Cyclic peptides targeting alpha-4-beta-7 integrin

Patent metadata

Field	Value
Publication number	US-11072616-B2
Application number	US-201615775309-A
Country	US
Kind code	B2
Filing date	Nov 14, 2016
Priority date	Nov 11, 2015
Publication date	Jul 27, 2021
Grant date	Jul 27, 2021

Abstract

There is described herein antagonists of α4β7 integrin, and more particularly to cyclic peptide antagonists. Accordingly, there is described herein a compound of formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are various substituents; stereocentres 1*, 2* and 3* are each independently selected from R and S; n is 1, 2, 3, or 4 and where n is 2-4, Z is an amino terminus of an amino acid; —C═O— adjacent L is the carboxy terminus of an amino acid; and L along with Z and —C═O— is a peptide.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein
R 1 is H; C 1 -C 6 alkyl; aryl; heteroaryl; alkenyl; or heterocycle; all of which are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkyl, alkoxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ester, ether, thioether, thioalkoxy, phosphino, and —NR a R b ,
wherein R a and R b are independently selected from C 1 -C 6 alkyl, aryl or benzyl;
and where the one or more substituents is not alkyl when R 1 is C 1 -C 6 alkyl;
R 2 and R 3 are each independently an amino acid side chain of a proteinogenic or a non-proteinogenic alpha-amino acid, or
R 2 and R 3 are covalently linked to each other to form a ring;

R 4 and R 5 are each independently H; C 1 -C 6 alkyl; aryl; heteroaryl; alkenyl; heterocycle; acids of the formula —C(O)OH; esters of the formula —C(O)OR* wherein R* is selected from alkyl and aryl; amides of the formula —C(O)NR**R***, wherein R** and R*** are independently selected from H, alkyl and aryl; —CH 2 C(O)R, wherein R is selected from —OH, C 1 -C 6 alkyl, aryl, —C 1 -C 6 alkyl-aryl, or NR a R b , where R a and R b are independently selected from C 1 -C 6 alkyl, aryl or benzyl; or —C(O)R c , wherein R c is selected from C 1 -C 6 alkyl, aryl or —C 1 -C 6 alkyl-aryl; or —C 1 -C 6 alkyl-OR d , wherein R d is an OH group or a protecting group selected from the group consisting of formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, alpha.-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, benzenesulfonyl, p-toluenesulfonyl, benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, alpha.-,alpha.-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, benzyl, triphenylmethyl, benzyloxymethyl, and trimethylsilyl; all of which are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkyl, alkoxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ester, ether, thioether, thioalkoxy, phosphino, and —NR a R b ,
wherein R a and R b are independently selected from C 1 -C 6 alkyl, aryl or benzyl; and where, when R 4 , R 5 , R, R a , R b or R c is C 1 -C 6 alkyl, the one or more substituents is not alkyl at that position; and wherein the one or more substituents is not —NR a R b when R is —NR a R b ;
or R 2 or R 3 are covalently linked to R 1 to form a cyclic secondary amine, and/or to R 4 or R 5 to form a ring, or R 4 and R 5 are covalently linked to each other to form a ring;

R 6 is H, C 1 -C 6 alkyl, benzyl, alkenyl, C 1 -C 6 alkyloxy; aryl; heteroaryl; heterocycle; —C(O)R****, wherein R**** is independently selected from alkyl, aryl, heteroaryl, amino, aminoalkyl, aminoaryl, aminoheteroaryl, alkoxy, aryloxy, heteroaryloxy; —CH 2 C(O)R; or —C(O)R c ; all of which are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkyl, alkoxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ester, ether, thioether, thioalkoxy, phosphino, and —NR a R b ,
wherein R a and R b are independently selected from C 1 -C 6 alkyl, aryl or benzyl, and where the one or more substituents is not alkyl when R 6 is C 1 -C 6 alkyl,
or R 6 forms, along with R 7 or R 8 , a cyclic side chain of a proteinogenic or a non-proteinogenic amino acid having, the N-terminus thereof being the N—R 6 , wherein the proteinogenic or a non-proteinogenic amino acid is optionally substituted with a substituent selected from the group consisting of hydroxyl, cyano, alkyl, alkoxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ester, ether, thioether, thioalkoxy, phosphino, and —NR a R b ,
wherein R a and R b are independently selected from C 1 -C 6 alkyl, aryl or benzyl;

R 7 and R 8 are independently selected from the amino acid side chains of a proteinogenic or a non-proteinogenic alpha-amino acid having the N-terminus thereof being the N—R 6 , or R 7 or R 8 forms a cyclic side chain with R 6 ;
stereocenters 1*, 2* and 3*, where present, are each independently selected from R and S;
n is 1, 2, 3, or 4 and where n is 2-4, each R 7 and each R 8 are independent of each other;
and

wherein Z is an amino terminus of an amino acid; —C═O— adjacent L is the carboxy terminus of an amino acid; and L along with Z and —C═O— is a peptide having the following formula:
X y —X z —X 1 —X 2 —X 3

wherein X y and X z are each independently a proteinogenic or non-proteinogenic amino acid, or X z is absent;
X 1 is Leucine or tert-butyl-Ala;
X 2 is Asp; and
X 3 is an amino acid selected from the group consisting of Thr, Thr(OBn), Thr(OEt), Pen, MeThr, alloThr, Abu, Val, Ile and Allolle,
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 or R 3 is covalently linked to R 1 to form proline having NR 1 as the N-terminus.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are not both H.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each independently selected from the group consisting of amino acid side chains of a proteinogenic or a non-proteinogenic alpha-amino acids.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are H and CH 3 respectively or vice versa.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 or R 3 is —CH 2 —S—R 5 , wherein R 5 is selected from C 1 -C 6 alkyl; C 1 -C 6 amino alkyl; aryl; heteroaryl; alkenyl; or heterocycle; all of which are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkyl, alkoxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ester, ether, thioether, thioalkoxy, phosphino, and —NR a R b ,
wherein R a and R b are independently selected from C 1 -C 6 alkyl, aryl or benzyl; wherein the one or more substituents is not alkyl when R 5 is C 1 -C 6 alkyl; preferably R 5 is phenyl or phenyl substituted with C 1 -C 6 alkyl, halogen; or C 1 -C 6 amino alkyl.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are not both H.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R** and R*** are not both H.

10. The compound of claim 1 or a p

Assignees

• Zealand Pharma As
• Univ Montreal

Inventors

• Vazquez Manuel Perez
• Morshed M Monzur
• Hickey Jennifer L
• Kafal Adam Paul
• Gillard James
• Patel Narendra
• Chakka Sai Kumar
• Roughton Andrew L
• Poupart Marc-André
• Yang Gaoqiang

Classifications

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07C271/22

  to carbon atoms of hydrocarbon radicals substituted by carboxyl groups · CPC title

• C07K1/1075

  by covalent attachment of amino acids or peptide residues · CPC title

• C07K7/64

  Cyclic peptides containing only normal peptide links · CPC title

• A61P25/24

  Antidepressants · CPC title