Patent GB-804492-A (GB)
Title: Aminopyrine, caffeine or quinine hydrochloride inclusion compounds
IPC: A61K31/00
Filed: 1955-04-25
Abstract: The invention comprises a water-soluble inclusion compound obtained by heating aminopyrine (4 - dimethylamino - 1,5 - dimethyl - 2-phenyl-3-pyrazolone), caffeine or quinine hydrochloride with at least the stoichiometric amount of at least one carbamic acid alkyl ester and not more than 30 per cent, calculated on the weight of said ester, of an alkyl derivative of urea, and by heating aminopyrine or caffeine with at least the stoichiometric amount of at least one carbamic acid alkyl ester, and the preparation thereof by the said method.  The addition compounds may be prepared by introducing the aminopyrine, caffeine or quinine hydrochloride into a melt of the carbamic acid ester, with or without the alkyl derivative of urea, and heating the mixture to 60-70 DEG  C.  The resulting melt may be solidified, dissolved and spray dried to form a powder.  At least two of the compounds aminopyrine, caffeine and quinine hydrochloride may be introduced into the melt.  The molar ratio of the aminopyrine, caffeine or quinine hydrochloride and the said complex-forming compounds may be adjusted to about 1 : 2.  The above process may also be carried out by mixing an aqueous concentrated solution of the aminopyrine, caffeine or quinine hydrochloride with an aqueous concentrated solution of the carbamic acid ester, with or without the alkyl derivative of urea, and either substantially removing all the water under reduced pressure and heating the resulting mixture to 60 DEG  to 70 DEG  C., or substantially removing all the water at a temperature of about 60 DEG  to 70 DEG  C.  Suitable alkyl methanes are methyl, ethyl and trichloroethyl methanes, and suitable alkyl derivatives of urea are monomethyl urea and sym. dimethyl urea.  In the examples: (1) an inclusion compound is formed from ethyl methane and aminopyrine in a mol. ratio of 2 : 1 and has a melting point of 53 DEG  C., and a solubility of 1 gm. in 1.5 cc. of water at 20 DEG C. and of 1 gm. in 1 cc. of water at 55 DEG  C.; similar results are obtained if up to 30 per cent, e.g. from 5 to 30 per cent, by weight of the ethyl methane is replaced by an alkyl urea, e.g. a methyl urea; (2) an inclusion compound is prepared containing 230 parts by weight of aminopyrine, 40 parts by weight of caffeine and 178 parts by weight of methyl methane and has a melting point of 60 DEG  C. and a solubility of 1 gm. in 1.5 cc. of water at 20 DEG  C.; (3) an inclusion compound is prepared containing 60 parts by weight of quinine hydrochloride, 37 parts by weight of methyl methane and 3 parts by weight of ethyl urea (or N,N1-dimethyl urea) and has a melting point of 45 DEG  C. and a solubility of 1 gm. in 2 gm. of water at about 35-40 DEG  C.; and (4) an inclusion compound is prepared containing 49 parts by weight of ethyl methane, 3 parts by weight of N,N1-dimethyl urea, 10 parts by weight of caffeine and 38 parts by weight of aminopyrine and has a melting point of 55-56 DEG C. and a solubility of 1 part in 2 parts of water at about 35-40 DEG C.ALSO:Solutions having an antipyretic effect are prepared by dissolving in water, oils or fats the inclusion compound obtained by heating aminopyrine (4 - dimethylamino - 1,5 - dimethyl - 2-phenyl - 3 - pyrazolone) with at least the stoichiometric amount of at least one carbamic acid alkyl ester with or without not more than 30 per cent, calculated on the weight of said ester, of an alkyl derivative of urea.  The solutions in oils and fats may be incorporated into suppositories.