Antimicrobial peptidomimetics

Patent metadata

Field	Value
Publication number	US-10787483-B2
Application number	US-201816038603-A
Country	US
Kind code	B2
Filing date	Jul 18, 2018
Priority date	Jan 22, 2014
Publication date	Sep 29, 2020
Grant date	Sep 29, 2020

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 method of treating a bacterial infection caused disease, disorder or condition in a subject in need of such treatment, comprising administering to said subject a compound of formula (I) or (Ic):

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 or 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 pharmaceutically acceptable salts thereof.

2. The method of claim 1 , wherein the bacterial infection is caused by bacteria that have gained a resistance against the penicillin-type antibiotics or vancomycin.

3. The method of claim 1 , wherein the bacterial infection is caused by a Gram-positive bacteria.

4. The method of claim 1 , wherein the bacterial infection is caused by a bacteria selected from Staphylococcus aureus, Streptococcus pyogenes and Streptococcus pneumoniae.

5. The method of claim 1 , wherein the disease, disorder or condition is a skin infection, a respiratory disease, food poisoning or any other life-threatening systemic disease.

6. The method of claim 1 , wherein the disease, disorder or condition is boils, sinusitis, pneumonia or food poisoning.

7. The method of claim 1 , wherein the bacterial infection is treated by topical use of the compound of formula (I) or (Ic).

8. The method according to claim 1 , wherein the compound is a compound of 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 or 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 pharmaceutically acceptable salt of such compound.

9. The method according to claim 1 , wherein the compound is a compound of formula (I):

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 3 -alkandiyl, —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, phenyl-C 1 -C 4 -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.

10. The method according to claim 1 , wherein the compound is a compound of formula (I):

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 -alkyl, biphenyl-C 1 -C 2 -alkyl or naphthyl-C 1 -C 2 -alkyl;
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 -alkyl, biphenyl-C 1 -C 2 -alkyl or naphthyl-C 1 -C 2 -alkyl;
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-, —CH(COOH)—C 1 -C 6 -alkyl-, —CH(CONH 2 )—C 3 H 6 — or —C 1 -C 6 -alkyl-phenyl-;
R 5 represent

Assignees

• Agency Science Tech & Res

Inventors

• Chia Brian Cheng San

Classifications

• C07K5/1024

  with the first amino acid being heterocyclic · CPC title

• C07K1/00

  General methods for the preparation of peptides {, i.e. processes for the organic chemical preparation of peptides or proteins of any length} · CPC title

• C07K1/10

  using coupling agents {(C07K1/006 takes precedence)} · CPC title

• C07K5/06095

  Arg-amino acid · 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