Formulations containing pyridazine compounds

Abstract

The invention relates to chemical compounds, compositions and methods of making and using the same. In particular, the invention provides selected pyridazine compounds of the formula I are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, cyano, halo, sulfate, sulfenyl, sulfinyl, sulfonyl, sulfonate, sulfoxide, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, phosphonate, ureido, carboxyl, carbonyl, carbamoyl, or carboxamide; and X is optionally substituted pyrimidinyl or pyridazinyl, an isomer, a pharmaceutically acceptable salt, or derivative thereof. The invention additional relates to compositions comprising the compounds, and methods of using the compounds and compositions for modulation of cellular pathways, for treatment or prevention of inflammatory diseases, for research, drug screening, and therapeutic applications.

1 . A composition effective to provide lower risk of side effects and/or a beneficial pharmacokinetic profile following treatment of a subject suffering from a neuroinflammatory disease comprising a therapeutically effective amount of a compound of formula I: 
     
       
         
         
             
             
         
       
       wherein R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14  are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, cyano, halo, sulfate, sulfenyl, sulfinyl, sulfonyl, sulfonate, sulfoxide, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, phosphonate, ureido, carboxyl, carbonyl, carbamoyl, or carboxamide; and X is optionally substituted pyrimidinyl or pyridazinyl, an isomer, a pharmaceutically acceptable salt, or derivative thereof. 
     
   
   
       2 . A composition according to  claim 1  wherein R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14  are independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6 alkoxy, C 2 -C 6  alkenyloxy, C 3 -C 10  cycloalkyl, C 4 -C 10 cycloalkenyl, C3-C 10 cycloalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-C 1 -C 3 alkoxy, C 6 -C 10 aroyl, C 6 -C 10 heteroaryl, C 3 -C 10 heterocyclic, C 1 -C 6 acyl, C 1 -C 6 acyloxy, —NH 2 , —NHR 28 , —NR 28 R 29 , ═NR 28 , —S(O) 2 R 28 , —SH, —SO 3 H, nitro, cyano, halo, haloalkyl, haloalkoxy, hydroxyalkyl, —CO 2 H, —CO 2 R 28 , —NHC(O)R 28 , —C(O)NH 2 , —C(O)NHR 28 , —C(O)NR 28 R 29 , —NHS(O) 2 R 28 , wherein R 28  and R 29  are independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 4 -C 10 cycloalkenyl, C 6 -C 10 aryl, C 6 -C 10  aryl C 1 -C 3 alkyl, C 6 -C 10  heteroaryl and C 3 -C 10 heterocyclic. 
   
   
       3 . A composition according to  claim 1  comprising a therapeutically effective amount of a compound of the formula II: 
     
       
         
         
             
             
         
       
       wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17  are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, cyano, halo, sulfoxide, sulfenyl, sulfinyl, sulfonyl, sulfonate, sulfate, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, phosphonate, ureido, carboxyl, carbonyl, carbamoyl, or carboxamide; or an isomer, a pharmaceutically acceptable salt, or derivative thereof. 
     
   
   
       4 . A composition according to  claim 3  wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 R 16 , and R 17  are independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6 alkoxy, C 2 -C 6  alkenyloxy, C 3 -C 10  cycloalkyl, C 4 -C 10 cycloalkenyl, C 3 -C 10 cycloalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-C 1 -C 3 alkoxy, C 6 -C 10 aroyl, C 6 -C 10 heteroaryl, C 3 -C 10 heterocyclic, C 1 -C 6 acyl, C 1 -C 6 acyloxy, —NH 2 , —NHR 28 , —NR 28 R 29 , ═NR 28 , —S(O) 2 R 28 , —SH, —SO 3 H, nitro, cyano, halo, haloalkyl, haloalkoxy, hydroxyalkyl, —CO 2 H, —CO 2 R 28 , —NHC(O)R 28 , —C(O)NH 2 , —C(O)NHR 28 , —C(O)NR 28 R 29 , —NHS(O) 2 R 28 , wherein R 28  and R 29  are independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 4 -C 10 cycloalkenyl, C 6 -C 10 aryl, C 6 -C 10  aryl C 1 -C 3 alkyl, C 6 -C 10  heteroaryl and C 3 -C 10 heterocyclic. 
   
   
       5 . A composition according to  claim 1  wherein R 1  is alkyl, cycloalkyl, or heteroaryl. 
   
   
       6 . A composition according to  claim 1  wherein R 1  is: 
     
       
         
         
             
             
         
       
       wherein R 15 , R 16  and R 17  are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkynyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, cyano, halo, sulfoxide, sulfate, sulfonyl, sulfenyl, sulfinyl, sulfonate, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, phosphonate, ureido, carboxyl, carbonyl, carbamoyl, or carboxamide. 
     
   
   
       7 . A composition according to  claim 6 , wherein R 15 , R 16  and R 17  are independently selected from hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6 alkoxy, C 2 -C 6  alkenyloxy, C 3 -C 10  cycloalkyl, C 4 -C 10 cycloalkenyl, C 3 -C 10 cycloalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-C 1 -C 3 alkoxy, C 6 -C 10 aroyl, C 6 -C 10 heteroaryl, C 3 -C 10 heterocyclic, C 1 -C 6 acyl, C 1 -C 6 acyloxy, —NH 2 , —NHR 28 , —NR 28 R 29 , ═NR 28 , —S(O) 2 R 28 —SH, —SO 3 H, nitro, cyano, halo, haloalkyl, haloalkoxy, hydroxyalkyl, —CO 2 H, —CO 2 R 28 , —NHC(O)R 28 , —C(O)NH 2 , —C(O)NHR 28 , —C(O)NR 28 R 29 , —NHS(O) 2 R 28 , wherein R 28  and R 29  are independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 4 -C 10 cycloalkenyl, C 6 -C 10 aryl, C 6 -C 10 aryl C 1 -C 3 alkyl, C 6 -C 10 heteroaryl and C 3 -C 10 heterocyclic. 
   
   
       8 . A composition effective to provide lower risk of side effects and/or a beneficial pharmacokinetic profile following treatment in a subject suffering from a neuroinflammatory disease comprising a therapeutically effective amount of a compound of the formula III: 
     
       
         
         
             
             
         
       
       wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17  hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, cyano, halo, sulfoxide, sulfate, sulfonyl, sulfenyl, sulfinyl, sulfonate, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, phosphonate, ureido, carboxyl, carbonyl, carbamoyl, or carboxamide; with the proviso that R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17  cannot all be hydrogen, or an isomer, a pharmaceutically acceptable salt, or derivative thereof, or an isomer, a pharmaceutically acceptable salt, or derivative thereof. 
     
   
   
       9 . A composition according to  claim 8  wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17  are independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6 alkoxy, C 2 -C 6  alkenyloxy, C 3 -C 10  cycloalkyl, C 4 -C 10 cycloalkenyl, C 3 -C 10 cycloalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-C 1 -C 3 alkoxy, C 6 -C 10 aroyl, C 6 -C 10 heteroaryl, C 3 -C 10 heterocyclic, C 1 -C 6 acyl, C 1 -C 6 acyloxy, —NH 2 , —NHR 28 , —NR 28 R 29 ═NR 28 , —S(O) 2 R 28 , —SH, —SO 3 H, nitro, cyano, halo, haloalkyl, haloalkoxy, hydroxyalkyl, —CO 2 H, —CO 2 R 28 , —NHC(O)R 28 , —C(O)NH 2 , —C(O)NHR 28 , —C(O)NR 28 R 29 , —NHS(O) 2 R 28  wherein R 28  and R 29  are independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 4 -C 10 cycloalkenyl, C 6 -C 10 aryl, C 6 -C 10 aryl C 1 -C 3 alkyl, C 6 -C 10  heteroaryl and C 3 -C 10 heterocyclic. 
   
   
       10 . A composition according to  claim 8  wherein in the compound of the formula III R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17  are hydrogen, hydroxyl, alkyl, and one or both of R 10  and R 11  are independently substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyalkyl, silyloxy, silylthio, ═O, ═S, carboxyl, carbonyl, or carbamoyl, or an isomer or a pharmaceutically acceptable salt thereof. 
   
   
       11 . A composition according to  claim 8  wherein in the compound of the formula III one of R 10  and R 11  is alkyl, in particular C 1 -C 6  alkyl and the other of R 10  and R 11  is hydrogen. 
   
   
       12 . A composition according to  claim 8  wherein in the compound of the formula III one of R 10  and R 11  is aryl, and the other of R 10  and R 11  is hydrogen. 
   
   
       13 . A composition according to  claim 8  wherein in the compound of the formula III one of R 10  and R 11  is a heteroaryl in particular an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, and the other of R 10  and R 11  is hydrogen. 
   
   
       14 . A composition according to  claim 8  wherein in the compound of the formula III R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17  are hydrogen, and R 11  is alkyl, alkenyl, alkynyl, alkylene, alkoxy, aryl, or an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms. 
   
   
       15 . A composition according to  claim 8  wherein in the compound of the formula III R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17  are hydrogen and R 11  is alkyl or pyridinyl. 
   
   
       16 . A composition according to  claim 8  wherein the compound of the formula III is 4-methyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine. 
   
   
       17 . A composition according to  claim 1  comprising a therapeutically effective amount of a compound to selectively reduce or block up-regulation of IL-1β and S100B, and/or reduce or prevent loss of PSD-95 and/or synaptophysin. 
   
   
       18 . A composition according to  claim 1  comprising a therapeutically effective amount of compound of the formula I, II or III to treat a neuroinflammatory disease while reducing inhibitory activity at hERG potassium channel. 
   
   
       19 . A composition according to  claim 1  comprising a therapeutically effective amount of a compound of the formula I, II or III to treat a neuroinflammatory disease while reducing hERG inhibition. 
   
   
       20 . A composition according to  claim 1  wherein the therapeutically effective amount is effective to selectively reduce or block up-regulation of IL-1β and S100B, reduce or prevent loss of PSD-95 and/or synaptophysin over a dosing period. 
   
   
       21 . A composition according to  claim 1  comprising a therapeutically effective amount of a compound of the formula I, II or III suitable for administration to a subject to provide effective concentrations of the compound in an environment of use or an effective dose that results in therapeutic effects in the prevention, treatment, or control of symptoms of a disease disclosed herein. 
   
   
       22 . A composition according to  claim 21  wherein the disease is a neuroinflammatory disease. 
   
   
       23 . A composition according to  claim 1  comprising a dose of compound of formula I, II or III of about 0.1 to 100 mg/kg, 0.1 to 50 mg/kg, 0.1 to 25 mg/kg, 0.1 to 20 mg/kg, 0.1 to 15 mg/kg, 0.1 to 10 mg/kg, 0.1 to 5 mg/kg, 0.1 to 4 mg/kg, 0.1 to 3 mg/kg, 0.1 to 2 mg/kg, or 0.1 to 1 mg/kg. 
   
   
       24 . A method of treating a neuroinflammatory disease in a subject comprising administering a composition of  claim 1  to the subject. 
   
   
       25 . Use of at least one compound of the formula I, II, or III as defined in  claim 1  for the preparation of a medicament for providing lower risks of side effects and/or a beneficial pharmacokinetic profile in treating a neuroinflammatory disease. 
   
   
       26 . A kit comprising one or more composition of  claim 1 , a container, and instructions for use.