Combinations of Organic Compounds

Abstract

The invention provides a pharmaceutical combination comprising: a) compounds that inhibit the binding of the Smac protein to IAPs; and b) a taxane, and a method for treating or preventing a proliferative disease using such a combination.

1 . A pharmaceutical combination comprising:
 (a) a compound that inhibit the binding of the Smac protein to Inhibitor of Apoptosis Proteins (IAPs) of formula (I)   
       
         
           
           
               
               
           
         
         wherein
 R 1  is H, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl or C 3 -C 10 cycloalkyl, which are unsubstituted or substituted; 
 R 2  is H, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl or C 3 -C 10 cycloalkyl, which are unsubstituted or substituted; 
 R 3  is H, —CF 3 , —C 2 F 5 , C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, —CH 2 -Z, wherein Z is H, —OH, F, Cl, —CH 3 , —CF 3 , —CH 2 Cl, —CH 2 F or —CH 2 OH, or 
 R 2  and R 3 , together with the nitrogen, form a het ring; 
 R 4  is C 1 -C 16 straight- or branched-alkyl, C 1 -C 16 alkenyl, C 1 -C 16 alkynyl or —C 3 -C 10 cycloalkyl, —(CH 2 ) 1-6 Z 1 , —(CH 2 ) 0-6 aryl and —(CH 2 ) 0-6 het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted, 
 wherein
 Z 1  is —N(R 8 )—C(O)—C 1 -C 10 alkyl, —N(R 8 )—C(O)—(CH 2 ) 1-6 C 3 -C 7 cycloalkyl, —N(R 8 )—C(O)—(CH 2 ) 0-6 phenyl, —N(R 8 )—C(O)—(CH 2 ) 1-6 het, —C(O)—N(R 9 )(R 10 ), —C(O)—O—C 1 -C 10 alkyl, —C(O)—O—(CH 2 ) 1-6 C 3 -C 7 cycloalkyl, —C(O)—O—(CH 2 ) 0-6 phenyl, —C(O)—O—(CH 2 ) 1-6 het, —O—C(O)C 1 -C 10 alkyl, —O—C(O)—(CH 2 ) 1-6 C 3 -C 7 cycloalkyl, —O—C(O)—(CH 2 ) 0-6 phenyl, —O—C(O)—(CH 2 ) 1-6 het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted; and 
 het is a 5- to 7-membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, or an 8- to 12-membered fused ring system including at least one 5- to 7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O, and S, which heterocyclic ring or fused ring system is unsubstituted or substituted on a carbon or nitrogen atom, 
 wherein
 R 8  is H, —CH 3 , —CF 3 , —CH 2 OH or —CH 2 Cl; 
 R 9  and R 10  are each independently H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, —(CH 2 ) 1-6 C 3 -C 7 cycloalkyl, —(CH 2 ) 0-6 phenyl, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted, or 
 R 9  and R 10 , together with the nitrogen, form het; 
 
 
 R 5  is H, C 1 -C 10 alkyl, aryl, phenyl, C 3 -C 7 cycloalkyl, —(CH 2 ) 1-6 C 3 -C 7 cycloalkyl, —C 1 -C 10 alkyl—aryl, —(CH 2 ) 0-6 C 3 -C 7 cycloalkyl-(CH 2 ) 0-6 phenyl, —(CH 2 ) 0-4 CH—((CH 2 ) 1-4 phenyl) 2 , —(CH 2 ) 0-6 CH(phenyl) 2 , -indanyl, —C(O)—C 1 -C 10 alkyl, —C(O)—(CH 2 ) 1-6 C 3 -C 7 -cycloalkyl, —C(O)—(CH 2 ) 0-6 phenyl, —(CH 2 ) 0-6 C(O)-phenyl, —(CH 2 ) 0-6 het, —C(O)—(CH 2 ) 1-6 het, or 
 R 5  is a residue of an amino acid, wherein the alkyl, cycloalkyl, phenyl and aryl substituents are unsubstituted or substituted; and 
 U is as shown in formula (II): 
 
       
       
         
           
           
               
               
           
         
         
           wherein
 n is 0-5; 
 X is —CH or N; 
 Ra and Rb are independently an O, S or N atom or C 0 -C 8 alkyl, wherein one or more of the carbon atoms in the alkyl chain may be replaced by a heteroatom selected from O, S or N, and where the alkyl may be unsubstituted or substituted; 
 Rd is selected from:
 (a) —Re-Q-(Rf) p (Rg) q ; or 
 (b) Ar 1 -D-Ar 2 , 
 wherein 
  p and q are independently 0 or 1; 
  Re is C 1 -C 8 alkyl or alkylidene and 
  Re which may be unsubstituted or substituted; 
  Q is N, O, S, S(O), or S(O) 2 ; 
  Ar 1  and Ar 2  are substituted or unsubstituted aryl or het; 
  Rf and Rg are each independently H, —C 1 -C 10 alkyl, C 1 -C 10 alkylaryl, —OH, —O—C 1 -C 10 alkyl, —(CH 2 ) 0-6 C 3 -C 7 cycloalkyl, —O—(CH 2 ) 0-6 aryl, phenyl, aryl, phenyl-phenyl, —(CH 2 ) 1-6 het, —O—(CH 2 ) 1-6 het, —OR 11 , —C(O)—R 11 , —C(O)—N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —S—R 11 , —S(O)—R 11 , —S(O) 2 —R 11 , —S(O) 2 —NR 11 R 12 , —NR 11 —S(O) 2 —R 12 , S—C 1 -C 10 alkyl, aryl-C 1 -C 4 alkyl, het-C 1 -C 4 -alkyl, wherein alkyl, cycloalkyl, het and aryl are unsubstituted or substituted, —SO 2 —C 1 -C 2 alkyl, —SO 2 —C 1 -C 2 alkylphenyl, —O—C 1 -C 4 alkyl, or 
  Rg and Rf form a ring selected from het or aryl; 
  D is —CO—, —C(O)—C 1 -C 7 alkylene or arylene, —CF 2 —, —O—, —S(O) r , where r is 0-2, 1,3-dioaxolane or C 1 -C 7 alkyl-OH, where alkyl, alkylene or arylene may be unsubstituted or substituted with one or more halogens, OH, —O—C 1 -C 6 alkyl, —S—C 1 -C 6 alkyl or —CF 3 , or 
  D is —N(Rh), wherein Rh is H, C 1 -C 7 alkyl (unsubstituted or substituted), aryl, —O(C 1 -C 7 cycloalkyl) (unsubstituted or substituted), C(O)—C 1 -C 10 alkyl, C(O)—C o -C 10 alkyl-aryl, C—O—C 1 -C 10 alkyl, C—O—C o -C 10 alkyl-aryl or SO 2 —C 1 -C 10 -alkyl, SO 2 -(C o -C 10 -alkylaryl); 
 
 Rc is H, or 
 Rc and Rd may together form a cycloalkyl or het, where if Rd and Rc form a cycloalkyl or het, R 5  is attached to the formed ring at a C or N atom; 
 R 6 , R 7 , R′ 6  and R′ 7  are each independently H, —C 1 -C 10 alkyl, —C 1 -C 10 alkoxy, aryl-C 1 -C 10 alkoxy, —OH, —O—C 1 -C 10 alkyl, —(CH 2 ) 0-6 C 3 -C 7 cycloalkyl, —O—(CH 2 ) 0-6 aryl, phenyl, —(CH 2 ) 1-6 het, —O—(CH 2 ) 1-6 het, —C(O)—R 11 , —C(O)—N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —S(O)—R 11 , —S(O) 2 —R 11 , —S(O) 2 —NR 11 R 12 , —NR 11 —S(O) 2 —R 12 , wherein alkyl, cycloalkyl and aryl are unsubstituted or substituted; and 
 R 6 , R 7 , R′ 6  and R′ 7  can be united to form a ring system, 
 wherein
 R 11  and R 12  are independently H, C 1 -C 10 alkyl, —(CH 2 ) 0-6 C 3 -C 7 cycloalkyl, —(CH 2 ) 0-6 (CH) 0-1 (aryl) 1-2 , —C(O)—C 1 -C 10 alkyl, —C(O)—(CH 2 ) 1-6 C 3 -C 7 cycloalkyl, —C(O)—O—(CH 2 ) 0-6 aryl, —C(O)—(CH 2 ) 0-6 O-fluorenyl, —C(O)—NH—(CH 2 ) 0-6 aryl, —C(O)—(CH 2 ) 0-6 aryl, —C(O)—(CH 2 ) 1-6 het, —C(S)—C 1 -C 10 alkyl, —C(S)—(CH 2 ) 1-6 C 3 -C 7 cycloalkyl, —C(S)—O—(CH 2 ) 0-6 aryl, —C(S)—(CH 2 ) 0-6 O-fluorenyl, —C(S)—NH—(CH 2 ) 0-6 aryl, —C(S)—(CH 2 ) 0-6 aryl, —C(S)—(CH 2 ) 1-6 het, wherein alkyl, cycloalkyl and aryl are unsubstituted or substituted, or 
 R 11  and R 12  are a substituent that facilitates transport of the molecule across a cell membrane, or 
 R 11  and R 12 , together with the nitrogen atom, form het, 
 wherein 
  the alkyl substituents of R 11  and R 12  may be unsubstituted or substituted by one or more substituents selected from C 1 -C 10 alkyl, halogen, OH, —O—C 1 -C 6 alkyl, —S—C 1 -C 6 alkyl or —CF 3 , 
  substituted cycloalkyl substituents of R 11  and R 12  are substituted by one or more substituents selected from a C 1 -C 10 alkene, C 1 -C 6 alkyl, halogen, OH, —O—C 1 -C 6 alkyl, —S—C 1 -C 6 alkyl or —CF 3 ; and 
  substituted phenyl or aryl of R 11  and R 12  are substituted by one or more substituents selected from halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro, —CN, —O—C(O)—C 1 -C 4 alkyl and —C(O)—O—C 1 -C 4 aryl; 
 
 or pharmaceutically acceptable salts thereof 
 
         
         or (IV) 
       
       
         
           
           
               
               
           
         
         wherein
 R 1  is H; 
 R 2  is H, C 1 -C 4 alkyl, which is unsubstituted or substituted by one or more substituents selected from halogen, —OH, —SH, —OCH 3 , —SCH 3 , —CN, —SCN and nitro; 
 R 3  is H, —CF 3 , —C 2 F 5 , —CH 2 -Z, wherein Z is H, —OH, F, Cl, —CH 3 , —CF 3 , —CH 2 Cl, —CH 2 F or —CH 2 OH, or 
 R 2  and R 3 , together with the nitrogen, form a C 3 -C 6 heteroaliphatic ring; 
 R 4  is C 1 -C 16 straight-chain alkyl, O 3 —C 10 branched-chain alkyl, —(CH 2 ) 0-6 C 3 -C 7 cycloalkyl, —(CH 2 ) 1-6 Z 1 , —(CH 2 ) 0-6 phenyl and —(CH 2 ) 0-6 het, wherein the alkyl, cycloalkyl and phenyl substituents are unsubstituted or substituted, 
 wherein
 Z 1  is —N(R 9 )—C(O)—C 1 -C 10 alkyl, —N(R 9 )—C(O)—(CH 2 ) 1-6 C 3 -C 7 cycloalkyl, —N(R 9 )—C(O)—(CH 2 ) 0-6 phenyl, —N(R 9 )—C(O)—(CH 2 ) 1-6 het, —C(O)—N(R 10 )(R 11 ), —C(O)—O—C 1 -C 10 alkyl, —C(O)—O—(CH 2 ) 1-6 C 3 -C 7 cycloalkyl, —C(O)—O—(CH 2 ) 0-6 phenyl, —C(O)—O—(CH 2 ) 1-6 het, —O—C(O)—C 1 -C 10 alkyl, —O—C(O)—(CH 2 ) 1-6 C 3 -C 7 cycloalkyl, —O—C(O)—(CH 2 ) 0-6 phenyl, —O—C(O)—(CH 2 ) 1-6 het, wherein the alkyl, cycloalkyl and phenyl substituents are unsubstituted or substituted, 
 wherein
 R 9  is H, —CH 3 , —CF 3 , —CH 2 OH or CH 2 Cl; 
 R 10  and R 11  are each independently H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, —(CH 2 ) 1-6 C 3 -C 7 cycloalkyl, —(CH 2 ) 0-6 phenyl, wherein the alkyl, cycloalkyl and phenyl substituents are unsubstituted or substituted, or 
 R 10  and R 11 , together with the nitrogen, are het; 
 
 het is a 5- to 7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O and S, or an 8- to 12-membered fused ring system including at least one 5- to 7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O and S, which heterocyclic ring or fused ring system is unsubstituted or substituted on a carbon atom by halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro, —O—C(O)—C 1 -C 4 alkyl or —C(O)—O—C 1 -C 4 alkyl or on a nitrogen by C 1 -C 4 alkyl, —O—C(O)—C 1 -C 4 alkyl or —C(O)—O—C 1 -C 4 alkyl; 
 
 X is CH or N; 
 R 5  is H, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, —(CH 2 ) 1-6 C 3 -C 7 cycloalkyl, —C 1 -C 10 alkyl aryl —(CH 2 ) 0-6 C 3 -C 7 cycloalkyl-(CH 2 ) 0-6 phenyl, —(CH 2 ) 0-4 CH—((CH 2 ) 1-4 phenyl) 2 . —(CH 2 ) 0-6 CH(phenyl) 2 , —C(O)—C 1 -C 10 alkyl, —C(O)—(CH 2 ) 1-6 C 3 -C 7 cycloalkyl, —C(O)—(CH 2 ) 0-6 phenyl, —(CH 2 ) 1-6 het, —C(O)—(CH 2 ) 1-6 het, or 
 R 5  is a residue of an amino acid, wherein the alkyl, cycloalkyl, phenyl and aryl substituents are unsubstituted or substituted; 
 R 6  is H, methyl, ethyl, —CF 3 , —CH 2 OH or —CH 2 Cl, or 
 R 5  and R 6 , together with the nitrogen, are het; 
 R 7  and R 8  are cis relative to the acyl substituent at the one position of the ring and are each independently H, C 1 -C 10 alkyl —OH, —O—C 1 -C 10 alkyl, —(CH 2 ) 0-6 C 3 -C 7 cycloalkyl, —O—(CH 2 ) 0-6 aryl, phenyl, —(CH 2 ) 1-6 het, —O—(CH 2 ) 1-6 het, —N(R 12 )(R 13 ), —S—R 12 , —S(O)—R 12 , —S(O) 2 —R 12 , —S(O) 2 —NR 12 R 13 , wherein the alkyl, cycloalkyl and aryl substituents are unsubstituted or substituted, 
 wherein
 R 12  and R 13  are independently H, C 1 -C 10 alkyl —(CH 2 ) 0-6 C 3 -C 7 cycloalkyl, —(CH 2 ) 0-6 (CH) 0-1 (aryl) 1-2 , —C(O)—C 1 -C 10 alkyl, —C(O)—(CH 2 ) 1-6 C 3 -C 7 cycloalkyl, —C(O)-O—(CH 2 ) 0-6 aryl, —C(O)—(CH 2 ) 0-6 O-fluorenyl, —C(O)—NH—(CH 2 ) 0-6 aryl, —C(O)—(CH 2 ) 0-6 aryl, —C(O)—(CH 2 ) 1-6 het, wherein the alkyl, cycloalkyl and aryl substituents are unsubstituted or substituted; or a substituent that facilitates transport of the molecule across a cell membrane, or 
 R 12  and R 13 , together with the nitrogen, are het; and aryl is phenyl or naphthyl which is unsubstituted or substituted; 
 n is 0, 1 or 2; and 
 (b) at least one taxane. 
 
 
       
     
     
         2 . A method for treating or preventing a proliferative disease in a subject in need thereof, comprising co-administration to said subject of a therapeutically effective amount of at least one taxane and a compound that inhibit the binding of the Smac protein to IAPs of formula (I) or (IV) according to  claim 1 . 
     
     
         3 . A pharmaceutical combination according to  claim 1 , for use in a method according to  claim 2 . 
     
     
         4 . A pharmaceutical combination according to  claim 1 , for use in the preparation of a medicament for use in a method according to  claim 2 . 
     
     
         5 . A pharmaceutical combination according to  claim 1 , wherein agent a) is N-[1-cyclohexyl-2-oxo-2-(6-phenethyl-octa hydro-pyrrolo[2,3-c]pyridin-1-yl-ethyl]-2-methylamino-propionamide of formula (III): 
       
         
           
           
               
               
           
         
       
     
     
         6 . A pharmaceutical combination according to  claim 1 , wherein agent b) is selected from Paclitaxel, docetaxel, vinorelbine and the epothilones and combinations thereof. 
     
     
         7 . A method for treating a proliferative disease comprising administering a combination of a taxane and a compound that inhibit the binding of the Smac protein to IAPs of formula (I) or (IV). 
     
     
         8 . A method for treating a proliferative disease comprising administering a combination of a taxane and a compound selected from N—[1-cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl-ethyl]-2-methylamino-propionamide of formula (III) and pharmaceutically acceptable salts thereof. 
     
     
         9 . A method for treating a proliferative disease comprising administering a combination of a taxane and a compound that inhibit the binding of the Smac protein to IAPs of formula (I) or (IV), wherein the taxane is selected from paclitaxel and docitaxel, and combinations thereof. 
     
     
         10 . A method for treating a proliferative disease selected from breast, ovarian and lung tumors comprising administering a combination of a taxane and a compound that inhibit the binding of the Smac protein to Inhibitor of Apoptosis Proteins (IAPs) of formula (I) or (IV). 
     
     
         11 . A method for treating a proliferative disease selected from breast, ovarian and lung tumors comprising administering a combination of a taxane and a compound selected from N-[1-cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl-ethyl]-2-methylamino-propionamide of formula (III) and pharmaceutically acceptable salts thereof.