered hetero rings (thiophene, furan, oxazole), which fundamentally alters the oral absorbability parameter while maintaining GnRH receptor blocking activity
Solution Approach 2:
The patent creates composite heterocyclic structures by fusing pyrimidine rings with 5-membered hetero rings, combining the properties of both ring systems to achieve both receptor binding affinity and improved oral absorbability that neither component alone could provide
2Ease of operation
If existing non-peptidic GnRH antagonists with pyrimidine ring fused with 5-membered hetero ring are used, then oral administration is possible, but oral absorbability is insufficient and blood kinetics are not well documented
Solution Approach 1:
The patent optimizes specific structural parameters including the fusion position of the 5-membered hetero ring to the pyrimidine ring, the type of hetero atom (sulfur in thiophene, oxygen in furan/oxazole), and substituent groups (aryl, heteroaryl, cycloalkyl) to maximize oral absorbability and blood kinetics
Solution Approach 2:
The patent introduces specific local structural features at key positions in the molecule, such as electron-donating or electron-withdrawing groups at particular locations on the heterocyclic rings, to enhance specific properties like membrane permeability and binding affinity independently
Data Source
AI summary
The present invention provides a compound useful as an agent for the prevention or treatment of a sex hormone-dependent disease or the like. That is, the present invention provides a fused heterocyclic derivative represented by the following general formula (I), a pharmaceutical composition containing the same, a medicinal use thereof and the like. In the formula (I), ring A represents 5-membered cyclic unsaturated hydrocarbon or 5-membered heteroaryl; RA represents halogen, alkyl, alkenyl, alkynyl, carboxy, alkoxy, carbamoyl, alkylcarbamoyl or the like; ring B represents aryl or heteroaryl; RB represents halogen, alkyl, carboxy, alkoxy, carbamoyl, alkylcarbamoyl or the like; E1 and E2 represent an oxygen atom or the like; U represents a single bond or alkylene; X represents a group represented by Y, -SO2-Y, -O-(alkylene)-Y, -O-Z in which Y represents Z, amino or the like; Z represents cycloalkyl, heterocycloalkyl, aryl, heteroaryl or the like; or the like.