PRIMARY AMINO ACYLANILIDES, METHODS OF MAKING THE SAME AND USE AS ANTIARRHYTHMIC DRUGS

• Main Authors: DUCE, BENJAMIN R, SMITH, EMIL R, BYRNES, EUGENE W, BOYES, ROBERT N
• Format: Patent
• Language: English
• Published: 17.01.1978
• Subjects: ACYCLIC OR CARBOCYCLIC COMPOUNDS; ADHESIVES; CHEMISTRY; DYES; HUMAN NECESSITIES; HYGIENE; LAKES; MEDICAL OR VETERINARY SCIENCE; METALLURGY; MISCELLANEOUS APPLICATIONS OF MATERIALS; MISCELLANEOUS COMPOSITIONS; MORDANTS; NATURAL RESINS; ORGANIC CHEMISTRY; ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES; PAINTS; POLISHES; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

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-41-butoxy-21,61- 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-21-ethyl- 61-methylpropionanilide (C) is prepared by reaction of 2-ethyl-6-methyl-aniline with 3- bromopropionyl chloride. 2 - Bromo - 21,61- dimethyl - 41 - propoxypropionanilide (D) is prepared similarly to (B) above. 2-Bromo-21- ethyl - 61- methyl - propionanilide (E) is prepared similarly to (C) above. 3-Bromo-21,61- dimethyl - 41 - propoxy - propionanilide (F) is prepared similarly to (C) above. 2-Chloro- 21,31,61 - trimethyl - acetanilide (G) is prepared by reaction of 2,3,6-trimethyl-aniline with chloroacetyl chloride. 2-Bromo-21,61-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.