Homodetic cyclic peptides targeting alpha-4-beta-7 integrin

Patent metadata

Field	Value
Publication number	US-11286281-B2
Application number	US-201816611518-A
Country	US
Kind code	B2
Filing date	May 10, 2018
Priority date	May 10, 2017
Publication date	Mar 29, 2022
Grant date	Mar 29, 2022

Abstract

There is described herein antagonists of α4β7 integrin, and more particularly cyclic peptide antagonists, such as compounds of formula (I).

First claim

The invention claimed is:

1. A dimer comprising two compounds of formula (I) covalently linked together, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the structure:

wherein
R 1 is H; lower alkyl; aryl; heteroaryl; alkenyl; or heterocycle; all of which are optionally substituted with one or more substituents selected from the group consisting of H; hydroxyl; cyano; alkyl; alkoxy; aryloxy; vinyl; alkenyl; alkynyl; formyl; haloalkyl; halide; aryl; heteroaryl; amide; acyl; ester; ethers and thioethers; thioalkoxy; phosphino; and —NR a R b , where R a and R b are independently selected from lower alkyl, aryl or benzyl;
R 2 and R 3 are each independently an amino acid side chain of a proteinogenic or a non-proteinogenic alpha-amino acid,
provided that R 2 and R 3 may be covalently linked to each other to form a ring or may be covalently linked to R 1 to form a cyclic secondary amine,

R 4
along with R 5 or R 6 forms a ring resulting in a proline residue having N—R 4 as its N-terminus;

R 5 and R 6 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 4 , or may form a cyclic side chain with R 4 ;
stereocenters 1*and 2* are each independently selected from R and S; 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 is a moiety comprising a radical of 3-aminomethyl-benzoic acid;
X z is absent;
X 1 is Leucine or tert-butyl-Ala;
X 2 is Asp; and
X 3 is Thr, Ile, MeThr, alloThr, Abu, Thr(OBn), Val, or allolle,
wherein the two compounds of formula (I) are linked together at a carbon associated with X y .

2. The dimer of claim 1 , wherein R 1 is H.

3. The dimer of claim 1 , wherein R 2 or R 3 is covalently linked to R to form proline having NR 1 as the N-terminus.

4. The dimer of claim 1 , wherein R 2 and R 3 are not both H.

5. The dimer of claim 1 , wherein R 2 and R 3 are H and CH 3 respectively or vice versa.

6. The dimer of claim 1 , wherein R 4 and R 6 form a ring resulting in a proline residue having N—R 4 as its N-terminus.

7. The dimer of claim 1 , wherein X 1 is Leu.

8. The dimer of claim 1 , wherein X 3 is selected from the group consisting of Thr, Val, and Ile.

9. The dimer of claim 1 , wherein X y comprises a radical of (3-aminomethyl-4-bromo-benzoic acid), (3-aminomethyl-4-morpholinyl-benzoic acid), (3-aminomethyl-4-piperidinyl-benzoic acid), (3-aminomethyl-5-bromo-benzoic acid), (3-aminomethyl-6-bromo-benzoic acid), (3-aminomethyl-benzoic acid), [3-aminomethyl-(4-methylpyrazole-3-yl)-benzoic acid], [3-aminomethyl-4-(2,5-dimethoxy-phenyl)-benzoic acid], [3-aminomethyl-4-(2,5-dimethyl-isoxazole)-benzoic acid], [3-aminomethyl-4-(2-aminomethylphenyl)-benzoic acid], [3-aminomethyl-4-(2-fluoro-pyridyl)-benzoic acid], [3-aminomethyl-4-(3-aminomethylphenyl)-benzoic acid], [3-aminomethyl-4-(3-aza-phenyl)-benzoic acid], [3-aminomethyl-4-(3-CF3-phenyl)-benzoic acid], [3-aminomethyl-4-(3-N,N-dimethylaniline)-benzoic acid], [3-aminomethyl-4-(3-N,N-dimethyl-diaryl ether)-benzoic acid], [3-aminomethyl-4-(3-quinolinyl)-benzoic acid], [3-aminomethyl-4-(3-thiophenyl)-benzoic acid], [3-aminoethyl-4-(4-aminomethylphenyl)-benzoic acid], [3-aminomethyl-4-(4-aza-phenyl)-benzoic acid], [3-aminomethyl-4-(4-carboxy)-phenyl)-benzoic acid], [3-aminomethyl-4-(4-hydroxy-phenyl)-benzoic acid], [3-aminomethyl-4-(4-N,N-dimethyl-carboxamide-phenyl)-benzoic acid], [3-aminomethyl-4-(4-pyridyl)-benzoic acid], [3-aminomethyl-4-(4-quinolinyl)]-benzoic acid, [3-aminomethyl-4-(5-pyrimidinyl)-benzoic acid], [3-aminomethyl-4-(5-quinolinyl)-benzoic acid], [3-aminomethyl-4-(N,N-dimethyl)-benzoic acid], [3-aminomethyl-4-(piperonyl)-benzoic acid], [3-aminomethyl-4-[(2,3,4-tri-methoxy)-phenyl]-benzoic acid], [3-aminomethyl-4-[2-(1-piperazinyl)phenyl]-benzoic acid], [3-aminomethyl-4-[2-(3-(piperidin-4-ylmethoxy)phenyl]-benzoic acid], [3-aminomethyl-4-[3-(1-piperazinyl)phenyl]-benzoic acid], [3-aminomethyl-4-[4-(1-piperazinyl)phenyl]-benzoic acid], [3-aminomethyl-4-[4-(1-piperazinyl)-phenyl]-benzoic acid], [3-aminomethyl-4-[4-(1-piperazinyl-4-AlexaFluor 647)phenyl]-benzoic acid], [3-aminomethyl-4-[4-(1-piperazinyl-4-FITC)phenyl]-benzoic acid], [3-aminomethyl-4-[5-(2,4-dimethyl)thiazole]-benzoic acid], and [3-aminomethyl-5-(4-aza-phenyl)-benzoic acid].

10. The dimer of claim 1 , wherein the compound comprises a 21-membered ring.

11. The dimer of claim 1 , being any one of the following compounds:

or a pharmaceutically acceptable salt thereof.

12. The dimer of claim 1 , wherein the two compounds are identical.

13. A pharmaceutical composition comprising the dimer of claim 1 along with a pharmaceutically acceptable carrier.

14. A method of treating inflammation or an autoimmune disease in a patient, comprising administering to the patient a therapeutically effective amount of the dimer of claim 1 .

15. The method of claim 14 , wherein the condition or disease is selected from the group consisting of Inflammatory Bowel Disease (IBD); ulcerative colitis; Crohn's disease; Celiac disease; nontropical Sprue; enteropathy; pouchitis; gastrointestinal cancer; pancreatitis; insulin-dependent diabetes mellitus; mastitis; cholecystitis; cholangitis; pericholangitis; chronic bronchitis; chronic sinusitis; asthma; primary sclerosing cholangitis; human immunodeficiency virus (HIV) infection; eosinophilic asthma; eosinophilic esophagitis; gastritis; colitis; microscopic colitis; graft-versus-host disease; osteoporosis; arthritis; multiple sclerosis and chronic pain.

16. A method for treating a disease or condition in a patient comprising administering to the patient a therapeutically effective amount of the dimer of claim 1 , wherein the disease or condition is a local or systemic infection of a virus or retrovirus.

17. A method for treating a disease or condition in a patient comprising administering to the patient a therapeutically effective amount of the dimer of claim 1 , wherein the disease or condition is selected from the group consisting of hepatitis A, B or C, hepatic encephalopathy, non-alcoholic steatohepatitis, cirrhosis, variceal bleeding, hemochromatosis, Wilson disease, tyrosinemia, alpha-1-antitrypsin deficiency, hepatocellular carcinoma, liver cancer, primary biliary cholangitis, primary biliary sclerosis, biliary tract disease, and autoimmune hepatitis.

18. The dimer of claim 1 , wherein the dimer is:

or a pharmaceutically acceptable salt thereof.

Assignees

• Zealand Pharma As

Inventors

• Vazquez Manuel Perez
• Morshed M Monzur
• Kafal Adam Paul
• Hickey Jennifer L
• Roughton Andrew

Classifications

• C07K7/64 Primary

  Cyclic peptides containing only normal peptide links · CPC title

• C07K7/56 Primary

  the cyclisation not occurring through 2,4-diamino-butanoic acid · CPC title

• A61P37/06

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

• A61P29/00 Primary

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