EP

1. A compound having the structural formula I:

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

Q is (CH 2 ) m , (CH 2 ) m C 6-10 aryl, (CH 2 ) m C 5-10 heterocyclyl, (CH 2 ) m C 3-10 heterocycloalkyl, (CH 2 ) m C 3-8 cycloalkyl, C(halo) 2 , said cycloalkyl, heterocycloalkyl, aryl or heterocyclyl unsubstituted or substituted with 1-3 groups of R a ;

X represents O,

Y represents CH 2 ;

U represents H, C1-3 alkyl or is not present when W is ═O;

W represents OH or ═O, provided that U is not present when W is ═O;

R 1 represents (CH 2 ) p hydroxy, (CH 2 ) p CN, (CH 2 ) p CO 2 R 10 , (CH 2 ) n SO 3 R 6 , —(CH 2 ) p CF 2 SO 2 NH 2 , —(CH 2 ) p SO 2 NH 2 , —(CH 2 ) p CONHSO 2 R 2 —(CH 2 ) p CONHSO 2 R 2 , —(CH 2 ) p SO 2 NHCOR 2 , —(CH 2 ) p PO(OH) 2 , (CH 2 ) p CONHPO 2 R 6 , (CH 2 ) p CONHR 8 , (CH 2 ) p C 1-4 alkoxy, —(CH 2 ) p cycloalkyl, or (CH 2 ) n heterocyclyl, said heterocyclyl unsubstituted or substituted with 1 to 3 groups of R a and optionally containing an acidic hydroxyl group;

R 2 independently represents C 1-10 alkyl, (CH 2 ) m C 6-10 aryl, (CH 2 ) m C 5-10 heterocyclyl, (CH 2 ) m C 3-10 heterocycloalkyl, (CH 2 ) m C 3-8 cycloalkyl, O—C 1-10 alkyl, O—C 6-10 aryl, O—C 3-10 cycloalkyl, O—C 3-10 heterocycloalkyl, O—C 3-10 heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or hetrocyclyl unsubstituted or substituted with 1-3 groups of R a ;

R 3 and R 4 independently represents hydrogen, halogen, or C 1-6 alkyl, or R 3 and R 4 may be taken together to form a 3-7 membered carbon ring optionally interrupted with 1-2 heteroatoms chosen from O, S, SO, SO 2 , and NR 9 ;

R 6 and R 7 independently represents hydrogen, or C 1-4 alkyl;

R 8 represents hydrogen, acyl, or sulfonyl;

R 9 represents hydrogen, C 1-6 alkyl, said alkyl optionally substituted with 1-3 halogen, CN, OH, C 1-6 alkoxy, C 1-6 acyloxy or amino;

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

Z represents a C≡C, O, S, (C(R b ) 2 ) n , or CH═CH;

R b represents hydrogen, C 1-6 alkyl or halogen;

R a represents C 1-6 alkoxy, C 1-6 alkyl, CF 3 , nitro, amino, cyano, C 1-6 alkylamino, halogen, SC 1-6 alkyl, SC 6-10 aryl, SC 5-10 heterocyclyl, CO 2 R 6 , OC 6-10 aryl, OC 5-10 heterocyclyl, CH 2 OC 1-6 alkyl, CH 2 SC 1-6 alkyl, CH 2 Oaryl, CH 2 Saryl;

represents a double or single bond;

p represents 0-3;

n represents 0-4; and

m represents 0-8.

2. A compound in accordance with claim 1 wherein R 1 is (CH 2 ) p CN, (CH 2 ) p CO 2 R 10 , —(CH 2 ) p PO(OH) 2 , (CH 2 ) p CONHPO 2 R 6 , (CH 2 ) p CONHR 8 , or (CH 2 ) n heterocyclyl, said heterocyclyl unsubstituted or substituted with 1 to 3 groups of R a and all other variables are as originally described.

3. A compound in accordance with claim 2 wherein Z is a bond or S, Y is CH 2 and X is O, S or CH 2 .

4. A compound in accordance with claim 1 wherein R 1 is (CH 2 ) p CO 2 R 10 , X is O, Y are is CH 2 , Z is (C(R b ) 2 ) n , Q is (CH 2 )m, and R 2 is (CH 2 ) m C 6-10 aryl, said aryl unsubstituted or substituted with 1 to 3 groups of R a .

5. A compound in accordance with claim 2 wherein R 1 is (CH 2 ) m C 5-10 heterocyclyl, U is H, or C 1-3 alkyl, W is OH, Z is a bond or S, R 2 is (CH 2 ) m C 6-10 aryl, said aryl unsubstituted or substituted with 1 to 3 groups of R a , said heterocyclyl unsubstituted or substituted with 1 to 3 groups of R a and all other variables are as originally described.

6. A compound which is:

7-{(4S)-4-[(3R)-3-hydroxy-4-phenylbutyl]-2-oxo-1,3-oxazinan-3-yl}heptanoic acid;

5-(3-{(4R)-4-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazinan-3-yl}propyl)thiophene-2-carboxylic acid;

isopropyl 5-(3-{(4R)-4-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazinan-3-yl}propyl)thiophene-2-carboxylate;

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

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

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

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

5-(3-{(4R)-4-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazinan-3-yl}propyl)thiophene-2-carboxylic acid;

(4R)-4-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{3-[5-(2H-tetraazol-5-yl)thien-2-yl]propyl}-1,3-oxazinan-2-one;

(4S)-4-[(3R)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-3-{3-[5-(2H-tetraazol-5-yl)thien-2-yl]propyl}-1,3-oxazinan-2-one;

isopropyl 5-(3-{(4R)-4-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazinan-3-yl}propyl)thiophene-2-carboxylate;

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

(5E)-7-{(4S)-4-[(3R)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-2-oxo-1,3-oxazinan-3-yl}hept-5-enoic acid;

Isopropyl-7-{(4R)-4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-en-yl]-2-oxo-1,3-oxanzinan-3-yl}heptanoate;

7-{(4R)-4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-en-yl]-2-oxo-1,3-oxanzinan-3-yl}heptanoic acid;

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

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I, as recited in claim 1 .

8. 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 claim 1 , said compound administered in a topical formulation as a solution or suspension.

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

10. The method according to claim 9 in which the topical formulation optionally contains xanthan gum or gellan gum.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I, as recited in claim 6.

12. The compound according to claim 6 which is: 7-{(4S)-4-[(3R)-3-hydroxy-4-phenylbutyl]-2-oxo-1,3-oxazinan-3-yl}heptanoic acid or a pharmaceutically acceptable salt, enantiomer, diastereomer, or mixture thereof.

13. The compound according to claim 6 which is 5-(3-{(4R)-4-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazinan-3-yl}propyl)thiophene-2-carboxylic acid or a pharmaceutically acceptable salt, enantiomer, diastereomer, or mixture thereof.

14. The compound according to claim 6 which is isopropyl 5-(3-{(4R)-4-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazinan-3-yl}propyl)thiophene-2-carboxylate or a pharmaceutically acceptable salt, enantiomer, diastereomer, or mixture thereof.

15. The compound according to claim 6 which is 7-{(4R)-4-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazinan-3-yl}heptanoic acid; 7-{(4S)-4-[(3R)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-2-oxo-1,3-oxazinan-3-yl}heptanoic acid or a pharmaceutically acceptable salt, enantiomer, diastereomer, or mixture thereof.

16. The compound according to claim 6 which is isopropyl 7-{(4R)-4-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazinan-3-yl}heptanoate or a pharmaceutically acceptable salt, enantiomer, diastereomer, or mixture thereof.

17. The compound according to claim 6 which is (5E)-7-{(4R)-4-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazinan-3-yl}hept-5-enoic acid or a pharmaceutically acceptable salt, enantiomer, diastereomer, or mixture thereof.

18. The compound according to claim 6 which is (5E)-7-{(4S)-4-[(3R)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-2-oxo-1,3-oxazinan-3-yl}hept-5-enoic acid or a pharmaceutically acceptable salt, enantiomer, diastereomer, or mixture thereof.

19. The compound according to claim 6 which is Isopropyl-7-{(4R)-4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-en-yl]-2-oxo-1,3-oxanzinan-3-yl}heptanoate or a pharmaceutically acceptable salt, enantiomer, diastereomer, or mixture thereof.

20. The compound according to claim 6 which is 7-{(4R)-4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-en-yl]-2-oxo-1,3-oxanzinan-3-yl}heptanoic acid or a pharmaceutically acceptable salt, enantiomer, diastereomer, or mixture thereof.