US 10,730,911 B2 · Backbone-cyclized peptidomimetics with GLP-1R modulating activity

Abstract

Novel backbone-cyclized peptidomimetics of the general formula cyclo[-P1-P2-P3-P4-P5-P6-P7-P8-T1-T2-] (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 modulate the GLP-1 receptor. They can be used as medicaments to treat, prevent, or delay the onset of diseases, disorders or conditions in which modulation of the human GLP-1 receptor is beneficial, such as type 2 diabetes. These backbone-cyclized 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 (I)

cyclo[-P1-P2-P3-P4-P5-P6-P7-P8-T1-T2-] (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
T1 is a D α-amino acid residue selected from the group consisting of
T2 is an L or D α-amino acid residue selected from the group consisting of
P1 is Phe;
Tyr;
3Pal;
2Thi;
or 3Thi;
P2 is Asp;
Asn;
Glu;
Hgl;
Gln;
hGln;
Cit;
or an L α-amino acid residue of formula
P3 is Leu;
Nle;
Cha;
Chg;
Asn;
Gln;
hGln;
or Cit;
P4 is Leu;
Nle;
Val;
or an L α-amino acid residue of formula
P5 is Ala;
Aib;
or Abu;
P6 is Trp;
Trp(5OH);
Tpi;
or Trp(1Me);
P7 is Asp;
Asn;
Glu;
Hgl;
Gln;
hGln;
or Cit;
P8 is Arg;
hArg;
Agp;
Lys;
hLys;
Orn;
or an L α-amino acid residue of formula
with the proviso that
if P3 is Asn;
Gln;
hGln;
or Cit;
then
P2 is an L α-amino acid residue of formula AA5;
P7 is Asp;
Glu;
Hgl;
or Cit;
or if P3 is Leu;
Nle;
Cha;
or Chg;
and P2 is Asn;
Gln;
hGln;
Cit;
or an L α-amino acid residue of formula AA5;
then
P7 is Glu;
or Hgl;
RAr is, with the proviso of containing less than 26 carbon- and/or heteroatoms, —(CR20R22)nR27;
—(CH2)nO(CH2)mR27;
—(CH2)nS(CH2)mR27;
or —(CH2)nNR25(CH2)mR27;
R1, R2 and R3 are independently
H;
CF3;
or CH3;
R4, R5 and R6 are independently
H;
F;
CF3;
C1-8-alkyl;
C2-8-alkenyl;
C2-8-alkynyl;
cycloalkyl;
heterocycloalkyl;
—(CHR12)oOR15;
—O(CO)R15;
—(CHR12)oSR15;
—(CHR12)oNR15R16;
—(CHR12)oOCONR15R16;
—(CHR12)oNR1CONR15R16;
—(CHR12)oNR1COOR15;
—(CHR12)oNR1COR15;
—(CHR12)oCOOR15;
—(CHR12)oCONR15R16;
—(CHR12)oPO(OR1)2;
—(CHR12)oSO2R15;
—(CHR12)oNR1SO2R15;
or —(CHR12)oSO2NR15R16;
R4 and R2;
or R5 and R6 taken together can form:
═O;
or —(CHR1)p-;
R4 and R5;
or R6 and R7 taken together can form:
—(CHR1)p—;
—(CH2)tO(CH2)u—;
—(CH2)tS(CH2)u—;
or —(CH2)tNR1(CH2)u—;
R7 is H;
F;
CF3;
C1-8-alkyl;
C2-8-alkenyl;
C2-8-alkynyl;
cycloalkyl;
heterocycloalkyl;
—(CHR12)rOR15;
—O(CO)R15;
—(CHR12)rSR15;
—(CHR10)rNR15R16;
—(CHR12)rOCONR15R16;
—(CHR12)rNR1CONR15R16;
—(CHR12)rNR1COOR15;
—(CHR12)rNR1COR15;
—(CHR12)oCOOR15;
—(CHR12)oCONR15R16;
—(CHR12)rPO(OR1)2;
—(CHR12)rSO2R15;
—(CHR12)rNR1SO2R15;
or —(CHR12)rSO2NR15R16;
R8 and R9 are, with the proviso of containing combined less than 26 carbon- and/or heteroatoms, independently
C1-8-alkyl;
C2-8-alkenyl;
C2-8-alkynyl;
cycloalkyl-C1-4-alkyl;
heterocycloalkyl-C1-4-alkyl;
—(CHR1)sOCF3;
—(CHR1)sOR18;
—(CHR1)sSCF3;
or —(CHR1)sSR18;
Z is selected from the group consisting of, with the proviso of containing less than 26 carbon- and/or heteroatoms,
—(CR2R12)q—;
—(CR2R12)kO(CR2R12)l—;
—(CR2R12)kS(CR2R12)l—;
A is O;
NR17;
S;
SO;
or SO2;
X is —CR19;
or N;
R10 and R11 are independently
H;
F;
C1;
Br;
I;
CF3;
OCF3;
OCHF2;
C1-4-alkyl;
C2-4-alkenyl;
or C2-4-alkynyl;
R12, R13 and R14 are independently
H;
F;
CF3;
or CH3;
R15 and R16 are independently
H;
C1-8-alkyl;
C2-8-alkenyl;
C2-8-alkynyl;
C1-6-alkoxy;
cycloalkyl;
heterocycloalkyl;
cycloalkyl-C1-6-alkyl;
or heterocycloalkyl-C1-6-alkyl;
or
the structural element —NR15R16 can form heterocycloalkyl;
R17 is H;
C1-4-alkyl;
C2-4-alkenyl;
or C2-4-alkynyl;
R18 is C1-4-alkyl;
C2-4-alkenyl;
or C2-4-alkynyl;
R19 is H;
F;
Cl;
Br;
I;
CN;
CF3;
OCHF2;
OCF3;
C1-4-alkyl;
C2-4-alkenyl;
or C2-4 alkynyl;
R20 and R21 are independently
H;
CF3;
C1-8-alkyl;
C2-8-alkenyl;
C2-8-alkynyl;
or aryl-C1-6-alkyl;
R22 is H;
F;
CF3;
C1-8-alkyl;
C2-8-alkenyl;
C2-8-alkynyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-6-alkyl;
heteroaryl-C1-6-alkyl;
—(CHR23)oOR25;
—O(CO)R25;
—(CHR23)oSR25;
—(CHR23)oNR25R26;
—(CHR23)oOCONR25R26;
—(CHR23)oNR20CONR25R26;
—(CHR23)oNR20COOR25;
—(CHR23)oNR20COR25;
—(CHR23)oCOOR25;
—(CHR23)oCONR25R26;
—(CHR23)oPO(OR20)2;
—(CHR23)oSO2R25;
—(CHR23)oNR20SO2R25;
—(CHR23)oSO2NR25R26;
—(CR20R23)oR27;
or —(CHR20)nO(CHR21)mR27;
R23 is H;
F;
CF3;
C1-8-alkyl;
C2-8-alkenyl;
C2-8-alkynyl;
cycloalkyl;
heterocycloalkyl;
cycloalkyl-C1-6-alkyl;
heterocycloalkyl-C1-6-alkyl;
aryl;
heteroaryl;
aryl-C1-6-alkyl;
heteroaryl-C1-6-alkyl;
—(CHR20)oOR25;
—OCOR20;
—(CHR20)NR25R26;
—COOR25;
—CONR25R26;
—SO2R25;
or -SO2NR25R26;
R24 is H;
CF3;
C1-8-alkyl;
C2-8-alkenyl;
C2-8-alkynyl;
cycloalkyl;
heterocycloalkyl;
cycloalkyl-C1-6-alkyl;
heterocycloalkyl-C1-6-alkyl;
aryl;
heteroaryl;
aryl-C1-6-alkyl;
heteroaryl-C1-6-alkyl;
cycloalkyl-aryl;
heterocycloalkyl-aryl;
cycloalkyl-heteroaryl;
heterocycloalkyl-heteroaryl;
aryl-cycloalkyl;
aryl-heterocycloalkyl;
heteroaryl-cycloalkyl;
heteroaryl-heterocycloalkyl;
—(CHR20)oOR25;
—(CHR20)oSR25;
—(CHR20)oNR25R26;
—(CHR20)oCOOR25;
—(CHR20)oCONR25R26;
or —(CHR20)oSO2R25;
R25 and R26 are independently
H;
C1-8-alkyl;
C2-8-alkenyl;
C2-8-alkynyl;
C1-6-alkoxy;
cycloalkyl;
heterocycloalkyl;
cycloalkyl-C1-6-alkyl;
heterocycloalkyl-C1-6-alkyl;
aryl;
heteroaryl;
aryl-C1-6-alkyl;
heteroaryl-C1-6-alkyl;
cycloalkyl-aryl;
heterocycloalkyl-aryl;
cycloalkyl-heteroaryl;
heterocycloalkyl-heteroaryl;
aryl-cycloalkyl;
aryl-heterocycloalkyl;
heteroaryl-cycloalkyl;
or heteroaryl-heterocycloalkyl;
or
the structural element —NR25R26 can independently form:
heterocycloalkyl;
aryl-heterocycloalkyl;
or heteroaryl-heterocycloalkyl;
R27 is an aryl group selected from the group consisting of
X, X′, X″ and X′″ are independently
—CR28;
or N;
R28 and R29 are independently
H;
F;
Cl;
Br;
I;
OH;
NH2;
NO2;
CN;
CF3;
OCHF2;
OCF3;
C1-8-alkyl;
C2-8-alkenyl;
C2-8-alkynyl;
aryl;
heteroaryl;
aryl-C1-6-alkyl;
heteroaryl-C1-6-alkyl;
—(CH2)oR30;
—(CH2)oOR25;
—O(CO)R25;-O(CH2)oR30;
—(CH2)oSR25;
—(CH2)oNR25R26;
—(CH2)oOCONR25R26;
—(CH2)oNR20CONR25R26;
—(CH2)oNR20COR25;
—(CH2)oCOOR25;
—(CH2)oCONR25R26;
—(CH2)oPO(OR20)2;
—(CH2)oSO2R24;
or —(CH2)oCOR25;
R30 is an aryl group of the formula
R31, R32 and R33 are independently
H;
F;
Cl;
Br;
I;
OH;
NH2;
NO2;
CN;
CF3;
OCHF2;
OCF3;
C1-8-alkyl;
C2-8-alkenyl;
C2-8-alkynyl;
—(CH2)oOR25;
—O(CO)R25;
—(CH2)oNR20R25;
—(CH2)oCOOR25;
or
—(CH2)oCONR20R25;
R34 is H;
Ac;
C1-8-alkyl;
or aryl-C1-6-alkyl;
k and 1 are independently an integer of 1-5 with the proviso that k+l≤6;
t and u are independently an integer of 0-3 with the proviso that t+u≥1 and t+u≤3;
n and m are independently an integer of 0-5 with the proviso that n+m≤6;
o is 0-4;
p is 2-4;
q is 3-7;
r is 1-3;
s is 1-4;
or a pharmaceutically acceptable salt thereof.

385 more elements

Backbone-cyclized peptidomimetics with GLP-1R modulating activity

Life of this patent

Backbone-cyclized peptidomimetics with GLP-1R modulating activity

Life of this patent

Abstract

Claims15