Antimicrobial peptidomimetics

Patent metadata

Field	Value
Publication number	US-10053490-B2
Application number	US-201515104186-A
Country	US
Kind code	B2
Filing date	Jan 22, 2015
Priority date	Jan 22, 2014
Publication date	Aug 21, 2018
Grant date	Aug 21, 2018

Abstract

The present invention relates to peptidomimetics of the formula (I) or (I)c wherein L 1 , L 2 , L 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, m, Q, X, Z 1 and Z 2 are defined as mentioned in the description and to salts and solvates of each of these compounds and to processes for the preparation thereof, compositions containing them and the uses of such compounds. It has been found that the compounds have a high microbicide activity and are suited to combat resistant bacteria, such as meticillin-resistant Staphylococcus aureus (MRSA) strains, at very low concentrations.

First claim

The invention claimed is:

1. A compound of the formula (I):

wherein
L 1 represents —CO—, alkandiyl, -alkyl-CO— or —CO-alkyl-;
L 2 represents —CO—, alkandiyl, -alkyl-CO— or —CO-alkyl-;
L 3 represents —CO—, alkandiyl, -alkyl-CO— or —CO-alkyl-;
R 1 represents hydrogen, acyl, carbamoyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylcarbonyl, cycloalkylcarbonyl or heterocyclylcarbonyl;
R 2 represents optionally substituted alkyl, aralkyl or heteroaralkyl;
R 3 represents hydrogen, or represents optionally substituted alkyl, aralkyl or heteroaralkyl;
R 4 represents optionally substituted alkandiyl, alkendiyl, alkyndiyl, cycloalkyldiyl, alkylcycloalkyldiyl, alkylcycloalkylalkyldiyl, aryldiyl, alkylaryldiyl, alkylarylalkyldiyl;
R 5 represents hydrogen, or represents optionally substituted alkyl, aralkyl or heteroaralkyl;
R 6 represents hydrogen, or represents optionally substituted alkyl, aralkyl or heteroaralkyl;
provided that at least two of the substituents R 2 , R 3 , R 5 and R 6 are optionally substituted aralkyl or heteroaralkyl;
wherein at least one of R 2 or R 3 is an optionally substituted biphenyl-C 1 -C 4 -alkyl;
n is 0, 1, 2, 3 or 4; and
m is 0 or 1;
Q is —NH 2 , —NH—C(NH)—NH 2 or —NH—C(N-alkyl)-NH-alkyl;
X is NH, O or S;
Z 1 is —CH 2 —;
Z 2 is a direct bond, alkandiyl, cycloalkyldiyl or aryldiyl;
or a salt of such compound.

2. A compound of formula (I) according to claim 1 , wherein
L 1 represents —CO—, C 1 -C 3 -alkandiyl, —C 1 -C 2 -alkyl-CO— or —CO— C 1 -C 2 -alkyl-;
L 2 represents —CO—, —C 1 -C 2 -alkyl-CO— or —CO— C 1 -C 2 -alkyl-;
L 3 represents —CO—, C 1 -C 3 -alkandiyl, —C 1 -C 2 -alkyl-CO— or —CO— C 1 -C 2 -alkyl-;
R 1 represents hydrogen, C 1 -C 20 -alkyl-CO—, C 2 -C 20 -alkenyl-CO—, C 1 -C 20 -alkyl-NH—CO—, (C 1 -C 20 -alkyl) 2 -N—CO—, arylcarbonyl having 6 or 10 carbon atoms in the aryl moiety, heterocyclylcarbonyl having 1 to 3 hetero atoms selected from N,O and S in a 3 to 6 membered ring, or C 3 -C 7 -cycloalkylcarbonyl;
R 2 represents optionally substituted C 1 -C 12 -alkyl, biphenyl-C 1 -C 4 -alkyl or naphthyl-C 1 -C 4 -alkyl;
R 3 represents hydrogen or represents optionally substituted C 1 -C 12 -alkyl, phenyl-C 1 -C 4 -alkyl, biphenyl-C 1 -C 4 -alkyl or naphthyl-C 1 -C 4 -alkyl;
R 4 represents optionally substituted C 1 -C 12 -alkandiyl, C 2 -C 12 -alkendiyl, C 2 -C 12 -alkyndiyl, C 3 -C 7 -cycloalkyldiyl, —C 1 -C 6 -alkyl-C 3 -C 7 -cycloalkyl-, —C 1 -C 6 -alkyl-C 3 -C 7 -cycloalkyl-C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-phenyl- or —C 1 -C 6 -alkyl-naphthyl-;
R 5 represents hydrogen or represents optionally substituted C 1 -C 12 -alkyl, phenyl-C 1 -C 4 -alkyl, biphenyl-C 1 -C 4 -alkyl or naphthyl-C 1 -C 4 -alkyl;
R 6 represents hydrogen or represents optionally substituted C 1 -C 12 -alkyl, phenyl-C 1 -C 4 -alkyl, biphenyl-C 1 -C 4 -alkyl or naphthyl-C 1 -C 4 -alkyl;
wherein at least one of R 2 or R 3 is an optionally substituted biphenyl-C 1 -C 4 -alkyl;
n is 0, 1, 2 or 3;
m is 0 or 1;
Q is —NH 2 , —NH—C(NH)—NH 2 or —NH—C(N—C 1 -C 2 -alkyl)-NH—C 1 -C 2 -alkyl;
X is NH or O;
Z 1 is —CH 2 —;
Z 2 is a direct bond, C 1 -C 3 -alkandiyl, cyclohexyldiyl or phenyldiyl;
or a pharmaceutically acceptable salt of such compound.

3. A compound of formula (I) according to claim 1 , wherein
L 1 represents —CO—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CO— or —CO—CH 2 —;
L 2 represents —CO—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CO— or —CO—CH 2 —;
L 3 represents —CO—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CO— or —CO—CH 2 —;
R 1 represents hydrogen, C 1 -C 16 -alkyl-CO—, C 2 -C 16 -alkenyl-CO—, C 1 -C 16 -alkyl-NH—CO—, (C 1 -C 16 -alkyl) 2 -N—CO—, heterocyclylcarbonyl having 1 to 2 hetero atoms selected from N, O and S in a 3 to 6 membered ring, or phenylcarbonyl;
R 2 represents optionally halogen substituted or optionally C 1 -C 4 -alkyl substituted C 1 -C 12 -alkyl, phenyl-C 1 -C 2 -alklyl, biphenyl-C 1 -C 2 -alklyl or naphthyl-C 1 -C 2 -alklyl;
R 3 represents hydrogen or represents optionally halogen substituted or optionally C 1 -C 4 -alkyl substituted C 1 -C 12 -alkyl, phenyl-C 1 -C 2 -alklyl, biphenyl-C 1 -C 2 -alklyl or naphthyl-C 1 -C 2 -alklyl;
R 4 represents C 2 -C 6 -alkandiyl, C 2 -C 6 -alkendiyl, C 2 -C 6 -alkyndiyl, C 3 -C 7 -cycloalkyldiyl, —C 1 -C 6 -alkyl-C 3 -C 7 -cycloalkyl-, —C 1 -C 6 -alkyl-C 3 -C 7 -cycloalkyl-C 1 -C 6 -alkyl-, —C H (COOH)—C 1 -C 6 -alkyl-, —C H (CONH 2 )—C 3 H 6 — or —C 1 -C 6 -alklyl-phenyl-;
R 5 represents hydrogen or represents optionally halogen substituted or optionally C 1 -C 4 -alkyl substituted C 1 -C 12 -alkyl, phenyl-C 1 -C 2 -alklyl, biphenyl-C 1 -C 2 -alklyl or naphthyl-C 1 -C 2 -alklyl;
R 6 represents hydrogen or represents optionally halogen substituted or optionally C 1 -C 4 -alkyl substituted C 1 -C 12 -alkyl, phenyl-C 1 -C 2 -alklyl, biphenyl-C 1 -C 2 -alklyl or naphthyl-C 1 -C 2 -alklyl;
wherein at least one of R 2 or R 3 is an optionally halogen substituted or optionally C 1 -C 4 -alkyl substituted biphenyl-C 1 -C 2 -alkyl;
n is 0, 1, 2 or 3;
m is 0 or 1;
Q is —NH 2 , —NH—C(NH)—NH 2 or —NH—C(N—CH 3 )—NH—CH 3 ;
X is NH or O;
Z 1 is —CH 2 —;
Z 2 is a direct bond, —CH 2 —, cyclohexyldiyl or phenyldiyl;
or a pharmaceutically acceptable salt of such compound.

4. A compound of formula (I) according to claim 1 , wherein
L 1 represents —CO— or —CH 2 —;
L 2 represents —CO—, —CH 2 — or —CH 2 —CO—;
L 3 represents —CO— or —CH 2 —;
R 1 represents hydrogen, methylcarbonyl, ethylcarbonyl, nonylcarbonyl or heterocyclylcarbonyl having 1 to 2 hetero atoms selected from N and O in a 3 to 6 membered ring;
R 2 represents optionally halogen substituted or optionally C 1 -C 4 -alkyl substituted benzyl, biphenylmethyl or naphthylmethyl;
R 3 represents hydrogen or represents optionally halogen substituted or optionally C 1 -C 4 -alkyl substituted benzyl, biphenylmethyl or naphthylylmethyl;
R 4 represents propandiyl, butandiyl, pentandiyl, butendiyl, butyndiyl, cyclohexyldiyl, —C H (COOH)—C 3 H 6 —, —C H (CONH 2 )—C 3 H 6 — or —CH 2 -phenyl;
R 5 represents hydrogen or represents optionally halogen substituted or optionally C 1 -C 4 -alkyl substituted benzyl, biphenylmethyl or naphthylmethyl;
R 6 represents hydrogen or represents optionally halogen substituted or optionally C 1 -C 4 -alkyl substituted methyl, benzyl, biphenylmethyl or naphthylmethyl;
wherein at least one of R 2 or R 3 is an optionally halogen substituted or optionally C 1 -C 4 -alkyl substituted biphenylmethyl;
n is 0, 1, 2 or 3;
m is 0 or 1;
Q is —NH 2 , —NH—C(NH)—NH 2 or —NH—C(N—CH 3 )—NH—CH 3 ;
X is NH or O;
Z 1 is —CH 2 —;
Z 2 is a direct bond, —CH 2 — or phenyldiyl;
or a pharmaceutically acceptable salt of such compound.

5. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or pharmaceutically acceptable salts thereof and a pharmaceutical acceptable excipient.

Assignees

• Agency Science Tech & Res

Inventors

• Chia Brian Cheng San

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• C07K5/1024

  with the first amino acid being heterocyclic · CPC title

• C07K5/0812 Primary

  and aromatic or cycloaliphatic · 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

• C07K5/06095

  Arg-amino acid · CPC title