Nitric oxide donating carnosine compounds
The present invention relates to nitric oxide donor carnosine derivatives having a great efficacy in reducing elevated intraocular pressure, to processes for their preparation and to their use in the treatment and/or prophylaxis of glaucoma and ocular hypertension.
1. A carnosine analogue of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein R is:
—(Y)—(CH 2 ) n —[CH(ONO 2 )] p —CH 2 —ONO 2 1)
—(Y)—(CH 2 ) n —X—(CH 2 ) n1 —[CH(ONO 2 )] p —CH 2 —ONO 2 2)
wherein:
Y is O, NH or a covalent single bond;
n is an integer from 1 to 10, preferably 1 to 4; with the proviso that in formula 2) when Y is O or NH, then n is not 1;
n 1 is an integer from 1 to 10, preferably 1 to 4;
p is 0 or 1;
X is O, NH or S;
R 1 is OH, —OR 2 , −NH 2 , —NHR 2 , wherein R 2 is (C 1 -C 10 ) linear or branched alkyl.
2. A carnosine analogue of formula (I) according to claim 1 wherein Y is a covalent single bond and X is O.
3. A carnosine analogue of formula (I) according to claim 1 wherein Y is a covalent single bond and R 1 is OH.
4. A carnosine analogue of formula (I) according to claim 3 wherein R is
—(Y)—(CH 2 ) n —[CH(ONO 2 )] p —CH 2 —ONO 2 1).
5. A carnosine analogue of formula (I) according to claim 3 wherein R is
—(Y)—(CH 2 ) n —X—(CH 2 ) n1 —[CH(ONO 2 )] p —CH 2 —ONO 2 2)
and X is O.
6. A carnosine analogue of formula (I) according to claim 1 wherein Y is a covalent single bond and R 1 is —OCH 3 .
7. A carnosine analogue of formula (I) according to claim 6 wherein R is
—(Y)—(CH 2 ) n —[CH(ONO 2 )] p —CH 2 —ONO 2 1).
8. A carnosine analogue of formula (I) according to claim 6 wherein R is
—(Y)—(CH 2 ) n —X—(CH 2 ) n1 —[CH(ONO 2 )] p —CH 2 —ONO 2 2)
and X is O.
9. A carnosine analogue of formula (I) according to claim 2 wherein p is 0.
10. A carnosine analogue of formula (I) according to claim 2 wherein p is 1.
11. A carnosine analogue according to claim 1 wherein carnosine is L-carnosine.
12. A carnosine analogue of formula (I) according to claim 1 or a pharmaceutically acceptable salt selected from the group consisting of:
(S)-methyl-3-(1H-imidazol-4-yl)-2-(3-(5-(nitrooxy)pentanamido)propanamido) propanoate (compound (1));
(S)-methyl-3-(1H-imidazol-4-yl)-2-(3-(5-(nitrooxy)pentanamido)propanamido) propanoate hydrochloride (compound 1a);
(S)-3-(1H-imidazol-4-yl)-2-(3-(5-(nitrooxy)pentanamido)propanamido)propanoic acid (compound (2));
(S)-3-(1H-imidazol-4-yl)-2-(3-(5-(nitrooxy)pentanamido)propanamido)propanoic acid 2,2,2-trifluoroacetate (compound (2a));
(S)-methyl-3-(1H-imidazol-4-yl)-2-(3-(6-(nitrooxy)hexanamido)propanamido) (compound (3));
(S)-methyl-3-(1H-imidazol-4-yl)-2-(3-(6-(nitrooxy)hexanamido)propanamido) 2,2,2-trifluoroacetate (compound (3a));
(S)-3-(1H-imidazol-4-yl)-2-(3-(6-(nitrooxy)hexanamido)propanamido)propanoic acid (to compound (4));
(S)-3-(1H-imidazol-4-yl)-2-(3-(6-(nitrooxy)hexanamido)propanamido)propanoic acid 2,2,2-trifluoroacetate (compound (4a));
(S)-methyl-3-(1H-imidazol-4-yl)-2-(3-(2-(2-(nitrooxy)ethoxy)acetamido) propanamido)propanoate (compound (5));
(S)-methyl-3-(1H-imidazol-4-yl)-2-(3-(2-(2-(nitrooxy)ethoxy)acetamido) propanamido)propanoate 2,2,2-trifluoroacetate (compound (5a));
(S)-3-(1H-imidazol-4-yl)-2-(3-(2-(2-(nitrooxy)ethoxy)acetamido)propanamido) propanoic acid (compound (6));
(S)-3-(1H-imidazol-4-yl)-2-(3-(2-(2-(nitrooxy)ethoxy)acetamido)propanamido) propanoic acid 2,2,2-trifluoroacetate (compound (6a));
(S)-methyl 2-(3-(2-((S)-2,3-bis(nitrooxy)propoxy)acetamido)propanamido)-3-(1H-imidazol-4-yl)propanoate (compound 7)
(S)-methyl 2-(3-(2-((S)-2,3-bis(nitrooxy)propoxy)acetamido)propanamido)-3-(1H-imidazol-4-yl)propanoate 2,2,2-trifluoroacetate (compound 7a)
(S)-2-(3-(2-((S)-2,3-bis(nitrooxy)propoxy)acetamido)propanamido)-3-(1H-imidazol-4-yl)propanoic acid (compound 8)
(S)-2-(3-(2-((S)-2,3-bis(nitrooxy)propoxy)acetamido)propanamido)-3-(1H-imidazol-4-yl)propanoic acid 2,2,2-trifluoroacetate (compound 8a)
(S)-methyl 2-(3-((5,6-bis(nitrooxy)hexanamido)propanamido)-3-(1H-imidazol-4-yl)propanoate (compound (9));
(S)-methyl 2-(3-((S)-5,6-bis(nitrooxy)hexanamido)propanamido)-3-(1H-imidazol-4-yl)propanoate 2,2,2-trifluoroacetate (compound (9a));
(S)-2-(3-((5,6-bis(nitrooxy)hexanamido)propanamido)-3-(1H-imidazol-4-yl)propanoic acid (compound (10));
(S)-2-(3-((S)-5,6-bis(nitrooxy)hexanamido)propanamido)-3-(1H-imidazol-4-yl)propanoic acid 2,2,2-trifluoroacetate (compound (10a));
(S)-2-(3-((S)-5,6-bis(nitrooxy)hexanamido)propanamido)-3-(1H-imidazol-4-yl)propanoic acid acetate (compound (10b)).
13. A composition comprising a carnosine analogue of formula (I) according to claim 1 and at least a further active ingredient selected from the group consisting of alpha adrenergic agonist, beta blocker, carbonic anhydrase inhibitor, prostaglandin analogs, non-steroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs.
14. A method of treating hypertensive glaucoma, normotensive glaucoma, and/or ocular hypertension, comprising administering to a subject in need thereof a carnosine analogue of formula (I) according to claim 1 .
15. A pharmaceutical formulation comprising a carnosine analogue according to claim 12 and an ophthalmically acceptable component and/or ophthalmically acceptable vehicle.
16. A method of treating hypertensive glaucoma, normotensive glaucoma, and/or ocular hypertension, comprising administering to a subject in need thereof a carnosine analogue according to claim 12 .
17. Pharmaceutical formulation comprising at least a carnosine analogue of formula (I) according to claim 1 and at least an ophthalmically acceptable component and/or ophthalmically acceptable vehicle.
18. Pharmaceutical formulation comprising at least a composition according to claim 13 and at least an ophthalmically acceptable component and/or ophthalmically acceptable vehicle.