Apramycin derivatives

Patent metadata

Field	Value
Publication number	US-11485751-B2
Application number	US-201816609788-A
Country	US
Kind code	B2
Filing date	May 1, 2018
Priority date	May 1, 2017
Publication date	Nov 1, 2022
Grant date	Nov 1, 2022

Abstract

The invention relates to derivatives of apramycin-based aminoglycoside antibacterial drugs modified in positions C5 and/or C6 and O5 and/or O6. The modifications impart favourable properties regarding increased selectivity and retention of activity in the presence of resistance determinants of the AAC(3) class. The invention further relates to said compounds for use in the therapy of bacterial infection by systemic administration, especially in instances where the infection is caused by a pathogen comprising a resistance determinant of the AAC(3) class, in particular AAC(3)-IV.

First claim

The invention claimed is:

1. A compound characterized by a general formula (100)

wherein
E is selected from H and (S)-4-amino-2-hydroxybutyryl,
(S)-3-amino-2-hydroxypropionyl, —CON(OH)(CH 2 ) 2 NH 2 ,
(2R,4S)-2-hydroxy-4,5-diamino-pentanoyl, and
(2S,4R)-2,5-dihydroxy-4-aminopentanoyl;

V is selected from H and CH 2 -D, wherein
D is selected from OH, NH 2 , NHCHO, NHR D and NHCONHR D , wherein R D is
selected from H, OH, unsubstituted or amino- and/or hydroxy-substituted C 1 to C 6
alkyl;

U and W are selected from the following alternatives:
one of U and W is —R W and the other one is selected from H, F and OH, or
one of U and W is —OR W and the other one is H,
wherein
R W is selected from an amino- and/or hydroxy-substituted C 1 to C 6 alkyl,
CH 2 (CH 2 ) n NH(CH 2 ) 3 NH 2 and CH 2 (CH 2 ) n —R N , wherein n is selected from 1, 2 or 3,
R N is selected from NXY and a moiety characterized by formula (400)

wherein
X and Y are independently selected from H, and unsubstituted or amino- and/or hydroxyl-substituted C 1 to C 3 alkyl, and Z is selected from O, NX and CH 2 ,
or
one of U and W is described by a moiety characterized by formula (300), (301), (304) or (305) and the other one of U and W is H

wherein R″ is selected from H and an amino- and/or hydroxy-substituted C 1 to C 6 alkyl.

2. The compound according to claim 1 , wherein V is selected from CH 2 OH, H, CH 2 NHCHO and CH 2 NHCONH 2 .

3. The compound according to claim 1 , wherein V is CH 2 NHR D .

4. The compound according to claim 1 , wherein E is H.

5. The compound according to claim 1 , wherein one of U and W is —R W and the other one is selected from H, F, OH, or one of U and W is —OR W and the other one is H.

6. The compound according to claim 1 , wherein R W is selected from (CH 2 ) 2 OH, (CH 2 ) 2 NH 2 , (CH 2 ) 2 NMe 2 , (CH 2 ) 2 NEt 2 , (CH 2 ) 2 NHMe, (CH 2 ) 2 NHEt, (CH 2 ) 3 OH, (CH 2 ) 3 NH 2 , (CH 2 ) 3 NMe 2 , (CH 2 ) 3 NEt 2 , (CH 2 ) 3 NHMe, (CH 2 ) 3 NHEt, CH 2 CHOHCH 2 OH, CH 2 CHOHCH 2 NH 2 , CH 2 CHOHCH 2 NMe 2 , CH 2 CHOHCH 2 NEt 2 , CH 2 CHOHCH 2 NHMe and CH 2 CHOHCH 2 NHEt.

7. The compound according to claim 1 , wherein
a. W is —R W and U is selected from H, F, OH, or
b. W is —OR W and U is H.

8. The compound according to claim 1 , characterized by a general formula (112), (113) or (114)

wherein R AP designates a moiety described by formula (2)

and denotes the position where the apramycin backbone is attached to the compound described by general formula (112), (113), or (114),
wherein U is selected from OH and F and n, R″, R N and V have the same meaning as indicated above.

9. The compound according to claim 8 , characterized by the general formula
a.(112), E is H, R N is OH, Vis CH 2 OH and n is 1 [5—O-β-[3″′-O-(2-hydroxyethyl)-D-ribofuranosyl] apramycin; DCWSU178];
b. (112), E is H, R N is NH 2 , V is CH 2 NH 2 and n is 1 [5—O-β-[5-amino-3-O-(2-aminoethyl)-5-deoxy-D-ribofuranosyl] apramycin; DCWSU185];
c.(112), wherein E is H, V is CH 2 NHCOH, R N is NH 2 and n is 1 [5—O-β-[3-O-(2-aminoethyl)-5-deoxy-5-formamido-D-ribofuranosyl] apramycin; DCWSU186].

10. The compound according to claim 1 , wherein
a. E, U and V are H and W is —OR W , and R W is selected from (CH 2 ) 2 OH, (CH 2 ) 2 NH 2 , (CH 2 ) 2 NMe 2 , (CH 2 ) 2 NEt 2 , (CH 2 ) 2 NHMe, (CH 2 ) 2 NHEt, (CH 2 ) 3 OH, (CH 2 ) 3 NH 2 , (CH 2 ) 3 NMe 2 , (CH 2 ) 3 NEt 2 , (CH 2 ) 3 NHMe, (CH 2 ) 3 NHEt, CH 2 CHOHCH 2 OH, CH 2 CHOHCH 2 NH 2 , CH 2 CHOHCH 2 NMe 2 , CH 2 CHOHCH 2 NEt 2 , CH 2 CHOHCH 2 NHMe and CH 2 CHOHCH 2 NHEt; or
b. E and U are H, V is CH 2 OH and W is a moiety described by formula (300), with R″ selected from H, (CH 2 ) 2 OH, (CH 2 ) 2 NH 2 , (CH 2 ) 2 NMe 2 , (CH 2 ) 2 NEt 2 , (CH 2 ) 2 NHMe and (CH 2 ) 3 NHEt.

11. The compound according to claim 1 , wherein D is selected from OH, NHCHO and NHCONH 2 .

12. The compound according to claim 1 , wherein X and Y are independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 OH or CH 2 CH 2 NH 2 .

13. The compound according to claim 1 , wherein one of U and W is

14. A method for treatment of a bacterial infection comprising:
systemically administering to a subject in need thereof the compound of claim 1 , wherein the infection is caused by a pathogen from family Enterobacteriaceae, thereby treating the bacterial infection.

Assignees

• Univ Wayne State
• Univ Zuerich

Inventors

• Bottger Erik C
• Hobbie Sven N
• Vasella Andrea
• Crich David
• Sonousi Amr
• Kato Takayuki
• Quirke Jonathan
• Rajasekaran Parasuraman
• Sarpe Vikram Ashok

Classifications

• A61K31/7036

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

• A61P31/04 Primary

  Antibacterial agents · CPC title

• C07H15/232

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

• C07H5/06 Primary

  Aminosugars · CPC title

• C07H15/224

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