Eicosanoid derivatives

Patent metadata

Field	Value
Publication number	US-9272991-B2
Application number	US-201013144301-A
Country	US
Kind code	B2
Filing date	Jan 13, 2010
Priority date	Jan 13, 2009
Publication date	Mar 1, 2016
Grant date	Mar 1, 2016

Abstract

The present invention provides compounds (n-3 PUFA derivatives) of formula (I) that modulate conditions associated with cardiac damage, especially cardiac arrhythmias.

First claim

The invention claimed is:

1. A compound of the general formula (I):

or a pharmacologically acceptable salt, solvate, hydrate or a pharmacologically acceptable formulation thereof, wherein R 1 is selected from

R 2 is hydroxy, heteroalkyl, alkoxy, polyalkoxyalkyl, NR 3 R 4 , (NHS(O) 2 -m-(C 6 H 4 )N 3 , or Xaa o ;
R 3 and R 4 are each and independently of each other selected from the group consisting of hydrogen atom, hydroxy, alkyl, heteroalkyl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl, or heteroaralkyl;
Xaa is Gly, a conventional D,L-, D- or L-amino acid, a non-conventional D,L-, D- or L-amino acid, or a 2- to 10-mer peptide, wherein Xaa is joined to —C(O) by an amide bond;
o is an integer selected from 1 to 10;
B is CH 2 , 0, or S;
m is an integer from 1 to 6;
T, U, and W are each —CH 2 CH 2 —;
V is cis or trans —CH═CH—;
X is absent, CH 2 , and NR 5 ;
Z is selected from CH 2 , and NR 5 ′;
R 5 and R 5 ′ are each and independently of each other selected from the group consisting a hydrogen atom, a hydroxy, alkyl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl, heteroaralkyl group;
Y is —C(O)—, —C(O)—C(O)—, or —S—; and
n is an integer from 0 to 6.

2. The compound according to claim 1 , wherein R 1 is —COR 2 .

3. The compound according to claim 1 wherein m is 1.

4. The compound according to claim 1 , wherein n is 0 or 1.

5. The compound according to claim 1 , wherein Y is —C(O)— or —C(O)—C(O)—.

6. The compound according to claim 1 , wherein X is NR 5 with R 5 being a hydrogen atom, a methyl, ethyl, propyl or iso-propyl group.

7. The compound according to claim 1 , wherein Z is NR 5 ′ with R 5 ′ being a hydrogen atom, a methyl, ethyl, propyl or iso-propyl group.

8. A compound of the general formula (I):

or a pharmacologically acceptable salt, solvate, hydrate or a pharmacologically acceptable formulation thereof, wherein
R 1 is —COR 2 ;
R 2 is hydroxy, heteroalkyl, alkoxy, polyalkoxyalkyl, NR 3 R 4 , (NHS(O) 2 -m-(C 6 H 4 )N 3 , or Xaa o ;
R 3 and R 4 are each and independently of each other selected from the group consisting of hydrogen atom, hydroxy, alkyl, heteroalkyl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl, or heteroaralkyl;
Xaa is Gly, a conventional D,L-, D- or L-amino acid, a non-conventional D,L-, D- or L-amino acid, or a 2- to 10-mer peptide, wherein Xaa is joined to —C(O) by an amide bond;
o is an integer selected from 1 to 10;
B is CH 2 , O, or S;
m is 1;
T, U, and W are each and independently of each other selected from the group consisting of —CH 2 CH 2 —, and cis —CH═CH—or trans —CH═CH—, with the proviso that at least one of T, U, or W is —CH 2 CH 2 —;
V is cis or trans —CH═CH—;
X is absent,—CH 2 or NR 5 ;
Z is selected from CH 2 and NR 5 ′;
R 5 and R 5 ′ are each and independently of each other selected from the group consisting of a hydrogen atom, a hydroxy, alkyl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl, or heteroaralkyl group;
Y is —C(O)—, —C(O)—C(O)—, —O—, or —S—; and
n is 0 or 1.

9. The compound according to claim 8 , wherein each of T, U and W is —CH 2 CH 2 —.

10. The compound according to claim 8 , wherein Y is — C(O)— or —C(O)—C(O).

11. The compound according to claim 8 , wherein X is NR 5 with R 5 being a hydrogen atom, a methyl, ethyl, propyl or iso-propyl group.

12. The compound according to claim 8 , wherein Z is NR 5 ′ with R 5 ′ being a hydrogen atom, a methyl, ethyl, propyl or iso-propyl group.

13. A compound of the general formula (I):

or a pharmacologically acceptable salt, solvate, hydrate or a pharmacologically acceptable formulation thereof, wherein
R 1 is —COR 2 ;
R 2 is hydroxy, heteroalkyl, alkoxy, polyalkoxyalkyl, NR 3 R 4 , (NHS(O) 2 -m-(C 6 H 4 )N 3 , or Xaa o ;
R 3 and R 4 are each and independently of each other selected from the group consisting of hydrogen atom, hydroxy, alkyl, heteroalkyl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl, or heteroaralkyl;
Xaa is Gly, a conventional D,L-, D- or L-amino acid, a non-conventional D,L-, D- or L-amino acid, or a 2- to 10-mer peptide, wherein Xaa is joined to —C(O) by an amide bond;
o is an integer selected from 1 to 10;
B is CH 2 , O, or S;
m is 1;
T, U, and W are each —CH 2 CH 2 —;
V is cis or trans —CH═CH—;
X is NR 5 with R 5 being a hydrogen atom, a methyl, ethyl, propyl or iso-propyl group;
Z is NR 5 ′ with R 5 ′ being a hydrogen atom, a methyl, ethyl, propyl or iso-propyl group;
Y is —C(O)— or —C(O)—C(O)—; and
n is 0 or 1.

14. A compound selected from the group consisting of:

15. A pharmaceutical composition that comprises at least one compound according to claim 1 and, optionally, a carrier substance and/or an adjuvant.

16. A method for treatment of conditions and/or diseases associated with heart failure and cardiac damage comprising pg, 121 administering to a patient in need thereof the pharmaceutical composition of claim 15 in a treatment of heart failure and cardiac damage effective amount.

17. The method of claim 16 , wherein the conditions and/or diseases are heart failure and cardiac damage.

18. The method of claim 16 , wherein the conditions and/or diseases are cardiac arrhythmias, heart failure based on coronary disease, dilatative cardiomyopathy, myocarditis, hypertensive heart disease, diabetes and inflammatory cardiomyopathy.

19. The method of claim 18 , wherein the cardiac arrhythmias are ventricular tachycardia, malignant ventricular tachycardia and/or atrial fibrillation.

20. The method of claim 19 , wherein the atrial fibrillation treated occurred after myocardial infarction.

Assignees

• Schunck Wolf-Hagen
• Wallukat Gerd
• Fischer Robert
• Arnold Cosima
• Mueller Dominik N
• Puli Narender
• Falck John R
• Max Delbrueck Centrum
• Univ Texas

Inventors

• Schunck Wolf-Hagen
• Wallukat Gerd
• Fischer Robert
• Arnold Cosima
• Mueller Dominik N
• Puli Narender
• Falck John R

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/06

  Antiarrhythmics · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title