Nitric oxide releasing steroids
The invention relates to nitrooxyderivative of corticosteroids of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof R—(Z) a —R x (I) wherein R is the corticosteroid residue of formula (II): wherein: R 1 is OH, R 2 —CH 3 , or R 1 and R 2 are taken together to form a group of formula (III) R 3 is Cl or F; R 4 is H or F; wherein R 1 , R 2 , R 3 and R 4 can be linked to the correspondent carbon atoms of the steroidal structure in position α or β; with the proviso that: when R 1 and R 2 are the group of formula (III) then R 3 is F and R 4 is H or F; The compounds are useful in the treatment of respiratory diseases, inflammatory diseases, dermatological diseases and ocular diseases.
1. A compound of formula (I) and pharmaceutically acceptable salts or stereoisomers thereof
R—(Z) a —R x (I)
wherein R is a corticosteroid residue of formula (II):
wherein:
R 1 and R 2 are taken together to form a group of formula (III)
R 3 is F and R 4 is H, R 1 , R 2 and R 3 are in position α;
wherein
a=0 and Z is absent,
R x is
C(O)—CH(R 1 )—NH-(T′—Y—ONO 2 )
wherein
R 1 is H
T′ is —C(O)—;
Y is selected from
a)
a straight or branched C 1 -C 10 alkylene,
a straight or branched C 1 -C 10 alkylene substituted with a —ONO 2 group.
2. A compound of formula (I) according to claim 1 and pharmaceutically acceptable salts or stereoisomers thereof selected from the group consisting of:
3. A medicament comprising a compound of formula (I) according to claim 1 .
4. A method of treating an ocular disease comprising administering to a subject the compound of formula (I) according to claim 1 , wherein the ocular disease is selected from the group consisting of: ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies.
5. A method of treating a respiratory disease, selected from asthma or chronic obstructive pulmonary disease (COPD), comprising administering to a subject the compound of formula (I) according to claim 1 .
6. A method of treating a dermatological disease, comprising administering to a subject the compound of formula (I) according to claim 1 , wherein the dermatological disease is selected from the group consisting of: dermatosis, atopic dermatitis, inflammation, eczema, erythema, papulation, scaling, erosion, oozing, crusting, pruritis, psoriasis, epidermalysis bullosa, erythema, hidradenitis suppurative, warts, diaper rash, and jock itch.
7. A pharmaceutical formulation comprising at least a compound of formula (I) as described in claim 1 and one or more pharmaceutical acceptable excipients.