US 2015/0307556 A1 · TEMPLATE-FIXED PEPTIDOMIMETICS WITH CXCR7 MODULATING ACTIVITY

Abstract

Novel template-fixed β-hairpin peptidomimetics of the general formula (I) wherein the single elements T or P are α-amino acid residues connected from the carbonyl (C═O) point of attachment to the nitrogen (N) of the next element in clockwise direction and wherein said elements, depending on their positions in the chain, are defined in the description and the claims have the property to act on the receptor CXCR7. Thus, these β-hairpin peptidomimetics can be useful in the treatment or prevention of diseases or conditions in the area of dermatological disorders, metabolic diseases, inflammatory diseases, fibrotic diseases, infectious diseases, neurological diseases, cardiovascular diseases, respiratory diseases, gastro-intestinal tract disorders, urological diseases, ophthalmic diseases, stomatological diseases, haematological diseases and cancer; or the mobilisation of stem cells.

Compounds of the general formula (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
either
T1 is an α-amino acid residue of one of the formulae
and
T2 is an α-amino acid residue of one of the formulae
or
T1 is an α-amino acid residue of one of the formulae
and
T2 is an α-amino acid residue of one of the formulae AA11 to AA17, hereinabove, or an α-amino acid residue of one of the formulae
P1, P3 and P4 are independently
—NR1CH(R29)CO—;
—NR1CH(R30)CO—;
or —NR1CH(R31)CO—;
P2 is an α-amino acid residue of one of the formulae
A is O;
NR17;
S;
SO;
or SO2;
X is OH;
NH2;
OR16;
NR1R16;
or NR17R18;
Y is NH2;
F;
OR16;
NR1R16;
or NR17R18;
R1, R2 and R3 are independently H;
CF3;
lower alkyl;
lower alkenyl;
aryl-lower alkyl;
or heteroaryl-lower alkyl;
R4, R5, R6, R7 and R8 are independently H;
F;
CF3;
lower alkyl;
lower alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-lower alkyl;
heteroaryl-lower alkyl;
—(CHR15)oOR17;
—(CHR15)oSR17;
—(CHR15)NR17R18;
—(CHR15)oOCONR17R18;
—(CHR15)oNR1CONR17R18;
—(CHR15)oNR1COR17;
—(CHR15)oCOOR17;
—(CHR15)oCONR17R18;
—(CHR15)oPO(OR1)2;
—(CHR15)oSO2R17;
—(CHR15)oNR1SO2R17;
—(CHR15)oSO2NR17R18;
—(CR1R15)oR35;
or —(CHR1)nO(CHR2)mR35;
or
R4 and R2 taken together can form ═O;
—(CHR15)p—;
—(CH2)nO(CH2)m—;
—(CH2)nS(CH2)m—;
or —(CH2)nNR1(CH2)m—;
or
R4 and R5;
R5 and R6;
R6 and R7;
R7 and R8;
or R6 and R9 taken together can form:
—(CHR15)p—;
—(CH2)nO(CH2)m—;
—(CH2)nS(CH2)m—;
or —(CH2)nNR1(CH2)m—;
or
R4 and R5 are independently X;
R9, R10, R11 and R12 are independently H;
F;
CF3;
lower alkyl;
lower alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-lower alkyl;
heteroaryl-lower alkyl;
—(CHR15)rOR17;
—(CHR15)rSR17;
—(CHR15)rNR17R18;
—(CHR15)rOCONR17R18;
—(CHR15)rNR1CONR17R18;
—(CHR15)rNR1COR17;
—(CHR15)oCOOR17;
—(CHR15)oCONR17R18;
—(CHR15)rPO(OR1)2;
—(CHR15)rSO2R17;
—(CHR15)rNR1SO2R17;
—(CHR15)rSO2NR17R18;
—(CR1R15)oR35;
or —(CHR1)rO(CHR1)oR35;
or
R11 and R12 taken together can form ═O;
or ═NR1;
R13 and R14 are independently H;
F;
Cl;
Br;
CF3;
OCF3;
OCHF2;
CN;
NO2;
lower alkyl;
lower alkenyl;
aryl;
heteroaryl;
aryl-lower alkyl;
heteroaryl-lower alkyl;
—(CHR15)oOR17;
—(CHR15)oSR17;
—(CHR15)oNR17R18;
—(CHR15)oOCONR17R18;
—(CHR15)oNR1CONR17R18;
—(CHR15)oNR1COR17;
—(CHR15)oCOOR17;
—(CHR15)oCONR17R18;
—(CHR15)oPO(OR1)2;
—(CHR15)oSO2R17;
—(CHR15)oNR1SO2R17;
—(CHR15)oSO2NR17R18;
—(CR1R15)oR35;
or —(CHR1)rO(CHR1)oR35;
R15 is H;
F;
CF3;
lower alkyl;
lower alkenyl;
cycloalkyl;
heterocycloalkyl;
cycloalkyl-lower alkyl;
heterocycloalkyl-lower alkyl;
aryl;
heteroaryl;
aryl-lower alkyl;
heteroaryl-lower alkyl;
—(CHR1)oOR17;
—(CHR1)oSR17;
—(CHR1)oNR17R18;
—(CHR1)NR20C(═NR19)NR17R18;
—(CHR1)oCOOR17;
—(CHR1)oCONR17R18;
—(CHR1)oSO2R17;
or —(CHR1)oSO2NR17R18;
R16 is CF3;
lower alkyl;
lower alkenyl;
cycloalkyl;
heterocycloalkyl;
cycloalkyl-lower alkyl;
heterocycloalkyl-lower alkyl;
aryl;
heteroaryl;
aryl-lower alkyl;
heteroaryl-lower alkyl;
cycloalkyl-aryl;
heterocycloalkyl-aryl;
cycloalkyl-heteroaryl;
heterocycloalkyl-heteroaryl;
aryl-cycloalkyl;
aryl-heterocycloalkyl;
heteroaryl-cycloalkyl;
heteroaryl-heterocycloalkyl;
—(CHR1)sOR17;
—(CHR1)sSR17;
—(CHR1)sNR17R18;
—(CHR1)oCOR17;
—(CHR1)oCOOR17;
—(CHR1)oCONR17R18;
or —(CHR1)oSO2R17;
R17, R18, R19 and R20 are independently H;
lower alkyl;
lower alkenyl;
lower alkoxy;
cycloalkyl;
heterocycloalkyl;
cycloalkyl-lower alkyl;
heterocycloalkyl-lower alkyl;
aryl;
heteroaryl;
aryl-lower alkyl;
heteroaryl-lower alkyl;
cycloalkyl-aryl;
heterocycloalkyl-aryl;
cycloalkyl-heteroaryl;
heterocycloalkyl-heteroaryl;
aryl-cycloalkyl;
aryl-heterocycloalkyl;
heteroaryl-cycloalkyl;
or heteroaryl-heterocycloalkyl;
or
the structural elements —NR17R18 and —NR19R20 can independently form:
heterocycloalkyl;
aryl-heterocycloalkyl;
or heteroaryl-heterocycloalkyl;
or a group of one of the formulae
Z, Z′ and Z″ are independently —CR39;
or N;
R21, R22, R23 and R24 are independently H;
F;
CF3;
lower alkyl;
lower alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-lower alkyl;
heteroaryl-lower alkyl;
—(CHR1)oOR17;
—(CHR1)oSR17;
—(CHR1)oNR2R17;
—(CHR1)oOCONR2R17;
—(CHR1)oNR2CONR3R17;
—(CHR1)oNR2COR17;
—(CHR1)oCOOR17;
—(CHR1)oCONR2R17;
—(CHR1)oPO(OR2)2;
—(CHR1)oSO2R17;
—(CHR1)oNR2SO2R17;
—(CHR1)oSO2NR2R17;
—(CR1R2)oR38;
or —(CHR1)nO(CHR2)mR38;
R25 and R26 are independently H;
F;
CF3;
lower alkyl;
lower alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-lower alkyl;
heteroaryl-lower alkyl;
—(CHR1)rOR17;
—(CHR1)rSR17;
—(CHR1)rNR2R17;
—(CHR1)rOCONR2R17;
—(CHR1)rNR2CONR3R17;
—(CHR1)rNR2COR17;
—(CHR1)oCOOR17;
—(CHR1)oCONR2R17;
—(CHR1)rPO(OR2)2;
—(CHR1)rSO2R17;
—(CHR1)rNR2SO2R17;
—(CHR1)rSO2NR2R17;
—(CR1R2)oR38;
or —(CHR1)rO(CHR2)oR38;
R27 is H;
F;
Cl;
Br;
CF3;
OCF3;
OCHF2;
CN;
NO2;
lower alkyl;
lower alkenyl;
aryl;
heteroaryl;
aryl-lower alkyl;
heteroaryl-lower alkyl;
—(CHR1)oOR17;
—(CHR1)oSR17;
—(CHR1)oNR2R17;
—(CHR1)oOCONR2R17;
—(CHR1)oNR2CONR3R17;
—(CHR1)oNR2COR17;
—(CHR1)oCOOR17;
—(CHR1)oCONR2R17;
—(CHR1)oPO(OR2)2;
—(CHR1)oSO2R17;
—(CHR1)oNR2SO2R17;
—(CHR1)oSO2NR2R17;
—(CR1R2)oR38;
or —(CHR1)rO(CHR2)oR38;
R29 is H;
alkyl;
alkenyl;
cycloalkyl-lower alkyl;
heterocycloalkyl-lower alkyl;
—(CHR4)oOR17;
—(CHR4)oSR17;
or —(CHR4)rNR17R18;
R30 is —(CR1R4)nR35;
—(CH2)nO(CH2)mR35;
—(CH2)nS(CH2)mR35;
or —(CH2)nNR1(CH2)mR35;
R31 is alkyl;
alkenyl;
—(CR1R15)qNR17R18;
—(CR1R15)qNR2R16;
—(CR1R15)qNR17R32;
—(CR1R15)qNR17COR18;
—(CH2)qC(═NR15)NR17R18;
—(CH2)qC(═NOR19)NR17R18;
—(CH2)qC(═NNR17R18)NR19R20;
—(CR1R15)qNR20C(═NR19)NR17R18;
—(CR1R15)qN═C(NR17R18)NR19R20;
—(CR1R15)qOR17;
—(CR1R15)qOR32;
—(CR1R15)qSR17;
—(CR1R15)qSO2R17;
—(CR1R15)qNR17SO2R18;
—(CR1R15)qSO2NR2R16;
—(CR1R15)qSO2NR17R18;
—(CR1R15)qNR19SO2NR17R18;
—(CR1R15)qPO(OR2)2;
—(CH2)nO(CH2)mNR17R18;
—(CH2)nO(CH2)mC(═NR19)NR17R18;
—(CH2)nO(CH2)mC(═NOR19)NR17R18;
—(CH2)nO(CH2)mC(═NNR17R18)NR19R20;
—(CH2)nO(CH2)mNR20C(═NR19)NR17R18;
—(CH2)nO(CH2)mN═C(NR17R18)NR19R20;
—(CH2)nS(CH2)mNR17R18;
—(CH2)nS(CH2)mC(═NR19)NR17R18;
—(CH2)nS(CH2)mC(═NOR19)NR17R18;
—(CH2)nS(CH2)mC(═NNR17R18)NR19R20;
—(CH2)nS(CH2)mNR20C(═NR19)NR17R18;
—(CH2)nS(CH2)mN═C(NR17R18)NR19R20;
—(CR1R15)qCOOR17;
—(CR1R15)qCONR17R18;
or —(CR1R15)qCOR33;
R32 is —COR29;
—COR30;
—CO(CR1R15)oR17;
—CO(CR1R15)oOR17;
—CO(CR1R15)oNR17R18;
—CO(CR1R15)oNR2R16;
—CO(CR1R29)NR17R18;
—CO(CR1R30)NR17R18;
—CO(CR1R34)NR17R18;
—CO(CHR1)oCONR17R18;
—CO(CHR1)oCONR17SO2R18;
—CO(CR1R15)oNR17SO2R18;
—CONR1(CHR17)nNR2(CHR15)mR16;
—CO(CHR17)nO(CHR15)mR16;
—CONR1(CHR17)nO(CHR15)mR16;
—SO2R29;
—SO2R30;
—SO2(CR1R15)oR17;
or —SO2(CR1R15)oNR17R18;
R33 is —NR1C(R2)(R29)COOR17;
—NR1C(R2)(R29)CONR17R18;
—NR1C(R2)(R30)COOR17;
—NR1C(R2)(R30)CONR17R18;
—NR1C(R2)(R34)COOR17;
or —NR1C(R2)(R34)CONR17R18;
R34 is —(CR1R15)qNR17R18;
—(CH2)qC(═NR19)NR17R18;
—(CH2)qC(═NOR19)NR17R18;
—(CH2)qC(═NNR17R18)NR19R20;
—(CR1R15)qNR2C(═NR19)NR17R18;
—(CR1R15)qN═C(NR17R18)NR19R20;
—(CR1R15)qOR17;
—(CR1R15)qSR17;
—(CR1R15)qSO2R17;
—(CR1R15)qNR17SO2R18;
—(CR1R15)qSO2NR1R16;
—(CR1R15)qSO2NR17R18;
—(CR1R15)qNR2SO2NR17R18;
—(CR1R15)qPO(OR1)2;
—(CH2)nO(CH2)mNR17R18;
—(CH2)nO(CH2)mC(═NR19)NR17R18;
—(CH2)nO(CH2)mC(═NOR19)NR17R18;
—(CH2)nO(CH2)mC(═NNR17R18)NR19R20;
—(CH2)nO(CH2)mNR20C(═NR19)NR17R18;
—(CH2)nO(CH2)mN═C(NR17R18)NR19R20;
—(CH2)nS(CH2)mNR17R18;
—(CH2)nS(CH2)mC(═NR19)NR17R18;
—(CH2)nS(CH2)mC(═NOR19)NR17R18;
—(CH2)nS(CH2)mC(═NNR17R18)NR19R20;
—(CH2)nS(CH2)mNR20C(═NR19)NR17R18;
—(CH2)nS(CH2)mN═C(NR17R18)NR19R20;
—(CR1R15)qCOOR17;
or —(CR1R15)qCONR17R18;
R35 is an aryl group of one of the formulae
or a heteroaryl group of one of the formulae
R36 and R37 are independently H;
F;
Cl;
Br;
CF3;
OCF3;
OCHF2;
CN;
NO2;
lower alkyl;
lower alkenyl;
aryl;
heteroaryl;
aryl-lower alkyl;
heteroaryl-lower alkyl;
—(CH2)oR38;
—(CH2)oOR17;
—O(CH2)oR38;
—(CH2)oSR17;
—(CH2)oNR17R18;
—(CH2)oOCONR17R18;
—(CH2)oNR1CONR17R18;
—(CH2)oNR1COR17;
—(CH2)oCOOR17;
—(CH2)oCONR17R18;
—(CH2)oPO(OR1)2;
—(CH2)oSO2R16;
or —(CH2)oCOR17;
R38 is an aryl group of the formula
R39, R40 and R41 are independently H;
F;
Cl;
Br;
OH;
NH2;
NO2;
CN;
CF3;
OCHF2;
OCF3;
—NR1R17;
—(CH2)oCOOR17;
—(CH2)oCONR1R17;
lower alkyl;
lower alkoxy;
or lower alkenyl;
R42 is H;
lower alkyl;
or aryl-lower alkyl;
n and m are independently an integer of 0-5 with the proviso that n+m≦6;
o is 0-4;
p is 2-6;
q is 1-6;
r is 1-3;
s is 0-4
and pharmaceutically acceptable salts thereof.

444 more elements

Template-fixed peptidomimetics with cxcr7 modulating activity

Life of this patent

Template-fixed peptidomimetics with cxcr7 modulating activity

Life of this patent

Abstract

Claims5