Levodopa fatty acid derivatives, formulations thereof, and their use for the treatment of Parkinson's disease - Patents.com

Abstract

The present invention provides a levodopa derivative, including a compound or a pharma- ceutically acceptable salt, hydrate, and / or solvate thereof, the compound including, in its entirety, a substituent that contains at least six carbon atoms that are bonded only to either other carbon atoms or to hydrogen atoms. The levodopa derivative may be formulated as a composition including one or more pharma- ceutically 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 pharma- ceutically acceptable polymer. The levodopa derivative 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 polymeric nanoparticle / microparticle formulations of levodopa derivatives. These compounds and compositions are useful in the treatment of Parkinson's disease.

[0002] Background technology Levodopa (otherwise called L-DOPA) is the generic name for (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid, as shown below. [ka]

[0003] Levodopa is an aromatic amino acid derivative that is the primary source of dopamine. In humans and other animals, levodopa is synthesized from the amino acid L-tyrosine and serves as a precursor in the synthesis of the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), collectively known as catecholamines.

[0004] Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects approximately 1-2% of the population over the age of 60. Symptoms include resting tremor, rigidity, bradykinesia, and postural instability caused by selective degeneration of dopaminergic neurons in the substantia nigra, resulting in disruption of the nigrostriatal pathway and reduced striatal dopamine levels. Olanow et al., Neurology. 2009;72(21 Suppl 4):S1-136.

[0005] 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). The U.S. Food and Drug Administration ("FDA") approved levodopa for the treatment of PD in 1970. Levodopa, unlike dopamine, is able to cross the blood-brain barrier (BBB) ​​and is converted to dopamine in the central nervous system as well as the peripheral circulation (peripheral circulation is the circulation before crossing the BBB). Most commonly, levodopa is used as a dopamine replacement agent for the treatment of PD and is particularly effective in controlling the bradycardial symptoms evident in PD. Levodopa is recommended for the symptomatic treatment of all stages of Parkinson's disease and is administered multiple times daily by the oral route. Levodopa is commonly administered with carbidopa, a dopamine decarboxylase inhibitor, to reduce the amount of levodopa converted to dopamine in the periphery, so that more levodopa crosses the BBB and is converted to dopamine. This combination therapy therefore allows more levodopa to cross the BBB. Once converted to dopamine, it activates postsynaptic dopaminergic receptors, compensating for the decrease in endogenous dopamine.

[0006] Levodopa is absorbed in the small intestine, and 95% of the administered oral dose is pre-systemically decarboxylated to dopamine by aromatic L-amino acid decarboxylase (AADC) in the lumen of the stomach, intestine, kidney, and liver. Levodopa can also be methoxylated by the hepatic catechol-O-methyltransferase (COMT) enzyme system to 3-O-methyldopa (3-OMD), which cannot be converted to central dopamine. Thus, only a small portion of an oral dose of levodopa is transported across the BBB to the central nervous system (CNS), where it is converted to the neurotransmitter dopamine by the brain AADC enzyme. Dopamine is further converted to sulfated or glucuronidated metabolites and homovanillic acid through various metabolic processes. The primary metabolites of levodopa are 3,4-dihydroxyphenylacetic acid (13-47%) and homovanillic acid (23-39%).

[0007] Because the AADC and COMT enzymes in the stomach break down levodopa, the drug levodopa may be administered with the following agents: i) a peripheral dopamine decarboxylase inhibitor (carbidopa) (in the absence of this agent, 90% of levodopa is metabolized in the intestinal wall), and ii) a COMT inhibitor (entacapone); to further improve the bioavailability of levodopa in the brain, the COMT inhibitor. 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.

[0008] AADC inhibitors and COMT inhibitors inhibit the decarboxylation of levodopa in the stomach and periphery, making more levodopa available for transport across the BBB and increasing brain dopamine content. Carbidopa, when administered with levodopa, reduces the amount of levodopa required to produce a given response by 75%. When coadministered with levodopa / carbidopa, a 200 mg dose of entacapone increases levodopa plasma exposure by 35-40%.

[0009] The plasma half-life of levodopa alone is approximately 50 minutes. When administered with carbidopa (Sinemet® and Sinemet® CR 50-200), its half-life increases to 1.5 hours (Sinemet® label, NDA 17555). The time to reach peak plasma concentration (T max) is approximately 0.5 hours for Sinemet® and 2 hours for Sinemet® CR, and the peak plasma concentration (C max ) was 1151 ng / mL vs. 3256 ng / mL for Sinemet® vs. Sinemet® CR (Sinemet® CR label, NDA 019856). After administration of Stalevo® (combination of carbidopa, levodopa and entacapone, 37.5 / 150 / 200 mg), t max is about 1.5 hours, and C max is 1270±329 ng / mL (STALEVO® label, NDA 21485).

[0010] Common side effects of levodopa include nausea, vomiting, dry mouth, loss of appetite, heartburn, diarrhea, constipation, dizziness, muscle pain, numbness or tingling, and sleep disorders. Serious side effects include mood changes, increased eye blinking / twitching, and worsening involuntary movements / convulsions. Motor fluctuations (including dyskinesias and abnormal involuntary movements) are closely related to the pharmacokinetics of levodopa, its erratic 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.

[0011] By using low doses of levodopa and maintaining constant dopamine levels, the development of dyskinesias can be avoided. Research is ongoing to find a route of delivery of levodopa to achieve continuous dopaminergic stimulation. Intrajejunal infusion developed by Abbvie (Duopa®) is performed by continuous infusion for the treatment of motor fluctuations in patients with advanced Parkinson's disease and was approved by the FDA in 2015. Levodopa inhalation powder Inbrija® by Acorda Therapeutics, Inc. was approved by the FDA in 2018. Several other formulations for continuous subcutaneous (SC) infusion are in development, such as ABBV-951 (Abbvie) and ND6012 (Neuroderm / Tanabe Mitsubishi).

[0012] Levodopa has been modified into water-soluble ester and amide derivatives for better brain uptake. See In 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.

[0013] Levodopa has two benzyl hydroxyl groups at the 3- and 4-positions of the benzene ring, one amine group at the 2-position of the alkyl chain, and one active carboxyl group at the end of the alkyl chain. The two hydroxyl groups of levodopa can be modified into ester derivatives. The methyl ester of levodopa (Levomet®) is already on the market. However, the ethyl ester derivative (etilevodopa, TV-1203) was found to be less effective than levodopa in phase III clinical trials.

[0014] WO 2020 / 264460 discloses a method for reducing the early response of levodopa. The present invention improves upon the invention of WO 2020 / 264460. The disclosure of WO 2020 / 264460 is incorporated herein by reference in its entirety.

[0015] Current therapies utilizing levodopa (or its prodrugs) for the treatment of PD have a very short plasma half-life, resulting in significant plasma drug concentration fluctuations, which in turn leads to fluctuating amounts of levodopa crossing the BBB and inconsistent dopamine levels in the brain. These fluctuations in plasma concentration are reflected as fluctuating treatment responses as the disease progresses. There is a need for a treatment that provides a stable level of plasma levodopa concentration and results in a stable amount crossing the BBB over a longer period of time. The present invention addresses all these needs.

[0016] Summary of the Invention

[0017] In one aspect, the present invention relates to a levodopa derivative, including a compound or a pharma- ceutically acceptable salt, hydrate, and / or solvate thereof, which includes a substituent containing at least 6 carbon atoms that are bonded only to other carbon atoms or hydrogen atoms as a whole. The levodopa derivative may include a substituent containing 8 to 100 carbon atoms that are bonded only to other carbon atoms or hydrogen atoms as a whole.

[0018] In one aspect of the invention, the levodopa derivative comprises a compound of formula I, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof: [ka] where R1 can be a branched or straight chain C4-34 group derived from a saturated or unsaturated fatty alcohol, which C4-34 group is linked directly or indirectly to a carbonyl 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, which R3 is linked directly or indirectly to an 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, which R4 is linked directly or indirectly to an oxygen to form an ester, carbonate or carbamate structure; R2 can be hydrogen or (C=O)R5, where R5 is C 1~3 The alkyl group may be a straight or branched chain alkyl group.

[0019] In another embodiment, the levodopa derivative comprises a compound of formula II or a pharma- ceutically acceptable salt, hydrate, or solvate thereof: [ka] wherein R6 may be a derivative of a saturated or unsaturated fatty alcohol; wherein R7 can be a derivative of a saturated or unsaturated fatty acid; wherein R8 can be a derivative of a saturated or unsaturated fatty acid; R2 is hydrogen or (C=O)R5, where R5 is C 1~3 A straight or branched chain alkyl group.

[0020] In yet another embodiment, the levodopa derivative comprises a compound of formula II or a pharma- ceutically acceptable salt, hydrate, or solvate thereof: [ka] In the formula, R6 is (a) -O-R9, where R9 may contain from 4 to 34 carbon atoms and may be an alkyl or alkenyl group that is branched or straight chain, substituted or unsubstituted; or (b) NH-R10, where R10 may contain from 4 to 34 carbon atoms and may be an alkyl or alkenyl group that is branched or straight chain, substituted or unsubstituted; or (c) -O-C=O-R, where R can be an alkyl or alkenyl group that contains 4 to 34 carbon atoms and is branched or straight chain, substituted or unsubstituted; In the formula, R7 is (a) an alkyl or alkenyl group, which may contain from 4 to 34 carbon atoms and which is branched or straight chain, substituted or unsubstituted; or (b) -NH-R12, where R12 may contain from 4 to 34 carbon atoms and may be an alkyl or alkenyl group that is branched or straight chain, substituted or unsubstituted; or (c) -O-R13, where R13 may contain 4 to 34 carbon atoms and includes alkyl or alkenyl groups that are branched or straight chain, substituted or unsubstituted; In the formula, R8 is (a) an alkyl or alkenyl group, which may contain from 4 to 34 carbon atoms and which is branched or straight chain, substituted or unsubstituted; or (b) -NH-R14, where R14 may contain from 4 to 34 carbon atoms and may be an alkyl or alkenyl group that is branched or straight chain, substituted or unsubstituted; or (c) -O-R15, where R15 may be an alkyl or alkenyl group that may contain from 4 to 34 carbon atoms and is branched or straight chain, substituted or unsubstituted; where R2 is hydrogen or (C=O)R5, where R5 is C 1~3 A straight or branched chain alkyl group.

[0021] In one aspect of the invention, in formula II, R6 is (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) 11CH2O-, 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 Selected from the group consisting of CH2O- and CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)2CH2O-.

[0022] In formula II, R7 and / or R8 are 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-, C H3(CH2)7CH=CH(CH2)7-, CH3(CH2)5CH=CH(CH2)9-, CH3(CH2)4CH=CHCH2CH=CH(CH2)7-(cis, cis), CH3(CH2)4C H=CHCH2CH=CH(CH2)7-(trans, trans), CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7-, CH3(CH2)4CH=CHCH2CH=CHCH 2CH=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=CHCH2CH=CHCH(CH2)2-.

[0023] In another aspect of the invention, the levodopa derivative may be a compound of formula II or a pharma- ceutically acceptable salt, hydrate or solvate thereof: [ka] In the formula, R6 is (a) -O-R9, where R9 can be an alkyl or alkenyl group containing from 4 to 34 carbon atoms and which is branched or straight chain, substituted or unsubstituted; or (b) NH-R10, where R10 can be an alkyl or alkenyl group containing from 4 to 34 carbon atoms and which is branched or straight chain, substituted or unsubstituted; or (c) -O-C=O-R, where R can be an alkyl or alkenyl group containing 4 to 34 carbon atoms and which is branched or straight chain, substituted or unsubstituted; In the formula, R7 is (a) an alkyl or alkenyl group, which contains 4 to 34 carbon atoms and is branched or straight-chained, substituted or unsubstituted; or (b) -NH-R12, where R12 can be an alkyl or alkenyl group containing from 4 to 34 carbon atoms and which is branched or straight chain, substituted or unsubstituted; or (c) -O-R13, where R13 can be an alkyl or alkenyl group containing 4 to 34 carbon atoms and which is branched or straight chain, substituted or unsubstituted; In the formula, R8 is (a) an alkyl or alkenyl group, which contains 4 to 34 carbon atoms and is branched or straight-chained, substituted or unsubstituted; or (b) -NH-R14, where R14 can be an alkyl or alkenyl group containing from 4 to 34 carbon atoms and which is branched or straight chain, substituted or unsubstituted; or (c) -O-R15, where R15 can be an alkyl or alkenyl group containing 4 to 34 carbon atoms and which is branched or straight chain, substituted or unsubstituted; where R2 is hydrogen or (C=O)R5, where R5 is C 1~3 A straight or branched chain alkyl group.

[0024] In the present invention, the levodopa derivative can be (S)-4-(2-amino-3-(dodecyloxy)-3-oxopropyl)-1,2-phenylenedidodecanoate, which is identified in the examples as DB104 and has the chemical formula C 45 H 79 NO6, molecular weight is 730.13. The levodopa derivative (DB104) may have the following molecular structure: [ka] Additionally, the present invention contemplates and provides for levodopa modified with other fatty acids or fatty alcohols.

[0025] In another embodiment, the levodopa derivative is an HCl salt having the following chemical formula: [ka]

[0026] The present invention may be directed to a composition comprising a pharma- ceutical effective amount of the levodopa derivative of the present invention and one or more pharma- ceutical acceptable carriers or excipients. Such compositions may be injectable, inhalable, ingestible, or topical. Such compositions may be in the form of liposomes or micelles. The pharma- ceutical acceptable carrier of the levodopa derivative may be castor oil or its derivatives.

[0027] In yet another aspect, the present invention may be directed to a pharmaceutical composition comprising a microparticle or nanoparticle comprising a pharma- ceutical effective amount of the levodopa derivative and a pharma- ceutical acceptable polymer, wherein the levodopa derivative is encapsulated in the pharma- ceutical acceptable polymer. The pharma- ceutical acceptable polymer may be selected from the group consisting of polyethylene glycol, poly(glycolide), poly(lactide), poly(caprolactone), poly(lactide-co-caprolactone), poly(lactide-co-glycolide), poly(lactic acid)-butanol, poly(vinylpyrrolidone), poly(vinyl 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(amidoamine) dendrimer, and mixtures, combinations, and copolymers thereof.

[0028] In yet another aspect, the invention may be directed to a method of treating Parkinson's disease, comprising administering to a mammal an amount of the levodopa derivative sufficient to treat Parkinson's disease. The levodopa derivative may be in the form of a composition that may be administered intravenously, intramuscularly, intraperitoneally, orally, or subcutaneously.

[0029] Compositions containing the levodopa derivatives may be co-administered with carbidopa and / or entacapone for the treatment of Parkinson's disease.

[0030] In another embodiment, the composition containing the levodopa derivative can be used to treat Parkinson's disease by administering it to a Parkinson's disease patient once a day. In another embodiment, the composition can be administered up to two or three times a week. In yet another embodiment, the composition can be administered once a week or once every other week. The composition can be administered once a month.

[0031] In one embodiment, the composition containing the levodopa derivative may be a pharmaceutical composition comprising a microparticle or nanoparticle containing a pharma- ceutical effective amount of the levodopa derivative and a pharma- ceutical acceptable polymer, and may be co-administered with carbidopa and / or entacapone to treat Parkinson's disease. Such compositions may be administered intravenously, intramuscularly, intraperitoneally, orally, or subcutaneously. Administration may be once a day, up to two or three times a week, once a week or every other week, or once a month. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] The detailed description set forth below is intended as a description of some, but not all, of the configurations of the subject technology, and is not intended to represent an exhaustive list. The detailed description includes specific details for the purpose of providing a thorough understanding of the invention and the subject technology. The invention and technology are not limited to the specific details described herein, and may be practiced without these specific details. In other examples, well-known structures and techniques have not been shown in detail so as not to obscure the present disclosure. Exemplary aspects may be described in detail below. While certain exemplary aspects may be described, it should be understood that this is done for illustrative purposes only. In describing and illustrating the exemplary aspects, specific terms may be used for clarity. However, the aspects are not intended to be limited to the specific terminology so selected. Those skilled in the art will recognize that other components and configurations may be used without departing from the spirit and scope of the aspects. It should be understood that each specific element encompasses all technical equivalents that operate in a similar manner to accomplish a similar purpose. The examples and aspects described herein are non-limiting examples.

[0033] All publications cited herein are incorporated herein by reference in their entirety. As used herein, the term "a" refers to one or more. Terms such as "including," "for example," "such as," "eg," "may be," and the like, mean including but not limited to the listed examples.

[0034] References to "one embodiment," "embodiment," "exemplary embodiment," "various embodiments," etc. may indicate that the embodiment of the invention so described may include a particular feature, structure, or characteristic, but not necessarily all embodiments include that particular feature, structure, or characteristic.

[0035] Additionally, repeated use of the phrases "in one embodiment" or "in an exemplary embodiment" do not necessarily refer to the same embodiment, but may. The various embodiments described herein can be combined and / or features of the embodiments can be combined to form new embodiments.

[0036] Although various aspects of the present invention have been described herein, it should be understood that they are presented by way of example only and not by way of limitation. Thus, the breadth and scope of the present invention should not be limited by any of the exemplary aspects described. The aspects of the present invention described may include features that can be removed or combined between the described aspects to derive additional aspects. Any ranges disclosed herein are intended to disclose and disclose any ranges within such disclosed ranges.

[0037] Headings and sub-headings, if any, are used for convenience only and do not limit the invention.

[0038] A phrase such as "an aspect" does not imply that such an aspect is essential to the subject technology or that such an aspect applies to all configurations of the subject technology. A disclosure of an aspect may apply to all configurations, or to one or more configurations. A phrase such as an aspect may refer to one or more aspects, and vice versa. A phrase such as "an aspect" does not imply that such an aspect is essential to the subject technology or that such an aspect applies to all configurations of the subject technology. A disclosure of an aspect may apply to all aspects, or to one or more aspects. A phrase such as an aspect may refer to one or more aspects, and vice versa.

[0039] All structural and functional equivalents to the elements of the various aspects described throughout this disclosure that are known or that later become known to those skilled in the art are intended to be expressly incorporated herein by reference and encompassed in the claims. Moreover, nothing disclosed herein is intended to be general, regardless of whether such disclosure is explicitly set forth in the claims. Furthermore, to the extent that terms such as "include," "have," and the like are used in the specification or claims, such terms are intended to be as inclusive as the terms "comprise," as "comprise" would be interpreted when used as a transitional term in a claim.

[0040] When levodopa is utilized alone to treat Parkinson's disease, it is largely degraded before it has a chance to pass through the BBB and increase dopamine levels appropriately.As part of the present invention, it has been found that by adding a "fatty" structure as part of the present levodopa derivative to protect levodopa from premature degradation, more levodopa becomes available to pass through the BBB.Therefore, patients can consume less active ingredient to get better results, which also results in a sustained passage of active ingredient to the BBB, so that there is a constant level of dopamine in the brain.

[0041] These "fatty" structures help protect the levodopa active portion of the molecule. In addition, it is believed that these "fatty" structures are more capable of crossing the BBB because they are more "fatty" and therefore more soluble in lipids, a desirable property for crossing the BBB. If the "fatty" portion of the molecule is too small, the levodopa active portion may not be protected from premature degradation and the levodopa derivative may not be effective at crossing the BBB. Alternatively, if the "fatty" portion is too large, it may be too difficult to break down the levodopa derivative into a usable form, which may also make it difficult to easily cross the BBB. The present invention addresses all of these challenges with new chemical structures and compositions, as described more fully below.

[0042] In essence, the compounds of the present invention have several advantages including increased bioavailability at lower doses, predictable drug release profile over a defined period of time following each administration, improved patient compliance, ease of application, improved systemic availability due to avoidance of first pass metabolism, reduced dosing frequency without compromising efficacy of treatment, reduced incidence of side effects, better BBB transport, and reduced overall cost of healthcare.

[0043] In one aspect, the present invention is directed to levodopa derivatives, including certain compounds as well as pharma- ceutically acceptable salts, hydrates, and / or solvates of such compounds. Levodopa derivatives, including compounds as well as pharma- ceutically acceptable salts, hydrates, and / or solvates of such compounds, are collectively identified as "derivatives" or "levodopa derivatives." Derivatives may include substituents that, in their entirety, contain at least 6 carbon atoms that are bonded only to either other carbon atoms or hydrogen atoms. This is part of the "fatty" portion of the molecule in the present invention. Derivatives may include substituents that, in their entirety, contain at least 8-100 carbon atoms that are bonded only to either other carbon atoms or hydrogen atoms. In other aspects, the number of carbons that are bonded only to either 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 of 8-100 carbon atoms, is contemplated in the present invention. Since the present invention contemplates the addition of "fatty" protecting groups to levodopa, derivatives can be synthesized using fatty acids and fatty alcohols, which are further described below, as well as further details regarding what types of molecules can be part of the derivatives.

[0044] Masking one or both of the reactive hydroxyl groups in the phenyl ring and / or carboxylic acid group of levodopa with aliphatic structures is one way of implementing the present invention. The amine groups of levodopa can also be masked. A fatty acid derivative can be reacted with the hydroxyl group in the phenyl ring of levodopa to add a "liphatic" structure to the molecule. The carboxylic acid group in levodopa can be reacted with a fatty alcohol derivative to further add such a "liphatic" structure. The fatty group can be attached to the hydroxyl group or carbonyl group, for example, by forming an ester group. These ester groups contain a bond that can be cleaved in vivo so that they can react in the body to ultimately become free levodopa, since free levodopa is needed to produce dopamine. The amines in levodopa, once masked, can also react to give 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 improving the subsequent availability of levodopa in the brain. The derivatives provide sustained plasma levels of levodopa and increase the delivery of levodopa to the brain, resulting in improved efficacy.

[0045] In one aspect of the invention, the derivative comprises a compound of formula I or a pharma- ceutically acceptable salt, hydrate and / or solvate thereof: [ka] where R1 can be a branched or straight chain C4-34 group derived from a saturated or unsaturated fatty alcohol, which C4-34 group is linked directly or indirectly to a carbonyl 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, which R3 is linked directly or indirectly to an 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, which R4 is linked directly or indirectly to an oxygen to form an ester, carbonate or carbamate structure; R2 can be hydrogen, or (C=O)R5, where R5 can be substituted or unsubstituted. 1~3 The number of carbons identified above for R1, R3 and R4 is 4 to 34, although various other ranges are possible. Other ranges can include C4 to C26, C6 to C30, C8 to C25, C10 to C20, and C11 to C15, and C12. Any range within the range of C4 to 34 is contemplated. The number of carbons in R1, R3 and R4 may be the same or different.

[0046] In another aspect, the derivative comprises a compound of formula II or a pharma- ceutically acceptable salt, hydrate or solvate thereof: [ka] wherein R6 may be a derivative of a saturated or unsaturated fatty alcohol; wherein R7 can be a derivative of a saturated or unsaturated fatty acid; wherein R8 can be a derivative of a saturated or unsaturated fatty acid; R2 is hydrogen or (C=O)R5, where R5 is a substituted or unsubstituted C 1~3 A straight or branched chain alkyl group.

[0047] In yet another embodiment, the derivative comprises a compound of formula II or a pharma- ceutically acceptable salt, hydrate or solvate thereof: [ka] In the formula, R6 is (a) -O-R9, where R9 may contain from 4 to 34 carbon atoms and may be an alkyl or alkenyl group that is branched or straight chain, substituted or unsubstituted; or (b) NH-R10, where R10 may contain from 4 to 34 carbon atoms and may be an alkyl or alkenyl group that is branched or straight chain, substituted or unsubstituted; or (c) -O-C=O-R, where R can be an alkyl or alkenyl group that contains 4 to 34 carbon atoms and is branched or straight chain, substituted or unsubstituted; In the formula, R7 is (a) an alkyl or alkenyl group, which may contain from 4 to 34 carbon atoms and which is branched or straight chain, substituted or unsubstituted; or (b) -NH-R12, where R12 may contain from 4 to 34 carbon atoms and may be an alkyl or alkenyl group that is branched or straight chain, substituted or unsubstituted; or (c) -O-R13, where R13 may be an alkyl or alkenyl group that may contain from 4 to 34 carbon atoms and is branched or straight chain, substituted or unsubstituted; In the formula, R8 is (a) an alkyl or alkenyl group, which may contain from 4 to 34 carbon atoms and which is branched or straight chain, substituted or unsubstituted; or (b) -NH-R14, where R14 may contain from 4 to 34 carbon atoms and may be an alkyl or alkenyl group that is branched or straight chain, substituted or unsubstituted; or (c) -O-R15, where R15 may be an alkyl or alkenyl group that may contain from 4 to 34 carbon atoms and is branched or straight chain, substituted or unsubstituted; where R2 is hydrogen or (C=O)R5, where R5 is C 1~3 is a straight or branched chain alkyl group, which may be substituted or unsubstituted.

[0048] R9, R10, R11, R12, R13, R14, and R15 can independently contain 4 to 34 carbon atoms. However, they can independently contain other ranges of carbon atoms. Other ranges can include C6 to C30, C8 to C25, C10 to C20, and C11 to C15, and C12. Any range within the range of C4 to 34 is contemplated. The number of carbon atoms in R9, R10, R11, R12, R13, R14, and R15 can be the same or different.

[0049] In one aspect of the 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=CHCH2CH=CH(CH2)2CH2O-.

[0050] In formula II, R7 and / or R8 are 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-, C H3(CH2)7CH=CH(CH2)7-, CH3(CH2)5CH=CH(CH2)9-, CH3(CH2)4CH=CHCH2CH=CH(CH2)7-(cis, cis), CH3(CH2)4C H=CHCH2CH=CH(CH2)7-(trans, trans), CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7-, CH3(CH2)4CH=CHCH2CH=CHCH 2CH=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=CHCH2CH=CHCH(CH2)2-. One way to make the structure of formula II is to react levodopa or its derivatives directly with fatty alcohol or fatty acid.Another way can first derivatize fatty alcohol or fatty acid with another functional group (such as amine functional group) and then react it with levodopa or its derivatives.For example, when fatty alcohol is derivatized with amine functional group and then fatty alcohol is reacted with carbonyl group on the right side of formula II, R6 can be NH-R10 as explained above.

[0051] In the present invention, the levodopa derivative can be (S)-4-(2-amino-3-(dodecyloxy)-3-oxopropyl)-1,2-phenylenedidodecanoate, which is also identified as DB104 in the examples below. The chemical formula is C 45 H 79 NO6 and has a molecular weight of 730.13. The levodopa derivative (DB104) of the present invention may have the following molecular structure: [ka]

[0052] In another embodiment, the levodopa derivative is an HCl salt having the following chemical formula: [ka]

[0053] The present invention may be directed to a composition comprising a pharma- ceutical effective amount of one or more derivatives of the present invention and one or more pharma- ceutical acceptable carriers or excipients. Such compositions may be injectable, inhalable, ingestible, or topical. Such compositions may be in the form of liposomes or micelles. The pharma- ceutical acceptable carrier for one or more derivatives may be castor oil or its derivatives. Various carriers and excipients, as well as methods for making compositions injectable, inhalable, ingestible, or topical, are known in the art. The formation of liposomes or micelles is also known in the pharmaceutical arts. Therefore, no further elaboration is required.

[0054] In some embodiments, the dosage form of the composition of the present invention is adapted for parenteral administration to a patient, including subcutaneous, intramuscular, intraperitoneal, intravenous or intradermal injection. In other embodiments, the composition may be administered as a depot. Parenteral injection of the derivative may result in enzymatic cleavage to produce levodopa.

[0055] In yet another aspect, the present invention may be directed to a pharmaceutical composition comprising microparticles or nanoparticles comprising a pharma- ceutical effective amount of one or more derivatives and a pharma- ceutical acceptable polymer, wherein the one or more derivatives are encapsulated in the pharma- ceutical acceptable polymer. The pharma-ceutical acceptable polymer may be selected from the group consisting of polyethylene glycol, poly(glycolide), poly(lactide), poly(caprolactone), poly(lactide-co-caprolactone), poly(lactide-co-glycolide), poly(lactic acid)-butanol, poly(vinylpyrrolidone), poly(vinyl 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(amidoamine) dendrimers, and 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 poly(lactide) (PLA), polyglycolide (PGA) and polyvinyl alcohol (PVA) are used in different ratios to encapsulate the compounds of the invention to form microparticles or nanoparticles. Due to its excellent biocompatibility, PLGA is a pharma-ceutically acceptable biodegradable polymer that is widely used for encapsulating a wide range of therapeutic agents including hydrophilic and hydrophobic small molecule drugs, DNA, and proteins. Other additives such as polyethylene glycol (PEG), poly(orthoesters), chitosan, alginate, caffeic acid, hyaluronic acid, etc. can be used to increase drug loading and efficiency in PLGA microparticles. PLGA can be various compositions of PLA and PGA with ratios of 20-80% PGA in PLA and vice versa, as well as any range within these ranges.

[0056] Polymer-encapsulated microparticles / nanoparticles may be prepared by methods known in the art. See, for example, Han et al., Front Pharmacol. 2016;7:185; Qutachi et al., Acta Biomater. 2014;10(12):5090-5098. Preparation of microparticles of derivatives may be performed as follows. Nanoprecipitation techniques may be used for preparation of levodopa microparticles. Briefly, derivatives and polymers (e.g., PLGA) are dissolved in a suitable solvent (e.g., dichloromethane) in different ratios, and the mixture is subjected to ultrasonication for 5-10 minutes to achieve dissolution as required. Dissolution of a hydrophilic non-ionic surfactant such as Pluronic F127 (e.g., triblock copolymer) in 50 mL of deionized water may be performed, and the derivative / PLGA solution may be added dropwise using a syringe with a flow rate of 1 mL / 10 min, while stirring at various speeds. Centrifugation and lyophilization of the resulting nanosuspension with a cryoprotectant (e.g., 2% sucrose) may be performed. The resulting particles can be characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray diffraction (XRD).

[0057] The term "encapsulated" in the context of the present invention means "coated by", "covered by" or "surrounded by" such that at least about 20% of the derivative is surrounded / covered / coated by the polymer. Preferably, about 20% to about 80% of the derivative is surrounded / covered / coated. The surrounding does not have to completely surround the derivative, but should be at least 30%. Thus, preferably, at least about 20% of the derivative in the form of microparticles / nanoparticles is covered, such coverage being at least 30% of the surface. Preferably, up to 80% of the surface is covered, but it is also possible to cover 100% of the surface with at least a portion of the particle.

[0058] Pharmaceutical compositions containing one or more derivatives may further include one or more pharma- ceutically acceptable carriers or excipients. Such compositions may be injectable, inhalable, orally ingestible, or topical, as described above. Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injections that may contain antioxidants, buffers, bacteriostatic agents, and solutes that make the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents. The compositions may be provided in unit-dose or multi-dose containers, such as sealed ampoules and vials.

[0059] The compositions may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials and may 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. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[0060] In yet another aspect, the invention may be directed to a method of treating Parkinson's disease comprising administering to a mammal one or more derivatives in an amount 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.

[0061] Compositions containing one or more derivatives can be co-administered with carbidopa and / or entacapone for the treatment of Parkinson's disease.As mentioned above, carbidopa helps to reduce the early decomposition of levodopa, so even if the derivative of the present invention loses some of the "fatty" portion, carbidopa can still help to reduce the amount of active ingredient that is decomposed and unavailable for the formation of dopamine.

[0062] In some embodiments, the amount of the derivative compound in the composition of the invention ranges from 100 mg to 2000 mg equivalent of levodopa administered once a day. Compositions containing 10 to 200 mg of carbidopa and / or 200 to 1600 mg of entacapone (or other COMT inhibitors) can be used in combination with the composition of the invention for the treatment of PD. Thus, the composition of the invention can include carbidopa and / 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 equivalent levodopa in the derivative. COMT inhibitors such as tolcapone, opicapone, and / or entacapone can be co-administered with the derivative in doses of 200 mg or more, and can be administered repeatedly as needed, with or without carbidopa also co-administered. 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 a compound or composition of the invention.

[0063] In another embodiment, a composition containing one or more derivatives can be used to treat Parkinson's disease by administering it to a Parkinson's disease patient once a day. In another embodiment, the composition can be administered up to two or three times a week. In yet another embodiment, the composition can be administered once a week or once every other week. The composition can be administered once a month.

[0064] In one embodiment, the composition containing one or more derivatives may be a pharmaceutical composition comprising a microparticle or nanoparticle containing a pharma- ceutical effective amount of one or more derivatives and a pharma- ceutical acceptable polymer, and may be co-administered with carbidopa and / or entacapone (or another COMT inhibitor) to treat Parkinson's disease. Such compositions may be administered intravenously, intramuscularly, intraperitoneally, orally, or subcutaneously. Administration may be once a day, up to two or three times a week, once a week or every other week, or once a month.

[0065] Example 1 below shows that the derivatives of the invention provide protection of the active ingredient, resulting in less premature degradation of levodopa and more availability of levodopa to form dopamine after crossing the BBB.

[0066] Example 1

[0067] 10 μM of DB104 (DB104 is identified above and is one of the derivatives of the present invention) was incubated in fresh plasma and phosphate buffered saline (PBS) in multiple aliquots, and each aliquot was divided into two equal parts at 0, 1, 2, 4, 6, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 and 264 hours. One half was quenched with ACN:MeOH containing 1% formic acid and analyzed by high resolution mass spectrometry (HRMS) to detect DB104 and any other possible intermediates. Labetalol was used as an internal standard (IS). The other half was quenched with perchloric acid and analyzed by an AB Sciex 7500 mass spectrometer to detect L-DOPA. Dopamine-d4 was used as the IS.

[0068] Possible intermediate structures from the above steps are as follows: [ka]

[0069] DB104 took approximately 4 hours and 1-4 hours to completely solubilize in human plasma and PBS, respectively. This was evident by an initial increase in peak area followed by degradation. All peak area ratios were normalized to the maximum peak area ratio value observed. DB104M3 and DB104M4, as well as L-DOPA, were observed in human plasma and PBS. DB104M1 was observed only 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.

[0070] The above studies resulted in an estimated in vitro half-life of DB104 of about 12 hours in both human plasma and PBS. L-DOPA was formed in detectable amounts up to 72 hours in both human plasma and PBS, demonstrating less peripheral degradation and more L-DOPA available to cross the BBB. DB104M4 was the major degradant in PBS. It is hypothesized that DB104 may also cross the BBB and that L-DOPA may be formed after crossing the BBB by the derivative.

[0071] The derivatives can be produced by using fatty acids and fatty alcohols. For example, in the above formula II, R6 can be produced by using fatty alcohols, and R7 and R8 can be produced by using fatty acids.

[0072] Fatty alcohols that may be used to make derivatives of levodopa include tert-butyl alcohol, tert-amyl alcohol, 3-methyl-3-pentanol, 1-heptanol (enanthic alcohol), 1-octanol (caprylic alcohol), pelargonic alcohol (1-nonanol), 1-decanol (decyl alcohol, capric alcohol), undecyl alcohol (1-undecanol, undecanol, hendecanol), lauryl alcohol (dodecanol, 1-dodecanol), tridecyl alcohol (1-tridecanol, tridecanol, isotridecanol), myristyl alcohol (1-tetradecanol), pentadecyl alcohol (1-pentadecanol, pentadecanol), cetyl alcohol (1-hexadecanol), palmitoleic alcohol (cis-9-hexadecen-1-ol), heptadecyl alcohol (1-n-heptadecanol, heptadecanol), 1-octadecanol), stearyl alcohol (1-octadecanol), oleyl alcohol (1-octadecenol), nonadecyl alcohol (1-nonadecanol), arachidyl alcohol (1-eicosanol), heneicosyl alcohol (1-heneicosanol), behenyl alcohol (1-docosanol), erucyl alcohol (cis-13-docosen-1-ol), lignoceryl alcohol (1-tetracosanol), seryl alcohol (1-hexacosanol), 1-heptacosanol, montanyl alcohol, crityl alcohol or 1-octacosanol, 1-nonacosanol, myricyl alcohol, melissyl alcohol or 1-triacontanol, 1-dotriacontanol (raceryl alcohol), geddyl alcohol (1-tetratriacontanol), trans-9-octadecenol, and cis,cis-9,12-octadecadien-1-ol. Other fatty alcohols may also be used.

[0073] The fatty acids that can be used to make derivatives of levodopa include, but are not limited to, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccinic acid, linoleic acid, linoelaidic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, and docosahexaenoic acid.Other fatty acids can also be used.

[0074] Example 2 below illustrates the use of levodopa to form specific examples of derivatives according to the invention.

[0075] Example 2 Preparation of dilauroxyl levodopadodecyl ester HCl salt: Molecules of interest: [ka]

[0076] Testing Procedure: 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 added slowly at room temperature and the reaction was stirred for 20 hours. After completion of the reaction, the solvent was evaporated under vacuum to reduce the volume by half. The organic material was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (100 mL) followed by 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 give a brown foamy solid. The crude product obtained was purified by column chromatography on silica gel (100-200 mesh) using dichloromethane and methanol (6:4) as the eluent system to obtain Boc-Levodopa (Yield: 10.5 gm, 30%).

[0077] Preparation of Boc-Levodopa-Dodecyl Ester: Boc-Levodopa (20 gm) was stirred with DMF (100 mL) in a round bottom flask at room temperature under nitrogen atmosphere. 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 under vacuum below 55°C to remove the solvent completely. Water (100 mL) was added to the residue and the pH was adjusted to 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) followed by brine (50 mL) and dried over anhydrous Na2SO4. Finally, the organic layer was concentrated under vacuum to obtain a brown thick liquid. The residue obtained 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%).

[0078] Preparation of dilauroxyl-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 by maintaining the temperature at 0-5°C. Lauroyl chloride (2.85 gm) in DCM (15 mL) was added dropwise to the reaction mixture. Lauroyl chloride is the acid chloride of lauric acid, 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 x 50 mL) and the organic layer was dried over anhydrous Na2SO4. The resulting DCM layer was concentrated under vacuum to obtain a thick orange coloured residue. The residue was purified by column chromatography using a mixture of ethyl acetate and n-hexane (6:4) as the eluent to obtain the pure product (Yield: 2.75 gm, 19%).

[0079] Preparation of Dilauroxyl-Levodopa-Dodecyl Ester HCl Salt: A mixture of Dilauroxyl-Boc-Levodopa-Dodecyl Ester (2.5 gm) and HCl / Dioxane (2N, 80 mL) was stirred at 25-30°C for 2-3 hours. After completion of reaction, the solvent was completely removed under vacuum at 30-35°C. The obtained residue, which is 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 pure target 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, benzyl CH2), 3.20 (1H, dd, benzyl 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). Thus, di-lauroyoxil-levodopa-dodecylester HCl salt is produced as a product and can be used to treat Parkinson's disease. It is also possible to use different fatty alcohols and fatty acids instead of those used above to react different chains as part of the derivative.

Claims

1. A compound of formula II, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof: 【Chemistry 1】 In the above formula, R ２ is H, R ６ is CH ３ (CH ２ ) １０ CH ２ O-, and R ７ and R ８ is CH ３ (CH ２ ) １０ It is.

2. 2. The compound of claim 1, which is the compound: 【Chemistry 2】

3. 2. The compound of claim 1 which is a hydrochloride salt having the formula: 【Chemistry 3】

4. 13. A composition comprising a pharma- ceutical effective amount of a compound of claim 1 and one or more pharma- ceutical acceptable carriers or excipients.

5. 5. The composition of claim 4, which is injectable, inhalable, ingestible, or topical.

6. The composition according to claim 4, in the form of a liposome or a micelle.

7. The composition of claim 4, wherein the pharma- ceutical acceptable carrier is castor oil or a derivative thereof.

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