Novel sulphonylpyrroles

Abstract

Compounds of a certain formula (I), in which R1, R2, R3, R4, R5, R6 and R7 have the meanings indicated in the description, are novel effective HDAC inhibitors.

1 - 20 . (canceled) 
     
     
         21 . A method for treating a disease in a patient, for treating benign and/or malignant neoplasia in a patient, for treating a non-malignant disease in a patient, or for treating a disease responsive or sensitive to inhibition of histone deacetylase activity in a patient, comprising administering to said patient a therapeutically effective and tolerable amount of a compound of formula I or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
       in which
 R1 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy, 
 R2 is hydrogen or 1-4C-alkyl, 
 R3 is hydrogen or 1-4C-alkyl, 
 R4 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy, 
 R5 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy, 
 R6 is -T1-Q1, in which 
 T1 is a bond, or 1-4C-alkylene, 
 Q1 is Aa1, Hh1, or Ah1, in which 
 Aa1 is a bisaryl radical made up of two aryl groups, which are independently selected from the group consisting of phenyl and naphthyl, and which are linked together via a single bond, 
 Hh1 is a bisheteroaryl radical made up of two heteroaryl groups, which are independently selected from the group consisting of monocyclic 5- or 6-membered heteroaryl radicals comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, and which are linked together via a single bond, 
 Ah1 is a heteroaryl-aryl radical or an aryl-heteroaryl radical made up of a heteroaryl group selected from the group consisting of monocyclic 5- or 6-membered heteroaryl radicals comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, and an aryl group selected from the group consisting of phenyl and naphthyl, whereby said heteroaryl and aryl groups are linked together via a single bond, 
 R7 is hydroxyl, or Cyc1, in which 
 Cyc1 is a ring system of formula Ia 
 
       
         
           
           
               
               
           
         
       
       in which
 A is C (carbon), 
 B is C (carbon), 
 R71 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy, 
 R72 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy, 
 M with inclusion of A and B is either a ring Ar2 or a ring Har2, in which 
 Ar2 is a benzene ring, 
 Har2 is a monocyclic 5- or 6-membered unsaturated heteroaromatic ring comprising one to three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur. 
 
     
     
         22 . A method according to  claim 21 , wherein in the compound of formula I
 R1 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,   R2 is hydrogen or 1-4C-alkyl,   R3 is hydrogen or 1-4C-alkyl,   R4 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,   R5 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,   R6 is -T1-Q1, in which   T1 is a bond, or 1-4C-alkylene,   Q1 is Aa1, Hh1, or Ah1, in which   Aa1 is a bisaryl radical made up of two aryl groups, which are independently selected from the group consisting of phenyl and naphthyl, and which are linked together via a single bond,   Hh1 is a bisheteroaryl radical made up of two heteroaryl groups, which are independently selected from the group consisting of monocyclic 5- or 6-membered heteroaryl radicals comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, and which are linked together via a single bond,   Ah1 is a heteroaryl-aryl radical or an aryl-heteroaryl radical made up of a heteroaryl group selected from the group consisting of monocyclic 5- or 6-membered heteroaryl radicals comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, and an aryl group selected from the group consisting of phenyl and naphthyl, whereby said heteroaryl and aryl groups are linked together via a single bond,   R7 is hydroxyl, or Cyc1, in which   Cyc1 is a ring system of formula Ia   
       
         
           
           
               
               
           
         
       
       in which
 A is C (carbon), 
 B is C (carbon), 
 R71 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy, 
 R72 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy, 
 M with inclusion of A and B is either a ring Ar2 or a ring Har2, in which 
 Ar2 is a benzene ring, 
 Har2 is a monocyclic 5- or 6-membered unsaturated heteroaromatic ring comprising one to three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur. 
 
     
     
         23 . A method according to  claim 21 , wherein in the compound of formula I
 R1 is hydrogen, or 1-4C-alkyl,   R2 is hydrogen, or 1-4C-alkyl,   R3 is hydrogen, or 1-4C-alkyl,   R4 is hydrogen, or 1-4C-alkyl,   R5 is hydrogen, or 1-4C-alkyl,   R6 is -T1-Q1, in which   T1 is a bond, or 1-4C-alkylene,   Q1 is Aa1, Hh1, or Ah1, in which   Aa1 is a biphenyl radical,   Hh1 is a bipyridyl, pyrazolyl-pyridinyl, imidazolyl-pyridinyl, or pyridinyl-thiophenyl radical,   Ah1 is a pyridinyl-phenyl, pyrazolyl-phenyl, or imidazolyl-phenyl radical,   R7 is hydroxyl, or 2-aminophenyl.   
     
     
         24 . A method according to  claim 21 , wherein in the compound of formula I
 R1 is hydrogen,   R2 is hydrogen,   R3 is hydrogen,   R4 is hydrogen,   R5 is hydrogen,   R6 is Aa1, Hh1, or Ah1, in which   Aa1 is a biphenyl radical,   Hh1 is a bipyridyl, pyrazolyl-pyridinyl, imidazolyl-pyridinyl, or pyridinyl-thiophenyl radical,   Ah1 is a pyridinyl-phenyl, pyrazolyl-phenyl, or imidazolyl-phenyl radical,   R7 is hydroxyl, or 2-aminophenyl.   
     
     
         25 . A method according to  claim 21 , wherein in the compound of formula I
 R1 is hydrogen,   R2 is hydrogen,   R3 is hydrogen,   R4 is hydrogen,   R5 is hydrogen,   R6 is Aa1, Hh1, or Ah1, in which   Aa1 is 1,1′-biphen-4-yl or 1,1′-biphen-3-yl,   Hh1 is a pyridinyl-thiophenyl radical,   Ah1 is a 3-(pyridinyl)-phenyl, 3-(pyrazolyl)-phenyl, 4-(pyridinyl)-phenyl or 4-(pyrazolyl)-phenyl radical,   R7 is hydroxyl, or 2-aminophenyl,   
       or a salt thereof. 
     
     
         26 . A method according to  claim 21 , wherein in the compound of formula I
 R1 is hydrogen,   R2 is hydrogen,   R3 is hydrogen,   R4 is hydrogen,   R5 is hydrogen,   R6 is Aa1, Hh1, or Ah1, in which   Aa1 is 1,1′-biphen-4-yl or 1,1′-biphen-3-yl,   Hh1 is a pyridinyl-thiophenyl radical,   Ah1 is a 3-(pyridinyl)-phenyl, 3-(pyrazolyl)-phenyl, 4-(pyridinyl)-phenyl or 4-(pyrazolyl)-phenyl radical,   R7 is hydroxyl, or 2-aminophenyl,   
       or a salt thereof. 
     
     
         27 . A method according to  claim 21 , wherein in the compound of formula I
 R1 is hydrogen,   R2 is hydrogen,   R3 is hydrogen,   R4 is hydrogen,   R5 is hydrogen,   R6 is Aa1, Hh1, or Ah1, in which   Aa1 is 1,1′-biphen-4-yl or 1,1′-biphen-3-yl,   Hh1 is 5-(pyridin-2-yl)-thiophen-2-yl,   Ah1 is 3-(pyridin-3-yl)-phenyl, 3-(pyridin-4-yl)-phenyl, 3-(pyrazol-1-yl)-phenyl, 3-(1H-pyrazol-4-yl)-phenyl, 4-(pyridin-3-yl)-phenyl, 4-(pyridin-4-yl)-phenyl, 4-(pyrazol-1-yl)-phenyl or 4-(1H-pyrazol-4-yl)-phenyl,   R7 is hydroxyl, or 2-aminophenyl,   
       or a salt thereof. 
     
     
         28 . A method according to  claim 21 , wherein in the compound of formula I
 R1 is hydrogen,   R2 is hydrogen,   R3 is hydrogen,   R4 is hydrogen,   R5 is hydrogen,   R6 is Aa1, Hh1, or Ah1, in which   Aa1 is 1,1′-biphen-4-yl or 1,1′-biphen-3-yl,   Hh1 is 5-(pyridin-2-yl)-thiophen-2-yl,   Ah1 is 3-(pyridin-3-yl)-phenyl, 3-(pyridin-4-yl)-phenyl, 3-(pyrazol-1-yl)-phenyl, 3-(1H-pyrazol-4-yl)-phenyl, 4-(pyridin-3-yl)-phenyl, 4-(pyridin-4-yl)-phenyl, 4-(pyrazol-1-yl)-phenyl or 4-(1H-pyrazol-4-yl)-phenyl,   R7 is hydroxyl,   
       or a salt thereof. 
     
     
         29 . A method according to  claim 21 , wherein in the compound of formula I
 R1 is hydrogen,   R2 is hydrogen,   R3 is hydrogen,   R4 is hydrogen,   R5 is hydrogen,   R6 is Aa1, Hh1, or Ah1, in which   Aa1 is 1,1′-biphen-4-yl or 1,1′-biphen-3-yl,   Hh1 is 5-(pyridin-2-yl)-thiophen-2-yl,   Ah1 is 3-(pyridin-3-yl)-phenyl, 3-(pyridin-4-yl)-phenyl, 3-(pyrazol-1-yl)-phenyl, 3-(1H-pyrazol-4-yl)-phenyl, 4-(pyridin-3-yl)-phenyl, 4-(pyridin-4-yl)-phenyl, 4-(pyrazol-1-yl)-phenyl or 4-(1H-pyrazol-4-yl)-phenyl,   R7 is 2-aminophenyl,   
       or a salt thereof. 
     
     
         30 . A method according to  claim 21 , wherein in the compound of formula I
 R1 is hydrogen,   R2 is hydrogen,   R3 is hydrogen,   R4 is hydrogen,   R5 is hydrogen,   R6 is biphenyl,   R7 is hydroxyl, or 2-aminophenyl,   
       or a salt thereof. 
     
     
         31 . A method according to  claim 21 , wherein in the compound of formula I
 R1 is hydrogen,   R2 is hydrogen,   R3 is hydrogen,   R4 is hydrogen,   R5 is hydrogen,   R6 is biphenyl,   R7 is hydroxyl, or 2-aminophenyl.   
     
     
         32 . A method according to  claim 21 , wherein the compound of formula I is selected from the group consisting of
 (E)-3-[1-(Biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide,   (E)-N-(2-Amino-phenyl)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylamide,   (E)-N-Hydroxy-3-[1-(4-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide,   (E)-N-Hydroxy-3-{1-[4-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide,   (E)-N-(2-Amino-phenyl)-3-[1-(4-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide,   (E)-N-(2-Amino-phenyl)-3-[1-(4-pyridin-3-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide,   (E)-N-(2-Amino-phenyl)-3-{1-[4-(1H-1-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide,   (E)-3-[1-(Biphenyl-3-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide,   (E)-N-Hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamide,   (E)-N-Hydroxy-3-[1-(4-pyrazol-1-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide,   (E)-N-(2-Amino-phenyl)-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamide,   (E)-N-Hydroxy-3-[1-(3-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide,   (E)-N-(2-Amino-phenyl)-3-[1-(3-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide,   (E)-N-(2-Amino-phenyl)-3-[1-(3-pyridin-3-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide,   (E)-N-Hydroxy-3-{1-[3-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide,   (E)-N-(2-Amino-phenyl)-3-{1-[3-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide,   
       and a pharmaceutically acceptable salt thereof. 
     
     
         33 . A method according to  claim 21 , wherein the compound of formula I is selected from the group consisting of
 (E)-3-[1-(Biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide   (E)-N-(2-Amino-phenyl)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylamide   
       and a pharmaceutically acceptable salt thereof. 
     
     
         34 . A method according to  claim 21 , wherein the compound of formula I is selected from the group consisting of
 (E)-N-Hydroxy-3-[1-(4-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide   (E)-N-Hydroxy-3-{1-[4-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide   (E)-N-(2-Amino-phenyl)-3-[1-(4-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide   (E)-N-(2-Amino-phenyl)-3-[1-(4-pyridin-3-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide   (E)-N-(2-Amino-phenyl)-3-{1-[4-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide   (E)-3-[1-(Biphenyl-3-sulfonyl)-1-pyrrol-3-yl]-N-hydroxy-acrylamide   (E)-N-Hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamide   (E)-N-Hydroxy-3-[1-(4-pyrazol-1-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide or   (E)-N-(2-Amino-phenyl)-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamide   
       and a pharmaceutically acceptable salt thereof. 
     
     
         35 . A method according to  claim 21 , which is for treating benign and/or malignant neoplasia in a patient. 
     
     
         36 . A method according to  claim 21 , which is for treating a non-malignant disease in a patient. 
     
     
         37 . A method according to  claim 21 , which is for treating a disease responsive or sensitive to inhibition of histone deacetylase activity in a patient. 
     
     
         38 . The method according to  claim 21 , wherein the benign and/or malignant neoplasia is cancer. 
     
     
         39 . The method according to  claim 21 , wherein the non-malignant disease is selected from the group consisting of arthropathies, osteopathological conditions, systemic lupus erythematosus, rheumatoid arthritis, smooth muscle cell proliferation, vascular proliferative disorders, atherosclerosis, restenosis and inflammatory conditions. 
     
     
         40 . The method according to  claim 21 , wherein the compound of formula I is administered simultaneously, sequentially or separately with one or more further therapeutic agents.