JP2024041865A - Novel highly permeable drugs and compositions thereof for the treatment of Parkinson's disease - Google Patents

Abstract

[Problem] One aspect of the present invention provides novel highly permeable compositions (HPCs) or highly permeable prodrugs (HPPs) for the treatment of Parkinson's disease. [Solution] HPCs/HPPs can be converted to the parent active drug or drug metabolites after crossing biological barriers, and thus can treat conditions treatable by the parent drug or metabolites. Furthermore, HPPs can reach areas inaccessible to the parent drug or can be at sufficient concentration in the target area, providing a novel treatment. HPCs/HPPs can be administered to a subject by various routes of administration, for example, delivered locally at high concentrations to the site of activity of a condition or administered systemically to a biological subject to enter the systemic circulation at a faster rate. [Selected Figure] None

Description

FIELD OF THE INVENTION The present invention relates to the field of pharmaceutical compositions. More particularly, one aspect of the invention provides pharmaceutical compositions capable of permeating one or more biological barriers and drugs for preventing and/or treating Parkinson's disease and/or Parkinson's syndrome in a subject. METHODS OF USE OF PHARMACEUTICAL COMPOSITIONS.

Background of the Invention Parkinson's disease (PD) is a neurological disorder characterized by degeneration of dopamine neurons in the substantia nigra and loss of dopamine in the putamen. Although it is considered a movement disorder, it also causes cognitive and behavioral symptoms. Parkinson's disease may result from the death of dopamine-producing cells within the substantia nigra, a region of the midbrain. The cause of this cell death may be unknown (primary parkisonism) or known (secondary parkinsonism). Parkinson's disease can result in many symptoms affecting a wide variety of functions including movement, attention and learning. The main symptoms of Parkinson's disease are due to decreased activity of dopamine-secreting cells caused by cell death in the pars compacta region of the substantia nigra. Although certain conceptual models of motor circuits and their PD-associated changes have been highly influential since 1980, several limitations have been noted that may lead to modifications [Obeso JA, Rodriguez-Oroz MC, Benitez-Temino B, et al. (2008). “Functional organization of the basal ganglia: therapeutic implications for Parkinson's Disease”. Mov. Disord. 23 (Suppl 3): S548-59]. In this model, the basal ganglia normally exert an inhibitory influence on a wide range of motor systems, preventing them from being activated at inappropriate times. When deciding to take a particular action, inhibition on the required motor system is reduced, thereby freeing it for activation. High levels of dopamine function tend to promote motor activity, as dopamine acts to facilitate this release of inhibition, whereas low levels of dopamine function, such as those that occur in PD, are less effective for any given exercise. It also requires greater effort. Therefore, the net effect of dopamine deficiency is to cause hypokinesia [Obeso JA, Rodriguez-Oroz MC, Benitez-Temino B, et al. (2008). “Functional organization of the basal ganglia: therapeutic implications for Parkinson's Disease”. Mov. Disord. 23 (Suppl 3): S548-59].

The main family of known drugs for treating motor symptoms are levodopa (usually in combination with DOPA decarboxylase inhibitors or COMT inhibitors), dopamine agonists, and MAO-B inhibitors [The National Collaborating Center for Chronic Conditions, ed. (2006). “Symptomatic pharmacological therapy in Parkinson's Disease”, Parkinson's Disease. London: Royal College of Physicians. pp. 59-100]. Although levodopa is well known to improve motor symptoms, its effects on cognitive and behavioral symptoms are more complex [Cools R (2006). “Dopaminergic modulation of cognitive function-implications for L-DOPA treatment in Parkinson's Disease”. Neurosci Biobehav Rev 30 (1): 1-23]. Levodopa preparations contribute to the development of motor complications in PD. These include abnormal involuntary movements, along with response fluctuations in which a person experiences ``wearing off'' of drug effects and/or unpredictable switching between ``on'' and ``off'' states. or dyskinesias, including athetosis and dystonia. At peak doses, levodopa can also cause nausea, vomiting, gastrointestinal bleeding, dyskinesia, and end-of-dose deterioration of function.
Therefore, there is a need to develop better treatments to address this problem.

BACKGROUND OF THE INVENTION One aspect of the present invention relates to HPPs of levodopa and/or dopamine.
Another aspect of the invention relates to pharmaceutical formulations comprising one or more HPPs disclosed herein. In certain embodiments, the pharmaceutical composition comprises one or more highly permeable prodrugs of an NSAID and one or more highly permeable prodrugs of dopamine and/or levodopa.
Here, the HPP parent drug may be the same or different and may be levodopa, dopamine, aspirin, ibuprofen, and/or other NSAIDs disclosed herein.
Another aspect of the invention relates to methods of using the compositions of the invention in penetrating one or more biological barriers of a biological subject.
Another aspect of the invention relates to methods of using the compositions of the invention, or pharmaceutical compositions thereof, in treating conditions in biological subjects.
Another aspect of the invention provides for the treatment of Parkinson's disease and/or its related conditions in a biological subject or subject by administering to the biological subject or subject one or more HPPs or pharmaceutical compositions thereof. The present invention relates to methods of using more than one type of HPP or pharmaceutical compositions thereof.

Residence time results in rotarod test after 1-3 weeks of treatment (n=12) (Example 31). Showing the fall velocity results in the rotarod test after 1-3 weeks of treatment (n=12) (Example 31). Residence time results in rotarod test after 4 weeks of treatment are shown (n=12) (Example 32). Figure 3 shows fall velocity results in rotarod test after 4 weeks of treatment (n=12) (Example 32). Residence time results in rotarod test after 4 weeks of treatment are shown (n=12) (Example 33). The fall velocity results in the rotarod test after 4 weeks of treatment are shown (n=12) (Example 33). Residence time results in rotarod test after 4 weeks of treatment are shown (n=12) (Example 34). Figure 3 shows fall velocity results in rotarod test after 4 weeks of treatment (n=12) (Example 34). Residence time results in rotarod test after 4 weeks of treatment are shown (n=12) (Example 35). Figure 3 shows fall velocity results in rotarod test after 4 weeks of treatment (n=12) (Example 35). Residence time results in rotarod test after 4 weeks of treatment are shown (n=12) (Example 36). Figure 3 shows fall velocity results in rotarod test after 4 weeks of treatment (n=12) (Example 36). Residence time results in rotarod test after 4 weeks of treatment are shown (n=12) (Example 37). Figure 3 shows fall velocity results in rotarod test after 4 weeks of treatment (n=12) (Example 37). Residence time results in rotarod test after 4 weeks of treatment are shown (n=12) (Example 38). The fall velocity results in the rotarod test after 4 weeks of treatment are shown (n=12) (Example 38).

Detailed description of the invention
I. A highly permeable prodrug of levodopa One embodiment of the present invention provides the following structures Pro-L-Dopa-1, Pro-L-Dopa-2, Pro-L-Dopa-3, Pro-L-Dopa-4 and Structure Pro-L-Dopa-5:

Highly permeable prodrugs of levodopa having a structure selected from the group consisting of (including stereoisomers and pharmaceutically acceptable salts thereof). Here, in the above structure,
W is H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl -yl, substituted and unsubstituted heteroaryl, protonatable amine group, pharmaceutically acceptable substituted and unsubstituted amine group, structure W-1, structure W-2, structure W-3, structure W -4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11, and Structure W-12:

selected from the group consisting of;
HA is present in the absence and pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfic acid, bisulfic acid, phosphoric acid, phosphorous acid, phosphonic acid. Acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucaronic acid, sugar acid , formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and pamoic acid;
R ₁ and R ₂ are independently H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted selected from the group consisting of alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues;
R ₁₁ to R ₁₅ are independently absent, H, CH ₂ C(=O)OR _11, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted selected from the group consisting of alkoxyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl. ;
X is selected from the group consisting of O, S, and _NR3 ;
X ₂ is absent, O, S, NR ₃ , CHR ₃ -O, CHR 3 -S, CHR ₃ -O, O-CHR ₃ -O, O-CHR _{3 -S} , S-CHR ₃ -O, and S-CHR ₃ -S;
X ₃ is absent, C=O, C=S, C(=O)-O, O, S, NR ₃ , C(=O)-O-CHR ₃ -O, C(=O)-O selected from the group consisting of -CHR ₃ -S, C(=O)-S-CHR ₃ -O, and C(=O)-S-CHR ₃ -S;
Y ₁ is selected from the group consisting of R ₃ C(=O), R ₃ OC(=O), and R ₃ SC(=O);
_Y2 is selected from the group consisting of _R3C (=O), _R3OC (=O), and _R3SC (=O);
_Y3 is selected from the group consisting of _R3 , _OR3 , _SR3 , _NR3R4 , O- _CHR3 - _OR4 , O- _CHR3 - _{SR4 ,} and S- _CHR3 - _OR4 ;
n and m are selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8.

R _c is absent, CH ₂ C(=O)OR _6, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl , substituted and unsubstituted alkyl halides, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, where any of R _CH2 may also be further replaced with O, S, P, or _NR6 ;
R is absent, _CH2C (=O)OR6 _, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, selected from the group consisting of substituted and unsubstituted alkyl halides, substituted and unsubstituted alkenyls, substituted and unsubstituted alkynyls, substituted and unsubstituted aryls, and substituted and unsubstituted heteroaryls, where any of R _CH2 may also be replaced by O, S, P or _NR6 ;
R ₃ and R ₄ are independently absent, CH ₂ C(=O)OR _6, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, selected from the group consisting of substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl; and any _CH2 in R may be further replaced with O, S, P, or _NR6 ;
Each R ₆ is independently H, F, Cl, Br, I, Na ⁺ , K ⁺ , C(=O)R _5, 2-oxo-1-imidazolidinyl, phenyl, 5-indanyl, 2,3- Dihydro-1H-inden-5-yl, 4-hydroxy-1,5-naphthyridin-3-yl, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkenyl , substituted and unsubstituted alkynyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, -C(=O)-W, -L ₁ -L ₄ -L ₂ -W, and W;
Each R ₅ is independently H, C(=O)NH ₂ , CH ₂ CH ₂ OR _6, CH ₂ CH ₂ N(CH ₃ ) ₂ , CH ₂ CH ₂ N(CH ₂ CH ₃ ) _2, Cl , F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl , substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, -C(=O)-W, L ₁ -L ₄ -L ₂ -W, and W. is;
L ₁ is absent, O, S, -OL ₃ -, -SL ₃ -, -N(L ₃ )-, -N(L ₃ )-CH ₂ -O, -N(L ₃ )-CH ₂ selected from the group consisting of -N( _L5 )-, -O- _CH2 -O-, -O-CH( _L3 )-O, and -S-CH( _L3 )-O-;
L ₂ is absent, O, S, -OL ₃ -, -SL ₃ -, -N(L ₃ )-, -N(L ₃ )-CH ₂ -O, -N(L ₃ )-CH ₂ -N(L ₅ )-, -O-CH ₂ -O-, -O-CH(L ₃ )-O, -S-CH(L ₃ )-O-, -OL ₃ -, -NL ₃ -, selected from the group consisting of -SL ₃ -, -N(L ₃ )-L ₅ - and L ₃ ;
L ₄ is absent, C=O, C=S,

selected from the group consisting of;
For each L ₁ , L ₂ , and L ₄ , each L ₃ and L ₅ , independently, absent, H, CH ₂ C(=O)OL ₆ , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl , substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl , and substituted and unsubstituted alkyl halides, wherein any carbon or hydrogen may be further independently replaced with O, S, P, or _NL3 ;
Each _L6 independently represents H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, selected from the group consisting of substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halides, wherein , any carbon or hydrogen can also be independently O, S, N, P(O)OL ₆ , CH=CH, C≡C, CHL ₆ , CL ₆ L ₇ , aryl, heteroaryl, or may be replaced with a cyclic group;
Each L ₇ is independently H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, selected from the group consisting of substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halides, wherein , any carbon or hydrogen may also be independently O, S, N, P(O)OL ₆ , CH=CH, C≡C, CHL ₆ , CL ₆ L ₇ , aryl, heteroaryl, or Optionally substituted with a cyclic group; and any CH ₂ group may be replaced with O, S, or NH.

II. Highly Permeable Prodrugs of Dopamine Another aspect of the present invention provides the following structures Pro-dopamine-1, Pro-dopamine-2, Pro-dopamine-3, Pro-dopamine-4, and Pro-dopamine- Five:

(including stereoisomers and pharmaceutically acceptable salts thereof) selected from the group consisting of: In the above structure, W, HA, X, _X2 , _X3 , _Y1 , _Y2 , _Y3 , n, m, _Rc , R, _R1 , _R2 , _R3 , _R4 , _R5 , R ₆ , R ₁₁ -R ₁₅ , L ₁ , L ₂ and L ₄ are defined as above.

III. A pharmaceutical composition comprising a highly permeable prodrug of an NSAID and one or more highly permeable prodrugs of dopamine and/or levodopa.
Another aspect of the invention relates to a pharmaceutical composition comprising one or more highly permeable prodrugs of an NSAID and one or more highly permeable prodrugs of dopamine and/or levodopa.
Highly permeable prodrugs of NSAID are as follows: NSAID-1, NSAID-2, NSAID-3, NSAID-4, NSAID-5, NSAID-6, NSAID-7, NSAID-8, NSAID-8 NSAID-9, Structural NSAID-10, Structural NSAID-11, Structural NSAID-12, and Structural NSAID-13:

including stereoisomers and pharmaceutically acceptable salts thereof. Here, in the above structure,
Aryl is the following aryl-1, aryl-2, aryl-3, aryl-4, aryl-5, aryl-6, aryl-7, aryl- aryl-8, aryl-9, aryl-10, aryl-11, aryl-12, aryl-13, aryl-14, aryl-15, aryl- 16, aryl-17, aryl-18, aryl-19, aryl-20, aryl-21, aryl-22, aryl-23, aryl-24, Aryl-25, Aryl-26, Aryl-27, Aryl-28, Aryl-29, Aryl-30, Aryl-31, Aryl-32, Aryl- aryl-33, aryl-34, aryl-35, aryl-36, aryl-37, aryl-38, aryl-39, aryl-40, aryl- 41, aryl-42, aryl-43, aryl-44, aryl-45, aryl-46, aryl-47, aryl-48, aryl-49, Aryl-50, Aryl-51, Aryl-52, Aryl-53, Aryl-54, Aryl-55, Aryl-56, Aryl-57, Aryl- aryl-58, aryl-59, aryl-60, aryl-61, aryl-62, aryl-63, aryl-64, aryl-65, aryl- 66, aryl-67, aryl-68, aryl-69, aryl-70, and aryl-71:

selected from the group consisting of;
W,HA,X, _X2 , _X3 , _Y1 , _Y2 , _Y3 ,n,m, _Rc ,R, _R1 , _R2 , _R3 , _R4 , _R5 , _R6 , _R11 ~R ₁₅ , L ₁ , L ₂ , and L ₄ are defined as above;
X ₆ and X ₈ are independently absent, consisting of C(=O), C(=S), OC(=O), OC(=S), CH ₂ , CH, S, O and NR ₅ selected from the group;
Y ₄ , Y ₅ , Y ₆ , Y ₇ , Y ₈ , and Y ₉ are independently H, OH, OW, OC(=O)W, L ₁ -L ₄ -L ₂ -W, OC(= O)CH ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , R ₆ , SO ₃ R ₆ , CH ₂ OR ₆ , CH ₂ OC(=O)R ₆ , CH ₂ C( _{= O} ) _OR8 , _OCH3 , _{OC2H5 , OR6} ,CH3SO2 _{, R6SO2} , _{CH3SO3 , R6SO3} , _NO2 ,CN, _{CF3 , OCF3} , _CH2 (CH ₂ ) _n NR ₅ R ₆ , CH ₂ (CH ₂ ) _n OR _6, CH(C(=O)NH ₂ )NHR ₆ , CH ₂ C(=O)NH _2, F, Br, I, Cl , CH=CHC(=O)NHCH ₂ C(=O)OW, CH=CHC(=O)NHCH ₂ L ₁ -L ₄ -L ₂ -W, NR ₈ C(=O)R ₅ , SO ₂ NR ₅ R ₈ , C(=O)R ₅ , SR ₅ , R ₆ OOCCH(NHR ₇ )(CH ₂ ) _n C(=O)NH-, R ₆ OOCCH(NHR ₇ )(CH ₂ ) _n SC(= O)NH-, CF ₃ SCH ₂ C(=O)NH-, CF ₃ CH ₂ C(=O)NH-, CHF ₂ SCH ₂ C(=O)NH-, CH ₂ FSCH ₂ C(=O) NH-, NH ₂ C(=O)CHFS-CH ₂ C(=O)NH-, R ₇ NHCH(C(=O)OW)CH ₂ SCH ₂ C(=O)NH-, R ₇ NHCH(L ₁ -L ₄ -L ₂ -W)CH ₂ SCH ₂ C(=O)NH-, CNCH ₂ SCH ₂ C(=O)NH-, CH ₃ (CH ₂ ) _n C(=O)NH-, R ₇ N=CHNR ₇ CH ₂ CH ₂ S-, R ₇ N=C(NHR ₇ )NHC(=O)-, R ₇ N=C(NHR ₇ )NHC(=O)CH ₂ , CH ₃ C(Cl )=CHCH ₂ SCH ₂ C(=O)NH-, (CH ₃ ) ₂ C(OR ₆ )-, CNCH ₂ C(=O)NH-, CNCH ₂ CH ₂ S-, R ₇ HN=CH(NR ₇ )CH ₂ CH ₂ S-, CH ₂ =CHCH ₂ SCH ₂ C(=O)NH-, CH ₃ CH(OH)-, CH ₃ CH(OR ₈ )-, CH ₃ CH(Y ₁ )-, (CH ₃ ) ₂ CH-, CH ₃ CH ₂ -, CH ₃ (CH ₂ ) _n CH=CH(CH ₂ ) _m C(=O)NH-, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkoxyl, selected from the group consisting of substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halides, and substituted and unsubstituted alkylcarbonyl;
Each R ₇ is independently H, F, Cl, Br, I, CH ₃ NHC(=O)CH ₂ CH(NHR ₈ )C(=O), R ₅ N=C(NHR ₆ )NHC(= O)-, C(=O)CH ₃ , C(=O)R ₆ , PO(OR ₅ )OR ₆ , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, L ₁ -L ₄ -L ₂ -W, and C-(=O)-W; and each R ₈ is independently H, F, Cl, Br, I, CH ₃ , C ₂ H ₅ , _CF3 , _{CH2CH2F , CH2CH2Cl , CH2CH2Br , CH2CH2I , CH2CHF2 , CH2CF3 , CH2F} , _CH2Cl , _CH2Br , CH ₂ I, CH ₂ NR ₆ R ₇ , CH(NHR ₇ )CH ₂ C(=O)NH ₂ , C ₃ H ₇ , C ₄ H ₉ , C ₅ H ₁₁ , R ₆ , C(=O) R ₆ , C(=O)NH ₂ , CH ₂ C(=O)NH ₂ , CH ₂ OC(=O)NH ₂ , PO(OR ₅ )OR ₆ , C(CH ₃ ) ₂ C(=O) OR ₆ , CH(CH ₃ )C(=O)OR ₆ , CH ₂ C(=O)OR ₆ , C(=O)-W, L ₁ -L ₄ -L ₂ -W, W, substitution and no Substituted perfluoroalkyl, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl selected from the group consisting of halides and substituted and unsubstituted alkylcarbonyls.

As used herein, the term "pharmaceutically acceptable salts" refers to those salts of the compounds of the invention that are safe for application to a subject. Pharmaceutically acceptable salts include acidic or basic salts present in the compounds of the invention. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates, bisulfates, phosphates, and superphosphates. , isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, Gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoic acid ( That is, 1,11-methylene-bis-(2-hydroxy-3-naphthoic acid)) salt is mentioned. Certain compounds of the invention are capable of forming pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. For a review regarding pharmaceutically acceptable salts, see BERGE ET AL., the contents of which are hereby incorporated by reference. , 66 J. PHARM. SCI. 1 - 19 (1977).

As used herein, unless otherwise specified, the term "alkyl" means a branched or unbranched saturated or unsaturated monovalent or polyvalent hydrocarbon group, including saturated alkyl, alkenyl, and alkynyl groups. is included. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, ethenyl, propenyl, butenyl. , isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, methylene, ethylene, propylene, iso Propylene, butylene, isobutylene, t-butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene and dodecylene are mentioned. In certain embodiments, the hydrocarbon group contains 1-30 carbons. In certain embodiments, the hydrocarbon group contains 1-20 carbons. In certain embodiments, the hydrocarbon group contains 1-12 carbons.
As used herein, unless otherwise specified, the term "cycloalkyl" means an alkyl containing at least one ring and no aromatic rings. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. In certain embodiments, the hydrocarbon chain contains 1-30 carbons. In certain embodiments, the hydrocarbon group contains 1-20 carbons. In certain embodiments, the hydrocarbon group contains 1-12 carbons.
As used herein, unless otherwise specified, the term "heterocycloalkyl" means a cycloalkyl in which at least one ring atom is a non-carbon atom. Examples of non-carbon ring atoms include, but are not limited to, S, O and N.

As used herein, unless otherwise specified, the term "alkoxyl" means an alkyl, cycloalkyl or heterocycloalkyl containing one or more oxygen atoms. Examples of alkoxyl include, but are not limited to, -CH ₂ -OH, -OCH ₃ , -OR _e , -R _e -OH, -R _e1 -OR _e2 - (where R _e , R _e1 and R _e2 can be the same or different alkyl, cycloalkyl or heterocycloalkyl).
As used herein, unless otherwise specified, the term "alkyl halide" means an alkyl, cycloalkyl or heterocycloalkyl containing one or more halogen atoms which may be the same or different. The term "halogen" means fluorine, chlorine, bromine or iodine. Examples of alkyl halides include, but are not limited to, -R _e -F, -R _e -Cl, -R _e -Br, -R _e -I, -R _e (F)-, -R _e ( Cl)-, -R _e (Br)- and -R _e (I)-, where R _e is alkyl, cycloalkyl or heterocycloalkyl.
As used herein, unless otherwise specified, the term "alkylthio" means an alkyl, cycloalkyl or heterocycloalkyl containing one or more sulfur atoms. Examples of alkylthio include, but are not limited to, -CH ₂ -SH, -SCH ₃ , -SR _e , -R _e -SH, -R _e1 -SR _e2 - (where R _e , R _e1 and R _e2 is the same or different alkyl, cycloalkyl or heterocycloalkyl).
As used herein, unless otherwise specified, the term "alkylamino" means an alkyl, cycloalkyl or heterocycloalkyl containing one or more nitrogen atoms. Examples of alkylamino include, but are not limited to, -CH ₂ -NH, -NCH ₃ , -N(R _e1 )-R _e2 , -NR _e , -R _e -NH ₂ , -R _e1 -NR _e2 and -R _e -N(R _e1 )-R _e2 (wherein R _e , R _e1 and R _e2 are the same or different alkyl, cycloalkyl or heterocycloalkyl).

As used herein, unless otherwise specified, the term "alkylcarbonyl" means an alkyl, cycloalkyl or heterocycloalkyl containing one or more carbonyl groups. Examples of alkylcarbonyl groups include, but are not limited to, aldehyde groups (-R _e -C(O)-H), ketone groups (-R _e -C(O)-R _e1 ), and carboxylic acid groups ( R _e -C(=O)OH), ester group (-R _e -C(=O)OR _e1 ), carboxamide (-R _e -C(=O)ON(R _e1 )R _e2 ), enone group ( -R _e -C(O)-C(R _e1 )=C(R _e2 )R _e3 ), acyl halide group (-R _e -C(O)-X _h ) and acid anhydride group (-R _e - C(O)-OC(O)-R _e1 ) (wherein R _e , R _e1 , R _e2 and R _e3 are the same or different alkyl, cycloalkyl, or heterocycloalkyl; X _h is halogen ) can be mentioned.
As used herein, unless otherwise specified, the term "perfluoroalkyl" means an alkyl, cycloalkyl or heterocycloalkyl containing one or more fluoro groups, including but not limited to perfluoro Examples include methyl, perfluoroethyl, and perfluoropropyl.

As used herein, unless otherwise specified, the term "aryl" refers to a chemical structure containing one or more aromatic rings. In certain embodiments, all ring atoms are carbon. In certain embodiments, one or more ring atoms are non-carbon, such as oxygen, nitrogen, or sulfur ("heteroaryl"). Examples of aryl include, but are not limited to, phenyl, benzyl, naphthalenyl, anthracenyl, pyridyl, quinoyl, isoquinoyl, pyrazinyl, quinoxalinyl, acridinyl, pyrimidinyl, quinazolinyl, pyridazinyl, cinnolinyl, imidazolyl, benzimidazolyl, purinyl, indolyl. , furanyl, benzofuranyl, isobenzofuranyl, pyrrolyl, indolyl, isoindolyl, thiophenyl, benzothiophenyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, thiaxoryl, quanidino and benzothiazolyl.

In certain embodiments, the pharmaceutical composition comprises at least one HPP or related compound thereof, a parent drug capable of treating Parkinson's disease, and a pharmaceutically acceptable carrier.
In certain embodiments, a pharmaceutical composition may include multiple HPPs of the same or different parent drugs. Different parent drugs belong to the same or different classes of drugs used to treat Parkinson's disease. For example, the pharmaceutical composition comprises an HPP of a parent drug or a related compound thereof, wherein the parent drug is selected from the group consisting of levodopa, dopamine, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), and any combination thereof. may include.
The pharmaceutical composition may further contain water.
The pharmaceutical composition may further contain an alcohol (eg, ethanol, glycerol, isopropanol, octanol, etc.).
In certain embodiments, the pharmaceutical composition is an HPP of parent drugs or related compounds thereof, wherein at least one of the parent drugs is levodopa (e.g., structure Pro-L-dopa-1, Pro-L-dopa- 2, HPP containing one or more structures of Pro-L-dopa-3, Pro-L-dopa-4, and/or Pro-L-dopa-5); HPP that is dopamine (e.g., the structure Pro-dopamine- 1, HPP containing one or more of the structures Pro-dopamine-2, Pro-dopamine-3, Pro-dopamine-4, and/or Pro-dopamine-5); and at least one of the parent drugs is aspin or other HPP, which is an anti-inflammatory drug (e.g. Structure NSAID-1, Structure NSAID-2, Structure NSAID-3, Structure NSAID-4, Structure NSAID-5, Structure NSAID-6, Structure NSAID-7, Structure NSAID-8, Structure NSAID -9, Structure NSAID-10, Structure NSAID-11, Structure NSAID-12, and Structure NSAID-13).

In certain embodiments, the pharmaceutical composition comprises 4-(2-(2-(methylamino)acetamido)ethyl)-1,2,-phenylenedibenzoate hydrochloride, 4-(2-(2-( Methylamino)acetamido)ethyl)-1,2,-phenylenedibenzoateacetic acid, 4-(6-methyl-4,8-dioxo-5,7-dioxa-2,9-diazadecane-11-yl)- 1,2,-Phenylene dibenzoate hydrobromide, 4-(2-(2-amino-3-phenylpropanamido)ethyl)-1,2,-phenylene dibenzoate hydrochloride, 4- (2-(((1-((pyrrolidine-2-carbonyl)oxy)ethoxy)amino)ethyl)-1,2,-phenylenedibenzoate hydrochloride, 4-(2-piperidine-4-carboxamido)ethyl )-1,2,-phenylenebis(2-ethylbutanoate) hydrochloride, 4-(2-((((-octahydro-1H-quinolidin-3-yl)oxy)carbonyl)amino)ethyl)-1, 2,-Phenylenebis(2-ethylbutanoato)acetate, 1-(((2-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1, 4]Dioxocin-8-yl)ethyl)carbamoyl)oxy)ethylisobutyrate-hydrofluoride, 1-(((2-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo) [b][1,4]dioxocin-8-yl)ethyl)carbamoyl)oxy)ethylisobutyrate-hydrofluoride, (-(2-((ethoxycarbonyl)amino)ethyl)-2-(2-methylamino )acetoxy)phenylbenzoate hydrochloride, 5-(2-((ethoxycarbonyl)amino)ethyl)-2-(2-methylamino)acetoxy)phenylbenzoate hydrochloride, 4-(2-amino) (ethyl)-1,2-phenylenedibenzoate hydrochloride, (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylenedibenzoate hydrochloride, ( S)-4-(2-amino-3-(heptan-4-yloxy)-3-oxopropyl)-1,2-phenylenedibenzoate hydrochloride, (S)-4-(2-amino-3 -isopropoxy-3-oxopropyl)-1,2-phenylenedipentano-to hydrochloride, (S)-4-(2-amino-3-ethoxy-3-oxopropyl)-1,2-phenylenedia Cetato hydrochloride, (S)-4-(2-amino-3-oxo-3-(pentan-3-yloxy)propyl)-1,2-phenylenebis(2-methylpropanoate) bromide Hydrogen salt, (S)-4-(2-aminoacetamido)-3-isopropoxy-3-oxopropyl)-1,2-phenylenedibenzoate hydrochloride, 4-((2S)-3-oxo -3-(pentan-3-yloxy)-2-(pyrrolidine-2-carboxamido)propyl)-1,2-phenylenedibenzoate hydrofluoride, (S)-4-(3-isopropoxy-3 -oxo-2-(piperidine-4-carboxamido)propyl)-1,2-phenylenedibenzoate hydrochloride, 4-((2S)-3-isopropoxy-3-2-(octahydro-1H-quinolidine) quiolizine)-2-carboxamide)-3-oxopropyl)-1,2-phenylenebis(2-methylpropanoate) hydrochloride, (2S)-isopropyl 3-(3-amino-2,5-dioxo- 2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)propano-atohydrogen bromide (2S)-isopropyl 3-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)-2-(( (1-(isobutyryloxy)ethoxy)carbonyl)amino)propano-ato-hydrobromide, 5-((2S)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino- 3-isopropoxy-3-oxopropyl)-2-(2-(methylamino)acetoxy)phenylbenzoate hydrochloride, 4-((2S)-2-(((1-(isobutyryloxy) ethoxy)carbonyl)amino-3-isopropoxy-3-oxopropyl)-2-(2-(methylamino)acetoxy)phenylbenzoate hydrochloride, 4-((2S)-3-isopropoxy-2- ((((octahydroindolizin-1-yl)oxy)carbonyl)amino)-3-oxopropyl)-1,2-phenylenedibenzoate acetate, 2-(diethylamino)ethyl 2-[(2, 6-Dichloro-3-methylphenyl)amino]benzoate. Acetate, (Z)-2-(diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl)acetate. AcOH, 2-(dimethylamino)ethyl 2-(3-phenoxyphenyl)propionate. Hydrochloride, S-(2-(dimethylamino)ethyl 2-(3-phenoxyphenyl)propanethioate hydrochloride, 2-(dipropylamino)ethyl 4-acetoxy-2',4'-difluoro-[1, 1'-biphenyl]-3-carboxylate hydrochloride, 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propionate hydrochloride, and/or 2-(diethylamino)ethyl 2-acetoxybenzoate Including.

In certain embodiments, the pharmaceutical composition further comprises one or more catechol-O-methyltransferase inhibitors. In certain embodiments, one or more catechol-O-methyltransferase inhibitors are administered orally.
Catechol-O-methyltransferase (COMT) metabolizes L-Dopa in the periphery to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD), which is linked to the blood-brain barrier (BBB). does not pass through easily. Entacapone and tolcapone are catechol-O-methyltransferase inhibitors that prevent COMT from metabolizing L-DOPA in the periphery to 3-methoxy-4-hydroxy-L-phenylalanine. Avoiding the undesirable effects of DOPA.

BERGE ET AL．, 66 J． PHARM． SCI． 1 - 19 (1977)。

BERGE ET AL. , 66 J. PHARM. SCI. 1-19 (1977).

For example, the pharmaceutical composition includes HPP of a parent drug or related compounds thereof, where the parent drug is selected from the group consisting of levodopa, dopamine, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), and any combination thereof. These include orally administered catechol-O-methyltransferase inhibitors (eg, entacapone, and tolcapone).
In certain embodiments, the pharmaceutical composition further comprises one or more aromatic L-amino acid decarboxylase (DOPA decarboxylase or DDC) inhibitor. In certain embodiments, the one or more aromatic L-amino acid decarboxylase inhibitors are administered orally. Aromatic L-amino acid decarboxylase (DOPA decarboxylase or DDC) is an important enzyme for the biosynthesis of L-DOPA to dopamine (DA). DDC exists both outside the blood-brain barrier (in the periphery of the body) and within the blood-brain barrier region. DDC inhibitors block DDC conversion of levodopa to dopamine. However, exogenously given levodopa is metabolized peripherally to its active metabolite dopamine before reaching the blood-brain barrier. Therefore, dopamine-deficient PD brains would receive less dopamine prodrug precursor levodopa due to peripheral DDC degradation. However, carbidopa as a peripheral DDC inhibitor and other DDC inhibitors can reduce peripheral DDC conversion of levodopa before it crosses the blood-brain barrier. In other words, carbidopa and other DDC inhibitors do not affect brain DDC conversion of levodopa to dopamine. Ultimately, a greater proportion of exogenously given levodopa reaches the brain.
Examples of DDC inhibitors include, but are not limited to, carbidopa, benserazide, difluoromethyldopa, and α-methyldopa.

In certain embodiments, the pharmaceutical composition may include one or more HPPs of various parent drugs. The various parent drugs may belong to the same or different classes of drugs used to treat Parkinson's disease. For example, the pharmaceutical composition includes HPP of a parent drug or related compounds thereof, where the parent drug is selected from the group consisting of levodopa, dopamine, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), and any combination thereof. and one or more DDC inhibitors selected from the group consisting of carbidopa, benserazide, difluoromethyldopa, alpha-methyldopa, and any other aromatic L-amino acid decarboxylase inhibitor.

In certain embodiments, the pharmaceutical composition comprises (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylene dibenzoate and 2-(diethylamino)ethyl 2 Contains -acetoxybenzoate.
In certain embodiments, the pharmaceutical composition comprises (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylene dibenzoate, 2-(diethylamino)ethyl 2 -acetoxybenzoate, carbidopa and/or entacapone.
In certain embodiments, the pharmaceutical composition comprises (S)-4-(2-amino-3-oxo-3-(pentan-3-yloxy)propyl)-1,2-phenylenebis(2-methylpropanol). -t) and 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propionate.
In certain embodiments, the pharmaceutical composition comprises 4-(2-(((1-((pyrrolidine-2-carbonyl)oxy)ethoxy)amino)ethyl)-1,2,-phenylenedibenzoate and 4 Contains -(dimethylamino)butyl 2-(3-phenoxyphenyl)propionate.
In certain embodiments, the pharmaceutical composition comprises (S)-4-(2-amino-3-oxo-3-(pentan-3-yloxy)propyl)-1,2-phenylenebis(2-methylpropanol). -t), 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propionate, carbidopa and/or entacapone.
In certain embodiments, the pharmaceutical composition comprises (S)-4-(2-amino-3-(heptan-4-yloxy)-3-oxopropyl)-1,2-phenylene dibenzoate; Contains -(dipropylamino)ethyl 4-acetoxy-2',4'-difluoro-[1,1'-biphenyl]-3-carboxylate.
In certain embodiments, the pharmaceutical composition comprises (S)-4-(2-amino-3-(heptan-4-yloxy)-3-oxopropyl)-1,2-phenylene dibenzoate; Contains -(dipropylamino)ethyl 4-acetoxy-2',4'-difluoro-[1,1'-biphenyl]-3-carboxylate, carbidopa and/or entacapone.

In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of one or more HPPs disclosed herein. As used herein, "therapeutically effective amount,""therapeutically effective concentration," or "therapeutically effective dose" means , a disorder, or a side effect, or a reduction in the rate of progression of a disease or disorder.
This amount may include, but is not limited to, the characteristics of the HPP disclosed herein or its pharmaceutical composition (including its activity, pharmacokinetics, pharmacokinetics and bioavailability), the subject to be treated or the physiology of the cells. physical condition (including age, sex, type and stage of disease, general health, responsiveness to a given dose, and type of drug), the nature of the pharmaceutically acceptable carrier in the formulation, and the administration It will vary depending on a variety of factors including route. Additionally, an effective or therapeutically effective amount may include administration of one or more HPPs or pharmaceutical compositions thereof disclosed herein alone or with other drugs, other therapies, or other treatment methods or modalities. This may vary depending on whether it is used in conjunction with Those skilled in the clinical and pharmacological arts can, by routine experimentation, monitor the response of a cell or subject to the administration of one or more HPPs or pharmaceutical compositions thereof disclosed herein, and prepare medicinal agents accordingly. By adjusting the amount, an effective or therapeutically effective amount can be determined. Typical dosages may range from about 0.1 mg/kg to about 100 mg/kg or more depending on the factors mentioned above. In other embodiments, the dosage can range from about 0.1 mg/kg to about 100 mg/kg, or from about 1 mg/kg to about 100 mg/kg, or from about 5 mg/kg to about 100 mg/kg. For further guidance, see Remington: The Science and Practice of Pharmacy, 21st Edition, Univ. of Sciences in Philadelphia (USIP), Lippincott Williams & Wilkins, Philadelphia, PA, 2005. This content is incorporated herein by reference as if fully set forth herein for further guidance in determining a therapeutically effective amount.

As used herein, the term "about" refers to ±10%, ±5%, or ±1% of the value that follows "about."
As used herein, the term "pharmaceutically acceptable carrier" refers to the term "pharmaceutically acceptable carrier," which refers to the transfer of a carrier from one place, body fluid, tissue, organ (internal or external), or part of the body to another body fluid, tissue, organ (internal or external). or a pharmaceutically acceptable material, composition or vehicle involved in carrying or transporting HPP to a part of the body, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
Each carrier is compatible with the other ingredients of the formulation, such as HPP, and is compatible with the tissues or organs of the biological subject without undue toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications. "Pharmaceutically acceptable" in the sense of being suitable for contact use and commensurate with a reasonable benefit/risk ratio.
In certain embodiments, pharmaceutically acceptable carriers include alcohols, acetone, esters, cellulose, mannitol, croscarmellose sodium, vegetable oils, hydroxypropylmethylcellulose, water, and aqueous solutions. selected from the group consisting of
Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and Potato starch; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) Gum tragacanth powder; (5) Malt; (6) Gelatin; (7) Talc; (8) Excipients, such as cocoa butter and suppository waxes; (9) Oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) Glyco -ols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar. (14) Buffers such as magnesium hydroxide and aluminum hydroxide; (15) Alginic acid; (16) Pyrogen-free water; (17) Isotonic saline; (18) Ringer's solution; (19) Alcohol; (20) Phosphate buffers; and (21) other non-toxic compatible substances utilized in pharmaceutical formulations, such as acetone.

The pharmaceutical composition contains pharmaceutically acceptable auxiliary substances necessary to approximate physiological conditions, such as pH regulators and buffers, toxicity regulators, etc., such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, lactic acid. It can contain sodium, etc.
In one embodiment, the pharmaceutically acceptable carrier is an aqueous carrier, such as a buffered saline solution. In certain embodiments, pharmaceutically acceptable carriers are polar solvents such as acetone and alcohols.
The concentration of HPP in these formulations may vary widely and will be selected primarily on the basis of fluid volume, viscosity, body weight, etc. according to the particular mode of administration chosen and the needs of the biological subject. For example, the concentration can be 0.0001% to 100%, 0.001% to 50%, 0.01% to 30%, 0.1% to 20%, 1% to 10%wt.
Compositions of the invention can be administered for prophylactic, therapeutic and/or hygienic uses. The administration may be topical, mucosal, eg, oral, nasal, intravaginal, rectal, parenteral, transdermal, subcutaneous, intramuscular, intravenous, by inhalation, ophthalmic and other convenient routes. Pharmaceutical compositions can be administered in a variety of unit dosage forms depending on the method of administration. For example, unit dosage forms suitable for oral administration include powders, tablets, pills, capsules, and lozenges, and for transdermal administration include solutions, suspensions, and gels.
Thus, typical pharmaceutical compositions for transdermal, oral, and intravenous administration range from about 10 ^-8 g to about 100 g, about 10 ^-8 g to about 10 ^-5 g, about 10 ^{- 6} g to about 1 g, about 10 ⁻⁶ g to about 100 g, about 0.001 g to about 100 g, about 0.01 g to about 10 g, or about 0.1 g to about 1 g. Dosages from about 0.001 mg to about 100 g per subject per day may be used. Actual methods for preparing parenterally administrable compositions are well known or apparent to those skilled in the art and are described in Remington: The Science and Practice of Pharmacy 21st ed. , Lippincott Williams & Wilkins, (2005).

IV. Application of HPP
i) How to penetrate biological barriers.
Another aspect of the invention relates to methods of using the compositions of the invention in penetrating one or more biological barriers in a biological subject. The method includes administering HPP or a pharmaceutical composition thereof to a biological subject. In certain embodiments, the HPP is about 20 times or more, 50 times or more, > about 100 times or more, > about 200 times or more, > about 300 times or more, > about 500 times or more, > about 1,000 times more than its parent drug. or higher, indicating permeability through one or more biological barriers.
The term "biological barrier" as used herein refers to a biological layer that separates an environment into different spatial regions or compartments, where this separation is caused by the transfer of substances from one compartment/area to another. can modulate (eg, control, limit, enhance, or take no action) the passage, permeation, or translocation of. Different spatial regions or compartments referred to herein may have the same or different chemical or biological environments. Biological layers referred to herein include, but are not limited to, biological membranes, cell layers, biological structures, internal surfaces of objects, organisms, organs or body cavities, external surfaces of objects, organisms, organs or body cavities. , or any combination or plurality thereof.

Examples of biological membranes include lipid bilayer structures, eukaryotic cell membranes, prokaryotic cell membranes, and intracellular membranes (e.g., nuclear membranes or organelle membranes, such as the membranes or envelope of the Golgi apparatus, rough and smooth membranes). Examples include reticulum (ER), ribosomes, vacuoles, vesicles, liposomes, mitochondria, lysosomes, nuclei, chloroplasts, plastids, peroxisomes, and microbodies).
Lipid bilayers as referred to herein are bilayers of lipid class molecules such as, but not limited to, phospholipids and cholesterol. In certain embodiments, the lipids of the bilayer are amphiphilic molecules consisting of a polar head group and a nonpolar fatty acid tail. This bilayer was arranged such that the hydrocarbon tails of the lipids faced each other to form an oily core held together by hydrophobic interactions, while the charged heads of the lipids faced the aqueous solution on either side of the membrane. It is composed of two layers of lipids. In another specific embodiment, the lipid bilayer may contain one or more embedded protein and/or sugar molecules.
Examples of cell layers include eukaryotic cell linings (e.g. epithelium, lamina propria and smooth muscle or muscularis mucosae (in the gastrointestinal tract)), prokaryotic cell linings (e.g. two cells composed of the same protein or glycoprotein). The superficial or S-layer refers to a dimensional structural monolayer; in particular, the S-layer refers to the part of the cell envelope commonly found in bacteria and archaea), biofilms (self-generated polymeric matrices), structured communities of microorganisms encapsulated within, living or attached to inert surfaces), and plant cell layers (eg, the epidermis). The cells may be normal cells or diseased cells (eg, diseased cells, cancer cells).
Examples of biological structures are structures sealed by tight junctions or tight junctions that provide barriers to the entry of toxins, bacteria, and viruses, such as the blood-milk barrier and the blood-brain barrier (BBB). In particular, the BBB is composed of an impermeable class of endothelium that exhibits both a physical barrier that contacts adjacent endothelial cells via tight junctions and a transport barrier that includes efflux transporters. A biological structure may include a mixture of cells, proteins and sugars (eg, a blood clot).

Examples of the inner surface of objects, organisms, organs, or body cavities include buccal mucosa, esophageal mucosa, gastric mucosa, intestinal mucosa, olfactory mucosa, oral mucosa, bronchial mucosa, uterine mucosa, and endometrium (uterine mucosa, pollen grain wall). the inner layer or the inner wall layer of the spore), or a combination or multiple thereof.
Examples of external surfaces of objects, organisms, organs or body cavities include capillaries (e.g. capillaries in heart tissue), mucous membranes in continuity with the skin (e.g. in the nostrils, lips, eyes, genital area, and anus), organs. External surfaces (e.g. liver, lungs, stomach, brain, kidneys, heart, ears, eyes, nose, mouth, tongue, colon, pancreas, bladder, duodenum, rectogastric, colorectal, intestinal tract, veins, respiratory system, blood vessels, anorectal and anorectal pruritus), skin, cuticle (e.g. the dead layer of epithelial cells or keratinocytes or the superficial layer of overlapping cells covering the hair shafts of animals, the extraepidermal multilayered structures of many invertebrates, the cuticle of plants or Polymer cutin and/or cutan (the outer layer of the pollen grain wall or the outer wall layer of the spore), and combinations or combinations thereof.
Additionally, the biological barrier may further include a sugar layer, a protein layer or any other biological layer, or a combination or combinations thereof. For example, the skin is a biological barrier with multiple biological layers. The skin includes an epidermis (outer layer), a dermal (demis) layer, and a subcutaneous layer. The epidermal layer contains several layers, including the basal cell layer, the spinous cell layer, the granular cell layer, and the stratum corneum. Cells within the epidermis are called keratinocytes. The stratum corneum (“stratum corneum”) is the outermost layer of the epidermis, where the cells are flat and scale-like (“scaly”) in shape. These cells contain large amounts of keratin and are arranged in overlapping layers, which give the skin's surface its hard, oil- and water-resistant properties.

ii) Methods of Treating Parkinson's Disease in a Biological Subject Another aspect of the invention relates to methods of using the compositions of the invention, or pharmaceutical compositions thereof, in treating conditions in a biological subject. The method includes administering a pharmaceutical composition to a biological subject.
The term "treating" as used herein means curing, alleviating, inhibiting, or preventing. As used herein, "treat" means cure, alleviate, inhibit, or prevent. "Treatment" as used herein means curing, alleviating, inhibiting, or preventing.
As used herein, the term "biological object" or "object" refers to an organ, group of organs, organism, or group of organisms that work together to perform a specific task. As used herein, the term "organism" refers to a collection of molecules that is stable in nature, functions as a whole, and has the characteristics of life, such as an animal, plant, fungus, or microorganism.
The term "animal" as used herein refers to a eukaryotic organism characterized by voluntary movement. Examples of animals include, but are not limited to, vertebrates (e.g., humans, mammals, birds, reptiles, amphibians, fish, marsipobranchiata and leptocardia), tunicata, ) (e.g. thaliacea, appendicularia, sorberacea and ascidioidea), articulata (e.g. insecta, myriapoda, malacapoda, spiders) gehyrea (anarthropoda), and helminths (e.g. rotifera).
Conditions that can be treated by this method include those that can be treated with HPP's parent drug, namely Parkinson's disease and related conditions.

iii). Methods of using one or more HPPs or pharmaceutical compositions thereof in the treatment of Parkinson's disease and related conditions.
Another aspect of the invention is a method of using one or more HPPs or pharmaceutical compositions thereof in treating Parkinson's disease and/or related conditions in a biological subject or subjects, the method comprising: or a method by administering the pharmaceutical composition to a biological subject or subject.
In certain embodiments, a method of treating Parkinson's disease and related conditions in a subject comprises administering to the subject a therapeutically effective amount of HPP, or a pharmaceutical composition thereof.
HPP or its pharmaceutical composition. It can be administered to a biological subject by any route of administration known in the art, including, but not limited to, oral, rectal, buccal, nasal, topical, rectal, intravaginal, and aerosol. , transmucosal, epidermal, transdermal, dermal, ocular, pulmonary, subcutaneous, and/or parenteral administration. Pharmaceutical compositions can be administered in a variety of unit dosage forms depending on the method of administration.
Preferred methods of administration are transdermal, dermal, and topical administration for certain compounds.
In certain embodiments, the method further comprises orally administering a therapeutically effective amount of one or more COMT inhibitors and/or DDC inhibitors.
When multiple drugs (eg, HPP, COMT inhibitor, and DDC inhibitor) are administered to a subject, the multiple HPPs and/or other drugs can be administered at substantially the same time or at different times. Multiple drugs may be mixed together prior to administration to a subject, or may be administered separately to a subject. In certain embodiments, some of the drugs are mixed prior to administration, and other drugs are administered separately. Each drug may be administered in any possible order and manner.

As used herein, a pharmaceutical composition may include multiple components that are administered to a subject by different routes of administration. For example, in a pharmaceutical composition comprising one or more HPPs and one or more COMT inhibitors and/or one or more DDC inhibitors, the one or more HPPs may be applied transdermally, topically, or dermis; On the other hand, one or more COMT inhibitors and/or one or more DDC inhibitors may be administered orally. These components can be applied in any order and in any possible combination.
HPP or a pharmaceutical composition thereof can be given to a subject in the form of a formulation suitable for each route of administration. Formulations useful in the methods of the invention include one or more HPPs, one or more pharmaceutically acceptable carriers therefor, and optionally other therapeutic ingredients. For convenience, the formulations may be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending on the subject treated and the particular mode of administration. The amount of HPP that can be mixed with a carrier material to provide a pharmaceutically effective dose will generally be that amount of HPP that provides a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent of HPP, preferably from about 1 percent to about 20 percent.

Methods for preparing these formulations or compositions include the step of bringing into association the HPP with one or more pharmaceutically acceptable carriers and, optionally, one or more accessory ingredients. Generally, formulations are prepared by uniformly and intimately bringing the HPP into association with a liquid carrier or a finely divided solid carrier, or both, and then optionally shaping the product.
Formulations suitable for oral administration include capsules, cachets, pills, tablets, lozenges (using flavor base ingredients, usually sucrose and acacia or gum tragacanth), powders, granules, or aqueous or In the form of a solution or suspension in a non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or in a pastille (an inert base, such as gelatin and glycerin, or (using sucrose and gum acacia) and/or as a mouthwash, each containing a predetermined amount of HPP as an active ingredient. The compounds may be administered as a bolus, lozenge, or paste.
In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules, etc.), HPP may be combined with one or more pharmaceutically acceptable carriers, such as sodium citrate or phosphate. dicalcium acid, and/or any of the following: (1) fillers or fillers such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binding (3) Water retention agents, such as glycerol; (4) Disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retardants, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) humectants, such as acetyl alcohols. (8) Absorbents, such as kaolin and bentonite clay; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. ; and (10) a coloring agent. In the case of capsules, tablets and pills, the pharmaceutical composition may also include a buffering agent. Solid compositions of a similar type may be utilized as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols and the like.

A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may contain binders (e.g. gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g. sodium starch glycolate or cross-linked sodium carboxymethylcellulose). , surface-active or dispersing agents. Molded tablets can be molded in a suitable machine from a mixture of powdered or moistened HPP mimicking peptide with an inert liquid diluent. Tablets and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or coated with coatings and shells, enteric coatings and other coatings well known in the pharmaceutical formulation art. It can be prepared using a coating. For example, using hydroxypropyl methylcellulose, other polymer matrices, liposomes and/or microspheres in varying proportions to give the desired release profile, delayed or controlled release of HPP therein. It may be formulated as such. For example, they may be sterilized by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that is dissolved in sterile water, or some other sterile injectable medium, immediately before use. You may. These compositions may optionally contain pacifying agents and may optionally be compositions that release HPP in a delayed manner, only or preferentially in certain parts of the gastrointestinal tract. good. Examples of embedding compositions that can be used include polymeric substances and waxes. The HPP may, if appropriate, be in microencapsulated form containing one or more of the above excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to HPP, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, Ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil) ), fatty acid esters of glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitol, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.
Suspensions contain, in addition to HPP, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, It may contain bentonite, agar and gum tragacanth, and mixtures thereof.

Formulations for rectal or intravaginal administration include one or more HPPs, such as cocoa butter, polyethylene glycol, suppository wax, or salicylates, which are solid at room temperature but liquid at body temperature, so that they can be administered rectally. or as a suppository, which can be prepared by mixing with one or more suitable non-irritating excipients or carriers that melt in the vaginal cavity and release the active agent. Formulations suitable for intravaginal administration include pessaries, tampons, creams, gels, pastes, foams or sprays containing such carriers as are known to be suitable in the art. -There are also formulations.
Formulations for topical or transdermal or epidermal or dermal administration of HPP compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required. Ointments, pastes, creams and gels may contain, in addition to the HPP composition, e.g. animal and vegetable fats, oils, waxes, paraffins, starches, gum tragacanth, cellulose derivatives, polyethylene glycols, silicones, It may contain excipients such as bentonite, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to HPP compositions, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. can. The syrup may further contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane. The best formulations for topical or transdermal administration are pure water, solutions, aqueous solutions, ethanol and water solutions, and isopropanol and water solutions.

Alternatively, the HPP or pharmaceutical composition thereof can be administered by aerosol. This can be achieved by preparing aqueous aerosols, liposomal formulations or solid particles containing HPP. Non-aqueous (eg, fluorocarbon propellant) suspensions could be used. Sonic nebulizers can also be used. Aqueous aerosols are made by formulating aqueous solutions or suspensions of the drug with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the needs of the particular compound, but typically include nonionic surfactants (Twin, Pluronic, or polyethylene glycols), non-toxic proteins such as serum albumin, sorbitan esters, These include amino acids such as oleic acid, lecithin, and glycine, buffers, salts, sugars, and sugar alcohols. Aerosols are generally prepared from isotonic solutions.
Transdermal patches can also be used to deliver HPP compositions to target sites. The formulation can be made by dissolving or dispersing the drug in the appropriate medium. Absorption enhancers can also be used to increase the flux of the peptidomimetic across the skin. The rate of flux can be controlled by providing a rate controlling membrane or by dispersing the peptidomimetic in a polymer matrix or gel.
Eye drop formulations, eye ointments, powders, solutions, and the like are also contemplated as being within the scope of this invention.

Preparations suitable for parenteral administration include one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile injectable solutions or dispersions immediately before use. The HPP is included as a sterile powder that can be reconstituted into a sterile powder and may contain antioxidants, buffers, bacteriostatic agents, solutes or suspending or thickening agents to make the preparation isotonic with the blood of the intended recipient.
Examples of suitable aqueous and non-aqueous carriers that may be employed in formulations suitable for parenteral administration include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.). , and appropriate mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, or by the use of surfactants.
Formulations suitable for parenteral administration may contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Inclusion of various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenolsorbic acid, etc., may ensure inhibition of the action of microorganisms. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. Additionally, delayed absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.
Injectable depot forms are made by forming microencapsule matrices of HPP or within biodegradable polymers such as polylactide-polyglycolide. Depending on the HPP to polymer ratio and the particular polymer utilized, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by encapsulating HPP in liposomes or microemulsions that are compatible with body tissues.

In certain embodiments, HPP or a pharmaceutical composition thereof is delivered to the site of action at a therapeutically effective dose. As is well known in the field of pharmacology, the precise pharmaceutically effective dose of HPP that will yield the most effective result in terms of therapeutic efficacy in a given patient depends on the activity of the individual HPP, e.g. , specific properties, pharmacokinetics, pharmacokinetics, and bioavailability, the physiological state of the subject (race, age, sex, body weight, dietary restrictions, type and stage of disease, general health status, for a given drug dose). the nature of the pharmaceutically acceptable carrier in the formulation, the route and frequency of administration used, and the severity or propensity of the condition to be treated. However, the above guidelines can be used as a basis for fine-tuning the treatment, e.g. determining the optimal dose of administration, and routine experimentation consisting of monitoring the subject and adjusting the dosage may be necessary. It's just necessary. Remington: The Science and Practice of Pharmacy (Gennaro ed. 20. sup. th edition, Williams & Wilkins PA, USA) (2000).

IV. Benefits Levodopa can cause nausea, vomiting, gastrointestinal bleeding, dyskinesias, and end-of-dose decline in function at peak doses. These problems can be addressed by transdermal administration of highly permeable compositions of L-Dopa and dopamine that consistently deliver minimal therapeutically effective doses, reducing gastrointestinal bleeding, dyskinesia, and functional end-products at peak doses. This can be solved by avoiding a decrease in the number of doses.
Recently, increasing evidence from human and animal studies suggests that neuroinflammation is an important contributing factor to neuronal loss in PD. Furthermore, the pro-inflammatory drug lipopolysaccharide itself may directly induce degeneration of dopamine-containing neurons or may exacerbate such degeneration in combination with other environmental factors such as the insecticide rotenone. These effects strongly support the involvement of inflammation in the pathogenesis of PD. Although dopamine supplementation can alleviate the symptoms of the disorder, no therapy has been proven to halt the underlying progressive degeneration of dopamine-containing neurons. Transdermal administration of highly permeable compositions of L-Dopa and/or dopamine along with highly permeable compositions of aspirin and/or other NSAIDs can not only alleviate the symptoms of Parkinson's disease but also reduce the underlying dopamine-containing -Can also halt the progressive degeneration of Ron.
When administering transdermally a highly permeable composition of L-Dopa and/or dopamine and a highly permeable composition of aspin and/or other NSAIDs, orally administered carbidopa, benserazide, difluoromethyldopa, alpha-methyldopa, and/or Other DDC inhibitors and/or entacapone, and tolcapone and/or other COMT inhibitors, allow a greater proportion of externally delivered levodopa or dopamine to reach the brain, reducing the side effects of L-Dopa and/or dopamine. It can be helpful.

V. EXAMPLES The following examples are provided to better illustrate the claimed invention and should not be construed as limiting the scope of the invention in any way. All specific compositions, materials, and methods described below fall within the scope of the present invention, in whole or in part. These specific compositions, materials, and methods are not intended to limit the invention, but are merely illustrative of specific embodiments that fall within the scope of the invention. Those skilled in the art can develop equivalent compositions, materials, and methods without using their inventive abilities and without departing from the scope of the invention. It will be appreciated that various modifications can be made to the procedures described herein and still remain within the scope of the invention. It is the inventors' intention to include such modifications within the scope of the invention. Additionally, all references cited herein are incorporated by reference in their entirety, as if set forth herein in their entirety.

Example 1. Preparation of 4-(2-(2-(methylamino)acetamido)ethyl)-1,2,-phenylenedibenzoate hydrochloride.

In this example, dopamine was extracted by adding dopamine HCl (19 g) to acetone (200 mL). A HCl solution was prepared. Water (200 mL) and sodium bicarbonate (R0090, 50 g) were added to the dopamine HCl solution to obtain a first mixture. Boc-N-methylglycine N-hydroxysuccinimide ester (Boc-Sar-OSu, 29 g) was then added to the first mixture to obtain a second mixture. The second mixture was stirred at RT overnight and ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a fourth mixture. The third solution and fourth mixture were combined and first pyridine (R0081, 30 mL) and then benzoyl chloride (R0488, 30 g) were added dropwise to obtain a fifth mixture. The fifth mixture was stirred at RT for 2 hours and then added with water (2 x 100 mL), 5% sodium bicarbonate (2 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and Each was washed with water (3 x 100 mL) and dried over sodium sulfate to obtain a sixth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a seventh solution. The sixth solution and the seventh solution were combined and concentrated to about 200 mL (eighth solution). Anisole (20 g) was added to the eighth solution, and then HCl gas (20 g) was bubbled in to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to obtain 4-(2-(2-(methylamino)acetamido)ethyl)-1,2-phenylenedibenzoate hydrochloride.

Example 2. Preparation of 4-(2-(2-(methylamino)acetamido)ethyl)-1,2,-phenylenedibenzoateacetic acid.
In this example, 4-(2-(2-(methylamino)acetamido)ethyl)-1,2,-phenylenedibenzoate hydrochloride (23 g) was dissolved in isopropanol (300 mL) to form a first mixture. I got it. Sodium acetate (4g) was added to the first mixture to obtain a second mixture. The second mixture was stirred at RT for 2 hours and filtered to remove the solids therein. The filtered solution was evaporated to dryness to give 4-(2-(2-(methylamino)acetamido)ethyl)-1,2,-phenylenedibenzoate acetate.

Example 3. Preparation of 4-(6-methyl-4,8-dioxo-5,7-dioxa-2,9-diazadecan-11-yl)-1,2-phenylenedibenzoate hydrobromide.

In this example, a dopamine.HCl solution was prepared by adding dopamine.HCl (19 g) to acetone (200 mL). Water (200 mL) and sodium bicarbonate (R0090, 50 g) were added to the dopamine HCl solution to obtain a first mixture. Di-tert-butyl dicarbonate (22 g) was then added to the first mixture to obtain a second mixture. The second mixture was stirred at RT overnight and ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a fourth mixture. The third solution and fourth mixture were combined and first pyridine (R0081, 30 mL) and then benzoyl chloride (R0488, 30 g) were added dropwise to obtain a fifth mixture. The fifth mixture was stirred at RT for 2 h, then water (2 x 100 mL), 5% sodium bicarbonate (2 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL) and dried over sodium sulfate to obtain a sixth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a seventh solution. The sixth solution and the seventh solution were combined and concentrated to about 200 mL (eighth solution). Anisole (20 g) was added to the eighth solution, and then HCl gas (20 g) was bubbled in to form a precipitate. The precipitated solid was collected, washed with ethyl acetate, and then suspended in DCM (200 mL) to yield a ninth mixture. Sodium hydrogen carbonate (20 g) and tetrabutylammonium hydrogen sulfate (11 g) were added to the ninth mixture to obtain a tenth mixture. Next, 1-chloroethyl chloroformate (16 g) was added to the 10th mixture to obtain an 11th mixture. The 11th mixture was stirred at RT overnight. The 11th mixture organic layer was then collected, washed with water (3 x 200 mL), and dried over anhydrous sodium sulfate to obtain the 12th solution. Sodium sulfate was removed by filtration and washed with DCM to obtain the 13th solution. The 12th and 13th solutions were combined and evaporated to dryness. The residue was dissolved in acetonitrile (200 mL) to obtain a 14th mixture. Boc-sarcosine (36g) was added to the 14th mixture to obtain the 15th mixture. First, a mixture of diisopropylethylamine (34 mL) and Boc-sarcosine (36 g) was prepared and then added to the 15th mixture to obtain the 16th mixture. The 16th mixture was stirred at 55° C. for 48 hours, then ethyl acetate (500 mL) was added with stirring. The resulting organic layer was collected, washed with 5% sodium bicarbonate (3 x 100 mL) and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain a 17th solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain the 18th solution. The 17th solution and the 18th solution were combined and concentrated to 300 mL. Anisole (20 g) was added to the concentrated solution and then HBr gas (30 g) was bubbled in to bring about precipitation. The precipitated solid was collected and washed with ethyl acetate to give 4-(6-methyl-4,8-dioxo-5,7-dioxa-2,9-diazadecan-11-yl)-1,2-phenylenedibenzoar- Hydrobromide was obtained.

Example 4. Preparation of 4-(2-(2-amino-3-phenylpropanamido)ethyl)-1,2-phenylenedibenzoate hydrochloride.

In this example, dopamine was extracted by adding dopamine HCl (19 g) to acetone (200 mL). A HCl solution was prepared. Water (200 mL) and sodium bicarbonate (R0090, 50 g) were added to the dopamine HCl solution to obtain a first mixture. Next, boc-phenylalanine N-hydroxysuccinimide ester (Boc-Phe-OSu, 36 g) was added to the first mixture to obtain a second mixture. The second mixture was stirred at RT overnight and ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a fourth mixture. The third solution and fourth mixture were combined and first pyridine (R0081, 30 mL) and then benzoyl chloride (R0488, 30 g) were added dropwise to obtain a fifth mixture. The fifth mixture was stirred at RT for 2 h, then water (2 x 100 mL), 5% sodium bicarbonate (2 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL) and dried over sodium sulfate to obtain a sixth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a seventh solution. The sixth solution and the seventh solution were combined and concentrated to about 200 mL (eighth solution). Anisole (20 g) was added to the eighth solution, and then HCl gas (20 g) was bubbled in to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to obtain 4-(2-(2-amino-3-phenylpropanamido)ethyl)-1,2-phenylenedibenzoate hydrochloride.

Example 5. Preparation of 4-(2-(((1-((pyrrolidine-2-carbonyl)oxy)ethoxy)amino)ethyl)-1,2-phenylenedibenzoate hydrochloride.

In this example, a dopamine·HCl solution was prepared by adding dopamine·HCl (19 g) to acetone (200 mL). Water (200 mL) and sodium bicarbonate (R0090, 50 g) were added to the dopamine·HCl solution to obtain a first mixture. Di-tert-butyl dicarbonate (22 g) was then added to the first mixture to obtain a second mixture. The second mixture was stirred at RT overnight, and ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2×100 mL), 20% citric acid (2×200 mL), and water (3×100 mL), respectively, and dried over sodium sulfate to obtain a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a fourth mixture. The third solution and the fourth mixture were combined, and pyridine (R0081, 30 mL) and then benzoyl chloride (R0488, 30 g) were added dropwise to obtain a fifth mixture. The fifth mixture was stirred at RT for 2 h, then washed with water (2×100 mL), 5% sodium bicarbonate (2×100 mL), water (100 mL), 20% citric acid (2×200 mL), and water (3×100 mL), respectively, and dried over sodium sulfate to obtain a sixth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a seventh solution. The sixth and seventh solutions were combined and concentrated to about 200 mL (eighth solution). Anisole (20 g) was added to the eighth solution, and HCl gas (20 g) was then bubbled in to form a precipitate. The precipitated solid was collected, washed with ethyl acetate, and suspended in DCM (200 mL) to obtain a ninth mixture. Sodium bicarbonate (20 g) and tetrabutylammonium hydrogen sulfate (11 g) were added to the ninth mixture to obtain a tenth mixture. 1-Chloroethyl chloroformate (16 g) was then added to the tenth mixture to obtain an eleventh mixture. The eleventh mixture was stirred at RT overnight. The organic layer of mixture 11 was then collected, washed with water (3×200 mL), and dried over anhydrous sodium sulfate to obtain solution 12. The sodium sulfate was removed by filtration and washed with DCM to obtain solution 13. Solutions 12 and 13 were combined and evaporated to dryness. The residue was dissolved in acetonitrile (200 mL) to obtain mixture 14. Boc-sarcosine (36 g) was added to mixture 14 to obtain mixture 15. A mixture of diisopropylethylamine (34 mL) and Boc-sarcosine (36 g) was first prepared and then added to mixture 15 to obtain mixture 16. Mixture 16 was stirred at 55° C. for 48 hours, and ethyl acetate (500 mL) was added with stirring. The resulting organic layer was collected, washed with 5% sodium bicarbonate (3×100 mL) and water (3×100 mL), respectively, and dried over anhydrous sodium sulfate to obtain solution 17. The sodium sulfate was filtered and washed with ethyl acetate to obtain solution 18. Solutions 17 and 18 were combined and concentrated to 300 mL. Anisole (20 g) was added to the concentrated solution and then HCl gas (30 g) was bubbled through to induce precipitation. The precipitated solid was collected and washed with ethyl acetate to give 4-(2-(((1-((pyrrolidine-2-carbonyl)oxy)ethoxy)amino)ethyl)-1,2-phenylenedibenzoate hydrochloride.

Example 6. Preparation of 4-(2-piperidine-4-carboxamido)ethyl)-1,2-phenylenebis(2-ethylbutanoate) hydrochloride.

In this example, dopamine was extracted by adding dopamine HCl (19 g) to acetone (200 mL). A HCl solution was prepared. Water (200 mL) and sodium bicarbonate (R0090, 50 g) were added to the dopamine HCl solution to obtain a first mixture. Boc-piperidine-4-carboxylic acid N-hydroxysuccinimide ester (Boc-Inp-OSu, 33 g) was then added to the first mixture to obtain a second mixture. The second mixture was stirred at RT overnight and ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a fourth mixture. The third solution and fourth mixture were combined and first pyridine (R0081, 30 mL) and then 2-ethylbutyryl chloride (28 g) were added dropwise to obtain a fifth mixture. The fifth mixture was stirred at RT for 2 h, then water (2 x 100 mL), 5% sodium bicarbonate (2 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL) and dried over sodium sulfate to obtain a sixth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a seventh solution. The sixth solution and the seventh solution were combined and concentrated to about 200 mL (eighth solution). Anisole (20 g) was added to the eighth solution, and then HCl gas (20 g) was bubbled in to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to obtain 4-(2-piperidine-4-carboxamido)ethyl)-1,2,-phenylenebis(2-ethylbutanoate) hydrochloride.

Example 7. Preparation of 4-(2-(((-octahydro-1H-quinolidin-3-yl)oxy)carbonyl)amino)ethyl)-1,2-phenylenebis(2-ethylbutanoate)acetate.

In this example, dopamine was extracted by adding dopamine HCl (19 g) to acetone (200 mL). A HCl solution was prepared. Water (200 mL) and sodium bicarbonate (R0090, 50 g) were added to the dopamine HCl solution to obtain a first mixture. Di-tert-butyl dicarbonate (22 g) was then added to the first mixture to obtain a second mixture. The second mixture was stirred at RT overnight and ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a fourth mixture. The third solution and fourth mixture were combined and first pyridine (R0081, 30 mL) and then 2-ethylbutyryl chloride (28 g) were added dropwise to obtain a fifth mixture. The fifth mixture was stirred at RT for 2 h, then water (2 x 100 mL), 5% sodium bicarbonate (2 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL) and dried over sodium sulfate to obtain a sixth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a seventh solution. The sixth solution and the seventh solution were combined and concentrated to about 200 mL (eighth solution). Anisole (20 g) was added to the eighth solution, and then HCl gas (20 g) was bubbled in to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give 4-(2-((((-octahydro-1H-quinolidin-3-yl)oxy)carbonyl)amino)ethyl)-1,2-phenylenebis(2- Ethyl butanoate) hydrochloride was obtained.
The solid was dissolved in ethyl acetate (200 mL) to obtain a ninth mixture. First add triethylamine (25 mL) to the ninth mixture, then add dropwise octahydro-1H-quinolidin-3-yl carbonochloride hydrochloride (22 g) in ethyl acetate (50 mL) to the tenth mixture. I got it. The 10th mixture was stirred for 2 hours at RT and washed with 5% sodium bicarbonate and water to obtain the 11th mixture. Acetic acid (6 g) was added to the 11th mixture, followed by hexane (200 mL) resulting in precipitation. Collect the precipitated solid by filtration and wash with ethyl acetate/hexane to obtain 4-(2-((((-octahydro-1H-quinolidin-3-yl)oxy)carbonyl)amino)ethyl)-1,2-phenylene. Bis(2-ethylbutanoate)acetate was obtained.

Example 8. 1-(((2-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)ethyl)carbamoyl)oxy)ethylisobutyra- Hydrofluoride and 1-(((2-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)ethyl) Preparation of carbamoyl)oxy)ethyl isobutyrate hydrofluoride.

In this example, a dopamine.HCl solution was prepared by adding dopamine.HCl (19 g) to acetone (200 mL). Water (200 mL) and sodium bicarbonate (R0090, 50 g) were added to the dopamine HCl solution to obtain a first mixture. Next, Nα-(benzyloxycarbonyloxy)succinimide (25 g) was added to the first mixture to obtain a second mixture. The second mixture was stirred at RT overnight and ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a fourth mixture. The third solution and fourth mixture were combined and evaporated to dryness. The obtained residue and Boc-L-aspartic acid (24 g) were dissolved in acetone (300 mL) to obtain a fifth mixture. 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 g) and 4-dimethylaminopyridine (22 g) were added to the fifth mixture to obtain a sixth mixture. The sixth mixture was stirred at RT overnight and evaporated to dryness. Ethyl acetate (500 mL) was added to the residue to obtain a seventh mixture containing water (2 x 100 mL), 5% sodium bicarbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and Each was washed with water (3 x 100 mL) and dried over sodium sulfate to obtain the eighth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a ninth solution. The eighth solution and the ninth solution were combined and evaporated to dryness. The residue was dissolved in methanol (R0084, 300 mL) to obtain a 10th mixture. Palladium on activated carbon (10 g, 10%) was first added to the 10th mixture under nitrogen and then hydrogen gas was bubbled to remove the benzyloxycarbonyl group at RT. The resulting mixture (11th mixture) was filtered to remove palladium on activated carbon and evaporated to dryness.
The residue was suspended in DCM (200 mL) to obtain a twelfth mixture. Sodium hydrogen carbonate (20 g) and tetrabutylammonium hydrogen sulfate (11 g) were added to the 12th mixture to obtain a 13th mixture. Next, 1-chloroethyl chloroformate (16 g) was added to the 13th mixture to obtain a 14th mixture. The 14th mixture was stirred at RT overnight. The organic layer of the 14th mixture was then collected, washed with water (3 x 200 mL), and dried over anhydrous sodium sulfate to obtain the 15th solution. Sodium sulfate was removed by filtration and washed with DCM to obtain the 16th solution. The 15th and 16th solutions were combined and evaporated to dryness. The residue was collected and dissolved in isobutyric acid (100 mL) to obtain mixture 17. First, a mixture of diisopropylethylamine (60 mL) and isobutyric acid (36 mL) was prepared and then added to the 17th mixture to obtain the 18th mixture. The 18th mixture was stirred at 55° C. for 48 hours and ethyl acetate (500 mL) was added with stirring. The resulting organic layer was collected, washed with 5% sodium bicarbonate (3 x 100 mL) and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain a 19th solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a 20th solution. The 19th solution and the 20th solution were combined and concentrated to 300 mL. Anisole (20 g) was added to the concentrated solution and then HF gas (20 g) was bubbled in to bring about precipitation. The precipitated solid was collected and washed with ethyl acetate to give 1-((2-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin- 8-yl)ethyl)carbamoyl)oxy)ethylisobutyrate-hydrofluoride and 1-(((2-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][ 1,4]dioxocin-8-yl)ethyl)carbamoyl)oxy)ethyl isobutyrate hydrofluoride was obtained.

Example 9. 4-(2-((ethoxycarbonyl)amino)ethyl)-2-(2-methylamino)acetoxy)phenylbenzoate hydrochloride and 5-(2-((ethoxycarbonyl)amino)ethyl)-2- Preparation of (2-methylamino)acetoxy)phenylbenzoate hydrochloride.

In this example, a dopamine.HCl solution was prepared by adding dopamine.HCl (19 g) to acetone (200 mL). Pyridine (40ml) was added to the dopamine HCl solution to obtain a first mixture. Next, N-(ethoxycarbonyloxy)succinimide (18 g) was added to the first mixture to obtain a second mixture. The second mixture was stirred at RT overnight and ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a fourth mixture. The third solution and fourth mixture were combined and evaporated to dryness. The obtained residue and Trt-sarcosine (36 g) were dissolved in acetone (300 mL) to obtain a fifth mixture. 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (20 g) and 4-dimethylaminopyridine (12 g) were added to the fifth mixture to obtain a sixth mixture. The sixth mixture was stirred at RT overnight and evaporated to dryness. Ethyl acetate (500 mL) was added to the residue to obtain a seventh mixture containing water (2 x 100 mL), 5% sodium bicarbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and Each was washed with water (3 x 100 mL) and dried over sodium sulfate to obtain the eighth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a ninth solution. Pyridine (20 mL) was added to the combined eighth and ninth solutions, and then benzoyl chloride (15 g) was added dropwise to obtain a tenth mixture.
The 10th mixture was stirred at RT for 4 hours and then mixed with water (2 x 100 mL), 5% sodium bicarbonate (2 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL). ) and dried over sodium sulfate to obtain the 11th solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain the 12th solution.
Anisole (20 g) was added to the combined 11th and 12th solutions, and then HCl gas (20 g) was bubbled in to bring about precipitation. The precipitated solid was collected and washed with ethyl acetate to form 4-(2-((ethoxycarbonyl)amino)ethyl)-2-(2-methylamino)acetoxy)phenylbenzoate hydrochloride and 5-(2- ((ethoxycarbonyl)amino)ethyl)-2-(2-methylamino)acetoxy)phenylbenzoate was obtained.

Example 10. Preparation of 4-(2-aminoethyl)-1,2-phenylenedibenzoate hydrochloride.

In this example, dopamine was extracted by adding dopamine HCl (19 g) to acetone (200 mL). A HCl solution was prepared. Water (200 mL) and sodium bicarbonate (R0090, 50 g) were added to the dopamine HCl solution to obtain a first mixture. Di-tert-butyl dicarbonate (22 g) was then added to the first mixture to obtain a second mixture. The second mixture was stirred at RT overnight and ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a fourth mixture. The third solution and fourth mixture were combined and first pyridine (R0081, 30 mL) and then benzoyl chloride (R0488, 30 g) were added dropwise to obtain a fifth mixture. The fifth mixture was stirred at RT for 2 h, then water (2 x 100 mL), 5% sodium bicarbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL) and dried over sodium sulfate to obtain a sixth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a seventh solution. The sixth solution and the seventh solution were combined and concentrated to about 300 mL (eighth solution). Anisole (20 g) was added to the eighth solution and then HCl gas (60 g) was bubbled in to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to obtain 4-(2-aminoethyl)-1,2-phenylene dibenzoate hydrochloride.

Example 11. Preparation of (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylene dibenzoate hydrochloride.

In this example, (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (20 g) was added to isopropanol (200 mL) to obtain a first mixture. HCl gas (20 g) was bubbled into the first mixture to obtain a second mixture. The second mixture was stirred at 60° C. for 2 days and then isopropyl acetate (200 mL) was added to cause precipitation. The precipitated solid was collected and washed with isopropyl acetate to obtain isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride.
Isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propano-ato hydrochloride (28 g) was added to acetone (200 mL) to obtain a third mixture. Water (200 mL) and sodium hydrogen carbonate (50 g) were added to the third mixture, and then di-tert-butyl dicarbonate (22 g) was added to obtain a fourth mixture. The fourth mixture was stirred at RT overnight and ethyl acetate (500 mL) was added. The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the sixth solution. Ta. Then the sodium sulfate was filtered and washed with ethyl acetate to obtain a seventh mixture. The sixth solution and seventh mixture were combined and first pyridine (R0081, 30 mL) and then benzoyl chloride (R0488, 30 g) were added dropwise to obtain an eighth mixture. The eighth mixture was stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium bicarbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL) and dried over sodium sulfate to obtain a ninth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a 10th solution. The 9th solution and the 10th solution were combined and concentrated to about 300 mL (11th solution). Anisole (20 g) was added to the 11th solution, and then HCl gas (20 g) was bubbled in to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to obtain (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylenedibenzoate hydrochloride.

Example 12. Preparation of (S)-4-(2-amino-3-(heptan-4-yloxy)-3-oxopropyl)-1,2-phenylene dibenzoate hydrochloride.

In this example, (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (20 g) was added to 4-heptanol (200 mL) to obtain a first mixture. HCl gas (20 g) was bubbled into the first mixture to obtain a second mixture. The second mixture was stirred at 60° C. for 2 days and then isopropyl acetate (200 mL) was added to cause precipitation. The precipitated solid was collected and washed with isopropyl acetate to obtain 4-heptyl(S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride.
4-heptyl(S)-2-amino-3-(3,4-dihydroxyphenyl)propano-ato hydrochloride (28 g) was added to acetone (200 mL) to obtain a third mixture. Water (200 mL) and sodium bicarbonate (50 g) were added to the third mixture, followed by di-tert-butyl dicarbonate (22 g) to obtain a fourth mixture. The fourth mixture was stirred at RT overnight and ethyl acetate (500 mL) was added. The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the sixth solution. Ta. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a seventh mixture. The sixth solution and seventh mixture were combined and first pyridine (R0081, 30 mL) and then benzoyl chloride (R0488, 30 g) were added dropwise to obtain an eighth mixture. The eighth mixture was stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium bicarbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL) and dried over sodium sulfate to obtain a ninth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a 10th solution. The 9th solution and the 10th solution were combined and concentrated to about 300 mL (11th solution). Anisole (20 g) was added to the 11th solution, and then HCl gas (20 g) was bubbled in to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give (S)-4-(2-amino-3-(heptan-4-yloxy)-3-oxopropyl)-1,2-phenylenedibenzoate hydrochloride. I got it.

Example 13. Preparation of (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylene dipentanoate hydrochloride.

In this example, (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (20 g) was added to isopropanol (200 mL) to obtain a first mixture. HCl gas (20 g) was bubbled into the first mixture to obtain a second mixture. The second mixture was stirred at 60° C. for 2 days and then isopropyl acetate (200 mL) was added to cause precipitation. The precipitated solid was collected and washed with isopropyl acetate to obtain isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride.
Isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propano-ato hydrochloride (28 g) was added to acetone (200 mL) to obtain a third mixture. Water (200 mL) and sodium bicarbonate (50 g) were added to the third mixture, followed by di-tert-butyl dicarbonate (22 g) to obtain a fourth mixture. The fourth mixture was stirred at RT overnight and ethyl acetate (500 mL) was added. The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the sixth solution. Ta. Then the sodium sulfate was filtered and washed with ethyl acetate to obtain a seventh mixture. The sixth solution and seventh mixture were combined, and first pyridine (R0081, 30 mL) and then pentanoyl chloride (24 g) were added dropwise to obtain an eighth mixture. The eighth mixture was stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium bicarbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL) and dried over sodium sulfate to obtain a ninth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a 10th solution. The 9th solution and the 10th solution were combined and concentrated to about 300 mL (11th solution). Anisole (20 g) was added to the 11th solution, and then HCl gas (20 g) was bubbled in to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to obtain (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylenedipentanoate hydrochloride.

Example 14. (S)-4-(2-amino-3-ethoxy-3-oxopropyl)-1,2-phenylene diacetate hydrochloride

In this example, (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (20 g) was added to ethanol (200 mL) to obtain a first mixture. HCl gas (20 g) was bubbled into the first mixture to obtain a second mixture. The second mixture was stirred at 60° C. for 2 days and then isopropyl acetate (200 mL) was added to cause precipitation. The precipitated solid was collected and washed with isopropyl acetate to obtain ethyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride.
Ethyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride (26 g) was added to acetone (200 mL) to obtain a third mixture. Water (200 mL) and sodium hydrogen carbonate (50 g) were added to the third mixture, and then di-tert-butyl dicarbonate (22 g) was added to obtain a fourth mixture. The fourth mixture was stirred at RT overnight and ethyl acetate (500 mL) was added. The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the sixth solution. Ta. Then the sodium sulfate was filtered and washed with ethyl acetate to obtain a seventh mixture. The sixth solution and seventh mixture were combined, and first pyridine (R0081, 30 mL) and then acetyl chloride (18 g) were added dropwise to obtain an eighth mixture. The eighth mixture was stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium bicarbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL) and dried over sodium sulfate to obtain a ninth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a 10th solution. The 9th solution and the 10th solution were combined and concentrated to about 300 mL (11th solution). Anisole (20 g) was added to the 11th solution, and then HCl gas (20 g) was bubbled in to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to obtain (S)-4-(2-amino-3-ethoxy-3-oxopropyl)-1,2-phenylene diacetate hydrochloride.

Example 15. Preparation of (S)-4-(2-amino-3-oxo-3-(pentan-3-yloxy)propyl)-1,2-phenylenebis(2-methylpropano-ato)hydrobromide.

In this example, (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (20 g) was added to 3-pentanol (200 mL) to obtain a first mixture. HCl gas (20 g) was bubbled into the first mixture to obtain a second mixture. The second mixture was stirred at 60° C. for 2 days and then isopropyl acetate (200 mL) was added to cause precipitation. The precipitated solid was collected and washed with isopropyl acetate to obtain isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride.
3-Pentyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propano-ato hydrochloride (28 g) was added to acetone (200 mL) to obtain a third mixture. Water (200 mL) and sodium hydrogen carbonate (50 g) were added to the third mixture, followed by di-tert-butyl dicarbonate (22 g) to obtain a fourth mixture. The fourth mixture was stirred at RT overnight and ethyl acetate (500 mL) was added. The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the sixth solution. Ta. Then the sodium sulfate was filtered and washed with ethyl acetate to obtain a seventh mixture. The sixth solution and seventh mixture were combined, and first pyridine (R0081, 30 mL) and then isobutyryl chloride (22 g) were added dropwise to obtain an eighth mixture. The eighth mixture was stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium bicarbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL) and dried over sodium sulfate to obtain a ninth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a 10th solution. The 9th solution and the 10th solution were combined and concentrated to about 300 mL (11th solution). Anisole (20 g) was added to the 11th solution, and then HCl gas (20 g) was bubbled in to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to obtain (S)-4-(2-amino-3-ethoxy-3-oxopropyl)-1,2-phenylene diacetate hydrochloride.

Example 16. Preparation of (S)-4-(2-aminoacetamido)-3-isopropoxy-3-oxopropyl)-1,2-phenylene dibenzoate hydrochloride.

In this example, (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (20 g) was added to isopropanol (200 mL) to obtain a first mixture. HCl gas (20 g) was bubbled into the first mixture to obtain a second mixture. The second mixture was stirred at 60° C. for 2 days and then isopropyl acetate (200 mL) was added to cause precipitation. The precipitated solid was collected and washed with isopropyl acetate to obtain isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride.
Isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propano-ato hydrochloride (28 g) was added to acetone (200 mL) to obtain a third mixture. Water (200 mL) and sodium bicarbonate (50 g) were added to the third mixture, followed by N-(tert-butoxycarbonyl-glycine N-hydroxysuccinimide ester (27 g)) to obtain a fourth mixture. The fourth mixture was brought to RT. Stir overnight and add ethyl acetate (500 mL). The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively. and dried over anhydrous sodium sulfate to obtain a sixth solution.Then, the sodium sulfate was filtered and washed with ethyl acetate to obtain a seventh mixture.The sixth solution and seventh mixture were combined and first Pyridine (R0081, 30 mL) was added dropwise, followed by benzoyl chloride (30 g) to give an eighth mixture. The eighth mixture was stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium bicarbonate. (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a ninth solution. The 10th solution was obtained by filtration and washing with ethyl acetate.The 9th and 10th solutions were combined and concentrated to about 300 mL (11th solution).Anisole (20g) was added to the 11th solution. HCl gas (20 g) was bubbled in to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give (S)-4-(2-aminoacetamido)-3-isopropoxy-3-oxopropyl)- 1,2-phenylene dibenzoate hydrochloride was obtained.

Example 17. Preparation of 4-((2S)-3-oxo-3-(pentan-3-yloxy)-2-(pyrrolidine-2-carboxamido)propyl)-1,2-phenylenedibenzoate hydrofluoride.

In this example, (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (20 g) was added to 3-pentanol (200 mL) to obtain a first mixture. HCl gas (20 g) was bubbled into the first mixture to obtain a second mixture. The second mixture was stirred at 60° C. for 2 days and then isopropyl acetate (200 mL) was added to cause precipitation. The precipitated solid was collected and washed with isopropyl acetate to obtain isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride.
3-Pentyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propano-ato hydrochloride (28 g) was added to acetone (200 mL) to obtain a third mixture. Water (200 mL) and sodium bicarbonate (50 g) were added to the third mixture, followed by N-(tert-butoxycarbonyl-proline N-hydroxysuccinimide ester (32 g)) to obtain a fourth mixture. The fourth mixture was brought to RT. Stir overnight at 100 mL and add ethyl acetate (500 mL). The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively. and dried over anhydrous sodium sulfate to obtain a sixth solution.Then, the sodium sulfate was filtered and washed with ethyl acetate to obtain a seventh mixture.The sixth solution and seventh mixture were combined and first Pyridine (R0081, 30 mL) was added dropwise, followed by benzoyl chloride (22 g) to give an eighth mixture. The eighth mixture was stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium bicarbonate. (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a ninth solution. The 10th solution was obtained by filtration and washing with ethyl acetate.The 9th and 10th solutions were combined and concentrated to about 300 mL (11th solution).Anisole (20g) was added to the 11th solution. HF gas (20 g) was bubbled through to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give 4-((2S)-3-oxo-3-(pentan-3-yloxy)-2-( Pyrrolidine-2-carboxamido)propyl)-1,2-phenylenedibenzoate hydrofluoride was obtained.

Example 18. Preparation of (S)-4-(3-isopropoxy-3-oxo-2-(piperidine-4-carboxamido)propyl)-1,2-phenylenedibenzoate hydrofluoride.

In this example, (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (20 g) was added to isopropanol (200 mL) to obtain a first mixture. HCl gas (20 g) was bubbled into the first mixture to obtain a second mixture. The second mixture was stirred at 60° C. for 2 days and then isopropyl acetate (200 mL) was added to cause precipitation. The precipitated solid was collected and washed with isopropyl acetate to obtain isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride.
Isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propano-ato hydrochloride (28 g) was added to acetone (200 mL) to obtain a third mixture. Water (200 mL) and sodium bicarbonate (50 g) were added to the third mixture, followed by Boc-piperidine-4-carboxylic acid N-hydroxysuccinimide ester (Boc-Inp-OSu, 33 g) to obtain a fourth mixture. The fourth mixture was stirred at RT overnight and ethyl acetate (500 mL) was added. The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the sixth solution. Ta. Then the sodium sulfate was filtered and washed with ethyl acetate to obtain a seventh mixture. The sixth solution and seventh mixture were combined, and first pyridine (R0081, 30 mL) and then benzoyl chloride (30 g) were added dropwise to obtain an eighth mixture. The eighth mixture was stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium bicarbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL) and dried over sodium sulfate to obtain a ninth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a 10th solution. The 9th solution and the 10th solution were combined and concentrated to about 300 mL (11th solution). Anisole (20 g) was added to the 11th solution, and then HF gas (20 g) was bubbled in to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to form (S)-4-(3-isopropoxy-3-oxo-2-(piperidine-4-carboxamido)propyl)-1,2-phenylenedibenzoate fluoride. Hydrogen salt was obtained.

Example 19. 4-((2S)-3-isopropoxy-3-2-(octahydro-1H-quinolidine-2-carboxamide)-3-oxopropyl)-1,2-phenylenebis(2-methylpropanoate) hydrochloride Preparation of salt.

In this example, (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (20 g) was added to isopropanol (200 mL) to obtain a first mixture. HCl gas (20 g) was bubbled into the first mixture to obtain a second mixture. The second mixture was stirred at 60° C. for 2 days and then isopropyl acetate (200 mL) was added to cause precipitation. The precipitated solid was collected and washed with isopropyl acetate to obtain isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride.
Isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propano-ato hydrochloride (28 g) was added to acetone (200 mL) to obtain a third mixture. Water (200 mL) and sodium hydrogen carbonate (50 g) were added to the third mixture, followed by octahydro-1H-quinolidine-2-carboxylic acid N-hydroxysuccinimide ester (28 g) to obtain a fourth mixture. The fourth mixture was stirred at RT overnight and ethyl acetate (500 mL) was added. The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the sixth solution. Ta. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a seventh mixture. The sixth solution and seventh mixture were combined, and first pyridine (R0081, 30 mL) and then isobutyryl chloride (22 g) were added dropwise to obtain an eighth mixture. The eighth mixture was stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium bicarbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL) and dried over sodium sulfate to obtain a ninth solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a 10th solution. The 9th solution and the 10th solution were combined and concentrated to about 100 mL (11th solution). Hexane (200 mL) and then acetic acid (6 g) were added to the 11th solution to form a precipitate. The precipitated solid was collected and washed with ethyl acetate/hexane to give 4-((2S)-3-isopropoxy-3-2-(octahydro-1H-quinolidine-2-carboxamide)-3-oxopropyl)-1, 2-phenylenebis(2-methylpropanoate) hydrochloride was obtained.

Example 20. (2S)-Isopropyl 3-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)-2-(((1- (isobutyryloxy)ethoxy)carbonyl)amino)propano-tohydrobromide and (2S)-isopropyl 3-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[ Preparation of b][1,4]dioxocin-8-yl)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)propano-ato hydrobromide.

In this example, (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (20 g) was added to isopropanol (200 mL) to obtain a first mixture. HCl gas (20 g) was bubbled into the first mixture to obtain a second mixture. The second mixture was stirred at 60° C. for 2 days and then isopropyl acetate (200 mL) was added to cause precipitation. The precipitated solid was collected and washed with isopropyl acetate to obtain isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride.
Isopropyl(S)-2-amino-3-(3 ,4-dihydroxyphenyl)propanoate hydrochloride solution was prepared. Water (200 mL) and sodium bicarbonate (R0090, 50 g) were added to the dopamine HCl solution to obtain a third mixture. Next, Nα-(benzyloxycarbonyloxy)succinimide (25 g) was added to the third mixture to obtain a fourth mixture. The fourth mixture was stirred at RT overnight and then ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a fifth solution. Next, the sodium sulfate was filtered and washed with ethyl acetate to obtain a sixth solution. The fifth solution and the sixth mixture were combined and evaporated to dryness. The obtained residue and Boc-L-aspartic acid (24 g) were dissolved in acetone (300 mL) to obtain a seventh mixture. 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 g) and 4-dimethylaminopyridine (22 g) were added to the seventh mixture to obtain an eighth mixture. The eighth mixture was stirred at RT overnight and evaporated to dryness. Ethyl acetate (500 ml) was added to the residue to obtain a ninth mixture containing water (2 x 100 ml), 5% sodium bicarbonate (3 x 100 ml), water (100 ml), 20% citric acid (2 x 200 ml), and Each was washed with water (3 x 100 mL) and dried over sodium sulfate to obtain the 10th solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain the 11th solution. The 10th solution and the 11th solution were combined and evaporated to dryness. The residue was dissolved in methanol (R0084, 300 mL) to obtain a 12th mixture. Palladium activated carbon (10 g, 10%) was first added to the twelfth mixture under nitrogen, and then hydrogen gas was bubbled through at RT to remove the benzyloxycarbonyl group. The resulting mixture (13th mixture) was filtered to remove palladium on activated carbon and evaporated to dryness.
The residue was suspended in DCM (200 mL) to obtain the 14th mixture. Sodium hydrogen carbonate (15 g) and tetrabutylammonium hydrogen sulfate (11 g) were added to the 14th mixture to obtain a 15th mixture. Next, 1-chloroethyl chloroformate (16 g) was added to the 15th mixture to obtain a 16th mixture. The 16th mixture was stirred at RT overnight. The organic layer of the 16th mixture was then collected, washed with water (3 x 200 mL), and dried over anhydrous sodium sulfate to obtain the 17th solution. Sodium sulfate was removed by filtration and washed with DCM to obtain solution No. 18. The 17th and 18th solutions were combined and evaporated to dryness. The residue was dissolved in isobutyric acid (100 mL) to obtain a 19th mixture. A mixture of diisopropylethylamine (60 mL) and isobutyric acid (36 mL) was first prepared and then added to the 19th mixture to obtain the 20th mixture. The 20th mixture was stirred at 55° C. for 48 hours and ethyl acetate (500 mL) was added with stirring. The resulting organic layer was collected, washed with 5% sodium bicarbonate (3 x 100 mL) and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain a 21st solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain a 22nd solution. The 21st solution and the 22nd solution were combined and concentrated to 300 mL. Anisole (20 g) was added to the concentrated solution and then HBr gas (30 g) was bubbled in to bring about precipitation. The precipitated solid was collected and washed with ethyl acetate to give (2S)-isopropyl 3-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin- 8-yl)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)propano-tohydrobromide and (2S)-isopropyl 3-(4-amino-2,5-dioxo -2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)propano-atobromide Hydrogen salt was obtained.

Example 21. 5-((2S)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino-3-isopropoxy-3-oxopropyl)-2-(2-(methylamino)acetoxy)phenylbenzo Ato hydrochloride and 4-((2S)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino-3-isopropoxy-3-oxopropyl)-2-(2-(methyl Preparation of amino)acetoxy)phenylbenzoate hydrochloride.

In this example, (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (20 g) was added to isopropanol (200 mL) to obtain a first mixture. HCl gas (20 g) was bubbled into the first mixture to obtain a second mixture. The second mixture was stirred at 60° C. for 2 days and then isopropyl acetate (200 mL) was added to cause precipitation. The precipitated solid was collected and washed with isopropyl acetate to obtain isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride.
Isopropyl(S)-2-amino-3-(3 ,4-dihydroxyphenyl)propanoate hydrochloride solution was prepared. Water (200 mL) and sodium bicarbonate (R0090, 50 g) were added to the dopamine HCl solution to obtain a third mixture. Next, Nα-(benzyloxycarbonyloxy)succinimide (25 g) was added to the third mixture to obtain a fourth mixture. The fourth mixture was stirred at RT overnight and ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a fifth solution. Next, the sodium sulfate was filtered and washed with ethyl acetate to obtain a sixth solution. The fifth solution and the sixth mixture were combined and evaporated to dryness.
The obtained residue and Trt-sarcosine (36 g) were dissolved in acetone (300 mL) to obtain a seventh mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (20 g) and 4-dimethylaminopyridine (12 g) were added to the seventh mixture to obtain an eighth mixture. The eighth mixture was stirred at RT overnight and evaporated to dryness. Ethyl acetate (500 ml) was added to the residue to obtain a ninth mixture containing water (2 x 100 ml), 5% sodium bicarbonate (3 x 100 ml), water (100 ml), 20% citric acid (2 x 200 ml), and Each was washed with water (3 x 100 mL) and dried over sodium sulfate to obtain the 10th solution. The sodium sulfate was filtered and washed with ethyl acetate to obtain the 11th solution. Pyridine (20 ml) was added to the 11th solution to obtain a 12th mixture, and benzoyl chloride (15 g) was added dropwise to the 12th mixture to obtain a 13th mixture. The 13th mixture was stirred at RT for 4 hours and the resulting mixture was mixed with water (2 x 100 ml), 5% sodium bicarbonate (2 x 100 ml), water (100 ml), 20% citric acid (2 x 200 ml), and Each was washed with water (3 x 100 ml) and dried over anhydrous sodium sulfate to obtain a 14th solution. Sodium sulfate was removed by filtration and washed with ethyl acetate to obtain a 15th solution. The 14th and 15th solutions were combined and evaporated to dryness.
The obtained residue was dissolved in methanol (300 mL) to obtain a 16th mixture. 10% palladium on activated carbon (10 g) was added to the 16th mixture under nitrogen and the resulting mixture was bubbled with hydrogen gas until substantially complete removal of benzyloxycarbonyl groups at RT. The palladium on activated carbon was removed by filtration and the resulting solution was evaporated to dryness.
The resulting residue was suspended in DCM (200 mL). Sodium bicarbonate (15 g) and tetrabutylammonium hydrogen sulfate (11 g) were added to the DCM suspension. 1-chloroethyl chloroformate (16 g) was added to the resulting reaction mixture. The reaction mixture was then stirred at RT overnight. The organic layer was collected and washed with water (3 x 200 mL). The solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration and washed with DCM. The DCM solution was evaporated to dryness.
The residue was dissolved in isobutyric acid (100 mL). Add a mixture of diisopropylethylamine (60 ml) and isobutyric acid (R0874, 36 mL) [mix before addition] to the reaction solution. The mixture is stirred at 55°C for 48 hours. Add ethyl acetate (500 ml) to the stirred reaction mixture. The organic solution is collected and washed with 5% sodium bicarbonate (3 x 100 ml) and water (3 x 100 ml). Dry the solution over anhydrous sodium sulfate. The sodium sulfate is removed by filtration and washed with ethyl acetate (3x). Concentrate this solution to 300ml. Add anisole (20g) to the ethyl acetate solution. Then HCl gas (30 g) is bubbled into the ethyl acetate solution. Collect the solid and wash with ethyl acetate.

Example 22. 4-((2S)-3-isopropoxy-2-((((octahydroindolizin-1-yl)oxy)carbonyl)amino)-3-oxopropyl)-1,2-phenylenedibenzoate-aceta- Preparation.

In this example, (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (20 g) was added to isopropanol (200 mL). HCl gas (20g) was bubbled into the mixture. The mixture was stirred at 60°C for 2 days. Isopropyl acetate (200 mL) was added to this mixture. The solid was collected and washed with isopropyl acetate.
Isopropyl (S)-2-amino-3-(3,4-dihydroxyphenyl)propano-ato hydrochloride (28 g) was added to acetone (200 mL). Water (200 mL) and sodium hydrogen carbonate (50 g) were added to the reaction mixture. Di-tert-butyl dicarbonate (22 g) was added to the reaction mixture. The mixture was stirred at RT overnight. Ethyl acetate (500 mL) was added to the mixture. The mixture was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL). The solution was dried over sodium sulfate. Sodium sulfate was removed by filtration and washed with ethyl acetate. Pyridine (30 mL) was added to the ethyl acetate solution. Benzoyl chloride (30g) was added dropwise to the reaction mixture. The solution was stirred at RT for 2 hours. The solution was washed with water (2 x 100 mL), 5% sodium bicarbonate (2 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL). The solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration and washed with ethyl acetate. This solution was concentrated to 200 mL. Anisole (20 g) was added to this ethyl acetate solution. Then HCl gas (20 g) was bubbled into the ethyl acetate solution.
The solid was collected and washed with ethyl acetate.
The solid was suspended in ethyl acetate (200 mL) and triethylamine (25 mL) was added to the mixture. Octahydroindolizin-1-ylcarbonochloridate hydrochloride (22 g) in ethyl acetate (50 mL) was added dropwise to the reaction mixture. The mixture was stirred at RT for 2 hours. The mixture was washed with 5% sodium bicarbonate and water (3x). Acetic acid (6g) was added to the mixture. Hexane (200 mL) was added to the mixture. The solid was collected by filtration and washed with ethyl acetate/hexane.

Example 23. 2-(diethylamino)ethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate. Preparation of acetate.

29.6 g (0.1 mol) of 2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid was dissolved in 300 mL of chloroform. 20.6 g of N,N'-dicyclohexylcarbodiimide was added to the reaction mixture. 11.7 g of diethylaminoethylamine was added to the reaction mixture. The mixture was stirred at RT for 3 hours. Solids were removed by filtration. The chloroform solution was washed with 5% NaHCO ₃ (2 x 100 mL) and water (3 x 100 mL). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added to the stirred reaction mixture. Hexane (200ml) was added. The solid product was collected by filtration.

Example 24. (Z)-2-(diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl)acetate. Preparation of AcOH

11.7 g (0.1 mol) of diethylaminoethanol was dissolved in 10% sodium bicarbonate (200 mL) and acetone (100 mL). 37.5 g (0.1 mol) of (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetyl chloride was added to the reaction mixture. The mixture was stirred at RT for 3 hours. The solvent was evaporated. The residue was suspended in ethyl acetate (500 mL). 5% sodium bicarbonate (200 mL) was added to the stirred reaction mixture. The ethyl acetate layer was collected and washed with water (3 x 500 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added to the stirred reaction mixture. The organic solution was evaporated.

Example 25. 2-(dimethylamino)ethyl 2-(3-phenoxyphenyl)propionate. Preparation of hydrochloride

26.1 g (0.1 mol) of 2-(3-phenoxyphenyl)propionyl chloride was dissolved in 300 ml of ethyl acetate. The mixture was cooled to 0°C. 8.9 g of dimethylaminoethanol was added to the reaction mixture. Sodium bicarbonate (30g) was added to the mixture. The mixture was stirred at RT for 5 hours. The mixture was washed with water (3 x 200 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate. HCl gas (5g) was bubbled into the mixture. The solids were collected by filtration and washed with ethyl acetate.

Example 26. Preparation of S-(2-(dimethylamino)ethyl 2-(3-phenoxyphenyl)propanethioate hydrochloride

10.4 g (0.1 mol) of dimethylaminoethyl mercaptan was dissolved in 10% sodium bicarbonate (200 mL) and acetone (100 mL). 27.3 g (0.1 mol) of 2-(3-phenoxyphenyl)propionyl chloride was added to the reaction mixture. The mixture was stirred at RT for 3 hours. The solvent was evaporated. The residue was suspended in ethyl acetate (500 mL). 5% sodium bicarbonate (200 mL) was added to the stirring reaction mixture. The ethyl acetate layer was collected and washed with water (3 x 500 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. Anhydrous HCl gas (5 g) was bubbled into the stirred reaction mixture. The solid was collected and washed with ethyl acetate.

Example 27. 2-(dipropylamino)ethyl 4-acetoxy-2',4'-difluoro-[1,1'-biphenyl]-3-carboxylate hydrochloride [2-(dipropylamino)ethyl 5-(2 Preparation of ,4-difluorophenyl)acetylsalicylate hydrochloride]

31.1 g (0.1 mol) of 5-(2,4-difluorophenyl)acetylsalicyl chloride was dissolved in 300 mL of ethyl acetate. The mixture was cooled to 0°C. 11.7 g (0.1 mol) diethylaminoethanol was added to the reaction mixture. Sodium bicarbonate (30g) was added to the reaction mixture. The mixture was stirred at RT for 3 hours. Water (200 mL) was then added to the mixture. The ethyl acetate layer was collected and washed with water (3x). The solution was dried over anhydrous sodium sulfate. Anhydrous HCl gas was bubbled into the stirred reaction mixture. The solid was collected and washed with ethyl acetate.

Example 28. Preparation of 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propionate hydrochloride.

41 g of ibuprofen was dissolved in 200 ml of ethyl acetate. 16 mL of thionyl chloride was added to the mixture. The mixture was refluxed for 2 hours. The mixture was completely evaporated to dryness. 500 mL of ethyl acetate was added to the residue and evaporated. 500 mL of ethyl acetate was added to the reaction mixture. The solution was cooled to 5°C in an ice-water bath. 23 g of N,N-diethylaminoethanol was added dropwise to the reaction mixture. _40g of _Na2CO3 was slowly added to the reaction mixture. The mixture was stirred at RT overnight. 200 mL of water was added to the mixture. The ethyl acetate solution was collected and washed with water (3 x 200 mL) and dried over _{anhydrous Na2SO4} . Sodium sulfate was removed by filtration and washed with ethyl acetate (3 x 100 mL). Anhydrous HCl gas (10 g) was bubbled into the mixture. The solid was collected and washed with ethyl acetate.

Example 29. Preparation of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride (2-(diethylamino)ethyl acetylsalicylate hydrochloride).

36g of aspirin was dissolved in 100mL of ethyl acetate. 16 mL of thionyl chloride was added to the mixture. The mixture was refluxed for 3 hours. The mixture was completely evaporated to dryness. 100 mL of ethyl acetate was added to the residue and evaporated. 500 mL of ethyl acetate was added to the reaction mixture. The solution was cooled to 5°C in an ice-water bath. 23 g of N-diethylaminoethanol was added dropwise to the reaction mixture. 40g of _NaHCO3 was slowly added to the reaction mixture. The mixture was stirred at RT overnight. 200 mL of water was added to the mixture. The ethyl acetate solution was collected and washed with water (3 x 100 mL) and dried over _{anhydrous Na2SO4} . Sodium sulfate was removed by filtration and washed with ethyl acetate (3 x 100 mL). Anhydrous HCl gas (10 g) was bubbled into the mixture. The solid was collected and washed with ethyl acetate.

Example 30. Measuring the permeation rate of HPP
4-(2-(2-(methylamino)acetamido)ethyl)-1,2,-phenylenedibenzoate hydrochloride (compound-1), 4-(2-(2-(methylamino)acetamido)ethyl )-1,2,-phenylenedibenzoateacetic acid (compound-2), 4-(6-methyl-4,8-dioxo-5,7-dioxa-2,9-diazadecane-11-yl)-1 ,2,-phenylenedibenzoate hydrobromide (compound-3), 4-(2-(2-amino-3-phenylpropanamido)ethyl)-1,2,-phenylenedibenzoate hydrochloride Salt (Compound-4), 4-(2-(((1-((pyrrolidine-2-carbonyl)oxy)ethoxy)amino)ethyl)-1,2,-phenylenedibenzoate hydrochloride (Compound-5 ), 4-(2-piperidine-4-carboxamido)ethyl)-1,2,-phenylenebis(2-ethylbutanoate) hydrochloride (compound-6), 4-(2-((((-octahydro- 1H-quinolidin-3-yl)oxy)carbonyl)amino)ethyl)-1,2,-phenylenebis(2-ethylbutanoato)acetate (compound-7), 1-(((2-(4- Amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)ethyl)carbamoyl)oxy)ethyl isobutyrate hydrofluoride (compound-8a) ), 1-(((2-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)ethyl)carbamoyl)oxy) Ethylisobutyrate hydrofluoride (Compound-8b), (5-(2-((ethoxycarbonyl)amino)ethyl)-2-(2-methylamino)acetoxy)phenylbenzoate hydrochloride (Compound- 9a), 5-(2-((ethoxycarbonyl)amino)ethyl)-2-(2-methylamino)acetoxy)phenylbenzoate hydrochloride (compound-9b), 4-(2-aminoethyl)- 1,2-phenylene dibenzoate hydrochloride (compound-10), (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylene dibenzoate hydrochloride (Compound-11), (S)-4-(2-amino-3-(heptan-4-yloxy)-3-oxopropyl)-1,2-phenylenedibenzoate hydrochloride (Compound-12), (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylenedipentanoate hydrochloride (compound-13), (S)-4-(2-amino -3-ethoxy-3-oxopropyl)-1,2-phenylene diacetate hydrochloride (compound-14), (S)-4-(2-amino-3-oxo-3-(pentane-3- (S)-4-(2-aminoacetamido)-3-isopropoxy-3 -oxopropyl)-1,2-phenylenedibenzoate hydrochloride (compound-16), 4-((2S)-3-oxo-3-(pentan-3-yloxy)-2-(pyrrolidine-2- (carboxamido)propyl)-1,2-phenylenedibenzoate hydrofluoride (compound-17), (S)-4-(3-isopropoxy-3-oxo-2-(piperidine-4-carboxamido)propyl) )-1,2-phenylene dibenzoate hydrochloride (compound-18), 4-((2S)-3-isopropoxy-3-2-(octahydro-1H-quinolidine-2-carboxamide)-3-oxo (2S)-isopropyl 3-(3-amino-2,5-dioxo-2,3,4, 5-Tetrahydrobenzo[b][1,4]dioxocin-8-yl)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)propano-tohydrobromide (Compound-20a ), (2S)-isopropyl 3-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)-2-((( 1-(isobutyryloxy)ethoxy)carbonyl)amino)propano-ato hydrobromide (compound-20b), 5-((2S)-2-(((1-(isobutyryloxy)ethoxy) carbonyl)amino-3-isopropoxy-3-oxopropyl)-2-(2-(methylamino)acetoxy)phenylbenzoate hydrochloride (compound-21a), 4-((2S)-2-(( (1-(isobutyryloxy)ethoxy)carbonyl)amino-3-isopropoxy-3-oxopropyl)-2-(2-(methylamino)acetoxy)phenylbenzoate hydrochloride (compound-21b), 4-((2S)-3-isopropoxy-2-((((octahydroindolizin-1-yl)oxy)carbonyl)amino)-3-oxopropyl)-1,2-phenylenedibenzoate-aceta- (Compound-22), 2-(diethylamino)ethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate. Acetate (compound-23), (Z)-2-(diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl) Acetate. AcOH (compound-24), 2-(dimethylamino)ethyl 2-(3-phenoxyphenyl)propionate. Hydrochloride (Compound-25), S-(2-(dimethylamino)ethyl 2-(3-phenoxyphenyl)propanethioate hydrochloride (Compound-26), 2-(dipropylamino)ethyl 4-acetoxy-2 ',4'-difluoro-[1,1'-biphenyl]-3-carboxylate hydrochloride (compound-27), 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propionate hydrochloride ( Compound-28), 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride (Compound-29), 4-(2-aminoethyl)benzene-1,2-diol hydrochloride (Compound-30) , 2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (L-Dopa, compound 31), acetylsalicylic acid (compound-32), 2-(ρ-isobutylphenyl)propionic acid (ibuprofen, compound-33) ), and 2-(3-phenoxyphenyl)propionic acid (compound-34) permeation rate through human skin isolated from anterior and posterior thigh human skin tissue (360-400 μm thickness). The measurements were carried out in vitro using a modified Franz cell. The receiving fluid consisted of 10 mL of pH 7.4 phosphate buffer (0.2 M) and is shown in Table 1. The results show that the positive charge of the amino groups It was suggested that it has a very important role in the passage of drugs across the skin barrier.

table 1. Cumulative doses of dopamine, L-Dopa, and NSAID prodrugs at 8 hours.

Example 31. The effect of (S)-4-(2-amino-3-iso- Efficacy of propoxy-3-oxopropyl)-1,2-phenylenedibenzoate hydrochloride (drug A) and 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride (drug B) Subjects tested according to the following protocol (Sprague-Dawley rats) were prepared, grouped, and tested.
1. Two hundred Sprague-Dawley rats (male, 200-230 g) underwent stereotaxic surgery after 1 week of acclimatization in the animal facility;
2. After anesthesia, a burr hole (1 mm in diameter) was drilled in the left skull using a motor drill based on the following coordinates: AP +0.5 mm, ML -2.8 mm, DV relative to bregma 6. 0mm;
3． 6-OHDA (20 μg at 5 mg/mL) or sterile saline was injected into the left striatum using a microsyringe equipped with a 26-gauge steel cannula. This chemical caused retrograde neurodegeneration in the distal substantia nigra, impairing dopamine transmission in the nigrostriatal pathway and ultimately resulting in dysfunction of motor activity;
Four. Animals were screened using apomorphine and the classic rotation test at the end of 3 weeks after 6-OHDA treatment. Animals matched for lesion type and apomorphine-induced rotation score were assigned to 11 groups; and
Five. The rats were divided into 11 groups (n=12), and drugs were administered to each group at the doses shown in Table 2 below.

Table 2. Doses and drugs administered to test animals

6. dosage prescription
(1) L-DOPA (3 mg/mL) in water was the positive control solution for group 1 (orally for group 1 and transdermally for groups 2 to 11). The dose volume was 2mL/kg. Vehicle solution (negative control solution for group 2) was 30% ethanol (v/v). The dose volume was 1286 μL/kg. Other test solutions (groups 3-11) were prepared fresh daily.
(2) Preparation method of test solution for groups 3 to 5: 50.33 mg of drug A was dissolved in 10 mL of 30% ethanol (v/v). This solution was a stock solution [(2)a].
a. Test solution for group 5 (high dose group) of drug A: Stock solution [(2)a] was the test solution for group 5. The dose volume was 1286 μL/kg.
b. Test solution for group 4 (medium dose group) of drug A: 3.00 mL of stock solution [(2)a] was diluted with 30% ethanol (v/v) to a final volume of 9.00 mL. This solution was the test solution for Group 4. The dose volume was 1286 μL/kg.
c. Test solution for Group 3 (low dose group) of drug A: 1.00 mL of stock solution [(2)a] was diluted with 30% ethanol (v/v) to a final volume of 9.00 mL. This solution was the test solution for Group 4. The dose volume was 1286 μL/kg.
(3) Method for preparing test solution for group 6: 5.67 mg of drug A and 264 mg of drug B were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 6.
(4) Method for preparing test solution for group 7: 16.67 mg of drug A and 264 mg of drug B were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 7.
(5) Method for preparing test solution for group 8: 264 mg of drug B was dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 8.
(6) Method for preparing test solution for group 9: 5.67 mg of drug A and 791 mg of drug B were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 9.
(7) Method for preparing test solution for group 10: 16.67 mg of drug A and 791 mg of drug B were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 10.
(8) Method for preparing test solution for group 11: 791 mg of drug A was dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 11.

7. The day before the scheduled dosing, use small animal clippers to cut the animal (all rats, including those in the positive control group using L-DOPA due to the double-blind design) from the upper back (around the neck and shoulders). Removed hair. Animals were re-shorn as necessary to maintain epidermal exposure throughout the course of the study. On the day of dosing, an aliquot (643 μL/kg) of the dosing formulation was administered to the animal in a 3 cm x 3 cm square (around the neck and shoulders) at approximately 9:00 am and repeated at approximately 4:00 pm.
8. Four weeks after the lesion, the group began receiving treatment.
9. Rotarod tests were performed weekly after treatment.

Figure 1 shows the residence time results in the rotarod test described above after 1 to 3 weeks of treatment (n=12). Figure 2 shows the fall velocity results in the rotarod test described above after 1 to 3 weeks of treatment (n=12).
It was assumed that the improved performance of PD animals would allow them to stay on the road longer and tolerate faster rotations (without the side effects of the test drug).
By pooling all batch data together (12 animals/group), the positive group (group 1, L-DOPA, 6 mg/kg, p.o.) compared to the vehicle group after 3 weeks of treatment. It did not show any efficacy. However, all study drug treatment groups (groups 2-11) showed stronger efficacy than the vehicle group after 3 weeks of treatment. Levodopa contributed to the development of motor complications in PD. Because levodopa caused nausea, vomiting, gastrointestinal bleeding, and dyskinesias at peak doses, as well as end-of-dose declines in function, the positive control group (group 1, L-DOPA, 6mg/ kg, orally) showed no efficacy compared to the vehicle group. However, transdermally administered prodrugs of L-Dopa (Drug A) avoided dyskinesias at peak doses and end-of-dose decline in function. The efficacy of low doses of drug A ( prodrug of L-Dopa, 0.67 mg/kg, group 3) was much greater than that of medium and high doses of drug A (2 mg and 6 mg/kg, groups 4 and 5). it was high. The results showed that the dose of transdermally administered prodrug of L-dopa was much lower (9 times lower) than orally administered L-dopa. Drug B ( prodrug of aspirin ) at 30 mg and 90 mg/kg showed better efficacy than the vehicle group and positive control group after 3 weeks of treatment. 30 mg of drug B (group 8) showed similar efficacy as 90 mg of drug B (group 11). The results showed that drug B was sufficient at a dose of 30 mg/kg and higher doses were not required. Administration of a combination of drug A and drug B (groups 6 and 9) to subjects performed much better than administration of either drug B (groups 8 and 11) or drug A (group 3) alone.
When administering a combination of multiple drugs (e.g., one or more HPPs and/or other drugs) to a subject, each drug can be administered separately, or one or more drugs can be administered substantially as separate drugs. can be administered simultaneously (e.g., the two or more drugs are sprayed substantially simultaneously without mixing before spraying), or the one or more drugs can be mixed together and then administered to the subject; or Combinations of any of the above methods of administration are also possible. Drugs can be administered in any possible order.

Example 32. Efficacy of Drug A (transdermal), Drug B (transdermal), and oral carbidopa in improving motor deficits and reducing nigrostriatal neurodegeneration induced by 6-OHDA in a Parkinson's Disease (PD) model in HDB.
Test subjects (Sprague-Dawley rats) were prepared as described in Example 31, and grouped and tested according to the following protocol.
1. Rats were divided into 11 groups (n=12) and administered drugs to each group at the doses shown in Table 3 below.

Table 3. Doses and drugs administered to test animals

2. dosage prescription
(1) L-DOPA (3 mg/ml) and carbidopa (1.5 mg/ml) in water were both used as positive control solutions in group 1 (oral), and the administration volume was 2 ml/kg. Carbidopa (3 mg/mL) in water was an aromatic L-amino acid decarboxylase inhibitor for groups 2-11 (oral), and the dose volume was 2 mL/kg. The vehicle solution (negative control solution for group 2) was 30% ethanol (v/v), and the dose volume was 1,286 μL/kg. Other test solutions (dermal, groups 3-11) were prepared fresh daily.
(2) Preparation method of test solution for groups 3 to 5: 50.33 mg of drug A was dissolved in 10 mL of 30% ethanol (v/v). This solution was the stock solution (2).
(a) Stock solution (2) was the test solution for drug A group 5 (high dose group). The dose volume was 1,286 μL/kg;
(b) Test solution for group 4 (medium dose group) of drug A: 3.00 mL of stock solution (2) was diluted with 30% ethanol (v/v) to a final volume of 9.00 mL. This solution was the test solution for Group 4. The dose volume was 1,286 μL/kg;
(c) Test solution for drug A group 3 (low dose group): 1.00 mL of stock solution (2) was diluted with 30% ethanol (v/v) to a final volume of 9.00 mL. This solution was the test solution for Group 3. The dose volume was 1,286 μL/kg.
(3) Method for preparing test solution for group 6: 5.67 mg of drug A and 264 mg of drug B were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for group 6;
(4) Method for preparing test solution for group 7: 16.67 mg of drug A and 264 mg of drug B were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for group 7;
(5) Method for preparing test solution for group 8: 264 mg of drug B was dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for group 8;
(6) Method for preparing test solution for group 9: 5.67 mg of drug A and 791 mg of drug B were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for group 9;
(7) Method for preparing test solution for group 10: 16.67 mg of drug A and 791 mg of drug B were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for group 10;
(8) Preparation method of test solution for group 11: 791 mg of drug B was dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 11.

3． The day before the scheduled dosing, use a small animal clipper to cut the animal (all rats, including those in the positive control group using L-DOPA due to the double-blind design) from the upper back (around the neck and shoulders). Removed hair. Animals were re-shorn as necessary to maintain epidermal exposure throughout the course of the study. On the day of dosing, an aliquot (643 μL/kg) of the dosing formulation was administered to the animal in a 3 cm x 3 cm square (around the neck and shoulders) at approximately 9:00 a.m. and repeated at approximately 4:00 p.m.
Four. Four weeks after the lesion, the group began receiving treatment.
Five. Rotarod test was performed 4 weeks after treatment.

Figure 3 shows the residence time results in the rotarod test described above after 4 weeks of treatment (n=12). Figure 4 shows the fall velocity results in the rotarod test described above after 4 weeks of treatment (n=12).
Carbidopa could reduce the peripheral DDC conversion of levodopa before it crosses the blood-brain barrier, thus reducing the side effects of L-Dopa. The results showed that carbidopa enhanced the efficacy of all L-Dopa and L-Dopa prodrug (drug A) treatment groups (groups 1, 3, 4, 5, 6, 7, 9, and 10); It is shown that the efficacy of the vehicle group and the aspirin prodrug treatment group (drug B) (groups 2, 8 and 11) was not altered.
When administering a combination of multiple drugs (e.g., one or more HPPs and/or other drugs) to a subject, each drug can be administered separately, or one or more drugs can be administered substantially as separate drugs. can be administered simultaneously (e.g., the two or more drugs are sprayed substantially simultaneously without mixing before spraying), or the one or more drugs can be mixed together and then administered to the subject; or Combinations of any of the above methods of administration are also possible. Drugs can be administered in any possible order.

Example 33. Efficacy of prodrugs of L-Dopa and ibuprofen in ameliorating motor function deficits and reducing nigrostriatal neurodegeneration induced by 6-OHDA in a Parkinson's disease (PD) model in HDB.
Test subjects (Sprague-Dawley rats) were prepared as described in Example 31 and grouped and tested according to the following protocol.
1. The rats were divided into 11 groups (n=12), and drugs were administered to each group at the doses shown in Table 4 below. Drug C is (S)-4-(2-amino-3-oxo-3-(pentan-3-yloxy)propyl)-1,2-phenylenebis(2-methylpropanoate) hydrobromide and drug D was 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propionate acetate.

Table 4. Doses and drugs administered to test animals

2. dosage prescription
(1) L-DOPA (3 mg/mL) in water was a positive control solution for group 1 (oral), and the administration volume was 2 mL/kg. The vehicle solution (negative control solution for group 2) was 30% ethanol (v/v), and the administration volume was 1286 μL/kg. Other test solutions (groups 3-11) were prepared fresh daily.
(2) Preparation method of test solution for groups 3 to 5: 50.33 mg of drug C was dissolved in 10 mL of 30% ethanol (v/v). This solution was the stock solution (2).
a) Test solution for group 5 (high dose group) of drug C: Stock solution (2) was the test solution for group 5. The dose volume was 1,286 μL/kg;
b) Test solution for group 4 (medium dose group) of drug C: 3.00 mL of stock solution (2) was diluted with 30% ethanol (v/v) to a final volume of 9.00 mL. This solution was the test solution for Group 4. The dose volume was 1,286 μL/kg;
c) Test solution for group 3 (low dose group) of drug C: 1.00 mL of stock solution (2) was diluted with 30% ethanol (v/v) to a final volume of 9.00 mL. This solution was the test solution for Group 3. The dose volume was 1,286 μL/kg.
(3) Method for preparing test solution for group 6: 5.67 mg of drug C and 132 mg of drug D were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 6.
(4) Method for preparing test solution for group 7: 16.67 mg of drug C and 132 mg of drug D were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 7.
(5) Preparation method of test solution for group 8: 132 mg of drug D was dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 8.
(6) Method for preparing test solution for group 9: 5.67 mg of drug C and 395.5 mg of drug D were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 9.
(7) Method for preparing test solution for group 10: 16.67 mg of drug C and 395.5 mg of drug D were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 10.
(8) Preparation method of test solution for group 11: 395.5 mg of drug D was dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 11.

3． The day before the scheduled dosing, use small animal clippers to cut the animals (all rats, including those in the positive control group using L-DOPA due to the double-blind design) from the upper back (around the neck and shoulders). Removed hair. Animals were re-shorn as necessary to maintain epidermal exposure throughout the course of the study. On the day of dosing, an aliquot (643 μL/kg) of the dosing formulation was administered to the animal in a 3 cm x 3 cm square (around the neck and shoulders) at approximately 9:00 am and repeated at approximately 4:00 pm.
Four. Four weeks after the lesion, the group began receiving treatment.
Five. A rotarod test will be performed 4 weeks after treatment.

Figure 5 shows the residence time results in the rotarod test described above after 4 weeks of treatment (n=12). Figure 6 shows the fall velocity results in the rotarod test described above after 4 weeks of treatment (n=12).
By pooling all batch data together (12 animals/group), the positive group (L-DOPA, 6 mg/kg, po) compared to the negative control group after 4 weeks of treatment. All test drug treatment groups showed greater efficacy than the vehicle group after 4 weeks of treatment. Because levodopa caused nausea, vomiting, gastrointestinal bleeding, and dyskinesias at peak doses and also resulted in end-of-dose decline in function, the positive group (L-DOPA, 6 mg/kg, orally) It showed no efficacy compared to the vehicle group. However, a prodrug of L-Dopa (Compound C) administered transdermally avoided dyskinesias at peak doses and end-of-dose decline in function. The efficacy of low doses of drug C (prodrug of L-Dopa, 0.67 mg/kg, group 3) is much greater than that of middle and high doses of drug C (2 mg and 6 mg/kg, groups 4 and 5). it was high. The results showed that the dose of transdermally administered prodrug of L-dopa was much lower than that of orally administered L-dopa. Drug D (prodrug of ibuprofen) at 15 mg and 45 mg/kg showed better efficacy than vehicle group and positive control group after 4 weeks of treatment. 15 mg of drug D (group 8) showed similar efficacy as 45 mg of drug D (group 11), so a dose of 15 mg/kg was sufficient and higher doses were not required. Administration of a combination of Drug C and Drug D (Group 6 and Group 9) to subjects performed much better than administration of either Drug D (Group 8 and 11) or Drug C (Group 3) alone.

Example 34. L-Dopa and ibuprofen prodrugs and 1.5 mg/kg on improving motor function deficits and reducing nigrostriatal neurodegeneration induced by 6-OHDA in Parkinson's disease (PD) model in HDB The potency of carbidopa.
Test subjects (Sprague-Dawley rats) were prepared as described in Example 31 and grouped and tested according to the following protocol.
1. The rats were divided into 11 groups (n=12), and drugs were administered to each group at the doses shown in Table 5 below.

Table 5. Doses and drugs administered to test animals

2. dosage prescription
(1) Both L-DOPA (3 mg/ml) and carbidopa (1.5 mg/ml) in water were used as positive control solutions for group 1 (oral). The dose volume was 2mL/kg. Carbidopa (1.5 mg/mL) in water was administered (orally) to groups 2 to 11 as an aromatic L-amino acid decarboxylase inhibitor, and the administration volume was 2 mL/kg. The vehicle solution (negative control solution for group 2) was 30% ethanol (v/v), and the dose volume was 1,286 μL/kg. Other test solutions (dermal, groups 3-11) were prepared fresh daily.
(2) Preparation method of test solution for groups 3 to 5: 50.33 mg of drug C was dissolved in 10 mL of 30% ethanol (v/v). This solution was the stock solution (2).
a. Preparation of drug C solution as test solution for group 5 (high dose group): Stock solution (2) was the test solution for group 5. The dose volume was 1,286 μL/kg;
b. Preparation of drug C solution as test solution for group 4 (medium dose group): 3.00 mL of stock solution (2) was diluted with 30% ethanol (v/v) to a final volume of 9.00 mL. This solution was the test solution for Group 4. The dose volume was 1,286 μL/kg;
c. Preparation of drug C solution as test solution for group 3 (low dose group): 1.00 mL of stock solution (2) was diluted with 30% ethanol (v/v) to a final volume of 9.00 mL. This solution was the test solution for Group 4. The dose volume was 1,286 μL/kg.
(3) Method for preparing test solution for group 6: 5.67 mg of drug C and 132 mg of drug D were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 6.
(4) Method for preparing test solution for group 7: 16.67 mg of drug C and 132 mg of drug D were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 7.
(5) Preparation method of test solution for group 8: 132 mg of drug D was dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 8.
(6) Method for preparing test solution for group 9: 5.67 mg of drug C and 395.5 mg of drug D were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 9.
(7) Method for preparing test solution for group 10: 16.67 mg of drug C and 395.5 mg of drug D were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 10.
(8) Preparation method of test solution for group 11: 395.5 mg of drug D was dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 11.

3． The day before the scheduled dosing, use small animal clippers to cut the animals (all rats, including those in the positive control group using L-DOPA due to the double-blind design) from the upper back (around the neck and shoulders). Removed hair. Animals were re-shorn as necessary to maintain epidermal exposure throughout the course of the study. On the day of dosing, an aliquot (643 μL/kg) of the dosing formulation was administered to the animal in a 3 cm x 3 cm square (around the neck and shoulders) at approximately 9:00 am and repeated at approximately 4:00 pm.
Four. Four weeks after the lesion, the group began receiving treatment.
Five. Rotarod test was performed 4 weeks after treatment.

Figure 7 shows the residence time results in the rotarod test described above after 4 weeks of treatment (n=12). Figure 8 shows the fall velocity results in the rotarod test described above after 4 weeks of treatment (n=12).
Carbidopa could reduce the peripheral DDC conversion of levodopa before it crosses the blood-brain barrier, thus reducing the side effects of L-Dopa. The results showed that carbidopa enhanced the efficacy of all L-Dopa and L-Dopa prodrug treatment groups (groups 1, 3, 4, 5, 6, 7, 9, 10), but the vehicle group and ibuprofen did not change the efficacy of the prodrug treatment groups (groups 2, 8 and 11).

Example 35. The effect of 4-(2-(((1-((1-pyrrolidine- 2-Carbonyl)oxy)ethoxy)amino)ethyl)-1,2,-phenylenedibenzoate hydrochloride (drug E) and 4-(dimethylamino)butyl 2-(3-phenoxyphenyl)propionate hydrochloride Efficacy of (drug F).
Test subjects (Sprague-Dawley rats) were prepared as described in Example 31 and grouped and tested according to the following protocol.
1. The rats were divided into 11 groups (n=12), and drugs were administered to each group at the doses shown in Table 6 below.

Table 6. Doses and drugs administered to test animals

2. dosage prescription
(1) L-DOPA (3 mg/ml) in water was a positive control solution for group 1 (oral for group 1). The dose volume was 2mL/kg. Vehicle solution (negative control solution for group 2) was 30% ethanol (v/v). The dose volume was 1,286 μL/kg. Other test solutions (groups 3-11) were prepared fresh daily.
(2) Preparation method of test solution for groups 3 to 5: 37.75 mg of drug E was dissolved in 10 mL of 30% ethanol (v/v). This solution was the stock solution (2).
a. Test solution for group 5 (high dose group) of drug E: Stock solution (2) was the test solution for group 5. The dose volume was 1,286 μL/kg;
b. Test solution for group 4 (medium dose group) of drug E: 3.00 mL of stock solution (2) was diluted with 30% ethanol (v/v) to a final volume of 9.00 mL. This solution was the test solution for Group 4. The dose volume was 1,286 μL/kg;
c. Test solution for Group 3 (low dose group) of drug E: 1.00 mL of stock solution (2) was diluted with 30% ethanol (v/v) to a final volume of 9.00 mL. This solution was the test solution for Group 3. The dose volume was 1,286 μL/kg.
(3) Method for preparing test solution for group 6: 4. 25 mg of drug E and 176 mg of drug E were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 6.
(4) Method for preparing test solution for group 7: 12.5 mg of drug E and 176 mg of drug E were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 7.
(5) Preparation method of test solution for group 8: 176 mg of drug E was dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 8.
(6) Method for preparing test solution for group 9: 4. 25 mg of drug E and 527 mg of drug E were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 9.
(7) Method for preparing test solution for group 10: 12.5 mg of drug E and 527 mg of drug E were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 10.
(8) Preparation method of test solution for group 11: 527 mg of drug E was dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 11.

3． The day before the scheduled dosing, use small animal clippers to cut the animal (all rats, including those in the positive control group using L-DOPA due to the double-blind design) from the upper back (around the neck and shoulders). Removed hair. Animals were re-shorn as necessary to maintain epidermal exposure throughout the course of the study. On the day of dosing, an aliquot (643 μL/kg) of the dosing formulation was administered to the animal in a 3 cm x 3 cm square (around the neck and shoulders) at approximately 9:00 am and repeated at approximately 4:00 pm.
Four. Four weeks after the lesion, the group began receiving treatment.
Five. Rotarod test was performed 4 weeks after treatment.

Figure 9 shows the residence time results in the rotarod test described above after 4 weeks of treatment (n=12). Figure 10 shows the fall velocity results in the rotarod test described above after 4 weeks of treatment (n=12).
By pooling all batch data together (12 animals/group), the positive group (L-DOPA, 6 mg/kg, po) showed no efficacy compared to the vehicle group after 4 weeks of treatment. Didn't show it. However, all study drug treatment groups showed stronger efficacy compared to the vehicle group after 4 weeks of treatment. Positive group (L-DOPA, 6 mg/kg, orally) because levodopa and dopamine caused nausea, vomiting, gastrointestinal bleeding, dyskinesia, and end-of-dose decline in function at peak doses. showed no efficacy compared to the vehicle group. However, prodrugs of dopamine administered transdermally avoided dyskinesias at peak doses and end-of-dose decline in function. The efficacy of a low dose of drug E (prodrug of dopamine, 0.5 mg/kg, group 3) is similar to that of intermediate and high doses of drug E (1.5 mg and 4.5 mg/kg, groups 4 and 5). higher doses of drug E may have caused even more side effects like L-dopa did. Drug F at 20 mg and 60 mg/kg showed better efficacy compared to vehicle group and positive control group after 4 weeks of treatment. 20 mg of drug F (group 8) showed similar efficacy as 60 mg of drug F (group 11). The results showed that a dose of 20 mg/kg was sufficient and higher doses were not necessary. Administration of a combination of Drug E and Drug F (Groups 6 and 9) to subjects performed much better than administration of either Drug F (Groups 8 and 11) or Drug E (Group 3) alone.
When administering a combination of multiple drugs (e.g., one or more HPPs and/or other drugs) to a subject, each drug can be administered separately, or one or more drugs can be administered substantially as separate drugs. can be administered simultaneously (e.g., the two or more drugs are sprayed substantially simultaneously without mixing before spraying), or the one or more drugs can be mixed together and then administered to the subject; or Combinations of any of the above methods of administration are also possible. Drugs can be administered in any possible order.

Example 36. The effect of drug G((S)-4-(2-amino- 3-(heptan-4-yloxy)-3-oxopropyl)-1,2-phenylenedibenzoate hydrochloride) and drug H(2-(dipropylamino)ethyl 4-acetoxy-2',4'- Test subjects (Sprague-Doli rats) were prepared as described in Example 31 and grouped according to the protocol below. was developed and tested.
1. The rats were divided into 11 groups (n=12), and drugs were administered to each group at the doses shown in Table 7 below.

Table 7. Doses and drugs administered to test animals

2. dosage prescription
(1) L-DOPA (3 mg/ml) in water was a positive control solution for group 1 (group 1), and the administration volume was 2 mL/kg. The vehicle solution (negative control solution for group 2) was 30% ethanol (v/v), and the dose volume was 1,286 μL/kg. Other test solutions (groups 3-11) were prepared fresh daily.
(2) Preparation method of test solution for groups 3 to 5: 50.33 mg of drug G was dissolved in 10 mL of 30% ethanol (v/v). This solution was the stock solution (2).
a. Test solution for group 5 (high dose group) of drug G: Stock solution (2) was the test solution for group 5. The dose volume was 1,286 μL/kg;
b. Test solution for group 4 (medium dose group) of drug G: 3.00 mL of stock solution (2) was diluted with 30% ethanol (v/v) to a final volume of 9.00 mL. This solution was the test solution for Group 4. The dose volume was 1,286 μL/kg;
c. Test solution for group 3 (low dose group) of drug G: 1.00 mL of stock solution (2) was diluted with 30% ethanol (v/v) to a final volume of 9.00 mL. This solution was the test solution for Group 3. The dose volume was 1,286 μL/kg.
(3) Method for preparing test solution for group 6: 5.67 mg of drug G and 132 mg of drug H were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 6.
(4) Method for preparing test solution for group 7: 16.67 mg of drug G and 132 mg of drug H were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 7.
(5) Method for preparing test solution for group 8: 132 mg of drug H was dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 8.
(6) Method for preparing test solution for group 9: 5.67 mg of drug G and 395.5 mg of drug H were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 9.
(7) Method for preparing test solution for group 10: 16.67 mg of drug G and 395.5 mg of drug H were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 10.
(8) Preparation method of test solution for group 11: 395.5 mg of drug H was dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 11.

3． The day before the scheduled dosing, use a small animal clipper to cut the animal (all rats, including those in the positive control group using L-DOPA due to the double-blind design) from the upper back (around the neck and shoulders). Removed hair. Animals were re-shorn as necessary to maintain epidermal exposure throughout the course of the study. On the day of dosing, an aliquot (643 μL/kg) of the dosing formulation was administered to the animal in a 3 cm x 3 cm square (around the neck and shoulders) at approximately 9:00 a.m. and repeated at approximately 4:00 p.m.
Four. Four weeks after the lesion, the group began receiving treatment.
Five. Rotarod test was performed 4 weeks after treatment.

Figure 11 shows the residence time results in the rotarod test described above after 4 weeks of treatment (n=12). Figure 12 shows the fall velocity results in the rotarod test described above after 4 weeks of treatment (n=12).
By pooling all batch data together (12 animals/group), the positive group (L-DOPA, 6 mg/kg, po) showed no efficacy compared to the vehicle group after 4 weeks of treatment. Didn't show it. However, all study drug treatment groups showed stronger efficacy compared to the vehicle group after 4 weeks of treatment. Because levodopa caused nausea, vomiting, gastrointestinal bleeding, dyskinesia, and end-of-dose decline in function at peak doses, the positive group (L-DOPA, 6 mg/kg, orally) received no vehicle treatment. showed no efficacy compared to the group. However, prodrugs of L-Dopa administered transdermally avoided dyskinesias at peak doses and end-of-dose decline in function. The efficacy of low doses of drug G (prodrug of L-Dopa, 0.67 mg/kg, group 3) is much greater than that of medium and high doses of drug G (2 mg and 6 mg/kg, groups 4 and 5). it was high. Higher doses may have caused side effects like L-dopa did. Drug H at 15 mg and 45 mg/kg showed better efficacy compared to vehicle group and positive control group after 4 weeks of treatment. 15 mg of drug H (group 8) showed similar efficacy as 45 mg of drug H (group 11). This suggested that a dose of 15 mg/kg was sufficient and higher doses were not necessary. Administration of the combination of drug G and drug H (groups 6 and 9) worked much better than administration of either drug H (groups 8 and 11) or drug G (group 3) alone.
When administering a combination of multiple drugs (e.g., one or more HPPs and/or other drugs) to a subject, each drug can be administered separately, or one or more drugs can be administered substantially as separate drugs. can be administered simultaneously (e.g., the two or more drugs are sprayed substantially simultaneously without mixing before spraying), or the one or more drugs can be mixed together and then administered to the subject; or Combinations of any of the above methods of administration are also possible. Drugs can be administered in any possible order.

Example 37. Drug A (transdermal), drug B (transdermal), and their effects on improving motor function defects and reducing nigrostriatal neurodegeneration induced by 6-OHDA in a Parkinson's disease (PD) model at HDB. and the efficacy of entacapone (oral).
Test subjects (Sprague-Dawley rats) were prepared as described in Example 31 and grouped and tested according to the following protocol.
1. The rats were divided into 11 groups (n=12), and drugs were administered to each group at the doses shown in Table 8 below.

Table 8. Doses and drugs administered to test animals

2. dosage prescription
(1) L-DOPA (3 mg/ml) and entacapone (12.5 mg/ml) in 0.5% CMC-Na (carboxymethylcellulose sodium salt) were positive controls for group 1 (oral). It was a solution, and the administration volume was 2 mL/kg. Entacapone (12.5 mg/ml) as a catechol-O-methyltransferase inhibitor in 0.5% CMC-Na was administered (orally) to groups 2-11, and the administration volume was 2 mL/kg. . The vehicle solution (negative control solution for group 2) was 30% ethanol (v/v) and the dose volume was 1,286 μL/kg. Other test solutions (dermal, groups 3-11) were prepared fresh daily.
(2) Preparation method of test solution for groups 3 to 5: 50.33 mg of drug A was dissolved in 10 mL of 30% ethanol (v/v). This solution was the stock solution (2).
a. Stock solution (2) was the test solution for drug A group 5 (high dose group). The dose volume was 1,286 μL/kg;
b. Test solution for Group 4 (medium dose group) of Drug A: 3.00 mL of stock solution (2) was diluted with 30% ethanol (v/v) to a final volume of 9.00 mL. This solution was the test solution for Group 4. The dose volume was 1,286 μL/kg;
c. Test solution for drug A group 3 (low dose group): 1.00 mL of stock solution (2) was diluted with 30% ethanol (v/v) to a final volume of 9.00 mL. This solution was the test solution for Group 4. The dose volume was 1,286 μL/kg.
(3) Method for preparing test solution for group 6: 5.67 mg of drug A and 264 mg of drug B were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for group 6;
(4) Method for preparing test solution for group 7: 16.67 mg of drug A and 264 mg of drug B were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for group 7;
(5) Preparation method of test solution for group 8: 264 mg of drug B was dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for group 8;
(6) Method for preparing test solution for group 9: 5.67 mg of drug A and 791 mg of drug B were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for group 9;
(7) Method for preparing test solution for group 10: 16.67 mg of drug A and 791 mg of drug B were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 10.
(8) Preparation method of test solution for group 11: 791 mg of drug B was dissolved in 10 mL of 30% ethanol (v/v). This solution was the Group 11 test solution.

3． The day before the scheduled dosing, use a small animal clipper to cut the animal (all rats, including those in the positive control group using L-DOPA due to the double-blind design) from the upper back (around the neck and shoulders). Removed hair. Animals were re-shorn as necessary to maintain epidermal exposure throughout the course of the study. On the day of dosing, an aliquot (643 μL/kg) of the dosing formulation was administered to the animal in a 3 cm x 3 cm square (around the neck and shoulders) at approximately 9:00 a.m. and repeated at approximately 4:00 p.m.
Four. Four weeks after the lesion, the group began receiving treatment.
Five. Rotarod test was performed 4 weeks after treatment.

Figure 13 shows the residence time results in the rotarod test described above after 4 weeks of treatment (n=12). Figure 14 shows the fall velocity results in the rotarod test described above after 4 weeks of treatment (n=12).
Entacapone is a catechol-O-methyltransferase inhibitor that prevents COMT from metabolizing L-DOPA in the periphery to 3-methoxy-4-hydroxy-L-phenylalanine. Avoid undesirable effects. The results show that entacapone enhances the efficacy of all L-Dopa and L-Dopa prodrug treatment groups (groups 1, 3, 4, 5, 6, 7, 9, 10), but not the vehicle group and aspirin. It was shown that the efficacy of the prodrug treatment groups (groups 2, 8 and 11) was not altered.
When administering a combination of multiple drugs (e.g., one or more HPPs and/or other drugs) to a subject, each drug can be administered separately, or one or more drugs can be administered substantially as separate drugs. can be administered simultaneously (e.g., the two or more drugs are sprayed substantially simultaneously without mixing before spraying), or the one or more drugs can be mixed together and then administered to the subject; or Combinations of any of the above methods of administration are also possible. Drugs can be administered in any possible order.

Example 38. Drug A (transdermal), drug B (transdermal), and their effects on improving motor function defects and reducing nigrostriatal neurodegeneration induced by 6-OHDA in a Parkinson's disease (PD) model at HDB. Efficacy of entacapone (oral) and carbidopa (oral).
Test subjects (Sprague-Dawley rats) were prepared as described in Example 31 and grouped and tested according to the following protocol.
1. The rats were divided into 11 groups (n=12), and drugs were administered to each group at the doses shown in Table 9 below.

Table 9. Doses and drugs administered to test animals

2. dosage prescription
(1) L-DOPA (3 mg/ml), entacapone (12.5 mg/ml), and carbidopa (1.5 mg/ml) in 0.5% CMC-Na were positive controls for group 1 (oral). The administration volume was 2 mL/kg. Entacapone (12.5 mg/ml) and carbidopa (1.5 mg/ml) in 0.5% CMC-Na were solutions for groups 2-11 (oral), and the dose volume was 2 ml/kg. . The vehicle solution (negative control solution for group 2) was 30% ethanol (v/v) and the dose volume was 1,286 μL/kg. Other test solutions (dermal, groups 3-11) were prepared fresh daily.
(2) Preparation method of test solution for groups 3 to 5: 50.33 mg of drug A was dissolved in 10 mL of 30% ethanol (v/v). This solution was the stock solution (2).
a. Stock solution (2) was the test solution for drug A group 5 (high dose group). The dose volume was 1,286 μL/kg;
b. Test solution for Group 4 (medium dose group) of Drug A: 3.00 mL of stock solution (2) was diluted with 30% ethanol (v/v) to a final volume of 9.00 mL. This solution was the test solution for Group 4. The dose volume was 1,286 μL/kg;
c. Test solution for drug A group 3 (low dose group): 1.00 mL of stock solution (2) was diluted with 30% ethanol (v/v) to a final volume of 9.00 mL. This solution was the test solution for Group 3. The dose volume was 1,286 μL/kg.
(3) Method for preparing test solution for group 6: 5.67 mg of drug A and 264 mg of drug B were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for group 6;
(4) Method for preparing test solution for group 7: 16.67 mg of drug A and 264 mg of drug B were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for group 7;
(5) Method for preparing test solution for group 8: 264 mg of drug B was dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for group 8;
(6) Method for preparing test solution for group 9: 5.67 mg of drug A and 791 mg of drug B were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for group 9;
(7) Method for preparing test solution for group 10: 16.67 mg of drug A and 791 mg of drug B were dissolved in 10 mL of 30% ethanol (v/v). This solution was the test solution for Group 10.
(8) Preparation method of test solution for group 11: 791 mg of drug B was dissolved in 10 mL of 30% ethanol (v/v). This solution was the Group 11 test solution.

3． The day before the scheduled dosing, use a small animal clipper to cut the animal (all rats, including those in the positive control group using L-DOPA due to the double-blind design) from the upper back (around the neck and shoulders). Removed hair. Animals were re-shorn as necessary to maintain epidermal exposure throughout the course of the study. On the day of dosing, an aliquot (643 μL/kg) of the dosing formulation was administered to the animal in a 3 cm x 3 cm square (around the neck and shoulders) at approximately 9:00 a.m. and repeated at approximately 4:00 p.m.
Four. Four weeks after the lesion, the group began receiving treatment.
Five. Rotarod test was performed 4 weeks after treatment.

Figure 15 shows the residence time results in the rotarod test described above after 4 weeks of treatment (n=12). Figure 16 shows the fall velocity results in the rotarod test described above after 4 weeks of treatment (n=12).
Administration of a combination of carbidopa and entacapone worked better than administration of either carbidopa or entacapone alone. This result shows that the combination of carbidopa and entacapone increases the efficacy of all L-Dopa and L-Dopa prodrug treatment groups (groups 1, 3, 4, 5, 6, 7, 9, 10), but vehicle group and aspirin prodrug treatment groups (groups 2, 8 and 11).
When administering a combination of multiple drugs (e.g., one or more HPP and/or other drugs) to a subject, each drug can be administered separately, or one or more drugs can be administered substantially as separate drugs. can be administered simultaneously (e.g., the two or more drugs are sprayed substantially simultaneously without mixing prior to spraying), or the one or more drugs can be mixed together and then administered to the subject; or Combinations of any of the above methods of administration are also possible. Drugs can be administered in any possible order.

Example 39. Treatment of Parkinson's disease and related conditions
A solution of 15 mg of drug A and 30 mg of drug B in 0.5 ml of water is administered to the skin of the subject's neck, chest, back, and any other area as needed every 3 to 10 hours (transdermal). do.
Example 40. Treatment of Parkinson's disease and related conditions
A solution of 10 mg of drug A and 20 mg of drug B in 0.5 ml of water is administered to the skin of the subject's neck, chest, back and any other area as needed every 3 to 10 hours (transdermal). do.
Example 41. Treatment of Parkinson's disease and related conditions
A solution of 20 mg of drug A and 40 mg of drug B in 0.5 ml of water is administered to the skin of the subject's neck, chest, back, and any other area as needed every 3 to 10 hours (transdermal). do.
Example 42. Treatment of Parkinson's disease and related conditions
A solution of 30 mg of drug A and 50 mg of drug B in 0.5 ml of water is administered to the skin of the subject's neck, chest, back, and any other area as needed every 3 to 10 hours (transdermal). do.
Example 43. Treatment of Parkinson's disease and related conditions
A solution of 15 mg of drug A and 30 mg of drug B in 0.5 ml of water is administered to the skin of the subject's neck, chest, back, and any other area as needed every 3 to 10 hours (transdermal). do. After or before administration of the above solution, tablets containing 10 mg of carbidopa and/or inactive ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulose, etc. It can be taken orally to enhance the efficacy of transdermal treatments.
Example 44. Treatment of Parkinson's disease and related conditions
A solution of 20 mg of drug A and 40 mg of drug B in 0.5 ml of water is administered to the skin of the subject's neck, chest, back, and any other area as needed every 3 to 10 hours (transdermal). do. After or before administration of the above solution, tablets containing 15 mg of carbidopa and/or inactive ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulose, etc. It can be taken orally to enhance the efficacy of transdermal treatments.
Example 45. Treatment of Parkinson's disease and related conditions
A solution of 15 mg of drug A and 30 mg of drug B in 0.5 ml of water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours. After or before administration of the above solution, add 15 mg of carbidopa, 70 mg of entacapone and/or inactive ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulose, etc. The tablet containing the drug is taken orally to enhance the efficacy of transdermal treatment.
Example 46. Treatment of Parkinson's disease and related conditions
A solution of 20 mg of drug A and 40 mg of drug B in 0.5 ml of water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours. After or before administration of the above solution, add 15 mg of carbidopa, 100 mg of entacapone and/or inactive ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose, etc. The tablet containing the drug is taken orally to enhance the efficacy of transdermal treatment.

Example 47. Treatment of Parkinson's disease and related conditions
A solution of 10 mg of drug C and 15 mg of drug D in 0.5 ml of water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours.
Example 49. Treatment of Parkinson's disease and related conditions
A solution of 30 mg of drug C and 30 mg of drug D in 0.5 ml of water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours.
Example 50. Treatment of Parkinson's disease and related conditions
A solution of 20 mg of drug C and 15 mg of drug D in 0.5 ml of water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours. After or before administration of the above solution, tablets containing 15 mg of carbidopa and/or inactive ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulose, etc. It can be taken orally to enhance the efficacy of transdermal treatments.
Example 51. Treatment of Parkinson's disease and related conditions
A solution of 10 mg of drug C and 10 mg of drug D in 0.5 ml of water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours. After or before administration of the above solution, add 15 mg of carbidopa, 100 mg of entacapone and/or inactive ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose, etc. The tablet containing the drug is taken orally to enhance the efficacy of transdermal treatment.
Example 52. Treatment of Parkinson's disease and related conditions
A solution of 30 mg of drug C and 20 mg of drug D in 0.5 ml of water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours. After or before administration of the above solution, add 15 mg of carbidopa, 70 mg of entacapone and/or inactive ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulose, etc. The tablet containing the drug is taken orally to enhance the efficacy of transdermal treatment.
Example 53. Treatment of Parkinson's disease and related conditions
A solution of 30 mg of drug C and 25 mg of drug D in 0.5 ml of water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours. After or before administration of the above solution, add 10 mg of carbidopa, 50 mg of entacapone and/or inactive ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulose, etc. The tablet containing the drug is taken orally to enhance the efficacy of transdermal treatment.

Example 54. Treatment of Parkinson's disease and related conditions
A solution of 10 mg of drug E and 10 mg of drug F in 0.5 ml of water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours.
Example 55. Treatment of Parkinson's disease and related conditions
A solution of 20 mg of drug E and 20 mg of drug F in 0.5 ml of water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours.
Example 56. Treatment of Parkinson's disease and related conditions
A solution of 5 mg of drug E and 10 mg of drug F in 0.5 ml of water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours.
Example 57. Treatment of Parkinson's disease and related conditions
A solution of 10 mg of drug G and 10 mg of drug H in 0.5 ml of water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours.
Example 58. Treatment of Parkinson's disease and related conditions
A solution of 15 mg of drug G and 15 mg of drug H in 0.5 ml of water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours.
Example 59. Treatment of Parkinson's disease and related conditions
A solution of 20 mg drug G and 15 mg drug H in 0.5 ml water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours.

Example 60. Treatment of Parkinson's disease and related conditions
A solution of 20 mg drug G and 15 mg drug H in 0.5 ml water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours. After or before administration of the above solution, add 10 mg of carbidopa, 70 mg of entacapone and/or inactive ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulose, etc. The tablet containing the drug is taken orally to enhance the efficacy of transdermal treatment.
Example 61. Treatment of Parkinson's disease and related conditions
A solution of 10 mg of drug G and 10 mg of drug H in 0.5 ml of water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours. After or before administration of the above solution, add 10 mg of carbidopa, 50 mg of entacapone and/or inactive ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulose, etc. The tablet containing the drug is taken orally to enhance the efficacy of transdermal treatment.

Example 62. Treatment of Parkinson's disease and related conditions
A solution of 20 mg drug G and 15 mg drug H in 0.5 ml water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours. After or before administration of the above solution, add 15 mg of carbidopa, 100 mg of entacapone and/or inactive ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose, etc. The tablet containing the drug is taken orally to enhance the efficacy of transdermal treatment.

から成る群より選択される構造（その立体異性体及び医薬的に許容できる塩を含めて）を含む化合物
（特定実施形態では、Wは下記構造W-1、構造W-2、構造W-3、構造W-4、構造W-5、構造W-6、構造W-7、構造W-8、構造W-9、構造W-10、構造W-11、構造W-12：

から成る群より選択され；
HAは、非存在、並びに医薬的に許容できる酸、例えば塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、重硫酸、リン酸、亜リン酸、ホスホン酸、イソニコチン酸、酢酸、乳酸、サリチル酸、クエン酸、酒石酸、パントテン酸、重酒石酸、アスコルビン酸、コハク酸、マレイン酸、ゲンチシン酸、フマル酸、グルコン酸、グルクロン酸、糖酸、ギ酸、安息香酸、グルタミン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸及びパモ酸から成る群より選択され；
Xは、O、S、及びNR ₃ から成る群より選択され；X ₂ は、非存在、O、S、NR ₃ 、CHR ₃ -O、CHR ₃ -S、CHR ₃ -O、O-CHR ₃ -O、O-CHR ₃ -S、S-CHR ₃ -O、及びS-CHR ₃ -Sから成る群より選択され；X ₃ は、非存在、C=O、C=S、C(=O)-O、O、S、NR ₃ 、C(=O)-O-CHR ₃ -O、C(=O)-O-CHR ₃ -S、C(=O)-S-CHR ₃ -O、及びC(=O)-S-CHR ₃ -Sから成る群より選択され；Y ₁ は、R ₃ C(=O)、R ₃ O-C(=O)、及びR ₃ S-C(=O)から成る群より選択され；Y ₂ は、R ₃ C(=O)、R ₃ O-C(=O)、及びR ₃ S-C(=O)から成る群より選択され；Y ₃ は、R ₃ 、OR ₃ 、SR ₃ 、NR ₃ R ₄ 、O-CHR ₃ -OR ₄ 、O-CHR ₃ -SR ₄ 、S-CHR ₃ -OR ₄ から成る群より選択され；
n及びmは、0、1、2、3、4、5、6、7、及び8から成る群より選択される。
Rcは、非存在、CH ₂ C(=O)OR _6、 置換及び無置換アルキル、置換及び無置換シクロアルキル、置換及び無置換ヘテロシクロアルキル、置換及び無置換アルコキシル、置換及び無置換ペルフルオロアルキル、置換及び無置換アルキルハライド、置換及び無置換アルケニル、置換及び無置換アルキニル、置換及び無置換アリール、並びに置換及び無置換ヘテロアリールから成る群より選択され、ここで、R中のいずれのCH ₂ もさらにO、S、P、NR ₆ 、又はいずれの他の医薬的に許容できる基と置き換わっていてもよく；
Rは、非存在、CH ₂ C(=O)OR ₆ 、置換及び無置換アルキル、置換及び無置換シクロアルキル、置換及び無置換ヘテロシクロアルキル、置換及び無置換アルコキシル、置換及び無置換ペルフルオロアルキル、置換及び無置換アルキルハライド、置換及び無置換アルケニル、置換及び無置換アルキニル、置換及び無置換アリール、並びに置換及び無置換ヘテロアリールから成る群より選択され、ここで、R中のいずれのCH ₂ もさらにO、S、P、NR ₆ 、又はいずれの他の医薬的に許容できる基と置き換わっていてもよく；
R ₃ 及びR ₄ は、非存在、CH ₂ C(=O)OR ₆ 、置換及び無置換アルキル、置換及び無置換シクロアルキル、置換及び無置換ヘテロシクロアルキル、置換及び無置換アルコキシル、置換及び無置換ペルフルオロアルキル、置換及び無置換アルキルハライド、置換及び無置換アルケニル、置換及び無置換アルキニル、置換及び無置換アリール、並びに置換及び無置換ヘテロアリールから成る群より選択され、ここで、R中のいずれのCH ₂ もさらにO、S、P、NR ₆ 、又はいずれの他の医薬的に許容できる基と置き換わっていてもよく；
各R ₆ は、独立に、H、F、Cl、Br、I、Na ⁺ 、K ⁺ 、C(=O)R _5、 2-オキソ-1-イミダゾリジニル、フェニル、5-インダニル、2,3-ジヒドロ-1H-インデン-5-イル、4-ヒドロキシ-1,5-ナフチリジン-3-イル、置換及び無置換アルキル、置換及び無置換シクロアルキル、置換及び無置換ヘテロシクロアルキル、置換及び無置換アルケニル、置換及び無置換アルキニル、置換及び無置換アルキルオキシル、置換及び無置換シクロアルキルオキシル、置換及び無置換アリール、置換及び無置換ヘテロアリール、-C(=O)-W、-L ₁ -L ₄ -L ₂ -W、及びWから成る群より選択され；
各R ₅ は、独立に、H、C(=O)NH ₂ 、CH ₂ CH ₂ OR _6、 CH ₂ CH ₂ N(CH ₃ ) ₂ 、CH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ 、Cl、F、Br、I、置換及び無置換アルキル、置換及び無置換シクロアルキル、置換及び無置換ヘテロシクロアルキル、置換及び無置換アルキルオキシル、置換及び無置換シクロアルキルオキシル、置換及び無置換アリール、置換及び無置換ヘテロアリール、置換及び無置換アルキルカルボニル、置換及び無置換アルキルアミノ、-C(=O)-W、L ₁ -L ₄ -L ₂ -W、及びWから成る群より選択され；
L ₁ は、非存在、O、S、-O-L ₃ -、-S-L ₃ -、-N(L ₃ )-、-N(L ₃ )-CH ₂ -O、-N(L ₃ )-CH ₂ -N(L ₅ )-、-O-CH ₂ -O-、-O-CH(L ₃ )-O、及び-S-CH(L ₃ )-O-から成る群より選択され；
L ₂ は、非存在、O、S、-O-L ₃ -、-S-L ₃ -、-N(L ₃ )-、-N(L ₃ )-CH ₂ -O、-N(L ₃ )-CH ₂ -N(L ₅ )-、-O-CH ₂ -O-、-O-CH(L ₃ )-O、-S-CH(L ₃ )-O-、-O-L ₃ -、-N-L ₃ -、-S-L ₃ -、-N(L ₃ )-L ₅ -及びL ₃

から成る群より選択され；
L ₄ は、非存在、C=O、C=S、

から成る群より選択され；
各L ₁ 、L ₂ 、及びL ₄ について、各L ₃ 及びL ₅ は、独立に、非存在、H、CH ₂ C(=O)OL ₆ 、置換及び無置換アルキル、置換及び無置換シクロアルキル、置換及び無置換ヘテロシクロアルキル、置換及び無置換アリール、置換及び無置換ヘテロアリール、置換及び無置換アルコキシル、置換及び無置換アルキルチオ、置換及び無置換アルキルアミノ、置換及び無置換ペルフルオロアルキル、並びに置換及び無置換アルキルハライドから成る群より選択され、ここで、いずれの炭素又は水素もさらに、独立に、O、S、P、NL ₃ 、又はいずれの他の医薬的に許容できる基と置き換わっていてもよく；
各L ₆ は、独立に、H、OH、Cl、F、Br、I、置換及び無置換アルキル、置換及び無置換シクロアルキル、並びに置換及び無置換ヘテロシクロアルキル、置換及び無置換アリール、置換及び無置換ヘテロアリール、置換及び無置換アルコキシル、置換及び無置換アルキルチオ、置換及び無置換アルキルアミノ、置換及び無置換ペルフルオロアルキル、並びに置換及び無置換アルキルハライドから成る群より選択され、ここで、いずれの炭素又は水素もさらに、独立に、O、S、N、P(O)OL ₆ 、CH=CH、C≡C、CHL ₆ 、CL ₆ L ₇ 、アリール、ヘテロアリール、又は環式基と置き換わっていてもよく；
各L ₇ は、独立に、H、OH、Cl、F、Br、I、置換及び無置換アルキル、置換及び無置換シクロアルキル、並びに置換及び無置換ヘテロシクロアルキル、置換及び無置換アリール、置換及び無置換ヘテロアリール、置換及び無置換アルコキシル、置換及び無置換アルキルチオ、置換及び無置換アルキルアミノ、置換及び無置換ペルフルオロアルキル、並びに置換及び無置換アルキルハライドから成る群より選択され、ここで、いずれの炭素又は水素もさらに、独立に、O、S、N、P(O)OL ₆ 、CH=CH、C≡C、CHL ₆ 、CL ₆ L ₇ 、アリール、ヘテロアリール、又は環式基と置き換わっていてもよく；
Wは、H、置換及び無置換アルキル、置換及び無置換シクロアルキル、置換及び無置換ヘテロシクロアルキル、置換及び無置換アルキルオキシ、置換及び無置換アルケニル、置換及び無置換アルキニル、置換及び無置換アリール、置換及び無置換ヘテロアリール、プロトン化可能アミン基、医薬的に許容できる置換及び無置換アミン基、構造Wa、構造W-1、構造W-2、構造W-3、構造W-4、構造W-5、構造W-6、構造W-7、構造W-8、構造W-9、構造W-10、構造W-11、構造W-12、構造W-13、構造W-14、構造W-15、構造W-16、構造W-17及び構造W-18から成る群より選択され；
R ₁ 及びR ₂ は、独立に、H、置換及び無置換アルキル、置換及び無置換シクロアルキル、置換及び無置換ヘテロシクロアルキル、置換及び無置換アルキルオキシル、置換及び無置換アルケニル、置換及び無置換アルキニル、置換及び無置換アリール、並びに置換及び無置換ヘテロアリール残基から成る群より選択され；
R ₁₁ ～R ₁₅ は、独立に、非存在、H、CH ₂ C(=O)OR _11、 置換及び無置換アルキル、置換及び無置換シクロアルキル、置換及び無置換ヘテロシクロアルキル、置換及び無置換アルコキシル、置換及び無置換ペルフルオロアルキル、置換及び無置換アルキルハライド、置換及び無置換アルケニル、置換及び無置換アルキニル、置換及び無置換アリール、並びに置換及び無置換ヘテロアリールから成る群より選択される）。
〔２〕前記〔1〕に記載の高透過プロドラッグ；構造NSAID-1、構造NSAID-2、構造NSAID-3、構造NSAID-4、構造NSAID-5、構造NSAID-6、構造NSAID-7、構造NSAID-8、構造NSAID-9、構造NSAID-10、構造NSAID-11、構造NSAID-12、及び構造NSAID-13から成る群より選択される構造を含む化合物；カルビドパ、ベンセラジド、ジフルオロメチルドパ、及びα-メチルドパから成る群より選択される芳香族L-アミノ酸脱炭酸酵素阻害薬；エンタカポン及びトルカポンから成る群より選択されるカテコール-O-メチル転移酵素阻害薬；並びに医薬的に許容できる担体を含む医薬組成物。
〔３〕前記医薬的に許容できる担体が、アルコール、アセトン、エステル、セルロース、マンニトール、クロスカルメロースナトリウム、植物油、ヒドロキシプロピルメチルセルロース、水、及び水溶液から成る群より選択される、前記〔2〕に記載の医薬組成物。
〔４〕レボドパ、ドパミン、アスピリン及び他の非ステロイド系抗炎症薬(NSAID)、並びにその任意の組み合わせの1種以上の高透過プロドラッグを含む医薬組成物。
〔５〕レボドパ、ドパミン、アスピリン及び他の非ステロイド系抗炎症薬(NSAID)、並びにその任意の組み合わせの高透過プロドラッグを含む、パーキンソン病及び関連状態の治療のための、経皮投与される医薬組成物であって、それに加えて、カルビドパ、ベンセラジド、ジフルオロメチルドパ、α-メチルドパ、他の芳香族L-アミノ酸脱炭酸酵素阻害薬、エンタカポン、トルカポン及び／又は他のカテコール-O-メチル転移酵素阻害薬を含有する経口投与される錠剤を含んでなる医薬組成物。
〔６〕4-(2-(2-(メチルアミノ)アセトアミド)エチル)-1,2,-フェニレンジベンゾアート塩酸塩、4-(2-(2-(メチルアミノ)アセトアミド)エチル)-1,2,-フェニレンジベンゾアート酢酸、4-(6-メチル-4,8-ジオキソ-5,7-ジオキサ-2,9-ジアザデカン-11-イル)-1,2,-フェニレンジベンゾアート臭化水素酸塩、4-(2-(2-アミノ-3-フェニルプロパンアミド)エチル)-1,2,-フェニレンジベンゾアート塩酸塩、4-(2-(((1-((ピロリジン-2-カルボニル)オキシ)エトキシ)アミノ)エチル)-1,2,-フェニレンジベンゾアート塩酸塩、4-(2-ピペリジン-4-カルボキサミド)エチル)-1,2,-フェニレンビス(2-エチルブタノアート)塩酸塩、4-(2-((((-オクタヒドロ-1H-キノリジン-3-イル)オキシ)カルボニル)アミノ)エチル)-1,2,-フェニレンビス(2-エチルブタノアート)アセタート、1-(((2-(4-アミノ-2,5-ジオキソ-2,3,4,5-テトラヒドロベンゾ[b][1,4]ジオキソシン-8-イル)エチル)カルバモイル)オキシ)エチルイソブチラートフッ化水素酸塩、1-(((2-(3-アミノ-2,5-ジオキソ-2,3,4,5-テトラヒドロベンゾ[b][1,4]ジオキソシン-8-イル)エチル)カルバモイル)オキシ)エチルイソブチラートフッ化水素酸塩、(-(2-((エトキシカルボニル)アミノ)エチル)-2-(2-メチルアミノ)アセトキシ)フェニルベンゾアート塩酸塩、5-(2-((エトキシカルボニル)アミノ)エチル)-2-(2-メチルアミノ)アセトキシ)フェニルベンゾアート塩酸塩、4-(2-アミノエチル)-1,2-フェニレンジベンゾアート塩酸塩、(S)-4-(2-アミノ-3-イソプロポキシ-3-オキソプロピル)-1,2-フェニレンジベンゾアート塩酸塩、(S)-4-(2-アミノ-3-(ヘプタン-4-イルオキシ)-3-オキソプロピル)-1,2-フェニレンジベンゾアート塩酸塩、(S)-4-(2-アミノ-3-イソプロポキシ-3-オキソプロピル)-1,2-フェニレンジペンタノアート塩酸塩、(S)-4-(2-アミノ-3-エトキシ-3-オキソプロピル)-1,2-フェニレンジアセタート塩酸塩、(S)-4-(2-アミノ-3-オキソ-3-(ペンタン-3-イルオキシ)プロピル)-1,2-フェニレンビス(2-メチルプロパノアート)臭化水素酸塩、(S)-4-(2-アミノアセトアミド)-3-イソプロポキシ-3-オキソプロピル)-1,2-フェニレンジベンゾアート塩酸塩、4-((2S)-3-オキソ-3-(ペンタン-3-イルオキシ)-2-(ピロリジン-2-カルボキサミド)プロピル)-1,2-フェニレンジベンゾアートフッ化水素酸塩、(S)-4-(3-イソプロポキシ-3-オキソ-2-(ピペリジン-4-カルボキサミド)プロピル)-1,2-フェニレンジベンゾアート塩酸塩、4-((2S)-3-イソプロポキシ-3-2-(オクタヒドロ-1H-キノリジン-2-カルボキサミド)-3-オキソプロピル)-1,2-フェニレンビス(2-メチルプロパノアート)塩酸塩、(2S)-イソプロピル3-(3-アミノ-2,5-ジオキソ-2,3,4,5-テトラヒドロベンゾ[b][1,4]ジオキソシン-8-イル)-2-(((1-(イソブチリルオキシ)エトキシ)カルボニル)アミノ)プロパノアート臭化水素酸塩、(2S)-イソプロピル3-(4-アミノ-2,5-ジオキソ-2,3,4,5-テトラヒドロベンゾ[b][1,4]ジオキソシン-8-イル)-2-(((1-(イソブチリルオキシ)エトキシ)カルボニル)アミノ)プロパノアート臭化水素酸塩、5-((2S)-2-(((1-(イソブチリルオキシ)エトキシ)カルボニル)アミノ-3-イソプロポキシ-3-オキソプロピル)-2-(2-(メチルアミノ)アセトキシ)フェニルベンゾアート塩酸塩、4-((2S)-2-(((1-(イソブチリルオキシ)エトキシ)カルボニル)アミノ-3-イソプロポキシ-3-オキソプロピル)-2-(2-(メチルアミノ)アセトキシ)フェニルベンゾアート塩酸塩、4-((2S)-3-イソプロポキシ-2-((((オクタヒドロインドリジン-1-イル)オキシ)カルボニル)アミノ)-3-オキソプロピル)-1,2-フェニレンジベンゾアートアセタート、2-(ジエチルアミノ)エチル2-[(2,6-ジクロロ-3-メチルフェニル)アミノ]ベンゾアート.アセタート、(Z)-2-(ジエチルアミノエチル)エチル2-(5-フルオロ-2-メチル-1-(4-メチルスルフィニル)ベンジリデン)-1H-インデン-1-イル)アセタート.AcOH、2-(ジメチルアミノ)エチル2-(3-フェノキシフェニル)プロピオナート.塩酸塩、S-(2-(ジメチルアミノ)エチル2-(3-フェノキシフェニル)プロパンチオアート塩酸塩、2-(ジプロピルアミノ)エチル4-アセトキシ-2’,4’-ジフルオロ-[1,1’-ビフェニル]-3-カルボキシラート塩酸塩、2-(ジエチルアミノ)エチル2-(4-イソブチルフェニル)プロピオナート塩酸塩、及び／又は2-(ジエチルアミノ)エチル2-アセトキシベンゾアート.塩酸塩を含む、パーキンソン病及び関連状態の治療のための、経皮投与される医薬組成物。
〔７〕(S)-4-(2-アミノ-3-イソプロポキシ-3-オキソプロピル)-1,2-フェニレンジベンゾアート及び2-(ジエチルアミノ)エチル2-アセトキシベンゾアートを含む、パーキンソン病及び関連状態の治療のための医薬組成物。
〔８〕(S)-4-(2-アミノ-3-イソプロポキシ-3-オキソプロピル)-1,2-フェニレンジベンゾアート、2-(ジエチルアミノ)エチル2-アセトキシベンゾアート、カルビドパ及び／又はエンタカポンを含む、パーキンソン病及び関連状態の治療のための医薬組成物。
〔９〕(S)-4-(2-アミノ-3-オキソ-3-(ペンタン-3-イルオキシ)プロピル)-1,2-フェニレンビス(2-メチルプロパノアート)及び2-(ジエチルアミノ)エチル2-(4-イソブチルフェニル)プロピオナートを含む、パーキンソン病及び関連状態の治療のための医薬組成物。
〔１０〕4-(2-(((1-((ピロリジン-2-カルボニル)オキシ)エトキシ)アミノ)エチル)-1,2,-フェニレンジベンゾアート及び4-(ジメチルアミノ)ブチル2-(3-フェノキシフェニル)プロピオナートを含む、パーキンソン病及び関連状態の治療のための医薬組成物。
〔１１〕(S)-4-(2-アミノ-3-オキソ-3-(ペンタン-3-イルオキシ)プロピル)-1,2-フェニレンビス(2-メチルプロパノアート)、2-(ジエチルアミノ)エチル2-(4-イソブチルフェニル)プロピオナート、カルビドパ及び／又はエンタカポンを含む、パーキンソン病及び関連状態の治療のための医薬組成物。
〔１２〕(S)-4-(2-アミノ-3-(ヘプタン-4-イルオキシ)-3-オキソプロピル)-1,2-フェニレンジベンゾアート、及び2-(ジプロピルアミノ)エチル4-アセトキシ-2’,4’-ジフルオロ-[1,1’-ビフェニル]-3-カルボキシラートを含む、パーキンソン病及び関連状態の治療のための医薬組成物。
〔１３〕(S)-4-(2-アミノ-3-(ヘプタン-4-イルオキシ)-3-オキソプロピル)-1,2-フェニレンジベンゾアート、及び2-(ジプロピルアミノ)エチル 4-アセトキシ-2’,4’-ジフルオロ-[1,1’-ビフェニル]-3-カルボキシラート、カルビドパ及び／又はエンタカポンを含む、パーキンソン病及び関連状態の治療のための医薬組成物。
〔１４〕対象のパーキンソン病の治療方法であって、前記〔2〕～〔13〕のいずれか1項に記載の医薬組成物を経皮投与する工程；並びにカルビドパ、ベンセラジド、ジフルオロメチルドパ、及びα-メチルドパから成る群より選択される芳香族L-アミノ酸脱炭酸酵素阻害薬；並びに／又はエンタカポン及びトルカポンから成る群より選択されるカテコール-O-メチル転移酵素阻害薬；又はその医薬組成物を経口投与する工程を含む方法。
Example 62. Treatment of Parkinson's disease and related conditions
A solution of 20 mg of drug G and 15 mg of drug H in 0.5 ml of water is administered (transdermally) to the skin of the subject's neck, chest, back and any other area every 3 to 10 hours. After or before administration of the above solution, add 15 mg of carbidopa, 100 mg of entacapone and/or inactive ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulose, etc. The tablet containing the drug is taken orally to enhance the efficacy of transdermal treatment.
Another aspect of the present invention may be as follows.
[1] The following structure Pro-L-Dopa-1, structure Pro-L-Dopa-2, structure Pro-L-Dopa-3, structure Pro-L-Dopa-4, structure Pro-L-Dopa-5, structure Pro-dopamine-1, structure Pro-dopamine-2, structure Pro-dopamine-3, structure Pro-dopamine-4, and structure Pro-dopamine-5:

A compound comprising a structure selected from the group consisting of (including stereoisomers and pharmaceutically acceptable salts thereof)
(In certain embodiments, W is the following Structure W-1, Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, structure W-10, structure W-11, structure W-12:

selected from the group consisting of;
HA is present in the absence and presence of pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, bisulfuric acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, Lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucuronic acid, sugar acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, selected from the group consisting of ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and pamoic acid;
X is selected from the group consisting of O, S, and NR3; X2 _{is absent} , O, S, NR3 _, CHR3 _- O, CHR3 -S, CHR3 _{- O} , O- _CHR3 selected from the group consisting of -O, O-CHR ₃ -S, S-CHR ₃ -O, and S-CHR ₃ -S; X ₃ is absent, C=O, C=S, C(=O )-O, O, S, NR ₃ , C(=O)-O-CHR ₃ -O, C(=O)-O-CHR ₃ -S, C(=O)-S-CHR ₃ -O, and C(=O)-S-CHR ₃ -S; Y ₁ consists of R ₃ C(=O), R ₃ OC(=O), and R ₃ SC(=O) Y ₂ is selected from the group consisting of R ₃ C(=O), R ₃ OC(=O), and R ₃ SC(=O); Y ₃ is selected from the group consisting of R ₃ , OR ₃ , selected from the group consisting of _{SR3 ,} NR3R4 , _O - CHR3 _- OR4 , O-CHR3 _- SR4 _, S- _CHR3 - _{OR4 ;}
n and m are selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8.
Rc is absent, CH2C ₍ =O)OR6 _, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, selected from the group consisting of substituted and unsubstituted alkyl halides, substituted and unsubstituted alkenyls, substituted and unsubstituted alkynyls, substituted and unsubstituted aryls, and substituted and unsubstituted heteroaryls, where any CH 2 _in R further substituted with O, S, P, NR6 _, or any other pharmaceutically acceptable group;
R is absent, CH ₂ C(=O)OR ₆ , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, selected from the group consisting of substituted and unsubstituted alkyl halides, substituted and unsubstituted alkenyls, substituted and unsubstituted alkynyls, substituted and unsubstituted aryls, and substituted and unsubstituted heteroaryls, where any CH 2 _in R further substituted with O, S, P, NR6 _, or any other pharmaceutically acceptable group;
R ₃ and R ₄ are absent, CH ₂ C(=O)OR ₆ , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted selected from the group consisting of substituted perfluoroalkyl, substituted and unsubstituted alkyl halides, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, where any of R CH2 may also be further replaced with O, S, P, NR6, or any other pharmaceutically _acceptable group _;
Each R ₆ is independently H, F, Cl, Br, I, Na ⁺ , K ⁺ , C(=O)R _5, 2-oxo-1-imidazolidinyl, phenyl, 5-indanyl, 2,3- Dihydro-1H-inden-5-yl, 4-hydroxy-1,5-naphthyridin-3-yl, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkenyl , substituted and unsubstituted alkynyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, -C(=O)-W, -L ₁ -L ₄ selected from the group consisting of -L ₂ -W, and W;
Each R ₅ is independently H, C(=O)NH ₂ , CH ₂ CH ₂ OR _6, CH ₂ CH ₂ N(CH ₃ ) ₂ , CH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ , Cl , F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, -C(=O)-W, L1 _- L4 _- L2 _- W, and W;
L ₁ is absent, O, S, -OL ₃ -, -SL ₃ -, -N(L ₃ )-, -N(L ₃ )-CH ₂ -O, -N(L ₃ )-CH ₂ selected from the group consisting of -N(L5 ₎ -, -O-CH2 _- O-, -O-CH(L3 ₎ -O, and -S-CH(L3 ₎ -O-;
L ₂ is absent, O, S, -OL ₃ -, -SL ₃ -, -N(L ₃ )-, -N(L ₃ )-CH ₂ -O, -N(L ₃ )-CH ₂ -N(L ₅ )-, -O-CH ₂ -O-, -O-CH(L ₃ )-O, -S-CH(L ₃ )-O-, -OL ₃ -, -NL ₃ -, -SL ₃ -, -N(L ₃ )-L ₅ - and L ₃

selected from the group consisting of;
L ₄ is absent, C=O, C=S,

selected from the group consisting of;
For each L ₁ , L ₂ , and L ₄ , each L ₃ and L ₅ are independently absent, H, CH ₂ C(=O)OL ₆ , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl , substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halides, wherein any carbon or hydrogen is further independently replaced with O, S, P, NL3 _, or any other pharmaceutically acceptable group. Also well;
Each L ₆ is independently H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and selected from the group consisting of unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halides; Carbon or hydrogen may also be independently substituted with O, S, N, P(O)OL6, CH=CH, C≡C, CHL6, CL6L7, aryl, heteroaryl _{, or} a _cyclic group _. It's good;
Each L ₇ is independently H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and selected from the group consisting of unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halides; Carbon or hydrogen may also be independently substituted with O, S, N, P(O)OL6, CH=CH, C≡C, CHL6, CL6L7, aryl, heteroaryl _{, or} a _cyclic group _. It's good;
W is H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl , substituted and unsubstituted heteroaryl, protonatable amine group, pharmaceutically acceptable substituted and unsubstituted amine group, structure Wa, structure W-1, structure W-2, structure W-3, structure W-4, structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11, Structure W-12, Structure W-13, Structure W-14, Structure selected from the group consisting of W-15, Structure W-16, Structure W-17, and Structure W-18;
R ₁ and R ₂ are independently H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted selected from the group consisting of alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues;
R ₁₁ to R ₁₅ are independently absent, H, CH ₂ C(=O)OR _11, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halides, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl).
[2] Highly permeable prodrug according to [1] above; structure NSAID-1, structure NSAID-2, structure NSAID-3, structure NSAID-4, structure NSAID-5, structure NSAID-6, structure NSAID-7, A compound comprising a structure selected from the group consisting of structure NSAID-8, structure NSAID-9, structure NSAID-10, structure NSAID-11, structure NSAID-12, and structure NSAID-13; carbidopa, benserazide, difluoromethyldopa, and an aromatic L-amino acid decarboxylase inhibitor selected from the group consisting of α-methyldopa; a catechol-O-methyltransferase inhibitor selected from the group consisting of entacapone and tolcapone; and a pharmaceutically acceptable carrier. Pharmaceutical composition.
[3] In the above [2], the pharmaceutically acceptable carrier is selected from the group consisting of alcohol, acetone, ester, cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulose, water, and an aqueous solution. Pharmaceutical compositions as described.
[4] A pharmaceutical composition comprising one or more highly permeable prodrugs of levodopa, dopamine, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and any combination thereof.
[5] Transdermally administered, highly permeable prodrugs of levodopa, dopamine, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and any combination thereof, for the treatment of Parkinson's disease and related conditions. A pharmaceutical composition comprising, in addition, carbidopa, benserazide, difluoromethyldopa, alpha-methyldopa, other aromatic L-amino acid decarboxylase inhibitors, entacapone, tolcapone and/or other catechol-O-methyltransferases. A pharmaceutical composition comprising an orally administered tablet containing an inhibitor.
[6] 4-(2-(2-(methylamino)acetamido)ethyl)-1,2,-phenylene dibenzoate hydrochloride, 4-(2-(2-(methylamino)acetamido)ethyl)-1, 2,-phenylene dibenzoate acetic acid, 4-(6-methyl-4,8-dioxo-5,7-dioxa-2,9-diazadecane-11-yl)-1,2,-phenylene dibenzoate hydrobromide Salt, 4-(2-(2-amino-3-phenylpropanamido)ethyl)-1,2,-phenylenedibenzoate hydrochloride, 4-(2-(((1-((pyrrolidine-2-carbonyl) oxy)ethoxy)amino)ethyl)-1,2,-phenylene dibenzoate hydrochloride, 4-(2-piperidine-4-carboxamido)ethyl)-1,2,-phenylenebis(2-ethylbutanoate) hydrochloride Salt, 4-(2-(((-octahydro-1H-quinolidin-3-yl)oxy)carbonyl)amino)ethyl)-1,2,-phenylenebis(2-ethylbutanoate)acetate, 1- (((2-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)ethyl)carbamoyl)oxy)ethylisobutyrate Hydrofluoride, 1-(((2-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)ethyl) Carbamoyl)oxy)ethylisobutyrate hydrofluoride, (-(2-((ethoxycarbonyl)amino)ethyl)-2-(2-methylamino)acetoxy)phenylbenzoate hydrochloride, 5-(2- ((ethoxycarbonyl)amino)ethyl)-2-(2-methylamino)acetoxy)phenylbenzoate hydrochloride, 4-(2-aminoethyl)-1,2-phenylenedibenzoate hydrochloride, (S)-4 -(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylenedibenzoate hydrochloride, (S)-4-(2-amino-3-(heptan-4-yloxy)-3- oxopropyl)-1,2-phenylene dibenzoate hydrochloride, (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylene dipentanoate hydrochloride, (S) )-4-(2-amino-3-ethoxy-3-oxopropyl)-1,2-phenylene diacetate hydrochloride, (S)-4-(2-amino-3-oxo-3-(pentane- (3-yloxy)propyl)-1,2-phenylenebis(2-methylpropanoate) hydrobromide, (S)-4-(2-aminoacetamido)-3-isopropoxy-3-oxopropyl) -1,2-phenylene dibenzoate hydrochloride, 4-((2S)-3-oxo-3-(pentan-3-yloxy)-2-(pyrrolidine-2-carboxamido)propyl)-1,2-phenylene dibenzo ate hydrofluoride, (S)-4-(3-isopropoxy-3-oxo-2-(piperidine-4-carboxamido)propyl)-1,2-phenylenedibenzoate hydrochloride, 4-((2S )-3-isopropoxy-3-2-(octahydro-1H-quinolidine-2-carboxamide)-3-oxopropyl)-1,2-phenylenebis(2-methylpropanoate) hydrochloride, (2S)- Isopropyl 3-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)-2-(((1-(isobutyryl) Oxy)ethoxy)carbonyl)amino)propanoate hydrobromide, (2S)-isopropyl 3-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4 ]dioxocin-8-yl)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)propanoate hydrobromide, 5-((2S)-2-(((1-(isobutyryloxy)ethoxy)carbonyl) butyryloxy)ethoxy)carbonyl)amino-3-isopropoxy-3-oxopropyl)-2-(2-(methylamino)acetoxy)phenylbenzoate hydrochloride, 4-((2S)-2-((( 1-(isobutyryloxy)ethoxy)carbonyl)amino-3-isopropoxy-3-oxopropyl)-2-(2-(methylamino)acetoxy)phenylbenzoate hydrochloride, 4-((2S)-3 -isopropoxy-2-((((octahydroindolizin-1-yl)oxy)carbonyl)amino)-3-oxopropyl)-1,2-phenylene dibenzoate acetate, 2-(diethylamino)ethyl 2- [(2,6-dichloro-3-methylphenyl)amino]benzoate acetate, (Z)-2-(diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl) benzylidene)-1H-inden-1-yl)acetate.AcOH, 2-(dimethylamino)ethyl 2-(3-phenoxyphenyl)propionate.hydrochloride, S-(2-(dimethylamino)ethyl 2-(3- Phenoxyphenyl)propanethioate hydrochloride, 2-(dipropylamino)ethyl 4-acetoxy-2',4'-difluoro-[1,1'-biphenyl]-3-carboxylate hydrochloride, 2-(diethylamino) Dermally administered medicaments for the treatment of Parkinson's disease and related conditions, including ethyl 2-(4-isobutylphenyl)propionate hydrochloride and/or 2-(diethylamino)ethyl 2-acetoxybenzoate.hydrochloride. Composition.
[7] Parkinson's disease and including (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylene dibenzoate and 2-(diethylamino)ethyl 2-acetoxybenzoate. Pharmaceutical compositions for the treatment of related conditions.
[8] (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylene dibenzoate, 2-(diethylamino)ethyl 2-acetoxybenzoate, carbidopa and/or entacapone A pharmaceutical composition for the treatment of Parkinson's disease and related conditions, comprising:
[9] (S)-4-(2-amino-3-oxo-3-(pentan-3-yloxy)propyl)-1,2-phenylenebis(2-methylpropanoate) and 2-(diethylamino) A pharmaceutical composition for the treatment of Parkinson's disease and related conditions, comprising ethyl 2-(4-isobutylphenyl)propionate.
[10] 4-(2-(((1-((pyrrolidine-2-carbonyl)oxy)ethoxy)amino)ethyl)-1,2,-phenylene dibenzoate and 4-(dimethylamino)butyl 2-(3 - A pharmaceutical composition for the treatment of Parkinson's disease and related conditions, comprising phenoxyphenyl)propionate.
[11] (S)-4-(2-amino-3-oxo-3-(pentan-3-yloxy)propyl)-1,2-phenylenebis(2-methylpropanoate), 2-(diethylamino) A pharmaceutical composition for the treatment of Parkinson's disease and related conditions, comprising ethyl 2-(4-isobutylphenyl)propionate, carbidopa and/or entacapone.
[12] (S)-4-(2-amino-3-(heptan-4-yloxy)-3-oxopropyl)-1,2-phenylene dibenzoate and 2-(dipropylamino)ethyl 4-acetoxy A pharmaceutical composition for the treatment of Parkinson's disease and related conditions, comprising -2',4'-difluoro-[1,1'-biphenyl]-3-carboxylate.
[13] (S)-4-(2-amino-3-(heptan-4-yloxy)-3-oxopropyl)-1,2-phenylene dibenzoate and 2-(dipropylamino)ethyl 4-acetoxy A pharmaceutical composition for the treatment of Parkinson's disease and related conditions, comprising -2',4'-difluoro-[1,1'-biphenyl]-3-carboxylate, carbidopa and/or entacapone.
[14] A method for treating Parkinson's disease in a subject, the step of transdermally administering the pharmaceutical composition according to any one of [2] to [13] above; and carbidopa, benserazide, difluoromethyldopa, and α - an aromatic L-amino acid decarboxylase inhibitor selected from the group consisting of methyldopa; and/or a catechol-O-methyltransferase inhibitor selected from the group consisting of entacapone and tolcapone; or a pharmaceutical composition thereof; A method comprising the step of administering.

Claims (14)

Below structure Pro-L-Dopa-1, structure Pro-L-Dopa-2, structure Pro-L-Dopa-3, structure Pro-L-Dopa-4, structure Pro-L-Dopa-5, structure Pro-Dopamine -1, structure Pro-dopamine-2, structure Pro-dopamine-3, structure Pro-dopamine-4, and structure Pro-dopamine-5:

(In certain embodiments, W is the structure W-1, structure W-2, structure W-3 below) (including stereoisomers and pharmaceutically acceptable salts thereof) selected from the group consisting of , Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11, Structure W-12:

selected from the group consisting of;
HA is present in the absence and presence of pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, bisulfuric acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, Lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucuronic acid, sugar acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, selected from the group consisting of ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and pamoic acid;
X is selected from the group consisting of O, S, and _NR3 ; _X2 is absent, O, S, _NR3 , _CHR3 -O, CHR3-S, _{CHR3 -} O, O- _CHR3 selected from the group consisting of -O, O-CHR ₃ -S, S-CHR ₃ -O, and S-CHR ₃ -S; X ₃ is absent, C=O, C=S, C(=O )-O, O, S, NR ₃ , C(=O)-O-CHR ₃ -O, C(=O)-O-CHR ₃ -S, C(=O)-S-CHR ₃ -O, and C(=O)-S-CHR ₃ -S; Y ₁ consists of R ₃ C(=O), R ₃ OC(=O), and R ₃ SC(=O) Y ₂ is selected from the group consisting of R ₃ C(=O), R ₃ OC(=O), and R ₃ SC(=O); Y ₃ is selected from the group consisting of R ₃ , OR ₃ , selected from the group consisting _{of SR3} , _NR3R4 , O- _CHR3 - _OR4 , O- _CHR3 - _SR4 , S- _CHR3 - _OR4 ;
n and m are selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8.
Rc is absent, _CH2C (=O)OR6 _, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, selected from the group consisting of substituted and unsubstituted alkyl halides, substituted and unsubstituted alkenyls, substituted and unsubstituted alkynyls, substituted and unsubstituted aryls, and substituted and unsubstituted heteroaryls, where any CH ₂ in R further substituted with O, S, P, _NR6 , or any other pharmaceutically acceptable group;
R is absent, CH ₂ C(=O)OR ₆ , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, selected from the group consisting of substituted and unsubstituted alkyl halides, substituted and unsubstituted alkenyls, substituted and unsubstituted alkynyls, substituted and unsubstituted aryls, and substituted and unsubstituted heteroaryls, where any CH ₂ in R further substituted with O, S, P, _NR6 , or any other pharmaceutically acceptable group;
R ₃ and R ₄ are absent, CH ₂ C(=O)OR ₆ , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted selected from the group consisting of substituted perfluoroalkyl, substituted and unsubstituted alkyl halides, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, where any of R _CH2 may also be further replaced with O, S, P, _NR6 , or any other pharmaceutically acceptable group;
Each R ₆ is independently H, F, Cl, Br, I, Na ⁺ , K ⁺ , C(=O)R _5, 2-oxo-1-imidazolidinyl, phenyl, 5-indanyl, 2,3- Dihydro-1H-inden-5-yl, 4-hydroxy-1,5-naphthyridin-3-yl, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkenyl , substituted and unsubstituted alkynyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, -C(=O)-W, -L ₁ -L ₄ selected from the group consisting of -L ₂ -W, and W;
Each R ₅ is independently H, C(=O)NH ₂ , CH ₂ CH ₂ OR _6, CH ₂ CH ₂ N(CH ₃ ) ₂ , CH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ , Cl , F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, -C(=O)-W, _L1 - _L4 - _L2 -W, and W;
L ₁ is absent, O, S, -OL ₃ -, -SL ₃ -, -N(L ₃ )-, -N(L ₃ )-CH ₂ -O, -N(L ₃ )-CH ₂ selected from the group consisting of -N( _L5 )-, -O- _CH2 -O-, -O-CH( _L3 )-O, and -S-CH( _L3 )-O-;
L ₂ is absent, O, S, -OL ₃ -, -SL ₃ -, -N(L ₃ )-, -N(L ₃ )-CH ₂ -O, -N(L ₃ )-CH ₂ -N(L ₅ )-, -O-CH ₂ -O-, -O-CH(L ₃ )-O, -S-CH(L ₃ )-O-, -OL ₃ -, -NL ₃ -, -SL ₃ -, -N(L ₃ )-L ₅ - and L ₃

selected from the group consisting of;
L ₄ is absent, C=O, C=S,

selected from the group consisting of;
For each L ₁ , L ₂ , and L ₄ , each L ₃ and L ₅ are independently absent, H, CH ₂ C(=O)OL ₆ , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl , substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halides, wherein any carbon or hydrogen is further independently replaced with O, S, P, _NL3 , or any other pharmaceutically acceptable group. Also well;
Each L ₆ is independently H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and selected from the group consisting of unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halides; Carbon or hydrogen may also be independently substituted with O, S, N, P(O _{) OL6} , CH=CH, C≡C, _CHL6 , _CL6L7 , aryl, heteroaryl, or a cyclic group. It's good;
Each L ₇ is independently H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and selected from the group consisting of unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halides; Carbon or hydrogen may also be independently substituted with O, S, N, P(O _{) OL6} , CH=CH, C≡C, _CHL6 , _CL6L7 , aryl, heteroaryl, or a cyclic group. It's good;
W is H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl , substituted and unsubstituted heteroaryl, protonatable amine group, pharmaceutically acceptable substituted and unsubstituted amine group, structure Wa, structure W-1, structure W-2, structure W-3, structure W-4, structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11, Structure W-12, Structure W-13, Structure W-14, Structure selected from the group consisting of W-15, Structure W-16, Structure W-17, and Structure W-18;
R ₁ and R ₂ are independently H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted selected from the group consisting of alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues;
R ₁₁ to R ₁₅ are independently absent, H, CH ₂ C(=O)OR _11, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halides, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl). Highly permeable prodrugs according to claim 1; Structure NSAID-1, Structure NSAID-2, Structure NSAID-3, Structure NSAID-4, Structure NSAID-5, Structure NSAID-6, Structure NSAID-7, Structure NSAID-8. , structure NSAID-9, structure NSAID-10, structure NSAID-11, structure NSAID-12, and structure NSAID-13; from carbidopa, benserazide, difluoromethyldopa, and alpha-methyldopa; A pharmaceutical composition comprising: an aromatic L-amino acid decarboxylase inhibitor selected from the group consisting of; a catechol-O-methyltransferase inhibitor selected from the group consisting of entacapone and tolcapone; and a pharmaceutically acceptable carrier. 3. The pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable carrier is selected from the group consisting of alcohol, acetone, esters, cellulose, mannitol, croscarmellose sodium, vegetable oils, hydroxypropyl methylcellulose, water, and aqueous solutions. thing. A pharmaceutical composition comprising one or more highly permeable prodrugs of levodopa, dopamine, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), and any combination thereof. Transdermally administered pharmaceutical compositions comprising highly permeable prodrugs of levodopa, dopamine, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and any combination thereof, for the treatment of Parkinson's disease and related conditions. in addition to carbidopa, benserazide, difluoromethyldopa, alpha-methyldopa, other aromatic L-amino acid decarboxylase inhibitors, entacapone, tolcapone and/or other catechol-O-methyltransferase inhibitors. A pharmaceutical composition comprising an orally administered tablet containing. 4-(2-(2-(methylamino)acetamido)ethyl)-1,2,-phenylenedibenzoate hydrochloride, 4-(2-(2-(methylamino)acetamido)ethyl)-1,2,- Phenylene dibenzoate acetic acid, 4-(6-methyl-4,8-dioxo-5,7-dioxa-2,9-diazadecan-11-yl)-1,2,-phenylene dibenzoate hydrobromide, 4 -(2-(2-amino-3-phenylpropanamido)ethyl)-1,2,-phenylenedibenzoate hydrochloride, 4-(2-(((1-((pyrrolidine-2-carbonyl)oxy)ethoxy )Amino)ethyl)-1,2,-phenylene dibenzoate hydrochloride, 4-(2-piperidine-4-carboxamido)ethyl)-1,2,-phenylenebis(2-ethylbutanoate) hydrochloride, 4 -(2-(((-octahydro-1H-quinolidin-3-yl)oxy)carbonyl)amino)ethyl)-1,2,-phenylenebis(2-ethylbutanoate)acetate, 1-((( 2-(4-Amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)ethyl)carbamoyl)oxy)ethylisobutyrate Hydrogen fluoride acid salt, 1-(((2-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)ethyl)carbamoyl)oxy )ethyl isobutyrate hydrofluoride, (-(2-((ethoxycarbonyl)amino)ethyl)-2-(2-methylamino)acetoxy)phenylbenzoate hydrochloride, 5-(2-((ethoxy Carbonyl)amino)ethyl)-2-(2-methylamino)acetoxy)phenylbenzoate hydrochloride, 4-(2-aminoethyl)-1,2-phenylenedibenzoate hydrochloride, (S)-4-(2 -amino-3-isopropoxy-3-oxopropyl)-1,2-phenylene dibenzoate hydrochloride, (S)-4-(2-amino-3-(heptan-4-yloxy)-3-oxopropyl) -1,2-phenylene dibenzoate hydrochloride, (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylene dipentanoate hydrochloride, (S)-4 -(2-amino-3-ethoxy-3-oxopropyl)-1,2-phenylene diacetate hydrochloride, (S)-4-(2-amino-3-oxo-3-(pentan-3-yloxy) )propyl)-1,2-phenylenebis(2-methylpropanoate) hydrobromide, (S)-4-(2-aminoacetamido)-3-isopropoxy-3-oxopropyl)-1, 2-phenylene dibenzoate hydrochloride, 4-((2S)-3-oxo-3-(pentan-3-yloxy)-2-(pyrrolidine-2-carboxamido)propyl)-1,2-phenylene dibenzoate fluoride Hydrogen salt, (S)-4-(3-isopropoxy-3-oxo-2-(piperidine-4-carboxamido)propyl)-1,2-phenylene dibenzoate hydrochloride, 4-((2S)-3 -isopropoxy-3-2-(octahydro-1H-quinolidine-2-carboxamide)-3-oxopropyl)-1,2-phenylenebis(2-methylpropanoate) hydrochloride, (2S)-isopropyl 3- (3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)-2-(((1-(isobutyryloxy)ethoxy )carbonyl)amino)propanoate hydrobromide, (2S)-isopropyl 3-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin- 8-yl)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)propanoate hydrobromide, 5-((2S)-2-(((1-(isobutyryloxy) )ethoxy)carbonyl)amino-3-isopropoxy-3-oxopropyl)-2-(2-(methylamino)acetoxy)phenylbenzoate hydrochloride, 4-((2S)-2-(((1-( isobutyryloxy)ethoxy)carbonyl)amino-3-isopropoxy-3-oxopropyl)-2-(2-(methylamino)acetoxy)phenylbenzoate hydrochloride, 4-((2S)-3-isopropoxy) -2-((((octahydroindolizin-1-yl)oxy)carbonyl)amino)-3-oxopropyl)-1,2-phenylene dibenzoate acetate, 2-(diethylamino)ethyl 2-[(2 ,6-dichloro-3-methylphenyl)amino]benzoate acetate, (Z)-2-(diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)- 1H-inden-1-yl)acetate.AcOH, 2-(dimethylamino)ethyl 2-(3-phenoxyphenyl)propionate.hydrochloride, S-(2-(dimethylamino)ethyl 2-(3-phenoxyphenyl) Propanethioate hydrochloride, 2-(dipropylamino)ethyl 4-acetoxy-2',4'-difluoro-[1,1'-biphenyl]-3-carboxylate hydrochloride, 2-(diethylamino)ethyl 2- A transdermally administered pharmaceutical composition for the treatment of Parkinson's disease and related conditions, comprising (4-isobutylphenyl)propionate hydrochloride and/or 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride. Contains (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylene dibenzoate and 2-(diethylamino)ethyl 2-acetoxybenzoate for Parkinson's disease and related conditions. Pharmaceutical composition for treatment. (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylene dibenzoate, 2-(diethylamino)ethyl 2-acetoxybenzoate, carbidopa and/or entacapone, Pharmaceutical compositions for the treatment of Parkinson's disease and related conditions. (S)-4-(2-amino-3-oxo-3-(pentan-3-yloxy)propyl)-1,2-phenylenebis(2-methylpropanoate) and 2-(diethylamino)ethyl 2- A pharmaceutical composition for the treatment of Parkinson's disease and related conditions, comprising (4-isobutylphenyl)propionate. 4-(2-(((1-((pyrrolidine-2-carbonyl)oxy)ethoxy)amino)ethyl)-1,2,-phenylene dibenzoate and 4-(dimethylamino)butyl 2-(3-phenoxyphenyl) ) A pharmaceutical composition comprising propionate for the treatment of Parkinson's disease and related conditions. (S)-4-(2-Amino-3-oxo-3-(pentan-3-yloxy)propyl)-1,2-phenylenebis(2-methylpropanoate), 2-(diethylamino)ethyl 2- A pharmaceutical composition for the treatment of Parkinson's disease and related conditions, comprising (4-isobutylphenyl)propionate, carbidopa and/or entacapone. (S)-4-(2-amino-3-(heptan-4-yloxy)-3-oxopropyl)-1,2-phenylene dibenzoate and 2-(dipropylamino)ethyl 4-acetoxy-2' ,4'-difluoro-[1,1'-biphenyl]-3-carboxylate for the treatment of Parkinson's disease and related conditions. (S)-4-(2-amino-3-(heptan-4-yloxy)-3-oxopropyl)-1,2-phenylene dibenzoate and 2-(dipropylamino)ethyl 4-acetoxy-2' , 4'-difluoro-[1,1'-biphenyl]-3-carboxylate, carbidopa and/or entacapone for the treatment of Parkinson's disease and related conditions. 14. A method of treating Parkinson's disease in a subject, comprising transdermally administering a pharmaceutical composition according to any one of claims 2 to 13; A method comprising orally administering a selected aromatic L-amino acid decarboxylase inhibitor; and/or a catechol-O-methyltransferase inhibitor selected from the group consisting of entacapone and tolcapone; or a pharmaceutical composition thereof. .

Images