MX2007014652A - Compositions and methods of treating retinal disease - Google Patents

Abstract

Compositions and methods for treating macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and/or lipofuscin, and, more specifically, for preventing the formation and/or accumulation of A2E are disclosed.

Description

COMPOSITIONS AND METHODS TO TREAT RETINAL DISEASE FIELD OF THE INVENTION This application is related to compositions and methods for treating macular degeneration and other forms of retinal disease, whose etiology involves the accumulation of A2E and / or lipofuscin in the retinal tissue, more specifically, to avoid the accumulation of A2E.

BACKGROUND OF THE INVENTION Two forms of retinal disease include Stargardt's disease, which afflicts young adults and age-related macular degeneration (AMD), which afflicts adults in middle life or later. Both forms are characterized by the progressive degeneration of the conical photoreceptors located in the region of the macular fossa, degeneration which leads to the loss of high acuity of vision in the central visual field. The disease has been associated with the accumulation of toxic biochemicals, including lipofuscin, within the cells of the retinal pigment epithelium (RPE) and extracellular druse, where the RPE cells are in contact with the Bruch membrane. The accumulation of these retinotoxic mixtures is one of the most important risk factors in the etiology of AMD. AMD begins as a "dry form" without vascular complications. Currently there are no known treatments for the dry form of AMD. A patient of ten progresses to a late-stage form of the disease, known as "wet form" AMD, which is characterized by choroidal neovascularization that invades the macula and breaks the retinal and RPE tissue. AMD treatments of the most common wet form suppress vascular growth or inflammatory processes. During the normal visual cycle (summarized in Figure 1), most of the trans-RAL is sequestered by the opsin proteins in the disc membranes of the outer segment of the photoreceptor. This mechanism of sequestration protects the trans-RAL group from reacting with the phosphatidylethanolamine (PE) before the trans-RAL dehydrogenase (RDH) converts the trans-RAL to the alcohol trans-retinol. Some trans-RAL molecules escape sequestration, however, and react with phosphatidylethanolamine to first form N-retinylidene-phosphatidylethanolamine (APE) and then N-retinylidene-N-retinyl-phosphatidylethanolamine (A2PE) in the disks of the external segments of the photoreceptor. Both A2PE and trans-RAL that have escaped sequestration are transported out of the photoreceptor disk membranes by an ATP binding cassette transporter, called Rim protein (RmP) or ABCA4 (formerly ABCR). After this transport, the trans-RAL is reduced to trans-retinol by RDH and crosses the plasma membrane of the outer segment (OS) to the extracellular space, where it is captured by the cells of the retinal pigment epithelium (RPE). A2PE is captured by the lysosomes of the RPE cells when the RPE cells ingest the outer segments of the photoreceptor that are released routinely. Once inside the lysosomes, the A2PE becomes irreversibly converted to A2E, which causes the lysosomal failure. Lysosomal failure poisons RPE cells and compromises their ability to provide biochemical support to the photoreceptors of the retina, leading to the progressive degeneration of both cell types. Multiple factors affect the speed of the accumulation of A2E, both genetic and environmental. For example, a hereditary mutation in both copies of the ABCA4 transporter gene increases the accumulation of A2E and leads to Stargardt disease in children and young adults. A late-onset form of Stargardt's disease is associated with ABCA4 mutations that are more benign. Many think that Stargardt's disease is an early onset form of AMD, where the normal age-related accumulation of A2E is accelerated by the ABCA4 mutation to a degree sufficient for the disease to be triggered decades before the AMD appears normally. With respect to environmental factors, it is well established in animal models that the speed of formation of the A2E varies with exposure to light. It has been shown that a fatty acid (phosphatidylglycerol) can protect RPE cells from cell death induced by A2E, and that other dietary factors can influence the progression of the disease, including zinc (which affects the activity of retinol oxidoreductase). There is a need for effective treatments of AMD in dry form and Stargardt's disease, which stop the progression of the disease and preserve or restore vision.

SUMMARY OF THE INVENTION The invention relates to compositions and methods for treating macular degeneration and other forms of retinal disease, the etiology of which involves the accumulation of A2E and / or lipofuscin in the retinal tissue. In one embodiment, the present invention provides compositions and methods for treating macular degeneration and other retinal disease with an etiology involving the accumulation of A2E and / or lipofuscin, limiting the formation of cytotoxic A2E. For example, the formation of A2E is avoided or reduced by limiting the amount of trans-RAL not sequestered for reaction with phosphatidyl ethanolamine (PE) in the outer segments of the photoreceptor. In one method, a therapeutic compound, i.e., a "RAL collector" is administered to a patient, whereby the drug competes with the PE for the trans-RAL, forming an adduct of a Schiff's base. "Free RAL" is defined as the RAL that is not linked to a protein of the visual cycle. In another embodiment, the invention relates to a method for identifying a drug for treating macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin, which may include administering a candidate agent to a subject having , or is at risk of developing macular degeneration and retinal disease, and measuring the formation of A2E in the presence of the candidate agent, in relation to the formation of A2E in the absence of the candidate agent. A wide variety of drugs is contemplated for use in the methods of the invention. In some embodiments, inhibitors of A2E formation include RAL collectors. For example, the pharmacological objective of such RAL collector compounds is trans-RAL, which has escaped from sequestration by opsins in the outer segments of the photoreceptor. RAL collectors include, for example, cyclic amines and heterocyclic amines of five and six members having one or more pairs of conjugated double bonds, and for example, can be aromatic. In some embodiments, the RAL collector is administered to a subject as a topical formulation for delivery by drops for the os or via a skin patch. The invention relates to a method for treating or preventing macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin in a subject, the method is by administering a composition that reduces the level of accumulation of A2E in relation to the level of accumulation of A2E in the subject, without the administration of the composition. The invention also relates to a method for treating or preventing macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin in a subject, by administering to the subject a composition that reduces the level of formation of A2E in relation to the level of A2E formation in the subject without the administration of the composition. In some embodiments, the methods of the invention further include, diagnosing macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin in the subject. In other modalities, the methods also include monitoring macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscma in the subject. In one aspect, the invention relates to the administration of a composition that includes a compound selected from benzocaine, procaine, orthocaine, tricaine (MS222, compound 6) and methyl anthranilate.

In one aspect, the methods of the invention include administering a composition that includes a compound of the Formula IV: IV, wherein X 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. Each D can be the same or different. In one modality, the D's are the same. U is a substituent selected from a halogen atom; cyano; lower alkyl, wherein one or more hydrogen atoms in the lower alkyl group are optionally substituted with groups selected from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic group containing one or more selected heteroatoms of nitrogen, oxygen and sulfur atoms; lower alkylthio, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; lower alkylsulfonyl, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N, N-di-lower alkylaminocarbonyl; Not me; 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 with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom; and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. In one embodiment, each D is methyl. In some embodiments, the substituents (U) are selected such that the first pKa of the NH2 ring is about 3.5. In one aspect, the methods of the invention include administering a composition that includes a compound of formula I: I, wherein, W, X, Y and Z are each, independently, N, S, O, CU or CH, and at least one of W, X, Y and Z is N; n is 0, 1, 2, 3 or 4, A is ; D is unbranched lower alkyl, R is a linear or unsubstituted alkyl chain of Cl, C2, C3, C4, C5, C6, C7 or C8, or a branched or unsubstituted alkyl chain, branched, of C3, C4, C5, C6, C7 or C8. U is a substituent selected from a halogen atom; cyano; lower alkyl, wherein one or more hydrogen atoms in the lower alkyl group are optionally substituted with groups selected from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms; lower alkylthio, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; lower alkylsulfonyl, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N, N-di-lower alkylaminocarbonyl; Not me; 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 with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom; and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. In one embodiment, the identity of W, X, Y and Z is such that the compound comprises a ring of pyridine, pyridazine or pyrazine. In some modalities, U is aryl. For example, U can be benzene. U can also be benzene substituted with halo.

In some modalities, A is In some modalities, A is and D is methyl In some embodiments, two adjacent U substituents are connected to form a 5 or 6 member ring optionally substituted. For example, the substituents can be connected to form a benzene ring, forming a compound having the structure according to the formula: wherein, X, Y and Z are each, independently, N, O, S, CH or are absent, so that at least one of X, Y and Z is N; p is 0, 1, 2 or 3, B is a halogen atom, hydroxyl, carbamoyl, substituted or unsubstituted aryl or amino, A is ; D is unbranched lower alkyl, R is a linear or unsubstituted alkyl chain of Cl, C2, C3, C4, C5, C6, C7 or C8, or a branched or unsubstituted alkyl chain, branched, of C3, C4, C5, C6, C7 or C8. The compounds of Formula 1 may include: In one modality, the composition used in the methods of the invention includes the compound or a pharmaceutically acceptable salt thereof. In one aspect, the methods of the invention include administering a composition that includes a compound of formula II or Ha: one, independently, N or NH, S, 0, CU or CH, so that at least one of Q, T and V is not CU or CH; the dotted line represents two double bonds within the ring, which meets the valence requirements of the atoms and heteroatoms present in the ring; m is 0, 1 or 2; A is ; D is unbranched lower alkyl, R is a linear or unsubstituted alkyl chain of Cl, C2, C3, C4, C5, Cß, C7 or C8, or a branched or unsubstituted alkyl chain, branched, of C3, C4, C5, Cß, C7 or C8. U is a substituent selected from a halogen atom; cyano; lower alkyl, wherein one or more hydrogen atoms in the lower alkyl group are optionally substituted with groups selected from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic group containing one or more selected heteroatoms of nitrogen, oxygen and sulfur atoms; lower alkylthio, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; lower alkylsulfonyl, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N, N-di-lower alkylaminocarbonyl; Not me; 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 with groups selected from a halogen atom, hydroxyl, carbamoyl, aryl and amino; and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms; and (sic) In one embodiment, in the compounds of formula II or II, U is aryl. For example, U can be benzene. U may also be a benzene ring substituted with halo. In some embodiments, in the compounds of formula II or Ha, A is In some compounds, each D is methyl. In one embodiment, in the compounds of formula II or Ha, Q, T and V are selected such that the composition includes a furan or thiophene ring. In one embodiment, in the compounds of formula II or Ha, U is lower alkyl. For example, U can be methyl. In one embodiment, in the compounds of formula II or Ha, U is a halogen atom. For example, U can be fluorine or chlorine. An example of a composition useful in the methods of the invention includes the compound , or a pharmaceutically acceptable salt thereof. In one aspect, the methods of the invention include administering a composition that includes a compound of formula III: I? , where L is a bond or CH2; A is ; D is unbranched lower alkyl, R is a linear or unsubstituted alkyl chain of Cl, C2, C3, C4, C5, Cß, C7 or C8, or a branched or unsubstituted alkyl chain, branched, of C3, C4, C5, Cß, C7 or C8 and k is 0, 1, 2, 3 or 4. U is a substituent selected from a halogen atom; cyano; lower alkyl, wherein one or more hydrogen atoms in the lower alkyl group are optionally substituted with groups selected from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic group containing one or more selected heteroatoms of nitrogen, oxygen and sulfur atoms; lower alkylthio, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; lower alkylsulfonyl, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N, N-di-lower alkylaminocarbonyl; Not me; N-lower alkylamino; N, N-di-alkylamino lower; formylamino; lower alkylcarbonylamino; aminosulfonylamino; (N-lower alkylamino) sulfonylamino; (N, N-di-lower alkylamino) sulfonylamino; aryl, optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom; and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. In some embodiments, in the compounds of formula III, A is In some compounds, each D is methyl. In some embodiments, in the compounds of formula III, U is aryl. For example, U can be benzene. In some embodiments, U is a benzene ring substituted with halo. In one aspect, the methods of the invention include administering a composition that includes a compound of formula III, wherein two adjacent U substituents are connected to form a 5 or β-member ring, optionally substituted. For example, the methods of the invention include administering a composition that includes a compound of formula III, wherein the adjacent U substituents are connected as a heterocyclic ring, forming a compound having the structure according to the formula Illa: where L is a single bond or CH2, X, Y and Z with each one, independently, N, NH, O, S, CB, CH or are absent, so that at least one of X, Y and Z is N or NH; p is 0, 1, 2 or 3; B is a halogen, hydroxyl, carbamoyl, aryl or amino atom; A is ; D is unbranched lower alkyl, R is a linear or unsubstituted alkyl chain of Cl, C2, C3, C4, C5, Cß, C7 or C8, or a branched or unsubstituted alkyl chain, branched, of C3, C4, C5, Cß, C7 or C8. In one embodiment, in the compound of formula Illa, the fused heterocyclic ring is a 6-membered ring. For example, the ring may be a pyridine ring. In one embodiment, in the compound of formula Illa, the fused heterocyclic ring is a 5-membered ring. For example, the ring can be a thiazole, oxazole or imidazole. In one embodiment, in the compound of formula Illa, B is aryl. For example, B is benzene. In one embodiment, the methods of the invention include administering a composition that includes a compound selected from or pharmaceutically acceptable salts thereof. In one aspect, methods of the invention include chronically administering a composition to treat or prevent macular degeneration and other forms of disease. retinal whose etiology involves the accumulation of A2E and / or lipofuscin. In one aspect, the invention also relates to a method for identifying a drug to treat or prevent macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin, by administering a candidate drug to a subject that has, or is at risk of developing macular degeneration or other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin; and measuring the accumulation of A2E in the subject; wherein the reduced accumulation of A2E in the presence of the candidate drug in relation to the accumulation of A2E in the absence of the candidate drug indicates that the candidate drug is a drug to treat or prevent macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin. In another aspect, the invention relates to a method for identifying a drug to treat or prevent macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin, by: contacting an in vitro model of the visual cycle with the candidate drug; and measure the accumulation of A2E; wherein the reduced accumulation of A2E in the presence of the candidate drug in relation to the accumulation of A2E in the absence of the candidate drug indicates that the candidate drug is a drug to treat or prevent macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin. The present invention relates to compounds and their use to treat macular degeneration, including the form dryness of AMD and Stargardt's disease, and other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin. An aspect of the invention includes a compound of formula I, II, Ha, III, Illa or IV, wherein the adduct of the Schiff Base of the compound and 11-cis-RAL, have an extinction coefficient equal to , or less than that of free 11-cis-RAL. In one embodiment, the absorbance peak of the Schiff Base adduct is at a wavelength equal to or less than that of free 11-cis-RAL. Another aspect of the invention includes a compound that has the formula IV: (IV), where X is O, N (H) or S and het is a 5- or 6-membered heterocycle, n represents 0, 1, 2 or 3, and each D is an unbranched lower alkyl group. U is a substituent selected from a halogen atom; cyano; lower alkyl, wherein one or more hydrogen atoms in the lower alkyl group are optionally substituted with groups selected from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic group containing one or more selected heteroatoms of nitrogen, oxygen and sulfur atoms; lower alkylthio, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; lower alkylsulfonyl, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N, N-di-lower alkylaminocarbonyl; Not me; 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 with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom; and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. In another modality, each D is methyl. In another embodiment, the pKa of the NH2 ring (NH2 - »NH) is approximately 3.5. Another aspect of the invention includes a compound represented by the general formula I: (I). W, X, Y and Z are each, independently, N, S, O, CU or CH, such that at least one of, X, Y and Z is N. A is D is unbranched lower alkyl. R is a linear or unsubstituted substituted alkyl chain of Cl, C2, C3, C4, C5, Cβ, C7 or C8, or a branched or unsubstituted, substituted alkyl chain of C3, C4, C5, Cß , C7 or C8. U is a substituent selected from a halogen atom; cyano; lower alkyl, wherein one or more hydrogen atoms in the lower alkyl group are optionally substituted with groups selected from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms; lower alkylthio, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; lower alkylsulfonyl, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N, N-di-lower alkylaminocarbonyl; Not me; 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 with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom; and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. n represents 0, 1, 2, 3 or 4. In one embodiment, the compound comprises a ring of pyridine, pyridazine or pyrazine. In another embodiment, U is an aryl. In another embodiment, U is a benzene. In another embodiment, U is a benzene substituted with halo, In one modality, A is and D is methyl. In another embodiment, two adjacent U substituents are connected to form an optionally substituted 5 or β-member ring. In another embodiment, two adjacent U substituents are connected to a benzene ring, forming a compound having the structure according to the formula: (the) . X, Y and Z are each, independently, N, O, S, C (H) or absent, so that at least one of X, Y and Z is N. p is 0, 1, 2 or 3. B is a halogen, hydroxyl, carbamoyl, aryl or amino atom. A is D is unbranched lower alkyl. R is a linear or unsubstituted substituted alkyl chain of Cl, C2, C3, C4, C5, Cβ, C7 or C8, or a branched or unsubstituted, substituted alkyl chain of C3, C4, C5, Cß , C7 or C8. In one embodiment, the composition comprises a compound selected from: In a modality In addition, the compound is selected from pharmaceutically acceptable salts thereof. Another aspect of the invention includes a compound represented by formula II or II: he has) . Q, T and V are each, independently, N (H), S, O, CU or CH, so that at least one of Q, T and V is not CU or CH. The ring in dotted lines represents two double bonds within the ring, which meets the valence requirements of the atoms and heteroatoms present in the ring, m is 0, 1 or 2. A is D is unbranched lower alkyl. R is a linear or unsubstituted substituted alkyl chain of Cl, C2, C3, C4, C5, Cβ, C7 or C8, or a branched or unsubstituted, substituted alkyl chain of C3, C4, C5, Cß , C7 or C8. U is a substituent selected from a halogen atom; cyano; lower alkyl, wherein one or more hydrogen atoms in the lower alkyl group are optionally substituted with groups selected from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic group containing one or more selected heteroatoms of nitrogen, oxygen and sulfur atoms; lower alkylthio, wherein one or more atoms of hydrogen in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; lower alkylsulfonyl, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N, N-di-lower alkylaminocarbonyl; Not me; 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 with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom; and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. In one embodiment, U is an aryl. In another embodiment, U is a benzene. In another embodiment, U is a benzene substituted with halo. In a modality, A is . In another modality, each D is methyl. In another embodiment, Q, T and V are selected such that the composition comprises a furan or thiophene ring. In another embodiment, U is lower alkyl. In another embodiment, U is methyl. In another embodiment, U is a halogen atom. In another modality, U is fluorine. In an additional mode, the The compound is selected from and pharmaceutically acceptable salts thereof. Another aspect of the invention includes a compound represented by general formula III: III L is a single bond or CH2. A is D is unbranched lower alkyl. R is a linear or unsubstituted substituted alkyl chain of Cl, C2, C3, C4, C5, Cβ, C7 or C8, or a branched or unsubstituted, substituted alkyl chain of C3, C4, C5, Cß , C7 or C8. U is a substituent selected from a halogen atom; cyano; lower alkyl, wherein one or more hydrogen atoms in the lower alkyl group are optionally substituted with groups selected from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic group containing one or more selected heteroatoms of nitrogen, oxygen and sulfur atoms; lower alkylthio, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; lower alkylsulfonyl, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N, N-di-lower alkylaminocarbonyl; Not me; 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 with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom; and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. k is 0, 1, 2, 3 or 4. In one modality, A is In another modality, each D is methyl. In another embodiment, U is an aryl. In another embodiment, U is a benzene. In another embodiment, U is a benzene substituted with halo. In another embodiment, two adjacent U substituents are connected to form an optionally substituted 5 or β-member ring. In another embodiment, two adjacent U substituents are connected as a heterocyclic ring, forming a compound having the structure according to the Illa formula: (Illa) X, Y and Z are each, independently, N, O, S, CB, CH or are absent, so that at least one of X, Y and Z is N. p is 0, 1, 2 or 3. B is a halogen, hydroxyl, carbamoyl, aryl or amino atom. A is D is unbranched lower alkyl. R is a linear or unsubstituted substituted alkyl chain of Cl, C2, C3, C4, C5, Cβ, C7 or C8, or a branched or unsubstituted, substituted alkyl chain of C3, C4, C5, Cß , C7 or C8. In one embodiment, the fused ring is a 6-membered ring. In another embodiment, the fused heterocyclic ring is a pyridine ring. In another embodiment, the fused heterocyclic ring is a 5-membered ring. In another embodiment, the fused heterocyclic ring is selected from thiazole, oxazole and imidazole. In another embodiment, B is aryl. In another embodiment, B is benzene. In another embodiment, the compound is selected from J and pharmaceutically acceptable salts thereof. Pharmaceutical compositions that include a compound of Formula I, II, Ha, III, Illa or IV or a pharmaceutically acceptable salt thereof, are used in the methods of the invention. In one embodiment, the compound of Formula I, II, Ha, III, Illa or IV or a pharmaceutically acceptable salt thereof is coadministered with one or more additional therapies. The above description fairly broadly discloses the most important features of the present invention, in order that the detailed description of the same that follows may be understood, and in order that the present contributions to the art may be better appreciated. Other objects and features of the present invention will become apparent from the following detailed description, considered in conjunction with the examples.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a diagram of the visual cycle. Figure 2 is a schematic of the reaction path of the formation of A2E. Figure 3 is a schematic of the formation of the Schiff base. Figure 4a is a UV-vis spectrum of compound 6 and RAL; Figure 4b is a graph of the formation of the adduct of a Schiff base. Figure 5 is a graph of the standard curve for the ERG measurement of the retinal responses to experimental stimuli of variable light intensity. Figure 6a is a graph of the ERG measurement of the dark adaptation rate of a photodecided rat during anesthesia, and Figure 6b is a graph of the EGR measurement of the dark adaptation of a photodecolorated rat without anesthesia. Figure 7 is a graph of the effect of compound 6 on the ERG light sensitivity of a rat adapted to darkness. Figure 8 is a graph showing the reaction kinetics of RAL-compound 8 by NMR.

DETAILED DESCRIPTION OF THE INVENTION The present application provides compositions and methods for treating macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin, for example, by limiting the formation of cytotoxic A2E. The formation of A2E can be avoided or reduced by limiting the amount of trans-RAL available for the reaction with phosphatidyl ethanolamine (PE). The progressive accumulation of A2E in RPE cells causes dry AMD. By reducing the amount of accumulation of A2E, the present invention prevents the onset and / or progression of dry AMD. In one procedure, a small molecule drug is administered, which competes with the PE for reaction with trans-RAL that has escaped sequestration by the opsins in the outer segments of the photoreceptor. As shown in Figure 2, the RAL contains an aldehyde group. The aldehyde group stabilizes the binding of 11-cis-RAL to the photoreceptor membrane protein called opsin, forming a Schiff base (Figure 3) with an amino acid side chain at the opsin binding site. Opsin releases the trans-RAL from this binding site after transducing the photoisomerization of the 11-cis-RAL bound through a second messenger path. Although the aldehyde group in the RAL is a useful molecular anchor for the binding of opsin, it is otherwise dangerous due to the reactivity of its Schiff base with other biological amines. To mitigate this risk, the visual cycle proteins have developed molecular mechanisms to continuously sequester the RAL molecules, and thus protect the aldehyde group from the lateral chemical reactions. However, these mechanisms that sequester proteins are not completely reliable.

Over time, as much as a trans-RAL molecule of three, it escapes the sequestration of proteins, where it is free to initiate a cascade of reactions that begins with the formation of A2PE in the outer segments of the photoreceptor and culminates in the formation of A2E in the lysosomes of RPE cells. Once formed in the lysosomes of the RPE cells, A2E inhibits the proton pump activated by ATP in the lysosome membranes and causes the lysosomal pH to increase. The increase in pH deactivates acid hydrolases and therefore causes lysosomal failure. Lysosomal failure is also caused by the detergent action of A2E, which solubilizes lysosomal membranes. Lysosomal failure poisons RPE cells and compromises their ability to provide biochemical support to retinal photoreceptors, leading to progressive degeneration of both cell types and visual impairment. The aromatic hydroxyl amine and amine compounds were described as aldehyde nucleophiles in the reactions of the Schiff base with the RAL by Hubbard in 1956. Hubbard, J. Am. Chem. Soc. 78: 4662, 1956; see also Rapp and Basinger, Vision Res. 22: 1097, 1982, and Fole et al, J. Photochem. Photobiol B8: 183, 1991. Two such compounds that have a history of insurance for human use for other purposes include methyl anthranilate, a natural product found in grapes, and MS-222, a fish anesthetic used by fish breeders who are exposed to it professionally, during the handling of the fish. However, MS-222 is pharmacologically active in the human retina and has no anesthetic activity in mammals.

In 1963, Do ling showed that anesthetics decrease the regeneration of rhodopsin and adaptation to darkness in rats. This was the first report that such small molecules could modulate retinal visual performance. Dowling, J. Gen. Physiol. 46: 1287, 1963. In 1982, Rapp & Basinger showed that certain local anesthetics form the basis of Schiffs with RAL and slow the adaptation to darkness in frogs. This was the first elucidation of the mechanism of the chemical reaction by which these compounds modulate retinal visual performance. Rapp and Basinger, Vision Res. 22: 1097, 1982. In 1997, Bernstein et al., Showed that MS222 (6) reversibly attenuates night vision in humans with occupational exposure. This was the first report that such a compound can be absorbed through the skin and reversibly modulate human retinal vision without known side effects. Bernstein et al, Am. J. Opthalmol, 124: 843, 1997.

Definitions For convenience, before further description of exemplary modalities, certain terms used in the specification, examples and appended claims are collected here. These definitions should be read in light of the rest of the description and as understood by a person skilled in the art. The articles "a" and "an" are used herein to refer to one or more than one (ie, at least one) of the grammatical object of the article. By way of example, "an element" means an element or more than one element. The terms "comprises," "comprising," "includes," "that includes," "has," and "that has" are used in the inclusive, open sense, meaning that additional elements may be included. The terms "such as", "for example", as used herein, are non-limiting and are for illustrative purposes only. "Including" and "including non-exclusively" are used interchangeably. The term "or" as used herein shall be understood to mean "and / or", unless the context clearly dictates otherwise. In the present specification, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present invention includes all isomers such as geometric isomers, optical isomers based on an asymmetric carbon, stereoisomer, tautomer and the like, which may occur structurally and a mixture of isomers and is not limited to the description of the formula for convenience, and may be any of an isomer or a mixture. Therefore, an asymmetric carbon atom may be present in the molecule and an optically active compound and a racemic compound may be present in the present compound, but the present invention is not limited thereto and includes any. In addition, a crystalline polymorphism may be present, but is not limiting, but any crystalline form may be a single crystal or a mixture of a crystalline form, or an anhydride or hydrate. In addition, the so-called metabolite that is produced by the degradation of the present compound in vivo is included within the scope of the present invention. It will be noted that the structure of some of the compounds of the invention include asymmetric (chiral) carbon atoms. It will be understood, consequently, that the isomers that arise from such asymmetry are included within the scope of the invention, unless otherwise indicated.

Such isomers can be obtained in substantially pure form by classical separation techniques and stereochemically controlled synthesis. The compounds of this invention can exist in stereoisomeric form, therefore, they can be produced as individual stereoisomers or as mixtures. "Isomerism" means compounds that have identical molecular formulas but that differ in the nature or sequence of the bonds of their atoms or in the arrangement of their atoms in space. The isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers", and stereoisomers that are non-superposable mirror images are referred to as "enantiomers" or sometimes optical isomers. A carbon atom attached to four non-identical substituents is termed a "chiral center". "Chiral isomer" means a compound with at least one chiral center. It has two enantiomeric forms of opposite chirality and can exist as a single 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_1 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center can exist as an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture". When a chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the arrangement in the space of the substituents attached to the chiral center. The substituents attached to the chiral center under qualification are classified according to 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" mean the diastereomers that owe their existence to the impeded rotation around the 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 side or the opposite of the double bond in the molecule, according to the rules of Cahn-Ingold- Prelog. In addition, the structures and other compounds discussed in this application include all atropic isomers thereof. "Atropic isomers" are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. The atropic isomers owe their existence to the restricted rotation caused by the impediment of the rotation of large groups around a central link. 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 selected instances. The terms "crystalline polymorphs" or "polymorphs" or "crystalline forms" mean crystalline 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 Crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. The solvent of recrystallization, the speed of crystallization, the storage temperature and other factors can cause a crystalline form to dominate. The crystalline polymorphs of the compounds can be prepared by crystallization under different conditions. In addition, the compounds of the present invention, for example, the salts of the compounds, can exist in hydrated or unhydrated form (the anhydrous form) or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc. "Solvates" means solvent addition forms that contain stoichiometric or non-stoichiometric amounts of the 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. The hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water maintains its molecular status as H20, such a combination is capable of forming one or more hydrates. "Tautomers" refers to compounds whose structures differ markedly in the arrangement of atoms, but which exist in a quick and easy equilibrium. It will be understood that the compounds of Formula I can be described as different tautomers. It should also be understood that when the compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the nomenclature of the compounds does not exclude any tautomeric form. Some compounds of the present invention may exist in a tautomeric form, which is also intended to be encompassed within the scope of the present invention. The compoundsSalts and prodrugs of the present invention can exist in various tautomeric forms, including the enol and imine form, and the keto and enamine form and the 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 a tautomer predominates. Although a tautomer can be described, the present invention includes all tautomers of the compounds present. A tautomer is one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. This reaction results in the formal migration of a hydrogen atom accompanied by a change in the adjacent conjugated double bonds. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be achieved. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible through tautomerizations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In the keto-enol tautomerism, a simultaneous displacement of electrons and a hydrogen atom occurs. Ring-chain tautomerism is exhibited by glucose. It arises as a result of the aldehyde group (-CHO) in the sugar chain molecule that reacts with one of the hydroxy groups (-0H) in the same molecule to give it a cyclic form (ring shape). The tautomerizations are catalysed by: Base: 1. deprotonation; 2. formation of a delocalized anion (for example, an enolate); 3. protonation in a different position of the anion; Acid: 1. protonation; 2. formation of a delocalised cation; 3. deprotonation in a different position adjacent to the cation. The common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactimate, amide-imide acid, tautomerism in heterocyclic rings (for example, in the nucleobases guanine, thymine and cytosine), amine-enamine and enamine-enamine. Examples include: As used herein, the term "analogue" refers to a chemical compound that is structurally similar to another, but differs slightly in composition (as in the replacement of an atom with an atom of a different element or in the presence of a particular functional group, or the replacement of a functional group by another functional group).

Thus, an analog is a compound that is similar or comparable in function and appearance, but is not structure or origin to the reference compound. As defined herein, the term "derivative" refers to compounds that have a common core structure, and are substituted with various groups as described herein. For example, all the compounds represented by the formula I are indole derivatives, and have the formula I as a common nucleus. The term "bioisostere" refers to a compound that results from the exchange of an atom or a group of atoms with another atom or group of atoms widely similar. The purpose of a bioisostomeric replacement is to create a new compound with biological properties similar to the original compound. The bioisostic replacement can be based physico-chemical or topological. Examples of bioisosteres of carboxylic acids include acyl sulfonimides, tetrazoles, sulfonates and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176 (1996). The phrases "parenteral administration" and "parenterally administered" are terms recognized in the art, and include modes of administration other than enteral and topical administration, such as injections, and include, but are not limited to, intravenous, intramuscular injection and infusion, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal. The term "treat" is recognized in the art and it includes inhibiting a disease, disorder or condition in a subject, for example, preventing its progress; and alleviating the disease, disorder or condition, for example, causing the regression of the disease, disorder and / or condition. The treatment of the disease or condition includes alleviating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected. The term "prevent" is recognized in the art and includes stopping a disease, disorder or condition occurring in a subject, which may be predisposed to the disease, disorder and / or condition, but which has not 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" is a formulation that contains the described compounds in a form suitable for administration to a subject. In a preferred embodiment, the pharmaceutical composition is in a bulk or 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 in an aerosol inhaler or a vial. The amount of the active ingredient (eg, a formulation of the described compound or salts thereof) in a unit dose of the 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 tuts are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal and the like. Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In a preferred embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any required preservatives, buffers or propellants. The term "instantaneous dose" refers to formulations of the compound which are rapidly dispersing dosage forms. The term "immediate release" is defined as a release of a compound from a dosage form in a relatively short period of time, generally up to about 60 minutes. The term "modified release" is defined to include delayed release, extended release and pulse release. The term "pulse release" is defined as a series of drug releases from a dosage form. The term "sustained release" or "extended release" is defined as the continuous release of a compound from a dosage form over a prolonged period. The phrase "pharmaceutically acceptable" is recognized in the art. In certain embodiments, the term includes compositions, polymers and other materials and / or dosage forms that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals, without excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio. The phrase "pharmaceutically acceptable carrier" is recognized in the art, and includes, for example, 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 composition from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a composition and not harmful to the patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials that can 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) damping agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) solutions buffered with phosphate and (21) other non-toxic compatible substances used in pharmaceutical formulations. The compounds of the invention are also capable of forming salts. All these forms are also contemplated within the scope of the claimed invention. "Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. For example, the salt can be an acid addition salt. One embodiment of an acid addition salt is a hydrochloride salt. The pharmaceutically acceptable salts of the present invention can be synthesized from an original compound containing a basic or acidic portion, by conventional chemical methods. Generally, such salts can be prepared by reacting the acid or free 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 two.; Generally, a non-aqueous medium such as ether, ethyl acetate, isopropanol or acetonitrile is preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990). For example, the salts may include, but are not limited to, the hydrochloride and acetate salts of the aliphatic, amine-containing, hydroxyl-containing, amine-containing, and imine-containing hydroxyl of the present invention. It should be understood that all references to pharmaceutically acceptable salts include the solvent addition forms (solvates) or crystalline forms (polymorphs) as defined herein, of the same salt. The compounds of the present invention can also be prepared as esters, for example, esters pharmaceutically acceptable For example, a group with a carboxylic acid function in a compound can be converted to its corresponding ester, for example, a methyl, ethyl and other ester. Also, an alcohol group in a compound can be converted to its corresponding ester, for example, an ester of acetate, propionate or other ester. The compounds of the present invention can also be prepared as prodrugs, for example, pharmaceutically acceptable prodrugs. The terms "pro-drugs" and "prodrugs" are used interchangeably herein and refer to any compound that releases an original active drug in vivo. Since it is known that prodrugs improve numerous desirable qualities of pharmaceutical products (eg, solubility, bioavailability, manufacture, etc.), the compounds of the present invention can be delivered in the form of a prodrug. Thus, the present invention aims to cover the prodrugs of the currently claimed compounds, the methods for supplying them and the compositions containing them. "Prodrugs" are intended to include any covalently linked carriers that release the active parent drug of the present invention in vivo, when such a prodrug is administered to a subject. The prodrugs of the present invention are prepared by modifying the functional groups present in the compound, such that the modifications are cleaved, either by routine manipulation or in vivo, to the original compound. Prodrugs include the compounds of the present invention, wherein a hydroxy, amino, sulfhydryl, carboxy or carbonyl group is attached to any group that can be cleaved in vivo, to form a free hydroxyl group, free amino, free sulfhydryl, free carboxy or carbonyl free, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate derivatives, dialkylaminoacetates, formates, phosphates, sulfates, and benzoate) and carbamates (e.g., N, N-dimethylaminocarbonyl) of hydroxy functional groups, ester groups ( for example, ethyl esters, morpholinoethanol esters) of carboxyl functional groups, N-acyl derivatives (e.g., N-acetyl) bases of N-Mannich, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals and enol esters of the ketone and aldehyde functional groups in the compounds of Formula I, and the like. See, Bundegaard, H.

"Design of Prodrugs" p 1-92, Elesevier, New York-Oxford (1985). "Protective group" refers to a grouping of atoms that, when bound to a reactive group in a molecule, masks, reduces or prevents that reactivity. Examples of protecting groups can be found in Green and Uts, Protective Groups in Organic Chemistry, (ile, 2nd 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, 3rd ed., 2003). The term "amine protecting group" is intended to mean a functional group that converts an amine, amide or other nitrogen-containing portion to a different chemical group that is substantially inert to the conditions of a particular chemical reaction. The amine protecting groups are preferably, easily and selectively removed in good yield under conditions that do not affect other functional groups of the molecule. Examples of amine protecting groups include, but are not limited to, formyl, acetyl, benzyl, t-butyldimethylsilyl, t-groups. butyldiphenylsilyl, t-butyloxycarbonyl (Boc), p-methoxybenzyl, methoxymethyl, tosyl, trifluoroacetyl, trimethylsilyl (TMS), fluorenyl-methyloxycarbonyl, 2-trimethylsilyl-ethoxycarbonyl, 1-methyl-1- (4-biphenylyl) ethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl (CBZ), 2-trimethylsilyl-ethanesulfonyl (SES), substituted triphenyl and triflyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratriloxycarbonyl (NVOC), and the like. Other suitable amine protecting groups are directly identified by those skilled in the art. Representative hydroxy protecting groups include those in which the hydroxy group is acylated or alkylated, such as benzyl and triphenyl ethers, as well as alkyl ethers of tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers. The term "pharmaceutically acceptable salts" is recognized in the art, and includes relatively non-toxic inorganic and organic acid addition salts, compositions, including non-exclusively, therapeutic agents, excipients, other materials, and the like. Examples of pharmaceutically acceptable salts include those derived from mineral acids, such as hydrochloric acid and sulfuric acid, and those derived from organic acids, such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Examples of inorganic bases suitable for the formation of salts include the hydroxides, carbonates and bicarbonates of ammonium, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc and the like. The salts can also be formed with suitable organic bases, including those that are not toxic and strong enough to form such salts. For purposes of illustration, the class of such organic bases they may include mono, di and trialkylamines, such as methylamine, dimethylamine and triethylamine; mono, di or trihydroxyalkylamines such as mono, di and triethanolamine; amino acids, such as arginine and lysine; guanidine; N-methylglucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; (trihydroxymethyl) aminoethane; and the similar. See, for example, J. Pharm. Sci. 66: 1-19 T1977. A "patient", "subject" or "host" to be treated by the method can mean any human or non-human animal, such as primates, mammals and vertebrates. The term "prophylactic or therapeutic" treatment is recognized in the art, and includes administration to the host of one or more of the compositions. If it is administered before the clinical manifestation of the unwanted condition (eg, the disease or other unwanted state of the host animal), then the treatment is prophylactic, that is, it protects the host against the development of the undesired condition, whereas if it is administered after the manifestation of the undesired condition, the treatment is therapeutic (that is, it is intended to decrease, reduce or stabilize the undesired existing condition or the side effects thereof). The terms "therapeutic agent", "drug", "medicament" and "bioactive substance" are recognized in the art, and include 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 macular degeneration or other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin. The terms include, but are not limited to, pharmaceutically acceptable salts thereof and prodrugs. Such agents can be acidic, basic or salts; they can be neutral molecules, polar molecules or molecular complexes capable of forming hydrogen bonds; they can be prodrugs in the form of ethers, esters, amides and the like, which are biologically activated when administered to a patient or subject. The phrase "therapeutically effective amount" is a term recognized in the art. In certain embodiments, the term refers to an amount of a therapeutic agent when incorporated into a polymer, produces some desired effect at a reasonable benefit / risk ratio applicable to any medical treatment. In certain embodiments, the term refers to a quantity necessary or sufficient to eliminate, reduce or maintain (e.g., prevent the spread of) a tumor or other objective of a particular therapeutic regimen. The effective amount may vary depending on factors such as the disease or condition being treated, the particular constructs selected being administered, the size of the subject or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound without undue experimentation. In certain embodiments, a therapeutically effective amount of a therapeutic agent for in vivo use will likely depend on several 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" is recognized in the art. In certain embodiments, ED50 means the dose of a drug that produces 50% of its response or maximum effect, or alternatively, the dose that produces a predetermined response in 50% of the subjects or test preparations. The term "LD50" is recognized in the art. In certain embodiments, LD50 means the dose of a drug that is lethal in 50% of the test subjects. The term "therapeutic index", is a term recognized in the art, which refers to the therapeutic index of a drug, defined as LD50 / ED50. The term "substituted", as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection of the indicated group, provided the normal valence of the designated atom is not exceeded, and that the substitution results in a stable compound. When the substituent is keto (ie, = 0), then 2 hydrogens in the atom are replaced. The double bonds in the ring, as used herein, are double bonds that are formed between two adjacent ring atoms (eg, C = C, C = N or N = N). With respect to any chemical compounds, the present invention is intended to include all isotopes of the atoms appearing in the present compounds. Isotopes include those atoms that have the same atomic number but differ in mass numbers. By way of general example and non-exclusively, the isotopes of hydrogen include tritium and deuterium, and the carbon isotopes include C-13 and C-14. The chemical compounds described herein may have asymmetric centers. The compounds of the present invention containing an asymmetrically substituted atom, can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by the resolution of racemic forms or by the synthesis of optically active raw materials. Many geometric isomers of olefins, C = N double bonds, and the like, may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. The cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms. All chiral, diastereomeric, racemic and geometric isomeric forms of a structure are intended, unless the specific stereochemistry or an isomeric form is specifically indicated. All processes used to prepare the compounds of the present invention and the intermediates made herein, where appropriate, are considered part of the present invention. All tautomers of the compounds shown or described as well, where appropriate, are considered part of the present invention. When a bond of a substituent is shown to cross a bond connecting two atoms in a ring, then such a substituent may be attached to any atom in the ring. When a substituent is listed without indicating the atom via which such a substituent is attached to the rest of the compound of a given formula, then such a substituent may be attached via any atom in such a substituent. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

When an atom or a chemical portion is followed by a numerical range in subscript (for example, Ci-β), the invention is intended to encompass such a number within the range, as well as all intermediate intervals. For example, "Ci-β alkyl" is intended 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. As used herein, "alkyl" is intended to include both a branched (eg, isopropyl, tert-butyl, isobutyl) and 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), cycloalkyl groups substituted with alkyl, and alkyl groups substituted with cycloalkyl. Such aliphatic hydrocarbon groups have a specified number of carbon atoms. For example, C? -6 alkyl is intended to include Ci, C2, C3, C4, C5 and C6 alkyl groups. As used herein, "lower alkyl" refers to alkyl groups having from 1 to 6 carbon atoms in the main chain of the carbon chain. "Alkyl" further includes alkyl groups having oxygen, nitrogen, sulfur or phosphorus atoms by replacing one or more carbon atoms of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkyl has six or fewer carbon atoms in its main chain (e.g., Ci-Cß for a straight chain, C3-C6 for a branched chain), e.g., four or less . Similarly, certain cycloalkyls have three to eight carbon atoms in their ring structure, such as five or six atoms in their ring structure. The term "substituted alkyls" refers to alkyl portions having substituents that replace a hydrogen at one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl , alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. The cycloalkyls can be further substituted, for example, with the substituents described above. An "alkylaryl" or "aralkyl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). As used herein, "alkenyl" is intended to include hydrocarbon chains of straight or branched configuration, having one or more carbon-carbon double bonds occurring at any stable point along the chain. For example, C2_6 alkenyl is intended to include alkenyl groups of C2, C3, C4, C5 and C6. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. As used herein, "alkynyl" is intended to include hydrocarbon chains of straight or branched configuration, having one or more triple carbon-carbon bonds that appear at any stable point throughout the chain. For example, C2-6 alkynyl is intended to include alkynyl groups of C2, C3, C4, C5 and? . Examples of alkynyl include, but are not limited to, ethynyl and propynyl. In addition, "alkyl", "alkenyl" and "alkynyl" are intended to include portions that are diradical, ie, have two attachment points. A non-limiting example of such an alkyl portion which is a diradical is -CH2CH2-, that is, a C2 alkyl group which is covalently linked via each terminal carbon atom to the rest of the molecule. "Aryl" includes groups with aromaticity, including "non-conjugated" 5 or 6-membered aromatic groups, or of a single ring, which may include from zero to four heteroatoms, as well as "conjugated", or multicyclic, systems with at least one aromatic ring. Examples of aryl groups include benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Furthermore, the term "aryl" includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran , desazapurina or indolizina. These aryl groups having heteroatoms in the ring structure can also be referred to as "aryl heterocycles", "heterocycles", "heteroaryls" or "heteroaromatics". The aromatic ring can be substituted at one or more positions on the ring with substituents such as those described above, such as, for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, 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 moiety or heteroaromatic. The aryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are non-aromatic, to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl). The terms "heterocyclyl" or "heterocyclic group" include closed ring structures, for example, rings from 3 to 10, or 4 to 7 members, 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 may 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 substituents such as described above, such such as halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, or an aromatic or heteroaromatic moiety. The heterocyclic groups can also be substituted on 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, -CF3, or -CN, or similar. As used herein, "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine. "Contraion" 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 intended to indicate a compound that is sufficiently robust to survive the isolation, and as appropriate, the purification of a reaction mixture, and the formulation into an effective therapeutic agent. "Free compound" is used herein to describe a compound in the unbound state. "Extinction coefficient" is a constant used in the Law of Beer-Lambert that is related to the concentration of the substance that is measured (in moles), with the absorbance of the substance in solution (how well the substance in solution blocks the light that passes in a beam through it so that it comes out the other side). It is an indicator of how much light a compound absorbs at a particular wavelength. In the specification, singular forms also include the plural, unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as are commonly understood by one of ordinary skill in the art to which the invention pertains. In the case of conflict, this specification will have control. Throughout the description, wherein the compositions are described as having, including or comprising specific components, it is contemplated that the compositions also consist essentially of, or consist of, the exposed compounds. Similarly, where the methods or processes are described as having, including or comprising specific process steps, the processes also consist essentially of, or consist of, the exposed processing steps. In addition, it will be understood that the order of the steps or the order to perform certain actions is not important, as long as the invention remains operable. In addition, two or more steps or actions can be performed simultaneously. "Small molecule" is a recognized term in the art. In certain embodiments, this term refers to a molecule having a molecular weight of less than about 2000 amu, or less than about 1000 amu, and even less than about 500 amu. All the percentages and relationships used in the present, unless otherwise indicated, are by weight. The "retina" is a region of the central nervous system with approximately 150 million neurons. It is located in the back of the eye, where it rests in a specialized epithelial tissue called retinal pigment epithelium or RPE. The retina initiates the first stage of visual processing, transducing the visual stimuli to specialized neurons called "photoreceptors". Their synaptic outputs are processed by neural networks made in the retina and then transmitted to the brain. The retina has developed two specialized classes of photoreceptors to operate under a wide range of light conditions. The "rod" photoreceptors transduce visual images under low light conditions and mediate achromatic vision. The "cone" photoreceptors transduce visual images in dim light to bright conditions and mediate color vision and high acuity vision. Every photoreceptor is compartmentalized in two regions called the "external" and "internal" segments. The inner segment is the neuronal cell body that contains the cell nuclei. The internal segment survives throughout life 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 external segment is released routinely and grows back into a diurnal process, called the renewal of the external segment. The released outer segments are ingested and metabolized by the RPE cells. The "macula" is the central region of the retina that contains the pit, where the visual images are processed by long thin cones in high spatial detail ("visual acuity"). "Macular degeneration" is a form of retinal neurodegeneration that attacks the macula and destroys the high visual acuity in the center of the visual field. AMD begins in a "dry form", characterized by residual lysosomal granules, called lipofuscin in the cells of the RPE, and extracellular deposits called "druse". Druse contains cellular waste products excreted by the RPE cells. The "lipofuscin" and the druse can be detected clinically by ophthalmologists and quantified using fluorescent techniques. These may be the first clinical signs of macular degeneration. Lipofuscin contains aggregates of A2E. Lipofuscin accumulates in RPE cells and poisons it by multiple known mechanisms. As the RPE cells become poisoned, their biochemical activities decline and photoreception begins to degenerate. The extracellular druse may further compromise the RPE cells by interfering with their supply of vascular nutrients. Druze also triggers inflammatory processes, which lead to choroidal neovascular invasions of the macula in a patient of ten, progressing to the wet form of AMD. Both the dry form and the wet form progress to blindness. "ERG" is an acronym for electroretinogram, which is the measurement of the potential of the electric field emitted by the neurons of the retina during its response to an experimentally defined luminous stimulus. The ERG is a non-invasive measurement that can be performed on living subjects (human or animal), or on a semi-sectioned eye in solution that has been surgically removed from a live animal. As used herein, the term "RAL" it means retinaldehyde. The term "RAL collector" means a therapeutic compound that binds to free RAL, and then prevents RAL from forming the condensation of Schiff's base with the phosphatidylethanolamine (PE) of the membrane. "Free RAL" is defined as RAL that is not bound to a protein of the visual cycle. The terms "trans-RAL" and "all trans-RAL" are used interchangeably and mean all trans-retinaldehyde. A2E is a by-product of the reaction of a complex biochemical trajectory called the "visual cycle", which operates collaboratively in the cells of the RPE and the outer segments of the photoreceptor. The visual cycle cycles back to a photoreagent aldehyde chromophore called "retinaldehyde," which is derived from vitamin A, and is essential for vision. In simplified terms, the visual cycle has four main steps: 1) converts vitamin A in the RPE to an aldehyde chromophore with a photoreactive double-stranded bond (11-cis-RAL); 2) transports 11-cis-RAL to the retina, where it binds to a specialized photoreceptor protein called opsin; 3) photoisomerizes light with 11-cis-RAL bound to trans-RAL, which initiates the release of bound RAL from the opsin binding site; 4) converts trans-RAL (an aldehyde) to vitamin A (an alcohol) and transports vitamin A back to the RPE, where the cycle begins again. The trajectory is illustrated in Figure 1, which shows the RPE cells at the top and the outer segments of the photoreceptor below (marked "OS"). The aldehyde group of RAL helps to bind the molecule to opsin, forming a reversible chemical bond to an amino acid side chain at the opsin binding site. Although the aldehyde group in the RAL is essential to anchor the The molecule in the opsin binding site is otherwise dangerous, due to its propensity to form Schiff bases with other biological amines. The cascade reaction for the formation of A2E is shown in Figure 2. The first three reactions take place in the outer segments of the photoreceptor and produce an intermediate product called A2PE. Once formed, the A2PE is divided into the lipid phase and accumulates in the membranes of the external segment of the photoreceptor. When the RPE cells ingest the discarded outer segments, their accumulated A2PE is routed to their lysosomes. The final reaction of Figure 2 takes place within the lysosomes of the RPE and ends in the formation of A2E. As described above, macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin, can be treated or prevented by decreasing the amount of A2E formed. Compounds useful for doing this include the RAL collector. The RAL collectors decrease the amount of A2E formed, for example, forming a covalent bond with the RAL that has escaped the sequestration. The RAL that has reacted with a RAL collector compound is therefore not available to react with the phosphatidyl ethanolamine. Without wishing to stick to a theory, it is thought that the treatment of a patient who has AMD with a RAL collector compound will reduce the rate of A2E formation without limiting the visual cycle speed, thus avoiding the visual deficit of night blindness . In contrast, it is thought that the therapeutic agents for the treatment of AMD that reduce the synthesis of A2E limit the speed of the visual cycle by means of the competitive inhibition of the sites of retinoid binding of the visual cycle proteins, so that the reduction in the speed of change of the visual cycle, causes a reduction in the speed of formation of the A2E. The present invention reduces the accumulation of A2E without the competitive inhibition of retinoid binding sites in the visual cycle proteins, which is known to cause night blindness. In certain embodiments, a RAL collector is a compound known to form reversible Schiff base adducts with RAL (Figure 3). The RAL collectors of the invention include cyclic amines, as well as cyclic and heterocyclic amines of 5 and 6 members which may have one or more pairs of conjugated double bonds. In one example, the cyclic amines are aromatic. Such compounds include, for example, amines aromatics, such as benzocaine procaine orthocaine MS222 (6) Tricaine methane sulfonate) ; and anthranilate of methyl Heterocyclic compounds include The useful controls to prove the effectiveness of RAL collectors are lidocaine, a local anesthetic that does not form a Schiff base, thus acting as a negative control; and the darkness that slows down or closes the visual cycle, as a positive control. In one embodiment, the RAL collector compound reacts with the free RAL in a two-step manner to form a stabilized adduct. For example, the RAL and a primary amine of a RAL collector compound condense to form an adduct of a Schiff base, and a reaction of Internal cyclization forms an uncharged ring containing the nitrogen of the amine. This formation of the ring serves to stabilize the RAL adduct making the dissociation more unfavorably energetic. This prevents free RAL (ie, RAL not bound to opsins or other proteins in the visual cycle) from being available to form the condensation products of Schiff's base with phosphatidylethanolamine and therefore prevents formation of the A2E. In addition, once the ring is closed, it prevents the nitrogen of the amine, now part of the ring, from condensing with a second RAL molecule. It is thought that the reaction of a RAL collector with a second RAL molecule is unfavorable, since such reaction would result in the formation of an adduct having a structure similar to A2E, which has double RAL groups, with castrated tails that they can cause problems of packaging of the lipids in the biological membranes, and therefore detergency of the membrane. In addition, a reaction of the nitrogen of the amine with a second RAL would cause the nitrogen to be charged, which would cause an unfavorable activity, including toxicity, such as poisoning of the lysosomal proton pump in the RPE cells. The compounds useful as the RAL collectors include those according to formula IV: IV, wherein X is O, N, N (H) or S, het is a 5- or 6-membered heterocycle optionally substituted, n is 0, 1, 2 or 3, and each D is an alkyl group lower not branched. Each D can be the same or different. U is a substituent selected from a halogen atom; cyano; lower alkyl, wherein one or more hydrogen atoms in the lower alkyl group are optionally substituted with groups selected from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic group containing one or more selected heteroatoms of nitrogen, oxygen and sulfur atoms; lower alkylthio, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; lower alkylsulfonyl, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N, N-di-lower alkylaminocarbonyl; Not me; 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 with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom; and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. In one embodiment, each D is methyl. In one embodiment, the ring substituents (U) are chosen such that the pKa of the first NH2 ring is about 3.5. Examples include the following annular systems with the pKa in parentheses: Thiophene (4.1 1) Oxazole (-0.76) Thiazole (0.28) 4-bromobenzyl alcohol (3.82) 4-methanesulfonyl-thiophene (2.26) 4-chloro- (3.96) 4-fluoro- (4.28) In one embodiment, such compounds react with the RAL according to the mechanism described in Reaction Scheme 1: The compounds of formula IV, can be synthesized from the corresponding ester A description of the reaction between the compound and the RAL, is presented in Reaction Scheme 2: Reaction Scheme 2 The compounds of the invention include RAL collectors having a 5 or 6 membered ring. For example, the compounds of the invention retain the absorption properties of 11-cis-RAL when the two compounds form an adduct of a Schiff base, ie, that adduct formation will not increase the extinction coefficient above that of free 11-cis-RAL nor displace its peak of absorbance at a longer wavelength. Without adhering to a theory, it is thought that this conservation of the absorption properties will minimize the side effects of the treatment in the vision, protecting the 11-cis-RAL from the photoisomerization in the adduct state, thus preserving its chromophore activity, if it dissociates later from the adduct and re-enters the visual cycle, where it will be available to join the opsin in its photoactive state. In certain embodiments, the RAL collector of the invention is a compound having a structure represented by general formula I: wherein, W, X, Y and Z are each, independently, N, O, S, CU or CH, so that at least one of W, X, Y and Z is N; n is 0, 1, 2, 3 or 4, A is , D is unbranched lower alkyl, and R is a linear or unsubstituted substituted alkyl chain of Cl, C2, C3, C4, C5, C6, C7 or C8, or a substituted or unsubstituted, branched alkyl chain , from C3, C4, C5, Cß, C7 or C8. Each D can be the same or different. Substituents on the alkyl chain of R include a halogen atom; Cl-Cß alkyl optionally substituted with a halogen atom, cyano, hydroxyl, carbamoyl, amino, formylamino, lower alkylcarbonylamino, aminosulfonylamino, or lower alkylthio; lower alkylcarbonyl wherein the alkyl portion of the lower alkylcarbonyl is optionally substituted with a halogen atom, cyano, hydroxyl, carbamoyl, amino, formylamino, lower alkylcarbonylamino, aminosulfonylamino or lower alkylthio; carbamoyl; or lower alkylthio, wherein the alkyl portion of the lower alkylthio is optionally substituted with a halogen atom, cyano, hydroxyl, carbamoyl, amino, formylamino, lower alkylcarbonylamino, aminosulfonylamino or lower alkylthio. U is a substituent selected from a halogen atom; cyano; lower alkyl, wherein one or more hydrogen atoms in the lower alkyl group are optionally substituted with groups selected from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic group containing one or more selected heteroatoms of nitrogen, oxygen and sulfur atoms; lower alkylthio, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; lower alkylsulfonyl, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl; N- β-lower alkylcarbamoyl; N, N-di-lower alkylaminocarbonyl; Not me; 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 with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom; and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. In one example, U is aryl, for example benzene.

In certain compounds, A is and D is methyl, In certain compounds, U is benzene substituted with halo. In other compounds, two U substituents on adjacent carbon atoms are bonded to form a 5 or 6 membered fused ring. Such rings are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom. In certain compounds, two adjacent U substituents can form a benzene. For example, such fused compounds have the structure: the , wherein X, Y and Z are each, independently, N, O, S, CH or absent, so that at least one of X, Y and Z is N; p is 0, 1, 2 or 3, B is a halogen, hydroxyl, carbamoyl, aryl or amino atom, A is , D is unbranched lower alkyl, and R is a linear or unsubstituted substituted alkyl chain of Cl, C2, C3, C4, C5, C6, C7 or C8, or a substituted or unsubstituted, branched alkyl chain , of C3, C4, C5, C6, C7 or C8. Examples of the compounds of formula I include pyridine, pyridazine, pyrazine and pyrimidine compounds. The pyridazine compounds include: the pyrazine compounds include: the pyrimidine compounds include: The compounds of formula I or the include: In certain embodiments, the RAL collector of the invention is a compound having the structure represented by general formula II or Ha: wherein, Q, T, and V are each, independently, N, NH, S, O, CU or CH, so that at least one of Q, T and V is not CU or CH; the dotted line represents two double bonds within the ring, which meets the valence requirements of the atoms and heteroatoms present in the ring, m is 0, 1 or 2, A is , wherein D is unbranched lower alkyl, R is a substituted or unsubstituted, linear alkyl chain of Cl, C2, C3, C4, C5, C6, C7 or C8, or a substituted or unsubstituted alkyl chain, branched, of C3, C4, C5, C6, C7 or C8. For example, R is C2 alkyl (ethyl). Substituents on the alkyl chain include a halogen atom; C 1 -C 6 alkyl optionally substituted with a halogen atom, cyano, hydroxyl, carbamoyl, amino, formylammo, lower alkylcarbonylammo, aminosulfonylamo or lower alkylthio; lower alkylcarbonyl, wherein the alkyl portion of the lower alkylcarbonyl is optionally substituted with a halogen atom, cyano, hydroxyl, carbamoyl, amino, formylamm, lower alkylcarbonylamm, ammonulfonylamine or lower alkylthio; carbamoyl; or lower alkylthio, wherein the alkyl portion of the lower alkylthio is optionally substituted with a halogen atom, cyano, hydroxyl, carbamoyl, ammo, formylamm, lower alkylcarbonylamine, aminosulfonylamine or lower alkylthio. U is a substituent selected from a halogen atom; cyano; lower alkyl, wherein one or more hydrogen atoms in the lower alkyl group are optionally substituted with groups selected from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic group containing one or more selected heteroatoms of nitrogen, oxygen and sulfur atoms; lower alkylthio, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; lower alkylsulfonyl, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl; N- lower alkylcarbamoyl; N, N-di-lower alkylaminocarbonyl; Not me; 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 with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom; and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. In one embodiment, for example, U is alkyl. For example, U is methyl, ethyl or propyl. In one embodiment, U is a halogen. For example, U is chlorine, fluorine or bromine. In certain compounds, two U substituents on adjacent carbon atoms are bonded to form a 5 or 6 membered fused ring. Such rings are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom. In one example, U is aryl, for example, benzene.

In certain compounds, A is , and D is methyl. In certain compounds, U is a benzene substituted with halo. Examples include furan and thiophene compounds, such as In certain embodiments, the RAL collector of the invention is a compound having the structure represented by general formula III: wherein, L is a single bond or CH2; k is 0, 1, where D is unbranched lower alkyl, R is a linear or unsubstituted alkyl chain of Cl, C2, C3, C4, C5, C6, C7 or C8, or a branched or unsubstituted alkyl chain, branched, of C3, C4, C5, C6, C7 or C8, k is 0, 1, 2, 3 or 4. Substituents on the alkyl chain include a halogen atom; C 1 -C 6 alkyl optionally substituted with a halogen atom, cyano, hydroxyl, carbamoyl, amino, formylamino, lower alkylcarbonylamino, aminosulfonylamino or lower alkylthio; lower alkylcarbonyl, wherein the alkyl portion of the lower alkylcarbonyl is optionally substituted with a halogen atom, cyano, hydroxyl, carbamoyl, amino, formylamino, lower alkylcarbonylamino, aminosulfonylamino or lower alkylthio; carbamoyl; or lower alkylthio, wherein the alkyl portion of the lower alkylthio is optionally substituted with a halogen atom, cyano, hydroxyl, carbamoyl, amino, formylamino, lower alkylcarbonylamino, aminosulfonylamino or lower alkylthio. U is a substituent selected from a halogen atom; cyano; lower alkyl, wherein one or more hydrogen atoms in the lower alkyl group are optionally substituted with groups selected from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic group containing one or more selected heteroatoms of nitrogen, oxygen and sulfur atoms; lower alkylthio, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; lower alkylsulfonyl, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N, N-di-lower alkylaminocarbonyl; Not me; N-lower alkylamino; N, N-di-alkylamino lower; formylamino; lower alkylcarbonylamino; aminosulfonylamino; (N-lower alkylamino) sulfonylamino; (N, N-di-lower alkylamino) sulfonylamino; aryl, optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom; and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. Examples include hydroxylamine compounds and alkyl amines.

In certain compounds, A is , and D is methyl. In certain compounds, U is a benzene substituted with halo. In other compounds, two U substituents on the adjacent carbon atoms are joined to form a 5 or 6 membered fused ring. Such rings are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom. For example, such fused compounds have the Illa structure: Illa, where, X, Y and Z are each, independently, N, O, S, CH, CB or is absent, so that at least one of X, Y and Z is N; p is 0, 1, 2 or 3, B is a halogen, hydroxyl, carbamoyl, aryl or amino atom, A is , D is unbranched lower alkyl, R is a linear or unsubstituted substituted alkyl chain of Cl, C2, C3, C4, C5, C6, C7 or C8, or a substituted or unsubstituted, branched alkyl chain, of C3, C4, C5, C6, C7 or C8, and L is a single bond or CH2. In some embodiments, two adjacent U substituents form a 6-membered fused heterocycle, for example, a pyridine ring. In other embodiments, two adjacent U substituents form a 5-membered fused heterocycle. For example, two adjacent U substituents form a thiazole ring. In other embodiments, two adjacent U substituents form an oxazole ring. In other embodiments, two adjacent U substituents form an imidazole ring. Examples of the compounds of formula III or Illa The reaction of the compound with RAL produces the following conjugate: Also included are pharmaceutically acceptable addition salts and complexes of the compounds of the formulas given above. In the cases in where the compounds may have one or more chiral centers, unless specified, the compounds contemplated herein may be a single stereoisomer or racemic mixtures of stereoisomers. The prodrugs, analogues and derivatives thereof are also included.

Methods As discussed above, a described composition can be administered to a subject for the purpose of treating or preventing macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin. Other diseases, disorders or conditions characterized by the accumulation of A2E can be treated in a similar manner. In one embodiment, a compound is administered to a subject, which reduces the formation of A2E. For example, the compound can compete with the PE for the reaction with the trans RAL, thereby reducing the amount of A2E formed. In another embodiment, a compound is administered to a subject, which prevents the accumulation of A2E. For example, the compound competes so successfully with PE by the reaction with trans RAL, that A2E is not formed. Individuals to be treated fall into three groups: (1) those who are clinically diagnosed with macular degeneration or other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin, based on visual deficits (including, but not limited to) , adaptation to darkness, sensitivity to contrast and acuity), as determined by visual examination and / or electroretinography and / or retinal health, as indicated by the fundoscopic examination of the retina and the tissue of the RPE for the accumulation of druse, tissue atrophy and / or fluorescence of lipofuscin; (2) those that are presymptomatic for degenerative macular disease, but are thought to be at risk, based on abnormal results in any or all of the same measures, and (3) those that are presymptomatic but are thought to be at risk genetically, based on family history of degenerative macular disease and / or genotyping results that show one or more alleles or polymorphisms associated with the disease. The compositions are administered topically or systemically one or more times per month, week or day. Dosages can be selected to avoid lateral effects, if any, on visual performance in dark adaptation. The treatment is continued for a period of at least one, three, six, twelve or more months. Patients can be tested at intervals of one, three, six, twelve months or longer to assess safety and efficacy. Efficacy is measured by visual examination and retinal health as described above. In one embodiment, a subject is diagnosed as having symptoms of macular degeneration, and then a described compound is administered. In another embodiment, a subject can be identified as being at risk of developing macular degeneration (risk factors include a history of smoking, age, female gender and family history), and then a described compound is administered. In another embodiment, a subject may have dry AMD in both eyes, and then a described compound is administered. In another embodiment, a subject may have wet AMD in one eye but dry AMD in the other eye, and then a described compound is administered. In yet another modality, a Subject can be diagnosed as having Stargardt's disease and then a described compound is administered. In another modality, a subject is diagnosed as having symptoms of other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin., and then the compound is administered. In another embodiment a subject can be identified as being at risk of developing other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin, and then the compound described is administered. In some embodiments, a compound is administered prophylactically. In some modalities, a subject has been diagnosed as having the disease before the retinal damage is evident. For example, a subject is found to carry a mutation of the gene for ABCA4 and is diagnosed as being at risk for Stargardt disease before any ophthalmological signs are manifest, or a subject is found to have early macular changes indicative of degeneration macular, before the subject realizes any effect on the vision. In some modalities, a human subject may know that he or she is in need of treatment or prevention for macular degeneration. In some modalities, a subject can be monitored for the degree of macular degeneration. A subject can be monitored in a variety of ways, such as by examination of the eye, dilated eye examination, fundoscopic examination, visual acuity test and / or biopsy. Surveillance can be done at various times. For example, a subject can be monitored after a compound is administered. Surveillance 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 period of time after the first administration of the compound. A subject can be monitored repeatedly. In some embodiments, the dose of a compound can be altered in response to surveillance. In some embodiments, the disclosed methods may be combined with other methods to treat or prevent macular degeneration or other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin, such as photodynamic therapy. For example, a patient may be treated with more than one therapy for one or more diseases or disorders. For example, a patient may have one eye afflicted with the dry form of AMD, which is treated with a compound of the invention, and the other eye afflicted with the wet form of AMD, which is treated, for example, with therapy photodynamic In some embodiments, a compound for treating or preventing macular degeneration or other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin, may be administered chronically. The compound can be administered daily, more than once a day, twice a week, three times a week, weekly, biweekly, monthly, bi-monthly, semi-annually, annually and / or bi-annually. The therapeutic agents can be administered by a wide variety of routes, as described above. In some embodiments, a compound can be administered orally, in the form of a tablet, a capsule, a liquid, a paste and / or a powder. In some embodiments, a compound can be administered locally, such as by intraocular injection. In some embodiments, a compound can be administered systemically in a form coated, masked or otherwise inactive and activated in the eye (such as by photodynamic therapy). In some embodiments, a compound may be administered in a depot form, so that sustained release of the compound is provided for a period of time, such as hours, days, weeks and / or months. Preferably, the compound is administered topically, as a formulation of eye drops. Typical dose ranges include 0.5 to 5 mg / lOOg for oral formulations and solutions of 0.5% to 5% for eye drops formulations. The compounds of the invention are provided in therapeutic compositions. The compound is present in an amount that is therapeutically effective, which varies widely depending on the particular compound being used. The preparation of the pharmaceutical or pharmacological compositions will be known to those skilled in the art, in light of the present disclosure. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for the solution in, or suspension in a liquid before injection; as tablets or other solids for oral administration; as temporary release capsules or in any other form currently used, including eye drops, creams, lotions, balms, inhalants and the like. The compositions can also be delivered via a microdevice, microparticle or sponge. After formulation, the therapeutic agents will be administered in a manner compatible with the dosage formulation, and in such amount as to be pharmacologically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like may also be employed. In this context, the amount of the active ingredient and the volume of the composition to be administered depends on the host animal to be treated. The precise amounts of the active compound required for administration depend on the judgment of the practitioner and are peculiar to each individual. A minimum volume of a composition required to disperse the active compounds is typically used. The regimes suitable for administration are also variable, but would be typified by initially administering the compound and verifying the results and then giving additional controlled doses at additional intervals. The amount of the compound incorporated in the composition also depends on the desired release profile, the concentration of the compound required for the biological effect and the time that the biologically active substance has to be released for treatment. In certain embodiments, the biologically active substance can be combined with a polymer matrix at different charge levels, in a room temperature mode and without the need for an organic solvent. In other embodiments, the compositions can be formulated as microspheres. In some embodiments, the compound can be formulated for sustained release. For oral administration in the form of a tablet or capsule (eg, a gelatin capsule), the active drug component can be combined with a non-toxic pharmaceutically acceptable inert oral carrier, such as ethanol, glycerol, water and the like. In addition, when desired or it is necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, magnesium aluminum silicate, starch paste, methylcellulose gelatin, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, polyethylene glycol, waxes and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, silica, talc, stearic acid, its magnesium or calcium salt and / or polyethylene glycol. and the similar. The disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, starches, agar, alginic acid or its sodium salt or effervescent mixtures and the like. Diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine. The injectable compositions are preferably aqueous isotonic solutions or suspensions, and the suppositories are advantageously prepared from fat emulsions or suspensions. The compositions can be sterilized and / or contain adjuvants, such as preservatives, stabilizers, humectants or emulsifiers, solution promoters, salts for regulating the osmotic pressure and / or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to the conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient. The compounds of the invention can also be administered in oral dosage forms such as tablets or capsules of temporary and sustained release, pills, powders, granules, elixirs, dyes, suspensions, syrups and emulsions. The compounds of the invention can also be administered topically, such as directly to the eye, for example, as eye drops or as an ophthalmic ointment. The drops for the odors typically comprise an effective amount of at least one compound of the invention and a carrier capable of being securely applied to the eye. For example, the eye drops are in the form of an isotonic solution, and the pH of the solution is adjusted so that there is no odor irritation. In many cases, the epithelial barrier interferes with the penetration of molecules into the eye. Thus, currently used ophthalmic drugs are supplemented with some form of penetration enhancer. These penetration enhancers work by loosening the tight joints of the uppermost epithelial cells (Burstem, 1985, Trans Ophthalmol Soc RU 104 (Pt 4): 402-9; Ashton et al, 1991, J Pharmacol Exp Ther 259 (2): 719-24; Green et al, 1971, Am J Ophthalmol 72 (5): 897-905). The most commonly used penetration enhancer is benzalcomo chloride (Tang et al, 1994, J Pharm Sci 83 (l): 85-90, Burstein et al, 1980, Invest Ophthalmol Vis Sci 19 (3): 308-13 ), which also works as a conservative against microbial contamination. It is typically applied at a final concentration of 0.01-0.05%.

Selection methods Suitable compounds can be identified by a variety of screening methods. For example, a candidate compound can be administered to a subject who has or is at risk of developing macular degeneration or other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin, and the accumulation of a retinotoxic compound, such as A2E , it can be measured. A drug that results in a reduced accumulation of a retinotoxic compound, compared to a control (absence of the drug) would be identified as an appropriate drug. Alternatively, RAL and RPE tissue can be analyzed for the presence of A2E and / or its precursors.

EXAMPLES EXAMPLE 1: Synthesis of the Compounds The compounds of the invention, and the related derivatives, can be synthesized by methods known to one of skill in the art. For example, a detailed method for the synthesis of compound 7 is described below in Reaction Scheme 3. Reaction Scheme 3 A mixture of acetonitrile (60 mL) and ethyl 2-amino-1,3, thiazole-4-carboxylate (0.54 g, 3 mmol) and N-fluorobenzenesulfonimide (3.3 g, 9 mmol) was heated to reflux temperature for 18 hours. The color changed from yellow to reddish. The reaction mixture was concentrated and purified using chromatographic methods: column chromatography (2-5% methanol-chloroform), preparative TLC (2% methanol-chloroform), preparative HPLC (column: Phenomenex Luna phenyl-hexyl (150x4. 6 mm ID, packed at 3 μm), ?? = 215 nm, flow rate: 0.8 mL / minute, injection volume: 5 mL, run time: 31 minutes, gradient of the mobile phase: A: water w 0.1 volume / volume of TFA, B MeCN w 0.1 volume / volume of TFA), and preparative TLC (10% of meOH-chloroform), to give a brown solid (380 mg). LCMS m / z: 145, 173, 191, 381 and 399.? H NMR (300 MHz, CDC13) d: 1.3 ppm (m, 3H Me) and 4.8 ppm (m, 2H, CH2).

EXAMPLE 2: In Vitro Confirmation of the Schiff Base UV / VIS spectroscopy was used to verify the condensation of the Schiff base of the RAL with the primary amine of a compound of the invention. The in vitro analysis of the condensation product of the Schiff base with the RAL was carried out for the compounds described 1, 2, 3, 4, 5 and 6 and the results are shown in Table 1. In the analysis in the solution phase, the max value of the free compound and the condensation product of the RAL and the Schiff base (RAL-SBC) is measured together with the tau value of RAL-SBC. As used herein, "RAL-SBC" means the condensation product of the Schiff base of the RAL and the RAL compound. The solution pass analysis is performed using a 100: 1 mixture of the compound and RAL, using protocols known in the art. Several solvent systems were tested, including aqueous, ethanol, octanol and chloroform: methanol (several, for example, 2: 1). The kinetics of the solution is measured and found to be highly dependent on solvent conditions. Figures 4a and 4b show the results of the condensation of the Schiff base of compound 6 and RAL (100: 1) in chloroform: methanol (2: 1). The solid phase analysis of the condensation of the Schiff base was also performed using a 1: 1 mixture of the compound at RAL. Solid phase analysis was performed using protocols known in the art. The mixture was dried under nitrogen and the condensation reaction occurred until completion. The analysis in lipid phase is carried out using protocols known in the art and measured? Max, tau (RAL-SBC vs. APE / A2PE) and competitive inhibition. The conditions of Liposomes are closer to in situ conditions.

EXAMPLE 3: Log P and values of pKa The values of log P are shown in Table 1 for compounds 1, 2, 3, 4, 5 and 6. The partition coefficient (log P) is the logarithm of the relationship [ X0rgánico] / [Xacuoso] for a compound X at a pH where X at a pH where X is neutral, not ionized. Values above zero denote lipophilic properties that increase and below zero, hydrophilic properties that increase. Octanol is commonly used as the organic solvent. The examples are as follows: Log P = 2 X is 102 more soluble in the organic solvent than in the aqueous Log P = 0 X is equally soluble in both Log P = -2 X is 102 more soluble in the aqueous solvent than in the organic The log P values are typically calculated algorithmically (not measured experimentally), through programs such as Pallas and ACDlabs. The results of the calculation vary with the product of the program and are considered as approximations of the order of magnitude. The pKa values are shown in Table 1 for compounds 1, 2, 3, 4, 5, 6 and 7. The pKa values are measured using methods known in the art. The acidity of a general acid, HA, is expressed by the chemical equation: HA + H20 'H30 + + A " Which is described by the equilibrium constant K. of According to the general definition of an equilibrium constant, K is expressed as Because in aqueous solution, [H20] will be constant at 55 mol l "1, that number can be incorporated in a new constant Ka, defined as the acidity constant: DH30 +] [A-]? A = moles I I [HA] This measurement, when put on a logarithmic scale, is pka = -logKa. An acid with a pKa less than 1 is defined as strong, one with a pKa greater than 4 is weak. The volume of distribution (V) of a drug can vary widely depending on the pKa of the compound. The volume of distribution is related to the amount of the compound in the body at the concentration of the compound in the blood or plasma.

Table 1.

EXAMPLE: ERG Analysis of Adaptation to Darkness Adaptation to darkness is the recovery of visual sensitivity after exposure to light. The adaptation to the dark has multiple components, including the fast processes (neuronal) and the slow process (photochemical). The regeneration of the visual pigment is related to the slow photochemical process. The dark adaptation speeds are measured for several reasons. Night blindness results from a failure to adapt to darkness (loss of sensitivity to light). It is possible to find a safe dose for night vision by measuring the effects of the drug on the sensitivity to adapted light. An electroretinogram (ERG) is used to measure adaptation to darkness under normal conditions vs. the drug. The ERG is the measurement of the potential of the field electrical energy emitted by retinal neurons during their response to an experimentally defined luminous stimulus. More specifically, the ERG measures the potentials of the retinal field in the cornea after a flash of light (for example, 50 ms). The field forces are 102 to 103 microvolts, originating in the retinal cells. The ERG is a non-invasive measurement that can be performed on live subjects (human or animal) or on a semi-sectioned eye in solution that has been surgically removed from a live animal. ERG requires general anesthesia that slows down adaptation to darkness and must be factored into an experimental design. In an ERG analysis typical of a dark adaptation experiment, each rat adapts to darkness for hours to reach a consistent state of sensitivity to light. The rat is then "photodecolorated" ie it is briefly exposed to a light strong enough to transiently impoverish the retina of free 11-cis-RAL (eg, 2 minutes at 300 lux). The rat is then returned to darkness immediately to begin adaptation to darkness, ie, recovery of sensitivity to light due to the regeneration of the visual pigment. The ERG is used to measure how quickly the rat adapts to darkness and regains sensitivity to light. Specifically, a variable response criterion is defined for sensitivity to light (see Figure 5). The ERG measurement is taken after a specific duration of a post-discoloration dark recovery (eg, 30 minutes), previously determined by a kinetic analysis (see Figures 6a and 6b). An adjustment of the curve is used to calculate the value for the variable of the sensitivity. Figure 6a shows the recovery with anesthesia in the same rat, including the dark adaptation kinetics for Y50 and s. A slower adaptation was observed with less sensitivity to light where Y50 reaches -4.0 and tau = 22.6 minutes. Figure 6b shows the recovery without anesthesia (5 different rats), including the kinetics of dark adaptation for Y50. A faster adaptation was observed with more sensitivity to light where Y50 reaches -5.5 and tau = 9.2 minutes. The same paradigm that was described above is followed for the variation of the dose. As shown below in Figure 7, in the dose variation protocol of the ERG, compound 6 i.p. decreases the sensitivity to light of rats adapted to darkness in a dose-dependent manner. The effect on vision decreases after 3 hours.

EXAMPLE 5: NMR Analysis of RAL Reactions NMR spectroscopy was used to verify the formation of Schiff's base condensation and the formation of the RAL ring with the primary amine of a compound of the invention. The EMN analysis of the RAL reactions was performed for the described compounds 6, 8 and 9, as shown in Figure 8 and Table 2. The rates of condensation in the pure chloroform are as follows: > 8 > 9.

Table 2 EXAMPLE 6: Inhibition of A2E Formation This experiment was designed to establish the proof of concept that the i.p. Chronicity of a RAL collector compound decreases the rate of A2E accumulation in wild type Sprague Dawley rats. These experiments compare the effectiveness of the treatment of the RAL collector compounds with that of the control compounds and the lack of treatment.

Materials and Methods: The study was conducted with wild type Sprague Dawley rats. Groups of treatment rats include, for example, 8 rats of mixed genus by treatment condition. Each animal was treated with one of the following conditions: - Controls: (1) 13-cis retinoic acid to inhibit the retinoid binding sites of the visual cycle proteins as a control protocol, in which such treatment reduces the amount of free trans-RAL that is released and therefore, that is available to form A2E, but with undesirable side effects of night blindness, and (2) a commercially available compound, known clinically to modulate retinal function in humans and known experimentally by forming an adduct of a Schiff base with free RAL, both in animal models in vitro and in vivo. - Vehicle - Compound - Not treated Several compounds are tested, for example, 4 compounds. The compounds are tested through a dose range that includes 1, 5, 15 and 50 mg / kg. The treatment is administered daily for 8 weeks by i.p injection ..

Chemistry: The experiments use a variety of chemistry services. For example, these experiments use commercially available compounds with analytical specification sheets to characterize the impurities. The compounds are also synthesized. The compounds are prepared in sufficient amounts for the required dosage. The formulations of the compound are suitable for use in initial animal safety studies involving intraperitoneal injection (i.p.). the following three attributes of the reaction product of the Schiff base of the trans-RAL with the compounds of the invention were determined: stability with respect to reaction rates absorption properties, specifically maximum uv-vis absorption and coefficients of extinction (see for example, Figure 5 in Rapp and Basinger, Vision Res. 22: 1097, 1982) or NMR spectrum analysis of reaction kinetics - solubility values log P and log D, for example, calculated Biology and Biochemistry: The experiments described here use a variety of biology and biochemistry services. A dose of "no effect level" (NOEL) of the compounds of the invention for the daily treatment with a formulation with eye drops is established, for example, in the rabbit with an ocular irritation protocol and in the rodent with a measurement of ERG from adaptation to darkness in visual responses to light stimulation. After the treatment and before enucleation of the eye, the following non-invasive tests were performed on the animals, for example, rabbits: - RPE and degeneration of the photoreceptor cells, as is evident from the background photography (Karan, et al. 2005, PNAS 102: 4164) Extracellular drusus and intracellular lipofuscin, as measured by fluorescent background photography (Karan et al 2005) Responses to light are characterized by an ERG (eng, et al, Cell 98:13, 1999) . The concentration of the intracellular A2E of the extracts of the retinal RPE cells is measured in all the treated animals after the conclusion of the treatment protocol using an analytical method, such as those described by Karan et al, 2005; Radu et al, 2003 and Parish et al, PNAS 95: 14609, 1998. For example, in a sample of treated animals, one eye is tested, and the other eye is saved for histological analysis (as described below). In the remaining animals, both eyes are tested separately for the formation of A2E. In post-treatment, the eyes set aside for histology (as described above), the morphology of the retinal tissue and the RPE are evaluated with histology techniques with light microscopy (Karan et al., 2005, with the exception that electron microscopy). it is not used in the experiments described herein). The safety of the treatment regimen is assessed, for example, using a combination of: - Daily documented observation of the animal's behavior and feeding habits throughout the period of treatment - Visual performance, as measured by the ERG at the end of the treatment period Ocular histology at the end of the treatment period.

Incorporation as Reference All the description of each of the patent documents, including the correction certificates, the patent application documents, the scientific articles, the government reports, the websites and other references in the present, are incorporated as a reference in its entirety for all purposes. In case of a conflict in the terminology, this specification will have control.

Other embodiments Although the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims. It will be understood by those skilled in the art that various changes may be made in the form and details thereof, without departing from the scope of the invention encompassed by the appended claims.

Claims (9)

1. CLAIMS: A compound represented by the general formula wherein, X, Y and Z are each, independently, N, S, O, CU or CH, so that at least one of W, X, Y and Z is N; D is unbranched lower alkyl; R is a linear or unsubstituted alkyl chain of Cl, C2, C3, C4, C5, C6, C7 or C8, or a branched or unsubstituted, substituted alkyl chain of C3, C4, C5, C6 , C7 or C8; U is a substituent selected from a halogen atom; cyano; lower alkyl, wherein one or more hydrogen atoms in the lower alkyl group are optionally substituted with groups selected from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic group containing one or more selected heteroatoms of nitrogen, oxygen and sulfur atoms; lower alkylthio, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; lower alkylsulfonyl, wherein one or more hydrogen atoms in the alkyl group are substituted optionally with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N, N-di-lower alkylaminocarbonyl; Not me; 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 with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom; and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms; and n is 0, 1, 2, 3 or 4. The compound according to claim 1, wherein the compound comprises a ring of pyridine, pyridazine or pyrazine. The compound according to claim 1, wherein two adjacent U substituents are connected as a benzene ring, forming a compound having the structure according to the formula la: (la), where X, Y and Z are each, independently, N, O, S, CH, or is absent, so that at least one of X, Y and Z is N; p is 0, 1, 2 or 3; B is a halogen, hydroxyl, carbamoyl, aryl or amino atom; A is ; D is unbranched lower alkyl; and R is a linear or substituted unsubstituted alkyl chain of Cl, C2, C3, C4, C5, C6, C7 or C8, or a substituted or unsubstituted, branched alkyl chain of C3, C4, C5, C6, C7 or C8. 4. The compound according to claim 1, wherein the composition comprises a compound selected from: A compound represented by formula II or l i a (II) or illa), wherein Q, T and V are each, independently, NH, S, 0, CU or CH, so that at least one of Q, T and V is not CU or CH; the dotted line represents two double bonds within the ring, which meets the valence requirements of the atoms and heteroatoms present in the ring; m is 0, 1 or 2; A is D is unbranched lower alkyl; R is a linear or unsubstituted alkyl chain of Cl, C2, C3, C4, C5, C6, C7 or C8, or a branched or unsubstituted, substituted alkyl chain of C3, C4, C5, C6 , C7 or C8; and U is a substituent selected from a halogen atom; cyano; lower alkyl, wherein one or more hydrogen atoms in the lower alkyl group are optionally substituted with groups selected from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic group containing one or more selected heteroatoms of nitrogen, oxygen and sulfur atoms; lower alkylthio, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; lower alkylsulfonyl, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N, N-di-alkylaminocarbonyl lower; Not me; 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 with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom; and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms; and 6. The compound according to claim 5, wherein, T and V are selected such that the composition comprises a furan or thiophene ring. 7. A compound represented by general formula III: wherein, L is a single bond or CH2; D is unbranched lower alkyl; R is a linear or unsubstituted alkyl chain of Cl, C2, C3, C4, C5, C6, C7 or C8, or a branched or unsubstituted, substituted alkyl chain of C3, C4, C5, C6 , C7 or C8; U is a substituent selected from a halogen atom; cyano; lower alkyl, wherein one or more hydrogen atoms in the lower alkyl group are substituted optionally with groups selected from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms; lower alkylthio, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; lower alkylsulfonyl, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N, N-di-lower alkylaminocarbonyl; Not me; 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 with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom; and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms; and k is 0, 1, 2, 3 or 4. The compound according to claim 7, wherein two adjacent U substituents are connected as a heterocyclic ring, forming a compound having the structure according to the formula Illa: (Illa), wherein X, Y and Z are each, independently, N, O, S, CB, CH3 or absent, so that at least one of X, Y and Z is N; p is O, 1, 2 or 3; B is a halogen, hydroxyl, carbamoyl, aryl or amino atom; A is D is unbranched lower alkyl; and R is a linear or substituted unsubstituted alkyl chain of Cl, C2, C3, C4, C5, C6, C7 or C8, or a substituted or unsubstituted, branched alkyl chain of C3, C4, C5, C6, C7 or C8. 9. The compound according to claim 8, wherein the fused heterocyclic ring is a 6-membered ring. The compound according to claim 9, wherein the fused heterocyclic ring is a pyridine ring. 11. The compound according to claim 8, wherein the fused heterocyclic ring is a 5-membered ring. The compound according to claim 11, wherein the fused heterocyclic ring is selected from thiazole, oxazole and imidazole.
2. 13. A compound of formula IV: (IV), wherein X is O, N (H) or S, het is a 5- or 6-membered heterocycle, "Q n is 0, 1, 2 or 3, and each D is unbranched lower alkyl, U is a substituent selected from a halogen atom; cyano; lower alkyl, wherein one or more hydrogen atoms in the lower alkyl group are optionally substituted with groups selected from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms; lower alkylthio, wherein one or more hydrogen atoms in The alkyl group is optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, amino and aryl atom; lower alkylsulfonyl, wherein one or more hydrogen atoms in the alkyl group are optionally substituted with groups selected from a halogen atom, 25 hydroxyl, carbamoyl, amino and aryl; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N, N-di-lower alkylaminocarbonyl; Not me; N-lower alkylamino; N, N-di-alkylamino 30 lower; formylamino; lower alkylcarbonylamino; aminosulfonylamino; (N-lower alkylamino) sulfonylamino; (N, N-di-lower alkylamino) sulfonylamino; aryl, optionally substituted with groups selected from a halogen, hydroxyl, carbamoyl, aryl and amino atom; and a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. The compound according to claim 13, wherein the first pK a of the NH 2 ring is about 3.5. 2 15 A compound selected from pharmaceutically acceptable salts thereof. 16. The compound according to any of claims 1, 5, 7, 13 and 15, wherein the adduct of the Schiff Base of the compound and the 11-cis-retinaldehyde has an extinction coefficient equal to or less than that of 11- free cis-retinaldehyde. 17. The compound according to claim 16, wherein the absorbance peak of the adduct is at a wavelength equal to or less than that of 11-cis-retinaldehyde. 18. The compound according to any of the claims 1, 5 and 7, wherein A is 19. The compound according to any of the claims 1 and 7, wherein two adjacent U substituents are connected to form a 5 or 6 member ring optionally substituted. 20. The compound according to any of claims 1 and 13, wherein n is selected from 0, 1, 2 or
3. 3. 21. The compound according to any of claims 1, 5, 7 and 13, wherein D is unbranched lower alkyl. 22. The compound according to claim 21, wherein D is methyl. 23. The compound according to any of claims 1, 5, 7 and 13, wherein U is aryl. 24. The compound according to claim 23, wherein U is benzene. 25. The compound according to any of claims 1, 5, 7 and 13, wherein U is benzene substituted with halo. 26. The compound according to any of claims 1, 5, 7 and 13, wherein U is alkyl. 27. The compound according to claim 26, wherein U is methyl. 28. The compound according to any of claims 1, 5, 7 and 13, wherein U is halo. 29. The compound according to claim 28, wherein U is fluorine. 30. The compound according to claim 3 or 8, wherein B is aryl. 31. The compound according to claim 30, wherein B is benzene. 32. A pharmaceutical composition comprising a compound according to any one of claims 1, 5, 7, 13 and 15 or a salt, solvate, hydrate or prodrug thereof, and at least one pharmaceutically acceptable excipient. 33. The use of a compound according to any of claims 1, 5, 7, 13 and 15 in the manufacture of a medicament for treating or preventing macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and / or Lipofuscin in retinal tissue in a subject, the drug reduces the level of accumulation of A2E relative to the level of accumulation of A2E in the subject without the administration of the composition. 34. The use of a compound according to any of claims 1, 5, 7, 13 and 15 in the manufacture of a medicament for diagnosing macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin in the retinal tissue in a bundle. 35. The use of a compound according to any of claims 1, 5, 7, 13 and 15 in the manufacture of a medicament for verifying macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin in the retinal tissue in a bundle. 34. The use according to claim 33, wherein the medicament comprises a compound selected from The use according to claim 33, wherein the medicament includes a comp. this selected from benzocaine, procaine, orthocaine, tricaine (MS222) and anthranilate.