Modified aminoglycoside compounds and uses thereof in disabling bacterial ribosome

Patent metadata

Field	Value
Publication number	US-12364706-B2
Application number	US-202117325361-A
Country	US
Kind code	B2
Filing date	May 20, 2021
Priority date	Nov 22, 2018
Publication date	Jul 22, 2025
Grant date	Jul 22, 2025

Abstract

Modified aminoglycoside compounds represented by Formula I as defined and described in the specification are provided. The modified aminoglycosides feature a diamine-containing functional moiety at one or more of positions 3′, 4′ and 6′. Uses of the modified aminoglycosides as antimicrobial (e.g., antibacterial) agents, and in treating medical conditions associated with microorganisms, are also provided.

First claim

What is claimed is:

1. A compound represented by Formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
the dashed line indicates a stereo-configuration of position 6′ being an R configuration or an S configuration;
X 1 is O;
Rx1, Rx2, Ry1 and Rz are each independently selected from hydrogen, alkyl and cycloalkyl;
Ry2-Ry9 and Rw1-Rw3 are each independently selected from hydrogen, alkyl, and cycloalkyl;
R 5 and R 6 are each independently OR 16 , wherein R 16 is independently selected from hydrogen, a monosaccharide moiety, and a disaccharide moiety;
R 7 -R 9 are each independently selected from the group consisting of hydrogen and acyl; and
R 3 is OR 20 , wherein R 20 is hydrogen, alkyl, or cycloalkyl;
and wherein either:
R 1 is NR 23 R 24 , and each of R 23 and R 24 is independently hydrogen, alkyl, cycloalkyl or acyl,
and wherein:
either:
R 4 is selected from:
OR 20 , wherein R 20 is a diamine-containing moiety which is:
-(L1) n -N1-(L2) m -N2

wherein:
n and m are each 1;
L1 and L2 are each independently an alkylene of 2 or 3 carbon atoms in length;
N1 is amine —NR′—, wherein R′ is hydrogen, alkyl, or cycloalkyl, wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms; and
N2 is selected from amine and guanidyl, said amine being —NR′R″ group, wherein R′ and R″ is each independently hydrogen, alkyl, or cycloalkyl, or R′ and R″ form together a heterocyclic group; and wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms,
and a diamine-containing moiety which is:
—N1-(L2) m -N2-(L3) k -(N3) a -(L4) j (N4) b

wherein:
m and k are each 1;
j is 0 or 1;
a is 1;
b is 0 or 1;
L2, L3 and L4, if present, are each independently an alkylene of 1, 2 or 3 carbon atoms in length;
N1 is amide;
N2 is amine —NR′—, wherein R′ is hydrogen, alkyl, or cycloalkyl, wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms;
N3 is amine —NR′—, wherein R′ is hydrogen, alkyl, or cycloalkyl, wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms, or, when b and j are each 0, N3 is amine —NR′R″, wherein R′ and R″ are each independently hydrogen, alkyl, or cycloalkyl, or R′ and R″ form together a heterocyclic group; and wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms; and
N4, if present, is amine —NR′R″, wherein R′ and R″ is each independently hydrogen, alkyl, or cycloalkyl, or R′ and R″ form together a heterocyclic group; and wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms,
or:
R 4 is OR 20 wherein R 20 is hydrogen, alkyl, or cycloalkyl, or NR 23 R 24 wherein each of R 23 and R 24 is independently hydrogen, alkyl, cycloalkyl or acyl; and
R 1 is a diamine-containing moiety which is:
—N1-(L2) m -N2-(L3) k -(N3) a -(L4) j -(N4) b

wherein:
m and k are each 1;
j is 0 or 1;
a is 1;
b is 0 or 1;
L2, L3 and L4, if present, are each independently an alkylene of 1, 2 or 3 carbon atoms in length;
N1 is amide;
N2 is amine —NR′—, wherein R′ is hydrogen, alkyl, or cycloalkyl, wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms;
N3 is amine —NR′—, wherein R′ is hydrogen, alkyl, or cycloalkyl, wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms, or, when b and j are each 0, N3 is amine —NR′R″, wherein R′ and R″ are each independently hydrogen, alkyl, or cycloalkyl, or R′ and R″ form together a heterocyclic group; and wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms; and
N4, if present, is amine —NR′R″, wherein R′ and R″ is each independently hydrogen, alkyl, or cycloalkyl, or R′ and R″ form together a heterocyclic group; and wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

2. The compound of claim 1 , wherein R 4 is OR 20 , and R 20 is said diamine-containing moiety, and wherein:
N1 is said amine —NR′— wherein R′ is hydrogen, L2 is ethylene, and N2 is said amine NR′R″ group, wherein R′ and R″ are each hydrogen, such that said diamine-containing moiety comprises an ethylene diamine moiety; or
N1 is said amine —NR′— wherein R′ is hydrogen, L2 is ethylene, and N2 is said amine NR′R″ group, wherein R′ is hydrogen and R″ is methyl, such that said diamine-containing moiety comprises a methyl ethylenediamine moiety; or
N1 is said amine —NR′— wherein R′ is hydrogen, L2 is ethylene, and N2 is said amine NR′R″ group, wherein R′ and R″ form together pyrrolidone, such that said diamine-containing moiety comprises a N-(2-aminoethyl)pyrrolidone moiety; or
N1 is said amine —NR′— wherein R′ is hydrogen, L2 is ethylene, and N2 is said guanidinyl, such that said diamine-containing moiety comprises a guanidine-ethyleneamine moiety.

3. The compound of claim 1 , wherein R 4 is OR 20 and R 20 is said diamine-containing moiety.

4. The compound of claim 1 , wherein at least one of R 5 and R 6 is OR 16 , and R 16 is a monosaccharide or a disaccharide.

5. The compound of claim 1 , wherein each of Rx1, Rx2, Ry1 and Rz is hydrogen.

6. The compound of claim 1 , wherein each of Ry2-Ry9 and Rw1-Rw3 is hydrogen.

7. The compound of claim 1 , wherein each of R 7 and R 9 is hydrogen.

8. The compound of claim 1 , selected from:

9. A pharmaceutical composition comprising a compound according to claim 1 .

10. The compound of claim 1 , wherein R 4 is said diamine-containing moiety which is:
—N1-(L2) m -N2-(L3) k -(N3) a -(L4) j -(N4) b

and wherein:
j and b are each 0, N2 is said amine —NR′— wherein R′ is hydrogen, L3 is ethylene, and N3 is said amine NR′R″ group, wherein R′ and R″ are each hydrogen, such that said diamine-containing moiety comprises an ethylene diamine moiety; or
j and b are each 0, N2 is said amine —NR′— wherein R′ is hydrogen, L3 is ethylene, and N3 is said amine NR′R″ group, wherein R′ is hydrogen and R″ is methyl, such that said diamine-containing moiety comprises a methyl ethylenediamine moiety; or
j and b are each 1, N2 is said amine —NR′— wherein R′ is hydrogen, L3 and L4 are each ethylene, N3 is said amine —NR′— wherein R′ is hydrogen, and N4 is said amine NR′R″ group, wherein R′ and R″ are each hydrogen, such that said diamine-containing moiety comprises a diethylenetriamine moiety.

11. A method of treating a bacterial infection caused by an aminoglycoside-resistant bacteria in a subject in need thereof, the method comprising administering to the subject a compound according to claim 1 .

Assignees

• Technion Res & Dev Foundation

Inventors

• Baasov Timor
• Smolkin Boris
• Khononov Alina
• Shavit Kishkober Michal
• Belakhov Valery

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• C07H15/224

  with only one saccharide radical directly attached to the cyclohexyl radical, e.g. destomycin, fortimicin, neamine · CPC title

• A61K31/7036 Primary

  having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins · CPC title

• C07H15/232 Primary

  with at least three saccharide radicals in the molecule, e.g. lividomycin, neomycin, paromomycin · CPC title