Antimicrobial Peptidomimetics

Patent metadata

Field	Value
Publication number	US-2016333048-A1
Application number	US-201515104186-A
Country	US
Kind code	A1
Filing date	Jan 22, 2015
Priority date	Jan 22, 2014
Publication date	Nov 17, 2016
Grant date	—

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

1 . A compound of the 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, cycloalkylarbonyl 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;
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 and solvate of such compound.

2 . A compound of formula (I) or (Ic) 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 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, C 3 -C 7 -cycloalkylcarbonyl or heterocyclylcarbonyl having 1 to 3 hetero atoms selected from N, O and S in the 3 to 6 membered ring; 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-naphtyl-; 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 naphtyl-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 naphtyl-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 and solvate of such compound.

3 . A compound of formula (I) or (Ic) 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—; phenylcarbonyl or heterocyclylcarbonyl having 1 to 2 hetero atoms selected from N, O and S in the 3 to 6 membered ring; R 2 represents optionally halogen or 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 or 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(COOH)—C 1 -C 6 -alkyl-, —C(CONH 2 )—C 3 H 6 — or —C 1 -C 6 -alklyl-phenyl-; R 5 represents hydrogen or represents optionally halogen or 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 or 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; 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.

4 . A compound of formula (I) or (Ic) 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 the 3 to 6 membered ring; R 2 represents optionally halogen or C 1 -C 4 -alkyl substituted benzyl, biphenylmethyl or naphtylmethyl; R 3 represents hydrogen or represents optionally halogen or C 1 -C 4 -alkyl substituted benzyl, biphenylmethyl or naphthylylmethyl; R 4 represents propandiyl, butandiyl, pentandiyl, butendiyl, butyndiyl, cyclohexyldiyl, —C(COOH)—C 3 H 6 —, —C(CONH 2 )—C 3 H 6 — or —CH 2 -phenyl; R 5 represents hydrogen or represents optionally halogen or C 1 -C 4 -alkyl substituted benzyl, biphenylmethyl or naphthylmethyl; R 6 represents hydrogen or represents optionally halogen or C 1 -C 4 -alkyl substituted methyl, benzyl, biphenylmethyl or naphthylmethyl; 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.

5 . (canceled)

6 . (canceled)

7 . A process for making compounds of the formula (I′)

wherein
R′ 1 represents hydrogen, acyl, carbamoyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylcarbonyl, cycloalkylarbonyl or heterocyclylcarbonyl;
R′ 2 represents optionally substituted alkyl, aralkyl or heteroaralkyl;
R′ 3 represents optionally substituted alkyl, aralkyl or heteroaralkyl;
R′ 4 represents optionally substituted alkandiyl, alkendiyl, alkyndiyl, cycloalkyldiyl, alkylcycloalkyl, alkylcycloalkylalkyl or alkylaryl;
n′ is 0, 1, 2, 3 or 4; and
m′ is 0 or 1;
by reacting compounds of the formula (II′)

in which R′ 3 , R′ 4 , m and n have the meaning given above
in the presence of an amide/peptide coupling reagent with compounds of the formula

wherein R′ 1 and R′ 2 are defined as mentioned above,
and deprotection with an acid.

8 .- 14 . (canceled)

15 . A method of treating a bacterial infection caused disease, disorder or condition in a subject in need of such treatment, comprising administering to said

Assignees

• Agency Science Tech & Res

Inventors

• Chia Brian Cheng San

Classifications

• C07K5/1024

  with the first amino acid being heterocyclic · CPC title

• C07K5/06095

  Arg-amino acid · 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

• A61P31/04

  Antibacterial agents · 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