Levodopa fatty acid derivatives, formulations thereof and use thereof in the treatment of parkinson's disease

Abstract

A levodopa derivative, including a compound or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein the compound includes substituents that collectively comprise at least 6 carbon atoms, which are bonded only to other carbon atoms or hydrogen atoms. The levodopa derivative can be formulated as a composition including one or more pharmaceutically acceptable carriers or excipients. The levodopa derivative can be part of a pharmaceutical composition including microparticles or nanoparticles, in which the levodopa derivative is encapsulated in a pharmaceutically acceptable polymer. The levodopa derivative can 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 polymeric nanoparticle / microparticle formulations of levodopa derivatives. These compounds and compositions are useful in the treatment of Parkinson's disease. BACKGROUND

[0002] Levodopa (hereinafter L-DOPA) is the common name for (S)-2-amino-3-(3,4- dihydroxyphenyl)propanoic acid, which is shown below:

[0003]

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

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

[0006] The therapeutic efficacy of high-dose levodopa (3-16 g / day) for 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 in the peripheral circulation (peripheral circulation is the circulation before crossing the blood-brain barrier). Most commonly, levodopa is used as a dopamine replacement agent for the treatment of Parkinson's disease, and is particularly effective in controlling the prominent bradykinetic symptoms of Parkinson's disease. Levodopa is recommended for the symptomatic treatment of all stages of Parkinson's disease, taken orally multiple times per day. Levodopa is usually taken with the dopamine decarboxylase inhibitor carbidopa to reduce the amount of levodopa converted to dopamine in the periphery, allowing more levodopa to cross the blood-brain barrier to be converted to dopamine. This combination therapy thus 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 oral dose administered is pre-systemically decarboxylated to dopamine by aromatic L-amino acid decarboxylase (AADC) enzymes in the stomach, intestinal lumen, kidneys, and liver. Levodopa can also be methoxylated to 3-methyldopa (3-OMD) by the liver catechol-O-methyltransferase (COMT) system, and 3-methyldopa cannot be converted to central dopamine. Thus, only a small fraction of the oral dose of levodopa crosses the blood-brain barrier into 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-dihydroxyphenyl acetic acid (13-47%) and homovanillic acid (23-39%).

[0008] Because of the degradation of levodopa by gastric AADC and COMT enzymes, the drug can be taken with i) a peripheral dopamine decarboxylase inhibitor (carbidopa), which, without carbidopa, 90% of levodopa is metabolized in the intestinal wall, and ii) a COMT inhibitor (entacapone), as COMT inhibitors can further increase the bioavailability of levodopa in the brain. See, e.g., 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 Future Developments. 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 dopamine levels in the brain. Carbidopa, when administered with levodopa, can reduce the amount of levodopa needed to produce a given response by 75%. Entacapone, in a 200 mg dose, can increase plasma exposure of levodopa by 35-40% when administered in combination with levodopa / carbidopa.

[0010] The plasma half-life of levodopa alone is approximately fifty (50) minutes. When taken with carbidopa, the plasma half-life of levodopa is increased to approximately 90 minutes. and CR 50-200) when administered together, 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 1151 ng / mL( ) and 3256 ng / mL ( CR). Application (carbidopa, levodopa and entacapone combination, 37.5 / 150 / 200 mg), 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 can be avoided by using lower doses of levodopa and maintaining stable dopamine levels. Research is currently underway to find delivery routes for levodopa that will allow for sustained dopaminergic stimulation. Abbvie ( ) developed by Acorda Therapeutics Co., Ltd. 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 received FDA approval 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 to be better absorbed by the brain. See Levodopa, Di Stefano A, Sozio P, Cerasa LS, Iannitelli A. L-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 3,4 position 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. Levodopa methyl ester ) has been marketed. However, in a phase III clinical trial, the ethyl ester derivative (Etilevodop, TV-1203) was found to be less effective than levodopa.

[0015] WO 2020 / 2264460 discloses a method of reducing levodopa's early response. 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 treatment of Parkinson's disease using levodopa (or its prodrugs), the plasma half-life of levodopa is very short, resulting in significant fluctuations in plasma drug concentration, which in turn results in fluctuations in the amount of levodopa crossing the blood-brain barrier, leading to inconsistent levels of dopamine in the brain. As the disease progresses, these fluctuations in plasma concentration are reflected in fluctuations in therapeutic response. There is a need for a treatment method that can provide a stable level of plasma levodopa concentration, thereby stably crossing the blood-brain barrier for a longer period of time. The present invention addresses all these needs. SUMMARY

[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 that contains a total of at least 6 carbon atoms, which are bound only to other carbon atoms or hydrogen atoms. The levodopa derivative can comprise a substituent that contains a total of 8-100 carbon atoms, which are bound only to other carbon atoms or hydrogen atoms.

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

[0019]

[0020]

[0021] wherein R1may be a branched or straight chain C4-34group derived from a saturated or unsaturated fatty alcohol and the C4-34group is directly or indirectly attached to a carbonyl group to form an ester, amide or anhydride structure. R3may be a branched or straight chain C4-34group derived from a saturated or unsaturated fatty acid and R3is directly or indirectly attached to an oxygen to form an ester, carbonate or carbamate structure. R4may be a branched or straight chain C4-34group derived from a saturated or unsaturated fatty acid and R4is directly or indirectly attached to an oxygen to form an ester, carbonate or carbamate structure. R2may be hydrogen or -(C=O)R5, wherein R5may be C 1-3 straight 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 R6may be a derivative of a saturated or unsaturated fatty alcohol, and

[0025] wherein R7may be a derivative of a saturated or unsaturated fatty acid, and

[0026] wherein R8may be a derivative of a saturated or unsaturated fatty acid, and wherein

[0027] R2is hydrogen or -(C=O)R5, wherein R5is C 1-3 straight 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] wherein R6may be:

[0031] (a) -O-R9, wherein R9may be an alkyl or alkenyl group which can comprise 4-34 carbon atoms and be branched or straight chained, substituted or unsubstituted, or

[0032] (b) NH-R10, where R10can be an alkyl or alkenyl group that can include 4-34 carbon atoms and is branched or straight chained, substituted or unsubstituted, or

[0033] (c) -O-C=O-R11, where R11can be an alkyl or alkenyl group that can include 4-34 carbon atoms and is branched or straight chained, substituted or unsubstituted, and

[0034] where R7can be:

[0035] (a) an alkyl or alkenyl group that can include 4-34 carbon atoms and is branched or straight chained, substituted or unsubstituted, or

[0036] (b) -NH-R12, where R12can be an alkyl or alkenyl group that can include 4-34 carbon atoms and is branched or straight chained, substituted or unsubstituted, or

[0037] (c) -O-R13, where R13includes an alkyl or alkenyl group that can include 4-34 carbon atoms and is branched or straight chained, substituted or unsubstituted, and

[0038] where R8can be

[0039] (a) an alkyl or alkenyl group that can include 4-34 carbon atoms and is branched or straight chained, substituted or unsubstituted, or

[0040] (b) -NH-R14, where R14can be an alkyl or alkenyl group that can include 4-34 carbon atoms and is branched or straight chained, substituted or unsubstituted, or

[0041] (c) -O-R15, where R15is an alkyl or alkenyl group that can include 4-34 carbon atoms and is branched or straight chained, substituted or unsubstituted, and

[0042] where R2is hydrogen, or -(C=O)R5, where R5is C 1-3 straight chained or branched alkyl.

[0043] In one aspect of the application, in Formula II, R6is selected from the group consisting of: (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, R7and / or R8may be independently selected from the group consisting of: 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-.

[0045] In another aspect of the application, the levodopa derivative can be a compound of Formula II, or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0046]

[0047] wherein R6may be the following groups:

[0048] (a) -O-R9, wherein R9may be an alkyl or alkenyl group comprising 4-34 carbon atoms and being branched or straight chained, substituted or unsubstituted, or

[0049] (b) NH-R10, wherein R10may be an alkyl or alkenyl group comprising 4-34 carbon atoms and being branched or straight chained, substituted or unsubstituted, or

[0050] (c) -O-C=O-R11, wherein R11may be an alkyl or alkenyl group comprising 4-34 carbon atoms and being branched or straight chained, substituted or unsubstituted, and

[0051] wherein R7may include:

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

[0053] (b) -NH-R12, wherein R12may be an alkyl or alkenyl group including 4-34 carbon atoms and being branched or straight chained, substituted or unsubstituted, or

[0054] (c) -O-R13, wherein R13may be an alkyl or alkenyl group including 4-34 carbon atoms and being branched or straight chained, substituted or unsubstituted, and

[0055] wherein R8may be

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

[0057] (b) -NH-R14, wherein R14may be an alkyl or alkenyl group including 4-34 carbon atoms and being branched or straight chained, substituted or unsubstituted, or

[0058] (c) -O-R15, wherein R15may be an alkyl or alkenyl group including 4-34 carbon atoms and being branched or straight chained, substituted or unsubstituted, and

[0059] wherein R2is hydrogen, or -(C=0)R5, wherein R5is C 1-3 straight chained or branched alkyl.

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

[0061]

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

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

[0064]

[0065] The present application can involve a composition comprising a pharmaceutically effective amount of a levodopa derivative of the present application and one or more pharmaceutically acceptable carriers or excipients. Such a composition can be injectable, inhalable, oral, or topically applied. Such a composition can be in the form of a liposome or a micelle. The pharmaceutically acceptable carrier of the levodopa derivative can be castor oil or a derivative thereof.

[0066] In another embodiment, the present application can involve a pharmaceutical composition comprising 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 can 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(vinylpyrrolidone), polyvinyl alcohol, poly(ethyleneimine), poly(malic acid), poly L-lysine, poly L-glutamic acid, poly((N-hydroxyalkyl)glutamine), dextrin, hydroxyethyl starch, polysialic acid, polyacetal, N-(2-hydroxypropyl)methacrylamide copolymer, poly(amido) dendrimers, and mixtures, compositions, and copolymers thereof.

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

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

[0069] In another aspect, the composition comprising a levodopa derivative can be used to treat Parkinson's disease by administering the composition once a day to a Parkinson's disease patient. 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 once every two weeks. The composition can be administered once a month.

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

[0071] The detailed description set forth below is intended as a description of some but not all configurations and is not intended to represent the only configurations in which the subject technology can be practiced. The detailed description includes specific details for the purpose of providing a thorough understanding of the innovative teachings. The subject technology is not limited to the specific details set forth herein and can be practiced with no, some, or all of the specific details. In other instances, well-known structures and processes are not shown in detail to avoid obscuring the subject matter. Example implementations can be discussed in detail below. Although specific example implementations can be discussed, it should be understood that these will be only used to illustrate the present disclosure. In describing and illustrating the example implementations, specific terminology will be used. However, the implementations are not intended to be limited to the specific terminology so selected. A person skilled in the relevant art will recognize that other components and configurations can be used without departing from the spirit and scope of the implementations. It will be understood that every particular element included in one implementation can be replaced by alternative elements serving a similar purpose to achieve a like result without departing from the spirit and scope of the implementations. Examples and implementations described herein are non-limiting implementations.

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

[0073] Reference to "one implementation", "an implementation", and "the example implementation", "various implementations", and the like, can mean that a described implementation of the application can include a particular feature, structure, or characteristic, but every implementation can not necessarily include the particular feature, structure, or characteristic.

[0074] Furthermore, repeated use of the phrases "in one implementation" or "in an implementation", as well as "in a specific implementation", does not necessarily refer to the same implementation, although they can. Various implementations described herein can be combined and / or the features of an implementation can be combined to form new implementations.

[0075] While various implementations of the application have been described herein, it should be understood that they have been presented by way of example only, and not limitation. Thus, the breadth and scope of the application should not be limited by any of the described implementations. The described implementations of the application can include features that can be removed or combined to derive additional implementations of the application. Any range disclosed herein is intended to disclose and encompass any range within such range.

[0076] Headings and subheadings (if any) are used for convenience only and do not limit the application.

[0077] Phrases such as “aspect” do not imply that a particular aspect is essential to the subject technology, or that the subject technology necessarily includes all configurations possible of that aspect. Disclosures relating to one aspect can apply to all or one or more aspects. Phrases such as aspect can refer to one or more aspects, and vice versa. Phrases such as “embodiment” do not imply that a particular embodiment is essential to the subject technology, or that the subject technology necessarily includes all configurations possible of that embodiment. Disclosures relating to one embodiment can apply to all or one or more embodiments. Phrases such as one embodiment can refer to one or more embodiments, and vice versa.

[0078] All structural and functional equivalents to the elements of the various aspects described throughout this disclosure that are known or later become known are expressly incorporated by reference and are intended to be encompassed by the claims. Moreover, nothing disclosed herein is intended to be dedicated to the public regardless of whether such disclosure is explicitly recited in the claims. Furthermore, to the extent that the terms “includes,” “has,” “contains,” and other similar factual descriptive terms are used, for purposes of the specification, such terms are used in the sense of being inclusive rather than mutual exclusive.

[0079] Levodopa, if used alone to treat Parkinson’s disease, is degraded in large amounts before it has a chance to cross the blood-brain barrier and appropriately cause an increase in dopamine levels. As part of the present invention, it has been discovered that by adding a “fatty” type of structure as part of the levodopa derivative to protect the levodopa from premature degradation, more of the levodopa can cross the blood-brain barrier. Thus, the patient can consume less of the active ingredient to get a better result, which also results in a consistent level of dopamine in the brain as the active ingredient continues to enter the blood-brain barrier.

[0080] These “fatty” type of structures help to protect the levodopa active portion of the molecule. Furthermore, it is believed that these “fatty” type of structures will cross the blood-brain barrier more readily because these structures are more “fatty” and thus soluble in lipids, which is a characteristic needed to cross the blood-brain protective barrier. If the “fatty” portion of the molecule is too small, the protection from premature degradation of the levodopa active portion can not be sufficient, and the levodopa derivative can not be able to cross the blood-brain barrier effectively. Or, if the “fatty” portion is too large, this can make it difficult for the levodopa derivative to break down into a usable form, and it can also make it more difficult to cross the blood-brain barrier easily. The present invention solves all of these challenges with new chemical structures and compositions, as set forth 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 transfer and overall reduction in healthcare costs.

[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 can include substituents that collectively contain at least 6 carbon atoms that are bonded only to other carbon atoms or hydrogen atoms. This is some of the "fatty" portion of the molecules of the present invention. The derivatives can include substituents that collectively contain 8-100 carbon atoms that are bonded only to other carbon atoms or hydrogen atoms. In other embodiments, the number of carbons bonded only 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, are contemplated in the present invention. Since the present invention seeks to add "fatty" protecting groups to levodopa, fatty acids and fatty alcohols can be used to synthesize the derivatives, which will be further explained below. In addition, further details will be described as to what types of molecules can be part of the derivatives.

[0083] Masking the reactive hydroxyl group of one or both of the benzene ring and / or carboxylic acid group of levodopa with a fatty type structure is one way of practicing the present invention. The amine group of levodopa can also be masked. The fatty acid derivative can react with the hydroxyl group on the benzene ring of levodopa, thereby adding a "fatty" type structure to the molecule. The carboxylic acid group in levodopa can react with a fatty alcohol derivative to add more of this "fatty" type structure. For example, the fatty group can bond with a hydroxyl or carbonyl group through the formation of an ester group. These ester groups contain bonds that are cleavable in the body, so they can react in the body to ultimately result in free levodopa, since free levodopa is needed to produce dopamine. The amine in levodopa can also be reacted once it is masked, resulting in free levodopa. The masking of the present invention also reduces the chance of peripheral degradation of levodopa to dopamine by AADC and COMT enzymes, thereby increasing the subsequent availability of levodopa in the brain. The derivatives provide sustained plasma levels of levodopa, increase the transport of levodopa to the brain, and thereby increase the efficacy of the treatment.

[0084] In one aspect of the present invention, the derivatives include a compound of Formula I, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof,

[0085]

[0086] wherein R1may be a branched or straight chain C4-34group derived from a saturated or unsaturated fatty alcohol and the C4-34group is directly or indirectly attached to a carbonyl group to form an ester, amide, or anhydride structure. R3may be a branched or straight chain C4-34group derived from a saturated or unsaturated fatty acid and R3is directly or indirectly attached to an oxygen to form an ester, carbonate, or carbamate structure. R4may be a branched or straight chain C4-34group derived from a saturated or unsaturated fatty acid and R4is directly or indirectly attached to an oxygen to form an ester, carbonate, or carbamate structure. R2may be hydrogen, or -(C=0)R5, wherein R5may be a C1-3straight chain or branched alkyl group, which can be substituted or unsubstituted. The carbon number for R1, R3, and R4as identified above is 4-34, however, various other ranges are possible. Other ranges can include C4-C26, C6-C30, C8-C25, C10-C20, C11-C15, and C12. All ranges within the C4-34range are also contemplated. The number of carbon atoms for R1, R3, and R4may 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 R6may be a derivative of a saturated or unsaturated fatty alcohol, and

[0090] wherein R7may be a derivative of a saturated or unsaturated fatty acid, and

[0091] wherein R8may be a derivative of a saturated or unsaturated fatty acid, and wherein

[0092] R2is hydrogen, or -(C=0)R5, wherein R5is a substituted or unsubstituted C 1-3 straight chain or branched alkyl group.

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

[0094]

[0095] wherein R6may be:

[0096] (a) -0-R9, wherein R9may be an alkyl or alkenyl group which can include 4-34 carbon atoms and be branched or straight chained, substituted or unsubstituted, or

[0097] (b) NH-R10, where R10can be an alkyl or alkenyl group that can include 4-34 carbon atoms and is branched or straight chained, substituted or unsubstituted, or

[0098] (c) -O-C=O-R11, where R11can be an alkyl or alkenyl group that can include 4-34 carbon atoms and is branched or straight chained, substituted or unsubstituted, and

[0099] where R7can be:

[0100] (a) an alkyl or alkenyl group that can include 4-34 carbon atoms and is branched or straight chained, substituted or unsubstituted, or

[0101] (b) -NH-R12, where R12can be an alkyl or alkenyl group that can include 4-34 carbon atoms and is branched or straight chained, substituted or unsubstituted, or

[0102] (c) -O-R13, where R13includes an alkyl or alkenyl group that can include 4-34 carbon atoms and is branched or straight chained, substituted or unsubstituted, and

[0103] where R8can be

[0104] (a) an alkyl or alkenyl group that can include 4-34 carbon atoms and is branched or straight chained, substituted or unsubstituted, or

[0105] (b) -NH-R14, where R14can be an alkyl or alkenyl group that can include 4-34 carbon atoms and is branched or straight chained, substituted or unsubstituted, or

[0106] (c) -O-R15, where R15is an alkyl or alkenyl group that can include 4-34 carbon atoms and is branched or straight chained, substituted or unsubstituted, and

[0107] where R2is hydrogen, or -(C=O)R5, where R5is C 1-3 straight chained or branched alkyl group that is substituted or unsubstituted.

[0108] R9, R10, R11, R12, R13, R14, and R15can independently include 4-34 carbon atoms. However, they can independently include other ranges of carbon atoms. Other ranges can include C6-C30, C8-C25, C10-C20, and C11-C15, as well as C12. All ranges within the C4-34 range are also contemplated. The number of carbon atoms of R9, R10, R11, R12, R13, R14, and R15may be the same or different.

[0109] In one aspect of the present invention, R6 in formula II is selected from the group consisting of: (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, R7and / or R8may be independently selected from the group consisting of: CH3(CH2)6-, 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 making the structure of Formula II is to react levodopa or a derivative thereof 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 be reacted with levodopa or a derivative thereof. For example, if the 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 R6can be NH-R10, as described above.

[0112] In the present invention, the levodopa derivative can be (S)-4-(2-amino-3- (dodecyloxy)-3-oxopropyl)-1,2-phenylene docosanoate, which is also identified as DB104 in the examples below. The chemical formula is C 45 H 79 NO6, with a molecular weight of 730.13. The levodopa derivative (DB104) can have the following molecular structure.

[0113]

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

[0115]

[0116] The present invention can involve 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 a composition can be injectable, inhalable, oral, or topically applied. Such a composition can be in the form of a liposome or a micelle. The pharmaceutically acceptable carrier of the one or more derivatives can be castor oil or a derivative thereof. Various carriers and excipients, and methods of making compositions injectable, inhalable, oral, or topically applied are known in the art. The formation of liposomes or micelles is also known in the pharmaceutical arts. Thus, 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 a patient, including subcutaneous, intramuscular, intraperitoneal, intravenous, or intradermal injection. In other embodiments, the composition can be administered as a depot. Upon parenteral injection of the derivative, enzymatic cleavage can occur, resulting in levodopa.

[0118] In another embodiment, the present application can relate 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 can 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(vinylpyrrolidone), polyvinyl alcohol, poly(ethyleneimine), poly(malic acid), poly L-lysine, poly L-glutamic acid, poly((N-hydroxyalkyl) glutamines), dextrin, hydroxyethyl starch, polysialic acid, polyacetals, N-(2-hydroxypropyl) methacrylamide copolymers, poly(amide) dendrimers, mixtures, combinations, 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 ratios to encapsulate the compounds of the present application to form microparticles or nanoparticles. PLGA is a pharmaceutically acceptable biodegradable polymer widely used to encapsulate a variety of therapeutic agents including hydrophilic and hydrophobic small molecule drugs, DNA, and proteins due to its excellent biocompatibility. Other additives such as polyethylene glycol (PEG), polyorthoesters, chitosan, alginate, caffeic acid, hyaluronic acid, and the like can be used to enhance drug loading and efficiency in PLGA microparticles. PLGA can be of different compositions of PLA and PGA, with a ratio of PGA to PLA of 20-80% or a ratio of PLA to PGA of 20-80%, as well as any range within these ranges.

[0119] Polymer-encapsulated microparticles / nanoparticles can be prepared by methods known in the art. See, e.g., Han et al., Front Pharmacol. 2016; 7: 185; Qutachi et al., Acta Biomater. 2014; 10(12):5090-5098. Preparation of derivative microparticles can be carried out as follows. Nanoprecipitation technique can be used to prepare levodopa microparticles. Briefly, the derivative and polymer (e.g., PLGA) are dissolved in a suitable solvent (e.g., dichloromethane) at different ratios, and if necessary, the mixture is subjected to ultrasonication for 5-10 minutes to achieve dissolution. A hydrophilic non-ionic surfactant (e.g., a triblock copolymer), such as Pluronic F127, can be dissolved in 50 mL of deionized water, and the derivative / PLGA solution can also be added dropwise using a syringe at a flow rate of 1 mL / 10 min while stirring at different speeds. The resulting nanosuspension can be subjected to centrifugation and freeze-drying with a cryoprotectant (e.g., 2% sucrose). The resulting 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 application, the term “encapsulated” means surrounded, covered, or enclosed by a polymer, such that at least about 20% of the derivative is encapsulated / covered / enclosed by the polymer. Preferably, from about 20% to about 80% of the derivative is encapsulated / covered / enclosed. The surrounding structure need not be complete enclosure of the derivative, but should surround at least 30% of the surface. Thus, preferably, the derivative in the form of microparticles / nanoparticles is covered by at least about 20%, and such covering will be at least 30% surface coverage. Preferably, up to 80% of the surface will be covered, although 100% surface coverage is possible at least for some particles.

[0121] Pharmaceutical compositions containing one or more derivatives can further include one or more pharmaceutically acceptable carriers or excipients. As noted above, such compositions can be injectable, inhalable, orally ingestible, or topically administrable. Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which can contain anti-oxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents. The compositions can be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials.

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

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

[0124] The composition 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 to reduce the premature degradation of levodopa, so even if the derivatives of the present application have lost some of the "fatty" moieties, carbidopa can still help to reduce the amount of active ingredient that is degraded and cannot be used to form dopamine.

[0125] In some embodiments, the amount of derivative compound in the composition of the present application is in the range of 100 mg to 2000 mg of levodopa equivalent per day, administered once a day. A composition comprising 10-200 mg of carbidopa and / or 200-1600 mg of entacapone (or other COMT inhibitor) can be combined with the composition of the present application for the treatment of PD. Thus, the compound of the present application can include carbidopa or entacapone in addition to the derivative compound. 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 derivative and / or the amount of levodopa equivalent in the derivative. COMT inhibitors, such as tolcapone, opicapone, and / or entacapone, can be co-administered with the derivative in a dose of 200 mg or more, and repeated as needed, with or without co-administration of carbidopa. Carbidopa in an amount of 10 mg to 200 mg per day and / or entacapone (or another COMT inhibitor) in an amount of 200 mg to 1600 mg per day can be co-administered with the compound or composition of the present application.

[0126] In another aspect, the composition containing one or more derivatives can be used to treat Parkinson's disease by administering to a Parkinson's disease patient once a day. 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 once 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 containing a pharmaceutically effective amount of one or several of the derivatives and a pharmaceutically acceptable polymer, and can be co-administered with carbidopa and / or entacapone (or other COMT inhibitor) for the treatment of Parkinson's disease. Such a composition can be administered intravenously, intramuscularly, intraperitoneally, orally, or subcutaneously. The administration can be once a day, up to two or three times a week, once a week or once every two weeks, or once a month.

[0128] Example 1 below demonstrates that the derivatives of the present application produce protection of the active ingredient, with less early degradation of levodopa, so that it is available to form dopamine after crossing the blood brain barrier.

[0129] Example 1

[0130] 10 mM DB104 (DB104 is one of the derivatives of the present application, as described above) was incubated in fresh human plasma and phosphate buffered saline (PBS) in multiple aliquots, each split 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 second 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 an IS.

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

[0132]

[0133] DB104 required approximately 4 hours and 1-4 hours to fully 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, as well as 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 test resulted in an in vitro half-life estimate of DB104 in human plasma and PBS of approximately 12 hours. Detectable amounts of L-DOPA were formed in human plasma or PBS for up to 72 hours, indicating less peripheral degradation and more L-DOPA available to cross the blood brain barrier. DB104M4 is the main degradant in PBS. It is hypothesized that DB104 can also cross the blood brain barrier and L-DOPA can form 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 made by using a fatty alcohol, and R7 and R8 can be made by using a fatty acid.

[0136] Fatty alcohols that can be used to prepare levodopa derivatives include, but are not limited to, t-butyl alcohol, t-amyl alcohol, 3-methyl-3-pentanol, 1-heptanol (n-heptanol), 1-octanol (n-octanol), nonanol (1-nonanol), 1-decanol (decyl alcohol, capric alcohol), undecanol (1-undecanol, undecyl alcohol, hendecanol), lauryl alcohol (dodecanol, 1-dodecanol), tridecanol (1-tridecanol, tridecyl alcohol, isotridecyl alcohol), myristyl alcohol (1-tetradecanol), pentadecanol (1-pentadecanol, pentadecyl alcohol), cetyl alcohol (1-hexadecanol), palmityl alcohol (cis-9-hexadecen-1-ol), 1-heptadecanol, stearyl alcohol (1-octadecanol), octadecenyl alcohol (1-octadecenol), nonadecanol (1-nonadecanol), eicosanol (1-eicosanol), heneicosanol (1-heneicosanol), behenyl alcohol (1-docosanol), geryl alcohol (cis-13-docosen-1-ol), lignoceryl alcohol (1-tetracosanol), cerotyl alcohol (1-hexacosanol), 1-heptacosanol, montanyl alcohol, cluytyl alcohol or 1-octacosanol, 1-nonacosanol, myricyl alcohol, melissyl alcohol, or 1-triacontanol, 1-dotriacontanol, 1-tetratriacontanol, trans-9-octadecenol, and cis,cis-9,12-octadecadien-1-ol. Other fatty alcohols can 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, myricyl-palmitate, palmitoleic acid, gallic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linolenic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, euric acid, docosahexaenoic acid. Other fatty acids can also be used.

[0138] The following Example 2 shows the use of levodopa in forming particular embodiments of derivatives of the present application.

[0139] Example 2

[0140] Preparation of dodecyl dodecanoyl ester of lauric acid levodopa hydrochloride:

[0141] Target molecules:

[0142]

[0143] Experimental procedure:

[0144] Preparation of N-(tert-butoxycarbonyl)-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), 1 M NaOH (100 mL) under nitrogen at room temperature for 30 min. tert-Butyl dicarbonate (35 gm, 0.160 mol) was added slowly at room temperature and the reaction was stirred for 20 h. After completion of the reaction, the solvent was evaporated under vacuum and the volume was reduced to half. The organic material was extracted using ethyl acetate (3 x 100 mL). The combined organic layer was washed with water (100 mL) followed by brine (50 mL) and the final organic layer was dried over anhydrous Na2S04. The organic layer was concentrated under vacuum at a temperature below 55 °C to obtain a brown foamy solid. The obtained crude product was purified by column chromatography on silica gel (100-200 mesh) using dichloromethane & methanol (6:4) as eluent system to obtain 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. Na2C03was added to the reaction mixture followed by 1-bromododecane, which can be derived from fatty alcohol dodecanol, and stirred for 16 h to complete the reaction. The reaction mixture was filtered and the filtrate was concentrated under vacuum at 55 °C to completely remove the solvent. Water (100 mL) was added to the residue and the pH was adjusted to acidic side using 6 N HC1 (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) followed by brine (50 mL) and dried over anhydrous Na2S04. 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 the pure product (yield: 9.2 gm, 28%).

[0146] Preparation of dodecyl lauryl alcohol-Boc L-dopa: Boc L-dopa dodecyl ester (8.5 gm) was stirred in a round bottom flask with DCM (10 mL) at room temperature under nitrogen. The reaction mixture was cooled in an ice bath, keeping the temperature between 0-5 °C. Dodecyl chloride (2.85 gm) in DCM (15 mL) was added drop wise to the reaction mixture. Dodecyl chloride is the acid chloride of lauric acid, which is a fatty acid. After 10 minutes of stirring, the reaction mixture was stirred at room temperature to complete the reaction. The reaction mass was washed with DI water (4 x 50 mL) and the organic layer was dried over anhydrous Na2S04. The obtained DCM layer was concentrated under vacuum to obtain an orange thick residue. The residue was purified by column chromatography using a mixture of ethyl acetate and n-hexane (6:4) as eluent to get the pure product (yield: 2.75 gm, 19%).

[0147] Preparation of dodecyl lauryl alcohol-Boc L-dopa: Boc L-dopa dodecyl ester (8.5 gm) was stirred in a round bottom flask with DCM (10 mL) at room temperature under nitrogen. The reaction mixture was cooled in an ice bath, keeping the temperature between 0-5 °C. Dodecyl chloride (2.85 gm) in DCM (15 mL) was added drop wise to the reaction mixture. Dodecyl chloride is the acid chloride of lauric acid, which is a fatty acid. After 10 minutes of stirring, the reaction mixture was stirred at room temperature to complete the reaction. The reaction mass was washed with DI water (4 x 50 mL) and the organic layer was dried over anhydrous Na2S04. The obtained DCM layer was concentrated under vacuum to obtain an orange thick residue. The residue was purified by column chromatography using a mixture of ethyl acetate and n-hexane (6:4) as eluent to get the pure product (yield: 2.75 gm, 19%). 1 H-NMR (DMSO-d6): δ 0.83-0.86 (9H, t, -CH3), 1.10-1.40 (52H, m, CH2aliphatic protons), 1.58-1.61 (4H, m, CH2aliphatic protons), 2.50-2.54 (4H, m, CH2-CO), 3.00 (1H, dd, benzylic CH2), 3.20 (1H, dd, benzylic 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 proton). Thus, dodecyl lauryl alcohol-L-dopa hydrochloride product is produced and can be used for the treatment of Parkinson’s disease. Different fatty alcohols and fatty acids can be used in place of those used above in order to react different chains as part of the derivative.

Claims

1. A compound of formula II or a pharmaceutically acceptable salt thereof, Where R2 is H, Where R6 is CH3(CH2) 10 CH2O-, and Where R7 and R8 are CH3(CH2) 10 .

2. The compound according to claim 1, wherein the compound is 3. The compound according to claim 1, wherein the compound is a hydrochloride salt having the following chemical formula:

4. A composition comprising a pharmaceutically effective amount of the compound of claim 1 and one or more pharmaceutically acceptable carriers or excipients.

5. The composition of claim 4, wherein the composition is injectable, inhalable, orally ingestible or topically administered.

6. The composition according to claim 4, wherein the composition is in the form of liposomes or micelles.

7. The composition of claim 4, wherein the pharmaceutically acceptable carrier is castor oil.

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