Creatine Fatty Ester Synthesis via Diprotected Creatinine Ring Opening

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Solution Overview

Problem

Current methods for producing creatine fatty esters have low yields, especially when using long-chain alcohols, and are not efficient for therapeutic and diagnostic applications, leading to poor bioavailability and side effects due to low solubility and absorption rates of creatine.

Innovation Solution

A method involving the ring opening of diprotected creatinine with fatty alcohols or molecules bearing an alcohol functional group, such as glucose, to produce creatine fatty esters with a yield of 45%, enhancing bioavailability and therapeutic potential.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If current methods for producing creatine fatty esters are used, then production can proceed with existing processes, but yields are low especially when using long-chain alcohols

Engineering Contradiction:

Improveyield of creatine fatty estersVSAvoidefficiency of production process

Core Design Contradiction:

ProductivityVSEase of manufacture

Solution Approach 1:

The patent changes the chemical parameters of the reaction process by using diprotected creatinine as the starting material and employing specific catalysts (such as trimethylsilyl diazomethane or boron trifluoride etherate) to optimize the ring-opening reaction conditions. This parameter change enables significantly improved yields of creatine fatty esters, particularly with long-chain alcohols, resolving the contradiction between productivity and ease of manufacture.

Inventive Principle:

Principle #35Parameter changes

2Quantity of substance

If creatine is administered in large amounts to overcome poor solubility and absorption, then adequate creatine levels can be achieved, but side effects such as bloating, gastrointestinal distress, and diarrhea occur

Engineering Contradiction:

Improveamount of creatine absorbedVSAvoidgastrointestinal side effects

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The patent modifies the local chemical property of creatine by converting it into creatine fatty esters through esterification with fatty acids. This structural modification changes the solubility and absorption characteristics of creatine locally at the molecular level, enabling better gastrointestinal absorption without requiring large doses, thus eliminating the harmful side effects while maintaining therapeutic effectiveness.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent uses fatty acid esters as intermediary compounds that facilitate the absorption and transport of creatine across biological membranes. These intermediary creatine fatty esters act as carriers that can cross the gastrointestinal barrier more efficiently than native creatine, then are converted back to creatine in the body, solving the contradiction between absorption efficiency and side effects.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If creatine is used for therapeutic applications requiring blood-brain barrier penetration, then neurological conditions can be treated, but creatine's poor lipophilicity prevents effective crossing of the blood-brain barrier

Engineering Contradiction:

Improvetherapeutic effectiveness for neurological conditionsVSAvoidlipophilicity and membrane permeability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent changes the lipophilicity parameter of creatine by attaching fatty acid chains through esterification. This parameter change increases the lipophilic character of the molecule, enabling it to cross the lipid-rich blood-brain barrier effectively. The diprotected creatinine starting material ensures proper stereochemistry and protection of functional groups during the esterification process, achieving both therapeutic reliability and improved membrane permeability.

Inventive Principle:

Principle #35Parameter changes

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 method achieves higher yields and improved bioavailability of creatine fatty esters, allowing for effective therapeutic and diagnostic applications, including crossing the blood-brain barrier, thereby addressing the limitations of existing creatine supplementation methods.

Implementation Method 1

A method involving the ring opening of diprotected creatinine with fatty alcohols or molecules bearing an alcohol functional group, such as glucose, to produce creatine fatty esters

Methodology Applied

Scientific EffectRing opening reaction: Chemical Bonding

Data Source

PatentUS10144705B2Method for preparing creatine fatty esters, creatine fatty esters thus prepared and uses thereof

Publication Date: 2018.12.04 COMMISSARIAT A LENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES

AI summary

The present invention concerns a method for preparing a creatine fatty ester or derivative thereof comprising at least one step consisting in reacting a diprotected creatinine with a molecule bearing at least one alcohol functional group and of formula R′—OH in which R′ represents a hydrocarbon radical containing at least 4 carbon atoms. The present invention also concerns particular creatine fatty esters or derivative thereof and medical uses thereof.