Levodopa fatty acid derivative, preparation thereof and application of levodopa fatty acid derivative in treatment of Parkinson's disease

Abstract

A levodopa derivative, including a compound or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where the compound includes substituents comprising in total at least 6 carbon atoms that bind only to other carbon atoms or hydrogen atoms. The levodopa derivatives may be formulated as compositions that include one or more pharmaceutically acceptable carriers or excipients. The levodopa derivative may be part of a pharmaceutical composition, including microparticles or nanoparticles, in which the levodopa derivative is encapsulated in a pharmaceutically acceptable polymer. Levodopa derivatives may be used to treat Parkinson's disease by administering to a mammal an amount sufficient to treat Parkinson's disease.

Description

Technical Field

[0001] The present invention relates to fatty acid and / or fatty alcohol derivatives of levodopa and polymer nanoparticle / microparticle preparations of levodopa derivatives. These compounds and compositions can be used to treat Parkinson's disease. Background Art

[0002] Levodopa (hereinafter referred to as L-DOPA) is the common name of (S)-2-amino-3-(3,4-dihydroxyphenyl)propionic acid, as shown below:

[0003]

[0004] L-DOPA is an aromatic amino acid derivative and the main source of dopamine. In humans and other animals, L-DOPA is synthesized from the amino acid L-tyrosine and is a precursor to the neurotransmitters dopamine, norepinephrine, and epinephrine, collectively known as catecholamines.

[0005] Parkinson's disease (PD) is a progressive neurodegenerative disease that affects approximately 1-2% of the population over the age of 60. Symptoms include resting tremor, rigidity, bradykinesia, and postural instability, which are caused by selective degeneration of substantia nigra dopaminergic neurons, resulting in disruption of the nigrostriatal pathway and decreased striatal dopamine levels. Olanow et al., Neurology. 2009; 72(21 Suppl 4): S1-136.

[0006] The efficacy of high-dose levodopa (3-16 g / day) in the treatment of PD was first reported in 1969 (Cotzias et al., N. Engl. J. Med. 1969; 280(7): 337-345; Yahr et al., Arch. Neurol. 1969; 21(4): 343-354). In 1970, the U.S. Food and Drug Administration (FDA) approved levodopa for the treatment of Parkinson's disease. Unlike dopamine, levodopa can cross the blood-brain barrier (BBB) ​​and is converted to dopamine in the central nervous system and peripheral circulation (peripheral circulation is the circulation before crossing the blood-brain barrier). Most commonly, levodopa is used as a dopamine replacement for the treatment of Parkinson's disease and is particularly effective in controlling the prominent bradykinesia symptoms of Parkinson's disease. Levodopa is recommended for symptomatic treatment of all stages of Parkinson's disease, taken orally multiple times a day. Levodopa is often taken with the dopamine decarboxylase inhibitor carbidopa to reduce the amount of levodopa converted to dopamine in the periphery, thereby allowing more levodopa to cross the blood-brain barrier and be converted to dopamine. Thus, this combination therapy allows more levodopa to cross the blood-brain barrier. Once converted to dopamine, it activates postsynaptic dopaminergic receptors and compensates for the reduction in endogenous dopamine.

[0007] Levodopa is absorbed in the small intestine, and 95% of the administered oral dose is previously systemically decarboxylated to dopamine by aromatic L-amino acid decarboxylase (AADC) in the stomach, intestinal lumen, kidneys, and liver. Levodopa may also be methoxylated to 3-methyldopa (3-OMD) by the hepatic catechol-O-methyltransferase (COMT) system, which cannot be converted to central dopamine. Therefore, only a small portion of an oral dose of levodopa crosses the blood-brain barrier and enters the central nervous system (CNS), where it is converted to the neurotransmitter dopamine by the brain's AADC enzyme. Dopamine is further converted to sulfated or glucuronidated metabolites and homovanillic acid by various metabolic processes. The major metabolites of levodopa are 3,4-dihydroxyphenylacetic acid (13-47%) and homovanillic acid (23-39%).

[0008] Since gastric AADC and COMT enzymes degrade levodopa, the drug can be taken with: i) peripheral dopamine decarboxylase inhibitors (carbidopa), as without carbidopa, 90% of levodopa is metabolized in the intestinal wall, and ii) COMT inhibitors (entacapone), as COMT inhibitors may further increase the bioavailability of levodopa in the brain. See, for example, Hauser RA. Levodopa: past, present, and future. Eur Neurol. 2009;62(1):1-8.doi:10.1159 / 000215875.Epub 2008 Sep 9. PMID:19407449; and Tambasco N, Romoli M, Calabresi P. Levodopa in Parkinson's Disease: Current Status and FutureDevelopments.Curr Neuropharmacol.2018;16(8):1239-1252.doi:10.2174 / 1570159X15666170510143821.PMID:28494719;PMCID:PMC6187751.

[0009] AADC and COMT inhibitors inhibit the decarboxylation of levodopa in the stomach and periphery, allowing more levodopa to be transported across the blood-brain barrier to increase brain dopamine levels. When administered with levodopa, carbidopa reduces the amount of levodopa required to produce a given response by 75%. A 200 mg dose of entacapone increases plasma exposure to levodopa by 35-40% when co-administered with levodopa / carbidopa.

[0010] The plasma half-life of levodopa alone is approximately fifty (50) minutes. and CR 50-200), the half-life increases to 1.5 hours ( label, NDA1755). Peak plasma concentration (T max ) takes about 0.5 hours. CR is 2 hours, and the peak blood concentration (C max ) were 1151ng / mL( ) and 3256ng / mL( CR). Application (Carbidopa, levodopa and entacapone combination, 37.5 / 150 / 200mg), t max About 1.5 hours, C max 1270±329ng / mL( Trademark, NDA 21485).

[0011] Common side effects of levodopa include nausea, vomiting, dry mouth, loss of appetite, heartburn, diarrhea, constipation, dizziness, muscle pain, numbness or tingling, and sleep disturbances. Severe side effects include mood changes, increased blinking / twitching, and worsening involuntary movements / spasms. Motor fluctuations, including dyskinesias and dyskinesias, are closely related to the pharmacokinetics of levodopa, its irregular uptake, short half-life, low bioavailability, and significant fluctuations in plasma concentrations. LeWitt, Mov. Disord. 2015; 30(1): 64-72; Tambasco et al., Curr Neuropharmacol. 2018; 16(8): 1239-1252.

[0012] The development of dyskinesias may be avoided by using lower doses of levodopa and maintaining stable dopamine levels. Research is ongoing to find delivery routes for levodopa that will allow for sustained dopaminergic stimulation. Abbvie( ) for the treatment of motor fluctuations in patients with advanced Parkinson's disease through continuous infusion and was approved by the FDA in 2015. A levodopa inhalation powder was approved by the FDA in 2018. Several other formulations for continuous subcutaneous (SC) infusion, such as ABBV-951 (Abbvie) and ND6012 (Neuroderm / Msubishi Tanabe), are in development.

[0013] Levodopa has been modified into water-soluble ester and amide derivatives for better absorption by the brain. See Levodopa, Di Stefano A, Sozio P, Cerasa LS, Iannitelli AL - Dopa prodrugs: an overview of trends for improving Parkinson's disease treatment. Curr Pharm Des. 2011; 17(32): 3482-93. doi: 10.2174 / 138161211798194495. PMID: 22074421.

[0014] In levodopa, there are two benzyl hydroxyl groups at the 3 and 4 positions of the benzene ring, an amine group at the 2 position of the alkyl chain, and an active carboxyl group at the end of the alkyl chain. The two hydroxyl groups of levodopa can be modified into ester derivatives. ) is already on the market. However, in Phase III clinical trials, it was found that the ethyl ester derivative (Etilevodop, TV-1203) was not as effective as levodopa.

[0015] WO 2020 / 2264460 discloses a method for reducing premature levodopa reaction. The present invention improves the invention in WO 2020 / 226460. The disclosure of WO 2020 / 2264460 is incorporated herein by reference in its entirety.

[0016] In current treatments for Parkinson's disease using levodopa (or its prodrugs), the plasma half-life of levodopa is very short, resulting in significant fluctuations in plasma drug concentrations, which in turn result in fluctuations in the amount of levodopa that crosses the blood-brain barrier, leading to inconsistent dopamine levels in the brain. As the disease progresses, these fluctuations in plasma concentrations are reflected in fluctuations in the response to treatment. A treatment method is needed that can provide a stable level of plasma levodopa concentrations that stably cross the blood-brain barrier over a longer period of time. The present invention addresses all of these needs. Summary of the invention

[0017] In one embodiment, the present invention relates to a levodopa derivative, comprising a compound or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein the levodopa derivative comprises a substituent having a total of at least 6 carbon atoms, which are only bonded to other carbon atoms or hydrogen atoms. The levodopa derivative may comprise a substituent having a total of 8-100 carbon atoms, which are only bonded to other carbon atoms or hydrogen atoms.

[0018] In one aspect of the present invention, the levodopa derivative comprises a compound of formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0019]

[0020]

[0021] Wherein R1 can be a branched or straight chain C4-34 group derived from a saturated or unsaturated fatty alcohol, and the C4-34 group is directly or indirectly connected to a carbonyl group to form an ester, amide or anhydride structure. R3 can be a branched or straight chain C4-34 group derived from a saturated or unsaturated fatty acid, and R3 is directly or indirectly connected to oxygen to form an ester, carbonate or carbamate structure. R4 can be a branched or straight chain C4-34 group derived from a saturated or unsaturated fatty acid, and R4 is directly or indirectly connected to oxygen to form an ester, carbonate or carbamate structure. R2 can be hydrogen or -(C=O)R5, wherein R5 can be C 1-3 Straight chain or branched chain alkyl.

[0022] In another aspect, the levodopa derivative comprises a compound of formula II, or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0023]

[0024] Wherein R6 can be a derivative of a saturated or unsaturated fatty alcohol, and

[0025] Wherein R7 can be a derivative of a saturated or unsaturated fatty acid, and

[0026] Wherein R8 can be a derivative of a saturated or unsaturated fatty acid, and wherein

[0027] R2 is hydrogen or -(C=O)R5, wherein R5 is C 1-3 Straight chain or branched chain alkyl.

[0028] In another aspect, the levodopa derivative comprises a compound of formula II, or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0029]

[0030] Where R6 can be:

[0031] (a) -O-R9, wherein R9 may be an alkyl or alkenyl group, which may include 4 to 34 carbon atoms and may be branched or linear, substituted or unsubstituted, or

[0032] (b) NH-R10, wherein R10 may be an alkyl or alkenyl group, which may include 4 to 34 carbon atoms and may be branched or linear, substituted or unsubstituted, or

[0033] (c) -OC=O-R11, wherein R11 may be an alkyl or alkenyl group, which may include 4 to 34 carbon atoms and may be branched or linear, substituted or unsubstituted, and

[0034] Where R7 can be:

[0035] (a) an alkyl or alkenyl group which may comprise 4 to 34 carbon atoms and may be branched or straight chain, substituted or unsubstituted, or

[0036] (b) -NH-R12, wherein R12 may be an alkyl or alkenyl group, which may include 4 to 34 carbon atoms and may be branched or linear, substituted or unsubstituted, or

[0037] (c) -O-R13, wherein R13 comprises an alkyl or alkenyl group, which may comprise 4 to 34 carbon atoms and is branched or linear, substituted or unsubstituted, and

[0038] Where R8 can be

[0039] (a) an alkyl or alkenyl group which may comprise 4 to 34 carbon atoms and may be branched or straight chain, substituted or unsubstituted, or

[0040] (b) -NH-R14, wherein R14 may be an alkyl or alkenyl group, which may include 4 to 34 carbon atoms and may be branched or linear, substituted or unsubstituted, or

[0041] (c) -O-R15, wherein R15 is an alkyl or alkenyl group which may comprise 4 to 34 carbon atoms and may be branched or linear, substituted or unsubstituted, and

[0042] wherein R2 is hydrogen, or -(C=O)R5, wherein R5 is C 1-3 Straight chain or branched chain alkyl.

[0043] In one aspect of the present invention, in Formula II, R6 is selected from: (CH3)3CO-, CH3CH2C(CH3)2O-, CH3CH2CCH3(O-)CH2CH3, CH3(CH2)6O-, CH3(CH2)7O-, CH3(CH2)8O-, CH3(CH2)8CH2O-, CH3(CH2) 10 CH2O-、CH3(CH2) 11 CH2O-、CH3(CH2) 12 CH2O-、CH3(CH2)13 CH2O-, CH3(CH2) 14 CH2O-, CH3(CH2)5CH=CH(CH2)7CH2O-, CH3(CH2) 15 CH2O-, CH3(CH2) 16 CH2O-, CH3(CH2)7-CH=CH-(CH2)8O-, CH3(CH2) 17 CH2O-, CH3(CH2) 18 CH2O-, CH3(CH2) 19 CH2O-, CH3(CH2) 20 CH2O-, CH3(CH2)7CH=CH(CH2) 11 CH2O-, CH3(CH2) 22 CH2O-, CH3(CH2) 24 CH2O-, CH3(CH2) 25 CH2O-, CH3(CH2) 26 CH2O-, CH3(CH2) 27 CH2O-, CH3(CH2) 28 CH2O-, CH3(CH2) 30 CH2O-, CH3(CH2) 32 CH2O-, CH3(CH2)3CH=CH(CH2)7CH2O-, CH3(CH2)8CH=CH(CH2)4CH2O-, CH3(CH2)7CH=CH(CH2)7CH2O-, CH3(CH2)5CH=CH(CH2)9CH2O-, CH3(CH2)4CH=CHCH2CH=CH(CH2)7CH2O-, CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7CH2O-, CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3CH2O-, CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3CH2O-, CH3(CH2)7CH=CH(CH2) 11 CH2O- and CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)2CH2O-.

[0044] In formula II, R7 and / or R8 can be independently selected from: CH3(CH2)6-, CH3(CH2)8-, CH3(CH2) 10 -, CH3(CH2)12 -、CH3(CH2) 14 -、CH3(CH2) 16 -、CH3(CH2) 18 -、CH3(CH2) 20 -、CH3(CH2) 22 -、CH3(CH2) 24 -, CH3(CH2)3CH=CH(CH2)7-, CH3(CH2)5CH=CH(CH2)7-, CH3(CH2)8CH=CH(CH2)4-, CH3(CH2)7CH=CH(CH2)7 -, CH3(CH2)7CH=CH(CH2)7-, CH3(CH2)5CH=CH(CH2)9-, CH3(CH2)4CH=CHCH2CH=CH(CH2)7-(cis, cis), CH3(CH2) 4CH=CHCH2CH=CH(CH2)7-(reverse, reverse), CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7-, CH3(CH2)4CH=CHCH2CH=CHCH2CH =CHCH2CH=CH(CH2)3-, CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3-, CH3(CH2)7CH=CH(CH2) 11 - and CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)2-.

[0045] In another aspect of the present invention, the levodopa derivative may be a compound of formula II, or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0046]

[0047] Wherein R6 can be the following groups:

[0048] (a) -O-R9, wherein R9 can be an alkyl or alkenyl group, which comprises 4 to 34 carbon atoms and is branched or linear, substituted or unsubstituted, or

[0049] (b) NH-R10, wherein R10 may be an alkyl or alkenyl group, comprising 4 to 34 carbon atoms and being branched or linear, substituted or unsubstituted, or

[0050] (c) -OC=O-R11, wherein R11 can be an alkyl or alkenyl group, which comprises 4 to 34 carbon atoms and is branched or linear, substituted or unsubstituted, and

[0051] R7 may include:

[0052] (a) an alkyl or alkenyl group comprising 4 to 34 carbon atoms and being branched or straight-chain, substituted or unsubstituted, or

[0053] (b) -NH-R12, wherein R12 can be an alkyl or alkenyl group, which comprises 4 to 34 carbon atoms and is branched or linear, substituted or unsubstituted, or

[0054] (c) -O-R13, wherein R13 may be an alkyl or alkenyl group, comprising 4 to 34 carbon atoms and being branched or linear, substituted or unsubstituted, and

[0055] Where R8 can be

[0056] (a) an alkyl or alkenyl group comprising 4 to 34 carbon atoms and being branched or straight-chain, substituted or unsubstituted, or

[0057] (b) -NH-R14, wherein R14 can be an alkyl or alkenyl group, which comprises 4 to 34 carbon atoms and is branched or linear, substituted or unsubstituted, or

[0058] (c) -O-R15, wherein R15 can be an alkyl or alkenyl group, which comprises 4 to 34 carbon atoms and is branched or linear, substituted or unsubstituted, and

[0059] wherein R2 is hydrogen, or -(C=O)R5, wherein R5 is C 1-3 A straight chain or branched chain alkyl group.

[0060] In the present invention, the levodopa derivative may be (S)-4-(2-amino-3-(dodecyloxy)-3-oxopropyl)-1,2-phenylene behenate, which is identified as DB104 in the examples and has a chemical formula of C 45 H 79 NO6, molecular weight is 730.13. Levodopa derivative (DB104) may have the following molecular structure.

[0061]

[0062] However, levodopa modified with other fatty acids or fatty alcohols is also contemplated in the present invention.

[0063] In another aspect, the levodopa derivative is a hydrochloride salt having the following formula:

[0064]

[0065] The present invention may relate to a composition comprising a pharmaceutically effective amount of a levodopa derivative of the present invention and one or more pharmaceutically acceptable carriers or excipients. Such a composition may be injectable, inhalable, orally administrable or topically administrable. Such a composition may be in the form of liposomes or micelles. The pharmaceutically acceptable carrier of the levodopa derivative may be castor oil or a derivative thereof.

[0066] In another embodiment, the present invention may be directed to a pharmaceutical composition containing microparticles or nanoparticles, the microparticles or nanoparticles comprising a pharmaceutically effective amount of a levodopa derivative and a pharmaceutically acceptable polymer, wherein the levodopa derivative is encapsulated in the pharmaceutically acceptable polymer. The pharmaceutically acceptable polymer may be selected from the group consisting of polyethylene glycol, polyglycolide, polylactide, polycaprolactone, poly(lactide-co-caprolactone), poly(lactide-co-glycolide), poly(lactic acid)-butanol, poly(vinyl pyrrolidone), polyvinyl alcohol, poly(ethyleneimine), polymalic acid, poly-L-lysine, poly-L-glutamic acid, poly((N-hydroxyalkyl)glutamine), dextrin, hydroxyethyl starch, polysialic acid, polyacetal, N-(2-hydroxypropyl)methacrylamide copolymer, poly(amide) dendrimer, and mixtures, compositions and copolymers thereof.

[0067] In another aspect, the present invention may relate to a method for treating Parkinson's disease, comprising administering to a mammal an amount of a levodopa derivative sufficient to treat Parkinson's disease. The levodopa derivative may be in the form of a composition, which may be administered intravenously, intramuscularly, intraperitoneally, orally or subcutaneously.

[0068] The composition containing the levodopa derivative can be co-administered with carbidopa and / or entacapone for the treatment of Parkinson's disease.

[0069] In another aspect, the composition containing the levodopa derivative can be used to treat Parkinson's disease by administering it once a day to a patient with Parkinson's disease. In another aspect, the composition can be administered up to two or three times a week. In another aspect, the composition can be administered once a week or every two weeks. The composition can be administered once a month.

[0070] In one embodiment, the composition containing the levodopa derivative can be a pharmaceutical composition comprising microparticles or nanoparticles containing a pharmaceutically effective amount of the levodopa derivative and a pharmaceutically acceptable polymer, and can be co-administered with carbidopa and / or entacapone to treat Parkinson's disease. Such a composition can be administered intravenously, intramuscularly, intraperitoneally, orally or subcutaneously. Administration can be once a day, up to twice or three times a week, once a week or every two weeks, or once a month. DETAILED DESCRIPTION

[0071] The specific embodiments described below are intended to describe some but not all configurations of the present technology, and are not intended to represent an exhaustive list. The specific embodiments include specific details for providing a comprehensive understanding of the present invention and subject technology. The present invention and technology are not limited to the specific details described herein, and can be practiced without these specific details. In other cases, well-known structures and technologies are not shown in detail to avoid confusion with the present disclosure. Exemplary embodiments may be discussed in detail below. Although specific exemplary embodiments may be discussed, it should be understood that this will be used only for illustrative purposes. When describing and illustrating exemplary embodiments, specific terms may be used for clarity. However, the embodiments are not intended to be limited to the specific terms so selected. Those skilled in the relevant art will recognize that other components and configurations may be used without departing from the spirit and scope of the embodiments. It should be understood that each specific element includes all technical equivalents that operate in a similar manner to achieve similar purposes. The examples and embodiments described herein are non-limiting embodiments.

[0072] All publications cited herein are incorporated herein by reference in their entirety. As used herein, the term "a" refers to one or more. The terms "including," "for example," "such as," "as," "may be," etc. are intended to include, but are not limited to, the listed examples.

[0073] References to "one embodiment," "an embodiment," "example embodiment," "various embodiments," etc. may indicate that the embodiments of the invention being described may include particular features, structures, or characteristics, but not every embodiment must include the particular features, structures, or characteristics.

[0074] Furthermore, repeated use of the phrase "in one embodiment" or "in an illustrative embodiment," does not necessarily refer to the same embodiment, although they may. The various embodiments described herein may be combined and / or features of the embodiments may be combined to form new embodiments.

[0075] Although various embodiments of the present invention have been described herein, it should be understood that this is only proposed by way of example and not limitation. Therefore, the breadth and scope of the present invention should not be limited by any of the illustrative embodiments described. The embodiments of the present invention described may include features that can be removed or combined between the described embodiments to derive additional embodiments. Any scope disclosed herein is intended to disclose and discloses any scope within such disclosed scope.

[0076] Headings and subheadings, if any, are used for convenience only and do not limit the invention.

[0077] Phrases such as "aspects" do not mean that the aspect is essential to the subject technology or that the aspect applies to all configurations of the subject technology. Disclosures related to an aspect may apply to all configurations, or one or more configurations. Phrases such as aspects may refer to one or more aspects and vice versa. Phrases such as "embodiments" do not mean that such embodiments are essential to the subject technology or that such embodiments apply to all configurations of the subject technology. Disclosures related to embodiments may apply to all embodiments or one or more embodiments. Phrases such as an embodiment may refer to one or more embodiments and vice versa.

[0078] All structural and functional equivalents of the elements of the various aspects described in this disclosure, which are known or later become known to those of ordinary skill in the art, are expressly incorporated herein by reference and are intended to be covered by the claims. In addition, nothing disclosed herein is intended to be dedicated to the public, regardless of whether such disclosure is explicitly recited in the claims. In addition, to the extent the terms "including," "having," and the like are used in the specification or claims, the terms are intended to be inclusive in a manner similar to how the term "comprising" is interpreted when used as a transition word in a claim.

[0079] L-dopa, if used alone to treat Parkinson's disease, is largely degraded before it has a chance to cross the blood-brain barrier and properly cause an increase in dopamine levels. As part of the present invention, it has been discovered that by adding a "fat" type structure as part of the L-dopa derivative to protect the L-dopa from premature degradation, more L-dopa can be achieved to cross the blood-brain barrier. Therefore, the patient can consume less of the active ingredient to achieve better results, which also results in a consistent entry of the active ingredient into the blood-brain barrier and therefore consistent dopamine levels in the brain.

[0080] These "fat" type structures help protect the levodopa active portion of the molecule. In addition, it is believed that these "fat" type structures will be more able to cross the blood-brain barrier because these structures are more "fatty" and therefore soluble in lipids, which is a required characteristic for crossing the blood-brain protective barrier. If the "fat" portion of the molecule is too small, the protection against premature degradation of the levodopa active portion may be insufficient, and the levodopa derivative may not effectively cross the blood-brain barrier. Alternatively, if the "fat" portion is too large, this may make it difficult for the levodopa derivative to be broken down into a usable form, and may also make it more difficult to easily cross the blood-brain barrier. The present invention solves all of these challenges through new chemical structures and compositions, as described more fully below.

[0081] In essence, the compounds of the present invention have several advantages, including improved bioavailability at lower doses; predictable drug release over a period of time after each administration; better patient compliance; ease of application; improved systemic availability by avoiding first-pass metabolism; reduced frequency of administration without compromising the effectiveness of the treatment; reduced incidence of side effects; better blood-brain barrier translocation and reduced overall cost of health care.

[0082] In one embodiment, the present invention relates to levodopa derivatives, including certain compounds and pharmaceutically acceptable salts, hydrates and / or solvates of these compounds. Levodopa derivatives, including these compounds and pharmaceutically acceptable salts, hydrates and / or solvates of these compounds, are collectively referred to as "derivatives" or "levodopa derivatives". The derivatives may include substituents containing at least 6 carbon atoms in total, which are only bonded to other carbon atoms or hydrogen atoms. This is some of the "fat" parts of the molecules described in the present invention. The derivatives may include substituents containing 8-100 carbon atoms in total, which are only bonded to other carbon atoms or hydrogen atoms. In other embodiments, the number of carbons that are only bonded to other carbon atoms or hydrogen atoms is 15-90, 25-80, 30-50, 32-40 and any range within these ranges, such as any range between 8-100 carbon atoms is foreseeable in the present invention. Since the present invention attempts to add "fat" protecting groups to levodopa, fatty acids and fatty alcohols can be used to synthesize derivatives, which will be further explained below. Additionally, additional details on what types of molecules may be part of the derivative will be described.

[0083] Masking the reactive hydroxyl groups of one or both of the benzene ring and / or carboxylic acid groups of levodopa with a fatty structure is one way to implement the present invention. The amine groups of levodopa can also be masked. Fatty acid derivatives can react with the hydroxyl groups on the benzene ring of levodopa, thereby adding a "fat" type structure to the molecule. The carboxylic acid groups in levodopa can react with fatty alcohol derivatives to add more of this "fat" type structure. For example, the fatty groups can be combined with hydroxyl or carbonyl groups through the formation of ester groups. These ester groups contain bonds that can be cleaved in vivo, so they can react in vivo to ultimately obtain free levodopa, because free levodopa is required to produce dopamine. Once masked, the amines in levodopa can also react to produce free levodopa. The masking of the present invention also reduces the probability of levodopa being peripherally degraded to dopamine by AADC and COMT enzymes, thereby increasing the subsequent utilization of levodopa in the brain. The derivatives provide sustained plasma levels of levodopa, increase the delivery of levodopa to the brain, and thus improve the efficacy.

[0084] In one aspect of the present invention, the derivative comprises a compound of formula I, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof,

[0085]

[0086] Wherein R1 can be a branched or straight chain C4-34 group derived from a saturated or unsaturated fatty alcohol, and the C4-34 group is directly or indirectly connected to a carbonyl group to form an ester, amide or anhydride structure. R3 can be a branched or straight chain C4-34 group derived from a saturated or unsaturated fatty acid, and R3 is directly or indirectly connected to oxygen to form an ester, carbonate or carbamate structure. R4 can be a branched or straight chain C4-34 group derived from a saturated or unsaturated fatty acid, and R4 is directly or indirectly connected to oxygen to form an ester, carbonate or carbamate structure. R2 can be hydrogen, or -(C=O)R5, wherein R5 can be a C1-3 straight or branched alkyl group, which can be substituted or unsubstituted. The carbon number of R1, R3 and R4 determined above is 4-34, however, various other ranges are also possible. Other ranges may include C4-C26, C6-C30, C8-C25, C10-C20, C11-C15 and C12. All ranges within the range of C4-34 are also foreseeable. The number of carbon atoms of R1, R3 and R4 may be the same or different.

[0087] In another aspect, the derivative comprises a compound of formula II or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0088]

[0089] Wherein R6 can be a derivative of a saturated or unsaturated fatty alcohol, and

[0090] Wherein R7 can be a derivative of a saturated or unsaturated fatty acid, and

[0091] Wherein R8 can be a derivative of a saturated or unsaturated fatty acid, and wherein

[0092] R2 is hydrogen, or -(C=O)R5, wherein R5 is substituted or unsubstituted C 1-3 Straight chain or branched chain alkyl.

[0093] In another aspect, the derivative comprises a compound of formula II, or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0094]

[0095] Where R6 can be:

[0096] (a) -O-R9, wherein R9 may be an alkyl or alkenyl group, which may include 4 to 34 carbon atoms and may be branched or linear, substituted or unsubstituted, or

[0097] (b) NH-R10, wherein R10 may be an alkyl or alkenyl group, which may include 4 to 34 carbon atoms and may be branched or linear, substituted or unsubstituted, or

[0098] (c) -OC=O-R11, wherein R11 may be an alkyl or alkenyl group, which may include 4 to 34 carbon atoms and may be branched or linear, substituted or unsubstituted, and

[0099] Where R7 can be:

[0100] (a) an alkyl or alkenyl group which may comprise 4 to 34 carbon atoms and may be branched or straight chain, substituted or unsubstituted, or

[0101] (b) -NH-R12, wherein R12 may be an alkyl or alkenyl group, which may include 4 to 34 carbon atoms and may be branched or linear, substituted or unsubstituted, or

[0102] (c) -O-R13, wherein R13 comprises an alkyl or alkenyl group, which may comprise 4 to 34 carbon atoms and is branched or linear, substituted or unsubstituted, and

[0103] Where R8 can be

[0104] (a) an alkyl or alkenyl group which may comprise 4 to 34 carbon atoms and may be branched or straight chain, substituted or unsubstituted, or

[0105] (b) -NH-R14, wherein R14 may be an alkyl or alkenyl group, which may include 4 to 34 carbon atoms and may be branched or linear, substituted or unsubstituted, or

[0106] (c) -O-R15, wherein R15 is an alkyl or alkenyl group which may comprise 4 to 34 carbon atoms and may be branched or linear, substituted or unsubstituted, and

[0107] wherein R2 is hydrogen, or -(C=O)R5, wherein R5 is C 1-3 A straight chain or branched chain alkyl group which may be substituted or unsubstituted.

[0108] R9, R10, R11, R12, R13, R14 and R15 can independently contain 4-34 carbon atoms. However, they can independently contain carbon atoms in other scopes. Other scopes can include C6-C30, C8-C25, C10-C20 and C11-C15 and C12. All scopes within the scope of C4-34 are also foreseeable. The carbon number of R9, R10, R11, R12, R13, R14 and R15 can be the same or different.

[0109] In one aspect of the present invention, R6 in Formula II is selected from: (CH3)3CO-, CH3CH2C(CH3)2O-, CH3CH2CCH3(O-)CH2CH3, CH3(CH2)6O-, CH3(CH2)7O-, CH3(CH2)8O-, CH3(CH2)8CH2O-, CH3(CH2) 10 CH2O-、CH3(CH2) 11 CH2O-、CH3(CH2) 12 CH2O-、CH3(CH2) 13 CH2O-、CH3(CH2) 14 CH2O-, CH3(CH2)5CH=CH(CH2)7CH2O-, CH3(CH2) 15 CH2O-、CH3(CH2) 16 CH2O-, CH3(CH2)7CH=CH(CH2)8O-, CH3(CH2) 17 CH2O-、CH3(CH2) 18 CH2O-、CH3(CH2) 19 CH2O-、CH3(CH2) 20 CH2O-、CH3(CH2)7CH=CH(CH2) 11 CH2O-、CH3(CH2) 22 CH2O-、CH3(CH2) 24 CH2O-、CH3(CH2) 25 CH2O-、CH3(CH2) 26 CH2O-、CH3(CH2) 27 CH2O-、CH3(CH2) 28 CH2O-、CH3(CH2) 30 CH2O-、CH3(CH2) 32CH2O-, CH3(CH2)3CH=CH(CH2)7CH2O-, CH3(CH2)8CH=CH(CH2)4CH2O-, CH3(CH2)7CH=CH(CH2)7CH2O-, CH3(CH2)5CH=CH(CH2)9CH2O-, CH3(CH2)4CH=CHCH2CH=CH(CH2)7CH2O-, CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7CH2O-, CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3CH2O-, CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3CH2O-, CH3(CH2)7CH=CH(CH2) 11 CH2O- and CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)2CH2O-.

[0110] In formula II, R7 and / or R8 can be independently selected from: CH3(CH2)6-, CH3(CH2)8-, CH3(CH2) 10 -, CH3(CH2) 12 -, CH3(CH2) 14 -, CH3(CH2) 16 -, CH3(CH2) 18 -, CH3(CH2) 20 -, CH3(CH2) 22 -, CH3(CH2) 24 -, CH3(CH2)3CH=CH(CH2)7-, CH3(CH2)5CH=CH(CH2)7-, CH3(CH2)8CH=CH(CH2)4-, CH3(CH2)7CH=CH(CH2)7-, CH3(CH2)7CH=CH(CH2)7-, CH3(CH2)5CH=CH(CH2)9-, CH3(CH2)4CH=CHCH2CH=CH(CH2)7- (cis, cis), CH3(CH2)4CH=CHCH2CH=CH(CH2)7- (trans, trans), CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7-, CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3-, CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3-, CH3(CH2)7CH=CH(CH2)11 - and CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)2-.

[0111] One method of preparing the structure of formula II is to react levodopa or its derivatives directly with a fatty alcohol or fatty acid. Another method is to first derivatize the fatty alcohol or fatty acid with another functional group (such as an amine functional group), which can then react with levodopa or its derivatives. For example, if a fatty alcohol is derivatized with an amine functional group, and then the fatty alcohol is reacted with the carbonyl group on the right side of formula II, then R6 can be NH-R10, as described above.

[0112] In the present invention, the levodopa derivative may be (S)-4-(2-amino-3-(dodecyloxy)-3-oxopropyl)-1,2-phenylene behenate, which is also identified as DB104 in the following examples. 45 H 79 NO6, molecular weight is 730.13. Levodopa derivative (DB104) may have the following molecular structure.

[0113]

[0114] In another aspect, the levodopa derivative is a hydrochloride salt having the following formula:

[0115]

[0116] The present invention may relate to a composition comprising a pharmaceutically effective amount of one or more derivatives of the present invention and one or more pharmaceutically acceptable carriers or excipients. Such compositions may be injectable, inhalable, orally administrable or topically administrable. Such compositions may be in the form of liposomes or micelles. The pharmaceutically acceptable carrier of one or more derivatives may be castor oil or a derivative thereof. Various carriers and excipients, as well as methods of making compositions injectable, inhalable, orally administrable or topically administrable are known in the art. The formation of liposomes or micelles is also known in the pharmaceutical arts. Therefore, no further elaboration is required.

[0117] In some embodiments, the dosage form of the composition of the present invention is suitable for parenteral administration to patients, including subcutaneous, intramuscular, intraperitoneal, intravenous or intradermal injection. In other embodiments, the composition can be administered as a depot. After parenteral injection of the derivative, enzymatic cleavage can occur to produce levodopa.

[0118] In another embodiment, the present invention may be directed to a pharmaceutical composition comprising microparticles or nanoparticles comprising a pharmaceutically effective amount of one or more of the derivatives and a pharmaceutically acceptable polymer, wherein the one or more of the derivatives are encapsulated in a pharmaceutically acceptable polymer. The pharmaceutically acceptable polymer may be selected from the group consisting of polyethylene glycol, polyglycolide, polylactide, polycaprolactone, poly(lactide-co-caprolactone), poly(lactide-glycolide), poly(lactic acid)-butanol, poly(vinyl pyrrolidone), polyvinyl alcohol, poly(ethyleneimine), polymalic acid, poly-L-lysine, poly-L-glutamic acid, poly((N-hydroxyalkyl)glutamine), dextrin, hydroxyethyl starch, polysialic acid, polyacetal, N-(2-hydroxypropyl)methacrylamide copolymer, poly(amide) dendrimer, and mixtures, compositions and copolymers thereof. These polymers are known in the art and do not require further elaboration. In some embodiments, poly(lactide-co-glycolide) (PLGA) and mixtures of PLGA with other polymers such as polypropylene glycol (PLA), polyglycolide (PGA) and polyvinyl alcohol (PVA) are used in different proportions to encapsulate the compounds of the present invention to form microparticles or nanoparticles. Due to its excellent biocompatibility, PLGA is a pharmaceutically acceptable biodegradable polymer that is widely used to encapsulate various therapeutic agents, including hydrophilic and hydrophobic small molecule drugs, DNA and proteins. Other additives such as polyethylene glycol (PEG), polyorthoesters, chitosan, alginate, caffeic acid, hyaluronic acid, etc. can be used to enhance the drug loading and efficiency in PLGA microparticles. PLGA can be different compositions of PLA and PGA, with a ratio of 20-80% PGA in PLA, or a ratio of 20-80% PLA in PGA, as well as any range within these ranges.

[0119] Polymer encapsulated microparticles / nanoparticles can be prepared by methods known in the art. For example, see Han et al., Front Pharmacol. 2016; 7: 185; Qutachi et al., Acta Biomater. 2014; 10 (12): 5090-5098. The preparation of derivative microparticles can be carried out as follows. Nanoprecipitation technology can be used to prepare levodopa microparticles. In brief, the derivative and polymer (e.g., PLGA) are dissolved in a suitable solvent (e.g., dichloromethane) in different proportions, and if necessary, the mixture is sonicated for 5-10 minutes to achieve dissolution. A hydrophilic nonionic surfactant (e.g., a triblock copolymer), such as Pluronic F127, can be dissolved in 50 mL of deionized water, or the derivative / PLGA solution can be added dropwise using a syringe at a flow rate of 1 mL / 10 min while stirring at different speeds. The obtained nanosuspension can be centrifuged and freeze-dried with a cryoprotectant (e.g., 2% sucrose). The obtained particles can be characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray diffraction (XRD).

[0120] In the context of the present invention, the term "encapsulated" refers to being wrapped, covered or surrounded by a polymer, so that at least about 20% of the derivative is encapsulated / covered / wrapped by the polymer. Preferably, about 20% to about 80% of the derivative is encapsulated / covered / wrapped. The surrounding structure does not necessarily completely surround the derivative, but should surround at least 30% of the surface. Therefore, preferably, the derivative in the form of microparticles / nanoparticles is covered by at least about 20%, and this coverage will be at least 30% of the surface coverage. Preferably, up to 80% of the surface will be covered, although 100% surface coverage is also possible at least for some particles.

[0121] The pharmaceutical composition containing one or more derivatives may further include one or more pharmaceutically acceptable carriers or excipients. As described above, such compositions may be injectable, inhalable, orally administrable or topically administrable. Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The composition may be stored in unit dose or multi-dose containers, for example, in sealed ampoules and vials.

[0122] The composition can be stored in unit dose or multi-dose containers, such as sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. External injection solutions and suspensions can be prepared from sterile powders, granules and tablets.

[0123] In another aspect, the present invention may relate to a method for treating Parkinson's disease, comprising administering to a mammal one or more derivatives sufficient to treat Parkinson's disease. The one or more derivatives may be in the form of a composition that may be administered intravenously, intramuscularly, intraperitoneally, orally or subcutaneously.

[0124] Compositions containing one or more derivatives can be co-administered with carbidopa and / or entacapone for the treatment of Parkinson's disease. As described above, carbidopa helps reduce premature degradation of levodopa, so even if the derivatives of the present invention lose some of the "fat" portion, carbidopa can still help reduce the amount of active ingredient that is degraded and unavailable for dopamine formation.

[0125] In some embodiments, the amount of the derivative compound in the composition of the present invention is within the range of 100 mg to 2000 mg equivalent of levodopa, and is administered once a day. Compositions comprising 10-200 mg of carbidopa and / or 200-1600 mg of entacapone (or other COMT inhibitors) can be used in combination with the composition of the present invention for the treatment of PD. Therefore, the compound of the present invention may also include carbidopa or entacapone in addition to the compound of the derivative. The amount of carbidopa co-administered with the derivative can be in a ratio of 1:10 to 1:4 relative to the amount of the derivative and / or the amount of equivalent levodopa in the derivative. COMT inhibitors, such as tolcapone, opicapone and / or entacapone, can be co-administered with the derivative at a dose of 200 mg or more, and repeated administration as needed, and carbidopa may also be co-administered or not co-administered. Carbidopa in an amount of 10 mg to 200 mg / day and / or entacapone (or another COMT inhibitor) in an amount of 200 mg to 1600 mg / day may be co-administered with a compound or composition of the invention.

[0126] In another aspect, a composition containing one or more derivatives can be used to treat Parkinson's disease by administering it once a day to a patient with Parkinson's disease. In another aspect, the composition can be administered up to two or three times a week. In another aspect, the composition can be administered once a week or every two weeks. The composition can be administered once a month.

[0127] In one embodiment, the composition containing one or more derivatives can be a pharmaceutical composition comprising microparticles or nanoparticles, which contain a pharmaceutically effective amount of one or more of the derivatives and a pharmaceutically acceptable polymer, and can be co-administered with carbidopa and / or entacapone (or other COMT inhibitors) to treat Parkinson's disease. Such compositions can be administered intravenously, intramuscularly, intraperitoneally, orally or subcutaneously. Administration can be once a day, up to twice or three times a week, once a week or every two weeks, or once a month.

[0128] Example 1 below demonstrates that the derivatives of the invention result in protection of the active ingredient, so that early degradation of levodopa is reduced, making it available for the formation of dopamine after crossing the blood-brain barrier.

[0129] Example 1

[0130] 10 μM DB104 (DB104 is one of the derivatives of the present invention as described above) was incubated in fresh plasma and phosphate buffered saline (PBS) and divided into multiple aliquots, each aliquot was divided into two equal parts at the following time points: 0, 1, 2, 4, 6, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 and 264 hours. The first half was quenched with ACN:MeOH containing 1% formic acid and analyzed on a high resolution mass spectrometer (HRMS) to detect DB104 and all other possible intermediates. Labetalol was used as an internal standard (IS). The other half was quenched with perchloric acid and analyzed on an AB Sciex 7500 mass spectrometer to detect L-DOPA. Dopamine-d4 will be used as IS.

[0131] Possible intermediate structures from the above steps are as follows:

[0132]

[0133] DB104 requires approximately 4 hours and 1-4 hours to completely dissolve in human plasma and PBS, respectively. This is evident from the initial increase in peak area and subsequent degradation. All peak area ratios were normalized to the maximum peak area ratio observed. DB104M3 and DB104M4 and L-DOPA were observed in human plasma and PBS. DB104M1 was only observed in PBS. DB104M2 was not observed in either human plasma or PBS. The in vitro half-life of DB104 in human plasma was 13.1±1.4 hours, which is significant. The in vitro half-life of DB104 in PBS was 12.4±2.6 hours, which is also significant.

[0134] The above tests lead to an estimated in vitro half-life of DB104 in human plasma and PBS of about 12 hours. It takes up to 72 hours for detectable amounts of L-DOPA to form in human plasma or PBS, indicating less peripheral degradation and more L-DOPA available to cross the blood-brain barrier. DB104M4 is the major degradant in PBS. It is hypothesized that DB104 may also cross the blood-brain barrier and that L-DOPA may be formed after the derivative crosses the blood-brain.

[0135] The derivatives can be produced by using fatty acids and fatty alcohols. For example, in the above formula II, R6 can be prepared by using fatty alcohols, and R7 and R8 can be prepared by using fatty acids.

[0136] The fatty alcohols that can be used to prepare levodopa derivatives include, but are not limited to, tert-butyl alcohol, tert-pentyl alcohol, 3-methyl-3-pentanol, 1-heptanol (n-heptanol), 1-octanol (n-octanol), nonanol (1-nonanol), 1-decanol (decyl alcohol), capric alcohol, and 1-decyl alcohol. alcohol), undecanol (1-undecanol, undecanol, hendecanol), lauryl alcohol (dodecyl alcohol, 1-dodecanol), tridecanol (1-tridecanol, tridecanol, isotridecanol), myristyl alcohol (1-tetradecanol), pentadecanol (1-pentadecanol, pentadecanol), hexadecanol (1-hexadecanol), palmityl alcohol (cis-9-hexadecene-1-ol), heptadecanol (1-n-heptadecanol, heptadecanol), stearyl alcohol (1-octadecanol), octadecanol (1-octadecenol), nonadecanol (1-nonadecanol), eicosanol (1-eicosanol), heneicosanol (1-heneicosanol), behenyl alcohol (1-docosapentaenoic acid), erucyl alcohol (cis-13-eicosanol-1-ol), tetracosanol (1-tetracosanol), hexacosanol (1-hexacosanol), 1-heptacosanol, nonacosanol (Montanyl alcohol), octacosanol (cluytyl alcohol Alcohol) or 1-octacosanol, 1-nonacosanol, myricyl alcohol, melissyl alcohol, or 1-triacontanol, 1-triacontanol, 1-triacontanol, 1-triacontanol, 1-tetraamantane alcohol, trans-9-octadecenol, and cis, cis-9,12-octadecadien-1-ol. Other fatty alcohols may also be used.

[0137] Fatty acids that can be used to prepare levodopa derivatives include, but are not limited to, the following: caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, gallic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linolenic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, mesic acid, and docosahexaenoic acid. Other fatty acids can also be used.

[0138] Example 2 below illustrates the use of levodopa in forming specific embodiments of the derivatives of the present invention.

[0139] Example 2

[0140] Preparation of dilauryl levodopa dodecyl ester hydrochloride:

[0141] Target molecules:

[0142]

[0143] Experimental Procedure:

[0144] Preparation of N-(tert-butyloxycarbonyl)-3,4-dihydroxy-L-phenylalanine (Boc-Levodopa): Levodopa (25 gm, 0.126 mol) was stirred in a mixture of dioxane (150 mL), water (100 mL), 1M NaOH (100 mL) at room temperature under nitrogen for 30 minutes. Tert-butyl dicarbonate (35 gm, 0.160 mol) was slowly added at room temperature and the reaction was stirred for 20 hours. After the reaction was completed, the solvent was evaporated under vacuum and the volume was reduced to half. The organic material was extracted using ethyl acetate (3×100 mL). The combined organic layers were washed with water (100 mL) and then with brine (50 mL), and the final organic layer was dried over anhydrous Na2SO4. The organic layer was concentrated under vacuum at a temperature below 55°C to obtain a brown foamy solid. The crude product obtained was purified by column chromatography on silica gel (100-200 mesh) using dichloromethane & methanol (6:4) as eluent system to afford Boc-Levodopa (yield: 10.5 gm, 30%).

[0145] Preparation of Boc-levodopa dodecyl ester: Boc-levodopa (20 gm) was stirred with DMF (100 mL) in a round bottom flask under nitrogen at room temperature. Na2CO3 was added to the reaction mixture, followed by 1-bromododecane (which can be derived from fatty alcohol dodecanol), and stirred for 16 hours to complete the reaction. The reaction mixture was filtered and the filtrate was concentrated in vacuo at 55°C to completely remove the solvent. Water (100 mL) was added to the residue, and the pH was adjusted to the acidic side using 6N HCl (8.3 mL), and the organic mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with water (50 mL), then with brine (50 ml), and dried over anhydrous Na2SO4. Finally, the organic layer was concentrated under vacuum to obtain a brown viscous liquid. The obtained residue was purified by column chromatography using a mixture of ethyl acetate and n-hexane (6:4) to obtain a pure product (yield: 9.2 gm, 28%).

[0146] Preparation of dilauryl alcohol-Boc levodopa dodecyl ester: Boc levodopa dodecyl ester (8.5 gm) was stirred with DCM (10 mL) in a round bottom flask under nitrogen at room temperature. The reaction mixture was cooled in an ice bath and the temperature was maintained between 0-5°C. DCM (15 mL) containing lauroyl chloride (2.85 gm) was added dropwise to the reaction mixture. Lauroyl chloride is the acyl chloride of lauric acid, which is a fatty acid. After stirring for 10 minutes, the reaction mixture was stirred at room temperature to complete the reaction. The reaction mass was washed with DI water (4×50 mL) and the organic layer was dried over anhydrous Na2SO4. The DCM layer obtained was concentrated under vacuum to obtain an orange thick residue. The residue was purified by column chromatography using ethyl acetate and n-hexane mixture (6:4) as eluent to obtain pure product (yield: 2.75 gm, 19%).

[0147] Preparation of Dilauryl-L-Dopa Dodecyl Ester Hydrochloride: A mixture of Dilauryl-Boc-L-Dopa-Dodecyl Ester (2.5 gm) and HCl / Dioxane (2N, 80 mL) was stirred at 25-30°C for 2-3 hours. After completion of the reaction, the solvent was completely removed under vacuum at 30-35°C. The resulting residue (HCl salt) was further stirred in fresh dioxane (25 mL) at 25-30°C for 2 hours. The solid was filtered and dried in a desiccator under vacuum for 8-10 hours to obtain the pure desired product (yield: 1.6 gm, 62%). HPLC purity: 98.69; mass (M+1): 730.59; 1 H-NMR (DMSO-d6): δ 0.83-0.86 (9H, t, -CH3), 1.10-1.40 (52H, m, CH2 aliphatic protons), 1.58-1.61 (4H, m, CH2 aliphatic protons), 2.50-2.54 (4H, m, CH2-CO), 3.00 (1H, dd, benzylated CH2), 3.20 (1H, dd, benzylated CH2), 3.98-4.01 (2H, m, OCH2), 4.27-4.30 (1H, m, CH-NH), 7.13-7.22 (3H, m, aromatic protons), 8.55 (3H, broad singlet, NH protons). Therefore, the dilauryl-levodopa-dodecyl ester hydrochloride product is produced and can be used to treat Parkinson's disease. Different fatty alcohols and fatty acids may be used in place of those used above in order to react different chains as part of the derivative.

Claims

1. A levodopa derivative comprising a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound comprises a substituent, the substituent comprising at least 6 carbon atoms in total, the carbon atoms being bonded only to other carbon atoms or hydrogen atoms.

2. The levodopa derivative according to claim 1, wherein the levodopa derivative comprises substituents, the substituents having a total of 8 to 100 carbon atoms, the carbon atoms being bonded only to other carbon atoms or hydrogen atoms.

3. The levodopa derivative according to claim 1, wherein the levodopa derivative comprises a compound of formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1 comprises a branched or linear C4-34 group derived from a saturated or unsaturated fatty alcohol, and the C4-34 group is directly or indirectly connected to a carbonyl group to form an ester, amide or anhydride structure, R3 comprises a branched or straight chain C4-34 group derived from a saturated or unsaturated fatty acid, and R3 is directly or indirectly connected to oxygen to form an ester, carbonate or carbamate structure, R4 comprises a branched or straight chain C4-34 group derived from a saturated or unsaturated fatty acid, and R4 is directly or indirectly connected to oxygen to form an ester, carbonate or carbamate structure, R2 includes hydrogen or -(C=O)R5, wherein R5 is C 1-3 Straight chain or branched chain alkyl.

4. The levodopa derivative according to claim 1, wherein the levodopa derivative comprises a compound of formula II or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R6 comprises a derivative of a saturated or unsaturated fatty alcohol, and wherein R7 comprises a derivative of a saturated or unsaturated fatty acid, and wherein R8 comprises a derivative of a saturated or unsaturated fatty acid, and wherein R2 is hydrogen or -(C=O)R5, wherein R5 is C 1-3 Straight chain or branched chain alkyl.

5. The levodopa derivative according to claim 1, wherein the levodopa derivative comprises a compound of formula II or a pharmaceutically acceptable salt, hydrate or solvate thereof, R6 includes: (a) -O-R9, wherein R-9 comprises an alkyl or alkenyl group, which contains 4 to 34 carbon atoms and is branched or linear, substituted or unsubstituted, or (b) NH-R10, wherein R10 comprises an alkyl or alkenyl group containing 4 to 34 carbon atoms and being branched or linear, substituted or unsubstituted, or (c) -OC=O-R11, wherein R11 comprises an alkyl or alkenyl group, which contains 4 to 34 carbon atoms and is branched or linear, substituted or unsubstituted, and R7 includes: (a) an alkyl or alkenyl group containing 4 to 34 carbon atoms and being branched or straight-chain, substituted or unsubstituted, or (b) -NH-R12, wherein R12 comprises an alkyl or alkenyl group containing 4 to 34 carbon atoms and being branched or linear, substituted or unsubstituted, or (c) -O-R13, wherein R13 comprises an alkyl or alkenyl group, which contains 4 to 34 carbon atoms and is branched or linear, substituted or unsubstituted, and R8 includes (a) an alkyl or alkenyl group containing 4 to 34 carbon atoms and being branched or straight-chain, substituted or unsubstituted, or (b) -NH-R14, wherein R14 comprises an alkyl or alkenyl group containing 4 to 34 carbon atoms and being branched or linear, substituted or unsubstituted, or (c) -O-R15, wherein R15 is an alkyl or alkenyl group containing 4 to 34 carbon atoms and being branched or linear, substituted or unsubstituted, and wherein R2 is hydrogen -(C=O)R5, wherein R5 is C 1-3 Straight chain or branched chain alkyl.

6. The levodopa derivative according to claim 4, wherein R6 is selected from: (CH3)3CO-, CH3CH2C(CH3)2O-, CH3CH2CCH3(O-)CH2CH3, CH3(CH2)6O-, CH3(CH2)7O-, CH3(CH2)8O-, CH3(CH2)8CH2O-, CH3(CH2) 10 CH2O-、CH3(CH2) 11 CH2O-、CH3(CH2) 12 CH2O-、CH3(CH2) 13 CH2O-、CH3(CH2) 14 CH2O-, CH3(CH2)5CH=CH(CH2)7CH2O-, CH3(CH2) 15 CH2O-、CH3(CH2) 16 CH2O-, CH3(CH2)7CH=CH(CH2)8O-, CH3(CH2) 17 CH2O-、CH3(CH2) 18 CH2O-、CH3(CH2) 19 CH2O-、CH3(CH2) 20 CH2O-、CH3(CH2)7CH=CH(CH2) 11 CH2O-、CH3(CH2) 22 CH2O-、CH3(CH2) 24 CH2O-、CH3(CH2) 25 CH2O-、CH3(CH2) 26 CH2O-、CH3(CH2) 27 CH2O-、CH3(CH2) 28 CH2O-、CH3(CH2) 30 CH2O-、CH3(CH2) 32 CH2O-, CH3(CH2)7CH=CH(CH2)7CH2O- and CH3(CH2)4CH=CHCH2CH=CH(CH2)7CH2O-.

7. The levodopa derivative according to claim 4, wherein R6 is selected from the group consisting of: CH3(CH2)3CH=CH(CH2)7CH2O-, CH3(CH2)8CH=CH(CH2)4CH2O-, CH3(CH2)5CH=CH(CH2)9CH2O-, CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)7CH2O-, CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3CH2O-, CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3CH2O-, CH3(CH2)7CH=CH(CH2) 11 CH2O- and CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)2CH2O-.

8. The levodopa derivative according to claim 4, wherein R7 and / or R8 are independently selected from: CH3(CH2)6-, CH3(CH2)8-, CH3(CH2) 10 -、CH3(CH2) 12 -、CH3(CH2) 14 -、CH3(CH2) 16 -、CH3(CH2) 18 -、CH3(CH2) 20 -、CH3(CH2) 22 -、CH3(CH2) 24 -, CH3(CH2)3CH=CH(CH2)7-, CH3(CH2)5CH=CH(CH2)7-, CH3(CH2)8CH=CH(CH2)4-, CH3(CH2)7CH=CH(CH2)7 -, CH3(CH2)7CH=CH(CH2)7-, CH3(CH2)5CH=CH(CH2)9-, CH3(CH2)4CH=CHCH2CH=CH(CH2)7-(cis, cis), CH3(CH2) 4CH=CHCH2CH=CH(CH2)7-(reverse, reverse), CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7-, CH3(CH2)4CH=CHCH2CH=CHCH2CH =CHCH2CH=CH(CH2)3-, CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3-, CH3(CH2)7CH=CH(CH2) 11 - and CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)2-.

9. The levodopa derivative according to claim 4, wherein the levodopa derivative is 10. The levodopa derivative according to claim 4, wherein the levodopa derivative is a hydrochloride having the following chemical formula:

11. A composition comprising a pharmaceutically effective amount of the levodopa derivative according to claim 1 and one or more pharmaceutically acceptable carriers or excipients.

12. The composition of claim 11, wherein the composition is injectable, inhalable, orally ingestible or topically administered.

13. The composition of claim 11, wherein the composition is in the form of liposomes or micelles.

14. The composition according to claim 11, wherein the pharmaceutically acceptable carrier is castor oil or a derivative thereof.

15. A pharmaceutical composition comprising microparticles or nanoparticles, wherein the microparticles or nanoparticles comprise a pharmaceutically effective amount of the levodopa derivative according to claim 1 and a pharmaceutically acceptable polymer, wherein the levodopa derivative according to claim 1 is encapsulated in the pharmaceutically acceptable polymer.

16. The pharmaceutical composition of claim 15, wherein the pharmaceutically acceptable polymer is selected from the group consisting of polyethylene glycol, polyglycolide, polylactide, polycaprolactone, poly(lactide-co-caprolactone), poly(lactide-co-glycolide), poly(lactic acid)-butanol, poly(vinyl pyrrolidone), polyvinyl alcohol, poly(ethyleneimine), polymalic acid, poly-L-lysine, poly-L-glutamic acid, poly((N-hydroxyalkyl)glutamine), dextrin, hydroxyethyl starch, polysialic acid, polyacetal, N-(2-hydroxypropyl)methacrylamide copolymer, poly(amide) dendrimer, and mixtures, combinations, and copolymers thereof.

17. The pharmaceutical composition of claim 15, wherein the composition further comprises one or more pharmaceutically acceptable carriers or excipients.

18. The composition of claim 15, wherein the composition is injectable, inhalable, orally ingestible, or topically administered.

19. A method for treating Parkinson's disease, comprising administering to a mammal an amount of the levodopa derivative of claim 1 sufficient to treat Parkinson's disease.

20. A method for treating Parkinson's disease, comprising administering to a mammal an amount of the composition of claim 11 sufficient to treat Parkinson's disease.

21. The method for treating Parkinson's disease according to claim 20, wherein the composition is administered intravenously, intramuscularly, intraperitoneally, orally or subcutaneously.

22. The method for treating Parkinson's disease according to claim 20, wherein the composition is co-administered with carbidopa and / or a COMT inhibitor.

23. The method for treating Parkinson's disease according to claim 20, wherein the composition is co-administered with carbidopa and / or entacapone.

24. The method for treating Parkinson's disease according to claim 20, wherein the composition is administered once a day.

25. The method of treating Parkinson's disease according to claim 20, wherein the composition is administered up to two or three times per week.

26. The method for treating Parkinson's disease according to claim 20, wherein the composition is administered once a week or once every two weeks.

27. The method for treating Parkinson's disease according to claim 20, wherein the composition is administered once a month.

28. A method for treating Parkinson's disease, comprising administering to a mammal an amount of the composition of claim 15 sufficient to treat Parkinson's disease.

29. The method for treating Parkinson's disease according to claim 28, wherein the composition is co-administered with carbidopa and / or a COMT inhibitor.

30. The method for treating Parkinson's disease according to claim 28, wherein the composition is co-administered with carbidopa and / or entacapone.

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