Patent GB-707251-A (GB)
Title: Process for the production of stable aqueous solutions of substituted xanthines
IPC: C07D473/08
Filed: 1951-10-03
Abstract: Stable aqueous solutions of substituted xanthines are prepared by dissolving a xanthine substituted by at least one substituent selected from alkyl, hydroxyalkyl, nitro and halogen, in water in the manner hereinafter defined and then adding at any time a salt of a sulphonic acid derivative of a hydroxyarylcarboxylic acid, the pH value of the resulting final solution being from 5 to 7.5. Solutions are prepared by (a) adding the xanthine and salt to water and heating; (b) dissolving the xanthine in an aqueous solution of a base and adding a sulphonic acid derivative of a hydroxyarylcarboxylic acid to form the salt in situ; (c) dissolving the xanthine in an aqueous solution of one of the free sulphonic acids referred to and adding a base to the specified pH; (d) adding the xanthine, acid and base to water and heating. Preferred heating is at 60-100 DEG  C. Specified xanthine are 1-methyl xanthine, 1.3-dimethyl xanthines (theophylline), 3.7-dimethyl xanthine (theobromine), 1.3.7 - trimethyl xanthine (caffeine), 1 . 3 - diethylxanthine 1.3 - di - (hydroxyethyl) xanthine, 8 - nitrotheophylline, 8 - chlorotheophylline, chloro - caffeine and chlorotheobromine. Specified sulphonic acids are 4-sulphosalicylic acid, 5-sulphosalicylic acid, 3-sulpho-4-hydroxy benzoic acid, 4 - sulpho - 3 - hydroxy benzoic acid, 5 - sulpho-3-methyl-2-hydroxy benzoic acid, 5-sulpho-b -resorcylic acid, 7-sulpho-3-hydroxy naphthoic (2) acid, 4-sulpho-1-hydroxy-naphthoic (2) acid, 5-sulpho-3-hydroxy-naphthoic (2) acid, 5.7-disulpho-3-hydroxy-naphthoic-(2)-acid and 7-sulpho-3.5-dihydroxy naphthoic (2) acid.  Specified bases are inorganic, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide and ammonia; aliphatic, e.g. ethylene diamine, hydroxyethylamine, diethanolamine and b -diethylaminoethanol; aromatic, e.g. benzylamine, phenylethylamine, N-methyl-1-phenyl-2-aminopropane, N-a -pyridyl-N-benzyl-N1,N1-dimethyl ethylene diamine, p-aminobenzoic acid diethylaminoethyl ester, dimethylaminoethyl benzhydryl ether, N-dimethylaminoethyl-N-p-methoxybenzyl-a -amino pyridine, phenylethylbarbituric acid and adrenaline; and heterocyclic, e.g. papaverine, quinidine, narcotine, substituted tetrahydroisoquinoline, lobeleine, ephedrine, atropine and g ,g -diphenylpropylamines substituted on the nitrogen.  Other additions are derivatives of pyridine carboxylic acids, especially salts of nicotinic acid and amides of nicotinic acid.  Xanthine solutions containing sugars may be obtained by hydrolysing a di- or-poly-saccharide, e.g. starch, insulin and cane sugar with the sulphonic acid derivative of a hydroxy aryl carboxylic acid, neutralizing with a base and then adding the xanthine.ALSO:Stable aqueous solutions of substituted xanthines are prepared by dissolving a xanthine substituted by at least one substituent selected from alkyl, hydroalkyl, nitro and halogen, in water in the manner hereinafter defined and then adding at any time a salt of a sulphonic acid derivative of a hydroxyarylcarboxylic acid, the pH value of the resulting final solution being from 5 to 7.5. Solutions are prepared by (a) adding the xanthine and salt to water and heating, (b) dissolving the xanthine in an aqueous solution of a base and adding a sulphonic acid derivative of a hydroxyarylcarboxylic acid to form the salt in situ, (c) dissolving the xanthine in an aqueous solution of one of the free sulphonic acids referred to and adding a base to specifled pH (d) adding the xanthine, acid and base to water and heating. Preferred heating is at 60-100 DEG C.  Specified xanthines are 1-methyl xanthine, 1,3-dimethyl xanthine (theophylline), 3,7-dimethyl xanthine (theobromine), 1,3,7-trimethyl xanthine (caffeine), 1,3-diethyl xanthine, 1,3-di(hydroxyethyl) xanthine, 8-nitrotheophylline, 8-chloro-theophylline. chloro-caffeine and chloro-theobromine. Specified sulphonic acids are 4-sulphosalicylic acid, 5-sulpho-salicylic acid, 3-sulpho-4-hydroxy benzoic acid, 4-sulpho-3 - hydroxy - benzoic p  acid, 5 - sulpho - 3-methyl-2-hydroxy benzoic acid, 5-sulpho-b -resorcylic acid, 7-sulpho-3-hydroxy naphthoic (2) acid, 4-sulpho-1 hydroxy-naphthoic-2-acid, 5-sulpho-3-hydroxy naphthoic-2-acid, 5,7- disulpho -3-hydroxy naphthoic -2-acid and 7-sulpho -3,5-dihydroxy naphthoic-2-acid.  Specified bases are inorganic e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide and ammonia; aliphatic e.g. ethylene diamine, hydroxyethylamine, diethanolamine and b -diethylaminoethanol; aromatic e.g. benzylamine, phenylethylamine, N-methyl-1-phenyl-2-aminopropane, N-a-pyridyl-N-benzyl N1N1 dimethyl ethylene diamine, p-aminobenzoic acid diethylaminoester, dimethylaminoethyl benzhydryl ether, N-dimethylaminoethyl N-p-methoxybenzyl a -amino pyridine, phenylethyl barbituric acid and adrenaline; and heterocyclic e.g. papaverine, quinidine, narcoteine, substituted tetrahydroisoquinoline, lobeline, ephedrine, atropine and d ,d -diphenyl-propyl amines substituted on the nitrogen.  Many of these bases are included for their therapeutic effect.  Other additions are sugars such as grape sugar, cane sugar; glucosides e.g. strophanthin, rutin, scilla glucosides and digitalis glucosides; and derivatives of pyridinecarboxylic acids especially salts of nicotinic acid and amides of nicotinic acid. Xanthine solutions containing sugars may be obtained by hydrolyzing a di- or poly-saccharide, e.g. starch, inulin and cane sugar with the sulphonic acid derivative of a hydroxyaryl carboxylic acid, neutralizing with a base, and then adding the xanthine.