IP Library › Granted Patent US 11,286,235
Granted Patent B2
US 11,286,235 · App. 17/063,497 · Granted Mar 29, 2022

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
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Quick Facts
Patent No.
US 11,286,235
App. No.
17/063,497
Granted
Mar 29, 2022
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 (650)

1. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound of one of Formulae 1-5 or a stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier:

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 H;

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

Z is CH 3 .

2. The pharmaceutical composition of claim 1 , wherein the compound is selected from the table 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. The pharmaceutical composition of claim 1 , wherein the compound is selected from the table 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. The pharmaceutical composition of claim 1 , wherein the compound is selected from the table 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. The pharmaceutical composition of claim 1 , wherein the compound is selected from the table 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. The pharmaceutical composition of claim 1 , wherein the compound is selected from the table 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

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. The pharmaceutical composition of claim 1 , wherein the compound is selected from the table 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. The pharmaceutical composition of claim 1 , wherein the compound is selected from the table 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. The pharmaceutical composition of claim 1 , wherein the compound is selected from the table 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 method of terminating or blocking the occurrence of an arrhythmia, comprising: administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 1 , 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.

11. A method of causing electrophysiological actions that are anti-arrhythmic, comprising: administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 1 , wherein the compound binds to the IKr and possibly IKs potassium channels, inhibiting them.

12. 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 the pharmaceutical composition of claim 1 .

13. 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 the pharmaceutical composition of claim 1 .

14. The method of claim 13 , wherein the patient had previously suffered from at least one of the symptoms and the therapy stops the reoccurrence of the symptom.

15. 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 the pharmaceutical composition of claim 1 .

16. The method of claim 15 , wherein the route of administration is selected from: intravenous, oral, topical, sublingual, and buccal.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 18, 2020
From: SOMBERG, JOHN; CHORVAT, ROBERT J
To: ACADEMIC PHARMACEUTICALS INCORPORATED
Reel/Frame 054401/0718 →
Continuity (3)
Continuation 16398368 · Apr 30, 2019
Provisional Application 62665584 · May 2, 2018
Related Publication 20210107867A1 · Apr 15, 2021
Cited By (5)
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