KR20010021682A - Prostaglandin derivatives devoid of side-effects for the treatment 0f glaucoma - Google Patents

Abstract

New methods and compositions are described for treating glaucoma and hypertension. The method of the present invention is based on the use of EP ₁ prostanoid receptor agonists which effectively reduce intraocular pressure but have no pigmentation or have the effect of reducing pigmentation. Prostaglandin analogs that are EP ₁ selective agonists apply topically to the eye.

Description

PROSTAGLANDIN DERIVATIVES DEVOID OF SIDE-EFFECTS FOR THE TREATMENT 0F GLAUCOMA}

Glaucoma is a visual disorder characterized by elevated intraocular pressure, depression of the optic nerve papilla, and progressive loss of vision. Abnormally high intraocular pressure is generally known to be harmful to the eyes, and in glaucoma it is an obvious indication that intraocular pressure is the most important factor causing degenerative changes in the retina and optic nerve papilla. However, the exact pathophysiological mechanism of open angle glaucoma is not yet known. If you do not treat glaucoma, blindness, or gradual loss of vision, may lead to a slow, typical disease process.

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

IOP = Pe + (Ft-Fu) × R

Where Pe is the episcleral venous pressure, Ft is the formation of aqueous humor, Fu is the portion of the aqueous fluid that flows out of the eye through the uveoscleral outflow pathway, and R Is resistance in the trabecular outflow pathway. In the anterior and posterior chambers of the eye, the intraocular water is produced by ciliary processes behind the iris. The intraocular fluid travels forward through the pupil and flows out of the eye through the trabecular meshwork and Schlemm's canal into the epithelial vein outside the eye. However, some of the water may be released from the eye through the uveal outflow route. Flow in this path is considered to be minimally affected by intraocular pressure (Bill, 1975).

Human intraocular pressure normally ranges from 12-22 mmHg. For example, at high pressures above 22 mmHg, there is an increased risk of eye damage. However, in normal tension glaucoma, one of the specific types of glaucoma, eye damage can occur even at intraocular pressure levels within the normal physiological range. It is known that in the opposite situation, in some individuals, abnormally high intraocular pressure may be present without obvious defects in visual field or optic nerve papilla. Such conditions are usually referred to as hypertension.

Glaucoma treatment can be done by medication, laser or surgery. The purpose of the drug treatment is to reduce the formation (Ft) of the water or resistance (R) to the outflow of the water and to reduce the intraocular pressure according to Equation 1 above; Alternatively, increased intraocular fluid outflow through the uveoscleral pathway decreases intraocular pressure following Equation I.

Prostaglandins and typically PGF _2α , esters and analogs thereof, mainly reduce the intraocular pressure by increasing the uveal outflow of the aqueous gland (Crawford and Kaufman, 1987; Nielsson et al., 1989; Toris et al., 1993; Stjernschantz et al., 1995). The use of prostaglandins and derivatives thereof has been described in several patents and patent applications, for example US Pat. No. 4,599,353 (Bito), US Pat. No. 4,952,581 (Bito), International Publication No. 89/03384 (Result) (Resul and Stjernschantz), European Patent No. 170258 (Cooper), European Patent No. 253094 (Goh), and European Patent No. 308135 (Ueno) It is.

Prostaglandins are fatty acids derived primarily from the precursors eicosatoenoic acid, eicosatetraenoic acid and eicosapentaenoic acid through metabolic steps involving oxidation. Natural prostaglandins typically have the general structure shown below.

Thus, prostaglandins have cyclopentane rings in two carbon chain rings, the upper chain is mainly called alpha chain, and the lower chain is mainly called omega chain. Prostaglandins such as the following general formulas are classified into subgroups A, B, C, D, E, F, H, I, and J according to the structure and substituents of the cyclopentane ring.

The alpha chain is the 7 carbon carboxy-terminated aliphatic chain, while the omega chain is the 8 carbon methyl-terminated aliphatic chain. Subscripts 1 to 3 are given according to the number of double bonds in these chains. Prostaglandins with 1 in the subscript, for example PGF _1α, have a double bond between carbon 13 and carbon 14 of the omega chain, indicating a trans configuration in natural prostaglandins. Prostaglandins with subscript 2, for example PGF _2α, have additional double bonds in the cis configuration between carbon 5 and 6 of the alpha chain, and finally, prostaglandins with subscript 3 have a third double bond Between carbon 17 and carbon 18 of the chain. Also in natural prostaglandins, this double bond represents the cis configuration. Natural prostaglandins all have hydroxy groups essential for bioactivity at carbon 15.

Receptor systems for natural prostaglandins have been discovered very recently. Thus most prostaglandin receptors are pharmacologically characterized and their molecular structures have been confirmed by molecular biotechnology (Coleman et al., 1994). Natural prostaglandins have specific receptors. Receptors of PGD, PGE, PGF, PGI ₂ (prostacycline) and TxA ₂ (thromoxane) are written with the abbreviations DP, EP, FP, IP, and TP, respectively. In addition, EP receptors can be classified into four receptors, namely EP ₁ , EP ₂ , EP ₃ and EP ₄ receptors. Depending on the evolutionary development of these autacoid systems in other species, specific tissues or cells may represent few or many of these receptors. For example, the cat's iris sphincter has a pronounced FP receptor and functionally binds to the pupil to mediate the contraction of the pupil, whereas the smooth muscle of the bovine eye exhibits the EP ₁ and TP receptors and activation of one of them is the contraction of the smooth muscle. It has been known to cause. Compounds that bind to and activate specific receptors are called agonists, whereas compounds that only bind without activating receptors are called antagonists.

Regarding whether many prostaglandins and their derivatives are substantially useful as drugs suitable for treating glaucoma or hypertension, the limiting factor may be the property of increasing pigmentation of the eye iris (Stjernschantz and Alm). , 1996). Thus, during long-term treatment of monkeys and humans, the color of the iris tends to become darker and turn brown. Obviously this is not a negative medical result, but it is obviously disadvantageous for the cosmetic aspect, especially for patients receiving only one eye. Therefore, it is desirable to identify prostaglandins that are effective in reducing intraocular pressure without causing side effects that increase pigmentation of the iris.

It is surprisingly found herein that prostaglandin derivatives and analogs, which are selective agonists for the EP ₁ subgroup of prostanoid receptors, meet the criteria of prostaglandin analogs that effectively reduce intraocular pressure without increasing pigment production (melanin formation) in the iris. lost. Background of the Invention In a study for identifying subtypes of prostanoid receptors in melanocytes of human iris, it was found that FP, EP ₂ , and EP ₃ receptors appeared in melanocytes, not EP ₁ and TP receptors. It became. Furthermore, studies herein have shown that some of the relatively selective EP ₁ agonists have the effect of reducing intraocular pressure, and found that such prostaglandin analogs effectively and potently reduce intraocular pressure in both cats and monkeys.

Therefore, it is clear that selective EP ₁ receptor agonists can be used to reduce intraocular pressure in primates and also in humans without significantly reducing or increasing melanin formation as a side effect, because the cells producing melanin, ie melanin. This is because the cells lack the specific receptors needed to signal the cells across the membrane. Since the induction time that causes pigmentation in the iris is often 6-12 months, very long and expensive experiments have to be carried out in primates, so we are currently clinically suggesting that such selective EP ₁ agonists do not increase pigmentation in the iris. While there is no evidence, it can nevertheless be concluded from the relevant in vitro studies that such an increase in pigmentation does not occur without a receptor that specifically signals the cell membrane of melanocytes.

Thus, the compounds used in the methods or compositions according to the invention are characterized by high selectivity or specificity for the EP ₁ receptor, comparable to other prostaglandin receptors in the eye. The more selective the compound is for the EP ₁ receptor, the better the result is obtained, but needless to say that there is also some benefit when interacting with other receptors. High selectivity in this regard means that the effect on the EP ₁ receptor is at least 5 times, in particular 10 times or more, and the effect on other prostaglandin receptors is 100 or 1000 times or more.

The present invention relates to a method for treating glaucoma and ocular hypertension using prostaglandin analogues or derivatives which have no melanin forming effects in the eye or which reduce melanin formation. The present invention also relates to an ophthalmic composition comprising a prostaglandin compound having no melanin forming effect in the eye or reducing melanin formation.

Specific prostaglandin analogs used to illustrate and demonstrate the invention include 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 such analogs are relatively selective EP ₁ receptor agonists. Receptor profiles of the test compounds are shown in Table I.

Receptor profile of the tested prostaglandin analogs (EC-50 values in mole / l in functional receptor assays) Prostaglandins FP EP ₁ EP ₂ EP ₃ DP / IP TP One 5 × 10 ^-6 10 ^-6 10 ^-5 〉 10 ^-4 〉 10 ^-3 〉 10 ^-3 3 10 ^-7 2 × 10 ^-8 〉 10 ^-4 〉 10 ^-4 〉 10 ^-4 〉 10 ^-4 2 × 10 ^-5 6 × 10 ^-9 2 × 10 ^-7 3 × 10 ^-8 # 〉 10 ^-4 〉 10 ^-4 7 6 × 10 ^-7 4 × 10 ^-8 5 × 10 ^-5 10 ^-6 # 〉 10 ^-4 〉 10 ^-4 Estimation Based on Differences in Receptor Analysis in the Guinea Pigs Tube

In one aspect, the present invention relates to the use of a selective prostaglandin EP ₁ receptor agonist with no melanin forming effect for treating glaucoma or hypertension. Methods of treating glaucoma or hypertension include contacting the eye surface with an amount of an effectively reducing intraocular pressure comprising EP ₁ selective prostaglandin as described above, which reduces the intraocular pressure and reduces the intraocular pressure to a reduced level. Is to maintain. The composition usually contains about 0.1-100 μg, in particular 1-30 μg, of the active substance each time it is applied. The composition is applied topically to the eyes 1-3 times daily.

Prostaglandin derivatives are mixed with known ophthalmologically compatible excipients. Excipients that may be used in the preparation of the compositions of the present invention include, for example, aqueous solutions such as physiological saline, emulsions, or ointments. In addition, excipients are ophthalmologically compatible, for example preservatives such as benzalkonium chloride, surfactants such as polysorbate 80, liposomes or polymers such as methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone and hyaluronic acid It may include; These may be used to increase the viscosity. In addition, it is also possible to use soluble or insoluble drug inserts.

In another aspect, the present invention provides an ophthalmology for the medical treatment of glaucoma or hypertension comprising a prostaglandin analog and an ophthalmologically compatible carrier which is an effective agonist of the EP ₁ receptor as defined above in an amount that effectively reduces intraocular pressure. It relates to a composition. Effective amounts usually comprise about 0.1-100 μg of the composition in about 10-50 μl. The compositions according to the invention are clearly improved compositions over existing prostaglandin compositions because they exhibit the selectivity of the active compound for the EP ₁ receptor comparable to other prostaglandin receptors, while eliminating or at least sufficiently reducing the risk of pigmentation.

In another aspect, the present invention relates to the use of prostaglandin analogs for the manufacture of a medicament for treating glaucoma and hypertension.

Preferably, the prostaglandin analog is derived from PGF or PGE type prostaglandin. In particular, the prostaglandin analog is a compound of Formula 1 or a pharmaceutically acceptable salt or ester thereof:

Where:

Dashed bonds represent α or β arrays, dotted bonds represent single bonds, triple bonds or double bonds in cis or trans arrangements,

R is hydrogen, saturated or unsaturated alkyl, preferably C _1-10 alkyl, cycloalkyl, preferably C _3-8 cycloalkyl, aryl, arylalkyl, preferably aryl-C _2-5 alkyl, or heteroaryl ego,

R 1 is a C _2-5 saturated or unsaturated alkyl group, optionally interrupted by a heteroatom selected from oxygen, sulfur, and nitrogen, or is cycloalkyl, preferably C _3-7 cycloalkyl, cycloalkenyl, preferably C _3-7 cycloalkenyl, aryl or heteroaryl,

X is C-OH or C = O,

R2 is hydrogen, hydroxy, methyl, ethyl, methoxy or OCOR4, where R4 is a straight or branched chain saturated or unsaturated alkyl group, preferably C _1-10 alkyl, in particular C _1-6 alkyl, or cycloalkyl, preferably Is a C _3-8 cycloalkyl, or aryl group,

R 3 is a straight or branched chain saturated or unsaturated alkyl group, preferably C _3-8 , in particular C _3-5 alkyl group, optionally interrupted by one species of heteroatom selected from oxygen, sulfur and nitrogen, each carbon atom Is optionally substituted with a substituent selected from C _1-5 alkyl, hydroxy and carbonyl groups, wherein carbon 15 of the prostaglandin structure is preferentially bonded to hydroxy and carbonyl, said alkyl group being cycloalkyl, preferably Optionally comprises a C _3-8 cycloalkyl, aryl or heteroaryl group, which may be one or independently complex substituted with C _1-3 alkyl, C _1-3 alkoxy, hydroxy, nitro, trifluoromethyl or halogen It may be.

Aryl is preferably substituted or unsubstituted phenyl.

Preferred heteroaryl groups are thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine.

Aryl, heteroaryl and cycloalkyl may be one or independently two or complex substituted by C _1-3 alkyl, C _1-3 alkoxy, hydroxy, nitro, trifluoromethyl or halogen.

Unsaturated alkyl may include one or more double and / or triple bonds.

Halogen is fluorine, chlorine, bromine or iodine, in particular fluorine, chlorine or bromine.

Prostaglandins may be epimer mixtures as well as individual epimer forms.

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

Identification of Prostaglandin Receptors

Prostaglandin receptors were identified using reversed transcriptase polymerase chain reaction (RT-PCR) technology. Specific primers were designed for FP, EP ₁ , EP ₂ , EP ₃ , and TP receptors. Primers used for analysis are shown in Table II below. RT-PCR was performed on the medium for mRNA isolated from melanocytes of human iris. Cultured cells were used for the preparation of mRNA. RT-PCR mixtures were analyzed on agarose gels and cloned and sequenced bands of expected size. The deduced sequence was analyzed to be similar to each prostaglandin receptor sequence.

Way

Melanocytes of human iris were isolated and cultured according to Hu et al. (1993) and used for initial passage. Cells were grown by confluence and enriched for mRNA.

mRNA was isolated using a Dynals mRNA Direct System (Dynal A / S, Norway) according to the manufacturer's instructions. 100,000-200,000 human melanocytes were used in abundance. mRNA was covalently bound to oligo-dT. labeled Dynabead. Reverse transcriptase was used to synthesize the first helix cDNA directly from dinavid labeled as oligo-diti as a reverse transcriptase primer. A second helix cDNA was synthesized using known 3 ′ sequence primers from each prostaglandin receptor to produce a double helix cDNA. The same set of denavides was used for each receptor RT-PCR. Receptor specific primers were used for PCR to amplify DNA from dinavid bound cDNA according to the manufacturer's instructions. PCR in FP and EP ₃ receptor reactions was performed in 50 μl final volume with each primer of 5% DMSO, 200 μM dNTPs and 20 pmoles. For other receptors, vigorous initiation with AmpliWax pellets (Perkin Elmer, USA) was used at 75 μl final volume with each primer of 5% DMSO, 200 μM dNTPs and 20 pmoles.

PCR mixtures of each reaction were analyzed on 1% LMP agarose gels (BioRad Laboratories, USA). DNA fragments of expected size were tee-cloned using a TA-cloning kit (Invitrogen Inc., USA) according to the manufacturer's instructions and their tag dioxy terminator cycles. The Tag Dye Dioxy Terminator cycle sequencing kit was sequenced in an Applied Biosystem Model 373A DNA sequence system according to the Applied Biosystems' protocol. The first data produced was processed on a VAX computer using a sequence analysis program from Madison Genetics Computer Group Inc., USA (Devereux j. Et al. Nucleic Acids Research 12 (1): 387-395 (1984)].

result

In melanocytes of human iris based on RT-PCR of the present application, we could see expression of FP, EP ₂ and EP ₃ receptors. However, the application did not see the presence of the EP ₁ and TP receptors (Table III). As a positive control, the EP ₁ and TP fragments expected from the cDNA aggregates of human kidney were amplified with the same primers. Poly A mRNA was enriched from melanocytes of human irises separated at two different times and subjected to PCR reactions several times to obtain the same result.

RT-PCR (secondary PCR primers) of melanocyte mRNA of human iris using prostaglandin receptor specific primers (see Table II). gene Corrected Fragment Size (bp) Sequence analysis observe prediction FP + 489 Same as FP EP ₁ - 397 - EP ₂ + 501 Same as EP ₂ EP ₃ + 372 Same as EP ₃ TP - 484 -

Synthesis of Prostaglandin Derivatives

The structure of the final compound prepared in the examples is shown in Scheme I, provided at the end of this specification.

Example 1 PGF _2β (Compound 1)

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

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 isopropyl iodide (222.6 mg, 1.34 mmol) was added dropwise. After 48 hours (TLC confirmed), the mixture was diluted with ethyl acetate (40 mL), and brine (30 mL), 3% citric acid (twice with 40 mL) and 5% sodium hydrogencarbonate (twice with 30 mL). Washed and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was chromatographed on silica gel using ethyl acetate: acetone 3: 1 as eluent. A colorless oil was obtained and the yield was 46 mg (68%).

Example 3: 17-phenyl-18,19,20-trinor-PGE ₂ (Compound 3)

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

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 isopropyl iodide (78.0 mg, 0.46 mmol) in acetonitrile (2 mL) was added dropwise. After stirring for 12 hours (TLC checked), the reaction mixture was quenched with water (8 mL), the mixture was extracted with ethyl acetate (twice with 50 mL) and the extract was brine (10 mL), 3% citric acid (10 mL). ) And finally with 5% sodium bicarbonate (10 mL). After drying over anhydrous sodium sulfate, the solvent was removed in vacuo and the residue oil was chromatographed on silica gel using ethyl acetate as eluent. 230 mg (69%) product of the title compound was obtained as a colorless oil: R _f = 0.516 (ethyl acetate: acetone: HOAc 1: 1: 0.02);

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

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

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

Scheme 2 schematically depicts 15RS-16,16-trimethyleneprostaglandin E ₂ synthesis (Skotnicki, S. et al., 1977). The following bold numbers indicate the structure of Scheme 2, respectively.

Ethyl 2,2-trimethylenehexanoate (9)

To a stirred solution of N-isopropylcyclohexylamine (56.2 mg, 398 mmol) in THF (400 mL) was quickly added n-BuLi (398 mmol, 159 mL in 2.5M n-BuLi in hexane) at -78 ° C. Ethyl cyclobutanecarboxylate (8) (50 g, 390 mmol) was added dropwise to the resulting solution, stirred for 30 minutes, then warmed to 0 ° C. and n-butyl iodine solution (2.5 mol in hexane) in DMSO (200 mL) n-BuI 398 mmol, 159 ml) was added dropwise. The reaction mixture was stirred at rt for 1 h (TLC check). The salt was removed 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 oil residue was distilled off (49-56 ° C., 1 mm Hg) to give 26.5 g (37%) of the product.

2,2-trimethylenehexan-1-ol (10)

To a stirred solution (26.5 g, 144 mmol) of ethyl 2,2-trimethylenehexanoate (9) in dry toluene (100 mL) was added DIBAL-H (1.4 mol DIBAL-H 289 mmol, 206 mL in toluene) at 0 ° C. I dropped it. The resulting solution was stirred for 3 h at room temperature (TLC checked) and poured into 5% HCl iced. The organic layer was separated and washed with 5% HCl, brine, dried, filtered and concentrated to give 30 g of product of oil.

2,2-trimethylenehexaaldehyde (11)

To a 2,2-trimethylenehexan-1-ol (10) stirred solution (30 g, 210 mmol) in DME (400 mL) dicyclohexanecarbodiimide (DCC) (130 g, 630 mmol), DMSO (120 mL) and ortho Phosphoric acid (10.3 g) was added. The mixture was stirred for 3 h at room temperature (TLC checked) and filtered. The filtrate was diluted with dichloromethane (300 mL) and washed with water. The organic layer was separated. The residue was removed by filtration. The filtrate was washed with brine (100 mL), dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel using hexane as eluent to give the title product (17.3 g) as an oil.

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

A solution of a lithium acetylide-ethylenediamine complex (12.2 g, 132 mmol) in DMSO (10 mL) at 0 ° C. under nitrogen at 2 ° C., 120 mmol) in 2,2-trimethylenehexaaldehyde (11) solution in DMSO (20 mL). Was added. The mixture was stirred for 24 h at room temperature (TLC checked) and 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 layers washed with brine, dried, filtered and concentrated in vacuo. The residue was chromatographed on silica gel using hexane: ethyl acetate 5: 1 as the eluent, to obtain 12 (7.6 g, 38%) of 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. for 24 hours. Was stirred (TLC confirmed). The residue was chromatographed on silica gel using hexane and hexane: ether 9: 1 as eluents, respectively, to give the title compound (13) (12.54 g, 91.4%) as an oil.

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

Imidazole (2.1 g, 30.6 mmol) and trimethyl chloride in a mixture (7 g, 15.3 mmol) of E-tributyltin-4,4-trimethylene-1-octen-3-ol (13) in DMF (100 mL) Silane (2.5 g, 23.0 mmol) was added. The reaction mixture was stirred at rt for 1 h (TLC check). 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 using hexane as the eluent to obtain 14 (5.53 g).

11,15-bistrimethylsilyloxy-16,16-trimethylene-5,6-didehydro-PGE ₂ methyl ester (17)

Copper (I) cyanide (928 mg, 10.4 mmol) and a magnetic rod are placed in a dried 100 ml three-neck flask. The flask was capped with a rubber septum and heated under vacuum to remove the remaining water and cooled to 0 ° C. under nitrogen. Dry THF was added and methyl lithium (22.4 mmol, 1.6 mol methyl lithium in diethyl ether, 14 mL) was added via syringe. The suspension became clear and homogeneous while the mixture was stirred at 0 ° C. for 15 minutes. A solution of E-tributyltin-4,4-trimethylene-3-trimethylsilyloxy-1-octene (14) in THF (10 mL) (5.9 g, 11.2 mmol) was added via syringe at 0 ° C. and room temperature Stirred for 30 minutes. To the resulting solution was added successively THF (6 mL), trimethylsilane chloride (4.35 g, 40 mmol) and triethylamine (8.1 g, 80 mmol) at -70 ° C, stirred at -70 ° C for 15 minutes again, Stirred at 0 ° C. for 15 minutes. 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 afford crude silyl enol ether of clean oil. Methyl lithium (1.6 mol methyl lithium 12.3 mmol in diethyl ether, 7.7 mL) was added to a stirred solution of silyl enol ether in THF (50 mL) under nitrogen at -30 ° C, stirred for 30 minutes, and then just prepared One methyl-1-triplate-2-hexinoate (16) (Erhardt, PW, et al., 1987; Caldwell AG et al., 1979) And stirred at −40 ° C. for 5 minutes. The resulting solution was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ether (3 times 100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel using hexane: ethyl acetate (1: 1) as eluent to give 15RS isomer mixture of clear oil (2.71 g, 57.3%). R _f = 0.36 (SiO ₂ , ether: hexane 1: 1)

¹ H NMR was performed on the decylated analog 16,16-trimethylene-5,6-didehydro-PGE ₂ methyl ester.

11,15-bistrimethylsilyloxy-16,16-trimethylene-PGE ₂ methyl ester

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

16,16-trimethylene-PGE ₂ methyl ester (6)

To 11,15-bistrimethylsilyloxy-16,16-trimethylene-PGE ₂ methyl ester solution (374 mg, 0.589 mmol) in THF (18 mL) at 40 ° C. HF 40% (3.5 mL) in THF (1 mL) ) Was added. The reaction mixture was stirred for 5 hours (TLC checked) and 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 (twice with 30 mL). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel using hexanes: ethyl acetate 1: 1, and ethyl acetate successively to give 6 (75 mg, 31%) of oil.

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. Bold numbers indicate each structure of Scheme 3.

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

A solution of dimethyl-2-oxo-propylphosphonate (23.12 g, 132.3) in THF (110 mL) at room temperature in a stirred suspension of sodium hydride (4.17 g, 138 mmol) prewashed with n-pentane in dry THF (250 mL). mmol) was added dropwise. The reaction mixture was stirred for 2 hours, cooled in an ice bath and treated with n-BuLi solution (10.2 g, 158.7 mmol) in hexane to form a dark brown solution. Stirring was continued for 2 hours at 0 ° C., and then brominated 3-fluorobenzene (25 g, 132.3 mmol) in THF (50 mL) was added dropwise. The reaction mixture was slowly warmed to rt and after 3 h (TLC checked), quenched with 10% HCl (20 mL). The mixture was poured into ice water (200 mL), extracted with CHCl ₃ (twice with 150 mL), the organic layer was collected, washed with brine (150 mL), and the eluent was continuously used with CH ₂ Cl ₂ and EtOAc. Chromatography on silica gel gave 19.5 g of a fine yellow oil. R _f = 0.37 (silica gel, EtOAc: acetone 1: 1)

(1S, 5R, 6R, 7R) -6-formyl-7- (4-phenyl benzoyloxy) -2-oxabicyclo [3.3.0] octan-3-one 19

An alcohol 18 solution (19.0 g, 53.9 mmol) in DME (100 mL) was cooled to 18 ° C., dicyclohexylcarbodiimide (DCC) (33.3 g, 161.8 mmol), DMSO (38.2 mL) and phosphoric acid (1.43 mL , 21.28 mmol) was added. The temperature of the reaction mixture was kept below 25 ° C. for 30 minutes. The reaction mixture was again stirred for 2 h at room temperature (TLC checked), the precipitate was filtered off and washed with ether (twice with 50 mL). The combined organic layers were washed with water (50 mL) and brine (twice with 50 mL), the aqueous solution was extracted with ether (100 mL), the combined organic layers were dried over sodium sulfate, filtered and used directly in the next step. TLC R _f = 0.37 (silica gel, EtOAc: toluene 2: 1).

(1S, 5R, 6R, 7R) -6- {3-oxo-5- (3-fluorophenyl) -1-E-pentenyl} -7- (4-phenyl benzoyloxy) -2-oxabicyclo [3.3.0] octane-3-one (20)

To a stirred suspension of NaH (1.9 g, 65.1 mmol) prewashed with n-pentane in DME (130 mL) under dimethyl 2-oxo-4- (3-fluorophenyl) butylforce in DME (100 mL) Phonates (Wardsworth, Jr., Ws., Et al., 1961) (19.3 g, 70.5 mmol) were added dropwise and stirred vigorously at room temperature for 1 hour. The mixture was cooled to -10 ° C and the crude aldehyde 19 solution was added dropwise. After 30 minutes at 0 ° C. and 2 hours at room temperature (TLC checked), the reaction mixture was neutralized with acetic acid, the solvent was removed in vacuo and the residue dissolved in EtOAc (200 mL), 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) and the resulting white precipitate was filtered and washed with cold ether to give white crystals (17 g, 58.5%). R _f = 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-oxabi Cyclo [3.3.0] octan-3-one (21)

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

(1S, 5R, 6R, 7R) -6- {3R-3-hydroxy-5- (3-fluorophenyl) -1-pentyl} -7- (4-phenylbenzoyloxy) -2-oxabicyclo [3.3.0] octan-3-ones (22)

To 21 solutions (3 g, 6.0 mmol) in ethanol (6.0 mL) was added sodium nitrite (3.6 mL, 1.8 mmol) and a 10% Pd / C suspension (0.1 g) in ethanol (15 mL). The mixture was stirred for 6 h under hydrogen atmosphere (TLC check) and quenched with 1M HCl solution. The catalyst was filtered off through a pad of celite and washed with anhydrous ethanol (15 mL). The solvent was removed in vacuo. The resulting oil was dissolved in EtOAc (100 mL) and washed with 15% brine (30 mL). The aqueous layer was washed with EtOAc (40 mL). The extracted organic layers were combined, dried over sodium sulfate and filtered. The solvent was removed in vacuo. The residue was chromatographed on silica gel using EtOAc as eluent to give 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. Octane-3-one (23)

Potassium carbonate (0.47 g, 3.3 mmol) was added to a lactone 22 solution (2.8 g, 5.65 mmol) in methanol (15 mL), and the mixture was stirred at room temperature for 6 hours (TLC check). The mixture was neutralized with 10% aqueous HCl solution and extracted with EtOAc (2 × 30 mL). The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was chromatographed on silica gel using EtOAc: acetone 1: 1 as eluent. The title compound 23 was obtained as white crystal product; Yield 1.6 g, R _f = 0.17 (silica gel, EtOAc);

(1S, 5R, 6R, 7R) -6- {3R-3-tert-butyl dimethylsilyloxy-5- (3-fluorophenyl) -1-pentyl} -7-R-tert-butyl dimethylsilyl Oxy-2-oxabicyclo [3.3.0] octan-3-ones (24)

Tert-butyldimethyl chloride in a solution of diol 23, triethyl amine (2.1 ml, 14.8 mmol) and 4-dimethylamino pyridine (0.06 g, 0.1 mmol) in dichloromethane (20 ml) with vigorous stirring at room temperature for 24 hours. Silane (2.3 g, 14.9 mmol) was added in one portion and the reaction mixture was concentrated in vacuo. The crude product was dissolved in ethyl acetate (50 mL) and washed with water (20 mL) and 5% aqueous sodium hydrogen carbonate solution (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel using dichloromethane as the eluent to give 3 g of the product of the oil. R _f = 0.68 (silica gel, ether).

(1S, 5R, 6R, 7R) -6- {3R-3-tert-butyl dimethylsilyloxy-5- (3-fluorophenyl) -1-pentyl} -7-R-tert-butyl dimethylsilyl Oxy-2-oxabicyclo [3.3.0] octan-3-ols (25)

Lactone 24 stirred solution (2.7 g, 4.95 mmol) in dry THF (30 mL) diisobutylaluminum hydride (DIBAL) solution (1.1 g, 7.43 mmol) in dry toluene (5.3 mL) at -72 / -80 ° C. I dropped it. After 1 hour (TLC checked), the reaction mixture was quenched with methanol (5 mL) and warmed to room temperature, water (50 mL), 10% aqueous HCl solution (50 mL) was added, EtOAc (2 × 50 mL) Extracted. The organic layer was dried over sodium sulfate, filtered, the solvent was removed in vacuo and the residue was chromatographed on silica gel using EtOAc and EtOAc: acetone 1: 1 as eluent, respectively, to give a yellow oil product (2.7 g), R _f = 0.85 (silica gel, ethyl acetate 1: 1).

13,14-dihydro-11,15-di-tert-butyldimethyl silyloxy-17- (3-fluorophenyl) -18,19, 20-trinor-PGF _2α (26)

To a brominated 4-carboxybutyl triphenyl phosphonium stirred suspension (8.78 g, 19.82 mmol) in THF (50 mL) was added potassium tert-butoxide (3.89 g, 34.6 mmol) under 0-5 ° C., nitrogen, and the mixture Was stirred at room temperature for 30 minutes. To the resulting red orange solution was added lactol 25 (2.7 g, 4.95 mmol) in THF (10 mL) at -15 / -10 ° C and the mixture was stirred for 3-4 hours (TLC check). The reaction mixture was diluted with water (30 mL) and washed with ether (4 times 40 mL). The aqueous layer was acidified to pH 4 with 5% citric acid aqueous solution and extracted with EtOAc (twice with 50 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo and the slurry 26 was used directly in the next step without separation.

13,14-dihydro-11,15-di-tert-butyldimethyl silyloxy 17- (3-fluorophenyl) -18,19, 20-trinor PGF _2α isopropyl ester (27)

To the crude product 26 stirred solution (3.16 g, 4.96 mmol) in acetone (20 mL) was added dropwise DBU (5.28 g, 34.7 mmol) at 0 ° C. The mixture was warmed to room temperature and isopropyl iodine (5.05 g, 29.7 mmol) was added dropwise. After 4 hours (TLC checked), the mixture was diluted with EtOAc (100 mL) and washed with brine (30 mL), 3% citric acid (twice with 25 mL) and 5% sodium hydrogencarbonate (twice with 25 mL). And dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was chromatographed on silica gel using ether: petroleum ether 1: 2 as eluent. A colorless oil was obtained with a yield of 1.7 g, R _f = 0.43 (silica gel, ether: petroleum ether 1: 2).

13,14-dihydro-11,15-di-tert-butyldimethyl silyloxy 17- (3-fluorophenyl) -18,19, 20-trinor PGE ₂ isopropyl ester (28)

To a 27 solution (1.7 g, 2.5 mmol) in dichloromethane (30 mL) was added a small portion of pyridinium dichlorochromate (2.43 g, 11.25 mmol) in aluminum oxide (20 g) and the mixture was stirred at room temperature (TLC checked). , Filtered and the precipitate was washed with ether: ethyl acetate 2: 1. The solvent was removed in vacuo. The residue was diluted with ether (100 mL) and washed with water (30 mL), 5% aqueous NaHCO ₃ solution (3 times with 20 mL), the organic layer was separated, dried over sodium sulfate and evaporated in vacuo to give 28 ( 1.3 g) was obtained. R _f = 0.72 (silica gel, ethyl acetate).

13,14-dihydro-17- (3-fluorophenyl) -18,19,20-trinor PGE ₂ isopropyl ester (7)

To 28 solutions (314 mg) in acetonitrile 15% hydrogen fluoride (12 mL) was added. The mixture was stirred at rt for 4 h (TLC check). The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3 times with 20 mL), dried and evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate as eluent to give an oily 7 (64 mg), R _f = 0.43 (silica gel, ethyl acetate).

Pharmacology

Effect of reducing intraocular pressure of test compound in cats and monkeys

The effect of reducing the intraocular pressure of the compound in the animal model was tested. Intraocular pressure was measured with a calibrated pneumotonometer. European breeding cats and cynomolgus monkeys were used as experimental animals. The cornea was anesthetized with oxybuprocaine before measurement. 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 The reduced intraocular pressures after topical treatment with -dihydro-17- (3-fluorophenyl) -18,19,20-trinor-PGE ₂ -isopropyl ester (7) are shown in Tables IV and V.

Intraocular pressure reduction effect of test compound 1-10 μg, effective against EP ₁ prostanoid receptor in cats. Control eyes received vehicle only (n = 5-6; mean ± SEM). Prostaglandins / eyes Reference Intraocular Pressure (mmHg) Intraocular pressure (mmHg) 3 hours after treatment 2 Experiment eye 24.2 ± 2.3 15.1 ± 2.8 ^* Contrasting eyes 24.5 ± 2.7 22.5 ± 3.4 4 Experiment eye 22.0 ± 1.7 14.2 ± 1.7 ^* Contrasting eyes 21.5 ± 1.7 18.7 ± 1.9 6 Experiment eye 19.2 ± 1.7 9.5 ± 0.5 ^* Contrasting eyes 19.3 ± 1.7 17.0 ± 1.3 7 Experiment eye 20.4 ± -2.0 14.2 ± 0.9 ^* Contrasting eyes 20.6 ± -1.8 18.4 ± 1.5 ^* p <0.01 (matched pair t-test between eyes)

Intraocular pressure reduction effect of test compounds effective against EP ₁ receptor in monkeys. The dose of PGF _2β -isopropyl ester was 30 μg, while 17-phenyl-18,19,20-trinor-PGE ₂ -isopropyl ester, and 15RS-16,16-trimethylene-PGE ₂ -isopropyl ester The dose of is 3 μg. Control eyes received vehicle only (n = 6; mean ± SEM). Prostaglandins / eyes Reference Intraocular Pressure (mmHg) Intraocular pressure (mmHg) 4 hours after treatment 2 Experiment eye 17.8 ± 1.4 14.1 ± 1.8 ^* Contrasting eyes 16.9 ± 1.2 17.5 ± 2.0 4 Experiment eye 14.1 ± 1.1 9.9 ± 0.9 ^* Contrasting eyes 13.9 ± 1.0 11.5 ± 0.8 6 Experiment eye 20.9 ± 1.6 15.3 ± 2.4 ^* Contrasting eyes 21.3 ± 1.5 19.0 ± 1.5 ^* p <0.05 (matched pair t-test between eyes)

It can be seen that all prostaglandin analogs that favor the EP ₁ receptor in both cats and monkeys effectively reduced intraocular pressure.

Accordingly, the present invention is directed to compounds having a selective stimulating effect on the EP ₁ receptor, which reduces intraocular pressure, and that compounds lack any melanin forming effect in the eye because pigment producing cells, ie, melanocytes, lack human EP ₁ receptor. It is disclosed that it has no effect or at least has an effect of effectively reducing melanin formation. Thus, during the long-term treatment with prostaglandins selective for the EP ₁ receptor, increased pigmentation of the iris, a common side effect, can be avoided.

reagent

a. N-isopropylcyclohexyl amine / THF, n-BuLi, ethylcyclobutanecarboxylate / DMSO

b. DIBAL-H, toluene

c. DCC / DME, DMSO, H ₃ PO ₄

d. Lithium-acetylide-ethylene diamine, DMSO

e. Tributyltin Hydride, AIBN

f. Trimethylsilane Chloride (TMSCl), imidazole / DMF

g. Li ₂ CuCN (CH ₃ ) ₂ , TMSCl, triethylamine, 4-tert-butyl-dimethylsilyloxy-2-cyclopentenone, 1-tributyltin-4,4-trimethylene-3-trimethylsilyloxy -1-octene, methyl-2-yn-8-octanoate

h. Pd-BaSO ₄ , Quinoline

i. HF / THF

reagent

a. DCC, DMSO, H ₂ SO ₄ , 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. K ₂ CO ₃ / methanol

f. TBDMS, TEA, 4-dimethylamino pyridine / dichloromethane

g. DIBAL-H / THF

h. Brominated 4-carboxybutyl triphenyl phosphonium

Potassium tert-butoxide, THF

i. DBU, Isopropyl Iodine / Acetone

j. Pyridinium chlorochromate, aluminum oxide / dichloromethane

k. HF / acetonitrile

references

Bill, A., "Blood circulation and fluid dynamics in the eye", 1975, Physiol. Rev. 55; 383-417].

Coleman, RA, Smith, WL, and Narumiya, S., “International Union of Pharmacology classification of prostanoid receptors: Properties, distribution and structure of the receptors and their subtypes ", 1994, VIII, Pharmacol. Rev. 46; 205-229].

Craford, K. and Kaufman, P., "Pilocarpine antagonizes PGF _2α -induced ocular hypotension in monkeys", 1987, Arch. Ophthalmol. 105; 1112-1116.

Ernhardt, P.W., Owens, A.H., "Facile Formation of Quaternary azetidinium compounds During Triflation of Dialkylaminopropanols", 1987, Synth. Commun. 17, 469-475].

Caldwell, AG, Harris, CJ, Stepney, R., Whittaker, N. "Hydantoin Prostaglandin analogues, Potent and Selective Inhibitors of Platelet Aggregation", 1979, JCS Chem. Commun. 561].

Skotnicki, S., Schaub, E., Weiss, J., Prostagladins and congeners. 14. Synthesis and Bronchodialator Activity of dl -16,16-trimethyleneprostaglandins ", 1977, J. Med. Chem. 20, 1042].

Hu, D-N., Et al., Investigative Ophthalmology and Visual Science 34; 2210-2219].

By Nielsson, SFE, Samuelsson, M., Bill, A., and Schernschanz, J. "Increased uveoscleral outflow as a possible mechanism of ocular hypotension caused by prostaglandin F2 _α- isopropyl ester in the cynomolgus monkey", 1989, Exp. Eye Res. 48; 707-716].

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

Stzernschantz, J. and Alm, A., “Latanoprost as a new horizon in the medical management of glaucoma”, 1996, Current Opinion in Ophthalmology 7; 2: 11-17.

Toris, C., Camras, C. B., and Yablonski, ME, “Effect of PhXA41, a new prostaglandin F2 _α. analogue, on aqueous humor dynamics in human eyes ", 1993, Ophthalmology 10; 1297-1304.

Wordsward, Jr. Wodswarth, Jr. W.S., Emon, W.D., The Utility of Phosphonate Carbanions in Olefin Synthesis, 1961, J. Am. Chem. Soc., 83, 1733].

Claims (12)

A composition for treating glaucoma and hypertension comprising a therapeutically active and physiologically acceptable amount of a prostaglandin analog, or a pharmaceutically acceptable salt or ester thereof, which is a selective agonist for the EP ₁ prostanoid receptor. The method of claim 1, A composition wherein the prostaglandin analog is derived from PGF or PGE type prostaglandin. The method according to claim 1 or 2, A composition wherein the prostaglandin analog is a compound of Formula 1 or a pharmaceutically acceptable salt or ester thereof. Formula 1 Where: Dashed bonds represent α or β arrays, dotted bonds represent single bonds, triple bonds or double bonds in cis or trans arrangements, R is hydrogen, saturated or unsaturated alkyl, preferably C _1-10 alkyl, cycloalkyl, preferably C _3-8 cycloalkyl, aryl, arylalkyl, preferably aryl-C _2-5 alkyl, or heteroaryl ego, R 1 is a C _2-5 saturated or unsaturated alkyl group, optionally interrupted by a heteroatom selected from oxygen, sulfur, and nitrogen, or is cycloalkyl, preferably C _3-7 cycloalkyl, cycloalkenyl, preferably C _3-7 cycloalkenyl, aryl or heteroaryl, X is C-OH or C = O, R2 is hydrogen, hydroxy, methyl, ethyl, methoxy or OCOR4, where R4 is a straight or branched chain saturated or unsaturated alkyl group, preferably C _1-10 alkyl, in particular C _1-6 alkyl, or cycloalkyl, preferably Is a C _3-8 cycloalkyl, or aryl group, R 3 is a straight or branched chain saturated or unsaturated alkyl group, preferably C _3-8 , in particular C _3-5 alkyl group, optionally interrupted by one species of heteroatom selected from oxygen, sulfur and nitrogen, each carbon atom Is optionally substituted with a substituent selected from C _1-5 alkyl, hydroxy and carbonyl groups, wherein carbon 15 of the prostaglandin structure is preferentially bonded to hydroxy and carbonyl, said alkyl group being cycloalkyl, preferably Optionally comprises a C _3-8 cycloalkyl, aryl or heteroaryl group, which may be one or independently complex substituted with C _1-3 alkyl, C _1-3 alkoxy, hydroxy, nitro, trifluoromethyl or halogen It may be. The method according to any one of claims 1 to 3, The prostaglandin analog is 15 (R, S) -16,16-trimethylene-PGE ₂ or an alkyl ester thereof. The method according to any one of claims 1 to 3, The prostaglandin analogue is 13,14-dihydro-17- (3-fluorophenyl) -18,19,20-trinor-PGE ₂ or an alkyl ester thereof. A patient, comprising contacting the surface of the eye with an intraocular pressure-reducing effective amount of a therapeutically active and physiologically acceptable prostaglandin analog, or a pharmaceutically acceptable salt or ester thereof, which is an optional agonist for the EP ₁ prostanoid receptor. How to treat glaucoma or hypertension of the eye. The method of claim 6, The prostaglandin analog is derived from PGF or PGE prostaglandin. The method according to claim 6 or 7, The prostaglandin analogue is a compound of Formula 1 or a pharmaceutically acceptable salt or ester thereof. Formula 1 Where: Dashed bonds represent α or β arrays, dotted bonds represent single bonds, triple bonds or double bonds in cis or trans arrangements, R is hydrogen, saturated or unsaturated alkyl, preferably C _1-10 alkyl, cycloalkyl, preferably C _3-8 cycloalkyl, aryl, arylalkyl, preferably aryl-C _2-5 alkyl, or heteroaryl ego, R 1 is a C _2-5 saturated or unsaturated alkyl group, optionally interrupted by a heteroatom selected from oxygen, sulfur, and nitrogen, or is cycloalkyl, preferably C _3-7 cycloalkyl, cycloalkenyl, preferably C _3-7 cycloalkenyl, aryl or heteroaryl, X is C-OH or C = O, R2 is hydrogen, hydroxy, methyl, ethyl, methoxy or OCOR4, where R4 is a straight or branched chain saturated or unsaturated alkyl group, preferably C _1-10 alkyl, in particular C _1-6 alkyl, or cycloalkyl, preferably Is a C _3-8 cycloalkyl, or aryl group, R 3 is a straight or branched chain saturated or unsaturated alkyl group, preferably C _3-8 , in particular C _3-5 alkyl group, optionally interrupted by one species of heteroatom selected from oxygen, sulfur and nitrogen, each carbon atom Is optionally substituted with a substituent selected from C _1-5 alkyl, hydroxy and carbonyl groups, wherein carbon 15 of the prostaglandin structure is preferentially bonded to hydroxy and carbonyl, said alkyl group being cycloalkyl, preferably Optionally comprises a C _3-8 cycloalkyl, aryl or heteroaryl group, which may be one or independently complex substituted with C _1-3 alkyl, C _1-3 alkoxy, hydroxy, nitro, trifluoromethyl or halogen It may be. The method according to any one of claims 6 to 8, The prostaglandin analog is 15 (R, S) -16,16-trimethylene-PGE ₂ or an alkyl ester thereof. The method according to any one of claims 6 to 8, The prostaglandin analog is 13,14-dihydro-17- (3-fluorophenyl) -18,19,20-trinor-PGE ₂ or an alkyl ester thereof. The method according to any one of claims 6 to 10, A method of topically administering a therapeutically active and physiologically acceptable composition comprising said prostaglandin analog to the eye one to three times daily. Use of a prostaglandin analog that is a selective agonist for the EP ₁ prostanoid receptor as defined in any one of claims 1 to 4 for the manufacture of a medicament for treating glaucoma and hypertension.