Cyclic peptides multimers targeting α-4-β-7 integrin

Patent metadata

Field	Value
Publication number	US-11713338-B2
Application number	US-202117234488-A
Country	US
Kind code	B2
Filing date	Apr 19, 2021
Priority date	Nov 11, 2016
Publication date	Aug 1, 2023
Grant date	Aug 1, 2023

Abstract

There is described herein, multimers comprising a plurality of compounds covalently linked together, the compounds independently being of formula (I).

First claim

The invention claimed is:

1. A multimer selected from the group consisting of a homodimer, a homotrimer and a homotetramer, the multimer comprising two, three or four compounds covalently linked together by a linker selected from the group consisting of an amide linker, an amine linker and a mixed amide/amine linker, the compounds being identical and having the formula (I):

or a pharmaceutically acceptable salt thereof, wherein
R 1 is H, C 1 -C 6 alkyl, aryl, heteroaryl, alkenyl, or heterocycle, all of which are optionally substituted at one or more substitutable positions with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, aryloxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ether, thioether, thioalkoxy, phosphino, and —NR a R b , where 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 —NRaRb, where Ra and Rb are independently selected from H, C 1 -C 6 alkyl, aryl or —C 1 -C 6 alkyl-aryl; or —C(O)Rc, wherein Rc is selected from C 1 -C 6 alkyl, aryl or —C 1 -C 6 alkyl-aryl, or —C 1 -C 6 alkyl-ORd, wherein Rd is a suitable protecting group or OH group; all of which are optionally substituted at one or more substitutable positions with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, aryloxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ether, thioether, thioalkoxy, phosphino, and —NR a R b , where 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 4 and/or R 5 is C 1 -C 6 alkyl;
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)Rc; all of which are optionally substituted at one or more substitutable positions with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, aryloxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ether, thioether, thioalkoxy, phosphino, and —NR a R b , where 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 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 non-proteinogenic amino acid is optionally substituted with a substituent selected from the group consisting of hydroxyl, cyano, alkoxy, aryloxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ether, thioether, thioalkoxy, phosphino, and —NR a R b , where 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 form a cyclic side chain with R 6 ;
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, 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 Val, Thr, Ile, Thr(OBn), Thr(OMe), Thr (OEt), Pen, MeThr, alloThr, Abu, and allolle;

wherein the compounds are linked together at a nitrogen atom associated with X y .

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

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

5. The multimer 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 acid.

6. The multimer 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 multimer of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 or R 3 is —CH 2 —S—R s , wherein R s 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 at one or more substitutable positions with one or more substituents selected from the group consisting of hydroxyl; cyano; alkoxy; aryloxy, vinyl; alkenyl; alkynyl; formyl; haloalkyl; halide; aryl; heteroaryl; amide; acyl; ether; thioether; thioalkoxy; phosphino; and —NR a R b , where 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 2 , R 3 and/or R s is C 1 -C 6 alkyl; preferably R s is phenyl or phenyl substituted with C 1 -C 6 alkyl, halogen; or C 1 -C 6 amino alkyl.

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

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

10. The multimer of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are each independently H, or C(O)—NHR t , wherein R t is H or a C 1 -C 6 alkyl.

11. The multimer of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R t is tert-butyl.

12. The multimer of claim 10 or a pharmaceutically acceptable salt thereof, wherein R t is H.

13. The multimer of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H.

14. The multimer of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 and either R 8 or R 9 form a ring resulting in a proline residue having N—R 6 as its N-terminus.

15. The multimer of claim 1 , or a pharmaceutically acceptable salt t

Assignees

• Zealand Pharma As

Inventors

• Morshed Mohammed Monzur
• Chakka Sai Kumar
• Hickey Jennifer L
• Vazquez Manuel Perez
• Roughton Andrew
• Kafal Adam Paul
• Patel Narendrakumar B

Classifications

• C07K7/52 Primary

  with only normal peptide links in the ring · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P37/06 Primary

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• C07K5/126

  Tetrapeptides · 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