WO2005108353A2

WO2005108353A2 - Compounds for treating neurologic diseases, otologic diseases, or ophthalmologic diseases and methods of use thereof

Info

Publication number: WO2005108353A2
Application number: PCT/US2005/016132
Authority: WO
Inventors: Alfred Stracher; Leo Kesner
Original assignee: Ceptor Corporation
Priority date: 2004-05-06
Filing date: 2005-05-06
Publication date: 2005-11-17
Also published as: WO2005108353A3

Abstract

Described herein are compounds and methods for treating or preventing a neurologic, otologic, or ophthalmologic disease in a subject.

Description

COMPOUNDS FOR TREATING NEUROLOGIC DISEASES, OTOLOGIC DISEASES, OR OPHTHALMOLOGIC DISEASES AND METHODS OF USE THEREOF CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application Serial No. 60/568,720, filed May 6, 2004, the entire disclosure of which is hereby incorporated by reference in its entirety for all purposes. BACKGROUND Neurologic, otologic, and ophthalmologic diseases in general are very debilitating to the patient and significantly reduce the quality of life of the subject. Additionally, due to their impact on the patient, neurologic, otologic, and ophthalmologic diseases can also be very difficult for family members of the patient as well. Although research has been conducted on the treatment and prevention of several neurologic, otologic, and ophthalmologic diseases, results have been limited. One such neurologic disease that is particularly debilitating is epilepsy. Epilepsy affects 1 to 2% of the world's population. In the United States alone, over 2.5 million people experience the devastating effects of epileptic seizures. In general, epileptic seizures are characterized by transient impairment of consciousness that leave the afflicted individual at risk of severe bodily harm. In addition, epilepsy may interfere with employment, education, or the other daily activities. Treatment of persons who suffer epileptic seizures is generally directed toward the symptom, i.e., attenuating the convulsant episode after it begins. At present, there is no effective treatment for preventing the recurrence of seizures. It is known that currently available antiepileptic drugs are far from ideal. For example, it is generally held that antiepileptic drugs demonstrate complete control of seizure activity in only about 50% of cases. In addition, these compounds may produce serious side effects ranging in severity from minor impairment of the central nervous system (CNS) to death from liver failure or aplastic anemia. Therefore, searching for new compounds such as, for example, antiepileptics that provide a therapeutic benefit coupled with less severe side effects is a major focus of medical research. One strategy for decreasing side effects would be to effectively target the therapeutic compound to the CNS, thereby permitting lower doses of the particular agent used. The result being that administering lower does would achieve the therapeutic benefit with reduced side effects. Described herein are compounds that have been modified so that when the compound is delivered to a subject and enters the cells of nervous tissue, it can facilitate the treatment of a subject suffering from a neurologic disease or aid in the prevention of contracting the neurologic disease.

SUMMARY Described herein are compounds and methods for treating or preventing a neurologic, otologic, and/or ophthalmologic disease in a subject. The advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects described below. Figure 1 shows the synthetic pathway for a therapeutic agent according to the invention. Figure 2 shows the results of experiments measuring the mean serum (MS) value, in arbitrary units, of propylpentanoyl-diaminobutyl-cysteic acid (PDC), at different times post injection. DETAILED DESCRIPTION Before the present compounds, compositions, articles, and/or methods are disclosed and described, it is to be understood that the aspects described below are not limited to specific compounds, synthetic methods, or uses as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings: It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like. "Optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, the phrase "optionally substituted lower alkyl" means that the lower alkyl group can or can not be substituted and that the description includes both unsubstituted lower alkyl and lower alkyl where there is substitution. Ranges may be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. A weight percent of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included. Variables such as R'-R⁴, m, n, o, p, L, W, X, Y, and Z used throughout the application are the same variables as previously defined unless stated to the contrary. The term "residue" as used herein refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. For example, a linker L that contains at least one -OH group can be represented by the formula L-OH, where L is the remainder (i.e., residue) of the linker. The term "alkyl group" as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 25 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, ra-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. A "lower alkyl" group is an alkyl group containing from one to six carbon atoms. The term "alkenyl group" is defined as a branched or unbranched hydrocarbon group of 2 to 24 carbon atoms and structural formula containing at least one carbon-carbon double bond. The term "aryl group" as used herein is any carbon-based aromatic group including, but not limited to, benzene, naphthalene, etc. The term "aryl group" also includes

"heteroaryl group," which is defined as an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy. The term "alkyl amino group" as used herein is an amino group having at least one alkyl group as defined above (i.e., -NHR or NRR'). The term "alkyl guanidinium group" as used herein is guanidine having at least one alkyl group as defined above on the imino or amino nitrogen. The term "polyalkylene group" as used herein is a group having two or more CH₂ groups linked to one another. The polyalkylene group can be represented by the formula -(CH₂)₀- where O is an integer of from 2 to 25. The polyalkylene group can be unsubstituted or, in the alternative, one or more hydrogen atoms can be replaced with a group such as, for example, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy, and the like. The term "polyether group" as used herein is a group having the formula -[(CHR)₀O]p- where R is hydrogen or a lower alkyl group, o is an integer of from 1 to 20, and p is an integer of from 1 to 100. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide. The term "polythioether group" as used herein is a group having the formula -[(CHR)₀S]_p- where R is hydrogen or a lower alkyl group, o is an integer of from 1 to 20, and p is an integer of from 1 to 100. The term "polyimino group" as used herein is a group having the formula

-[(CHR)₀NR]p-, where each R is, independently, hydrogen or a lower alkyl group, o is an integer of from 1 to 20, and p is an integer of from 1 to 100. The term "polyester group" as used herein is a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups. The term "polyamide group" as used herein is a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two unsubstituted or monosubstituted amino groups. By "subject" is meant an individual. Preferably, the subject is a mammal such as a primate, and, more preferably, a human. The term "subject" can include domesticated animals, such as cats, dogs, etc., livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.). "Treatment" or "treating" means to administer a composition to a subject or a system with an undesired condition. The effect of the administration of the composition to the subject can have the effect of, but is not limited to, reducing or preventing the symptoms of the condition, a reduction in the severity of the condition, or the complete ablation of the condition. By "prevent" or "preventing" means the administration of a composition to a subject or a system at risk for an undesirable condition. The condition can include a disease or a predisposition to a disease. Prevention can range from a reduction in the severity of the condition to the complete ablation of the condition. By "effective amount" is meant a therapeutic amount needed to achieve the desired result or results, e.g., inhibiting enzymatic activity. Herein, "inhibition" means to reduce activity as compared to a control. It is understood that inhibition can mean a slight reduction in activity to the complete ablation of all activity. An "inhibitor" can be anything that reduces the targeted activity. Disclosed are compounds, compositions, and components that can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a number of different linkers and compounds for treating or preventing a neurologic disease are disclosed and discussed, each and every combination and permutation of the linker and compound are specifically contemplated unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited, each is individually and collectively contemplated. Thus, in this example, each of the combinations A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D. Likewise, any subset or combination of these is also specifically contemplated and disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed. I. Compounds Described herein are compounds that can be used to treat a neurologic, otologic, or ophthalmologic disease in a subject. In one aspect, the compound has the formula I

wherein R¹ and R² comprise, independently, hydrogen or an alkyl group;

L is an optional linker; X is a residue of a compound for treating or preventing a neurologic disease, an ophthalmologic disease, or an otologic disease, wherein X is not a protease inhibitor; wherein when L is not present, X is covalently bonded to C_α, or the pharmaceutically acceptable salt or ester thereof, wherein the compound having the formula I is racemic or the substantially pure enantiomer. The compounds having the formula I can be the substantially pure L- or D-isomer, or a mixture thereof. The term "substantially pure" with respect to the L- or D-isomer refers to greater than 95%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%, or 100% of one isomer with respect to the other enantiomer. The portion of the molecule in formula I having the formula -C_α(O)CH(NR¹R²)CH₂SO₃H is referred to herein as "the carrier molecule." The carrier molecule and X can be directly or indirectly bonded to one another. In one aspect, R¹ and R² are both hydrogen. When the carrier molecule and X are directly bonded to one another, a new covalent bond is formed between the carrier molecule and X. For example, the COOH group of cysteic acid can react with an amino group present on X to form a new amide linkage. In another embodiment, functional groups present on the carrier molecule and/or X can be chemically modified prior to direct or indirect bonding. Referring to formula I, when the carrier molecule is directly attached to X, L is not present, and X is covalently attached to C_α. In one aspect, the linker is not present in formula I. Alternatively, the carrier molecule and X can be indirectly bonded to one another with the use of a linker molecule. A "linker molecule," which is denoted as "L" in formula I, is any compound that has at least one group that can form a covalent bond with the carrier molecule and at least one group that can form a covalent bond with X. In one aspect, the linker group can have up to 25 carbon atoms. In another aspect, the linker can be a polyalkylene group, a polyether group, a polyamide group, a polyimino group, a polyester, an aryl group, or a polythioether group having two or more groups capable of reacting with the carrier molecule and protease inhibitor. It is contemplated that the linker can be of varying molecular weight. In another aspect, the linker has the formula Z-Y-W, wherein W and Z are, independently, O, S, or NR , wherein R is hydrogen or branched or straight chain alkyl, and Y is a branched or straight chain alkyl group, a branched or straight chain alkylene group, or an aryl group. In a further aspect, L has the formula Z-(CH )_m-W, wherein W and Z are, independently, O, S, or NR , wherein R is hydrogen or branched or straight chain alkyl, and m is from 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 2 to 8, 3 to 8, 4 to 8, or 4 to 6. In one aspect, both W and Z can be O, both W and Z can be NH, or W can be O and Z can be NH. Thus, in these aspects, any combination of ester and amide linkages is contemplated between the linker, the carrier molecule, and X. In another aspect, L has the formula -(CH₂)₀-CH(R )-(CH₂)p-, wherein R⁴ is hydrogen, hydroxyl, an alkyl hydroxyl group (e.g., CH OH or CH₂CH OH), an alkyl guanidinium group, or an alkyl amino group. In one aspect, L has the formula HN-(CH₂)„-NH, wherein n is from 1 to 6, 2 to 6, 3 to 6 or 4 to 6. In a further aspect, L has the formula HN-(CH₂)₄-NH. In one aspect, L is a polar or charged amino acid that is covalently bonded to C_α and X via an amide linkage. In this aspect, one or more amino acids can be charged (e.g., a salt). Alternatively, the amino acid can be derivatized so that the resultant amino acid is more polar or charged relative to the starting amino acid. A single amino acid or two or more amino acids (e.g., a peptide) can be used in this aspect. In one aspect, the carrier molecule and X each possess a COOH group and the linker possesses two amino groups, where the amino groups of the linker react with the COOH groups of the carrier molecule and X to produce an amide bond (C(O)N-). In another aspect, the linker can be a polyamine such as, for example, spermine, spermidine, lysine, or a polypeptide. In one aspect, in formula I, X can be the residue of any compound that can treat or prevent a neurological disease. In one aspect, X is a residue of valproic acid or a derivative thereof. Derivatives of valproic acid are known in the art. In one aspect, the derivatives of valproic acid possess one or more groups capable of forming a covalent bond with the carrier molecule and/or the linker. Examples of such groups include, but are not limited to, amino, halo, ester, ketone, aldehyde, hydroxy, carboxylic acid, alkoxy, and the like. For example, U.S. Patent No. 5,440,023, which is incorporated by reference with respect to its teachings of making derivatives of valproic acid, discloses methods for adding carboxyl or amino groups at the δ-carbon of valproic acid. Other derivatives of valproic acid are disclosed in U.S. Patent Nos. 4,261,974 and 6,313,106, which are also incorporated by reference with respect to the different types of derivatives of valproic acid useful herein. In one aspect, X comprises a residue of valpromide. The term "valpromide" as used herein is valproic acid or a substituted form of valproic acid where the carboxylic acid group is converted to a substituted or unsubstituted amide. When the amide is substituted, one or both hydrogen atoms on the amide nitrogen can be substituted with an alkyl group, aryl group, cycloalkyl group, alkenyl group, alkynyl group, and the like. It is also contemplated that the group(s) present on the amide nitrogen can possess groups capable of forming covalent bonds with the carrier molecule and/or linker. The valpromide compounds disclosed in Tasso et al., "Characterization of the Anticonvulsant Profile of Valpromide Derivatives," Bioinorganic & Medicinal Chemistry 12, (2004) 3857-3869, are useful herein. In another aspect, when the compound is used to treat a neurologic or otologic disease, X can be a peptide or peptide-like compound (e.g. glucagon-like-peptides 1 and 2, the peptide Abeta(l-42), or fragments thereof), a steroid (e.g. methyl prednisolone and related steroidal compounds), a monoamine oxidase inhibitor (e.g., propargylamine, 1- deprenyl, and related compounds), agents for chelating of metal ions, agents that increase or decrease phosphatidylcholine metabolism (e.g., cytidine 5'-diphosphocholine), cholinesterase inhibitors, gabapentin, pregabalin and analogs thereof, inhibitors of GAB A transaminase, calcineurin inhibitors, sigma-1 receptor modulators, inhibitors of kinases that induce cellular degeneration (e.g., ERK, p38, and mixed-lineage kinases), anti-oxidative agents (e.g., glutathione and vitamin E), inhibitors of carbonic anhydrase (e.g. dorzolamide and acetazolimide), or inhibitors of nitric oxide synthase. In another aspect, when the compound is used to treat an ophthalmologic disease, X can be can be a peptide or peptide-like compound (e.g. glucagon-like-peptides 1 and 2, the peptide Abeta(l-42), or fragments thereof), a steroid (e.g. methylprednisolone and related steroidal compounds), a monoamine oxidase inhibitor (e.g., propargylamine, 1-deprenyl, and related compounds), agents for chelating of metal ions, agents that increase or decrease phosphatidylcholine metabolism (e.g., cytidine 5'-diphosphocholine), cholinesterase inhibitors, gabapentin, pregabalin and analogs thereof, inhibitors of GAB A transaminase, calcineurin inhibitors, sigma-1 receptor modulators, inhibitors of kinases that induce cellular degeneration (e.g., ERK, p38, and mixed-lineage kinases), anti-oxidative agents (e.g., glutathione and vitamin E), inhibitors of carbonic anhydrase (e.g. dorzolamide and acetazolimide), a tetracycline class antibiotics (e.g. minocycline), aurintrucarboxylic acid and derivatives thereof, an anti-angiogenic compound, or an inhibitor of nitric oxide synthase. In one aspect, the compound is propylpentanoyl-diaminobutyl-cysteic acid, which is depicted as compound 8 in Figure 1. When a linker is employed, it is contemplated that the linker molecule can be covalently attached to the carrier molecule and/or X prior to linking the carrier molecule to X using standard organic techniques known in the art. It is also contemplated that when a linker is used, the linker can be covalently attached to the carrier molecule first prior to covalent attachment of the linker to X. Alternatively, the linker can be covalently attached to X followed by covalent attachment of the linker to the carrier molecule. Various protecting groups can be used during the synthesis of the compounds, the selection of which will vary depending upon starting materials that are selected. Any of the compounds described herein can exist as a prodrug. The term "prodrug" is defined herein as an inactive form of a parent drug that has been created to overcome one or more barriers to its effective use. For example, a prodrug can be a compound that has a protecting group that is cleaved upon administration to a subject to produce the active form of the drug. The term "protecting group" as used herein is a group that can be chemically bound to an atom, and subsequently removed (either chemically, in vitro, or in vivo) from the atom by predictable methods. Examples of many of the possible protective groups can be found in Protective Groups in Organic Synthesis by T.W. Green, John Wiley and Sons, 1981, which is incorporated herein by reference in its entirety. It is contemplated that the carrier molecule, the linker, and/or X can be modified to produce a prodrug of the compound in formula I. Any of the compounds described herein can be the pharmaceutically-accep table salt thereof. In one aspect, pharmaceutically-acceptable salts are prepared by treating the free acid with an appropriate amount of a pharmaceutically-acceptable base. For example, one or more hydrogen atoms of the SO H group can be removed with a base. Representative pharmaceutically-acceptable bases are ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, aluminum hydroxide, ferric hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2- dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, and the like. In another aspect, if the compound possesses a basic group, it can be protonated with an acid such as, for example, HCl or H₂SO₄, to produce the cationic salt. In one aspect, the reaction of the compound with the acid or base is conducted in water, alone or in combination with an inert, water-miscible organic solvent, at a temperature of from about 0 °C to about 100 °C such as at room temperature. In certain aspects where applicable, the molar ratio of the compounds described herein to base used are chosen to provide the ratio desired for any particular salts. For preparing, for example, the ammonium salts of the free acid starting material, the starting material can be treated with approximately one equivalent of pharmaceutically-acceptable base to yield a neutral salt. It is contemplated that the pharmaceutically-acceptable salts of the compounds described herein can be used as prodrugs or precursors to the active compound prior to the administration. For example, if the active compound is unstable, it can be prepared as its salt form in order to increase stability in dry form (e.g., powder). II. Methods of Use Delivery As used throughout, administration of any of the compounds described herein can occur in conjunction with other therapeutic agents. Thus, the compound can be administered alone or in combination with one or more therapeutic agents. For example, a subject can be treated with a compound alone, or in combination with chemotherapeutic agents, antibodies, antivirals, steroidal and non-steroidal anti-inflammatories, conventional immunotherapeutic agents, cytokines, chemokines, and/or growth factors'. Combinations may be administered either concomitantly (e.g., as an admixture), separately but simultaneously (e.g., via separate intravenous lines into the same subject), or sequentially (e.g., one of the compounds or agents is given first followed by the second). Thus, the term "combination" or "combined" is used to refer to either concomitant, simultaneous, or sequential administration of two or more agents. The compounds can be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Administration may be topically (including ophthalmically, vaginally, rectally, intranasally), orally, by swallowing or inhalation, or parenterally, for example by intravenous drip, subcutaneous, intracutaneous, intraperitoneal or intramuscular injection. In one aspect, the compounds can be delivered intrathecally. It is also contemplated that the compounds can be administered transdermally via, for example, a patch or ionotophoresis. The disclosed compounds can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, intraocularly (e.g., intravitreally), transdermally, intracisternally, intraventricularly, intratracheally, extracorporeally, or topically (e.g., topical intranasal admimstration or administration by inhalant). As used herein, "topical intranasal administration" means delivery of the compositions into the nose and nasal passages through one or both of the nares and can comprise delivery by a spraying mechanism. The latter can be effective when a large number of subjects are to be treated simultaneously. Administration of the compositions by inhalant can be through the nose or mouth via delivery by a spraying mechanism or droplet mechanism. Delivery can also be directly to any area of the respiratory system (e.g., lungs) via intubation. In one aspect, when the compound is a prodrug, the compound can be administered orally so that after ingestion, the acidic conditions present in the stomach can convert the prodrug to the active form. Parenteral administration of the compound, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution of suspension in liquid prior to injection, or as emulsions. Alternatively, parenteral admimstration can involve the use of a slow release or sustained release system such that a constant dosage is maintained. The exact amount of the compounds described herein required will vary from subject to subject, depending on the species, age, weight and general condition of the subject, the severity of the disorder being treated, the particular neurologic disorder to be targeted, its mode of administration and the like. Thus, it is not possible to specify an exact amount for every compound. However, an appropriate amount can be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein. The time at which the compounds can be administered will also vary depending upon the subject, the disorder, mode of administration, etc. The compound can be administered to the subject prior to the onset of the neurologic disorder or during a time when the subject is experiencing symptoms of the disorder. The compound can be administered over several weeks or months at varying intervals depending upon the subject and disorder to be treated. In one aspect, any of the compounds described herein can be administered to treat a neurologic disease or used as a therapeutic at a dosage from 0.01 mg/kg to 1,000 mg/kg. In another aspect, the lower endpoint of the dosage is 0.01, 0.05, 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 15.0, 20.0, 25.0, 30.0, 35.0, 40.0, 45.0, 50.0, 60.0, 70.0, 80.0, 90.0, 100.0, 150.0, 200.0, 250.0, 300.0, 350.0, 400.0, 450.0, 500.0, 600.0, 700.0, 800.0, or 900.0 mg/kg, and the upper endpoint of the dosage is 1.0, 2.0. 3.0. 4.0. 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 80.0, 90.0, 100.0, 150.0, 200.0, 250.0, 300.0, 350.0, 400.0, 450.0, 500.0, 550.0, 600.0, 650.0, 700.0, 750.0, 800.0, 850.0, 900.0, 950.0, or 1,000.0 mg/kg, where any lower endpoint can be used with any upper endpoint, where the lower endpoint is less than the upper endpoint. In another aspect, the dosage is from 1 to 10 mg/kg or 1 to 5 mg/kg. Pharmaceutically-Λcceptable Carriers In one aspect, any of the compounds described above can be combined with at least one pharmaceutically-acceptable carrier to produce a pharmaceutical composition. The pharmaceutical compositions can be prepared using techniques known in the art. In one aspect, the composition is prepared by admixing the compound with a pharmaceutically- acceptable carrier. The term "admixing" is defined as mixing the two components together. Depending upon the components to be admixed, there may or may not be a chemical or physical interaction between two or more components. Pharmaceutically-acceptable carriers are known to those skilled in the art. These most typically would be standard carriers for administration to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. Molecules intended for pharmaceutical delivery may be formulated in a pharmaceutical composition. Pharmaceutical compositions may include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice. Pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like. The pharmaceutical composition may be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Administration may be topically (including ophthalmically, vaginally, rectally, intranasally). Preparations for admimstration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles, if needed for collateral use of the disclosed compositions and methods, include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles, if needed for collateral use of the disclosed compositions and methods, include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like. Formulations for topical administration may include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. It will be appreciated that the actual preferred amounts of active compound in a specified case will vary according to the specific compound being utilized, the particular compositions formulated, the mode of application, and the particular situs and mammal being treated. Dosages for a given host can be determined using conventional considerations, e.g. by customary comparison of the differential activities of the subject compounds and of a known agent, e.g., by means of an appropriate conventional pharmacological protocol. Physicians and formulators, skilled in the art of determining doses of pharmaceutical compounds, will have no problems determining dose according to standard recommendations (Physicians Desk Reference, Barnhart Publishing (2004). In another aspect, any of the compounds described herein can be administered to a subject with the use of a liposome. In one aspect, the carrier molecule and/or X in formula I can be covalently attached to the liposome by reacting the carrier molecule and/or X with the fatty acid used to produce the liposome. In another aspect, the compounds described herein can be enclosed within the inner volume of the liposome and not covalently attached to the liposome. Examples of liposomes useful herein include, but are not limited to, conventional liposomes, long-circulating liposomes, immunoliposomes, and cationic liposomes. The methods disclosed in U.S. Patent Nos. 4,866,040; 5,008,288; and 5,876,747, which are incorporated by reference, can be used to produce liposome formulations with the compounds described herein. In another aspect, the compounds described herein can be delivered to a subject via micelles, nanoparticles, microspheres, and lipoproteins. Therapeutic Uses In one aspect, disclosed are methods for preventing or treating a neurologic, otologic, or ophthalmologic disease in a subject disease in a subject, which involves administering an effective amount of any of the compounds described herein to a subject in need of such treatment or prevention. The term "neurologic disease" is any disease that adversely affects neural tissue. For example, an injury to the spinal cord or brain (i.e., direct injury to nervous tissue) can result in damage to neural tissue and, thus, produce a neurologic disease. The neurologic disease can be the result of one or more events including, but not limited to, injury to the central nervous system, degeneration of neural and non-neural tissue (e.g., age related or genetic predisposition to the neurologic disorder), and dystrophies associated with neural tissue. Examples of neurologic diseases that can be treated or prevented by the methods described herein include, but are not limited to, amyotrophic lateral sclerosis, myasthenia gravis, a seizure disorder, a mood disorder, depression, Alzheimer's disease, spinocerebellar atrophies, spinocerebellar ataxias, triplet repeat disorders such as Huntington's disease, Parkinson's disease, multiple sclerosis, spinal muscle atrophy, migraines, bipolar disease, chronic inflammatory demyelinating polyneuropathy, and acute inflammatory demyelinating polyneuropathy. The term "otologic disease" is any disease that adversely affects hearing of a subject or tissue associated with the ear. Examples of otologic diseases include, but are not limited to, hearing loss or ototoxicity. The term "ophthalmologic disease" is any disease that adversely affects the sight of a subject or tissue associated with the eye. Examples of ophthalmologic diseases include, but are not limited to, retinal degeneration, retinal injury, macular degeneration (wet and dry forms, dystrophies of the macula), retinitis pigmentosa, glaucoma, or cataracts. The efficacy of the compounds described herein can be assessed using techniques known in the art. For example, the compounds disclosed herein can be assayed for anticonvulsant effects in animal models. This "seizure-type model" can first test the compound's efficiency in attenuating or eradicating electrical or chemical induced seizures. (J.P. Stables and H.J. Kupferberg, NIH Anticonvulsant Screening Program, 2003). These methods require limited technical expertise and permit comparisons between anticonvulsant profiles of test compounds to known clinically effective therapeutic agents. Thus, performing these tests is within the capability of persons of ordinary skill in this field. In addition to the electrical induced seizures exemplified above, it is known that subcutaneous administration of the compound pentylenetetrazol ("PTZ") induces seizures that are assessed behaviorally. The pharmacological profile of these seizures has been found to be consistent with the human condition. (E. A. Swinyard, et al., 1989). PTZ induces clonic seizures that last about 5 seconds. The compounds described herein can be administered intraperitoneally or orally, and the compound's ability to prevent the clonic spasms can be subsequently assessed. To date, all clinically active anticonvulsants have been found to be protective in either the PTZ test or the electroshock induced seizure test system exemplified above. Thus, persons of ordinary skill would able to determine the efficacy of the compounds described herein using well-established procedures. (Reviewed by Stables and Kupferberg, 2003). EXAMPLES The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, and methods described and claimed herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, desired solvents, solvent mixtures, temperatures, pressures and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions.

Example 1. Synthesis of propylpentanoyl-diaminobutyl-cysteic acid hydrochloride (PDC) In the example presented here, diaminobutane is the linking agent. Many other diamino compounds can be substituted. Other molecules having other linkable functional groups are known in the art. In the example provided below, the carboxyl group of cysteic acid is linked to the carboxyl group of valproic acid. Thus, in this example, the taurine transport system can be used to transfer valproic acid or other second generation valproic acid derivatives into cells. This includes cells in the brain which is believed to be the site of origin of seizures. The synthetic scheme for the conjugate propylpentanoyl-diaminobutyl-cysteic acid hydrochloride (PDC) is shown in Figure 1, and is described in detail below. Valproic acid [1] and Boc-diaminobutane [2] were condensed using PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate) and DIE A (N,N-diisopropylethylamine) in DMF (dimethyl formamide) to afford compound [3]. The crude product was purified by column chromatography to yield a white solid, 5.7 g, 92%. The Boc group was removed with TFA in CH₂C1₂ to yield an off-white waxy solid, compound [4], 6.9 g. Compound [4 ] was coupled with Fmoc-S-4-methoxytrityl-L-cysteine [5] using PyBOP and DIEA to obtain compound [ 6]. The product was purified by column chromatography to yield a yellow solid, 11.4 g, 78%. Oxidation of [6] with performic acid afforded [7] as a brown oil. Without further purification, crude [7] was deprotected using 20% piperidine in DMF. The product was purified by preparative LC to give 1.9 g of PDC [8] as the hydrochloride salt.

Example 2. Time-course of post-injection changes in PDC plasma concentration The concentration of PDC in blood plasma of rats injected intraperitoneally was 0.23 mmoles PDC/kg body weight in 90% propylene glycol/10% ethanol. The kinetics indicate that the plasma level of PDC reaches its maximal concentration within about 2 hours postinjection. Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the compounds, compositions and methods described herein. Various modifications and variations can be made to the compounds, compositions and methods described herein. Other aspects of the compounds, compositions and methods described herein will be apparent from consideration of the specification and practice of the compounds, compositions and methods disclosed herein. It is intended that the specification and examples be considered as exemplary.

REFERENCES Elmazar MM, Hauck RS, Nau H. Anticonvulsant and neurotoxic activities of twelve analogues of valproic acid. Glia. 2002 Feb;37(2): 153-68. Geggel HS, Ament ME, Heckenlively JR, Martin DA, Kopple JD. Nutritional requirement for taurine in patients receiving long-term parenteral nutrition. N Engl J Med. 1985 Jan 17;312(3):142-6. Huxtable RJ. Taurine. Past, present, and future. Adv Exp Med Biol. 1996;403:641- 50. Isoherranen N, Yagen B, Bialer M. New CNS-active drugs which are second- generation valproic acid: can they lead to the development of a magic bullet? Cun Opin Neurol. 2003 Apr;16(2):203-l l. Izumi K, Igisu H, Fukuda T. Effects of edetate on seizure suppressing actions of taurine and GAB A. Brain Res. 1975 May 9;88(3):576-9. El Idrissi A, Messing J, Scalia J, Trenkner E. Prevention of epileptic seizures by taurine. Adv Exp Med Biol. 2003;526:515-25. Kishi M, Ohkuma S, Kimori M, Kuriyama K. Characteristics of taurine transport system and its developmental pattern in mouse cerebral cortical neurons in primary culture-Biochim Biophys Acta. 1988 Apr 22;939(3):615-23. Koyama Y, Baba A, Iwata H. Characteristics of Cl(-)-dependent L-[35S]cysteic acid transport into rat brain synaptic membrane vesicles. Neurochem Res. 1990 Dec;15(12):1153-8. Lahdesmaki, P and Oja, SS On the mechanism of taurine transport at brain cell membranes J Neurochem 1973 20: 1411-1417. Loscher W. Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs. 2002; 16(10):669-94. Review. Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience.CNS Drugs. 2002;16(10):695-714. Review. Pow, DV, Sullivan, R, Reye, P, Hermanussen, S, Localization of taurine transporters, taurine, and (3)H taurine accumulation in the rat retina, pituitary, and brain. : J Pharm Sci. 1993 Dec;82(12): 1255-8. Schuller-Levis GB, Park E. Taurine: new implications for an old amino acid. FEMS Microbiol Lett. 2003 Sep 26;226(2): 195-202. James P. Stables and Harvey J. Kupferberg, Chapter 16, The NIH Anticonvulsant Drug Development (ADD) Program: preclinical anticonvulsant screening project. Swinyard, E.A., Woodhead, J.H., White, H.S. & Franklin, M.R. (1989): General principles: experimental selection, quantification, and evaluation of anticonvulsants. In: Antiepileptic Drugs, Third Edition R.H. Levy, R.H. Mattson, B. Melrum, J.K. Penry and F.E. Dreifuss eds, pp. 85-102. New York: Raven Press. U.S. Patent No. 4,261,974 U.S. Patent No. 5,440,023 U.S. Patent No. 6,313,106

Claims

What is claimed:

1. A compound comprising the formula I

wherein R¹ and R² comprise, independently, hydrogen or an alkyl group; L is an optional linker; X is a residue of a compound for treating or preventing a neurologic disease, an ophthalmologic disease, or an otologic disease, wherein X is not a protease inhibitor; wherein when L is not present, X is covalently bonded to C_α, or the pharmaceutically acceptable salt or ester thereof, wherein the compound having the formula I is racemic or the substantially pure enantiomer.

2. The compound of claim 1, wherein R¹ and R² are both hydrogen.

3. The compound of claim 1, wherein L is present, wherein L comprises a polyalkylene group, a polyether group, a polyamide group, a polyimino group, a polyester, an aryl group, or a polythioether group.

4. The compound of claim 1, wherein L is present, wherein L has the formula Z-Y-W, wherein W and Z are, independently, O, S, or NR³, wherein R³ is hydrogen or branched or straight chain alkyl, and m is from 1 to 12, and Y is a branched or straight chain alkyl group, a branched or straight chain alkylene group, or an aryl group.

5. The compound of claim 1, wherein L is present, wherein L has the formula Z- (CH₂)_m-W, wherein W and Z are, independently, O, S, or NR³, wherein R³ is hydrogen or branched or straight chain alkyl, and m is from 1 to 12.

6. The compound of claim 5, wherein both W and Z are O or both W and Z are NH.

7. The compound of claim 1, wherein L is present, wherein L has the formula -(CH₂)₀-CH(R )-(CH₂)_P-, wherein R⁴ is hydrogen, hydroxyl, an alkyl hydroxyl group, an alkyl guanidinium group, or an alkyl amino group.

8. The compound of claim 7, wherein the alkyl hydroxyl group is CH₂OH or CH₂CH₂OH.

9. The compound of claim 1 , wherein L is present, wherein L is a polar or charged amino acid that is covalently bonded to C_α and X via an amide linkage.

10. The compound of claim 1, wherein L is present, wherein L has the formula HN- (CH₂)_n-NH, wherein m is from 1 to 6.

11. The compound of claim 1, wherein L is present, wherein L has the formula HN- (CH₂)₄-NH.

12. The compound of claim 1, wherein when the compound is used to treat a neurologic or otologic disease, X is a peptide, a steroid, a monoamine oxidase inhibitor, an agent for chelating of a metal ion, an agents that increases or deceases phosphatidylcholine metabolism, an inhibitor of GAB A transaminase, a calcineurin inhibitor, a sigma-1 receptor modulator, an inhibitor of kinases that induces cellular degeneration, an anti-oxidative agent, an inhibitor of carbonic anhydrase, or an inhibitor of nitric oxide synthase.

13. The compound of claim 1, wherein when the compound is used to treat an ophthalmologic disease, X can be can be a peptide, a steroid, a monoamine oxidase inhibitor, an agent for chelating of metal ions, an agent that increases or decreases phosphatidylcholine metabolism, a cholinesterase inhibitor, gabapentin, pregabalin and analogs thereof, an inhibitor of GAB A transaminase, a calcineurin inhibitor, a sigma-1 receptor modulator, an inhibitor of kinases that induce cellular degeneration, an anti-oxidative agent, an inhibitor of carbonic anhydrase, a tetracycline class antibiotic, an aurintrucarboxylic acid or derivative thereof, an anti- angiogenic compound, or an inhibitor of nitric oxide synthase.

14. The compound of claim 1, wherein X is a residue of valproic acid or a derivative thereof.

15. The compound of claim 1, wherein X is a residue of valpromide.

16. The compound of claim 1, wherein the compound is the substantially pure L-isomer.

17. The compound of claim 1, wherein the compound is the substantially pure D- isomer.

18. The compound of claim 1, wherein the compound is propylpentanoyl-diaminobutyl- cysteic acid.

19. A pharmaceutical composition comprising a compound in any of claims 1-19 and a pharmaceutically-acceptable carrier.

20. A method for treating or preventing a neurologic disease in a subject diagnosed with the neurologic disease comprising administering to the subject an effective amount of one or more compounds in any of claims 1-19.

21. The method in claim 19, wherein the neurologic disease is amyotrophic lateral sclerosis, myasthenia gravis, a seizure disorder, a mood disorder, depression, Alzheimer's disease, spinocerebellar atrophies, spinocerebellar ataxias, triplet repeat disorders such as Huntington's disease, Parkinson's disease, multiple sclerosis, spinal muscle atrophy, migraines, bipolar disease, chronic inflammatory demyelinating polyneuropathy, and acute inflammatory demyelinating polyneuropathy.

22. The method in claim 19, wherein the neurologic disease is epilepsy.

23. A method for treating or preventing an ophthalmologic disease in a subject diagnosed with the ophthalmologic disease comprising administering to the subject an effective amount of one or more compounds in any of claims 1-19.

24. The method in claim 23, wherein the ophthalmologic disease is retinal degeneration, retinal injury, macular degeneration, retinitis pigmentosa, glaucoma, or cataracts.

25. A method for treating or preventing an otologic disease in a subject diagnosed with the otologic disease comprising administering to the subject an effective amount of one or more compounds in any of claims 1-19.

26. The method in claim 25, wherein the otologic disease is hearing loss or ototoxicity.