Nitric oxide donor compounds
View Patent ↗The invention relates to nitric oxide donors of the formula (I) and pharmaceutically acceptable salts or stereoisomers thereof: wherein A and A′ are independently selected from the group consisting of H and —(X) s —Y with the proviso that at least one of A or A′ is not H; wherein s is 0 or 1; X is selected from the group consisting of: —CO—, —COO—, —CONH— and —SO 2 — or Y is straight or branched C 1 -C 20 alkyl chain, preferably C 1 -C 10 alkyl chain, substituted with one or two —ONO 2 ; or C 1 -C 6 alkylenoxy-C 1 -C 5 alkyl wherein the alkyl group is substituted by one or two —ONO 2 groups. The invention also provides novel compositions comprising at least one compound of the invention and at least one therapeutic agent.
1. A compound of the formula (I) and pharmaceutically acceptable salts or stereoisomers thereof:
wherein A and A′ are independently selected from the group consisting of H and —(X) s —Y with the proviso that at least one of A or A′ is not H and at least one of A or A′ is H;
wherein
s is 0 or 1;
X is selected from the group consisting of:
—CO—, —COO—, —CONH— and —SO 2 — or
Y is
selected from the group consisting of:
1) Z—CH 2 —ONO 2 ,
wherein Z is a straight or branched C 1 -C 10 alkylene;
2) (CH 2 ) n R 1 ,
3) (CH 2 ) n —O—CH 2 —R 1 ,
wherein
R 1 is —CH(ONO 2 )R 2 ;
R 2 is —CH 3 or C 1-4 alkyl;
n is an integer from 1 to 6;
4) Y 1 —R 3 ,
wherein
R 3 is —CH(ONO 2 )CH(ONO 2 )R 4 ;
R 4 is selected from —CH 3 , —CH 2 CH 3 and —CH(CH 3 ) 2 ;
Y 1 is —(CH 2 ) 1-4 —(X 1 ) 0-1 —(CH 2 ) 0-4 , wherein X 1 is —O— or —CR 5 R 6 —; and R 5 and R 6 are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; and
5) Y 1 —CH(ONO 2 )CH 2 (ONO 2 )
wherein Y 1 is as above defined, with the proviso that when s is 0, then Y 1 is not —CH 2 —.
2. A compound of formula (I) according to claim 1 selected from the group consisting of:
wherein A and A′ are as defined in claim 1 .
3. A compound of formula (I) according to claim 1 selected from the group consisting of:
wherein A and A′ are as defined in claim 1 .
4. A compound of formula (I) according to claim 1 , wherein the compound is selected from the group consisting of:
wherein A is H and A′ is —CO—Y or —COO—Y.
5. A compound of formula (I) according to claim 1 , wherein the compound is selected from the group consisting of:
wherein A is H, A′ —(X) s —Y wherein s is 0.
6. A compound of formula (I) according to claim 1 wherein the compound is selected from the group consisting of:
wherein A is H and A′ is
7. A compound of formula (I) according to claim 1 , Y is selected from the group consisting of:
8. A compound of formula (I) according to claim 1 selected from the group consisting of:
or steroisomers thereof.
9. A medicament comprising a compound of formula (I) or pharmaceutically acceptable salts or stereoisomers thereof according to claim 1 .
10. A combination comprising a compound of formula (I) or pharmaceutically acceptable salts or stereoisomers thereof according to claim 1 and at least one therapeutic agent selected from:
non steroidal anti-inflammatory drugs, anti-thrombotic drugs, steroidal anti-inflammatory drugs, ACE inhibitors, Angiotensin II receptor antagonist, β-adrenergic receptor blockers, β-adrenergic receptor agonists, statins, prostaglandins.
11. Pharmaceutical formulation comprising a compound of formula (I) or pharmaceutically acceptable salts or stereoisomers thereof according to claim 1 and a pharmaceutical acceptable excipient.
12. The compound of claim 1 , wherein Z is a straight or branched C 1 -C 6 alkylene.