Patent GB-806880-A (GB)
Title: New mercurial diuretics and preparation thereof
IPC: C07F3/14
Filed: 1956-06-05
Abstract: The invention comprises 8-R-3-R1Hg-4-R11O-1,6,8 - triazabicyclo[4,3,0]nonane - 7,9 - diones of formula <FORM:0806880/IV (b)/1> wherein R is hydrogen, an alkali metal or the residue of an alkylating agent having a molecular weight less than about 300, R1 is an anion, R11 is hydrogen or an alkyl, hydroxy-alkyl, alkoxy-alkyl or a hydroxy-alkoxy-alkyl group (the alkyl and alkoxy groups having 1-6 carbon atoms), and Y and Y1 are hydrogen or C1-C4 alkyl groups. Specified R groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, octyl, decyl, dodecyl, pentadecyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, benzyl, 2-phenylethyl, 5-phenylpentyl, carboxymethyl, carbethoxymethyl, 2-hydroxyethyl, 2,3-dihydroxypropyl, 2 - hydroxy - 3 - carboxypropyl, tris - (hydroxymethyl) methyl and other alkyl, cycloalkyl, cycloalkyl alkyl and monocarbocyclic aryl alkyl groups. The monocarbocyclic aryl-alkyl groups may contain nitro, halogen, alkyl, alkoxy, trifluoromethyl and other substituent groups inert under the reaction conditions for preparing the compounds of the invention. R1 can be hydroxyl, halide, nitrate, sulphate, thiosulphate, phosphate, acetoxy, propionoxy, butyroxy, methylmercapto, carboxymethylmercapto, carbethoxymethylmercapto, 2 - hydroxyethylmercapto, aminoethylmercapto, propylmercapto, isopropylmercapto, 2-amino-3-carboxypropylmercapto, hydroxyacetoxy and other anions derived from non-toxic inorganic acids, and alkanoyloxy and alkylmercapto groups containing 1-6 carbon atoms, straight or branched chain and substituted, if desired, by hydroxy, carboxy, carboalkoxy and amino groups. R1 may also be derived from nitrogen compounds such as succinimide, phthalimide and theophylline. Specified R11 groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, isohexyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethoxyethyl, 2-propoxyethyl and 2-(2-hydroxyethoxy)-ethyl. They may be prepared by reacting an 8-R-1,6,8-triazabicyclo - [4,3,0] - 3 - nonene - 7,9 - dione of formula <FORM:0806880/IV (b)/2> where R is hydrogen or the residue of an alkylating agent and Y-Y1 are hydrogen or C1-C4 alkyl with a mercuric salt in the presence of water, an alkanol, hydroxyalkanol, alkoxyalkanol or hydroxy alkoxyalkanol (the alkyl and alkoxy groups containing 1 to 6 carbon atoms), the said mercuric salts being at least partially soluble in the reaction medium.  Compounds in which R1 is hydroxyl may be derived by hydrolysis of compounds in which R1 is an anion, e.g. acetoxy.  The anions R1 may be interchanged by double decomposition.  The compounds of the invention are diuretics and may be administered intramuscularly, subcutaneously or orally, as themselves, or if acidic, as their sodium, potassium, ammonium, diethylammonium or diethanolammonium salts.  d  - R - 1,6,8 - triazabicyclo - [4,3,0] - 3 - nonene - 7,9 - diones may be prepared by reacting a conjugated alkadiene with azodicarboxamide to give a 1,2-dicarbamyl-1,2,3,6-tetrahydropyridazin <FORM:0806880/IV (b)/3> This compound on pyrolysis gives <FORM:0806880/IV (b)/4> which on alkylation with RX (X being the anion of a strong acid such as chloride, bromide, iodide or sulphate) in the presence of caustic soda gives <FORM:0806880/IV (b)/5> Specified alkadienes are 1,3-butadiene, 1,3-pentadiene, 2,4-hexadiene, 3,5-octadiene, 2,7-dimethyl-3,5-octadiene and 5,7-dodecadiene.  Heterocyclic diketones specified include 2,5-dimethyl-, 2,5-dipropyl-, 8-methyl-, 2,5,8-trimethyl-, 8-cyclopentyl-, 8-cyclohexylmethyl-, 8 - benzyl -, 8 - (2 - phenylethyl) -, 8 - (p - chlorobenzyl) -, 8 - carboxymethyl -, 8 - (m - methoxybenzyl) -, 8 - (2,3 - dihydroxypropyl) -, 8 - (1,2 - dicarboxyethyl) -, 8 - (2 - carbomethoxy - methyl) -, and the unsubstituted 1,6,8 - triazabicyclo - [4,3,0] - 3 - nonene - 7,9 - dione.  Preparation of 1,2-dicarbamyl-1,2,3,6-tetrahydropyridazine.-Azodicarboxamide, dimethylformamide and butadiene are heated at 100 DEG  C. for 4 hours in an autoclave.  After cooling, the mixture is rinsed from the vessel with benzene, the solid filtered off, washed with n-pentane and air-dried.  Preparation of 1,6,8-triazabicyclo-[4,3,0]-3-nonene-7,9-dione.-1,2 - dicarbamyl - 1,2,3,6 - tetrahydropyridazine is heated at 275-285 DEG  C.  The product is dissolved in sodium hydroxide, treated with activated charcoal and filtered.  The filtrate is acidified with HCl, the solid filtered off and recrystallized from water.  Other intermediates the preparation of which is described in the examples include 2,5-dimethyl - 1,6,8 - triazobicyclo - [4,3,0] - 3 - nonene-7,9-dione (Example 1); 8-carbethoxymethyl - 1,6,8 - triazabicyclo - [4,3,0] - 3 - nonene - 7,9 - dione (Example 6); 8 - carboxymethyl - 1,6,8 - triazabicyclo - [4,3,0] - 3 - nonene - 7,9 - dione (Example 7); 8 - methyl - 1,6,8 - triazabicyclo - [4,3,0] - 3 - nonene - 7,9 - dione (Example 9); 8-(2-hydroxyethyl)-1,6,8-triazabicyclo - [4,3,0] - 3 - nonene - 7,9 - dione (Example 10); 8 - dodecyl - 1,6,8 - triazabicyclo - [4,3,0] - 3 - nonene - 7,9 - dione (Example 11); 8 - (p - nitrobenzyl) - 1,6,8 - triazabicyclo - [4,3,0] - 3 - nonene - 7,9 - dione, 8 - cyclohexyl - 1,6,8 - triazabicyclo - [4,3,0] - 3 - nonene - 7,9 - dione, and 8 - (2,3,4 - trihydroxybutyl) - 1,6,8 - triazabicyclo - [4,3,0] - 3 - nonene-7,9-dione (Example 12). Preparation of mercurial derivatives.-In Example 1, 1,6,8-triazabicyclo-[4,3,0]-3-nonene-7,9-dione is reacted in boiling methanol to yield 3 - acetoxymercuri - 4 - methoxy - 1,6,8 - triazabicyclo - [4,3,0] - nonane - 7,9 - dione.  The conversion of this compound into other 3-R1-mercuri compounds and the preparation of numerous other compounds are described.