Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension

The invention relates to ophthalmological compositions for topical treatment of glaucoma or ocular hypertension comprising an effective intraocular pressure reducing amount of a prostaglandin derivative of PGA, PGB, PGD, PGE or PGF, in which the omega chain contains a ring structure, in an ophthalmologically compatible carrier. The invention further relates to the preparation of said compositions and their use for treatment of glaucoma or ocular hypertension.

EXAMPLE 1 
 Preparation of 16-phenyl-17,18,19,20-tetranor PGF 2&agr; -isopropyl Ester (1) A 50 ml round bottom flask equipped with a magnetic stirring bar was charged with 17.5 mg (0.04 mmol) 16-phenyl-17,18,19,20-tetranor PGF 2&agr; (Cayman Chemical), 5 ml CH 2 Cl 2 ,30.2 mg (0.23 mmol) diisopropylethylamine. This solution was stirred at −10° C. and 13.5 mg (0.07 mmol) of isopropyltriflate (freshly prepared) was added. This solution was allowed to stand at −10° C. for 15 min and was then slowly warmed to room temperature. When the esterification was complete according to TLC (usually after 3-4 h at room temperature) the solvent was removed in vacuo. The residue was diluted with 20 ml ethylacetate, washed with 2×10 ml 5% sodium hydrogencarbonate and 2×10 ml 3% citric acid. The organic layer was dried over unhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel-60 using ethyl acetate: aceton 2:1 as eluent. The title compound was obtained as a colourless oily substance (71% yield). Nuclear Magnetic Resonance Spectrum (CDCl 3 )-ppm: &dgr; 1 1.2 (6H d) 3.3 (1H q) 2.85 (2H d) 5.0 (1H m) 3.85 (1H m) 5.3-5.7 (4H m) 4.15 (1H t) 7.15-7.35 (5H m) 
 EXAMPLE 2 
 Preparation of 17-phenyl-18,19,20-trinor PGF 2&agr; -isopropyl Ester (2) A 50 ml round bottom flask equipped with a magnetic stirring bar was charged whith 20 mg (0.05 mmol) 17-phenyl-18,19,20-trinor PGF 2&agr; (Cayman Chemicals), 6 ml acetone, 39.2 mg (0.25 mmol) DBU and 42.5 mg (0.25 mmol) isopropyl iodide. The solution was allowed to stand at room temperature for 24 h, the solvent was removed in vacuo and the residue was diluted with 30 ml of ethyl acetate, washed twice with 10 ml 5% sodiumhydrogen carbonate and 10 ml 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 (CDCl 3 )-ppm: &dgr; 2 1.2 (6 m) 4.9 (1H m) 3.9 (1H m) 5.4-5.6 (4H m) 4.1 (1H t) 7.1-7.3 (5H m) 4.2 (1H m) 
 EXAMPLE 3 
 Preparation of 15-dehydro-17-phenyl-18,19,20-trinor PGF 2&agr; -isopropyl Ester (3) 20.9 mg (0.092 mmol) DDQ was added to a solution of 10 mg (0.023 mmol) 17-phenyl-18,19,20 trinor PGF 2&agr; -isopropyl ester (2) in 8 ml dioxane. The reaction mixture immediately turned brown, the reaction mixture was stirred at room temperature for 24 h. The precipitate formed was filtered, washed with 10 ml ethyl acetate, the filtrate was diluted with 10 ml ethylacetate washed with 2×10 ml water, 2×10 ml NaOH IM and 20 ml brine. The organic layer was dried on unhydrous sodium sulfate and the solvent was removed in vacuo, 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 colourless oily substance (76% yield). Nuclear Magnetic Resonance Spectrum (CDCl 3 ),-ppm: &dgr; 3 1.2 (6H d) 5.4 (2H m) 4.0 (1H m) 6.2 (1H d) 4.2 (1H m) 6.7 (1H q) 5.0 (1H m) 7.15-7.35 (5H m) 
 EXAMPLE 4 
 Preparation of 16-phenoxy-17,18,19,20-tetranor PGF 2&agr; -isopropyl Ester(4) Following a procedure similar to that described in example 2 using 20 mg (0.051 mmol) 16-phenoxy-17,18,19,20-tetranor PGF 2&agr; (Cayman Chemicals). The title compound (4) was an oily substance (53.2% yield). Nuclear Magnetic Resonance Spectrum (CDCl 3 )-ppm: &dgr; 4 1.2 (6H d) 5.4 (2H m) 3.9 (3H m) 5.7 (2H m) 4.2 (1H m) 6.9 (3H m) 4.5 (1H m) 7.3 (2H m) 5.0 (1H m) 
 EXAMPLE 5 
 Preparation of 17-phenyl-18,19,20-trinor PGE 2 -isopropyl Ester (5) Following a procedure similar to that described in example 2 using 10 mg (0.026 mmol) 17-phenyl-18,19,20-trinor PGE 2 (Cayman Chemicals). The crude product was purified by column chromatography on silica gel-60 using ether as eluent. The title compound (5) was an oily substance (38.9% yield). Nuclear Magnetic Resonance Spectrum (CDCl 3 )-ppm: &dgr; 5 1.2 (6H d) 5.3 (2H m) 3.9-4.1 (2H m) 5.6 (2H m) 4.9 (1H m) 7.2 (5H m) 
 EXAMPLE 6 
 Preparation of 13,14-dihydro-17-phenyl-18,19,20-trinor PGA 2 -isopropyl Ester (6) Following a procedure similar to that described in example 2 using 10 mg (0.026 mmol) 13,14-dihydro-17-phenyl PGA 2 (Cayman Chemicals). The crude product was chromatographed on silica gel-60 using ether as eluent. Nuclear Magnetic Resonance Spectrum (CDCl 3 )-ppm: &dgr; 6 1.2 (6H d) 5.4 (2H m) 4.35 (1H m) 7.3 (5H m) 5.0 (1H m) 
 EXAMPLE 7 
 Preparation of 15-(R)-17-phenyl-18,19,20-trinor PGF 2&agr; -isopropyl Ester (7). (Table II) 7.1 Preparation of 1-(S)-2-oxa-3-oxo-6-(R)-(3-oxo-5-phenyl-1-trans-pentenyl)-7-(R)-(4-phenylbenzoyloxy)-cis-bicyclo &lsqb;3,3,0&rsqb; Octane (13). 18 g (0.05 mol) alcohol (11), 32 g (0.15 mol) DCC, 39.1 g (0.5 mol) DMSO (newly distilled from CaH 2 ) and 30 ml DME were charged to a 200 ml flask under nitrogen. Ortho-phosphoric acid was added in one portion, and an exothermic reaction occured. The reaction mixture was stirred mechanically at room temperature for 2 h, and the resultant precipitate was filtered and washed with DME. The filtrate (12) can be used directly for Emmon condensation reaction. To a suspension of 1.2 g (0.04 mol) NaH (80% washed with n-pentane to remove mineral oil) in 100 ml DME under nitrogen was added dropwise 12.3 g (0.048) dimethyl-2-oxo-4-phenyl-butyl-phosphonate in 30 ml DME. The mixture was stirred mechanically for 1 h at room temperature, then cooled to −10° C. and a solution of the crude aldehyde (12) was added in dropwise. After 15 min at 0° C. and 1 h at room temperature the reaction mixture was neutralized with glacial acetic acid, the solvent was removed under vaccum, and to the residue was added 100 ml ethyl acetate, washed with 50 ml water and 50 ml brine. The organic layer was dried over unhydrous sodium sulfate. The solvent was removed in vacuo and the resulting white precipitate filtered and washed with cold ether. The title compound (13) was obtained as a crystalline substance mp 134.5-135.5 (53% yield). 7.2 Preparation of 1-(S)-2-oxa-3oxo-6-(R)-&lsqb;3-(R,S)-hydroxy-4-phenyl-1-trans-pentenyl&rsqb;-7-(R)-(4-phenylbenzoyloxy) cis-bicyclo &lsqb;3,3,0&rsqb;Octane (14). 10 g (0.021 mol) enone (13) and 3.1 g (0,008 mol) cerous-chloride heptahydrate in 50 ml methanol and 20 ml CH 2 Cl 2 were charged to a 200 ml round bottom flask equipped with a magnetic stirring bar and was cooled to −78° C. under nitrogen. Sodium borohydride was added in small portions, after 30 min the reaction mixture was quenched by addition of saturuted NH 4 Cl, and extracted with 2×50 ml ethyl acetate. The extracts were dried and concentrated to leave a colourless oil (98% yield). 7.3 Preparation of 1-(S)-2-oxa-3-oxo-6-(R)-&lsqb;3-(R,S)-hydroxy-4-phenyl-1-trans-pentenyl&rsqb;-7-(R)-hydroxy-cis-bicyclo-&lsqb;3,3,0&rsqb; Octane (15). To a solution of 9.8 g (0.02 mol) ketal (14) in 100 ml absolute methanol was added 1.7 (0.012 mol) potassium carbonate. The mixture was stirred with a magnetic bar, at room temperature after 3 h. The mixture was neutralized with 40 ml HCl 1 M, and extracted with 2×50 ml ethyl acetate. The extracts were then dried on unhydrous sodium sulfate and concentrated. The crude product was chromatographed on silica gel using ethyl acetate: acetone as eluent. The title compound (15) was obtained as an oily substance (85% yield). 7.4 Preparation of 1-(S)-2-oxa-3-hydroxy-6-(R)-&lsqb;3-(R,S)-hydroxy-4-phenyl-1-trans-pentenyl&rsqb;-7-(R)-hydroxy-cis-bicyclo&lsqb;3,3,0&rsqb; (16). To a solution of 3 g(0.011 mol) lactone (15) in 60 ml unhydrous THF, stirred magnetically and cooled to −78° C., 4.5 g (0.0315 mol) DIBAL-H in toluene was added dropwise. After 2 h the reaction mixture was quenched by addition of 75 ml methanol. The mixture was filtered, the filtrate was concentrated 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 semisolid substance (78% yield). 7.5 Preparation of 15-(R,S)-17-phenyl-18,19,20-trinor PGF 2&agr; (17). 2.5 g (25 mmol) sodium methyl sulfinylmethide in DMSO (freshly prepared from sodium anhydride and DMSO) was added dropwise to a solution of 5.6 g (12.6 mmol) 4-caboxybutyl triphenyl-phosphonium bromide in 12 ml DMSO. To the resultant red solution of the ylide was added dropwise a solution of the 1.2 g (4.2 mmol) hemiacetal (16) in 13 ml DMSO, and the mixture was stirred for 1 h. The reaction mixture was diluted with 10 g ice and 10 ml water and extracted with 2×50 ml ethyl acetate, whereafter the aqueous layer was cooled, acidified with HCl 1 M and extracted with ethyl acetate, and then the organic layer was dried and concentrated. The resulting crude product was a colourless substance. The purity of the title compound (17) was estimated by TLC on silica gel using ethyl acetate: acetone: acetic acid 1:1:0.2 v/v/v as eluent. 7.6 Preparation of 15-(R)-17-phenyl-18,19,20-trinor PGF 2&agr; -isopropyl Ester (7). The crude product (17) was esterified following a procedure similar to that described in example 2 the product was purified by column chromatography on silica gel-60 using ethyl acetate as eluent and the resulting mixture of C 15 epimeric alcohol were separated. The title compound (7) was obtained as a colourless oily substance (46% yield). Nuclear Magnetic Resonance Spectrum (CDCl 3 ),-ppm: &dgr; 7 1.2 (6H m) 5.4 (2H m) 3.9 (1H m) 5.6 (2H m) 4.15 (2H m) 7.2 (5H m) 4.95 (1H m) 
 EXAMPLE 8 
 Preparation of 16-&lsqb;4-(methoxy)phenyl&rsqb;-17,18,19,20-tetranor PGF 2&agr; -isopropyl Ester (8) 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-3-&lsqb;4-(methoxy)phenyl&rsqb;-propylphosphonate and was purified by column chromatography on silica gel-60 using ethyl acetate: toluene 1:1 as eluent. A colourless oily substance was obtained (57% yield). The title compound 16-&lsqb;4-(methoxy)phenyl&rsqb;-17,18,19,20-tetranor PGF 2&agr; -isopropyl ester (8) was obtained as an oily substance, and purified by column chromatography on silica gel-60 using ethyl acetate as eluent (46% yield). Nuclear Magnetic Resonance Spectrum (CDCl 3 )-ppm: &dgr; 8 1.2 (6H d) 5.0 (1H m) 2.8 (2H d) 5.4 (2H m) 3.75 (3H S) 5.6 (2H m) 3.9 (1H m) 6.8 (2H d) 4.15 (1H m) 7.2 (2H d) 4.3 (1H m) 
 EXAMPLE 9 
 Preparation of 13,14-dihydro-17-phenyl-18,19,20-trinor PGF 2&agr; -isopropyl Ester (9) Following a procedure similar to that described in example 7, with minor modification, 5 g (0.018 mol) enone (13) in 100 ml THF was reduced using 2.03 g 10% pd/c under hydrogen atmosphere. After completion of the reaction (as determined by TLC on silica gel using ethylacetate: toluene 1:1 as eluent) the mixture was filtered on celite. The filtrate was concentrated in vacuo and an oily substance was obtained (86% yield). The final product 13,14-dihydro-17-phenyl-18,19,20-trinor PGF 2&agr; -isopropyl ester containing a mixture of C 15 epimeric alcohols were separated by preparative liquid chromatography using 40% CH 3 CN in water v/v as eluent. Nuclear Magnetic Renonance Spectrum (CDCl 3 )-ppm: &dgr; 9 1.2 (6H d) 5.0 (1H m) 3.6 (1H m) 5.4 (2H m) 3.9 (1H m) 7.2 (5H m) 4.15 (1H m) 
 EXAMPLE 10 
 Preparation of 18-phenyl-19,20-trinor PGF 2&agr; -isopropyl Ester (10) Following a procedure similar to that described in example (7) with modified step 7-2. The aldehyde (12) described in 7-2 was reacted with dimethyl-2-oxo-5-phenyl pentyl phosphonate gave a crystalline substance trans-enone lactone (67% yield). The final product 18-phenyl-19,20-dinor PGF 2&agr; -isopropyl ester (10) was purified by column chromatography on silica gel-60 using ethyl acetate as eluent gave a colourless oil (41% yield). 10 1.2 (6H d) 5.0 (1H m) 3.95 (1H m) 5.4 (2H m) 4.10 (1H m) 5.6 (2H q) 4.20 (1H m) 7.2 (5H m) 
 EXAMPLE 11 
 Preparation of 19-phenyl-20-nor-PGF 2&agr; -isopropyl Ester (20) Following a procedure similar to that described in example (7) with modified step (7-2). The aldehyde (12) described in (7-2) was reacted with dimethyl-2-oxo-6-phenyl-hexylphosphonate gave a colourless oil trans-enone lactone (56% yield). The final product 19-phenyl-20-nor-PGF 2&agr; -isopropyl ester (20) was a colourless oil, and was purified by column chromatography on silica gel-60 using ethyl acetate as eluent (30% yield). Nuclear Magnetic Resonance Spectrum (CDCl 3 )-ppm: &dgr; 11 1.2 (6H d) 5.0 (1H m) 2.6 (2H t) 5.4 (2H m) 3.9 (1H m) 5.5 (2H t) 4.1 (1H m) 7.2 (5H m) 4.2 (1H m) Studies of Eye Pressure Lowering Effect and Adverse Reactions The intraocular pressure (IOP) was determined in animals with a pneumatonometer (Digilab Modular One™, Bio Rad), specially calibrated for the eye of the particular species. The cornea was anaesthetized with 1-2 drops of oxibuprocain before each IOP measurement. In healthy human volunteers IOP was measured with applanation tonometry or with an air puff tonometer (Keeler pulsair). For applanation tonometry either a pneumatonometer (Digilab) or Goldmann's applanation tonometer mounted on a slit lamp microscope was used. The cornea was anaesthetized with oxibuprocain before each measurement with applanation tonometry. No local anaesthesia was employed before measurement with the pulsair tonometer. The ocular discomfort after application of the test substances was evaluated in cats. The behaviour of cats after topical application of the test drug was followed and ocular discomfort was graded on a scale from 0 to 3, 0 indicating complete absence of any signs of discomfort, and 3 indicating maximal irritation as obvious from complete lid closure. Conjunctival hyperemia after topical application of the test substances was evaluated in rabbits. The conjunctiva at the insertion of the superior rectus muscle of the eye was inspected or photographed with regular intervals and the degree of hyperemia was later evaluated from the color photographs in a blind manner. Conjunctival hyperemia was evaluated on a scale from 0 to 4, 0 indicating complete absence of any hyperemia, and 4 indicating marked hyperemia with conjunctival chemosis. For determination of the effects on the intraocular pressure, primarily monkeys (cynomolgus) were employed. The reason for this is that the monkey eye is highly reminiscent of the human eye and therefor, generally, drug effects are readily extrapolated to the human eye. However, the disadvantage of using the monkey eye as a model is that the conjunctiva in this species is pigmented making it impossible to evaluate conjunctival hyperemia and furthermore, the monkey eye is relatively insensitive to irritation. Therefore, the cat eye, being very sensitive to prostaglandins was used for evaluating ocular discomfort and the rabbit eye with pronounced tendency to hyperemic reactions was used for evaluating conjunctival and episcleral hyperemia. It is evident from Table III that modification of the omega chain of the prostaglandin skeleton introduced new and unexpected features to the prostaglandins with respect to ocular irritation (discomfort). Particularly 17-phenyl,18,19,20-trinor-PGF 2&agr; -IE and analogs were unique in exhibiting a complete loss of ocular irritation with retained IOP lowering effect in monkeys. Whereas the 17-phenyl,18,19,20-trinor-PGF 2&agr; derivatives were extremely well tolerated, 16-phenyl-17,18,19,20-tetranor-PGF 2&agr; -IE caused clear ocular discomfort although to a lesser degree than PGF 2&agr; -IE or 15-propionate-PGE 2 -IE (Table III). However, substituting a hydrogen atom in the phenyl ring with a methoxy group having electron donating properties rendered the molecule practically free of ocular irritating effect, Table III. It is also evident from Table III that 18-phenyl-19,20,-dinor-PGF 2&agr; IE, 19-phenyl-20-nor-PGF 2&agr; -IE as well as 17-phenyl-18,19,20-trinor-PGE 2 -IE and 13,14-dihydro-17-phenyl-18,19,20-trinor-PGA 2 -IE, had no or very little irritating effect in the eye of cats. This indicates that the invention not only is valid for 16-, and 17-tetra- and trinor analogs of PGF 2&agr; but for a range of omega chain modified and ring substituted analogs of PGF 2&agr; (as exemplified with 16-phenyl-17,18,19,20-tetranor-PGF 2&agr; -IE to 19-phenyl-20-nor-PGF 2&agr; -IE), and more importantly even for different members of the prostaglandin family such as PGE 2 and PGA 2 modified in an analogous way (Table III). Thus, modifying the omega chain and substituting a carbon atom in the chain with a ring structure introduces completely new, unexpected and advantageous qualities to naturally occuring prostaglandins in that the irritating effect in the conjunctiva and cornea is abolished. In the case of 16-phenyl-17,18,19,20-tetranor-PGF 2&agr; -IE exhibiting some irritating effect substituting a hydrogen atom in the ring structure with e.g. a methoxy group attenuates or abolishes the irritating effect. In addition to the lack of ocular discomfort the omega chain modified analogs also exhibited an advantage over naturally occuring prostalgandins in that they caused considerably less conjunctival hyperemia as studied in the rabbit eye (Table IV). Particularly, 15-dehydro-17-phenyl-18,19,20-trinor-PGF 2&agr; -IE,13,14-dihydro-17-phenyl-18,19,20-trinor-PGF 2&agr; -IE, and 13,14-dihydro-17-phenyl-18,19,20-trinor PGA 2 -IE were advantageous in this respect. Also 18-phenyl-19,20-dinor-PGF 2&agr; -IE and 19-Phenyl-20-nor-PGF 2&agr; -IE induced very little conjunctival hyperemia (TableIV). The intraocular pressure lowering effect of omega chain modified and ring-substituted prostaglandin analogs is demonstrated in Table V. It can be seen that particularly 16-phenyl-tetranor and 17-phenyl-trinor prostaglandin analogs significantly reduced IOP in animal eyes (Table V). In all but two series of experiments cynomolgus monkeys were used. It is of particular interest to note that 17-phenyl-18,19,20-trinor PGF 2&agr; -derivatives exhibiting no ocular irritation and only modest conjunctival/episcleral hyperemia significantly lowered IOP in primates. It should furthermore be observed that both 16-phenyl-17,18,19,20-tetranor-PGF &agr; -IE, 18-phenyl-19,20-dinor-PGF 2&agr; -IE and 19-phenyl-20-nor-PGF &agr; -IE reduced the intraocular pressure, thus, modification of the omega chain and substituting a carbon atom in the chain with a ring structure do not render the molecule inactive with respect to the effect on the intraocular pressure. Furthermore, it should be observed that substituting a hydrogen on the ring structure of 16-phenyl,17,18,19,20-tetranor-PGF 2&agr; -IE with a methoxy group eliminated much of the ocular irritating effect preserving most of the intraocular pressure lowering effect. Thus, omega chain modified and ring substituted prostaglandin analogs reduce IOP effectively in animals. It is further demonstrated in Table V that 16-phenoxy-17,18,19,10-tetranor-PGF 2&agr; -IE effectively lowers the intraocular pressure as studied in cats. Thus, substituting carbon 17 in the omega chain with a hetero atom, in this case oxygen, does not render the molecule inactive with respect to the effect on IOP. It is noteworthy that most of the 17-phenyl,18,19,20-trinor-prostaglandin analogs had poor intraocular pressure lowering effect in cats, even at high doses. It is to be observed that the doses at which compounds were used presented in Table III are lower than those e.g. in Table V. Doses presented in Table III should be explicitly compared with those of the naturally occuring prostaglandins in the same table. The same is true for Table IV. It is clear that with increasing dose side effects may increase. However, the doses of prostaglandin derivatives used in monkeys are comparatively similar to those used in human volunteers, (Table VI) being practically free of side effects. The effect of some omega chain modified prostaglandin analogs, more specifically 17-phenyl-18,19,20-trinor-PGF 2&agr; -IE, 15-dehydro-17-phenyl-18,19,20-trinor-PGF 2&agr; -IE, 15-(R)-17-phenyl-18,19,20-trinor-PGF 2&agr; -IE, 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF 2&agr; -IE, and 18-phenyl-19-20-dinor-PGF 2&agr; -IE on the intraocular pressure of healthy human volunteers is demonstrated in Table VI. All compounds significantly reduced the intraocular pressure. It is particularly significant in this respect that none of the compounds had any significant irritating effect (ocular discomfort) and that 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF 2&agr; -IE and 15-dehydro-17-phenyl-18,19,20-trinor-PGF 2&agr; -IE caused very little if any conjunctival/episcleral hyperemia in man. Thus, omega chain modified, and ring substituted prostaglandin analogs seem to be unique in that these compounds reduce IOP without causing significant ocular side effects such as hyperemia and discomfort. The present invention thus describes a group of compounds exhibiting the unique property of causing insignificant ocular side effects while retaining the intraocular pressure lowering effect. From the foregoing it is evident that the crucial modification of the molecule is a ring structure in the omega chain. Furthermore, substituents in the ring structure and/or in the omega chain may be introduced in certain molecules still exhibiting some side-effects in the eye. Hetero atoms may also be introduced into the ring substituted omega chain. Presently, particularly 17-phenyl-18,19,20-trinor-PGF 2&agr; -derivatives seem very promising for therapeutic use in glaucoma. From the scientific literature it is evident that PGE 2 and PGA 2 or their esters lower IOP in the monkey (see Bito et al, 1989). Clinical studies with PGE 2 have also been performed demonstrating IOP-lowering effect in man (Flach and Eliason (1988)). Thus, the analogy with PGF 2&agr; and its esters lowering IOP in the primate eye is logic. It is most reasonable to assume that other prostaglandins with modified omega chain exhibit essentially the same properties as PGF 2&agr; with modified omega chain, i.e. IOP lowering effect without side effects. 12 TABLE I 5 6 7 8 9 10 11 12 13 14 15 13 TABLE II 16 17 18 19 Reagents: a) DCC/DMSO/DME b) NaH/dimethyl-2-oxo-4-phenylbutyl phosphonate/DME c) CeCl 3 .7H 2 O/NaBH 4 /CH − 3 OH/−78° C. d) K 2 CO 3 /CH 3 OH e) Dibal/−78° C. f) NaCH 2 SOCH 3 /(4-carboxybutyl)-triphenylphosphonium bromide/DMSO g) DBU/iprI/acetone 14 TABLE III Irritative effect of naturally occuring prosta- glandins (PGF 2&agr; , PGD 2 and PGE 2 ), and omega chain modified analogs applied as isopropylester on the cat eye. The avarage degree of discomfort was evaluated during 60 min after topical application of the respective test drug. The numbers within paranthesis refer to Table I. Dose Degree of Substance (pg) occular irritation PGF 2&agr; -isopropylester (-IE) 1 3.0 ± 0.0 15-propionate-PGE 2 -IE 0.1-1 3.0 ± 0.0 15-propionate-PGD 2 -IE 1 1.3 ± 0.2 17-phenyl-18,19,20- (2) 1-5 0 trinor-PGF 2&agr; -IE 15-dehydro-17-phenyl- (3) 5 0 18,19,20-trinor- 15-(R)-17-phenyl- 18,19,20-trinor-PGF 2&agr; -IE (7) 1-5 0 13,14-dihydro-17-phenyl- (9) 1 0 16,19,20-trinor-PGF 2&agr; -IE 17-phenyl-18,19,20- (5) 0.3 0 trinor-PGE 2 -IE 13,14-dihydro-17-phenyl- (6) 1 0 18,19,20-trinor-pGA 2 -IE 16-phenyl-17,18,19,20- (1) 1 2.2 ± 0.3 tetranor-PGF 2&agr; -IE 16-&lsqb;4-(methoxy)-phenyl&rsqb;- (8) 1 0.2 ± 0.1 17,18,19,20-tetranor- PGF 2&agr; -IE 18-phenyl-19,20-dinor- (10) 1 0.7 ± 0.1 PGF 2&agr; -IE 19-phenyl-20-nor-pGF 2&agr; -IE (20) 1 0.5 ± 0.1 16-phenoxy-17,18,19,20- (4) 5 0.3 ± 0.2 tetranor-PGF 2&agr; -IE 15 TABLE IV Degree of conjunctival hyperemia in the rabbit eye after application of naturally occuring prostaglandins (PGF 2&agr; , and PGE 2 ), and omega chain modified analogs applied as isopropylesters. Dose Degree of Substance (&mgr;g) hyperemia PGF 2&agr; -isopropylester (-IE) 0.1 2.8 ± 0.2 15-propionate-PGE 2 -IE 0.5 2.7 ± 0.3 16-phenyl-17,18,19,20- (1) 0.5 1.3 ± 0.9 tetranor-PGF 2&agr; -IE 17-phenyl-18,19,20-trinor- (2) 0.5 2.0 ± 0.3 PGF 2&agr; -IE 15-dehydro-17-phenyl- (3) 0.5 0.7 ± 0.3 18,19,20-trinor-PGF 2&agr; -IE 15-(R)-17-phenyl-18,19,20- (7) 0.5 2.0 ± 0.0 trinor-PGF 2&agr; -IE 13,14-dihydro-17-phenyl- (9) 0.5 1.3 ± 0.3 18,19,20-trinor-PGF 2&agr; -IE 17-phenyl-18,19,20-trinor- (5) 0.5 2.7 ± 0.2 PGE 2 -IE 13,14-dihydro-17-phenyl- (6) 0.5 0.3 ± 0.3 18,19,20-trinor-PGA 2 -IE 18-phenyl-19,20-dinor- (10) 0.5 0.3 ± 0.2 PGF 2&agr; -IE 19-phenyl-20-nor-PGF 2&agr; -IE (20) 0.5 0.2 ± 0.2 16-phenoxy-17,18,19,20- (4) 0.5 2.3 ± 0.3 tetranor-PGF 2&agr; -IE 16 TABLE V Intraocular pressure reducing effect of naturally occuring prostaglandin (PGF 2&agr; ) and omega chain modified analogs as determined in cynomolgus monkeys or cats. Unless specified data were obtained in monkeys. The figures within parenthesis refer to formulas given in Table I. Time after administration (hour) 0 1-2 3-4 6 Substance Dose (&mgr;g) (mmHg) (mmHg) (mmHg) (mmHg) E 11.4 ± 0.7 8.3 ± 0.5 8.0 ± 0.6 9.3 ± 0.8 * * PGF 2&agr; -isopropylester (IE) 1.5 C 11.0 ± 0.7 10.7 ± 0.4 10.1 ± 0.4 10.6 ± 0.9 16-phenyl-17, 18, 19, 20- 3.2 E 12.7 ± 1.1 11.8 ± 1.1 9.1 ± 0.8 8.4 ± 0.7 * * tetranor-PGF 2&agr; -IE (1) C 12.8 ± 0.5 14.0 ± 0.2 13.0 ± 0.8 11.7 ± 0.8 17-phenyl-18, 19, 20- 3.2 E 12.8 ± 0.6 11.9 ± 0.5 8.6 ± 0.3 9.5 ± 0.7 * trinor-PGF 2&agr; -IE (2) C 13.4 ± 0.6 11.7 ± 0.6 12.4 ± 0.2 11.9 ± 0.7 13, 14-dihydro-17—phenyl- 10.4 E 11.1 ± 0.9 8.3 ± 0.6 6.9 ± 0.4 7.7 ± 0.8 * 18, 19, 20-trinor-PGF 2&agr; -IE (9) C 10.6 ± 0.7 8.8 ± 0.9 10.3 ± 1.1 9.5 ± 1.0 18-phenyl-19, 20-donor- 3.1 E  9.7 ± 0.9 9.6 ± 1.1 9.6 ± 1.1 8.8 ± 0.9 * PGF 2&agr; -IE (10) C 10.1 ± 1.0 9.4 ± 1.2 9.8 ± 1.2 9.4 ± 0.9 16-phenoxy-17, 18, 19, 20 5 ** E 20.5 ± 1.2 25.7 ± 1.2 19.2 ± 1.8 15.0 ± 1.2 * tetranor-PGF 2&agr; -IE (4) C 20.7 ± 1.2 22.7 ± 1.1 19.5 ± 0.9 19.2 ± 0.8 16-&lsqb;4-(methoxy)-phenyl&rsqb;- 3.2 E 11.2 ± 0.9 10.5 ± 1.3 9.8 ± 1.4 9.2 ± 0.9 17, 18, 19, 20-tetranor- * PGF 2&agr; -IE (8) C 10.4 ± 1.1 10.9 ± 1.0 11.3 ± 1.4 9.2 ± 0.6 19-phenyl-20-nor- 1 ** E 16.9 ± 1.0 16.6 ± 0.7 15.8 ± 0.8 18.1 ± 1.2 * PGF 2&agr; -IE (20) C 17.1 ± 0.4 18.1 ± 0.6 18.9 ± 0.6 19.2 ± 0.8 * Indicates statistical significance p <0.05. The substances were applied topically. ** Data obtained in cat eyes. 17 TABLE VI Intraocular pressure reducing effect of different omega chain modified and ring substituted PGF 2&agr; -IE analogs, in healthy human volunteers. The substance number is given within paranthesis. Time after administration (hours) Dose 0 4 6 8 Substance (&mgr;g) n Eye (mmHg) (mmHg) (mmHg) (mmHg) 17-phenyl-18, 19, 20-trinor- 1 4 Exp 11.9 ± 1.7 11.0 ± 0.9 10.1 ± 0.7 9.8 ± 0.7 PGF 2&agr; -isop * * * ropylester (IE) (2) Contr 12.7 ± 1.7 13.9 ± 0.7 13.5 ± 1.2 12.5 ± 0.7 15-(R)-17-phenyl-18, 19, 20- 10 3 Exp 12.9 ± 0.9 11.8 ± 0.6 11.0 ± 0.3 11.2 ± 1.3 * trinor-PGF 2&agr; -IE (7) Contr 13.2 ± 1.4 13.7 ± 0.9 13.8 ± 1.0 15.1 ± 1.3 15-dehydro-17-phenyl- 10 4 Exp 17.7 ± 0.6 14.6 ± 0.2 13.6 ± 0.7 — * * 18, 19, 20-trinor-PGF 2&agr; IE (3) Contr 17.5 ± 0.7 16.4 ± 0.5 16.3 ± 1.0 — 13, 14-dihydro-l7-phenyl- 1 4 Exp 14.2 ± 0.5 13.3 ± 1.1 12.2 ± 0.4 12.5 ± 0.9 * 18, 19, 20-trinor-PGF 2&agr; IE (9) Contr 13.5 ± 0.6 14.2 ± 1.2 15.2 ± 1.0 15.1 ± 0.7 18-phenyl-19, 20-dinor- 5 3 Exp 14.4 ± 1.0 12.2 ± 1.1 12.4 ± 1.2 11.9 ± 0.7 * PGF 2&agr; -IE (10) Contr 15.2 ± 0.1 13.7 ± 1.2 14.4 ± 0.2 13.2 ± 0.5 * Indicates statistical significance p <0.05. 
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