Stable liquid compositions comprising levodopa-tyrosine conjugates and uses thereof

Abstract

Disclosed herein are levodopa prodrug compounds and methods for their use. Further disclosed herein are liquid pharmaceutical formulations comprising levodopa-tyrosine conjugates and stabilizers, which may further comprise a decarboxylase inhibitor, such as carbidopa, an antioxidant, a solvent, or any other pharma- ceutically acceptable excipient. Further disclosed are methods for treating generative conditions and / or conditions characterized by reduced levels of dopamine in the brain, such as Parkinson's disease, comprising administering the disclosed prodrugs and / or liquid pharmaceutical formulations.

Description

Related Applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 159,236, filed March 10, 2021, and U.S. Provisional Application No. 62 / 296,032, filed January 3, 2022, the entire disclosures of each of which are incorporated herein by reference in their entirety. [Technical field]

[0002]

[0002] The present invention relates to levodopa prodrug compounds and their pharmaceutical uses. The present invention is also directed to stable compositions comprising levodopa-tyrosine conjugate (LD-Tyr) and their salts, methods for preparing the LD-Tyr compositions, and methods of using the same in the treatment of conditions characterized by neurodegeneration and / or reduced levels of dopamine in the brain, such as Parkinson's disease. [Background technology]

[0003]

[0003] Parkinson's disease is a degenerative condition characterized by a decrease in the concentration of the neurotransmitter dopamine in the brain. Levodopa (L-dopa or L-3,4-dihydroxyphenylalanine), unlike dopamine, is able to cross the blood-brain barrier and is the immediate metabolic precursor of dopamine that is most commonly used to restore dopamine concentrations in the brain. Over the past 40 years, levodopa remains the most effective therapy for the treatment of Parkinson's disease.

[0004]

[0004] However, conventional treatment for Parkinson's disease with levodopa has proven inadequate for many reasons documented in the medical literature. For example, some patients eventually become hyporesponsive to levodopa, such that previously effective doses eventually fail to provide any therapeutic benefit. Thus, systemic administration of levodopa, while initially providing clinically beneficial effects, is accompanied by the need to increase the dose to high doses that may result in side effects. For these reasons, the benefits of levodopa treatment often begin to wane after about three or four years of therapy, regardless of the initial therapeutic response.

[0005]

[0005] When levodopa is administered peripherally, only about 1-3% of the administered levodopa can enter the brain unaltered, with the further fact that the majority of levodopa is metabolized outside the brain, mainly by decarboxylating levodopa to dopamine, does not cross the blood-brain barrier, and is therefore ineffective in treatment. The metabolic conversion of levodopa to dopamine is catalyzed by the aromatic L-amino acid decarboxylase enzyme, a ubiquitous enzyme with particularly high concentrations in the intestinal mucosa, liver, brain, and brain capillaries. The possibility of metabolizing levodopa outside the brain requires the administration of large amounts of levodopa, resulting in high extracerebral concentrations of dopamine. Coadministration of levodopa and peripheral dopamine decarboxylase (aromatic L-amino acid decarboxylase) inhibitors, such as carbidopa or benserazide, has been found to reduce the required dose of levodopa, respectively, and some of the side effects; however, the reduction obtained is often insufficient.

[0006] Finally, some fluctuations in the clinical response to levodopa occur with increasing frequency with prolonged treatment. In some patients, these fluctuations are related to the timing of levodopa intake, known as the "wearing-off reaction" or "end-of-dose akinesia." In other instances, the fluctuations in clinical state are not related to the timing of administration and are commonly referred to as the "on-off phenomenon." In the on-off phenomenon, "off periods" of marked akinesia and bradykinesia alternate for several hours with "on periods" of improved mobility, and these are often accompanied by troublesome dyskinesias.

[0007]

[0007] In order to maintain a desired dopamine concentration in the brain, a method for continuously administering a formulation containing levodopa using a pump has been developed. As an example, a method for continuous enteral delivery of L-dopa / carbidopagel (known as DuoDopa® in Europe and Duopa® in the United States) is known, and this method is used to treat Parkinson's disease. However, since it requires insertion into the intestine, it is a burden on the patient, and therefore a less invasive and pharmacokinetically stable delivery system is required. One example of a less invasive delivery system is a method for subcutaneous administration of a solution formulation using a pump. Such a formulation is currently under investigation, but is not yet on the market.

[0008]

[0008] As mentioned above, when developing an optimal formulation for a continuous delivery system in the treatment of Parkinson's disease, it is necessary that the active ingredient is soluble and stable in the formulation. Many different approaches can be considered, but in order to improve the solubility of the active ingredient itself, the creation of a new levodopa prodrug can be one approach. For example, a prodrug that adds an amino acid to the levodopa molecule is known (U.S. Patent No. 3,803,120). In addition, a levodopa prodrug compound having a phosphate ester is also known (International Patent Publication No. WO2017 / 184871).

[0009]

[0009] Moreover, it is widely accepted in the art that many of the above-mentioned disadvantages result from the unfavorable pharmacokinetic properties of levodopa, more particularly from its poor water solubility, bioavailability and rapid degradation in vivo. Another approach could be to develop effective therapeutic formulations with enhanced stability for the treatment of disorders such as Parkinson's disease.

[0010]

[0010] Amino acids, containing amino and carboxylic acid groups, are the basic units of proteins. In general, amino acids are known to play a major role in the body and participate in tissue protein formation and enzyme hormone formation. Therefore, any deficiency of amino acids affects protein synthesis. Amino acids are also known to regulate processes related to gene expression, and further, amino acids modify protein functions involved in messenger RNA translation. Some amino acids, such as tyrosine, are synthesized in the human body, while those known as essential amino acids, such as arginine and lysine, are consumed through the diet. Lanthionine amino acid is a natural, but non-proteinogenic, diamino diacid, structurally related to the amino acid cysteine. Lanthionine has a single central sulfur moiety that is bonded to two alanine residues (R / S configuration), allowing the possibility of different stereomeric forms of lanthionine.

[0011]

[0011] Amino acids are ionized in aqueous solutions, and the pH of the solution affects the ionic species of the amino acid, determining whether it is in the form of a zwitterion, cation, or anion. The permeability coefficients of various compounds through the skin depend on their ionic form, with non-ionized species generally having higher permeability coefficients compared to ionized species, and cations generally having higher permeability coefficients than anions.

[0012]

[0012] US Patent No. 3,803,120, US Patent No. 4,035,507, US Patent No. 5,686,423 and US Patent Application No. 2002 / 099013 disclose some levodopa amino acid and levodopa peptide conjugates; however, no details on formulations are given therein, and when given, only solid oral formulations are considered. The theoretical option of preparing liquid compositions is briefly mentioned in US Patent No. 3,803,120 (column 3, lines 49-53 in US'120); however, no such compositions are prepared, and furthermore, it is erroneously disclosed that the conjugates are soluble (column 3, lines 65-66).

[0013]

[0013] Furthermore, levodopa amino acid conjugates, such as LD-Tyr, may be unstable and / or form impurities over time. For example, LD-Tyr has a tendency to form diketopiperazine (DKP) impurities, as shown in the following scheme:

[0014] [ka]

[0015] As detailed above, there remains a need for effective, stable formulations, particularly liquid formulations, for treating disorders such as Parkinson's disease. Summary of the Invention

[0016]

[0015] The present disclosure contemplates providing novel compounds that have improved solubility and stability in solution compared to levodopa by creating novel prodrugs, enabling the compounds to be converted to levodopa in the body.

[0017]

[0016] As a result of extensive research to solve the above problems, the inventors have discovered that levodopa prodrug compounds represented by general formula (I) or (III) have high levodopa conversion efficiency and good solubility and stability in solution, and have thus completed the present invention.

[0018]

[0017] Thus, in one embodiment, the present disclosure provides a levodopa amino acid conjugate represented by the following formula (I) or (III) or a pharma- ceutically acceptable salt thereof: [Chemical formula 1]

[0019] [ka]

[0020] wherein R is an amino acid side chain that can be substituted; R 1 and R 2 may be the same or different, and each independently represents a hydrogen atom, C 1 ~C 6 Alkyl, C 1 ~C 6 alkanoyl, phosphono, sulfino, or optionally substituted glycosyl, provided that R 1 and R 2 is not a hydrogen atom at the same time; R 3 and R 4 may be the same or different, and each independently represents a hydrogen atom or C 1 ~C 6 is alkyl; R 5 is a hydrogen atom, or [Chemical formula 3]

[0021] [ka]

[0022] [In the formula, R 11 and R 12are the same or different and are hydrogen, alkyl, alkanoyl, P(=O)(OH), 2 , S(═O)(OH) or optionally substituted glycosyl; R 13 is optionally substituted alkyl, -R 15 -OR 16 or a 5-membered heterocyclyl containing at least one nitrogen atom, R 15 is alkylene, and R 16 is hydrogen, alkyl, P(=O)(OH) 2 , S(═O)(OH), or glycosyl which may be substituted; R 14 is hydrogen or alkyl; However, the following compounds: (2S)-2-[(2-aminoacetyl)amino]-3-(3,4-diacetyloxyphenyl)propanoic acid, (2S)-2-[[(2S)-2-amino-6-[(2-chlorophenyl)methoxycarbonylamino]hexanoyl]amino]-3-(3,4-dimethoxyphenyl)propanoic acid, (2S)-2-[[(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl]amino]-3-(4-hydroxy-3-methoxyphenyl)propanoic acid, (2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-3-(3,4-dimethoxyphenyl)propanoic acid, (2S)-2-[[(2R)-2-amino-3-phenylpropanoyl]amino]-3-(3,4-diacetyloxyphenyl)propanoic acid, and (2S)-2-[[(2S)-2-amino-5-methoxy-5-oxopentanoyl]amino]-3-(3,4-dimethoxyphenyl)propanoic acid excluding].

[0023]

[0018] In certain embodiments, the present disclosure further relates to a levodopa amino acid conjugate according to (1) above, or a pharma ceutically acceptable salt thereof, Wherein R3, R4 and R5 are hydrogen atoms. R1 and R 2 are the same or different and each is a hydrogen atom, acetyl or phosphono, provided that R 1 and R 2 is not a hydrogen atom at the same time.

[0024]

[0019] In certain embodiments, the present disclosure further relates to a levodopa amino acid conjugate or a pharma ceutically acceptable salt thereof according to (1) or (2) above, Wherein R3, R4 and R5 are hydrogen atoms.

[0025] R 1 is a hydrogen atom; R 2 is phosphono.

[0020] In certain embodiments, the present disclosure further relates to a levodopa amino acid conjugate described in any one of the above embodiments, or a pharma- ceutically acceptable salt thereof, wherein the amino acid in the amino acid side chain is glutamic acid, valine, alanine, lysine, 3,4-dihydroxyphenylalanine or tyrosine.

[0026] In certain embodiments, the present disclosure further comprises: (2S)-2-[[(2S)-2-amino-3-phosphonooxypropanoyl]amino]-3-(3,4-dihydroxyphenyl)propanoic acid, (2S)-2-[[(2S)-2-amino-3-(4-phosphonooxyphenyl)propanoyl]amino]-3-(3,4-dihydroxyphenyl)propanoic acid, (2S)-2-amino-5-[[(1S)-1-carboxy-2-(3,4-diacetoxyphenyl)ethyl]amino]-5-oxo-pentanoic acid, (2S)-3-(3,4-dihydroxyphenyl)-2-[(2-methyl-2-phosphonooxypropanoyl)amino]propanoic acid, and (2S)-2-[[(2S)-2-amino-3-[4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]propanoyl]amino]-3-(3,4-dihydroxyphenyl)propanoic acid The present invention relates to a levodopa amino acid conjugate selected from the group consisting of:

[0027]

[0022] In certain embodiments, the present disclosure further relates to a liquid pharmaceutical composition comprising, as an active ingredient, a levodopa amino acid complex or a pharma- ceutically acceptable salt thereof according to any one of the above embodiments.

[0028] In certain embodiments, the present disclosure further relates to a therapeutic agent for treating a neurodegenerative disease and / or a disease or condition caused by a decrease in dopamine concentration in the brain, the therapeutic agent comprising the levodopa amino acid complex or a pharma- ceutically acceptable salt thereof according to any one of the above embodiments as an active ingredient. In certain embodiments, the neurodegenerative disease and / or a disease or condition caused by a decrease in dopamine concentration in the brain is Parkinson's disease.

[0029]

[0024] Provided herein are, inter alia, compositions, e.g., pharma- ceutically acceptable compositions, e.g., liquid pharmaceutical compositions, with improved stability, comprising levodopa-tyrosine conjugate (LD-Tyr) or a salt thereof (e.g., a pharma- ceutically acceptable salt thereof). Methods of preparing such compositions are also described herein. Also disclosed are compositions comprising LD-Tyr and pharma- ceutically acceptable salts thereof, and methods of using compositions comprising same, for example, in the treatment of conditions characterized by neurodegeneration and / or reduced levels of dopamine in the brain, e.g., Parkinson's disease.

[0030] Disclosed herein is a method for producing a medicament for the treatment of a chronic pulmonary disease, comprising: Formula (II):

[0031] [ka]

[0032] a levodopa-tyrosine (LD-Tyr) conjugate of, an enantiomer, diastereomer, racemate, ion, zwitterion, a pharma- ceutically acceptable salt thereof, or any combination thereof; and a stabilizer.

[0033]

[0026] In some embodiments, the liquid pharmaceutical compositions disclosed herein contain between about 10 and about 45% w / v, at least 30% w / v, or between about 30 and about 45% w / v LD-Tyr, or an enantiomer, diastereomer, racemate, ion, zwitterion, pharma- ceutically acceptable salt thereof, or any combination thereof.

[0034] In some embodiments, the stabilizer is present in an amount of about 0.1 to about 30% w / v. In some embodiments, the stabilizer comprises a base. In some embodiments, the base is arginine, NaOH, NH 4 OH, tris(hydroxymethyl)aminomethane (TRIS), ethylenediamine, diethylamine, ethanolamine, diethanolamine, meglumine, and any combination thereof. In some embodiments, the base is selected from the group consisting of arginine, NH 4 OH, ethylenediamine, diethylamine, ethanolamine, diethanolamine, meglumine, and any combination thereof. In some embodiments, the base is selected from the group consisting of L-Arg, diethylamine, and combinations thereof. In some embodiments, the base is selected from the group consisting of L-Arg, ethanolamine, and combinations thereof.

[0035] In some embodiments, the liquid pharmaceutical composition comprises between about 0.1 and about 30% w / v of a base. In some embodiments, the liquid pharmaceutical composition comprises between about 1.5 and about 20% w / v of a base.

[0036] In some embodiments, the liquid pharmaceutical compositions disclosed herein have a pH range of between about 5 and about 10 at about 25° C. In some embodiments, the liquid pharmaceutical compositions disclosed herein have a pH range of between about 8 and about 10. In some embodiments, the liquid pharmaceutical compositions disclosed herein have a pH range of between about 8 and about 9.

[0037]

[0031] In some embodiments, the liquid pharmaceutical compositions disclosed herein can include the free base and a counterion of the compound of formula II. In some embodiments, the liquid pharmaceutical compositions disclosed herein may also include a decarboxylase inhibitor. For example, in some embodiments, the decarboxylase inhibitor is carbidopa. In some embodiments, the liquid pharmaceutical compositions disclosed herein may also include between about 0.25 and about 2.0% w / v of the decarboxylase inhibitor.

[0038] Any of the foregoing liquid pharmaceutical compositions described herein may further comprise one or a combination of two or more antioxidants. For example, in some embodiments, the liquid pharmaceutical compositions described herein may further comprise one or a combination of two or more antioxidants, such as ascorbic acid or a salt thereof, cysteine, e.g., N-acetylcysteine ​​(NAC), bisulfite or a salt thereof, glutathione, a tyrosinase inhibitor, Cu 2+ In some embodiments, the liquid pharmaceutical composition described herein may comprise between about 0.05 and about 1.5% w / v of one or a combination of antioxidants. In some embodiments, the liquid pharmaceutical composition comprises a combination of ascorbic acid and NAC.

[0039] Any of the aforementioned liquid pharmaceutical compositions described herein may further comprise at least one of a catechol-O-methyltransferase (COMT) inhibitor, a monoamine oxidase (MAO) inhibitor, a surfactant, a buffer, an acid, a base, a solvent, or any combination thereof. In some embodiments, the liquid pharmaceutical composition comprises between about 5.0 and about 40.0% w / v of a buffer, a base, or a solvent. For example, in some embodiments, the liquid pharmaceutical composition described herein may comprise a solvent, which may be N-methylpyrrolidone (NMP), tris(hydroxymethyl)aminomethane (tromethamine, TRIS), an ether, such as tetrahydrofuran and 1,4-dioxane, an amide, such as N,N-dimethylformamide and N-methylpyrrolidone, a nitrile, such as acetonitrile, a halogenated aliphatic hydrocarbon, such as chloroform and dichloromethane, an aromatic hydrocarbon, such as toluene, or any combination thereof. It should be noted that some materials, such as tromethamine (TRIS), can be added to the composition and function, such as, for example, a base, a buffer, a solvent, or any combination thereof. In some embodiments, the liquid pharmaceutical composition described herein can include a surfactant, where the surfactant is Tween-80. In some embodiments, the liquid pharmaceutical composition described herein can include a solvent and a surfactant, where the solvent is NMP and the surfactant is Tween-80. In some embodiments, the liquid pharmaceutical composition can include between about 0.1 and about 1.0% w / v of a surfactant, for example, between 0.1 and about 1.0% w / v of Tween-80. In some embodiments, the liquid pharmaceutical composition can include between about 5.0 and about 40.0% w / v of a solvent, for example, between about 5.0 and about 40.0% w / v of NMP.

[0040]

[0035] In some embodiments, the solvent is TRIS. In certain embodiments, the stabilizer comprises polyethylene glycol. In certain embodiments, the liquid pharmaceutical composition comprises less than about 1.5% w / v LD-Tyr-diketopiperazine after 2 weeks at 2-8° C. In certain embodiments, the liquid pharmaceutical composition comprises less than about 0.8% w / v LD-Tyr-diketopiperazine after 2 weeks at 2-8° C. In certain embodiments, the liquid pharmaceutical composition comprises less than about 5.0% w / v LD-Tyr-diketopiperazine after 2 weeks at 25° C. In certain embodiments, the liquid pharmaceutical composition comprises no more than about 4% w / v LD-Tyr-diketopiperazine after 2 weeks at 25° C.

[0041]

[0037] Also disclosed herein is a method for treating a neurodegenerative condition and / or a condition characterized by reduced levels of dopamine in the brain, the method comprising administering a liquid pharmaceutical composition described herein.

[0042]

[0038] For example, disclosed herein is a method for treating a neurodegenerative condition and / or a condition characterized by reduced levels of dopamine in the brain, the method comprising administering a liquid pharmaceutical composition comprising LD-Tyr and a stabilizer.

[0043]

[0039] Disclosed herein is a method of treating a neurodegenerative condition and / or a condition characterized by reduced levels of dopamine in the brain, the neurodegenerative condition being Parkinson's disease.

[0044] In some embodiments of the disclosed methods of treating, the liquid pharmaceutical composition is administered simultaneously with an additional active ingredient. For example, in some embodiments, the additional active ingredient is a decarboxylase inhibitor, a COMT inhibitor, an MAO inhibitor, or any combination thereof.

[0045] In some embodiments of the methods of treating disclosed herein, the liquid pharmaceutical composition is administered substantially continuously, hi some embodiments, the liquid pharmaceutical composition is administered subcutaneously.

[0046]

[0042] Also disclosed herein is a liquid pharmaceutical composition for use in treating a neurodegenerative condition and / or a condition characterized by reduced levels of dopamine in the brain.

[0043] Disclosed herein is a liquid pharmaceutical composition for use in the treatment of a neurodegenerative condition and / or a condition characterized by reduced levels of dopamine in the brain, the neurodegenerative condition being Parkinson's disease.

[0047] According to some embodiments, the liquid pharmaceutical composition is administered simultaneously to a patient with additional active ingredients, such as, for example, decarboxylase inhibitors, COMT inhibitors, MAO inhibitors, and any combination thereof.

[0048] According to some embodiments, the liquid pharmaceutical composition is administered to the patient on a substantially continuous basis. According to further embodiments, the liquid pharmaceutical composition is administered subcutaneously.

[0046] Embodiments of the present invention are further directed to a method of treating Parkinson's disease in a patient in need thereof comprising subcutaneously administering to the patient an effective amount of a liquid pharmaceutical composition as disclosed herein. Further embodiments of the present invention are directed to the use of the liquid pharmaceutical formulations disclosed herein for treating neurodegenerative conditions and / or conditions characterized by reduced levels of dopamine in the brain, e.g., Parkinson's disease.

[0049]

[0047] Also disclosed herein is a method for preparing a liquid pharmaceutical composition, the method comprising the steps of: providing a pharma- ceutically acceptable salt of LD-Tyr; combining the pharma- ceutically acceptable salt with at least one solvent, thereby forming a solution, gel, cream, emulsion, or suspension; combining the solution, gel, cream, emulsion, or suspension with a stabilizer; and adjusting the pH of the solution, gel, cream, emulsion, or suspension to a physiologically acceptable pH value, thereby producing the liquid pharmaceutical composition.

[0050]

[0048] In some embodiments, the method for preparing the liquid pharmaceutical composition described herein includes the step of providing a pharma- ceutically acceptable salt, enantiomer, diastereomer, racemate, ion, zwitterion, a pharma- ceutically acceptable salt thereof, or any combination thereof of LD-Tyr.

[0051] In some embodiments of the methods described herein, the LD-Tyr compound of formula (II) in the form of a pharma- ceutically acceptable salt is mixed with at least one solvent and at least one stabilizer, thereby forming a solution. In some embodiments, the method includes a step of adjusting the pH, including a step of adding a basic solution. For example, in some embodiments, the method includes a step of adjusting the pH, including a step of adding a basic solution, the basic solution including NaOH. In some embodiments, the method does not include heating. [Brief description of the drawings]

[0052] [Figure 1] FIG. 1 is a graph showing the rate of formation of LD-Tyr-diketopiperazine (LD-Tyr-DKP) over time at 2-8° C. in LD-Tyr formulations with the indicated bases. [Diagram 2] FIG. 1 is a graph showing the rate of formation of LD-Tyr-diketopiperazine (LD-Tyr-DKP) over time at 25° C. in LD-Tyr formulations with the indicated bases. [Diagram 3]

[0052] Figure 1 shows KRBC / PL of LD-Tyr after incubation in rat blood. [Figure 4]

[0053] FIG. 1 shows KRBC / PL of LD-Tyr after incubation in minipig blood. [Diagram 5]

[0054] FIG. 2 shows the KKRBC / PL of LD-Tyr after incubation in human blood. [Figure 6]

[0055] FIG. 1 shows the combined mean plasma LD-Tyr concentration versus time profile in domestic pigs after 18 hours of continuous subcutaneous infusion. [Figure 7]

[0056] FIG. 1 shows the composite mean plasma LD concentration versus time profile in domestic pigs after 18-h continuous subcutaneous infusion of LD-Tyr. [Figure 8]

[0057] FIG. 1 shows the combined mean plasma LD concentration versus time profiles in domestic pigs after 18-h continuous subcutaneous infusion of increasing concentrations of LD-Tyr and 1% CD. [Figure 9]

[0058] FIG. 1 shows the combined mean plasma LD concentration versus time profiles in domestic pigs after 18-h continuous subcutaneous infusion of increasing concentrations of LD-Tyr and 0.5% CD. [Figure 10]

[0059] FIG. 1 shows the combined mean plasma LD concentration versus time profile in domestic pigs after 18-h continuous subcutaneous infusion of LD-Tyr and various amounts of CD. [Figure 11]

[0060] FIG. 1 shows the composite mean normalized LD plasma concentration versus time profiles in domestic pigs after 18-h continuous SC infusion of 30% LD-Tyr with different CD concentrations. [Figure 12]

[0061] FIG. 1 shows the combined mean plasma LD concentration versus time profile following bolus injection of different volumes of 30% LD-Tyr and 1% CD and continuous SC infusion for 2 hours in domestic pigs. [Figure 13]

[0062] Figure 1 shows the composite mean plasma LD-Tyr and LD concentration versus time profiles for the 2700 mg dosing regimen.PK parameters are also shown. [Figure 14]

[0063] Figure 1 shows the composite mean plasma LD-Tyr and LD concentration versus time profiles for the 5400 mg dosing regimen.PK parameters are also shown. [Figure 15]

[0064] FIG. 1 shows the composite mean plasma LD concentration versus time profiles for the 2700 mg and 5400 mg dosing regimens. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0053]

[0065] The features and other details of the present disclosure are described in more detail herein. Some terms used in the present specification, examples and appended claims are collected here. These definitions should be read in light of the following parts of this disclosure and understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0054]

[0066] The terms "treat", "treatment", "treating" and the like are used herein to generally mean obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic in terms of partially or completely curing the disease and / or adverse effects caused by the disease. The term "treatment", as used herein, includes any treatment of a disease in a mammal, particularly a human, including (a) suppressing the disease, i.e., preventing the disease from increasing in severity or extent; (b) relieving the disease, i.e., causing partial or complete remission of the disease; or (c) preventing recurrence of the disease, i.e., preventing the disease from returning to an active state following a previous successful treatment of the symptoms of the disease or treatment of the disease.

[0055]

[0067] "Preventing" includes delaying the onset of clinical symptoms, complications, or biochemical signs of a condition, disorder, disease, or condition that manifest in a subject who may be afflicted by or predisposed to the condition, disorder, disease, or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder, disease, or condition. "Preventing" includes prophylactically treating a condition, disorder, disease, or condition in or that manifests in a subject, including prophylactically treating clinical symptoms, complications, or biochemical signs of a condition, disorder, disease, or condition in or that manifests in a subject.

[0056]

[0068] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein, interchangeably refer to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration.

[0057]

[0069] The terms "pharmaceutical composition" and "pharmaceutical formulation" as used herein refer to a composition or formulation that includes at least one biologically active compound, such as a levodopa amino acid conjugate, or a pharma- ceutical acceptable salt thereof, as disclosed herein, formulated with one or more pharma- ceutical acceptable excipients. It should be noted that the terms "formulation" and "composition" are interchangeable unless otherwise specifically stated or understood by those skilled in the art.

[0058]

[0070] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts of acidic or basic groups that can be formed with the conjugates used in the compositions disclosed herein.

[0059]

[0071] "Individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or non-human primates, and humans. In some embodiments, the mammal treated in the methods of the invention is a human suffering from a neurodegenerative condition, e.g., Parkinson's disease and / or a disease or condition caused by reduced dopamine levels in the brain.

[0060]

[0072] The term "about," as used herein, is intended to encompass a range of ±10% of the recited value(s) unless specifically stated otherwise or would be understood by one of ordinary skill in the art. It is further noted that any value provided may still be considered to encompass a range of ±10% of that value without the use of the term "about." This includes values ​​in the Examples section, which may vary depending on the tools and machinery used, the purity of the compounds, and the like.

[0061]

[0073] The term "stable" as used herein refers to a state of a substance that does not decompose or is not easily decomposed in a solution, unless otherwise specified.Therefore, as used herein, the term "stable" means that, for example, when a solution of a substance is prepared and the peak area ratio of the substance measured by the area percentage method of high performance liquid chromatography (HPLC) immediately after the solution is prepared is compared with the peak area ratio of the substance after standing at 25°C for about 1 day, no decrease in the peak area ratio is observed or the degree of decrease in the peak area ratio is small.In another embodiment, the term "stable" refers to a substance that is physically stable after a specified period of time, such as a formulation, when viewed visually at a magnification of at least x1.75, no precipitate is visible.

[0062]

[0074] As used herein, the term "stabilizer" refers to a substance that prevents or delays the occurrence of precipitation or impurities in, for example, liquid pharmaceutical formulations, unless otherwise specified or understood by those skilled in the art. Thus, as used herein, the term "stabilizer" refers to any excipient that provides enhanced stability, for example, physical and / or chemical stability, to liquid pharmaceutical compositions. A stabilizer may be, for example, a solvent, a buffer, a base, an acid, or any combination thereof, and therefore, any excipient referred to herein, for example, as a solvent, a buffer, may also be considered a stabilizer.

[0063]

[0075] The term "liquid," as used herein, unless specifically stated otherwise or as would be understood by one of ordinary skill in the art, means any type of fluid, including gels, aqueous and non-aqueous compositions, and the like.

[0064]

[0076] As used herein, the term "in combination" means, unless specifically stated otherwise, the administration of two or more active ingredients in combination, including the administration of those active ingredients separately or simultaneously in the same composition, and including the administration of two or more active ingredients consecutively on the same day, and the administration of the active ingredients separated from each other by a predetermined time, and further including the administration of two or more active ingredients on different days.

[0065]

[0077] The term "concurrently," as used herein, unless specifically stated otherwise or as would be understood by one of ordinary skill in the art, means any type of co-administration of two or more active ingredients, including administration of those active ingredients at the same time, in separate or the same composition, as well as administration of two or more active ingredients sequentially, consecutively, on the same day, with a defined period of time separating the administration of the active ingredients from one another, etc.

[0066]

[0078] The terms "continuously" and "nearly continuously", as used herein, unless specifically stated otherwise or as would be understood by one of skill in the art, refer to a period during which the composition is administered with rests of less than about 24 hours, about 12 hours, about 5 hours, about 3 hours, about 1 hour, about 30 minutes, about 15 minutes, about 5 minutes, or about 1 minute for the entire period. The period during which the composition is administered can be at least about 6 hours, about 8 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, 3 days, 7 days, 2 weeks, 1 month, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, 10 years, etc.

[0067]

[0079] The term "physiologically acceptable pH value" and the like, as used herein, means a pH value ranging between about 4.5 and about 10, unless specifically stated otherwise or as would be understood by one of ordinary skill in the art. It is further noted that where pH values ​​are given, including in these examples, these values ​​may range from about ±0.1 and / or ±10% of the recited value(s), such that if the measured pH is 8.1, the same formulation may be prepared to exhibit a pH of about 8.0 or 8.2. Such differences may be due to temperature changes, different measurement devices, and the like.

[0068] I. Prodrugs

[0080] The compound of the present invention or a pharma- ceutically acceptable salt thereof has good conversion efficiency to levodopa and is useful as a prophylactic or therapeutic agent for a neurodegenerative disease and / or a disease or symptom caused by a decrease in dopamine concentration in the brain, such as Parkinson's disease.

[0069]

[0081] Furthermore, the compounds of the present invention or pharma- ceutically acceptable salts thereof are highly soluble, highly stable in solution, and easy to handle in solution, and therefore highly suitable for use in the form of a stationary delivery system.

[0070]

[0082] In the present invention, alkyl refers to an alkyl group having 1 to 6 carbon atoms (C 1~6) refers to a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms (C 1~4 ) is preferred. Specific examples thereof include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, i-pentyl, and n-hexyl. Methyl is particularly preferred.

[0071]

[0083] Alkanoyl refers to a monovalent group in which the aforementioned alkyl is bonded to a carbonyl, examples of which include alkyl groups having 1 to 6 carbon atoms (C 1~6 ) and straight or branched alkyl-CO-. Specific examples thereof include acetyl, propionyl, butyryl, pivaloyl, pentanoyl, hexanoyl, heptanoyl, etc. In particular, acetyl is preferred.

[0072]

[0084] Amino acid side chain refers to the amino acid side chain of a natural, synthetic, non-natural, or non-proteinogenic amino acid, examples of which include arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, lanthionine, selenocysteine, pyrrolidine, ADDA amino acids ((2S,3S,4E,6E,8S,9S)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldec-4,6-dienoic acid), β-alanine, 4-aminobenzoic acid, γ-amino These include butyric acid, S-aminoethyl-L-cysteine, 2-aminoisobutyric acid, aminolevulinic acid, azetidine-2-carboxylic acid, canaline, canavanine, carboxyglutamic acid, chloroalanine, cystine, dehydroalanine, diaminopimelic acid, dihydroxyphenylglycine, endouracidine, homoserine, 4-phenylglycine, hydroxyproline, hypusine, β-leucine, norleucine, norvaline, ornithine, penicillamine, placohipaphorin, pyroglutamic acid, quisqualic acid, sarcosine, theanine, tranexamic acid, tricolominic acid, and 3,4-dihydroxyphenylalanine. In particular, glutamic acid, valine, alanine, lysine, 3,4-dihydroxyphenylalanine, and tyrosine are preferred.

[0073]

[0085] As used herein, the amino acid side chains of the present invention can be substituted, for example, -P(O)(OR 6 ) 2 (In the formula, R 6is hydrogen, alkyl, etc.), glucosyl groups (e.g., [(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl], etc.), and groups which bond to an adjacent group to form an alkylene group which can be substituted (examples of the substituents include alkyl groups, alkoxy groups, etc.). Examples of substituted amino acid side chains include those in which a tyrosine side chain, a serine side chain, a threonine side chain, or an amino acid side chain bearing a hydroxyl such as, for example, (3,4-dihydroxyphenyl)methyl is substituted, specific examples of which include phosphonooxymethyl, (4-phosphonooxyphenyl)methyl, [4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxyphenyl]methyl, (2,2-dimethyl-1,3-benzodioxol-5-yl)methyl, (2-ethoxy-2-methyl-1,3-benzodioxol-5-yl)methyl, and the like.

[0074]

[0086] In the present invention, the monosaccharides from which glycosyl is generated include aldoses such as glucose (dextrose), ribose, erythrose, xylose, arabinose, mannose, galactose, and ketoses such as ribulose, psicose, fructose, sorbose, and tagatose. These monosaccharides can be of d-, l-, or dl-type. Herein, the monosaccharides in the present invention can be substituted, and examples of the substituents include carbonyl, acetylamino, sulfinoxy, and phosphonooxy groups. Specific examples of substituted monosaccharides include glucuronic acid, N-acetylglucosamine, glucopyranoside-6-(hydrogen sulfate), and the like.

[0075]

[0087] In one embodiment, the present invention provides a levodopa amino acid conjugate represented by general formula (I) or (III) or a pharma- ceutically acceptable salt thereof: [Chemical formula 1]

[0076] [ka]

[0077] wherein R is an amino acid side chain that can be substituted; R 1 and R 2 may be the same or different, and each independently represents a hydrogen atom, C 1 ~C 6 Alkyl, C 1 ~C 6 alkanoyl, phosphono, sulfino, or optionally substituted glycosyl, provided that R 1 and R 2 is not a hydrogen atom at the same time; R 3 and R 4 may be the same or different, and each independently represents a hydrogen atom or C 1 ~C 6 is alkyl; R 5 is a hydrogen atom, or [Chemical formula 3]

[0078] [ka]

[0079] [In the formula, R 11 and R 12 are the same or different and are hydrogen, alkyl, alkanoyl, P(=O)(OH), 2 , S(═O)(OH) or optionally substituted glycosyl; R 13 is optionally substituted alkyl, -R 15 -OR 16 or a 5-membered heterocyclyl containing at least one nitrogen atom, R 15 is alkylene, and R 16 is hydrogen, alkyl, P(=O)(OH) 2 , S(═O)(OH), or glycosyl which may be substituted; R 14 is hydrogen or alkyl; However, the following compounds: (2S)-2-[(2-aminoacetyl)amino]-3-(3,4-diacetyloxyphenyl)propanoic acid, (2S)-2-[[(2S)-2-amino-6-[(2-chlorophenyl)methoxycarbonylamino]hexanoyl]amino]-3-(3,4-dimethoxyphenyl)propanoic acid, (2S)-2-[[(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl]amino]-3-(4-hydroxy-3-methoxyphenyl)propanoic acid, (2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-3-(3,4-dimethoxyphenyl)propanoic acid, (2S)-2-[[(2R)-2-amino-3-phenylpropanoyl]amino]-3-(3,4-diacetyloxyphenyl)propanoic acid, and (2S)-2-[[(2S)-2-amino-5-methoxy-5-oxopentanoyl]amino]-3-(3,4-dimethoxyphenyl)propanoic acid [Excluding] is included.

[0080]

[0088] When the compound (I) or (III) of the present invention has an asymmetric carbon atom in its molecule, stereoisomers (optical isomers, diastereoisomers) based on the asymmetric carbon atom may exist. The compound (I) or (III) of the present invention includes any one of these stereoisomers and a mixture thereof.

[0081]

[0089] The compounds (I) or (III) of the present invention include compounds labeled with isotopes (e.g., 3H, 13C, 14C, 15N, 18F, 32P, 35S, 125I, etc.), including deuterium conversion compounds.

[0082]

[0090] Compound (I) or (III) of the present invention can be used for pharmaceutical purposes in either free form or in the form of a pharma- ceutically acceptable salt or co-crystal form. Examples of the pharmacologically acceptable salt of compound (I) or (III) of the present invention include inorganic acid addition salts (e.g., salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), organic acid addition salts (e.g., salts of methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid, methylsulfuric acid, etc.), inorganic base addition salts (sodium salt, potassium salt, calcium salt, magnesium salt, etc.), amino acid salts (salts of glutamic acid, aspartic acid, arginine, lysine, etc.), etc.

[0083]

[0091] The compound (I) or (III) of the present invention or a pharmacologically acceptable salt thereof includes any of their intramolecular salts or adducts, their solvates or hydrates, and the like.

[0084]

[0092] The compound (I) or (III) of the present invention or its pharmaceutically acceptable salt can be administered orally or parenterally, either alone or as a pharmaceutical composition comprising compound (I) or (III) or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.The pharmaceutically acceptable carrier can be the carrier commonly used in the art, and examples thereof include diluents, binders (e.g., syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, etc.), excipients (e.g., lactose, sucrose, corn starch, potassium phosphate, sorbitol, glycine, etc.), lubricants (e.g., magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrants (e.g., potassium starch, etc.), wetting agents (e.g., sodium lauryl sulfate, etc.), etc. Furthermore, when preparing a liquid pharmaceutical composition, for example, an injection or infusion, a carrier generally used in the art can be used, and examples thereof include aqueous solvents (e.g., water for injection, purified water, etc.), isotonic agents (e.g., sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borax, glucose, propylene glycol, etc.), buffer solutions (e.g., phosphate buffer, acetate buffer, borate buffer, carbonate buffer, citrate buffer, Tris buffer, glutamate buffer, ε-aminocaproic acid buffer, etc.), preservatives (e.g., methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, benzalkonium chloride, sodium dehydroacetate, sodium edetate, etc.), and the like. sodium, boric acid, and borax, etc.), soothing agents (e.g., lidocaine hydrochloride, procaine hydrochloride, benzyl alcohol, and chlorobutanol, etc.), thickening agents (e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyethylene glycol, etc.), stabilizers (e.g., sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid, and dibutylhydroxytoluene, etc.), pH adjusting agents (e.g., hydrochloric acid, sodium hydroxide, phosphoric acid, and acetic acid, etc.), and the like.The liquid pharmaceutical composition can be prepared by dissolving or dispersing the compound of the present invention described above in a solution to which these carriers are appropriately added. Such pharma-ceutically acceptable additives can be appropriately selected by those skilled in the art according to the purpose, and conditions such as the amount of addition can also be appropriately set. Furthermore, if necessary, a solubilizer, etc. may be used.

[0085]

[0093] The dosage form of such a pharmaceutical composition is not particularly limited, and examples thereof include conventional pharmaceutical formulations such as tablets, granules, capsules, powders, injections, inhalants, and suppositories. In particular, a liquid pharmaceutical composition containing an injection can be used.

[0086]

[0094] The compound (I) or (III) of the present invention or its pharma- ceutically acceptable salt can be formulated in the form of a liquid pharmaceutical composition, for example, as a formulation applicable to all suitable routes of administration by parenteral administration, such as bolus administration, continuous administration or continuous administration. In particular, the liquid pharmaceutical composition containing the compound of the present invention can be formulated for subcutaneous administration, transdermal administration, intradermal administration, transmucosal administration, intravenous administration, intraarterial administration, intramuscular administration, intraperitoneal administration, intratracheal administration, intrathecal administration, intraduodenal administration, intrapleural administration, intranasal administration, sublingual administration, buccal administration, buccal administration, intraintestinal administration, intraduodenal administration, rectal administration, intraocular administration or oral administration. In addition, the composition can also be formulated for inhalation or direct absorption through mucosal tissue.

[0087]

[0095] The dosage of the compound (I) or (III) of the present invention or a pharma- ceutically acceptable salt thereof varies depending on the administration method, the age, weight, condition, etc. of the patient. However, when administered as a liquid pharmaceutical composition, it is usually 1 to 200 mg / kg per day.

[0088]

[0096] The compound (I) or (III) of the present invention or a pharma- ceutically acceptable salt thereof can be used alone or in combination with one or more other therapeutic agents depending on the disease to be treated (e.g., Parkinson's disease). Such therapeutic agents can be, for example, one or more agents selected from the group consisting of dopamine decarboxylase inhibitors (e.g., carbidopa and benserazide), catechol-O-methyltransferase ("COMT") inhibitors (e.g., entacapone and tolcapone), and monoamine oxidase A ("MAO-A") or monoamine oxidase B ("MAO-B") inhibitors (e.g., moclobemide, rasagiline, selegiline, and safinamide).

[0089]

[0097] The compound (I) or (III) of the present invention or its pharmaceutically acceptable salt can be administered simultaneously with the above-mentioned therapeutic agent, which can be used in combination or can be administered separately.Furthermore, when the compound of the present invention is used therapeutically together with the above-mentioned therapeutic agent, which can be used in combination, the compound of the present invention and the therapeutic agent can be administered in the same dosage form, such as parenteral administration, or in different dosage forms, such as one being parenteral administration and the other being oral administration.

[0090]

[0098] Preferred embodiments of the present invention are shown in the table below.

[0091] [Table 1]

[0092]

[0099] The compounds of the present invention or pharma- ceutically acceptable salts thereof can be prepared, for example, as follows.

[0100] General synthesis method (A)

[0093] [ka]

[0094] [In the formula, Bn represents benzyl, Cbz represents carbobenzoxy, and the other symbols have the same meanings as above].

[0101] Among the target compounds [I] of the present invention, the compound represented by the general formula [Ia] can be produced, for example, as follows: Compound [a-1] and compound [b-1] or compound [b-2] are subjected to a condensation reaction to obtain compound [c], and then compound [c] is subjected to phosphite esterification and oxidation, or to phosphate esterification, thereby obtaining compound [f]. On the other hand, compound [f] can also be obtained by condensing compound [e] and compound [b-1] or compound [b-2]. Compound [Ia] can be produced by subjecting the compound [f] thus obtained to deprotection or hydrolysis and then deprotection.

[0095] Step 1

[0102] The condensation of compound [a-1] with compound [b-1] or its salt or [b-2] can be carried out in the presence or absence of a base, in the presence or absence of a condensing agent, and in the presence or absence of an activating agent in a suitable solvent according to a conventional method. Any solvent that does not affect the reaction can be used as the solvent. Examples of the solvent include ethers, such as tetrahydrofuran and 1,4-dioxane; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; nitriles, such as acetonitrile; halogenated aliphatic hydrocarbons, such as chloroform and dichloromethane; aromatic hydrocarbons, such as toluene; or a mixture of these compounds. Examples of the base include triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and the like. Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, etc. Examples of the activating agent include 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), 4-dimethylaminopyridine, etc.

[0096]

[0103] The amount of the compound [b-1] or [b-2] to be used may be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in terms of molar ratio to the compound [a-1].

[0097]

[0104] The amount of the base to be used may be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in terms of molar ratio to the compound [a-1].

[0105] The amount of the condensing agent to be used may be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, in terms of molar ratio to the compound [a-1].

[0098]

[0106] The amount of the activator to be used may be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, in terms of molar ratio to the compound [a-1].

[0107] This reaction can be carried out at room temperature or under heating, for example, at room temperature to 80°C, preferably at room temperature to 50°C.

[0099] Step 2

[0108] The condensation of compound [c] and a phosphite esterifying agent can be carried out in a suitable solvent in the presence of an activating agent according to a conventional method. Any solvent that does not affect the reaction can be used as the solvent. Examples of the solvent include nitriles, such as acetonitrile; halogenated aliphatic hydrocarbons, such as chloroform and dichloromethane; or a mixture of these compounds. An example of the phosphite esterifying agent is dibenzyl N,N-diisopropyl phosphoramidite. An example of the activating agent is 1-tetrazole.

[0100]

[0109] The amount of the phosphite esterifying agent to be used may be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in terms of molar ratio to the compound [c].

[0110] The amount of the activating agent to be used may be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in terms of molar ratio to the compound [c].

[0101]

[0111] This reaction can be carried out under ice-cooling or heating, for example, at 0°C to 80°C, preferably at room temperature to 50°C. Step 3

[0112] The oxidation of compound [d] can be carried out in the presence of an oxidizing agent in a suitable solvent according to a conventional method. Any solvent that does not affect the reaction can be used as the solvent. Examples of the solvent include nitriles, such as acetonitrile; halogenated aliphatic hydrocarbons, such as chloroform and dichloromethane; or a mixture of these compounds. Examples of the oxidizing agent include hydrogen peroxide solution, tert-butyl hydroperoxide, metachloroperbenzoic acid, and the like.

[0102]

[0113] The amount of the oxidizing agent to be used may be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in terms of molar ratio to the compound [d].

[0114] This reaction can be carried out under ice-cooling or heating, for example, at 0°C to 80°C, preferably at room temperature to 50°C.

[0103] Step 4

[0115] The condensation of compound [c] and a phosphorylating agent can be carried out in a suitable solvent in the presence or absence of a base according to a conventional method. Any solvent that does not affect the reaction can be used as the solvent. Examples of the solvent include nitriles, such as acetonitrile; halogenated aliphatic hydrocarbons, such as chloroform and dichloromethane; or a mixture of these compounds. Examples of the phosphorylating agent include dibenzyl phosphoryl chloride, tetrabenzyl pyrophosphate, and the like. Examples of the base include alkali metal alkoxides, such as sodium t-butoxide and potassium t-butoxide; alkylamines, such as triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene, and the like.

[0104]

[0116] The amount of the phosphating agent to be used may be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in terms of molar ratio to the compound [c].

[0117] The amount of the base to be used may be 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, in terms of molar ratio to the compound [c].

[0105]

[0118] This reaction can be carried out at room temperature or under heating, for example, at room temperature to 100°C, preferably at room temperature to 70°C. Step 5

[0119] The condensation of compound [e] and compound [b-1] or its salt or [b-2] can be carried out in the same manner as the condensation of compound [a-1] and compound [b-1] or its salt or [b-2] in general synthetic method (A).

[0106] Step 6

[0120] The deprotection of compound [f] can be carried out in a conventional manner by treating with a catalyst in a suitable solvent under a hydrogen atmosphere.

[0107]

[0121] As the solvent, any solvent that does not affect the reaction can be used. Examples of the solvent include ethers, such as tetrahydrofuran and 1,4-dioxane, alcohols, such as methanol, ethanol and isopropanol, water, or a mixture of these compounds.

[0108]

[0122] Examples of catalysts include palladium on carbon and the like.

[0123] This reaction can be carried out at room temperature or under heating, for example, at room temperature to 80°C, preferably at room temperature to 50°C.

[0109] Step 7

[0124] The hydrolysis of compound [g] can be carried out in the presence of a base and water in a suitable solvent according to a conventional method. Any solvent that does not affect the reaction can be used. Examples of the solvent include alcohols such as methanol, ethanol, and isopropanol; ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; water; or a mixture thereof. Examples of the base include alkali metal hydroxides such as sodium hydroxide and lithium hydroxide.

[0110]

[0125] This reaction can be carried out under ice-cooling or heating, for example, at 0° C. to 50° C., preferably at room temperature.

[0126] The amount of the base to be used may be 1.0 to 10.0 equivalents, preferably 1.0 to 4.0 equivalents, relative to the compound [g].

[0111] Step 8

[0127] The deprotection of compound [g] can be carried out in the same manner as the deprotection of compound [f] in the general synthesis method (A).

[0112]

[0128] General synthesis method (B)

[0113] [ka]

[0114] [wherein the symbols have the same meanings as above]

[0129] Among the target compounds [I] of the present invention, the compound represented by the general formula [Ib] can be produced, for example, as follows: Compound [a-2] and compound [b-3] are subjected to a condensation reaction to obtain compound [h], and then compound [h] is subjected to phosphite esterification and oxidation, or phosphite esterification, thereby obtaining compound [J]. Compound [Ib] can be produced by deprotecting compound [j].

[0115] Step 1

[0130] The condensation of compound [a-2] and compound [b-3] or a salt thereof can be carried out in the same manner as the condensation of compound [a-1] and compound [b-1] or a salt thereof in general synthetic method (A).

[0116] Step 2

[0131] The condensation of compound [h] with a phosphite esterifying agent can be carried out in the same manner as the condensation of compound [c] with a phosphite esterifying agent in general synthesis method (A).

[0117] Step 3

[0132] The oxidation of compound [i] can be carried out in the same manner as the oxidation of compound [d] in general synthesis method (A).

[0118] Step 4

[0133] The condensation of compound [h] with a phosphating agent can be carried out in the same manner as the condensation of compound [c] with a phosphating agent in general synthesis method (A).

[0119] Step 5

[0134] The deprotection of compound [j] can be carried out in the same manner as the deprotection of compound [f] in general synthesis method (A).

[0120]

[0135] General synthesis method (C)

[0121] [ka]

[0122] [wherein Ac represents acetyl, and the other symbols have the same meanings as above]

[0136] Among the target compounds [I] of the present invention, the compound represented by the general formula [Ic] can be produced, for example, as follows: Compound [a-3] and compound [b-1] are subjected to a condensation reaction to obtain compound [k], which is then subjected to deprotection to produce compound [Ic].

[0123] Step 1

[0137] The condensation of compound [a-3] and compound [b-1] or a salt thereof can be carried out in the same manner as the condensation of compound [a-1] and compound [b-1] or a salt thereof in general synthetic method (A).

[0124] Step 2

[0138] The deprotection of compound [k] can be carried out in the same manner as the deprotection of compound [f] in general synthesis method (A).

[0125]

[0139] General synthesis method (D)

[0126] [ka]

[0127] [wherein the symbols have the same meanings as above]

[0140] Among the target compounds [I] of the present invention, the compound represented by the general formula [Id] can be produced, for example, as follows: Compound [a-2] and compound [b-1] are subjected to a condensation reaction to obtain compound [l], which is then subjected to deprotection to produce compound [Id].

[0128] Step 1

[0141] The condensation of compound [a-2] and compound [b-1] or a salt thereof can be carried out in the same manner as the condensation of compound [a-1] and compound [b-1] or a salt thereof in general synthetic method (A).

[0129] Step 2

[0142] The deprotection of compound [l] can be carried out in the same manner as the deprotection of compound [f] in the general synthesis method (A).

[0130]

[0143] The starting compounds in the above processes can be produced by known methods and / or methods similar to those described in the Examples below.

[0144] Introduction of a protecting group into a functional group and removal of a protecting group from a functional group can be carried out with reference to known methods (such as PROTECTIVE GROUPS in ORGANIC SYNTHESIS (Theodora W. Greene, Peter GMWuts)).

[0131]

[0145] The compound of the present invention or the starting compound produced as described above is isolated and purified in its free form or as its salt. The salt can be produced by a commonly used salt preparation process. Isolation and purification can be carried out by applying conventional chemical procedures such as extraction, concentration, crystallization, filtration, recrystallization, and various types of chromatography.

[0132]

[0146] When the compound of the present invention or a pharma- ceutical acceptable salt thereof exists as an optical isomer based on asymmetric carbon atom, it can be separated into individual optical isomers by conventional optical resolution means (e.g., fractional crystallization and separation using chiral column).In addition, optical isomers can be synthesized using optically pure starting materials.In addition, optical isomers can be synthesized by stereoselectively carrying out each reaction using an asymmetric auxiliary or an asymmetric catalyst.

[0133]

[0147] The compounds of the present invention or pharma- ceutically acceptable salts thereof are useful for the prevention or treatment of neurodegenerative diseases and / or diseases or conditions caused by decreased dopamine concentration in the brain. In particular, the compounds of the present invention and combination medicaments are useful for the prevention or treatment of Parkinson's disease, secondary parkinsonism, Huntington's disease, parkinsonian syndrome, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), Shy-Drager syndrome, dystonia, Alzheimer's disease, dementia with Lewy bodies (LBD), akinesia, bradykinesia and hypokinesia, preferably for the prevention or treatment of Parkinson's disease. Furthermore, the compounds of the present invention and combination medicaments are useful for the prevention or treatment of diseases or conditions caused by brain damage, including carbon monoxide poisoning or manganese poisoning, or diseases or conditions associated with neurological diseases or neurological disorders, including alcoholism, drug addiction or erectile dysfunction.

[0134] II. Stable LD-Tyr formulations

[0148] An embodiment of the present invention is a compound of formula (II):

[0135] [ka]

[0136] The present invention is directed to a liquid pharmaceutical composition comprising a levodopa-tyrosine conjugate of the formula (I), an enantiomer, a diastereomer, a racemate, an ion, a zwitterion, a pharma- ceutically acceptable salt thereof, or any combination thereof, and a stabilizer.

[0137]

[0149] According to some embodiments, the liquid pharmaceutical composition comprises the LD-Tyr compound in the form of a pharma- ceutically acceptable salt. According to some embodiments, the LD-Tyr salt is a trifluoroacetic acid (TFA) salt, an HCl salt, a fumarate salt, a lactate salt, a maleate salt, a gluceptic acid salt, or the like. salt), phosphate, sulfate, Hbr salt, nitrate, acetate, propionate, hexanoate, cyclopentanepropionate, glycolate, pyruvate, lactate, hippurate, methanesulfonate, ascorbate, malonate, oxalate, maleate, tartrate, citrate, succinate, benzoate, cinnamate, sulfonate, lauryl sulfate, gluconate, glutamate, hydroxynaphthoate, salicylate, stearate, muconate, alkali metal salts, for example the lithium salt, sodium salt or potassium salt, alkaline earth metal salts, for example the calcium salt or magnesium salt, aluminium salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, N-methylglucamine salt, dicyclohexylamine salt, adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, borate, butyrate, camphorate butyrate salt, camphorsulfonate butyrate salt, digluconate butyrate salt, dodecylsulfate butyrate salt, ethanesulfonate butyrate salt, glucoheptonate butyrate salt, glycerophosphate butyrate salt, gluconate butyrate salt, hemisulfate butyrate salt, heptanoate butyrate salt, hydroiodide butyrate, 2-hydroxyethanesulfonate butyratesalt, lactobionate butyrate salt, laurate butyrate salt, methanesulfonate butyrate salt, 2-naphthalenesulfonate butyrate salt, nicotinate butyrate salt, oleate butyrate salt, palmitate butyrate salt, pamoate butyrate salt, pectinate butyrate salt, persulfate butyrate salt, 3-phenylpropionate butyrate salt, phosphate butyrate salt, picrate butyrate salt, pivalate butyrate salt, tartrate butyrate salt, thiocyanate butyrate salt, p-toluenesulfonate butyrate salt, undecanoate butyrate salt, valerate salt, or any combination thereof.

[0138]

[0150] The liquid pharmaceutical composition of the present invention can contain between about 2.5 and about 70% w / v of the LD-Tyr compound, enantiomer, diastereomer, racemate, ion, zwitterion, pharma- ceutically acceptable salt thereof, or any combination thereof, or any combination of two or more LD-Tyr enantiomers, diastereomers, racemates, ions, zwitterions, pharma- ceutically acceptable salts thereof, or any combination thereof.According to some embodiments, the liquid pharmaceutical composition may be at least about 30%, at least about 30%, at least about 30% w / v, ... between about 30 and about 70% w / v, between about 40 and about 45% w / v, between about 45 and about 50% w / v, between about 50 and about 55% w / v, between about 55 and about 60% w / v, between about 60 and about 65% w / v, between about 65 and about 70% w / v, between about 10 and about 12.5% ​​w / v, between about 12.5 and about 17.5% w / v, between about 17.5 and about 22.5% w / v, between about 22.5 and about 27.5% w / v, between about 27.5 and about 32.5% w / v, between about 32.5 and about 37.5% w / v between about 37.5 and about 42.5% w / v, between about 42.5 and about 45% w / v, about 10% w / v, about 12.5% ​​w / v, about 15% w / v, about 17.5% w / v, about 20% w / v, about 22.5% w / v, about 25% w / v, about 27.5% w / v, about 30% w / v, about 32.5% w / v, about 35% w / v, about 37.5% w / v, about 40% w / v, about 42.5% w / v, about 45% w / v, about 47.5% w / v, about 50% w / v, about 52.5% w / v, about 55% w / v v, about 57.5% w / v, about 60% w / v, about 62.5% w / v, about 65% w / v, about 67.5% w / v, about 70% w / v of the LD-Tyr compound, enantiomer, diastereomer, racemate, ion, zwitterion, pharma- ceutically acceptable salt thereof, or any combination thereof, or any combination of two or more LD-Tyr enantiomers, diastereomers, racemates, ions, zwitterions, pharma- ceutically acceptable salts thereof, or any combination thereof.

[0139]

[0151] The liquid formulations described herein include stabilizers that prevent or retard precipitation of the formulation and / or prevent or retard accumulation of impurities in the formulation. LD-Tyr has a tendency to form diketopiperazine (DKP) impurities, as shown in the following scheme:

[0140] [ka]

[0141]

[0152] Thus, in certain embodiments, the stabilizers described herein are added to or included in the liquid pharmaceutical composition to prevent the formation of diketopiperazines. Thus, in certain embodiments, the liquid pharmaceutical composition contains less than about 1.5% w / v LD-Tyr-diketopiperazine (LD-Tyr DKP) after 2 weeks at 2-8° C. In certain embodiments, the liquid pharmaceutical composition contains less than about 0.8% w / v LD-Tyr-diketopiperazine after 2 weeks at 2-8° C. For example, the liquid pharmaceutical composition can contain about 0.8% w / v, 0.7% w / v, 0.6% w / v, 0.5% w / v, 0.4% w / v, 0.3% w / v, 0.2% w / v, or 0.1% w / v LD-Tyr-diketopiperazine after 2 weeks at 2-8° C. In certain embodiments, the liquid pharmaceutical composition comprises less than about 4.0% w / v of LD-Tyr-diketopiperazine after 2 weeks at 25° C. For example, the liquid pharmaceutical composition can comprise less than about 5.0% w / v, 4.5% w / v, 4.0% w / v, 3.5% w / v, 3.0% w / v, 2.5% w / v, 2.0% w / v, 1.5% w / v, or 1.0% w / v of LD-Tyr-diketopiperazine after 2 weeks at 25° C. In certain embodiments, the liquid pharmaceutical composition comprises less than about 4.0% w / v of LD-Tyr-diketopiperazine after 2 weeks at 25° C. Methods for measuring DKP are known in the art and include, for example, high performance liquid chromatography (HPLC) and liquid chromatography mass spectrometry (LC-MS).

[0142]

[0153] In certain embodiments, the liquid pharmaceutical composition comprises between about 0.1% and about 30% w / v of a stabilizer, hi certain embodiments, the liquid pharmaceutical composition comprises between about 1.5 and about 20% w / v of a stabilizer. For example, the liquid pharmaceutical composition may be about 1.5 to about 5.0%, about 1.5 to about 10.0% w / v, about 1.5 to about 15.0% w / v, about 1.5 to about 20.0% w / v, about 1.5 to about 25.0% w / v, about 3.0 to about 5.0% w / v, about 3.0 to about 10.0% w / v, about 3.0 to about 15.0% w / v, about 3.0 to about 20.0% w / v, about 3 to about 25.0% w / v, about 3.0 to about 30.0% w / v, about 5.0 to about 10.0% w / v, about 5 to about 15.0% w / v, about 5.0 to about 20.0% w / v, about 5.0 to about 25 The stabilizer may be between about 0.0% w / v, about 5.0 to about 30.0% w / v, about 7.0 to about 10.0% w / v, about 7.0 to about 15.0% w / v, about 7.0 to about 20.0% w / v, about 7.0 to about 25.0% w / v, about 7.0 to about 30.0% w / v, about 10.0 to about 15.0% w / v, about 10.0 to about 20.0% w / v, about 10 to about 25.0% w / v, about 10.0 to about 30.0% w / v, about 15.0 to about 20.0% w / v, about 15.0 to about 25.0% w / v, or about 15.0 to about 30.0% w / v. In certain embodiments, the liquid pharmaceutical composition comprises a combination of two, three, or four stabilizers, each individual stabilizer being present in the amounts described above, or the combination of stabilizers being present in the amounts described above.

[0143]

[0154] According to certain embodiments, the stabilizer comprises a base. In other embodiments, the liquid pharmaceutical composition comprises a stabilizer and further comprises a base, for example to provide the composition with a predefined pH. According to some embodiments, the base is NaOH, NH 4 OH, Ca(OH) 2, ammonium hydroxide, arginine, magnesium hydroxide, potassium hydroxide, meglumine, tromethamine (TRIS), triethylamine, ethylenediamine, diethylamine, ethanolamine, diisopropylethylamine, diazabicycloundecene, or any combination thereof. The liquid pharmaceutical composition can contain between about 0.1 and about 30.0% w / v base. According to some embodiments, the liquid pharmaceutical composition may be between about 0.1 and about 1.0% w / v, between about 1.0 and about 2.0% w / v, between about 2.0 and about 3.0% w / v, between about 3.0 and about 4.0% w / v, between about 4.0 and about 5.0% w / v, between about 5.0 and about 6.0% w / v, between about 6.0 and about 7.0% w / v, between about 8.0 and about 9.0% w / v, between about 9.0 and about 10.0% w / v, between about 10.0 and about 11.0% w / v, between about 11.0 and about 12.0% w / v, between about 12.0 and about 13.0% w / v, between about 13.0 and about 14.0% w / v, between about 14.0 and about 15.0% w / v, between about 15.0 and about 16. between about 16.0 and about 17.0% w / v, between about 17.0 and about 18.0% w / v, between about 18.0 and about 19.0% w / v, between about 19.0 and about 20.0% w / v, between about 20.0 and about 21.0% w / v, between about 21.0 and about 22.0% w / v, between about 22.0 and about 23.0% w / v between about 23.0 and about 24.0% w / v, between about 24.0 and about 25.0% w / v, between about 25.0 and about 26.0% w / v, between about 26.0 and about 27.0% w / v, between about 27.0 and about 28.0% w / v, between about 28.0 and about 29.0% w / v, between about 29.0 and about 30.0% w / v of a base.

[0144]

[0155] In certain embodiments, the stabilizer is arginine, NaOH, NH 4 OH, tris(hydroxymethyl)aminomethane (TRIS), ethylenediamine, diethylamine, ethanolamine, diethanolamine, meglumine, triethanolamine, and any combination thereof. In certain embodiments, the base is arginine, NH 4In certain embodiments, the base is selected from the group consisting of L-Arg, diethylamine, ethanolamine, diethanolamine, meglumine, and combinations thereof. In certain embodiments, the base is selected from the group consisting of L-Arg, diethylamine, and combinations thereof. In certain embodiments, the base is selected from the group consisting of L-Arg, ethanolamine, and combinations thereof. In some embodiments, the liquid pharmaceutical composition comprises between about 0.1% w / v and about 30.0% w / v of a base. In some embodiments, the liquid pharmaceutical composition comprises between about 1.5% and about 20.0% w / v of a base. For example, the liquid pharmaceutical composition may be between about 1.5 to about 5.0% w / v, between about 1.5 to about 10.0% w / v, between about 1.5 to about 15.0% w / v, between about 1.5 to about 20.0% w / v, between about 1.5 to about 25.0% w / v, between about 3.0 to about 5.0% w / v, between about 3.0 to about 10.0% w / v, between about 3.0 to about 15.0% w / v, between about 3.0 to about 20.0% w / v, between about 3.0 to about 25.0% w / v, between about 3.0 to about 30.0% w / v, between about 5.0 to about 10.0% w / v, between about 5.0 to about 15.0% w / v, between about 5.0 to about 20.0% w / v, between about 5.0 to about 25.0% w / v, between about 5.0 to about 30.0% w / v, between about 7.0 to about 10.0% w / v, between about 7.0 to about 15.0% w / v, between about 7.0 to about 20.0% w / v, between about 7.0 to about 25.0% w / v, between about 7.0 to about 30.0% w / v, between about 10.0 to about 15.0% w / v, between about 10.0 to about 20.0% w / v, between about 10.0 to about 25.0% w / v, between about 10.0 to about 30.0% w / v, between about 15.0 to about 20.0% w / v, between about 15.0 to about 25.0% w / v, between about 15.0 to about 30.0% w / v. In certain embodiments, the liquid pharmaceutical composition comprises a combination of two, three, or four stabilizers. For example, in certain embodiments, the liquid pharmaceutical composition comprises arginine, NH 4The formulation comprises an additional base selected from the group consisting of OH, ethylenediamine, diethylamine, ethanolamine, diethanolamine, and meglumine. In certain embodiments, each individual stabilizer is present in the amount previously described, or the combination of stabilizers is present in the amounts previously described. In certain embodiments, arginine is present in an amount of about 7.0 to about 8.0% w / v, and the additional base is present in an amount of about 3.0 to about 8.0% w / v. In certain embodiments, the formulation comprises about 7.0 to about 8.0% (e.g., 7.2%) w / v L-Arg and about 3.0 to about 8.0% (e.g., about 5.4%) w / v diethylamine. In certain embodiments, the formulation comprises about 7.0 to about 8.0% (e.g., 7.2%) w / v L-Arg and about 2.0 to about 7.0% (e.g., about 4.5%) w / v ethanolamine.

[0145]

[0156] In certain embodiments, stabilizers include polyethylene glycol (e.g., PEG-300, PEG-400, PEG-600), propylene glycol, choline, sodium or ammonium ions, amino acids (e.g., Lys or His), benzyl alcohol, ethanol, Group IIA metal complexes (e.g., CaCl 2 and Ca, such as Ca ascorbate 2+ salts), citric acid, lactic acid, or acetic acid, electrophiles (e.g. Lewis acids, e.g. Na + , K + , Ca2 + , boron compounds, Fe 3+ , Al 3+ , Cu 2+ and α-β unsaturated carbonyls, e.g., maleic acid, etc.), phosphate buffer, Zn 2+ions, reducing sugars such as glucose, sodium acetate, hydroxypropyl beta cyclodextrin, soluble beta cyclodextrin, medium chain triglycerides such as octanoic acid, mixed micelles of glycocholic acid / lecithin, N-methylpyrrolidone, dimethylacetamide, soybean oil, sesame oil, castor oil, dimethylsulfoxide, glycerin, Tris buffer, ammonium acetate, or guanidine HCl. In certain embodiments, the stabilizer includes surfactants such as those described herein, such as poloxamer, Tween-80, Tween-20, and Kolliphor.

[0146]

[0157] According to some embodiments, the liquid pharmaceutical composition further comprises an acid, for example, to provide the composition with a predefined pH. According to some embodiments, the acid is selected from HCl, HBr, methanesulfonic acid, ascorbic acid, acetic acid, citric acid, or any combination thereof. The liquid pharmaceutical composition can comprise between about 0.1 and about 30.0% w / v acid. According to some embodiments, the liquid pharmaceutical composition may be between about 0.1 and about 1.0% w / v, between about 1.0 and about 2.0% w / v, between about 2.0 and about 3.0% w / v, between about 3.0 and about 4.0% w / v, between about 4.0 and about 5.0% w / v, between about 5.0 and about 6.0% w / v, between about 6.0 and about 7.0% w / v, between about 8.0 and about 9.0% w / v, between about 9.0 and about 10.0% w / v, between about 10.0 and about 11.0% w / v, between about 11.0 and about 12.0% w / v, between about 12.0 and about 13.0% w / v, between about 13.0 and about 14.0% w / v, between about 14.0 and about 15.0% w / v, between about 15.0 and about 16.0% w / v, between about 16.0 and about 17.0% w / v, between about 17.0 and about 18.0% w / v, between about 18.0 and about 19.0% w / v, between about 19.0 and about 20.0% w / v, between about 20.0 and about 21.0% w / v, between about 21.0 and about 22.0% w / v, between about 22.0 and about 23.0% w / v, between about 23.0 and about 24.0% w / v, between about 24.0 and about 25.0% w / v, between about 25.0 and about 26.0% w / v, between about 26.0 and about 27.0% w / v, between about 27.0 and about 28.0% w / v, between about 2 Between 6.0% w / v, between about 16.0 and about 17.0% w / v, between about 17.0 and about 18.0% w / v, between about 18.0 and about 19.0% w / v, between about 19.0 and about 20.0% w / v, between about 20.0 and about 21.0% w / v, between about 21.0 and about 22.0% w / v, between about 22.0 and about 23.0% w / v 23.0 to about 24.0% w / v, between about 24.0 to about 25.0% w / v, between about 25.0 to about 26.0% w / v, between about 26.0 to about 27.0% w / v, between about 27.0 to about 28.0% w / v, between about 28.0 to about 29.0% w / v, between about 29.0 to about 30.0% w / v.

[0147]

[0158] The pH of the liquid pharmaceutical composition of the present invention may be between about 4.5 and about 10 at about 25°C. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 4.5 and about 5 at about 25°C. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 5 and about 6 at about 25°C. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 6 and about 7 at about 25°C. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 7 and about 8 at about 25°C. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 8 and about 9 at about 25°C. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 9 and about 10 at about 25°C. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 4.5 and about 5.5 at about 25°C. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 5.5 and about 6.5 at about 25°C. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 6.5 and about 7.5 at about 25° C. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 7.5 and about 8.5 at about 25° C. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 8.5 and about 9.5 at about 25° C. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 9.5 and about 10 at about 25° C.

[0148]

[0159] According to some embodiments, the liquid pharmaceutical composition further comprises a decarboxylase inhibitor. According to some embodiments, the decarboxylase inhibitor is selected from carbidopa, benserazide, methyldopa, 3',4',5,7-tetrahydroxy-8-methoxyisoflavone, α-difluoromethyl-dopa, or any combination thereof. According to some embodiments, the decarboxylase inhibitor is carbidopa.

[0149]

[0160] Liquid pharmaceutical compositions of the present invention can contain between about 0.25 and about 3.0% w / v of a decarboxylase inhibitor, such as carbidopa. According to some embodiments, the liquid pharmaceutical composition may be between about 0.25 to about 0.5% w / v, between about 0.5 to about 0.75% w / v, between about 0.75 to about 1.0% w / v, between about 1.0 to about 1.25% w / v, between about 1.25 to about 1.5% w / v, between about 1.5 to about 1.75% w / v, between about 1.75 to about 2.0% w / v, between about 2.0 to about 2.25% w / v, between about 2.25 to about 2.5% w / v, between about 2.5 to about 2.75% w / v, between about 2.75 to about 3.0% w / v, between about 0.5 to about 1.0% w / v, between about 1.0 to about 1.5% w / v, between about 0.75 to about 1.4% w / v, Between about 0.6 and about 0.9% w / v, between about 0.7 and about 0.8% w / v, about 0.5% w / v, about 0.55% w / v, about 0.6% w / v, about 0.65% w / v, about 0.7% w / v, about 0.75% w / v, about 0.8% w / v, about 0.85% w / v, about 0.9% w / v, about 0.95% w / v, about 1. 0% w / v, about 1.05% w / v, about 1.1% w / v, about 1.15% w / v, about 1.2% w / v, about 1.25% w / v, about 1.3% w / v, about 1.35% w / v, about 1.4% w / v, about 1.45% w / v, about 1.5% w / v of a decarboxylase inhibitor, such as carbidopa.

[0150]

[0161] According to some embodiments, the stabilizer comprises a buffer. According to some embodiments, the liquid pharmaceutical composition comprises a stabilizer and further comprises a buffer. According to some embodiments, the buffer is selected from citrate buffer, citrate buffer, sodium acetate buffer, acetate buffer, tartrate buffer, phosphate buffer, succinate buffer, Tris buffer, glycine buffer, hydrochloric acid buffer, potassium hydrogen phthalate buffer, sodium buffer, citrate sodium tartrate buffer, sodium hydroxide buffer, sodium dihydrogen phosphate buffer, disodium hydrogen phosphate buffer, tromethamine (Tris), or any combination thereof. The liquid pharmaceutical composition can comprise between about 0.1 and about 30.0% w / v of the buffer. According to some embodiments, the liquid pharmaceutical composition comprises a buffer solution of between about 0.1 to about 1.0% w / v, between about 1.0 to about 2.0% w / v, between about 2.0 to about 3.0% w / v, between about 3.0 to about 4.0% w / v, between about 4.0 to about 5.0% w / v, between about 5.0 to about 6.0% w / v, between about 6.0 to about 7.0% w / v, between about 8.0 to about 9.0% w / v, between about 9.0 to about 10.0% w / v, between about 10.0 to about 15.0% w / v, between about 15.0 to about 20.0% w / v, between about 20.0 to about 25.0% w / v, between about 25.0 to about 30.0% w / v.

[0151]

[0162] According to some embodiments, the liquid pharmaceutical composition further comprises an antioxidant. According to some embodiments, the antioxidant is ascorbic acid or a salt thereof, cysteine, bisulfite or a salt thereof, glutathione, a tyrosinase inhibitor, a divalent cation, e.g., Cu +2 The chelating agent is selected from butylated hydroxytoluene (BHT), beta hydroxy acid (BHA) tocopherol, gentisic acid, tocopherol, tocopherol derivatives such as tocopherol acetate or tocopherol succinate, thioglycerol, or any combination thereof.

[0152]

[0163] According to some embodiments, the antioxidant is an ascorbate selected from sodium ascorbate, calcium ascorbate, potassium ascorbate, or any combination thereof. According to some embodiments, the antioxidant is cysteine ​​selected from L-cysteine, N-acetylcysteine ​​(NAC), or any combination thereof. According to some embodiments, the antioxidant is the bisulfite salt, sodium metabisulfite. According to some embodiments, the antioxidant is the tyrosinase inhibitor captopril. According to some embodiments, the antioxidant is Cu +2 It is a chelating agent and is a Na 2 -EDTA and Na 2 -EDTA-Ca, or any combination thereof.

[0153]

[0164] According to some embodiments, the antioxidant is methimazole, quercetin, arbutin, aloesin, N-acetylglucosamine, retinoic acid, alpha-tocopheryl ferulate, magnesium ascorbyl phosphate (MAP), substrate analogs such as sodium benzoate, L-phenylalanine, dimercaptosuccinic acid, D-penicillamine, trientine HCl, dimercaprol, clioquinol, sodium thiosulfate, triethylenetetramine, tetraethylenepentamine, curcumin, neocuproine, tannin, cuprizone. , a sulfite, such as sodium bisulfite or sodium metabisulfite, lipoic acid, CB4 (N-acetylCysGlyProCysamide), CB3 (N-acetylCysProCysamide), AD4 (N-acetylcysteineamide), AD6 (N-acetylGluCysGlyamide), AD7 (N-acetylCysGlyamide), vitamin E, di-tert-butylmethylphenol, tert-butyl-methoxyphenol, polyphenols, tocopherol, ubiquinone, caffeic acid, or any combination thereof.

[0154]

[0165] The liquid pharmaceutical composition of the present invention may comprise one or a combination of antioxidants at between about 0.05 to about 2.0% w / v. According to some embodiments, the liquid pharmaceutical composition may comprise between about 0.05 to about 0.1% w / v, about 0.1 to about 0.2% w / v, about 0.2 to about 0.3% w / v, about 0.3 to about 0.4% w / v, about 0.4 to about 0.5% w / v, about 0.5 to about 0.6% w / v, about 0.7 to about 0.8% w / v, about 0.8 to about 0.9% w / v, about 0.9 to about 1.0% w / v, about 1.0 to about 1.1% w / v, about 1.1 to about 1.2% w / v, about 1.2 to about 1.3% w / v, about 1.3 to about 1.4% w / v, or about 1.5 to about 1.6% w / v. , about 1.4 to about 1.5% w / v, about 1.5 to about 1.6% w / v, about 1.6 to about 1.7% w / v, about 1.7 to about 1.8% w / v, about 1.8 to about 1.9% w / v, about 1.9 to about 2.0% w / v, about 0.75% w / v, about 0.8% w / v, about 0.85% w / v, about 0.9% w / v, about 0.95% w / v, about 1.0% w / v, about 1.05% w / v, about 1.1% w / v, about 1.15% w / v, about 1.2% w / v of one or a combination of antioxidants.

[0155]

[0166] According to some embodiments, the liquid pharmaceutical composition comprises a combination of two antioxidants, each antioxidant is present in an amount between about 0% w / v and about 2% w / v, and the total amount of antioxidants is present in an amount between about 0% w / v and about 2% w / v. According to some embodiments, the liquid pharmaceutical composition comprises a combination of two antioxidants, each antioxidant is present in an amount between about 0% w / v and about 2% w / v. According to some embodiments, the liquid pharmaceutical composition comprises a combination of two antioxidants, each antioxidant is present in an amount between about 0% w / v and about 2% w / v. According to some embodiments, the liquid pharmaceutical composition comprises a combination of two antioxidants, each antioxidant is present in an amount between about 0.05 to about 0.1% w / v, about 0.1 to about 0.2% w / v, about 0.2 to about 0.3% w / v, about 0.3 to about 0.4% w / v, about 0.4 to about 0.5% w / v, about 0.5 to about 0.6% w / v, about 0.7 to about 0.8% w / v, about 0.8 to about 0.9% w / v, about 0.9 to about 1.0% w / v, about 1.0 to about 2 ... A first antioxidant between about 1.1% w / v, about 1.1 to about 1.2% w / v, about 1.2 to about 1.3% w / v, about 1.3 to about 1.4% w / v, about 1.4 to about 1.5% w / v, about 1.5 to about 1.6% w / v, about 1.6 to about 1.7% w / v, about 1.7 to about 1.8% w / v, about 1.8 to about 1.9% w / v, about 1.9 to about 2.0% w / v, and about 0.05 to about 0.5% w / v. 1%w / v, about 0.1 to about 0.2%w / v, about 0.2 to about 0.3%w / v, about 0.3 to about 0.4%w / v, about 0.4 to about 0.5%w / v, about 0.5 to about 0.6%w / v, about 0 .7~about 0.8%w / v, about 0.8~about 0.9%w / v, about 0.9~about 1.0%w / v, about 1.0~about 1.1%w / v, about 1.1~about 1.2%w / v, about 1.2~about 1.3% and a second antioxidant between about 1.3 to about 1.4% w / v, about 1.4 to about 1.5% w / v, about 1.5 to about 1.6% w / v, about 1.6 to about 1.7% w / v, about 1.7 to about 1.8% w / v, about 1.8 to about 1.9% w / v, or about 1.9 to about 2.0% w / v, and the combination of the first and second antioxidants is present in an amount of about 2% w / v or less of the liquid pharmaceutical composition. In certain embodiments, the first and second antioxidants comprise N-acetylcysteine ​​(NAC) and ascorbic acid or a salt thereof. In certain embodiments, the liquid pharmaceutical composition comprises 0, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, or about 2% NAC and 0, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, or about 2% ascorbic acid or a salt thereof, wherein the liquid pharmaceutical composition comprises no more than 2% of a combination of NAC and ascorbic acid or a salt thereof.In certain embodiments, the liquid pharmaceutical composition comprises about 1% NAC and no ascorbic acid, about 1% NAC and about 1% ascorbic acid or a salt thereof, about 2% NAC and no ascorbic acid, or about 2% ascorbic acid or a salt thereof and no NAC.

[0156]

[0167] According to some embodiments, the liquid pharmaceutical composition further comprises a catechol-O-methyltransferase (COMT) inhibitor. According to some embodiments, the COMT inhibitor is selected from entacapone, tolcapone, opicapone, or any combination thereof. According to some embodiments, the liquid pharmaceutical composition comprises between about 0.1 and about 5.0% w / v of the COMT inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 0.1 and about 1.0% w / v of the COMT inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 1.0 and about 2.0% w / v of the COMT inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 2.0 and about 3.0% w / v of the COMT inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 3.0 and about 4.0% w / v of the COMT inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 4.0 and about 5.0% w / v of the COMT inhibitor. According to some embodiments, the liquid pharmaceutical composition can be administered simultaneously with the COMT inhibitor.

[0157]

[0168] According to some embodiments, the liquid pharmaceutical composition further comprises a monoamine oxidase (MAO) inhibitor. The MAO inhibitor may be an MAO-A inhibitor or an MAO-B inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 0.1 and about 5.0% w / v of the MAO inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 0.1 and about 1.0% w / v of the MAO inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 1.0 and about 2.0% w / v of the MAO inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 2.0 and about 3.0% w / v of the MAO inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 3.0 and about 4.0% w / v of the MAO inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 4.0 and about 5.0% w / v of the MAO inhibitor. According to some embodiments, the MAO inhibitor is selected from moclobemide, rasagiline, selegiline, safinamide, or any combination thereof. According to some embodiments, the liquid pharmaceutical composition can be administered simultaneously with the MAO inhibitor.

[0158]

[0169] According to some embodiments, the liquid pharmaceutical composition further comprises a surfactant. According to some embodiments, the surfactant is selected from Tween-80, Tween-60, Tween-40, Tween-20, Tween-65, Tween-85, Span20, Span40, Span60, Span80, Span85, polyoxyl 35 castor oil (Cremophor EL), polyoxyethylene-660-hydroxystearate (macrogol 660), or poloxamer 188 (Pluronic® F-68), or any combination thereof. The liquid pharmaceutical composition of the present invention may comprise between about 0.1 and about 3.0% w / v of a surfactant or a combination of two or more surfactants. According to some embodiments, the liquid pharmaceutical composition comprises between about 0.1 to about 0.2% w / v, between about 0.2 to about 0.3% w / v, between about 0.3 to about 0.4% w / v, between about 0.4 to about 0.5% w / v, between about 0.5 to about 0.6% w / v, between about 0.6 to about 0.7% w / v, between about 0.7 to about 0.8% w / v, between about 0.8 to about 0.9% w / v, between about 0.9 to about 1.0% w / v, between about 1.0 to about 1.5% w / v, between about 1.5 to about 2.0% w / v, between about 2.0 to about 2.5% w / v, between about 2.5 to about 3.0% w / v of a surfactant or a combination of two or more surfactants.

[0159]

[0170] The liquid pharmaceutical composition may further comprise additional pharma- ceutically acceptable excipients, such as N-methylpyrrolidone (NMP), polyvinylpyrrolidone (PVP), propylene glycol, preservatives, pharma- ceutically acceptable vehicles, stabilizers, dispersants, suspending agents, amino sugars, calcium chelators, protease inhibitors, or any combination thereof. The liquid pharmaceutical composition of the present invention may comprise between about 5.0 and about 80.0% w / v of additional pharma- ceutically acceptable excipients, such as solvents, buffers, or any other co-solvents.

[0160]

[0171] According to some embodiments, the liquid pharmaceutical composition of the present invention is between about 5.0 to about 10.0% w / v, between about 10.0 to about 15.0% w / v, between about 15.0 to about 20.0% w / v, between about 20.0 to about 25.0% w / v, between about 25.0 to about 30.0% w / v, between about 30.0 to about 35.0% w / v, between about 35.0 to about 40.0% w / v, between about 40.0 to about Between 45.0% w / v, between about 45.0 and about 50.0% w / v, between about 50.0 and about 55.0% w / v, between about 55.0 and about 60.0% w / v, between about 60.0 and about 65.0% w / v, between about 65.0 and about 70.0% w / v, between about 70.0 and about 75.0% w / v, between about 75.0 and about 80.0% w / v of the solvent, buffer or any other co-solvent.

[0161]

[0172] It should be noted that any one of the components disclosed herein or any combination of any of them can be added to the liquid pharmaceutical compositions of the present invention.

[0162]

[0173] The liquid pharmaceutical composition of the present invention may be in the form of a solution, gel, cream, emulsion, or suspension. According to some embodiments, the liquid pharmaceutical composition of the present invention can be dried, for example, by lyophilization, to produce a solid, and the dry material, for example, a lyophilisate, can be constituted to produce a liquid composition, for example, by adding a solvent, for example, water. When a dry composition is constituted, antioxidants, surfactants, etc. can also be added. According to some embodiments, the dry composition is reconstituted using a dedicated solution, for example, including a solvent, antioxidants, surfactants, and any other required excipients. According to some embodiments, the liquid pharmaceutical composition of the present invention is an aqueous composition.

[0163]

[0174] The liquid pharmaceutical composition of the present invention can be formulated for any suitable route of administration, for example, for parenteral administration, for example, by bolus administration or continuous administration.The liquid pharmaceutical composition of the present invention can be formulated for subcutaneous, transdermal, intradermal, transmucosal, intravenous, intraarterial, intramuscular, intraperitoneal, intratracheal, intrathecal, intraduodenal, intrapleural, intranasal, sublingual, buccal, intestinal, intraduodenal, rectal, intraocular, or oral administration.The composition can also be formulated for inhalation or direct absorption through mucosal tissue.

[0164]

[0175] A further embodiment of the present invention is directed to a method for preparing a liquid pharmaceutical composition, said method comprising: In the form of a pharma- ceutically acceptable salt, the compound of formula (II):

[0165] [ka]

[0166] with at least one solvent and / or stabilizer, thereby forming a solution, gel, cream, emulsion or suspension; and adjusting the pH of the solution, gel, cream, emulsion or suspension to a physiologically acceptable pH value, thereby producing a liquid pharmaceutical composition.

[0167]

[0176] According to some embodiments, the method includes mixing the LD-Tyr compound of formula (II) in the form of a pharma- ceutically acceptable salt with at least one stabilizer, thereby forming a solution. According to some embodiments, the method includes mixing the LD-Tyr compound of formula (II) in the form of a pharma- ceutically acceptable solid salt with at least one stabilizer. According to some embodiments, the method of the present invention includes further mixing the LD-Tyr compound of formula (II) with any additional pharma- ceutical active ingredient and / or pharma- ceutical acceptable excipient, as detailed for the liquid pharmaceutical composition of the present invention. In certain embodiments, the mixing is performed without heating. In certain embodiments, the mixing is performed at room temperature.

[0168]

[0177] According to some embodiments, the method comprises mixing a salt form of LD-Tyr with at least one solvent and / or stabilizer, the salt being selected from the group consisting of TFA salt, HCl salt, fumarate salt, lactate salt, maleate salt, gluceptic acid salt, phosphate salt, sulfate salt, HBr salt, nitrate salt, acetate salt, propionate salt, hexanoate salt, cyclopentanepropionate salt, glycolate salt, pyruvate salt, lactate salt, hippurate salt, methanesulfonate salt, ascorbate salt, malonate salt, oxalate salt, maleate salt, tartrate salt, citrate salt, succinate salt, benzoate salt, cinnamate salt, sulfonic acid salt, lauryl sulfate salt, gluconate salt, glutamate salt, hydroxynaphthoate salt, salicylate salt, stearate salt, muconate salt, alkali metal salt, such as lithium salt, sodium salt or potassium salt, alkaline earth metal salt, such as calcium salt or magnesium salt, aluminum salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, N-methyl-2-pyridine salt, ... Tilglucamine salt, dicyclohexylamine salt, adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, borate, butyrate, camphoric acid butyrate, camphorsulfonic acid butyrate, digluconic acid butyrate, dodecylsulfate butyrate, ethanesulfonic acid butyrate, glucoheptanoic acid butyrate, glycerophosphate butyrate, gluconic acid butyrate, hemisulfate butyrate, heptanoic acid butyrate, hydroiodide butyrate, 2-hydroxyethanesulfate butyrate, lactobionic acid butyrate, lauric acid butyrate, methanesulfonic acid butyrate, 2-naphthalenesulfonic acid butyrate, nicotinic acid butyrate, oleic acid butyrate, palmitic acid butyrate, pamoic acid butyrate, pectic acid butyrate, persulfate butyrate, 3-phenylpropionic acid butyrate, phosphate butyrate, picrate butyrate, pivalic acid butyrate, tartrate butyrate, thiocyanate butyrate, p-toluenesulfonic acid butyrate, undecanoic acid butyrate, valeric acid butyrate, or any combination thereof.

[0169]

[0178] A further embodiment of the present invention is directed to a liquid pharmaceutical composition prepared according to the method of the present invention.

[0179] Some embodiments of the present invention are directed to liquid pharmaceutical compositions in which the LD-Tyr compound, enantiomer, diastereomer, racemate, ion, zwitterion, a pharma- ceutically acceptable salt thereof, or any combination thereof, has a solubility of between about 100 and about 1000 mg / L at a physiologically acceptable pH. According to some embodiments, the solubility of the LD-Tyr compound, enantiomer, diastereomer, racemate, ion, zwitterion, pharma- ceutically acceptable salt thereof, or any combination thereof, is between about 100 and about 200 mg / L, between about 200 and about 300 mg / L, between about 300 and about 400 mg / L, between about 400 and about 500 mg / L, between about 500 and about 600 mg / L, between about 600 and about 700 mg / L, between about 700 and about 800 mg / L, between about 800 and about 900 mg / L, or between about 900 and about 1000 mg / L at a physiologically acceptable pH.

[0170]

[0180] A further embodiment of the present invention is directed to a method of treating a neurodegenerative condition and / or a condition characterized by reduced levels of dopamine in the brain, the method comprising administering a liquid pharmaceutical composition comprising a stabilizer and a compound of formula (II):

[0171] [ka]

[0172] levodopa-tyrosine (LD-Tyr) conjugate of, an enantiomer, diastereomer, racemate, ion, zwitterion, a pharma- ceutically acceptable salt thereof, or any combination thereof.

[0173]

[0181] According to some embodiments, the neurodegenerative condition and / or the condition characterized by reducing the level of dopamine in the brain is selected from conditions involving neurological diseases or disorders, including Parkinson's disease, secondary parkinsonism, Huntington's disease, parkinson-like syndromes, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), Shy-Drager syndrome, dystonia, Alzheimer's disease, Lewy body dementia (LBD), akinesia, bradykinesia, and hypokinesia, conditions resulting from brain damage, including carbon monoxide or manganese poisoning, alcoholism, opiate addiction, and erectile dysfunction. According to some embodiments, the neurodegenerative condition and / or the condition characterized by reducing the level of dopamine in the brain is Parkinson's disease.

[0174]

[0182] According to some embodiments, the method of the present invention comprises administering the LD-Tyr compound of formula (II), enantiomer, diastereomer, racemate, ion, zwitterion, pharmaceutically acceptable salt thereof, or any combination thereof, or any combination of two or more LD-Tyr enantiomers, diastereomers, racemates, ions, zwitterions, pharmaceutically acceptable salts thereof, or any combination thereof, simultaneously with additional active ingredients, such as decarboxylase inhibitors, such as carbidopa, COMT inhibitors, MAO inhibitors, or any combination thereof. According to some embodiments, the LD-Tyr compound is administered together with a decarboxylase inhibitor, such as carbidopa, and the LD-Tyr compound and the decarboxylase inhibitor are administered in a single formulation.

[0175]

[0183] According to some embodiments, the method of the present invention comprises the step of substantially continuous administration of the liquid pharmaceutical composition. According to some embodiments, the liquid pharmaceutical composition is administered subcutaneously. According to some embodiments, the liquid pharmaceutical composition is administered subcutaneously via a designated pump device.

[0176]

[0184] The specified pump embodiments may be, for example, any of the pump embodiments disclosed in US62 / 529784, US62 / 576362, PCT / IB2018 / 054962, US16 / 027804, US16 / 027710, US16 / 351072, US16 / 351076, US16 / 351061, USD29 / 655583, USD29 / 655587, USD29 / 655589, USD29 / 655591, USD29 / 655592, USD29 / 655594, USD29 / 655597, US62 / 851903, and US29 / 723714, all of which are incorporated by reference in their entireties herein.

[0177]

[0185] According to some embodiments, the method of the present invention includes administering the liquid pharmaceutical composition at one site, two sites, or three or more sites, the location of these sites may be changed at any suitable, possibly scheduled, interval. According to some embodiments, after administration via a particular site, administration via the same site or in the vicinity of the site may only be possible after a predetermined, possibly predefined, period of time. According to some embodiments, the location of any one of these sites is changed after 12, 24, 36, 48, 60 or 72 hours. According to some embodiments, the location of the site is changed after 4, 5, 6 or 7 days. According to some embodiments, the location of the site is changed after 2, 3 or 4 weeks. According to some embodiments, the location of the site is changed when needed or desired, for example, by subjective data received from the patient and / or by objective data received, for example, from a sensor located at or in the vicinity of the injection site(s).

[0178]

[0186] According to some embodiments, the administered volume and / or administration rate is the same at all or at least two sites. According to other embodiments, the administered rate and / or administered volume varies from site to site. Each site can be independently controlled, or alternatively, all sites can be controlled dependently on each other.

[0179]

[0187] According to some embodiments, the method of the present invention comprises administering subcutaneously between about 1 and about 15 ml of a liquid pharmaceutical composition of the present invention over a 24 hour period. According to some embodiments, the method of the present invention comprises administering subcutaneously between about 1 and about 2, between about 2 and about 3, between about 3 and about 4, between about 4 and about 5, between about 5 and about 6, between about 6 and about 7, between about 7 and about 8, between about 8 and about 9, between about 9 and about 10, between about 10 and about 11, between about 11 and about 12, between about 12 and about 13, between about 13 and about 14, or between about 14 and about 15 ml of the liquid pharmaceutical composition of the present invention over a 24 hour period.

[0180]

[0188] It should be noted that the administration rate may be constant over a 24-hour period or may vary over a 24-hour period. For example, according to some embodiments, there may be one rate for high activity / daytime hours and a different rate for low activity / nighttime hours. The high activity / daytime hours may be, for example, about 15, about 16, about 17, about 18, or about 19 hours, respectively, and the low activity / nighttime hours may be about 9, about 8, about 7, about 6, or about 5 hours, respectively. According to some embodiments, the high activity / daytime rate runs for about 18 hours, and the low activity / nighttime rate runs for about 6 hours. According to some embodiments, the high activity / daytime rate runs for about 16 hours, and the low activity / nighttime rate runs for about 8 hours.

[0181]

[0189] According to some embodiments, the administration rate is constant over a 24-hour period. According to some embodiments, the liquid pharmaceutical formulation is administered for a certain period of time during each 24-hour period, for example, 8 hours per day, 9 hours per day, 10 hours per day, 11 hours per day, 12 hours per day, 13 hours per day, 14 hours per day, 15 hours per day, 16 hours per day, 17 hours per day, 18 hours per day, 19 hours per day, 20 hours per day, 21 hours per day, 22 hours per day, or 23 hours per day. According to some embodiments, the number of hours of administration per day can be constant for a certain number of days, for example, 7 days, 14 days, 21 days, 28 days, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, or more. According to some embodiments, the number of hours of administration per day may vary from day to day depending on the patient's condition, caregiver or physician decisions, input from sensors, etc. Additionally, it should be noted that while only whole hours are specifically mentioned, any fraction of an hour, day, month, etc. may be administered, e.g., 16.5 hours per day, 7.5 days, etc.

[0182]

[0190] The administration rate may be between about 0.01 mL / site / hour and about 1 mL / site / hour. According to some embodiments, the administration rate is between about 0.01 and 0.02 mL / site / hour. According to some embodiments, the administration rate is between about 0.02 and 0.03 mL / site / hour. According to some embodiments, the administration rate is between about 0.03 and 0.04 mL / site / hour. According to some embodiments, the administration rate is between about 0.04 and 0.05 mL / site / hour. According to some embodiments, the administration rate is between about 0.05 and 0.06 mL / site / hour. According to some embodiments, the administration rate is between about 0.06 and 0.07 mL / site / hour. According to some embodiments, the administration rate is between about 0.07 and 0.08 mL / site / hour. According to some embodiments, the administration rate is between about 0.08 and 0.09 mL / site / hour. According to some embodiments, the administration rate is between about 0.09-0.1 mL / site / hour. According to some embodiments, the administration rate is between about 0.1-0.15 mL / site / hour. According to some embodiments, the administration rate is between about 0.15-0.2 mL / site / hour. According to some embodiments, the administration rate is between about 0.2-0.25 mL / site / hour. According to some embodiments, the administration rate is between about 0.25-0.3 mL / site / hour. According to some embodiments, the administration rate is between about 0.3-0.35 mL / site / hour. According to some embodiments, the administration rate is between about 0.35-0.4 mL / site / hour. According to some embodiments, the administration rate is between about 0.4-0.45 mL / site / hour. According to some embodiments, the administration rate is between about 0.45-0.5 mL / site / hour. According to some embodiments, the administration rate is between about 0.5-0.55 mL / site / hour. According to some embodiments, the administration rate is between about 0.55-0.6 mL / site / hour. According to some embodiments, the administration rate is between about 0.6-0.65 mL / site / hour. According to some embodiments, the administration rate is between about 0.65-0.7 mL / site / hour. According to some embodiments, the administration rate is between about 0.7-0.75 mL / site / hour. According to some embodiments, the administration rate is between about 0.75-0.8 mL / site / hour.According to some embodiments, the administration rate is between about 0.8-0.85 mL / site / hour. According to some embodiments, the administration rate is between about 0.85-0.9 mL / site / hour. According to some embodiments, the administration rate is between about 0.9-0.95 mL / site / hour. According to some embodiments, the administration rate is between about 0.95-1.0 mL / site / hour.

[0183]

[0191] According to some embodiments, the administration rate during low activity / nighttime is between about 0.01-0.15 mL / site / hour. According to some embodiments, the administration rate during low activity / nighttime is between about 0.01-0.02 mL / site / hour. According to some embodiments, the administration rate during low activity / nighttime is between about 0.02-0.03 mL / site / hour. According to some embodiments, the administration rate during low activity / nighttime is between about 0.03-0.04 mL / site / hour. According to some embodiments, the administration rate during low activity / nighttime is between about 0.04-0.05 mL / site / hour. According to some embodiments, the administration rate during low activity / nighttime is between about 0.05-0.06 mL / site / hour. According to some embodiments, the administration rate during low activity / nighttime is between about 0.06-0.07 mL / site / hour. According to some embodiments, the administration rate during low activity / nighttime is between about 0.07-0.08 mL / site / hour. According to some embodiments, the administration rate during low activity / nighttime is between about 0.08-0.09 mL / site / hour. According to some embodiments, the administration rate during low activity / nighttime is between about 0.09-0.1 mL / site / hour. According to some embodiments, the administration rate during low activity / nighttime is between about 0.1-0.11 mL / site / hour. According to some embodiments, the administration rate during low activity / nighttime is between about 0.11-0.12 mL / site / hour. According to some embodiments, the administration rate during low activity / nighttime is between about 0.12-0.13 mL / site / hour. According to some embodiments, the administration rate during low activity / nighttime is between about 0.13-0.14 mL / site / hour. According to some embodiments, the administration rate during low activity / nighttime is between about 0.14-0.15 mL / site / hour. According to some embodiments, the administration rate during low activity / nighttime is about 0.04 mL / site / hour.

[0184]

[0192] According to some embodiments, the administration rate during high activity / daytime hours is between about 0.15-1.0 mL / site / hour. According to some embodiments, the administration rate during high activity / daytime hours is between about 0.15-0.2 mL / site / hour. According to some embodiments, the administration rate during high activity / daytime hours is between about 0.2-0.25 mL / site / hour. According to some embodiments, the administration rate during high activity / daytime hours is between about 0.25-0.3 mL / site / hour. According to some embodiments, the administration rate during high activity / daytime hours is between about 0.3-0.35 mL / site / hour. According to some embodiments, the administration rate during high activity / daytime hours is between about 0.35-0.4 mL / site / hour. According to some embodiments, the administration rate during high activity / daytime hours is between about 0.4-0.45 mL / site / hour. According to some embodiments, the administration rate during high activity / daytime hours is between about 0.45-0.5 mL / site / hour. According to some embodiments, the administration rate during high activity / daytime hours is between about 0.5-0.55 mL / site / hour. According to some embodiments, the administration rate during high activity / daytime hours is between about 0.55-0.6 mL / site / hour. According to some embodiments, the administration rate during high activity / daytime hours is between about 0.6-0.65 mL / site / hour. According to some embodiments, the administration rate during high activity / daytime hours is between about 0.65-0.7 mL / site / hour. According to some embodiments, the administration rate during high activity / daytime hours is between about 0.7-0.75 mL / site / hour. According to some embodiments, the administration rate during high activity / daytime hours is between about 0.75-0.8 mL / site / hour. According to some embodiments, the administration rate during high activity / daytime hours is between about 0.8-0.85 mL / site / hour. According to some embodiments, the administration rate during high activity / daytime hours is between about 0.85-0.9 mL / site / hour. According to some embodiments, the administration rate during high activity / daytime hours is between about 0.9-0.95 mL / site / hour.According to some embodiments, the administration rate during high activity / daytime hours is between about 0.95-1.0 mL / site / hour. According to some embodiments, the administration rate during high activity / daytime hours is about 0.32 mL / site / hour.

[0185]

[0193] It is further noted that the administered volume and / or administration rate may be constant throughout the treatment or may vary during different times of the day, different days, weeks or months of treatment, etc. According to some embodiments, the patient is monitored, e.g., independently, by a caretaker, or electronically, e.g., by a sensor, which may be found in a dedicated device, e.g., a watch-like device, an administration pump, etc. According to such embodiments, the administration volume and / or rate is determined according to data received from such monitoring.

[0186]

[0194] Some embodiments are directed to a method for administering a bolus subcutaneous injection of the liquid pharmaceutical composition of the present invention. According to some embodiments, the bolus injection comprises between about 0.5 and about 2.0 mL / Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 0.5 and about 0.75 mL / Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 0.75 and about 1.0 mL / Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.0 and about 1.25 mL / Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.25 and about 1.5 mL / Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.5 and about 1.75 mL / Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.75 and about 2.0 mL / Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 0.75 and about 1.25 mL / Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises about 1.0 mL / Kg of the liquid pharmaceutical composition.

[0187]

[0195] The bolus subcutaneous injection can be administered at any time with respect to any possible continuous subcutaneous administration, for example, before, during or after the continuous administration.

[0196] According to some embodiments, the administered dose may be doubled, tripled or more by using more than one pump, more than one injection site for each pump, etc.

[0188]

[0197] According to some embodiments, the liquid pharmaceutical composition is administered for a defined period of time, such as days, weeks, months, or years. According to some embodiments, the liquid pharmaceutical composition is administered repeatedly indefinitely for the treatment of chronic conditions.

[0189]

[0198] A further embodiment of the present invention is directed to a liquid pharmaceutical composition for use in the treatment of a neurodegenerative condition and / or a condition characterized by reduced levels of dopamine in the brain, the liquid pharmaceutical composition comprising a stabilizer and a compound of formula (II):

[0190] [ka]

[0191] levodopa-tyrosine (LD-Tyr) conjugate of, an enantiomer, diastereomer, racemate, ion, zwitterion, a pharma- ceutically acceptable salt thereof, or any combination thereof.

[0192]

[0199] According to some embodiments, the liquid pharmaceutical composition is for use in the treatment of conditions involving neurological diseases or disorders, including Parkinson's disease, secondary parkinsonism, Huntington's disease, parkinson-like syndromes, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), Shy-Drager syndrome, dystonia, Alzheimer's disease, Lewy body dementia (LBD), akinesia, bradykinesia, and hypokinesia, conditions resulting from brain injury, including carbon monoxide or manganese poisoning, alcoholism, opiate addiction, and erectile dysfunction. Some embodiments of the present invention are directed to the liquid pharmaceutical composition of the present invention in the treatment of Parkinson's disease.

[0193]

[0200] The composition for use according to the present invention can include any of the additional materials, any of the amounts of these materials, as detailed herein with respect to the embodiment of the composition of the present invention.Furthermore, the form, pH, etc. of the composition for use according to the present invention can be as detailed herein with respect to the embodiment of the composition of the present invention.Furthermore, the composition of the present invention can be used with COMT inhibitors, MAO inhibitors, or any other active ingredient, as detailed herein.

[0194]

[0202] Unless expressly indicated, the method embodiments described herein are not bound to a particular order or sequence. Furthermore, the method embodiments described, or some of their elements, may occur or be performed at the same time, at the same time, or concurrently.

[0195]

[0203] It will be understood that certain features of the invention can also be provided in combination in a single embodiment. Conversely, various elements of the invention that are described in the context of a single embodiment can also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Moreover, certain features that are described in the context of various embodiments are not to be construed as essential features of those embodiments, unless the embodiment does not operate without those elements.

[0196]

[0204] Various embodiments and aspects of the present invention, as delineated above and claimed in the claims section below, can be supported by; but are not limited to; the following examples. EXAMPLES

[0197] Part I: Prodrugs Example 1: Preparation of (2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-(3-hydroxy-4-phosphonooxyphenyl)propanoic acid

[0198] [ka]

[0199]

[0205] (2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-[[(2S)-2-(phenylmethoxycarbonylamino)propanoyl]amino]benzyl propanoate (551 mg) was dissolved in a mixed solvent of ethanol (2 mL) and tetrahydrofuran (2 mL), palladium / carbon (aqueous) (69 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 7 hours. The reaction mixture was filtered through a membrane filter (cellulose acetate) to remove insoluble matter. The insoluble matter was washed with water / ethanol (2:1, 12 mL), and the filtrate was distilled under reduced pressure until the volume was reduced to about 1 mL, followed by lyophilization, and the title compound (214 mg, yield: 100%) was obtained as a white powder. MS(ESI); m / z 349.1[M+H]+.

[0200] Examples 2 to 19 and 120 to 131

[0206] The corresponding starting compounds were treated in the same manner as in Example 1, respectively, to obtain the compounds shown in Table 2 below. Some of the compounds shown in Table 2 below can be obtained in the same manner as in the above examples.

[0201] [Table 2-1]

[0202] [Table 2-2]

[0203] [Table 2-3]

[0204] [Table 2-4]

[0205] [Table 2-5]

[0206] Example 20: Preparation of (2S)-2-[[(2S)-2-amino-5-carbamimidamide pentanoyl]amino]-3-(3,4-dihydroxyphenyl)propanoic acid; hydrochloride salt

[0207] [ka]

[0208] (2S)-3-[3,4-Bis(phenylmethoxy)phenyl]-2-[[(2S)-5-[(N-nitrocarbamimideyl)amino]-2-(phenylmethoxycarbonylamino)pentanoyl]amino]benzylpropanoate (257 mg) was dissolved in a mixture of tetrahydrofuran (2 mL), 2-propanol (3 mL) and 2M hydrochloric acid (0.80 mL), palladium on carbon (wet) (341 mg) was added and the mixture was stirred at room temperature under hydrogen atmosphere for 24 hours. 2-Propanol (4 mL) and water (6 mL) were added to the reaction mixture and insoluble matter was removed using a membrane filter. The insoluble matter was washed with water (6 mL), 2-propanol (25 mL) was added and the mixture was distilled under reduced pressure. Diisopropyl ether was added to the residue and the precipitated solid was collected by filtration and dried under reduced pressure, which afforded the title compound (144 mg, yield: 100%) as a tan powder. MS(ESI); m / z 354.2[M+H]+.

[0209] Examples 21 to 28 The compounds shown in Table 3 below can be obtained in the same manner as the above examples.

[0210] [Table 3]

[0211] Reference Example 1: Production of (2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-[[(2S)-3-(2-ethoxy-2-methyl-1,3-benzodioxol-5)-yl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]propanoic acid (proanoic acid)

[0212] [ka]

[0213]

[0209] (2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-[[(2S)-3-(2-ethoxy-2-methyl-1,3-benzodioxol-5-yl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]benzyl propanoate (208 mg) was dissolved in a mixed solvent of water (0.41 mL) and tetrahydrofuran (1.0 mL), lithium hydroxide monohydrate (9.4 mg) was added under ice bath, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and then a saturated aqueous citric acid solution was added until the pH of the mixture became 6, and extraction with ethyl acetate was performed. The organic layer was dried over magnesium sulfate, and the insoluble matter was filtered off. The solvent was then distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: hexane / (ethyl acetate)=70 / 30 to 0 / 100, (ethyl acetate) / methanol=100 / 0 to 85 / 15), thereby obtaining the title compound (179 mg, yield: 94%) as a colorless viscous substance. MS(ESI);m / z 929.3[MH]-.

[0214] Reference Example 2: Production of (2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-[[(2S)-2-(phenylmethoxycarbonylamino)propanoyl]amino]benzyl propanoate

[0215] [ka]

[0216]

[0210] 1H-tetrazole (72 mg) and dibenzyl N,N-diisopropyl phosphoramidite (0.38 mL) were added to a mixture of (2S)-3-(4-hydroxy-3-phenylmethoxyphenyl)-2-[[(2S)-2-(phenylmethoxycarbonylamino)propanoyl]amino]benzyl propanoate (387 mg), dichloromethane (4 mL) and acetonitrile (1.6 mL) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was ice-cooled, and a tert-butyl hydroperoxydodecane solution (5.5 M) (0.18 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction mixture was distilled off under reduced pressure, and then toluene was added, and the insoluble matter was removed with a Phase-separator (registered trademark). The filtrate was purified by silica gel column chromatography (solvent: hexane / (ethyl acetate)=67 / 33 to 40 / 60), thereby obtaining the title compound (551 mg, yield: 90%) as a colorless viscous substance. MS(ESI); m / z 843.7[M+H]+.

[0217] Reference examples 3~16:

[0211] The corresponding starting compounds were treated in the same manner as in Reference Example 2 to give the compounds shown in Table 4 below.

[0218] [Table 4-1]

[0219] [Table 4-2]

[0220] [Table 4-3]

[0221] [Table 4-4]

[0222] Reference example 101: Preparation of benzyl (2S)-3-[4-bis(phenylmethoxy)phosphoryloxy-3-phenylmethoxyphenyl]-2-[[(2S)-4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]propanoate

[0223] [ka]

[0224] 1,8-diazabicyclo[5.4.0]undec-7-ene (223 uL) and tetrabenzyl diphosphate (805 mg) were added to a mixture of benzyl (2S)-3-(4-hydroxy-3-phenylmethoxyphenyl)-2-[[(2S)-4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]propanoate (623 mg) and acetonitrile (5 mL) under ice cooling, and the mixture was gradually warmed to room temperature and stirred for 21 hours. 1,8-diazabicyclo[5.4.0]undec-7-ene (74 uL) and tetrabenzyl diphosphate (266 mg) were added to the mixture, and the mixture was stirred for 3.5 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane / (ethyl acetate)=67 / 33 to 40 / 60), thereby obtaining the title compound (702 mg, yield 80%) as a colorless viscous liquid. MS(ESI); m / z 885.3[M+H]+.

[0225] Reference examples 102~112: The corresponding starting compounds were treated in the same manner as in Reference Example 101 to obtain the compounds shown in Table 8-5 below. Some of the compounds shown in Table 8-5 below can be obtained in the same manner as in the above examples.

[0226] [Table 5A-1]

[0227] [Table 5A-2]

[0228] [Table 5A-3]

[0229] Reference Example 17: Production of (2S)-3-(4-hydroxy-3-phenylmethoxyphenyl)-2-[[(2S)-2-(phenylmethoxycarbonylamino)propanoyl]amino]benzyl propanoate

[0230] [ka]

[0231]

[0212] (2S)-2-(benzyloxycarbonylamino)propanoic acid (1.02 g), 1-hydroxy-7-azabenzotriazole (HOAt) (712 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCI) (1.03 g) and N,N-diisopropylethylamine (0.750 mL) were added to a mixture of (2S)-2-amino-3-(4-hydroxy-3-phenylmethoxyphenyl)benzylpropanoate; hydrochloride (1.87 g) and N,N-dimethylformamide (18 mL), and the mixture was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate and water were added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water and saturated sodium chloride solution, and dried over magnesium sulfate. Insoluble matter was filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / (ethyl acetate)=67 / 33 to 45 / 55), thereby obtaining the title compound (2.56 g, yield: 99%) as a white powder. MS(ESI); m / z 583.6[M+H]+.

[0232] Reference examples 18~34:

[0213] The corresponding starting compounds were treated in the same manner as in Reference Example 17 to give the compounds shown in Table 5 below.

[0233]

Table 5B-1

[0234]

Table 5B-2

[0235]

Table 5B-3

[0236]

Table 5B-4

[0237]

Table 5B-5

[0238]

Table 5B-6

[0239] Reference Example 35: Preparation of (2S)-2-acetamido-3-(3,4-diacetyloxyphenyl)benzylpropanoate

[0240]

change

[0241]

[0214] To a mixture of (2S)-2-amino-3-(3,4-dihydroxyphenyl)benzylpropanoate; hydrochloride (253 mg) and pyridine (1 mL) was added acetic anhydride (0.291 mL) under ice cooling, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and extraction with chloroform was performed. The organic layer was washed with a saturated sodium chloride solution, dehydrated with sodium sulfate, and insoluble matter was filtered, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane / (ethyl acetate) = 80 / 20 to 0 / 100), thereby obtaining the title compound (280 mg, yield: 72%) as a colorless viscous substance. MS(ESI); m / z 414.2[M+H]+.

[0242] Reference Examples 36 and 37:

[0215] The corresponding starting compounds were treated in the same manner as in Reference Example 35 to give the compounds shown in Table 6 below.

[0243] [Table 6]

[0244] Reference Example 38: (2S)-2-amino-3-[3,4-bis(phenylmethoxy)phenyl]benzylpropanoate; Formation of hydrochloride

[0245] [ka]

[0246]

[0216] 4M hydrogen chloride in dioxane (43 mL) was added to (2S)-3-[3,4-bis(phenylmethoxy)phenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]benzylpropanoate (13.2 g) under ice cooling, and the mixture was stirred at room temperature for 3 hours. 4M hydrogen chloride in ethyl acetate (3 mL) was added, and the mixture was stirred for 2 hours. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was suspended in diisopropyl ether, and the precipitated solid was collected by filtration and dried under reduced pressure, thereby obtaining the title compound (10.4 mg, yield: 96%) as a white powder. MS(ESI); m / z 468.3[M+H]+.

[0247] Reference example 39:

[0217] The corresponding starting compounds were treated in the same manner as in Reference Example 33 to give the compounds shown in Table 7 below.

[0248] [Table 7]

[0249] Reference Example 40: (2S)-2-amino-3-(3-benzyloxy-4-hydroxyphenyl)benzylpropanoate; Formation of hydrochloride

[0250] [ka]

[0251] (1) N-(tert-butoxycarbonyl)-phosphonoglycine trimethyl ester (10 g) and 1,1,3,3-tetramethylguanidine (5 mL) were added to a mixture of compound A-1 (8.31 g) and dichloromethane (90 mL) under ice cooling, and the mixture was stirred at room temperature for 24 hours. Saturated aqueous sodium bicarbonate and water were added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was passed through a silica gel column chromatography (solvent: ethyl acetate), and the solvent of the filtrate was distilled off under reduced pressure. The residue was suspended in ethanol, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain compound A-2 (10.7 g, yield: 79%) as a white powder. MS(ESI); m / z 440.3[M−H]-.

[0252]

[0219] (2) (+)-1,2-bis((2S,5S)-2,5-diethylphosphorano)benzene(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate ((S,S)-Et-DUPHOS-Rh) (144 mg) was added to a mixture of compound A-2 (9.65 g) and tetrahydrofuran (80 mL), and the mixture was stirred under a hydrogen pressure atmosphere (800 kPa) at 35°C for 3 hours. The reaction mixture was passed through silica gel column chromatography (solvent: hexane / (ethyl acetate) = 50 / 50), and the solvent of the filtrate was distilled off under reduced pressure. The residue was suspended in ethanol, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain compound A-3 (9.00 g, yield: 93%) as a white powder. MS(ESI); m / z 442.2[M−H]-.

[0253] (3) Compound A-3 (7.52 g) was dissolved in a mixed solvent of tetrahydrofuran (40 mL), methanol (20 mL) and distilled water (15 mL), and 4M lithium hydroxide aqueous solution (20 mL) was added under ice cooling, and the mixture was stirred at 0° C. for 7 hours. 1M hydrochloric acid (60 mL) was added to the reaction mixture, and extraction with ethyl acetate (100 mL) was performed. The organic layer was washed with saturated sodium chloride solution, dehydrated with magnesium sulfate, insoluble matter was filtered, and the solvent was distilled off under reduced pressure, thereby obtaining compound A-4 (7.52 g, 88 wt%, yield: 100%) as a yellow viscous substance. MS(ESI); m / z 386.2[MH]-.

[0254]

[0221] (4)-1 Cesium carbonate (3.97 g) and benzyl bromide (2.40 mL) were added to a mixture of compound A-4 (7.46 g, 88 wt%) and N,N-dimethylformamide (4 mL) at room temperature, and the mixture was stirred at the same temperature for 4 hours. Saturated sodium chloride solution and water were added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water and saturated sodium chloride solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane / (ethyl acetate) = 80 / 20 to 67 / 33), thereby obtaining compound A-5 (8.81 g, 90 wt%, 98%) as a white powder. MS(ESI); m / z 476.2[M−H]-.

[0255] (4)-2 (Another synthesis method of compound A-5) Iodine (153 mg) was added to a mixture of activated zinc (923 mg) and N,N-dimethylformamide (7 mL) at 5° C. under nitrogen atmosphere. The temperature was raised to 20° C., and the mixture was stirred for 10 minutes. The reaction mixture was cooled again to 6° C., and compound A-6 (1890 mg) was added in portions at or below 20° C., and the mixture was stirred at 20° C. for 30 minutes, thereby obtaining a solution of compound A-7.

[0256]

[0223] Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (31 mg), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyldicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (30 mg), and compound A-8 (1309 mg) were added in sequence, and the mixture was stirred at room temperature for 16 hours. Hexane / (ethyl acetate) (1:1) was added to the reaction mixture, and the insoluble matter was removed by filtration through Celite. The insoluble matter was washed with hexane / (ethyl acetate) (1:1) and water, and the filtrate was washed successively with a saturated aqueous ammonium chloride solution and a saturated sodium chloride solution. The organic layer was dehydrated over anhydrous magnesium sulfate, the insoluble matter was filtered, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane / (ethyl acetate)=80 / 20 to 67 / 33), thereby obtaining compound A-5 (1.84 g, yield: 90%) as a yellow viscous substance. MS(ESI); m / z 378.2 [M+H-Boc]+.

[0257] (5) 4M hydrogen chloride in dioxane (6 mL) was added to a mixture of compound A-5 (1.63 g) and 1,4-dioxane (15 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. 4M hydrogen chloride in dioxane (6 mL) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure until its volume was about 1 / 10. The residue was suspended in ethyl acetate, and the precipitated solid was collected by filtration and dried under reduced pressure, thereby obtaining compound [a-1] (1288 mg, yield: 90%) as a white powder. MS(ESI); m / z 378.4[M+H]+.

[0258] Reference Example 41: (2S)-2-amino-3-(3,4-diacetoxyphenyl)benzylpropanoate; Formation of hydrochloride

[0259] [ka]

[0260] (1) Cesium carbonate (1.43 g) and benzyl bromide (0.58 mL) were added to a mixture of compound B-1 (2.0 g) and N,N-dimethylformamide (19 mL), and the mixture was stirred at room temperature for 2 hours. Saturated sodium chloride solution and water were added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water and saturated sodium chloride solution, dehydrated with magnesium sulfate, the insoluble matter was filtered, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography, thereby obtaining compound B-2 (1.68 g, yield: 75%) as a colorless viscous substance. MS(ESI); m / z 372.1 [M+H-Boc]+.

[0261] (2) 4M hydrogen chloride ethyl acetate solution (0.5mL) was added to a solution of compound B-2 (515mg) in ethyl acetate (5mL) under ice cooling, and the mixture was stirred at room temperature for 4 hours. 4M hydrogen chloride ethyl acetate solution (3mL) was added, and the mixture was stirred at room temperature for 2.5 hours. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was suspended in ethyl acetate, and the precipitated solid was collected by filtration and dried under reduced pressure, thereby obtaining compound B (409mg, yield: 98%) as a white powder. MS(ESI); m / z 372.1[M+H]+.

[0262] Reference Example 42: Production of (2S)-2-(benzyloxycarbonylamino)-3-(2,2-dimethyl-1,3-benzodioxol-5-yl)propanoic acid

[0263] [ka]

[0264]

[0227] p-Toluenesulfonic acid (175 mg) and 2,2-dimethoxypropane (12.5 mL) were added to a mixture of compound C-1 (3.66 g) and toluene (102 mL), and the mixture was heated to reflux for 14 hours using a Dean-Stark apparatus. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was dried over magnesium sulfate, the insoluble matter was filtered, and the solvent was then evaporated under reduced pressure to obtain the crude product of compound C-2 as a yellow viscous material.

[0265]

[0228] The crude product of compound C-2 was dissolved in a mixed solvent of methanol (25 mL), water (20 mL) and tetrahydrofuran (51 mL), and lithium hydroxide monohydrate (855 mg) was added under ice bath, and the mixture was stirred at the same temperature for 40 minutes, and then stirred at room temperature for 1 hour. The reaction mixture was diluted with water and washed with diethyl ether. Ethyl acetate was added to the aqueous layer, and a saturated aqueous citric acid solution was added until the pH of the mixture became 6, and extraction with ethyl acetate was performed. The organic layer was dehydrated with magnesium sulfate, and the insoluble matter was filtered, and then the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: ethyl acetate), thereby obtaining compound C (2.40 g, two-step yield: 63%) as a yellow viscous substance. MS(ESI); m / z 370.2[M−H]-.

[0266] Reference Example 43: Production of (2S)-2-(benzyloxycarbonylamino)-3-(2-ethoxy-2-methyl-1,3-benzodioxol-5-yl)propanoic acid

[0267] [ka]

[0268]

[0229] (1) Compound D-1 (1.35 g) was dissolved in 1-butyl-3-methylimidazolium hexafluorophosphate (7.51 mL), triethyl orthoacetate (1.38 mL) was added, and the mixture was stirred at 80°C for 3 hours. Water was added to the reaction mixture, and then extraction with ethyl acetate was performed. The organic layer was dehydrated with magnesium sulfate, insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / (ethyl acetate) = 85 / 15 to 70 / 30), thereby obtaining compound D-2 (1.41 g, yield: 87%) as a colorless viscous substance. MS(ESI); m / z 430.0[M+H]+.

[0269]

[0230] (2) Compound D-2 (1.35 g) was dissolved in a mixed solvent of methanol (3.9 mL), water (6.3 mL) and tetrahydrofuran (6.3 mL), lithium hydroxide monohydrate (264 mg) was added under ice bath, and the mixture was stirred at room temperature for 10 hours. After adding ethyl acetate to the reaction mixture, a saturated aqueous ammonium chloride solution was added until the pH of the mixture became 6, and extraction with ethyl acetate was performed. The organic layer was dehydrated with magnesium sulfate, insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: (ethyl acetate) / methanol = 100 / 0-95 / 5), thereby obtaining compound D (816 mg, yield: 65%) as a colorless solid. MS(ESI); m / z 400.2[M−H]-.

[0270] Experimental example 1: Evaluation of in vitro conversion efficiency using human hepatocytes

[0231] The conversion efficiency of the prodrug to levodopa was evaluated in a metabolism test using human hepatocytes. The prodrug was incubated with human hepatocytes at 37°C for 4 hours. A portion of the reaction solution was sampled at each predetermined time and mixed with an organic solvent to stop the reaction. The reaction-stopped solution was centrifuged, and the resulting supernatant was analyzed using liquid chromatography / tandem mass spectrometry. The conversion efficiency to levodopa was evaluated as the amount of levodopa produced after 4 hours of incubation. Table 8 shows the amount of levodopa produced by the compounds as part of the examples of the present invention.

[0271] [Table 8]

[0272]

[0232] As shown in the results of the above test, all the compounds were confirmed to produce levodopa. From these results, efficient production of levodopa in vivo is predicted, and it is considered that the compounds are particularly useful as pharmaceuticals for treating Parkinson's disease.

[0273] Experimental Example 2-1: Evaluation of solution stability

[0233] Phosphate buffer of pH 7.4 was added to each compound to dissolve each compound, and NaOH solution was added to adjust the pH of the mixture as necessary to prepare a solution of about 1 mg / mL. The solution was stored at 25°C for about 1 day, and then the HPLC purity (area percentage, %) was measured. The HPLC purity of the solution immediately after preparation, or the HPLC purity of the compound, was subtracted from the HPLC purity after storage at 25°C for about 1 day to obtain the difference in HPLC purity. Table 9 shows the solution stability of some compounds of the examples of the present invention. In Tables 9-1 and 9-2, "LDP-Ala" stands for L-tyrosine, NL-alanyl-3-hydroxy-(9CI), which has the following structural formula:

[0274] [ka]

[0275] [Table 9-1]

[0276] Experimental Example 2-2: Evaluation of solution stability Phosphate buffer of pH 7.4 is added to each compound to dissolve each compound, and NaOH solution is added to adjust the pH of the mixture as necessary to prepare a solution of about 1 mg / mL. The solution is stored at 60°C for about 1 day, and then the HPLC purity (area percentage, %) is measured. The HPLC purity of the solution immediately after preparation, or the HPLC purity of the compound is subtracted from the HPLC purity after storing at 60°C for about 1 day to obtain the difference in HPLC purity. Table 9-2 shows the solution stability of some compounds of the examples of the present invention.

[0277] [Table 9-2]

[0278]

[0234] As shown by the results of the above tests, it was confirmed that the compounds of the present invention are stable in aqueous solutions around neutral pH, and among them, the compounds of Examples 1 and 8 are particularly stable.

[0279]

[0235] From the above results, the compounds of the present invention are expected to have high solution stability at pH 6 to 8, and are considered to be useful as solution formulations. Experimental Example 3: Evaluation of solubility

[0236] Water was added to each compound to prepare a suspension, which was shaken at 25°C for 24 hours, and then filtered through a filter to obtain a filtrate. The compound concentration in the filtrate was quantified using HPLC to obtain the solubility. In addition, the pH of the filtrate was measured. Table 10-1 shows the solubility of some compounds of the examples of the present invention.

[0280] [Table 10-1]

[0281]

[0237] As shown in the results of the above tests, it was confirmed that all the compounds exhibited good solubility at a pH close to the isoelectric point.

[0238] From the above results, the compound is expected to exhibit high solubility at pH 6 to 8, and is considered to be particularly useful as a solution formulation.

[0282] (Method of preparation of the formulation) Methods for preparing LDP-Ala / CD formulations

[0239] The NaOH solution was added to LDP-Ala and stirred at room temperature to dissolve LDP-Ala. Carbidopa and antioxidants (N-acetylcysteine ​​and ascorbic acid) were added to the mixture and dissolved while adjusting the pH by adding NaOH solution as necessary. Polysorbate 80 and NaOH aqueous solution were then added to make the formulation composition in Table 10-2, and the volume was adjusted with ultrapure water as appropriate. The above solution was filtered through a 0.22 μm filter and filled into vials while replacing the headspace with nitrogen.

[0283] [Table 10-2]

[0284] Method for preparing LDP-Lys / CD formulations

[0240] KOH solution and meglumine were added to LDP-Lys and stirred at room temperature to dissolve LDP-Lys. Carbidopa and antioxidants (N-acetylcysteine ​​and ascorbic acid) were added to the mixture and dissolved while adjusting the pH by adding KOH solution as necessary. Polysorbate 80 and KOH solution were then added to prepare the formulation composition in Table 10-3, and the volume was adjusted with ultrapure water as appropriate. The above solution was filtered through a 0.22 μm filter and filled into a vial while replacing the headspace with nitrogen.

[0285] [Table 10-3]

[0286] (Results of stability evaluation of LDP-Ala and LDP-Lys combinations)

[0241] The formulations prepared as shown in Tables 10-2 and 10-3 were stored refrigerated (2-8°C) for 2 weeks. After that, the appearance of each formulation was visually inspected and evaluated for the presence of precipitate. HPLC was also used to determine the quantity and purity of LDP-Ala and LDP-Lys.

[0287]

[0242] In both formulations shown in Tables 10-2 and 10-3, no precipitation was observed after 2 weeks of refrigeration, and no significant changes in quantitative values ​​were observed, indicating that the formulations are considered stable up to 2 weeks under refrigeration. The results of the stability evaluation of the formulations shown in Tables 10-2 and 10-3 are shown in Tables 10-4 and 10-5, respectively.

[0288] [Table 10-4]

[0289] [Table 10-5]

[0290] Part II: LD-Tyr formulations Experimental Example 4 - Long-term stability of 30% LD-Tyrosine / 0.75% Carbidopa at 2-8°C A formulation containing LD-Tyrosine (LD-Tyr) 300 mg / mL (30%) and Carbidopa 7.5 mg / mL (0.75%) was prepared with 5.5% L-arginine and 11.5% Tris. This formulation also contained 0.5% Ascorbic Acid (Asc), 0.5% N-Acetyl Cysteine ​​(NAC), 0.3% Tween 80. The formulation was stored at 2-8°C for the indicated times and tested for % recovery and % LD-Tyr-DKP (impurity) formation. The results are shown in Table 11. Percent recovery remained high over time. DKP impurity accumulated over time.

[0291] [Table 11]

[0292] Example 5 - Solubility in co-solvents The solubility of LD-Tyr was tested in various co-solvents as shown in Table 12. The formulations were stored at 2-8°C or 25°C for the indicated times and tested for stability (measured by the presence of precipitate) and % DKP formation (impurities). As shown in Table 12, the formulations containing propylene glycol were stable at 2-8°C for at least one month and at 25°C for at least two weeks, and showed less accumulation of DKP than the formulation containing 5.5% L-arginine and 11.5% Tris shown in Example 1. The formulation containing PEG300 was unstable at 2-8°C and showed more accumulation of DKP than the other formulations tested. Formulations containing DMA at 5%, 10%, and 15% were also prepared. Significant levels of DKP were detected at T=0 for all concentrations.

[0293] [Table 12]

[0294] Example 6 - Effect of various additives on the stability of 30% LD-Tyrosine-L-Arginine based formulations Formulations were prepared with LD-Tyr 300 mg / mL, NAC 5 mg / mL (0.5%), ascorbic acid 5 mg / mL (0.5%), L-Arg 18.1%, and the additives shown in Table 13. PVP K17 is an abbreviation for polyvinylpyrrolidone low molecular weight (PVP K17). All formulations were physically stable at 2-8°C and 25°C for at least 2 weeks. As shown in Table 13, none of the additives tested demonstrated the ability to inhibit or prevent the formation of DKP.

[0295] [Table 13]

[0296] Example 7 - Solubility and physical stability of bases (organic and inorganic) In this example, LD-tyrosine was added in portions to a 0.8M solution of counterion and antioxidant with stirring. The L-arginine formulation was heated with stirring, the other formulations were not heated. The pH was not adjusted. Solubility was confirmed after filtration by HPLC. Physical stability was measured after 2 weeks and 1 month storage at 2-8°C or 25°C. As shown in Table 14, LD-tyrosine solubilized in ethanolamine, diethylamine, and ammonium hydroxide was physically stable (no evidence of precipitation) at 2-8°C and 25°C for up to at least 1 month. Solubility and stability were dependent on the particular base used, not just pH.

[0297] [Table 14]

[0298] In addition to stability, the formation of impurities (DKPs) was measured for each formulation. As shown in Table 15, DKP formation was minimal in the formulation with sodium hydroxide at 25° C. DKP formation was slightly higher for diethylamine, ethanolamine, and ammonium hydroxide, respectively.

[0299] [Table 15]

[0300] Formulations were prepared with LD-Tyr 300 mg / mL, NAC 5 mg / mL (0.5%), ascorbic acid 5 mg / mL (0.5%), and 17.2% meglumine or 18.1% L-Arg. All formulations were physically stable for at least 2 weeks at 2-8° C. and 25° C. Lower DKP levels were observed with L-Arg compared to meglumine, as shown in Table 16.

[0301] [Table 16]

[0302] Example 8 - Effect of various amines and inorganic bases on the stability of 30% LD-tyrosine In this example, LD-Tyrosine formulations 300 mg / mL (30%) were prepared with the ingredients shown in Table 17, as well as the antioxidants ascorbic acid (0.5%) and N-acetylcysteine ​​(NAC) (0.5%). No heat was used to prepare these formulations.

[0303] [Table 17]

[0304] As shown in Table 17 and Figures 1 and 2, the formulation containing diethylamine and L-Arg resulted in the formation of the lowest DKP levels, followed by diethanolamine and L-Arg and ethanolamine and L-Arg. Among the amines tested, the highest amounts of DKPs were exhibited in the formulation containing ethylenediamine and L-Arg and the formulation containing ethylenediamine alone (no L-Arg). The relative DKP levels formed were similar at 2-8°C and 25°C.

[0305]

[0251] Formulations were prepared with LD-Tyr 300 mg / mL, NAC 5 mg / mL (0.5%) and ascorbic acid 5 mg / mL (0.5%), and the base combinations shown in Table 18. All formulations were physically stable at 2-8°C for at least 70 days.

[0306] [Table 18]

[0307]

[0252] Formulations were prepared with LD-Tyr 300 mg / mL, NAC 5 mg / mL (0.5%), ascorbic acid 5 mg / mL (0.5%), 7.2% L-Arg, and sodium hydroxide or ammonium hydroxide as shown in Table 19. As shown in Table 19, the formulations containing sodium hydroxide demonstrated physical instability.

[0308] [Table 19]

[0309] Example 9 - Effect of ethanolamine on the stability of 30% LD-tyrosine In this example, LD-Tyrosine formulations 300 mg / mL (30%) were prepared with L-arginine and ethanolamine alone and in combination at different concentrations, as well as the antioxidants ascorbic acid (0.5%) and N-acetylcysteine ​​(NAC) (0.5%), as shown in Table 20. Only the formulation containing 18.1% L-Arg was heated during preparation.

[0310] [Table 20]

[0311]

[0254] The formulations were then tested for DKP accumulation and physical stability at 2-8°C and 25°C over a two week period. As shown in Table 21, the formulation containing L-Arg alone had the lowest levels of DKP accumulation, and the amount of DKP accumulation generally increased as the ethanolamine to L-Arg ratio increased. No evidence of precipitation was observed in any of the formulations tested. Only the formulation containing 18.1% L-Arg was heated during preparation.

[0312] [Table 21]

[0313]

[0255] Table 22 shows additional LD-Tyrosine formulations 300 mg / mL (30%) prepared with L-arginine and ethanolamine or diethylamine, and the antioxidants ascorbic acid (0.5%) and N-acetylcysteine ​​(NAC) (0.5%).

[0314] [Table 22]

[0315] Example 10 - Blood / Plasma Ratio

[0256] The blood / plasma ratio (R B ) was investigated ex vivo in rat, minipig, and human blood to understand its partitioning into red blood cells (RBCs). The partition coefficients (K RBC / PL ) values ​​were below 5, indicating limited RBC binding. In rat blood, K RBC / PL increased with incubation time (see Figure 3). In minipig blood, K RBC / PL increased with incubation time for the two higher concentrations (150 and 2500 ng / mL), but reached 1 at 15 and 30 min for the lower concentration (50 ng / mL), followed by K RBC / PL In human blood, the measured total K RBC / PL was below 1, indicating no RBC binding (see FIG. 5).

[0316] Example 11 - Safety test in rats and minipigs

[0257] In vivo nonclinical safety studies were conducted in both rats and minipigs. Additionally, local injection site reactions of LD-Tyr were evaluated as part of PK studies in domestic pigs. A summary of the in vivo nonclinical safety results obtained in various nonclinical studies of LD-Tyr is shown in Table 23.

[0317] [Table 23]

[0318] Example 12 - Effect of various additives on the stability of 20% LD-Tyrosine-L-Arginine based formulations A formulation was prepared with LD-Tyr 200 mg / mL, NAC 5 mg / mL (0.5%), ascorbic acid 5 mg / mL (0.5%), 15.5% L-Arg, and the additives shown in Table 24. As shown in Table 24, the additives tested were able to limit DKP formation at 2-8°C, but the amount of DKP at room temperature was still significant. Additionally, MgCl 2 It should be noted that formulations containing DMA demonstrated relatively high viscosities. The solubility of LD-Tyr was DMA > ethanol > PEG300, and the viscosity of the formulations was higher in ethanol than in DMA. <DMA<PEG300であった。

[0319] [Table 24]

[0320] Example 13 - Effect of Ethanol and / or PEG300 on Formulation Characteristics The stability and saturation of the formulations in Table 25 were evaluated. F1 proved stable for 1 week at 5° C. even when the amount of LD-Tyr was increased to 400 mg / ml. On the other hand, F2-F4 remained unstable even when the amount of LD-Tyr was increased to 400 mg / ml. To maintain physical stability, L-arginine was added to formulations F2-F4 and the pH was adjusted to the original level. After this, F2-F4 remained stable for 1 week at 5° C. even when the amount of LD-Tyr was increased to 400 mg / ml.

[0321] [Table 25]

[0322] Visual inspection after one month also confirmed the physical stability of the formulations in Table 25 (the formulations remained clear and no precipitation was evident). Stability was also tested by HPLC, with results showing approximately 100% recovery after five days. Additionally, one-month stability HPLC studies on formulations held at 2-8°C or 25°C for one month showed that stability was maintained under both conditions. The primary difference between the formulations is in the amount of DKP formed over time, with DKP formation inhibited at 2-8°C but not at 25°C. In this regard, it is noted that the amount of DKP produced in F1 is less than that produced in any of F2-F4.

[0323] Example 14 - Pharmacokinetics of LD-Tyr in domestic pigs A series of PK studies were completed in domestic pigs using several LD-Tyr formulations detailed in Table 26 and dosing regimens detailed in Table 27. The PK profile of LD-Tyr and therefore the LD were determined after 18 hours of continuous SC infusion in female domestic pigs. Each formulation was administered at one infusion site per animal using a Crono-ND infusion pump (Cane SpA Medical Technology, Rivoli, Italy) connected to an infusion set (Accu-chek®, FlexLink, Roche).

[0324]

[0262] Blood samples for determination of LD-Tyr and LD plasma levels were taken from the pigs at the following times after the start of infusion: 0 (pre-dose), 30 minutes, 1 hour, 2 hours, 6 hours, 8 hours, 9 hours, 10 hours, 12 hours, 14 hours, 18 hours, 18.5 hours, 19 hours, 21 hours, 23 hours and 26 hours.

[0325] [Table 26]

[0326]

[0263] A summary of the PK parameters for each study as well as the dosing regimens are detailed in Table 27.

[0327] [Table 27]

[0328]

[0264] The combined mean concentrations of LD-Tyr and the resulting LDs from the studies detailed above are shown in Figures 6 and 7, respectively. Example 15 - Pharmacokinetic and local site reaction study of a high concentration LD-Tyr formulation with TRIS in domestic pigs Experimental Example 15A - 1%CD A series of PK and local toxicity studies were completed in domestic pigs using several high concentration LD-Tyr formulations with 1% CD and various amounts of TRIS, detailed in Table 28, and dosing regimens detailed in Table 29. The PK profile of LD-Tyr and therefore the LD were determined after 18 hours of continuous SC infusion in female domestic pigs. Each formulation was administered at one infusion site per animal using a Crono-ND infusion pump (Cane SpA Medical Technology, Rivoli, Italy) connected to an infusion set (Accu-chek®, FlexLink, Roche).

[0329]

[0266] Blood samples for determination of LD-Tyr and LD plasma levels were taken from the pigs at the following times after the start of infusion: 0 (pre-dose), 30 minutes, 1 hour, 2 hours, 6 hours, 8 hours, 9 hours, 10 hours, 12 hours, 14 hours, 18 hours, 18.5 hours, 19 hours, 21 hours, 23 hours and 26 hours.

[0330] [Table 28]

[0331] [Table 29]

[0332] PK result A summary of the PK parameters obtained in

[0267] is shown in Table 30.

[0333] [Table 30]

[0334]

[0268] The combined mean concentrations of LD from the studies detailed above are shown in FIG.

[0269] Based on the results of this study and under the conditions of this study, it can be concluded that no significant differences in systemic exposure to LD were observed following injection of LD-Tyr 30% at 9 mL, LD-Tyr 37% at 7.5 mL, or LD-Tyr 44% at 6 mL.

[0335] Local site reactions

[0270] Immediately after removal of the pump, the infusion site was inspected for any local reactions. Any skin reactions (e.g., erythema, edema / swelling) were recorded and scored according to the 5-point Draize scale for scoring skin irritation, as shown in Table 31.

[0336] [Table 31]

[0337]

[0271] The results showed that no significant local skin reactions were induced by any of the test formulations. As shown in Table 32, minimal to marked erythema and edema (grades 1-2) were observed immediately after pump removal.

[0338] [Table 32]

[0339] Experimental Example 15B - 0.5% CD A series of PK and local toxicity studies were completed in domestic pigs with several high concentration LD-Tyr formulations containing 0.5% CD and various amounts of TRIS, detailed in Table 33, and dosing regimens detailed in Table 34. The PK profile of LD-Tyr and therefore the LD were determined after 18 hours of continuous SC infusion in female domestic pigs. Each formulation was administered at one infusion site per animal using a Crono-ND infusion pump (Cane SpA Medical Technology, Rivoli, Italy) connected to an infusion set (Accu-chek®, FlexLink, Roche).

[0340]

[0273] Blood samples for determination of LD-Tyr and LD plasma levels were taken from pigs at the following time points:

[0274] 0 (pre-dose), 30 minutes, 1 hour, 2 hours, 6 hours, 8 hours, 9 hours, 10 hours, 12 hours, 14 hours, 18 hours, 18.5 hours, 19 hours, 21 hours, 23 hours and 26 hours after the start of the infusion.

[0341] [Table 33]

[0342] [Table 34]

[0343] PK result

[0275] A summary of the PK parameters obtained is shown in Table 35.

[0344] [Table 35]

[0345]

[0276] The combined mean concentrations of LD from the studies detailed above are shown in Figure 9.

[0277] Based on the results of this study and under the conditions of this study, it can be concluded that no significant differences in systemic exposure to LD were observed following injection of LD-Tyr 30% at 9 mL, LD-Tyr 37% at 7.5 mL, or LD-Tyr 44% at 6 mL.

[0346] Local site reactions

[0278] Immediately after removal of the pump, the infusion site was inspected for any local reactions. Any skin reactions (e.g., erythema, edema / swelling) were recorded and scored according to the 5-point Draize scale for scoring skin irritation, as shown in Table 31.

[0347]

[0279] No significant local skin reactions were observed in most treatment sites. Reactions observed immediately after pump removal consisted of minimal to moderate (grades 1-3) erythema and edema, as shown in Table 36.

[0348] [Table 36]

[0349] Example 16 - Pharmacokinetic and local site reaction studies in domestic pigs receiving formulations containing various concentrations of LD-Tyr and CD A series of PK and local site reaction studies were completed in domestic pigs using several concentrations of LD-Tyr formulations with various amounts of CD, as detailed in Table 37, and dosing regimens, as detailed in Table 38. The PK profile of LD-Tyr and therefore the LD were determined after 18 hours of continuous SC infusion in female domestic pigs. Each formulation was administered at one infusion site per animal using a Crono-ND infusion pump (Cane SpA Medical Technology, Rivoli, Italy) connected to an infusion set (Accu-chek®, FlexLink, Roche).

[0350]

[0281] Blood samples for determination of LD-Tyr and LD plasma levels were taken from pigs at the following time points:

[0282] 0 (pre-dose), 30 minutes, 1 hour, 2 hours, 6 hours, 8 hours, 9 hours, 10 hours, 12 hours, 14 hours, 18 hours, 18.5 hours, 19 hours, 21 hours, 23 hours and 26 hours after start of infusion.

[0351] [Table 37]

[0352] [Table 38]

[0353] PK result

[0283] A summary of the PK parameters obtained is shown in Table 39.

[0354] [Table 39]

[0355]

[0284] The combined mean concentrations of LD from the studies detailed above are shown in FIG. Local site reactions

[0285] Immediately after removal of the pump, the infusion site was inspected for any local reactions. Any skin reactions (e.g., erythema, edema / swelling) were recorded and scored according to the 5-point Draize scale for scoring skin irritation, as shown in Table 31.

[0356]

[0286] No significant local skin reactions were observed at any treatment site. Reactions observed immediately after pump removal ranged from minimal to well-defined erythema (Grades 1-2), as shown in Table 40.

[0357] [Table 40]

[0358] Example 17 - CD titration The effect of CD dose on the systemic exposure of LD was evaluated by comparing the plasma concentration of LD after continuous SC injection of LD-Tyr30% and a combination of different concentrations of CD (0.5-1.5%). Data were obtained from various preclinical studies (see Table 41) and normalized according to the animal's body weight. Figure 11 shows the normalized composite mean plasma concentration of LD.

[0359] [Table 41]

[0360]

[0288] It should be noted that these results show that the LD plasma concentrations after infusion of various CD concentrations of LD-Tyr30% were similar to each other, regardless of the CD dose.

[0361] Example 18 - PK and local site reaction studies following bolus and subcutaneous administration of 30% LD-Tyr formulation A series of PK and local toxicity studies were completed in domestic pigs using several concentrations of LD-Tyr formulations with various amounts of CD, as detailed in Table 42, and the dosing regimens detailed in Table 43. The PK profile of LD-Tyr and therefore the LD were determined after 18 hours of continuous SC infusion in female domestic pigs. Each formulation was administered at one infusion site per animal using a Crono-ND infusion pump (Cane SpA Medical Technology, Rivoli, Italy) connected to an infusion set (Accu-chek®, FlexLink, Roche).

[0362]

[0290] Blood samples for determination of LD-Tyr and LD plasma levels were taken from pigs at the following time points:

[0291] 0 (pre-dose), 10 minutes (end of bolus), 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 120 minutes and 240 minutes after the start of bolus administration.

[0363] [Table 42]

[0364] [Table 43]

[0365] PK result

[0292] The composite mean PK parameters of LD-Tyr and the resulting LD in domestic pigs are shown in Table 44. The composite mean plasma concentrations of LD-Tyr and the resulting LD are shown in Figure 12.

[0366] [Table 44]

[0367]

[0293] Based on the results and under the conditions of this study, it can be concluded that increasing the bolus injection volume from 0.7 mL to 1.2 mL and then to 1.7 mL, followed by a 2-hour continuous infusion at the same LD-Tyr / CD concentration (30% / 1%), increases systemic exposure to LD in a dose-proportional manner.

[0368]

[0294] These results also suggest that bolus injection of LD-Tyr followed by continuous SC infusion can decrease LD tmax compared to continuous SC infusion of LD-Tyr without bolus injection.

[0369] Local injection site reactions

[0295] Immediately after removal of the pump, the infusion site was inspected for any local reactions. Any skin reactions (e.g., erythema, edema / swelling) were recorded and scored according to the 5-point Draize scale for scoring skin irritation, as shown in Table 31.

[0370]

[0296] No significant local skin reactions were observed at any treatment site. Reactions observed immediately after pump removal ranged from minimal to well-defined edema (grades 1-2), as shown in Table 45.

[0371] [Table 45]

[0372] Example 19 – Local Tolerance and Pathological Study of Various Formulations after 2-hour SC Administration in Domestic Pigs

[0297] The formulations and vehicles detailed in Table 46, according to the dosing regimen detailed in Table 47, were tested in domestic pigs for local tolerability and pathology at the injection site 24 hours after SC administration.

[0373] [Table 46]

[0374] [Table 47]

[0375] result Based on the histopathological results, it was concluded that the ethanolamine-, diethanolamine-, and diethylamine-based formulations (F2–F5 and V2–V5) were not tolerated after 24-hour SC injection in a volume of 9 mL, whereas the non-amine-based F1 / V1 formulation was well tolerated.

[0376] Example 20 – Local Tolerance and Pathological Study of Additional Formulations Following 24-Hour SC Administration in Domestic Pigs

[0301] The formulations and vehicles detailed in Table 48 according to the dosing regimen detailed in Table 49 were tested in domestic pigs for local tolerability and pathology at the injection site 24 hours after SC administration.

[0377] [Table 48]

[0378] [Table 49]

[0379] result Based on the histopathological results, it can be concluded that all test formulations were well tolerated after 24-hour SC injection in a volume of 9 mL. Considering additional chemistry experiments (e.g., stability), we decided to focus on formulations F1 and F4, noting that F4 demonstrated better local tolerability than F1.

[0380] Example 21 - Local Tolerance Study of Formulations Containing PEG300 and / or Ethanol After 24-Hour SC Administration in Domestic Pigs

[0301] The formulations and vehicles detailed in Table 50, according to the dosing regimen detailed in Table 51, were tested in domestic pigs for local tolerability and pathology at the injection site 24 hours after SC administration.

[0381] [Table 50]

[0382] [Table 51]

[0383] result

[0302] Immediately after removal of the pump, the infusion site was inspected for any local reactions. Any skin reactions (e.g., erythema, edema / swelling) were recorded and scored according to the 5-point Draize scale for scoring skin irritation, as shown in Table 31.

[0384]

[0303] No significant local skin reactions were observed at any treatment site. Reactions observed immediately after pump removal consisted of minimal to moderate (grades 1-3) erythema or edema, as shown in Table 52.

[0385] [Table 52]

[0386]

[0304] Furthermore, based on the histopathological results and under the conditions of this study, it can be concluded that all three formulations (F1-F3) were well tolerated after SC injection in a volume of 9 mL for 24 hours.

[0387] Example 22 - Pharmacokinetics (PK) of Levodopa (LD) following SC administration of LD-Tyr in a formulation containing ethanol The purpose of this study is to determine the pharmacokinetics (PK) of LD-Tyr after 18-hour continuous subcutaneous (SC) administration of a formulation containing 30&LD-Tyr and ethanol to domestic pigs. Table 53 shows the LD-Tyr formulations tested in this study.

[0388] [Table 53]

[0389]

[0306] Animals were dosed with 2700 mg or 5400 mg of LD-Tyr in the formulation of Table 53, administered subcutaneously over 18 hours in continuous injection volumes of 9 ml or 18 ml (9 ml x 2 sites).

[0390]

[0307] Figure 13 shows the composite mean plasma LD-Tyr and LD concentration versus time profiles for the 2700 mg dosing regimen. PK parameters are also shown.

[0308] Figure 14 shows the composite mean plasma LD-Tyr and LD concentration versus time profiles for the 5400 mg dosing regimen. PK parameters are also shown.

[0391]

[0309] Figure 15 shows the composite mean plasma LD concentration versus time profiles for the 2700 mg and 5400 mg dosing regimens.

[0310] A summary of the PK results is shown in Table 54. The results shown in Figure 15 and Table 54 demonstrate dose proportionality of LD-Tyr.

[0392] [Table 54]

[0393] Experimental Example 23

[0311] To optimize the antioxidants in the LD-Tyr formulations, the following formulations were prepared and analytically evaluated.

[0394] [Table 55]

[0395] [Table 56]

[0396]

[0312] The results, shown in Table 56, indicate that neither antioxidant alone prevented impurities, nor did the combination of the two. Thus, the final amounts of each of ascorbic acid and NAC are between about 0.1% and about 1%.

[0397]

[0313] The following additional formulations, detailed in Table 57, were also prepared and their analyses at time 0 were determined using the two analytical methods detailed in Tables 58a and 58b.

[0398] [Table 57]

[0399] [Table 58a]

[0400] [Table 58b]

[0401]

[0314] Once the amount of ascorbic acid is optimized, the amount of NAC is optimized as well. The planned formulations used to optimize the amount of NAC are shown in Table 59 below:

[0402] [Table 59]

[0403] Equivalent

[0315] While several features of the present invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents may occur to those skilled in the art. It is therefore to be understood that the appended claims are intended to cover all such modifications and changes that fall within the true spirit of the present invention. All numbers expressing quantities of ingredients, reaction conditions, and the like used in this specification should be understood to be modified in all cases by the term "about", even if the term "about" is not specifically recited with respect to any of the disclosed embodiments.

[0404] Incorporation by Reference

[0316] The entire contents of all patents, published patent applications, websites, and other references referenced herein are expressly incorporated herein by reference in their entirety. [Industrial Applicability]

[0405]

[0201] In the present invention, the levodopa prodrug compounds and stabilized formulations described herein are useful for the prevention or treatment of neurodegenerative diseases and / or diseases or conditions caused by decreased dopamine concentration in the brain, such as Parkinson's disease and related conditions. Therefore, the present invention is highly useful in the pharmaceutical industry.

Claims

1. A levodopa amino acid conjugate represented by the following formula (I) or (III) or a pharma- ceutically acceptable salt thereof: [Chemical formula 1] 【Chemistry 1】 wherein R is an amino acid side chain that can be substituted; R １ and R ２ may be the same or different, and each independently represents a hydrogen atom, C １ ~C ６ Alkyl, C １ ~C ６ alkanoyl, phosphono, sulfino, or optionally substituted glycosyl, where R １ and R ２ is not a hydrogen atom at the same time; R ３ and R ４ may be the same or different, and each independently represents a hydrogen atom or C １ ~C ６ is alkyl; R ５ is a hydrogen atom; or [Chemical formula 3] 【Chemistry 2】 [In the formula, R １１ and R １２ are the same or different and each represents hydrogen, alkyl, alkanoyl, P(=O)(OH) ２ , S(═O)(OH) or optionally substituted glycosyl; R １３ is optionally substituted alkyl, -R １５ -O-R １６ or a 5-membered heterocyclyl containing at least one nitrogen atom, R １５ is alkylene, R １６ is hydrogen, alkyl, P(=O)(OH) ２ , S(═O)(OH), or optionally substituted glycosyl; R １４ is hydrogen or alkyl; However, the following compounds: (2S)-2-[(2-aminoacetyl)amino]-3-(3,4-diacetyloxyphenyl)propanoic acid, (2S)-2-[[(2S)-2-amino-6-[(2-chlorophenyl)methoxycarbonylamino]hexanoyl]amino]-3-(3,4-dimethoxyphenyl)propanoic acid, (2S)-2-[[(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl]amino]-3-(4-hydroxy-3-methoxyphenyl)propanoic acid, (2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-3-(3,4-dimethoxyphenyl)propanoic acid, (2S)-2-[[(2R)-2-amino-3-phenylpropanoyl]amino]-3-(3,4-diacetyloxyphenyl)propanoic acid, and (2S)-2-[[(2S)-2-amino-5-methoxy-5-oxopentanoyl]amino]-3-(3,4-dimethoxyphenyl)propanoic acid Except for A levodopa amino acid complex or a pharma- ceutically acceptable salt thereof.

2. R ３ , R ４ and R ５ is a hydrogen atom, R １ and R ２ are the same or different and each is a hydrogen atom, acetyl or phosphono, provided that R １ and R ２ But at the same time, it is not a hydrogen atom. The levodopa amino acid complex of claim 1 or a pharma- ceutically acceptable salt thereof.

3. R ３ , R ４ and R ５ is a hydrogen atom, R １ is a hydrogen atom; R ２ But it is phosphono. The levodopa amino acid complex of claim 1 or 2, or a pharma- ceutically acceptable salt thereof.

4. The levodopa amino acid conjugate or pharma- ceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the amino acid in the amino acid side chain is glutamic acid, valine, alanine, lysine, 3,4-dihydroxyphenylalanine or tyrosine.

5. (2S)-2-[[(2S)-2-amino-3-phosphonooxypropanoyl]amino]-3-(3,4-dihydroxyphenyl)propanoic acid, (2S)-2-[[(2S)-2-amino-3-(4-phosphonooxyphenyl)propanoyl]amino]-3-(3,4-dihydroxyphenyl)propanoic acid, (2S)-2-amino-5-[[(1S)-1-carboxy-2-(3,4-diacetoxyphenyl)ethyl]amino]-5-oxo-pentanoic acid, (2S)-3-(3,4-dihydroxyphenyl)-2-[(2-methyl-2-phosphonooxypropanoyl)amino]propanoic acid, and (2S)-2-[[(2S)-2-amino-3-[4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]propanoyl]amino]-3-(3,4-dihydroxyphenyl)propanoic acid A levodopa amino acid conjugate selected from the group consisting of:

6. A liquid pharmaceutical composition comprising, as an active ingredient, the levodopa amino acid complex or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 5.

7. A therapeutic agent for a neurodegenerative disease and / or a disease or symptom caused by a decrease in dopamine concentration in the brain, comprising the levodopa amino acid complex according to any one of claims 1 to 5 or a pharma- ceutical acceptable salt thereof as an active ingredient.

8. The therapeutic agent according to claim 7, wherein the disease or symptom caused by a neurodegenerative disease and / or a decrease in dopamine concentration in the brain is Parkinson's disease.

9. Formula (II): 【Chemistry 3】 levodopa-tyrosine conjugate (LD-Tyr), an enantiomer, diastereomer, racemate, ion, zwitterion, a pharma- ceutically acceptable salt thereof, or any combination thereof; and Stabilizer 1. A liquid pharmaceutical composition comprising:

10. 10. The liquid pharmaceutical composition of claim 9, comprising between about 10 and about 45% w / v of LD-Tyr, enantiomer, diastereomer, racemate, ion, zwitterion, pharma- ceutically acceptable salt thereof, or any combination thereof.

11. 10. The liquid pharmaceutical composition of claim 9, comprising at least about 30% w / v of LD-Tyr, an enantiomer, a diastereomer, a racemate, an ion, a zwitterion, a pharma- ceutically acceptable salt thereof, or any combination thereof.

12. 12. The liquid pharmaceutical composition of claim 10 or 11, comprising between about 30 to about 45% w / v of LD-Tyr, enantiomer, diastereomer, racemate, ion, zwitterion, pharma- ceutically acceptable salt thereof, or any combination thereof.

13. The liquid pharmaceutical composition according to any one of claims 9 to 12, wherein the stabilizer is present in an amount of about 0.1 to about 30% w / v.

14. The liquid pharmaceutical composition according to any one of claims 9 to 13, wherein the stabilizer comprises a base.

15. The base is arginine, NaOH, NH ４ 15. The liquid pharmaceutical composition of claim 14, wherein the amine is selected from the group consisting of OH, tris(hydroxymethyl)aminomethane (TRIS), ethylenediamine, diethylamine, ethanolamine, diethanolamine, meglumine, and any combination thereof.

16. The base is arginine, NH ４ 16. The liquid pharmaceutical composition of claim 15, wherein the amine is selected from the group consisting of OH, ethylenediamine, diethylamine, ethanolamine, diethanolamine, meglumine, and any combination thereof.

17. 17. The liquid pharmaceutical composition of claim 16, wherein the base is selected from the group consisting of L-Arg, diethylamine, and combinations thereof.

18. 18. The liquid pharmaceutical composition of claim 17, wherein the base is selected from the group consisting of L-Arg, ethanolamine, and combinations thereof.

19. 19. The liquid pharmaceutical composition according to any one of claims 14 to 18, comprising between about 0.1 to about 30% w / v of base.

20. 20. The liquid pharmaceutical composition according to any one of claims 19, comprising between about 1.5 and about 20% w / v of base.

21. The liquid pharmaceutical composition according to any one of claims 9 to 20, having a pH in the range between about 5 and about 10 at about 25°C.

22. 22. The liquid pharmaceutical composition of claim 21, having a pH in the range of between about 8 to about 10 at about 25°C.

23. 23. The liquid pharmaceutical composition of claim 22, having a pH in the range of between about 8 and about 9 at about 25°C.

24. The liquid pharmaceutical composition according to any one of claims 9 to 23, further comprising a decarboxylase inhibitor.

25. 25. The liquid pharmaceutical composition of claim 24, wherein the decarboxylase inhibitor is carbidopa.

26. 26. The liquid pharmaceutical composition of claim 24 or 25, comprising between about 0.25 to about 1.5% w / v of a decarboxylase inhibitor.

27. The liquid pharmaceutical composition according to any one of claims 9 to 26, further comprising an antioxidant or a combination of two or more antioxidants.

28. The antioxidants are each independently selected from the group consisting of ascorbic acid or a salt thereof, cysteine, bisulfite or a salt thereof, glutathione, a tyrosinase inhibitor, Cu ２＋ 28. The liquid pharmaceutical composition of claim 27, wherein the active ingredient is selected from the group consisting of: a chelating agent, a stearate agent, a stearate inhibitor ... and any combination thereof.

29. 29. The liquid pharmaceutical composition of claim 28, wherein the cysteine ​​is N-acetylcysteine ​​(NAC).

30. The liquid pharmaceutical composition according to any one of claims 27 to 29, wherein the antioxidant is a combination of ascorbic acid and NAC.

31. 31. The liquid pharmaceutical composition according to any one of claims 27 to 30, comprising between about 0.05 to about 1.5% w / v of one or a combination of antioxidants.

32. 32. The liquid pharmaceutical composition of any one of claims 1 to 31, further comprising at least one of a catechol-O-methyltransferase (COMT) inhibitor, a monoamine oxidase (MAO) inhibitor, a surfactant, a buffer, an acid, a solvent, or any combination thereof.

33. 33. The liquid pharmaceutical composition of claim 32, wherein the buffer is TRIS.

34. 34. The liquid pharmaceutical composition of any one of claims 32 or 33, comprising between about 5.0 and about 40.0% w / v buffer.

35. The liquid pharmaceutical composition according to any one of claims 1 to 34, wherein the stabilizer comprises polyethylene glycol.

36. 36. The liquid pharmaceutical composition of any one of claims 1 to 35, comprising less than about 1.5% w / v LD-Tyr-diketopiperazine after 2 weeks at 2-8°C.

37. 37. The liquid pharmaceutical composition of claim 36, comprising less than about 0.8% w / v LD-Tyr-diketopiperazine after 2 weeks at 2-8°C.

38. 37. The liquid pharmaceutical composition of any one of claims 1 to 36, comprising less than about 5.0% w / v LD-Tyr-diketopiperazine after 2 weeks at 25°C.

39. 40. The liquid pharmaceutical composition of claim 38, comprising about 4.0% w / v or less LD-Tyr-diketopiperazine after 2 weeks at 25°C.

40. A liquid pharmaceutical composition according to any one of claims 1 to 39 for use in the treatment of neurodegenerative conditions and / or conditions characterised by reduced levels of dopamine in the brain.

41. 41. The liquid pharmaceutical composition of claim 40, wherein the neurodegenerative condition is Parkinson's disease.

42. 42. The liquid pharmaceutical composition of claim 40 or 41, which is administered to a patient simultaneously with an additional active ingredient.

43. 43. The liquid pharmaceutical composition of claim 42, wherein the additional active ingredient is selected from the group consisting of a decarboxylase inhibitor, a COMT inhibitor, an MAO inhibitor, and any combination thereof.

44. The liquid pharmaceutical composition according to any one of claims 40 to 43, which is administered to a patient on a substantially continuous basis.

45. The liquid pharmaceutical composition according to any one of claims 40 to 44, which is administered subcutaneously.

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