Carbidopa and l-dopa prodrugs and methods of use

Abstract

To provide 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.SOLUTION: The present disclosure provides (a) carbidopa prodrugs, (b) pharmaceutical combinations and pharmaceutical compositions comprising a carbidopa prodrug and / or an L-dopa prodrug, and (c) methods of treating Parkinson's disease and associated conditions comprising administering a carbidopa prodrug and an L-dopa prodrug to a subject with Parkinson's disease.SELECTED DRAWING: None

Description

[Technical Field]

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

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

[0003] [ka]

[0004] The conversion of L-dopa to dopamine is catalyzed by aromatic L-amino acid decarboxylase, a ubiquitous enzyme that facilitates 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 increase peripheral dopamine levels, which can cause nausea in some patients. To overcome these problems, L-dopa is usually administered in combination with a peripheral aromatic L-amino acid decarboxylase inhibitor, such as carbidopa (i.e., (2S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoic acid).

[0005] [ka] Coadministration of carbidopa with L-dopa inhibits the peripheral metabolism of L-dopa to dopamine, which significantly reduces the L-dopa dose required for a therapeutically effective response and reduces associated side effects. Summary of the Invention [Problem to be solved by the invention]

[0006] However, even when L-dopa and carbidopa are administered concomitantly, consistently maintaining desired dopamine levels in the brain is difficult due to the relatively short half-life of L-dopa in plasma. Furthermore, many patients' tolerance to variability in brain dopamine levels decreases as the disease progresses. One approach that has been effective in reducing variability in dopamine levels is continuous enteral delivery of an adjustable-dose L-dopa / carbidopa gel (known as DuoDopa® in Europe and Duopa® in the United States). DuoDopa® / Duopa® is a suspension of L-dopa / carbidopa monohydrate (4:1 ratio of L-dopa:carbidopa monohydrate) in an aqueous gel (sodium carboxymethylcellulose) with a viscosity that allows for uniform distribution of micronized particles. The gel is delivered to the proximal small intestine through an air-conditioning tube inserted through a percutaneous endoscopic gastrostomy opening. DuoDopa® / Duopa® is delivered continuously via a software-controlled ambulatory infusion pump in a medication cassette reservoir. While L-dopa and carbidopa have been administered in combination to treat Parkinson's disease for decades, no pharmacokinetically consistent delivery system that does not require intestinal insertion is commercially available.

[0007] A major challenge in developing less invasive or improved L-dopa and carbidopa dosage forms has been the solubility of these compounds. Each has low aqueous solubility in the pH range required for injection. Stable, more concentrated, and / or less viscous formulations containing L-dopa and / or carbidopa (or compounds biotransformable in vivo to L-dopa and / or carbidopa) are desirable. Such formulations could offer advantages over existing enteral infusion therapies, such as (a) reducing the volume of the formulation delivered to the patient and improving pumpability (which could also reduce the size and weight of the delivery device); (b) reducing formulation degradation and improving formulation stability, thereby extending the shelf life of the formulation; and / or (c) reducing or eliminating the need for low-temperature storage of the formulation, thereby increasing patient flexibility in managing their therapy (e.g., longer periods for handling the formulation outside of refrigerated storage). Such stable, more concentrated, and / or less viscous formulations could also be used in less invasive administration forms (e.g., subcutaneous injection).

[0008] Thus, there remains a need for improved compositions and methods that can provide continuous, steady-state 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 problem]

[0009] In one aspect, the present disclosure relates to compounds corresponding in structure to Formula (I) or a pharmaceutically acceptable salt thereof.

[0010] [ka] In the formula, R 1 are independently hydrogen,

[0011] [ka] R 2 and R3 are each independently hydrogen,

[0012] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 are independently hydrogen,

[0013] [ka] is selected from the group consisting of:

[0014] In another aspect, the present disclosure relates to compounds corresponding in structure to Formula (II) or a pharmaceutically acceptable salt thereof.

[0015] [ka] In the formula, R 6 are independently hydrogen,

[0016] [ka] R 7 and R 8 are each independently hydrogen,

[0017] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9 are independently hydrogen,

[0018] [ka] is selected from the group consisting of:

[0019] In another aspect, the present disclosure relates to a pharmaceutical combination comprising a first compound corresponding in structure to Formula (I) or a pharmaceutically acceptable salt thereof, and a second compound corresponding in structure to Formula (II) or a pharmaceutically acceptable salt thereof.

[0020] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a first compound corresponding in structure to Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain aspects, the pharmaceutical composition can further comprise a second compound corresponding in structure to Formula (II) or a pharmaceutically acceptable salt thereof.

[0021] In another aspect, the disclosure relates to a method of treating Parkinson's disease or a related condition in a patient, comprising administering to the patient a therapeutically effective amount of a pharmaceutical combination comprising a first compound corresponding in structure to Formula (I) or a pharmaceutically acceptable salt thereof, and a second compound corresponding in structure to Formula (II) or a pharmaceutically acceptable salt thereof. In certain embodiments, the method comprises administering, in a single pharmaceutical composition or in separate pharmaceutical compositions, a first compound corresponding in structure to Formula (I) or a pharmaceutically acceptable salt thereof, and a second compound corresponding in structure to Formula (II).

[0022] Further details of the present disclosure will be apparent to those skilled in the art upon reading this patent application. The disclosed embodiments set forth in the following paragraphs are intended to illustrate the present invention and should not be considered to narrow the scope of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0023] This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any of the disclosed carbidopa prodrugs or pharmaceutical compositions, and performing any of the disclosed methods or processes. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art.

[0024] Such other examples are intended to be encompassed by the claims if they have elements that do not differ from the literal words of the claims or if they contain equivalent elements.

[0025] I. Definition The section headings used in this section and throughout the disclosure are not intended to be limiting.

[0026] Where numerical ranges are recited, each intervening number within the range is expressly contemplated with the same degree of precision. For example, the range 6 to 9 specifically contemplates the numbers 7 and 8 in addition to 6 and 9, and the range 6.0 to 7.0 specifically contemplates 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. Similarly, all recited ratios include all subratios within the broader ratio.

[0027] The singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise.

[0028] The term "and / or" as used herein in expressions such as "A and / or B" includes "A and B," "A or B," "A," and "B."

[0029] The term "about" refers to a range of numbers that one of ordinary skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In many instances, the term "about" may include numbers that are rounded to the nearest significant figure.

[0030] Unless the context otherwise requires, the terms "comprise," "comprises," and "comprising" are used with the clear understanding that they are to be interpreted inclusively rather than exclusively, and that applicant intends that each of these terms be so interpreted in interpreting this patent, including the appended claims.

[0031] The terms "ameliorate" and "amelioration" have their plain and ordinary meanings to one skilled in the art of pharmacy or medicine, and specifically include ameliorating the effects of Parkinson's disease or reducing or lessening the side effects of Parkinson's disease.

[0032] The term "patient" includes mammals and humans, especially humans.

[0033] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, preservatives, antioxidants, coatings, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.

[0034] The term "pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include (1) salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or salts formed with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2. Acid addition salts formed with organic acids such as 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, and muconic acid; and (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, or dicyclohexylamine, is coordinated.

[0035] The terms "reduce" and "reduction" have their plain and ordinary meanings to one skilled in the art of pharmacy or medicine, and specifically include lessening or decreasing the frequency, duration, or intensity of Parkinson's disease side effects, such as dyskinesias or hallucinations.

[0036] The term "therapeutically effective amount" means the amount of a compound that, when administered alone or in combination with another therapy to a patient suffering from or susceptible to Parkinson's disease or a related condition, effects treatment of Parkinson's disease or a related condition. A "therapeutically effective amount" will vary depending, for example, on the compound, the condition being treated and its severity, and the age and weight of the patient being treated.

[0037] The terms "treat" and "treatment" have their plain and ordinary meaning to one skilled in the art of pharmacy or medicine, and specifically include improving the quality of life or reducing the symptoms or side effects of Parkinson's disease.

[0038] II. Carbidopa and L-dopa prodrugs As noted above, the inherently low aqueous solubility of L-dopa and carbidopa at physiologically acceptable pH for injection presents significant technical challenges to the development of improved pharmaceutical compositions and methods of treatment. Such challenges include, for example, difficulties in achieving appropriate dosage volumes and formulation stability within the required pH range. These challenges are further complicated by the requirement that the pharmaceutical compositions and methods of treatment provide pharmacokinetically appropriate and pharmacokinetically consistent control of dopamine levels in the patient's brain.

[0039] Previous prodrug approaches have been unsuccessful for a number of reasons, including technical issues (such as poor chemical stability, poor solubility, and in vivo biotransformation problems), resulting in no successful commercialization of injectable L-dopa or carbidopa prodrugs. However, the prodrugs, pharmaceutical combinations, and pharmaceutical compositions, and treatment methods of the present disclosure overcome these problems. They can be used to treat patients suffering from Parkinson's disease and related conditions without always requiring invasive surgery. In various embodiments of the present disclosure, the compositions contain L-dopa and carbidopa prodrugs that convert to L-dopa and carbidopa in vivo, enabling delivery via continuous administration methods such as intragastric, intramuscular, intravenous, and subcutaneous administration. These novel prodrugs, combinations, compositions, and methods of the present disclosure represent an advance in the treatment of Parkinson's disease and other related conditions.

[0040] A. Carbidopa Prodrug Accordingly, in one embodiment, the present disclosure relates to compounds corresponding in structure to Formula (I): or a pharmaceutically acceptable salt thereof:

[0041] [ka] In the formula, R 1 are independently hydrogen,

[0042] [ka] R 2 and R 3 are each independently hydrogen,

[0043] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 are independently hydrogen,

[0044] [ka] In one embodiment, the compound corresponds in structure to Formula (I). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (I).

[0045] In one embodiment, R 2 and R 3 are both the same (e.g., both are hydrogen, both are

[0046] [ka] In another embodiment, R 2 and R 3 are different (e.g., R 2 is hydrogen and R 3 teeth,

[0047] [ka] etc.).

[0048] Additionally or alternatively, R 2 is hydrogen and R 3 is hydrogen,

[0049] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl.

[0050] Additionally or alternatively, R 2 is hydrogen and R 3 teeth,

[0051] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl.

[0052] Additionally or alternatively, R 2 is hydrogen and R 3 teeth

[0053] [ka] is.

[0054] Additionally or alternatively, R 2 is hydrogen and R 3 teeth

[0055] [ka] is.

[0056] Additionally or alternatively, R 2 is hydrogen and R 3 teeth

[0057] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl.

[0058] Additionally or alternatively, R 2 is hydrogen and R 3 teeth

[0059] [ka] is.

[0060] Additionally or alternatively, R 2 is hydrogen and R 3 teeth

[0061] [ka] is.

[0062] Additionally or alternatively, R 2 is hydrogen and R 3 teeth

[0063] [ka] is.

[0064] Additionally or alternatively, R 2 is hydrogen and R 3 is hydrogen.

[0065] Additionally or alternatively, R 2 is hydrogen,

[0066] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; R 3 is hydrogen.

[0067] Additionally or alternatively, R 2teeth,

[0068] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; R 3 is hydrogen.

[0069] Additionally or alternatively, R 2 teeth

[0070] [ka] and R 3 is hydrogen.

[0071] Additionally or alternatively, R 2 teeth

[0072] [ka] and R 3 is hydrogen.

[0073] Additionally or alternatively, R 2 teeth

[0074] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; R 3 is hydrogen.

[0075] Additionally or alternatively, R 2 teeth

[0076] [ka] and R 3 is hydrogen.

[0077] Additionally or alternatively, R 2 teeth

[0078] [ka] and R 3 is hydrogen.

[0079] Additionally or alternatively, R 2 teeth

[0080] [ka] and R 3 is hydrogen.

[0081] In another embodiment, the present disclosure provides R 1 are independently hydrogen,

[0082] [ka] R 2 and R 3 are hydrogen, and R 4 are independently hydrogen,

[0083] [ka] The present invention relates to a compound corresponding in structure to Formula (I) or a pharmaceutically acceptable salt thereof, selected from the group consisting of: In one embodiment, the compound corresponds in structure to Formula (I). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (I).

[0084] In another embodiment, the present disclosure provides R 1 is hydrogen; R 2 and R 3 are each independently hydrogen,

[0085] [ka] and R5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 are independently hydrogen,

[0086] [ka] The present invention relates to a compound corresponding in structure to Formula (I) or a pharmaceutically acceptable salt thereof, selected from the group consisting of: In one embodiment, the compound corresponds in structure to Formula (I). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (I).

[0087] In another embodiment, the present disclosure provides R 1 is hydrogen; R 2 and R 3 is hydrogen; and R 4 are independently hydrogen,

[0088] [ka] The present invention relates to a compound corresponding in structure to Formula (I) or a pharmaceutically acceptable salt thereof, selected from the group consisting of: In one embodiment, the compound corresponds in structure to Formula (I). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (I).

[0089] In another embodiment, the present disclosure provides a compound corresponding in structure to Formula (Ia):

[0090] [ka] or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (Ia). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (Ia).

[0091] In another embodiment, the present disclosure provides a compound corresponding in structure to Formula (Ib):

[0092] [ka] or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (Ib). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (Ib).

[0093] In another embodiment, the present disclosure provides R 1 are independently hydrogen,

[0094] [ka] R 2 and R 3 are each independently hydrogen,

[0095] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 is hydrogen, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (I). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (I).

[0096] In another embodiment, the present disclosure provides R 1 is hydrogen; R 2 and R 3 are each independently hydrogen,

[0097] [ka] and R 5is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 is hydrogen, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (I). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (I).

[0098] In another embodiment, the present disclosure provides R 1 Independently,

[0099] [ka] R 2 and R 3 is hydrogen; and R 4 are independently hydrogen,

[0100] [ka] The present invention relates to a compound corresponding in structure to Formula (I) or a pharmaceutically acceptable salt thereof, selected from the group consisting of: In one embodiment, the compound corresponds in structure to Formula (I). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (I).

[0101] In another embodiment, the present disclosure provides R 1 Independently,

[0102] [ka] R 2 and R 3 are each independently hydrogen,

[0103] [ka] and R 5is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 is hydrogen, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (I). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (I).

[0104] In another embodiment, the present disclosure provides R 1 Independently,

[0105] [ka] R 2 and R 3 are each independently hydrogen,

[0106] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 is hydrogen, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (I). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (I).

[0107] In another embodiment, the present disclosure provides R 1 Independently,

[0108] [ka] R 2 and R 3 is hydrogen; and R 4is hydrogen, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (I). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (I).

[0109] Various other compounds corresponding in structure to Formula (I) or pharmaceutically acceptable salts thereof are contemplated by the present invention. Examples of suitable compounds corresponding in structure to Formula (I) are provided in Table 1 below, where R 1 , R 2 , R 3 , R 4 and / or R 5 Substituents are provided.

[0110] [Table 1] TIFF2025163273000051.tif228170TIFF2025163273000052.tif234170TIFF2025163273000053.tif178170

[0111] In various embodiments, the present disclosure relates to a compound corresponding in structure to any one of formulas (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (I-aa), (I-ab), or (I-ac), or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to any one of formulas (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (I-aa), (I-ab), or (I-ac). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to any one of Formulas (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (I-aa), (I-ab), or (I-ac).

[0112] BL-dopa prodrug In another embodiment, the present disclosure relates to a compound corresponding in structure to formula (II) or a pharmaceutically acceptable salt thereof:

[0113] [ka] In the formula, R 6 are independently hydrogen,

[0114] [ka] R 7 and R 8 are each independently hydrogen,

[0115] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9 are independently hydrogen,

[0116] [ka] is selected from the group consisting of:

[0117] In one embodiment, the compound corresponds in structure to Formula (II): In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II).

[0118] In one embodiment, R 7 and R 8 are both the same (e.g., both are hydrogen, both are

[0119] [ka] , etc.). In another embodiment, R 7 and R 8 are different (e.g., R 7 is hydrogen and R 8 teeth

[0120] [ka] etc.).

[0121] Additionally or alternatively, R 7 is hydrogen and R 8 is hydrogen,

[0122] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl.

[0123] Additionally or alternatively, R 7 is hydrogen and R 8 teeth,

[0124] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl.

[0125] Additionally or alternatively, R 7 is hydrogen and R 8 teeth

[0126] [ka] is.

[0127] Additionally or alternatively, R 7 is hydrogen and R 8 teeth

[0128] [ka] is.

[0129] Additionally or alternatively, R 7 is hydrogen and R 8 teeth

[0130] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl.

[0131] Additionally or alternatively, R 7 is hydrogen and R 8 teeth

[0132] [ka] is.

[0133] Additionally or alternatively, R 7 is hydrogen and R 8 teeth

[0134] [ka] is.

[0135] Additionally or alternatively, R 7 is hydrogen and R 8 teeth

[0136] [ka] is.

[0137] Additionally or alternatively, R 7 is hydrogen and R 8 is hydrogen.

[0138] Additionally or alternatively, R 7 is hydrogen,

[0139] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; R 8 is hydrogen.

[0140] Additionally or alternatively, R 7 teeth,

[0141] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; R8 is hydrogen.

[0142] Additionally or alternatively, R 7 teeth

[0143] [ka] and R 8 is hydrogen.

[0144] Additionally or alternatively, R 7 teeth

[0145] [ka] and R 8 is hydrogen.

[0146] Additionally or alternatively, R 7 teeth

[0147] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; R 8 is hydrogen.

[0148] Additionally or alternatively, R 7 teeth

[0149] [ka] and R 8 is hydrogen.

[0150] Additionally or alternatively, R 7 teeth

[0151] [ka] and R 8 is hydrogen.

[0152] Additionally or alternatively, R 7 teeth

[0153] [ka] and R 8 is hydrogen.

[0154] In another embodiment, the present disclosure provides R 6 are independently hydrogen,

[0155] [ka] R 7 and R 8 are hydrogen, and R 9 are independently hydrogen,

[0156] [ka] or a pharmaceutically acceptable salt thereof, wherein the compound corresponds in structure to Formula (II), and is selected from the group consisting of: In one embodiment, the compound corresponds in structure to Formula (II), In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II).

[0157] In another embodiment, the present disclosure provides R 6 is hydrogen; R 7 and R 8 are each independently hydrogen,

[0158] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9 are independently hydrogen,

[0159] [ka] or a pharmaceutically acceptable salt thereof, wherein the compound corresponds in structure to Formula (II), and is selected from the group consisting of: In one embodiment, the compound corresponds in structure to Formula (II), In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II).

[0160] In another embodiment, the present disclosure provides R 6 is hydrogen; R 7 and R 8 is hydrogen; and R 9 are independently hydrogen,

[0161] [ka] or a pharmaceutically acceptable salt thereof, wherein the compound corresponds in structure to Formula (II), and is selected from the group consisting of: In one embodiment, the compound corresponds in structure to Formula (II), In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II).

[0162] In another embodiment, the present disclosure relates to compounds corresponding in structure to Formula (II-a) or a pharmaceutically acceptable salt thereof.

[0163] [ka] In one embodiment, the compound corresponds in structure to Formula (II-a): In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II-a):

[0164] In another embodiment, the present disclosure relates to compounds corresponding in structure to Formula (II-b) or a pharmaceutically acceptable salt thereof.

[0165] [ka] In one embodiment, the compound corresponds in structure to Formula (II-b): In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II-b):

[0166] In another embodiment, the present disclosure provides R 6 is hydrogen; R 7 and R 8 are each independently hydrogen,

[0167] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9 are independently hydrogen,

[0168] [ka] or a pharmaceutically acceptable salt thereof, wherein the compound corresponds in structure to Formula (II), selected from the group consisting of: In one embodiment, the compound corresponds in structure to Formula (II), In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II).

[0169] In another embodiment, the present disclosure provides R 6 are independently hydrogen,

[0170] [ka] R 7 and R 8 are each independently hydrogen,

[0171] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R9 is hydrogen, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (II). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II).

[0172] In another embodiment, the present disclosure provides R 6 are independently hydrogen,

[0173] [ka] R 7 But hydrogen,

[0174] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; R 8 is hydrogen; and R 9 are independently hydrogen,

[0175] [ka] or a pharmaceutically acceptable salt thereof, wherein the compound corresponds in structure to Formula (II), and is selected from the group consisting of: In one embodiment, the compound corresponds in structure to Formula (II), In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II).

[0176] In another embodiment, the present disclosure provides R 6 is hydrogen; R 7 But hydrogen,

[0177] [ka] and R 5is selected from the group consisting of hydrogen, methyl, and isopropyl; R 8 is hydrogen; and R 9 is hydrogen, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (II). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding to Formula (II).

[0178] In another embodiment, the present disclosure provides R 6 is hydrogen; R 7 and R 8 are each independently hydrogen,

[0179] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9 is hydrogen, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (II). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II).

[0180] In another embodiment, the present disclosure provides R 6 are independently hydrogen,

[0181] [ka] R 7 and R 8 are each independently hydrogen,

[0182] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9is hydrogen, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (II). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II).

[0183] In another embodiment, the present disclosure provides R 6 are independently hydrogen,

[0184] [ka] R 7 and R 8 is hydrogen; and R 9 are independently hydrogen,

[0185] [ka] or a pharmaceutically acceptable salt thereof, wherein the compound corresponds in structure to Formula (II), and is selected from the group consisting of: In one embodiment, the compound corresponds in structure to Formula (II), In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II).

[0186] In another embodiment, the present disclosure provides R 6 are independently hydrogen,

[0187] [ka] R 7 and R 8 is hydrogen; and R 9 is hydrogen, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to Formula (II). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to Formula (II).

[0188] Various other compounds corresponding in structure to Formula (II) or pharmaceutically acceptable salts thereof are contemplated herein. Examples of suitable compounds corresponding in structure to Formula (I) are provided below in Table 2, where R 6 , R 7 , R 8 , R 9 and / or R 5 Substituents are provided.

[0189] [Table 2] TIFF2025163273000098.tif237170TIFF2025163273000099.tif238170TIFF2025163273000100.tif166170

[0190] In various embodiments, the present disclosure relates to a compound corresponding in structure to any one of formulas (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-s), (II-t), (II-u), (II-v), (II-x), (II-y), (II-z), (II-aa), or (II-ab), or a pharmaceutically acceptable salt thereof. In one embodiment, the compound corresponds in structure to any one of formulas (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-s), (II-t), (II-u), (II-v), (II-x), (II-y), (II-z), (II-aa), or (II-ab). In another embodiment, the compound is a pharmaceutically acceptable salt of a compound corresponding in structure to any one of Formulas (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-s), (II-t), (II-u), (II-v), (II-x), (II-y), (II-z), (II-aa), or (II-ab).

[0191] III. Combination drugs / pharmaceutical compositions The present disclosure also relates to pharmaceutical combinations and compositions that include carbidopa prodrugs and / or L-dopa prodrugs.

[0192] In some embodiments, the pharmaceutical composition comprises a carbidopa prodrug. In other embodiments, the pharmaceutical composition comprises an L-dopa prodrug. In yet other embodiments, the pharmaceutical composition comprises both a carbidopa prodrug and an L-dopa prodrug.

[0193] The carbidopa and L-dopa prodrugs (and their pharmaceutically acceptable salts) disclosed herein can be formulated in the same pharmaceutical composition or can be present in separate pharmaceutical compositions. For example, a pharmaceutical combination disclosed herein can include a carbidopa prodrug in a first pharmaceutical composition and an L-dopa prodrug in a separate, second pharmaceutical composition. Alternatively, the pharmaceutical combination can include a carbidopa prodrug and an L-dopa prodrug in the same pharmaceutical composition.

[0194] A. First Compound and Second Compound In one embodiment, the pharmaceutical composition comprises a first compound corresponding in structure to Formula (I):

[0195] [ka] or a pharmaceutically acceptable salt thereof, 1 are independently hydrogen,

[0196] [ka] R 2 and R 3 are each independently hydrogen,

[0197] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 are independently hydrogen,

[0198] [ka] In one embodiment, the composition comprises a first compound corresponding in structure to Formula (I). In another embodiment, the composition comprises a pharmaceutically acceptable salt of a first compound corresponding in structure to Formula (I).

[0199] In another embodiment, a pharmaceutical composition comprises a first compound corresponding in structure to Formula (Ia) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one aspect, the composition comprises a first compound corresponding in structure to Formula (Ia). In another aspect, the composition comprises a pharmaceutically acceptable salt of a first compound corresponding in structure to Formula (Ia).

[0200] In another embodiment, a pharmaceutical composition comprises a first compound corresponding in structure to Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one aspect, the composition comprises a first compound corresponding in structure to Formula (Ib). In another aspect, the composition comprises a pharmaceutically acceptable salt of a first compound corresponding in structure to Formula (Ib).

[0201] In another embodiment, the pharmaceutical composition comprises a first compound corresponding in structure to any one of Formulas (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (I-aa), (I-ab), or (I-ac), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one embodiment, the composition comprises a first compound corresponding in structure to any one of Formulas (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (I-aa), (I-ab), or (I-ac). In another embodiment, the composition comprises a pharmaceutically acceptable salt of a first compound corresponding in structure to any one of Formulas (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (I-aa), (I-ab), or (I-ac).

[0202] In one embodiment, the pharmaceutical composition comprises a second compound corresponding in structure to Formula (II):

[0203] [ka] or a pharmaceutically acceptable salt thereof, 6 are independently hydrogen,

[0204] [ka] R7 and R 8 are each independently hydrogen,

[0205] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9 are independently hydrogen,

[0206] [ka] In one embodiment, the composition comprises a second compound corresponding in structure to Formula (II). In another embodiment, the composition comprises a pharmaceutically acceptable salt of a first compound corresponding in structure to Formula (II).

[0207] In another embodiment, the pharmaceutical composition comprises a second compound corresponding in structure to Formula (II-a) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one aspect, the composition comprises a second compound corresponding in structure to Formula (II-a). In another aspect, the composition comprises a pharmaceutically acceptable salt of a second compound corresponding in structure to Formula (II-a).

[0208] In another embodiment, the pharmaceutical composition comprises a second compound corresponding in structure to Formula (II-b) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one aspect, the composition comprises a second compound corresponding in structure to Formula (II-b). In another aspect, the composition comprises a pharmaceutically acceptable salt of a second compound corresponding in structure to Formula (II-b).

[0209] In another embodiment, the pharmaceutical composition comprises a second compound corresponding in structure to any one of Formulas (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-s), (II-t), (II-u), (II-v), (II-x), (II-y), (II-z), (II-aa), or (II-ab), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one embodiment, the composition comprises a second compound corresponding in structure to any one of Formulas ((II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-s), (II-t), (II-u), (II-v), (II-x), (II-y), (II-z), (II-aa), or (II-ab). wherein the composition comprises a pharmaceutically acceptable salt of a second compound corresponding in structure to any one of Formulas (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-s), (II-t), (II-u), (II-v), (II-x), (II-y), (II-z), (II-aa), or (II-ab).

[0210] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound has the structure of formula (I):

[0211] [ka] or a pharmaceutically acceptable salt thereof, R 1 are independently hydrogen,

[0212] [ka] R 2 and R 3 are each independently hydrogen,

[0213] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 are independently hydrogen,

[0214] [ka] selected from the group consisting of: The second compound has the formula (II) in structure:

[0215] [ka] or a pharmaceutically acceptable salt thereof, R 6 are independently hydrogen,

[0216] [ka] R 7 and R 8 are each independently hydrogen,

[0217] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9 are independently hydrogen,

[0218] [ka] is selected from the group consisting of:

[0219] The composition can independently comprise a first compound and a second compound, either as the free compounds or as pharmaceutically acceptable salts of the compounds. In one embodiment, the composition comprises a first compound in free form. In another embodiment, the composition comprises a pharmaceutically acceptable salt of the first compound. In another embodiment, the composition comprises a second compound in free form. In another embodiment, the composition comprises a pharmaceutically acceptable salt of the second compound. In another embodiment, the composition comprises a first compound in free form and a second compound in free form. In another embodiment, the composition comprises a pharmaceutically acceptable salt of the first compound and a pharmaceutically acceptable salt of the second compound.

[0220] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ia) or a pharmaceutically acceptable salt thereof; The second compound has the formula (II) in structure:

[0221] [ka] or a pharmaceutically acceptable salt thereof, R 6 are independently hydrogen,

[0222] [ka] R 7 and R 8 are each independently hydrogen,

[0223] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9 are independently hydrogen,

[0224] [ka] is selected from the group consisting of:

[0225] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ib) or a pharmaceutically acceptable salt thereof; The second compound has the formula (II) in structure:

[0226] [ka] or a pharmaceutically acceptable salt thereof, R 6 are independently hydrogen,

[0227] [ka] R 7 and R 8 are each independently hydrogen,

[0228] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9 are independently hydrogen,

[0229] [ka] is selected from the group consisting of:

[0230] 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 any one of formulas (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (I-aa), (I-ab), or (I-ac), or a pharmaceutically acceptable salt thereof; The second compound has the formula (II) in structure:

[0231] [ka] or a pharmaceutically acceptable salt thereof, R 6 are independently hydrogen,

[0232] [ka] R 7 and R 8 are each independently hydrogen,

[0233] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9 are independently hydrogen,

[0234] [ka] is selected from the group consisting of:

[0235] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound has the structure of formula (I):

[0236] [ka] or a pharmaceutically acceptable salt thereof, R 1 are independently hydrogen,

[0237] [ka] R 2 and R 3 are each independently hydrogen,

[0238] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 are independently hydrogen,

[0239] [ka] is selected from the group consisting of The second compound corresponds in structure to Formula (II-a) or a pharmaceutically acceptable salt thereof.

[0240] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound has the structure of formula (I):

[0241] [ka] or a pharmaceutically acceptable salt thereof, R 1 are independently hydrogen,

[0242] [ka] R 2 and R 3 are each independently hydrogen,

[0243] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 are independently hydrogen,

[0244] [ka] is selected from the group consisting of The second compound corresponds in structure to Formula (II-b) or a pharmaceutically acceptable salt thereof.

[0245] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound has the structure of formula (I):

[0246] [ka] or a pharmaceutically acceptable salt thereof, R 1 are independently hydrogen,

[0247] [ka] R 2 and R 3 are each independently hydrogen,

[0248] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 are independently hydrogen,

[0249] [ka] is selected from the group consisting of The second compound corresponds in structure to Formula (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-s), or (II-t), or a pharmaceutically acceptable salt thereof.

[0250] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ia) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-a) or a pharmaceutically acceptable salt thereof.

[0251] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ib) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-a) or a pharmaceutically acceptable salt thereof.

[0252] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ic) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-a) or a pharmaceutically acceptable salt thereof.

[0253] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Id) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-a) or a pharmaceutically acceptable salt thereof.

[0254] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ie) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-a) or a pharmaceutically acceptable salt thereof.

[0255] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to formula (If) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-a) or a pharmaceutically acceptable salt thereof.

[0256] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ia) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-b) or a pharmaceutically acceptable salt thereof.

[0257] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ib) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-b) or a pharmaceutically acceptable salt thereof.

[0258] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ic) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-b) or a pharmaceutically acceptable salt thereof.

[0259] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Id) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-b) or a pharmaceutically acceptable salt thereof.

[0260] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ie) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-b) or a pharmaceutically acceptable salt thereof.

[0261] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to formula (If) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-b) or a pharmaceutically acceptable salt thereof.

[0262] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ia) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-c) or a pharmaceutically acceptable salt thereof.

[0263] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ib) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-c) or a pharmaceutically acceptable salt thereof.

[0264] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ic) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-c) or a pharmaceutically acceptable salt thereof.

[0265] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Id) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-c) or a pharmaceutically acceptable salt thereof.

[0266] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ie) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-c) or a pharmaceutically acceptable salt thereof.

[0267] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to formula (If) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-c) or a pharmaceutically acceptable salt thereof.

[0268] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ia) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-d) or a pharmaceutically acceptable salt thereof.

[0269] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ib) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-d) or a pharmaceutically acceptable salt thereof.

[0270] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ic) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-d) or a pharmaceutically acceptable salt thereof.

[0271] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Id) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-d) or a pharmaceutically acceptable salt thereof.

[0272] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ie) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-d) or a pharmaceutically acceptable salt thereof.

[0273] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to formula (If) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-d) or a pharmaceutically acceptable salt thereof.

[0274] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ia) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-e) or a pharmaceutically acceptable salt thereof.

[0275] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ib) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-e) or a pharmaceutically acceptable salt thereof.

[0276] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ic) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-e) or a pharmaceutically acceptable salt thereof.

[0277] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Id) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-e) or a pharmaceutically acceptable salt thereof.

[0278] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to Formula (Ie) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-e) or a pharmaceutically acceptable salt thereof.

[0279] In another embodiment, the pharmaceutical composition comprises a first compound, a second compound, and a pharmaceutically acceptable carrier; The first compound corresponds in structure to formula (If) or a pharmaceutically acceptable salt thereof; The second compound corresponds in structure to Formula (II-e) or a pharmaceutically acceptable salt thereof.

[0280] Pharmaceutical compositions of the present disclosure that include both a first compound and a second compound generally contain the first compound and the second compound in a weight ratio of about 1:1 to about 1:50. In one embodiment, the weight ratio is about 1:2 to about 1:15. In another embodiment, the weight ratio is about 1:4 to about 1:10. In another embodiment, the weight ratio is about 1:4. In another embodiment, the weight ratio is about 1:7.5. In another embodiment, the weight ratio is about 1:10.

[0281] B. Another excipient The pharmaceutical compositions of the present disclosure may include one or more additional pharmaceutically acceptable excipients. The term "excipient" refers to any substance that is not itself a therapeutic agent but is used as a carrier or vehicle for delivering a therapeutic agent to a subject, or that is added to a pharmaceutical composition to enhance handling or storage, or to enable or facilitate the formation of a unit dose of the composition.

[0282] Excipients include, for example, antioxidants, agents for adjusting pH and osmolality, preservatives, thickeners, colorants, buffers, bactericides, and stabilizers. When an excipient is present, it is typically present in an amount of from about 0.001% to about 95%, from about 0.01% to about 80%, from about 0.02% to about 25%, or from about 0.3% to about 10% by weight.

[0283] In one embodiment, the pharmaceutical composition may include an antioxidant. Suitable antioxidants for use in the pharmaceutical composition include, for example, butylated hydroxytoluene, butylated hydroxyanisole, potassium metabisulfite, and the like.

[0284] In one embodiment, the pharmaceutical composition may include a buffering agent. Buffering agents include agents that reduce pH changes. Suitable types of buffering agents for use in various embodiments of the present invention include Group IA metal salts, such as Group IA metal bicarbonates, Group IA metal carbonates, alkali or alkaline earth metal buffers, aluminum buffers, calcium buffers, sodium buffers, or magnesium buffers. Suitable buffering agents also include carbonates, phosphates, bicarbonates, citrates, borates, acetates, phthalates, tartrates, succinates of any of the foregoing, including sodium or potassium phosphoric acid, citric acid, boric acid, acetic acid, bicarbonates, and carbonates.

[0285] C. Formulation solid composition In one embodiment, the pharmaceutical composition is a solid composition.

[0286] In another embodiment, the pharmaceutical composition is a solid composition suitable for oral administration. The first and second compounds can be present as separate, separate solid formulations or can be combined in the same solid formulation. Suitable solid formulations include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the first and / or second compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerin; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as cetyl alcohol and glyceryl monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0287] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such carriers as lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0288] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical industry. They may also contain opacifying agents and can be of a composition so that they release only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0289] The first and / or second compounds may, if appropriate, also be in microencapsulated form (separately or together) with one or more of the above-mentioned carriers.

[0290] liquid composition In one embodiment, the pharmaceutical composition is a liquid composition, hi one aspect, the composition comprises water and is suitable for injection.

[0291] In another embodiment, the pharmaceutical composition is a liquid composition suitable for intragastric, intestinal (e.g., intraduodenal, intrajejunal), nasal, subcutaneous, intramuscular, or intravenous administration. In one aspect, the composition is suitable for intragastric administration. In another aspect, the composition is suitable for subcutaneous administration. In another aspect, the composition is suitable for intramuscular administration. In another aspect, the composition is suitable for intravenous administration. In another aspect, the composition is suitable for intestinal administration. In another aspect, the composition is suitable for intraduodenal administration. In another aspect, the composition is suitable for intrajejunal administration. In another aspect, the composition is suitable for intranasal administration.

[0292] In another embodiment, the pharmaceutical composition is an aqueous pharmaceutical composition having an L-dopa prodrug concentration of at least about 5 mg / mL. In one embodiment, the L-dopa prodrug concentration is at least about 10 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 20 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 30 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 50 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 100 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 150 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 200 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 250 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 300 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 350 mg / mL. In another embodiment, the L-dopa prodrug concentration is at least about 400 mg / mL. In particular, the L-dopa prodrug concentration can be an L-dopa acid prodrug concentration, specifically a compound corresponding in structure to Formula (II-a) and / or a compound corresponding in structure to Formula (II-b).

[0293] 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 carbidopa prodrug concentration can be a carbidopa acid prodrug concentration, specifically a compound corresponding in structure to Formula (Ia) and / or a compound corresponding in structure to Formula (Ib).

[0294] D. pH level In one embodiment, the pharmaceutical composition can have a pH of ≥ about 2.0, ≥ about 2.5, ≥ about 3.0, ≥ about 3.5, ≥ about 4.0, ≥ about 4.5, ≥ about 5.0, ≥ about 5.5, ≥ about 6.0, ≥ about 6.2, ≥ about 6.4, ≥ about 6.5, ≥ about 6.6, ≥ about 6.8, ≥ about 7.0, ≥ about 7.1, ≥ about 7.2, ≥ about 7.3, ≥ about 7.4, ≥ about 7.5, ≥ about 7.6, ≥ about 7.7, ≥ about 7.8, ≥ about 7.9, ≥ about 8.0, ≥ about 8.2, ≥ about 8.4, ≥ about 8.6, ≥ about 8.8, or ≥ about 9.0. In particular, the pH is ≥ about 7.4. Expressly disclosed ranges include any combination of the values ​​recited above, such as about 2.0 to about 7.5, about 6.0 to about 9.0, about 6.4 to about 7.7, about 7.0 to about 7.9, and about 7.3 to about 8.2. In one embodiment, the pH is about 2 to about 8. In one embodiment, the pH is about 2.0 to about 7.5. In another embodiment, the pH is about 3.0 to about 7.5. In another embodiment, the pH is about 4.0 to about 7.5. In another embodiment, the pH is about 5.0 to about 7.5. In another embodiment, the pH is about 6.0 to about 7.5.

[0295] E. Stability In another embodiment, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) in the pharmaceutical composition can advantageously remain stable in a liquid composition (e.g., an aqueous solution) at the above pH for ≥ about 24 hours, ≥ about 36 hours, ≥ about 48 hours, ≥ about 60 hours, ≥ about 72 hours, ≥ about 84 hours, ≥ about 96 hours, ≥ about 108 hours, ≥ about 120 hours, ≥ about 132 hours, ≥ about 136 hours, ≥ about 144 hours, ≥ about 156 hours, ≥ about 168 hours, or ≥ about 180 hours. In particular, the pharmaceutical composition can remain stable in an aqueous solution at a pH of about 6 to about 8 for ≥ about 24 hours. Explicitly disclosed ranges include any combination of the above-listed values, such as about 24 hours to about 180 hours, about 24 hours to about 168 hours, about 36 hours to about 72 hours, etc. Such enhanced stability is important for liquid compositions of pharmaceutical compositions, since the liquid compositions are typically stored prior to administration (e.g., intragastric, subcutaneous, intrajejunal, nasal, intramuscular and / or intravenous), and therefore the first and second compounds must remain stable and undergo little or no degradation during storage.

[0296] F. Solubility In another embodiment, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) in the pharmaceutical composition unexpectedly have high solubility in a liquid composition (e.g., an aqueous solution). For example, the first compound and / or the second compound may have a pH of ≥ about 90 mg / mL, ≥ about 100 mg / mL, ≥ about 110 mg / mL, ≥ about 120 mg / mL, ≥ about 130 mg / mL, ≥ about 140 mg / mL, ≥ about 150 mg / mL, ≥ about 160 mg / mL, ≥ about 170 mg / mL, ≥ about 180 mg / mL, ≥ about 190 mg / mL, ≥ about 200 mg / mL, ≥ about 210 mg / mL, ≥ about 220 mg / mL, ≥ about 230 mg / mL, ≥ about 240 mg / mL, ≥ about 250 mg / mL, ≥ about 260 mg / mL, ≥ about 270 mg / mL, ≥ 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, ≥ about 500 mg / mL, ≥ about 510 mg / mL, ≥ about 520 mg / mL, ≥ about 530 mg / mL, and / or ≥ about 400 mg / mL, ≥ about 410 mg / mL, ≥ about 420 mg / mL, ≥ about 430 mg / mL, ≥ about 440 mg / mL, ≥ about 450 mg / mL, ≥ about 460 mg / mL, ≥ about 470 mg / mL, ≥ about 480 mg / mL, ≥ about 490 mg / mL, or ≥ about 500 mg / mL. Expressly disclosed ranges include any combination of the above-listed values, such as about 90 mg / mL to about 500 mg / mL, about 100 mg / mL to about 300 mg / mL, and about 200 mg / mL to about 500 mg / mL. In particular, the first compound has a solubility of ≧about 160 mg / mL, particularly ≧about 200 mg / mL, at a neutral pH of, for example, about 7.4. In particular, the second compound has a solubility of ≧about 370 mg / mL, particularly ≧about 400 mg / mL, at a neutral pH of, for example, about 7.4. This increased solubility allows for higher concentrations of the first and / or second compounds in the pharmaceutical composition, thereby resulting in more effective and higher systemic levels of the first and / or second compounds upon administration to a patient.

[0297] G. Immediate-use agents In yet another embodiment, the present disclosure relates to a ready-to-use vial or cartridge or container or enclosure suitable for containing a liquid pharmaceutical formulation. Such enclosure can serve to hold a liquid formulation containing one or more carbidopa prodrugs and / or one or more L-dopa prodrugs. The vial can also serve as a storage container for carbidopa prodrugs and / or L-dopa prodrugs in powder form, such that the vial can be in a ready-to-use format that allows for injection or loading into a patient by reconstitution with an aqueous medium.

[0298] H. Combination Medicines As described above, a pharmaceutical combination comprising a first compound and a second compound is 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 can be present in separate pharmaceutical compositions. If separate, they can be co-administered as described in more detail herein.

[0299] Thus, in one embodiment, the present invention provides a first compound corresponding in structure to formula (I):

[0300] [ka] or a pharmaceutically acceptable salt thereof (R 1 are independently hydrogen,

[0301] [ka] R 2 and R 3 are each independently hydrogen,

[0302] [ka] and R 5is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 are independently hydrogen,

[0303] [ka] ; and A second compound corresponding in structure to formula (II):

[0304] [ka] or a pharmaceutically acceptable salt thereof (R 6 are independently hydrogen,

[0305] [ka] R 7 and R 8 are each independently hydrogen,

[0306] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9 are independently hydrogen,

[0307] [ka] A pharmaceutical combination comprising:

[0308] IV. Treatment method The present disclosure further relates to methods for treating Parkinson's disease and related conditions, comprising administering to a patient effective amounts of a carbidopa prodrug and an L-dopa prodrug.

[0309] In some embodiments, methods for treating Parkinson's disease and related conditions include providing rescue therapy for the treatment of Parkinson's disease and related conditions. As used herein, the term "rescue therapy" refers to any acute or intermittent therapy that can be used to treat sudden re-immersion of motor symptoms (e.g., sudden "off" episodes or "end-of-dose wearing-off" and unpredictable "on / off" episodes). Patients with severe motor complications may cycle between "off" periods, defined as periods of hypokinesia, slowness, and rigidity, and "on" periods, defined as periods of good motor system control without bothersome motor impairments.

[0310] In some embodiments, the carbidopa acid prodrug and the L-dopa prodrug are administered to the patient in a pharmaceutical composition containing both prodrugs. In other embodiments, the carbidopa prodrug and the L-dopa prodrug are administered to the patient separately.

[0311] A. First Compound and Second Compound and Combinations Thereof In one embodiment, the disclosure provides a method of treating a condition in a subject (e.g., a patient) in need thereof, comprising administering to the patient a pharmaceutical combination comprising a first compound and a second compound; The first compound has the structure of formula (I):

[0312] [ka] or a pharmaceutically acceptable salt thereof [R 1 are independently hydrogen,

[0313] [ka] R 2 and R 3 are each independently hydrogen,

[0314] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 are independently hydrogen,

[0315] [ka] selected from the group consisting of: The second compound has the formula (II) in structure:

[0316] [ka] or a pharmaceutically acceptable salt thereof [R 6 are independently hydrogen,

[0317] [ka] and R 7 and R 8 are each independently hydrogen,

[0318] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9 are independently hydrogen,

[0319] [ka] The present invention relates to a method for producing a pharmaceutical composition comprising the steps of:

[0320] In one embodiment, the first compound and the second compound are administered together in amounts that provide a therapeutic effect to a subject (eg, a patient).

[0321] In one embodiment, the first compound corresponds in structure to Formula (Ia) and the second compound corresponds in structure to Formula (II-a).

[0322] In another embodiment, the first compound corresponds in structure to Formula (Ib) and the second compound corresponds in structure to Formula (II-a).

[0323] In another embodiment, the first compound corresponds in structure to Formula (Ic) and the second compound corresponds in structure to Formula (II-a).

[0324] In another embodiment, the first compound corresponds in structure to Formula (Id) and the second compound corresponds in structure to Formula (II-a).

[0325] In another embodiment, the first compound corresponds in structure to Formula (Ie) and the second compound corresponds in structure to Formula (II-a).

[0326] In another embodiment, the first compound corresponds in structure to Formula (If) and the second compound corresponds in structure to Formula (II-a).

[0327] In another embodiment, a first compound corresponds in structure to Formula (Ia) and a second compound corresponds in structure to Formula (II-b).

[0328] In another embodiment, the first compound corresponds in structure to Formula (Ib) and the second compound corresponds in structure to Formula (II-b).

[0329] In another embodiment, the first compound corresponds in structure to Formula (Ic) and the second compound corresponds in structure to Formula (II-b).

[0330] In another embodiment, the first compound corresponds in structure to Formula (Id) and the second compound corresponds in structure to Formula (II-b).

[0331] In another embodiment, the first compound corresponds in structure to Formula (Ie) and the second compound corresponds in structure to Formula (II-b).

[0332] In another embodiment, the first compound corresponds in structure to Formula (If) and the second compound corresponds in structure to Formula (II-b).

[0333] In another embodiment, a first compound corresponds in structure to Formula (Ia) and a second compound corresponds in structure to Formula (II-c).

[0334] In another embodiment, a first compound corresponds in structure to Formula (Ib) and a second compound corresponds in structure to Formula (II-c).

[0335] In another embodiment, the first compound corresponds in structure to Formula (Ic) and the second compound corresponds in structure to Formula (II-c).

[0336] In another embodiment, the first compound corresponds in structure to Formula (Id) and the second compound corresponds in structure to Formula (II-c).

[0337] In another embodiment, the first compound corresponds in structure to Formula (Ie) and the second compound corresponds in structure to Formula (II-c).

[0338] In another embodiment, the first compound corresponds in structure to Formula (If) and the second compound corresponds in structure to Formula (II-c).

[0339] In another embodiment, a first compound corresponds in structure to Formula (Ia) and a second compound corresponds in structure to Formula (II-d).

[0340] In another embodiment, the first compound corresponds in structure to Formula (Ib) and the second compound corresponds in structure to Formula (II-d).

[0341] In another embodiment, the first compound corresponds in structure to Formula (Ic) and the second compound corresponds in structure to Formula (II-d).

[0342] In another embodiment, the first compound corresponds in structure to Formula (Id) and the second compound corresponds in structure to Formula (II-d).

[0343] In another embodiment, the first compound corresponds in structure to Formula (Ie) and the second compound corresponds in structure to Formula (II-d).

[0344] In another embodiment, the first compound corresponds in structure to Formula (If) and the second compound corresponds in structure to Formula (II-d).

[0345] In another embodiment, a first compound corresponds in structure to Formula (Ia) and a second compound corresponds in structure to Formula (II-e).

[0346] In another embodiment, a first compound corresponds in structure to Formula (Ib) and a second compound corresponds in structure to Formula (II-e).

[0347] In another embodiment, the first compound corresponds in structure to Formula (Ic) and the second compound corresponds in structure to Formula (II-e).

[0348] In another embodiment, the first compound corresponds in structure to Formula (Id) and the second compound corresponds in structure to Formula (II-e).

[0349] In another embodiment, the first compound corresponds in structure to Formula (Ie) and the second compound corresponds in structure to Formula (II-e).

[0350] In another embodiment, the first compound corresponds in structure to Formula (If) and the second compound corresponds in structure to Formula (II-e).

[0351] B. The condition being treated In one embodiment, the condition treated by administering the first compound and the second compound is Parkinson's disease.

[0352] In another embodiment, the condition treated by administering the first compound and the second compound is a sleep disorder in a Parkinson's disease patient (ie, a method of reducing a sleep disorder in a Parkinson's disease patient).

[0353] In another embodiment, the condition treated by administering the first compound and the second compound is impaired motor performance in Parkinson's disease patients (i.e., a method of improving motor performance in Parkinson's disease patients).

[0354] In another embodiment, the condition treated by administering the first compound and the second compound is nighttime performance impairment in Parkinson's disease patients (i.e., a method of reducing nighttime performance impairment in Parkinson's disease patients).

[0355] In another embodiment, a first compound and a second compound are administered to treat motor fluctuations in a patient with Parkinson's disease.

[0356] In another embodiment, a first compound and a second compound are administered to treat dyskinesia in a patient with Parkinson's disease.

[0357] 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.

[0358] In another embodiment, a first compound and a second compound are administered to delay the onset of dyskinesias in a patient with Parkinson's disease.

[0359] C. Administration of Pharmaceutical Compositions In one embodiment, the present disclosure relates to a method for treating a condition in need of treatment, comprising administering to a subject (e.g., a patient) a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0360] In one embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ia) and a second compound corresponding in structure to Formula (II-a).

[0361] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ib) and a second compound corresponding in structure to Formula (II-a).

[0362] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ic) and a second compound corresponding in structure to Formula (II-a).

[0363] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Id) and a second compound corresponding in structure to Formula (II-a).

[0364] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ie) and a second compound corresponding in structure to Formula (II-a).

[0365] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (If) and a second compound corresponding in structure to Formula (II-a).

[0366] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ia) and a second compound corresponding in structure to Formula (II-b).

[0367] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ib) and a second compound corresponding in structure to Formula (II-b).

[0368] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ic) and a second compound corresponding in structure to Formula (II-b).

[0369] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Id) and a second compound corresponding in structure to Formula (II-b).

[0370] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ie) and a second compound corresponding in structure to Formula (II-b).

[0371] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (If) and a second compound corresponding in structure to Formula (II-b).

[0372] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ia) and a second compound corresponding in structure to Formula (II-c).

[0373] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ib) and a second compound corresponding in structure to Formula (II-c).

[0374] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ic) and a second compound corresponding in structure to Formula (II-c).

[0375] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Id) and a second compound corresponding in structure to Formula (II-c).

[0376] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ie) and a second compound corresponding in structure to Formula (II-c).

[0377] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (If) and a second compound corresponding in structure to Formula (II-c).

[0378] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ia) and a second compound corresponding in structure to Formula (II-d).

[0379] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ib) and a second compound corresponding in structure to Formula (II-d).

[0380] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ic) and a second compound corresponding in structure to Formula (II-d).

[0381] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Id) and a second compound corresponding in structure to Formula (II-d).

[0382] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ie) and a second compound corresponding in structure to Formula (II-d).

[0383] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (If) and a second compound corresponding in structure to Formula (II-d).

[0384] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ia) and a second compound corresponding in structure to Formula (II-e).

[0385] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ib) and a second compound corresponding in structure to Formula (II-e).

[0386] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ic) and a second compound corresponding in structure to Formula (II-e).

[0387] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Id) and a second compound corresponding in structure to Formula (II-e).

[0388] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (Ie) and a second compound corresponding in structure to Formula (II-e).

[0389] In another embodiment, the composition administered comprises a first compound corresponding in structure to Formula (If) and a second compound corresponding in structure to Formula (II-e).

[0390] D. The condition being treated In one embodiment, the condition treated by administering the pharmaceutical composition is Parkinson's disease.

[0391] In another embodiment, the condition treated by administering the pharmaceutical composition is sleep disturbance in Parkinson's disease patients (ie, a method of reducing sleep disturbance in Parkinson's disease patients).

[0392] In another embodiment, the condition treated by administering the pharmaceutical composition is impaired motor performance in Parkinson's disease patients (ie, a method of improving motor performance in Parkinson's disease patients).

[0393] In another embodiment, the pharmaceutical composition is administered to treat motor fluctuations in a patient with Parkinson's disease.

[0394] In another embodiment, the pharmaceutical composition is administered to treat dyskinesias in patients with Parkinson's disease.

[0395] In another embodiment, the pharmaceutical composition is administered to delay the onset of motor fluctuations in a patient with Parkinson's disease. In another embodiment, the pharmaceutical composition is administered to delay the onset of dyskinesias in a patient with Parkinson's disease.

[0396] In another embodiment, the condition treated by administering the pharmaceutical composition is nighttime disability in Parkinson's disease patients (ie, a method of reducing nighttime disability in Parkinson's disease patients).

[0397] E. Weight Ratio and Route of Administration Generally, the weight ratio of the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) administered to a patient (separately or together in a single pharmaceutical composition) is from about 1:1 to about 1:50. In one embodiment, the weight ratio is from about 1:2 to about 1:15. In another embodiment, the weight ratio is from about 1:4 to about 1:10. In another embodiment, the weight ratio is about 1:4. In another embodiment, the weight ratio is about 1:7.5. In another embodiment, the weight ratio is about 1:10.

[0398] In one embodiment, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) are administered to the patient in the form of a solid composition (or multiple solid compositions). In one aspect, the composition is suitable for oral administration.

[0399] In one embodiment, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) are administered to the patient in the form of a liquid composition (or multiple liquid compositions). In one aspect, the composition comprises water and is suitable for injection.

[0400] In another embodiment, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) are administered to the patient as liquid compositions (separately or in the same pharmaceutical composition) suitable for intragastric, subcutaneous, nasal, intramuscular, or intravenous administration. In one 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.

[0401] In another embodiment, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) are administered by enteral administration (e.g., intrajejunal, intraduodenal) (separately or in the same pharmaceutical composition). They can be administered (or "injected") directly into the intestine, e.g., the duodenum or jejunum, by a permanent tube inserted, e.g., by percutaneous endoscopic gastrostomy using an external transperitoneal tube and an internal enteral 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 radiological gastrojejunostomy. In another aspect, the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) are administered via a temporary nasoduodenal tube that is initially inserted into the patient to determine whether the patient will respond well to therapy before inserting a permanent tube.

[0402] 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, administration can be accomplished using a portable pump, such as the pump sold under the trade name CADD-Legacy DuoDopa.RTM. Pump®. Specifically, a cassette, bag, or vial containing the first compound (e.g., a phosphate prodrug) and the second compound (e.g., a phosphate prodrug) can be attached to the pump to create a delivery system. The delivery system is then connected to a nasoduodenal tube, a transabdominal port, a duodenal tube, or a jejunal tube for enteral administration.

[0403] In one embodiment, the method comprises administering (together or separately) a first compound (e.g., a phosphate prodrug) and a second compound (e.g., a phosphate prodrug) to a patient substantially continuously 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 subcutaneously substantially continuously over a period of at least about 16 hours.

[0404] F. Dosage and Plasma Concentration In one embodiment, the dosages of the first compound (e.g., phosphate prodrug) and the second compound (e.g., phosphate prodrug) administered to the patient are adjusted to optimize the clinical response achieved by the subject (e.g., patient), which means maximizing functional ON time during the day by reducing the number and duration of OFF time episodes (i.e., bradykinesia) and ON time with severe dyskinesias.

[0405] In one embodiment, the daily dose of an L-dopa prodrug (i.e., the second compound) administered to a patient according to the methods of the present disclosure can be, for example, about 20 to about 1,000,000 mg, about 20 to about 100,000 mg, about 20 to about 10,000 mg, about 20 to about 5,000 mg, about 20 to about 4,000 mg, about 20 to about 3,000 mg, about 20 to about 2,000 mg, or about 20 to about 1,000 mg per day. In particular, an L-dopa acid prodrug, specifically a compound structurally corresponding to Formula (II-a) and / or a compound structurally corresponding to Formula (II-b), is administered at the above daily doses.

[0406] In one embodiment, the daily dose of a carbidopa prodrug (i.e., a first compound) administered to a patient according to the methods of the present disclosure can be, for example, 0 mg to about 2500 mg, 0 mg to about 1250 mg, 0 mg to about 1000 mg, 0 mg to about 750 mg, 0 mg to about 625 mg, 0 mg to about 500 mg, 0 mg to about 375 mg, 0 mg to about 250 mg, or 5 mg to about 125 mg per day. In particular, a carbidopa acid prodrug, specifically a compound corresponding in structure to Formula (Ia) and / or a compound corresponding in structure to Formula (Ib), is administered at the above daily doses.

[0407] In some embodiments, the amount of the first compound and the amount of the second compound administered are sufficient in combination to achieve an L-dopa plasma level in the patient of at least about 100 ng / mL. In one embodiment, the L-dopa plasma level is at least about 200 ng / mL. In another embodiment, the L-dopa plasma level is at least about 300 ng / mL. In another embodiment, the L-dopa plasma level is at least about 400 ng / mL. In another embodiment, the L-dopa plasma level is at least about 500 ng / mL. In another embodiment, the L-dopa plasma level is at least about 600 ng / mL. In another embodiment, the L-dopa plasma level is at least about 700 ng / mL. In another embodiment, the L-dopa plasma level is at least about 800 ng / mL. In another embodiment, the L-dopa plasma level is at least about 900 ng / mL. In another embodiment, the L-dopa plasma level is at least about 1,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 1,500 ng / mL. In another embodiment, the L-dopa plasma level is at least about 2,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 3,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 4,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 5,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 6,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 7,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 8,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 9,000 ng / mL. In particular, the first compound can be a carbidopa acid prodrug, particularly a compound corresponding in structure to Formula (Ia) and / or a compound corresponding in structure to Formula (Ib). In particular, the second compound can be an L-doparinic acid prodrug, particularly a compound corresponding in structure to formula (II-a) and / or a compound corresponding in structure to formula (II-b).

[0408] In some embodiments, the amount of the first compound and the amount of the second compound administered are sufficient, in combination, to achieve an L-dopa plasma level of about 10 ng / mL to about 9,000 ng / mL. In one embodiment, the L-dopa plasma level is about 10 ng / mL to about 8,000 ng / mL. In another embodiment, the L-dopa plasma level is about 25 ng / mL to about 6,000 ng / mL. In another embodiment, the L-dopa plasma level is about 50 ng / mL to about 4,000 ng / mL. In another embodiment, the L-dopa plasma level is about 100 ng / mL to about 2,000 ng / mL. In another embodiment, the L-dopa plasma level is about 25 ng / mL to about 1,200 ng / mL. In another embodiment, the L-dopa plasma level is about 10 ng / mL to about 500 ng / mL. In another embodiment, the L-dopa plasma level is about 25 ng / mL to about 500 ng / mL. In particular, the first compound can be a carbidoparinic acid prodrug, specifically a compound corresponding in structure to Formula (Ia) and / or a compound corresponding in structure to Formula (Ib). In particular, the second compound can be an L-doparinic acid prodrug, specifically a compound corresponding in structure to Formula (II-a) and / or a compound corresponding in structure to Formula (II-b).

[0409] In some embodiments, the L-dopa concentration ranges can be maintained over at least about 1 hour intervals, 2 hours intervals, 3 hours intervals, 4 hours intervals, 5 hours intervals, 6 hours intervals, 7 hours intervals, 8 hours intervals, 9 hours intervals, 10 hours intervals, 11 hours intervals, 12 hours intervals, 13 hours intervals, 14 hours intervals, 15 hours intervals, 16 hours intervals, 17 hours intervals, 18 hours intervals, 19 hours intervals, 20 hours intervals, 21 hours intervals, 22 hours intervals, 23 hours intervals, or 24 hours intervals.

[0410] In some embodiments, the amount of the first compound and the amount of the second compound are administered sufficient to maintain a carbidopa plasma level of less than about 2500 ng / mL. In one embodiment, the carbidopa plasma level is less than about 2000 ng / mL. In another embodiment, the carbidopa plasma level is less than about 1500 ng / mL. In another embodiment, the carbidopa plasma level is less than about 1000 ng / mL. In another embodiment, the carbidopa plasma level is less than about 500 ng / mL. In another embodiment, the carbidopa plasma level is less than about 250 ng / mL. In another embodiment, the carbidopa plasma level is less than about 100 ng / mL. In another embodiment, the carbidopa plasma level is less than about 50 ng / mL. In another embodiment, the carbidopa plasma level is less than about 25 ng / mL.

[0411] 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.

[0412] V. Combination and / or additional therapy The therapeutic methods of the present disclosure may further comprise administering one or more therapeutic agents for treating Parkinson's disease (e.g., antiparkinsonian drugs) in addition to the L-dopa prodrug and carbidopa prodrug. In one embodiment, the additional therapeutic agent is selected from the group consisting of a decarboxylase inhibitor other than carbidopa (e.g., benserazide), a catechol-O-methyltransferase ("COMT") inhibitor (e.g., entacapone and tolcapone), and a monoamine oxidase A ("MAO-A") or monoamine oxidase B ("MAO-B") inhibitor (e.g., moclobemide, rasagiline, selegiline, and safinamide). In one embodiment, the additional therapeutic agent is selected from the group consisting of a decarboxylase inhibitor other than carbidopa. In another embodiment, the additional therapeutic agent is selected from the group consisting of a COMT inhibitor, such as entacapone. In another embodiment, the additional therapeutic agent is selected from the group consisting of an MAO-A inhibitor. In another embodiment, the additional therapeutic agent is selected from the group consisting of an MAO-B inhibitor.

[0413] The additional therapeutic agent and the first and second compounds can be administered together or separately, and substantially simultaneously or sequentially. Furthermore, the additional therapeutic agent and the first and second compounds can be in separate formulations, which can be the same or different. For example, entacapone can be administered concomitantly and orally, and the first and second compounds described herein can be administered subcutaneously (separately or together in the same pharmaceutical composition). Furthermore, the therapeutic agent and the first and second compounds can be packaged together, for example, in a single container or in multiple containers within a single package, or can be provided simultaneously in separate packages ("common provision").

[0414] Similarly, the pharmaceutical compositions of the present disclosure may further comprise one or more additional therapeutic agents for the treatment of Parkinson's disease as described above.

[0415] VI. kit The present disclosure also relates to kits containing one or more pharmaceutical formulations comprising a carbidoparinic acid prodrug, kits containing one or more pharmaceutical formulations comprising an L-doparinic acid prodrug, and kits containing one or more pharmaceutical formulations comprising both a carbidoparinic acid prodrug and an L-doparinic acid prodrug, which kits may also include one or more additional therapeutic agents and / or instructions, such as instructions for using the kit to treat patients with Parkinson's disease and related conditions.

[0416] 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.

[0417] Since dopamine is an achiral compound, it is considered that the above-described various embodiments may be applicable when a D-doparinic acid prodrug or a racemate of a D-doparinic acid prodrug and an L-doparinic acid prodrug is used instead of an L-doparinic acid prodrug. [Example]

[0418] VII. Example The following non-limiting examples are provided to further illustrate the present disclosure. Abbreviations used in the examples below include:

[0419] "DBU" means 1,8-diazabicyclo[5.4.0]-undec-7-ene.

[0420] "DCM" means dichloromethane.

[0421] "EDTA" means ethylenediaminetetraacetic acid.

[0422] "FCC" means flash column chromatography.

[0423] "HPLC" means high performance liquid chromatography.

[0424] "IPA" means isopropanol.

[0425] "LC-MS" means liquid chromatography-mass spectrometry.

[0426] "m-CPBA" means meta-chloroperbenzoic acid.

[0427] "MTBE" means methyl tert-butyl ether.

[0428] "pa" means peak area.

[0429] "THF" means tetrahydrofuran.

[0430] "TLC" means thin layer chromatography.

[0431] "t 1 / 2 " means biological half-life, i.e., the time required for half of a drug or other substance administered to a living organism to be metabolized or excreted by normal physiological processes.

[0432] [Example 1] L-DopaR 7 or R 8 Synthesis of monoprodrugs L-Dopa 3'-monoprodrug and L-Dopa 4'-monoprodrug were prepared as shown in Scheme 1 below.

[0433] [ka]

[0434] Specifically, L-dopa 3'-monoprodrug and L-dopa 4'-monoprodrug were prepared according to the methods described in steps 1 to 5B below.

[0435] Phase 1 A solution of sodium hydroxide (40 g, 1.0 mol) in water (300 mL) was added dropwise to a suspension of compound 1 (100 g, 0.5 mol) in water (300 mL) at 0° C. over a period of 20 minutes. Benzyl chloroformate (103.9 g, 0.6 mol) in dioxane (400 mL) was added dropwise to the suspension at 0° C. over a period of 30 minutes, and the reaction was then stirred at room temperature for 16 hours. Reaction completion was monitored by TLC. After complete consumption of the starting material, the reaction was basified to pH=10 with 10% sodium hydroxide (200 mL) and extracted with MTBE (500 mL). The organic layer was separated and discarded. The aqueous layer was acidified to pH=2 with 6 N HCl (150 mL) and extracted with MTBE (2×500 mL). The combined organic layers were washed with water (500 mL), saturated sodium chloride solution (500 mL), dried over sodium sulfate, and concentrated under reduced pressure at 45-50° C. to give crude compound 2 as a viscous liquid (120 g, 72%).

[0436] Phase 2 Cesium carbonate (123 g, 0.37 mol) was added in two lots to a solution of compound 2 (250 g, 0.75 mol) in dimethylformamide (2 L) at 0°C. To this mixture, benzyl bromide (90.3 mL, 0.75 mol) was added dropwise over a 30-minute period at 0°C, and the reaction was then stirred at room temperature for 16 hours. Reaction completion was monitored by TLC. After complete consumption of the starting material, the reaction was diluted with water (5 L) and extracted with MTBE (2 x 1 L). The combined organic layers were washed with water (1 L), saturated sodium chloride solution (0.5 L), dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C to give crude compound 3 (250 g) as a viscous liquid.

[0437] Stage 3 Cesium carbonate (698.5 g, 2.14 mol) was added in four portions to a solution of compound 3 (900 g, 2.14 mol) in dimethylformamide (7.2 L) at 0°C. To this mixture, benzyl bromide (512 mL, 4.28 mol) was added dropwise over a 1-hour period at 0°C, and the reaction was then stirred at room temperature for 16 hours. Reaction completion was monitored by TLC. After complete consumption of the starting material, the reaction was diluted with water (15 L) and extracted with MTBE (2 x 3 L). The combined organic layers were washed with water (3 L), saturated sodium chloride solution (1.5 L), dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C to give the crude product (1 kg) as a viscous liquid.

[0438] The resulting crude product was mixed with the crude product from the previous batch (1.6 kg in total) and repeatedly purified by flash column chromatography on silica gel (230-400 mesh) using 10% to 20% ethyl acetate / petroleum ether to give compounds 4a (270 g) and 4b (255 g).

[0439] Stage 4A An appropriate base was added to a solution of compound 4a in tetrahydrofuran at 0°C. To this mixture, a solution of an alkylating or acylating agent was added dropwise over a 30-minute period at 0°C, and the reaction was then stirred at room temperature for 2 hours. Reaction completion was monitored by thin-layer chromatography. After complete consumption of the starting material, the reaction was cooled to 0-5°C and quenched with water. The organic layer was separated, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, saturated NaCl solution, dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C. The resulting crude product was purified by column chromatography on silica gel (230-400 mesh) using 30-40% ethyl acetate / petroleum ether to give compound 5a.

[0440] Stage 4B An appropriate base was added to a solution of compound 4b in tetrahydrofuran at 0°C. To this mixture, a solution of an alkylating or acylating agent was added dropwise over a period of 30 minutes at 0°C. After the addition was complete, the reaction was stirred at room temperature for 2 hours. Reaction completion was monitored by thin layer chromatography. After completion, the reaction was cooled to 0-5°C and quenched with water. The organic layer was separated, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, saturated NaCl solution, dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C. The crude product was purified by column chromatography on silica gel (230-400 mesh) using 30-40% ethyl acetate / petroleum ether to give compound 5b.

[0441] Stage 5A 10% Pd / C was added to a solution of compound 5a in ethanol and water (4:1 ratio) under a nitrogen atmosphere. The reaction flask was evacuated and purged with hydrogen gas three times, then purged with 4 kg / cm 2 2 The mixture was hydrogenated at a pressure (approximately 4 atm) for 16 hours. After completion of the reaction, water was added to the reaction mixture, and the catalyst was removed by filtration through a K100 cellulose filter layer. The filtrate was concentrated under reduced pressure. The resulting crude product was stirred with ethanol, filtered, and dried under vacuum to give L-dopa prodrug compound 6A.

[0442] Stage 5B 10% Pd / C was added to a solution of compound 5b in ethanol and water (4:1 ratio) under a nitrogen atmosphere. The reaction flask was evacuated and purged with hydrogen gas three times, then purged with 4 kg / cm. 2 The mixture was hydrogenated at a pressure (approximately 4 atm) for 16 hours. After completion of the reaction, water was added to the reaction mixture, and the catalyst was removed by filtration through a K100 cellulose filter layer. The filtrate was concentrated under reduced pressure. The resulting crude product was stirred with ethanol, filtered, and dried under vacuum to give L-dopa prodrug compound 6B.

[0443] [Example 2] Synthesis of L-dopane diprodrug The L-dopa 3',4'-diprodrug was prepared as shown in Scheme 2 below.

[0444] [ka]

[0445] R 7 and R 8 are the same group selected from the following:

[0446] [ka]

[0447] Specifically, the L-dopane diprodrug was prepared as described in steps 6 and 7 below.

[0448] Stage 6 Cesium carbonate was added in two lots to a solution of compound 3 in dimethylformamide at 0°C. A solution of alkylating or acylating agent was added dropwise to this mixture over a period of 1 hour at 0°C, and the reaction was then stirred at room temperature for 2 hours. Reaction completion was monitored by TLC. After complete consumption of the starting material, the reaction was cooled to 0-5°C and quenched with water. The organic layer was separated, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, saturated sodium chloride solution, 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 7.

[0449] Stage 7 10% Pd / C was added to a solution of compound 7 in THF under a nitrogen atmosphere. The reaction flask was evacuated and purged with hydrogen gas three times, then hydrogenated at 6 kg pressure for 8 hours. After the reaction was complete, water was added to the reaction mixture, and the catalyst was removed by filtration through a K100 cellulose filter pad. The filtrate was concentrated under reduced pressure to give L-dopane diprodrug compound 8.

[0450] [Example 3] Synthesis of Carbidopa Monoprodrugs and Carbidopa Diprodrugs. The carbidopa prodrug was prepared as shown in Scheme 3 below.

[0451] [ka]

[0452] R 2 and R 3 are all H or the same group selected from the following:

[0453] [ka]

[0454] R 2 and R 3 can also be independently H or a group selected from the above.

[0455] Specifically, carbidopa prodrugs were prepared as described in steps 1-4 below.

[0456] Phase 1 A slurry of carbidopa monohydrate (20.0 g, 82 mmol), sodium bicarbonate (7.57 g, 90 mmol), water (200 mL), and THF (100 mL) was cooled to 5–10°C, and N-(benzyloxycarbonyloxy)succinimide (20.4 g, 82 mmol) was added. The mixture was warmed to ambient temperature and became a nearly homogeneous solution over 5 h, at which time LC-MS indicated near completion of the reaction. The solution was diluted with MTBE (100 mL), the layers were separated, and the organic layer was extracted with saturated NaHCO3 (100 mL). The aqueous layer was acidified with 2 N HCl (160 mL), and the acidic aqueous layer was extracted with MTBE (2×100 mL). During the second back-extraction, a small amount of product began to precipitate. The combined organic layers were washed with brine (20 mL), and the remaining solids were washed from the separatory funnel with MTBE (20 mL). The remaining mixture was concentrated to a total mass of 43 g, and 10% THF / MTBE (60 mL) was added. The mixture was too viscous to stir, so additional MTBE (60 mL in 6 volumes of 5% THF / MTBE) was added. The resulting white slurry was then heated to 50°C. The slurry was cooled to ambient temperature over 1 hour and then stirred for 14 hours. The white solid was filtered, washed with 5% THF / MTBE (20 mL), and dried in a vacuum oven (50°C) to give the THF-containing preparation of (S)-2-(2-((benzyloxy)carbonyl)-hydrazinyl)-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid (4:3) (31.1 g, 71.9 mmol, 91% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.66(d, J=9.0Hz, 2H), 8.18(brs, 1H), 7.49-7.17(m, 5H), 6.59(dd, J=5.0, 3.0Hz, 2H), 6.44(d d, J=8.0, 2.0Hz, 1H), 5.04(s, 2H), 2.73(d, J=13.4Hz, 1H), 2.59(d, J=13.3Hz, 1H), 1.07(s, 3H);MS(ESI)m / z361[M+H] + .

[0457] Phase 2 A solution of benzophenone hydrazone (20.0 g, 102 mmol) in DCM (100 mL) was cooled to <0 °C, and iodine (0.052 g, 0.204 mmol) and 1,1,3,3-tetramethylguanidine (25.6 mL, 204 mmol) were added. m-CPBA (30.5 g, 132 mmol) was added portionwise over 5 min at -10 °C to 0 °C (dry ice / acetone bath for control of exotherm). The mixture was stirred for 15 min at 0 °C to 12 °C and then washed with water (3 x 200 mL). The resulting mixture was dried (Na2SO4), concentrated to a total volume of 76 mL, and washed into a 125 mL Erlenmeyer flask with an additional 16 mL of DCM to prepare a ca. 1 M dark purple solution of (diazomethylene)dibenzene. In a separate flask, a slurry of (S)-2-(2-((benzyloxy)carbonyl)hydrazinyl)-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid in tetrahydrofuran (4:3) (30.7 g, 74.0 mmol) in IPA (300 mL) was cooled to <10 °C, and a solution of (diazomethylene)dibenzene (78 mL, 78 mmol) was added. The resulting mixture was warmed to room temperature, but LC-MS indicated the reaction had stalled after 30 min. Additional diphenyldiazomethane (0.2 equiv., 14 mL) was added, and stirring was continued at room temperature. After 35 min, the remaining diphenyldiazomethane solution (9 mL) was added. After 2 h 20 min, the purple color persisted, and LC-MS indicated the reaction was complete. The reaction mixture was concentrated to approximately 60 mL, and 20% aqueous CH3CN (300 mL) was added. The mixture was washed with cyclohexane (10 x 300 mL), ethyl acetate (450 mL) was added, and the mixture was washed with saturated aqueous NaHCO (150 mL) and brine (60 mL). The mixture was dried (NaSO) and concentrated to give compound 9, (S)-benzyl 2-(1-(benzhydryloxy)-3-(3,4-dihydroxyphenyl)-2-methyl-1-oxopropan-2-yl)hydrazine-carboxylate (39.4 g, 74.8 mmol, >99% yield). 1H NMR (400MHz, DMSO-d6) δ8.65(brs, 2H), 8.19(brs, 1H), 7.43-7.20(m, 15H), 6.70(s, 1H), 6.55(d, J=2.0Hz, 1H), 6.45(d, J=8.0Hz, 1H), 6.20 (dd, J=7.9, 2.0Hz, 1H), 4.95(d, J=3.4Hz, 2H), 2.81(d, J=13.6Hz, 1H), 2.67(d, J=13.7Hz, 1H), 1.17(d, J=3.1Hz, 3H);MS(ESI)m / z549[M+Na] + .

[0458] Stage 3 A solution of (S)-benzyl 2-(1-(benzhydryloxy)-3-(3,4-dihydroxyphenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate and CHCN was cooled to below 0°C, and DBU and a prodrug alkylating or acylating agent were added below 0°C. After 40 minutes, water was added to give a biphasic solution. The layers were separated; the lower layer was washed with cold 1:1 CHCN / water, then diluted with ethyl acetate and washed with brine, and the mixture was dried (NaSO) and concentrated. FCC (50 to 100% MTBE / heptane) afforded a mixture of carbidopa prodrug compounds 10.

[0459] Stage 4 In a stainless steel pressure bottle, a solution of the carbidopa prodrug mixture prepared in Step 3 in THF was added to 5% Pd / C (wet grade JM#9). The mixture was shaken under 60 psi of hydrogen at 22°C for 2 hours. Water was then added, and hydrogenation was continued for an additional 17 hours. The mixture was filtered through a nylon membrane using a 100 mL 1:1 THF-water wash. The mixture was diluted with MTBE, and the layers were separated. The aqueous layer was washed with MTBE and then concentrated to a total mass on a rotary evaporator and lyophilized for 3 days to yield a white glass. The amorphous solid was crushed and lyophilized for 1 day to remove traces of additional water, yielding carbidopa prodrugs, Compounds 11a, 11b, and 11c.

[0460] [Example 4] Synthesis of L-dopamine prodrugs The L-dopamine prodrug was prepared as shown in Scheme 4 below.

[0461] [ka]

[0462] Specifically, the L-dopamine prodrugs in steps 1 to 5 below are

[0463] Phase 1 Compound 12 was combined with triethylamine and BOC anhydride in methylene chloride and allowed to stand at room temperature for 1 hour. Reaction completion was monitored by TLC. After complete consumption of the starting material, the reaction was washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C to give crude compound 13.

[0464] Phase 2 Cesium carbonate was added to a solution of compound 13 in dimethylformamide at 0°C. Benzyl bromide was added dropwise to this mixture over 30 minutes at 0°C, and the reaction was then stirred at room temperature for 16 hours. Reaction completion was monitored by TLC. After complete consumption of the starting material, the reaction was washed with water and extracted with MTBE. The combined organic layers were washed with water, saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C to give crude compound 14 as a viscous liquid.

[0465] Stage 3 Compound 14 was dissolved in dichloromethane and treated with trifluoroacetic acid to give compound 15. Reaction completion was monitored by TLC. After complete consumption of the starting material, the reaction was quenched with saturated sodium bicarbonate solution and extracted with MTBE. The combined organic layers were washed with water, saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure at 45°C-50°C to give the crude product.

[0466] Stage 4 An appropriate base was added to a solution of compound 15 in tetrahydrofuran at 0°C. A solution of the acylating agent was added dropwise to this mixture over 30 minutes at 0°C, and the reaction was then stirred at room temperature for 2 hours. Reaction completion was monitored by thin-layer chromatography. After complete consumption of the starting material, the reaction was cooled to 0-5°C and quenched with water. The organic layer was separated, and the aqueous layer was extracted with toluene (500 mL). The combined organic layers were washed with water, saturated NaCl solution, dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C. The resulting crude product was purified by column chromatography on silica gel (230-400 mesh) using 30-40% ethyl acetate / petroleum ether to give compound 16.

[0467] Stage 5 10% Pd / C was added to a solution of compound 16 in ethanol and water (4:1) under a nitrogen atmosphere. The reaction flask was evacuated and purged with hydrogen gas three times, then purged with 4 kg / cm. 2 The mixture was hydrogenated at high pressure (approximately 4 atm) for 16 hours. After completion of the reaction, water was added to the reaction mixture, and the catalyst was removed by filtration through a K100 cellulose filter pad. The filtrate was concentrated under reduced pressure. The resulting crude product was stirred with ethanol, filtered, and sucked dry to give L-dopa prodrug compound 17.

[0468] [Example 5] Synthesis of carbidopamine prodrugs The carbidopa prodrug was prepared as shown in Scheme 5 below.

[0469] [ka]

[0470] Specifically, the carbidopamine prodrugs in steps 1 to 5 below are

[0471] Phase 1 Compound 18 was combined with triethylamine and BOC anhydride in methylene chloride and allowed to stand at room temperature for 1 hour. Reaction completion was monitored by TLC. After complete consumption of the starting material, the reaction was washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C to give crude compound 19.

[0472] Phase 2 Cesium carbonate was added to a solution of compound 19 in dimethylformamide at 0°C. Benzyl bromide was added dropwise to this mixture over 30 minutes at 0°C, and the reaction was then stirred at room temperature for 16 hours. Reaction completion was monitored by TLC. After complete consumption of the starting material, the reaction was washed with water and extracted with MTBE. The combined organic layers were washed with water, saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C to give crude compound 20 as a viscous liquid.

[0473] Stage 3 Compound 20 was dissolved in dichloromethane and treated with trifluoroacetic acid to give compound 21. Reaction completion was monitored by TLC. After complete consumption of the starting material, the reaction was quenched with saturated sodium bicarbonate solution and extracted with MTBE. The combined organic layers were washed with water, saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure at 45°C-50°C to give the crude product.

[0474] Stage 4 An appropriate base was added to a solution of compound 21 in tetrahydrofuran at 0°C. A solution of acylating agent was added dropwise to this mixture over 30 minutes at 0°C, and the reaction was stirred at room temperature for 2 hours. Reaction completion was monitored by thin-layer chromatography. After complete consumption of the starting material, the reaction was cooled to 0-5°C and quenched with water. The organic layer was separated, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, saturated NaCl solution, dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C. The resulting crude product was purified by column chromatography on silica gel (230-400 mesh) using 30-40% ethyl acetate / petroleum ether to give compound 22.

[0475] Stage 5 10% Pd / C was added to a solution of compound 22 in ethanol and water (4:1) under a nitrogen atmosphere. The reaction flask was evacuated and purged with hydrogen gas three times, then purged with 4 kg / cm. 2 The reaction mixture was hydrogenated at high pressure (approximately 4 atm) for 16 hours. After completion of the reaction, water was added to the reaction mixture, and the catalyst was removed by filtration through a K100 cellulose filter pad. The filtrate was concentrated under reduced pressure. The resulting crude product was stirred with ethanol, filtered, and sucked dry to give carbidopa prodrug compound 23.

[0476] [Example 6] Synthesis of Levodopa Carboxylic Acid Prodrugs Levodopa carboxylic acid prodrugs were prepared as shown in Scheme 6 below.

[0477] [ka]

[0478] Specifically, a levodopa carboxylic acid prodrug was prepared in the following steps 1 to 4.

[0479] Phase 1 Cesium carbonate was added to a solution of compound 24 in dimethylformamide at 0°C. Benzyl bromide was added dropwise to the mixture over 30 minutes at 0°C, and the reaction was stirred at room temperature for 16 hours. Reaction completion was monitored by TLC. After complete consumption of the starting material, the reaction was diluted with water and extracted with MTBE. The combined organic layers were washed with water, saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C to give crude compound 25 as a viscous liquid.

[0480] Phase 2 Compound 25 was dissolved in a mixture of THF and water (3:1) and treated with lithium hydroxide solution. After complete consumption of the starting material, the reaction was quenched with 1N hydrochloric acid solution and extracted with MTBE. The combined organic layers were washed with water, saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C to give crude compound 26 as a viscous liquid.

[0481] Stage 3 An appropriate base was added to a solution of compound 26 in tetrahydrofuran at 0°C. A solution of the acylating agent was added dropwise to this mixture over 30 minutes at 0°C, and the reaction was stirred at room temperature for 2 hours. Reaction completion was monitored by thin-layer chromatography. After complete consumption of the starting material, the reaction was cooled to 0-5°C and quenched with water. The organic layer was separated, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, saturated NaCl solution, dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C. The resulting crude product was purified by column chromatography on silica gel (230-400 mesh) using 30-40% ethyl acetate / petroleum ether to give compound 27.

[0482] Stage 4 10% Pd / C was added to a solution of compound 27 in ethanol and water (4:1) under a nitrogen atmosphere. The reaction flask was evacuated and purged with hydrogen gas three times, then purged with 4 kg / cm. 2 The mixture was hydrogenated at high pressure (approximately 4 atm) for 16 hours. After completion of the reaction, water was added to the reaction mixture, and the catalyst was removed by filtration through a K100 cellulose filter layer. The filtrate was concentrated under reduced pressure. The resulting crude product was stirred with ethanol, filtered, and dried by suction to give levodopa carboxylic acid prodrug compound 28.

[0483] [Example 7] Synthesis of carbidopacarboxylic acid prodrugs The carbidopa carboxylic acid prodrug was prepared as shown in Scheme 7 below.

[0484] [ka]

[0485] Specifically, a carbidopa carboxylic acid prodrug was prepared in steps 1 to 4 below.

[0486] Phase 1 Cesium carbonate was added to a solution of compound 29 in dimethylformamide at 0°C. Benzyl bromide was added dropwise to the mixture over 30 minutes at 0°C, and the reaction was then stirred at room temperature for 16 hours. Reaction completion was monitored by TLC. After complete consumption of the starting material, the reaction was diluted with water and extracted with MTBE. The combined organic layers were washed with water, saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C to give crude compound 30 as a viscous liquid.

[0487] Phase 2 Compound 30 was dissolved in a mixture of THF and water (3:1) and treated with lithium hydroxide solution. After complete consumption of the starting material, the reaction was quenched with 1N hydrochloric acid solution and extracted with MTBE. The combined organic layers were washed with water, saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C to give crude compound 31 as a viscous liquid.

[0488] Stage 3 An appropriate base was added to a solution of compound 31 in tetrahydrofuran at 0°C. A solution of the acylating agent was added dropwise to this mixture over 30 minutes at 0°C, and the reaction was stirred at room temperature for 2 hours. Reaction completion was monitored by thin-layer chromatography. After complete consumption of the starting material, the reaction was cooled to 0-5°C and quenched with water. The organic layer was separated, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, saturated NaCl solution, dried over sodium sulfate, and concentrated under reduced pressure at 45-50°C. The resulting crude product was purified by column chromatography on silica gel (230-400 mesh) using 30-40% ethyl acetate / petroleum ether to give compound 32.

[0489] Stage 4 10% Pd / C was added to a solution of compound 32 in ethanol and water (4:1) under a nitrogen atmosphere. The reaction flask was evacuated and purged with hydrogen gas three times, then purged with 4 kg / cm. 2 The reaction mixture was hydrogenated at high pressure (approximately 4 atm) for 16 hours. After completion of the reaction, water was added to the reaction mixture, and the catalyst was removed by filtration through a K100 cellulose filter pad. The filtrate was concentrated under reduced pressure. The resulting crude product was stirred with ethanol, filtered, and sucked dry to give carbidopa carboxylic acid prodrug compound 33.

[0490] VIII. Further embodiments Embodiment 1. A first compound corresponding in structure to Formula (I):

[0491] [ka] or a pharmaceutically acceptable salt thereof [R 1 are independently hydrogen,

[0492] [ka] R 2 and R 3 are each independently hydrogen,

[0493] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 are independently hydrogen,

[0494] [ka] and A second compound corresponding in structure to formula (II):

[0495] [ka] or a pharmaceutically acceptable salt thereof [R 6 are independently hydrogen,

[0496] [ka] R 7 and R 8 are each independently hydrogen,

[0497] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9 are independently hydrogen,

[0498] [ka] is selected from the group consisting of: A combination medicine comprising:

[0499] Embodiment 2. The first compound is

[0500] [ka] The pharmaceutical combination of embodiment 1, wherein

[0501] Embodiment 3. The second compound is:

[0502] [ka] The pharmaceutical combination of embodiment 1 or 2, wherein

[0503] Embodiment 4. The pharmaceutical combination of any one of embodiments 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.

[0504] Embodiment 5. The combination pharmaceutical of any one of Embodiments 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, and more preferably about 1:4.

[0505] Embodiment 6. The pharmaceutical combination of any one of embodiments 1-5, wherein the first compound or a pharmaceutically acceptable salt thereof has a solubility of at least about 200 mg / mL in aqueous solution at about neutral pH, and the second compound or a pharmaceutically acceptable salt thereof has a solubility of at least about 400 mg / mL in aqueous solution at about neutral pH.

[0506] Embodiment 7. The pharmaceutical combination of any one of embodiments 1 to 6, wherein the combination is an aqueous combination suitable for intragastric, subcutaneous, intramuscular, intrajejunal, oral, nasal or intravenous administration.

[0507] Embodiment 8. The pharmaceutical combination of any one of embodiments 1 to 7, wherein the combination is an aqueous combination suitable for subcutaneous administration.

[0508] Embodiment 9. The first compound corresponds in structure to Formula (Ia):

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

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

[0511] Embodiment 10. The first compound corresponds in structure to Formula (Ia):

[0512] [ka] or a pharmaceutically acceptable salt thereof; wherein said second compound corresponds in structure to formula (II-b):

[0513] [ka] 10. The pharmaceutical combination of any one of embodiments 1 to 9, wherein:

[0514] Embodiment 11. The first compound corresponds in structure to Formula (Ib):

[0515] [ka] or a pharmaceutically acceptable salt thereof; wherein said second compound corresponds in structure to formula (II-a):

[0516] [ka] 11. The pharmaceutical combination of any one of embodiments 1 to 10, wherein

[0517] Embodiment 12. The first compound corresponds in structure to Formula (Ib):

[0518] [ka] or a pharmaceutically acceptable salt thereof; wherein said second compound corresponds in structure to formula (II-b):

[0519] [ka] 12. The pharmaceutical combination of any one of embodiments 1 to 11, wherein the compound is:

[0520] Embodiment 13. A method for treating Parkinson's disease in a subject in need thereof and / or a method for providing rescue therapy in a subject having Parkinson's disease, comprising administering to the subject a therapeutically effective amount of the combination pharmaceutical of any one of embodiments 1-12.

[0521] Embodiment 14. The method of embodiment 13, 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.

[0522] Embodiment 15 The method of embodiment 13 or 14 comprising intragastric, subcutaneous, intrajejunal, oral, intranasal, intramuscular, or intravenous administration of said first compound and said second compound.

[0523] Embodiment 16 The method of any one of embodiments 13-15, comprising subcutaneous administration of the first compound and the second compound.

[0524] Embodiment 17 The method of any one of embodiments 13-16, comprising substantially continuous administration of said first compound and said second compound over a period of at least about 12 hours.

[0525] Embodiment 18. The method of any one of embodiments 13-17, wherein the weight ratio of the first compound administered to the second compound administered is from about 1:1 to about 1:50.

[0526] Embodiment 19. The method of any one of embodiments 13-18, wherein the weight ratio of the first compound administered to the second compound administered is from about 1:2 to about 1:15.

[0527] Embodiment 20. The method of any one of embodiments 13-19, wherein the weight ratio of the first compound administered to the second compound administered is from about 1:4 to about 1:10.

[0528] Embodiment 21 The method of any one of embodiments 13-20, wherein the weight ratio of the first compound administered to the second compound administered is about 1:4.

[0529] Embodiment 22 The method of any one of embodiments 13-21, wherein the weight ratio of the first compound administered to the second compound administered is about 1:7.5.

[0530] Embodiment 23 The method of any one of embodiments 13-22, wherein the weight ratio of the first compound administered to the second compound administered is about 1:10.

[0531] Embodiment 24. The first compound is:

[0532] [ka] and said second compound is selected from the group consisting of:

[0533] [ka] 24. The method of any one of embodiments 13 to 23, selected from the group consisting of:

[0534] Embodiment 25 The method of any one of embodiments 13-24, further comprising administering to the subject another anti-Parkinson's drug.

[0535] Embodiment 26. The method of any one of embodiments 13 to 25, wherein the pharmaceutical combination is an aqueous combination.

[0536] Embodiment 27 The method of Embodiment 26, wherein the aqueous combination pharmaceutical is administered intragastrically, subcutaneously, intramuscularly, intranasally, intrajejunally, orally, or intravenously.

[0537] Embodiment 28 The method of embodiment 26 or 27, wherein the aqueous combination is administered by subcutaneous administration.

[0538] Embodiment 29. A compound corresponding in structure to Formula (I) or a pharmaceutically acceptable salt thereof.

[0539] [ka] [In the formula, R 1 are independently hydrogen,

[0540] [ka] R 2 and R 3 are each independently hydrogen,

[0541] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 are independently hydrogen,

[0542] [ka] is selected from the group consisting of:

[0543] Embodiment 30.R 1 is hydrogen; R 2 and R 3 are each independently hydrogen,

[0544] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 are independently hydrogen,

[0545] [ka] 30. The compound of embodiment 29, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[0546] Embodiment 31.R 1 is hydrogen; R 2 and R 3 is hydrogen; and R 4 are independently hydrogen,

[0547] [ka] 31. The compound of embodiment 29 or 30, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[0548] Embodiment 32. The compound has the structure of formula (Ia):

[0549] [ka] 32. The compound or salt of any one of embodiments 29 to 31, corresponding to:

[0550] Embodiment 33. The compound has the structure of formula (Ib):

[0551] [ka] 32. The compound or salt of any one of embodiments 29 to 31, corresponding to:

[0552] Embodiment 34. A compound corresponding in structure to Formula (II) or a pharmaceutically acceptable salt thereof.

[0553] [ka] [In the formula, R 6 are independently hydrogen,

[0554] [ka] R 7 and R 8 are each independently hydrogen,

[0555] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9 are independently hydrogen,

[0556] [ka] is selected from the group consisting of:

[0557] Embodiment 35.R 6 is hydrogen; R 7 and R 8 are each independently hydrogen,

[0558] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9 are independently hydrogen,

[0559] [ka] 35. The compound or salt of embodiment 34, selected from the group consisting of:

[0560] Embodiment 36.R6 is hydrogen; R 7 and R 8 is hydrogen; and R 9 are independently hydrogen,

[0561] [ka] 36. The compound or salt of embodiment 34 or 35, selected from the group consisting of:

[0562] Embodiment 37. The compound has the structure of formula (II-a):

[0563] [ka] 37. The compound or salt of any one of embodiments 34 to 36, corresponding to:

[0564] Embodiment 38. The compound has the structure of formula (II-b):

[0565] [ka] 37. The compound or salt of any one of embodiments 34 to 36, corresponding to:

[0566] Embodiment 39. A first compound corresponding in structure to Formula (I):

[0567] [ka] or a pharmaceutically acceptable salt thereof (R 1 are independently hydrogen,

[0568] [ka] R 2 and R 3 are each independently hydrogen,

[0569] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 are independently hydrogen,

[0570] [ka] ); and a pharmaceutically acceptable carrier.

[0571] Embodiment 40. The first compound has the structure of Formula (Ia):

[0572] [ka] 40. The pharmaceutical composition of embodiment 39, which corresponds to

[0573] Embodiment 41. The first compound has the structure of Formula (Ib):

[0574] [ka] 40. The pharmaceutical composition of embodiment 39, which corresponds to

[0575] Embodiment 42. The composition further comprises a second compound corresponding in structure to Formula (II):

[0576] [ka] or a pharmaceutically acceptable salt thereof [R 6 are independently hydrogen,

[0577] [ka] R 7 and R 8 are each independently hydrogen,

[0578] [ka] R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9 are independently hydrogen,

[0579] [ka] 42. The pharmaceutical composition of any one of embodiments 39 to 41, comprising:

[0580] Embodiment 43. The second compound has the structure of Formula (II-a):

[0581] [ka] 43. The pharmaceutical composition of embodiment 42, which corresponds to

[0582] Embodiment 44. The second compound has the structure of Formula (II-b):

[0583] [ka] 43. The pharmaceutical composition of embodiment 42, which corresponds to

[0584] Embodiment 45. A pharmaceutical composition comprising a first compound corresponding in structure to Formula (II) or a pharmaceutically acceptable salt thereof.

[0585] [ka] [In the formula, R 6 are independently hydrogen,

[0586] [ka] R 7 and R 8are each independently hydrogen,

[0587] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 9 are independently hydrogen,

[0588] [ka] is selected from the group consisting of:

[0589] Embodiment 46 The pharmaceutical composition of embodiment 45, wherein the first compound corresponds in structure to Formula (II-a).

[0590] [ka]

[0591] Embodiment 47 The pharmaceutical composition of embodiment 45, wherein the second compound corresponds in structure to formula (II-b).

[0592] [ka]

[0593] Embodiment 48. The composition further comprises a second compound corresponding in structure to Formula (I):

[0594] [ka] or a pharmaceutically acceptable salt thereof [wherein R 1 are independently hydrogen,

[0595] [ka] R 2 and R3 are each independently hydrogen,

[0596] [ka] and R 5 is selected from the group consisting of hydrogen, methyl, and isopropyl; and R 4 are independently hydrogen,

[0597] [ka] 48. The pharmaceutical composition according to any one of embodiments 45 to 47, comprising:

[0598] Embodiment 49. The second compound has the structure of Formula (Ia):

[0599] [ka] 49. The pharmaceutical composition of embodiment 48, which corresponds to

[0600] Embodiment 50. The second compound has the structure of Formula (Ib):

[0601] [ka] 49. The pharmaceutical composition of embodiment 48, which corresponds to

[0602] Embodiment 51. The pharmaceutical composition of any one of embodiments 39 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.

[0603] Embodiment 52. The pharmaceutical composition of any one of Embodiments 39-51, wherein the weight ratio of the first compound to the second compound is about 1:4.

[0604] Embodiment 53 The pharmaceutical composition of any one of embodiments 39-51, wherein the weight ratio of the first compound to the second compound is about 1:7.5.

[0605] Embodiment 54. The pharmaceutical composition of any one of embodiments 39-51, wherein the weight ratio of the first compound to the second compound is about 1:10.

[0606] Embodiment 55. The pharmaceutical composition of any one of Embodiments 39 to 54, wherein the composition further comprises water and is suitable for injection.

[0607] Embodiment 56. A kit comprising the combination pharmaceutical of any one of Embodiments 1 to 12.

[0608] Embodiment 57. A kit comprising the pharmaceutical composition of any one of embodiments 39 to 55.

[0609] It is to be understood that the foregoing detailed description and accompanying examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention, which is defined solely by the appended claims and their equivalents.

[0610] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, including, but not limited to, those relating to chemical structure, substituents, derivatives, intermediates, synthesis, compositions, formulations, or methods of use of the invention, can be made without departing from the spirit and scope of the invention.

Claims

1. A first compound corresponding in structure to formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof [R １ are independently hydrogen, 【Chemistry 2】 R ２ and R ３ are each independently hydrogen, 【Transformation 3】 and R ５ is selected from the group consisting of hydrogen, methyl, and isopropyl; and R ４ are independently hydrogen, 【Chemistry 4】 and A second compound corresponding in structure to formula (II): 【Transformation 5】 or a pharmaceutically acceptable salt thereof [R ６ are independently hydrogen, 【Transformation 6】 R ７ and R ８ are each independently hydrogen, 【Transformation 7】 and R ５ is selected from the group consisting of hydrogen, methyl, and isopropyl; and R ９ are independently hydrogen, 【Transformation 8】 is selected from the group consisting of: A combination medicine comprising:

2. The first compound 【Chemistry 9】 The pharmaceutical combination according to claim 1, wherein

3. The second compound is 【Chemistry 10】 The combination pharmaceutical according to claim 1 or 2, wherein

4. 4. The pharmaceutical combination 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.

5. The pharmaceutical combination 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, and more preferably about 1:

4.

6. 6. The pharmaceutical combination 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 aqueous solution at about neutral pH, and the second compound or a pharmaceutically acceptable salt thereof has a solubility of at least about 400 mg / mL in aqueous solution at about neutral pH.

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

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

9. The first compound corresponds in structure to formula (Ia): 【Chemistry 11】 or a pharmaceutically acceptable salt thereof; wherein said second compound corresponds in structure to formula (II-a): 【Chemistry 12】 The combination pharmaceutical according to any one of claims 1 to 8, which is a pharmaceutically acceptable salt thereof.

10. The first compound corresponds in structure to formula (Ia): 【Chemistry 13】 or a pharmaceutically acceptable salt thereof; and said second compound corresponds in structure to formula (II-b): 【Chemistry 14】 The combination pharmaceutical according to any one of claims 1 to 9, which is a pharmaceutically acceptable salt thereof.

11. The first compound corresponds in structure to formula (I-b): 【Chemistry 15】 or a pharmaceutically acceptable salt thereof; wherein said second compound corresponds in structure to formula (II-a): 【Chemistry 16】 The combination pharmaceutical according to any one of claims 1 to 10, which is a pharmaceutically acceptable salt thereof.

12. The first compound corresponds in structure to formula (I-b): 【Chemistry 17】 or a pharmaceutically acceptable salt thereof; and said second compound corresponds in structure to formula (II-b): [Chemistry 18] The combination pharmaceutical according to any one of claims 1 to 11, which is a pharmaceutically acceptable salt thereof.

13. 13. A method for treating Parkinson's disease in a subject in need thereof and / or a method for providing rescue therapy in a subject having Parkinson's disease, comprising administering to the subject a therapeutically effective amount of the pharmaceutical combination of any one of claims 1 to 12.

14. 14. The method of claim 13, 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.

15. 15. The method of claim 13 or 14, comprising intragastric, subcutaneous, intrajejunal, oral, intranasal, intramuscular or intravenous administration of said first compound and said second compound.

16. 16. The method of any one of claims 13 to 15, comprising subcutaneous administration of said first compound and said second compound.

17. 17. The method of any one of claims 13 to 16, comprising substantially continuous administration of said first compound and said second compound over a period of at least about 12 hours.

18. 18. The method of any one of claims 13 to 17, wherein the weight ratio of the first compound administered to the second compound administered is from about 1:1 to about 1:

50.

19. 19. The method of any one of claims 13 to 18, wherein the weight ratio of the first compound administered to the second compound administered is from about 1:2 to about 1:

15.

20. 20. The method of any one of claims 13 to 19, wherein the weight ratio of the first compound administered to the second compound administered is from about 1:4 to about 1:

10.

21. 21. The method of any one of claims 13 to 20, wherein the weight ratio of the first compound administered to the second compound administered is about 1:

4.

22. 22. The method of any one of claims 13 to 21, wherein the weight ratio of the first compound administered to the second compound administered is about 1:7.

5.

23. 23. The method of any one of claims 13 to 22, wherein the weight ratio of the first compound administered to the second compound administered is about 1:

10.

24. The first compound is 【Chemistry 19】 and said second compound is selected from the group consisting of: 【Chemistry 20】 The method of any one of claims 13 to 23, selected from the group consisting of:

25. The method of any one of claims 13 to 24, further comprising administering to the subject another anti-Parkinson's drug.

26. The method of any one of claims 13 to 25, wherein the pharmaceutical combination is an aqueous combination.

27. 27. The method of claim 26, wherein the aqueous combination medicine is administered intragastrically, subcutaneously, intramuscularly, intranasally, intrajejunally, orally or intravenously.

28. 28. The method of claim 26 or 27, wherein the aqueous combination drug is administered by subcutaneous administration.

29. A compound corresponding in structure to formula (I) or a pharmaceutically acceptable salt thereof. 【Chemistry 21】 [In the formula, R １ are independently hydrogen, 【Chemistry 22】 R ２ and R ３ are each independently hydrogen, 【Chemistry 23】 and R ５ is selected from the group consisting of hydrogen, methyl, and isopropyl; and R ４ are independently hydrogen, 【Chemistry 24】 is selected from the group consisting of:

30. R １ is hydrogen; R ２ and R ３ are each independently hydrogen, 【Chemistry 25】 and R ５ is selected from the group consisting of hydrogen, methyl, and isopropyl; and R ４ are independently hydrogen, 【Chemistry 26】 30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

31. R １ is hydrogen; R ２ and R ３ is hydrogen; and R ４ are independently hydrogen, 【Chemistry 27】 31. The compound of claim 29 or 30, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

32. The compound has the structure of formula (I-a): 【Chemistry 28】 32. The compound or salt according to any one of claims 29 to 31, which corresponds to:

33. The compound has the structure of formula (I-b): 【Chemistry 29】 32. The compound or salt according to any one of claims 29 to 31, which corresponds to:

34. A compound corresponding in structure to formula (II) or a pharmaceutically acceptable salt thereof. 【Transformation 30】 [In the formula, R ６ are independently hydrogen, 【Chemistry 31】 R ７ and R ８ are each independently hydrogen, 【Chemistry 32】 and R ５ is selected from the group consisting of hydrogen, methyl, and isopropyl; and R ９ are independently hydrogen, 【Transformation 33】 is selected from the group consisting of:

35. R ６ is hydrogen; R ７ and R ８ are each independently hydrogen, 【Transformation 34】 and R ５ is selected from the group consisting of hydrogen, methyl, and isopropyl; and R ９ are independently hydrogen, 【Chemistry 35】 35. The compound or salt of claim 34, selected from the group consisting of:

36. R ６ is hydrogen; R ７ and R ８ is hydrogen; and R ９ are independently hydrogen, 【Transformation 36】 36. A compound or salt according to claim 34 or 35, selected from the group consisting of:

37. The compound has the structure of formula (II-a): 【Chemistry 37】 The compound or salt according to any one of claims 34 to 36, which corresponds to

38. The compound has the structure of formula (II-b): 【Transformation 38】 The compound or salt according to any one of claims 34 to 36, which corresponds to

39. A first compound corresponding in structure to formula (I): 【Chemistry 39】 or a pharmaceutically acceptable salt thereof (R １ are independently hydrogen, 【Chemistry 40】 R ２ and R ３ are each independently hydrogen, 【Chemistry 41】 and R ５ is selected from the group consisting of hydrogen, methyl, and isopropyl; and R ４ are independently hydrogen, 【Chemistry 42】 and a pharmaceutically acceptable carrier.

40. The first compound has the structure of formula (Ia): 【Chemistry 43】 40. The pharmaceutical composition of claim 39, which corresponds to:

41. The first compound has the structure of formula (I-b): 【Chemistry 44】 40. The pharmaceutical composition of claim 39, which corresponds to:

42. The composition further comprises a second compound corresponding in structure to formula (II): 【Chemistry 45】 or a pharmaceutically acceptable salt thereof [R ６ are independently hydrogen, 【Chemistry 46】 R ７ and R ８ are each independently hydrogen, 【Chemistry 47】 R ５ is selected from the group consisting of hydrogen, methyl, and isopropyl; and R ９ are independently hydrogen, 【Chemistry 48】 The pharmaceutical composition of any one of claims 39 to 41, comprising:

43. The second compound has the structure of formula (II-a): 【Chemistry 49】 43. The pharmaceutical composition of claim 42, wherein

44. The second compound has the structure of formula (II-b): [Transformation 50] 43. The pharmaceutical composition of claim 42, wherein

45. A pharmaceutical composition comprising a first compound corresponding in structure to formula (II) or a pharmaceutically acceptable salt thereof. 【Chemistry 51】 [In the formula, R ６ are independently hydrogen, 【Chemistry 52】 R ７ and R ８ are each independently hydrogen, 【Chemistry 53】 and R ５ is selected from the group consisting of hydrogen, methyl, and isopropyl; and R ９ are independently hydrogen, 【Chemistry 54】 is selected from the group consisting of:

46. 46. ​​The pharmaceutical composition of claim 45, wherein the first compound corresponds in structure to Formula (II-a). 【Transformation 55】

47. 46. ​​The pharmaceutical composition of claim 45, wherein the second compound corresponds in structure to formula (II-b). 【Transformation 56】

48. The composition further comprises a second compound corresponding in structure to Formula (I): 【Chemistry 57】 or a pharmaceutically acceptable salt thereof [wherein R １ are independently hydrogen, 【Chemistry 58】 R ２ and R ３ are each independently hydrogen, 【Chemistry 59】 and R ５ is selected from the group consisting of hydrogen, methyl, and isopropyl; and R ４ are independently hydrogen, 【Transformation 60】 and a pharmaceutically acceptable carrier.

49. The second compound has the structure of formula (Ia): 【Chemistry 61】 49. The pharmaceutical composition of claim 48, wherein

50. The second compound has the structure of formula (I-b): 【Transformation 62】 49. The pharmaceutical composition of claim 48, wherein

51. 45. The pharmaceutical composition of any one of claims 39 to 44, wherein the weight ratio of said first compound to said 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.

52. 52. The pharmaceutical composition of any one of claims 39 to 51, wherein the weight ratio of said first compound to said second compound is about 1:

4.

53. 52. The pharmaceutical composition of any one of claims 39 to 51, wherein the weight ratio of said first compound to said second compound is about 1:7.

5.

54. 52. The pharmaceutical composition of any one of claims 39 to 51, wherein the weight ratio of said first compound to said second compound is about 1:

10.

55. 55. The pharmaceutical composition of any one of claims 39 to 54, wherein the composition further comprises water and is suitable for injection.

56. A kit comprising the pharmaceutical combination according to any one of claims 1 to 12.

57. A kit comprising the pharmaceutical composition of any one of claims 39 to 55.

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