Peptide macrocycles against acinetobacter baumannii

Patent metadata

Field	Value
Publication number	US-10030047-B2
Application number	US-201615336128-A
Country	US
Kind code	B2
Filing date	Oct 27, 2016
Priority date	Oct 27, 2015
Publication date	Jul 24, 2018
Grant date	Jul 24, 2018

Abstract

The present invention provides 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. Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments for the treatment of diseases and infections caused by Acinetobacter baumannii.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein:
X 1 is C-L 1 -R 11 or N,
X 2 is C-L 2 -R 12 or N,
X 3 is C-L 3 -R 13 or N,
X 4 is C-L 4 -R 14 or N, with the proviso that not more than three of X 1 , X 2 , X 3 and X 4 are N;
X 5 is C-L 5 -R 15 or N,
X 6 is C-L 6 -R 16 or N,
X 7 is C-L 7 R 17 or N,
X 8 is C-L 8 -R 18 or N, with the proviso that not more than three of X 5 , X 6 , X 7 and X 8 are N;
R 1 is —(CH 2 ) m -heteroaryl or —(CH 2 ) m -heterocycloalkyl, wherein heteroaryl is optionally substituted with one or more halo, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl, C 3-7 -cycloalkyl or C 1-7 -alkoxy;
R 2 , R 4 and R 6 are each individually selected from hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl, and C 3-7 -cycloalkyl;
R 3 is —C 1-7 -alkyl, —(CH 2 ) n —NR 20 R 21 , —(CH 2 ) n —C(O)NR 20 R 21 or —(CH 2 ) n —O—(CH 2 ) q —NR 20 R 21 ;
R 5 is hydrogen, C 1-7 -alkyl, hydroxy-C 1-7 -alkyl, —(CH 2 ) o —NR 22 R 23 , —(CH 2 ) o —C(O)—NR 22 R 23 , —(CH 2 ) o —O—(CH 2 ) q —NR 20 R 21 , —(CH 2 ) o —NH—C(NH)—NR 22 R 23 , —(CH 2 ) o —NH—C(O)—NR 22 R 23 , —(CH 2 ) o —NH—C(O)—OR 26 , —(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 -alkoxy or aryl;
R 5′ is hydrogen or C 1-7 -alkyl;
R 7 and R 8 are each individually selected from hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl, C 3-7 -cycloalkyl and C 1-7 -alkoxy;
R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each individually selected from hydrogen, halogen, cyano, 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, —B(OH) 2 , benzyloxy-propynyl (—C≡C—CH 2 —O-benzyl), C 3-7 -cycloalkyl, heterocycloalkyl, aryl and heteroaryl,
wherein heteroaryl is optionally substituted with one C 1-7 -haloalkyl or C 1-7 -alkoxy;

R 17 is hydrogen, halogen, cyano, 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, B(OH) 2 , benzyloxy-prop-1-ynyl, C 3-7 -cycloalkyl, 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, cyano, 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, cyano, 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 , C 3-7 -cycloalkyl, heterocycloalkyl, 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 ) r —OH, —CO—NH—(CH 2 ) r -heterocycloalkyl, —CO—OH, —O—C 1-7 -hydroxyalkyl, —O—(CH 2 ) r —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;

R 20 and R 22 are each individually selected from hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl, C 3-7 -cycloalkyl and —C(NH)—NH 2 ;
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;
R 26 is hydrogen, C 1-7 -alkyl or benzyl;
L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are each individually selected from a single bond, —C(O)—, —SO 2 —, —(CH 2 ) p —, —CH═CH— and —C≡C—;
m is 1, 2, 3, or 4;
n is 1, 2, 3, or 4;
o is 0, 1, 2, 3, or 4;
p is 1, 2, 3, or 4;
q is 1, 2, 3, or 4;
r is 1, 2, 3, or 4;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein the compound has a structure of formula (I′)

wherein:
X 1 is C-L 1 -R 11 or N,
X 2 is C-L 2 -R 12 or N,
X 3 is C-L 3 -R 13 or N,
X 4 is C-L 4 -R 14 or N, with the proviso that not more than three of X 1 , X 2 , X 3 and X 4 are N;
X 5 is C-L 5 -R 15 or N,
X 6 is C-L 6 -R 16 or N,
X 7 is C-L 7 R 17 or N,
X 8 is C-L 8 -R 18 or N, with the proviso that not more than three of X 5 , X 6 , X 7 and X 8 are N;
R 1 is —(CH 2 ) m -heteroaryl, wherein heteroaryl is optionally substituted with one or more halo, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl, C 3-7 -cycloalkyl or C 1-7 -alkoxy;
R 2 , R 4 and R 6 are each individually selected from hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl, and C 3-7 -cycloalkyl;
R 3 is —(CH 2 ) n —NR 20 R 21 ;
R 5 is C 1-7 -alkyl, hydroxy-C 1-7 -alkyl, —(CH 2 ) o —NR 22 R 23 , —(CH 2 ) o —C(O)—NR 22 R 23 , —(CH 2 ) o —NH—C(O)—NR 22 R 23 , —(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 or C 1-7 -alkoxy;
R 7 and R 8 are each individually selected from hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl, C 3-7 -cycloalkyl and C 1-7 -alkoxy;
R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each individually selected from hydrogen, halogen, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl, —NR 24 R 25 , hydroxy, C 1-7 -alkoxy, haloC 1-7 -alkoxy, C 3-7 -cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
R 20 and R 22 are each individually selected from hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl, C 3-7 -cycloalkyl and —C(═NH)—NH 2 ;
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, and C 3-7 -cycloalkyl;
L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are each individually selected from a single bond, —C(O)—, —SO 2 —, —(CH 2 ) p —, —CH═CH— and —C≡C—;
m, n, o and p are each individually selected from 1, 2, 3 and 4;
or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein:
X 1 is CR 11 or N,
X 2 is CR 12 or N,
X 3 is CR 13 or N,
X 4 is CR 14 or N, with the proviso that not more than two of X 1 , X 2 , X 3 and X 4 are N;
X 5 is CR 15 or N,
X 6 is CR 16 or N,
X 7 is CR 17 or N,
X 8 is CR 18 or N, with the proviso that not more than two of X 5 , X 6 , X 7 and X 8 are N;
R 1 is —(CH 2 ) m -heteroaryl or —(CH 2 ) m -heterocycloalkyl; wherein heteroaryl is optionally substituted with one or more halo, cyano, C 1-7 -alkyl, C 1-7 -haloalkyl, C 3-7 -cycloalkyl or C 1-7 -alkoxy; and wherein heterocycloalkyl is partly unsaturated;
R 2 , R 4 and R 6 are each individually selected from hydrogen, C 1-7 -alkyl, C 1-7 -haloalkyl, and C 3-7 -cycloalkyl;
R 3 is —C 1-7 -alkyl, —(CH 2 ) n —NR 20 R 21 , —(CH 2 ) n —C(O)NR 20 R 21 or —(CH 2 ) n —O—(CH 2 ) q —NR 20 R 21 ;
R 5 is hydrogen, C 1-7 -alkyl, hydroxy-C 1-7 -alkyl, —(CH 2 ) o —NR 22 R 23 , —(CH 2 ) o —C(O)—NR 22 R 23 ,

Assignees

• Hoffmann La Roche

Inventors

• Alanine Alexander
• Beignet Julien
• Bleicher Konrad
• Fasching Bernhard
• Hilpert Hans
• Hu taishan
• Macdonald Dwight
• Jackson Stephen
• Kolczewski Sabine
• Kroll Carsten
• Schaeublin Adrian
• Shen Hong
• Stoll Theodor
• Thomas Helmut
• Wahhab Amal
• Zampaloni Claudia

Classifications

• A61K31/04 Primary

  Nitro compounds · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K5/0808

  the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu · CPC title

• C07K5/0821

  with the first amino acid being heterocyclic, e.g. His, Pro, Trp · CPC title

• C07K5/0812

  and aromatic or cycloaliphatic · CPC title