Compositions and treatments using pyridazine compounds and cholinesterase inhibitors

Abstract

The invention relates to compositions, conjugates and methods comprising pyridazine compounds and cholinesterase inhibitors for modulation of cellular pathways (e.g., signal transduction pathways), for treatment or prevention of inflammatory diseases (e.g., Alzheimer's disease), for research, drug screening, and therapeutic applications.

1 .- 2 . (canceled) 
     
     
         3 . A pharmaceutical composition comprising therapeutically effective amounts of at least one pyridazine compound and at least one cholinesterase inhibitor that provides beneficial effects relative to each compound alone, and a pharmaceutically acceptable carrier, excipient, or vehicle, wherein the pyridazine compound has the Formula Ia or Ib 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , and R 3  are independently substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, phosphonate, carboxyl, carbonyl, carbamoyl, or carboxamide; R 7  is substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, phosphonate, carboxyl, carbonyl, carbamoyl, or carboxamide or R 7  may be absent and there is a double bond between N at position 1 and C at position 6; R 4 , R 5 , and R 6  are independently hydrogen, alkyl, alkoxy, halo, or nitro; or R 1  and R 2 , R 1  and R 7 , or R 2  and R 3  may form a heteroaryl or heterocyclic ring; or an isomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . A pharmaceutical composition according to  claim 3  wherein the pyridazine compound has the Formula II: 
       
         
           
           
               
               
           
         
         wherein R 10  and R 11  are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, phosphonate, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl, carbonyl, carbamoyl, or carboxamide; or an isomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 .- 7 . (canceled) 
     
     
         8 . A pharmaceutical composition according to  claim 4  wherein the therapeutically effective amounts are suboptimal relative to the amount of each compound administered alone for treatment of an inflammatory disease. 
     
     
         9 . (canceled) 
     
     
         10 . A pharmaceutical composition according to  claim 4  wherein the pyridazine compound is used in combination with the cholinesterase inhibitor at therapeutically effective weight ratios of between about 1:1.5 to 1:150. 
     
     
         11 . (canceled) 
     
     
         12 . A pharmaceutical composition according to  claim 4  comprising a synergistically effective amount of a pyridazine compound and a cholinesterase inhibitor in a pharmaceutically acceptable excipient, carrier, or vehicle. 
     
     
         13 .- 14 . (canceled) 
     
     
         15 . A pharmaceutical composition according to  claim 12  wherein the cholinesterase inhibitor is one or more of tacrine or tacrine analogues, huperzine A or its analogues, galantamine or its analogues, rivastigmine or its analogues, donepezil or its analogues, zifrosilone or its analogues, or pharmaceutically acceptable salts thereof. 
     
     
         16 .- 17 . (canceled) 
     
     
         18 . A method for treating in a subject a disease involving or characterized by inflammation comprising administering a therapeutically effective amount of pyridazine compound and a cholinesterase inhibitor or a composition as claimed in  claim 12 . 
     
     
         19 .- 22 . (canceled) 
     
     
         23 . A method for ameliorating progression of a neuroinflammatory disease or obtaining a less severe stage of a neuroinflammatory disease in a subject suffering from such disease comprising administering therapeutically effective amounts of a pyridazine compound and a cholinesterase inhibitor or a composition as claimed in  claim 12 . 
     
     
         24 . A method of  claim 18  wherein the disease is a dementing disorder, a neurodegenerative disorder, a CNS demyelinating disorder, an autoimmune disorder, or a peripheral inflammatory disease. 
     
     
         25 . A method of  claim 18  wherein the disease is Alzheimer's disease. 
     
     
         26 .- 27 . (canceled) 
     
     
         28 . A method of  claim 18  wherein therapeutically effective amounts of the pyridazine compound and the cholinesterase inhibitor are combined prior to administration to the subject. 
     
     
         29 . A method of  claim 18  wherein therapeutically effective amounts of the pyridazine compound and the cholinesterase inhibitor are administered to the subject sequentially. 
     
     
         30 .- 31 . (canceled) 
     
     
         32 . A kit comprising a pyridazine compound and a cholinesterase inhibitor or a composition as claimed in  claim 12  for treating an inflammatory disease, a container, and instructions for its use. 
     
     
         33 . A composition of  claim 4  wherein R 11  is hydrogen, halo, substituted alkyl, pyridinyl, piperidinyl, morpholinyl, piperazinyl or phenyl. 
     
     
         34 . A composition of  claim 4  wherein the pyridazine compound has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         35 . A method of  claim 18  wherein, in the compound of the formula II, R 11  is hydrogen, halo, substituted alkyl, pyridinyl, piperidinyl, morpholinyl, piperazinyl or phenyl. 
     
     
         36 . A method of  claim 18  wherein the pyridazine compound has the following formula: