EP4 Receptor Agonist, Compositions and Methods Thereof

Abstract

This invention relates to potent selective agonists of the EP 4 subtype of prostaglandin E2 receptors, their use or a formulation thereof in the treatment of glaucoma and other conditions, which are related to elevated intraocular pressure in the eye of a patient. This invention further relates to the use of the compounds of this invention for mediating the bone modeling and remodeling processes of the osteoblasts and osteoclasts.

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 and Y independently represent CH 2 , O, NR 9  or S, provided however, that X and Y are not O, NR 9  or S at the same time; 
         U represents H, C 1-3  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 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, (CH 2 ) p -hydroxymethylketone 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, provided that when R 2  is O—C 1-10 alkyl, O—C 6-10 aryl, O—C 3-10 cycloalkyl, O—C 3-10  heterocycloalkyl, or O—C 3-10  heterocycloalkyl, R 3  and R 4  are not halogen, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heterocyclyl 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  cyclcoalkyl, (CH 2 )pC 6-10  aryl, (CH 2 )pC 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 triple bond, O, S, (C(R b ) 2 ) n , or Ch=CH; 
         R b  represents hydrogen, C1-6 alkyl or halogen; 
         R a  represents C 1-6  alkoxy, C 1-6  alkyl, CF 3 ; nitro, amino, cyano, C 1-6  alkylamino, halogen, or Ra further represents for aryls and heterocyclyl, 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 and Y are CH 2 , Z is (C(R b ) 2 ) p , Q is (CH 2 ) m , R 3  and R 4  are halogen, 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-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}heptanoic acid;   7-{(4R)-4-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazinan-3-yl}heptanoic acid;   7-{(4R)-4-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazinan-3-yl}heptanoic acid;   7-{(2R)-2-[(3R)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-6-oxopiperidin-1-yl}heptanoic acid;   7-{(4S)-4-[(3R)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-2-oxo-1,3-oxazinan-3-yl}heptanoic acid;   7-{(4S)-4-[(3R)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-2-oxo-1,3-thiazinan-3-yl}heptanoic acid;   7-{(2R)-2-[(3R)-3-hydroxy-4-phenylbutyl]-6-oxopiperidin-1-yl}heptanoic acid;   7-{(4S)-4-[(3R)-3-hydroxy-4-phenylbutyl]-2-oxo-1,3-oxazinan-3-yl}heptanoic acid;   7-{(4S)-4-[(3R)-3-hydroxy-4-phenylbutyl]-2-oxo-1,3-thiazinan-3-yl}heptanoic acid;   isopropyl 7-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}heptanoate;   isopropyl 7-{(4R)-4-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazinan-3-yl}heptanoate;   isopropyl 7-{(4R)-4-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazinan-3-yl}heptanoate;   (6R)-6-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-1-[6-(2H-tetraazol-5-yl)hexyl]piperidin-2-one;   (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;   (4R)-4-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-[6-(2H-tetraazol-5-yl)hexyl]-1,3-thiazinan-2-one;   (5S)-5-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-4-[6-(2H-tetraazol-5-yl)hexyl]morpholin-3-one;   (6S)-6-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-1-[6-(2H-tetraazol-5-yl)hexyl]piperazin-2-one;   (5S)-5-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-4-[6-(2H-tetraazol-5-yl)hexyl]thiomorpholin-3-one;   5-(3-{(2R)-2-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}propyl)thiophene-2-carboxylic 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;   5-(3-{(4R)-4-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazinan-3-yl}propyl)thiophene-2-carboxylic acid;   5-(3-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}propyl)thiophene-2-carboxylic acid;   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;   5-(3-{(4R)-4-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazinan-3-yl}propyl)thiophene-2-carboxylic acid;   (6R)-6-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-1-{3-[5-(2H-tetraazol-5-yl)thien-2-yl]propyl}piperidin-2-one;   (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;   (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-thiazinan-2-one;   (6R)-6-[(3R)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-1-{3-[5-(2H-tetraazol-5-yl)thien-2-yl]propyl}piperidin-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;   (4S)-4-[(3R)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-3-{3-[5-(2H-tetraazol-5-yl)thien-2-yl]propyl}-1,3-thiazinan-2-one;   isopropyl 5-(3-{(2R)-2-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}propyl)thiophene-2-carboxylate;   isopropyl 5-(3-{(4R)-4-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazinan-3-yl}propyl)thiophene-2-carboxylate;   isopropyl 5-(3-{(4R)-4-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazinan-3-yl}propyl)thiophene-2-carboxylate;   isopropyl 5-(3-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}propyl)thiophene-2-carboxylate;   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;   isopropyl 5-(3-{(4R)-4-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazinan-3-yl}propyl)thiophene-2-carboxylate;   (5E)-7-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}hept-5-enoic acid;   (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-{(4R)-4-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazinan-3-yl}hept-5-enoic acid;   (5E)-7-{(2R)-2-[(3R)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-6-oxopiperidin-1-yl}hept-5-enoic acid;   (5E)-7-{(45)-4-[(3R)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-2-oxo-1,3-oxazinan-3-yl}hept-5-enoic acid;   (5E)-7-{(45)-4-[(3R)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-2-oxo-1,3-thiazinan-3-yl}hept-5-enoic acid;   2-(3-{(2R)-2-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}propyl)-1,3-thiazole-5-carboxylic acid;   5-(3-{(2R)-2-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}propyl)-1,3-thiazole-2-carboxylic acid;   5-(3-{(2R)-2-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}propyl)-1,3-oxazole-2-carboxylic acid;   2-(3-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}propyl)-1,3-oxazole-5-carboxylic acid;   5-(3-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}propyl)-1H-imidazole-2-carboxylic acid;   2-(3-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}propyl)-1H-imidazole-5-carboxylic acid;   2-(3-{(2R)-2-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}propyl)-1,3-oxazole-5-carboxylic acid;   5-(3-{(2R)-2-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}propyl)-1,2λ 5 ,5λ 5 -oxadiazole-2-carboxylic acid;   5-(3-{(2R)-2-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}propyl)-4H-1,2,4-triazole-3-carboxylic acid;   5-((1E)-3-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}prop-1-enyl)thiophene-2-carboxylic acid;   5-(3-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}prop-1-ynyl)thiophene-2-carboxylic acid;   5-((1Z)-3-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}prop-1-enyl)thiophene-2-carboxylic acid;   (6R)-6-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-1-{(2Z)-4-[(1H-tetraazol-5-ylmethyl)thio]but-2-enyl}piperidin-2-one;   [(4-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}but-2-ynyl)thio]acetic acid;   [((2Z)-4-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}but-2-enyl)thio]acetic acid;   [(4-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}butyl)thio]acetic acid;   (4-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}butoxy)acetic acid;   3-[(3-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}propyl)thio]propanoic acid;   7-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-3-methyl-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}heptanoic acid;   7-{(2R)-2-[(1E,3S)-4,4-difluoro-3-hydroxy-3-methyl-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}heptanoic acid;   7-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-(2-naphthyl)but-1-enyl]-6-oxopiperidin-1-yl}heptanoic acid;   (6R)-6-[(1E,3R)-4,4-difluoro-3-hydroxy-3-methyl-4-phenylbut-1-enyl]-1-[6-(1H-tetraazol-5-yl)hexyl]piperidin-2-one;   (6R)-6-[(1E,3S)-4,4-difluoro-3-hydroxy-3-methyl-4-phenylbut-1-enyl]-1-[6-(1H-tetraazol-5-yl)hexyl]piperidin-2-one;   7-{(2R)-2-[(1E,3R)-4-(1-benzothien-2-yl)-4,4-difluoro-3-hydroxybut-1-enyl]-6-oxopiperidin-1-yl}heptanoic acid;   (6R)-6-[(3R)-4,4-difluoro-3-hydroxy-3-methyl-4-phenylbutyl]-1-[6-(1H-tetraazol-5-yl)hexyl]piperidin-2-one;   (6R)-6-[(3S)-4,4-difluoro-3-hydroxy-3-methyl-4-phenylbutyl]-1-[6-(1H-tetraazol-5-yl)hexyl]piperidin-2-one;   7-{(2R)-2-[(1E,3R)-4-(1-benzofuran-2-yl)-4,4-difluoro-3-hydroxybut-1-enyl]-6-oxopiperidin-1-yl}heptanoic acid;   7-{(2R)-2-[(1E,3R)-4-(3-chlorophenyl)-4,4-difluoro-3-hydroxybut-1-enyl]-6-oxopiperidin-1-yl}heptanoic acid;   7-{(2R)-2-[(1E,3R)-4-(3-chlorophenyl)-4,4-difluoro-3-hydroxybut-1-enyl]-6-oxopiperidin-1-yl}heptanoic acid;   7-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-(3-methoxyphenyl)but-1-enyl]-6-oxopiperidin-1-yl}heptanoic acid;   6-[(1E)-(3R)-3-hydroxy-4-phenyl-but-1-enyl]-1-[6-(1H-tetrazol-5-yl)-hexyl]-piperidin-2-one;   7-{[(1E)-(2R)-2-(3S)-3-hydroxy-4-phenyl-but-1-enyl]-6-oxo-piperidin-1-yl}heptanoic acid;   isopropyl 7-{[(1E)-(2R)-2-(3S)-3-hydroxy-4-phenyl-but-1-enyl]-6-oxo-piperidin-1-yl}heptanoate;   isopropyl 7-{(2R)-2-[(3R)-3-hydroxy-4-phenyl-butyl]-6-oxo-piperidin-1-yl}heptanoate;   7-{[(2R)-2-(3R)-3-hydroxy-4-phenyl-butyl]-6-oxo-piperidin-1-yl}heptanoic acid;   methyl 5-{3-[(2R)-2-((1E)-(3S)3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-propyl}-thiophene-2-carboxylate;   5-{3-[(2R)-2-((1E)-(3S)3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-propyl}-thiophene-2-carboxylic acid;   5-{3-[(2R)-2-((3S)3-hydroxy-4-phenyl-butyl)-6-oxo-piperidin-1-yl]-propyl}-thiophene-2-carboxylic acid;   isopropyl 5-{3-[(2R)-2-((1E)-(3S)3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-propyl}-thiophene-2-carboxylate;   isopropyl 5-{3-[(2R)-2-((3S)3-hydroxy-4-phenyl-butyl)-6-oxo-piperidin-1-yl]-propyl}-thiophene-2-carboxylate;   6-[(3R)-3-hydroxy-4-phenyl-butyl]-1-[6-(1H-tetrazol-5-yl)-hexyl]-piperidin-2-one;   isopropyl 7-{(2R)-2-[(1E)-4,4-difluoro-3-oxo-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}heptanoate;   7-{(2R)-2-[(3R)-4-(3-bromophenyl)-4,4-difluoro-3-hydroxybutyl]-6-oxopiperidin-1-yl}heptanoic acid;   methyl 5-{3-[(2R)-2-((1E)-(3S)3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-propyl}-thiophene-2-carboxylate;   5-{3-[(2R)-2-((3S)3-hydroxy-4-phenyl-butyl)-6-oxo-piperidin-1-yl]-propyl}-thiophene-2-carboxylic acid;   isopropyl 5-{3-[(2R)-2-((3S)3-hydroxy-4-phenyl-butyl)-6-oxo-piperidin-1-yl]-propyl}-thiophene-2-carboxylate;   6-[(3R)-3-hydroxy-4-phenyl-butyl]-1-[6-(1H-tetrazol-5-yl)-hexyl]-piperidin-2-one;   isopropyl (5Z)-7-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-en-1-yl]-6-oxopiperidin-1-yl}hept-5-enoate;   (5Z)-7-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-en-1-yl]-6-oxopiperidin-1-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 compound according to  claim 6  which is:
 7-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}heptanoic acid; 
 7-{(4R)-4-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazinan-3-yl}heptanoic acid; 
 isopropyl 7-{(2R)-2-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}heptanoate; 
 isopropyl 7-{(4R)-4-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazinan-3-yl}heptanoate; 
 isopropyl 7-{(2R)-2-[(1E)-4,4-difluoro-3-oxo-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl}heptanoate; 
 7-{(2R)-2-[(3R)-4-(3-bromophenyl)-4,4-difluoro-3-hydroxybutyl]-6-oxopiperidin-1-yl}heptanoic 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. 
 
     
     
         8 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I, as recited in  claim 1 . 
     
     
         9 . 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. 
     
     
         10 . The method according to  claim 9  wherein one or more active ingredients 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 topical formulation. 
     
     
         11 . The method according to  claim 10  wherein the β-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; COSOPT®, the Maxi-K is Penitrem A, paspalicine, charybdotoxin, iberiotoxin, Paxicillan, Aflitram, Verroculogen, 1-(1-isobutyl-6-methoxy-1H-indazol-3-yl)-2-methylpropan-1-one; 1-[1-(2,2-dimethylpropyl)-6-methoxy-1H-indazol-3-yl]-2-methylpropan-1-one; 1-[1-(cyclohexylmethyl)-6-methoxy-1H-indazol-3-yl]-2-methylpropan-1-one; 1-(1-hexyl-6-methoxy-1H-indazol-3-yl)-2-methylpropan-1-one; 1-[1-(2-ethylhexyl)-6-methoxy-1H-indazol-3-yl]-2-methylpropan-1-one; 1-(3-isobutyryl-6-methoxy-1H-indazol-1-yl)buan-2-one; 1-(3-isobutyryl-6-methoxy-1H-indazol-1-yl)-3,3-dimethylbutan-2-one; 1-(3-cyclopentylcarbonyl)-6-methoxy-1H-indazol-1-yl)-3,3-dimethylbutan-2-one; 1-(3,3-dimethyl-2-oxobutyl)-6-methoxy-1H-indazole-3-carboxylic acid; and 1-[3-(3-hydroxypropanoyl)-6-methoxy-1H-indazol-1-yl]-3,3-dimethylbutan-2-one, 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. 
     
     
         12 . 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 or providing a neuroprotection, 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 . 
     
     
         13 . The method according to  claim 9  in which the topical formulation optionally contains xanthan gum or gellan gum. 
     
     
         14 . A method for stimulating bone formation, treating or reducing the risk of contracting a disease state or condition related to abnormal bone resorption, in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound as recited in  claim 1 . 
     
     
         15 . The method according to  claim 14  wherein said disease state or condition is selected from the group consisting of osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma. 
     
     
         16 . The method according to  claim 14  wherein a bisphosphonate active selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, neridronate, olpandronate, risedronate, piridronate, pamidronate, zolendronate, pharmaceutically acceptable salts thereof, and mixtures thereof is optionally added. 
     
     
         17 . The method according to  claim 16  comprising administering another agent selected from an organic bisphosphonate; a cathepsin K inhibitor, an estrogen, an estrogen receptor modulator, an androgen receptor modulator, an inhibitor of osteoclast proton ATPase, an inhibitor of HMG-CoA reductase, an integrin receptor antagonist, an osteoblast anabolic agent, calcitonin, vitamin D, a synthetic Vitamin D analogue, or a pharmaceutically acceptable salt or mixture thereof.