WO2011071995A2 - Compounds and methods of treating ocular disorders - Google Patents

Compounds and methods of treating ocular disorders Download PDF

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Publication number
WO2011071995A2
WO2011071995A2 PCT/US2010/059426 US2010059426W WO2011071995A2 WO 2011071995 A2 WO2011071995 A2 WO 2011071995A2 US 2010059426 W US2010059426 W US 2010059426W WO 2011071995 A2 WO2011071995 A2 WO 2011071995A2
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Prior art keywords
aminomethyl
methyl
acid
hexanoic acid
phenoxy
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PCT/US2010/059426
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English (en)
French (fr)
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WO2011071995A9 (en
Inventor
Krzysztof Palczewski
Akiko Maeda
Marcin Golczak
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Case Western Reserve University
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Publication date
Application filed by Case Western Reserve University filed Critical Case Western Reserve University
Priority to ES10836598T priority Critical patent/ES2758554T3/es
Priority to CA2783699A priority patent/CA2783699C/en
Priority to AU2010328186A priority patent/AU2010328186B2/en
Priority to JP2012543237A priority patent/JP5815552B2/ja
Priority to EP10836598.2A priority patent/EP2509596B1/en
Publication of WO2011071995A2 publication Critical patent/WO2011071995A2/en
Publication of WO2011071995A9 publication Critical patent/WO2011071995A9/en
Priority to US13/492,193 priority patent/US8722669B2/en
Priority to US14/272,131 priority patent/US20140235604A1/en
Priority to US14/460,108 priority patent/US20140357611A1/en
Priority to US15/634,159 priority patent/US10208049B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/50—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals
    • C07C251/58—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/36—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears

Definitions

  • This application relates to compounds and methods of treating ocular and/or retinal disorders that are associated with aberrant all-irans-retinal clearance in the retina, and more particularly to compounds and methods of treating retinal degeneration and/or retinal disorders using primary amine compounds.
  • the retinoid (visual) cycle is a complex enzymatic pathway essential for regeneration of the visual chromophore, 1 l-cis- retinal, a component of rhodopsin and cone opsins that undergoes activation by light in vertebrate eyes. Maintaining continuous vision and preserving the health of photoreceptors requires an adequate continuing supply of this aldehyde so vertebrates evolved the retinoid cycle to achieve this objective.
  • the pathway operates in both photoreceptor cells and the retinal pigmented epithelium (RPE), converting all-irans-retinal back to l l-cis -retinal by several chemical iransformations.
  • RPE65-based chromophore production may also be important for cone function.
  • chromophore, ll-cis -retinal can adversely affect vertebrate rhodopsin regeneration and visual congenital or progressive blindness in humans.
  • Inactivation of non-redundant enzymes of the retinoid cycle e.g., either LRAT that esterifies all-irans-retinol or the retinoid isomerase called RPE65, produces Leber congenital amaurosis (LCA), a leading cause of inherited childhood blindness.
  • LCA is an autosomal recessive, early onset severe retinal dystrophy that accounts for 5% of all inherited retinal dystrophies. Insufficient vitamin A in the diet also can lead to progressive deterioration of vision and ultimately blindness, a major problem in underdeveloped countries.
  • RDH8 retinol dehydrogenase 8
  • ABCA4 also known as ABCR or the rim protein, localizes to the rim of photoreceptor discs and transfers all-irans-retinal from the inside to the outside of disc membranes after it is released from visual pigments. Mutations in ABCA4 can cause
  • A2E and RALdi conjugates are the major fluorophores of lipofuscins produced from all-irans-retinal. Even in the presence of a functional transporter, both A2E and RALdi can accumulate as a consequence of aging together with light exposure and produce toxic effects on RPE cells. Patients affected by age- related macular degeneration, Stargardt disease with a disabled ABCA4 gene or other retinal diseases associated with lipofuscin accumulation develop retinal degeneration. ABCA4 mutations also are linked to a high risk of AMD.
  • This application relates to compounds and methods of treating an ocular disorder in a subject associated with aberrant all-irans-retinal clearance in the retina.
  • the ocular disorder can include, for example, retinal disorders, such as retinal degeneration, macular degeneration, including age-related macular degeneration, Stargardt disease, and retinitis pigmentosa.
  • the method of treating the ocular disorder in a subject can include administering to the subject a therapeutically effective amount of a primary amine compound of formula:
  • Ri is an aliphatic and/or aromatic compound.
  • the primary amine compound upon administration to the subject forms a reversible Schiff-base with the all- irans-retinal without adversely affecting normal retinoid cycle performance.
  • the primary amine compound when administered to a Rd 1 ' Abca4 ' mouse increases the optical coherence tomography score of the mouse, which reflects severity in retinal morphology, to at least about 2.5 and increases ll-cis -retinal amount at least about 30% in comparison to untreated control animal.
  • the primary amine compound is not a local anesthetic, which includes an aromatic amine that demonstrates sodium channel blockade when administered to the subject.
  • the primary amine compound does not inhibit RPE65 enzymatic activity or any other proteins involved in retinoid metabolism in the eye of the subject.
  • the primary amine compounds can reduce the formation of A2E and/or retinal dimer in the subject's retina and promote 11-ds-retinal production in the subject.
  • the primary amine compound does not induce night blindness.
  • the primary amine compound can have a molecular weight less than about 500 and be delivered to the subject by at least one of topical administration, systemic administration, intravitreal injection, and/or intraocular delivery.
  • the primary amine can be provided in an ocular preparation for sustained delivery.
  • Fig. 1 is a schematic illustration of the visual cycle.
  • Fig. 2 is a schematic illustration of retinoid flow and all-irans-retinal clearance in the visual cycle.
  • Figs. 3A-B illustrate UV/Vis spectra for active and inactive primary amine compounds in accordance with an aspect of the application.
  • Figs. 4A-B illustrate UV/Vis spectra for active and inactive primary amine compounds in accordance with an aspect of the application.
  • Fig. 5 illustrates UV/Vis spectra for an active primary amine compound in accordance with an aspect of the invention.
  • Fig. 6 illustrates a chromatogram of HPLC separation of retinoids.
  • Fig. 7 illustrates a MS/MS spectrum of ritinyl imine fragments in eyes of mice.
  • FIG. 8 illustrates SD-OCT images of retinas from WT and Rdh8 ⁇ Abca4 ⁇ mice.
  • Fig. 9 illustrates OCT images showing grading of retinas.
  • isomerism refers to compounds that have identical molecular formulae but that differ in the nature or the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereoisomers”, and stereoisomers that are non-superimposable mirror images are termed “enantiomers”, or sometimes optical isomers. A carbon atom bonded to four nonidentical substituents is termed a "chiral center".
  • chiral isomer refers to a compound with at least one chiral center. It has two enantiomeric forms of opposite chirality and may exist either as an individual enantiomer or as a mixture of enantiomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture”. A compound that has more than one chiral center has 2n-l enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture".
  • a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center.
  • Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • the substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al, Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J., Chem. Educ. 1964, 41, 116).
  • geometric isomers refer to the diastereomers that owe their existence to hindered rotation about double bonds. These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold- Prelog rules.
  • atropic isomers are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.
  • crystal polymorphs or “polymorphs” or “crystal forms” means crystal structures in which a compound (or salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions.
  • derivative refers to compounds that have a common core structure, and are substituted with various groups as described herein.
  • all of the compounds represented by formula I are primary amines and have formula I as a common core.
  • bioisostere refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms.
  • the objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound.
  • the bioisosteric replacement may be physicochemically or topologically based.
  • Examples of carboxylic acid bioisosteres include acyl sulfonimides, tetrazoles, sulfonates, and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147- 3176 (1996).
  • parenteral administration and “administered parenterally” refer to modes of administration other than enteral and topical administration, such as injections, and include, without limitation, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
  • treating refers to inhibiting a disease, disorder or condition in a subject, e.g., impeding its progress; and relieving the disease, disorder or condition, e.g. , causing regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected.
  • preventing refers to stopping a disease, disorder or condition from occurring in a subject, which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it. Preventing a condition related to a disease includes stopping the condition from occurring after the disease has been diagnosed but before the condition has been diagnosed.
  • a pharmaceutical composition refers to a formulation containing the disclosed compounds in a form suitable for administration to a subject.
  • the pharmaceutical composition can be in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial.
  • the quantity of active ingredient (e.g., a formulation of the disclosed compound or salts thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient.
  • the dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
  • flash dose refers to compound formulations that are rapidly dispersing dosage forms.
  • immediate release refers to a release of compound from a dosage form in a relatively brief period of time, generally up to about 60 minutes.
  • modified release is defined to include delayed release, extended release, and pulsed release.
  • pulsed release is defined as a series of releases of drug from a dosage form.
  • sustained release or extended release is defined as continuous release of a compound from a dosage form over a prolonged period.
  • compositions, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier refers to pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically acceptable carrier is non-pyrogenic.
  • materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alg
  • phrases "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • the salt can be an acid addition salt.
  • an acid addition salt is a hydrochloride salt
  • the pharmaceutically acceptable salts can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods.
  • salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of salts are found in Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990).
  • salts can include, but are not limited to, the hydrochloride and acetate salts of the aliphatic amine-containing, hydroxyl amine-containing, and imine-containing compounds of the present invention.
  • all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.
  • esters for example pharmaceutically acceptable esters.
  • a carboxylic acid function group in a compound can be converted to its corresponding ester, e.g., a methyl, ethyl, or other ester.
  • an alcohol group in a compound can be converted to its corresponding ester, e.g., an acetate, propionate, or other ester.
  • the compounds described herein can also be prepared as prodrugs, for example pharmaceutically acceptable prodrugs.
  • pro-drug and “prodrug” are used interchangeably herein and refer to any compound, which releases an active parent drug in vivo. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention can be delivered in prodrug form. Thus, the present application is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers that release an active parent drug in vivo when such prodrug is administered to a subject.
  • Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include compounds described herein wherein a hydroxy, amino, sulfhydryl, carboxy, or carbonyl group is bonded to any group that may be cleaved in vivo to form a free hydroxyl, free amino, free sulftydryl, free carboxy or free carbonyl group, respectively.
  • prodrugs include, but are not limited to, esters (e.g., acetate, dialkylaminoacetates, formates, phosphates, sulfates, and benzoate derivatives) and carbamates (e.g., ⁇ , ⁇ -dimethylaminocarbonyl) of hydroxy functional groups, ester groups (e.g., ethyl esters, morpholinoethanol esters) of carboxyl functional groups, N-acyl derivatives (e.g., N-acetyl) N-Mannich bases, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups in compounds of Formula I, and the like (e.g., Bundegaard, H.
  • esters e.g., acetate, dialkylaminoacetates, formates, phosphates, sulfates, and benzoate derivatives
  • protecting group refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found in Green and Wuts, Protective Groups in Organic Chemistry, (Wiley, 2 nd ed. 1991); Harrison and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996); and Kocienski, Protecting Groups, (Verlag, 3 rd ed. 2003).
  • amine protecting group refers to a functional group that converts an amine, amide, or other nitrogen-containing moiety into a different chemical group that is substantially inert to the conditions of a particular chemical reaction. Amine protecting groups can be removed easily and selectively in good yield under conditions that do not affect other functional groups of the molecule.
  • amine protecting groups include, but are not limited to, formyl, acetyl, benzyl, t-butyldimethylsilyl, t-butdyldiphenylsilyl, t-butyloxycarbonyl (Boc), p-methoxybenzyl, methoxymethyl, tosyl, trifluoroacetyl, trimethylsilyl (TMS), fluorenyl-methyloxycarbonyl, 2-trimethylsilyl-ethyoxycarbonyl,
  • FMOC 9-fluorenylmethyloxycarbonyl
  • NVOC nitro-veratryloxycarbonyl
  • Other amine protecting groups can be identified by those of skill in the art.
  • Representative hydroxy protecting groups include those where the hydroxy group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.
  • the salts of the compounds described herein can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • Nonlimiting examples of hydrates include monohydrates, dihydrates, etc.
  • Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.
  • solvates refers to solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as 3 ⁇ 40, such combination being able to form one or more hydrate.
  • the compounds, salts and prodrugs described herein can exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the present invention.
  • Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present application includes all tautomers of the present compounds.
  • a tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This reaction results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds.
  • tautomerism In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism.
  • keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.
  • Tautomerizations can be catalyzed by: Base: 1. deprotonation; 2. formation of a delocalized anion (e.g. an enolate); 3. protonation at a different position of the anion; Acid: 1. protonation; 2. formation of a delocalized cation; 3. deprotonation at a different position adjacent to the cation.
  • Base 1. deprotonation; 2. formation of a delocalized anion (e.g. an enolate); 3. protonation at a different position of the anion
  • Acid 1. protonation; 2. formation of a delocalized cation; 3. deprotonation at a different position adjacent to the cation.
  • analog refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group).
  • an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
  • a "patient,” “subject,” or “host” to be treated by the subject method may mean either a human or non-human animal, such as primates, mammals, and vertebrates.
  • prophylactic or therapeutic treatment refers to administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • the unwanted condition e.g., disease or other unwanted state of the host animal
  • therapeutic agent refers to molecules and other agents that are biologically, physiologically, or
  • pharmacologically active substances that act locally or systemically in a patient or subject to treat a disease or condition, such as retinal degeneration or other forms of retinal disease whose etiology involves aberrant clearance of all irans-retinal.
  • the terms include without limitation pharmaceutically acceptable salts thereof and prodrugs.
  • Such agents may be acidic, basic, or salts; they may be neutral molecules, polar molecules, or molecular complexes capable of hydrogen bonding; they may be prodrugs in the form of ethers, esters, amides and the like that are biologically activated when administered into a patient or subject.
  • terapéuticaally effective amount is an art-recognized term.
  • the term refers to an amount of a therapeutic agent that, when incorporated into a polymer, produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the term refers to that amount necessary or sufficient to eliminate, reduce or maintain a target of a particular therapeutic regimen.
  • the effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular compound without necessitating undue experimentation.
  • a therapeutically effective amount of a therapeutic agent for in vivo use will likely depend on a number of factors, including: the rate of release of an agent from a polymer matrix, which will depend in part on the chemical and physical characteristics of the polymer; the identity of the agent; the mode and method of administration; and any other materials incorporated in the polymer matrix in addition to the agent.
  • the term "ED50” refer to the dose of a drug, which produces 50% of its maximum response or effect, or alternatively, the dose, which produces a pre-determined response in 50% of test subjects or preparations.
  • the term “LD50” refers to the dose of a drug, which is lethal in 50% of test subjects.
  • therapeutic index refers to the therapeutic index of a drug, defined as LD50/ED50.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include C-13 and C-14.
  • Ci-6 a subscripted numeric range
  • the invention is meant to encompass each number within the range as well as all intermediate ranges.
  • Ci_ 6 alkyl is meant to include alkyl groups with 1, 2, 3, 4, 5, 6, 1-6, 1-5, 1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6 carbons.
  • alkyl is intended to include both branched (e.g., isopropyl, tert-butyl, isobutyl), straight-chain e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), and cycloalkyl (e.g., alicyclic) groups (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • branched e.g., isopropyl, tert-butyl, isobutyl
  • straight-chain e.g., methyl, ethyl, propyl, butyl, pentyl, hexy
  • Ci_6 alkyl is intended to include Ci, C 2 , C3, C 4 , C5, and C 6 alkyl groups.
  • lower alkyl refers to alkyl groups having from 1 to 6 carbon atoms in the backbone of the carbon chain.
  • Alkyl further includes alkyl groups that have oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbon atoms.
  • a straight chain or branched chain alkyl has six or fewer carbon atoms in its backbone (e.g., Ci-C 6 for straight chain, C3-C6 for branched chain), for example four or fewer.
  • certain cycloalkyls have from three to eight carbon atoms in their ring structure, such as five or six carbons in the ring structure.
  • substituted alkyls refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and
  • alkylarylamino acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
  • Cycloalkyls can be further substituted, e.g., with the substituents described above.
  • An "alkylaryl" or an “aralkyl” moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
  • alkenyl is intended to include hydrocarbon chains of either straight or branched configuration having one or more carbon-carbon double bonds occurring at any stable point along the chain.
  • C 2 _ 6 alkenyl is intended to include C 2 , C 3 , C 4 , C 5 , and C 6 alkenyl groups.
  • alkenyl include, but are not limited to, ethenyl and propenyl.
  • alkynyl is intended to include hydrocarbon chains of either straight or branched configuration having one or more carbon-carbon triple bonds occurring at any stable point along the chain.
  • C 2 -6 alkynyl is intended to include C 2 , C 3 , C 4 , C 5 , and C 6 alkynyl groups.
  • alkynyl include, but are not limited to, ethynyl and propynyl.
  • alkyl alkenyl
  • alkynyl moieties which are diradicals, i.e. , having two points of attachment.
  • a nonlimiting example of such an alkyl moiety that is a diradical is— CH 2 CH 2 — , i.e., a C 2 alkyl group that is covalently bonded via each terminal carbon atom to the remainder of the molecule.
  • Aryl includes groups with aromaticity, including 5- and 6-membered
  • unconjugated or single-ring, aromatic groups that may include from zero to four heteroatoms, as well as “conjugated”, or multicyclic, systems with at least one aromatic ring.
  • aryl groups include benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • aryl includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine.
  • aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles", “heterocycles,” “heteroaryls” or “heteroaromatics”.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diaryl amino, and al kylaryl amino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urei
  • Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl).
  • heterocyclyl or “heterocyclic group” include closed ring structures, e.g. , 3- to 10-, or 4- to 7-membered rings, which include one or more heteroatoms.
  • Heteroatom includes atoms of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur and phosphorus.
  • Heterocyclyl groups can be saturated or unsaturated and include pyrrolidine, oxolane, thiolane, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, and sultones.
  • Heterocyclic groups such as pyrrole and furan can have aromatic character. They include fused ring structures such as quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine.
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamo
  • Heterocyclic groups can also be substituted at one or more constituent atoms with, for example, a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, a hydroxyl,— CF 3 , or— CN, or the like.
  • halo or halogen refers to fluoro, chloro, bromo, and iodo.
  • Counterion is used to represent a small, negatively charged species such as fluoride, chloride, bromide, iodide, hydroxide, acetate, and sulfate.
  • Stable compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation, and as appropriate, purification from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • Free compound is used herein to describe a compound in the unbound state.
  • Extinction coefficient is a constant used in the Beer-Lambert Law which relates the concentration of the substance being measured (in moles) to the absorbance of the substance in solution (how well the substance in solution blocks light beamed through it from getting out on the other side). It is an indicator of how much light a compound absorbs at a particular wavelength.
  • compositions are described as having, including, or comprising, specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components.
  • methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps.
  • order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
  • Small molecule refers to a molecule, which has a molecular weight of less than about 2000 amu, or less than about 1000 amu, and even less than about 500 amu. [0079] All percentages and ratios used herein, unless otherwise indicated, are by weight.
  • the term "retina” refers to a region of the central nervous system with approximately 150 million neurons. It is located at the back of the eye where it rests upon a specialized epithelial tissue called retinal pigment epithelium or RPE.
  • the retina initiates the first stage of visual processing by transducing visual stimuli in specialized neurons called "photoreceptors". Their synaptic outputs are processed by elaborate neural networks in the retina and then transmitted to the brain.
  • the retina has evolved two specialized classes of photoreceptors to operate under a wide range of light conditions. "Rod” photoreceptors transduce visual images under low light conditions and mediate achromatic vision. "Cone” photoreceptors transduce visual images in dim to bright light conditions and mediate both color vision and high acuity vision.
  • Every photoreceptor is compartmentalized into two regions called the "outer” and “inner” segment.
  • the inner segment is the neuronal cell body containing the cell nucleus. The inner segment survives for a lifetime in the absence of retinal disease.
  • the outer segment is the region where the light sensitive visual pigment molecules are concentrated in a dense array of stacked membrane structures. Part of the outer segment is routinely shed and regrown in a diurnal process called outer segment renewal. Shed outer segments are ingested and metabolized by RPE cells.
  • the term "macula” refers to the central region of the retina, which contains the fovea where visual images are processed by long slender cones in high spatial detail (“visual acuity”).
  • "Macular degeneration” is a form of retinal neurodegeneration, which attacks the macula and destroys high acuity vision in the center of the visual field.
  • AMD can be in a "dry form” characterized by residual lysosomal granules called lipofuscin in RPE cells, and by extracellular deposits called “drusen”. Drusen contain cellular waste products excreted by RPE cells.
  • Lipofuscin” and drusen can be detected clinically by ophthalmologists and quantified using fluorescence techniques. They can be the first clinical signs of macular degeneration.
  • Lipfuscin contains aggregations of A2E. Lipofuscin accumulates in RPE cells and poisons them by multiple known mechanisms. As RPE cells become poisoned, their biochemical activities decline and photoreceptors begin to degenerate. Extracellular drusen may further compromise RPE cells by interfering with their supply of vascular nutrients. Drusen also trigger inflammatory processes, which leads to choroidal neovascular invasions of the macula in one patient in ten who progresses to wet form AMD. Both the dry form and wet form progress to blindness.
  • ERG is an acronym for electroretinogram, which is the measurement of the electric field potential emitted by retinal neurons during their response to an experimentally defined light stimulus.
  • ERG is a non- invasive measurement, which can be performed on either living subjects (human or animal) or a hemisected eye in solution that has been removed surgically from a living animal.
  • RAL retinaldehyde.
  • Free RAL is defined as RAL that is not bound to a visual cycle protein.
  • irans-RAL and “all-irans-RAL” are used interchangeably and mean all-irans-retinaldehyde.
  • An embodiment of the application relates to compounds and methods of treating an ocular disorder in a subject associated with aberrant all-irans-retinal clearance in the retina.
  • the ocular disorder can include, for example, retinal disorders, such as macular degeneration, including age-related macular degeneration, Stargardt disease, and retinitis pigmentosa.
  • Figs. 1 and 2 show the retinoid flow in the visual cycle including condensation of all-irans-RAL, and all-irans-RAL clearance.
  • the resulting visual chromophore ll-ds-retinylidene is photoisomerized to all- irans-retinylidene, the precursor or all-irans-RAL that is later released.
  • Most of the & ⁇ -trans- RAL dissociates from opsin into the cytoplasm before it is reduced to all-irans-retinol by RDHs including RDH8.
  • the fraction of all-irans-RAL that dissociates into disc lumens is transported by ABCA4 before is it is reduced. Thus, condensation products can be generated both within the disc lumens and the cytoplasm before it is reduced.
  • compounds used to treat an ocular disorder associated with aberrant all-irans-RAL clearance can include primary amines (i. e. , primary amine compounds) that form reversible Schiff-bases with free all-irans-RAL, which has escaped sequestering in photoreceptor outer segments of the retina without adversely affecting normal retinoid cycle.
  • Primary amines i. e. , primary amine compounds
  • Formation of a reversible Schiff base between RAL and the primary amine compounds described herein can control or modulate all-irans-RAL levels in the retina and prevent retina degeneration.
  • the stability of the Schiff-bases formed between the primary amine compounds and the free RAL under physiologic conditions of the retina can be used to determine the efficacy of these compounds in treating the ocular disorder.
  • the stability of the Schiff-bases formed from the primary amine compounds should be such that the level of free RAL in the retina is reduced to a level that is effective to mitigate retinal degeneration but not impair the normal retinoid cycle.
  • the primary amine compounds that can form stable Schiff-bases with all-irans-RAL under physiological conditions of the retina and that can inhibit retinal degeneration upon administration to a subject can be selected using an in vitro assay that measures the ability of a primary amine compound to form a Schiff base with retinal under physiological condition of the retina and in vivo assays that measure, respectively, 11-c/s-retinal formation and the optical coherence tomography score of retinas mice.
  • the primary amine compound can include the structural formula (I):
  • Ri is an aliphatic and/or aromatic compound.
  • Primary amine compounds having formula I that are used to treat retinal degeneration in accordance with an embodiment of the application can upon administration to the subject form a reversible Schiff-base with the all-irans-RAL without adversely affecting normal retinoid cycle performance and when administered to a Rd 1 ' Abca4 ' mouse increase the optical coherence tomography score of the mouse to at least about 2.5 and increase l l-cis -retinal amount at least about 30% in comparison to untreated control animal.
  • Primary amine compounds in accordance with the application do not include and are not a local anesthetic, which includes an aromatic amine that demonstrates sodium channel blockade when administered to the subject.
  • the primary amine compounds in accordance with the application do not inhibit RPE65 enzymatic activity or any other proteins involved in retinoid metabolism in the eye of the subject.
  • the primary amine compounds can reduce the formation of A2E and/or retinal dimer in the subject's retina, promote 11-ds-retinal production in the subject, and does not cause night blindness.
  • primary compounds having formula I that upon administration to a subject form a reversible Schiff-base with the all-irans-RAL without adversely affecting normal retinoid cycle performance and that when administered to a Rdh8 Abca4 mouse increase the optical coherence tomography score of the mouse to at least about 2.5 and increase ll-cis -retinal amount at least about 30% in comparison to untreated control animal can be selected using the methods described in the Examples from known primary amine compounds.
  • the primary amine compounds can include known primary amine compounds having the following structural formulas:
  • R 2 is hydrogen or (Ci-Ce) straight chain or branched unsubstituted or substituted alkyl
  • R 3 is straight or branched unsubstituted or substituted alkyl of from 1 to 8 carbon atoms, straight or branched alkenyl of from 2 to 8 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, alkoxy of from 1 to 6 carbon atoms, -alkylcycloalkyl, -alkylalkoxy, -alkyl, OH, -alkylphenyl, -alkylphenoxy, -phenyl or substituted phenyl;
  • R4 is hydrogen or (Ci-Ce) straight chain or branched unsubstituted or substituted alkyl, or carboxyl;
  • Ar is phenyl which is unsubstituted or substituted with 1-5 of R7, wherein R7 is independently selected from the group consisting of:
  • Ci-6 alkyl which is linear or branched and is unsubstituted or substituted with 1-5 halogens
  • X is selected from the group consisting of:
  • R5 and R 6 are independently selected from the group consisting of:
  • Ci-10 alkyl which is linear or branched and which is unsubstituted or substituted with 1-5 halogens or phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, Rs, ORs, NHS0 2 Rs, S0 2 Rs, C0 2 H, and C0 2 Ci_6 alkyl, wherein the C0 2 Ci_6 alkyl is linear or branched, (4) phenyl which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R 8 , OR 8 , NHS0 2 R 8 , S0 2 R 8 , C0 2 H, and C0 2 Ci-6 alkyl, wherein the C0 2 Ci_6 alkyl is linear or branched, and
  • a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising 1-4 heteroatoms independently selected from N, S and O, the heterocycle being unsubstituted or substituted with 1-3 substituents independently selected from oxo, OH, halogen, Ci_6 alkyl, and OCi_6 alkyl, wherein the Ci_6 alkyl and OCi_6 alkyl are linear or branched and optionally substituted with 1-5 halogens;
  • R 8 is Ci-6 alkyl, which is linear or branched and which is unsubstituted or substituted with 1-5 groups independently selected from halogen, C0 2 H, and C0 2 Ci_6 alkyl, wherein the C0 2 Ci_6 alkyl is linear or branched;
  • R9 and Rio may be the same or different and are hydrogen, straight or branched alkyl of from one to six carbon atoms, lower alkylaryl, lower alkenyl, phenyl, CF 3 , hydroxy, lower alkoxy, lower alkylthio, lower alkylsulphonyl, CF 3 O, at the six position halogen, nitro, carboxy, lower alkoxycarbonyl, NRnRi 2 CO, NRnRi 2 , RnCONRi 2 , CN, NRiiR] 2 S0 2 , wherein Rn and R] 2 may be the same or different and are hydrogen, lower alkyl, or aryl; R9 and Rio may together form a carbocyclic or methylenedioxy ring;
  • Ri4 is cyano, cyanomethyl, methoxymethyl, or ethoxymethyl
  • X 2 is O, N(H), or S, het is a 5 or 6-membered heterocycle, n is 0, 1, 2, or 3, and each D is an unbranched lower alkyl group;
  • U is a substituent selected from halogen atom; cyano; lower alkyl wherein one or more hydrogen atoms on the lower alkyl group are optionally substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic group containing one or more hetero-atoms selected from nitrogen, oxygen, and sulfur atoms; lower alkylthio wherein one or more hydrogen atoms on the alkyl group are optionally substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino, and aryl; lower alkylsulfonyl wherein one or more hydrogen atoms on the alkyl group are optionally substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino, and aryl; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl;
  • arylcarbonyl carboxyl; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N,N-di- lower alkylaminocarbonyl; amino; N-lower alkylamino; N,N-di-lower alkylamino;
  • formylamino lower alkylcarbonylamino; aminosulfonylamino; (N-lower alkylamino)sulfonylamino; (N,N-di-lower alkylamino)sulfonylamino; aryl, optionally substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, aryl and amino; and a monocyclic or bicyclic heterocyclic group containing one or more hetero-atoms selected from nitrogen, oxygen, and sulfur atoms;
  • Q, T, and V are each, independently, N, S, O CU or CH;
  • W, X, Y, and Z are each, independently, N, S, O CU or CH, such that at least one of W, X, Y, and Z is N;
  • D is unbranched lower alkyl
  • Ri5 and R] 6 are each independently substituted or unsubstituted Ci, C 2 , C 3 , C 4 , C5, C 6 , C 7 , or C 8 , straight chain alkyl, or substituted or unsubstituted C 3 , C 4 , C5, C 6 , C 7 , or C 8 , branched chain alkyl;
  • L is a single bond or CH 2 ;
  • n 0, 1, or 2;
  • n 0, 1, 2, 3, or 4;
  • Yi is ⁇ (CH 2) 2 --, --(CH 2)3 -, -CH 2 CH(CH 3) __ or -CH 2 C(CH 3)2 -;
  • Ri7 is aryl or heteroaryl
  • Ri 8 and R19 are each independently Ci -C 4 alkyl or 2-methoxyethyl;
  • R 2 o is hydrogen, Ci -C 4 alkyl, 2-(Ci -C 4 alkoxy)ethyl, cyclopropylmethyl, benzyl, or— (CH 2)m ]COR 2 i where ml is 1, 2 or 3 and R 21 is hydroxy, Ci -C 4 alkoxy or -NR 22 where R 22 hydrogen or Ci -C 4 alkyl;
  • R 23 and R 24 can be the same or different and are hydrogen, methyl, or ethyl as well as pharmaceutically acceptable salts thereof.
  • the primary amine compound can be selected from the group consisting of:
  • the primary amine compound can be selected from the group consisting of:
  • the primary compound can have the following structural formula
  • Ar is phenyl which is unsubstituted or substituted with 1-5 substitutents which are independently selected from the group consisting of: (1) fluoro, (2) bromo, and (3) CF 3
  • R5 is selected from the group consisting of: (1) hydrogen
  • Ci_6 alkyl which is linear or branched and which is unsubstituted or substituted with phenyl or 1-5 fluoro.
  • Ar is selected from the group consisting of: (1) phenyl, (2) 2-fluorophenyl, (3) 3,4-difluorophenyl,
  • the primary amine compound can be a monobasic dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl) butan-2-amine of the following structural formula:
  • the crystalline hydrate can be a crystalline monohydrate of the dihydrogenphosphate salt.
  • the dihydrogenphosphate salt shown above has a center of asymmetry at the stereogenic carbon atom indicated with an * and can thus occur as a racemate, racemic mixture, and single enantiomers, with all isomeric forms being included in the present invention.
  • the separate enantiomers, substantially free of the other, are included within the scope of the invention, as well as mixtures of the two enantiomers.
  • the primary amine compound can be a
  • the primary amine compound can be a dihydrogenphosphate salt of (2S)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro[l,2,4]triazolo[4,3-a]pyrazi- n-7(8H)-yl]-l-(2,4,5-trifluorophenyl) butan-2-amine of the following structural formula:
  • the primary amine compound is a compound having the
  • R 2 is hydrogen or (C -Ce) straight chain or branched unsubstituted or substituted alkyl
  • R3 is straight or branched unsubstituted or substituted alkyl of from 1 to 8 carbon atoms, straight or branched alkenyl of from 2 to 8 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, alkoxy of from 1 to 6 carbon atoms, -alkylcycloalkyl, -alkylalkoxy, -alkyl, OH, -alkylphenyl, -alkylphenoxy, -phenyl or substituted phenyl;
  • R4 is hydrogen or (Ci-Ce) straight chain or branched unsubstituted or substituted alkyl, or carboxyl;
  • the primary amine compound is a compound having the following structural formula:
  • R 2 is hydrogen, straight or branched alkyl of from 1 to 6 carbon atoms or phenyl;
  • R 3 is straight or branched alkyl of from 1 to 8 carbon atoms, straight or branched alkenyl of from 2 to 8 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, alkoxy of from 1 to 6 carbon atoms, -alkylcycloalkyl, -alkylalkoxy, -alkyl OH -alkylphenyl, - alkylphenoxy, -phenyl or substituted phenyl; and
  • R4 is hydrogen, and R 2 is straight or branched alkyl of from 1 to 6 carbon atoms or phenyl when R 3 is methyl, or a pharmaceutically acceptable salt thereof.
  • the primary amine compound can have the following structural formula:
  • R 2 is methyl, R 3 is an alkyl, and R 4 is a hydrogen, or a pharmaceutically acceptable salt thereof;
  • 3-Aminomethyl-5-methyl-dodecanoic acid 3-Aminomethyl-5-methyl-tridecanoic acid; 3-Aminomethyl-5-cyclopropyl-hexanoic acid; 3-Aminomethyl-5-cyclobutyl-hexanoic acid; 3-Aminomethyl-5-cyclopentyl-hexanoic acid; 3-Aminomethyl-5-cyclohexyl-hexanoic acid; 3-Aminomethyl-5-trifluoromethyl-hexanoic acid; 3-Aminomethyl-5-phenyl-hexanoic acid; 3-Aminomethyl-5-(2-chlorophenyl)-hexanoic acid; 3-Aminomethyl-5-(3-chlorophenyl)- hexanoic acid; 3-Aminomethyl-5-(4-chlorophenyl)-hexanoic acid; 3-Aminomethyl-5-(2- methoxyphenyl)-hexanoic acid; 3-Amino
  • the primary amine compound can comprise at least one of (S)-3-(Aminomethyl)-5-methylhexanoic acid or (R)-3-(Aminomethyl)-5-methylhexanoic acid.
  • the primary amine compound can include a mixture of (S)- 3-(Aminomethyl)-5-methylhexanoic acid and (R)-3-(Aminomethyl)-5-methylhexanoic acid.
  • the primary amine compound can comprise a racemic mixture of (S)-3- (Aminomethyl)-5-methylhexanoic acid and (R)-3-(Aminomethyl)-5-methylhexanoic acid.
  • the primary amine compound can comprise a mixture of: less than about 50% by weight (S)-3-(Aminomethyl)-5-methylhexanoic acid and greater than about 50% by weight (R)-3-(Aminomethyl)-5-methylhexanoic acid, less than about 25% by weight (S)-3- (Aminomethyl)-5-methylhexanoic acid and greater than about 75% by weight (R)-3- (Aminomethyl)-5-methylhexanoic acid, less than about 10% by weight (S)-3- (Aminomethyl)-5-methylhexanoic acid and greater than about 90% by weight (R)-3- (Aminomethyl)-5-methylhexanoic acid, less than about 1% by weight (S)-3-(Aminomethyl)- 5-methylhexanoic acid and greater than about 99% by weight (R)-3-(Aminomethyl)-5- methylhexanoic acid, greater than about 50% by weight (S)-3-(Aminomethyl)-5-
  • the primary amine compound can consist essentially of or consist of (S)-3-(Aminomethyl)-5-methylhexanoic acid. In yet another embodiment, the primary amine compound can consist essentially of or consist of (R)-3- (Aminomethyl)-5-methylhexanoic acid.
  • the primary amine compound is a compound having the following structural formula:
  • R 25 is hydrogen or a lower alky, such as a (C -Ce) straight chain or branched unsubstituted or substituted alkyl, n is 4, 5, or 6 and pharmaceutically acceptable salts thereof.
  • R 25 is hydrogen or a lower alky, such as a (C -Ce) straight chain or branched unsubstituted or substituted alkyl, n is 4, 5, or 6 and pharmaceutically acceptable salts thereof.
  • the primary amine compound is a compound having the following structural formula:
  • a primary compound having this structural formula is also referred to as gabapentin and is sold under the trade name Neurontin.
  • the primary amine compound can have the following structural formula:
  • R] 4 is a methoxymethyl or ethoxymethyl groups.
  • the primary amine compound can have the following structural formula:
  • Rn is 2-chlorophenyl, 2-fluorophenyl, 2-methoxyphenyl, 3- chlorophenyl, 2-chloro-3-hydroxyphenyl, 2-chloro-6-fluorophenyl, unsubstituted phenyl or 2,3-dichlorophenyl; Ris is preferably CI3 ⁇ 4; R19 is C 2 3 ⁇ 4; R 2 o is H or CH 3 ; and Yi is (CH 2 ) 2 or CH 2 CH(CH 3 ).
  • the primary amine compound can have the following structural formula:
  • R9 and Rio are hydrogen, straight or branched alkyl of from one to six carbon atoms, lower alkylaryl, alkenyl, phenyl, CF 3 , lower alkoxy, lower alkyl thio, lower alkylsulphonyl, CF 3 O at the six position, halogen, nitro, NRnRi 2 , RnCONRn, or CN.
  • the primary amine compound can be selected using an in vitro assay that measures the ability of the primary amine compound to improve viability of RPE cells treated with retinal.
  • an in vitro assay that measures the ability of the primary amine compound to improve viability of RPE cells treated with retinal.
  • primary amine compounds can be selected using an in vitro assay that measures the ability of the primary amine compound to improve viability of RPE cells treated with retinal.
  • RPE cells treated with retinal that improved the viability of the RPE cells at least 15% compared to untreated cells are selected from the group consisting of:
  • primary amine compounds administered to RPE cells treated with retinal that improved the viability of the RPE cells at least 15% compared to untreated cells are selected from the group consisting of: 5-amino-2,3-dihydrophthalazine- 1,4-dione, 3,4-diethoxyaniline, l-isopropyl-2-methyl-benzimidazol-5-amine, N2-(4- dimethylaminophenyl) -1,3 -benzothiazole-2 , 6-diamine, N- [(3 - aminophenyl)methyl] - 6- methoxy-chroman-4-amine, l-[[4-(aminomethyl)phenyl]methyl]hexahydropyrimidin-2-one,
  • the primary amine compounds used in methods described herein can be administered to the subject to treat the ocular disorder (e.g., macular degeneration or Stargardt disease) using standard delivery methods including, for example, ophthalmic, topical, parenteral, subcutaneous, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, intradermal injections, or by transdermal, buccal, oromucosal, oral routes or via inhalation.
  • ocular disorder e.g., macular degeneration or Stargardt disease
  • standard delivery methods including, for example, ophthalmic, topical, parenteral, subcutaneous, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, intradermal injections, or by transdermal, buccal, oromucosal, oral routes or via inhalation.
  • the particular approach and dosage used for a particular subject depends on several factors including, for example, the general health, weight, and age of the subject. Based on factors such as these
  • Treatment according to the method described herein can be altered, stopped, or re-initiated in a subject depending on the status of ocular disorder. Treatment can be carried out as intervals determined to be appropriate by those skilled in the art. For example, the administration can be carried out 1, 2, 3, or 4 times a day. In another embodiment, the primary amine compound can be administered after induction of macular degeneration has occurred.
  • the treatment methods can include administering to the subject a therapeutically effective amount of the primary amine compound. Determination of a therapeutically effective amount is within the capability of those skilled in the art. The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the subject's condition.
  • the primary amine compound can be provided in an ophthalmic preparation that can be administered to the subject's eye.
  • the ophthalmic preparation can contain the primary amine compound in a pharmaceutically acceptable solution, suspension or ointment. Some variations in concentration will necessarily occur, depending on the particular primary amine compound employed, the condition of the subject to be treated and the like, and the person responsible for treatment will determine the most suitable concentration for the individual subject.
  • the ophthalmic preparation can be in the form of a sterile aqueous solution containing, if desired, additional ingredients, for example, preservatives, buffers, tonicity agents, antioxidants, stabilizers, nonionic wetting or clarifying agents, and viscosity increasing agents.
  • Examples of preservatives for use in such a solution include benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal and the like.
  • Examples of buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, sodium acetate, and sodium biphosphate, in amounts sufficient to maintain the pH at between about pH 6 and about pH 8, and for example, between about pH 7 and about pH 7.5.
  • Examples of tonicity agents are dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, and sodium chloride.
  • antioxidants and stabilizers include sodium bisulfite, sodium metabisulfite, sodium thiosulfite, and thiourea.
  • wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol.
  • viscosity-increasing agents include gelatin, glycerin, hydroxyethylcellulose,
  • the ophthalmic preparation will be administered topically to the eye of the subject in need of treatment by conventional methods, for example, in the form of drops or by bathing the eye in the ophthalmic solution.
  • the primary amine compound can also be formulated for topical administration through the skin.
  • Topical delivery systems also include transdermal patches containing the ingredient to be administered. Delivery through the skin can further be achieved by iontophoresis or electrotransport, if desired.
  • Formulations for topical administration to the skin can include, for example, ointments, creams, gels and pastes comprising the primary amine compound in a
  • the formulation of the primary amine compound for topical use includes the preparation of oleaginous or water-soluble ointment bases, as is well known to those in the art.
  • these formulations may include vegetable oils, animal fats, and, for example, semisolid hydrocarbons obtained from petroleum.
  • Particular components used may include white ointment, yellow ointment, cetyl esters wax, oleic acid, olive oil, paraffin, petrolatum, white petrolatum, spermaceti, starch glycerite, white wax, yellow wax, lanolin, anhydrous lanolin and glyceryl monostearate.
  • Various water-soluble ointment bases may also be used, including glycol ethers and derivatives, polyethylene glycols, polyoxyl 40 stearate and polysorbates.
  • Subjects affected with or at risk of macular degeneration, which are not readily accessible or suitable for ophthalmic (e.g. eye-drops) and/or topical administration can be treated by a systemic approach, such as intravenous infusion.
  • the primary amine compound can be administered at a low dosage by continuous intravenous infusion.
  • the primary amine compound can be administered intermittently (e.g., every 12-24 hours).
  • the initial or loading dose can be followed by maintenance doses that are less than, (e.g., half) the loading dose or by continuous infusion.
  • the duration of such treatment can be determined by those having skill in the art, based on factors, for example, the severity of the condition and the observation of improvements.
  • devices and equipment e.g., catheters, such as central or peripheral venous catheters, tubing, drip chambers, flashback bulbs, injection Y sites, stopcocks, and infusion bags
  • catheters such as central or peripheral venous catheters, tubing, drip chambers, flashback bulbs, injection Y sites, stopcocks, and infusion bags
  • the primary amine compounds may be administered to a subject in order to treat or prevent macular degeneration and other forms of retinal disease whose etiology involves aberrant all-irans-RAL clearance. Other diseases, disorders, or conditions characterized by aberrant all-irans-RAL may be similarly treated.
  • a subject is diagnosed as having symptoms of macular degeneration, and then a disclosed compound is administered.
  • a subject may be identified as being at risk for developing macular degeneration (risk factors include a history of smoking, age, female gender, and family history), and then a disclosed compound is administered.
  • a subject may have dry AMD in both eye, and then a disclosed compound is administered.
  • a subject may have wet AMD in one eye but dry AMD in the other eye, and then a disclosed compound is administered.
  • a subject may be diagnosed as having Stargardt disease and then a disclosed compound is administered.
  • a subject is diagnosed as having symptoms of other forms of retinal disease whose etiology involves aberrant all-irans-RAL clearance, and then the compound is administered.
  • a subject may be identified as being at risk for developing other forms of retinal disease whose etiology involves all-irans-RAL clearance, and then the disclosed compound is administered.
  • a compound is administered prophylactically.
  • a subject has been diagnosed as having the disease before retinal damage is apparent.
  • a human subject may know that he or she is in need of the macular generation treatment or prevention.
  • a subject may be monitored for the extent of macular degeneration.
  • a subject may be monitored in a variety of ways, such as by eye examination, dilated eye examination, fundoscopic examination, visual acuity test, and/or biopsy.
  • Monitoring can be performed at a variety of times. For example, a subject may be monitored after a compound is administered. The monitoring can occur, for example, one day, one week, two weeks, one month, two months, six months, one year, two years, five years, or any other time period after the first administration of a compound. A subject can be repeatedly monitored. In some embodiments, the dose of a compound may be altered in response to monitoring.
  • the disclosed methods may be combined with other methods for treating or preventing macular degeneration or other forms of retinal disease whose etiology involves aberrant all-irans-RAL clearance, such as photodynamic therapy.
  • a patient may be treated with more than one therapy for one or more diseases or disorders.
  • a patient may have one eye afflicted with dry form AMD, which is treated with a compound of the invention, and the other eye afflicted with wet form AMD, which is treated with, e.g., photodynamic therapy.
  • the primary amine compound described herein can be administered as part of a combinatorial therapy with additional therapeutic agents.
  • the phrase "combinatorial therapy” or “combination therapy” embraces the administration of a primary amine compound, and one or more therapeutic agents as part of a specific treatment regimen intended to provide beneficial effect from the co-action of these therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined period (usually minutes, hours, days or weeks depending upon the combination selected).
  • “Combinatorial therapy” or “combination therapy” is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example by administering to the subject an individual dose having a fixed ratio of each therapeutic agent or in multiple, individual doses for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissue.
  • the therapeutic agents can be administered by the same route or by different routes. The sequence in which the therapeutic agents are administered is not narrowly critical.
  • Figs. 3-5 illustrate UV/Vis spectra for the FDA approved drugs.
  • FDA approved drugs that were active readily formed a Schiff base with all-irans-RAL as evidenced by a substantial differential between spectra of unprotonated and protonated Schiff base.
  • Rdh8 ' mice were generated and genotyped as previously described in J. Biol. Chem. 280, 188-18832 (2005). Abca4 'A mice also were generated by standard procedures (Ingenious Targeting, Inc., Stony Brook, NY). The targeting vector was constructed by replacing exon 1 with the neo cassette as described by Cell, 98 13-23 (1999). No
  • Abca4 'A mice were maintained with either pigmented 129Sv/Ev or C57BL/6 mixed backgrounds, and their siblings were used for most experiments.
  • Rdh8 'A Abca4 ⁇ mice were established by crossbreeding Abca4 ⁇ mice with Rdh8 ' mice.
  • Genotyping or mice was carried out by PCR with primers ABCR1 (5'- gcccagtggtcgatctgtctagc-3') d ABCR2 (5'-cacaaaggccgctaggaccacg-3') for wild type (WT) (619 bp) and AO (5'-ccacagcacacatcagcatttctcc-3') and Nl (5'-tgcgaggccagaggccacttgtgtagc- 3') for targeted deletion (455 bp). PCR products were cloned and sequenced to verify their identities. Rdh8 'A Abca4 ' mice were fertile and showed no obvious developmental abnormalities.
  • retinoids Three main classes of retinoids (retinyl esters, retinal oximes, and retinols) as well as their geometrical isomers was separated in single run by normal phase HPLC by using an Agilent Si, 5 ⁇ , 4.5 x 250 mm column and a stepwise gradient of ethylacetate in hexane (0.5% for 15 min, and 6% for up to 60 min) at a flow rate of 1.4 ml/min (Fig. 6). Retinoids were detected at 325 nm (retinyl esters and retinols) and 350 nm (retinyl oximes) with a diode array detector. Those of interest were quantified based on the areas under their peaks calculated with the help of HP Chemstation A.03.03 software and compared with areas calculated based on known amounts of synthetic standards plotted as a standard curve.
  • the conjugated polyene chain of retinoids contributes to relatively strong light absorption at UV and visible wavelengths.
  • absorbance spectra provided information about the number of conjugated double bonds.
  • slight differences in wavelengths of maximum absorbance and shapes of the spectra permitted precise identification of retinoid isomers.
  • a limitation of this method is the low selectivity of its UV-Vis absorbance, which mandates carefully designed chromatographic conditions and precise identification of the compounds being analyzed. This analysis can become especially challenging when multiple geometric isomers of retinoids at low abundance (less than 3 pmols/eye) or unidentified compounds are present.
  • LC-MS high performance liquid chromatography
  • Mass spectra of retinoids was acquired by using a LXQ high throughput linear ion trap mass spectrometer (Thermo Scientific, Waltham, MA) connected with an Agilent 1100 HPLC system and interfaced with an atmospheric pressure chemical ionization (APCI) source.
  • the APCI source in a positive ionization mode is chosen for LC-MS methodology because of its wide dynamic range and capacity to operate at the high flow rates required for HPLC retinoid separation.
  • Retinal conjugates were detected and identified with a LXQ mass spectrometer equipped with an APCI source. MS scans were recorded in a SIM mode for each individual compound (Fig. 7 M3). The identity of detected adducts will be confirmed based on their MS 2 spectra. Amounts of retinal-amine conjugates will be quantified with the aid of isotopically labeled synthetic standards added prior to extraction.
  • Bioptigen OCT systems utilize a narrow single-mode beam from a wide bandwidth light source to probe the structure of retina at a higher resolution (2.0 ⁇ ) than normal OCT systems.
  • Mice were anesthetized by intraperitoneal (IP) injection of 20 ⁇ /g bw of 6 mg/ml ketamine and 0.44 mg/ml xylazine diluted with 10 mM sodium phosphate, pH 7.2, containing 100 mM NaCl. Pupils were dilated with 1% tropicamide.
  • SD-OCT images were obtained from both eyes. Four pictures acquired in a B-scan mode were used to construct the final averaged images (Fig. 8). SD-OCT imaging enabled us to identify early pathological changes in the retina and monitor progression or amelioration/prevention of pathological lesions quantitatively under various therapeutic regimens in the same live animal at a resolution comparable to that obtained by current histopathological methods that employ cross sections of the retina.
  • FIG. 9 illustrates Rdh8 Abca4 'A mouse without light shows healthy retina, whereas light with 10,000 lux for 30 min cause severe retinal degeneration (left panel). Preventive effects of compounds in retinal morphology are indicated as OCT score (right panel).
  • Score 4 regional retinal degeneration (less than 1000 ⁇ width)

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