CA2129287C - Use of cloprostenol, fluprostenol and their analogues to treat glaucoma and ocular hypertension - Google Patents

Abstract

Disclosed is the use of cloprostenol, fluprostenol, their analogues and their pharmaceutically acceptable salts and esters for the treatment of glaucoma and ocular hypertension. Also disclosed are ophthalmic compositions comprising said compounds.

Description

USE OF CLOPROSTENOL, FI_UPROSTENOL AND THEIR ANALOGUES
TO TREAT GLAUCC>MA AND OCULAR HYPERTENSION
BACKGROUND OF THE INVENTI~N_ The present invention relates to the treatment of glaucoma and ocular hypertension. In particular, the present invention relates to the use of cloprostenol, fluprostenol, their analogues and their pharmaceutically acceptable salts and esters to treat glaucoma and ocular hyyertension.
Cloprostenol and fluprostesnol, both known compounds, are synthetic io analogues of PGF2a, a naturally-occurring F-series prostaglandin (PG).
Structures for PGF2a (I), cloprostenol (II), and fluprostenol (III), are shown below:
~ 7 ~4 ~2 alpha chain g 5 3 C~OH
11 '4 16 18 12 ~ 15 ~20 HO 13 ~ 1~/ X19' m'nega chain OH (I) HO
:,.y/'~./'~'C02H
H~~ _ ~ ~ , OH.
ci (ll) ,,,,~'~/~co2H
'G~~~O
HO OH
cF3 (III) The chemical name for cloprostenol is 16-(3-chlorophenoxy)-17,18,19,20-tetranor PGFza. Monograph No. 2397 (page 375) of The Merck Index, 11 th Edition (1989) describes the preparation and knawn pharmacologiical profiles of cloprostenol. Fluprastenol has the chemical name 16-(3-tnrifluoromethylphenoxy)-17,18,19,20-tetranor PGF2a.
Monograph No. 4121 (pages 656-657) of T~~wtei~rc~ Index, 11th Edition (1989) describes the preparation arid _ known pharmacological profiles of fluprostenol. Claprostenol and fluprostenol are 16-aryloxy PGs and, in addition to the substituted aromatic ring, differ from the io ~ natural product, PGF2a in that an oxygen atom is embedded within the lower (omega) chain. This oxygen interruption forms an ether functionality.
Naturally-occurring prostaglandins are known to lower intraocular pressure (IOP) after topical ocular instillation, Ibut generally cause inflammation, as well as surface irritation characteri;'ed by conjunctiva) hyperemia and edema. Many synthetic prostaglandins halve been observed to lower intraocular pressure, but such compounds also produce the aforementioned side effects, Various methods have been used in attempting to overcome the ocular side effects associated with prostaglandins. Stjernschantz et al. (EP 364 417 A1 ) have synthesized derivatives 20 or analogues of naturally-occurring prostaglandins in arder to design out selectively the undesired side effects while maintaining the IOP-lowering effect. Others, including Ueno et al. (EP 330 511 A2) and Wheeler (EP 435 682 A2) have tried complexing prostaglandins with various cyclodextrins. ' The Stjernschantz et al. publication is of particular interest, as it demonstrates that certain synthetically-modified PGF2a analogues retain the potent IOP-lowering effect of the parent (PGF2a isopropyl ester) while decreasing the degree of conjunctiva) hyperemia. In this publication, the only modification to the PG structure is to the omega chain: the chain length is 4-13 carbon atoms 30 "optionally interrupted by preferably not more than two heteroatoms (O, S, or N)"
and includes a phenyl ring (substituted or unsubstituted) on the terminus (see page 3,. line 44 to page 4, line 7). Stjernschaniiz et al. exemplify two subclasses within this definition:
(1 ) carbon-only omega chains, ~i.e., ', HO,, 14 ' 1s ~Ph HO ' 3 n =1-10 OH
and (2) heteroatom-interrupted omega chains, i.e., HO, ,,,~~~

is n ~~Ph HO '3 off n=1-10 ,o ' In particular, the 17-phenyl-18,'19,20-trinor analogue of PGF2~, isopropyl ester (formula 1, n=2) displayed a superior separation of toward and untoward activities.
Furthermore, the 13,14-dihydro~ analogue of 17-phenyl-18,19,20-trinor PGF2a ,5 i sopropyl ester displayed an even more favorable separation of activities.
Both 17-phenyl PGFza and its 13,14-dihydro congener fall into the former (formula 1, carbon-only omega chain) subl:lass. Additional synthetic analogues employing the phenyl substituent on the end of the omega chain explored the effects of chain elongation, chain contraction, and substitution on the phenyl ring. However, such o analogues showed no apparent therapeutic improvement over the preferred formulation, 13,14-dihydro-17-phenyl-18,19,20-trinor PGF2~ isopropyl ester.
Because they contain h~=teroatom (O) interruption of the omega chain, both cloprostenol and fluprostenol a.re generically included in the subclass defined in 25 formula 2 by Stjernschantz et al. However, neither compound is specifically mentioned by Stjernschantz et al. and the disclosure is primarily related to carbon-only omega chains. The only example of a heteroatom-interrupted omega chain ~L,, disclosed by Stjernschantz et al. is 1fi-phenoxy-17,18,19,20 tetranor PGF2a isopropyl ester (see formula 2, n=1 ). The IOP data revealed by Stjernschantz et al.
for 16-phenoxy-17,18,19,20-tetranor PGF2~ isopropyl ester (see Stjernschantz et al, page 17, Table V) indicate an initial increase in IOP (1-2 hours after administratian) s followed by a decrease. Moreover, this compound displays unacceptable hyperemia (see Stjernschantz ~et al., Table 1V, line 40). In short, data from Stjernschantz et al. demonstrate that the oxygen-interrupted omega chain subgeneric class of compound:; (see formula 2) displays an unacceptable therapeutic profile.
,o :iIJMMAFiY OF THE INVENTIC1N
It has now been unexpectedly found that cloprostenol, fluprostenol, and their ,5 pharmaceutically acceptable ss~lts and esters show significantly greater IOP
reduction than the compounds of Stjernschantz et al., while having a similar or lower side effect profile. In particular, it appears that the addition of a chlorine atom or a trifluoromethyl group to the meta position on the phenoxy ring at the end o~f the omega chain provides a compound having excellent IOP reduction without o the significant side effects found with other, closely related compounds.
In addition, it has also b~,en unexpectedly found that certain novel cloprostenol and fluprostenol analogues are useful in treating glaucoma and ocular hypertension. In particular, topical application of ophthalmic compositions z5 comprising these novel clopros~tenol and fluprostenol analogues result in significant IOP reduction.

i r~=, IgBIFF ~,~~61F'Tl~t~.F THE DRAWINt3, Figure 1 Is a graph showing the rs~iative hyperemia scaraa (cumulative) of five te$ted campounds (see Talala 2, below), two a~ which era compaund$ of the s present lnventivn.
Figure ~ is a graph shpwing the relative IC7P-lowering affects of flue tested oampaunds ($ae Table ~, balaw), two of which era cor~npounds of the present invention. The dose for each a1' the tasted campounds was 0.3 Ng.
Figure 3 is a graph simils~r to that c>f Figure ~, showing relative 1~P-fawering affects of different cancentratlans of A (cloprostenoi, isopropyl ester) and E
(13,14-dit~ydro-17-phenyl-18,1~,~~-trinr,r PU'F2a, Isopropyl ester), 16 ' .G.~TAII.Ed ~? F.~~.C~LG7:~IE1NV~.l~lll~2.d, The oornpounds useful In the present invantian have the following general formula:
..,,,.UFi1 X
.~ ~' ''\
O~i~ ~~
Y
(IV) wherein:
R, a H; C~-Ci2 straight-~hs~in or bre~nched alkyl; C,-C,2 straight-chain ar branched aryl; ~3-C.8 cycioalkyl; a cationic salt moiety; or a pharmaceutically acceptable amine moiety;
R~, R3 = H, or C,-C5 straight-chain or branched alkyl; or R2 and R3 taken together may represent (~;
ty 6' t:;.r;
_ c~~_.~
X = O, S, or CH2;
_-- represents any combination of a single bond, or a cls or traps double bard for the alpha (upper) chain; and a single bond or frees double bond far the omega flowery chain;
R~ ~ H, C,-C,o straight-c~iain or branched alkyl, or C,-C,o straight-chain or branched aryl;
R" - H, ~,-C,o straight-chain ar branched alkyl, or C,-C1U ,straight-chain or branched aryl;
'~ = U; or hl and C7R,~ in either configuration, wherein R,6 = H, C,-C,o str~xight-chain or branched alkyl, or C,-C,n straight-chain or branched aryl;
Z = CI ar f~F3;
with the proviso that when R~ and R3 taken together represent O, then R, ~ C,-C,2 ~' strsright-chaln or branched aryl; and when R2 - i~3 ~ H, then R, ~ a cationic salt 15 moiety or a pharmaceutically acneptable amine moiety, The compounds of the present invention include free acids, alkali and alkaline earth metal salts, ammonium and amine salts, and esters. Preferred Baits are those involving aikali and alkaline earth metal rations, particularly sodium and potassium, and amine Salts, especially the tris(hydroxymethyi)aminamethane ("tramethamine") salts. Praferren esters are C,-C,2 alkyl esters, particularly straight or branched C,-CB alkyl ostgrs, especially methyl, ethyl, isopropyl, cyclopropyl, cyclopropyl methyl, butyl, cyciobutyl, isobutyl, t-butyl or pentyl.
Particularly preferred compounds of formula (IV) Bra the sodium and tromethamlne salts ~R
NaQ, CH3N*(CH2OH)3) and the m~sthyl, isopropyl, and t-butyl eskers (s~ = CH3, Chf (CH3)a~ C(CH3)3), Alkali metal salts and alka'~~Ine earth metal salts may be formed conventionally from the acid form. The acid may ba converted to the 9ster by conventional condensation with an alcohol (e,g., C,-C3 alkyl alcohol) or by reaction with an alkyl electrophile (e.g., C,-C, alkyl iodide) fn the presence of base, _.
according to known procedures, In a simi9ar manner, other esterlflcations may be effected as Is known in the art employing other low alkyl, cycloalkyl, cycloalkyalkyl, aryl, ar arylalkyl alcohols anrflc~r'halides such as i$opropanol, ayalaprapanol, cyclaprapylmethanoi, ar phenyl r~r hanzyl Hir:c~hnl nr InrlirfA. ~inra such esterification reactions era well known, they are net further described here.
Preferred compounds include ciaprastenol isopropyl ester (Table II, compound A), fluprostenol isopropyl ester (compound B), the 3-axe form of cloprostanol Isopropyl aster (Tab'le 1, compound 5), 13,1-dlhydrofluprostenal isopropyl ester (compound 6), cloprostenol-1-0l (compound 'Y), and 13,14-dihydraaloprostenol-1-of pivaloates (compound g).
The campavnd9 of fc~rrttulf~ (IV) are useful in lowering intraocular pressure and thus era useful in the treatment of glaucoma. The preferred route of administration is tapfaal. 'The da,3age range far topical administration is generally between about I~.UU1 and about 1000 micrograms per eys (pgpaya) and Is preferably between about 0.01 acrd about 100 pg/eye and most preferably between about U.US and 10 yglaye. Tha c;ampoundls of the present invention can be administered as solutions, suspensions, or emulsions (dispersions) In a suitable ophthalmic veltlcla.
In forming compositions far topical a.dministratlon, the compounds of the present Invention are gartArally fa~rrriulated as between about O.Ot~00~ to about 3 par~;ant by weight (wt%) solutlon4; In water at a pH between 4.5 to 8Ø The corr~pounds are preferably formulated as between about 0.0003 to about 0.3 wt°/a and, most preferably, between ar~out 0.003 and about 0.03 wt°/o, While the precise regimen Is left to the discretion of the clinician, it Is recommended that the resulting solution ba topically applied by ple~clng one drag irt each eye one or two times a day.

f~~' 1. ~~Y ....
Other ~Ingredi~nts wllch rtlay i~o ('iesirahie tv use Irt the ophthalmic preparations of the present Invention Include preservatives, co-solvents and viscosity building agents, Antlrnicrobla) Pre~~,r t~ Ives,:
C~phthalrnic products arA typrc;erly pgckaged In rrtuitidose form, whlolt generally require the addition of preservatives to prevent rrticrobiai contamination during use, ~ultable preservatives include; benzaikortium chloride, titimerosal, chiorobutanal, methyl parar>sn, propyl paraben, pftenylethyl alcohol, edetate disodium, sorbic acid, (~narner MQ~, or other ager~fs known to those skilled In thg art. such preservatives arsr typically employed at a concentration between about x.001 °/o c~r~rd about 1.0% by weight.
Co-~oivent~:
Prostaglandlns, end ;particularly ester derivatives, kypleelly Rave limited solubility fn water and tf~erefc~re stay require a surfactant or athAr appropriate co-solvent in the composition, Suah ro-solvants Include; t'olysorbat~ 20, r30 and 80;
F'luronic~ F-88, F-8d and P-1 C~;~; Tyloxepolrlb; ~remophor~ EI_, sodium dodecyl sulfate; glycerol; P~Q d04; propylene glycol; cycladextrins; or other agents known a!o to those skilled In the art. ~3uch co-solvents are typically employed at a concentration between about Q.01 % and about ~b/o by weight.
Y1.~~.c.~_I~g n ~;
Viscosity greater than that of simple aqueous $olutlons may be desirable to Increase ocular absorption of the active compound, to decrease variability in dispensing the formulations, to decrease physical separation of cornpanents of a suspension or emulsion of f~ormulatlon and/or otherwise to Improve the c~phthalrrila formulation. such viscosity building agents Include, far exarrtple, polyvinyl airat7oi, polyvinyl pyrrolidone, rnethy! cellulose, hydroxy propyl methylcellulase, hyrir~~xyett~yl i r ~.
ce0lulose, car'ty. c~xymethyl ceilulos>e, hydroxy propyi eellulos~ or other agents known to those skliled fn the art. Such agents are typloa9ly employed at a concentration batween about O.Oi % and about 2% by weight.
Tebie 1 ' aeeaw~n,s CUMPOUND NAME: CC9MPOl~ND ~TRUCTUIgE
~-oxecloprostenoi Isopropyl Ho ester ~.~ ,,,~~°'--o--~'~-co2--Hc3 off ~ 13,14-dihydrofiuprostenol Ho isopropyl ester ,,,,~~'~~,~-""~--~'"'-Cc~p-HO OH

T cloprostenol-1-of ,,tv''~~'"~..~''...'~,OH
Hc7~l off 8 1 x,14-dihydrocloprostenol-1-of Ho w .r o' pivaloate ~,,~~-~.~~wV..~-~...~,,~, W' HO O
OH
GI

~3 ~j ~ i !n the examples below, the following standard abbreviations are used: g =
grams (mg = milligrams); mol := moles (rnmol = millimoles); mol% = mole percent;
mL = milliliters; mm Hg = millirneters of mercury; mp = melting point; by =
boiling point; h = hours; and min = minutes. In addition, "NMR" refers to nuclear magnetic resonance spectroscopy and "CI MS" refers to chemical ionization mass spectrometry.

~

~' ~a ;
~r' EXAMPLE 1: Synthesws of 3-Oxaclop~oster~ol (5) a c~ ci ~ ~ °" ~~"o~.co,Et ' ~ ~ p~P~°~'~
o to tt O
~~'l~p ~ o o f ago o " ci - T ----~-O
011 ~ 011 a a 14 if I

f~oH
( 0 ~~ THPO ~~ THPO
a a is t7 Et~ )wlO~a Et~SIO :~..J
(~Y~(of~aM~
~/u~~~O _ ~~~0 ao THPd ~ 1HPQ
a a a a g~°~~~y~~, n~ea~ ~~ ~ ,f.iao a of na~ nia~ na~o IHPo J! ~ ~4 a , C, G ~ ~", r~ ~
A° Eth~ri {3-chlorophenoxy~~cetate (10~
Acetone (320 ml), 75 g (450 mmol) of ethyl bromoacetate, and 40.0 g (310 mmol) of 3-chlorophenol were mixed together, then 69.8 g (505 mmol) of potassium carbonate was added. The mixture was mechanically stirred and heated s to reflux for 4 h, and after cooling to room temperature, was poured into 350 mL of ethyl acetate. To this was then cautiouslyr added 400 mL of 1 M HCI, taking care to avoid excess foaming. The layers were separated and the aqueous layer was extracted with portions of ethyl acetate (3 X 200 mL). The combined organic layers were dried over MgS04, filtered;, concentrated, and the resulting solid was ,o recrystallized from hexane to af?ford 58 g (87%) of 10 as a white solid, m.p. _ 39-40°C. 'H NMR S 7.20-7.08 (m, 1 H), 8.95-6.82 (m, 2 H), 6.75-6.70 (m, 1 H), 4.53 (s, 2 H), 4.21 {q, J = 7.2 Hz, 2 H), 1.23 (t, J = 7.2 Hz, 3 H).
B: Dimethyrl ~3~- 3-chlor~ghencz -2- x ~~~~rllahosi~honate X11) ,s To 20.6. g (166 mmol, 238 mol%) of dimethyl methylphosphonate in 110 mL
of THF at -78 °C was added drc>pwise 65 mL (162 mmol, 232 mol%) of a 2.5 M
solution of n-BuLi in hexanes. a4fter addition was Complete, the mixture was stirred for an additional 1 h, after which 15.0 g (69.9 mmol) of aryloxyester 10 in 40 mL of THF was added dropwise. The reaction was stirred for 1 h and then quenched by zo the addition of 100 mL of saturated NH~CI. The mixture was poured into 200 mL of a 111 mixture of saturated NaCl,/ethyl acetate, layers were separated, and the aqueous layer was further extracted with ethyl acetate (2 X 100 mL). Combined arganic layers were dried over MgS04, filtered, and concentrated, to afford 20.5 g (100%) of 11 as a viscous ail. 'H NMR ~ 7.22 (t, J = 8.1 Hz, 1 H), 7.05-6.90 (m, 2 25 H), 6.85-6.78 (m, 1 H), 4.72 (s, 2 H), 3.84 (s, 3 H), 3.78 (s, 3 H), 3.27 {d, J = 22.8 Hz, 2 H).

C;.-(3aR 4R 5R SaS,-~5-l,Benz:ovlox~-4~-[(E)-4-~(3-chloro~henoxy)-3-oxo-1-butenvfl-hexah~dro-2H-c5/Clopenta~[b]furan-2- ne X13) Phosphonate 11 (20.5 g,, 70.0 mmol), 2.6 g (62 mmol) of LiCI, and 200 mL
of THF were mixed together at 0 °C and 6.10 g (60.4 mmol) of NEt3 was added.
Aldehyde 12 (14.0 g, 51.1 mmol) dissolved in 50 mL of CH2C12 was then added dropwise. After 1 h, the reaction was poured into 200 mL of a 1/1 mixture of saturated NH~CI/ethyl acetate, 1fie layers were separated, and the aqueous layer was extracted with ethyl acetatE~ (2 X 100 mL). Combined organic layers were dried over MgS(~4, filtered, concentrated, and the residue was chromatographed on ,o silica gel eluting with ethyl acet:atelhexanes, 3/2, to afford 16.2 g (72%) of 13 as a white crystalline solid, m.p. = 101.0-102.0 °C. 'H NMR 8 8.0-7.9 (m, 2 H), 7.62-7.52 (m, 1 H), 7.50-7.38 (m, 2 I-I), 7.18 (t, J = 8.2 Hz, 1 H), 7.0-fi.82 (m, 3 H), 6.75-6.70 {m, 1 H), 6.54 (d, J = 15.1 Hz, 1 H), 5.32 (q, J = 6.2 Hz, 1 H), 5.12-5.05 (m, 1 H), 4.66 (s, 2 H), 3.0-2.8 (m, 3 H), 2.7-2.2 {m, 3 H).
,s ~: ~3aR 4R 5R 6aS)-5-(,Benzovloxvl-4-((E)-(3R)-~3-chloro henoxy;h,3-h~rdrox,, b4~ten~rll-hexahydro-2H cycloaenta[b]fu ran-2-~n 14 To a solution of 9.70 g (22.0 mmol) of enone 13 in 60 mL of THF at -23 °C
was added dropwise a solution of 11.1 g (34.6 mmol of (-)-B-chlorodiisopino-2o campheylborane in 30 mL of ThiF. After 4 h, the reaction was quenched by the dropwise addition of 5 mL of mE=thanol and then warmed to room temperature.
After pouring into 200 mL of a 2/1 mixtures of ethyl acetate/saturated NH4CI, the layers were separated, and the aqueous phase was extracted with ethyl acetate (2 X 100 mL). Combined organic layers were dried over MgS04, filtered, 2s concentrated, and the residue was chromatographed on silica gel eluting with ethyl acetate/hexanes, 3/2, to afford 4.7 g (48°/',) of 14 as a white solid, m. p. 101.0-102.5 °C. 'H NMR 8 8.05-7.95 (m, 2 H), '7.62-7.40 (m, 3 H), 7.18 (t, J
= 8.0 Hz, 1 H), 7.0-6.92 (m, 1 H), 6.85 (t, J = 2.1 Hz, 1 H), 6.77-6.70 (m, 1 H), 5.85 (d of d, J =

6.2, 15.5 Hz, 1 H), 5.72 (d of d, J = 4.5, 15.5 Hz, 1 H), 5.30 (q, J = 5.8 Hz, 1 H), so 5.12-5.04 (m, 1 H), 4.58-4.48 (m, 1 H), 3.92 (d of d, J = 3.5, 9.3 Hz, 1 H), 3.80 (d of d, J = 7.3, 9.4 Hz, 1 H), 2.9-2.2 (m, 8 hi).

~~.~'' E.: y3aR.4R. 5R.'6aS~-4-[(E)-(3R)-~3-ChIarQ h~~ enoxy~-3-(tetrahvdrop,~n-2-r~lox~-1-butenyll-hexahydro-~ (tetrahvdrvpyran-2-yrlox),Cap-2H-c)~cloaenta(~lfuran-2-one (16~
To a mixture of 5.1 g (11.5 mmol) of 14 in 200 mL of methanol was added 11.7 g (12 mmol) of K2C03. After 1 h, the mixture was poured into 100 mL of 0.5 P~1 HCI and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed successively with water (2 X 100 mL) and saturated NaCI (2 X
100 mL). The organic layer was dried over MgSO4, filtered, and concentrated to afford 4.85 g of crude diol 15, °uvhich was used in the next step without further purification.
,o To a mixture of 4.85 g of crude 15 and 2.4 g (28 mmol) of 3,4-dihydro-2H-pyran in 75 mL of CH2C12 at 0 "C was added 370 mg (1.9 mmol) of p-toluenesulfonic acid monohydrate. After stirring for 45 min, the reaction was poured into 40 mL of saturated NaHCO3, layers were separated, and the aqueous layer was extracted with CH2C12 (2 X 40 mL). The combined organic layers were ,s dried over MgSO~, filtered, and concentrated. The residue was chromatographed an silica gel eluting with 40% ethyl acetate in hexanes, to afford 6.0 g (100%) of 1G
as an oil. ' H NM R (CDC13) 8 (characteri stic peaks only) 7.25-7. i 4 (m, 1 H), 6.95-~i.87 (m, 2 H), 6.83-6.72 (m, 1 H), 5.8-5.4 (m, 4 H), 5.1-4.8 (m, 2 H).
zo _F~~13~-(9S. 11 R~15R_~:11 15_Bis(i.etrahydropyran-2-yrlo_x)~) =16-~~3-chlor~c ~hPnoxv)-2.3.4,5.~.17.18.19.20-nc~nanor-9-trieth~lsila~lox5r-l3~rr~steng~~riethXl~il)~th~r (18) To a suspension of 400 mg (10.5 mmol) of lithium aluminum hydride in 20 rnL of THF at 0 °C was added dropwise a solution of 4.5 g (8.8 mural) of lactone 1~ 6 in 20 mL of THF. After 1 h at 0 °C the mixture was cautiously poured into 100 s rnL of a 1/1 mixture of ice-cold saturated NH4CI/ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 X 50 mL).
l'he combined organic layers were dried over MgSO~, filtered, and concentrated to afford 4.5 g (100%) of diol 17 ~Nhich was used in the next step without further purification.
30 ' Triethylsilyl chloride (3.0 g, 20 mmol) was added to a mixture of 4.5 g (8.8 rnmol) of crude 17, 40 mL of DMF, 1.85 g (27.0 mmol) of imidazole, and 310 mg (2.5 mmol) of 4-(dimethylamino)pyridine. After 2 h, the reaction was poured into 1100 mL of a 1/1 mixture of ethyl acetate/saturated NH4C1, layers were separated, s and the aqueous layer was extracted with ethyl acetate (2 X 25 mL). The combined organic layers were washed with water (3 X 25 mL), dried over MgS04, and concentrated. The residue was chromatographed on silica gel eluting with 20% ethyl acetate in hexane to afford 5.2 g (80%) of i8. 'H NMR (CDC13) 8 ' (,characteristic peaks only) 7.22-7.12 (m, 1 H), 6.95-6.88 (m, 2 H), 6.83-6.71 (m, 1 ,o H), 5.8-5.4 (m, 4 H), 5.1-4.8 (m, 2 H), 1.0-0.85 (m, 18 H), 0.7-0.5 (m, 12 H).
c~~l3E]-l9S 11 R 15R)-11 l~Bi r hy~ro~yran-2-vlox~~-16- 3-chloroohenoxv)-a~ 4 5 6.17.18.19.20-nonanor-~-triethyl_silvlox) -~ 13- rp ostP~nal (191 To a mixture of 1.6 g (12.6 mmol)~ of oxalyl chloride and 15 mL of CH2C12 at ,5 -78 °C was added dropwise a solution of 1.54 g (19.7 mmol) of DMSO
in 2 mL of GH2Clz . After 10 min, 4.6 g (fi.2 mmol) of bissilane 18 in 8 mL of CH2C12 was .added dropwise. After 95 min, 3.0 g (30 mmol) of NEt3 was added. The mixture was then warmed to room temperature ;and poured into 70 mL of saturated NH4C1.
The solution was extracted with of CH2GI2 ( 3 X 70 mL) and the combined organic zo Ilayers were dried over MgS04, filtered, <~nd concentrated. The residue was chromatographed on silica gel eluting with 20% ethyl acetate in hexane to afford 2.06 g (53%) of 19 as well as 1.5 g (26%) recovered 18. 'H NMR (CDC13) 8 (characteristic peaks only) 9.78 (t, J = 1.4 Hz, 1 H), 7.22-7.12 (m, 1 H), 6.95-6.88 (m, 2 H), 6.83-6.71 (m, 1 H), fi.8-5.4 (m, 4 H) 5.1-4.8 (m, 2 H), 1.0-0.85 (m, 18 H), 2s 0.7-0.5 (m, 12 H).

H-(,~Z 13E~j9S 11 R 15R)-11-15-Bid(tetrahydrol~s,Lan-2~yrlQxy)-1~3-chloro-I henoxy)-2.3 4.17 18 19 20-he~ptanor-9-triethylsilyloxv-5.13-arostadienoic acid ~nethyrl est r 21 To a solution of 1.35 g (4.24 mmol} of phosphonate 20 and 2.60 g (9.84 s mmol) of 18-crown-6 in 20 mL of THF at -78 °C was added dropwise 6.9 mL (3.45 mmol) of a 0.5 M solution in toluene of potassium hexamethyldisilazane. After stirring for 15 min, a solution of 1.65 g (2.64 mmol) of aldehyde 19 in 20 mL
of THF was added dropwise. One hour later, the mixture was poured into 100 mL of saturated NH4CI/ethyl acetate, 1/1, layers were separated, and the aqueous layer ,o eras extracted with ethyl acetaite (3 X 30 mL). The combined organic layers were dried over MgS04, filtered, concentrated and the residue was chromatographed on silica gel eluting with 20% ethyl acetate in hexane to afford 1.135 g (63%) of 21.
'H NMR (CDC13) S (characteristic peaks only) 7.22-7.11 (m, 1 H), 6.97-6.86 (m, H), 6.85-6.75 (m, 1 H), 6.4-6.2 (m, 1 H), 5.8-5.32 (m, 3 H), 3.66 (s, 3 H).
I: (5Z. l3Ey-(9S 11 R, 1581-1'I .15-Bi,~hv ro~yrran-2-a IoC~yr)~-16-~w3-chloro-phenox~C)-2 3.4 17 18 19 20-heatanor-9-triethylsilyi_ox< -~ 5 13_l~rostadien-1-of X221 To a solution of 850 mg (1.25 mmol) of ester 21 in 10 mL of THF at 0 °C
was added 2.4 mL (3.6 mmol) of a 1.5 M solution in toluene of diisobutylaluminum 2o hydride. After 1 h, the mixture was poured into 20 mL of saturated NHbCI
and was extracted with ethyl acetate (3 X 20 mL). Combined organic layers were dried over MgS04, filtered, and concentrated down to 800 mg (98%) of 22 as an oil. 'H NMR
(CDCI3) 8 (characteristic peaks only) 7.25-7.15 (m, 1 H), 6.97-6.90 (m, 2 H), 6.86-6.75 (m, 1 H), 5.81-5.41 (m, 4 H).
,~!~ l5Z l3El~9S 11 R 15F~-1'~-Bis(tetrahydro~yran-2-yl~i,~ 16-~(~'~-chloro hp enox)C~.-53-ox -a 17 18,19 20-teit~nQr-9-triethylsilyloxy-5 13-pr~~dienoictacid ~~~rol~arl ester l23) To a solution of 415 mg (6.37 mmol) of alcohol 22 in 4 mL of THF at -78 °C
so ~rras added dropwise 0.35 mL (0.87 mol) of a 2.5 M solution in hexane of n-BuLi.
After 15 min, this solution was transferred via syringe to a -78 °C
solution of 195 img (1.08 mmol) of isopropyl bromoacetate in 2 mL of THF. The mixture was kept at -78 °C for 40 min, warmed to room temperature overnight, and then poured into 20 mL of a 1/1 mixture of saturated NH4CI/ethyl acetate. Layers were separated, and the aqueous layer was extracted with ethyl acetate ( 2 X 10 mL). The s combined organic layers were dried over MgSOa, filtered, concentrated, and the c~esidue was chromatographed on silica gel (20% ethyl acetate in hexane) to afford 242 mg (53%) of 23 as an oil. 'H NMR (CDC13) 8 (characteristic peaks only) 7.24-7.15 (m, 1 H), 6.97-6.90 (m, 2 H), 6.86-6.75 (m, 1 H), 5.81-5.41 (m, 4 H), 1.57 (d, J
_. 5.7 Hz, 6 H). ' ,o fC: ~(5ZL13~-1,9S 11 R 15~ 16-(3-ChIQr9~henox,r)-3-oxa-17 18 1 ~ ~0-t r r-~l 11 15-i~rih~rdroy -5 13 ros ~clienoic ~~d isopro~~yr_~~,S~,Q~"~,~, To a solution of 230 mg (0.32 mmol) of silane 23 in 5 mL of THF at room temperature was added 0.33 rroL (0.33 mmol) of a 1 M solution of Bu4NF in THF.
,s After 20 min, the reaction was poured into 4 mL of saturated NH4C1 and was extracted with ethyl acetate (4 X 5 mL). The combined organic layers were dried over MgS04, filtered, concentre~ted, and the residue was chromatographed on silica gel (ethyl acetate/hexane, 1/1 ), to afford 126 mg (65%) of desilylated compound 2.4.
2o To 120 mg of 24 in 5 ml_ of methanol was added 0.4 mL of 2 M HCI. After 1 h, the mixture was added to :3 mL of saturated NaHC03, and the resulting mixture was extracted with ethyl acetate (3 X 8 mL). Combined organic layers ' were dried over MgS04, filtered, concentrated. The resulting residue was then chromatographed on silica gel eluting with ethyl acetate to afford 54 mg (56%) of 5.
2s '3C NMR (CDC13) & 169.92 (C), 159.26 (C), 135,13 (CH), 134.95 (CH), 134.81 (C), 124.93 (CH), 121.22 (CH), 115.06 (CH), 113.08 (CH), 77.75 (CH), 72.02 (CH), ', 71.94 (CH2), 70.76 (CH2), 68.7i' (CH), 67.78 (CH2), 66.50 (CH2), 55.46 (CH), 49.93 (t~H), 42.47 (CH2), 25.85 (CH2)" 21.75 (CH3), CI MS, m/z calcd. for C24H34~7CI, (fNH'), 469.1993, found 469.19!33.

._ ,.
EXAMPLE 2: Synthesis of 13,14-Dihydrofluprostenol Isopropyl Ester v o o~
o-CF' CFA
O ~
THPO THPO
CFA CFs ~~~e~~~~
THP~ THP
hlPO ~ O
~CF~ CFA
~t ~! fr~,~/~/
CFA
a ~~ ~ ~~~ ~, A~ (3aR 4R 5R ~aS~i-Hey;ahyrdrp~h~rdroxy~4-j(~f3)-~3-trifl~~~nethyrla~hen~L
3-h~ d~ roxy~-1-bu~yrll 2H c..ytclo~(~ran-2-onQ (2S) A mixture of 1.2 g (3.2 mmol) of diol 25 (for synthesis of diol 25, see U.S.
Patent 4,321,275) and 0.05 g of 10% (wt/wt) Pd/C in 20 mL of methanol was hydrogenated at 30 psi for 1.5 hours. After filtration through a short pad of Celite~
concentration afforded 1.2 g of 26 as a colorless oil. 'H NMR (CDC13) 8 7.44 (m, 2 H), 7.12 (m, 2 H), 4.95 (dt, 1 H), 4.15-3.80 (m, 4 H), 2.82 {dd, J = 10.8, 1 H), 2.55 (m, 2 H), 2.3 (m, 1 H), 2.1-1.3 (m, 6 H). , to B' (3aR 4R 5LR3 6aS, -LHe~~h_ydro-5_ltetrah~ drop' rar_. n~2-) I(~r)-4:j~3y-4-(3-triflsaoromethyrl,~hgnoxy,~-3- ( etrahyrdrol~yrran2-ylox)t)i-1-buty~~~y~lo,penta[~lfuran_ 2-one (27) A mixture of 1.2 g (3.2 mmol) of diol 26 and 0.05 g of p-toluenesulfonic acid monohydrate in 100 mL of ~CHzCl2 at 0 °C was treated with dihydropyran (1.1 ml, 12 mmol) and the salution was stirred for 2 h at 0 °C. After pouring into saturated NaHC03, phases were separated and the organic layer was dried over MgS04, filtered, concentrated, and purified by chromatography on silica gel (1/1, hexanes/
EtOAc) to afford 1.1 g of 2T as a clear, colorless oil. 'H NMR (CDCI3) 8 8.04 (dd, J = 7.0, 1.6, 1 H), 7.44 (m, 2 H), 7.12 (m, 1 H), 4.95 (dt, 1 H), 4.8 (m, 1 H), 4.7 (m, 2o 2 H), 4.15-3.80 (m, 4 H), 3.5 (m, 2 H), 2.82 (dd, J = 10.8, 1 H), 2.55 (m, 2 H), 2.3 (m, 1 H), 2.1-1.3 (m, 6 H).
C: (5ZLr(~,~~ ~( R. ~y-11 r -17 1 1 tetranor-16-(3-triflu_Qr~methvlahenoxv)-5-arostenoic acid isonronvl ester 1317 To a solution of 2.1 g (3.9 mmol) of 27 in 100 mL of THF at -78 °C
was added 3.9 mL (5.8 mmol) of a 1.5 M solution of diisobutyaluminum hydride in toluene. The solution was stirred for 2 h, then quenched by the sequential addition of 0.4 mL of isopropanol at -78 °C followed by 0.4 mL of water at 23 °C. Volatiles were removed under reduced pressure and the aqueous solution was extracted with Et20/EtOAc {1/1 ). Organic extracts were dried over MgSO~, filtered, and concentrated to furnish 1.9 g of lactof 28.
To a 250 mL 3-necked round boiltom flask equipped with a mechanical stirrer and a thermometer were added anhydrous DMSO (100 mL) and NaH (80%
dispersion in mineral oil; 0.48 g, 16 mmol). The mixture was heated to 75 °C
(internal) for 30 min, after which it was allowed to cool to room temperature for 1 h.
Phosphonium bromide 29 (3.5 g, 8 mmol) was then added. After stirring for 30 ,o minutes, 1.9 g {3.5 mmol) of l;actol 28 in 50 mL of DMSO was added, and the resulting solution was heated to 50 °C for 2 h and then brought to room temperature for 16 h. The solution was then poured into 100 mL of water and approximately 2 mL of 50% NaOH added. The aqueous phase was extracted with ether (3 X 100 mL), then made acidic (pH = 5.5) by the addition of a 10%
citric ,s acid solution, and extracted with Et2O:hexanes 2:1 (3 X 100 mL). The combined organic extracts were dried over MgS04., filtered, and concentrated to afford 1.9 g of 30 as a colorless oil.
To 1.9 g of carboxylic acid 30 dissolved in 10 mL acetone was added 0.95 g (6.0 mmol) of DBU and 1.0 g x;6.1 mmol) of isopropyl iodide 1.0 g (6.1 mmol) at 23 °C. After 16 h, the solutions was poured into 100 mL of water and extracted with 100 mL of EtOAc. The organic extract was dried over MgS04, filtered, concentrated, and purified by ;silica gel chromatography (3/2, hexanes/EtOAc) to afford 1.9 g of isopropyl ester 31 as a colorless oil. 'H NMR (CDC13) ~ 7.44 {t, 1 IH), 7.12 (d, 1 H), 7.12 (dd, 2 H), 5.5-5.3 (m, 2 H), 4.99 (heptet, 1 H), 4.15-3.80 (m, z5 4 H), 2.82 {dd, J = 10.8, 1 H), 2.55 (rn, 2 H), 2.3 (m, 1 H), 2.1-1.3 (m, 24 H), 1.23 {s, 3 H), 1.20 (s, 3 H).

,. ("r fT ~, .
Dy (5Z)-(9S 11 R 15R)-17.18.1 c~ 20-Tetranor-16=(3~rifluorom t~hyl)-9 11.15-~r_iydrox~r-5-arostenoic a i~soor~~l_ este_r~~.
Ester 31 (1.9 g, 2.8 mmol) was dissolved in 14 mL of a mixture of AcOH/THFIH20 (4I2I1 ) and the solution was heated to 50 °C for 1 h, allowed to s cool to 23 °C, poured into a saturated solution of NaHC03, and extracted with Et20 (2 X 100 mL) and EtOAc (100 rnL). The combined organic extracts were dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (1/1, hexanesIEtOAc) to furnish 0.5 g of triol 6 as a clear, colorless oil. 'H NMR
(CDC13) 8 7.44 (t, J = 7.8, 1 H), 7.12 (dd, J = 7.8, 2.0, 1 H), 7.12 (ddd, J =
15.6, ,0 7.2, 2.0, 2 H), 5.5-5.3 (m, 2 H), 4.99 (heptet, J = 6.3, 1 H), 4.15-3.80 (m, 4 H), 3.2 (d, 1 H), 2.95 (s, 1 H), 2.82 (dd, J = 10.8, 1 H), 2.75 (d, J = 5,9, 1 H), 2.55 (m, 2 H), 2.3 (m, 1 H), 2.1-1.3 (m, 24 H), 1.23 (s, 3 H), 1.20 (s, 3 H). CMR (CDC13) ~
173.5, 158.7, 132.1, 131.5, 130.0, 129.5, 129.2, 123.3, 120.8, 117.7, 117.6, 11 i .4, 111.4, 78.6, 74.4, 72.4, 69.9, 6 ~'.6, 52.6, .51.7, 42.5, 34.0, 31.5, 29.4, 26.8, 26.6, ,s 24.9, 21.7.
EXAMPLE 3: Synthesis of Cloprostenoi-1-of (7) o a-i i t ~ ~yccN~a~
° ~° ~ /
n.~PO APO niPO n~Pa a a is a ° _.... ~~°~ ~ ~
n~r~ ~~ n~PO ,rPo a a a se A: (5Z. 13EL(9S, 11 R, l5Ry-11.l5;Bis~(tetrahydropvran-2-yloxy~-16-(3-chlorophenox~r~-9-h~ di rox~ -ii 7.18.19,20-tei:ranor-5.13 prosta ienoic acid i~S~~ro~yrl A 1.5 M solution of diisobutylaluminum hydride in toluene (10 mL, 15 mmol) was added dropwise to a solution of 5.8 g (11.4 mmol) of lactone 16 in 55 mL
of THF at -78 °C. After 1 h, 10 ml_ of methanol was added dropwise, and the mixture was stirred for 10 rnin at -78 °C before being warmed to room temperature. The ', ,o mixture was then poured into 100 mL of a 1/1 solution of saturated aqueous potassium sodium tartrate/ethyl acetate and stirred. After separating layers, the aqueous phase was extracted vvith ethyl acetate (2 X 40 mL). Combined organic layers were dried over MgS04, filtered, concentrated, and purified by silica gel chromatography (3/2, ethyl acei:ate/hexane), to afford 4.4 g (76%) of lactol 33, ,s which was used immediately in the next step.
A 1 M solution of potassium t butoxide in THF (50.0 mi) was added dropwise to 12.1 g (27.3 mmol) of phosplnonium salt 29 in 100 mL of THF at 0 °C.
After 30 min, a solution of 4.4 g (8.6 mmol) of lactol 33 in 20 mL of THF was added dropwise, and the mixture was stirred at room temperature overnight. The solution was then poured into 150 mL of a 1/1 mixture of ethyl acetatelsaturated NH4C1.
Layers were separated and the aqueous layer was extracted with ethyl acetate (2 X 100 mL). Combined organic layers were dried over MgSO~, filtered, concentrated, and the residue vvas redissolved in 80 mL of acetone. To this was added 6.5 g (45 mmol) of DBU followed by 7.3 g (43 mmol) of isopropyl iodide.
25 After stirring overnight, the reacaion was poured into 100 mL of a 1/1 mixture of ethyl acetate/saturated NH4C1. Layers were then separated and the aqueous phase was further extracted with ethyl acetate (2 X 100 mL). The combined organic layers were dried over MgS04, fi8tered, concentrated, and purified by silica gel chromatography (40% ethyl acetate in hexane) to afford 2.92 g (53% from so lactone 16) of ester 34.
,?2 8~ ~.SZ. 13 E~ (9S. 11 R. 15 Ry-1 fi- 3-Chlorol~henox)~, -17.1$,19.20-tetranor-9.11.15-trihvdrox) -5.~ 13-orQstadienol (7) ' A solution of 500 mg (0.79 mmol) of 34 in 10 mL of THF was added dropwise to 61 mg (1.60 mmol) of lithium aluminum hydride in 20 mL of THF at s 0 °C. After 40 min, the reaction was poured into 15 mL of saturated NH4C1, and the mixture was then extracted with ethyl acetate ( 3 X 40 mL). Combined organic layers were dried over MgS04 , filtered, and concentrated to afford 500 mg of crude 35.
To a solution of 500 mg of 35 in 20 mL of methanol was added 0.5 mL of 2 ,o H4 HCI. After 1 h, the reaction was quenched with 20 mL of saturated NaHC03 and the mixture was extracted with ethyl acetate (4 X 30 mL). The combined organic layers were dried over MgS04, filtered, aind concentrated. Silica gel chromatography (EtOAc) provided 101 mg (31 % from 34} of 7. '3C NMR (CDC13) 8 159.27 (C), 135.44 (CH), 134.82 (C), 13C).64 (CH), 130.26 (CH), 128.23 (CH), ,s 121.25 (CH), 115.07 (CH), 113..08 (CH}, 77.35 (CH), 72.35 (CH), 71.90 (CH?), ' 70.89 (CH), 62.22 (CHZ), 55.40 (CH), 49.87 (CH), 42.79 (CH2), 31.83 (CH2), 26.77 (CH2), 25.60 (CH2), 25.33 (CH2). CI MS m/z calcd for C22H3205C1, (MH+) 411.1938, found 411.1938.

'~~~~ ~_ EXAMPLE 4: Synthesis oif 13,14-Dilhydrocloprosteno!-1-cal Pivaloate (S) o~
o~ ~ r ero ~ °~ ezo ~ °~ , c.

O
_ gt~ Ph~P'fCH~I~
THPO THPO 1~ ~ Ly ~OOaPr-1 THPO
THPO TH

4d ~qa l~p,~p~ ~ ~"~~./~' t~ . ~ ~ Me, p~ ~ ~ ~ ,~ w ~tr~ tt~ rNPO ~~ a ci a ~ v 4a ~;~
r A~3aR 4R 5R 6aS -4-fl3R~~-4- 3- hlo~phenox~~)-3-h~rdroxa~rl] hexahy dry 0 5 hyrdrox~ -~ 2H-cycloloentaL~~f .~~n-2-one (3~:
A mixture of 2.4 g (5.4 mmol) of 14 and 250 mg of 10% {wt/wt) PdIC in 35 s mL of ethyl acetate was hydrogenated at 40 psi for 1 h. After filtration through a short pad of Celite, the filtrate was evaporated down to 2.3 g (100%) of hydrogenated product 36.
The crude benzoate 36 was dissolved in 25 mL of methanol, and 610 mg (4.4 mmol) of K2C03 was add~sd. After 3.5 h, the mixture was poured into 100 mL
,o of water/ethyl acetate (1/1 ). Layers were separated, and the aqueous phase was further extracted with ethyl acetate (2 X 50 mL). The combined organic layers were dried over MgS04, filtered and concentrated. Silica gel chromatography (EtoAc) provided 1.50 g (82%) of 37 as a white solid, m.p. = 102.0-103.5 °C. 'H
NMR ~ 7.22 (t, J = 8.2 Hz, 1 H), 7.0-6.94 (m, 1 H), 6.91-6.88 (t, J = 2.1 Hz, 1 H), ,s 6.83-6.77 (m, 1 H), 4.97 (dt, J = 3.0, 8.3 Hz, 1 W), 4.12-3.91 {m, 3 H), 3.82 (dd, J =
7.4, 9.0 Hz, 1 H), 2.85 (dd, J == 8.0, 16.5 Hz, 1 H), 2.6-1.4 (m, 11 H).
IB: (3aR. 4R 5R. 6a,~,1-4-f(3R'n-4-(3-Chloral henoxy~-3-(~etr~hy~iroa~~rran 2 y,Loxxybu~~]-hexah~ dry o-5-(tPtrahvdroavran-2-~ I~ox~y-2H-~y~~ nta~'~-jfuran-2-one (38) Dial 37 (3.4 g, 10 mmol) and 2.2 g (26 mmol) of 3,4-dihydro-21-d pyran were dissolved in 80 mL of CH2C12, and 240 mg (1.3 mmol) of p-toluenesulfonic acid monohydrate was added at 0 "C. After 1 h, the reaction was poured into 50 mL
of saturated NaHC03 and the mi;dure was extracted with CH2CI2 (3 X 40 mL). The combined organic layers were dried over MgS04, filtered, concentrated, and the s residue was chromatographed on silica gel (hexane/ethyl acetate, 1/1) to afford 4.5 c,~ (87%) of bis-THP ether 38.

~~i C: ~5Z)-(9S 11 R 15R,-1~-Bisltetrah~~o~~~ rr an-2yloxy~-1~-(3-chloropenoxy~-9-~droxy-17 18,19 20-tetranor-;5prostenoic acid iso~l r~oh~Lester (41,) A 1.5 M solution of diisobutylaluminum hydride in toluene (1.8 mL, 2.7 mmol) was added to the solution 1Ø5 g (2.06 mmol) of 38 in 10 mL of THF at -78 °C.
s After 1 h, 4 mL of methanol was added and the mixture was warmed to 25 °C, then poured into 40 mL of ethyl ac,=tate/saturated aqueous potassium sodium tartrate (1l1). Layers were separated and the aqueous phase was further extracted with ethyl acetate (3 X 30 mL). The combined organic layers were then dried over MgSO4, filtered, concentrated, and the residue was chromatographed on silica gel ,o (ethyl acetate) to afford 740 mg (70%) of lactol 39.
A 1.5 M solution of potassium t butoxide in THF (8.6 mL, 8.6 mmol) was added dropwise to a mixture of 15 mL of THF and 1.92 g (4.33 mmol) of phosphonium salt 29 at 0 °C. After stirring 1 h, a solution of 740 mg (1.45 mmol) of lactol 39 in 5 mL of THF was added dropwise, and the reaction was allowed to ,s warm to 25 °C overnight. The mixture vvas then poured into 100 mL of ethyl acetate/saturated NH4C1 (1/1). Layers were separated, and the aqueous phase 'was further extracted with eth,rl acetate (2 X 70 mL). Combined organic layers were dried over MgS04, filtered, and concentrated to afford 1.6 g of crude acid 40.
Crude acid 40 (1.6 g) was dissolved in 11 mL of acetone and cooled to 0 °C, ilhen 850 mg (5.6 mmol) of De~U was added dropwise to the solution. The resulting mixture was stirred for 15 min at 0 °C and 30 min at 25 °C, after which 850 mg (5.0 mmol) of isopropyl iodide was added. The reaction was stirred overnight, poured into 100 mL of ethyl acetatels<~turated NH4C1 (1l1 ). Layers were separated, and l:he aqueous phase was further extracted with ethyl acetate (2 X 50 mL).
2s Combined organic layers were dried over MgSO~, filtered and concentrated.
The resulting residue was purified by silica gel chromatography (ethyl acetate/hexanes, 3/2) to afford 560 mg (61 % from lactol 39) of isopropyl ester 41.

D' ~5Z)-(9S 11 R. 15R~-16- 3-c;hloronhenoxy.~;17 18 19.20-tetranor-9.11.15-trih~droxy-5-prostenyl pivaloate A solution of 400 mg (0.63 mmol) of 41 in 5 mL of THF was added dropwise to a suspension of 35 mg (0.92 mmol) of lithium aluminum hydride in 5 mL of THF
s at 0 °C. After 2 h, the reaction was poured into 50 mL of a 1/1 mixture of ethyl acetate/saturated NaHC03. Tha layers were then separated, and the aqueous phase was extracted with ethyl acetate (2 X 2 mL). Combined organic layers were dried over MgS04, filtered, and concentrated. The resulting residue purified by silica gel chromatography (ethyl acetate) to afford 350 mg (95%) of dial 42.
,o Pivaloyl chloride (90 mg, 0.75 mmol) was added to a mixture of 350 mg (0.60 mmol) of 42, 60 mg (0.76 mmol) of pyridine, 22 mg (0.18 moral) of 4-(dimethylamino)pyridine, and 7 mL of CH2CIz. After 1.5 h the mixture was poured into 30 mL of saturated NH4C1/ethyl acetate (1/1 ). Layers were then separated and the aqueous phase was extracted with ethyl acetate (2 X 20 mL). The combined ,s organic layers were dried over MgS04, filtered, concentrated, and purified by silica gel chromatography (ethyl acetate/hexane, 3/2) to afford 370 mg (93°/~) of pivaloate 43.
Water (10 drops) and concentrated HCI (3 drops) were added to a solution of 370 mg (0.56 mmol) of 43 inn 5 mL of methanol. After stirring overnight, the zo reaction was quenched by the addition of 20 mL of saturated NaHC03, and the mixture was extracted with ethyl acetate (3 X 20 mL). The combined organic layers were dried over MgS04, filtered, and concentrated. The residue was chromatographed on silica gel (ethyl acetate/hexane, 312), to afford 165 mg (59%) of trio) 8. '3C NMR (CDC13) 8 178.77 (G), 159.27 (C), 134.80 (C), 130.20 (CH), zs 128.62 (CH), 121.19 (CH), 11 4.97 (CH), 112.97 (CH), 78.50 (CH), 74.46 (CH), 72.31 (CHz), 69.86 (CH), 64.16 (CHz), 52.53 (CH), 51.67 (CH), 42.50 (CHz), 31.51 (CHz), 29.40 (CHz), 28.10 (CHz), 27.12 (CH3), 26.77 (CHz), 26.65 (CHz), 25.77 (CHz). CI MS, mlz calcd for Cz7H4,OsCl, (MH+), 497.2670, found 497.2656 The studies detailed in the following Examples 5-9 compared the IOP
lowering activity and side effects of five compounds: A) Cloprostenol, isopropyl ester; B) Fluprostenol, isopropyl ester; C~) 16-Phenoxy-17,18,19,20-tetranor PGF2a, isopropyl ester; D) 17-Phenyl-18,19,20-trinor PGF2a, isopropyl ester; and E) 13,14-s Dihydro-17-phenyl-18,19,20-trir~or PGF2a, isopropyl ester (latanoprost). The structures of these compounds are shown in the following Table 2.

Table 2 COMPOUND NAAAE COMPOUND STRUCTURE
A Cloprostenol, isopropyl Ester HO ,.\ °~
~~ v °
Ho = ° \ /
OH
CI
B Fluprostenol, isopropyl ester O-° ', HO = ° \
OH
C 16-Phenoxy-17,18,19,20-tetranor PGF2a, isopropyl ester O
~o Ho = ° \ /
off D 17-Phenyl-18,19,20-trinor PGF2a, isopropyl ester ~ °
'~ ~ O
Ho OH \
E 13,14-Dihydro-17-phenyl 18,19,20-trinor PGFza, isopropyl ~ °
ester s HO - \
OH

~~t ~u As is apparent in Table 2, the five compounds differ only slightly in structure;
(however, as Examples 5 and s5 will show, such seemingly slight structural differences produce greatly different IOP-lowering effects and levels of hyperemia.

Compounds A-E (Table 2, abovey were tested for hyperemia in the guinea pig. The objective of the guinea pig conjunctiva) hyperemia model is to provide a ,o primary screening indication ov the potential of a prostaglandin for inducing conjunctiva) hyperemia in humans.
Guinea pigs were maintained in their cages during the study, and removed only for scoring and dosing. Eyes were evaluated using a magnifying lens with fluorescent illumination and scores far conjunctiva) hyperemia were recorded for ,5 upper bulbar conjunctiva according to the following criteria:
0 = Narmal appearance of vessels at limbus and on superior recfus muscle +1 - Enlargement of vessels normally visible of limbus and on superior rectus muscle zo f2 = Branch of vessels at limbus, new vessels visible f3 = New vessels visible in open bulbar conjunctiva) areas f4 - Diffuse redness i'n open bulbar conjunctiva) areas Scores of 0 or 1 indicated no hyperemia, and scores of 2-4 indicated hyperemia (a zs score of 4 indicating the most hyperemia). Only integer scores were permitted in order to minimize subjectivity.
Baseline observations were made prior tv unilateral dosing with a 10 NL. ', aliquot of either the prostaglandin test formulation or the control formulation, followed by observations at 1, 2, 3 and 4 hours after dosing. Groups typically so contained four animals, but ranged up to eight animals per group. The results of the study are presented in Taiole 3, below, as percent frequency of each score, and in Figure 1 as percent incidence of hyperemia, defined as the percent of scores of +2 or +3 relative to the total number of observations for each dose.

p * M N CO N

Z N r r M et c0 ~ N O

N ~ M M ~ ~

Z

O m ', r O

U ~ ~ ~ iW ~

.
t7 o co ~ o T ~

r ~ ~ ~ ~

Z N

M M '~t00 N O

M

* I

~ ~ ' N M Q~ N h O

O N (O N ' C

r r O <] r CO tn CO CO

ih ' C

O N h- O ~ ~

* (O t0~ Ln C Z N r ~C OL t- ', M O O O N O ~

V

N t~.O tf) M O
O
.

. r m ~i r O
U
O

Cn r M 00 ~-- N ~
C N

M C~ h t0 O O N d!' M u1 .- N h-M

O * tn t0 Ca (O ~ p ,0 z N

M O O O O O
I~I

s O

N O ~ M O O
W

~ U

r O O ~i' '~f O
t0 t~ U,7 t1y N

V
C

M ~ m C

a0 N m m ~

m ~ N O~ ' N
O
~

G ~ ~
N ' ~ C

_ ~ ~ ~ C.
~. V1 tn m N tD O
;

O Q.. O O p_ ~ O ~ ' t!f .C et p~ ~' ' C~
m a ~. a- m o ~~ ~ N M

" ~ ~ co ~ ' ~
~ . c LL o . . U U_..~r ~r ~Q. ~
p lLC ~

Q a1 ~J~ .. W r~ Zz m G9~a . *

N ~ N N

~iscussion:
Compound C (16-phenoxy-17,18,19,20-tetranor PGF2a, isopropyl ester) produces significant hyperemia at low doses, and at 0.3 and 1.0 Ng doses, all eyes received one or more scores of +3. Compound D (17-phenyl-18,19,20-trinor PGFZa, isopropyl ester) produce's less hyperemia than compound C, but significantly more than compound E (13,14-dihydro-17-phenyl-18,19,20-trinor PGF2a, isopropyl ester), which produces only mild hyperemia. The hyperemia produced by compound A (cloprostenol, isopropyl ester) and compound B ', ,o (fluprostenol, isopropyl ester) appear to be intermediate between that of compound ~ and compound E, but this degree of hyperemia is also mild, and cannot be distinguished from that produced by compound E.
,s EXAIMPLE 6 In the study presented below, compounds A-E (Table 2, above) were tested for IOP-lowering effect in cynornolgus monkey eyes.
The right eyes of the cynomolgus monkeys used in this study were zo previously given laser trabeculoplasty to induce ocular hypertension in the lasered eye. Animals had been trained to sit in restraint chairs and conditioned to accept experimental procedures without chemical restraint. IOP was determined with a pneumatonometer after light corneal anesthesia with dilute proparacaine. The test protocol included a five-dose treatment regimen because of the typical delayed 2s response to prostaglandins. The designated test formulations were administered to tlhe lasered right eyes, and the normal left eyes remained untreated, although IOP
measurements were taken. l3a;seline IOF' values were determined prior to treatment vvith the test formulation, and then IOP was determined from 1 to 7 hours after the first dose, 16 hours after the fourth dose, and 1 to 4 hours after the fifth dose.
o Results are presented in Tables 4 and 5, below, and in Figures 2 and 3, as the rnean percent reduction of IOP from baseline t SEM. Prostaglandin doses are .
micrograms of compound contained in each treatment with 10 IaL of the test formulation. In Table 4, the same amount (0.3 lag) of each of compounds A-E
were compared for IOP reduction. In Table 5, various amounts of compound A (0.3 and 1.0 lag) were compared against various amounts of compound E (0.3, 1.0 and 3.0 s lag) in order to determine the dose responses of the two different compounds.
Table 4: Percent IOP (Reduction in Lasered Gynomofgus Monkeys Percent IOP Reduction Compound Baseline (H ours afterst Dose/Dose#) La IOP (mm ,o (isopropyl ester) Hg) 16/4 2/5 4/5 6/5 A (Cloprostenol)36.9 23.6 t 30.2 t 31.2 t 24.4 t 3.3 4.5 6.8 6.9 B (Fluprostenol)41.6 18.4 t 31.2 t 30.3 t 26.6 t 5.9 3.7 3.8 3.6 C (16-Phenoxy-38.2 30.2 t 25.3 t 23.6 t 28.9 t 4.4 4.5 3.8 3.0 17,18,19,20-,s tetranor PGF2~

D (17-Phenyl-18,40.8 25.6 t 36.0 t 39.8 t 30.3 t 2.6 2.4 3.1 2.8 19,20-trinor PGFz~

E(13,14-Dihydro-39.7 7.612.9 3.612.7 7.512.7 8.013.4 2o i7-phenyl-18,19, ', 20-trinor PGF2~

a f~ ~~
(~ ' ~~: ~J
Table 5:
Gornparison of Percent IOP
Reduction Baseline Percent Compound Dose IOP Reduction IOP (rrlm(Hours after Last DoseIDose#) (N9) 9) 1 614 2/5 4l5 6/5 A' 0.3 36.9 23.6:3.3 24.416.9 30.214.5 31.216.8 s A 1 39.6 34.8 ~: 35.8 ~
4.5 36.7 5.1 1 5.8 38.7 1 5.9 E 0.3 39.7 7.6 t 8.0 t 2.9 3.6 3.4 t 2.7 7.5 t 2.7 E** 1 38.9 23.2 3: 20.2 t 3.6 22.0 4.0 t 4.0 18.8 t 5.2 E 3 30.1 11.6 3: 12.7 1 6.5 17.6 5.0 1 5.8 13.1 1 5.0 4tV~JlVJIE711V1, ISVEJPV~YI F3Slf3f ,o *"13,14-Dihydro-17-phenyl-18,19,20-trinor PGF2a, isopropyl ester Discussion:
Table 4. shows that compounds A, B, C, and D produce similar degrees of IOP reduction with 0.3 Ng doses; however, compound E is essentially inactive at ,s . this dose.
In Table 5, it is apparenii that the 90P reduction with 1 Ng of compound A is greater than that produced by 0.3 Ng of compound A, and the response to either of these doses of compound A is greater than the maximum reduction produced by either dose of compound E. Tlhese obss~rvations indicate that compound A
zo (cloprostenol, isopropyl ester) i both more potent and produces a greater rnaximum response for IOP reduction than compound E (13,14-dihydro-17-phenyl-18,19,20-trinor PGF2~. , EXAi'VI P LE 7 PGF2a analogues are known to contract the iris sphincter of cats and this s assay is a generally accepted ~~eference for activity. For this reason, the pupil diameter of cats may be used to define i:he activity of PGFza analogues and, as demonstrated by Stjernschantz and Resul (Drugs Future, 17:691-704 (1992)), predict the IOP-lowering potency.
,o Compounds of the present invention were therefore screened for pupillary constriction in the cat. Data for compounds 6, 7, and 8 are presented in Table 6, below. The response is quantitated as l~rea ,_5 values (area under the pupil cliameter versus time curve from 1-5 hours), and the equivalent response dose (ED5) is estimated from its doss response relationship.
,s Table 6: Cat Pupil Diameter Response Compound EDs ~I~g) PGF2a Isopropyl Ester 0.02 o Cloprostenol Isopropyl Ester 0.01 0.2 0.02 8 0.06 25 Discussion:
The two standard compounds, PGF2a isopropyl ester and cloprostenol isopropyl ester, produced marked change in cat pupillary diameter, displaying EDS
values of 0.02 and 0.01 Ng, res;pectively. Compound 7 (cloprostenol-1-0l) and compound 8 (13,14-dihydrocloprostenol-1-0l pivaioate), displayed nearly equivalent so potency. 13,14-Dihydrofluprostenol isopropyl ester (compound 6) was approximately one order of magnitude less potent, with an EDS of 0.2 lag.

ft, ~~ ~'h In the study presented below, cornpound 6 (Table 1, above) was tested for IOP-lowering effect in cynomolgus monkey eyes. ', s The right eyes of the cynomolgus monkeys used in this study were previously given laser trabeculoplasty to induce ocular hypertension in the lasered eye. Animals had been trained to sit in restraint ehairs and conditioned to accept experimental procedures without chemical restraint. IOP was determined with a pneumatonometer after light corneal anesthesia with c'ilute proparacaine. The test ,o protocol included a five-dose treatment regimen because of the typical delayed response to prostaglandins. The designated test formulations were administered to t:he lasered right eyes, and the normal left eyes remained untreated, although IOP
measurements were taken. Baseline IOF' values were determined prior to treatment rnrith the test formulation, and then IOP vvas determined from 1 to 7 hours after the ,s first dose, 16 hours after the fourth dose, and 1 to 4 hours after the fifth dose.
The equivalent responsE; dose (El~2o) is estimated from the dose response relationship to be the dose producing a 20% peak reduction in IOP.
Tables 7: Monkey lop Response Compound ED2o (N9) PGF2a Isopropyl Ester 0.4 6 0.3 l7iscussion:
As can be seen in Table 7, above, compound 6, the 13,14-dihydro analogue of fluprostenol was quite potent in the monkey IOP model, producing a 20%
reduction at 0.3 Ng. This was even more potent than the standard compound, 3o IPGF2a isopropyl ester. ', r The following Formulations 1-8 are representative pharmaceutical compositions of the invention for topical ring of intraocular pressure.
use in lowe Each of Formulations 1 through 8 may be formulated in accordance with procedures known to those skilled in the art.

FORMULATION ~

,o Ingredient Amount ~wt/4) Cloprostenol isopropyl ester 0.002 (Table 2, Compound A) Dextran 70 0.1 ,5 Hydroxypropyl methylcellulose 0.3 Sodium Chloride 0.77 Potassium chloride 0.12 Disodium EDTA (Edetate 0.05 disodium) 2o Benzalkonium chloride 0.01 ', HCI andlor NaOH pH 7.2 - 7.5 Purified water q.s. to 100%

~a ~A '~ , ~, _ _ ~.' .

Ingredient Amount (wt°/p) Cloprostenol, t butyl ester 0.01 s Monobasic sodium phosphate 0.05 Dibasic sodium phosphate 0.15 (anhydrous) Sodium chloride 0.75 Disodium EDTA (Edetate disodium) 0.01 ,o Benzalkonium chloride 0.02 Polysorbate 80 0.15 HCI and/or NaOH pH 7.3 - 7.4 ', Purified water q.s. to 100%

Ingredient: Amount {wt%) zo Cloprostenol, methyl eater 0.001 Dextran 70 0.1 Hydroxypropyl methylc~ellulose 0.5 Monobasic sodium phosphate 0.05 Dibasic sodium phosphate 0.15 2s (anhydrous) Sodium chloride 0.75 Disodium EDTA (Edeta.te disadium) 0.05 Benzalkonium chloride 0.01 NaOH and/or HCI pH 7.3 - 7.4 so Purified water q.s. to 100%

wr Ingredient Amount (wt%) Fluprostenol isopropyl ester 0.003 (Table 2, Compound B) ', Monobasic sodium phosphate 0.05 Dibasic sodium phosph<~te 0.15 (anhydrous) ,o Sodium chloride 0.75 Disodium EDTA (Edetate disodiurn) 0.05 Benzalkonium chloride 0.01 HCI and/or NaOH pH 7.3 ~ 7.4 Purified water q.s. to 100%

o ingredient Amount Qwt%j Compound 5 (Table 1 ) 0.002 Dextran 70 0.1 Hydroxypropyl methylcellulose 0.3 Sodium chloride 0.77 z5 Potassium chloride 0.12 Disodium EDTA 0.05 Benzalkonium chloride 0.01 HCI andlor NaOH , pH 7.2 - 7.5 Purified water q.s. to i 00%

,~s' G
E,r ,rr ...

Ingredient Amount (wt%) s Compound 6 (Table 1 ) 0.01 Monobasic sodium pho;>phate 0.05 Dibasic sodium phosphate 0.15 {anhydrous) Sodium chloride 0.75 ,o Disodium EDTA 0.01 Benzalkonium chloride 0.02 ';

Polysorbate 80 0.15 ', HCI and/or NaOH pH 7.3 - 7.4 Purified water q.s. to 100% ', ,5 0 Ingredient Amount (wt%) Compound 7 (Table 1 ) 0.001 Dextran 70 0.1 Hydroxypropyl methylce~llulose 0.5 Monobasic sodium phosphate 0.05 25 Dibasic sodium phosphate 0.15 ', (anhydrous) Sodium chloride 0.75 Disodium EDTA 0.05 Benzalkonium chloride 0.01 so NaOH andlor HCI pH 7.3 - 7.4 Purified water q.s. to 100%

~:
FC?RMUL_ATION :3 Ingredient Amount (wt%) ', s Compound 8 (Table 1 ) 0.003 Monobasic sodium pho:~phate 0.05 Dibasic sodium phosphate 0.15 (anhydrous) Sodium chloride 0.75 ,o Disodium EDTA 0.05 ', Benzalkonium chloride 0.01 HCI and/or NaOH pH 7.3 - 7.4 ', Purified water q.s. to 100%
,s The invention has been described by reference to certain preferred embodiments; however, it should be understood that it may be embodied in other specific forms or variations thereof without departing from its spirit or essential 2o characteristics. The embodiments described above are therefore considered to be illustrative in all respects and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description.

Claims (54)

1. Use of a therapeutically effective amount of a compound of formula:
wherein:
R1 = H; C1-C12 straight-chain or branched alkyl;
C1-C12 straight-chain or branched acyl; C3-C8 cycloalkyl; a cationic salt moiety; or a pharmaceutically acceptable amine moiety;
R2, R3 = H, or C1-C5 straight-chain or branched alkyl;
or R2 and R3 taken together may represent O;
X = O, S, or CH2;
represents any combination of a single bond, or a cis or trans double bond for the alpha (upper) chain; and a single bond or trans double bond for the omega (lower) chain;
R9 = H, C1-C10 straight-chain or branched alkyl, or C1-C10 straight-chain or branched acyl;
R11 = H, C1-C10 straight-chain or branched alkyl, or C1-C10 straight-chain or branched acyl;
Y = O; or H and OR15 in either configuration wherein R15 - H, C1-C15 straight-chain or branched alkyl, or C1-C10 straight-chain or branched acyl; and Z = C1 or CF3;
with the proviso that when R2 and R3 taken together represent O, then R1 .noteq. H; cationic salt moiety; C1-C12 straight-chain or branched acyl; and when R2 = R3 = H, then R1 .noteq. a cationic salt moiety or a pharmaceutically acceptable amine moiety; and with the further proviso that the following compound be excluded:
cyclopentaneheptanol-5-cis-2-(3-.alpha.hydroxy-4-m-chlorophenoxy-1-trans-butenyl)-3,5 dihydroxy, [1.alpha., 2.beta., 3.alpha., 5.alpha.], for the treatment of glaucoma and ocular hypertension.

2. The use of claim 1, wherein: R2 =R3 =H, or R2 and R3 taken together represent O; X = O or CH2; R9 = R11 =
H; Y = H and OR15; and R15 = H.

3. The use of claim 2, wherein: R1 - C1-C12 straight chain or branched alkyl; and R2 and R3 taken together represent O.

4. The use of claim 3, wherein the compound of formula (IV) is selected from the group consisting of 3-oxacloprostenol, 13,14-dihydrofluprostenol, and their pharma-ceutically acceptable esters and salts.

5. The use of claim 2, wherein: R1 = H or C1-C12 straight chain or branched acyl; and R2 = R3 =H.

6. The use of claim 5, wherein the compound of formula (IV) is selected from the group consisting of cloprostenol-1-ol and 13,14-dihydrocloprostenol-1-ol pivaloate.

7. The use of claim 2, wherein R2 and R3 taken together represent O; and X = CH2.

8. The use of claim 7, wherein: R1 = C1-C6 straight-chain or branched alkyl; or a pharmaceutically acceptable amine moiety.

9. The use of claim 8, wherein the compound of formula (IV) is selected from the group consisting of the pharmaceutically acceptable esters of cloprostenol and fluprostenol.

10. The use of claim 9, wherein the compound of formula (IV) is selected from the group consisting of the pharmaceutically acceptable esters of cloprostenol.

11. The use of claim 10, wherein the compound of formula (IV) is cloprostenol isopropyl ester.

12. The use of claim 9, wherein the compound of formula (IV) is selected from the group consisting of the pharmaceutically acceptable esters of fluprostenol.

13. The use of any one of claims 1 to 12, wherein said therapeutically effective amount of the compound is between 0.01 and 1000 µg/eye.

14. The use of claim 13, wherein the therapeu-tically effective amount is between 0.01 and 100 µg/eye.

15. The use of claim 14, wherein the therapeu-tically effective between 0.05 and 10 µ,g/eye.

16. A topical ophthalmic composition for the treatment of glaucoma and ocular hypertension comprising a therapeutically effective amount of a compound of formula:
wherein:
R1 = H; C1-C12 straight-chain or branched alkyl;
C1-C12 straight-chain or branched acyl; C3-C8 cycloalkyl; a cationic salt moiety; or a pharmaceutically acceptable amine moiety;
R2, R3 - H, or C1-C5 straight-chain or branched alkyl;
or R2 and R3 taken together represent O; with the proviso that if R2 and R3 taken together = O, then R1 .noteq. H or a cationic salt moiety;
and X = O, S, or CH2;
represents any combination of a single bond, or a cis or trans double bond for the alpha (upper) chain; and a single bond or trans double bond for the omega (lower) chain;
R9 - H, C1-C10 straight-chain or branched alkyl, or C1-C10 straight-chain or branched acyl;
R11 = H, C1-C10 straight-chain or branched alkyl, or C1-C10 straight-chain or branched acyl;
Y = O; or H and OR15 in either configuration wherein R15 = H, C1-C10 straight-chain or branched alkyl, or C1-C10 straight-chain or branched acyl; and Z = Cl or CF3;
with the proviso that when R2 and R3 taken together represent O, them R1 .noteq. C1-C12 straight-chain or branched acyl; and when R2 = R3 = H, then R1 .noteq. a cationic salt moiety; and with the further proviso that the following compound be excluded:
cyclopentaneheptanol-5-cis-2-(3-.alpha.hydroxy-4-m-chlorophenoxy-1-trans-butenyl)-3,5 dihydroxy, [1.alpha., 2.beta., 3.alpha., 5.alpha.]..

17. The composition of claim 16, wherein: R2 - R3 = H, or R2 and R3 taken together represent O; X = O or CH2;
R9 = R11 = H; Y = H and OR15; and R15 - H.

18. The composition of claim 17, wherein: R1 =
C1-C12 straight chain or branched alkyl; and R2 and R3 taken together represent O.

19. The composition of claim 18, wherein the compound for formula (IV) is selected from the group consisting of 3-oxacloprostenol, 13,14-dihydrofluprostenol, and their pharmaceutically acceptable esters and salts.

20. The composition of claim 17, wherein: R1 = H
or C1-C12 straight chain or branched aryl; and R2 = R3 = H.

21. The composition of claim 20, wherein the compound of formula (IV) is selected from the group consisting of cloprostenol-1-ol and 13,14-dihydro-cloprostenol-1-ol pivaloate.

22. The composition of claim 17, wherein: R2 and R3 taken together represent O; and X = CH2.

23. The composition of claim 22, wherein: R1 =
C1-C6 straight-chain or branched alkyl; or a pharma-ceutically acceptable amine moiety.

24. The composition of claim 23, wherein the compound of formula (IV) is selected from the group consisting of the pharmaceutically acceptable esters of cloprostenol and fluprostenol.

25. The composition of claim 24, wherein the compound of formula (IV) is selected from the group consisting of the pharmaceutically acceptable esters of cloprostenol.

26. The composition of claim 25, wherein the compound of formula (IV) is cloprostenol isopropyl ester.

27. The composition of claim 24, wherein the compound of formula (IV) is selected from the group consisting of the pharmaceutically acceptable esters of fluprostenol.

28. The composition of any one of claims 16 to 27, wherein the concentration of the compound of formula (IV) is between 0.00003 and 3 wt%.

29. The composition of claim 28, wherein the concentration of the compound of formula (IV) is between 0.0003 and 0.3 wt%.

30. The composition of claim 29, wherein the concentration of the compound of formula (IV) is between 0.003 and 0.03 wt%.

31. A compound of formula:
wherein:
R1 = H; C1-C12 straight-chain or branched alkyl;
C1-C12 straight-chain or branched acyl; C3-C8 cycloalkyl; a cationic salt moiety; or a pharmaceutically acceptable amine moiety;
R2, R3 - H, or C1-C5 straight-chain or branched alkyl;
or R2 and R3 taken together may represent O;

X = O;
represents any combination of a single bond, or a cis or trans double bond for the alpha (upper) chain; and a single bond or trans double bond for the omega (lower) chain;
R9 = H, C1-C10 straight-chain or branched alkyl, or C1-C10 straight-chain or branched acyl;
R11 = H, C1-C10 straight-chain or branched alkyl, or C1-C10 straight-chain or branched acyl;
Y = O; or H and OR15 in either configuration wherein R15 = H, C1-C10 straight-chain or branched alkyl, or C1-C10 straight-chain or branched acyl; and Z = Cl or CF3;
with the proviso that when R2 and R3 taken together represent O, then R1 .noteq. C1-C12 straight-chain or branched acyl; and when R2 = R3 = H, then R1 .noteq. a cationic salt moiety or a pharmaceutically acceptable amine moiety.

32. The compound of claim 31, having the formula:

33. Use of a therapeutically effective amount of a compound having the absolute stereochemical structure of the following formula (IV), and being substantially free of the enantiomer of said compound:

wherein:
R1 = H; C1-C12 straight-chain or branched alkyl;
C1-C12 straight-chain or branched acyl; C3-C8 cycloalkyl; a cationic salt moiety;
R2, R3 = H, or C1-C5 straight-chain or branched alkyl;
or R2 and R3 taken together may represent O;
X = O, S, or CH2;
represents any combination of a single bond, or a cis or traps double bond for the alpha (upper) chain; and a single bond or traps double bond for the omega (lower) chain;
R9 = H, C1-C10 straight-chain or branched alkyl, or C1-C10 straight-chain or branched acyl;
R11 = H, C1-C10 straight-chain or branched alkyl, or C1-C10 straight-chain or branched aryl;
Y = O; or H and OR15 in either configuration wherein R15 = H, C1-C10 straight-chain or branched alkyl, or C1-C10 straight-chain or branched aryl; and Z = Cl or CF3;
with the proviso that when R2 and R3 taken together represent O, then R1 .noteq. H; cationic salt moiety; C1-C12 straight-chain or branched acyl; and when R2 = R3 = H, then R1 .noteq. a cationic salt moiety;

with the further proviso that the following compound be excluded:
cyclopentaneheptanol-5-cis-2-(3-.alpha.hydroxy-4-m-chlorophenoxy-1-trans-butenyl)-3,5 dihydroxy, [1.alpha., 2.beta., 3.alpha., 5.alpha.], for the treatment of glaucoma and ocular hypertension.

34. The use of claim 33, wherein for the compound (IV):
R2, R3 taken together represent O;
X = CH2;
represents a cis double bond for the alpha (upper) chain and a trans double bond for the omega (lower) chain;
R9 and R11 = H; and Y = OH in the alpha configuration and H in the beta configuration,

35. The use of claim 39, wherein for the compound (IV): Z = CF3.

36. The use of claim 33, wherein R2 = R3 = H, or R2 and R3 taken together represent O; X = O or CH2; R9 =
R11 = H; Y = H and OR15; and R15 = H.

37. The use of claim 36, wherein: R1 = C1-C12 straight chain or branched alkyl or cationic salt moiety;
and R2 and R3 taken together represent O.

38. The use of claim 37, wherein the compound of formula (IV) is selected from the group consisting of 3-oxacloprostenol, 13, 14-dihydrofluprostenol, and their pharmaceutically acceptable esters and salts.

39. The use of claim 36, wherein: R1 = H or C1-C12 straight chain or branched acyl; and R2 = R3 = H.

40. The use of claim 39, wherein the compound formula (IV) is 13,14-dihydrocloprostenol-1-ol pivaloate.

41. The use of claim 33, wherein the therapeu-tically effective amount of the compound is between 0.01 and 1000 µg/eye.

42. The use of claim 41, wherein the therapeu-tically effective amount of the compound is between 0.1 and 100 µg/eye.

43. The use of claim 42, wherein the therapeu-tically effective amount of the compound is between 0.1 and µg/eye.

44. A topical ophthalmic composition for the treatment of glaucoma and ocular hypertension comprising an ophthalmically acceptable carrier and a therapeutically effective amount of a compound having the absolute stereochemical structure of the following formula (IV), and being substantially free of the enantiomer of said compound:
wherein R2 = H; C1-C12 straight-chain or branched alkyl;
C1-C12 straight-chain or branched acyl; C3-C8 cycloalkyl; a cationic salt moiety;
R2, R3 = H, or C1-C5 straight-chain or branched alkyl;

or R2 and R3 taken together may represent O;
X = O, S, or CH2;
represents any combination of a single bond, or a cis or trans double bond for the alpha (upper) chain; and a single bond or trans double bond for the omega (lower) chain;
R9 = H, C1-C10 straight-chain or branched alkyl, or C1-C10 straight-chain or branched acyl;
R11 = H, C1-C10 straight-chain or branched alkyl, or C1-C10 straight-chain or branched acyl;
Y = O; or H and OR15 in either configuration wherein R15 = H, C1-C10 straight-chain or branched alkyl, or C1-C10 straight-chain or branched aryl; and Z = C1 or CF3;
with the proviso that when R2 and R3 taken together represent O, then R1 .noteq. C1-C12 straight-chain or branched acyl; and when R2 = R3 = H, then R1 .noteq. a cationic salt moiety; and with the further proviso that the following compound be excluded:
cyclopentaneheptanol-5-cis-2-(3-.alpha.hydroxy-4-m-chlorophenoxy-1-trans-butenyl)-3,5 dihydroxy, [1.alpha., 2.beta., 3.alpha., 5.alpha.].

45. The composition of claim 44, wherein for the compound (IV):
R2, R3 taken together represent O;
X = CH2;
represents a cis double bond for the alpha (upper) chain and a trans double bond for the omege (lower) chain;
R9 and R11 = H; and Y = OH in the alpha configuration and H in the beta configuration.

46. The composition of claim 45, wherein for the compound (IV): Z = CF3.

47. The composition of claim 44, wherein: R2 = R3 = H, or R2 and R3 taken together represent O; X = O or CH2;
R9 = R11 = H; Y = H and OR15; and R15 = H.

48. The composition of claim 47, wherein: R1 = H, C1-C12 straight chain or branched alkyl, or cationic salt moiety; and R2 and R3 taken together represent O.

49. The composition of claim 48, wherein the compound of formula (IV) is selected from the group consisting of 3-oxacloprostenol, 13,14-dihydrofluprostenol, and their pharmaceutically acceptable esters and salts.

50. The composition of claim 47, wherein: R1 = H
or C1-C12 straight chain or branched acyl; and R2 = R3 = H.

51. The composition of claim 50, wherein the compound of formula (IV) is 13,14-dihydrocloprostenol-1-ol pivaloate.

52. The composition of claim 44, wherein the concentration of the compound of formula (IV) is between 0.00003 and 3 wt%.

53. The composition of claim 52, wherein the concentration of the compound of formula (IV) is between 0.0003 and 0.3 wt%.

54. The composition of claim 53, wherein the concentration of the compound of formula (IV) is between 0.003 and 0.03 wt%.