JP6596483B2 - Novel high-permeability drug and its composition for treating Parkinson's disease - Google Patents

Description

The present invention relates to the field of pharmaceutical compositions. More particularly, one aspect of the present invention provides a pharmaceutical composition capable of permeating one or more biological barriers and the subject for preventing and / or treating Parkinson's disease and / or Parkinsonism in a subject. It relates to a method of using the pharmaceutical composition.

BACKGROUND OF THE INVENTION Parkinson's disease (PD) is a neurological disorder characterized by degeneration of dopamine neurones in the substantia nigra and disappearance of dopamine in the putamen. It is considered a movement disorder but also causes cognitive and behavioral symptoms. Parkinson's disease can result from the death of dopaminergic cells in the substantia nigra, the midbrain region. The cause of this cell death can be unknown (primary parkinism) or known (secondary parkinsonism). Parkinson's disease can cause many symptoms in a wide variety of functions, including exercise, attention and learning. The main symptom of Parkinson's disease is due to decreased activity of dopamine secreting cells caused by cell death in the substantia nigra region. Certain conceptual models of motor circuits and their PD-related changes have been influential since 1980, but some limitations have been pointed out [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 usually have a certain inhibitory effect on a wide range of motor systems so that they are not activated when inappropriate. When making a decision to take a specific action, the inhibition on the required motor system is reduced, thereby releasing the motor system for activation. High levels of dopamine function tend to promote motor activity, as dopamine acts and promotes this release of suppression, but low levels of dopamine function, such as those that occur in PD, are due to any given exercise It also requires greater effort. Thus, the net effect of dopamine deletion is to cause hypoactivity [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 series of known drugs for treating motor symptoms are levodopa (usually combined 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]. Levodopa is well known to improve motor symptoms, but 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 formulations contribute to the development of motor complications in PD. These are abnormal involuntary movements, along with reaction fluctuations in which a person experiences unpredictable switching between “wearing off” and / or “on” and “off” states of drug effects. Or dyskinesias, such as athetosis and dystonia. Levodopa also causes nausea, vomiting, gastrointestinal bleeding, dyskinesia at peak doses, and may also cause end-of-dose deterioration of function.
Therefore, there is a need to develop better treatments to address the problem.

BACKGROUND OF THE INVENTION One aspect of the present invention relates to HPO of levodopa and / or dopamine.
Another aspect of the invention pertains to pharmaceutical formulations comprising one or more HPPs disclosed herein. In certain embodiments, the pharmaceutical composition comprises one or more highly permeable prodrugs of NSAID and one or more highly permeable prodrugs of dopamine and / or levodopa.
Here, the parent drug of the HPP 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 a method of using a composition of the invention in permeating one or more biological barriers of a biological object.
Another aspect of the invention relates to a method of using a composition of the invention, or a pharmaceutical composition thereof, in treating a condition in a biological subject.
Another aspect of the invention is to treat Parkinson's disease and / or related conditions in a biological subject or subject by administering one or more HPPs or pharmaceutical compositions thereof to the biological subject or subject. It relates to a method of using more than one species of HPP or a pharmaceutical composition thereof.

The residence time result in the rotor rod test after 1 to 3 weeks of treatment is shown (n = 12) (Example 31). The drop speed result in the rotor rod test after 1 to 3 weeks of treatment is shown (n = 12) (Example 31). The residence time results in the rotarod test after 4 weeks of treatment are shown (n = 12) (Example 32). The drop speed result in the rotor rod test after 4 weeks of treatment is shown (n = 12) (Example 32). The residence time result in the rotor rod test after 4 weeks of treatment is shown (n = 12) (Example 33). The drop speed result in the rotor rod test after 4 weeks of treatment is shown (n = 12) (Example 33). The residence time result in the rotor rod test after 4 weeks of treatment is shown (n = 12) (Example 34). The drop speed result in the rotor rod test after 4 weeks of treatment is shown (n = 12) (Example 34). The residence time result in the rotor rod test after 4 weeks of treatment is shown (n = 12) (Example 35). The drop speed result in the rotor rod test after 4 weeks of treatment is shown (n = 12) (Example 35). The residence time results in the rotarod test after 4 weeks of treatment are shown (n = 12) (Example 36). The drop speed result in the rotor rod test after 4 weeks of treatment is shown (n = 12) (Example 36). The residence time result in the rotor rod test after 4 weeks of treatment is shown (n = 12) (Example 37). The drop speed result in the rotor rod test after 4 weeks of treatment is shown (n = 12) (Example 37). The residence time result in the rotor rod test after 4 weeks of treatment is shown (n = 12) (Example 38). The drop speed result in the rotor rod test after 4 weeks of treatment is shown (n = 12) (Example 38).

Detailed Description of the Invention
I. One embodiment of the present invention includes a structure Pro-L-Dopa-1, a structure Pro-L-Dopa-2, a structure Pro-L-Dopa-3, a structure Pro-L-Dopa-4, and Structure Pro-L-Dopa-5:

Relates to a highly permeant prodrug of levodopa having a structure selected from the group consisting of including stereoisomers and pharmaceutically acceptable salts thereof. Here, in the above structure,
W represents 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 heteroaryls, protonatable amine groups, pharmaceutically acceptable substituted and unsubstituted amine groups, 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 absent, as well as pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, bisulfic acid, phosphoric acid, phosphorous acid, phosphonic acid. Acids, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucuronic acid, sugar acid Selected from the group consisting of 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 NR ₃ ;
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 selected from the group consisting of 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);
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 , SR ₃ , NR ₃ R ₄ , O—CHR ₃ —OR ₄ , O—CHR ₃ —SR ₄ , and S—CHR ₃ —OR ₄ ;
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 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, wherein CH ₂ may also be replaced by O, S, P, or NR ₆ ;
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, wherein any of R CH ₂ may also be replaced by O, S, P, or NR ₆ ;
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 CH ₂ in R may be further replaced by O, S, P, or NR ₆ ;
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 Selected from the group consisting of -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 (L ₅ )-, -O-CH ₂ -O-, -O-CH (L ₃ ) -O, and -S-CH (L ₃ ) -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 is 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 independently further replaced with O, S, P, or NL ₃ ;
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, 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 is further independently, O, S, N, P (O) OL ₆ , CH═CH, C≡C, CHL ₆ , CL ₆ L ₇ , aryl, heteroaryl, or May be substituted with a cyclic group;
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, 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 is further independently, O, S, N, P (O) OL ₆ , CH═CH, C≡C, CHL ₆ , CL ₆ L ₇ , aryl, heteroaryl, or May be replaced by a cyclic group; and any CH ₂ group may be replaced by O, S, or NH.

II. High Permeability Prodrugs of Dopamine Another aspect of the present invention is the following structure Pro-dopamine-1, structure Pro-dopamine-2, structure Pro-dopamine-3, and structure Pro-dopamine-4, and structure Pro-dopamine- Five:

Relates to a highly permeant prodrug of dopamine comprising a structure selected from the group consisting of including stereoisomers and pharmaceutically acceptable salts thereof. The above structures, W, HA, X, X 2, X 3, Y 1, Y 2, Y 3, n, m, R c, R, R 1, R 2, R 3, R 4, R 5, R ₆ , R _{11 to} R ₁₅ , L ₁ , L ₂ , and L ₄ are defined in the same manner as described above.

III. A pharmaceutical composition comprising a highly permeable prodrug of 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 NSAID and one or more highly permeable prodrugs of dopamine and / or levodopa.
NSAID high-permeability prodrugs are: 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:

A structure selected from the group consisting of including stereoisomers and pharmaceutically acceptable salts thereof. Here, in the above structure,
The following items are available for the following items: ARR-1, ARL-2, ARL-3, ARL-4, ARL-5, ARL-6, ARL-7, ARL Ale-8, Ale-9, Alele-10, Alele-11, Alele-12, Alele-13, Alele-14, Alele-15, Alele 16, Arle-17, Arle-18, Arle-19, Arlele-20, Arlele-21, Arlele-22, Arlele-23, Arlele-24, Ar-25, ar-26, ar-27, ar-28, ar-29, ar-30, ar-31, ar-32, ar Rule 33, Entry 34, Entry 35, Entry 36, Entry 37, Entry 38, Entry 39, Entry 40, Entry 40 41, Ar-42, Ar-43, Ar-44, Ar-45, Ar-46, Ar-47, Ar-48, Ar-49, Arlele-50, Arlele-51, Arlele-52, Arlele-53, Arlele-54, Arlele-55, Arlele-56, Arlele-57, Alier Rule-58, Entry-59, Entry-60, Entry-61, Entry- 62, aryl-63, aryl-64, aryl-65, aryl-66, aryl-67, aryl-68, aryl-69, aryl-70, And allyl-71:

Selected from the group consisting of;
_{W, HA, X, X 2} , X 3, Y 1, Y 2, Y 3, n, m, R c, R, R 1, R 2, R 3, R 4, R 5, R 6, R 11 _{~R 15, L 1, L 2} , and L ₄ are defined the same as above;
X ₆ and X ₈ independently consist of non-existing, 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) OR ₈ , OCH ₃ , OC ₂ H ₅ , OR ₆ , CH ₃ SO ₂ , R ₆ SO ₂ , CH ₃ SO ₃ , R ₆ SO ₃ , NO ₂ , CN, CF ₃ , OCF ₃ , CH ₂ (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 S CH 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, substituted and unsubstituted Selected from the group consisting of 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 , CF ₃ , CH ₂ CH ₂ F, CH ₂ CH ₂ Cl, CH ₂ CH ₂ Br, CH ₂ CH ₂ I, CH ₂ CHF ₂ , CH ₂ CF ₃ , CH ₂ F, CH ₂ Cl, CH ₂ Br , 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, substituted and unsubstituted 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 halides and substituted and unsubstituted alkylcarbonyl.

  As used herein, the term “pharmaceutically acceptable salt” means that salt of a compound of the invention that is safe to apply 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, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, and superphosphate , Isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, Gluconate, glucaronate, sugar, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoic acid ( That is, 1,11-methylene-bis- (2-hydroxy-3-naphthoic acid)) salt can be mentioned. The specific compounds of the present invention can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts, and diethylamine salts. For a review of pharmaceutically acceptable salts, please refer to the contents of BERGE ET AL. 66 J. PHARM. SCI. See 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, saturated alkyl group, alkenyl group, and alkynyl group. 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, methylene Examples include propylene, butylene, isobutylene, t-butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene and dodecylene. In certain embodiments, the hydrocarbon group contains 1 to 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 to 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” refers to a cycloalkyl in which at least one ring atom is a non-carbon atom. Examples of non-carbocyclic 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 may 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 ), 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 There is).
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” means a chemical structure containing one or more aromatic rings. In certain embodiments, all ring atoms are carbon. In certain embodiments, one or more of the ring atoms is non-carbon, such as oxygen, nitrogen, or sulfur (“heteroaryl”). Examples of aryls 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, benzoisoxazolyl, thiaxolyl, quinidino and benzothiazolyl.

In certain embodiments, the pharmaceutical composition comprises at least one HPP or related compound of a parent drug capable of treating Parkinson's disease and a pharmaceutically acceptable carrier.
In certain embodiments, the pharmaceutical composition may comprise 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 can be an HPP of a parent drug or related compound 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. Can be included.
The pharmaceutical composition may further comprise 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 a parent drug or related compound, wherein at least one of the parent drugs is levodopa (e.g., the structures Pro-L-dopa-1, Pro-L-dopa- 2, HPP comprising one or more structures of Pro-L-dopa-3, Pro-L-dopa-4, and / or Pro-L-dopa-5); HPP that is dopamine (eg, the structure Pro-dopamine- 1, HPP comprising one or more structures of Pro-dopamine-2, Pro-dopamine-3, Pro-dopamine-4, and / or structure Pro-dopamine-5); and at least one of the parent drugs is aspin or other HPP (e.g., structure NSAID-1, structure NSAID-2, structure NSAID-3, structure NSAID-4, structure NSAID-5, structure NSAID-6, structure NSAID-7, NSAID-8, structure NSAID -9, HPS including one or more structures selected from the group consisting of structure NSAID-10, structure NSAID-11, structure NSAID-12, and structure NSAID-13).

  In certain embodiments, the pharmaceutical composition is 4- (2- (2- (methylamino) acetamido) ethyl) -1,2, -phenylenedibenzoate hydrochloride, 4- (2- (2- ( Methylamino) acetamido) ethyl) -1,2, -phenylenedibenzoatoacetic 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, -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-ethylbutanoate) acetate, 1-(((2- (4-amino-2,5-dioxo -2,3,4,5-tetrahydrobenzo [b] [1,4] dioxocin-8-yl) ethyl) carbamoyl) oxy) ethyl isobutyrate hydrofluoride, 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-((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-phenylenedibenzoa -Tohydrochloride, (S) -4- (2-amino-3-isopropoxy-3 -Oxopropyl) -1,2-phenylenedipentanoate hydrochloride, (S) -4- (2-amino-3-ethoxy-3-oxopropyl) -1,2-phenylenediacetate 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-phenylenedibenzoate hydrochloride, 4-((2S) -3-oxo-3- (pentane) -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-quinolizine-2- Carboxamide) -3-oxopropyl) -1,2-phenylenebis (2-methylpropanoate) salt Salt, (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-tetrahydro Benzo [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) phenylbenzo Artohydrochloride, 4-((2S) -3-isopropoxy-2-((((octahydroindolizin-1-yl ) Oxy) carbonyl) amino) -3-oxopropyl) -1,2-phenylenedibenzoatoacetate, 2- (diethylamino) ethyl 2-[(2,6-dichloro-3-methylphenyl) amino] benzoa -G. 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-acetoxybenzoa- 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 the blood-brain barrier (BBB) Does not pass easily. Entacapone and tolcapone are catechol-O-methyltransferase inhibitors that prevent L-DOPA from metabolizing L-DOPA in the periphery to 3-methoxy-4-hydroxy-L-phenylalanine. Avoid the undesirable effects of DOPA.

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

For example, the pharmaceutical composition may be added to the parent drug or its related compound HPP, 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. 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) inhibitors. 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 biosynthesis of L-DOPA to dopamine (DA). DDC exists outside the blood brain barrier (periphery of the body) and within the region of the blood brain barrier. DDC inhibitors block DDC conversion of levodopa to dopamine. However, exogenously given levodopa is metabolized in the periphery and becomes its active metabolite dopamine before reaching the blood brain barrier. Thus, dopamine-deficient PD brains will not receive much the dopamine prodrug precursor levodopa due to peripheral DDC degradation. However, carbidopa and other DDC inhibitors as peripheral DDC inhibitors can reduce peripheral DDC conversion of levodopa before levodopa crosses the blood brain barrier. In other words, carbidopa and other DDC inhibitors do not affect brain DDC conversion of levodopa to dopamine. Eventually, a greater proportion of externally applied 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 comprise one or more HPPs of various parent drugs. The various parent drugs can belong to the same or different classes of drugs used to treat Parkinson's disease. For example, the pharmaceutical composition may include the parent drug or its related compound HPP 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, α-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-phenylenedibenzoate 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 -Contains 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-methylpropanoate) -To) 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 -(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-methylpropanoate) -To), 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-phenylenedibenzoate, and 2 -(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-phenylenedibenzoate, and 2 -(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” refers to the disease as compared to the corresponding subject not receiving the amount. An amount that results in improved treatment, cure, prevention, or amelioration of the disorder or side effect, or a reduction in the rate of progression of the disease or disorder.
This amount includes, but is not limited to, the characteristics of the HPP or its pharmaceutical composition disclosed herein (including its activity, pharmacokinetics, pharmacokinetics and bioavailability), the subject being treated or the physiology of the cell. Status (including age, gender, disease type and stage, general health, responsiveness to a given dose, and drug type), the nature of the pharmaceutically acceptable carrier in the formulation, and administration It will vary depending on various factors, including the route. In addition, an effective amount or a therapeutically effective amount can be one or more HPPs or pharmaceutical compositions thereof disclosed herein administered alone or other drugs, other therapies or other treatment methods or modalities. It can change depending on whether it is used together. Those of ordinary skill in the clinical and pharmacological fields will monitor the response of a cell or subject to the administration of one or more HPPs or pharmaceutical compositions thereof disclosed by routine experimentation, i.e., a pharmaceutical composition thereof. By adjusting the amount, one can determine an effective amount or a therapeutically effective amount. Typical dosages can range from about 0.1 mg / kg to about 100 mg / kg or more depending on the above factors. 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. See of Sciences in Philadelphia (USIP), Lippincott Williams & Wilkins, Philadelphia, PA, 2005. This content is hereby incorporated by reference as if fully set forth herein for further guidance for 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 a location, body fluid, tissue, organ (internal or external), or part of a body, another location, body fluid, tissue, organ (internal or external). Or a pharmaceutically acceptable material, composition or vehicle involved in carrying or transporting HPP to the body part, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
Each carrier is compatible with other components of the formulation, e.g., HPP, and with the tissue or organ of the biological subject without undue toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications. “Pharmaceutically acceptable” in the sense that it is suitable for use in contact and is balanced with a reasonable benefit / risk ratio.
In certain embodiments, the pharmaceutically acceptable carrier is from alcohol, acetone, ester, cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulose, water, and aqueous solution. Selected from the group consisting of
Some examples of materials that may 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) tragacanth gum powder; (5) malt; (6) gelatin; (7) (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glyco (11) Polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) Esters such as ethyl oleate and ethyl laurate; (13) Agar (14) Buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) Alginic acid; (16) Pyrogen-removing water; (17) Isotonic saline; (18) Ringer's solution; (19) Alcohol, such as Ethyl alcohol and propane alcohol; (20) phosphate buffer; and (21) other non-toxic compatible materials utilized in pharmaceutical formulations, such as acetone.

The pharmaceutical composition comprises pharmaceutically acceptable auxiliary substances necessary to approximate a physiological state, such as pH adjusting agents and buffers, toxicity adjusting agents, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, lactic acid. Sodium etc. can be contained.
In one embodiment, the pharmaceutically acceptable carrier is an aqueous carrier, such as buffered saline. In certain embodiments, pharmaceutically acceptable carriers are polar solvents such as acetone and alcohol.
The concentration of HPP in these formulations may vary widely and will be selected primarily based on fluid volume, viscosity, weight, etc., according to the particular mode of administration selected 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.
The compositions of the invention can be administered for prophylactic, therapeutic and / or hygienic uses. The administration may be topical, mucosal, such as oral, nasal, intravaginal, rectal, parenteral, transdermal, subcutaneous, intramuscular, intravenous, inhalation, instillation and other convenient routes. The pharmaceutical composition can be administered in various 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 are from about 10 ⁻⁸ g to about 100 g, from about 10 ⁻⁸ g to about 10 ⁻⁵ g, about 10 ^{− It will be from 6} g to about 1 g, from about 10 ⁻⁶ g to about 100 g, from about 0.001 g to about 100 g, from about 0.01 g to about 10 g, or from about 0.1 g to about 1 g. A dosage of about 0.001 mg to about 100 g per subject per day may be used. The actual method of preparing parenterally administrable compositions is well known or apparent to those skilled in the art and is described in Remington: The Science and Practice of Pharmacy 21st ed. , Lippincott Williams & Wilkins, (2005).

IV. Applying HPP
i) Biological barrier permeation method.
Another aspect of the invention relates to a method of using a composition of the invention in permeating one or more biological barriers in a biological subject. The method includes administering to the biological subject HPP or a pharmaceutical composition thereof. 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 or more than its parent drug. Higher transmission rates through one or more biological barriers.
As used herein, the term “biological barrier” refers to a biological layer that separates one environment into different spatial regions or compartments, and this separation is a substance from one compartment / region to another compartment / region. Can pass through, permeate, or translocate (eg, control, limit, enhance, or take no action). Different spatial regions or compartments referred to herein may have the same or different chemical or biological environments. The biological layer referred to herein includes, but is not limited to, a biological membrane, a cell layer, a biological structure, an inner surface of a subject, an organism, an organ, or a body cavity, an outer surface of an object, an organism, an organ, or a body cavity. , 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 Golgi membranes or envelopes, rough surfaces and small smooth surfaces). Endoplasmic reticulum (ER), ribosome, vacuole, vesicle, liposome, mitochondria, lysosome, nucleus, chloroplast, plastid, peroxisome, or microbody).
The lipid bilayer referred to herein is a bilayer such as, but not limited to, lipid class molecules such as phospholipids and cholesterol. In certain embodiments, the bilayer lipid is an amphiphilic molecule consisting of a polar head group and a nonpolar fatty acid tail. This bilayer was positioned so that the lipid hydrocarbon tails face each other to form an oily core held together by hydrophobic action, while the lipid charged heads face the aqueous solution on both sides of the membrane It consists of two layers of lipids. In another specific embodiment, the lipid bilayer may contain one or more embedded proteins and / or sugar molecules.
Examples of cell layers include eukaryotic cell lining (e.g. epithelium, lamina propria and smooth muscle or mucosal muscularis (in the gastrointestinal tract)), prokaryotic cell lining (e.g. two of the same protein or glycoprotein) Surface layer or S layer, which refers to a dimensional structural monolayer, in particular, the S layer refers to a portion of the cell envelope commonly found in bacteria and archaea, biofilms (self-generated polymer-matrix) A structured community of microorganisms that are encapsulated within and adhere to a living or inert surface), and plant cell layers (eg, epidermis). The cells may be normal cells or pathological cells (eg, disease cells, cancer cells).
Examples of biological structures include tight junctions or tight junctions that provide a barrier to toxin, bacteria and virus entry, such as the blood milk barrier and the blood brain barrier (BBB). In particular, the BBB is composed of an impermeable class of endothelium and exhibits both a physical barrier that contacts tightly bound endothelial cells via tight junctions and a transport barrier that includes an efflux transporter. Biological structures may include a mixture of cells, proteins and sugars (eg, blood clots).

Examples of internal surfaces of subjects, 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 An inner layer or an inner wall layer of a spore), or a combination or a plurality thereof.
Examples of the outer surface of a subject, organism, organ or body cavity include capillaries (e.g. capillaries in heart tissue), mucous membranes continuous with the skin (e.g. in nostrils, lips, eyes, genitals and anus), organs External surface (e.g. liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, bladder, duodenum, rectal stomach, colorectal, intestine, vein, respiratory system, blood vessel, Anorectal and anal pruritus), skin, cuticle (e.g. epithelial cells or keratinocyte dead layer or superficial layer of overlapping cells covering the hair shaft of animals, multi-layered structure outside the epidermis of many invertebrates, plant cuticles or Polymer cutin and / or cutan, pollen grain wall outer layer or spore outer wall layer), and combinations or combinations thereof.
Further, the biological barrier further includes a sugar layer, a protein layer or any other biological layer, or a combination or plurality thereof. For example, the skin is a biological barrier that has multiple biological layers. The skin includes an epidermal layer (outer layer), a dermis layer and a subcutaneous layer. The epidermal layer contains several layers, including a basal cell layer, spinous cell layer, granule cell layer, and stratum corneum. Cells in the epidermis are called keratinocytes. The stratum corneum (“horny layer”) is the outermost layer of the epidermis, where the cells are flat and the shape is scaly (“scale-like”). These cells contain a large number of keratins and are arranged in overlapping layers, which give the skin surface a firm oil and water resistant property.

ii) Method for treating Parkinson's disease in a biological subject Another aspect of the present invention relates to a method of using a composition of the present invention, or a pharmaceutical composition thereof, in treating a condition in a biological subject. The method includes administering a pharmaceutical composition to the biological subject.
As used herein, the term “treating” means to cure, alleviate, inhibit or prevent. As used herein, “treating” means to cure, alleviate, inhibit or prevent. As used herein, “treatment” means cure, alleviation, inhibition, or prevention.
As used herein, the term “biological object” or “subject” means an organ, group of organisms, organisms, or groups of organisms that work together to perform a specific task. As used herein, the term “organism” means a collection of molecules that function as a virtually stable whole and have the properties of life, such as animals, plants, fungi, or microorganisms.
As used herein, the term “animal” refers to a eukaryote characterized by voluntary movement. Examples of animals include, but are not limited to, vertebrates (e.g., humans, mammals, birds, reptiles, amphibians, fish, marsipobranchiata and amphipods), tunicata ) (E.g. thaliacea, appendicularia, sorberacea and ascidioidea), articulata (e.g. insect class, polypod, malacapoda, moth Examples include morphs, sea spiders, knotts, crustaceans and annelids), gehyrea (anarthropoda), and helminths (eg, rotifers).
Conditions that can be treated by this method include those that can be treated with the parent drug of HPP, ie, Parkinson's disease and related conditions.

iii). Use of 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 a biological subject or Parkinson's disease and / or related conditions in a subject, wherein the one or more HPPs 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.
What is HPP or its pharmaceutical composition? It can be administered to a biological subject by any route known in the art and includes, but is not limited to, oral, enteral, buccal, nasal, topical, rectal, intravaginal, aerosol Transmucosal, epidermal, transdermal, dermal, ocular, pulmonary, subcutaneous, and / or parenteral administration. The pharmaceutical composition can be administered in various unit dosage forms depending on the method of administration.
Preferred administration methods are transdermal, dermal and topical administration for certain compounds.
In certain embodiments, the method further comprises orally administering a therapeutically effective amount of the one or more COMT inhibitors and / or DDC inhibitors.
When multiple drugs (eg, HPP, COMT inhibitor and DDC inhibitor) are administered to a subject, multiple HPPs and / or other drugs can be administered substantially simultaneously or at different times. Multiple drugs may be mixed together before being administered to a subject or administered separately to a subject. In certain embodiments, some of the plurality of drugs are mixed prior to administration and the other drugs are administered separately. Each drug may be administered in any possible order and in any manner.

As used herein, a pharmaceutical composition may comprise 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, one or more HPPs are applied to the skin, topical, or dermis, On the other hand, the one or more COMT inhibitors and / or one or more DDC inhibitors may be orally administered. These multiple 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. A formulation useful in the methods of the invention includes one or more HPPs, one or more pharmaceutically acceptable carriers therefor, and optionally other therapeutic ingredients. For convenience, the formulation may be provided in unit dosage form and may be prepared by any method well known in the pharmaceutical arts. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the subject being 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, preferably from about 1 percent to about 20 percent of HPP.

Methods for preparing these formulations or compositions include the step of associating HPP with one or more pharmaceutically acceptable carriers and optionally one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the HPP into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
Formulations suitable for oral administration include capsules, cachets, pills, tablets, lozenges (using flavor-based ingredients, usually sucrose and acacia or gum tragacanth), powders, granules, or aqueous or In the form of solutions or suspensions in non-aqueous liquids, or as oil-in-water or water-in-oil emulsions, or as elixirs or syrups, or pastilles (inert bases such as gelatin and glycerin, or Sucrose and acacia gum) and / or mouthwash, etc., each containing a predetermined amount of HPP as the active ingredient. The compound may be administered as a bolus, electuary or paste.
In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules, etc.), HPP can be combined with one or more pharmaceutically acceptable carriers such as sodium citrate or phosphate. Dicalcium acid and / or any of the following: (1) Filler or bulking agent such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binding Agents such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia gum; (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) wetting agents such as Cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and its Mixtures; and (10) colorants. In the case of capsules, tablets and pills, the pharmaceutical composition may comprise a buffer. Similar types of solid compositions may be utilized as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose, and high molecular weight polyethylene glycols.

  A tablet may 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 glucose or cross-linked sodium carboxymethylcellulose). May be prepared using surface active or dispersing agents. Molded tablets can be molded in a suitable machine with a mixture of HPP moistened with a powder or an inert liquid diluent to mimic the peptide. Tablets and other solid dosage forms such as dragees, capsules, pills and granules may optionally be scored or otherwise known in the art of coatings and shells, enteric coatings and other pharmaceutical formulations It can be prepared using a coating. For example, using hydroxypropylmethylcellulose, other polymer matrices, liposomes and / or microspheres at varying ratios to give the desired release profile, slow release or controlled release of HPP in them It may be formulated as possible. For example, they may be sterilized by filtration through bacteria-retaining filters, or sterilized by incorporating a sterilant in the form of a sterile solid composition that is dissolved in sterile water or some other sterile injectable medium immediately before use. May be. These compositions may optionally contain pacifying agents and optionally may be compositions that release HPP in a delayed manner, only in certain parts of the gastrointestinal tract, or preferentially. Good. Examples of embedding compositions that can be used are polymeric substances and waxes. HPP may be in microencapsulated form, if appropriate, 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 are 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, oil (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. In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying agents, suspending agents, sweeteners, seasonings, coloring agents, flavoring agents and preservatives.
Suspensions are in addition to HPP, suspension 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 vaginal administration contain one or more HPPs, such as cocoa butter, polyethylene glycol, suppository wax or salicylate, and are solid at room temperature but liquid at body temperature, so Alternatively, it can be provided as a suppository that can be prepared by mixing with one or more suitable nonirritating excipients or carriers that melt in the vaginal cavity to release the active agent. Formulations suitable for intravaginal administration include pessaries, tampons, creams, gels, pastes, foams or sprays containing the carrier, as are known to be suitable in the art. -There are preparations.
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 component can be admixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ointments, pastes, creams and gels can be used in addition to HPP compositions such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth gums, cellulose derivatives, polyethylene glycols, silicones, Excipients such as bentonite, silicic acid, talc and zinc oxide, or mixtures thereof may be included. Powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances, in addition to the HPP composition. it 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, HPP or a pharmaceutical composition thereof can be administered by aerosol. This can be accomplished by preparing an aqueous aerosol, liposomal formulation or solid particles containing HPP. Non-aqueous (eg, fluorocarbon propellant) suspensions could be used. Sonic atomizers can also be used. Aqueous aerosols are made by formulating an aqueous solution or suspension of the drug together with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the individual compound, but are typically nonionic surfactants (tween, pluronic or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, Amino acids such as oleic acid, lecithin, glycine, buffers, salts, sugars or sugar alcohols are included. Aerosols are generally prepared from isotonic solutions.
Transdermal patches can also be used to deliver the HPP composition to the target site. The formulation can be made by dissolving or dispersing the drug in a suitable medium. Absorption enhancers can also be used to increase the flux of peptidomimetics across the skin. The rate of the flux can be controlled by providing a rate controlling membrane or by dispersing the peptidomimetic in a polymer matrix or gel.
Eye drops, ophthalmic ointments, powders, solutions and the like are also contemplated as being within the scope of this invention.

Formulations 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. HPP with sterile powders that can be reconstituted into, can contain antioxidants, buffers, bacteriostats, solutes or suspensions or thickeners that make the intended recipient's blood and formulation isotonic.
Examples of suitable aqueous and non-aqueous carriers that may be utilized in formulations suitable for parenteral administration include water, ethanol, polyol (eg, glycerol, propylene glycol, polyethylene glycol, etc.) And suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersion or by the use of surfactants.
Formulations suitable for parenteral administration may contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. The inclusion of various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol sorbic acid and the like can be guaranteed to prevent the action of microorganisms. It may be desirable to include isotonic agents such as sugars, sodium chloride in the composition. In addition, delayed absorption of the injectable pharmaceutical form may 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 in biodegradable polymers such as polylactide-polyglycolide. Depending on the HPP to polymer ratio and the particular polymer utilized, the drug release rate can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the 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 exact amount of a pharmaceutically effective dose of HPP that will yield the most effective results in terms of therapeutic efficiency in a given patient is, for example, the activity of an individual HPP , Specific properties, pharmacokinetics, pharmacokinetics, and bioavailability, subject's physiological condition (race, age, gender, weight, dietary restriction, disease type and stage, general health status, for a given dose It will depend on 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 (including reactivity and drug type). However, the above guidelines can be used as a basis for fine-tuning treatment, for example, determining the optimal dose of administration, and routine experiments consisting of monitoring the subject and adjusting the dosage are It is only necessary. Remington: The Science and Practice of Pharmacy (Gennaro ed. 20.sup.th edition, Williams & Wilkins PA, USA) (2000).

IV. Benefits Levodopa causes nausea, vomiting, gastrointestinal bleeding, dyskinesia at peak doses, and may result in an end-of-dose loss of function. These problems are due to transdermal administration of a highly permeable composition of L-Dopa and dopamine that can deliver a minimal therapeutically effective amount consistently at peak doses of gastrointestinal bleeding, dyskinesia, and end-of-function. It can be resolved by avoiding the loss of dose.
Recently, there is increasing evidence from human and animal studies that suggest that neuroinflammation is an important contributor to neuronal loss in PD. In addition, the pro-inflammatory drug lipopolysaccharide itself can directly cause the denaturation of dopamine-containing neurons or, in combination with other environmental factors such as the insecticide rotenone, can exacerbate the degeneration. 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 demonstrated to stop the progressive degeneration of the underlying dopamine-containing neuron. Transdermal administration of L-Dopa and / or dopamine high-permeability compositions with aspirin and / or other NSAID high-permeability compositions not only reduces the symptoms of Parkinson's disease, but also provides the underlying dopamine-containing -Ron's progressive degeneration can be stopped.
Carbidopa, benserazide, difluoromethyldopa, α-methyldopa, and / or orally administered when transdermally administered L-Dopa and / or dopamine high-permeability compositions and aspin and / or other NSAID high-permeability compositions Other DDC inhibitors and / or entacapone and tolcapone and / or other COMT inhibitors reduce the side effects of L-Dopa and / or dopamine when a higher proportion of externally supplied levodopa or dopamine reaches the brain Can help.

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 merely exemplify specific embodiments that fall within the scope of the invention. One of ordinary skill in the art can develop equivalent compositions, materials, and methods without exerting inventive ability and without departing from the scope of the present invention. It will be appreciated that various modifications can be made to the procedures described herein but still remain within the scope of the invention. It is the inventors' intention to include such modifications within the scope of the present invention. Moreover, all references cited herein are incorporated by reference in their entirety as if specified in full herein.

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

  In this example, dopamine.HCl (19 g) was added to acetone (200 mL) by adding dopamine.HCl. 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-N-methylglycine N-hydroxysuccinimide ester (Boc-Sar-OSu, 29 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 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively, and dried over sodium sulfate to give a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to give a fourth mixture. The third solution and the fourth mixture were combined and first pyridine (R0081, 30 mL) was added dropwise followed by benzoyl chloride (R0488, 30 g) to give a fifth mixture. The fifth mixture was stirred at RT for 2 h before water (2 × 100 mL), 5% sodium bucarbonate (2 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and Each was washed with water (3 × 100 mL) and dried over sodium sulfate to obtain a sixth solution. 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 HCl gas (20 g) was bubbled to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give 4- (2- (2- (methylamino) acetamido) ethyl) -1,2-phenylenedibenzoate hydrochloride.

Example 2 Preparation of 4- (2- (2- (methylamino) acetamido) ethyl) -1,2, -phenylenedibenzoatoacetic acid.
In this example, 4- (2- (2- (methylamino) acetamido) ethyl) -1,2, -phenylenedibenzoate hydrochloride (23 g) was dissolved in isopropanol (300 mL) to obtain a first mixture. Got. Sodium acetate (4 g) 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 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 give 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 give a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to give a fourth mixture. The third solution and the fourth mixture were combined and first pyridine (R0081, 30 mL) was added dropwise followed by benzoyl chloride (R0488, 30 g) to give a fifth mixture. The fifth mixture was stirred at RT for 2 h before water (2 × 100 mL), 5% sodium bicarbonate (2 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL) and dried over sodium sulfate to obtain a sixth solution. 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 HCl gas (20 g) was bubbled to form a precipitate. The precipitated solid was collected, washed with ethyl acetate and then suspended in DCM (200 mL) to give a ninth mixture. Sodium bicarbonate (20 g) and tetrabutylammonium hydrogen sulfate (11 g) were added to the ninth mixture to obtain a tenth mixture. Then 1-chloroethyl chloroformate (16 g) was added to the 10th mixture to give an 11th mixture. The eleventh mixture was stirred overnight at RT. The 11th mixture organic layer was then collected, washed with water (3 × 200 mL) and dried over anhydrous sodium sulfate to give a 12th solution. Sodium sulfate was removed by filtration and washed with DCM to obtain a thirteenth solution. The 12th and 13th solutions were combined and evaporated to dryness. The residue was dissolved in acetonitrile (200 mL) to give a fourteenth mixture. Boc-sarcosine (36 g) was added to the 14th mixture to give a 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 a 16th mixture. The sixteenth mixture was stirred at 55 ° C. for 48 hours and then 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 a 17th solution. Sodium sulfate was filtered and washed with ethyl acetate to obtain an 18th solution. The 17th and 18th solutions were combined and concentrated to 300 mL. Anisole (20 g) was added to the concentrated solution and then HBr gas (30 g) was bubbled to cause 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-phenylenedibenzoa- The hydrobromide salt was obtained.

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

  In this example, dopamine.HCl (19 g) was added to acetone (200 mL) by adding dopamine.HCl. 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 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively, and dried over sodium sulfate to give a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to give a fourth mixture. The third solution and the fourth mixture were combined and first pyridine (R0081, 30 mL) was added dropwise followed by benzoyl chloride (R0488, 30 g) to give a fifth mixture. The fifth mixture was stirred at RT for 2 h before water (2 × 100 mL), 5% sodium bicarbonate (2 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL) and dried over sodium sulfate to obtain a sixth solution. 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 HCl gas (20 g) was bubbled to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give 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 give 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 give a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to give a fourth mixture. The third solution and the fourth mixture were combined and first pyridine (R0081, 30 mL) was added dropwise followed by benzoyl chloride (R0488, 30 g) to give a fifth mixture. The fifth mixture was stirred at RT for 2 h before water (2 × 100 mL), 5% sodium bicarbonate (2 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL) and dried over sodium sulfate to obtain a sixth solution. 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 HCl gas (20 g) was bubbled to form a precipitate. The precipitated solid was collected, washed with ethyl acetate and then suspended in DCM (200 mL) to give a ninth mixture. Sodium bicarbonate (20 g) and tetrabutylammonium hydrogen sulfate (11 g) were added to the ninth mixture to obtain a tenth mixture. Then 1-chloroethyl chloroformate (16 g) was added to the 10th mixture to give an 11th mixture. The eleventh mixture was stirred overnight at RT. The organic layer of the eleventh mixture was then collected, washed with water (3 × 200 mL) and dried over anhydrous sodium sulfate to give a twelfth solution. Sodium sulfate was removed by filtration and washed with DCM to obtain a thirteenth solution. The 12th and 13th solutions were combined and evaporated to dryness. The residue was dissolved in acetonitrile (200 mL) to give a fourteenth mixture. Boc-sarcosine (36 g) was added to the 14th mixture to give a 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 a 16th mixture. The sixteenth 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 × 100 mL) and water (3 × 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain a 17th solution. Sodium sulfate was filtered and washed with ethyl acetate to obtain an 18th solution. The 17th and 18th solutions were combined and concentrated to 300 mL. Anisole (20 g) was added to the concentrated solution and then HCl gas (30 g) was bubbled to cause precipitation. The precipitated solid is collected and washed with ethyl acetate to give 4- (2-(((1-((pyrrolidine-2-carbonyl) oxy) ethoxy) amino) ethyl) -1,2, -phenylenedibenzoate hydrochloride Salt was obtained.

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

  In this example, dopamine.HCl (19 g) was added to acetone (200 mL) by adding dopamine.HCl. 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-piperidine-4-carboxylic acid N-hydroxysuccinimide ester (Boc-Inp-OSu, 33 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 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively, and dried over sodium sulfate to give a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to give a fourth mixture. The third solution and the fourth mixture were combined and first pyridine (R0081, 30 mL) was added dropwise followed by 2-ethylbutyryl chloride (28 g) to give a fifth mixture. The fifth mixture was stirred at RT for 2 h before water (2 × 100 mL), 5% sodium bicarbonate (2 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL) and dried over sodium sulfate to obtain a sixth solution. 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 HCl gas (20 g) was bubbled to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give 4- (2-piperidine-4-carboxamido) ethyl) -1,2, -phenylenebis (2-ethylbutanoate) hydrochloride.

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

In this example, dopamine.HCl (19 g) was added to acetone (200 mL) by adding dopamine.HCl. 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 give 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 give a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to give a fourth mixture. The third solution and the fourth mixture were combined and first pyridine (R0081, 30 mL) was added dropwise followed by 2-ethylbutyryl chloride (28 g) to give a fifth mixture. The fifth mixture was stirred at RT for 2 h before water (2 × 100 mL), 5% sodium bicarbonate (2 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL) and dried over sodium sulfate to obtain a sixth solution. 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 HCl gas (20 g) was bubbled to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give 4- (2-((((-octahydro-1H-quinolinidin-3-yl) oxy) carbonyl) amino) ethyl) -1,2-phenylenebis (2- Ethylbutanoate) hydrochloride was obtained.
The solid was dissolved in ethyl acetate (200 mL) to give a ninth mixture. Triethylamine (25 mL) is first added to the ninth mixture, followed by the dropwise addition of octahydro-1H-quinolizin-3-ylcarbonochloride hydrochloride (22 g) in ethyl acetate (50 mL). Got. The tenth mixture was stirred for 2 hours at RT and washed with 5% sodium bicarbonate and water to give an eleventh mixture. Acetic acid (6 g) was added to the 11th mixture followed by hexane (200 mL) resulting in precipitation. The precipitated solid was collected by filtration, washed with ethyl acetate / hexane and washed with 4- (2-((((-octahydro-1H-quinolizin-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. Nα- (benzyloxycarbonyloxy) succinimide (25 g) was then added to the first mixture to give 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 give a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to give a fourth mixture. The third solution and the 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 give 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 give a seventh mixture, water (2 × 100 mL), 5% sodium bicarbonate (3 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and Each was washed with water (3 × 100 mL) and dried over sodium sulfate to obtain an eighth solution. Sodium sulfate was filtered and washed with ethyl acetate to obtain a ninth solution. The eighth and ninth solutions were combined and evaporated to dryness. The residue was dissolved in methanol (R0084, 300 mL) to give a tenth mixture. Palladium activated carbon (10 g, 10%) was first added to the tenth mixture under nitrogen and then bubbled with hydrogen gas 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 give a twelfth mixture. Sodium bicarbonate (20 g) and tetrabutylammonium hydrogen sulfate (11 g) were added to the twelfth mixture to obtain a thirteenth mixture. Next, 1-chloroethyl chloroformate (16 g) was added to the thirteenth mixture to give a fourteenth mixture. The 14th mixture was stirred overnight at RT. The organic layer of the 14th mixture was then collected, washed with water (3 × 200 mL) and dried over anhydrous sodium sulfate to give a 15th solution. Sodium sulfate was removed by filtration and washed with DCM to give a sixteenth solution. The 15th and 16th solutions were combined and evaporated to dryness. The residue was collected and dissolved in isobutyric acid (100 mL) to give a 17th mixture. First, a mixture of diisopropylethylamine (60 mL) and isobutyric acid (36 mL) was prepared and then added to the 17th mixture to obtain an 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 × 100 mL) and water (3 × 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain a nineteenth solution. 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 to cause 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) ethyl isobutyrate-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) phenyl benzoate hydrochloride and 5- (2-((ethoxycarbonyl) amino) ethyl) -2- Preparation of (2-methylamino) acetoxy) phenyl benzoate hydrochloride.

In this example, a dopamine · HCl solution was prepared by adding dopamine · HCl (19 g) to acetone (200 mL). Pyridine (40 ml) was added to the dopamine / HCl solution to obtain a first mixture. N- (ethoxycarbonyloxy) succinimide (18 g) was then added to the first mixture to give 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 give a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to give a fourth mixture. The third solution and the 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 give 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 give a seventh mixture, water (2 × 100 mL), 5% sodium bicarbonate (3 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and Each was washed with water (3 × 100 mL) and dried over sodium sulfate to obtain an eighth solution. Sodium sulfate was filtered and washed with ethyl acetate to obtain a ninth solution. Pyridine (20 mL) was added to the combined 8th and 9th solutions, followed by dropwise addition of benzoyl chloride (15 g) to give a 10th mixture.
The 10th mixture was stirred at RT for 4 h, water (2 × 100 mL), 5% sodium bicarbonate (2 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL) ), And dried over sodium sulfate to obtain an eleventh solution. Sodium sulfate was filtered and washed with ethyl acetate to obtain a twelfth solution.
Anisole (20 g) was added to the combined 11th and 12th solutions and then HCl gas (20 g) was bubbled to cause precipitation. The precipitated solid was collected and washed with ethyl acetate to give 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.HCl (19 g) was added to acetone (200 mL) by adding dopamine.HCl. 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 give 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 give a third solution. The sodium sulfate was then filtered and washed with ethyl acetate to give a fourth mixture. The third solution and the fourth mixture were combined and first pyridine (R0081, 30 mL) was added dropwise followed by benzoyl chloride (R0488, 30 g) to give a fifth mixture. The fifth mixture was stirred at RT for 2 h before water (2 × 100 mL), 5% sodium bicarbonate (3 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL) and dried over sodium sulfate to obtain a sixth solution. 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 HCl gas (60 g) was bubbled to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give 4- (2-aminoethyl) -1,2-phenylenedibenzoate hydrochloride.

Example 11 Preparation of (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylenedibenzoate 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 through the first mixture to obtain a second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added resulting in precipitation. The precipitated solid was collected and washed with isopropyl acetate to give isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride.
Isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride (28 g) was added to acetone (200 mL) to give 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 (5th mixture) was washed with water (2 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain a sixth solution. It was. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a seventh mixture. The sixth solution and the seventh mixture were combined and first pyridine (R0081, 30 mL) was added dropwise followed by benzoyl chloride (R0488, 30 g) to give an eighth mixture. The eighth mixture was stirred at RT for 2 h before water (2 × 100 mL), 5% sodium bicarbonate (3 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and water (3 × Each was washed with 100 mL) and dried over sodium sulfate to obtain a ninth solution. Sodium sulfate was filtered and washed with ethyl acetate to obtain a tenth solution. The ninth solution and the tenth solution were combined and concentrated to about 300 mL (the eleventh solution). Anisole (20 g) was added to the eleventh solution, and HCl gas (20 g) was bubbled to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give (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-phenylenedibenzoate 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 through the first mixture to obtain a second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added resulting in precipitation. The precipitated solid was collected and washed with isopropyl acetate to give 4-heptyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride.
4-Heptyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride (28 g) was added to acetone (200 mL) to give 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 (5th mixture) was washed with water (2 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain a sixth solution. It was. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a seventh mixture. The sixth solution and the seventh mixture were combined and first pyridine (R0081, 30 mL) was added dropwise followed by benzoyl chloride (R0488, 30 g) to give an eighth mixture. The eighth mixture was stirred at RT for 2 h before water (2 × 100 mL), 5% sodium bicarbonate (3 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and water (3 × Each was washed with 100 mL) and dried over sodium sulfate to obtain a ninth solution. Sodium sulfate was filtered and washed with ethyl acetate to obtain a tenth solution. The ninth solution and the tenth solution were combined and concentrated to about 300 mL (the eleventh solution). Anisole (20 g) was added to the eleventh solution, and HCl gas (20 g) was bubbled to form a precipitate. The precipitated solid was collected, washed with ethyl acetate and (S) -4- (2-amino-3- (heptan-4-yloxy) -3-oxopropyl) -1,2-phenylenedibenzoate hydrochloride Got.

Example 13. Preparation of (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylenedipentanoate 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 through the first mixture to obtain a second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added resulting in precipitation. The precipitated solid was collected and washed with isopropyl acetate to give isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride.
Isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride (28 g) was added to acetone (200 mL) to give 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 (5th mixture) was washed with water (2 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain a sixth solution. It was. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a seventh mixture. The sixth solution and the seventh mixture were combined and first pyridine (R0081, 30 mL) was added dropwise followed by pentanoyl chloride (24 g) to give an eighth mixture. The eighth mixture was stirred at RT for 2 h before water (2 × 100 mL), 5% sodium bicarbonate (3 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and water (3 × Each was washed with 100 mL) and dried over sodium sulfate to obtain a ninth solution. Sodium sulfate was filtered and washed with ethyl acetate to obtain a tenth solution. The ninth solution and the tenth solution were combined and concentrated to about 300 mL (the eleventh solution). Anisole (20 g) was added to the eleventh solution, and HCl gas (20 g) was bubbled to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylenedipentanoate hydrochloride.

Example 14 (S) -4- (2-Amino-3-ethoxy-3-oxopropyl) -1,2-phenylenediacetate 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 through the first mixture to obtain a second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added resulting in precipitation. The precipitated solid was collected and washed with isopropyl acetate to give 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 give 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 (5th mixture) was washed with water (2 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain a sixth solution. It was. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a seventh mixture. The sixth solution and the seventh mixture were combined and first pyridine (R0081, 30 mL) was added dropwise followed by acetyl chloride (18 g) to give an eighth mixture. The eighth mixture was stirred at RT for 2 h before water (2 × 100 mL), 5% sodium bicarbonate (3 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and water (3 × Each was washed with 100 mL) and dried over sodium sulfate to obtain a ninth solution. Sodium sulfate was filtered and washed with ethyl acetate to obtain a tenth solution. The ninth solution and the tenth solution were combined and concentrated to about 300 mL (the eleventh solution). Anisole (20 g) was added to the eleventh solution, and HCl gas (20 g) was bubbled to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give (S) -4- (2-amino-3-ethoxy-3-oxopropyl) -1,2-phenylenediacetate hydrochloride.

Example 15. Preparation of (S) -4- (2-amino-3-oxo-3- (pentan-3-yloxy) propyl) -1,2-phenylenebis (2-methylpropanoate) 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 through the first mixture to obtain a second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added resulting in precipitation. The precipitated solid was collected and washed with isopropyl acetate to give isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride.
3-Pentyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride (28 g) was added to acetone (200 mL) to give a third mixture. To the third mixture was added water (200 mL) and sodium bicarbonate (50 g), then di-tert-butyl dicarbonate (22 g) to give a fourth mixture. The fourth mixture was stirred at RT overnight and ethyl acetate (500 mL) was added. The organic layer (5th mixture) was washed with water (2 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain a sixth solution. It was. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a seventh mixture. The sixth solution and the seventh mixture were combined and first pyridine (R0081, 30 mL) was added dropwise followed by isobutyryl chloride (22 g) to give an eighth mixture. The eighth mixture was stirred at RT for 2 h before water (2 × 100 mL), 5% sodium bicarbonate (3 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and water (3 × Each was washed with 100 mL) and dried over sodium sulfate to obtain a ninth solution. Sodium sulfate was filtered and washed with ethyl acetate to obtain a tenth solution. The ninth solution and the tenth solution were combined and concentrated to about 300 mL (the eleventh solution). Anisole (20 g) was added to the eleventh solution, and HCl gas (20 g) was bubbled to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give (S) -4- (2-amino-3-ethoxy-3-oxopropyl) -1,2-phenylenediacetate hydrochloride.

Example 16 Preparation of (S) -4- (2-aminoacetamido) -3-isopropoxy-3-oxopropyl) -1,2-phenylenedibenzoate 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 through the first mixture to obtain a second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added resulting in precipitation. The precipitated solid was collected and washed with isopropyl acetate to give isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride.
Isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride (28 g) was added to acetone (200 mL) to give a third mixture. To the third mixture was added water (200 mL) and sodium bicarbonate (50 g), followed by N- (tert-butoxycarbonyl-glycine N-hydroxysuccinimide ester (27 g) to give a fourth mixture. The mixture was stirred overnight with ethyl acetate (500 mL) and the organic layer (5th mixture) was washed with water (2 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively. And dried over anhydrous sodium sulfate to obtain a sixth solution, which was then filtered and washed with ethyl acetate to obtain a seventh mixture, which was combined first Pyridine (R0081, 30 mL) was added dropwise followed by benzoyl chloride (30 g) to give an eighth mixture, which was stirred at RT for 2 h before water (2 × 100 mL), 5% sodium bicarbonate. (9 × 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 ninth solution. The solution was filtered and washed with ethyl acetate to obtain a tenth solution, the ninth and tenth solutions were combined and concentrated to about 300 mL (the eleventh solution), and anisole (20 g) was added to the eleventh solution. In addition, HCl gas (20 g) was bubbled to form a precipitate, and the precipitated solid was collected, washed with ethyl acetate and (S) -4- (2-aminoacetamido) -3-isopropoxy-3-oxopropyl ) -1,2-phenylenedibenzoate 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 through the first mixture to obtain a second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added resulting in precipitation. The precipitated solid was collected and washed with isopropyl acetate to give isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride.
3-Pentyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride (28 g) was added to acetone (200 mL) to give 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 mixture was stirred overnight with ethyl acetate (500 mL) and the organic layer (5th mixture) was washed with water (2 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively. And dried over anhydrous sodium sulfate to obtain a sixth solution, which was then filtered and washed with ethyl acetate to obtain a seventh mixture, which was combined first Pyridine (R0081, 30 mL) was added dropwise followed by benzoyl chloride (22 g) to give an eighth mixture, which was stirred at RT for 2 h before water (2 × 100 mL), 5% sodium bicarbonate. (9 × 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 ninth solution. The solution was filtered and washed with ethyl acetate to obtain a tenth solution, the ninth and tenth solutions were combined and concentrated to about 300 mL (the eleventh solution), and anisole (20 g) was added to the eleventh solution. In addition, HF gas (20 g) was bubbled to form a precipitate that 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 through the first mixture to obtain a second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added resulting in precipitation. The precipitated solid was collected and washed with isopropyl acetate to give isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride.
Isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride (28 g) was added to acetone (200 mL) to give 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 (5th mixture) was washed with water (2 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain a sixth solution. It was. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a seventh mixture. The sixth solution and the 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 h before water (2 × 100 mL), 5% sodium bicarbonate (3 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and water (3 × Each was washed with 100 mL) and dried over sodium sulfate to obtain a ninth solution. Sodium sulfate was filtered and washed with ethyl acetate to obtain a tenth solution. The ninth solution and the tenth solution were combined and concentrated to about 300 mL (the eleventh solution). Anisole (20 g) was added to the eleventh solution, and then HF gas (20 g) was bubbled to form a precipitate. The precipitated solid was collected, washed with ethyl acetate and (S) -4- (3-isopropoxy-3-oxo-2- (piperidine-4-carboxamido) propyl) -1,2-phenylenedibenzoate fluoride The hydrogen salt was obtained.

Example 19. 4-((2S) -3-Isopropoxy-3-2- (octahydro-1H-quinolidine-2-carboxamido) -3-oxopropyl) -1,2-phenylenebis (2-methylpropanoate) hydrochloric acid Salt preparation.

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 through the first mixture to obtain a second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added resulting in precipitation. The precipitated solid was collected and washed with isopropyl acetate to give isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride.
Isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride (28 g) was added to acetone (200 mL) to give a third mixture. Water (200 mL) and sodium bicarbonate (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 (5th mixture) was washed with water (2 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain a sixth solution. It was. The sodium sulfate was then filtered and washed with ethyl acetate to obtain a seventh mixture. The sixth solution and the seventh mixture were combined and first pyridine (R0081, 30 mL) was added dropwise followed by isobutyryl chloride (22 g) to give an eighth mixture. The eighth mixture was stirred at RT for 2 h before water (2 × 100 mL), 5% sodium bicarbonate (3 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and water (3 × Each was washed with 100 mL) and dried over sodium sulfate to obtain a ninth solution. Sodium sulfate was filtered and washed with ethyl acetate to obtain a tenth solution. The ninth solution and the tenth solution were combined and concentrated to about 100 mL (the eleventh solution). To the eleventh solution was added hexane (200 mL) and then acetic acid (6 g) 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) propanoate hydrobromide and (2S) -isopropyl 3- (4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo [ b] Preparation of [1,4] dioxocin-8-yl) -2-(((1- (isobutyryloxy) ethoxy) carbonyl) amino) propanoate 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 through the first mixture to obtain a second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added resulting in precipitation. The precipitated solid was collected and washed with isopropyl acetate to give isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride.
Isopropyl (S) -2-amino-3- (3) by adding isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride (28 g) to acetone (200 mL). , 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 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively, and dried over sodium sulfate to give a fifth solution. Next, 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 give 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 give a ninth mixture, water (2 × 100 mL), 5% sodium bicarbonate (3 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and Each was washed with water (3 × 100 mL) and dried over sodium sulfate to give a tenth solution. Sodium sulfate was filtered and washed with ethyl acetate to obtain an eleventh solution. The tenth and eleventh solutions were combined and evaporated to dryness. The residue was dissolved in methanol (R0084, 300 mL) to give a twelfth mixture. First, palladium activated carbon (10 g, 10%) was added to the twelfth mixture under nitrogen, and then hydrogen gas was bubbled 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 give a fourteenth mixture. Sodium bicarbonate (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 give a 16th mixture. The sixteenth mixture was stirred overnight at RT. The organic layer of the sixteenth mixture was then collected, washed with water (3 × 200 mL) and dried over anhydrous sodium sulfate to give a seventeenth solution. Sodium sulfate was removed by filtration and washed with DCM to give an 18th solution. The 17th and 18th solutions were combined and evaporated to dryness. The residue was dissolved in isobutyric acid (100 mL) to obtain a nineteenth mixture. A mixture of diisopropylethylamine (60 mL) and isobutyric acid (36 mL) was first prepared and then added to the 19th mixture to obtain a 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 × 100 mL) and water (3 × 100 mL), respectively, and dried over anhydrous sodium sulfate to give a 21st solution. Sodium sulfate was filtered and washed with ethyl acetate to obtain a 22nd solution. The 21st and 22nd solutions were combined and concentrated to 300 mL. Anisole (20 g) was added to the concentrated solution and then HBr gas (30 g) was bubbled to cause precipitation. The precipitated solid was collected, washed with ethyl acetate and washed with (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 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) propanoate bromide The hydrogen salt was obtained.

Example 21. 5-((2S) -2-(((1- (isobutyryloxy) ethoxy) carbonyl) amino-3-isopropoxy-3-oxopropyl) -2- (2- (methylamino) acetoxy) phenylbenzo Artato hydrochloride and 4-((2S) -2-(((1- (isobutyryloxy) ethoxy) carbonyl) amino-3-isopropoxy-3-oxopropyl) -2- (2- (methyl Preparation of amino) acetoxy) phenyl benzoate 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 through the first mixture to obtain a second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added resulting in precipitation. The precipitated solid was collected and washed with isopropyl acetate to give isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride.
Isopropyl (S) -2-amino-3- (3) by adding isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride (28 g) to acetone (200 mL). , 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 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 100 mL), respectively, and dried over sodium sulfate to give a fifth solution. Next, 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 give 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 give a ninth mixture, water (2 × 100 mL), 5% sodium bicarbonate (3 × 100 mL), water (100 mL), 20% citric acid (2 × 200 mL), and Each was washed with water (3 × 100 mL) and dried over sodium sulfate to give a tenth solution. Sodium sulfate was filtered and washed with ethyl acetate to obtain an eleventh solution. Pyridine (20 ml) was added to the eleventh solution to give a twelfth mixture, and benzoyl chloride (15 g) was added dropwise to the twelfth mixture to give a thirteenth mixture. The thirteenth mixture was stirred for 4 h at RT and the resulting mixture was water (2 × 100 ml), 5% sodium bicarbonate (2 × 100 ml), water (100 ml), 20% citric acid (2 × 200 ml), and Each was washed with water (3 × 100 ml) and dried over anhydrous sodium sulfate to obtain a fourteenth 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 sixteenth mixture. 10% palladium on activated carbon (10 g) was added to the 16th mixture under nitrogen and hydrogen gas was bubbled through the resulting mixture until the benzyloxycarbonyl group was substantially completely removed at RT. The palladium 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. To the resulting reaction mixture was added 1-chloroethyl chloroformate (16 g). The reaction mixture was then stirred overnight at RT. The organic layer was collected and washed with water (3 × 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). A mixture of diisopropylethylamine (60 ml) and isobutyric acid (R0874, 36 mL) [mixed before addition] is added to the reaction solution. The mixture is stirred at 55 ° C. for 48 hours. Ethyl acetate (500 ml) is added to the stirred reaction mixture. The organic solution is collected and washed with 5% sodium bicarbonate (3 × 100 ml) and water (3 × 100 ml). The solution is dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration and washed with ethyl acetate (3 ×). Concentrate this solution to 300 ml. Anisole (20 g) is added to the ethyl acetate solution. HCl gas (30 g) is then bubbled through 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-phenylenedibenzo-toaceta- Preparation.

In this example, (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoic acid (20 g) was added to isopropanol (200 mL). HCl gas (20 g) was bubbled through the mixture. The mixture was stirred at 60 ° C. for 2 days. To this mixture was added isopropyl acetate (200 mL). The solid was collected and washed with isopropyl acetate.
Isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride (28 g) was added to acetone (200 mL). Water (200 mL) and sodium bicarbonate (50 g) were added to the reaction mixture. To the reaction mixture was added di-tert-butyl dicarbonate (22 g). The mixture was stirred overnight at RT. Ethyl acetate (500 mL) was added to the mixture. The mixture was washed with water (2 × 100 mL), 20% citric acid (2 × 200 mL), and water (3 × 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 (30 g) was added dropwise to the reaction mixture. The solution was stirred at RT for 2 hours. The solution was 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). 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 the ethyl acetate solution. Next, HCl gas (20 g) was bubbled through 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 (6 g) 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 N, N′-dicyclohexylcarbodiimide was added to the reaction mixture. 11.7 g diethylaminoethylamine was added to the reaction mixture. The mixture was stirred at RT for 3 hours. The solid was removed by filtration. The chloroform solution was washed with 5% NaHCO ₃ (2 × 100 mL) and water (3 × 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 (200 ml) 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). To the stirred reaction mixture was added 5% sodium bicarbonate (200 mL). The ethyl acetate layer was collected and washed with water (3 × 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 (30 g) was added to the mixture. The mixture was stirred at RT for 5 hours. The mixture was washed with water (3 × 200 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate. HCl gas (5 g) was bubbled through the mixture. The solid was 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 hydrogen carbonate (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 stirred reaction mixture. The ethyl acetate layer was collected and washed with water (3 × 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 Of (4-Difluorophenyl) acetyl salicylate hydrochloride]

  It was dissolved in 31.1 g (0.1 mol) of 5- (2,4-difluorophenyl) acetylsalicyl chloride in 300 mL of ethyl acetate. The mixture was cooled to 0 ° C. 11.7 g (0.1 mol) of diethylaminoethanol was added to the reaction mixture. Sodium bicarbonate (30 g) 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 through 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. with an ice water bath. 23 g of N, N-diethylaminoethanol was added dropwise to the reaction mixture. 40 g Na ₂ CO ₃ was slowly added to the reaction mixture. The mixture was stirred overnight at RT. 200 mL of water was added to the mixture. The ethyl acetate solution was collected and washed with water (3 × 200 mL) and dried over anhydrous Na ₂ SO ₄ . Sodium sulfate was removed by filtration and washed with ethyl acetate (3 × 100 mL). Anhydrous HCl gas (10 g) was bubbled through the mixture. The solid was collected and washed with ethyl acetate.

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

36 g of aspirin was dissolved in 100 mL 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. with an ice-water bath. 23 g of N-diethylaminoethanol was added dropwise to the reaction mixture. 40 g NaHCO ₃ was slowly added to the reaction mixture. The mixture was stirred overnight at RT. 200 mL of water was added to the mixture. The ethyl acetate solution was collected and washed with water (3 × 100 mL) and dried over anhydrous Na ₂ SO ₄ . Sodium sulfate was removed by filtration and washed with ethyl acetate (3 × 100 mL). Anhydrous HCl gas (10 g) was bubbled through the mixture. The solid was collected and washed with ethyl acetate.

Example 30. FIG. Measurement of HPP transmission rate
4- (2- (2- (methylamino) acetamido) ethyl) -1,2, -phenylenedibenzoate hydrochloride (Compound-1), 4- (2- (2- (methylamino) acetamido) ethyl ) -1,2, -phenylenedibenzoatoacetic acid (compound-2), 4- (6-methyl-4,8-dioxo-5,7-dioxa-2,9-diazadecan-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-quinolizin-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) Ethylisobutyrate Hydrofluoride (Compound-8a), 1-(((2- (3-Amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo [b] [1,4] Dioxocin-8-yl) ethyl) carbamoyl) oxy) ethyl isobutyrate 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-phenylenedibenzoate hydrochloride (compound-10), (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) 1,2-phenylenedibenzoate hydrochloride (compound-11), (S) -4- (2-amino-3- (heptane-4-ylo) (Xy) -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-phenylenediacetate hydrochloride (Compound) -14), (S) -4- (2-amino-3-oxo-3- (pentan-3-yloxy) propyl) -1,2-phenylenebis (2-methylpropanoate) hydrobromic acid Salt (compound-15), (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-phenylenedibenzoate Hydrochloride (Compound-18), 4-((2S) -3-Isopropoxy-3-2- (octahydro-1H-quinolidine-2-carboxamido) -3-oxopropyl) -1,2-phenylenebis (2 -Methylpropanoate) hydrochloride (compound-19), (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 (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) propanoate-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- (iso (Tyryloxy) 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-phenylenedibenzoatoacetate (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) permeate through human skin from the human skin tissue of the anterior and posterior thighs (360-400 μm thick). Measured in vitro using a detached modified Franz cell, the receiving fluid consists of 10 mL pH 7.4 phosphate buffer (0.2 M) and is shown in Table 1. The results show that the positive charge of the amino group is the membrane And suggested that it has a very important role in the passage of drugs across the skin barrier.

table 1. Cumulative amounts of prodrugs of dopamine, L-Dopa, and NSAID over 8 hours.

Example 31. Effects of (S) -4- (2-amino-3-iso) on the improvement of motor function defect and reduction of nigrostriatal neurodegeneration induced by 6-OHDA in Parkinson's disease (PD) model in HDB Efficacy of propoxy-3-oxopropyl) -1,2-phenylenedibenzoate hydrochloride (drug A) and 2- (diethylamino) ethyl 2-acetoxybenzoate hydrochloride (drug B) (Sprague-Dawley rats) were prepared, grouped and tested.
1． 200 Sprague-Dawley rats (male, 200-230 g) underwent stereotaxic surgery after 1 week of acclimatization at the animal facility;
2． After anesthesia, a burr hole (diameter 1mm) was drilled in the left skull based on the following coordinates using a motor drill: AP + 0.5mm, ML -2.8mm, DV for Bregma. 0mm;
3． 6-OHDA (20 μg at 5 mg / mL) or sterile saline was injected into the left striatum with a microsyringe equipped with a 26 gauge steel cannula. This chemical causes retrograde neurodegeneration in the distal substantia nigra, impairing dopamine transmission in the nigrostriatal pathway and ultimately resulting in impaired motor activity;
Four. At the end of 3 weeks after 6-OHDA treatment, animals were screened with apomorphine and classical rotation tests. Animals with matched lesion type and apomorphine-induced rotation score were assigned to 11 groups; and
Five. 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. Dose and drug administered to test animals

6． Dose prescription
(1) L-DOPA (3 mg / mL) in water was a positive control solution of group 1 (oral in group 1 and transdermal in groups 2-11). The dosing volume was 2 mL / kg. The vehicle solution (negative control solution for group 2) was 30% ethanol (v / v). The dosing volume was 1286 μL / kg. Other test solutions (groups 3-11) were prepared fresh daily.
(2) Preparation method of test solutions 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. Drug A group 5 (high dose group) test solution: stock solution [(2) a] was the test solution for group 5. The dosing 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 dosing volume was 1286 μL / kg.
c. Test solution for drug A group 3 (low dose group): 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 dosing 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) 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) Preparation method of 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 administration, from the upper back (around the neck and shoulders) of the animals (all rats including those in the positive control group using L-DOPA for double-blind mode) using a small animal clipper The hair was removed. Animal hair was reaped as needed to maintain epidermal exposure throughout the course of the study. On the day of administration, an aliquot (643 μL / kg) of the preparation was administered to a 3 cm × 3 cm square part of the animal (neck and shoulder area) around 9 am and repeated around 4 pm.
8． Four weeks after the lesion, the group began to receive treatment.
9． A rotarod test was performed weekly after treatment.

FIG. 1 shows the residence time results in the above rotarod test after 1-3 weeks of treatment (n = 12). FIG. 2 shows the drop velocity results in the above-mentioned Rotarod test after 1-3 weeks of treatment (n = 12).
As the performance of PD animals improved, it was assumed that they would stay longer on the load and withstand higher speed rotation (if no side effects of the test drug).
By pulling all batch data together (12 animals / group), the positive group (Group 1, L-DOPA, 6 mg / kg, oral) was compared to the vehicle group after 3 weeks of treatment. Showed no 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 occurrence of motor complications in PD. Levodopa caused nausea, vomiting, gastrointestinal bleeding, dyskinesia at peak doses, and reduced end-of-dosage of function, so the positive control group (Group 1, L-DOPA, 6 mg / kg (oral) showed no efficacy compared to the vehicle group. However, the transdermal L-Dopa prodrug (drug A) avoided dyskinesia at peak doses and end-of-dose functional decline. The efficacy of the low dose of drug A ( L-Dopa prodrug, 0.67 mg / kg, group 3) is much higher than the efficacy of the medium and high doses of drug A (2 mg and 6 mg / kg, groups 4 and 5) it was high. The results indicated that the dose of prodrug administered transdermally with L-dopa was much lower (9 times less) than L-dopa administered orally. 30 mg and 90 mg / kg of drug B ( aspirin prodrug ) showed better efficacy than the vehicle group and the positive control group after 3 weeks of treatment. 30 mg Drug B (Group 8) was as potent as 90 mg Drug B (Group 11). This result indicated that a dose of 30 mg / kg was sufficient for drug B and a higher dose was not required. Administration of drug A and drug B combinations (Group 6 and Group 9) to subjects performed much better than administration of either Drug B (Groups 8 and 11) or Drug A (Group 3) alone.
When a combination of multiple drugs (e.g., one or more HPPs and / or other drugs) is administered to a subject, each drug can be administered separately, or one or more drugs can be substantially separated as separate drugs. Can be administered at the same time (e.g., spraying substantially simultaneously without mixing two or more drugs before spraying), or can be administered to a subject after mixing one or more drugs together, or Any combination of the above administration methods is also possible. The drugs can be administered in any order possible.

Example 32. Drug A (transdermal), drug B (transdermal), which affects the improvement of motor function defects and reduction of nigrostriatal neurodegeneration induced by 6-OHDA in Parkinson's disease (PD) model in HDB, And efficacy of oral carbidopa.
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 drugs were administered to each group at the doses shown in Table 3 below.

Table 3. Dose and drug administered to test animals

2． Dose prescription
(1) Both L-DOPA (3 mg / ml) and carbidopa (1.5 mg / mL) in water were used as group 1 (oral) positive control solutions 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 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 1,286 μL / kg. Other test solutions (transdermal, groups 3-11) were prepared fresh daily.
(2) Preparation method of test solutions 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 administration 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 administration volume was 1,286 μL / kg;
(c) Test solution for Group 3 (low dose group) of Drug A: 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 dosing 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) Preparation method of 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 administration, from the upper back (around the neck and shoulders) of the animals (all rats including those in the positive control group using L-DOPA for double-blind mode) using a small animal clipper The hair was removed. Animal hair was reaped as needed to maintain epidermal exposure throughout the course of the study. On the day of administration, an aliquot (643 μL / kg) of the preparation was administered to a 3 cm × 3 cm square part of the animal (neck and shoulder area) around 9 am and repeated around 4 pm.
Four. Four weeks after the lesion, the group began to receive treatment.
Five. A rotarod test was performed 4 weeks after treatment.

FIG. 3 shows the residence time results in the above rotarod test after 4 weeks of treatment (n = 12). FIG. 4 shows the drop velocity results in the above-mentioned Rotarod test after 4 weeks of treatment (n = 12).
Carbidopa was able to reduce its peripheral DDC conversion before levodopa crossed the blood brain barrier, thus reducing the side effects of L-Dopa. This result 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, 10). Shows that the efficacy of the vehicle group and the aspirin prodrug treatment group (Drug B) (Groups 2, 8, and 11) was not altered.
When a combination of multiple drugs (e.g., one or more HPPs and / or other drugs) is administered to a subject, each drug can be administered separately, or one or more drugs can be substantially separated as separate drugs. Can be administered at the same time (e.g., spraying substantially simultaneously without mixing two or more drugs before spraying), or can be administered to a subject after mixing one or more drugs together, or Any combination of the above administration methods is also possible. The drugs can be administered in any order possible.

Example 33. Efficacy of prodrugs of L-Dopa and ibuprofen on improving motor function deficits and reducing nigrostriatal neurodegeneration induced by 6-OHDA in 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 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 Drug D was 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate acetate.

Table 4. Dose and drug administered to test animals

2． Dose 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) Method for preparing test solutions for groups 3-5: 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 dosing 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 administration 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 dosing volume was 1,286 μL / kg.
(3) Preparation method of 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) Method for preparing 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) Method for preparing 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 administration, from the upper back (around the neck and shoulders) of the animals (all rats including those in the positive control group using L-DOPA for double-blind mode) using a small animal clipper The hair was removed. Animal hair was reaped as needed to maintain epidermal exposure throughout the course of the study. On the day of administration, an aliquot (643 μL / kg) of the preparation was administered to a 3 cm × 3 cm square part of the animal (neck and shoulder area) around 9 am and repeated around 4 pm.
Four. Four weeks after the lesion, the group began to receive treatment.
Five. A rotarod test will be performed 4 weeks after treatment.

FIG. 5 shows the residence time results in the above rotarod test after 4 weeks of treatment (n = 12). FIG. 6 shows the drop velocity results in the above-mentioned Rotarod test after 4 weeks of treatment (n = 12).
By pulling all batch data together (12 animals / group), the positive group (L-DOPA, 6 mg / kg, oral) was compared to the negative control group after 4 weeks of treatment. However, all study drug treatment groups were more potent than the vehicle group after 4 weeks of treatment. Since levodopa caused nausea, vomiting, gastrointestinal bleeding, dyskinesia at peak doses and reduced end-of-dose of function, the positive group (L-DOPA, 6 mg / kg, oral) Not as effective as the vehicle group. However, transdermally administered L-Dopa prodrug (Compound C) avoided dyskinesia at peak doses and end-of-dose functional decline. The low dose potency of drug C (L-Dopa prodrug, 0.67 mg / kg, group 3) is much higher than the potency of medium and high doses of drug C (2 mg and 6 mg / kg, groups 4 and 5) it was high. This result indicated that the dose of prodrug administered transdermally with L-dopa was much lower than L-dopa administered orally. 15 mg and 45 mg / kg of Drug D (a prodrug of ibuprofen) showed better efficacy than the vehicle group and the 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 a higher dose was 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 (Groups 8 and 11) or Drug C (Group 3) alone.

Example 34. L-Dopa and ibuprofen prodrugs and 1.5 mg / kg on improvement of motor function defects and reduction of nigrostriatal neurodegeneration induced by 6-OHDA in Parkinson's disease (PD) model in HDB The efficacy of carbidopa.
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 drugs were administered to each group at the doses shown in Table 5 below.

Table 5. Dose and drug administered to test animals

2． Dose prescription
(1) L-DOPA (3 mg / ml) and carbidopa (1.5 mg / mL) in water were both used as positive control solutions for group 1 (oral). The dosing volume was 2 mL / kg. Carbidopa (1.5 mg / mL) in water was administered to groups 2-11 as an aromatic L-amino acid decarboxylase inhibitor (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 1,286 μL / kg. Other test solutions (transdermal, groups 3-11) were prepared fresh daily.
(2) Method for preparing test solutions for groups 3-5: 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 administration 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 administration 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 dosing volume was 1,286 μL / kg.
(3) Preparation method of 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) Method for preparing 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) Method for preparing 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 administration, from the upper back (around the neck and shoulders) of the animals (all rats including those in the positive control group using L-DOPA for double-blind mode) using a small animal clipper The hair was removed. Animal hair was reaped as needed to maintain epidermal exposure throughout the course of the study. On the day of administration, an aliquot (643 μL / kg) of the preparation was administered to a 3 cm × 3 cm square part of the animal (neck and shoulder area) around 9 am and repeated around 4 pm.
Four. Four weeks after the lesion, the group began to receive treatment.
Five. A rotarod test was performed 4 weeks after treatment.

FIG. 7 shows the residence time results in the above rotarod test after 4 weeks of treatment (n = 12). FIG. 8 shows the drop velocity results in the above-mentioned Rotarod test after 4 weeks of treatment (n = 12).
Carbidopa was able to reduce its peripheral DDC conversion before levodopa crossed the blood brain barrier, thus reducing the side effects of L-Dopa. This result 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. It shows that the efficacy of the prodrug treatment groups (groups 2, 8, and 11) was not changed.

Example 35. 4- (2-(((1-((Pyrrolidine-(Pyrrolidine--) on the improvement of motor function deficits and reduction of nigrostriatal neurodegeneration induced by 6-OHDA in Parkinson disease (PD) model in HDB 2-carbonyl) oxy) ethoxy) amino) ethyl) -1,2, -phenylenedibenzoate hydrochloride (drug E) and 4- (dimethylamino) butyl 2- (3-phenoxyphenyl) propionate hydrochloride (Drug F) efficacy.
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 drugs were administered to each group at the doses shown in Table 6 below.

Table 6. Dose and drug administered to test animals

2． Dose prescription
(1) L-DOPA (3 mg / ml) in water was a positive control solution for group 1 (oral for group 1). The dosing volume was 2 mL / kg. The vehicle solution (negative control solution for group 2) was 30% ethanol (v / v). The dosing volume was 1,286 μL / kg. Other test solutions (groups 3-11) were prepared fresh daily.
(2) Method for preparing test solutions for groups 3-5: 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 drug E group 5 (high dose group): stock solution (2) was the test solution for group 5. The dosing volume was 1,286 μL / kg;
b. Test solution for drug E 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 administration volume was 1,286 μL / kg;
c. Test solution for drug E 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 dosing 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) Preparation method of 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) Method for preparing 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 administration, from the upper back (around the neck and shoulders) of the animals (all rats including those in the positive control group using L-DOPA for double-blind mode) using a small animal clipper The hair was removed. Animal hair was reaped as needed to maintain epidermal exposure throughout the course of the study. On the day of administration, an aliquot (643 μL / kg) of the preparation was administered to a 3 cm × 3 cm square part of the animal (neck and shoulder area) around 9 am and repeated around 4 pm.
Four. Four weeks after the lesion, the group began to receive treatment.
Five. A rotarod test was performed 4 weeks after treatment.

FIG. 9 shows the residence time results in the above rotarod test after 4 weeks of treatment (n = 12). FIG. 10 shows the drop speed results in the above-mentioned rotor rod test after 4 weeks of treatment (n = 12).
By pulling all batch data together (12 animals / group), the positive group (L-DOPA, 6 mg / kg po) was more effective than the vehicle group after 4 weeks of treatment. Not shown. However, all study drug treatment groups showed stronger efficacy than the vehicle group after 4 weeks of treatment. Levodopa and dopamine caused nausea, vomiting, gastrointestinal hemorrhage, dyskinesia at peak dose and reduced end-of-dose of function, positive group (L-DOPA, 6 mg / kg, oral) Was not as effective as the vehicle group. However, transdermally administered prodrugs of dopamine avoided dyskinesias at peak doses and end-of-dose functional loss. Drug E low dose efficacy (dopamine prodrug, 0.5 mg / kg, group 3) is the drug E medium and high dose (1.5 mg and 4.5 mg / kg, groups 4 and 5) efficacy Since it was much higher, higher doses of Drug E may have caused more side effects than L-dopa did. Drug F at 20 mg and 60 mg / kg showed better efficacy after 4 weeks of treatment compared to the vehicle group and the positive control group. 20 mg Drug F (Group 8) showed similar efficacy as 60 mg Drug F (Group 11). This result indicated that a dose of 20 mg / kg was sufficient and a higher dose was not necessary. Administration of a combination of Drug E and Drug F (Group 6 and Group 9) to subjects performed much better than administration of either Drug F (Groups 8 and 11) or Drug E (Group 3) alone.
When a combination of multiple drugs (e.g., one or more HPPs and / or other drugs) is administered to a subject, each drug can be administered separately, or one or more drugs can be substantially separated as separate drugs. Can be administered at the same time (e.g., spraying substantially simultaneously without mixing two or more drugs before spraying), or can be administered to a subject after mixing one or more drugs together, or Any combination of the above administration methods is also possible. The drugs can be administered in any order possible.

Example 36. The effect of drug G ((S) -4- (2-amino- 3- (Heptan-4-yloxy) -3-oxopropyl) -1,2-phenylenedibenzoate hydrochloride) and the drug H (2- (dipropylamino) ethyl 4-acetoxy-2 ′, 4′- Efficacy of difluoro- [1,1'-biphenyl] -3-carboxylate hydrochloride) Test subjects (Sprague-Dawley rats) were prepared as described in Example 31 and the groups were And tested.
1． 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. Dose and drug administered to test animals

2． Dose 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 administration volume was 1,286 μL / kg. Other test solutions (groups 3-11) were prepared fresh daily.
(2) Method for preparing test solutions for groups 3-5: 50.33 mg of drug G was dissolved in 10 mL of 30% ethanol (v / v). This solution was the stock solution (2).
a. Drug G group 5 (high dose group) test solution: Storage solution (2) was the group 5 test solution. The dosing volume was 1,286 μL / kg;
b. Test solution for drug G 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 administration volume was 1,286 μL / kg;
c. Test solution for drug G 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 dosing 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) Preparation method of 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) Method for preparing 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 administration, from the upper back (around the neck and shoulders) of the animals (all rats including those in the positive control group using L-DOPA for double-blind mode) using a small animal clipper The hair was removed. Animal hair was reaped as needed to maintain epidermal exposure throughout the course of the study. On the day of administration, an aliquot (643 μL / kg) of the preparation was administered to a 3 cm × 3 cm square part of the animal (neck and shoulder area) around 9 am and repeated around 4 pm.
Four. Four weeks after the lesion, the group began to receive treatment.
Five. A rotarod test was performed 4 weeks after treatment.

FIG. 11 shows the residence time results in the above rotarod test after 4 weeks of treatment (n = 12). FIG. 12 shows the drop velocity results in the above-mentioned Rotarod test after 4 weeks of treatment (n = 12).
By pulling all batch data together (12 animals / group), the positive group (L-DOPA, 6 mg / kg po) was more effective than the vehicle group after 4 weeks of treatment. Not shown. However, all study drug treatment groups showed stronger efficacy than the vehicle group after 4 weeks of treatment. Levodopa caused nausea, vomiting, gastrointestinal bleeding, dyskinesia at peak doses and reduced end-of-dosage of function, so the positive group (L-DOPA, 6 mg / kg, oral) It showed no efficacy compared to the group. However, transdermal L-Dopa prodrugs avoided dyskinesia at peak doses and end-of-dose functional loss. The efficacy of the low dose of drug G (L-Dopa prodrug, 0.67 mg / kg, group 3) is much higher than the efficacy of the 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, as did L-dopa. Drug H at 15 mg and 45 mg / kg showed better efficacy after 4 weeks of treatment compared to the vehicle group and the positive control group. 15 mg of drug H (group 8) was as potent as 45 mg of drug H (group 11). This suggested that a dose of 15 mg / kg was sufficient and a higher dose was not necessary. Administration of the combination of Drug G and Drug H (Group 6 and Group 9) performed much better than administration of either Drug H (Groups 8 and 11) or Drug G (Group 3) alone.
When a combination of multiple drugs (e.g., one or more HPPs and / or other drugs) is administered to a subject, each drug can be administered separately, or one or more drugs can be substantially separated as separate drugs. Can be administered at the same time (e.g., spraying substantially simultaneously without mixing two or more drugs before spraying), or can be administered to a subject after mixing one or more drugs together, or Any combination of the above administration methods is also possible. The drugs can be administered in any order possible.

Example 37. Drug A (percutaneous), drug B (percutaneous), effects on improvement of motor function defect and reduction of nigrostriatal neurodegeneration induced by 6-OHDA in Parkinson's disease (PD) model in HDB And Entacapone (oral) efficacy.
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 drugs were administered to each group at the doses shown in Table 8 below.

Table 8. Dose and drug administered to test animals

2． Dose prescription
(1) L-DOPA (3 mg / ml) and Entacapone (12.5 mg / mL) in 0.5% CMC-Na (carboxymethylcellulose sodium salt) are 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 to groups 2-11 (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 1,286 μL / kg. Other test solutions (transdermal, groups 3-11) were prepared fresh daily.
(2) Preparation method of test solutions 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 Group 5 (high dose group) of Drug A. The administration volume was 1,286 μL / kg;
b. Test solution for drug A 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 administration 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 dosing 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) Preparation method of 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 Group 11 test solution.

3． The day before the scheduled administration, from the upper back (around the neck and shoulders) of the animals (all rats including those in the positive control group using L-DOPA for double-blind mode) using a small animal clipper The hair was removed. Animal hair was reaped as needed to maintain epidermal exposure throughout the course of the study. On the day of administration, an aliquot (643 μL / kg) of the preparation was administered to a 3 cm × 3 cm square part of the animal (neck and shoulder area) around 9 am and repeated around 4 pm.
Four. Four weeks after the lesion, the group began to receive treatment.
Five. A rotarod test was performed 4 weeks after treatment.

FIG. 13 shows the residence time results in the above rotarod test after 4 weeks of treatment (n = 12). FIG. 14 shows the drop velocity results in the above-mentioned Rotarod test after 4 weeks of treatment (n = 12).
Entacapone is a catechol-O-methyltransferase inhibitor that blocks COMT from metabolizing L-DOPA to 3-methoxy-4-hydroxy-L-phenylalanine in the periphery. Avoid undesirable effects. This result indicates 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 the vehicle group and aspirin It was shown that the prodrug treatment group (groups 2, 8 and 11) did not change the efficacy.
When a combination of multiple drugs (e.g., one or more HPPs and / or other drugs) is administered to a subject, each drug can be administered separately, or one or more drugs can be substantially separated as separate drugs. Can be administered at the same time (e.g., spraying substantially simultaneously without mixing two or more drugs before spraying), or can be administered to a subject after mixing one or more drugs together, or Any combination of the above administration methods is also possible. The drugs can be administered in any order possible.

Example 38. Drug A (percutaneous), drug B (percutaneous), effects on improvement of motor function defect and reduction of nigrostriatal neurodegeneration induced by 6-OHDA in Parkinson's disease (PD) model in 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． 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. Dose and drug administered to test animals

2． Dose 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 control for group 1 (oral). -The volume of administration 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 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 1,286 μL / kg. Other test solutions (transdermal, groups 3-11) were prepared fresh daily.
(2) Preparation method of test solutions 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 Group 5 (high dose group) of Drug A. The administration volume was 1,286 μL / kg;
b. Test solution for drug A 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 administration 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 dosing 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) Preparation method of 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 Group 11 test solution.

3． The day before the scheduled administration, from the upper back (around the neck and shoulders) of the animals (all rats including those in the positive control group using L-DOPA for double-blind mode) using a small animal clipper The hair was removed. Animal hair was reaped as needed to maintain epidermal exposure throughout the course of the study. On the day of administration, an aliquot (643 μL / kg) of the preparation was administered to a 3 cm × 3 cm square part of the animal (neck and shoulder area) around 9 am and repeated around 4 pm.
Four. Four weeks after the lesion, the group began to receive treatment.
Five. A rotarod test was performed 4 weeks after treatment.

FIG. 15 shows the residence time results in the above rotarod test after 4 weeks of treatment (n = 12). FIG. 16 shows the drop velocity results in the above-mentioned Rotarod test after 4 weeks of treatment (n = 12).
Administration of the combination of carbidopa and entacapone performed better than administration of either carbidopa or entacapone alone. This result shows that the combination of carbidopa and entacapone enhances the efficacy of all L-Dopa and L-Dopa prodrug treatment groups (Groups 1, 3, 4, 5, 6, 7, 9, 10). It was shown that the efficacy of the group and the aspirin prodrug treatment group (groups 2, 8, and 11) was not changed.
When a combination of multiple drugs (e.g., one or more HPPs and / or other drugs) is administered to a subject, each drug can be administered separately, or one or more drugs can be substantially separated as separate drugs. Can be administered at the same time (e.g., spraying substantially simultaneously without mixing two or more drugs before spraying), or can be administered to a subject after mixing one or more drugs together, or Any combination of the above administration methods is also possible. The drugs can be administered in any order possible.

Example 39. Treatment of Parkinson's disease and related conditions
Administer a solution of 15 mg Drug A and 30 mg Drug B in 0.5 ml water to the skin of the subject's neck, chest, back and any other part every 3-10 hours as needed (transdermal) To do.
Example 40. Treatment of Parkinson's disease and related conditions
Administer a solution of 10 mg Drug A and 20 mg Drug B in 0.5 ml water to the skin of the subject's neck, chest, back and any other part every 3-10 hours as needed (transdermal) To do.
Example 41. Treatment of Parkinson's disease and related conditions
Administer a solution of 20 mg Drug A and 40 mg Drug B in 0.5 ml of water to the skin of the subject's neck, chest, back and any other part every 3-10 hours as needed (transdermal) To do.
Example 42. Treatment of Parkinson's disease and related conditions
Administer a solution of 30 mg Drug A and 50 mg Drug B in 0.5 ml of water to the skin of the subject's neck, chest, back and any other part every 3-10 hours as needed (transdermal) To do.
Example 43. Treatment of Parkinson's disease and related conditions
Administer a solution of 15 mg Drug A and 30 mg Drug B in 0.5 ml water to the skin of the subject's neck, chest, back and any other part every 3-10 hours as needed (transdermal) To do. Tablets containing 10 mg carbidopa and / or inert ingredients such as cellulose, mannitol, sodium croscarmellose, vegetable oil, hydroxypropylmethylcellulose, etc. after or before administration of the above solution Increase the efficacy of transdermal treatment by taking orally.
Example 44. Treatment of Parkinson's disease and related conditions
Administer a solution of 20 mg Drug A and 40 mg Drug B in 0.5 ml of water to the skin of the subject's neck, chest, back and any other part every 3-10 hours as needed (transdermal) To do. Tablets containing 15 mg carbidopa and / or inert ingredients such as cellulose, mannitol, sodium croscarmellose, vegetable oil, hydroxypropylmethylcellulose, etc. after or before administration of the above solution Increase the efficacy of transdermal treatment by taking orally.
Example 45. Treatment of Parkinson's disease and related conditions
A solution of 15 mg Drug A and 30 mg Drug B in 0.5 ml of water is administered (transdermally) to the subject's neck, chest, back and any other part of the skin every 3-10 hours. After or before administration of the above solution, 15 mg carbidopa, 70 mg entacapone and / or inert ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose, etc. Increase the efficacy of transdermal treatment by taking the contained tablets orally.
Example 46. Treatment of Parkinson's disease and related conditions
A solution of 20 mg Drug A and 40 mg Drug B in 0.5 ml water is administered (transdermal) to the skin of the subject's neck, chest, back and any other part every 3-10 hours. After or before administration of the above solution, 15 mg carbidopa, 100 mg entacapone and / or inert ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose, etc. Increase the efficacy of transdermal treatment by taking the contained tablets orally.

Example 47. Treatment of Parkinson's disease and related conditions
A solution of 10 mg Drug C and 15 mg Drug D in 0.5 ml water is administered (transdermal) to the skin of the subject's neck, chest, back and any other part every 3-10 hours.
Example 49. Treatment of Parkinson's disease and related conditions
A solution of 30 mg Drug C and 30 mg Drug D in 0.5 ml water is administered (transdermally) to the skin of the subject's neck, chest, back and any other part every 3-10 hours.
Example 50. Treatment of Parkinson's disease and related conditions
A solution of 20 mg Drug C and 15 mg Drug D in 0.5 ml water is administered (transdermal) to the skin of the subject's neck, chest, back and any other part every 3-10 hours. Tablets containing 15 mg carbidopa and / or inert ingredients such as cellulose, mannitol, sodium croscarmellose, vegetable oil, hydroxypropylmethylcellulose, etc. after or before administration of the above solution Increase the efficacy of transdermal treatment by taking orally.
Example 51. Treatment of Parkinson's disease and related conditions
A solution of 10 mg Drug C and 10 mg Drug D in 0.5 ml of water is administered (transdermally) to the subject's neck, chest, back and any other part of the skin every 3-10 hours. After or before administration of the above solution, 15 mg carbidopa, 100 mg entacapone and / or inert ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose, etc. Increase the efficacy of transdermal treatment by taking the contained tablets orally.
Example 52. Treatment of Parkinson's disease and related conditions
A solution of 30 mg Drug C and 20 mg Drug D in 0.5 ml water is administered (transdermally) to the subject's neck, chest, back and any other part of the skin every 3-10 hours. After or before administration of the above solution, 15 mg carbidopa, 70 mg entacapone and / or inert ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose, etc. Increase the efficacy of transdermal treatment by taking the contained tablets orally.
Example 53. Treatment of Parkinson's disease and related conditions
A solution of 30 mg Drug C and 25 mg Drug D in 0.5 ml water is administered (transdermal) to the subject's neck, chest, back and any other part of the skin every 3-10 hours. After or before administration of the above solution, 10 mg carbidopa, 50 mg entacapone and / or inert ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose, etc. Increase the efficacy of transdermal treatment by taking the contained tablets orally.

Example 54. Treatment of Parkinson's disease and related conditions
A solution of 10 mg Drug E and 10 mg Drug F in 0.5 ml water is administered (transdermal) to the skin of the subject's neck, chest, back and any other part every 3-10 hours.
Example 55. Treatment of Parkinson's disease and related conditions
A solution of 20 mg Drug E and 20 mg Drug F in 0.5 ml water is administered (transdermal) to the subject's neck, chest, back and any other part of the skin every 3-10 hours.
Example 56. Treatment of Parkinson's disease and related conditions
A solution of 5 mg Drug E and 10 mg Drug F in 0.5 ml water is administered (transdermally) to the subject's neck, chest, back and any other part of the skin every 3-10 hours.
Example 57. Treatment of Parkinson's disease and related conditions
A solution of 10 mg Drug G and 10 mg Drug H in 0.5 ml water is administered (transdermally) to the skin of the subject's neck, chest, back and any other part every 3-10 hours.
Example 58. Treatment of Parkinson's disease and related conditions
A solution of 15 mg Drug G and 15 mg Drug H in 0.5 ml water is administered (transdermal) to the skin of the subject's neck, chest, back and any other part every 3-10 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 part every 3-10 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 part every 3-10 hours. After or before administration of the above solution, 10 mg carbidopa, 70 mg entacapone and / or inactive ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose, etc. Increase the efficacy of transdermal treatment by taking the contained tablets orally.
Example 61. Treatment of Parkinson's disease and related conditions
A solution of 10 mg Drug G and 10 mg Drug H in 0.5 ml water is administered (transdermally) to the skin of the subject's neck, chest, back and any other part every 3-10 hours. After or before administration of the above solution, 10 mg carbidopa, 50 mg entacapone and / or inert ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose, etc. Increase the efficacy of transdermal treatment by taking the contained tablets orally.

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 part every 3-10 hours. After or before administration of the above solution, 15 mg carbidopa, 100 mg entacapone and / or inert ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose, etc. Increase the efficacy of transdermal treatment by taking the contained tablets orally.
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, structural Pro-dopamine-2, structural Pro-dopamine-3, structural Pro-dopamine-4, and structural Pro-dopamine-5:

A compound comprising a structure selected from the group consisting of including stereoisomers and pharmaceutically acceptable salts thereof
(In a specific embodiment, 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 absent and 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, tartaric 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 NR ₃ ; X ₂ is absent, O, S, NR ₃ , CHR ₃ —O, CHR ₃ —S, CHR ₃ —O, O—CHR ₃ 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 is composed of R ₃ C (═O), R ₃ OC (═O), and R ₃ SC (═O) Selected from the group; 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 R ₃ , OR ₃ , _{SR 3, NR 3 R 4,} O-CHR 3 -OR 4, O-CHR 3 -SR 4, is selected from the group consisting of S-CHR ₃ -OR _4;
n and m are selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8.
Rc 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, wherein any CH _{2 in} R is May be further substituted with O, S, P, NR ₆ , 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, wherein any CH _{2 in} R is May be further substituted with O, S, P, NR ₆ , 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 halide, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, wherein any of R CH ₂ may also be further replaced by O, S, P, NR ₆ , 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 selected from the group consisting of unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, -C (= O) -W, L ₁ -L ₄ -L ₂ -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 (L ₅ )-, -O -CH ₂ -O-, -O-CH (L ₃ ) -O, and -S-CH (L ₃ ) -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 is independently absent, H, CH ₂ C (═O) OL ₆ , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl Substituted, 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 any carbon or hydrogen further independently substituted with O, S, P, NL ₃ , or any other pharmaceutically acceptable group. 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, wherein Carbon or hydrogen is also independently replaced by O, S, N, P (O) OL ₆ , CH═CH, C≡C, CHL ₆ , CL ₆ L ₇ , aryl, heteroaryl, or a cyclic group. May be;
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, wherein Carbon or hydrogen is also independently replaced by O, S, N, P (O) OL ₆ , CH═CH, C≡C, CHL ₆ , CL ₆ L ₇ , aryl, heteroaryl, or a cyclic group. May be;
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 groups, pharmaceutically acceptable substituted and unsubstituted amine groups, 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 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).
[2] The high-permeability prodrug according to [1]; 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. The pharmaceutical composition as described.
[4] A pharmaceutical composition comprising levodopa, dopamine, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), and one or more high-permeability prodrugs of any combination thereof.
[5] Administered transdermally for the treatment of Parkinson's disease and related conditions, including levodopa, dopamine, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), and any combination of highly permeable prodrugs Pharmaceutical composition, in addition to carbidopa, benserazide, difluoromethyldopa, α-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, -phenylenedibenzoate hydrochloride, 4- (2- (2- (methylamino) acetamido) ethyl) -1, 2, -phenylenedibenzoate acetic acid, 4- (6-methyl-4,8-dioxo-5,7-dioxa-2,9-diazadecan-11-yl) -1,2, -phenylenedibenzoate hydrobromic acid Salt, 4- (2- (2-amino-3-phenylpropanamido) ethyl) -1,2, -phenylenedibenzoate 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) hydrochloric acid Salt, 4- (2-((((-octahydro-1H-quinolizin-3-yl) oxy) carbonyl) amino) ethyl) -1,2, -phenylenebis (2-ethylbutanoate) acetate, 1- (((2- (4-Amino-2,5-dioxo-2,3,4,5-tetrahydride Benzo [b] [1,4] dioxocin-8-yl) ethyl) carbamoyl) oxy) ethyl isobutyrate hydrofluoride, 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) phenyl benzoate hydrochloride, 5- (2-((ethoxycarbonyl) amino) ethyl) -2- (2-methylamino) acetoxy) phenyl benzoate hydrochloride 4- (2-aminoethyl) -1,2-phenylenedibenzoate hydrochloride, (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylenedibenzoate hydrochloride Salt, (S) -4- (2-amino-3- (heptan-4-yloxy) -3-oxopropyl) -1,2-phenylenedibenzoate hydrochloride, (S) -4- (2-amino- 3-Isopropoxy-3-oxo (Lopyl) -1,2-phenylenedipentanoate hydrochloride, (S) -4- (2-amino-3-ethoxy-3-oxopropyl) -1,2-phenylenediacetate 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-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-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- (iso Butyryloxy) 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) Xyl) 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- (dimethyl Amino) 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 hydrochloride, Parkinson's disease For the treatment of fine-related conditions, the pharmaceutical composition to be administered transdermally
[7] Parkinson's disease including (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylene dibenzoate and 2- (diethylamino) ethyl 2-acetoxybenzoate and A pharmaceutical composition 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.
[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, -phenylenedibenzoate 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-phenylenedibenzoate 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-phenylenedibenzoate 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]; 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 orally Administering a step of administering.

Claims (14)

The following structure Pro-L-Dopa-2, structure Pro-L-Dopa-3, structure Pro-L-Dopa-4, and structure Pro-L-Dopa-5:
And a compound comprising a structure selected from the group consisting of its stereoisomers or pharmaceutically acceptable salts thereof,
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 and structure W-12:
Selected from the group consisting of;
HA is selected from the group consisting of absent and pharmaceutically acceptable acids;
HA ₁ is a pharmaceutically acceptable acid;
X is selected from the group consisting of O, S, and NR ₃ ;
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 selected from the group consisting of 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);
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 , SR ₃ , NR ₃ R ₄ , O—CHR ₃ —OR ₄ , O—CHR ₃ —SR ₄ , S—CHR ₃ —OR ₄ ;
n and m are independently selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8;
Rc is absent, substituted and unsubstituted alkylene, substituted and unsubstituted cycloalkyl alkylene, substituted and unsubstituted heterocycloalkylene, substituted and unsubstituted aralkyl Kiren'okishi, substituted and unsubstituted perfluoroalkylene, substituted and unsubstituted alkylene halides, substituted and unsubstituted alkenyl alkylene, substituted and unsubstituted arylene, and is selected from the group consisting of substituted and unsubstituted heteroarylene Len, where any of the CH ₂ is also O in Rc, S, P, or NR ₆ It may be replaced with;
R _{is, CH 2 C (= O)} OR 6, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy shea, substituted and unsubstituted perfluoroalkyl, substituted and Selected from the group consisting of unsubstituted alkyl halides, substituted and unsubstituted alkenyls, substituted and unsubstituted alkynyls, substituted and unsubstituted aryls, and substituted and unsubstituted heteroaryls, wherein any CH _{2 in} R is O, May be replaced with S, P, or NR ₆ ;
R ₃ and R ₄ are _{independently, CH 2 C (= O)} OR 6, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy shea, substituted and Selected from the group consisting of unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halides, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, wherein R ₃ or Any CH ₂ in R ₄ may be replaced by O, S, P, or NR ₆ ;
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 Arukiruoki shea, substituted and unsubstituted cycloalkyl Oki shea, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, -C (= O) -W, -L 1 -L Selected from the group consisting of ₄ -L ₂ -W, and W;
Each R ₅ is independently H, C (= O) NH ₂ , 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 Arukiruoki shea, substituted and unsubstituted cycloalkyl Oki shea, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, Selected from the group consisting of substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, —C (═O) —W, L ₁ -L ₄ -L ₂ -W, and W;
L ₁ is _{absent, O, S, -OL 5 -} , - SL 5 -, - N (L 3) -, - N (L 3) -CH 2 -O, -N (L 3) -CH 2 Selected from the group consisting of -N (L ₃ )-, -O-CH ₂ -O-, -O-CH (L ₃ ) -O, and -S-CH (L ₃ ) -O-;
L ₂ is _{absent, O, S, -OL 5 -} , - SL 5 -, - N (L 3) -, - N (L 3) -CH 2 -O, -N (L 3) -CH 2 -N (L ₃ )-, -O-CH ₂ -O-, -O-CH (L ₃ ) -O, -S-CH (L ₃ ) -O-, -NH-L _5- , -N ( L ₃ ) -L ₅ -and L ₅ ,

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 is independently H, CH ₂ C (═O) OL ₆ , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted hetero cycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy shea, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halides It is selected from the group consisting of, wherein any of the carbon or hydrogen even further, independently, O, may be replaced S, or a P;
For each L ₁ , L ₂ , and L ₄ , each L ₅ is independently CHC (═O) OL ₆ , substituted and unsubstituted alkylene, substituted and unsubstituted cycloalkylene, substituted and unsubstituted heterocycloalkylene, substituted and unsubstituted arylene, substituted and unsubstituted heteroarylene, substituted and unsubstituted aralkyl key alkyleneoxy, substituted and unsubstituted A alkylene thio, substituted and unsubstituted A alkylene amino, substituted and unsubstituted perfluoroalkylene, and substituted and unsubstituted alkylene It is selected from the group consisting of halide, wherein any of the carbon or hydrogen even further, independently, O, may be replaced S, or a P;
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 unsubstituted heteroaryl, substituted and unsubstituted alkoxy shea, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and is selected from the group consisting of substituted and unsubstituted alkyl halide, wherein any Or may independently be replaced with O, S, N, CH═CH, C≡C, aryl, heteroaryl, or a cyclic group;
R ₁ is, H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted Arukiruoki shea, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted Selected from the group consisting of aryl and substituted and unsubstituted heteroaryl residues;
R ₂ is unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted Arukiruoki shea, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted And selected from the group consisting of unsubstituted heteroaryl residues;
R ₁₁ to R ₁₅ are independently substituted and unsubstituted alkylene, substituted and unsubstituted cycloalkylene, substituted and unsubstituted heterocycloalkylene, substituted and unsubstituted alkyleneoxy, substituted and unsubstituted perfluoroalkylene, substituted and unsubstituted alkylene Selected from the group consisting of halide , substituted and unsubstituted arylene, and substituted and unsubstituted heteroarylene.
Said compound. A compound according to claim 1; a pharmaceutically acceptable carrier; an aromatic L-amino acid decarboxylase inhibitor selected from the group consisting of carbidopa, benserazide, difluoromethyldopa, and α-methyldopa; a group consisting of entacapone and tolcapone A catechol-O-methyltransferase inhibitor selected from: and structure NSAID-1, structure NSAID-2, structure NSAID-3, structure NSAID-4, structure NSAID-5, structure NSAID-6, structure NSAID-7, A pharmaceutical composition comprising 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.
In the structure,
All-Rail, All-Rule-1, All-Rule-2, All-Rail-3, All-Rail-4, All-Rail-5, All-Rail-6, All-Rail-7, All-Rail -8, Arle-9, Arle-10, Arle-11, Arle-12, Arle-13, Arle-14, Arle-15, Arle-16 , Arle-17, Arle-18, Arle-19, Arlele-20, Arlele-21, Arlele-22, Arlele-23, Arlele-24, Ali -Role-25, Ale-26, Alele-27, Alele-28, Alele-29, Alele-30, Alele-31, Alele-32, Alele -33, All-34, All-35, All-36, All-37, All-38, All-39, All--40, All-41 , Ar-42, Ar-43, Ar-44, Ar-45, Ar-46, Ar-47, Ar-48, Ar-49, Ali -50, All-51, All-52, All-53, All-54, All-55, All-56, All-57, All-all -58, aryl-59, aryl-60, aryl-61, aryl-62, Reel-63, aryl-64, aryl-65, aryl-66, aryl-67, aryl-68, aryl-69, aryl-70, and ant -Selected from the group consisting of Le-71:
_{W, HA, X, X 2} , X 3, Y 1, Y 2, Y 3, n, m, R c, R, R 1, R 2, R 3, R 4, R 5, R 6, R 11 to R _15, L _1, L _2, and L ₄ are as defined in claim 1,
X ₆ and X ₈ independently consist of non-existing, 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) OR ₈ , OCH ₃ , OC ₂ H ₅ , OR ₆ , CH ₃ SO ₂ , R ₆ SO ₂ , CH ₃ SO ₃ , R ₆ SO ₃ , NO ₂ , CN, CF ₃ , OCF ₃ , CH ₂ (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 S CH 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 alkoxy shea, substituted and unsubstituted Selected from the group consisting of substituted 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 Arukiruoki shea, 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 Selected from the group consisting of -L ₂ -W, and C-(= O) -W;
Each R ₈ is independently H, F, Cl, Br, I, CH ₃ , C ₂ H ₅ , CF ₃ , CH ₂ CH ₂ F, CH ₂ CH ₂ Cl, CH ₂ CH ₂ Br, CH ₂ CH ₂ I, CH ₂ CHF ₂ , CH ₂ CF ₃ , CH ₂ F, CH ₂ Cl, CH ₂ Br, 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, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and an unsubstituted an alkoxy, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, it is selected from the group consisting of substituted and unsubstituted alkyl halide and substituted and unsubstituted alkylcarbonyl.   The pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable carrier is selected from the group consisting of alcohol, acetone, ester, cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulose, water, and aqueous solution. object.   A pharmaceutical composition comprising one or more compounds according to claim 1. (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylenedibenzoate hydrochloride, (S) -4- (2-amino-3- (heptane-4- (Iloxy) -3-oxopropyl) -1,2-phenylenedibenzoate hydrochloride, (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylenedipentanoate 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-phenylenedibenzoate hydrochloride, 4-((2S) -3-oxo-3- (pentane- 3-yloxy) -2- (pyrrolidine-2-carboxamido) propyl) -1,2-phenylenedibenzoate hydrofluorate, (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-carboxamido) -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-isopropyl Xyl-3-oxopropyl) -2- (2- (methylamino) acetoxy) phenylbenzoate hydrochloride, 4-((2S) -3-isopropoxy-2-((((octahydroindolizine-1- For the treatment of Parkinson's disease and related conditions comprising a highly permeant prodrug selected from yl) oxy) carbonyl) amino) -3-oxopropyl) -1,2-phenylenedibenzoate acetate, and combinations thereof A pharmaceutical composition for transdermal administration,
Furthermore, 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, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate acetate, 2- (diethylamino) ethyl 2-acetoxy One or more selected from benzoate hydrochloride and combinations thereof Of high-permeability prodrugs,
Further, selected from carbidopa, benserazide, difluoromethyldopa, α-methyldopa, other aromatic L-amino acid decarboxylase inhibitors, entacapone, tolcapone, other catechol-O-methyltransferase inhibitors, and combinations thereof May contain additional therapeutic agents that are administered orally,
Said pharmaceutical composition. As the high transmission prodrug, (S)-4-(2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylenediamine benzoate hydrochloride and 2- (diethylamino) ethyl 2-acetoxy benzoate 6. The pharmaceutical composition according to claim 5, comprising hydrochloride. As the high transmission prodrug, (S)-4-(2-Amino-3-oxo-3- (pentan-3-yloxy) propyl) -1,2-phenylene bis (2-methylpropanoate) bromide 6. The pharmaceutical composition according to claim 5, comprising hydrate and 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate acetate. Examples of the highly permeable prodrugs include (S) -4- (2-amino-3- (heptan-4-yloxy) -3-oxopropyl) -1,2-phenylenedibenzoate hydrochloride and 2- (dipropylamino) 6. The pharmaceutical composition according to claim 5 comprising ethyl 4-acetoxy-2 ', 4'-difluoro- [1,1'-biphenyl] -3-carboxylate hydrochloride. The pharmaceutical composition according to any one of claims 2 to 8, for treating Parkinson's disease, wherein the pharmaceutical composition is administered transdermally, and carbidopa, benserazide, difluoromethyldopa, an aromatic L-amino acid decarboxylase inhibitor selected from the group consisting of α-methyldopa, and combinations thereof; and / or a catechol-O-methyltransferase inhibitor selected from the group consisting of entacapone and tolcapone In combination with a pharmaceutical composition for oral administration, or a pharmaceutical composition for oral administration containing the aromatic L-amino acid decarboxylase inhibitor, and a pharmaceutical composition for oral administration containing the catechol-O-methyltransferase inhibitor The pharmaceutical composition used. A compound according to claim 1 and a structure NSAID-1, structure NSAID-2, structure NSAID-3, structure NSAID-4, structure NSAID-5, structure NSAID-6, structure NSAID as defined in claim 2 -7, comprising 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, A pharmaceutical composition for treatment, said pharmaceutical composition being administered transdermally and an aromatic selected from the group consisting of carbidopa, benserazide, difluoromethyldopa, α-methyldopa, and combinations thereof L-amino acid decarboxylase inhibitor; and / or a pharmaceutical composition for oral administration comprising a catechol-O-methyltransferase inhibitor selected from the group consisting of entacapone and tolcapone, or the aromatic L-amino acid decarboxylase Pharmaceutical composition for oral administration comprising an inhibitor And used in combination with pharmaceutical composition for oral administration comprising the catechol -O- methyltransferase enzyme inhibitors, pharmaceutical compositions.   (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylenedibenzoate hydrochloride, (S) -4- (2-amino-3- (heptane-4- (Iloxy) -3-oxopropyl) -1,2-phenylenedibenzoate hydrochloride, (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylenedipentanoate 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-phenylenedibenzoate hydrochloride, 4-((2S) -3-oxo-3- (pentane- 3-yloxy) -2- (pyrrolidine-2-carboxamido) propyl) -1,2-phenylenedibenzoate hydrofluorate, (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-carboxamido) -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 Ci-3-oxopropyl) -2- (2- (methylamino) acetoxy) phenylbenzoate hydrochloride and 4-((2S) -3-isopropoxy-2-((((octahydroindolizine-1 A compound selected from -yl) oxy) carbonyl) amino) -3-oxopropyl) -1,2-phenylenedibenzoate acetate.   A pharmaceutical composition comprising one or more compounds according to claim 11.   13. A transdermal patch comprising the composition of claim 4 or 12, wherein the transdermal patch is used to deliver the composition to a target site.   14. A transdermal patch according to claim 13, wherein the composition is formulated as a powder, spray, ointment, paste, cream, lotion, gel or solution.