5-Alkyloxy-Indolin-2-One Derivatives for V2 Receptor Selectivity
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Solution Overview
Problem
Current compounds for targeting vasopressin V2 receptors lack sufficient selectivity and metabolic stability, which are crucial for effective pharmacological applications.
Innovation Solution
Development of 5-alkyloxy-indolin-2-one derivatives that exhibit high affinity and selectivity for vasopressin V2 receptors, with improved metabolic stability, particularly on human liver microsomes, making them suitable for therapeutic use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current compounds are used to target vasopressin V2 receptors, then receptor binding occurs, but selectivity and metabolic stability are insufficient
Solution Approach 1:
The patent applies parameter changes by systematically modifying chemical parameters of the indolin-2-one core structure, including substituting different alkoxy groups at position 5, varying R1, Z1, Z2, R3, R4, and R5 substituents to optimize both V2 receptor selectivity and metabolic stability. This is evident in the extensive series of compounds with different alkyl, fluoroalkyl, cyclopropyl, and heterocyclic substitutions that achieve improved pharmacological properties while maintaining target engagement
Solution Approach 2:
The patent employs composite material principles by creating hybrid molecular structures that combine the indolin-2-one core with various functional groups including alkoxy chains, fluorinated groups, cyclopropyl moieties, and heterocyclic systems. These composite structures leverage the synergistic effects of different molecular components to simultaneously enhance receptor selectivity and resist metabolic degradation
2Reliability
If compound selectivity for V2 receptors is increased, then therapeutic effectiveness improves, but metabolic stability may be compromised
Solution Approach 1:
The patent applies local quality by introducing specific functional groups at particular positions on the indolin-2-one core to address local metabolic vulnerability. For example, fluorine substitution at aromatic positions provides local metabolic stability without affecting overall V2 selectivity, while alkoxy groups at position 5 provide local hydrophobic interactions for receptor binding. This localized optimization allows simultaneous improvement of both selectivity and metabolic stability
3Reliability
If new compound structures are developed for V2 receptor affinity, then selectivity improves, but development complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the molecule into distinct functional modules: the indolin-2-one core provides the essential pharmacophore for V2 binding, while separate substituent groups (R0, R1, Z1, Z2, R3, R4, R5) can be independently optimized for selectivity, metabolic stability, and pharmacokinetic properties. This modular approach simplifies the development process by allowing systematic variation of individual segments rather than redesigning the entire molecule
Data Source
AI summary
The invention relates to compounds of the formula (I) in which: R0 is (C1-C4)alkyl, mono or polyfluoro-(C1C4)alkyl, cyclopropyl or -CH2- cyclopropyl, (C2-C4)alkenyl or (C2-C4)alkynyl; R1 is H, (C1-C5)alkyl, mono or polyfluoro-(C1C5)alkyl, hydroxy-(C2-C5)alkyl, -(CH2)m-(C3-C5)cycloalkyl; Z1 is H or halogen, (C1C4)alkyl, mono or polyfluoro-(C-1-C4)alkyl, (C1- C4)alkoxy, mono or PoIy[IuOrO-(C1-C4)Alkoxy, cyclopropyl or -CH2-yclopropyle, optionally substituted; Z2is a halogen atom or a T1W group, in which T1 is a -(CH2)n- group, and W is one or more of H, (C1- C4)alkyl, mono or polyfluoro-(C-1-C4)alkyl or cyclopropyl optionally substituted, or W is -C(O)OR19, or W is -C(O)NR6R7, or W is a -NR8C(O)R9 group, or W is -NR10R11, or W is a -OR12 group; R4 is (CrC4)alkyl, mono or polyfluoro-(C1C4)alkyl, OH, (C1- C4)alkoxy, (C2-C4) alkenyl, nitro, COORCl, benzyloxy, or R4 is - C(O)NR13R14, or R4 is -NR15R16, or R4 is -NR17C(O)R18; R3 and R5 are H or halogen, (CrC4)alkyl, mono or polyfluoro-(CrC4)alkyl, (C1- C4)alkoxy or mono or polyfluoro-(C1C4)alkoxy; m = 0, 1 or 2; n = 0 or 1; said compounds being in their base, hydrate or solvate state, in the form of cis/trans isomers, or mixtures thereof. The invention also relates to a method for the preparation of the compounds of the formula (I) and to the use thereof in therapy.