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 methods of treating Parkinson's disease and related conditions, including (a) carbidopa prodrugs, (b) L-dopa prodrugs, (c) pharmaceutical combinations and compositions comprising carbidopa prodrugs and / or L-dopa prodrugs, and (d) administering carbidopa prodrugs and L-dopa prodrugs to subjects with Parkinson's disease.

Background Art

[0002] Parkinson's disease is a chronic and progressive neurodegenerative condition characterized by a decrease in the level of the neurotransmitter dopamine (i.e., 3,4-dihydroxyphenethylamine) in the brain. Administration of L-dopa (i.e., L-3,4-dihydroxyphenylalanine) is currently the most effective treatment for patients with Parkinson's disease. Unlike dopamine, L-dopa, which can cross the blood-brain barrier, undergoes enzymatic conversion in the brain to dopamine, resulting in an increase in dopamine levels.

[0003]

Chemical

[0004] The conversion of L-dopa to dopamine is catalyzed by aromatic L-amino acid decarboxylase, a ubiquitous enzyme that promotes the central and peripheral metabolism of L-dopa to dopamine. Due to the 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 can result in elevated peripheral dopamine levels that can cause nausea in some patients. To overcome these problems, L-dopa is usually co-administered 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]

Chem.

[0006] By co-administering carbidopa with L-dopa, the peripheral metabolism of L-dopa to dopamine is inhibited, whereby the L-dopa dosage required for a therapeutically effective response is greatly reduced and the associated side effects are greatly alleviated.

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

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

[0008] The main problem in developing less invasive or otherwise improved forms of L-dopa and carbidopa administration has been the solubility of these compounds. They each have low aqueous solubility in the pH range required for infusion. Stable, more highly concentrated, and / or lower viscosity formulations containing L-dopa and / or carbidopa (or compounds having the in vivo bioconversion ability of L-dopa and / or carbidopa) are desirable. Such formulations would provide advantages over existing infusion therapies such as (a) reduction in the volume of the formulation delivered to the patient and improvement in pumpability, which would also allow for a reduction in the size and weight of the delivery device; (b) extension of the shelf life of the formulation by reducing degradation and improving stability; and / or (c) providing high flexibility in managing patient treatment by reducing or eliminating the cold storage requirements of the formulation (e.g., increasing the time the formulation can be handled outside of refrigerated storage). Such stable, higher concentration, and / or lower viscosity formulations could also be used in less invasive forms of administration (e.g., subcutaneous injection).

[0009] Accordingly, there is a continuing need for improved compositions and methods that can provide continuous and consistent dopamine levels in the brain to effectively treat movement disorders such as Parkinson's disease. The present disclosure provides such improved compositions and methods. [[Means for Solving the Problems]]

[0010] In one aspect, the present disclosure relates to a compound corresponding in structure to the following formula (I) or a pharmaceutically acceptable salt thereof.

[0011] [Chemical Formula] Wherein R 1 and R 2 are each independently selected from the group consisting of hydrogen, -P(O)(OH) 2 , and -R 5 -O-P(O)(OH) 2 ; R 5 is C 1 -C4 -alkyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 1 and R 2 is -P(O)(OH) 2 or -R 5 -O-P(O)(OH) 2 .

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

[0013] [Chemical formula] wherein R 3 and R 4 are each independently selected from the group consisting of hydrogen, -P(O)(OH) 2 , and -R 5 -O-P(O)(OH) 2 ; R 5 is C 1 -C 4 -alkyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 3 and R 4 is -P(O)(OH) 2 or -R 5 -O-P(O)(OH) 2 .

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

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

[0016] In another aspect, the present 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 to formula (I) in structure or a pharmaceutically acceptable salt thereof, and a second compound corresponding to formula (II) in structure or a pharmaceutically acceptable salt thereof. In certain aspects, the method comprises administering the first compound corresponding to formula (I) in structure or a pharmaceutically acceptable salt thereof, and the second compound corresponding to formula (II) in structure, either in a single pharmaceutical composition or in separate pharmaceutical compositions.

[0017] Upon reading this patent application, further advantages of the present disclosure will become apparent to those skilled in the art. The embodiments of the disclosure described in the following paragraphs are for the purpose of illustrating the present invention and should not be considered as narrowing the scope of the present invention.

Brief Description of the Drawings

[0018]

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BEST MODE FOR CARRYING OUT THE INVENTION

[0019] This description discloses the present invention, such as the best mode, by way of example, and further discloses the manufacture and use of the disclosed carbidopa phosphate prodrugs or pharmaceutical compositions, and the practice of the disclosed methods or processes, so that those skilled in the art can practice the present invention. The scope of the present invention that can be patented is defined by the claims, and can include other examples that occur to those skilled in the art. Such other examples shall be included in the claims as if they had elements that do not differ from the language of the claims, or as if they included equivalent elements.

[0020] I. Definition The section headings used in this section and throughout the disclosure do not limit the invention.

[0021] When a numerical range is recited, each intermediate number within that range is clearly contemplated with the same degree of precision. For example, for the range from 6 to 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range from 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 clearly contemplated. Similarly, all recited ratios also include all sub-ratios included within the broader ratio.

[0022] The singular forms "a", "one", and "the" include the plural reference unless the context clearly dictates otherwise.

[0023] The term "and / or" as used in expressions such as "A and / or B" in this specification shall include "A and B", "A or B", "A", and "B".

[0024] The term "about" refers to a range of numbers that are considered by those skilled in the art to be equivalent to the recited value (i.e., having the same function or result). In many cases, the term "about" may include numbers that are rounded to the nearest significant digit.

[0025] Unless the context requires otherwise, the terms "comprise", "comprises", and "comprising" should be construed inclusively rather than exclusively, and are used based on the understanding that the applicant intends that each of these terms be so construed when interpreting this patent, which includes the appended claims.

[0026] The terms "ameliorate" and "amelioration" have a clear and ordinary meaning to those skilled in the art of pharmacy or medicine, and specifically include alleviating the effects of Parkinson's disease, or reducing or decreasing the side effects of Parkinson's disease.

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

[0028] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any solvent, dispersion medium, preservative, antioxidant, coating agent, isotonic agent, absorption delaying agent, etc. that is compatible with pharmaceutical administration.

[0029] The term "pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include (1) those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or 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[2.2.2]-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, mucic acid, etc.; and (2) salts formed when the acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion; or when an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine is coordinated.

[0030] The terms "reduce" and "reduction" have a clear and ordinary meaning to those skilled in the art of pharmacy or medicine, and specifically include reducing or lowering the frequency, duration or intensity of the occurrence of Parkinson's disease side effects such as dyskinesia or hallucinations.

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

[0032] The terms "treat" and "treatment" have a clear and ordinary meaning to those skilled in the art of pharmacy or medicine, and specifically include enhancing the quality of life or reducing the symptoms or side effects of Parkinson's disease.

[0033] II. Carbidopa and L-Dopa prodrugs As described above, due to the inherently low aqueous solubility of L-DOPA and carbidopa at physiologically acceptable pHs for injection, significant technical problems arise in the development of improved pharmaceutical compositions and treatment methods. Such problems include, for example, the difficulty of achieving formulation stability within an appropriate dosing volume and required pH range. These problems are further complicated by the requirement that the pharmaceutical compositions and treatment methods provide pharmacokinetically appropriate and pharmacokinetically consistent control of dopamine levels in the patient's brain.

[0034] Previous prodrug approaches have heretofore been unsuccessful for a number of reasons due to these technical problems (such as insufficient chemical stability, insufficient solubility, in vivo bioconversion problems, etc.), and there has been no success in commercializing injectable L-dopa prodrugs or carbidopa prodrugs. However, the prodrugs, pharmaceutical combinations and compositions, and treatment methods of the present disclosure overcome these problems. Using them, patients suffering from Parkinson's disease and related conditions can be treated, and invasive surgery is not always required. In various embodiments of the present disclosure, the compositions include L-dopa and carbidopa prodrugs that convert in vivo to L-dopa and carbidopa, enabling delivery by continuous administration methods such as intragastric, intramuscular, intravenous, and subcutaneous administration. These novel prodrugs, combinations, compositions, and methods of the present disclosure represent an advancement in the treatment of Parkinson's disease and other related conditions.

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

[0036] [Chemical Formula] Wherein, R 1 and R 2 are each independently selected from the group consisting of hydrogen, -P(O)(OH) 2 , and -R 5 -O-P(O)(OH) 2 ; R 5 is C 1 -C 4 -alkyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 1 and R 2 is -P(O)(OH) 2 or -R 5 -O-P(O)(OH) 2It is so. In one aspect, the compound corresponds to formula (I) in structure. In another aspect, the compound is a pharmaceutically acceptable salt of a compound corresponding to formula (I) in structure.

[0037] In another embodiment, the present disclosure is directed to R 1 and R 2 each independently selected from the group consisting of hydrogen and -P(O)(OH) 2 ; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 1 and R 2 is -P(O)(OH) 2 and relates to a compound corresponding to formula (I) in structure or a pharmaceutically acceptable salt thereof. In one aspect, the compound corresponds to formula (I) in structure. In another aspect, the compound is a pharmaceutically acceptable salt of a compound corresponding to formula (I) in structure.

[0038] In another embodiment, the present disclosure is directed to a compound corresponding to formula (I-a) in structure:

[0039]

Chemical formula

[0040] In another embodiment, the present disclosure is directed to a compound corresponding to formula (I-b) in structure:

[0041]

Chemical formula

[0042] In another embodiment, the present disclosure relates to a compound corresponding to formula (I-c) in structure:

[0043]

Chemical formula

[0044] In another embodiment, the present disclosure relates to R 1 and R 2 each independently selected from the group consisting of hydrogen and -R 5 -O-P(O)(OH) 2 ; R 5 is C 1 -C 4 -alkyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 1 and R 2 is -R 5 -O-P(O)(OH) 2 and relates to a compound corresponding to formula (I) in structure or a pharmaceutically acceptable salt thereof.

[0045] In another embodiment, the present disclosure relates to R 1 and R 2 each independently selected from the group consisting of hydrogen and -R 5 -O-P(O)(OH) 2 ; R 5 is methyl; R 6 is hydrogen or C 1 -C 4-alkyl; provided that R 1 and R 2 at least one of which is -R 5 -O-P(O)(OH) 2 relates to a compound corresponding to formula (I) in structure or a pharmaceutically acceptable salt thereof.

[0046] In another embodiment, the present disclosure provides that R 1 and R 2 are each independently selected from the group consisting of hydrogen and -R 5 -O-P(O)(OH) 2 ; R 5 is ethyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that R 1 and R 2 at least one of which is -R 5 -O-P(O)(OH) 2 relates to a compound corresponding to formula (I) in structure or a pharmaceutically acceptable salt thereof.

[0047] In another embodiment, the present disclosure provides that R 1 and R 2 are each independently selected from the group consisting of hydrogen and -R 5 -O-P(O)(OH) 2 ; R 5 is propyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that R 1 and R 2 at least one of which is -R 5 -O-P(O)(OH) 2 relates to a compound corresponding to formula (I) in structure or a pharmaceutically acceptable salt thereof.

[0048] In another embodiment, the present disclosure provides that R 1 and R 2 are each independently selected from the group consisting of hydrogen and -R 5 -O-P(O)(OH) 2selected from the group consisting of; R 5 is butyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that R 1 and R 2 at least one of which is -R 5 -O-P(O)(OH) 2 and relates to a compound corresponding to formula (I) in structure or a pharmaceutically acceptable salt thereof.

[0049] In another embodiment, the present disclosure provides that R 1 and R 2 are each independently hydrogen, -P(O)(OH) 2 and -R 5 -O-P(O)(OH) 2 selected from the group consisting of; R 5 is C 1 -C 2 -alkyl; R 6 is hydrogen; provided that R 1 and R 2 at least one of which is -P(O)(OH) 2 or -R 5 -O-P(O)(OH) 2 and relates to a compound corresponding to formula (I) in structure or a pharmaceutically acceptable salt thereof.

[0050] In another embodiment, the present disclosure provides that R 1 and R 2 are each independently hydrogen or -R 5 -O-P(O)(OH) 2 ; R 5 is C 1 -C 2 -alkyl; R 6 is hydrogen; provided that R 1 and R 2 one of which is -R 5 -O-P(O)(OH) 2 and relates to a compound corresponding to formula (I) in structure or a pharmaceutically acceptable salt thereof.

[0051] In another embodiment, the present disclosure relates to a compound corresponding to formula (I-d) in structure:

[0052]

Chemical formula

[0053] In another embodiment, the present disclosure relates to a compound corresponding to formula (I-e) in structure:

[0054]

Chemical formula

[0055] In another embodiment, the present disclosure relates to R 1 And R 2 Are each independently selected from the group consisting of hydrogen and -P(O)(OH) 2 ; R 6 Is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 1 And R 2 Is -P(O)(OH) 2 A compound corresponding to formula (I) in structure or a pharmaceutically acceptable salt thereof.

[0056] In another embodiment, the present disclosure relates to R 1 And R 2 Are each independently selected from the group consisting of hydrogen and -P(O)(OH) 2 ; R 6 Is methyl; provided that R1 and R 2 at least one of which is -P(O)(OH) 2 relates to a compound corresponding to formula (I) in structure or a pharmaceutically acceptable salt thereof.

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

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

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

[0060] In another embodiment, the present disclosure provides that R 1 and R 2each independently is hydrogen, -P(O)(OH) 2 or -R 5 -O-P(O)(OH) 2 ; R 5 is C 1 -C 2 -alkyl; R 6 is C 1 -C 2 -alkyl; provided that one of R 1 and R 2 is -P(O)(OH) 2 or -R 5 -O-P(O)(OH) 2 relates to a compound corresponding to formula (I) in structure or a pharmaceutically acceptable salt thereof.

[0061] In another embodiment, the present disclosure relates to a compound corresponding to the following formula (I-f) in structure:

[0062]

Chemical formula

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

[0064]

Chemical formula

[0065] In another embodiment, the present disclosure relates to a compound wherein R 3 and R 4 are each independently selected from the group consisting of hydrogen and -P(O)(OH) 2 ; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 3 and R 4 is -P(O)(OH) 2 or a pharmaceutically acceptable salt thereof, which corresponds to formula (II) in structure. In one embodiment, the compound corresponds to formula (II) in structure. In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding to formula (II) in structure.

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

[0067]

Chemical formula

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

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

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

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

[0072] In another embodiment, the present disclosure relates to R 3 and R 4 each independently selected from the group consisting of hydrogen and -R 5 -O-P(O)(OH) 2 ; R 5 is C 1 -C 4 -alkyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 3 and R 4 is -R 5 -O-P(O)(OH) 2 ; and relates to a compound corresponding to formula (II) in structure or a pharmaceutically acceptable salt thereof.

[0073] In another embodiment, the present disclosure relates to R 3 and R 4are each independently hydrogen and -R 5 -O-P(O)(OH) 2 selected from the group consisting of; R 5 is methyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 3 and R 4 is -R 5 -O-P(O)(OH) 2 in the structure relates to a compound corresponding to formula (II).

[0074] In another embodiment, the present disclosure provides that R 3 and R 4 are each independently hydrogen and -R 5 -O-P(O)(OH) 2 selected from the group consisting of; R 5 is ethyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 3 and R 4 is -R 5 -O-P(O)(OH) 2 in the structure relates to a compound corresponding to formula (II).

[0075] In another embodiment, the present disclosure provides that R 3 and R 4 are each independently hydrogen and -R 5 -O-P(O)(OH) 2 selected from the group consisting of; R 5 is propyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 3 and R 4 is -R 5 -O-P(O)(OH) 2 in the structure relates to a compound corresponding to formula (II).

[0076] In another embodiment, the present disclosure is directed to R 3 and R 4 each independently selected from the group consisting of hydrogen and -R 5 -O-P(O)(OH) 2 ; R 5 is butyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 3 and R 4 is -R 5 -O-P(O)(OH) 2 and relates to a compound corresponding to formula (II) in structure.

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

[0078]

Chemical formula

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

[0080]

Chemical formula

[0081] In another embodiment, the present disclosure is directed to R 3 and R 4 each independently selected from the group consisting of hydrogen and -P(O)(OH) 2 ; R6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 3 and R 4 is -P(O)(OH) 2 relates to a compound corresponding to formula (II) in structure or a pharmaceutically acceptable salt thereof.

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

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

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

[0085] In another embodiment, the present disclosure relates to R 3 and R 4 each independently selected from the group consisting of hydrogen and -P(O)(OH) 2 ; R 6 is butyl; provided that at least one of R 3 and R 4 is -P(O)(OH) 2 , to a compound corresponding to formula (II) in structure or a pharmaceutically acceptable salt thereof.

[0086] In another embodiment, the present disclosure relates to R 3 being hydrogen; R 4 being -P(O)(OH) 2 ; R 6 being methyl, to a compound corresponding to formula (II) in structure or a pharmaceutically acceptable salt thereof.

[0087] III. Intermediate By the novel synthetic routes disclosed herein for producing L-doparic acid and carbidoparic acid, the following novel intermediate compounds have been obtained.

[0088]

Chemical formula

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

[0090] IV. Pharmaceutical combination / composition 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 still 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, the pharmaceutical combinations disclosed herein can comprise a carbidopa prodrug in a first pharmaceutical composition and an L-DOPA prodrug in a separate second pharmaceutical composition. Alternatively, the pharmaceutical combination can comprise a carbidopa prodrug and an L-DOPA prodrug in the same pharmaceutical composition.

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

[0094] [Chemical formula] [Wherein, R 1 and R 2 are each independently selected from the group consisting of hydrogen, -P(O)(OH) 2 , and -R 5 -O-P(O)(OH) 2 ; R 5 is C 1 -C 4 -alkyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 1 and R 2 is -P(O)(OH) 2 or -R 5 -O-P(O)(OH) 2or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier thereof. In one embodiment, the composition comprises a first compound corresponding to formula (I) in structure. In another embodiment, the composition comprises a pharmaceutically acceptable salt of the first compound corresponding to formula (I) in structure.

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

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

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

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

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

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

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

[0102]

Chemical formula

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

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

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

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

[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, wherein the first compound corresponds in structure to formula (I):

[0109]

Chemical formula

[0110]

Chemical formula

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

[0112] In another embodiment, the pharmaceutical composition contains the first compound, the second compound, and a pharmaceutically acceptable carrier, the first compound corresponds in structure to formula (I-a) or a pharmaceutically acceptable salt thereof; the second compound corresponds in structure to formula (II):

[0113]

Chemical formula

[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 (I-b) or a pharmaceutically acceptable salt thereof; the second compound corresponds in structure to formula (II):

[0115] [Chemical formula] or a pharmaceutically acceptable salt thereof, R 3 and R 4 are each independently hydrogen, -P(O)(OH) 2 , and -R 5 -O-P(O)(OH) 2 selected from the group consisting of; R 5 is C 1 -C 4 -alkyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 3 and R 4 is -P(O)(OH) 2 or -R 5 -O-P(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 (I-c) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to formula (II):

[0117]

Chemical formula

[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 (I-d) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to formula (II):

[0119]

Chemical formula

[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 (I-e) or a pharmaceutically acceptable salt thereof; the second compound corresponds in structure to formula (II):

[0121]

Chemical formula

[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 (I-f) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to formula (II):

[0123]

Chemical formula

[0124] 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 (I):

[0125]

Chemical formula

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

[0127]

Chemical formula

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

[0129] [Chemical] or a pharmaceutically acceptable salt thereof, and R 1 and R 2 are each independently selected from the group consisting of hydrogen, -P(O)(OH) 2 , and -R 5 -O-P(O)(OH) 2 ; R 5 is C 1 -C 4 -alkyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 1 and R 2 is -P(O)(OH) 2 or -R 5 -O-P(O)(OH) 2 ; The second compound corresponds to formula (II-c) or a pharmaceutically acceptable salt thereof in structure.

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

[0131] [Chemical] or a pharmaceutically acceptable salt thereof, and R 1 and R 2 are each independently selected from the group consisting of hydrogen, -P(O)(OH) 2 , and -R 5 -O-P(O)(OH) 2 ; R 5 is C 1 -C 4 -alkyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 1 and R 2 is -P(O)(OH)2 or -R 5 -O-P(O)(OH) 2 and; 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 corresponds in structure to formula (I):

[0133]

Chemical formula

[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 (I-a) 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 (I-b) 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 (I-c) 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 (I-d) 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 (I-e) 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 (I-f) 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, wherein the first compound corresponds in structure to formula (I-a) or a pharmaceutically acceptable salt thereof; and 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, wherein the first compound corresponds in structure to formula (I-b) or a pharmaceutically acceptable salt thereof; and 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, wherein the first compound corresponds in structure to formula (I-c) or a pharmaceutically acceptable salt thereof; and 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, wherein the first compound corresponds in structure to formula (I-d) or a pharmaceutically acceptable salt thereof; and 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, wherein the first compound corresponds in structure to formula (I-e) 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 (I-f) 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 (I-a) 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 (I-b) 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 (I-c) 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 (I-d) 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 (I-e) 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 (I-f) 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 (I-a) 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 (I-b) 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 (I-c) 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 (I-d) 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 (I-e) 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 (I-f) 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 (I-a) 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, wherein the first compound corresponds in structure to formula (I-b) or a pharmaceutically acceptable salt thereof; and 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, wherein the first compound corresponds in structure to formula (I-c) or a pharmaceutically acceptable salt thereof; and 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, wherein the first compound corresponds in structure to formula (I-d) or a pharmaceutically acceptable salt thereof; and 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, wherein the first compound corresponds in structure to formula (I-e) or a pharmaceutically acceptable salt thereof; and 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, wherein the first compound corresponds in structure to formula (I-f) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to formula (II-e) or a pharmaceutically acceptable salt thereof.

[0164] The pharmaceutical composition of the present disclosure containing both the first compound and the second compound will contain the first compound and the second compound in a weight ratio of 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.

[0165] B. Another excipient The pharmaceutical composition of the present disclosure may contain one or more other pharmaceutically acceptable excipients. The term "excipient" refers to a substance that is not a therapeutic agent per se but is used as a carrier or medium for delivering a therapeutic agent to a subject, or is added to a pharmaceutical composition to enhance handleability or storability, enable the formation of a unit dose of the composition, or make it easier to do so.

[0166] Excipients include, for example, antioxidants, agents for adjusting pH and osmolality, preservatives, thickeners, coloring agents, buffering agents, bactericidal agents, and stabilizers. When an excipient is present, it is usually present in an amount of from about 0.001% to about 95% by weight, from about 0.01% to about 80% by weight, from about 0.02% to about 25% by weight, or from about 0.3% to about 10% by weight.

[0167] In one embodiment, the pharmaceutical composition may contain an antioxidant. Antioxidants suitable 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 contain a buffering agent. Examples of buffering agents include agents that minimize pH changes. Suitable types of buffering agents for use in the various embodiments of the present invention include salts of Group IA metals, such as bicarbonates of Group IA metals, carbonates of Group IA metals, alkali or alkaline earth metal buffering agents, aluminum buffering agents, calcium buffering agents, sodium buffering agents, or magnesium buffering agents. Suitable buffering agents further include any of the above carbonates, phosphates, bicarbonates, citrates, borates, acetates, phthalates, tartrates, succinates, such as phosphoric acid, citric acid, boric acid, acetic acid, bicarbonate, and sodium or potassium carbonate.

[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 exist as separate and distinct 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 compounds are combined with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or bulking agents 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) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retardants such as paraffin; f) absorption promoters such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol 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 formulation can also contain buffering agents.

[0171] Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using carriers such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0172] Solid formulations of tablets, dragees, capsules, and granules can be prepared with coating agents and shell agents such as enteric coatings and other coatings known in the pharmaceutical industry. They can contain opacifying agents and can be of a composition that preferentially releases, appropriately and with delay, in a certain part of the intestinal tract. Embedding compositions that can be used include polymeric substances and waxes.

[0173] The first and / or second compound(s) can, where appropriate, also be in the form of microcapsules (separately or together) comprising one or more of the above 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 nasal 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 aspect, the L-DOPA prodrug concentration is at least about 10 mg / mL. In another aspect, the L-DOPA prodrug concentration is at least about 20 mg / mL. In another aspect, the L-DOPA prodrug concentration is at least about 30 mg / mL. In another aspect, the L-DOPA prodrug concentration is at least about 50 mg / mL. In another aspect, the L-DOPA prodrug concentration is at least about 100 mg / mL. In another aspect, the L-DOPA prodrug concentration is at least about 150 mg / mL. In another aspect, the L-DOPA prodrug concentration is at least about 200 mg / mL. In another aspect, the L-DOPA prodrug concentration is at least about 250 mg / mL. In another aspect, the L-DOPA prodrug concentration is at least about 300 mg / mL. In another aspect, the L-DOPA prodrug concentration is at least about 350 mg / mL. In another aspect, 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, specifically 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 aspect, the carbidopa prodrug concentration is at least about 10 mg / mL. In another aspect, the carbidopa prodrug concentration is at least about 20 mg / mL. In another aspect, the carbidopa prodrug concentration is at least about 30 mg / mL. In another aspect, the carbidopa prodrug concentration is at least about 50 mg / mL. In another aspect, the carbidopa prodrug concentration is at least about 100 mg / mL. In another aspect, the carbidopa prodrug concentration is at least about 150 mg / mL. In another aspect, the carbidopa prodrug concentration is at least about 200 mg / mL. In particular, the above 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, its pH is ≧ about 7.4. The explicitly disclosed ranges include any combination of the values listed above, for example, from about 2.0 to about 7.5, from about 6.0 to about 9.0, from about 6.4 to about 7.7, from about 7.0 to about 7.9, from about 7.3 to about 8.2, etc. In one aspect, the pH is from about 2 to about 8. In one aspect, the pH is from about 2.0 to about 7.5. In another aspect, the pH is from about 3.0 to about 7.5. In another aspect, the pH is from about 4.0 to about 7.5. In another aspect, the pH is from about 5.0 to about 7.5. In another aspect, the pH is from 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 in a stable state in a liquid composition (e.g., an aqueous solution) 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 at the above pH. In particular, the pharmaceutical composition can remain in a stable state in an aqueous solution for ≧ about 24 hours at a pH of about 6 to about 8. The explicitly disclosed ranges include any combination of the values listed above, e.g., from about 24 hours to about 180 hours, from about 24 hours to about 168 hours, from about 36 hours to about 72 hours, etc. Typically, the liquid composition is stored prior to administration (e.g., intragastric, subcutaneous, jejunal, nasal, intramuscular and / or intravenous), and thus, during the storage period, the first compound and the second compound must remain in a stable state and hardly decompose. Therefore, such an improvement in stability is important for the liquid composition of the pharmaceutical composition.

[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 have a solubility 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, ≧ 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 at a pH of about 5 to about 8, or in particular at a nearly neutral pH of about 6.9 to about 7.5. The explicitly disclosed ranges include any combination of the values listed above, for example, about 90 mg / mL to about 500 mg / mL, about 100 mg / mL to about 300 mg / mL, about 200 mg / mL to about 500 mg / mL, etc. In particular, the first compound has a solubility of ≧ about 160 mg / mL, particularly ≧ about 200 mg / mL, at a neutral pH of about 7.4, for example. In particular, the second compound has a solubility of ≧ about 370 mg / mL, particularly ≧ about 400 mg / mL, at a neutral pH of about 7.4, for example. This high solubility allows for a higher concentration of the first compound and / or the second compound in the pharmaceutical composition, thereby resulting in a more effective and higher systemic level of the first compound and / or the second compound when administered 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) can release a certain amount of hydrazine, which is a carcinogen. Therefore, it is important to reduce the release of hydrazine from the pharmaceutical composition. Unexpectedly, at a pH of about 5 to about 8 (e.g., 7.4), the pharmaceutical compositions described herein release hydrazine in an amount of ≤ about 60 ppm / hour, ≤ about 55 ppm / hour, ≤ about 50 ppm / hour, ≤ about 45 ppm / hour, ≤ about 40 ppm / hour, ≤ about 35 ppm / hour, ≤ about 30 ppm / hour, ≤ about 25 ppm / hour, ≤ about 20 ppm / hour, ≤ about 15 ppm / hour, ≤ about 10 ppm / hour, ≤ about 5 ppm / hour, ≤ about 4 ppm / hour, ≤ about 3 ppm / hour, ≤ about 2 ppm / hour, ≤ about 1 ppm / hour, or ≤ about 0.5 ppm / hour. The explicitly disclosed ranges include any combination of the values listed above, e.g., about 0.5 to about 60 ppm / hour, about 1 ppm / hour to about 40 ppm / hour, about 1 ppm / hour to about 10 ppm / hour, about 2 ppm / hour to about 4 ppm / hour, etc. In particular, the pharmaceutical composition releases less than about 1 ppm / hour of hydrazine.

[0182] H. Ready-to-Use Agent In yet other embodiments, the disclosure relates to ready-to-use vials or cartridges or containers or enclosures suitable for containing liquid pharmaceutical formulations. Such enclosures can function 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 the carbidopa prodrug and / or L-dopa prodrug in powder form such that the vial can be in a ready-to-use format that allows for reconstitution with an aqueous medium to enable injection or dosing to a patient.

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

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

[0185]

Chemical formula

[0186]

Chemical formula

[0187] V. Treatment method The present disclosure further relates to a method of 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, the method of treating Parkinson's disease and related conditions comprises providing rescue therapy for the treatment of Parkinson's disease and related conditions. As used herein, the term "rescue therapy" refers to acute and intermittent therapies that can be used to treat the sudden re-immergence of motor symptoms (e.g., sudden "off" episodes or "end-of-dose" wearing-off and unpredictable "on / off" episodes). Patients with severe motor complications can alternate between "off" periods defined as periods of hypokinesia, slowness, and rigidity, and "on" periods defined as periods of good motor system control without troublesome dyskinesias.

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

[0190] A. The first compound and the second compound and combinations thereof In one embodiment, the present disclosure is a method of treating a condition in a subject (e.g., a patient) in need of treatment, the method 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]

Chemical formula

[0192]

Chemical formula

[0193] In one embodiment, the first compound and the second compound are administered together to a subject (e.g., a patient) in an amount that provides a therapeutically effective amount.

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

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

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

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

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

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

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

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

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

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

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

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

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

[0207] In another embodiment, the first compound corresponds to formula (I-b) in structure, and the second compound corresponds to formula (II-c) in structure.

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

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

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

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

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

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

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

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

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

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

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

[0219] In another embodiment, the first compound corresponds to formula (I-b) in structure, and the second compound corresponds to formula (II-e) in structure.

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

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

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

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

[0224] B. Conditions to be 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 sleep disorder in Parkinson's disease patients (i.e., a method for reducing sleep disorder in Parkinson's disease patients).

[0226] In another embodiment, the condition treated by administering the first compound and the second compound is motor ability disorder in Parkinson's disease patients (i.e., a method for improving motor ability in Parkinson's disease patients).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0263] D. Conditions to be Treated 1 In an 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 disorder in a Parkinson's disease patient (i.e., a method for reducing sleep disorder in a Parkinson's disease patient).

[0265] In another embodiment, the condition treated by administering the pharmaceutical composition is motor ability disorder in a Parkinson's disease patient (i.e., a method for improving motor ability in a Parkinson's disease patient).

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

[0267] In another embodiment, the pharmaceutical composition is administered to treat abnormal movements in a Parkinson's disease patient.

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

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

[0270] In another embodiment, the condition treated by administering the pharmaceutical composition is nocturnal ability disorder in a Parkinson's disease patient (i.e., a method for reducing nocturnal ability disorder in a Parkinson's disease patient).

[0271] E. Weight ratio and administration route 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 (either 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 a patient in the form of a solid composition (or a plurality of 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 a patient in the form of a liquid composition (or a plurality of liquid compositions). In one aspect, the composition contains 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 a patient as a liquid composition (either separately or in the same pharmaceutical composition) suitable for intragastric, subcutaneous, nasal, intramuscular or intravenous administration. In one aspect, the liquid composition is suitable for intragastric administration. In another aspect, the liquid composition is suitable for subcutaneous administration. In another aspect, the liquid composition is suitable for intramuscular administration. In another aspect, the liquid composition is suitable for intravenous administration. In another aspect, 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., into the jejunum, into the duodenum) (separately or in the same pharmaceutical composition). They can be administered (or "infused") directly into the intestine, e.g., into the duodenum or jejunum, by a permanent tube inserted by percutaneous endoscopic gastrostomy using, for example, an extracorporeal transabdominal tube and an in vivo intestinal tube. In one aspect, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) are administered via a tube inserted by a radiological gastrojejunostomy. In another aspect, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) are first administered via a temporary nasoduodenal tube inserted into the patient to determine whether the patient responds well to the treatment prior to insertion of the permanent tube.

[0276] In some embodiments where the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) are administered via enteral administration, the administration can be performed using a portable pump such as the pump sold under the trade name CADD-Legacy DuoDopa.RTM. 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, transabdominal port, duodenal tube or jejunal tube for enteral administration.

[0277] 1. In one embodiment, the method includes administering (either 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 over 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 over 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 substantially continuously subcutaneously over a period of at least about 16 hours.

[0278] F. Dosage and Plasma Concentration 1. In one embodiment, the dosages of the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) administered to a patient are adjusted to optimize the clinical response achieved by the subject (e.g., the patient), which means maximizing the functional ON - time during the day by reducing the number and duration of OFF - time episodes (i.e., bradykinesia) and shortening the ON - time with severe dyskinesia.

[0279] 1. In one embodiment, the daily dose of the L - dopa prodrug (i.e., the second compound) administered to a patient according to the methods of the present disclosure can be, for example, from about 20 to about 1000000 mg per day, from about 20 to about 100000 mg per day, from about 20 to about 10000 mg per day, from about 20 to about 5000 mg per day, from about 20 mg to about 4000 mg per day, from about 20 mg to about 3000 mg per day, from about 20 mg to about 2000 mg per day, or from about 20 mg to about 1000 mg per day. In particular, L - dopa phosphate prodrugs, specifically L - dopa 3′ - monophosphate prodrug, L - dopa 4′ - monophosphate prodrug, and / or L - dopa 3′,4′ - diphosphate prodrug are administered at the above - mentioned daily doses.

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

[0281] In some embodiments, administer an amount of a first compound and an amount of a second compound that, in combination, are sufficient to achieve an L-DOPA plasma level of at least about 100 ng / mL in a patient. In one aspect, the L-DOPA plasma level is at least about 200 ng / mL. In another aspect, the L-DOPA plasma level is at least about 300 ng / mL. In another aspect, the L-DOPA plasma level is at least about 400 ng / mL. In another aspect, the L-DOPA plasma level is at least about 500 ng / mL. In another aspect, the L-DOPA plasma level is at least about 600 ng / mL. In another aspect, the L-DOPA plasma level is at least about 700 ng / mL. In another aspect, the L-DOPA plasma level is at least about 800 ng / mL. In another aspect, the L-DOPA plasma level is at least about 900 ng / mL. In another aspect, the L-DOPA plasma level is at least about 1,000 ng / mL. In another aspect, the L-DOPA plasma level is at least about 1,500 ng / mL. In another aspect, the L-DOPA plasma level is at least about 2,000 ng / mL. In another aspect, the L-DOPA plasma level is at least about 3,000 ng / mL. In another aspect, the L-DOPA plasma level is at least about 4,000 ng / mL. In another aspect, the L-DOPA plasma level is at least about 5,000 ng / mL. In another aspect, the L-DOPA plasma level is at least about 6,000 ng / mL. In another aspect, the L-DOPA plasma level is at least about 7,000 ng / mL. In another aspect, the L-DOPA plasma level is at least about 8,000 ng / mL. In another aspect, the L-DOPA plasma level is at least about 9,000 ng / mL. In particular, the first compound can be a carbidopa phosphate prodrug, specifically 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-dopamine phosphate prodrug, specifically 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, an amount of the first compound and an 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 aspect, the L-dopa plasma level is from about 10 ng / mL to about 8,000 ng / mL. In another aspect, the L-dopa plasma level is from about 25 ng / mL to about 6,000 ng / mL. In another aspect, the L-dopa plasma level is from about 50 ng / mL to about 4,000 ng / mL. In another aspect, the L-dopa plasma level is from about 100 ng / mL to about 2,000 ng / mL. In another aspect, the L-dopa plasma level is from about 25 ng / mL to about 1,200 ng / mL. In another aspect, the L-dopa plasma level is from about 10 ng / mL to about 500 ng / mL. In another aspect, the L-dopa plasma level is from about 25 ng / mL to about 500 ng / mL. In particular, the first compound can be a carbidopa phosphate prodrug, specifically 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-dopamine phosphate prodrug, specifically 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 range can be maintained over at least about 1-hour intervals, 2-hour intervals, 3-hour intervals, 4-hour intervals, 5-hour intervals, 6-hour intervals, 7-hour intervals, 8-hour intervals, 9-hour intervals, 10-hour intervals, 11-hour intervals, 12-hour intervals, 13-hour intervals, 14-hour intervals, 15-hour intervals, 16-hour intervals, 17-hour intervals, 18-hour intervals, 19-hour intervals, 20-hour intervals, 21-hour intervals, 22-hour intervals, 23-hour intervals, or 24-hour intervals.

[0285] Plasma levels of G. L-dopamine prodrug and carbidopa prodrug 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., the L-dopamine prodrug, remains in the plasma and is not converted to L-dopa. Further, there can be an unexpected concentration of the first compound, i.e., the carbidopa prodrug, that remains in the plasma and is not converted to carbidopa. Surprisingly, the L-dopamine prodrug and / or the carbidopa prodrug can remain in the plasma over the entire duration of 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-dopamine prodrug plasma levels of from about 0 ng / mL to about 3600 ng / mL, from about 1 ng / mL to about 3600 ng / mL, or from about 10 ng / mL to about 3600 ng / mL. In one aspect, the L-dopamine prodrug plasma levels are from about 10 ng / mL to about 3200 ng / mL. In another aspect, the L-dopamine prodrug plasma levels are from about 25 ng / mL to about 2800 ng / mL. In another aspect, the L-dopamine prodrug plasma levels are from about 50 ng / mL to about 2400 ng / mL. In another aspect, the L-dopamine prodrug plasma levels are from about 10 ng / mL to about 2000 ng / mL. In another aspect, the L-dopamine prodrug plasma levels are from about 25 ng / mL to about 1600 ng / mL. In another aspect, the L-dopamine prodrug plasma levels are from about 25 ng / mL to about 1200 ng / mL. In another aspect, the L-dopamine prodrug plasma levels are from about 10 ng / mL to about 800 ng / mL. In another aspect, the L-dopamine prodrug plasma levels are from about 10 ng / mL to about 400 ng / mL. In another aspect, the L-dopamine prodrug plasma levels are from about 10 ng / mL to about 200 ng / mL. In another aspect, the L-dopamine 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 carbidopa-levodopa prodrug plasma levels of from about 0 ng / mL to about 600 ng / mL, from about 1 ng / mL to about 600 ng / mL or from about 10 ng / mL to 600 ng / mL. In one aspect, the carbidopa-levodopa prodrug plasma levels are from about 10 ng / mL to about 500 ng / mL. In another aspect, the carbidopa-levodopa prodrug plasma levels are from about 10 ng / mL to about 400 ng / mL. In another aspect, the carbidopa-levodopa prodrug plasma levels are from about 10 ng / mL to about 300 ng / mL. In another aspect, the carbidopa-levodopa prodrug plasma levels are from about 10 ng / mL to about 200 ng / mL. In another aspect, the carbidopa-levodopa prodrug plasma levels are from about 10 ng / mL to about 100 ng / mL. In another aspect, the carbidopa-levodopa prodrug plasma levels are from about 25 ng / mL to about 600 ng / mL. In another aspect, the carbidopa-levodopa prodrug plasma levels are from about 25 ng / mL to about 500 ng / mL. In another aspect, the carbidopa-levodopa prodrug plasma levels are from about 25 ng / mL to about 400 ng / mL. In another aspect, the carbidopa-levodopa prodrug plasma levels are from about 25 ng / mL to about 300 ng / mL. In another aspect, the carbidopa-levodopa prodrug plasma levels are from about 25 ng / mL to about 200 ng / mL. In another aspect, the carbidopa-levodopa prodrug plasma levels are from about 25 ng / mL to about 100 ng / mL.

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

[0289] In some embodiments, an amount of the first compound and an amount of the second compound are administered that are sufficient to maintain the carbidopa plasma level below about 2500 ng / mL. In one aspect, the carbidopa plasma level is less than about 2000 ng / mL. In another aspect, the carbidopa plasma level is less than about 1500 ng / mL. In another aspect, the carbidopa plasma level is less than about 1000 ng / mL. In another aspect, the carbidopa plasma level is less than about 500 ng / mL. In another aspect, the carbidopa plasma level is less than about 250 ng / mL. In another aspect, the carbidopa plasma level is less than about 100 ng / mL. In another aspect, the carbidopa plasma level is less than about 50 ng / mL. In another aspect, 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 interval, 2 hour interval, 3 hour interval, 4 hour interval, 5 hour interval, 6 hour interval, 7 hour interval, 8 hour interval, 9 hour interval, 10 hour interval, 11 hour interval, 12 hour interval, 13 hour interval, 14 hour interval, 15 hour interval, 16 hour interval, 17 hour interval, 18 hour interval, 19 hour interval, 20 hour interval, 21 hour interval, 22 hour interval, 23 hour interval or 24 hour interval.

[0291] H. Phosphorus Load In some embodiments, administering an amount of a first compound and an amount of a second compound to a subject can achieve a phosphorus uptake 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 limit of the acceptable tolerance uptake level. See DRI Dietary Reference Intakes for Calcium, Phosphorus, Vitamin D and Fluoride at www.nap.edu / ctalog / 5776. In further embodiments, administering therapeutic concentrations of the first and second compounds to the subject results in a total phosphorus load of from about 350 mg / day to about 550 mg / day, or from about 400 mg / day to about 500 mg / day, or from about 400 mg / day to about 450 mg / day, or about 427 mg / day. The average dietary phosphorus intake in the United States population is about 1500 mg / day. See Ervin R.B., 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 the 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 upper limit of the acceptable tolerance intake level of 3000 mg / day.

[0292] VI. Combined administration and / or additional therapy The treatment method of the present disclosure may further include administering one or more therapeutic agents (e.g., anti-Parkinson's disease drugs) for the treatment of Parkinson's disease in addition to the L-dopa prodrug and the carbidopa prodrug. In one embodiment, the therapeutic agent for recall is 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), and is selected from the group consisting of. In one aspect, the additional therapeutic agent is selected from the group consisting of decarboxylase inhibitors other than carbidopa. In another aspect, the additional therapeutic agent is selected from the group consisting of COMT inhibitors such as entacapone. In another aspect, the additional therapeutic agent is selected from the group consisting of MAO-A inhibitors. In another aspect, the additional therapeutic agent is selected from the group consisting of MAO-B inhibitors.

[0293] The additional therapeutic agent and the first and second compounds can be administered together or separately, and substantially simultaneously or sequentially with each other. Further, the additional therapeutic agent and the first and second compounds can be separate formulations that may be the same or different. For example, entacapone can be used in combination, can be administered orally, and the first and second compounds described herein can be administered subcutaneously (separately or together in the same pharmaceutical composition). Further, the therapeutic agent and the first and second compounds may be packaged together, for example, in a single container or in a plurality of containers within a single outer package, or may be provided simultaneously in separate packages ("general provision").

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

[0295] VII. Kit The present disclosure also relates to kits comprising one or more pharmaceutical formulations comprising a carbidopa prodrug; kits comprising one or more pharmaceutical formulations comprising an L-dopa prodrug; and kits comprising one or more pharmaceutical formulations comprising both a carbidopa prodrug and an L-dopa prodrug. The kits may include one or more other therapeutic agents and / or instructions, for example, instructions for kit use for treating 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 contemplated that the above various embodiments may be adapted when using a D-dopa prodrug or a racemate of a D-dopa prodrug and an L-dopa prodrug instead of the L-dopa prodrug.

[0298] VIII. L-Dopa and Carbidopa Prodrug Polymorphs Specific crystal forms of the above L-dopa prodrugs and carbidopa prodrugs have also been identified and are described herein. Specifically, such crystal forms are L-dopa 4'-monophosphate anhydride (i), L-dopa 4'-monophosphate anhydride (ii), L-dopa 3'-monophosphate, L-dopa 3',4'-diphosphate trihydrate, carbidopa 4'-monophosphate trihydrate, carbidopa 4'-monophosphate dihydrate, carbidopa 4'-monophosphate anhydride, carbidopa 3'-monophosphate (i), carbidopa 3'-monophosphate (ii), and sodium carbidopa 3',4'-diphosphate.

[0299] A. L-dopa prodrug polymorphs The L-dopa 4'-monophosphate anhydride (i) crystalline solid is identifiable by characteristic peaks in its powder X-ray diffraction pattern (Figure 13). One of ordinary skill in analytical chemistry would likely consider it possible to readily identify the L-dopa 4'-monophosphate anhydride (i) solid by just one characteristic peak in the powder X-ray diffraction pattern. Thus, in one or more embodiments, a crystalline L-dopa 4'-monophosphate anhydride (i) showing at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or 15 characteristic peaks in the 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 is provided. 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, giving a lattice volume of 1105.68 Å 3 was obtained (a, b, and c are the individual lengths of the crystal lattice, respectively), which was confirmed.

[0300] The L-dopa 4'-monophosphate anhydride (ii) crystalline solid can be identified by its characteristic peaks in its powder X-ray diffraction pattern (Figure 14). One of ordinary skill in analytical chemistry would likely consider it possible to readily identify the L-dopa 4'-monophosphate anhydride (ii) solid by just one characteristic peak in the powder X-ray diffraction pattern. Thus, in one or more embodiments, crystalline L-dopa 4'-monophosphate anhydride (ii) is provided that exhibits at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or 15 characteristic peaks in the 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, 25.647 ± 0.20.

[0301] The L-dopa 3'-monophosphate crystalline solid can be identified by its characteristic peaks in its powder X-ray diffraction pattern (Figure 15). One of ordinary skill in the art of analytical chemistry would likely be able to readily identify the L-dopa 3'-monophosphate solid by just one characteristic peak in the powder X-ray diffraction pattern. Thus, in one or more embodiments, crystalline L-dopa 3'-monophosphate showing at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14 or 15 characteristic peaks in the 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 is provided.

[0302] The L-dopa 3′,4′-diphosphate trihydrate crystalline solid can be identified by its characteristic peaks in its powder X-ray diffraction pattern (Figure 16). One of ordinary skill in the art of analytical chemistry would likely consider that the L-dopa 3′,4′-diphosphate trihydrate solid can be readily identified by just one characteristic peak in the powder X-ray diffraction pattern. Thus, in one or more embodiments, crystalline L-dopa 3′,4′-diphosphate trihydrate showing at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14 or 15 characteristic peaks in the powder X-ray 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 is provided.

[0303] B. Carbidopa prodrug polymorphs Carbidopa 4'-monophosphate trihydrate crystalline solid can be identified by its characteristic peaks in the powder X-ray diffraction pattern (Figure 17). A person skilled in analytical chemistry would consider that the carbidopa 4'-monophosphate trihydrate solid can be easily identified by just one characteristic peak in the powder X-ray diffraction pattern. Thus, in one or more embodiments, crystalline carbidopa 4'-monophosphate trihydrate showing at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14 or 15 characteristic peaks in the 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 is provided. The crystal 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, whereby a lattice volume of 1568.25 Å 3 is obtained (a, b, and c are the individual lengths of the crystal lattice, respectively). It was confirmed that this is the case.

[0304] Carbidopa 4'-monophosphate dihydrate crystalline solid can be identified by its characteristic peaks in the powder X-ray diffraction pattern (Figure 18). A person skilled in analytical chemistry would consider it possible to easily identify the carbidopa 4'-monophosphate dihydrate solid by just one characteristic peak in the powder X-ray diffraction pattern. Thus, in one or more embodiments, crystalline carbidopa 4'-monophosphate dihydrate showing at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14 or 15 characteristic peaks in the powder X-ray diffraction pattern at 2θ 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 is provided. (Figure 19). A person skilled in analytical chemistry would consider it possible to easily identify the carbidopa 4'-monophosphate anhydrate solid by just one characteristic peak in the powder X-ray diffraction pattern. Thus, in one or more embodiments, crystalline carbidopa 4'-monophosphate anhydrate showing at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 characteristic peaks in the 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 is provided (Figure 20). A person skilled in analytical chemistry would consider it possible to easily identify the carbidopa 3'-monophosphate (i) solid by just one characteristic peak in the powder X-ray diffraction pattern.Accordingly, in one or more embodiments, crystalline carbide P3′-monophosphate (i) is provided that exhibits at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 characteristic peaks in the 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.

[0305] The carbide P3′-monophosphate (ii) crystalline solid can be identified by its characteristic peaks in its powder X-ray diffraction pattern (Figure 21). One of ordinary skill in analytical chemistry would likely be able to readily identify the carbide P3′-monophosphate (ii) solid by even a single characteristic peak in the powder X-ray diffraction pattern. Accordingly, in one or more embodiments, crystalline carbide P3′-monophosphate (ii) is provided that exhibits at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 characteristic peaks in the 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.

[0306] The crystalline solid of carbidopa 3′,4′-diphosphate sodium salt can be identified by its characteristic peaks in the powder X-ray diffraction pattern (Figure 22). Those skilled in the art of analytical chemistry would consider that the carbidopa 3′,4′-diphosphate sodium salt solid can be easily identified by just one characteristic peak in the powder X-ray diffraction pattern. Thus, in one or more embodiments, there is provided a crystalline carbidopa 3′,4′-diphosphate sodium salt showing at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14 or 15 characteristic peaks in the 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.

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

[0308] Powder X-ray diffraction (PXRD) analysis of the samples was performed as follows. On the sample holder, the sample was spread in a thin layer and gently flattened with a microscope slide glass to prepare the sample for X-ray diffraction analysis. For example, the sample may be ground into fine powder with a mortar and pestle or, in the case of a limited amount of sample, with a microscope slide glass. The sample was examined in one of three forms: a circular bulk holder, a quartz zero background plate, or a hot stage mount (a stage similar to the zero background plate). Cu-K α1 diffraction patterns were collected using an Inel G3000 diffractometer equipped with an incident beam germanium monochromator that provides a Cu-K line. 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 monitors all diffraction data simultaneously. The detector was calibrated by collecting the attenuated direct beam at 1° intervals for 7 seconds over a 2θ range of 90°. The calibration was checked against a silicon line position reference standard (NIST640c). The sample was placed on an aluminum sample holder and flattened with a slide glass.

[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 speed: 1 to 5° / min) or a Scintag X1 or X2 diffractometer (a germanium solid detector cooled with either liquid nitrogen or a Peltier; 45 kV and 40 mA; X-ray source: Cu; range: 2.00 to 40.00° 2θ; scan speed: 1 to 5° / min with a 2 kW normal focus X-ray tube attached).

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

[0311] Single crystal X-ray diffraction analysis of the sample was carried out by the following method. A sample for X-ray diffraction analysis was prepared by fixing a selected crystal to a glass pin with an epoxy adhesive. X-ray diffraction data was collected using a Bruker SMART system with an APEX area detector (50 kv and 40 mA; X-ray source: Mo). The data was collected at -100°C.

Example

[0312] IX. Example The following non-limiting examples are provided to further illustrate the present disclosure. The abbreviations used in the following examples include the following. 「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 the biological half-life, i.e., the time required for half of the dose 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]

Chemical formula

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

[0316] Step 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) over a period of 20 minutes at 0 °C. 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 then the reaction mixture was stirred at room temperature for 16 hours. Completion of the reaction was monitored by TLC. After the raw materials were completely consumed, the reaction mixture was made basic to pH = 10 using 10% sodium hydroxide (200 mL) and extracted with MTBE (500 mL). The organic layer was separated and discarded. The aqueous layer was made acidic to pH = 2 using 6N HCl (150 mL) and extracted with MTBE (twice with 500 mL). The combined organic layers were washed with water (500 mL) and saturated sodium chloride solution (500 mL), dehydrated with sodium sulfate, and concentrated under reduced pressure at 45 °C to 50 °C to obtain crude compound 2 as a viscous liquid (120 g, 72%).

[0317] Step 2 Cesium carbonate (123 g, 0.37 mol) was added in two portions to a solution of compound 2 (250 g, 0.75 mol) in dimethylformamide (2 liters) at 0 °C. Benzyl bromide (90.3 mL, 0.75 mol) was added dropwise to this mixture over a period of 30 minutes at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. Completion of the reaction was monitored by TLC. After the raw materials were completely consumed, the reaction mixture was diluted with water (5 liters) and extracted with MTBE (twice with 1 liter). The combined organic layers were washed with water (1 liter) and saturated sodium chloride solution (0.5 liter), dehydrated with sodium sulfate, and concentrated under reduced pressure at 45 °C to 50 °C to obtain crude compound 4 as a viscous liquid (250 g).

[0318] Step 3 Cesium carbonate (698.5 g, 2.14 mol) was added in 4 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 at 0 °C over a period of 1 hour, and the reaction mixture was stirred at room temperature for 16 hours. Completion of the reaction was monitored by TLC. After the raw materials were completely consumed, the reaction mixture was diluted with water (15 L) and extracted with MTBE (2 times with 3 L). The combined organic layers were washed with water (3 L) and saturated sodium chloride solution (1.5 L), dried over sodium sulfate, and concentrated under reduced pressure at 45 °C to 50 °C to obtain the crude product as a viscous liquid (1 kg).

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

[0320] Step 4A Potassium tert-butoxide (65.6 g, 0.58 mol) was added in 4 portions to a solution of compound 4a (200 g, 0.39 mol) in tetrahydrofuran (2.0 L) at 0 °C. To this mixture, a 10 wt% dibenzylphosphoryl chloride / toluene solution (2.31 kg, 0.78 mol) was added dropwise at 0 °C over a period of 30 minutes, and the reaction mixture was stirred at room temperature for 2 hours. Completion of the reaction was monitored by thin layer chromatography. After the raw materials were completely consumed, the reaction mixture was cooled to 0 °C - 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) and saturated NaCl solution (500 mL), dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography on silica gel (230 - 400 mesh) using 30% - 40% ethyl acetate / petroleum ether to obtain compound 5a as a viscous liquid (185 g, 61.6%).

[0321] Step 4B Potassium tert-butoxide (68.9 g, 0.61 mol) was added in 4 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 / toluene (2.43 kg, 0.82 mol) was added dropwise at 0 °C over a period of 30 minutes. After completion of the addition, the reaction mixture was stirred at room temperature for 2 hours. Completion of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mixture was cooled to 0 °C to 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) and saturated NaCl solution (500 mL), dried over sodium sulfate, and concentrated under reduced pressure at 45 °C to 50 °C. The crude product obtained from this batch was mixed with the crude product (45 g) from another batch and purified by column chromatography on silica gel (230 - 400 mesh) using 30% to 40% ethyl acetate / petroleum ether to give compound 5b as a viscous liquid (250 g, 65%).

[0322] Step 5A 10% Pd / C (30 g, 50% water content) 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 three times with hydrogen gas, and then hydrogenated at 4 kg / cm 2 pressure (about 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 layer (diameter 520 mm). The filtrate was concentrated under reduced pressure. The crude product obtained 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. 1 H NMR (300 MHz, D 2O) δ 7.1 (d, J = 8.1 Hz, 1H), 6.7 (s, 1H), 6.68 (d, J = 8.1 Hz, 1H), 4.1 (q, J = 5.1 Hz, 1H), 3.15 (dd, J = 14.7 Hz, 4.5 Hz, 1H), 3.0 - 2.93 (m, 1H); MS (LCMS) m / z 278 [M+H] + 。

[0323] Step 5B 10% Pd / C (30 g, 50% water content product) was added to a solution of compound 5b (100 g, 0.13 mol) in ethanol and water (1 liter, 4:1) under a nitrogen atmosphere. The reaction flask was evacuated and purged three times with hydrogen gas, and hydrogenated at 4 kg / cm 2 pressure (about 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 layer (diameter 520 mm). The filtrate was concentrated under reduced pressure. The obtained crude product was stirred with ethanol (60 mL), filtered, and dried under suction to obtain (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 (300 MHz, D 2 O) δ 7.06 (s, 1H), 6.85 (s, 2H), 4.08 (q, J = 4.8 Hz, 1H), 3.16 (dd, J = 14.7 Hz, 5.1 Hz, 1H), 3.0 - 2.92 (m, 1H); MS (LCMS) m / z 278 [M+H] + 。

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

[0325]

Chemical formula

[0326] Specifically, L-DOPA 3′,4′-bisphosphate was prepared according to the method described in Steps 6 and 7 below.

[0327] Step 6 Cesium carbonate (484 g, 1.48 mol) was added in two portions to a solution of compound 3 (250 g, 0.59 mol) in dimethylformamide (2.5 L) at 0 °C. A 10 wt% dibenzylphosphoryl chloride / toluene solution (3.52 kg, 1.18 mol) was added dropwise to this mixture at 0 °C over a period of 1 h, and the reaction mixture was stirred at room temperature for 2 h. Completion of the reaction was monitored by TLC. After the starting materials were completely consumed, the reaction mixture 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) and 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 liquid gum of intermediate purity (240 g).

[0328] Step 7 10% Pd / C (20 g, 50% water-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, purged three times with hydrogen gas, 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 bed (520 mm in diameter). The filtrate was concentrated under reduced pressure. The resulting crude product was stirred with ethanol (30 mL), filtered, and dried under suction to give L-DOPA (3,4-phosphate) (12.8 g, 64%, corrected purity) as an off-white solid. 1 H NMR (300 MHz, D 2 O) δ 7.21 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 6.95 (d, J = 7.8 Hz, 1H), 4.23 (q, J = 2.7 Hz, 1H), 3.24 (dd, J = 15 Hz, 4.8 Hz, 1H), 3.08 - 3.01 (m, 1H); MS (LCMS) m / z 358 [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]

Chem.

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

[0332] Step 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 and allowed to stand for 15 minutes to obtain a clear solution. The solution was cooled back to 50 °C, and carbidopa monohydrate (0.400 g, 1.64 mmol) was added. After 3 hours, the solution was cooled to room temperature, stirred for 14 hours, and then heated to 35 °C. After 24 hours, the solution was cooled to room temperature and stirred for 60 hours. Water (2 mL, which heated to 50 °C) was added, and the solution was stirred for 5 minutes. Analysis by HPLC (Agilent Poroshell 120 EC-C18 #693975-902 4.6×150 mm column, 1 mL / min 0.1% H 3 PO 4 aqueous solution / CH 3 CN, gradient to 97:3 in 3 minutes, 70:30 in 4 minutes, 0:100 in 2 minutes, held for 1 minute, detected at 220 nm) showed carbidopa (6.7 minutes): 2.6 pa%, phosphate 1 (5.1 minutes): 38.2 pa%, phosphate 2 (5.7 minutes): 37.7 pa%, diphosphate (2.3 minutes): 5.9 pa%. The aqueous solution was diluted with water (5-fold), and preparative HPLC (Kromasil Phenyl 3 cm (inner diameter)×25 cm, 5 micron column, 30 mL / min 0.1% formic acid / CH 3Purified by CN, gradient to 10 min 97:3, gradient to 5 min 93:7, gradient to 0.5 min 100:0, detected at 277 nm). The pure fractions of the separated monophosphates were combined, concentrated on a rotary evaporator (bath temperature 35 °C) to 10 mL each, freeze-dried to obtain carbidopa 4′-phosphate 1 (152 mg, yield 30%) and carbidopa 3′-phosphate 2 (137 mg, yield 27%) as white amorphous powders. Carbidopa 3′-monophosphate: 1 H NMR (400 MHz, deuterium oxide) δ 7.20 (dd, J = 8.2, 1.2 Hz, 1H), 6.84 (d, J = 2.1 Hz, 1H), 6.77 (dd, J = 8.3, 2.2 Hz, 1H), 3.19 (d, J = 14.2 Hz, 1H), 2.99 (d, J = 14.2 Hz, 1H), 1.52 (s, 3H); MS (ESI) m / z 307 [M + H] + For carbidopa 4′-monophosphate: 1H NMR (400 MHz, deuterium oxide) δ 7.14 (t, J = 1.4 Hz, 1H), 7.01 - 6.83 (m, 2H), 3.19 (d, J = 14.3 Hz, 1H), 3.00 (d, J = 14.4 Hz, 1H), 1.52 (s, 3H); MS (ESI) m / z 307 [M + H] + 。

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

[0334]

Chemical formula

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

[0336] Step 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 °C 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 hours, at which point LC-MS indicated nearly complete reaction. The solution was diluted with MTBE (100 mL), the layers were separated, and the organic layer was extracted with saturated NaHCO 3 aqueous solution (100 mL). The aqueous layer was acidified with 2N HCl (160 mL), and the acidic aqueous layer was extracted with MTBE (2 × 100 mL). During the second back extraction, a small amount of the product began to precipitate. The combined organic layers were washed with brine (20 mL), and the residual 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. Since the mixture was too viscous to stir, additional MTBE (60 mL relative to 6 volumes of 5% THF / MTBE) was added. Next, the resulting white slurry was 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 dryer (50 °C) to give the (S)-2-(2-((benzyloxy)carbonyl)-hydrazinyl)-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid compound and THF (4:3) (31.1 g, 71.9 mmol, 91% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.66 (d, J = 9.0 Hz, 2H), 8.18 (brs, 1H), 7.49 - 7.17 (m, 5H), 6.59 (dd, J = 5.0, 3.0 Hz, 2H), 6.44 (dd, J = 8.0, 2.0 Hz, 1H), 5.04 (s, 2H), 2.73 (d, J = 13.4 Hz, 1H), 2.59 (d, J = 13.3 Hz, 1H), 1.07 (s, 3H); MS (ESI) m / z 361 [M + H] + .

[0337] Step 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 from -10 °C to 0 °C over 5 minutes (exothermic, controlled by dry ice / acetone bath). The mixture was stirred at 0 °C to 12 °C for 15 minutes and then washed with water (3 times with 200 mL). The resulting mixture was dehydrated (Na 2 SO 4 ), concentrated to a total volume of 76 mL, rinsed into a 125 mL Erlenmeyer flask with an additional 16 mL of DCM to give an approximately 1 M dark purple (diazomethylidene)dibenzene solution. In a separate flask, a slurry of (S)-2-(2-((benzyloxy)carbonyl)hydrazinyl)-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid compound and tetrahydrofuran (4:3) (30.7 g, 74.0 mmol) in IPA (300 mL) was cooled to below 10 °C, and the (diazomethylidene)dibenzene solution (78 mL, 78 mmol) was added. The resulting mixture was warmed to room temperature, and LC-MS indicated that the reaction had stalled after 30 minutes. Additional diphenyldiazomethane (0.2 equiv, 14 mL) was added, and stirring was continued at room temperature. After 35 minutes, the remaining diphenyldiazomethane solution (9 mL) was added. After 2 hours and 20 minutes, the purple color disappeared, and LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to approximately 60 mL, and 20% CH 3 CN aqueous solution (300 mL) was added. The mixture was washed with cyclohexane (10 times with 300 mL), ethyl acetate (450 mL) was added, and the mixture was washed with saturated NaHCO 3 aqueous solution (150 mL) and brine (60 mL). The mixture was dehydrated (Na 2 SO 4 ), 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, yield >99%). 1 H NMR (400 MHz, DMSO-d6 ) δ 8.65 (brs, 2H), 8.19 (brs, 1H), 7.43 - 7.20 (m, 15H), 6.70 (s, 1H), 6.55 (d, J = 2.0 Hz, 1H), 6.45 (d, J = 8.0 Hz, 1H), 6.20 (dd, J = 7.9, 2.0 Hz, 1H), 4.95 (d, J = 3.4 Hz, 2H), 2.81 (d, J = 13.6 Hz, 1H), 2.67 (d, J = 13.7 Hz, 1H), 1.17 (d, J = 3.1 Hz, 3H); MS(ESI) m / z 549 [M + Na] + 。

[0338] Step 3 (S)-Benzyl 2-(1-(benzhydryloxy)-3-(3,4-dihydroxyphenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate (39.4 g, 74.8 mmol) and a solution of CH 3 CN (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 minutes, water (400 mL) was added to obtain a two-phase solution. The layers were separated, and the lower (yellow oil) layer (about 100 mL) was washed with cold 1:1 CH 3 CN / water (twice with 100 mL), diluted with ethyl acetate (400 mL), and washed with brine (80 mL). The mixture was dried (Na 2 SO 4 ) and concentrated. By FCC (50% to 100% MTBE / heptane), (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) was obtained as a clear oil. 1 1H NMR (400 MHz, DMSO-d 6) δ 7.45 - 7.16 (m, 35H), 7.06 (d, J = 8.6 Hz, 1H), 6.88 (dd, J = 8.7, 2.0 Hz, 1H), 6.71 (s, 1H), 5.12 (ddt, J = 9.9, 7.0, 3.9 Hz, 10H), 4.99 - 4.80 (m, 2H), 2.95 - 2.76 (m, 2H), 1.11 (d, J = 1.8 Hz, 3H); MS(ESI) m / z 1069 [M + Na] + 。

[0339] Step 4 In a 2 - liter 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 (hydrous product JM#9) (12.1 g, 56.9 mmol). The mixture was shaken at 22 °C for 2 hours under hydrogen at about 0.41 MPa (60 psi). The starting temperature was 12.4 °C (the solution was stored in the freezer.), and T max was 31.6 °C. Deionized water (275 mL) was added and hydrogenation was continued for an additional 17 hours. The mixture was filtered through a nylon membrane while 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 times with 100 mL each) and concentrated on a rotary evaporator (bath temperature 35 °C) to a total mass of 100 g and freeze - dried for 3 days to obtain a white glassy solid. The amorphous solid was crushed and freeze - dried for 1 day to remove trace amounts of additional moisture, yielding carbidopa diphosphate (22.3 g, >99%), which still contained 10 to 15 wt% moisture by Karl Fischer titration (corrected yield 85%). 1 1H NMR (500 MHz, DMSO - d 6 ) δ 7.15 (d, J = 8.3 Hz, 1H), 7.11 (s, 1H), 6.89 (dd, J = 8.1, 2.1 Hz, 1H), 3.00 - 2.82 (m, 2H), 1.31 (s, 3H); MS(ESI) m / z 387 [M + H] +。HPLC (Agilent Poroshell 120 EC-C18 #693975-902 4.6×150 mm column, 1 mL / min 0.1% H 3 PO 4 aqueous solution / CH 3 CN, gradient to 97.5:2.5 at 3 min, 70:30 at 4 min, gradient to 0:100 at 2 min, hold for 1 min, detection at 220 nm), the obtained product has a purity of 96.4% (peak area% at 220 nm; diphosphate retention time = 2.37 min).

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

[0341]

Chemical formula

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

[0343] Step 1 A solution of sodium hydroxide (7.24 g, 183 mol) in water (76 mL) was added dropwise to a suspension of S(−)-carbidopa (25 g, 92 mmol) in water (76 mL) at <5 °C over a period of 20 minutes. After adding the base, 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 period of 30 minutes, and the reaction mixture was warmed to room temperature. The reaction mixture was stirred at 25 °C for 1 hour. After 1 hour, an additional 0.2 equivalent 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 made basic to pH = 9 using 10% sodium hydroxide and extracted with MTBE (3 times with 150 mL). The organic layer was separated and discarded. The aqueous layer (pH = 8.6) was made acidic to pH = 2.75 using 6N HCl and extracted with MTBE (3 times with 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, 250 mL of THF was added, and it was again partially concentrated (75%) under reduced pressure. To the resulting yellow solution, 250 mL of MTBE was added, and it was concentrated to 50 volume %. The resulting white slurry was cooled to 0 °C, filtered, and the solid was washed with cold MTBE to obtain 32.31 g of Compound 1 (white solid) (titer 84.5 wt%, 95.6% pa, PAY83%).

[0344] Step 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 at 2 °C over a period of 10 minutes. 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 times with 150 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (MgSO 4) Filtered, concentrated, and obtained 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 / z 541 [M+H] + .

[0345] Step 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 warmed to room temperature. After 1 hour, the reaction mixture was quenched with water (300 mL), extracted with MTBE (twice with 150 mL), washed with water (150 mL) and brine (150 mL), dried (MgSO 4 ), filtered, and concentrated to obtain 24.69 g of Compounds 4 and 5 in 92% yield. Compound 4, MS(ESI) m / z 972 [M+H] + .

[0346] Step 4 In a glass-lined 20 mL Barnstead vessel, tetrahydrofuran (10.00 mL) was added to Compounds 4 and 5 (1.026 g, 0.980 mmol) and 5% Pd / C (50% water content, JM#9) (0.199 g, 1.870 mmol, dry weight 0.10 g). The mixture was stirred at 25 °C for 1.5 hours under hydrogen at about 0.55 MPa (80 psi). Water (5.00 mL) was added and the mixture was hydrogenated for an additional 1.5 hours. After 1.5 hours, the mixture was filtered through a polypropylene membrane, 2.5 mL of MTBE was added, the mixture was shaken in a separatory funnel, and the lower aqueous layer was withdrawn. The aqueous solution was washed twice with 2.5 mL of MTBE, resulting in a significant volume reduction (THF and toluene went into the MTBE phase). The colorless aqueous solution (aqueous layer) was lyophilized for 3 days to obtain 385 mg of the desired product (93.9% pa) Compound 6.

[0347] Example 5: Separate synthesis of L-Dopa 4′-monophosphate L-DOPA 4'-monophosphate was produced according to the method shown in Scheme 5 below.

[0348]

Chem.

[0349] Specifically, L-DOPA 4'-monophosphate was produced according to the method described in Steps 1 to 5 below.

[0350] Step 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 (about 20 to 25 °C) for 60 minutes. The reaction mixture was quenched with water (400 mL) and extracted with MTBE (3 times with 100 mL). The organic layer was washed with saturated sodium bicarbonate solution (150 mL), water (150 mL), and saturated sodium chloride solution (150 mL), and concentrated to obtain Compound 2 (20.7 g, purity 96.5%, yield 93%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 7.67 (dd, J = 1.8, 0.9 Hz, 1H), 7.54 (dd, J = 8.1, 1.8 Hz, 1H), 7.48 - 7.39 (m, 3H), 7.35 - 7.22 (m, 13H), 5.22 (s, 2H), 5.09 (dd, J = 8.2, 2.1 Hz, 4H).

[0351] Step 2 (+ / -)-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) were added 1,1,3,3-tetramethylguanidine (TMG) (11.78 g, 102 mmol) at 2 °C. 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. Next, Compound 3 was 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. Next, Compound 3 was precipitated at 4 °C and slurried in 350 mL of MTBE at 4 °C for 1 hour. Next, the slurry was filtered and the solid was washed with cold MTBE. The solid was dried overnight in a vacuum dryer at 40 °C to give 50.4 g of Compound 3 (purity 99.6%, yield 85%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.60 (t, J = 1.4 Hz, 1H), 7.44 - 7.18 (m, 23H), 5.10 (qd, J = 5.9, 2.6 Hz, 8H), 3.72 (s, 3H).

[0352] Step 3 Into a 2.0 gallon reactor was placed 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. N 2 was bubbled through this solution for 30 minutes. Into another 2.0 gallon reactor was placed 1,2-bis[(2S,5S)-2,5-diethylphospholano]benzene(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (3.44 g, 5.21 mmol), purged 10 times with N 2 and N 2 was bubbled through for 30 minutes. Next, the feed solution was transferred into this reactor using N 2 pressure. The line was flushed with H 2Purge with, and then the reactor with H 2 Purge three times with. The reaction solution was stirred at 35 °C under H 2 at 100 psi. After 20 hours, compound 4 with 99% ee was shown by HPLC. Next, the reaction solution was transferred to a 12-liter extraction apparatus, and 3.6 liters of ethyl acetate was added. The solution was washed twice with 3.7 liters of 5 wt% cysteine / 8% sodium bicarbonate and then with 3.6 liters of 5 wt% aqueous NaCl solution. The organic layer was separated and stirred with 43.4 g of ENO-PC activated carbon overnight under N 2 at. The mixture was filtered, and the filtrate was concentrated to obtain 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 as is in the next step. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.85 (d, J = 8.1 Hz, 1H), 7.46 - 7.16 (m, 21H), 7.09 (dd, J = 8.2, 1.4 Hz, 1H), 6.81 (dd, J = 8.2, 1.9 Hz, 1H), 5.09 - 4.98 (m, 8H), 4.31 (ddd, J = 10.2, 8.1, 5.0 Hz, 1H), 3.63 (s, 3H), 3.08 - 2.78 (m, 2H).

[0353] Step 4 To a 150 mL Parr hydrogenation apparatus, 10 wt% of 5% Pd / C (1.33 g, the catalyst contains 63.6% H 2 O) on a dry weight basis was added. 2.9 wt% aqueous sodium bicarbonate solution (20.7 g) was placed in the reactor. Compound 4 (5.70 g, 85% titer) was dissolved in THF (48.5 mL, 10 mL / g of substrate) and then transferred to the reactor. The reactor was pressurized with argon to 60 psi, the pressure was released to 10 psi, and a total of 6 argon pressure purges were performed. Similarly, the reactor was purged three times with hydrogen (filled to 50 psi and released to 5 psi). The reactor was filled with H 2Refilled until, and stirred at 750 rpm for at least 2 hours at 25 °C. After completion of the reaction, the two-phase solution was filtered to remove the catalyst. The reactor and the filter cake were washed with water (4.1 mL, 2 mL / g based on the theoretical yield of the 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. Next, the aqueous layer was transferred to a 250 mL flask, and a sufficient amount of 6M aqueous HCl was added to adjust the pH to 1.8. The solution was vigorously mixed, and iPrOH (73 mL) was added to make the final solvent composition 3:1 iPrOH / water. The slurry was stirred overnight. The crystallization slurry was filtered, and the wet cake solid was washed with iPrOH. The white solid was dried in a vacuum dryer at 50 °C to obtain Compound 5 (1.72 g, crystalline solid, yield 85%). 1 H NMR (400 MHz, deuterium oxide) δ 7.25 (dt, J = 8.3, 1.1 Hz, 1H), 6.87 (t, J = 1.5 Hz, 1H), 6.80 (dd, J = 8.3, 2.2 Hz, 1H), 4.41 (ddd, J = 7.9, 5.4, 0.7 Hz, 1H), 3.87 (d, J = 0.7 Hz, 3H), 3.36 - 3.08 (m, 2H).

[0354] Step 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) at 15 to 20 °C, 22.89 mL (4.0 equivalents) of 6N NaOH was added. When the pH reached 7 to 8, the solution was filtered to make it clear. After making it clear, the pH adjustment was continued. After adding the base, 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 equivalents of 6N HCl (137 mmol, 22.89 mL). The final pH was adjusted to 1.8. After 10 minutes, the rxn mixture became turbid, and 200 mL of IPA was added. The slurry was stirred for 30 minutes, the solid was filtered, and washed with IPA. The solid was dried in a vacuum dryer at 40 °C overnight to obtain Compound 6, (S)-2-amino-3-(3-hydroxy-4-(phosphonooxy)phenyl)propanoic acid (7.85 g, purity 99%, yield 87%, 99.6% ee). 11H NMR (400 MHz, deuterium oxide) δ 7.24 (dd, J = 8.3, 1.3 Hz, 1H), 6.91 (d, J = 2.1 Hz, 1H), 6.83 (dd, J = 8.3, 2.2 Hz, 1H), 4.25 (dd, J = 8.0, 5.2 Hz, 1H), 3.35 - 3.05 (m, 2H).

[0355] Example 6: Separate synthesis of L-Dopa 4′-monophosphate L-DOPA 4'-monophosphate was produced according to the method shown below.

[0356]

Chemical formula

[0357] Step 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 minutes to bring the temperature to 10 °C, and the addition of NaOH turned the solution dark.) It was cooled back down to <5 °C, and while maintaining the temperature at <5 °C, sodium hypochlorite (247 mL, 400 mmol) was added dropwise. After 10 minutes, 500 mL of MeOH was removed by a rotary evaporator, MTBE (730 mL) and 2N HCl (909 mL, 1818 mmol) were added, and 1N Na 2 S 2 O 3 (130 mL three times; the color lightened each time.) and washed with brine (64 mL), dehydrated (Na 2 SO 4 ), concentrated, and washed with cyclohexane (100 mL) to obtain a crude yellow solid. Cyclohexane (130 mL) was added, heated to 55 °C (yellow solution), cooled slowly, and seed addition was carried out at 45 °C (approx. 50 mg - solution) and 40 °C (approx. 50 mg, slurry formation). Cooling was continued to room temperature (approx. 20 to 25 °C), and high stirring was carried out overnight. Filtered and washed with cyclohexane (64 mL) to obtain Product 1 (69.93 g, 59%, 1By \(^1H\) NMR, it was a very high purity, slightly off-white solid. The mother liquor was concentrated to about 70 mL, seeded, aged for 1 hour, and a viscous dark-colored product precipitated along with the product. MTBE (7 mL) was added, sonicated (good for decolorization), stirred for 20 minutes, and filtered. It was washed with 10% MTBE / cyclohexane (32 mL) to obtain Product 2 (4.65 g, 1 There were some minor impurities by \(^1H\) NMR. Overall, 2-(benzyloxy)-4-iodophenol was isolated (74.6 g, 229 mmol, 62.9% yield). 1 \(^1H\) NMR (501 MHz, DMSO-d 6 ) δ 9.33 (s, 1H), 7.49 - 7.42 (m, 2H), 7.42 - 7.35 (m, 2H), 7.35 - 7.29 (m, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 8.3, 2.1 Hz, 1H), 6.64 (d, J = 8.3 Hz, 1H), 5.09 (s, 2H).

[0358] Step 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 (without exotherm). After 20 minutes at 5 to -5 °C, it was completed by LC-MS. After 30 minutes, sodium bicarbonate (19.13 g, 228 mmol) and MTBE (750 mL, the temperature reached 8 °C.) were added, and water was carefully added while maintaining the temperature below 20 °C (750 mL, a small amount of CO 2 was generated at the initial stage of addition). At pH about 8, additional water (750 mL, total 1.5 L, 10 volumes) and MTBE (750 mL, total 1.5 L, 10 volumes) were poured into the separatory funnel for washing. The layers were separated, the organic layer was washed with brine (300 mL), and the layers were checked by LC-MS. Dehydrated (Na 2 SO 4) Concentrate to the minimum volume (total mass 401 g), add MeOH (3.0 L, yellow solution). Add water (1.5 L) over 30 minutes, add 300 mL of 2 volumes of water, and then seed with the previously isolated crystals (0.1 wt%, 150 mg) (did not dissolve). After gradually becoming a slurry, 650 mL of water was added and it rapidly thickened. After stirring at ambient temperature for 30 minutes, the white slurry was filtered, washed with 2:1 MeOH / water (300 mL of slurry wash solution, 300 mL of displacement wash solution), and left under reduced pressure on a glass frit for 12 hours. Add MeOH (2.25 L, 15 volumes) to the wet cake, stir vigorously for 30 minutes to disperse the slurry, add water (1.125 L) over 30 minutes, stir for an additional 15 minutes, filter, and wash with 2:1 MeOH / water (300 mL of displacement wash solution). Dry the white solid in a vacuum dryer at 50 °C to a constant weight to obtain (R)-benzyl 2-(((benzyloxy)carbonyl)amino)-3-iodopropanoate (173 g, 394 mmol, 86% yield). K f By titration, it was found to be 253 ppm of water. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.96 (d, J = 8.3 Hz, 1H), 7.44 - 7.14 (m, 10H), 5.10 (d, J = 33.8 Hz, 4H), 4.38 (td, J = 8.7, 4.6 Hz, 1H), 3.55 (dd, J = 10.3, 4.6 Hz, 1H), 3.37 (t, J = 9.7 Hz, 1H). MS (ESI) m / z 457 [M + NH 4 + 。

[0359] Step 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 by magnetic stirring. The gray slurry was cooled in an ice bath to 16 °C, and iodine (7.60 g, 29.9 mmol) was added (immediate exotherm, temperature rose from 16 to 27 °C, turning from yellow to a clear supernatant). It 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 minutes. After an additional 10 minutes at 20 - 25 °C, complete zinc insertion was indicated by LCMS (the reaction was quenched with small aliquots of 2N HCl). Pd 2 (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 all at once (without exotherm), and the mixture was stirred at room temperature (start = 2:30). After 1 hour, since an exotherm to 27 °C was observed, it was cooled back to 20 - 25 °C in a room temperature water bath and stirred overnight. After 15 hours and 40 minutes, LC-MS indicated a complete and clean reaction. MTBE (650 mL) and silica (65 g) were added, stirred for 15 minutes, the gray slurry was filtered, and the gray solid was washed with MTBE (325 + 130 mL). The yellow filtrate was washed with saturated NH 4 Cl aqueous solution (325 mL, pH about 5 to 6 with a slight evolution of H 2 resulting in the temperature reaching 27 °C) and brine (130 mL), dehydrated (Na 2 SO 4 ), concentrated, and by FCC (800 g column, 50% to 100% DCM / heptane then 10% MTBE / DCM; separating only non-polar highly colored impurities and baseline material, HPLC purity increased from 91% to 93%), (S)-benzyl 3-(3-(benzyloxy)-4-hydroxyphenyl)-2-(((benzyloxy)carbonyl)amino)propanoate (106 g, 207 mmol, 104% yield) was obtained as a light brown oil. 1By \(^1\)H NMR, protonation of excess alkyl zinc during workup showed a major excess mass of mainly CBz alanine Bn ester. Assuming quantitative yield, it was used in the next step without further purification. 1 \(^1\)H NMR (501 MHz, DMSO-d 6 ) δ 8.86 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.41 - 7.08 (m, 13H), 6.94 (d, J = 2.0 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.63 (dd, J = 8.0, 1.9 Hz, 1H), 5.15 - 4.93 (m, 6H), 4.27 (ddd, J = 9.7, 7.9, 5.5 Hz, 1H), 2.93 (dd, J = 13.8, 5.5 Hz, 1H), 2.78 (dd, J = 13.8, 9.8 Hz, 1H). MS (ESI) m / z 512 [M + H] + .

[0360] Step 4 (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. The mixture was cooled in an ice bath and DBU (45.2 mL, 300 mmol) was added over 10 min while maintaining the temperature at 20 - 25 °C. After 30 min, LC-MS indicated completion of the reaction. MTBE (1.0 liter) and water (510 mL) were added, the layers were separated (with a very small loss of water by LCMS), and the organic layer was washed with brine (3 times with 200 mL). It was dehydrated (Na 2 SO 4 ) and concentrated, and purified by FCC (in two parts, using an 800 g column with a gradient elution of 25 - 75% MTBE / heptane for each part and combining the fractions) to give (S)-benzyl 3-(3-(benzyloxy)-4-((bis(benzyloxy)phosphoryl)oxy)phenyl)-2-(((benzyloxy)carbonyl)amino)propanoate (132 g, 171 mmol, 86% yield) as a pale yellow oil. 1 \(^1\)H NMR (400 MHz, DMSO-d6 ) δ 7.87 (d, J = 8.1 Hz, 1H), 7.43 - 7.17 (m, 26H), 7.07 (dd, J = 8.2, 1.3 Hz, 1H), 6.79 (dd, J = 8.3, 1.9 Hz, 1H), 5.14 - 4.91 (m, 10H), 4.38 (ddd, J = 10.0, 8.0, 5.2 Hz, 1H), 3.05 (dd, J = 13.8, 5.2 Hz, 1H), 2.88 (dd, J = 13.8, 10.1 Hz, 1H). MS(ESI) m / z 789 [M + NH 4 + 。

[0361] The production of levodopa 4'-monophosphate was carried out in the same manner as in step 5a from Example 1.

[0362] Example 7: Separate synthesis of Carbidopa 4′-monophosphate Carbidopa 4'-monophosphate was produced according to the method shown in the following Scheme 7.

[0363]

Chemical formula

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

[0365] Step 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 stirring bar. A thermocouple, a reflux condenser, and a stopper were attached to the three necks of the flask. The flask was purged with nitrogen for 1 hour. During that period, dioxane (200.0 mL), 2-methylprop-2-en-1-ol (8.30 mL, 99 mmol), and N-cyclohexyl-N-methylcyclohexanamine (30.0 mL, 140 mmol) were placed in a second flask, and nitrogen was bubbled through this flask for 1 hour. Next, the dioxane solution was transferred by cannula to the flask containing compound 1, palladium, and the ligand. The reaction mixture was heated to 100 °C and allowed to proceed for 1 hour. Thereafter, the reaction solution was cooled to 35 °C and diluted with ethyl acetate (250 mL) and 1.0 M HCl (250 mL). The two-phase 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 withdrawn from the reaction solution, and the first ethyl acetate was returned to the reactor. This combined mixture was washed with a 5% N-acetylcysteine / 8% sodium bicarbonate mixture (twice for 10 minutes with stirring). After separating the aqueous waste liquid after each wash, the yellow organic solution was filtered through Celite® diatomaceous earth. Karl Fischer titration of the organic reaction mixture indicated that the water content was 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 and allowed to proceed for 13 hours. Thereafter, the precipitate was filtered, and the solid was washed with ethyl acetate (three times with 100 mL), and a white solid was obtained in a yield of 64.2%. The titer of the obtained product was confirmed to be 60.0% by Q-NMR spectrum measurement. 1 H NMR (400 MHz, D 2O, 1:1 diastereomer): δ ppm 7.48 - 7.36 (m, 5H), 6.92 (m, 1H), 6.86 (dd, J = 8.0, 4.0 Hz, 1H), 6.76 (dd, J = 8.0, 4.0 Hz, 1H), 5.21 - 5.19 (m, 2H), 4.27 - 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 = 8.0 Hz, 1.5H), 0.84 (d, J = 8.0 Hz, 1.5H).

[0366] Step 2a To a 500 mL three-necked round-bottom flask equipped with a thermocouple and an overhead stirrer, 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) were added. The resulting biphasic suspension was vigorously stirred at 25 °C. After the raw materials were completely consumed, the reaction solution 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 obtain compound 2 as a white solid (6.22 g, 62.9%). 1 H NMR (400 MHz, CDCl 3 ): δ ppm 9.68 (d, J = 2.0 Hz, 1H), 7.46 - 7.32 (m, 5H), 6.86 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 1.6 Hz, 1H), 6.68 (dd, J = 8.0, 1.6 Hz, 1H), 5.58 (s, 1H), 5.08 (s, 2H), 2.98 (dd, J = 13.6, 6.0 Hz, 1H), 2.65 - 2.56 (m, 1H), 2.53 (dd, J = 13.6, 8.0 Hz, 1H), 1.05 (d, J = 6.8 Hz, 3H).

[0367] Step 2b To a 250 mL three-necked flask equipped with a thermocouple and an overhead stirrer, compound 2 (6.29 g, 23.22 mmol) was added, and then acetonitrile (63 mL) was added. Next, tetrabenzyl pyrophosphate (13.54 g, 24.38 mmol) was added at 25 °C. The reaction solution was cooled in an ice bath to 2.1 °C, and DBU (4.55 mL, 30.2 mmol) was added dropwise to the reaction mixture, and the resulting solution was stirred at 2 °C. After the raw materials were completely consumed, the reaction solution was diluted with water (65 mL) and extracted with MTBE (130 mL). The combined organic layers were washed with water (65 mL) and 5% sodium chloride solution (30 mL), dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain crude compound 4 as a yellow oil (11.38 g, 92.4%). 1 H NMR (400 MHz, CDCl 3 ): δ ppm 9.75 (d, J = 1.2 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.36 - 7.23 (m, 13H), 7.17 (dd, J = 8.0, 1.2 Hz, 1H), 6.81 (dd, J = 2.0, 1.2 Hz, 1H), 6.72 (dd, J = 8.0, 2.0 Hz, 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, 8.0 Hz, 1H), 1.09 (d, J = 7.2 Hz, 3H).

[0368] Step 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)-dibenzyl diazenedicarboxylate (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 a cannula. The resulting solution was stirred at 25 °C. After complete consumption of the starting materials, the reaction mixture was diluted with acetonitrile (88 mL) and water (58 mL) was added to precipitate the product. The resulting slurry was stirred at 25 °C overnight, filtered, and washed with 28 wt% water / acetonitrile (30 mL) to afford compound 5 (8.9 g, 50% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ): δ ppm 9.72 (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] Step 4 A thermocouple was attached to a 100 mL three-necked round-bottom flask, and compound 5 (5.10 g, 6.15 mmol), acetonitrile (50.0 mL), and dimethyl sulfoxide (DMSO) (1.00 mL, 14.1 mmol) were added. The white suspension was stirred, and an aqueous solution of 2.0 mL (1.78 g, 12.90 mmol) of sodium dihydrogen phosphate monohydrate was prepared and added to the reaction solution. After this addition, 2.0 mL (2.88 g (80 wt% ), 25.5 mmol) of an aqueous sodium chlorite solution was added dropwise over 90 seconds. The turbid reaction solution turned bright yellow and then darker yellow, and became more transparent as the reaction proceeded. After 90 minutes, the reaction was stopped with 6.0 mL (1.60 g, 12.7 mmol) of an aqueous sodium sulfite solution. The reaction solution was stirred for 20 minutes after the addition of the sulfite. Then, the reaction solution was 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 layer and the organic layer were separated. The organic layer was washed with 50 mL of water. Shaking the layers produced an emulsion. Here, 20 mL of brine was added, and when the turbidity disappeared, the phases were separated. An additional 50 mL of isopropyl acetate was added to the reaction solution, and the flask was placed on a rotary evaporator until the reaction mixture appeared turbid. 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. Then, the white solid formed was collected, washed with 20 mL of isopropyl acetate, and dried in vacuo to obtain compound 6 in a yield of 75.0%. 1 H NMR (400 MHz, CDCl 3 ): δ ppm 7.58 - 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] Step 5 5 wt% of 5% Pd / C (63.6% H in a 1 gallon pearl reactor 2O (15.0 g), water (182 mL) and 5 wt% aqueous sodium bicarbonate solution (215 mL) were added. To this aqueous catalyst slurry, a THF solution (1090 mL) of compound 6 (109 g, 85% potency) was added. The reactor was assembled, inactivated with nitrogen, and then purged with hydrogen four times at 30 psi. Next, the reactor was repressurized with hydrogen to 30 psi. The reactor was stirred vigorously at 25 °C for at least 1 hour. When complete reaction conversion was obtained, the hydrogen was vented and the reactor was inactivated with nitrogen. The two-phase reaction mixture was filtered to remove the catalyst and then washed with water (93 mL). The resulting two-phase reaction mixture was diluted with MTBE (370 mL). The mixture was stirred for 15 minutes and then allowed to stand 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 described above.

[0371] Using a sufficient amount of 6M aqueous HCl solution, the solution was made acidic to pH 1.9. 0.1 wt% of compound 7 was seeded into the aqueous solution 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 mother liquor was recycled as the wash liquor 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% potency-adjusted yield). 1 H NMR (400 MHz, D 2 O): δ ppm 7.21 (d, J = 8.0 Hz), 6.87 (d, J = 2.0 Hz, 1H), 6.77 (dd, J = 8.0, 2.0 Hz, 1H), 3.19 (d, J = 16.0 Hz, 1H), 3.00 (d, J = 16.0 Hz, 1H), 1.54 (s, 3H).

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

[0373]

Chemical formula

[0374] Specifically, L-dopa 3'-phonoxy methyl ester was produced according to the method described in the following steps 1 to 6.

[0375] Step 1 To a solution of 4-(benzyloxy)-4-hydroxybenzaldehyde, Compound 1 (10.0 g, 43.8 mmol) in acetonitrile (133 mL) was added di-tert-butyl (chloromethyl) phosphate (12.53 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. After the addition, the reaction mixture was warmed to room temperature (about 20 to 25 °C) and heated to 50 °C for 39 hours. After 22 hours, the reaction mixture was cooled to room temperature, quenched with water (400 mL), and extracted with MTBE (3 times with 100 mL). The organic layer was washed with saturated sodium bicarbonate solution (150 mL), water (150 mL), and saturated sodium chloride solution (150 mL), and concentrated to obtain Compound 2 (19.48 g, purity 49%, yield 50%). The crude product was passed through a silica gel column using an ethyl acetate - hexane gradient to obtain 8.08 g of Compound 2 (purity 94%, yield 40%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.66 (dd, J = 8.3, 1.9 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.43 - 7.32 (m, 4H), 5.65 (d, J = 12.0 Hz, 2H), 5.25 (s, 2H), 1.36 (d, J = 0.6 Hz, 18H).

[0376] Step 2 (+ / -)-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) were added 1,1,3,3-tetramethylguanidine (TMG) (2.0 g, 17.60 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature overnight. The next day, the reaction mixture was washed three times with 35 mL of water and concentrated to give 13.11 g of the crude product. Next, the crude product was purified by column chromatography on silica gel using an ethyl acetate - hexane gradient to give 7.34 g of Compound 3 (purity 81%, yield 62%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.50 - 7.28 (m, 13H), 7.21 (s, 1H), 7.16 (s, 1H), 5.59 (d, J = 11.9 Hz, 2H), 5.18 (s, 2H), 5.09 (d, J = 12.1 Hz, 2H), 3.69 (s, 3H), 1.35 (d, J = 0.5 Hz, 18H).

[0377] Step 3 Into a 120 mL Pearl reactor were placed 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-diethylphospholano]benzene(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (0.060 g, 0.091 mmol) and tetrahydrofuran (59.5 mL). The mixture was purged with H 2 and the reaction mixture was stirred at 35 °C for 20 h under H 2 at 100 psi. 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 (purity 76%, yield 69%, 98% ee). 1 H NMR (400 MHz, DMSO-d 6)δ 7.80 (d, J = 8.0 Hz, 1H), 7.48 - 7.25 (m, 10H), 7.04 (d, J = 2.1 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.89 (dd, J = 8.3, 2.1 Hz, 1H), 5.55 (dd, J = 11.6, 1.6 Hz, 2H), 5.08 (s, 2H), 4.99 (d, J = 2.7 Hz, 2H), 4.22 (ddd, J = 9.8, 7.9, 5.2 Hz, 1H), ), 3.62 (s, 3H), 3.03 - 2.67 (m, 2H), 1.37 (d, J = 1.2 Hz, 18H).

[0378] Step 4 5% Pd / C (JM#9) (0.418 g, 2.311 mmol) was placed in a 50 mL pearl reactor. (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 placed in the reactor and purged with argon and then H 2 2. The reaction mixture was stirred at room temperature for 1 hour under 50 psi of H 2 2. 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 obtain 1.04 g of Compound 4 (purity 95%, yield 98%). 1 1H NMR (400 MHz, DMSO-d 6 6) δ 9.13 (s, 1H), 6.88 (d, J = 1.9 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 5.50 (d, J = 11.4 Hz, 2H), 3.58 (s, 3H), 3.49 (t, J = 6.6 Hz, 1H), 2.81 - 2.58 (m, 2H), 1.70 (s, 2H), 1.39 (d, J = 0.6 Hz, 18H).

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

[0380] Step 6 (S)-Methyl 2-amino-3-(4-hydroxy-3-((phosphonooxy)methoxy)phenyl)propanoate, compound 6, (752 mg, 2.341 mmol) in water 4 mL was added dropwise with 6N NaOH 2.62 mL over 5 minutes to adjust the pH to 12.5 at 5 °C. 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. IPA was added to this solution until the product precipitated while maintaining pH 1.9. The product, compound 7, was filtered and washed with IPA to obtain 630 mg with a purity of 90%. 1 H NMR (400 MHz, deuterium oxide) δ 7.17 (d, J = 1.8 Hz, 1H), 6.99 - 6.96 (m, 1H), 6.94 (dd, J = 8.3, 1.8 Hz, 1H), 5.57 (d, J = 12.6 Hz, 2H), 4.16 (dd, J = 7.9, 5.1 Hz, 1H), 3.33 - 3.05 (m, 2H).

[0381] Example 9: Synthesis of L-Dopa 4′-phonoxy methyl ester L-DOPA 4′-phonoxymethyl ester was prepared according to the method shown in Scheme 9 below.

[0382]

Chemical Structure

[0383] Specifically, L-dopa 4′-phonoxy methyl ester was produced according to the method described in Steps 1 to 6 below.

[0384] Step 1 To a solution of 3-(benzyloxy)-4-hydroxybenzaldehyde, Compound 1, (10.0 g, 43.8 mmol) in acetonitrile (133 mL) was added di-tert-butyl (chloromethyl) phosphate (12.53 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. After the addition, the reaction mixture was warmed to room temperature (about 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 times with 100 mL). The organic layer was washed with saturated sodium bicarbonate solution (150 mL), water (150 mL), and saturated sodium chloride solution (150 mL), and concentrated to obtain Compound 2 (20.0 g, purity 70%, yield 73%). The crude product was passed through a silica gel column using an ethyl acetate - hexane gradient to obtain 8.77 g of Compound 2 (purity 91%, yield 41%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.87 (s, 1H), 7.59 (d, J = 7.0 Hz, 2H), 7.49 - 7.45 (m, 2H), 7.43 - 7.31 (m, 4H), 5.72 (d, J = 12.7 Hz, 2H), 5.20 (s, 2H), 1.37 (d, J = 0.6 Hz, 18H).

[0385] Step 2 (+ / -)-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) were added 1,1,3,3-tetramethylguanidine (2.09 g, 18.16 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature overnight. The next day, the reaction mixture was washed three times with 35 mL of water and concentrated to give 13.11 g of the 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 (purity 85%, yield 72%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.54 (d, J = 2.0 Hz, 1H), 7.50 - 7.21 (m, 13H), 7.16 (d, J = 8.5 Hz, 1H), 5.63 (d, J = 12.1 Hz, 2H), 5.09 (d, J = 19.1 Hz, 4H), 3.71 (s, 3H), 1.37 (d, J = 0.5 Hz, 18H).

[0386] Step 3 Into a 120 mL Pearl reactor were placed methyl 3-(3-(benzyloxy)-4-(((di-tert-butoxyphosphoryl)oxy)methoxy)phenyl)-2-(((benzyloxy)carbonyl)amino)acrylate (8.37 g, 10.85 mmol) and 1,2-bis[(2S,5S)-2,5-diethylphospholano]benzene(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (0.072 g, 0.109 mmol) and tetrahydrofuran (70.5 mL). The mixture was purged with H 2 and the reaction mixture was stirred at 35 °C under 100 psi of H 2 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 (purity 78%, yield 69%, 97% ee). 1 H NMR (400 MHz, DMSO-d 6)δ 7.80 (d, J = 8.1 Hz, 1H), 7.54 - 7.22 (m, 10H), 7.12 - 6.97 (m, 2H), 6.80 (dd, J = 8.2, 2.0 Hz, 1H), 5.54 (d, J = 11.3 Hz, 2H), 5.13 - 4.90 (m, 4H), 4.25 (ddd, J = 10.1, 8.1, 5.0 Hz, 1H), 3.62 (s, 3H), 3.04 - 2.73 (m, 2H), 1.35 (d, J = 0.5 Hz, 18H).

[0387] Step 4 5% Pd / C (JM#9) (0.429 g, 2.372 mmol) was placed in a 50 mL pearl reactor. (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 placed in the reactor and purged with argon and then H 2 followed by purging with H 2 The reaction mixture was stirred at room temperature for 1 hour under 50 psi of H 1 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 obtain 1.08 g of Compound 4 (purity 94%, yield 99%). 6 1H NMR (400 MHz, DMSO-d

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

[0389] Step 6 (S)-Methyl 2-amino-3-(3-hydroxy-4-((phosphonooxy)methoxy)phenyl)propanoate, compound 6, (752 mg, 2.341 mmol) in 3 mL of water was added dropwise with 6N NaOH over 5 minutes to make pH = 12.5 at 5 °C. 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, IPA was added while maintaining pH 1.9 until the product precipitated. The product, compound 7, was filtered and washed with IPA to obtain 850 mg, which was 88% pure. 1 1H NMR (400 MHz, deuterium oxide) δ 7.09 (dd, J = 8.2, 0.7 Hz, 1H), 6.76 (d, J = 2.1 Hz, 1H), 6.73 (dt, J = 8.3, 1.3 Hz, 1H), 5.43 (dd, J = 12.6, 0.7 Hz, 2H), 4.08 - 3.97 (m, 1H), 3.21 - 2.89 (m, 2H).

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

[0391]

Chemical formula

[0392] Specifically, carbidopa 3′-phonoxy methyl ester and carbidopa 4′-phonoxy methyl 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) To a 500 mL round-bottom flask were added (S)-2-(2-((benzyloxy)carbonyl)hydrazinyl)-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid compound 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 dropwise. The mixture was stirred in the ice bath overnight. The slurry was filtered, and the cake was washed with methyl t-butyl ether. The filtrate was mixed 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 product was purified by flash chromatography using a 220 g silica column (0% to 30% ethyl acetate / heptane) to obtain 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) To a 100 mL round-bottom flask were added 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 the ice bath for 30 minutes and then stirred 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 product 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, and 20% Pd(OH) 2 / C (50 mg, 0.036 mmol) was added. The mixture was stirred at 50 psi and room temperature for 1 hour. The reaction mixture was filtered. The filtrate was mixed with water and extracted twice with methyl t-butyl ether. The aqueous phase was dried by a freeze dryer. The concentrate was purified by RP-HPLC (Kromacil Phenyl 3.0 cm i.d. × 25 cm, 5 μ column with 0% to 10% [0.1% formic acid / acetonitrile] / [0.1% formic acid / water]). Two isomers were separated. The collected fractions were combined and dried by a freeze dryer to obtain Compound 4 and Compound 5 as loose white solids, respectively.

[0398] Compound 4 (16.5 mg, 16.1%): 1 H NMR (501 MHz, DMSO-d 6 ) δ 6.94 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 2.1 Hz, 1H), 6.54 (dd, J = 8.1, 2.1 Hz, 1H), 5.28 (d, J = 14.6 Hz, 2H), 2.86 (d, J = 13.6 Hz, 1H), 2.78 (d, J = 13.6 Hz, 1H), 1.26 (s, 3H). MS (ESI+) 337.0.

[0399] Compound 5 (30.9 mg, 30.2%): 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.00 (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 Methyl 4'-Phosphate of Carbidopa Methyl carbidopa 4′-monophosphate was prepared according to the method shown in Scheme 11 below.

[0401]

Chemical formula

[0402] Step 1 Into a 100 mL round-bottom flask were placed (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 stirring bar. To this stirred mixture was added 4-(dimethylamino)pyridine (88 mg, 0.720 mmol) in one portion, and the reaction solution was further stirred for 48 hours. Thereafter, the solvent was removed by a rotary evaporator to obtain a pale yellow residue. The residue was suspended in acetonitrile (40 mL) and stirred at 5 °C for 2 hours. The suspension was filtered through a silica gel layer and eluted with 400 mL of acetonitrile. Removal of the acetonitrile by a rotary evaporator gave a pale yellow oil in 94% yield, which was used directly in the next step. LC / MS [M+H]: 859.40.

[0403] Step 2 5% Pd / C (0.794 mg, 3.36 mmol) was placed into a 150 mL pearl reactor. The catalyst was slurried with water (4.83 mL) and 5 wt% aqueous sodium bicarbonate solution (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 H 2 (4 times at 50 psi). Next, the reactor was charged with H 2It was repressurized and stirred at ambient temperature for 60 minutes. Thereafter, the two-phase reaction mixture was filtered through Celite (R) diatomaceous earth, washed with water (2.2 mL), and the residue in the reactor was filtered. The resulting two-phase mixture was diluted with MTBE (8 mL), stirred for 5 minutes, and charged into a separatory funnel. The aqueous layer was separated and washed with DCM (3 times with 30 mL). The aqueous layer was collected and dried by a freeze dryer to obtain Compound 3 in 68% yield as an off-white solid. 1 H NMR (400 MHz, D 2 O): δ 1.46 (s, 3H), 2.92 (d, J = 12 Hz, 1H), 3.05 (d, J = 12 Hz, 1H), 3.79 (s, 3H), 6.65 - 6.72 (m, 2H), 7.11 (d, J = 8.0 Hz, 1H).

[0404] Example 12: Stability Test of Phosphate Prodrug 1-Day Stability Test L-Doparic acid prodrug and carbidoparic acid prodrug were evaluated in stability tests. An aqueous solution of the prodrug (80 μg / mL) was monitored over a wide range of pH values under ambient storage conditions throughout the day to indicate the possibility of administration during injection. Table 12-A below reports the results of this test and confirms that the prodrug has good stability at room temperature for one day.

[0405]

Table 1

[0406] Furthermore, a solution combining the diphosphates of each compound (35 mg / mL of L-Dopa 3′,4′-diphosphate and 8.7 mg / mL of carbidopa 3′,4′-diphosphate) was monitored at room temperature over one day. This sample was purged with nitrogen to remove oxygen. Table 12-B below reports the results of this test and confirms the good stability of the combined solution for which nitrogen purging was carried out at room temperature over one day.

[0407]

Table 2

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

[0409]

Table 3

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

[0411]

Table 4

[0412] Figure 1 shows that the solubility of L-dopa 4'-monophosphate and carbidopa 4'-monophosphate is higher compared to L-dopa and carbidopa.

[0413] Example 14: Hydrazine Release Test A solution combining 50 mg / mL of L-DOPA 4'-monophosphate and 12.5 mg / mL of carbidopa 4'-monophosphate was monitored for hydrazine release over 7 days. These solutions were prepared at pH 5 to pH 8, purged with nitrogen to remove oxygen, and held at room temperature. As shown in Figure 2, a significant decrease in hydrazine release was observed at a pH of approximately 7.4. For comparison, the amount of hydrazine released from Duopa(R) was also measured. As shown in Figure 3, unexpectedly, a 4:1 ratio solution of L-DOPA 4'-monophosphate and carbidopa 4'-monophosphate at a pH of approximately 7.4 had significantly lower hydrazine release compared to Duopa(R).

[0414] Example 15: In Vitro Biotransformation Test The in vitro bioconversion of L-DOPA phosphate prodrugs to L-DOPA and carbidopa phosphate prodrugs to carbidopa was evaluated in several tests. 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 homogenates (3 mg / mL), liver microsomes (1 mg / mL), liver S9 fractions (1 mg / mL), kidney S9 fractions (1 mg / mL), and intestinal S9 fractions (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 prodrug, L-DOPA, or carbidopa. The in vitro bioconversion was evaluated by monitoring both the lack of time dependence of the prodrug and the corresponding formation of L-DOPA or carbidopa.

[0415] Table 15-A below reports the test results 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 / 2is the shortest in the minipig, followed by the rat, and then the human. The diphosphate prodrugs of carbidopa and L-dopa were also dephosphorylated in rat blood at t 1 / 2 53 minutes and 6 minutes, respectively, with the corresponding formation of L-dopa or carbidopa. The dephosphorylation of the diphosphate prodrug of L-dopa was relatively slow in human and minipig blood, at t 1 / 2 138 minutes and 125 minutes, respectively. A corresponding time-dependent formation of L-dopa was observed in both minipig and human blood incubations. However, the diphosphate prodrug of carbidopa was not dephosphorylated in minipig and human blood. No formation of carbidopa was observed in blood incubations.

[0416]

Table 5

[0417] The following Table 15-B reports the results of the tests in skin homogenates. In skin homogenates, the four monophosphate prodrugs were slowly dephosphorylated, with t 1 / 2 ranging from 114 minutes 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 formation of L-dopa or carbidopa was observed in the incubations.

[0418]

Table 6

[0419] In human liver microsomes, the four prodrugs (the 3′-phosphate and diphosphate prodrugs of L-dopa, and the 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, mini-pigs, and humans, four prodrugs (the 4'-phosphate and diphosphate prodrugs of L-DOPA, and the 4'-phosphate and diphosphate prodrugs of carbidopa) were stable, and the formation of L-DOPA or carbidopa was not observed.

[0421] In the kidney S9 fractions of rats and humans, four prodrugs (the 4'-phosphate and diphosphate prodrugs of L-DOPA, and the 4'-phosphate and diphosphate prodrugs of carbidopa) were stable, and the formation of L-DOPA or carbidopa was not observed.

[0422] Table 14-C below reports the test results in the intestinal S9 fraction. In the intestinal S9 fractions of rats and humans, four prodrugs (the 4'-phosphate and diphosphate prodrugs of L-DOPA and the 4'-phosphate and diphosphate prodrugs of carbidopa) were rapidly dephosphorylated. t 1 / 2 appeared to be shorter for human intestinal S9 than for rat intestinal S9. Time-dependent formation of the corresponding L-DOPA or carbidopa was observed upon incubation of the prodrugs with the rat or human intestinal S9 fractions. The results suggest that phosphatase activity is high in the small intestines of rats and humans.

[0423]

Table 7

[0424] Example 16: Pharmacokinetics Test in Rats The in vivo conversion of L-dopamine prodrug to L-dopa and carbidopa prodrug to carbidopa was evaluated in a rat pharmacokinetic study by intravenous or subcutaneous administration of the prodrugs to rats. For comparison, rat pharmacokinetic studies using L-dopa and carbidopa were conducted to aid in the evaluation of in vivo conversion of the prodrugs. The test designs and measured exposures of L-dopa and carbidopa are summarized in Tables 16-A and 16-B, respectively. That is, groups of three male Sprague-Dawley rats were administered (1) aqueous solutions of L-dopa and carbidopa, or (2) aqueous solutions of the individual prodrugs intravenously or subcutaneously. Blood was collected at multiple time points over 24 hours into blood collection tubes containing NaAsO 4 , EDTA, and ascorbic acid. Plasma was separated from the blood, and protein precipitation was performed with 2 to 3 volumes of 5% aqueous trichloroacetic acid, followed by centrifugation. LC-MS analysis was performed on the supernatant for quantification of the prodrug, L-dopa, or carbidopa.

[0425]

Table 8

[0426]

Table 9

[0427] By comparing the in vivo exposures of L-dopa or carbidopa obtained from administration of the prodrug with the exposures obtained from administration of L-dopa or carbidopa alone, the in vivo conversion of the corresponding L-dopa or carbidopa of the prodrug was estimated to exceed 66%.

[0428] Example 17: Ratio Test of L-Dopa Diphosphate / Carbidopa Diphosphate The effects of various dose ratios of carbidopa phosphate:L-dopa phosphate on the steady-state level of L-dopa were evaluated in a rat pharmacokinetic study. In that study, an aqueous solution of a combination of L-dopa phosphate (fixed dose) and carbidopa phosphate (various doses) was subcutaneously infused into rats for 16 hours. That is, groups of three male Sprague-Dawley rats were administered combinations of L-dopa phosphate and carbidopa phosphate having different dose ratios. Table 17-A provides a summary of the study design. First, the rats were administered a subcutaneous bolus dose at a dose volume of 1 mL / kg over 1 minute. After 1.5 hours, a continuous infusion dose was administered at a dose volume of 10 mL / kg over the subsequent 14.5 hours. Blood samples were taken 0.25, 0.5, 1, 6, 16, and 20 hours after the bolus dose. The blood samples were processed in the same manner as described in Example 16. Another small blood sample was taken for hydrazine measurement.

[0429]

Table 10

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

[0431] The following Table 17-B reports the measured steady-state blood levels of L-dopa ("LD") and carbidopa ("CD"). Figure 6 graphically represents the same data. The ratio of L-dopa phosphate:carbidopa phosphate had a major effect on the steady-state level of L-dopa. For example, after administration of L-dopa phosphate alone, the average plasma concentration of L-dopa at 6 hours (C 6h) was 0.164 μg / mL. When a combination of L-dopa diphosphate and carbidopa diphosphate was administered at a dose ratio of 50:1, the average plasma concentration of L-dopa (C 6h ) increased to 0.55 μg / mL. When a combination of L-dopa diphosphate and carbidopa diphosphate was administered at a dose ratio of 1:1, the average plasma concentration of L-dopa (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: Pharmacokinetics Test of L-Dopa 4'-Phosphate / Carbidopa 4'-Phosphate in Rats The effect of a 4:1 ratio of L-dopa 4′-monophosphate:carbidopa 4′-phosphate on the steady-state level of L-dopa was evaluated in a rat pharmacokinetic study.

[0434] 16-Hour Subcutaneous Infusion In this study, an aqueous solution of a combination of L-DOPA 4'-monophosphate and carbidopa 4'-monophosphate at a dose ratio of 4:1 was first administered to rats via subcutaneous bolus at a dose of 60 / 14 mg / kg over 1 minute. After 1.5 hours, the combination was readministered via continuous infusion at a dose of 300 / 71 mg / kg over the next 14.5 hours. Blood samples were taken at 1, 0.25, 1, 6, 16, and 24 hours after administration. The blood samples were processed in the same manner as described in Example 15. Another aliquot of blood sample was taken for hydrazine measurement. Figure 7 provides the time-concentration profiles for L-DOPA and L-DOPA 4'-monophosphate blood levels after administration of a combination of 4'-monophosphate prodrugs at 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., about 10 μg / mL), which meet and / or exceed the plasma levels (e.g., about 3 μg / mL) achieved with Duopa(R) shown in Figure 8. A steady-state concentration of about 1 μg / mL was maintained over the infusion period of carbidopa. The exposure of residual L-DOPA 4'-monophosphate and carbidopa 4'-monophosphate was about 22% and about 8% of levodopa and carbidopa, respectively. Those doses were well tolerated in rats and no hydrazine was detected in rat plasma samples. Figure 9 provides the time-concentration profiles for carbidopa and carbidopa 4'-monophosphate blood levels after administration of a combination of 4'-monophosphate prodrugs at a 4:1 ratio.

[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 combination of L-DOPA (LD) 4'-monophosphate and carbidopa (CD) 4'-monophosphate at a dose ratio of 4:1 over 7 days. Table 18-A below reports the measured steady-state concentrations of levodopa with various amounts of 4:1 ratio L-DOPA 4'-monophosphate and carbidopa 4'-monophosphate.

[0436] [Table 12]

[0437] Example 19: Pharmacokinetics Test of L-Dopa Diphosphate and Carbidopa Diphosphate in Miniature Swine The in vivo conversion of carbidopa diphosphate to carbidopa was evaluated in a pharmacokinetic study in minipigs in which the prodrug was administered subcutaneously as an aqueous solution to a group of three minipigs. For comparison, a pharmacokinetic study using 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 rate of carbidopa diphosphate to carbidopa was approximately 100% based on the carbidopa exposure.

[0438] [Table 13]

[0439] The effects of various dose ratios of carbidopa diphosphate:L-dopa diphosphate on the steady-state level of L-dopa were evaluated in a pharmacokinetic study in minipigs. In this study, minipigs were given a 16-hour subcutaneous infusion of an aqueous solution of a combination of L-dopa diphosphate and carbidopa diphosphate at the specified dose ratios. After a washout period, each dose ratio was used. The study design is summarized in Table 19-B below and was the same as the design of the aforementioned rat study except that there was no initial subcutaneous bolus administration. Blood samples were taken at 1, 2, 4, 6, 8, 10, 14, 16, and 24 hours after administration. Blood samples were processed in the same manner as described in Example 12. Another aliquot of blood sample was taken for dopamine measurement.

[0440] [Table 14]

[0441] Figure 10 provides the time-concentration profiles for L-dopa blood levels after administration of combinations of diphosphate prodrugs at different ratios. Dopamine was not detected in the minipig plasma samples.

[0442] Example 20: Pharmacokinetics Test of 15:1 L-Dopa 4'-Phosphate / Carbidopa 4'-Phosphate in Miniature Swine The effect of a 15:1 ratio of L-dopa 4'-monophosphate:carbidopa 4'-phosphate on the steady-state level of L-dopa was evaluated in a mini-pig pharmacokinetic study.

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

[0444]

Table 15

[0445] Figure 11 provides the time-concentration profiles for L-DOPA and L-DOPA 4'-monophosphate blood levels after administration of a combination of 4'-monophosphate prodrugs at a 15:1 ratio. 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., about 5.5 μg / mL) that met and / or exceeded the plasma levels (e.g., about 3 μg / mL) achieved with Duopa(R) as shown in Figure 8. The plasma levels of levodopa increased over time and were near steady state at about 10 hours after dosing. A steady state levodopa plasma concentration of about 5.5 μg / mL was achieved. The exposure of residual L-DOPA 4'-monophosphate was about 10% of the levodopa exposure. The carbidopa plasma concentration reached steady state at about 3 hours after dosing and the steady state concentration was about 0.2 μg / mL. The exposure of residual carbidopa 4'-monophosphate was about 22% of the carbidopa exposure. Those doses were well tolerated in minipigs and no hydrazine was detected in minipig plasma samples. Figure 12 provides the time-concentration profiles for carbidopa and carbidopa 4'-monophosphate blood levels after administration of a combination of 4'-monophosphate prodrugs at a 15:1 ratio.

[0446] Example 21: Pharmacokinetics Test of L-Dopa 4'-Phosphate and Carbidopa 4'-Phosphate in Dogs In this study, an aqueous solution of a combination of L-DOPA (LD) 4'-monophosphate and carbidopa (CD) 4'-monophosphate at a dose ratio of 4:1 was subcutaneously infused into dogs for 24 hours. Table 21-A below reports the steady-state concentrations of levodopa (L-DOPA) at various amounts of L-DOPA 4'-monophosphate and carbidopa 4'-monophosphate at a 4:1 ratio. There were no deaths, and all dogs survived until 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 in levodopa and carbidopa 4'-monophosphate prodrugs were a slight increase in neutrophil and monocyte counts at 400 / 100 mg / kg; a slight decrease in triglycerides in animals dosed at >200 / 50 mg / kg; a slight increase in bilirubin in animals dosed at >200 / 50 mg / kg; an increase in urine specific gravity at all doses; and a slight increase in the urinary phosphorus:creatinine ratio and the excretion fraction of phosphorus at 400 / 100 mg / kg. Conclusion: Administration of L-DOPA (LD) 4'-monophosphate and carbidopa (CD) 4'-monophosphate at doses up to 400 / 100 mg / kg resulted in 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 a rat was administered an L-DOPA diphosphate / carbidopa diphosphate prodrug composition (i.e., a diphosphate composition), there was an increase in serum phosphate at a dose ≧ 300 / 75 mg / kg / day. This increase in serum phosphate did not occur in rats administered an L-DOPA 4'-monophosphate / carbidopa 4'-monophosphate composition (i.e., a monophosphate composition) at a dose of 750 / 187.5 mg / kg / day or less.

[0449] Example 23: Safety and Tolerance The local irritation and pain at the injection site were investigated.

[0450] Local tolerance: Using intravenous, paravenous, and subcutaneous bolus injections of LD / CD diphosphate at a concentration of 200 / 50 mg / mL, the pain during injection was evaluated in rabbits. Immediately after injection and throughout the 24-hour observation period, there were no signs of injection site pain or local tissue irritation. In rats administered a single SC bolus dose of LD diphosphate at a concentration of 125 mg / mL or less, and in mini-pigs subcutaneously infused with LD / CD diphosphate at 200 / 50 mg / mL for 24 hours, there were no harmful clinical signs or microscopic findings indicating local intolerance.

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

[0452] Rodent toxicity: A 7-day IV infusion toxicity test was 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 80 / 20, 240 / 60, or 720 / 180 mg / kg per day for 7 consecutive days for 18 hours each day. The rats in the 720 / 180 mg / kg group showed an increase in serum phosphorus, but no harmful clinical signs, clinical pathology findings, or histopathology findings were observed other than weight loss and decreased feed 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] The 7-day SC injection toxicity test 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 showed elevated serum phosphorus, but no adverse clinical signs, clinical pathology findings, or histopathology findings were observed, with the exception of weight loss and decreased feed consumption. The dose of 750 / 187.5 mg / kg resulted in a levodopa plasma concentration of 19.6 μg / mL.

[0454] The 7-day SC injection toxicity test was also conducted with an aqueous solution of the L-DOPA and carbidopa mixed monophosphate combination. Male Sprague-Dawley rats (n = 4 or 5 / group) were administered doses of 100 / 25, 300 / 75, or 750 / 187.5 mg / kg for 24 hours per day for 7 consecutive days. Rats in the 750 / 187.5 mg / kg group showed clinical signs such as aggressive behavior and hyperactivity. The findings were sufficiently prominent to affect their SC catheter placement and patency, and some animals dropped out of the study before completing the full dosing schedule. The average body weight after the end of the test in the 300 / 75 mg / kg group was -18% lower compared to the start of dosing on day 1. There were no significant effects on serum phosphate or urinary phosphate, and no adverse clinical pathology findings or histopathology findings. The levodopa plasma concentration was 9.4 μg / mL in the 300 / 75 mg / kg group.

[0455] Example 24: Steady-State Exposure of L-Dopa and L-Dopa 4'-Phosphate, Carbidopa and Carbidopa 4'-Phosphate, and Human Prediction of Daily Phosphorus Load Major factors in human prediction include the following. 1) Linear human pharmacokinetics; 2) Estimate the biotransformation ratio of the prodrug in humans with the average biotransformation ratio 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 prodrug 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 completed after SC administration. The predicted PK parameters for the monophosphate prodrug and the active drug are shown in Table 24-A.

[0456]

Table 17

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

[0458]

Table 18

[0459] The water solubility of L-dopa 4'-monophosphate can reach a high value of >300 mg / mL. It is considered that >6000 mg / day of L-dopa 4'-monophosphate is delivered by a dose solution of one 20 mL vial per day, which is considered to deliver a Css of levodopa of >5 μg / mL assuming linear human pharmacokinetics.

[0460] Example 25: Production of Crystalline Carbidopa-4'-Phosphate 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 the solid had dissolved, 500 μL of isopropyl alcohol was added. After adding the isopropyl alcohol, the solution became turbid. The turbid suspension was stirred using 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. Next, the wet cake was 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: Production of Crystalline Carbidopa-4'-Phosphate 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 using 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: Production of Crystalline Carbidopa-4'-Phosphate Dihydrate 103 mg of amorphous carbidopa-4'-monophosphate was weighed into a 4 mL vial. 200 μL of water was added. After all the solid 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, solid was observed in the vial. At that point, 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: Production of Crystalline Carbidopa-4'-Phosphate Anhydrate Approximately 10 mg of carbidopa-4′-monophosphate trihydrate was placed on an aluminum pan weighed by DVS Advantage (Surface Measurement Systems Ltd, Alperton, United Kingdom). For the sample, at 25 °C, the following humidity conditions were applied: placed under 30 - 0 - 90 - 0 - 30% relative humidity (RH) at 10% RH intervals. At each stage, the dm / dt (mass change / time change) criterion was 0.001% in 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. Before PXRD analysis, the DVS post-sample was maintained at 30% RH. The PXRD pattern for crystalline carbidopa-4′-monophosphate dehydrate is shown in Figure 19.

[0464] Example 28: Production of Crystalline L-Dopa-3'-Phosphate According to Example 1 above (Stages 1, 2, 3, 4b, 5b), crystalline L-dopa-3′-monophosphate was produced. The PXRD pattern for crystalline L-dopa-3′-monophosphate is shown in Figure 15.

[0465] Example 29: Production of Crystalline L-Dopa-4'-Phosphate Anhydride (i) According to Example 5 above, crystalline L-dopa-4′-monophosphate anhydride (i) was produced. The PXRD pattern for crystalline L-dopa-4′-monophosphate anhydride (i) is shown in Figure 13.

[0466] Example 30: Production of Crystalline L-Dopa-4'-Phosphate Anhydride (ii) 204 mg of L-dopa-4′-monophosphate anhydride (i) was weighed in a 4 mL vial. 1 mL of dimethyl sulfoxide and 1 mL of water were added. The resulting slurry was stirred at 24 °C. Next, the solid was 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: Production of Crystalline Carbidopa-3'-Phosphate (i) 100 mg of amorphous carbidopa-3'-monophosphate was weighed into a 4 mL vial. 300 μL of water was added. When the solid had dissolved, 600 μL of isopropanol was added. The resulting clear solution was stirred with a magnetic stir bar at room temperature overnight until a solid appeared 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 dryer 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: Production of Crystalline Carbidopa-3'-Phosphate (ii) 25 mg of carbidopa-3'-monophosphate (i) was weighed in 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 subjected to the following heating / cooling cycles while stirring with a magnetic stir bar: ramp to 50 °C at 10 °C / h, hold for 4 hours, ramp to -15 °C at 20 °C / h, hold for 4 hours, ramp to 50 °C at 10 °C / h, hold for 4 hours, ramp to -15 °C at 10 °C / h, hold for 4 hours, ramp to 50 °C at 10 °C / h, hold for 4 hours, ramp to -15 °C at 5 °C / h, hold for 4 hours, ramp to 25 °C at 10 °C / h, and hold until PXRD analysis. Next, the solid was 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: Production of Crystalline Sodium Carbidopa-3',4'-Diphosphate 46 mg of amorphous carbidopa 3',4'-diphosphate and 5.6 mg of sodium hydroxide pellet 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. Next, the solid was filtered and analyzed by PXRD. The PXRD pattern for crystalline sodium carbidopa-3',4'-diphosphate is shown in Figure 22.

[0470] Example 34: Production of Crystalline L-Dopa-3',4'-Diphosphate Trihydrate 62.1 mg of amorphous L-dopa 3′,4′-diphosphate was weighed in 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 while subject to the following heating / cooling cycles: a ramp to 50 °C at 10 °C / h, hold for 4 h, a ramp to -15 °C at 20 °C / h, hold for 4 h, a ramp to 50 °C at 10 °C / h, hold for 4 h, a ramp to -15 °C at 10 °C / h, hold for 4 h, a ramp to 50 °C at 10 °C / h, hold for 4 h, a ramp to -15 °C at 5 °C / h, hold for 4 h, a ramp to 25 °C at 10 °C / h, and held until PXRD analysis. Next, the solid was filtered and the wet cake was analyzed by PXRD. The PXRD pattern for crystalline L-dopa-3′,4′-diphosphate trihydrate is shown in Figure 16.

[0471] Alternatively, it is also possible to crystallize L-dopa-3′,4′-diphosphate trihydrate using ethyl acetate, isopropanol, water-saturated ethyl acetate, methyl ethyl ketone, acetone, tetrahydrofuran, toluene, 2-methyl THF, dichloromethane, tert-tributylamine, isobutyl acetate, 1,4-dioxane as solvents. The following solvent mixtures at a 1:1 volume ratio: acetone / water, isopropyl acetate / heptane can also be used.

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

[0473]

Chemical formula

[0474]

Chemical formula

[0475] Embodiment 2. The pharmaceutical combination of Embodiment 1, wherein the first compound is

[0476]

Chemical formula

[0477] Embodiment 3. The pharmaceutical combination of Embodiment 1, wherein the second compound is

[0478] [Chemical formula] The pharmaceutical combination of Embodiment 1 or 2, which is TIFF0007688087000075.tif52158.

[0479] Embodiment 4. The pharmaceutical combination according to any one of the above embodiments, 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.

[0480] Embodiment 5. The pharmaceutical combination according to any one of the above embodiments, 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.

[0481] Embodiment 6. The pharmaceutical combination according to any one of the above embodiments, 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 a nearly 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 a nearly neutral pH.

[0482] Embodiment 7. The pharmaceutical combination according to any one of the above 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 according to any one of the above embodiments, wherein the combination is an aqueous combination suitable for subcutaneous administration.

[0484] Embodiment 9. The first compound is a compound corresponding to formula (I-a) in structure:

[0485] [Chemical formula] or a pharmaceutically acceptable salt thereof; wherein the second compound is a compound corresponding to formula (II-a) in structure:

[0486]

Chem.

[0487] Embodiment 10. The first compound is a compound corresponding to formula (I-b) in structure:

[0488]

Chem.

[0489]

Chem.

[0490] Embodiment 11. The first compound is a compound corresponding to formula (I-c) in structure

[0491]

Chem.

[0492]

Chem.

[0493] Embodiment 12. The first compound is a compound corresponding to formula (I-a) in structure:

[0494]

Chemical formula

[0495]

Chemical formula

[0496] Embodiment 13. The first compound is a compound corresponding to formula (I-b) in structure:

[0497]

Chemical formula

[0498]

Chemical formula

[0499] Embodiment 14. The first compound is a compound corresponding to formula (I-c) in structure:

[0500]

Chemical formula

[0501]

Chemical formula

[0502] Embodiment 15. The first compound is a compound corresponding to formula (I-a) in structure:

[0503]

Chemical formula

[0504]

Chemical formula

[0505] Embodiment 16. The first compound is a compound corresponding to formula (I-b) in structure:

[0506]

Chemical formula

[0507]

Chemical formula

[0508] Embodiment 17. The first compound is a compound corresponding to formula (I-c) in structure:

[0509]

Chemical formula

[0510] [Chemical] A pharmaceutical combination according to any one of the above embodiments, or a pharmaceutically acceptable salt thereof.

[0511] Embodiment 18. A method for treating Parkinson's disease in a subject in need of treatment 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 the above 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, jejunal, oral, nasal, intramuscular or intravenous administration of the first compound and the second compound.

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

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

[0516] Embodiment 23. The method according to 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 according to 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 according to any one of Embodiments 18 to 24, wherein the weight ratio of the first compound to be administered to the second compound to be administered is from about 1:4 to about 1:10.

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

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

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

[0522] Embodiment 29. The first compound is

[0523]

Chemical formula

[0524]

Chemical formula

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

[0526] Embodiment 31. The method according to 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 by intragastric, subcutaneous, intramuscular, nasal, jejunal, oral or intravenous administration.

[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 to formula (I) in structure or a pharmaceutically acceptable salt thereof.

[0530] [Chemical formula] [wherein, R 1 and R 2 are each independently selected from the group consisting of hydrogen, -P(O)(OH) 2 , and -R 5 -O-P(O)(OH) 2 ; R 5 is C 1 -C 4 -alkyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 1 and R 2 is -P(O)(OH) 2 or -R 5 -O-P(O)(OH) 2 .]

[0531] Embodiment 35. R 1 and R 2 are each independently selected from the group consisting of hydrogen, -P(O)(OH) 2 , and -R 5 -O-P(O)(OH) 2 ; R 5 is C 1 -C 2 -alkyl; R 6 is hydrogen; provided that at least one of R 1 and R 2 is -P(O)(OH) 2 or -R5 -O-P(O)(OH) 2 which is the compound of Embodiment 34 or a pharmaceutically acceptable salt thereof.

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

[0533] Embodiment 37.R 1 and R 2 are each independently hydrogen or -R 5 -O-P(O)(OH) 2 ; R 5 is C 1 -C 2 -alkyl; R 6 is hydrogen; provided that R 1 and R 2 one of which is -R 5 -O-P(O)(OH) 2 which is the compound of Embodiment 34 or 35 or a pharmaceutically acceptable salt thereof.

[0534] Embodiment 38.R 1 and R 2 are each independently hydrogen, -P(O)(OH) 2 or -R 5 -O-P(O)(OH) 2 ; 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 which is -P(O)(OH) 2 or -R 5 -O-P(O)(OH) 2The compound of Embodiment 34 or a pharmaceutically acceptable salt thereof.

[0535] Embodiment 39. The compound is a compound or salt according to any one of Embodiments 34 to 36, corresponding to formula (I-a) in structure.

[0536] [Chemical formula]

[0537] Embodiment 40. The compound is a compound or salt according to any one of Embodiments 34 to 36, corresponding to formula (I-b) in structure.

[0538] [Chemical formula]

[0539] Embodiment 41. The compound is a compound or salt according to any one of Embodiments 34 to 36, corresponding to formula (I-c) in structure.

[0540] [Chemical formula]

[0541] Embodiment 42. The compound is a compound or salt according to any one of Embodiments 34, 35 or 37, corresponding to formula (I-d) in structure.

[0542] [Chemical formula]

[0543] Embodiment 43. The compound is a compound or salt according to any one of Embodiments 34, 35 or 37, corresponding to formula (I-e) in structure.

[0544] [Chemical formula]

[0545] Embodiment 44. The compound according to any one of Embodiment 34 or 38, or a salt thereof, wherein the compound corresponds to formula (I-f) in structure.

[0546]

Chemical formula

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

[0548]

Chemical formula

[0549] Embodiment 46. R 3 and R 4 are each independently hydrogen or -R 5 -O-P(O)(OH) 2 ; R 5 is C 1 -C 2 -alkyl; R 6 is hydrogen; provided that one of R 3 and R 4 is -R 5 -O-P(O)(OH) 2The compound or salt of Embodiment 45.

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

[0551] [Chemical formula]

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

[0553] [Chemical formula]

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

[0555] [Chemical formula] or a pharmaceutically acceptable salt thereof [wherein, R 1 and R 2 are each independently selected from the group consisting of hydrogen, -P(O)(OH) 2 , and -R 5 -O-P(O)(OH) 2 ; R 5 is C 1 -C 4 -alkyl; R 6 is hydrogen or C 1 -C 4 -alkyl; provided that at least one of R 1 and R 2 is -P(O)(OH) 2 or -R 5 -O-P(O)(OH) 2 . And a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0556] Embodiment 50. The pharmaceutical composition of Embodiment 49, wherein the first compound corresponds to formula (I-a) in structure.

[0557]

Chemical formula

[0558] Embodiment 51. The pharmaceutical composition of Embodiment 49, wherein the first compound corresponds to formula (I-b) in structure.

[0559]

Chemical formula

[0560] Embodiment 52. The pharmaceutical composition of Embodiment 49, wherein the first compound corresponds to formula (I-c) in structure.

[0561]

Chemical formula

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

[0563]

Chemical formula

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

[0565]

Chemical formula

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

[0567]

Chemical formula

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

[0569]

Chemical formula

[0570] Embodiment 57. The pharmaceutical composition according to 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 according to 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 according to 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. A pharmaceutical composition according to 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. A pharmaceutical composition according to any one of embodiments 49 to 60, wherein the composition further contains water and is suitable for injection.

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

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

[0577] Embodiment 64.

[0578]

Chemical formula

[0579] Embodiment 65. A crystalline polymorph of L-dopa 4'-monophosphate identified by powder X-ray diffraction, wherein the crystalline polymorph shows at least one characteristic peak in the 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, crystalline L-dopa 4'-monophosphate anhydrate (i); or Crystalline L-dopa 4'-monophosphate anhydride (ii) showing at least one characteristic peak in the 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, 25.647 ± 0.20 which is a crystalline polymorph

[0580] Embodiment 66. Crystalline L-dopa 3'-monophosphate showing at least one characteristic peak in the 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

[0581] Embodiment 67. Crystalline L-dopa 3'4-diphosphate trihydrate showing at least one characteristic peak in the powder X-ray 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

[0582] Embodiment 68. A crystalline polymorph of carbidopa 4'-monophosphate identified by powder X-ray diffraction, wherein the crystalline polymorph Crystalline carbide p4'-monophosphate trihydrate showing at least one characteristic peak in the 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 carbide p4'-monophosphate dihydrate showing at least one characteristic peak in the powder X-ray diffraction pattern at 2θ 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 carbide p4'-monophosphate anhydride showing at least one characteristic peak in the 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 which is a crystalline polymorph.

[0583] Embodiment 69. A crystalline polymorph of carbide p3'-monophosphate identified by powder X-ray diffraction, wherein the crystalline polymorph is Crystalline carbide p3'-monophosphate (i) showing at least one characteristic peak in the 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 carbide pa3'-monophosphate (ii) showing at least one characteristic peak in the 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 which is a crystalline polymorph.

[0584] Embodiment 70.2θ 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 showing at least one characteristic peak in the powder X-ray diffraction pattern of crystalline carbide pa3'4-diphosphate sodium salt.

[0585] It should be understood that the foregoing detailed description and accompanying examples are for illustrative purposes only and should not be construed as limiting the scope of the invention, which is defined only 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. Such changes and modifications, such as those related to the chemical structure, substituents, derivatives, intermediates, synthesis, compositions, formulations or methods of use of the present invention (but not limited thereto), can be made without departing from the spirit and scope of the present invention.

Claims

1. A pharmaceutical composition comprising a first compound corresponding to formula (I) in structure: 【Chemical 1】 or a pharmaceutically acceptable salt of the compound [wherein, R １ and R ２ are each independently hydrogen, -P(O)(OH) ２ , and -R ５ -O-P(O)(OH) ２ selected from the group consisting of; R ５ is C １ -C ４ -alkyl; R ６ is hydrogen or C １ -C ４ -alkyl; provided that at least one of R １ and R ２ is -P(O)(OH) ２ or -R ５ -O-P(O)(OH) ２ is.]; and A second compound corresponding to formula (II) in structure: 【Chemical 2】 or a pharmaceutically acceptable salt of the compound [wherein, R ３ and R ４ are each independently hydrogen, -P(O)(OH) ２ and -R ５ -O-P(O)(OH) ２ selected from the group consisting of; R ５ is C １ -C ４ -alkyl; R ６ is hydrogen or C １ -C ４ -alkyl; provided that at least one of R ３ and R ４ is -P(O)(OH) ２ or -R ５ -O-P(O)(OH) ２ .]

2. The pharmaceutical composition according to claim 1, wherein the first compound is

3. 【Chemical Formula 3】 【Chem.】 The pharmaceutical composition according to claim 1 or 2, wherein the second compound is

4. The pharmaceutical composition according to any one of claims 1 to 3, 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. 【Chemical Formula 4】

5. The pharmaceutical composition according to 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. The pharmaceutical composition according to 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 of approximately 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 of approximately neutral pH.

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

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

9. The first compound is a compound corresponding to formula (I-a) in structure: Or a pharmaceutically acceptable salt of the compound; the second compound is a compound corresponding to formula (II-a) in structure: Or a pharmaceutically acceptable salt of the compound, and the pharmaceutical composition according to any one of claims 1 to 8.

10. [Chemical Formula 5] The first compound is a compound corresponding to formula (I-b) in structure: 【Chemical Formula 6】 Or a pharmaceutically acceptable salt of the compound; the second compound is a compound corresponding to formula (II-a) in structure: Or a pharmaceutically acceptable salt of the compound, and the pharmaceutical composition according to any one of claims 1 to 9. ​ [Chemical Formula 7] ​ 【Chemical 8】 ​

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