WO2009039420A1 - Procédés et compositions pour traiter des maladies oculaires véhiculées par une mort neuronale - Google Patents

Procédés et compositions pour traiter des maladies oculaires véhiculées par une mort neuronale Download PDF

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WO2009039420A1
WO2009039420A1 PCT/US2008/077090 US2008077090W WO2009039420A1 WO 2009039420 A1 WO2009039420 A1 WO 2009039420A1 US 2008077090 W US2008077090 W US 2008077090W WO 2009039420 A1 WO2009039420 A1 WO 2009039420A1
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indole
pyrido
tetrahydro
methyl
dimethyl
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PCT/US2008/077090
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WO2009039420A9 (fr
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David T. Hung
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Medivation Neurology, Inc.
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Publication of WO2009039420A9 publication Critical patent/WO2009039420A9/fr

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    • 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
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin

Definitions

  • the present invention relates to methods and compositions useful for treating, preventing and/or delaying the onset and/or development of neuronal death mediated ocular diseases by administering a hydrogenated pyrido[4,3-b]indole, or a pharmaceutically acceptable salt thereof to an individual.
  • Neurodegenerative diseases are generally characterized by a degeneration of neurons in either the brain or the nervous system of an individual. These diseases can be debilitating, and the damage that they cause is often irreversible. Neuronal death mediated ocular diseases present a major health issue. Certain neuronal death mediated ocular diseases are especially prevalent, such as age-related macular degeneration (ARMD), which is the leading cause of loss of sight and blindness in humans age 60 and older.
  • age-related macular degeneration AMD
  • Various ocular diseases are neuronal death mediated.
  • the disease involves death of photoreceptor cells, which leads to a decrease or loss of vision.
  • the disease involves retinal cell death, which leads to a decrease or loss of vision.
  • the neuronal death mediated ocular disease involves neuron death by apoptosis. Certain particular diseases falling within one or more classes of neuronal death mediated ocular diseases are described in more detailed below.
  • Age-related macular degeneration (ARMD), the most prevalent macular degeneration, is associated with progressive diminution of visual acuity in the central portion of the visual field, changes in color vision, and abnormal dark adaptation and sensitivity.
  • Two principal clinical manifestations of ARMD have been described as the "dry”, or atrophic, form, and the "wet”, or exudative, form.
  • the most significant risk factor for the development of both forms are age and the deposition of drusen, which are abnormal extracellular deposits that accumulate behind the retinal pigment epithelium (RPE). Drusen causes a lateral stretching of the RPE monolayer and physical displacement of the RPE from its immediate vascular supply, the choriocapillaris.
  • ARMD is angiogenesis-mediated and involves choroidal neovascularization growth under the RPE and retina with subsequent hemorrhage.
  • ML Malattia Leventinese
  • ML also termed Doyne's honeycomb choroiditis or dominant drusen
  • ML Malattia Leventinese
  • MM Malattia Leventinese
  • MM also termed Doyne's honeycomb choroiditis or dominant drusen
  • This disease is phenotypically similar to age-related macular degeneration (ARMD).
  • ARMD age-related macular degeneration
  • the occurrence of sub-RPE deposits in ML make it a valuable model for understanding pathways that participate in age-related macular degeneration (ARMD).
  • ARMD Among these are: impaired macrophage recruitment may allow accumulation of C5a and IgG in the eye, which in turn induces vascular endothelial growth factor (VEGF) production by RPE, possibly mediating development of choroidal neovascularization, the primary cause of visual loss in the exudative or wet form of ARMD.
  • VEGF vascular endothelial growth factor
  • RPE retinal pigment epithelium
  • TUNEL terminal deoxynucleotidyl transferase dUTP nick end-labeling
  • Sections were also labeled for Fas, a cell surface receptor that triggers apoptosis in other cell types.
  • Maculas with ARMD had statistically significant increases in TUNEL-positive cells in the inner choroid, retinal pigment epithelium (RPE), photoreceptors, and inner nuclear layers compared with normal retinas.
  • RPE retinal pigment epithelium
  • TUNEL-positive rod and RPE cell nuclei were present near edges of RPE atrophy.
  • Photoreceptors in the maculas of eyes with ARMD were strongly Fas-positive, while normal photoreceptors were only weakly labeled.
  • Glaucoma a group of ocular disorders characterized by degeneration of the optic nerve, is also one of the leading causes of blindness worldwide.
  • One major risk factor for developing glaucoma is family history as several different inherited forms of glaucoma have been described.
  • Glaucoma includes without limitation: primary congenital or infantile glaucoma, primary open angle glaucoma, juvenile-onset primary open angle glaucoma, and adult- or late-onset primary open angle glaucoma (which is the most common form of glaucoma).
  • M.H. Kuehn et al. describe retinal ganglion cell death as it relates to glaucoma.
  • various cellular and molecular mechanisms may lead to apoptotic cell death of retinal ganglion cells in glaucoma. These cellular mechanisms include neurotrophic factor deprivation, ischemia, glial cell activation, glutamate excitotoxicity, and abnormal immune response.
  • Diabetic retinopathy is a form of visual impairment suffered by diabetics. The prevalence of blind diabetics in the population has been reported at about 100 people per million. As described in J. Alistair et al. (J. Clin. Invest. Volume 102, Number 4, August 1998, 783-791), retinal neural cell death occurs early in diabetes and neurodegeneration is an important component of diabetic retinopathy. See also J. Clin Invest. 1998. 102:783-791.
  • Certain neuronal death mediated ocular diseases may involve mechanisms by which pressure increases in the eye, which ultimately kills neurons. For instance, leaky blood vessels (such as may occur upon neovascularization associated with wet ARMD) in the eye can lead to retinal eye bleeding, increased pressure in the eye and eventually cell death.
  • ocular diseases affect the health and well- being of individuals suffering from such diseases, which include ocular diseases such as congenital stationary night blindness (Oguchi disease), childhood onset severe retinal dystrophy, Leber congenital amaurosis, color blindness, Bardet-Biedle syndrome, Usher syndrome, blindness from an optic neuropathy and Leber's hereditary optic neuropathy.
  • Oguchi disease congenital stationary night blindness
  • Leber congenital amaurosis childhood onset severe retinal dystrophy
  • Leber congenital amaurosis color blindness
  • Bardet-Biedle syndrome Bardet-Biedle syndrome
  • Usher syndrome blindness from an optic neuropathy and Leber's hereditary optic neuropathy.
  • carbidine (dicarbine) (cis( ⁇ )-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-lH- pyrido[4,3-b]indole dihydrochloride) is a neuroleptic agent having an antidepressive effect (L. N. Yakhontov, R. G. Glushkov, Synthetic Drugs, ed. by A. G. Natradze, Moscow, “Meditzina” Publishers, 1983, p.
  • gevotroline 8-fluoro-2-(3-(3-pyridyl)propyl)-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole dihydrochloride is an antipsychotic and anxiolytic agent (Abou-Gharbi M., Patel U. R., Webb M. B., Moyer J. A., Ardnee T.
  • Dimebon has been used in medicine as an antiallergic agent (Inventor's Certificate No. 1138164, IP Class A61K 31/47,5, C07 D 209/52, published on Feb. 7, 1985) in Russia for over 20 years.
  • hydrogenated pyrido[4,3-b]indole derivatives such as dimebon
  • have NMDA antagonist properties which make them useful for treating neurodegenerative diseases, such as Alzheimer's disease.
  • hydrogenated pyrido[4,3-b]indole derivatives, such as dimebon are useful as human or veterinary geroprotectors e.g., by delaying the onset and/or development of an age-associated or related manifestation and/or pathology or condition, including disturbance in skin-hair integument, vision disturbance and weight loss.
  • 11/543,529 (U.S. Publication No. 20070117835) and 11/543,341 (U.S. Publication No. 20070117834) disclose hydrogenated pyrido[4,3-b]indole derivatives, such as dimebon, as neuroprotectors for use in treating and/or preventing and/or slowing the progression or onset and/or development of Huntington's disease.
  • WO 2007/087425 published August 2, 2007, describes hydrogenated pyrido[4,3-b]indole derivatives, such as dimebon, for use in treating schizophrenia.
  • neuronal death mediated ocular diseases including but not limited to the particular diseases macular degeneration, glaucoma, retinitis pigmentosa, congenital stationary night blindness (Oguchi disease), childhood onset severe retinal dystrophy, Leber congenital amaurosis, Bardet-Biedle syndrome, Usher syndrome, blindness from an optic neuropathy, Leber's hereditary optic neuropathy, color blindness and Hansen-Larson-Berg syndrome.
  • the therapeutic agents can improve the quality of life for patients with a neuronal death mediated ocular disease.
  • compositions for treating and/or preventing and/or delaying the onset and/or the development of a neuronal death mediated ocular disease using a hydrogenated [4,3-b]indole or pharmaceutically acceptable salt thereof are described.
  • the methods and compositions may comprise the compounds detailed herein, including without limitation the compound dimebon (2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-2,3,4,5- tetrahydro-lH-pyrido[4,3-b]indole dihydrochloride).
  • the present invention provides a method of treating a neuronal death mediated ocular disease in an individual in need thereof by administering to the individual an effective amount of a hydrogenated pyrido[4,3-b]indole or pharmaceutically acceptable salt thereof.
  • the present invention provides a method of preventing or slowing the onset and/or development of a neuronal death mediated ocular disease in an individual who is at risk for developing a neuronal death mediated ocular disease.
  • the present invention provides a method of slowing the progression of a neuronal death mediated ocular disease in an individual who has been diagnosed with a neuronal death mediated ocular disease by administering to the individual an effective amount of a hydrogenated pyrido[4,3-b]indole or pharmaceutically acceptable salt thereof.
  • the hydrogenated pyrido[4,3-b]indole may be dimebon.
  • Any of the methods disclosed herein may be methods for neuronal death mediated ocular diseases, including but not limited to, neuronal death mediated ocular diseases that involve death of photoreceptor cells or involve retinal cell death or involve neuron death by apoptosis.
  • any of the methods disclosed herein may be methods for particular neuronal death mediated ocular diseases including, but not limited to, diseases selected from the group consisting of macular degeneration, glaucoma, retinitis pigmentosa, congenital stationary night blindness (Oguchi disease), childhood onset severe retinal dystrophy, Leber congenital amaurosis, Bardet-Biedle syndrome, Usher syndrome, blindness from an optic neuropathy, Leber's hereditary optic neuropathy, color blindness and Hansen-Larson-Berg syndrome.
  • the methods disclosed herein are methods for the treatment and/or prevention and/or slowing the onset and/or development of macular degeneration.
  • the methods disclosed herein are methods for the treatment and/or prevention and/or slowing the onset and/or development of dry form macular degeneration or Stargardt Macular Degeneration (STGD).
  • STGD Stargardt Macular Degeneration
  • Figure 1 illustrates the minimal toxicity of dimebon in Drosophila (fruit fly).
  • Figure 2 illustrates dimebon' s ability to suppress degeneration of photoreceptor neurons in a Drosophila (fruit fly) model.
  • Figure 3 illustrates the water intake of ELOVL4 mutant mice over 9 weeks, presented as the total per mouse per week.
  • Figure 4 illustrates the photoreceptor cell numbers of low and high dose-treated mice relative to control. Error bars indicate +/- SEM.
  • Figure 5 illustrates the effect of dimebon on ionomycin-induced toxicity of SK-N- SH cells.
  • Figure 6 illustrates the effect of dimebon on ionomycin-induced toxicity of SY- SH5Y cells.
  • Neuron mediated ocular disease intends ocular diseases in which death of the neuron is implicated in whole or in part.
  • the disease may involve death of photoreceptors.
  • the disease may involve retinal cell death.
  • the disease may involve ocular nerve death by apoptosis.
  • Particular neuronal death mediated ocular diseases include, but are not limited to, macular degeneration, glaucoma, retinitis pigmentosa, congenital stationary night blindness (Oguchi disease), childhood onset severe retinal dystrophy, Leber congenital amaurosis, Bardet- Biedle syndrome, Usher syndrome, blindness from an optic neuropathy, Leber's hereditary optic neuropathy, color blindness and Hansen-Larson-Berg syndrome.
  • macular degeneration includes all forms and classifications of macular degeneration known in the art, including, but not limited to, diseases that are characterized by a progressive loss of central vision associated with abnormalities of Bruch's membrane, the choroid, the neural retina and/or the retinal pigment epithelium.
  • the term thus encompasses disorders such as age-related macular degeneration (ARMD) as well as rarer, earlier-onset dystrophies that in some cases can be detected in the first decade of life.
  • AMD age-related macular degeneration
  • Other maculopathies include North Carolina macular dystrophy, Sorsby's fundus dystrophy, Stargardt's disease, pattern dystrophy, Best disease, and Malattia Leventinese.
  • an individual intends a mammal, including, but not limited to, a human.
  • the individual may be a human who has been diagnosed with or is suspected of having a neuronal death mediated ocular disease.
  • the individual may be a human who exhibits one or more symptoms associated with a neuronal death mediated ocular disease.
  • the individual may be a human who is genetically or otherwise predisposed to developing a neuronal death mediated ocular disease.
  • the individual is a human who has not been diagnosed with and/or is not considered at risk for developing Alzheimer's disease, Huntington's disease or schizophrenia.
  • the individual is a human who does not have a cognition impairment associated with aging or does not have a non-life threatening condition associated with the aging process (such as loss of sight (cataract), deterioration of the dermatohairy integument (alopecia) or an age-associated decrease in weight due to the death of muscular and fatty cells) or a combination thereof.
  • a cognition impairment associated with aging such as loss of sight (cataract), deterioration of the dermatohairy integument (alopecia) or an age-associated decrease in weight due to the death of muscular and fatty cells
  • an "at risk” individual is an individual who is at risk of developing a neuronal death mediated ocular disease.
  • An individual “at risk” may or may not have detectable disease, and may or may not have displayed detectable disease prior to the treatment methods described herein.
  • At risk denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a neuronal death mediated ocular disease. An individual having one or more of these risk factors has a higher probability of developing a neuronal death mediated ocular disease than an individual without these risk factor(s).
  • risk factors include, but are not limited to, age, sex, race, diet, history of previous disease, presence of precursor disease, genetic (i.e., hereditary) considerations, and environmental exposure.
  • Individuals at risk for a neuronal death mediated ocular disease include, e.g., those having relatives who have experienced this disease, and those whose risk is determined by analysis of genetic or biochemical markers.
  • treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: decreasing one or more symptoms resulting from the disease, increasing the quality of life, decreasing the dose of one or more other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival.
  • an individual or combination therapy of the invention reduces the severity of one or more symptoms associated with a neuronal death mediated ocular disease by at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95% compared to the corresponding symptom in the same subject prior to treatment or compared to the corresponding symptom in other subjects not receiving the therapy.
  • "delaying" development of a neuronal death mediated ocular disease means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated.
  • a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease.
  • a method that "delays" development of a neuronal death mediated ocular disease is a method that reduces probability of disease development in a given time frame and/or reduces extent of the disease in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects.
  • Neuronal death mediated ocular disease development can be detectable using standard clinical techniques. Development may also refer to disease progression that may be initially undetectable and includes occurrence, recurrence and onset.
  • combination therapy is meant a first therapy that includes one or more hydrogenated pyrido[4,3-b]indoles or pharmaceutically acceptable salts thereof (such as dimebon) in conjunction with a second therapy that includes one or more other compounds (or pharmaceutically acceptable salts thereof ) or therapies (e.g., surgical procedures) useful for treating, preventing and/or delaying the onset and/or development of a neuronal death mediated ocular disease.
  • Administration in "conjunction with” another compound includes administration in the same or different composition, either sequentially, simultaneously, or continuously.
  • the combination therapy includes (i) one or more hydrogenated pyrido[4,3- b] indoles or pharmaceutically acceptable salts thereof, such as dimebon, and (ii) one or more retinoids, agents that destroy the abnormal blood vessels associated with wet age-related macular degeneration, photodynamic therapy systems, anti- vascular endothelial growth factor (VEGF) agents, angiogenesis inhibitors, protein kinase C (PKC) inhibitors, Flt3 (FLK1/STK1) inhibitors, endothelial cell activation, migration and/or proliferation blockers, glucocorticoids, antiinflammatories, anti-pruritics, vasoconstrictive agents, vascular disrupting agents, apoptosis inducers, tubulin polymerization inhibitors, antimitotic agents, antisense inhibitors of c-Raf kinase, ciliary neurotrophic factors (CNTF), anti- VEGF small interfering RNA (siRNA), or
  • the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and/or inert substances.
  • pharmaceutically active compound As used herein, by “pharmaceutically active compound,” “pharmacologically active compound” or “active ingredient” is meant a chemical compound that induces a desired effect, e.g., treating and/or preventing and/or delaying the onset and/or the development of a neuronal death mediated ocular disease.
  • an effective amount intends such amount of a compound (e.g., a component of a combination therapy of the invention such as a compound described by the Formula (1), (2), (A), or (B) or a second therapy described herein) or a combination therapy, which in combination with its parameters of efficacy and toxicity, as well as based on the knowledge of the practicing specialist should be effective in a given therapeutic form.
  • a compound e.g., a component of a combination therapy of the invention such as a compound described by the Formula (1), (2), (A), or (B) or a second therapy described herein
  • a combination therapy which in combination with its parameters of efficacy and toxicity, as well as based on the knowledge of the practicing specialist should be effective in a given therapeutic form.
  • an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
  • the amount of the first therapy, the second therapy, or the combined therapy is an amount sufficient to modulate the amount or activity of one or more of the following: abnormal blood vessels, anti-vascular endothelial growth factor (VEGF), angiogenesis, protein kinase C (PKC), Flt3 (FLK1/STK1), endothelial cells, inflammation, pruritis, vasoconstriction, vasculature, apoptosis, tubulin polymerization, mitosis, c-Raf kinase, ciliary neurotrophic factors (CNTF) or any combination of two or more of the foregoing.
  • VEGF anti-vascular endothelial growth factor
  • PLC protein kinase C
  • Flt3 Flt3 (FLK1/STK1)
  • endothelial cells inflammation, pruritis, vasoconstriction, vasculature, apoptosis, tubulin polymerization, mitosis, c-Raf
  • one or more of these amounts or activities changes by at least or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, 500% or more as compared to the corresponding amount or activity in the same subject prior to treatment or compared to the corresponding activity in other subjects not receiving the individual or combination therapy.
  • Standard methods can be used to measure the magnitude of this effect, such as in vitro assays with purified enzyme, cell-based assays, animal models, or human testing.
  • an effective dosage of a drug, compound or pharmaceutical composition that contains a compound described by the Formula (1) or by Formula (2) or any compound described herein may be achieved in conjunction with another drug, compound or pharmaceutical composition (such as a second therapy described herein).
  • an effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • the compounds in a combination therapy of the invention may be administered sequentially, simultaneously, or continuously using the same or different routes of administration for each compound.
  • an effective amount of a combination therapy includes an amount of the first therapy and an amount of the second therapy that when administered sequentially, simultaneously, or continuously produces a desired outcome.
  • Suitable doses of any of the coadministered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
  • treatment with the combination of the first and second therapies may result in an additive or even synergistic (e.g., greater than additive) result compared to administration of either therapy alone.
  • a lower amount of each pharmaceutically active compound is used as part of a combination therapy compared to the amount generally used for individual therapy.
  • the same or greater therapeutic benefit is achieved using a combination therapy than by using any of the individual compounds alone.
  • the same or greater therapeutic benefit is achieved using a smaller amount (e.g., a lower dose or a less frequent dosing schedule) of a pharmaceutically active compound in a combination therapy than the amount generally used for individual therapy.
  • the use of a smaller amount of pharmaceutically active compound results in a reduction in the number, severity, frequency, or duration of one or more side-effects associated with the compound.
  • a “therapeutically effective amount” refers to an amount of a compound or a combination therapy sufficient to produce a desired therapeutic outcome (e.g., reducing the severity or duration of, stabilizing the severity of, or eliminating one or more symptoms of a neuronal death mediated ocular disease).
  • beneficial or desired results include, e.g., clinical results such as decreasing one or more symptoms resulting from the disease (biochemical, histologic and/or behavioral), including its complications and intermediate pathological phenotypes presenting during development of the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing the effect of another medication, delaying the progression of the disease and/or prolonging survival of patients.
  • a “prophylactically effective amount” refers to an amount of a compound or a combination therapy sufficient to prevent or reduce the severity of one or more future symptoms of a neuronal death mediated ocular disease when administered to an individual who is susceptible and/or who may develop a neuronal death mediated ocular disease.
  • beneficial or desired results include, e.g., results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histologic and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
  • the term "simultaneous administration,” as used herein, means that a first therapy and second therapy in a combination therapy are administered with a time separation of no more than about 15 minutes, such as no more than about any of 10, 5, or 1 minutes.
  • the first and second therapies may be contained in the same composition (e.g., a composition comprising both a hydrogenated pyrido[4,3-b]indole and a second therapy) or in separate compositions (e.g., a hydrogenated pyrido[4,3-b]indole is contained in one composition and a second therapy is contained in another composition).
  • the term "sequential administration” means that the first therapy and second therapy in a combination therapy are administered with a time separation of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, 60 or more minutes. Either the first therapy or the second therapy may be administered first.
  • the first and second therapies are contained in separate compositions, which may be contained in the same or different packages or kits.
  • controlled release refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a "controlled release” formulation, administration does not result in immediate release of the drug into an absorption pool.
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • activator agonist
  • enhancer is meant an individual or combination therapy that increases the amount of, or an activity of, a biologically- active compound or cell.
  • the activator, agonist, or enhancer increases an activity by at least or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, 500% or more as compared to the corresponding activity in the same subject prior to treatment or compared to the corresponding activity in other subjects not receiving the individual or combination therapy.
  • inhibitor an individual or combination therapy that reduces or eliminates the amount of, or an activity of, a biologically- active compound or cell, such as protein kinase C (PKC), Flt3 (FLK1/STK1) and tubulin polymerization.
  • PLC protein kinase C
  • Flt3 Flt3
  • tubulin polymerization a biologically- active compound or cell
  • the inhibitor, antagonist, or blocker reduces an activity by at least or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to the corresponding activity in the same subject prior to treatment or compared to the corresponding activity in other subjects not receiving the individual or combination therapy.
  • module an individual or combination therapy that increases or decreases the amount of, or an activity of, a biologically- active compound or cell, such as retinoids, agents that destroy the abnormal blood vessels associated with wet age-related macular degeneration, photodynamic therapy systems, anti- vascular endothelial growth factor (VEGF) agents, angiogenesis inhibitors, protein kinase C (PKC) inhibitors, Flt3 (FLK1/STK1) inhibitors, endothelial cell activation, migration and/or proliferation blockers, glucocorticoids, antiinflammatories, anti-pruritics, vasoconstrictive agents, vascular disrupting agents, apoptosis inducers, tubulin polymerization inhibitors, antimitotic agents, antisense inhibitors of c-Raf kinase, ciliary neurotrophic factors (CNTF), anti- VEGF small interfering RNA (siRNA), or any combination of two or more of the retinoids, agents that destroy the abnormal blood vessels associated with
  • the compound alters an activity by at least or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, 500% or more as compared to the corresponding activity in the same subject prior to treatment or compared to the corresponding activity in other subjects not receiving the individual or combination therapy.
  • anti-inflammatory agent an individual or combination therapy that reduces or eliminates inflammation.
  • the compound reduces inflammation by at least or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%.
  • the hydrogenated pyrido[4,3-b]indoles described herein may be used to treat, prevent and/or delay the onset and/or the development of a neuronal death mediated ocular disease in mammals, such as humans.
  • the representative hydrogenated pyrido[4,3-b]indole dimebon did not show significant toxicity in a Drosophila model for toxicity at doses below 1 mM. Additionally, dimebon showed a neuroprotective effect in a Drosophila model of Huntington's disease (Example 2).
  • the present invention provides a variety of methods, such as those described in the "Brief Summary of the Invention" and elsewhere in this disclosure.
  • the methods of the invention employ the compounds described herein.
  • the present invention provides a method of treating a neuronal death mediated ocular disease in a patient in need thereof comprising administering to the individual an effective amount of a hydrogenated pyrido[4,3-b]indole, such as dimebon or pharmaceutically acceptable salt thereof.
  • the present invention provides a method of delaying the onset and/or development of a neuronal death mediated ocular disease in an individual who is considered at risk for developing a neuronal death mediated ocular disease ⁇ e.g., an individual whose one or more family members have had genetically implicated neuronal death mediated ocular disease or an individual who has been diagnosed as having a genetic mutation associated with a neuronal death mediated ocular disease) comprising administering to the individual an effective amount of a hydrogenated pyrido[4,3-b]indole, such as dimebon or pharmaceutically acceptable salt thereof.
  • a hydrogenated pyrido[4,3-b]indole such as dimebon or pharmaceutically acceptable salt thereof.
  • the present invention provides a method of delaying the onset and/or development of a neuronal death mediated ocular disease in an individual who is genetically predisposed to developing a neuronal death mediated ocular disease comprising administering to the individual an effective amount of a hydrogenated pyrido[4,3-b]indole, such as dimebon or pharmaceutically acceptable salt thereof.
  • the present invention provides a method of delaying the onset and/or development of a neuronal death mediated ocular disease in an individual having a mutated or abnormal gene associated with a neuronal death mediated ocular disease (such as the ELOVL4 gene) but who has not been diagnosed with a neuronal death mediated ocular disease comprising administering to the individual an effective amount of a hydrogenated pyrido[4,3-b]indole, such as dimebon or pharmaceutically acceptable salt thereof.
  • a mutated or abnormal gene associated with a neuronal death mediated ocular disease such as the ELOVL4 gene
  • the present invention provides a method of preventing a neuronal death mediated ocular disease in an individual who is genetically predisposed to developing a neuronal death mediated ocular disease or who has a mutated or abnormal gene associated with a neuronal death mediated ocular disease but who has not been diagnosed with a neuronal death mediated ocular disease comprising administering to the individual an effective amount of a hydrogenated pyrido[4,3-b]indole, such as dimebon or pharmaceutically acceptable salt thereof.
  • a hydrogenated pyrido[4,3-b]indole such as dimebon or pharmaceutically acceptable salt thereof.
  • the present invention provides a method of preventing the onset and/or development of a neuronal death mediated ocular disease in an individual who is not identified as genetically predisposed to developing a neuronal death mediated ocular disease comprising administering to the individual an effective amount of a hydrogenated pyrido[4,3-b]indole, such as dimebon or pharmaceutically acceptable salt thereof.
  • the present invention provides a method of decreasing the intensity or severity of the symptoms of a neuronal death mediated ocular disease in an individual who is diagnosed with a neuronal death mediated ocular disease comprising administering to the individual an effective amount of a hydrogenated pyrido[4,3-b]indole, such as dimebon or pharmaceutically acceptable salt thereof.
  • the present invention provides a method of enhancing the quality of life of an individual diagnosed with a neuronal death mediated ocular disease comprising administering to the individual an effective amount of a hydrogenated pyrido[4,3-b]indole, such as dimebon or pharmaceutically acceptable salt thereof.
  • the method comprises the manufacture of a medicament for use in any of the above methods, e.g., treating and/or preventing and/or delaying the onset or development of a neuronal death mediated ocular disease, such as macular degeneration in a human.
  • a neuronal death mediated ocular disease such as macular degeneration in a human.
  • alkyl intends and includes linear, branched or cyclic hydrocarbon structures and combinations thereof.
  • Preferred alkyl groups are those having 20 carbon atoms (C20) or fewer. More preferred alkyl groups are those having fewer than 15 or fewer than 10 or fewer than 8 carbon atoms.
  • lower alkyl refers to alkyl groups of from 1 to 5 carbon atoms.
  • lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl and the like.
  • Lower alkyl is a subset of alkyl.
  • aryl refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H- 1,4- benzoxain-3(4H)-one-7-yl), and the like.
  • Preferred aryls includes phenyl and naphthyl.
  • heteroaryl refers to an aromatic carbocyclic group of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring.
  • Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).
  • heteroaryl residues include, e.g., imidazolyl, pyridinyl, indolyl, thiopheneyl, thiazolyl, furanyl, benzimidazolyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrazinyl, tetrazolyl and pyrazolyl.
  • aralkyl refers to a residue in which an aryl moiety is attached to the parent structure via an alkyl residue. Examples are benzyl, phenethyl and the like.
  • heteroarylkyl refers to a residue in which a heteroaryl moiety is attached to the parent structure via an alkyl residue. Examples include furanylmethyl, pyridinylmethyl, pyrimidinylethyl and the like.
  • substituted heteroaralkyl refers to heteroaryl groups which are substituted with from 1 to 3 substituents, such as residues selected from the group consisting of hydroxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aryl, carboxyl, halo, nitro and amino.
  • halo refers to fluoro, chloro, bromo and iodo.
  • Compounds for use in the systems, methods and kits described herein are hydrogenated pyrido[4,3-b]indoles or pharmaceutically acceptable salts thereof, such as an acid or base salt thereof.
  • a hydrogenated pyrido[4,3-b]indole can be a tetrahydro pyrido[4,3-b]indole or pharmaceutically acceptable salt thereof.
  • the hydrogenated pyrido[4,3-b]indole can also be a hexahydro pyrido[4,3-b]indole or pharmaceutically acceptable salt thereof.
  • the hydrogenated pyrido[4,3-b]indole compounds can be substituted with 1 to 3 substituents, although unsubstituted hydrogenated pyrido [4,3 -b] indole compounds or hydrogenated pyrido[4,3- b]indole compounds with more than 3 substituents are also contemplated.
  • Suitable substituents include but are not limited to alkyl, lower alkyl, aralkyl, heteroaralkyl, substituted heteroaralkyl, and halo.
  • R 1 is selected from the group consisting of alkyl, lower alkyl and aralkyl
  • R 2 is selected from the group consisting of hydrogen, aralkyl and substituted heteroaralkyl
  • R 3 is selected from the group consisting of hydrogen, alkyl, lower alkyl and halo.
  • R 1 is alkyl, such as an alkyl selected from the group consisting of
  • Ci-Cisalkyl C 10 -C 15 alkyl, Ci-Cioalkyl, C 2 -C 15 alkyl, C 2 -C 10 alkyl, C 2 -C 8 alkyl, C 4 -C 8 alkyl, C 6 - C 8 alkyl, C 6 -Ci 5 alkyl, Ci 5 -C 2 oalkyl; Ci-C 8 alkyl and Ci-C 6 alkyl.
  • R 1 is aralkyl.
  • R 1 is lower alkyl, such as a lower alkyl selected from the group consisting of Ci-C 2 alkyl, Ci-C 4 alkyl, C 2 -C 4 alkyl, Ci-C 5 alkyl, Ci-C 3 alkyl, and C 2 -C 5 alkyl.
  • R 1 is a straight chain alkyl group. In one variation, R 1 is a branched alkyl group. In one variation, R 1 is a cyclic alkyl group.
  • R 1 is methyl. In one variation, R 1 is ethyl. In one variation, R 1 is methyl or ethyl. In one variation, R 1 is methyl or an aralkyl group such as benzyl. In one variation, R 1 is ethyl or an aralkyl group such as benzyl. [0066] In one variation, R 1 is an aralkyl group.
  • R 1 is an aralkyl group where any one of the alkyl or lower alkyl substituents listed in the preceding paragraphs is further substituted with an aryl group (e.g., Ar-Ci-C ⁇ alkyl, Ar-Ci-C 3 alkyl or Ar-Ci-Cisalkyl).
  • R 1 is an aralkyl group where any one of the alkyl or lower alkyl substituents listed in the preceding paragraphs is substituted with a single ring aryl residue.
  • R 1 is an aralkyl group where any one of the alkyl or lower alkyl substituents listed in the preceding paragraphs is further substituted with a phenyl group (e.g., Ph-Ci-C ⁇ Alkyl or Ph-CpCsAlkyl, Ph-Ci-Ci 5 alkyl). In one variation, R 1 is benzyl.
  • R 2 is H. In one variation, R 2 is an aralkyl group. In one variation,
  • R 2 is a substituted heteroaralkyl group. In one variation, R 2 is hydrogen or an aralkyl group. In one variation, R 2 is hydrogen or a substituted heteroaralkyl group. In one variation, R 2 is an aralkyl group or a substituted heteroaralkyl group. In one variation, R 2 is selected from the group consisting of hydrogen, an aralkyl group and a substituted heteroaralkyl group.
  • R 2 is an aralkyl group where R 2 can be any one of the aralkyl groups noted for R 1 above, the same as if each and every aralkyl variation listed for R 1 is separately and individually listed for R 2 .
  • R 2 is a substituted heteroaralkyl group, where the alkyl moiety of the heteroaralkyl can be any alkyl or lower alkyl group, such as those listed above for R 1 .
  • R 2 is a substituted heteroaralkyl where the heteroaryl group is substituted with 1 to 3 C 1 -C 3 alkyl substituents (e.g., 6-methyl-3-pyridylethyl).
  • R 2 is a substituted heteroaralkyl group wherein the heteroaryl group is substituted with 1 to 3 methyl groups.
  • R 2 is a substituted heteroaralkyl group wherein the heteroaryl group is substituted with one lower alkyl substituent.
  • R is a substituted heteroaralkyl group wherein the heteroaryl group is substituted with one C 1 -C 3 alkyl substituent.
  • R 2 is a substituted heteroaralkyl group wherein the heteroaryl group is substituted with one or two methyl groups.
  • R 2 is a substituted heteroaralkyl group wherein the heteroaryl group is substituted with one methyl group.
  • R is any one of the substituted heteroaralkyl groups in the immediately preceding paragraph where the heteroaryl moiety of the heteroaralkyl group is a single ring heteroaryl group.
  • R 2 is any one of the substituted heteroaralkyl groups in the immediately preceding paragraph where the heteroaryl moiety of the heteroaralkyl group is a multiple condensed ring heteroaryl group. In other variations, R 2 is any one of the substituted heteroaralkyl groups in the immediately preceding paragraph where the heteroaralkyl moiety is a pyridyl group (Py).
  • R 2 is 6-CH 3 -3-Py-(CH 2 ) 2 -.
  • R 3 is hydrogen. In other variations, R 3 is any one of the alkyl groups noted for R 1 above, the same as if each and every alkyl variation listed for R 1 is separately and individually listed for R 3 . In another variation, R 3 is a halo group. In one variation, R 3 is hydrogen or an alkyl group. In one variation, R 3 is a halo or alkyl group. In one variation, R 3 is hydrogen or a halo group. In one variation, R 3 is selected from the group consisting of hydrogen, alkyl and halo. In one variation, R 3 is Br. In one variation, R 3 is I. In one variation, R 3 is F. In one variation, R 3 is Cl.
  • the hydrogenated pyrido[4,3-b]indole is 2,8-dimethyl-5-(2-
  • the hydrogenated pyrido[4,3-b]indoles can be in the form of pharmaceutically acceptable salts thereof, which are readily known to those of skill in the art.
  • the pharmaceutically acceptable salts include pharmaceutically acceptable acid salts. Examples of particular pharmaceutically acceptable salts include hydrochloride salts or dihydrochloride salts.
  • the hydrogenated pyrido[4,3-b]indole is a pharmaceutically acceptable salt of 2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole, such as 2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-2,3,4,5-tetrahydro- lH-pyrido[4,3-b]indole dihydrochloride (dimebon).
  • R 1 represents -CH 3 , CH 3 CH 2 -, or PhCH 2 - (benzyl);
  • R 2 is -H, PhCH 2 -, or 6CH 3 -3-Py-(CH2) 2 -;
  • R 3 is -H, -CH 3 , or -Br
  • any compound herein may be in a form of salts with pharmaceutically acceptable acids and in a form of quaternized derivatives.
  • the compound may be Formula (1), where R 1 is -CH 3 , R 2 is -H, and R 3 is -CH 3 .
  • the compound may be Formula (2), where R 1 is represented by -CH 3 , CH 3 CH 2 -, or PhCH 2 -; R 2 is -H, PhCH 2 -, or 6CH 3 -3-Py-(CH 2 ) 2 -; R 3 is -H, -CH 3 , or -Br.
  • the compound may be Formula (2), where R 1 is CH 3 CH 2 - or PhCH 2 -, R 2 is -H, and R 3 is -H; or a compound, where R 1 is -CH 3 , R 2 is PhCH 2 -, R 3 is -CH 3 ; or a compound, where R 1 is -CH 3 , R 2 is 6-CH 3 -3-Py-(CH 2 ) 2 -, and R 3 is -CH 3 ; or a compound, where R 1 is -CH 3 , R 2 is -H, R 3 is -H or -CH 3 ; or a compound, where R 1 is -CH 3 , R 2 is -H, R 3 is -Br.
  • the compound is of the Formula A or B and R 1 is selected from a lower alkyl or benzyl; R 2 is selected from a hydrogen, benzyl or 6-CH 3 -S-Py-(CHi) 2 - and R 3 is selected from hydrogen, lower alkyl or halo, or any pharmaceutically acceptable salt thereof.
  • R 1 is selected from -CH 3 , CH 3 CH 2 -, or benzyl; R 2 is selected from -H, benzyl, or 6-CH 3 -3-Py-(CH 2 ) 2 -; and R 3 is selected from -H, -CH 3 or -Br, or any pharmaceutically acceptable salt thereof.
  • the compound is selected from the group consisting of: cis( ⁇ ) 2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indole as a racemic mixture or in the substantially pure (+) or substantially pure (-) form; 2-ethyl-2,3,4,5-tetrahydro-lH- pyrido[4,3-b]indole; 2-benzyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole; 2,8-dimethyl-5- benzyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole; 2-methyl-5-(2-methyl-3-pyridyl)ethyl- 2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole; 2,8-dimethyl-5-(2-(6-methyl-3-pyrid
  • the compound is of the Formula A or B wherein R 1 is -CH 3 , R 2 is - H and R 3 is -CH 3 or any pharmaceutically acceptable salt thereof.
  • the compound may be of the Formula A or B where R 1 CH 3 CH 2 - or benzyl, R 2 is -H, and R 3 is -CH 3 or any pharmaceutically acceptable salt thereof.
  • the compound may be of the Formula A or B where R 1 is -CH 3 , R 2 is benzyl, and R 3 is -CH 3 or any pharmaceutically acceptable salt thereof.
  • the compound may be of the Formula A or B where R 1 is -CH 3 , R 2 is 6-CH 3 -3-Py-(CH 2 ) 2 -, and R 3 is -H or any pharmaceutically acceptable salt thereof.
  • the compound may be of the Formula A or B where R 2 is 6-CH 3 -3-Py-(CH 2 ) 2 - or any pharmaceutically acceptable salt thereof.
  • the compound may be of the Formula A or B where R 1 is -CH 3 , R 2 is -H, and R 3 is -H or -CH 3 or any pharmaceutically acceptable salt, thereof.
  • the compound may be of the Formula A or B where R 1 is -CH 3 , R 2 is -H, and R 3 is -Br, or any pharmaceutically acceptable salt thereof.
  • the compound may be of the Formula A or B where R 1 is selected from a lower alkyl or aralkyl, R 2 is selected from a hydrogen, aralkyl or substituted heteroaralkyl and R 3 is selected from hydrogen, lower alkyl or halo.
  • the compound for use in the systems and methods may be 2,8-dimethyl-5-(2-(6- methyl-3-pyridyl)ethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole or any pharmaceutically acceptable salt thereof, such as an acid salt, a hydrochloride salt or a dihydrochloride salt thereof.
  • any of the compounds disclosed herein having two stereocenters in the pyrido[4,3- b]indole ring structure includes compounds whose stereocenters are in a cis or a trans form.
  • a composition may comprise such a compound in substantially pure form, such as a composition of substantially pure S, S or R,R or S,R or R,S compound.
  • a composition of substantially pure compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% impurity of the compound in a different stereochemical form.
  • a composition of substantially pure S, S compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the R,R or S,R or R,S form of the compound.
  • a composition may contain the compound as mixtures of such stereoisomers, where the mixture may be enanteomers (e.g., S, S and R,R) or diastereomers (e.g., S, S and R,S or S,R) in equal or unequal amounts.
  • a composition may contain the compound as a mixture of 2 or 3 or 4 such stereoisomers in any ratio of stereoisomers.
  • the invention also features combination therapies that include a first therapy comprising a hydrogenated pyrido[4,3-b]indole (such as a compound described by the Formula (1), (2), (A) or (B), including dimebon) and a second therapy comprising one or more other compounds (such as a compound or pharmaceutically acceptable salt thereof that is useful for treating, preventing and/or delaying the onset and/or development of a neuronal death mediated ocular disease).
  • a first therapy comprising a hydrogenated pyrido[4,3-b]indole (such as a compound described by the Formula (1), (2), (A) or (B), including dimebon)
  • a second therapy comprising one or more other compounds (such as a compound or pharmaceutically acceptable salt thereof that is useful for treating, preventing and/or delaying the onset and/or development of a neuronal death mediated ocular disease).
  • Exemplary second therapies comprise one or more of the following: retinoids, agents that destroy the abnormal blood vessels associated with wet age-related macular degeneration, photodynamic therapy systems, anti- vascular endothelial growth factor (VEGF) agents, angiogenesis inhibitors, protein kinase C (PKC) inhibitors, Flt3 (FLK1/STK1) inhibitors, endothelial cell activation, migration and/or proliferation blockers, glucocorticoids, antiinflammatories, anti-pruritics, vasoconstrictive agents, vascular disrupting agents, apoptosis inducers, tubulin polymerization inhibitors, antimitotic agents, antisense inhibitors of c-Raf kinase, ciliary neurotrophic factors (CNTF) and anti- VEGF small interfering RNA (siRNA), or any combination of two or more of the foregoing.
  • retinoids agents that destroy the abnormal blood vessels associated with wet age-related macular degeneration
  • VEGF
  • the second therapy includes two or more compounds that each has an activity that the other compound(s) does not have. In some embodiments, the second therapy includes one compound that has two or more different activities.
  • An exemplary retinoid is Fenretinide, a novel synthetic retinoid.
  • Phase II trials and preclinical studies are ongoing at Sirion Therapeutics for the treatment of geographic atrophy in patients with age-related macular degeneration and for the treatment of dry age-related macular degeneration, respectively.
  • PhotrexTM rostaporfin
  • ALD wet age-related macular degeneration
  • PhotrexTM rostaporfin
  • the product candidate is awaiting regulatory approval in the U.S. Fifteen minutes after PhotrexTM is administered, a low-power, non-thermal red light is directed into the eye to activate the drug. Accordingly, it is also an example of a photodynamic therapy.
  • Another exemplary photodynamic therapy system is Laserphyrin®, a next- generation photodynamic therapy system which applies Light Sciences' Light Infusion TechnologyTM (LitxTM), specifically the light-emitting diode (LED)-based light infusion device, to activate the injected drug talaporfin sodium.
  • LitxTM Light Sciences' Light Infusion TechnologyTM
  • LED light-emitting diode
  • Phase I trials had been under way to evaluate the system for the treatment of advanced age-related macular degeneration (AMD), however, the trial was terminated.
  • vascular endothelial growth factor (VEGF) agents are compounds such as pegaptanib sodium (Macugen, OSI/Eyetech) and ranibizumab, bevacizumab, avastin (Lucentis, Genentech).
  • Aflibercept a recombinant fusion protein composed of the second Ig domain of VEGFRl and the third Ig domain of VEGFR2 fused to the Fc region of human IgGl and Des-432-ly sine- [human vascular endothelial growth factor receptor l-(103-204)-peptide (containing Ig-like C2-type 2 domain) fusion protein with human vascular endothelial growth factor receptor 2-(206-308)-peptide (containing Ig-like C2-type 3 domain fragment) fusion protein with human immunoglobulin Gl -(227 C-terminal residues)- peptide (Fc fragment)], (211-2H':214-214')-bisdisulfide dimer.
  • angiogenesis inhibitors are thalidomide, carboxyamidotriazole, midostaurin, squalamine and interferon beta.
  • Midostaurin is a protein kinase C (PKC) and Flt3 (FLK2/STK1) inhibitor.
  • PPC protein kinase C
  • Flt3 Flt3
  • AMD age-related macular degeneration
  • Carboxyamidotriazole is an angiogenesis inhibitor. MacuSight is testing the potential of an extended-release liquid formulation by injection for the treatment of diabetic macular edema and wet age-related macular degeneration (AMD).
  • Squalamine is a novel antiagiogenic aminosterol that directly blocks endothelial cell activation, migration and proliferation by multiple growth factors, including vascular endothelial growth factor (VEGF), cytoskeleton and integrin expression.
  • VEGF vascular endothelial growth factor
  • the compound has been investigated by Genaera, originator of the compound. In 2007, the company discontinued development of the compound for the treatment of choroidal neovascularization associated with age-related macular degeneration (wet AMD) based on difficulty in attaining patient enrollment believed to be the result of market competition from recently introduced products for the treatment of wet AMD.
  • Another exemplary angiogenesis inhibitor is anecortave acetate, developed by Alcon and launched in 2006 in Australia for the treatment of wet age- related macular degeneration (AMD).
  • the drug an angiostatic cortisene derived from the steroid class, is engineered to remove chemical groups responsible for adverse effects, such as the development of cataracts and elevated intraocular pressure leading to glaucoma. It is administered via a blunt-tipped, curved cannula which delivers the drug behind the eye without risk of puncturing the eyeball.
  • MMP matrix metalloproteinase
  • Phase II clinical trials are under way at the company for the treatment of pseudovitellium detachment, glaucoma, and steroid- induced intraocular pressure elevation.
  • Phase I clinical trials are also ongoing for diabetic retinopathy.
  • Early clinical studies are under way for the treatment of chronic central serous chorioretinopathy.
  • An exemplary protein kinase C (PKC) inhibitor is Midostaurin.
  • Flt3 (FLK1/STK1) inhibitor is Midostaurin.
  • An exemplary endothelial cell activation, migration and/or proliferation blocker is squalamine.
  • An exemplary glucocorticoid is fluocinolone acetonide, a glucocorticoid that was launched over 45 years ago for the topical treatment of steroid-responsive dermatoses.
  • the product was commercialized in 2005 by Bausch & Lomb as an intravitreal implant using the company's proprietary Envision TDTM reservoir for the treatment of chronic, non-infectious posterior uveitis.
  • the implant is a tiny polymer shell containing about two milligrams of fluocinolone, placed on the end of a plastic strip. Once the device is secure, a tiny port in the polymer shell slowly releases the drug into the eye for up to three years, reducing retinal inflammation.
  • the product is also available as a cream, ointment and spray solution.
  • the drug is in phase III clinical trials at Alimera and pSivida for the treatment of diabetic macular edema (DME) as an implant formulation called MedidurTM.
  • MedidurTM is small enough to be injected through a needle during an in-office procedure and is expected to provide sustained delivery of fluocinolone to the back of the eye for up to three years.
  • corticosteroids such as fluocinonide
  • corticosteroids are thought to be effective primarily because of their antiinflammatory, anti-pruritic, and vasoconstrictive actions.
  • An exemplary vascular disrupting agent is Combretastatin A-4 phosphate
  • An exemplary antisense inhibitors of c-Raf kinase is ISIS- 13650.
  • INDs have been filed in the U.S. seeking FDA approval to commence clinical evaluation of iCo-007 for the treatment of diabetic retinopathy and age-related macular degeneration (AMD).
  • the drug candidate is an antisense inhibitor of c-Raf kinase, an enzyme associated with the formation of new and often abnormal or fragile blood vessels in the eye.
  • c-Raf kinase is an important part of the signal transduction pathway that is triggered by vascular endothelial growth factor (VEGF) and other growth factors.
  • VEGF vascular endothelial growth factor
  • ciliary neurotrophic factor is ECT-CNTF, an encapsulated cell technology (ECT) product which delivers ciliary neurotrophic factor (CNTF) to the eye.
  • NT-501 is an intraocular polymer implant in phase II clinical trials at Neurotech for the treatment of dry age-related macular degeneration (AMD) and in phase I trials for the treatment of retinitis pigmentosa.
  • the implant consists of a 6 mm long, hollow, semi-permeable fiber membrane with a suture loop at one end to anchor it to the sclera, allowing for ease of retrieval. It contains genetically-modified human cells that continuously secrete ciliary neurotrophic factor (CNTF), a protein that was found in preclinical studies to be effective in retarding vision loss from photoreceptor cell death. This method effectively overcomes the challenge of delivering therapeutic medications directly to the retina as the placement of the implant in the vitreous body allows the CNTF to bypass the blood-retina barrier.
  • CNTF ciliary neurotrophic factor
  • An exemplary anti-VEGF small interfering RNA is bevasiranib, also referred to as Cand5.
  • Cand5 is a vascular endothelial growth factor (VEGF) inhibitor under development for use as intravitreal injections in phase III clinical trials at Opko for the treatment of wet age-related macular degeneration in combination with Lucentis(R). Phase II trials are also under way for the treatment of diabetic macular edema.
  • VEGF vascular endothelial growth factor
  • the VEGF protein is a factor in the development of abnormal blood vessels in eyes with wet AMD.
  • Cand5 reduces the production of VEGF by a newly discovered technology known as RNA Interference. The drug has been shown to reduce VEGF in human retinal pigment epithelial cells and to slow the growth and leakage of abnormal blood vessels in disease models of wet AMD.
  • One or several compounds described herein can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art.
  • a pharmacologically acceptable carrier which are known in the art.
  • the carrier may be in various forms.
  • pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • Preparations comprising the compound, such as dimebon may also contain other substances which have valuable therapeutic properties.
  • Therapeutic forms may be represented by a usual standard dose and may be prepared by a known pharmaceutical method. Suitable formulations can be found, e.g., in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20 th ed. (2000), which is incorporated herein by reference.
  • Formulations comprising a combination therapy of the invention are also included, as are unit dosage forms thereof.
  • a unit dosage form comprising (a) a first therapy comprising a hydrogenated pyrido [4,3 -b] indole or pharmaceutically acceptable salt thereof (such as dimebon), (b) a second therapy comprising another compound or pharmaceutically acceptable salt thereof that is useful for treating, preventing and/or delaying the onset and/or development of a neuronal death mediated ocular disease, either alone or in combination with a hydrogenated pyrido[4,3-b]indole or pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable carrier.
  • a first therapy comprising a hydrogenated pyrido [4,3 -b] indole or pharmaceutically acceptable salt thereof (such as dimebon)
  • a second therapy comprising another compound or pharmaceutically acceptable salt thereof that is useful for treating, preventing and/or delaying the onset and/or development of a neuronal death mediated
  • a compound or combination therapy of the invention may be administered to the individual by any available dosage form.
  • the compound or combination therapy is administered to the individual as a conventional immediate release dosage form.
  • the compound or combination therapy is administered to the individual as a sustained release form or part of a sustained release system, such as a system capable of sustaining the rate of delivery of a compound to an individual for a desired duration, which may be an extended duration such as a duration that is longer than the time required for a corresponding immediate-release dosage form to release the same amount (e.g., by weight or by moles) of compound or combination therapy, and can be hours or days.
  • a desired duration may be at least the drug elimination half life of the administered compound or combination therapy and may be about any of, e.g., at least about 6 hours or at least about 12 hours or at least about 24 hours or at least about 30 hours or at least about 36 hours or at least about 48 hours or at least about 72 hours or at least about 96 hours or at least about 120 hours or at least about 144 or more hours, and can be at least about one week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 8 weeks, or at least about 16 weeks or more.
  • the compound or combination therapy may be formulated for any available delivery route, whether immediate or sustained release, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical or transdermal delivery form.
  • oral, mucosal e.g., nasal, sublingual, vaginal, buccal or rectal
  • parenteral e.g., intramuscular, subcutaneous, or intravenous
  • topical or transdermal delivery form e.g., topical or transdermal delivery form.
  • a compound or combination therapy may be formulated with suitable carriers to provide delivery forms, which may be, but are not required to, be sustained release forms, that include, but are not limited to: tablets, caplets, capsules (such as hard gelatin capsules and soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
  • suitable carriers may be, but are not required to, be sustained release forms, that include, but are not limited to: tablets, caplets, capsules (such as hard gelatin capsules and soft elastic gelatin capsules), cachets, troches, lo
  • the amount of compound, such as dimebon, in a delivery form may be any effective amount, which may be from about 10 ng to about 1,500 mg or more of the single active ingredient compound of a monotherapy or of more than one active ingredient compound of a combination therapy.
  • a delivery form, such as a sustained release system comprises less than about 30 mg of compound.
  • a delivery form, such as a single sustained release system capable of multi-day administration comprises an amount of compound such that the daily dose of compound is less than about 30 mg of compound.
  • a treatment regimen involving a dosage form of compound, whether immediate release or a sustained release system, may involve administering the compound to the individual in dose of between about 0.1 and about 10 mg/kg of body weight, at least once a day and during the period of time required to achieve the therapeutic effect.
  • the daily dose (or other dosage frequency) of a hydrogenated pyrido [4,3 -b] indole as described herein is between about 0.1 and about 8 mg/kg; or between about 0.1 to about 6 mg/kg; or between about 0.1 and about 4 mg/kg; or between about 0.1 and about 2 mg/kg; or between about 0.1 and about 1 mg/kg; or between about 0.5 and about 10 mg/kg; or between about 1 and about 10 mg/kg; or between about 2 and about 10 mg/kg; or between about 4 to about 10 mg/kg; or between about 6 to about 10 mg/kg; or between about 8 to about 10 mg/kg; or between about 0.1 and about 5 mg/kg; or between about 0.1 and about 4 mg/kg; or between about 0.5 and about 5 mg/kg; or between about 1 and about 5 mg/kg; or between about 1 and about 4 mg/kg; or between about 2 and about 4 mg/kg; or between about 1 and about 3 mg/kg; or between about 1.5 and about 3 mg/kg;
  • the compound such as dimebon
  • the compound is administered on a daily or intermittent schedule for the duration of the individual's life.
  • the dosing frequency can be about a once weekly dosing.
  • the dosing frequency can be about a once daily dosing.
  • the dosing frequency can be more than about once weekly dosing.
  • the dosing frequency can be less than three times a day dosing.
  • the dosing frequency can be less than about three times a day.
  • the dosing frequency can be about three times a week dosing.
  • the dosing frequency can be about a four times a week dosing.
  • the dosing frequency can be about a two times a week dosing.
  • the dosing frequency can be more than about once weekly dosing but less than about daily dosing.
  • the dosing frequency can be about a once monthly dosing.
  • the dosing frequency can be about a twice weekly dosing.
  • the dosing frequency can be more than about once monthly dosing but less than about once weekly dosing.
  • the dosing frequency can be intermittent (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more).
  • the dosing frequency can be continuous (e.g., once weekly dosing for continuous weeks). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein, for example, the dosing frequency can be a once daily dosage of less than 0.1 mg/kg or less than about 0.05 mg/kg of dimebon.
  • dimebon is administered in a dose of 5 mg once a day. In one variation, dimebon is administered in a dose of 5 mg twice a day. In one variation, dimebon is administered in a dose of 5 mg three times a day. In one variation, dimebon is administered in a dose of 10 mg once a day. In one variation, dimebon is administered in a dose of 10 mg twice a day. In one variation, dimebon is administered in a dose of 10 mg three times a day. In one variation, dimebon is administered in a dose of 20 mg once a day. In one variation, dimebon is administered in a dose of 20 mg twice a day.
  • dimebon is administered in a dose of 20 mg three times a day. In one variation, dimebon is administered in a dose of 40 mg once a day. I n one variation, dimebon is administered in a dose of 40 mg twice a day. In one variation, dimebon is administered in a dose of 40 mg three times a day.
  • kits comprising one or more compounds as described herein.
  • the kits may employ any of the compounds disclosed herein and instructions for use.
  • the kit employs dimebon.
  • the compound may be formulated in any acceptable form.
  • the kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for any one or more of the stated uses ⁇ e.g., treating and/or preventing and/or delaying the onset and/or the development of a neuronal death mediated ocular disease).
  • Kits generally comprise suitable packaging.
  • the kits may comprise one or more containers comprising any compound described herein.
  • Each component if there is more than one component
  • kits may optionally include a set of instructions, generally written instructions, although electronic storage media ⁇ e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention ⁇ e.g., treating, preventing and/or delaying the onset and/or the development of a neuronal death mediated ocular disease).
  • the instructions included with the kit generally include information as to the components and their administration to an individual.
  • Example 1 Determination of toxicity properties of dimebon.
  • R 1 and R 3 are methyls
  • R 2 is 2-(6-methyl-3-pyridyl)-ethyl
  • Dimebon was evaluated for toxicity levels in wildtype Drosophila fruit flies as described in U.S. Provisional Patent Application No. 60/723,403. Dimebon was administered daily at doses ranging from 10 ⁇ M to 1 mM to explore its toxicity. An untreated control group was also studied in this experiment. The concentrations given were concentrations of dimebon in the food that animals drink/eat ad libitum. The food consisted of cornmeal, dextrose, yeast and agar.
  • Example 2 Determination of dimebon' s ability to inhibit huntingtin-induced neurodegeneration of photoreceptor neurons in Drosophila eyes.
  • dimebon a representative member of a class of compounds disclosed herein, had strikingly positive results in the art- accepted Drosophila model of Huntington's disease, and exhibited enhanced protective effects when compared to a control. This result supports the ability of the hydrogenated pyrido[4,3-b]indoles described herein to inhibit neuronal cell death, which is a characteristic of a neuronal death mediated ocular diseases such as macular degeneration.
  • the Drosophila fruit fly is considered an excellent choice for modeling neurodegenerative diseases because it contains a fully functional nervous system with an architecture that separates specialized functions such as vision, smell, learning and memory in a manner not unlike that of mammalian nervous systems. Furthermore, the compound eye of the fruit fly is made up of hundreds of repeating constellations of specialized neurons which can be directly visualized through a microscope and upon which the ability of potential neuroprotective drugs to directly block neuronal cell death can easily be assessed. Finally, among human genes known to be associated with disease, approximately 75% have a Drosophila fruit fly counterpart.
  • mutant huntingtin protein in Drosophila fruit flies results in a fly phenotype that exhibits some of the features of human Huntington's disease.
  • the presumed etiologic agent in Huntington's disease is encoded by a repeated triplet of nucleotides (CAG) which are called polyglutamine or polyQ repeats.
  • CAG nucleotides
  • the severity of Huntington's disease is correlated with the length of polyQ repeats. The same polyQ length dependency is seen in Drosophila.
  • R 1 and R 3 are methyls
  • R 2 is 2-(6-methyl-3-pyridyl)-ethyl
  • Dimebon was administered to one group of transgenic Drosophila engineered to express the mutant huntingtin protein in all their neurons as described in U.S. Provisional Patent Application No. 60/723,403. This was accomplished by cloning a foreign gene into transposable p-element DNA vectors under control of a yeast upstream activator sequence that was activated by the yeast GAL4 transcription factor. These promoter fusions were injected into fly embryos to produce transgenic animals. The foreign gene is silent until crossed to another transgenic strain of flies expressing the GAL4 gene in a tissue specific manner. The Elav>Gal4 which expresses the transgene in all neurons from birth until death was used in the experiments described.
  • the two types of transgenic animals were crossed in order to collect enough closely matched aged controls to study.
  • the crossed aged-matched adults (20 per dosing group) were placed on drug containing food for 7 days. Animals were transferred to fresh food daily to minimize any effects caused by instability of the compounds. Survival was scored daily. At day 7, animals were sacrificed and the number of photoreceptor neurons surviving was counted. Scoring was by the pseudopupil method where individual functioning photoreceptors were revealed by light focused on the back of the head and visualized as focused points of light under a compound microscope focused at the photoreceptor level of the eye. Dimebon was found to protect photoreceptors in a dose-dependant manner.
  • Example 3 Use of an in vivo model to determine the ability of compounds of the invention to treat, prevent and/or delay the onset and/or the development of a neuronal death mediated ocular disease
  • In vivo models of ocular diseases can be used to determine the ability of any of the hydrogenated pyrido[4,3-b]indoles described herein (e.g., dimebon) or combination therapies to treat and/or prevent and/or delay the onset and/or the development of a neuronal death mediated ocular disease.
  • any of the hydrogenated pyrido[4,3-b]indoles described herein e.g., dimebon
  • combination therapies to treat and/or prevent and/or delay the onset and/or the development of a neuronal death mediated ocular disease.
  • This model involves transgenic mice expressing a mutant form of ELO VL4, which causes the mice to develop significant lipofuscin accumulation by the retinal pigment epithelium (RPE) followed by RPE death and photoreceptor degeneration. While mice apparently do not have maculas (the area within the central retina that is the most acutely involved with visual acuity), this model does cause degeneration and death of retinal cells in the center of the retina, similar to ARMD, and also causes retinal deposits that are very similar to the deposits (drusen) seen in ARMD. This model is believed to closely resemble human dry form macular degeneration and STGD.
  • Histological sectioning and quantification may be by the methods described by G. Karan (Proceedings of the National Academy of Sciences, 2005, 102(11): 4164-4169), such as those involving microscopy.
  • mice from all groups drank similar amounts. Each mouse started off at ⁇ 4 ml/day at 3 weeks of age. By 6-7 weeks of age, each mouse was drinking ⁇ 6 ml/day (-40 ml/week), and this amount remained fairly constant for the remainder of the experiment. The average weight of the mice at 6 weeks old was 21.1 gm (+/- 0.5 s.e.m.) - i.e. approximately as predicted by the experimental design above, so that the actual dose received was ⁇ 2x as designed. [0131] Photoreceptor cell number. Photoreceptor cell death was determined by counting photoreceptor cell number in the central retina, 500 nm dorsal to the optic nerve head. Neither the low or high dose treatment effected a significant rescue over no treatment (Fig. 4). No significant effect of dimebon treatment on the extent of retinal degeneration at 19 weeks of age was found.
  • Example 4 Use of human clinical trials to determine the ability of compounds of the invention to treat, prevent and/or delay the onset and/or the development of a neuronal death mediated ocular disease
  • any of the hydrogenated pyrido[4,3-b]indoles described herein can also be tested in humans to determine the ability of the compound to treat, prevent and/or delay the onset and/or the development of a neuronal death mediated ocular disease. Standard methods can be used for these clinical trials.
  • subjects with a neuronal death mediated ocular disease are enrolled in a tolerability, pharmacokinetics and pharmacodynamics Phase I study of a hydrogenated pyrido[4,3-b]indole using standard protocols. Then a Phase II, double-blind randomized controlled trial is performed to determine the efficacy of the hydrogenated pyrido[4,3-b]indole.
  • dimebon The ability of dimebon to protect human glioblastoma cell lines from the neurotoxicant ionomycin was investigated. The neuroprotective effects of dimebon indicated that the compound has direct and broad neuroprotective properties on cell lines and would be beneficial in the treatment of neuronal death mediated ocular diseases.
  • N-SH cells and SY-SH5Y cells were maintained in EMEM supplemented with 10% FBS, at 37°C, 5% CO 2 .
  • SH-SY5Y cells were maintained in a 1:1 mixture of EMEM and F12 medium, supplemented with 10% FBS at 37°C, 5% CO 2 .
  • Cells were seeded at 3x10 4 cells per well in 96- well plates containing 100 ⁇ l of the required medium. A day after seeding, cells were treated with different concentrations of ionomycin in MEM medium without serum (assay medium) in triplicate for 24 h in a final volume of 100 ⁇ l. Cell viability was determined by the MTS reduction assay as follows. MTS (20 ⁇ l) was added to each well for at least 1 h at 37°C. Absorbance at 490 nm was measured using a microplate reader. Dimebon at various concentrations was used to study the effect on ionomycin-treated cells. Cells were seeded at the same density as previously detailed.
  • the cells were treated for 24 h with a solution containing 1.5 ⁇ M ionomycin and different concentrations of Dimebon in a final volume of 100 ⁇ l. Each experiment was performed in triplicate and the cell viability was determined by the MTS reduction assay. The results were graphed using control cells (incubated with assay medium only) as reference. Percent (%) Viability is the percent of MTS signal for each sample relative to the control (no Dimebon and no ionomycin treatment). Three independent experiments were considered for the statistical analysis. A non- parametric ANOVA followed by a Dunnett Multiple Comparisons Post Test analysis was used. Figures 5 and 6 illustrate the effect of dimebon on ionomycin-induced toxicity of SK-N-SH cells and SY-SH5Y cells, respectively.
  • dimebon The ability of dimebon to protect primary chick neurons from low serum was investigated.
  • the neuroprotective effects of dimebon indicate that the compound has direct and broad neuroprotective properties and would be beneficial in the treatment of neuronal death mediated ocular diseases.
  • tissue covering the telencephalon was removed and hemispheres collected. After removing any loose tissue and remaining meningeal membranes, hemispheres were transferred into a dish containing nutrition medium.
  • the tissue was dissociated mechanically by using a ImI pipette and by squeezing 3 times through a sterile nylon sieve with a pore size of 100 ⁇ m.
  • Low Serum Culture Conditions The low serum medium used for the 2% growth factor withdrawal experiments described here included EMEM with Ig glucose/1 and 2% FCS.
  • the control medium included DMEM with 4.5g glucose/1 and 5% Nu Serum.
  • gentamycin sulphate 0.1 mg/ml nutrition medium was added to DMEM and EMEM.

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Abstract

La présente invention concerne des procédés pour traiter et/ou prévenir et/ou ralentir le départ et/ou le développement d'une maladie oculaire véhiculée par une mort neuronale utilisant des pyrido[4,3-b]indoles hydrogénés, tels que le dimébon.
PCT/US2008/077090 2007-09-21 2008-09-19 Procédés et compositions pour traiter des maladies oculaires véhiculées par une mort neuronale WO2009039420A1 (fr)

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