IP Library › Granted Patent US 10,793,519
Granted Patent B2
US 10,793,519 · App. 16/398,368 · Granted Oct 6, 2020

Ultra short acting anti-arrhythmic agents

Inventors: John Somberg (Lake Forest, IL); Robert J Chorvat (Chadds Ford, PA)
Assignee: Academic Pharmaceuticals Incorporated
C07C311/08A61P9/06C07C311/00C07C311/24
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 10,793,519
App. No.
16/398,368
Granted
Oct 6, 2020
Kind
B2
Abstract

The present invention provides novel sotalol derivatives and pharmaceutical compositions containing the same that are are useful as pharmaceutical agents in the treatment of supraventricular and ventricular arrhythmias.

Claims (651)

1. A compound of one of Formulae 1-5 or a stereoisomer or a pharmaceutically acceptable salt thereof:

wherein:

R is selected from H, C 1-6 alkyl, C 3-6 alkenyl, and C 3-6 alkynyl;

m is selected from 0, 1, and 2;

n is selected from 0, 1, 2, and 3;

X, X 1 , X 2 , and X 3 are independently selected from H, —O—C 1-3 alkyl, C 1-3 alkyl, halogen, CF 3 , nitro, and —CN;

Y is selected from H and C 1-3 alkyl; and,

Z is from H, CH 3 , CH 2 OH, and CH(CH 3 )OH.

2. A compound of claim 1 wherein the compound is selected from Table 1 below:

Ex. #

R

m

Y

1.

CH 3

0

H

2.

CH 2 CH 3

0

H

3.

CH 2 CH 2 CH 3

0

H

4.

CH 2 CH═CH 2

0

H

5.

CH 3

1

H

6.

CH 2 CH 3

1

H

7.

CH 2 CH 2 CH 3

1

H

8.

CH 2 CH═CH 2

1

H

9.

CH 3

2

H

10.

CH 2 CH 3

2

H

11.

CH 2 CH 2 CH 3

2

H

12.

CH 2 CH═CH 2

2

H

13.

CH 3

0

CH 3

14.

CH 2 CH 3

0

CH 3

15.

CH 2 CH 2 CH 3

0

CH 3

16.

CH 2 CH═CH 2

0

CH 3

17.

CH 3

1

CH 3

18.

CH 2 CH 3

1

CH 3

19.

CH 2 CH 2 CH 3

1

CH 3

20.

CH 2 CH═CH 2

1

CH 3

21.

CH 3

2

CH 3

22.

CH 2 CH 3

2

CH 3

23.

CH 2 CH 2 CH 3

2

CH 3

24.

CH 2 CH═CH 2

2

CH 3

or a stereoisomer or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 wherein the compound is selected from Table 2 below:

Ex. #

R

m

Y

1

CH 3

0

H

2

CH 2 CH 3

0

H

3

CH 2 CH 2 CH 3

0

H

4

CH 2 CH═CH 2

0

H

5

CH 3

1

H

6

CH 2 CH 3

1

H

7

CH 2 CH 2 CH 3

1

H

8

CH 2 CH═CH 2

1

H

9

CH 3

2

H

10

CH 2 CH 3

2

H

11

CH 2 CH 2 CH 3

2

H

12

CH 2 CH═CH 2

2

H

13

CH 3

0

CH 3

14

CH 2 CH 3

0

CH 3

15

CH 2 CH 2 CH 3

0

CH 3

16

CH 2 CH═CH 2

0

CH 3

17

CH 3

1

CH 3

18

CH 2 CH 3

1

CH 3

19

CH 2 CH 2 CH 3

1

CH 3

20

CH 2 CH═CH 2

1

CH 3

21

CH 3

2

CH 3

22

CH 2 CH 3

2

CH 3

23

CH 2 CH 2 CH 3

2

CH 3

24

CH 2 CH═CH 2

2

CH 3

or a stereoisomer or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 wherein the compound is selected from Table 3 below:

Ex. #

R

m

Chain position

1

CH 3

0

1

2

CH 2 CH 3

0

1

3

CH 2 CH 2 CH 3

0

1

4

CH 2 CH═CH 2

0

1

5

CH 3

0

2

6

CH 2 CH 3

0

2

7

CH 2 CH 2 CH 3

0

2

8

CH 2 CH═CH 2

0

2

9

CH 3

1

1

10

CH 2 CH 3

1

1

11

CH 2 CH 2 CH 3

1

1

12

CH 2 CH═CH 2

1

1

13

CH 3

1

2

14

CH 2 CH 3

1

2

15

CH 2 CH 2 CH 3

1

2

16

CH 2 CH═CH 2

1

2

or a stereoisomer or a pharmaceutically acceptable salt thereof.

5. A compound of claim 1 wherein the compound is selected from Table 4 below:

Ex. #

R

m

Chain position

1

CH 3

0

1

2

CH 2 CH 3

0

1

3

CH 2 CH 2 CH 3

0

1

4

CH 2 CH═CH 2

0

1

5

CH 3

0

2

6

CH 2 CH 3

0

2

7

CH 2 CH 2 CH 3

0

2

8

CH 2 CH═CH 2

0

2

9

CH 3

1

1

10

CH 2 CH 3

1

1

11

CH 2 CH 2 CH 3

1

1

12

CH 2 CH═CH 2

1

1

13

CH 3

1

2

14

CH 2 CH 3

1

2

15

CH 2 CH 2 CH 3

1

2

16

CH 2 CH═CH 2

1

2

or a stereoisomer or a pharmaceutically acceptable salt thereof.

6. A compound of claim 1 wherein the compound is selected from Table 5 below:

Chain

Ex. #

R

m

position

1

CH 3

0

1

2

CH 2 CH 3

0

1

3

CH 2 CH 2 CH 3

0

1

4

CH 2 CH═CH 2

0

1

5

CH 3

0

2

6

CH 2 CH 3

0

2

7

CH 2 CH 2 CH 3

0

2

8

CH 2 CH═CH 2

0

2

9

CH 3

0

3

10

CH 2 CH 3

0

3

11

CH 2 CH 2 CH 3

0

3

12

CH 2 CH═CH 2

0

3

13

CH 3

1

1

14

CH 2 CH 3

1

1

15

CH 2 CH 2 CH 3

1

1

16

CH 2 CH═CH 2

1

1

17

CH 3

1

2

18

CH 2 CH 3

1

2

19

CH 2 CH 2 CH 3

1

2

20

CH 2 CH═CH 2

1

2

21

CH 3

0

3

22

CH 2 CH 3

0

3

23

CH 2 CH 2 CH 3

0

3

24

CH 2 CH═CH 2

0

3

or a stereoisomer or a pharmaceutically acceptable salt thereof.

7. A compound of claim 1 wherein the compound is selected from Table 6 below:

Ex. #

R

m

1

CH 3

0

2

CH 2 CH 3

0

3

CH 2 CH 2 CH 3

0

4

CH 2 CH═CH 2

0

5

CH 3

1

6

CH 2 CH 3

1

7

CH 2 CH 2 CH 3

1

8

CH 2 CH═CH 2

1

or a stereoisomer or a pharmaceutically acceptable salt thereof.

8. A compound of claim 1 wherein the compound is selected from Table 7 below:

Ex. #

R

m

Chain position

1

CH 3

0

1

2

CH 2 CH 3

0

1

3

CH 2 CH 2 CH 3

0

1

4

CH 2 CH═CH 2

0

1

5

CH 3

1

1

6

CH 2 CH 3

1

1

7

CH 2 CH 2 CH 3

1

1

8

CH 2 CH═CH 2

1

1

9

CH 3

0

2

10

CH 2 CH 3

0

2

11

CH 2 CH 2 CH 3

0

2

12

CH 2 CH═CH 2

0

2

13

CH 3

1

2

14

CH 2 CH 3

1

2

15

CH 2 CH 2 CH 3

1

2

16

CH 2 CH═CH 2

1

2

or a stereoisomer or a pharmaceutically acceptable salt thereof.

9. A compound of claim 1 wherein the compound is selected from Table 8 below:

N-Chain

O-Chain

Ex. #

R

n

position

position

1

CH 3

1

3

4

2

CH 2 CH 3

1

3

4

3

CH 2 CH 2 CH 3

1

3

4

4

CH 2 CH═CH 2

1

3

4

5

CH 3

1

4

3

6

CH 2 CH 3

1

4

3

7

CH 2 CH 2 CH 3

1

4

3

8

CH 2 CH═CH 2

1

4

3

9

CH 3

2

3

4

10

CH 2 CH 3

2

3

4

11

CH 2 CH 2 CH 3

2

3

4

12

CH 2 CH═CH 2

2

3

4

13

CH 3

2

4

3

14

CH 2 CH 3

2

4

3

15

CH 2 CH 2 CH 3

2

4

3

16

CH 2 CH═CH 2

2

4

3

or a stereoisomer or a pharmaceutically acceptable salt thereof.

10. 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.

11. 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.

12. A method of causing electrophysiological actions that are anti-arrhythmic, 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 compound binds to the IKr and possibly IKs potassium channels, inhibiting them.

13. A method of terminating a symptom selected from: paroxysmal atrial tachycardia, junctional ectopic tachycardia, atrial flutter, atrial fibrillation, atrial tachycardia, junctional tachycardia, ventricular tachycardia, and ventricular fibrillation, 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.

14. A method of blocking the development of or blocking a symptom selected from: paroxysmal atrial tachycardia, junctional ectopic tachycardia, atrial flutter, atrial fibrillation, atrial tachycardia, junctional tachycardia, ventricular tachycardia, and ventricular fibrillation, 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.

15. The method of claim 14 , wherein the patient had previously suffered from at least one of the symptoms and the therapy stops the reoccurrence of the symptom.

16. A method of treating a symptom selected from: paroxysmal atrial tachycardia junctional ectopic tachycardia, atrial flutter, and atrial fibrillation that occurs peri or post-operatively in the pediatric or adult population, 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.

17. The method of claim 11 , wherein the route of administration is selected from: intravenous, oral, topical, sublingual, and bucal.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 13, 2019
From: SOMBERG, JOHN; CHORVAT, ROBERT J
To: ACADEMIC PHARMACEUTICALS INCORPORATED
Reel/Frame 050033/0572 →
Continuity (2)
Provisional Application 62665584 · May 2, 2018
Related Publication 20190352257A1 · Nov 21, 2019
Cited By (5)
US 12,258,309 US 12,390,431 US 12,396,970 US 12,403,109 US 12,740,947