Patent GB-1454777-A (GB)
Title: Dioxamates and the preparation thereof
IPC: A61K31/22
Filed: 1973-11-28
Abstract: 1454777 Dioxamate derivatives UPJOHN CO 28 Nov 1973 [20 Dec 1972 26 July 1973] 55208/73 Heading C2C Novel compounds I (in which N(L)COOR group is at 3- or 4- position; R is H, 1-6 C alkyl, phenyl, a cation, or -(CH 2 ) n NR<SP>3</SP>R<SP>4</SP>; n is 2 or 3; R<SP>3</SP> and R<SP>4</SP> are H or 1-3 C alkyl or NR<SP>3</SP>R<SP>4</SP> is an alicyclic ring of 4-6 C; W, X, Y and Z are H, 1-6 C alkyl, 1-6 C alkoxy, phenyl, OH, NO 2 , halo, CF 3 , CN or -COQ; Q is -OD, -NR<SP>1</SP>R<SP>2</SP>, or D is H, a cation, 1-6 C alkyl, phenyl or -(CH 2 ) m NR<SP>1</SP>R<SP>2</SP>; m is 2 or 3; R<SP>1</SP> and R<SP>2</SP> are as defined above for R<SP>3</SP> and R<SP>4</SP>; with the provisos that any -CN group is meta to both groups, that D is the same as R if R is H, a cation or -(CH 2 ) n R<SP>3</SP>R<SP>4</SP> or is H, alkyl, phenyl or -(CH 2 ) m NR<SP>1</SP>R<SP>2</SP> when R is alkyl or phenyl; and L is H, 1-6 C alkyl, benzyl or benzyl substituted by 1-4 C alkyl or halo; with the overall provisos that (1) when L is H then W, X, Y and Z are not all H and (2) when L and two of W, X, Y and Z are H, R is 1-6 C alkyl or phenyl and the third member of W-Z is 1-4 C alkyl, 1-4 C alkoxy or halo; the fourth is not H, 1-4 C alkyl, 1-4 C alkoxy or halo) and pharmaceutically acceptable salts thereof are prepared by reacting a compound II with a compound Hal-CO-CO-alkyl or alkyl O-CO-CO-O-alkyl followed where necessary by conventional modifications to give other products of Formula I. Intermediates isolated are 3,5-diaminobenzonitrile, prepared by reduction of 3,5-dinitrobenzonitrile; 4 - chloro - 3,5 - diamino - benzonitrile, prepared similarly; 3,5-diamino - benzamide, prepared by catalytic hydrogenation of 3,5 - dinitrobenzamide; 2 - chloro - 3,5 - diamino - benzonitrile, prepared by reaction of 2 - chloro - 3,5 - dinitrobenzoic acid with PCl 5  to give 2 - chloro - 3,5 - dinitro - benzoyl chloride, reaction of this with NH 4 OH to give 2-chloro- 3,5-dinitro-benzamide, reaction of this with POCl 3  to give 2-chloro-3,5-dinitrobenzonitrile, and reduction of this: 4 - chloro - 3,5 - diamino - α,α,α - trifluoro - toluene, prepared by reduction of 3,5 - dinitro - 4 - chloro - benzofluoride; 1,3 - diamino - 4,6 - dichlorobenzene, prepared by reduction of the corresponding 1,3- dinitro - derivative; 3,5 - diamino - p - toluic acid, prepared by hydrogenation of the corresponding 3,5-dinitro derivative; methyl 3,5- diamino - 4 - chlorobenzoate, prepared by reaction of 4-chloro-3,5-dinitro-benzoic acid with MeOH to give the methyl ester and reduction of this ester; methyl 2,6-diamino-benzoate, prepared by reaction of 2,6-dinitrobenzoic acid with 1 - methyl - 3 - p - tolyl - triazene to give the methyl ester, followed by catalytic hydrogenation; 3,5 - diamino - anisole, prepared by hydrogenation of the corresponding 3,5-dinitro derivative; 3,5-diamino-4-chloro-toluene, prepared by reduction of the corresponding dinitro compound; and 4-chloro-3,5-diaminoacetophenone, prepared by reaction of 4-chloro- 3,5-dinitro-benzoic acid with PCl 5  to give the acid chloride, reaction of this with Mg and diethyl malonate, followed by reaction with concentrated H 2 SO 4  to give 4-chloro-3,5-dinitro-acetophenone, followed by reduction. Pharmaceutical compositions, useful in prophylaxis of animals for allergy and all anaphylactic reactions, comprise a compound I as a suitable salt.