US 10,370,411 B2Granted

Beta-hairpin peptidomimetics

AssigneePolyphor AG

InventorsDaniel Obrecht, Anatol Luther, Francesca Bernardini, Peter Zbinden

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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.

Claims18

Dependent claims

A method for the treatment of infections caused by gram-negative bacteria or for the treatment or prevention of the onset of diseases related to such infections, comprising:

administering a compound to a subject in need thereof,
wherein said infections relate to respiratory diseases or skin or soft tissue diseases or gastrointestinal diseases or eye diseases or ear diseases or CNS diseases or bone diseases or cardiovascular diseases or genitourinary diseases, or nosocomial infections, or catheter-related and non-catheter-related infections, or urinary tract infections, or bloodstream infections, and
wherein said compound is a compound of the general formula (I),
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
T1 is DPro;
T2 is Pro;
Pro((3S)OH);
Pro((4S)OBn);
Pic;
Oic;
or Tic(7OH);
P1 is Ala(CF3);
Ala(2ClPhUr);
Ala(4ClPhUr);
Leu;
Ile;
Val;
Nva;
Trp;
Phe, Tyr;
Tza;
or Thr;
P2 is Ala;
Abu;
Ala(2ClPhUr);
Ala(3PyrMeUr);
Ala(4butoxyPhUr);
Ala(iPrUr);
Dab(2PyrMe);
Dap;
Dap(2,3-OHpropionyl);
Dap(AcThr);
Dap(iPr);
Dap(Thr);
Ser;
Ser(Me);
Hse;
Thr;
alloThr;
Asp;
Asn;
or Gly;
P3 is Chg;
Cha;
tBuGly;
Phe;
Phe(4NH2);
Phe(4F);
Tyr(3F);
Phe(4CF3);
Tyr;
Tyr(Me);
or Trp;
P4 is Dab;
Dab(2PyrMe);
Dap;
Orn;
or Arg;
P5 is Lys;
Orn;
Orn(iPr);
Dap;
Dab;
or Arg;
P6 is Dab;
DDab;
or Pip;
P7 is Dab;
Dab(2PyrMe);
Dap;
Orn;
Arg;
or DDab;
P8 is Trp;
P9 is Hse;
Dab;
Dap;
Arg;
or Lys;
P10 is tBuGly;
Ile;
Val;
Nva;
Chg;
Cha;
Trp;
Tyr;
Tyr(Me);
or Phg;
P11 is Ala;
Ser;
Ser(Me);
Tza;
Agp;
Tyr;
Dab;
Thr;
Asn;
Asp;
or DAla;
and
P12 is Ser;
Thr;
Dap;
Ala(iPrUr);
Leu;
or Tyr;
or a pharmaceutically acceptable salt thereof;
with the proviso that
if P2 is Ala(2ClPhUr);
Ala(3PyrMeUr);
Ala(4butoxyPhUr);
Ala(iPrUr);
Dab(2PyrMe);
Dap;
Dap(2,3-OHpropionyl);
Dap(AcThr);
Dap(iPr);
Dap(Thr);
Ser(Me);
Asp;
or Asn;
then P11 is Ala;
Ser;
Ser(Me);
Thr;
Asn;
Asp;
or DAla.

127 more elements

A method for disinfecting or preserving foodstuffs, cosmetics, medicaments or other nutrient-containing materials against gram-negative, comprising the step:

adding a compound to foodstuffs, cosmetics, medicaments or other nutrient-containing materials, thereby disinfecting or preserving said foodstuffs, cosmetics, medicaments or other nutrient-containing materials,
wherein said compound is a compound of the general formula (I),
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
T1 is DPro;
T2 is Pro;
Pro((3S)OH);
Pro((4S)OBn);
Pic;
Oic;
or Tic(7OH);
P1 is Ala(CF3);
Ala(2ClPhUr);
Ala(4ClPhUr);
Leu;
Ile;
Val;
Nva;
Trp;
Phe, Tyr;
Tza;
or Thr;
P2 is Ala;
Abu;
Ala(2ClPhUr);
Ala(3PyrMeUr);
Ala(4butoxyPhUr);
Ala(iPrUr);
Dab(2PyrMe);
Dap;
Dap(2,3-OHpropionyl);
Dap(AcThr);
Dap(iPr);
Dap(Thr);
Ser;
Ser(Me);
Hse;
Thr;
alloThr;
Asp;
Asn;
or Gly;
P3 is Chg;
Cha;
tBuGly;
Phe;
Phe(4NH2);
Phe(4F);
Tyr(3F);
Phe(4CF3);
Tyr;
Tyr(Me);
or Trp;
P4 is Dab;
Dab(2PyrMe);
Dap;
Orn;
or Arg;
P5 is Lys;
Orn;
Orn(iPr);
Dap;
Dab;
or Arg;
P6 is Dab;
DDab;
or Pip;
P7 is Dab;
Dab(2PyrMe);
Dap;
Orn;
Arg;
or DDab;
P8 is Trp;
P9 is Hse;
Dab;
Dap;
Arg;
or Lys;
P10 is tBuGly;
Ile;
Val;
Nva;
Chg;
Cha;
Trp;
Tyr;
Tyr(Me);
or Phg;
P11 is Ala;
Ser;
Ser(Me);
Tza;
Agp;
Tyr;
Dab;
Thr;
Asn;
Asp;
or DAla;
and
P12 is Ser;
Thr;
Dap;
Ala(iPrUr);
Leu;
or Tyr;
or a pharmaceutically acceptable salt thereof;
with the proviso that
if P2 is Ala(2ClPhUr);
Ala(3PyrMeUr);
Ala(4butoxyPhUr);
Ala(iPrUr);
Dab(2PyrMe);
Dap;
Dap(2,3-OHpropionyl);
Dap(AcThr);
Dap(iPr);
Dap(Thr);
Ser(Me);
Asp;
or Asn;
then P11 is Ala;
Ser;
Ser(Me);
Thr;
Asn;
Asp;
or DAla.

126 more elements

A method for the manufacture of a medicament to treat infections caused by gram-negative bacteria or to treat or prevent the onset of diseases related to such infections, comprising the step:

formulating a compound with one or more physiologically acceptable carriers, diluents, excipients, or auxiliaries,
wherein said infections relate to respiratory diseases or skin or soft tissue diseases or gastrointestinal diseases or eye diseases or ear diseases or CNS diseases or bone diseases or cardiovascular diseases or genitourinary diseases, or nosocomial infections, or catheter-related and non-catheter-related infections, or urinary tract infections, or bloodstream infections;
wherein said compound is a compound of the general formula (I),
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
T1 is DPro;
T2 is Pro;
Pro((3S)OH);
Pro((4S)OBn);
Pic;
Oic;
or Tic(7OH);
P1 is Ala(CF3);
Ala(2ClPhUr);
Ala(4ClPhUr);
Leu;
Ile;
Val;
Nva;
Trp;
Phe, Tyr;
Tza;
or Thr;
P2 is Ala;
Abu;
Ala(2ClPhUr);
Ala(3PyrMeUr);
Ala(4butoxyPhUr);
Ala(iPrUr);
Dab(2PyrMe);
Dap;
Dap(2,3-OHpropionyl);
Dap(AcThr);
Dap(iPr);
Dap(Thr);
Ser;
Ser(Me);
Hse;
Thr;
alloThr;
Asp;
Asn;
or Gly;
P3 is Chg;
Cha;
tBuGly;
Phe;
Phe(4NH2);
Phe(4F);
Tyr(3F);
Phe(4CF3);
Tyr;
Tyr(Me);
or Trp;
P4 is Dab;
Dab(2PyrMe);
Dap;
Orn;
or Arg;
P5 is Lys;
Orn;
Orn(iPr);
Dap;
Dab;
or Arg;
P6 is Dab;
DDab;
or Pip;
P7 is Dab;
Dab(2PyrMe);
Dap;
Orn;
Arg;
or DDab;
P8 is Trp;
P9 is Hse;
Dab;
Dap;
Arg;
or Lys;
P10 is tBuGly;
Ile;
Val;
Nva;
Chg;
Cha;
Trp;
Tyr;
Tyr(Me);
or Phg;
P11 is Ala;
Ser;
Ser(Me);
Tza;
Agp;
Tyr;
Dab;
Thr;
Asn;
Asp;
or DAla;
and
P12 is Ser;
Thr;
Dap;
Ala(iPrUr);
Leu;
or Tyr;
or a pharmaceutically acceptable salt thereof;
with the proviso that
if P2 is Ala(2ClPhUr);
Ala(3PyrMeUr);
Ala(4butoxyPhUr);
Ala(iPrUr);
Dab(2PyrMe);
Dap;
Dap(2,3-OHpropionyl);
Dap(AcThr);
Dap(iPr);
Dap(Thr);
Ser(Me);
Asp;
or Asn;
then P1 is Ala;
Ser;
Ser(Me);
Thr;
Asn;
Asp;
or DAla.

127 more elements

A method for the manufacture of a disinfectant or preservative against gram-negative bacteria for foodstuffs, cosmetics, medicaments and other nutrient-containing materials, comprising the step:

formulating a compound with one or more physiologically acceptable carriers, diluents, excipients, or auxiliaries,
wherein said compound is a compound of the general formula (I),
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
T1 is DPro;
T2 is Pro;
Pro((3S)OH);
Pro((4S)OBn);
Pic;
Oic;
or Tic(7OH);
P1 is Ala(CF3);
Ala(2ClPhUr);
Ala(4ClPhUr);
Leu;
Ile;
Val;
Nva;
Trp;
Phe, Tyr;
Tza;
or Thr;
P2 is Ala;
Abu;
Ala(2ClPhUr);
Ala(3PyrMeUr);
Ala(4butoxyPhUr);
Ala(iPrUr);
Dab(2PyrMe);
Dap;
Dap(2,3-OHpropionyl);
Dap(AcThr);
Dap(iPr);
Dap(Thr);
Ser;
Ser(Me);
Hse;
Thr;
alloThr;
Asp;
Asn;
or Gly;
P3 is Chg;
Cha;
tBuGly;
Phe;
Phe(4NH2);
Phe(4F);
Tyr(3F);
Phe(4CF3);
Tyr;
Tyr(Me);
or Trp;
P4 is Dab;
Dab(2PyrMe);
Dap;
Orn;
or Arg;
P5 is Lys;
Orn;
Orn(iPr);
Dap;
Dab;
or Arg;
P6 is Dab;
DDab;
or Pip;
P7 is Dab;
Dab(2PyrMe);
Dap;
Orn;
Arg;
or DDab;
P8 is Trp;
P9 is Hse;
Dab;
Dap;
Arg;
or Lys;
P10 is tBuGly;
Ile;
Val;
Nva;
Chg;
Cha;
Trp;
Tyr;
Tyr(Me);
or Phg;
P11 is Ala;
Ser;
Ser(Me);
Tza;
Agp;
Tyr;
Dab;
Thr;
Asn;
Asp;
or DAla;
and
P12 is Ser;
Thr;
Dap;
Ala(iPrUr);
Leu;
or Tyr;
or a pharmaceutically acceptable salt thereof;
with the proviso that
if P2 is Ala(2ClPhUr);
Ala(3PyrMeUr);
Ala(4butoxyPhUr);
Ala(iPrUr);
Dab(2PyrMe);
Dap;
Dap(2,3-OHpropionyl);
Dap(AcThr);
Dap(iPr);
Dap(Thr);
Ser(Me);
Asp;
or Asn;
then P5 is Ala;
Ser;
Ser(Me);
Thr;
Asn;
Asp;
or DAla.

126 more elements

A method of treating an infection caused by gram-negative bacteria or a disease or disorder associated with an infection caused by gram-negative bacteria, comprising

administering to a subject in need thereof a pharmaceutically acceptable amount of a compound or a pharmaceutical composition,
wherein said compound is a compound of the general formula (I),
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
T1 is DPro;
T2 is Pro;
Pro((3S)OH);
Pro((4S)OBn);
Pic;
Oic;
or Tic(7OH);
P1 is Ala(CF3);
Ala(2ClPhUr);
Ala(4ClPhUr);
Leu;
Ile;
Val;
Nva;
Trp;
Phe, Tyr;
Tza;
or Thr;
P2 is Ala;
Abu;
Ala(2ClPhUr);
Ala(3PyrMeUr);
Ala(4butoxyPhUr);
Ala(iPrUr);
Dab(2PyrMe);
Dap;
Dap(2,3-OHpropionyl);
Dap(AcThr);
Dap(iPr);
Dap(Thr);
Ser;
Ser(Me);
Hse;
Thr;
alloThr;
Asp;
Asn;
or Gly;
P3 is Chg;
Cha;
tBuGly;
Phe;
Phe(4NH2);
Phe(4F);
Tyr(3F);
Phe(4CF3);
Tyr;
Tyr(Me);
or Trp;
P4 is Dab;
Dab(2PyrMe);
Dap;
Orn;
or Arg;
P5 is Lys;
Orn;
Orn(iPr);
Dap;
Dab;
or Arg;
P6 is Dab;
DDab;
or Pip;
P7 is Dab;
Dab(2PyrMe);
Dap;
Orn;
Arg;
or DDab;
P8 is Trp;
P9 is Hse;
Dab;
Dap;
Arg;
or Lys;
P10 is tBuGly;
Ile;
Val;
Nva;
Chg;
Cha;
Trp;
Tyr;
Tyr(Me);
or Phg;
P11 is Ala;
Ser;
Ser(Me);
Tza;
Agp;
Tyr;
Dab;
Thr;
Asn;
Asp;
or DAla;
and
P12 is Ser;
Thr;
Dap;
Ala(iPrUr);
Leu;
or Tyr;
or a pharmaceutically acceptable salt thereof;
with the proviso that
if P2 is Ala(2ClPhUr);
Ala(3PyrMeUr);
Ala(4butoxyPhUr);
Ala(iPrUr);
Dab(2PyrMe);
Dap;
Dap(2,3-OHpropionyl);
Dap(AcThr);
Dap(iPr);
Dap(Thr);
Ser(Me);
Asp;
or Asn;
then P11 is Ala;
Ser;
Ser(Me);
Thr;
Asn;
Asp;
or DAla;
and
wherein said 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.

128 more elements

A method for the treatment of infections caused by gram-negative bacteria or for the treatment or prevention of the onset of diseases related to such infections, comprising:

administering a composition to a subject in need thereof,
wherein said infections relate to respiratory diseases or skin or soft tissue diseases or gastrointestinal diseases or eye diseases or ear diseases or CNS diseases or bone diseases or cardiovascular diseases or genitourinary diseases, or nosocomial infections, or catheter-related and non-catheter-related infections, or urinary tract infections, or bloodstream infections,
wherein said composition contains a compound of the general formula (I) or a mixture of compounds of general formula (I) and at least one pharmaceutically inert carrier,
wherein general formula (I) is
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
T1 is DPro;
T2 is Pro;
Pro((3S)OH);
Pro((4S)OBn);
Pic;
Oic;
or Tic(7OH);
P1 is Ala(CF3);
Ala(2ClPhUr);
Ala(4ClPhUr);
Leu;
Ile;
Val;
Nva;
Trp;
Phe, Tyr;
Tza;
or Thr;
P2 is Ala;
Abu;
Ala(2ClPhUr);
Ala(3PyrMeUr);
Ala(4butoxyPhUr);
Ala(iPrUr);
Dab(2PyrMe);
Dap;
Dap(2,3-OHpropionyl);
Dap(AcThr);
Dap(iPr);
Dap(Thr);
Ser;
Ser(Me);
Hse;
Thr;
alloThr;
Asp;
Asn;
or Gly;
P3 is Chg;
Cha;
tBuGly;
Phe;
Phe(4NH2);
Phe(4F);
Tyr(3F);
Phe(4CF3);
Tyr;
Tyr(Me);
or Trp;
P4 is Dab;
Dab(2PyrMe);
Dap;
Orn;
or Arg;
P5 is Lys;
Orn;
Orn(iPr);
Dap;
Dab;
or Arg;
P6 is Dab;
DDab;
or Pip;
P7 is Dab;
Dab(2PyrMe);
Dap;
Orn;
Arg;
or DDab;
P8 is Trp;
P9 is Hse;
Dab;
Dap;
Arg;
or Lys;
P10 is tBuGly;
Ile;
Val;
Nva;
Chg;
Cha;
Trp;
Tyr;
Tyr(Me);
or Phg;
P11 is Ala;
Ser;
Ser(Me);
Tza;
Agp;
Tyr;
Dab;
Thr;
Asn;
Asp;
or DAla;
and
P12 is Ser;
Thr;
Dap;
Ala(iPrUr);
Leu;
or Tyr;
or a pharmaceutically acceptable salt thereof;
with the proviso that
if P2 is Ala(2ClPhUr);
Ala(3PyrMeUr);
Ala(4butoxyPhUr);
Ala(iPrUr);
Dab(2PyrMe);
Dap;
Dap(2,3-OHpropionyl);
Dap(AcThr);
Dap(iPr);
Dap(Thr);
Ser(Me);
Asp;
or Asn;
then P5 is Ala;
Ser;
Ser(Me);
Thr;
Asn;
Asp;
or DAla.

128 more elements

A method for disinfecting or preserving foodstuffs, cosmetics, medicaments or other nutrient-containing materials against gram-negative bacteria, comprising the step:

adding a composition to foodstuffs, cosmetics, medicaments or other nutrient-containing materials, thereby disinfecting or preserving said foodstuffs, cosmetics, medicaments or other nutrient-containing materials,
wherein said composition contains a compound of the general formula (I) or a mixture of compounds of general formula (I) and at least one pharmaceutically inert carrier,
wherein general formula (I) is
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
T1 is DPro;
T2 is Pro;
Pro((3S)OH);
Pro((4S)OBn);
Pic;
Oic;
or Tic(7OH);
P1 is Ala(CF3);
Ala(2ClPhUr);
Ala(4ClPhUr);
Leu;
Ile;
Val;
Nva;
Trp;
Phe, Tyr;
Tza;
or Thr;
P2 is Ala;
Abu;
Ala(2ClPhUr);
Ala(3PyrMeUr);
Ala(4butoxyPhUr);
Ala(iPrUr);
Dab(2PyrMe);
Dap;
Dap(2,3-OHpropionyl);
Dap(AcThr);
Dap(iPr);
Dap(Thr);
Ser;
Ser(Me);
Hse;
Thr;
alloThr;
Asp;
Asn;
or Gly;
P3 is Chg;
Cha;
tBuGly;
Phe;
Phe(4NH2);
Phe(4F);
Tyr(3F);
Phe(4CF3);
Tyr;
Tyr(Me);
or Trp;
P4 is Dab;
Dab(2PyrMe);
Dap;
Orn;
or Arg;
P5 is Lys;
Orn;
Orn(iPr);
Dap;
Dab;
or Arg;
P6 is Dab;
DDab;
or Pip;
P7 is Dab;
Dab(2PyrMe);
Dap;
Orn;
Arg;
or DDab;
P8 is Trp;
P9 is Hse;
Dab;
Dap;
Arg;
or Lys;
P10 is tBuGly;
Ile;
Val;
Nva;
Chg;
Cha;
Trp;
Tyr;
Tyr(Me);
or Phg;
P11 is Ala;
Ser;
Ser(Me);
Tza;
Agp;
Tyr;
Dab;
Thr;
Asn;
Asp;
or DAla;
and
P12 is Ser;
Thr;
Dap;
Ala(iPrUr);
Leu;
or Tyr;
or a pharmaceutically acceptable salt thereof;
with the proviso that
if P2 is Ala(2ClPhUr);
Ala(3PyrMeUr);
Ala(4butoxyPhUr);
Ala(iPrUr);
Dab(2PyrMe);
Dap;
Dap(2,3-OHpropionyl);
Dap(AcThr);
Dap(iPr);
Dap(Thr);
Ser(Me);
Asp;
or Asn;
then P5 is Ala;
Ser;
Ser(Me);
Thr;
Asn;
Asp;
or DAla.

127 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/791,087Filed 23 Oct 2017 · division
Priority: EP 1300165630 Mar 2013
Published: US 2018/0044380 A115 Feb 2018
Granted: 6 Aug 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification27 codes

C07K 7/64
Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof: cyclic peptides containing only normal peptide links
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/12
Drugs for disorders of the alimentary tract or the digestive system: antidiarrhoeals

Family

PCT/EP2014/056278Parent of this division · filed 28 Mar 2014
US 2018/0044380 A1Pre-grant publication · published 15 Feb 2018
Application14/781,247Parent of this division
US 9,938,322 B2Parent of this division
US 2016/0052971 A1Published application
US 10,370,411 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

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