WO2001034551A1 - Hydroxyeicosatetraenoic acid analogs and methods of their use in treating dry eye disorders - Google Patents

Hydroxyeicosatetraenoic acid analogs and methods of their use in treating dry eye disorders Download PDF

Info

Publication number
WO2001034551A1
WO2001034551A1 PCT/US2000/029243 US0029243W WO0134551A1 WO 2001034551 A1 WO2001034551 A1 WO 2001034551A1 US 0029243 W US0029243 W US 0029243W WO 0134551 A1 WO0134551 A1 WO 0134551A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
chch
group
forms
ophthalmically acceptable
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2000/029243
Other languages
English (en)
French (fr)
Inventor
Peter G. Klimko
Mark R. Hellberg
John R. Falck
Raymond E. Conrow
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Alcon Universal Ltd
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 Alcon Universal Ltd filed Critical Alcon Universal Ltd
Priority to AU12262/01A priority Critical patent/AU776254B2/en
Priority to AT00973791T priority patent/ATE271534T1/de
Priority to BR0015424-5A priority patent/BR0015424A/pt
Priority to HK02107320.4A priority patent/HK1045983B/en
Priority to DE60012358T priority patent/DE60012358T2/de
Priority to MXPA02004704A priority patent/MXPA02004704A/es
Priority to JP2001536502A priority patent/JP4663193B2/ja
Priority to PL356105A priority patent/PL202040B1/pl
Priority to CA002386627A priority patent/CA2386627C/en
Priority to DK00973791T priority patent/DK1228029T3/da
Priority to EP00973791A priority patent/EP1228029B1/en
Publication of WO2001034551A1 publication Critical patent/WO2001034551A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • 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
    • 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
    • A61P27/04—Artificial tears; Irrigation solutions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/46—Unsaturated compounds containing hydroxy or O-metal groups containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention is directed to compositions containing
  • Dry eye also known genetically as keratoconjunctivitis sicca, is a common
  • tear substitution approach examples include the use of buffered,
  • dry eye include 3,991,759 (Urquhart).
  • Other semi-solid therapy has included the administration of carrageenans (5,403,841, Lang) which gel upon contact with
  • microfine particles of one or more retinoids for ocular tissue normalization.
  • Mucins are proteins that are heavily glycosylated with glucosamine-based
  • Mucins provide protective and lubricating effects to epithelial cells
  • Mucins have been shown to be secreted by
  • Mucins are also produced and secreted in other parts of the body including
  • Marom has reported the production of mucosal glycoproteins in human lung by HETE derivatives (Marom et al., Human Airway Monohydroxy- eicosatetraenoic Acid
  • the conventional treatment for dry eye includes
  • vasoactive intestinal for increasing ocular mucin and/or tear production include vasoactive intestinal
  • the present invention is directed to compositions and methods for the
  • the present invention discloses analogs of (5Z,8Z,11Z,13E)-15- hydroxyeicosa-5,8,l l,14-tetraenoic acid (15-H ⁇ T ⁇ ) and methods using the same for
  • compositions are preferably administered
  • R 1 is CO 2 R, CONR 2 R 3 , CH 2 OR 4 , CH 2 NR 5 R 6 , CH 2 N 3 , CH 2 Hal, CH 2 NO 2 , CH 2 SR 20 , COSR 21 , or 2,3,4,5-tetrazol-l-yl, where:
  • R is H or a pharmaceutically acceptable cation, or CO 2 R forms a pharmaceutically acceptable ester moiety
  • NR 2 R 3 , NR 5 R 6 are the same or different and comprise a free or functionally modified amino group
  • OR 4 comprises a free or functionally modified hydroxy group
  • Hal is F, Cl, Br, or I
  • R 20 is H, alkyl, acyl
  • R 21 is H or a pharmaceutically acceptable cation, or COSR 21 forms a pharmaceutically acceptable thioester moiety
  • A is L ⁇ -A]-L 2 , L ⁇ -A 2 -L 2 , L 3 -A 2 -L 4 , or L 5 -A 2 -L 3 ;
  • L 2 is CH 2 -K-CH 2 CH 2 ;
  • L 4 is X-CH 2 CH 2 ;
  • L 5 is CH 2 CH 2 -B-D
  • Y is C(O) (i.e. a carbonyl group) or Y is
  • R 9 O constitutes a free or functionally modified hydroxy group.
  • the compounds of formula I may also be incorporated into phospholipids as
  • phospholipid formula I esters will comprise various phospholipids.
  • Phospholipid Phospholipid
  • esters of the compounds of formula I will typically comprise a formula I compound
  • ester class does not contain an ester of a compound of formula I, then such carbon positions of the glycerol backbone will comprise a methylene, ether or ester moiety
  • alkyl(cycloalkyl)alkyl alkyl(cycloalkyl);
  • alkyl halo, hydroxy, or functionally modified hydroxy
  • M is O or S
  • Q is H, alkyl
  • alkyl(cycloalkyl)alkyl alkyl(cycloalkyl)alkyl, alkyl(cycloalkyl), alkyl(heteroaryl) or alkyl(heteroaryl)alkyl.
  • Preferred phospholipid-formula I) esters will be of the
  • the individual enantiomers can be enantioselectively synthesized from the
  • non-racemic mixtures by a number of known methods, e.g. by purification of a sample
  • racemic and non-racemic mixtures may be obtained by several means, including
  • ophthalmically acceptable salt and “ophthalmically acceptable ester” means any pharmaceutically acceptable
  • modified hydroxy group means an OH which has been functionalized to form: an ether, in which an alkyl, aryl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl,
  • heterocycloalkenyl, alkynyl, or heteroaryl group is substituted for the hydrogen;
  • ester in which an acyl group is substituted for the hydrogen; a carbamate, in which an
  • aminocarbonyl group is substituted for the hydrogen; or a carbonate, in which an
  • moieties include OH, OCH 2 C(O)CH 3 ,OCH 2 C(O)C 2 H 5 ,
  • OCH 3 OCH 2 CH 3 , OC(O)CH 3 , and OC(O)C 2 H 5 .
  • free amino group means an NH 2 .
  • functionally modified means an NH 2 .
  • amino group means an NH 2 which has been functionalized to form: an aryloxy-,
  • moieties include NH 2 , NHCH 3 , NHC 2 H 5 , N(CH 3 ) 2 , NHC(O)CH 3 , NHOH, and NH(OCH 3 ).
  • thiol group means an SH which has been functionalized to form: a thioether, where
  • alkyl an alkyl, aryl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl,
  • alkynyl, or heteroaryl group is substituted for the hydrogen; or a thioester, in which an
  • acyl group is substituted for the hydrogen.
  • Preferred moieties include SH, SC(O)CH 3 ,
  • acyl represents a group that is linked by a carbon atom that has a
  • alkyl includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms.
  • the alkyl groups may be
  • heteroatoms such as oxygen, nitrogen, or sulfur, and may be interrupted by one or more heteroatoms, such as oxygen, nitrogen, or sulfur, and may be interrupted by one or more heteroatoms, such as oxygen, nitrogen, or sulfur, and may be interrupted by one or more heteroatoms, such as oxygen, nitrogen, or sulfur, and may be interrupted by one or more heteroatoms, such as oxygen, nitrogen, or sulfur, and may be interrupted by one or more heteroatoms, such as oxygen, nitrogen, or sulfur, and may
  • Preferred straight or branched alkyl groups include methyl, ethyl, propyl,
  • cycloalkyl includes straight or branched chain, saturated or
  • the rings may be substituted with other groups, such as
  • groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • heterocycloalkyl refers to cycloalkyl rings that contain at least one
  • heteroatom such as O, S, or N in the ring, and can be fused or isolated.
  • the rings may
  • heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, piperazinyl, and tetrahydropyranyl.
  • alkenyl includes straight or branched chain hydrocarbon groups
  • the chain hydrogens may be optionally interrupted by one or more heteroatoms.
  • the chain hydrogens may be optionally interrupted by one or more heteroatoms.
  • alkeny groups include, allyl, 1-butenyl, l-methyl-2-propenyl and 4-pentenyl.
  • cycloalkenyl includes straight or branched chain, saturated or
  • aromatic rings containing a carbon-carbon double bond which can be fused or isolated.
  • the rings may be substituted with other groups, such as halogen, hydroxyl,
  • cycloalkenyl groups include cyclopentenyl
  • heterocycloalkenyl refers to cycloalkenyl rings which contain one
  • heteroatoms such as O, N, or S in the ring, and can be fused or isolated.
  • rings may be substituted with other groups, such as halogen, hydroxyl, aryl, aryloxy,
  • heterocycloalkenyl groups include pyrrolidinyl
  • carbonyl group represents a carbon atom double bonded to an
  • oxygen atom wherein the carbon atom has two free valencies.
  • aminocarbonyl represents a free or functionally modified amino
  • lower alkyl represents alkyl groups containing one to six carbons
  • halogen represents fluoro, chloro, bromo, or iodo.
  • aryl refers to carbon-based rings which are aromatic.
  • ring hydrogens may be isolated, such as phenyl, or fused, such as naphthyl.
  • the ring hydrogens may be isolated, such as phenyl, or fused, such as naphthyl.
  • the ring hydrogens may be isolated, such as phenyl, or fused, such as naphthyl.
  • the ring hydrogens may be isolated, such as phenyl, or fused, such as naphthyl.
  • aryl groups include phenyl, 3-
  • heteroaryl refers to aromatic hydrocarbon rings which contain at
  • heteroaryl rings may be isolated, with 5 to 6 ring atoms, or fused, with 8 to 10 atoms.
  • heteroatoms with open valency may be substituted with other groups, such as lower
  • heteroaryl groups include imidazole, pyridine, indole, quinoline, furan, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, and
  • heterocycloalkoxy "alkenyloxy”, “cycloalkenyloxy”, “heterocycloalkenyloxy", and
  • alkynyloxy represent an aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkenyl,
  • alkoxycarbonyl "aryloxycarbonyl”, “heteroaryloxycarbonyl",
  • alkynyloxycarbonyl represent an alkoxy, aryloxy, heteroaryloxy, cycloalkoxy, heterocycloalkoxy, alkenyloxy, cycloalkenyloxy, heterocycloalkenyloxy, or
  • Preferred compounds of the present invention include those of formula I,
  • R 1 is CO R, where R is H or an ophthalmically acceptable cationic salt, or CO R forms an ophthalmically acceptable ester moiety;
  • A is L ⁇ -A ⁇ -L 2 or L ⁇ -A 2 -L ;
  • A is CH 2 CH 2 ;
  • L 2 is CH 2 -K-CH 2 CH 2 ;
  • R 1 is CO R, where R is H or an ophthalmically acceptable cationic salt, or CO 2 R forms an ophthalmically acceptable ester moiety;
  • A is L 3 -A 2 -L 4 ;
  • L 4 is X-CH 2 CH 2 ;
  • Still other preferred compounds of the present invention include those of
  • R 1 is CO R, where R is H or an ophthalmically acceptable cationic salt, or CO 2 R forms an ophthalmically acceptable ester moiety;
  • A is L 5 -A 2 -L 3 ;
  • L 5 is CH 2 CH 2 -B-D
  • TPAP perruthenate
  • diene 16 which is treated with 3,4-dihydro-2H-pyran (D ⁇ P) and a catalytic
  • DIBAL-H diisobutylaluminum hydride
  • diiodomethane affords cyclopropane 34, which is reduced to diol 35 with LiAlH 4 .
  • Oxidation of 43 to aldehyde 44 is achieved using TPAP/NMO. This aldehyde is reacted with Ph P(CH 2 ) 4 CO 2 H Br in the presence of KOBu', and the
  • Alcohol 15 is protected as its THP ether 45 by treatment with DHP and TsOH.
  • THP ether 48 Treatment of enynol 27 with DHP and TsOH affords THP ether 48, which is
  • TsOH gives THP ether 58, which is desilylated with TBAF in THF to yield alcohol
  • 86 is converted to aldehyde 87 by reduction with
  • diazomethane provides olefin 88.
  • alkynol 95 which is protected as its t-butyldiphenylsilyl
  • protecting group from 95 is accomplished by treatment with TsO ⁇ in hot T ⁇ F/water,
  • olefin 109 is deprotected using TBAF in THF to give
  • Alcohol 106 is oxidized using TPAP/NMO to give aldehyde 115, which is
  • ynol 117 is protected as its THP ether by treatment with DHP and TsOH to give
  • iodide 127 is treated sequentially with with t-butyllithium at -78 °C,
  • TBAF butylammonium fluoride
  • TPAP propylammonium perrruthernate
  • Ester 157 is treated with KOH in MeOH/water followed by chromatographic
  • the compounds of the present invention may be contained in various types of
  • compositions in accordance with formulation techniques known to
  • the present invention may have an impact on the HETE derivative's biological activity. Although the precise relationship has not been defined, it is preferable to use
  • HETE derivative raw material supplies containing peroxy compounds at levels no
  • compositions of the present invention will include one or
  • Aqueous solutions are generally preferred,
  • compositions such as suspensions, viscous or semi-viscous gels, or other types of solid or semi-solid compositions.
  • compositions of the present invention may also be used as ophthalmic compositions of the present invention.
  • ingredients such as buffers, preservatives, co-solvents and
  • An appropriate buffer system e.g., sodium phosphate, sodium acetate or
  • sodium borate may be added to prevent pH drift under storage conditions.
  • Antioxidants may be added to compositions of the present invention to protect
  • antioxidants examples include sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite
  • vitamin E include vitamin E and analogs thereof, ascorbic acid and butylated hydroxytoluene
  • Ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable
  • preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid,
  • polyquaternium-1 or other agents known to those skilled in the art.
  • preservatives are typically employed at a level of from 0.001 to 1.0% weight/volume
  • amount refers to an amount which improves the dry eye condition in a human
  • compositions When the compositions are dosed topically, they will generally be in a concentration range of from 0.001 to about 1.0% w/v, with 1-2 drops administered 1-4
  • pharmaceutically acceptable carrier refers to any pharmaceutically acceptable carrier
  • the ophthalmic compositions of the present invention will be described in one embodiment.
  • effective concentration of ethanol refers to a concentration that enhances the
  • compositions may be proportionally less than analogous compositions containing
  • compositions containing formula (I) concentrations range from about 0.001-2% w/v.
  • w/v preferably will contain ethanol in a concentration of
  • Example 20 is provided below.
  • Example 20 is provided below.
  • the above composition is prepared by the following method.
  • the batch is prepared by the following method.
  • polyquaternium- 1 are weighed and dissolved by stirring in 90%> of the batch quantity
  • the above process is performed using glass, plastic or other non-removable object,

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Ophthalmology & Optometry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Steroid Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/US2000/029243 1999-11-09 2000-10-23 Hydroxyeicosatetraenoic acid analogs and methods of their use in treating dry eye disorders Ceased WO2001034551A1 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
AU12262/01A AU776254B2 (en) 1999-11-09 2000-10-23 Hydroxyeicosatetraenoic acid analogs and methods of their use in treating dry eye disorders
AT00973791T ATE271534T1 (de) 1999-11-09 2000-10-23 Hydroxyeicosatetraensäureanaloge und verfahren deren verwendung zur behandlung des trockenen auges
BR0015424-5A BR0015424A (pt) 1999-11-09 2000-10-23 Análogos de ácido hidroxieicosatetraenóico e, métodos de seu uso em tratamento de distúrbios de olho seco
HK02107320.4A HK1045983B (en) 1999-11-09 2000-10-23 Hydroxyeicosatetraenoic acid analogs and methods of their use in treating dry eye disorders
DE60012358T DE60012358T2 (de) 1999-11-09 2000-10-23 Hydroxyeicosatetraensäureanaloge und Verfahren zu deren Verwendung zur Behandlung des trockenen Auges
MXPA02004704A MXPA02004704A (es) 1999-11-09 2000-10-23 Analogos de acido hidroxieicosatetraenoico y sus metodos de uso en el tratamiento de trastornos de resequedad del ojo.
JP2001536502A JP4663193B2 (ja) 1999-11-09 2000-10-23 ヒドロキシエイコサテトラエン酸アナログおよびドライアイ障害の処置におけるその使用方法
PL356105A PL202040B1 (pl) 1999-11-09 2000-10-23 Analogi kwasu hydroksyeikozatetraenowego, ich zastosowanie i zawierająca je kompozycja do leczenia zespołu suchego oka
CA002386627A CA2386627C (en) 1999-11-09 2000-10-23 Hydroxyeicosatetraenoic acid analogs and methods of their use in treating dry eye disorders
DK00973791T DK1228029T3 (da) 1999-11-09 2000-10-23 Hydroxyicosatetraensyreanaloger og fremgangsmåder til deres anvendelse til behandling af öjentörhedslidelser
EP00973791A EP1228029B1 (en) 1999-11-09 2000-10-23 Hydroxyeicosatetraenoic acid analogs and methods of their use in treating dry eye disorders

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US16437199P 1999-11-09 1999-11-09
US16438699P 1999-11-09 1999-11-09
US16436999P 1999-11-09 1999-11-09
US60/164,371 1999-11-09
US60/164,369 1999-11-09
US60/164,386 1999-11-09

Publications (1)

Publication Number Publication Date
WO2001034551A1 true WO2001034551A1 (en) 2001-05-17

Family

ID=27389011

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/029243 Ceased WO2001034551A1 (en) 1999-11-09 2000-10-23 Hydroxyeicosatetraenoic acid analogs and methods of their use in treating dry eye disorders

Country Status (18)

Country Link
EP (1) EP1228029B1 (https=)
JP (1) JP4663193B2 (https=)
KR (1) KR100781354B1 (https=)
CN (1) CN1390191A (https=)
AR (1) AR029769A1 (https=)
AT (2) ATE271534T1 (https=)
AU (1) AU776254B2 (https=)
BR (1) BR0015424A (https=)
CA (1) CA2386627C (https=)
DE (2) DE60017810T2 (https=)
DK (1) DK1228029T3 (https=)
ES (2) ES2233921T3 (https=)
HK (1) HK1045983B (https=)
MX (1) MXPA02004704A (https=)
PL (1) PL202040B1 (https=)
PT (2) PT1418167E (https=)
TW (1) TWI281395B (https=)
WO (1) WO2001034551A1 (https=)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003030894A1 (en) * 2001-10-11 2003-04-17 Alcon, Inc. Methods for treating dry eye
US20100210727A1 (en) * 2006-04-19 2010-08-19 Evolva S.A. Hepoxilin analog enantiomers

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4906467A (en) 1988-03-24 1990-03-06 New York Medical College Novel, long-duration treatment for glaucoma
US5696166A (en) * 1995-10-31 1997-12-09 Yanni; John M. Compositions containing hydroxyeicosatetraenoic acid derivatives and methods of use in treating dry eye disorders

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LOW, C-E.; PUPILLO, M.; BRYANT, R.; BAILEY, J: "Inhibition of phytohemagglutinin-induced lymphocyte mitogenesis by lipoxygenase metabolites of arachidonic acid: structure-activity relationships", JOURNAL OF LIPID RESEARCH, vol. 25, no. 10, 1 October 1984 (1984-10-01), pages 1090 - 1095, XP000990320 *
PETRICH, K.; LUDWIG, P.; KÜHN, H.; SCHEWE, T.: "The suppression of 5-lipoxygenation of arachidonic acid in human polymorphonuclear leucocytes by the 15-lipoxygenase product (15S)-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid: structure-activity relationship and mechanism of action", BIOCHEMICAL JOURNAL, vol. 314, no. 3, 1996, pages 911 - 916, XP000990343 *
STEFFENRUD, S.; BORGEAT, P.: "Gas Chromatography-mass spectrometry of monohydroxyeicosatetraenoic acids as their methyl esters trimethylsilyl, allyldimethylsilyl and tert.-butyldimethylsilyl ethers", JOURNAL OF CHROMATOGRAPHY, vol. 416, no. 2, 1987, pages 219 - 235, XP000990117 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003030894A1 (en) * 2001-10-11 2003-04-17 Alcon, Inc. Methods for treating dry eye
US20100210727A1 (en) * 2006-04-19 2010-08-19 Evolva S.A. Hepoxilin analog enantiomers
US8710252B2 (en) * 2006-04-19 2014-04-29 Cecil Pace-Asciak Hepodxilin analog enantiomers

Also Published As

Publication number Publication date
DE60017810D1 (de) 2005-03-03
CN1390191A (zh) 2003-01-08
ES2220559T3 (es) 2004-12-16
DE60012358D1 (de) 2004-08-26
PL356105A1 (en) 2004-06-14
BR0015424A (pt) 2002-07-16
PT1418167E (pt) 2005-05-31
AU1226201A (en) 2001-06-06
ATE287866T1 (de) 2005-02-15
ATE271534T1 (de) 2004-08-15
HK1045983A1 (en) 2002-12-20
PT1228029E (pt) 2004-10-29
KR100781354B1 (ko) 2007-11-30
TWI281395B (en) 2007-05-21
DE60017810T2 (de) 2005-08-25
MXPA02004704A (es) 2004-09-10
ES2233921T3 (es) 2005-06-16
KR20020040849A (ko) 2002-05-30
JP4663193B2 (ja) 2011-03-30
CA2386627A1 (en) 2001-05-17
CA2386627C (en) 2008-12-23
PL202040B1 (pl) 2009-05-29
DE60012358T2 (de) 2005-02-17
AR029769A1 (es) 2003-07-16
DK1228029T3 (da) 2004-10-25
JP2003528042A (ja) 2003-09-24
HK1045983B (en) 2004-12-24
HK1063623A1 (en) 2005-01-07
EP1228029B1 (en) 2004-07-21
EP1228029A1 (en) 2002-08-07
AU776254B2 (en) 2004-09-02

Similar Documents

Publication Publication Date Title
US6576663B2 (en) 6-Keto prostaglandin F1α and analogs for treating dry eye
US6552084B2 (en) Hydroxyeicosatetraenoic acid analogs and methods of their use in treating dry eye disorders
US6326499B1 (en) Omega chain modified 15-hydroxyeicosatetraenoic acid derivatives and methods of their use for the treatment of dry eye
US6331644B1 (en) 3-heteroatom substituted and two carbon homologs of 15-HETE and methods of use
EP1228029B1 (en) Hydroxyeicosatetraenoic acid analogs and methods of their use in treating dry eye disorders
EP1418167B1 (en) Hydroxyeicosatetraenoic acid analogs and methods of their use in treating dry eye disorders
US6803385B2 (en) Hydroxyeicosatetraenoic acid analogs and methods of their use in treating dry eye disorders
EP1228030A2 (en) Benzenoid derivatives of 15-hydroxyeicosatetraenoic acid and methods of their use in treating dry eye disorders
HK1063623B (en) Hydroxyeicosatetraenoic acid analogs and methods of their use in treating dry eye disorders
ZA200202279B (en) Hydroxyeicosatetraenoic acid and analogs and methods of their use in treating dry eye disorders.
ZA200202281B (en) Omega chain modified 15-hydroxyeicosatetraenoic acid derivatives and methods of their use for the treatment of dry eye.

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BR CA CN JP KR MX PL TR US ZA

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2000973791

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2002/02279

Country of ref document: ZA

Ref document number: 200202279

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 2386627

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 12262/01

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 1020027004596

Country of ref document: KR

ENP Entry into the national phase

Ref document number: 2001 536502

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2002/01247

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: PA/a/2002/004704

Country of ref document: MX

Ref document number: 008154929

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 1020027004596

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 2000973791

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 2000973791

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 12262/01

Country of ref document: AU