Patent GB-1461602-A (GB)
Title: Primary amino acylanilides methods of making the same and use as antiarrhythmic drugs
IPC: C07C231/12
Filed: 1974-01-07
Abstract: 1461602 Primary amino acylanilides ASTRA PHARMACEUTICAL PRODUCTS Inc 7 Jan 1974 [8 Jan 1973 (2)] 00570/74 Heading C2C Novel compounds I (R 1  is H, CH 3 , C 2 H 5 , or C 3 H 7 ; R 2  is CH 3 , C 2 H 5 , Cl, OCH 3  or OC 2 H 5 ; R 3  is H or CH 3 ; R 4  is H, CH 3  or 1-4C alkoxy; R 6  is CH 3 , C 2 H 5 , Cl, OCH 3  or OC 2 H 5 ; R 7  is H, CH 3  or C 2 H 5 ; R 8  is H; R 9  is H, CH 3  or C 2 H 5 ; R 10  is H and n is either 0 or 1 with the provisos that (a) when n is 0, R 8  may also be CH 3 ; (b) when n is 1, R 7  is H and R 9  is H or CH 3 , then R 10  may also be CH 3 ; (c) when R 1  is H, R 2  is CH 3 , R 3  is H, R 6  is CH 3 , R 7  and R 8  are H and n is 0, then R 4  is only 2-3C alkoxy; (d) when R 1  is H, R 2  is CH 3 , R 3 , R 4 , R 7  and R 8  are H and n is 0, then R 6  is OCH 3 , OC 2 H 5  or C 2 H 5  only; (e) when R 1  is H, R 2  is CH 3 , R 3  and R 4  are H, R 7  is CH 3 , R 8  is H and n is 0, then R 6  is OCH 3 , OC 2 H 5 , C 2 H 5  or Cl only; (f) when R 1  is H, R 2  is CH 3 , R 3  and R 4  are H, R 6  and R 7  are CH 3 , R 8  is H and n is 0, then the compound is an optically active isomer only) and salts thereof are prepared by reacting ammonia with a compound II (X is Cl, Br, iodo or p-tosyloxy) ; by reaction of a compound II (X is Cl, Br or iodo) with a phthalimide salt to form an N-substituted phthalimide, reacting this with hydrazine and heating the resulting intermediate; by reacting ammonia with a compound III to give a compound I where n is 1 and R 8  and R 10  are H; by reduction of a compound IV to give a compound I where n is 1 and R 9  and R 10  are H; by reduction of a compound V by reaction of a compound VI with a compound (X is OH, Cl or Br and P is an amino-protecting group), followed by removal of the group P; by reaction of a compound VII with ammonia and a compound R 7 COR 8  to give a compound I where n is 0 and R 1  is H; or by conventional salt formation or optical isomerization. N - Methyl - N - (2,6 - dimethylphenyl) - 2- bromopropionamide (A) is prepared by reaction of 2-bromopropionyl bromide with N-methyl- 2,6-dimethyl-aniline. 2-Bromo-4<SP>1</SP>-butoxy-2<SP>1</SP>,6<SP>1</SP>- dimethylpropionanilide (B) is prepared by reaction of 2,6-dimethyl-4-hydroxy-azobenzene with sodium in ethanol and then 1-bromo-butane to give 4 - butoxy - 2,6 - dimethylazobenzene, reaction of this with Na 2 S 2 O 4  to give 4-butoxy- 2,6-dimethylaniline, and reaction of this with 2-bromo-propionyl bromide. 3-Bromo-2<SP>1</SP>-ethyl- 6<SP>1</SP>-methylpropionanilide (C) is prepared by reaction of 2-ethyl-6-methyl-aniline with 3- bromopropionyl chloride. 2 - Bromo - 2<SP>1</SP>,6<SP>1</SP>- dimethyl - 4<SP>1</SP> - propoxypropionanilide (D) is prepared similarly to (B) above. 2-Bromo-2<SP>1</SP>- ethyl - 6<SP>1</SP>- methyl - propionanilide (E) is prepared similarly to (C) above. 3-Bromo-2<SP>1</SP>,6<SP>1</SP>- dimethyl - 4<SP>1 </SP>- propoxy - propionanilide (F) is prepared similarly to (C) above. 2-Chloro- 2<SP>1</SP>,3<SP>1</SP>,6<SP>1</SP> - trimethyl - acetanilide (G) is prepared by reaction of 2,3,6-trimethyl-aniline with chloroacetyl chloride. 2-Bromo-2<SP>1</SP>,6<SP>1</SP>-diethylpropionanilide (H) is prepared similarly to (C) above. N - Ethyl - N - (2,6 - dimethylphenyl)- 2 - bromo - propionamide (J) is prepared similarly to (A) above. N-(2,6-dimethylphenyl)- 2-methyl-acrylamide (K) is prepared by reaction of 2,6-xylidine with ethyl magnesium bromide, then with methyl methacrylate. Pharmaceutical compositions, useful as antiarrhythmic agents, comprise a compound I together with a suitable carrier or diluent and are administered orally or parenterally.