Fumarate compounds, pharmaceutical compositions thereof, and methods of use

Abstract

Fumarate compounds, pharmaceutical compositions comprising the fumarate compounds, and methods of using fumarate compounds and pharmaceutical compositions for treating neurodegenerative, inflammatory, and autoimmune disorders including multiple sclerosis, psoriasis, irritable bowel disorder, ulcerative colitis, arthritis, chronic obstructive pulmonary disease, asthma, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are disclosed.

1 . A method of treating a patient suffering from a disease chosen from psoriasis, multiple sclerosis, Huntington's disease, asthma, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, ulcerative colitis and psoriatic arthritis, comprising administering to a patient in need thereof a compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 each R 1  is independently chosen from methyl, ethyl, and isopropyl; 
 R 2  is chosen from a null, hydrogen, methyl, ethyl, and n-propyl; 
 R 3  and R 4  are independently chosen from hydrogen, C 1-6  alkyl, C 1-6  heteroalkyl, C 3-12  cycloalkyl, C 4-12  cycloalkylalkyl, C 3-12  heterocycloalkyl, C 4-12  heterocycloalkylalkyl, C 6-10  aryl, C 7-12  arylalkyl, C 5-10  heteroaryl, and C 5-10  heteroarylalkyl; or R 3  and R 4  together with the nitrogen atom to which they are bonded form a ring chosen from C 3-12  heterocycloalkyl, substituted C 3-12  heterocycloalkyl, C 5-10  heteroaryl, and substituted C 5-10  heteroaryl; and 
 each X 1  and X 2  is independently chosen from a bond and C 1-6  alkane-diyl; 
 wherein each substituent group is independently chosen from halogen, —OH, —CN, —CF 3 , ═O, —NO 2 , phenyl, benzyl, —C(O)NR 21   2 , —R 21 , —OR 21 , —C(O)R 21 , —C(O)OR 21 , —NR 21   2 , —NR 21 C(O)R 21 , and —O(O)R 21 , wherein each R 21  is independently chosen from hydrogen, C 1-4  alkyl, and C 6-10  aryl. 
 
     
     
         2 . The method of  claim 1 , wherein the disease is chosen from psoriasis and multiple sclerosis. 
     
     
         3 . The method of  claim 1 , comprising administering a second therapeutic agent effective in treating psoriasis or multiple sclerosis. 
     
     
         4 . The method of  claim 1 , wherein each R 1  is independently chosen from methyl, ethyl, and isopropyl; and R 2  is chosen from a null, hydrogen, and methyl. 
     
     
         5 . The method of  claim 1 , wherein each R 1  is methyl; and R 2  is hydrogen. 
     
     
         6 . The method of  claim 1 , wherein R 3  and R 4  are independently chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2-hydroxyethyl, 2-methoxyethyl, 3-hydroxypropyl, and 3-methoxypropyl. 
     
     
         7 . The method of  claim 1 , wherein R 3  and R 4  are independently chosen from methyl, ethyl, and 2-methoxyethyl. 
     
     
         8 . The method of  claim 1 , wherein R 3  and R 4  together with the nitrogen atom to which they are bonded form a ring chosen from morpholin-4-yl and 1-piperidyl. 
     
     
         9 . The method of  claim 1 , wherein each X 1  and X 2  is independently chosen from a bond, methane-diyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,2-diyl, propane-1,3-diyl, 2-methylpropane-1,2-diyl, 2,2-dimethylpropane-1,3-diyl, butane-1,2-diyl, butane-1,3-diyl, butane-1,4-diyl, butane-2,3-diyl, 2,3-dimethylbutane-2,3-diyl, pentane-1,5-diyl, and hexane-1,6-diyl. 
     
     
         10 . The method of  claim 1 , wherein each X 1  and X 2  is independently chosen from a bond, methane-diyl, and ethane-1,2-diyl. 
     
     
         11 . The method of  claim 1 , wherein each R 1  is independently chosen from methyl, ethyl, and isopropyl; R 2  is chosen from a null, hydrogen, methyl, ethyl, and n-propyl; R 3  and R 4  are independently chosen from hydrogen, methyl, ethyl, and 2-methoxyethyl; or R 3  and R 4  together with the nitrogen atom to which they are bonded form a ring chosen from morpholin-4-yl and 1-piperidyl; each X 1  and X 2  is independently chosen from a bond, methane-diyl, and ethane-1,2-diyl; and n is 2 or 3. 
     
     
         12 . The method of  claim 1 , wherein each R 1  is methyl; R 2  is chosen from a null and hydrogen; R 3  and R 4  are independently chosen from methyl, ethyl, and 2-methoxyethyl; or R 3  and R 4  together with the nitrogen atom to which they are bonded form a ring chosen from morpholin-4-yl and 1-piperidyl; each X 1  is independently chosen from a bond, methane-diyl, and ethane-1,2-diyl; X 2  is chosen from a bond, methane-diyl, and ethane-1,2-diyl; and n is 2 or 3. 
     
     
         13 . The method of  claim 1 , wherein each R 1  is methyl; R 2  is hydrogen; R 3  is methyl; R 4  is methyl; each X 1  is independently chosen from a bond and methane-diyl; X 2  is methane-diyl; and n is 2. 
     
     
         14 . The method of  claim 1 , wherein each R 1  is methyl; R 2  is hydrogen; R 3  and R 4  together with the nitrogen atom to which they are bonded form a morpholin-4-yl ring; each X 1  is independently chosen from a bond and methane-diyl; X 2  is methane-diyl; and n is 2. 
     
     
         15 . The method of  claim 1 , wherein the compound is chosen from the compound of Formula (I-A-1), Formula (I-A-2), Formula (I-A-3), Formula (I-A-5), Formula (I-A-6), Formula (I-A-7), Formula (I-B-1), Formula (I-B-2), Formula (I-B-3), Formula (I-C-1), Formula (I-C-2), Formula (I-C-3), and a pharmaceutically acceptable salt of any of the foregoing: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 1 , wherein the compound is in an oral formulation. 
     
     
         17 . The method of  claim 16 , wherein the oral formulation is an oral sustained release formulation. 
     
     
         18 . The method of  claim 1 , wherein the compound is the compound of Formula (I-C-1). 
     
     
         19 . The method of  claim 18 , wherein the disease is psoriasis. 
     
     
         20 . The method of  claim 18 , wherein the disease is multiple sclerosis. 
     
     
         21 . The method of  claim 18 , wherein the compound is in an oral formulation. 
     
     
         22 . The method of  claim 21 , wherein the oral formulation is an oral sustained release formulation.