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WO2006007227A2 - Cannabidiols anormaux utilises comme agents pour abaisser la pression intraoculaire et apporter un effet neuroprotecteur a l'oeil - Google Patents

Cannabidiols anormaux utilises comme agents pour abaisser la pression intraoculaire et apporter un effet neuroprotecteur a l'oeil Download PDF

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Publication number
WO2006007227A2
WO2006007227A2 PCT/US2005/018830 US2005018830W WO2006007227A2 WO 2006007227 A2 WO2006007227 A2 WO 2006007227A2 US 2005018830 W US2005018830 W US 2005018830W WO 2006007227 A2 WO2006007227 A2 WO 2006007227A2
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WO
WIPO (PCT)
Prior art keywords
compound
eye
formula
glaucoma
mammal
Prior art date
Application number
PCT/US2005/018830
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English (en)
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WO2006007227A3 (fr
Inventor
June Chen
David F. Woodward
Original Assignee
Allergan, 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 claimed from US10/874,441 external-priority patent/US20050282913A1/en
Priority claimed from US10/874,440 external-priority patent/US20050282912A1/en
Priority claimed from US11/073,209 external-priority patent/US20050282902A1/en
Priority claimed from US11/121,528 external-priority patent/US20060247321A1/en
Application filed by Allergan, Inc. filed Critical Allergan, Inc.
Priority to BRPI0512525-1A priority Critical patent/BRPI0512525A/pt
Priority to CA002570853A priority patent/CA2570853A1/fr
Priority to EP05784443A priority patent/EP1765315A2/fr
Priority to JP2007518081A priority patent/JP2008503577A/ja
Publication of WO2006007227A2 publication Critical patent/WO2006007227A2/fr
Publication of WO2006007227A3 publication Critical patent/WO2006007227A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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

Definitions

  • the present invention relates to the use of Abnormal Cannabidiols to lower the intraocular pressure of mammals and thus are useful in treating glaucoma. These compounds are also useful as neuroprotective agents in the eye.
  • Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post- laser trabeculectomy ocular hypertensive episodes, glaucoma, and as presurgical adjuncts.
  • Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
  • the increased intraocular tension is due to the obstruction of aqueous humor outflow.
  • chronic open-angle glaucoma the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded.
  • acute or chronic angle-closure the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of the iris forward against the angle, and may produce pupilary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity.
  • Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm.
  • Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe, and may plug the drainage channel with exudates.
  • Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
  • glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision.
  • topical ⁇ -adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.
  • glaucoma as a disorder of increased intraocular pressure (IOP) oversimplifies the clinical situation.
  • IOP intraocular pressure
  • Another possible factor in the etiology of glaucoma may be regulation of the regional microvasculature of the anterior optic nerve.
  • microvascular factors are important is that many microvascular diseases are associated with glaucomatous optic neuropathy. Subsequent to Cioffi, et al., Matusi published a paper on the
  • systemic vasculitis such as polyarteritis nodosa, giant cell angitis and aortitis syndrome were reviewed.
  • Systemic lupus erythematosus is not categorized as systemic vasculitis, however its ocular findings are microangiopathic. Therefore, review of its ocular findings was included in this paper.
  • the most common fundus finding in these diseases is ischemic optic neuropathy or retinal vascular occlusions. Therefore several points in diagnosis or pathogenesis of optic neuropathy and retinal and choroidal vaso-occlusion were discussed.
  • Choroidal ischemia has come to be able to be diagnosed clinically, since fluorescein angiography was applied in these lesions.
  • retinal pigment epithelium When choroidal arteries are occluded, overlying retinal pigment epithelium is damaged. This causes disruption of barrier function of the epithelium and allows fluid from choroidal vasculatures to pass into subsensory retinal spaces. This is a pathogenesis of serous detachment of the retina. The retinal arterial occlusion formed non-perfused retina. Such hypoxic retina released angiogenesis factors which stimulate retinal and iris neovascularizations and iris neovascularizations may cause neovascular glaucoma.
  • Abnormal Cannabidiols are potent ocular hypotensive agents.
  • Abnormal Cannabidiols and homologues and derivatives thereof are especially useful in the treatment of glaucoma and surprisingly, cause no or significantly lower ocular surface hyperemia than the other compounds that are useful in lowering intraocular pressure, e.g. PGF 2a and lower alkyl esters thereof.
  • Abnormal Cannabidiols are potent neuroprotective agents.
  • Abnormal Cannabidiols and homologues and derivatives thereof are especially useful in providing a neuroprotective effect to the eye of a mammal, e.g. a human.
  • the present invention relates to methods of treating ocular hypertension in and providing neuroprotection to the eye, e.g. the eye of a mammal, such as a human, which comprises administering an effective a a I
  • R is selected from the group consisting of (CH 2 ) X wherein x is 0 or an integer of from 1 to 7.
  • the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formulae (I), in admixture with an non-toxic, pharmaceutically acceptable liquid vehicle.
  • Figure 1 shows the effect of 0.1% Abnormal Cannabidiol on Dog Intraocular Pressure versus time.
  • Figure 2 shows the effect of 0.1% Abnormal Cannabidiol on Monkey Intraocular Pressure versus time.
  • Figure 3 shows the change from baseline IOP of Monkey dosed with 0.1% Abnormal Cannabidiol versus time.
  • the present invention relates to the use of Abnormal Cannabidiols as ocular hypotensives. These therapeutic agents are represented by compounds having the formula I: as defined above.
  • the preferred compounds used in accordance with the present invention are encompassed by the following structural formula
  • the straight lines represent bonds. Where there is no symbol for the atoms between the bonds, the appropriate carbon-containing radical is to be inferred.
  • the radical extending from the phenyl ring is a polymethylene (CH 2 ) radical terminated with a methyl radical, i.e. a butylenylmethyl radical.
  • compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, as an active ingredient, with conventional ophthalmically acceptable pharmaceutical excipients, and by preparation of unit dosage forms suitable for topical ocular use.
  • the therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 1.0% (w/v) in liquid formulations.
  • solutions are prepared using a physiological saline solution as a major vehicle.
  • the pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential.
  • the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.
  • a preferred surfactant is, for example, Tween 80.
  • various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
  • Tonicity adjusters may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
  • buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
  • an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • excipient components which may be included in the ophthalmic preparations are chelating agents.
  • the preferred chelating agent is edentate disodium, although other chelating agents may also be used in place or in conjunction with it.
  • the ingredients are usually used in the following amounts:
  • Table 1 Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative 0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10 pH adjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purified water as needed to make 100%
  • the actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
  • the ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate application to the eye.
  • Containers suitable for dropwise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution.
  • One package may contain one or more unit doses.
  • Especially preservative-free solutions are often formulated in non- resealable containers containing up to about ten, preferably up to about five unit doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops.
  • the volume of one drop usually is about
  • the compounds disclosed herein for use in the method of this invention i.e. the treatment of glaucoma or elevated intraocular pressure, may also be used in combination with other drugs useful for the treatment of glaucoma or elevated intraocular pressure.
  • ⁇ -Blockers or ⁇ -adrenergic antagonists
  • ⁇ -Adrenergic antagonists including carteolol, levobunolol, metipranolol, timolol hemihydrate, timolol maleate, ⁇ l-selective antagonists such as betaxolol, and the like, or pharmaceutically acceptable salts or prodrugs thereof
  • Adrenergic Agonists including non-selective adrenergic agonists such as epinephrine borate, epinephrine hydrochloride, and dipivefrin, and the like, or pharmaceutically acceptable salts or prodrugs thereof
  • ⁇ s -selective adrenergic agonists such as apraclonidine, brimonidine, and the like, or pharmaceutically acceptable salts or prodrugs thereof
  • Glutamate Antagonists such as memantine, amantadine, rimantadine, nitroglycerin, dextrophan, detromethorphan, CGS-19755, dihydropyridines, verapamil, emopamil, benzothiazepines, bepridil, diphenylbutylpiperidines, diphenylpiperazines, HOE 166 and related drugs, fluspirilene, eliprodil, ifenprodil, CP-101,606, tibalosine, 2309BT, and 840S, flunarizine, nicardipine, nifedimpine, nimodipine, barnidipine, lidoflazine, prenylamine lactate, amiloride, and the like, or pharmaceutically acceptable salts or prodrugs thereof; Prostamides such as bimatoprost, or pharmaceutically acceptable salts or prodrugs thereof; and
  • Prostaglandins including travoprost, UFO-21, chloprostenol, fluprostenol, 13,14-dihydro-chloprostenol, isopropyl unoprostone, latanoprost and the like.
  • the invention is further illustrated by the following non-limiting
  • Abnormal Cannabidiol also named as Abn-CBD (4-[(lR,6R)-3 ⁇ Methyl-6-(l-methylethenyl)-2-cyclohexen-l-yl]-5-pentyl-l,3-benzenediol,
  • M. W. 314.47 may be purchased from Tocris Cookson Inc., Ellisville, MO, USA.
  • Example 2 The above compound is well known and may be purchased or synthesized by methods known in the art.
  • Example 2 The above compound is well known and may be purchased or synthesized by methods known in the art.
  • Intraocular pressure was measured by applanation pneumatonometry in conscious animals. The test compound was administered topically to one eye while vehicle was given to the fellow eye in a masked fashion. Ocular normotensive Beagle dogs (males, females) were dosed once daily for five days. Laser-induced unilaterally ocular hypertensive Cynomolgus monkeys (females) were dosed once daily for 4 days. Student's paired i-test was used for statistical comparisons. Differences were considered statistically significant if the P- value is less than 0.05.
  • Figure 2 shows the effect of 0.1% Abnormal Cannabidiol on Monkey Intraocular Pressure versus time.
  • Figure 3 shows the change from baseline IOP of Monkey dosed "with 0.1% Abnormal Cannabidiol versus time.
  • Abnormal Cannabidiol receptor activity may be measured in accordance with the procedure disclosed in (Wagner JA et al., Hypertension 33 [part II], 429 (1999); Jarai Z et al., PNAS 96, 14136 (1999), which is hereby incorporated by reference in its entirety.
  • the dissection and dissociation of the rat hippocampal neuron cell cultures is carried out. Briefly, whole cerebral neocortices are removed from fetal rats, gestation age 15-19 days and kept in calcium free and magnesium free Hanks' balanced salt solution. The hippocampi are removed under a dissecting microscope and the meninges are stripped away. When all the hippocampi are removed, the tissues are incubated in 0.05% trypsin solution for 30 minutes at 37 0 C.
  • the trypsin solution is replaced with plating medium (minimal essential medium supplemented with 2% Hyclone horse serum, 1% fetal calf serum, 25 mM glucose, 1% glutamine and 1% penicillin/streptomycin and N 2 supplement). Then the tissues are triturated with a Pasteur pipette 10 times and then again with a pipette whose tip has been fire polished to about half the normal diameter. The dissociated neuronal cells then are plated on poly D-lysine coated, 15 mm 24 well plates (2xlO 5 cells/well) in plating medium.
  • plating medium minimum essential medium supplemented with 2% Hyclone horse serum, 1% fetal calf serum, 25 mM glucose, 1% glutamine and 1% penicillin/streptomycin and N 2 supplement.
  • the cell cultures are kept at 37°C in a humidified, 5% CO 2 containing atmosphere. After 1-2 days, the horse serum level in the plating media is increased to 8%. After 4-7 days, the non-neuronal cell division is halted by 24 hours exposure to 10 "6 M Cytosine arabinoside (ARA-C), and the cells are then placed into growing medium with 4% horse serum, 1% fetal calf serum, 25 mM glucose, 1% glutamine and 1% penicillin/ streptomycin and N 2 supplement. Subsequent medium replacement is carried out every other day until the neuronal cells mature (15-20 days). Only matured cell cultures are selected for study.
  • ARA-C Cytosine arabinoside
  • LDH lactate dehydrogenase
  • LDH is measured at room temperature using Promega non ⁇ radioactive cytotoxicity assay kit.
  • the absorbance of the reaction mixture is measured at 490 nm.
  • the effect of the Abnormal Cannabidiol of Example 1 on NMDA- induced neurotoxicity shows that the compound of Example 1 has a neuroprotective effect.
  • Example 4 The Experiment of Example 4 is repeated with other Abnormal Cannabidiols and the results are essentially as shown for the compound of Example 1.
  • a combination product containing an Abnormal Cannabidiols component and an ocular hypotensive agents component that enhances aqueous humor outflow via either or both the trabecular and uveoscleral outflow pathways is contemplated for effective reduction of intraocular pressure based on different modes of action and complementary pharmacology of the active ingredients.
  • Cholinergic agonists including direct acting cholinergic agonists such as carbachol, pilocarpine hydrochloride, pilocarpine nitrate, pilocarpine, and the like, or pharmaceutically acceptable salts or prodrugs thereof; cholinesterase inhibitors such as demecarium, echothiophate, physostigrnine, and the like, or pharmaceutically acceptable salts or prodrugs thereof; prostamides such as bimatoprost, or pharmaceutically acceptable salts or prodrugs thereof; prostaglandins including travoprost, UFO-21, cloprostenol, fluprostenol, 13,14-dihydro- cloprostenol, isopropyl unoprostone, latanoprost, prostaglandin EP analogs such as butaprost, AH-13205 and the like.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des cannabidiols anormaux utilisés comme hypotenseurs oculaires puissants, qui sont particulièrement appropriés pour le traitement du glaucome. L'invention concerne en particulier des composés de formule (I) ou de formule (II) ou de formule (III), dont il a été également découvert qu'ils apportent un effet neuroprotecteur à l'oeil.
PCT/US2005/018830 2004-06-22 2005-05-26 Cannabidiols anormaux utilises comme agents pour abaisser la pression intraoculaire et apporter un effet neuroprotecteur a l'oeil WO2006007227A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
BRPI0512525-1A BRPI0512525A (pt) 2004-06-22 2005-05-26 canabidióis anormais como agentes para diminuir a pressão intraocular e fornecer efeito neuroprotetor ao olho
CA002570853A CA2570853A1 (fr) 2004-06-22 2005-05-26 Cannabidiols anormaux utilises comme agents pour abaisser la pression intraoculaire et apporter un effet neuroprotecteur a l'oeil
EP05784443A EP1765315A2 (fr) 2004-06-22 2005-05-26 Cannabidiols anormaux pour abaisser la pression intraoculaire
JP2007518081A JP2008503577A (ja) 2004-06-22 2005-05-26 眼圧を降下するためのアブノーマル・カンナビジオール化合物

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US10/874,441 US20050282913A1 (en) 2004-06-22 2004-06-22 Abnormal cannabidiols as agents for lowering intraocular pressure
US10/874,441 2004-06-22
US10/874,440 US20050282912A1 (en) 2004-06-22 2004-06-22 Abnormal cannabidiols as neuroprotective agents for the eye
US10/874,440 2004-06-22
US11/073,209 US20050282902A1 (en) 2004-06-22 2005-03-05 Abnormal cannabidiols as agents for lowering intraocular pressure
US11/073,209 2005-03-05
US11/121,528 2005-05-02
US11/121,528 US20060247321A1 (en) 2005-05-02 2005-05-02 Abnormal Cannabidiols as agents useful in combination therapy for lowering intraocular pressure

Publications (2)

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WO2006007227A2 true WO2006007227A2 (fr) 2006-01-19
WO2006007227A3 WO2006007227A3 (fr) 2006-05-18

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EP (1) EP1765315A2 (fr)
JP (1) JP2008503577A (fr)
AU (1) AU2005262652A1 (fr)
BR (1) BRPI0512525A (fr)
CA (1) CA2570853A1 (fr)
WO (1) WO2006007227A2 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007127711A2 (fr) * 2006-04-24 2007-11-08 Allergan, Inc. Cannabidiols anormaux utiles comme agents destinés à faire baisser la pression intraoculaire
US7612101B2 (en) 2006-04-24 2009-11-03 Allergan, Inc. Abnormal cannabidiols as agents for lowering intraocular pressure
US7618966B2 (en) 2006-04-24 2009-11-17 Allergan, Inc. Abnormal Cannabidiols as agents for lowering intraocular pressure
US7718830B2 (en) 2006-04-24 2010-05-18 Allergan, Inc. Abnormal cannabidiols as agents for lowering intraocular pressure
WO2019159168A1 (fr) * 2018-02-13 2019-08-22 Beetlebung Pharma Ltd. Dérivés et conjugués de cannabinoïdes et leurs utilisations
CN115006404A (zh) * 2022-08-09 2022-09-06 昆药集团股份有限公司 一种具有视神经保护功效的药物组合物及其应用

Citations (3)

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US5939429A (en) * 1997-09-30 1999-08-17 Virginia Commonwealth University Cardiovascular uses of cannabinoid compounds
WO2001003690A1 (fr) * 1999-07-12 2001-01-18 Virginia Commonwealth University Nouveaux analogues de cannabinoides vasodilatateurs
WO2003091189A1 (fr) * 2002-04-25 2003-11-06 Virginia Commonwealth University Cannabinoides

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US5939429A (en) * 1997-09-30 1999-08-17 Virginia Commonwealth University Cardiovascular uses of cannabinoid compounds
WO2001003690A1 (fr) * 1999-07-12 2001-01-18 Virginia Commonwealth University Nouveaux analogues de cannabinoides vasodilatateurs
WO2003091189A1 (fr) * 2002-04-25 2003-11-06 Virginia Commonwealth University Cannabinoides

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COMPTON, DAVID R. ET AL: "Synthesis and pharmacological evaluation of amino, azido, and nitrogen mustard analogs of 10-substituted cannabidiol and 11- or 12-substituted .DELTA.8-tetrahydrocannabinol" JOURNAL OF MEDICINAL CHEMISTRY , 33(5), 1437-43 CODEN: JMCMAR; ISSN: 0022-2623, 1990, XP001076889 *
HO, W.-S. VANESSA ET AL: "Vasodilator actions of abnormal-cannabidiol in rat isolated small mesenteric artery" BRITISH JOURNAL OF PHARMACOLOGY , 138(7), 1320-1332 CODEN: BJPCBM; ISSN: 0007-1188, 2003, XP008060537 *
ULISS, D. B. ET AL: "Hashish. Importance of the phenolic hydroxyl group in tetrahydrocannabinols" JOURNAL OF MEDICINAL CHEMISTRY , 18(2), 213-15 CODEN: JMCMAR; ISSN: 0022-2623, 1975, XP008060536 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007127711A2 (fr) * 2006-04-24 2007-11-08 Allergan, Inc. Cannabidiols anormaux utiles comme agents destinés à faire baisser la pression intraoculaire
WO2007127711A3 (fr) * 2006-04-24 2008-03-27 Allergan Inc Cannabidiols anormaux utiles comme agents destinés à faire baisser la pression intraoculaire
JP2009536623A (ja) * 2006-04-24 2009-10-15 アラーガン、インコーポレイテッド 眼圧降下剤としてのアブノーマル・カンナビジオール化合物
US7612101B2 (en) 2006-04-24 2009-11-03 Allergan, Inc. Abnormal cannabidiols as agents for lowering intraocular pressure
US7618966B2 (en) 2006-04-24 2009-11-17 Allergan, Inc. Abnormal Cannabidiols as agents for lowering intraocular pressure
EP2123264A1 (fr) * 2006-04-24 2009-11-25 Allergan, Inc. Dérivés hétérocycliques comme agents cannabidiols anormaux pour diminuer la pression intra-oculaire
US7718830B2 (en) 2006-04-24 2010-05-18 Allergan, Inc. Abnormal cannabidiols as agents for lowering intraocular pressure
US7968711B2 (en) 2006-04-24 2011-06-28 Allergan, Inc. Abnormal cannabidiols as agents for lowering intraocular pressure
US8420637B2 (en) 2006-04-24 2013-04-16 Allergan, Inc. Abnormal cannabidiols as agents for lowering intraocular pressure
AU2007244978B2 (en) * 2006-04-24 2013-05-30 Allergan, Inc. Abnormal Cannabidiols as agents for lowering intraocular pressure
JP2014058536A (ja) * 2006-04-24 2014-04-03 Allergan Inc 眼圧降下剤としてのアブノーマル・カンナビジオール化合物
WO2019159168A1 (fr) * 2018-02-13 2019-08-22 Beetlebung Pharma Ltd. Dérivés et conjugués de cannabinoïdes et leurs utilisations
CN115006404A (zh) * 2022-08-09 2022-09-06 昆药集团股份有限公司 一种具有视神经保护功效的药物组合物及其应用

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CA2570853A1 (fr) 2006-01-19
JP2008503577A (ja) 2008-02-07
WO2006007227A3 (fr) 2006-05-18
BRPI0512525A (pt) 2008-03-11
AU2005262652A1 (en) 2006-01-19
EP1765315A2 (fr) 2007-03-28

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