US 8,895,499 B2 · β-hairpin peptidomimetics

Abstract

β-Hairpin peptidomimetics of the general formula Cyclo(-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-), enantiomers and pharmaceutically acceptable salts thereof, with Xaa1-Xaa14 being amino acid residues of certain types which are defined in the description and the claims, have anti-infective activity, e.g. to selectively inhibit the growth of or to kill microorganisms such as Bacillus subtilis and/or Shigella boydii. 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.

Compounds of the general formula Cyclo(-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-), wherein the amino acid residues Xaa1 to Xaa14 are:

Xaa1:
amino acid residue of type C, or of type D,
as described herein below;
Xaa2:
amino acid residue of type E,
as described herein below;
Xaa3:
amino acid residue of type C, or of type F,
as described herein below;
Xaa4:
amino acid residue of type C, or of type E,
as described herein below;
Xaa5:
amino acid residue of type C,
as described herein below;
Xaa6:
amino acid residue of type E, as described herein below;
or the D-isomer of an amino acid residue of type E, as described herein below;
Xaa7:
amino acid residue of type F,
as described herein below, or Gly;
Xaa8:
amino acid residue of type E,
as described herein below;
Xaa9:
amino acid residue of type E,
as described herein below;
Xaa10:
amino acid residue of type C, or of type F,
as described herein below;
Xaa11:
amino acid residue of type E, or of type F,
as described herein below;
Xaa12:
amino acid residue of type C, or of type E,
or of type F, as described herein below;
Xaa13:
amino acid residue of formula -A-CO—,
as described herein below;
Xaa14:
amino acid residue of formula —B—CO—,
as described herein below;
with the proviso that if
Xaa9 is an amino acid residue of type E,
as described herein below,
then Xaa9 is Dab;
and/or if
Xaa12 is an amino acid residue of type F,
as described herein below,
then Xaa12 is Gln;
and/or
at least two of the amino acid residues of Cyclo(-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-) are non-canonical amino acid residues,
as described herein below;
or
compounds of the general formula Cyclo(-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-), wherein the amino acid residues Xaa1 to Xaa14 are:
Xaa1:
amino acid residue of type D,
as described herein below;
Xaa2:
amino acid residue of type E,
as described herein below;
Xaa3:
amino acid residue of type C, or of type F,
as described herein below;
Xaa4:
amino acid residue of type E,
as described herein below;
Xaa5:
amino acid residue of type C,
as described herein below;
Xaa6:
amino acid residue of type E, or the D-isomer of an amino acid residue of type E,
as described herein below;
Xaa7:
amino acid residue of type C, or of type D,
or of type E, or of type F,
as described herein below, or Gly;
Xaa8:
amino acid residue of type F,
as described herein below;
Xaa9:
amino acid residue of type E,
as described herein below;
Xaa10:
amino acid residue of type C, or of type D,
or of type F, as described herein below;
Xaa11:
amino acid residue of type E, or or type F,
as described herein below;
Xaa12:
amino acid residue of type C or of type E,
as described herein below;
Xaa13:
amino acid residue of formula -A-CO—,
as described herein below;
Xaa14:
amino acid residue of formula —B—CO—,
as described herein below;
with the proviso that if
Xaa7 is an amino acid residue of type F,
as described herein below,
then Xaa7 is Gln or Thr;
and/or if
Xaa10 is an amino acid residue of type F,
as described herein below,
then Xaa10 is Ser;
and/or
at least one of the amino acid residues of Cyclo(-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-) is a non-canonical amino acid residue,
as described herein below;
or
compounds of the general formula Cyclo(-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-), wherein the amino acid residues Xaa1 to Xaa14 are:
Xaa1:
amino acid residue of type D,
as described herein below;
Xaa2:
amino acid residue of type E,
as described herein below;
Xaa3:
amino acid residue of type C,
as described herein below;
Xaa4:
amino acid residue of type E,
as described herein below;
Xaa5:
amino acid residue of type C,
as described herein below;
Xaa6:
amino acid residue of type E, as described herein below, or the D-isomer of an amino acid residue of type E, as described herein below;
Xaa7:
amino acid residue of type F,
as described herein below;
Xaa8:
amino acid residue of type D,
as described herein below;
Xaa9:
amino acid residue of type E,
as described herein below;
Xaa10:
amino acid residue of type F,
as described herein below;
Xaa11:
amino acid residue of type E,
as described herein below;
Xaa12:
amino acid residue of type E,
as described herein below;
Xaa13:
amino acid residue of formula -A-CO—,
as described herein below;
Xaa14:
amino acid residue of formula —B—CO—,
as described herein below;
or
compounds of the general formula Cyclo(-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14- wherein the amino acid residues Xaa1 to Xaa14 are:
Xaa1:
amino acid residue of type D,
as described herein below;
Xaa2:
amino acid residue of type E,
as described herein below;
Xaa3:
amino acid residue of type E,
as described herein below;
Xaa4:
amino acid residue of type E,
as described herein below;
Xaa5:
amino acid residue of type C,
as described herein below, or Gly;
Xaa6:
amino acid residue of type E, or of type F,
as described herein below, or the D-isomer of an amino acid residue of type E, as described herein below, or —B—CO—, as described herein below or Gly;
Xaa7:
amino acid residue of type E, as described herein below, or the D-isomer of an amino acid residue of type E, as described herein below, or Gly;
Xaa8:
amino acid residue of type F,
as described herein below, or Gly;
Xaa9:
amino acid residue of type E,
as described herein below;
Xaa10:
amino acid residue of type F,
as described herein below;
Xaa11:
amino acid residue of type E,
as described herein below;
Xaa12:
amino acid residue of type E,
as described herein below;
Xaa13:
amino acid residue of formula -A-CO—,
as described herein below;
Xaa14:
amino acid residue of formula —B—CO—,
as described herein below;
with the proviso that at least one of the amino acid residues of Cyclo(-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-) is a non-canonical amino acid residue, as described herein below;
or
compounds of the general formula Cyclo(-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-), wherein the amino acid residues Xaa1 to Xaa14 are:
Xaa1:
amino acid residue of type E,
as described herein below;
Xaa2:
amino acid residue of type E,
as described herein below;
Xaa3:
amino acid residue of type C, or of type F,
as described herein below;
Xaa4:
amino acid residue of type E,
as described herein below;
Xaa5:
amino acid residue of type C, or of type F,
as described herein below;
Xaa6:
amino acid residue of type E, as described herein below, or the D-isomer of an amino acid residue of type E, as described herein below;
Xaa7:
Gly;
Xaa8:
amino acid residue of type E, or of type F,
as described herein below;
Xaa9:
amino acid residue of type E,
as described herein below;
Xaa10:
amino acid residue of type C, or of type F,
as described herein below;
Xaa11:
amino acid residue of type E,
as described herein below;
Xaa12:
amino acid residue of type E,
as described herein below;
Xaa13:
amino acid residue of formula -A-CO—,
as described herein below;
Xaa14:
amino acid residue of formula —B—CO—,
as described herein below;
with the proviso that at least two of the amino acid residues of Cyclo(-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-) are non-canonical amino acid residues;
or
compounds of the general formula Cyclo(-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-), wherein the amino acid residues Xaa1 to Xaa14 are:
Xaa1:
amino acid residue of type E,
as described herein below;
Xaa2:
amino acid residue of type C, or of type F,
as described herein below;
Xaa3:
amino acid residue of type E,
as described herein below;
Xaa4:
amino acid residue of type E,
as described herein below;
Xaa5:
amino acid residue of type C,
as described herein below;
Xaa6:
amino acid residue of type E,
as described herein below;
Xaa7:
Gly;
Xaa8:
amino acid residue of type F,
as described herein below;
Xaa9:
amino acid residue of type E,
as described herein below;
Xaa10:
amino acid residue of type E, or of type F,
as described herein below;
Xaa11:
amino acid residue of type E, or of type F,
as described herein below;
Xaa12:
amino acid residue of type E,
as described herein below;
Xaa13:
amino acid residue of formula -A-CO—,
as described herein below;
Xaa14:
amino acid residue of formula —B—CO—,
as described herein below;
the amino acid residues Xaa2 and Xaa11, taken together,
can form an amino acid residue of type H,
as described herein below;
with the proviso that at least one of the amino acid residues of Cyclo(-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-) are non-canonical amino acid residues;
or
compounds of the general formula Cyclo(-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-), wherein the amino acid residues Xaa1 to Xaa14 are:
Xaa1:
amino acid residue of type, E or of type F,
as described herein below;
Xaa2:
amino acid residue of type C, or of type D, or of type E, or of type F, as described herein below;
Xaa3:
amino acid residue of type E, as described herein below, or the D-isomer of an amino acid residue of type E, as described herein below, or Gly;
Xaa4:
amino acid residue of type C, or of type D, or of type E, or of type F, as described herein below;
Xaa5:
amino acid residue of type E,
as described herein below;
Xaa6:
amino acid residue of type E, or of type F,
as described herein below, or Gly;
Xaa7:
amino acid residue of type D, or of type E, or of type F, as described herein below, or Gly;
Xaa8:
amino acid residue of type E,
as described herein below;
Xaa9:
amino acid residue of type D, or of type E,
as described herein below;
Xaa10:
amino acid residue of type C, or of type D, or of type E, or of type F, as described herein below;
Xaa11:
amino acid residue of type D, or of type E, or of type F, as described herein below, or Gly;
Xaa12:
amino acid residue of type C, or of type D, or of type E, or of type F, as described herein below;
Xaa13:
amino acid residue of formula -A-CO—,
as described herein below;
Xaa14:
amino acid residue of formula —B—CO—,
as described herein below;
the amino acid residues Xaa2 and Xaa11, taken together,
can form an amino acid residue of type H,
as described herein below;
with the proviso that at least two of the amino acid residues of Cyclo(-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-) are non-canonical amino acid residues;
—B—CO— is Gly, NMeGly or the residue of an L-α-amino acid with B being a residue of formula —NR20CH(R71)—, or —NR20CH(R72)—, or —NR20CH(R73)—, or —NR20CH(R74)—, or —NR20CH(R84)—, or the enantiomer of one of the groups A1 to A69 as defined hereinafter;
A of -A-CO— is a group of one of the formulae
R1 is H;
lower alkyl;
lower cycloalkyl;
lower alkyl-aryl or aryl-lower alkyl;
R2 is H;
alkyl;
alkenyl;
—(CH2)p(CHR61)sOR55;
—(CH2)p(CHR61)sSR5;
—(CH2)p(CHR61)sNR33R34;
—(CH2)p(CHR61)OCONR33R75;
—(CH2)p(CHR61)NR20CONR33R82;
—(CH2)o(CHR61)sCOO57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sSR77;
R3 is alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH2)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R4 is H;
alkyl;
alkenyl;
—(CH2)m(CHR61)sOR55;
—(CH2)m(CHR61)sSR56;
—(CH2)m(CHR61)sR33R34;
—(CH2)m(CHR61)sOCONR33R75;
—(CH2)m(CHR61)sNR20CONR33R82;
—(CH2)p(CHR61)sCOOR57;
—(CH2)p(CHR61)sCONR58R59;
—(CH2)p(CHR61)sPO(OR60)2;
—(CH2)p(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R5 is H;
alkyl;
alkenyl;
—(CH2)m(CHR61)sOR55;
—(CH2)m(CHR61)sSR56;
—(CH2)m(CHR61)sNR33R34;
—(CH2)m(CHR61)sOCONR33R75;
—(CH2)m(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)COOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H48;
R6 is H;
alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH2)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)6C6H48;
R7 is alkyl;
alkenyl;
—(CH2)q(CHR61)sOR55;
—(CH2)q(CHR61)sNR33R34;
—(CH2)q(CHR61)sOCONR33R75;
—(CH2)q(CHR61)sNR20CONR33R82;
—(CH2)r(CHR61)sCOOR57;
—(CH2)r(CHR61)sCONR58R59;
—(CH2)r(CHR61)sO(OR60)2;
—(CH2)r(CHR61)sSO2R62;
or —(CH2)r(CHR61)sC6H4R8;
R8 is H;
Cl;
F;
CF3;
NO2;
lower alkyl;
lower cycloalkyl;
lower alkenyl;
aryl;
lower alkyl-aryl;
aryl-lower alkyl;
—(CH2)o(CHR61)sR77
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH2)o(CHR61)NR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)COR64;
R9 is alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH2)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R10 is alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH2)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61) % CONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)C6H4R8;
R11 is H;
alkyl;
alkenyl;
—(CH2)m(CHR61)sOR55;
—(CH2)m(CHR61)sNR33R34;
—(CH2)m(CHR61)sOCONR33R75;
—(CH2)m(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R12 is H;
alkyl;
alkenyl;
—(CH2)m(CHR61)sOR55;
—(CH2)m(CHR61)sSR56;
—(CH2)m(CHR61)sNR33R34;
—(CH2)m(CHR61)sOCONR33R75;
—(CH2)m(CHR61)sNR20CONR33R82;
—(CH2)r(CHR6)sCOOR57;
—(CH2)r(CHR61)sCONR58R59;
—(CH2)r(CHR61)sPO(OR60)2;
—(CH2)r(CHR61)sSO2R62;
or —(CH2)r(CHR61)sC6H4R8;
R13 is alkyl;
alkenyl;
—(CH2)q(CHR61)sOR55;
—(CH2)q(CHR61)sSR56;
—(CH2)q(CHR61)sNR33R34;
—(CH2)q(CHR61)sOCONR33R75;
—(CH2)q(CHR61)sNR20CONR33R82;
—(CH2)q(CHR61)sCOOR57;
—(CH2)q(CHR61)sCONR58R59;
—(CH2)q(CHR61)sPO(OR60)2;
—(CH2)q(CHR61)sSO2R62;
or —(CH2)q(CHR61)C6H4R8;
R14 is H;
alkyl;
alkenyl;
—(CH2)m(CHR61)sOR55;
—(CH2)m(CHR61)sNR33R34;
—(CH2)m(CHR61)sOCONR33R75;
—(CH2)m(CHR61)sNR20CONR33R82;
—(CH2)q(CHR61)sCOOR57;
—(CH2)q(CHR61)sCONR58R59;
—(CH2)q(CHR61)sPO(OR60)2;
—(CH2)q(CHR61)sSOR62;
or —(CH2)q(CHR61)sC6H4R8;
R15 is alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH2)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R16 is alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH2)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R17 is alkyl;
alkenyl;
—(CH2)q(CHR61)sOR55;
—(CH2)q(CHR61)sSR16;
—(CH2)q(CHR61)sNR33R34;
—(CH2)q(CHR61)sOCONR33R75;
—(CH2)q(CHR61)sNR20CONR33R82;
—(CH2)q(CHR61)sCOR57;
—(CH2)q(CHR61)sCONR58R59;
—(CH2)q(CHR61)sPO(OR60)2;
—(CH2)q(CHR61)sSO2R62;
or —(CH2)q(CHR61)sC6H4R8;
R18 is alkyl;
alkenyl;
—(CH2)p(CHR61)sOR55;
—(CH2)p(CHR61)sSR56;
—(CH2)p(CHR61)sNR33R34;
—(CH2)p(CHR61)sOCONR33R75;
(CH2)p(CHR61)sNR20CONR33R82;
—(CH2)p(CHR61)sCOOR57;
—(CH2)p(CHR61)sCONR58R59;
—(CH2)p(CHR61)sPO(OR60)2;
—(CH2)p(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R19 is lower alkyl;
—(CH2)p(CHR61)sOR55;
—(CH2)p(CHR61)sSR56;
—(CH2)p(CHR61)sNR33R34;
—(CH2)p(CHR61)sOCONR33R75;
—(CH2)p(CHR61)sNR20CONR33R82;
—(CH2)p(CHR61)sCOOR57;
—(CH2)p(CHR61)sCONR58R59;
—(CH2)p(CHR61)sPO(OR60)2;
—(CH2)p(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
or
R18 and R19 taken together can form:
—(CH2)2-6—;
—(CH2)2O(CH2)2—;
—(CH2)2S(CH2)2—;
or —(CH2)2NR57(CH2)2—;
R20 is H;
alkyl;
lower cycloalkyl;
alkenyl;
lower alkyl-aryl;
or aryl-lower alkyl;
R21 is H;
alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH2)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R22 is H;
alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH2)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R23 is alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH2)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R24 is alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH2)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R25 is H;
alkyl;
alkenyl;
—(CH2)m(CHR61)sOR55;
—(CH2)m(CHR61)sSR56;
—(CH2)m(CHR61)sNR33R34;
—(CH2)m(CHR61)sOCONR33R75;
—(CH2)m(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R26 is H;
alkyl;
alkenyl;
—(CH2)m(CHR61)sOR55;
—(CH2)m(CHR61)sSR56;
—(CH2)m(CHR61)sNR33R34;
—(CH2)m(CHR61)sOCONR33R75;
—(CH2)m(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61):CONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
or
R25 and R26 taken together can form:
—(CH2)2-6—;
—(CH2)rO(CH2)r;
—(CH2)rS(CH2)r—;
or —(CH2)rNR57(CH2)r—;
R27 is H;
alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH2)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61), SO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R28 is alkyl;
alkenyl;
—(CH2)o(CHR61)s—OR55;
—(CH2)o(CHR61)sSR56;
—(CH2)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R29 is alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH2)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R33 is H;
alkyl, alkenyl;
—(CH2)m(CHR61)sOR55;
—(CH2)m(CHR61)sNR34R63;
—(CH2)m(CHR61)sOCONR75R82;
—(CH2)m(CHR61)sNR20CONR78R82;
—(CH2)o(CHR61)sCOR64;
—(CH2)o(CHR61)6—CONR58R59,
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R34 is H;
lower alkyl;
lower cycloalkyl;
lower alkyl-aryl;
aryl or aryl-lower alkyl;
or
R33 and R34 taken together can form:
—(CH2)2-6—;
—(CH2)2O(CH2)2—;
—(CH2)2S(CH2)2—;
or —(CH2)2NR57(CH2)2—;
R50 is H;
lower alkyl;
lower cycloalkyl;
lower alkyl-aryl;
or
aryl-lower alkyl;
R55 is H;
lower alkyl;
lower alkenyl;
lower cycloalkyl;
lower alkyl-aryl;
aryl-lower alkyl;
—(CH2)m(CHR61)sOR57;
—(CH2)m(CHR61)sNR34R63;
—(CH2)m(CHR61)sOCONR75R82;
—(CH2)m(CHR61)sNR20CONR78R82;
—(CH2)o(CHR61)s—COR64;
—(CH2)o(CHR61)COOR57;
or
—(CH2)o(CHR61)sCONR58R59;
R56 is H;
lower alkyl;
lower alkenyl;
lower alkyl-aryl;
aryl-lower alkyl;
—(CH2)m(CHR61)sOR57;
—(CH2)m(CHR61)sR34R63;
—(CH2)m(CHR61)sOCONR75R82;
—(CH2)m(CHR61)sNR20CONR78R82;
—(CH2)o(CHR61)s—COR64;
or
—(CH2)o(CHR61)sCONR58R59;
R57 is H;
lower alkyl;
lower alkenyl;
lower cycloalkyl;
lower alkyl-aryl;
aryl-lower alkyl;
lower alkyl-heteroaryl;
or heteroaryl-lower alkyl;
R58 is H;
lower alkyl;
lower alkenyl;
lower cycloalkyl;
lower alkyl-aryl;
aryl-lower alkyl;
lower alkyl-heteroaryl;
or heteroaryl-lower alkyl;
R59 is H;
lower alkyl;
lower alkenyl;
lower cycloalkyl;
lower alkyl-aryl;
aryl-lower alkyl;
lower alkyl-heteroaryl;
or heteroaryl-lower alkyl;
or
R58 and R59 taken together can form:
—(CH2)2-6—;
—(CH2)2O(CH2)2—;
—(CH2)2S(CH2)2—;
or —(CH2)2NR57(CH2)2—;
R60 is H;
lower alkyl;
lower alkenyl;
lower cycloalkyl;
lower alkyl-aryl;
aryl;
or aryl-lower alkyl;
R61 is alkyl;
alkenyl;
lower cycloalkyl;
lower alkyl-aryl;
lower alkyl-heteroaryl;
aryl;
heteroaryl;
aryl-lower alkyl;
heteroaryl-lower alkyl;
—(CH2)pOR55;
—(CH2)pNR33R34;
—(CH2)pOCONR75R82;
—(CH2)pNR20CONR78R82;
—(CH2)oCOOR37;
or —(CH2)oPO(OR60)2;
R62 is H;
lower alkyl;
lower alkenyl;
lower cycloalkyl;
lower alkyl-aryl;
lower alkyl-heteroaryl;
aryl;
heteroaryl;
aryl-lower alkyl;
or
heteroaryl-lower alkyl;
R63 is H;
lower alkyl;
lower alkenyl;
lower cycloalkyl;
lower alkyl-aryl;
lower alkyl-heteroaryl;
aryl;
heteroaryl;
aryl-lower alkyl;
or
heteroaryl-lower alkyl;
—COR64;
—COOR57;
—CONR58R59;
—SO2R62;
or —PO(OR60)2;
or
R34 and R63 taken together can form:
—(CH2)2-6—;
—(CH2)2O(CH2)2—;
—(CH2)2S(CH2)2—;
or —(CH2)2NR57(CH2)2—;
R64 is H;
lower alkyl;
lower alkenyl;
lower cycloalkyl;
lower alkyl-aryl;
lower alkyl-heteroaryl;
aryl;
heteroaryl;
aryl-lower alkyl;
or
heteroaryl-lower alkyl;
—(CH2)p(CHR61)sOR65;
—(CH2)p(CHR61)sSR66;
—(CH2)p(CHR61)sNR34R63;
—(CH2)p(CHR61)OCONR75R82;
or —(CH2)P(CHR61)sNR20CONR78R82;
R65 is H;
lower alkyl;
lower alkenyl;
lower cycloalkyl;
lower alkyl-aryl;
lower alkyl-heteroaryl;
aryl;
heteroaryl;
aryl-lower alkyl;
or
heteroaryl-lower alkyl;
—COR57;
—COOR57;
or —CONR58R59;
R66 is H;
lower alkyl;
lower alkenyl;
lower cycloalkyl;
lower alkyl-aryl;
lower alkyl-heteroaryl;
aryl;
heteroaryl;
aryl-lower alkyl;
or
heteroaryl-lower alkyl;
or —CONR58R59;
R67 is H;
Cl;
Br;
F;
NO2;
—NR34COR57;
—CF3;
CN;
—OCF3;
—OCHF2;
—OR57;
—SR62;
lower alkyl;
or
lower alkenyl;
R68 is H;
Cl;
Br;
F;
NO2;
—NR34COR57;
—CF3;
CN;
—OCF3;
—OCHF2;
—OR57;
—SR62;
lower alkyl;
or
lower alkenyl;
R69 is H;
Cl;
Br;
F;
NO2;
—NR34COR57;
—CF3;
CN;
—OCF3;
—OCHF2;
—OR57;
—SR62;
lower alkyl;
or
lower alkenyl;
R70 is H;
Cl;
Br;
F;
NO2;
—NR34COR57;
—CF3;
CN;
—OCF3;
—OCHF2;
—OR57;
—SR62;
lower alkyl;
or
lower alkenyl;
R71 is lower alkyl;
lower alkenyl;
—(CH2)p(CHR61)sOR75;
—(CH2)p(CHR61)sSR75;
—(CH2)p(CHR61)sNR33R34;
—(CH2)p(CHR61)sOCONR33R75;
—(CH2)p(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR75;
—(CH2)pCONR58R59;
—(CH2)pPO(OR62)2;
—(CH2)pSO2R62;
or
—(CH2)o—C6R67R68R69R70R76;
R72 is alkyl;
alkenyl;
lower cycloalkcyl;
—(CH2)p(CHR61)sOR85;
or
—(CH2)p(CHR61)sSR85;
R73 is —(CH2)OR77;
—(CH2)rO(CH2)OR77;
—(CH2)rS(CH2)oR77;
or
—(CH2)rNR20(CH2)OR77;
R74 is —(CH2)pNR78R79;
—(CH2)pNR77R80;
—(CH2)pC(═NR80)NR78R79;
—(CH2)pC(═NOR50)NR78R79;
—(CH2)pC(═NNR78R79)NR78R79;
—(CH2)pNR80C(═NR80)NR78R79;
—(CH2)pN═C(NR78R80)NR79R80;
—(CH2)pC6H4NR78R79;
—(CH2)pC6H4NR77R80;
—(CH2)pC6H4C(═NR80)NR78R79;
—(CH2)pC6H4C(═NOR50)NR78R79;
—(CH2)pC6H4C(═NNR78R79)NR78R79;
—(CH2)pC6H4NR80C(═NR80)NR78R79;
—(CH2)pC6H4C(═NR78R80)NR79R80;
—(CH2)rO(CH2)mNR78R79;
—(CH2)rO(CH2)mNR77R80;
—(CH2)rO(CH2)pC(═NR80)NR78R79;
—(CH2)rO(CH2)pC(═NOR50)NR78R79;
—(CH2)rO(CH2)p(═NNR78R79)NR78R79;
—(CH2)rO(CH2)mNR80C(═NR80)NR78R79;
—(CH2)rO(CH2)mN═C(NR78R80)NR79R80;
—(CH2)rO(CH2)pC6H4CNR78R79;
—(CH2)rO(CH2)pC6H4C(═NR80)NR78R79;
—(CH2)rO(CH2)pC6H4C(═NOR50)NR78R79;
—(CH2)rO(CH2)pC6H4C(═NNR78R79)NR78R79;
—(CH2)rO(CH2)pC6H4NR80(═NR80)NR78R79;
—(CH2)rS(CH2)mNR78R79;
—(CH2)rS(CH2)mNR77R80;
—(CH2)rS(CH2)pC(═NR80)NR78R79;
—(CH2)rS(CH2)pC(═NOR50)NR78R79;
—(CH2)rS(CH2)pC(═NNR78R79)NR78R79;
—(CH2)rS(CH2)mNR80C(═NR80)NR78R79;
—(CH2)rS(CH2)mN═C(NR78R80)NR79R80;
—(CH2)rS(CH2)pC6H4CNR78R79;
—(CH2)rS(CH2)pC6H4C(═NR80)NR78R79;
—(CH2)rS(CH2)pC6H4C(═NOR50)NR78R79;
—(CH2)rS(CH2)pC6H4C(═NNR78R79)NR78R79;
—(CH2)rS(CH2)pC6H4NR80C(═NR80)NR78R79;
—(CH2)pNR80COR64;
—(CH2)pNR80COR77;
—(CH2)pNR80CONR78R79;
or —(CH2)pC6H4NR80CONR78R79;
R75 is lower alkyl;
lower alkenyl;
lower cycloalkyl;
lower-alkyl-aryl;
or aryl-lower alkyl;
or
R33 and R75 taken together can form:
—(CH2)2-6—;
—(CH2)2O(CH2)2—;
—(CH2)2S(CH2)2—;
or —(CH2)2NR57(CH2)2—;
or
R75 and R82 taken together can form:
—(CH2)2-6—;
—(CH2)2O(CH2)2—;
—(CH2)2S(CH2)2—;
or —(CH2)2NR57(CH2)2—;
R76 is H;
lower alkyl;
lower alkenyl;
lower cycloalkyl;
lower-alkyl-aryl;
aryl-lower alkyl;
—(CH2)oOR72;
—(CH2)oSR72;
—(CH2)oNR33R34;
—(CH2)oOCONR33R75;
—(CH2)oNR20CONR33R81;
—(CH2)COOR75;
—(CH2)oCONR58R59;
—(CH2)oPO(OR60)2;
—(CH2)pSO2R62;
or
—(CH2)oCOR64;
R77 is —C6R67R68R69R70R76 with the proviso that at least two of R67, R68, R69 and R70 are H;
or a heteroaryl group of one of the formulae
R78 is H;
lower alkyl;
lower cycloalkyl;
lower alkyl-aryl;
aryl;
or aryl-lower alkyl;
or
R78 and R82 taken together can form:
—(CH2)2-6—;
—(CH2)2O(CH2)2—;
—(CH2)2S(CH2)2—;
or
—(CH2)2NR57(CH2)2—;
R79 is H;
lower alkyl;
lower alkyl-aryl;
aryl;
or
aryl-lower alkyl;
or
R78 and R79, taken together, can be —(CH2)2-7—;
—(CH2)2O(CH2)2—;
or —(CH2)2NR57(CH2)2—;
R80 is H;
or lower alkyl;
R81 is H;
lower alkyl;
lower cycloalkyl;
lower alkyl-aryl;
or
aryl-lower alkyl;
or
R33 and R81 taken together can form:
—(CH2)2-6—;
—(CH2)2O(CH2)2—;
—(CH2)2S(CH2)2—;
or
—(CH2)2NR57(CH2)2—;
R82 is H;
—CF3;
—OCF3;
—OCHF2;
lower alkyl;
aryl;
heteroaryl;
or aryl-lower alkyl;
R83 is H;
lower alkyl;
aryl;
or —NR78R79;
R84 is —(CH2)p(CHR61)sOH;
—(CH2)pCOOR80;
—(CH2)p(CHR61)sSH;
—(CH2)pCONR78R79;
—(CH2)pNR80CONR78R79;
—(CH2)pC6H4CONR78R79;
or —(CH2)pC6H4NR80CONR78R79;
R85 is lower alkyl;
or lower alkenyl;
R86 is R74;
—(CH2)OR77;
—(CH2)o—CHR33R75;
R84;
—[(CH2)u—X′]t—(CH2)vNR78R79;
—[(CH2)u—X′]t—(CH2)v—C(═NR80)NR78R79;
—[(CH2)u—X′]t—(CH2)vOR78;
—[(CH2)u—X′]t—(CH2)v—CONR78R79;
—[(CH2)u—X′]t—(CH2)v—NR80CONR78R79;
—[(CH2)u—X′]t—(CH2)vSR78 where X′ is —O—, —NR20—, —S—;
or —OCOO—, u is 1-3, t is 1-6, and v is 1-3;
m is 2-4;
o is 0-4;
p is 1-4;
q is 0-2;
r is 1 or 2;
s is 0 or 1;
the amino acid residue of type C is a residue of formula
—NR20CH(R72)CO—;
the amino acid residue of type D is a residue of formula
—NR20CH(R73)CO—;
the amino acid residue of type E is a residue of the formula —NR20CH(R74)CO—;
the amino acid residue of type F is a residue of the formula —NR20CH(R84)CO—;
the amino acid residue of type H is a residue of the one of the formulae —NR20—CH(CO—)-alkylene-CH(CO—)—NR20—;
—NR20—CH(CO—)-alkenylene-CH(CO—)—NR20—;
—NR20—CH(CO—)-alkynylene-CH(CO—)—NR20—;
—NR20—CH(CO—)—(CH2)pSS(CH2)p—CH(CO—)—NR20—;
—NR20—CH(CO—)—(—(CH2)pNR20CO(CH2)p—CH(CO—)—NR20—;
and
—NR20—CH(CO—)—(—(CH2)pNR20CONR20(CH2)p—CH(CO—)—NR20—;
non-canonical amino acid residues designate those amino acid residues being neither glycine nor the L- or D-isomers of alanine, arginine, aspartic acid, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
and pharmaceutically acceptable salts thereof.

1,124 more elements

β-hairpin peptidomimetics

Life of this patent

β-hairpin peptidomimetics

Life of this patent

Abstract

Claims16