Anti-bacterial peptide macrocycles and use thereof

Patent metadata

Field	Value
Publication number	US-11066443-B2
Application number	US-201816485200-A
Country	US
Kind code	B2
Filing date	Apr 9, 2018
Priority date	Apr 10, 2017
Publication date	Jul 20, 2021
Grant date	Jul 20, 2021

Abstract

The present invention relates to compounds of formula (I)

wherein X 1 to X 8 and R 1 to R 8 are as described herein, as well as pharmaceutically acceptable salts thereof for the use in the treatment or prevention of infections and resulting diseases caused by Pseudomonas aeruginosa.

First claim

The invention claimed is:

1. A method for the treatment of infections and resulting diseases caused by Pseudomonas aeruginosa , comprising the step of administering to a human being or animal in need thereof a compound of formula (I):

wherein:
X 1 is C—R 11 ;
X 2 is C—R 12 ;
X 3 is C—R 13 ;
X 4 is N;
X 5 is C—R 15 ;
X 6 is C—R 16 ;
X 7 is C—R 17 ;
X 8 is C—R 18 ;
R 1 is —(CH 2 )m-heteroaryl optionally substituted with one or more halo or C 1-7 -alkyl;
R 2 , R 4 and R 6 are each individually selected from hydrogen or C 1-7 -alkyl;
R 3 and R 5 are each independently selected from hydrogen, —C 1-7 -alkyl, hydroxy-C 1-7 -alkyl, —(CH 2 ) m —NR 20 R 21 , —(CH 2 ) m —C(O)NR 20 R 21 , —(CH 2 ) m —CF 2 —(CH 2 ) m —NR 20 R 21 , —(CH 2 ) m —NH—C(O)—(CH 2 ) m —NR 20 R 21 or —(CH 2 ) m —O—(CH 2 ) n —NR 20 R 21 , —(CH 2 ) m —NH—C(NH)—NR 20 R 21 , —(CH 2 ) m —NH—C(O)—OR 21 , —(CH 2 ) o —C 3-7 -cycloalkyl, —(CH 2 ) o -heterocycloalkyl, —(CH 2 ) o -heteroaryl, —(CH 2 )o-aryl, wherein cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted by halo, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl, C 1-7 -hydroxyalkyl, C 1-7 -alkoxy or aryl;
R 5′ is hydrogen or C 1-7 -alkyl;
R 7 , R 7′ and R 8 , R 8′ are each individually selected from hydrogen or C 1-7 -alkyl;
R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each individually selected from hydrogen, halogen, C 1-7 -alkyl, C 1-7 -haloalkyl, hydroxy, C 1-7 -hydroxyalkyl, C 1-7 -alkoxy, C 1-7 -haloalkoxy, —NR 24 R 25 , C 1-7 -alkyl-NR 24 R 25 , aryl-C 1-7 -alkyl-O—C 1-7 -alkinyl-, aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted with one, two or three substituents selected from the list of halogen, cyano, C 1-7 -alkyl C 1-7 -haloalkyl, hydroxy, C 1-7 -alkoxy, —NR 24 R 25 , C 1-7 -alkyl-NR 24 R 25 , —CO—NH—(CH 2 ) n —NR 24 R 25 , —CO—NH—(CH 2 ) r —OH, —CO—NH—(CH 2 ) o -heterocycloalkyl, —CO—OH, —O—C 1-7 -hydroxyalkyl, —O—(CH 2 ) o —CO—OH, —SO 2 —C 1-7 -alkyl, —SO 2 —NR 24 R 25 , heterocycloalkyl, —O—heterocycloalkyl and heterocycloalkyl substituted with C 1-7 -alkyl or oxo;
R 20 and R 22 are each individually selected from hydrogen, C 1-7 -alkyl and benzyl;
R 21 and R 23 are each individually selected from hydrogen and C 1-7 -alkyl;
R 24 and R 25 are each individually selected from hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl, C 1-7 -hydroxyalkyl, and C 3-7 -cycloalkyl;
m is 1, 2, 3, 4, 5 or 6;
n is 2, 3, 4, 5 or 6; and
o is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , wherein the compound has a structure of formula (Ia)

wherein:
X 1 is CR 11 ,
X 2 is CR 12 ,
X 3 is CR 13 ,
X 4 is N;
X 5 is CR 15 ,
X 6 is CR 16 ,
X 7 is CR 17 ,
X 8 is CR 18 ;
R 2 , R 4 and R 6 are each individually selected from hydrogen or C 1-7 -alkyl;
R 3 is —(CH 2 ) m —NR 20 R 21 ;
R 5 is —(CH 2 ) m —NR 22 R 23 or —(CH 2 ) o -heterocycloalkyl, wherein heterocycloalkyl is optionally substituted by halo or C 1-7 -alkyl;
R 7 and R 8 are hydrogen;
R 9 is hydrogen, halo or C 1-7 -alkyl;
R 10 is hydrogen or C 1-7 -alkyl;
R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each individually selected from hydrogen, halogen, C 1-7 -alkyl, C 1-7 -haloalkyl, hydroxy, C 1-7 -hydroxyalkyl, C 1-7 -alkoxy, C 1-7 -haloalkoxy, —NR 24 R 25 , C 1-7 -alkyl-NR 24 R 25 , aryl-C 1-7 -alkyl-O—C 1-7 -alkinyl-, aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted with one, two or three substituents selected from the list of halogen, cyano, C 1-7 -alkyl C 1-7 -haloalkyl, hydroxy, C 1-7 -alkoxy, —NR 24 R 25 , C 1-7 -alkyl-NR 24 R 25 , —CO—NH—(CH 2 ) n —NR 24 R 25 , —CO—NH—(CH 2 ) r —OH, —CO—NH—(CH 2 ) o -heterocycloalkyl, —CO—OH, —O—C 1-7 -hydroxyalkyl, —O—(CH 2 ) o —CO—OH, —SO 2 —C 1-7 -alkyl, —SO 2 —NR 24 R 25 , heterocycloalkyl, —O— heterocycloalkyl and heterocycloalkyl substituted with C 1-7 -alkyl or oxo;
R 19 is hydrogen, halo, C 1-7 -alkyl;
R 20 , R 21 , R 22 and R 23 are hydrogen; and
R 24 and R 25 are each individually selected from hydrogen and C 1-7 -alkyl;
or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 , wherein the compound has a structure of formula (Ib)

wherein:
X 1 is CR 11 ;
X 4 is N;
R 2 is selected from hydrogen and C 1-7 -alkyl;
R 9 is hydrogen, halo or C 1-7 -alkyl;
R 15 is hydrogen, halogen, C 1-7 -alkyl, C 1-7 -haloalkyl, —NR 24 R 25 , C 1-7 -alkyl-NR 24 R 25 , hydroxy, C 1-7 -alkoxy, haloC 1-7 -alkoxy, benzyloxy-propynyl (—C≡C—CH 2 —O-benzyl), heterocycloalkyl, aryl and heteroaryl,
wherein aryl is optionally substituted with one —NR 20 R 21 or heterocycloalkyl substituted with C 1-7 -alkyl;

R 17 is hydrogen, halogen, C 1-7 -alkyl, C 1-7 -haloalkyl, —NR 24 R 25 , C 1-7 -alkyl-NR 24 R 25 , hydroxy, C 1-7 -alkoxy, haloC 1-7 -alkoxy, benzyloxy-prop-1-ynyl, heterocycloalkyl, aryl and heteroaryl,
wherein heterocycloalkyl is optionally substituted with one —NR 24 R 25 ,
wherein aryl and heteroaryl are optionally substituted with one, two or three substituents selected from the list of halogen, C 1-7 -alkyl, C 1-7 -haloalkyl, C 1-7 -hydroxyalkyl, hydroxy, C 1-7 -alkoxy, —NR 24 R 25 , SO 2 —C 1-7 -alkyl, —SO 2 —NR 24 R 25 , heterocycloalkyl and heterocycloalkyl substituted with C 1-7 -alkyl;

R 18 is hydrogen, halogen, C 1-7 -alkyl, C 1-7 -haloalkyl, hydroxy, C 1-7 -hydroxyalkyl, C 1-7 -alkoxy, C 1-7 -haloalkoxy, —NR 24 R 25 , C 1-7 -alkyl-NR 24 R 25 , aryl and heteroaryl,
wherein aryl and heteroaryl are optionally substituted with one, two or three substituents selected from the list of halogen, cyano, C 1-7 -alkyl C 1-7 -haloalkyl, hydroxy, C 1-7 -alkoxy, —NR 24 R 25 , C 1-7 -alkyl-NR 24 R 25 , —CO—NH—(CH 2 ) r —NR 24 R 25 , —CO—NH—(CH 2 ) o —OH, —CO—NH—(CH 2 ) o -heterocycloalkyl, —CO—OH, —O—C 1-7 -hydroxyalkyl, —O—(CH 2 ) r —CO—OH, —SO 2 —C 1-7 -alkyl, —SO 2 —N 24 R 25 , heterocycloalkyl, —O—heterocycloalkyl and heterocycloalkyl substituted with C 1-7 -alkyl or oxo;

R 19 is hydrogen, halo, C 1-7 -alkyl;
R 20 , R 21 , R 22 and R 23 are hydrogen;
R 24 and R 25 are each individually selected from hydrogen and C 1-7 -alkyl; and
and Y is —CH 2 — or —CO—;
or a pharmaceutically acceptable salt thereof.

4. The method according to claim 1 , wherein said compound is selected from the group consisting of:
(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;
(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-5-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;
(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;
(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-5-trif

Assignees

• Hoffmann La Roche

Inventors

• Alanine Alexander
• Amrein Kurt
• Bleicher Konrad
• Fasching Bernhard
• Hilpert Hans
• Kolczewski Sabine
• Kroll Carsten
• Schaeublin Adrian
• Zampaloni Claudia

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07K5/0815 Primary

  with the first amino acid being basic · CPC title

• C07K5/0202 Primary

  containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids · CPC title

• C07K5/0819

  with the first amino acid being acidic · CPC title

• C07K5/02 Primary

  containing at least one abnormal peptide link · CPC title