Cyclic peptides targeting alpha-4-beta-7 integrin

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 R1, R2, R3, R4, R5, R6, R7 and R8 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.

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: 
       
       
         
           
           
               
               
           
         
         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 Thr(OMe); 
 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  and R 3  are H and CH 3  respectively or vice versa. 
     
     
         4 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 4  and R 5  are each independently H or C(O)—NHR***, wherein R*** is H or a C 1 -C 6  alkyl. 
     
     
         5 . The compound of  claim 4  or a pharmaceutically acceptable salt thereof, wherein R*** is tert-butyl. 
     
     
         6 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 6  and either R 7  or R 8  form a ring resulting in a proline residue having N—R 6  as its N-terminus. 
     
     
         7 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein n is 1. 
     
     
         8 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein X 1  is Leu. 
     
     
         9 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein X 2  is Asp. 
     
     
         10 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein X y  is Tyr. 
     
     
         11 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein X z  is absent. 
     
     
         12 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein X y  is F and X z  is absent. 
     
     
         13 . The compound of  claim 1 , being compound 40 or a pharmaceutically acceptable salt thereof. 
     
     
         14 . A pharmaceutical composition comprising the compound of  claim 1  or a pharmaceutically acceptable salt thereof along with the pharmaceutically acceptable carrier. 
     
     
         15 . The pharmaceutical composition of  claim 14 , formulated for oral delivery. 
     
     
         16 . The pharmaceutical composition of  claim 14 , formulated for topical delivery. 
     
     
         17 . The pharmaceutical composition of  claim 14 , formulated for parenteral delivery. 
     
     
         18 . A method of treating inflammation or an autoimmune disease in a patient, comprising administering to the patient a therapeutically effective amount of the compound of  claim 1 . 
     
     
         19 . The method of  claim 18 , wherein the inflammation or an autoimmune disease is gastrointestinal. 
     
     
         20 . The method of  claim 18 , wherein the condition or disease is Inflammatory Bowel Disease (IBD); ulcerative colitis; Crohn's disease; Celiac disease; enteropathy associated with seronegative arthropathies; microscopic colitis; collagenous colitis; eosinophilic gastroenteritis; radiotherapy; chemotherapy; pouchitis resulting after proctocolectomy and ileoanal anastomosis; gastrointestinal cancer; pancreatitis; insulin-dependent diabetes mellitus; mastitis; cholecystitis; cholangitis; pericholangitis; chronic bronchitis; chronic sinusitis; asthma; primary sclerosing cholangitis; human immunodeficiency virus (HIV) infection in the GI tract; eosinophilic asthma; eosinophilic esophagitis; gastritis; colitis; microscopic colitis; graft versus host disease; colitis associated with radio- or chemo-therapy; colitis associated with disorders of innate immunity; leukocyte adhesion deficiency-1; chronic granulomatous disease; glycogen storage disease type 1 b; Hermansky-Pudlak syndrome; Chediak-Higashi syndrome; and Wiskott-Aldrich Syndrome; osteoporosis; arthritis; multiple sclerosis; chronic pain; weight gain; or depression. 
     
     
         21 . The method of  claim 20 , wherein the condition is an inflammatory bowel disease. 
     
     
         22 . The method of  claim 21 , wherein the inflammatory bowel disease is ulcerative colitis. 
     
     
         23 . The method of  claim 21 , wherein the inflammatory bowel disease is Crohn's disease. 
     
     
         24 . The method of  claim 18 , wherein the compound inhibits binding of α4β7 integrin to MAdCAM. 
     
     
         25 . The method of  claim 18 , wherein the patient is a human.