WO2003027275A1 - Inhibitors of glycogen synthase kinase-3 (gsk-3) for treating glaucoma - Google Patents

Inhibitors of glycogen synthase kinase-3 (gsk-3) for treating glaucoma Download PDF

Info

Publication number
WO2003027275A1
WO2003027275A1 PCT/US2002/030059 US0230059W WO03027275A1 WO 2003027275 A1 WO2003027275 A1 WO 2003027275A1 US 0230059 W US0230059 W US 0230059W WO 03027275 A1 WO03027275 A1 WO 03027275A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
triazole
anilino
phenylaminothiazol
methanone
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/US2002/030059
Other languages
English (en)
French (fr)
Inventor
Mark R. Hellberg
Abbot F. Clark
Iok-Hou Pang
Peggy Elizabeth Hellberg
Loretta Graves Mcnatt
Wan-Heng Wang
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.)
Alcon Inc
Original Assignee
Alcon Inc
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
Priority to US10/488,496 priority Critical patent/US7598288B2/en
Priority to JP2003530847A priority patent/JP2005504101A/ja
Priority to KR10-2004-7003638A priority patent/KR20040047824A/ko
Priority to EP02799603A priority patent/EP1430120A4/en
Priority to CA2460000A priority patent/CA2460000C/en
Priority to MXPA04002137A priority patent/MXPA04002137A/es
Application filed by Alcon Inc filed Critical Alcon Inc
Priority to AU2002334635A priority patent/AU2002334635B2/en
Priority to BR0212924-8A priority patent/BR0212924A/pt
Publication of WO2003027275A1 publication Critical patent/WO2003027275A1/en
Anticipated expiration legal-status Critical
Priority to US12/545,611 priority patent/US20090312390A1/en
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention is directed to inhibitors of glycogen synthase kinase-3 for lowering and controlling normal or elevated intraocular pressure (IOP) and treating glaucoma.
  • IOP intraocular pressure
  • glaucoma The disease state referred to as glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve.
  • IOP The several mo ⁇ hologically or functionally distinct types of glaucoma are typically characterized by elevated IOP, which is considered to be causally related to the pathological course of the disease.
  • Ocular hypertension is a condition wherein intraocular pressure is elevated, but no apparent loss of visual function has occurred; such patients are considered to be a high risk for the eventual development of the visual loss associated with glaucoma.
  • Some patients with glaucomatous field loss have relatively low intraocular pressure. These so called normotension or low tension glaucoma patients can also benefit from agents that lower and control IOP.
  • Drug therapies that have proven to be effective for the reduction of intraocular pressure include both agents that decrease aqueous humor production and agents that increase the outflow facility. Such therapies are in general administered by one of two possible routes, topically (direct application to the eye) or orally. There are some individuals who do not respond well when treated with certain existing glaucoma therapies. There is, therefore, a need for other topical therapeutic agents that control IOP.
  • the present invention is directed to inhibitors of GSK-3 which can be used to treat glaucomatous optic neuropathy and/or lower and control IOP associated with normal- tension glaucoma, ocular hypertension, and or glaucoma in warm blooded animals, including man.
  • the compounds are formulated in pharmaceutical compositions suitable for topical delivery to the eye.
  • Elevated intraocular pressure is often an indicator of glaucoma. Left unchecked, continual and long term elevated IOP can contribute to the progressive deterioration of the retina and the loss of visual function. Therefore, lowering IOP is often an objective in the treatment of glaucoma patients in order to decrease the potential for or severity of glaucomatous retinopathy. It has been shown that even those glaucoma patients who do not exhibit elevated levels of IOP benefit from agents that lower and control IOP. Unfortunately, some individuals do not respond well when treated with certain existing glaucoma therapies.
  • Wnt proteins comprise a large family of structurally related ligands that activate the Wnt signaling pathway.
  • the frizzle family of proteins are key components in this pathway serving as membrane bound receptors for Wnt.
  • the frizzle proteins are a family of seven transmembrane proteins that have an N-terminal extracelluar cysteine rich domain and a cytoplasmic carboxylate tail. Binding of Wnt to frizzle initiates a cascade of events one of which results in the inhibition of (GSK-3) preventing the phosphorylation of ⁇ -catenin. Phosphorylation of ⁇ -catenin leads to its degradation.
  • Activation of the Wnt pathway increases the intracellular concentration of uncomplexed ⁇ -catenin which can activate ⁇ -catenin- T cell factor/Lymphoid enhancer factor (TCF/Lef) dependent gene transcription.
  • Frizzle Related Proteins are a family of secreted proteins with cysteine rich regions that are homologous to those of the frizzle family of proteins but lack the membrane-spanning segments of the frizzle proteins.
  • the secreted FRP acts to antagonize the Wnt signaling pathway by binding extracelluar Wnt and preventing it from interacting with frizzle proteins or by forming a nonfunctional complexes with the frizzled receptor.
  • FRP frizzled related protein
  • GSK-3 inhibitors circumvent the FRP mediated antagonism of the Wnt signaling pathway caused by the elevated levels of FRP and counteract the increase in outflow resistance that results from the increase in production of FRP in individuals with glaucoma.
  • RP retinitis pigmentosa
  • glaucoma is the selective loss of retinal ganglion cells and not photoreceptor cells toxicity mediated by increased expression of FRP or by other mechanism governed by a GSK-3 mediated pathway may contribute to the loss of retinal ganglion cells in glaucoma. Therefore GSK-3 inhibitors would treat the loss of retinal ganglion and also reduce intraocular pressure by increasing aqueous humor outflow.
  • GSK-3 inhibitors While not being bound by theory the inventors believe that inhibition of GSK-3 will lower and control normal or elevated intraocular pressure (IOP) and treat glaucomatous optic neuropathy.
  • IOP intraocular pressure
  • Compounds that act as GSK-3 inhibitors are well known and have shown a variety of utilities, primarily for disorders or conditions associated with diabetes, dementias such as Alzheimer's disease and manic depression.
  • U.S. Patent No. 6,057,1 17 discloses the use of selective inhibitors of GSK-3 for the treatment of diseases that are mediated by GSK-3 activity including diabetes mellitus.
  • WO 00/38675 discloses a method of treatment of conditions associated with a need for the inhibition of GSK-3, such as diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, manic depression, mood disorders such as schizophrenia, neurotraumatic disorders such as acute stroke, hair loss and cancer.
  • WO 00/21927 discloses certain pyrrole-2,5-dione derivatives that are GSK-3 inhibitors for the treatment of diabetes, dementias such as Alzheimer's disease and manic depression.
  • WO 01/56567 describes 2,4-dimainothiazole derivatives and their use as GSK-3 inhibitors
  • WO 01/49709 describes peptide inhibitors of GSK-3
  • WO 01/47533 discloses the development of modulatory strategies for the treatment of various diseases.
  • WO 01/41768 discloses the use of hymenialdisine or derivatives for inhibiting cyclin dependent kinases, GSK-3 beta and casein kinase 1 for treating neurodegenerative disorders such as Alzheimer's disease, diabetes, inflammatory pathologies and cancers.
  • WO 01/37819 discloses the use of indirubine derivatives for making medicines inhibiting GSK-3 beta.
  • Hymenialdisine is an inhibitor of GSK-3. It was suggested to have potential in treating neurodegenerative disorders (Thunnissen et al. 2000). The protein kinase C inhibitors GF1092 and Ro 31-8220 have been reported to be inhibitors of GSK-3 (Tavare et al. 1999).
  • Indirubines inhibit GSK-3 (Gamier et al. 2001). A potential application for the use of the indirubines as a treatment of neurodegenerative disorders was disclosed.
  • GSK-3 inhibitors SB-415286 and SB216763 protected both central and peripheral neurons grown in culture from death induced by reduced phosphatidyl inositol pathway activity (Cross et al. 2000).
  • IOP intraocular pressure
  • This invention is directed at the treatment of glaucoma by the inhibition of GSK-3. It is contemplated that any GSK-3 inhibiting compound will be useful in the methods of the present invention.
  • the inventors contemplate that any of the compounds disclosed in WO 00/38675; WO 00/21927; Coglan et al. 2000; Leost et al. 2001 ; Smith et al. 2001 ; Gamier et al. 2001 ; Cross et al. 2001 ; Thunnissen et al. 2000; Tavare et al. 1999 (as discussed above, all herein inco ⁇ orated by reference) will be particularly useful.
  • the compound for use in the methods of the invention will be selected from compounds defined in WO 00/21927, EP 470490, WO 93/18766, WO 93/18765, EP 397060, WO 98/11103, WO 98/11102, WO 98/04552, WO
  • Preferred compounds include compounds of the formula:
  • R 3 H, C,. 6 alkyl, (un)substituted phenyl, C,. 6 alkyl-NR 6 R 7 , C,. 7 cycloalkyl, C, .6 alkyl- OR 6 , C,. 6 alkylC(O) 2 R 5 , C, ⁇ alkylC(O)NR 6 R 7 ;
  • R 4 H, or one or more substituents C,. 6 alkyl, (un)substituted phenyl, -OR 6 , -SR 6 , halogen, (un)substituted phenoxy, -CN, -NO 2 , C,. 6 alkyl-NR 6 R 7 , -NR 6 R 7 , C, .7 cycloalkyl,
  • R 5 , R 6 , R 7 H, C ⁇ alkyl, (un)substituted phenyl.
  • R 3 H, C,. 6 alkyl, C,. 6 alkyl-NR 6 R 7 , C,. 6 alkyl-OR 6 , C,. 6 alkylC(O) 2 R 5 , C,. 6 alkylC(O)NR 6 R 7 ;
  • R 4 H, or one or more substituents C,. 6 alkyl, (un)substituted phenyl, -OR 6 , halogen,
  • R 5 , R 6 , R 7 H, C,. 3 alkyl.
  • the most preferred compounds for use in the methods of the invention include: 3 -( 1 - [3 -aminopropyl]-3 -indoyl)-4-(2-chlorophenyl)pyrrole-2 , 5 -dione and 3-( 1 -[3-hydroxypropyl]-3-indolyl)-4-(2-chlorophenyl)pyrrole-2,5-dione.
  • compounds useful in the methods of the invention will be selected from the indimbine analogs defined in WO 01/37819.
  • Generally preferred compounds include indimbine, 5-iodo-indirubine-3'monoxime, 5- (hydroxyethylsulfonamide) indimbine, indirubine-3'-monoxime, 5-(methyl)sulfonamide indimbine, and 5-(dimethyl)sulfonamide indimbine.
  • Additional embodiments of the invention include the use of compounds selected from the 2,4-diaminothiazole analog defined in WO 01/37819.
  • Preferred compounds include:
  • compounds selected from the 1 ,2,4-triazole-carboxylic acid derivative or analog defined in WO 01/09106 will be useful in the methods of the invention.
  • Preferred 1 ,2,4-triazole-carboxylic acid derivatives include:
  • Hymenialdisine or derivative or analog defined in WO 01/41768 may also be useful in certain embodiments of the invention.
  • Preferred such compounds include: Hymenialdisine (4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-4,5,6,7-tetrahydropyrrolo(2,3- c)azepine-8-one), 4-(2-amino-4-oxo-2-imidazolin-5-ylidene) — 2-bromo-4,5,6,7-tetrahydropyrrolo(2,3- c)azepine-8-one, and (4-(2-amino-4-oxo-2-imidazolin-5-ylidene) — 3-bromo-4,5,6,7-tetrahydropyrrolo(2,3- c)azepine-8-one.
  • paullone analogs including 9-nitropaullone, 9-bromopaullone, 9-chloropaullone, and 9-bromo-12- methoxycarbonylmethypaullone in the methods of the invention.
  • the Compounds of this invention can be inco ⁇ orated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant).
  • the Compounds are preferably inco ⁇ orated into topical ophthalmic formulations for delivery to the eye.
  • the Compounds may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution.
  • Ophthalmic solution formulations may be prepared by dissolving a Compound in a physiologically acceptable isotonic aqueous buffer.
  • the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the Compound.
  • the ophthalmic solution may contain an agent to increase viscosity, such as, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac.
  • Gelling agents can also be used, including, but not limited to, gellan and xanthan gum.
  • the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum.
  • Sterile ophthalmic gel formulations may be prepared by suspending the Compound in a hydrophilic base prepared from the combination of, for example, carbopol-974, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be inco ⁇ orated.
  • the Compounds are preferably formulated as topical ophthalmic suspensions or solutions, with a pH of about 4 to 8.
  • the establishment of a specific dosage regimen for each individual is left to the discretion of the clinicians.
  • the Compounds will normally be contained in these formulations in an amount 0.01% to 5% by weight, but preferably in an amount of 0.05% to 2% and most preferably in an amount 0.1 to 1.0% by weight.
  • the dosage form may be a solution, suspension microemulsion.
  • 1 to 2 drops of these formulations would be delivered to the surface of the eye 1 to 4 times per day according to the discretion of a skilled clinician.
  • the Compounds can also be used in combination with other agents for treating glaucoma, such as, but not limited to, ⁇ -blockers, prostaglandins, carbonic anhydrase inhibitors, ⁇ 2 agonists, miotics, and neuroprotectants.
  • agents for treating glaucoma such as, but not limited to, ⁇ -blockers, prostaglandins, carbonic anhydrase inhibitors, ⁇ 2 agonists, miotics, and neuroprotectants.
  • Example 1 GSK-3 inhibition Inhibition of GSK-3 can be assayed by the methods described in WO 00/38675.
  • Biot-KYRRAAVPPSPSLSRHSSPHQ(SP)EDEEE is used as the substrate peptide where (SP) is a prephosphorylated serine and S are the three consensus phosphorylation sites for GSK-3 specific phosphorylation.
  • GSK-3 kinase (lOnM final concentration) in a pH 7.0 MOPS buffer containing Tween-20 0.01%, glycerol 5%, 2- mercaptoethanol 7.5mM, magnesium acetate lOmM, substrate peptide 8 ⁇ M, [ ⁇ - 3 P]-ATP 10 ⁇ M and inhibitor are incubated at room temperature for 1 hour. The reaction is stopped by the addition of an aqueous mM EDTA solution containing Strepavidin coated SPA beads. Following centrifugation radioactivity is counted using a beta scintillation counter.
  • Example 2 Example 2
  • Human ocular anterior segments are perfused with Dulbecco's modified Eagle's medium (DMEM) at a constant pressure of 11 mm Hg.
  • DMEM Dulbecco's modified Eagle's medium
  • the outflow rate of each eye is measured by weighing its reservoir at specified periods. After a stabilization period, the eyes are perfused with either vehicle or FRP-1 (10 ⁇ g/ml) and their outflow rates monitored for 2-5 days. The perfusion of FRP-1 caused a decrease in aqueous humor outflow. Inhibitor is added and the anterior segment is perfused for an additional 2-4 days. Outflow rate is measured by weighing its reservoir at specific periods.
  • DMEM Dulbecco's modified Eagle's medium
  • compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and structurally related may be substituted for the agents described herein to achieve similar results. Such substitutions and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Hospice & Palliative Care (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Indole Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
PCT/US2002/030059 2001-09-27 2002-09-23 Inhibitors of glycogen synthase kinase-3 (gsk-3) for treating glaucoma Ceased WO2003027275A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
JP2003530847A JP2005504101A (ja) 2001-09-27 2002-09-23 緑内障を治療するためのグリコゲンシンターゼキナーゼ−３（ｇｓｋ−３）インヒビター
KR10-2004-7003638A KR20040047824A (ko) 2001-09-27 2002-09-23 녹내장 치료를 위한 글리코겐 신타아제키나제-3(ｇｓｋ-3) 저해제
EP02799603A EP1430120A4 (en) 2001-09-27 2002-09-23 GLYCOGEN SYNTHASE KINASE-3 INHIBITORS (GSK-3) FOR GLUCKOM TREATMENT
CA2460000A CA2460000C (en) 2001-09-27 2002-09-23 Inhibitors of glycogen synthase kinase-3 (gsk-3) for treating glaucoma
MXPA04002137A MXPA04002137A (es) 2001-09-27 2002-09-23 Inhibidores de glicogen sintasa quinasa-3 (gsk-3) para el tratamiento del glaucoma.
US10/488,496 US7598288B2 (en) 2001-09-27 2002-09-23 Inhibitors of glycogen synthase kinase-3 (GSK-3) for treating glaucoma
AU2002334635A AU2002334635B2 (en) 2001-09-27 2002-09-23 Inhibitors of glycogen synthase kinase-3 (GSK-3) for treating glaucoma
BR0212924-8A BR0212924A (pt) 2001-09-27 2002-09-23 Inibidores de glicogênio sintase quinase-3 (gsk-3) para o tratamento de glaucoma
US12/545,611 US20090312390A1 (en) 2001-09-27 2009-08-21 Inhibitors of glycogen synthase kinase-3 (gsk-3) for treating glaucoma

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US32539001P 2001-09-27 2001-09-27
US60/325,390 2001-09-27

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/545,611 Division US20090312390A1 (en) 2001-09-27 2009-08-21 Inhibitors of glycogen synthase kinase-3 (gsk-3) for treating glaucoma

Publications (1)

Publication Number Publication Date
WO2003027275A1 true WO2003027275A1 (en) 2003-04-03

Family

ID=23267686

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/030059 Ceased WO2003027275A1 (en) 2001-09-27 2002-09-23 Inhibitors of glycogen synthase kinase-3 (gsk-3) for treating glaucoma

Country Status (15)

Country Link
US (2) US7598288B2 (https=)
EP (2) EP2281560A1 (https=)
JP (2) JP2005504101A (https=)
KR (1) KR20040047824A (https=)
CN (2) CN1561393A (https=)
AR (1) AR036684A1 (https=)
AU (1) AU2002334635B2 (https=)
BR (1) BR0212924A (https=)
CA (1) CA2460000C (https=)
MX (1) MXPA04002137A (https=)
PL (1) PL207022B1 (https=)
RU (1) RU2297243C2 (https=)
TW (2) TW201041580A (https=)
WO (1) WO2003027275A1 (https=)
ZA (1) ZA200401846B (https=)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003092584A3 (en) * 2002-04-30 2004-07-01 Alcon Inc Agents which regulate, inhibit, or modulate the activity and/or expression of connective tissue growth factor (ctgf) as a unique means to both lower intraocular pressure and treat glaucomatous retinopathies/optic neuropathies
WO2005063022A1 (en) * 2003-12-24 2005-07-14 Bayer Cropscience Gmbh Plant growth regulation
WO2005063252A1 (en) * 2003-12-22 2005-07-14 Alcon, Inc. Cdk2 antagonists as short form c-maf transcription factor antagonists for treatment of glaucoma
WO2005107465A1 (en) * 2004-05-12 2005-11-17 Bayer Cropscience Gmbh Plant growth regulation
EP1616568A3 (en) * 2002-04-30 2006-06-21 Alcon, Inc GSK-3 inhibitors and CDK inhibitors as anti-glaucoma agents
WO2006089874A1 (en) * 2005-02-22 2006-08-31 Gpc Biotech Ag Benzo[2,3]azepino[4,5-b]indol-6-ones
WO2006117212A2 (en) 2005-05-04 2006-11-09 Develogen Aktiengesellschaft Use of gsk-3 inhibitors for preventing and treating pancreatic autoimmune disorders
US7193079B1 (en) 2003-05-19 2007-03-20 Board Of Trustees Of Michigan State University Preparation of hymenialdisine derivatives and use thereof
WO2007030680A3 (en) * 2005-09-07 2007-05-18 Rigel Pharmaceuticals Inc Triazole derivatives useful as axl inhibitors
US7709482B2 (en) 2006-12-29 2010-05-04 Rigel Pharmaceuticals, Inc. Polycyclic heteroaryl substituted triazoles useful as Axl inhibitors
US7872000B2 (en) 2006-12-29 2011-01-18 Rigel Pharmaceuticals, Inc. Bicyclic aryl and bicyclic heteroaryl substituted triazoles useful as Axl inhibitors
EP2032130A4 (en) * 2006-06-12 2011-03-02 Merck Sharp & Dohme OPHTHALMIC COMPOSITIONS FOR THE TREATMENT OF EYE HIGH PRESSURE
US7935693B2 (en) 2007-10-26 2011-05-03 Rigel Pharmaceuticals, Inc. Polycyclic aryl substituted triazoles and polycyclic heteroaryl substituted triazoles useful as Axl inhibitors
US8012965B2 (en) 2006-12-29 2011-09-06 Rigel Pharmaceuticals, Inc. Bridged bicyclic aryl and bridged bicyclic heteroaryl substituted triazoles useful as axl inhibitors
CN102731379A (zh) * 2009-03-02 2012-10-17 Irm责任有限公司 用作wnt信号调节剂的n-(杂)芳基、2-(杂)芳基取代的乙酰胺类
US8349838B2 (en) 2008-07-09 2013-01-08 Rigel Pharmaceuticals, Inc. Polycyclic heteroaryl substituted triazoles useful as Axl inhibitors
US8431594B2 (en) 2008-07-09 2013-04-30 Rigel Pharmaceuticals, Inc. Bridged bicyclic heteroaryl substituted triazoles useful as AXL inhibitors
US8546433B2 (en) 2009-01-16 2013-10-01 Rigel Pharmaceuticals, Inc. Axl inhibitors for use in combination therapy for preventing, treating or managing metastatic cancer
US8796259B2 (en) 2006-12-29 2014-08-05 Rigel Pharmaceuticals, Inc. N3-heteroaryl substituted triazoles and N5-heteroaryl substituted triazoles useful as axl inhibitors
US8906922B2 (en) 2006-12-29 2014-12-09 Rigel Pharmaceuticals, Inc. Substituted triazoles useful as AXl inhibitors
WO2015103480A1 (en) * 2014-01-02 2015-07-09 Massachusetts Eye & Ear Infirmary Treating ocular neovascularization
US11591599B2 (en) 2013-03-15 2023-02-28 Fundació Institut De Recerca Biomèdica (Irb Barcelona) Method for the diagnosis, prognosis and treatment of cancer metastasis

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7101666B2 (en) * 2001-08-31 2006-09-05 Centre For Addiction And Mental Health Involvement of the BDNF gene in mood disorders
EP1696926A1 (en) * 2003-12-22 2006-09-06 Alcon, Inc. Agents for treatment of diabetic retinopathy and drusen formation in macular degeneration
PL1696958T3 (pl) * 2003-12-22 2007-08-31 Alcon Inc Środki do leczenia retinopatii jaskrowej i neuropatii wzrokowej
US20080096238A1 (en) * 2004-03-30 2008-04-24 Alcon, Inc. High throughput assay for human rho kinase activity with enhanced signal-to-noise ratio
WO2005102345A1 (en) * 2004-03-30 2005-11-03 Alcon, Inc. Use of rho kinase inhibitors in the treatment of hearing loss, tinnitus and improving body balance
KR20080018858A (ko) 2005-03-11 2008-02-28 알콘, 인코퍼레이티드 녹내장 치료용 플리즐 관련 단백질―１의 ＲＮＡⅰ－중재저해
RU2284192C1 (ru) * 2005-04-01 2006-09-27 Государственное учреждение Межотраслевой научно-технический комплекс "Микрохирургия глаза" им. акад. С.Н. Федорова Министерства здравоохранения РФ Способ лечения глаукомной оптической нейропатии
EP1757607A1 (en) 2005-08-24 2007-02-28 Molisa GmbH N5-substituted benzo¬2,3|azepino¬4,5-b|indol-6-ones for treating tropical diseases
RU2456266C1 (ru) * 2011-04-06 2012-07-20 Максим Эдуардович Запольский Производные 4,4'-бифениламидов, обладающие фармакологической активностью, и лекарственные средства на их основе
US20170165230A1 (en) 2014-04-09 2017-06-15 Christopher Rudd Use of gsk-3 inhibitors or activators which modulate pd-1 or t-bet expression to modulate t cell immunity
US11045352B2 (en) 2014-05-12 2021-06-29 Gholam A. Peyman Methods for treatment of dry eye and other acute or chronic inflammatory processes
US10583221B2 (en) 2014-05-12 2020-03-10 Gholam A. Peyman Method of corneal transplantation or corneal inlay implantation with cross-linking
US10881503B2 (en) 2014-05-12 2021-01-05 Gholam A. Peyman Method of corneal transplantation or corneal inlay implantation with cross-linking
US11666777B2 (en) 2014-05-12 2023-06-06 Gholam A. Peyman Photodynamic therapy technique for preventing damage to the fovea of the eye or another body portion of a patient
US10925889B2 (en) 2014-05-12 2021-02-23 Gholam A. Peyman Method of treating, reducing, or alleviating a medical condition in a patient
US11338059B2 (en) 2014-05-12 2022-05-24 Gholam A. Peyman Method of corneal and scleral inlay crosslinking and preservation
US11565023B2 (en) 2014-05-12 2023-01-31 Gholam A. Peyman Method of corneal transplantation or corneal inlay implantation with cross-linking
US11648261B2 (en) 2014-05-12 2023-05-16 Gholam A. Peyman Method of treating, reducing, or alleviating a medical condition in a patient
US12396889B2 (en) 2014-05-12 2025-08-26 Gholam A. Peyman Lamellar corneal autologous or homologous graft in refractive surgery
TWI677489B (zh) 2014-06-20 2019-11-21 美商基利科學股份有限公司 多環型胺甲醯基吡啶酮化合物之合成
WO2019221959A1 (en) * 2018-05-16 2019-11-21 Peyman Gholam A Method of treating, reducing, or alleviating a medical condition in a patient
US11707518B2 (en) 2019-04-28 2023-07-25 Gholam A. Peyman Method of treating, reducing, or alleviating a medical condition in a patient
US12226478B2 (en) 2019-04-28 2025-02-18 Gholam A. Peyman Method of treating, reducing, or alleviating a medical condition in a patient
US12110278B2 (en) * 2020-10-13 2024-10-08 Yale University Selective JAK2 pseudokinase ligands and methods of use

Citations (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0328026A1 (de) 1988-02-10 1989-08-16 F. Hoffmann-La Roche Ag Substituierte Pyrrole
EP0384349A1 (de) 1989-02-23 1990-08-29 F. Hoffmann-La Roche Ag Substituierte Pyrrole
DE3914764A1 (de) 1989-05-05 1990-11-08 Goedecke Ag Maleinimid-derivate und deren verwendung als arzneimittel
EP0397060A2 (de) 1989-05-05 1990-11-14 Gödecke Aktiengesellschaft Maleinimid-Derivate und deren Verwendung als Arzneimittel
DE4005969A1 (de) 1990-02-26 1991-08-29 Boehringer Mannheim Gmbh Neue trisubstituierte pyrrole, verfahren zu ihrer herstellung sowie arzneimittel, die diese verbindungen enthalten
DE4005970A1 (de) 1990-02-26 1991-08-29 Boehringer Mannheim Gmbh Neue trisubstituierte maleinimide, verfahren zu ihrer herstellung sowie arzneimittel, die diese verbindungen enthalten
EP0470490A1 (en) 1990-08-07 1992-02-12 F. Hoffmann-La Roche Ag Substituted pyrroles
EP0508792A1 (en) 1991-04-11 1992-10-14 Schering Corporation Anti-tumor and anti-psoriatic agents
EP0540956A1 (en) 1991-11-04 1993-05-12 F. Hoffmann-La Roche Ag Process for the manufacture of substituted maleimides
WO1993018766A1 (en) 1992-03-20 1993-09-30 The Wellcome Foundation Limited Further indole derivatives with antiviral activity
WO1993018765A1 (en) 1992-03-20 1993-09-30 The Wellcome Foundation Limited Indole derivatives with antiviral activity
DE4217964A1 (de) 1992-05-30 1993-12-02 Goedecke Ag Indolocarbazol-Imide und deren Verwendung
DE4243321A1 (de) 1992-12-21 1994-06-23 Goedecke Ag Aminosäurederivate von Heterocyclen als PKC-Inhibitoren
WO1995007910A1 (en) 1993-09-17 1995-03-23 The Wellcome Foundation Limited Antiviral indole derivatives
WO1996004906A1 (en) 1994-08-13 1996-02-22 The Wellcome Foundation Limited Compounds for the treatment of restenosis
WO1998004551A1 (en) 1996-07-29 1998-02-05 F. Hoffmann-La Roche Ag Substituted bisindolylmaleimides for the inhibition of cell proliferation
WO1998004552A1 (en) 1996-07-29 1998-02-05 F. Hoffmann-La Roche Ag Substituted bisindolylmaleimides for the inhibition of cell proliferation
WO1998011102A1 (en) 1996-09-10 1998-03-19 Astra Aktiebolag New pharmaceutically active compounds
WO1998011103A1 (en) 1996-09-10 1998-03-19 Astra Aktiebolag New pharmaceutically active compounds
US5891901A (en) 1996-07-29 1999-04-06 Hoffmann-La Roche Inc. Substituted pyrroles
WO1999042100A1 (en) 1998-02-23 1999-08-26 Sagami Chemical Research Center Cell death inhibitors
WO1999062503A2 (en) * 1998-05-29 1999-12-09 Cnrs (Centre National De Recherche Scientifique) France Innovation Scientifique Et Transfert Use of indigoid bisindole derivatives for the manufacture of a medicament to inhibit cyclin dependent kinases
WO2000021927A2 (en) 1998-10-08 2000-04-20 Smithkline Beecham Plc Pyrrole-2,5-diones as gsk-3 inhibitors
US6057117A (en) 1996-04-04 2000-05-02 Chiron Corporation Identification and use of selective inhibitors of glycogen synthase kinase 3
WO2000038675A1 (en) 1998-12-23 2000-07-06 Smithkline Beecham Plc Treatment of conditions with a need for the inhibition of gsk-3
WO2001009106A1 (en) 1999-08-02 2001-02-08 Smithkline Beecham P.L.C. Diamino-1,2,4-triazole-carboxylic and derivatives as gsk-3 inhibitors
WO2001037819A2 (fr) 1999-11-23 2001-05-31 Centre National De La Recherche Scientifique (C.N.R.S.) Utilisation de derives d'indirubine pour la fabrication de medicaments
WO2001041768A2 (en) 1999-12-08 2001-06-14 Centre National De La Recherche Scientifique (C.N.R.S.) Use of hymenialdisine or derivatives thereof in the manufacture of medicaments
WO2001047533A2 (en) 1999-12-23 2001-07-05 The Ontario Cancer Institute INHIBITION OF GSK-3$g(b)
WO2001049709A1 (en) 2000-01-03 2001-07-12 Ramot University Authority For Applied Research & Industrial Development Ltd. Glycogen synthase kinase-3 inhibitors
WO2001056567A1 (en) 2000-02-04 2001-08-09 Novo Nordisk A/S 2,4-diaminothiazole derivatives and their use as glycogen synthase kinase-3 (gsk-3) inhibitors
WO2001064949A2 (en) 2000-02-29 2001-09-07 Alcon Laboratories, Inc. Diagnostics and therapeutics for glaucoma

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5681854A (en) * 1995-11-22 1997-10-28 Alcon Laboratories, Inc. Use of aliphatic carboxylic acid derivatives in ophthalmic disorders
EP1019043A4 (en) * 1996-05-07 2003-07-30 Univ Pennsylvania INHIBITORS OF GLYCOGEN SYNTHESIS KINASE 3 AND METHOD FOR THEIR IDENTIFICATION AND USE
CA2297967A1 (en) * 1997-08-07 1999-02-18 The Regents Of The University Of California Purine inhibitor of protein kinases, g proteins and polymerases
AU6593600A (en) * 1999-08-20 2001-03-19 Rei Asakai Drugs inhibiting cell death
EP1136099A1 (en) * 2000-03-23 2001-09-26 Sanofi-Synthelabo 2-(Indolylalkylamino)pyrimidone derivatives as GSK3beta inhibitors
AU2001248365A1 (en) * 2000-03-23 2001-10-03 Mitsubishi Pharma Corporation 2-(arylalkylamino)pyrimidone derivatives and 2-(heteroarylalkylamino)pyrimidone derivatives
EP1136482A1 (en) * 2000-03-23 2001-09-26 Sanofi-Synthelabo 2-Amino-3-(alkyl)-pyrimidone derivatives as GSK3beta inhibitors
AU2002350487C1 (en) 2001-09-21 2008-10-02 Mitsubishi Pharma Corporation Substituted 2-pyridinyl-6,7,8,9- tetrahydropyrimido[1,2-a]pyrimidin-4-one and 7-pyridinyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one derivatives

Patent Citations (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0328026A1 (de) 1988-02-10 1989-08-16 F. Hoffmann-La Roche Ag Substituierte Pyrrole
EP0384349A1 (de) 1989-02-23 1990-08-29 F. Hoffmann-La Roche Ag Substituierte Pyrrole
DE3914764A1 (de) 1989-05-05 1990-11-08 Goedecke Ag Maleinimid-derivate und deren verwendung als arzneimittel
EP0397060A2 (de) 1989-05-05 1990-11-14 Gödecke Aktiengesellschaft Maleinimid-Derivate und deren Verwendung als Arzneimittel
DE4005969A1 (de) 1990-02-26 1991-08-29 Boehringer Mannheim Gmbh Neue trisubstituierte pyrrole, verfahren zu ihrer herstellung sowie arzneimittel, die diese verbindungen enthalten
DE4005970A1 (de) 1990-02-26 1991-08-29 Boehringer Mannheim Gmbh Neue trisubstituierte maleinimide, verfahren zu ihrer herstellung sowie arzneimittel, die diese verbindungen enthalten
EP0470490A1 (en) 1990-08-07 1992-02-12 F. Hoffmann-La Roche Ag Substituted pyrroles
EP0508792A1 (en) 1991-04-11 1992-10-14 Schering Corporation Anti-tumor and anti-psoriatic agents
EP0540956A1 (en) 1991-11-04 1993-05-12 F. Hoffmann-La Roche Ag Process for the manufacture of substituted maleimides
WO1993018766A1 (en) 1992-03-20 1993-09-30 The Wellcome Foundation Limited Further indole derivatives with antiviral activity
WO1993018765A1 (en) 1992-03-20 1993-09-30 The Wellcome Foundation Limited Indole derivatives with antiviral activity
DE4217964A1 (de) 1992-05-30 1993-12-02 Goedecke Ag Indolocarbazol-Imide und deren Verwendung
DE4243321A1 (de) 1992-12-21 1994-06-23 Goedecke Ag Aminosäurederivate von Heterocyclen als PKC-Inhibitoren
WO1995007910A1 (en) 1993-09-17 1995-03-23 The Wellcome Foundation Limited Antiviral indole derivatives
WO1996004906A1 (en) 1994-08-13 1996-02-22 The Wellcome Foundation Limited Compounds for the treatment of restenosis
US6057117A (en) 1996-04-04 2000-05-02 Chiron Corporation Identification and use of selective inhibitors of glycogen synthase kinase 3
WO1998004551A1 (en) 1996-07-29 1998-02-05 F. Hoffmann-La Roche Ag Substituted bisindolylmaleimides for the inhibition of cell proliferation
WO1998004552A1 (en) 1996-07-29 1998-02-05 F. Hoffmann-La Roche Ag Substituted bisindolylmaleimides for the inhibition of cell proliferation
US5856517A (en) 1996-07-29 1999-01-05 Hoffmann-La Roche Inc. Substituted pyrroles
US5891901A (en) 1996-07-29 1999-04-06 Hoffmann-La Roche Inc. Substituted pyrroles
WO1998011103A1 (en) 1996-09-10 1998-03-19 Astra Aktiebolag New pharmaceutically active compounds
WO1998011102A1 (en) 1996-09-10 1998-03-19 Astra Aktiebolag New pharmaceutically active compounds
WO1999042100A1 (en) 1998-02-23 1999-08-26 Sagami Chemical Research Center Cell death inhibitors
WO1999062503A2 (en) * 1998-05-29 1999-12-09 Cnrs (Centre National De Recherche Scientifique) France Innovation Scientifique Et Transfert Use of indigoid bisindole derivatives for the manufacture of a medicament to inhibit cyclin dependent kinases
WO2000021927A2 (en) 1998-10-08 2000-04-20 Smithkline Beecham Plc Pyrrole-2,5-diones as gsk-3 inhibitors
WO2000038675A1 (en) 1998-12-23 2000-07-06 Smithkline Beecham Plc Treatment of conditions with a need for the inhibition of gsk-3
WO2001009106A1 (en) 1999-08-02 2001-02-08 Smithkline Beecham P.L.C. Diamino-1,2,4-triazole-carboxylic and derivatives as gsk-3 inhibitors
WO2001037819A2 (fr) 1999-11-23 2001-05-31 Centre National De La Recherche Scientifique (C.N.R.S.) Utilisation de derives d'indirubine pour la fabrication de medicaments
WO2001041768A2 (en) 1999-12-08 2001-06-14 Centre National De La Recherche Scientifique (C.N.R.S.) Use of hymenialdisine or derivatives thereof in the manufacture of medicaments
WO2001047533A2 (en) 1999-12-23 2001-07-05 The Ontario Cancer Institute INHIBITION OF GSK-3$g(b)
WO2001049709A1 (en) 2000-01-03 2001-07-12 Ramot University Authority For Applied Research & Industrial Development Ltd. Glycogen synthase kinase-3 inhibitors
WO2001056567A1 (en) 2000-02-04 2001-08-09 Novo Nordisk A/S 2,4-diaminothiazole derivatives and their use as glycogen synthase kinase-3 (gsk-3) inhibitors
WO2001064949A2 (en) 2000-02-29 2001-09-07 Alcon Laboratories, Inc. Diagnostics and therapeutics for glaucoma

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
BAFICO ET AL., J. BIOL. CHEM., vol. 274, no. 23, 1999, pages 16180 - 16187
COGLAN ET AL., CHEM. & BIO., vol. 7, no. 10, 2000, pages 793 - 803
CROSS ET AL., J. NEUROCHEM., vol. 77, 2001, pages 94 - 102
GAMIER ET AL., J. BIOL. CHEM., vol. 276, no. 1, 2001, pages 251 - 260
LEOST ET AL., EUR. J. BIOCHEM., vol. 267, 2001, pages 5983 - 5994
See also references of EP1430120A4
SMITH ET AL., BIOORGANIC & MED. CHEM. LETTERS, vol. 11, 2001, pages 635 - 639
TAVARE ET AL., FEBS LETTERS, vol. 460, 1999, pages 433 - 436
THUNNISSEN ET AL., CHEM. & BIO., vol. 7, 2000, pages 51 - 63

Cited By (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003092584A3 (en) * 2002-04-30 2004-07-01 Alcon Inc Agents which regulate, inhibit, or modulate the activity and/or expression of connective tissue growth factor (ctgf) as a unique means to both lower intraocular pressure and treat glaucomatous retinopathies/optic neuropathies
EP1616568A3 (en) * 2002-04-30 2006-06-21 Alcon, Inc GSK-3 inhibitors and CDK inhibitors as anti-glaucoma agents
US7351407B2 (en) 2002-04-30 2008-04-01 Alcon, Inc. Agents which regulate, inhibit, or modulate the activity and/or expression of connective tissue growth factor (CTGF) as a unique means to both lower intraocular pressure and treat glaucomatous retinopathies/optic neuropathies
US7335769B2 (en) 2003-05-19 2008-02-26 Board Of Trustees Of Michigan State University Preparation of hymenialdsine derivatives and use thereof
US7732436B2 (en) 2003-05-19 2010-06-08 Board Of Trustees Of Michigan State University Preparation of hymenialdisine derivatives and use thereof
US7601710B2 (en) 2003-05-19 2009-10-13 Board Of Trustees Of Michigan State University Preparation of hymenialdisine derivatives and use thereof
US7385055B2 (en) 2003-05-19 2008-06-10 Board Of Trustees Of Michigan State University Preparation of hymenialdisine derivatives and use thereof
US7193079B1 (en) 2003-05-19 2007-03-20 Board Of Trustees Of Michigan State University Preparation of hymenialdisine derivatives and use thereof
JP2007515426A (ja) * 2003-12-22 2007-06-14 アルコン，インコーポレイテッド 緑内障の処置のための短い形態のｃ−Ｍａｆ転写因子アンタゴニストとしてのｃｄｋ２アンタゴニスト
AU2004308938B2 (en) * 2003-12-22 2011-06-23 Alcon, Inc. CDK2 antagonists as short form c-Maf transcription factor antagonists for treatment of glaucoma
WO2005063252A1 (en) * 2003-12-22 2005-07-14 Alcon, Inc. Cdk2 antagonists as short form c-maf transcription factor antagonists for treatment of glaucoma
WO2005063022A1 (en) * 2003-12-24 2005-07-14 Bayer Cropscience Gmbh Plant growth regulation
AU2005239812B2 (en) * 2004-05-12 2011-04-14 Bayer Cropscience Ag Plant growth regulation
WO2005107465A1 (en) * 2004-05-12 2005-11-17 Bayer Cropscience Gmbh Plant growth regulation
EA012601B1 (ru) * 2004-05-12 2009-10-30 Байер Кропсайенс Аг Регулирование роста растений
WO2006089874A1 (en) * 2005-02-22 2006-08-31 Gpc Biotech Ag Benzo[2,3]azepino[4,5-b]indol-6-ones
WO2006117212A2 (en) 2005-05-04 2006-11-09 Develogen Aktiengesellschaft Use of gsk-3 inhibitors for preventing and treating pancreatic autoimmune disorders
US7884119B2 (en) 2005-09-07 2011-02-08 Rigel Pharmaceuticals, Inc. Triazole derivatives useful as Axl inhibitors
WO2007030680A3 (en) * 2005-09-07 2007-05-18 Rigel Pharmaceuticals Inc Triazole derivatives useful as axl inhibitors
US8389557B2 (en) 2005-09-07 2013-03-05 Rigel Pharmaceuticals, Inc. Triazole derivatives useful as Axl inhibitors
EP2032130A4 (en) * 2006-06-12 2011-03-02 Merck Sharp & Dohme OPHTHALMIC COMPOSITIONS FOR THE TREATMENT OF EYE HIGH PRESSURE
US9650391B2 (en) 2006-12-29 2017-05-16 Rigel Pharmaceuticals Inc. N3-heteroaryl substituted triazoles and N5-heteroaryl substituted triazoles useful as Axl inhibitors
US8741898B2 (en) 2006-12-29 2014-06-03 Rigel Pharmaceuticals, Inc. Polycyclic heteroaryl substituted triazoles useful as Axl inhibitors
US8012965B2 (en) 2006-12-29 2011-09-06 Rigel Pharmaceuticals, Inc. Bridged bicyclic aryl and bridged bicyclic heteroaryl substituted triazoles useful as axl inhibitors
US8168636B2 (en) 2006-12-29 2012-05-01 Rigel Pharmaceuticals, Inc. Polycyclic heteroaryl substituted triazoles useful as Axl inhibitors
US10166216B2 (en) 2006-12-29 2019-01-01 Rigel Pharmaceuticals, Inc. Substituted triazoles useful as Axl inhibitors
US8906922B2 (en) 2006-12-29 2014-12-09 Rigel Pharmaceuticals, Inc. Substituted triazoles useful as AXl inhibitors
US7872000B2 (en) 2006-12-29 2011-01-18 Rigel Pharmaceuticals, Inc. Bicyclic aryl and bicyclic heteroaryl substituted triazoles useful as Axl inhibitors
US9156820B2 (en) 2006-12-29 2015-10-13 Rigel Pharmaceuticals, Inc. Polycyclic heteroaryl substituted triazoles useful as axl inhibitors
US8492373B2 (en) 2006-12-29 2013-07-23 Rigel Pharmaceuticals, Inc. Bicyclic aryl and bicyclic heteroaryl substituted triazoles useful as Axl inhibitors
US9353126B2 (en) 2006-12-29 2016-05-31 Rigel Pharmaceuticals, Inc. Substituted triazoles useful as Axl inhibitors
US8609650B2 (en) 2006-12-29 2013-12-17 Rigel Pharmaceuticals, Inc. Bridged bicyclic aryl and bridged bicyclic heteroaryl substituted triazoles useful as Axl inhibitors
US8618331B2 (en) 2006-12-29 2013-12-31 Rigel Pharmaceuticals Inc. Polycyclic heteroaryl substituted triazoles useful as axl inhibitors
US9353124B2 (en) 2006-12-29 2016-05-31 Rigel Pharmaceuticals, Inc. Bridged bicyclic aryl and bridged bicyclic heteroaryl substituted triazoles useful as axl inhibitors
US7709482B2 (en) 2006-12-29 2010-05-04 Rigel Pharmaceuticals, Inc. Polycyclic heteroaryl substituted triazoles useful as Axl inhibitors
US8796259B2 (en) 2006-12-29 2014-08-05 Rigel Pharmaceuticals, Inc. N3-heteroaryl substituted triazoles and N5-heteroaryl substituted triazoles useful as axl inhibitors
US8809347B2 (en) 2006-12-29 2014-08-19 Rigel Pharmaceuticals, Inc. Bicyclic aryl and bicyclic heteroaryl substituted triazoles useful as AXL inhibitors
US8809364B2 (en) 2007-10-26 2014-08-19 Rigel Pharmaceuticals, Inc. Polycyclic aryl substituted triazoles and polycyclic heteroaryl substituted triazoles useful as axl inhibitors
US7935693B2 (en) 2007-10-26 2011-05-03 Rigel Pharmaceuticals, Inc. Polycyclic aryl substituted triazoles and polycyclic heteroaryl substituted triazoles useful as Axl inhibitors
US8349838B2 (en) 2008-07-09 2013-01-08 Rigel Pharmaceuticals, Inc. Polycyclic heteroaryl substituted triazoles useful as Axl inhibitors
US9079898B2 (en) 2008-07-09 2015-07-14 Rigel Pharmaceuticals, Inc. Polycyclic heteroaryl substituted triazoles useful as Axl inhibitors
US8933080B2 (en) 2008-07-09 2015-01-13 Rigel Pharmaceuticals, Inc. Bridged bicyclic heteroaryl substituted triazoles useful as axl inhibitors
US9173882B2 (en) 2008-07-09 2015-11-03 Rigel Pharmaceuticals, Inc. Polycyclic heteroaryl substituted triazoles useful as Axl inhibitors
US9206161B2 (en) 2008-07-09 2015-12-08 Rigel Pharmaceuticals, Inc. Bridged bicyclic heteroaryl substituted triazoles useful as Axl inhibitors
US8658669B2 (en) 2008-07-09 2014-02-25 Rigel Pharmaceuticals, Inc. Bridged bicyclic heteroaryl substituted triazoles useful as Axl inhibitors
US8431594B2 (en) 2008-07-09 2013-04-30 Rigel Pharmaceuticals, Inc. Bridged bicyclic heteroaryl substituted triazoles useful as AXL inhibitors
US8546433B2 (en) 2009-01-16 2013-10-01 Rigel Pharmaceuticals, Inc. Axl inhibitors for use in combination therapy for preventing, treating or managing metastatic cancer
CN102731379B (zh) * 2009-03-02 2015-05-06 Irm责任有限公司 用作wnt信号调节剂的n-(杂)芳基、2-(杂)芳基取代的乙酰胺类
CN102731379A (zh) * 2009-03-02 2012-10-17 Irm责任有限公司 用作wnt信号调节剂的n-(杂)芳基、2-(杂)芳基取代的乙酰胺类
US11591599B2 (en) 2013-03-15 2023-02-28 Fundació Institut De Recerca Biomèdica (Irb Barcelona) Method for the diagnosis, prognosis and treatment of cancer metastasis
WO2015103480A1 (en) * 2014-01-02 2015-07-09 Massachusetts Eye & Ear Infirmary Treating ocular neovascularization
US10143703B2 (en) 2014-01-02 2018-12-04 Massachusetts Eye And Ear Infirmary Treating ocular neovascularization

Also Published As

Publication number Publication date
US7598288B2 (en) 2009-10-06
TWI335221B (en) 2011-01-01
RU2004112766A (ru) 2005-03-27
CA2460000A1 (en) 2003-04-03
PL207022B1 (pl) 2010-10-29
EP2281560A1 (en) 2011-02-09
PL369130A1 (en) 2005-04-18
US20040186159A1 (en) 2004-09-23
RU2297243C2 (ru) 2007-04-20
JP2005504101A (ja) 2005-02-10
EP1430120A4 (en) 2007-06-20
AU2002334635B2 (en) 2007-06-21
AR036684A1 (es) 2004-09-29
MXPA04002137A (es) 2004-06-29
ZA200401846B (en) 2005-03-07
EP1430120A1 (en) 2004-06-23
TW201041580A (en) 2010-12-01
KR20040047824A (ko) 2004-06-05
CN101380319A (zh) 2009-03-11
CA2460000C (en) 2013-01-29
US20090312390A1 (en) 2009-12-17
BR0212924A (pt) 2005-01-04
JP2005320350A (ja) 2005-11-17
CN1561393A (zh) 2005-01-05

Similar Documents

Publication Publication Date Title
AU2002334635B2 (en) Inhibitors of glycogen synthase kinase-3 (GSK-3) for treating glaucoma
AU2002334635A1 (en) Inhibitors of glycogen synthase kinase-3 (GSK-3) for treating glaucoma
JP4934653B2 (ja) Ｒｈｏキナーゼ阻害剤とβ遮断薬からなる緑内障治療剤
JP4482726B2 (ja) Ｒｈｏキナーゼ阻害剤とプロスタグランジン類からなる緑内障治療剤
US12290511B2 (en) Pharmaceutical preparation containing pyridyl aminoacetic acid compound
EP3730138B1 (en) Combination of sepetaprost and ripasudil for use in the prophylaxis or treatment of glaucoma or ocular hypertension
TW202220666A (zh) 含有賽佩普斯特（ｓｅｐｅｔａｐｒｏｓｔ）之醫藥製劑
HK1153935A (en) Inhibitors of glycogen synthase kinase-3 (gsk-3) for treating glaucomatous optic neuropathy
EP1859795A1 (en) Therapeutic agent for ophthalmic disease
US20060211700A1 (en) (R)-8,9-dichloro-2,3,4,4a-tetrahydro-1H,6H-pyrazino[1,2-a]quinoxalin-5-one for controlling IOP and treating glaucoma
US9295665B2 (en) Inhibition of neovascularization by simultaneous inhibition of prostanoid IP and EP4 receptors
HK40102807B (en) Combination of sepetaprost and netarsudil for use in the prophylaxis or treatment of glaucoma or ocular hypertension
EP3730143A1 (en) Omidenepag combination
HK40031074A (en) Pharmaceutical preparation containing pyridyl aminoacetic acid compound
HK40029829A (en) Combination of sepetaprost and ripasudil for use in the prophylaxis or treatment of glaucoma or ocular hypertension
HK40029829B (en) Combination of sepetaprost and ripasudil for use in the prophylaxis or treatment of glaucoma or ocular hypertension
HK40029828A (en) Omidenepag combination
CA2434691A1 (en) Use of propentofylline to control intraocular pressure

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BY BZ CA CH CN CO CR CU CZ DE DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR LC LK LR LS LT LU LV MA MD MG MN MW MX MZ NO NZ OM PH PL PT RU SD SE SG SI SK SL TJ TM TN TR TZ UA UG US UZ VC VN YU ZA ZM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FR GB GR IE IT LU MC NL PT SE SK TR

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: 10488496

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 2002334635

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2002799603

Country of ref document: EP

Ref document number: 2004/01846

Country of ref document: ZA

Ref document number: 200401846

Country of ref document: ZA

Ref document number: PA/A/2004/002137

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2460000

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1020047003638

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2003530847

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 20028190106

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 2002799603

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 1-2004-500360

Country of ref document: PH

WWG Wipo information: grant in national office

Ref document number: 2002334635

Country of ref document: AU