CA2138181A1 - Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension - Google Patents

Abstract

Certain prostaglandin analogues are useful in the treatment of glaucoma and ocular hypertension. Also disclosed are ophthalmic, pharmaceutical compositions comprising such prostaglandin analogues and their use.

Description

USE OF CERTAIN pRo8T~aT~NnIN ~N~TO5UE8 TO TREAT GLA~COMA AND OCULAR HYPERTEN8ION

Background of the Invention The present invention relates to the use of certain prostaglandins and prostaglandin analogues for the treatment of glaucoma and ocular hypertension. As used herein, the terms "prostaglandin" and "PG" shall refer to prostaglandins and derivatives and analogues thereof, except as otherwise indicated by context.

Naturally-occurring prostaglandins are known to lower intraocular pressure (IOP) after topical ocular instillation, but generally cause inflammation, as well as surface irritation characterized by conjunctival hyperemia and edema. Many synthetic prostaglandins have been observed to lower intraocular pressure, but such compounds also produce the aforementioned side effects. Various attempts have been made to overcome the ocular side effects associated with prostaglandins.
Stjernschantz et al. (EP 364 417 B1) have synthesized derivatives or analogues of naturally-occurring prostaglandins in order 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.

Summary of the Invention It has now been unexpectedly discovered that certain D series prostaglandin analogues are significantly more effective in lowering IOP than other known prostaglandins. In particular, the prostaglandin analogues of the present invention have unexpectedly been found to lower IOP to a greater degree than other known PGs without significant inflammation or associated side effects which often accompany topical ocular administration of D series prostaglandins.

Detailed DescriPtion of the Invention The prostaglandins which are useful in the compositions of the present invention have the general formulae (I) and (II): .

X~,~"~R, R, (I) wherein:
Rl = CO2Rz, wherein R2 = H, a cationic salt moiety, or an ophthalmically acceptable ammonium moiety; or Rl may also represent an ophthalmically acceptable ester moiety;
X = halogen, particularly Cl or F, in either configuration;
Y = CH2 or O;
--- = single or trans double bond;
R3, R4 can be the same or different, and are selected from: free or functionally modified hydroxy groups; and n = 0 or 1.

X R~ R2 <~""`~A~W X
~Y~
~ (II) wherein:
Rl = CH2R, CO2R4;

21381~1 R = OH or functionally modified hydroxy group;
R2 and R3 can be the same or different and are selected from: H and CH3;
R4 = H, a cationic salt moiety, an ophthalmically acceptable ammonium moiety, substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, heteroaryl, or (heteroaryl)alkyl, wherein substituents include alkyl, halo, a free or functionally modified hydroxy group, or a free or functionally modified thiol;
W = CH2, O, S()m wherein m = O, 1, 2;
A = CH2CH2, cis or trans CH=CH, or CQC;
X = Cl, F or R in either configuration, or H;
Zl1 may be selected from O (i.e. a carbonyl), H and R in either configuration, or H and H;
Z,5 may be selected from O (i.e., a carbonyl) H and R in either configuration or H and H;
Y = CH2CH2 or trans CH=CH, or CQC; and n = 0 or 1.

As used in this specification, the term "ophthalmically acceptable ester moiety" refers to an ester moiety which is non-toxic and does not cause undue irritation to the ocular tissues. For compounds of formula (I), examples of ophthalmically acceptable esters include, but are not limited to: R2 =
substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, heteroaryl, or (heteroaryl)alkyl, wherein substituents include alkyl, halo, a free or functionally modified hydroxy group, or a free or functionally modified thiol. As used in this specification, the term "heteroaryl" refers to a monocyclic ring system of 5 or 6 atoms composed of C, N, O, and/or S, such as furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isothiazole, thiazole, thiadiazole, pyridine, 21381~1 pyrimidine, pyradazine and pyrazine. The term "functionally modified hydroxy groups" refers to either etherified hydroxy groups or acylated (esterified) hydroxy groups. Similarly, the term "functionally modified thiol" refers to an alkylated thiol.

Preferred compounds of formula (I) include those wherein: Rl = CO2R2; R2 = H, methyl, ethyl, n-propyl, isopropyl, t-butyl, or benzyl; X = Cl in the ~ (R) configuration; Y = O or CH2; R3 and R4 = OH; and n = 1.
The most preferred compounds of formula (I) are those wherein: Rl = CO2R2; R2 = H, methyl, ethyl, isopropyl, or t-butyl; X = Cl in the ~ (R) configuration; Y = O;
R3 and R4 = OH; and n = 1.

Preferred compounds of formula (II) include those wherein: W = CH2 or 0; A = cis CH=CH; X = Cl or H; Z
= R and H in either configuration or H and H; Y =
CH2CH2, or trans CH=CH; and n = 1. The most preferred compounds of formula (II) are those wherein: R2, R3 =
H; X = Cl in ~ (Rj configuration or H; Zll = H and R in either configuration; Z15 = H and R in either configuration; R1=CO2R4; and R4=H, a cationic salt moiety, or substituted or unsubstituted C1-C10 alkyl.

Some of the compounds of formula (II) are novel.
The novel compounds of formula (II) are those wherein:
25 Rl = CH2R, CO2R4; R = OH or a functionally modified hydroxy group; R2 and R3 can be the same or different and are selected from: H and CH3; R4 = H, a cationic salt moiety, substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, heteroaryl, or (heteroaryl)alkyl, wherein substituents include alkyl, halo, a free or functionally modified hydroxy group, or a free or functionally modified thiol; W = O, S(O)m, wherein m = O, 1, 2; A = CH2CH2, cis or trans CH=CH, or CQC; X = H; Zll and Z15 may be the same or different and may be selected from O (i.e., a carbonyl), H and R in either configuration, or H and H; Y = CH2CH2 or trans CH=CH, or CÇC; and n = O or 1.

The preferred novel compounds of formula (II) are those wherein: Rl = CO2R4; R2 and R3 = H; R4=H, a cationic salt moiety, or a substituted or unsubstituted Cl-C10 alkyl; W = O, A = cis CH=CH; Zll = R and H in either configuration; Y = CH2CH2, or trans CH=CH; Z15 = R and H
in either configuration; and n = O or 1.

The following Table 1 contains examples of some preferred compounds of the present invention.

213Sl~l - TAR~

COMPOUND NAME COMPOUND STRUCTURE
III (5Z, 13E)~9R,llR,lSS)-9 Chloro-15- cl ~
cyclohexyl-11,15 dihydroxy~ ` CO2CH3 16,17,18,19,2~1t~or-5,13- ~ I ~
prostadienoic Acid Methyl Ester à~ ~¦

OH
IV (5Z, 13E)~9R,llR 155)-9 Chloro-15- a ~
cyclohexyl-11,15 dihyd~oA~-3-oxa- ~ . O co2c(cH3)s 16,17,18,19,20-~1~anor-5,13- < I
prostadienoic Acid t-Butyl Ester OH
V (5Z)~9R, 11R, 15R)-9~hloro 15- a ` ~
cyclohexyl-11,15 dihydroxy-3-oxa- ~ . ` ~o co2C~CH3)3 16,17,18,19,2~nl~lor-5 -~
~ros~oic Acid t-Butyl Ester OH --OH
Vl (5Z)~9R, 11R, 15R)-9 Chloro-15- a ``
cyclohexyl-11,15-dil~lroA~oxa- ~.: ~ co2cH(aH3)2 16,17,18,19,20--~LldlWl--S < I /~
prOsl~oic Acid I~o~l Ester ~ J -OH
VII (5Z)~9R, 11R, 15R)~loro-15- a cyclohexyl-11,15 dihydroxy- ~ CO2CH(CH3)2 16,17,18,19,20-~lanor-5 < I , ~, ~icAcid ~opropyl E~ter ~ J

OH
VIII (5Z)~9R, 11R, 15R)-9-Chloro-15- a cydohexyl-ll-l~ A~ 5~ ~ = Q~co2ca~
me~oxy-3-oxa-16,17,18,19,'~ < I ~
~t~or-5 ~Y)5l~WiC Acid ~-8utyl ~J
Oa~3 IX (5E)~llR, 15~)-15~ydohexyl-11,15-dihydroxy-3-oxa~ ~`O~CO2CH(CH3)2 16,17,18,19,20-~n~or-5-prostadienoic Acid Isopropyl Ester ~y HO HO

X (5E, 13E)-(llR, 15S)-15~ydohexyl-11,15~ihydroxy-3-oxa- ~` ~O~CO2CH(CH3)2 16,17,18,19,20-~ anor-5,13- \~
prostadienoic Acid Iso~.o~l Ester HO H~--) XI (5Z)~9R, 11R, 15R)-9~hloro-15- a cydohexyl-11,15 dihydroxy-3-oxa- ~ .~"`~ o~CH20H
16,17,18,19,20-y~lt~u~r-5 ?ro3~nol < I I f~
~
OH
XII (5Z)~9R, 11R, 15S)-9~hloro-15- a cydohexyl-11,15-dil.ydloA~-3-oxa- ~ ~= 0 CH20H
16,17,18,19,20-y~ll~ or-5,13 prosta~
OH
XIII (5E, 13E)-(9R, 11R, 15S)-9-Chloro- a 15-cycdohexyl 11,15 dil~y~oAr 3 ~ ~ ~ ~O~CO2C~CH~, oxa-16,17,18,19,20-~-~or-5,13-prostadienoic Acid t-Butyl Ester J

OH
XIV (5Z)-(9R, 11R, 15S)~loro-15- a cydohexyl-11,15 dil~y~OAy- ~ = o~CO2CH~H~2 16,17,18,19,20-~l~.or-5-prwtenoic Aad I~o~l Ester ~J
OH
XV (5Z)-(9R, 11R, 15R)-9-Chloro~15- a cycdohexyl-ll,15 dil-ydroAy-3 oxa- ~ ~ Q )2a~çH~, 16,17,18,19,20-~ænta~or-5 < I~ ~
~r~5t~0ic Acit Neo~ll~rl Ester _~J
OH OH

213~

XVI (SZ,13E)-(1 lR,lSS)-lS{:yclohexyl- ~ ~"~O~CO2C~(CH3)2 ll,lS dihydroxy-3-oxa- \_1~ ~
16,17,18,19,20-~ or-5,13- ~ ) proshdienoic acid isopropyl ester HO HO ~--Some of the above-mentioned prostaglandins are disclosed in US 5,004,752 (Raduechel et al.) and EP 299 914 (Buchmann et al.). To the extent that US 5,004,752 and EP 299 914 teach the preparation of the prostaglandins of the present invention, these patents are hereby incorporated by reference herein. In addition, the syntheses of some of the prostaglandins of Table 1, above, are detailed below in Examples 1-12.

In the following Examples 1-12, the following standard abbreviations are used: g = grams (mg =
milligrams); mol = moles (mmol = millimoles); mol~ =
mole percent; mL = milliliters; mm Hg = millimeters of mercury; mp = melting point; bp = 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.

EXAMPLE 1: SYNTHESIS OF COMPOUND V

21381~1 A: Dimethyl (2-cyclohexyl-2-oxo)ethylPhosphonate (2):
A solution of dimethyl methylphosphonate (100 g, 0.8 mol) in 1.0 L of anhydrous THF was cooled to -70C
and n-BuLi (2.5 M in hexanes, 320 mL, 0.8 mol) was S added dropwise such that the temperature remained below -60C. The mixture was stirred for 10 min at -70C and then methyl cyclohexanecarboxylate (57.3 mL, 0.4 mol) was added dropwise, via syringe, over a period of 15 min. The resulting mixture was then stirred for 14 h at room temperature. The reaction was quenched by first cooling to 0C followed by the addition of 2 M
HCl until the aqueous layer was at pH 2. The layers were separated and the aqueous layer was extracted with 2 X 200 mL of CH2Cl2. The organic layers were combined and washed sequentially with 200 mL each of water and brine and then dried (MgSO4). Filtration and solvent removal gave a yellow oil which was distilled under vacuum to afford 67.3 g (72%) of 2 as a clear colorless liquid: bp=100-115C (0.01 mmHg); IH NMR (CDCl3) ~ 3.74 (d, J = 12.0 Hz, 6H), 3.08 (d, J = 22 Hz, 2H), 2.55 (m, lH), l.9S - 1.60 (m, SH), 1.40 - l.lS (m, SH).

B: (3aR, 4R, SR, 6aS)-S-(Benzoyloxy)-4-[(E)-3-cyclohexyl-3-oxo-1-propenyl]-hexahydro-2H-cyclopentarb~furan-2-one (4):
A solution of anhydrous THF (1.4 L), LiCl (11.7 g, 0.28 mol) and the phosphonate 2 (67.0 g, 0.28 mol) was cooled to 0C and triethylamine (39.2 mL, 0.28 mol) was added dropwise. A solution of the aldehyde 3 (68.5 g, 0.25 mol) in dry CH2Cl2 (320 mL) was added dropwise to the cold suspension and the resulting mixture was stirred at 0C for 3 h. The reaction mixture was then poured into S00 mL of 2 M HCl, and layers were separated. The aqueous layer was extracted with S00 mL
of CH2Cl2. The combined organic layers were washed with 100 mL each of water and brine followed by drying over MgSO4. Filtration and solvent removal gave a yellow solid which was recrystallized from EtOAc to afford 85.8 g (89%) of 4 as a white solid: mp 151-153C; IH NMR
(CDCl3) ô 8.01 (d, J = 2.0 Hz, 2H), 7.65 - 7.40 (m, 3H), 6.70 (dd, J = 12, 6 Hz, lH), 6.35 (d, J = 12 Hz, lH), 5.32 (m, lH), 5.15 (m, lH), 2.93 (m, 3H), 2.72 -2.25 (m, 4H), 1.85 - 1.56 (m, 6H), 1.40 - 1.15 (m, 5H).

C: (3aR, 4R, 5R, 6aS)-5-(Benzoyloxy)-4-~(E)-(3S)-3-cyclohexyl-3-hydroxy-1-propenyl~-hexahydro-2H-cyclopenta r b~furan-2-one (5):
A solution of CeCl3-7H2O (19.5 g, 52.3 mmol) and enone 4 (20.0 g, 52.3 mmol) in 150 mL of CH30H and 70 mL of CH2Cl2 was prepared. NaBH4 (1.92 g, 52.3 mmol) was added in small portions over a period of 5 min.
The resulting mixture was stirred at ambient temperature for 45 min and then was poured into a separatory funnel containing 100 mL each of 25% (v/v) aqueous acetic acid and CH2Cl2. The layers were separated and the aqueous layer was extracted with 3 X
50 mL of CH2Cl2. The combined organic layers were washed with sat. NaHCO3 (50 mL), and brine (50 mL), and then dried (MgSO4). Upon solvent removal, 23.7 g of a colorless oil containing nearly equal amounts of the two diastereomeric allyl alcohols was obtained. The diastereomers were separated by HPLC (40%
EtOAc/hexane), affording 5 (9.34 g (46%), the less polar component) as a white solid. IH NMR (CDCl3) ~
8.01 (d, J = 8 Hz, 2H), 7.62 - 7.28 (m, 3H), 5.61 (m, 2H), 5.25 (m, lH), 5.08 (m, lH), 3.85 (m, lH), 2.95 -2.45 (m, 5H), 2.30 (m, 2H), 1.95 - 1.55 (m, 6H), 1.50 -0.80 (m, 5H).

D: (3aR, 4R 5R 6aS)-4-[(3R)-3-Cyclohexyl-3-hydroxYpropyl~-hexahydro-5-hydroxy-2H-cyclopenta[blfuran-2-one (7):
A solution of the allyl alcohol 5 (10.0 g, 26.0 35 mmol) in warm methanol (100 mL) was cooled to ambient temperature. Anhydrous K2CO3 (3.6 g, 26.0 mmol) was added and the resulting mixture was stirred at ambient temperature for 3 h. The reaction mixture was concentrated and the residue was partitioned between 100 mL each of EtOAc and 1 M HCl. The layers were separated and the aqueous phase was extracted with 3 X
50 mL of EtOAc. The combined organic layers were washed with 50 mL of water, 2 X 50 mL of sat. NaHCO3, 50 mL of brine, and dried over MgSO4. Filtration and evaporation gave the diol 6 (9.8 g, 92% yield, ~
=0.26, 100% EtOAc), which was used in the subsequent reaction without further purification.
The crude diol 6 (9.8 g, 26 mmol) was dissolved in 50 mL of EtOAc and a catalytic amount (0.1 g) of 5%
Pd/C was added. This mixture was hydrogenated at 30-40 psi in a Parr hydrogenation apparatus for 3 h and then filtered through a short pad of Celite. The filtrate was concentrated and the crude yellow oil was purified by passage through a short column of silica (~ =0.26, EtOAc) to afford 7 (5.06 g, 70% yield from 5) as a colorless, viscous oil which solidified upon standing.
H NMR (CDCl3) ~ 4.95 (m, lH), 4.05 (m, lH), 3.35 (m, lH), 2.80 (m, lH), 2.58 (m, 2H), 2.30 (m, lH), 2.00 (m, 14H).

E: (3aR, 4R, 5R, 6aS)-4-~(3R)-3-Cyclohexyl- 3-(tetrahYdropyran-2-yloxy)propyl~-hexahydro-5-(tetrahydropyran-2-yloxy)-2H-cyclopentarb1furan-2-one (8):
A solution of the diol 7 (6.0 g, 21.2 mmol) and dihydropyran (7.80 mL, 84.8 mmol) in CH2Cl2 (100 mL) was cooled to 0C. A catalytic amount of p-TsOH (0.05 g, 0.26 mmol) was added and the mixture was stirred for 30 min at 0C. The reaction was then quenched by adding sat. aqueous NaHCO3 (10 mL). The layers were separated and the aqueous phase was extracted with 2 X 25 mL of CH2Cl2. The combined organic layers were dried over 21~181 anhydrous K2CO3, filtered and concentrated to afford a colorless oil which was purified by passage through a short column of silica (Rf =0.46, 1:1 EtOAc/hexanes).
The bis-THP ether 8 (8.59 g, 89~ yield) was isolated as a colorless oil which solidified upon standing. IH NMR
(CDCl3) ~ (characteristic peaks only) 5.00 (m, lH), 4.75 - 4.45 (m, 2H), 3.85 (m, 2H), 3.60 - 3.30 (m, 4H).

F: (9S, llR, 15R)-11,15-Bis-(tetrahydropyran-2-yloxy)-15-cyclohexyl-2,3,4,5,6,16,17,18,19,20-decanor-9-(triethylsilyloxy)prostanol Triethylsilyl Ether (10):
A suspension of lithium aluminum hydride (1.43 g,38.0 mmol) in 50 mL of anhydrous THF was cooled to 0C
and a solution of the lactone 8 (8.59 g, 19.0 mmol) in THF (100 mL) was added dropwise. The resulting mixture was stirred at 0C for 3 h, after which 1.5 mL of H2O, 1.5 mL of 15~ NaOH and 4.5 mL of H2O were sequentially added. After warming to ambient temperature, 100 mL of EtOAc was added and the solids were filtered off. The filter cake was washed thoroughly with 3 X 50 mL of EtOAc and the filtrates were dried by passage through a short pad of anhydrous MgSO4. Evaporation afforded 9 (9.02 g) as a colorless oil which was used in the subsequent step without further purification (Rf =0.31, 80:20 EtOAc/hexanes).
A mixture of the crude diol 9 (9.02 g, 19.0 mmol), triethylsilyl chloride (9.65 mL, 57.0 mmol), dimethylaminopyridine (0.41 g, 3.42 mmol), triethylamine (16.0 mL, 114 mmol) and anhydrous N,N-dimethylformamide (50 mL) was stirred at ambient temperature for 14 h under N2. The reaction mixture was then diluted with 250 mL of CH2Cl2 and the solution was washed with 3 X 50 mL of H2O. The combined water washes were extracted with 2 X 50 mL of CH2Cl2. The organic layers were combined, dried (MgSO4), filtered and concentrated to afford a yellow oil which was chromatographed on silica (Rf =0.4, 1:9 EtOAc/hexanes).

Pure 10 (11.23 g, 86% yield from 8) was obtained as a slightly yellow oil. lH NMR (CDCl3) ~ (characteristic peaks only) 4.62 (m, 2H), 4.15 - 3.25 (broad m, 7H), 2.30 - 1.15 (broad m, 18H), 0.95 (broad t, 18H), 0.65 (broad q, 12H).

G: (9S, llR, 15R)-11,15-Bis-(tetrahYdropyran-2-yloxy)-15-cyclohexyl-2,3,4,5,6,16 17,18,19 20-decanor-9-(triethylsilyloxy)prostanal (11):
A solution of oxalyl chloride (0.51 mL, 0.57 mmol) in anhydrous CH2Cl2 (15 mL) was cooled to -78C under N2.
A solution of anhydrous DMSO (0.81 mL, 11.4 mmol) in CH2Cl2 (2.0 mL) was then added dropwise. After 2 min, a solution of 10 (2.6 g, 3.8 mmol) in 8 mL of dry CH2Cl2 was introduced dropwise via syringe over a period of 2 min. The resulting mixture was stirred at -78C for 2 h at which time triethylamine (2.7 mL, 19.0 mmol) was added. The reaction was stirred for 15 min and then allowed to warm to ambient temperature. The mixture was partitioned between 100 mL of EtOAc and 10 mL of H2O and the organic layer was washed with an additional 10 mL of H2O, 10 mL of brine and dried (MgSO4). Solvent removal gave a yellow oil which was subjected to chromatography on silica gel (Rf 0.2, 10%
EtOAc/hexanes) to afford 11 (1.4 g, 65% yield) and some starting material (0.83 g). IH NMR (CDCl3) ~ 9.80 (broad s, lH), 4.62 (m, 2H), 4.20 (m, lHj, 3.85 - 3.60 (m, 3H), 3.40 (m, 3H), 2.80 (m, lH), 2.45 - 2.05 (m, 4H), 1.95 - 1.10 (broad m, 27H), 0.95 (broad t, 9H), 0.55 (broad q, 6H).

H: (5Z)-(9S, llR, 15R~-11,15-Bis-(tetrahydropyran-2-yloxy)-15-cyclohexyl-2,3,4,16,17,18,19,20-octanor-9-(triethylsilyloxy)-5-prostenoic Acid Methyl Ester (12):
A solution of 18-crown-6 (8.50 g, 32.1 mmol) and bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (3.72 g, 11.7 mmol) 213~181 in 110 mL of THF was cooled to -78C. KHMDS (0.5 M in toluene, 23.4 mL, 11.7 mmol) was added to the above mixture and the solution was stirred for 15 min.
Aldehyde 11 (6.11 g, 10.7 mmol) in 5.0 mL of THF was added dropwise over a period of 15 min. The reaction was stirred at -78C for 2 h, then warmed up to 0C and stirred at that temperature for 2 more hours. The reaction was quenched by adding 50 mL of saturated aqueous NH4Cl and the mixture was allowed to warm to room temperature. The layers were separated and the aqueous layer was extracted with 2 X 50 mL of EtOAc.
The combined organic layers were washed with 2 X 50 mL
of brine and dried (K2CO3). Filtration and solvent removal gave a crude yellow oil which was purified by passage through a short plug of silica to afford a mixture of 12 and its E isomer (9:1 ratio, 6.28 g, 95%
yield). The isomers were separated by chromatography on silica gel (~ =0.56, and 0.47, for the major and minor isomers respectively, 40% Et2O/hexane); 4.57 g of pure 12 and 0.97 g of a 1:1 E/Z mixture were isolated.
IH NMR (CDCl3) ~ 6.35 (m, lH), 5.78 (broad d, J = 12.0 Hz, lH), 4.65 (m, 2H), 4.28 (m, lH), 3.90 (m, 2H), 3.70 (s, 3H), 3.55-3.30 (m, 3H), 2.80 (m, 2H), 2.35-2.05 (m, lH), 2.00-1.10 (broad m, 30H), 0.95 (broad t, 9H), 0.60 (broad q, 6H).

I: (5Z)-(9S, llR, 15R)-11,15-Bis-(tetrahydropyran-2-yloxy)-15-cyclohexyl-2,3 4,16,17 18,19 20-octanor-9-(triethylsilyloxy)-5-prosten-1-ol (13):
A solution of 12 (2.0 g, 3.22 mmol) in 20 mL of anhydrous THF was cooled to 0C under N2. A solution of diisobutylaluminum hydride (1.5 M in toluene, 6.5 mL, 9.66 mmol) was added dropwise and the resulting mixture was stirred at 0C for 2 h. The reaction was then quenched by careful addition of CH30H (5 mL), allowed to warm up to ambient temperature, and diluted with 50 mL of THF. The resulting cloudy solution was treated 21381~1 with 50 mL of a saturated aqueous solution of sodium potassium tartrate and the biphasic mixture was stirred for 1 h. The layers were then separated and the aqueous layer was extracted with 2 X 50 mL of THF. The organic extracts were combined, washed with brine (50 mL), and dried (MgSO4). Filtration and solvent removal gave a pale yellow oil which was purified by chromatography on silica gel (~ =0.26, 4:6 Et2O/hexane) to yield 13 (1.95 g, 95% yield) as a colorless oil.
This compound was used immediately in the subsequent reaction. IH NMR (CDCl3) ~ 5.65 (m, 2H), 4.65 (m, 2H), 4.30-3.25 (broad m, 5H), 2.40-2.05 (broad m, 4H), 2.00-1.10 (broad m, 32H), 1.00 (broad t, 9H), 0.60 (broad q, 6H).

J: (5Z)-(9S, llR, 15R)-11,15-Bis-(tetrahydropyran-2-yloxy)-15-cYclohexyl-9-hYdroxy-3-oxa-16,17 18,19,20-pentanor-5-prostenoic Acid t-Butyl Ester (15):
A mixture of 13 (1.95 g, 3.28 mmol), t-butyl bromoacetate (5.11 g, 26.24 mmol), tetrabutylammonium hydrogen sulfate (0.8 g, 2.35 mmol), toluene (45 mL) and 25% (w/w) aqueous NaOH (30 mL) was stirred vigorously at room temperature for 18 h. The layers were separated and the aqueous layer was extracted with 2 X 25 mL of EtOAc. The combined organic extracts were washed with brine (15 mL), dried (MgSO4), and concentrated. The crude product was purified by chromatography on silica gel (~F0.56, 20%
EtOAc/hexane) to yield 2.19 g of 14 (contaminated with some t-butyl bromoacetate) and 0.48 g of the starting allyl alcohol 13. The allyl ether 14 thus obtained was used in the desilylation reaction without further purification.
The silyl ether 14 (0.5 g) obtained above was dissolved in 3.0 mL of DMSO and to it was added 2.2 mL
of tetrabutylammonium fluoride (1.0 M in THF, 2.2 mmol). The mixture was stirred at ambient temperature 213~
for 30 min and then partitioned between 50 mL EtOAc and 10 mL of brine. The aqueous layer was extracted with 2 X 10 mL of EtOAc and the combined organic extracts were dried over MgSO4. Evaporation and chromatography on silica gel (Rf =0.44, 50% EtOAc/hexane) afforded 0.28 g of 15 as a colorless oil. IH NMR (CDCl3) ~ 5.65 (m, 2H), 4.62 (m, 2H), 4.16 (m,. lH), 4.10-3.75 (m, 3H), 3.95 (s, 2H), 3.45 (m, 2H), 2.50-0.90 (broad m, 35H), 1.46 (s, 9H); High Resolution CI MS m/z (CI) calcd.
for C34H59O8 (MH+) 595.4209, found 595.4208.

K: (5Z)-(9R, llR 15R)-9-Chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16 17 18,19,20-pentanor-5-prostenoic Acid t-Butyl Ester (V):
The hydroxyester 15 (0.28 g, 0.47 mmol) was dissolved in 4.0 mL of a stock solution containing 48.0 mL of CH3CN, 0.79 mL of pyridine, and 0.97 mL of CCl4.
Triphenylphosphine (0.18 g, 0.70 mmol) was added and the resulting mixture was stirred at ambient temperature for 17 h. The reaction mixture was treated with 10 mL of a 1:1 solution of Et2O/hexanes and the precipitate formed was filtered off. The filtrate was concentrated and purified by chromatography (silica gel, Rf =0.47, 40:60 Et2O/hexanes) to yield pure 16 (90 mg, 34%) as a colorless oil.
A solution of 16 (80 mg, 0.13 mmol) in 7.0 mL of 65% (v/v) aqueous acetic acid was heated to 65-70~C for 45 min. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was redissolved in anhydrous EtOH and the solvent was again evaporated. The residue thus obtained was purified by chromatography on silica gel (~ =0.4, 60:40 EtOAc/hexanes) to yield 60 mg (100%) of V as a colorless, viscous oil. lH NMR (CDCl3) ~ 5.69 (m, 2H), 4.32 - 3.85 (m, 5H), 3.38 (m, lH), 2.50 - 1.95 (m, 5H), 1.95 - 0.80 (broad m, 29H) 1.43 (s, 9H); l3C NMR (CDCl3) ~ 169.9, 131.7, 126.8, 82.0, 75.6, 75.1, 67.9, 66.6, 54.2, 51.0, 44.3, 43.7, 31.4, 30.3, 30.1, 29.3, 28.1, 28.0, 26.5, 26.3, 26.1; High Resolution Cl MS m/z calcd. for C24H42OsCl (MH+) 445.2720, found 445.2716.

E~CAMPLE 2: 8Y~n~:sI8 OF CONPOIJND VI

~O~CO~u~ S,~ o~COz~ O~CO~
~0 ~0 ~0 "
THP~ Tl IPO T~P~ THI~ Pd t7 a .~=~OAco~ cl ~=~o~
T~ ~0 A: (5Z)-(9S, llR 15~)-11,15-Bis-(tetrahydropyran-2-yloxy)-15-cyclohexyl-9-hydroxY-3-oxa-16 17 18,19.20-pentanor-5-prostenoic Acid (17):
Hydroxyester 15 (0.454 g; 0.76 mmol; see Example 1) was dissolved in 10 mL of methanol and 2 mL of water. Lithium hydroxide monohydrate (0.16 g; 500 mol%) was added and the mixture was stirred at room temperature. After 18 h, 20 mL of saturated, aqueous KH2PO4 and 20 mL CH2Cl2 were added, the layers were separated, and the aqueous phase was washed with additional CH2Cl2 (3 X 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated, affording 0.47 g of a colorless oil which was used directly in the next reaction.

B: (5Z)-(9S l}R 15R)-11 15-Bis-ttetrahydropYran-2-yloxy3-15-cyclohexyl-9-hydroxy-3-oxa-16.17 18.19.20-pentanor-5-prostenoic Acid Isopropyl Ester (18):
Crude acid 17 from above (0.23 g; 0.43 mmol) was dissolved in 10 mL of acetone. DBU (0.25 mL; 400 mol%) and isopropyl iodide (0.21 g; 300 mol%) were added and the mixture was stirred for 12 h at room temperature.
After evaporation, the residue was applied to a silica gel column and eluted with hexane/EtOAc, 1/1, to afford 0.157 g (63%) of isopropyl ester 18 as a colorless oil 2I3Sl~l (Rf -0.49). lH NMR (CDCl3) ~ (characteristic peaks only) 5.80-5.52 (m, 2H), 5.15 (sep, lH, J=6.2 Hz), 4.03 (broad s, 2H), 1.27 (d, 6H, J=6.2 Hz).

C: (5Z)-(9R llR 15R)-9-Chloro-15-cyclohexY~ l5 dihYdroxY-3-oxa-16.17 18 19 20-pentanor-5-~rostenoic Acid IsopropYl Ester (VI):
The hydroxyester 18 (0.146 g; 0.25 mmol) was dissolved in 3.0 mL of a stock solution containing 48 mL of CH3CN, 0.79 mL of pyridine, and 0.97 mL of CC14.
Triphenylphosphine (0.10 g; 150 mol%) was added and the resulting mixture was stirred at room temperature for 17 h. The reaction mixture was treated with 10 mL of a 1:1 solution of Et2O/hexanes and the precipitate was filtered off. The filtrate was concentrated and chromatographed on silica gel (hexane/EtOAc, 4/1), affording 0.108 g of a colorless oil which consisted of a nearly equimolar mixture of desired chlorinated material 19 with its undesired 5,8-diene elimination product.
A solution of crude l9 from above in 10 mL of 65%
(v/v) aqueous acetic acid was warmed to 65C for 45 min. The mixture was then cooled to room temperature and concentrated. The resulting residue was then purified by silica gel chromatography (hexane/EtOAc, 2/3), affording 27 mg (25% based on 18) of pure VI (~
=0.56) as a colorless oil, and 69 mg of a mixture of VI
and its 5,8-diene elimination product (~ =0.45). IH
NMR (CDCl3) ~ 5.67 (m, 2H), 5.08 (sep, lH, J=6.1), 4.30-3.95 (m, 6H), 3.40 (m, lH), 2.35 (m, 2H), 2.30-2.00 (m, 3H), 1.93-1.35 (m, 12H), 1.25 (d, 6H, J=6.2 Hz), 1.22-0.90 (m, 6H); l3C NMR (CDCl3) ~ 170.2, 131.8, 126.7, 75.7, 75.2, 68.8, 67.6, 66.7, 61.2, 54.2, 51.1, 44.4, 43.6, 31.4, 30.2, 30.1, 29.3, 28.0, 26.5, 26.3, 26.1, 21.8; High Resolution CI MS m/z calcd. for C23 H40OsCl (MH+) 431.2564, found 431.2569.

21381~1 E~P~B 3: 8YNTHB~I8 OF COMPOIJND VII

o a~

~ ~ V~
A: (5Z)-(9S llR, lSR)-11 15-Bis-(tetrahYdropYran-2-ylox~)-15-cyclohexyl-9-hydroxy-16 17,18,19 20-pentanor-5-prostenoic Acid Isopropyl Ester (22):
To a solution of 5.0 g (11 mmol) of lactone 8 (see Example 1) in 40 mL of THF at -78C was added dropwise 9.6 mL (14.4 mmol) of a 1.5 M solution of diisobutylaluminum hydride in toluene. After 1.5 h, 5 mL of MeOH was added, the mixture was stirred for 10 min at -78C and then warmed to room temperature. This solution was then added to a mixture of 20 mL of saturated, aqueous NH4Cl, 35 mL of EtOAc, and 35 mL of saturated, aqueous sodium potassium tartrate. The mixture was stirred for 20 min, layers were separated, and the agueous layer was washed with EtOAc (3 X 40 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated. The resulting residue was purified by silica gel chromatography (EtOAc/hexane, 1/1), affording 4.5 g (90%) of lactol 20 which was used directly in the next reaction.
To a solution of 14.1 g (31.8 mmol) of (1-carboxypent-5-yl)triphenyl-phosphonium bromide in 100 mL of THF at 0C was added dropwise 59 mL (59 mmol) of a 1 M solution of potassium t-butoxide in THF. After 20 min, 4.5 g (9.9 mmol) of lactol 20 in 20 mL of THF
was added dropwise. The reaction was quenched after 2 h by pouring into 150 mL of a 1/1 (v/v) mixture of EtOAc/saturated, aqueous NH4Cl . The layers were 213~181 separated and the aqueous layer was extracted with EtOAc (3 X 70 mL). The combined organic layers were dried over MgSO4, filtered and evaporated, leaving 7.6 g of crude acid 21 as an oil.
Crude acid 21 (7.6 g) was dissolved in 55 mL of acetone, cooled to 0C, and 8.6 g (56 mmol) of DBU was added dropwise. The reaction was warmed to room temperature and 8.5 g (50 mmol) of isopropyl iodide was added dropwise. After stirring for 14 h, the mixture was poured into 100 mL of a 1/1 (v/v) mixture of EtOAc/saturated, aqueous NH4Cl. The layers were separated and the aqueous phase was extracted with additional EtOAc (2 X 100 mL). The combined organic layers were dried over MgSO4, filtered, evaporated, and chromatographed on silica gel (EtOAc/hexane, 2/3) affording 1.98 g (35% from lactol 20) of 22. IH NMR
(CDCl3) ~ (characteristic peaks only) 5.58-5.28 (m, 2H), 4.97 (sep, J=6.2 Hz, lH), 1.1 (d, J=6.2 Hz, 6 H).

B: (5Z)-(9R llR 15R)-9-Chloro-15-cyclohexyl-11,15-dihydroxy-16,17 18,19,20-pentanor-5-prostenoic Acid Isopropyl Ester (VII):
Hydroxyester 22 (513.1 mg; 0.8864 mmol) was dissolved in 6.6 mL of a stock solution containing 48.0 mL of CH3CN, 0.79 mL of pyridine, and 0.97 mL of CCl4.
Triphenylphosphine (348.8 mg; 150 mol%) was added and the mixture was stirred for 45 h at room temperature.
The reaction was then diluted with 7 mL of Et2O and 14 mL of hexane. After stirring for 10 min, solids were filtered off and the filtrate was evaporated. The resulting solids were triturated three times with 15 mL
of hexane/Et2O (1/2). Combined hexane/Et2O washes were concentrated down to 0.75 g of a white solid which was then redissolved in hexane/Et2O and chromatographed on silica gel. Elution with hexane/Et2O, 5/1, afforded 21381~1 372.8 mg of semipure 23 which was used directly in the next reaction.
Crude 23 from above was dissolved in 20 mL of 65 (v/v) aqueous HOAc and warmed to room temperature.
After 1.5 h, the reaction was concentrated, 15 mL of H2O was added, and the solution was reconcentrated.
Absolute EtOH (15 mL) was added followed, again, by reconcentration. The resulting oil was purified by silica gel chromatography (hexane/EtOAc, 2/1), affording 244.1 mg of a mixture of VII contaminated with an approximately equal quantity of the 5,8-diene side product. An 8.2 mg sample was then further purified by reverse phase HPLC, giving 4.4 mg of pure VII as a clear, viscous oil. IH NMR (CDCl3) ~ 5.47 (m, J=8.5 Hz, 2H),-5.01 (sep, J=6.3Hz, lH), 4.10 (dt, J=4.0, 6.2 Hz, lH), 4.04 (q, J=7.6 Hz, lH), 3.37 (m, lH), 2.35-2.24 (m, 4H), 2.20-2.07 (m, 4 H), 1.82 (br s, 2H), 1.80-1.50 (m, 13H), 1.36-0.96 (m, 12H). ~3C NNR
(CDCl3) ~ 173.2, 131.0, 126.8, 76.2, 76.0, 67.5, 60.8, 54.3, 51.7, 44.5, 43.5, 34.0, 31.7, 30.0, 29.2 (two overlapping resonances), 27.9, 26.6, 26.4, 26.2, 26.1, 24.9, 21.8. High Resolution CI MS m/z calcd. for C24H42O4Cl (MH+) 429.2772, found 429.2763.

EXANPLE 4: 8YNTHE8I8 OF CONPOUND VIII

v~

A: (5Z)-(9R, llR, 15R)-11-(t-ButyldimethYlsiloxy)-9-chloro-15-cyclohexyl-15-hydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester (24):
To a mixture of 127 mg (0.285 mmol) of Compound V
(Example 1), 49 mg (0.72 mmol) of imidazole, 10 mg (0.082 mmol) of 4-(dimethylamino)pyridine (DMAP), and 5 mL of CH2Cl2 was added 90 mg (0.59 mmol) of tert-butyldimethylsilyl chloride. After stirring overnight, 10 mL of saturated NH4Cl was added, the mixture was extracted with CH2Cl2 (3 X 10 mL), the combined organic layers were dried over MgSO4, filtered and concentrated, and the residue was chromatographed on silica gel (20% ethyl acetate in hexane) to afford 87 mg (55%) of 24.

B: (5Z)-(9R, llR, 15R)-11-(t-Butyldimethylsiloxy)-9-chloro-15-cyclohexyl-15-methoxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester (25):
A mixture of 80 mg (0.14 mmol) of 24, 100 mg (0.52 mmol) of 2,6-di-t-butylpyridine, 80 mg (0.51 mmol) of methyl trifluoromethanesulfonate, and 2 mL of CH2Cl2 was refluxed overnight. The reaction was cooled to room temperature, poured into 10 mL of saturated NaHC03, extracted with CH2Cl2 (3 X 10 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel (10% ethyl acetate in hexane) to afford 35 mg (44%) of 25.

C: (5Z)-(9R, llR, 15R)-9-Chloro-15-cyclohexYl-ll-hydroxy-15-methoxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester (VIII):
To a mixture of 32 mg (0.056 mmol) of 25 and 1.5 mL of THF was added 0.12 mL (0.12 mmol) of 1 M
tetrabutylammonium fluoride (TBAF) in THF. After 30 min, 4 mL of saturated NH4Cl was added, the mixture was extracted with ethyl acetate (3 X 5 mL), the combined 21~81~1 organic layers were dried over MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel (40% ethyl acetate in hexane) to afford 24 mg (93%) of VIII. 13C NMR (CDCl3) ~ 169.77 (C), 130.90 (CH), 127.43 (CH), 85.89 (CH), 81.69 (C), 76.05 (CH), 67.83 (CH2), 66.56 (CH2), 61.00 (CH), 57.83 (CH3), 54.06 (CH), 51.92 (CH), 44.45 (CH2), 40.65 (CH), 29.92 (CH2), 29.83 (CH2), 29.02 (CH2), 28.42 (CH3), 28.10 (CH2), 26.64 (CH2), 26.37 (CH2). CI MS, m/z calcd. for C25H~O5Cl (MH+) 459.2877, found 459.2877.

EXAMPLB 5: 8YNTHE8I8 OF CONPOUND IX

~ ~

A: (5E)-(llR 15R~-15-CyclohexYl-11.15-dihYdroxY-3-oxa-16 17 18 19 20-pentanor-5-prostenoic acid isopropyl ester (IX):
To a solution of the ester VI (390 mg, 0.90 mmol) (see example 2) and AIBN (10 mg) in anhydrous toluene (9.0 mL) was added n-Bu3SnH (0.47 mL, 1.80 mmol). The resulting mixture was heated at reflux for 4 h. The solvent was evaporated and the residue was applied to a silica gel column for purification. The product IX
( ~ 0.4, 60% EtOAc/hexane) was isolated as a colorless oil (340 mg isolated, 95% yield). IH NMR (CDCl3) ~
5.60 (m, 2H), 5.05 (septet, J = 6.5 Hz, lH), 3.98 (m, 4H), 3.85 (m, lH), 3.30 (m, lH), 2.22 (m, lH), 2.00 (m, lH), 1.80 - 0.85 (broad m, 23H), 1.21 (d, J = 6.4 Hz, 6H); C NMR (CDCl3) ~ 170.11, 134.59, 126.54, 79.15, 76.35, 72.07, 68.50, 67.18, 53.57, 44.21, 43.62, 38.21, 34.19, 32.05, 29.47, 29.32, 28.94, 27.98, 26.56, 26.36, 26.21, 21.84.

213~181 EXAMPLE 6: SY~.-n~;8IS OF COMPOIJND X

HO dH l~d ~ ~ ~T~

~

A: (3aR, 4R 5R, 6aS)-4-[(E)-(3S)-3-Cyclohexyl-3-(tetrahydropyran-2-yloxy)Propenyll-hexahydro-5-(tetrahydropyran-2-yloxy)-2H-cyclopenta[b~furan-2-one (26):
To 15.7 g (55.9 mmol) of diol 6 (Example 1) in 120 mL of CH2Cl2 at 0C was added 12.0 g (142 mmol) of 3,4-dihydro-2H-pyran (DHP) and 520 mg (2.7 mmol) of p-toluenesulfonic acid monohydrate (pTSA). After 1 h at 0C, 100 mL of saturated NaHCO3 was added, the mixture was extracted with CH2C12 (3 X 100 mL), the combined organic layers were dried over MgSO4, filtered and concentrated and the residue was chromatographed on silica gel (40% ethyl acetate in hexane) to afford 13.3 g (53%) of bis-THP ether 26.

B: (13E)-(9S~llR~155)-11~15-Bis(tetrahydropYran-2 yloxy)-15-cYclohexyl-2~3~4~5~6~l6~l7~l8~l9~2o-decanor 9-hydroxy-13-prostenol (27):
To a solution of 15.0 g (33.4 mmol) of 26 in 150 mL of THF at 0C was added 53 mL (80 mmol) of 1.5 N
solution of diisobutylaluminum hydride (DIBAL-H) in toluene. After 3 h the reaction was poured into 300 mL
of 1:1 ethyl acetate:saturated sodium potassium tartrate and stirred for 1 h. The layers were separated, the aqueous layer was extracted with ethyl acetate (3 X 100 mL), the combined organic layers were dried over MgSO4, filtered and concentrated to afford 14.89 g (98%) of crude diol 27.

C: (13E)-(9S llR 15S)-11 15-Bis(tetrahydropyran-2-yloxy)-15-cYclohexyl-2~3~4~5~6~l6~l7~l8~l9~2o-decanor 9-(triethylsiloxy)-13-prostenol triethylsilyl ether (28):
To a mixture of 14.8 g (32.7 mmol) of 27, 5.94 g (87.4 mmol) of imidazole, 0.44 g (3.6 mmol) of DMAP, and 150 mL of CH2Cl2 was added 11.5 g (76.3 mmol) of triethylsilyl chloride. After 5 h, 150 mL of saturated NH4Cl was added, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 X 100 mL).
The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel (10% ethyl acetate in hexane) to afford 21.9 g (100%) of bis-silyl ether 28.

D: (13E)-(9S,llR,155)-11,15-Bis(tetrahydropyran-2-yloxy)-15-cyclohexyl-2,3,4,5,6,16,17,18,19,20-decanor-9-(triethylsiloxy)-13-prostenal (29):
To 12.5 g (98.6 mmol) of oxalyl chloride in 150 mL
of CH2Cl2 at -78C was added dropwise a solution of DMSO
(13.0 g, 166 mmol) in 15 mL of CH2Cl2. After 30 min, a solution of 28 (22.4 g, 32.9 mmol) in 60 mL of CH2Cl2.
After 5 h, 36 g (360 mmol) of NEt3 was added, and the reaction was stirred for 30 min at -78C and then at room temperature for 30 min. The mixture was poured into 200 mL of saturated NH4Cl and extracted with CH2Cl2 (3 X 150 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel (20% ethyl acetate in hexane) to afford 18.3 g (99%) of aldehyde 29.

E: (5Z, 13E)-(9S,llR, 155)-11,15-Bisftetrahydropyran-2-yloxy)-15-cyclohexyl-2,3,4,16,17,18,19,20-octanor-9-(triethylsiloxy)-5,13-prostadienoic acid methyl ester (30):
To a mixture of 16.5 g (51.9 mmol) of bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate, 28.2 g (107 mmol) of 18-crown-6, and 200 mL of THF at -78C was added dropwise 85 mL (42.5 mmol) of 0.5 N
KHMDS in toluene. After 30 min, a solution of 18.3 g (32.4 mmol) of 29 in 50 mL of THF was added dropwise and the reaction stirred for 2 h. The mixture was poured into 150 mL of saturated NH4Cl, extracted with ethyl acetate (3 X 100 mL), the combined organic layers were dried over MgSO4, filtered and concentrated, and 213~

the residue was chromatographed on silica gel (15%
ethyl acetate in hexane) to afford 9.78 g (49%) of crotonate 30, as well as 3.58 g (18%) of a mixture of olefin cis: trans isomers.

F: (5Z, 13E)-(9S,llR, 15S)-11,15-Bis(tetrahydropyran-2-Yloxy)-15-cyclohexyl-2,3,4,16,17,18,19,20-octanor-9-(triethylsiloxy)-5,13-prostadienol (31):
To a solution of 9.11 g (14.7 mmol) of 30 in 40 mL
of THF at 0C was added dropwise 24 mL (36 mmol) of a 1.5 M solution of DIBAL-H in toluene. After 1 h, the reaction was added to 100 mL of saturated NH4Cl, extracted with ethyl acetate (3 X 75 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated to afford 8.7 g (100%) of crude allyl alcohol 31.

G: (5Z, 13E)-(9S,llR, 15S)-11,15-Bis(tetrahYdropyran-2-yloxY)-l5-cyclohexyl-9-hydroxy-2~3~4~l6~l7~l8~l9~2 octanor-5,13-prostadienol (32):
To a solution of 8.7 g (14.7 mmol) of 31 in 60 mL
of THF at 0C was added 20 mL (20 mmol) of a 1 M
solution of TBAF in THF. After lh, 75 mL of saturated NH4Cl was added, the mixture was extracted with ethyl acetate (3 X 75 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel (3/2 ethyl acetate/hexane) to afford 3.79 g (54%) of diol 32.

H: (5Z, 13E)-(9S,llR, 15S)-11,15-Bis(tetrahydropyran-2-yloxy)-15-cyclohexyl-9-hYdroxy-3-oxa-16,17,18,19,20-pentanor-5,13-prostadienoic acid isopropyl ester (33):
A mixture of 32 (3.76 g, 7.7 mmol), NaOH (6.1 g, 150 mmol), water (30 mL), toluene (30 mL), tetrabutylammonium hydrogen sulfate (1.05 g, 3.1 mmol), and isopropyl bromoacetate (3.63 g, 20.1 mmol) at room temperature was vigorously stirred for 30 min. The 2~3~181 layers were separated, the aqueous layer was extracted with ethyl acetate (2 X 30 mL), the combined organic layers were dried over MgSO4, filtered and concentrated, and the residue was chromatographed on silica gel (40% ethyl acetate in hexane) to afford ester 33 (3.06 g, 69%).

I: (5Z 13E)-(9R llR 15S)-11 15-Bis(tetrahydropyran-2-yloxY)-9-chloro-15-cyclohexyl-3-oxa-16 17 18 19 20-pentanor-5 13-prostadienoic acid isopropyl ester (34):
To a mixture of 33 (3.0 g, 5.2 mmol) and 30 mL of pyridine at 0C was added methanesulfonyl chloride (1.48 g, 12.9 mmol). The reaction was brought to room temperature after 15 min, stirred for an additional 1.5 h, and poured into a suspension of Bu4NCl (14.5 g, 52.2 mmol) in 45 mL of toluene. The mixture was stirred at room temperature overnight, at 55-60C for 2 h, poured into 100 mL of saturated NH4Cl, extracted with ethyl acetate (3 X 75 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel (30% ethyl acetate in hexane) to afford 3.0 g of an oil which consisted of a mixture of chlorinated compound 34 and the 8,9-olefin elimination by-product. This mixture was used in the next step without further purification.

J: (5Z 13E)-(9R llR 15S)-9-Chloro-15-cyclohexyl-11 15-dihydroxy-3-oxa-16 17 18 19 20-pentanor-5 13-prostadienoic acid isopropyl ester (35):
The sample from above (3.0 g) was dissolved in 40 mL of isopropyl alcohol and 5 mL of water was added, followed by 2.3 mL of 12 M HCl. After 3 h, saturated NaHC03 was added (50 mL), the mixture was extracted with ethyl acetate (3 X 50 mL), the combined organic layers were dried over MgS04, filtered, and concentrated, and the residue was purified by radial chromatography (20/1 toluene/isopropanol) to afford 324 21381~1 mg of pure chloride 35 (32%), as well as 278 mg (28~, calculated as the chloride) of a mixture of 35 with the 8,9-olefin. ~3C NMR (CDCl3) ~ 170.04 (C), 134.51 (CH), 132.64 (CH), 130.43 (CH), 127.58 (CH), 77.34 (CH), 75.40 (CH), 68.60 (CH), 67.60 (CH2), 66.64 (CH2), 59.64 (CH), 55.95 (CH), 53.36 (CH), 43.61 (CH), 43.57 (CH2), 28.83 (CH2), 28.70 (CH2), 26.49 (CH2), 26.06 (CH2), 25.99 (CH2), 21.82 (CH3). CI MS, m/z calcd. for C23H38O5Cl (MH+) 429.2408, found 429.2408.

K: (5E, 13E)-(llR, 15S)-15-CyclohexYl-11 15-dihydroxy-3-oxa-16 17,18 19 20-pentanor-5,13-prostadienoic acid isopropYl ester (X):
A mixture of 35 (60 mg, 0.14 mmol), benzene (3 mL), AIBN (10 mg), and Bu3SnH (90 mg, 0.31 mmol) was deoxygenated by purging with N2 for 15 min, and heated at reflux for 1 h. The reaction was concentrated and chromatographed on silica gel (3:2 ethyl acetate:hexane) to afford 43 mg (78~) of dechlorinated product X 13C NMR (CDCl3) ~ 169.98 (C), 134.27 (CH), 134.22 (CH), 133.94 (CH), 126.62 (CH), 77.76 (CH), 77.72 (CH), 71.92 (CH2), 68.41 (CH), 67.06 (CH2), 58.01 (CH), 43.33 (CH), 42.18 (CH), 36.99 (CH2), 32.02 (CH2), 28.94 (CH2), 28.72 (CH2), 27.38 (CH2), 26.48 (CH2), 26.03 (CH2), 25.96 (CH2), 21.74 (CH3). CI MS, m/z calcd. for C23H39O5 (MH+) 395.2798, found 395.2798.

B2CAMPLE: 7: 8YIITHE:8I~ OF COMPOlrND XI

cl~ c~ 20H

11~ ~

(5Z)-(9R llR. 15R)-9-Chloro-15-cYclohexyl-11.15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenol (XI):
A solution of the ester 16 (150 mg, 0.24 mmol;
Example 1) in THF (5.0 mL) was cooled to 0C and to it DIBAL-H (1.5 M in toluene, 0.5 mL, 0.72 mmol) was added and the resulting mixture was stirred at 0C for 2.5 h.
The reaction was carefully quenched with a saturated solution of potassium sodium tartrate (10 mL) and the biphasic mixture was stirred at ambient temperature for lh. The organic layer was then separated and the aqueous layer was extracted with EtOAc (5 X 10 mL).
The combined organic layers were dried (Na2SO4), filtered, and concentrated to afford a pale yellow liquid which was purified by chromatography on silica gel. The intermediate alcohol (RfO.15, 30%
EtOAc/hexanes) was isolated (114 mg, 87% yield) as a colorless oil and was used in the subsequent reaction.
The above alcohol (54 mg, 0.09 mmol) was mixed with 65% acetic acid/water (15 mL) and then heated at 70C for 1 h. The solvent was evaporated and the crude was applied to a column of silica gel for purification.
The triol XI (RfO.15 EtOAc) was isolated as a colorless oil (33 mg, 88% yield). 1H NMR (CDC13) ~ 5.68 (m, 2H), 4.08 (m, 4H), 3.74 (m, 2H), 3.57 (m, 2H), 3.42 (m, lH), 2.37 (m, 2H), 2.35-1.90 (m, 4H), 1.85-0.90 (broad m, 18H); l3C NMR (CDCl3) ~ 131.06, 127.52, 75.80, 75.54, 71.94, 66.38, 61.82, 60.82, 54.05, 50.87, 44.69, 43.60, 31.29, 29.71, 29.46, 29.22, 28.08, 26.48, 26.28, 26.14; CI MS calcd. for C20H36O4Cl (MH+) 375.2302, found 375.2299.

EXAMPLE 8: S~..n~8I8 OF COMPOUND XII

c~ ~o~co~l cl~ O~c~
~0 ~0 3~ XJI

(5Z, 13E) - (9R.llR. 155)-9-Chloro-15-cvclohexlYl-11.15-dihydroxy-3-oxa-16.17.18.19.20-pentanor-5,13-prostadienol (XII):
S To a solution of ester 36 (41 mg, 0.093 mmol) (German patent DE 3724189) in 5 mL of THF at 0C was added a 1.5 M solution of DIBAL-H (0.7 mL, 1.05 mmol).
After warming to room temperature and stirring for 1.5 h, 15 mL of saturated NH4Cl was added, the mixture was extracted with ethyl acetate (3 X 15 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel (ethyl acetate) to afford triol XII (21 mg, 68%). IC NMR ~CDCl3) ~ 134.59 (CH), 133.00 (CH), 129.61 (CH), 128.21 (CH), 77.56 (CH), 75.16 (CH), 71.54 (CH2), 67.93 (CH2), 66.46 (CH2), 61.76 (CH2), 59.49 (CH), 55.85 (CH), 53.23 (CH), 43.43 (CH), 28.81 (CH2), 28.56 (CH2), 26.46 (CH2), 26.02 (CH2), 26.94 (CH2), 25.57 (CH2). CI MS, m/z calcd. for C20H34O4Cl (MH+) 373.2146, found 373.2101.

E~ANP~E 9: 8YNTHE8I8 OF CONPO~ND XIII
O OH

2~

~CO-M _ a d~
~ 4.

A: (3aR. 4R, 5R. 6aS)-4-~(E)-(35)-3-CYclohexyl-3-(tetrahydropyran-2-yloxv)~ropenvl]-hexahydro-5-(tetrahydropyran-Z-yloxy)-2H-cYclopentarb~furan-2-ol (37~:
To a solution of lactone 26 (5.7 g, 12.7 mmol;
Example 6) in 40 mL of THF at -78C was added dropwise a 1.5 M solution of DIBAL-H in toluene (11.5 mL, 17.2 mmol). After 2 h, the reaction was poured into 70 mL
of a saturated solution of sodium potassium tartrate and was stirred for 30 min. The mixture was extracted with ethyl acetate (3 X 50 mL), the combined organic layers were dried over MgSO4, filtered and concentrated, and the residue was chromatographed on silica gel (1/1 hexane/ethyl acetate) to afford 4.7 g (82%) of lactol 37.

B: (5E. 13E)-(9S. llR. 155)-11.15-Bis(tetrahydro~Yran-2-YloxY)-15-cyclohexyl-9-hydroxy-2,3,4,16,17,18,19,20-octanor-5.13-prostadienoic acid methyl ester (38):
A mixture of 37 (5.1 g, 11.3 mmol), Ph3PCH=CO2Me 213~181 (6.6 g, 19.7 mmol), CH2Cl2 (50 mL), and acetic acid (8 drops) was stirred overnight at room temperature. The mixture was concentrated and chromatographed on silica gel (1/1 hexane/ethyl acetate) to afford 5.7 g (99%) of trans-crotonate 38.

C: (5E 13E)-(9S llR, 15S)-11 15-Bis(tetrahYdropyran-2-yloxY)-9-(t-butYldimethylsiloxY)-15-cyclohexyl-2 3 4 16,17 18 19 20-octanor-5 13-prostadienoic acid methYl ester (39):
A mixture of 38 (5.7 g, 11.6 mmol), CH2Cl2 (150 mL), imidazole (1.46 g, 21.5 mmol), DMAP (500 mg, 4.1 mmol), and t-butyldimethylsilyl chloride (2.54 g, 16.9 mmol) was stirred for 1 h, 50 mL of saturated NH4Cl was added, the layers were separated, the aqueous layer was extracted with CH2Cl2 (2 X 50 mL), the combined organic layers were dried over MgSO4, filtered and concentrated, and the residue was chromatographed on silica gel (20% ethyl acetate in hexane) to afford 39 (6.05 g, 84%).

D: (5E 13E)-(9S, 11~ 155)-11 15-Bis(tetrahydropyran-2-yloxy)-9-(t-butyldimethylsiloxy)-15-cyclohexyl-2 3 4 16 17 18 19 20-octanor-5 13-prostadienol (40):
To a solution of 39 (6.0 g, 9.8 mmol) in THF (50 mL) at 0C was added dropwise a 1.5 M solution of DIBAL-H in toluene (16 mL, 24 mmol). The reaction was brought to room temperature and was stirred for 2 h, 75 mL of a saturated solution of sodium potassium tartrate was added, and the mixture was stirred for 35 min. The layers were separated, the aqueous layer was extracted with ethyl acetate (2 X 50 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel (25% ethyl acetate in hexane) to afford 40 (4.28 g, 74%).

213~181 E: (5E. 13E)-(9S, llR. 155)-11.15-Bis(tetrahydropyran-2-yloxy)-9-(t-butyldimethylsiloxy)-15-cyclohexyl-3-oxa-16.17.18,19,20-pentanor-5,13-prostadienoic acid t-butyl ester (41):
A mixture of 40 (2.4 g, 4.1 mmol), water (25 mL), toluene (30 mL), NaOH (3.8 g, 95 mmol), Bu4NHSO4 (300 mg, 0.88 mmol), and t-butyl bromoacetate (5.0 g, 25.6 mmol) was stirred vigorously overnight. The layers were separated, the aqueous layer was extracted with ethyl acetate (2 X 50 mL), the combined organic layers were dried over MgSO4, filtered and concentrated, and the residue was chromatographed on silica gel (20%
ethyl acetate in hexane) to afford 41 (1.48 g, 48%).

F: (5E 13E)-(9S llR 15S)-11.15-Bis(tetrahydropyran-2-Yloxy)-15-cyclohexYl-9-hydroxy-3-oxa-16 17 18 19 20-pentanor-5,13-prostadienoic acid t-butyl ester (42):
A mixture of 41 (1.4 g, 2.0 mmol), THF (20 mL), and a 1 M solution of TBAF in THF (6 mL, 6 mmol) was stirred for 2 h, saturated NH4Cl was added (30 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (2 X 40 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel (1/1 hexane/ethyl acetate) to afford 42 (0.45 g, 38%).

G: (5E 13E)-(9R llR. 15S)-11 15-Bis(tetrahydropyran-2-yloxy)-9-chloro-15-cyclohexyl-3-oxa-16 17 18 19 20-pentanor-5 13-prostadienoic acid t-butyl ester (43):
A mixture of 42 (430 mg, 0.72 mmol), PPh3 (350 mg, 1.34 mmol), CH3CN (6 mL), pyridine (112 mg, 1.42 mmol), and CCl4 (240 mg, 1.55 mmol) was stirred overnight.
The reaction was concentrated and the residue was chromatographed on silica gel (20% ethyl acetate in hexane) to afford 43 as a mixture with the corresponding 8,9-olefin (362 mg, 82% calculated as the 21381~1 chloride). This mixture was separated in the next step.

H: (5E, 13E)-(9R, llR, 15S)-9-Chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5,13-prostadienoic acid t-butyl ester (XIII):
A mixture of 43 (310 mg, 0.51 mmol calculated as the chloride), THF (5 mL), water (1 mL), and acetic acid (9 mL) was heated at 65C for 1 h. The reaction was concentrated and the residue was chromatographed on silica gel (4/1 ethyl acetate/hexane) to afford XIII as a mixture with the corresponding 8,9-olefin (188 mg, 83% calculated as the chloride). The mixture was separated by reverse-phase HPLC to afford pure XIII (58 mg, 26% from alcohol 46). 13C NMR (CDCl3) ~ 169.67 (C), 134.67 (CH), 133.09 (CH), 131.18 (CH), 128.56 (CH), 81.62 (C), 77.31 (CH), 75.04 (CH), 71.63 (CH2), 67.59 (CH2), 59.38 (CH), 56.34 (CH), 53.08 (CH), 43.32 (CH), 43.38 (CH2), 33.88 (CH2), 28.87 (CH2), 28.77 (CH2), 28.10 (CH3), 26.48 (CH2), 26.05 (CH2), 25.97 (CH2). CI MS m/z calcd. for C24H40O5Cl 445.2535, found 445.2574.

~13~

EXAMPLE 10: 8YN~HE8I8 OF COMPOIJND VIV

'~ ~ ~
I

s~ sl s~

ndC a~rH ' ~;=~
S~ s~ s~ ~3 n DV

21381~1 .

A: 3aR 4R. 5R 6aS)-5-(Benzoyloxy)-4-r(E)-(3R)-3-cyclohexyl-3-hydroxy-1-propenyll-hexahydro-2H-cyclopentarb]furan-2-one (44):
To a solution of enone 4 (150 g, 392 mmol; Example 1), cerium trichloride heptahydrate (152 g, 408 mmol), methanol (500 mL), and CH2Cl2 (1.5 L) at 0C was added NaBH4 (14.4 g) in 0.2 g portions over 1 h. After stirring for 2 h, the reaction was poured into 1 M HCl (500 mL), the layers were separated, the aqueous layer was extracted with CH2Cl2 (2 X 300 mL), and the combined organic layers were dried over MgS04, filtered, and concentrated to provide 150.4 g (100%) of a 1:1 mixture of the two diastereomeric allylic alcohols. Separation of 200 g of the mixture (from several combined reactions) by HPLC (40% ethyl acetate in hexane) afforded 23.7 g (12%) of alcohol 44.

B: (3aR 4R 5R 6aS)-4-~(E)-(3R)-3-Cyclohexyl-3-hydroxy-1-propenyl]-hexahydro-5-hydroxy-2N-cyclopentarb]furan-2-one (45):
To a solution of 44 (7.35 g, 19.1 mmol) in methanol (100 mL) was added K2CO3 (2.64 g, 19.1 mmol).
After 2 h, 200 mL of 2 M HCl was added, the mixture was extracted with ethyl acetate (3 X 100 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated to afford crude diol 45 (5.53 g), which was used in the next step without purification.

C: (3aR, 4R, 5R 6aS)-4-r(3S)-3-Cyclohexyl-3-hydroxypropyl~-hexahydro-5-hydroxy-2H-cyclopenta~b]furan-2-one (46):
A mixture of 45 (5.3 g, 18.9 mmol), 10% w/w Pd/C
(320 mg), ethyl acetate (30 mL), and CH2Cl2 (10 mL) was hydrogenated in a Parr hydrogenation apparatus for 3 h at 45 psi. The mixture was filtered through Celite and concentrated, and the residue was chromatographed on silica gel (ethyl acetate) to afford 46 (4.3 g, 80%).
3C NMR (CDCl3) ~ 177.64 (C), 83.87 (CH), 77.21 (CH), 76.02 (CH), 53.45 (CH), 43.84 (CH), 42.96 (CH), 40.46 (CH2), 35.88 (CH2), 31.37 (CH2), 29.23 (CH2), 29.10 (CH2), 27.85 (CH2), 26.41 (CH2), 26.22 (CH2), 26.08 ( CH2 ) .

D: (3aR, 4R, 5R, 6aS)-4-~(3S)-3-Cyclohexyl-3-(tetrahydroPYran-2-yloxy)propyl~-hexahydro-5-(tetrahydropyran-2-yloxy)-2H-cyclopenta~b~furan-2-one (47):
To a mixture of 46 (3.7 g, 12.9 mmol), DHP (2.9 g, 35 mmol), and CH2Cl2 (80 mL) at 0C was added pTSA (300 mg, 1.58 mmol). After 30 min 50 mL of saturated NaHC03 was added, the layers were separated, the aqueous layer was extracted with CH2CL2 (2 X 50 mL), the combined organic layers were dried over MgS04, filtered, and concentrated, and the residue was chromatographed on silica gel (1/1 hexane/ethyl acetate) to afford bis-THP
ether 47 (4.89 g, 89%).

E: (9S, llR, 15S)-11,15-Bis(tetrahYdropyran-2-yloxy)-15-cyclohexyl-2,3,4,5,6,16,17,18,19,20-decanor-9-hYdroxYprostanol (48):
To a suspension of lithium aluminum hydride (920 mg, 24.2 mmol) in 50 mL of THF at 0C was added dropwise a solution of lactone 47 (10.87 g, 24.1 mmol) in THF (100 mL). After stirring for 1 h, ethyl acetate was cautiously added dropwise (50 mL), followed by saturated NH4Cl (100 mL). The mixture was extracted with ethyl acetate (3 X 100 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated to provide crude diol 48 (9.73 g, 89%), which was used in the next step without purification.

F: (9S, llR 15S)-11,15-Bis(tetrahydropyran-2-yloxy)-15-cyclohexyl- 2 3 4,5 6 16 17 18 19 20-decanor-9-(triethylsiloxy)prostanol triethylsilyl ether (49):
A mixture of 48 (9.7 g, 21.3 mmol), triethylsilyl chloride (7.36 g, 48.9 mmol), DMAP (289 mg, 2.36 mmol), NEt3 (5.3 g, 52 mmol), and CH2Cl2 (100 mL) was stirred overnight at room temperature. The mixture was poured into 100 mL of saturated NH4Cl, the layers were separated, the aqueous layer was extracted with CH2Cl2 (50 mL), the combined organic layers were dried over MgS04, filtered, and concentrated, and the residue was chromatographed on silica gel (15% ethyl acetate in hexane) to afford 49 (11.75 g, 81%).

G: (9S llR 15S)-11 15-Bis(tetrahydropyran-2-yloxy)-15-cyclohexyl- 2 3 4 5,6 16 17 18 19 20-decanor-9-(triethylsiloxy)prostanal (50):
To a solution of oxalyl chloride (6.5 g, 51 mmol) in 30 mL of CH2Cl2 at -78C was added dropwise a solution of DMSO (6.7 g, 86 mmol) in 10 mL of CH2Cl2.
After 30 min, a solution of 49 (11.75 g, 17.2 mmol) in 90 mL of CH2Cl2 was added dropwise. After 6 h, NEt3 (18.9 g, 187 mmol) was added and the reaction was warmed to room temperature. The mixture was added to 150 mL of saturated NH4Cl, the layers were separated, the aqueous layer was extracted with CH2Cl2 (2 X 50 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel (10% ethyl acetate in hexane) to afford aldehyde 50 (8.75 g, 90%).

30 H: (5Z)-(9S, llR, 15S)-11,15-Bis(tetrahydropyran-2-yloxy)-15-cyclohexyl- 2 3 4 16 17 18 19 20-octanor-9-(triethylsiloxy)-5-prostenoic acid methyl ester (51):
To a mixture of 18-crown-6 (13.1 g, 49.6 mmol), bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (7.8 g, 24.6 mmol), ~1381~1 and 75 mL of THF at -78C was added dropwise a 0.5 M
solution of KHMDS in toluene (42 mL, 21.5 mmol).
After 30 min, a solution of 54 (8.75 g, 15.4 mmol) in THF (75 mL) was added dropwise. After 2.5 h methanol was added (10 mL), the reaction was warmed to room temperature and added to saturated NH4Cl (100 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (2 X 50 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel (15% ethyl acetate in hexane) to afford cis-crotonate 51 (4.05 g, 44%), as well as a mixture of cis:trans olefin isomers (2.3 g, 25%).

I: (5Z)-(95,llR, 15S)-11,15-Bis(tetrahydropyran-2-yloxy)-15-cyclohexyl- 2,3,4,16,17,18,19,20-octanor-9-(triethylsiloxy)-5-prostenol (52):
To a solution of 51 (4.0 g, 6.4 mmol) in 25 mL of THF at 0C was added dropwise a 1.5 M solution of DIBAL-H in toluene (10 mL, 15 mmol). The reaction was brought to room temperature and stirred overnight. The mixture was added to 75 mL of saturated sodium potassium tartrate and stirred for 30 min, the layers were separated, the aqueous layer was extracted with ethyl acetate (2 X 50 mL), the combined organic layers were dried over MgS04, filtered, and concentrated, and the residue was chromatographed on silica gel (20%
ethyl acetate in hexane) to provide allyl alcohol 52 (2.84 g, 75%).

J: (5Z)-(9S llR 155)-11,15-Bis(tetrahydropyran-2-yloxy)-15-cyclohexyl-9-hydroxy- 2,3,4,16,17,18,19,20-octanor-5-prostenol (53):
To a solution of 52 (1.7 g, 2.9 mmol) in 20 mL of THF at 0C was added a 1 M solution of TBAF in THF (4.6 mL, 4.6 mmol). After 30 min 30 mL of saturated NH4Cl was added, the mixture was extracted with ethyl acetate (3 X 30 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel (3/2 ethyl acetate/hexane) to yield diol 53 (1.29 g, 93%).

K: (5Z)-(9S, llR, 15S)-11,15-Bis(tetrahydropyran-2-yloxy)-15-cyclohexyl-9-hydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester (54):
A mixture of 53 (1.29 g, 2.68 mmol), toluene (20 mL), 25% w/w aqueous NaOH (20 mL), BU4NHSO4 (175 mg, 0.52 mmol), and t-butyl bromoacetate (2.6 g, 13.5 mmol) was vigorously stirred for 10 min at 0C and 45 min at room temperature. The layers were separated, the aqueous layer was extracted with ethyl acetate (2 X 20 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel (40% ethyl acetate in hexane) to afford 54 (1.56 g, 98%).

L: (5Z)-(9S, llR, 155)-11,15-Bis(tetrahydropyran-2-yloxy)-15-cyclohexyl-9-hydroxy-3- oxa-16,17,18,19,20-pentanor-5-prostenoic acid (55):
A mixture of 54 (2.0 g, 3.4 mmol), lithium hydroxide monohydrate (830 mg, 20 mmol), methanol (20 mL), and water (1 mL) was stirred for 1.5 h, 35 mL of saturated KH2PO4 was added to adjust the pH to ca. 6, and the mixture was extracted with ethyl acetate (3 X
25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to provide crude acid 55, which was used in the next step without purification.

M: (5Z)-(9S, llR, 155)-11,15-Bis(tetrahydropyran-2-yloxy)-15-cyclohexyl-9-hydroxy-3- oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester (56):
A mixture of 55 from above, acetone (34 mL), isopropyl iodide (2.9 g, 17 mmol), and DBU (3.0 g, 20 mmol) was stirred overnight. The reaction was added to 40 mL of saturated NH4Cl, the mixture was extracted with ethyl acetate (3 X 25 mL), the combined organic layers were dried over MgS04, filtered, and concentrated, and the residue was chromatographed on silica gel (1/1 ethyl acetate/hexane) to yield isopropyl ester 56 (1.26 g, 64% from t-butyl ester 58).

N: (5Z)-(9R, llR, 15S)-11,15-Bis(tetrahydropYran-2-yloxy)-9-chloro-15-cyclohexYl-3- oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester (57):
To a solution of 56 (1.26 g, 2.2 mmol) in 13 mL of pyridine at 0C was added dropwise methanesulfonyl chloride (600 mg, 5.2 mmol). After 2 h, the mixture was added to a suspension of BU4NCl (6.1 g, 21.9 mmol) in toluene (9 mL) and heated at 55-63C for 4 h. After the reaction cooled to room temperature, 30 mL of saturated NH4Cl was added, the mixture was extracted with ethyl acetate (3 X 30 mL), the combined organic layers were dried over MgS04, filtered, and concentrated, and the residue was chromatographed on silica gel (20% ethyl acetate in hexane) to provide chlorinated product 57 as a mixture with the corresponding 8,9-olefin (1.07 g, 81% calculated as the chloride). The 8,9-olefin by-product was separated in the next step.

0: (5Z)-(9R, llR, 15S)-9-Chloro-15-cYclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester (XIV):
The mixture from above containing 57 and the 8,9-olefin (1.07 g, 1.79 mmol, calculated as the chloride)was added to a solution of isopropanol (14 mL), water (1 mL), and 12 M HCl (2 mL), and was stirred for 2 h.
The reaction was added to 50 mL of saturated NaHC03, the mixture was extracted with ethyl acetate (3 X 30 mL), the combined organic layers were dried over MgS04, filtered, and concentrated, and the residue was purified by radial chromatography (5% isopropanol in toluene) to afford pure XIV (172 mg, 22%), as well as a mixture of containing mostly XIV and a smaller proportion (ca. 30%) of the corresponding 8,9-olefin (333 mg, 42% calculated as the chloride). 13C NMR
(CDCl3) o~ 170.21 (C), 131.12 (CH), 127.19 (CH), 76.75 (CH), 75.44 (CH), 68.70 (CH), 67.67 (CH2), 66.78 (CH2), 61.02 (CH), 54.28 (CH), 51.18 (CH), 44.31 (CH2), 44.19 10 (CH), 31.35 (CH2), 31.19 (CH2), 29.73 (CH2), 29.17 (CH2), 27.60 (CH2) 26.50 (CH2), 26.31 (CH2), 26.16 (CH2), 21.80 (CH3). CI MS, m/z calcd. for C23H~O5Cl (MH+) 431, found 431.

EXA~P~E 11S 8YNTHE8I8 OF CONrOu~v XV

v s~ s~

C~ a~ C~_o~co2a~-~0--~0 ~0 .. .. ..

.~o~c~
HO~Q
~V
A: (SZ)-(9R, llR, 15R)-9-Chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17 18,19,20-~entanor-S-prostenoic acid (58):
To a solution of 32 mg (0.072 mmol) of V (Example 1) in a mixture of 2.5 mL of methanol and 1.2 mL of water was added lS mg (0.36 mmol) of lithium hydroxide monohydrate. After 9 h, 5 mL of 0.1 M HCl was added, and the mixture was extracted with CHC13 (S X 5 mL).
The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to afford 30 mg (100%) of 58 as a colorless oil. 13C NMR (CDCl3) ~ 173.17 (C), 132.77 (CH), 126.03 (CH), 75.68 (CH), 75.24 (CH), 66.89 (CH2), 66.40 (CH2), 61.32 (CH), 54.12 (CH), 50.62 (CH), 43.59 (CH2), 43.33 (CH), 30.92 (CH2), 30.73 (CH2), 29.89 (CH2), 29.30 (CH2), 27.95 (CH2), 26.44 (CH2), 26.25 (CH2), 26.09 (CH2).

B: (5Z~-(9R, llR, 15R)-9-Chloro-15-cYclohexy~ l5-dihydroxy-3-oxa-16 17 18 19 20-pentanor-5-~rostenoic acid methyl ester (59):
To a solution of 58 (22 mg, 0.057 mmol) in 20 mL
of ether was added excess diazomethane as a solution in ether. After 20 min residual diazomethane was removed from solution by a stream of N2 and the solution was concentrated. The residue was chromatographed on silica gel (40% ethyl acetate in hexane) to afford 59 (21 mg, 91%). 13C NMR (CDCl3) ~ 171.06 (C), 131.75 (CH), 126.74 (CH), 75.73 (CH), 75.47 (CH), 67.34 (CH2), 66.77 (CH2), 61.08 (CH), 54.19 (CH), 51.94 (CH3), 51.29 (CH), 44.47 (CH2), 43.62 (CH), 31.49 (CH2), 30.03 (CH2), 29.30 (CH2), 27.98 (CH2), 26.49 (CH2), 26.28 (CH2), 26.13 (CH2) .

C: (5Z)-(9R llR, 15R)-11 15-Bis(tetrahydropyran-2-yloxy)-9-chloro-15-cyclohexyl-3-oxa-16,17 18 19,20-pentanor-5-prostenoic acid methyl ester (60):
To a mixture of diol 59 (645 mg, 0.65 mmol), DHP
(0.56 mL, 6.4 mmol), and CH2Cl2 (10 mL) at 0C was added pTSA (10 mg, 0.053 mmol). After 15 min, 15 mL of saturated NaHC03 was added, the layers were separated, the aqueous layer was extracted with CH2Cl2 (3 X 15 mL), the combined organic layers were dried over MgS04, filtered, and concentrated, and the residue was chromatographed on silica gel (30% ethyl acetate in hexane) to afford 781 mg (86%) of bis-THP ether 60.

.
D: (5Z)-(9R, llR, 15R)-11,15-Bis(tetrahydropyran-2-yloxy)-9-chloro-15-cyclohexyl-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid (61):
A solution of 60 (342 mg, 0.65 mmol) and lithium hydroxide monohydrate (96 mg, 2.3 mmol) in methanol (20 mL) was stirred for 2 h, the pH of the solution was adjusted to pH 6 with saturated KH2P04, and the mixture was extracted with CH2Cl2 (6 X 20 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated to afford acid 61 (334 mg, 92%).

E: (5Z)-(9R, llR, 15R)-11,15-Bis(tetrahydropyran-2-yloxY)-9-chloro-15-cYclohexyl-3-oxa-16 17,18,19 20-pentanor-5-prostenoic acid neopentyl ester (62):
A mixture of 61 (80 mg, 0.14 mmol), dicyclohexylcarbodiimide (30 mg, 0.18 mmol), DMAP (8 mg, 0.07 mmol), 2,2-dimethyl-1-propanol (60 mg, 0.7 mmol), and CH2Cl2 (1 mL) was stirred for 3 h at room temperature, the solution was concentrated, and the residue was chromatographed on silica gel (20% ethyl acetate in hexane) to provide 62 contaminated with some dicyclohexyl urea (110 mg total). The sample was used in the next reaction without further purification.

F: (5Z)-(9R, llR, 15R)-9-Chloro-15-cyclohexyl-11,15-dihYdroxy-3-oxa-16,17,18,19,20-pentanor-5-Prostenoic acid neopentyl ester (XV):
The llo mg sample from above was dissolved in a mixture of methanol (10 mL) and water (1 mL) at 0C, and 10 drops of 12 N HCl was added. After 15 min, the solution was warmed to room temperature for 30 min.
The solution was added to CH2Cl2 (10 mL), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 X 10 mL). The combined organic layers were dried over MgSO4, filtered, concentrated, and chromatographed on silica gel (1/1 ethyl acetate/hexane) to afford XV (46 mg, 71% from 61).

3C NMR (CDCl3) ~ 170.88 (C), 131.82 (CH), 126.72 (CH), 75.68 (CH), 75.23 (CH), 74.20 (CH2), 67.34 (CH2) 66.76 (CH2), 61.23 (CH), 54.24 (CH), 51.19 (CH), 44.43 (CH2), 43.65 (CH), 31.44 (CH2), 31.34 (C), 30.23 (CH2), 30.09 5 (CH2), 29.33 (CH2), 28.00 (CH2), 26.50 (CH2), 26.37 (CH3), 26.28 (CH2), 26.14 (CH2) . CI MS m/z calcd. for C25H~OsCl (MH+) 459.2877, found 459.2872.

21381~1 EXA~IPLE: 12 s ~ I8 OF COMPOUND ~

.f~ H t .~ o^co~ o^~l,OH
~0 O ' ' ~0 '' 32 o ~

~3 ~

A: (5Z. 13E)-(9S, llR, 15S)-11,15-Bis(tetrahydropYran-2-Yloxy)-15-cyclohexyl-9-hydroxY-3-oxa-16,17,18,19,20-pentanor-5,13-prostadienoic acid t-butYl ester (63) To a vigorously stirring mixture of diol 32 (see Example 6) (925 mg, 1.93 mmol), toluene (25 mL), BrCH2CO2Bu' (1.2 g, 6.3 mmol), and Bu4HSO4 (200 mg, 0.59 mmol) was added 20 mL of a 20% w/w aqueous solution of NaOH. After 40 min the layers were separated, the aqueous layer was extracted with ethyl acetate (2 X 30 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel eluting with 40% ethyl acetate in hexanes to afford 63 (1.10 g, 96%, ~0.5).

B: (5Z 13E)-(llR, 15S)-11,15-Bis(tetrahydropyran-2-YloxY)-15-cyclohexYl-3-oxa-16,17 18,19 20-~entanor-5,13-prostadienol (64) To a mixture of 63 (1.09 g, 1.84 mmol) and pyridine (11 mL) at 0C was added dropwise ~
methanesulfonyl chloride (0.51 g, 4.5 mmol). The reaction was stirred at 0C~for 30 min and for 2 h at room temperature, 40 mL of saturated NH4Cl was added, and the mixture was extracted with ethyl acetate (2 X
40 mL). The combined organic layers were dried over 213~181 MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel eluting with 1:1 hexane:ethyl acetate to afford the intermediate 9~-mesylate (1.08 g, 87%, RfO.5).
To a mixture of the mesylate in THF (11 mL) at 0C
was added dropwise 1 M LiEt3BH in THF (11 mL, 11 mmol) and the reaction was stirred overnight at room temperature. The mixture was poured into 50 mL of a 1:1 mixture of saturated NH4Cl:ethyl acetate, the layers were separated, and the aqueous layer was extracted with ethyl acetate (2 X 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel eluting with 40% ethyl acetate in hexane to afford 64 (642 mg, 79%, RfO.4).

C: (5Z, 13E)-(llR, 15S)-11,15-Bis(tetrahydropyran-2-yloxy)-15-cyclohexyl-3-oxa-16,17,18,19,20-pentanor-5,13-prostadienoic acid isopropyl ester (65) To a mixture of 64 (560 mg, 1.12 mmol) and DMF (5 mL) was added pyridinium dichromate (1.32 g, 3.51 mmol). After stirring for 48 h, 20 mL of water was added, and the mixture was extracted with ethyl acetate (4 X 20 mL). The combined organic layers were filtered and concentrated, the residue was dissolved in acetone (20 mL), and DBU was added (780 mg, 5.12 mmol), followed in 15 min by the addition of isopropyl iodide (850 mg, 5.0 mmol). After 20 h, the reaction was concentrated, and the residue was chromatographed on silica gel eluting with 20% ethyl acetate in hexane to afford 65 (238 mg, 38%, RfO.4).

D: (5Z, 13E)-(llR, 15S)-15-Cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5,13-prostadienoic acid isopropyl ester (XVI) To a mixture of 65 (230 mg, 0.41 mmol), isopropanol (18 mL), and water (2 mL) was added 12 M

2 1 ~

HCl (1 mL). After 2 h, 20 mL of saturated NaHCO3 was added, the mixture was extracted with ethyl acetate (3 X 20 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel eluting with 3:2 ethyl acetate:hexane to afford XVI (120 mg, 74%, ~0.25).
3C NMR (CDCl3) ~ 170.00 (C), 134.17 (CH), 132.73 (CH), 125.97 (CH), 77.92 (CH), 77.68 (CH), 68.47 (CH), 67.38 (CH2), 66.73 (CH2), 58.02 (CH), 43.44 (CH), 42.77 (CH), 32.15 (CH2), 28.89 (CH2), 28.80 (CH2), 27.63 (CH2), 26.51 (CH2), 26.06 (CH2), 25.94 (CH2), 21.97 (CH3).
The compounds of formulae (I) and (II) are useful in lowering intraocular pressure and thus are useful in the treatment of glaucoma. The preferred route of administration is topical. The dosage range for topical administration is generally between about 0.001 and about 1000 micrograms per eye (~g/eye) and is preferably between about 0.01 and about 100 ~g/eye and most preferably between about 0.05 and 50 ~g/eye. The compounds of the present invention can be administered as solutions, suspensions, or emulsions (dispersions) in a suitable ophthalmic vehicle.

In forming compositions for topical administration, the compounds of the present invention are generally formulated as between about 0.00002 to about 0.5 percent by weight (wt%) solutions in water at a pH between about 4.5 and about 8Ø The compounds are preferably formulated as between about 0.0001 to about 0.1 wt% and, most preferably, between about 0.001 and about 0.05 wt%. While the precise regimen is left to the discretion of the clinician, it is recommended that the compositions be topically applied by placing one or more drops in each eye one or more times a day.

Other ingredients which may be desirable to use in the ophthalmic preparations of the present invention ~138181 include preservatives, co-solvents and viscosity building agents.

Antimicrobial Preservatives:
Ophthalmic products are typically packaged in multidose form, which generally require the addition of preservatives to prevent microbial contamination during use. Suitable preseryatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, ONAMER M~, or other agents known to those skilled in the art. Such preservatives are typically employed at a concentration between about 0.001 and about 1.0 wt%.

Co-Solvents:
Prostaglandins, and particularly ester derivatives, typically have limited solubility in water and therefore may require a surfactant or other appropriate co-solvent in the composition. Such co-solvents include: Polysorbate 20, 60 and 80; Pluronic F-68, F-84 and P-103; Tyloxapol; Cremophor EL; sodium dodecyl sulfate; glycerol; PEG 400; propylene glycol;
cyclodextrins; or other agents known to those skilled in the art. Such co-solvents are typically employed at a concentration between about 0.01 and about 2 wt%.
Viscosity Agents:
Viscosity greater than that of simple aqueous solutions may be desirable to increase ocular absorption of the active compound, to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation and/or otherwise to improve the ophthalmic formulation. Such viscosity building agents include: polyvinyl alcohol; polyvinyl pyrrolidone;
cellulosic polymers, such as methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose;
carboxy vinyl polymers, such as carbomer 910, carbomer 940, carbomer 934P and carbomer 1342; or other agents known to those skilled in the art. Such agents are typically used at a concentration between about 0.01 and about 2 wt~.

213Sl~l The following Tables 2-4 containing Formulations A-M are representative pharmaceutical compositions of the invention for topical use in lowering of intraocular pressure. Each of Formulations A-M may be formulated in accordance with procedures known to those skilled in the art.

FORMULATION (wt%) INGREDIENT A B C D
Compound lll --- 0.01 --- ---Compound IV 0.002 --- --- ---Compound XVI --- --- 0 05 ---Compound XVII --- --- --- 0.1 Dextran 70 0.1 0.1 -- ---Hydroxypropyl 0.3 0.5 --- ---Methylcellulose Monobasic Sodium --- 0.05 0.05 0.05 Phosphate Dibasic Sodium --- 0.15 0.15 0.15 Phosphate (anhydrous) Sodium Chloride 0.77 0.75 0.5 0.6 Potassium Chloride0.12 --- --- ---Disodium EDTA 0.05 0.05 --- ---Hydroxypropyl-,~- --- --- 1.0 ---cyclodextrin Tyloxapol --- 0.1 --- 0.4 Benzalkonium Chloride 0.01 0.01 0.01 0.02 Polysorbate 80 0.01 --- --- ---HCI and/or NaOHq.s. to pHq.s. to pHq.s. to pHq.s. to pH
7.2-7.5 7.3-7.4 6.3-6.6 6.3-6.6 Purified Water q.s. to q.s. to q.s. to q.s. to 100% 100% 100% 100%

FORMULATION (wt%) INGREDIENT E F G H
Compound V 0.01 --- --- ---Compound Vl --- 0.01 --- ---Compound XVII --- --- 0.1 ---Compound XIX --- --- --- 0.2 Monobasic Sodium 0.05 0.05 0.05 0.05 Phosphate Dibasic Sodium 0.15 0.15 0.15 0.15 Phosphate (anhydrous) Sodium Chloride 0.75 0.75 0.5 0.6 Disodium EDTA 0.01 0.05 --- ---Cremophor~ EL --- 01 --- ---Hydroxypropyl-,~- --- , --- 4.0 ---cyclodextrin Tyloxapol --- --- --- 0.5 Benzalkonium Chloride 0.02 0.01 0.01 0.02 Polysorbate 80 0.05 --- --- ~~~
HCI and/or NaOHq.s. to pHq.s. to pHq.s. to pHq.s. to pH
7.3-7.4 7.3-7.4 6.3-6.6 6.3-6.6 Purified Water q.s. to q.s. to q.s. to q.s. to 100% 100/0 100% 100%

21~8181 FORMULATION (wt%) INGREDIENT J K L M
Compound Vlll 0.01 --- --- ---Compound IX --- 0.01 --- ---Compound X --- --- 0.1 0.2 Monobasic Sodium 0.05 0.05 0.05 0.05 Phosphate Dibasic Sodium 0.1 5 0.1 5 0.1 5 0.1 5 Phosphate (anhydrous) Sodium Chloride 0.75 0.75 0.5 0.6 Disodium EDTA 0.01 0.05 --- ---Cremophor~ EL --- 0 01 --- ---Hydroxypropyl-,~- --- --- 4.0 ---cyclodextrin Tyloxapol --- --- --- 0.5 Benzalkonium Chloride 0.02 0.01 0.01 0.02 Polysorbate 80 0.05 --- --- ~~~
HCI and/or NaOHq.s. to pHq.s. to pHq.s. to pHq.s. to pH
7.3-7.4 7.3-7.4 6.3-6.6 6.3-6.6 Purified Water q.s. to q.s. to q.s. to q.s. to 100% 100% 100% 100%

213~

The ability of certain compounds of the present invention to reduce intraocular pressure (IOP) was evaluated in cynomolgus monkeys with ocular hypertension produced by previous laser trabeculoplasty in the right 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 treatment regimen consisting of 5 divided doses administered over a period of 2 and 1/2 days.
Doses Z-5 were given 8, 24, 32 and 48 hours after the initial dose. Baseline IOP values were determined prior to treatment with the test formulation, and then IOP was determined 16 hours after the fourth dose, and 2, 4 and 6 hours after the fifth dose. Prostaglandin doses are micrograms of compound contained in each treatment.
The two tested compounds are the previously identified Compounds III-VII.

Baseline Percent IOP Reduction at Hours after Dose/Dose~
Compound PG Dose IOP
(mm Hg) 16/4 215 415 615 111 1/J9 31.1 15.6+4.733.7+5.5 28.1 +4.131.0~4.6 IV 1,ug 31.3 47.6+2.652.8+3.3 54.7+3.8 53.1 +4.1 V 5 ~9 36.3 38.3+3.047.5+5.1 43.7+5.6 36.5+5.8 Vl 1 IJ9 36.9 22.3+2.730.8+4.7 26.4+4.7 24.9+4.0 Vll 20,ug 32.6 13.9+2.730.1 i4.822.4+5.2 19.3~4.3 2 C~

213~

Results are presented in Table S, above.
Compounds III-VII produced significant reduction of intraocular pressure at doses which are marginal or ineffective for other prostaglandins in published clinical studies. Compound IV was especially potent, producing greater than 50% reduction of intraocular pressure with just 1 ~g of compound. In contrast, Nakajima et al. (Graefe's Arch. Clin. Exp. Ophthalmol., 229:411-413 (1991)) reported that 50 ~g of PGD2 and 2.5 ~g of BW245C (a PGD2 analogue) reduced intraocular pressure in human eyes by 12% and 10%, respectively.
Other studies (Woodward et al., Invest. Ophthalmol.
Vis. Sci., 31:138-146 (1990)) reported for these reference compounds in rabbits describe a maximum IOP
reduction of approximately 28% for 250 ~g of PGD2 and 22% for 25 ~g of BW245C. These comparisons indicate the unexpected potency of Compounds III - VII in reducing intraocular pressure. No indications of inflammation were observed during these studies.

The ability of certain compounds of the present invention to reduce intraocular pressure (IOP) was evaluated in cynomolgus monkeys with ocular hypertension produced by previous laser trabeculoplasty in the right 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 two compounds tested are those previously identified as Compound XI and Compound XII.

2l38I8l MAXIMUM PERCENT IOP
REDUCTION FROM
COMPOUND PG DOSE BASELINE
Xl 3,ug 42 Xll 0.3,ug 44 Compounds XI and XII produced significant reduction of intraocular pressure at doses which are marginal or ineffective for other prostaglandins in published clinical studies. By comparison, Nakajima et al. (Graefe's Arch. Clin. Exp. OPhthalmol. 229:411-413 (1991)) reported that 50 ~g of PGD2 and 2.5 ~g of BW245C (a PGD2 analogue) reduce intraocular pressure in human eyes by 12% and 10%, respectively. Other studies (Woodward et al., Invest. Ophthalmol. Vis. Sci. 31:138-146 (1990)) reported for these reference compounds in rabbits describe a maximum IOP reduction of approximately 28% for 250 ~g of PGD2 and 22% for 25 ~g of BW245C. These comparisons indicate the unexpected potency of compounds of the present invention in reducing intraocular pressure. No indications of inflammation were observed during these studies.

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 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 (27)

1. A topical ophthalmic composition for the treatment of glaucoma and ocular hypertension, said composition comprising an ophthalmically acceptable vehicle and a therapeutically effective amount of a compound of formula:

(I) wherein:
R1 = CO2R2, wherein R2 = H, a cationic salt moiety, or an ophthalmically acceptable ammonium moiety; or R1 may also represent an ophthalmically acceptable ester moiety;
X = halogen, particularly Cl or F, in either configuration;
Y = CH2 or O;
? = single or trans double bond;
R3, R4 can be the same or different, and are selected from: free or functionally modified hydroxy groups; and n = 0 or 1.

2. The composition of claim 1, wherein: R1 = CO2R2; R2 = substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, heteroaryl, or (heteroaryl)alkyl, wherein substituents are selected from the group consisting of: alkyl, halogen, a free or functionally modified hydroxy group, or a free or functionally modified thiol; and X = F or Cl in either configuration.

3. The composition of claim 2, wherein: R1 = CO2R2; R2 = H, methyl, ethyl, n-propyl, isopropyl, t-butyl or benzyl; X = Cl in the .beta. (R) configuration; Y = O; R3 and R4 = OH; and n = 1.

4. The composition of claim 3, wherein: R2 = t-butyl.

5. The composition of claim 2, wherein: R1 = CO2R2; R2 = H, methyl, ethyl, n-propyl, isopropyl, t-butyl, or benzyl; X = Cl in the .beta. (R) configuration; Y = CH2; R3 and R4 = OH; and n = 1.

6. The composition of claim 5, wherein: R2 = methyl.

7. The composition of any of claims 1-5, wherein the compound of formula (I) is present at a concentration between about 0.00002 and about 0.5 percent by weight.

8. The composition of claim 7, wherein the compound of formula (I) is present at a concentration between about 0.0001 and about 0.1 percent by weight.

9. The composition of claim 8, wherein the compound of formula (I) is present at a concentration between about 0.001 and about 0.05 percent by weight.

10. Use of the composition of any of claims 1-5, comprising topically administering said composition to a glaucomatous or hypertensive eye.

11. Use according to claim 10, wherein between about 0.001 and about 1000 micrograms of a compound of formula (I) is administered.

12. Use according to claim 11, wherein between about 0.01 and about 100 micrograms of a compound of formula (I) is administered.

13. Use according to claim 12, wherein between about 0.05 and about 50 micrograms of a compound of formula (I) is administered.

14. A topical ophthalmic composition for the treatment of glaucoma and ocular hypertension, said composition comprising an ophthalmically acceptable vehicle and a therapeutically effective amount of a compound of formula:

(II) wherein:
R1 = CH2R, CO2R4;
R = OH or functionally modified hydroxy group;
R2 and R3 can be the same or different and are selected from: H and CH3;
R4 = H, a cationic salt moiety, substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, heteroaryl, or (heteroaryl)alkyl, wherein substituents include alkyl, halo, a free or functionally modified hydroxy group or a free or functionally modified thiol;
W = CH2, O, S(O)m wherein m = 0, 1, 2;
A = CH2CH2, cis or trans CH=CH, or C?C;
X = Cl, F or R in either configuration, or H;
Z11 and Z15 may be the same or different and may be selected from O, H and R in either configuration, or H and H;
Y = CH2CH2 or trans CH=CH, or C?C; and n = 0 or 1;
with the proviso that the following compounds be excluded:

wherein R4 is as defined above.

15. The composition of claim 14, wherein: W = CH2 or O; A = cis CH=CH; X = Cl or H; Z11 = R and H in either configuration, or H and H; Y = CH2CH2, or trans CH=CH;
and n = 1.

16. The composition of claim 15, wherein: R2, R3 = H; X
= Cl in .beta.-configuration, or H; Z15 = H and R in either configuration; and R4=H, a cationic salt moiety, or substituted or unsubstituted C1-C10 alkyl.

17. The composition of any of claims 14-16, wherein the compound of formula (II) is present at a concentration between about 0.00002 and about 0.5 percent by weight.

18. The composition of claim 17, wherein the compound of formula (II) is present at a concentration between about 0.0001 and about 0.1 percent by weight.

19. The composition of claim 18, wherein the compound of formula (II) is present at a concentration between about 0.001 and about 0.05 percent by weight.

20. Use of the composition of any of claims 14-16, comprising topically administering said composition to a glaucomatous or hypertensive eye.

21. Use according to claim 20, wherein between about 0.001 and about 1000 micrograms of a compound of formula (II) is administered.

22. Use according to claim 21, wherein between about 0.01 and about 100 micrograms of a compound of formula (II) is administered.

23. Use according to claim 22, wherein between about 0.05 and about 50 micrograms of a compound of formula (II) is administered.

24. A compound of formula:

(II) wherein:
R1 = CH2R, CO2R4;
R = OH or functionally modified (i.e., etherified and acylated) hydroxy group;
R2 and R3 can be the same or different and are selected from: H and CH3;
R4 = H, a cationic salt moiety, substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, heteroaryl, or (heteroaryl)alkyl, wherein substituents include alkyl, halo, a free or functionally modified hydroxy group or a free or functionally modified thiol;
W = O, S(O)m wherein m = 0, 1, 2;
A = CH2CH2, cis or trans CH=CH, or C?C;
X = H;
Z11 and Z15 may be the same or different and may be selected from O, H and R in either configuration or H and H;
Y = CH2CH2 or trans CH=CH, or C?C; and n = 0 or 1.

25. A compound of claim 24 wherein: R1 = CO2R4; R2 and R3 = H; R4=H, a cationic salt moiety, or a substituted or unsubstituted C1-C10 alkyl; W = O, A = cis CH=CH; Z11 and Z 15 = R and H in either configuration; Y = CH2CH2, or trans CH=CH; and n = 0 or 1.

26. A compound of claim 25, having the formula:

27. A compound of claim 25, having the formula: