DETAILED DESCRIPTION OF THE INVENTION

[0030] In all of the above formulae the dotted lines on bonds between carbons 5 and 6 (C-5) of the a chain, between carbons 13 and 14 (C-13) of the w chain, and between carbons 10 and 11 (C-11) of the cyclopentane ring, indicate a single or a double bond which can be in the cis or trans configuration (Of course, the C-10 and C-11 double bonds being part of the cyclopentane ring will exist only as cis double bonds). If two solid lines are used that indicates a specific configuration for that double bond. Hatched lines at positions C-8, C-9, C-11, C-12 and C-15 indicate the a configuration. If one were to draw the b configuration, a solid triangular line would be used.

[0031] In the compounds used in accordance with the present invention, compounds having the C-8, C-9, C-11, C-12 or C-15 substituents in the a or b configuration are contemplated.

[0032] For the purpose of this invention, unless further limited, the term “alkyl” refers to alkyl groups having from one to ten carbon atoms, the term “cycloalkyl” refers to cycloalkyl groups having from three to seven carbon atoms, the term “aryl” refers to aryl groups having from four to ten carbon atoms. The term “hydrocarbyl” means radicals having up to 20 carbon atoms and the remaining atoms comprising said hydrocarbyl radical are hydrogen. In the “heteroatom-substituted” radicals any of the carbon atoms or the hydrogen atoms may be replaced by one of the above defined heteroatoms. Such hydrocarbyl radicals include aryl, alkyl, alkenyl and alkynyl groups of appropriate lengths, and may be methyl, ethyl, propyl, butyl, pentyl, or hexyl, or an isomeric form thereof; ethenyl, propenyl, etc.; phenyl, etc.

[0033] In FIG. 1 PGF _2a or 17-phenyl (18, 19, 20 trinor) PGF _2a is reacted with diazomethane to convert such compounds to the corresponding 1-methyl ester. In this scheme R ₄ is n-propyl or phenyl. Subsequently, as shown in Reaction 1b and further illustrated in Examples 1 and 3, the above 1-methyl esters are reacted with an organoiodide, represented by R ₁ I, R ₂ I or R ₃ I, in the presence of Ag ₂ O and dimethyl formamide, e.g. at 23° C.

[0034] In FIG. 2 the 1-methyl ester, prepared according to the reaction 1b of FIG. 1 , is reacted to provide various compounds of this invention. As shown in Reaction 2d and Example 7, the 1-methyl ester may be hydrolyzed with 0.5 N aqueous LiOH in tetrahydrofuran (THF) to yield the corresponding acid. Alternatively, the 1-methylester may be reduced with LiBH ₄ in ethylether, in accordance with Reaction 2c and as illustrated in Example 6, to yield the corresponding alcohol. This alcohol may be subsequently converted into the 5-t-butyl dimethyl siloxy derivative and reacted, in accordance with Reaction 2e, with 2,6-di-t-butyl pyridine in CH ₂ Cl ₂ and subsequently reacted with methyl triflate (MeOTF) to form the 1-methoxy derivative. To provide other 1-hydrocarbyloxy esters the alternate Reaction 2e may be utilized whereby the 1-alcohol may be reacted with the hydrocarbyl chloride, R ₇ Cl, wherein R ₇ is a hydrocarbyl radical comprising up to 20 carbon atoms, e.g. a C1 to C4 alkyl chloride, in the presence 4-dimethylaminopyridine (DMAP) in triethylamine and CH ₂ Cl ₂ . Finally, the 1-methylester may be reacted, in accordance with Reaction 2a and as illustrated in Example 4, with an amine, R ₅ R ₆ NH, wherein R ₅ and R ₆ are selected from the group consisting of hydrogen and hydrocarbyl radicals, preferably hydrogen and C ₁ to C ₄ alkyl radicals, in CH ₃ OH, for example at a temperature of 55° C., to yield the corresponding amides. Such amides may be subsequently reduced with LiAlH ₄ in THF, in accordance with Reaction 2b and as illustrated by Example 5, to yield the corresponding amines.

[0035] In FIG. 3 the 1-methyl ester, prepared according to the reaction scheme of FIG. 1 , is reacted in accordance with Reaction 3a of FIG. 3 and as illustrated by Example 17 to yield the 15-pivaloyl ester of said 1-methyl ester. The compound is subsequently reacted in accordance with Reaction 3b of FIG. 3 and as illustrated by Example 17a to yield the 11-methoxy derivative. This compound may then be converted to the 1-acid in accordance with Reaction 3c, as illustrated by Example 17b, to yield the 11-methoxy, 15 pivaloyloxy acid of the invention.

[0036] In FIG. 4 , the 1-methylester prepared in accordance with the reaction scheme of FIG. 1 , is consecutively reacted according to Reactions 1a through 1c, as illustrated in Example 18 to yield the 5-trans compounds of this invention.

[0037] The following novel compounds may be used in the pharmaceutical compositions and the methods of treatment of the present invention.

[0038] Methyl 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cycl opentyl]-5Z-heptenoate

[0039] 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cycl opentyl]-5Z-heptenoic acid

[0040] 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cycl opentyl]-5Z-hepten-1-ol

[0041] 7-[5α-Hydroxy-2β-(3α-pivalyl-1E-octenyl)-3α-methoxy-cycl opentyl]-5Z-heptenoic acid

[0042] Methyl 7-[5α-Hydroxy-2β-(3α-pivalyl-1E-octenyl)-3α-methoxy-cycl opentyl]-5Z-heptenoate

[0043] 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cycl opentyl]-5Z-hepten-1-pivalate

[0044] Methyl 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cycl opentyl]-5E-heptenoate

[0045] 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cycl opentyl]-5E-heptenoic acid

[0046] 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cycl opentyl]-5E-hepten-1-ol

[0047] Methyl 7-[3α-ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclo pentyl]-5Z-heptenoate

[0048] 7-[3α-Ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclo pentyl]-5Z-heptenoic acid

[0049] 7-[3α-Ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclo pentyl]-5Z-hepten-1-ol

[0050] 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cycl opentyl]-5Z-heptenamide

[0051] N,N-Dimethyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α -methoxy-cyclopentyl]-5Z-heptenamide

[0052] Methyl 7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-(2-propenoxy )-cyclopentyl]-5Z-heptenoate

[0053] 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-(2-propenoxy )-cyclopentyl]-5Z-hepten-1-ol

[0054] 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-(2-propenoxy )-cyclopentyl]-5Z-heptenoic acid

[0055] Methyl 7-[3α,5α-dimethoxy-2β-(3α-hydroxy-1E-octenyl)-cyclopenty l]-5Z-heptenoate

[0056] 7-[3α,5α-dimethoxy-2β-(3α-hydroxy-1E-octenyl)-cyclopenty l]-5Z-heptenoic acid

[0057] 7-[3α,5α-dimethoxy-2β-(3α-hydroxy-1E-octenyl)-cyclopenty l]-5Z-hepten-1-ol

[0058] Methyl 7-[3α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-5α-methoxy-cycl opentyl]-5Z-heptenoate

[0059] 7-[3α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-5α-methoxy-cycl opentyl]-5Z-heptenoic acid

[0060] 7-[3α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-5α-methoxy-cycl opentyl]-5Z-hepten-1-ol

[0061] N-Isopropyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α- methoxy-cyclopentyl]-5Z-heptenamide

[0062] N-Isopropyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α- methoxy-cyclopentyl]-5Z-heptenamine

[0063] N,N-Dimethyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α -methoxy-cyclopentyl]-5Z-heptenamine

[0064] 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxy-cycl opentyl)-5Z-hepten-1-ol

[0065] 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxy-cycl opentyl)-5Z-heptenoic acid

[0066] Methyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3αpropox y-cyclopentyl]-5Z-heptenoate

[0067] Methyl-7-[3α,5α-dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyc lopentyl]-5Z-heptenoate

[0068] 7-[3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopenty l]-5Z-heptenoic acid

[0069] 7-[3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopenty l]-5Z-hepten-1-ol

[0070] 1-Acetoxy-7-[3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)- cyclopentyl]-5Z-heptene

[0071] 7-[3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopenty l]-1-methoxy-5Z-heptene

[0072] 7-[3α-ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclo pentyl]-5Z-heptenamide

[0073] N-Isopropyl-7-[3α-ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-oc tenyl)-cyclopentyl]-5Z-heptenamide

[0074] N-Isopropyl-7-[3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl )-cyclopentyl]-5Z-heptenamide

[0075] Methyl-7-[3α,5α-Dihydroxy-2β-(3α-ethoxy-1E-octenyl)-cycl opentyl]-5Z-heptenoate

[0076] 7-[3α,5α-Dihydroxy-2β-(3α-ethoxy-1E-octenyl)-cyclopentyl ]-5Z-heptenoic acid

[0077] Methyl 7-[3α-Butoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclo pentyl]-5Z-heptenoate

[0078] 7-[3α-Butoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclo pentyl]-5Z-hepten-1-ol

[0079] 7-[3α-Butoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclo pentyl]-5Z-heptenoic acid

[0080] N-Isopropyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α- propoxy-cyclopentyl]-5Z-heptenamide

[0081] 7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxy-cycl opentyl]-5Z-heptenamide

[0082] Isopropyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-pr opoxy-cyclopentyl]-5Z-heptenoate

[0083] 7-[3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopenty l]-5Z-heptenamide

[0084] Isopropyl-7-[3α,5α-dihydroxy-2β-(3α-methoxy-1E-octenyl)- cyclopentyl]-5Z-heptenoate

[0085] Methyl-7-[3α,5α-Dihydroxy-2β-(3α-methoxy-5-phenyl-1E-pen tenyl)-cyclopentyl]-5Z-heptenoate

[0086] 7-[3α,5α-Dihydroxy-2β-(3α-methoxy-5-phenyl-1E-pentenyl)- cyclopentyl]-5Z-heptenoic acid

[0087] 7-[3α,5α-Dihydroxy-2β-(3α-methoxy-5phenyl-1E-pentenyl)-c yclopentyl]-5Z-heptenamide

[0088] 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. Such salts are those formed with pharmaceutically acceptable cations, e.g., alkali metals, alkali earth metals, etc.

[0089] 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 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.

[0090] 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 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.

[0091] 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 cyclodextrin and purified water.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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 of or in conjunction with it.

[0096] The ingredients are usually used in the following amounts: 1

[0097] 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.

[0098] 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 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. One package may contain one or more unit doses.

[0099] Especially preservative-free solutions are often formulated in non-resealable containers containing up to about ten, preferably up to about five units doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops. The volume of one drop usually is about 20-35 ml.

[0100] The invention is further illustrated by the following non-limiting Examples.

EXAMPLE 1

Methyl 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cycl opentyl]-5Z-heptenoate

[0101] In accordance with Reaction 1b of Scheme 1, 300 mg. (0.815 mmols) of the 1-methylester of PGF _2α were dissolved in 1.0 mL of dimethylformamide (DMF). To this solution was added 150.5 mg. (0.649 mmol) of Ag ₂ O and 173.6 mg. (1.22 mmol) of methyliodide (MeI) and the resulting solution was stirred at 23° C. to obtain (8% yield) of the named compound in admixture with the 9-mono (4% yield), 15-mono and 11, 15 bis (14% yield) methyl ethers of the 1-methylester of PGF _2α . (The compounds obtained in admixture with the named compound may also be referred to as the 5α-methoxy, 2β-(3α-methoxy-1E-octenyl) and 2β-(3α-methoxy-1E-octenyl)-3α methoxy analogues of the named compound, respectively. The ethers were separated using high pressure liquid chromatography (HPLC) and eluting the admixture with a 1 to 1 mixture of hexane (hex) and ethylacetate (EtOAc) over a Whatman PARTISIL 10 PAK column.

EXAMPLE 1a

Methyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-p ropoxycyclopentyl]-5Z-heptenoate

[0102] The named compound may be prepared by substitution of n-propyliodide for methyl iodide in the procedure of Example 1.

EXAMPLE 1b

Methyl-7-[3α-ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-oct enyl)-cyclopentyl]-5Z-heptenoate

[0103] The named compound may be prepared by substitution of ethyliodide for methyl iodide in the procedure of Example 1.

EXAMPLE 1c

Methyl-7-[3α-Butoxy-5α-hydroxy-2β-(3α-hydroxy-1E-oct enyl]-cyclopentyl]-5Z-heptenoate

[0104] The named compound may be prepared by substitution of n-butyliodide for methyl iodide in the procedure of Example 1.

EXAMPLE 1d

Methyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-( 2-propenoxy)-cyclopentyl]-5Z-heptenoate

[0105] The procedure of Example 1 is repeated using allyliodide in place of methyliodide to yield the named compound.

EXAMPLE 2

Isopropyl 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cycl opentyl]-5Z-heptenoate

[0106] The procedure of Example 1 was repeated except that the 1-isopropylester of PGF _2α was utilized as the reactant in place of the corresponding methyl ester to yield a reaction solution containing an admixture of mono and bis methyl ethers. The reaction solution was diluted with CH ₂ Cl ₂ and filtered through Celite. The filtrate was concentrated under vacuum, diluted with ethylether (Et ₂ O) and washed twice with water. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under vacuum. The residue was purified by flash column chromatography (FCC) with an eluant of 1 to 1 hex/EtOAc to yield 120 mg. (59% yield) of the named compound and the 15-methyl ether analogue, thereof. 80% of the purified mixture was the named compound.

EXAMPLE 3

Isopropyl 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxy-cycl opentyl]-5Z-heptenoate

[0107] 20 mg. (0.050 mmol) of PGF _2α was combined with 47 mg (0.252 mmol of O-isopropyl N,N′-diisopropyl isourea in 1.0 mL of benzene and heated at 85° C. for 20 hours. The reaction mixture was concentrated in vacuo and the residue was purified by FCC using a 3 to 1 mixture of hexane and EtOAc to yield 16.3 mg. (74% yield) of the 11-isopropylester of PGF _2α . The named compound may be prepared from said 11-isopropyl ester by substitution of propyliodide for methyliodide in the procedure of Example 2.

EXAMPLE 4

N-Isopropyl-7-(5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)- 3α-methoxy-cyclopentyl]-5Z-heptenamide

[0108] In accordance with Reaction 2a of FIG. 2, 220 mg. (0.5759 mmol) of the compound of Example 1 were mixed with 549 mg (5.759 mmol) of isopropylamine hydrochloride in 6.0 mL of isopropylamine and heated in a sealed tube for 72 hours at 75° C. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with water. The organic layer was treated as in Example 2 to yield 23.5 mg (10% yield) of the named compound.

EXAMPLE 4a

N,N-Dimethyl-7-(5α-hydroxy-2β-(3α-hydroxy-1E-octenyl) -3α-methoxy-cyclopentyl]-5Z-heptenamide

[0109] The named compound is prepared in accordance with the procedure of Example 4 by using methylamine hydrochloride in methylamine.

EXAMPLE 4b

N-Isopropyl-7-(3α-ethoxy-5α-hydroxy-2β-(3α-hydroxy-1 E-octenyl)-cyclopentyl]-5Z-heptenamide

[0110] The named compound is prepared by substituting the compound of Example 1b in the process of Example 4.

EXAMPLE 4c

N-Isopropyl-7-(5α-hydroxy-2β-(α-hydroxy-1E-octenyl)-3 α-propoxy-cyclopentyl]-5Z-heptenamide

[0111] The named compound is prepared by substituting the compound of Example 1a in the process of Example 4.

EXAMPLE 4d

N,N-Dimethyl-7-(5α-hydroxy-2β-(3α-hydroxy-1E-octenyl) -3α-methoxy-cyclopentyl]-5Z-heptenamide

[0112] Dimethylamine (˜5 ml) was condensed in a tube containing 100 mg (0.1639 mmol) of the 5-t-butyldimethylsiloxy, 3-methoxy derivative of PGF _2α , methylester dissolved in 6.0 mL of CH ₃ OH. The resultant solution was stirred in a sealed glass tube for 48 hours and concentrated in vacuo. The residue diluted with THF (1.0 mL) and treated with Bu ₄ NF (0.26 mL of a 1.0M solution, 0.262 mmol) at 23° C. After 16 hours, the reaction was diluted with Et ₂ O and washed with H ₂ O. The organic portion was dried (MgSO ₄ ), filtered and concentrated in vacuo. FCC (100% EtOAc followed by 9:1 CH ₂ Cl ₂ /MeOH) gave 24.2 mg. (39%) of the product.

EXAMPLE 5

N-Isopropyl-7-(5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)- 3α-methoxy-cyclopentyl]-5Z-heptenamine

[0113] In accordance with Reaction 2b of FIG. 2, 75 mg of the compound of Example 4, dissolved in 2.0 mL of tetrahydrofuran (THF) were treated with 34.6 mg. (0.9165 mmol) of lithium aluminumhydride (LAH) at 23° C. After 24 hours, the reaction mixture was quenched with 2.0 N NaOH and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under vacuum. The residue was purified with FCC using a 6:1:0.1 mixture of CH ₂ Cl ₂ /MeOH/NH ₄ OH to yield 19.0 mg. (26% yield) of the named compound.

EXAMPLE 5a

N,N-Dimethyl-7-(5α-hydroxy-2β-(3α-hydroxy-1E-octenyl) -3α-methoxy-cyclopentyl]-5Z-heptenamine

[0114] The named compound is prepared by substitution of the compound of Example 4a in the procedure of Example 5.

EXAMPLE 6

7-(5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy- cyclopentyl]-5Z-hepten-1-ol

[0115] In accordance with Reaction 2c of FIG. 2, 20.2 mg (0.0529 mmol) of the compound of Example 1 were dissolved in 1.5 mL of Et ₂ O and treated with 2.3 mg (0.105 mmol) of LiBH ₄ to yield a reaction mixture comprising the named product. The resulting product was purified by FCC with a 1 to 1 mixture of hex/EtOAc followed by 100% EtOAc to yield 16.3 mg. (87%) of the named compound.

EXAMPLE 6a

7-[3α-Ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-c yclopentyl]-5Z-hepten-1-ol

[0116] The named compound is prepared by substituting the compound of Example 1b in the process of Example 6.

EXAMPLE 6b

7-[3α-Butoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-c yclopentyl]-5Z-hepten-1-ol

[0117] The named compound is prepared by substituting the compound of Example 1c in the process of Example 6.

EXAMPLE 6c

7-[3α-Propoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)- cyclopentyl]-5Z-hepten-1-ol

[0118] The named compound is prepared by substituting the compound of Example 1(a) in the process of Example 6.

EXAMPLE 6d

7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-(2-prope noxy)-cyclopentyl]-5Z-hepten-1-ol

[0119] The procedure of Example 6 is repeated using the compound of Example 1(d) as the starting material to yield the named compound.

EXAMPLE 7

7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy- cyclopentyl]-5Z-heptenoic Acid

[0120] 40 mg (0.1047 mmol) of the compound of Example 1 were dissolved in a mixture of 0.31 mL of 0.5 N aqueous LiOH and 0.62 mL of THF in accordance with Reaction 2d of Scheme 2. After the reaction mixture was acidified with 10% aqueous citric acid and extracted with CH ₂ Cl ₂ . The organic portion was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by FCC using a 95 to 5 mixture of EtOAc and MeOH to yield 28.6 mg. (75% yield) of the named compound.

EXAMPLE 7a

7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxy- cyclopentyl]-5Z-heptenoic Acid

[0121] The named compound is prepared by substituting the compound of Example 1a in the procedure of Example 7.

EXAMPLE 7b

7-[3α-Ethoxy-5α-hydroxy-2β-(3-hydroxy-1E-octenyl)-cyc lopentyl]-5Z-heptenoic Acid

[0122] The named compound is prepared by substituting the compound of Example 1b in the procedure of Example 7.

EXAMPLE 7c

7-[3α-Butoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-c yclopentyl]-5Z-heptenoic Acid

[0123] The named compound is prepared by substituting the compound of Example 1c in the procedure of Example 7.

EXAMPLE 7d

7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-(2-prope noxy)-cyclopentyl]-5Z-heptenoic Acid

[0124] The named compound is prepared by substituting the compound of Example 1d in the procedure of Example 7.

EXAMPLE 8

7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy- cyclopentyl]-5Z-heptenamide

[0125] According to the procedures described for Example 4, the compound of Example 1 is reacted with NH ₄ Cl dissolved in NH ₃ to yield the named compound.

EXAMPLE 8a

7-[3α-Ethoxy-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-c yclopentyl]-5Z-heptenamide

[0126] In accordance with Example 8, 100 mg (0.252 mmol) of the compound of Example 1(b) is reacted with 135 mg (2.52 mmol) of NH ₄ Cl dissolved in 5 mL of NH ₃ to give the named compound in 69% yield.

EXAMPLE 8b

7-[5α-Hydroxy-2β-(3α-hydroxy-1-octenyl)-3α-propoxy-c yclopentyl]-5Z-heptenamide

[0127] In accordance with Example 8, 52 mg (0.127 mmol) of the compound of Example 1(a) is reacted with 68 mg (1.27 mmol) of NH ₄ Cl dissolved in 4.5 mL of NH ₃ to give the named compound in 86% yield.

EXAMPLE 9

7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy- cyclopentyl]-1-pivaloyloxy 5Z-heptene

[0128] The 1-t-butyldimethylsilyl ester of 3-methoxy PGF _2α and 5.2 mg (0.239 mmol) of LiBH ₄ was dissolved in 1.0 mL of ethylether and stirred for 16 hours at 23° C. The reaction mixture was quenched with 2.0 N aqueous NaOH and extracted with CH ₂ Cl ₂ . The organic portion was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was dissolved in 0.5 mL of pyridine and cooled to 0° C. 17.7 uL(0.143 mmol) of trimethylacetyl chloride were added and after 24 hours the reaction was diluted with EtOAc, washed with saturated aqueous NH ₄ Cl and brine and dried over anhydrous MgSO ₄ . The dried product was filtered and concentrated under vacuum before purifying by use of FCC and a 1 to 1 mixture of hexane and EtOAc to yield 15.9 mg (31% yield of the named compound).

EXAMPLE 10

7-[3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclop entyl]-1-methoxy-5Z-heptene

[0129] In accordance with Reaction 2e of Scheme 2, a solution of the compound of Example 6 and 0.46 mL 2, 6di-t-butylpyridine (2.058 mmol) in 2.0 mL CH ₂ Cl ₂ was treated with methyl triflate (194 ul, 1.715 mmol) and stirred for 48 hours at 23° C. The reaction mixture was quenched with saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ . The combined organic portion was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was diluted with 2.0 mL of THF and 1.4 mL of a 1.0M solution of Bu ₄ NF in THF. After 16 hours, the reaction was diluted with EtOAc and washed with H ₂ O. The organic portion was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. Treating by FCC with 1:1 hex/EtOAc gave 66.1 mg (53% yield) of the named compound.

EXAMPLE 11

1-Acetoxy-7-[3α-5α-Dihydroxy-2β-(3α-methoxy-1E-octen yl)-cyclopentyl]-5Z-heptene

[0130] 1-Acetoxy-7-[3α,5α-t-butyldimethylsiloxy-2β-(3α-methoxy- 1E-octenyl)-cyclopentyl]-5Z-heptene is reacted with Bu ₄ NF in THF at room temperature to yield the named compound.

EXAMPLE 12

Methyl 7-[3α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-5α-methoxy-cycl opentyl]-5Z-heptenoate

[0131] The named compound is prepared in accordance with the procedure of Example 1.

EXAMPLE 12a

7-[3α-Hydroxy-2β-(3α-hydro-1E-octenyl)-5α-methoxy-cy clopentyl]-5Z-heptenoic Acid

[0132] The named compound is prepared by reacting the compound of Example 12 in accordance with the process of Example 7.

EXAMPLE 12b

7-[3α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-5α-methoxy- cyclopentyl]-5Z-hepten-1-ol

[0133] The named compound is prepared by reacting the 1-t-butyl dimethylsiloxy ester of the compound of Example 12(a) in accordance with the process of Example 6.

EXAMPLE 13

7-[3α-5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclop entyl]-5Z-hepten-1-ol

[0134] The 15-monomethyl ether of Example 1 is reacted in accordance with the process of Example 6 to yield the named compound.

EXAMPLE 13a

7-[3α-5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclop entyl]-5Z-heptenoic Acid

[0135] The 15-monomethyl ester of Example 1 is reacted in accordance with the process of Example 7 to yield the named compound.

EXAMPLE 13b

Isopropyl-7-[3α-5α-Dihydroxy-2β-(3α-methoxy-1E-octen yl)-cyclopentyl-5Z-heptenamide

[0136] The 15-monomethyl ester of Example 1 is reacted in accordance with the process of Example 4 to yield the named compound.

EXAMPLE 13c

7-[3α-5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclop entyl]-5Z-heptenamide

[0137] The 15-monomethyl ester of Example 1 is reacted in accordance with the process of Example 8 to yield the named compound.

EXAMPLE 14

Methyl-7-[3α-5α-Dihydroxy-2β-(3α-ethoxy-1E-octenyl)- cyclopentyl]-5Z-heptenoate

[0138] The named compound is prepared in accordance with the process of Example 1 by replacing methyliodide with ethyl iodide.

EXAMPLE 14a

7-[3α-5α-Dihydroxy-2β-(3α-ethoxy-1E-octenyl)-cyclope ntyl]-5Z-heptenoic Acid

[0139] The named compound is prepared by reacting the compound of Example 14 in accordance with the process of Example 7.

EXAMPLE 14b

[0140] N-Isopropyl-7-[3α-5α-Dihydroxy-2β-(3α-ethoxy-1E-octenyl) -cyclopentyl]-5Z-heptenamide

[0141] The named compound is prepared by reacting the compound of Example 14 in accordance with the process of Example 4.

EXAMPLE 14c

7-[3α-5α-Dihydroxy-2β-(3α-ethoxy-1E-octenyl)-cyclope ntyl]-5Z-heptenamide

[0142] The named compound is prepared by reacting the compound of Example 14 in accordance with the process of Example 8.

EXAMPLE 15

Methyl-7-[3α-5α-Dimethoxy-2β-(3α-hydroxy-1E-octenyl) -cyclopentyl]-5Z-heptenoate

[0143] The named compound is isolated from the reaction product of Example 1.

EXAMPLE 15a

7-[3α-5α-Dimethoxy-2β-(3α-hydroxy-1E-octenyl)-cyclop entyl]-5Z-heptenoic Acid

[0144] The named compound is prepared by substituting the 3, 5-dimethylether of Example 15 in the process of Example 7.

EXAMPLE 15b

7-[3α-5α-Dimethoxy-2β-(3α-hydroxy-1E-octenyl)-cyclop entyl]-5Z-hepten-1-ol

[0145] The named compound is prepared by substituting the 3, 5-dimethylether of Example 15 in the process of Example 6.

EXAMPLE 16

Methyl-7-[3α-5α-Dihydroxy-2β-(3α-methoxy-5-phenyl-1E -pentenyl)-cyclopentyl]-5Z-heptenoate

[0146] The named compound is prepared according to the process described in Example 1 by substituting the 1-methylester of 17-phenyl, 18, 19, 20-trinor PGF _2α for the 1-methylester of PGF _2α .

EXAMPLE 16a

7-[3α-5α-Dihydroxy-2β-(3α-methoxy-5-phenyl-1E-penten yl)-cyclopentyl]-5Z-heptenoic Acid

[0147] The named compound is prepared by substituting the compound of Example 16 in the process of Example 7.

EXAMPLE 16b

7-[3α-5α-Dihydroxy-2β-(3α-methoxy-5-phenyl-1E-penten yl)-cyclopentyl]-5Z-heptenamide

[0148] The named compound is prepared by substituting the compound of Example 16 in the process of Example 8.

EXAMPLE 17

[0149] Methyl 7-[3α,5α Dihydroxy-2β (3α-pivalyl]-1E-octenyl)-cyclopentyl]-5Z-heptenoate

[0150] PGF _2α (40.4 mg 0.114 mmol) was suspended in Et ₂ O (1 mL) and cooled to 0°. A solution of CH ₂ N ₂ in Et ₂ O was added dropwise to the above suspension until a yellow color persisted. The solution was warmed to 25° for 30 minutes before concentration to yield the PGF _2α methyl ester as an oil. The crude ester was combined with 14 mg., (0.137 mmol) n-butyl boronic acid (BuB(OH) ₂ ) in 0.25 mL of CH ₂ Cl ₂ and heated at reflux temperature for 30 minutes. The reaction mixture was concentrated and the residue dissolved in dry benzene. The benzene was evaporated under reduced pressure. The process was repeated twice to remove traces of water present from the reaction, leading to boronate ester, which was subsequently dissolved in 0.2 mL of dry pyridine and treated with pivalyl chloride (0.043 mL, 0.34 mmol) and 4-DMAP (about 1 mg). The reaction mixture was stirred at 25° for 14 h before being concentrated. The residue was dissolved in EtOAc (10 mL) and washed with 10% citric acid (7 mL). The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated. The residue was dissolved in MeOH (3 mL) and stirred at 25° for 2h. The solvent was removed and replaced with fresh MeOH. This process was repeated once more. After removal of solvent, the residue was purified by chromatography (silica, 50-60% EtOAc/hexane) to yield the named product as an oil.

EXAMPLE 17a

Methyl-7-[5α-Hydroxy-2β-(3α-pivalyl-1E-octenyl)-3α-m ethoxy-cyclopentyl]-5Z-heptenoate

[0151] The named compound is prepared by substituting compound of Example 17 for the 1-methylester of PGF _2α in the process of Example 1. (See Reaction 3b of FIG. 3 .)

EXAMPLE 17b

7-[5α-Hydroxy-2β-(3α-pivalyl-1E-octenyl)-3α-methoxy- cyclopentyl]-5Z-heptenoic Acid

[0152] The named compound is prepared by substituting the compound of Example 17a in the process of Example 7. (See Reaction 3c of FIG. 3 .)

EXAMPLE 18

Methyl-7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-m ethoxy-cyclopentyl]-5E-heptenoate

[0153] 987 mg (2.68 mmol) of the 1-methyl ester of PGF _2α was mixed with 1.43 g (13.41 mmol) of 2, 6-lutidine and 2.48 g (9.38 mmol) of t-butyldimethylsiloxytriflate [(TB)(CH ₃ )SiOSO ₂ CF ₃ ] in 13.4 mL of CH ₂ Cl ₂ and the solution was stirred for 16 h to yield the tri-(t-butyldimethylsiloxy) ester of the 1-methyl ester of PGF _2α . (See Reaction 4a of FIG. 4 .) The triester was purified by elution (using FCC techniques) with a 30 to 1 solution of hexane and EtOAc 312 mg (0.439 mmols) of the resulting triester was combined with 2.7 mg (0.0088 mmol) of diphenylsulfide in 4.4 mL of benzene and the resulting solution was stirred under long wave UV light exposure for 12 hours. (See Reaction 4b of FIG. 4 .) The resulting solution was concentrated under vacuum and purified by elution, as above, with a 20 to 1 solution of hexane and EtOAc to yield 296.1 mg (95% yield) of the 5-trans triester. 318 mg (0.447 mmol) of the 5-trans triester were combined with 2.7 mL of a 1.0M solution of Bu ₄ NF in THF and 4.4 mL of THF. The solution was stirred overnight at 23° C., diluted with EtOAc, washed with H ₂ O and brine and the organic portion was filtered, concentrated under vacuum and purified, using FCC techniques and 100% EtOAc. to yield 123.3 mg (75% yield) of the triol of the 5-trans 1-methyl ester of PGF _2α .

[0154] The triol was substituted in the process of Example 1 to yield the named compound. (See Reaction 4c of FIG. 4 .)

EXAMPLE 18a

7-[5α-Hydroxy-2β-(3α-Hydroxy-1E-octenyl)-3α-methoxy- cyclopentyl]-5E-heptenoic Acid

[0155] The named compound is prepared by substituting the compound of Example 18 in the process of Example 7.

EXAMPLE 18b

7-[5α-Hydroxy-2β-(3α-Hydroxy-1E-octenyl)-3α-methoxy- cyclopentyl]-5E-hepten-1-ol

[0156] The named compound is prepared by substituting the compound of Example 18 in the process of Example 6.

EXAMPLE 19

Methyl-7-[3α-methoxy-5α-hydroxy-2β-(3α-methoxy-1E-oc tenyl)-cyclopentyl]-5Z-heptenoate

[0157] The named compound is isolated from the reaction product of Example 1.

EXAMPLE 19a

7-[3α-methoxy-5α-hydroxy-2β-(3α-methoxy-1E-octenyl)- cyclopentyl]-5Z-heptenoic Acid

[0158] The named compound is prepared by substituting the dimethylether of Example 19 in the process of Example 7.

EXAMPLE 19b

7-[3α-methoxy-5α-hydroxy-2β-(3α-methoxy-1E-octenyl)- cyclopentyl]-5Z-hepten-1-ol

[0159] The named compound is prepared by substituting the dimethylether of Example 19 in the process of Example 6.

EXAMPLE 20

Effects on Intraocular Pressure

[0160] The effects of certain of the above examples on intraocular pressure are provided in the following Table 1. 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 ul to the ocular surface, the contralateral eye received vehicle as a control. Intraocular pressure was measured by application pneumatonometry. Dog intraocular pressure was measured immediately before drug administration and at 4 hours thereafter.

[0161] The examples which show excellent IOP-lowering effect include Examples 1, 1a, 1b, 6 and 6a wherein the 11 position is substituted with a lower alkyl ether, i.e. a C ₁ to C ₃ alkyl ether and the 1-position is a lower alkyl ester, e.g. a methyl ester, or an alcohol group. Furthermore, a comparison of Example 1 and 18 shows that the 5-trans or 5-cis isomers are substantially similar in their IOP-lowering effect. Finally, the 9 and 15-substituted lower alkyl ether derivatives wherein the 1-position is substituted with a lower alkyl ester group are also very effective in lowering IOP. (Compare Examples 12 and the 15-monoester of Example 1.) In contrast, various derivatives wherein the 11-position is substituted with a lower alkyl ether group and the 1-position is an acid or an amino group showing lower effect in lowering IOP at a concentration of 0.1%. (See Examples 4a, 4b, 4c, 5, 7d, 18a, 19a and 19b.) However, it is believed that higher concentrations would have greater effect in lowering IOP.

[0162] In Table 1, hyperemia is measured by visual estimation. Slight hyperemia would be given a value between 0 and 0.5; moderate hyperemia would be given a value from 0.5 to 1.0 and severe hyperemia would be given a value of greater than 1.0. Miosis would be evaluated as 0 (nothing), slight (slite) or pinpoint (pin), i.e., the pupil would be the size of a pinpoint. 2

[0163] 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 from 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 results. 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.