WO2003011178A2 - Procede de traitement pour l'hypertension oculaire et le glaucome - Google Patents

Procede de traitement pour l'hypertension oculaire et le glaucome Download PDF

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Publication number
WO2003011178A2
WO2003011178A2 PCT/US2002/024072 US0224072W WO03011178A2 WO 2003011178 A2 WO2003011178 A2 WO 2003011178A2 US 0224072 W US0224072 W US 0224072W WO 03011178 A2 WO03011178 A2 WO 03011178A2
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WO
WIPO (PCT)
Prior art keywords
keto
alkyl
prostaglandin compound
glaucoma
compound
Prior art date
Application number
PCT/US2002/024072
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English (en)
Inventor
Ryuji Ueno
Original Assignee
Sucampo, A.G.
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.)
Filing date
Publication date
Application filed by Sucampo, A.G. filed Critical Sucampo, A.G.
Publication of WO2003011178A2 publication Critical patent/WO2003011178A2/fr

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Classifications

    • 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 that is associated with substantially reduced ocular irritation such as conjunctival hyperemia, which comprises administration of a 15-keto- prostaglandin compound having a ring structure at the end of the ⁇ chain to mammal eyes in a high dose.
  • 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 2 5,6- and 13, 14-diunsaturated-15-OH
  • Subscript3 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 (the hydroxyl group is of a ⁇ -configuration) .
  • PGE 1 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 3c( 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 glaucoma (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) .
  • latanoprost i.e., 13,14- dihydro-17-phenyl-18, 19, 20-trinor-PGF 2 ⁇ 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, the clinical dose of latanoprost is about 1.5 ⁇ g-1.75 ⁇ g per eye.
  • 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 to mammal eyes even in a high dose substantially reduces an ocular irritation such as conjunctival hyperemia, which has resulted in the completion of the present invention.
  • the present invention relates to a method for ) treating ocular hypertension and glaucoma, which comprises administration of a 15-keto-prostaglandin compound having a ring structure at the end of the ⁇ chain to mammal eyes in a dose of more than 5 ⁇ g and less than 50 ⁇ g per eye.
  • the present invention particularly provides a method for treating ocular hypertension and glaucoma
  • the present invention further relates to a composition for treating ocular hypertension and glaucoma of mammals, which comprises, as an active ingredient thereof, a 15-keto- prostaglandin compound having a ring structure at the end of the ⁇ chain in a dose of more than 5 ⁇ g and less than 50 ⁇ g per eye..
  • the present invention further relates to a use of a 15-keto-prostaglandin compound having a ring structure at the end of the ⁇ chain for manufacturing a composition for treating ocular hypertension and glaucoma of mammals in a dose of more than 5 ⁇ g and less than 50 ⁇ g per eye.
  • 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 ⁇ or ⁇ chain.
  • a preferred compound used in the present invention is represented by the formula (I]
  • W x , 2 and 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;
  • 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.
  • 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
  • Ri 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
  • 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 14 carbon atoms (for a side chain, 1 to 3 carbon atoms are preferable) and preferably 1 to 10, especially 6 to 10 carbon atoms for R x and 1 to 10, especially 1 to 8 carbon atoms for R a .
  • halogen atom covers fluorine, chlorine, bromine and iodine.
  • lower alkyl refers to a straight or branched chain saturated hydrocarbon group containing 1 to 6 carbon atoms and includes, for example, 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) lkyl 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, benzimidazolyl, benzimidazolinyl, benzothiazolyl, phenothiazo
  • 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, diethanola ine 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; hydrox (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-sulfonyla ides such as methylsulfonylamide, 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 16, 16-difluoro type.
  • Preferred R_ is a hydrocarbon containing 1-10 carbon atoms, preferably, 6-10 carbon atoms.
  • R- ⁇ examples include, for example, the following groups :
  • 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 a- and/or ⁇ chains in the above formula (I) and (II) maybe 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 present compound 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.
  • 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 isomer 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. Further, while 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 exlclude 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.
  • treatment 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.
  • the present compound is applied by means of eye local administration (eye drop and eye ointment, etc.).
  • the formulation may be manufactured in a conventional manner.
  • the dosage form may be any formulations for local eye administration used in the ophthalmic field such as eye drop and eye ointment .
  • the eye drops may be prepared by dissolving the active ingredients in a sterile aqueous solution such as saline and buffering solution, or by providing the active ingredients as combined powder composition to be dissolved in the aqueous solution before use.
  • Eye drops such as the ones as described in EP-A-0406791 are preferred.
  • 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 e.g., sodium chloride
  • buffering agent e.g., bo
  • Eye ointment can be prepared by mixing the active ingredient into a base component ordinarily used for a conventional eye ointment and formulating it according to an ordinary method under a sterile condition.
  • a base component ordinarily used for a conventional eye ointment and formulating it according to an ordinary method under a sterile condition.
  • the base 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 above-mentioned additives such as the preservatives and the like can be combined, if necessary.
  • the present eye drops may be formulated as a sterile unit dose type eye drops containing no preservatives.
  • the dose and frequency of administration of the active ingredients of eye drops used in the present invention may vary according to the compound to be used, the type of subject such as animals or human, age, weight, symptom to be treated, desirable therapeutic effect, administration route, administration amount and period for treatment.
  • suitable concentration and frequency may be chosen as desired, formulations adjusted for administration of the active ingredients to an adult human within the range of more than 5 ⁇ g and less than 50 ⁇ g per eye may be administered at least once a day.
  • formulations adjusted for administration of the active ingredients within the range of more than 5 ⁇ g and less than 50 ⁇ g per eye may be applied several times a day, preferably one to six times, more preferably one to four times .
  • the present formulations may contain a single active ingredient or a combination of two or more active ingredients .
  • their respective contents may be suitably increased or decreased in consideration of their therapeutic effects and safety.
  • present formulations may suitably contain any other pharmaceutically active ingredients as far as they are not contrary to the objects of the present invention.
  • the present invention particularly provides a method for treating ocular hypertension and glaucoma, associated with substantially reduced ocular irritation such as conjunctival hyperemia, comprising administering a 15-keto-prostaglandin compound having a ring structure at the end of the ⁇ chain to mammal eyes in a dose of more than 5 ⁇ g and less than 50 ⁇ g per eye.
  • the method allows to conduct a safe and comfortable treatment of ocular hypertension and glaucoma for a long period of time.
  • the present preparations 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.
  • 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 ⁇ isopropyl ester and 13,14- dihydro-17-phenyl-18, 19, 20-trinor-PGF 2 ⁇ isopropyl ester.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé pour le traitement de l'hypertension oculaire et du glaucome, qui consiste à administrer dans les yeux d'un mammifère un composé de 15-kéto-prostaglandine à structure cyclique à l'extrémité de la chaîne φ, selon une dose supérieure à 5 νg et inférieure à 50 νg par oeil.
PCT/US2002/024072 2001-07-31 2002-07-31 Procede de traitement pour l'hypertension oculaire et le glaucome WO2003011178A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US30858901P 2001-07-31 2001-07-31
US60/308,589 2001-07-31

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Publication Number Publication Date
WO2003011178A2 true WO2003011178A2 (fr) 2003-02-13

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Family Applications (2)

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PCT/JP2002/007699 WO2003011299A2 (fr) 2001-07-31 2002-07-30 Procede et composition pour le traitement de l'hypertension oculaire et des glaucomes
PCT/US2002/024072 WO2003011178A2 (fr) 2001-07-31 2002-07-31 Procede de traitement pour l'hypertension oculaire et le glaucome

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PCT/JP2002/007699 WO2003011299A2 (fr) 2001-07-31 2002-07-30 Procede et composition pour le traitement de l'hypertension oculaire et des glaucomes

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EP (1) EP1411950A2 (fr)
JP (1) JP2004538306A (fr)
KR (1) KR20040023707A (fr)
CN (1) CN1646134A (fr)
BR (1) BR0211545A (fr)
CA (1) CA2454422A1 (fr)
MX (1) MXPA04000980A (fr)
WO (2) WO2003011299A2 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005519978A (ja) * 2002-03-28 2005-07-07 スキャンポ・アーゲー 高眼圧症および緑内障の処置方法
AR043161A1 (es) * 2003-02-14 2005-07-20 Sucampo Pharmaceuticals Inc Composicion oftalmica para tratar hipertension ocular y glaucoma
JP5532302B2 (ja) * 2006-07-10 2014-06-25 アラーガン インコーポレイテッド 治療化合物
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

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0366279B1 (fr) * 1988-10-01 1994-09-21 R-Tech Ueno Ltd. Agents oculaires hypotenseurs
NZ521325A (en) * 2000-03-16 2004-05-28 Sucampo Ag Use of prostaglandins for the treatment of ocular hypertension and glaucoma
US20020035148A1 (en) * 2000-07-20 2002-03-21 Ryuji Ueno Treatment of ocular hypertension

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CA2454422A1 (fr) 2003-02-13
MXPA04000980A (es) 2004-04-20
BR0211545A (pt) 2004-07-13
EP1411950A2 (fr) 2004-04-28
WO2003011299A2 (fr) 2003-02-13
KR20040023707A (ko) 2004-03-18
WO2003011299A3 (fr) 2003-10-30
CN1646134A (zh) 2005-07-27
JP2004538306A (ja) 2004-12-24

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