Tertiary amines for use in the treatment of cardiac disorders

Patent metadata

Field	Value
Publication number	US-9556111-B2
Application number	US-201314402037-A
Country	US
Kind code	B2
Filing date	May 17, 2013
Priority date	May 18, 2012
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

The present invention relates to tertiary amines of formula (I) for use in therapy, particularly for use in treating cardiovascular disorders. The compounds have been found to regulate phospholamban phosphorylation by interfering with the A-kinase anchor protein 18delta (AKAP185) binding to the PKA substrate phospholamban. The compounds share a tri(alkylaryl/alkylheteroaryl)amine structure.

First claim

The invention claimed is:

1. A method of treating a cardiovascular disease or disorder associated with phospholamban phoshorylation, comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of formula (I) or a physiologically acceptable salt thereof:

wherein
L 1 , L 2 and L 3 independently denote C 1 -C 4 -alkylene optionally substituted with one phenyl;
Ar 1 , Ar 2 and Ar 3 independently denote phenyl optionally substituted with one or more R;
wherein R independently denotes F, Cl, Br, I, C 1 -C 4 -haloalkyl, OR 1 , SR 1 , NO 2 , NR 2 R 3 , R 4 , C(═O)Y, SO 3 H, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl-phenyl, a 5-membered heteroaryl; or a phenyl substituted with a 5-membered heteroaryl;
R 1 denotes H, C 1 -C 4 -alkyl or C 1 -C 4 -alkyl-phenyl; or
together two adjacent OR 1 groups denote —O—CH 2 —O—;
R 2 and R 3 independently denote H or C 1 -C 4 -alkyl; or
NR 2 R 3 denotes —NHC(═O)—NHAr 5 ; or
together two adjacent NR 2 R 3 groups denote —NR 2 —CH—N— or —NR 2 —CH 2 —NR 2 —; or
together with an adjacent OR 1 group, NR 2 R 3 denotes —NR 2 —CH 2 —O— or —N—CH—O—; or
together with an adjacent SR 1 group, NR 2 R 3 denotes —NR 2 —CH 2 —S— or —N—CH—S—;
Ar 5 denotes phenyl optionally substituted with R h ;
R h denotes halogen or C 1 -C 4 alkyl;
R 4 denotes C 1 -C 4 -alkyl; or
together with an adjacent OR 1 group, R 4 denotes —CH 2 CH 2 —O—; or
together two adjacent R 4 groups denote —(CH) 4 — or —(CH 2 ) 4 —;
Y denotes OR 5 or NR 6 R 7 ;
R 5 denotes H or C 1 -C 4 -alkyl; and
R 6 and R 7 independently denote H, C 1 -C 8 -alkyl or C 3 -C 6 cycloalkyl;
wherein the cardiovascular disease or disorder associated with phospholamban phosphorylation is selected from congenital heart failure, myocardial infarction, post infarction heart failure, congestive heart failure, reperfusion damage, dilated cardiomyopathy, and arrhythmia.

2. The method of claim 1 , wherein the compound has formula (I′):

wherein
L 1 , L 2 and L 3 independently denote C 1 -C 4 -alkylene optionally substituted with one phenyl;
Ar 1 , Ar 2 and Ar 3 independently denote phenyl optionally substituted with one or more R;
wherein R independently denotes F, Cl, Br, I, C 1 -C 4 -haloalkyl, OR 1 , SR 1 , NO 2 , NR 2 R 3 , R 4 , C(═O)Y, SO 3 H, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl-phenyl, a 5-membered heteroaryl; or a phenyl substituted with a 5-membered heteroaryl;
R 1 denotes H, C 1 -C 4 -alkyl or C 1 -C 4 -alkyl-phenyl; or
together two adjacent OR 1 groups denote —O—CH 2 —O—;
R 2 and R 3 independently denote H or C 1 -C 4 -alkyl; or
together two adjacent NR 2 R 3 groups denote —NR 2 —CH—N— or —NR 2 —CH 2 —NR 2 —; or
together with an adjacent OR 1 group, NR 2 R 3 denotes —NR 2 —CH 2 —O— or —N—CH—O—; or
together with an adjacent SR 1 group, NR 2 R 3 denotes —NR 2 —CH 2 —S— or —N—CH—S—;
R 4 denotes C 1 -C 4 -alkyl; or
together with an adjacent OR 1 group, R 4 denotes —CH 2 CH 2 —O—; or
together two adjacent R 4 groups denote —(CH) 4 — or —(CH 2 ) 4 —;
Y denotes OR 5 or NR 6 R 7 ;
R 5 denotes H or C 1 -C 4 -alkyl; and
R 6 and R 7 independently denote H, C 1 -C 8 -alkyl or C 3 -C 6 cycloalkyl.

3. The method of claim 1 , wherein the compound has formula (Ia):

wherein
L 1 , L 2 and L 3 independently denote C 1 -C 4 -alkylene optionally substituted with one phenyl;
Ar 1 , Ar 2 and Ar 3 independently denote phenyl optionally substituted with one or more R;
wherein R independently denotes F, Cl, CF 3 , OR 1 , NO 2 , NR 2 R 3 , R 4 , C(═O)Y, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl-phenyl, 5-tetrazolyl or

R 1 denotes H, C 1 -C 4 -alkyl or C 1 -C 4 -alkyl-phenyl; or
together two adjacent OR 1 groups denote —O—CH 2 —O—;
R 2 and R 3 independently denote H or C 1 -C 4 -alkyl;
R 4 denotes C 1 -C 4 -alkyl; or
together with an adjacent OR 1 group, R 4 denotes —CH 2 CH 2 —O—;
Y denotes OR 5 or NR 6 R 7 ;
R 5 denotes H or C 1 -C 4 -alkyl;
R 6 and R 7 independently denote H, C 1 -C 8 -alkyl or C 3 -C 6 cycloalkyl.

4. The method of claim 1 , wherein L 1 , L 2 and L 3 in formula (I) independently denote C 1 -C 3 -alkylene optionally substituted with one phenyl.

5. The method of claim 1 , wherein the compound has formula (II):

wherein
r denotes 0, 1 or 2;
L 3 denotes C 1 -C 3 -alkylene optionally substituted with one phenyl; and
Ar 3 denotes phenyl optionally substituted with one or two R.

6. The method of claim 1 , wherein R independently denotes F, Cl, CF 3 , OR 1 , NO 2 , NR 2 R 3 , R 4 , C(═O)Y, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl-phenyl, or

7. The method of claim 1 , wherein the compound contains at least one group capable of acting as a hydrogen bond donor, and/or at least one group capable of acting as a hydrogen bond acceptor.

8. The method of claim 1 wherein L 1 , L 2 , and L 3 are C 1 -C 4 alkylene, Ar 1 is phenyl, and Ar 2 and Ar 3 are phenyl substituted with one or more R.

9. The method of claim 8 wherein L 1 , L 2 , and L 3 are methylene.

10. The method of claim 9 wherein each R is NR 2 R 3 .

11. The method of claim 10 wherein each R 2 and R 3 is methyl.

12. The method of claim 1 , wherein the disease or disorder associated with phospholamban phosphorylation is myocardial infarction.

13. The method of claim 1 wherein the disease or disorder associated with phospholamban phosphorylation is reperfusion damage.

Assignees

• Univ Oslo

Inventors

• Tasken Kjetil
• Lygren Birgitte
• Ostensen Ellen
• Klaveness Jo

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• C07C229/38

  having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton · CPC title