DK176053B1 - Topical compsn. for treating glaucoma or ocular hypertension - comprises prostaglandin deriv. with omega side chain contg. ring structure - Google Patents

Abstract

Ophthalmological compsn. for topical treatment of glaucoma or ocular hypertension comprises an effective amt. of a deriv. of prostaglandin PGA, PGB, PGD, PGE or OGF in which the omega chain is of formula (I) -C-B-C-D-R2 where C = carbon; B = single, double or triple bond; D = chain with 1-10C opt. interrupted by O, N or 5 heteroatoms, the substits. on each C being H, alkyl (pref. 1-5C) carbonyl or OH; R2 = ring structure such as phenyl opt. substd. by 1-5C alkyl, 1-4C alkoxy, CF3, 1-3C acylamino, NO2, halogen or phenyl gp(s); or an aromatic 5-6-membered heterocycle, e.g. thiazole, imidazole, pyrrolidine, thiophene or oxazole, or 3-7C cycloalkyl or cycloalkenyl opt. substd. by 1-5C alkyl gp(s); in an ophthalmologically compatible carrier.

Description

DK 176053 B1

The present invention relates to the use of prostaglandin derivatives of PGA, PGB, PGD, PGE and PGF, in which the omega chain has been modified with the common feature of containing a ring structure, for the treatment of glaucoma or increased ocular pressure. The invention also relates to ophthalmic agents containing an active amount of these prostaglandin derivatives as well as the preparation of such agents.

Glaucoma is an eye disease characterized by increased intraocular pressure, erosion of the optic nerve head and gradual loss of visual field It is well known that abnormally high intraocular pressure is harmful to the eye and there is clear evidence that 10 in glaucoma patients this is probably the most important factor causing degenerative changes in the retina. However, the pathophysiological mechanism of open-angle glaucoma is still unknown. Unless treated successfully, glaucoma will sooner or later lead to blindness, as its progression toward this stage is typically slow with gradual loss of vision.

15

The intraocular pressure, IOP (short for intraocular pressure), can be defined according to the formula: IOP = Pe + F x R (1) 20 where Pe is the episcleral venous pressure generally considered to be approx. 9 mm Hg, F is the flow of aqueous fluid, and R is the resistance to the flow of aqueous fluid through the trabecular plant and adjacent tissues into Schlemm's channel. 1 2 3 4 5 6

In addition to passing through Schlemm's canal, water fluid can also pass through the ciliary muscle into the suprachoroidal compartment and eventually leave the increased through the sclera. This 3 uveoscleral route has been described by e.g. Bill (1975). The pressure gradient in this 4 trap is negligible compared to the gradient over the inner wall of Schlemm's channel 5 and adjacent tissue in the previous case. The current limiting step along the non-oscleral pathway is assumed to be the flow from the anterior chamber into the suprachoroidal compartment.

2 DK 176053 B1

A more complete formula is given by: IOP = Pe + (Ft- Fu) x R (2) 5 where Pe and R are as defined above, F, is the total outflow of water liquid and Fu is the fraction passing through it uveoscleral pathway.

IOP in humans is usually in the range of 12-22 mm Hg. At higher values, e.g. above 22 mm Hg, there is a risk that the eye may be affected. In a special form of 10 glaucoma, low tension glaucoma, damage can occur at intraocular pressure levels that are otherwise considered physiologically normal. The reason for this could be that the eye in these individuals is unusually sensitive to pressure. The opposite situation that some individuals may exhibit abnormally high intraocular pressure without any manifestation of defects in the visual field or optic nerve head is also known. Such conditions are usually referred to as increased ocular pressure.

Glaucoma treatments can be given by drugs, laser or surgery. In drug treatment, the purpose is to lower either the current (F) or the resistance (R), which, in accordance with the above formula (1), will result in a reduced IOP; alternatively increasing the flow along the uveoscleral route, which, in accordance with formula (2), also results in a decrease in pressure. Cholinergic agonists, e.g. pi-locarpin, decreases intraocular pressure mainly by increasing the outflow through Schlemm's duct. 1 30

Prostaglandins, which have recently experienced a growing interest as IOP lowering agents, may be active in that they will cause an increase in uveoscleral outflow (Crawford et al., 1987, and Nilsson et al., 1987). However, they do not appear to have any effect on the formation of aqueous fluid or on the conventional outflow through Schlemm's channel (Crawford et al., 1987).

3 DK 176053 B1

The use of prostaglandins and their derivatives is e.g. disclosed in U.S. Patent No. 4,599,353 and EP Printing No. 87 103714.9 and by L.Z. Bito et al. (1983), C.B.

Camras et al. (1981, 1987a, 1987b, 1988), G. Giuffré (1985), P. L. Kaufman (1986), J.

R. Kersetter et al. (1988), P. Y. Lee et al. (1988) and J. Willumsen et al. (1989).

5

As to the practical utility of some of the previously described prostaglandins and derivatives as suitable drugs for the treatment of glaucoma or increased ocular pressure, their ability to cause superficial irritation and vasodilation in the conjunctiva is a limiting factor. Furthermore, it is likely that prostaglandins 10 have an irritant effect on the corneal sensory nerves. Thus, local side effects will appear in the eye already when the prostaglandin levels administered are quite small ie. already when the doses are less than the doses that would be desirable to achieve maximum pressure reduction. Thus, it has e.g. It has been found that for this reason it is clinically impossible to use PGF2-1-isopropyl ester in the amount that would give a maximum pressure reduction. Prostaglandins, which are naturally occurring autacoids, are highly pharmacologically active and affect both the sensory nerves and the smooth muscle of the blood vessels.

Since the effects of administering PGF 2 and its esters to the eye, in addition to pressure reduction, also include irritation and hyperemia (increased blood flow), the doses currently available in clinical trials are necessarily very low. The irritation that is experienced when PGF2e or its esters are used consists mainly of a feeling of truth or of having a foreign body in its eye, this being usually accompanied by increased tearful discharge.

It has now been found that a solution to the above-mentioned problems consists in the use of certain derivatives of the prostaglandins A, B, D, E and F, in which the omega chain has been modified with the common feature of containing a ring structure, to treatment of glaucoma or increased ocular pressure.

The prostaglandin derivatives have the general structural formula 30 A, __-α-chain - · w-chain 5 wherein A represents the alicyclic ring C8-C12, and the bonds between the ring and side chains represent the various isomers. In PGA, PGB, PGD, PGE and PGF, A has the formula

0 O OH O OH

V) L ss ^ x \% · α α α α α

// ri 0 OH OH

PGA PGB PGD PGE PGF

I II. III IV V

The invention is based on the use of derivatives characterized by their ω-chain, and various modifications of the o-chain are therefore possible with continued application of the present invention, the α-chain typically being the naturally occurring o-chain which is esterified to the structural formula wherein R 1 is an alkyl group, preferably of 1-10 carbon atoms, especially 1-6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl or benzyl, or a derivative which imparts equivalent properties as a glaucoma agent to the final compound.

Preferably, the chain could be a C6-C10 chain which may be saturated or unsaturated and have one or more double bonds, and allenes, or a triple bond, and the chain may contain one or more substituents such as alkyl groups, alicyclic rings or aromatic rings with or without heteroatoms. The 1 ω chain is defined by the following formula: 5 C is a carbon atom (the number is given in parentheses), B is a single bond, a double bond or a triple bond, D is a chain of 1-10, preferably 2-8 and especially 2-5 and most preferably 3 carbon atoms, optionally interrupted by preferably no more than two heteroatoms (O, S or N), the substituent on each carbon atom are H, alkyl groups, preferably lower alkyl groups having 1 to 5 carbon atoms, a carbonyl group or a hydroxyl group, wherein the substituent on C 15 is preferably a carbonyl group, or (R) -OH or (S) -OH; preferably each D chain contains at most three hydroxyl groups or at most three carbonyl groups, R 2 is a ring structure such as a phenyl group which is unsubstituted or has at least one substituent selected from C 1 -C 5 alkyl groups, C 1 -C 4 alkoxy groups, trifluoromethyl groups, C 1 -C 3 aliphatic acylamino groups, nitro groups, halogen atoms and the phenyl group; or an aromatic heterocyclic group having 5-6 ring atoms such as thiazole, imidazole, pyrrolidine, thiophene and oxazole; or a cycloalkane or a cycloalkene of 3-7 carbon atoms in the ring, optionally substituted with lower alkyl groups of 1-5 carbon atoms.

Some examples of derivatives that were evaluated are the following (see Table I for structure information): 25 (1) 16-phenyl-17,18,19,20-tetranor-PGF2a isopropyl ester (2) 17-phenyl-18, 19,20-trinor-PGF2a-isopropyl ester (3) 15-dehydro-17-phenyl-18,19,20-trinor-PGF2a-isopropyl ester (4) 16-phenoxy-17,18,19,20-tetranor-PGF2a isopropyl ester 30 (5) 17-phenyl-18,19,20-trinor-PGE2a-isopropyl ester (6) 13,14-dihydro-17-phenyl-18,19,20-trinor-PG A2-isopropyl ester 6 DK 176053 B1 ( 7) 15- (R) -17-phenyl-18,19,20-trinor-PGF2a-isopropyl ester (8) 16- [4- (methoxy) -phenyl] -17,18,19,20-tetranor-PGF2a isopropyl ester (9) 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2e-isopropyl ester (10) 18-phenyl-19,20-dinor-PGF2cr-isopropyl ester 5 (20) 19-phenyl-20 -nor-PGF 2a isopropyl ester.

The most preferred derivatives are currently the derivatives in which the ω chain of the prostaglandin has the 18,19,20-trinor form, and in particular the 17-phenyl analogs such as 15- (R) -, 15-de-hydro and 13,14 dihydro-17-phenyl-18,19,20-trinor-formeme. Such derivatives are represented by (3), (6), (7) and (9) among the formulas shown in Table I.

In the formula shown above, the currently most preferred structure is obtained when the prostaglandin is a derivative of PGA, PGD, PGE or PGF, especially of PGA2, PGD2, PGE2 and PGF2a. B is a single bond or a double bond, D is a carbon chain with 2-5 and especially 3 atoms; wherein C55 has a carbonyl or (S) -OH substituent and C) 6-C99 has lower alkyl substituents, or preferably H, and R₂ is a phenyl ring optionally having substituents selected from alkyl and alkoxy groups.

Thus, the invention relates to the use of certain derivatives of PGA, PGB, PGD, PGE and PGF for the treatment of glaucoma or increased ocular pressure. Among these derivatives defined above, it has been found that some are irritating or otherwise not optimal and in some cases not equally useful due to adverse effects, and these are excluded by limiting the group of prostaglandin derivatives defined above to therapeutically effective and physiologically acceptable derivatives. Thus, e.g. (1) 16-phenyl-17,18,19,20-tetranor-PGF2a isopropyl ester is annoying, but this can be eliminated by replacing the phenyl ring with a methoxy group to give the formula (8) which represents a therapeutic more useful compound.

The method of treating glaucoma or increased ocular tension consists in contacting an effective intraocular pressure reducing amount of an agent as stated above with the eye to reduce eye pressure and to maintain said pressure at a reduced level. The agent contains 0.1-30 µg, in particular 1-10 µg of the active substance per administration, ie. a therapeutically active and physiologically acceptable derivative from the group defined above. Advantageously, the treatment may be carried out by providing a drop of the agent corresponding to ca. 30 μΐ is administered approx. 1 to 2 times a day to the patient's eye. This therapy is applicable to both humans and animals.

The invention further relates to the use of therapeutically active and physiologically acceptable prostaglandin derivatives of the above defined group for the preparation of an ophthalmological agent for the treatment of glaucoma or increased ocular pressure.

The prostaglandin derivative is mixed with an ophthalmologically compatible carrier known per se. The carrier which can be used to prepare the compositions of the invention comprises aqueous solutions such as, for example, physiological saline solutions, oil solutions or ointments. The carrier may further contain ophthalmologically compatible preservatives such as e.g. benzalkonium chloride, surfactants such as, for example, polysorbate 80, liposomes or polymers, e.g. methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone and hyaluronic acid. These can be used to increase the viscosity. Furthermore, it is also possible to use soluble or insoluble drug inserts when the drug is to be administered.

The invention also relates to ophthalmological agents for topical treatment of glaucoma or increased ocular pressure, which agents comprise an effective intraocular pressure reducing amount of a prostaglandin derivative as defined above, and an ophthalmologically compatible carrier, the effective amount comprising a dose of approx. 0.1-30 µ to approx. 10-50 µ of the agent.

8 DK 176053 B1

In the experiments performed in the study, the active compound, in an amount varying with the potency of the drug, was dissolved from 30 µg to 300 µg / ml in a sterilized aqueous solution (0.9% saline solution) containing 0.5% polysorbate 80 as a solubilizing substance.

5

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

Synthesis of Prostaglandin Derivatives Example 1: Preparation of 16-phenyl-17.18.19.20-tetranor-PGF 2 -isopropyl ester (Π.

A 50 ml round bottom flask equipped with a magnetic stir bar was charged with 17.5 mg (0.04 mmol) of 16-phenyl-17,18,19,20-tetranor-PGF2a (Cayman Chemical), 5 ml of CH2 Cl2 and 30.2 mg (0.23 mmol) of diisopropylethylamine. This solution was stirred at -10 ° C and 13.5 mg (0.07 mmol) of isopropyl triflate (freshly prepared) was added. This solution was allowed to stand at -10 ° C for 15 minutes and then slowly warmed to room temperature. After the esterification was completed by TLC (usually after 3-4 hours at room temperature), the solvent was removed in vacuo. The residue was diluted with 20 ml of ethyl acetate, washed with 2 x 10 ml of 5% sodium bicarbonate 20 and 2 x 10 ml of 3% citric acid. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel-60 using ethyl acetate: acetone, 2: 1 as eluent. The title compound was obtained as a colorless oily substance (71% yield).

Nuclear Magnetic Resonance Spectrum (CDC13) - ppm: h 1.2 (6H d) 3.3 (1H q) 2.8 (2H d) 5.0 (1H m) 3.8 (1H m) 5.3-5.7 (4Hm ) 4.1 (1H t) 7.1-7.3 (5Hm) 9 DK 176053 B1

Example 2: Preparation of 17-phenyl-18,19,20-trinor-PGFv »-isopropyl ester (2V

A 50 ml round bottom flask equipped with a magnetic stir bar was charged with 20 mg (0.05 mmol) of 17-phenyl-18,19,20-trinor-PGF2a (Cayman Chemical), 6 ml of acetone, 39.2 DBU and 42.5 mg (0.25 mmol) of isopropyl iodide. The solution was allowed to stand at room temperature for 24 hours, then the solvent was left under vacuum and the residue was diluted with 30 ml of ethyl acetate, washed twice with 10 ml of 5% sodium bicarbonate and 10 ml of 3% citric acid. The solvent was removed in vacuo and the crude product was chromatographed on silica gel-60 using ethyl acetate: acetone, 2: 1 as eluent. The title compound (2) was obtained as an oily substance (65% yield).

Nuclear Magnetic Resonance Spectrum (CDCl3) - ppm: 6 1.2 (6H d) 4.9 (1Hm) 3.9 (1H m) 5.4-5.6 (4Hm) 4.1 (1H t) 7.1-7.3 (5Hm) 4.2 (1Hm) Example 3: Preparation of 15-dehydro-17-phenyl-18.19.20-trinor-PGF2O-isopropyl ester (3).

20.9 mg (0.092 mmol) of DDQ was added to a solution of 10 mg (0.023 mmol) of 17-phenyl-18,19,20-trinor-PGF2a * isopropyl ester (2) in 8 ml of dioxane. The reaction mixture was immediately browned and the reaction mixture was stirred at room temperature for 24 hours. The precipitate formed was filtered off, washed with 10 ml of ethyl acetate and the filtrate was diluted with 10 ml of ethyl acetate and washed with 2 x 10 ml of water, 2 x 10 ml of 1M NaOH and 20 ml of brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel using ethyl acetate: ether, 1: 1 as eluent. The title compound (3) was obtained as a colorless oily substance (76% yield).

10 DK 176053 B1

Nuclear Magnetic Resonance Spectrum (CDC13) - ppm: δ 1.2 (6H d) 5.4 (2H m) 4.0 (1H m) 6.2 (1Hd) 4.2 (1H m) 6.7 (1Hq) 5.0 (1H m) ) 7.1-7.3 (5Hm)

Example 4: Preparation of 16-phenoxy-17,18,19-20-tetranor-PGF 2 -isopropyl ester

10 (4X

A procedure similar to that described in Example 2 was followed using 20 mg (0.051 mmol) of 16-phenoxy-17,18,19,20-tetranor-PGF2a (Cayman Chemicals).

The crude product was purified by column chromatography on silica gel-60 using 15 ethyl acetate: acetone, 2: 1 as eluent. The title compound (4) was an oily substance (53.2% yield).

Nuclear Magnetic Resonance Spectrum (CDC13) - ppm: 1.2 (6H d) 5.4 (2Hm) 3.9 (3H m) 5.7 (2Hm) 4.2 (1H m) 6.9 (3H m) 4, 5 (1H m) 7.3 (2Hm) 5.0 (1Hm).

25

Example 5: Preparation of 17-phenyl-18,19,20-trinor-PGE 2 isopropyl ester (51.

A procedure similar to that described in Example 2 was followed using 10 mg (0.026 mmol) of 17-phenyl-18,19,20-trinor-PGE 2 (Cayman Chemicals). The crude product was washed by column chromatography on silica gel-60 using ether as eluant. The title compound (5) was an oily substance (38.9% yield).

DK 176053 B1! π

Nuclear Magnetic Resonance Spectrum (CDCl3) - ppm: 6; 1.2 (6H d) 5.3 (2Hm) 3.0-4.1 (2Hm) 5.6 (2Hm) 5.9.9 (1H m) 7.2 (5H m).

Example 6: Preparation of 13.14-dihydro-17-phenyl-18.19.20-trinor-PGA2-isopropyl ester (3).

A procedure similar to that described in Example 2 was followed using 10 mg (0.026 mmol) of 13,14-dihydro-17-phenyl-PGA 2 (Cayman Chemicals). The crude product was chromatographed on silica gel 60 using ether as the eluent.

Nuclear Magnetic Resonance Spectrum (CDCl3) - ppm: b 1.2 (6H d) 5.4 (2H m) 4.3 (1H m) 7.3 (5Hm) 5.0 (1H m) 20

Example 7: Preparation of 15-fRV 17-phenyl-18,19,20-trinor-PGF 2 -isopropyl ester

(7). (Table ID

7.1 Preparation of 1- (S) -2-oxa-3-oxo-6- (R) - (3-oxo-5-phenyl-1-trans-pentenyl) -7- (R) -25 (4-phenylbenzoyloxy) ) -cis-bicyclo- [3,3,0] octane (13). 1 g (0.05 mole) of alcohol (11), 32 g (0.15 mole) of DCC, 39.1 g (0.5 mole) of DMSO (freshly distilled from CaH 2) and 30 ml of DME were charged to a 200 ml flask under nitrogen. Ortho-phosphoric acid was added in one portion and an exothermic reaction took place. The reaction mixture was stirred mechanically at room temperature for 2 hours and the resulting precipitate was filtered off and washed with DME. The filtrate (12) can be used directly for the Emmon condensation reaction.

To a suspension of 1.2 g (0.04 mole) of NaH (80% washed with n-pentane to remove 5 mineral oil) in 100 ml of DME under nitrogen was added dropwise 12.3 g (0.048 mole) of dimethyl ether. 2-oxo-4-phenylbutyl phosphonate in 30 ml DME. The mixture was stirred mechanically for 1 hour at room temperature, then cooled to -10 ° C and a solution of the crude aldehyde (12) added dropwise. After 15 minutes at 0 ° C and 1 hour at room temperature, the reaction mixture was neutralized with glacial acetic acid, the solvent was removed under vacuum and to the residue was added 100 ml of ethyl acetate, then washed with 50 ml of water and 50 ml of brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the resulting white precipitate was filtered off and washed with cold ether. The title compound (13) was obtained as a crystalline substance, mp 134.5-135.5 ° C (53% yield).

7.2 Preparation of 1- (S) -2-oxa-3-oxo-6- (R) - [3- (R, S) -hydroxy-5-phenyl-1-trans-pentanyl] -7- (R) - (4 phenylbenzoyloxy) -cis-bi-cyclo- [3,3,0] octane (14).

20 g (0.021 mol) of enon (13) and 3.1 g (0.008 mol) of cerium chloride heptahydrate in 50 ml of methanol and 20 ml of CH 2 Cl 2 were charged to a 200 ml round bottom flask equipped with a magnetic stir bar and cooled. to -78 ° C under nitrogen. Sodium borohydride was added in small portions and after 30 minutes the reaction mixture was cooled by the addition of saturated NH 4 Cl, then extracted with 2 x 50 ml of ethyl acetate.

The extracts were dried and evaporated to leave a colorless oil (98% yield).

7.3 Preparation of 1- (S) -2-oxa-3-oxo-6- (R) - [3- (R, S) -hydroxy-5-phenyl-1-trans-pentanyl] -7- ( R) -hydroxy-cis-bicyclo- [3,3,0] -octane (15).

30 13 DK 176053 B1

To a solution of 9.8 g (0.02 mole) of lactone (14) in 100 ml of absolute methanol was added 1.7 g (0.012 mole) of potassium carbonate. The mixture was stirred with a magnetic rod at room temperature for 3 hours. After 3 hours, the mixture was neutralized with 40 ml of 1M HCl and extracted with 2 x 50 ml of ethyl acetate. The extracts were then dried over anhydrous sodium sulfate and evaporated. The crude product was chromatographed on silica gel using ethyl acetate: acetone as eluant. The title compound (15) was obtained as an oily substance (85% yield).

7.4 Preparation of 1- (S) -2-oxa-3-hydroxy-6- (R) - [3- (R, S) -hydroxy-5-phenyl-1-trans-pentenyl] -7- (R ) -hydroxy-cis-bicyclo- [3,3,0] octane (16).

To a solution of 3 g (0.011 mol) of lactone (15) in 60 ml of anhydrous THF, which was magnetically stirred and cooled to -78 ° C, was added dropwise 4.5 g (0.0315 mol) of DIBAL H in toluene. After 2 hours, the reaction mixture was cooled by the addition of 75 ml of methanol. The mixture was filtered, the filtrate was evaporated in vacuo and the residue was chromatographed on silica gel 60 using ethyl acetate: acetone, 1: 1 as eluent. The title compound (16) was obtained as a semi-solid (78% yield).

7.5 Preparation of 15- (R, S) -17-phenyl-18,19,20-trinor-PGF2e (17).

2.5 g (25 mmol) of sodium methylsulfinyl methide in DMSO (freshly prepared from sodium anhydride and DMSO) was added dropwise to a solution of 5.6 g (12.6 mmol) of 4-carboxybutyltriphenylphosphonium bromide in 12 ml of DMSO. To the resulting red solution of the ylide was added dropwise a solution of the 1.2 g (4.2 mmol) hemiacetal (16) in 13 ml of DMSO and the mixture was stirred for 1 hour. The reaction mixture was diluted with 10 g of ice and 10 ml of water and extracted with 2 x 50 ml of ethyl acetate, then the aqueous layer was cooled, acidified with 1 M HCl and extracted with ethyl acetate, then the organic layer was dried and evaporated. The resulting crude product was a colorless substance. The purity of the title compound (17) was evaluated by TLC on silica gel using ethyl acetate: acetone: acetic acid, 1: 1: 0.2 v / v / v, as the eluent.

7.6 Preparation of 15- (R) -1,7-phenyl-1,8,19,20-trinor-PGF2a isopropyl ester (7).

5 ------------------------------------------------- -------------------------------------------------- -

The crude product (17) was esterified following a procedure similar to that described in Example 2, and the product was purified by column chromatography on silica gel 60 using ethyl acetate as the eluent and the resulting mixture of 10 Ct5 epimer alcohol separated.

The title compound (7) was obtained as a colorless oily substance (46% yield).

Nuclear Magnetic Resonance Spectrum (CDC13) - ppm: δ 1.2 (6H m) 5.4 (2Hm) 3.9 (1H m) 5.6 (2Hm) 4.15 (2H m) 7.2 (5Hm) 4 , 95 (1H m) 20

Example 8: Preparation of 16-4- (methoxy) -dhenyl-17.18.19.20-tetranor-PGF 2 -1 -isopropyl ester (8).

Following a procedure similar to that described in Example 7 with modification of step 7-2, the aldehyde 12 described in step 7-2 was reacted with dimethyl-2-oxo-3- [4- (methoxy) phenyl ] propyl phosphonate and purified by column chromatography on silica gel-60 using ethyl acetate: toluene, 1: 1, as eluent. A colorless oily substance (57% yield) was obtained.

15 DK 176053 B1

The title compound 16- [4- (methoxy) phenyl] -17,18,19,20-tetranor-PGF 2 -orisopropyl ester (8) was obtained as an oily substance and purified by column chromatography on silica gel-60 using ethyl acetate as eluant (46% yield).

Nuclear Magnetic Resonance Spectrum (CDC13) - ppm: b 1.2 (6H d) 5.0 (1Hm) 2.8 (2H d) 5.4 (2H m) 3.75 (3H s) 5.6 (2Hm) , 9 (1H m) 6.8 (2Hd) 4.15 (1H m) 7.2 (2Hd) 4.3 (1H m).

Example 9: Preparation of 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF 20: -isopro-15 polyester Γ9).

Following a procedure similar to that described in Example 7, with minor modification, 5 g (0.018 mol) of enon (13) in 100 ml of THF was reduced using 2.03 g of 10% pd / c under hydrogen atmosphere. After completion of the reaction (determined by TLC on silica gel using ethyl acetate: toluene, 1: 1, as eluent), the mixture was filtered on "celite". The filtrate was evaporated in vacuo to give oily substance (86% yield).

The final product 13,14-dihydro-17-phenyl-18,19,20-trinor PGF2a isopropyl ester containing a mixture of Q 5 epimeric alcohols was separated by preparative liquid chromatography using 40% CH 3 CN in water, vol. / vol, as eluent.

Nuclear Magnetic Resonance Spectrum (CDC13) - ppm: b 1.2 (6H d) 5.0 (1H m) 16 (17H m) 5.4 (2Hm) 3.9 (1H m) 7, 2 (5Hm) 4.15 (1Hm)

Example 10: Preparation of 18-phenyl-19,20-trinor-PGF ^-isopropyl ester (10Y

Following a procedure similar to that described in Example 7, with modified step 7-2, the aldehyde (12) described in step 7-2 was reacted with dimethyl 2-oxo-5-phenyl-pentylphosphonate, resulting in in a crystalline substance, trans-enon-lactone (67% yield).

The final product 18-phenyl-19,20-dinor-PGF2a isopropyl ester (10) was purified by column chromatography on silica gel-60 using ethyl acetate as the eluent and a colorless oil (41% yield) was obtained.

15

Nuclear Magnetic Resonance Spectrum (CDC13) - ppm: h 1.2 (6 Hm) 5.0 (1Hm) 3.95 (1H m) 5.4 (2Hm) 4.10 (1H m) 5.6 (2Hq) 4, 20 (1H m) 7.2 (5Hm).

Example 11: Preparation of 19-Phenyl-20-nor-PGFwisopropyl ester (201) A procedure similar to that described in Example 7 was followed with modified steps 7-2.

The aldehyde (12) described in steps 7-2 was reacted with dimethyl 2-oxo-6-phenylhexyl phosphonate to give a colorless oil, trans-enon lactone (56% yield).

30 17 DK 176053 B1

The final product 19-phenyl-20-nor-PGF2a isopropyl ester (20) was a colorless oil which was purified by column chromatography on silica gel-60 using ethyl acetate as eluant (30% yield).

Nuclear Magnetic Resonance Spectrum (CDC13) - ppm: b 1.2 (6H d) 5.0 (1H m) 2.6 (2H t) 5.4 (2H m) 3.9 (1H m) 5.5 (2Ht) 10 4.1 (1H m) 7.2 (5Hm) 4.2 (1H m).

Eye-dropping effects studies and adverse reactions.

The intraocular pressure (IOP) was determined in animals with a pneumatonometer ("Digalab Modular One" 7, Bio Rad) specially calibrated to the eye of that species. The cornea was anesthetized with 1-2 drops of oxibuprocaine before each IOP measurement. In healthy human volunteers, IOP was measured with applanation tonometry or with an air-breathing tonometer (Keeler pulsair). Applanation tonometry used either a pneumatonometer (Di-20 gilab) or Goldmann's applanation tonometer mounted on a slit lamp microscope. The cornea was anesthetized with oxibuprocaine before each measurement with applanation tonometry. No local anesthetic was used before measurement with the pulsair tonometer.

The eyeshot after administration of the test materials was assessed on cats. Cat's behavior after topical administration of the test drug was followed and the eyeball was divided on a scale of 0 to 3, with 0 indicating complete absence of any signs of discomfort, and 3 indicating maximum irritation as evidenced by complete closure of the eyelid.

Conjunctival hyperemia after topical administration of the test materials was assessed in rabbits. Concjunctiva at the entrance of the eye's upper rectus muscle was inspected or photographed at regular intervals, and the degree of hyperemia was later judged from the color photographs in a blind trial. Conjunctival hyperemia was assessed on a scale of 0 to 4, with 0 indicating complete absence of any hyperemia, and 4 indicating pronounced hyperemia with conjunctival chemosis.

5 To determine the effects on intraocular pressure, monkeys (cynomolgus) were used primarily. The reason for this is that the monkey eye is very similar to the human eye, and therefore drug effects are generally easy to extrapolate to the human eye. However, the disadvantage of using the monkey eye as a model is that conjunctiva in this species is pigmented, making it impossible to judge conjunctival hyperemia, and furthermore, monkey eye 10 is relatively insensitive to irritation. Therefore, the cat eye, which is very sensitive to prostaglandins, was used to assess eye discomfort and the rabbit eye with pronounced tendency to hyperemia reactions was used to assess conjunctival and episcleral hyperemia.

15 It can be seen from Table III that modification of the ω-chain of the prostaglandin skeleton provided new and unexpected features with regard to eye irritation (eye irritation) to the prostaglandins.

In particular, 17-phenyl-18,19,20-trinor-PGF20-IE and analogs were unique in showing a complete loss of eye irritation while preserving IOP-lowering effect in monkeys. While the 17-phenyl-18.1 O-O-trinor-PGFia derivatives were tolerated extremely well, 16-phenyl-17,18,19,20-tetranor-PGF2a-IE showed clear eye discomfort, albeit to a lesser extent than PGF2a-EE or 15-propionate-PGE2-IE (Table III). However, replacing a hydrogen atom in the phenyl ring with a methoxy group with electron-donating properties rendered the molecule virtually free of eye irritation, see Table III. It is also shown in Table ΙΠ that 18-phenyl-1,9,20-dinor-PGF 2 -IE, 19-phenyl-20-nor-PGF 2a-25 DE, and 17-phenyl-18,19,20-trinor-PG Β-IE and 13,14-dihydro-17-phenyl-18,19,20-tri-nor-PGA2-IE had no or very slight irritant effect in cats' eyes. This demonstrates that the invention is not only valid for 16- and 17-tetra and trinor analogs of PGF2a> but for a variety of ω-chain modified and ring-substituted analogs of PGF2a (as exemplified by 16-phenyl-17,18,19,20- tetranor-PGF2a-IE to 19-phenyl-20-nor-30 PGF2a-IE), and more importantly also to various members of the prostaglandin family, such as PGE2 and PGA2, modified in an analogous manner (Table III). Thus, modification of the B1 ω chain and substitution of a carbon atom in the chain with a ring structure introduces completely new, unexpected and advantageous properties of naturally occurring prostaglandins in the sense of abolishing the irritant effect in conjunctiva and cornea. If 16-phenyl-17,18,19,20-tetranor-PGF2a-IE exhibits any irritant effect, replacement of a hydrogen atom in the ring structure by e.g. a methoxy group diminishes or abolishes the irritant effect.

In addition to the lack of eye discomfort, the ω-chain modified analogs also showed an advantage over naturally occurring prostaglandins in that they caused significantly less conjunctival hyperemia in rabbit eye examination (Table IV). In particular, 15-dehydro-17-phenyl-18,19,20-trinor-PGF2e-IE, 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2a-IE and 13,14-dihydro -17-phenyl-1 8,19,20-trinor-PGA2-IE was advantageous in this regard. Also 18-phenyl-19,20-dinor-PGF2a-IE and 19-phenyl-20-nor-PGF2a-IE caused very little conjunctival hyperemia (Table IV).

15

The intraocular pressure-reducing effect of ω-chain-modified and ring-substituted prostaglandin analogs is shown in Table V. In particular, 16-phenyl-tetranor and 17-phenyl-trinor-prostaglandin analogs reduced IOP significantly in animal eyes (Table V). In all but two rows of experiments, cynomolgus monkeys were used. It is of particular interest to note that 17-phenyl-18,19,20-trinor PGF2a derivatives exhibit no eye irritation and only moderate conjunctival / episcleral hyperemia and significantly decreased IOP in primates. It should also be noted that both 16-phenyl-17,18,19,20-tetranor-PGFe-IE, 18-phenyl-19,20-dinor-PGF2a-IE and 19-phenyl-20-nor-PGFcrIE reduced it. thus, modifying the ω chain and replacing a carbon atom in the chain with a ring structure does not render the molecule inactive for the effect on the intraocular pressure.

It should also be noted that replacement of a hydrogen atom in the ring structure of 16-phenyl-17,18,19,20-tetranor-PGF20-IE with a methoxy group eliminated much of the eye irritation effect while retaining most of the intraocular pressure-lowering effect. Thus, ω-chain modified and ring-substituted prostaglandin analogs effectively reduce IOP in animals. It is further shown in Table V that 16-phenoxy-17.18.19.20-tetranor-PGF2e-IE effectively lowers intraocular pressure according to studies in cats. Thus, replacing the carbon atom 17 in the ω chain with a heteroatom, in this case oxygen, does not render the molecule inactive for its effect on IOP.

5

Remarkably, most of the 17-phenyl-18,19,20-trinor-prostaglandinana logs had little intraocular pressure-lowering effect in cats, even at high doses.

It will be seen that the doses at which compounds were used as shown in Table III are less than e.g. the doses used in Table V. The doses shown in Table III should be explicitly compared with the doses of the naturally occurring prostaglandins in the same table.

The same is true for Table IV. It is clear that with increasing doses side effects can increase. However, the doses of prostaglandin derivatives used in monkeys are approximately the same as those used in human volunteers (Table VI) and are virtually free of side effects.

15

The effect of some ω-chain modified prostaglandin analogs, more specifically 17-phenyl-18,19,20-trinor-PGF2tt-IE, 15-dehydro-17-phenyl-18,19,20-trinor-PGF2e-IE, 15- (R ) -17-phenyl-18,19,20-trinor-PGF2a-IE, 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF20-IE and 18-phenyl-19,20-dinor PGF2α-IE, at the intraocular pressure of healthy human volunteers is shown in Table VI. All compounds significantly reduce intraocular pressure. It is particularly significant in this regard that none of the compounds had any significant irritant effect (eye discomfort) and that 13,14-dihydro-17-phenyl-18.19.20-trinor-PGF2a-IE and 15-dehydro-17-phenyl 18,19,20-trinor PGF2a-IE caused very little if any conjunctival / episcleral hyperemia in humans at all. Thus, ω-chain modified and ring-substituted prostaglandin analogs appear to be unique in that these compounds reduce IOP without causing significant eye side effects such as hyperemia and discomfort.

Thus, the present invention relates to a group of compounds which exhibit the unique property of causing negligible eye side effects while maintaining the intraocular pressure lowering effect. From the foregoing it is clear that the modifying modification of the molecule consists in a ring structure in the ω chain. Furthermore, the substituents in the ring structure and / or in the ω chain can be introduced into certain molecules while continuing to exhibit some side effects in the eye. Hetero atoms can also be introduced into the ring-substituted ω chain. At present, in particular, 17-phenyl-18,19,20-trinor-PGF2α derivatives appear to be very promising for therapeutic use in the case of glaucoma. From the scientific literature, it is clear that PGE2 and PGA2 or their esters lower IOP in monkeys (see Bito et al., 1989). Clinical studies with PGE2 have also been performed and show IOP-lowering effect in humans (Flach and Eliason (1988)). Thus, the analogy with PGF2a and its esters, which lower the IOP in the prime eye, is logical. It is most reasonable to assume that other modified ω-chain prostaglandins exhibit essentially the same effects as modified ω-chain PGF2a, ie. IOP lowering effect without side effects.

22 DK 176053 B1 TABLE I.

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Reagents: a) DCC / DMSO / DME

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c) CeCl3.7H2O / NaBH4 / CH3Y -78 ° C

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Table III. Irritation effect of naturally occurring prostaglandins (PGF2a, PGD2 and PGE2) as well as ω-chain modified analogues applied as an isopropyl ester to the cat's eye. The average level of discomfort was assessed within 60 minutes after topical administration of the test drug in question. The numbers in parentheses refer to Table I.

Dose Degree of

Compound (µg) eye irritation PGF2a isopropyl ester (-EE) 1 3.0 ± 0.0 15-propionate-PGE2-EE 0.1 1 3.0 ± 0.0 15-propionate PGD2-IE 1 1, 3 ± 0.2 17-phenyl-18,19,20-trinor-PGF2a-IE (2) 1-5 0 15-dehydro-17-phenyl-18,19,20-trinor-PGF2e-IE (3) 15- (R) -17-phenyl-18.19.20-trinor-PGF2e-IE (7) 1-5 0 13.14-dihydro-17-phenyl-18.19.20-trinor-PGF2e-IE (9) 1 0 17-phenyl-18,19,20-trinor-PGE2-IE (5) 0.3 0 13.14-dihydro-17-phenyl-18.19.20-trinor-PGA2-IE (6) 10 16-phenyl-17 , 18,19,20-tetranor-PGF2a-IE (1) 1 2.2 ± 0.3 16- [4- (methoxy) phenyl] -17,18,19,20-tetranor-PGF2a-IE ( 8) 1 0.2 ± 0.1 18-phenyl-19,20-dinor-PGF2a-IE (10) 1 0.7 ± 0.1 19-phenyl-20-nor-PGF2a-IE (20) 5 ± 0.1 16-phenoxy-17,18,19,20-tetranor PGF2a-IE (4) 5 0.3 ± 0.2 DK 176053 B1

Table IV. Degree of conjunctival hyperaemia in the rabbit eye following administration of naturally occurring prostaglandins (PGF2e and PGE2) as well as ω-chain modified analogs used as isopropyl esters.

5 Dose Degree of

Compound Uncorrected) Hyperemia PGF2 Crisopropyl Ester (-IE) 0.1 2.8 ± 0.2 15-Propionate-PGE2-IE 0.5 2.7 ± 03 10 16-phenyl-17,18,19,20-tetranor-PGF2e -1E (1) 0.5 1.3 ± 0.9 17-phenyl-18,19,20-trinor-PGF2a-IE (2) 0.5 2.0 ± 0.3 15-dehydro-17-phenyl -18,19,20-trinor-PGF2a-IE (3) 0.5 0.7 ± 0.3 15- (R) -17-phenyl-18,19,20-trinor-PGF2a-IE (7) 0.5 2.0 ± 0.0 13.14-dihydro-17-phenyl-18.19.20-trinor-PGF2a-IE (9) 0.5 1.3 ± 0.3 17-phenyl-18.19, 20-trinor-PGE2e-IE (5) 0.5 2.7 ± 0.2 13.14-dihydro-17-phenyl-18.19.20-trinor-PGA2-IE (6) 0.5 0.3 ± 0.3 18-phenyl-19,20-dinor-PGF2a-IE (10) 0.5 0.3 ± 0.2 19-phenyl-20-nor-PGF2a-IE (20) 0.5 0.2 ± 0.2 16-phenoxy-17,18,19,20-tetranor PGF2e-IE (4) 0.5 2.3 ± 0.3 DK 176053 B1 c 26 o -i ·

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REFERENCES

Bill A (1975). Blood circulation and fluid dynamics in the eye. Physiol. Rew. 55: 383-417.

Bito LZ, Draga A, Blanco DJ, Camras CB (1983). Long-term maintenance of reduced intraocular pressure by daily or twice daily topical application of prostaglandins to cat or rhesus monkey eyes. Invest Ophthalmol Vis Sci 24: 312-319.

Bito LZ, Camras CB, Gum GG and_Resul B (1989).

The ocular hypotensive effects and side effects of prostaglandins on the eyes of experimental animals.

Progress in clinical and biological research, Vol 312.

Ed Laszlo Z Bito and Johan Stjemschantz; Alan R Liss, Inc.,

New York.

Camras CB, Bito LZ (1981). Reduction of intraocular pressure in normal and glaucomatous primate (Aotus trivirgatus) eyes by topically applied prostaglandin F2a * Curr EYe Res 1: 205-209.

Camras CB, Podos SM, Rosenthal JS, Lee PY, Severin CH (1987a). Multiple dosing of prostaglandin F2a or epinephrine on cynomolgus monkey eyes. I. Aqueous humor dynamics. Invest Ophthalmol Vis Sci 28: 463-469.

Camras CB, Bhuyan KC, Podos SM, Bhuyan DK Master RWP (1987b). Multiple dosing of prostaglandin F2fl or epinephrine on cynomolgus monkey eyes. II. Slit lamp biomicroscopy, aqueous humor analysis, and fluorescein angiography. Invest Ophthalmol.

Vis Sci 28: 921–926.

Camras CB, Siebold EC, Lustgarten JS, Series JB, Frisch SC,

Podos SM, Bito LZ (1988). Reduction of IOP by prostaglandin F2a ~ l -isopropyl ester topically applied in glaucoma patients. Ophthalmology 95 (Suppl): 129.

30 DK 176053 B1

Crawford K, Kaufman P L, and True Gabel, B'A (-1987).

Pilocarpine antagonizes PGF2a-induced ocular hyptension:

Evidence for enhancement of uveoscleral outflow by PGF2a ·

Invest. Ophthalmol. View Sci p. 11.

Flat AJ, Eliason JA (1988). Topical prostaglandin E ^ effects on normal human intraocular pressure. J Ocu Pharmacol 4: 13-18.

Giuffré G (1985). The effects of prostaglandin F2a in the human eye. Graefes Arch Clin Exp Ophthalmol 222: 139-141.

Kaufman PL (1986). Effects on intracamerally infused prostate. glandins on outflow facility in cynomolgus monkey eyes with intact or retrodisplaced ciliary muscle. Exp Eye Res 43: 819-827.

Kerstetter JR, Brubaker RF, Wilson SE, Kullerstrand LJ (1988). Prostaglandin F2a-l-isopropyl ester lowers intraocular pressure without decreasing aqueous humor flow. Am J Ophthalmol 105: 30-34.

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Invest Ophthalmol Vis Sci 29: 1474-1477.

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Nilsson S F E, Stjernschantz J and Bill A (1987).

PGF2a increases uveoscleral outflow. Invest. Ophthalmol. View Sci Suppl p 284.

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Claims (7)

Use of a prostaglandin derivative of the general formula: 5 'alpha chain € C' omega chain where A represents the alicyclic ring C8-C12 and has the formula 10 HO HO 15 wherein the alpha chain has the formula: 1 30 where R is an alkyl group having 1 to 10 carbon atoms; and wherein the omega chain has the formula: (13) (14) (15-17) c B C - D - R2 25 ---- where C is a carbon atom (the number is given in brackets); B is a single bond or a double bond; DK 176053 B1 D is a chain of 2-3 carbon atoms, optionally interrupted by heteroatoms O, S or N, the substituents on each carbon atom being H, lower alkyl groups having 1-5 carbon atoms or a hydroxyl group wherein C 15 is substituted by (R) -OH or (S) -OH; Use according to claim 1, wherein the ω chain is interrupted by an oxygen atom. Use according to claim 1 or claim 2, wherein R 1 is an i-propyl group. 15 Use according to any one of the preceding claims, wherein D is a chain of 2 carbon atoms. Use according to any one of the preceding claims, wherein the prostaglandin derivative is 16-20 phenoxy-17,18,19,20-tetranor-PGF 2 t -isopropyl ester. R 2 is a phenyl group which is unsubstituted or has at least one substituent selected from C 1 -C 5 alkyl groups, C 1 -C 4 alkoxy groups, trifluoromethyl groups, C 1 -C 3 aliphatic acyl amino groups, nitro groups, halogen atoms and a phenyl group for preparation of an ophthalmologic agent for the treatment of glaucoma or increased ocular scar pressure. An ophthalmologic agent for topical treatment of glaucoma or increased ocular pressure, comprising a derivative of prostaglandin PGF, as defined in claim 1, in an ophthalmologically acceptable carrier. 25 The ophthalmic agent of claim 6 containing 0.1-30 µg of the prostaglandin derivative. An ophthalmic agent according to claim 7 containing 1-10 / Ag of the prostaglandin derivative.