MX2008007236A - Levodopa prodrug mesylate, compositions thereof, and uses thereof - Google Patents

Abstract

(2R)-2-Phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate and crystalline form thereof, methods of making the same, pharmaceutical compositions thereof, and methods of using the same to treat diseases or disorders such as Parkinson's disease are provided.

Description

MESILATO PROFÁRMACO OF LEVODOPA. COMPOSITIONS OF THE SAME. AND USES OF THE SAME The present application claims the benefit of Provisional Application E.U.A No. 60 / 741,876 filed December 5, 2005, which is incorporated herein by reference in its entirety. Field of the Invention A mesylate salt of a prodrug of levodopa and a crystalline form thereof, and pharmaceutical compositions containing the same, useful for treating diseases or disorders such as Parkinson's disease is described herein. BACKGROUND OF THE INVENTION Parkinson's disease is a progressive, disabling disease that affects one in 1,000 people and usually occurs in people over 50 years of age. Patients with Parkinson's disease have a deficiency of the neurotransmitter dopamine in the brain as a result of the rupture of the nigrostrial pathway caused by the degeneration of the substance nigra. Levodopa (L-dopa or L-3,4-dihydroxyphenylalanine), an immediate precursor of dopamine, is the most commonly prescribed drug for the treatment of this disease. Brief Description of the Invention After oral administration, levodopa is rapidly absorbed by means of an amino acid transporter present in the upper small intestine. Due to the close distribution of this transport system, the window available for the absorption of levodopa is limited and the extent of absorption may depend on the range in which the drug passes through the upper gastrointestinal tract. The intestinal metabolism of levodopa is the main source of this first loss of passage of the drug. Approximately 35% of a levodopa administered dose reaches the systemic circulation as intact levodopa after oral administration in patients (Sasahara, J. Pharm, Sci 1990, 69, 261). Once absorbed, levodopa is rapidly metabolized to dopamine by L-aromatic amino acid decarboxylase enzymes (AADC) in peripheral tissues (eg, intestines and liver). For this reason, levodopa is normally co-administered with an enzyme decarboxylase inhibitor such as carbidopa or benserazide. When administered with carbidopa, the plasma concentration of intact levodopa is increased and thus more levodopa is available for transport in the central nervous system when converted to dopamine. Carbidopa and benserazide do not cross the bloodstream barrier to a significant extent and therefore do not inhibit the required conversion of levodopa to dopamine in the brain.

The use of levodopa prodrugs has been proposed to improve the pharmacokinetics of levodopa. Many of these prodrugs are simple levodopa esters (see U.S. Patent Nos. 5,017,607, 4,826,875, 4,873,263, 4,771,073, 4,663,349, 4,311,706, Japanese Patent No. JP58024547, Juncos et al, Neurology 1987, 37, 1242, and Cooper et al, J. Pharm. Pharmacol. 1987, 39, 627-635). An oral formulation of levodopa methyl ester (Levomet®, CHF 1301) (Chiesi Pharmaceuticals) has been described. The ethyl ester of levodopa (TV-1203) is under clinical investigation as a potential therapy for Parkinson's disease when co-administered with carbidopa (U.S. Patent No. 5,607,969, which is incorporated in its totoality to the present invention as reference). A sustained-release cellulose formulation of ethyl ester of levodopa in a mixture of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, and a carboxyvinyl polymer has also been described (U.S. Patent No. 5,840,756). However, oral administration of this formulation to healthy adults previously treated with carbidopa produces a terminal half-life of levodopa in plasma of only 2 hours, comparable to that of Sinemet® CR. The pivaloyl ester of levodopa (NB-355) has been described (European Patent No. 0 309 827). After oral administration of NB-355, a rapid increase in plasma concentration or levodopa elimination was not observed and the duration of circulating levodopa was prolonged, although levodopa plasma concentrations were low. The potential for using levodopa ester prodrugs to increase rectal uptake of the drug has also been described (U.S. Patent Nos. 4,663,349; 4,771,073; and 4,873,263). Notably, the absorption of simple alkyl esters of levodopa has been shown to be greater after rectal absorption than after oral dosing (Fix, et al, Pharm. Res. 1989, 6, 501-5; and Fix, et al, Pharm. Res. 1990, 4, 384-7). This effect is attributed to the reduced abundance of esterases in the large intestine in relation to the small intestine. Therefore, selective administration of a prodrug of levodopa to the large intestine in a sustained release formulation can be expected to provide increased oral bioavailability and prolonged systemic exposure to the drug. sS has described a series of prodrugs containing levodopa glycolic acid ester (Wermuth, U.S. Patent No. 4,134,991). Lipid conjugates of levodopa to facilitate entry into cells and tissues have also been described (Yatvin, U.S. Patent No. 5,827,819). In this way, the development of levodopa prodrugs that can be efficiently absorbed through the gastrointestinal tract, including the colon, and that reduce the first-pass metabolism of levodopa is highly desirable. The gastrointestinal tract includes the small intestine and the large intestine. The human small intestine is a co-enclosed tube about 6.09 meters (twenty feet) in length between the stomach and the small intestine. The small intestine is subdivided into the duodenum, the jejunum, and the ileum. The large intestine is about 1.52 meters (5 feet) in length and runs from the ileum to the anus. The large intestine is divided into the caecum (cecum), colon, and rectum. The colon is divided into four parts that include the ascending, traverse, descending, and sigmoid curvature. In general, an orally ingested compound resides around 1 to 6 hours in the stomach, about 2 to 7 hours in the small intestine, and about 8 to 18 hours in the colon. In this way, the longest period of time for sustained release of a compound occurs when the compound passes through the colon. It is known that certain active transporter proteins are expressed through the gastrointestinal tract. An active transporter refers to a protein bound to the membrane that recognizes a substrate and affects the entry of the substrate into or out of a cell by transport mediated by the barrier or transport mediated by the receptor. Active transport includes the movement of molecules through cell membranes that directly or indirectly depend on the process mediated by energy, such as for example by the process driven by ATP hydrolysis, or by an ion gradient, which is presented by the facilitated diffusion mediated by the interaction with specific transporter proteins through a modulated solute channel. Examples of transporters that mediate the solute include organic cation transporters such as OCTN1 and OCTN2, which are expressed in the epithelial cells lining the human colon as well as in the small intestine. More recently, levodopa prodrugs designed to be absorbed in both the small and large intestine have been described in Xiang et al, Application Publication EUA Nos. 2005/0282891 and 2006/0020028, each of which is incorporated in its entirety. to the present invention as reference herein for reference in its entirety. These prodrugs of levodopa can achieve an oral bioavailability of levodopa that is at least two times greater than the oral bioavailability of levodopa when administered orally or on an equivalent molar basis. More specifically, Xiang et al, Application Publication E.U.A. No. 2005/0282891 describes the compound (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride in a crystalline or amorphous form (see Example 8 of Xiang et al) . Prodrugs described by Xiang et al., Can be effectively incorporated into sustained release formulations that include osmotic delivery devices to provide a sustained systemic exposure to levodopa during oral administration to the patient. In general, crystalline forms of drugs are preferred over amorphous forms of drugs, in part, because of their superior stability. For example, in many situations, an amorphous drug is converted to a crystalline drug form during storage. Because the amorphous and crystalline forms of a drug typically have different physical properties, chemical properties, potencies, and / or bioavailabilities, interconversion for safety reasons is undesirable in pharmaceutical use. A key feature of any crystalline drug is the polymorphic behavior of such material. Polymorphs are crystals of the same molecule, which have different physical properties because the crystal grid contains a different configuration of molecules. The different physical properties exhibited by the polymorphs can affect important pharmaceutical parameters such as storage, stability, compressibility, density (important in the formulation and manufacture of the product), and dissolution ratios (important for determining bioavailability). Such differences in stability can result from changes in chemical reactivity (eg, differential hydrolysis or oxidation, such that the dosage form comprising a certain polymorph can discolor more rapidly than a dose form comprising a different polymorph), mechanical changes (for example, tablets may fall apart in storage as a kinetically preferred crystalline form is converted to a thermodynamically more stable crystalline form), or both (for example, polymorph tablets may be more susceptible to high-level rupture) humidity). The differences in solubility between polymorphs can, in extreme situations, result in transitions to crystalline forms that lack potency and / or are toxic. In addition, the physical properties of a crystalline form can also be important in pharmaceutical processing. For example, a particular crystalline form can form solvates more rapidly or it can be more difficult to filter and clean impurities than other crystalline forms (that is, the particle shape and size distribution can be different between a crystalline form in relation to other crystalline forms). shapes). Agencies such as the Food and Drug Administration of the United States may require that the polymorphic content of a drug product be monitored and controlled if the most thermodynamically stable polymorphic form of the drug is not used and / or the different polymorphic forms of the drug are not used. they can affect the quality, safety, and / or efficacy of the drug product. In this way, medical and commercial reasons favor the commercialization and synthesis of solid drugs as a thermodynamically stable polymorph, substantially free of kinetically preferred polymorphs. Accordingly, there is a need for prodrugs of levodopa and crystalline forms thereof that exhibit physicochemical properties that can be advantageously used in pharmaceutical processing and in pharmaceutical compositions, and that are also sufficiently unstable under physiological conditions to provide therapeutically effective plasma concentrations of levodopa, particularly when the prodrug of levodopa is administered orally. In a first aspect, the mesylate compound of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate is provided. In a second aspect, the mesylate of (2 R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate crystalline. In a third aspect, there are provided compositions comprising (2R) -2-phenylcarbonyloxypropyl mesylate (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate and at least one other diastereomer of 2-phenylcarbonyloxypropyl-2 mesylate -amino-3- (3,4-dihydroxyphenyl) propanoate wherein the diastereomeric purity of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate is at least around 97%.

In a fourth aspect, pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate are provided. or crystalline form thereof. In a fifth aspect, methods are provided for treating a disease in a patient which comprise administering to the patient in need of such treatment a therapeutically effective amount of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- mesylate. (3,4-dihydroxyphenyl) propanoate or a crystalline form thereof. In a sixth aspect, pharmaceutical compositions comprising an oral sustained release formulation of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate formulation or crystalline form thereof are provided. . In a seventh aspect, methods are provided for preparing (2R) -2-phenylcarbonyloxypropyl mesylate (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate comprising providing a solution of (2R) -2-phenylcarbonyloxypropyl (2S) -2- (tert-butoxycarbonyl) amino-3- (3,4-dihydroxyphenyl) propanoate in a solvent, add an acid to convert (2R) -2-phenylcarbonyloxypropyl (2S) -2- (tert-butoxycarbonyl) ) amino-3- (3,4-dihydroxyphenyl) propanoate to the salt of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate, add methanesulfonic acid to convert the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate (2R) -2- phenylcarbonyloxypropyl (2S) -2-amino-3- (3 , 4-dihydroxyphenyl) propanoate, and isolate the (2R) -2-phenylcarbonyloxypropyl (25) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate from the solvent. In an eighth aspect, methods are provided for preparing (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate comprising providing a solution of (2R) -2- phenylcarbonyloxypropyl (2S) -2- (tert-butoxycarbonyl) amino-3- (3,4-dihydroxyphenyl) propanoate in a solvent, add methanesulfonic acid to convert (2R) -2-phenylcarbonyloxypropyl (2S) -2- (tert- butoxycarbonyl) amino-3- (3,4-dihydroxyphenyl) propanoate to (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate, and isolate mesylate from (2R) ) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate of the solvent. In a ninth aspect, methods are provided for preparing crystalline (2R) -2-phenylcarbonyloxypropyl (25) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate comprising providing a solution of (2R) -2- phenylcarbonyloxypropyl (2S) -2- (tert-bu to rbonyl) amino-3- (3,4-dihydroxyphenyl) propanoate in a first solvent, deprotecting the tert-butoxycarbonyl group with an acid to provide (2R) - 2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate, remove the first solvent and add water to the salt of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3 acid - (3,4-dihydroxyphenyl) propanoate, neutralize the salt of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate with a base to provide (2R) -2 phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate, extract (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate with a second solvent, add methanesulfonic acid (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate extracted to convert (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3, 4-dihydroxyphenyl) propanoate to the crystallized mesylate (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate, and isolate the mesylate (2R) -2-phenylcarbonyloxypropyl (2S) - Crystalline 2-amino-3- (3,4-dihydroxyphenyl) propanoate of the second solvent. In the present description these and other features are established and provided. BRIEF DESCRIPTION OF THE DRAWINGS The skilled artisan will understand that the drawings, described herein, are for illustration purposes only. The drawings are not intended to limit the scope provided by the present disclosure. Figure 1 shows a differential scanning calorimetric thermogram of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate crystallized from isopropanol. Figure 2 shows an X-ray powder diffraction pattern of crystallized (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate crystallized from 1% water in isopropanol Figure 3 shows an X-ray powder diffraction pattern of the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate crystallized from isopropanol. Figure 4 shows an X-ray powder diffraction pattern of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate crystallized from methanol / methyl ether -tert-butyl (1: 7). Figure 5 shows an X-ray powder diffraction pattern of crystallized (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate crystallized from 0.5% water in methanol / methyl tert-butyl ether (1: 5). Figure 6 shows an X-ray powder diffraction pattern of the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate crystallized from 1% water in acetonitrile. Definitions "AUC" is the area under the curve that represents the concentration of a compound or metabolite thereof in a biological fluid in a patient as a function of time after administration of the compound to the patient. In certain embodiments, the compound may be a prodrug and the metabolite may be a drug. Examples of biological fluids include blood and plasma. AUC can be determined by measuring the concentration of the compound or metabolite thereof in a biological fluid such as plasma or blood using methods such as tandem mass spectrometry-liquid chromatography (LC / MS / MS), at various time intervals, and calculate the area under the curve of plasma concentration against time. Appropriate methods for calculating the AUC of a drug concentration versus time curve are well known in the art. As is relevant to the description herein, an AUC for levodopa can be determined by measuring the concentration of levodopa in the plasma or blood of a patient after oral administration of a dosage form comprising (2R) -2- mesylate. phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate or crystalline form thereof. "Bioavailability" refers to the amount of a drug that reaches the systemic circulation of a patient after the administration of the drug or prodrug thereof to the patient and can be determined by evaluating, for example, the plasma or blood concentration profile against time. for a drug. Useful parameters for characterizing a plasma concentration curve or blood against time include the area under the curve (AUC), the time for the peak concentration (Tmax), and the maximum drug concentration (Cmax), where (Cmax) is the maximum concentration of a drug in the plasma or blood of a patient after the administration of a dose of the drug or prodrug thereof to the patient, and Tmax is the time for the maximum concentration (Cmax) of a drug in the plasma or blood of the patient after administration of a dose of the drug or prodrug thereof to the patient. "Diastereomeric purity" refers to the percentage of a diastereomer of a compound relative to all other diastereomers of the compound in a composition that contains more than one diastereomer of the compound. For example, a composition having a diastereomeric purity of 97% mesylate of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate when about 97% of the mesylate of phenylcarbonyloxypropyl-2-amino-3- (3,4-dihydroxyphenyl) propanoate in the composition is the diastereomer of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-d) mesylate hydroxyphenyl) propanoate and about 3% of the 2-phenylcarbonyloxypropyl-2-amino-3- (3,4-dihydroxy-phenyl) propanoate mesylate in the composition comprises one or more of the other isomers such as the isomers (2R ) - (2R) -, (2S) - (2R) -, and / or (2S) - (2S) -. In some embodiments, the diastereomeric purity is, for example, greater than or equal to at least 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about of 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%. "Levodopa prodrug mesylate" refers to (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate and the crystalline form thereof. "Parkinson's disease" is a clinical syndrome that includes bradykinesia (lethargy and lack of movement), muscle stiffness, latent tremor (which usually diminishes during voluntary movement), and a deficit in the balance of posture that leads to gait disorders and falls. Other symptoms include gait and posture disorders such as heaviness, reduction in arm swing, "block" turn, stooping, forward reflexive posture, festering, frozen and gait dystonia.; speech and swallowing disorders such as hypophonia, speech with festination, drooling, non-motor causes of speech / language disorders in both expressive and receptor language, and dysphagia; as well as fatigue, parkinsonian facies (mask), micrograph, dexterity and impaired fine motor coordination, impaired gross motor coordination, and lack of movement. Non-motor mood disorders associated with Parkinson's disease include mood disorders such as depression; cognitive disorders such as delayed reaction time, performance dysfunction, dementia, memory loss, and medication effects; sleep disorders such as excessive daytime sleepiness, insomnia, and disturbances in REM sleep; sensory disorders such as impaired visual perception, dizziness and syncope, impaired proprioception, reduction or loss of the sense of smell, and pain; and autonomic disorders such as oily skin and seborrheic dermatitis, urinary incontinence, constipation and gastric immobility, altered sexual function, and weight loss. The ratio scale of unified Parkinson's disease is the primary clinical tool used for the diagnosis of Parkinson's disease (see, for example, Gelb et al, Arch Neurol 1999, 56 (1), 33-9) and Goetz, Mov Disord 2003, 18 (7), 738-50). "Patient" includes animals and mammals, for example humans. "Pharmaceutical composition" refers to a composition comprising (2R) -2-phenylcarbonyloxypropyl mesylate (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate or crystalline form thereof and at least one pharmaceutically acceptable carrier with which the compound is administered to a patient. "Pharmaceutically acceptable" means approved or that may be approved by a federal or state government regulatory agency, listed in the US Pharmacopoeia, or listed in another pharmacopoeia generally recognized for use in mammals, including humans. "Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or carrier with which the mesylate of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate or crystalline thereof is administered to a patient. "Prodrug" refers to a derivative of a drug molecule that requires a transformation within the body to release the active drug. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the precursor drug. A carboxyl-containing drug can be converted to, for example, an ester either single alkyl or acyloxyalkyl prodrug, which can be hydrolyzed in vivo to provide the carboxyl-containing drug. Prodrugs for drugs with functional groups other than those listed above are well known to those skilled in the art. "Pro portion" refers to a form of protecting group that when used to disguise a functional group within a drug converts the drug into a prodrug. Typically, the pro portion will bind to the drug via bonds that are cleaved enzymatically or nonenzymatically in vivo. "Protective group" refers to a grouping of atoms that, when linked to a reactive functional group in a hidden molecule, reduces or prevents the reactivity of the functional group. Examples of protecting groups can be found in Green et al, "Protective Groups in Organic Chemistry," (Wiley, 2nd ed.1991) and Harrison et al, "Compendium of Synthetic Organic Methods," Vols. 1-8 (John Wiley and Sons, 1971-1996). Examples of amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), 2- (trimethylsilyl) ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC), 6-nitroveratryloxycarbonyl (NVOC), and the like. Examples of protective hydroxy groups include, but are not limited to those where the hydroxy group is either acylated or alkylated such as benzyl, and trityl esters as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers. "Sustained release" refers to the release of a therapeutic or preventive amount of a drug or an active metabolite thereof for a period of time that is longer than that of the conventional formulation of the drug. For oral formulations, the term "sustained release" typically means releasing the drug within the lumen of the gastrointestinal tract for a period of time ranging from about 2 to about 30 hours, and in certain modalities, over a period of time in the range from around 4 to around 24 hours. Sustained-release formulations achieve therapeutically effective concentrations of the drug in the systemic circulation for a prolonged period of time relative to that achieved through oral administration of a conventional drug formulation. "Prolonged release" refers to a release of the drug or an active metabolite thereof in the gastrointestinal lumen after a prolonged period of time, for example, a prolongation of about 1 to about 12 hours, relative to that reached by oral administration of a conventional formulation of the drug. "Treating" or "treating" the disease refers to stopping or alleviating a disease, disorder, or at least one of the clinical symptoms of a disease or disorder. In certain embodiments, "treating" or "treatment" refers to stopping or alleviating at least one physical parameter of the disease or disorder, which may or may not be discernible by the patient. In certain embodiments, "treating" or "treatment" refers to inhibiting or controlling the disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both. In certain embodiments, "treating" or "treatment" refers to delaying, in some cases indefinitely, the onset of the disease or disorder. "Therapeutically effective amount" means the amount of a compound that, when administered to a patient to treat the disease in the patient, is sufficient to effect such treatment of the disease. The "therapeutically effective amount" varies depending on the compound, the disease and its severity and the age, weight, etc., of the patient having the disease to be treated. Reference is now made in detail to certain embodiments of compounds, compositions, and methods. The described modalities that are limiting of the claims are not intended. On the contrary, it is intended that the claims cover all alternatives, modifications, and equivalents of the described modalities. Compounds The prodrug of levodopa, (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate 1: (1) prodrug and the crystalline form thereof are described. One of skill in the art will appreciate that although (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate is disclosed, a (2R) mesylate sample is disclosed. -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate may have several compositional and diastereomeric purities. In certain embodiments, the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate or crystalline form thereof may exhibit a composition purity of at least about 90% , at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, and in certain embodiments, in excess of at least about 99%. In certain modalities, the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate or crystalline form thereof may exhibit a diastereomeric purity of at least about 90%, at least about of 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, and in certain modalities, in excess of at least about 99%. The (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate may exist in various tautomeric forms. Accordingly, all possible tautomeric forms of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate are covered unless otherwise specified. Also encompassed are all isotopically-labeled forms of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate unless otherwise specified. Examples of isotopes that can be incorporated into the mesylate of (2R) -2-phenylcarbonyloxy pro pyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate include, but are not limited to, 2H, 3H , 1 C, 3 C, 14 C, 15 N, 180, and 170. In certain embodiments, the mesylate of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate is a form crystalline In certain embodiments, an X-ray powder diffraction pattern of crystalline (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dydroxy-phenyl) propanoate mesylate exhibits diffraction peaks characteristic (° 2T) at 4.7 ± 0.2, 5.0 ± 0.2, 8.5 ± 0.2, 9.6 ± 0.2, 13.6 + 0.2, 15.0 ± 0.2, 17.0 ± 0.2, 17.4 ± 0.2, 17.7 ± 0.2, 19.1 ± 0.2, 19.5 ± 0.2, 20.0 ± 0.2, 20.4 ± 0.2, 21.1 ± 0.2, 22.3 ± 0.2, 22.9 + 0.2, 23.1 ± 0.2, 23.3 ± 0.2, 24.3 ± 0.2, 25.0 ± 0.2, 25.3 ± 0.2, 25.7 ± 0.2, 25.8 ± 0.2, 26.9 + 0.2, 27.3 ± 0.2, 28.2 ± 0.2, 30.1 ± 0.2, 30.5 ± 0.2, 32.0 ± 0.2, 33.8 ± 0.2, 34.3 ± 0.2, 37.6 ± 0.2, and 38.4 ± 0.2. In certain embodiments, crystalline (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate exhibits an X-ray powder diffraction pattern substantially as shown in any of the Figures 2-6. Someone skilled in the art will recognize that slight variations in ° 2T diffraction angles can be expected based on, for example, the specific diffractometer employed, the analyst, and the sample preparation technique. A greater variation can be expected for the relative peak intensities. The comparison of diffraction patterns can be based mainly on the observed ° 2T diffraction angles with minor importance attributed to the relative peak intensities. The diffraction patterns demonstrate the variations in observed ° 2T diffraction angles and peak intensities for the crystallized crystalline (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate from different solvents is shown in Figures 2-6. For the X-ray powder diffraction patterns shown in Figures 2-6, the peaks exhibiting generally the greatest intensity are located at the ° 2T diffraction angles of 5.0 ± 0.2, 8.5 + 0.2, 13.6 ± 0.2, 15.0 ± 0.2, 17.0 + 0.2, 17.7 ± 0.2, 20.4 ± 0.2, 21.1 ± 0.2, 25.0 ± 0.2, 25.8 ± 0.2, 28.2 ± 0.2, 30.1 ± 0.2, and 37.6 ± 0.2. An X-ray powder diffraction pattern that exhibits characteristic diffraction peaks (° 2T) at 5.0 ± 0.2, 8.5 ± 0.2, 13.6 ± 0.2, 15.0 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 20.4 ± 0.2, 21.1 ± 0.2, 25.0 ± 0.2, 25.8 ± 0.2, 28.2 ± 0.2, 30.1 ± 0.2, and 37.6 ± 0.2 will be substantially the same as the X-ray powder diffraction pattern of the (2R) -2-phenylcarbonyloxypropyl mesylate (2S) - Crystalline 2-amino-3- (3,4-dihydroxyphenyl) propanoate. In certain embodiments, the crystalline (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate exhibits a melting point from about 157 ° C to about 162 ° C. . In certain modalities, the crystalline (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate is characterized by a differential scanning calorimetry (DSC) thermogram having an endothermic peak around of 164.5 ° C, and in certain modalities to around 164.5 ± 2.5 ° C. An example of a DSC thermogram of crystalline (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate is shown in Figure 1. In certain embodiments, the mesylate crystalline (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate is stable, for example, does not absorb moisture and / or is converted to another isomorphic form under processing conditions and / or typical pharmaceutical storage. The physical properties and characteristics of the mesylate of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate crystalline prepared by methods provided by the present disclosure are consistent with those of a single isomorph. In contrast, the crystalline (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride prepared by similar methods can exhibit three isomorphic forms. The environmental stability of the simple isomorphic form of (2R) -2-phenylcarbonylloxy propyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate is recommended for use in pharmaceutical compositions. Synthesis The (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate 1 can be prepared by the synthetic method illustrated in the Reaction 1 scheme. 1 Reaction Scheme 1 Useful starting materials for preparing these compounds and intermediates thereof are commercially available or can be prepared by well-known synthetic methods (Harrison et al, "Compendium of Synthetic Organic Methods," Vols. 1-8, John Wiley and Sons, 1971-1996, "Beilstein Handbook of Organic Chemistry," Beilstein Institute of Organic Chemistry, Frankfurt, Germany, Feiser et al, "Reagents for Organic Synthesis," Volumes 1-17, Wiley Interscience, Trost et al, "Comprehensive Organic Synthesis, "Pergamon Press, 1991;" Theilheimer's Synthetic Methods of Organic Chemistry, "Volumes 1-45, Karger, 1991; March, "Advanced Organic Chemistry," Wiley Interscience, 1991; Larock "Comprehensive Organic Transformations," VCH Publishers, 1989; and Paquette, "Encyclopedia of Reagents for Organic Synthesis," John Wiley & Sons, 1995). Methods for synthesizing prodrugs of carboxyl ester levodopa are described in Xiang et al, Application Publications of E.U.A. Nos. 2005/0282891 and 2006/0020028, each of which is incorporated in its entirety to the present invention as reference herein for reference in its entirety. Other methods for synthesizing the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate will be apparent to one of skill in the art. Accordingly, the method presented in Reaction Scheme 1 is illustrative rather than detailed. For example, (2R) -2-phenylcarbonyloxypropyl mesylate (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate 1 can be prepared from the corresponding precursor 2 of (2R) -2-phenylcarboxyloxypropyl (2S) -2-amino-3- (3,4- dihydroxyphenyl) propanoate, suitably protected by means of a direct or indirect route as shown in Reaction Scheme 1. When Pg is Boc (tert-butoxycarbonyl), the treatment of precursor 2 with an appropriate acid such as hydrochloric acid in a solvent organic in which the precursor 2 is soluble such as, for example, dioxane, dichloromethane, tetrahydrofuran, or combinations of any of the above at room temperature, followed by removal of the solvent and crystallization of the resulting residue using an appropriate solvent such as acetonitrile, can provide the hydrochloride salt 3. Other suitable acids include volatile acids such as trifluoroacetic acid and hydrogen bromide. The conversion of the hydrochloride salt 3 to the corresponding mesylate salt 1 can be carried out by neutralizing the hydrochloride salt with an appropriate base such as sodium bicarbonate (NaHCO 3) or potassium bicarbonate (KHCO 3) in an appropriate solvent such as water. dichloromethane (DCM), remove DCM from the water, and add methanesulfonic acid to the DCM solution. The mesylate salt 1 can be precipitated from the DCM. In certain embodiments, the precursor 2 can be converted directly to the mesylate salt 1 by treating the precursor 2 with an excess of methanesulfonic acid, for example, 1.1-100 equivalents, in an organic solvent in which the precursor 2 is soluble such such as dioxane, dichloromethane, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, or mixtures of any of the foregoing at a temperature of from about 20 ° C to about 100 ° C. The mesylate salt 1 can then be precipitated in a non-polar solvent such as methyl tert-butyl ether (MTBE), dichloromethane, or mixtures of the foregoing. In certain embodiments, precursor 2 can be converted to the mesylate salt 1 using a one-pot procedure by treating precursor 2 with an excess of hydrogen chloride in dioxane to produce the deprotected hydrochloride salt 3, and then adding methanesulfonic acid to converting the hydrochloride salt 3 to the mesylate salt 1. The mesylate salt 1 can be crystallized from a solvent in which the mesylate salt 1 is soluble and in which the solubility of the mesylate salt 1 depends on the temperature, such as isopropanol, methanol / MTBE, 1% water in isopropanol, 1% water in acetonitrile, or 3% water in ethyl acetate, to provide the crystalline mesylate salt 1. In certain embodiments, the solvent used to crystallize the mesylate salt 1 may be selected from acetonitrile, methanol, ethanol, isopropanol, MTBE, dioxane, acetone, ethyl acetate, ethyl formate, hexane, dichloromethane, and mixtures of any of the foregoing. In certain solvent mixtures comprising two solvents, the ratio of the two solvents may be in the range from about 1:10 to about 10: 1. In certain embodiments, the solvent may further comprise less than about 10% water by volume, and in certain embodiments, less than about 5% water by volume. In certain embodiments, the solvent used to crystallize the mesylate salt 1 may comprise a mixture of methanol and MTBE in which the ratio (v / v) of methanol to MTBE is from about 1: 5 to about 1: 7. In certain embodiments, the solvent used to crystallize the mesylate salt 1 may comprise from about 1% to about 4 volume% water in isopropanol. Examples of solvents useful for crystallizing the mesylate salt 1 are described in Table 1. To prepare the crystalline mesylate salt 1, a solvent in which the solubility of the mesylate salt 1 depends on the temperature and mesylate salt 1 , can be heated to provide a solution. In certain embodiments, the solvent may be heated to the reflux temperature, and in certain embodiments, to a temperature of less than 75 ° C. In certain embodiments, the concentration of the mesylate salt 1 in the solution is less than about 500 mg / mL and in certain embodiments it is from about 50 mg / mL to about 200 mg / mL. The temperature of the solution can then be changed to reduce the solubility of the mesylate salt 1 in the solvent. For example, the temperature of the solution can be reduced to room temperature (for example, around 25 ° C), and in certain modes to 0 ° C. The time for cooling the solution can be selected to optimize the yield, purity of composition, and / or optical purity of the crystalline mesylate salt 1. In some embodiments, the solution can be cooled to a first temperature and the crystallized mesylate salt 1 isolated , and the solution is further cooled in a second crystallization and the additional crystalline mesylate salt 1 is isolated. The crystalline mesylate salt 1 can be isolated from the solvent by filtration. The filter cake can be washed in an appropriate solvent, such as, for example, a low boiling point solvent which minimizes the amount of residue remaining in the crystalline mesylate salt 1. Examples of suitable washing solvents include acetonitrile, methanol, ethanol, isopropanol, MTBE, dioxane, acetone, ethyl acetate, ethyl formate, hexane, dichloromethane, and mixtures of any of the foregoing. One skilled in the art may appreciate that other methods for crystallizing mesylate salt 1 can be used, including, for example, methods comprising agitation and / or seeding. In certain embodiments, the crystalline mesylate salt 1 obtained by any of the preceding methods is characterized by an X-ray powder diffraction pattern having peaks (° 2T) at 4.7 ± 0.2, 5.0 ± 0.2, 8.5 ± 0.2. , 9.6 ± 0.2, 13.6 ± 0.2, 15.0 ± 0.2, 17.0 ± 0.2, 17.4 ± 0.2, 17.7 ± 0.2, 19.1 ± 0.2, 19.5 ± 0.2, 20.0 ± 0.2, 20.4 ± 0.2, 21.1 ± 0.2, 22.3 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 23.3 ± 0.2, 24.3 ± 0.2, 25.0 ± 0.2, 25.3 ± 0.2, 25.7 ± 0.2, 25.8 ± 0.2, 26.9 ± 0.2, 27.3 ± 0.2, 28.2 ± 0.2, 30.1 ± 0.2, 30.5 ± 0.2 , 32.0 ± 0.2, 33.8 ± 0.2, 34.3 ± 0.2, 37.6 ± 0.2, and 38.4 ± 0.2. In certain embodiments, the crystalline mesylate salt 1 obtained by any of the foregoing methods is characterized by an X-ray powder diffraction pattern having major peaks (° 2T) at 5.0 ± 0.2, 8.5 ± 0.2, 13.6 ± 0.2, 15.0 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 20.4 ± 0.2, 21.1 ± 0.2, 25.0 ± 0.2, 25.8 ± 0.2, 28.2 ± 0.2, 30.1 ± 0.2, and 37.6 ± 0.2. In certain embodiments, the formation and crystallization of the mesylate salt 1 can be carried out in a one-pot procedure at about room temperature, eg, 25 ° C. For example, after deprotection and neutralization, (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate can be dissolved in a solvent such as ethyl acetate, sodium propane / dichloromethane, or isopropanol / ethyl acetate and treated with 0.9-1.2 equivalents of methanesulfonic acid at room temperature. The mesylate salt 1 can be crystallized from the solution with or without agitation or seeded. As an example of a canister procedure for preparing crystalline (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate, a solution of (2R) -2- is prepared phenylcarbonyloxypropyl (2S) -2- (tert-butoxycarbonyl) amino-3- (3,4-dihydroxyphenyl) propanoate in a solvent in which it is soluble. Examples of suitable solvents include dichloromethane and dioxane. The tert-butoxycarbonyl group is deprotected by adding an acid to provide the salt of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate. Suitable acids are not limited to volatile acids. Examples of suitable acids for deprotecting the tert-butoxycarbonyl group include hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, and hydrogen bromide. After deprotection, the first solvent can be removed and water added to the salt of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate. The salt of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate can be neutralized with a base such as NaHCO 3 or KHCO 3 to provide (2R) -2-phenylcarbonyloxypropyl ( 2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate. The (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate can then be extracted with a second solvent such as methyl tert-butyl ether, dichloromethane, ethyl acetate, or a mixture of ethyl acetate and isopropanol. Methanesulfonic acid can be added to (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate extracted to convert (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino- 3- (3,4-dihydroxyphenyl) propanoate to the crystalline (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate. The crystalline (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate can then be isolated from the second solvent by filtration. One of skill in the art will appreciate that the methods provided by the present disclosure can be used to prepare the mesylate of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate 1 or the crystalline form thereof having a high purity of composition and diastereomeric. For example, in certain embodiments, the purity of composition of the mesylate salt 1 may be at least about 95%, in certain embodiments, at least about 97%, in certain embodiments, at least about 98%, and in certain embodiments, it can be at least about 99%, and in certain embodiments, the diastereomeric purity can be at least about 95%, in certain modalities, at least about 97%, in certain modalities, at least about 98%, and in certain modalities, at least about 99%. Uses Prodrugs of levodopa are dopamine precursors. In this manner, the levodopa prodrug mesylate provided by the present disclosure can be administered to a patient suffering from any of the disease or disorder for which the precursor drug, levodopa, is known or subsequently discovered to be therapeutically effective. The levodopa prodrug mesylate can be administered to the patient, such as a human, to treat a disease or disorder such as Parkinson's disease. The methods comprise administering to a patient in need of such treatment a therapeutically effective amount of levodopa prodrug mesylate. In therapeutic methods provided by the present disclosure, a therapeutically effective amount of levodopa prodrug mesylate can be administered to a patient suffering from a disease such as Parkinson's disease, depression, attention deficit disorder, schizophrenia, manic depression, cognitive impairment, restless leg syndrome, periodic limb movement disorder, tardive dyskinesia, Huntington's disease, Tourette's syndrome, hypertension, addictive disorders, congestive heart failure, or excessive daytime sleepiness. In prophylactic methods provided by the present disclosure, a therapeutically effective amount of levodopa prodrug mesylate can be administered to a patient at risk of developing a disease such as Parkinson's disease, depression, attention deficit disorder; schizophrenia, manic depression, cognitive impairment disorders, restless legs syndrome, periodic limb movement disorder, tardive dyskinesia, Huntington's disease, Tourette's syndrome, hypertension, addictive disorders, congestive heart failure, or excessive daytime sleepiness. In certain embodiments, the prodrug mesylate of levodopa or pharmaceutical composition thereof may be co-administered with another therapeutic agent or drug, such as a decarboxylase inhibitor or a prodrug thereof, which may act as a protector to inhibit or prevent decarboxylation of the prodrug mesylate of levodopa and / or the metabolite of levodopa. The prodrug mesylate of levodopa can be administered from the same dosage form as the L-aromatic amino acid decarboxylase inhibitor or a different dosage form. The prodrug mesylate of levodopa can be administered at the same time as, before, or subsequent to, the administration of a decarboxylase inhibitor. The prodrug mesylate of levodopa together with a decarboxylase inhibitor or decarboxylase inhibitor prodrug or derivative can be administered to a patient, such as a human, to treat a disease or disorder such as Parkinson's disease. In certain embodiments, the prodrug mesylate of levodopa or pharmaceutical composition thereof together with at least one decarboxylase inhibitor or at least one decarboxylase inhibiting prodrug or derivative can be advantageously used in human medicine. In certain embodiments, the prodrug mesylate of levodopa or pharmaceutical composition thereof may be useful for the treatment of Parkinson's disease. When used to treat Parkinson's disease, the levodopa prodrug mesylate or pharmaceutical composition thereof may be administered or applied in combination with a decarboxylase inhibitor such as carbidopa, a prodrug of carbidopa, benserazide, and / or a prodrug of benserazide. Additionally, the therapeutic effectiveness of the above combinations may be increased by the co-administration of another pharmaceutically active agent such as a catechol-O-methyltransferase (COMT) inhibitor such as entacapone, a prodrug of entacapone, tolecapone, and / or a prodrug. of tolecapona. In addition, in certain embodiments, the prodrug mesylate of levodopa or pharmaceutical composition thereof can be administered to a patient, such as a human, together with (i) a decarboxylase inhibitor such as carbidopa, a prodrug of carbidopa, benserazide, or a benserazide prodrug, and (ii) a pharmaceutically active agent such as a COMT inhibitor or prodrug thereof, for treating a disease or disorder such as Parkinson's disease. The (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate can be included in a pharmaceutical composition and / or dosage form adapted for oral administration, although mesylate of (2R) -2-phenylcarbonyloxy pro pyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate can also be administered by any other convenient route, such as, for example, by injection, infusion, inhalation, transdermal, or absorption through epithelial or mucosal membranes (eg, oral, rectal, and / or intestinal mucosa). The (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate or pharmaceutical compositions thereof may provide therapeutic or prophylactic plasma and / or blood concentrations of levodopa after administration. oral administration to a patient. The pro portion of the carboxyl ester of (2R) -2-phenylcarbonyloxypropyl mesylate (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate can be split in vivo either chemically and / or enzymatically to release the drug precursor, levodopa. One or more enzymes present in the stomach, intestinal lumen, intestinal tissue, blood, liver, brain, or any other appropriate tissue of a patient can enzymatically unbundle the pro portion of the administered compounds. For example, the pro portion of the carboxyl ester of the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate can be cleaved before absorption from the gastrointestinal tract (e.g. of the stomach or intestinal lumen) and / or after absorption from the gastrointestinal tract (e.g., in intestinal tissue, blood, liver, or other appropriate tissue of a mammal). In certain embodiments, the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate can be actively transported through the intestinal endothelium by organic cation transporters expressed through the tract gastrointestinal including the small intestine and colon. Levodopa can be kept conjugated to the pro portion of the carboxyl ester during transit through the intestinal mucosal barrier to prevent or minimize presystemic metabolism. In certain embodiments, (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate is essentially not metabolised to levodopa within gastrointestinal entericitos, but metabolized to levodopa within the systemic circulation, for example in the plasma. In such embodiments, the mesylate of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate can be absorbed into the systemic circulation from the small and large intestines either by active transport , passive diffusion, or by both active and passive processes. The cleavage of the pro portion of the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate after absorption from the gastrointestinal tract may allow the prodrug mesylate of levodopa It is absorbed into the systemic circulation either by active transport, passive diffusion, or by both active and passive processes. The unfolding mechanism is not important for the current modalities. For example, the pro portion of carboxyl ester can be cleaved after absorption from the gastrointestinal tract, for example, in intestinal tissue, blood, liver, or other appropriate tissue of a mammal. The (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate can be administered to a mammal subject in need of treatment, in similar amounts and using a similar program as described in art for levodopa. For example, (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate may be useful for the treatment of Parkinson's disease by the administration of (2R) mesylate. -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate together with a decarboxylase inhibitor such as carbidopa or a prodrug of carbidopa, in certain embodiments by the oral route. In a human subject weighing about 70 kg, the mesylate of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate can be administered in one dose for as long as it has a equivalent weight of levodopa from about 10 mg to about 10 g per day, and in certain embodiments, an equivalent weight of levodopa from about 100 mg to about 3 g per day. A dose of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate taken at any time may have an equivalent weight of levodopa from about 10 mg to about 3 g. A dose can be adjusted by someone skilled in the art based on several factors, including, for example, the body weight and / or condition of the subject treated, the dose of the decarboxylase inhibitor or prodrug of a decarboxylase inhibitor to be administered, the severity of the disease to be treated, the incidence of side effects, the manner of administration, and the judgment of the prescribing physician. The dosage ranges may be determined by methods known to one of skill in the art. The mesylate of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3, 4-dihydroxyphenyl) propanoate can be evaluated in vitro and in vivo with respect to the desired therapeutic or prophylactic activity before being used in humans. For example, in vitro assays can be used to determine whether the administration of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate is a substrate of a carrier protein, including organic cation transporters such as OCTN1 and OCTN2. Examples of certain applicable test methods for analyzing the ability of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate to act as a substrate for a carrier protein are described in Zerangue et al, U.S. Application Publication No. 2003/0158254, which is incorporated in its entirety by reference to the present invention. In vivo assays can also be used to determine whether the administration of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate is therapeutically effective. The (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate can also show that it is effective and safe using animal model systems. In certain embodiments, a therapeutically effective dose of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate may provide therapeutic benefit without causing substantial toxicity. The toxicity of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate can be determined using standard pharmaceutical methods and can be determined by one skilled in the art. The dose ratio between the toxic and therapeutic effect is the therapeutic index. A dose of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate may be within a range capable of establishing and maintaining a plasma and / or circulating blood concentration Therapeutically effective levodopa that exhibits little or no toxicity. In addition to the use of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate and compositions comprising (2R) -2-phenylcarbonyloxypropyl mesylate (2S) -2- amino-3- (3,4-dihydroxyphenyl) propanoate provided by the present disclosure for treating Parkinson's disease, the prodrug mesylate of levodopa and compositions thereof may also be used to treat other dopamine-related diseases. Dopamine-related diseases can be characterized by insufficient or excessive functional dopaminergic activity in the central nervous system. Examples of other dopamine-related diseases include, but are not limited to, affective disorders such as depression and attention deficit disorder, psychotic disorders such as schizophrenia and manic depression, cognitive impairment disorders such as mild cognitive impairment, movement disorders. such as restless leg syndrome, periodic limb movement disorder, tardive dyskinesia, hypertension, Huntington's disease, and Tourette's syndrome, addictive disorders such as alcohol addiction or abuse, nicotine addiction or abuse, and addiction or abuse of drugs, congestive heart failure, and excessive daytime sleepiness. For the treatment of these and other dopamine-related diseases, (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate can be co-administered with an additional active agent such as, for example, a decarboxylase inhibitor and / or a COMT inhibitor. Therapeutically effective doses for the treatment of dopamine-related diseases can be determined by the methods described herein for the treatment of Parkinson's disease and / or by methods known in the art. Pharmaceutical Compositions The pharmaceutical compositions provided by the present disclosure may comprise a therapeutically effective amount of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3-mesylate., 4-dihydroxyphenyl) propanoate, and in certain embodiments, in purified form, together with an appropriate amount of one or more pharmaceutically acceptable carriers, so as to provide a composition for appropriate administration to a patient. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, clay, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol, water, ethanol, and the like. Current compositions may also contain wetting agents, emulsifying agents, and / or pH-dampening agents. In addition, auxiliary agents, stabilizers, thickeners, lubricants, and / or colorants can be used. In certain embodiments, the pharmaceutical compositions may be in the form of a capsule (see for example, Grosswald et al., U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical vehicles are described in the art (see, for example, "Remington's Pharmaceutical Sciences," Lippincott Williams &; Wiikins, 21st Edition, 2005). Pharmaceutical compositions comprising (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate or the crystalline form thereof can be manufactured by means of mixing, dissolving, granulating processes , dragee manufacture, pulverization, emulsification, encapsulation, trapping, or conventional lyophilizer. The pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients, or auxiliaries, which facilitate the processing of the levodopa prodrug mesylate or crystalline form thereof and one or more pharmaceutically acceptable carriers in formulations that can used pharmaceutically The appropriate formulation depends on the chosen route of administration. In certain embodiments, a pharmaceutical composition comprising levodopa prodrug mesylate or crystalline form thereof can be formulated for oral administration and in certain embodiments for sustained release oral administration. The pharmaceutical compositions provided by the present disclosure may take the form of solutions, suspensions, emulsions, tablets, pills, pallets, capsules, capsules containing liquid, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form appropriate for use. Oral Pharmaceutical Compositions In certain embodiments, the mesylate of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate may be incorporated into pharmaceutical compositions for oral administration. Oral administration of such pharmaceutical compositions can result in the absorption of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate through the intestine and entry into the system circulatory. Such compositions can be prepared in a manner known in the pharmaceutical art and comprise (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate and at least one pharmaceutically acceptable carrier. The pharmaceutical compositions may include a therapeutically effective amount of (2R) -2-phenylcarbonyloxypropyl mesylate (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate, in some embodiments, in purified form, together with an inhibitor of decarboxylase such as carbidopa, a prodrug of carbidopa, benserazide, or a prodrug of benserazide, and an appropriate amount of a pharmaceutically acceptable carrier, so as to provide a form suitable for administration to a patient. Pharmaceutical compositions for oral administration may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. Orally administered pharmaceutical compositions may contain one or more optional agents, for example, sweetening agents such as fructose, aspartame or saccharin, flavoring agents such as peppermint, spearmint oil, or cherry coloring agents and preservatives, to provide a preparation pharmaceutically pleasant taste. On the other hand, in tablet or pill forms, the pharmaceutical compositions can be coated to retard disintegration and absorption in the gastrointestinal tract, so that a sustained action is provided for an extended period of time. Selectively permeable membranes surrounding an osmotically active conducting compound are also suitable for orally administered compounds and pharmaceutical compositions. In these latter platforms, the fluid in the environment surrounding the capsule is absorbed by the conductive compound, which swells to displace the agent or agent composition through an opening. These administration platforms can provide an essentially zero order administration profile as opposed to the aggregate profiles of the immediate release formulations. A time retardant material such as glycerol monostearate or glycerol stearate can also be used. Oral pharmaceutical compositions may include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such vehicles can be pharmaceutical grade. For oral liquid preparations such as suspensions, elixirs and solutions, suitable carriers, excipients, or diluents including water, saline, alkylene, glycols (e.g., propylene glycol), polyalkylene glycols (e.g., polyethylene glycol), oils, alcohols, may be included. , slightly acidic buffer solutions from about pH 4 to about pH 6 (eg, acetate, citrate, ascorbate from about 5 mM to about 50 mM), etc. In addition, flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines, and the like can be added. Certain embodiments also include compositions comprising, as the active ingredient, (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate associated with at least one pharmaceutically acceptable carrier including excipients , carriers, diluents and / or adjuvants. In forming the compositions, the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate can be mixed with an excipient, diluted through a diluent or enclosed with a carrier , which may be in the form of a capsule, sachet, paper or other container. When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which can act as a vehicle, carrier, or medium for (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino mesylate -3- (3,4-dihydroxyphenyl) propanoate. In this way, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, wafers, elixirs, suspensions, emulsions, solutions, and syrups containing, for example, up to about 90% by weight of mesylate. (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate using, for example, soft and hard gelatin capsules. In preparing the composition, it may be useful to grind the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate to provide an appropriate particle size before being combined with other ingredients . The ground particle size of the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate can be adjusted depending on the aqueous solubility, and in certain embodiments, can be less about 200 mesh and in certain embodiments, about 40 mesh. Examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The compositions may additionally include lubricating agents such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl- and propylhydroxybenzoates, sweetening agents, adjusting agents and pH buffers, agents that adjust toxicity, flavoring agents, and the like. The compositions may be formulated so as to provide a rapid, sustained, or prolonged release of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate after administration to the patient employing procedures known in the art. A composition can be formulated in unit dosage form, each dosage comprising an equivalent weight of levodopa in the range from about 10 mg to about 10 g. The unit dosage form refers to a physically different unit appropriate as a unit dose for humans and other mammals, each unit containing a predetermined quantity of active material calculated to produce the intended therapeutic effect, in association with an excipient, diluent, carrier and / or appropriate pharmaceutical adjuvant.

The (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate can be administered to a patient in a therapeutically effective amount. It will be understood, however, that the amount of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate currently administered will be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the route of administration chosen, the current compound administered, the age, weight, and response of the individual patient, the disease to be treated, the severity of the patient's symptoms, and the like. To prepare solid compositions such as tablets, (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate can be mixed with a pharmaceutical excipient, diluent, carrier and / or adjuvant to form a solid pre-formulation composition containing a homogeneous mixture containing (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate. When referring to these pre-formulation compositions as homogeneous, it means that the mesylate of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate is evenly dispersed throughout. of the composition so that the composition can be rapidly subdivided into equally effective unit dosage forms such as tablets, pills, or capsules. This pre-formulation can then be subdivided into unit dosage forms of the type described herein which comprises, for example, an equivalent weight of levodopa in the range from about 10 mg to about 10 g. Tablets or pills comprising (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate may be coated or otherwise made into a compound to provide a dosage form that provides the advantage of sustained release. For example, a tablet or pill may comprise an internal dosage and external dosage component, the latter being in the form of an envelope on and / or enclosing the latter. The two components can be separated by an enteric layer. The enteric layer can serve to resist disintegration in the stomach and allows the internal component to pass intact into the duodenum, or for prolonged release. A variety of materials can be used for such enteric layers or shells. For example, such materials include a number of acids and polymer blends of polymeric acids with materials such as lacquer, cetyl alcohol, or cellulose acetate. Liquid dosage forms in which (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate compositions can be incorporated for oral administration or by injection include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Oral Sustained Release Dosage Forms The (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate can be practiced with a different number of dosage forms, which can be adapted to provide sustained release of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate during oral administration. In certain embodiments, the sustained release oral dosage form may comprise beads which in solution or diffusion release the prodrug over an extended period of hours, in certain embodiments, for a period of at least about 4 hours, in some embodiments, during a period of at least about 8 hours, for a period of at least about 12 hours, for a period of at least about 16 hours, during a period of at least about 20 hours, during a period of at least about 24 hours, and in certain modalities, for a period of more than about 24 hours. The beads releasing the prodrug can have a core or core composition comprising (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate and at least one pharmaceutically acceptable carrier. , and may include a lubricant, antioxidant, and / or optional buffer solution. Examples of appropriate time-release beads are described, for example, in Lu, Int. J. Pharm. 1994, 112, 117-124; "Remington's Pharmaceutical Sciences," 21st Edition, Lippincott Williams & Wilcox, (2005); Fincher, J. Pharm. Sci 1968, 57, 1825-1835; and Patent E.U.A. No. 4,083,949). Examples of suitable sustained release tablets are described, for example, in "Remington's Pharmaceutical Sciences," 21st Edition, Lippincott Williams & Wilcox, (2005). In certain embodiments, an oral sustained release pump may be used (see Langer, Science 1990, 249, 1527-1533; Sefton, CRC, Ref. Biomed, Eng. 1987, 14, 201; and Saudek et al, N. Engl. J. Med. 1989, 321, 574). In certain embodiments, polymeric materials for sustained release administration may be used as described, for example, in "Medical Applications of Controlled Relay," Langer and Wise (eds.), CRC Press, Boca Raton, Florida (1974); "Controlled Drug Bioavailability, Drug Product Design and Performance," Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J Macromol. Sci.

Rev. Macromol Chem 1983, 23, 61; Levy et al, Science 1985, 228, 190; During et al, Ann. Neurol 1989, 25, 351; and Howard et al, J. Neurosurg 1989, 71, 105. In certain embodiments, enteric coating preparations can be used for sustained release oral administration. In certain embodiments, the materials include polymers with a pH-dependent solubility (ie, controlled release by pH), polymers with a slow range of swelling, dissolution or erosion or pH-dependent (ie, time controlled release), polymers that can be degraded by enzymes (ie, enzyme controlled release) and polymers that form firm layers that can be destroyed by an increase in pressure (ie, controlled release by pressure). In certain embodiments, drug release lipid matrices or pro-drug releasing waxes can be used for sustained release oral administration. In certain embodiments, the controlled release systems may be placed in the vicinity of the target of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate or levodopa metabolite, this way requiring only a fraction of the systemic dose (see Goodson, in "Medical Applications of Controlled Relay," vol.2, 115-138 (1984)). Other controlled-release systems discussed in Langer, Science 1990, 249, 1527-1533, may also be used. In certain embodiments, the dosage forms may comprise (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate coated on a polymer substrate. The polymer can be a degradable or non-degradable polymer. Biodegradable polymers are described, for example, in Rosoff, "Controlled Relay of Drugs," Chap. 2, 53-95 (1989); and Patents E.U.A. Nos. 3,811,444; 3,962,414; 4,066,747; 4,070,347; 4,079,038; and 4,093,709. In certain embodiments, the dosage form can comprise (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate charged to a polymer that releases the prodrug by diffusion through of a polymer, or it may flow through pores or through the breakdown of a polymer matrix as described, for example, in Coleman et al, Polymers 1990, 31, 1187-1231; Roerdink et al, Drug Carrier Systems 1989, 9, 57-100; Leong et al, Adv. Drug Delivery Rev. 1987, 1, 199-233; Roff et al, "Handbook of Common Polymers," 1971, CRC Press; and Patent E.U.A. No. 3,992,518. In certain embodiments, the osmotic delivery systems are used for sustained release oral administration (Verma et al, DrugDev, Ind. Pharm. 2000, 26, 695-708). In certain embodiments, OROS ™ osmotic devices are used for sustained release oral delivery devices (Theeuwes et al, U.S. Patent No. 3,845,770; Theeuwes et al, U.S. Patent No. 3,916,899). Regardless of the specific form of the oral sustained release dosage form used, (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate can be released from a dosage form such as a dosage form administered orally, for a period of time sufficient to provide prolonged therapeutic concentrations of levodopa in the blood of a patient allowing the administration of the dosage form on a one-time basis only or twice a day. After oral administration, dosage forms comprising (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate can provide a therapeutic or prophylactic concentration of levodopa in the plasma and / or blood of a patient for a period of at least about 4 hours, in certain modalities, for at least about 8 hours, for at least about 12 hours, for at least about 16 hours, for at least around 20 hours, and in certain modalities, for at least about 24 hours after oral administration to the patient of the dosage form. A therapeutically or prophylactically effective concentration of levodopa in the blood and / or plasma of a patient may depend on a number of factors including, for example, the disease to be treated, the severity of the disease, the patient's weight, the patient's health , etc. The pharmaceutical compositions provided by the present disclosure can be administered for therapeutic or prophylactic treatments. A therapeutic amount is an amount sufficient to remedy a disease state or symptoms, or otherwise prevent, impede, delay, or reverse the progress of the disease or any other unwanted symptoms in any form of any kind. In prophylactic applications, the pharmaceutical compositions or the present disclosure can be administered to a patient susceptible to or otherwise at risk of a particular disease or infection. Therefore, a prophylactically effective amount is an amount sufficient to prevent, impede or retard the disease state or its symptoms. An appropriate dose of the pharmaceutical composition can be determined according to any of several well-established protocols. For example, animal studies, such as studies using mice or rats, can be used to determine an appropriate dose of the pharmaceutical compound. The results of animal studies can be extrapolated to determine the dose to be used in other species, such as, for example, humans. For example, the efficacy of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate and compositions thereof to treat Parkinson's disease can be evaluated using animal models and humans from Parkinson's disease and clinical studies. Animal and human models of Parkinson's disease are known (see, for example, O'Neil et al, CNS Drug Rev. 2005, 11 (1), 77-96).; Faulkner et al, Ann. Pharmacother. 2003, 37 (2), 282-6; Olson et al, Am. J. Med. 1997, 102 (1), 60-6; Van Blercom et al, Clin Neuropharmacol. 2004, 27 (3), 124-8; Cho et al, Biochem. Biophys. Res. Commun. 2006, 341, 6-12; Emborg, J. Neuro. Meth. 2004, 139, 121-143; Tolwani et al, Lab Anim Sci 1999, 49 (4), 363-71; Hirsch et al, J Neural Transm Suppl 2003, 65, 89-100; Orth and Tabrizi, Mov Disord 2003, 18 (7), 729-37; and Betarbet et al, Bioessays 2002, 24 (4), 308-18). The (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate or pharmaceutical compositions thereof can be administered as sustained release systems, and in certain embodiments, as delivery systems sustained orally administered. In certain embodiments, the compounds may be administered by sustained release oral administration. In certain embodiments, the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate or pharmaceutical compositions thereof may be administered twice a day, in certain embodiments, once per day, and in certain modalities at intervals greater than once per day.

Combination Therapy In certain embodiments, the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate or crystalline form thereof can be used in combination therapy with at least one other therapeutic agent. The pharmaceutical compositions provided by the present disclosure may include, in addition to the mesylate of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate, one or more effective therapeutic agents for treating the same or different disease, disorder, or condition. Methods are provided through the present disclosure which include the administration of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate or pharmaceutical compositions thereof and one or more of other therapeutic agents, with the proviso that the combined administration does not inhibit the therapeutic efficacy of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate and / or levodopa; or does not produce adverse combination effects. The (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate and other therapeutic agent (s) can act in an additive or synergistic manner. In certain embodiments, the pharmaceutical compositions provided by the present disclosure may be administered concurrently with the administration of another therapeutic agent, which may be contained in the same pharmaceutical composition as, or in a composition different from that which contains the (2R) mesylate. 2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate. In certain embodiments, the mesylate of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate may be administered before or after the administration of another therapeutic agent. In certain combination therapy modalities, the combination therapy may comprise alternating between administering a composition provided by the present disclosure and a composition comprising another therapeutic agent, for example, to minimize adverse side effects associated with a particular drug. When the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate or crystalline form thereof is administered concurrently with another therapeutic agent which can potentially produce adverse side effects including, but they are not limited to toxicity, the therapeutic agent can advantageously be administered at a dose below the threshold at which the adverse side effect occurs. In certain embodiments, the mesylate of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate can also be administered together with one or more compounds that increase, modulate, and / or control the release, bioavailability, therapeutic efficacy, therapeutic potency, and / or stability of the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate or crystalline form thereof and / or levodopa. For example, to increase the therapeutic efficacy, the levodopa prodrug mesylate can be co-administered with one or more active agents to increase the absorption or diffusion of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3 mesylate. - (3,4-dihydroxyphenyl) propanoate or crystalline form thereof and / or levodopa through the gastrointestinal tract, or to modify the degradation of the mesylate of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- ( 3,4-dihydroxyphenyl) propanoate or crystalline form thereof and / or levodopa in the systemic circulation. In certain embodiments, (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate can be co-administered with an active agent having pharmacological effects that increase the therapeutic efficacy of levodopa after they are released from the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate or crystalline form thereof. In certain modalities, the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate can be co-administered with an active agent having pharmacological effects that increase the therapeutic efficacy of dopamine after that have been released from levodopa. In certain embodiments, the mesylate of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate or crystalline form thereof or pharmaceutical compositions comprising mesylate of (2R) -2- phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate or crystalline form thereof can be administered to a patient together with another compound to treat Parkinson's disease, depression, attention deficit disorder, schizophrenia, Manic depression, cognitive impairment disorders, restless leg syndrome, periodic limb movement disorder, tardive dyskinesia, Huntington's disease, Tourette's syndrome, hypertension, addictive disorders, congestive heart failure, or excessive daytime sleepiness. Examples of drugs useful in treating Parkinson's disease include amantadine, baclofen, biperiden, benztropine, orphenadrine, procyclidine, trihexyphenidyl, levodopa, carbidopa, andropinirole, apomorphine, benserazide, bromocriptine, budipine, cabergoline, eliprodil, eptastigmine, ergoline, galantamine, lazabemide, lisuride, mazindol, memantine, mofegiline, pergolide, piribedil, pramipexole, propentofylline, rasagiline, remacemide, ropinirole, selegiline, globoine, terguride, entacapone, and tolcapone. Examples of drugs useful in treating mood disorders such as depression include tricyclic antidepressants such as amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, and trimipramine.; selective serotonin reuptake inhibitors such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; serotonin-noradrenaline reuptake inhibitors such as venlafaxine, duloxetine, sibutramine, and milnacipran; monoamine oxidase inhibitors such as phenelzine and tranylcypromine; and psychostimulants such as dextroamphetamine and methylphenidate. Other antidepressants include benmoxina, butriptilina, dosulepin, imipramina, citanserina, lofepramina, medifoxamina, mianserina, mirtazapina, viloxaziha, cotinina, nisoxetina, reboxetina, tianeptin, acetafenazina, binedalina, brofaromina, cericlamina, clovoxamina, iproniazid, isocarboxazid, moclobemida, fenihidrazina, selegilina , sibutramine, ademetionin, adrafinil, amesergidae, amisulpride, amperozide, benazizine, bupropion, caroxazone, gepirone, idazoxan, metralindol, minaprine, nefazodone, nomifensin, ritanserin, roxindol, S-adenosylmethionine, escitalopram, tofenacin, trazodone, tryptophan, zalospirone, and Grass of San Juan. The (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate or crystalline form thereof and pharmaceutical compositions thereof may also be used in conjunction with psychotherapy or electroconvulsive therapy to treat mood disorders such as depression. Examples of drugs useful in treating attention deficit disorders include atomoxetine, bupropion, dexmethylphenidate, dextroamfetamine, metamfetamine, methylphenidate, and pemoline. Examples of drugs for treating schizophrenia include aripiprazole, loxapine, mesoridazine, quetiapine, reserpine, thioridazine, trifluoperazine, and ziprasidone. Examples of drugs useful in treating manic depression include carbamazepine, clonazepam, clonidine, valproic acid, verapamil, lamotrigine, gabapentin, topiramate, lithium, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, clonazepam, lorazepam, zolipidem, St. John's wort, Omega-3 fatty acids. Examples of drugs useful in treating memory or cognitive disorders include antipsychotic drugs such as chlorpromazine, fluphenazine, haloperidol, loxapine, mesoridazine, molindone, perphenazine, pimozide, thioridazine, thiothixene, trifluoperazine, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone; sedatives such as diazepam and lorazepam; benzodiazepines such as alprazolan, chlordiazepoxide, clonazepam, clorazepate, diazepam, lorazepam, and oxazepam; non-steroidal anti-inflammatory drugs such as aceclofenac, acetaminophen, alminoprofen, amfenac, aminopropilon, amixetrin, aspirin, benoxaprofen, bromfenac, bufexamac, carprofen, celecoxib, choline, salicylate, cinchofen, cinmetacin, clopriaco, clometacin, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, indoprofen, ketoprofen, ketorolac, mazipredone, meclofenamate, nabumetone, naproxen, parecoxib, piroxicam, pirprofen, rofecoxib, sulindac, tolfenamate, tolmetin, and valdecoxib; acetylcholinesterase inhibitors such as donepezil, galantamine, rivastigmine, physostigmine, and tacrine; and N-methyl-D-aspartate (NMDA) receptor blockers such as memantine. Examples of drugs useful in treating restless legs syndrome include dopaminergics such as levodopa, pergolide mesylate, pramipexole, and rinirol hydrochloride, benzodiazepines such as clonazepam and diazepam, opioids such as codeine, propoxyphene, and oxycodone, and anticonvulsants such as gabapentin. and carbamazepine. Examples of drugs useful in treating movement disorders such as tardive dyskinesia include reserpine, tetrabenazine, and vitamin E. Examples of drugs useful in treating Huntington's disease include antipsychotics such as haloperidol, chlorpromazine, and olanzapine; antidepressants such as fluoxetine, sertraline chlore-hydrate, and nortriptyline; tranquilizers such as benzodiazepines, paroxetine, venlafaxin, and beta-blockers; mood stabilizers such as lithium, valproate, and carbamazepine; and Botulinum toxin. Examples of drugs useful in treating Tourette syndrome include haloperidol, pergolide, and pimozide. Examples of drugs useful in treating hypertension include acebutolol, amiloride, amlodipine, atenolol, benazepril, betaxolol, bisoprolol, candesartan captopril, careolol, carvedilol, chlorothiazide, chlorthalidone, clonidine, diltiazem, aoxazosin, enalapril, eplerenone, eprosartan, felodipine, fosinopril, furosemide, guanabenz, guanetidine, guanfacine, hydralazine, hydrochlorothiazide, indapamide, irbesartan, isradipine, labetalol, lisinopril, losartan, methyldopa, metolazone, metoprolol, minoxidil, moexipril, nadolol, nicardipine, nifedipine, nisoldipine, nitroglycerin, olmesartan, perindopril, pindolol, prazosin, propranolol, quinapril, ramipril, reserpine, spironolactone, telmisartan, terazosin, timolol, torsemide, trandolapril, valsartan, and verapamil. Examples of drugs useful in treating alcohol addiction or abuse include disulfiram, naltrexone, clonidine, methadone, 1-acetylmethadol, buprenorphine, and bupropion. Examples of drugs useful in treating narcotic addiction or abuse include buprenorphine, tramadol, methadone, and naltrexone. Examples of drugs useful in treating nicotine addiction or abuse include bupropion, clonidine, and nicotine. Examples of drugs useful for treating congestive heart failure include allopurinol, amiloride, amlodipine, benazepril, bisoprolol, carvedilol, digoxin, enalapril, eplerenone, fosinopril, furosemide, hydrochlorothiazide, hydralazine, isosorbide dinitrate, isosorbide mononitrate, lisinopril, metoprolol, moexipril. , nesiritide, nicardipine, nifedipine, nitroglycerin, perindopril, prazosin, quinapril, ramipril, spironolactone, torsemide, trandolapril, triamcinolone, and valsartan. Examples of drugs useful in treating excessive daytime sleepiness include dextroamphetamine, methylphenidate, modafmil, and sodium oxybate. Examples The following examples describe in detail the preparation of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate and the crystalline form thereof, pharmaceutical compositions thereof, and uses thereof. It will be apparent to someone of experience in the art that many modifications, both for materials and methods, can be practiced without departing from the scope of the description. Example 7 is predictive. In the examples, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. ACN = acetonitrile DCM = dichloromethane EtOAc = ethyl acetate eq = equivalents g = gram h = hour J = Joules kg = kilogram kV = kilovolts LC / MS = liquid chromatography / mass spectroscopy MeOH = methanol min = minute m A = milliamperes mg = milligram m L = milliliter mm = millimeter mmol = millimoles MTBE = methyl tert-butyl ether g = microgram μ? _ = microliter Example 1 (2R) -2-Phenylcarbonyloxypropyl (2S) -2- (tert-Butoxycarbonyl) amino- 3- (3,4-dihydroxyphenyl) propanoate (2) Stage A: (2S -3- (3,4-Dihydroxy-phenyl-2-f (tert-butoxycarboni-D-aminopropropanoic acid, Tetrabutylammonium salt A solution of N-Boc- (L) -Dopa (175 g, 0.59 mol) in methanol (1 L) was carefully mixed with a methanolic solution of tetrabutylammonium hydroxide (1.0 M, 0.55 L) at 0 ° C for 30 min.The mixture was then concentrated under reduced pressure and dried by azeotropic process with toluene twice, the residue crystallized after cooling to 4 ° C for 16 h The resulting crystalline solid was washed with acetone (400 ml_ x 3), collected in a Buchner funnel, and then dried under high vacuum to provide 245 g (83% yield) of the title compound. 1 H NMR (400 MHz, DMSO-de): d 0.94 (t, J = 7.6 Hz, 12H), 1.30 (m, 17H), 1.60 (m, 8H), 3.18 (m, 8H), 4.58 (m, 1H ), 5.68 (d, J = 5.6 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 6.46 (d, J = 8.0 Hz, 1H), 6.51 (s, 1H), 8.85 (s, 1H) ); 8.94 (s, 1H). Step B: (1 R) -2-Bromo-1-methylethyl Benzoate A solution of (2R) -propylene glycol (20.0 g, 262.8 mmol), benzaldehyde (33.4 mL_, 328.6 mmol, 1.25 eq) and p-toluenesulfonic acid (2.5 g, 0.05 eq) in benzene (200 mL) was refluxed for 8 h with removal of water by means of a Dean-Stark apparatus. The cold solution was diluted with diethyl ether (100 mL), washed with NaOH a, brine (15%, 100 mL), brine (100 mL) and dried over Na2SO4. After filtration, removal of the solvent under reduced pressure yields 44 g of benzaldehyde (2R) -propylene glycollacetal crude as an oil. To a solution of the above crude (2R) -propylene glycollacetal benzaldehyde (10.0 g, 60.9 mmol) in hexane (100 ml_) was added N-bromosuccinamide (NBS) (11.9 g, 67 mmol, 1.1 eq). The resulting mixture was stirred at room temperature overnight. The suspension was filtered through Celite and the filtrate was diluted with hexane (300 mL), washed with NaHCC > Saturated (100 mL), brine (100 mL) was added, and dried over Na2SO4. After filtration, removal of the solvent under reduced pressure yields the title compound (quantitative yield) as an oil. H NMR (400 MHz, CDCl 3): d 1.48 (d, J = 6.4 Hz, 3H), 3.58 (m, 2H), 5.31 (m, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.53 ( t, J = 7.6 Hz, 1H), 8.05 (d, J = 7.2 Hz, 2H). Step C: (2R) -2-phen i read rbon i loxi propi lo (2) (2S -2- (tert-Butoxycarbonyl) amino-3- (3,4-dihydroxyphenyl) propanoate A suspension of benzoate of (1 R) - 2-bromo-1-methylethyl (4.98 g, 20.6 mmol), N-Boc-L-DOP A-COOH (7.3 g, 25 mmol), and cesium bicarbonate (4.85 g, 25 mmol) in N, N-dimethylacetamide (100 mL) was stirred at 55 ° C for 16 h, the solvent was evaporated under vacuum, ethyl acetate was added to the residue and the resulting solution was washed with water, then 5% NaHCO 3, brine, and dried over Na 2 SO 4. After removing the solvent under reduced pressure, chromatography (silica gel, 30% ethyl acetate in hexane) of the residue afforded 6.3 g (68% yield) of the title compound 2 as a white solid. 400 MHz, CD3OD): d 1.25 (s, 9H), 1.40 (d, J = 6.4 Hz, 3H), 2.99 (dd, J = 7.6, 14.4 Hz, 1H), 3.10 (dd, J = 5.6, 14.4 Hz , 1H), 4.24 (dd, J = 5.6, 7.4 Hz, 1H), 4.38 (dd, J = 6.8, 11.6 Hz, 1H), 4.52 (dd, J = 3.2, 11.6 Hz, 1H), 5.40 (m, 1H), 6.53 (dd, J = 2.2, 8.4 Hz, 1H), 6.66 (d, J = 2.2 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 1.6 Hz, 2H), 7.60 (t, J = 1.6 Hz, 1H), 8.02 (d, J = 7.6 Hz, 2H). MS (ESI) m / z 360.15 (M + H) + and 358.09 (MH) \ Example 2 (2R-2-phenylcarbonyloxypropyl (2S) -2-Am i-3- (3,4-dihydroxy-phenylpropanoate) mesylate Method (1) Method 1: Stage A: (2R) -2-Phenylcarbonyloxypropyl (2S) -2-Amino-3- (3,4-dihydroxy-phenylpropanoate (3) hydrochloride A solution of (2R) -2-phenylcarbonyloxypropyl (2S) -2- ( tert-butoxycarbonyl) amino-3- (3,4-dihydroxyphenyl) propanoate 2 (6.3 g, 13.7 mmol) in 50 ml of 4N HCl in dioxane was stirred at room temperature for 30 min.The reaction mixture was concentrated until dried under reduced pressure The resulting residue was dissolved in about 20 mL of anhydrous acetonitrile and 4 mL of ether.The solution was cooled, and the resulting white precipitate was filtered, washed with ether, and dried under vacuum to provide 4.7 g. (87% yield) of the hydrochloride salt 3 as a white solid.1H NMR (400 MHz, CD3OD): d 1.40 (d, J = 6.4 Hz, 3H), 2.99 (dd, J = 7.6, 14.4 Hz, 1H), 3.10 (dd, J = 5.6, 14.4 Hz, 1H), 4. 24 (dd, J = 6, 8 Hz, 1H), 4.38 (dd, J = 6.8, 11.6 Hz, 1H), 4.52 (dd, J = 3.2, 11.6 Hz, 1H), 5.40 (m, 1H), 6.52 (dd, J = 2.2, 8.4 Hz, 1H), 6.66 (d, J = 2.2 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.60 (t, J = 7.6 Hz, 1H), 8.02 (d, J = 1.6 Hz, .2H). MS (ESI) m / z 360.15 (M + H) + and 358.09 (MH). "Step B: (2R) -2-Phenylcarbonyloxypropyl (2S) -2- Amino-3- (3,4-dihydroxy-phenylpropanoate) mesylate (1) A solution of NaHCO3 (9.87 g, 117.5 mmol) in water (80 ml_) was slowly added to a solution of the hydrochloride salt 3 (31.0 g)., 78.3 mmol) in water (300 ml_). The resulting aqueous suspension was extracted with EtOAc (2 x 400 ml_). The combined EtOAc extract was washed with water, then brine, dried through MgSO4. Methanesulfonic acid (6.04 ml_, 93.12 mmol) was slowly added to the EtOAc solution while stirring. The white precipitate formed as soon as the methanesulfonic acid addition was complete. The suspension was stirred for another 30 min and then filtered. The filter cake was washed three times with EtOAc and dried under vacuum overnight to provide 35.4 g (quantitative) of the mesylate salt 1 as a white solid. 1 H NMR (400 MHz, CD3OD): d 1.40 (d, J = 6.4 Hz, 3H), "2.70 (s, 3H), 2.98 (dd, J = 7.8, 14.6 Hz, 1H), 3.10 (dd, J = 5.6, 14.4 Hz, 1H), 4.24 (dd, J = 5.8, 7.8 Hz, 1H), 4.38 (dd, J = 6.8, 12.0 Hz, 1H), 4.52 (dd, J = 3.4, 11.8 Hz, 1H), 5.40 (dp, J = 3.2, 6.4 Hz, 1H), 6.52 (dd, J = 2.2, 8.2 Hz, 1H), 6.67 (d, J = 2.2 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H ), 7.47 (t, J = 7.6 Hz, 2H), 7.60 (br t, J = 7.4 Hz, 1H), 8.01 (d, J = 7.6 Hz, 2H). MS (ESI) m / z 360.07 (M + H) + and 358.01 (MH). "Method 2: Methanesulfonic acid (3.9 mL, 60.1 mmol) was slowly added to a solution of (2R) -2-phenylcarbonyloxypropyl (2S) ) -2- (tert-butoxycarbonyl) amino-3- (3,4-dihydroxyphenyl) propanoate 2 (11.0 g, 22.1 mmol) in 1,4-dioxane (30 mL) while stirring at room temperature. The solution was slowly added to methyl tert-butyl ether (MTBE) (600 mL) with vigorous stirring The resulting suspension was filtered The filter cake was washed three times with methyl tert-butyl ether and dried with air to provide 5.48 g (54% yield) of the mesylate salt 1 as an opaque white solid Method 3: A solution of (2R) -2-phenylcarbonyloxypropyl (2S) -2- (tert-butoxycarbonyl) ) amino-3- (3,4-dihydroxyphenyl) propanoate 2 (10.5 g, 21.1 mmol) in 34 mL (6.0 eq) of 4.0 N HCI / 1,4-dioxane was stirred at room temperature for 1 h. to the acid reaction mixture Methanesulfonic acid (1.48 mL, 22.8 mmol) was added while stirring at room temperature. The solution was concentrated under vacuum to provide the mesylate salt 1 as a brown solid.

Example 3 Preparation of (2R) -2-Phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate (1) The mesylate salt 1 (10.0 g, 22.0 mmol) was dissolved in 200 mL of isopropanol at 70 ° C and the resulting solution was cooled to room temperature. Filtration provides 5.8 g (58% yield) of the crystalline mesylate salt 1 as a white crystalline solid, (mp 160.5-161.3 ° C). The crystallization of the mesylate salt 1 was carried out in several solvents of single component or mixed component including those listed in Table 1. Differential scanning calorimetry (DSC) was used to evaluate the number of crystalline forms of the salt of mesylate 1 produced by the various solvents. A DSC thermogram of the crystalline mesylate salt 1 obtained by crystallization from isopropanol is shown in Figure 1. The DSC analysis of the crystallized mesylate salt 1 crystallized from each solvent listed in Table 1 shows an endothermic event represented by a accurate peak, single at 165.8 ± 1.1 ° C (scanning ratio 10 ° C / min or 15 ° C / min). Table 1 shows the examples of solvents used for crystallization of the mesylate salt 1 and the corresponding DSC parameters, endothermic temperature (° C) and ?? (J / g).

Table 1 Solvent Endothermic temperature ?? (J / g) (° C) H20 at 1% in ACN 166.8 89.9 H20 at 3% in ACN 165.4 84.5 H20 at 1% in sopropanol 165.1 91.5 Isopropanol 165.8 90.2 MeOH / TBE (1: 7) 166.9 92.3 MeOH / MTBE (1: 6) 164.9 90.4 MeOH / MTBE (1: 5) 166.0 97.2 0.5% H20 in MeOH / MTBE (1: 5) 165.1 98.3 Dioxane 165.2 87.9 Acetone 165.3 90.0 H20 at 3% in EtOAc 166.8 115.9 H2O at 2% in acetone / MTBE (5: 3) 165.8 90.1 ½0 to 0.75% in acetone / ACN (1: 1) 165.7 90.9 H20 at 2.5% in EtOAc 165.8 90.1 EtOH / EtOAc (1: 3) 165.3 94.5 Example 4 Synthesis and crystallization of (2R) -2- Phenylcarbonyloxypropyl mesylate (2S) -2-Amino-3- (3,4-dihydroxy-phenylpropanoate (1) To an aqueous solution of the hydrochloride salt 3 (65.0 g, 164 mmol, 200 mL) was added aqueous NaHCO3 solution (20.7 g, 246 mmol, 200 mL) and then extracted with EtOAc (2 x 400 mL). The pooled organic extracts were washed with brine and dried over Na2SO4. After filtration, methanesulfonic acid (12.8 mL, 197 mmol) was slowly added to the filtrate while stirring at room temperature. The resulting white crystals were filtered through a porous funnel, washed with EtOAc (3 x 1000 mL) and dried under high vacuum at 50 ° C to provide 73.6 g (98.4% yield) of the mesylate salt 1. 1 H NMR (400 MHz, CD 3 OD): d 1.40 (d, J = 6.4 Hz, 3 H), 2.70 (s, 3 H), 2.98 (dd, J = 7.8, 14.6 Hz, 1 H), 3.10 (dd, J = 5.6 , 14.4 Hz, 1H), 4.24 (dd, J = 5.8, 7.8 Hz, 1H), 4.38 (dd, J = 6.8, 12.0 Hz, 1H), 4.52 (dd, J = 3.4, 11.8 Hz, 1H), 5.40 (dp, J = 3.2, 6.4 Hz, 1H), 6.52 (dd, J = 2.2, 8.2 Hz, 1H), 6.67 (d, J = 2.2 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H) , 7.47 (t, J = 7.6 Hz, 2H), 7.60 (br t, J = 7.4 Hz, 1H), 8.01 (d, J = 1.6 Hz, 2H). MS (ESI) m / z 360.07 (M + H) + and 358.01 (MH) \ Example 5 X-ray powder diffraction analysis (XRPD) of (2R) -2-f-mesylatecarbonyloxypropyl mesylate (2S) -2- Am ino-3- (crystalline 3,4-dihydroxyphenimpropanoate (1) XRPD analyzes were performed using a Shimadzu XRD-6000 X-ray powder diffractometer with Cu Ka radiation. The instrument was equipped with a long fine-focus X-ray tube. The tube voltage and current were placed up to 40 kV and 40 mA, respectively The divergence and healed slits were placed at 1o and the slit received was placed at 0.15 mm The diffractioned radiation was detected using a Nal scintillation detector. A continuous T-2T scan at 37 min (0.4 sec / 0.02 ° stage) from 2.5 to 40 ° 2T was used The aligned instrument was verified by analyzing a silicon standard Data was collected and analyzed using the XRD-6000 software v.4.1 Five representative diffraction patterns of crystallized mesylate salt 1 cri stalized from 1% H20 in isopropanol, isopropanol, MeOH / MTBE (1: 7), 0.5% H2Q in MeOH / MTBE (1: 5), and 1% H20 in acetonitrile are shown in Figures 2-6, respectively. The presence of clearly resolved peaks at similar diffraction angles confirms that the same crystalline form of the mesylate salt 1 occurred during the crystallization of these solvents. EXAMPLE 6 Absorption of Levodopa Prodrugs After Administration of Prodrugs of Levodopa and Carbidopa in Rats Sustained-release oral dosage forms, which release the drug slowly for periods of from about 6 to about 24 hours, generally release a significant proportion of the dose inside the colon. In this manner, drugs suitable for use in such dosage forms should be colonicly absorbed. This experiment was conducted to evaluate the absorption and resulting plasma / blood levodopa levels, after intracolonic administration of the levodopa prodrug mesylate with the co-administration of carbidopa (intracolonically, intraperitoneally, or orally), and is therefore determined the ability of the prodrug mesylate of levodopa for use in an oral sustained release dosage form. The bioavailability of levodopa after co-administration of levodopa prodrug and carbidopa mesylate was calculated in relation to oral co-administration of levodopa and carbidopa. Stage A: Administration protocol The rats were commercially obtained and pre-channeled in both the ascending colon and the jugular vein. The animals were aware at the time of the experiment. All animals were fasted overnight and up to 4 hours after dosing the levodopa prodrug. Carbidopa was administered as a solution in water or citrate buffer either orally, intraperitoneally, or intracolonically at a dose equivalent to 25 mg carbidopa per kg. Either at the same time or 1 hour after dosing with carbidopa, the HCl salt of levodopa or (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate is administered as a solution (in water) directly in the colon by means of a cannula in a dose equivalent to 75 mg of levodopa per kg. Blood samples (0.3 mL) were obtained from the jugular cannula at intervals over 8 hours and were immediately quenched with sodium metabisulfite to prevent oxidation of levodopa and levodopa prodrug.

Subsequently, the blood was further quenched with methanol / perchloric acid to prevent hydrolysis of the prodrug of levodopa. The blood samples were analyzed as described below. Step B: Sample preparation for colony-absorbed drug Methanol / perchloric acid (300 μm) was added to 1.5 ml white Eppendorf tubes. Rat blood (300 μl) was collected in EDTA tubes containing 75 μl of sodium metabisulfite at different times and placed in a vortex to mix. A fixed volume of blood (100 μ? _) Was added immediately into the Eppendorf tube and placed in a vortex to mix. Ten microliters of standard levodopa stock solution (0.04, 0.2, 1, 5, 25, and 100 pg / mL) were added and 10 μl of the 10% sodium metabisulfite solution was added to 80 μm. of the rat blood blank to make a final calibration standard (0.004, 0.02, 0.1, 0.5, 2.5, and 10 pg / mL). Methanol / perchloric acid (300 requests 50/50) was then added to each tube followed by the addition of 20 μl of p-chlorophenylalanine. The samples were vortexed and centrifuged at 14,000 rpm for 10 min. The supernatant was analyzed by LC / MS / MS. Step C: LC / MS / MS Analysis An API 4000 CL / MS / MS spectrometer equipped with Agilent 1100 binary pumps and an HTS-PAL CTC autosampler were used in the analysis. A Zorbax XDB C8 4.6 x 150 mm column was used during the analysis. The mobile phases were (A) 0.1% formic acid, and (B) acetonitrile with 0.1% formic acid. The gradient condition was: 5% B for 0.5 min, then up to 98% B in 3 min, then maintained at 98% B for 2.5 min. The mobile phase returned to 2% B for 2 min. A TurbolonSpray source was used in the API 4000. The analysis was done in positive ion mode and the MRM transition for each material for analysis was optimized using standard solution. Was injected 5 μ? of each sample. A non-compartment analysis was performed using WinNonlin software (v.3.1 Professional, Pharsight Corporation, Mountain View, California) on individual animal profiles. The statistics summarized in main parameter estimates were made for Cmax (observed peak concentration after dosing), Tmax (time for maximum concentration is the time in which the peak concentration was observed), AUC (0-t) (low area the serum concentration-time curve from time zero to the last collection time, estimated using the linear trapezoidal method log), AUC (0 ..) (area under the time curve blood concentration from time zero to infinity, estimated using the trapezoidal linear-log method for the last collection time with extrapolation to infinity), and ti / 2, z (terminal half-life). The maximum concentrations of levodopa in the blood (Cmax values) and the values of the time curve against the blood concentration under the area (AUC) after intracolonic dosing of (2R) -2-phenylcarbonyloxypropyl mesylate or (2S) -2- amino-3- (3,4-dihydroxyphenyl) propanoate 1 with carbidopa were significantly higher (> 2 times) than those achieved by colonic administration of levodopa with carbidopa. The intracolonic co-administration of levodopa and carbidopa results in very low relative bioavailability of levodopa (ie, only 3% of levodopa and carbidopa orally co-administered). In comparison, coadministration of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) -propanoate 1 mesylate with carbidopa exhibits a relative bioavailability of levodopa at least 2-fold. The data demonstrate that certain prodrugs of levodopa can be formulated as appropriate compositions for sustained sustained oral delivery and absorption of levodopa prodrug mesylate and / or levodopa from the colon. Example 7 Use of (2R) -2-phenylcarbonyloxypropyl methylate (crystalline 2S-amino-3-f-3,4-dihydroxyphenyl) propanoate (1) to treat Parkinson's disease The following clinical study may be used to evaluate the efficacy of the Crystalline mesylate salt 1 in the treatment of Parkinson's disease. Patients with language PD who meet the criteria of the Queen Square Brain Bank (Gibb et al, J Neurol Neurosurg Psychiatry 1988, 51, 745-752) with motor fluctuations and a response to levodopa of defined short duration (1.5-4 hours) are eligible for inclusion. Clinically relevant peak dose dyskinesias after each morning dose of your current medication are an additional prerequisite. Patients also need to be stable at a fixed dose of treatment for a period of at least one month before starting the study. Patients are excluded if their current drug regimen includes sustained release formulations of levodopa, COMT inhibitors, selegiline, anticholinergic drugs, or other drugs that could potentially interfere with gastric absorption (eg, antacids). Other exclusion criteria include patients with psychotic symptoms or those in patients with antipsychotic treatment with a record of clinically relevant cognitive impairment, defined as MMS (MiniMental State) of less than 24 (Folstein et al., J Psychiatr Res 1975, 12, 189-198), risk of pregnancy, Hoehn & amp; amp;; Yahr stage 5 in an inactive situation, unstable, severe diabetes mellitus, and medical conditions such as unstable cardiovascular disease or moderate to severe renal or hepatic impairment. Blood, liver and kidney function blood tests were taken at the baseline and after completing the study.

A selected, double-blind, cross-over study design is used. Each patient is drawn in the order in which either LD / DC or one of the two dosages of the test compound is administered in a single-dose stimulation in a double-simulation manner in three consecutive sessions. The selection is by computer generation of the treatment number, assigned to each patient according to the order of entry into the study. Patients are admitted to the hospital for an overnight stay before the administration of the crystallized mesylate salt 1 the following morning on three separate occasions at weekly intervals. After removal of all anti-parkinsonian drugs from midnight on the previous day, the crystalline mesylate salt 1 is administered exactly at the same time in the morning in each patient under fasting conditions. Patients are sorted by the order of the days in which they "receive placebo or salt of crystalline mesylate 1. The pharmacokinetics of the crystalline mesylate salt 1 can be evaluated by what is observed from the concentration of levodopa in the plasma over time. of the administration, a 22 G intravenous catheter is inserted into the patient's forearm Blood samples of 5 ml each are taken at the baseline and 15, 30, 45, 60, 75, 90, 105, 120, 140, 160 , 180, 210, and 240 minutes after administering the crystalline mesylate salt 1 or until a complete quenched state is reached if this occurs earlier than 240 minutes after ingestion of the drug.The samples are centrifuged immediately at the end of each evaluation and stored in deep frozen until they are evaluated.Levodopa and 3-O-methyl-Dopa levels in plasma are evaluated by high pressure liquid chromatography (HPLC) .In the last evaluation the additional blood can be extracted for routine hematology, blood sugar, liver function, and kidney. For clinical evaluation, motor function was evaluated using the UPDRS motor record (Unified Parkinson's Disease relation scale) and BrainTest (Giovanni et al, J Neurol Neurosurg Psychiatry 1999, 67, 624-629.), which is a puncture test performed with the patient's most affected hand on the dashboard of a laptop. These tests are carried out at the baseline and then immediately after each blood sample until the patients reach their full ignition stage, and subsequently at 3 20-minute intervals, and 30-minute intervals until patients reach their states. muted baseline. Once the patients reach their full on state, video recordings are made three times at 20 minute intervals. The following motor and mental tasks, which have been shown for increased dyskinesia (Duriff et al, Mov Disord 1999, 14, 242-245) were observed during each video session: (1) still sedated for 1 minute; (2) performance of mental calculations; (3) place and button the sack; (4) drink and drink from a cup of water; and (5) walking. Video tapes are recorded using, for example, versions of the Gotees placement scale and the scale of abnormal involuntary movements to document a possible increase in the dyskinesia induced by the test compound. The current presentation and severity of dyskinesia is measured with a Dyskinesia monitor (Manson et al, J Neurol Neurosurg Psychiatry 2000, 68, 196-201). The device is attached with tape to the patient's shoulder on its most affected side. The monitor registers during the entire time of the confrontation session and provides a measurement of the frequency and severity of dyskinesias that occur. The results can be analyzed using appropriate statistical methods. Finally, it should be noted that there are alternative ways of implementing the embodiments described in the present invention. Consequently, these modalities are considered as illustrative and not restrictive. Additionally, the claims are not limited to the details given herein, and their full scope and equivalents thereof are authorized.

Claims (24)

1. CLAIMS 1. A compound, characterized in that it is mesylate of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate.
2. 2. The compound according to claim 1, characterized in that it is in crystalline form.
3. 3. The compound according to claim 2, characterized in that the crystalline form has characteristic peaks (° 2T) at 5.0 ± 0.2, 8.5 ± 0.2, 13.6 ± 0.2, 15.0 ± 0.2, 17.0 ± 0.2, 17.7 ± 0.2, 20.4 ± 0.2, 21.1 ± 0.2, 25.0 ± 0.2, 25.8 ± 0.2, 28.2 ± 0.2, 30.1 ± 0.2, and 37.6 ± 0.2 in an X-ray powder diffraction pattern.
4. 4. The compound according to claim 2, characterized in that The crystalline form is characterized by a differential scanning calorimetric thermogram that has an endothermic peak around 164.5 ± 2.
5. 5 ° C. A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to any of claims 1 and 2.
6. 6. The pharmaceutical composition according to claim 5, and at least one other mesylate diastereomer of 2-phenylcarbonyloxypropyl-2-amino-3- (3,4-dihydroxyphenyl) propanoate, characterized in that the diastereomeric purity of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-) mesylate dihydroxyphenyl) propanoate is at least about 90%.
7. 7. The pharmaceutical composition according to claim 5, further characterized in that it comprises an L-aromatic amino acid decarboxylase inhibitor.
8. 8. The pharmaceutical composition according to claim 5, further characterized in that it comprises a catechol-O-methyltransferase inhibitor.
9. 9. The pharmaceutical composition according to claim 5, characterized in that it is formulated for oral administration of sustained release.
10. A method for treating a disease in a patient, characterized in that it comprises administering to the patient in need of such treatment a therapeutically effective amount of the compound according to any of claims 1 and 2.
11. 11. The method according to claim 10 , characterized in that the disease is Parkinson's disease.
12. The method according to claim 10, characterized in that the disease is selected from depression, attention deficit disorder, schizophrenia, manic depression, cognitive impairment disorders, restless legs syndrome, periodic limb movement disorder, tardive dyskinesia , Huntington's disease, Tourette syndrome, hypertension, addictive disorders, congestive heart failure, and excessive daytime sleepiness.
13. 13. A method for preparing (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate, characterized in that it comprises: providing a solution of (2R) -2-phenylcarbonyloxypropyl ( 2S) -2- (tert-butoxycarbonyl) amino-3- (3,4-dihydroxyphenyl) propanoate in a solvent; add an acid to convert (2R) -2-phenylcarbonyloxypropyl (2S) -2- (tert-butoxycarbonyl) amino-3- (3,4-dihydroxyphenyl) propanoate to (2R) -2-phenylcarbonyloxypropyl (2S) acid salt -2-amino-3- (3,4-dihydroxyphenyl) propanoate; add methanesulfonic acid to convert (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate acid salt to (2R) -2-phenylcarbonyloxypropyl mesylate (2S) -2- amino-3- (3,4-dihydroxyphenyl) propanoate; and isolating the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate from the solvent.
14. The method according to claim 13, characterized in that the solvent is selected from dichloromethane and dioxane.
15. 15. A method for preparing (2R) -2-phenylcarbonyloxypropyl mesylate (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate, characterized in that it comprises: providing a solution of (2R) -2- phenylcarbonyloxypropyl (2S) -2- (tert-butoxycarbonyl) amino-3- (3,4-dihydroxyphenyl) propanoate in a solvent; add methanesulfonic acid to convert (2R) -2-phenylcarbonyloxypropyl (2S) -2- (tert-butoxycarbonyl) amino-3- (3,4-dihydroxyphenyl) propanoate to (2R) -2-phenylcarbonyloxypropyl mesylate (2S) - 2-amino-3- (3,4-dihydroxyphenyl) propanoate; and isolating the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate from the solvent.
16. 16. The method according to claim 15, characterized in that the solvent is selected from dichloromethane, ethyl acetate, methyl tert-butyl ether, and dioxane.
17. 17. A method for preparing crystalline (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate, characterized in that it comprises: providing a mesylate solution of (2R) ) -2-phenylcarbonyloxy pro pyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate in a solvent, where the solubility of (2R) -2-phenylcarbonyloxypropyl mesylate (2S) -2- amino-3- (3,4-dihydroxyphenyl) propanoate in the solvent depends on the temperature; changing the temperature of the solution to reduce the solubility of the mesylate of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate in the solvent; and isolating the crystalline (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate from the solvent.
18. The method according to claim 17, characterized in that the solvent is selected from acetonitrile, methanol, ethanol, isopropanol, methyl tert-butyl ether, dioxane, acetone, ethyl acetate, ethyl formate, hexane, dichloromethane, and mixtures of any of the foregoing.
19. 19. A method for preparing crystalline (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate, characterized in that it comprises: providing a solution of (2R) -2-phenylcarbonyloxypropyl (2S) -2- (tert-butoxycarbonyl) amino-3- (3,4-dihydroxyphenyl) propanoate in a first solvent; deprotecting the tert-butoxycarbonyl group with an acid to provide the salt of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate; remove the first solvent and add water to the salt of (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate; neutralizing the (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate acid salt with a base to provide (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino- 3- (3,4-dihydroxyphenyl) propanoate; extract (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate with a second solvent; add methanesulfonic acid to (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate extracted to convert (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate to the crystalline (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate; and isolating the crystalline (2R) -2-phenylcarbonyloxypropyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate mesylate from the second solvent.
20. The method according to claim 19, characterized in that the first solvent is selected from dichloromethane and dioxane.
21. The method according to claim 19, characterized in that the second solvent is selected from dichloromethane, ethyl acetate, and a mixture of ethyl acetate and isopropanol.
22. 22. The method according to claim 19, characterized in that the temperature of the solution in each stage is around 25 ° C.
23. 23. The method according to claim 19, characterized in that the deprotection comprises adding to the solution an acid selected from hydrochloric acid, trifluoroacetic acid, and methanesulfonic acid.
24. 24. The method according to claim 19, characterized in that neutralizing comprises adding a base selected from NaHCO3 and KHC03 to the solution.