Lipoxygenase Inhibitors

Abstract

The disclosure provides bisindole suitable for inhibiting lipoxygenases or Aβ-formation, and treating associated diseases, such as Alzheimer's disease. The bisindoles are indolo[2,3-b]carbazole derivatives, and may be administered to a patient as part of a pharmaceutical formulation.

What is claimed is: 
     
         1 . A method of inhibiting a lipoxygenase in cells determined to be in need thereof, comprising contacting the cells with a bisindole of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 11  are substituents independently selected from the group consisting of hydrogen, C 1 -C 24  alkyl, C 2 -C 24  alkenyl, C 2 -C 24  alkynyl, C 5 -C 20  aryl, C 6 -C 24  alkaryl, C 6 -C 24  aralkyl, halo, hydroxyl, sulfhydryl, C 1 -C 24  alkoxy, C 2 -C 24  alkenyloxy, C 2 -C 24  alkynyloxy, C 5 -C 20  aryloxy, acyl, acyloxy, C 2 -C 24  alkoxycarbonyl, C 6 -C 20  aryloxycarbonyl, C 2 -C 24  alkylcarbonyl, C 6 -C 20  arylcarbonyl, halocarbonyl, C 2 -C 24  alkylcarbonato, C 6 -C 20  arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C 1 -C 24  alkyl)-substituted carbamoyl, di-(C 1 -C 24  alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, dihydroxyboryl, di-(C 1 -C 24 )-alkoxyboryl, isothiocyanato, azido, formyl, thioformyl, amino, mono- and di-(C 1 -C 24  alkyl)-substituted amino, mono- and di-(C 5 -C 20  aryl)-substituted amino, C 2 -C 24  alkylamido, C 6 -C 20  arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C 1 -C 24  alkylsulfanyl, arylsulfanyl, C 1 -C 24  alkylsulfinyl, C 5 -C 20  arylsulfinyl, C 1 -C 24  alkylsulfonyl, C 5 -C 20  arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, and combinations thereof, and further wherein any two adjacent (ortho) substituents selected from R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  may be linked to form a cyclic structure selected from five-membered rings, six-membered rings, and fused five-membered and/or six-membered rings, wherein the cyclic structure is aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and has zero to 4 non-hydrogen substituents and zero to 3 heteroatoms; and 
 R 11  and R 12  are independently selected from the group consisting of hydrogen, formyl, C 1 -C 24  alkyl, C 6 -C 24  aralkyl, C 2 -C 24  alkoxycarbonyl, amino-substituted C 1 -C 24  alkyl, (C 1 -C 24  alkylamino)-substituted C 1 -C 24  alkyl, di-(C 1 -C 24  alkyl)amino-substituted C 1 -C 24  alkyl, and nitrogen protecting groups; 
 or a salt thereof. 
 
     
     
         2 . The method of  claim 1  wherein the cells are isolated human cells in vitro. 
     
     
         3 . The method of  claim 1  wherein the cells are in situ as part of a person determined to be in need of lipoxygenase inhibition or suffering from a disease associated with pathogenic lipoxygenase activity, other than a bacterial or viral infection, cancer or estrogen-dependent disorder. 
     
     
         4 . The method of  claim 1  wherein the cells are in situ as part of a person determined to be in need of lipoxygenase inhibition or suffering from a disease associated with pathogenic lipoxygenase activity, other than a bacterial or viral infection, cancer or estrogen-dependent disorder, wherein the disease is selected from an acute or chronic inflammatory disease and a neurodegenerative disease. 
     
     
         5 . A method for treating a person with a neurodegenerative disease, comprising administering to the person an effective amount of a composition comprising a bisindole of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  are substituents independently selected from the group consisting of hydrogen, C 1 -C 24  alkyl, C 2 -C 24  alkenyl, C 2 -C 24  alkynyl, C 5 -C 20  aryl, C 6 -C 24  alkaryl, C 6 -C 24  aralkyl, halo, hydroxyl, sulfhydryl, C 1 -C 24  alkoxy, C 2 -C 24  alkenyloxy, C 2 -C 24  alkynyloxy, C 5 -C 20  aryloxy, acyl, acyloxy, C 2 -C 24  alkoxycarbonyl, C 6 -C 20  aryloxycarbonyl, C 2 -C 24  alkylcarbonyl, C 6 -C 20  arylcarbonyl, halocarbonyl, C 2 -C 24  alkylcarbonato, C 6 -C 20  arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C 1 -C 24  alkyl)-substituted carbamoyl, di-(C 1 -C 24  alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, dihydroxyboryl, di-(C 1 -C 24 )-alkoxyboryl, isothiocyanato, azido, formyl, thioformyl, amino, mono- and di-(C 1 -C 24  alkyl)-substituted amino, mono- and di-(C 5 -C 20  aryl)-substituted amino, C 2 -C 24  alkylamido, C 6 -C 20  arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C 1 -C 24  alkylsulfanyl, arylsulfanyl, C 1 -C 24  alkylsulfinyl, C 5 -C 20  arylsulfinyl, C 1 -C 24  alkylsulfonyl, C 5 -C 20  arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, and combinations thereof, and further wherein any two adjacent (ortho) substituents selected from R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  may be linked to form a cyclic structure selected from five-membered rings, six-membered rings, and fused five-membered and/or six-membered rings, wherein the cyclic structure is aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and has zero to 4 non-hydrogen substituents and zero to 3 heteroatoms; and 
 R 1  and R 12  are independently selected from the group consisting of hydrogen, formyl, C 1 -C 24  alkyl, C 6 -C 24  aralkyl, C 2 -C 24  alkoxycarbonyl, amino-substituted C 1 -C 24  alkyl, (C 1 -C 24  alkylamino)-substituted C 1 -C 24  alkyl, di-(C 1 -C 24  alkyl)amino-substituted C 1 -C 24  alkyl, and nitrogen protecting groups; 
 or a salt thereof. 
 
     
     
         6 . The method of  claim 5 , wherein R 1 , R 3 , R 4 , R 5 , R 7  and R 8  are hydrogen. 
     
     
         7 . The method of  claim 1 , wherein R 1 , R 3 , R 4 , R 5 , R 7 , R 8 , R 11 , and R 12  are hydrogen. 
     
     
         8 . The method of  claim 5 , wherein R 1 , R 3 , R 4 , R 5 , R 7 , R 8 , R 11 , and R 12  are hydrogen. 
     
     
         9 . The method of  claim 1 , wherein:
 R 1 , R 3 , R 4 , R 5 , R 7  and R 8  are hydrogen;   R 2  and R 6  are independently selected from H, electron withdrawing groups;   R 1 , and R 12  are hydrogen or methyl;   R 9  is selected from H, optionally substituted, optionally hetero-, optionally cyclic C 1 -C 24  alkyl, N, which may be an optionally substituted, optionally cyclic, optionally substituted C 1 -C 24  alkoxy, optionally substituted C 1 -C 24  alkynyl, and optionally substituted nitrile, each of which may optionally comprise a heteroatom, and electron withdrawing groups; and/or   R 10  is selected from optionally substituted C 1 -C 24  alkyl, optionally substituted C 1 -C 24  alkoxy, optionally substituted C 1 -C 24  alkynyl, and optionally substituted nitrile, each of which may optionally comprise a heteroatom.   
     
     
         10 . The method of  claim 5 , wherein:
 R 1 , R 3 , R 4 , R 5 , R 7  and R 8  are hydrogen;   R 2  and R 6  are independently selected from H, electron withdrawing groups;   R 11 , and R 12  are hydrogen or methyl;   R 9  is selected from H, optionally substituted, optionally hetero-, optionally cyclic C 1 -C 24  alkyl, N, which may be an optionally substituted, optionally cyclic, optionally substituted C 1 -C 24  alkoxy, optionally substituted C 1 -C 24  alkynyl, and optionally substituted nitrile, each of which may optionally comprise a heteroatom, and electron withdrawing groups; and/or   R 10  is selected from optionally substituted C 1 -C 24  alkyl, optionally substituted C 1 -C 24  alkoxy, optionally substituted C 1 -C 24  alkynyl, and optionally substituted nitrile, each of which may optionally comprise a heteroatom.   
     
     
         11 . The method of  claim 1  wherein the bisindole is selected from compound 1 and a compound of Table 1, 2, 3, 4 or 5, or a salt thereof. 
     
     
         12 . The method of  claim 5  wherein the bisindole is selected from compound 1 and a compound of Table 1, 2, 3, 4 or 5, or a salt thereof. 
     
     
         13 . The method of  claim 5  wherein the bisindole is selected from compound 1 and a compound of Table 3 or 4, or a salt thereof. 
     
     
         14 . The method of  claim 1  wherein the bisindole is compound 1: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         15 . The method of  claim 4  wherein the bisindole is compound 1: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         16 . The method of  claim 5  wherein the bisindole is compound 1: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         17 . The method of  claim 5 , further comprising: (i) measuring a lipoxygenase activity in a sample of the person; (ii) determining a level of a lipoxygenase metabolite in a sample of the person; or (iii) determining the person has the disease. 
     
     
         18 . The method of  claim 1 , wherein the disease is: (i) an acute or chronic inflammatory disease that is asthma, rheumatoid arthritis, inflammatory bowel disease, psoriasis, hereditary ichthyosis, dermatitis, nephritis, atherosclerosis, or cardiovascular disease, or (ii) a neurodegenerative disease that is age-related neurodegeneration, amyloid beta- associated disease, Alzheimer's Disease, ischemia-related disorder, creutzfeldt-jakob dosease/prion peptide toxicity, ALS, dementia or Parkinson Disease. 
     
     
         19 . A composition comprising a compound of formula (I), supra, and a second anti-neurodegenerative disease drug. 
     
     
         20 . A method for identifying a lipoxygenase inhibitor, comprising the step of screening for lipoxygenase inhibitory activity of a compound of  claim 19 .