Patent GB-1007021-A (GB)
Title: Salts of substituted 1,2-dihydro-s-triazines
Filed: 1963-04-18
Abstract: The invention comprises salts of substituted 1,2-dihydro-s-triazines of the formula <F\1> where R is halogen, C1-5 alkyl, C1-5 alkoxy, benzyloxy, C1-5 alkylthio or trifluoromethyl, R1 is C1-5 alkyl and R2 is hydrogen or methyl; with the following acids:  (a) an acid of the formula <F\2> where X is a 51-methylene-(61-hydroxy-21 -naphthoic acid), 41-methylene-(11-hydroxy-21 -naphthoic acid), 41-(31-hydroxy-21-naphthoic acid), 41-benzylidene-(31-hydroxy-21-naphthoic acid), 41 - ethylidene - (31 - hydroxy - 21 - naphthoic acid), 41 - methylene - (71,81 - dibromo -31 - hydroxy - 21 - naphthoic acid), or 3-carboxy-4-hydroxybenzyl radical;  (b) an acid of the formula <F\3> where Y is a 41-(71-bromo-31-hydroxy -21-naphthoic acid), 41 - methylene - (71 - bromo-31 - hydroxy - 21 - naphthoic acid), 41 - methylene - (31 - hydroxy - 21 - naphthoic acid), 41 - methylene - (11 - hydroxy - 21 - naphthoic acid), 51 - methylene - (61 - hydroxy - 21 - naphthoic acid), 41 - methylene - (71,81 - dibromo - 31 - hydroxy - 21 - naphthoic acid), or 3-carboxy-4-hydroxybenzyl radical;  (c) an acid of the formula <F\4> where Z is a 41-(11-hydroxy-21-naphthoic acid), 41 - methylene - (11 - hydroxy - 21 - naphthoic acid), 41 - benzylidene - (11 - hydroxy - 21 - naphthoic acid), or 41-methylene-(7181-dibromo-31 -hydroxy-21-naphthoic acid) radical; (d) an acid of the formula <F\5> where B is a 41-methylene-(71,81-dibromo -31 -hydroxy - 21 - naphthoic acid), 41 - (71,81 -dibromo - 31 - hydroxy - 21 - naphthoic acid), 5 - methylene - (61 - hydroxy - 21 - naphthoic acid), or 3 - carboxy - 4 - hydroxybenzyl radical;  (e) an acid of the formula <F\6> where Ar is a 4-(3-hydroxy-2-naphthoic acid) or 5-(2-hydroxybenzoic acid) radical;  (f) an acid of the formula <F\7> and acids of the same formula substituted at any of positions 21,41,51 and 71 with a halogen atom or a nitro group; and  (g) an acid of the formula <F\8> These compounds may be prepared by reacting a 4,6 - diamino - 1,2 - dihydro - 2 - alkyl - 1 - aryl-s-triazine of the above formula with the appropriate acid, or by reacting a soluble salt of the 4,6-diamino-1,2-dihydro-2-alkyl-1-aryl-s-triazine with a soluble salt of the appropriate acid.  The 4,6-diamino-1,2-dihydro-2-alkyl-1-aryl-s-triazines used as starting materials may be prepared by reacting a 1-arylbiguanide of the formula <F\9> with an aliphatic aldehyde or ketone R1R2CO in the presence of a strong acid, or by reacting together the aldehyde or ketone, dicyandiamide and an aniline derivative of the formula <F\10> 7 - Bromo - 4 - (chloromethyl) - 3 - hydroxy-2-naphthoic acid methyl ester is prepared by reacting 7 - bromo - 3 - hydroxy - 2 - naphthoic acid methyl ester with formalin and concentrated hydrochloric acid. 3,11 - Dihydroxy - 4,41 - methylenedi - 2 - naphthoic acid is prepared by reacting 4-(chloromethyl) - 3 - hydroxy - 2 - naphthoic acid methyl ester with 1-hydroxy-2-naphthoic acid and hydrolysing the resulting 3,11-dihydroxy4,41 - methylenedi 2 naphthoic acid 2 - methyl ester.  The following acids are prepared in a similar manner: 3,61-dihydroxy-4,51-methylenedi-2-naphthoic acid from 4-(chloromethyl)-3-hydroxy-2-naphthoic acid methyl ester and 6-hydroxy - 2 - naphthoic acid; 7 - bromo - 4,41-methylenebis - (3 - hydroxy - 2 - naphthoic acid) from 4 - (chloromethyl) - 3 - hydroxy - 2 - naphthoic acid methyl ester and 7-bromo-3-hydroxy-2-naphthoic acid; 7 - bromo - 3,11 - dihydroxy-4,41 - methylenedi - 2 - naphthoic acid from 7 - bromo - 4 - (chloromethyl) - 3 - hydroxy-2-naphthoic acid methyl ester and 1-hydroxy-2 - naphthoic acid; 7 - bromo - 3,61 - dihydroxy-4,51 - methylenedi - 2 - naphthoic acid from 7 - bromo - 4 - (chloromethyl) - 3 - hydroxy-2-naphthoic acid methyl ester and 6-hydroxy-2 - naphthoic acid; 4 - (3 - carboxy - 4 - hydroxybenzyl) - 3 - hydroxy - 2 - naphthoic acid from 4 - (chloromethyl) - 3 - hydroxy - 2 - naphthoic acid and salicylic acid; 7-bromo-4-(3-carboxy-4 - hydroxybenzyl) - 3 - hydroxy - 2 - naphthoic acid from 7 - bromo - 4 - (chloromethyl) - 3 - hydroxy - 2 - naphthoic acid methyl ester and salicylic acid; 7,8 - dibromo - 4 - (3 - carboxy - 4 - hydroxybenzyl) - 3 - hydroxy - 2 - naphthoic acid from 7,8 - dibromo - 4 - (chloromethyl) - 3 - hydroxy - 2 - naphthoic acid methyl ester and salicylic acid; 7,71,8-tribromo - 4,41 - methylenebis - [3 - hydroxy - 2 - naphthoic acid] from 7-bromo-4-(chloromethyl)-3-hydroxy-2-naphthoic acid methyl ester and 7,8 - dibromo - 3 - hydroxy - 2 - naphthoic acid; 7,8 - dibromo - 4,41 - methylenebis - [3-hydroxy-2-naphthoic acid] from 4-(chloromethyl)-7,8 - dibromo - 3 - naphthoic acid] from 4-7,8 - dibromo - 3 - hydroxy - 2 - naphthoic acid methyl ester and 3-hydroxy-2-naphthoic acid; 7,8 - dibromo - 3,61 - dihydroxy - 4,51 - methylenedi - 2 - naphthoic acid from 4 - (chloromethyl)-7,8 - dibromo - 3 - hydroxy - 2 - naphthoic acid methyl ester and 6-hydroxy-2-naphthoic acid; and 7,8 - dibromo - 3,11 - dihydroxy - 4,41-methylenedi-2-naphthoic acid from 4-(chloromethyl) - 7,8 - dibromo - 3 - hydroxy - 2 - naphthoic acid methyl ester and 1-hydroxy-2-naphthoic acid.  6,61 - Dibromo - 2,21 - dihydroxy - (1,11-binaphthalene) - 3,31 - dicarboxylic acid, 4,41-dihydroxy - (1,11 - binaphthalene) - 3,31 - dicarboxylic acid and 5,51,6,61-tetrabromo-2,21-dihydroxy - [1,11 - binaphthalene] - 3,31 - dicarboxylic acid are prepared by heating 7-bromo-3-hydroxy - 2 - naphthoic acid, 1 - hydroxy - 2 - naphthoic acid and 7,8-dibromo-3-hydroxy-2-naphthoic acid respectively in the presence of sodium hydroxide and ferric chloride.  4,41 - Methylenebis - (7 - bromo - 3 - hydroxy-2-naphthoic acid) is prepared by reacting 7-bromo 3 hydroxy - 2 - naphthaoic acid with formaldehyde.  The following acids are prepared in a similarly: 4,41 - ethylidenebis - (3 - hydroxy-2 - naphthoic acid) from 3 - hydroxy - 2 - naphthoic acid and paraldehyde; 4,41-methylenebis - (1-hydroxy-2-naphthoic acid) from 1-hydroxy-2-naphthoic acid and formaldehyde; 4,41-benzylidenebis - (1 - hydroxy - 2 - naphthoic acid) from 1 - hydroxy - 2 - naphthoic acid and benzaldehyde; and 4,41 - methylenebis - [7,8 - dibromo - 3 - hydroxy - 2 - naphthoic acid] from 7,8-dibromo - 3 - hydroxy - 2 - naphthoic acid and formaldehyde.  4,41 - Thiobis - (3 - hydroxy - 2 - naphthoic acid) is prepared by reacting 3-hydroxy-2-naphthoic acid methyl acid with thionyl chloride in the presence of copper powder and hydrolysing the intermediate formed.  Pharmaceutical compositions having repository antimalarial activity comprise a salt of the invention together with a pharmaceutical carrier and/or excipient. The compositions may be administered parenterally in the form of injectable solutions or suspensions.  Reference has been directed by the Comptroller to Specifications 709,906 and 813,560.