Novel CD40:CD154 binding interruptor compounds and use thereof to treat immunological complications

Abstract

The present invention relates to novel CD40:CD154 binding interrupter compounds and use of these compounds and pharmaceutical compositions comprising them, to treat conditions associated with inappropriate CD154 activation in a subject. Specifically, this invention provides compounds which are identified by screening a library of small molecules for those that are capable of specifically binding CD154 and interrupting CD40:CD154 interaction.

1 . A compound, which interrupts CD40:CD154 interaction, of the formula:  
     
       
         
         
             
             
         
       
       Formula I,  
       wherein,  
       R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are independently selected from the group consisting of H, C1-5 alkyl, C1-5 alkyl-aryl, C1-5 alkyl-cycloalkyl, C1-5 alkyl-heteroaryl, C1-5 alkenyl-heterocyclo, cycloalkyl, cycloalkyl-aryl, C1-5 alkenyl-aryl, CR g R h CO 2 H and CR g R h CO 2 alkyl; wherein aryl or heteroaryl are optionally substituted with one to four substituents selected from R d  and alkyl is optionally substituted with R i ; or R 1  and R 2 , R 3  and R 4 , R 5  and R 6 , and R 7  and R 8  independently form, together with the nitrogen to which they are attached, a 5-6 membered ring which is optionally substituted with a heteroatom selected from the group consisting of nitrogen, sulfur and oxygen, wherein the nitrogen may optionally be substituted with alkyl or alkyl-aryl and the ring may optionally be substituted with R j ;  
       R a , R b  and R c  are independently selected from the group consisting of H, alkyl and alkyl-aryl;  
       R d  is selected from the group consisting of halogen, alkyloxy, NO 2 , NH 2 , alkyl, SO 2 NH 2 , hydroxyl and aryl;  
       R e  and R f  are independently selected from the group consisting of H, alkyl and cycloalkyl; or R e R f  together with the atom to which they are attached form a 4-7 membered ring containing zero to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein R e R f  together with the atom to which they are attached may be fused to one or two aromatic rings;  
       R g  and R h  are independently selected from the group consisting of H, alkyl, aryl, cycloalkyl, alkyl-aryl and alkyl-cycloalkyl; wherein alkyl is optionally substituted with R k ; and aryl is optionally substituted with R l ; or R g R h  together with the carbon to which they are attached form a 5-8 membered ring which may be bicyclic;  
       R i  is selected from the group consisting of: NR e R f , alkyloxy, aryloxy, C(O)aryl, aryl, OC(O)alkyl, alkylaryloxy and hydroxyl; wherein alkyl is optionally substituted with halogen and aryl is optionally substituted with R d ;  
       R j  is selected from the group consisting of (CH 2 ) y NR e R f , (CH 2 ) z OH, CO 2 H, C(O)N(alkyl) 2 , C(O)NH 2 , alkylaryl and aryl;  
       wherein aryl is optionally substituted with one to four substituents selected from R d ;  
       R k  is selected from the group consisting of C(O)NH 2 , C(O)OH, alkylthio, NH 2 , heteroaryl, heteroalkyl, NHC(NH)NH 2 , C1-5 alkylhydroxyl, hydroxyl and alkyloxy; R l  is selected from the group consisting of hydroxyl, NO 2  and C1-5 alkyl;  
       U is selected from the group consisting of O, S(O) y , NR c , NR c C(O), NR c C(O)NR c ;  
       W is selected from the group consisting of (CR a R b ) x , (CR a R b ) y U(CR a R b ) y , C2-3 alkynyl, C2-3 alkenyl;  
       each X is independently 0-3;  
       each Y is independently 0-2;  
       each Z is independently 1-2.  
     
   
   
       2 . A compound, which interrupts CD40:CD154 interaction, of the formula:  
     
       
         
         
             
             
         
       
       R 9  is selected from the group consisting of C1-5 alkyl-aryl, cycloalkyl and alkenylaryl; wherein the alkyl is optionally substituted with aryl and the aryl is optionally substituted with one to four halogens, aryl, NH 2  or NO 2 ;  
       R 10  is selected from the group consisting of alkyl and cycloalkyl; and  
       R 11  is selected from the group consisting of H and alkyl.  
     
   
   
       3 . A compound, which interrupts CD40:CD154 interaction, of the formula:  
     
       
         
         
             
             
         
       
       wherein,  
       R 9  is selected from the group consisting of C1-5 alkyl-aryl; wherein alkyl and aryl are optionally substituted with aryl.  
     
   
   
       4 . The compound according to  claim 1 , wherein said compound is derived from S-amines and wherein said compound is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       5 . The compound according to  claim 1  or  2 , wherein said compound is derived from S-amines and wherein said compound is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       6 . The compound according to any one of claims  1 ,  2  or  3 , wherein said compound is derived from S-amines and wherein said compound is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       7 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims  1 - 6 .  
   
   
       8 . A method for attenuating severity of a condition associated with inappropriate CD154 mediated activation in a subject, comprising the step of administering an effective amount of a pharmaceutical composition according to  claim 7  to the subject.  
   
   
       9 . A method for suppressing effects of a condition associated with inappropriate CD154 mediated activation in a subject, comprising the step of administering an effective amount of a pharmaceutical composition according to  claim 7  to the subject.  
   
   
       10 . A method for preventing development of a condition associated with inappropriate CD154 mediated activation in a subject, comprising the step of administering an effective amount of a pharmaceutical composition according to  claim 7  to the subject.  
   
   
       11 . A method for delaying onset of a condition associated with inappropriate CD154 mediated activation in a subject, comprising the step of administering an effective amount of a pharmaceutical composition according to  claim 7  to the subject.  
   
   
       12 . A method for inhibiting a condition associated with inappropriate CD154 mediated activation in a subject, comprising the step of administering an effective amount of a pharmaceutical composition according to  claim 7  to the subject.  
   
   
       13 . A method for reversing a condition associated with inappropriate CD154 mediated activation in a subject, comprising the step of administering an effective amount of a pharmaceutical composition according to  claim 7  to the subject.  
   
   
       14 . A method for treating a condition associated with inappropriate CD154 mediated activation in a subject, comprising the step of administering an effective amount of a pharmaceutical composition according to  claim 7  to the subject.  
   
   
       15 . A method for preventing a condition associated with inappropriate CD154 mediated activation in a subject, comprising the step of administering an effective amount of a pharmaceutical composition according to  claim 7  to the subject.  
   
   
       16 . The method according to any one of claims  8 - 15 , wherein the subject is a primate.  
   
   
       17 . The method according  claim 16 , wherein said primate is a human.  
   
   
       18 . The method according to any one of claims  8 - 15 , wherein the condition is an unwanted immune response.  
   
   
       19 . The method according to any one of claims  8 - 15 , wherein the condition is an unwanted inflammatory response.  
   
   
       20 . The method according to any one of claims  8 - 15 , wherein the condition is an autoimmune disease.  
   
   
       21 . The method according to any one of claims  8 - 15 , wherein the condition is an allergy.  
   
   
       22 . The method according to any one of claims  8 - 15 , wherein the condition is an inhibitor response to a therapeutic agent.  
   
   
       23 . The method according to any one of claims  8 - 15 , wherein the condition is rejection of a donor organ.  
   
   
       24 . The method according to any one of claims  8 - 15 , wherein the condition is a B cell cancer.  
   
   
       25 . The method according to any one of claims  8 - 15 , wherein the condition is selected from the group consisting of: systemic lupus erythematosis, lupus nephritis, lupus neuritis, asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, multiple sclerosis, uveitis, Alzheimer's disease, traumatic spinal cord injury, stroke, atherosclerosis, coronary restenosis, ischemic congestive heart failure, cirrhosis, hepatitis C, diabetic nephropathy, glomerulonephritis, osteoarthritis, rheumatoid arthritis, psoriasis, atopic dermatitis, systemic sclerosis, radiation-induced fibrosis, Crohn's disease, ulcerative colitis, multiple myeloma and cachexia.  
   
   
       26 . A compound, which interrupts CD40:CD154 interaction, of the formula: