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

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.