Ultra short acting anti-arrhythmic agents
Some aspects provide novel dofetilide derivatives and pharmaceutical compositions containing the same that are useful as pharmaceutical agents in the treatment of supraventricular and ventricular arrhythmias.
1. A compound of Formula I-VI or a stereoisomer thereof:
Formula
#
Formula
I
II
III
IV
V
VI
wherein:
R is selected from H, C 1-6 alkyl, C 3-6 alkenyl, and C 3-6 alkynyl;
R′ is selected from C 1-3 alkyl and —COCH 3 ;
provided that when the compound is of formula I, R′ is also selected from —CH 2 C 6 H 5 ,
provided that when the compound is of formula VI, R′ is selected from C 1-3 alkyl;
Y, at each occurrence, is independently selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , and CH(CH 3 ) 2 ;
Z is selected from H, C 1-6 alkyl, CH 2 OH, CH(CH 3 )OH, C(CH 3 ) 2 OH, and (CH 2 ) n -phenyl;
n, at each occurrence, is independently selected from 0 and 1,
m is selected from 0 and 1; and,
p is selected from 1 and 2;
or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 , wherein the compound is of Formula I or a stereoisomer or pharmaceutically acceptable salt thereof:
wherein:
R is selected from H, C 1-6 alkyl, C 3-6 alkenyl, and C 3-6 alkynyl;
R′ is selected from H, C 1-6 alkyl, —CH 2 C 6 H 5 , and —COCH 3 ;
Y, at each occurrence, is independently selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , and CH(CH 3 ) 2 ; and,
p is selected from 1 and 2.
3. A compound of claim 2 , wherein the compound is of Formula I-A or a stereoisomer or pharmaceutically acceptable salt thereof:
4. A compound of claim 1 , wherein the compound is of Formula II or a stereoisomer or pharmaceutically acceptable salt thereof:
wherein:
R is selected from H, C 1-6 alkyl, C 3-6 alkenyl, and C 3-6 alkynyl;
R′ is selected from C 1-3 alkyl and —COCH 3 ;
Z is selected from H, C 1-6 alkyl, CH 2 OH, CH(CH 3 )OH, C(CH 3 ) 2 OH, and (CH 2 ) n -phenyl;
Y, at each occurrence, is independently selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , and CH(CH 3 ) 2 ; and,
p is selected from 1 and 2.
5. A compound of claim 4 , wherein the compound is of Formula II-A or a stereoisomer or pharmaceutically acceptable salt thereof:
6. A compound of claim 1 , wherein the compound is of Formula III or a stereoisomer or pharmaceutically acceptable salt thereof:
wherein:
R is selected from H, C 1-6 alkyl, C 3-6 alkenyl, and C 3-6 alkynyl;
R′ is selected from H, C 1-3 alkyl, and —COCH 3 ;
Y, at each occurrence, is independently selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , and CH(CH 3 ) 2 ;
m is selected from 0 and 1; and,
n, at each occurrence, is independently selected from 0 and 1.
7. A compound of claim 6 , wherein the compound is of Formula III-A or a stereoisomer or pharmaceutically acceptable salt thereof:
8. A compound of claim 1 , wherein the compound is of Formula IV or a stereoisomer or pharmaceutically acceptable salt thereof:
wherein:
R is selected from H, C 1-6 alkyl, C 3-6 alkenyl, and C 3-6 alkynyl;
R′ is selected from H, C 1-3 alkyl, and —COCH 3 ; and, Y, at each occurrence, is independently selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , and CH(CH 3 ) 2 .
9. A compound of claim 8 , wherein the compound is of Formula IV-A or a stereoisomer or pharmaceutically acceptable salt thereof:
10. A compound of claim 8 , wherein the compound is of Formula IV-B or a stereoisomer or pharmaceutically acceptable salt thereof:
11. A compound of claim 8 , wherein the compound is of Formula IV-C or a stereoisomer or pharmaceutically acceptable salt thereof:
12. A compound of claim 1 , wherein the compound is of Formula V or a stereoisomer or pharmaceutically acceptable salt thereof:
wherein:
R is selected from H, C 1-6 alkyl, C 3-6 alkenyl, and C 3-6 alkynyl;
R′ is selected from H, C 1-3 alkyl, and —COCH 3 ;
Z is selected from H, C 1-6 alkyl, CH 2 OH, CH(CH 3 )OH C(CH 3 ) 2 OH, and (CH 2 ) n -phenyl;
Y, at each occurrence, is independently selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , and CH(CH 3 ) 2 .
13. A compound of claim 12 , wherein the compound is of Formula V-A or a stereoisomer or pharmaceutically acceptable salt thereof:
14. A compound of claim 12 , wherein the compound is of Formula V-B or a stereoisomer or pharmaceutically acceptable salt thereof:
15. A compound of claim 12 , wherein the compound is of Formula V-C or a stereoisomer or pharmaceutically acceptable salt thereof:
16. A compound of claim 1 , wherein the compound is of Formula VI or a stereoisomer or pharmaceutically acceptable salt thereof:
wherein:
R is selected from H, C 1-6 alkyl, C 3-6 alkenyl, and C 3-6 alkynyl;
R′ is selected from C 1-3 alkyl;
Y, at each occurrence, is independently selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , and CH(CH 3 ) 2 ;
m is selected from 0 and 1; and,
n is selected from 0 and 1.
17. A compound of claim 16 , wherein the compound is of Formula VI-A or a stereoisomer or pharmaceutically acceptable salt thereof:
18. A compound of claim 16 , wherein the compound is of Formula VI-B or a stereoisomer or pharmaceutically acceptable salt thereof:
19. A compound of claim 16 , wherein the compound is of Formula VI-C or a stereoisomer or pharmaceutically acceptable salt thereof:
20. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound of claim 1 or a stereoisomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
21. A method of terminating or blocking the occurrence of an arrhythmia, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the arrhythmia is selected from: paroxysmal atrial tachycardia, junctional ectopic tachycardia, atrial flutter, atrial fibrillation, atrial tachycardia, ventricular tachycardia, junctional tachycardia, and ventricular fibrillation.