WO2003011299A2 - Procede et composition pour le traitement de l'hypertension oculaire et des glaucomes - Google Patents

Procede et composition pour le traitement de l'hypertension oculaire et des glaucomes Download PDF

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Publication number
WO2003011299A2
WO2003011299A2 PCT/JP2002/007699 JP0207699W WO03011299A2 WO 2003011299 A2 WO2003011299 A2 WO 2003011299A2 JP 0207699 W JP0207699 W JP 0207699W WO 03011299 A2 WO03011299 A2 WO 03011299A2
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Prior art keywords
keto
prostaglandin compound
alkyl
composition
hydroxy
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PCT/JP2002/007699
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English (en)
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WO2003011299A3 (fr
Inventor
Ryuji Ueno
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Sucampo Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Sucampo Ag filed Critical Sucampo Ag
Priority to CA002454422A priority Critical patent/CA2454422A1/fr
Priority to JP2003516529A priority patent/JP2004538306A/ja
Priority to EP02751774A priority patent/EP1411950A2/fr
Priority to MXPA04000980A priority patent/MXPA04000980A/es
Priority to KR10-2004-7001587A priority patent/KR20040023707A/ko
Priority to BR0211545-0A priority patent/BR0211545A/pt
Priority to US10/485,370 priority patent/US20040254247A1/en
Publication of WO2003011299A2 publication Critical patent/WO2003011299A2/fr
Publication of WO2003011299A3 publication Critical patent/WO2003011299A3/fr

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    • 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
    • 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
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present invention relates to a method for treating ocular hypertension and glaucoma, which causes reduced or substantially no ocular irritation such as conjunctival hyperemia.
  • the present invention also provides a composition useful for treatment of the present invention.
  • Prostaglandins are the members of class of organic carboxylic acids that are contained in the tissues or organs of humans or other mammals and exhibit a wide range of physiological activity.
  • PGs found in nature primary PGs
  • primary PGs generally have a prostanoic acid skeleton as shown in the formula (A) :
  • the primary PGs are classified to PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to the structure of the five-membered ring moiety, and further classified into the following three types by the number and position of the unsaturated bond at the carbon chain moiety: Subscript 1: 13, 14-unsaturated-15-OH
  • Subscript 3 5,6-, 13,14-, and 17, 18-triunsaturated-15-OH.
  • the PGFs are classified, according to the configuration of the hydroxyl group at the 9-position, into type (the hydroxyl group is of an -configuration) and ⁇ type
  • PGE- L , PGE 2 and PGE 3 are known to have vasodilation, hypotension, gastric secretion decreasing, intestinal tract movement enhancement, uterine contraction, diuretic, bronchodilation and anti ulcer activities.
  • PGF l ⁇ , PGF 2 ⁇ and PGF 3 ⁇ have been known to have hypertension, vasoconstriction, intestinal tract movement enhancement, uterine contraction, lutein body atrophy and bronchoconstriction activities.
  • 15-keto i.e., having oxo at the 15-position instead of hydroxy
  • 13 14-dihydro-15-keto-PGs are known as the substances naturally produced by the action of enzymes during the metabolism of primary PGs. It is also known that some 15-keto-PG compounds have intraocular pressure reducing effects and are effective for the treatment of ocular hypertension and g ' laucoma (U.S. Patent Nos. 5,001,153, 5,151,444, 5,166,178 and 5,212,200, all of which are incorporated herein by reference) .
  • Xalatan ® that has been launched as an eye drops for ocular hypertension and glaucoma contains, as an active ingredient thereof, latanoprost, i.e., 13,14- dihydro-17-phenyl-18, 19, 20-trinor-PGF 2 a isopropyl ester, which is a prostaglandin derivative having a ring structure at the end of the ⁇ chain and having hydroxy at the 15-position.
  • the clinical concentration of latanoprost in the "Xalatan ® " eye drops is 0.005% and, estimating from about 30-35 ⁇ l of one drop volume of "Xalatan eye drops, the clinical dose of latanoprost is about 1.5 ⁇ g-l .75 ⁇ g per eye per administration .
  • Problematic side effects of this eye drops in clinically applied dose including iris pigmentation, ocular irritation such as conjunctival hyperemia and chemosis of conjunctiva have been reported (American Journal of Ophthalmology 2001; 131: 631- 635, Survey of Ophthalmology 1997; 41: S105-S110, the cited references are herein incorporated by reference) .
  • U.S. Patent No. 5,321,128 describes that administration of 13, 14-dihydro-15-keto- 17- phenyl-18, 19, 20-trinor-PGF 2 ⁇ isopropyl ester to healthy human eyes and monkey eyes in a dose of 5 ⁇ g and 3 ⁇ g, respectively, showed intraocular pressure reducing effects, and showed no side effect such as conjunctival hyperemia, ocular irritation and foreign body sensation in the human.
  • the present inventor has conducted intensive studies on the biological activity of a 15-keto-prostaglandin compound having a ring structure at the end of the ⁇ chain, and found that administration of said compound topically to mammal eyes effectively lowered the intraocular pressure while causes substantially no or reduced ocular irritation such as conjunctival hyperemia, even in a high dose.
  • the present invention relates to a method for treatment of ocular hypertension and glaucoma, which comprises administrating a 15-keto-prostaglandin compound having a ring structure at the end of the ⁇ chain topically to the eyes of a mammalian subject in need of such treatment more than 5 ⁇ g and less than 50 ⁇ g per eye per administration.
  • intra ocular pressure of the subject is effectively lowered while substantially no or reduced ocular irritation, such as conjunctival hyperemia, is observed despite of the high dose.
  • the present invention further relates to an ophthalmic composition for treating ocular hypertension and glaucoma of a mammalian subject, which comprises a 15-keto-prostaglandin compound having a ring structure at the end of the ⁇ chain in an amount to provide a dose of more than 5 ⁇ g and less than 50 ⁇ g per eye per administration.
  • the present invention further relates to use of a 15-keto-prostaglandin compound having a ring structure at the end of the ⁇ chain for manufacturing an ophthalmic composition for treating ocular hypertension and glaucoma of a mammalian subject, wherein said composition comprises the 15-keto- prostaglandin compound in an amount to provide a dose of more than 5 ⁇ g and less than 50 ⁇ g per eye per administration.
  • the "15-keto-prostaglandin compound” may include any of derivatives or analogs (including substituted derivatives) of a compound having an oxo group at 15-position of the prostanoic acid skeleton instead of the hydroxy group, irrespective of the configuration of the five-membered ring, " the number of double bonds, presence or absence of a substituent, or any other modification in the a or ⁇ chain.
  • a preferred compound used in the present invention is represented by the formula (I) :
  • x , W 2 and W 3 are carbon atom or oxygen atom
  • L, M and N are hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl or oxo (wherein at least one of L and M is a group other than hydrogen, and the five-membered ring may have at least one double bond) ;
  • A is -CH 2 OH, -COCH 2 OH, -COOH or a functional derivative thereof;
  • R- L is a saturated or unsaturated bivalent lower or medium aliphatic hydrocarbon residue, which is unsubstituted or substituted by halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group; and Ra is a saturated or unsaturated lower or medium aliphatic hydrocarbon residue, which is substituted at the end by cyclo (lower) alkyl, cyclo (lower) alkyloxy, aryl, aryloxy, heterocyclic group or hetrocyclic-oxy group.
  • a group of particularly preferable compounds among the above-described compounds are represented by the formula (ID :
  • L and M are hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl or oxo (wherein at least one of L and M is a group other than hydrogen, and the five-membered ring may have at least one double bond) ;
  • A is -CH 2 OH, -COCH 2 OH, -COOH or a functional derivative thereof;
  • X- L and X 2 are hydrogen, lower alkyl, or halogen
  • R x is a saturated or unsaturated bivalent lower or medium aliphatic hydrocarbon residue, which is unsubstituted or substituted with halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group;
  • R 2 is a single bond or lower alkylene; and R 3 is cyclo (lower) alkyl, cyclo (lower) alkyloxy, aryl, aryloxy, heterocyclic group or heterocyclic-oxy group.
  • the term "unsaturated" in the definitions for R x and Ra is intended to include at least one or more double bonds and/or triple bonds that are isolatedly, separately or serially present between carbon atoms of the main and/or side chains. According.to the usual nomenclature, an unsaturated bond between two serial positions is represented by denoting the lower number of the two positions, and an unsaturated bond between two distal positions is represented by denoting both of the positions.
  • lower or medium aliphatic hydrocarbon refers to a straight or branched chain hydrocarbon group having 1 to
  • halogen atom covers fluorine, chlorine, bromine and iodine.
  • lower throughout the specification is intended to include a group having 1 to 6 carbon atoms unless otherwise specified.
  • lower alkyl refers to a straight or branched chain saturated hydrocarbon group containing 1 to 6 carbon atoms and includes, for ex ' ample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl .
  • lower alkoxy refers to a group of lower alkyl-O-, wherein lower alkyl is as defined above.
  • hydroxy (lower) alkyl refers to a lower alkyl as defined above which is substituted with at least one hydroxy group such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-methyl-l-hydroxyethyl.
  • lower alkanoyloxy refers to a group represented by the formula RCO-0-, wherein RCO- is an acyl group formed by oxidation of a lower alkyl group as defined above, such as acetyl.
  • cyclo (lower) alkyl refers to a cyclic group formed by cyclization of a lower alkyl group as defined above but contains three or more carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cyclo (lower) alkyloxy refers to the group of cyclo (lower) alkyl-O-, wherein cyclo (lower) alkyl is as defined above .
  • aryl may include unsubstituted or substituted aromatic hydrocarbon rings (preferably monocyclic groups) , for example, phenyl, tolyl, xylyl.
  • substituents include halogen atom and halo substituted (lower) alkyl, wherein halogen atom and lower alkyl are as defined above.
  • aryloxy refers to a group represented by the formula ArO-, wherein Ar is aryl as defined above.
  • heterocyclic group may include • mono- to tri-cyclic, preferably monocyclic heterocyclic group which is 5 to 14, preferably 5 to 10 membered ring having optionally substituted carbon atom(s) and 1 to 4, preferably 1 to 3 of 1 or 2 type of hetero atoms selected from nitrogen atom, oxygen atom and sulfer atom.
  • heterocyclic group examples include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, furazanyl, pyranyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 2-pyrrolinyl, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidino, piperazinyl, morpholino, indolyl, benzothienyl, quinolyl, isoquinolyl, purinyl, quinazolinyl, carbazolyl, acridinyl, phenanthridinyl, benzi idazolyl, benzimidazolinyl, benzothiazolyl, pheno
  • heterocyclic-oxy group means a group represented by the formula HcO-, wherein He is a heterocyclic group as described above.
  • the term "functional derivative" of A includes salts (preferably pharmaceutically acceptable salts), ethers, esters and amides.
  • Suitable "pharmaceutically acceptable salts” include conventionally used non-toxic salts, for example a salt with an inorganic base such as an alkali metal salt (such as sodium salt and potassium salt) , an alkaline earth metal salt (such as calcium salt and magnesium salt) , an ammonium salt; or a salt with an organic base, for example, an amine salt (such as methylamine salt, dimethylamine salt, cyclohexylamine salt, benzylamine salt, piperidine salt, ethylenediamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino) ethane salt, monomethyl- monoethanolamine salt, lysine salt, procaine salt and caffeine salt) , a basic amino acid salt (such as arginine salt and lysine salt), tetraalkyl ammonium salt and the like. These salts may be prepared by a conventional process, for example from the corresponding acid and base or by salt interchange.
  • ethers examples include alkyl ethers, for example, lower alkyl ethers such as methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, t-butyl ether, pentyl ether and 1-cyclopropyl ethyl ether; and medium or higher alkyl ethers such as octyl ether, diethylhexyl ether, lauryl ether and cetyl ether; unsaturated ethers such as oleyl ether and linolenyl ether; lower alkenyl ethers such as vinyl ether, allyl ether; lower alkynyl ethers such as ethynyl ether and propynyl ether; hydroxy (lower) alkyl ethers such as hydroxyethyl ether and hydroxyisopropyl ether; lower alkoxy (lower
  • esters examples include aliphatic esters, for example, lower alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester and 1-cyclopropylethyl ester; lower alkenyl esters such as vinyl ester and allyl ester; lower alkynyl esters such as ethynyl ester and propynyl ester; hydroxy (lower) alkyl ester such as hydroxyethyl ester; lower alkoxy (lower) alkyl esters such as methoxymethyl ester and 1-methoxyethyl ester; and optionally substituted aryl esters such as, for example, phenyl ester, tolyl ester, t-butylphenyl ester, salicyl ester, 3, 4-di-methoxyphenyl ester,
  • the amide of A means a group represented by the formula -CONR'R", wherein each of R' and R" is hydrogen atom, lower alkyl, aryl, alkyl- or aryl-sulfonyl, lower alkenyl and lower alkynyl, and include for example lower alkyl amides such as methylamide, ethylamide, dimethylamide and diethylamide; arylamides such as anilide and toluidide; and alkyl- or aryl-sulfonylamides such as methylsulfonyla ide, ethylsulfonyl-amide and tolylsulfonylamide.
  • L and M include hydroxy which provides a 5-membered ring structure of, so called, PGF type.
  • Preferred A is -COOH, its pharmaceutically acceptable salt, ester or amide thereof.
  • Preferred B is -CH 2 -CH 2 -, which provide the structure of so-called, 13, 14-dihydro type.
  • X x and X 2 are that at least one of them is halogen, more preferably, both of them are halogen, especially, fluorine that provides a structure of, so called 10 16, 16-difluoro type.
  • Preferred R ⁇ is a hydrocarbon containing 1-10 carbon atoms, preferably, 6-10 carbon atoms.
  • R x examples include, for example, the following groups: 15 —CH 2 —CH 2 — CH 2 _ CH 2 -CH 2 —CH 2 —,
  • Preferred Ra " is a hydrocarbon containing 1-10 carbon atoms, more preferably, 1-8 carbon atoms which is substituted by aryl or aryloxy at the end.
  • the configuration of the ring and the - and/or ⁇ chains in the above formula (I) and (II) may be the same as or different from that of the primary PGs.
  • the present invention also includes a mixture of a compound having a primary type configuration and a compound of a non-primary type configuration.
  • the typical example of the compound used in the invention is a 13, 14-dihydro-15-keto-17-phenyl-18, 19, 20-trinor- prostaglandin F compound and its derivative or analogue.
  • the 15-keto-PG compound of the present invention may be in the keto-hemiacetal equilibrium by formation of a hemiacetal between hydroxy at position 11 and oxo at position 15. If such tautomeric isomers as above are present, the proportion of both tautomeric isomers varies with the structure of the rest of the molecule or the kind of the substituent present,. Sometimes one iso er may predominantly be present in comparison with the other. However, it is to be appreciated that the 15-keto-PG compounds used in the invention include both isomers .
  • the compounds used in the invention may be represented by a structure formula or name based on keto-type regardless of the presence or absence of the isomers, it is to be noted that such structure or name does not intend to exclude the hemiacetal type compound.
  • any of isomers such as the individual tautomeric isomers, the mixture thereof, or optical isomers, the mixture thereof, a racemic mixture, and other steric isomers may be used in the same purpose.
  • Some of the compounds used in the present invention may be prepared by the method disclosed in USP Nos. 5,073,569, 5,166,174, 5,221,763, 5,212,324, 5,739,161 and 6,242,485 (these cited references are herein incorporated by reference) .
  • treatment “treat” or “treating” used herein includes any means of control such as prevention, care, relief of the condition, attenuation of the condition, arrest of progression of the condition.
  • a subject in need of such treatment means a subject who is suffering from a disease in which a reduction in his/her intraocular pressure is desirable, for example, glaucoma and ocular hypertension, or a subject who is susceptible to suffering from such disease as discussed above.
  • the subject may be any mammalian subject including human beings .
  • the 15-keto-PG compound described as above may be formulated as an ophthalmic composition and applied topically to the eyes of a mammalian subject.
  • the ophthalmic composition of the present invention may be any form for local eye administration used in the ophthalmic field such as eye drops and eye ointment.
  • the ophthalmic composition may be prepared in a conventional manner known to the art.
  • the eye drops may be prepared by dissolving the active ingredients in a sterile aqueous solution such as saline and buffering solution, or the eye drop composition may be provided as a combined powder composition comprising the active ingredient to be dissolved in the aqueous solution before use .
  • Eye drops such as the ones as described in EP-A-0406791 are preferably used in the present invention (the cited reference is herein incorporated by reference) .
  • additives ordinarily used in conventional eye drops may be added.
  • Such additives may include isotonizing agents (e.g., sodium chloride), buffering agent (e.g., boric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate) , preservatives (e.g., benzalkonium chloride, benzethonium chloride, chlorobutanol) , thickeners (e.g., saccharide such as lactose, mannitol, maltose; hyaluronic acid or its salt such as sodium hyaluronate, potassium hyaluronate; mucopolysaccharide such as chondroitin sulfate; sodium polyacrylate, carboxyvinyl polymer, crosslinked polyacrylate.)
  • isotonizing agents
  • the eye drops may be formulated as a sterile unit dose type eye drops containing no preservatives.
  • Eye ointment may also be prepared in a conventional manner known to the art. For example, it may be prepared by mixing the active " ingredient into a base component conventionally used for known eye ointments under a sterile condition.
  • a base component conventionally used for known eye ointments under a sterile condition.
  • the base components for the eye ointment include petrolatum, selen 50, Plastibase and macrogol, but not limited thereto.
  • a surface-active agent can be added to the composition.
  • the eye ointment may also contain the above- mentioned additives such as the preservatives and the like, if desired.
  • more than 5 ⁇ g and less than 50 ⁇ g per eye of the above-defined 15-keto-compound is topically administered to the subject per administration.
  • the dose of the 15-keto-compound is preferably less than 30 ⁇ g, more preferably less than 20 ⁇ g, further more preferably less than 15 ⁇ g and still further preferably less than 12 ⁇ g per eye per administration.
  • the lower limit of the dose may be more than 7 ⁇ g or more than lO ⁇ g per eye per administration.
  • the dose of the above-defined 15-keto-compound may vary within the range defined as above depending on the compound to be used, the type of subject such as animals or human, age, weight, symptom to be treated, desirable therapeutic effect, period for treatment and the like.
  • the frequency of the administration of the above-defined 15-keto-prostaglandin compound may vary depending on the compound to be used, the type of subject such as animals or human, age, weight, symptom to be treated, desirable therapeutic effect, period for treatment and the like.
  • the frequency of administration may be at least once a day and preferably, one to six times, more preferably, one to four times a day. Since the 15-keto-prostaglandin compound used in the invention causes substantially no or reduced ocular irritation even in a high dose, the treatment of the instant invention may be carried out for a long period of time.
  • the ophthalmic composition of the invention may contain a single active ingredient or a combination of two or more active ingredients. In a combination of plural active ingredients, their respective contents may be suitably increased or decreased in consideration of their therapeutic effects and safety.
  • concentration of the 15-keto-prostaglandin compound in the ophthalmic composition of the present invention is adjusted so that the amount of the compound to be administrated is within the range of more than 5 ⁇ g and less than 50 ⁇ g, preferably less than 30 ⁇ g, more preferably less than 20 ⁇ g, further more preferably less than 15 ⁇ g and still further preferably less than 12 ⁇ g per eye per administration.
  • the lower limit of the amount may be more than 7 ⁇ g or more than lO ⁇ g per eye per administration.
  • the ophthalmic composition of the present invention may contain any other pharmaceutically active ingredients as far as they are not contrary to the objects of the present invention.
  • the present ophthalmic composition may be administered safely to subjects with ocular hypertension and glaucoma having some disorders on their cornea or conjunctiva such as allergic disease and dry eye.
  • EXAMPLE 1 The incidence rate of conjunctival hyperemia was compared between the present compound 13, 14-dihydro-15-keto- 17-phenyl-18, 19, 20-trinor-PGF 2 a isopropyl ester and 13,14- dihydro-17-phenyl-18, 19, 20-trinor-PGF 2o isopropyl ester.
  • Table 1 shows the results.
  • EXAMPLE 4 Nine male cynomolgus monkeys (body weights of animals ranged between 3.2 and 5.4 kg) without abnormalities in the anterior segment of the eye were used.
  • Intraocular pressure (IOP) measurements were conducted by means of an applanation pneumatonometer (Model 30 ClassicTM, Mentor 0 & 0, Inc., USA) immediately before the administration
  • Redness refers to palpebral conjunctivae only
  • the maximum total score is the sum of all scores obtained for the cornea, iris and conjunctivae.

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Abstract

Cette invention se rapporte à un procédé servant à traiter l'hypertension oculaire et les glaucomes et qui consiste à administrer en mode topique dans les yeux d'un sujet mammifère nécessitant un tel traitement plus de 5 νg et moins de 50 νg par oeil par administration d'un composé de 15-céto-prostaglandine comportant une structure cyclique à l'extrémité de la chaîne φ. Le traitement faisant l'objet de cette invention ne produit pour ainsi dire pas d'effets secondaires irritants l'oeil ou en produit à un niveau réduit, même à une telle dose élevée.
PCT/JP2002/007699 2001-07-31 2002-07-30 Procede et composition pour le traitement de l'hypertension oculaire et des glaucomes WO2003011299A2 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CA002454422A CA2454422A1 (fr) 2001-07-31 2002-07-30 Procede et composition pour le traitement de l'hypertension oculaire et des glaucomes
JP2003516529A JP2004538306A (ja) 2001-07-31 2002-07-30 高眼圧症および緑内障の処置
EP02751774A EP1411950A2 (fr) 2001-07-31 2002-07-30 Procede et composition pour le traitement de l'hypertension oculaire et des glaucomes
MXPA04000980A MXPA04000980A (es) 2001-07-31 2002-07-30 Tratamiento de hipertension ocular y glaucoma.
KR10-2004-7001587A KR20040023707A (ko) 2001-07-31 2002-07-30 안내압항진 및 녹내장의 치료
BR0211545-0A BR0211545A (pt) 2001-07-31 2002-07-30 Método e composição para tratamento de hipertensão ocular e glaucoma
US10/485,370 US20040254247A1 (en) 2001-07-31 2002-07-30 Method and composition for treatnment of ocular hypertension and glaucoma

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US30858901P 2001-07-31 2001-07-31
US60/308,589 2001-07-31

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KR (1) KR20040023707A (fr)
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CA (1) CA2454422A1 (fr)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003082257A2 (fr) * 2002-03-28 2003-10-09 Sucampo Ag Methode de traitement de l'hypertension oculaire et du glaucome
WO2004071514A1 (fr) * 2003-02-14 2004-08-26 Sucampo Ag Derives de 15-ceto-prostaglandine pour le traitement de l'hypertension oculaire et du glaucome

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US7605178B2 (en) * 2006-07-10 2009-10-20 Allergan, Inc. Therapeutic compounds
US20080015219A1 (en) * 2006-07-11 2008-01-17 Allergan, Inc. Therapeutic compounds
WO2008008718A2 (fr) * 2006-07-11 2008-01-17 Allergan, Inc. Composés thérapeutiques
NZ582705A (en) * 2007-07-03 2012-06-29 Allergan Inc Therapeutic substituted cyclopentanes for reducing intraocular pressure

Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0366279A2 (fr) * 1988-10-01 1990-05-02 R-Tech Ueno Ltd. Agents oculaires hypotenseurs
WO2001068072A2 (fr) * 2000-03-16 2001-09-20 Sucampo Ag Traitement de l'hypertension oculaire et du glaucome
WO2002007731A2 (fr) * 2000-07-20 2002-01-31 Sucampo Ag Composition destinee au traitement de l'hypertension oculaire et du glaucome

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
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WO2003082257A3 (fr) * 2002-03-28 2003-12-24 Sucampo Ag Methode de traitement de l'hypertension oculaire et du glaucome
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CA2454422A1 (fr) 2003-02-13
JP2004538306A (ja) 2004-12-24
BR0211545A (pt) 2004-07-13
MXPA04000980A (es) 2004-04-20
WO2003011178A2 (fr) 2003-02-13
KR20040023707A (ko) 2004-03-18
CN1646134A (zh) 2005-07-27
WO2003011299A3 (fr) 2003-10-30

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