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