Modulators of Cellular Adhesion

Abstract

The present invention provides compounds having formula (I): and pharmaceutically acceptable derivatives thereof, wherein R 1 -R 4 , n, p, A, B, D, E, L and AR 1 are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of disorders mediated by the CD11/CD18 family of cellular adhesion molecules (e.g., LFA-1).

1 . An isolated compound having the structure (I): 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable derivatives thereof; 
         wherein Wand R 2  are each independently hydrogen, an amino acid side chain, —(CH 2 ) m OH, —(CH 2 ) m aryl, —(CH 2 ) m heteroaryl, wherein m is 0-6, —CH(R 1A )(OR 1B ), —CH(R 1A )(NHR 1B ), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally substituted with U-T-Q, 
         wherein U is absent, —O—, —S(O) 0-2 —, —SO 2 N(R 1A ), —N(R 1A )—, —N(R 1A )C(═O)—, —N(R 1A )C(═O)—O—, —N(R 1A )C(═O)—N(R 1B )—, —N(R 1A )—SO 2 —, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R 1A )—, —OC(═O)N(R 1A )—, —C(═N—R 1E )—, —C(═N—R 1E )—O—, —C(═N—R 1E )—N(R 1A )—, —O—C(═N—R 1E )—N(R 1A )—, —N(R 1A )C(═N—R 1E )—, —N(R 1A )C(═N—R 1E )—O—, —N(R 1A )C(═N—R 1E )—N(R 1B )—, —P(═O)(OR 1A )—O—, or —P(═O)(R 1A )—O—; 
         T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and 
         Q is hydrogen, halogen, cyano, isocyanate, —OR 1B ; —SR 1B ; —N(R 1B ) 2 , —NHC(═O)OR 1B , —NHC(═O)N(R 1B ) 2 , —NHC(═O)R 1B , —NHSO 2 R 1B , NHSO 2 N(R 1B ) 2 , —NHSO 2 NHC(═O)OR 1B , —NHC(═O)NHSO 2 R 1B , —C(═O)NHC(═O)OR 1B , C(═O)NHC(═O)R 1B , —C(═O)NHC(═O)N(R 1B ) 2 , —C(═O)NHSO 2 R 1B , —C(═O)NHSO 2 N(R 1B ) 2 , C(═S)N(R 1B ) 2 , —SO 2 R 1B , —SO 2 OR 1B , —SO 2 N(R 1B ) 2 , —SO 2 —NHC (═O)OR 1B , —OC(═O)—N(R 1B )2, —OC(═O)R 1B , —OC(═O)NHC(═O)R 1B , —OC(═O)NHSO 2 R 1B , —OSO 2 R 1B  or an aliphatic heteroaliphatic, aryl or heteroaryl moiety, or wherein R 1  and R 2  taken together are an alicyclic or heterocyclic moiety, or together are 
       
       
         
           
           
               
               
           
         
         wherein each occurrence of R 1A  and R 1B  is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —C(═O)R 1C , or —C(═O)NR 1C R 1D ; wherein each occurrence of R 1C  and R 1D  is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R 1E  is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR 1C , —NR 1C R 1D  or —SO2R 1C ; 
         R 3  is —C(═O)OR 3A , —C(═O)H, —CH 2 OR 3A , —CH 2 OC(═O)-alkyl, —C(═O)NH(R 3A )—CH 2 X 0 ; wherein each occurrence of R 3A  is independently hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl heteroalkylheteroaryl moiety, or pharmaceutically acceptable salt or ester, or R 3A , taken together with R 1  and R 2 , forms a heterocyclic moiety; wherein X 0  is a halogen selected from F, Br or I; 
         R 4  for each occurrence, is independently hydrogen, halogen, —CN, —NO 2 , an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is GR G1  wherein G is —O—, —S—, NR G2 —, —CO—, —SO—, —SO 2 —, C(═O)O—, —C(═O)NR G2 —, C(═O)—, —NR G2 C(═O)— or —SO 2 NR G2 —, and R G1  and R G2  are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; 
         n is an integer from 0-4; 
         AR 1  is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; 
         A, B, D and E are connected by either a single or double bond, as valency permits; wherein each occurrence of A, B, D and E is independently C═O, CR i i R ii , NR i , CR i , N, O, S, —S(═O) or SO 2 ; wherein each occurrence of R i  is independently hydrogen, halogen, —CN, —NO 2 , an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR G1  wherein G is —O—, —S—, —NR G2 , —CO—, —SO—, —C(═O)O—, —C(═O)NR G2 —, —OC(═O)—, —NR G2 C(═O)— or —SO 2 NR G2 —, and R G1  and R G2  are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or any two adjacent occurrences of taken together, represent an alicyclic, heteroalicyclic, aryl, or heteroaryl moiety; 
         p is an integer from 0-4; and, 
         L is absent or is V—W—X—Y—Z, wherein each occurrence of V, W, X, Y and Z is independently absent, C═O, NR L1 , —O—, —C(R L1 )═, ═C(R L1 )—, —C(R L1 )(R L2 ), C(═N—O R L1 ), C(═NR L1 ), —N═, S(O) 0-2 ; a substituted or unsubstituted C 1-6  alkenylidene or C 2-6  alkenylidine chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO 2 —, —C(═O)C(═O)—, —C(C═O)NR L3 —, —OC(═O)—, —OC(═O)NR L3 —, —NR L3 NR L4 —, —NR L3 NR L4 C(═O)—, —NR L3 C(═O)—, NR L3 CO 2 —, NR L3 C(═O)NR L4 —, —S(═O)—, —SO 2 —, —NR L3 SO 2 —, —SO 2 NR L3 , —NR L3 SO 2 NR L4 , —O—, —S—, or —NR L3 —; wherein each occurrence of R L3  and R L4  is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl; or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and each occurrence of R L1  and R L2  is independently hydrogen, hydroxyl, protected hydroxyl, amino, protected amino, thio, protected thio, halogen, cyano, isocyanate, carboxy, carboxyalkyl, formyl, formyloxy, azido, nitro, ureido, thioureido, thiocyanato, alkoxy, aryloxy, mercapto, sulfonamido, benzamido, tosyl, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or wherein one or more occurrences of R L1  and R L2 , taken together, or taken together with one of V, W, X, Y or Z form an alicyclic or heterocyclic moiety or form an aryl or heteroaryl moiety. 
       
     
     
         2 . A composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         3 . A kit comprising the composition of  claim 2  in unit dosage form. 
     
     
         4 . A method of treating an immune or inflammatory disorder in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         5 . A method according to  claim 4 , wherein said immune or inflammatory disorder is mediated through an interaction of a CD11a/CD18 leukointegrin with a member of the ICAM family of cellular adhesion molecules. 
     
     
         6 . A method according to  claim 5 , wherein said compound is a competitive inhibitor of said interaction. 
     
     
         7 . A method according to  claim 4 , wherein said subject is a non-human animal. 
     
     
         8 . A method according to  claim 7 , wherein said non-human animal is a mammal. 
     
     
         9 . A method according to  claim 8 , wherein said mammal is selected from the group consisting of a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig. 
     
     
         10 . A method according to  claim 4 , wherein said immune or inflammatory disorder is selected from the group consisting of psoriasis, inflammatory bowel disease, dermatitis, meningitis, encephalitis, uveitis, eczema, asthma, poison ivy, poison oak, atherosclerosis, rheumatoid arthritis, systemic lupus erythematosus (SLE), diabetes mellitus, multiple sclerosis, Raynaud's syndrome, autoimmune thyroiditis, experimental autoimmune encephalomyelitis, Sjorgen's syndrome, type 1 diabetes, juvenile onset diabetes, tuberculosis, sarcoidosis, polymyositis, granulomatosis, vasculitis, pernicious anemia, CNS inflammatory disorder autoimmune haemolytic anemia, myasthenia gravis, graft vs. host disease, host vs. graft disease, HIV infection, rhinovirus infection, and pulmonary fibrosis. 
     
     
         11 . A method according to  claim 4 , wherein said treatment is palliative. 
     
     
         12 . A method according to  claim 4 , wherein said treatment further comprises administration with one or more additional therapeutics or medical procedures. 
     
     
         13 . A method of diagnosing an immune or inflammatory disorder in a subject, said method comprising administering a compound according to  claim 1  to said subject or to a biological sample from said subject, and measuring the interaction between LFA-1 and ICAM-1 in the presence of said compound in said subject or in a biological sample from said subject. 
     
     
         14 . A method of predicting responsiveness of an immune or inflammatory disorder in a subject to treatment with a compound according to  claim 1 , said method comprising administering said compound to said subject or to a biological sample from said subject, and measuring the interaction between LFA-1 and ICAM-1 in the presence of said compound in said subject or in a biological sample from said subject. 
     
     
         15 . A method of assaying the interaction between LFA-1 and ICAM-1 in a biological sample, said method comprising administering to said biological sample a compound according to  claim 1 , and measuring the interaction between LFA-1 and ICAM-1 in the presence of said compound. 
     
     
         16 . A method according to  claim 15 , wherein said biological sample is a human cell line. 
     
     
         17 . A method of synthesizing a compound according to  claim 1 , said method comprising formation of an amide bond. 
     
     
         18 . A method of purifying a compound according to  claim 1 , said method comprising crystallizing said compound from a reaction mixture. 
     
     
         19 . A method of purifying a compound according to  claim 1 , said method comprising crystallizing said compound from crude compound. 
     
     
         20 . A method of purifying a compound according to  claim 1 , said method comprising chromatography of said compound from crude compound.