the present invention relates to the use of nonacidic cyclopentane heptan ( ene ) oic acid , 2 - heteroaryl alkenyl derivatives as therapeutic agents , e . g . as ocular hypotensives . the compounds used in accordance with the present invention are encompassed by the following structural formula i : ## str4 ## wherein the substituents and symbols are as hereinabove defined . the dotted lines on bonds between carbons 5 and 6 ( c - 5 ) and carbons 13 and 14 ( c - 13 ) indicate a single or double bond . if two solid lines are used at c - 5 , or c - 13 , it indicates a specific configuration for that double bond . hatched lines used at position c - 8 , c - 9 and c - 11 indicate the α configuration . a triangle at position c - 12 represents β orientation a preferred group of the compounds of the present invention includes compounds that have the following structural formula ii : ## str5 ## wherein z is selected from the group consisting of o and s , a is selected from the group consisting of n , -- ch , and c , r 2 is selected from the group consisting of hydrogen , halogen , and lower alkyl having from 1 to 6 carbon atoms , r 3 and r 4 are selected from the group consisting of hydrogen , halogen , lower alkyl having from 1 to 6 carbon atoms , or , together with ## str6 ## r 3 and r 4 forms a condensed aryl ring . preferably , when x is -- n ( r 1 ) 2 , y is ═ o . more preferably , at least one of r 2 , r 3 or r 4 are independently selected from the group consisting of chloro , bromo and lower alkyl . in one aspect of the invention , at least one of r 2 , r 3 or r 4 is chloro or bromo , and more preferably at least one of r 2 , r 3 or r 4 is bromo or at least two of r 2 , r 3 or r 4 are chloro . in another aspect of this invention , at least one of r 2 , r 3 or r 4 is ethyl , propyl , or butyl . in the above formulae , the substituents and symbols are as hereinabove defined and r 5 is hydrogen or methyl . the above compounds of the present invention may be prepared by methods that are known in the art or according to the working examples below . the compounds , below , are especially preferred representative of the compounds of the present invention . a pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or undesirable effect on the subject to whom it is administered and in the context in which it is administered . of particular interest are salts formed with inorganic ions , such as sodium , potassium , calcium , magnesium and zinc . pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention , or a pharmaceutically acceptable acid addition salt thereof , as an active ingredient , with conventional ophthalmically acceptable pharmaceutical excipients , and by preparation of unit dosage forms suitable for topical ocular use . the therapeutically efficient amount typically is between about 0 . 0001 and about 5 % ( w / v ), preferably about 0 . 001 to about 1 . 0 % ( w / v ) in liquid formulations . for ophthalmic application , preferably solutions are prepared using a physiological saline solution as a major vehicle . the ph of such ophthalmic solutions should preferably be maintained between 6 . 5 and 7 . 2 with an appropriate buffer system . the formulations may also contain conventional , pharmaceutically acceptable preservatives , stabilizers and surfactants . preferred preservatives that may be used in the pharmaceutical compositions of the present invention include , but are not limited to , benzalkonium chloride , chlorobutanol , thimerosal , phenylmercuric acetate and phenylmercuric nitrate . a preferred surfactant is , for example , tween 80 . likewise , various preferred vehicles may be used in the ophthalmic preparations of the present invention . these vehicles include , but are not limited to , polyvinyl alcohol , povidone , hydroxypropyl methyl cellulose , poloxamers , carboxymethyl cellulose , hydroxyethyl cellulose and purified water . tonicity adjustors may be added as needed or convenient . they include , but are not limited to , salts , particularly sodium chloride , potassium chloride , mannitol and glycerin , or any other suitable ophthalmically acceptable tonicity adjustor . various buffers and means for adjusting ph may be used so long as the resulting preparation is ophthalmically acceptable . accordingly , buffers include acetate buffers , citrate buffers , phosphate buffers and borate buffers . acids or bases may be used to adjust the ph of these formulations as needed . in a similar vein , an ophthalmically acceptable antioxidant for use in the present invention includes , but is not limited to , sodium metabisulfite , sodium thiosulfate , acetylcysteine , butylated hydroxyanisole and butylated hydroxytoluene . other excipient components which may be included in the ophthalmic preparations are chelating agents . the preferred chelating agent is edentate disodium , although other chelating agents may also be used in place or in conjunction with it . ______________________________________ingredient amount (% w / v ) ______________________________________active ingredient about 0 . 001 - 5preservative 0 - 0 . 10vehicle 0 - 40tonicity adjustor 1 - 10buffer 0 . 01 - 10ph adjustor q . s . ph 4 . 5 - 7 . 5antioxidant as neededsurfactant as neededpurified water as needed to make 100 % ______________________________________ the actual dose of the active compounds of the present invention depends on the specific compound , and on the condition to be treated ; the selection of the appropriate dose is well within the knowledge of the skilled artisan . the ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application , such as in containers equipped with a dropper , to facilitate the application to the eye . containers suitable for dropwise application are usually made of suitable inert , non - toxic plastic material , and generally contain between about 0 . 5 and about 15 ml solution . the invention is further illustrated by the following non - limiting examples , which are summarized in the reaction schemes of fig1 through 4 , wherein the compounds are identified by the same designator in both the examples and the figures . to a suspension of sodium hydride ( 36 mg , 1 . 50 mmol ) in thf ( 4 . 5 ml ) cooled to 0 ° c . was added dimethyl 4 -( 3 -( 2 - methyl ) thienyl )- 2 - oxo - butylphosphonate ( 414 mg , 1 . 50 mmol ) in thf ( 3 . 0 ml ). after 0 . 25 h a solution of the aldehyde 1 ( 438 mg , 1 . 00 mmol ) in thf ( 3 . 0 ml ) was added and the reaction was allowed to slowly warm to 23 ° c . over a period of 8 h . the reaction solution was quenched with saturated aqueous nh 4 cl and extracted w / etoac . the aqueous phase was made slightly acidic before extraction with etoac . the combined organics were washed with brine , dried ( mgso 4 ), filtered and concentrated in vacuo . flash column chromatography ( silica gel , 2 : 1 hex / etoac ) gave 544 mg ( 93 %) of the enone 2a . sodium tetrahydriodoborate ( 35 mg , 0 . 93 mmol ) was added to a solution of the enone 2a ( 544 mg , 0 . 93 mmol ) in meoh ( 4 . 5 ml ) at 0 ° c . after 2 h the solvent was removed in vacuo and the residue was stirred with 1n naoh / etoac . the organic portion was separated , dried ( mgso 4 ), filtered and concentrated in vacuo . the 3a - alcohol was separated by flash column chromatography or hplc ( silica gel , 3 : 1 hex / etoac ). a solution of alcohol 3a and pyridinium p - toluene sulfonate ( 116 mg , 0 . 462 mmol ) in meoh ( 4 . 5 ml ) was heated at 40 ° c . for 4 h . the solvent was removed in vacuo and the residue was diluted with etoac followed by washing with 1n hcl , saturated aqueous nahco 3 and brine . the organic portion was dried ( mgso 4 ), filtered and concentrated in vacuo . the residue was diluted with thf ( 0 . 78 ml ) and lithium hydroxide ( 0 . 39 ml of a 0 . 5n solution in h 2 o , 0 . 194 mmol ) was added . after 16 h the reaction was acidified with 1n hcl and extracted with etoac . the organic portion was washed with brine , dried ( mgso 4 ), and concentrated in vacuo to give 37 . 6 mg of the acid 4a . 1 h nmr ( 300 mh 2 , cdcl 3 ) δ12 . 1 ( brs , 1h ), 6 . 98 ( d , j = 5 . 1 hz ), 6 . 81 ( d , j = 5 . 1 hz , 1h ), 5 . 30 - 5 . 64 ( m , 4h ), 4 . 92 ( brs , 3h ), 4 . 07 - 4 . 17 ( m , 2h ), 3 . 89 - 3 . 93 ( m , 1h ), 2 . 55 - 2 . 59 ( m , 2h ), 2 . 35 ( δ , 3h ), 2 . 07 - 2 . 33 ( m , 10h ), 1 . 42 - 1 . 86 ( m , 4h ). by methods described for compound 4a , steps 1 through 3 , the following compounds were prepared . ( the compounds below are also identified by their nmr spectra .) according to the procedures described above for 4a , the use of dimethyl 4 -( 2 -( 5 - methyl ) thienyl )- 2 - oxo - butylphosphonate afforded 26 mg of free acid 4b . 1 h nmr ( 300 mh 2 , cdcl 3 ) δ12 . 1 ( brs , 1h ), 6 . 56 ( d , j = 3 . 4 hz , 1h ), 6 . 54 ( d , j = 3 . 4 hz , 1h ), 5 . 34 - 5 . 64 ( m , 4h ), 4 . 70 ( brs , 3h ), 4 . 13 - 4 . 20 ( m , 2h ), 3 . 91 - 3 . 93 ( m , 1h ), 2 . 82 ( t , j = 7 . 7 hz , 2h ), 2 . 42 ( δ , 3h ), 2 . 05 - 2 . 38 ( m , 11h ), 1 . 44 - 1 . 96 ( m , 5h ). according to the procedures described above for 4a , the use of dimethyl 4 -( 3 -( 2 - methyl ) thienyl )- 2 - oxo - butyl phosphonate afforded 25 mg of free acid 4c . 1 h nmr ( 300 mh 2 , cdcl 3 ) δ12 . 0 ( brs , 1h ), 6 . 67 ( s , 1h ), 6 . 60 ( s , 1h ), 5 . 34 - 5 . 62 ( m , 4h ), 4 . 42 ( brs , 3h ), 4 . 10 - 4 . 17 ( m , 2h ), 3 . 89 - 3 . 93 ( m , 1h ), 2 . 57 - 2 . 60 ( m , 2h ), 2 . 44 ( δ , 3h ), 2 . 09 - 2 . 36 ( m , 8h ), 1 . 44 - 1 . 87 ( m , 6h ). according to the procedures described above for 4a , the use of dimethyl 4 -( 3 -( 2 - chloro ) thienyl )- 2 - oxo - butylphosphonate afforded 25 mg of free acid 4d . 1 h nmr ( 300 mh 2 , cdcl 3 ) δ12 . 0 ( brs , 1h ), 6 . 99 ( d , j = 5 . 7h 2 ), 6 . 78 ( d , j = 5 . 7 hz , 1h ), 5 . 29 - 5 . 60 ( m , 4h ), 4 . 02 - 4 . 11 ( m , 2h ), 3 . 84 - 3 . 87 ( m , 1h ), 3 . 37 ( brs , 3h ), 2 . 56 - 2 . 63 ( m , 2h ), 2 . 01 - 2 . 32 ( m , 8h ), 1 . 38 - 1 . 83 ( m , 7h ). according to the procedures described above for 4a , the use of dimethyl 4 -( 2 -( 4 - bromo ) thienyl )- 2 - oxo - butylphosphonate afforded 10 mg of free acid 4e . 1 h nmr ( 300 mh 2 , cdcl 3 ) δ12 . 01 ( brs , 1h ), 6 . 95 ( s , 1h ), 6 . 65 ( s , 1h ), 5 . 24 - 5 . 53 ( m , 4h ), 3 . 99 - 4 . 08 ( m , 2h ), 3 . 76 - 3 . 80 ( m , 1h ), 2 . 70 - 2 . 79 ( m , 2 . 44 ( s , 3h ), 2 . 09 - 2 . 36 ( m , 8h ), 1 . 44 - 1 . 87 ( m , 6h ). according to the procedures described above for 4a , the use of dimethyl 4 -( 2 -( 5 - bromo ) thienyl )- 2 - oxo - butylphosphonate afforded 50 mg of free acid 4f . 1 h nmr ( 300 mh 2 , cdcl 3 ) δ12 . 0 ( brs , 1h ), 6 . 80 ( d , j = 3 . 6 hz , 1h ), 6 . 51 ( d , j = 3 . 9 hz , 1h ), 5 . 33 - 5 . 55 ( m , 4h ), 4 . 05 - 4 . 12 ( m , 2h ), 3 . 82 - 3 . 88 ( m , 1h ), 2 . 75 - 2 . 81 ( m , 2h ), 1 . 38 - 2 . 28 ( m , 14h ). according to the procedures described above for 4a , the use of dimethyl 4 -( 3 -( 2 , 5 - dichloro ) thienyl )- 2 - oxo - butylphosphonate afforded 18 mg of free acid 4g . 1 h nmr ( 300 mhz , cdcl 3 ) δ12 . 01 ( brs , 1h ), 6 . 64 ( s , 1h ), 5 . 27 - 5 . 56 ( m , 4h ), 4 . 05 - 4 . 15 ( m , 2h ), 3 . 85 - 3 . 92 ( m , 1h ), 1 . 42 - 2 . 31 ( m , 18h ). according to the procedures described above for 4a , the use of dimethyl 4 -( 2 -( 3 - chloro ) thienyl )- 2 - oxo - butylphosphonate afforded 10 mg of free acid 4 h . 1 h nmr ( 300 mhz , cdcl 3 ) δ12 . 0 ( brs , 1h ), 7 . 13 ( d , j = 5 . 4 hz , 1h ), 6 . 75 ( d , j = 5 . 4 hz , 1h ), 5 . 19 - 5 . 46 ( m , 4h ), 3 . 96 - 3 . 98 ( m , 2h ), 3 . 69 - 3 . 76 ( m , 1h ), 2 . 75 ( m , 2h ), 1 . 35 - 2 . 28 ( m , 17h ). according to the procedures described above for 4a , the use of dimethyl 4 -( 2 - benzothienyl )- 2 - oxo - butylphosphonate afforded 22 mg of free acid 4i . 1 h nmr ( 300 mhz , cdcl 3 ) δ11 . 8 ( brs , 1h ), 7 . 73 ( d , j = 7 . 7 hz , 1h ), 7 . 63 ( d , j = 6 . 9 hz , 1h ), 7 . 23 - 7 . 31 ( m , 2h ), 7 . 00 ( s , 1h ), 5 . 31 - 5 . 65 ( m , 4h ), 4 . 86 ( brs , 3h ), 4 . 16 - 4 . 22 ( m , 2h ), 3 . 89 - 3 . 93 ( m , 1h ), 2 . 96 ( t , j = 7 . 6 hz , 2h ) 1 . 86 - 10h ), 1 . 44 - 1 . 78 ( m , 4h ). according to the procedures described above for 4a , the use of dimethyl 4 -( 2 - benzofuranyl )- 2 - oxo - butylphosphonate afforded 30 . 5 mg of free acid 4j . 1 h nmr ( 300 mhz , cdcl 3 ) δ12 . 1 ( brs , 1h ), 7 . 37 - 7 . 47 ( m , 2h ), 7 . 15 - 7 . 19 ( m , 2h ), 6 . 38 ( s , 1h ), 5 . 30 - 5 . 66 ( m , 4h ), 5 . 04 ( brs , 3h ), 4 . 10 - 4 . 20 ( m , 2h ), 3 . 86 - 3 . 94 ( m , 1h ), 2 . 84 ( t , j = 7 . 6 hz , 2h ) 1 . 90 - 2 . 33 ( m , 10h ), 1 . 38 - 1 . 78 ( m , 4h ). according to the procedures described above for 4a , the use of dimethyl 4 -( 3 - furanyl )- 2 - oxo - butylphosphonate afforded 10 . 1 mg of free acid 4k . 1 h nmr ( 300 mh 2 , cdcl 3 ) δ12 . 0 ( brs , 1h ), 7 . 35 ( d , j = 1 . 7 hz , 1h ), 7 . 23 ( s , 1h ), 6 . 28 ( d , j = 1 . 7 hz , 1h ), 5 . 34 - 5 . 64 ( m , 4h ), 4 . 15 - 4 . 20 ( m , 2h ), 3 . 90 - 3 . 94 ( m , 1h ), 3 . 70 ( brs , 3h ), 2 . 09 - 2 . 52 ( m , 12h ), 1 . 40 - 1 . 88 ( m , 4h ). according to the procedures described above for 4a , the use of dimethyl 4 -( 2 - furanyl )- 2 - oxo - butylphosphonate afforded 33 . 3 mg of free acid 4l . 1 h nmr ( 300 mhz , cdcl 3 ) δ11 . 8 ( brs , 1h ), 7 . 29 ( s , 1h ), ( d , j = 3 . 0 hz 1h ), 6 . 26 ( dd , j = 3 . 0 , 1 . 8 hz , 1h ), 5 . 99 ( d , j = 1 . 8 hz , 1h ) 5 . 34 - 5 . 64 ( m , 4h ), 4 . 82 ( brs , 3h ), 4 . 11 - 4 . 17 ( m , 2h ), 3 . 89 - 3 . 93 ( m , 1h ), 2 . 69 ( t , j = 8 . 4 hz , 2h ), 2 . 05 - 2 . 34 ( m , 10h ), 1 . 40 - 1 . 94 ( m , 4h ). according to the procedures described above for 4a , the use of dimethyl 4 -( 2 - thiazolyl )- 2 - oxo - butylphosphonate afforded 32 . 2 mg of free acid 4m . 1 h nmr ( 300 mhz , cd 3 od ) δ7 . 47 ( d , j = 3 . 3 hz , 1h ), 7 . 23 ( d , j = 3 . 3 hz , 1h ), 3 . 86 - 3 . 93 ( m , 2h ), 3 . 60 - 3 . 65 ( m , 1h ), 2 . 88 - 2 . 95 ( m , 2h ), 1 . 75 - 2 . 20 ( m , 10h ), 1 . 22 - 1 . 44 ( m , 4h ). according to the procedures described above for 4a , the use of dimethyl 4 -( 2 - thienyl )- 2 - oxo - butylphosphonate afforded 15 . 0 mg of free acid 4n . 1 h nmr ( 300 mhz , cdcl 3 ) δ11 . 9 ( brs , 1h ), 7 . 11 , ( d , j = 5 . 1 hz , 1h ), 6 . 92 ( dd , j = 5 . 1 , 3 . 3 hz , 1h ), 6 . 00 ( d , j = 3 . 3 hz , 1h ) 5 . 32 - 5 . 64 ( m , 4h ), 4 . 15 - 4 . 19 ( m , 2h ), 3 . 93 - 3 . 97 ( m , 1h ), 3 . 61 ( brs , 3h ), 2 . 89 - 2 . 95 ( m , 2h ), 2 . 09 - 2 . 35 ( m , 8h ), 1 . 46 - 1 . 98 ( m , 6h ). the 3β - isomer of 3n was isolated from the reaction mixture obtained in step 2 during preparation of 4n and subjected to step 3 to afford 14 . 3 mg of free acid 4o . 1 h nmr ( 300 mhz , cdcl 3 ) δ11 . 5 ( brs , 1h ), 7 . 11 , ( d , j = 5 . 1 hz 1h ), 6 . 92 ( dd , j = 5 . 1 , 3 . 3 hz , 1h ), 6 . 81 ( d , j = 3 . 3 hz , 1h ) 5 . 36 - 5 . 64 ( m , 4h ), 4 . 62 ( brs , 3h ), 4 . 17 - 4 . 21 ( m , 2h ), 3 . 95 - 3 . 98 ( m , 1h ), 2 . 90 - 2 . 96 ( m , 2h ), 2 . 08 - 2 . 34 ( m , 8h ), 1 . 40 - 1 . 98 ( m , 6h ). according to the procedures described above for 4a , the use of dimethyl 4 -( 3 - thienyl )- 2 - oxo - butylphosphonate afforded 9 . 6 mg of free acid 4p . while this compound is not a substituted heteroaryl derivative within the scope of general formula i , above , it represents another aspect of this invention in view of its excellent ability to lower intraocular pressure as shown below . 1 h nmr ( 300 mhz , cdcl 3 ) δ12 . 0 ( brs , 1h ), 7 . 23 - 7 . 27 ( m , 1h ), 6 . 94 - 6 . 95 ( m , 2h ), 5 . 36 - 5 . 65 ( m , 4h ), 4 . 10 - 4 . 17 ( m , 2h ), 3 . 94 ( brs , 3h ), 3 . 90 - 3 . 94 m , 1h ), 2 . 68 - 2 . 74 ( m , 2h ), 2 . 00 - 2 . 35 ( m , 8h ), 1 . 44 - 1 . 96 ( m , 6h ). the 3β - isomer of 3p was isolated from the reaction mixture obtained in step 2 during preparation of 4p and subjected to step 3 to afford 36 . 2 mg of free acid 4q . 1 h nmr ( 300 mhz , cdcl 3 ) δ11 . 9 ( brs , 1h ), 7 . 23 - 7 . 27 ( m , 1h ), 6 . 94 - 6 . 95 ( m , 2h ), 5 . 32 - 5 . 65 ( m , 4h ), 4 . 72 ( brs , 3h ), 4 . 12 - 4 . 19 ( m , 2h ), 3 . 93 - 3 . 97 ( m , 1h ), 2 . 69 - 2 . 76 ( m , 2h ), 2 . 07 - 2 . 33 ( m , 8h ), 1 . 39 - 1 . 90 ( m , 6h ). according to the procedures described above for 4a , the use of dimethyl 4 -( 2 ( 5 - ethyl ) thienyl ) 2 - oxo - butylphosphonate will result in the free acid 4r . according to the procedures described above for 4a , the use of dimethyl 4 -( 2 -( 5 - butyl ) thienyl ) 2 - oxo - butylphosphonate will result in the free acid 4s . according to the procedures described above for 4a , the use of dimethyl 4 -( 2 -( 5 - propyl ) thienyl ) 2 - oxo - butylphosphonate will result in the free acid 4t . according to the procedures described above for 4a , the use of dimethyl 4 -( 2 -( 5 - methoxy ) thienyl ) 2 - oxo - butylphosphonate will result in the free acid 4u . the 3β isomer of 3m was isolated from the reaction mixture obtained in step 2 during preparation of 4m and subjected to step 3 to afford the free acid 4v . alcohol ( 400 mg , 0 . 694 mmol ) obtained in step 2 of preparation of 4p was treated with silver triflate ( 803 mg , 3 . 12 mmol ), 2 , 6 - di - t - butyl - pyridine ( 0 . 89 ml , 3 . 98 mmol ) and iodomethane ( 0 . 21 ml , 3 . 4 mmol ) in ch 2 cl 2 ( 11 ml ) at 0 ° c . after 12 h the reaction mixture was filtered through celite , concentrated in vacuo and purified by flash column chromatography to give the 3α - methoxy product 5 . further subjection of 5 to the procedures described above in step 3 of preparation of 4a provided 41 . 2 mg of free acid 6 . 1 h nmr ( 300 mhz , cdcl 3 ) δ11 . 6 ( brs , 1h ), 7 . 24 - 7 . 28 ( m , 2h ), 6 . 93 ( d , j = 3 . 3 hz , 1h ), 5 . 34 - 5 . 60 ( m , 4h ), 4 . 90 ( brs , 3h ), 4 . 20 - 4 . 23 ( m , 1h ), 3 . 99 - 4 . 02 ( m , 1h ), 3 . 54 - 3 . 64 ( m , 1h ), 3 . 30 ( s , 3h ), 2 . 69 ( t , j = 7 . 3 hz , 2h ), 2 . 07 - 2 . 42 ( m , 9h ), 1 . 50 - 2 . 01 ( m , 5h ). the racemate of the alcohol prepared according to step 2 of preparation 4 h is treated according to the procedures described above for 6 and results in the free acid 6a . the 3α - alcohol 3p , isolated from step 2 during preparation of 4p , was deprotected with pyridinium p - toluenesulfonate in meoh at 45 ° c . for 4 h and after the usual work - up gave triol 7p . a mixture of 7p and ammonium chloride in liquid ammonia was heated to 55 ° c . for 48 h in a sealed tube . the tube was recooled to - 70 ° c ., vented , and then allowed to warm to room temperature on its own accord . the residue was dissolved in 1 : 1 etoac / h 2 o . the organic portion was separated , dried ( mgso 4 ), filtered and concentrated in vacuo . flash column chromatography ( silica gel , 9 : 1 ch 2 cl 2 / meoh ) gave 10 . 9 mg of the title compound 8p . 1 h nmr ( 300 mhz , cdcl 3 ) δ7 . 24 - 7 . 27 ( m , 1h ), 6 . 95 - 6 . 96 ( m , 2h ), 5 . 76 ( brs , 1h ), 5 . 34 - 5 . 63 ( m , 4h ), 4 . 08 - 4 . 19 ( m , 2h ), 3 . 94 - 3 . 98 ( m , 1h ), 2 . 95 ( brs , 3h ), 2 . 69 - 2 . 76 ( m , 2h ), 2 . 05 - 2 . 39 ( m , 8h ), 1 . 48 - 1 . 96 ( m , 6h ). according to the procedures described for preparation of 8p the 3β - alcohol 3 g was converted to the title compound 8q . 1 h nmr ( 300 mhz , cdcl 3 ) δ7 . 24 - 7 . 27 ( m , 1h ) 6 . 95 - 6 . 97 ( m , 2h ), 5 . 72 ( brs , 2h ), 5 . 34 - 5 . 66 ( m , 4h ), 4 . 08 - 4 . 19 ( m , 2h ), 3 . 95 - 3 . 99 ( m , 1h ), 3 . 04 ( brs , 1h ), 2 . 70 - 2 . 84 ( m , 4h ), 2 . 08 - 2 . 36 ( m , 9h ), 1 . 42 - 1 . 89 ( m , 5h ). according to the procedures described for preparation of 8p the alcohol 3r was converted to the title compound 8r . 1 h nmr ( 300 mhz , cdcl 3 ) δ6 . 64 ( s , 1h ), 5 . 26 - 5 . 68 ( m , 6h ), 4 . 07 - 4 . 10 ( m , 1h ), 3 . 97 - 4 . 03 ( m , 1h ), 3 . 83 - 3 . 86 ( m , 1h ), 2 . 50 - 2 . 56 ( m , 2h ), 1 . 96 - 2 . 30 ( m , 11h ), 1 . 39 - 1 . 80 ( m , 6h ). to a suspension of sodium hydride 271 mg ( 11 . 30 mmol ) in thf ( 21 ml ) cooled to 0 ° c . was added a solution of dimethyl 4 -( 3 - thienyl )- 2 - oxo - butylphosphonate ( 2 . 96 g , 11 . 30 mmol ) in thf ( 10 ml ). after stirring for 0 . 5 h a solution of aldehyde 9 ( 2 . 80 g , 10 . 28 mmol ) in thf ( 10 ml ) was added dropwise . the reaction was allowed to warm to room temperature and stirred for a total of 12 h before quenching with saturated aqueous nh 4 cl . the mixture was extracted with etoac and the organic portion was washed with saturated aqueous nahco 3 , brine , dried ( mgso 4 ), filtered and concentrated in vacuo . the residue was purified by flash column chromatography ( silica gel , 1 : 1 hex / etoac ) to afford 3 . 98 , ( 95 %) of enone . immediately , a solution of the enone ( 3 . 98 g , 9 . 75 mmol ) in meoh ( 22 ml ) was cooled to 0 ° c . and sodium tetrahydridoborate ( 369 mg , 9 . 75 mmol ) was added . after 2 h the reaction was quenched with saturated aqueous nh 4 cl and extracted with etoac . the organic portion was washed with brine , dried ( mgso 4 ) filtered and concentrated in vacuo . purification by hplc ( waters partisil - 10 , 1 : 1 hex / etoac ) afforded 1 . 30 g ( 33 %) of the α - alcohol 10 . 1 h nmr ( 300 mhz , cdcl 3 ) δ7 . 97 ( d , j = 7 . 2 hz , 2h ), 7 . 21 - 7 . 57 , ( m , 4h ), 6 . 88 ( d , j = 4 . 1 hz , 2h ), 5 . 54 - 5 . 70 ( m , 2h ), 5 . 23 ( q , j = 6 . 1 hz , 1h ), 5 . 04 ( t , j = 6 . 5 hz , 1h ), 4 . 10 ( q , j = 7 . 1 hz 1h ), 2 . 45 - 2 . 89 ( m , 7h ), 2 . 18 - 2 . 26 ( m , 2h ), 1 . 76 - 1 . 84 ( m , 2h ). potassium carbonate ( 523 mg , 3 . 78 mmol ) was added to a solution of benzoate 10 ( 1 . 3 g , 3 . 15 mmol ) in meoh ( 6 . 5 ml ). after 16 h the reaction solvent was removed in vacuo and the residue was dissolved in etoac / saturated aqueous nh 4 cl . the organic portion was washed with brine , dried ( mgso 4 ), filtered and concentrated in vacuo . the residue was dissolved in thf ( 6 . 5 ml ) and triphenylphosphine rhodium chloride ( 400 mg ) was added . the solution was degassed and purged under an atmosphere of hydrogen gas at 40 - 45 psi . after 16 h the reaction was concentrated in vacuo , and the residue purified by flash column chromatography ( silica gel , 3 : 1 hex / etoac ) to afford the apparent saturated diol after evaporation of the solvents . the apparent diol was dissolved in ch 2 cl 2 ( 6 . 5 ml ) and 2 , 6 - lutidine ( 2 . 0 ml , 16 . 5 mmol ) was added followed by t - butyldimethylsilyl triflate ( 3 . 0 ml , 13 . 2 mmol ). the reaction was quenched with saturated aqueous nahco 3 and washed with brine , dried ( mgso 4 ), filtered and concentrated in vacuo . flash column chromatography ( 9 : 1 hex / etoac ) gave 1 . 29 g ( 94 %) of the bis - tbdms ether 11 . 1 h nmr ( 300 mhz , cdcl 3 ) δ7 . 22 - 7 . 25 ( m , 1h ), 7 . 22 - 7 . 23 ( m , 2h ), 4 . 92 - 4 . 98 ( m , 1h ), 3 . 90 - 3 . 94 ( m , 1h ), 3 . 64 - 3 . 70 ( m , 1h ), 2 . 45 - 2 . 82 ( m , 5h ), 1 . 95 - 2 . 16 ( m , 2h ), 1 . 71 - 1 . 77 ( m , 3h ), 1 . 05 - 1 . 51 ( m , 4h ), 0 . 88 ( s , 9h ), 0 . 85 ( s , 9h ), 0 . 03 ( s , 9h ), 0 . 02 ( s , 3h ). lactone 11 ( 170 mg , 0 . 315 mmol ) was dissolved in ch 2 cl 2 ( 1 . 0 ml ) and cooled to - 70 ° c . dibal - h ( 0 . 47 ml of a 1 . 0m solution in ch 2 cl 2 , 0 . 47 mmol ) was added . after 2 h the reaction was quenched with meoh , allowed to warm to room temperature , and extracted with ch 2 cl 2 . the organic portion was dried ( na 2 so 4 ), filtered and concentrated in vacuo to give the lactol as a clear , viscous oil . to a suspension of ( 4 - carboxybutyl ) triphenylphosphonium bromide ( 558 mg , 1 . 26 mmol ) in thf ( 2 . 5 ml ) was added potassium bis ( trimethylsilyl ) amide ( 503 mg , 2 . 52 mmol ) at 0 ° c . after 0 . 5 h the solution was cooled to - 70 ° c . and a solution of the lactol in thf ( 2 . 5 ml ) was added . the reaction was allowed to warm to room temperature on its own accord , quenched with saturated aqueous nh 4 cl , and extracted with etoac . the organic portion was washed with saturated aqueous nahco 3 , brine , dried ( mgso 4 ), filtered and concentrated in vacuo . the residue was diluted with et 2 o and excess diazomethane in et 2 o was added until the reaction solution persisted yellow . evaporation of the solvent gave 140 mg ( 70 %) of ester 12 . 1 h nmr ( 300 mhz , cdcl 3 ) δ7 . 22 - 7 . 24 ( m , 1h ), 6 . 90 - 6 . 92 ( m , 2h ), 5 . 28 - 5 . 52 ( m , 2h ), 4 . 02 - 4 . 06 ( m , 1h ), 3 . 95 - 3 . 96 ( m , 1h ), 3 . 63 - 3 . 67 ( m , 1h ), 3 . 63 ( s , 3h ), 2 . 52 - 2 . 70 ( m , 2h ), 2 . 00 - 2 . 32 ( m , 5h ), 1 . 20 - 1 . 84 ( m , 14h ), 0 . 88 ( s , 9h ), 0 . 86 ( s , 9h ), 0 . 108 - 0 . 055 ( m , 12h ), ( d , j = 7 . 2 hz , 2h ), 7 . 21 - 7 . 57 , ( m , 4h ), 6 . 88 ( d , j = 4 . 1 hz , 2h ), 5 . 54 - 5 . 70 ( m , 2h ), 5 . 23 ( q , j = 6 . 1 hz , 1h ), 5 . 4 (+, j = 6 . 5 hz , 1h ), 4 . 10 ( q , j - 7 . 1 hz 1h ), 2 . 45 - 2 . 89 ( m , 7h ), 2 . 18 - 2 . 26 ( m , 2h ), 1 . 76 - 1 . 84 ( m , 2h ). to a solution of bis - tbdms ether 12 ( 25 mg , 0 . 040 mmol ) in thf ( 0 . 24 ml ) was added bu 4 nf ( 0 . 12 ml of a 1 . 0m solution in thf , 0 . 12 mmol ). after 16 h the reaction was concentrated in vacuo and purified by flash column chromatography ( silica gel , 3 : 1 hex / etoac ) to yield 13 . 0 mg ( 79 %) of the triol . lithium hydroxide ( 0 . 15 ml of a 0 . 5n solution in h 2 o , 0 . 073 mmol ) was added to a solution of the ester ( 13 . 0 mg , 0 . 0316 mmol ) in thf ( 0 . 3 ml ). after 16 h the reaction was acidified with 1n hcl and extracted with etoac . the organic portion was dried ( mgso 4 ), filtered and concentrated in vacuo to give 7 . 0 mg ( 56 %) of free acid 13 . 1 h nmr ( 300 mhz , cdcl 3 ) δ12 . 0 ( brs , 1h ), 7 . 19 - 7 . 22 ( m , 1h ), 6 . 90 - 6 . 92 ( m , 2h ), 5 . 31 - 5 . 48 ( m , 2h ), 4 . 10 (+, j = 3 . 9 hz , 1h ), 3 . 86 - 3 . 88 ( m , 1h ), 3 . 59 - 3 . 65 ( m , 1h ), 2 . 65 - 2 . 82 ( m , 2h ), 1 . 20 - 2 . 30 ( m , 21h ). a mixture of the enone ( 137 mg , 0 . 245 mmol ) obtained in step 2 of preparation of 4k above , aliquat 336 ( 34 μl , 0 . 074 mmol ), sodium dithionite ( 384 . 7 mg , 2 . 21 mmol ) and sodium bicarbonate ( 371 . 3 mg , 4 . 42 mmol ) in benzene : h 2 o ( 1 : 1 , 6 . 0 ml ) was heated to 75 ° c . for 1 . 5 h . the reaction mixture was allowed to cool to room temperature , was diluted with etoac , and was washed with h 2 o and brine . the organic portion was dried ( mgso 4 ), filtered and the filtrate was concentrated in vacuo . purification by flash column chromatography ( silica gel , 4 : 1 hex / etoac ) gave 113 . 3 mg ( 83 %) of the ketone 14 . sodium tetrahydridoborate ( 14 . 2 mg , 0 . 375 mmol ) was added to a solution of the ketone ( 210 mg , 0 . 375 mmol ) in meoh ( 3 . 0 ml ) cooled to 0 ° c . after 30 minutes the reaction was quenched with saturated aqueous ammonium chloride and allowed to warm to room temperature . the mixture was extracted with et 2 o and the organic portion was dried ( mgso 4 ), filtered and concentrated in vacuo . the residue was diluted with meoh ( 3 . 0 ml ) and pyridinium p - toluene sulfonate ( 141 mg , 0 . 562 mmol ) was added . after heating to 45 ° c . for 16 h the reaction was concentrated in vacuo , diluted with etoac and washed with 1n hcl , saturated aqueous sodium bicarbonate , brine , dried ( mgso 4 ), filtered and concentrated in vacuo . flash column chromatography ( silica gel , 2 : 1 hex / etoac ) followed by 100 % etoac ) gave 123 mg ( 83 %) of a mixture of alcohols which were homogenous by tlc . the mixture of alcohols ( 52 . 3 mg , 0 . 132 mmol ) was diluted with thf ( 1 . 0 ml ) and lithium hydroxide ( 0 . 53 ml of a 0 . 5n solution in h 2 o , 0 . 265 mmol ) was added . after 16 h the reaction was acidified with 1n hcl and extracted with etoac . the organic portion was washed with brine , dried ( mgso 4 ) filtered and concentrated in vacuo to afford 44 . 6 mg ( 89 %) of free acid 15 . 1 h nmr ( 300 mhz , cdcl 3 ) δ7 . 34 ( d , j = 1 . 8 hz , 1h ), 7 . 23 ( s , 1h ), 6 . 2 ( d , j = 1 . 8 hz , 1h ), 5 . 30 - 5 . 52 ( m , 2h ), 4 . 81 ( brs , 3h ) 4 . 16 ( brs , 1h ), 3 . 95 ( brs , 1h ), 3 . 61 - 3 . 72 ( m , 1h ), 2 . 10 - 2 . 64 ( m , 7h ), 2 . 17 ( s , 3h ), 1 . 34 - 1 . 91 ( m , 10h ). certain of the above compounds were tested for activity in the various in vitro assays described below and the results are reported in tables 1 through 4 , below . activity at different prostanoid receptors was measured in vitro in isolated smooth muscle preparations . fp - activity was measured as contraction of the isolated feline iris sphincter . ep 1 - activity was measured as contraction of the longitudinal smooth muscle of the isolated guinea pig ileum . ep 3 - activity was measured as inhibition of the twitch response induced by electrical field stimulation in the isolated guinea pig was deferens and as contraction of the longitudinal smooth muscle of the isolated chick ileum . activity was also measured as relaxation of smooth muscle of isolated rabbit jugular vein a preparation which appears to contain a unique pgf 2 α - sensitive receptor provisionally termed fp vasc . tp - vasoconstrictor activity was measured as contraction of rings of the isolated rat thoracic aorta . effects on platelets from healthy human donors were measured by incubating platelet - rich plasma with the compounds described herein . inhibition of aggregation was determined by the ability of the compounds described herein to inhibit platelet aggregation in platelet - rich plasma induced by 20 μm adp . in addition to stimulating the fp receptor associated with the cat iris , several examples also stimulated the ep 3 receptor . compounds with agonist activity at ep 3 receptors may also be used for treating gastric or duodenal ulcer by virtue of their cytoprotective and anti - secretory properties . they may also be used as adjunctive therapy in combination with aspirin - like drugs and steroids to limit gastrointestinal side effects . ep 3 agonists stimulate uterine smooth muscle and may be used to terminate pregnancy in human females . ep 3 agonists are also useful in the cervical ripening process and could be used for inducing labor . other potential therapeutic applications are in osteoporosis , constipation , renal disorders , sexual dysfunction , baldness , diabetes , cancer and in disorder of immune regulation . many examples also have pronounced activity at the fp receptor , provisionally termed fp vasc associated with the vascular endothelium in the rabbit jugular vein preparation . since such agents would be vasodilators they have potential in hypertension and any disease where tissue blood perfusion is compromised . such indications include , but are not limited to , systemic hypertension , angina , stroke , retinal vascular diseases , claudication , raynauds disease , diabetes , and pulmonary hypertension . the effects of the compounds of this invention on intraocular pressure are also provided in the following tables . the compounds were prepared at the said concentrations in a vehicle comprising 0 . 1 % polysorbate 80 and 10 mm tris base . dogs were treated by administering 25 μl to the ocular surface , the contralateral eye received vehicle as a control . intraocular pressure was measured by applanation pneumatonometry . dog intraocular pressure was measured immediately before drug administration and at 6 hours thereafter . compound 4 g was examined and showed a pronounced ocular hypotensive effect in dogs . __________________________________________________________________________ ec . sub . 50 ( nm ) platelets dog hyp / agn -# fp ep . sub . 1 ep . sub . 3 fp . sub . vasc tp aggreg inhib ( 1 miosis__________________________________________________________________________ ## str8 ## 4 . 2 & gt ; 10 . sup . 4 43 p . a . 1230 20 4010 na na 0 . 1 %/- 2 . 8 0 . 38 / pinpt ## str9 ## 82 & gt ; 10 . sup . 4 & gt ; 10 . sup . 4 1820 31 & gt ; 10 . sup . 4 0 . 1 %/- 4 . 2 0 . 79 / pinpt ## str10 ## 0 . 8 2000 400 178 9 . 2 2460 na na 0 . 1 %/- 6 . 0 0 . 6 / pinpoint ## str11 ## 3 . 5 & gt ; 10 . sup . 4 & gt ; 10 . sup . 4 5000 3 . 6 & gt ; 10 . sup . 4 ## str12 ## 30 58 ## str13 ## 170 0 . 1 %/- 3 . 3 0 . 72 */ pin ## str14 ## 0 . 8 & gt ; 10 . sup . 4 pa 189pa 1060 2 . 1 ˜ 10 . sup . 4 na na 0 . 1 %/- 2 . 1 0 . 83 / pinpt ## str15 ## 10 & gt ; 10 . sup . 4 105pa 2400 545 4740 na na ## str16 ## 19 & gt ; 10 . sup . 4 83 2510 5400 0 . 1 %/- 3 . 6 0 . 01 %/ - 2 . 5 0 . 38 / pinpoint . 83 / mild ## str17 ## 137 & gt ; 5882 ## str18 ## 9 & gt ; 10 . sup . 4 44 1150 & gt ; 7692 ˜ 10 . sup . 4 0 . 1 %/- 4 . 3 0 . 01 %/ - 1 . 7 0 . 67 / pinpoint . 54 / mild ## str19 ## 12 & gt ; 10 . sup . 4 355 3470 & gt ; 833 3980 ## str20 ## 190 9000pa & gt ; 68966 0 . 1 %/ 0 0 . 01 %/ 0 . 13 / 0 0 . 17 / 0 ## str21 ## 291 ˜ 10 . sup . 4 2664 ## str22 ## 4 & gt ; 10 . sup . 4 1000pa 6170 47 2450 0 . 1 %/- 3 . 3 1 . 13 / pinpoint 4 ## str23 ## 7 & gt ; 10 . sup . 4 341 pa 8710 & gt ; 7692 & gt ; 10 . sup . 4 ## str24 ## 3 & gt ; 10 . sup . 4 305 pa 2040 & gt ; 7143 ˜ 10 . sup . 4 0 . 1 %/- 4 . 5 0 . 01 %/ - 2 . 9 1 . 38 / pinpt 0 . 42 / pinpt ## str25 ## 0 . 8 & gt ; 10 . sup . 4 50 pa 2190 16 371 ## str26 ## 0 . 49 & gt ; 10 . sup . 4 & gt ; 10 . sup . 4 pa & gt ; 10 . sup . 4 7 . 7 2300 0 . 1 %/- 5 . 6 0 . 5 / pinpt ## str27 ## 4 & gt ; 10 . sup . 4 36pa 7410 8 . 5 5080 0 . 1 %/- 4 . 8 1 . 0 / pinpoint ## str28 ## 503 1003 0 . 1 %/- 3 . 2 0 . 6 / pinpoint ## str29 ## 4230 28325 ## str30 ## 13 & gt ; 10 . sup . 4 & gt ; 10 . sup . 4 = 10 . sup . 4 pa 122 3530 ## str31 ## 33 21 & gt ; 10 . sup . 4 ## str32 ## 202 ## str33 ## 2940 ## str34 ## 53 ## str35 ## 0 . 70 na 82 & gt ; 10 . sup . 4 0 . 1 %/- 5 . 8 1 . 2 / pinpoint__________________________________________________________________________ the compounds of the invention may also be useful in the treatment of various pathophysiological diseases including acute myocardial infarction , vascular thrombosis , hypertension , pulmonary hypertension , ischemic heart disease , congestive heat failure , and angina pectoris , in which case the compounds may be administered by any means that effect vasodilation and thereby relieve the symptoms of the disease . for example , administration may be by oral , transdermal , parenterial , subcutaneous , intravenous , intramuscular , intraperitoneal , transdermal , or buccal routes . the compounds of the invention may be used alone , or in combination with other of the known vasodilator drugs . the compounds of the invention may be formulated into an ointment containing about 0 . 10 to 10 % of the active ingredient in a suitable base of , for example , white petrolatum , mineral oil and petrolatum and lanolin alcohol . other suitable bases will be readily apparent to those skilled in the art . the pharmaceutical preparations of the present invention are manufactured in a manner which is itself known , for example , by means of conventional dissolving or suspending the compounds , which are all either water soluble or suspendable . for administration in the treatment of the other mentioned pathophysiological disorders . the pharmaceutical preparations which can be used orally include push - fit capsules made of gelatin , as well as soft , sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol . the push - fit capsules can contain the active compounds in liquid form that may be mixed with fillers such as lactose , binders such as starches , and / or lubricants such as talc or magnesium stearate and , optionally , stabilizers . in soft capsules , the active compounds are preferably dissolved or suspended in suitable liquids , such as in buffered salt solution . in addition , stabilizers may be added . in addition to being provided in a liquid form , for example in gelatin capsule or other suitable vehicle , the pharmaceutical preparations may contain suitable excipients to facilitate the processing of the active compounds into preparations that can be used pharmaceutically . thus , pharmaceutical preparations for oral use can be obtained by adhering the solution of the active compounds to a solid support , optionally grinding the resulting mixture and processing the mixture of granules , after adding suitable auxiliaries , if desired or necessary , to obtain tablets or dragee cores . suitable excipients are , in particular , fillers such as sugars , for example lactose or sucrose , mannitol or sorbitol , cellulose preparations and / or calcium phosphates , for example tricalcium phosphate or calcium hydrogen phosphate , as well as inders such as starch , paste using for example , maize starch , wheat starch , rich starch potato starch , gelatin , tragacanth , methyl cellulose , hydroxypropylmethylcellulose , sodium carboxymethylcellulose , and / or polyvinyl pyrrolidone . if desired , disintegrating agents may be added such as the above - mentioned starches and also carboxymethyl - starch , crosslinked polyvinyl pyrrolidone , agar , or algenic acid or a salt thereof , such as sodium alginate . auxiliaries are , above all , flow - regulating agents and lubricants , for example , silica , talc , stearic acid or salts thereof , such as magnesium stearate or calcium stearate , and / or polyethylene glycol . dragee cores are provided with suitable coatings which if desired , are resistant to gastric juices . for this purpose , concentrated sugar solutions may be used , which may optionally contain gum arabic , talc , polyvinyl pyrrolidone , polyethylene glycol and / or titanium dioxide , lacquer solutions and suitable organic solvents or solvent mixtures . in order to produce coatings resistant to gastric juices , solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl - cellulose phthalate , are used . dye stuffs or pigments may be added to the tablets or dragee coatings , for example , for identification or in order to characterize combinations of active compound doses . suitable formulations for intravenous or parenteral administration include aqueous solutions of the active compounds . in addition , suspensions of the active compounds as oily injection suspensions may be administered . aqueous injection suspensions may contain substances which increase the viscosity of the suspension include , for example , sodium carboxymethyl cellulose , soribitol , and / or dextran . optionally , the suspension may also contain stabilizers . the foregoing description details specific methods and compositions that can be employed to practice the present invention , and represents the best mode contemplated . however , it is apparent for one of ordinary skill in the art that further compounds with the desired pharmacological properties can be prepared in an analogous manner , and that the disclosed compounds can also be obtained from different starting compounds via different chemical reactions . similarly , different pharmaceutical compositions may be prepared and used with substantially the same result . thus , however detailed the foregoing may appear in text , it should not be construed as limiting the overall scope hereof ; rather , the ambit of the present invention is to be governed only by the lawful construction of the appended claims .
the invention relates to the use of derivatives of f - type prostaglandins as ocular hypotensives . the pgf derivatives used in accordance with the invention are represented by the following formula i : ## str1 ## wherein wavy line attachments indicate either the alpha or beta configuration ; hatched segments indicate α configuration , solid triangles are used to indicate β configuration , dashed bonds represent a double bond , or a single bond , r is a substituted heteroaryl radical , r 1 is hydrogen or a lower alkyl radical having up to six carbon atoms , x is selected from the group consisting of -- or 1 and -- n 2 , y is ═ o or represents 2 hydrogen radicals . certain of the compounds represented by formula i comprise another aspect of the present invention .