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Last Updated: September 26, 2022

Claims for Patent: 7,273,946


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Summary for Patent: 7,273,946
Title:Prostaglandin derivatives
Abstract: Prostaglandin nitroderivatives having improved pharmacological activity and enhanced tolerability are described. They can be employed for the treatment of glaucoma and ocular hypertension.
Inventor(s): Ongini; Eninnio (Milan, IT), Chiroli; Valerio (Milan, IT), Benedini; Francesca (Milan, IT), Soldato; Piero Del (Milan, IT)
Assignee: Nicox S.A. (Valbonne, FR)
Application Number:11/029,698
Patent Claims: 1. A compound of general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof R--X--Y--ONO.sub.2 (I) wherein R is the prostaglandin residue of formula (II): ##STR00049## wherein the symbol represents a single bond or a double bond; L is selected from the following groups: ##STR00050## X is --O--, --S-- or --NH--; Y is a bivalent radical having the following meaning: a) straight or branched C.sub.1-C.sub.20 alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, --ONO.sub.2 or T, wherein T is --OC(O)(C.sub.1-C.sub.10 alkyl)--ONO.sub.2 or --O(C.sub.1-C.sub.10 alkyl)--ONO.sub.2; cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains T.sub.1, wherein T.sub.1 is straight or branched C.sub.1-C.sub.10 alkyl; ##STR00051## wherein n is an integer from 0 to 20, and n.sup.1 is an integer from 1 to 20; ##STR00052## wherein X.sub.1=--OCO-- or --COO-- and R.sub.2 is H or CH.sub.3; Z is --(CH).sub.n.sup.1-- or the bivalent radical defined above under b) n.sup.1 is as defined above and n.sup.2 is an integer from 0 to 2; ##STR00053## wherein: Y.sup.1 is --CH.sub.2--CH.sub.2--(CH.sub.2).sub.n.sup.2--; or CH.dbd.CH--(CH.sub.2).sub.n.sup.2--; Z is --(CH).sub.n.sup.1-- or the bivalent radical defined above under b) n.sup.1, n.sup.2, R.sup.2 and X.sub.1 are as defined above; ##STR00054## wherein: n.sup.1 and R.sup.2 are as defined above, R.sup.3 is H or --COCH.sub.3; with the proviso that when Y is selected from the bivalent radicals mentioned under b)-f), the --ONO.sub.2 group is bound to --(CH.sub.2).sub.n.sup.1; ##STR00055## wherein X.sub.2 is --O-- or --S--, n.sup.3 is an integer from 1 to 6 and R.sup.2 is as defined above; ##STR00056## wherein: n.sup.4 is an integer from 0 to 10; n.sup.5 is an integer from 1 to 10; R.sup.4, R.sup.5, R.sup.6, R.sup.7 are the same or different, and are H or straight or branched C.sub.1-C.sub.4 alkyl; wherein the --ONO.sub.2 group is linked to ##STR00057## wherein n.sup.5 is as defined above; Y.sup.2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from ##STR00058## ##STR00059##

2. A compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof wherein R, L, X are as defined in claim 1 and Y is a bivalent radical having the following meaning: a) straight or branched C.sub.1-C.sub.20 alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, --ONO.sub.2 or T, wherein T is --OC(O)(C.sub.1-C.sub.10 alkyl)--ONO.sub.2 or --O(C.sub.1-C.sub.10 alkyl)--ONO.sub.2; cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains T.sub.1, wherein T.sub.1 is straight or branched C.sub.1-C.sub.10 alkyl; ##STR00060## wherein n is an integer from 0 to 20, and n.sup.1 is an integer from 1 to 20; ##STR00061## wherein: n.sup.1 is as defined above and n.sup.2 is an integer from 0 to 2; ##STR00062## wherein: n.sup.1, n.sup.2, R.sup.2 and X.sub.1 are as defined above; Y.sup.1 is --CH.sub.2--CH.sub.2-- or --CH.dbd.CH--(CH.sub.2).sub.n.sup.2--; ##STR00063## wherein: n.sup.1 and R.sup.2 are as defined above, R.sup.3 is H or --COCH.sub.3; with the proviso that when Y is selected from the bivalent radicals mentioned under b)-f), the --ONO.sub.2 group is bound to --(CH.sub.2).sub.n.sup.1; ##STR00064## wherein X.sub.2 is --O-- or --S--, n.sup.3 is an integer from 1 to 6 and R.sup.2 is as defined above; ##STR00065## wherein: n.sup.4 is an integer from 0 to 10; n.sup.5 is an integer from 1 to 10; R.sup.4, R.sup.5, R.sup.6, R.sup.7 are the same or different, and are H or straight or branched C.sub.1-C.sub.4 alkyl; wherein the --ONO.sub.2 group is linked to ##STR00066## wherein n.sup.5 is as defined above; Y.sup.2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from ##STR00067## ##STR00068##

3. A compound of general formula (I) according to claim 1 or 2, wherein L is selected from the following groups: ##STR00069##

4. A compound of general formula (I) according to anyone of the claims from 1 to 3, wherein the residue R is selected from the group consisting of travoprost, unoprostone and cloprostenol;

5. A compound of general formula (I) according to claim 1 or 2 wherein the residue R is latanoprost.

6. A compound of general formula (I) according to anyone of the claims from 1 to 5, wherein X is --O-- or --S--.

7. A compound of general formula (I) according to anyone of the claims from 1 to 6, wherein Y is a bivalent radical having the following meaning: a) straight or branched C.sub.2-C.sub.6 alkylene, being optionally substituted with --ONO.sub.2 or T, wherein T is as defined in claim 1; ##STR00070## wherein n is an integer from 0 to 5, and n.sup.1 is an integer from 1 to 5; ##STR00071## wherein X.sub.2 is --O-- or --S--, n.sup.3 is 1, R.sup.2 is as defined in claim 1.

8. A compound of general formula (I) according to any one of claims 1 to 6 wherein Y is a bivalent radical having the following meaning: a) straight or branched C.sub.2-C.sub.6 alkylene being substituted with --ONO.sub.2 or T, wherein T is as defined in claim 1; ##STR00072## wherein n is 0, and n.sup.1 is 1; ##STR00073## wherein X.sub.2 is --O-- or --S--, n.sup.3 is 1, R.sup.2 is hydrogen;

9. A compound of formula (I) according to any one of claims 1 to 6 wherein Y is a bivalent radical having the following meaning: ##STR00074## wherein X.sub.1=--OCO-- or --COO-- and R.sup.2 is H or CH.sub.3; Z is --(CH).sub.n.sup.1-- or the bivalent radical defined in claim 1 under b) wherein n is an integer from 0 to 5; n.sup.1 is an integer from 1 to 5 and n.sup.2 is an integer from 0 to 2; ##STR00075## wherein: Y.sup.1 is --CH.sub.2--CH.sub.2--(CH.sub.2).sub.n.sup.2--; or --CH.dbd.CH--(CH.sub.2).sub.n.sup.2--; Z is --(CH).sub.n.sup.1-- or the bivalent radical defined above under b) n.sup.1, n.sup.2, R.sup.2 and X.sub.1 are as defined above; ##STR00076## wherein: n.sup.1 and R.sup.2 are as defined above, R.sup.3 is H or COCH.sub.3; with the proviso that when Y is selected from the bivalent radicals mentioned under b)-f), the --ONO.sub.2 group is bound to --(CH.sub.2).sub.n.sup.1; ##STR00077## wherein: n.sup.4 is an integer from 0 to 3; n.sup.5 is an integer from 1 to 3; R.sup.4, R.sup.5, R.sup.6, R.sup.7 are the same and are H; and wherein the --ONO.sub.2 group is linked to ##STR00078## Y.sup.2 is a 6 member saturated, unsaturated or aromatic heterocyclic ring, containing one or two atoms of nitrogen and selected for example from ##STR00079##

10. A compound according to claim 1, selected from the group consisting of: ##STR00080## ##STR00081## ##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094## ##STR00095##

11. A process for preparing a compound of general formula (I) as defined in claim 1, which process comprises: i) reacting a compound of formula (III) ##STR00096## wherein L is as defined in claim 1; P is H or a hydroxylic protecting group and W is --OH, Cl, or --OC(O)R.sub.1 wherein R.sub.1 is a linear or branched C.sub.1-C.sub.5 alkyl; with a compound of formula (IV) Z-Y-Q wherein Y is as defined in claim 1, Z is HX or Z.sub.1, being X as defined in claim 1 and Z.sub.1 selected from the group consisting of: chlorine, bromine, iodine, mesyl, tosyl; Q is --ONO.sub.2 or Z.sub.1 and ii) when Q is Z.sub.1, converting the compound obtained in the step i) into nitro derivative by reaction with a nitrate source and iii) optionally deprotecting the compounds obtained in step i) or ii).

12. A compound of general formula (I) according to any one of claims 1-10 for use as a medicament.

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of general formula (I) and/or a salt or stereoisomer thereof as defined in any one of claims 1-10.

14. A pharmaceutical composition according to claim 13 in a suitable form for topical administration.

15. A pharmaceutical composition according to claim 13 or 14 for the treatment of glaucoma and ocular hypertension.

16. A pharmaceutical composition according to claim 13, wherein the compound of general formula (I) is administered as a solution, suspension or emulsion in an ophthalmically acceptable vehicle.

17. A method for treating glaucoma or ocular hypertension, said method comprising contacting an effective intraocular pressure reducing amount of a pharmaceutical composition according to any one of claims 13-16, with the eye in order to reduce eye pressure and to maintain said pressure on a reduced level.

18. A pharmaceutical composition comprising a mixture of a compound of formula (I) as defined in claim 1 and (i) a beta-blocker or (ii) a carbonic anhydrase inhibitor or (iii) an adrenergic agonist or a nitrooxy derivative thereof.

19. A pharmaceutical composition comprising a mixture of a compound of formula (I) as defined in claim 1 and timolol or a nitrooxy derivative thereof.

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