Patent GB-705944-A (GB)
Title: Process for the preparation of solutions of xanthines substituted in the 1.3-position
Filed: 1951-08-01
Abstract: Stable solutions of xanthines substituted in the 1:3-positions by alkyl or substituted alkyl (e.g. hydroxyethyl) groups are prepared by dissolving the xanthine in water with the aid of heat, or with an alkali followed by neutralization, and adding at any stage of the process one or more of the following pyridine derivatives:-salts, esters and unsubstituted amides of sulphonic, arsonic and phosphinic acids, and salts and esters of carboxylic acids.  A known solubilizing agent may also be present, e.g. nicotinamide, a salicylate, m-hydroxybenzoate, resorcylate, urethane, amide of a lower aliphatic acid, or a xanthine- or indole-acetic acid.  When a salt of the pyridine acid is used this may be formed in situ; the base may be an alkali or alkaline earth metal, ammonia, an aliphatic amine (e.g. ethanolamines, ethylene diamine, butylamine), aromatic amine, alkaloid or other physiologically active base.  The solution is preferably prepared at 80-100 DEG C. and pH 5.5-7; the water may be mixed with another liquid, e.g. a lactic ester or propylene glycol.  The solution may be evaporated to dryness.  Other substances may be added, e.g. glucose and glycosides such as strophanthin and digitoxin. Preferably 1-10 mol. of pyridine compound is used per mol. of xanthine.  In the examples, (1) theophylline is warmed with sodium nicotinate, or (2) with sodium picolinate; (3) theophylline is warmed with nicotinic acid and ethylene diamine and further nicotinic acid added; (4) theophylline is warmed with ephedrine and nicotinic acid and caustic soda added; (5) caffeine is warmed with sodium nicotinate; (6) theophylline is warmed with ethyl nicotinate, or (7) with disodium pyridine-2:6-dicarboxylate; (8) theophylline is mixed with sodium 5-chloronicotinate; (9) theophylline is warmed with sodium pyridine-3-sulphonate, or (10) with sodium 2-chloro-pyridine - 5 - sulphonate, or (11) with sodium 2-pyridone-5-sulphonate, or (12) with a mixture of sodium picoline-3-and -5-sulphonates; (13) theophylline is warmed with the ethylene diamine salt of pyridine-3:5-disulphonic acid and papaverine added followed by more pyridine - 3:5 - disulphonic acid; (14) theophylline is warmed with pyridine-3-sulphonamide, or (15) with pyridine-3:5-disulphonamide; (16) theophylline is warmed with water and sodium nicotinate added. Other suitable pyridine compounds are mentioned.  The use of pyridine carboxylic amides is acknowledged as known.  Specifications 218,982, [Class 2 (iii)], and 518,996 are referred to.ALSO:Stable solutions of xanthines substituted in the 1 : 3-positions by alkyl or substituted alkyl (e.g. hydroxyethyl) groups are prepared by dissolving the xanthine in water with the aid of heat, or with an alkali followed by neutralization, and adding at any stage of the process one or more of the following pyridine derivatives: salts, esters and unsubstituted amides of sulphonic, arsonic and phosphinic acids, and salts and esters of carboxylic acids.  A known solubilizing agent may also be present, e.g. nicotinamide, a salicylate, m-hydroxy-benzoate, resorcylate, urethane, amide of a lower aliphatic acid, or a xanthine- or indole-acetic acid.  When a salt of the pyridine acid is used this may be formed in situ; the base may be an alkali or alkaline earth metal, ammonia, an aliphatic or aromatic amine, alkaloid or other physiologically active base.  Specified organic bases are mono-, di- and tri-ethanolamine, ethylene diamine, butylamine, ephedrine, adrenaline, papaverine and quinidine.  The solution is preferably prepared at 80-100 DEG C and pH 5.5-7; the water may be mixed with another liquid, e.g. a lactic ester or propylene glycol.  The solution may be evaporated to dryness. Other substances may be added, e.g. glucose and glycosides such as strophanthin and digitoxin.  Preferably 1-10 mol of pyridine compound is used per mol xanthine.  Examples show compositions of theophylline with (1) sodium nicotinate, (2) sodium picolinate, (3) nicotinic acid and ethylene diamine, (4) ephedrine and sodium nicotinate, (5) ethyl nicotinate, (6) disodium pyridine-2 : 6-dicarboxylate, (7) sodium 5-chloronicotinate, (8) sodium pyridine-3-sulphonate, (9) sodium 2-choloropyridine-5-sulphonate, (10) sodium 2-pyridone-5-sulphonate, (11) a mixture of sodium picoline-3- and -5-sulphonates, (12) ethylene diamine and papaverine salts of pyridine-3 : 5-disulphonic acid, (13) pyridine-3-sulphonamide, and (14) pyridine-3 : 5-disulphonamide.  A further example shows caffein with sodium nicotinate.  Other suitable pyridine compounds are mentioned.  The use of pyridine carboxylic amides is acknowledged as known. Specifications 218,982, [Class 81(i)], and 518,996 are referred to.