Histone Deacetylase Inhibitors

Abstract

Histone deacetylase is a metallo-enzyme with zinc at the active site. Compounds having a zinc-binding moiety, such as, for example, a hydroxamic acid group or a carboxylic acid group, can inhibit histone deacetylase. Histone deacetylase can repress gene expression, including expression of genes related to tumor suppression. Accordingly, inhibition of histone deacetylase can provide an alternate route for treating cancer, hematological disorders, e.g., hemoglobinopathies, and genetic related metabolic disorders, e.g., cystic fibrosis and adrenoleukodystrophy.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         A is a cyclic moiety selected from the group consisting of C 3-14  cycloalkyl, 3-14 membered heterocycloalkyl, C 4-14  cycloalkenyl, 3-14 membered heterocycloalkenyl, monocyclic aryl, or monocyclic heteroaryl; the cyclic moiety being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl; 
         each of X 1  and X 2 , independently, is O or S; 
         Y 1  is —CH 2 —, —O—, —S—, —N(R a )—, —N(R a )—C(O)—O—, —O—C(O)—N(R a )—, —N(R a )—C(O)—N(R b )—, —C(O)—O—, —O—C(O)—O—, or a bond; each of R a  and R b , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; 
         Y 2  is a bond; 
         L is an unsaturated straight C 4-12  hydrocarbon chain containing at least two double bonds, at least one triple bond, or at least one double bond and one triple bond; said unsaturated hydrocarbon chain being optionally substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C 1-4  alkylcarbonyloxy, C 1-4  alkyloxycarbonyl, 
         C 1-4  alkylcarbonyl, or formyl; and further being optionally interrupted by —O—, —N(R g )—, —N(R g )—C(O)—O—, —O—C(O)—N(R g )—, —N(R g )—C(O)—N(R h )—, —O—C(O)—, —C(O)—O—, or —O—C(O)—O—; 
         each of R g  and R h , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl, wherein the carbon bonded to Y 2  is unsaturated, and provided that when L is a C 4-5  hydrocarbon chain and contains two double bonds, Y 1  is not CH 2  or a bond, and provided that when Y 1  is a bond, and L is a C 6  hydrocarbon chain, L is not substituted; 
         R 1  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, haloalkyl, or an amino protecting group; and 
         R 2  is hydrogen, alkyl, hydroxylalkyl, haloalkyl, or a hydroxyl protecting group; 
         or a salt thereof, provided the compound is not 5-phenyl-2,4-pentadienoylhydroxamic acid or 7-phenyl-2,4,6-heptatrienoylhydroxamic acid. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is hydrogen. 
     
     
         3 . The compound of  claim 1 , wherein R 2  is hydrogen. 
     
     
         4 . The compound of  claim 1 , wherein X 1  is O. 
     
     
         5 . The compound of  claim 1 , wherein X 2  is O. 
     
     
         6 . The compound of  claim 1 , wherein Y 1  is —CH 2 —, —O—, —N(R a )—, or a bond. 
     
     
         7 . The compound of  claim 1 , wherein L is an unsaturated straight C 4-10  hydrocarbon chain substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, or amino. 
     
     
         8 . The compound of  claim 1 , wherein L is an unsaturated straight C 5-8  hydrocarbon chain substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, or amino. 
     
     
         9 . The compound of  claim 1 , wherein L is an unsaturated straight C 4-6  hydrocarbon chain. 
     
     
         10 . The compound of  claim 1 , wherein L is an unsaturated straight C 4-10  hydrocarbon chain containing 2-5 double bonds optionally substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, or C 1-4  alkoxy. 
     
     
         11 . The compound of  claim 1 , wherein L is —(CH═CH) m — where m is 2 or 3, L being optionally substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, or C 1-4  alkoxy. 
     
     
         12 . The compound of  claim 1 , wherein L is an unsaturated straight C 4-10  hydrocarbon chain containing 1-2 double bonds and 1-2 triple bonds, said hydrocarbon chain being optionally substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, or C 1-4  alkoxy. 
     
     
         13 . The compound of  claim 1 , wherein L is an unsaturated straight C 4-8  hydrocarbon chain containing 1-2 double bonds and 1-2 triple bonds, said hydrocarbon chain being optionally substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, or C 1-4  alkoxy. 
     
     
         14 . The compound of  claim 1 , wherein L is —C≡C—(CH═CH) n — where n is 1 or 2, L being optionally substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, or C 1-4  alkoxy. 
     
     
         15 . The compound of  claim 1 , wherein A is phenyl. 
     
     
         16 . The compound of  claim 1 , wherein A is phenyl optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, or amino. 
     
     
         17 . The compound of  claim 1 , said compound being N-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 3-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 4-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 4-chloro-5-phenyl-2,4-pentadienoyl hydroxamic acid, 5-(4-dimethylaminophenyl)-2,4-pentadienoyl hydroxamic acid, 5-phenyl-2-en-4-yn-pentanoyl hydroxamic acid or N-methyl-6-phenyl-3,5-hexadienoyl hydroxamic acid. 
     
     
         18 . A pharmaceutical composition, comprising an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         A is a cyclic moiety selected from the group consisting of C 3-14  cycloalkyl, 3-14 membered heterocycloalkyl, C 4-14  cycloalkenyl, 3-14 membered heterocycloalkenyl, monocyclic aryl, or monocyclic heteroaryl; the cyclic moiety being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl; 
         each of X 1  and X 2 , independently, is O or S; 
         Y 1  is —CH 2 —, —O—, —S—, —N(R a )—, —N(R a )—C(O)—O—, —O—C(O)—N(R a )—, —N(R a )—C(O)—N(R b )—, —C(O)—O—, —O—C(O)—O—, or a bond; each of R a  and R b , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; 
         Y 2  is a bond; 
         L is an unsaturated straight C 4-12  hydrocarbon chain containing at least two double bonds, at least one triple bond, or at least one double bond and one triple bond; said unsaturated hydrocarbon chain being optionally substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C 1-4  alkylcarbonyloxy, C 1-4  alkyloxycarbonyl, C 1-4  alkylcarbonyl, or formyl; and further being optionally interrupted by —O—, —N(R g )—, 
         —N(R g )—C(O)—O—, —O—C(O)—N(R g )—, —N(R g )—C(O)—N(R h )—, —O—C(O)—, —C(O)—O—, or —O—C(O)—O—; 
         each of R g  and R h , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl, wherein the carbon bonded to Y 2  is unsaturated, and provided that when L is a C 4-5  hydrocarbon chain and contains two double bonds, Y 1  is not CH 2  or a bond and provided that when Y 1  is a bond, and L is a C 6  hydrocarbon chain, L is not substituted; 
         R 1  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, haloalkyl, or an amino protecting group; and 
         R 2  is hydrogen, alkyl, hydroxylalkyl, haloalkyl, or a hydroxyl protecting group; 
         or a salt thereof, and a pharmaceutically acceptable carrier. 
       
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the compound is selected from the group of N-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 3-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 4-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 4-chloro-5-phenyl-2,4-pentadienoyl hydroxamic acid, 5-(4-dimethylaminophenyl)-2,4-pentadienoyl hydroxamic acid, 5-phenyl-2-en-4-yn-pentanoyl hydroxamic acid, or N-methyl-6-phenyl-3,5-hexadienoyl hydroxamic acid. 
     
     
         20 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         A is unsubstituted phenyl; 
         each of X 1  and X 2 , independently, is O or S; 
         Y 1  is —CH 2 —, —O—, —S—, —N(R a )—, or a bond; R a  being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; 
         Y 2  is a bond; 
         L is an unsaturated straight C 6-12  hydrocarbon chain containing at least two double bonds, at least one triple bond, or at least one double bond and one triple bond; said unsaturated hydrocarbon chain being optionally substituted with C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, C 3-6  cycloalkyl, 3-6 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C 1-4  alkylcarbonyloxy, C 1-4  alkyloxycarbonyl, 
         C 1-4  alkylcarbonyl, or formyl; and further being optionally interrupted by —O—, —N(R g )—, —N(R g )—C(O)—O—, —O—C(O)—N(R g )—, —N(R g )—C(O)—N(R h )—, —O—C(O)—, —C(O)—O—, or —O—C(O)—O—; 
         each of R g  and R h , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl, wherein the carbon bonded to Y 2  is unsaturated; 
         R 1  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, haloalkyl, or an amino protecting group; and 
         R 2  is hydrogen, alkyl, hydroxylalkyl, haloalkyl, or a hydroxyl protecting group; 
         or a salt thereof, provided the compound is not 5-phenyl-2,4-pentadienoylhydroxamic acid or 7-phenyl-2,4,6-heptatrienoylhydroxamic acid.