Claims for Patent: 4,218,477

Summary for Patent: 4,218,477

Title:	Primary aminoacylanilides, methods of making the same and use as antiarrhythmic drugs
Abstract:	Primary amino acylanilides of the formula ##STR1## wherein R.sub.1 is selected from the group consisting of hydrogen, methyl, ethyl and propyl, R.sub.2 is selected from the group consisting of methyl, ethyl, chlorine, methoxy and ethoxy, R.sub.3 is selected from the group consisting of hydrogen and methyl, R.sub.4 is selected from the group consisting of hydrogen, methyl, and a C.sub.1 -C.sub.4 alkoxy group, R.sub.6 is selected from the group consisting of methyl, ethyl, chlorine, methoxy and ethoxy, R.sub.7 is hydrogen, methyl or ethyl, R.sub.8 is hydrogen, R.sub.9 is hydrogen, methyl or ethyl, R.sub.10 is hydrogen, and n is 0 or 1, with the provisions that (a) when n is 0, R.sub.8 can also be methyl; (b) when n is 1, and R.sub.7 is hydrogen, and R.sub.9 is hydrogen or methyl, then R.sub.10 can also be methyl; (c) when R.sub.1 is hydrogen, R.sub.2 is methyl, R.sub.3 is hydrogen, R.sub.6 is methyl, R.sub.7 is hydrogen, R.sub.8 is hydrogen, and n is 0, then R.sub.4 can be ethoxy or propoxy only; (d) when R.sub.1 is hydrogen, R.sub.2 is methyl, R.sub.3, R.sub.4, R.sub.7 and R.sub.8 are hydrogen, and n is 0, then R.sub.6 is methoxy, ethoxy, or ethyl only; and the therapeutically acceptable salts thereof. Compounds of this type have been found to be effective longlasting cardiac antiarrhythmic agents, especially when administered by the oral route.
Inventor(s):	Boyes; Robert N. (Auburn, MA), Duce; Benjamin R. (Westborough, MA), Smith; Emil R. (Shrewsbury, MA), Byrnes; Eugene W. (Holden, MA)
Assignee:	Astra Pharmaceutical Products, Inc. (Worcester, MA)
Application Number:	05/651,420
Patent Claims:	1. A process for the suppression of cardiac arrhythmias in mammals comprising administering to the mammal an amount effective for the suppression of cardiac arrhythmias of a compound selected from the group consisting of ##STR11## wherein R.sub.1 is selected from the group consisting of hydrogen, methyl, ethyl, and propyl, R.sub.2 is selected from the group consisting of methyl, ethyl, chlorine, methoxy, and ethoxy, R.sub.3 is selected from the group consisting of hydrogen and methyl, R.sub.4 is selected from the group consisting of hydrogen, methyl, and a C.sub.1 -C.sub.4 alkoxy group, R.sub.6 is selected from the group consisting of methyl, ethyl, chlorine, methoxy, and ethoxy, R.sub.7 is selected from the group consisting of hydrogen, methyl and ethyl, R.sub.8 is hydrogen, R.sub.9 is selected from the group consisting of hydrogen, methyl and ethyl, R.sub.10 is hydrogen, and n is 0 or 1, provided that when R.sub.1 is hydrogen, R.sub.2 is methyl, R.sub.3 is hydrogen, R.sub.6 is methyl, R.sub.7 and R.sub.8 are hydrogen, and n is 0, then R.sub.4 can be methyl, ethoxy, propoxy, or butoxy only; the optically active isomers of such compounds as have an asymmetric carbon atom, and the therapeutically acceptable salts thereof. 2. A process for the suppression of cardiac arrhythmias in mammals comprising administering to the mammal an amount effective for the suppression of cardiac arrhythmias of a compound selected from the group consisting of: ##STR12## wherein R.sub.6 is selected from the group consisting of methyl and ethyl, R.sub.4 is selected from the group consisting of hydrogen, methyl, propoxy and butoxy, R.sub.1 and R.sub.7 are both selected from the group consisting of hydrogen, methyl and ethyl, n is an integer no larger than 1, and R.sub.9 is selected from the group consisting of hydrogen and methyl, provided that when R.sub.6 is methyl, and R.sub.4, R.sub.1 and R.sub.7 are all also hydrogen, then n is not 0, and therapeutically acceptable salts thereof. 3. A process for the suppression of cardiac arrhythmias in mammals comprising administering to the mammal an amount effective for the suppression of cardiac arrhythmias of a compound selected from the group consisting of 2-amino-2',6'-propionoxylidide; (+)-2-amino-2',6'-propionoxylidide; (-)-2-amino-2',6'-propionoxylidide; 2-amino-N-ethyl-2',6'-propionoxylidide; 2-amino-2',6'-butyroxylidide; 2-amino-2'-ethyl-6'-methylpropionanilide; 2-amino-N-methyl-2',6'-acetoxylidide; 2-amino-N-methyl-2',6'-propionoxylidide; 2-amino-N-ethyl-2',6'-acetoxylidide; 3-amino-2',6'-propionoxylidide; 3-amino-2',6'-butyroxylidide; 3-amino-2'-ethyl-6'-methylpropionanilide; 2-amino-2',6'-diethylpropionanilide; 3-amino-2-methyl-2',6'-propionoxylidide; 3-amino-2',4',6'-propionomesidide; 3-amino-2',6'-dimethyl-4'-propoxypropionanilide; 2-amino-4'-butoxy-2',6'-dimethylpropionanilide; 2-amino-2',6'-dimethyl-4'-propoxypropionanilide; 2-amino-2'-methyl-6'-ethyl-acetonanilide; 2-amino-2',6'-diethyl-acetoanilide; 3-amino-2',3',6'-trimethyl-propionanilide; 2-amino-2-methyl-2',6'-propionoxylidide; 3-amino-2'-methyl-6'-ethyl-butyranilide; 3-amino-2',4',6'-butyromesidide; 3-amino-2',3',6'-trimethyl-butyroanilide; 3-amino-2',6'-valeroxylidide; 3-amino-3-methyl-2',6'-butyroxylidide; 3-amino-2-methyl-2',6'-butyroxylidide; 3-amino-2',6'-dimethoxybutyranilide; 2-amino-2',6'-diethoxyacetanilide; 2-amino-N-propyl-2',6'-acetoxylidide; 3-amino-2'-chloro-6'-methylbutyranilide; 3-amino-4'-methoxy-2',6'-dimethylbutranilide; 3-amino-4'-ethoxy-2',6'-dimethylbutyranilide, 2-amino-2',6'-dichloropropionanilide, and therapeutically acceptable salts thereof. 4. The process according to claim 3 which comprises administering 2-amino-2',6'-propionoxylidide or a therapeutically acceptable salt thereof. 5. The process according to claim 3 which comprises administering (+)-2-amino-2',6'-propionoxylidide or a therapeutically acceptable salt thereof. 6. The process according to claim 3 which comprises administering (-)-2-amino-2',6'-propionoxylidide or a therapeutically acceptable salt thereof. 7. The process according to claim 3 which comprises administering 2-amino-N-ethyl-2',6'-propionoxylidide of a therapeutically acceptable salt thereof. 8. The process according to claim 3 which comprises administering 2-amino-2',6'-butyroxylidide or a therapeutically acceptable salt thereof. 9. The process according to claim 3 which comprises administering 2-amino-2'-ethyl-6'-methylpropionanilide or a therapeutically acceptable salt thereof. 10. The process according to claim 3 which comprises administering 2-amino-N-methyl-2',6'-acetoxylidide or a therapeutically acceptable salt thereof. 11. The process according to claim 3 which comprises administering 2-amino-N-methyl-2',6'-propionoxylidide or a therapeutically acceptable salt thereof. 12. The process according to claim 3 which comprises administering 2-amino-N-ethyl-2',6'-acetoxylidide or a therapeutically acceptable salt thereof. 13. The process according to claim 3 which comprises administering 3-amino-2',6'-propionoxylidide or a therapeutically acceptable salt thereof. 14. The process according to claim 3 which comprises administering 3-amino-2',6'-butyroxylidide or a therapeutically acceptable salt thereof. 15. The process according to claim 3 which comprises administering 3-amino-2'-ethyl-6'-methylpropionanilide or a therapeutically acceptable salt thereof. 16. The process according to claim 3 which comprises administering 2-amino-2',6'-diethylpropionanilide or a therapeutically acceptable salt thereof. 17. The process according to claim 3 which comprises administering 3-amino-2-methyl-2',6'-propionoxylidide or a therapeutically acceptable salt thereof. 18. The process according to claim 3 which comprises administering 3-amino-2',4',6'-propionomesidide or a therapeutically acceptable salt thereof. 19. The process according to claim 3 which comprises administering 3-amino-2',6'-dimethyl-4'-propoxypropionanilide or a therapeutically acceptable salt thereof. 20. The process according to claim 3 which comprises administering 2-amino-4'-butoxy-2',6'-dimethylpropionanilide or a therapeutically acceptable salt thereof. 21. The process according to claim 3 which comprises administering 2-amino-2',6'-dimethyl-4'-propoxypropionanilide or a therapeutically acceptable salt thereof. 22. The process according to claim 3 which comprises administering 2-amino-2'-methyl-6'-ethyl-acetonanilide or a therapeutically acceptable salt thereof. 23. The process according to claim 3 which comprises administering 2-amino-2',6'-diethyl-acetonanilide or a therapeutically acceptable salt thereof. 24. The process according to claim 3 which comprises administering 3-amino-2',3',6'-trimethyl-propionanilide or a therapeutically acceptable salt thereof. 25. The process according to claim 3 which comprises administering 2-amino-2-methyl-2',6'-propionoxylidide or a therapeutically acceptable salt thereof. 26. The process according to claim 3 which comprises administering 3-amino-2'-methyl-6'-ethyl-butyranilide or a therapeutically acceptable salt thereof. 27. The process according to claim 3 which comprises administering 3-amino-2',4',6'-butyromesidide or a therapeutically acceptable salt thereof. 28. The process according to claim 3 which comprises administering 3-amino-2',3',6'-trimethyl butyroanilide or a therapeutically acceptable salt thereof. 29. The process according to claim 3 which comprises administering 3-amino-2',6'-valeroxylidide or a therapeutically acceptable salt thereof. 30. The process according to claim 3 which comprises administering 3-amino-3-methyl-2',6'-butyroxylidide or a therapeutically acceptable salt thereof. 31. The process according to claim 3 which comprises administering 3-amino-2-methyl-2',6'-butyroxylidide or a therapeutically acceptable salt thereof. 32. The process according to claim 3 which comprises administering 3-amino-2',6'-dimethoxybutyranilide or a therapeutically acceptable salt thereof. 33. The process according to claim 3 which comprises administering 2-amino-2',6'-diethoxyacetanilide or a therapeutically acceptable salt thereof. 34. The process according to claim 3 which comprises administering 2-amino-N-propyl-2',6'-acetoxylidide or a therapeutically acceptable salt thereof. 35. The process according to claim 3 which comprises administering 3-amino-2'-chloro-6-methylbutyranilide or a therapeutically acceptable salt thereof. 36. The process according to claim 3 which comprises administering 3-amino-4'-methoxy-2',6'-dimethylbutyranilide or a therapeutically acceptable salt thereof. 37. The process according to claim 3 which comprises administering 3-amino-4'-ethoxy-2',6'-dimethylbutyranilide or a therapeutically acceptable salt thereof. 38. The process according to claim 3 which comprises administering 2-amino-2-,6'-dichloropropionanilide or a therapeutically acceptable salt thereof. 39. A pharmaceutical preparation for the suppression of cardiac arrhythmias in mammals comprising as an active ingredient an amount effective for the suppression of cardiac arrhythmias of a compound selected from the group consisting of 2-amino-2',6'-propionoxylidide; (+)-2-amino-2',6'-propionoxylidide; (-)-2-amino-2',6'-propionoxylidide; 2-amino-2'-ethyl-6'-methylpropionanilide; 2-amino-N-methyl-2',6'-propionoxylidide; 3-amino-2',6'-butyroxylidide; 2-amino-2',6'-diethylpropionanilide; 3-amino-2',4',6'-propionomesidide; 2-amino-4'-butoxy-2',6'-dimethylpropionanilide; 3-amino-2'-methyl-6'-ethyl-butyranilide; 3-amino-2',4',6'-butyromesidide; 3-amino-2',6'-valeroxylidide; and therapeutically acceptable salts thereof, together with a pharmaceutically acceptable carrier. 40. The pharmaceutical preparation according to claim 39 which comprises the compound 2-amino-2',6'-propionoxylidide or a therapeutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 41. The pharmaceutical preparation according to claim 39 which comprises the compound (+)-2-amino-2',6'-propionoxylidide or a therapeutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 42. The pharmaceutical preparation according to claim 39 which comprises the compound (-)-2-amino-2',6'-propionoxylidide or a therapeutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 43. The pharmaceutical preparation according to claim 39 which comprises the compound 2-amino-2'-ethyl-6'-methylpropionanilide or a therapeutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 44. The pharmaceutical preparation according to claim 39 which comprises the compound 2-amino-N-methyl-2',6'-propionoxylidide or a therapeutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 45. The pharmaceutical preparation according to claim 39 which comprises the compound 3-amino-2',6'-butyroxylidide or a therapeutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 46. The pharmaceutical preparation according to claim 39 which comprises the compound 2-amino-2',6'-diethylpropionanilide or a therapeutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 47. The pharmaceutical preparation according to claim 39 which comprises the compound 3-amino-2',4',6'-propionomesidide or a therapeutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 48. The pharmaceutical preparation according to claim 39 which comprises the compound 2-amino-4'-butoxy-2',6'-dimethylpropionanilide or a therapeutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 49. The pharmaceutical preparation according to claim 39 which comprises the compound 3-amino-2'-methyl-6'-ethyl-butyranilide or a therapeutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 50. The pharmaceutical preparation according to claim 39 which comprises the compound 3-amino-2',4',6'-butyromesidide or a therapeutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 51. The pharmaceutical preparation according to claim 39 which comprises the compound 3-amino-2',6'-valeroxylidide or a therapeutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.