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WO2018224419A1 - Dérivés d'isomannide donneurs d'oxyde nitrique - Google Patents

Dérivés d'isomannide donneurs d'oxyde nitrique Download PDF

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Publication number
WO2018224419A1
WO2018224419A1 PCT/EP2018/064568 EP2018064568W WO2018224419A1 WO 2018224419 A1 WO2018224419 A1 WO 2018224419A1 EP 2018064568 W EP2018064568 W EP 2018064568W WO 2018224419 A1 WO2018224419 A1 WO 2018224419A1
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Prior art keywords
compound
nitrooxy
furan
bis
hexahydrofuro
Prior art date
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Ceased
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PCT/EP2018/064568
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English (en)
Inventor
Nicoletta Almirante
Stefania Brambilla
Laura Storoni
Elena Bastia
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Nicox SA
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Nicox SA
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Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • 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 nitric oxide donating isomannide derivatives, then- use for treating glaucoma and ocular hypertension and formulations containing them.
  • the present invention also relates to compositions comprising a nitric oxide donating isomannide derivative and one or more further active ingredients for the use in the treatment of glaucoma and ocular hypertension.
  • Glaucoma is a group of eye disorders leading to progressive damage to the optic nerve, and is characterized by loss of nerve tissue resulting in loss of vision.
  • the most common form of glaucoma, primary open-angle glaucoma, is associated with an increase in the fluid pressure inside the eye. This increase in pressure may cause progressive damage to the optic nerve and loss of nerve fibers. Advanced glaucoma may even cause blindness.
  • Glaucoma is the second leading cause of blindness in the U.S. It most often occurs in people over age 40, although a congenital or infantile form of glaucoma exists.
  • glaucoma There are many types of glaucoma. The most common form of glaucoma, primary open-angle glaucoma, develops slowly and usually without any symptoms. It initially affects peripheral or side vision, but can advance to central vision loss. If left untreated, glaucoma can lead to significant loss of vision in both eyes, and may even lead to blindness.
  • Secondary glaucoma occurs as a result of an injury or other eye disease. It may be caused by a variety of medical conditions, physical injuries, and eye abnormalities. Infrequently, eye surgery can be associated with secondary glaucoma.
  • Normal-tension glaucoma also known as low-tension glaucoma, is characterized by progressive optic nerve damage and visual field loss with normal intra ocular pressure (IOP) and may account for as many as one-third of the cases of open-angle glaucoma in U.S.
  • IOP intra ocular pressure
  • Normal-tension glaucoma is thought to be, in part, due to poor blood flow to the optic nerve, which leads to death of the ganglion cells which carry impulses from the retina to the brain. A pressure lower than normal is necessary to prevent further visual loss.
  • the most common first line treatment of glaucoma is drug treatment.
  • drugs acting by different mechanisms are used as topically administered ocular therapy to lower IOP.
  • beta adrenergic blockers e.g., timolol
  • topical carbonic anhydrase inhibitors e.g., dorzolamide
  • alpha 2-adrenergic receptor agonists e.g., brimonidine
  • Pilocarpine and epinephrine lower IOP in glaucomatous eyes by decreasing the resistance in the trabecular meshwork outflow channels.
  • Prostaglandin analogues have met an increasing interest for glaucoma therapy as IOP-lowering substances which act primarily by increasing the uveoscleral outflow.
  • NO nitric oxide
  • nitric oxide (NO)-donating prostaglandin F2a analogs have been studied for the reduction of intraocular pressure (IOP)-lowering for the treatment of glaucoma and there are some publications on the studies.
  • IOP intraocular pressure
  • For example Valentina Borghi et al., Journal of Ocular Pharmacology and Therapeutics (2010), 26(2), 125-131, and Achim Krauss et al., Experimental Eye Research (2011), 93(3), 250-255 disclose the IOP lower effect of two nitric oxide donating latanoprost acid derivatives that are NCX 125 and BOL-303259-X.
  • the compound known as BOL-303259-X is now in clinical development for the treatment of primary open-angle glaucoma.
  • US patent 4,590,207 discloses ophthalmic solution containing isosorbide mononitrate as an active ingredient for treating and/or preventing intraocular hypertension and glaucoma.
  • EP 2 114 398 discloses 2-thio-substituted isosorbide-5-mononitrate derivatives for the treatment of ocular hypertension.
  • EP 2 238 143 discloses nitric oxide releasing isohexide derivatives that show a potent vasodilatory effect on isolated vessels and systemic hypotensive effect.
  • Intraocular pressure is the primary risk factor for glaucoma and lowering IOP to prevent optic nerve injury is the only proven effective treatment.
  • Kass MA et al., Arch Ophthalmol, 2002, 120:701-703; The AGIS Investigators, Am J Ophthalmol, 2000, 130:429- 440
  • patients with glaucoma need to continue treatment for the rest of their lives.
  • all the treatments evolved over decades produces a variety of ocular and systemic adverse effects that impact patient compliance. Compliance is of major importance to get the full potential efficacy of the drug treatment.
  • the present invention provides compounds for treating ocular hypertension, glaucoma and disease mediated by elevated intraocular pressure.
  • R is selected from the following structures:
  • Ri is -(CH 2 ) m -[0-(CH 2 ) protest]p-(CH-ON02)q-CH 2 -ON0 2
  • p 1 or 0
  • q 1 or 0
  • n is an integer ranging from 1 to 10; preferably m is from 1 to 6;
  • n is an integer ranging from 1 to 6; preferably n is 1 or 2;
  • preferred Ki are selected from the following structures:
  • Another embodiment of the invention relates to compounds of formula (I) or a pharmaceutical acceptable salt or stereoisomers thereof,
  • Ri is -(CH 2 ) m -[0-(CH 2 )n] P -(CH-ON0 2 ) q -CH 2 -ON02
  • Another embodiment of the invention relates to compounds of formula (I) or a pharmaceutical acceptable salt or stereoisomers thereof,
  • R is selected from the group of the following structures:
  • n 1 to 6.
  • Another embodiment of the invention relates to compounds of formula (I) or a pharmaceutical acceptable salt or stereoisomers thereof,
  • R is selected from the group of the following structures:
  • Ri is -(CH 2 ) m -[0-(CH 2 )n]p-(CH-ON0 2 ) q -CH 2 -ON0 2
  • p 1;
  • q is 0 or 1 ;
  • n 1 to 6;
  • n 1 or 2.
  • Another embodiment of the invention relates to compounds of formula (I) or a pharmaceutical acceptable salt or stereoisomers thereof,
  • R is selected from the group of the following structures:
  • Another embodiment of the invention includes compounds of formula (I) or a pharmaceutical acceptable salt or stereoisomers thereof,
  • Ri is -(CH 2 ) m -[0-(CH 2 ) complicat]p-(CH-ON0 2 ) q -CH 2 -ON0 2
  • Another embodiment of the invention includes compounds of formula (I) or a pharmaceutical acceptable salt or stereoisomers thereof,
  • Ri is -(CH2)m-[0-(CH 2 ) admir]p-(CH-ON0 2 )q-CH 2 -ON02
  • n 1 to 6.
  • Another embodiment of the invention includes compounds of formula (I) or a pharmaceutical acceptable salt or stereoisomers thereof,
  • Ri is -(CH 2 ) m -[0-(CH 2 ) complicat]p-(CH-ON0 2 ) q -CH 2 -ON0 2
  • q is 0 or 1 ;
  • n 1 to 6;
  • n 1 or 2.
  • Another embodiment of the invention includes compounds of formula (I) wherein:
  • Ri are selected from the following structures: (a) -(CH 2 ) 3 -(CH-ON0 2 )-CH 2 -ON0 2 ,
  • Anothermbodiment of the invention includes compounds with structures of formulae (1) to (15) as reported below, or a pharmaceutical acceptable salt or stereoisomers thereof:
  • the compounds of formula (I) have an improved IOP -reducing efficacy and a prolonged IOP effect as compared to the known nitric oxide donating compounds.
  • Certain specific compounds of the present invention contain a basic group that allows the compounds to be converted into acid salts.
  • the compounds of the present invention may exist as salts.
  • Example of such salts includes hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric, methylsulfonic, ethanesulfonic, benzenesulfonic, formic and the like.
  • Another embodiment provides the use of compounds of formula (I) for treating ocular hypertension or drug-induced ocular hypertension.
  • Another embodiment provides the use of the compounds of formula (I) for treating glaucoma in particular primary open angle glaucoma, normal intraocular tension glaucoma, pseudoexfoliation glaucoma, acute angle-closure glaucoma, chronic closed angle glaucoma.
  • compositions comprising a compound of formula (I) and at least another active agent selected from the following classes of drugs:
  • Beta-adrenergic antagonists wherein the beta-adrenergic antagonist is selected from: carteolol, levobunolol, metipranolol or timolol hemihydrate;
  • Prostaglandin analogues wherein the prostaglandin analogue is selected from: latanoprost, travoprost, tafluprost or bimatoprost;
  • Adrenergic agonists wherein the adrenergic agonist is selected from: epinephrine borate, epinephrine hydrochloride, dipivefrin or apraclonidine; Carbonic anhydrase inhibitors wherein the carbonic anhydrase inhibitor is selected from acetazolamide, dichlorphenamide, methazolamide, brinzolamide or dorzolamide;
  • Cholinergic agonists wherein the cholinergic agonist is selected from carbachol, pilocarpine hydrochloride, pilocarpine nitrate or pilocarpine;
  • Steroids wherein the steroid is selected from fluocinolone, fluticasone propionate, triamcinolone or dexamethasone;
  • Cholinesterase inhibitors wherein the cholinesterase inhibitor is selected from demecarium, echothiophate or physostigmine.
  • composition which is a kit comprising a topical ocular dosage form comprising a compound of formula (I) or salts thereof and another topical ocular dosage form comprising an active agent selected from the following classes of drugs: prostaglandin analogues, beta-adrenergic antagonists, carbonic anhydrase inhibitors, cholinergic agonists, steroids or cholinesterase inhibitors.
  • an active agent selected from the following classes of drugs: prostaglandin analogues, beta-adrenergic antagonists, carbonic anhydrase inhibitors, cholinergic agonists, steroids or cholinesterase inhibitors.
  • compositions comprising compound of formula (I) and at least another active agent reported above for treating ocular hypertension.
  • compositions comprising a compound of formula (I) and at least another active agent reported above for treating glaucoma in particular primary open angle glaucoma, normal intraocular tension glaucoma, pseudoexfoliation glaucoma, acute angle-closure glaucoma, chronic closed angle glaucoma.
  • Another embodiment of the invention provides a compound of formula (I) for use in the treatment of ocular hypertension and glaucoma wherein the compound of formula (I) is simultaneously, separately or sequentially administered with another active agent selected from the following classes of drugs: prostaglandin analogues, beta-adrenergic antagonists carbonic anhydrase inhibitors, cholinergic agonists, steroids or cholinesterase inhibitors.
  • another active agent selected from the following classes of drugs: prostaglandin analogues, beta-adrenergic antagonists carbonic anhydrase inhibitors, cholinergic agonists, steroids or cholinesterase inhibitors.
  • the compounds of formula (I) and their compositions may be provided as part of a pharmaceutical compositions as described therein.
  • the compounds of the present invention are generally formulated as between 0.0003% to 3% (w/v) solutions in water at a pH from 4.5 to 8.0.
  • the compounds are preferably formulated as between 0.003 to 1% (w/v) and, most preferably between 0.03% to 1% (w/v).
  • a topical ocular pharmaceutical composition comprising a compound of formula (I) or salts thereof and a pharmaceutically acceptable excipient.
  • Acceptable excipients may include preservatives, dissolving agents and viscosity agents.
  • R is selected from the following structures:
  • Ri is -(CH 2 ) m -[0-(CH 2 ) n ]p-(CH-ON0 2 ) q -CH 2 -ON0 2
  • a coupling agent such as ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), 0-(benzotriazol-l- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or
  • DCC ⁇ , ⁇ '-dicyclohexylcarbodiimide
  • EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • HBTU 0-(benzotriazol-l- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • compound of formula (la) is reacted with a compound of formulae (IIB), (VB), (VIIB)-(IXB)
  • aprotic polar/non polar solvent such as acetonitrile, DMF, methyl tert-butyl ether (MTBE) or CH 2 C1 , at temperature ranging from 0°C to 80°C.
  • R is selected from the following structures:
  • reaction is carried out in an aprotic polar/non polar solvent such as THF, DMF or CH2CI2, in presence of ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC), O-(benzotriazol-l-yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium-hexafluorophosphate (HBTU) or
  • p is 1 or 0 and q is 1 or 0
  • m is an integer ranging from 1 to 10
  • n is an integer ranging from 1 to 6.
  • the reaction is carried out in an aprotic polar/non polar solvent such as THF, DMF or CH2CI2, in presence of ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), 0-(benzotriazol-l- yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HBTU) or 1 - [bis(dimethylamino)methylene] - 1 H- 1 ,2,3 -triazolo[4,5-b]pyridinium-3-oxide-hexafluoro phosphate (FiATU), or other coupling reagents, in presence of catalytic amount of DMAP at temperature ranging from 0°C to 80°C.
  • DCC ⁇ , ⁇ '-dicyclohexylcarbodiimide
  • Intermediate compound (lb) is prepared by reacting l,4:3,6-dianhydro-D-mannitol with 3,4-dihydro-2H-pyran in the presence of a catalytic amount of p-toluenesulfonic acid. Details of the reaction procedure and purification of Intermediate (lb) are disclosed in Example 1, Step 6.
  • R is the structures (X) and Ri are as defined above can be generally prepared by reacting compound of formula (I) wherein R is the structure (III)
  • reaction is carried out in an aprotic polar/non polar solvent such as THF, DMF or CH 2 C1 2 , in presence of ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC), O-(benzotriazol-l-yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium hexafluorophosphate (HBTU) or
  • DCC ⁇ , ⁇ '-dicyclohexylcarbodiimide
  • EDC l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride
  • HBTU O-(benzotriazol-l-yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium hexafluorophosphate
  • Ri is as above defined and R is selected from the following structures:
  • reaction is carried out in an aprotic polar/non polar solvent such as THF, DMF or CH 2 C1 2 , in presence of ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), 0-(benzotriazol-l- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or
  • DCC ⁇ , ⁇ '-dicyclohexylcarbodiimide
  • EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • HBTU 0-(benzotriazol-l- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • Intermediate compound (Ic) is prepared by reacting l,4:3,6-dianhydro-D-mannitol with the appropriate compound of formula (IIB), (VB), (VIIB)-(IXB):
  • aprotic polar/non polar solvent such as acetonitrile, DMF, methyl tert-butyl ether (MTBE) or CH 2 C1 2 , at temperature ranging from 0°C to 80°C.
  • Step 2 synthesis of (55)- 5,6-dihydroxyhexyl 4-nitrobenzoate.
  • Step 3 synthesis of (5S)-5,6-bis(nitrooxy)hexyl 4-nitrobenzoate.
  • Step 4 Synthesis of (2S)-6-hydroxy-2-(nitrooxy)hexyl nitrate.
  • Step 5 synthesis of (5S)-5,6-bis(nitrooxy)hexanoic acid.
  • Step 6 Synthesis of (3R,3aR,6R,6aR)-6-(tetrahydro-2H-pyran-2- yloxy)hexahydrofuro [3 ,2-b]furan-3 -ol.
  • Step 7 Synthesis of (5S)-((3R,3aR,6R,6aR)-6-(tetrahydro-2H-pyran-2- yloxy)hexahydrofuro[3,2-b]furan-3-yl) 5,6-bis(nitrooxy)hexanoate
  • Step 8 Synthesis of (S)-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan- 3-yl) 5,6-bis(nitrooxy)hexanoate.
  • Step 9 Synthesis of (S)-((3R,3aR,6R,6aR)-6-(pivaloyloxy)hexahydrofuro[3,2- b]furan-3-yl) 5,6-bis(nitrooxy)hexanoate ((S)-isomer of Compound (2)).
  • Compound (1) can be prepared by the following synthesis:
  • the obtained oil was purified on a 340g silica cartridge using Cyclohexane/EtOAc (from 6/4 to 4/6) as eluent.
  • the fractions containing clean product were pooled together and the solvent was removed under vacuum to give 5.4 g (24% yield) of the desired product as a clear oil.
  • Step 2' Synthesis of (S)-((3R,3aR,6R,6aR)-6-( ivaloyloxy)hexahydrofuro[3,2- b]furan-3-yl) 5,6-bis(nitrooxy)hexanoate ((S)-isomer of Compound (2)).
  • the obtained crude was purified on a 240 g silica cartridge using Cyclohexane/EtOAc (from 8/2 to 7/3) as eluent.
  • the fractions containing clean product were pooled together and the solvent was removed under vacuum (water bath 30°C max) to give 3.8 g (81% yield) of the desired product as a light yellow oil.
  • Step 1 Synthesis of (S)-((3R,3aR,6R,6aR)-6-((S)-2-(tert-butoxycarbonylamino)- 3-methylbutanoyloxy)hexahydrofuro[3,2-b]furan-3-yl) 5,6-bis(nitrooxy)hexanoate.
  • Step 2 Synthesis of (S)-((3R,3aR,6R,6aR)-6-((S)-2-amino-3-methylbutanoyloxy) hexahydrofuro [3 ,2-b] furan-3 -yl) 5,6-bis(nitrooxy)hexanoate trifluoro acetic acid salt ((S)-isomer of compound (6)-trifluoroacetic salt).
  • Step 1 Synthesis of (S)-((3R,3aR,6R,6aR)-6-((S)-2-(tert-butoxycarbonylamino)-3- phenylpropanoyloxy)hexahydrofuro [3 ,2-b] furan-3 -yl) 5,6-bis(nitrooxy)hexanoate.
  • Step 2 Synthesis of (S)-((3R,3aR,6R,6aR)-6-((S)-2-amino-3-phenylpropanoyloxy) hexahydrofuro[3,2-b]furan-3-yl) 5,6-bis(nitrooxy)hexanoate, trifluoroacetic acid salt ((S)-isomer of compound (9)-trifluoroacetic acid salt).
  • the residue was purified by reversed-phase chromatography (H 2 0/CH 3 CN with 0.01% TFA, from 80:20 to 40:60). DCM and a saturated solution of NaHC0 3 were added to the residue after purification. The two phases were separated and the aqueous phase extracted twice with DCM. The combined organic phases were dried over MgS0 4 and concentrated under reduced pressure. The obtained residue was further purified by flash chromatography (cyclohexane/ethyl acetate from 50:50 to 20:80), to give 71 mg of the desired product (yield: 55.2%).
  • Step 1 synthesis of (3R,3aR,6R,6aR)-6-(((tert-butoxycarbonyl)-L- valyl)oxy)hexahydrofuro [3 ,2-b] furan-3 -yl (5)-5,6-bis(nitrooxy)hexanoate
  • Step 2 synthesis of (S)-l-(((3R,3aR,6R,6aR)-6-(((S)-5,6- bis(nitrobxy)hexanoyl)oxy)hexahydrofuro [3 ,2-b] furan-3 -yl)oxy)-3 -methyl- 1 -oxobutan-2- aminium trifluoroacetate
  • Step 3 synthesis of (3R,3aR,6R,6aR)-6-(((S)-2-(((tert-butoxycarbonyl)-L- valyl)oxy)-3 -methylbutanoyl)oxy)hexahydrofuro [3 ,2-b] furan-3 -yl (S)-5 ,6- bis(nitrooxy)hexanoate
  • N-Boc-L-valine (151 mg, 0.696 mmol) was added, then the mixture was allowed to reach room temperature and stirred for 1 hour. The solid was filtered off, water and DCM were added to the mixture, the two phases were separated and the aqueous phase extracted twice with DCM. The combined organic phases were dried over MgS0 4 and concentrated under reduced pressure.
  • Step 4 synthesis of l-((l-(((3i?,3atf,6i?,6ai?)-6-(((S)-5,6- bis(nitrooxy)hexanoyl)oxy) hexahydrofuro [3 ,2-b] furan-3 -yl)oxy)-3 -methyl- 1 -oxobutan-2- yl)amino)-3-methyl-l-oxobutan-2-aminium trifluoroacetate
  • IOP Intraocular pressure
  • IOP intraocular pressure
  • RF reference compound
  • Reference compound is a compound included in the prior art document EP 2 238 143;
  • IOP was measured using a pneumatonometer 30 CLASSICTM before topical application (basal) and at different time points (30, 60, 180, 240 and 300 min) thereafter. Eyes were randomly assigned to different treatment groups.
  • ISMN isosorbide mononitrate
  • Isosorbide mononitrate is a known nitric oxide donating compound.
  • IOP Intraocular pressure
  • IOP Intraocular pressure
  • IOP was measured using a pneumatonometer 30 CLASSICTM before topical application (basal) and at different time points (60, 120 and 240) thereafter. Eyes were randomly assigned to different treatment groups.
  • IOP Intraocular pressure

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  • Ophthalmology & Optometry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

La présente invention concerne des dérivés d'isomannide donneurs d'oxyde nitrique, leur utilisation pour le traitement du glaucome et de l'hypertension oculaire et des formulations les contenant. La présente invention concerne également des compositions comprenant un dérivé d'isomannide donneur d'oxyde nitrique et un ou plusieurs autres principes actifs pour l'utilisation dans le traitement du glaucome et de l'hypertension oculaire.
PCT/EP2018/064568 2017-06-06 2018-06-04 Dérivés d'isomannide donneurs d'oxyde nitrique Ceased WO2018224419A1 (fr)

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EP17174615 2017-06-06

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4590207A (en) 1984-01-18 1986-05-20 Eisai Co., Ltd. Therapeutic and/or preventive ophthalmic solution for intraocular hypertension and glaucoma
WO2009098113A1 (fr) * 2008-02-07 2009-08-13 Nicox S.A. Composés donneurs d'oxyde nitrique
EP2114398A1 (fr) 2006-12-28 2009-11-11 Lacer, S.A. Dérivés de mononitrate d'isosorbide pour le traitement de l'hypertension oculaire

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4590207A (en) 1984-01-18 1986-05-20 Eisai Co., Ltd. Therapeutic and/or preventive ophthalmic solution for intraocular hypertension and glaucoma
EP2114398A1 (fr) 2006-12-28 2009-11-11 Lacer, S.A. Dérivés de mononitrate d'isosorbide pour le traitement de l'hypertension oculaire
WO2009098113A1 (fr) * 2008-02-07 2009-08-13 Nicox S.A. Composés donneurs d'oxyde nitrique
EP2238143A1 (fr) 2008-02-07 2010-10-13 Nicox S.A. Composés donneurs d'oxyde nitrique

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ACHIM KRAUSS ET AL., EXPERIMENTAL EYE RESEARCH, vol. 93, no. 3, 2011, pages 250 - 255
AM J OPHTHALMOL, vol. 130, 2000, pages 429 - 440
ANDERS HEIJL, THE LANCET, vol. 385, 2015, pages 1264 - 1266
KASS MA ET AL., ARCH OPHTHALMOL, vol. 120, 2002, pages 701 - 703
T.W. GREENE; P. G. M. WUTS: "Protective groups in organic Synthesis", 2006, J. WILEY & SONS
VALENTINA BORGHI ET AL., JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS, vol. 26, no. 2, 2010, pages 125 - 131

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