EP1263434A1 - Composes a activite agoniste sur les recepteurs 5-ht 2? et 5-ht 1a? destines au traitement du glaucome - Google Patents

Composes a activite agoniste sur les recepteurs 5-ht 2? et 5-ht 1a? destines au traitement du glaucome

Info

Publication number
EP1263434A1
EP1263434A1 EP01911005A EP01911005A EP1263434A1 EP 1263434 A1 EP1263434 A1 EP 1263434A1 EP 01911005 A EP01911005 A EP 01911005A EP 01911005 A EP01911005 A EP 01911005A EP 1263434 A1 EP1263434 A1 EP 1263434A1
Authority
EP
European Patent Office
Prior art keywords
compounds
aminopropyl
compound
methyl
group
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.)
Withdrawn
Application number
EP01911005A
Other languages
German (de)
English (en)
Inventor
Robert J. Collier, Jr.
Thomas R. Dean
Mark R. Hellberg
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
Application filed by Alcon Inc filed Critical Alcon Inc
Publication of EP1263434A1 publication Critical patent/EP1263434A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • 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
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention is directed to compounds with 5-HT 2 and 5-HT ⁇ A agonist activity useful for lowering and controlling intraocular pressure (IOP) and the treatment of glaucomatous optic neuropathy.
  • IOP intraocular pressure
  • Glaucoma is a family of diseases, each of which is distinguished by a particular characteristic of that disease form.
  • Primary open-angle glaucoma POAG
  • POAG Primary open-angle glaucoma
  • NTG Normotension glaucoma
  • Other forms of glaucoma include closed-angle glaucoma and pigmentary dispersion glaucoma. All these forms of glaucoma are similar in that patients suffer from the continued loss of nerve fiber layer and vision.
  • Current therapies for the treatment of glaucoma, in particular POAG and NTG strive to slow the progression of the disease by lowering and controlling intraocular pressure. This is done either by
  • ALT argon laser trabeculoplasty
  • GFS glaucoma filtration surgery
  • Betaxolol's neuroprotection properties are believed to arise from its calcium channel blocking activities and its ability to stimulate the expression of key neuroprotective factors such as CNTF, bFGF, and BDNF.
  • Brimonidine is an ⁇ 2 agonist and is believed to stimulate the production of bFGF.
  • Serotonergic - agonists have been reported as being neuroprotective in animal models and many of these agents have been evaluated for the treatment of acute stroke
  • 5-HT! and 5-HT ⁇ . ⁇ ke agonists for the treatment of glaucoma (elevated IOP).
  • These anti-migraine compounds are 5-HT 1B>D.E,F agonists, e.g., sumatriptan and naratriptan and related compounds.
  • 5-HT 2 agonists have been shown to be a new class of potent ocular hypotensive agents useful for the treatment of elevated IOP and glaucoma.
  • This invention is directed to compounds that have potent agonist activity at the 5-HT 2 and 5-HT 1A receptors. They are useful for lowering and controlling IOP and treating glaucomatous optic neuropathy (Compounds).
  • the Compounds are delivered topically and are believed to be able to penetrate directly to the back of the eye and protect retinal ganglion cells and cells associated with the optic nerve head and lamina cribrosa.
  • Compounds of the present invention have both 5-HT 2 and
  • 5-HT ⁇ A activity and are useful for lowering and controlling IOP and treating glaucomatous optic neuropathy via topical ocular administration.
  • the IOP lowering effects of the Compounds are attributable to their 5-HT 2 activity.
  • Neuroprotection is derived from their 5-HT ⁇ A activity.
  • Compounds within this invention are characterized by the following parameters which can be determined using the below described methods.
  • Compounds of this invention have ligand binding IC 50 values against 5-HT 2 receptors ranging up to about 100 nM (preferably less than 50 nM).
  • Compounds of this invention are either full or partial agonists with EC 50 values ranging up to about 1 ⁇ M (preferably less than 500 nM).
  • Compounds also have potent affinity for 5-HT ⁇ A receptors with IC 50 values that range up to about 500 nM (preferably less than 100 nM). These Compounds are also either full or partial agonists with IC 50 values ranging up to about 1 ⁇ M (preferably less than 500 nM).
  • -Methyl 5- hydroxytryptamine (3-(2-aminopropyl)-lH-indol-5-ol) which is a potent 5- ⁇ T 2 agonist based on ligand binding and functional assays (Table 1).
  • This Compound also has potent affinity for the 5-HT ⁇ A receptor (Table 2 and J. Med. Chem. 33, 755 (1990)) and is an agonist.
  • Topical ocular delivery to hypertensive monkey eyes results in a potent reduction in IOP (Table 3). It is also neuroprotective in the rat photooxidative induced retinopathy model after ip administration (Table 4).
  • ⁇ -Methyl 5-hydroxytryptamine is believed to penetrate to the back of the eye in high enough concentrations to confer neuroprotection upon topical ocular dosing.
  • 5-HT 2 receptors is determined as described below with minor modification of the literature procedure [Neuropharmacology, 26, 1803 (1987)]. Aliquots of post mortem rat or human cerebral cortex homogenates (400 ⁇ l) dispersed in 50 mM TrisHCl buffer (pH 7.4) are incubated with [ I]DOI (80 pM final) in the absence or presence of methiothepin (10 ⁇ M final) to define total and non-specific binding, respectively, in a total volume of 0.5 ml. The assay mixture is incubated for 1 hour at 23°C in polypropylene tubes and the assays terminated by rapid vacuum filtration over Whatman GF/B glass fiber filters previously soaked in 0.3% polyethyleneimine using ice-cold buffer.
  • Test compounds (at different concentrations) are substituted for methiothepin. Filter-bound radioactivity is determined by scintillation spectrometry on a beta counter. The data are analyzed using a non-linear, iterative curve-fitting computer program [Trends Pharmacol. Sci., 16, 413 (1995)] to determine the compound affinity parameter. The concentration of the compound needed to inhibit the [ 125 I]DOI binding by 50% of the maximum is termed the IC 50 or K, value.
  • the relative agonist activity of serotonergic compounds at the 5-HT 2 receptor can be determined in vitro using the ability of the compounds to stimulate the production of [ Hjinositol phosphates in [ H]myo-inositol-labeled A7r5 rat vascular smooth muscle cells by their ability to activate the enzyme phospholipase C.
  • These cells are grown in culture plates, maintained in a humidified atmosphere of 5% CO and 95% air and fed semi-weekly with Dulbecco's modified Eagle medium (DMEM) containing 4.5 g/1 glucose and supplemented with 2mM glutamine, 10 ⁇ g/ml gentamicin, and 10% fetal bovine serum.
  • DMEM Dulbecco's modified Eagle medium
  • the A7r5 cells are cultured in 24-well plates as previously [J. Pharmacol. Expt. Ther., 286, 411 (1998)]. Confluent cells are exposed for 24-30 hrs to 1.5 ⁇ Ci [ 3 H]-myo-inositol (18.3 Ci/mmol) in 0.5 ml of serum- free medium. Cells are then rinsed once with DMEM/F-12 containing 10 mM
  • Concentration-response data are analyzed by the sigmoidal fit function of the Origin Scientific Graphics software (Microcal Software, Northampton, MA) to determine agonist potency (EC 50 value) and efficacy (Emax).
  • Serotonin (5-HT) is used as a positive control (standard) agonist compound and the efficacy of test compounds is compared to that of 5-HT (set at 100%).
  • the concentration of the compound needed to stimulate the production of [ 3 H]-IPs by 50% of the maximum response is termed the EC 50 value.
  • 5-HT ⁇ A binding studies were performed with human cloned receptors expressed in Chinese hamster ovary (CHO) cells using ( 3 H)8-OH DP AT as the ligand.
  • Membranes from Chinese hamster ovary cells (CHO) expressing cloned 5-HT ⁇ A receptors were homogenized in approximately 40 volumes of 50 mM Tris pH 7.4 for 5 sec. Drug dilutions were made using a Beckman Biomek 2000 robot (Beckman Instruments, Fullerton, CA).
  • Ligand binding studies can also be run using membrane preparations from calf and rat brain (local source) and human cortex membranes. Specific brain regions were dissected out, homogenized in 10 volumes of 0.32 M sucrose and centrifuged for 10 min at 700 x g. The resulting supernatant was centrifuged at 43,500 x g for 10 min and the pellet re-suspended in 50 mM Tris-HCl (pH 7.7, 25°C) using a 10 sec polytron treatment. Aliquots were stored at -140° C. To remove endogenous serotonin, the preps were incubated at 37° C for 10 min prior to the experiment.
  • the function of Compounds of the present invention can be determined using a variety of methods to assess the functional activity of 5-HT 1A agonists.
  • One such assay is performed using hippocampal slices from male Sprague-Dawley rats, measuring the inhibition of forskolin-stimated adenylate cyclase [J. Med. Chem. 42.
  • Rat hippocampal membranes were homogenized in 25 volumes of 0.3 M sucrose containing ImM EGTA, 5 mM EDTA, 5 mM dithiothreitol, and 20 mM Tris-HCl, pH
  • the homogenate was centrifuged for 10 m in at 1 ,000 x g. The supernatant subsequently was centrifuged at 39,000 x g for 10 min. The resulting pellet was re-suspended in homogenization buffer at a protein concentration of approximately 1 mg/ml and aliquots were stored at -140°C. Prior to use, the membranes were rehomogenized in a Potter-Elvehjem homogenizer. Fifty ⁇ l of the membrane suspension (50 ⁇ g protein) were added to an incubation buffer containing
  • Cyclic AMP production was calculated as the ratio [ 3 H]cAMP/([ 3 H]cAMP + [ 3 H]ATP).
  • Intraocular pressure was determined with an Alcon Pneumatonometer after light corneal anesthesia with 0.1 % proparacaine. Eyes were washed with saline after each measurement. After a baseline IOP measurement, test compound was instilled in one 30 ⁇ L aliquot to the right eyes only of nine cynomolgus monkeys. Vehicle was instilled in the right eyes of six additional animals. Subsequent IOP measurements were taken at 1, 3, and 6 hours. The profile of the IOP response following topical administration is provided in Table 3.
  • ERG electroretinogram
  • the electroretinogram (ERG) was recorded after a five day recovery period from dark-adapted anesthetized rats (Ketamine-HCl, 75 mg/Kg; Xylazine, 6 mg/Kg).
  • the eye's electrical response to a flash of light was elicited by viewing a ganzfeld.
  • ERGs to a series of light flashes increasing in intensity were digitized to analyze temporal characteristics of the waveform and determine the response voltage-log intensity (Vlogl) relationship. Changes in the ERG a-wave are associated with photoreceptor and retinal pigment epithelium damage while damage to the inner retina is reflected in changes in the ERG b-wave.
  • New Zealand Albino or Dutch-belted rabbits (3 to 5 per arm) can be dosed topically with a solution formulation of ⁇ -methyl-5-hydroxytryptamine (1%>) in the right eye and with vehicle in the left eye twice a day for a period of up to one week.
  • the ocular fluids and tissues are collected and analyzed for the presence of the drug via HPLC analysis.
  • the difference between the dosed eye and the contralateral vehicle dosed eye is a measure of the ability of the test item to penetrate directly to the retina/optic nerve head via topical ocular drug delivery.
  • the drug concentrations in the vehicle dosed eye represent delivery from systemic circulation.
  • Compounds of this invention are dosed topically to the eye to lower and control IOP and treat glaucomatous optic neuropathy.
  • the Compounds can be incorporated into various types of 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 the Compounds in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the Compounds.
  • 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 Compounds are 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 active ingredient 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 incorporated.
  • the Compounds are preferably formulated as a topical ophthalmic suspension or solution, with a pH of about 4 to 8.
  • the Compounds will normally be contained in these formulations in an amount 0.003%) to 5%> by weight, but preferably in an amount of 0.01%) to 2% by weight.
  • 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 (e.g., timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol), carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide), i antagonists (e.g. nipradolol), ⁇ agonists
  • ⁇ -blockers e.g., timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol
  • carbonic anhydrase inhibitors e.g., brinzolamide and dorzolamide
  • i antagonists e.g. nipradolol
  • ⁇ agonists e.g., nipradolol
  • iopidine and brimonidine miotics
  • miotics e.g., pilocarpine and epinephrine
  • prostaglandin analogues e.g., latanoprost, travaprost, unoprostone, bimatoprost, and compounds set forth in U.S. Patent Nos. 5,889,052; 5,296,504; 5,422,368; 5,688,819; and 5,151,444, "hypotensive lipids" (e.g., compounds set forth in 5,352,708), and neuroprotectants (e.g., compounds from U.S. Patent No. 4,690,931 , particularly eliprodil and R-eliprodil, as set forth in a pending application U.S.S.N. 06/203350, and appropriate compounds from WO94/13275, such as, memantine.
  • U.S. Patent No. 4,690,931 particularly eliprodil and R
  • topical ophthalmaic formulations are useful according to the present invention administered 1-4 times per day according to the discretion of a skilled clinician.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Indole Compounds (AREA)
  • Crystals, And After-Treatments Of Crystals (AREA)
  • Liquid Crystal Substances (AREA)

Abstract

L'invention concerne des composés ayant une activité agoniste vis-à-vis des deux récepteurs 5-HT2 et 5-HT1A, lesquels composés servent à abaisser ou à réguler la tension intraoculaire et sont donc utilisés dans le traitement de la neuropathie optique glaucomateuse.
EP01911005A 2000-03-17 2001-02-20 Composes a activite agoniste sur les recepteurs 5-ht 2? et 5-ht 1a? destines au traitement du glaucome Withdrawn EP1263434A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US19027900P 2000-03-17 2000-03-17
US190279P 2000-03-17
PCT/US2001/005432 WO2001070223A1 (fr) 2000-03-17 2001-02-20 Composes a activite agoniste sur les recepteurs 5-ht2 et 5-ht1a destines au traitement du glaucome

Publications (1)

Publication Number Publication Date
EP1263434A1 true EP1263434A1 (fr) 2002-12-11

Family

ID=22700682

Family Applications (3)

Application Number Title Priority Date Filing Date
EP01911005A Withdrawn EP1263434A1 (fr) 2000-03-17 2001-02-20 Composes a activite agoniste sur les recepteurs 5-ht 2? et 5-ht 1a? destines au traitement du glaucome
EP01918208A Expired - Lifetime EP1263504B1 (fr) 2000-03-17 2001-02-23 Utilisation de composes a activite agoniste sur le recepteur 5-ht1a destines au traitement des affections de la retine externe
EP01914447A Withdrawn EP1267878A2 (fr) 2000-03-17 2001-02-23 Composes a activite agoniste sur le recepteur 5-ht utilises pour enrayer la perte du champ visuel

Family Applications After (2)

Application Number Title Priority Date Filing Date
EP01918208A Expired - Lifetime EP1263504B1 (fr) 2000-03-17 2001-02-23 Utilisation de composes a activite agoniste sur le recepteur 5-ht1a destines au traitement des affections de la retine externe
EP01914447A Withdrawn EP1267878A2 (fr) 2000-03-17 2001-02-23 Composes a activite agoniste sur le recepteur 5-ht utilises pour enrayer la perte du champ visuel

Country Status (19)

Country Link
EP (3) EP1263434A1 (fr)
JP (5) JP2003527423A (fr)
KR (3) KR20030016239A (fr)
CN (2) CN1418100A (fr)
AR (1) AR028258A1 (fr)
AT (1) ATE247507T1 (fr)
AU (5) AU2001238552A1 (fr)
BR (3) BR0109193A (fr)
CA (3) CA2400637A1 (fr)
DE (1) DE60100625T2 (fr)
DK (1) DK1263504T3 (fr)
ES (1) ES2204848T3 (fr)
HK (1) HK1051504A1 (fr)
MX (3) MXPA02009071A (fr)
PL (1) PL203709B1 (fr)
PT (1) PT1263504E (fr)
TW (1) TWI268777B (fr)
WO (3) WO2001070223A1 (fr)
ZA (1) ZA200206350B (fr)

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US20030207890A1 (en) 2001-02-23 2003-11-06 Collier Robert J Compounds with 5-ht1a activity useful for treating disorders of the outer retina
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WO2005058911A2 (fr) 2003-12-15 2005-06-30 Alcon, Inc. [1,4]oxazino[2,3-g]indazoles substitues pour traiter le glaucome
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US7425572B2 (en) 2004-12-08 2008-09-16 Alcon, Inc. Use of dioxindoindazoles and dioxoloindazoles for treating glaucoma
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TW201010727A (en) * 2008-09-03 2010-03-16 Alcon Res Ltd Pharmaceutical composition having relatively low ionic strength
PL2498783T3 (pl) 2009-11-09 2019-04-30 Allergan Inc Kompozycje i sposoby stymulowania wzrostu włosów
JPWO2011071136A1 (ja) 2009-12-11 2013-04-22 アステラス製薬株式会社 線維筋痛症治療剤
EP2956096A1 (fr) 2013-02-15 2015-12-23 Allergan, Inc. Implant à administration de médicament prolongée
JPWO2019131902A1 (ja) 2017-12-27 2020-12-10 武田薬品工業株式会社 腹圧性尿失禁および便失禁の治療薬
WO2020176599A1 (fr) 2019-02-27 2020-09-03 The Regents Of The University Of California Azépino-indoles et autres hétérocycles pour traiter des troubles du cerveau
JP2022523774A (ja) 2019-02-27 2022-04-26 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 脳障害を治療するためのｎ－置換インドール及び他の複素環化合物
CN118715014A (zh) * 2021-12-23 2024-09-27 西尔卡雷德夫公司 用于治疗听力疾病的4-苯基-四氢吡啶衍生物

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JP2011037901A (ja) 2011-02-24
WO2001070230A3 (fr) 2002-04-25
DE60100625D1 (de) 2003-09-25
AU2001238552A1 (en) 2001-10-03
BR0109211A (pt) 2003-02-11
ES2204848T3 (es) 2004-05-01
AU2001239836A1 (en) 2001-10-03
BR0109230A (pt) 2003-06-03
MXPA02009071A (es) 2003-05-23
AU2005202600B2 (en) 2008-07-31
JP2011153158A (ja) 2011-08-11
MXPA02009072A (es) 2003-03-12
CA2400639A1 (fr) 2001-09-27
JP4789231B2 (ja) 2011-10-12
ATE247507T1 (de) 2003-09-15
EP1263504B1 (fr) 2003-08-20
KR100749191B1 (ko) 2007-08-13
CA2399985A1 (fr) 2001-09-27
PT1263504E (pt) 2003-12-31
AU2001245310B2 (en) 2005-03-17
AU2005202600A1 (en) 2005-07-07
TWI268777B (en) 2006-12-21
KR20030009390A (ko) 2003-01-29
KR20020082885A (ko) 2002-10-31
AR028258A1 (es) 2003-04-30
CN1418121A (zh) 2003-05-14
EP1263504A2 (fr) 2002-12-11
WO2001070222A2 (fr) 2001-09-27
CN1198605C (zh) 2005-04-27
JP2003527422A (ja) 2003-09-16
WO2001070222A3 (fr) 2002-07-25
JP2003527423A (ja) 2003-09-16
DK1263504T3 (da) 2003-12-08
WO2001070230A2 (fr) 2001-09-27
WO2001070223A1 (fr) 2001-09-27
KR20030016239A (ko) 2003-02-26
JP2003527427A (ja) 2003-09-16
ZA200206350B (en) 2003-08-08
MXPA02009073A (es) 2003-03-12
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PL203709B1 (pl) 2009-11-30
CA2400639C (fr) 2011-08-16
BR0109193A (pt) 2003-05-27
EP1267878A2 (fr) 2003-01-02
AU4531001A (en) 2001-10-03
DE60100625T2 (de) 2004-02-26
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CA2400637A1 (fr) 2001-09-27
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