Multimeric VLA-4 Antagonists Comprising Polymers Moieties

Abstract

Disclosed are conjugates which bind VLA-4. Certain of these conjugates also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such conjugates are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The conjugates can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

1 . A conjugate of the formula I: 
       
         
           
           
               
               
           
         
         B is a bio-compatible polymer moiety optionally covalently attached to a branched-arm hub molecule; 
         q is from about 2 to about 100; 
         A at each occurrence is independently a compound of formula II 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         J is selected from:
 a) a group of formula (a): 
 
       
       
         
           
           
               
               
           
         
         
           wherein R 31  is a covalent bond to the polymer moiety which optionally comprises a linker, or R 31  is selected from the group consisting of —H, R 31′ , —NH 2 , —NHR 31′ , —N(R 31′ ) 2 , —NC 3 -C 6 cyclic, —OR 31′ , and —SR 31′ , wherein each R 31′  is independently an optionally substituted straight or branched C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, 
           and R 32  is a covalent bond to the polymer moiety which optionally comprises a linker, or R 32  is selected from the group consisting of —H, —NO 2 , haloalkyl, and —N(MR 41 )R 42  wherein M is a covalent bond, —C(O)— or —SO 2 —, and R 41  is R 41′ , N(R 41′ ) 2 , or —OR 41′ , 
           wherein each R 41′  is independently hydrogen, an optionally substituted straight or branched C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic or an optionally substituted heteroaryl, wherein optional substitutions are halide, C 1 -C 6 alkyl, or —OC 1 -C 6 alkyl, 
           and R 42  is hydrogen, R 41′ , alkynyl, or substituted alkynyl; and 
           b) a group of formula (b): 
         
       
       
         
           
           
               
               
           
         
         
           wherein R is selected from the group consisting of a hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
           Ar 1  is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl wherein each of aryl, substituted aryl, heteroaryl and substituted heteroaryl is optionally covalently bound to the polymer moiety wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar 1 ; 
           Ar 2  is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, alkylamino, and substituted alkylamino, wherein Ar 2  is optionally covalently bound to the polymer moiety and wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar 2 ; 
           X is selected from the group consisting of —NR 1 —, —O—, —S—, —SO—, —SO 2  and optionally substituted —CH 2 — which is optionally covalently bound to the polymer moiety wherein, in each case, the polymer moiety optionally comprises a linker which covalently links the polymer moiety; 
           where R 1  is selected from the group consisting of hydrogen and alkyl; 
         
         T is selected from:
 a) a group of formula (c) 
 
       
       
         
           
           
               
               
           
         
         
           wherein Y is selected from the group consisting of —O— and —NR 1 — wherein R 1  is selected from the group consisting of hydrogen and alkyl; 
           W is selected from the group consisting of a covalent bond to a polymer moiety which optionally comprises a linker and —NR 2 R 3  wherein R 2  and R 3  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, and where R 2  and R 3 , together with the nitrogen atom bound thereto, form a heterocyclic ring or a substituted heterocyclic ring wherein each of alkyl, substituted alkyl, heterocyclic and substituted heterocyclic is optionally covalently bound to a polymer moiety which further optionally comprises a linker; 
           m is an integer equal to 0, 1 or 2; 
           n is an integer equal to 0, 1 or 2; and 
           b) a group of formula (d) 
         
       
       
         
           
           
               
               
           
         
         
           wherein G is an optionally substituted aryl or optionally substituted heteroaryl 5 or 6 membered ring containing 0 to 3 nitrogens, wherein said aryl or heteroaryl optionally further comprises a covalent bond to a polymer moiety which optionally comprises a linker; 
           R 6  is a covalent bond to a polymer moiety which optionally comprises a linker, or R 6  is —H, alkyl, substituted alkyl, or —CH 2 C(O)R 17 , wherein R 17  is —OH, —OR 18 , or —NHR 18 , wherein R 18  is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; 
           R 55  is —OH or a hydrolyzable ester, or R 55  forms a hydrolyzable polymer ester with the polymer moiety, optionally through a linker; 
         
         provided that:
 A. at least one of J, R 55 , and T contains a covalent bond to the polymer moiety; 
 B. when X is —O—, then m is two; and 
 C. the conjugate of formula I has a molecular weight of no more than about 80,000. 
 
       
     
     
         2 . The conjugate according to  claim 1 , wherein only one of J, R 55  and T contains a covalent bond to a polymer moiety. 
     
     
         3 . The conjugate according to  claim 1 , wherein n is 2, R at each occurrence is C 1 -C 3  alkyl, and both R groups are on the same carbon. 
     
     
         4 . The conjugate according to  claim 1 , wherein, q is an integer of from 2 to about 20. 
     
     
         5 . The conjugate according to  claim 1 , wherein q is an integer of from 2 to about 8. 
     
     
         6 . (canceled) 
     
     
         7 . The conjugate according to  claim 1 , wherein A at each occurrence is independently a compound of formula IIb: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The conjugate according to  claim 1 , wherein A at each occurrence is independently a compound of IIc: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 - 10 . (canceled) 
     
     
         11 . The conjugate according to  claim 1 , wherein A at each occurrence is independently a compound of formula IIf: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 R 4  is covalently bound to a polymer moiety which optionally comprises a linker; 
 R 5  is selected from the group consisting of alkyl and substituted alkyl; and 
 Ar 3  is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl. 
 
       
     
     
         12 - 14 . (canceled) 
     
     
         15 . The conjugate according to claim  14  wherein m is 1, X is S, and R at each occurrence is independently selected from hydroxyl, alkyloxy, alkyl, or a covalent bond to the polymer moiety. 
     
     
         16 . The conjugate according to  claim 15  wherein n is 2, and Rat both occurrences is methyl. 
     
     
         17 . The conjugate according to  claim 1 , wherein A at each occurrence is independently a compound of formula IIj below: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         18 - 19 . (canceled) 
     
     
         20 . The conjugate according to  claim 17  wherein G is pyridinyl, R 31  is hydrogen or dialkylamino, and R 32  is sulfonamide, amide, or urea. 
     
     
         21 . The conjugate according to  claim 1 , wherein A and B are as shown below: 
       
         
           
                 
                 
               
                     
                 
                   B Moieties 
                   A Moieties 
                 
                     
                 
                   —C(O)O(CH 2 CH 2 O) p C(O)— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Z 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   —C(O)O(CH 2 CH 2 O) p C(O)— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Z 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   —C(O)O(CH 2 CH 2 O) p C(O)— 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   ZZ (total Mw of conjugate is about 42,000) 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   ZZ (total Mw of conjugate is about 42,000) 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   ZZZ (total Mw of conjugate is about 41,000) 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein 
         Z is 
       
       
         
           
           
               
               
           
         
         ZZ is 
       
       
         
           
           
               
               
           
         
          and 
         ZZZ is 
       
       
         
           
           
               
               
           
         
         where the sum of all p's is from 100 to 1360. 
       
     
     
         22 . A conjugate according to  claim 1 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and a pharmaceutically acceptable salt thereof. 
       
     
     
         23 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a conjugate according to  claim 1  or mixtures thereof. 
     
     
         24 - 31 . (canceled) 
     
     
         32 . A method for treating a disease state caused or exacerbated at least in part by alpha 4 integrin-mediated leukocyte binding in a patient, which method comprises administering an effective amount of a conjugate according to  claim 1 . 
     
     
         33 - 37 . (canceled) 
     
     
         38 . The method of  claim 32  wherein the disease state is multiple sclerosis, meningitis, encephalitis, stroke, and other cerebral traumas 
     
     
         39 . The method of  claim 32  wherein the disease state is multiple sclerosis. 
     
     
         40 - 48 . (canceled) 
     
     
         49 . A pharmaceutical composition comprising a conjugate according to  claim 1  in combination with an α 4 β 7  inhibitor. 
     
     
         50 . (canceled)