JP6987104B2 - A novel hyperpermeable drug for the treatment of Parkinson's disease and its composition - Google Patents

Description

Field of Invention The present invention relates to the field of pharmaceutical compositions. More specifically, one aspect of the invention is a pharmaceutical composition capable of penetrating one or more biological barriers and the subject to prevent and / or treat Parkinson's disease and / or Parkinson's syndrome. The present invention relates to a method of using a pharmaceutical composition.

Background of the Invention Parkinson's disease (PD) is a neuropathy characterized by degeneration of dopamine neuron in the substantia nigra and disappearance of dopamine in the putamen. Although it is considered a movement disorder, it also causes cognitive and behavioral symptoms. Parkinson's disease can result from the death of dopamine-producing cells in the substantia nigra, a region of the midbrain. The cause of this cell death can be unknown (primary parkisonism) or known (secondary parkisonism). 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 dense area. Certain conceptual models of kinetic circuits and their PD-related changes have had great influence since 1980, but some limitations leading to corrections have been noted [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 exerts certain inhibitory effects on a wide range of motor systems, preventing them from being activated at inappropriate times. When making a decision to take a particular action, inhibition of 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 to promote this release of inhibition, whereas low levels of dopamine function, such as those that occur in PD, are due to any given exercise. Also requires greater effort. Therefore, the net effect of dopamine deletion is to cause hypokinesia [Obeso JA, Rodriguez-Oroz MC, Benitez-Temino B, et al. (2008). “Functional organization of the basal ganglia: therapeutic implications for Parkinson's Disease”. Mov. Disord. 23 (Suppl 3): S548-59].

The main line of known drugs for treating motor symptoms is levodopa (usually in combination with dopa decarboxylase inhibitors or COMT inhibitors), dopamine agonists and MAO-B inhibitors [The National Collaborating Center]. for Chronic Conditions, ed. (2006). “Symptomatic pharmacological therapy in Parkinson's Disease”, Parkinson's Disease. London: Royal College of Physicians. pp. 59-100]. Levodopa is well known to improve motor symptoms, but its effect on cognitive and behavioral symptoms is 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 preparation contributes 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 the "wearing off" and / or "on" and "off" states of the drug effect. Or include dyskinesias such as atetosis and dystonia. Levodopa also causes nausea, vomiting, gastrointestinal bleeding, dyskinesia at peak doses, and may also result in 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 invention relates to the HPP of levodopa and / or dopamine.
Another aspect of the invention relates to a pharmaceutical formulation comprising one or more HPPs disclosed herein. In certain embodiments, the pharmaceutical composition comprises one or more hyperpermeable prodrugs of NSAIDs and one or more hyperpermeable prodrugs of dopamine and / or levodopa.
Here, the parent drug of 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 the composition of the invention in penetrating one or more biological barriers of a biological subject.
Another aspect of the invention relates to the composition of the invention, or a method of using a pharmaceutical composition thereof, in treating a condition of a biological subject.
Another aspect of the invention is in treating Parkinson's disease and / or related conditions of a biological subject or subject by administering one or more HPPs or pharmaceutical compositions thereof to the biological subject or subject. Concerning how to use more than a species of HPP or a pharmaceutical composition thereof.

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

Detailed description of the invention
I. Highly permeable prodrug of levodopa One aspect of the present invention is the following structures Pro-L-Dopa-1, structure Pro-L-Dopa-2, structure Pro-L-Dopa-3, structure Pro-L-Dopa-4 and Structure Pro-L-Dopa-5:

It relates to a highly permeable prodrug of levodopa having a structure selected from the group consisting of (including its stereoisomers and pharmaceutically acceptable salts). Here, in the above structure,
W is H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted ally. -L, substituted and unsubstituted heteroary, protonatable amine group, pharmaceutically acceptable substituted and unsubstituted amine group, Structure W-1, Structure W-2, Structure W-3, Structure W below. -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 a non-existent and pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitrate, sulfate acid, bisulfic acid, phosphoric acid, phosphite, phosphon. Acids, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartrate acid, pantothenic acid, heavy tartrate acid, ascorbic acid, succinic acid, maleic acid, gentic acid, fumaric acid, gluconic acid, glucaronic acid, sugar acid , Formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and pamoic acid;
R ₁ and R ₂ are independently H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkenyl, substituted and unsubstituted. Selected from the group consisting of alkynyl, substituted and unsubstituted alleles and substituted and unsubstituted heteroary residues;
R _{11 to} R ₁₅ are independently non-existent, 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 alkoxyls, substituted and unsubstituted perfluoroalkyls, substituted and unsubstituted alkyl halides, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyls, substituted and unsubstituted allells, and substituted and unsubstituted heteroallyl. ;
X is selected from the group consisting of O, S, and NR _3;
X ₂ is non-existent, 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 non-existent, 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. , Substituent and unsubstituted alkyl halides, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted allells, and substituted and unsubstituted heteroary allyls, which are here in R. CH ₂ may also be replaced with 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 alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted allells, and substituted and unsubstituted heteroallyl, whichever is in R. CH ₂ may also be replaced with 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 perfluoroalkyls, substituted and unsubstituted alkyl halides, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyls, substituted and unsubstituted allyls, and substituted and unsubstituted heteroallyl. So, 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-naphthylidine-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 allyl, substituted and unsubstituted heteroary, -C (= O) -W, -L ₁ -L ₄ -L ₂ -W, selected from the group consisting of 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 allyl. , Substituted and unsubstituted heteroary, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, -C (= O) -W, L ₁ -L ₄ -L ₂ -W, and W. Beed;
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 non-existent, C = O, C = S,

Selected from the group consisting of;
For each L ₁ , L ₂ , and L ₄ , each L ₃ and L ₅ , independently absent, H, CH ₂ C (= O) OL ₆ , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl. , Substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alleles, substituted and unsubstituted heteroallyl, substituted and unsubstituted alkoxyls, substituted and unsubstituted alkylthios, substituted and unsubstituted alkylaminos, substituted and unsubstituted perfluoroalkyls. , And a group consisting of substituted and unsubstituted alkyl halides, where any carbon or hydrogen may be further independently 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 allele, Selected from the group consisting of substituted and unsubstituted heteroaries, substituted and unsubstituted alkoxyls, substituted and unsubstituted alkylthios, substituted and unsubstituted alkylaminos, substituted and unsubstituted perfluoroalkyls, and substituted and unsubstituted alkyl halides. , Either carbon or hydrogen, independently, O, S, N, P (O) OL ₆ , CH = CH, C≡C, CHL ₆ , CL ₆ L ₇ , all, hetero all, or May be replaced with a cyclic group;
Each L ₇ is independently H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, Selected from the group consisting of substituted and unsubstituted heteroaries, substituted and unsubstituted alkoxyls, substituted and unsubstituted alkylthios, substituted and unsubstituted alkylaminos, substituted and unsubstituted perfluoroalkyls, and substituted and unsubstituted alkyl halides. , Either carbon or hydrogen is also independently O, S, N, P (O) OL ₆ , CH = CH, C≡C, CHL ₆ , CL ₆ L ₇ , aryl, heteroary, or It may be replaced with a cyclic group; and any CH ₂ group may be replaced with O, S, or NH.

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

With respect to a highly permeable prodrug of dopamine comprising a structure selected from the group consisting of (including its stereoisomers and pharmaceutically acceptable salts). In the above structure, 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 as 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 NSAIDs and one or more highly permeable prodrugs of dopamine and / or levodopa.
Highly transparent prodrugs of NSAIDs include the following structures 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, Structural NSAID-10, Structural NSAID-11, Structural NSAID-12, and Structural NSAID-13:

Includes structures selected from the group consisting of (including its stereoisomers and pharmaceutically acceptable salts). Here, in the above structure,
All-le is the following all-le-1, all-le-2, all-le-3, all-le-4, all-le-5, all-le-6, all-le-7, all-le- Le-8, All-le-9, All-le-10, All-le-11, All-le-12, All-le-13, All-le-14, All-le-15, All-le- 16, Ali-le-17, Ali-le-18, Ali-le-19, Ali-le-20, Ali-le-21, Ali-le-22, Ali-le-23, Ali-le-24, Ali-le-25, Ali-le-26, Ali-le-27, Ali-le-28, Ali-le-29, Ali-le-30, Ali-le-31, Ali-le-32, Ali-le- Le-33, Ali-le-34, Ali-le-35, Ali-le-36, Ali-le-37, Ali-le-38, Ali-le-39, Ali-le-40, All-le- 41, Ari-le-42, Ari-le-43, Ari-le-44, Ari-le-45, Ari-le-46, Ari-le-47, Ari-le-48, Ari-le-49, Ali-le-50, Ali-le-51, Ali-le-52, Ali-le-53, Ali-le-54, Ali-le-55, Ali-le-56, Ali-le-57, Ali-le- Le-58, All-le-59, All-le-60, All-le-61, All-le-62, All-le-63, All-le-64, All-le-65, All-le- 66, All-le-67, All-le-68, All-le-69, All-le-70, and All-le-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 as above;
X ₆ and X ₈ independently consist of non-existence, 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 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 SCH ₂ C (= _{O) NH-, (CH 3} ) ₂ C (OR ₆ )-, CNCH ₂ C (= O) NH-, CNCH ₂ CH ₂ S-, R ₇ HN = CH (NR) ₇ ) CH ₂ CH ₂ S-, CH ₂ = CHCH ₂ SCH ₂ C (= O) NH-, CH ₃ CH (OH)- , CH ₃ CH (OR ₈ )-, CH ₃ CH (Y ₁ )-, (CH ₃ ) ₂ CH-, CH ₃ CH _2- , CH ₃ (CH ₂ ) _n CH = CH (CH ₂ ) _m C ( = O) NH-, substituted and unsubstituted perfluoroalkyls, substituted and unsubstituted alkoxyls, substituted and unsubstituted alkylthios, substituted and unsubstituted alkylaminos, substituted and unsubstituted perfluoroalkyls, substituted and unsubstituted alkyl halides and substituted and unsubstituted alkyl halides. Selected from the group consisting of alkylcarbonyl;
Each R ₇ independently has 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 alkyloxyls, substituted and unsubstituted alkoxys, substituted and unsubstituted alkynyls, substituted and unsubstituted allyls, substituted and unsubstituted heteroallyl, substituted and unsubstituted alkylcarbonyls, substituted and unsubstituted alkylaminos, L ₁ Selected from the group consisting of -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, substitution and none Substituent Perfluoroalkyls, Substituent and Displaced Alkynes, Substituent and Displaced Cycloalkyls, Substituent and Displaced Heterocycloalkyls, Substituent and Displaced Alkoxyls, Substituent and Displaced Alkoxy Aminoes, Substituent and Displaced Perfluoroalkyls, Substituent and Displaced Alkynes It is selected from the group consisting of halides and substituted and unsubstituted alkylcarbonyls.

As used herein, the term "pharmaceutically acceptable salt" means such 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, hydrochlorides, hydrobromides, hydroiodide, nitrates, sulfates, bicarbonates, phosphates, perphosphates. , Isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, heavy tartrate, ascorbate, succinate, maleate, gentisate, fumarate, Gluconate, glucaronate, glycosate, 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 compound of the present invention can form a pharmaceutically acceptable salt 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 dietanolamine salts. For scrutiny of pharmaceutically acceptable salts, the content is incorporated herein by reference to BERGE ET AL. , 66 J. PHARM. SCI. See 1 -19 (1977).

As used herein, unless otherwise specified, the term "alkyl" means a branched or unsaturated saturated or unsaturated monovalent or polyvalent hydrocarbon group, a saturated alkyl group, an alkenyl group and an alkynyl group. Is included. Examples of alkyl are, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, etenyl, propenyl, butenyl. , Isobutenyl, pentyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, heptinyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, ethylene Examples thereof include propylene, butylene, isobutylene, t-butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene and dodecylene. In certain embodiments, the hydrocarbon group contains 1-30 carbons. In certain embodiments, the hydrocarbon group contains 1 to 20 carbons. In certain embodiments, the hydrocarbon group contains 1-12 carbons.
As used herein, unless otherwise specified, the term "cycloalkyl" means an alkyl that contains at least one ring and does not contain an aromatic ring. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. In certain embodiments, the hydrocarbon chain contains 1-30 carbons. In certain embodiments, the hydrocarbon group contains 1 to 20 carbons. In certain embodiments, the hydrocarbon group contains 1-12 carbons.
As used herein, unless otherwise specified, the term "heterocycloalkyl" means cycloalkyl in which at least one ring atom is a non-carbon atom. Examples of non-carbon ring atoms include, but are not limited to, S, O and N.

As used herein, unless otherwise specified, the term "alkoxy" means an alkyl, cycloalkyl or heterocycloalkyl containing one or more oxygen atoms. Examples of alkoxyls are, but are not limited to, -CH ₂ -OH, -OCH ₃ , -OR _e , -R _e -OH, -R _e1 -OR _e2- (in the formula, R _e , R _{e 1} and R _e2 can be the same or different alkyl, cycloalkyl or heterocycloalkyl).
As used herein, unless otherwise specified, the term "alkyl halide" means an alkyl, cycloalkyl or heterocycloalkyl containing one or more identical or different halogen atoms. The term "halogen" means fluorine, chlorine, bromine or iodine. Examples of alkyl halides are, 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)-(in the formula, R _e is an 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 alkylthios are, but are not limited to, -CH ₂ -SH, -SCH ₃ , -SR _e , -R _e -SH, -R _e1 -SR _e2- (in the equation, R _e , R _{e 1} 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 alkylaminos are, 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 (in the formula, 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 are, 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) -R e1). R _e -C (= O) OH), ester group (-R _e -C (= O) OR _e1 ), carboxamide (-R _e -C (= O) ON (R _e1 ) R _e2 ), enon group (-R e -C (= O) ON (R e1) R e2) -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 ) (in the equation, R _e , R _{e1 , R e 2} and R _{e 3} 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, but is not limited to, alkyl, cycloalkyl or heterocycloalkyl containing one or more fluorogroups. Examples thereof 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, the ring atoms are all carbon. In certain embodiments, one or more ring atoms are non-carbon, such as oxygen, nitrogen, or sulfur (“heteroary”). Examples of aryls include, but are not limited to, phenyl, benzyl, naphthalenyl, anthracenyl, pyridyl, quinoyl, isoquinoyl, pyrazinyl, quinoxalinyl, acridinyl, pyrimidinyl, quinazolinyl, pyridadinyl, cinnolinyl, imidazolyl, benzoimidazolyl, prynyl, indrill. , Furanyl, benzofuranyl, isobenzofuranyl, pyrrolyl, indrill, isoindrill, thiophenyl, benzothiophenyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isooxazolyl, benzoisoxazolyl, thiaxolyl, quanizino and benzothiazolyl.

In certain embodiments, the pharmaceutical composition comprises at least one HPP of a parent drug capable of treating Parkinson's disease or a related compound thereof, and a pharmaceutically acceptable carrier.
In certain embodiments, the pharmaceutical composition may comprise multiple HPPs of the same or different parent drug. Different parental drugs belong to the same or different classifications of drugs used to treat Parkinson's disease. For example, the pharmaceutical composition is the HPP of the parent drug or a related compound thereof, wherein the parent drug is selected from the group consisting of levodopa, dopamine, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), and any combination thereof. May include.
The pharmaceutical composition may further contain water.
The pharmaceutical composition may further contain alcohol (eg, etanol, glycerol, isopropanol, octanol, etc.).
In certain embodiments, the pharmaceutical composition is an HPP of the parent drug or its related compound, wherein at least one of the parent drugs is levodopa (eg, structural Pro-L-dopa-1, Pro-L-dopa-). 2, Pro-L-dopa-3, Pro-L-dopa-4, and / or HPP containing one or more structures of Pro-L-dopa-5); HPP which is dopamine (eg, structure Pro-dopamin- 1, Pro-dopamin-2, Pro-dopamin-3, Pro-dopamin-4, and / or structure HPP containing one or more structures of Pro-dopamin-5); and at least one of the parent drug is Aspin or others HPP (eg Structural NSAID-1, Structural NSAID-2, Structural NSAID-3, Structural NSAID-4, Structural NSAID-5, Structural NSAID-6, Structural NSAID-7, NSAID-8, Structural NSAID -9, HPP containing 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 comprises 4- (2- (2- (methylamino) acetamide) ethyl) -1,2,-phenylenedibenzoate hydrochloride, 4- (2- (2- (2- (2-( Methylamino) acetamide) ethyl) -1,2,-phenylenedibenzoate-acetic acid, 4- (6-methyl-4,8-dioxo-5,7-dioxa-2,9-diazadecan-11-yl)- 1,2,-Phenylenedibenzoate-hydrobromide, 4- (2- (2-amino-3-phenylpropanamide) ethyl) -1,2,-Phenylenedibenzoate-hydrochloride, 4- (2-((((1-((Pyrrolidine-2-carbonyl) oxy) ethoxy) amino) ethyl) -1,2,-phenylenedibenzoate hydrochloride, 4- (2-piperidin-4-carboxamide) ethyl ) -1,2,-Phenylenebis (2-ethylbutanoate) hydrochloride, 4-(2-((((-octahydro-1H-quinolidine-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] Dioxosin-8-yl) ethyl) carbamoyl) oxy) ethylisobutyrate-hydrofluoride, 1-(((2- (3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo) [b] [1,4] Dioxocin-8-yl) ethyl) carbamoyl) oxy) 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-amino) Ethyl) -1,2-phenylenedibenzoate hydrochloride, (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylenedibenzoate hydrochloride, ( S) -4- (2-amino-3- (heptane-4-yloxy) -3-oxopropyl) -1,2-phenylenedibenzoate hydrochloride, (S) -4- (2-amino-3) -Isopropoxy-3-oxopropyl) -1,2-phenylenedipentanoate hydrochloride, (S) -4- (2-amino-3-ethoxy-3-oxopropyl) -1,2-phenylenedia Seta-to hydrochloride, (S) -4- (2-) Amino-3-oxo-3- (pentan-3-yloxy) propyl) -1,2-phenylenebis (2-methylpropanol) hydrobromide, (S) -4- (2-aminoacetamide) ) -3-Isopropoxy-3-oxopropyl) -1,2-phenylenedibenzoate hydrochloride, 4-((2S) -3-oxo-3- (pentan-3-yloxy) -2- (pyrrolidin) -2-Carboxamide) Propyl) -1,2-phenylenedibenzoate-hydrofluoride, (S) -4- (3-isopropoxy-3-oxo-2- (piperidine-4-carboxamide) propyl)- 1,2-phenylenedibenzoate hydrochloride, 4-((2S) -3-isopropoxy-3-2- (octahydro-1H-quiolizine-2-carboxamide) -3-oxopropyl) -1 , 2-Phenylenebis (2-methylpropanol) hydrochloride, (2S) -isopropyl3- (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) -isopropyl3- (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-((((octahydroindrin-1-yl) oxy)) Carbonyl) amino) -3-oxopropyl) -1,2-phenylenedibenzoate-toacetate, 2- (diethylamino) ethyl 2-[(2,6-dichloro-3-methylphenyl) amino] benzoate. Aceta-to, (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) propanthioate 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 orally administered.
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 COMT from metabolizing L-DOPA in the periphery to 3-methoxy-4-hydroxy-L-phenylalanine. Avoid the unwanted effects of DOPA.

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

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

For example, the pharmaceutical composition is in addition to the HPP of the parent drug or a related compound selected from the group in which the parent drug consists of levodopa, dopamine, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), and any combination thereof. Includes 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, one or more aromatic L-amino acid decarboxylase inhibitors are orally administered. Aromatic L-amino acid decarboxylase (DOPA decarboxylase or DDC) is an important enzyme for the biosynthesis of L-DOPA to dopamine (DA). DDCs are present both outside the blood-brain barrier (peripheral of the body) and within the area of the blood-brain barrier. DDC inhibitors block the conversion of levodopa to dopamine. However, levodopa given from the outside is metabolized peripherally to its active metabolite dopamine before it reaches the blood-brain barrier. Therefore, dopamine-deficient PD brains will receive less dopamine prodrug precursor levodopa due to peripheral DDC degradation. However, carbidopa as a peripheral DDC inhibitor and other DDC inhibitors can reduce levodopa's peripheral DDC conversion before it crosses the blood-brain barrier. In other words, carbidopa and other DDC inhibitors do not affect the conversion of levodopa to dopamine in the brain. Eventually, a larger proportion of levodopa given from outside reaches the brain.
Examples of DDC inhibitors include, but are not limited to, the following carbidopa, benserazide, difluoromethyldopa, and α-methyldopa.

In certain embodiments, the pharmaceutical composition may comprise one or more HPPs of various parent drugs. The various parental drugs may belong to the same or different classifications of drugs used to treat Parkinson's disease. For example, the pharmaceutical composition is in addition to the HPP of the parent drug or a related compound selected from the group in which the parent drug consists of levodopa, dopamine, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), and any combination thereof. Can include 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-phenylenedibenzoate, 2- (diethylamino) ethyl 2 -Includes acetoxybenzoate, carbidopa and / or entacapone.
In certain embodiments, the pharmaceutical composition comprises (S) -4- (2-amino-3-oxo-3- (pentane-3-yloxy) propyl) -1,2-phenylenebis (2-methylpropanol). -To) and 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate are included.
In certain embodiments, the pharmaceutical composition comprises 4- (2-((((1-((pyrrolidin-2-carbonyl) oxy) ethoxy) amino) ethyl) -1,2, -phenylenedibenzoate and 4 -Contains (dimethylamino) butyl 2- (3-phenoxyphenyl) propionate.
In certain embodiments, the pharmaceutical composition comprises (S) -4- (2-amino-3-oxo-3- (pentane-3-yloxy) propyl) -1,2-phenylenebis (2-methylpropanoa). -To), 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate, carbidopa and / or entacapone.
In certain embodiments, the pharmaceutical composition comprises (S) -4- (2-amino-3- (heptane-4-yloxy) -3-oxopropyl) -1,2-phenylenedibenzoate, and 2 -Contains (dipropylamino) ethyl 4-acetoxy-2', 4'-difluoro- [1,1'-biphenyl] -3-carboxylate.
In certain embodiments, the pharmaceutical composition comprises (S) -4- (2-amino-3- (heptan-4-yloxy) -3-oxopropyl) -1,2-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, a "therapeutically effective amount,""therapeutically effective concentration," or "therapeutically effective dose" is a disease as compared to a corresponding subject who has not received the amount. An amount that results in improved treatment, cure, prevention, or recovery of the disorder, or side effects, or a reduction in the rate of progression of the disease or disorder.
This amount is, but is not limited to, the characteristics of the HPP or pharmaceutical composition thereof disclosed herein (including its activity, pharmacokinetics, pharmacokinetics and bioavailability), the physiology of the subject or cell. The condition (including age, gender, type and stage of disease, general health, responsiveness to a given dosage, and type of drug), 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 or therapeutically effective amount may be the administration of one or more HPPs or pharmaceutical compositions thereof disclosed herein alone or other drugs, other therapies or other therapeutic methods or modality. It may change depending on whether it is used in combination with. Those skilled in the art of clinical and pharmacology will monitor the response of cells or subjects to the administration of one or more HPPs or pharmaceutical compositions thereof disclosed herein by routine experiment, and medicate accordingly. By adjusting the amount, an effective amount or a therapeutically effective amount could be determined. Typical dosages can range from about 0.1 mg / kg to about 100 mg / kg or more, depending on the factors mentioned above. In other embodiments, the dosage can range from about 0.1 mg / kg to about 100 mg / kg, or about 1 mg / kg to about 100 mg / kg, or about 5 mg / kg to about 100 mg / kg. For further guidance, 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 incorporated herein by reference as if fully specified herein for further guidance in determining a therapeutically effective amount.

As used herein, the term "about" represents ± 10%, ± 5%, or ± 1% of the value following "about".
As used herein, the term "pharmaceutically acceptable carrier" refers to one location, body fluid, tissue, organ (internal or external), or part of the body to another location, body fluid, tissue, organ (internal or external). , Or a pharmaceutically acceptable material, composition or vehicle involved in transporting or transporting HPP to a body part, such as a liquid or solid filler, a diluent, an excipient, a solvent or an encapsulating material.
Each carrier is compatible with other components of the pharmaceutical product, such as HPP, and with tissues or organs of biological subject without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications. It is "medically acceptable" in the sense that it is suitable for contact use and is balanced with a reasonable benefit / risk ratio.
In certain embodiments, the pharmaceutically acceptable carriers are from alcohol, acetone, esters, cellulos, mannitol, croscarmellose sodium, vegetable oils, hydroxypropylmethylcelluloses, water, and aqueous solutions. Selected from the group consisting of.
Some examples of materials that may serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucos and sucrose; (2) starches such as corn starch and Potato starch; (3) Cellulose and its derivatives such as sodium carboxymethyl cellulosic, ethyl cellulosic and cellacetate acetate; (4) Tragacant rubber powder; (5) malt; (6) gelatin; (7) Starch; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, red flower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glyco -Les, eg propylene glycol; (11) polyoles, eg glycerin, sorbitol, mannitole and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar. (14) Buffers such as magnesium hydroxide and aluminum hydroxide; (15) Arginic acid; (16) Exothermic depleted water; (17) Isotonic saline; (18) Ringer's solution; (19) Alcor, For example, ethyl alcohol and propane alcohol; (20) phosphate buffer; and (21) other non-toxic compatibles used in pharmaceutical formulations, such as acetone.

The pharmaceutical composition comprises pharmaceutically acceptable auxiliary substances necessary for approaching a physiological state, such as pH regulators and buffers, toxicity regulators, etc., such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, lactic acid. It can contain sodium and the like.
In one embodiment, the pharmaceutically acceptable carrier is an aqueous carrier, such as buffered saline. In certain embodiments, the 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, body weight, etc., according to the individual dosage regimen 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 use. The administration may be by instillation and other convenient routes by topical, mucosal, eg oral, nasal, vaginal, rectal, parenteral, transdermal, subcutaneous, intramuscular, intravenous, inhalation. The pharmaceutical composition can be administered in various unit dosage forms depending on the administration method. 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.
Accordingly, transdermal, oral, and a typical pharmaceutical composition for intravenous administration is about 10 ^-8 g to about 100g per day subject, about 10 ^-8 g to about 10 ^-5 g, about 10 ^{- It} may be 6 g to about 1 g, about ^10-6 g to about 100 g, about 0.001 g to about 100 g, about 0.01 g to about 10 g, or about 0.1 g to about 1 g. Dosages from about 0.001 mg to about 100 g can be used per subject per day. The actual method of preparing a parenteral administrable composition is well known or apparent to those of skill in the art, Remington: The Science and Practice of Pharmacy 21st ed. , Lippincott Williams & Wilkins, (2005).

IV. Application of HPP
i) Methods of permeation of biological barriers.
Another aspect of the invention relates to a method of using the composition of the invention in permeating one or more biological barriers in a biological subject. The method comprises the step of administering HPP or a pharmaceutical composition thereof to a biological subject. In certain embodiments, 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 that of its parent drug. Shows higher permeability through one or more biological barriers.
As used herein, the term "biological barrier" refers to a biological layer that separates an environment into different spatial regions or compartments, which separation is a substance from one compartment / region to another. Can be regulated (eg, controlled, restricted, enhanced or take no action) through, permeate or translocate. The different spatial regions or compartments referred to herein can have the same or different chemical or biological environments. Biological layers referred to herein are, but are not limited to, biological membranes, cell layers, biological structures, objects, organisms, organs or inner surfaces of body cavities, objects, organisms, organs or outer surfaces of body cavities. , Or any combination thereof or a plurality of them.

Examples of biological membranes include lipid bilayer structures, eukaryotic cell membranes, prokaryotic cell membranes, and intracellular membranes (eg, nuclear envelopes or organelle membranes, such as Golgi membranes or envelopes, rough surfaces and small smooth surfaces. Includes vesicles (ER), ribosomes, vacuoles, vesicles, liposomes, mitochondria, lithosomes, nuclear envelopes, chloroplasts, pigments, peroxysomes or microbes.
The lipid bilayer referred to herein is a lipid class molecule, such as, but not limited to, a bilayer of phospholipids and cholesterol. In certain embodiments, the bilayer lipid is an amphipathic molecule consisting of a polar head group and a non-polar fatty acid tail. This double layer forms an oily core in which the hydrocarbon tails of the lipid face each other and are held together by hydrophobic action, while the charged head of the lipid is placed facing the aqueous solution on both sides of the membrane. It is composed of two layers of lipids. In another particular embodiment, the lipid bilayer may contain one or more embedded proteins and / or sugar molecules.
Examples of cell layers include eukaryotic cell linings (eg, epithelium, mucosal eigenlayers and smooth muscle or mucosal muscle plates (in the gastrointestinal tract)), prokaryotic cell linings (eg, composed of the same protein or glycoprotein). Dimensional structure A surface or S layer that refers to a monomolecular layer, specifically the S layer refers to some of the cellular envelopes commonly found in bacteria and paleontology), biofilms (self-generated polymer-matrix). Bacterial communities of microorganisms that are encapsulated and adhere to living or inert surfaces), and plant cell layers (eg, epidermis). The cells may be normal cells or pathogenic cells (eg, diseased cells, cancer cells).
Examples of biological structures include structures that are blocked by tight junctions or tight junctions that provide a barrier to the invasion of toxins, bacteria and viruses, such as the blood-brain barrier and blood-brain barrier (BBB). In particular, the BBB is composed of an impermeable class of endothelium and exhibits both a physical barrier that contacts adjacent endothelial cells via tight junctions and a transport barrier that includes efflux transporters. Biological structures may include a mixture of cells, proteins and sugars (eg, blood clots).

Examples of the inner surface of a subject, organism, organ or body cavity are buccal mucosa, esophageal mucosa, gastric mucosa, intestinal mucosa, olfactory mucosa, oral mucosa, bronchial mucosa, uterine mucosa and endometrial membrane (uterine mucosa, pollen grain wall). Inner layer or inner wall layer of spores), or a combination thereof or a plurality of them.
Examples of the outer surface of a subject, organism, organ or body cavity are capillaries (eg, capillaries within the heart tissue), mucous membranes continuous with the skin (eg, in the nasal passages, lips, eyes, genitals, and anus), organs. External surfaces (eg liver, lungs, stomach, brain, kidneys, heart, ears, eyes, nose, mouth, tongue, colon, pancreas, bladder, duodenum, rectal gastric, colonic rectal, intestinal tract, veins, respiratory system, blood vessels, Anal rectal and pruritus), skin, keratin (eg, epithelial cells or dead layer of keratinocytes or superficial layers of overlapping cells covering animal hair shafts, extradermal multilayered structures in many invertebrates, plant cuticles or Polymactin (cutin) and / or cutan (cutan), the outer layer of the pollen grain wall or the outer wall layer of the spores), and combinations thereof or the like.
In addition, biological barriers further include a sugar layer, a protein layer or any other biological layer, or a combination or plural thereof. For example, the skin is a biological barrier with multiple biological layers. The skin includes an epidermal layer (outer layer), a dermis (demis) layer and a subcutaneous layer. The epidermal layer contains several layers, including a basal cell layer, a stratum spinosum, a granule cell layer, and a stratum corneum. The cells in the epidermis are called keratinocytes. The stratum corneum (“stratum corneum”) is the outermost layer of the epidermis, where the cells are flat and scaly (“scaly”) in shape. These cells contain a large number of keratins and are arranged in a layered state, which imparts firm oil and water resistance to the surface of the skin.

ii) Method of treating Parkinson's disease in a biological subject Another aspect of the present invention relates to a method of using the composition of the present invention or a pharmaceutical composition thereof in treating a condition of a biological subject. The method comprises the step of administering the pharmaceutical composition to a biological subject.
As used herein, the term "treating" means to cure, alleviate, inhibit, or prevent. As used herein, "treat" means cure, alleviate, inhibit, or prevent. As used herein, "treatment" means cure, alleviation, inhibition, or prevention.
As used herein, the term "biological object" or "object" means an organ, a group of organs, organisms, or groups of organisms that work together to perform a particular task. As used herein, the term "organism" means a collection of molecules that are virtually stable as a whole and have the properties of life, such as animals, plants, fungi, or microorganisms.
As used herein, the term "animal" means a eukaryote characterized by voluntary movements. Examples of animals include, but are not limited to, vertebrates (eg, humans, mammals, birds, reptiles, amphibians, fish, marsipobranchiata and leptocardia), tunicata. ) (For example, thaliacea, appendicularia, sorberacea and ascidioidea), articulata (eg, insects, polyfoot, malacapoda, arachnids) Examples include ascidians, arachnids, arachnids, shellfish and ring-shaped animals), gehyrea (anarthropoda), and ascidians (eg, ascidians).
Conditions that can be treated by this method include conditions that can be treated with the parent drug of HPP, namely Parkinson's disease and related conditions.

iii). How to use 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 subject Parkinson's disease and / or related conditions, 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.
HPP or its pharmaceutical composition. It can be administered to biological subjects by any of the technically well-known routes of administration, including, but not limited to, oral, enteral, buccal, nasal, topical, rectal, intravaginal, and aerosol. , Transmucosa, epidermis, transdermal, dermis, eye, lung, subcutaneous, and / or parenteral administration. The pharmaceutical composition can be administered in various unit dosage forms depending on the administration method.
The preferred method of administration is transdermal, dermis, or topical administration for certain compounds.
In certain embodiments, the method further comprises the step of orally administering a therapeutically effective amount of one or more of the above COMT and / or DDC inhibitors.
When multiple drugs (eg, HPP, COMT inhibitors and DDC inhibitors) are administered to a subject, multiple HPP and / or other drugs can be administered at substantially the same time or at different times. Multiple drugs may be mixed together or administered separately to the subject prior to administration to the subject. In certain embodiments, some of the plurality of drugs are mixed prior to administration and the other drug is 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 to be 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 may be applied transdermally, topically, or dermally. On the other hand, one or more of the above COMT inhibitors and / or one or more DDC inhibitors may be orally administered. These plurality of components are applicable 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 pharmaceutical product suitable for each route of administration. Formulations useful for the methods of the invention include one or more HPPs, one or more pharmaceutically acceptable carriers for it, 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 field of pharmacy. The amount of active ingredient that can be mixed with the carrier material to produce a single dosage form will vary depending on the subject being treated and the individual mode of administration. The amount of HPP that can be mixed with the carrier material to provide a pharmaceutically effective dose will generally be that amount of HPP that provides a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent of HPP, preferably about 1 percent to about 20 percent.

The method for preparing these formulations or compositions comprises the step of associating HPP with one or more pharmaceutically acceptable carriers and, optionally, one or more accessory components. Generally, the HPP is uniformly and closely associated with a liquid carrier, a micronized solid carrier, or both, and then, if necessary, the product is prepared by molding.
Suitable formulations for oral administration are capsules, cashews, pills, tablets, lozenge (flavor-based ingredients, usually using scrolls and acacia or tragacant gum), powders, granules, or aqueous or aqueous. In the form of a solution or suspension in a non-aqueous liquid, or as an oil or water emulsion in water, or as an elixir or syrup, or pastille (inert substrate, eg gelatin and glycerin, or (Use capsules and acacia gum) and / or as a mouthwash, etc., each containing a predetermined amount of HPP as an active ingredient. The compound may be administered as a bolus, lick, or paste.
In solid dosage forms for oral administration (eg, capsules, tablets, rounds, dragee, powders, granules, etc.), HPP is one or more pharmaceutically acceptable carriers such as sodium citrate or phosphorus. Dicalcium acid and / or any of the following: (1) fillers or bulking agents such as starch, lactose, scrouse, glucos, mannitol, and / or alginic acid; (2) binding. Agents such as carboxymethyl cellulos, alginate, gelatin, polyvinylpyrrolidone, scrouse 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 retarders such as paraffin, (6) absorption enhancers such as quaternary ammonium compounds; (7) wetting agents such as acetylarco -Le and glycero-le monostearate; (8) absorbents such as kaolin and bentonite clay; (9) abundant agents such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. ; And (10) colorant. In the case of capsules, tablets and pills, the pharmaceutical composition may include a buffer. Excipients such as lactose or lactose, and solid compositions of the same type may be used as fillers in soft and hard packed gelatin capsules using high molecular weight polyethylene glycol and the like.

Tablets can optionally be made by compression or molding with one or more accessory components. Compressed tablets include binders (eg gelatin or hydroxypropylmethylcellulos), abundant agents, inert diluents, preservatives, disintegrants (eg sodium starch glucolate or crosslinked sodium carboxymethylcellulos). , Surface active or dispersant can be used. Molded tablets can be machined with a suitable machine to form a mixture of HPP powdered or moistened by mimicking the peptide with an inert liquid diluent. Tablets and other solid dosage forms such as sugar-coated tablets, capsules, pills and granules may be optionally nicked or are well known in the field of coatings and shells, enteric coatings and other pharmaceutical formulations. It can be prepared using coating. For example, using hydroxypropylmethylcellulos, other polymer-matrix, liposome and / or microspheres in varying proportions to give the desired release profile, delayed or controlled release of HPP within them. It may be formulated as possible. For example, they may be sterilized by filtration through a bacterial retention filter, or sterilized by incorporating a sterile agent in the form of sterile solid composition that can be dissolved in sterile water or some other sterile injection medium immediately before use. You may. These compositions may optionally contain a pacifying agent and, optionally, in a delayed manner, even those that release HPP only in specific parts of the gastrointestinal tract or preferentially. good. Examples of usable embedding compositions are polymer substances and waxes. HPP may be in microencapsulated form containing one or more of the above excipients, where appropriate.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms in addition to HPP include inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, etc. 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 the Inactive Diluent, the oral composition may also include adjuvants such as wetting agents, emulsifying agents, suspending agents, sweeteners, seasonings, colorants, flavors and preservatives.
In addition to HPP, suspensions include suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulos, aluminum metahydroxides, and the like. It may contain bentonite, agar and tragacant gum, and mixtures thereof.

Formulas for rectal or intravaginal administration contain one or more HPPs, such as cocoa butter, polyethylene glycol, suppository wax or salicylate, which are solid at room temperature but liquid at body temperature and therefore rectal. Alternatively, it can be provided as a suppository which can be prepared by mixing with one or more suitable non-irritating excipients or carriers that melt in the vaginal cavity to release the active agent. Suitable formulations for vaginal administration include pessaries, tampons, creams, gels, pastes, foams or sprays containing the carrier, as known to be suitable in the art. -There is also a formulation.
Formulations for topical or transdermal or epidermal or dermal administration of HPP compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredient can be mixed with a pharmaceutically acceptable carrier under sterile conditions and, if necessary, any preservative, buffer, or spray. Ointments, pastes, creams and gels, in addition to HPP compositions, include, for example, animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth gums, cellulosic derivatives, polyethylene glycols, silicones, etc. It may contain excipients such as bentinite, silicic acid, talc and zinc oxide, or mixtures thereof. In addition to the HPP composition, the powder and spray may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. can. The syrup may further contain conventional sprays 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.

Instead, HPP or a pharmaceutical composition thereof can be administered as an aerosol. This can be achieved by preparing an aqueous aerosol, liposome formulation or solid particles containing HPP. A non-aqueous (eg, fluorocarbon spray) suspension could be used. A sonic atomizer can also be used. Aqueous aerosols are made by blending an aqueous solution or suspension of a drug with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers will vary depending on the requirements of the individual compounds, 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 and glycine, buffers, salts, sugars or sugar alcohols are included. Aerosols are generally prepared from isotonic solutions.
The HPP composition can also be delivered to the target site using a transdermal patch. The preparation can be made by dissolving or dispersing the drug in a suitable medium. Absorption enhancers can also be used to increase the flux of peptide mimetics that pass through the skin. The rate of the flux can be controlled by providing a rate control membrane or by dispersing the peptide mimetic in a polymer matrix or gel.
It is also contemplated that eye drops, ointments for the eyes, powders, solutions and the like are within the scope of the present invention.

Suitable formulations for parenteral administration are one or more pharmaceutically acceptable sterile and isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile injectable or dispersions immediately prior to use. Contains HPP with sterile powders that can be reconstituted in, and may contain antioxidants, buffers, bacteriostatic agents, solutes or suspensions or thickeners that make the intended recipient's blood and pharmaceuticals isotonic.
Examples of suitable aqueous and non-aqueous carriers available in formulations suitable for parenteral administration include water, ester, polyol (eg, glycerol, propylene glycol, polyethylene glycol, etc.). , And suitable mixtures thereof, vegetable oils such as olive oil and the like, and organic esters for injection such as ethyl oleate. For example, by using a coating material such as lecithin, by maintaining the required particle size in the case of dispersion, or by using a surfactant, appropriate fluidity can be maintained.
Formulations suitable for parenteral administration may contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersants. The inclusion of various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenolsorbic acid, etc., can be guaranteed to prevent the action of microorganisms. It may be desirable to include isotonic agents such as sugar and sodium chloride in the composition. In addition, delayed absorption in the form of injectable pharmaceuticals can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.
Depot forms for injection are made by forming a microencapsulated matrix of HPP or within a biodegradable polymer such as polylactide-polyglycolide. Depending on the HPP to polymer ratio and the individual polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoester) and poly (anhydride). Depot injection formulations are also prepared by encapsulating HPP in a liposome or microemulsion that is compatible with body tissue.

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 give the most effective results in terms of therapeutic efficiency in a given patient is, for example, the activity of the individual HPP. , Specific properties, drug rate theory, pharmacology, and bioavailability, physiological condition of the subject (race, age, gender, weight, dietary restriction, type and stage of disease, general health condition, for a given dosage) It will depend on the nature of the pharmaceutically acceptable carrier in the formulation (including reactivity and type of drug), the route and frequency of administration used, and the severity or propensity of the condition to be treated. However, the above guidelines can be used as a basis for fine-tuning the treatment, eg, determining the optimal dose of administration, and routine experiments consisting of monitoring the subject and adjusting the dose. You just need it. 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, dyskinesias at peak doses, and may also result in an end-of-dose decline in function. These problems are addressed by transdermal administration of a highly permeable composition of L-Dopa and dopamine capable of consistently delivering the smallest therapeutically effective amounts of gastrointestinal bleeding, dyskinesias, and end-of-function at peak doses. It can be solved by avoiding the decrease in dose.
Recently, there has been increasing evidence from human and animal studies suggesting that neuroinflammation is an important contributor to neuron loss in PD. In addition, the pro-inflammatory agent lipopolysaccharide itself may directly induce degeneration of dopamine-containing neuron or, in combination with other environmental factors such as the insecticide rotenone, may exacerbate the degeneration. These effects strongly support the involvement of inflammation in the pathogenesis of PD. Although dopamine supplementation can reduce the symptoms of the disorder, no therapy has been proven to stop the progressive degeneration of the underlying dopamine-containing neuron. Transdermal administration of L-Dopa and / or dopamine hyperpermeability along with aspirin and / or other NSAID hyperpermeability not only can reduce the symptoms of Parkinson's disease, but also the underlying dopamine-containing nu. -It is also possible to stop the progressive degeneration of Ron.
When transdermally administered a highly permeable composition of L-Dopa and / or dopamine and a highly permeable composition of aspin and / or other NSAIDs, carvidopa, benserazide, difluoromethyldopa, α-methyldopa, and / or administered orally. Other DDC inhibitors and / or entakapon, and tolcapone, and / or other COMT inhibitors allow a larger proportion of externally supplied levodopa or dopamine to reach the brain and reduce the side effects of L-Dopa and / or dopamine. Can be useful for.

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 case. All specific compositions, materials, and methods described below fall within the scope of the invention in whole or in part. These specific compositions, materials, and methods are not intended to limit the invention, but merely illustrate specific embodiments that fall within the scope of the invention. Those skilled in the art can develop equivalent compositions, materials, and methods without exercising their ability to invent and without departing from the scope of the invention. It will be found that various modifications can be made to the procedures described herein, but still remain within the scope of the invention. It is the inventor's intention to include the modification within the scope of the present invention. In addition, all references cited herein are incorporated by reference in their entirety, as if specified herein in their entirety.

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

In this example, dopamine by adding dopamine HCl (19 g) to acetone (200 mL). An HCl solution was prepared. Water (200 mL) and sodium hydrogen carbonate (R0090, 50 g) were added to the dopamine-HCl solution to give the 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 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. 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 pyridine (R0081,30 mL) was added first, and then benzoyl chloride (R0488, 30 g) was added drop by drop to obtain the fifth mixture. The fifth mixture is stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium bucarbonate (2 x 100 mL), water (100 mL), 20% citric acid (2 x 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 give a seventh solution. The 6th and 7th solutions were combined and concentrated to about 200 mL (8th solution). Anisol (20 g) was added to the 8th solution, and then HCl gas (20 g) was whipped to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give 4- (2- (2- (methylamino) acetamide) ethyl) -1,2-phenylenedibenzoate hydrochloride.

Example 2. Preparation of 4- (2- (2- (methylamino) acetamide) ethyl) -1,2,-phenylenedibenzoate-acetic acid.
In this example, 4- (2- (2- (methylamino) acetamide) ethyl) -1,2,-phenylenedibenzoate hydrochloride (23 g) is dissolved in isopropanol (300 mL) to form the first mixture. Got Sodium acetate (4 g) was added to the first mixture to give a second mixture. The second mixture was stirred at RT for 2 hours and filtered to remove the solid in it. The filtered solution was evaporated to dryness to give 4- (2- (2- (methylamino) acetamide) 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 hydrogen carbonate (R0090, 50 g) were added to the dopamine-HCl solution to give the first mixture. Then di-tert-butyl dicarbonate (22 g) was 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 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. 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 pyridine (R0081,30 mL) was added first, and then benzoyl chloride (R0488, 30 g) was added drop by drop to obtain the fifth mixture. The fifth mixture is stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium hydrogen carbonate (2 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x). Each was washed with 100 mL) and dried over sodium sulfate to obtain a sixth solution. Sodium sulfate was filtered and washed with ethyl acetate to give a seventh solution. The 6th and 7th solutions were combined and concentrated to about 200 mL (8th solution). Anisol (20 g) was added to the 8th solution, and then HCl gas (20 g) was whipped to form a precipitate. The precipitated solid was collected, washed with ethyl acetate and then suspended in DCM (200 mL) to give the ninth mixture. Sodium hydrogen carbonate (20 g) and tetrabutylammonium hydrogen sulfate (11 g) were added to the 9th mixture to give the 10th mixture. Next, 1-chloroethyl chloroformate (16 g) was added to the 10th mixture to obtain the 11th mixture. The eleventh mixture was stirred at RT overnight. The 11th mixture organic layer was then collected, washed with water (3 x 200 mL) and dried over anhydrous sodium sulfate to give the 12th solution. Sodium sulfate was removed by filtration and washed with DCM to obtain the 13th solution. The twelfth solution and the thirteenth solution were combined and evaporated to dryness. The residue was dissolved in acetonitrile (200 mL) to give the 14th mixture. Boc-sarcosine (36 g) was added to the 14th mixture to give the 15th mixture. First, a mixture of diisopropylethylamine (34 mL) and Boc-sarcosine (36 g) was prepared and then added to the 15th mixture to obtain the 16th mixture. The 16th mixture was stirred at 55 ° C. for 48 hours, then ethyl acetate (500 mL) was added with stirring. The obtained organic layer was collected, washed with 5% sodium hydrogen carbonate (3 × 100 mL) and water (3 × 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the 17th solution. Sodium sulfate was filtered and washed with ethyl acetate to give solution 18. The 17th solution and the 18th solution were combined and concentrated to 300 mL. Anisol (20 g) was added to the concentrated solution and then HBr gas (30 g) was whipped to give a precipitate. Precipitated solids are collected, washed with ethyl acetate and washed with 4- (6-methyl-4,8-dioxo-5,7-dioxa-2,9-diazadecan-11-yl) -1,2-phenylenedibenzoa- Hydrobromide was obtained.

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

In this example, dopamine by adding dopamine HCl (19 g) to acetone (200 mL). An HCl solution was prepared. Water (200 mL) and sodium hydrogen carbonate (R0090, 50 g) were added to the dopamine-HCl solution to give the first mixture. Next, boc-phenylalanine N-hydroxysuccinimide ester (Boc-Phe-OSu, 36 g) was added to the first mixture to obtain a second mixture. The second mixture was stirred at RT overnight and ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. 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 pyridine (R0081,30 mL) was added first, and then benzoyl chloride (R0488, 30 g) was added drop by drop to obtain the fifth mixture. The fifth mixture is stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium hydrogen carbonate (2 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x). Each was washed with 100 mL) and dried over sodium sulfate to obtain a sixth solution. Sodium sulfate was filtered and washed with ethyl acetate to give a seventh solution. The 6th and 7th solutions were combined and concentrated to about 200 mL (8th solution). Anisol (20 g) was added to the 8th solution, and then HCl gas (20 g) was whipped to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give 4- (2- (2-amino-3-phenylpropanamide) ethyl) -1,2-phenylenedibenzoate hydrochloride.

Example 5. Preparation of 4- (2-((((1-((pyrrolidin-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 hydrogen carbonate (R0090, 50 g) were added to the dopamine-HCl solution to give the first mixture. Then di-tert-butyl dicarbonate (22 g) was 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 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. 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 pyridine (R0081,30 mL) was added first, and then benzoyl chloride (R0488, 30 g) was added drop by drop to obtain the fifth mixture. The fifth mixture is stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium hydrogen carbonate (2 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x). Each was washed with 100 mL) and dried over sodium sulfate to obtain a sixth solution. Sodium sulfate was filtered and washed with ethyl acetate to give a seventh solution. The 6th and 7th solutions were combined and concentrated to about 200 mL (8th solution). Anisol (20 g) was added to the 8th solution, and then HCl gas (20 g) was whipped to form a precipitate. The precipitated solid was collected, washed with ethyl acetate and then suspended in DCM (200 mL) to give the ninth mixture. Sodium hydrogen carbonate (20 g) and tetrabutylammonium hydrogen sulfate (11 g) were added to the 9th mixture to give the 10th mixture. Next, 1-chloroethyl chloroformate (16 g) was added to the 10th mixture to obtain the 11th mixture. The eleventh mixture was stirred at RT overnight. The organic layer of the 11th mixture was then collected, washed with water (3 x 200 mL) and dried over anhydrous sodium sulfate to give the 12th solution. Sodium sulfate was removed by filtration and washed with DCM to obtain the 13th solution. The twelfth solution and the thirteenth solution were combined and evaporated to dryness. The residue was dissolved in acetonitrile (200 mL) to give the 14th mixture. Boc-sarcosine (36 g) was added to the 14th mixture to give the 15th mixture. First, a mixture of diisopropylethylamine (34 mL) and Boc-sarcosine (36 g) was prepared and then added to the 15th mixture to obtain the 16th mixture. The 16th mixture was stirred at 55 ° C. for 48 hours and ethyl acetate (500 mL) was added with stirring. The obtained organic layer was collected, washed with 5% sodium hydrogen carbonate (3 × 100 mL) and water (3 × 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the 17th solution. Sodium sulfate was filtered and washed with ethyl acetate to give solution 18. The 17th solution and the 18th solution were combined and concentrated to 300 mL. Anisol (20 g) was added to the concentrated solution and then HCl gas (30 g) was whipped to give a precipitate. Precipitated solids are collected, washed with ethyl acetate and washed with 4- (2-((((1-((pyrrolidin-2-carbonyl) oxy) ethoxy) amino) ethyl) -1,2, -phenylenedibenzoate-hydrochloride. I got salt.

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

In this example, dopamine by adding dopamine HCl (19 g) to acetone (200 mL). An HCl solution was prepared. Water (200 mL) and sodium hydrogen carbonate (R0090, 50 g) were added to the dopamine-HCl solution to give the 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 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. 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 pyridine (R0081, 30 mL) was added first, and then 2-ethylbutyryl chloride (28 g) was added drop by drop to obtain the fifth mixture. The fifth mixture is stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium hydrogen carbonate (2 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x). Each was washed with 100 mL) and dried over sodium sulfate to obtain a sixth solution. Sodium sulfate was filtered and washed with ethyl acetate to give a seventh solution. The 6th and 7th solutions were combined and concentrated to about 200 mL (8th solution). Anisol (20 g) was added to the 8th solution, and then HCl gas (20 g) was whipped to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give 4- (2-piperidin-4-carboxamide) ethyl) -1,2,-phenylenebis (2-ethylbutanoate) hydrochloride.

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

In this example, dopamine by adding dopamine HCl (19 g) to acetone (200 mL). An HCl solution was prepared. Water (200 mL) and sodium hydrogen carbonate (R0090, 50 g) were added to the dopamine-HCl solution to give the first mixture. Then di-tert-butyl dicarbonate (22 g) was 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 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. 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 pyridine (R0081, 30 mL) was added first, and then 2-ethylbutyryl chloride (28 g) was added drop by drop to obtain the fifth mixture. The fifth mixture is stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium hydrogen carbonate (2 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x). Each was washed with 100 mL) and dried over sodium sulfate to obtain a sixth solution. Sodium sulfate was filtered and washed with ethyl acetate to give a seventh solution. The 6th and 7th solutions were combined and concentrated to about 200 mL (8th solution). Anisol (20 g) was added to the 8th solution, and then HCl gas (20 g) was whipped to form a precipitate. Precipitated solids are collected, washed with ethyl acetate and washed with 4- (2-((((-octahydro-1H-quinolidine-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 9th mixture, then octahydro-1H-quinolidine-3-ylcarbonochloride hydrochloride (22 g) in ethyl acetate (50 mL) is added drop by drop to the 10th mixture. Got The 10th mixture was stirred at RT for 2 hours and washed with 5% sodium hydrogen carbonate and water to give the 11th mixture. After adding acetic acid (6 g) to the eleventh mixture, hexane (200 mL) was added to give a precipitate. Precipitated solids are collected by filtration, washed with ethyl acetate / hexanes and 4-(2-((((-octahydro-1H-quinolidine-3-yl) oxy) carbonyl) amino) ethyl) -1,2-phenylene. A 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) ethyl isobutyra- Hydrohydrochloride and 1-(((2- (3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo [b] [1,4] dioxocin-8-yl) ethyl)) Preparation of carbamoyl) oxy) ethylisobutyrate-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 hydrogen carbonate (R0090, 50 g) were added to the dopamine-HCl solution to give the first mixture. Next, Nα- (benzyloxycarbonyloxy) succinimide (25 g) was added to the first mixture to obtain a second mixture. The second mixture was stirred at RT overnight and ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. 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 the 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 the 7th mixture, water (2 x 100 mL), 5% sodium hydrogen carbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and Each was washed with water (3 x 100 mL) and dried over sodium sulfate to give the eighth solution. Sodium sulfate was filtered and washed with ethyl acetate to give a ninth solution. The 8th solution and the 9th solution were combined and evaporated to dryness. The residue was dissolved in metalnol (R0084, 300 mL) to give the tenth mixture. Palladium activated carbon (10 g, 10%) was first added to the 10th mixture under nitrogen and then foamed with hydrogen gas to remove the benzyloxycarbonyl group with RT. The obtained mixture (11th mixture) was filtered to remove palladium activated carbon, and the mixture was evaporated to dryness.
The residue was suspended in DCM (200 mL) to give a twelfth mixture. Sodium hydrogen carbonate (20 g) and tetrabutylammonium hydrogen sulfate (11 g) were added to the 12th mixture to give the 13th mixture. Then 1-chloroformic acid (16 g) was added to the 13th mixture to give the 14th mixture. The 14th mixture was stirred at RT overnight. The organic layer of the 14th mixture was then collected, washed with water (3 x 200 mL) and dried over anhydrous sodium sulfate to give the 15th solution. Sodium sulfate was removed by filtration and washed with DCM to obtain the 16th solution. The 15th solution and the 16th solution were combined and evaporated to dryness. The residue was collected and dissolved in isobutyric acid (100 mL) to give the 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 the 18th mixture. The 18th mixture was stirred at 55 ° C. for 48 hours and ethyl acetate (500 mL) was added with stirring. The obtained organic layer was collected, washed with 5% sodium hydrogen carbonate (3 × 100 mL) and water (3 × 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the 19th solution. Sodium sulfate was filtered and washed with ethyl acetate to give a 20th solution. The 19th solution and the 20th solution were combined and concentrated to 300 mL. Anisol (20 g) was added to the concentrated solution and then HF gas (20 g) was whipped to give a precipitate. The precipitated solid is collected, washed with ethyl acetate and washed with 1-(((2- (4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo [b] [1,4] dioxosin-). 8-yl) ethyl) carbamoyl) oxy) ethylisobutyrate-hydrofluoride and 1-(((2- (3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo [b] [b] [ 1,4] Dioxocin-8-yl) ethyl) carbamoyl) oxy) ethylisobutyrate-hydrofluoride hydrolyzate was obtained.

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

In this example, a dopamine-HCl solution was prepared by adding dopamine-HCl (19 g) to acetone (200 mL). Pyridine (40 ml) was added to the dopamine-HCl solution to give the first mixture. Next, N- (ethoxycarbonyloxy) succinimide (18 g) was added to the first mixture to obtain a second mixture. The second mixture was stirred at RT overnight and ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. 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 the 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 the 7th mixture, water (2 x 100 mL), 5% sodium hydrogen carbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and Each was washed with water (3 x 100 mL) and dried over sodium sulfate to give the eighth solution. Sodium sulfate was filtered and washed with ethyl acetate to give a ninth solution. Pyridine (20 mL) was added to the combined 8th and 9th solutions, and then benzoyl chloride (15 g) was added drop by drop to obtain the 10th mixture.
The 10th mixture was stirred at RT for 4 hours, water (2 x 100 mL), 5% sodium hydrogen carbonate (2 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL). ), And dried over sodium sulfate to obtain the eleventh solution. Sodium sulfate was filtered and washed with ethyl acetate to give a twelfth solution.
Anisol (20 g) was added to the combined 11th and 12th solutions, and then HCl gas (20 g) was whipped to give a precipitate. Precipitated solids are collected, washed with ethyl acetate and washed with 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 by adding dopamine HCl (19 g) to acetone (200 mL). An HCl solution was prepared. Water (200 mL) and sodium hydrogen carbonate (R0090, 50 g) were added to the dopamine-HCl solution to give the first mixture. Then di-tert-butyl dicarbonate (22 g) was 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 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a third solution. 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 pyridine (R0081,30 mL) was added first, and then benzoyl chloride (R0488, 30 g) was added drop by drop to obtain the fifth mixture. The fifth mixture is stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium hydrogen carbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x). Each was washed with 100 mL) and dried over sodium sulfate to obtain a sixth solution. Sodium sulfate was filtered and washed with ethyl acetate to give a seventh solution. The 6th and 7th solutions were combined and concentrated to about 300 mL (8th solution). Anisol (20 g) was added to the 8th solution, and then HCl gas (60 g) was whipped 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 give the first mixture. HCl gas (20 g) was aerated through the first mixture to give the second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added to give a precipitate. Precipitated solids were collected and washed with isopropyl acetate (isopropayl) 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 hydrogen carbonate (50 g) were added to the third mixture, and then di-tert-butyl dicarbonate (22 g) was added to obtain a fourth mixture. The fourth mixture was stirred at RT overnight and ethyl acetate (500 mL) was added. The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the sixth solution. rice field. Sodium sulfate was then filtered and washed with ethyl acetate to give a seventh mixture. The sixth solution and the seventh mixture were combined, and pyridine (R0081,30 mL) was added first, and then benzoyl chloride (R0488, 30 g) was added drop by drop to obtain the eighth mixture. Stir the 8th mixture at RT for 2 hours, then water (2 x 100 mL), 5% sodium hydrogen carbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x). 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 give the 10th solution. The 9th and 10th solutions were combined and concentrated to about 300 mL (11th solution). Anisol (20 g) was added to the eleventh solution, and then HCl gas (20 g) was whipped 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- (heptane-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 give the first mixture. HCl gas (20 g) was aerated through the first mixture to give the second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added to give a precipitate. 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 hydrogen carbonate (50 g) were added to the third mixture, and then di-tert-butyl dicarbonate (22 g) was added to obtain a fourth mixture. The fourth mixture was stirred at RT overnight and ethyl acetate (500 mL) was added. The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the sixth solution. rice field. Sodium sulfate was then filtered and washed with ethyl acetate to give a seventh mixture. The sixth solution and the seventh mixture were combined, and pyridine (R0081,30 mL) was added first, and then benzoyl chloride (R0488, 30 g) was added drop by drop to obtain the eighth mixture. Stir the 8th mixture at RT for 2 hours, then water (2 x 100 mL), 5% sodium hydrogen carbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x). 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 give the 10th solution. The 9th and 10th solutions were combined and concentrated to about 300 mL (11th solution). Anisol (20 g) was added to the eleventh solution, and then HCl gas (20 g) was whipped to form a precipitate. Precipitated solids are collected and washed with ethyl acetate (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 give the first mixture. HCl gas (20 g) was aerated through the first mixture to give the second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added to give a precipitate. 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 hydrogen carbonate (50 g) were added to the third mixture, and then di-tert-butyl dicarbonate (22 g) was added to obtain a fourth mixture. The fourth mixture was stirred at RT overnight and ethyl acetate (500 mL) was added. The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the sixth solution. rice field. Sodium sulfate was then filtered and washed with ethyl acetate to give a seventh mixture. The 6th solution and the 7th mixture were combined, and pyridine (R0081, 30mL) was added first, and then pentanoyl chloride (24g) was added drop by drop to obtain the 8th mixture. Stir the 8th mixture at RT for 2 hours, then water (2 x 100 mL), 5% sodium hydrogen carbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x). 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 give the 10th solution. The 9th and 10th solutions were combined and concentrated to about 300 mL (11th solution). Anisol (20 g) was added to the eleventh solution, and then HCl gas (20 g) was whipped 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) propionic acid (20 g) was added to etanol (200 mL) to give the first mixture. HCl gas (20 g) was aerated through the first mixture to give the second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added to give a precipitate. 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 hydrogen carbonate (50 g) were added to the third mixture, and then di-tert-butyl dicarbonate (22 g) was added to obtain a fourth mixture. The fourth mixture was stirred at RT overnight and ethyl acetate (500 mL) was added. The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the sixth solution. rice field. Sodium sulfate was then filtered and washed with ethyl acetate to give a seventh mixture. The 6th solution and the 7th mixture were combined, and pyridine (R0081, 30mL) was added first, and then acetyl chloride (18g) was added drop by drop to obtain the 8th mixture. Stir the 8th mixture at RT for 2 hours, then water (2 x 100 mL), 5% sodium hydrogen carbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x). 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 give the tenth solution. The 9th and 10th solutions were combined and concentrated to about 300 mL (11th solution). Anisol (20 g) was added to the eleventh solution, and then HCl gas (20 g) was whipped 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- (pentane-3-yloxy) propyl) -1,2-phenylenebis (2-methylpropanol-) hydrobromide.

In this example, (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoic acid (20 g) was added to 3-pentanol (200 mL) to give the first mixture. HCl gas (20 g) was aerated through the first mixture to give the second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added to give a precipitate. 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), sodium hydrogen carbonate (50 g) and then di-tert-butyl dicarbonate (22 g) were added to the third mixture to give the fourth mixture. The fourth mixture was stirred at RT overnight and ethyl acetate (500 mL) was added. The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the sixth solution. rice field. Sodium sulfate was then filtered and washed with ethyl acetate to give a seventh mixture. The 6th solution and the 7th mixture were combined, and pyridine (R0081, 30mL) was added first, and then isobutyryl chloride (22g) was added drop by drop to obtain the 8th mixture. Stir the 8th mixture at RT for 2 hours, then water (2 x 100 mL), 5% sodium hydrogen carbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x). 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 give the 10th solution. The 9th and 10th solutions were combined and concentrated to about 300 mL (11th solution). Anisol (20 g) was added to the eleventh solution, and then HCl gas (20 g) was whipped 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-aminoacetamide) -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 give the first mixture. HCl gas (20 g) was aerated through the first mixture to give the second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added to give a precipitate. 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), sodium hydrogen carbonate (50 g) and then N- (tert-butoxycarbonyl-glycine N-hydroxysuccinimide ester (27 g) were added to the third mixture to give the fourth mixture. RT the fourth mixture. Ethyl acetate (500 mL) was added. The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% succinimide (2 x 200 mL), and water (3 x 100 mL), respectively. And dried over anhydrous sodium sulfate to give the sixth solution. Then the sodium sulfate was filtered and washed with ethyl acetate to obtain the seventh mixture. The sixth solution and the seventh mixture were combined and first. Ppyridine (R0081, 30 mL) followed by benzoyl chloride (30 g) was added drop by drop to give the 8th mixture. The 8th mixture was stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium hydrogen carbonate. It was washed with (3 x 100 mL), water (100 mL), 20% citrate (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to give a ninth solution. It was filtered and washed with ethyl acetate to obtain the 10th solution. The 9th solution and the 10th solution were combined and concentrated to about 300 mL (11th solution). Anisodium (20 g) was added to the 11th solution. HCl gas (20 g) was whipped to form a precipitate. The precipitated solid was collected and washed with ethyl acetate (S) -4- (2-aminoacetamide) -3-isopropoxy-3-oxopropyl)-. A 1,2-phenylenedibenzoate hydrochloride was obtained.

Example 17. Preparation of 4-((2S) -3-oxo-3- (pentane-3-yloxy) -2- (pyrrolidin-2-carboxamide) propyl) -1,2-phenylenedibenzoate-hydrofluorate.

In this example, (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoic acid (20 g) was added to 3-pentanol (200 mL) to give the first mixture. HCl gas (20 g) was aerated through the first mixture to give the second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added to give a precipitate. 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), sodium hydrogen carbonate (50 g) and then N- (tert-butoxycarbonyl-proline N-hydroxysuccinimide ester (32 g) were added to the third mixture to give the fourth mixture. RT the fourth mixture. Ethyl acetate (500 mL) was added. The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% citrate (2 x 200 mL), and water (3 x 100 mL), respectively. And dried over anhydrous sodium sulfate to give the 6th solution. Then the sodium sulfate was filtered and washed with ethyl acetate to obtain the 7th mixture. The 6th solution and the 7th mixture were combined and first. The eighth mixture was obtained by adding pyridine (R0081, 30 mL), then benzoyl chloride (22 g), drop by drop. The eighth mixture was stirred at RT for 2 hours, then water (2 x 100 mL), 5% sodium hydrogen carbonate. Each was washed with (3 x 100 mL), water (100 mL), 20% citrate (2 x 200 mL), and water (3 x 100 mL) and dried over sodium sulfate to give the ninth solution. It was filtered and washed with ethyl acetate to obtain the 10th solution. The 9th solution and the 10th solution were combined and concentrated to about 300 mL (11th solution). Anisol (20 g) was added to the 11th solution. HF gas (20 g) was whipped to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to 4-((2S) -3-oxo-3- (pentan-3-yloxy) -2- (. Pyrrolidine-2-carboxamide) propyl) -1,2-phenylenedibenzoate-bicarbonate was obtained.

Example 18. Preparation of (S) -4- (3-isopropoxy-3-oxo-2- (piperidine-4-carboxamide) propyl) -1,2-phenylenedibenzoate-hydrofluorinated salt.

In this example, (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoic acid (20 g) was added to isopropanol (200 mL) to give the first mixture. HCl gas (20 g) was aerated through the first mixture to give the second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added to give a precipitate. 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), sodium hydrogen carbonate (50 g), and then Boc-piperidin-4-carboxylic acid N-hydroxysuccinimide ester (Boc-Inp-OSu, 33 g) were added to the third mixture to obtain the fourth mixture. The fourth mixture was stirred at RT overnight and ethyl acetate (500 mL) was added. The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the sixth solution. rice field. Sodium sulfate was then filtered and washed with ethyl acetate to give a seventh mixture. The 6th solution and the 7th mixture were combined, and pyridine (R0081, 30mL) was added first, and then benzoyl chloride (30g) was added drop by drop to obtain the 8th mixture. Stir the 8th mixture at RT for 2 hours, then water (2 x 100 mL), 5% sodium hydrogen carbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x). 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 give the tenth solution. The 9th and 10th solutions were combined and concentrated to about 300 mL (11th solution). Anisol (20 g) was added to the eleventh solution, and then HF gas (20 g) was whipped to form a precipitate. Precipitated solids are collected and washed with ethyl acetate (S) -4- (3-isopropoxy-3-oxo-2- (piperidine-4-carboxamide) propyl) -1,2-phenylenedibenzoate-fluoride. Hydrochloride was obtained.

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

In this example, (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoic acid (20 g) was added to isopropanol (200 mL) to give the first mixture. HCl gas (20 g) was aerated through the first mixture to give the second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added to give a precipitate. 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), sodium hydrogen carbonate (50 g), and then octahydro-1H-quinolidine-2-carboxylic acid N-hydroxysuccinimide ester (28 g) were added to the third mixture to obtain a fourth mixture. The fourth mixture was stirred at RT overnight and ethyl acetate (500 mL) was added. The organic layer (fifth mixture) was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the sixth solution. rice field. Sodium sulfate was then filtered and washed with ethyl acetate to give a seventh mixture. The 6th solution and the 7th mixture were combined, and pyridine (R0081, 30mL) was added first, and then isobutyryl chloride (22g) was added drop by drop to obtain the 8th mixture. Stir the 8th mixture at RT for 2 hours, then water (2 x 100 mL), 5% sodium hydrogen carbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x). 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 give the tenth solution. The 9th and 10th solutions were combined and concentrated to about 100 mL (11th solution). Hexane (200 mL) and then acetic acid (6 g) were added to the 11th solution to form a precipitate. Precipitated solids are collected and washed with ethyl acetate / hexane and washed with 4-((2S) -3-isopropoxy-3-2- (octahydro-1H-quinolidine-2-carboxamide) -3-oxopropyl) -1, 2-Phenylenebis (2-methylpropanol) hydrochloride was obtained.

Example 20. (2S) -Isopropyl3- (3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo [b] [1,4] dioxosin-8-yl) -2-(((1-1-yl) (Isobutyryloxy) ethoxy) carbonyl) amino) propanoate hydrobromide and (2S) -isopropyl3- (4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo [ b] [1,4] Preparation of 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 give the first mixture. HCl gas (20 g) was aerated through the first mixture to give the second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added to give a precipitate. 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) Acetone hydrochloride solution was prepared. Water (200 mL) and sodium hydrogen carbonate (R0090, 50 g) were added to the dopamine / HCl solution to give a third mixture. Next, Nα- (benzyloxycarbonyloxy) succinimide (25 g) was added to the third mixture to obtain a fourth mixture. The fourth mixture was stirred at RT overnight and then ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a fifth solution. Next, sodium sulfate was filtered and washed with ethyl acetate to obtain a sixth solution. The 5th solution and the 6th 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 7th mixture to give the 8th mixture. The eighth mixture was stirred at RT overnight to evaporate to dryness. Ethyl acetate (500 ml) was added to the residue to give the ninth mixture, water (2 x 100 mL), 5% sodium hydrogen carbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and Each was washed with water (3 x 100 mL) and dried over sodium sulfate to give the 10th solution. Sodium sulfate was filtered and washed with ethyl acetate to give the eleventh solution. The 10th solution and the 11th solution were combined and evaporated to dryness. The residue was dissolved in metalnol (R0084, 300 mL) to give a twelfth mixture. Palladium activated carbon (10 g, 10%) was first added to the twelfth mixture under nitrogen, and then hydrogen gas was aerated with RT to remove the benzyloxycarbonyl group. The obtained mixture (13th mixture) was filtered to remove palladium activated carbon, and the mixture was evaporated to dryness.
The residue was suspended in DCM (200 mL) to give the 14th mixture. Sodium hydrogen carbonate (15 g) and tetrabutylammonium hydrogen sulfate (11 g) were added to the 14th mixture to give the 15th mixture. Next, 1-chloroformic acid (16 g) was added to the 15th mixture to obtain the 16th mixture. The 16th mixture was stirred at RT overnight. The organic layer of the 16th mixture was then collected, washed with water (3 x 200 mL) and dried over anhydrous sodium sulfate to give the 17th solution. Sodium sulfate was removed by filtration and washed with DCM to obtain the 18th solution. The 17th solution and the 18th solution were combined and evaporated to dryness. The residue was dissolved in isobutyric acid (100 mL) to give the 19th mixture. A mixture of diisopropylethylamine (60 mL) and isobutyric acid (36 mL) was first prepared and then added to the 19th mixture to give the 20th mixture. The 20th mixture was stirred at 55 ° C. for 48 hours and ethyl acetate (500 mL) was added with stirring. The obtained organic layer was collected, washed with 5% sodium hydrogen carbonate (3 × 100 mL) and water (3 × 100 mL), respectively, and dried over anhydrous sodium sulfate to obtain the 21st solution. Sodium sulfate was filtered and washed with ethyl acetate to give the 22nd solution. The 21st solution and the 22nd solution were combined and concentrated to 300 mL. Anisol (20 g) was added to the concentrated solution and then HBr gas (30 g) was whipped to give a precipitate. Precipitated solids are collected and washed with ethyl acetate (2S) -isopropyl3- (3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo [b] [1,4] dioxosin- 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 hydrobromide Hydrobromide was obtained.

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

In this example, (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoic acid (20 g) was added to isopropanol (200 mL) to give the first mixture. HCl gas (20 g) was aerated through the first mixture to give the second mixture. The second mixture was stirred for 2 days at 60 ° C. and then isopropyl acetate (200 mL) was added to give a precipitate. 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) Acetone hydrochloride solution was prepared. Water (200 mLl) and sodium hydrogen carbonate (R0090, 50 g) were added to a dopamine-HCl solution to give a third mixture. Next, Nα- (benzyloxycarbonyloxy) succinimide (25 g) was added to the third mixture to obtain a fourth mixture. The fourth mixture was stirred at RT overnight and ethyl acetate (R0061, 500 mL) was added for extraction. The organic layer was separated, washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL), respectively, and dried over sodium sulfate to obtain a fifth solution. Next, sodium sulfate was filtered and washed with ethyl acetate to obtain a sixth solution. The 5th solution and the 6th 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 7th mixture to give the 8th mixture. The eighth mixture was stirred at RT overnight and evaporated to dryness. Ethyl acetate (500 ml) was added to the residue to give the ninth mixture, water (2 x 100 mL), 5% sodium hydrogen carbonate (3 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and Each was washed with water (3 x 100 mL) and dried over sodium sulfate to give the 10th solution. Sodium sulfate was filtered and washed with ethyl acetate to give the eleventh solution. Pyridine (20 ml) was added to solution 11 to give the twelfth mixture, and benzoyl chloride (15 g) was added drop by drop to the twelfth mixture to give the thirteenth mixture. The thirteenth mixture was stirred at RT for 4 hours and the resulting mixture was water (2 x 100 ml), 5% sodium hydrogen carbonate (2 x 100 ml), water (100 ml), 20% citric acid (2 x 200 ml), and Each was washed with water (3 × 100 ml) and dried over anhydrous sodium sulfate to obtain the 14th solution. Sodium sulfate was removed by filtration and washed with ethyl acetate to obtain the 15th solution. The 14th solution and the 15th solution were combined and evaporated to dryness.
The obtained residue was dissolved in metall (300 mL) to obtain the 16th mixture. 10% palladium activated carbon (10 g) was added to the 16th mixture under nitrogen and the resulting mixture was aerated with hydrogen gas at RT until the benzyloxycarbonyl group was substantially completely removed. Palladium activated carbon was removed by filtration, and the obtained solution was evaporated to dryness.
The obtained residue was suspended in DCM (200 mL). Sodium hydrogen carbonate (15 g) and tetrabutylammonium hydrogen sulfate (11 g) were added to the DCM suspension. 1-Chloroformic acid 1-chloroethyl (16 g) was added to the resulting reaction mixture. The reaction mixture was then stirred at RT overnight. The organic layer was collected and washed with water (3 x 200 mL). The solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration and washed with DCM. This 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) [mix 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. Collect the organic solution and wash with 5% sodium bicarbonate (3 x 100 ml) and water (3 x 100 ml). Dry the solution over anhydrous sodium sulfate. Sodium sulphate is removed by filtration and washed with ethyl acetate (3x). Concentrate this solution to 300 ml. Anisol (20 g) is added to the ethyl acetate solution. Next, HCl gas (30 g) is aerated in the ethyl acetate solution. The solid is collected and washed with ethyl acetate.

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

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 aerated through this mixture. The mixture was stirred at 60 ° C. for 2 days. Isopropyl acetate (200 mL) was added to this mixture. The solid was collected and washed with isopropyl acetate.
Isopropyl (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate hydrochloride (28 g) was added to acetone (200 mL). Water (200 mL) and sodium hydrogen carbonate (50 g) were added to the reaction mixture. Di-tert-butyl dicarbonate (22 g) was added to the reaction mixture. The mixture was stirred at RT overnight. Ethyl acetate (500 mL) was added to the mixture. The mixture was washed with water (2 x 100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL). The solution was dried over sodium sulfate. Sodium sulfate was removed by filtration and washed with ethyl acetate. Pyridine (30 mL) was added to the ethyl acetate solution. Benzoyl chloride (30 g) was added drop by drop to the reaction mixture. The solution was stirred at RT for 2 hours. The solution was washed with water (2 x 100 mL), 5% sodium bicarbonate (2 x 100 mL), water (100 mL), 20% citric acid (2 x 200 mL), and water (3 x 100 mL). The solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration and washed with ethyl acetate. This solution was concentrated to 200 mL. Anisole (20 g) was added to this ethyl acetate solution. Next, HCl gas (20 g) was aerated in 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. Octahydroindolizine-1-ylcarbonochloride 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 aceta.

29.6 g (0.1 mol) of 2-[(2,6-dichloro-3-methylphenyl) amino] benzoic acid was dissolved in 300 mL of chloroform. 20.6 g of N, N'-dicyclohexylcarbodiimide was added to the reaction mixture. 11.7 g of diethylaminoethylamine was added to the reaction mixture. The mixture was stirred at RT for 3 hours. The solid was removed by filtration. The chloroform solution was washed with 5% NaHCO ₃ (2 x 100 mL) and water (3 x 100 mL). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added to the stirred reaction mixture. Hexane (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 hydrogen carbonate (200 mL) and acetone (100 mL). 37.5 g (0.1 mol) of (Z) -5-fluoro-2-methyl-1-[(4-methylsulfinyl) phenylmethylene] -1H-inden-3-acetylchloride 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 hydrogen carbonate (200 mL) was added to the stirred reaction mixture. The ethyl acetate layer was collected and washed with water (3 x 500 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added to the stirred reaction mixture. The organic solution was evaporated.

Example 25. 2- (Dimethylamino) Ethyl 2- (3-Phenoxyphenyl) propionate. Preparation of hydrochloride

26.1 g (0.1 mol) of 2- (3-phenoxyphenyl) propionyl chloride was dissolved in 300 ml of ethyl acetate. The mixture was cooled to 0 ° C. 8.9 g of dimethylaminoethanol was added to the reaction mixture. Sodium hydrogen carbonate (30 g) was added to the mixture. The mixture was stirred at RT for 5 hours. The mixture was washed with water (3 x 200 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate. HCl gas (5 g) was aerated 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) propanthioate hydrochloride

10.4 g (0.1 mol) of dimethylaminoethyl mercaptan was dissolved in 10% sodium bicarbonate (200 mL) and acetone (100 mL). 27.3 g (0.1 mol) of 2- (3-phenoxyphenyl) propionyl chloride was added to the reaction mixture. The mixture was stirred at RT for 3 hours. The solvent was evaporated. The residue was suspended in ethyl acetate (500 mL). 5% sodium bicarbonate (200 mL) was added to the stirred reaction mixture. The ethyl acetate layer was collected and washed with water (3 x 500 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. Anhydrous HCl gas (5 g) was aerated through 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) , 4-Difluorophenyl) Acetylsalicylate-hydrochloride] preparation

It was dissolved in 31.1 g (0.1 mol) of 5- (2,4-difluorophenyl) acetylsalicylic 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 hydrogen carbonate (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 aerated 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. in an ice water bath. 23 g of N, N-diethylaminoethanol was added drop by drop to the reaction mixture. 40 g of Na ₂ CO ₃ was added slowly to the reaction mixture. The mixture was stirred at RT overnight. 200 mL of water was added to the mixture. Ethyl acetate solution was collected, washed with water (3 x 200 mL) and dried over anhydrous Na ₂ SO ₄ . Sodium sulfate was removed by filtration and washed with ethyl acetate (3 x 100 mL). Anhydrous HCl gas (10 g) was aerated 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. in an ice water bath. 23 g of N-diethylaminoethanol was added drop by drop to the reaction mixture. 40 g of NaHCO ₃ was slowly added to the reaction mixture. The mixture was stirred at RT overnight. 200 mL of water was added to the mixture. Ethyl acetate solution was collected, washed with water (3 x 100 mL) and dried over anhydrous Na ₂ SO ₄ . Sodium sulfate was removed by filtration and washed with ethyl acetate (3 x 100 mL). Anhydrous HCl gas (10 g) was aerated through the mixture. The solid was collected and washed with ethyl acetate.

Example 30. Measurement of HPP transmission rate
4- (2- (2- (Methylamino) acetamide) ethyl) -1,2,-phenylenedibenzoate hydrochloride (Compound-1), 4- (2- (2- (Methylamino) acetamide) ethyl ) -1,2,-Phoenylene benzoa-toacetic acid (Compound-2), 4- (6-Methyl-4,8-Dioxo-5,7-Dioxa-2,9-Diazadecane-11-yl) -1 , 2,-Phenylrange benzoate hydrobromide (Compound-3), 4- (2- (2-amino-3-phenylpropanamide) ethyl) -1,2,-Phenylrange benzoate-hydrochloride Salt (Compound-4), 4- (2-((((1-((Pyrrolidine-2-carbonyl) Oxy) ethoxy) Amino) Ethyl) -1,2,-Phenylenedibenzoate-hydrochloride (Compound-5) ), 4- (2-piperidin-4-carboxamide) ethyl) -1,2,-phenylenebis (2-ethylbutanoate) hydrochloride (Compound-6), 4- (2-((((-Octahydro-) 1H-quinolidine-3-yl) oxy) carbonyl) amino) ethyl) -1,2,-phenylenebis (2-ethylbutanoate) aceta-to (Compound-7), 1-(((2- (4- (4- (4-) 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) Ethylisobutyrate-hydrofluoride (Compound-8b), (5-(2-((ethoxycarbonyl) amino) ethyl) -2- (2-methylamino) acetoxy) phenylbenzoate hydrochloride (Compound-) 9a), 5- (2-((ethoxycarbonyl) amino) ethyl) -2- (2-methylamino) acetoxy) phenylbenzoate hydrochloride (Compound-9b), 4- (2-aminoethyl)- 1,2-Phenylrange benzoate hydrochloride (Compound-10), (S) -4- (2-Amino-3-isopropoxy-3-oxopropyl) -1,2-Phenylrange benzoate hydrochloride (Compound-11), (S) -4- (2-amino-3- (heptane-4-yloxy) -3-oxopropyl) -1,2-phenylenedibenzoate hydrochloride (Compound-12), (S) -4- (2-Amino-3-isopropoxy- 3-oxopropyl) -1,2-phenylenedipentanoate hydrochloride (Compound-13), (S) -4- (2-amino-3-ethoxy-3-oxopropyl) -1,2-phenylene Diacetate hydrochloride (Compound-14), (S) -4- (2-Amino-3-oxo-3- (pentan-3-yloxy) propyl) -1,2-phenylenebis (2-methylpropa) Noat) Hydrobromide (Compound-15), (S) -4- (2-Aminoacetamide) -3-isopropoxy-3-oxopropyl) -1,2-phenylenedibenzoate hydrochloride (Compound-16), 4-((2S) -3-oxo-3- (pentane-3-yloxy) -2- (pyrrolidin-2-carboxamide) propyl) -1,2-phenylenedibenzoate-hydrogen fluoride Hydrochloride (Compound-17), (S) -4- (3-isopropoxy-3-oxo-2- (piperidin-4-carboxamide) propyl) -1,2-phenylenedibenzoate hydrochloride (Compound- 18), 4-((2S) -3-isopropoxy-3-2- (octahydro-1H-quinolidine-2-carboxamide) -3-oxopropyl) -1,2-phenylenebis (2-methylpropanol- G) Hydrochloride (Compound-19), (2S) -Isopropyl3- (3-Amino-2,5-Dioxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Dioxocin-8- Il) -2-(((1- (isobutyryloxy) ethoxy) carbonyl) amino) propanoate-hydrobromide (Compound-20a), (2S) -isopropyl3- (4-amino-2,, 5-Dioxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] dioxocin-8-yl) -2-(((1- (isobutyryloxy) ethoxy) carbonyl) amino) compound- Hydrobromide (Compound-20b), 5-((2S) -2-(((1- (isobutyryloxy) ethoxy) carbonyl) amino-3-isopropoxy-3-oxopropyl) -2 -(2- (Methylamino) acetoxy) phenylbenzoate-hydrochloride (Compound-21a), 4-((2S) -2-(((1- (isobutyryloxy) ethoxy) carbonyl) amino-3 -Isopropoxy-3-oxopropyl) -2- (2- (methylamino) acetoxy) phenylbenzoate-hydrochloride (Compound-21b), 4-((2S) -3-isopropoxy-2-(((2S) -3-isopropoxy-2-(() ((Octahydroindrins) -1-yl) oxy) carbonyl) amino) -3-oxopropyl) -1,2-phenylenedibenzoate-toacetate (Compound-22), 2- (diethylamino) ethyl 2-[(2,6-dichloro) -3-Methylphenyl) amino] benzoate. Aceta-to (Compound-23), (Z) -2- (diethylaminoethyl) ethyl 2- (5-fluoro-2-methyl-1- (4-methylsulfinyl) benzylidene) -1H-inden-1-yl) Benzyl. AcOH (Compound-24), 2- (dimethylamino) ethyl 2- (3-phenoxyphenyl) propionate. Hydrochloride (Compound-25), S- (2- (dimethylamino) ethyl 2- (3-phenoxyphenyl) propanthioate 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) isolate the permeation rate through human skin from human skin tissue (360-400 μm thick) in the anterior and posterior thighs. Measured in vitro using the modified Franz cell. The received fluid consisted of 10 mL of pH 7.4 phosphate buffer (0.2 M) and is shown in Table 1. The results show that the positive charge of the amino group is the membrane and It has been suggested that it has a very important role in the passage of drugs across skin barriers.

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

Example 31. In HDB Parkinson's disease (PD) model, 6-OHDA-induced improvement of motor dysfunction and reduction of substantia nigra striatal neurodegeneration (S) -4- (2-amino-3-iso) Efficacy of propoxy-3-oxopropyl) -1,2-phenylenedibenzoate hydrochloride (drug A) and 2- (diethylamino) ethyl 2-acetoxybenzoate hydrochloride (drug B) Subject to test according to the protocol below (Sprague-gli-rat) were prepared, grouped and tested.
1. 1. 200 Splatoon-li-rats (male, 200-230 g) underwent brain stereotactic surgery after 1 week of acclimatization at an animal facility;
2. After anesthesia, a burr hole (1 mm in diameter) was drilled in the left skull using a motor drill based on the coordinates below: AP + 0.5 mm, ML -2.8 mm, DV 6. 0mm;
3. 3. The left striatum was infused with 6-OHDA (20 μg at 5 mg / mL) or sterile saline with a microsyringe equipped with a 26-gauge steel cannula. This chemical causes retrograde neurodegeneration in the distal substantia nigra, impairs dopamine transmission in the substantia nigra striatal pathway, and ultimately results in impaired motor activity;
Four. At the end of 3 weeks after 6-OHDA treatment, animals were screened with apomorphine and a classical rotation test. Animals with matching lesion types and apomorphine-induced turnover scores were assigned to 11 groups; and
Five. The rats were divided into 11 groups (n = 12), and each group was administered the drug at the dose shown in Table 2 below.

Table 2. Dose and drug administered to test animals

6. Dosage prescription
(1) L-DOPA (3 mg / mL) in water was a positive control solution in group 1 (oral in group 1 and transdermal in groups 2-11). The dose volume was 2 mL / kg. The vehicle solution (negative control solution for group 2) was 30% ethanol (v / v). The dose volume was 1286 μL / kg. Other test solutions (Groups 3-11) were freshly prepared daily.
(2) Preparation method of test solution for groups 3-5: 50.33 mg of drug A was dissolved in 10 mL of 30% ethanol (v / v). This solution was a conservative solution [(2) a].
a. Test solution for group 5 (high dose group) of drug A: The storage solution [(2) a] was the test solution for group 5. The dose volume was 1286 μL / kg.
b. Test solution for group 4 (medium dose group) of drug A: 3.00 mL of storage solution [(2) a] was diluted with 30% ethanol (v / v) to a final volume of 9.00 mL. This solution was a test solution for Group 4. The dose volume was 1286 μL / kg.
c. Test solution for group 3 (low dose group) of drug A: 1.00 mL of storage solution [(2) a] was diluted with 30% ethanol (v / v) to a final volume of 9.00 mL. This solution was a test solution for Group 4. The dose volume was 1286 μL / kg.
(3) Preparation method of 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) Preparation method of 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 a 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 a test solution for Group 8.
(6) Preparation method of 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 a test solution for group 10.
(8) Preparation method of 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. 7. From the upper back (around the neck and shoulders) of animals (all rats including those in the positive control group using L-DOPA due to the double-blind mode) using the small animal clipper on the day before the scheduled administration. The hair was removed. Animal hair was re-cut as needed to maintain epidermal exposure throughout the course of the study. On the day of administration, a fixed amount (643 μL / kg) of the pharmaceutical product was administered to a 3 cm × 3 cm square part (neck and shoulder area) of the animal at about 9 am, and repeated at about 4 pm.
8. Four weeks after the lesion, the group began receiving treatment.
9. A rotor rod test was performed weekly after treatment.

FIG. 1 shows the residence time results in the above rotor rod test after 1 to 3 weeks of treatment (n = 12). FIG. 2 shows the drop velocity results in the above rotor rod test after 1 to 3 weeks of treatment (n = 12).
It was assumed that as the PD animal's ability improved, it would stay longer on the load and withstand faster rotations (without the side effects of the study drug).
By pooling all batch data together (12 animals / group), the positive group (group 1, L-DOPA, 6 mg / kg, oral) compared to the vehicle group after 3 weeks of treatment. Did not show any effect. However, all study drug treatment groups (groups 2-11) showed stronger efficacy than the vehicle group after 3 weeks of treatment. Levodopa contributed to the development of motor complications in PD. Levodopa caused nausea, vomiting, gastrointestinal bleeding, dyskinesia at peak doses, and also resulted in an end-of-dose decline in function, so the positive control group (Group 1, L-DOPA, 6 mg /) kg, oral) showed no efficacy compared to the vehicle group. However, transdermally administered L-Dopa prodrug (drug A) avoided dyskinesias and end-of-dose reduction in function at peak doses. The efficacy of low doses of drug A ( L-Dopa prodrug, 0.67 mg / kg, group 3) is much higher than the efficacy of medium and high doses of drug A (2 mg and 6 mg / kg, groups 4 and 5). it was high. The results showed that the dose of transdermally administered prodrug of L-dopa was much lower (9-fold less) than that of orally administered L-dopa. Drug B (30 mg and 90 mg / kg ) (aspirin prodrug ) showed better efficacy than the vehicle and positive control groups after 3 weeks of treatment. 30 mg of drug B (group 8) showed similar efficacy to 90 mg of drug B (group 11). The results showed that a dose of 30 mg / kg was sufficient for drug B and no higher dose was needed. Administration of a combination of Drug A and Drug B (Groups 6 and 9) to a subject performed much better than administration of either Drug B (Groups 8 and 11) or Drug A (Group 3) alone.
When administering a combination of multiple drugs (eg, one or more HPPs and / or other drugs) to a subject, each drug can be administered separately, or one or more drugs can be substantially treated as separate drugs. It can be administered simultaneously (eg, two or more drugs are sprayed substantially simultaneously without mixing before spraying), or one or more drugs can be mixed together and then administered to the subject, or Any combination of the above administration methods is also possible. The drugs can be administered in any possible order.

Example 32. Drug A (percutaneous), drug B (percutaneous), which contributes to the improvement of 6-OHDA-induced motor dysfunction and the reduction of substantia nigra striatal neurodegeneration in the Parkinson's disease (PD) model in HDB. And the efficacy of oral carbidopa.
Test subjects (Splatoon-re-rats) were prepared as described in Example 31, grouped and tested according to the protocol below.
1. 1. The rats were divided into 11 groups (n = 12), and the drug was administered to each group at the doses shown in Table 3 below.

Table 3. Dose and drug administered to test animals

2. Dosage prescription
(1) Both L-DOPA (3 mg / ml) and carbidopa (1.5 mg / mL) in water were used as 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) with a dose volume of 2 mL / kg. The vehicle solution (negative control solution for Group 2) was 30% ethanol (v / v) and the dose volume was 1,286 μL / kg. Other test solutions (transdermal, groups 3-11) were freshly prepared daily.
(2) Preparation method of test solution for groups 3-5: 50.33 mg of drug A was dissolved in 10 mL of 30% ethanol (v / v). This solution was the preservation solution (2).
(a) Conservation solution (2) was a test solution for group 5 (high dose group) of drug A. The dose volume was 1,286 μL / kg;
(b) Test solution for group 4 (medium dose group) of drug A: 3.00 mL of storage solution (2) was diluted with 30% ethanol (v / v) to a final volume of 9.00 mL. This solution was a test solution for Group 4. The dose volume was 1,286 μL / kg;
(c) Test solution for group 3 (low dose group) of drug A: 1.00 mL of storage solution (2) was diluted with 30% ethanol (v / v) to a final volume of 9.00 mL. This solution was a test solution for Group 3. The dose volume was 1,286 μL / kg.
(3) Preparation method of 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 a test solution for Group 6;
(4) Preparation method of 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 a 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 a test solution for Group 8;
(6) Preparation method of 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 a 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 a 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. 3. From the upper back (around the neck and shoulders) of animals (all rats including those in the positive control group using L-DOPA due to the double-blind mode) using the small animal clipper on the day before the scheduled administration. The hair was removed. Animal hair was re-cut as needed to maintain epidermal exposure throughout the course of the study. On the day of administration, a fixed amount (643 μL / kg) of the pharmaceutical product was administered to a 3 cm × 3 cm square part (neck and shoulder area) of the animal at about 9 am, and repeated at about 4 pm.
Four. Four weeks after the lesion, the group began receiving treatment.
Five. A rotor rod test was performed 4 weeks after treatment.

FIG. 3 shows the residence time results in the above rotor rod test after 4 weeks of treatment (n = 12). FIG. 4 shows the drop velocity results in the above rotor rod test after 4 weeks of treatment (n = 12).
Carbidopa was able to reduce its peripheral DDC conversion before levodopa crossed the blood-brain barrier, resulting in reduced side effects of L-Dopa. The results showed that carbidopa enhanced the efficacy of all L-Dopa and L-Dopa prodrug (drug A) treatment groups (Groups 1, 3, 4, 5, 6, 7, 9, 10). It is shown that the efficacy of the vehicle group and the prodrug treatment group of aspirin (drug B) (groups 2, 8 and 11) was not changed.
When administering a combination of multiple drugs (eg, one or more HPPs and / or other drugs) to a subject, each drug can be administered separately, or one or more drugs can be substantially treated as separate drugs. It can be administered simultaneously (eg, two or more drugs are sprayed substantially simultaneously without mixing before spraying), or one or more drugs can be mixed together and then administered to the subject, or Any combination of the above administration methods is also possible. The drugs can be administered in any possible order.

Example 33. Efficacy of L-Dopa and ibuprofen prodrugs on improvement of 6-OHDA-induced motor dysfunction and reduction of substantia nigra striatal neurodegeneration in the Parkinson's disease (PD) model in HDB.
Test subjects (Splatoon-re-rats) were prepared as described in Example 31, grouped and tested according to the protocol below.
1. 1. The rats were divided into 11 groups (n = 12), and the drug was administered to each group at the doses shown in Table 4 below. Drug C is (S) -4- (2-amino-3-oxo-3- (pentane-3-yloxy) propyl) -1,2-phenylenebis (2-methylpropanol-hydrobromide) And drug D was 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate acetate.

Table 4. Dose and drug administered to test animals

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

3. 3. From the upper back (around the neck and shoulders) of animals (all rats including those in the positive control group using L-DOPA due to the double-blind mode) using the small animal clipper on the day before the scheduled administration. The hair was removed. Animal hair was re-cut as needed to maintain epidermal exposure throughout the course of the study. On the day of administration, a fixed amount (643 μL / kg) of the pharmaceutical product was administered to a 3 cm × 3 cm square part (neck and shoulder area) of the animal at about 9 am, and repeated at about 4 pm.
Four. Four weeks after the lesion, the group began receiving treatment.
Five. A rotor rod test will be performed 4 weeks after treatment.

FIG. 5 shows the residence time results in the above rotor rod test after 4 weeks of treatment (n = 12). FIG. 6 shows the drop velocity results in the above rotor rod test after 4 weeks of treatment (n = 12).
By pooling all batch data together (12 animals / group), the positive group (L-DOPA, 6 mg / kg, oral) compared to the negative control group after 4 weeks of treatment. However, all study drug treatment groups showed stronger efficacy than the vehicle group after 4 weeks of treatment. The positive group (L-DOPA, 6 mg / kg, oral) showed that levodopa caused nausea, vomiting, gastrointestinal bleeding, dyskinesias, and an end-of-dose decline in function at peak doses. It was less effective than the vehicle group. However, transdermally administered L-Dopa prodrug (Compound C) avoided dyskinesias and end-of-dose reduction in function at peak doses. The efficacy of low doses of drug C (L-Dopa prodrug, 0.67 mg / kg, group 3) is much higher than the efficacy of medium and high doses of drug C (2 mg and 6 mg / kg, groups 4 and 5). it was high. The results showed that the dose of transdermally administered prodrug of L-dopa was much lower than that of orally administered L-dopa. Drug D (15 mg and 45 mg / kg) (prodrug of ibuprofen) showed better efficacy than the vehicle and positive control groups after 4 weeks of treatment. The 15 mg drug D (group 8) showed similar efficacy to the 45 mg drug D (group 11), so a dose of 15 mg / kg was sufficient and no higher dose was needed. Administration of a combination of drug C and drug D (groups 6 and 9) to a subject performed much better than administration of either drug D (groups 8 and 11) or drug C (group 3) alone.

Example 34. Prodrugs of L-Dopa and ibuprofen on improvement of 6-OHDA-induced motor dysfunction and reduction of substantia nigra striatal neurodegeneration in the Parkinson's disease (PD) model in HDB and 1.5 mg / kg The efficacy of Carbidopa.
Test subjects (Splatoon-re-rat) were prepared as described in Example 31, grouped and tested according to the protocol below.
1. 1. The rats were divided into 11 groups (n = 12), and the drug was administered to each group at the doses shown in Table 5 below.

Table 5. Dose and drug administered to test animals

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

3. 3. From the upper back (around the neck and shoulders) of animals (all rats including those in the positive control group using L-DOPA due to the double-blind mode) using the small animal clipper on the day before the scheduled administration. The hair was removed. Animal hair was re-cut as needed to maintain epidermal exposure throughout the course of the study. On the day of administration, a fixed amount (643 μL / kg) of the pharmaceutical product was administered to a 3 cm × 3 cm square part (neck and shoulder area) of the animal at about 9 am, and repeated at about 4 pm.
Four. Four weeks after the lesion, the group began receiving treatment.
Five. A rotor rod test was performed 4 weeks after treatment.

FIG. 7 shows the residence time results in the above rotor rod test after 4 weeks of treatment (n = 12). FIG. 8 shows the drop velocity results in the above rotor rod test after 4 weeks of treatment (n = 12).
Carbidopa was able to reduce its peripheral DDC conversion before levodopa crossed the blood-brain barrier, resulting in reduced side effects of L-Dopa. The results showed that carbidopa enhanced the efficacy of all L-Dopa and L-Dopa prodrug treatment groups (groups 1, 3, 4, 5, 6, 7, 9, 10), but the vehicle group and ibuprofen. It shows that the efficacy of the prodrug treatment group (Groups 2, 8 and 11) was not changed.

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

Table 6. Dose and drug administered to test animals

2. Dosage prescription
(1) L-DOPA (3 mg / ml) in water was a positive control solution for group 1 (oral for group 1). The dose volume was 2 mL / kg. The vehicle solution (negative control solution for group 2) was 30% ethanol (v / v). The dose volume was 1,286 μL / kg. Other test solutions (Groups 3-11) were freshly prepared daily.
(2) Preparation method of test solution for groups 3 to 5: 37.75 mg of drug E was dissolved in 10 mL of 30% ethanol (v / v). This solution was the preservation solution (2).
a. Test solution for group 5 (high dose group) of drug E: Preservative solution (2) was the test solution for group 5. The dose volume was 1,286 μL / kg;
b. Test solution for group 4 (medium dose group) of drug E: 3.00 mL of storage solution (2) was diluted with 30% ethanol (v / v) to a final volume of 9.00 mL. This solution was a test solution for Group 4. The dose volume was 1,286 μL / kg;
c. Test solution for group 3 (low dose group) of drug E: 1.00 mL of storage solution (2) was diluted with 30% ethanol (v / v) to a final volume of 9.00 mL. This solution was a test solution for Group 3. The dose volume was 1,286 μL / kg.
(3) Preparation method of 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) Preparation method of 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 a 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 a test solution for Group 8.
(6) Preparation method of 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 a test solution for group 10.
(8) Preparation method of test solution for group 11: 527 mg of drug E was dissolved in 10 mL of 30% ethanol (v / v). This solution was the test solution for Group 11.

3. 3. From the upper back (around the neck and shoulders) of animals (all rats including those in the positive control group using L-DOPA due to the double-blind mode) using the small animal clipper on the day before the scheduled administration. The hair was removed. Animal hair was re-cut as needed to maintain epidermal exposure throughout the course of the study. On the day of administration, a fixed amount (643 μL / kg) of the pharmaceutical product was administered to a 3 cm × 3 cm square part (neck and shoulder area) of the animal at about 9 am, and repeated at about 4 pm.
Four. Four weeks after the lesion, the group began receiving treatment.
Five. A rotor rod test was performed 4 weeks after treatment.

FIG. 9 shows the residence time results in the above rotor rod test after 4 weeks of treatment (n = 12). FIG. 10 shows the drop velocity results in the above rotor rod test after 4 weeks of treatment (n = 12).
By pooling all batch data together (12 animals / group), the positive group (L-DOPA, 6 mg / kg, oral) 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 bleeding, dyskinesia at peak doses and also resulted in an end-of-dose decline in function, so positive group (L-DOPA, 6 mg / kg, oral) Was less effective than the vehicle group. However, transdermal dopamine prodrugs avoided dyskinesias and end-of-dose reduction in function at peak doses. The low dose efficacy of drug E (prodrug of dopamine, 0.5 mg / kg, group 3) is the efficacy of medium and high doses of drug E (1.5 mg and 4.5 mg / kg, groups 4 and 5). Higher doses of drug E may have caused more side effects as L-dopa caused, as they were much higher. The 20 mg and 60 mg / kg drug F showed better efficacy after 4 weeks of treatment compared to the vehicle and positive control groups. The 20 mg drug F (group 8) showed similar efficacy to the 60 mg drug F (group 11). The results showed that a dose of 20 mg / kg was sufficient and no higher dose was needed. Administration of a combination of drug E and drug F (groups 6 and 9) to a subject performed much better than administration of either drug F (groups 8 and 11) or drug E (group 3) alone.
When administering a combination of multiple drugs (eg, one or more HPPs and / or other drugs) to a subject, each drug can be administered separately, or one or more drugs can be substantially treated as separate drugs. It can be administered simultaneously (eg, two or more drugs are sprayed substantially simultaneously without mixing before spraying), or one or more drugs can be mixed together and then administered to the subject, or Any combination of the above administration methods is also possible. The drugs can be administered in any possible order.

Example 36. Drug G ((S) -4- (2-amino-) on HDB for improvement of 6-OHDA-induced motor dysfunction and reduction of substantia nigra striatal nerve degeneration in PK / Kinson's disease (PD) model 3- (Heptane-4-yloxy) -3-oxopropyl) -1,2-phenylenedibenzoate hydrochloride) and drug H (2- (dipropylamino) ethyl 4-acetoxy-2', 4'- Efficacy of difluoro- [1,1'-biphenyl] -3-carboxylate hydrochloride) Test subjects (spragued-ly-rat) were prepared as described in Example 31 and grouped according to the following protocol. And tested.
1. 1. The rats were divided into 11 groups (n = 12), and the drug was administered to each group at the doses shown in Table 7 below.

Table 7. Dose and drug administered to test animals

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

3. 3. From the upper back (around the neck and shoulders) of animals (all rats including those in the positive control group using L-DOPA due to the double-blind mode) using the small animal clipper on the day before the scheduled administration. The hair was removed. Animal hair was re-cut as needed to maintain epidermal exposure throughout the course of the study. On the day of administration, a fixed amount (643 μL / kg) of the pharmaceutical product was administered to a 3 cm × 3 cm square part (neck and shoulder area) of the animal at about 9 am, and repeated at about 4 pm.
Four. Four weeks after the lesion, the group began receiving treatment.
Five. A rotor rod test was performed 4 weeks after treatment.

FIG. 11 shows the residence time results in the above rotor rod test after 4 weeks of treatment (n = 12). FIG. 12 shows the drop velocity results in the above rotor rod test after 4 weeks of treatment (n = 12).
By pooling all batch data together (12 animals / group), the positive group (L-DOPA, 6 mg / kg, oral) 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. The positive group (L-DOPA, 6 mg / kg, oral) was a vehicle because levodopa caused nausea, vomiting, gastrointestinal bleeding, dyskinesia at peak doses and also resulted in an end-of-dose decline in function. It showed no efficacy compared to the group. However, transdermally administered L-Dopa prodrugs avoided dyskinesias and end-of-dose decline in function at peak doses. The efficacy of low doses of drug G (L-Dopa prodrug, 0.67 mg / kg, group 3) is much higher than the efficacy of medium and high doses of drug G (2 mg and 6 mg / kg, groups 4 and 5). it was high. Higher doses may have caused side effects as L-dopa did. Drug H at 15 mg and 45 mg / kg showed better efficacy than the vehicle and positive control groups after 4 weeks of treatment. 15 mg of drug H (group 8) showed similar efficacy to 45 mg of drug H (group 11). This suggested that a dose of 15 mg / kg was sufficient and no higher dose was needed. Administration of the combination of drug G and drug H (groups 6 and 9) worked much better than administration of either drug H (groups 8 and 11) or drug G (group 3) alone.
When administering a combination of multiple drugs (eg, one or more HPPs and / or other drugs) to a subject, each drug can be administered separately, or one or more drugs can be substantially treated as separate drugs. It can be administered simultaneously (eg, two or more drugs are sprayed substantially simultaneously without mixing before spraying), or one or more drugs can be mixed together and then administered to the subject, or Any combination of the above administration methods is also possible. The drugs can be administered in any possible order.

Example 37. Drug A (percutaneous), drug B (percutaneous), which contributes to the improvement of 6-OHDA-induced motor dysfunction and the reduction of substantia nigra striatal neurodegeneration in the Parkinson's disease (PD) model in HDB. And the efficacy of Entacapone (oral).
Test subjects (Splatoon-re-rats) were prepared as described in Example 31, grouped and tested according to the protocol below.
1. 1. The rats were divided into 11 groups (n = 12), and the drug was administered to each group at the doses shown in Table 8 below.

Table 8. Dose and drug administered to test animals

2. Dosage prescription
(1) L-DOPA (3 mg / ml) and entacapone (12.5 mg / mL) in 0.5% CMC-Na (carboxymethyl cellulosic sodium salt) are positive controls for group 1 (oral). It was a solution and the dose 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 (orally) and the dose volume was 2 mL / kg. .. The vehicle solution (negative control solution for Group 2) was 30% ethanol (v / v) and the dose volume was 1,286 μL / kg. Other test solutions (transdermal, groups 3-11) were freshly prepared daily.
(2) Preparation method of test solution for groups 3-5: 50.33 mg of drug A was dissolved in 10 mL of 30% ethanol (v / v). This solution was the preservation solution (2).
a. The storage solution (2) was a test solution for group 5 (high dose group) of drug A. The dose volume was 1,286 μL / kg;
b. Test solution for group 4 (medium dose group) of drug A: 3.00 mL of storage solution (2) was diluted with 30% ethanol (v / v) to a final volume of 9.00 mL. This solution was a test solution for Group 4. The dose volume was 1,286 μL / kg;
c. Test solution for group 3 (low dose group) of drug A: 1.00 mL of storage solution (2) was diluted with 30% ethanol (v / v) to a final volume of 9.00 mL. This solution was a test solution for Group 4. The dose volume was 1,286 μL / kg.
(3) Preparation method of 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 a test solution for Group 6;
(4) Preparation method of 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 a 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 a test solution for Group 8;
(6) Preparation method of 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 a 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 a 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 of group 11.

3. 3. From the upper back (around the neck and shoulders) of animals (all rats including those in the positive control group using L-DOPA due to the double-blind mode) using the small animal clipper on the day before the scheduled administration. The hair was removed. Animal hair was re-cut as needed to maintain epidermal exposure throughout the course of the study. On the day of administration, a fixed amount (643 μL / kg) of the pharmaceutical product was administered to a 3 cm × 3 cm square part (neck and shoulder area) of the animal at about 9 am, and repeated at about 4 pm.
Four. Four weeks after the lesion, the group began receiving treatment.
Five. A rotor rod test was performed 4 weeks after treatment.

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

Example 38. Drug A (percutaneous), drug B (percutaneous), which contributes to the improvement of 6-OHDA-induced motor dysfunction and reduction of substantia nigra striatal neurodegeneration in the Parkinson's disease (PD) model in HDB. Efficacy of entacapone (oral) and carbidopa (oral).
Test subjects (Splatoon-re-rats) were prepared as described in Example 31, grouped and tested according to the protocol below.
1. 1. The rats were divided into 11 groups (n = 12), and the drug was administered to each group at the doses shown in Table 9 below.

Table 9. Dose and drug administered to test animals

2. Dosage prescription
(1) L-DOPA (3 mg / ml), entacapone (12.5 mg / ml), and carbidopa (1.5 mg / mL) in 0.5% CMC-Na are positive controls for group 1 (oral). -It was a solution, and the dose volume was 2 mL / kg. Entacapone (12.5 mg / ml) and carbidopa (1.5 mg / mL) in 0.5% CMC-Na were solutions for groups 2-11 (oral), with a dosing volume of 2 mL / kg. .. The vehicle solution (negative control solution for Group 2) was 30% ethanol (v / v) and the dose volume was 1,286 μL / kg. Other test solutions (transdermal, groups 3-11) were freshly prepared daily.
(2) Preparation method of test solution for groups 3-5: 50.33 mg of drug A was dissolved in 10 mL of 30% ethanol (v / v). This solution was the preservation solution (2).
a. The storage solution (2) was a test solution for group 5 (high dose group) of drug A. The dose volume was 1,286 μL / kg;
b. Test solution for group 4 (medium dose group) of drug A: 3.00 mL of storage solution (2) was diluted with 30% ethanol (v / v) to a final volume of 9.00 mL. This solution was a test solution for Group 4. The dose volume was 1,286 μL / kg;
c. Test solution for group 3 (low dose group) of drug A: 1.00 mL of storage solution (2) was diluted with 30% ethanol (v / v) to a final volume of 9.00 mL. This solution was a test solution for Group 3. The dose volume was 1,286 μL / kg.
(3) Preparation method of 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 a test solution for Group 6;
(4) Preparation method of 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 a 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 a test solution for Group 8;
(6) Preparation method of 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 a 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 a 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 of group 11.

3. 3. From the upper back (around the neck and shoulders) of animals (all rats including those in the positive control group using L-DOPA due to the double-blind mode) using the small animal clipper on the day before the scheduled administration. The hair was removed. Animal hair was re-cut as needed to maintain epidermal exposure throughout the course of the study. On the day of administration, a fixed amount (643 μL / kg) of the pharmaceutical product was administered to a 3 cm × 3 cm square part (neck and shoulder area) of the animal at about 9 am, and repeated at about 4 pm.
Four. Four weeks after the lesion, the group began receiving treatment.
Five. A rotor rod test was performed 4 weeks after treatment.

FIG. 15 shows the residence time results in the above rotor rod test after 4 weeks of treatment (n = 12). FIG. 16 shows the drop velocity results in the above rotor rod test after 4 weeks of treatment (n = 12).
Administration of the combination of carbidopa and entacapone worked better than administration of either carbidopa or entacapone alone. The results show 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), but the vehicle. It was shown that the efficacy of the group and the prodrug-treated group of aspirin (groups 2, 8 and 11) was not changed.
When administering a combination of multiple drugs (eg, one or more HPPs and / or other drugs) to a subject, each drug can be administered separately, or one or more drugs can be substantially treated as separate drugs. It can be administered simultaneously (eg, two or more drugs are sprayed substantially simultaneously without mixing before spraying), or one or more drugs can be mixed together and then administered to the subject, or Any combination of the above administration methods is also possible. The drugs can be administered in any possible order.

Example 39. 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 was administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 10 hours as needed. do.
Example 40. Treatment of Parkinson's disease and related conditions
A solution of 10 mg Drug A and 20 mg Drug B in 0.5 ml of water is administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 10 hours as needed. do.
Example 41. Treatment of Parkinson's disease and related conditions
A solution of 20 mg Drug A and 40 mg Drug B in 0.5 ml of water is administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 10 hours as needed. do.
Example 42. Treatment of Parkinson's disease and related conditions
A solution of 30 mg Drug A and 50 mg Drug B in 0.5 ml of water is administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 10 hours as needed. do.
Example 43. 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 was administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 10 hours as needed. do. After or before administration of the above solution, a tablet containing 10 mg of carbidopa and / or an inert ingredient such as cellulosic, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethyl cellulose and the like. Take it orally to increase the efficacy of transdermal treatment.
Example 44. Treatment of Parkinson's disease and related conditions
A solution of 20 mg Drug A and 40 mg Drug B in 0.5 ml of water is administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 10 hours as needed. do. After or before administration of the above solution, a tablet containing 15 mg of carbidopa and / or an inert ingredient such as cellulosic, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethyl cellulose and the like. Take it orally to increase the efficacy of transdermal treatment.
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 (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 10 hours. After or before administration of the above solution, 15 mg of carbidopa, 70 mg of entacapone and / or an inert ingredient such as cellulos, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulos, etc. The tablets contained therein are taken orally to enhance the efficacy of transdermal treatment.
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 of water is administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 10 hours. After or before administration of the above solution, 15 mg of carbidopa, 100 mg of entacapone and / or an inert ingredient such as cellulos, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulos, etc. The tablets contained therein are taken orally to enhance the efficacy of transdermal treatment.

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 of water is administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 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 of water is administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 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 of water is administered (percutaneously) 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, a tablet containing 15 mg of carbidopa and / or an inert ingredient such as cellulosic, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethyl cellulose and the like. Take it orally to increase the efficacy of transdermal treatment.
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 (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 10 hours. After or before administration of the above solution, 15 mg of carbidopa, 100 mg of entacapone and / or an inert ingredient such as cellulos, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulos, etc. The tablets contained therein are taken orally to enhance the efficacy of transdermal treatment.
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 of water is administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 10 hours. After or before administration of the above solution, 15 mg of carbidopa, 70 mg of entacapone and / or an inert ingredient such as cellulos, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulos, etc. The tablets contained therein are taken orally to enhance the efficacy of transdermal treatment.
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 of water is administered (percutaneously) 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 of carbidopa, 50 mg of entacapone and / or an inert ingredient such as cellulos, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulos, etc. The tablets contained therein are taken orally to enhance the efficacy of transdermal treatment.

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 of water is administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 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 of water is administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 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 of water is administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 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 of water is administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 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 of water is administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 10 hours.
Example 59. Treatment of Parkinson's disease and related conditions
A solution of 20 mg drug G and 15 mg drug H in 0.5 ml of water is administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 10 hours.

Example 60. Treatment of Parkinson's disease and related conditions
A solution of 20 mg drug G and 15 mg drug H in 0.5 ml of water is administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 10 hours. After or before administration of the above solution, 10 mg of carbidopa, 70 mg of entacapone and / or an inert ingredient such as cellulos, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulos, etc. The tablets contained therein are taken orally to enhance the efficacy of transdermal treatment.
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 of water is administered (percutaneously) to the skin of the subject's neck, chest, back and any other part every 3 to 10 hours. After or before administration of the above solution, 10 mg of carbidopa, 50 mg of entacapone and / or an inert ingredient such as cellulos, mannitol, croscarmellose sodium, vegetable oil, hydroxypropylmethylcellulos, etc. The tablets contained therein are taken orally to enhance the efficacy of transdermal treatment.

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

から成る群より選択され；
HAは、非存在、並びに医薬的に許容できる酸、例えば塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、重硫酸、リン酸、亜リン酸、ホスホン酸、イソニコチン酸、酢酸、乳酸、サリチル酸、クエン酸、酒石酸、パントテン酸、重酒石酸、アスコルビン酸、コハク酸、マレイン酸、ゲンチシン酸、フマル酸、グルコン酸、グルクロン酸、糖酸、ギ酸、安息香酸、グルタミン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸及びパモ酸から成る群より選択され；
Xは、O、S、及びNR ₃ から成る群より選択され；X ₂ は、非存在、O、S、NR ₃ 、CHR ₃ -O、CHR ₃ -S、CHR ₃ -O、O-CHR ₃ -O、O-CHR ₃ -S、S-CHR ₃ -O、及びS-CHR ₃ -Sから成る群より選択され；X ₃ は、非存在、C=O、C=S、C(=O)-O、O、S、NR ₃ 、C(=O)-O-CHR ₃ -O、C(=O)-O-CHR ₃ -S、C(=O)-S-CHR ₃ -O、及びC(=O)-S-CHR ₃ -Sから成る群より選択され；Y ₁ は、R ₃ C(=O)、R ₃ O-C(=O)、及びR ₃ S-C(=O)から成る群より選択され；Y ₂ は、R ₃ C(=O)、R ₃ O-C(=O)、及びR ₃ S-C(=O)から成る群より選択され；Y ₃ は、R ₃ 、OR ₃ 、SR ₃ 、NR ₃ R ₄ 、O-CHR ₃ -OR ₄ 、O-CHR ₃ -SR ₄ 、S-CHR ₃ -OR ₄ から成る群より選択され；
n及びmは、0、1、2、3、4、5、6、7、及び8から成る群より選択される。
Rcは、非存在、CH ₂ C(=O)OR _6、 置換及び無置換アルキル、置換及び無置換シクロアルキル、置換及び無置換ヘテロシクロアルキル、置換及び無置換アルコキシル、置換及び無置換ペルフルオロアルキル、置換及び無置換アルキルハライド、置換及び無置換アルケニル、置換及び無置換アルキニル、置換及び無置換アリール、並びに置換及び無置換ヘテロアリールから成る群より選択され、ここで、R中のいずれのCH ₂ もさらにO、S、P、NR ₆ 、又はいずれの他の医薬的に許容できる基と置き換わっていてもよく；
Rは、非存在、CH ₂ C(=O)OR _6、 置換及び無置換アルキル、置換及び無置換シクロアルキル、置換及び無置換ヘテロシクロアルキル、置換及び無置換アルコキシル、置換及び無置換ペルフルオロアルキル、置換及び無置換アルキルハライド、置換及び無置換アルケニル、置換及び無置換アルキニル、置換及び無置換アリール、並びに置換及び無置換ヘテロアリールから成る群より選択され、ここで、R中のいずれのCH ₂ もさらにO、S、P、NR ₆ 、又はいずれの他の医薬的に許容できる基と置き換わっていてもよく；
R ₃ 及びR ₄ は、非存在、CH ₂ C(=O)OR _6、 置換及び無置換アルキル、置換及び無置換シクロアルキル、置換及び無置換ヘテロシクロアルキル、置換及び無置換アルコキシル、置換及び無置換ペルフルオロアルキル、置換及び無置換アルキルハライド、置換及び無置換アルケニル、置換及び無置換アルキニル、置換及び無置換アリール、並びに置換及び無置換ヘテロアリールから成る群より選択され、ここで、R中のいずれのCH ₂ もさらにO、S、P、NR ₆ 、又はいずれの他の医薬的に許容できる基と置き換わっていてもよく；
各R ₆ は、独立に、H、F、Cl、Br、I、Na ⁺ 、K ⁺ 、C(=O)R _5、 2-オキソ-1-イミダゾリジニル、フェニル、5-インダニル、2,3-ジヒドロ-1H-インデン-5-イル、4-ヒドロキシ-1,5-ナフチリジン-3-イル、置換及び無置換アルキル、置換及び無置換シクロアルキル、置換及び無置換ヘテロシクロアルキル、置換及び無置換アルケニル、置換及び無置換アルキニル、置換及び無置換アルキルオキシル、置換及び無置換シクロアルキルオキシル、置換及び無置換アリール、置換及び無置換ヘテロアリール、-C(=O)-W、-L ₁ -L ₄ -L ₂ -W、及びWから成る群より選択され；
各R ₅ は、独立に、H、C(=O)NH ₂ 、CH ₂ CH ₂ OR _6、 CH ₂ CH ₂ N(CH ₃ ) ₂ 、CH ₂ CH ₂ N(CH ₂ CH ₃ ) _2、 Cl、F、Br、I、置換及び無置換アルキル、置換及び無置換シクロアルキル、置換及び無置換ヘテロシクロアルキル、置換及び無置換アルキルオキシル、置換及び無置換シクロアルキルオキシル、置換及び無置換アリール、置換及び無置換ヘテロアリール、置換及び無置換アルキルカルボニル、置換及び無置換アルキルアミノ、-C(=O)-W、L ₁ -L ₄ -L ₂ -W、及びWから成る群より選択され；
L ₁ は、非存在、O、S、-O-L ₃ -、-S-L ₃ -、-N(L ₃ )-、-N(L ₃ )-CH ₂ -O、-N(L ₃ )-CH ₂ -N(L ₅ )-、-O-CH ₂ -O-、-O-CH(L ₃ )-O、及び-S-CH(L ₃ )-O-から成る群より選択され；
L ₂ は、非存在、O、S、-O-L ₃ -、-S-L ₃ -、-N(L ₃ )-、-N(L ₃ )-CH ₂ -O、-N(L ₃ )-CH ₂ -N(L ₅ )-、-O-CH ₂ -O-、-O-CH(L ₃ )-O、-S-CH(L ₃ )-O-、-O-L ₃ -、-N-L ₃ -、-S-L ₃ -、-N(L ₃ )-L ₅ -及びL ₃

から成る群より選択され；
L ₄ は、非存在、C=O、C=S、

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

A compound containing a structure selected from the group consisting of (including its stereoisomers and pharmaceutically acceptable salts).
(In the 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 a non-existent and pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitrate, sulfuric acid, heavy sulfuric acid, phosphoric acid, phobic acid, phosphonic acid, isonicotinic acid, acetic acid, Lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, heavy 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 selected from the group; Y ₁ consists 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 , Selected from the group consisting of 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 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, substituted and unsubstituted alkyl halides, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and is selected from the group consisting of substituted and unsubstituted heteroaryl, wherein any of the CH ₂ in R also In addition, it may be replaced 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, substituted and unsubstituted alkyl halides, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and is selected from the group consisting of substituted and unsubstituted heteroaryl, wherein any of the CH ₂ in R also In addition, it may be replaced 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 non-substituted. Selected from the group consisting of substituted perfluoroalkyls, substituted and unsubstituted alkyl halides, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyls, substituted and unsubstituted aryls, and substituted and unsubstituted heteroaryls, wherein any of R is used. CH ₂ may also be further replaced with 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-naphthylidine-3-yl, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkenyl , Substituted and unsubstituted alkynyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, -C (= O) -W, -L ₁ -L ₄ -L ₂ -W, and selected from the group consisting of 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 selected from the group;
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 non-existent, C = O, C = S,

Selected from the group consisting of;
For each L ₁ , L ₂ , and L ₄ , each L ₃ and L ₅ , independently absent, H, CH ₂ C (= O) OL ₆ , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl. , Substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted heteroaryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyls, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted. And the group consisting of unsubstituted alkyl halides, where any carbon or hydrogen is further independently _{replaced 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 heteroaryls, substituted and unsubstituted alkoxyls, substituted and unsubstituted alkyl thios, substituted and unsubstituted alkylaminos, substituted and unsubstituted perfluoroalkyls, and substituted and unsubstituted alkyl halides, whichever is here. Carbon or hydrogen is also independently replaced with O, S, N, P (O) OL ₆ , CH = CH, C≡C, CHL ₆ , CL ₆ L ₇ , aryl, heteroaryl, or cyclic groups. May;
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 heteroaryls, substituted and unsubstituted alkoxyls, substituted and unsubstituted alkyl thios, substituted and unsubstituted alkylaminos, substituted and unsubstituted perfluoroalkyls, and substituted and unsubstituted alkyl halides, whichever is here. Carbon or hydrogen is also independently replaced with O, S, N, P (O) OL ₆ , CH = CH, C≡C, CHL ₆ , CL ₆ L ₇ , aryl, heteroaryl, or cyclic groups. May;
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. , Substituent and unsubstituted heteroaryl, protonizable amine group, pharmaceutically acceptable substituted and unsubstituted amine group, Structure Wa, Structure W-1, Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11, Structure W-12, Structure W-13, Structure W-14, Structure Selected from the group consisting of W-15, Structure W-16, Structure W-17 and Structure W-18;
R ₁ and R ₂ are independently H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted 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. Select from the group consisting of alkoxyls, substituted and unsubstituted perfluoroalkyls, substituted and unsubstituted alkyl halides, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl).
[2] The highly transparent prodrug according to the above [1]; structure NSAID-1, structure NSAID-2, structure NSAID-3, structure NSAID-4, structure NSAID-5, structure NSAID-6, structure NSAID-7, Compounds containing structures selected from the group consisting of structural NSAID-8, structural NSAID-9, structural NSAID-10, structural NSAID-11, structural NSAID-12, and structural NSAID-13; carbidopa, venceradide, difluoromethyldopa, and. Includes aromatic L-aminosteroidal decarboxylase inhibitors selected from the group consisting of α-methyldopa; catechol-O-methyltransferase inhibitors selected from the group consisting of Entakapon and Torkapon; and pharmaceutically acceptable carriers. Pharmaceutical composition.
[3] 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, according to the above [2]. The pharmaceutical composition described.
[4] A pharmaceutical composition comprising levodopa, dopamine, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), and any combination thereof, one or more hyperpermeable prodrugs.
[5] Transdermally administered for the treatment of Parkinson's disease and related conditions, including levodopa, dopamine, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and any combination of hyperpermeable prodrugs thereof. Pharmaceutical compositions, in addition to which are carvidopa, benserazide, difluoromethyldopa, α-methyldopa, other aromatic L-amino acid decarboxylase inhibitors, entacapone, tolucapon and / or other catechol-O-methyltransferases. A pharmaceutical composition comprising an orally administered tablet containing an inhibitor.
[6] 4- (2- (2- (Methylamino) acetamide) ethyl) -1,2,-phenylenedibenzoate hydrochloride, 4- (2- (2- (methylamino) acetamide) ethyl) -1, 2,-Phenylenedibenzoate acetic acid, 4- (6-methyl-4,8-dioxo-5,7-dioxa-2,9-diazadecan-11-yl) -1,2,-Phenylenedibenzoate hydrobromide Salt, 4- (2- (2-amino-3-phenylpropanamide) ethyl) -1,2,-phenylenedibenzoate hydrochloride, 4-(2-((((1-((pyrrolidin-2-carbonyl)) Oxy) ethoxy) amino) ethyl) -1,2,-phenylenedibenzoate hydrochloride, 4- (2-piperidin-4-carboxamide) ethyl) -1,2,-phenylenebis (2-ethylbutanoate) hydrochloride Salt, 4- (2-((((-octahydro-1H-quinolidine-3-yl) oxy) carbonyl) amino) ethyl) -1,2,-phenylenebis (2-ethylbutanoate) acetate, 1- (((2- (4-Amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo [b] [1,4] dioxocin-8-yl) ethyl) carbamoyl) oxy) ethylisobutyrate Hydrofluoride salt, 1-(((2- (3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo [b] [1,4] dioxocin-8-yl) ethyl)) Carbamoyl) oxy) ethyl isobutyrate fluorinated hydrochloride, (-(2-((ethoxycarbonyl) amino) ethyl) -2- (2-methylamino) acetoxy) phenylbenzoate hydrochloride, 5- (2- (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-phenylenedibenzoate hydrochloride, (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- (pe) Ntan-3-yloxy) propyl) -1,2-phenylenebis (2-methylpropanoate) hydrobromide, (S) -4- (2-aminoacetamide) -3-isopropoxy-3-oxo Propyl) -1,2-phenylenedibenzoate hydrochloride, 4-((2S) -3-oxo-3- (pentane-3-yloxy) -2- (pyrrolidin-2-carboxamide) propyl) -1,2- Phenylene dibenzoate hydrofluoride, (S) -4- (3-isopropoxy-3-oxo-2- (piperidin-4-carboxamide) 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) )-Isopropyl3- (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) -isopropyl3- (4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo [b] [1 , 4] Dioxocin-8-yl) -2-(((1- (isobutyryloxy) ethoxy) carbonyl) amino) propanoate hydride, 5-((2S) -2-(((1-11-) (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-((((octahydroindrin-1-yl) oxy) carbonyl) amino) -3-oxopropyl) -1,2-phenylenedibenzoate acetate, 2- (diethylamino) ethyl 2-[(2,6-dichloro-3-methylphenyl) amino] benzoate. Acetate, (Z) -2- (diethylaminoethyl) ethyl 2- (5-fluoro-2-methyl-1- (4-methyl) Sulfinyl) benziliden) -1H-inden-1-yl) acetate.AcOH, 2- (dime) Thylamino) Ethyl 2- (3-Phenoxyphenyl) Propionate. Hydrochloride, S- (2- (Dimethylamino) Ethyl 2- (3-Phenoxyphenyl) Propylthioart 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. A pharmaceutical composition administered transdermally for the treatment of Parkinson's disease and related conditions, comprising hydrochloride.
[7] Parkinson's disease and containing (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylenedibenzoate and 2- (diethylamino) ethyl2-acetoxybenzoate. A pharmaceutical composition for the treatment of related conditions.
[8] (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylenedibenzoate, 2- (diethylamino) ethyl2-acetoxybenzoate, carbidopa and / or entacapone A pharmaceutical composition for the treatment of Parkinson's disease and related conditions, including.
[9] (S) -4- (2-amino-3-oxo-3- (pentane-3-yloxy) propyl) -1,2-phenylenebis (2-methylpropanoate) and 2- (diethylamino) A pharmaceutical composition comprising ethyl 2- (4-isobutylphenyl) propionate for the treatment of Parkinson's disease and related conditions.
[10] 4- (2-((((1-((Pyrrolidine-2-carbonyl) oxy) ethoxy) amino) ethyl) -1,2,-phenylenedibenzoate and 4- (dimethylamino) butyl 2- (3) -Phenoxyphenyl) A pharmaceutical composition comprising propionate for the treatment of Parkinson's disease and related conditions.
[11] (S) -4- (2-amino-3-oxo-3- (pentane-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- (heptane-4-yloxy) -3-oxopropyl) -1,2-phenylenedibenzoate and 2- (dipropylamino) ethyl 4-acetoxy A pharmaceutical composition comprising -2', 4'-difluoro- [1,1'-biphenyl] -3-carboxylate for the treatment of Parkinson's disease and related conditions.
[13] (S) -4- (2-amino-3- (heptane-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 step of transdermally administering the pharmaceutical composition according to any one of [2] to [13] above, which is a method for treating Parkinson's disease of the subject; and carbidopa, benserazide, difluoromethyldopa, and α. -Aromatic L-amino acid decarboxylase inhibitors selected from the group consisting of methyldopa; and / or catechol-O-methyltransferase inhibitors selected from the group consisting of entacapone and tolcapone; or oral pharmaceutical compositions thereof. A method comprising the step of administration.

Claims (1)

4- (2- (2- (Methylamino) acetamide) ethyl) -1,2,-Phenylene benzoart HA,
4- (6-Methyl-4,8-dioxo-5,7-dioxa-2,9-diazadecan-11-yl) -1,2-phenylenedibenzoart HA,
4- (2- (2-Amino-3-phenylpropaneamide) ethyl) -1,2-phenylenedibenzoate HA,
4- (2-((((1-((Pyrrolidine-2-carbonyl) oxy) ethoxy) carbonyl) amino) ethyl) -1,2-phenylenedibenzoart HA,
4- (2- (Piperidin-4-carboxamide) ethyl) -1,2-phenylenebis (2-ethylbutanoate) ・ HA,
4- (2-((((Octahydro-1H-quinolidine-3-yl) oxy) carbonyl) amino) ethyl) -1,2-phenylenebis (2-ethylbutanoate) ・ HA,
1-(((2- (4-Amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo [b] [1,4] dioxocin-8-yl) ethyl) carbamoyl) oxy) ethyliso Butyrat HA,
1-(((2- (3-Amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo [b] [1,4] dioxocin-8-yl) ethyl) carbamoyl) oxy) ethyliso Butyrat HA,
4- (2-((ethoxycarbonyl) Amino) Ethyl) -2- (2- (Methylamino) Acetoxy) Phenylbenzoate HA, and
5- (2-((ethoxycarbonyl) Amino) Ethyl) -2- (2- (Methylamino) Acetoxy) Phenylbenzoate HA
A compound that will be selected from the group consisting of,
HA is Ru is selected from the absence and the pharmaceutically acceptable acid or al the group consisting,
The compound.

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