Backbone-cyclized peptidomimetics with GLP-1R modulating activity

Patent metadata

Field	Value
Publication number	US-10730911-B2
Application number	US-201615564539-A
Country	US
Kind code	B2
Filing date	Apr 6, 2016
Priority date	Apr 8, 2015
Publication date	Aug 4, 2020
Grant date	Aug 4, 2020

Abstract

Novel backbone-cyclized peptidomimetics of the general formula

cyclo[-P 1 -P 2 -P 3 -P 4 -P 5 -P 6 -P 7 -P 8 -T 1 -T 2 -]   (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.

First claim

The invention claimed is:

1. A compound of the general formula (I)
cyclo[-P 1 -P 2 -P 3 -P 4 -P 5 -P 6 -P 7 -P 8 -T 1 -T 2 -]   (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
T 1 is a D α-amino acid residue selected from the group consisting of

T 2 is an L or D α-amino acid residue selected from the group consisting of

P 1 is Phe; Tyr; 3Pal; 2Thi; or 3Thi;
P 2 is Asp; Asn; Glu; Hgl; Gln; hGln; Cit; or an L α-amino acid residue of formula

P 3 is Leu; Nle; Cha; Chg; Asn; Gln; hGln; or Cit;
P 4 is Leu; Nle; Val; or an L α-amino acid residue of formula

P 5 is Ala; Aib; or Abu;
P 6 is Trp; Trp(5OH); Tpi; or Trp(1Me);
P 7 is Asp; Asn; Glu; Hgl; Gln; hGln; or Cit;
P 8 is Arg; hArg; Agp; Lys; hLys; Orn; or an L α-amino acid residue of formula

with the proviso that
if P 3 is Asn; Gln; hGln; or Cit; then
P 2 is an L α-amino acid residue of formula AA5;
P 7 is Asp; Glu; Hgl; or Cit;

or if P 3 is Leu; Nle; Cha; or Chg; and P 2 is Asn; Gln; hGln; Cit; or an L α-amino acid residue of formula AA5; then
P 7 is Glu; or Hgl;

R Ar is, with the proviso of containing less than 26 carbon- and/or heteroatoms, —(CR 20 R 22 ) n R 27 ; —(CH 2 ) n O(CH 2 ) m R 27 ; —(CH 2 ) n S(CH 2 ) m R 27 ; or —(CH 2 ) n NR 25 (CH 2 ) m R 27 ;
R 1 , R 2 and R 3 are independently
H; CF 3 ; or CH 3 ;

R 4 , R 5 and R 6 are independently
H; F; CF 3 ; C 1-8 -alkyl; C 2-8 -alkenyl; C 2-8 -alkynyl; cycloalkyl; heterocycloalkyl; —(CHR 12 ) o OR 15 ; —O(CO)R 15 ; —(CHR 12 ) o SR 15 ; —(CHR 12 ) o NR 15 R 16 ; —(CHR 12 ) o OCONR 15 R 16 ; —(CHR 12 ) o NR 1 CONR 15 R 16 ; —(CHR 12 ) o NR 1 COOR 15 ; —(CHR 12 ) o NR 1 COR 15 ; —(CHR 12 ) o COOR 15 ; —(CHR 12 ) o CONR 15 R 16 ; —(CHR 12 ) o PO(OR 1 ) 2 ; —(CHR 12 ) o SO 2 R 15 ; —(CHR 12 ) o NR 1 SO 2 R 15 ; or —(CHR 12 ) o SO 2 NR 15 R 16 ;

R 4 and R 2 ; or R 5 and R 6 taken together can form:
═O; or —(CHR 1 ) p -;

R 4 and R 5 ; or R 6 and R 7 taken together can form:
—(CHR 1 ) p —; —(CH 2 ) t O(CH 2 ) u —; —(CH 2 ) t S(CH 2 ) u —; or —(CH 2 ) t NR 1 (CH 2 ) u —;

R 7 is H; F; CF 3 ; C 1-8 -alkyl; C 2-8 -alkenyl; C 2-8 -alkynyl; cycloalkyl; heterocycloalkyl; —(CHR 12 ) r OR 15 ; —O(CO)R 15 ; —(CHR 12 ) r SR 15 ; —(CHR 10 ) r NR 15 R 16 ; —(CHR 12 ) r OCONR 15 R 16 ; —(CHR 12 ) r NR 1 CONR 15 R 16 ; —(CHR 12 ) r NR 1 COOR 15 ; —(CHR 12 ) r NR 1 COR 15 ; —(CHR 12 ) o COOR 15 ; —(CHR 12 ) o CONR 15 R 16 ; —(CHR 12 ) r PO(OR 1 ) 2 ; —(CHR 12 ) r SO 2 R 15 ; —(CHR 12 ) r NR 1 SO 2 R 15 ; or —(CHR 12 ) r SO 2 NR 15 R 16 ;
R 8 and R 9 are, with the proviso of containing combined less than 26 carbon- and/or heteroatoms, independently
C 1-8 -alkyl; C 2-8 -alkenyl; C 2-8 -alkynyl; cycloalkyl-C 1-4 -alkyl; heterocycloalkyl-C 1-4 -alkyl; —(CHR 1 ) s OCF 3 ; —(CHR 1 ) s OR 18 ; —(CHR 1 ) s SCF 3 ; or —(CHR 1 ) s SR 18 ;

Z is selected from the group consisting of, with the proviso of containing less than 26 carbon- and/or heteroatoms,
—(CR 2 R 12 ) q —; —(CR 2 R 12 ) k O(CR 2 R 12 ) l —; —(CR 2 R 12 ) k S(CR 2 R 12 ) l —;

A is O; NR 17 ; S; SO; or SO 2 ;
X is —CR 19 ; or N;

R 10 and R 11 are independently
H; F; C 1 ; Br; I; CF 3 ; OCF 3 ; OCHF 2 ; C 1-4 -alkyl; C 2-4 -alkenyl; or C 2-4 -alkynyl;

R 12 , R 13 and R 14 are independently
H; F; CF 3 ; or CH 3 ;

R 15 and R 16 are independently
H; C 1-8 -alkyl; C 2-8 -alkenyl; C 2-8 -alkynyl; C 1-6 -alkoxy; cycloalkyl; heterocycloalkyl; cycloalkyl-C 1-6 -alkyl; or heterocycloalkyl-C 1-6 -alkyl; or

the structural element —NR 15 R 16 can form heterocycloalkyl;
R 17 is H; C 1-4 -alkyl; C 2-4 -alkenyl; or C 2-4 -alkynyl;
R 18 is C 1-4 -alkyl; C 2-4 -alkenyl; or C 2-4 -alkynyl;
R 19 is H; F; Cl; Br; I; CN; CF 3 ; OCHF 2 ; OCF 3 ; C 1-4 -alkyl; C 2-4 -alkenyl; or C 2-4 alkynyl;
R 20 and R 21 are independently
H; CF 3 ; C 1-8 -alkyl; C 2-8 -alkenyl; C 2-8 -alkynyl; or aryl-C 1-6 -alkyl;

R 22 is H; F; CF 3 ; C 1-8 -alkyl; C 2-8 -alkenyl; C 2-8 -alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CHR 23 ) o OR 25 ; —O(CO)R 25 ; —(CHR 23 ) o SR 25 ; —(CHR 23 ) o NR 25 R 26 ; —(CHR 23 ) o OCONR 25 R 26 ; —(CHR 23 ) o NR 20 CONR 25 R 26 ; —(CHR 23 ) o NR 20 COOR 25 ; —(CHR 23 ) o NR 20 COR 25 ; —(CHR 23 ) o COOR 25 ; —(CHR 23 ) o CONR 25 R 26 ; —(CHR 23 ) o PO(OR 20 ) 2 ; —(CHR 23 ) o SO 2 R 25 ; —(CHR 23 ) o NR 20 SO 2 R 25 ; —(CHR 23 ) o SO 2 NR 25 R 26 ; —(CR 20 R 23 ) o R 27 ; or —(CHR 20 ) n O(CHR 21 ) m R 27 ;
R 23 is H; F; CF 3 ; C 1-8 -alkyl; C 2-8 -alkenyl; C 2-8 -alkynyl; cycloalkyl; heterocycloalkyl; cycloalkyl-C 1-6 -alkyl; heterocycloalkyl-C 1-6 -alkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CHR 20 ) o OR 25 ; —OCOR 20 ; —(CHR 20 )NR 25 R 26 ; —COOR 25 ; —CONR 25 R 26 ; —SO 2 R 25 ; or -SO 2 NR 25 R 26 ;
R 24 is H; CF 3 ; C 1-8 -alkyl; C 2-8 -alkenyl; C 2-8 -alkynyl; cycloalkyl; heterocycloalkyl; cycloalkyl-C 1-6 -alkyl; heterocycloalkyl-C 1-6 -alkyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; cycloalkyl-aryl; heterocycloalkyl-aryl; cycloalkyl-heteroaryl; heterocycloalkyl-heteroaryl; aryl-cycloalkyl; aryl-heterocycloalkyl; heteroaryl-cycloalkyl; heteroaryl-heterocycloalkyl; —(CHR 20 ) o OR 25 ; —(CHR 20 ) o SR 25 ; —(CHR 20 ) o NR 25 R 26 ; —(CHR 20 ) o COOR 25 ; —(CHR 20 ) o CONR 25 R 26 ; or —(CHR 20 ) o SO 2 R 25 ;
R 25 and R 26 are independently
H; C 1-8 -alkyl; C 2-8 -alkenyl; C 2-8 -alkynyl; C 1-6 -alkoxy; cycloalkyl; heterocycloalkyl; cycloalkyl-C 1-6 -alkyl; heterocycloalkyl-C 1-6 -alkyl; aryl; heteroaryl;
aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; cycloalkyl-aryl; heterocycloalkyl-aryl; cycloalkyl-heteroaryl; heterocycloalkyl-heteroaryl; aryl-cycloalkyl;
aryl-heterocycloalkyl; heteroaryl-cycloalkyl; or heteroaryl-heterocycloalkyl; or

the structural element —NR 25 R 26 can independently form:
heterocycloalkyl; aryl-heterocycloalkyl; or heteroaryl-heterocycloalkyl;

R 27 is an aryl group selected from the group consisting of

X, X′, X″ and X′″ are independently
—CR 28 ; or N;

R 28 and R 29 are independently
H; F; Cl; Br; I; OH; NH 2 ; NO 2 ; CN; CF 3 ; OCHF 2 ; OCF 3 ; C 1-8 -alkyl; C 2-8 -alkenyl;
C 2-8 -alkynyl; aryl; heteroaryl; aryl-C 1-6 -alkyl; heteroaryl-C 1-6 -alkyl; —(CH 2 ) o R 30 ;
—(CH 2 ) o OR 25 ; —O(CO)R 25 ;-O(CH 2 ) o R 30 ; —(CH 2 ) o SR 25 ; —(CH 2 ) o NR 25 R 26 ;
—(CH 2 ) o OCONR 25 R 26 ; —(CH 2 ) o NR 20 CONR 25 R 26 ; —(CH 2 ) o NR 20 COR 25 ; —(CH 2 ) o COOR 25 ;
—(CH 2 ) o CONR 25 R 26 ; —(CH 2 ) o PO(OR 20 ) 2 ; —(CH 2 ) o SO 2 R 24 ; or —(CH 2 ) o COR 25 ;

R 30 is an aryl group of the formula

Assignees

• Polyphor Ag
• Univ Zuerich

Inventors

• Obrecht Daniel
• Bisang Christian
• Luther Anatol
• Weinbrenner Steffen
• Robinson John Anthony
• Moehle Kerstin
• Steuer Christian
• Drury Iii William J

Classifications

• C07K7/64 Primary

  Cyclic peptides containing only normal peptide links · CPC title

• C07K14/723

  G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH receptor · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K38/02

  Peptides of undefined number of amino acids; Derivatives thereof · CPC title

• C07K14/4702

  Regulators; Modulating activity · CPC title