Claims for Patent: 7,273,946

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):	Eninnio Ongini, Valerio Chiroli, Francesca Benedini, Piero Del Soldato
Assignee:	Nicox SA
Application Number:	US11/029,698
Patent Claims:	1. A compound of general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof R—X—Y—ONO2 (I) wherein R is the prostaglandin residue of formula (II): wherein the symbol represents a single bond or a double bond; L is selected from the following groups: X is —O—, —S— or —NH—; Y is a bivalent radical having the following meaning: a) straight or branched C1-C20 alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO2 or T, wherein T is —OC(O)(C1-C10 alkyl)—ONO2 or —O(C1-C10 alkyl)—ONO2; cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains T1, wherein T1 is straight or branched C1-C10 alkyl; wherein n is an integer from 0 to 20, and n1 is an integer from 1 to 20; wherein X1=—OCO— or —COO— and R2 is H or CH3; Z is —(CH)n 1— or the bivalent radical defined above under b) n1 is as defined above and n2 is an integer from 0 to 2; wherein: Y1 is —CH2—CH2—(CH2)n 2—; or CH═CH—(CH2)n 2—; Z is —(CH)n 1— or the bivalent radical defined above under b) n1, n2, R2 and X1 are as defined above; wherein: n1 and R2 are as defined above, R3 is H or —COCH3; with the proviso that when Y is selected from the bivalent radicals mentioned under b)-f), the —ONO2 group is bound to —(CH2)n 1; wherein X2 is —O— or —S—, n3 is an integer from 1 to 6 and R2 is as defined above; wherein: n4 is an integer from 0 to 10; n5 is an integer from 1 to 10; R4, R5, R6, R7 are the same or different, and are H or straight or branched C1-C4 alkyl; wherein the —ONO2 group is linked to wherein n5 is as defined above; Y2 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 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 C1-C20 alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO2 or T, wherein T is —OC(O)(C1-C10 alkyl)—ONO2 or —O(C1-C10 alkyl)—ONO2; cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains T1, wherein T1 is straight or branched C1-C10 alkyl; wherein n is an integer from 0 to 20, and n1 is an integer from 1 to 20; wherein: n1 is as defined above and n2 is an integer from 0 to 2; wherein: n1, n2, R2 and X1 are as defined above; Y1 is —CH2—CH2— or —CH═CH—(CH2)n 2—; wherein: n1 and R2 are as defined above, R3 is H or —COCH3; with the proviso that when Y is selected from the bivalent radicals mentioned under b)-f), the —ONO2 group is bound to —(CH2)n 1; wherein X2 is —O— or —S—, n3 is an integer from 1 to 6 and R2 is as defined above; wherein: n4 is an integer from 0 to 10; n5 is an integer from 1 to 10; R4, R5, R6, R7 are the same or different, and are H or straight or branched C1-C4 alkyl; wherein the —ONO2 group is linked to wherein n5 is as defined above; Y2 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 3. A compound of general formula (I) according to claim 1 or 2, wherein L is selected from the following groups: 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 C2-C6 alkylene, being optionally substituted with —ONO2 or T, wherein T is as defined in claim 1; wherein n is an integer from 0 to 5, and n1 is an integer from 1 to 5; wherein X2 is —O— or —S—, n3 is 1, R2 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 C2-C6 alkylene being substituted with —ONO2 or T, wherein T is as defined in claim 1; wherein n is 0, and n1 is 1; wherein X2 is —O— or —S—, n3 is 1, R2 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: wherein X1=—OCO— or —COO— and R2 is H or CH3; Z is —(CH)n 1— or the bivalent radical defined in claim 1 under b) wherein n is an integer from 0 to 5; n1 is an integer from 1 to 5 and n2 is an integer from 0 to 2; wherein: Y1 is —CH2—CH2—(CH2)n 2—; or —CH═CH—(CH2)n 2—; Z is —(CH)n 1— or the bivalent radical defined above under b) n1, n2, R2 and X1 are as defined above; wherein: n1 and R2 are as defined above, R3 is H or COCH3; with the proviso that when Y is selected from the bivalent radicals mentioned under b)-f), the —ONO2 group is bound to —(CH2)n 1; wherein: n4 is an integer from 0 to 3; n5 is an integer from 1 to 3; R4, R5, R6, R7 are the same and are H; and wherein the —ONO2 group is linked to Y2 is a 6 member saturated, unsaturated or aromatic heterocyclic ring, containing one or two atoms of nitrogen and selected for example from 10. A compound according to claim 1, selected from the group consisting of: 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) wherein L is as defined in claim 1; P is H or a hydroxylic protecting group and W is —OH, Cl, or —OC(O)R1 wherein R1 is a linear or branched C1-C5 alkyl; with a compound of formula (IV) Z-Y-Q wherein Y is as defined in claim 1, Z is HX or Z1, being X as defined in claim 1 and Z1 selected from the group consisting of: chlorine, bromine, iodine, mesyl, tosyl; Q is —ONO2 or Z1 and ii) when Q is Z1, 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.