Patent GB-915264-A (GB)
Title: Anti-inflammatory compositions comprising 3,4-dihydroquinazolone-4 and 3,4-dihydropyrimidine-4 derivatives
IPC: A61K31/00
Filed: 1959-03-23
Abstract: Derivatives of 3,4-dihydro-pyrimidone-4 and 3,4-dihydro-quinazolone-4 of the general formula:-  <FORM:0915264/IV (b)/1> wherein (1) R1 is a hydrogen atom; R2 is an alkyl, aryl or aralkyl radical; R3 is a hydrogen atom and R4 is a hydrogen atom or an alkyl radical; or (2) R1 and R2 together form a benzo radical optionally hydrogenated or substituted by a nitro, alkyl, amino, acetamido or alkoxy group or by a halogen atom; R3 is a hydrogen atom or a C1-C6 alkyl radical, and R4 is a hydrogen atom or an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, quinazolyl or amino radical, and compounds having the general formula:-  <FORM:0915264/IV (b)/2> wherein R5 is an alkyl or aryl radical are prepared by the following methods: Method A (R1 and R2 form a benzo or substituted benzo radical, R3 = R4 = hydrogen) the parent anthranilic acid is reacted with formamide at 130 DEG -140 DEG C. and the product is obtained by recrystallisation.  Method B (R1 and R2 form a benzo or substituted benzo radical, R3 is hydrogen and R4 is an alkyl radical) the parent anthranilic acid is reacted with an N-alkylformamide at 130 DEG -140 DEG C. followed by recrystallisation.  Method C (R1, R2 and R3 are as in method B above, R4 is an alkyl, alkenyl or alkynyl radical) the N(3)-sodium or potassium derivative is converted to the corresponding 3-R4-derivative by reaction with a compound Y-R4 wherein Y is a halogen atom or 1/2 SO-4- group in a solvent until an aliquot of the reaction mixture when agitated with water has a pH <7.0. Method D (for compounds of general formula II) wherein the corresponding 4-chloro compound is reacted with a solution or suspension of an alkali metal alcoholate or phenate in an inert solvent.  By method A are prepared 3,4-dihydroquinazolone-4 and its 6-methyl, 8-methyl, 6-nitro and 6-methoxy derivatives.  By method B is prepared 3-methyl-3,4-dihydro-quinazolone-4.  By Method C are prepared the 3-n-propyl-; 3-ethyl-; 3-alkyl-; 3-propargyl-; 3-quinazolyl(4)-; 3-methyl-6-nitro- and 3-methyl-6-acetamido-derivatives of 3,4-dihydro-quinazolone-4.  By method D are prepared 4-methoxy-; 4-ethoxy- and 4-phenoxy-quinazoline.  Also described are the preparations of 6-methyl-; 6-n-propyl-; 6-benzyl- and 6-phenyl derivatives of 3,4-dihydro-pyrimidone-4 by the desulphurisation of the corresponding 6-substituted-2-mercapto - 4 - hydroxy - pyrimidines by means of Raney nickel.  The sodium derivative of the above 3,4-dihydro-6-phenyl-pyrimidone-4 is converted to 3-methyl-3,4-dihydro-6-phenyl-pyrimidone-4 by heating with excess methyl iodide in a closed vessel.  The following preparations are also described: (i) 3-cyclohexyl-3,4-dihydro-quinazolone-4 by heating an equimolecular mixture of 3,1(4H)-benzoxazone-4 and cyclohexylamine to 130 DEG C. for 5 hours; (ii) 3-methyl-3,4-dihydro-6-amino-quinazolone-4 by the reduction of 3-methyl-3,4-dihydro-6-nitro-quinazolone-4 with hydrogen in the presence of palladium on carbon; (iii) 3,4-dihydro-6-chloro-quinazolone-4 by diazotizing 3,4-dihydro-6-amino-quinazolone-4 and treating the solution of the diazonium salt with a solution of cuprous chloride in hydrochloric acid.  The preparation by known methods of the following compounds are also mentioned: 3-phenyl-3,4-dihydro-quinazolone-4; 3-amino-3,4-dihydroquinazolone-4; 2-methyl-3,4-dihydro-quinazolone-4; 2-methyl-3,4-dihydro-5,6,7,8-tetrahydro-quinazolone-4; 3,4-dihydro-6-amino-quinazolone-4 and 3,4-dihydro-6-acetamido-quinazolone-4.ALSO:Anti-inflammatory pharmaceutical compositions comprise a carrier and a compound (or an acid addition, quaternary ammonium or metal salt thereof) of general formula <FORM:0915264/VI/1> wherein (1) R1 is a hydrogen atom; R2 is an alkyl, aryl or aralkyl radical; R3 is a hydrogen atom and R4 is a hydrogen atom or an alkyl radical; or (2) R1 and R2 together form a benzo radical optionally hydrogenated or substituted by an alkyl, nitro, amino, acetamido, or alkoxy group or by a halogen atom; R3 is a hydrogen atom or a C1-6 alkyl radical, and R4 is a hydrogen atom or an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, quinazolyl or amino radical; or (3) a compound of the alternative tautomeric form <FORM:0915264/VI/2> wherein R5 is an alkyl or aryl radical. Specified compounds of type 1 are the 6-methyl, 6-n-propyl, 6-benzyl, 6-phenyl and 3-methyl-6-phenyl derivatives of 3,4-dihydro-pyrimidene-4; of type 2: 3,4-dihydro-quinazolene-4 and its 3-methyl; 3-ethyl; 3-n-propyl; 3-allyl; 3-propargyl; 3-cyclohexyl; 3-phenyl; 3-quinazolyl (4); 3-amino; 2-methyl; 2-methyl-5,6,7,8-tetrahydro; 6-methyl; 8-methyl; 6-nitro; 3-methyl-6-nitro; 6-amino; 3-methyl-6-amino; 6-acetamido; 3-methyl-6-acetamido; 6-methoxy and 6-chloro derivatives and of type 3; 4-methoxy, 4-ethoxy and 4-phenoxy quinazoline.  The compositions may be in conventional pharmaceutical forms suitable for oral or parenteral administration, e.g. tablets, elexirs, sterile solutions and dispersions.