Novel compounds

Abstract

The present invention relates to compounds, compositions, combinations and medicaments containing said compounds and processes for their preparation. The invention also relates to the use of said compounds, combinations, compositions and medicaments, for example as modulators of alpha I antitrypsin and treating diseases associated with alpha antitrypsin, particularly liver diseases.

What is claimed: 
     
         1 . A compound having a molecular weight of 1000 Daltons or less that is capable of inhibiting α 1 -antitrypsin polymerisation; or a pharmaceutically acceptable solvate, complex, tautomer, isotopically labelled derivative or prodrug thereof. 
     
     
         2 - 33 . (canceled) 
     
     
         34 . The compound of  claim 1 , wherein the compound is capable of binding to α 1 -antitrypsin by inducing formation of a cryptic binding site within the α 1 -antitrypsin protein structure, said α 1 -antitrypsin comprising the sequence of SEQ ID NO: 1. 
     
     
         35 . The compound of  claim 1 , wherein the binding site is located between β-sheet-A and β-sheet-B of said α 1 -antitrypsin, wherein:
 a) said β-sheet-A comprises the amino acids corresponding to residues 140-144, 111-121, 181-191, 330-340 and 292-299 of SEQ ID NO: 1; and
 said β-sheet-B comprises the amino acids corresponding to residues 228-231, 236-244, 248-256, 369-376, 381-389, and 49-53 of SEQ ID NO: 1 or 
 
 b) wherein the binding site is located between amino acid strands corresponding to each of: (a) residues 191-194 of SEQ ID NO: 1; (b) residues 288-293 of SEQ ID NO: 1; (c) residues 371-374 of SEQ ID NO: 1; (d) residues 249-253 of SEQ ID NO: 1; and (e) residues 240-243 of SEQ ID NO: 1; and optionally also (f) residues 338-341 of SEQ ID NO: 1. 
 
     
     
         36 . The compound of  claim 35 , wherein the binding site comprises one or more of W194, Y244, L291, P289, F252, K290, I293, L338, I340, F372 and M374 of SEQ ID NO: 1. 
     
     
         37 . The compound of  claim 34 , wherein:
 the K D  of the compound to M-α 1 -antitrypsin is less than about 250 nM, said M-α 1 -antitrypsin comprising the sequence of SEQ ID NO: 2; or   wherein the K D  of the compound to Z-α 1 -antitrypsin is less than about 25 nM, said Z-α 1 -antitrypsin comprising the sequence of SEQ ID NO: 3; or   wherein the K D  of the compound to Z-α 1 -antitrypsin is at least ten times lower than the K D  of the compound to M-α 1 -antitrypsin, said M-α 1 -antitrypsin comprising the sequence of SEQ ID NO: 2 and said Z-α 1 -antitrypsin comprising the sequence of SEQ ID NO: 3.   
     
     
         38 . The compound of  claim 1 , wherein the compound comprises a tetravalent moiety of formula (IA) 
       
         
           
           
               
               
           
         
         wherein the compound is capable of binding to α 1 -antitrypsin comprising the sequence of SEQ ID NO: 1 by hydrogen bond formation between: (i) hydroxyl group I and L291 of SEQ ID NO: 1; (ii) NH group II and P289 of SEQ ID NO: 1; and (iii) carbonyl group III and Y244 of SEQ ID NO: 1. 
       
     
     
         39 . The compound of  claim 1 , wherein the compound comprises a divalent moiety of formula (IB) 
       
         
           
           
               
               
           
         
       
       wherein:
 the compound is capable of binding to α 1 -antitrypsin comprising the sequence of SEQ ID NO: 1 by hydrogen bond formation between: (i) hydroxyl group I and L291 of SEQ ID NO: 1; (ii) NH group II and P289 of SEQ ID NO: 1; and (iii) carbonyl group III and Y244 of SEQ ID NO: 1; 
 R 4  is selected from hydrogen, C 1-5  alkyl, C 2-5  alkenyl, C 2-5  alkynyl and C 1-4  alkoxy; and 
 R 5  is selected from hydrogen, C 1-5  alkyl, C 2-5  alkenyl, C 2-5  alkynyl and C 1-4  alkoxy. 
 
     
     
         40 . The compound of  claim 39 , wherein
 R 5  is hydrogen; and/or   R 4  is C 2-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl or C 1-3  alkoxy; and/or   R 4  is n-propyl.   
     
     
         41 . The compound of  claim 1 , wherein the compound comprises a monovalent moiety of formula (IC) 
       
         
           
           
               
               
           
         
         wherein:
 the compound is capable of binding to α 1 -antitrypsin comprising the sequence of SEQ ID NO: 1 by hydrogen bond formation between: (i) hydroxyl group I and L291 of SEQ ID NO: 1; (ii) NH group II and P289 of SEQ ID NO: 1; and (iii) carbonyl group III and Y244 of SEQ ID NO: 1; 
 R 4  is selected from hydrogen, C 1-5  alkyl, C 2-5  alkenyl, C 2-5  alkynyl and C 1-4  alkoxy; and 
 R 5  is selected from hydrogen, C 1-5  alkyl, C 2-5  alkenyl, C 2-5  alkynyl and C 1-4  alkoxy; and 
 R 6  is a substituted or unsubstituted aryl or heteroaryl group capable of stacking with the side chain of W194 of SEQ ID NO: 1. 
 
       
     
     
         42 . The compound of  claim 41 , wherein:
 R 6  is a substituted or unsubstituted 4-oxindolyl group; or   R 6  is a group of formula R 6 ′   
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of H, F, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, Cl, Br and I. 
       
     
     
         43 . The compound of  claim 42 , wherein R 1  is selected from the group consisting of H, F, CH 3 , NH 2 , OH and Cl; optionally wherein R 1  is selected from the group consisting of H and F. 
     
     
         44 . The compound of  claim 1 , wherein the compound has the formula (ID) 
       
         
           
           
               
               
           
         
         wherein:
 the compound is capable of binding to α 1 -antitrypsin comprising the sequence of SEQ ID NO: 1 by hydrogen bond formation between: (i) hydroxyl group I and L291 of SEQ ID NO: 1; (ii) NH group II and P289 of SEQ ID NO: 1; and (iii) carbonyl group III and Y244 of SEQ ID NO: 1; 
 R 4  is selected from hydrogen, C 1-5  alkyl, C 2-5  alkenyl, C 2-5  alkynyl and C 1-4  alkoxy; 
 R 5  is selected from hydrogen, C 1-5  alkyl, C 2-5  alkenyl, C 2-5  alkynyl and C 1-4  alkoxy; 
 R 6  is a group of formula R 6 ′ 
 
       
       
         
           
           
               
               
           
         
         
           wherein R 1  is selected from the group consisting of H, F, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, Cl, Br and I; and 
           R 7  is a substituted or unsubstituted aryl or heteroaryl group. 
         
       
     
     
         45 . The compound of  claim 44 , wherein R 7  is a substituted or unsubstituted phenyl group; optionally wherein R 7  is a group of formula R 7 ′ 
       
         
           
           
               
               
           
         
         wherein:
 R 2  is selected from the group consisting of CH 3 , Cl, CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, SH, CN, F, Br and I; and 
 R 3  is selected from the group consisting of F, Cl, CN, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, Br, I and SH. 
 
       
     
     
         46 . The compound of  claim 45 , wherein
 R 2  is selected from the group consisting of CH 3 , Cl, NH 2 , OH, SH, CN and F, optionally wherein R 2  is selected from the group consisting of CH 3  and Cl; and   R 3  is selected from the group consisting of F, Cl, CN, CH 3 , NH 2 , OH and SH, optionally wherein R 3  is selected from the group consisting of F, Cl and CN.   
     
     
         47 . The compound of  claim 1 , wherein the compound has the formula (I) 
       
         
           
           
               
               
           
         
         wherein
 R 1  is selected from the group consisting of H, F, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, Cl, Br and I; 
 R 2  is selected from the group consisting of CH 3 , Cl, CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, SH, CN, F, Br and I; and 
 R 3  is selected from the group consisting of F, Cl, CN, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, Br, I and SH. 
 
       
     
     
         48 . The compound of  claim 47 , wherein
 R 1  is selected from the group consisting of H, F, CH 3 , NH 2 , OH and Cl, optionally wherein R 1  is selected from the group consisting of H and F;   R 2  is selected from the group consisting of CH 3 , Cl, NH 2 , OH, SH, CN and F, optionally wherein R 2  is selected from the group consisting of CH 3  and Cl; and   R 3  is selected from the group consisting of F, Cl, CN, CH 3 , NH 2 , OH and SH, optionally wherein R 3  is selected from the group consisting of F, Cl and CN.   
     
     
         49 . The compound of  claim 48 , wherein
 R 1  is H, R 2  is CH 3  and R 3  is F, or   R 1  is H, R 2  is CH 3  and R 3  is Cl, or   R 1  is F, R 2  is Cl and R 3  is CN, or   R 1  is F, R 2  is Cl and R 3  is F.   
     
     
         50 . A method for treating of a disease or condition mediated by α 1 -antitrypsinpolymerisation, comprising administering to a patient in need thereof a compound according to  claim 1 . 
     
     
         51 . The method of  claim 50 , wherein the disease or condition is mediated by Z-α 1 -antitrypsin polymerisation and the compound is capable of inhibiting Z-α 1 -antitrypsin polymerisation. 
     
     
         52 . A method for identifying a drug candidate compound, the method comprising:
 i) contacting the drug candidate compound with α 1 -antitrypsin comprising the sequence of SEQ ID NO: 1 to form a complex between the drug candidate compound and said α 1 -antitrypsin;   ii) resolving the structure of the complex; and   iii) determining whether, in the complex, the drug candidate compound is present in a binding site as defined in  claim 35 ;   optionally wherein said contacting the drug candidate compound with said α 1 -antitrypsin comprises forming a crystal of said α 1 -antitrypsin and contacting said crystal with said drug candidate.