Quinone based nitric oxide donating compounds for ophthalmic use
View Patent ↗The present invention relates to nitric oxide donor compounds having a quinone based structure, to processes for their preparation and to their use in the treatment and/or prophylaxis of glaucoma and ocular hypertension.
1. A compound of formula (I)
or stereoisomers thereof, wherein:
R 1 is selected from H, methyl, methoxy;
R 2 is H or methyl;
R 3 is selected from H, methyl, methoxy;
or R 1 and R 3 together form —CH═CH—CH═CH—;
R 4 and R 5 are methyl and n is 1, or
R 4 is H, R 5 is selected from phenyl, para-fluorophenyl, para-methoxyphenyl, para-isopropylphenyl, para-trifluoromethyl phenyl or para-methylphenyl and n is 2;
m is an integer from 1 to 10;
p is 0 or 1;
R 6 is H or methyl.
2. A compound of formula (I) according to claim 1 wherein
R 2 is methyl;
R 4 and R 5 are methyl and n is 1.
3. A compound of formula (I) according to claim 1 wherein
R 2 is methyl;
R 4 is H, R 5 is selected from phenyl, para-fluorophenyl, para-methoxyphenyl, para-isopropylphenyl,
para-trifluoromethylphenyl or para-methylphenyl and n is 2.
4. A compound of formula (I) according to claim 2 wherein
R 1 and R 3 are methyl.
5. A compound of formula (I) according to claim 2 wherein
R 1 and R 3 are methoxy.
6. A compound of formula (I) according to claim 2 wherein R 1 and R 3 together form —CH═CH—CH═CH—.
7. A compound of formula (I) according to claim 2 wherein R 1 is methyl and R 3 is methoxy.
8. A compound of formula (I) according to claim 2 wherein R 1 is methoxy and R 3 is methyl.
9. A compound of formula (I) according to claim 4 wherein p is 0 and R 6 is H.
10. A compound of formula (I) according to claim 4 wherein p is 1.
11. A compound of formula (I) according to claim 3 wherein R 1 and R 3 are methyl.
12. A compound of formula (I) according to claim 3 wherein
R 1 and R 3 are methoxy.
13. A compound of formula (I) according to claim 3 wherein R 1 and R 3 together form —CH═CH—CH═CH—.
14. A compound of formula (I) according to claim 3 wherein R 1 is methyl and R 3 is methoxy.
15. A compound of formula (I) according to claim 3 wherein R 1 is methoxy and R 3 is methyl.
16. A compound of formula (I) according to claim 11 wherein p is 0 and R 6 is H.
17. A compound of formula (I) according to claim 11 wherein p is 1.
18. A compound of formula (I) according to claim 1 selected from:
4-(nitrooxy)butyl 3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanoate (Compound 1);
6-(nitrooxy)hexyl 3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanoate (Compound 2);
6-(nitrooxy)hexyl 4-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanoate (Compound 3);
4-(nitrooxy)butyl 3-methyl-3-(3-methyl-1,4-dioxo-1,4-dihydro naphthalene-2-yl)butanoate (Compound 4);
6-(nitrooxy)hexyl 4-(4-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanoate (Compound 5);
4-(nitrooxy)butyl 4-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanoate (Compound 6);
4-(nitrooxy)butyl 4-(4-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanoate (Compound 7);
(5S,6R)-5,6-bis(nitrooxy)heptyl 3-methyl-3-(2,4,5-trimethyl-3,6-dioxo cyclohexa-1,4-dienyl)butanoate (Compound 8);
4-(nitrooxy)butyl 4-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienyl)-4-phenylbutanoate (Compound 9);
5,6-bis(nitrooxy)hexyl-3-methyl 3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanoate (Compound 10)
5,6-bis(nitrooxy)hexyl 3-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienyl)-3-methylbutanoate (Compound 11)
4-(nitrooxy)butyl 3-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienyl)-3-methylbutanoate (Compound 12)
5,6-bis(nitrooxy)hexyl 4-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienyl)-4-phenylbutanoate (Compound 13)
5,6-bis(nitrooxy)hexyl 4-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanoate (Compound 14)
(S)-5,6-bis(nitrooxy)hexyl 3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanoate (Compound 15)
(R)-5, 6-bis(nitrooxy)hexyl 3-methyl-3-(2, 4, 5-trimethyl-3, 6-dioxocyclohexa-1,4-dienyl)butanoate (Compound 16)
(S)-5,6-bis(nitrooxy)hexyl-3-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienyl)-3-methylbutanoate (Compound 17),
and stereoisomers thereof.
19. A method for treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and/or ocular hypertension comprising administering to a subject in need thereof the compound of formula (I).
20. A method for treating age related macular degeneration, diabetic retinopathy, macular degeneration, inflammatory retinal disease, and/or uveitis comprising administering to a subject in need thereof the compound according to claim 1 .
21. An ophthalmic composition comprising a compound of formula (I) according to claim 1 and at least an ophthalmically acceptable component and/or ophthalmically acceptable vehicle.
22. A composition comprising a compound of formula (I) according to claim 1 and one or more further active ingredients selected from alpha adrenergic agonists, beta blockers, carbonic anhydrase inhibitors, prostaglandin analogs, non-steroidal anti-inflammatory drugs, or a steroidal anti-inflammatory drugs.
23. A method for treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and/or ocular hypertension comprising administering to a subject in need thereof of composition according to claim 22 .
24. A method for treating age related macular degeneration, diabetic retinopathy, macular degeneration, inflammatory retinal disease, and/or uveitis comprising administering to a subject in need thereof the composition according to claim 21 .
25. An ophthalmic composition comprising a composition according to claim 22 and at least an ophthalmically acceptable component and/or ophthalmically acceptable vehicle.