Cyclic tetrapeptides and therapeutic applications thereof

Abstract

There are provided compounds of formula I wherein k, m, n, p, R, R′, R″, R′″, R3 and R4 are as defined in the application. Other embodiments are also disclosed.

1 . A compound having the formula I: 
       
         
           
           
               
               
           
         
         wherein 
         k, m, n and p are each independently 0, 1 or 2, provided that at least one of k, m, n and p is not 0; 
         R and R′ are each independently selected from H and C 1-3  alkyl, or, when taken together, R and R′ are —CR 1 R 1′ —X—CH 2 —, wherein CR 1 R 1′  is attached to the backbone nitrogen, R 1  and R 1′  are each independently selected from H and C 1-3  alkyl, and X is selected from —CH 2 —, —CH 2 CH 2 —, —CH(OH)—, —O—, —S— and —NH—; 
         R″ and R′″ are each independently selected from H and C 1-3  alkyl, or, when taken together, R″ and R′″ are —CR 2 R 2′ —X′—CH 2 —, wherein CR 2 R 2′  is attached to the backbone nitrogen, R 2  and R 2′  are each independently selected from H and C 1-3  alkyl, and X′ is selected from —CH 2 —, —CH 2 CH 2 —, —CH(OH)—, —O—, —S— and —NH—; and 
         R 3  and R 4  are each independently selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 - 243 . (canceled) 
     
     
         244 . A compound according to  claim 1  wherein at least one of R 3  and R 4  is selected from the group consisting of phenyl, 4-hydroxyphenyl, 4-t-butoxyphenyl and 2-indolyl. 
     
     
         245 . A compound according to  claim 1  wherein one of R 3  and R 4  is phenyl and the other of R 3  and R 4  is selected from the group consisting of phenyl, 4-hydroxyphenyl, 4-t-butoxyphenyl, and 2-indolyl. 
     
     
         246 . A compound according to  claim 1  wherein at least one of the following is true: (a) one of k, m, n and p is 1, and the remainder of k, m, n and p are 0; (b) two of k, m, n and p are 1, and the remainder of k, m, n and p are 0; (c) at least one of k and m is not 0; (d) at least one of n and p is not 0; (e) at least one of k and m is not 0 and at least one of n and p is not 0; (f) both k and n are 0; (g) both k and n are 0, one of m and p is 0, and the other of m and p is 1; (h) both k and n are 0 and both m and p are 1. 
     
     
         247 . A compound according to  claim 1  wherein at least one of the following is true: (a) R and R′ are taken together to form —(CH 2 ) 3 —; (b) R″ and R′″ are taken together to form —(CH 2 ) 3 —; (c) R and R′ are taken together to form —(CH 2 ) 4 —; (d) R″ and R′″ are taken together to form —(CH 2 ) 4 —; (e) R and R′ are taken together to form —CH 2 —CH(OH)—CH 2 — (f) R″ and R′″ are taken together to form —CH 2 —CH(OH)—CH 2 —. 
     
     
         248 . A compound according to  claim 1  wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         249 . A compound according to  claim 248  which is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         250 . A pharmaceutical composition comprising a compound having the formula I: 
       
         
           
           
               
               
           
         
         wherein 
         k, m, n and p are each independently 0, 1 or 2, provided that at least one of k, m, n and p is not 0; 
         R and R′ are each independently selected from H and C 1-3  alkyl, or, when taken together, R and R′ are —CR 1 R 1′ —X—CH 2 —, wherein CR 1 R 1′  is attached to the backbone nitrogen, R 1  and R 1′  are each independently selected from H and C 1-3  alkyl, and X is selected from —CH 2 —, —CH 2 CH 2 —, —CH(OH)—, —O—, —S— and —NH—; 
         R″ and R′″ are each independently selected from H and C 1-3  alkyl, or, when taken together, R″ and R′″ are —CR 2 R 2′ —X′—CH 2 —, wherein CR 2 R 2′  is attached to the backbone nitrogen, R 2  and R 2′  are each independently selected from H and C 1-3  alkyl, and X′ is selected from —CH 2 —, —CH 2 CH 2 —, —CH(OH)—, —O—, —S— and —NH—; and 
         R 3  and R 4  are each independently selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; 
         or a pharmaceutically acceptable salt thereof, 
       
       and a pharmaceutically acceptable carrier, excipient or diluent therefor. 
     
     
         251 . A pharmaceutical composition according to  claim 250  wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         252 . A pharmaceutical composition according to  claim 251  wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         253 . A pharmaceutical composition according to  claim 250  wherein at least one of the following is true of the compound of formula I: (a) R and R′ are taken together and the carbon at which R′ is attached has absolute (S)-stereochemistry; (b) R″ and R′″ are taken together and the carbon at which R′″ is attached has absolute (S)-stereochemistry. 
     
     
         254 . A pharmaceutical composition according to  claim 250  wherein the carbon to which —CH 2 —R 3  is attached has absolute (S)-stereochemistry and the carbon which —CH 2 —R 4  is attached has absolute (S)-stereochemistry. 
     
     
         255 . A pharmaceutical composition according to  claim 250  wherein at least one of the carbons to which R′, R′″, —CH 2 R 3  and —CH 2 R 4  are respectively attached has absolute (R)-stereochemistry. 
     
     
         256 . A method of suppressing immune response in a patient, or of treating or preventing an immune-mediated disease or condition in a patient, comprising administering to a patient in need thereof an efficacious amount of a compound of formula I: 
       
         
           
           
               
               
           
         
         wherein 
         k, m, n and p are each independently 0, 1 or 2, provided that at least one of k, m, n and p is not 0; 
         R and R′ are each independently selected from H and C 1-3  alkyl, or, when taken together, R and R′ are —CR 1 R 1′ —X—CH 2 —, wherein CR 1 R 1′  is attached to the backbone nitrogen, R 1  and R 1′  are each independently selected from H and C 1-3  alkyl, and X is selected from —CH 2 —, —CH 2 CH 2 —, —CH(OH)—, —O—, —S— and —NH—; 
         R″ and R′″ are each independently selected from H and C 1-3  alkyl, or, when taken together, R″ and R′″ are —CR 2 R 2′ —X′—CH 2 —, wherein CR 2 R 2′  is attached to the backbone nitrogen, R 2  and R 2′  are each independently selected from H and C 1-3  alkyl, and X′ is selected from —CH 2 —, —CH 2 CH 2 —, —CH(OH)—, —O—, —S— and —NH—; and 
         R 3  and R 4  are each independently selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         257 . A method according to  claim 256  wherein the immune-mediated disease or condition is selected from the group consisting of (a) the group consisting of auto-immune diseases, inflammation processes, transplant rejection, and allergic reactions, (b) the group consisting of Psoriasis, lichen planus and other papulosquamous disorders, (c) the group consisting of eczema and dermatitis (including eczema, atopic eczema, seborrheic dermatitis, and pompholyx), (d) a skin reaction to light, (e) the group consisting of non-specific skin irritation and insect bite, (f) a urticaria, and (g) the group consisting of rheumatoid arthritis (both autoimmune and elicited by infection), Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, a neurodegenerative disease (e.g. multiple sclerosis), Graft-versus-Host reaction, severe psoriasis and atopic dermatitis. 
     
     
         258 . A compound according to  claim 1  wherein at least one of the following is true: (a) R and R′ are taken together and the carbon at which R′ is attached has absolute (S)-stereochemistry; (b) R″ and R′″ are taken together and the carbon at which R′″ is attached has absolute (S)-stereochemistry. 
     
     
         259 . A compound according to  claim 1  wherein the carbon to which —CH 2 —R 3  is attached has absolute (S)-stereochemistry and the carbon which —CH 2 —R 4  is attached has absolute (S)-stereochemistry. 
     
     
         260 . A compound according to  claim 1  wherein one or more amino groups in the compound of Formula I are in protected form. 
     
     
         261 . A compound according to  claim 1  wherein at least one of the carbons to which R′, R′″, —CH 2 R 3  and —CH 2 R 4  are respectively attached has absolute (R)-stereochemistry. 
     
     
         262 . The compound according to  claim 1  which is the compound of formula I-A or a pharmaceutically acceptable salt thereof.