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 - 75 . (canceled) 
     
     
         76 . A method for inhibiting the interaction between LFA-1 and ICAM-1 in a patient in need thereof, comprising administering to the patient a compound of Formula I or its pharmaceutically acceptable salt or ester 
       
         
           
           
               
               
           
         
       
       wherein —C(═O)NHC(R 1 )(R 2 )R 3  is a moiety having the following structure: 
       
         
           
           
               
               
           
         
         R 3A  is hydrogen; 
         R S  is hydrogen; 
         Ar 2  is: 
       
       
         
           
           
               
               
           
         
         s is an integer of 1; 
         each occurrence of R P1  is independently hydrogen, halogen, or -GR G1 , wherein G is —SO 2 — or —SO 2 NR G2 —; and R G1  and R G2  are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety; 
         R B1 , R B2  and R E  are hydrogen; 
         R 4A  and R 4B  are each Cl; 
         L is C═O; and Ar 1  is 
       
       
         
           
           
               
               
           
         
       
     
     
         77 . The method of  claim 76 , wherein the compound is present in an amount effective to inhibit the interaction between LFA-1 and ICAM-1 in the patient. 
     
     
         78 . The method of  claim 76 , wherein the Compound of formula I is a sodium, potassium, lithium, magnesium, or calcium salt. 
     
     
         79 . The method of  claim 78 , wherein the compound of formula I is in a pharmaceutically acceptable topical formulation. 
     
     
         80 . The method of  claim 79 , wherein the formulation is in the form of an ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant, patch, suspension, emulsion, crystalline form, oil, plaster, liposome, microemulsion, or buffered solution. 
     
     
         81 . The method of  claim 79 , wherein the pharmaceutically acceptable topical formulation comprises an acceptable excipient. 
     
     
         82 . The method of  claim 81 , wherein the excipient is selected from the group consisting of alcohols, quaternary amines, organic acids, parabens, phenols, ascorbic acid, ascorbic acid esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, chelating agents, glycerine, sorbitol, polyethylene glycols, urea, propylene glycol, citric buffer, hydrochloric buffer, lactic acid buffer, quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, polysorbates, vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, zinc oxide, and combinations thereof. 
     
     
         83 . The method of  claim 81 , further comprising a topical penetration enhancer. 
     
     
         84 . The method of  claim 83 , wherein the penetration enhancer is triglycerides, aloe compositions, ethyl alcohol, isopropyl alcohol, octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, fatty acid esters, N-methylpyrrolidone, or combinations thereof. 
     
     
         85 . The method of  claim 79 , further comprising at least one additional therapeutic agent, wherein the additional therapeutic agent is selected from the group consisting of an anti-inflammatory agent, painkillers, antinausea medications, anti-sickness drugs, a MAC-1 modulator, and an LFA-1 modulator. 
     
     
         86 . The method of  claim 79 , wherein the formulation is topically applied to skin or eyes. 
     
     
         87 . The method of  claim 76 , wherein the patient suffers from an inflammatory or immune related disorder selected from the group consisting of psoriasis, Crohn's disease, ulcerative colitis, dermatitis, meningitis, encephalitis, uveitis, eczema, asthma, artherosclerosis, rheumatoid arthritis, diabetes mellitus, multiple sclerosis, Reynaud's syndrome, autoimmune thyroiditis, experimental autoimmune encephalomyelitis, Sjogren's syndrome, juvenile onset diabetes, sarcoidosis, polymyositis, granulomatosis, vasculitis, pernicious anemia, multiple organ injury syndrome secondary to septicaemia or trauma, autoimmune hemolytic anemia, myasthemia gravis, HIV, rhinovirus infection, and pulmonary fibrosis. 
     
     
         88 . The method of  claim 76 , wherein R P1  is selected from the group consisting of halogen and -GR G1 , wherein G is —SO 2 — and R G1  is methyl. 
     
     
         89 . The method of  claim 76 , wherein Ar 1  is 
       
         
           
           
               
               
           
         
       
       and R P1  is selected from the group consisting of F and SO 2 CH 3 .