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
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • 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
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • 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
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
• • 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
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• • 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
  • 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

• Disclosed herein is a method of treating disorders of the eye by administering to a patient in need of such treatment certain 3-Substituted-[1 ,2,3]-Benzotriazinone compounds.
• Ampakines are a class of compounds known to enhance attention span and alertness, and facilitate learning and memory.
• the ampakines take their name from the glutamatergic AMPA receptor with which they strongly interact.
• the AMPA receptor gets its name from AMPA, which selectively binds to it.
• ampakines do not seem to have unpleasant, long-lasting side effects such as sleeplessness.
• ADHD Attention Deficit Hyperactivity Disorder
• Ampakine activity has been established as one of the modes of action of the well- established class of nootropics, the racetam drugs such as piracetam, aniracetam, oxiracetam and pramiracetam, however these drugs have multiple modes of action and produce only weak AMPA receptor activation, and it is unclear how significant their ampakine actions are in producing their nootropic effects. More recently developed ampakine compounds are much more potent and selective for the AMPA receptor target.
• the present invention provides a method for treating a disorder of the eye, the method comprising the step of administering to a patient in need of said treatment a compound represented by the formula
• R1 and R2 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, alkynyl, substituted alkynyl, cyano, alkoxy, carboxamido, substituted carboxamido, and if R1 and R2 are alkyl, R1 and R2 may be joined with a bond or ⁇ (CH 2 )m ⁇ to produce a cycloalkyl, R3 and R4 are independently hydrogen, alkyl, hydroxyl, alkoxy, cyano, fluoro, and if R3 and R4 are alkyl, R3 and R4 may be joined with a bond or ⁇ (CH 2 ) m - to produce a cycloalkyl, Q may be absent, hydrogen, alkyl, cycloalkyl, cycloalkenyl, alkoxy, substituted alkoxy, substituted thio, cyano, thionitrile, sulfonamide, substituted sulfonamide,
• Figure 1 shows a dose-dependent facilitation of long-term potentiation in rat visual cortex by the compound, benzo[1 ,2,5]oxadiazol-5-yl-piperidin-1 -yl-methanone.
• the method of the invention comprises administering to a patient a compound
• R1 , R2, R3, R4, R5, R6, R7, L, Q, Z, m and n are as defined above.
• R5 and R6 together form a morpholino ring and L is absent, then neither R1 , nor R2 may be alkynlyl; or in the compounds of the formula when R5 is cyclopropyl, R1 , R2, R3, R4, and R6 may not all be hydrogen, or Q may not be meta-fluorophenyl,
• the above compounds may be used to treat a patient suffering from disorders of the eye.
• To "treat,” as used here, means to deal with medically. It includes, for example, administering one or more of the above compounds to prevent the onset of a disorder, to alleviate its severity, and to prevent its reoccurrence.
• disorders which may be treated with the above compounds include macular edema, dry and wet macular degeneration, choroidal neovascularization, diabetic retinopathy, acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, and diabetic macular edema, uveitis, retinitis, choroiditis, acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot
• retinochoroidopathy syphilis, lyme, tuberculosis, toxoplasmosis, intermediate uveitis (pars planitis), multifocal choroiditis, multiple evanescent white dot syndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-and Harada syndrome; retinal arterial occlusive disease, anterior uveitis, retinal vein occlusion, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat's disease, parafoveal telangiectasis, hemiretinal vein occlusion, papillophlebitis, central retinal artery o
• V1 is one synapse removed from the eye and is essential for decoding, processing and transforming visual inputs originating from the retina.
• Visual disorders mediated by V1 include, but are not limited to, amblyopia, stroke-induced blindness, visual dysfunction in Parkinson's disease and Alzheimer's disease, seizure-induced cortical blindness, induced visual dysfunction, and epileptic blindness.
• the visual cortex integrates visual signals generated by the retina, and proper visual cortical function is necessary for normal vision.
• Amblyopia is defined as poor or indistinct vision by an eye that is physically normal. Amblyopia can be initiated by poor transmission of the visual image to the visual cortex during childhood. Abnormal visual processing may be caused by form deprivation (i.e. cataracts), anisomometropia (different retinal image size, or magnification, in each eye), or suppression resulting from strabismus (misalignment of the eyes).
• a prolonged transmission of poor quality visual images induces in a physiological change within the visual cortex that alters the perception within the visual cortex. Briefly, the visual cortex will "ignore" the poor vision from one eye. Hence amblyopics often lack visual acuity and stereopsis.
• the above compounds may be administered at pharmaceutically effective amounts. Such amounts are normally the minimum dose necessary to achieve the desired therapeutic effect.
• the actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the ophthalmic condition, the age and weight of the patient, the patient's general physical condition, and the route of administration.
• the patient may be given the above compounds orally or by local delivery to the eye.
• Local delivery includes topical delivery, in which an ophthalnnically acceptable formulation is instilled in the eye via an eye dropper or other applicator, delivery by injection into the eye, or delivery by a drug delivery system that is implanted into the eye or eye lid and releases drug over a period of time.
• the above compounds are administered in combination with an ophthalmically- acceptable carrier or vehicle.
• a composition which is ophthalnnically acceptable is formulated such that it can be administered topically to the eye.
• the comfort should be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort.
• the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use.
• an ophthalnnically acceptable liquid should either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
• solutions or medicaments are often prepared using a physiological saline solution as a major vehicle.
• Ophthalmic solutions are often maintained at a comfortable pH with an appropriate buffer system.
• the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
• Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalnnically acceptable. Accordingly, buffers include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
• Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.
• compositions contain solubility enhancing components (SECs) in amounts effective to enhance the solubility of the above compounds at a given pH.
• SECs may be anionic in nature, and can be polymeric in nature.
• the SEC is a cellulose derivative, in another embodiment the SEC is not a cellulose derivative or a cyclodextrin.
• the SEC is used to enhance the solubility of the compound. In other words, in two compositions containing the compound which are identical except for the presence of an effective amount of the SEC, more compound will be dissolved in the composition containing the SEC than the in the composition not containing the SEC.
• the SEC may include a non-ionic or polyanionic component.
• polyanionic component refers to a chemical entity, for example, an ionically charged species, such as an ionically charged polymeric material, which includes multiple discrete anionic charges.
• Non-ionic SECs may include polyvinyl alcohol (PVA), polyvinyl pyrrol idone (povidone), and various gums and other non-ionic agents.
• Useful surfactants include, but are not limited to sorbitan esters, Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, stearates, glyceryl stearate, isopropyl stearate, polyoxyl stearate, propylene glycol stearate, sucrose stearate, polyethylene glycol, polyethylene oxide, polypropylene oxide, polyethylene oxide-polypropylene oxide copolymers, alcohol ethoxylates, alkylphenol ethoxylates, alkyl glycosides, alkyl polyglycosides, fatty alcohols, phospholipids, phosphatidyl chloline, phosphatidyl serine, and the like.
• various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
• a useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
• Compositions may be aqueous solutions or emulsions, or some other acceptable liquid form.
• one or more oils will be used to form the emulsion, and in some instances one or more surfactants and/or emulsion stabilization excipients will be required.
• Suitable oils include, but are not limited to anise oil, castor oil, clove oil, cassia oil, cinnamon oil, almond oil, corn oil, arachis oil, cottonseed oil, safflower oil, maize oil, linseed oil, rapeseed oil, soybean oil, olive oil, caraway oil, rosemary oil, peanut oil, peppermint oil, sunflower oil, eucalyptus oil, sesame oil, and the like.
• composition of the present invention will comprise an effective amount of one or more of the compounds of the above formula.
• the ophthalmic composition may comprise from 0.01 % to 10%, preferably 0.1 to 5%, and most preferably from 0.1 % to 1 %, e.g. 0.2%, by weight, of one or more of the compounds of the above formula.
• LTP long-term potentiation
• the visual cortex is one synapse removed from the eye and integrates visual signals generated by the retina. It is thus essential for decoding, processing and transforming visual inputs originating in the eye, and proper visual cortical function is necessary for normal vision.
• Visual cortex LTP in particular has been demonstrated to have functional consequences on visual evoked responses. It was discovered that the compound produces a marked and dose-dependent enhancement of visual cortex LTP. (See Fig. 1 , which shows a dose-dependent facilitation of LTP in rat visual cortex by the compound.)
• a block of visual cortex was created by removing the frontal 2/3 portion of the brain and the cerebellum.
• Coronal visual cortex slices of 350 ⁇ thick were prepared from young adult (200-300g) male Sprague-Dawley rats using a vibratome (VT 1000 S; Leica). The slices were maintained in an interface recording chamber perfused with preheated ACSF.
• Slices were continuously perfused with this solution at a rate of 1 .00 -1 .50 ml/min while the surface of the slices was exposed to warm, humidified 95%O2 5%CO2 and maintained at 31 ⁇ 1 °C.
• Visual cortex slices were allowed to recover for 1 hr before recording began.
• a single stimulating and recording electrode was placed in layer IV and III, respectively, to generate and record field excitatory postsynaptic potentials (fEPSPs). Pulses were administered at 0.05 Hz using a current that produced a fEPSP that is 50 % of the maximum spike free response.
• An input-output (IO) curve is done to determine the stimulation needed to achieve a stable baseline.
• retina-based visual dysfunctions e.g. glaucoma, dry and wet ARMD, geographic atrophy, optic neuritis, rod dystrophies, cone dystrophies, retinopathy, retinitis pigmentosa and other retinopathies
• retina-based visual dysfunctions e.g. glaucoma, dry and wet ARMD, geographic atrophy, optic neuritis, rod dystrophies, cone dystrophies, retinopathy, retinitis pigmentosa and other retinopathies
• a common final symptom i.e., prolonged dysfunctional signal transmission between eye and visual cortex.

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• 2011
  • 2011-04-12 US US13/085,241 patent/US20110257186A1/en not_active Abandoned
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  • 2011-04-13 AU AU2011239683A patent/AU2011239683A1/en not_active Abandoned
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  • 2011-04-13 WO PCT/US2011/032325 patent/WO2011130411A1/en not_active Ceased
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