New pradimicin derivatives for the treatment of diseases caused by kinetoplastids

A method of treating or reducing the risk of a kinetoplastid infection in a subject comprising administering to the subject a compound according to formula A or I in an amount effective to treat or reduce the risk of a kinetoplastid infection in a subject;

• wherein formula A has the structure:
• wherein formula I has the structure:
• wherein
• Ra is selected from the group consisting of OH, —NR7R8, —NHNR7R8, —NHCH2CO2H and (D)-NHCH(CH3)CO2H;
• R7 is H and R8 is selected from the group consisting of H, (C1-6)alkyl, (C3-6)cycloalkyl, (C6-10)aryl, and (C7-15)aralkyl;
• or R7 and R8 are independently (C1-6)alkyl;
• or R7, R8 and the nitrogen to which they are attached form a 3- to 6-membered ring;
• R1 is H, methyl, or hydroxymethyl;
• R2 is OH or NR3R4, wherein R3 and R4 are independently selected from the group consisting of H;
• optionally substituted (C1-5)alkyl;
• optionally substituted (C2-5)alkenyl;
• (C2-5)alkynyl, wherein the substituent for both the alkyl and alkenyl is a group selected from the group consisting of, carboxy, (C1-5)alkoxycarbonyl, carbamyl, (C1-5)alkylcarbamyl, di(C1-5)alkylcarbamyl, and sulfonyl;
• (C1-5)alkanoyl substituted with a group selected from the group consisting of amino, (C1-5)alkylamino, and di(C1-5)alkylamino;
• L-glutamyl;
• formyl;
• benzyl;
• p-tolylsulfonylcarbamyl;
• —CN;
• —NO;
• R5 is H or R5 is represented by the general formula II:
• wherein represents the point of attachment to the oxygen atom of structural formula I or to the oxygen atom of formula A;
• wherein R6 is H or sulfonic acid;
• and
• wherein R9 is H or CH2OH;
• or a pharmaceutically acceptable salt, solvate, tautomer or isomer thereof.

A medicine for treating or reducing the risk of a kinetoplastid infection in a subject, the medicine comprising a compound according to formula A or I in an amount effective to treat or reduce the risk of a kinetoplastid infection in a subject;

• wherein formula A has the structure:
• wherein formula I has the structure:
• wherein
• Ra is selected from the group consisting of OH, —NR7R8, —NHNR7R8, —NHCH2CO2H and (D)-NHCH(CH3)CO2H;
• R7 is H and R8 is selected from the group consisting of H, (C1-6)alkyl, (C3-6)cycloalkyl, (C6-10)aryl, and (C7-15)aralkyl;
• or R7 and R8 are independently (C1-6)alkyl;
• or R7, R8 and the nitrogen to which they are attached form a 3- to 6-membered ring;
• R1 is H, methyl, or hydroxymethyl;
• R2 is OH or NR3R4, wherein R3 and R4 are independently selected from the group consisting of H;
• optionally substituted (C1-5)alkyl;
• optionally substituted (C2-5)alkenyl;
• (C2-5)alkynyl, wherein the substituent for both the alkyl and alkenyl is a group selected from the group consisting of, carboxy, (C1-5)alkoxycarbonyl, carbamyl, (C1-5)alkylcarbamyl, di(C1-5)alkylcarbamyl, and sulfonyl;
• (C1-5)alkanoyl substituted with a group selected from the group consisting of amino, (C1-5)alkylamino, and di(C1-5)alkylamino;
• L-glutamyl;
• formyl;
• benzyl;
• p-tolylsulfonylcarbamyl;
• —CN;
• —NO;
• R5 is H or R5 is represented by the general formula II:
• wherein represents the point of attachment to the oxygen atom of structural formula I or to the oxygen atom of formula A;
• wherein R6 is H or sulfonic acid;
• and
• wherein R9 is H or CH2OH;
• or a pharmaceutically acceptable salt, solvate, tautomer or isomer thereof.

A pharmaceutical composition for treating or reducing the risk of a kinetoplastid infection in a subject, comprising a compound according to formula A or I in an amount effective to treat or reduce the risk of a kinetoplastid infection in a subject;

• wherein formula A has the structure:
• wherein formula I has the structure:
• wherein
• Ra is selected from the group consisting of OH, —NR7R8, —NHNR7R8, —NHCH2CO2H and (D)-NHCH(CH3)CO2H;
• R7 is H and R8 is selected from the group consisting of H, (C1-6)alkyl, (C3-6)cycloalkyl, (C6-10)aryl, and (C7-15)aralkyl;
• or R7 and R8 are independently (C1-6)alkyl;
• or R7, R8 and the nitrogen to which they are attached form a 3- to 6-membered ring;
• R1 is H, methyl, or hydroxymethyl;
• R2 is OH or NR3R4, wherein R3 and R4 are independently selected from the group consisting of H;
• optionally substituted (C1-5)alkyl;
• optionally substituted (C2-5)alkenyl;
• (C2-5)alkynyl, wherein the substituent for both the alkyl and alkenyl is a group selected from the group consisting of, carboxy, (C1-5)alkoxycarbonyl, carbamyl, (C1-5)alkylcarbamyl, di(C1-5)alkylcarbamyl, and sulfonyl;
• (C1-5)alkanoyl substituted with a group selected from the group consisting of amino, (C1-5)alkylamino, and di(C1-5)alkylamino;
• L-glutamyl;
• formyl;
• benzyl;
• p-tolylsulfonylcarbamyl;
• —CN;
• —NO;
• R5 is H or R5 is represented by the general formula II:
• wherein represents the point of attachment to the oxygen atom of structural formula I or to the oxygen atom of formula A;
• wherein R6 is H or sulfonic acid;
• and
• wherein R9 is H or CH2OH;
• or a pharmaceutically acceptable salt, solvate, tautomer or isomer thereof, in association with a pharmaceutically acceptable carrier.