Amine Compound S1P Modulator for Transplant Immunosuppression
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Solution Overview
Problem
Current amine compounds used for immunosuppression in organ transplantation, such as cyclosporine, exhibit adverse side effects like renal toxicity and neurotoxicity, and existing modifications do not adequately address transient bradycardia and safety concerns, limiting their effectiveness as pharmaceutical agents.
Innovation Solution
Development of novel amine compounds with specific structural formulas, including 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol and its derivatives, which act as S1P receptor modulators with reduced side effects and enhanced immunosuppressive action.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional 2-aminopropane-1,3-diol compounds are used for immunosuppression, then immunosuppressive action is achieved, but transient bradycardia and other side effects occur
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of 2-aminopropane-1,3-diol compounds through introducing specific substituents (trihaloalkyl groups, cyano groups, or alkoxyl groups) at defined positions on the molecular framework. These structural parameter changes result in compounds that maintain immunosuppressive efficacy while reducing or eliminating transient bradycardia side effects, as demonstrated by the novel compounds of formula (I) and (II) described in the patent.
2Reliability
If calcineurin inhibitors such as cyclosporine are used for organ transplantation, then rejection suppression is achieved, but renal toxicity, liver toxicity and neurotoxicity occur
Solution Approach 1:
The patent employs parameter changes by developing novel amine compounds with modified molecular structures that differ from conventional calcineurin inhibitors. The specific structural modifications (introduction of trihaloalkyl, cyano, or alkoxyl groups) create compounds that achieve rejection suppression through alternative mechanisms while avoiding the toxicities associated with cyclosporine and FK506, as evidenced by the improved safety profile described in the patent.
3Object-affected harmful factors
If existing modifications of 2-aminopropane-1,3-diol compounds are made to reduce side effects, then some safety improvements are achieved, but satisfactory safety level is not reached
Solution Approach 1:
The patent applies systematic parameter changes by exploring multiple substituent types (trihaloalkyl groups, cyano groups, alkoxyl groups) at specific positions on the 2-aminopropane-1,3-diol framework. This comprehensive structural modification approach, going beyond previous modifications, achieves a satisfactory safety level by eliminating transient bradycardia while maintaining immunosuppressive efficacy, as demonstrated by the novel compounds disclosed in the patent.
4Adaptability or versatility
If a trihaloalkyl group is introduced as a substituent on the benzene ring, then novel structure is created, but safety level remains insufficient
Solution Approach 1:
The patent applies parameter changes by combining trihaloalkyl groups with other specific substituents (cyano groups or alkoxyl groups) in defined structural arrangements. This multi-parameter structural optimization, rather than simple substitution, achieves the required safety level while maintaining structural diversity and immunosuppressive activity, as evidenced by the specific compounds of formula (I) and (II) disclosed in the patent.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The new compounds demonstrate superior peripheral blood lymphocyte decreasing action with reduced side effects like bradycardia, offering improved safety and efficacy as immunosuppressive agents for transplantation and autoimmune disease treatment.
Implementation Method 1
FTY720 is rapidly converted to phospho-FTY720 (hereinafter to be sometimes referred to as FTY720-P, e.g., 2-amino-2-phosphoryloxymethyl-4-(4-octylphenyl)butanol) by sphingosine kinase in vivo
Data Source
AI summary
A novel amine compound represented by the following formula (I), which is superior in immunosuppressive action, rejection suppressive action and the like, and shows reduced side effects such as bradycardia and the like, or a pharmaceutically acceptable acid addition salt thereof, or hydrates thereof, or solvate, as well as a pharmaceutical composition containing this compound and a pharmaceutically acceptable carrier.wherein R is a hydrogen atom or P(═O)(OH)2, X is an oxygen atom or a sulfur atom, Y is CH2CH2 or CH═CH, R1 is cyano or alkyl having a carbon number of 1 to 4 and substituted by a halogen atom(s), R2 is alkyl having a carbon number of 1 to 4 and optionally substituted by a hydroxyl group(s) or a halogen atom(s), R3 and R4 may be the same or different and each is a hydrogen atom or alkyl having a carbon number of 1 to 4, and n is 5-8.