1,5-distributed pyrrolid-2-one derivatives for use as ep4 receptor agonists in the teatment of eye diseases such as glaucoma

1 . A method for treating ocular hypertension or glaucoma comprising administration to a patient in need of such treatment a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug or mixture thereof, wherein,

X is (CH 2 ) n , O or S;

Y represents (C(R b ) 2 ) n , triple bond,

R 1 represents hydroxy, CN, CHO, NHSO 2 R 6 , CONHSO 2 R 6 , CON(R 6 ) 2 hydroxymethylketone, (CH 2 ) p CO 2 R 6 , (CH 2 ) n SO 3 R 6 , C 1-4 alkoxy, or (CH 2 ) n C 5-10 heterocyclyl, said heterocyclyl unsubstituted or substituted with 1 to 3 groups of R a and optionally containing an acidic hydroxyl group, with the proviso that when X is a bond R 1 is not (CH 2 ) p CO 2 R 6 , C 1-4 alkoxy, —(CH 2 ) n NR 6 R 7 , CHO, NHSO 2 R 6 , CONHSO 2 R 6 , CON(R 6 ) 2 , or hydroxymethylketone;

R 2 and R 3 independently represents hydrogen, or C 1-4 alkyl;

R 6 and R 7 independently represents hydrogen, or C 1-6 alkyl, C 3-10 cyclcoalkyl, (CH 2 ) p C 6-10 aryl, (CH 2 ) p C 5-10 heterocyclyl, CR 2 R 3 OC(O)OC 3-10 cyclalkyl or CR 2 R 3 OC(O)O C 1-10 alkyl;

Ar 2 independently represent (CH 2 ) m C 6-10 aryl, (CH 2 ) m C 5-10 heteroaryl, (CH 2 ) m C 3-10 heterocycloalkyl, (CH 2 ) m C 3-8 cycloalkyl said cycloalkyl, heterocycloalkyl, aryl or heteroaryl unsubstituted or substituted with 1-3 groups of R a ;

R a represents C 1-6 alkoxy, C 1-6 alkyl, CF 3 , nitro, amino, cyano, C 1-6 alkylamino, or halogen;

R b independently represents H, halogen, C 1-6 alkyl, C 3-6 cylcoalkyl or

represents a double or single bond;

p represents 1-3;

n represents 0-4; and

m represents 0-8.

2 . The method according to claim 1 wherein R 1 is CN, (CH 2 ) n C 5-10 heterocyclyl, (CH 2 ) p CO 2 R 6 or (CH 2 ) n SO 3 R 6 , said heterocyclyl unsubstituted or substituted with 1 to 3 groups of R a and all other variables are as originally described.

3 . The method according to claim 2 wherein X and Y are (CH 2 ) n ,.

4 . The method according to claim 1 wherein Y is a double bond as described by

and all other variables are as originally described.

5 . The method according to claim 1 wherein R 1 is (CH 2 ) n C 5-10 heterocyclyl, said heterocyclyl unsubstituted or substituted with 1 to 3 groups of R a , X is (CH 2 ) n , and Y is (CH 2 ) n or C(halo) 2 .

6 . The method according to claim 1 wherein R 1 is (CH 2 ) p CO 2 R 6 , X is (CH 2 ) n , and Y is (CH 2 ) n .

7 . The method according to claim 1 wherein Ar 2 is (CH 2 ) m C 6-10 aryl, said aryl unsubstituted or substituted with 1 to 3 groups of R a and all other variables are as originally described.

8 . The method according to claim 1 wherein R 1 is a tetrazole unsubstituted or substituted with an R a group X is (CH 2 ) n , and Y is (CH 2 ) n , C(halo) 2 or a double bond as described by

9 . The method according to claim 1 wherein Ar 2 is a phenyl unsubstituted or substituted with 1 to 3 groups of R a , R 1 is tetrazolyl, said tetrazolyl unsubstituted or substituted with a R a group and phenyl is unsubstituted or substituted with 1-3 groups of R a , and all other variables are as originally described.

10 . The method according to claim wherein the compound is:

(5R)-5-[(1E)-3-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-1-{4-[(1-methyl-1H-tetrazol-5-yl)]butyl}pyrrolidin-2-one,

4-{(2R)-2-[(1E)-3-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl cyanate,

3-[4-{(2R)-2-[(1E)-3-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl)]propanoic acid,

[4-{(2R)-2-[(1E)-3-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl)]methanesulfonic acid,

(5R)-5-[(1E)-3-hydroxy-4,4-fluoro-4-phenylbut-1-enyl]-1-{4-[1H-tetrazol-5-ylmethyl)butyl}pyrrolidin-2-one,

[4-{(2R)-2-[(1E)-3-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl)]acetic acid,

(5R)-5-[(1E)-3-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-1-{4-[(1-methyl-1H-tetrazol-5-yl)thio]butyl}pyrrolidin-2-one,

(5R)-5-[(1E)-3-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-1-[4-(1H-tetrazol-5-ylthio)butyl]pyrrolidin-2-one,

3-[4-{(2R)-2-[(1E)-3-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl)thio]propanoic acid,

[4-{(2R-2-[(1E)-3-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl)thio]methanesulfonic acid,

(5R)-5-[(1E)-3-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-1-[4-(methylsulfonyl)butyl]-pyrrolidin-2-one,

[4-{(2R-2-[(1E)-3-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl)thio]acetic acid,

(5R)-5[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-1-[6-(1H-tetrazol-5-yl)hexyl]pyrrolidin-2-one,

7-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}heptanoic acid,

isopropyl 7-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}heptanoate,

7-{(2S)-2-[(3R)4,4-difluoro-3-hydroxy-4-phenylbutyl]-5-oxopyrrolidin-1-yl}heptanoic acid,

(5Z)-7-{(R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}hept-5-enoic acid,

isopropyl (5Z)-7-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}hept-5-enoate,

7-{(2R)-2-[(1E,3R)-4-(3-chlorophenyl)-4,4-difluoro-3-hydroxybut-1-enyl]-5-oxopyrrolidin-1-yl}heptanoic acid,

isopropyl 7-{(2R)-2-[(1E,3R)-4-(3-chlorophenyl)-4,4-difluoro-3-hydroxybut-1-enyl]-5-oxopyrrolidin-1-yl}heptanoate,

7-((2R)-2-{(1E,3R)-4,4-difluoro-3-hydroxy-4-[3-trifluoromethyl)phenyl]but-1-enyl}-5-oxopyrrolidin-1-yl)heptanoic acid,

isopropyl 7-{(2R)-2-{(1E,3R)-4,4-difluoro-3-hydroxy-4-[3-(trifluoromethyl)phenyl]but-1-enyl}-5-oxopyrrolidin-1-yl)heptanoate,

cyclopentyl 7-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}heptanoate,

7-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-3-methyl-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}heptanoic acid,

isopropyl 7-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-3-methyl-4-phenylbut-1-enyl]-5-oxopyirolidin-1-yl}heptanoate,

isobutyl 7-{(2R)-2-[(1E,3R)-4, fluoro-3-hydroxy-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}heptanoate,

cyclohexyl 7-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}heptanoate,

(5R)-5-[(1E)-(3R)-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-1-{4-[(1-methyl-1H-tetrazol-5-yl)]butyl}pyrrolidin-2-one,

4-{(2R)-2-[(1E)-(3R)-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl cyanate,

3-[4-{(2R}2-[(1E)-(3R)-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl)]propanoic acid,

[4{(2R)-2-[(1E)-(3R)-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl)]methanesulfonic acid,

(5R)-5-[(1E)-(3R)-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-1-{4-[1H-tetrazol-5-ylmethyl)butyl}pyrrolidin-2-one,

[4-{(2R)-2-[(1E)-(3R)-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl)]acetic acid,

(5R)-5-[(1E)-(3R)-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-1-{4-[(1-methyl-1H-tetrazol-5-yl)thio]butyl}pyrrolidin-2-one,

(5R)-5-[(1E)-(3R)-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-1-[4-(1H-tetrazol-5-ylthio)butyl]pyrrolidin-2-one,

3-[4-{(2R)-2-[(1E)-(3R)-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl)thio]propanoic acid,

[4-{(2R)-2-[(1E)-(3R)-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl)thio]methanesulfonic acid,

(5R)-5-[(1E)-(3R)-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-1-[4-(methylsulfonyl)butyl]-pyrrolidin-2-one,

[4{(2R)-2-[(1E)-(3R)-hydroxy-4,4-difluoro-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl)thio]acetic acid, or

(5R)-5 [(1E)-4,4-difluoro-(3R)-hydroxy-4-phenylbut-1-enyl]-1-[6-(1H-tetrazol-5-yl)hexyl]pyrrolidin-2-one, a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug, or mixture thereof.

11 . A method according to claim 1 , which is administered in a topical formulation as a solution or suspension.

12 . A method according to claim 1 wherein a second active ingredient belonging to the group consisting of: O-adrenergic blocking agent, parasympatho-mimetic agent, sympathomimetic agent, carbonic anhydrase inhibitor, Maxi-K channel blocker, and a prostaglandin, hypotensive lipid, neuroprotectant, and 5-HT2 receptor agonist is added to the topical formulation.

13 . A method according to claim 12 wherein the O-adrenergic blocking agent is timolol, betaxolol, levobetaxolol, carteolol, or levobunolol; the parasympathomimetic agent is pilocarpine; the sympathomimetic agent is epinephrine, brimonidine, iopidine, clonidine, or para-aminoclonidine, the carbonic anhydrase inhibitor is dorzolamide, acetazolamide, metazolamide or brinzolamide; the prostaglandin is latanoprost, travaprost, unoprostone, rescula, or S1033, the hypotensive lipid is lumigan, the neuroprotectant is eliprodil, R-eliprodil or memantine; and the 5-HT2 receptor agonist is 1-(2-aminopropyl)-3-methyl-1H-imdazol-6-ol fumarate or 2-(3-chloro-6-methoxy-indazol-1-yl)-1-methyl-ethylamine.

14 . A method for treating macular edema, macular degeneration, treating dry eye, increasing retinal and optic nerve head blood velocity, increasing retinal and optic nerve oxygen tension or providing a neuroprotection comprising administration to a patient in need of such treatment a pharmaceutically effective amount of a compound of formula I as recited in claim 1

15 . The method according to claim 14 wherein the compound of formula I is applied as a topical formulation and an active ingredient belonging to the group consisting of β-adrenergic blocking agent, parasympatho-mimetic agent, sympathomimetic agent, carbonic anhydrase inhibitor, Maxi-K channel blocker and a prostaglandin, hypotensive lipid, neuroprotectant, and 5-HT2 receptor agonist is added to the formulation.

16 . A method according to claim 15 wherein the the β-adrenergic blocking agent is timolol, betaxolol, levobetaxolol, carteolol, or levobunolol; the parasympathomimetic agent is pilocarpine; the sympathornimetic agent is epinephrine brimonidine, iopidine, clonidine, or para-aminoclonidine, the carbonic anhydrase inhibitor is dorzolamide, acetazolamide, metazolamide or brinzolamide; the prostaglandin is latanoprost, travaprost, unoprostone, rescula, or S1033, the hypotensive lipid is lumigan, the neuroprotectant is eliprodil, R-eliprodil or memantine; and the 5-HT2 receptor agonist is 1-(2-aminopropyl)-3-methyl-1H-imdazol-6-ol fumarate or 2-(3-chloro-6-methoxy-indazol-1-yl)-1-methyl-ethylamine.

17 . A compound of structural formula I:

or a pharmaceutically acceptable salt, enantiomer, diastereomer, pro drug or mixture thereof, wherein

X is (CH 2 ) n , O or S;

Y represents (C(R b ) 2 ) n , triple bond,

Ar 2 independently represent (CH 2 ) m C 6-10 aryl, (CH 2 ) m C 5-10 heteroaryl, (CH 2 ) m C 3-10 heterocycloalkyl, (CH 2 ) m C 3-8 cycloalkyl said cycloalkyl, heterocycloalkyl, aryl or heteroaryl unsubstituted or substituted with 1-3 groups of R a ;

R a represents C 1-6 alkoxy, C 1-6 alkyl, CF 3 , nitro, amino, cyano, C 1-6 alkylamino, or halogen;

R b independently represents H, halogen, C 1-6 alkyl, C 3-6 cylcoalkyl or

represents a double or single bond;

n represents 0-4; and

m represents 0-8.

18 . The compound according to claim 17 wherein X and Y are (CH 2 ) n ,

represents a double bond; and AR 2 is phenyl.

19 . The compound according to claim 18 wherein X is (CH 2 ) n and n is 1 and Y is (CH 2 ) n and n is 3.

20 . Use of a compound of formula I, as defined in any one of claims 1 to 10 , or a pharmaceutically acceptable salt, enantiomer, diasteromer, prodrug, or mixture thereof, in the manufacture of a medicament for treating hypertension or glaucoma

21 . A pharmaceutical composition for treating hypertension or glaucoma comprising a therapeutically effective amount of a compound of formula I, as defined in any one of claims 1 to 10 , or a pharmaceutically acceptable salt, enantiomer, diasteromer, prodrug, or mixture thereof, in association with a pharmaceutically acceptable carrier.

22 . A composition according to claim 21 in a form for topical administration as a solution or suspension and further comprising a second active ingredient as defined in claim 12 or 13 .

23 . Use of a compound of formula I, as defined in any one of claims 1 to 10 , or a pharmaceutically acceptable salt, enantiomer, diasteromer, prodrug, or mixture thereof, in the manufacture of a medicament for treating macular edema, macular degeneration, dry eye, increasing retinal and optic nerve velocity, increasing retinal and optic nerve oxygen tension or providing a neuroprotection.

24 . A pharmaceutical composition for treating macular edema, macular degeneration, dry eye, increasing retinal and optic nerve velocity, increasing retinal and optic nerve oxygen tension or providing a neuroprotection comprising a therapeutically effective amount of a compound of formula I, as defined in any one of claims 1 to 10 , or a pharmaceutically acceptable salt, enantiomer, diasteromer, prodrug, or mixture thereof, in association with a pharmaceutically acceptable carrier.

25 . A composition according to claim 24 in a form for topical administration and further comprising an active ingredient as defined in claim 15 or 16 .

26 . A compound of claim 17 , 18 or 19 for use in medicinal therapy.