Non-sedating barbiturate compounds as neuroprotective agents

Abstract

Methods of providing neuroprotection are disclosed comprising administering a non-sedative barbiturate compound in an amount sufficient to achieve neuroprotection in a mammalian subject. Preferred compounds are in the family of diphenylbarbituric acid and analogs. Preferred doses for a neuroprotective effect exceed the dosage of a corresponding sedative barbiturate without sedative side-effects such as anesthesia and death.

1 - 25 . (canceled)  
     
     
         26 . A method for providing neuroprotection to a mammal in need of neuroprotection, comprising administering to the mammal an effective neuroprotective dose of at least one non-sedating barbiturate selected from the group consisting of 1,3-dimethoxymethyl 5,5-diphenyl-barbituric acid (DMMDPB), 1-monomethoxymethyl 5,5-diphenylbarbituric acid (MMMDPB), diphenyl barbituric acid (DPB), a precursor thereof, a derivative thereof, an analog thereof, and a salt thereof.  
     
     
         27 . The method of  claim 26 , wherein the non-sedating barbiturate is 1,3-dimethoxymethyl 5,5-diphenyl-barbituric acid (DMMDPB).  
     
     
         28 . The method of  claim 26 , wherein the non-sedating barbiturate is 1-monomethoxymethyl 5,5-diphenylbarbituric acid (MMMDPB).  
     
     
         29 . The method of  claim 26 , wherein the non-sedating barbiturate is a salt of 1-monomethoxymethyl 5,5-diphenylbarbituric acid (MMMDPB).  
     
     
         30 . A method for providing neuroprotection in a mammal at risk for cerebral ischemia, comprising administering to the mammal an effective neuroprotective dose of a non-sedating barbiturate, wherein the non-sedating barbiturate is administered in an oral form as a tablet, capsule, or liquid.  
     
     
         31 . A method for providing neuroprotection in a mammal at risk for cerebral ischemia, comprising administering to the mammal an effective neuroprotective dose of a non-sedating barbiturate, wherein the non-sedating barbiturate is administered transdermally or transpulmonarily by means of a particulate or aerosol inhalant.  
     
     
         32 . A method for providing neuroprotection to a mammal in need of neuroprotection, comprising administering to the mammal a non-sedating barbiturate in an amount that exceeds the coma-producing dosage of a sedative barbiturate.  
     
     
         33 . A method for providing neuroprotection to a mammal in need of neuroprotection, comprising administering to the mammal a non-sedating barbiturate in an amount that exceeds the minimum anticonvulsant dosage of a sedative barbiturate.  
     
     
         34 . The method of  claim 33 , wherein the non-sedating barbiturate is administered in an amount from about 2 times to about 5 times the minimum anticonvulsant dosage of a sedative barbiturate.  
     
     
         35 . The method of  claim 33 , wherein the non-sedating barbiturate is administered in an amount from about 5 times to about 10 times the minimum anticonvulsant dosage of a sedative barbiturate.  
     
     
         36 . A method for providing neuroprotection to a patient in need of neuroprotection, comprising the steps of: 
 (a) diagnosing a patient's need for cerebral neuroprotection;    (b) selecting a non-sedative barbiturate; and    (c) providing to the patient a dose of the non-sedative barbiturate sufficient to raise the concentration in the patient's brain to a level effective to provide neuroprotection.    
     
     
         37 . An article of manufacture comprising a container, a pharmaceutical composition and a label with indications for use as a neuroprotectant, the pharmaceutical composition comprising: 
 (a) a non-sedating barbiturate compound in an amount effective for neuroprotection upon administration to a subject in need of neuroprotection; and    (b) a pharmaceutically acceptable carrier or excipient.    
     
     
         38 . The article of  claim 37  wherein the non-sedating barbiturate compound is at least one compound selected from the group consisting of 1,3-dimethoxymethyl 5,5-diphenyl-barbituric acid (DMMDPB), 1-monomethoxymethyl 5,5-diphenylbarbituric acid (MMMDPB), diphenyl barbituric acid (DPB), a precursor thereof, a derivative thereof, an analogue thereof, and a salt thereof.  
     
     
         39 . A method for providing neuroprotection to a mammal in need of neuroprotection, comprising administering to the mammal an effective neuroprotective dose of a non-sedating barbiturate having the structure:  
       
         
           
           
               
               
           
         
       
       and salts thereof, wherein 
 R 1  and R 2  may be the same or different and are independently hydrogen; lower alkyl, optionally substituted by lower alkoxy; CH 2 OR 5 , wherein R 5  is lower alkyl, alkylaryl or benzyl; CO 2 R 6 , wherein R 6  is lower alkyl or aryl; COR 7 , wherein R 7  is hydrogen, lower alkyl or aryl; or CH(OR 8 ) 2 , wherein R 8  is a lower alkyl group; and  
 R 3  and R 4  may be the same or different and are independently aryl; phenyl; substituted phenyl; benzyl; substituted benzyl; lower alkyl; or lower alkyl substituted with an aromatic moiety; provided that at least one of R 3  and R 4  is an aromatic ring containing moiety.  
 
     
     
         40 . The method of  claim 39 , wherein R 3  and R 4  may be the same or different and are independently aryl; phenyl; phenyl substituted with methyl, ethyl, and/or fluorine; benzyl; benzyl substituted on the ring with methyl, ethyl, and/or fluorine; lower alkyl; or lower alkyl substituted with an aromatic moiety; provided that at least one of R 3  and R 4  is an aromatic ring containing moiety.  
     
     
         41 . The method of  claim 39 , wherein at least one of R 3  and R 4 is phenyl or substituted phenyl.  
     
     
         42 . The method of  claim 41 , wherein R 3  and R 4  may be the same or different and are independently phenyl or substituted phenyl.  
     
     
         43 . The method of  claim 42 , wherein R 3  and R 4  are both phenyl.  
     
     
         44 . The method of  claim 39 , wherein R 3  and R 4  may be the same or different and are independently aryl; phenyl; phenyl substituted with a halogen or lower alkyl group; benzyl; ring substituted benzyl having one or more halogens, lower alkyl groups or both; lower alkyl; or lower alkyl substituted with an aromatic moiety; provided that at least one of R 3  and R 4  is phenyl or phenyl substituted with a halogen or lower alkyl group.  
     
     
         45 . The method of  claim 39 , wherein R 3  and R 4  may be the same or different and are independently aryl; phenyl; substituted phenyl; benzyl; or substituted benzyl.  
     
     
         46 . The method of  claim 39 , wherein one of R 1  and R 2  is hydrogen.  
     
     
         47 . The method of  claim 46 , wherein one of R 1  and R 2  is hydrogen, and the other of R 1  and R 2  is methyl or alkoxymethyl; or R 1  and R 2  are each independently methyl or alkoxymethyl.  
     
     
         48 . The method of  claim 47 , wherein R 1  and R 2  are methoxymethyl.  
     
     
         49 . The method of  claim 47 , wherein R 3  and R 4  may be the same or different and are independently aryl; phenyl; phenyl substituted with a halogen or lower alkyl group; benzyl; ring substituted benzyl having one or more halogens, lower alkyl groups or both; lower alkyl; or lower alkyl substituted with an aromatic moiety; provided that at least one of R 3  and R 4  is an aromatic ring containing moiety.  
     
     
         50 . The method of  claim 47 , wherein at least one of R 3  and R 4  is phenyl, tolyl, fluorophenyl, or ethylphenyl.  
     
     
         51 . The method of  claim 47 , wherein R 3  and R 4  may be the same or different and are independently phenyl or substituted phenyl.  
     
     
         52 . The method of  claim 51 , wherein R 3  and R 4  are both phenyl.