Template-fixed peptidomimetics with CCR10 antagonistic activity

摘要

Novel template-fixed β-hairpin peptidomimetics of the general formula (I) wherein the single elements T or P are α-amino acid residues connected in either direction which, depending on their positions in the chain, are as defined in the description and the claims, and salts thereof, have the property to antagonize the receptor CCR10. They can be used as medicaments to treat or prevent diseases or conditions in the area of dermatological and cutaneous disorders, inflammation, allergic disorders, respiratory diseases, diseases of the gastro-intestinal tract, ophthalmic diseases, haematology and cancer. These β-hairpin peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.;

主权项

1. Compounds of the general formula (I) wherein the single elements T or P are connected in either direction from the carbonyl (C═0) point of attachment to the nitrogen (N) of the next element and wherein T1 and T2 are independently
an L or D α-amino acid of one of the formulae P1 and P3 are independently
—NR1 CH(R19)CO—; P2 is —NR1C(R20)(R21)CO—; or —NR1 C(Z)CO—; P4 is —NR1CH(R24)CO—; A is O; NR9; S; SO; or SO2 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; —(CHR13)oOR15; —(CHR13)oSR15; —(CHR13)oNR15 R16; —(CHR13)oOCONR15R16 ; —(CHR13)oNR1CONR15R16; —(CHR13)oNR1COR15; —(CHR13)oCOOR15; —(CHR13)oCONR15R16; —(CHR13)oPO(OR1)2; —(CHR13)oSO2R15; —(CHR13)oNR1SO2R15; —(CHR13)oSO2NR15R16; —(CR13)oR30; or —(CHR1)nO(CHR2)mR30; or R4 and R2 taken together can form:
═O; —(CHR19)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:
—(CHR19)p—; —(CH2)n,O(CH2)m—; —(CH2)nS(CH2)m—; or —(CH2)nNR1(CH2)m—; R9 and R10are independently
H; F; CF3; lower alkyl; lower alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl; —(CHR13)rOR15; —(CHR13)rSR15; —(CHR10)rNR15R16; —(CHR13)rOCONR15R16; —(CHR13)rNR1CONR15R16; —(CHR13)rNR1COR15; —(CHR 13)oCOOR15; —(CHR13)oCONR15R16; —(CHR13)rPO(OR1)2; —(CHR13)rSO2R15; —(CHR13)rNR15SO2Rl5; —(CHR13)R13SO2NR15R16; —(CR1R13)oR30; or —(CHR1)rO(CHR1)OR30; R11 and R12 are independently
H; F; Cl; Br; CF3; OCF3; OCHF2; CN; NO2; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl; —(CHR13)oOR15; —(CHR13)oSR15; —(CHR13)oNR15R16; —(CHR13)oOCONR15R16; —(CHR13)oNR1CONR15R16; —(CHR13)oNR1COR15; —(CHR13)oCOOR15; —(CHR13)oCONR15R16; —(CHR13)oPO(OR1)2; —(CHR13)oSO2R15; —(CHR13)oNR1SO2R15; —(CHR13)oSO2NR15R16; or —(CR1R13)oR30; R13 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)oOR15; —(CHR1)oSR15; —(CHR1)oNR15R16; —(CHR1)oNC(═NR17)NR15R16; —(CHR 1)0COOR15; —(CHR1)oCONRl5R16; —(CHR1)oSO2R15; or —(CHR1)oSO2NR15R16; R14 is H; 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)oOR15; —(CHR1)oSR15; —(CHR1)oNR15R16; —(CHR1)oCOOR15; —(CHR1)oCONR15R16; or —(CHR1)oSO2R15; R15, R16, R17 and R18 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 —NR15R16 and —NR17R18 can independently form:
heterocycloalkyl; aryl-heterocycloalkyl; or heteroaryl-heterocycloalkyl;or a group of one of the following formulae X and Y are independently
—CR45; or N; R19 is alkyl; alkenyl; cycloalkyl-lower alkyl; heterocycloalkyl-lower alkyl; —(CR1R4)nR30; —(CH2)nO(CH2)mR30; —(CH2)nS(CH2)mR30; or —(CH2)nNR14(CH2)mR30; R20 and R21 are independently
alkyl; alkenyl; —(CHR4)oOR15; —(CHR4)oSR15; or —(CHR4)rNR15R16; Z is —(CR22R23)(n+m+1)—; —(CR22R23)nNR15(CR22R23)m—; —(CR22R23)nO(CR22R23)m—; —(CR22R23)nS(CR22R23)m—; —O(CR22R23)rO —;
or a group of one of the formulae R22 and R23 are independently
H; F; CF3; alkyl; alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-lower alkyl; or heteroaryl-lower alkyl; —(CR1R13)oOR15; —(CR1R13)oSR15; —(CR1R13)oNR15R16; —(CR1R13)oCOOR15R16; —(CR1R13)oCONR15R16; or —(CR1R13)oSO2R15; or R22 and R23 taken together can form:
═O; ═NR1; ═NOR1; ═NOCF3; —(CHR1)p—; or —O(CR1R2)rO—; R24 is alkyl; alkenyl; —(CR1R13),qNR15R16; —(CR1R13)qNR25R26; —(CR1R13)qNR14R27; —(CH2)qC(═NR13)NR15R16; —(CH2)qC(═NOR17)NR15R16; —(CH2)qC(═NNR15R16)NR17R18; —(CR1R13)qNR2C(═NR17)NR15R16; —(CR1R13)qN═C(NR15R16)NR17R18; —(CR1R13)qOR14; —(CR1R13OR25; —(CR1R13)qOR27; —(CR1R13)qSR15; —(CR1R13)qSO2R15; —(CR1R13)qNR14SO2R15; —(CR1R13)qSO2NR1R14; —(CR1R13)qNR14SO2NR15R16; —(CR1R13)qSO2NR15R16; —(CR1R13)qPO(OR1)2; —(CH2)nO(CH2)mNR15R16; —(CH2)nO(CH2)mC(═NR17)NR15R16; —(CH2)nO(CH2)mC(═NOR17)NR15R16; —(CH2)nO(CH2)mC(═NNR15R16)NR17R18; —(CH2)nO(CH2)mNR1C(═NR17)NR15R16; —(CH2)nO(CH2)mN═C(NR15R16)NR17R18; —(CH2)nS(CH2)mNR15R16; —(CH2)nS(CH2)mC(═NR17)NR15R16; —(CH2)nS(CH2)mC(═NOR17)NR15R16; —(CH2)nS(CH2)mC(═NNR15R16)NR17R18; —(CH2)nS(CH2)mNR1C(═NR17)NR15R16; —(CH2)nS(CH2)mN═C(NR15R16)NR17R18; —(CR1R13)qCOOR15; —(CR1R13)qCOOR25; —(CR1R13)qCOOR28; —(CR1R13)qCONR15R16; or —(CR1R13)qCONR25R26;
or alternatively heteroaryl; or heteroarylalkyl; R25 and R26 are independently
H; —CH3; —[(CH2)2O]rCH3; or —[(CH2)2O]rCF3 R27 is —COR19;—CO(CR1R13)oR15; —CO(CR1R13)oOR14; —CO(CR1R13)oNR15R16; —CO(CR1R13)oNR2R14; —CO(CR1R19)NR15R16; —CO(CR1R29)NR15R16; —CO(CHR1)oCONR15R16; —CO(CHR1)oCONR2SO2R15; —CO(CR1R13)oNR2SO2R15; —CONR1(CHR15)nNR2(CHR13)mR14; —CO(CHR15)nO(CHR13)mR14; —CONR1(CHR15)nO(CHR13)mR14; —SO2R19; —SO2(CR1R13)OR15; —SO2(CR1R13)oNR15R16; or —SO2(CR1R13)oNR1R25; R28 is —NR1C(R2)(R19)COOR15; —NR1C(R2)(R19)CONR15R16; —NR1C(R2)(R29)COOR15; —NR1C(R2)(R29)CONR15R16; R29 is —(CR1R13),1NR15R16; —(CH2)qC(═NR17)NR15R16; —(CH2)qC(═NOR17)NR15R16; —(CH2)qC(═NNR15R16)NR17R18; —(CR1R13)qNR2C(═NR16)NR14R15; —(CR1R13)qN═C(NR15R16)NR17R18; —(CR1 R13)qOR14; —(CR1 R13 )qSR15; —(CR1R13)qSO2R15; —(CR1R13)qNR14SO2R15; —(CR1R13)qSO2NR1R14; —(CR1R13SO2NR15R16; —(CR1R13)qNR2SO2NR15R16; —(CR1R13)qPO(OR1)2; —(CH2)nO(CH2)mNR15R16; —(CH2)nO(CH2)mC(═NR17)NR15R16; —(CH2)nO(CH2)mC(═NOR17)NR15R16; —(CH2)nO(CH2)mC(═NNR15R16)NR17R18; —(CH2)nO(CH2)mNR14C(═NR17)NR15R16; —(CH2)nO(CH2)mN═C(NR15R16)NR17R18; —(CH2)nS(CH2)mNR15R1 6; —(CH2)nS(CH2)mNR15R16; —(CH2)S(CH2)mC(═NR17)NR15R16; —(CH2)nS(CH2)nC(═NOR17)NR15R16; —(CH2)nS(CH2)mC(═NNR15R16)NR17R18; —(CH2)nS(CH2)mNR14C(═NR17)NR15R16; —(CH2)nS(CH2)mN═C(NR15R16)NR17R18; —(CR1R13)qCOOR15; or —(CR1R13)qCONR15R16; R30is an aryl group of one of the formulae or a heteroaryl group of one of the formulae R31 and R32 are independently
H; F; Cl; Br; NO2; CN; CF3; OCHF2; OCF3; lower alkyl; lower alkenyl; aryl-lower alkyl; aryl; heteroaryl; —(CH2)oR33; —(CH2)oOR15; —O(CH2)OR33; —(CH2)oSR15; —(CH2)oNR15R16; —(CH2)oCONR15R16; —(CH2)oNR1CONR15R16; —(CH2)oNR1COR15; —(CH2)oCOOR15; —(CH2)oCONR15R16; —(CH2)oPO (OR1)2; —(CH2)oSO2R14; or —(CH2)oCOR15; R33 is an aryl group of the formula R34, R35 and R36 are independently
H; F; Cl; Br; OH; NH2; NO2; CN; CF3; OCHF2; OCF3; —NR1R15; —(CH2)oCOOR15; —(CH2)oCONR1R15; lower alkyl; lower alkoxy; or lower alkenyl; R37 is H; lower alkyl; or aryl-lower alkyl; R38, R39, R40 and R41 are independently
H; F; CF3; lower alkyl; lower alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl; —(CHR1)oOR15; —(CHR1)oSR15; —(CHR1)oNR2R15; —(CHR1)oOCONR2R15; —(CHR1)oNR2CONR3R15; —(CHR1)oNR2COR15; —(CHR1)oCOOR15; —(CHR1)oCONR2R15; —(CHR1)oPO(OR2)2; —(CHR1)oSO2R15; —(CHR1)oNR2SO2R15; —(CHR1)oSO2NR2R15; —(CR1R2)oR33; or —(CHR1)nO(CHR2)mR33; R42 and R43 are independently
H; F; CF3; lower alkyl; lower alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl; —(CHR1)rOR15; —(CHR1)rSR15; —(CHR1),NR2R15; —(CHR1)rOCONR2R15; —(CHR1)rNR2CONR3R15; —(CHR1)rNR2COR15; —(CHR1)oCOOR15; —(CHR1)oCONR2R15; —(CHR1)rPO(OR2)2; (CHR1)rSO2R15; —(CHR1)rNR2SO2R15; —(CHR1)rSO2NR2R15; —(CR1R2)oR33; or —(CHR1)rO(CHR2)oR33; R44 and R45 are independently
H; F; Cl; Br; CF3; OCF3; OCHF2; CN; NO2; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl; —(CHR1)oOR15; —(CHR1)oSR15; —(CHR1)oNR2R15; —(CHR1)oOCONR2R15; —(CHR1)oNR2CONR3R15; —(CHR)oNR2COR15; —(CHR1)oCOOR15; —(CHR1)oCONR2R15; —(CHR1)oPO(OR2)2; —(CHR1)oSO2R15; —(CHR1)oNR2SO2R15; —(CHR1)oSO2NR2R15; or —(CR1R2)oR33; 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; or pharmaceutically acceptable salts thereof.