Use of amidoxime carboxylic acid esters and n-hydroxyguanidine carboxylic acid esters for producing prodrugs

Abstract

The invention relates to a method for improving the bioavailability of pharmaceutical substances and for allowing the pharmaceutical substances to permeate the blood-brain barrier, the pharmaceutical substances having at least one or more amidine, guanidine, N-hydroxyamidine (amidoxime) or N-hydroxyguanidine functions. The invention also relates to medicaments containing the correspondingly modified pharmaceutical substances.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a Continuation of International Application No. PCT / EP2009 / 051132, filed Feb. 2, 2009, which was published in the German language on Aug. 6, 2009, under International Publication No. WO 2009 095499 A1 and the disclosure of which is incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to use of an amidoxime carboxylic acid ester in a method for improving the bioavailability and enabling the blood-brain barrier crossing of medicinal substances, which have at least one or more amidine functions, guanidine functions, N-hydroxyamidine (amidoxime) functions or N-hydroxyguanidine functions, and drugs containing correspondingly modified medicinal substances.BACKGROUND OF THE INVENTION[0003]N-hydroxyamidines (amidoximes) and N-hydroxyguanidines represent known prodrug principles for increasing the oral bioavailability of amidines [Clement, B. Methoden zur Behandlung und Prophylaxe der Pneum...

AI Technical Summary

Benefits of technology

[0019]as a substitute for one or more amidine functions, N-hydroxyamidine (amidoxime) functions, guanidine functions or N-hydroxyguanidine functions of a prodrug for a medicinal substance for improving the solubility, bioavailability and / or capacity of the medicinal substance to pass the blood-brain barrier, wherein n=0, . . . , 12, and R1 is selected from the group consisting of hydrogen, an alkyl radical and an aryl radical and the salts thereof, the medicinal substance is selected from the group consisting of protease inhibitors, the DNA-intercalating and RNA-intercalating compounds, inhibitors of viral enzymes and N-methyl-D-aspartate receptor antagonists.

Problems solved by technology

Another problem in the medication of many diseases is the necessity to cross the blood-brain barrier.

Particularly in developing countries, these diseases represent a serious problem involving high mortality rates.

Efficiency is no longer provided in the 2nd stage of the African sleeping sickness, the meningo-encephalitic stage, since the blood-brain barrier cannot be passed successfully.

As a result, highly toxic arsenic compounds must be administered.

There is a lack of medicinal substances which are efficient in the 2nd stage of the African sleeping sickness.

It is likely that all of the active agents, which have an amidine or a guanidine as a functional group, exhibit an insufficient resorption in the oral application, if they can only be resorbed by passive diffusion.

Furthermore, the reduced water solubility induces the disadvantage that an administration of the medicinal substance is no longer possible by injecting aqueous solutions.

This is a problem, particularly when an oral administration is out of question.

Images