WO1992013836A1 - 2-decarboxyl-2-hydroxyalkyl-5-trans prostaglandin f derivatives - Google Patents
2-decarboxyl-2-hydroxyalkyl-5-trans prostaglandin f derivatives Download PDFInfo
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- WO1992013836A1 WO1992013836A1 PCT/US1992/000929 US9200929W WO9213836A1 WO 1992013836 A1 WO1992013836 A1 WO 1992013836A1 US 9200929 W US9200929 W US 9200929W WO 9213836 A1 WO9213836 A1 WO 9213836A1
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- trans
- configuration
- decarboxyl
- pgf
- compound
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 229940001474 sodium thiosulfate Drugs 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0016—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing only hydroxy, etherified or esterified hydroxy groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
Definitions
- the present invention relates to novel 2-decarboxyl-2-hydroxyalkyl derivatives of 5-trans prostaglandins of the F series.
- the invention further concerns pharmaceutical compositions and methods for reducing or maintaining intraocular pressure by applying to the eye one or more of these compounds.
- prostan-1-ols and their esters are disclosed in the U.S. Patent No. 4,156,745.
- the prostan-1-ol esters are described as useful for inducing menstruation or interrupting a pregnancy similarly to the corresponding natural prostaglandins but exhibiting a stronger and substantially longer effectiveness, whereas the corresponding prostan-1-ol compounds are mentioned as intermediates for their preparation.
- the general formulas in this patent encompass a vast number of compounds, including prostaglandin 1-ols and 1-ol esters both in the naturally occurring 5-cis configuration and the corresponding 5-trans derivatives, all compounds shown in the examples or specifically listed, belong to the 5-cis series. There is no mention of any ocular use for these compounds.
- Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy ocular hypertensive episodes, glaucoma, and as presurgical adjuncts.
- Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
- the underlying causes of primary glaucoma are not yet known.
- the increased intraocular tension is due to the obstruction of aqueous humor outflow.
- chronic openangle glaucoma the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded.
- acute or chronic angle-closure glaucoma the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of iris forward against the angle, and may produce pupillary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity.
- Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm.
- Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe, and may plug the drainage channel with exudates.
- Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
- glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision.
- topical ⁇ -adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.
- Prostaglandins were earlier regarded as potent ocular hypertensives., however, evidence accumulated in the last decade showsthat some protaglandins are highly effective ocular hypotensive agents, and are ideally suited for the long-term medical management of glaucoma (see, for example, Bito, L. Z. Biological Protection with Prostaglandins Cohen, M. M., ed., Boca Raton, Fla, CRC Press Inc., 1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the Medical Treatment of Glaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune & Stratton, 1984, pp.
- Such prostaglandins include PGF 2 ⁇ , PGF 1 ⁇ , PGE 2 , and certain lipid-soluble esters, such as C 1 to C 5 alkyl esters, e.g. 1-isopropyl ester, of such compounds.
- the isopropyl ester of PGF 2 ⁇ has been shown to have significantly greater hypotensive potency than the parent compound, which was attributed to its more effective penetration through the cornea. In 1987 this compound was described as "the most potent ocular hypotensive agent ever reported" [see, for example, Bito, L. Z., Arch. Ophthalmol. 105, 1036 (1987), and Siebold et al., Prodrug 5 , 3 (1989)].
- prostaglandins appear to be devoid of significant intraocular side effects
- ocular surface (conjunctival) hyperemia and foreign-body sensation have been consistently associated with the topical ocular use of such compounds, in particular PGF 2 ⁇ and its prodrugs, e.g. its 1-isopropyl ester, in humans.
- the clinical potential of prostaglandins in the management of conditions associated with increased ocular pressure, e.g. glaucoma are greatly limited by these side effects.
- Intraocular pressure reducing 15-acyl prostaglandins are disclosed in the co-pending application USSN 357,394 (filed
- 5-trans PGF 2 ⁇ as an ocular hypotensive agent causing minimal or no ocular surface hyperemia, is disclosed in the co-pending application USSN 496,879 filed 19 March 1990.
- the present invention relates to new 2-decarboxyl-2-hydroxyalkyl derivatives of 5-trans prostaglandin F compounds, including their 1a-homo- and 1-nor derivatives, and to their use for the treatment of glaucoma and ocular hypertension when formulated in a pharmaceutically acceptable vehicle.
- the alcohol derivatives of 5-trans prostaglandin compounds, where the 5,6-double bond is in the trans rather than the natural cis configuration are more potent ocular hypotensives than the respective 5-cis compounds and show significantly reduced adverse side effects, notably ocular surface hyperemia.
- the present invention concerns 2-decarboxyl-2-hydroxyalkyl 5-trans PGF derivatives of the formula (I)
- R is hydrogen or a -(CO)R 4 group; R 1 , R 2 and R 3 independently are hydroxyl, or -O(CO)R 5 groups, wherein R 4 and R 5 independently stand for saturated or unsaturated acyclic hydrocarbons having from 1 to about 20 carbon atoms, or -(CH 2 ) n R 6 where n is 0-10, and R 6 is an aliphatic, aromatic or heteroaromatic ring, X is a -C(R 7 ,R 8 )- group, wherein R 7 and R 8 independently are hydrogen or alkyl of one to about
- the present invention concerns ophthalmically acceptable pharmaceutical compositions comprising an amount effective in lowering ocular pressure of a compound of formula (I), as hereinabove defined, or a pharmaceutically acceptable salt thereof, in admixture with a non-toxic, pharmaceutical carrier.
- ophthalmic solutions are specifically contemplated.
- the present invention relates to a method of treating ocular hypertension which comprises administering to a mammal having ocular hypertension an amount effective in lowering ocular pressure of a compound of formula (I), as hereinabove defined, or a pharmaceutically acceptable salt thereof.
- the present invention relates to a pharmaceutical product, comprising
- a container adapted to dispense its contents in metered form
- the present invention relates to novel 2-decarboxyl-2-hydroxyalkyl derivatives of 5-trans prostaglandin compounds and their use as potent ocular hypotensive agents.
- Prostaglandins can be described as derivatives of prostanoic acid which has the following structural formula:
- prostaglandins are known, depending on the structure and substituents carried on the alicyclic ring of the prostanoic acid skeleton. Further classification is based on the number of unsaturated bonds in the side chain indicated by numerical subscripts after the generic type of prostaglandin [e.g. prostaglandin F,
- PPF 1 prostaglandin E 2
- PGE 2 prostaglandin E 2
- ⁇ or ⁇ the configuration of the substituents on the alicyclic ring indicated by ⁇ or ⁇ [e.g. prostaglandin F 2 ⁇ (PGF 2 ⁇ )].
- the present invention relates to 2-decarboxyl-2-hydroxyalkyl PGF 2 and PGF 3 derivatives in which at least the
- PGF 2 ⁇ The naturally occurring stereochemistry of PGF 2 ⁇ includes the C-9, C-11, and C-15 hydroxyl groups in the ⁇ configuration.
- prostaglandins having the C-9 or C-11 or C-15 substituents in ⁇ configuration are also contemplated.
- broken line attachments to the cyclopentane ring indicate substituents in the o configuration.
- Thickened solid line attachments to the cyclopentane ring indicate substituents in the ⁇ configuration.
- 9 ⁇ -PGF compounds have the same structure as PGF ⁇ compounds, except that the hydroxyl at the C-9 position is in the ⁇ configuration.
- the broken line attachment of the hydroxyl group or other substituent to the C-11 and C-15 carbon atoms signifies the ⁇ configuration; therefore, compounds with the epi configuration for the hydroxyl group at C-15 are designated by using 15 ⁇ and if there is no indication of the ⁇ configuration, the configuration is assumed ⁇ .
- Preferred representatives of the compounds according to the present invention are the 5-trans PGF 2 ⁇ derivative of the following formula (II)
- the thickened solid line attachment indicates the beta configuration.
- the broken line attachments of the R 1 , R 2 and R 3 substituents indicate that these substituents are in alpha configuration.
- the term "alkyl" group" is used to refer to straight of branched chained saturated aliphatic hydrocarbon groups having from one to about 6, preferably one to about 4 carbon atoms. Such groups include, e.g. methyl, ethyl, propyl, butyl, pentyl, or hexyl, or an isomeric form thereof.
- R 4 and R 5 includes a cyclic component
- R 6 is an aliphatic ring from about 3 to about 7 carbon atoms, or an aromatic or heteroaromatic ring.
- the "aliphatic ring” may be saturated or unsaturated, and preferably is a saturated ring having 3-7 carbon atoms, inclusive.
- R 7 preferably is phenyl, and the heteroaromatic rings have oxygen, nitrogen or sulfur as a heteroatom.
- n is o-4.
- n preferably is 1-6, more preferably 1-4, most preferably 4.
- R is hydrogen
- R 1 R 2 and R 3 independently are hydroxyl, or -O(CO)R 5
- R 5 is a saturated or unsaturated acyclic hydrocarbon having from 1 to about 20, preferably 1 to about 6 carbon atoms, and m is 4, and their pharmaceutically acceptable salts.
- Particularly preferred are those compounds in which X is a -CH 2 - group (R 7 and R 8 are hydrogen) and pharmaceutically acceptable salts thereof.
- a pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or undesirable effect on the subject to which it is administered and in the context in which it is administered.
- Suitable pharmaceutically acceptable salts may be derived from either an organic or inorganic base. Such a salt may comprise a mono- or polyvalent ion.
- inorganic cations such as sodium, potassium, calcium, magnesium and zinc.
- Particularly preferred compounds within the scope of the present invention are:
- the compounds according to the present invention can be conveniently prepared by the reduction of the 1-carboxyl group of 5-trans PGF 2 ⁇ , on the analogy of the process described by Maddox et al., Nature 273. 549 (1978) for the preparation of 5-cis PGF 2 ⁇ -l-OH, or in the U.S. Patent No.
- the reduction may be performed by chemical reducing agents conventionally used for the conversion of carboxylic acids to alcohols.
- Chemical reducing agents include, but are not restricted to hydrides, such as lithium aluminium hydride or diisobutylaluminium hydride.
- the PGF acid may be converted into a corresponding 1-ester before reduction, and the obtained 1-ester may be reduced by chemical reduction.
- the 5-trans PG-1-OH compounds are esterified in a conventional manner, with suitable agents known in the art.
- the starting compound contains, in addition to the hydroxyl in the 1-position, still other hydroxyl groups in one or more of the 9-, 11- and 15-positions, these further hydroxyls are also esterified.
- suitable protecting groups such as readily cleavable ether, e.g. tetrahydropyranyl (THP) residues.
- THP readily cleavable ether
- the tetrahydropyranyl groups may be split off under acidic conditions, at temperatures between about 20oC and 80oC.
- the secondary and tertiary alcohols are usually prepared from the corresponding primary alcohols via oxydation to aldehydes or ketones and subsequent reaction with a suitable Grignard reagent. These reactions are well known in the organic chemistry.
- the 1-carboxyl group of the 5-trans PG starting compound is first esterified with a suitable esterfying agent, such as diazohydrocarbon, e.g. diazomethane, diazoethane, or diazopropane, preferably diazomethane.
- a suitable esterfying agent such as diazohydrocarbon, e.g. diazomethane, diazoethane, or diazopropane, preferably diazomethane.
- the 5-trans ester, e.g. methyl ester is then reduced with a chemical reducing agent, e.g. diisobutylaluminium hydride in an organic solvent or solvent mixture.
- Suitable solvents include tetrahydrofurane and methylene chloride.
- compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, as an active ingredient, with conventional ophthalmically acceptable pharmaceutical excipients, and by preparation of unit dosage forms suitable for topical ocular use.
- the therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 1.0% (w/v) in liquid formulations.
- solutions are prepared using a physiological saline solution as a major vehicle.
- the pH of such ophthalmic solutions should preferably be maintained between 6.5 and 7.2 with an appropriate buffer system.
- the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
- Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.
- a preferred surfactant is, for example, Tween 80.
- various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
- Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable opthalmically acceptable tonicity adjuster.
- buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers.
- Acids or bases may be used to adjust the pH of these formulations as needed.
- an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
- excipient components which may be included in the ophthalmic preparations are chelating agents.
- the preferred chelating agent is edentate disodium, although other chelating agents may also be used in place or in conjunction with it.
- the ingredients are usually used in the following amounts:
- the ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate the application to the eye.
- Containers suitable for dropwise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution.
- the crude ester above was dissolved in dry tetrahydrofuran (THF, 1 ml) and cooled to -78oC in a dry ice-acetone bath.
- a solution of diisobutylaluminum hydride in methylene chloride (1.0 M, 0.23 ml) was added.
- the dry ice-acetone bath was replaced with an ice bath after 15 min and stirring was continued for 2.5 hr at 0oC.
- Methanol (0.25 ml) was added to destroy excess diisobutylaluminum hydride.
- the crude reaction mixture was diluted with 10% citric acid solution and extracted with 4X8 ml ethyl acetate.
- test compounds were prepared in an ophthalmic formulation containing 0.1% polysorbate (Tween 80) - 10 mM TRIS.
- One eye of each experimental animal was treated by applying one 25 ⁇ l drop of the drug formulation to the ocular surface, the contralateral eye received 25 ⁇ l of vehicle as a control.
- Intraocular pressure was measured by applanation pneumatonometry immediately before drug administration and at subsequent, predetermined times thereafter.
- the experimental animals were New Zealand albino cross rabbits and cynomolgous monkeys.
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Abstract
The present invention relates to novel 2-decarboxyl-2-hydroxyalkyl derivatives of 5-trans prostaglandins of the F series. The invention further concerns pharmaceutical compositions and methods for reducing or maintaining intraocular pressure by applying to the eye one or more of these compounds.
Description
2-DECARBOXYL-2-HYDROXYALKYL-5-TRANS PROSTAGLANDIN F
DERIVATIVES
Field of the Invention
The present invention relates to novel 2-decarboxyl-2-hydroxyalkyl derivatives of 5-trans prostaglandins of the F series. The invention further concerns pharmaceutical compositions and methods for reducing or maintaining intraocular pressure by applying to the eye one or more of these compounds.
Background of the Invention
Certain prostan-1-ols and their esters are disclosed in the U.S. Patent No. 4,156,745. The prostan-1-ol esters are described as useful for inducing menstruation or interrupting a pregnancy similarly to the corresponding natural prostaglandins but exhibiting a stronger and substantially longer effectiveness, whereas the corresponding prostan-1-ol compounds are mentioned as intermediates for their preparation. Although the general formulas in this patent encompass a vast number of compounds, including prostaglandin 1-ols and 1-ol esters both in the naturally occurring 5-cis configuration and the corresponding 5-trans derivatives, all compounds shown in the examples or specifically listed, belong to the 5-cis series. There is no mention of any ocular use for these compounds.
Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy ocular hypertensive episodes, glaucoma, and as presurgical adjuncts.
Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults
(congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
The underlying causes of primary glaucoma are not yet known. The increased intraocular tension is due to the obstruction of aqueous humor outflow. In chronic openangle glaucoma, the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded. In acute or chronic angle-closure glaucoma, the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of iris forward against the angle, and may produce pupillary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity.
Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm. Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe, and may plug the drainage channel with exudates. Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
Considering all types together, glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision. In cases where surgery is not indicated, topical β-adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.
Prostaglandins were earlier regarded as potent ocular hypertensives., however, evidence accumulated in the last
decade showsthat some protaglandins are highly effective ocular hypotensive agents, and are ideally suited for the long-term medical management of glaucoma (see, for example, Bito, L. Z. Biological Protection with Prostaglandins Cohen, M. M., ed., Boca Raton, Fla, CRC Press Inc., 1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the Medical Treatment of Glaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune & Stratton, 1984, pp. 477-505). Such prostaglandins include PGF2α, PGF1α, PGE2, and certain lipid-soluble esters, such as C1 to C5 alkyl esters, e.g. 1-isopropyl ester, of such compounds.
In the United States Patent No. 4,599,353 certain prostaglandins and their derivatives, in particular PGE2 and PGF2α and the C1 to C5 alkyl esters of the latter compound, were reported to possess ocular hypotensive activity and were recommended for use in glaucoma management.
Although the precise mechanism is not yet known, recent experimental results indicate that the prostaglandin-induced reduction in intraocular pressure results from increased uveoscleral outflow [Nilsson et al., Invest. Ophthalmol. Vis. Sci. 28(suppl), 284 (1987)].
The isopropyl ester of PGF2α has been shown to have significantly greater hypotensive potency than the parent compound, which was attributed to its more effective penetration through the cornea. In 1987 this compound was described as "the most potent ocular hypotensive agent ever reported" [see, for example, Bito, L. Z., Arch. Ophthalmol. 105, 1036 (1987), and Siebold et al., Prodrug 5 , 3 (1989)].
Whereas prostaglandins appear to be devoid of significant intraocular side effects, ocular surface (conjunctival) hyperemia and foreign-body sensation have been consistently associated with the topical ocular use of such compounds, in particular PGF2α and its prodrugs, e.g. its 1-isopropyl ester, in humans. The clinical potential
of prostaglandins in the management of conditions associated with increased ocular pressure, e.g. glaucoma are greatly limited by these side effects.
In a series of co-pending United States patent applications assigned to Allergan, Inc. prostaglandin esters with increased ocular hypotensive activity accompanied with no or substantially reduced side-effects are disclosed. The continuation application of USSN
386,835 (filed 27 July 1989), relates to certain 11-acyl- prostaglandins, such as 11-pivaloyl, 11-acetyl, 11- isobutyryl, 11-valeryl, and 11-isovaleryl PGF2α.
Intraocular pressure reducing 15-acyl prostaglandins are disclosed in the co-pending application USSN 357,394 (filed
25 May 1989). Similarly, 11,15- 9,15- and 9,11-diesters of prostaglandins, for example 11,15-dipivaloyl PGF2α are known to have ocular hypotensive activity. See the co-pending patent applications USSN No. 385,645 (filed 27 July 1989), USSN 584,370 which is a continuation of USSN 386,312 (filed
27 July 1989), USSN 585,284 which is a continuation of USSN 385,834 (filed 27 July 1989).
1-Alcohols of 5-cis PGF compounds and their use as ocular hypotensives are disclosed in co-pending patent application USSN 07/538,204 (filed 14 June 1990).
The use of 5-trans PGF2α as an ocular hypotensive agent causing minimal or no ocular surface hyperemia, is disclosed in the co-pending application USSN 496,879 filed 19 March 1990.
The disclosures of these patent applications, all assigned to Allergan, Inc., are hereby expressly incorporated by reference.
Summary of the Invention
The present invention relates to new 2-decarboxyl-2-hydroxyalkyl derivatives of 5-trans prostaglandin F compounds, including their 1a-homo- and 1-nor derivatives, and to their use for the treatment of glaucoma and ocular
hypertension when formulated in a pharmaceutically acceptable vehicle. Quite surprisingly, the alcohol derivatives of 5-trans prostaglandin compounds, where the 5,6-double bond is in the trans rather than the natural cis configuration, are more potent ocular hypotensives than the respective 5-cis compounds and show significantly reduced adverse side effects, notably ocular surface hyperemia. These compounds are, therefore, excellent candidates for therapeutic treatment of a variety of ocular hypertensive conditions such as open-angle glaucoma, closed-angle glaucoma, ocular hypertensive episodes, post-surgical and post-laser trabeculectomy, and as presurgical adjuvants.
In one aspect, the present invention concerns 2-decarboxyl-2-hydroxyalkyl 5-trans PGF derivatives of the formula (I)
wherein wavy line attachments indicate either the alpha (α) or beta (β) configuration; hatched lines indicate α configuration, solid triangles are used to indicate β configuration; the 5,6-double bond is in the trans-configuration; the dashed bond in the 17,18-position represents a double bond or a single bond, the double bond being either in the cis- or in the trans-configuration; R is hydrogen or a -(CO)R4 group; R1, R2 and R3 independently are hydroxyl, or -O(CO)R5 groups, wherein R4 and R5 independently stand for saturated or unsaturated acyclic hydrocarbons having from 1 to about 20 carbon atoms, or -(CH2)nR6 where n is 0-10, and R6 is an aliphatic, aromatic or heteroaromatic ring, X is a -C(R7,R8)- group, wherein R7
and R8 independently are hydrogen or alkyl of one to about
6 carbon atoms, and m is 1-8, and pharmaceutically acceptable salts of these compounds.
In a further aspect, the present invention concerns ophthalmically acceptable pharmaceutical compositions comprising an amount effective in lowering ocular pressure of a compound of formula (I), as hereinabove defined, or a pharmaceutically acceptable salt thereof, in admixture with a non-toxic, pharmaceutical carrier. Of such pharmaceutical compositions, ophthalmic solutions are specifically contemplated.
In a still further aspect, the present invention relates to a method of treating ocular hypertension which comprises administering to a mammal having ocular hypertension an amount effective in lowering ocular pressure of a compound of formula (I), as hereinabove defined, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a pharmaceutical product, comprising
a container adapted to dispense its contents in metered form; and
an ophthalmic solution therein, as hereinabove defined.
Detailed Description of the Invention
The present invention relates to novel 2-decarboxyl-2-hydroxyalkyl derivatives of 5-trans prostaglandin compounds and their use as potent ocular hypotensive agents.
Prostaglandins can be described as derivatives of prostanoic acid which has the following structural formula:
Various types of prostaglandins are known, depending on the structure and substituents carried on the alicyclic ring of the prostanoic acid skeleton. Further classification is based on the number of unsaturated bonds in the side chain indicated by numerical subscripts after the generic type of prostaglandin [e.g. prostaglandin F,
(PGF1), prostaglandin E2 (PGE2)], and on the configuration of the substituents on the alicyclic ring indicated by α or β [e.g. prostaglandin F2α (PGF2α)].
The present invention relates to 2-decarboxyl-2-hydroxyalkyl PGF2 and PGF3 derivatives in which at least the
5,6-double bond is always in trans configuration. These compounds are represented by the formula (I)
wherein the symbols and substituents are as defined hereinabove.
The naturally occurring stereochemistry of PGF2α includes the C-9, C-11, and C-15 hydroxyl groups in the α configuration. In the compounds used in accorance with the present invention, however, prostaglandins having the C-9 or C-11 or C-15 substituents in β configuration are also contemplated. As hereinabove mentioned, in all formulas provided herein broken line attachments to the cyclopentane ring indicate substituents in the o configuration. Thickened solid line attachments to the cyclopentane ring indicate substituents in the β configuration. For instance, 9β-PGF compounds have the same structure as PGFα compounds, except that the hydroxyl at the C-9 position is in the β configuration. Also, the broken line attachment
of the hydroxyl group or other substituent to the C-11 and C-15 carbon atoms signifies the α configuration; therefore, compounds with the epi configuration for the hydroxyl group at C-15 are designated by using 15β and if there is no indication of the β configuration, the configuration is assumed α.
Preferred representatives of the compounds according to the present invention are the 5-trans PGF2α derivative of the following formula (II)
wherein the 17, 18-double bond is in the cis-configuration, and the symbols and substituents are as hereinabove defined.
In the foregoing formulas the thickened solid line attachment indicates the beta configuration. The broken line attachments of the R1, R2 and R3 substituents indicate that these substituents are in alpha configuration.
In the definition of R7 and R8 the term "alkyl" group" is used to refer to straight of branched chained saturated aliphatic hydrocarbon groups having from one to about 6, preferably one to about 4 carbon atoms. Such groups include, e.g. methyl, ethyl, propyl, butyl, pentyl, or hexyl, or an isomeric form thereof.
The definition of R4 and R5 includes a cyclic component,
-(CH2)nR6, wherein n is 0-10, R6 is an aliphatic ring from about 3 to about 7 carbon atoms, or an aromatic or heteroaromatic ring. The "aliphatic ring" may be saturated or unsaturated, and preferably is a saturated ring having 3-7 carbon atoms, inclusive. As an aromatic ring, R7 preferably is phenyl, and the heteroaromatic rings have oxygen, nitrogen or sulfur as a heteroatom. Preferably n is o-4.
n preferably is 1-6, more preferably 1-4, most preferably 4.
In both the PGF2α and the PGF3α series, preferred are those compounds, in which R is hydrogen, and R1 R2 and R3 independently are hydroxyl, or -O(CO)R5, wherein R5 is a saturated or unsaturated acyclic hydrocarbon having from 1 to about 20, preferably 1 to about 6 carbon atoms, and m is 4, and their pharmaceutically acceptable salts. Particularly preferred are those compounds in which X is a -CH2- group (R7 and R8 are hydrogen) and pharmaceutically acceptable salts thereof.
A pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or undesirable effect on the subject to which it is administered and in the context in which it is administered. Suitable pharmaceutically acceptable salts may be derived from either an organic or inorganic base. Such a salt may comprise a mono- or polyvalent ion. Of particular interest are inorganic cations such as sodium, potassium, calcium, magnesium and zinc.
Particularly preferred compounds within the scope of the present invention are:
2-decarboxyl-2-hydroxymethyl-5-trans PGF2α;
2-decarboxy1-2-hydroxyethy1-5-trans PGF2α;
2-decarboxyl-2-hydroxymethyl-5-trans PGF3α;
2-decarboxyl-2-hydroxyethyl-5-trans PGF3α;
and pharmaceutically acceptable salts of these compounds.
The compounds according to the present invention can be conveniently prepared by the reduction of the 1-carboxyl group of 5-trans PGF2α, on the analogy of the process described by Maddox et al., Nature 273. 549 (1978) for the preparation of 5-cis PGF2α-l-OH, or in the U.S. Patent No.
4,256,745.
In general, the reduction may be performed by chemical reducing agents conventionally used for the conversion of carboxylic acids to alcohols. Chemical reducing agents include, but are not restricted to hydrides, such as lithium aluminium hydride or diisobutylaluminium hydride.
As an alternative to direct reduction, the PGF acid may be converted into a corresponding 1-ester before reduction, and the obtained 1-ester may be reduced by chemical reduction.
If compounds, in which R is a -(CO)R4 group are desired, the 5-trans PG-1-OH compounds are esterified in a conventional manner, with suitable agents known in the art.
If the starting compound contains, in addition to the hydroxyl in the 1-position, still other hydroxyl groups in one or more of the 9-, 11- and 15-positions, these further hydroxyls are also esterified. If compounds containing one or more free hydroxyl groups are desired, such hydroxyl groups should be blocked in the starting compounds by suitable protecting groups, such as readily cleavable ether, e.g. tetrahydropyranyl (THP) residues. For instance, the tetrahydropyranyl groups may be split off under acidic conditions, at temperatures between about 20ºC and 80ºC.
The secondary and tertiary alcohols are usually prepared from the corresponding primary alcohols via oxydation to aldehydes or ketones and subsequent reaction with a suitable Grignard reagent. These reactions are well known in the organic chemistry.
According to a preferred process, the 1-carboxyl group of the 5-trans PG starting compound is first esterified with a suitable esterfying agent, such as diazohydrocarbon, e.g. diazomethane, diazoethane, or diazopropane, preferably diazomethane. The 5-trans ester, e.g. methyl ester is then reduced with a chemical reducing agent, e.g. diisobutylaluminium hydride in an organic solvent or solvent mixture. Suitable solvents include tetrahydrofurane and methylene chloride. The synthesis route is illustrated in the attached Reaction Scheme, and in Example 1.
Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, as an active ingredient, with conventional ophthalmically acceptable pharmaceutical excipients, and by preparation of unit dosage forms suitable for topical ocular use. The therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 1.0% (w/v) in liquid formulations.
For ophthalmic application, preferably solutions are prepared using a physiological saline solution as a major vehicle. The pH of such ophthalmic solutions should preferably be maintained between 6.5 and 7.2 with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and
phenylmercuric nitrate. A preferred surfactant is, for example, Tween 80. Likewise, various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable opthalmically acceptable tonicity adjuster.
Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers.
Acids or bases may be used to adjust the pH of these formulations as needed.
In a similar vein, an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
Other excipient components which may be included in the ophthalmic preparations are chelating agents. The preferred chelating agent is edentate disodium, although other chelating agents may also be used in place or in conjunction with it.
The ingredients are usually used in the following amounts:
Ingredient Amount (% w/v)
active ingredient about 0.001-5
preservative 0-0.10
vehicle 0-40
tonicity adjustor 0-10
buffer 0.01-10
pH adjustor q.s. pH 4.5-7.5
antioxidant as needed
surfactant as needed
purified water as needed to make 100% The actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
The ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate the application to the eye. Containers suitable for dropwise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution.
The invention is further illustrated by the following non-limiting Examples.
Example 1
Preparation of 2-Decarboxyl-2-hvdroxymethyl-5-trans PGF2α
A solution of diazomethane in ether was added dropwise to a solution of 5-trans PGF2a (obtained from
Cayman Chemical Company, 10 mg), in 1.5 ml methanol at
0ºC until a yellowish color persisted. The solution was stirred at 0ºC for a further 10 min and the solvents were evaporated under reduced pressure to
10.7 mg of 5-trans PGF2α methyl ester as a colorless semi-solid.
1H NMR (CDCl3 MHz): 55.56 (1H, 1/2 ABX, JAB=15.2, JAX=6.7 Hz), 5.4-5.5 (3H, m), 4.20 (1H, t, J=4 Hz),
4.06 (1H, q, J=6.6 Hz), 3.96 (1H, m) , 3.67 (3H, s, methyl ester), 2.30 (2H, t J=7.5 Hz), 2.0-2.6 (9H, m),
1.2-1.8 (9H, m), 1.2-1.8 (12H, m), and 0.89 ppm (3H, t
J=6.7 Hz).
The crude ester above was dissolved in dry tetrahydrofuran (THF, 1 ml) and cooled to -78ºC in a
dry ice-acetone bath. A solution of diisobutylaluminum hydride in methylene chloride (1.0 M, 0.23 ml) was added. The dry ice-acetone bath was replaced with an ice bath after 15 min and stirring was continued for 2.5 hr at 0ºC. Methanol (0.25 ml) was added to destroy excess diisobutylaluminum hydride. The crude reaction mixture was diluted with 10% citric acid solution and extracted with 4X8 ml ethyl acetate. The combined organic extracts were washed with saturated sodium carbonate and brine, dried over magnesium sulfate and concentrated to give 8 mg crude product. Purification was achieved by column chromatography over silica gel using gradient elution (ethyl acetate to 5% methanol in ethyl acetate) giving 6.0 mg pure 2-decarboxyl-2- hydroxymethyl-5-trans prostaglandin F2α (62% yield overall).
1H NMR (300 MHZ, CDCl3): 55.55 (1H, 1/2 ABX, JAB=15.3, JAX=6.9 Hz, H-14), 5.4-5.5 (3H, m), 4.19 (1H distorted t, J=4 HZ), 4.05 (1H, q, J=6.6 Hz), 3.85-3.95 (1H, m), 3.63 (2H, t, J=6.5 Hz, CH2OH), 3.2 (1H, br s), 2.5 (2H, br s), 1.8-2.4 (7H, m), 1.73 (1H, 1/2 ABX, JAB=15, JAX=-2.8 Hz), 1.2-1.6 (13H, m) and 0.89 ppm (3H, distorted t, J=7Hz);
13C NMR (75 MHz, CDCl3); 613.78 (CH3), 22.41 (CH2), 25.02 (CH2), 25.31 (CH2), 30.95 (CH2), 31.54 (CH2), 31.91 (CH2), 32.02 (CH2), 37.12 (CH2), 42.50 (CH2), 49.85 (CH), 55.55 (CH), 62.67 (CH2), 73.01 (CH), 77.20 (CH), 78.04 (CH), 129.17 (CH), 131.70 (CH), 132.75 (CH) and 135.37 (CH) ppm;
IR (CHCl3): 3200-3600, 1225, 1130, 1100, 970 and 928 cm-1.
MS (EI, TMS derivative): m/z 628 (M+, 0.2%), 217 (26%), 191 (100%), 173 (73%), 129 (46%), 73 (60%).
HRMS (El, TMS derivative): calculated for C32H68O4Si4: 628.4163, found: 628.4179.
Example 2
Intraocular Pressure Reducing Activity
Experimental quantities of the test compounds were prepared in an ophthalmic formulation containing 0.1% polysorbate (Tween 80) - 10 mM TRIS. One eye of each experimental animal was treated by applying one 25 μl drop of the drug formulation to the ocular surface, the contralateral eye received 25 μl of vehicle as a control.
Intraocular pressure was measured by applanation pneumatonometry immediately before drug administration and at subsequent, predetermined times thereafter. The experimental animals were New Zealand albino cross rabbits and cynomolgous monkeys.
The data obtained are shown in the following Tables.
The foregoing description details specific methods and compositions that can be employed to practice the present invention, and represents the best mode
contemplated. However, it is apparent for one of
ordinary skill in the art that further compounds with the desired pharmacological properties can be prepared in an analogous manner, and that the disclosed compounds can also be obtained from different starting compounds via different chemical reactions. Similarly, different pharmaceutical compositions may be prepared and used with substantially the same results. Thus, however detailed the foregoing may appear in text, it should not be construed as limiting the overall scope hereof; rather, the ambit of the present invention is to be governed only by the lawful construction of the appended claims.
Claims
1. A compound of the formula (I)
wherein wavy line attachments indicate either the alpha (α) or beta (β) configuration; hatched lines indicate α configuration, solid triangles are used to indicate β configuration; the 5,6-double bond is in the trans- configuration; the dashed bond in the 17,18-position represents a double bond or a single bond, the double bond being either in the cis- or in the transconfiguration; R is hydrogen or a -(CO)R4 group; R1, R2 and R3 independently are hydroxyl, or -O(CO)R5 groups, wherein R4 and R5 independently stand for saturated or unsaturated acyclic hydrocarbons having from 1 to about 20 carbon atoms, or
-(CH2)nR6 where n is 0-10, and R6 is an aliphatic,
aromatic or heteroaromatic ring, X is a -C(R7,R8)- group, wherein R7 and R8 independently are hydrogen or alkyl of one to about 6 carbon atoms, and m is 1-8; or a
pharmaceutically acceptable salt thereof.
2. The compound according to Claim 1 having the formula (II)
3. The compound according to Claim 1 having the formula (III)
wherein the 17,18-double bond is in cis-configuration and the symbols and substituents are as defined in Claim 1, or a pharmaceutically acceptable salt thereof.
4. The compound according to Claim 1 selected from the group consisting of
2-decarboxyl-2-hydroxymethyl-5-trans PGF2α;
2-decarboxyl-2-hydroxyethyl-5-trans PGF2α;
2-decarboxyl-2-hydroxymethyl-5-trans PGF3α;
2-decarboxyl-2-hydroxyethyl-5-trans PGF3α;
and a pharmaceutically acceptable salt of these
compounds.
5. A pharmaceutical composition for the treatment of ocular hypertension, comprising an amount sufficient to treat ocular hypertension of a compound of formula (I)
wherein wavy line attachments indicate either the alpha (α) or beta (β) configuration; hatched lines indicate α configuration, solid triangles are used to indicate β configuration; the 5,6-double bond is in the trans- configuration; the dashed bond in the 17, 18-position represents a double bond or a single bond, the double bond being either in the cis- or in the trans- configuration; R is hydrogen or a -(CO)R4 group; R1, R2 and R3 independently are hydroxyl, or -0(CO)R5 groups, wherein R4. and R5 independently stand for saturated or unsaturated acyclic hydrocarbons having from 1 to about 20 carbon atoms, or
-(CH2)nR6 where n is 0-10, and R6 is an aliphatic, aromatic or heteroaromatic ring, X is a -C(R7,R8)- group, wherein R7 and R8 independently are hydrogen or alkyl of one to about 6 carbon atoms, and m is 1-8; or a
pharmaceutically acceptable salt thereof.
6. The composition according to claim 5 wherein said compound has the formula (II)
wherein the symbols and substituents are as defined in Claim 5, or a pharmaceutically acceptable salt thereof.
7. The composition according to Claim 5 wherein said compound has the formula (III)
8. The composition according to Claim 5 wherein said compound is selected from the group consisting of
2-decarboxy1-2-hydroxymethy1-5-trans PGF2α;
2-decarboxyl-2-hydroxyethyl-5-trans PGF2α;
2-decarboxyl-2-hydroxymethyl-5-trans PGF3α;
2-decarboxyl-2-hydroxyethyl-5-trans PGF3α;
and a pharmaceutically acceptable salt of these
compounds.
9. A method of treating ocular hypertension which comprises applying to the eye an amount sufficient to treat ocular hypertension of a compound of formula (I)
wherein wavy line attachments indicate either the alpha (α) or beta (β) configuration; hatched lines indicate α configuration, solid triangles are used to indicate β configuration; the 5,6-double bond is in the trans-configuration; the dashed bond in the 17,18-position represents a double bond or a single bond, the double bond being either in the cis- or in the trans-configuration; R is hydrogen or a -(CO)R4 group; R1, R2 and R3 independently are hydroxyl, or -O(CO)R5 groups, wherein R4 and R5 independently stand for saturated or unsaturated acyclic hydrocarbons having from 1 to about 20 carbon atoms, or
-(CH2)nR6 where n is 0-10, and R6 is an aliphatic,
aromatic or heteroaromatic ring, X is a -C(R7,R8)- group, wherein R7 and R8 independently are hydrogen or alkyl of
one to about 6 carbon atoms, and m is 1-8; or a
pharmaceutically acceptable salt thereof.
10. The method according to Claim 9 wherein said compound has the formula (II)
wherein the 17,18-double bond is in the cis-configuration and the symbols and substituents are as defined in
Claim 9, or a pharmaceutically acceptable salt thereof.
11. The method according to Claim 9 wherein said compound has the formula (III)
wherein the 17,18-double bond is in the cis-configuration and the symbols and substituents are as defined in
Claim 9, or a pharmaceutically acceptable salt thereof.
12. The method according to Claim 9 wherein said compound is selected from the group consisting of
2-decarboxyl-2-hydroxymethyl-5-trans PGF2α;
2-decarboxyl-2-hydroxyethyl-5-trans PGF2α;
2-decarboxyl-2-hydroxymethyl-5-trans PGF3α;
2-decarboxyl-2-hydroxyethyl-5-trans PGF3α;
and a pharmaceutically acceptable salt of these
compounds.
13. An ophthalmic solution for the treatment of ocular hypertension, comprising an amount sufficient to treat ocular hypertension of a compound of formula (I) according to Claim 1, in admixture with a non-toxic, ophthalmically acceptable liquid vehicle.
14. The ophthalmic solution according to Claim 13 packaged in a container suitable for metered application.
15. The ophthalmic solution according to Claim 14 wherein said container contains a unit dose of said solution.
16. The ophthalmic solution according to Claim 13 wherein said compound is selected from the group
consisting of
2-decarboxyl-2-hydroxymethyl-5-trans PGF2α;
2-decarboxyl-2-hydroxyethyl-5-trans PGF2α;
2-decarboxy1-2-hydroxymethyl-5-trans PGF3α;
2-decarboxyl-2-hydroxyethyl-5-trans PGF3α;
and a pharmaceutically acceptable salt of these
compounds.
17. A pharmaceutical product, comprising
a container adapted to dispense its contents in metered form; and
an ophthalmic solution therein, as defined in
Claim 13.
AMENDED CLAIMS
[received by the International Bureau on 20 July 1992 (20.07.92); original claims 1 - 8 and 17 deleted; original claim 9 amended; new claims 18 and 19 added; remaining claims unchanged (5 pages)]
1. (Cancelled).
2. (Cancelled).
3. (Cancelled).
4. (Cancelled).
5. (Cancelled).
6. (Cancelled). 7. (Cancelled).
8. (Cancelled).
9. (Amended). A method of treating ocular hypertension which comprises applying to the eye an amount sufficient to treat ocular hypertension of a compound of formula (I)
wherein wavy line attachments indicate either the alpha (α) or beta (β ) configuration; hatched lines indicate α configuration, solid triangles are used to indicate β configuration; the 5,6-double bond is in the trans-configuration; the dashed bond in the 17,18-position represents a double bond or a single bond, the double bond being either in the cis- or in the trans-configuration; R is hydrogen or a -(CO)R1 group; R1, R2 and R3 independently are hydroxyl, or -O(CO)R5 groups, wherein R4 and R5 independently stand for saturated or unsaturated acyclic hydrocarbons having from 1 to 20 carbon atoms, or -(CH2)nR6 where n is 0-10, and R6 is an aliphatic, aromatic or heteroaromatic ring, wherein said aliphatic ring comprises from 3 to 7 carbon atoms, said aromatic ring comprises phenyl, and said heteroaromatic ring comprises oxygen, nitrogen or sulfur as a heteroatom, X is a -C(R7,R8)- group, wherein R7 and R8 independently are hydrogen or alkyl of one to 6 carbon atoms, and m is 1-8; or a pharmaceutically acceptable salt thereof.
13. An ophthalmic solution for the treatment of ocular hypertension, comprising an amount sufficient to treat ocular hypertension of a compound of formula (I) according to Claim 1, in admixture with a non-toxic, ophthalmically acceptable liquid vehicle.
14. The ophthalmic solution according to Claim 13 packaged in a container suitable for metered application. 15. The ophthalmic solution according to Claim 14 wherein said container contains a unit dose of said solution.
16. The ophthalmic solution according to Claim 13 wherein said compound is selected from the group consisting of
2-decarboxyl-2-hydroxymethyl-5-trans PGF2α;
2-decarboxyl-2-hydroxyethyl-5-trans PGF2α;
2-decarboxyl-2-hydroxymethyl-5-trans PGF3α;
2-decarboxyl-2-hydroxyethyl-5-trans PGF3α;
17. (Cancelled).
18. A compound selected from the group consisting of
2-decarboxyl-2-hydroxymethyl-5-trans PGF2α;
2-decarboxyl-2-hydroxyethyl-5-trans PGF2α;
2-decarboxyl-2-hydroxymethyl-5-trans PGF3α;
2-decarboxyl-2-hydroxyethyl-5-trans PGF3α;
19. A compound according to Claim 18 wherein said compound is 2-decarboxyl-2-hydroxymethyl-5-trans PGF2α.
STATEMENT UNDER ARTICLE 19
The invention, as now claimed, provides a method of treating ocular hypertension which comprises applying to the eyes an amount sufficient to treat ocular hypertension of a compound of formula (I)
wherein wavy line attachments indicate either the alpha (α) or beta (β) configuration; hatched lines indicate α configuration; solid triangles are used to indicate β configuration; the 5,6-double bond is in the trans-configuration; the dashed bond in the 17, 18-position represents a double bond or a single bond, the double bond being either in the cis- or in the trans-configuration; R is hydrogen or a -(CO)R4 group; R1, R2 and R3 independently are hydroxyl, or -O(CO)R5 groups, wherein R4 and R5 independently stand for saturated or unsaturated acyclic hydrocarbons having from 1 to 20 carbon atoms, or -(CH2)nR6 where n is 0-10, and R6 is an aliphatic, aromatic or heteroaromatic ring, wherein said aliphatic ring comprises from 3 to 7 carbon atoms, said aromatic ring comprises phenyl, and said heteroaromatic ring comprises oxygen, nitrogen or sulfur as a heteroatom, X is a -C(R7, R8)-group, wherein R7 and R8 independently are hydrogen or alkyl of one to 6 carbon atoms, and m i s 1-8; or a pharmaceutically acceptable salt thereof.
The present invention also claims certain 2-decarboxyl-2-hydroxymethyl or ethyl-5-trans PGF derivatives, e.g., 2-decarboxyl-2-hydroxymethyl-5-trans PGF2α.
Claims 9 to 16, 18 and 19 in the replacement pages are the result of amendments to original Claims 1 to
17. Claims 1 to 8 and 17 have been cancelled. Claim 9 has been amended. Claims 18 and 19 are new.
Claim 9 has been amended to cancel the word "about", two places. Furthermore Claim 9 has been amended to further limit the definition for R6. Support for this limitation is found at page 9, lines 8 to 14.
Claims 18 and 19 claim compounds which are specifically named in original Claims 4, 18, 12 and 16 and Examples 1 and 2.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US65217991A | 1991-02-07 | 1991-02-07 | |
US652,179 | 1991-02-07 |
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WO1992013836A1 true WO1992013836A1 (en) | 1992-08-20 |
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ID=24615825
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PCT/US1992/000929 WO1992013836A1 (en) | 1991-02-07 | 1992-02-06 | 2-decarboxyl-2-hydroxyalkyl-5-trans prostaglandin f derivatives |
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IE (1) | IE920397A1 (en) |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0533828A1 (en) * | 1990-06-14 | 1993-03-31 | Allergan Inc | Pgf 1-alcohols and their use as ocular hypotensives. |
WO1994008587A1 (en) * | 1992-10-21 | 1994-04-28 | Allergan, Inc. | Novel 7-(5-substituted cyclopentyl) and (5-substituted cyclopentenyl) heptyl alcohols, heptylamines and heptanoic acid amines, and method of lowering intraocular pressure in the eye of a mammal by administration of these novel compounds |
WO1998041208A1 (en) * | 1997-03-17 | 1998-09-24 | Novartis Ag | Compositions and methods for reducing ocular hypertension |
US6770675B2 (en) | 1997-03-17 | 2004-08-03 | Novartis Ag | Compositions and methods for reducing ocular hypertension |
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FR2236492A1 (en) * | 1973-07-11 | 1975-02-07 | Ici Ltd | |
FR2312240A1 (en) * | 1975-05-26 | 1976-12-24 | Schering Ag | PROSTANE DERIVATIVES AND MEDICINAL PRODUCTS CONTAINING IT |
EP0399839A2 (en) * | 1989-05-25 | 1990-11-28 | Allergan, Inc | Intraocular pressure reducing 15-acyl prostaglandins |
WO1991019490A1 (en) * | 1990-06-14 | 1991-12-26 | Allergan, Inc. | Pgf 1-alcohols and their use as ocular hypotensives |
-
1992
- 1992-02-06 WO PCT/US1992/000929 patent/WO1992013836A1/en active Application Filing
- 1992-02-06 AU AU14275/92A patent/AU1427592A/en not_active Abandoned
- 1992-02-06 IE IE039792A patent/IE920397A1/en unknown
Patent Citations (4)
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FR2236492A1 (en) * | 1973-07-11 | 1975-02-07 | Ici Ltd | |
FR2312240A1 (en) * | 1975-05-26 | 1976-12-24 | Schering Ag | PROSTANE DERIVATIVES AND MEDICINAL PRODUCTS CONTAINING IT |
EP0399839A2 (en) * | 1989-05-25 | 1990-11-28 | Allergan, Inc | Intraocular pressure reducing 15-acyl prostaglandins |
WO1991019490A1 (en) * | 1990-06-14 | 1991-12-26 | Allergan, Inc. | Pgf 1-alcohols and their use as ocular hypotensives |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0533828A1 (en) * | 1990-06-14 | 1993-03-31 | Allergan Inc | Pgf 1-alcohols and their use as ocular hypotensives. |
EP0533828A4 (en) * | 1990-06-14 | 1993-08-11 | Allergan, Inc. | Pgf 1-alcohols and their use as ocular hypotensives |
WO1994008587A1 (en) * | 1992-10-21 | 1994-04-28 | Allergan, Inc. | Novel 7-(5-substituted cyclopentyl) and (5-substituted cyclopentenyl) heptyl alcohols, heptylamines and heptanoic acid amines, and method of lowering intraocular pressure in the eye of a mammal by administration of these novel compounds |
WO1998041208A1 (en) * | 1997-03-17 | 1998-09-24 | Novartis Ag | Compositions and methods for reducing ocular hypertension |
US6770675B2 (en) | 1997-03-17 | 2004-08-03 | Novartis Ag | Compositions and methods for reducing ocular hypertension |
KR100555818B1 (en) * | 1997-03-17 | 2006-03-03 | 노파르티스 아게 | Compositions and methods for reducing ocular hypertension |
CZ299833B6 (en) * | 1997-03-17 | 2008-12-10 | Novartis Ag | Ophthalmic composition for reducing ocular hypertension containing prostaglandin active substance |
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AU1427592A (en) | 1992-09-07 |
IE920397A1 (en) | 1992-08-12 |
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