US 2005/0239693 A1 · Template-fixed peptidomimetics with antibacterial activity

Abstract

Template-fixed β-hairpin peptidomimetics of the general formula wherein Z is a template-fixed chain of 12 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid) are Gly, or Pro, or of certain types which, as the remaining symbols in the above formula, are defined in the description and the claims, and salts thereof, have the property to selectively inhibit the growth of or to kill microorganisms such as Pseudomonas aeruginosa and Acinetobacter. They can be used as disinfectants for foodstuffs, cosmetics, medicaments or other nutrient-containing materials, or as medicaments to treat or prevent infections. These β-hairpin peptidomimetics can be manufactured by processes which are based on a mixed solid- and solution phase synthetic strategy.

Compounds of the general formula

wherein
is a group of one of the formulae
wherein
is the residue of an L-α-amino acid with B being a residue of formula —NR20CH(R71)— or the one of the groups A1 to A69 as defined hereinafter;
is a group of one of the formulae
R1 is H;
lower alkyl;
or aryl-lower alkyl;
R2 is H;
alkyl;
alkenyl;
—(CH2)m(CHR61)sOR55;
—(CH2)m(CHR61)sSR56;
—(CH2)m(CHR61)sNR33R34;
—(CH2)m(CHR61)sOCONR33 R75;
—(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)sC6H4R8;
R3 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;
R4 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)p(CHR61)sCOOR57;
—(CH2)p(CHR61)sCONR58R59;
—(CH2)p(CHR61)sPO(OR60)2;
—(CH2)p(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R5 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;
R6 is H;
alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH2)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR 20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
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)5PO(OR)2;
—(CH2)r(CHR61)sSO2R62;
or —(CH2)r(CHR61)sC6H4R8;
R8 is H;
Cl;
F;
CF3;
NO2;
lower alkyl;
lower alkenyl;
aryl;
aryl-lower alkyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH2)o(CHR61)NR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR 33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)s(CHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sCOR64;
R9 is alkyl;
alkenyl;
—(CH2)o(CHR6)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)sSO2R6;
or —(CH2)o(CHR61)sC6H4R8;
R10 is alkyl;
alkenyl;
—(CH2)o(CHR6)sOR55;
—(CH2)o(CHR61),SR56;
—(CH2)o(CHR6)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;
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)sCONR58 R59;
—(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(CHR61)sCOOR57;
—(CH2)r(CHR61)sCONR58R59;
—(CH2)r(CHR61)sPO(OR60)2;
—(CH2)r(CHR61)sSO2R62;
or —(CH2)(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(OR61)2;
—(CH2)q(CHR61)sSO2R62;
or —(CH2)q(CHR61)sC6H4R8;
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(OR61)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R17 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)sC6H4R8;
R18 is alkyl;
alkenyl;
—(CH2)p(CHR61)sOR55;
—(CH2)p(CHR)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;
alkenyl;
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)sNR20OCONR33R82;
—(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)oOR55;
—(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(OR61)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(CHR6 )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)sCONR58R59;
—(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)sSO2R62;
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(OR61)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(CHR6 )sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R30 is H;
alkyl;
alkenyl;
or aryl-lower alkyl;
R31 is H;
alkyl;
alkenyl;
—(CH2)p(CHR61)sOR55;
—(CH2)p(CHR61)sNR33R34;
—(CH2)p(CHR61)sOCONR33R75;
—(CH2)p(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;
R32 is H;
lower alkyl;
or aryl-lower alkyl;
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)s—CONR58R59, —(CH2)o(CHR61)sPO(OR(60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R34 is H;
lower alkyl;
aryl, or aryl-lower alkyl;
R33 and R34 taken together can form:
—(CH2)2-6—;
—(CH2)2O(CH2)2—;
—(CH2)2S(CH2)2—;
or —(CH2)2NR57(CH2)2—;
R35 is H;
alkyl;
alkenyl;
—(CH2)m(CHR61)sOR55;
—(CH2)m(CHR61)sNR33R34;
—(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)p(CHR61)sC6H4R8;
R36 is H, alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)p(CHR61)sNR33R34;
—(CH2)p(CHR61)sOCONR33R75;
—(CH2)p(CHR61)NR20CONR33R82;
—(CH2)p(CHR61)sCOOR57;
—(CH2)p(CHR61)sCONR58R59;
—(CH2)p(CHR61)sPO(OR60)2;
—(CH2)p(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R37 is H;
F;
Br;
Cl;
NO2;
CF3;
lower alkyl;
—(CH2)p(CHR61)sOR55;
—(CH2)p(CHR61)sNR33R34;
—(CH2)p(CHR61)sOCONR33R75;
—(CH2)p(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;
R38 is H;
F;
Br;
Cl;
NO2;
CF3;
alkyl;
alkenyl;
—(CH2)p(CHR61)sOR55;
—(CH2)p(CHR61)sNR33R34;
—(CH2)p(CHR61)sOCONR33R75;
—(CH2)p(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;
R39 is H;
alkyl;
alkenyl;
or aryl-lower alkyl;
R40 is H;
alkyl;
alkenyl;
or aryl-lower alkyl;
R41 is H;
F;
Br;
Cl;
NO2;
CF3;
alkyl;
alkenyl;
—(CH2)p(CHR61)sOR55;
—(CH2)p(CHR61)sNR33R34;
—(CH2)p(CHR61)sOCONR33R75;
—(CH2)p(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;
R42 is H;
F;
Br;
Cl;
NO2;
CF3;
alkyl;
alkenyl;
—(CH2)p(CHR61)sOR55;
—(CH2)p(CHR61)sNR33R34;
—(CH2)p(CHR61)sOCONR33R75;
—(CH2)p(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;
R43 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;
R44 is alkyl;
alkenyl;
—(CH2)r(CHR61)sOR55;
—(CH2)r(CHR61)sSR56;
—(CH2)o(CHR61)sNR33R34;
—(CH2)r(CHR61)sOCONR33R75;
—(CH2)r(CHR61)sNR20CONR33R82;
—(CH2)r(CHR61)sCOOR57;
—(CH2)r(CHR61)sCONR58R59;
—(CH2)r(CHR61)sPO(OR60)2;
—(CH2)r(CHR61)sSO2R62;
or —(CH2)r(CHR61)sC6H4R8;
R45 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)s(CHR61)sCONR58R59;
—(CH2)s(CHR61)sPO(OR60)2;
—(CH2)s(CHR61)sSO2R62;
or —(CH2)s(CHR61)sC6H4R8;
R46 is H;
alkyl;
alkenyl;
or —(CH2)o(CHR61)pC6H4R8;
R47 is H;
alkyl;
alkenyl;
or —(CH2)o(CHR61)sOR55;
R48 is H;
lower alkyl;
lower alkenyl;
or aryl-lower alkyl;
R49 is H;
alkyl;
alkenyl;
—(CHR61)sCOOR57;
(CHR6l)sCONR58R59;
(CHR61)sPO(OR60)2;
—(CHR61)sSOR62;
or —(CHR61)sC62H4R8;
R50 is H;
lower alkyl;
or aryl-lower alkyl;
R51 is H;
alkyl;
alkenyl;
—(CH2)m(CHR61)sOR55;
—(CH2)m(CHR61)sSR56;
—(CH2)o(CHR61)sNR33R34;
—(CH2)m(CHR61)sOCONR33R75;
—(CH2)m(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)pPO(OR60)2;
—(CH2)p(CHR61)sSO2R62;
or —(CH2)p(CHR61)sC6H4R8;
R52 is H;
alkyl;
alkenyl;
—(CH2)m(CHR61)sOR55;
—(CH2)m(CHR61)sSR56;
—(CH2)m(CHR61)sNR33R34;
—(CH2)m(CHR61)sOCONR 33R75;
—(CH2)m(CHR61)sNR2OCONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)o(CHR61)pPO(OR60)2;
—(CH2)p(CHR61)sSO2R62;
or —(CH2)p(CHR61)sC6H4R8;
R53 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)pPO(OR60)2;
—(CH2)p(CHR61)sSO2R62;
or —(CH2)p(CHR61)sC6H4R8;
R54 is H;
alkyl;
alkenyl;
—(CH2)m(CHR61)sOR55;
—(CH2)m(CHR61)sNR33R34;
—(CH2)m(CHR61)sOCONR33R75;
—(CH2)m(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)COOR57;
—(CH2)o(CHR61)sCONR58R59;
or —(CH2)o(CHR61)sC6H4R8;
R55 is H;
lower alkyl;
lower alkenyl;
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;
aryl-lower alkyl;
—(CH2)m(CHR61)sOR57;
—(CH2)m(CHR61)sNR34R63;
—(CH2)m(CHR61)sOCONR 75R82;
—(CH2)o(CHR61)sNR20CONR78R82;
—(CH2)o(CHR61)s—COR64;
or —(CH2)o(CHR61)sCONR58R59;
R57 is H;
lower alkyl;
lower alkenyl;
aryl lower alkyl;
or heteroaryl lower alkyl;
R58 is H;
lower alkyl;
lower alkenyl;
aryl;
heteroaryl;
aryl-lower alkyl;
or heteroaryl-lower alkyl;
R59 is H;
lower alkyl;
lower alkenyl;
aryl;
heteroaryl;
aryl-lower alkyl;
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;
aryl;
or aryl-lower alkyl;
R61 is alkyl;
alkenyl;
aryl;
heteroaryl;
aryl-lower alkyl;
heteroaryl-lower alkyl;
—(CH2)mOR55;
—(CH2)mNR33R34;
—(CH2)mOCONR75R82;
—(CH2)mNR20CONR78R82;
—(CH2)oCOOR37;
—(CH2)oNR58R59;
or —(CH2)oPO(COR60)2;
R62 is lower alkyl;
lower alkenyl;
aryl, heteroaryl;
or aryl-lower alkyl;
R63 is H;
lower alkyl;
lower alkenyl;
aryl, heteroaryl;
aryl-lower alkyl;
heteroaryl-lower alkyl;
—COR64;
—COOR57;
—CONR58R59;
—SO2R62;
or —PO(OR60)2;
R34and R63 taken together can forn:
—(CH2)2-6—;
—(CH2)2O(CH2)2—;
—(CH2)2S(CH2)2—;
or —(CH2)2NR57(CH2)2—;
R64 is H;
lower alkyl;
lower alkenyl;
aryl;
heteroaryl;
aryl-lower alkyl;
heteroaryl-lower alkyl;
—(CH2)p(CHR61)sOR65;
—(CH2)p(CHR61)sSR66;
or —(CH2)p(CHR61)sNR34R63;
—(CH2)p(CHR61)sOCONR75R82;
—(CH2)p(CHR61)sNR20CONR78R82;
R65 is H;
lower alkyl;
lower alkenyl;
aryl, aryl-lower alkyl;
heteroaryl-lower alkyl;
—COR57;
—COOR57;
or —CONR58R59;
R66 is H;
lower alkyl;
lower alkenyl;
aryl;
aryl-lower alkyl;
heteroaryl-lower alkyl;
or —CONR58R59;
mis 2-4;
o is 0-4;
p is 1-4;
q is 0-2;
r is 1 or 2;
s is 0 or 1;
Z is a chain of 12 α-amino acid residues, the positions of said amino acid residues in said chain being counted starting from the N-terminal amino acid, whereby these amino acid residues are, depending on their position in the chain, Gly or Pro, or of formula —A—CO—, or of formula —B—CO—, or of one of the types
C:
—NR20CH(R72)CO—;
D:
—NR20CH(R73)CO—;
E:
—NR20CH(R74)CO—;
F:
—NR20CH(R84)CO—;
and
H:
—NR20—CH(CO—)—(CH2)4-7—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—;
R71 is H;
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)—C6R67R68R69R70R76;
R72 is H;
lower alkyl;
lower alkenyl;
—(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)pC6H4N═C(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)pC(═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)pC6H4NR80C(═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)pNR80OCONR78R79;
or —(CH2)pC6H4NR80CONR78R79;
R75 is lower alkyl;
lower alkenyl;
or aryl-lower alkyl;
R33 and R75 taken together can form:
—(CH2)2-6—;
—(CH2)2O(CH2)2—;
—(CH2)2S(CH2)2—;
or —(CH2)2NR57(CH2)2—;
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;
aryl-lower alkyl;
—(CH2)oOR72;
—(CH2)oSR72;
—(CH2)oNR33R34;
—(CH2)oOCONR33R75;
—(CH2)oNR20CONR33R82;
—(CH2)sCOOR75;
—(CH2)oCONR58R59;
—(CH2)oPO(OR60)2;
—(CH2)pSO2R62;
or —(CH2)oCOR64;
R77 is —C6R67R68R69R70R76;
or a heteroaryl group of one of the formulae
R78 is H;
lower alkyl;
aryl;
or aryl-lower alkyl;
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;
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;
or aryl-lower alkyl;
R82 is H;
lower alkyl;
aryl;
heteroaryl;
or aryl-lower alkyl;
R33 and R82 taken together can form:
—(CH2)2-6—;
—(CH2)2O(CH2)2—;
—(CH2)2S(CH2)2—;
or —(CH2)2NR57(CH2)2—;
R83 is H;
lower alkyl;
aryl;
or —NR 78R79;
R84 is —(CH2)m(CHR61)sOH;
—(CH2)pCONR78R79;
—(CH2)pNR80CONR78R79;
—(CH2)pC6H4CONR78R79;
or —(CH2)pC6H4NR8OCONR78R79;
R85 is lower alkyl;
or lower alkenyl;
with the proviso that in said chain of 12 α-amino acid residues Z the amino acid residues in positions 1 to 12 are:
P1:
of type C or of type D or of type E or of type F, or the residue is Pro;
P2:
oftype D;
P3:
of type C, or of type D, or the residue is Pro;
P4:
of type C, or of type D, or of type E;
P5:
of type E, or of type D, or of type C, or of type F, or the residue is Gly or Pro;
P6:
of type E, or of type F or of formula —A—CO—, or the residue is Gly;
P7:
of type C, or of type E or of type F or of formula —B—CO—;
P8:
of type D, or of type C, or of type F, or the residue is Pro;
P9:
of type C, or of type E or of type D or of type F;
P10:
of type F, or of type D or of type C, or the residue is Pro;
P11:
of type E or of type D or of type C or of type F;
and
P12:
of type C or of type D or of type E or of type F, or the residue is Pro;
or
P4 and P9 and/or P2 and P11, taken together, can form a group of type H;
and at P6 and P7 also D-isomers being possible;
with the further proviso that
the amino acid residue in P4 is of type C;
and/or
the amino acid residue in P5 is of type F;
and/or
the amino acid residue in P7 is of type C;
and/or
the amino acid residue in P8 is of type F;
and/or
the amino acid residue in P9 is of type C;
and/or
the amino acid residue in P10 is of type F;
and/or
the amino acid residue in P11 is of type C or of type F;
and pharmaceutically acceptable salts thereof.

916 more elements

Template-fixed peptidomimetics with antibacterial activity

Life of this patent

Template-fixed peptidomimetics with antibacterial activity

Life of this patent

Abstract

Claims35