Antimicrobial peptidomimetics
AssigneeAgency for Science, Technology and Research
InventorBrian Cheng San Chia
Life of this patent
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Abstract
The present invention relates to peptidomimetics of the formula (I) or (I)c wherein L1, L2, L3, R1, R2, R3, R4, R5, R6, n, m, Q, X, Z1 and Z2 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.
Claims12
1-17. (canceled)
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
- L1 represents —CO—, alkandiyl, -alkyl-CO— or —CO-alkyl-;
- L2 represents —CO—, alkandiyl, -alkyl-CO— or —CO-alkyl-;
- L3 represents —CO—, alkandiyl, -alkyl-CO— or —CO-alkyl-;
- R1 represents hydrogen, acyl, carbamoyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylcarbonyl, cycloalkylcarbonyl or heterocyclylcarbonyl;
- R2 represents optionally substituted alkyl, aralkyl or heteroaralkyl;
- R3 represents hydrogen, or represents optionally substituted alkyl, aralkyl or heteroaralkyl;
- R4 represents optionally substituted alkandiyl, alkendiyl, alkyndiyl, cycloalkyldiyl, alkylcycloalkyldiyl, alkylcycloalkylalkyldiyl, aryldiyl, alkylaryldiyl, alkylarylalkyldiyl;
- R5 represents hydrogen, or represents optionally substituted alkyl, aralkyl or heteroaralkyl;
- R6 represents hydrogen, or represents optionally substituted alkyl, aralkyl or heteroaralkyl;
- provided that at least two of the substituents R2, R3, R5 and R6 are optionally substituted aralkyl or heteroaralkyl;
- n is 0, 1, 2, 3 or 4;
- and
- m is 0 or 1;
- Q is —NH2, —NH—C(NH)—NH2 or —NH—C(N-alkyl)-NH-alkyl;
- X is NH, O or S;
- Z1 is —CH2—;
- Z2 is a direct bond, alkandiyl, cycloalkyldiyl or aryldiyl;
- or pharmaceutically acceptable salts and solvates thereof.
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.
The method of claim 1, wherein the bacterial infection is caused by a Gram-positive bacteria.
The method of claim 1, wherein the bacterial infection is caused by a bacteria selected from Staphylococcus aureus, Streptococcus pyogenes and Streptococcus pneumoniae.
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.
The method of claim 1, wherein the disease, disorder or condition is boils, sinusitis, pneumonia or food poisoning.
The method of claim 1, wherein the bacterial infection is treated by topical use of the compound of formula (I) or (Ic).
The method according to claim 1, wherein the compound is a compound of formula (I):
- wherein
- L1 represents —CO—, alkandiyl, -alkyl-CO— or —CO-alkyl-;
- L2 represents —CO—, alkandiyl, -alkyl-CO— or —CO-alkyl-;
- L3 represents —CO—, alkandiyl, -alkyl-CO— or —CO-alkyl-;
- R1 represents hydrogen, acyl, carbamoyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylcarbonyl, cycloalkylcarbonyl or heterocyclylcarbonyl;
- R2 represents optionally substituted alkyl, aralkyl or heteroaralkyl;
- R3 represents hydrogen, or represents optionally substituted alkyl, aralkyl or heteroaralkyl;
- R4 represents optionally substituted alkandiyl, alkendiyl, alkyndiyl, cycloalkyldiyl, alkylcycloalkyldiyl, alkylcycloalkylalkyldiyl, aryldiyl, alkylaryldiyl, alkylarylalkyldiyl;
- R5 represents hydrogen, or represents optionally substituted alkyl, aralkyl or heteroaralkyl;
- R6 represents hydrogen, or represents optionally substituted alkyl, aralkyl or heteroaralkyl;
- provided that at least two of the substituents R2, R3, R5 and R6 are optionally substituted aralkyl or heteroaralkyl;
- wherein at least one of R2 or R3 is an optionally substituted biphenyl-C1-C4-alkyl;
- n is 0, 1, 2, 3 or 4;
- and
- m is 0 or 1;
- Q is —NH2, —NH—C(NH)—NH2 or —NH—C(N-alkyl)-NH-alkyl;
- X is NH, O or S;
- Z1 is —CH2—;
- Z2 is a direct bond, alkandiyl, cycloalkyldiyl or aryldiyl;
- or a salt of such compound.
The method according to claim 1, wherein the compound is a compound of formula (I):
- wherein
- L1 represents —CO—, C1-C3-alkandiyl, —C1-C2-alkyl-CO— or —CO— C1-C2-alkyl-;
- L2 represents —CO—, C1-C3-alkandiyl, —C1-C2-alkyl-CO— or —CO— C1-C2-alkyl-;
- L3 represents —CO—, C1-C3-alkandiyl, —C1-C2-alkyl-CO— or —CO— C1-C2-alkyl-;
- R1 represents hydrogen, C1-C20-alkyl-CO—, C2-C20-alkenyl-CO—, CO—, (C1-C20-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 the 3 to 6 membered ring, or C3-C7-cycloalkylcarbonyl;
- R2 represents optionally substituted C1-C12-alkyl, phenyl-C1-C4-alkyl, biphenyl-C1-C4-alkyl or naphthyl-C1-C4-alkyl;
- R3 represents hydrogen or represents optionally substituted C1-C12-alkyl, phenyl-C1-C4-alkyl, biphenyl-C1-C4-alkyl or naphthyl-C1-C4-alkyl;
- R4 represents optionally substituted C1-C12-alkandiyl, C2-C12-alkendiyl, C2-C12-alkyndiyl, C3-C7-cycloalkyldiyl, —C1-C6-alkyl-C3-C7-cycloalkyl-, —C1-C6-alkyl-C3-C7-cycloalkyl-C1-C6-alkyl-, —C1-C6-alkyl-phenyl- or —C1-C6-alkyl-naphthyl-;
- R5 represents hydrogen or represents optionally substituted C1-C12-alkyl, phenyl-C1-C4-alkyl, biphenyl-C1-C4-alkyl or naphthyl-C1-C4-alkyl;
- R6 represents hydrogen or represents optionally substituted C1-C12-alkyl, phenyl-C1-C4-alkyl, biphenyl-C1-C4-alkyl or naphthyl-C1-C4-alkyl;
- wherein at least one of R2 or R3 is an optionally substituted biphenyl-C1-C4-alkyl;
- n is 0, 1, 2 or 3;
- m is 0 or 1;
- Q is —NH2, —NH—C(NH)—NH2 or —NH—C(N—C1-C2-alkyl)-NH—C1-C2-alkyl;
- X is NH or O;
- Z1 is —CH2—;
- Z2 is a direct bond, C1-C3-alkandiyl, cyclohexyldiyl or phenyldiyl;
- or a pharmaceutically acceptable salt of such compound.
The method according to claim 1, wherein the compound is a compound of formula (I):
- wherein
- L1 represents —CO—, —CH2—, —CH2—CH2—, —CH2—CO— or —CO—CH2—;
- L2 represents —CO—, —CH2—, —CH2—CH2—, —CH2—CO— or —CO—CH2—;
- L3 represents —CO—, —CH2—, —CH2—CH2—, —CH2—CO— or —CO—CH2—;
- R1 represents hydrogen, C1-C16-alkyl-CO—, C2-C16-alkenyl-CO—, C1-C16-alkyl-NH—CO—, (C1-C16-alkyl)2-N—CO—, heterocyclylcarbonyl having 1 to 2 hetero atoms selected from N, O and S in the 3 to 6 membered ring, or phenylcarbonyl;
- R2 represents optionally halogen substituted or optionally C1-C4-alkyl substituted C1-C12-phenyl-C1-C2-alklyl, biphenyl-C1-C2-alklyl or naphthyl-C1-C2-alklyl;
- R3 represents hydrogen or represents optionally halogen substituted or optionally C1-C4-alkyl substituted C1-C12-alkyl, phenyl-C1-C2-alklyl, biphenyl-C1-C2-alklyl or naphthyl-C1-C2-alklyl;
- R4 represents C2-C6-alkandiyl, C2-C6-alkendiyl, C2-C6-alkyndiyl, C3-C7-cycloalkyldiyl, —C1-C6-alkyl-C3-C7-cycloalkyl-, —C1-C6-alkyl-C3-C7-cycloalkyl-C1-C6-alkyl-, —CH(COOH)—C1-C6-alkyl-, —CH(CONH2)—C3H6— or —C1-C6-alklyl-phenyl-;
- R5 represents hydrogen or represents optionally halogen substituted or optionally C1-C4-alkyl substituted C1-C12-alkyl, phenyl-C1-C2-alklyl, biphenyl-C1-C2-alklyl or naphthyl-C1-C2-alklyl;
- R6 represents hydrogen or represents optionally halogen substituted or optionally C1-C4-alkyl substituted C1-C12-alkyl, phenyl-C1-C2-alklyl, biphenyl-C1-C2-alklyl or naphthyl-C1-C2-alklyl;
- wherein at least one of R2 or R3 is an optionally halogen substituted or optionally C1-C4-alkyl substituted biphenyl-C1-C2-alkyl;
- n is 0, 1, 2 or 3;
- m is 0 or 1;
- Q is —NH2, —NH—C(NH)—NH2 or —NH—C(N—CH3)—NH—CH3;
- X is NH or O;
- Z1 is —CH2—;
- Z2 is a direct bond, —CH2—, cyclohexyldiyl or phenyldiyl;
- or a pharmaceutically acceptable salt of such compound.
The method according to claim 1, wherein the compound is a compound of formula (I):
- wherein
- L1 represents —CO— or —CH2—;
- L2 represents —CO—, —CH2— or —CH2—CO—;
- L3 represents —CO— or —CH2—;
- R1 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;
- R2 represents optionally halogen substituted or optionally C1-C4-alkyl substituted benzyl, biphenylmethyl or naphthylmethyl;
- R3 represents hydrogen or represents optionally halogen substituted or optionally C1-C4-alkyl substituted benzyl, biphenylmethyl or naphthylylmethyl;
- R4 represents propandiyl, butandiyl, pentandiyl, butendiyl, butyndiyl, cyclohexyldiyl, —CH(COOH)—C3H6—, —CH(CONH2)—C3H6— or —CH2-phenyl;
- R5 represents hydrogen or represents optionally halogen substituted or optionally C1-C4-alkyl substituted benzyl, biphenylmethyl or naphthylmethyl;
- R6 represents hydrogen or represents optionally halogen substituted or optionally C1-C4-alkyl substituted methyl, benzyl, biphenylmethyl or naphthylmethyl;
- wherein at least one of R2 or R3 is an optionally halogen substituted or optionally C1-C4-alkyl substituted biphenylmethyl;
- n is 0, 1, 2 or 3;
- m is 0 or 1;
- Q is —NH2, —NH—C(NH)—NH2 or —NH—C(N—CH3)—NH—CH3;
- X is NH or O;
- Z1 is —CH2—;
- Z2 is a direct bond, —CH2— or phenyldiyl;
- or a pharmaceutically acceptable salt of such compound.
Dependencies are inferred from the claim text.