Nitrooxyderivatives of carvedilol and other beta blockers as antihypertensive

1. A compound of general formula A-(Y—ONO 2 ) s (I) and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof, wherein

s is an integer equal to 1;

A is selected from the following β-adrenergic blockers residues of formula (II):

wherein

R 1 is

R 2 is

Z is —C(O)—;

Z 1 is H;

Y is a bivalent radical selected from the group consisting of:

a)

straight or branched C 1 -C 20 alkylene being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO 2 or T, wherein T is —OC(O)(C 1 -C 10 alkyl)-ONO 2 , —O(C 1 -C 10 alkyl)-ONO 2 ;

b)

wherein:

n is an integer from 0 to 20,

n1 is an integer from 1 to 20;

n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1,

R 3 and R 4 are independently selected from H or CH 3 ,

Y 1 is —CH 2 — or —(CH 2 ) na —CH═CH— wherein na is an integer from 0 to 20;

X 1 is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH; and

c)

wherein

X 2 is O or S,

n10a, n10 and n12 are integer independently selected from 0 to 20,

n11 is an integer from 0 to 6;

R 11 is H, CH 3 or nitrooxy group;

R 11a is CH 3 or nitrooxy group;

and wherein (Y—ONO 2 ) s bonds with Z of formula (II).

2. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1 wherein Y is a straight or branched C 1 -C 10 alkylene.

3. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1 wherein

Y is

wherein

n is an integer from 0 to 20,

n1 is an integer from 1 to 20;

n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1;

R 3 and R 4 are independently selected from H or CH 3 ;

Y 1 is —CH 2 — or —CH 2 ) na —CH═CH— wherein na is an integer from 0 to 20;

X 1 is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH.

4. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 3 wherein

n2, n3, n4, n5 are equal to 0,

n1 is 1,

n is an integer from 0 to 10,

Y 1 is CH 2 .

5. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 3 wherein

n, n2, n5 are 1,

n3 and n4 are equal to 0, and

n1 is an integer from 1 to 10,

Y 1 is —(CH 2 ) na —CH═CH— wherein na is 0,

X 1 is —WC(O)— wherein W is oxygen and X 1 is bound to the phenyl ring through the [C] 4 ,

R 4 is CH 3 and the group (OR 4 ) is bound to the phenyl ring through the [C] 3 .

6. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1 wherein

Y is

wherein

X 2 is O or S,

n10a, n10 and n12 are integers independently selected from 0 to 20;

n11 is an integer from 0 to 6;

R 11 is H, CH 3 or a nitrooxy group;

R 11a is CH 3 or a nitrooxy group.

7. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 6 wherein

Y is

wherein

X 2 is O or S,

n10a is an integer from 0 to 10

n11 are 0,

n12 is an integer from 1 to 10,

R 11 is H or a nitrooxy group;

wherein the —ONO 2 group is bound to the —(CH 2 ) n12 — group.

8. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1 wherein

Y is a straight or branched C 1 -C 20 alkylene being optionally substituted with one or more of the substituents selected from the group consisting of halogen atoms, hydroxy, —ONO 2 or T, wherein T is —OC(O)(C 1 -C 10 alkyl)-ONO 2 , —O(C 1 -C 10 alkyl)-ONO 2 .

9. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 8 wherein Y is a straight or branched C 3 -C 6 alkylene.

10. Compounds and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to any one of claims 1 , 8 or 9 wherein the compounds are:

11. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts according to claim 1 , that is 4-(Nitrooxymethyl)benzoic acid 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanoate.

12. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts according to any one of claim 1 , 8 or 9 , that is 6-(nitrooxy)hexanoic acid 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanol hydrochloride.

13. A medicament comprising a compound of formula (I) and/or the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof as defined in claim 1 .

14. A method for the treatment or prophylaxis of hypertension, cardiovascular and vascular diseases using a drug comprising a compound of formula (I) and/or the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof as defined in claim 1 .

15. A method for the treatment of glaucoma and elevated intraocular pressure using a drug comprising a compound of formula (I) and/or the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof as defined in claim 1 .

16. A pharmaceutical composition comprising a compound of formula (I) and/or the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof as defined in claim 1 and at least one pharmaceutically acceptable carrier.