Beta-sheet mimetics and composition and methods relating thereto

Abstract

Compounds having the following structure: including pharmaceutically acceptable salts and stereoisomers thereof, wherein A, A′, B, X, Y, R 2 , R 3 , R 4 and R 5 are as defined herein. Such compounds have utility over a wide range of applications, including use as diagnostic and therapeutic agents. In particular, compounds of this invention, and pharmaceutical compositions containing such compounds, are tryptase antagonists.

1 . A compound having the structure:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or stereoisomer thereof, 
 wherein  
 A and A′ are the same or different and independently N or CH;  
 B is —C(R 1 )(NHZ)-, —N(Z)- or —C(R)(Z)-;  
 X is a substituted or unsubstituted divalent heterocycle;  
 Y and Z represent the remainder of the molecule;  
 R 1 , R 2 , R 3 , R 4  and R 5  are the same or different and independently an amino acid side chain moiety or an amino acid side chain derivative; and  
 any two adjacent CH groups or adjacent NH and CH groups of the fused bicyclo compound optionally form a double bond.  
 
   
   
       2 . The compound according to  claim 1  wherein B is —C(R 1 )(NHZ)-.  
   
   
       3 . The compound according to  claim 1  wherein A is CH.  
   
   
       4 . The compound according to  claim 1  wherein A′ is CH.  
   
   
       5 . The compound according to  claim 1  wherein B is —C(R 1 )(Z)-.  
   
   
       6 . The compound according to  claim 5  wherein A is CH.  
   
   
       7 . The compound according to  claim 5  wherein A′ is CH.  
   
   
       8 . The compound according to  claim 1  wherein B is —N(Z)-.  
   
   
       9 . The compound according to  claim 8  wherein A is CH.  
   
   
       10 . The compound according to  claim 8  wherein A′ is CH.  
   
   
       11 . The compound according to  claim 8  wherein R 2  is hydrogen.  
   
   
       12 . The compound according to  claim 11  wherein R 3  is hydrogen.  
   
   
       13 . The compound according to  claim 8  having the structure:  
     
       
         
         
             
             
         
       
     
   
   
       14 . The compound according to  claim 1  wherein Y and Z are the same or different and independently an amino acid side chain moiety or an amino acid side chain derivative.  
   
   
       15 . The compound according to  claim 1  wherein Y and Z are the same or different and independently a substituted or unsubstituted alkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, heteroaryl or heteroarylalkyl.  
   
   
       16 . The compound according to  claim 13  wherein  
     Y is —NHR 6 ; 
 R 6  is  
 1) —(CH 2 ) l —NHR t ,  
 2) —(CH 2 ) l -Het-NHR t ,  
 3) —(CH 2 ) o -aryl-(CH 2 ) n —R t ,  
 4) —(CH 2 ) o -aryl-(CH 2 ) n —NHR t ,  
 5) —(CH 2 ) o -cyclohexyl-(CH 2 ) m —NHR t ,  
 6) —(CH═CH) k —(CH 2 ) p —NHR t ,  
                     
 R t  is  
 1) hydrogen,  
 2) —C(═NH)—NH 2 , or  
 3) a group selected from: —C(═O)O—R 7 , —C(═O)NH—R 7 , —S(O 2 )—R 7 , —C(═O)—R 7 , and hydrogen,  
 wherein  
 R 7  is R 7a , R 7b , R 7c  or R 7d ;  
 R 7a  is alkyl or aminoalkyl optionally and independently substituted with one or more substituents independently selected from R s ;  
 R 7b  is aryl, arylalkyl or Het optionally and independently substituted with one or more substituents independently selected from R s ;  
 R 7c  is phenyl, benzyl or phenethyl optionally and independently substituted with one or more substituents independently selected from R s ;  
 R 7d  is  
 1) —(CH 2 ) l —NR d R d′ ,  
 2) —(CH 2 ) l —CO 2 R e ,  
 3) —(CH 2 ) m -aryl-(CH 2 ) n —NR d R d′ ,  
 4) —(CH(NR d R d′ )—(CH 2 ) o —NR d R d′ ,  
 5) —(CH 2 ) m -1,4cyclohexyl-(CH 2 ) n —NR d R d′ ,  
 6) —(CH═CH) k —(CH 2 ) p —NR d R d′ ,  
                     
 R d  and R d′  are the same or different and independently selected from  
 1) hydrogen,  
 2) —C(═O)-alkyl,  
 3) —C(═O)-alkenyl,  
 4) —C(═O)-alkynyl,  
 5) —C(═O)-aryl,  
 6) —C(═O)-arylalkyl,  
 7) —C(═O)-Het,  
 8) a group selected from: —C(═O)O—R 7 , —C(═O)NH—R 7 , —S(O 2 )—R 7 , —C(═O)—R 7 , and hydrogen,  
 9) —C(═O)-alkyl-NH 2 ,  
 10) —C(═O)(CH 2 ) m -aryl-(CH 2 ) n —NH 2 ,  
 11) —C(═O)(CH 2 ) m -aryl-(CH 2 ) n -Het,  
 12) —C(═O)(CH 2 ) m -1,4 cyclohexyl-(CH 2 ) n —NH 2 ,  
 13) —C(═O)(CH 2 ) m -aryl-OH,  
 14) —C(═O)(CH 2 ) m -aryl-SO 2 —NH 2 ,  
 15) —C(═O)(CH 2 ) m -aryl-(CH 2 ) n —NHC(═O)-alkyl,  
 16) —C(═O)(CH 2 ) m -Het,  
 17) —C(═O)(CH 2 ) m —S-Het,  
 18) —SO 2 -aryl,  
 19) —SO 2 -aryloxy, and  
 20) —SO2-arylalkyl,  
 wherein alkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxy and Het are optionally and independently substituted with one or more substituents independently selected from R s ;  
 R e  and R e′  are the same or different and independently selected from  
 1) hydrogen,  
 2) alkyl,  
 3) alkenyl,  
 4) alkynyl,  
 5) aryl,  
 6) arylalkyl,  
 7) Het,  
 8) -alkylaryl,  
 9) —(CH 2 ) o -aryl-(CH 2 ) m —NH 2 ,  
 10) —(CH 2 ) o —NH-aryl,  
 11) —(CH 2 ) o -1,4cyclohexyl-(CH 2 ) m —NH 2 ,  
 12) —(CH 2 ) o -aryloxy,  
 13) —(CH 2 ) o -aryl-NH 2 ,  
                     
 wherein alkyl, alkenyl, alkynyl, aryl, arylalkyl and Het are optionally and independently substituted with one or more substituents independently selected from R s ;  
 R s  is  
 1) halogen,  
 2) hydrogen,  
 3) lower alkyl  
 4) —CN,  
 5) —CF 3 ,  
 6) —C(═O)OR e ,  
 7) —C(═O)R e ,  
 8) —C(═NH)—NH 2 ,  
 9) —C(═NR d )(NR d R d′ ),  
 10) —NR d R d′ ,  
 11) —NR e C(═O)R e ,  
 12) —NR e C(═O)OR e ,  
 13) —NR e C(═O)NR e R e′ ,  
 14) —NH—C(═NH)NH 2 ,  
 15) —NO 2 ,  
 16) —OCF 3 ,  
 17) —OH,  
 18) —OR e ,  
 19) —OC(═O)R e ,  
 20) —OC(═O)NR e R e′ ,  
 21) —SR e ,  
 22) —S(O) k R e ,  
 23) —S(O) 2 OR e ,  
 24) —S(O) k NR e R e′ , or  
 25) a group selected from: —C(═O)O—R 7 , —C(═O)NH—R 7 , —S(O 2 )—R 7 , —C(═O)—R 7 , and hydrogen;  
 R d  and R d′  taken together with the atoms to which they are attached form a mono- or bi-cyclic heterocyclic ring of 3 to 7 members each containing 0-3 additional heteroatoms each independently selected from nitrogen, oxygen and sulfur;  
 R e  and R e′  taken together with the atoms to which they are attached form a mono- or bi-cyclic heterocyclic ring of 3 to 7 members each containing 0-3 additional heteroatoms each independently selected from nitrogen, oxygen and sulfur;  
 k is an integer from 1 to 2;  
 l is an integer from 1 to 10;  
 m is a number from 0 to 4;  
 n is a number from 0 to 4;  
 o is an integer from 1 to 4;  
 p is an integer from 1 to 2; and  
 Het is heterocycle, heterocyclealkyl, heteroaryl or heteroarylalkyl.  
 
   
   
       17 . The compound of  claim 16 ,  
     wherein 
 Z is  
 1) hydrogen,  
 2) alkyl,  
 3) alkoxy,  
 4) phenyl,  
 5) benzyl,  
 6) phenethyl,  
 7) 1-napthylmethyl,  
 8) 2-napthylmethyl,  
 9) phenylbenzyl,  
 10) biphenyl,  
 11) aminoalkyl,  
 12) aryl,  
 13) arylalkyl,  
 14) Het,  
 b  15 ) a group selected from R 7d ,  
 16) —(CH 2 ) o —N(R d R d′ ),  
 17) —(CH 2 ) m -aryl-NHR t    
 18) —(CH 2 ) m -aryl-NR d R d′ ,  
 19) —(CH 2 ) o —CO 2 R e ,  
 20) —(CH 2 ) o —C(═O)—NR e R e′ ,  
 21) —(CH 2 ) o —O—R f ,  
 22) —(CH 2 ) o —SO 2 -aryl, or  
 23) —(CH 2 ) o -Het,  
 wherein alkyl, phenyl, benzyl, phenethyl, 1-napthylmethyl, 2-napthylmethyl, phenylbenzyl, biphenyl, aminoalkyl, aryl, arylalky and Het are optionally and independently substituted with one or more substituents independently selected from R s ;  
 R f  is selected from  
 1) hydrogen,  
 2) alkyl,  
 3) alkenyl,  
 4) alkynyl,  
 5) aryl,  
 6) arylalkyl,  
 7) Het,  
 8) alkylaryl,  
 9) —C(═O)-alkyl,  
 10) —C(═O)-aryl,  
 11) —C(═O)-arylalkyl,  
 12) —C(═O)-Het,  
 13) —C(═O)-alkylaryl,  
 14) —C(═O)—NH-alkyl,  
 15) —C(═O)—NH-aryl,  
 16) —C(═O)—NH-arylalkyl,  
 17) —C(═O)—NH-Het, and  
 18) —C(═O)—NH-alkylaryl.  
 
   
   
       18 . The compound according to  claim 1  having one of the following conformations:  
     
       
         
         
             
             
         
       
     
   
   
       19 . The compound according to claim I having one of the following conformations:  
     
       
         
         
             
             
         
       
     
   
   
       20 . The compound according to  claim 1  having one of the following conformations:  
     
       
         
         
             
             
         
       
     
   
   
       21 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       22 . A library of compounds comprising a plurality of library members, wherein at least one library member is a compound of  claim 1 .  
   
   
       23 . A method for treating an inflammatory disorder comprising administering to a warm-blooded animal in need thereof an effective amount of the composition of  claim 21 .  
   
   
       24 . The method of  claim 23  wherein the disorder is allergic airway inflammation.  
   
   
       25 . A method of treating a condition in a mammal, the treatment of which is effected or facilitated by a decrease in tryptase activation, comprising administering to a mammal in need thereof an effective amount of the composition of  claim 21 .  
   
   
       26 . The method of  claim 25  wherein the condition is asthma, pulmonary fibrosis, interstitial pneumonia, nephritis, hepatic fibrosis, hepatitis, hepatic cirrhosis, scleroderma, psoriasis, atopic dermatitis, chronic rheumatoid arthritis, influenza, Crohn's disease, ulcerative colitis, inflammatory bowel disease, nasal allergy, atherosclerosis or post-operative ileus, comprising administering to a mammal in need of such treatment an amount of the composition effective in treating such condition.  
   
   
       27 . The method of  claim 26  wherein the condition is post-operative ileus.