US 8,895,695 B2 · Template-fixed beta-hairpin peptidomimetics with CXCR4 antagonizing activity

Abstract

Template-fixed β-hairpin peptidomimetics of the general formula (I) wherein Z is a template-fixed chain of 12, 14 or 18 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid), are Gly, NMeGly, Pro or Pip, 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 CXCR4 antagonizing properties. These β-hairpin peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

A compound of the general formula

wherein
is a group of one of the formulae
is Gly or the residue of an L-α-amino acid with B being a residue of formula —NR20CH(R71)— or the enantiomer of 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)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;
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)sSR55;
—(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)pCHR61)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)sNR20CONR33R82;
—(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)rCHR61)sPO(OR60)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)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)oCHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sCOR64;
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)oCHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R10 is alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)oCHR61)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)sCONR58R59;
—(CH2)oCHR61)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;
—(CH2r(CHR61)sSO2R62;
or —(CH2)r(CHR61)sC6H4R8;
R13 is alkyl;
alkenyl;
—(CH2)q(CHR61)sOR55;
—(CH2)q(CHR61)sSR56;
—(CH)q(CHR61)sNR33R34;
—(CH2)q(CHR61)sOCONR33R75;
—(CH2)q(CHR61)sNR20CONR33R82;
—(CH2)q(CHR61)sCOOR57;
—(CH2)q(CHR61)sCONR58R59;
—(CH2)qCHR61)sPO(OR60)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;
—m(CH2)m(CHR61)sNR20CONR33R82;
—(CH2)q(CHR61)sCOOR57;
—(CH2)q(CHR61)sCONR58R59;
—(CH2)qCHR61)sPO(OR60)2;
—(CH2)q(CHR61)sSOR62;
or —(CH2)q(CHR61)sC6H4R8;
R15 is alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)oCHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R16 is alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)oCHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R17 is alkyl;
alkenyl;
—(CH2)q(CHR61)sOR55;
—(CH2)q(CHR61)sSR56;
—(CH)q(CHR61)sNR33R34;
—(CH2)q(CHR61)sOCONR33R75;
—(CH2)q(CHR61)sNR20CONR33R82;
—(CH2)q(CHR61)sCOOR57;
—(CH2)q(CHR61)sCONR58R59;
—(CH2)qCHR61)sPO(OR60)2;
—(CH2)q(CHR61)sSO2R62;
or —(CH2)q(CHR61)sC6H4R8;
R18 is alkyl;
alkenyl;
—(CH2)p(CHR61)sOR55;
—(CH2)p(CHR61)sSR56;
—(CH)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;
—(CH2p(CHR61)sNR33R34;
—(CH2)p(CHR61)sOCONR33R75;
—(CH2)p(CHR61)sNR20CONR33R82;
—(CH2)p(CHR61)sCOOR57;
—(CH2)p(CHR61)sCONR58R59;
—(CH2)pCHR61)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)2(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)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)sR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o)CHR61)sCONR58R59;
—(CH2)oCHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R23 is alkyl;
alkenyl;
—(CH2)o(CHR61)sOR55;
—(CH2)o(CHR61)sSR56;
—(CH)o(CHR61)sNR33R34;
—(CH2)o(CHR61)sOCONR33R75;
—(CH2)o(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)oCHR61)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)oCHR61)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)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)oCHR61)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)oCHR61)sPO(OR60)2;
—(CH2)o(CHR61)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)oCHR61)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(OR60)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)2(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)pCHR61)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)sNR20CONR33R82;
—(CH2)p(CHR61)sCOOR57;
—(CH2)p(CHR61)sCONR58R59;
—(CH2)pCHR61)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(CHR1)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(CHR1)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(CHR1)sNR33R34;
—(CH2)p(CHR61)sOCONR33R75;
—(CH2)p(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH(CH2)(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(CHR1)sNR33R34;
—(CH2)p(CHR61)sOCONR33R75;
—(CH2)p(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR57;
—(CH2)o(CHR61)sCONR58R59;
—(CH2)oCHR61)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)oCHR61)sPO(OR60)2;
—(CH2)o(CHR61)sSO2R62;
or —(CH2)o(CHR61)sC6H4R8;
R44 is alkyl;
alkenyl;
—(CH2)r(CHR61)sOR55;
—(CH2)r(CHR61)sSR56;
—(CH)r(CHR61)sNR33R34;
—(CH2)r(CHR61)sOCONR33R75;
—(CH2)r(CHR61)sNR20CONR33R82;
—(CH2)r(CHR61)sCOOR57;
—(CH2)r(CHR61)sCONR58R59;
—(CH2)rCHR61)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)sCHR61)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;
(CHR61)sCONR58R59;
(CHR61)sPO(OR602;
—(CHR61)sSOR62;
or —(CHR61)sC6H4R8;
R50 is H;
lower alkyl;
or aryl-lower alkyl;
R51 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(OR6)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)sOCONR33R75;
—(CH2)mCHR61)sNR20CONR33R82;
—(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(OR6)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(CHR1)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)sOCONR75R82;
—(CH2)m(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;
13 (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 form:
—(CH2)2-6—;
—(CH2)2O(CH2)2—;
—(CH2)2(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(CHR61sN34R63;
—(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;
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;
Z is a chain of n α-amino acid residues, n being the integer 18 and 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 chains, Gly, NMeGly, Pro or Pip, 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—;
I:
—NR86CH2CO—;
R71 is lower alkyl;
lower alkenyl;
—(CH2)p(CHR61)sOR75;
—(CH2)p(CHR61)sSR75;
—(CH2)p(CHR61)sNR33R34;
—(CH2)p(CHR61)sOCONR33R75;
—(CH2p(CHR61)sNR20CONR33R82;
—(CH2)o(CHR61)sCOOR75;
—(CH2)pCONR58R59;
—(CH2)pPO(OR62)2;
13 (CH2)pSO2R62;
or —(CH2)o—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)NR8R79;
—(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)pNR80CONR78R79;
—(CH2)pC6H4NR80CONR78R79;
or —(CH2)pNR20CO—[(CH2)u—X]t—CH3 where X is —O—;
—NR20—, or —S—;
u is 1-3, and t is 1-6;
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)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)oCOOR75;
—(CH2)oCONR58R59;
—(CH2)oPO(OR60)2;
—(CH2)pSO2R62;
or —(CH2)oCOR64;
R77 is 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 —NR78R79;
R84 is —(CH2)m(CHR61)sOH;
—(CH2)pCOOR80;
—(CH2)m(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;
or —[(CH2)u—X′]t—(CH2)vNR78R79;
or —[(CH2)u—X′]t—(CH2)v—C(═NR80)NR78R79 where X is —O—, —NR20—, —S—;
or —OCOO—, u is 1-3, t is 1-6, and v is 1-3;
with the proviso that
the amino acid residues in positions 1 to 18 are:
P1:
of type D or of type E or of type C, or of the type F;
P2:
of type E, or of type F, or of type D;
P3:
or of type C, of type D;
P4:
of type E, or of type D, or of type F;
P5:
of type D, or of type C, or of type E;
P6:
of type C, or of type E, or of type F;
P7:
of type C, or of type D, or of type E or of type F;
P8:
of type F, or of type E, or the residue is Gly or NMeGly;
P9:
of type C, or of type D, or of type F;
P10:
of type C, or of type E, or of formula -A-CO—, or the residue is Pro or Pip;
P11:
of type C, or of type E, or of formula —B—CO—, or the residue is Gly, NMeGly, Pro or Pip;
P12:
of type D, or of type C, or of type F;
P13:
of type E, or of type F, or the residue is Gly or NMeGly;
P14:
of type C, or of type D, or of type F;
P15:
of type E, or of type F;
P16:
of type D, or of type E, or of type F;
P17:
of type E, or of type F, and;
P18:
of type C, or of type D, or of type E, or of type F;
or
P4 and P17 and/or P6 and P15 and/or P8 and P13, taken together, can form a group of type H;
at P10, P11 and P12 also D-isomers being possible;
and pharmaceutically acceptable salts thereof.

925 more elements

Template-fixed beta-hairpin peptidomimetics with CXCR4 antagonizing activity

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Template-fixed beta-hairpin peptidomimetics with CXCR4 antagonizing activity

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Abstract

Claims35