US 11,753,446 B2 · Beta-hairpin peptidomimetics

Abstract

Beta-hairpin peptidomimetics of the general formula (I), cyclo[P1-P2-P3-P4-P5-P6-P7-P8-P9-P10-P11-P12-T1-T2], and pharmaceutically acceptable salts thereof, with P1 to P12, T1 and T2 being elements as defined in the description and the claims, have Gram-negative antimicrobial activity to e.g. inhibit the growth or to kill microorganisms such as Klebsiella pneumoniae and/or Acinetobacter baumannii and/or Escherichia coli. They can be used as medicaments to treat or prevent infections or as disinfectants for foodstuffs, cosmetics, medicaments or other nutrient-containing materials. These peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

A method of treating infections by Gram-negative bacteria, the method comprising

administering to a subject in need thereof a pharmaceutically acceptable amount of a compound or pharmaceutical composition,
wherein the Gram-negative infections are respiratory infections, skin or soft tissue infections, gastrointestinal infections, eye infections, ear infections, CNS infections, bone infections, cardiovascular infections, or genitourinary infections;
and
wherein the compound is a compound of the general formula (I) or a pharmaceutically acceptable salt thereof,
cyclo[P1-P2-P3-P4-P5-P6-P7-P8-P9-P10-P11-P12-T1-T2] (I)
wherein the single elements T or P are connected in either direction from the carbonyl (C═O) point of attachment to the nitrogen (N) of the next element;
and
wherein the compound is selected from
the group consisting of β-hairpin peptidomimetics of general formula (I) having a disulfide linkage;
a lactam linkage;
or a 1,2,3-triazole linkage between P2 and P11:
cyclo(-Leu-Cys-Tyr-Ala-Dab-Dab-Dab-Trp-Ala-Val-
Cys-Val-DPro-Arg-);
cyclo(-Leu-Cys-Tyr-Ala-Dab-DDab-Dab-Trp-Ala-Val-
Cys-Val-DPro-Arg-);
cyclo(-Leu-Cys-Tyr-Ala-Orn-DDab-Dab-Trp-Ala-Val-
Cys-Val-DPro-Arg-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Leu-Ser-
tBuGly-Cys-Val-DDab-Arg-);
cyclo(-Ile-Cys-Tyr-Asn-Orn-DDab-Dab-Leu-Ser-Val-
Cys-Tyr-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-
tBuGly-Cys-Thr-DDab-Dab-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Thr-DDab-Dab-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Ser-DDab-Dab-);
cyclo(-Val-Cys-Tyr-Dab-Dap-DDab-Dab-Trp-Dab-
tBuGly-Cys-Ser-NMeAla-Pro-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Tyr-DDab-Arg-);
cyclo(-Ile-Cys-Tyr-Dab-Orn-DDab-Dab-Trp-Dab-
tBuGly-Cys-Ser-DDab-Arg-);
cyclo(-Ile-Cys-Tyr-Dab-Orn-DDab-Dab-Trp-Dab-
tBuGly-Cys-Ser-DDab-Ala-);
cyclo(-Ile-Cys-Tyr-Dab-Orn-DDab-Dab-Trp-Dab-
tBuGly-Cys-Ser-DDab-Pro-);
cyclo(-Val-Cys-Tyr-Dab-Dap-Dab-Dab-Trp-Dab-
tBuGly-Cys-Thr-DTyr-Pro-);
cyclo(-Ile-Cys-Tyr-Dab-Orn-DDab-Dab-Trp-Dab-
tBuGly-Cys-Ser-DAla-Tyr-);
cyclo(-Leu-Cys-Tyr-Ala-Orn-DDab-Dab-Trp-Ala-Tyr-
Cys-Tyr-DDab-Arg-);
cyclo(-Leu-Cys-Val-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Ala-Orn-DDab-Dab-Phe-Ala-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Leu-Cys-Val-Val-Orn-DDab-Dab-Trp-Tyr-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Val-Orn-DDab-Dab-Trp-Tyr-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Val-Orn-DDab-Dab-Trp-Tyr-Tyr-
Cys-Tyr-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Ala-Orn-DDab-Dab-Trp-Ala-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Phe-Cys-Val-Thr-Orn-DDab-Dab-Trp-Thr-Tyr-
Cys-Dab-DDab-Arg-);
cyclo(-Leu-Cys-Val-Thr-Orn-DDab-Dab-Trp-Thr-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Val-DDab-Dab-);
cyclo(-Leu-Cys-Tyr-Ser-Orn-DDab-Dab-Trp-Asn-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Asn-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Asn-Tyr-
Cys-Val-DDab-Dab-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-Dab-Dab-Trp-Ser-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Asn-Dab-DDab-Dab-Trp-Ser-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Val-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Cpa-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Cpg-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Nva-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Abu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Gln-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Leu-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-tBuGly-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Val-DLys-Arg-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Val-DArg-Arg-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Val-DDab-Lys-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Val-DDab-Dap-);
cyclo(-Val-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Leu-DDab-Arg-);
cyclo(-Ile-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Ala-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Dap-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Val-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Dab-Orn-DDab-Dab-Trp-Asn-Tyr-
Cys-Val-DAla-Arg-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-Tyr-
Cys-Thr-DDab-Arg-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Dab-Tyr-
Cys-Val-DPro-Arg-);
cyclo(-Leu-Cys-Tyr-Asn-Orn-DDab-Dab-Trp-Dab-Tyr-
Cys-Val-DAla-Arg-);
cyclo(-Leu-Pen-tBuGly-Dab-Orn-DDab-Dab-Trp-Dab-
Chg-Pen-Ser-DPro-Pro-);
cyclo(-Leu-Dab-Tyr-Dab-Dab-Dab-Dab-Trp-Dab-
tBuGly-Asp-Ser-DAla-Pro-);
cyclo(-Val-Dab-Tyr-Dab-Dap-DDab-Dab-Trp-Dab-
tBuGly-Asp-Ser-DAla-Pro-);
cyclo(-Val-Dab-Tyr-Dab-Dap-DDab-Dab-Trp-Dab-Val-
Asp-Thr-DAla-Pro-);
cyclo(-Val-Dab-Tyr-Dab-Dap-DDab-Dab-Trp-Dab-
tBuGly-Asp-Thr-DThr-Pro-);
cyclo(-Val-Dab-Tyr-Dab-Dab-DDab-Dab-Trp-Dab-
tBuGly-Asp-Ser-DAla-Ala-);
cyclo(-Val-Dab-Tyr-Dab-Dap-DDab-Dab-Trp-Dap-
tBuGly-Asp-Ser-DAla-Tyr-);
cyclo(-Val-Dab-Tyr-Dab-Dab-Dab-Dab-Trp-Dab-
tBuGly-Asp-Ser-Sar-Pro-);
cyclo(-Leu-Asp-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-
tBuGly-Dab-Thr-DDab-Arg-);
cyclo(-Leu-Asp-Tyr-Asn-Orn-DDab-Dab-Trp-Ser-
tBuGly-Dab-Thr-DDab-Dab-);
cyclo(-Leu-Asp-Tyr-Dab-Orn-DDab-Dab-Trp-Dab-Tyr-
Dab-Ser-DAla-Pro-);
cyclo(-Val-Pra-Tyr-Dab-Dap-DDab-Dab-Trp-Dab-
tBuGly-Abu(4N3)-Ser-DPro-Pro-);
or a pharmaceutically acceptable salt thereof;
and/or
the group consisting of β-hairpin peptidomimetics of general formula (I) having a disulfide linkage;
or a lactam linkage between P4 and P9;
or disulfide linkages between P2 and P11, and P4 and P9:
cyclo(-Leu-Thr-Tyr-Cys-Dab-Dab-Dab-Trp-Cys-Val-
Thr-Val-DPro-Arg-);
cyclo(-Leu-Thr-Tyr-Cys-Dab-DDab-Dab-Trp-Cys-Val-
Thr-Val-DPro-Arg-);
cyclo(-Leu-Thr-Tyr-Cys-Dab-DDab-Dab-Trp-Cys-Val-
Thr-Val-DPro-Dab-);
cyclo(-Leu-Ser-Tyr-Cys-Orn-DDab-Dab-Trp-Cys-Tyr-
Ala-Ser-DDab-Dab-);
cyclo(-Leu-Ser-Tyr-Cys-Orn-DDab-Dab-Phe-Cys-Val-
Ser-Val-DDab-Arg-);
cyclo(-Leu-Ser-Tyr-Cys-Orn-Gly-Dab-Trp-Cys-Val-
Ala-Val-DDab-Arg-);
cyclo(-Leu-Tyr-Tyr-Dab-Orn-DDab-Dab-Trp-Asp-
tBuGly-Val-Ser-DDab-Pro-);
cyclo(-Leu-Cys-Tyr-Cys-Dab-Dab-Dab-Trp-Cys-Tyr-
Cys-Val-DPro-Arg-);
cyclo(-Leu-Cys-Tyr-Cys-Dab-DDab-Dab-Trp-Cys-Tyr-
Cys-Val-DPro-Arg-);
or a pharmaceutically acceptable salt thereof;
and/or
the group consisting of β-hairpin peptidomimetics of general formula (I)
cyclo(-Val-Ser-Tyr-Dab-Dap-DDab-Dab-Trp-Dab-
tBuGly-Ala-Ser-DPro-NMeAla-);
cyclo(-Val-Dap-Tyr-Dab-Dap-DDab-Dab-Trp-Dab-
tBuGly-Ser-Thr-DAla-Pro-);
cyclo(-Val-Dap-Tyr-Dab-Dab-DDab-Dab-Trp-Dab-
tBuGly-Ser-Thr-DAla-Pro-);
cyclo(-Ile-Thr-Tyr-Dab-Orn-DDab-Dab-Trp-Dab-
tBuGly-Ala-Ser-DPro-Tyr-);
cyclo(-Ile-Thr-Tyr-Dab-Orn-DDab-Dab-Trp-Dab-
tBuGly-Ala-Ser-DDab-Pro-);
cyclo(-Ile-Thr-Tyr-Dab-Orn-DDab-Dab-Trp-Dab-
tBuGly-Ala-Ser-DAla-Tyr-);
cyclo(-Phe-Dap-Tyr-Dab-Orn-DDab-Dab-Trp-Dab-
tBuGly-Ala-Ser-DDab-Pro-);
or a pharmaceutically acceptable salt thereof;
wherein said pharmaceutical composition contains said compound of the general formula (I) or a mixture of compounds of general formula (I) and at least one pharmaceutically inert carrier.

176 more elements

Beta-hairpin peptidomimetics

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Beta-hairpin peptidomimetics

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Abstract

Claims2