Method and reagents for N-alkylating ureides

Abstract

A method of N-alkoxyalkylating ureides according to the invention comprises reacting a ureide of structure I with an alkylating agent of structure III in the presence of a basic catalyst in an aprotic reaction medium. The ureide may be a 5,5-disubstituted barbituric acid, or it may be phenytoin, glutethimide, and ethosuximide. The alkylating agent is an ester of a sulfonic acid. The base may be a hydride or amine. A preferred process comprises N-alkoxyalkylating 5,5-diphenyl-barbituric acid with methoxymethyl methanesulfonate in the presence of di-isopropyl ethyl amine and isolating the resultant N,N′-bismethoxymethyl-5,5-diphenyl-barbituric acid. The invention also contemplates the novel compounds N-methoxymethyl-5,5-diphenylbarbituric acid, N-methoxymethyl ethosuximide, and N-methoxymethyl glutethimide, and a method comprising administering them to a patient.

1. A method of N-alkylating ureides comprising reacting a ureide of formula I 
                 
 
       with an ester of a sulfonic acid of formula III 
                 
 
       in the presence of a base in an aprotic reaction medium, to provide a corresponding alkylated ureide, wherein R 1  and R 2  are each either non-cyclic alkyl, aryl, arylalkyl, or R 1  and R 2  together form a cyclic group having a total of at least 5 atoms each of which is selected from the group consisting of carbon, nitrogen and oxygen, and wherein R 3 =H, lower alkyl, phenyl, or alkyl substituted phenyl, R 4 =H, lower alkyl, phenyl, or alkyl substituted phenyl, and R 5 =lower alkyl, phenyl, or alkyl substituted phenyl. 
     
     
       2. A process of N-alkylation of a ureide comprising:
 reacting a ureide of formula I 
                 
 
 with an ester of a sulfonic acid of Formula III 
                 
 
 in the presence of a base and an aprotic solvent, wherein one of R 1  and R 2  is NH 2 , NHCOCH 3 , or non-cyclic alkyl, aryl, arylalkyl, or haloalkyl, and the other of R 1  and R 2  is non-cyclic alkyl, aryl, arylalkyl, or haloalkyl, or wherein R 1  and R 2  together form a cyclic group selected from the group consisting of NHCOC(R 6 )(R 7 ), NHC(R 6 )(R 7 ), CH 2 CH 2 C(R 6 ) (R 7 ), OC(R 6 )(R 7 ) and CH 2 C(R 6 )(R 7 ), wherein R 6  and R 7 , are each either noncyclic alkyl, aryl or arylalkyl, and wherein R 3 =H, lower alkyl, phenyl, or alkyl substituted phenyl, R 4 =H, lower alkyl, phenyl, or alkyl substituted phenyl, and R 5 =lower alkyl, phenyl, or alkyl substituted phenyl, to provide a resultant N-alkoxyalkylated ureide.  
 
     
     
       3. A process according to  claim 2 , wherein the ureide is a 5,5-disubstituted barbituric acid. 
     
     
       4. A process according to  claim 2 , wherein the ureide is 5,5-diphenyl barbituric acid, the ester of a sulfonic acid is selected from the group consisting of methoxymethyl methanesulfonate, methoxymethyl ethanesulfonate, methoxymethyl benzenesulfonate, and methoxymethyl p-toluenesulfonate, the base is di-isopropyl ethyl amine, and the resultant ureide is N,N′-bismethoxymethyl-5,5-diphenyl barbituric acid. 
     
     
       5. A process according to  claim 2 , wherein the ureide is selected from the group consisting of 5,5-diphenyl barbituric acid, phenytoin, glutethimide, ethosuximide, 5-phenyl-5-ethylbarbituric acid, and 5,5-diethylbarbituric acid. 
     
     
       6. A process according to  claim 2 , wherein the ureide is selected from the group consisting of acecarbromal, apronalide, bromisolvalum, capuride, carbromal, ectylurea, hydantoins, glutarimides, oxazolidinediones, succinimides, and barbiturates. 
     
     
       7. A process according to  claim 2 , wherein the ester of a sulfonic acid is methoxymethyl methanesulfonate. 
     
     
       8. A process according to  claim 2 , wherein the ester of a sulfonic acid is selected from the group consisting of ethoxymethyl methanesulfonate, benzyloxymethyl methanesulfonate, methoxymethyl ethanesulfonate, methoxymethyl benzenesulfonate, methoxymethyl p-toluenesulfonate, methoxylbenzylidene methanesulfonate, and methoxyethylidene methanesulfonate. 
     
     
       9. A process according to  claim 2 , wherein the base is non-aqueous with a strength between sodium hydride and a tertiary amine. 
     
     
       10. A process according to  claim 2 , wherein the base is a tertiary amine. 
     
     
       11. A process according to  claim 2 , wherein the base is selected from the group consisting of sodium hydride, potassium hydride, lithium hydride, triethyl amine tri-n-propylamine, and di-isopropy ethyl amine. 
     
     
       12. A process according to  claim 2 , wherein the ester of a sulfonic acid is produced in situ and is combined directly with the ureide without isolating the ester of a sulfonic acid. 
     
     
       13. A process according to  claim 2 , further comprising reacting a mixed anhydride of acetic acid and a sulfonic acid with a dialkoxymethane to provide the ester of the sulfonic acid in situ and combined with the ureide without isolating the ester of the sulfonic acid. 
     
     
       14. A process according to  claim 2 , wherein the ureide is 5,5-disubstituted barbituric acid, which is converted to its di-anion salt with a strong base, and one equivalent of the ester of a sulfonic acid is added, to provide the corresponding mono-alkylated barbituric acid. 
     
     
       15. A process according to  claim 2 , wherein the aprotic reaction medium is a dipolar solvent. 
     
     
       16. A process according to  claim 2 , wherein the dipolar solvent is selected from the group consisting of dimethyl formamide, dimethyl sulfoxide, dimethylacetamide, sulfolane, and N-methylpyrrolidione. 
     
     
       17. A process according to  claim 3 , wherein the the  ureide is 5,5-diphenyl barbituric acid, the ester of a sulfonic acid is selected from the group consisting of methoxymethyl methanesulfonate, ethoxymethyl methanesulfonate, benzyloxymethyl methanesulfonate, methoxymethyl ethanesulfonate, methoxymethyl benzenesulfonate, methoxymethyl p-toluenesulfonate, methoxylbenzylidene methanesulfonate, and methoxyethylidene methanesulfonate, the base is a non-aqueous base selected from a hydride or an amine, and the process further comprises isolating the resultant alkoxyalkylated 5,5-diphenyl-barbituric acid. 
     
     
       18. A process according to  claim 17 , wherein the ureide is alkoxyalkylated to an N-mono-alkoxyalkylated 5,5-diphenyl barbituric acid. 
     
     
       19. A process according to  claim 18 , wherein the ester is a methoxymethyl ester, the base is very strong and is present in excess, and the isolated compound is N-methoxymethyl-5,5-diphenylbarbituric acid. 
     
     
       20. An alkoxyalkylated ureide compound selected from the group consisting of N-methoxymethyl ethosuximide,  and N-methoxymethyl glutethimide, and N-methoxymethyl-5,5-diphenylbarbituric acid . 
     
     
       21. A compound according to  claim 20 , wherein the compound is N-methoxymethyl ethosuximide. 
     
     
       22. A compound according to  claim 20 , wherein the compound is N-methoxymethyl glutethimide. 
     
     
       23. A compound according to  claim 20 , wherein the compound is N-methoxymethyl-5,5-diphenylbarbituric acid. 
     
     
       24. A method of treating a mammal for a condition selected from the group consisting of convulsions, seizures, muscle stiffness, or anxiety comprising administering to a patient in need of such treatment an effective amount of a pharmaceutical agent comprising a compound according to  claim 20 . 
     
     
       25. A method of N-alkylating ureides comprising reacting a ureide of formula I 
                 
 
       with an ester of a sulfonic acid of formula III 
                 
 
       in the presence of a base in an aprotic reaction medium, to provide a corresponding alkylated ureide, wherein R 1  and R 2  together form a cyclic group having a total of at least 5 atoms each of which is selected from the group consisting of carbon nitrogen and oxygen, and wherein R 3 =H, lower alkyl, phenyl, or alkyl substituted phenyl, R4=H, lower alkyl, phenyl, or alkyl substituted phenyl, and R 5 =lower alkyl, phenyl, or alkyl substituted phenyl. 
     
     
       26. A process for N-alkoxyalkylation of a ureide comprising:
 reacting a ureide of formula IV 
                 
 
 with an ester of a sulfonic acid of Formula III 
                 
 
 in the presence of a base and an aprotic solvent,  
 wherein X is O, NH, CH 2 , CH 2 —CH 2  or C(O)NH, and wherein R 6  and R 7  are each either noncyclic alkyl, aryl or arylalkyl, and wherein R 3 =H, lower alkyl, phenyl, or alkyl substituted phenyl, R 4 =H, lower alkyl, phenyl or alkyl substituted phenyl, and R 5 =lower alky  alkyl, phenyl, or alkyl substituted phenyl, to provide a resultant N-alkoxyalkylated ureide.  
 
     
     
       27. Isolated N- methoxymethyl -   5 , 5   - diphenylbarbituric acid.   
     
     
       28. A method of treating a mammal in need of treatment for a condition selected from the group consisting of convulsions, seizures, muscle stiffness, and anxiety, comprising administering to the mammal an effective amount of a pharmaceutical agent comprising N- methoxymethyl -   5 , 5   - diphenylbarbituric acid.   
     
     
       29. The method of  claim 28 , wherein the condition is convulsions. 
     
     
       30. The method of  claim 28 , wherein the condition is seizures. 
     
     
       31. The method of  claim 28 , wherein the condition is muscle stiffness. 
     
     
       32. The method of  claim 28 , wherein the condition is anxiety.