Nicorandil derivatives

Abstract

Disclosed herein are pyridyl compounds. Also described are specific conjugated nicorandil compounds. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the pyridyl compounds are disclosed for the treatment of diseases or conditions related to kidney or kidney functions.

1 . A method for treating a disease or a condition related to kidney in a mammal, where the method comprises administering to the mammal an effective disease-treating or condition-treating amount of a compound according to formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutical composition thereof, 
         wherein X −  is a counter ion; Y is —C(H) 2 —, —O—, or —N(R 3 )—; 
         R 1  is substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 7 -cycloalkyl, or substituted or unsubstituted 4-7 membered heterocycloalkyl; 
         R 2  is H or C 1 -C 4  alkyl; and 
         R 3  is H or substituted or unsubstituted C 1 -C 4  alkyl; or R 1  and R 3  are joined together to form a 4-7 membered substituted or unsubstituted heterocycloalkyl. 
       
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein R 2  is H, Me, Et, or i-Pr. 
     
     
         4 . The method of  claim 1 , wherein R 2  is H. 
     
     
         5 . (canceled) 
     
     
         6 . The method according to  claim 1 , wherein Y is —O—. 
     
     
         7 . The method according to  claim 1 , wherein Y is —N(R 3 )—. 
     
     
         8 . The method according to  claim 1 , wherein the compound is according to formula (IIa), (IIb), or (IIc): 
       
         
           
           
               
               
           
         
         wherein 
         X −  is a counter ion; R 1  is substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 3 -C 7 -cycloalkyl, or substituted or unsubstituted 4-7 membered heterocycloalkyl; 
         R 2  is H or C 1 -C 4  alkyl; and 
         R 3  is H or substituted or unsubstituted C 1 -C 4  alkyl; or R 1  and R 3  are joined together to form a 4-7 membered substituted or unsubstituted heterocycloalkyl. 
       
     
     
         9 . The method according to  claim 1 , wherein R 1  is substituted or unsubstituted C 1 -C 4  alkyl. 
     
     
         10 . The method according to  claim 1 , wherein R 1  is C 1 -C 4  alkyl, unsubstituted or substituted with C 3 -C 7  cycloalkyl. 
     
     
         11 . The method according to  claim 1 , wherein R 1  is Me, Et, i-Pr, n-Pr, n-Bu, i-Bu, sec-Bu, or t-Bu. 
     
     
         12 . The method according to  claim 1 , wherein R 1  is Me or Et substituted with cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 
     
     
         13 . The method according to  claim 1 , wherein R 1  is C 3 -C 7 -cycloalkyl unsubstituted or substituted with Me or Et. 
     
     
         14 . The method according to  claim 1 , wherein R 1  is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 
     
     
         15 . (canceled) 
     
     
         16 . The method according to  claim 1 , wherein R 3  is H. 
     
     
         17 .- 19 . (canceled) 
     
     
         20 . The method according to  claim 1 , wherein the compound is according to formula (IIIa), or (IIIb): 
       
         
           
           
               
               
           
         
         wherein 
         X −  is a counter ion; R 2  is H or C 1 -C 4  alkyl; and 
         R 3  is H or substituted or unsubstituted C 1 -C 4  alkyl. 
       
     
     
         21 . The method according to  claim 20 , wherein R 3  is H, Me, Et, or i-Pr. 
     
     
         22 . The method according to  claim 20 , wherein R 3  is H. 
     
     
         23 . The method according to  claim 1 , wherein R 2  is H or Me. 
     
     
         24 . The method according to  claim 1 , wherein the compound is according to formula (IIIb); and each R 2  and R 3  is H. 
     
     
         25 . The method according to  claim 1 , wherein the compound is according to formula (IVa): 
       
         
           
           
               
               
           
         
         wherein X −  is a counter ion. 
       
     
     
         26 . The method according to  claim 1 , wherein the compound is according to formula (Va): 
       
         
           
           
               
               
           
         
         wherein X −  is a counter ion. 
       
     
     
         27 . The method according to  claim 1 , wherein X −  is F − , Cl − , Br − , I − , or MeSO 2 O − . 
     
     
         28 . The method according to  claim 1 , wherein X −  is Cl − , or I − . 
     
     
         29 . The method according to  claim 1 , wherein the pharmaceutical composition comprises a pharmaceutically acceptable excipient. 
     
     
         30 . The pharmaceutical composition of  claim 29  that is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration. 
     
     
         31 . The method according to  claim 1 , wherein the disease or condition is Chronic Kidney Disease, Diabetic Nephropathy, IgA Nephropathy, Acute Kidney Failure, Acute tubular necrosis, Transplant related Ischemia, Acute Kidney Disease and types of AKI such as Cisplatin induced AKI, Aminoglycosides induced AKI, Tenofovir induced AKI, Contrast Induced Nephropathy, AKI after surgery for partial nephrectomy, AKI post kidney transplant, AKI in patients with Dialysis, AKI after Cardiac surgery, AKI in patients inside ICU, AKI caused by Cirrhosis or Sepsis and AKI caused by hepatorenal syndrome. 
     
     
         32 . The method according to  claim 1 , wherein the disease or condition is Chronic Kidney Disease. 
     
     
         33 . The method according to  claim 1 , wherein the disease or condition is Acute Kidney Failure. 
     
     
         34 . The method of  claim 1 , wherein the compound of formula (I) is administered orally. 
     
     
         35 . The method according to  claim 1 , wherein the compound is according to formula (IVb): 
       
         
           
           
               
               
           
         
         wherein X −  is a counter ion. 
       
     
     
         36 . The method according to  claim 1 , wherein the compound is according to formula (Vb): 
       
         
           
           
               
               
           
         
       
       wherein X −  is a counter ion.