the present invention relates to the use of cyclopentane heptan ( ene ) oic acid , 2 - thiocarbamoyloxy and 2 - carbamoyloxy 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 : wherein the substituents and symbols are as hereinabove defined . the dotted line on the bond between carbons 5 and 6 ( c - 5 ) indicates a single or double bond . if two solid lines are used at c - 5 , it indicates a specific configuration for that double bond . a preferred group of the compounds of the present invention includes compounds that have the following structural formula ii : wherein n is 0 or 1 , 2 or 4 ; hatched lines at position c - 8 , c - 9 and c - 11 indicate the α configuration ; and the triangle at position c - 12 represents β orientation . preferably y is ═ o . more preferably , ar is selected from the group consisting of phenyl , furyl and thienyl . in compounds of formula iii , preferably x is — or 1 or n ( r 1 ) 2 and y is ═ o , e . g . the 1 - position is a carboxylic acid or carboxylamide radical . preferably x is oh , nh 2 , nhc 2 h 5 or nhc 2 h 4 oh 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 . 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 scheme of fig1 wherein like numbers refer to the same compounds . phenylisocyanate ( 68 μl , 0 . 63 mmol ) was added to a solution of 1 , 4 - c - diazabicyclo [ 2 . 2 . 2 ] octane ( 76 . 5 mg , 0 . 68 mmol ) and alcohol 1 ( 250 mg , 0 . 57 mmol ) in thf ( 3 . 0 ml at 23 ° c . after 16 h the reaction was concentrated in vacuo and the residue was purified by flash column chromatography ( silica gel , 3 : 1 hexane / etoac ) to afford the title compound . a solution of bis - thp ether 2a obtained above and pyridinium p - toluenesulfonate ( 150 mg , 0 . 60 mmol ) in meoh ( 6 . 0 ml ) was stirred at 23 ° c . for 12 h . the solvent was removed in vacuo . the residue was diluted with etoac and washed with 1n hcl , saturated aqueous nahco 3 and brine . the organic portion was dried ( mgso 4 ), filtered and concentrated in vacuo . flash column chromatography ( silica gel , 100 % etoac ) of the residue provided 208 mg ( 93 % over two steps ) of the title compound . a mixture of ester 3a ( 64 mg , 0 . 163 mmol ) and lithium hydroxide ( 0 . 66 ml of a 0 . 5 n solution in h 2 o , 0 . 33 mmol ) in thf ( 1 . 3 ml ) was stirred at 23 ° c . for 12 h . the reaction was acidified with 1n hcl and extracted with etoac . the organic portion was washed with brine ( 2x ), dried ( mgso 4 ), filtered and concentrated in vacuo . the residue was purified by flash column chromatography ( silica gel , 9 : 1 etoac / meoh ) to afford 55 . 3 mg ( 90 %) of the title compound . according to the procedures described for 2a the reaction of alcohol 1 ( 275 mg , 0 . 63 mmol ), 1 , 4diazabicyclo [ 2 . 2 . 2 ] octane ( 83 . 6 mg , 0 . 75 mmol ), and benzylisocyanate ( 99 . 3 mg , 0 . 75 mmol ) afforded 182 . 6 mg ( 51 %) of the title compound after purification by flash column chromatography ( silica gel , 2 : 1 hexane / etoac ). according to the procedures described for 3a the reaction of bis - thp ether 2b ( 240 mg , 0 . 42 mmol ) and pyridinium p - toluenesulfonate ( 100 mg , 0 . 40 mmol ) afforded 153 . 1 mg ( 90 %) of the title compound after purification by flash column chromatography ( silica gel , 1 : 1 hexane / etoac ). according to the procedures described for 4a the reaction of ester 3b ( 40 mg , 0 . 99 mmol ) and lithium hydroxide hydroxide ( 0 . 40 ml of a 0 . 5 n solution in h 2 o , 0 . 20 mmol ) afforded 35 . 6 mg ( 92 %) of the title compound after purification by flash column chromatography ( silica gel , 100 % etoac ). according to the procedures described for 2a the reaction of alcohol 1 ( 300 mg , 0 . 68 mmol ), 1 , 4 - diazabicyclo [ 2 . 2 . 2 ] octane ( 153 . 0 mg , 1 . 36 mmol ), and benzylthioisocyanate ( 0 . 14 ml , 1 . 02 mmol ) afforded 380 . 3 mg ( 95 %) of the title compound after purification by flash column chromatography ( silica gel , 3 : 1 hexane / etoac ). according to the procedures described for 3a the reaction of bis - thp ether 2c ( 3 80 . 3 mg , 0 . 65 mmol ) and pyridinium p - toluenesulfonate ( 200 mg , 0 . 78 mmol ) afforded 246 . 4 mg ( 91 %) of the title compound after purification by flash column chromatography ( silica gel , 1 : 1 hexane / etoac ). according to the procedures described for 4a the reaction of ester 3c ( 60 mg , 0 . 142 mmol ) and lithium hydroxide ( 0 . 57 ml of a 0 . 5 n solution in h 2 o , 0 . 29 mmol ) afforded 9 . 7 mg ( 17 %) of the title compound after purification by flash column chromatography ( silica gel , 100 % etoac ). according to the procedures described above in examples 1 , 2 and 3 for conversion of alcohol 1 to 4a , the use of ( 2 - thiophen - 2 - ylethylimino ) ethenone afforded 80 mg of the title compound after purification by flash column chromatography ( silica gel , 100 % etoac ). according to the procedures described above in examples 1 , 2 and 3 for conversion of alcohol 1 to 4a , the use of ( butylimino ) ethenethione in refluxing thf afforded 20 mg of the title compound after purification by flash column chromatography ( silica gel , 100 % etoac ). according to the procedures described above in examples 1 , 2 and 3 for conversion of alcohol 1 to 4a , the use of ( 3 - chlorobenzylimino ) ethenethione in refluxing thf afforded 30 . 5 mg of the title compound after purification by flash column chromatography ( silica gel , 100 % etoac ). according to the procedures described above in examples 1 , 2 and 3 for conversion of alcohol 1 to 4a , the use of ( 3 - trifluoromethylbenzylthio ) ethenone afforded 20 mg of the title compound after purification by flash column chromatography ( silica gel , 100 % etoac ). according to the procedures described above in examples 1 , 2 and 3 for conversion of alcohol 1 to 4a , the use of ( 3 - trifluoromethylbenzylthio ) ethenethione in refluxing thf afforded 22 . 7 mg of the title compound after purification by flash column chromatography ( silica gel , 100 % etoac ). ( 3 - chlorobenzylimino ) ethenethione ( 826 . 6 mg , 4 . 5 mmol ) was added to a solution of alcohol 5 ( 717 mg , 1 . 54 mmol ) and 1 , 4diazabicyclo [ 2 . 2 . 2 ] octane ( 345 . 5 mg , 3 . 08 mmol ) in thf ( 10 ml ) and refluxed for 24 h . the mixture was concentrated in vacuo and the residue was purified by flash column chromatography ( silica gel , 2 : 1 hex / etoac ) to afford 614 mg ( 63 %) of the above titled compound . a solution of ester 6 ( 614 mg , 0 . 97 mmol ) and lithium hydroxide ( 62 mg , 1 . 5 mmol ) in thf / h 2 o ( 1 : 1 , 20 ml ) was stirred at 23 ° c . for 72 h . the mixture was acidified with 1n hcl and extracted with etoac . the organic portion was washed with brine , dried ( na 2 so 4 ), filtered and concentrated in vacuo to give 430 mg of the above titled compound . a solution of acid 7 ( 60 mg , 0 . 10 mmol ) and triethylamine ( 30 mg , 0 . 30 mmol ) in ch 2 cl 2 ( 2 ml ) was cooled to 0 ° c . and ethylchloroformate ( 11 μl , 0 . 12 mmol ) was added . after 0 . 5 h ethanolamine ( 7 . 2 μl , 0 . 12 mmol ) was added and the reaction was allowed to warm to room temperature for 12 h . the reaction was diluted with etoac and washed with 1n hcl , saturated aqueous nahco 3 and brine . the organic portion was dried ( na 2 so 4 ), filtered and concentrated in vacuo . purification of the residue by flash column chromatography ( silica gel , 100 % etoac followed by 19 : 1 etoac / meoh ) provided 40 mg of the above titled compound . a solution of bis - thp ether 8a ( 40 mg , 0 . 062 mmol ) and pyridinium p - toluenesulfonate ( 5 mg ) in meoh ( 1 . 5 ml ) was stirred at 23 ° c . for 16 h . the solvent was removed in vacuo and the residue was diluted with etoac and washed with 1n hcl , saturated aqueous nahco 3 and brine . the organic portion was dried ( na 2 so 4 ), filtered and concentrated in vacuo . purification of the residue by flash column chromatography ( silica gel , 100 % etoac followed by 9 : 1 etoac / meoh ) provided 20 mg of the above titled compound . according to the procedures described above in examples 17 and 18 acid 7 was converted with use of ethylamine to 30 mg of the above titled compound . according to the procedures described above in examples 17 and 18 acid 7 was converted with use of ammonia to 10 mg of the above titled compound . certain of the above compounds were tested for activity in the various in vitro assays described below and the results are reported in table 1 , 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 . activity was also measured as relaxation of smooth muscle of isolated rabbit jugular vein a preparation which appears to contain a unique pgf 2α - sensitive receptor provisionally termed fp vasc . tp - vasoconstrictor activity was measured as contraction of rings of the isolated rat thoracic aorta . 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 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 fig3 and 4 . 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 . the compounds of examples 9 and 12 both lowered intraocular pressure . 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 petroatum 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 binders such as starch , paste using for example , maize starch , wheat starch , rice 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 containing 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 cyclopentane heptanoic acid , 2 - thiocarbamoyloxy and carbamoyloxy as therapeutic agents e . g . as ocular hypotensives . the compounds used in accordance with the invention are represented by the following formula i : wherein a wavy segments indicate either the alpha or beta configuration ; the dashed bond represents a double bond or a single bond ; ar is selected from the group consisting of aryl or heteroaryl radicals having from 4 to 10 carbon atoms and substituted derivatives of said aryl and heteroaryl radicals ; n is 0 or an integer of from 1 to 4 ; x and y are 1 or 0 , provided that when x is 1 , y is 0 and when x is 0 , y is 1 ; r 1 is hydrogen or a lower alkyl radical or a substituted 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 , and the 9 and / or 11 esters thereof and / or the pharmaceutically acceptable salts of said compounds and / or esters .