SK183499A3 - Prostaglandin derivatives devoid of side-effects for the treatment of glaucoma - Google Patents

Abstract

A new method and compositions for the treatment of glaucoma and ocular hypertension are described. The method is based on the usage of EP1 prostanoid receptor agonists which effectively reduce the intraocular pressure but have no, or reduced effect on iris pigmentation. The prostaglandin analogue which is an EP1 selective agonist is applied topically on the eye.

Description

Technical field

The invention relates to a method of treating glaucoma and ocular hypertension using prostaglandin analogues or derivatives which do not have or reduce melanogenic effects in the eye. The invention also relates to ophthalmic compositions containing prostaglandin compounds which do not have or reduce the melanogenic effect in the eye.

BACKGROUND OF THE INVENTION

Glaucoma is an eye disorder characterized by increased intraocular pressure, ocular nerve head overlay and gradual loss of visual field. It is commonly known that abnormally high intraocular pressure is detrimental to the eye and there are clear indications that intra-ocular pressure is the most important factor causing degenerative changes in the retina and optic nerve head in glaucoma. However, the exact pathophysiological mechanism of blunt glaucoma is still unknown. If left untreated, glaucoma can lead to blindness, and the course of the disease is usually slow with progressive vision loss.

Intraocular pressure (IOP) can be defined according to formula (1):

(1) IOP = Pe + (Ft-Fu) xR where Pe is the episcleral venous pressure, Ft is the formation of water, Fu is the part of the water that escapes from the eye through the uveoscleral outflow path and R is the resistance in the trabecular outflow path. The aqueous fluid in the anterior and posterior chambers of the eye produces ciliary processes beyond the iris. It then flows through the pupil into the anterior chamber and normally exits from the eye through the trabecular network and the Schlemm's canal into the episcleral veins outside the ocular sphere. However, part of the water can leave the eye through the uveoscleral outflow path. The flow in this pathway is considered to be minimally influenced by intraocular pressure (Bili, 1975).

Normal intraocular pressure in humans is in the range of 12-22 mm Hg. At higher pressures, i. above 22 mm Hg, there is an increased risk of eye damage. However, in one particular form of glaucoma, normotensive glaucoma, eye damage can also occur at intraocular pressure at the normal physiological range. The reverse situation is also known, i. some individuals may have high intraocular pressure without any apparent visual field or optic nerve head defects. Such conditions are commonly referred to as ocular hypertension.

Treatment of glaucoma can be provided by means of a drug, a laser or a surgical procedure. In drug treatment, the purpose is to reduce either the formation of water (Ft) or resistance to the outflow of the watercourse (R), which will result in a reduced intraocular pressure according to formula (1) above; alternatively, the outflow of aqueous fluid through the uveoscleral pathway can be increased, which also reduces intraocular pressure according to formula (1).

Prostaglandins, and typically PGF2®, its esters and analogs, reduce intraocular pressure, in particular by increasing uveoscleral effluent (Crawford and Kaufman, 1987; Nilsson et al., 1989; Toris et al., 1993; Stjernschantz et al., 1995). The use of prostaglandins and derivatives thereof is described in several patents and patent applications, for example US 4,599,353 (Bito), US 4,952,581 (Bito), WO89I03384 (Resul and Stjernschantz), EP 170258 (Cooper), EP 253094 (Goh), and vEP 308135 (Ueno).

Prostaglandins are fatty acids usually derived from eicosatrienoic, eicosatetraenoic and eicosapentanoic acid precursors through metabolic steps involving oxygenation. Naturally occurring prostaglandins mostly have the structure shown in Figure 1.

.COOH

? H

Fig. 1

Thus, prostaglandins have a cyclopentane ring to which two carbon chains are attached, the upper chain being commonly called the alpha chain, and the lower chain usually being called the omega chain. Prostaglandins are classified in subgroups A, B, C, D, E, F, G, H, I, and J depending on the structure and substituents on the cyclopentane ring as shown in Figure 2.

PGA

OH

The alpha chain is a 7-carbon aliphatic chain terminated by carboxyl, while the omega chain is an 8-carbon aliphatic chain terminated by methyl. Depending on the number of double bonds in these chains, subscripts 1 to 3 are reported. For prostaglandins with subscript 1, e.g. _And PGF, the double bond is situated between carbons 13 and 14 in the omega chain, and naturally occurring prostaglandins have the bond of trans configuration. In prostaglandins with subscript 2, e.g. PGF ₂ α, there is another double bond in the cis configuration between carbons 5 and 6 in the alpha chain, and finally in the lower-index prostaglandins 3 there is a third double bond between the 17 and 18 carbons in the omega chain. This double bond also has a cis configuration in naturally occurring prostaglandins. All naturally occurring prostaglandins have a hydroxyl group on carbon 15 which is important for biological activity.

The receptor system for naturally occurring prostaglandins has only recently been elucidated. As a result, most prostaglandin receptors have been pharmacologically characterized and their molecular structure identified by molecular biology techniques (Coleman et al., 1994). There are specific receptors for naturally occurring prostaglandins. These are receptors for PGD, PGE, PGF,

PGI ₂ (prostacyclin) and TxA ₂ (thromboxane), which are abbreviated as DP, EP, FP, IP and TP. Furthermore, it has been shown that the EP receptor can be further subdivided into four receptors, namely EP1 receptors EP ₂₁ EP ₃ and EP4. Specific tissues or cells can secrete only a few or many of these receptors in different species, depending on the evolutionary development of this autacoid system. For example, it has been shown that the cat pupil sphincter mainly secrets FP receptors that are functionally coupled and mediate pupil constriction, while the corresponding bovine eye smooth muscle secretes EP1 and TP receptors, activating either of them will result in muscle contraction. A compound that binds to and activates a specific receptor is called an agonist, while a compound that only binds to a receptor without activating it is called an antagonist.

Given the practical usefulness of many prostaglandins and their derivatives as suitable drugs for the treatment of glaucoma or ocular hypertension, their property of increased iris pigmentation of the eye may be a limiting factor (Stjernschantz and Alm, 1996). The color of the iris during chronic treatment in monkeys and humans tends to darken and turn brown. Although this does not seem to have any health implications, this is a clear cosmetic disadvantage, especially in patients with only one eye being treated. It would therefore be desirable to identify prostaglandins that effectively reduce intraocular pressure without causing the side effect of increased iris pigmentation.

SUMMARY OF THE INVENTION

We have now unexpectedly found that prostaglandin derivatives and analogs, which are selective agonists for the EP1 subset of prostanoid receptors, meet the criterion for prostaglandin analogue which effectively reduces intraocular pressure without causing iris pigment production (melanogenesis). The starting point of this finding is that when trying to identify subtypes of prostanoid receptors in the human melanocytes of the iris, we found that these cells secrete in their cell walls FP, EP ₂ and EP 3 receptors but not abstracts and TP receptors. In addition, we investigated the effect of lowering the intraocular pressure of several relatively selective EP1 agonists and found that these prostaglandin analogues effectively and potently reduce intraocular pressure in both cats and monkeys.

Therefore, it is now clear that the use of selective EP 1 receptor agonists can reduce intraocular pressure in primates and hence in humans without increased melanogenesis or with significantly reduced melanogenesis as a side effect, since melanin-producing cells, melanocytes, do not have the specific receptor required for transmembrane signaling cells. . While there is currently no clinical evidence that such a selective EPi agonist will not result in increased iris pigmentation, as the induction time of this phenomenon is often 6 to 12 months, ie extremely long and expensive experiments on primates, we can still conclude on the relevant in vitro studies that such increased pigmentation will not occur in the absence of a specific signaling receptor in the melanocyte cell wall.

Thus, high selectivity or specificity for the EP 1 receptor over other prostaglandin receptors in the eye characterizes the compounds used in the method or compositions of the present invention. Needless to say, the more selective the compound at the EP 1 receptor, the better the results will be obtained, but of course some benefit will also be obtained in cases of some interaction with other receptors. High selectivity in this connection means that the effect on the EP 1 receptor is at least more than 5 times, preferably more than 10 times, and most preferably more than 100 or 1000 times higher than the effect on other prostaglandin receptors.

The specific prostaglandin analogs we used as examples and to verify this invention were PGF _2β (1), PGF _2β isopropyl ester (2), 17-phenyl-18,19,20 trinor-PGE ₂ (3), 17-phenyl- 18,19,20-trinor-PGE ₂ isopropyl ester (4), 15 (R, S) -16,16-trimethylene-PGE ₂ (5), 15 (R, S) -16,16-trimethylene-PGE ₂ methyl ester (6), and 13,14-dihydro-17- (3-fluorophenyl) -18,19,20 trinor-PGE ₂ -isopropyl ester (7). All of these analogs are relatively selective EP 1 receptor agonists. Receptor profiles of tested

The compounds I are listed in Table I.

Table I. Receptor profile of prostaglandin analogues tested (EC-50 values expressed as moles / l in functional receptor assays).

prostaglandin FP EPI ep ₂ ep ₃ DP / IP TP 1 όχΙΟ ^-6 1o * ΪΟ ⁵ 3 « ⁷ 2x10 * > 10 * > 10 * > 10 * > 10 * 5 2x10 ^b 6x10 * 2x10 ^'of 3x10 * # > 10 * > 10 * 7 6x10 ' ^/ 4x10 * 5x10 * * 10 # > 10 * > 10 *

# estimate based on difference in receptor assay between swine semen and chicken ileum.

In one aspect, the invention relates to the use of selective EP ₁ receptor agonists that do not have a melanogenic effect in the treatment of glaucoma or ocular hypertension. A method of treating glaucoma or ocular hypertension comprises contacting the eye surface with an amount of a composition effective to reduce intraocular pressure, comprising the EPi selective prostaglandin as above, to reduce intraocular pressure and to maintain this pressure at a reduced level. The composition typically contains about 0.1 to 100 pg, preferably 1 to 30 pg, per administration of the active ingredient. The composition is applied topically to the eye 1 to 3 times a day.

The prostaglandin derivative is mixed with a known ophthalmologically compatible vehicle. The vehicle that can be used to prepare the compositions of this invention may be aqueous solutions, e.g. saline, oily solutions or ointments. The vehicle may further comprise ophthalmologically compatible preservatives such as benzalkonium chloride, surfactants such as polysorbate 80, liposomes or polymers such as methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and hyaluronic acid; these can be used to increase viscosity. In addition, soluble or insoluble drug cartridges may be used.

In another aspect, the invention relates to ophthalmic compositions for the medical treatment of glaucoma or ocular hypertension comprising an effective amount of a prostaglandin analogue that is a selective EP 1 receptor agonist as defined above and a 1 · ¹ ophthalmologically compatible carrier for reducing intraocular pressure. An effective amount usually represents a dose of about 0.1 to 100 µg in about 10 to 50 µl of the composition. The compositions of the present invention are clear improvements over the prior art prostaglandin compositions with respect to the selectivity of the active compound to EPI receptors as compared to other prostaglandin receptors to eliminate or at least substantially reduce the risk of pigmentation.

In another aspect, the invention relates to the use of a prostaglandin analogue for the preparation of a medicament for the treatment of glaucoma and ocular hypertension.

The prostaglandin analog is preferably derived from PGF or PGE-type prostaglandins. In particular, the prostaglandin analog is a compound of the formula:

.COOR where:

the wavy lines represent the α or β configuration and the dashed bonds represent the single bond, triple bond, or double bond in the cis or trans configuration;

R is hydrogen, saturated or unsaturated alkyl group, preferably a C _r Cio-alkyl, cycloalkyl, preferably C ₃ -C 8 cycloalkyl, aryl, arylalkyl, preferably aryl-C ₂ -C ₅ -alkyl, or heteroaryl;

R ¹ is a saturated or unsaturated alkyl group having 2-5 carbon atoms, optionally interrupted by heteroatoms selected from oxygen, sulfur and nitrogen, cycloalkyl, preferably C ₃ -C 7 cycloalkyl, cycloalkenyl, preferably C ₃ -C ₇ -cycloalkenyl, aryl, or heteroaryl;

X is C-OH or C = O;

R ² is hydrogen, hydroxy, methyl, ethyl, methoxy or -OCOR ⁴ wherein R ⁴ is a linear or branched saturated or unsaturated alkyl group, preferably _R Clo C, in particular _Ci-C6 alkyl, or cycloalkyl, preferably C ₃ -C ₈ -cycloalkyl, or aryl;

R ³ is a linear or branched saturated or unsaturated alkyl chain preferably containing 3 to 8 carbon atoms, more preferably 3 to 5 carbon atoms, optionally interrupted by one or more heteroatoms selected from oxygen, sulfur and nitrogen, each carbon atom being optionally substituted with a substituent selected from: C ₁ -C ₅ -alkyl, hydroxy and carbonyl, wherein the hydroxy and carbonyl are preferably attached to the carbon 15 of the prostaglandin structure, and wherein the alkyl optionally contains a cycloalkyl, preferably a C ₃ -C ₈ cycloalkyl, aryl or heteroaryl, which may be mono- or independently multiply substituted with C 1 -C 3 -alkyl, C 1 -C ₃ -alkoxy, hydroxyl, nitro, trifluoromethyl or halogen;

or a pharmaceutically acceptable salt or ester thereof.

Aryl is preferably substituted or unsubstituted phenyl.

Examples of heteroaryl groups include thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine.

Aryl, heteroaryl and cycloalkyl may be mono- or independently multiply substituted with C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, hydroxyl, nitro, trifluoromethyl or halogen.

The unsaturated alkyl may contain one or more double and / or triple bonds.

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

Prostaglandins may be in epimeric mixtures as well as in the form of individual epimers.

DETAILED DESCRIPTION OF THE INVENTION

The invention is illustrated by the following non-limiting examples:

Identification of prostaglandin receptors. Prostaglandin receptors have been identified by the reverse-transcriptase polymerase chain reaction (RT-PCR) technique. Specific primers have been designed for FP, EP1, EP2, EP3, and TP receptors. The primers used in the assays are shown in Table II. RT-PCR was performed on mRNA isolated from human iris melanocytes in culture. The cultured cells were used to prepare mRNA. The RT-PCR reaction mixture was analyzed on an agarose gel and the expected size bands were cloned and sequenced. The deduced sequences were analyzed for similarity to each prostaglandin receptor sequence.

Methods. Human iris melanocytes were isolated and cultured according to Hu et al. (1993) and used in the early stages. Cells were grown to confluence and then harvested for mRNA enrichment.

gene Correct fragment size (bp) Sequence analysis observed expected FP + 489 Identity with F P EPI - 397 - ep ₂ + 501 Identity with EP ₂ EPs + 372 Identity with EP ₃ TP - 484 -

Synthesis of prostaglandin derivatives

The structures of the final compounds prepared in the examples are shown in Scheme 1 at the end of the description.

Example 1: PGF _2p (Compound 1)

The title compound was purchased from Cayman Chemicals Company, Ann Arbor, Michigan, USA.

Example 2: PGF _2β isopropyl ester (compound 2)

DBU (163.5 mg, 1.01 mmol) was added to a stirred solution of PGF _2β (Cayman Chemicals) (60 mg, 0.169 mmol) in acetone (20 mL) at 0 ° C. The mixture was allowed to warm to room temperature and then isopropyl iodide (222.6 mg, 1.34 mmol) was added dropwise. After 48 h (TLC monitoring), the mixture was diluted with ethyl acetate (40 mL), washed with brine (30 mL), 3% citric acid (2 x 40 mL) and 5% sodium bicarbonate (2 x 30 mL), and dried over anhydrous sulfate. sulfate. The solvent was removed in vacuo and the residue was chromatographed on silica gel using 3: 1 ethyl acetate: acetone as eluent. This gave a colorless oil in a yield of 46 mg (68%). ¹ H NMR (CDCl 3) d 1.3 (d, 6H), 1.6-1.7 (dm, 4H), 2.0-2.2 (dm, 6H), 23 (t, 2H), 4 0-4.1 (m, 3H), 5.0 (5t, 1H), 5.5 (m, 2H), 5.6 (m, 2H). ¹³ C NMR (CDCl 3) d 135.9, 132.2, 130.5, 128.0, 75.3, 74.8, 72.85, 67.6, 56.23, 52.25, 51.59, 42.32, 37 , 35, 33.44, 31.74, 29.14, 26.66, 24.79, 22.6, 21.8, 14.03.

Example 3: 17-Phenyl-18,19,20-trinor-PGE ₂ (compound 3)

The title compound was purchased from Cayman Chemicals Company, Ann Arbor, Michigan, USA.

Example 4: 17-Phenyl-18,19,20-trinor-PGE 2 isopropyl ester (Compound 4)

DBU (43.5 mg, 0.29 mmol) in acetonitrile (1 mL) was added dropwise to a stirred solution of compound 3 (22.1 mg, 0.057 mmol) in acetonitrile (3 mL) at 0 ° C. The mixture was allowed to warm to room temperature and then isopropyl iodide (78.0 mg, 0.46 mmol) in acetonitrile (2 mL) was added dropwise. After stirring for 12 hours (TLC monitoring), the reaction was quenched with water (8 mL), extracted with ethyl acetate (2 x 50 mL) and the extract was washed with brine (10 mL), citric acid 3% (10 mL) and finally 5% sodium bicarbonate (10 mL). After drying over anhydrous sodium sulfate, the solvent was removed in vacuo and the residual oil was chromatographed on silica gel using ethyl acetate as eluent. Thus, 230 mg (69%) of the title compound were obtained as a colorless oil: Rf = 0.516 (ethyl acetate: acetone: HOAc 1: 1: 0.02); ¹ H NMR (CDCl 3) d 0.89 (m, 3H), 1.3 (d, 6H), 2.6-2.8 (m, 2H), 4.1 (m, 2H), 5.0 (m, 1H), 5.3-5.7 (dm, 4H), 7.2 (m, 5H). ¹³ C NMR (CDCl 3) d 10.9, 13.9, 21.8, 22.9, 23.8, 24.49, 24.8, 25.17, 25.6, 26.68, 28.93 , 30.45, 31.77, 33.90, 34.01, 34.07, 38.8, 46.22, 533, 54.48, 66.83, 67.62, 68.18, 71.77 , 72.21, 76.35, 77.00, 77.2, 77.64, 125.93, 126.46, 128.39, 128.44, 128.79, 130.63, 130.81, 131 , 04.137.79, 213.88.

Example 5: 15RS-16,16-trimethylene-PGE ₂ (compound 5)

To a stirred solution of 15RS-16,16-trimethylene-PGE ₂ methyl ester (52 mg, 0.13 mmol) in acetone (0.4 mL) and phosphate buffer pH 7 (4 mL) was added lipase VII (40 mg). . The mixture was stirred at room temperature for 24 hours (TLC monitoring). The reaction was quenched with ethanol (3 mL) and extracted with ethyl acetate (2 x 10 mL). The organic layer was washed with brine, dried (sodium sulfate) and concentrated in vacuo to give 46 mg of the product as an oil.

Example 6: 15RS-16,16-trimethylene-PGE ₂ methyl ester (Compound 6)

The synthesis of 15RS-16,16-trimethyleneprostaglandin E2 (Skotnicki, S. et al. 1977) is schematically shown in Scheme 2. The numbers printed in bold text below refer to the corresponding structures in Scheme 2.

Ethyl 2,2-trimethylene hexanoate (9)

To a stirred solution of N-isopropylcyclohexylamine (56.2 g, 398 mmol) in THF (400 mL) at -78 ° C was added n-BuLi (159 mL, 398 mmol, 2.5 M in hexane) quickly. Ethylcyclobutanecarboxylate (8) (50 g, 390 mmol) was added dropwise to the obtained solution, and the mixture was stirred for 30 minutes, then warmed to 0 ° C and added dropwise to a solution of n-butyl iodide (159 mL, 398 mmol, 2.5). mol in hexane) in DMSO (200 mL). The reaction mixture was stirred at room temperature for 1 hour (TLC monitoring). The salt was collected by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in hexane and washed with 2% HCl, brine and water, then dried over sodium sulfate and evaporated in vacuo. The residual oil was distilled (49 - 56 ° C, 1 mm Hg) to give 26.5 g (37%) of the product.

¹ H NMR (CDCl ₃ ) d 0.9 (t, 3H), 1.2 (t, 3H), 1.8-2.0 (dm, 5H), 2.2-2.5 (m, 3H) 4.2 (m, 2H).

2.2- Trimethylenehexan-1-ol (10)

To a stirred solution of ethyl 2,2-trimethylene hexanoate (9) (26.5 g, 144 mmol) in dry toluene (100 mL) was added dropwise DIBAL-H (206 mL, 289 mmol, 1.4 mol in toluene) at Low: 14 ° C. The resulting solution was stirred at room temperature for 3 hours (TLC monitoring) and then poured into ice-cooled 5% HCl. The organic layer was separated and washed with 5% HCl, brine, dried, filtered and concentrated to give 30 g of the product as an oil. ¹ H NMR (CDCl 3) d 0.9 (t, 3H), 1.8-2.0 (dm, 5H), 2.5 (m, 1H), 3.0 (m, 1H), 3, Δ (m, 2H).

2.2- Trimethylene hexaldehyde (11)

To a solution of 2,2-trimethylenehexan-1-ol (10) (30 g, 210 mmol) in DME (400 mL) was added dicyclohexanecarbodiimide (DCC) (130 g, 630 mmol), DMSO (120 mL) and orthophosphoric acid ( 10.3 g). The mixture was stirred at room temperature for 3 hours (TLC monitoring) and filtered. The filtrate was diluted with dichloromethane (300 mL) and washed with water. The organic layer was separated. The residue was collected by filtration. The filtrate was washed with brine (100 mL), dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with hexane to give the title compound (17.3 g) as an oil. ¹ H NMR (CDCl ₃ ) d 0.9 (t, 3H), 1.2 (t, 3H), t, 8-2.0 (dm, 5H), 8.8 (s, 1H).

4,4-Trimethylene-1-octin-3-ol (12)

To a solution of lithium acetylide-ethylenediamine complex (12.2 g, 132 mmol) in DMSO (10 mL) was added a solution of 2,2-trimethylene hexaldehyde (11) (17 g, 120 mmol) in DMSO (20 mL) at 0 ° C under N2. The mixture was stirred at room temperature for 24 hours (TLC monitoring) and then poured into ice cold 2% HCl (50 mL) and ether (50 mL). The organic layer was separated and the aqueous layer was extracted with ether (50 mL), the combined organic phases were washed with brine, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5: 1 hexane: ethyl acetate to give 12 (7.6 g, 38%) as an oil.

E-Tributyltin-4,4-trimethylene-1-octen-3-ol (13)

A mixture of 4,4-trimethylene-1-octin-3-ol (12) (5.0 g, 30 mmol), tributyltin hydride (14.6 mL, 54.2 mmol) and AIBN (30 mg) was stirred at 130 ° C. ° C over 24 hours (TLC monitoring). The residue was chromatographed on silica gel eluting with hexane and hexane / ether 9: 1 to give the title compound (13) (12.54 g, 91.4%) as an oil.

E-T-Ributyltin-4,4-trimethylene-3-trimethylsilyloxy-1-octene (14)

To a mixture of E-tributyltin-4,4-trimethylene-1-octen-3-ol (13) (7 g, 15.3 mmol) in DMF (100 mL) was added imidazole (2.1 g, 30.6 mmol). ) and trimethylsilyl chloride (2.5 g, 23.0 mmol). The reaction mixture was stirred at room temperature for 1 hour (TLC monitoring). The mixture was partitioned between water (200 mL) and ether (200 mL). The organic phase was dried and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane to give compound 14 (5.53 g).

11,15-bis Trimethylsilyloxy-16,16-trimethylene-5,6-didehydro-PGE2 methyl ester (17)

To a dry 100 mL three-necked flask was added copper cyanide (928 mg, 10.4 mmol) and a magnetic stirrer. The flask was sealed with a rubber whisper and heated under vacuum to remove any trace of water and then cooled to 0 ° C under N 2. THF was added via syringe followed by methyl lithium (14 mL, 22.4 mmol, 1.6 molar in diethyl ether). The mixture was stirred at 0 ° C for 15 minutes, during which time the suspension became clear and homogenized. A solution of E-tributyltin-4,4-trimethylene-3-trimethylsilyloxy-1-octene (14) (5.9 g, 11.2 mmol) in THF (10 mL) was added via syringe at 0 ° C and the solution was stirred for 30 minutes at temperature rooms. A solution of 4- (t-butyldimethylsilyloxy) -cyclopentenone (15) (1.7 g, 8 mmol) in THF (6 mL), trimethylsilyl chloride (4.35 g, 40 mmol) and triethylamine (8, 1 g, 80 mmol) at -70 ° C and the mixture was stirred at -70 ° C for an additional 15 minutes and then 15 minutes at 0 ° C. The mixture was partitioned between hexane (600 mL) and water (300 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude silylenol ether as a clear oil. To a stirred solution of silylenol ether in THF (50 mL) under N ₂ at -30 ° C was added methyl lithium (7.7 mL, 123 mmol, 1.6 molar in diethyl ether) and the mixture was stirred for 30 minutes, followed by the addition of fresh of prepared methyl 1-triflate-2-hexinoate (16) (Erhardt, PW et al. 1987; Caldwell AG et al. 1979) and the solution was stirred at -40 ° C for 5 minutes. The resulting solution was neutralized with saturated aqueous ammonium chloride solution (30 mL) and extracted with ether (3 x 100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane / ethyl acetate (1: 1) to give a clear oil of a mixture of 15RS isomers (2.71 g, 57.3%) R _f = 0.36 (SiO ₂ , ether: hexane 1: 1). ¹ H NMR CDCl 3) d 0.2 (dm, 12H), 0.8-0.9 (ms, 18H), 1.8 (m, 2H), 2.3 (m, 4H), 3.7 ( s, 3H), 3.9-4.1 (dm, 2H), 5.5-5.6 (2H). ¹ H NMR was also performed on a desilylated analog, 16,16-trimethylene-5,6-didehydroPGE 2 methyl ester. ¹ H NMR (CDCl ₃ ) d 0.9 (t, 3H), 1.2-1.3 (m, 3H), 1.9-2.1 (m, 4H), 3.7 (s, 3H) 4.1 (m, 2H), 5.6-5.9 (dm, 2H).

11,15-bis Trimethylsilyloxy-16,16-trimethylene-PGE ₂ methyl ester

I I

I

To a stirred solution of 11,15-bis trimethylsilyloxy-16,16-trimethylene-5,6didehydro-PGE ₂ methyl ester (17) (500 mg, 0.8 mmol) in benzene and cyclohexane 1: 1 (50 mL) was added Pd- BaSO ₄ (250 mg) and quinoline (250 mg) and the mixture was stirred at -40 ° C under H ₂ atmosphere for 5 hours (TLC monitoring). The reaction mixture was diluted with ether, filtered through celite, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane / ethyl acetate 9: 1 to give 442 mg of the corresponding product.

16,16-Trimethylene-PGE2 methyl ester (6)

To a solution of 11,15-bis trimethylsilyloxy-16,16-trimethylene-PGE2 methyl ester (374 mg, 0.589 mmol) in THF (18 mL) was added 40% HF (3.5 mL) in THF (1 mL) at 0 ° C. The reaction mixture was stirred for 5 hours (TLC monitoring) and then poured into a mixture of 5% sodium bicarbonate (30 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer was washed with ethyl acetate (2 x 30 mL). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1: 1 hexane: ethyl acetate then ethyl acetate to afford 6 (75 mg, 31%) as an oil. ¹ H NMR (CDCl 3) d 0.9 (t, 3H), 1.3 (t, 6H), 2.0-2.6 (mm, 9H), (dm, 5H), 3.6 (s, 3H), 4.1 (m, 2H), 5.4 (m, 2H), 5.6-5.8 (dm, 2H); ¹³ C NMR (CDCl 3) d 14.222, 14.9, 23.7, 24.7, 25.2, 26.2, 26.5, 26.6, 26.8, 29.7, 33.4, 36 , 5, 44.9, 46.0, 51.6, 54.0, 54.6, 71.9, 76.7, 77.06, 77.1, 77.38,126.5, 126.9, 127.7, 130 , 9,132.5, 132.9, 133.36, 133.46, 174.15, 214.32.

Example 7: Synthesis of 13,14-dihydro-17- (3-fluorophenyl) -18,19,20-trinor PGE 2 isopropyl ester (Compound 7)

The synthesis of the title compound is shown schematically in Scheme 3. The numbers printed in bold refer to the corresponding structures in Scheme 3.

Dimethyl (2-oxo-4- (3-fluorophenylbutyl) phosphonate

To a stirred suspension of sodium hydride (4.17 g, 138 mmol) previously washed with n-pentane in dry THF (250 mL) at room temperature was added dropwise a solution of dimethyl 2-oxo-propylphosphonate (23.12 g, 132.3). mmol) in THF (110 mL). The reaction mixture was stirred for 2 hours then cooled in an ice bath and a solution of nBuLi (10.2 g, 158.7 mmol) in hexane was added to give a dark brown solution. Stirring was continued for 2 hours at 0 ° C, followed by dropwise addition of 3-fluorobenzyl bromide (25 g, 132.3 mmol) in THF (50 mL). The reaction mixture was gradually warmed to room temperature and after 3 hours (TLC monitoring) the reaction was quenched by addition of 10% HCl (20 mL). The mixture was poured into ice water (200 mL), extracted into CHCl 3 (2 x 150 mL), the organic layers were separated, washed with brine (150 mL), chromatographed on silica gel eluting successively with CH ₂ Cl ₂ and EtOAc to give

19.5 g of light yellow oil. R f = 0.37 (silica gel, EtOAc: 1: 1 acetone) (1S, 5R, 6R, 7R) -6-Formyl-7- (4-phenylbenzoyloxy-2-oxabicyclo [3.3.0] octan-3-one (19)

To a solution of alcohol 18 (19.0 g, 53.9 mmol) in DME (100 mL) cooled to 18 ° C was added dicyclohexylcarbodiimide (DCC) (33.3, 161.8 mmol), DMSO (38.2 mL). and phosphoric acid (1.43 mL, 21.28 mmol). The temperature of the reaction mixture was kept below 25 ° C for 30 minutes. The reaction mixture was stirred at room temperature for a further 2 hours (TLC monitoring) and the precipitate was collected by filtration and washed with ether (2 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (2 x 50 mL), the aqueous solution was extracted with ether (100 mL), the organic layers were separated and dried over sodium sulfate, filtered and used directly in the next step. TLC R f = 0.37 (silica, EtOAc: toluene 2: 1) (1S, 5R, 6R, 7R) -6- {3-Oxo-5- (3-fluorophenyl) -1-E-pentenyl} -7- (4-Phenylbenzoyloxy) -2-oxabicyclo [3.3.0] octan-3-one (20)

To a stirred suspension of NaH (1.9 g, 65.1 mmol) washed with n-pentane in DME (130 mL) under nitrogen was added dropwise dimethyl 2-oxo-4- (3-fluorophenyl) butyl phosphonate (Wadswort, Jr.). (WS et al. 1961) (19.3 g, 70.5 mmol) in DME (100 mL) and stirred vigorously for 1 hour at room temperature. The mixture was then cooled to 10 DEG C. and a solution of the crude aldehyde 19. After 30 minutes at 0 ^and C, and 2 hours at room temperature (TLC monitoring), the reaction mixture was neutralized with acetic acid, the solvent was removed in vacuo and the residue was dissolved in EtOAc (200 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was stirred with ether (100 mL), the resulting white precipitate was filtered off and washed with cold ether to give a white crystalline solid (17 g, 58.5%) Rf = 0.56 (silica gel, ethyl acetate: toluene 2: 1) (1S, 5R, 6R, 7R) -6- (3S-3-Hydroxy-5- (3-fluorophenyl) -1-pentenyl) -7- (4-phenylbenzoyloxy) -2-oxabicyclo [3.3.0] octane-3 -one (21)

To a stirred solution of enone 20 (17.1 g, 34.3 mmol) in THF (20 mL) and cerium chloride (CeCl 3 7H ₂ O) (3.8 g, 10.3 mmol) in a mixture of THF and ether 1 : 2 (60 mL) cooled to -20 ° C under nitrogen was added sodium borohydride (0.8 g, 20.57 mmol) in small portions. The reaction mixture was stirred for 2 hours (TLC monitoring). The temperature was raised to ± 0 ° C, then quenched by addition of water (20 mL) and 10% HCl aqueous solution to pH 4 and extracted with EtOAc (50 mL). The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and chromatographed twice on silica gel eluting with toluene / EtOAc successively 2: 1 and 1: 1 to give compound 4 (5 g) as a white crystalline product. with Rf = 0.32 (silica gel, EtOAc: toluene 2: 1).

(1S, 5R, 6R, 7R) -6- {3R-3-Hydroxy-5- (3-fluoro] phenyl) -1-pentyl} -7- (4-phenylbenzoyloxy) -2oxabicyk! O [3.3.0] octan-3-one (22)

To a suspension of 10% Pd / C (0.1 g) in sodium nitrite (3.6 mL, 1.8 mmol) and ethanol (15 mL) was added a solution of 21 (3 g, 6.0 mmol) in ethanol (6 mL). , 0 mL). The mixture was stirred under nitrogen for 6 hours (TLC monitoring) and quenched by the addition of 1M HCl solution. The catalyst was removed by filtration through a pad of Celite and washed with absolute ethanol (15 mL). The solvent was removed in vacuo. The obtained oil was dissolved in EtOAc (100 mL) and washed with 15% brine (30 mL). The aqueous phase was washed with EtOAc (40 mL). The combined organic extracts were dried over sodium sulfate and filtered. The solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with EtOAc to give compound 5 (2.94 g), R f = 0.25 (silica gel, EtOAc).

(1S, 5R, 6R, 7R) -6- {3R-3-Hydroxy-5- (3-fluorophenyl) -1-pentyl} -7-R-hydroxy-2-oxabicyclo [3.3.0] octan-3-one (23)

To a solution of lactone 22 (2.8 g, 5.65 mmol) in methanol (15 mL) was added potassium carbonate (0.47 g, 3.3 mmol) and the mixture was stirred at room temperature for 6 hours (TLC monitoring). The mixture was neutralized with 10% aqueous HCl and extracted and the ₍₄

EtOAc (2 x 30 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was chromatographed on silica gel eluting with EtOAc: acetone 1: 1. The title compound 23 was obtained as a white crystalline product in a yield of 1.6 g, R f = 0.17 (silica gel, EtOAc). ¹ H NMR (CDCl ₃ ) d 1.2-1.4 (m, 1H), 1.54 (m, 3H), 1.8 (m, 3H), 2.1 (m, 1H), 2, 2 (m, 1H), 2.3 (m, 1H), 2.6 (m, 2H), 2.67 (m, 1H), 2.8 (m, 2H), 3.60 (m, CH) _? CHOHCH _? ). 4.0 (m, CHOH) 4.92 (m, CHOC = O), 6.8-7.0 (m, 3H), 7.28 (m, 1H).

(1S, 5R, 6R, 7R) -6- {3R-3-tbutyldimetylsilyloxy-5-3-fluorophenyl) -1-pentyl} -7-R-tbutyldimetylsilyloxy-2-oxabicyclo [3.3.0] octan-3 -one (24) t-Butyldimethylsilyl chloride (2.3 g, 14.9 mmol) was added in one portion to a solution of diol 23, triethylamine (2.1 mL, 14.8 mmol) and 4-dimethylaminopyridine (0.06 g, 0). , 1 mmol) in dichloromethane (20 mL) with vigorous stirring at room temperature for 24 hours and the reaction mixture was concentrated in vacuo. The crude product was dissolved in ethyl acetate (50 mL), washed with water (20 mL) and 5% aqueous sodium bicarbonate (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane to give 3 g of the product as an oil. _Rf = 0.68 (silica gel, ether) (1S, 5R, 6R, 7R) -6- {3R-3-tbutyldimetylsilyloxy-5- (3-fluorophenyl) -1-pentyl} -7-R-tbutyldimetylsilyloxy -2-oxabicyclo [3.3.0] octan-3-ol (25)

A solution of diisobutylaluminium hydride (DIBAL) (1.1 g, 7.43 mmol) in dry toluene (5.3 m) was added dropwise to a stirred solution of lactone 24 (2.7 g, 4.95 mmol) in dry THF (30 mL). ml) at -72 / -80 ° C. After 1 hour (TLC monitoring), the reaction mixture was neutralized with methanol (5 mL), warmed to room temperature and water (50 mL), 10% aqueous HCl (50 mL) was added, and the mixture was extracted with EtOAc (2 x 50 mL). ). The organic layer was dried over sodium sulfate, filtered, the solvent removed in vacuo and the residue chromatographed on silica gel eluting with EtOAc and 1: 1 EtOAc / acetone to give the product as a yellow oil (2.7 g), Rf = 0, 85 (silica gel, ethyl acetate 1: 1).

13,14-Dihydro-11,15-di-t-butyldimethylsilyloxy-17- (3-fluorophenyl) -18,19,20-trinor-PGF _2a (26)

To a stirred suspension of 4-carboxybutyltriphenylphosphonium bromide (8.78 g, 19.82 mmol) in THF (50 mL) under nitrogen at 0-5 ° C was added potassium t-butoxide (3.89 g,

34.6 mmol). and the mixture was stirred at room temperature for 30 minutes. To the obtained red-orange solution of ylide at -15 / -10 ° C was added lactol 25 (2.7 g, 4.95 mmol) in THF (10 mL) and the mixture was stirred for 3-4 hours (TLC monitoring). The reaction mixture was diluted with water (30 mL) and washed with ether (4 x 40 mL). The aqueous layer was acidified to pH 4 with 5% aqueous citric acid and extracted with EtOAc (2 x 50 mL). The organic phase was washed with brine (30 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo and the suspension 26 was used without isolation in the next step.

13.14-Dihydro-11,15-di-t-butyldimethyl Isilyloxy-17- (3-fluorophenyl) -18,19,20-trinor-PGF _2e isopropyl ester (27)

DBU (5.28 g, 34.7 mmol) was added dropwise to a stirred solution of crude product 26 (3.16 g, 4.96 mmol) in acetone (20 mL) at 0 ° C. The mixture was allowed to warm to room temperature and then isopropyl iodide (5.05 g, 29.7 mmol) was added dropwise. After 4 h (TLC monitoring), the mixture was diluted with ethyl acetate (100 mL), washed with brine (30 mL), 3% citric acid (2 x 25 mL) and 5% sodium bicarbonate (2 x 25 mL) and dried over anhydrous sulfate. sulfate. The solvent was removed in vacuo and the residue was chromatographed on silica gel using a 1: 2 mixture of ether and petroleum ether as eluent. This gave a colorless oil in a yield of 1.7 g, Rf = 0.43 (silica gel, ether and petroleum ether 1: 2). ¹ H NMR (CDCl 3) d 0.1 (m, 9H), 0.9 (m, 16H), 1.2 (m, 9H), 1.6-1.8 (mm, 10H), 2.12 (m, 2H), 2.22 to 233 (m, 2H), 2.6-2.9 (dm, 2H), 3.65 (m, _CH CHOH 3.94 (m, CHpCHOH). 4. 16 (m, _CH? OH). 5.0 (sept, 1H), 5.38 (m, db), 5.47 (m, db), 6.8-7.0 (dm, Ar, 3H) 7.2 (m, Ar, 1 H).

13.14-Dihydro-11,15-di-t-butyldimethylsilyloxy-17- (3-fluorophenyl) -18,19,20-trinor-PGE ₂ isopropyl ether (28)

Pyridine dichloromethane (2.43 g, 11.25 mmol) on alumina (20 g) was added in small portions to a solution of 27 (1.7 g, 2.5 mmol) in dichloromethane (30 mL) and the mixture was stirred at at room temperature (TLC monitoring), filtered and the precipitate was washed with a 2: 1 mixture of ether and ethyl acetate. The solvent was removed in vacuo. The residue was diluted with ether (100 mL) and washed with water (30 mL), 5% aqueous NaHCO ₃ (3 x 20 mL), the organic phase was separated and dried over sodium sulfate and evaporated in vacuo to give compound 28 ( 1.3 g) as an oil. R f = 0.72 (silica gel, ethyl acetate).

13,14-Dihydro-17- (3-fluorophenyl) -18,19,20-trinone PGE ₂ isopropyl ester (7)% hydrogen fluoride (12 mL) was added to a solution of 28 (314 mg) in acetonitrile. The mixture was stirred at room temperature for 4 hours (TLC monitoring). The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (3 x 20 mL), dried and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate to give compound 7 (64 mg) as an oil, R _f = 0.43 (silica gel, ethyl acetate). ¹ H NMR (CDCl ₃ ) d 1.2 (d, 6H), 1.6-1.8 (m, 6H), 1.8 (m, 2H), 2.12 (m, 2H), 2.2- 2.3 (m, 2H), 2.6-2.8 (dm, 2H), 3.6 (m, CH2CHOHCH2). 4.16 (m, CH p CHOH). 5.0 (sept, 1H), 5.38 (m, db), 5.47 (m, db), 6.8-7.0 (dm; Ar, 3H), 7.2 (m, Ar, 1H).

pharmacology

Effect of decreasing intraocular pressure in cats and monkeys for test compounds

The compounds were tested for the effect of decreasing intraocular pressure in animal models. Intraocular pressure was measured with a calibrated pneumotonometer. European cats and cynomolgus monkeys were used as experimental animals. The cornea was anesthetized with oxibuprocaine before measurement. Reduction of intraocular pressures following local action of PGF _2β isopropyl ester (2), 17-phenyl-18,19,20-trinor-PGE ₂ isopropyl ester (4), 15RS-16,16-trimethylene methyl ester (6) and 13,14-dihydro-17 - (3-Fluorophenyl) -18,19,20-trinor-PGE ₂ -isopropyl ester (7) are shown in Tables IV and V.

Table IV. Intraocular pressure lowering effect for 1 - 10 µg test compounds with prostanoid EP1 receptor activity in cats. The control eye received vehicle only. (n = 5-6; mean ± standard error)

Prostaglandin / eye Initial pressure (mm Hg) Pressure 3 h after treatment (mm Hg) 2 Experimental eye 24.2 ± 2.3 15.1 ± 2.8 * Control eye 24.5 ± 2.7 22.5 ± 3.4 4 Experimental eye 22.0 ± 1.7 14.2 ± 1.7 * Control eye 21.5 ± 1.7 18.7 ± 1.9 6 Experimental eye 19.2 ± 1.7 9.5 ± 0.5 * Control eye 19.3 ± 1.7 17.0 ± 1.3 7 Experimental eye 20.4 ± -2.0 14.2 ± 0.9 * Control eye 20.6 ± -1.8 18.4 ± 1.5

* p <0.01 (paired t-test between eyes)

Table V. Intraocular pressure lowering effect for test compounds with effect on EPi receptor in monkeys. The dose of PGF2β-isopropyl ester was 30 µg, while the dose of 17-phenyl-18,19,20-trinor-PGE ₂ -isopropyl ester and 15RS-16,16-trimethylene-PGE ₂ isopropyl ester was 3 µg. The control eye received vehicle only. (n = 6; mean ± standard error)

Prostaglandin / eye Initial pressure (mm Hg) Pressure 4 h after treatment (mm Hg) 2 Experimental eye 17.8 ± 1.4 14.1 ± 1.8 * Control eye 16.9 ± 1.2 17.5 ± 2.0 4 Experimental eye 14.1 ± 1.1 9.9 ± 0.9 * Control eye 13.9 ± 1.0 11.5 ± 0.8 6 Experimental eye 20.9 ± 1.6 15.3 ± 2.4 * Control eye 21.3 ± 1.5 19.0 ± 1.5

* p <0.05 (paired t-test between eyes)

As can be seen, in both cats and monkeys, all prostaglandin analogues I, with preference for the EP 1 receptor, significantly reduced intraocular pressure.

Accordingly, the present invention discloses that compounds having a selective stimulatory effect on EP 1 receptors reduce intraocular pressure and that such compounds may have no melanogenic effect, or at least have a significantly reduced effect in the eye, since pigment producing cells do not have melanocytes in humans. ΕΡτ receptor. Thus, the common side effect of increased iris pigmentation can be avoided during chronic therapy * 1. with prostaglandins selective for ΕΡτ receptors.

Scheme 1

Scheme 2

OTMS

Reagents a - N-isopropylcyclohexylamine / THF, n-BuLi, ethylcyclobutanecarboxylate / DMSO b - DIBAL-H / toluene c - DCC / DME, DMSO, H ₃ PO ₄₁ . d - Lithium acetylide-ethylenediamine, DMSO e-tributyltin hydride, AIBN f - Trimethylsilyl chloride (TMSCI), imidazole / DMF g - Li ₂ CuCN (CH ₃ ) 2, TMSCI, triethylamine, 4-t-butyl-dimethylsilyloxy-2-cyclopentenone 1,1-Tributyltin-4,4, -trimethylene-3-trimethylsilyloxy-1-octene, methyl-2-yne-8-octanoate h - Pd-BaSO ₄₁ quinoline, i - HF / THF

Scheme 3

o o

OH

Reagents a - DCC, DMSO, H ₂ SO _4i DME, H 3 PO 4 b - NaH, dimethyl 2-oxo-4- (3-fluorophenyl) butylphosphonate c-NaBH ₄ , CeCl ₃ .7H ₂ O (THF d - Pd) C, NaNO ₂ / THF e - KaCO 3 / methanol f - TBDMS, TEA, 4-dimethylaminopyridine / dichloromethane g - DIBAL-H / THF h - 4-carboxybutyltriphenylphosphonium bromide, potassium t-butoxide, THF i-DBU, isopropyl iodide / acetone pyridinium chlorochromate, alumina / dichloromethane to - HF / acetonitrile

References

Bili, A. (1975). Blood circulation and fluid dynamics in the eye. Physiol. Rev. 55; 383-417.

Coleman, R. A., Smith, W. L. and Narumiya, S. (1994). VIII. International Union of Pharmacology classification of prostanoid receptors: Properties, distribution and structure of the receptors and their subtypes. Pharmacol. Rev. 46; 205-229.

Crawford, K. and Kaufman, P. (1987). Pilocarpine antagonizes PGF _2a -induced ocular hypotension in monkeys. Arch. Ophthalmol. 105; 1112-1116.

Ernhardt, P.W., Owens, A.H. (1987) Facile Formation of Quaternary Azetidinium Compounds During Triflation of Dialkylaminopropanols. . Synth.

I

Commun. 17, '469-475.

Caldwell, A., G. Harris, C.J., Stepny, R., Whittaker, N. (1979). Hydantoin Prostaglandin analogues, Potent and Selective Inhibitors of Plateiet Aggregation. Chem. Commun. 561st

Skotnicki, S., Schaub, E., and Weiss, J. (1977). Prostaglandins and congeners. Synthesis and Bronchodialator Activity of dl-16,16-trimethyleneprostaglandins. J. Med. Chem. 20.1042.

Hu, D-N. et al. (1993). Investigative Ophthalmology and Visual Science 34; 2210-2219.

Nilsson, SFE, Samuelsson, M., Bili, A., and Stjernschantz, J. (1989). Increased uveoscleral outflow as a possible mechanism of ocular hypotension caused by prostaglandin F2 _and isopropyl ester in the cynomolgus monkey. Exp. Eye Res. 48; 707-716.

Stjernschantz, J., Selen, G., Soyquist, B., and Resul, B. (1995). Preclinical pharmacology of latanoprost. Advances in Prostaglandin, Thromboxane and Leukotriene Research 23; 513-518.

Stjernschantz, J. and Alm, A. (1996). Latanoprost as a new horizon in medical management of glaucoma. Current Opinion in Ophthalmology 7; 2: 11-17.

Toris, C., Camras, CB, and Yablonski, ME (1993). Effects of PhXA4l, a new prostaglandin F2 _and analogue, on aqueous humor dynamics in human eyes. Ophthalmology 10; 1297-1304.

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Claims (12)

PATENT CLAIMS A composition for treating glaucoma and ocular hypertension, comprising a therapeutically active and physiologically acceptable amount of a prostaglandin analogue that is a selective agonist for EP 1 prostanoid receptors, or a pharmaceutically acceptable salt or ester thereof. The composition of claim 1, wherein the prostaglandin analog is derived from a prostaglandin type of PGF or PGE. The composition of claim 1 or 2, wherein the prostaglandin analog is a compound of the general formula: COOR where: the wavy lines represent the α or β configuration and the dashed bonds represent the single bond, triple bond, or double bond in the cis or trans configuration; R is hydrogen, saturated or unsaturated alkyl group, preferably a C _r Cio-alkyl, cycloalkyl, preferably C 3 -C ₈ cycloalkyl, aryl, arylalkyl, preferably aryl-C 2 -C ₅ -alkyl, or heteroaryl; R ¹ is a saturated or unsaturated alkyl group having 2 to 5 carbon atoms, • * ¹⁾ optionally interrupted by heteroatoms selected from oxygen, sulfur and nitrogen, cycloalkyl, preferably C ₃ -C ₇ cycloalkyl, cycloalkenyl, preferably C ₃ -C ₇ -cycloalkenyl, aryl or heteroaryl; X is C-OH or C = O; R ² is hydrogen, hydroxy, methyl, ethyl, methoxy or -OCOR ⁴ wherein R ⁴ is a linear or branched saturated or unsaturated alkyl group, preferably _R Clo C, in particular -C ₆ alkyl, or cycloalkyl, preferably C 3 -C ₈ -cycloalkyl, or aryl; R ³ is a linear or branched saturated or unsaturated alkyl chain preferably containing 3 to 8 carbon atoms, more preferably 3 to 5 carbon atoms, optionally interrupted by one or more heteroatoms selected from oxygen, sulfur and nitrogen, each carbon atom being optionally substituted a substituent selected from the following: C 1 -C 8 -alkyl, hydroxy and carbonyl, wherein the hydroxy and carbonyl are preferably attached to the carbon 15 of the prostaglandin structure, and wherein said alkyl optionally contains cycloalkyl, preferably C 3 -C ₈ -cycloalkyl, aryl or heteroaryl, which may be mono- or independently multiply substituted with C 1 -C 3 -alkyl, C 1 -C 3 alkoxy, hydroxyl, nitro, trifluoromethyl or halogen; or a pharmaceutically acceptable salt or ester thereof. The composition of claim 1, 2 or 3, wherein the prostaglandin analog is 15 (R, S) -16,16-trimethylene-PGE ₂ or an alkyl ester thereof. The composition of claim 1, 2 or 3, wherein the prostaglandin analog is 13,14-dihydro-17- (3-fluorophenyl) -18,19,20-trinorPGE ₂ or an alkyl ester thereof. 6. A method of treating glaucoma or ocular hypertension in an eye of a subject comprising contacting the eye surface with an intraocular pressure effectively reducing an amount of a therapeutically active and physiologically acceptable prostaglandin analogue that is a selective agonist for EPi prostanoid receptors, or a pharmaceutically acceptable salt thereof, or ester. I, J The method of claim 6, wherein the prostaglandin analog is derived from PGF or PGE-type prostaglandins. The method of claim 6 or 7, wherein the prostaglandin analog is a compound of the formula: R2 where: the wavy lines represent the α or β configuration and the dashed bonds represent the single bond, triple bond, or double bond in the cis or trans configuration; R is hydrogen, saturated or unsaturated alkyl group, preferably a Ci-Ci ₀ alkyl, cycloalkyl, preferably C 3 -C 8 -cycloalkyl, aryl, arylalkyl, preferably aryl-C 2 -C ₅ -alkyl, or heteroaryl; R ¹ is a saturated or unsaturated alkyl group of 2 to 5 carbon atoms, optionally interrupted by heteroatoms selected from oxygen, sulfur and nitrogen, cycloalkyl, preferably C 3 -C ₇ -cycloalkyl, cycloalkenyl, preferably C 3 -C 7 cycloalkenyl, aryl or heteroaryl; X is C-OH or C = O; R ² is hydrogen, hydroxy, methyl, ethyl, methoxy or OCOR ⁴ , wherein R ⁴ is a linear or branched saturated or unsaturated alkyl chain, preferably C 1 -C 10 alkyl, especially C 1 -C ₆ -alkyl, or cycloalkyl, preferably C ₃ -C ₈ -cycloalkyl, or aryl; R ³ is a linear or branched saturated or unsaturated alkyl chain preferably containing 3 to 8 carbon atoms, more preferably 3 to 5 carbon atoms, optionally interrupted by one or more heteroatoms selected from oxygen, sulfur and nitrogen, each carbon atom being optionally substituted a substituent selected from the following: C ₁ -C ₅ -alkyl, hydroxy and carbonyl, wherein the hydroxy and carbonyl are preferably attached to the carbon 15 of the prostaglandin structure, and wherein said alkyl optionally contains cycloalkyl, preferably C 3 -C ₈ -cycloalkyl, aryl or heteroaryl which they may be mono- or independently multiply substituted with C ₁ -C ₃ -alkyl, C 1 -C 3 alkoxy, hydroxyl, nitro, trifluoromethyl or halogen; or a pharmaceutically acceptable salt or ester thereof. The composition of claim 6, 7 or 8, wherein the prostaglandin analog is 15 (R, S) -16,16-trimethylene-PGE ₂ or an alkyl ester thereof. The composition of claim 6, 7 or 8, wherein the prostaglandin analog is 13,14-dihydro-17- (3-fluorophenyl) -18,19,20-trinorPGE ₂ or an alkyl ester thereof. The method of any one of claims 6 to 10, wherein the therapeutically active and physiologically acceptable composition comprising said prostaglandin analogue is administered topically to the eye 1 to 3 times daily. Use of a prostaglandin analogue which is a selective agonist for EP 1 prostanoid receptors as defined in any one of claims 1 to 4 for the preparation of a medicament for the treatment of glaucoma and ocular hypertension.