Potassium channel blockers

Patent metadata

Field	Value
Publication number	US-9447033-B2
Application number	US-201514724195-A
Country	US
Kind code	B2
Filing date	May 28, 2015
Priority date	Aug 29, 2008
Publication date	Sep 20, 2016
Grant date	Sep 20, 2016

Abstract

The present invention provides a compound of formula (I)

or its salts or pharmaceutically acceptable derivatives thereof wherein X 1 , R 1 , R 2 , R 3 , R 4 , and R 5 are defined as set forth in the specification. The compounds are useful as potassium ion channel inhibitors.

First claim

The invention claimed is:

1. A compound of formula (I):

or its salts or pharmaceutically acceptable derivatives thereof;
wherein:
X 1 is selected from a group consisting of CH 2 , C(═O), C(═NH), and NHC(═O);
R 1 is selected from the group consisting of optionally substituted arylalkyl, and optionally substituted heteroarylalkyl;
R 2 is selected from the group consisting of optionally substituted aryl, heteroaryl, and NR 24 R 25 ;
R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, optionally substituted alkyl, optionally substituted amino, optionally substituted amino sulfonyl, and nitrile;
R 4 is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroaryl;
R 5 is selected from the group consisting of hydrogen and optionally substituted alkyl;
R 24 and R 25 are the same or different and each represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl;
m=1, 2 or 3;
with the proviso that when X 1 is C═O and R 5 is H then R 4 is not:

wherein
R 10 a is H or C 1-6 alkyl; and
R 11 a is C 1-6 alkyl or aryl-C 1-6 alkyl; and
wherein optionally substituted means a group may be substituted by one or more substituents, which may be the same or different, and which are selected from alkyl, cycloalkyl, —OC(halogen) 3 , biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl, acyl, amidino, amido, amino, alkyloxyamino, carbamoyl, carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl, sulfonyl, sulphinyl, sulphenyl, sulfonamido, and urea.

2. A compound according to claim 1 , wherein X 1 is C(═O).

3. A compound according to claim 2 , wherein R 2 is NR 24 R 25 .

4. A compound according to claim 3 , wherein R 24 and R 25 are the same or different and each represents hydrogen, or optionally substituted C 1-3 alkyl.

5. A compound according to claim 2 , wherein R 2 is selected from formula (III), (IV) and (V):

wherein:
A, D, E, G, and J are the same or different and each represents C or N with the provisos that in each instance
1) at least one of A, D, E, G, or J is N;
2) when R 2 is formula (III), E may also represent O or S; and
3) when R 2 is formula (IV), A may also represent O or S;
R 9 and R 10 are the same or different and each represents hydrogen, halogen, hydroxy, nitrile, optionally substituted amino, optionally substituted acyl, optionally substituted C 1-3 alkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl or may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ring.

6. A compound according to claim 2 , wherein R 2 is formula (VI):

wherein R 11 , R 12 , R 13 , R 14 , and R 15 are the same or different and each represents hydrogen, halogen, hydroxy, optionally substituted amino, optionally substituted acyl, nitrile, and optionally substituted C 1-3 alkyl or any of the pairs R 11 and R 12 , or R 12 and R 13 , or R 13 and R 14 , or R 14 and R 15 may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ring.

7. A compound according to claim 1 , wherein R 1 has the formula (VII):

wherein:
R 16 , R 17 , R 18 , R 19 and R 20 are the same or different and each represents hydrogen, halogen, hydroxy, optionally substituted amino, optionally substituted acyl, nitrile, optionally substituted C 1-3 alkyl or optionally substituted alkoxy; and
R 21 and R 22 are the same or different and each represents hydrogen, hydroxy, and optionally substituted C 1-3 alkyl.

8. A compound according to claim 1 , wherein R 3 is H, F, or CH 3 .

9. A compound according to claim 8 , wherein R 3 is H or F.

10. A compound according to claim 1 , wherein R 4 is selected from the group consisting of cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, -phenyl, benzyl, phenethyl, 3-phenylpropyl, indazolyl, pyridyl, thiadiazolyl, and thiazolyl, each of which is optionally substituted.

11. A compound according to claim 1 , wherein R 5 is hydrogen or CH 3 .

12. A compound according to claim 1 , wherein the compound is of formula (VIII):

wherein:
R 2 is selected from the group consisting of NR 24 R 25 , formula (III), formula (IV), formula (V), and formula (VI):

wherein:
A, D, E, G, and J are the same or different and each is C or N, with the provisos that in each instance:
1) at least one of A, D, E, G, or J is N;
2) when R 2 is formula (III), E may also be O or S; and
3) when R 2 is formula (IV), A may also be O or S;
R 9 and R 10 are the same or different and each is hydrogen, halogen, hydroxy, cyano, amino, acyl, optionally substituted C 1-3 alkyl, optionally substituted arylalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ring;
R 11 , R 12 , R 13 , R 14 , and R 15 are the same or different and each represents hydrogen, halogen, hydroxy, amino, acyl, cyano, and optionally substituted C 1-3 alkyl, or any of the pairs R 11 and R 12 , or R 12 and R 13 , or R 13 and R 14 , or R 14 and R 15 may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ring; and
R 16 , R 17 , R 18 , R 19 and R 20 are the same or different and each represents hydrogen, halogen, hydroxy, amino, acyl, cyano, optionally substituted C 1-3 alkyl, or optionally substituted alkoxy.

13. A compound according to claim 12 , wherein the compound is of formula (IX):

14. A compound according to claim 1 selected from the group consisting of:
3-(Benzenesulfonyl-benzyl-amino)-N-(1H-indazol-6-yl)-benzamide;
3-(Benzenesulfonyl-benzyl-amino)-N-pyridin-2-ylmethyl-benzamide;
3-(Benzenesulfonyl-benzyl-amino)-N-(1H-indazol-5-yl)-benzamide;
3-(Benzenesulfonyl-benzyl-amino)-N-(4-imidazol-1-yl-phenyl)-benzamide;
3-(Benzenesulfonyl-benzyl-amino)-N-(4-pyrazol-1-yl-phenyl)-benzamide;
3-(Benzenesulfonyl-benzyl-amino)-N-[1,3,4]thiadiazol-2-yl-benzamide;
3-(Benzenesulfonyl-benzyl-amino)-N-thiazol-2-yl-benzamide;
N-[4-(Aminocarbonyl)phenyl]-3-[benzyl(phenylsulfonyl)amino]benzamide;
N-[3-(Aminocarbonyl)phenyl]-3-[benzyl(phenylsulfonyl)amino]benzam

Assignees

• Japan Tobacco Inc

Inventors

• Mulla Mushtaq
• John Derek Edward
• Hamlyn Richard John
• Garrett Sasha Louise
• Hartzoulakis Basil
• Madge David
• Ford John

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07C317/32

  with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title