Carbidopa and l-dopa prodrugs and methods of using the same

Abstract

To provide compositions for treating Parkinson's disease and associated conditions.SOLUTION: Pharmaceutical combinations and compositions comprise a carbidopa prodrug such as formula (I-a) and an L-dopa prodrug such as formula (II-a).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to (a) carbidopa prodrugs, (b) L-dopa prodrugs, (c) pharmaceutical combinations and compositions comprising carbidopa prodrugs and / or L-dopa prodrugs, and (d) methods of treating Parkinson's disease and related conditions comprising administering a carbidopa prodrug and an L-dopa prodrug to a subject with Parkinson's disease. [Background technology]

[0002] Parkinson's disease is a chronic and progressive neurodegenerative condition characterized by decreased brain levels of the neurotransmitter dopamine (i.e., 3,4-dihydroxyphenethylamine). Administration of L-dopa (i.e., L-3,4-dihydroxyphenylalanine) is currently the most effective treatment for treating patients with Parkinson's disease. Unlike dopamine, L-dopa can cross the blood-brain barrier and is enzymatically converted to dopamine in the brain, resulting in increased dopamine levels.

[0003] [ka]

[0004] The conversion of L-dopa to dopamine is catalyzed by aromatic L-amino acid decarboxylase, a ubiquitous enzyme that facilitates central and peripheral metabolism of L-dopa to dopamine. Due to peripheral metabolism of L-dopa, relatively large doses of L-dopa are required to achieve therapeutically effective dopamine levels in the brain. Administration of such large L-dopa doses results in elevated peripheral dopamine levels, which can cause nausea in some patients. To overcome these problems, L-dopa is typically administered in combination with a peripheral aromatic L-amino acid decarboxylase inhibitor, such as carbidopa (i.e., (2S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoic acid).

[0005] [ka]

[0006] Coadministration of carbidopa with L-dopa inhibits the peripheral metabolism of L-dopa to dopamine, thereby significantly lowering the L-dopa dose required for a therapeutically effective response and significantly reducing associated side effects. Summary of the Invention [Problem to be solved by the invention]

[0007] However, even when L-dopa and carbidopa are administered concomitantly, maintaining desired dopamine levels in the brain is difficult due to the relatively short half-life of L-dopa in plasma. Furthermore, as the disease progresses, many patients' tolerance to variability in dopamine levels in the brain decreases. One approach that has been effective in reducing variability in dopamine levels is the continuous intestinal delivery of an adjustable amount of L-dopa / carbidopa gel, known by the trade name DuoDopa® in Europe and Duopa® in the United States. DuoDopa® / Duopa® is a suspension of L-dopa / carbidopa monohydrate (4:1 ratio of L-dopa:carbidopa monohydrate) in an aqueous gel (sodium carboxymethylcellulose) with a viscosity that allows uniform distribution of micronized particles. The gel is delivered to the proximal small intestine through a jejunal tube inserted through a percutaneous endoscopic gastrostomy port. DuoDopa® / Duopa® is contained in a drug cassette reservoir and is administered continuously via a software-controlled ambulatory infusion pump. L-dopa and carbidopa have been administered in combination for the treatment of Parkinson's disease for decades, but a pharmacokinetically consistent delivery system that does not require intestinal insertion is not commercially available.

[0008] A major challenge in developing less invasive or otherwise improved L-dopa and carbidopa dosage forms has been the solubility of these compounds. Each has low aqueous solubility in the pH range required for infusion. Stable, more highly concentrated, and / or less viscous formulations containing L-dopa and / or carbidopa (or compounds capable of in vivo biotransformation of L-dopa and / or carbidopa) are desirable. Such formulations could offer advantages over existing enema therapies, such as (a) a reduced volume of the formulation delivered to the patient and improved pumpability, which also allows for a reduction in the size and weight of the delivery device; (b) an extended shelf life of the formulation due to reduced degradation and improved stability; and / or (c) greater flexibility for patients in managing their therapy by reducing or eliminating the requirement for cold storage of the formulation (e.g., longer handling times for the formulation outside of refrigerated storage). Such stable, more concentrated, and / or less viscous formulations could also be used in minimally invasive dosage forms (e.g., subcutaneous injection).

[0009] Thus, there is a continuing need for improved compositions and methods that can provide continuous and consistent dopamine levels in the brain for the effective treatment of movement disorders such as Parkinson's disease. The present disclosure provides such improved compositions and methods. [Means for solving the problem]

[0010] In one aspect, the present disclosure relates to compounds corresponding in structure to Formula (I): or a pharmaceutically acceptable salt thereof:

[0011] [ka] In the formula, R 1 and R 2 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2.

[0012] In another aspect, the present disclosure relates to compounds corresponding in structure to Formula (II): or a pharmaceutically acceptable salt thereof:

[0013] [ka] In the formula, R 3 and R 4 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2.

[0014] In another aspect, the present disclosure relates to a pharmaceutical combination comprising a first compound corresponding in structure to Formula (I) or a pharmaceutically acceptable salt thereof, and a second compound corresponding in structure to Formula (II) or a pharmaceutically acceptable salt thereof.

[0015] In another aspect, the disclosure relates to a pharmaceutical composition comprising a first compound corresponding in structure to Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition can further comprise a second compound corresponding in structure to Formula (II) or a pharmaceutically acceptable salt thereof.

[0016] In another aspect, the disclosure relates to a method for treating Parkinson's disease or a related condition in a patient, comprising administering to the patient a therapeutically effective amount of a pharmaceutical combination comprising a first compound corresponding in structure to Formula (I) or a pharmaceutically acceptable salt thereof, and a second compound corresponding in structure to Formula (II) or a pharmaceutically acceptable salt thereof, hi certain embodiments, the method comprises administering, in a single pharmaceutical composition or in separate pharmaceutical compositions, a first compound corresponding in structure to Formula (I) or a pharmaceutically acceptable salt thereof, and a second compound corresponding in structure to Formula (II).

[0017] Further benefits of the present disclosure will become apparent to those skilled in the art upon reading this patent application. The disclosed embodiments set forth in the following paragraphs are intended to illustrate the present invention and should not be considered to narrow the scope of the present invention. [Brief explanation of the drawings]

[0018] [Figure 1] 1 is a graph of the solubility of L-dopa 4'-monophosphate and carbidopa 4'-monophosphate and the solubility of L-dopa and carbidopa at pH 7.4. [Figure 2] 1 is a graph of hydrazine release from a 4:1 ratio solution of L-dopa 4'-monophosphate and carbidopa 4'-phosphate at various pH levels. [Figure 3] 1 is a graph comparing hydrazine release between Duopa® and a 4:1 ratio solution of L-dopa 4′-monophosphate and carbidopa 4′-monophosphate. [Figure 4] 1 shows time-concentration profiles of L-dopa blood levels in rats after combined administration of L-dopa 3',4'-diphosphate and carbidopa 3',4'-diphosphate at different dose ratios. [Figure 5] 1 shows time-concentration profiles of carbidopa blood levels in rats after combined administration of L-dopa 3',4'-diphosphate and carbidopa 3',4'-diphosphate at different dose ratios. [Figure 6]1 is a graph of quantitative state blood levels of L-dopa and carbidopa in rats after administration of a combination of L-dopa 3',4'-diphosphate and carbidopa 3',4'-diphosphate at different dose ratios. [Figure 7] 1 shows time-concentration profiles of L-dopa and L-dopa 4'-monophosphate blood levels in rats after administration of a combination of L-dopa 4'-monophosphate and carbidopa 4'-monophosphate in a 4:1 ratio. [Figure 8] 1 is a time-concentration profile of L-dopa blood levels in humans after administration of Duopa®. [Figure 9] 1 is a time-concentration profile of carbidopa and carbidopa 4'-monophosphate blood levels in rats after administration of a combination of L-dopa 4'-monophosphate and carbidopa 4'-monophosphate in a 4:1 ratio. [Figure 10] 1 shows time-concentration profiles of L-dopa blood levels in minipigs after administration of a combination of L-dopa 3',4'-diphosphate and carbidopa 3',4'-diphosphate at different dose ratios. [Figure 11] 1 shows time-concentration profiles of L-dopa and L-dopa 4'-monophosphate blood levels in minipigs after administration of a combination of L-dopa 4'-monophosphate and carbidopa 4'-monophosphate in a 15:1 ratio. [Figure 12] 1 is a time-concentration profile of carbidopa and carbidopa 4'-monophosphate blood levels in minipigs after administration of a combination of L-dopa 4'-monophosphate and carbidopa 4'-monophosphate in a 15:1 ratio. [Figure 13] 1 is a powder X-ray diffraction pattern of L-DOPA 4'-monophosphate anhydrate (i). [Figure 14] Powder X-ray diffraction pattern of L-dopa 4'-monophosphate anhydrate (ii). [Figure 15] 1 is a powder X-ray diffraction pattern of L-dopa 3'-monophosphate. [Figure 16] 1 is a powder X-ray diffraction pattern of L-dopa 3',4'-diphosphate trihydrate. [Figure 17] 1 is a powder X-ray diffraction pattern of carbidopa 4'-monophosphate trihydrate. [Figure 18] 1 is a powder X-ray diffraction pattern of carbidopa 4'-monophosphate dihydrate. [Figure 19] 1 is a powder X-ray diffraction pattern of carbidopa 4'-monophosphate dehydrate. [Figure 20] Powder X-ray diffraction pattern of carbidopa 3'-monophosphate (i). [Figure 21] Powder X-ray diffraction pattern of carbidopa 3'-monophosphate (ii). [Figure 22] 1 is a powder X-ray diffraction pattern of carbidopa 3',4'-diphosphate sodium salt. DETAILED DESCRIPTION OF THE INVENTION

[0019] This written description uses examples to disclose the invention, including the best mode, and also to enable one skilled in the art to practice the invention, including making and using the disclosed carbidoparinic acid prodrugs or pharmaceutical compositions, and performing the disclosed methods or processes. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be encompassed by the claims as if they contained elements no different from the literal language of the claims, or as if they contained equivalent elements.

[0020] I. definition The section headings used in this section and throughout the disclosure are not intended to limit the invention.

[0021] Where numerical ranges are recited, each intervening number within the range is expressly contemplated with the same degree of precision. For example, in the range 6 to 9, the numbers 7 and 8 are expressly contemplated in addition to 6 and 9, and in the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are expressly contemplated. Similarly, all recited ratios include all subratios included within the broader ratio.

[0022] The singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise.

[0023] The term "and / or" as used herein in expressions such as "A and / or B" is intended to include "A and B," "A or B," "A," and "B."

[0024] The term "about" refers to a range of numbers that one of ordinary skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In many instances, the term "about" may include numbers that are rounded to the nearest significant figure.

[0025] Unless the context otherwise requires, the terms "comprise," "comprises," and "comprising" are used with the clear understanding that they are to be interpreted inclusively rather than exclusively, and that applicant intends that each of these terms be so interpreted in interpreting this patent, including the appended claims.

[0026] The terms "ameliorate" and "amelioration" have their plain and ordinary meanings to one skilled in the art of pharmacy or medicine, and specifically include ameliorating the effects of Parkinson's disease or reducing or lessening the side effects of Parkinson's disease.

[0027] The term "patient" includes mammals and humans, especially humans.

[0028] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, preservatives, antioxidants, coatings, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.

[0029] The term "pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include (1) salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or salts formed with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2]sulfonic acid, and the like. acid addition salts formed with organic acids such as 2-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid; and (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, or dicyclohexylamine, is coordinated.

[0030] The terms "reduce" and "reduction" have their plain and ordinary meanings to those skilled in the art of pharmacy or medicine, and specifically include lessening or decreasing the frequency, duration, or intensity of Parkinson's disease side effects, such as dyskinesias or hallucinations.

[0031] The term "therapeutically effective amount" means the amount of a compound that, when administered alone or in combination with another therapy to a patient suffering from or susceptible to Parkinson's disease or a related condition, effects treatment of Parkinson's disease or a related condition. A "therapeutically effective amount" will vary depending, for example, on the compound, the condition being treated and its severity, and the age and weight of the patient being treated.

[0032] The terms "treat" and "treatment" have their plain and ordinary meaning to one of ordinary skill in the art of pharmaceutical or medical sciences, and specifically include increasing the quality of life or reducing the symptoms or side effects of Parkinson's disease.

[0033] II. Carbidopa and L-dopa prodrugs As noted above, the inherently low aqueous solubility of L-dopa and carbidopa at physiologically acceptable pH for injection presents significant technical challenges to the development of improved pharmaceutical compositions and methods of treatment. Such challenges include, for example, difficulties in achieving appropriate dosage volumes and formulation stability within the required pH range. These challenges are further complicated by the requirement that the pharmaceutical compositions and methods of treatment provide pharmacokinetically appropriate and pharmacokinetically consistent management of dopamine levels in the patient's brain.

[0034] Previous prodrug approaches have been unsuccessful for a number of reasons, including technical issues (such as poor chemical stability, poor solubility, and in vivo biotransformation problems), resulting in no successful commercialization of injectable L-dopa or carbidopa prodrugs. However, the prodrugs, pharmaceutical combinations, compositions, and treatment methods of the present disclosure overcome these problems. They can be used to treat patients suffering from Parkinson's disease and related conditions without always requiring invasive surgery. In various embodiments of the present disclosure, the compositions contain L-dopa and carbidopa prodrugs that convert to L-dopa and carbidopa in vivo, allowing for delivery via continuous administration methods such as intragastric, intramuscular, intravenous, and subcutaneous administration. These novel prodrugs, combinations, compositions, and methods of the present disclosure represent an advance in the treatment of Parkinson's disease and other related conditions.

[0035] A. Carbidopa Prodrug Accordingly, in one embodiment, the present disclosure relates to compounds corresponding in structure to Formula (I): or a pharmaceutically acceptable salt thereof:

[0036] [ka] During the ceremony, R 1 and R 2 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of the groups is -P(O)(OH)2 or -R 5 -OP(O)(OH). In one embodiment, the compound corresponds in structure to Formula (I). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (I).

[0037] In another embodiment, the present disclosure provides R 1 and R 2 are each independently selected from the group consisting of hydrogen and —P(O)(OH); R 6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 is —P(O)(OH)2. In one embodiment, the compound corresponds in structure to Formula (I). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (I).

[0038] In another embodiment, the present disclosure provides a compound corresponding in structure to Formula (Ia):

[0039] [ka] or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (Ia). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (Ia).

[0040] In another embodiment, the present disclosure provides a compound corresponding in structure to Formula (Ib):

[0041] [ka] or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (Ib). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (Ib).

[0042] In another embodiment, the present disclosure provides a compound corresponding in structure to Formula (Ic):

[0043] [ka] or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (Ic). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (Ic).

[0044] In another embodiment, the present disclosure provides R 1 and R 2 are each independently hydrogen and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of them is -R 5 The present invention relates to a compound corresponding to formula (I) in structure -OP(O)(OH)2 or a pharmaceutically acceptable salt thereof.

[0045] In another embodiment, the present disclosure provides R 1 and R 2 are each independently hydrogen and -R 5 -OP(O)(OH); R 5 is methyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of them is -R 5 or a pharmaceutically acceptable salt thereof.

[0046] In another embodiment, the present disclosure provides R 1 and R 2 are each independently hydrogen and -R 5 -OP(O)(OH); R 5 is ethyl; R 6 is hydrogen or C1-C4-alkyl; provided that R1 and R 2 At least one of them is -R 5 or a pharmaceutically acceptable salt thereof.

[0047] In another embodiment, the present disclosure provides R 1 and R 2 are each independently hydrogen and -R 5 -OP(O)(OH); R 5 is propyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of them is -R 5 or a pharmaceutically acceptable salt thereof.

[0048] In another embodiment, the present disclosure provides R 1 and R 2 are each independently hydrogen and -R 5 -OP(O)(OH); R 5 is butyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of them is -R 5 or a pharmaceutically acceptable salt thereof.

[0049] In another embodiment, the present disclosure provides R 1 and R 2 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C2-alkyl; R 6 is hydrogen; provided that R 1 and R 2 At least one of the following is -P(O)(OH)2 or -R5 or a pharmaceutically acceptable salt thereof.

[0050] In another embodiment, the present disclosure provides R 1 and R 2 are each independently hydrogen or -R 5 -OP(O)(OH)2; R 5 is C1-C2-alkyl; R 6 is hydrogen; provided that R 1 and R 2 One of them is -R 5 or a pharmaceutically acceptable salt thereof.

[0051] In another embodiment, the present disclosure provides a compound corresponding in structure to formula (Id):

[0052] [ka] or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (Id). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (Id).

[0053] In another embodiment, the present disclosure provides a compound corresponding in structure to Formula (Ie):

[0054] [ka] or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (Ie). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (Ie).

[0055] In another embodiment, the present disclosure provides R 1 and R 2are each independently selected from the group consisting of hydrogen and —P(O)(OH); R 6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 or a pharmaceutically acceptable salt thereof, wherein at least one of is —P(O)(OH) 2 .

[0056] In another embodiment, the present disclosure provides R 1 and R 2 are each independently selected from the group consisting of hydrogen and —P(O)(OH); R 6 is methyl; provided that R 1 and R 2 or a pharmaceutically acceptable salt thereof, wherein at least one of is —P(O)(OH) 2 .

[0057] In another embodiment, the present disclosure provides R 1 and R 2 are each independently selected from the group consisting of hydrogen and —P(O)(OH); R 6 is ethyl; provided that R 1 and R 2 or a pharmaceutically acceptable salt thereof, wherein at least one of is —P(O)(OH) 2 .

[0058] In another embodiment, the present disclosure provides R 1 and R 2 are each independently selected from the group consisting of hydrogen and —P(O)(OH); R 6 is propyl; provided that R 1 and R 2 or a pharmaceutically acceptable salt thereof, wherein at least one of is —P(O)(OH) 2 .

[0059] In another embodiment, the present disclosure provides R 1 and R 2are each independently selected from the group consisting of hydrogen and —P(O)(OH); R 6 is butyl; provided that R 1 and R 2 or a pharmaceutically acceptable salt thereof, wherein at least one of is —P(O)(OH) 2 .

[0060] In another embodiment, the present disclosure provides R 1 and R 2 are each independently hydrogen, -P(O)(OH)2, or -R 5 -OP(O)(OH)2; R 5 is C1-C2-alkyl; R 6 is C1-C2-alkyl; provided that R 1 and R 2 One of the groups is -P(O)(OH)2 or -R 5 or a pharmaceutically acceptable salt thereof.

[0061] In another embodiment, the present disclosure provides a compound corresponding in structure to formula (If):

[0062] [ka] or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to formula (If). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to formula (If).

[0063] BL-Dopa prodrug In another embodiment, the present disclosure relates to compounds corresponding in structure to Formula (II) or a pharmaceutically acceptable salt thereof.

[0064] [ka] In the formula, R 3 and R4 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH). In one embodiment, the compound corresponds in structure to Formula (II). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II).

[0065] In another embodiment, the present disclosure provides R 3 and R 4 are each independently selected from the group consisting of hydrogen and —P(O)(OH); R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 is —P(O)(OH)2. In one embodiment, the compound corresponds in structure to Formula (II). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II).

[0066] In another embodiment, the present disclosure provides a compound corresponding in structure to formula (II-a):

[0067] [ka] or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (II-a). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II-a).

[0068] In another embodiment, the present disclosure provides a compound corresponding in structure to formula (II-b):

[0069] [ka] or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (II-b). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II-b).

[0070] In another embodiment, the present disclosure provides a compound corresponding in structure to formula (II-c):

[0071] [ka] or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (II-c). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II-c).

[0072] In another embodiment, the present disclosure provides R 3 and R 4 are each independently hydrogen and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of them is -R 5 The present invention relates to a compound corresponding in structure to formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0073] In another embodiment, the present disclosure provides R 3 and R 4 are each independently hydrogen and -R 5 -OP(O)(OH); R 5is methyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of them is -R 5 The present invention relates to compounds corresponding in structure to formula (II), wherein:

[0074] In another embodiment, the present disclosure provides R 3 and R 4 are each independently hydrogen and -R 5 -OP(O)(OH); R 5 is ethyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of them is -R 5 The present invention relates to compounds corresponding in structure to formula (II), wherein:

[0075] In another embodiment, the present disclosure provides R 3 and R 4 are each independently hydrogen and -R 5 -OP(O)(OH); R 5 is propyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of them is -R 5 The present invention relates to compounds corresponding in structure to formula (II), wherein:

[0076] In another embodiment, the present disclosure provides R 3 and R 4 are each independently hydrogen and -R 5 -OP(O)(OH); R 5 is butyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of them is -R 5The present invention relates to compounds corresponding in structure to formula (II), wherein:

[0077] In another embodiment, the present disclosure provides a compound corresponding in structure to formula (II-d):

[0078] [ka] or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (II-d). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II-d).

[0079] In another embodiment, the present disclosure provides a compound corresponding in structure to formula (II-e):

[0080] [ka] or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (II-e). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II-e).

[0081] In another embodiment, the present disclosure provides R 3 and R 4 are each independently selected from the group consisting of hydrogen and —P(O)(OH); R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 or a pharmaceutically acceptable salt thereof, wherein at least one of is —P(O)(OH)2.

[0082] In another embodiment, the present disclosure provides R 3 and R 4 are each independently selected from the group consisting of hydrogen and —P(O)(OH); R 6is methyl; provided that R 3 and R 4 or a pharmaceutically acceptable salt thereof, wherein at least one of is —P(O)(OH)2.

[0083] In another embodiment, the present disclosure provides R 3 and R 4 are each independently selected from the group consisting of hydrogen and —P(O)(OH); R 6 is ethyl; provided that R 3 and R 4 or a pharmaceutically acceptable salt thereof, wherein at least one of is —P(O)(OH)2.

[0084] In another embodiment, the present disclosure provides R 3 and R 4 are each independently selected from the group consisting of hydrogen and —P(O)(OH); R 6 is propyl; provided that R 3 and R 4 or a pharmaceutically acceptable salt thereof, wherein at least one of is —P(O)(OH)2.

[0085] In another embodiment, the present disclosure provides R 3 and R 4 are each independently selected from the group consisting of hydrogen and —P(O)(OH); R 6 is butyl; provided that R 3 and R 4 or a pharmaceutically acceptable salt thereof, wherein at least one of is —P(O)(OH)2.

[0086] In another embodiment, the present disclosure provides R 3 is hydrogen; R 4 is -P(O)(OH)2; R 6is methyl, or a pharmaceutically acceptable salt thereof.

[0087] III. Intermediates The novel synthetic routes disclosed herein for producing L-doparinic acid and carbidoparinic acid provide the following novel intermediate compounds:

[0088] [ka] TIFF2025118978000019.tif220163TIFF2025118978000020.tif176157

[0089] As used herein, "Bn" refers to a benzyl group and "Cbz" refers to a carboxybenzyl group.

[0090] IV. Pharmaceutical Combinations / Compositions The present disclosure also relates to pharmaceutical combinations and compositions comprising carbidopa prodrugs and / or L-dopa prodrugs.

[0091] In some embodiments, the pharmaceutical composition comprises a carbidopa prodrug. In other embodiments, the pharmaceutical composition comprises an L-dopa prodrug. In yet other embodiments, the pharmaceutical composition comprises both a carbidopa prodrug and an L-dopa prodrug.

[0092] The carbidopa and L-dopa prodrugs (and their pharmaceutically acceptable salts) disclosed herein can be formulated in the same pharmaceutical composition or can be present in separate pharmaceutical compositions. For example, a pharmaceutical combination disclosed herein can include a carbidopa prodrug in a first pharmaceutical composition and an L-dopa prodrug in a separate, second pharmaceutical composition. Alternatively, the pharmaceutical combination can include a carbidopa prodrug and an L-dopa prodrug in the same pharmaceutical composition.

[0093] A. First Compound and Second Compound In one embodiment, the pharmaceutical composition comprises a first compound corresponding in structure to Formula (I):

[0094] [ka] [In the formula, R 1 and R 2 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2. ] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In one embodiment, the composition comprises a first compound corresponding in structure to Formula (I). In another embodiment, the composition comprises a pharmaceutically acceptable salt of a first compound corresponding in structure to Formula (I).

[0095] In another embodiment, the pharmaceutical composition comprises a first compound corresponding in structure to Formula (Ia) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one aspect, the composition comprises a first compound corresponding in structure to Formula (Ia). In another aspect, the composition comprises a pharmaceutically acceptable salt of a first compound corresponding in structure to Formula (Ia).

[0096] In another embodiment, the pharmaceutical composition comprises a first compound corresponding in structure to Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one aspect, the composition comprises a first compound corresponding in structure to Formula (Ib). In another aspect, the composition comprises a pharmaceutically acceptable salt of a first compound corresponding in structure to Formula (Ib).

[0097] In another embodiment, the pharmaceutical composition comprises a first compound corresponding in structure to Formula (Ic) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one aspect, the composition comprises a first compound corresponding in structure to Formula (Ic). In another aspect, the composition comprises a pharmaceutically acceptable salt of a first compound corresponding in structure to Formula (Ic).

[0098] In another embodiment, the pharmaceutical composition comprises a first compound corresponding in structure to Formula (Id) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one aspect, the composition comprises a first compound corresponding in structure to Formula (Id). In another aspect, the composition comprises a pharmaceutically acceptable salt of a first compound corresponding in structure to Formula (Id).

[0099] In another embodiment, the pharmaceutical composition comprises a first compound corresponding in structure to Formula (Ie) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one aspect, the composition comprises a first compound corresponding in structure to Formula (Ie). In another aspect, the composition comprises a pharmaceutically acceptable salt of a first compound corresponding in structure to Formula (Ie).

[0100] In another embodiment, the pharmaceutical composition comprises a first compound corresponding in structure to Formula (If) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one aspect, the composition comprises a first compound corresponding in structure to Formula (If). In another aspect, the composition comprises a pharmaceutically acceptable salt of a first compound corresponding in structure to Formula (If).

[0101] In one embodiment, the pharmaceutical composition comprises a second compound corresponding in structure to Formula (II):

[0102] [ka] [In the formula, R 3 and R 4 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2. ] or a pharmaceutically acceptable salt thereof. In one embodiment, the composition comprises a second compound corresponding in structure to Formula (II). In another embodiment, the composition comprises a pharmaceutically acceptable salt of a first compound corresponding in structure to Formula (II).

[0103] In another embodiment, the pharmaceutical composition comprises a second compound corresponding in structure to Formula (II-a) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one aspect, the composition comprises a second compound corresponding in structure to Formula (II-a). In another aspect, the composition comprises a pharmaceutically acceptable salt of a second compound corresponding in structure to Formula (II-a).

[0104] In another embodiment, the pharmaceutical composition comprises a second compound corresponding in structure to Formula (II-b) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one aspect, the composition comprises a second compound corresponding in structure to Formula (II-b). In another aspect, the composition comprises a pharmaceutically acceptable salt of a second compound corresponding in structure to Formula (II-b).

[0105] In another embodiment, the pharmaceutical composition comprises a second compound corresponding in structure to Formula (II-c) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one aspect, the composition comprises a second compound corresponding in structure to Formula (II-c). In another aspect, the composition comprises a pharmaceutically acceptable salt of a second compound corresponding in structure to Formula (II-c).

[0106] In another embodiment, the pharmaceutical composition comprises a second compound corresponding in structure to Formula (II-d) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one aspect, the composition comprises a second compound corresponding in structure to Formula (II-d). In another aspect, the composition comprises a pharmaceutically acceptable salt of a second compound corresponding in structure to Formula (II-d).

[0107] In another embodiment, the pharmaceutical composition comprises a second compound corresponding in structure to Formula (II-e) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one aspect, the composition comprises a second compound corresponding in structure to Formula (II-e). In another aspect, the composition comprises a pharmaceutically acceptable salt of a second compound corresponding in structure to Formula (II-e).

[0108] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound has the formula (I) in structure:

[0109] [ka] or a pharmaceutically acceptable salt thereof, R 1 and R 2 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2; The second compound has the formula (II) in structure:

[0110] [ka] or a pharmaceutically acceptable salt thereof, R 3 and R 4 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2.

[0111] The composition can independently comprise a first compound and a second compound as the free form of the compound or as a pharmaceutically acceptable salt of the compound. In one embodiment, the composition comprises the first compound in free form. In another embodiment, the composition comprises a pharmaceutically acceptable salt of the first compound. In another embodiment, the composition comprises the second compound in free form. In another embodiment, the composition comprises a pharmaceutically acceptable salt of the second compound. In another embodiment, the composition comprises the first compound in free form and the second compound in free form. In another embodiment, the composition comprises a pharmaceutically acceptable salt of the first compound and a pharmaceutically acceptable salt of the second compound.

[0112] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ia) or a pharmaceutically acceptable salt thereof; The second compound has the formula (II) in structure:

[0113] [ka] or a pharmaceutically acceptable salt thereof, R 3 and R 4 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2.

[0114] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ib) or a pharmaceutically acceptable salt thereof; The second compound has the formula (II) in structure:

[0115] [ka] or a pharmaceutically acceptable salt thereof, R 3 and R 4 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2.

[0116] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ic) or a pharmaceutically acceptable salt thereof; The second compound has the formula (II) in structure:

[0117] [ka] or a pharmaceutically acceptable salt thereof, R 3 and R 4 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2.

[0118] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Id) or a pharmaceutically acceptable salt thereof; The second compound has the formula (II) in structure:

[0119] [ka] or a pharmaceutically acceptable salt thereof, R 3 and R 4 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2.

[0120] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ie) or a pharmaceutically acceptable salt thereof; The second compound has the formula (II) in structure:

[0121] [ka] or a pharmaceutically acceptable salt thereof, R 3 and R 4 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R3 and R 4 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2.

[0122] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to formula (If) or a pharmaceutically acceptable salt thereof; The second compound has the formula (II) in structure:

[0123] [ka] or a pharmaceutically acceptable salt thereof, R 3 and R 4 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2.

[0124] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound has the structure of formula (I):

[0125] [ka] or a pharmaceutically acceptable salt thereof, R 1 and R 2 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2; The second compound corresponds in structure to Formula (II-a) or a pharmaceutically acceptable salt thereof.

[0126] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound has the structure of formula (I):

[0127] [ka] or a pharmaceutically acceptable salt thereof, R 1 and R 2 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2; The second compound corresponds in structure to Formula (II-b) or a pharmaceutically acceptable salt thereof.

[0128] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound has the structure of formula (I):

[0129] [ka] or a pharmaceutically acceptable salt thereof, R 1 and R 2are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2; The second compound corresponds in structure to Formula (II-c) or a pharmaceutically acceptable salt thereof.

[0130] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound has the structure of formula (I):

[0131] [ka] or a pharmaceutically acceptable salt thereof, R 1 and R 2 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2; The second compound corresponds in structure to Formula (II-d) or a pharmaceutically acceptable salt thereof.

[0132] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound has the structure of formula (I):

[0133] [ka] or a pharmaceutically acceptable salt thereof, R 1 and R 2 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2; The second compound corresponds in structure to Formula (II-e) or a pharmaceutically acceptable salt thereof.

[0134] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ia) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-a) or a pharmaceutically acceptable salt thereof.

[0135] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ib) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-a) or a pharmaceutically acceptable salt thereof.

[0136] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ic) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-a) or a pharmaceutically acceptable salt thereof.

[0137] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Id) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-a) or a pharmaceutically acceptable salt thereof.

[0138] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ie) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-a) or a pharmaceutically acceptable salt thereof.

[0139] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to formula (If) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-a) or a pharmaceutically acceptable salt thereof.

[0140] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ia) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-b) or a pharmaceutically acceptable salt thereof.

[0141] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ib) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-b) or a pharmaceutically acceptable salt thereof.

[0142] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ic) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-b) or a pharmaceutically acceptable salt thereof.

[0143] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Id) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-b) or a pharmaceutically acceptable salt thereof.

[0144] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ie) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-b) or a pharmaceutically acceptable salt thereof.

[0145] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to formula (If) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-b) or a pharmaceutically acceptable salt thereof.

[0146] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ia) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-c) or a pharmaceutically acceptable salt thereof.

[0147] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ib) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-c) or a pharmaceutically acceptable salt thereof.

[0148] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ic) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-c) or a pharmaceutically acceptable salt thereof.

[0149] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Id) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-c) or a pharmaceutically acceptable salt thereof.

[0150] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ie) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-c) or a pharmaceutically acceptable salt thereof.

[0151] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to formula (If) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-c) or a pharmaceutically acceptable salt thereof.

[0152] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ia) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-d) or a pharmaceutically acceptable salt thereof.

[0153] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ib) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-d) or a pharmaceutically acceptable salt thereof.

[0154] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ic) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-d) or a pharmaceutically acceptable salt thereof.

[0155] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Id) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-d) or a pharmaceutically acceptable salt thereof.

[0156] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ie) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-d) or a pharmaceutically acceptable salt thereof.

[0157] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to formula (If) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-d) or a pharmaceutically acceptable salt thereof.

[0158] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ia) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-e) or a pharmaceutically acceptable salt thereof.

[0159] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ib) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-e) or a pharmaceutically acceptable salt thereof.

[0160] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ic) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-e) or a pharmaceutically acceptable salt thereof.

[0161] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Id) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-e) or a pharmaceutically acceptable salt thereof.

[0162] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ie) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-e) or a pharmaceutically acceptable salt thereof.

[0163] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to formula (If) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-e) or a pharmaceutically acceptable salt thereof.

[0164] Pharmaceutical compositions of the present disclosure that include both a first compound and a second compound will contain the first compound and the second compound in a weight ratio of about 1:1 to about 1:50. In one embodiment, the weight ratio is about 1:2 to about 1:15. In another embodiment, the weight ratio is about 1:4 to about 1:10. In another embodiment, the weight ratio is about 1:4. In another embodiment, the weight ratio is about 1:7.5. In another embodiment, the weight ratio is about 1:10.

[0165] B. Another excipient The pharmaceutical compositions of the present disclosure may include one or more additional pharmaceutically acceptable excipients. The term "excipient" refers to a substance that is not itself a therapeutic agent, but is used as a carrier or vehicle for delivering a therapeutic agent to a subject, or that is added to a pharmaceutical composition to enhance handling or storage, or to enable or facilitate the formation of a unit dose of the composition.

[0166] Excipients include, for example, antioxidants, agents that adjust pH and osmolality, preservatives, thickeners, colorants, buffers, bactericides, stabilizers, etc. When present, an excipient is typically present in an amount of from about 0.001% to about 95%, from about 0.01% to about 80%, from about 0.02% to about 25%, or from about 0.3% to about 10% by weight.

[0167] In one embodiment, the pharmaceutical composition may include an antioxidant. Suitable antioxidants for use in the pharmaceutical composition include, for example, butylated hydroxytoluene, butylated hydroxyanisole, potassium metabisulfite, and the like.

[0168] In one embodiment, the pharmaceutical composition may include a buffering agent. Buffering agents include agents that reduce pH changes. Suitable types of buffering agents for use in various embodiments of the present invention include Group IA metal salts, such as Group IA metal bicarbonates, Group IA metal carbonates, alkali or alkaline earth metal buffers, aluminum buffers, calcium buffers, sodium buffers, or magnesium buffers. Suitable buffering agents also include carbonates, phosphates, bicarbonates, citrates, borates, acetates, phthalates, tartrates, succinates of any of the foregoing, including sodium or potassium phosphoric acid, citric acid, boric acid, acetic acid, bicarbonates, and carbonates.

[0169] C. Formulation solid composition In one embodiment, the pharmaceutical composition is a solid composition.

[0170] In another embodiment, the pharmaceutical composition is a solid composition suitable for oral administration.The first and second compounds can be present as separate, separate solid formulations, or can be combined in the same solid formulation.Suitable solid formulations include capsules, tablets, pills, powders and granules. In such solid formulations, the first and / or second compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerin; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0171] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such carriers as lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0172] Solid dosage forms such as tablets, dragees, capsules, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings known in the pharmaceutical industry. They may also contain opacifying agents and can be formulated so as to preferentially release the drug in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0173] The first and / or second compounds may, if appropriate, also be in microencapsulated form (separately or together) with one or more of the above-mentioned carriers.

[0174] liquid composition In one embodiment, the pharmaceutical composition is a liquid composition. In one aspect, the composition contains water and is suitable for injection.

[0175] In another embodiment, the pharmaceutical composition is a liquid composition suitable for intragastric, intestinal (e.g., intraduodenal, intrajejunal), nasal, subcutaneous, intramuscular, or intravenous administration. In one aspect, the composition is suitable for intragastric administration. In another aspect, the composition is suitable for subcutaneous administration. In another aspect, the composition is suitable for intramuscular administration. In another aspect, the composition is suitable for intravenous administration. In another aspect, the composition is suitable for intestinal administration. In another aspect, the composition is suitable for intraduodenal administration. In another aspect, the composition is suitable for intrajejunal administration. In another aspect, the composition is suitable for intranasal administration.

[0176] In another embodiment, the pharmaceutical composition is an aqueous pharmaceutical composition having an L-dopa prodrug concentration of at least about 5 mg / mL. In one embodiment, the L-dopa prodrug concentration is at least about 10 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 20 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 30 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 50 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 100 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 150 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 200 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 250 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 300 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 350 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 400 mg / mL. In particular, the L-dopa prodrug concentration can be an L-dopa phosphate prodrug concentration, particularly an L-dopa 3'-monophosphate prodrug, an L-dopa 4'-monophosphate prodrug, and / or an L-dopa 3',4'-diphosphate prodrug concentration.

[0177] In another embodiment, the pharmaceutical composition is an aqueous pharmaceutical composition having a carbidopa prodrug concentration of at least about 5 mg / mL. In one embodiment, the carbidopa prodrug concentration is at least about 10 mg / mL. In another embodiment, the carbidopa prodrug concentration is at least about 20 mg / mL. In another embodiment, the carbidopa prodrug concentration is at least about 30 mg / mL. In another embodiment, the carbidopa prodrug concentration is at least about 50 mg / mL. In another embodiment, the carbidopa prodrug concentration is at least about 100 mg / mL. In another embodiment, the carbidopa prodrug concentration is at least about 150 mg / mL. In another embodiment, the carbidopa prodrug concentration is at least about 200 mg / mL. In particular, the carbidopa prodrug concentration can be a carbidopa phosphate prodrug concentration, specifically a carbidopa 3'-monophosphate prodrug, a carbidopa 4'-monophosphate prodrug, and / or a carbidopa 3',4'-diphosphate prodrug concentration.

[0178] D. pH level In one embodiment, the pharmaceutical composition can have a pH of ≥ about 2.0, ≥ about 2.5, ≥ about 3.0, ≥ about 3.5, ≥ about 4.0, ≥ about 4.5, ≥ about 5.0, ≥ about 5.5, ≥ about 6.0, ≥ about 6.2, ≥ about 6.4, ≥ about 6.5, ≥ about 6.6, ≥ about 6.8, ≥ about 7.0, ≥ about 7.1, ≥ about 7.2, ≥ about 7.3, ≥ about 7.4, ≥ about 7.5, ≥ about 7.6, ≥ about 7.7, ≥ about 7.8, ≥ about 7.9, ≥ about 8.0, ≥ about 8.2, ≥ about 8.4, ≥ about 8.6, ≥ about 8.8, or ≥ about 9.0. In particular, the pH is ≥ about 7.4. Expressly disclosed ranges include any combination of the above-listed values, such as about 2.0 to about 7.5, about 6.0 to about 9.0, about 6.4 to about 7.7, about 7.0 to about 7.9, about 7.3 to about 8.2, etc. In one embodiment, the pH is about 2 to about 8. In one embodiment, the pH is about 2.0 to about 7.5. In another embodiment, the pH is about 3.0 to about 7.5. In another embodiment, the pH is about 4.0 to about 7.5. In another embodiment, the pH is about 5.0 to about 7.5. In another embodiment, the pH is about 6.0 to about 7.5.

[0179] E. Stability In another embodiment, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) in the pharmaceutical composition can advantageously remain stable in a liquid composition (e.g., an aqueous solution) at the above pH for ≥ about 24 hours, ≥ about 36 hours, ≥ about 48 hours, ≥ about 60 hours, ≥ about 72 hours, ≥ about 84 hours, ≥ about 96 hours, ≥ about 108 hours, ≥ about 120 hours, ≥ about 132 hours, ≥ about 136 hours, ≥ about 144 hours, ≥ about 156 hours, ≥ about 168 hours, or ≥ about 180 hours. In particular, the pharmaceutical composition can remain stable in an aqueous solution for ≥ about 24 hours at a pH of about 6 to about 8. Expressly disclosed ranges include any combination of the above-listed values, such as about 24 hours to about 180 hours, about 24 hours to about 168 hours, about 36 hours to about 72 hours, etc. Such enhanced stability is important for liquid compositions of pharmaceutical compositions, since the liquid compositions are typically stored prior to administration (e.g., intragastric, subcutaneous, intrajejunal, nasal, intramuscular and / or intravenous), and therefore the first and second compounds must remain stable and undergo little or no degradation during storage.

[0180] F. Solubility In another embodiment, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) in the pharmaceutical composition unexpectedly have high solubility in a liquid composition (e.g., an aqueous solution). For example, the first compound and / or the second compound may have a pH of ≥ about 90 mg / mL, ≥ about 100 mg / mL, ≥ about 110 mg / mL, ≥ about 120 mg / mL, ≥ about 130 mg / mL, ≥ about 140 mg / mL, ≥ about 150 mg / mL, ≥ about 160 mg / mL, ≥ about 170 mg / mL, ≥ about 180 mg / mL, ≥ about 190 mg / mL, ≥ about 200 mg / mL, ≥ about 210 mg / mL, ≥ about 220 mg / mL, ≥ about 230 mg / mL, ≥ about 240 mg / mL, ≥ about 250 mg / mL, ≥ about 260 mg / mL, ≥ about 270 mg / mL at a pH of about 5 to about 8, or particularly at a near neutral pH of about 6.9 to about 7.5. , ≥ about 280 mg / mL, ≥ about 290 mg / mL, ≥ about 300 mg / mL, ≥ about 310 mg / mL, ≥ about 320 mg / mL, ≥ about 330 mg / mL, ≥ about 340 mg / mL, ≥ about 350 mg / mL, ≥ about 360 mg / mL, ≥ about 370 mg / mL, ≥ about 380 mg / mL, ≥ about 390 mg / mL, ≥ about 400 mg / mL, ≥ about 410 mg / mL, ≥ about 420 mg / mL, ≥ about 430 mg / mL, ≥ about 440 mg / mL, ≥ about 450 mg / mL, ≥ about 460 mg / mL, ≥ about 470 mg / mL, ≥ about 480 mg / mL, ≥ about 490 mg / mL, or ≥ about 500 mg / mL. Expressly disclosed ranges include any combination of the above-listed values, such as about 90 mg / mL to about 500 mg / mL, about 100 mg / mL to about 300 mg / mL, and about 200 mg / mL to about 500 mg / mL. In particular, the first compound has a solubility of ≧ about 160 mg / mL, particularly ≧ about 200 mg / mL, at a neutral pH of, for example, about 7.4. In particular, the second compound has a solubility of ≧ about 370 mg / mL, particularly ≧ about 400 mg / mL, at a neutral pH of, for example, about 7.4. This high solubility allows for a higher concentration of the first compound and / or the second compound in the pharmaceutical composition, thereby resulting in more effective and higher systemic levels of the first compound and / or the second compound upon administration to a patient.

[0181] G. Hydrazine release The first compound (e.g., a phosphate prodrug) and / or the second compound (e.g., a phosphate prodrug) may release hydrazine, a carcinogen, in certain amounts. Therefore, it is important to reduce hydrazine release from pharmaceutical compositions. Unexpectedly, at a pH of about 5 to about 8 (e.g., 7.4), the pharmaceutical compositions described herein have been found to release hydrazine in amounts of ≦about 60 ppm / hr, ≦about 55 ppm / hr, ≦about 50 ppm / hr, ≦about 45 ppm / hr, ≦about 40 ppm / hr, ≦about 35 ppm / hr, ≦about 30 ppm / hr, ≦about 25 ppm / hr, ≦about 20 ppm / hr, ≦about 15 ppm / hr, ≦about 10 ppm / hr, ≦about 5 ppm / hr, ≦about 4 ppm / hr, ≦about 3 ppm / hr, ≦about 2 ppm / hr, ≦about 1 ppm / hr, or ≦about 0.5 ppm / hr. Expressly disclosed ranges include any combination of the above-recited values, for example, about 0.5 to about 60 ppm / hr, about 1 ppm / hr to about 40 ppm / hr, about 1 ppm / hr to about 10 ppm / hr, about 2 ppm / hr to about 4 ppm / hr, etc. In particular, the pharmaceutical composition releases hydrazine at less than about 1 ppm / hr.

[0182] H. Ready-to-use agents In yet another embodiment, the present disclosure relates to a ready-to-use vial or cartridge or container or enclosure suitable for containing a liquid pharmaceutical formulation. Such enclosure can serve to hold a liquid formulation containing one or more carbidopa prodrugs and / or one or more L-dopa prodrugs. The vial can also serve as a storage container for carbidopa prodrugs and / or L-dopa prodrugs in powder form, such that the vial can be in a ready-to-use format that allows for injection or loading into a patient by reconstitution with an aqueous medium.

[0183] I. Drug Combinations As mentioned above, pharmaceutical combinations comprising a first compound and a second compound are also disclosed herein.The first compound or its pharmaceutically acceptable salt and the second compound or its pharmaceutically acceptable salt can both be present in one pharmaceutical composition, or can be present in separate pharmaceutical compositions.If separate, they can be co-administered as described in more detail herein.

[0184] Thus, in one embodiment, a first compound corresponding in structure to Formula (I):

[0185] [ka] or a pharmaceutically acceptable salt thereof [R 1 and R 2 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2; and A second compound corresponding in structure to formula (II):

[0186] [ka] or a pharmaceutically acceptable salt thereof [R 3 and R 4 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of the following is -P(O)(OH)2 or -R5 -OP(O)(OH). Provided herein is a pharmaceutical combination comprising:

[0187] V. Treatment method The present disclosure further relates to a method for treating Parkinson's disease and related conditions, comprising administering to a patient an effective amount of a carbidopa prodrug and an L-dopa prodrug.

[0188] In some embodiments, methods for treating Parkinson's disease and related conditions include providing rescue therapy for the treatment of Parkinson's disease and related conditions. The term "rescue therapy," as used herein, refers to acute and intermittent treatments that can be used to treat sudden re-immersion of motor symptoms (e.g., sudden "off" episodes or "end-of-dose wearing-off" and unpredictable "on / off" episodes). Patients with severe motor complications may cycle between "off" periods, defined as periods of hypokinesia, slowness, and rigidity, and "on" periods, defined as periods of good motor system control without bothersome motor impairments.

[0189] In some embodiments, the carbidopa acid prodrug and the L-dopa prodrug are administered to the patient in a pharmaceutical composition containing both prodrugs. In other embodiments, the carbidopa prodrug and the L-dopa prodrug are administered to the patient separately.

[0190] A. First Compound and Second Compound and Combinations Thereof In one embodiment, the disclosure provides a method of treating a condition in a subject (e.g., a patient) in need thereof, comprising administering to the patient a pharmaceutical combination comprising a first compound and a second compound; The first compound has the structure of formula (I):

[0191] [ka] or a pharmaceutically acceptable salt thereof [R 1 and R 2 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2. ]; The second compound has the formula (II) in structure:

[0192] [ka] or a pharmaceutically acceptable salt thereof [R 3 and R 4 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2.

[0193] In one embodiment, the first compound and the second compound are administered together in amounts that provide a therapeutically effective amount to a subject (eg, a patient).

[0194] In one embodiment, the first compound corresponds in structure to Formula (Ia) and the second compound corresponds in structure to Formula (II-a).

[0195] In another embodiment, the first compound corresponds in structure to Formula (Ib) and the second compound corresponds in structure to Formula (II-a).

[0196] In another embodiment, the first compound corresponds in structure to Formula (Ic) and the second compound corresponds in structure to Formula (II-a).

[0197] In another embodiment, the first compound corresponds in structure to Formula (Id) and the second compound corresponds in structure to Formula (II-a).

[0198] In another embodiment, the first compound corresponds in structure to Formula (Ie) and the second compound corresponds in structure to Formula (II-a).

[0199] In another embodiment, the first compound corresponds in structure to Formula (If) and the second compound corresponds in structure to Formula (II-a).

[0200] In another embodiment, a first compound corresponds in structure to Formula (Ia) and a second compound corresponds in structure to Formula (II-b).

[0201] In another embodiment, the first compound corresponds in structure to Formula (Ib) and the second compound corresponds in structure to Formula (II-b).

[0202] In another embodiment, the first compound corresponds in structure to Formula (Ic) and the second compound corresponds in structure to Formula (II-b).

[0203] In another embodiment, the first compound corresponds in structure to Formula (Id) and the second compound corresponds in structure to Formula (II-b).

[0204] In another embodiment, the first compound corresponds in structure to Formula (Ie) and the second compound corresponds in structure to Formula (II-b).

[0205] In another embodiment, the first compound corresponds in structure to Formula (If) and the second compound corresponds in structure to Formula (II-b).

[0206] In another embodiment, a first compound corresponds in structure to Formula (Ia) and a second compound corresponds in structure to Formula (II-c).

[0207] In another embodiment, a first compound corresponds in structure to Formula (Ib) and a second compound corresponds in structure to Formula (II-c).

[0208] In another embodiment, the first compound corresponds in structure to Formula (Ic) and the second compound corresponds in structure to Formula (II-c).

[0209] In another embodiment, the first compound corresponds in structure to Formula (Id) and the second compound corresponds in structure to Formula (II-c).

[0210] In another embodiment, the first compound corresponds in structure to Formula (Ie) and the second compound corresponds in structure to Formula (II-c).

[0211] In another embodiment, the first compound corresponds in structure to Formula (If) and the second compound corresponds in structure to Formula (II-c).

[0212] In another embodiment, a first compound corresponds in structure to Formula (Ia) and a second compound corresponds in structure to Formula (II-d).

[0213] In another embodiment, the first compound corresponds in structure to Formula (Ib) and the second compound corresponds in structure to Formula (II-d).

[0214] In another embodiment, the first compound corresponds in structure to Formula (Ic) and the second compound corresponds in structure to Formula (II-d).

[0215] In another embodiment, the first compound corresponds in structure to Formula (Id) and the second compound corresponds in structure to Formula (II-d).

[0216] In another embodiment, the first compound corresponds in structure to Formula (Ie) and the second compound corresponds in structure to Formula (II-d).

[0217] In another embodiment, the first compound corresponds in structure to Formula (If) and the second compound corresponds in structure to Formula (II-d).

[0218] In another embodiment, a first compound corresponds in structure to Formula (Ia) and a second compound corresponds in structure to Formula (II-e).

[0219] In another embodiment, a first compound corresponds in structure to Formula (Ib) and a second compound corresponds in structure to Formula (II-e).

[0220] In another embodiment, the first compound corresponds in structure to Formula (Ic) and the second compound corresponds in structure to Formula (II-e).

[0221] In another embodiment, the first compound corresponds in structure to Formula (Id) and the second compound corresponds in structure to Formula (II-e).

[0222] In another embodiment, the first compound corresponds in structure to Formula (Ie) and the second compound corresponds in structure to Formula (II-e).

[0223] In another embodiment, the first compound corresponds in structure to Formula (If) and the second compound corresponds in structure to Formula (II-e).

[0224] B. The condition being treated In one embodiment, the condition treated by administering the first compound and the second compound is Parkinson's disease.

[0225] In another embodiment, the condition treated by administering the first compound and the second compound is a sleep disorder in a Parkinson's disease patient (ie, a method of reducing a sleep disorder in a Parkinson's disease patient).

[0226] In another embodiment, the condition treated by administering the first compound and the second compound is impaired motor performance in Parkinson's disease patients (ie, a method of improving motor performance in Parkinson's disease patients).

[0227] In another embodiment, the condition treated by administering the first compound and the second compound is nighttime disability in Parkinson's disease patients (i.e., a method of reducing nighttime disability in Parkinson's disease patients).

[0228] In another embodiment, a first compound and a second compound are administered to treat motor fluctuations in a patient with Parkinson's disease.

[0229] In another embodiment, a first compound and a second compound are administered to treat dyskinesia in a patient with Parkinson's disease.

[0230] In another embodiment, a first compound and a second compound are administered to delay the onset of motor fluctuations in a patient with Parkinson's disease.

[0231] In another embodiment, a first compound and a second compound are administered to delay the onset of dyskinesias in a Parkinson's disease patient.

[0232] C. Administration of Pharmaceutical Compositions In one embodiment, the present disclosure relates to a method for treating a condition in need of treatment, comprising administering to a subject (e.g., a patient) a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0233] In one embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ia) and a second compound corresponding in structure to Formula (II-a).

[0234] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ib) and a second compound corresponding in structure to Formula (II-a).

[0235] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ic) and a second compound corresponding in structure to Formula (II-a).

[0236] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Id) and a second compound corresponding in structure to Formula (II-a).

[0237] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ie) and a second compound corresponding in structure to Formula (II-a).

[0238] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (If) and a second compound corresponding in structure to Formula (II-a).

[0239] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ia) and a second compound corresponding in structure to Formula (II-b).

[0240] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ib) and a second compound corresponding in structure to Formula (II-b).

[0241] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ic) and a second compound corresponding in structure to Formula (II-b).

[0242] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Id) and a second compound corresponding in structure to Formula (II-b).

[0243] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ie) and a second compound corresponding in structure to Formula (II-b).

[0244] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (If) and a second compound corresponding in structure to Formula (II-b).

[0245] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ia) and a second compound corresponding in structure to Formula (II-c).

[0246] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ib) and a second compound corresponding in structure to Formula (II-c).

[0247] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ic) and a second compound corresponding in structure to Formula (II-c).

[0248] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Id) and a second compound corresponding in structure to Formula (II-c).

[0249] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ie) and a second compound corresponding in structure to Formula (II-c).

[0250] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (If) and a second compound corresponding in structure to Formula (II-c).

[0251] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ia) and a second compound corresponding in structure to Formula (II-d).

[0252] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ib) and a second compound corresponding in structure to Formula (II-d).

[0253] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ic) and a second compound corresponding in structure to Formula (II-d).

[0254] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Id) and a second compound corresponding in structure to Formula (II-d).

[0255] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ie) and a second compound corresponding in structure to Formula (II-d).

[0256] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (If) and a second compound corresponding in structure to Formula (II-d).

[0257] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ia) and a second compound corresponding in structure to Formula (II-e).

[0258] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ib) and a second compound corresponding in structure to Formula (II-e).

[0259] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ic) and a second compound corresponding in structure to Formula (II-e).

[0260] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Id) and a second compound corresponding in structure to Formula (II-e).

[0261] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ie) and a second compound corresponding in structure to Formula (II-e).

[0262] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (If) and a second compound corresponding in structure to Formula (II-e).

[0263] D. The condition being treated In one embodiment, the condition treated by administering the pharmaceutical composition is Parkinson's disease.

[0264] In another embodiment, the condition treated by administering the pharmaceutical composition is sleep disturbance in Parkinson's disease patients (ie, a method of reducing sleep disturbance in Parkinson's disease patients).

[0265] In another embodiment, the condition treated by administering the pharmaceutical composition is impaired motor performance in Parkinson's disease patients (ie, a method of improving motor performance in Parkinson's disease patients).

[0266] In another embodiment, the pharmaceutical composition is administered to treat motor fluctuations in a patient with Parkinson's disease.

[0267] In another embodiment, the pharmaceutical composition is administered to treat dyskinesias in patients with Parkinson's disease.

[0268] In another embodiment, the pharmaceutical composition is administered to delay the onset of motor fluctuations in a patient with Parkinson's disease.

[0269] In another embodiment, the pharmaceutical composition is administered to delay the onset of dyskinesias in a patient with Parkinson's disease.

[0270] In another embodiment, the condition treated by administering the pharmaceutical composition is nighttime disability in Parkinson's disease patients (ie, a method of reducing nighttime disability in Parkinson's disease patients).

[0271] E. Weight Ratio and Route of Administration Generally, the weight ratio of the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) administered to a patient (separately or together in a single pharmaceutical composition) is from about 1:1 to about 1:50. In one embodiment, the weight ratio is from about 1:2 to about 1:15. In another embodiment, the weight ratio is from about 1:4 to about 1:10. In another embodiment, the weight ratio is about 1:4. In another embodiment, the weight ratio is about 1:7.5. In another embodiment, the weight ratio is about 1:10.

[0272] In one embodiment, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) are administered to the patient in the form of a solid composition (or multiple solid compositions). In one aspect, the composition is suitable for oral administration.

[0273] In one embodiment, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) are administered to the patient in the form of a liquid composition (or liquid compositions). In one aspect, the composition comprises water and is suitable for injection.

[0274] In another embodiment, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) are administered to the patient as liquid compositions (separately or in the same pharmaceutical composition) suitable for intragastric, subcutaneous, nasal, intramuscular, or intravenous administration. In one embodiment, the liquid composition is suitable for intragastric administration. In another embodiment, the liquid composition is suitable for subcutaneous administration. In another embodiment, the liquid composition is suitable for intramuscular administration. In another embodiment, the liquid composition is suitable for intravenous administration. In another embodiment, the liquid composition is suitable for nasal administration.

[0275] In another embodiment, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) are administered by enteral administration (e.g., intrajejunal, intraduodenal) (separately or in the same pharmaceutical composition). They can be administered (or "injected") directly into the intestine, e.g., the duodenum or jejunum, by a permanent tube inserted, e.g., by percutaneous endoscopic gastrostomy using an external abdominal tube and an internal intestinal tube. In one embodiment, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) are administered via a tube inserted by radiological gastrojejunostomy. In another embodiment, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) are administered via a temporary nasoduodenal tube that is initially inserted into the patient to determine whether the patient will respond well to therapy before inserting a permanent tube.

[0276] In some embodiments in which the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) are administered via enteral administration, administration can be accomplished using a portable pump, such as the pump sold under the trade name CADD-Legacy DuoDopa.RTM. Pump®. Specifically, a cassette, bag, or vial containing the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) can be attached to the pump to create a delivery system. The delivery system is then connected to a nasoduodenal tube, a transabdominal port, a duodenal tube, or a jejunal tube for enteral administration.

[0277] In one embodiment, the method comprises administering (together or separately) a first compound (e.g., a phosphate prodrug) and a second compound (e.g., a phosphate prodrug) to a patient substantially continuously for a period of at least about 12 hours. In another aspect, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) are administered substantially continuously for a period of at least about 16 hours, at least about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, or more. In particular, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) can be administered subcutaneously substantially continuously for a period of at least about 16 hours.

[0278] F. Dosage and Plasma Concentration In one embodiment, the dosages of the first compound (e.g., phosphate prodrug) and the second compound (e.g., phosphate prodrug) administered to the patient are adjusted to optimize the clinical response achieved by the subject (e.g., patient), which means maximizing functional ON time during the day by reducing the number and duration of OFF time episodes (i.e., bradykinesia) and ON time with severe dyskinesias.

[0279] In one embodiment, the daily dose of an L-dopa prodrug (i.e., second compound) administered to a patient according to the methods of the present disclosure can be, for example, about 20 to about 1,000,000 mg, about 20 to about 100,000 mg, about 20 to about 10,000 mg, about 20 to about 5,000 mg, about 20 to about 4,000 mg, about 20 to about 3,000 mg, about 20 to about 2,000 mg, or about 20 to about 1,000 mg per day. In particular, an L-dopa phosphate prodrug, particularly an L-dopa 3'-monophosphate prodrug, an L-dopa 4'-monophosphate prodrug, and / or an L-dopa 3',4'-diphosphate prodrug, is administered at the above daily doses.

[0280] In one embodiment, the daily dose of a carbidopa prodrug (i.e., the first compound) administered to a patient according to the methods of the present disclosure can be, for example, 0 mg to about 2500 mg, 0 mg to about 1250 mg, 0 mg to about 1000 mg, 0 mg to about 750 mg, 0 mg to about 625 mg, 0 mg to about 500 mg, 0 mg to about 375 mg, 0 mg to about 250 mg, or 5 mg to about 125 mg per day. In particular, carbidopa phosphate prodrugs, particularly carbidopa 3'-monophosphate prodrug, carbidopa 4'-monophosphate prodrug, and / or carbidopa 3',4'-diphosphate prodrug, are administered in the above daily doses.

[0281] In some embodiments, the amount of the first compound and the amount of the second compound administered are sufficient in combination to achieve an L-dopa plasma level of at least about 100 ng / mL in the patient. In one embodiment, the L-dopa plasma level is at least about 200 ng / mL. In another embodiment, the L-dopa plasma level is at least about 300 ng / mL. In another embodiment, the L-dopa plasma level is at least about 400 ng / mL. In another embodiment, the L-dopa plasma level is at least about 500 ng / mL. In another embodiment, the L-dopa plasma level is at least about 600 ng / mL. In another embodiment, the L-dopa plasma level is at least about 700 ng / mL. In another embodiment, the L-dopa plasma level is at least about 800 ng / mL. In another embodiment, the L-dopa plasma level is at least about 900 ng / mL. In another embodiment, the L-dopa plasma level is at least about 1,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 1,500 ng / mL. In another embodiment, the L-dopa plasma level is at least about 2,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 3,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 4,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 5,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 6,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 7,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 8,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 9,000 ng / mL. In particular, the first compound can be a carbidopa phosphate prodrug, particularly a carbidopa 3'-monophosphate prodrug, a carbidopa 4'-monophosphate prodrug and / or a carbidopa 3',4'-diphosphate prodrug.In particular, the second compound can be an L-dopa phosphate prodrug, particularly an L-dopa 3'-monophosphate prodrug, an L-dopa 4'-monophosphate prodrug and / or an L-dopa 3',4'-diphosphate prodrug.

[0282] In some embodiments, the amount of the first compound and the amount of the second compound are administered that, in combination, are sufficient to achieve an L-dopa plasma level of from about 10 ng / mL to about 9,000 ng / mL.

[0283] In one embodiment, L-dopa plasma levels are from about 10 ng / mL to about 8,000 ng / mL. In another embodiment, L-dopa plasma levels are from about 25 ng / mL to about 6,000 ng / mL. In another embodiment, L-dopa plasma levels are from about 50 ng / mL to about 4,000 ng / mL. In another embodiment, L-dopa plasma levels are from about 100 ng / mL to about 2,000 ng / mL. In another embodiment, L-dopa plasma levels are from about 25 ng / mL to about 1,200 ng / mL. In another embodiment, L-dopa plasma levels are from about 10 ng / mL to about 500 ng / mL. In another embodiment, L-dopa plasma levels are from about 25 ng / mL to about 500 ng / mL. In particular, the first compound can be a carbidopa phosphate prodrug, particularly a carbidopa 3'-monophosphate prodrug, a carbidopa 4'-monophosphate prodrug, and / or a carbidopa 3',4'-diphosphate prodrug. In particular, the second compound can be an L-dopa phosphate prodrug, particularly an L-dopa 3'-monophosphate prodrug, an L-dopa 4'-monophosphate prodrug, and / or an L-dopa 3',4'-diphosphate prodrug.

[0284] In some embodiments, the L-dopa concentration ranges may be maintained over at least about 1 hour intervals, 2 hours intervals, 3 hours intervals, 4 hours intervals, 5 hours intervals, 6 hours intervals, 7 hours intervals, 8 hours intervals, 9 hours intervals, 10 hours intervals, 11 hours intervals, 12 hours intervals, 13 hours intervals, 14 hours intervals, 15 hours intervals, 16 hours intervals, 17 hours intervals, 18 hours intervals, 19 hours intervals, 20 hours intervals, 21 hours intervals, 22 hours intervals, 23 hours intervals, or 24 hours intervals.

[0285] Plasma levels of GL-doparinic acid prodrugs and carbidoparinic acid prodrugs In some embodiments, it has been discovered that after administration of the first compound and the second compound, an unexpected concentration of the second compound, i.e., L-dopa phosphate prodrug, remains in the plasma and is not converted to L-dopa. Furthermore, an unexpected concentration of the first compound, i.e., carbidopa phosphate prodrug, may remain in the plasma and not be converted to carbidopa. Surprisingly, the L-dopa phosphate prodrug and / or carbidopa phosphate prodrug may remain in the plasma throughout the entire duration of the continuous infusion of the first compound and / or the second compound.

[0286] Thus, in some embodiments, administration of the first and second compounds results in L-dopa phosphate prodrug plasma levels of about 0 ng / mL to about 3600 ng / mL, about 1 ng / mL to about 3600 ng / mL, or about 10 ng / mL to about 3600 ng / mL. In one embodiment, the L-dopa phosphate prodrug plasma level is about 10 ng / mL to about 3200 ng / mL. In another embodiment, the L-dopa phosphate prodrug plasma level is about 25 ng / mL to about 2800 ng / mL. In another embodiment, the L-dopa phosphate prodrug plasma level is about 50 ng / mL to about 2400 ng / mL. In another embodiment, the L-dopa phosphate prodrug plasma level is about 10 ng / mL to about 2000 ng / mL. In another embodiment, the L-dopa phosphate prodrug plasma level is about 25 ng / mL to about 1600 ng / mL. In another embodiment, L-dopa phosphate prodrug plasma levels are from about 25 ng / mL to about 1200 ng / mL. In another embodiment, L-dopa phosphate prodrug plasma levels are from about 10 ng / mL to about 800 ng / mL. In another embodiment, L-dopa phosphate prodrug plasma levels are from about 10 ng / mL to about 400 ng / mL. In another embodiment, L-dopa phosphate prodrug plasma levels are from about 10 ng / mL to about 200 ng / mL. In another embodiment, L-dopa phosphate prodrug plasma levels are from about 10 ng / mL to about 100 ng / mL.

[0287] In some embodiments, administration of the first and second compounds results in carbidoparinic acid prodrug plasma levels of about 0 ng / mL to about 600 ng / mL, about 1 ng / mL to about 600 ng / mL, or about 10 ng / mL to 600 ng / mL. In one embodiment, the carbidoparinic acid prodrug plasma level is about 10 ng / mL to about 500 ng / mL. In another embodiment, the carbidoparinic acid prodrug plasma level is about 10 ng / mL to about 400 ng / mL. In another embodiment, the carbidoparinic acid prodrug plasma level is about 10 ng / mL to about 300 ng / mL. In another embodiment, the carbidoparinic acid prodrug plasma level is about 10 ng / mL to about 200 ng / mL. In another embodiment, the carbidoparinic acid prodrug plasma level is about 10 ng / mL to about 100 ng / mL. In another embodiment, the carbidoparinic acid prodrug plasma level is about 25 ng / mL to about 600 ng / mL. In another embodiment, the carbidoparinic acid prodrug plasma level is about 25 ng / mL to about 500 ng / mL. In another embodiment, the carbidoparinic acid prodrug plasma level is about 25 ng / mL to about 400 ng / mL. In another embodiment, the carbidoparinic acid prodrug plasma level is about 25 ng / mL to about 300 ng / mL. In another embodiment, the carbidoparinic acid prodrug plasma level is about 25 ng / mL to about 200 ng / mL. In another embodiment, the carbidoparinic acid prodrug plasma level is about 25 ng / mL to about 100 ng / mL.

[0288] The L-dopa phosphate prodrug concentration range and / or carbidoparinic acid prodrug plasma concentration range can be maintained at least about 1 hour interval, 2 hours interval, 3 hours interval, 4 hours interval, 5 hours interval, 6 hours interval, 7 hours interval, 8 hours interval, 9 hours interval, 10 hours interval, 11 hours interval, 12 hours interval, 13 hours interval, 14 hours interval, 15 hours interval, 16 hours interval, 17 hours interval, 18 hours interval, 19 hours interval, 20 hours interval, 21 hours interval, 22 hours interval, 23 hours interval, or 24 hours interval. Furthermore, the L-dopa phosphate prodrug concentration range and / or carbidoparinic acid prodrug concentration range can be maintained at the above intervals daily, for example, for 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. Without being bound by theory, this can be facilitated by sequential administration (together or separately) of the first and second compounds.

[0289] In some embodiments, the amount of the first compound and the amount of the second compound are administered sufficient to maintain a carbidopa plasma level of less than about 2500 ng / mL. In one embodiment, the carbidopa plasma level is less than about 2000 ng / mL. In another embodiment, the carbidopa plasma level is less than about 1500 ng / mL. In another embodiment, the carbidopa plasma level is less than about 1000 ng / mL. In another embodiment, the carbidopa plasma level is less than about 500 ng / mL. In another embodiment, the carbidopa plasma level is less than about 250 ng / mL. In another embodiment, the carbidopa plasma level is less than about 100 ng / mL. In another embodiment, the carbidopa plasma level is less than about 50 ng / mL. In another embodiment, the carbidopa plasma level is less than about 25 ng / mL.

[0290] In some embodiments, the carbidopa plasma concentration range is maintained over at least about 1 hour intervals, 2 hours intervals, 3 hours intervals, 4 hours intervals, 5 hours intervals, 6 hours intervals, 7 hours intervals, 8 hours intervals, 9 hours intervals, 10 hours intervals, 11 hours intervals, 12 hours intervals, 13 hours intervals, 14 hours intervals, 15 hours intervals, 16 hours intervals, 17 hours intervals, 18 hours intervals, 19 hours intervals, 20 hours intervals, 21 hours intervals, 22 hours intervals, 23 hours intervals, or 24 hours intervals.

[0291] H. Phosphorus Loading In some embodiments, a subject can be administered an amount of a first compound and an amount of a second compound to achieve a phosphorus intake of less than about 2000 mg / day, or less than about 2500 mg / day, or less than about 3000 mg / day. The value of 3000 mg / day is the upper tolerable intake level that is acceptable. See DRI Dietary Reference Intakes for Calcium, Phosphorus, Vitamin D and Fluoride at www.nap.edu / ctalog / 5776. In further embodiments, a subject is administered therapeutic concentrations of the first and second compounds to achieve a total phosphorus load of about 350 mg / day to about 550 mg / day, or about 400 mg / day to about 500 mg / day, or about 400 mg / day to about 450 mg / day, or about 427 mg / day. The average dietary phosphorus intake of the US population is about 1500 mg / day. See Ervin RB, et al. 2004. Dietary intake of selected minerals for the United States population: 1999-2000. Adv Data. Apr 27;(341):1-5. Thus, the total phosphorus exposure from administration of the first and second compounds can be from about 1850 mg / day to about 2000 mg / day, or from about 1900 mg / day to about 1950 mg / day or about 1927 mg / day, which is significantly less than the accepted upper tolerable intake level of 3000 mg / day.

[0292] VI. Combination and / or additional therapy The therapeutic methods of the present disclosure may further comprise administering one or more therapeutic agents for treating Parkinson's disease (e.g., antiparkinsonian drugs) in addition to the L-dopa prodrug and carbidopa prodrug. In one embodiment, the additional therapeutic agent is selected from the group consisting of a decarboxylase inhibitor other than carbidopa (e.g., benserazide), a catechol-O-methyltransferase ("COMT") inhibitor (e.g., entacapone and tolcapone), and a monoamine oxidase A ("MAO-A") or monoamine oxidase B ("MAO-B") inhibitor (e.g., moclobemide, rasagiline, selegiline, and safinamide). In one embodiment, the additional therapeutic agent is selected from the group consisting of a decarboxylase inhibitor other than carbidopa. In another embodiment, the additional therapeutic agent is selected from the group consisting of a COMT inhibitor, such as entacapone. In another embodiment, the additional therapeutic agent is selected from the group consisting of an MAO-A inhibitor. In another embodiment, the additional therapeutic agent is selected from the group consisting of an MAO-B inhibitor.

[0293] The additional therapeutic agent and the first and second compounds can be administered together or separately, and substantially simultaneously or sequentially. Furthermore, the additional therapeutic agent and the first and second compounds can be in separate formulations, which can be the same or different. For example, entacapone can be administered concomitantly and orally, and the first and second compounds described herein can be administered subcutaneously (separately or together in the same pharmaceutical composition). Furthermore, the therapeutic agent and the first and second compounds can be packaged together, for example, in a single container or in multiple containers within a single package, or can be provided simultaneously in separate packages ("common provision").

[0294] Similarly, the pharmaceutical compositions of the present disclosure may further comprise one or more additional therapeutic agents for the treatment of Parkinson's disease as described above.

[0295] VII. kit The present disclosure also relates to kits containing one or more pharmaceutical formulations comprising a carbidoparinic acid prodrug, kits containing one or more pharmaceutical formulations comprising an L-dopa phosphate prodrug, and kits containing one or more pharmaceutical formulations comprising both a carbidoparinic acid prodrug and an L-dopa phosphate prodrug, which kits may include one or more additional therapeutic agents and / or instructions, e.g., instructions for using the kit to treat patients with Parkinson's disease and related conditions.

[0296] In one embodiment, the kit comprises a first pharmaceutical formulation, the first pharmaceutical formulation comprising a first compound corresponding in structure to Formula (I) or a pharmaceutically acceptable salt thereof. In one aspect, the kit comprises a second pharmaceutical formulation comprising a second compound corresponding in structure to Formula (II) or a pharmaceutically acceptable salt thereof. In another aspect, the first pharmaceutical formulation further comprises a second compound corresponding in structure to Formula (II) or a pharmaceutically acceptable salt thereof. In another aspect, the first pharmaceutical formulation and, where applicable, the second pharmaceutical formulation are liquid pharmaceutical formulations.

[0297] Since dopamine is an achiral compound, it is considered that the above-described various embodiments may be applicable when a D-dopa phosphate prodrug or a racemate of a D-dopa phosphate prodrug and an L-dopa phosphate prodrug is used instead of an L-dopa phosphate prodrug.

[0298] VIII. L-DOPA AND CARBIDOPA PRODRUG POLYMORPHOMS Specific crystalline forms of the above L-dopa and carbidopa prodrugs have also been identified and are described herein. Specifically, these crystalline forms are L-dopa 4'-monophosphate anhydrate (i), L-dopa 4'-monophosphate anhydrate (ii), L-dopa 3'-monophosphate, L-dopa 3',4'-diphosphate trihydrate, carbidopa 4'-monophosphate trihydrate, carbidopa 4'-monophosphate dihydrate, carbidopa 4'-monophosphate dehydrate, carbidopa 3'-monophosphate (i), carbidopa 3'-monophosphate (ii), and carbidopa 3',4'-diphosphate sodium salt.

[0299] AL-Dopa Prodrug Polymorphs L-DOPA 4'-monophosphate anhydride (i) crystalline solid can be identified by characteristic peaks in its powder X-ray diffraction pattern (Figure 13). It is believed that a person skilled in the art of analytical chemistry can easily identify L-DOPA 4'-monophosphate anhydride (i) solid by only one characteristic peak in the powder X-ray diffraction pattern. Thus, in one or more embodiments, the 2θ values are 10.261±0.20, 12.053±0.20, 13.759±0.20, 14.932±0.20, 16.147±0.20, 16.718±0.20, 17.34±0.20, 19.254±0.20, 20.654±0.20, 22.078±0.20, 23.599±0.20, 24.198±0.20, 25.898±0.20, 26.338±0.20, and Crystalline L-DOPA 4'-monophosphate anhydride (i) is provided, which exhibits at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, or fifteen characteristic peaks in a powder X-ray diffraction pattern at 27.117±0.20 and 27.117±0.20. The crystal unit cell parameters of L-DOPA 4'-monophosphate anhydride (i) are also obtained, with a being 7.0508 Å, b being 10.6253 Å, and c being 14.7588 Å, resulting in a lattice volume of 1105.68 Å. 3 It was confirmed that the following equation was obtained (where a, b, and c are the individual lengths of the crystal lattice).

[0300] L-DOPA 4'-monophosphate anhydride(II) crystalline solid can be identified by characteristic peaks in its powder X-ray diffraction pattern (Figure 14). It is believed that a person skilled in the art of analytical chemistry can easily identify L-DOPA 4'-monophosphate anhydride(II) solid by only one characteristic peak in the powder X-ray diffraction pattern. Thus, in one or more embodiments, the 2θ values are 8.468±0.20, 10.234±0.20, 11.821±0.20, 13.084±0.20, 13.503±0.20, 15.48±0.20, 15.848±0.20, 16.513±0.20, 18.447±0.20, 19.346±0.20, 20.239±0.20, 21.139±0.20, 24.221±0.20, 24.865±0.20, Crystalline L-DOPA 4'-monophosphate anhydride (ii) is provided, which exhibits at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, or fifteen characteristic peaks in a powder X-ray diffraction pattern at 25.647±0.20.

[0301] L-DOPA-3'-monophosphate crystalline solids can be identified by characteristic peaks in their powder X-ray diffraction pattern (Figure 15). It is believed that one skilled in the art of analytical chemistry can readily identify L-DOPA-3'-monophosphate solids by just one characteristic peak in a powder X-ray diffraction pattern. Thus, in one or more embodiments, the 2θ values are 8.662±0.20, 11.286±0.20, 15.079±0.20, 15.678±0.20, 16.786±0.20, 17.288±0.20, 18.438±0.20, 19.682±0.20, 20.946±0.20, 22.188±0.20, 22.671±0.20, 23.088±0.20, 24.144±0.20, 24.744±0.20, and 25.084±0.20. Crystalline L-dopa 3'-monophosphate is provided, which exhibits at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, or fifteen characteristic peaks in a powder X-ray diffraction pattern at 25.383±0.20, 25.383±0.0, and 25.383±0.20.

[0302] L-DOPA 3',4'-diphosphate trihydrate crystalline solid can be identified by characteristic peaks in its powder X-ray diffraction pattern (Figure 16). One skilled in the art of analytical chemistry would be able to readily identify L-DOPA 3',4'-diphosphate trihydrate solid by just one characteristic peak in the powder X-ray diffraction pattern. Thus, in one or more embodiments, the 2θ values are 7.118±0.20, 10.342±0.20, 11.355±0.20, 12.161±0.20, 14.201±0.20, 17.36±0.20, 17.632±0.20, 19.196±0.20, 19.444±0.20, 20.83±0.20, 21.504±0.20, 22.491±0.20, 23.085±0.20, 24.487±0.20, and and 25.11±0.20 in an X-ray powder diffraction pattern.

[0303] B. Carbidopa Prodrug Polymorphs Carbidopa 4'-monophosphate trihydrate crystalline solids can be identified by characteristic peaks in their powder X-ray diffraction patterns (Figure 17). One skilled in the art of analytical chemistry would be able to readily identify carbidopa 4'-monophosphate trihydrate solids by as little as one characteristic peak in a powder X-ray diffraction pattern. Thus, in one or more embodiments, the 2θ values are 7.484±0.20, 10.05±0.20, 11.971±0.20, 13.085±0.20, 14.923±0.20, 16.095±0.20, 16.85±0.20, 17.359±0.20, 17.635±0.20, 19.269±0.20, 19.544±0.20, 21.842±0.20, 22.578±0.20, 22.921±0.20, and Crystalline carbidopa 4'-monophosphate trihydrate is provided, which exhibits at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, or fifteen characteristic peaks in a powder X-ray diffraction pattern at 23.822±0.20 and 23.822±0.20. The crystalline unit cell parameters of carbidopa 4'-monophosphate trihydrate are also obtained, with a being 7.0226 Å, b being 9.4565 Å, and c being 23.615 Å, resulting in a lattice volume of 1568.25 Å. 3 It was confirmed that the following equation was obtained (where a, b, and c are the individual lengths of the crystal lattice).

[0304] Carbidopa 4'-monophosphate dihydrate crystalline solids can be identified by characteristic peaks in their powder X-ray diffraction patterns (Figure 18). It is believed that a person skilled in the art of analytical chemistry can easily identify carbidopa 4'-monophosphate dihydrate solids by just one characteristic peak in a powder X-ray diffraction pattern. Thus, in one or more embodiments, the 2θ values are 7.925±0.20, 10.28±0.20, 12.344±0.20, 15.002±0.20, 15.841±0.20, 16.158±0.20, 17.565±0.20, 18.506±0.20, 19.058±0.20, 19.473±0.20, 19.702±0.20, 20.188±0.20, 20.668±0.20, 22.37±0.20, and Crystalline carbidopa 4'-monophosphate dihydrate is provided, which exhibits at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, or fifteen characteristic peaks in a powder X-ray diffraction pattern at 24.167±0.20 and 24.167±0.20 (FIG. 19). One skilled in the art of analytical chemistry would be able to readily identify carbidopa 4'-monophosphate dehydrate solids based on as little as one characteristic peak in a powder X-ray diffraction pattern. Thus, in one or more embodiments, crystalline carbidopa 4'-monophosphate dehydrate is provided, which exhibits at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten characteristic peaks in a powder X-ray diffraction pattern at 2θ values of 9.492±0.20, 10.528±0.20, 15.356±0.20, 15.907±0.20, 16.165±0.20, 17.933±0.20, 18.737±0.20, 19.429±0.20, 21.176±0.20, and 22.626±0.20 (FIG. 20). Those skilled in the art of analytical chemistry will be able to readily identify carbidopa 3'-monophosphate (i) solids based on as little as one characteristic peak in a powder X-ray diffraction pattern.Thus, in one or more embodiments, there is provided crystalline carbidopa-3'-monophosphate (i) exhibiting at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten characteristic peaks in an X-ray powder diffraction pattern at 2θ values of 9.171±0.20, 13.539±0.20, 14.23±0.20, 15.589±0.20, 15.979±0.20, 18.394±0.20, 18.832±0.20, 19.315±0.20, 22.143±0.20, and 22.81±0.20.

[0305] Carbidopa-3'-monophosphate(II) crystalline solids can be identified by characteristic peaks in their powder X-ray diffraction patterns (Figure 21). One skilled in the art of analytical chemistry would be able to readily identify carbidopa-3'-monophosphate(II) solids by just one characteristic peak in a powder X-ray diffraction pattern. Thus, in one or more embodiments, there is provided crystalline carbidopa 3'-monophosphate (ii) having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten characteristic peaks in an X-ray powder diffraction pattern at 2θ values of 4.433±0.20, 8.917±0.20, 9.654±0.20, 13.192±0.20, 15.288±0.20, 15.747±0.20, 17.886±0.20, 19.291±0.20, 20.554±0.20, and 21.797.

[0306] Carbidopa 3',4'-diphosphate sodium salt crystalline solid can be identified by characteristic peaks in its powder X-ray diffraction pattern (Figure 22). One skilled in the art of analytical chemistry would be able to readily identify carbidopa 3',4'-diphosphate sodium salt solid by just one characteristic peak in the powder X-ray diffraction pattern. Thus, in one or more embodiments, the 2θ values are 5.852±0.20, 6.861±0.20, 7.338±0.20, 11.159±0.20, 11.729±0.20, 12.953±0.20, 13.714±0.20, 14.381±0.20, 14.686±0.20, 15.479±0.20, 16.676±0.20, 17.179±0.20, 17.592±0.20, 18.861±0.20, and 2 Crystalline carbidopa 3',4'-diphosphate sodium salt is provided, which exhibits at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least 12, at least 13, at least 14, or 15 characteristic peaks in a powder X-ray diffraction pattern at 0.305±0.20.

[0307] Compositions and combinations containing the above L-dopa and carbidopa polymorphs are also contemplated. Accordingly, in one or more embodiments, provided are pharmaceutical compositions and combinations containing the above L-dopa and carbidopa polymorphs, and methods of treating Parkinson's disease by administering such pharmaceutical compositions and combinations. In particular, provided are methods of treating Parkinson's disease by administering a pharmaceutical composition containing one or more of the L-dopa and carbidopa polymorphs identified by characteristic peaks in the powder X-ray diffraction pattern of any one of Figures 13 to 22.

[0308] Powder X-ray diffraction (PXRD) analysis of the samples was performed as follows. Samples were prepared for X-ray diffraction analysis by spreading the sample in a thin layer on a sample holder and gently flattening the sample with a microscope slide. For example, samples may be ground to a fine powder with a mortar and pestle, or with a microscope slide in the case of limited sample volume. Samples were examined in one of three configurations: a circular bulk holder, a quartz zero-background plate, or a hot stage mount (similar to a zero-background plate). Cu-K α1 Diffraction patterns were collected using an Inel G3000 diffractometer equipped with a line-giving incident beam germanium monochromator. The X-ray generator was operated at a voltage of 40 kV and a current of 30 mA. The Inel G3000 is equipped with a position-sensitive detector that simultaneously monitors all diffraction data. The detector was calibrated by collecting an attenuated direct beam for 7 seconds at 1° intervals over a 2θ range of 90°. The calibration was checked against a silicon line position reference standard (NIST 640c). Samples were mounted on aluminum sample holders and flattened with a glass slide.

[0309] Alternatively, X-ray powder diffraction can be performed using a Rigaku Miniflex diffractometer (30 kV and 15 mA; X-ray source: Cu; range: 2.00 to 40.00°2θ; scan rate: 1 to 5° / min) or a Scintag X1 or X2 diffractometer (2 kW normal focus X-ray tube fitted with either liquid nitrogen or Peltier cooled germanium solid state detector; 45 kV and 40 mA; X-ray source: Cu; range: 2.00 to 40.00°2θ; scan rate: 1 to 5° / min).

[0310] Characteristic powder X-ray diffraction pattern peak positions are reported as angular positions (2θ) with an allowable variability of ±0.20°. When comparing two powder X-ray diffraction patterns, a variability of ±0.10° should be used. In practice, if a diffraction pattern peak from one pattern is assigned to a range of angular positions (2θ) as measured peak positions ±0.20° and a diffraction pattern peak from another pattern is assigned to a range of angular positions (2θ) as measured peak positions ±0.20°, and the ranges of peak positions overlap, the two peaks are considered to have the same angular position (2θ). For example, for comparison, if a diffraction pattern peak from one pattern is measured to have a peak position of 5.20°, the allowable variability allows that peak to be assigned to a position ranging from 5.00° to 5.40°. If a comparison peak from another diffraction pattern is measured to have a peak position of 5.35° and, with allowable variability, the peak can be assigned to a position in the range of 5.15° to 5.55°, then the two compared peaks are considered to have the same angular position (2θ) since there is overlap between the two peak position ranges.

[0311] Single crystal X-ray diffraction analysis of the samples was performed as follows. Samples for X-ray diffraction analysis were prepared by fixing selected crystals to glass pins with epoxy adhesive. X-ray diffraction data were collected using a Broker SMART system with an APEX area detector (50 kV and 40 mA; X-ray source: Mo). Data were collected at -100°C. [Example]

[0312] IX. Example The following non-limiting examples are provided to further illustrate the present disclosure. Abbreviations used in the examples below include: "DBU" means 1,8-diazabicyclo[5.4.0]-undec-7-ene. "DCM" means dichloromethane. "EDTA" means ethylenediaminetetraacetic acid. "FCC" means flash column chromatography. "HPLC" means high performance liquid chromatography. "IPA" means isopropanol. "LC-MS" means liquid chromatography-mass spectrometry. "m-CPBA" means meta-chloroperbenzoic acid. "MTBE" means methyl tert-butyl ether. "pa" means peak area. "THF" means tetrahydrofuran. "TLC" means thin layer chromatography. "t 1 / 2 " means biological half-life, i.e., the time required for half of a drug or other substance administered to a living organism to be metabolized or excreted by normal physiological processes.

[0313] Example 1: Synthesis of L-dopa monophosphates L-DOPA 3'-monophosphate and L-DOPA 4'-monophosphate were prepared according to the method shown in Scheme 1 below.

[0314] [ka]

[0315] Specifically, L-dopa 3'-monophosphate and L-dopa 4'-monophosphate were prepared according to the methods described in steps 1 to 5B below.

[0316] Phase 1 A solution of sodium hydroxide (40 g, 1.0 mol) in water (300 mL) was added dropwise to a suspension of compound 1 (100 g, 0.5 mol) in water (300 mL) at 0° C. over a period of 20 minutes. Benzyl chloroformate (103.9 g, 0.6 mol) in dioxane (400 mL) was added dropwise to the suspension over a period of 30 minutes at 0° C., and the reaction was then stirred at room temperature for 16 hours. Reaction completion was monitored by TLC. After complete consumption of the starting material, the reaction was basified to pH=10 with 10% sodium hydroxide (200 mL) and extracted with MTBE (500 mL). The organic layer was separated and discarded. The aqueous layer was acidified to pH=2 with 6 N HCl (150 mL) and extracted with MTBE (2×500 mL). The combined organic layers were washed with water (500 mL), saturated sodium chloride solution (500 mL), dried over sodium sulfate, and concentrated under reduced pressure at 45 to 50° C. to give crude compound 2 as a viscous liquid (120 g, 72%).

[0317] Phase 2 Cesium carbonate (123 g, 0.37 mol) was added in two lots to a solution of compound 2 (250 g, 0.75 mol) in dimethylformamide (2 L) at 0° C. To this mixture, benzyl bromide (90.3 mL, 0.75 mol) was added dropwise over a period of 30 minutes at 0° C. The reaction was stirred at room temperature for 16 hours. Completion of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction was diluted with water (5 L) and extracted with MTBE (2×1 L). The combined organic layers were washed with water (1 L), saturated sodium chloride solution (0.5 L), dried over sodium sulfate, and concentrated under reduced pressure at 45° C. to 50° C. to give crude compound 4 (250 g) as a viscous liquid.

[0318] Stage 3 Cesium carbonate (698.5 g, 2.14 mol) was added in four portions to a solution of compound 3 (900 g, 2.14 mol) in dimethylformamide (7.2 L) at 0° C. To this mixture, benzyl bromide (512 mL, 4.28 mol) was added dropwise over a period of 1 hour at 0° C., and the reaction was stirred at room temperature for 16 hours. Reaction completion was monitored by TLC. After complete consumption of the starting material, the reaction was diluted with water (15 L) and extracted with MTBE (2×3 L). The combined organic layers were washed with water (3 L), saturated sodium chloride solution (1.5 L), dried over sodium sulfate, and concentrated under reduced pressure at 45° C. to 50° C. to give the crude product (1 kg) as a viscous liquid.

[0319] The resulting crude product was mixed with the crude product from the previous batch (1.6 kg in total) and repeatedly purified by flash column chromatography on silica gel (230-400 mesh) using 10-20% ethyl acetate / petroleum ether to give compounds 4a (270 g) and 4b (255 g).

[0320] Stage 4A Potassium tert-butoxide (65.6 g, 0.58 mol) was added in four portions to a solution of compound 4a (200 g, 0.39 mol) in tetrahydrofuran (2.0 L) at 0°C. To this mixture, 10 wt% dibenzylphosphoryl chloride / toluene solution (2.31 kg, 0.78 mol) was added dropwise over a 30-minute period at 0°C, and the reaction was stirred at room temperature for 2 hours. Reaction completion was monitored by thin-layer chromatography. After complete consumption of the starting material, the reaction was cooled to 0-5°C and quenched with water (1.0 L). The organic layer was separated, and the aqueous layer was extracted with toluene (500 mL). The combined organic layers were washed with water (1 L), saturated NaCl solution (500 mL), dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C. The resulting crude product was purified by column chromatography on silica gel (230-400 mesh) using 30-40% ethyl acetate / petroleum ether to give compound 5a as a viscous liquid (185 g, 61.6%).

[0321] Stage 4B Potassium tert-butoxide (68.9 g, 0.61 mol) was added in four portions to a solution of compound 4b (210 g, 0.41 mol) in tetrahydrofuran (2.2 L) at 0°C. To this mixture, a 10 wt% solution of dibenzylphosphoryl chloride in toluene (2.43 kg, 0.82 mol) was added dropwise over a 30-minute period at 0°C. After the addition was complete, the reaction was stirred at room temperature for 2 hours. Reaction completion was monitored by thin-layer chromatography. After completion, the reaction was cooled to 0-5°C and quenched with water (1.0 L). The organic layer was separated, and the aqueous layer was extracted with toluene (500 mL). The combined organic layers were washed with water (1 L), saturated NaCl solution (500 mL), dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C. The crude product from this batch was mixed with crude product from another batch (45 g) and purified by column chromatography on silica gel (230-400 mesh) using 30-40% ethyl acetate / petroleum ether to give compound 5b as a viscous liquid (250 g, 65%).

[0322] Stage 5A 10% Pd / C (30 g, 50% wet) was added to a solution of compound 5a (100 g, 0.13 mol) in ethanol and water (1 L, 4:1) under a nitrogen atmosphere. The reaction flask was evacuated and purged with hydrogen gas three times, then purged with 4 kg / cm. 2 The mixture was hydrogenated at a pressure (approximately 4 atm) for 16 hours. After completion of the reaction, water (500 mL) was added to the reaction mixture, and the catalyst was removed by filtration through a K100 cellulose filter pad (diameter 520 mm). The filtrate was concentrated under reduced pressure. The resulting crude product was stirred with ethanol (60 mL), filtered, and dried under suction to give (S-2-amino-3-(3-hydroxy-4-(phosphonooxy)phenyl)-propanoic acid; L-DOPA(4-phosphate) (17 g, 47%) as an off-white solid. 1H NMR (300MHz, D2O) δ7.1(d, J=8.1Hz, 1H), 6.7(s, 1H), 6.68(d, J=8.1Hz, 1H), 4.1(q, J= 5.1Hz, 1H), 3.15(dd, J=14.7Hz, 4.5Hz, 1H), 3.0-2.93(m, 1H);MS(LCMS)m / z278[M+H] + .

[0323] Stage 5B 10% Pd / C (30 g, 50% wet) was added to a solution of compound 5b (100 g, 0.13 mol) in ethanol and water (1 L, 4:1) under a nitrogen atmosphere. The reaction flask was evacuated and purged with hydrogen gas three times at 4 kg / cm. 2 The mixture was hydrogenated at a pressure (approximately 4 atm) for 16 hours. After completion of the reaction, water (500 mL) was added to the reaction mixture, and the catalyst was removed by filtration through a K100 cellulose filter pad (diameter 520 mm). The filtrate was concentrated under reduced pressure. The resulting crude product was stirred with ethanol (60 mL), filtered, and dried under suction to give (S-2-amino-3-(4-hydroxy-3-(phosphonooxy)phenyl)-propanoic acid; L-dopa(3-phosphate) (21 g, 58.5%) as an off-white solid. 1 H NMR (300MHz, D2O) δ7.06(s, 1H), 6.85(s, 2H), 4.08(q, J=4.8Hz, 1H), 3.16(dd, J=14.7Hz, 5.1Hz, 1H), 3.0-2.92(m, 1H); MS(LCMS) m / z278[M+H] + .

[0324] Example 2: Synthesis of L-dopa diphosphate L-Dopa 3',4'-diphosphate was prepared according to the method shown in Scheme 2 below.

[0325] [ka]

[0326] Specifically, L-dopa 3',4'-diphosphate was prepared according to the methods described in steps 6 and 7 below.

[0327] Stage 6 Cesium carbonate (484 g, 1.48 mol) was added in two lots to a solution of compound 3 (250 g, 0.59 mol) in dimethylformamide (2.5 L) at 0°C. A 10 wt% solution of dibenzylphosphoryl chloride in toluene (3.52 kg, 1.18 mol) was added dropwise to the mixture over a period of 1 hour at 0°C, and the reaction was stirred at room temperature for 2 hours. Reaction completion was monitored by TLC. After complete consumption of the starting material, the reaction was cooled to 0-5°C and quenched with water (5 L). The organic layer was separated, and the aqueous layer was extracted with toluene (1 L). The combined organic layers were washed with water (1 L), saturated sodium chloride solution (0.5 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure at 45-50°C. The resulting crude product was purified by column chromatography on silica gel (230-400 mesh) using 10-15% ethyl acetate / petroleum ether to give compound 6 as a gummy liquid of intermediate purity (240 g).

[0328] Stage 7 10% Pd / C (20 g, 50% wet) was added to a solution of compound 6 (50 g, 0.05 mol) in THF (500 mL) under a nitrogen atmosphere. The reaction flask was evacuated and purged with hydrogen gas three times and hydrogenated at 6 kg pressure for 8 h. After completion of the reaction, water (250 mL) was added to the reaction mixture, and the catalyst was removed by filtration through a K100 cellulose filter pad (520 mm diameter). The filtrate was concentrated under reduced pressure. The resulting crude product was stirred with ethanol (30 mL), filtered, and dried under vacuum to give L-DOPA(3,4-phosphate) (12.8 g, 64%, corrected purity) as an off-white solid. 1 H NMR (300MHz, D2O) δ7.21(d, J=8.4Hz, 1H), 7.16(s, 1H), 6.95(d, J=7.8Hz, 1H), 4.23(q, J=2.7Hz, 1H), 3.24(dd, J=15Hz, 4.8Hz, 1H), 3.08-3.01(m, 1H);MS(LCMS)m / z358[M+H] + .

[0329] Example 3: Synthesis of carbidopa monophosphate Carbidopa 3'-phosphate and carbidopa 4'-phosphate were prepared according to the method shown in Scheme 3 below.

[0330] [ka]

[0331] Specifically, carbidopa 3'-phosphate and carbidopa 4'-phosphate were prepared according to the method described in Step 1 below.

[0332] Phase 1 A viscous mixture of phosphorus pentoxide (2.325 g, 16.38 mmol) and phosphoric acid (85% aqueous solution, 1.79 mL, 26.2 mmol) was heated to 100 °C for 15 min to give a clear solution. The solution was cooled back to 50 °C, and carbidopa monohydrate (0.400 g, 1.64 mmol) was added. After 3 h, the solution was cooled to room temperature, stirred for 14 h, and warmed to 35 °C. After 24 h, the solution was cooled to room temperature and stirred for 60 h. Water (2 mL, exothermic to 50° C.) was added, and the solution was stirred for 5 minutes and analyzed by HPLC (Agilent Poroshell 120EC-C18 #693975-902 4.6×150 mm column, 1 mL / min 0.1% HPO in CHCN, 3 min 97:3, 4 min gradient to 70:30, 2 min gradient to 0:100, 1 min hold, detection at 220 nm) showing carbidopa (6.7 min): 2.6 pa%, phosphate 1 (5.1 min): 38.2 pa%, phosphate 2 (5.7 min): 37.7 pa%, diphosphate (2.3 min): 5.9 pa%. The aqueous solution was diluted with water (5x) and purified by preparative HPLC (Kromasil Phenyl 3 cm (ID) x 25 cm, 5 micron column, 30 mL / min 0.1% formic acid / CH3CN, 97:3 in 10 min, 93:7 in 5 min, 100:0 in 0.5 min, detection at 277 nm). The pure fractions of the separated monophosphate were combined, concentrated on a rotary evaporator (bath temperature 35 °C) to 10 mL each, and lyophilized to give carbidopa 4'-phosphate 1 (152 mg, 30% yield) and carbidopa 3'-phosphate 2 (137 mg, 27% yield) as white amorphous powders. Carbidopa 3'-monophosphate: 1 H NMR (400MHz, heavy water) δ7.20 (dd, J=8.2, 1.2Hz, 1H), 6.84 (d, J=2.1Hz, 1H), 6.77 (dd, J=8.3, 2.2 Hz, 1H), 3.19(d, J=14.2Hz, 1H), 2.99(d, J=14.2Hz, 1H), 1.52(s, 3H);MS(ESI)m / z307[M+H] +. Carbidopa 4'-monophosphate:1H NMR (400MHz, heavy water) δ7.14(t, J=1.4Hz, 1H), 7.01-6.83(m, 2H), 3.19(d, J=14.3Hz, 1H), 3.00(d, J=14.4Hz, 1H), 1.52(s, 3H); MS(ESI) m / z307[M+H] + .

[0333] Example 4a: Synthesis of carbidopane diphosphate Carbidopa 3',4'-diphosphate was prepared according to the method shown in Scheme 4a below.

[0334] [ka]

[0335] Specifically, carbidopa 3',4'-diphosphate was prepared according to the method described in steps 1 to 4 below.

[0336] Phase 1 A slurry of carbidopa monohydrate (20.0 g, 82 mmol), sodium bicarbonate (7.57 g, 90 mmol), water (200 mL), and THF (100 mL) was cooled to 5 to 10 °C, and N-(benzyloxycarbonyloxy)succinimide (20.4 g, 82 mmol) was added. The mixture was warmed to ambient temperature and became a nearly homogeneous solution over 5 h, at which point LC-MS indicated near completion of the reaction. The solution was diluted with MTBE (100 mL), the layers were separated, and the organic layer was extracted with saturated aqueous NaHCO3 (100 mL). The aqueous layer was acidified with 2 N HCl (160 mL), and the acidic aqueous layer was extracted with MTBE (2 x 100 mL). During the second back-extraction, a small amount of product began to precipitate. The combined organic layers were washed with brine (20 mL), and the remaining solid was washed from the separatory funnel with MTBE (20 mL). The resulting mixture was concentrated to a total mass of 43 g, and 10% THF / MTBE (60 mL) was added. The mixture was too viscous to stir, so additional MTBE (60 mL in 6 volumes of 5% THF / MTBE) was added. The resulting white slurry was then heated to 50°C. The slurry was cooled to ambient temperature over 1 hour and then stirred for 14 hours. The white solid was filtered, washed with 5% THF / MTBE (20 mL), and dried in a vacuum oven (50°C) to give (S)-2-(2-((benzyloxy)carbonyl)-hydrazinyl)-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid and THF (4:3) (31.1 g, 71.9 mmol, 91% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.66(d, J=9.0Hz, 2H), 8.18(brs, 1H), 7.49-7.17(m, 5H), 6.59(dd, J=5.0, 3.0Hz, 2H), 6.44(d d, J=8.0, 2.0Hz, 1H), 5.04(s, 2H), 2.73(d, J=13.4Hz, 1H), 2.59(d, J=13.3Hz, 1H), 1.07(s, 3H);MS(ESI)m / z361[M+H] + .

[0337] Phase 2 A solution of benzophenone hydrazone (20.0 g, 102 mmol) in DCM (100 mL) was cooled to <0 °C, and iodine (0.052 g, 0.204 mmol) and 1,1,3,3-tetramethylguanidine (25.6 mL, 204 mmol) were added. m-CPBA (30.5 g, 132 mmol) was added portionwise over 5 min at -10 °C to 0 °C (exothermic, controlled by a dry ice / acetone bath). The mixture was stirred at 0 °C to 12 °C for 15 min and then washed with water (3 x 200 mL). The resulting mixture was dried (Na2SO4), concentrated to a total volume of 76 mL, and washed into a 125 mL Erlenmeyer flask with an additional 16 mL of DCM to give a dark purple (approximately 1 M) solution of (diazomethylene)dibenzene. In a separate flask, a slurry of (S)-2-(2-((benzyloxy)carbonyl)hydrazinyl)-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid and tetrahydrofuran (4:3) (30.7 g, 74.0 mmol) in IPA (300 mL) was cooled to <10 °C, and a solution of (diazomethylene)dibenzene (78 mL, 78 mmol) was added. The resulting mixture was warmed to room temperature, and LC-MS indicated the reaction had stalled after 30 min. Additional diphenyldiazomethane (0.2 equiv., 14 mL) was added, and stirring was continued at room temperature. After 35 min, the remaining diphenyldiazomethane solution (9 mL) was added. After 2 h 20 min, the purple color persisted, and LC-MS indicated the reaction was complete. The reaction mixture was concentrated to approximately 60 mL, and 20% aqueous CH3CN (300 mL) was added. The mixture was washed with cyclohexane (10 x 300 mL), ethyl acetate (450 mL) was added, and the mixture was washed with saturated aqueous NaHCO (150 mL) and brine (60 mL). The mixture was dried (NaSO) and concentrated to give (S)-benzyl 2-(1-(benzhydryloxy)-3-(3,4-dihydroxyphenyl)-2-methyl-1-oxopropan-2-yl)hydrazine-carboxylate (39.4 g, 74.8 mmol, >99% yield). 1H NMR (400MHz, DMSO-d6) δ8.65(brs, 2H), 8.19(brs, 1H), 7.43-7.20(m, 15H), 6.70(s, 1H), 6.55(d, J=2.0Hz, 1H), 6.45(d, J=8.0Hz, 1H), 6.20 (dd, J=7.9, 2.0Hz, 1H), 4.95(d, J=3.4Hz, 2H), 2.81(d, J=13.6Hz, 1H), 2.67(d, J=13.7Hz, 1H), 1.17(d, J=3.1Hz, 3H);MS(ESI)m / z549[M+Na] + .

[0338] Stage 3 A solution of (S)-benzyl 2-(1-(benzhydryloxy)-3-(3,4-dihydroxyphenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate (39.4 g, 74.8 mmol) and CHCN (394 mL) was cooled to below 0 °C, and DBU (27.1 mL, 180 mmol) and tetrabenzyl pyrophosphate (89 g, 165 mmol) were added below 0 °C. After 40 min, water (400 mL) was added to give a biphasic solution. The layers were separated, and the lower (yellow oil) layer (approximately 100 mL) was washed with cold 1:1 CHCN / water (2 x 100 mL), diluted with ethyl acetate (400 mL), and washed with brine (80 mL). The mixture was dried (NaSO) and concentrated. FCC (50% to 100% MTBE / heptane) gave (S)-benzyl 2-(1-(benzhydryloxy)-3-(3,4-bis((bis(benzyloxy)phosphoryl)oxy)phenyl)-2-methyl-1-oxopropan-2-yl)hydrazine-carboxylate (67.2 g, 64.2 mmol, 86% yield) as a clear oil. 1 H NMR (400MHz, DMSO-d6) δ7.45-7.16(m, 35H), 7.06(d, J=8.6Hz, 1H), 6.88(dd, J=8.7, 2.0Hz, 1H), 6.71(s, 1H), 5.12( ddt, J=9.9, 7.0, 3.9Hz, 10H), 4.99-4.80(m, 2H), 2.95-2.76(m, 2H), 1.11(d, J=1.8Hz, 3H);MS(ESI)m / z1069[M+Na]+ .

[0339] Stage 4 In a 2-L stainless steel pressure bottle, a solution of (S)-benzyl 2-(1-(benzhydryloxy)-3-(3,4-bis((bis(benzyloxy)-phosphoryl)oxy)phenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate (60.6 g, 57.9 mmol) in THF (550 mL) was added to 5% Pd / C (wet JM#9) (12.1 g, 56.9 mmol). The mixture was shaken under 60 psi of hydrogen at 22°C for 2 hours. The onset temperature was 12.4°C (the solution had been stored in a freezer), and the T max The pH was 31.6°C. Water (deionized, 275 mL) was added, and hydrogenation was continued for an additional 17 hours. The mixture was filtered through a nylon membrane, washing with 100 mL of 1:1 THF-water. The mixture was diluted with MTBE (100 mL), and the layers were separated. The aqueous layer was washed with MTBE (3 x 100 mL), concentrated on a rotary evaporator (bath temperature 35°C) to a total mass of 100 g, and lyophilized for 3 days to give a white glass. The amorphous solid was crushed and lyophilized for 1 day to remove traces of additional water to give carbidopane diphosphate (22.3 g, >99%), which still contained 10 to 15 wt% water by Karl Fischer titration (corrected yield 85%). 1 H NMR (500MHz, DMSO-d6) δ7.15(d, J=8.3Hz, 1H), 7.11(s, 1H), 6.89(dd, J=8.1, 2.1Hz, 1H), 3.00-2.82(m, 2H), 1.31(s, 3H); MS(ESI) m / z387[M+H] + By HPLC (Agilent Poroshell 120EC-C18 #693975-902 4.6 x 150 mm column, 1 mL / min 0.1% H3PO4 in CH3CN, 3 min 97.5:2.5, 4 min gradient to 70:30, 2 min gradient to 0:100, 1 min hold, detection at 220 nm), the material was found to be 96.4% pure (peak area % at 220 nm; diphosphate retention time = 2.37 min).

[0340] Example 4b: Synthesis of Carbidopaniphosphate Carbidopa 3',4'-diphosphate was prepared according to the method shown in Scheme 4b below.

[0341] [ka]

[0342] Specifically, carbidopa 3',4'-diphosphate was prepared according to the method described in steps 1 to 4 below.

[0343] Phase 1 To a suspension of S(-)-carbidopa (25 g, 92 mmol) in water (76 mL) was added a solution of sodium hydroxide (7.24 g, 183 mol) in water (76 mL) dropwise at <5°C over a 20-minute period. After the base was added, the mixture was stirred for 15 minutes or until the reaction mixture became a solution. To this solution, benzyl chloroformate (18.67 g, 110 mmol) in THF (101 mL) was added dropwise at <10°C over a 30-minute period, and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at 25°C for 1 hour. After 1 hour, an additional 0.2 equivalents of benzyl chloroformate (3.74 g, 3.12 mL) was added, and the reaction mixture was stirred at 25°C for 1.5 hours. After 1.5 hours, the reaction mixture (pH = 5.75) was basified to pH = 9 with 10% sodium hydroxide and extracted with MTBE (3 x 150 mL). The organic layer was separated and discarded. The aqueous layer (pH = 8.6) was acidified to pH = 2.75 with 6N HCl and extracted with MTBE (3 x 150 mL). The combined organic layers were washed with saturated sodium chloride solution (150 mL), dried over magnesium sulfate, and partially concentrated (75%) under reduced pressure. To the solution was added 250 mL of THF and again partially concentrated (75%) under reduced pressure. To the resulting yellow solution was added 250 mL of MTBE and concentrated to 50% by volume. The resulting white slurry was cooled to 0°C, filtered, and the solid was washed with cold MTBE to give 32.31 g of compound 1 (white solid) (potency 84.5 wt%, 95.6% pA, PAY 83%).

[0344] Phase 2 Cesium carbonate (2.3 g, 7.08 mmol) was added to a solution of compound 2 (5.0 g, 11.79 mmol) in DMF (50 mL) at 2° C. The mixture was stirred for 10 minutes. To this mixture, benzyl bromide (2.0 g, 11.79 mmol, 1.4 mL) was added dropwise over a 10-minute period at 2° C. After the addition, the reaction mixture was stirred at 25° C. for 64 hours. After 64 hours, the reaction mixture was diluted with water (150 mL) and extracted with MTBE (3×150 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (MgSO), filtered, and concentrated to give 5.36 g of compounds 2 and 3 in 88% yield. Compound 2: MS (ESI) m / z 451 [M+H] + , Compound 3, MS(ESI)m / z541[M+H] + .

[0345] Stage 3 To a solution of compounds 2 and 3 (9.8 g, 21.75 mmol) in ACN (100 mL) was added tetrabenzyl pyrophosphate (29.9 g, 54.4 mmol) at −14° C. DBU (8.61 mL, 56.6 mmol) was added dropwise to the reaction mixture at −7° C. The reaction mixture was stirred at <0° C. for 30 minutes. After 30 minutes, the reaction mixture was allowed to warm to room temperature. After 1 hour, the reaction mixture was quenched with water (300 mL), extracted with MTBE (2×150 mL), washed with water (150 mL), brine (150 mL), dried (MgSO), filtered, and concentrated to give compounds 4 and 5 (24.69 g) in 92% yield. Compound 4, MS (ESI) m / z 972 [M+H] + .

[0346] Stage 4 Compounds 4 and 5 (1.026 g, 0.980 mmol) and 5% Pd / C (50% wet, JM#9) (0.199 g, 1.870 mmol, dry weight 0.10 g) were added to tetrahydrofuran (10.00 mL) in a glass-lined 20 mL Barnstead vessel. The mixture was stirred at 25 °C under 80 psi hydrogen for 1.5 h. Water (5.00 mL) was added, and the mixture was hydrogenated for an additional 1.5 h. After 1.5 h, the mixture was filtered through a polypropylene membrane, 2.5 mL of MTBE was added, and the mixture was shaken in a separatory funnel, and the lower aqueous layer was drained. The aqueous solution was washed twice with 2.5 mL of MTBE, resulting in a significant volume loss (THF and toluene were transferred to the MTBE phase). The colorless aqueous solution (aqueous layer) was lyophilized for 3 days to give 385 mg of the desired product (93.9% pa) Compound 6.

[0347] Example 5: Alternative synthesis of L-dopa 4'-monophosphate L-Dopa 4'-monophosphate was prepared according to the method shown in Scheme 5 below.

[0348] [ka]

[0349] Specifically, L-dopa 4'-monophosphate was prepared according to the method described in steps 1 to 5 below.

[0350] Phase 1 To a solution of 3-(benzyloxy)-4-hydroxybenzaldehyde, compound 1 (10.0 g, 43.8 mmol), in acetonitrile (100 mL) was added tetrabenzyl diphosphate (TBPP) (24.8 g, 46.0 mmol) at 25 °C. The reaction mixture was cooled to 4 °C, and DBU (7.67 g, 50.4 mmol) was added to the reaction mixture. After the addition, the reaction mixture was warmed to room temperature and stirred at room temperature (approximately 20 to 25 °C) for 60 minutes. The reaction mixture was quenched with water (400 mL) and extracted with MTBE (3 x 100 mL). The organic layer was washed with saturated sodium bicarbonate solution (150 mL), water (150 mL), saturated sodium chloride solution (150 mL), and concentrated to give compound 2 (20.7 g, 96.5% purity, 93% yield). 1 H NMR (400MHz, DMSO-d6) δ9.92(s, 1H), 7.67(dd, J=1.8, 0.9Hz, 1H), 7.54(dd, J=8.1, 1.8H z, 1H), 7.48-7.39(m, 3H), 7.35-7.22(m, 13H), 5.22(s, 2H), 5.09(dd, J=8.2, 2.1Hz, 4H).

[0351] Phase 2 To a solution of (+ / -)-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester (31.1 g, 94 mmol) and dibenzyl (2-(benzyloxy)-4-formylphenyl)phosphate, compound 2, (44.3 g, 94% purity, 85 mmol) in DCM (443 mL) at 2° C. was added 1,1,3,3-tetramethylguanidine (TMG) (11.78 g, 102 mmol). The resulting mixture was stirred at room temperature overnight. The next day, the reaction mixture was washed three times with 222 mL of water and concentrated to give 68.9 g of compound 3. Compound 3 was then slurried with 40.5 g of silica gel 60 in 689 mL of ethyl acetate for 1 hour and filtered. The filtrate was concentrated to give 73.4 g of compound 3 as an oil. Compound 3 was then precipitated at 4° C. and slurried in 350 mL of MTBE at 4° C. for 1 hour. The slurry was then filtered and the solid was washed with cold MTBE. The solid was dried overnight in a vacuum oven at 40° C. to give 50.4 g of compound 3 (99.6% purity, 85% yield). 1H NMR (400MHz, DMSO-d6) δ7.60 (t, J=1.4Hz, 1H), 7.44-7.18 (m, 23H), 5.10 (qd, J=5.9, 2.6Hz, 8H), 3.72 (s, 3H).

[0352] Stage 3 A 2.0 gallon reactor was charged with compound 3, methyl 3-(3-(benzyloxy)-4-((bis(benzyloxy)phosphoryl)oxy)phenyl)-2-(((benzyloxy)carbonyl)amino)acrylate (446.31 g, 521 mmol) in 3.6 liters of THF. This solution was sparged with N for 30 minutes. A separate 2.0 gallon reactor was charged with 1,2-bis[(2S,5S)-2,5-diethylphosphorano]benzene(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (3.44 g, 5.21 mmol), purged with N 10 times, and sparged with N for 30 minutes. The feed solution was then transferred to this reactor using N pressure. The lines were purged with H, and then the reactor was purged with H three times. The reaction mixture was stirred at 35°C under 100 psi of H2. After 20 hours, HPLC showed compound 4 with 99% ee. The reaction mixture was then transferred to a 12 L extractor, and 3.6 L of ethyl acetate was added. The solution was washed twice with 3.7 L of 5 wt% cysteine / 8% sodium bicarbonate, followed by 3.6 L of 5 wt% aqueous NaCl. The organic layer was separated and stirred with 43.4 g of ENO-PC activated carbon at room temperature under N2 overnight. The mixture was filtered, and the filtrate was concentrated to give compound 4 (420.1 g, oil), 88% wt purity, 100% yield, chiral purity: 99% ee. The crude product, (S)-methyl 3-(3-(benzyloxy)-4-((bis(benzyloxy)phosphoryl)oxy)phenyl)-2-(((benzyloxy)carbonyl)amino)propanoate, compound 4, was used directly in the next step. 1H NMR (400MHz, DMSO-d6) δ7.85(d, J=8.1Hz, 1H), 7.46-7.16(m, 21H), 7.09(dd, J=8.2, 1.4Hz, 1H), 6.81(dd, J=8.2, 1.9Hz, 1H), 5.09-4.98(m, 8H), 4.31(ddd, J=10.2, 8.1, 5.0Hz, 1H), 3.63(s, 3H), 3.08-2.78(m, 2H).

[0353] Stage 4 A 150 mL Parr hydrogenation apparatus was charged with 10 wt. % 5% Pd / C (1.33 g, catalyst containing 63.6% HO) on a dry weight basis. 2.9 wt. % aqueous sodium bicarbonate solution (20.7 g) was added to the reactor. Compound 4 (5.70 g, 85% titer) was dissolved in THF (48.5 mL, 10 mL / g substrate) and then transferred to the reactor. The reactor was pressurized with argon to 60 psi, released to 10 psi, and argon pressure purged a total of six times. Similarly, the reactor was pressure purged three times with hydrogen (filled to 50 psi, released to 5 psi). The reactor was backfilled to 50 psi H2 and stirred at 750 rpm for at least 2 hours at 25 °C. After the reaction was complete, the two-phase solution was filtered to remove the catalyst. The reactor and filter cake were washed with water (4.1 mL, 2 mL / g of theoretical yield of product). The two-phase reaction mixture was diluted with 16 mL of MTBE. The aqueous layer was removed and washed with 16 mL of MTBE. The aqueous layer was then transferred to a 250 mL flask and sufficient 6 M aqueous HCl was added to adjust the pH to 1.8. The solution was mixed vigorously, and iPrOH (73 mL) was added to give a final solvent composition of 3:1 iPrOH / water. The slurry was stirred overnight. The crystallized slurry was filtered, and the wet cake solid was washed with iPrOH. The white solid was dried in a vacuum oven at 50 °C to give compound 5 (1.72 g, crystalline solid, 85% yield). 1H NMR (400MHz, heavy water) δ7.25(dt, J=8.3, 1.1Hz, 1H), 6.87(t, J=1.5Hz, 1H), 6.80(dd, J=8.3, 2 .2Hz, 1H), 4.41(ddd, J=7.9, 5.4, 0.7Hz, 1H), 3.87(d, J=0.7Hz, 3H), 3.36-3.08(m, 2H).

[0354] Stage 5 To a solution of compound 5, (S)-methyl 2-amino-3-(3-hydroxy-4-(phosphonooxy)phenyl)propanoate (10.0 g, 34.3 mmol) in water (40 mL) was added 22.89 mL (4.0 equiv.) of 6N NaOH at 15-20°C. When the pH reached 7-8, the solution was filtered to clarify. After clarification, pH adjustment continued. After the base was added, the rxn mixture was stirred at 25°C for 60 minutes (pH = 12.06). After 60 minutes, the reaction mixture was acidified with 4.0 equiv. of 6N HCl (137 mmol, 22.89 mL). The final pH was adjusted to 1.8. After 10 minutes, the rxn mixture became cloudy, and 200 mL of IPA was added. The slurry was stirred for 30 minutes, and the solid was filtered and washed with IPA. The solid was dried overnight in a vacuum oven at 40° C. to give compound 6, (S)-2-amino-3-(3-hydroxy-4-(phosphonooxy)phenyl)propanoic acid (7.85 g, 99% purity, 87% yield, 99.6% ee). 1 H NMR (400MHz, heavy water) δ7.24 (dd, J=8.3, 1.3Hz, 1H), 6.91 (d, J=2.1Hz, 1H), 6.83 (dd, J=8.3, 2.2Hz, 1H), 4.25 (dd, J=8.0, 5.2Hz, 1H), 3.35-3.05 (m, 2H).

[0355] Example 6: Alternative synthesis of L-dopa 4'-monophosphate L-Dopa 4'-monophosphate was prepared according to the method shown below.

[0356] [ka]

[0357] Phase 1 A solution of 2-(benzyloxy)phenol (63.7 mL, 364 mmol) in MeOH (1050 mL) was cooled to -10°C and sodium iodide (54.5 g, 364 mmol) and sodium hydroxide (382 mL, 764 mmol) were added (NaOH was added over 5 min to bring the temperature to 10°C and a dark solution was obtained upon addition of NaOH). It was cooled back to <5°C and sodium hypochlorite (247 mL, 400 mmol) was added dropwise, maintaining the temperature at <5°C. After 10 min, 500 mL of MeOH was removed by rotary evaporation, and MTBE (730 mL) and 2 N HCl (909 mL, 1818 mmol) were added. The mixture was washed with 1 N NaSO (3 x 130 mL; each time the color lightened) and brine (64 mL), dried (NaSO), concentrated, and washed with cyclohexane (100 mL) to give a crude yellow solid. Cyclohexane (130 mL) was added, heated to 55 °C (yellow solution), cooled slowly, and seeded at 45 °C (approximately 50 mg solution) and 40 °C (approximately 50 mg, slurry developed). Cooling was continued to room temperature (approximately 20-25 °C) and stirred vigorously overnight. Filtration and washing with cyclohexane (64 mL) gave product 1 (69.93 g, 59%, 1 Very pure by H NMR, slightly off-white solid. The mother liquor was concentrated to approximately 70 mL, seeded, and aged for 1 h, resulting in a viscous dark material precipitating with the product. MTBE (7 mL) was added, sonicated (good for dissolving the color), stirred for 20 min, and filtered. Washing with 10% MTBE / cyclohexane (32 mL) gave material 2 (4.65 g, 1 H NMR showed some minor impurities). Overall, 2-(benzyloxy)-4-iodophenol was isolated (74.6 g, 229 mmol, 62.9% yield). 1H NMR(501MHz、DMSO-d6)δ9.33(s、1H)、7.49-7.42(m、2H)、7.42-7.35(m、2H)、7.35-7.29(m、1H)、7.24(d、J=2.0Hz、1H)、7.09(dd、J=8.3、2.1Hz、1H)、6.64(d、J=8.3Hz、1H)、5.09(s、2H)。

[0358] Phase 2 A solution of (S)-benzyl 2-(((benzyloxy)carbonyl)amino)-3-hydroxypropanoate (150 g, 455 mmol) in DMF (750 mL) was cooled to 0°C and methyltriphenoxyphosphonium iodide (247 g, 547 mmol) was added (no exotherm). After 20 min at 5 to -5°C, reaction was complete by LC-MS. After 30 min, sodium bicarbonate (19.13 g, 228 mmol) and MTBE (750 mL, temperature reached 8°C) were added, followed by careful addition of water (750 mL, slight CO evolution at initial addition) while maintaining the temperature at <20°C. At pH ∼8, the separatory funnel was washed with additional water (750 mL, 1.5 L total, 10 vol) and MTBE (750 mL, 1.5 L total, 10 vol). The layers were separated, the organic layer washed with brine (300 mL), and the layers checked by LC-MS. It was dried (NaSO) and concentrated to a minimum volume (401 g total mass), and MeOH was added (3.0 L, yellow solution). Water (1.5 L) was added over 30 minutes, and seeded with previously isolated crystals (0.1 wt%, 150 mg) after adding two volumes of 300 mL water (did not dissolve). A gradual slurry formed, which quickly thickened after 650 mL of water was added. After stirring at ambient temperature for 30 minutes, the white slurry was filtered, washed with 2:1 MeOH / water (300 mL slurry wash, 300 mL displacement wash), and placed on a glass frit under vacuum for 12 hours. MeOH (2.25 L, 15 vol) was added to the wet cake and stirred vigorously for 30 minutes to disperse the slurry. Water (1.125 L) was added over 30 minutes, stirred for an additional 15 minutes, filtered, and washed with 2:1 MeOH / water (displacement wash, 300 mL). The white solid was dried to constant weight in a vacuum oven at 50°C to give (R)-benzyl 2-(((benzyloxy)carbonyl)amino)-3-iodopropanoate (173 g, 394 mmol, 86% yield). f Titration revealed 253 ppm water. 1H NMR(400MHz、DMSO-d6)δ7.96(d、J=8.3Hz、1H)、7.44-7.14(m、10H)、5.10(d、J=33.8Hz、4H)、4.38(td、J=8.7、4.6Hz、1H)、3.55(dd、J=10.3、4.6Hz、1H)、3.37(t、J=9.7Hz、1H)。MS(ESI)m / z457[M+NH4] + 。

[0359] Stage 3 In a 2 L, three-necked, round-bottom flask, a slurry of zinc (47.0 g, 719 mmol) and DMF (325 mL) was stirred magnetically. The gray slurry was cooled to 16 °C in an ice bath, and iodine (7.60 g, 29.9 mmol) was added (an immediate exotherm occurred from 16 to 27 °C, resulting in a yellow to clear supernatant). The mixture was cooled back to 10 °C, and at <25 °C, (R)-benzyl 2-(((benzyloxy)carbonyl)amino)-3-iodopropanoate (105 g, 240 mmol) was added in small portions over 10 min. After an additional 10 min at 20 to 25 °C, LCMS indicated complete zinc insertion (quenched with 2 N HCl in small portions). Pd2(dba)3 (0.457 g, 0.499 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.410 g, 0.998 mmol), and 2-(benzyloxy)-4-iodophenol (65.1 g, 200 mmol) were added in one portion (no exotherm) and stirred at room temperature (start = 2:30). After 1 h, an exotherm to 27 °C was observed, so the mixture was cooled back to 20-25 °C in a room temperature water bath and stirred overnight. After 15 h 40 min, LC-MS indicated a complete and clean reaction. MTBE (650 mL) and silica (65 g) were added, stirred for 15 min, and the gray slurry was filtered, washing the gray solid with MTBE (325 + 130 mL). The yellow filtrate was washed with saturated aqueous NH4Cl (325 mL, pH ∼5-6, temperature reached 27 °C with slight H2 evolution) and brine (130 mL), dried (Na2SO4), concentrated, and purified by FCC (800 g column, 50% to 100% DCM / heptane then 10% MTBE / DCM; separating only nonpolar, highly colored impurities and baseline material, HPLC pa% increased from 91 to 93 pa%) to give (S)-benzyl 3-(3-(benzyloxy)-4-hydroxyphenyl)-2-(((benzyloxy)carbonyl)amino)propanoate (106 g, 207 mmol, 104% yield) as a light brown oil. 1 H NMR showed the excess mass was primarily CBz alanine Bn ester from protonation of the excess alkyl zinc during workup. Assuming quantitative yield, it was used in the next step without further purification. 1H NMR (501MHz, DMSO-d6) δ8.86(s, 1H), 7.80(d, J=8.0Hz, 1H), 7.47-7.41(m, 2H), 7.41-7.08(m, 13H), 6.94(d, J=2.0Hz, 1H), 6.70(d, J=8.0Hz, 1H) , 6.63(dd, J=8.0, 1.9Hz, 1H), 5.15-4.93(m, 6H), 4.27(ddd, J=9.7, 7.9, 5.5Hz, 1H), 2.93(dd, J=13.8, 5.5Hz, 1H), 2.78(dd, J=13.8, 9.8Hz, 1H). MS(ESI)m / z512[M+H] + .

[0360] Stage 4 A solution of (S)-benzyl 3-(3-(benzyloxy)-4-hydroxyphenyl)-2-(((benzyloxy)carbonyl)amino)propanoate (102 g, 200 mmol) in ACN (510 mL) was stirred at room temperature and tetrabenzyl pyrophosphate (118 g, 220 mmol) was added. Cooled in an ice bath, DBU (45.2 mL, 300 mmol) was added over 10 minutes while maintaining the temperature between 20 and 25° C. After 30 minutes, LC-MS showed the reaction was complete. MTBE (1.0 L) and water (510 mL) were added, the layers were separated (negligible water loss by LCMS), and the organic layer was washed with brine (3×200 mL). Drying (NaSO), concentration, and FCC (two portions, each purified on an 800 g column using a 25 to 75% MTBE / heptane gradient elution, and then combined) gave (S)-benzyl 3-(3-(benzyloxy)-4-((bis(benzyloxy)phosphoryl)oxy)phenyl)-2-(((benzyloxy)carbonyl)amino)propanoate (132 g, 171 mmol, 86% yield) as an amber oil. 1H NMR (400MHz, DMSO-d6) δ7.87(d, J=8.1Hz, 1H), 7.43-7.17(m, 26H), 7.07(dd, J=8.2, 1.3Hz, 1H), 6.79(dd, J=8.3, 1.9Hz, 1 H), 5.14-4.91(m, 10H), 4.38(ddd, J=10.0, 8.0, 5.2Hz, 1H), 3.05(dd, J=13.8, 5.2Hz, 1H), 2.88(dd, J=13.8, 10.1Hz, 1H). MS(ESI)m / z789[M+NH4] + .

[0361] Levodopa 4'-monophosphate was prepared similarly to step 5a from Example 1.

[0362] Example 7: Alternative synthesis of carbidopa 4'-monophosphate Carbidopa 4'-monophosphate was prepared according to the method shown in Scheme 7 below.

[0363] [ka]

[0364] Specifically, carbidopa 4'-monophosphate was prepared according to the method described in steps 1 to 5 below.

[0365] Phase 1 A 500 mL three-necked round-bottom flask was charged with compound 1 (25.04 g, 90 mmol), tris(dibenzylideneacetone)palladium (1.23 g, 1.343 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.875 g, 3.02 mmol), and a stir bar. A thermocouple, reflux condenser, and stopper were attached to the third neck of the flask. The flask was purged with nitrogen for 1 hour. During this time, a second flask was charged with dioxane (200 mL), 2-methylprop-2-en-1-ol (8.30 mL, 99 mmol), and N-cyclohexyl-N-methylcyclohexanamine (30 mL, 140 mmol), and nitrogen was bubbled through this flask for 1 hour. The dioxane solution was then transferred via cannula to the flask containing compound 1, palladium, and ligand. The reaction mixture was heated to 100°C for 1 hour. The reaction was then cooled to 35°C and diluted with ethyl acetate (250 mL) and 1.0 M HCl (250 mL). The biphasic mixture was stirred for 10 minutes, and the phases were separated. The organic solution was removed from the reactor, and the aqueous phase was returned. Ethyl acetate (150 mL) was added to the aqueous phase, and the mixture was stirred for 10 minutes. The aqueous layer was drained from the reaction, and the original ethyl acetate was returned to the reactor. This combined mixture was washed with a 5% N-acetylcysteine / 8% sodium bicarbonate mixture (two 10-minute washes with stirring). After separating the aqueous effluent from each wash, the yellow organic solution was filtered through Celite® diatomaceous earth. Karl Fischer titration of the organic reaction mixture indicated a water content of 3.3 wt%. The yellow organic solution was returned to the reactor, and sodium bisulfite (18.67 g, 179 mmol) was added with stirring. The reaction mixture was heated to 40°C for 13 hours. The precipitate was then filtered and the solid was washed with ethyl acetate (100 mL x 3) to give a white solid in 64.2% yield, the titer of which was confirmed to be 60.0% by Q-NMR spectroscopy. 1H NMR (400MHz, D2O, 1:1 diastereomer): δppm7.48-7.36(m, 5H), 6.92(m, 1H), 6.86(dd, J=8.0, 4.0Hz, 1H), 6.76(dd, J=8.0, 4.0Hz, 1H), 5.21-5.19(m, 2H), 4.2 7-4.25(m, 1H), 3.10-3.05(m, 0.5H), 2.68-2.63(m, 0.5H), 2.52-2.49(m, 0. 5H), 2.38-2.16(m, 1.5H), 0.94(d, J=8.0Hz, 1.5H), 0.84(d, J=8.0Hz, 1.5H).

[0366] Stage 2a A 500 mL three-necked round-bottom flask equipped with a thermocouple and overhead stirrer was charged with compound 3 (15.05 g, 63.3 wt%, 23.2 mol), sodium bicarbonate (16.97 g, 202 mmol), water (155 mL), and ethyl acetate (140 mL). The resulting biphasic suspension was vigorously stirred at 25 °C. After complete consumption of the starting material, the reaction was transferred to a separatory funnel and the layers were separated. The organic layer was washed with brine (75 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give compound 2 as a white solid (6.22 g, 62.9%). 1 H NMR (400MHz, CDCl3): δppm9.68(d, J=2.0Hz, 1H), 7.46-7.32(m, 5H), 6.86(d, J=8.0Hz, 1H), 6.73(d, J=1.6Hz, 1H), 6.68(dd, J=8.0, 1.6H z, 1H), 5.58(s, 1H), 5.08(s, 2H), 2.98(dd, J=13.6, 6.0Hz, 1H), 2.65-2.56(m, 1H), 2.53(dd, J=13.6, 8.0Hz, 1H), 1.05(d, J=6.8Hz, 3H).

[0367] Stage 2b To a 250 mL three-neck flask equipped with a thermocouple and overhead stirrer was added compound 2 (6.29 g, 23.22 mmol) followed by acetonitrile (63 mL). Tetrabenzyl pyrophosphate (13.54 g, 24.38 mmol) was then added at 25 °C. The reaction was cooled to 2.1 °C in an ice bath, and DBU (4.55 mL, 30.2 mmol) was added dropwise to the reaction mixture. The resulting solution was stirred at 2 °C. After complete consumption of the starting material, the reaction was diluted with water (65 mL) and extracted with MTBE (130 mL). The combined organic layers were washed with water (65 mL), 5% sodium chloride solution (30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude compound 4 (11.38 g, 92.4%) as a yellow oil. 1 H NMR (400MHz, CDCl3): δppm9.75 (d, J=1.2Hz, 1H), 7.46-7.42 (m, 2H), 7.36-7.23 (m, 13H), 7.17(dd, J=8.0, 1.2Hz, 1H), 6.81(dd, J=2.0, 1.2Hz, 1H), 6.72(dd, J= 8.0, 2.0Hz, 1H), 5.11(s, 2H), 5.10(s, 2H), 5.07(s, 2H), 3.05(dd, J=13.6, 5.6, Hz, 1H), 2.69-2.59(m, 1H), 2.56(dd, J=13.6, 8.0Hz, 1H), 1.09(d, J=7.2Hz, 3H).

[0368] Stage 3 A 500 mL three-necked round-bottom flask equipped with a thermocouple was charged with (R)-5-(pyrrolidin-2-yl)-1H-tetrazole (0.15 g, 1.07 mmol) and acetonitrile (40 mL). TFA (0.084 mL, 1.07 mmol) was added, followed by (E)-dibenzyldiazene-1,2-dicarboxylate (8.25 g, 27.7 mmol). Next, a solution of compound 4 (11.4 g, 21.49 mmol) in acetonitrile (70 mL) was added via cannula. The resulting solution was stirred at 25 °C. After complete consumption of the starting material, the reaction mixture was diluted with acetonitrile (88 mL), and water (58 mL) was added to precipitate the product. The resulting slurry was stirred overnight at 25 °C, filtered, and washed with 28 wt% water / acetonitrile (30 mL) to give compound 5 (8.9 g, 50% yield) as a white solid. 1 H NMR (400MHz, CDCl3): δppm9.72(s, 1H), 7.42-7.17(m, 25H), 7.09-7.05(m, 1H), 6.67-6.34(m, 2H ), 5.80 (bs, 1H), 5.30-4.80 (m, 10H), 3.39-3.21 (m, 1H), 2.92-2.77 (m, 1H), 1.14-1.00 (bs, 3H).

[0369] Stage 4 A 100 mL three-necked round-bottom flask equipped with a thermocouple was charged with compound 5 (5.10 g, 6.15 mmol), acetonitrile (50.0 mL), and dimethyl sulfoxide (DMSO) (1.00 mL, 14.1 mmol). The resulting white suspension was stirred, and 2.0 mL of aqueous sodium dihydrogen phosphate monohydrate (1.78 g, 12.90 mmol) was prepared and added to the reaction mixture. Following this addition, 2.0 mL of aqueous sodium chlorite (2.88 g (80 wt%), 25.5 mmol) was added dropwise over 90 seconds. The cloudy reaction mixture turned bright yellow and then deeper yellow, becoming more transparent as the reaction proceeded. After 90 minutes, the reaction was quenched with 6.0 mL of aqueous sodium sulfite (1.60 g, 12.7 mmol). The reaction mixture was stirred for 20 minutes after the sulfite addition. The reaction mixture was then poured into a separatory funnel, and the round-bottom flask was washed with 50 mL of isopropyl acetate and 50 mL of water. The aqueous and organic layers were separated. The organic layer was washed with 50 mL of water. Shaking the layers resulted in the formation of an emulsion. At this point, 20 mL of brine was added, and once the emulsion disappeared, the phases were separated. An additional 50 mL of isopropyl acetate was added to the reaction mixture, and the flask was placed on a rotary evaporator until the reaction mixture appeared cloudy. The total volume of the reaction mixture after distillation was approximately 10 mL. The reaction flask was placed in a refrigerator at 4 °C for 16 hours. The resulting white solid was then collected, washed with 20 mL of isopropyl acetate, and dried under vacuum to obtain compound 6 in 75.0% yield. 1 H NMR (400MHz, CDCl3): δppm7.58-7.14(m, 26H), 7.01-6.84(m, 1H), 6.41-6.29(m , 1H), 5.46-4.64(m, 10H), 3.80-3.49(m, 1H), 3.02-2.94(m, 1H), 1.19(brs, 3H).

[0370] Stage 5 A 1-gallon Parr reactor was charged with 5% dry weight of 5% Pd / C (63.6% HO, 15.0 g), water (182 mL), and 5% wt. aqueous sodium bicarbonate (215 mL). To the aqueous catalyst slurry was added a THF solution (1090 mL) of compound 6 (109 g, 85% titer). The reactor was assembled, inerted with nitrogen, and purged with hydrogen (30 psi purges four times). The reactor was then repressurized to 30 psi with hydrogen. The reactor was vigorously stirred at 25 °C for at least 1 hour. Upon complete reaction conversion, the hydrogen was vented and the reactor was inerted with nitrogen. The biphasic reaction mixture was filtered to remove the catalyst and then washed with water (93 mL). The resulting biphasic reaction mixture was diluted with MTBE (370 mL). The mixture was stirred for 15 minutes and then allowed to settle for 10 minutes. (Note: The product is contained in the aqueous layer.) The layers were separated and the aqueous layer was washed with MTBE (370 mL) as above.

[0371] The solution was acidified to pH 1.9 using a sufficient amount of 6 M aqueous HCl. The aqueous solution was seeded with 0.1 wt % compound 7 to induce nucleation. Isopropanol (1326 mL) was added to the seed slurry and mixed at ambient temperature for at least 5 hours. The slurry was filtered to recover the product, and the liquid was recycled as a wash, if necessary. The wet cake solid was washed with isopropanol (370 mL). The product solid was air-dried on the funnel for 2 hours. 38.5 g of compound 7 as the trihydrate was isolated (97.2% titer-adjusted yield). 1 H NMR (400MHz, D2O): δppm7.21(d, J=8.0Hz), 6.87(d, J=2.0Hz, 1H), 6.77(dd, J= 8.0, 2.0Hz, 1H), 3.19(d, J=16.0Hz, 1H), 3.00(d, J=16.0Hz, 1H), 1.54(s, 3H).

[0372] Example 8: Synthesis of L-Dopa 3'-Phonoxymethyl Ester L-Dopa 3'-phonoxymethyl ester was prepared according to the method shown in Scheme 8 below.

[0373] [ka]

[0374] Specifically, L-dopa 3'-phonoxymethyl ester was prepared according to the method described in steps 1 to 6 below.

[0375] Phase 1 To a solution of 4-(benzyloxy)-4-hydroxybenzaldehyde, compound 1 (10.0 g, 43.8 mmol), in acetonitrile (133 mL) at 25° C. was added di-tert-butyl(chloromethyl)phosphate (12.53 g, 46.0 mmol). The reaction mixture was cooled to 4° C., and DBU (7.67 g, 50.4 mmol) was added. After the addition, the reaction mixture was warmed to room temperature (approximately 20 to 25° C.) and heated to 50° C. for 39 h. After 22 h, the reaction mixture was cooled to room temperature, quenched with water (400 mL), and extracted with MTBE (3×100 mL). The organic layer was washed with saturated sodium bicarbonate solution (150 mL), water (150 mL), saturated sodium chloride solution (150 mL), and concentrated to give compound 2 (19.48 g, 49% purity, 50% yield). The crude product was run on a silica gel column using an ethyl acetate-hexane gradient to give 8.08 g of compound 2 (94% purity, 40% yield). 1 H NMR (400MHz, DMSO-d6) δ9.85(s, 1H), 7.66(dd, J=8.3, 1.9Hz, 1H), 7.63(d, J=2.0Hz, 1H), 7.49 -7.44(m, 2H), 7.43-7.32(m, 4H), 5.65(d, J=12.0Hz, 2H), 5.25(s, 2H), 1.36(d, J=0.6Hz, 18H).

[0376] Phase 2 To a solution of (+ / -)-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester (5.35 g, 16.14 mmol) and 2-(benzyloxy)-5-formylphenoxy)methyl di-tert-butyl phosphate, compound 2, (6.78 g, 14.67 mmol) in DCM (70 mL) was added 1,1,3,3-tetramethylguanidine (TMG) (2.0 g, 17.60 mmol) at 0° C. The resulting reaction mixture was stirred overnight at room temperature. The next day, the reaction mixture was washed three times with 35 mL of water and concentrated to give 13.11 g of crude product. The crude product was then purified by column chromatography on silica gel using an ethyl acetate-hexane gradient to give 7.34 g of compound 3 (81% purity, 62% yield). 1 H NMR (400MHz, DMSO-d6) δ7.50-7.28(m, 13H), 7.21(s, 1H), 7.16(s, 1H), 5.59(d, J=11) .9Hz, 2H), 5.18(s, 2H), 5.09(d, J=12.1Hz, 2H), 3.69(s, 3H), 1.35(d, J=0.5Hz, 18H).

[0377] Stage 3 A 120 mL Parr reactor was charged with methyl 3-(4-(benzyloxy)-3-(((di-tert-butoxyphosphoryl)oxy)methoxy)phenyl)-2-(((benzyloxy)carbonyl)amino)acrylate, compound 3 (7.34 g, 9.07 mmol), and 1,2-bis[(2S,5S)-2,5-diethylphosphorano]benzene(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (0.060 g, 0.091 mmol) and tetrahydrofuran (59.5 mL). The mixture was purged with H, and the reaction mixture was stirred under 100 psi of H at 35 °C for 20 h. After 20 h, the reaction mixture was concentrated and purified by column chromatography on silica gel using an ethyl acetate-hexane gradient to give 5.44 g of compound 4 (76% purity, 69% yield, 98% ee). 1H NMR (400MHz, DMSO-d6) δ7.80(d, J=8.0Hz, 1H), 7.48-7.25(m, 10H), 7.04(d, J=2.1Hz, 1H), 7.01(d, J=8.4Hz, 1H), 6.89(dd, J=8.3, 2.1Hz, 1H), 5.55(dd , J=11.6, 1.6Hz, 2H), 5.08(s, 2H), 4.99(d, J=2.7Hz, 2H), 4.22(ddd, J=9.8, 7.9, 5.2Hz, 1H), ), 3.62(s, 3H), 3.03-2.67(m, 2H), 1.37(d, J=1.2Hz, 18H).

[0378] Stage 4 A 50 mL Parr reactor was charged with 5% Pd / C (JM#9) (0.418 g, 2.311 mmol). (S)-Methyl 3-(4-(benzyloxy)-3-(((di-tert-butoxyphosphoryl)oxy)methoxy)phenyl)-2-(((benzyloxy)carbonyl)amino)propanoate, compound 4 (2.0 g, 2.311 mmol), was dissolved in tetrahydrofuran (15.2 mL). This solution was charged to the reactor and purged with argon and then H. The reaction mixture was stirred under 50 psi of H at room temperature for 1 hour. After 1 hour, the catalyst was filtered off and washed with THF. The solution was concentrated and purified by column chromatography on silica gel using ethyl acetate-methanol to give 1.04 g of compound 4 (95% purity, 98% yield). 1 H NMR (400MHz, DMSO-d6) δ9.13(s, 1H), 6.88(d, J=1.9Hz, 1H), 6.74(d, J=8.1Hz, 1H), 6.71(d, J=2.0Hz, 1H), 5.50 (d, J=11.4Hz, 2H), 3.58(s, 3H), 3.49(t, J=6.6Hz, 1H), 2.81-2.58(m, 2H), 1.70(s, 2H), 1.39(d, J=0.6Hz, 18H).

[0379] Stage 5 To (S)-methyl 2-amino-3-(3-(((di-tert-butoxyphosphoryl)oxy)methoxy)-4-hydroxyphenyl)propanoate, compound 5, (1.04 g, 2.34 mmol) in 10 mL of DCM was added 876 μL (5.0 equiv.) of trifluoroacetic acid dropwise at 5° C. The reaction mixture was stirred at 25° C. until completion. After 60 min, the starting material was consumed and the product came out of the DCM layer. The product, compound 6, was extracted from the DCM layer with 3 mL of water. The aqueous layer was used directly in the next step. LC / MS [M+1]=322.1.

[0380] Stage 6 To (S)-methyl 2-amino-3-(4-hydroxy-3-((phosphonooxy)methoxy)phenyl)propanoate, compound 6, (752 mg, 2.341 mmol) in 4 mL of water at 5° C. was added 2.62 mL of 6N NaOH dropwise over 5 minutes to pH=12.5. The rxn mixture was stirred at 25° C. until completion. After 60 minutes, the reaction mixture was acidified to pH=1.9 with 6N HCl. To this solution was added IPA while maintaining a pH of 1.9 until the product precipitated. The product, compound 7, was filtered and washed with IPA to give 630 mg of 90% purity. 1 H NMR (400MHz, heavy water) δ7.17(d, J=1.8Hz, 1H), 6.99-6.96(m, 1H), 6.94(dd, J=8.3, 1.8 Hz, 1H), 5.57(d, J=12.6Hz, 2H), 4.16(dd, J=7.9, 5.1Hz, 1H), 3.33-3.05(m, 2H).

[0381] Example 9: Synthesis of L-Dopa 4'-Phonoxymethyl Ester L-Dopa 4'-phonoxymethyl ester was prepared according to the method shown in Scheme 9 below.

[0382] [ka]

[0383] Specifically, L-dopa 4'-phonoxymethyl ester was prepared according to the method described in steps 1 to 6 below.

[0384] Phase 1 To a solution of 3-(benzyloxy)-4-hydroxybenzaldehyde, compound 1 (10.0 g, 43.8 mmol), in acetonitrile (133 mL) at 25° C. was added di-tert-butyl(chloromethyl)phosphate (12.53 g, 46.0 mmol). The reaction mixture was cooled to 4° C., and DBU (7.67 g, 50.4 mmol) was added. After the addition, the reaction mixture was warmed to room temperature (approximately 20 to 25° C.) and then heated to 50° C. for 22 hours. After 22 hours, the reaction mixture was cooled to room temperature, quenched with water (400 mL), and extracted with MTBE (3×100 mL). The organic layer was washed with saturated sodium bicarbonate solution (150 mL), water (150 mL), saturated sodium chloride solution (150 mL), and concentrated to give compound 2 (20.0 g, 70% purity, 73% yield). The crude product was passed through a silica gel column with an ethyl acetate-hexane gradient to give 8.77 g of compound 2 (91% purity, 41% yield). 1 H NMR (400MHz, DMSO-d6) δ9.87 (s, 1H), 7.59 (d, J=7.0Hz, 2H), 7.49-7.45 (m, 2H), 7.43-7.31(m, 4H), 5.72(d, J=12.7Hz, 2H), 5.20(s, 2H), 1.37(d, J=0.6Hz, 18H).

[0385] Phase 2 To a solution of (+ / -)-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester (5.51 g, 16.64 mmol) and (2-(benzyloxy)-4-formylphenoxy)methyl di-tert-butyl phosphate, compound 2, (7.49 g, 15.13 mmol) in DCM (75 mL) was added 1,1,3,3-tetramethylguanidine (2.09 g, 18.16 mmol) at 0° C. The resulting reaction mixture was stirred overnight at room temperature. The next day, the reaction mixture was washed three times with 35 mL of water and concentrated to give 13.11 g of crude product. The crude product was purified by column chromatography on silica gel using an ethyl acetate-hexane gradient to give 8.37 g of compound 3 (85% purity, 72% yield). 1 H NMR (400MHz, DMSO-d6) δ7.54(d, J=2.0Hz, 1H), 7.50-7.21(m, 13H), 7.16(d, J=8.5Hz, 1H ), 5.63(d, J=12.1Hz, 2H), 5.09(d, J=19.1Hz, 4H), 3.71(s, 3H), 1.37(d, J=0.5Hz, 18H).

[0386] Stage 3 A 120 mL Parr reactor was charged with methyl 3-(3-(benzyloxy)-4-(((di-tert-butoxyphosphoryl)oxy)methoxy)phenyl)-2-(((benzyloxy)carbonyl)amino)acrylate (8.37 g, 10.85 mmol), 1,2-bis[(2S,5S)-2,5-diethylphosphorano]benzene(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (0.072 g, 0.109 mmol), and tetrahydrofuran (70.5 mL). The mixture was purged with H, and the reaction mixture was stirred at 35 °C under 100 psi of H for 20 h. After 20 h, the reaction mixture was concentrated and purified by column chromatography on silica gel using an ethyl acetate-hexane gradient to give 6.34 g of compound 4 (78% purity, 69% yield, 97% ee). 1H NMR (400MHz, DMSO-d6) δ7.80(d, J=8.1Hz, 1H), 7.54-7.22(m, 10H), 7.12-6.97(m, 2H), 6.80(dd, J=8.2, 2.0Hz, 1H), 5.54(d, J =11.3Hz, 2H), 5.13-4.90(m, 4H), 4.25(ddd, J=10.1, 8.1, 5.0Hz, 1H), 3.62(s, 3H), 3.04-2.73(m, 2H), 1.35(d, J=0.5Hz, 18H).

[0387] Stage 4 A 50 mL Parr reactor was charged with 5% Pd / C (JM#9) (0.429 g, 2.372 mmol). (S)-Methyl 3-(3-(benzyloxy)-4-(((di-tert-butoxyphosphoryl)oxy)methoxy)phenyl)-2-(((benzyloxy)carbonyl)amino)propanoate, compound 4 (2.0 g, 2.372 mmol), was dissolved in tetrahydrofuran (THF) (15.6 mL). This solution was charged to the reactor and purged with argon and then H. The reaction mixture was stirred under 50 psi of H at room temperature for 1 hour. After 1 hour, the catalyst was filtered off and washed with THF. The solution was concentrated and purified by column chromatography on silica gel using ethyl acetate-methanol to give 1.08 g of compound 4 (94% purity, 99% yield). 1 H NMR (400MHz, DMSO-d6) δ9.20(s, 1H), 6.95(d, J=8.2Hz, 1H), 6.66(d, J=2.1Hz, 1H), 6.54(dd, J=8.2, 2.1Hz, 1H), 5. 49(d, J=11.3Hz, 2H), 3.57(s, 3H), 3.50(t, J=6.6Hz, 1H), 2.79-2.59(m, 2H), 1.72(2, 2H), 1.38(d, J=0.5Hz, 18H).

[0388] Stage 5 To (S)-methyl 2-amino-3-(4-(((di-tert-butoxyphosphoryl)oxy)methoxy)-3-hydroxyphenyl)propanoate, compound 5, (1.08 g, 2.34 mmol) in 11 mL of DCM was added 901 μL (5.0 equiv.) of trifluoroacetic acid dropwise at 5° C. The rxn mixture was stirred at 25° C. until completion. After 60 min, the starting material was consumed and the product came out of the DCM layer. The product, compound 6, was extracted from the DCM layer with 3 mL of water. The aqueous layer was used directly in the next step. LC / MS [M+1]=322.1.

[0389] Stage 6 To (S)-methyl 2-amino-3-(3-hydroxy-4-((phosphonooxy)methoxy)phenyl)propanoate, compound 6, (752 mg, 2.341 mmol) in 3 mL of water at 5° C. was added 6 N NaOH dropwise over 5 minutes to pH=12.5. The rxn mixture was stirred at 25° C. until completion. After 60 minutes, the reaction mixture was acidified to pH=1.9 with 6 N HCl. To this solution was added IPA, maintaining the pH at 1.9, until the product precipitated. The product, compound 7, was filtered and washed with IPA to give 850 mg, which was 88% pure. 1 H NMR (400MHz, heavy water) δ7.09(dd, J=8.2, 0.7Hz, 1H), 6.76(d, J=2.1Hz, 1H), 6.73(dt, J=8 .3, 1.3Hz, 1H), 5.43(dd, J=12.6, 0.7Hz, 2H), 4.08-3.97(m, 1H), 3.21-2.89(m, 2H).

[0390] Example 10: Synthesis of carbidopa 3'-phonoxymethyl ester and carbidopa 4'-phonoxymethyl ester Carbidopa 3'-phonoxymethyl ester and carbidopa 4'-phonoxymethyl ester were prepared according to the method shown in Scheme 10 below.

[0391] [ka]

[0392] Specifically, carbidopa 3'-phonoxymethyl ester and carbidopa 4'-phonoxymethyl ester were prepared according to the methods described in steps 1 to 3 below.

[0393] Step 1: Preparation of -(S)-benzyl 2-benzyl-2-(1-(benzyloxy)-3-(3-(benzyloxy)-4-hydroxyphenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate (mixture of 3' and 4') (Compound 2) A 500 mL round-bottom flask was charged with (S)-2-(2-((benzyloxy)carbonyl)hydrazinyl)-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid and tetrahydrofuran (1:1), compound 1 (10 g, 84 wt%, 19.42 mmol), and 100 mL of DMF. Cesium carbonate (11.39 g, 35 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. The mixture was cooled in an ice bath. Benzyl bromide (7.38 mL, 62.2 mmol) was added in small portions. The mixture was stirred in an ice bath overnight. The slurry was filtered, and the cake was washed with methyl t-butyl ether. The filtrate was combined with water, and the layers were separated. The aqueous layer was extracted with methyl t-butyl ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by flash chromatography using a 220 g silica column (0% to 30% ethyl acetate / heptane) to give compound 2 as a colorless viscous oil (1.20 g, 9.8%).

[0394] MS(ESI+)631.1.

[0395] Step 2 Preparation of -(S)-benzyl 2-benzyl-2-(1-(benzyloxy)-3-(3-(benzyloxy)-4-(((bis(benzyloxy)phosphoryl)oxy)methoxy)phenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate (mixture of 3' and 4') (Compound 3) A 100 mL round-bottom flask was charged with dibenzyl(chloromethyl)phosphate (1.632 g, 4.99 mmol), (S)-benzyl 2-benzyl-2-(1-(benzyloxy)-3-(3-(benzyloxy)-4-hydroxyphenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate, compound 2, (2.1 g, 3.33 mmol), and 25 mL of acetonitrile. The mixture was cooled in an ice bath. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.745 mL, 4.99 mmol) was added, and the mixture was stirred in an ice bath for 30 minutes and then at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified first by flash chromatography using a 120 g silica column (0% to 50% ethyl acetate / heptane) and then by RP-HPLC (60% to 100% acetonitrile / 0.1% TFA / water on a Phenonemex C18 5μ column) to give compound 3 as a colorless oil (247 mg, 8%).

[0396] LC / MS(APCI+) m / z=921.2(M+H).

[0397] Step 3 Preparation of (S)-2-hydrazinyl-3-(3-hydroxy-4-((phosphonooxy)methoxy)phenyl)-2-methylpropanoic acid (Compound 4) and (S)-2-hydrazinyl-3-(4-hydroxy-3-((phosphonooxy)methoxy)phenyl)-2-methylpropanoic acid (Compound 5) In a 50 mL pressure bottle, (S)-benzyl 2-benzyl-2-(1-(benzyloxy)-3-(3-(benzyloxy)-4-(((bis(benzyloxy)phosphoryl)oxy)methoxy)phenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate, compound 3 (240 mg, 0.261 mmol), 10 mL of tetrahydrofuran, and 5 mL of water were added to 20% Pd(OH)2 / C, wet (50 mg, 0.036 mmol). The mixture was stirred at 50 psi and room temperature for 1 hour. The reaction mixture was filtered. The filtrate was combined with water and extracted twice with methyl t-butyl ether. The aqueous phase was dried using a freeze dryer. The concentrate was purified by RP-HPLC (Kromacil Phenyl 3.0 cm i.d. × 25 cm, 5 μ column, 0% to 10% [0.1% formic acid / acetonitrile] / [0.1% formic acid / water]). Two isomers were separated. The collected fractions were combined and dried using a lyophilizer to give Compounds 4 and 5, respectively, as loose white solids.

[0398] Compound 4 (16.5mg, 16.1%): 1 H NMR (501MHz, DMSO-d6) δ6.94(d, J=8.1Hz, 1H), 6.62(d, J=2.1Hz, 1H), 6.54(dd, J=8.1, 2.1H z, 1H), 5.28(d, J=14.6Hz, 2H), 2.86(d, J=13.6Hz, 1H), 2.78(d, J=13.6Hz, 1H), 1.26(s, 3H). MS(ESI+)337.0.

[0399] Compound 5 (30.9mg, 30.2%): 1 H NMR (400MHz, DMSO-d6) δ7.00(s, 1H), 6.68(m, 2H), 5.32(m, 2H), 2.91-2.77(m, 2H), 1.26(s, 3H). MS(ESI+)337.0.

[0400] Example 11: Synthesis of carbidopa 4'-monophosphate methyl ester Carbidopa 4'-monophosphate methyl ester was prepared according to the method shown in Scheme 11 below.

[0401] [ka]

[0402] Phase 1 A 100 mL round-bottom flask was charged with (S)-3-(3-(benzyloxy)-4-((bis(benzyloxy)phosphoryl)oxy)phenyl)-2-(1,2-bis((benzyloxy)carbonyl)hydrazinyl)-2-methylpropanoic acid (3.03 g, 3.59 mmol) (1), DCC (0.889 g, 4.31 mmol), 25 mL of methanol, and a stir bar. To this stirred mixture was added 4-(dimethylamino)pyridine (88 mg, 0.720 mmol) in one portion, and the reaction was stirred for an additional 48 h. After this time, the solvent was removed by rotary evaporation to give a light yellow residue. The residue was suspended in acetonitrile (40 mL) and stirred at 5 °C for 2 h. The suspension was filtered through a pad of silica gel, eluting with 400 mL of acetonitrile. Removal of the acetonitrile on a rotary evaporator gave a 94% yield of a pale yellow oil which was used directly in the next step. LC / MS [M+H]: 859.40.

[0403] Phase 2 A 150 mL Parr reactor was charged with 5% Pd / C (0.794 mg, 3.36 mmol). The catalyst was slurried with water (4.83 mL) and 5 wt% aqueous sodium bicarbonate (5.61 mL, 3.36 mmol). To this slurry was added a solution of (S)-dibenzyl 1-(3-(3-(benzyloxy)-4-((bis(benzyloxy)phosphoryl)oxy)phenyl)-1-methoxy-2-methyl-1-oxopropan-2-yl)hydrazine-1,2-dicarboxylate (2.89 g, 3.36 mmol) (2) in tetrahydrofuran (29 mL). The reactor was sealed and purged with argon (4 times at 40 psi) and then H2 (4 times at 50 psi). The reactor was then repressurized with 50 psi H2 and stirred at ambient temperature for 60 min. The biphasic reaction mixture was then filtered through Celite® diatomaceous earth, washed with water (2.2 mL), and the residue in the reactor was filtered. The resulting biphasic mixture was diluted with MTBE (8 mL), stirred for 5 minutes, and poured into a separatory funnel. The aqueous layer was separated and washed with DCM (30 mL x 3). The aqueous layer was collected and dried on a lyophilizer to give compound 3 as an off-white solid in 68% yield. 1 H NMR (400MHz, D2O): δ1.46(s, 3H), 2.92(d, J=12Hz, 1H), 3.05(d, J=12Hz, 1H), 3.79(s, 3H), 6.65-6.72(m, 2H), 7.11(d, J=8.0Hz, 1H).

[0404] Example 12: Phosphate Prodrug Stability Test 1-day stability test L-dopa phosphate prodrugs and carbidopa phosphate prodrugs were evaluated in a stability study. Aqueous solutions of the prodrugs (80 μg / mL) were monitored over a wide range of pH values at ambient storage conditions throughout the day to demonstrate the feasibility of administration over the course of an infusion. Table 12-A below reports the results of this study, which confirm that the prodrugs have good stability at room temperature over a one-day period.

[0405] [Table 1]

[0406] Additionally, a combined diphosphate solution of each compound (35 mg / mL L-dopa 3',4'-diphosphate and 8.7 mg / mL carbidopa 3',4'-diphosphate) was monitored over a one-day period at room temperature. The sample was purged with nitrogen to remove oxygen. Table 12-B below reports the results of this study, confirming good stability for the combined solution purged with nitrogen at room temperature over a one-day period.

[0407] [Table 2]

[0408] 7-day stability test Additionally, a combined solution of 200 mg / mL L-dopa 4'-monophosphate and 50 mg / mL carbidopa 4'-monophosphate was monitored over a 7-day period at room temperature. These samples were prepared with and without nitrogen purging to remove oxygen. Table 12-C below reports the results of this study, confirming good stability for the combined solution over a 7-day period at room temperature.

[0409] [Table 3]

[0410] Example 13: Phosphate Prodrug Solution Testing L-dopa phosphate prodrugs and carbidopa phosphate prodrugs were evaluated in a solubility test. The aqueous solubility values of the phosphate prodrugs under ambient conditions were determined by visual evaluation. Table 13-A reports the results of this test and includes measurements for L-dopa and carbidopa.

[0411] [Table 4]

[0412] FIG. 1 shows the higher solubility of L-dopa 4′-monophosphate and carbidopa 4′-monophosphate compared to L-dopa and carbidopa.

[0413] Example 14: Hydrazine Release Test Solutions combining 50 mg / mL L-dopa 4'-monophosphate and 12.5 mg / mL carbidopa 4'-monophosphate were monitored for hydrazine release over a 7-day period. These solutions were prepared at pH 5 to 8, purged with nitrogen to remove oxygen, and kept at room temperature. As shown in Figure 2, a significant drop in hydrazine release was observed at a pH of approximately 7.4. For comparison, the amount of hydrazine released from Duopa® was also measured. Unexpectedly, as shown in Figure 3, a 4:1 ratio L-dopa 4'-monophosphate and carbidopa 4'-monophosphate solution at a pH of approximately 7.4 exhibited significantly lower hydrazine release compared to Duopa®.

[0414] Example 15: In vitro biotransformation studies The in vitro bioconversion of L-dopa phosphate prodrugs to L-dopa and carbidopa phosphate prodrugs to carbidopa was evaluated in several studies. Specifically, L-dopa and carbidopa phosphate prodrugs (2.5 μg / mL) were incubated with tissue homogenates or fractions from rats, minipigs, or humans, such as blood, skin homogenate (3 mg / mL), liver microsomes (1 mg / mL), liver S9 fraction (1 mg / mL), kidney S9 fraction (1 mg / mL), and intestinal S9 fraction (1 mg / mL). The reaction mixtures were incubated at 37°C for 5 to 6 time points within 1 to 2 hours. After each time point, the reaction mixtures were quenched with 2 to 3 volumes of 5% aqueous trichloroacetic acid. After quenching, the mixtures were centrifuged at 3000 rpm for 20 minutes, and the supernatants were analyzed by LC-MS for quantification of the prodrugs, L-dopa or carbidopa. In vitro biotransformation was assessed by monitoring both the time-dependent depletion of the prodrug and the formation of the corresponding L-dopa or carbidopa.

[0415] Table 15-A below reports the results of studies in blood. In blood, all four monophosphate prodrugs were rapidly dephosphorylated in rats, minipigs, and humans, with corresponding time-dependent formation of L-dopa or carbidopa. Generally, t 1 / 2 The diphosphate prodrugs of carbidopa and L-dopa also have the shortest t in rat blood, respectively. 1 / 2 Dephosphorylation of the diphosphate prodrug of L-dopa was relatively slow in human and minipig blood, with corresponding formation of L-dopa or carbidopa at 53 and 6 min, respectively. 1 / 2 The time-dependent formation of L-dopa was observed in both the minipig and human blood incubations, at 138 and 125 minutes, respectively. However, the diphosphate prodrug of carbidopa was not dephosphorylated in the minipig and human blood. No formation of carbidopa was observed in the blood incubations.

[0416] [Table 5]

[0417] Table 15-B below reports the results of tests in skin homogenates. In skin homogenates, the four monophosphate prodrugs slowly dephosphorylated, resulting in t 1 / 2 The time to release ranged from 114 to 992 minutes, with the corresponding formation of L-dopa or carbidopa. The two diphosphate prodrugs were stable in rat, minipig, and human skin homogenates. No L-dopa or carbidopa formation was observed upon incubation.

[0418] [Table 6]

[0419] In human liver microsomes, the four prodrugs (3'-phosphate and diphosphate prodrugs of L-dopa and 4'-phosphate and diphosphate prodrugs of carbidopa) were stable, and no formation of L-dopa or carbidopa was observed.

[0420] In the liver S9 fractions of rats, minipigs, and humans, the four prodrugs (4'-phosphate and diphosphate prodrugs of L-dopa and 4'-phosphate and diphosphate prodrugs of carbidopa) were stable, and no formation of L-dopa or carbidopa was observed.

[0421] In rat and human kidney S9 fractions, the four prodrugs (4'-phosphate and diphosphate prodrugs of L-dopa and 4'-phosphate and diphosphate prodrugs of carbidopa) were stable, and no formation of L-dopa or carbidopa was observed.

[0422] Table 14-C below reports the results of studies in intestinal S9 fractions. Four prodrugs (4'-phosphate and diphosphate prodrugs of L-dopa and 4'-phosphate and diphosphate prodrugs of carbidopa) were rapidly dephosphorylated in rat and human intestinal S9 fractions. 1 / 2 appeared to be shorter in human intestinal S9 than in rat intestinal S9. Time-dependent formation of the corresponding L-dopa or carbidopa was observed upon incubation of the prodrug with rat or human intestinal S9 fractions. The results suggest that phosphatase activity is high in rat and human small intestine.

[0423] [Table 7]

[0424] Example 16: Pharmacokinetic study in rats The in vivo conversion of the L-dopa phosphate prodrug to L-dopa and the carbidopa phosphate prodrug to carbidopa was evaluated in rat pharmacokinetic studies in which the prodrugs were administered intravenously or subcutaneously to rats. For comparison, rat pharmacokinetic studies using L-dopa and carbidopa were also conducted to assess in vivo conversion to the prodrugs. The study design and measured exposures for L-dopa and carbidopa are summarized in Tables 16-A and 16-B, respectively. Groups of three male Sprague-Dawley rats were administered either intravenously or subcutaneously with (1) aqueous solutions of L-dopa and carbidopa, or (2) aqueous solutions of the individual prodrugs. Blood was collected at multiple time points over a 24-hour period into collection tubes containing NaAsO4, EDTA, and ascorbic acid. Plasma was separated from the blood and protein precipitated with 2 to 3 volumes of 5% aqueous trichloroacetic acid followed by centrifugation. The supernatant was subjected to LC-MS analysis for quantification of the prodrug, L-dopa or carbidopa.

[0425] [Table 8]

[0426] [Table 9]

[0427] By comparing the in vivo exposure of L-dopa or carbidopa resulting from administration of the prodrug with that resulting from administration of L-dopa or carbidopa alone, the in vivo conversion of the prodrug to its corresponding L-dopa or carbidopa was estimated to be greater than 66%.

[0428] Example 17: L-dopa diphosphate / carbidopa diphosphate ratio test The effect of various dose ratios of carbidopa diphosphate:L-dopa diphosphate on steady-state L-dopa levels was evaluated in a rat pharmacokinetic study. In the study, rats were subcutaneously infused with an aqueous solution of a combination of L-dopa diphosphate (fixed dose) and carbidopa diphosphate (various doses) for 16 hours. Specifically, groups of three male Sprague-Dawley rats were administered combinations of L-dopa diphosphate and carbidopa diphosphate with different dose ratios. Table 17-A provides a summary of the study design. Rats were first administered a subcutaneous bolus dose over 1 minute at a dose volume of 1 mL / kg. 1.5 hours later, a continuous infusion dose was administered over the next 14.5 hours at a dose volume of 10 mL / kg. Blood samples were collected at 0.25, 0.5, 1, 6, 16, and 20 hours after bolus administration. Blood samples were processed in the same manner as described in Example 16. A separate aliquot of blood was collected for hydrazine measurement.

[0429] [Table 10]

[0430] Both L-dopa and carbidopa levels were well maintained over the 1- to 16-hour continuous infusion period in each dose group. Figure 4 provides time-concentration profiles for L-dopa blood levels after administration of the diphosphate prodrug combination at different ratios. Figure 5 provides time-concentration profiles for carbidopa blood levels after administration of the diphosphate prodrug combination at different ratios.

[0431] Table 17-B below reports the measured steady-state blood levels of L-dopa ("LD") and carbidopa ("CD"). Figure 6 shows a graphical representation of the same data. The ratio of L-dopa diphosphate:carbidopa phosphate significantly affected the steady-state levels of L-dopa. For example, after administration of L-dopa diphosphate alone, the mean plasma concentration of L-dopa (C) at 6 hours was 0.05. 6hWhen the combination of L-dopa diphosphate and carbidopa diphosphate was administered at a dose ratio of 50:1, the mean plasma concentration of L-dopa at 6 hours (C 6h ) increased to 0.55 μg / mL. When the combination of L-dopa diphosphate and carbidopa diphosphate was administered at a dose ratio of 1:1, the mean plasma concentration of L-dopa at 6 hours (C 6h ) further increased to 1.47 μg / mL. In all groups, hydrazine levels were below the limit of quantification (0.5 ng / mL).

[0432] [Table 11]

[0433] Example 18: L-dopa 4'-monophosphate / carbidopa 4'-monophosphate pharmacokinetic study in rats The effect of a 4:1 ratio of L-dopa 4'-monophosphate:carbidopa 4'-phosphate on steady-state levels of L-dopa was evaluated in a rat pharmacokinetic study.

[0434] 16-hour subcutaneous infusion In this study, rats were first administered an aqueous combination of L-dopa 4'-monophosphate and carbidopa 4'-monophosphate in a 4:1 ratio via subcutaneous bolus at a dose of 60 / 14 mg / kg over 1 minute. 1.5 hours later, the combination was administered again via continuous infusion at a dose of 300 / 71 mg / kg over the next 14.5 hours. Blood samples were collected at 1, 0.25, 1, 6, 16, and 24 hours after administration. Blood samples were processed in the same manner as described in Example 15. Separate aliquots of blood were collected for hydrazine determination. Figure 7 provides time-concentration profiles for L-dopa and L-dopa 4'-monophosphate blood levels after administration of the 4'-monophosphate prodrug combination in a 4:1 ratio. As shown in Figure 7, continuous subcutaneous infusion of 4:1 L-dopa 4'-monophosphate and carbidopa 4'-monophosphate delivered high systemic levels of L-dopa (e.g., approximately 10 μg / mL), which met and / or exceeded the plasma levels achieved with Duopa® (e.g., approximately 3 μg / mL) shown in Figure 8. A steady-state concentration of approximately 1 μg / mL was maintained throughout the carbidopa infusion period. Residual L-dopa 4'-monophosphate and carbidopa 4'-monophosphate exposures were approximately 22% and approximately 8% of those of levodopa and carbidopa, respectively. The doses were well tolerated in rats, and no hydrazine was detected in rat plasma samples. Figure 9 provides time-concentration profiles for carbidopa and carbidopa 4'-monophosphate blood levels after administration of a 4:1 ratio of 4'-monophosphate prodrug combinations.

[0435] 24-hour subcutaneous infusion for 7 days In this study, rats were given a 24-hour subcutaneous infusion of an aqueous solution of a 4:1 dose ratio combination of L-dopa (LD) 4'-monophosphate and carbidopa (CD) 4'-monophosphate for 7 days. Table 18-A below reports the measured steady-state concentrations of levodopa at various doses of a 4:1 ratio of L-dopa 4'-monophosphate and carbidopa 4'-monophosphate.

[0436] [Table 12]

[0437] Example 19: Pharmacokinetic study of L-dopa diphosphate and carbidopa diphosphate in minipigs The in vivo conversion of carbidopa diphosphate to carbidopa was evaluated in a minipig pharmacokinetic study in which the prodrug was administered subcutaneously in aqueous solution to groups of three minipig. For comparison, a pharmacokinetic study with carbidopa was also conducted to help evaluate the in vivo conversion of the carbidopa prodrug. Table 19-A reports the measured carbidopa exposure. The estimated in vivo conversion of carbidopa diphosphate to carbidopa was approximately 100% based on carbidopa exposure.

[0438] [Table 13]

[0439] The effects of various dose ratios of carbidopa diphosphate:L-dopa diphosphate on steady-state L-dopa levels were evaluated in a minipig pharmacokinetic study. In this study, minipigs received a 16-hour subcutaneous infusion of an aqueous solution of L-dopa diphosphate and carbidopa diphosphate combinations at the designated dose ratios. A washout period was followed by each dose ratio. The study design is summarized in Table 19-B below and was similar to the design of the previously described rat study, except that there was no initial subcutaneous bolus dose. Blood samples were collected 1, 2, 4, 6, 8, 10, 14, 16, and 24 hours after dosing. Blood samples were processed in the same manner as described in Example 12. A separate blood aliquot was collected for dopamine measurements.

[0440] [Table 14]

[0441] Figure 10 provides time-concentration profiles for L-dopa blood levels after administration of different ratios of the diphosphate prodrug combination. No dopamine was detected in the minipig plasma samples.

[0442] Example 20: 15:1 L-dopa 4'-monophosphate / carbidopa 4'-monophosphate pharmacokinetic study in minipigs The effect of a 15:1 ratio of L-dopa 4'-monophosphate:carbidopa 4'-phosphate on steady-state levels of L-dopa was evaluated in a minipig pharmacokinetic study.

[0443] In this study, pigs received a 16-hour subcutaneous infusion of an aqueous solution of a combination of L-dopa 4'-monophosphate and carbidopa 4'-monophosphate in a 15:1 dose ratio without an initial bolus dose. The doses were 48 mg / kg L-dopa 4'-monophosphate and 3.2 mg / kg carbidopa 4'-monophosphate, respectively. Blood samples were collected at 1, 3, 6, 8, 10, 14, and 24 hours post-dose. Blood samples were processed in the same manner as described in Example 12. Separate aliquots of blood were collected for hydrazine determination. Table 20-A summarizes the measured exposures of L-dopa 4'-monophosphate and L-dopa in minipigs.

[0444] [Table 15]

[0445] Figure 11 provides time-concentration profiles for L-dopa and L-dopa 4'-monophosphate blood levels after administration of a 15:1 ratio combination of 4'-monophosphate prodrugs. As shown in Figure 11, continuous subcutaneous infusion of 15:1 L-dopa 4'-monophosphate and carbidopa 4'-phosphate delivered high systemic levels of L-dopa (e.g., approximately 5.5 μg / mL) that met and / or exceeded the plasma levels achieved with Duopa® (e.g., approximately 3 μg / mL), as shown in Figure 8. Levodopa plasma levels increased over time and approached steady state approximately 10 hours after administration. A steady-state levodopa plasma concentration of approximately 5.5 μg / mL was achieved. Residual L-dopa 4'-monophosphate exposure was approximately 10% of levodopa exposure. Carbidopa plasma concentrations reached steady state approximately 3 hours after administration, with a steady-state concentration of approximately 0.2 μg / mL. Residual carbidopa 4'-monophosphate exposure was approximately 22% of carbidopa exposure. The doses were well tolerated in minipigs, and hydrazine was not detected in minipigs' plasma samples. Figure 12 provides time-concentration profiles for carbidopa and carbidopa 4'-monophosphate blood levels after administration of a 15:1 ratio of the 4'-monophosphate prodrug combination.

[0446] Example 21: L-dopa 4'-monophosphate and carbidopa 4'-monophosphate pharmacokinetic study in dogs In this study, dogs were infused subcutaneously for 24 hours with an aqueous solution of a 4:1 dose ratio combination of L-dopa (LD) 4'-monophosphate and carbidopa (CD) 4'-monophosphate. Table 21-A below reports the measured steady-state concentrations of levodopa (L-dopa) at various doses of a 4:1 ratio of L-dopa 4'-monophosphate and carbidopa 4'-monophosphate. No deaths occurred, and all dogs survived to the end of the study. The LD 4'-monophosphate and carbidopa (CD) 4'-monophosphate drugs were well tolerated. Test article-related clinical signs at 400 / 100 mg / kg consisted of vomiting in both dogs, which occurred early during the dosing period. Clinical pathology findings for levodopa and carbidopa 4'-monophosphate prodrugs consisted of mildly elevated neutrophil and monocyte counts at 400 / 100 mg / kg; mildly decreased triglycerides in animals dosed >200 / 50 mg / kg; mildly elevated bilirubin in animals dosed >200 / 50 mg / kg; elevated urine specific gravity at all doses; and slight increases in the urinary phosphorus:creatinine ratio and fractional excretion of phosphorus at 400 / 100 mg / kg. Conclusions: Administration of L-dopa (LD) 4'-monophosphate and carbidopa (CD) 4'-monophosphate at doses up to 400 / 100 mg / kg produced no adverse findings. This resulted in levodopa concentrations of 18.3 μg / mL and carbidopa concentrations of 2.88 μg / mL.

[0447] [Table 16]

[0448] Example 22: Phosphorus Loading When rats were administered an L-dopa diphosphate / carbidopa diphosphate prodrug composition (i.e., the diphosphate composition), there was an increase in serum phosphate at doses of 300 / 75 mg / kg / day or greater. This increase in serum phosphate did not occur in rats receiving an L-dopa 4'-monophosphate / carbidopa 4'-monophosphate composition (i.e., the monophosphate composition) at doses of 750 / 187.5 mg / kg / day or less.

[0449] Example 23: Safety and Tolerability Local irritation and pain at the injection site were examined.

[0450] Local tolerance: Injection pain was evaluated in rabbits using intravenous, paravenous, and subcutaneous bolus injections of LD / CD diphosphate at a concentration of 200 / 50 mg / mL. There was no evidence of injection site pain or local tissue irritation immediately upon injection or throughout the 24-hour observation period. There were no adverse clinical signs or microscopic findings indicating local intolerance in rats receiving a single SC bolus dose of LD diphosphate at concentrations up to 125 mg / mL or in minipigs receiving subcutaneous infusions of LD / CD diphosphate at 200 / 50 mg / mL over 24 hours.

[0451] In a 7-day SC infusion study in rats, there were no signs of injection site irritation or intolerance with either LD / CD diphosphate or LD / CD monophosphate when infused at 41 / 10 and 75 / 18.75 mg / mL, respectively, for 18 or 24 hours per day. When LD / CD monophosphate (200 / 50 mg / mL) was infused subcutaneously in dogs for 24 hours, there was no obvious macroscopic irritation at the injection site. Cumulative data support a low risk of injection pain and local tissue irritation when infused at the same site over a 24-hour period.

[0452] Rodent toxicity: A 7-day IV infusion toxicity study was conducted with an aqueous solution of L-dopa and carbidopa diphosphate prodrug combination. Sprague-Dawley rats (n=5 / sex / group) were administered doses of 80 / 20, 240 / 60, or 720 / 180 mg / kg for 18 hours per day for 7 consecutive days. Rats in the 720 / 180 mg / kg group exhibited elevated serum phosphorus, but no adverse clinical signs, clinical pathology, or histopathology findings were observed other than weight loss and decreased food consumption. The 720 / 180 mg / kg dose of L-dopa diphosphate and carbidopa diphosphate prodrug resulted in a levodopa plasma concentration of 15.2 μg / mL.

[0453] A 7-day SC infusion toxicity study was also conducted with an aqueous solution of the L-dopa and carbidopa diphosphate prodrug combination. Sprague-Dawley rats (n=5 / sex / group) were administered doses of 100 / 25, 300 / 75, or 750 / 187.5 mg / kg for 18 hours per day for 7 consecutive days. Male rats in the 300 / 75 group and male and female rats in the 750 / 187.5 mg / kg group exhibited elevated serum phosphorus, but no adverse clinical signs, clinical pathology, or histopathology findings were observed, except for weight loss and decreased food consumption. The 750 / 187.5 mg / kg dose resulted in a levodopa plasma concentration of 19.6 μg / mL.

[0454] A 7-day SC infusion toxicity study was also conducted with an aqueous solution of L-dopa and carbidopa mixed monophosphate combination. Male Sprague-Dawley rats (n = 4 or 5 per group) were administered doses of 100 / 25, 300 / 75, or 750 / 187.5 mg / kg 24 hours per day for 7 consecutive days. Rats in the 750 / 187.5 mg / kg group exhibited clinical signs, including aggressive behavior and hyperactivity. These findings were significant enough to affect SC catheter placement and patency, causing some animals to withdraw from the study before completing the full dosing schedule. The mean body weight at the end of the study in the 300 / 75 mg / kg group was -18% lower than at the start of dosing on Day 1. There were no significant effects on serum or urinary phosphate, and no adverse clinical or histopathological findings. Levodopa plasma concentrations were 9.4 μg / mL in the 300 / 75 mg / kg group.

[0455] Example 24: Human predictions of steady-state exposure and daily phosphorus burden for L-dopa and L-dopa 4'-monophosphate, carbidopa and carbidopa 4'-monophosphate Key factors in human prediction include: 1) Linear human pharmacokinetics; 2) biotransformation ratios of the prodrugs in humans estimated by the average biotransformation ratios observed in preclinical animals (0.9 for L-dopa 4′-monophosphate and 0.7 for carbidopa 4′-monophosphate); 3) high bioavailability (F) of the monophosphate prodrugs after subcutaneous (SC) administration (0.75 for L-dopa 4′-monophosphate and 0.65 for carbidopa 4′-monophosphate); 4) Phosphate release from the prodrug is complete after SC administration. The predicted PK parameters for the monophosphate prodrug and active drug are shown in Table 24-A.

[0456] [Table 17]

[0457] Using point estimates, a simulation of a 150 / 38 mg / hour (L-dopa 4'-monophosphate / carbidopa 4'-monophosphate) continuous SC infusion resulted in a levodopa steady-state concentration (Css) of 3000 ng / mL with a phosphorus loading of 427 mg / day, as shown in Table 24-B.

[0458] [Table 18]

[0459] The aqueous solubility of L-dopa 4'-monophosphate can reach values as high as >300 mg / mL. A single 20 mL vial of the daily dose solution would deliver >6000 mg / day of L-dopa 4'-monophosphate, which, assuming linear human pharmacokinetics, would deliver a Css of >5 μg / mL of levodopa.

[0460] Example 25: Preparation of crystalline carbidopa-4'-monophosphate trihydrate A 95 mg sample of amorphous carbidopa-4'-monophosphate was weighed into an 8 mL vial and dissolved in 200 μL of water. After all solids had dissolved, 500 μL of isopropyl alcohol was added. The solution became cloudy after the isopropanol was added. The cloudy suspension was stirred with a magnetic stir bar for 15 minutes at room temperature. Next, 200 μL of IPA was added. The slurry was stirred for 1 hour and filtered. The wet cake was then washed with 1 mL of IPA. The solid was air-dried overnight and analyzed by powder X-ray diffraction (PXRD) the next day. The PXRD pattern for crystalline carbidopa-4'-monophosphate trihydrate is shown in Figure 17.

[0461] Example 26a: Preparation of Crystalline Carbidopa-4'-Monophosphate Dihydrate 420 mg of carbidopa-4'-monophosphate trihydrate was weighed into a 20 mL vial. 8.4 mL of n-butanol was added to the vial, and the contents were stirred overnight at 30°C with a magnetic stir bar. A wet cake sample was isolated and analyzed by PXRD. The PXRD pattern for crystalline carbidopa-4'-monophosphate dihydrate is shown in Figure 18.

[0462] Example 26b: Preparation of Crystalline Carbidopa-4'-Monophosphate Dihydrate 103 mg of amorphous carbidopa-4'-monophosphate was weighed into a 4 mL vial. 200 μL of water was added. After all solids had dissolved, 500 μL of isopropyl alcohol was added, and the solution was stirred at room temperature using a magnetic stir bar. After 30 minutes, solids were observed in the vial. At that time, 200 μL of IPA was added, and the slurry was stirred for an additional 30 minutes. The solid was isolated, and the PXRD pattern of the wet cake was analyzed. The PXRD pattern of the wet cake was consistent with the PXRD pattern shown in Figure 18.

[0463] Example 27: Preparation of crystalline carbidopa-4'-monophosphate dehydrate Approximately 10 mg of carbidopa-4'-monophosphate trihydrate was placed in a tared aluminum pan in a DVS Advantage (Surface Measurement Systems Ltd, Alperton, United Kingdom). The sample was subjected to the following humidity conditions at 25°C: 30-0-90-0-30% relative humidity (RH) in 10% RH intervals. At each step, the dm / dt (change in mass / change in time) criterion was 0.001% over 5 minutes, with a minimum dm / dt time of 30 minutes and a maximum dm / dt of 120 minutes. The nitrogen flow rate during analysis was 200 cc / min. The post-DVS sample was maintained at 30% RH prior to PXRD analysis. The PXRD pattern for crystalline carbidopa-4'-monophosphate dehydrate is shown in Figure 19.

[0464] Example 28: Preparation of crystalline L-dopa-3'-monophosphate Crystalline L-dopa-3'-monophosphate was prepared according to Example 1 above (Steps 1, 2, 3, 4b, 5b). The PXRD pattern for the crystalline L-dopa-3'-monophosphate is shown in Figure 15.

[0465] Example 29: Preparation of crystalline L-dopa-4'-monophosphate anhydride (i) Crystalline L-DOPA-4'-monophosphate anhydride (i) was prepared according to Example 5 above. The PXRD pattern for crystalline L-DOPA-4'-monophosphate anhydride (i) is shown in Figure 13.

[0466] Example 30: Preparation of crystalline L-dopa-4'-monophosphate anhydride (ii) 204 mg of L-DOPA-4'-monophosphate anhydride (i) was weighed into a 4 mL vial. 1 mL of dimethyl sulfoxide and 1 mL of water were added. The resulting slurry was stirred at 24°C. The solid was then filtered, air-dried, and analyzed by PXRD. The PXRD pattern for crystalline L-DOPA-4'-monophosphate anhydride (ii) is shown in Figure 14.

[0467] Example 31: Preparation of crystalline carbidopa-3'-monophosphate (i) 100 mg of amorphous carbidopa-3'-monophosphate was weighed into a 4 mL vial. 300 μL of water was added. Once the solid dissolved, 600 μL of isopropanol was added. The resulting clear solution was stirred with a magnetic stir bar at room temperature overnight until the solid emerged from the solution. 300 μL of isopropanol was added, and the suspension was stirred for 15 minutes. The suspension was filtered, and the resulting solid was dried in a vacuum oven at room temperature. The dried solid was analyzed by PXRD. The PXRD pattern for crystalline carbidopa-3'-monophosphate (i) is shown in Figure 20.

[0468] Example 32: Preparation of crystalline carbidopa-3'-monophosphate (ii) 25 mg of carbidopa-3'-monophosphate (i) was weighed into a 2 mL vial. 100 μL of water was added to dissolve the solid. The vial was placed in a Crystal 16 apparatus (Avantium Technologies, Amsterdam, Netherlands) and stirred with a magnetic stir bar using the following heating / cooling cycle: ramp 10°C / h to 50°C, hold for 4 hours, ramp 20°C / h to -15°C, hold for 4 hours, ramp 10°C / h to 50°C, hold for 4 hours, ramp 10°C / h to -15°C, hold for 4 hours, ramp 10°C / h to 50°C, hold for 4 hours, ramp 5°C / h to -15°C, hold for 4 hours, ramp 10°C / h to 50°C, hold for 4 hours, ramp 5°C / h to -15°C, hold for 4 hours, ramp 10°C / h to 45°C, hold for 4 hours, ramp 5°C / h to 25°C, and hold until PXRD analysis. The solid was then filtered, and the wet cake was analyzed by PXRD. The PXRD pattern for crystalline carbidopa-3'-monophosphate (ii) is shown in Figure 21.

[0469] Example 33: Preparation of crystalline carbidopa-3',4'-diphosphate sodium salt 46 mg of amorphous carbidopa-3',4'-diphosphate and 5.6 mg of sodium hydroxide pellets were dissolved in 500 μL of dimethyl sulfoxide and 200 μL of water. 400 mg of IPA was added. The solution was heated to 35°C and then allowed to cool to room temperature. The solution was stirred with a magnetic stir bar until needles precipitated. The solid was then filtered and analyzed by PXRD. The PXRD pattern for crystalline carbidopa-3',4'-diphosphate sodium salt is shown in Figure 22.

[0470] Example 34: Preparation of crystalline L-dopa-3',4'-diphosphate trihydrate 62.1 mg of amorphous L-DOPA 3',4'-diphosphate was weighed into a 2 mL vial. 200 μL of water was added to dissolve the solid. The vial was placed in a Crystal 16 apparatus (Avantium Technologies, Amsterdam, Netherlands) and stirred with a magnetic stir bar using the following heating / cooling cycle: ramp 10°C / h to 50°C, hold for 4 hours, ramp 20°C / h to -15°C, hold for 4 hours, ramp 10°C / h to 50°C, hold for 4 hours, ramp 10°C / h to -15°C, hold for 4 hours, ramp 10°C / h to 50°C, hold for 4 hours, ramp 5°C / h to -15°C, hold for 4 hours, ramp 10°C / h to 50°C, hold for 4 hours, ramp 5°C / h to -15°C, hold for 4 hours, ramp 10°C / h to 25°C, and hold until PXRD analysis. The solid was then filtered, and the wet cake was analyzed by PXRD. The PXRD pattern for crystalline L-dopa-3',4'-diphosphate trihydrate is shown in FIG.

[0471] Alternatively, L-DOPA-3',4'-diphosphate trihydrate can be crystallized using ethyl acetate, isopropanol, water-saturated ethyl acetate, methyl ethyl ketone, acetone, tetrahydrofuran, toluene, 2-methyl-THF, dichloromethane, tert-tributylamine, isobutyl acetate, and 1,4-dioxane as solvents. The following solvent mixtures in a 1:1 volume ratio can also be used: acetone / water, isopropyl acetate / heptane.

[0472] X. Further embodiments Embodiment 1. A first compound corresponding in structure to Formula (I):

[0473] [ka] or a pharmaceutically acceptable salt thereof [R 1 and R 2 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2; and A second compound corresponding in structure to formula (II):

[0474] [ka] or a pharmaceutically acceptable salt thereof [R 3 and R 4 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2. 10. A pharmaceutical combination comprising:

[0475] Embodiment 2. The first compound is

[0476] [ka] The pharmaceutical combination of embodiment 1, which is TIFF2025118978000073.tif31160.

[0477] Embodiment 3. The second compound is

[0478] [ka] The pharmaceutical combination of embodiment 1 or 2, wherein the pharmaceutical combination is TIFF2025118978000075.tif52158.

[0479] Embodiment 4. The pharmaceutical combination of any one of the preceding embodiments, wherein said first compound, or a pharmaceutically acceptable salt thereof, and said second compound, or a pharmaceutically acceptable salt thereof, are present in separate pharmaceutical compositions or both are present in the same pharmaceutical composition.

[0480] Embodiment 5. The pharmaceutical combination of any one of the preceding embodiments, wherein the weight ratio of said first compound, or a pharmaceutically acceptable salt thereof, to said second compound, or a pharmaceutically acceptable salt thereof, is from about 1:1 to about 1:50, preferably from about 1:2 to about 1:15, preferably from about 1:4 to about 1:10, and more preferably about 1:4.

[0481] Embodiment 6. The pharmaceutical combination of any one of the preceding embodiments, wherein said first compound or a pharmaceutically acceptable salt thereof has a solubility of at least about 200 mg / mL in aqueous solution at about neutral pH, and said second compound or a pharmaceutically acceptable salt thereof has a solubility of at least about 400 mg / mL in aqueous solution at about neutral pH.

[0482] Embodiment 7. The pharmaceutical combination of any one of the preceding embodiments, wherein the combination is an aqueous combination suitable for intragastric, subcutaneous, intramuscular, intrajejunal, oral, nasal or intravenous administration.

[0483] Embodiment 8. The pharmaceutical combination of any one of the preceding embodiments, wherein the combination is an aqueous combination suitable for subcutaneous administration.

[0484] Embodiment 9. The first compound corresponds in structure to Formula (Ia):

[0485] [ka] or a pharmaceutically acceptable salt thereof; wherein said second compound corresponds in structure to formula (II-a):

[0486] [ka] or a pharmaceutically acceptable salt thereof.

[0487] Embodiment 10. The first compound corresponds in structure to Formula (Ib):

[0488] [ka] or a pharmaceutically acceptable salt thereof; wherein said second compound corresponds in structure to formula (II-a):

[0489] [ka] or a pharmaceutically acceptable salt thereof.

[0490] Embodiment 11. The first compound corresponds in structure to Formula (Ic)

[0491] [ka] or a pharmaceutically acceptable salt thereof; wherein said second compound corresponds in structure to formula (II-a):

[0492] [ka] or a pharmaceutically acceptable salt thereof.

[0493] Embodiment 12. The first compound corresponds in structure to Formula (Ia):

[0494] [ka] or a pharmaceutically acceptable salt thereof; wherein said second compound corresponds in structure to formula (II-b):

[0495] [ka] or a pharmaceutically acceptable salt thereof.

[0496] Embodiment 13. The first compound corresponds in structure to Formula (Ib):

[0497] [ka] or a pharmaceutically acceptable salt thereof; wherein said second compound corresponds in structure to formula (II-b):

[0498] [ka] or a pharmaceutically acceptable salt thereof.

[0499] Embodiment 14. The first compound corresponds in structure to Formula (Ic):

[0500] [ka] or a pharmaceutically acceptable salt thereof; wherein said second compound corresponds in structure to formula (II-b):

[0501] [ka] or a pharmaceutically acceptable salt thereof.

[0502] Embodiment 15. The first compound corresponds in structure to Formula (Ia):

[0503] [ka] or a pharmaceutically acceptable salt thereof; wherein said second compound corresponds in structure to formula (II-c):

[0504] [ka] or a pharmaceutically acceptable salt thereof.

[0505] Embodiment 16. The first compound corresponds in structure to Formula (Ib):

[0506] [ka] or a pharmaceutically acceptable salt thereof; wherein said second compound corresponds in structure to formula (II-c):

[0507] [ka] or a pharmaceutically acceptable salt thereof.

[0508] Embodiment 17. The first compound corresponds in structure to Formula (Ic):

[0509] [ka] or a pharmaceutically acceptable salt thereof; wherein said second compound corresponds in structure to formula (II-c):

[0510] [ka] or a pharmaceutically acceptable salt thereof.

[0511] Embodiment 18. A method for treating Parkinson's disease in a subject in need thereof and / or providing rescue therapy in a subject having Parkinson's disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination according to any one of the preceding embodiments.

[0512] Embodiment 19. The method of embodiment 18, wherein the first compound and the second compound are administered to the subject in separate pharmaceutical compositions, or the first compound and the second compound are administered to the subject in the same pharmaceutical composition comprising the first compound and the second compound.

[0513] Embodiment 20 The method of embodiment 18 or 19, comprising intragastric, subcutaneous, intrajejunal, oral, intranasal, intramuscular, or intravenous administration of said first compound and said second compound.

[0514] Embodiment 21 The method of any one of embodiments 18 to 20, comprising subcutaneous administration of the first compound and the second compound.

[0515] Embodiment 22 The method of any one of embodiments 18 to 21, comprising substantially continuous administration of said first compound and said second compound over a period of at least about 12 hours.

[0516] Embodiment 23 The method of any one of embodiments 18 to 22, wherein the weight ratio of the first compound administered to the second compound administered is from about 1:1 to about 1:50.

[0517] Embodiment 24 The method of any one of embodiments 18 to 23, wherein the weight ratio of the first compound administered to the second compound administered is from about 1:2 to about 1:15.

[0518] Embodiment 25 The method of any one of embodiments 18 to 24, wherein the weight ratio of the first compound administered to the second compound administered is from about 1:4 to about 1:10.

[0519] Embodiment 26 The method of any one of embodiments 18 to 25, wherein the weight ratio of the first compound administered to the second compound administered is about 1:4.

[0520] Embodiment 27 The method of any one of embodiments 18 to 26, wherein the weight ratio of the first compound administered to the second compound administered is about 1:7.5.

[0521] Embodiment 28 The method of any one of embodiments 18 to 27, wherein the weight ratio of the first compound administered to the second compound administered is about 1:10.

[0522] Embodiment 29. The first compound is:

[0523] [ka] selected from the group consisting of: The second compound

[0524] [ka] 29. The method of any one of embodiments 18 to 28, wherein the .tif is selected from the group consisting of: TIFF2025118978000096.tif43158.

[0525] Embodiment 30 The method of any one of embodiments 18 to 29, further comprising administering to the subject another anti-Parkinson's drug.

[0526] Embodiment 31 The method of any one of embodiments 18 to 30, wherein the aqueous pharmaceutical combination is an aqueous combination.

[0527] Embodiment 32 The method of embodiment 31, wherein the pharmaceutical combination is administered intragastrically, subcutaneously, intramuscularly, intranasally, intrajejunally, orally, or intravenously.

[0528] Embodiment 33 The method of embodiment 31 or 32, wherein the aqueous pharmaceutical combination is administered by subcutaneous administration.

[0529] Embodiment 34. A compound corresponding in structure to Formula (I) or a pharmaceutically acceptable salt thereof.

[0530] [ka] [In the formula, R 1 and R 2 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2.

[0531] Embodiment 35.R 1 and R 2 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C2-alkyl; R 6 is hydrogen; provided that R 1 and R 2 At least one of the following is -P(O)(OH)2 or -R 5 35. The compound of embodiment 34, or a pharmaceutically acceptable salt thereof, wherein: —OP(O)(OH) 2 .

[0532] Embodiment 36.R 1 and R 2 are each independently hydrogen or -P(O)(OH); R 6 is hydrogen; R 1 and R 2 36. The compound or pharmaceutically acceptable salt of embodiment 34 or 35, wherein one of is -P(O)(OH)2.

[0533] Embodiment 37.R 1 and R 2 are each independently hydrogen or -R 5 -OP(O)(OH)2; R 5 is C1-C2-alkyl; R 6 is hydrogen; provided that R 1 and R 2 One of them is -R 5 36. The compound or pharmaceutically acceptable salt of embodiment 34 or 35, wherein -OP(O)(OH)2.

[0534] Embodiment 38.R 1 and R 2 are each independently hydrogen, -P(O)(OH)2, or -R 5 -OP(O)(OH)2; R 5 is C1-C2-alkyl; R 6 is C1-C2-alkyl; provided that R 1 and R 2 One of the groups is -P(O)(OH)2 or -R 5 35. The compound of embodiment 34, or a pharmaceutically acceptable salt thereof, wherein: —OP(O)(OH) 2 .

[0535] Embodiment 39. The compound or salt of any one of Embodiments 34 to 36, wherein the compound corresponds in structure to Formula (Ia):

[0536] [ka]

[0537] Embodiment 40. The compound or salt of any one of embodiments 34 to 36, wherein the compound corresponds in structure to Formula (Ib):

[0538] [ka]

[0539] Embodiment 41. The compound or salt of any one of embodiments 34 to 36, wherein the compound corresponds in structure to Formula (Ic):

[0540] [ka]

[0541] Embodiment 42. The compound or salt of any one of embodiments 34, 35, or 37, wherein said compound corresponds in structure to formula (Id):

[0542] [ka]

[0543] Embodiment 43. The compound or salt of any one of Embodiments 34, 35, or 37, wherein said compound corresponds in structure to Formula (Ie):

[0544] [ka]

[0545] Embodiment 44. The compound or salt of any one of Embodiments 34 or 38, wherein said compound corresponds in structure to Formula (If):

[0546] [ka]

[0547] Embodiment 45. A compound corresponding in structure to Formula (II) or a pharmaceutically acceptable salt thereof.

[0548] [ka] [In the formula, R 3 and R 4 are each independently hydrogen, -P(O)(OH)2, and -R 5-OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2.

[0549] Embodiment 46.R 3 and R 4 are each independently hydrogen or -R 5 -OP(O)(OH)2; R 5 is C1-C2-alkyl; R 6 is hydrogen; provided that R 3 and R 4 One of them is -R 5 46. The compound or salt of embodiment 45, wherein:

[0550] Embodiment 47. The compound or salt of embodiment 45 or 46, wherein said compound corresponds in structure to formula (II-d).

[0551] [ka]

[0552] Embodiment 48. The compound or salt of embodiment 45 or 46, wherein said compound corresponds in structure to formula (II-e):

[0553] [ka]

[0554] Embodiment 49. A first compound corresponding in structure to Formula (I):

[0555] [ka] or a pharmaceutically acceptable salt thereof [wherein R1 and R 2 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 1 and R 2 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2] and a pharmaceutically acceptable carrier.

[0556] Embodiment 50. The pharmaceutical composition of embodiment 49, wherein said first compound corresponds in structure to Formula (Ia).

[0557] [ka]

[0558] Embodiment 51 The pharmaceutical composition of embodiment 49, wherein the first compound corresponds in structure to Formula (Ib).

[0559] [ka]

[0560] Embodiment 52 The pharmaceutical composition of embodiment 49, wherein the first compound corresponds in structure to Formula (Ic).

[0561] [ka]

[0562] Embodiment 53 The pharmaceutical composition of any one of embodiments 49 to 52, wherein the composition further comprises a second compound corresponding in structure to Formula (II) or a pharmaceutically acceptable salt thereof.

[0563] [ka] [In the formula, R 3 and R 4 are each independently hydrogen, -P(O)(OH)2, and -R 5 -OP(O)(OH); R 5 is C1-C4-alkyl; R 6 is hydrogen or C1-C4-alkyl; provided that R 3 and R 4 At least one of the following is -P(O)(OH)2 or -R 5 -OP(O)(OH)2.

[0564] Embodiment 54 The pharmaceutical composition of embodiment 53, wherein the second compound corresponds in structure to Formula (II-a).

[0565] [ka]

[0566] Embodiment 55 The pharmaceutical composition of embodiment 53, wherein the second compound corresponds in structure to formula (II-b).

[0567] [ka]

[0568] Embodiment 56 The pharmaceutical composition of embodiment 53, wherein the second compound corresponds in structure to formula (II-c).

[0569] [ka]

[0570] Embodiment 57. The pharmaceutical composition of any one of embodiments 37 to 44, wherein the weight ratio of the first compound to the second compound is from about 1:1 to about 1:50, preferably from about 1:2 to about 1:15, and even more preferably from about 1:4 to about 1:10.

[0571] Embodiment 58 The pharmaceutical composition of any one of embodiments 49 to 57, wherein the weight ratio of the first compound to the second compound is about 1:4.

[0572] Embodiment 59 The pharmaceutical composition of any one of embodiments 49 to 57, wherein the weight ratio of the first compound to the second compound is about 1:7.5.

[0573] Embodiment 60 The pharmaceutical composition of any one of embodiments 49 to 57, wherein the weight ratio of the first compound to the second compound is about 1:10.

[0574] Embodiment 61. The pharmaceutical composition of any one of embodiments 49 to 60, wherein the composition further comprises water and is suitable for injection.

[0575] Embodiment 62. A kit comprising the pharmaceutical combination of any one of embodiments 1 to 17.

[0576] Embodiment 63. A kit comprising the pharmaceutical composition of any one of embodiments 49 to 62.

[0577] Embodiment 64.

[0578] [ka] A compound selected from the group consisting of TIFF2025118978000116.tif190159TIFF2025118978000117.tif122154.

[0579] Embodiment 65. A crystalline polymorph of L-dopa 4'-monophosphate identified by powder X-ray diffraction, wherein the crystalline polymorph is: crystalline L-dopa 4'-monophosphate anhydride (i) exhibiting at least one characteristic peak in a powder X-ray diffraction pattern at 2θ values of 10.261±0.20, 12.053±0.20, 13.759±0.20, 14.932±0.20, 16.147±0.20, 16.718±0.20, 17.34±0.20, 19.254±0.20, 20.654±0.20, 22.078±0.20, 23.599±0.20, 24.198±0.20, 25.898±0.20, 26.338±0.20, and 27.117±0.20; or Crystalline L-DOPA 4'-monophosphate anhydride (ii) exhibiting at least one characteristic peak in a powder X-ray diffraction pattern at 2θ values of 8.468±0.20, 10.234±0.20, 11.821±0.20, 13.084±0.20, 13.503±0.20, 15.48±0.20, 15.848±0.20, 16.513±0.20, 18.447±0.20, 19.346±0.20, 20.239±0.20, 21.139±0.20, 24.221±0.20, 24.865±0.20, and 25.647±0.20. A crystalline polymorph that is

[0580] Embodiment 66. Crystalline L-dopa-3'-monophosphate exhibiting at least one characteristic peak in a powder X-ray diffraction pattern at 6.2θ values of 8.662±0.20, 11.286±0.20, 15.079±0.20, 15.678±0.20, 16.786±0.20, 17.288±0.20, 18.438±0.20, 19.682±0.20, 20.946±0.20, 22.188±0.20, 22.671±0.20, 23.088±0.20, 24.144±0.20, 24.744±0.20, and 25.383±0.20.

[0581] Embodiment 67.2 Crystalline L-dopa 3'4-diphosphate trihydrate exhibiting at least one characteristic peak in a powder X-ray diffraction pattern at the following theta values: 7.118±0.20, 10.342±0.20, 11.355±0.20, 12.161±0.20, 14.201±0.20, 17.36±0.20, 17.632±0.20, 19.196±0.20, 19.444±0.20, 20.83±0.20, 21.504±0.20, 22.491±0.20, 23.085±0.20, 24.487±0.20, and 25.11±0.20.

[0582] Embodiment 68. A crystalline polymorph of carbidopa 4'-monophosphate identified by powder X-ray diffraction, wherein the crystalline polymorph is: crystalline carbidopa 4'-monophosphate trihydrate exhibiting at least one characteristic peak in a powder X-ray diffraction pattern at 2θ values of 7.484±0.20, 10.05±0.20, 11.971±0.20, 13.085±0.20, 14.923±0.20, 16.095±0.20, 16.85±0.20, 17.359±0.20, 17.635±0.20, 19.269±0.20, 19.544±0.20, 21.842±0.20, 22.578±0.20, 22.921±0.20, and 23.822±0.20; crystalline carbidopa 4'-monophosphate dihydrate exhibiting at least one characteristic peak in a powder X-ray diffraction pattern at 2-theta values of 7.925±0.20, 10.28±0.20, 12.344±0.20, 15.002±0.20, 15.841±0.20, 16.158±0.20, 17.565±0.20, 18.506±0.20, 19.058±0.20, 19.473±0.20, 19.702±0.20, 20.188±0.20, 20.668±0.20, 22.37±0.20, and 24.167±0.20; or Crystalline carbidopa 4'-monophosphate dehydrate exhibiting at least one characteristic peak in a powder X-ray diffraction pattern at 2θ values of 9.492±0.20, 10.528±0.20, 15.356±0.20, 15.907±0.20, 16.165±0.20, 17.933±0.20, 18.737±0.20, 19.429±0.20, 21.176±0.20, and 22.626±0.20. A crystalline polymorph that is

[0583] Embodiment 69. A crystalline polymorph of carbidopa 3'-monophosphate identified by powder X-ray diffraction, wherein the crystalline polymorph is: crystalline carbidopa 3'-monophosphate(i) exhibiting at least one characteristic peak in a powder X-ray diffraction pattern at 2θ values of 9.171±0.20, 13.539±0.20, 14.23±0.20, 15.589±0.20, 15.979±0.20, 18.394±0.20, 18.832±0.20, 19.315±0.20, 22.143±0.20, and 22.81±0.20; or Crystalline carbidopa 3'-monophosphate (ii) exhibiting at least one characteristic peak in a powder X-ray diffraction pattern at 2θ values of 4.433±0.20, 8.917±0.20, 9.654±0.20, 13.192±0.20, 15.288±0.20, 15.747±0.20, 17.886±0.20, 19.291±0.20, 20.554±0.20, and 21.797. A crystalline polymorph that is

[0584] Embodiment 70. Crystalline carbidopa-3'-diphosphate sodium salt exhibiting at least one characteristic peak in a powder X-ray diffraction pattern at 2θ values of 5.852±0.20, 6.861±0.20, 7.338±0.20, 11.159±0.20, 11.729±0.20, 12.953±0.20, 13.714±0.20, 14.381±0.20, 14.686±0.20, 15.479±0.20, 16.676±0.20, 17.179±0.20, 17.592±0.20, 18.861±0.20, and 20.305±0.20.

[0585] It is to be understood that the foregoing detailed description and accompanying examples are illustrative only and should not be construed as limiting the scope of the invention, which is defined solely by the appended claims and their equivalents.

[0586] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, including, but not limited to, those relating to chemical structure, substituents, derivatives, intermediates, synthesis, compositions, formulations, or methods of use of the invention, can be made without departing from the spirit and scope of the invention.

Claims

1. A first compound corresponding in structure to formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt of said compound [wherein R １ and R ２ are each independently hydrogen, -P(O)(OH) ２ , and -R ５ -OP(O)(OH) ２ R ５ is C １ -C ４ - alkyl; R ６ is hydrogen or C １ -C ４ -alkyl; provided that R １ and R ２ At least one of the following is -P(O)(OH) ２ or -R ５ -OP(O)(OH) ２ and A second compound corresponding in structure to formula (II): 【Chemistry 2】 or a pharmaceutically acceptable salt of said compound [wherein R ３ and R ４ are each independently hydrogen, -P(O)(OH) ２ , and -R ５ -OP(O)(OH) ２ R ５ is C １ -C ４ - alkyl; R ６ is hydrogen or C １ -C ４ -alkyl; provided that R ３ and R ４ At least one of the following is -P(O)(OH) ２ or -R ５ -OP(O)(OH) ２ It is.] 10. A pharmaceutical combination comprising:

2. The first compound 【Chemistry 3】 【change】 The pharmaceutical combination according to claim 1, wherein

3. The second compound 【Chemistry 4】 The pharmaceutical combination according to claim 1 or 2, wherein

4. 4. The pharmaceutical combination of claim 1, wherein the first compound or a pharmaceutically acceptable salt thereof and the second compound or a pharmaceutically acceptable salt thereof are present in separate pharmaceutical compositions or both are present in the same pharmaceutical composition.

5. 5. The pharmaceutical combination of any one of claims 1 to 4, wherein the weight ratio of the first compound, or a pharmaceutically acceptable salt thereof, to the second compound, or a pharmaceutically acceptable salt thereof, is from about 1:1 to about 1:50, preferably from about 1:2 to about 1:15, preferably from about 1:4 to about 1:10, more preferably about 1:

4.

6. 6. The pharmaceutical combination of any one of claims 1 to 5, wherein the first compound or a pharmaceutically acceptable salt thereof has a solubility of at least about 200 mg / mL in an aqueous solution at about neutral pH, and the second compound or a pharmaceutically acceptable salt thereof has a solubility of at least about 400 mg / mL in an aqueous solution at about neutral pH.

7. 7. The pharmaceutical combination according to any one of claims 1 to 6, wherein the combination is an aqueous combination suitable for intragastric, subcutaneous, intramuscular, intrajejunal, oral, nasal or intravenous administration.

8. 8. The pharmaceutical combination according to any one of claims 1 to 7, wherein the combination is an aqueous combination suitable for subcutaneous administration.

9. The first compound corresponds in structure to formula (Ia): 【Chemistry 5】 or a pharmaceutically acceptable salt thereof; wherein the second compound corresponds in structure to formula (II-a): 【Chemistry 6】 9. The pharmaceutical combination according to claim 1, wherein the compound is a pharmaceutically acceptable salt thereof.

10. The first compound corresponds in structure to formula (I-b): 【Chemistry 7】 or a pharmaceutically acceptable salt thereof; wherein the second compound corresponds in structure to formula (II-a): 【Chemistry 8】 10. The pharmaceutical combination according to claim 1, wherein the compound is a pharmaceutically acceptable salt thereof.

11. The first compound corresponds in structure to formula (I-c) 【Chemistry 9】 or a pharmaceutically acceptable salt thereof; wherein the second compound corresponds in structure to formula (II-a): 【Chemistry 10】 11. The pharmaceutical combination according to claim 1, wherein the compound is a pharmaceutically acceptable salt thereof.

12. The first compound corresponds in structure to formula (Ia): 【Chemistry 11】 or a pharmaceutically acceptable salt thereof; wherein the second compound corresponds in structure to formula (II-b): 【Chemistry 12】 12. The pharmaceutical combination according to claim 1, wherein the compound is a pharmaceutically acceptable salt thereof.

13. The first compound corresponds in structure to formula (I-b): 【Chemistry 13】 or a pharmaceutically acceptable salt thereof; wherein the second compound corresponds in structure to formula (II-b): 【Chemistry 14】 13. The pharmaceutical combination according to any one of claims 1 to 12, wherein the compound is a pharmaceutically acceptable salt thereof.

14. The first compound corresponds in structure to formula (I-c): 【Chemistry 15】 or a pharmaceutically acceptable salt thereof; wherein the second compound corresponds in structure to formula (II-b): 【Chemistry 16】 14. The pharmaceutical combination according to any one of claims 1 to 13, wherein the compound is a pharmaceutically acceptable salt thereof.

15. The first compound corresponds in structure to formula (Ia): 【Chemistry 17】 or a pharmaceutically acceptable salt thereof; wherein the second compound corresponds in structure to formula (II-c): 【Chemistry 18】 15. The pharmaceutical combination according to any one of claims 1 to 14, wherein the compound is a pharmaceutically acceptable salt thereof.

16. The first compound corresponds in structure to formula (I-b): 【Chemistry 19】 or a pharmaceutically acceptable salt thereof; wherein the second compound corresponds in structure to formula (II-c): 【Chemistry 20】 16. The pharmaceutical combination according to any one of claims 1 to 15, wherein the compound is a pharmaceutically acceptable salt thereof.

17. The first compound corresponds in structure to formula (I-c): 【Chemical 21】 or a pharmaceutically acceptable salt thereof; wherein the second compound corresponds in structure to formula (II-c): 【Chemical 22】 17. The pharmaceutical combination according to any one of claims 1 to 16, wherein the compound is a pharmaceutically acceptable salt thereof.

18. 20. A method for treating Parkinson's disease in a subject in need thereof and / or a method for providing rescue therapy in a subject having Parkinson's disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination according to any one of claims 1 to 17.

19. 20. The method of claim 18, wherein the first compound and the second compound are administered to the subject in separate pharmaceutical compositions, or the first compound and the second compound are administered to the subject in the same pharmaceutical composition comprising the first compound and the second compound.

20. 20. The method of claim 18 or 19, comprising intragastric, subcutaneous, intrajejunal, oral, intranasal, intramuscular or intravenous administration of said first compound and said second compound.

21. 21. The method of any one of claims 18 to 20, comprising subcutaneous administration of the first compound and the second compound.

22. 22. The method of any one of claims 18 to 21, comprising substantially continuous administration of said first compound and said second compound over a period of at least about 12 hours.

23. 23. The method of any one of claims 18 to 22, wherein the weight ratio of the first compound administered to the second compound administered is from about 1:1 to about 1:

50.

24. 24. The method of any one of claims 18 to 23, wherein the weight ratio of the first compound administered to the second compound administered is from about 1:2 to about 1:

15.

25. 25. The method of any one of claims 18 to 24, wherein the weight ratio of the first compound administered to the second compound administered is from about 1:4 to about 1:

10.

26. 26. The method of any one of claims 18 to 25, wherein the weight ratio of the first compound administered to the second compound administered is about 1:

4.

27. 27. The method of any one of claims 18 to 26, wherein the weight ratio of the first compound administered to the second compound administered is about 1:7.

5.

28. 28. The method of any one of claims 18 to 27, wherein the weight ratio of the first compound administered to the second compound administered is about 1:

10.

29. The first compound is 【Chemical 23】 selected from the group consisting of: The second compound 【Chemistry 24】 【change】 29. The method of any one of claims 18 to 28, selected from the group consisting of:

30. 30. The method of any one of claims 18 to 29, further comprising administering to the subject another anti-Parkinson's drug.

31. 31. The method of any one of claims 18 to 30, wherein the pharmaceutical combination is an aqueous combination.

32. 32. The method of claim 31, wherein the aqueous pharmaceutical combination is administered by intragastric, subcutaneous, intramuscular, intranasal, intrajejunal, oral or intravenous administration.

33. 33. The method of claim 31 or 32, wherein the aqueous pharmaceutical combination is administered by subcutaneous administration.

34. A compound corresponding in structure to formula (I) or a pharmaceutically acceptable salt thereof. 【Chemistry 25】 [In the formula, R １ and R ２ are each independently hydrogen, -P(O)(OH) ２ , and -R ５ -OP(O)(OH) ２ R ５ is C １ -C ４ - alkyl; R ６ is hydrogen or C １ -C ４ -alkyl; provided that R １ and R ２ At least one of the following is -P(O)(OH) ２ or -R ５ -OP(O)(OH) ２ It is.]

35. R １ and R ２ are each independently hydrogen, -P(O)(OH) ２ , and -R ５ -OP(O)(OH) ２ R ５ is C １ -C ２ - alkyl; R ６ is hydrogen; １ and R ２ At least one of the following is -P(O)(OH) ２ or -R ５ -OP(O)(OH) ２ 35. The compound of claim 34, or a pharmaceutically acceptable salt thereof:

36. R １ and R ２ are each independently hydrogen or —P(O)(OH) ２ and R ６ is hydrogen; R １ and R ２ One of the two is -P(O)(OH) ２ 36. The compound or pharmaceutically acceptable salt of claim 34 or 35, wherein:

37. R １ and R ２ are each independently hydrogen or —R ５ -OP(O)(OH) ２ and R ５ is C １ -C ２ - alkyl; R ６ is hydrogen; １ and R ２ One of them is -R ５ -OP(O)(OH) ２ 36. The compound or pharmaceutically acceptable salt of claim 34 or 35, wherein:

38. R １ and R ２ are each independently hydrogen, -P(O)(OH) ２ or -R ５ -OP(O)(OH) ２ and R ５ is C １ -C ２ - alkyl; R ６ is C １ -C ２ -alkyl; provided that R １ and R ２ One of the two is -P(O)(OH) ２ or -R ５ -OP(O)(OH) ２ 35. The compound of claim 34, or a pharmaceutically acceptable salt thereof:

39. 37. The compound or salt of any one of claims 34 to 36, wherein the compound corresponds in structure to formula (Ia): 【Chemical 26】

40. 37. The compound or salt of any one of claims 34 to 36, wherein the compound corresponds in structure to formula (Ib): 【Chemical 27】

41. 37. The compound or salt of any one of claims 34 to 36, wherein the compound corresponds in structure to formula (Ic): 【Chemical 28】

42. 38. The compound or salt of any one of claims 34, 35 or 37, wherein the compound corresponds in structure to formula (I-d): 【Chemical Formula 29】

43. 38. The compound or salt of any one of claims 34, 35 or 37, wherein the compound corresponds in structure to formula (Ie): 【Chemistry 30】

44. 39. The compound or salt of any one of claims 34 or 38, wherein the compound corresponds in structure to formula (If). 【Chemical 31】

45. A compound corresponding in structure to formula (II) or a pharmaceutically acceptable salt thereof: 【Chemical 32】 [In the formula, R ３ and R ４ are each independently hydrogen, -P(O)(OH) ２ , and -R ５ -OP(O)(OH) ２ R ５ is C １ -C ４ - alkyl; R ６ is hydrogen or C １ -C ４ -alkyl; provided that R ３ and R ４ At least one of the following is -P(O)(OH) ２ or -R ５ -OP(O)(OH) ２ It is.]

46. R ３ and R ４ are each independently hydrogen or —R ５ -OP(O)(OH) ２ and R ５ is C １ -C ２ - alkyl; R ６ is hydrogen; ３ and R ４ One of them is -R ５ -OP(O)(OH) ２ 46. The compound or salt of claim 45, wherein:

47. 47. The compound or salt of claim 45 or 46, wherein the compound corresponds in structure to formula (II-d): 【Chemical 33】

48. 47. The compound or salt of claim 45 or 46, wherein the compound corresponds in structure to formula (II-e): 【Chemical 34】

49. A first compound corresponding in structure to formula (I): 【Chemistry 35】 or a pharmaceutically acceptable salt of said compound [wherein R １ and R ２ are each independently hydrogen, -P(O)(OH) ２ , and -R ５ -OP(O)(OH) ２ R ５ is C １ -C ４ - alkyl; R ６ is hydrogen or C １ -C ４ -alkyl; provided that R １ and R ２ At least one of the following is -P(O)(OH) ２ or -R ５ -OP(O)(OH) ２ and a pharmaceutically acceptable carrier.

50. 50. The pharmaceutical composition of claim 49, wherein the first compound corresponds in structure to Formula (Ia). 【Chemical 36】

51. 50. The pharmaceutical composition of claim 49, wherein the first compound corresponds in structure to Formula (Ib). 【Chemical 37】

52. 50. The pharmaceutical composition of claim 49, wherein the first compound corresponds in structure to formula (I-c). 【Chemical Formula 38】

53. 53. The pharmaceutical composition of any one of claims 49 to 52, wherein the composition further comprises a second compound corresponding in structure to Formula (II) or a pharmaceutically acceptable salt thereof. 【Chemical Formula 39】 [In the formula, R ３ and R ４ are each independently hydrogen, -P(O)(OH) ２ , and -R ５ -OP(O)(OH) ２ R ５ is C １ -C ４ - alkyl; R ６ is hydrogen or C １ -C ４ -alkyl; provided that R ３ and R ４ At least one of the following is -P(O)(OH) ２ or -R ５ -OP(O)(OH) ２ It is.]

54. 54. The pharmaceutical composition of claim 53, wherein the second compound corresponds in structure to Formula (II-a). 【Chemistry 40】

55. 54. The pharmaceutical composition of claim 53, wherein the second compound corresponds in structure to formula (II-b). 【Chemistry 41】

56. 54. The pharmaceutical composition of claim 53, wherein the second compound corresponds in structure to formula (II-c): 【Chemistry 42】

57. 45. The pharmaceutical composition of any one of claims 37 to 44, wherein the weight ratio of the first compound to the second compound is from about 1:1 to about 1:50, preferably from about 1:2 to about 1:15, and even more preferably from about 1:4 to about 1:

10.

58. 58. The pharmaceutical composition of any one of claims 49 to 57, wherein the weight ratio of the first compound to the second compound is about 1:

4.

59. 58. The pharmaceutical composition of any one of claims 49 to 57, wherein the weight ratio of the first compound to the second compound is about 1:7.

5.

60. 58. The pharmaceutical composition of any one of claims 49 to 57, wherein the weight ratio of the first compound to the second compound is about 1:

10.

61. 61. The pharmaceutical composition of any one of claims 49 to 60, wherein the composition further comprises water and is suitable for injection.

62. A kit comprising the pharmaceutical combination of any one of claims 1 to 17.

63. 62. A kit comprising the pharmaceutical composition of any one of claims 49 to 61. 【Request 64】 【Chemical 43】 【change】 【change】 A compound selected from the group consisting of:

65. A crystalline polymorph of L-dopa 4'-monophosphate identified by powder X-ray diffraction, said crystalline polymorph being: crystalline L-dopa 4'-monophosphate anhydride (i) exhibiting at least one characteristic peak in an X-ray powder diffraction pattern at 2θ values of 10.261±0.20, 12.053±0.20, 13.759±0.20, 14.932±0.20, 16.147±0.20, 16.718±0.20, 17.34±0.20, 19.254±0.20, 20.654±0.20, 22.078±0.20, 23.599±0.20, 24.198±0.20, 25.898±0.20, 26.338±0.20, and 27.117±0.20; or Crystalline L-dopa 4'-monophosphate anhydride (ii) exhibiting at least one characteristic peak in a powder X-ray diffraction pattern at 2θ values of 8.468±0.20, 10.234±0.20, 11.821±0.20, 13.084±0.20, 13.503±0.20, 15.48±0.20, 15.848±0.20, 16.513±0.20, 18.447±0.20, 19.346±0.20, 20.239±0.20, 21.139±0.20, 24.221±0.20, 24.865±0.20, and 25.647±0.

20. A crystalline polymorph that is

66. Crystalline L-dopa-3'-monophosphate exhibiting at least one characteristic peak in a powder X-ray diffraction pattern at 2θ values of 8.662±0.20, 11.286±0.20, 15.079±0.20, 15.678±0.20, 16.786±0.20, 17.288±0.20, 18.438±0.20, 19.682±0.20, 20.946±0.20, 22.188±0.20, 22.671±0.20, 23.088±0.20, 24.144±0.20, 24.744±0.20, and 25.383±0.

20.

67. Crystalline L-dopa-3',4-diphosphate trihydrate exhibiting at least one characteristic peak in an X-ray powder diffraction pattern at 2θ values of 7.118±0.20, 10.342±0.20, 11.355±0.20, 12.161±0.20, 14.201±0.20, 17.36±0.20, 17.632±0.20, 19.196±0.20, 19.444±0.20, 20.83±0.20, 21.504±0.20, 22.491±0.20, 23.085±0.20, 24.487±0.20, and 25.11±0.

20.

68. A crystalline polymorph of carbidopa 4'-monophosphate identified by powder X-ray diffraction, said crystalline polymorph being: crystalline carbidopa 4'-monophosphate trihydrate exhibiting at least one characteristic peak in an X-ray powder diffraction pattern at 2θ values of 7.484±0.20, 10.05±0.20, 11.971±0.20, 13.085±0.20, 14.923±0.20, 16.095±0.20, 16.85±0.20, 17.359±0.20, 17.635±0.20, 19.269±0.20, 19.544±0.20, 21.842±0.20, 22.578±0.20, 22.921±0.20, and 23.822±0.20; crystalline carbidopa 4'-monophosphate dihydrate exhibiting at least one characteristic peak in an X-ray powder diffraction pattern at 2-theta values of 7.925±0.20, 10.28±0.20, 12.344±0.20, 15.002±0.20, 15.841±0.20, 16.158±0.20, 17.565±0.20, 18.506±0.20, 19.058±0.20, 19.473±0.20, 19.702±0.20, 20.188±0.20, 20.668±0.20, 22.37±0.20, and 24.167±0.20; or Crystalline carbidopa 4'-monophosphate dehydrate exhibiting at least one characteristic peak in a powder X-ray diffraction pattern at 2θ values of 9.492±0.20, 10.528±0.20, 15.356±0.20, 15.907±0.20, 16.165±0.20, 17.933±0.20, 18.737±0.20, 19.429±0.20, 21.176±0.20, and 22.626±0.

20. A crystalline polymorph that is

69. A crystalline polymorph of carbidopa 3'-monophosphate identified by powder X-ray diffraction, said crystalline polymorph being: Crystalline carbidopa 3'-monophosphate (i) exhibiting at least one characteristic peak in an X-ray powder diffraction pattern at 2θ values of 9.171±0.20, 13.539±0.20, 14.23±0.20, 15.589±0.20, 15.979±0.20, 18.394±0.20, 18.832±0.20, 19.315±0.20, 22.143±0.20, and 22.81±0.20; or Crystalline carbidopa 3'-monophosphate (ii) exhibiting at least one characteristic peak in a powder X-ray diffraction pattern at 2θ values of 4.433±0.20, 8.917±0.20, 9.654±0.20, 13.192±0.20, 15.288±0.20, 15.747±0.20, 17.886±0.20, 19.291±0.20, 20.554±0.20, and 21.

797. A crystalline polymorph that is

70. Crystalline carbidopa-3',4-diphosphate sodium salt exhibiting at least one characteristic peak in a powder X-ray diffraction pattern at 2θ values of 5.852±0.20, 6.861±0.20, 7.338±0.20, 11.159±0.20, 11.729±0.20, 12.953±0.20, 13.714±0.20, 14.381±0.20, 14.686±0.20, 15.479±0.20, 16.676±0.20, 17.179±0.20, 17.592±0.20, 18.861±0.20, and 20.305±0.20.

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