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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • 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
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/15—Depsipeptides; Derivatives thereof
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention is directed to compounds which function as histone deacetylase (HDAC) inhibitors for treating persons suffering from acute or chronic degenerative conditions or diseases of the eye.
• HDAC histone deacetylase
• Glaucoma is a family of diseases, each of which is distinguished by a particular characteristic of that disease form.
• Primary open angle glaucoma POAG
• POAG Primary open angle glaucoma
• IOP elevated intraocular pressure
• NVG Normotension glaucoma
• NVG low tension glaucoma
• Other forms of glaucoma include closed angle glaucoma and pigmentary dispersion glaucoma. All these forms of glaucoma are similar in that patients suffer from the continued loss of nerve fiber layer and visual field.
• Drug therapies that both lower IOP and provide additional protection to the retina and optic nerve head have been developed.
• Compounds such as betaxolol and brimonidine have been shown to be neuroprotective in animal models. Both have been suggested to provide neuroprotection in glaucoma by direct penetration to the back of the eye after topical ocular administration.
• Betaxolol's neuroprotection properties are believed to arise from its calcium channel blocking activities and its ability to stimulate the expression of key neuroprotective factors such as CNTF, bFGF, and BDNF.
• Brimonidine is an ⁇ 2 agonist and is believed to stimulate the production of bFGF.
• Age-related macular degeneration is the leading cause of blindness in the elderly, with an incidence of about 20% in adults 65 years of age increasing to 37% in individuals 75 years or older.
• Non-exudative AMD (Dry AMD) is characterized by drusen accumulation and atrophy of rod and cone photoreceptors in the outer retina, retinal pigment epithelium (RPE), Bruch's membrane and choriocapillaris; while exudative AMD leads to choroidal neovascularization (Green and Enger, Ophthalmol, Vol. 100:1519-1535, 1993; Green et al., Ophthalmol, Vol. 92:615-627, 1985; Green and Key, Trans Am Ophthalmol Soc, Vol.
• Retinitis pigmentosa represents a group of hereditary dystrophies characterized by rod degeneration with secondary atrophy of cone photoreceptors and underlying pigment epithelium.
• retinal degenerative diseases such as AMD and RP
• the pathogenesis of retinal degenerative diseases is multifaceted and can be triggered by environmental factors in normal individuals or in those who are genetically predisposed. To date more than 100 genes have been mapped or cloned that may be associated with various outer retinal degenerations.
• Light exposure is an environmental factor that has been identified as a contributing factor to the progression of retinal degenerative disorders such as AMD (Young, Sur Ophthal, Vol. 32:252-269, 1988; Taylor, et al., Arch Ophthal, Vol. 110:99-104, 1992; Cruickshank, et al., Arch Ophthal, Vol. 111 :514-518, 1993).
• Photo-oxidative stress leading to light damage to retinal cells has been shown to be a useful model for studying retinal degenerative diseases for the following reasons: damage is primarily to the photoreceptors and retinal pigment epithelium (RPE) of the outer retina, the same cells that are affected in heredodegenerative diseases (Noell et al., Invest Ophthal Vis Sci, Vol.
• RPE retinal pigment epithelium
• apoptosis is the cell death mechanism by which photoreceptor and RPE cells are lost in dry AMD and RP, as well as following a photo-oxidative induced cell injury (Ge-Zhi et al., Trans AM Ophthal Soc, Vol. 4:411-430, 1996; Abler et al., Res Commun Mol Pathol Pharmacol, Vol. 92:177-189, 1996; Nickells and Zack, Ophthalmic Genet, Vol.
• antioxidants such as ascorbate (Organisciak et al., Invest Ophthal Vis Sci, Vol. 26:1589-1598, 1985), dimethylthiourea (Organisciak et al., Invest Ophthal Vis Sci, Vol. 33:1599-1609, 1992; Lam et al., Arch Ophthal, Vol. 108:1751-1752, 1990), ⁇ -tocopherol (Kozaki et al., Nippon Ganka Gakkai Zasshi, Vol. 98:948-954, 1994) and ⁇ -carotene (Rapp et al., Cur Eye Res, Vol.
• antioxidants such as ascorbate (Organisciak et al., Invest Ophthal Vis Sci, Vol. 26:1589-1598, 1985), dimethylthiourea (Organisciak et al., Invest Ophthal Vis Sci, Vol. 33:1599-1609, 1992; Lam et al., Arch Ophthal, Vol. 108:
• calcium antagonists such as flunarizine (Li et al., Exp Eye Res, Vol. 56:71-78, 1993; Edward et al., Arch Ophthal, Vol. 109:554-622, 1992; Collier et al., Invest Ophthal Vis Sci, Vol. 36:S516); growth factors such as basic-fibroblast growth factor, brain derived nerve factor, ciliary neurotrophic factor, and interleukin-1- ⁇ (LaVail et al., Proc Nat Acad Sci, Vol.
• glucocorticoids such as methylprednisolone (Lam et al., Graefes Arch Clin Exp Ophthal, Vol. 231 :729- 736, 1993) and dexamethasone (Fu et al., Exp Eye Res, Vol. 54:583-594, 1992); iron chelators such as desferrioxamine (Li et al., Cur Eye Res, Vol. 2:133-144, 1991); NMDA-antagonists such as eliprodil and MK-801 (Collier et al., Invest Ophthal Vis Sci, Vol. 40:S159, 1999).
• Histone acetyltransferase/deacetylases are important players in higher order chromatin design and gene transcriptions. Acetylation of histones is associated with a transcriptionally active chromatin state; whereas, deacetylation is correlated with a closed chromatin state which would cause gene repression. It has been shown that HDAC inhibitors can reactivate gene expression and inhibit the growth and survival of tumor cells (Johnstone, Nature Reviews, Drug Discovery, Vol. 1 , April 2002). HDAC inhibitors are now being tested for their usefulness as anticancer agents (e.g.
• HDAC inhibitors have not been suggested for use in treating persons suffering from degenerative conditions or diseases of the eye.
• the present invention is directed to the use of HDAC inhibitors or
• Compounds to treat persons suffering from acute or chronic degenerative conditions or diseases of the eye, particularly: glaucoma, dry AMD; RP and other forms of heredodegenerative retinal disease; retinal detachment and tears; macular pucker; ischemia affecting the outer retina; cellular damage associated with diabetic retinopathy and retinal ischemia; damage associated with laser therapy (grid, focal, and panretinal) including photodynamic therapy (PDT); trauma; surgical (retinal translocation, subretinal surgery, or vitrectomy) or light- induced iatrogenic retinopathy; and preservation of retinal transplants.
• Acute or chronic degenerative conditions or diseases of the eye include, in addition to glaucoma, acute and chronic environmentally induced (trauma, ischemia, photo-oxidative stress) degenerative conditions of the photoreceptors and RPE cells in normal or genetically predisposed individuals.
• laser therapy grid, focal and panretinal
• PDT photodynamic therapy
• thermal or cryotherapy trauma
• surgical surgical translocation, subretinal surgery or vitrectomy
• light induced iatrogenic retinopathy preservation of retinal transplants.
• the Compounds of this invention are administered orally with daily dosage of these Compounds ranging between about 0.001 and about 500 milligrams.
• the preferred total daily dose ranges between about 1 and about 100 milligrams.
• Non-oral administration such as, intravitreal, topical ocular, transdermal patch, subdermal, parenteral, intraocular, subconjunctival, or retrobulbar or subtenon's injection, trans scleral (including iontophoresis), or slow release biodegradable polymers or liposomes may require an adjustment of the total daily dose necessary to provide a therapeutically effective amount of the compound.
• the Compounds can also be delivered in ocular irrigating solutions. Concentrations should range from about 0.001 ⁇ M to about 100 ⁇ M, preferably about 0.01 ⁇ M to about 10 ⁇ M.
• the Compounds can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, intravitreal, or via an implant). They may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, gelling agents, penetration enhancers, buffers, sodium chloride, and water to form aqueous, sterile ophthalmic suspensions or solutions or preformed gels or gels formed in situ.
• Ophthalmic solution formulations may be prepared by dissolving the compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound.
• the ophthalmic solutions may contain a viscosity enhancer, such as, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl-pyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac.
• a viscosity enhancer such as, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl-pyrrolidone, or the like.
• the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum.
• Sterile ophthalmic gel formulations may be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, carbopol-940, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated.
• the Compounds are preferably formulated as topical ophthalmic suspensions or solutions, with a pH of about 4 to 8.
• the Compounds will normally be contained in these formulations in an amount .001% to 5% by weight, but preferably in an amount of .01% to 2% by weight.
• 1 to 2 drops of these formulations would be delivered to the surface of the eye 1 to 4 times per day according to the discretion of a skilled clinician.
• HDAC inhibitors useful according to the present invention include: suberoylanilide hydroxamic acid (SAHA), MS-275, oxamflatin, trichostatin A, depsipeptides, and suberic bishydroxamate (SBHA).
• SAHA suberoylanilide hydroxamic acid
• MS-275 MS-275
• oxamflatin trichostatin A
• depsipeptides trichostatin A
• SBHA suberic bishydroxamate
• the Compounds can also be used in combination with other agents for treating glaucoma, such as, but not limited to, ⁇ -blockers (e.g., timolol, betaxolol, levobetaxolol, carteolol, levobunolol, metipranolol), carbonic anhydrase inhibitors (e.g., brinzolamide, dorzolamide, acetazolamide), oc, antagonists (e.g.
• ⁇ 2 agonists e.g., opraclonidine and brimonidine
• miotics e.g., pilocarpine
• adrenergics epinephrine
• prostaglandin analogues e.g., latanoprost, travoprost, unoprostone, bimatoprost, and compounds set forth in U.S. Patent Nos. 5,889,052; 5,296,504; 5,422,368; 5,688,819; and 5,151 ,444, "hypotensive lipids" (e.g., compounds set forth in 5,352,708), neuroprotectants (e.g., compounds from U.S.
• Patent No. 4,690,931 particularly eliprodil and R-eliprodil, as set forth in a pending application U.S.S.N. 06/203350, and appropriate compounds from W094/13275, such as memantine, and serotonergics (5-HT 2 agonists), such as S-(+)-1-(2-aminopropyl)-indazole-6-ol and other 5-HT 2 agonists.

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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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• Proteomics, Peptides & Aminoacids (AREA)
• Gastroenterology & Hepatology (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2003
  • 2003-10-27 CN CNA2003801029350A patent/CN1711086A/zh active Pending
  • 2003-10-27 AU AU2003286686A patent/AU2003286686B2/en not_active Ceased
  • 2003-10-27 KR KR1020057008066A patent/KR20050074547A/ko not_active Ceased
  • 2003-10-27 BR BR0316163-3A patent/BR0316163A/pt not_active IP Right Cessation
  • 2003-10-27 US US10/694,309 patent/US20040092431A1/en not_active Abandoned
  • 2003-10-27 RU RU2005118108/14A patent/RU2324483C2/ru not_active IP Right Cessation
  • 2003-10-27 CA CA002504226A patent/CA2504226A1/en not_active Abandoned
  • 2003-10-27 MX MXPA05004738A patent/MXPA05004738A/es active IP Right Grant
  • 2003-10-27 EP EP03777895A patent/EP1562592A4/en not_active Withdrawn
  • 2003-10-27 JP JP2004551572A patent/JP2006508120A/ja not_active Withdrawn
  • 2003-10-27 WO PCT/US2003/033873 patent/WO2004043348A2/en not_active Ceased
  • 2003-10-27 US US10/531,747 patent/US20070088045A1/en not_active Abandoned
• 2005
  • 2005-04-21 ZA ZA200503230A patent/ZA200503230B/en unknown

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