Novel high-penetration medicine for treating Parkinson's disease and medicine composition thereof

文档序号：871084 发布日期：2021-03-19 浏览：19次中文

阅读说明：本技术 治疗帕金森疾病的新型高穿透力药物及其药物组合物 (Novel high-penetration medicine for treating Parkinson's disease and medicine composition thereof ) 是由于崇曦徐丽娜于 2013-03-15 设计创作，主要内容包括：本发明涉及治疗帕金森疾病的新型高穿透力药物及其药物组合物。高穿透力组合物或高穿透力前药的组合物在穿过生物屏障后能转变成母体活性药物或其代谢物,因此可以治疗母药或其代谢物可治疗的疾病。(The invention relates to a novel high-penetration medicament for treating Parkinson's disease and a medicinal composition thereof. The high penetration composition or the high penetration prodrug composition can be converted into the parent active drug or the metabolite thereof after crossing the biological barrier, thereby treating the disease which can be treated by the parent drug or the metabolite thereof.)

1. A compound comprising a structure selected from the group consisting of formula Pro-L-dpa-1, formula Pro-L-dpa-2, formula Pro-L-dpa-3, formula Pro-L-dpa-4, formula Pro-L-dpa-5, formula Pro-dopamine-1, formula Pro-dopamine-3, formula Pro-dopamine-4, and formula Pro-dopamine-5:

including stereoisomers and pharmaceutically acceptable salts thereof,

wherein, W is selected from a structural formula W-1, a structural formula W-2, a structural formula W-3, a structural formula W-4, a structural formula W-5, a structural formula W-6, a structural formula W-7, a structural formula W-8, a structural formula W-9, a structural formula W-10, a structural formula W-11 and a structural formula W-12:

HA is selected from the group consisting of nothing (none) and pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, hydrogen sulfate, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and pamoic acid;

x is selected from O, S, and NR₃；

X₂Selected from the group consisting of no eastWest (none), O, S, NR₃、CHR₃-O、CHR₃-S、CHR₃-O、O-CHR₃-O、O-CHR₃-S、S-CHR₃-O, and S-CHR₃-S；

X₃Selected from nothing (nothing), C-O, C-S, C (O) -O, O, S, NR₃、C(＝O)-O-CHR₃-O、C(＝O)-O-CHR₃-S、C(＝O)-S-CHR₃-O, and C (═ O) -S-CHR₃-S；

Y₁Is selected from R₃C(＝O)、R₃O-C (═ O), and R₃S-C(＝O)；

Y₂Is selected from R₃C(＝O)、R₃O-C (═ O), and R₃S-C(＝O)；

Y₃Is selected from R₃、OR₃、SR₃、NR₃R₄、O-CHR₃-OR₄、O-CHR₃-SR₄、S-CHR₃-OR₄；

n and m are selected from 0, 1,2, 3, 4, 5, 6, 7, and 8.

Rc is selected from nothing (nothing), CH₂C(＝O)OR₆Substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted haloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, wherein any CH in R is₂Can be further O, S, P, NR₆Or any other pharmaceutically acceptable group substitution;

r is selected from nothing (nothing), CH₂C(＝O)OR₆Substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted haloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, wherein any CH in R is₂Can be further O, S, P, NR₆Or any other pharmaceutically acceptable group substitution;

R₃and R₄Selected from nothing (nothing), CH₂C(＝O)OR₆Substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted haloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, wherein any CH in R is₂Can be further O, S, P, NR₆Or any other pharmaceutically acceptable group substitution;

each R₆Independently selected from H, F, Cl, Br, I, Na⁺、K⁺、C(＝O)R₅2-oxo-1-imidazolidinyl, phenyl, 5-indanyl, 2, 3-dihydro-1H-inden-5-yl, 4-hydroxy-1, 5-naphthyridin-3-yl, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkoxy, substituted and unsubstituted cycloalkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, -C (═ O) -W, -L₁-L₄-L₂-W, and W;

each R₅Independently selected from H, C (═ O) NH₂、CH₂CH₂OR₆、CH₂CH₂N(CH₃)₂、CH₂CH₂N(CH₂CH₃)₂Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted cycloalkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, -C (═ O) -W, L₁-L₄-L₂-W, and W;

L₁selected from nothing (nothing),O、S、-O-L₃-、-S-L₃-、-N(L₃)-、-N(L₃)-CH₂-O、-N(L₃)-CH₂-N(L₅)-、-O-CH₂-O-、-O-CH(L₃) -O, and-S-CH (L)₃)-O-；

L₂Selected from nothing (none), O, S, -O-L₃-、-S-L₃-、-N(L₃)-、-N(L₃)-CH₂-O、-N(L₃)-CH₂-N(L₅)-、-O-CH₂-O-、-O-CH(L₃)-O、-S-CH(L₃)-O-、-O-L₃-、-N-L₃-、-S-L₃-、-N(L₃)-L₅-and L₃；C＝O、C＝S、

L₄Selected from nothing (none), C-O, C-S,

For each L₁、L₂And L₄Each of L₃And L₅Independently selected from nothing (nothing), H, CH₂C(＝O)OL₆Substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted haloalkyl, wherein any carbon or hydrogen atom, respectively, can be further replaced by O, S, P, NL₃Or any other pharmaceutically acceptable group.

Each L₆Independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted haloalkyl, wherein any carbon or hydrogen atom may be further independently replaced by O, S, N, P (O) OL₆、CH＝CH、C≡C、CHL₆、CL₆L₇Aryl, heteroaryl, or cyclyl substitution.

Each L₇Independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted haloalkyl, wherein any carbon or hydrogen atom may be further independently replaced by O, S, N, P (O) OL₆、CH＝CH、C≡C、CHL₆、CL₆L₇Aryl, heteroaryl, or cyclyl substitution.

W is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, protonatable amino, pharmaceutically acceptable substituted and unsubstituted amino, structural formula Wa, structural formula W-1, structural formula W-2, structural formula W-3, structural formula W-4, structural formula W-5, structural formula W-6, structural formula W-7, structural formula W-8, structural formula W-9, structural formula W-10, structural formula W-11, structural formula W-12, structural formula W-13, structural formula W-14, structural formula W-15, structural formula W-16, Structural formula W-17 and structural formula W-18;

R₁and R₂Independently selected from H, substituted and unsubstituted alkyl, substituted and unsubstitutedSubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues;

R₁₁-R₁₅independently selected from nothing (nothing), H, CH₂C(＝O)OR₁₁Substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted haloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl.

2. A pharmaceutical composition comprising: the high penetration prodrug of claim 1; a compound comprising a structure selected from the group consisting of formula NSAID-1, formula NSAID-2, formula NSAID-3, formula NSAID-4, formula NSAID-5, formula NSAID-6, formula NSAID-7, formula NSAID-8, formula NSAID-9, formula NSAID-10, formula NSAID-11, formula NSAID-12 and formula NSAID-13; an aromatic-L-amino acid decarboxylase inhibitor selected from carbidopa, benserazide, difluoromethyl dopa, and alpha-methyldopa; a catechol-O-methyltransferase inhibitor selected from entacapone and tolcapone; and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable carrier is selected from the group consisting of ethanol, acetone, esters, cellulose, mannitol, croscarmellose sodium, vegetable oils, hydroxypropylmethylcellulose, water, and aqueous solutions.

4. A pharmaceutical composition comprising one or more high penetration prodrugs of levodopa, dopamine, aspirin, and other non-steroidal anti-inflammatory drugs (NSAIDs), and any combination thereof.

5. A pharmaceutical composition for transdermal administration for the treatment of Parkinson's disease and related diseases comprising high penetration prodrugs of levodopa, dopamine, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), and any combination thereof, plus oral tablets containing carbidopa, benserazide, difluoromethyl dopa, alpha-methyldopa, other aromatic-L-amino acid decarboxylase inhibitors, entacapone, tolcapone, and/or other catechol-O-methyltransferase inhibitors.

6. A pharmaceutical composition for transdermal administration for the treatment of Parkinson's disease and related disorders, comprising 1- (((2- (4-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) ethyl) carbamoyl) oxy) ethyl isobutyrate hydrofluoride, 1- (((2- (3-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) ethyl) carbamoyl) oxy) ethyl isobutyrate hydrofluoride, 4- (2- ((ethoxycarbonyl) amino) ethyl) -2- (2-methylamino) acetoxy) phenyl benzoate hydrochloride, benzoic acid 5- (2- ((ethoxycarbonyl) amino) ethyl) -2- (2-methylamino) acetoxy) phenyl ester hydrochloride, dibenzoic acid 4- (2-aminoethyl) -1,2-phenylene ester hydrochloride, dibenzoic acid (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylene ester hydrochloride, dibenzoic acid (S) -4- (2-amino-3- (hept-4-yloxy) -3-oxopropyl) -1,2-phenylene ester hydrochloride, divaricatic acid (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylene ester hydrochloride, bis (2-methylpropionic acid) (S) -4- (2-amino-3-ethoxy-3-oxopropyl) -1,2-phenylene ester hydrochloride, bis (2-methylpropionic acid) (S) -4- (2-amino-3-oxo-3- (pentan-3-yloxy) propyl) -1,2-phenylene ester hydrobromide, (S) -4- (2-aminoacetamino) -3-isopropoxy-3-oxopropyl) -1,2-phenylene dibenzoate hydrochloride, 4- ((2S) -3-oxo-3- (pentan-3-yloxy) -2- (pyrrolidine-2-carboxamido) propyl) -1-dibenzoate 2-phenylene hydrofluoride, dibenzoic acid (S) -4- (3-isopropoxy-3-oxo-2- (piperidine-4-carboxamido) propyl) -1,2-phenylene hydrochloride, bis (2-methylpropionic acid) 4- ((2S) -3-isopropoxy-3-2- (octahydro-1H-quinolizine-2-carboxamido) -3-oxopropyl) -1,2-phenylene ester hydrochloride, (2S) -3- (3-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino) propionic acid isocy-anate Propyl ester hydrobromide, (2S) -3- (4-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino) propionic acid isopropyl ester hydrobromide, benzoic acid 5- ((2S) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino-3-isopropoxy-3-oxopropyl) -2- (2- (methylamino) acetoxy) phenyl ester hydrochloride, benzoic acid 4- ((2S) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino-3-isopropoxy-3-oxopropyl) -2- (2- (isobutyryloxy) carbonyl) acetyl) phenyl ester hydrochloride - (methylamino) acetoxy) phenyl ester hydrochloride, dibenzoic acid 4- ((2S) -3-isopropoxy-2- ((((octahydroindolizin-1-yl) oxy) carbonyl) amino) -3-oxopropyl) -1,2-phenylene acetate, 2- [ (2, 6-dichloro-3-methylphenyl) amino ] benzoic acid 2- (diethylamino) ethyl ester acetate, (Z) -2- (5-fluoro-2-methyl-1- (4-methylsulfinyl) benzylidene) -1H-inden-1-yl) acetic acid 2- (diethylaminoethyl) ethyl ester acetate, 2- (3-phenoxyphenyl) propionic acid 2- (dimethylamino) ethyl ester hydrochloride, 2- (dimethylamino) ethanethiol hydrochloride, 4-acetoxy-2 ', 4 ' -difluoro- [1, 1 ' -biphenyl ] -3-carboxylic acid 2- (dipropylamino) ethyl ester hydrochloride, 2- (diethylamino) ethyl2- (4-isobutylphenyl) propanoate hydrochloride, and/or 2- (diethylamino) ethyl 2-acetoxybenzoic acid hydrochloride.

7. A pharmaceutical composition comprising (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylene dibenzoate and 2- (diethylamino) ethyl 2-acetoxybenzoate for use in the treatment of parkinson' S disease and related diseases.

8. A pharmaceutical composition comprising (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylene dibenzoate, 2- (diethylamino) ethyl 2-acetoxybenzoate, carbidopa and/or entacapone for the treatment of parkinson' S disease and related diseases.

9. A pharmaceutical composition comprising (S) -4- (2-amino-3-oxo-3- (pentan-3-yloxy) propyl) -1,2-phenylene bis (2-methylpropionate) and 2- (diethylamino) ethyl2- (4-isobutylphenyl) propionate for the treatment of parkinson' S disease and related diseases.

10. A pharmaceutical composition comprising (S) -4- (2-amino-3-oxo-3- (pentan-3-yloxy) propyl) -1,2-phenylene bis (2-methylpropionate), 2- (diethylamino) ethyl2- (4-isobutylphenyl) propionate, carbidopa and/or entacapone for the treatment of parkinson' S disease and related diseases.

11. A pharmaceutical composition comprising (S) -4- (2-amino-3- (heptan-4-yloxy) -3-oxopropyl) -1,2-phenylene dibenzoate and 2- (dipropylamino) ethyl 4-acetoxy-2 ', 4' -difluoro- [1, 1 '-biphenyl ] -3-carboxylate for the treatment of parkinson' S disease and related diseases.

12. A pharmaceutical composition comprising (S) -4- (2-amino-3- (heptan-4-yloxy) -3-oxopropyl) -1,2-phenylene dibenzoate and 2- (dipropylamino) ethyl 4-acetoxy-2 ', 4' -difluoro- [1, 1 '-biphenyl ] -3-carboxylate, carbidopa and/or entacapone for the treatment of parkinson' S disease and related diseases.

13. Use of a pharmaceutical composition according to any one of claims 2-12 in the manufacture of a medicament for treating parkinson's disease in a subject, for use in a method comprising:

administering said drug transdermally; and

orally administering an aromatic-L-amino acid decarboxylase inhibitor selected from carbidopa, benserazide, difluoromethyl dopa, and alpha-methyldopa; and/or a catechol-O-methyltransferase inhibitor selected from entacapone and tolcapone; or a pharmaceutical composition thereof.

Technical Field

The present invention relates to the field of pharmaceutical compositions. More particularly, one aspect of the present invention relates to pharmaceutical compositions capable of crossing one or more biological barriers and the use of these pharmaceutical compositions for the prevention and/or treatment of parkinson's disease and/or parkinsonism in a subject.

Background

Parkinson's Disease (PD) is a neurological disease characterized by degeneration of dopaminergic neurons in the substantia nigra region and loss of dopamine from the putamen. It is described as a motor neurological disease, but it also causes cognitive and behavioral symptoms. Parkinson's disease may be caused by dopamine-producing cell death in the substantia nigra (a region of the midbrain). The cause of these cell deaths may be unknown (primary parkinson's disease) or known (secondary parkinson's disease). Parkinson's disease may produce many functional syndromes including movement, attention or learning. Cell death at the pars compacta of the substantia nigra causes a decrease in dopamine-secreting cell activity leading to primary parkinson's disease. A particular motor circuit and its conceptual model of changes due to parkinson's disease have important implications since 1980, with some modifications, although some limitations have been noted. [ Obeso JA, Rodriguez-Oroz MC, Benitez-termino B, et al (2008). ], "Functional organization of the basal ganglia: thermal diagnostics for Parkinson's disease ", Mov. disease.23 (Suppl 3): s548-59 in this model, the basal ganglia generally release a stable inhibitory influence on a wide variety of motor systems to prevent the motor systems from becoming active at inappropriate times. When a command to perform a particular action is made, the necessary motor system's suppression is reduced, thereby releasing the activated signal. Dopamine helps to promote these inhibitory effects, so high levels of dopamine tend to enhance muscle activation, while low levels of dopamine (e.g. parkinson's disease) require more effort for any given activity. The net effect of dopamine depletion is therefore to produce hypokinesia. [ Obeso JA, Rodri i guez-Oroz MC, Benitez-termino B, et al (2008). ], "Functional organization of the basal anglia: thermal diagnostics for Parkinson's disease ", Mov. disease.23 (Suppl 3): s54859].

Drugs used for the treatment of motor syndromes mainly include levodopa (usually in combination with dopa decarboxylase inhibitors or COMT inhibitors), dopamine agonists and monoamine oxidase inhibitors. [ The National colouring center for viral Conditions, ed. (2006), "systematic pharmaceutical therapy in Parkinson's disease", Parkinson's disease. Royal College of physicians pp.59-100. although levodopa can improve motor syndromes, its effect on cognitive and behavioral symptoms is more complex [ Cools R (2006). "dominical modulation of cognitive functions-observations for L-DOPA treatment in Parkinson's disease". Neurosci Biobehav Rev 30 (1): 1-23]. Levodopa formulations cause motor complications in parkinson's patients, including abnormal involuntary movements or movement disorders (e.g. athetosis and dystonia). Patients also experience fluctuations in response due to "fading" effects of drug efficacy and/or unexpected transitions between "responsive to drug" and "non-responsive to drug" states. Therefore, better treatment of parkinson's disease is needed. Levodopa can also cause nausea, vomiting, gastrointestinal bleeding, motor aberrations at peak doses, and diminished efficacy at peak and trough doses.

Therefore, there is a need to develop better treatments to address these problems.

Disclosure of Invention

One aspect of the invention relates to High Penetration Prodrugs (HPPs) of levodopa and/or dopamine.

Another aspect of the present invention relates to pharmaceutical compositions comprising one or more High Penetration Prodrugs (HPPs) disclosed herein. In certain embodiments, the pharmaceutical composition comprises one or more high penetration prodrugs of an NSAID and one or more high penetration prodrugs of dopamine and/or levodopa.

Wherein the parent drugs for these HPPs may be the same or different and may be levodopa, dopamine, aspirin, bronofen, and/or other NSAIDs disclosed herein.

Another aspect of the invention relates to a method of crossing one or more biological barriers in a biological subject using the composition of the invention.

Another aspect of the invention relates to a method of treating a condition in a biological subject with a composition of the invention or a pharmaceutical composition thereof.

Another aspect of the present invention relates to a method of treating parkinson's disease and/or related conditions in a biological subject or a subject with one or more HPPs or a composition thereof by administering the one or more HPPs or a pharmaceutical composition thereof to the biological subject or subject.

Drawings

Figure 1.1-3 weeks post-treatment residence time results in Totarod test (n-12) (example 31).

Fig. 2.1-3 weeks post-treatment Totarod test spin rate results at drop (n-12) (example 31).

Figure 3.residence time results in Totarod test after 1-3 weeks treatment (n-12) (example 32).

Fig. 4.4 weeks post-treatment Totarod test spin rate results at time of drop (n-12) (example 32).

Fig. 5.4 weeks post-treatment residence time results in Totarod test (n-12) (example 33).

Fig. 6.4 weeks post-treatment Totarod test spin rate results at time of drop (n-12) (example 33).

Fig. 7.4 weeks post-treatment residence time results in Totarod test (n-12) (example 34).

Fig. 8.4 weeks post-treatment Totarod test spin rate results at time of drop (n-12) (example 34).

Fig. 9.4 weeks post-treatment Totarod test spin rate results at time of drop (n-12) (example 35).

Fig. 10.4 weeks post-treatment Totarod test spin rate results at time of drop (n-12) (example 35).

Fig. 11.4 weeks post-treatment residence time results in Totarod test (n-12) (example 36).

Fig. 12.4 weeks post-treatment Totarod test spin rate results at time of drop (n-12) (example 36).

Fig. 13.4 weeks post-treatment residence time results in Totarod test (n-12) (example 37).

Fig. 14.4 weeks post-treatment Totarod test spin rate results at time of drop (n-12) (example 37).

Figure 15.4 residence time results in Totarod test after week treatment (n-12) (example 38).

Fig. 16.4 weeks post-treatment Totarod test spin rate results at time of drop (n-12) (example 38).

Detailed Description

I. High penetration prodrugs of levodopa

One aspect of the present invention relates to a high penetration prodrug of levodopa comprising a structure selected from the group consisting of formula Pro-L-Dopa-1, formula Pro-L-Dopa-2, formula Pro-L-Dopa-3, formula Pro-L-Dopa-4, and formula Pro-L-Dopa-5:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

w is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, protonatable amine, pharmaceutically acceptable substituted and unsubstituted amine, structural formula W-1, structural formula W-2, structural formula W-3, structural formula W-4, structural formula W-5, structural formula W-6, structural formula W-7, structural formula W-8, structural formula W-9, structural formula W-10, structural formula W-11, and structural formula W-12:

HA is selected from the group consisting of nothing (nothing), and pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid (sulfic acid), bisulfic acid (bisulfic acid), phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucuronic acid (glucaronic acid), saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid (bezenesulfonic acid), p-toluenesulfonic acid, and pamoic acid (pamoic acid);

R₁and R₂Is independently selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues;

R₁₁to R₁₅Independently selected from none, H, CH₂(C＝O)OR₁₁Substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted haloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl;

x is selected from O, S, and NR₃；

X₂Selected from nothing (nothing), O, S, NR₃、CHR₃-O、CHR₃-S、CHR₃-O、O-CHR₃-O、O-CHR₃-S、S-CHR₃-O, and S-CHR₃-S；

X₃Selected from nothing (nothing), C-O, C-S, C (O) -O, O, S, NR₃、C(＝O)-O-CHR₃-O、C(＝O)-O-CHR₃-S、C(＝O)-S-CHR₃-O, and C (═ O) -S-CHR₃-S；

Y₁Is selected from R₃C(＝O)、R₃O-C (═ O), and R₃S-C(＝O)；

Y₂Is selected from R₃C(＝O)、R₃O-C (═ O), and R₃S-C(＝O)；

Y₃Is selected from R₃、OR₃、SR₃、NR₃R₄、O-CHR₃-OR₄、O-CHR₃-SR₄And S-CHR₃-OR₄；

n and m are selected from 0, 1,2, 3, 4, 5, 6, 7, and 8.

R_cSelected from nothing (nothing), CH₂C(＝O)OR₆Substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted haloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, wherein any CH on R is₂May be further O, S, P, or NR₆Replacement;

r is selected from nothing (nothing), CH₂C(＝O)OR₆Substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted haloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, wherein any CH on R is₂May be further O, S, P, or NR₆Replacement;

R₃and R₄Independently selected from nothing (nothing), CH₂C(＝O)OR₆Substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted haloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl, wherein any one CH in R is₂May be further O, S, P, or NR₆Replacement;

L₁selected from nothing (none), O, S, -O-L₃-、-S-L₃-、-N(L₃)-、-N(L₃)-CH₂-O、-N(L₃)-CH₂-N(L₅)-、-O-CH₂-O-、-O-CH(L₃) -O, and-S-CH (L)₃)-O-；

L₄Selected from the group consisting ofEast west (nothing), C O, C S,

For each L₁、L₂And L₄Each of L₃And L₅Independently selected from nothing (nothing), H, CH₂C(＝O)OL₆Substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted haloalkyl, wherein any carbon or hydrogen atom may be further independently replaced by O, S, P, or NL₃Replacing;

each L₆Independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted haloalkyl, wherein any carbon or hydrogen atom may be further independently replaced by O, S, N, P (O) OL6, CH ═ CH, C ≡ C, CHL6, Cl6L7, aryl, heteroaryl, or cyclic groups;

each L₇Independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted haloalkyl, wherein any carbon or hydrogen atom may be further independently replaced by O, S, N, P (O) OL6, CH ═ CH,c ≡ C, CHL6, CL6L7, aryl, heteroaryl, or cyclic group substitution; and

all CH₂The group may be replaced with O, S, or NH.

High penetration prodrugs of dopamine

Another aspect of the present invention relates to a high penetration prodrug of dopamine comprising a structure selected from the group consisting of structural formula Pro-dopamine-1, structural formula Pro-dopamine-2, structural formula Pro-dopamine-3, and structural formula Pro-dopamine-4, and structural formula Pro-dopamine-5:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

W，HA，X，X₂，X₃，Y₁，Y₂，Y₃，n，m，R_c，R，R₁，R₂，R₃，R₄，R₅，R₆，R₁₁-R₁₅，L₁，L₂and L₄As defined above.

A pharmaceutical composition comprising a high penetration prodrug of an NSAID and one or more high penetration prodrugs of dopamine and/or levodopa.

Another aspect of the invention relates to a pharmaceutical composition comprising one or more high penetration prodrugs of an NSAID and one or more high penetration prodrugs of dopamine and/or levodopa.

The high penetration prodrug of an NSAID comprises a structure selected from the group consisting of formula 1 NSAID-1, formula 2 NSAID-3, formula 4 NSAID-5, formula 6 NSAID-7, formula 8 NSAID-9, formula 10 NSAID-11, formula 12 NSAID-13:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein

Aryl (Aryl) is selected from the group consisting of Aryl-1, Aryl-2, Aryl-3, Aryl-4, Aryl-5, Aryl-6, Aryl-7, Aryl-8, Aryl-9, Aryl-10, Aryl-11, Aryl-12, Aryl-13, Aryl-14, Aryl-15, Aryl-16, Aryl-17, Aryl-18, Aryl-19, Aryl-20, Aryl-21, Aryl-22, Aryl-23, Aryl-24, Aryl-25, Aryl-26, Aryl-27, Aryl-28, Aryl-29, Aryl-30, Aryl-31, Aryl-32, Aryl-33, Aryl-34, Aryl-35, Aryl-36, Aryl-15, Aryl-6, Aryl-9, Aryl-10, Aryl-9, Aryl-7, Aryl-6, Aryl-7, Aryl-, Aryl-37, aryl-38, aryl-39, aryl-40, aryl-41, aryl-42, aryl-43, aryl-44, aryl-45, aryl-46, aryl-47, aryl-48, aryl-49, aryl-50, aryl-51, aryl-52, aryl-53, aryl-54, aryl-55, aryl-56, aryl-57, aryl-58, aryl-59, aryl-60, aryl-61, aryl-62, aryl-63, aryl-64, aryl-65, aryl-66, aryl-67, aryl-68, aryl-69, aryl-70, and aryl-71;

W，HA，X，X₂，X₃，Y₁，Y₂，Y₃，n，m，R_c，R，R₁，R₂，R₃，R₄，R₅，R₆，R₁₁-R₁₅，L₁，L₂and L₄As defined above;

X₆and X₈Independently selected from nothing (none), C (═ O), C (═ S), OC (═ O), OC (═ S), CH₂CH, S, O and NR₅；

Y₄、Y₅、Y₆、Y₇、Y₈And Y₉Independently selected from H, OH, OW, OC (═ O) W, L₁-L₄-L₂-W、OC(＝O)CH₃、CH₃、C₂H₅、C₃H₇、C₄H₉、R₆、SO₃R₆、CH₂OR₆、CH₂OC(＝O)R₆、CH₂C(＝O)OR₈、OCH₃、OC₂H₅、OR₆、CH₃SO₂、R₆SO₂、CH₃SO₃、R₆SO₃、NO₂、CN、CF₃、OCF₃、CH₂(CH₂)_nNR₅R₆、CH₂(CH₂)_nOR₆、CH(C(＝O)NH₂)NHR₆、CH₂C(＝O)NH₂、F、Br、I、Cl、CH＝CHC(＝O)NHCH₂C(＝O)OW、CH＝CHC(＝O)NHCH₂L₁-L₄-L₂-W、NR₈C(＝O)R₅、SO₂NR₅R₈、C(＝O)R₅、SR₅、R₆OOCCH(NHR₇)(CH₂)_nC(＝O)NH-、R₆OOCCH(NHR₇)(CH₂)_nSC(＝O)NH-、CF₃SCH₂C(＝O)NH-、CF₃CH₂C(＝O)NH-、CHF₂SCH₂C(＝O)NH-、CH₂FSCH₂C(＝O)NH-、NH₂C(＝O)CHFS-CH₂C(＝O)NH-、R₇NHCH(C(＝O)OW)CH₂SCH₂C(＝O)NH-、R₇NHCH(L₁-L₄-L₂-W)CH₂SCH₂C(＝O)NH-、CNCH₂SCH₂C(＝O)NH-、CH₃(CH₂)_nC(＝O)NH-、R₇N＝CHNR₇CH₂CH₂S-、R₇N＝C(NHR₇)NHC(＝O)-、R₇N＝C(NHR₇)NHC(＝O)CH₂、CH₃C(C1)＝CHCH₂SCH₂C(＝O)NH-、(CH₃)₂C(OR₆)-、CNCH₂C(＝O)NH-、CNCH₂CH₂S-、R₇HN＝CH(NR₇)CH₂CH₂S-、CH₂＝CHCH₂SCH₂C(＝O)NH-、CH₃CH(OH)-、CH₃CH(OR₈)-、CH₃CH(Y₁)-、(CH₃)₂CH-、CH₃CH₂-、CH₃(CH₂)_nCH＝CH(CH₂)_mC (═ O) NH-, substituted and unsubstituted perfluoroalkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted alkylthio groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted perfluoroalkyl groups, substituted and unsubstituted haloalkyl groups, and substituted and unsubstituted alkylcarbonyl groups;

each R₇Independently selected from H, F, Cl, Br, I, CH₃NHC(＝O)CH₂CH(NHR₈)C(＝O)、R₅N＝C(NHR₆)NHC(＝O)-、C(＝O)CH₃、C(＝O)R₆、PO(OR₅)OR₆Substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, L₁-L₄-L₂-W, and C- (═ O) -W; and

each R₈Independently selected from H, F, Cl, Br, I, CH₃、C₂H₅、CF₃、CH₂CH₂F、CH₂CH₂Cl、CH₂CH₂Br、CH₂CH₂I、CH₂CHF₂、CH₂CF₃、CH₂F、CH₂Cl、CH₂Br、CH₂I、CH₂NR₆R₇、CH(NHR₇)CH₂C(＝O)NH₂、C₃H₇、C₄H₉、C₅H₁₁、R₆、C(＝O)R₆、C(＝O)NH₂、CH₂C(＝O)NH₂、CH₂OC(＝O)NH₂、PO(OR₅)OR₆、C(CH₃)₂C(＝O)OR₆、CH(CH₃)C(＝O)OR₆、CH₂C(＝O)OR₆、C(＝O)-W、L₁-L₄-L₂-W, W, substituted and unsubstituted perfluoroalkyl groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted perfluoroalkyl groups, substituted and unsubstituted haloalkyl groups, and substituted and unsubstituted alkylcarbonyl groups.

In the present invention, the term "pharmaceutically acceptable salts" refers to those salts of the compounds of the present invention which are safe for use in a subject. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the compounds of the invention. Pharmaceutically acceptable acid addition salts include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts (i.e., 1, 11-methylene-bis- (2-hydroxy-3-naphthoate)). Certain compounds of the invention may form pharmaceutically acceptable salts with various amino acids. Suitable basic salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. The present invention cites the review article BERGE ET AL., 66j. arm. sci.1-19(1977) as a reference for pharmaceutically acceptable salts.

In the present invention, unless otherwise specified, the term "alkyl" refers to a branched or unbranched, saturated or unsaturated, monovalent or multivalent hydrocarbon group, including saturated alkyl, alkenyl, and alkynyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, vinyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, ethynyl, propynyl, butynyl, isobutenyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecenyl, dodecynyl, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, tert-butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, and dodecylene. In certain embodiments, the hydrocarbyl group contains 1 to 30 carbon atoms. In certain embodiments, the hydrocarbyl group contains 1 to 20 carbon atoms. In certain embodiments, the hydrocarbyl group contains 1 to 12 carbon atoms.

In the present invention, unless otherwise specified, the term "cycloalkyl" refers to an alkyl group containing at least one ring and being a non-aromatic ring. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. In certain embodiments, the hydrocarbon chain contains 1 to 30 carbon atoms. In certain embodiments, the hydrocarbyl group contains 1 to 20 carbon atoms. In certain embodiments, the hydrocarbyl group contains 1 to 12 carbon atoms.

In the present invention, unless otherwise specified, the term "heterocycloalkyl" refers to a cycloalkyl group in which at least one ring atom is not a carbon atom. Non-carbon ring atoms include, but are not limited to, S, O and N.

In the present invention, unless otherwise specified, the term "alkoxy" refers to an alkyl, cycloalkyl or heterocycloalkyl group containing one or more oxygen atoms. Alkoxy groups include, but are not limited to, -CH₂-OH，-OCH₃，-O-R_e，-R_e-OH，-R_e1-O-R_e2-, wherein R_e，R_e1And R_e2May be the same or different alkyl, cycloalkyl or heterocycloalkyl.

In the present invention, unless otherwise specified, the term "haloalkyl" refers to an alkyl, cycloalkyl or heterocycloalkyl group containing one or more halogen atoms, wherein the halogen atoms may be the same or different. The term "halogen" refers to a fluorine, chlorine, bromine or iodine atom. Examples of haloalkyl groups include, but are not limited to, -R_e-F，-R_e-Cl，-R_e-Br，-R_e-I，-R_e(F)-，-R_e(Cl)-，-R_e(Br) -and-R_e(I) -, wherein R_eIs alkyl, cycloalkyl or heterocycloalkyl.

In the present invention, unless otherwise specified, the term "alkylthio" refers to an alkyl, cycloalkyl or heterocycloalkyl group containing one or more sulfur atoms. Examples of alkylthio groups include, but are not limited to, -CH₂-SH，-SCH₃，-S-R_e，-R_e-SH，-R_e1-S-R_e2-, wherein R_e，R_e1And R_e2Are the same or different alkyl, cycloalkyl or heterocycloalkyl groups.

In the present invention, unless otherwise specifiedThe term "alkylamino" refers to an alkyl, cycloalkyl or heterocycloalkyl group containing one or more nitrogen atoms. Examples of alkylamino include, but are not limited to, -CH₂-NH，-NCH₃，-N(R_e1)-R_e2，-N-R_e，-R_e-NH₂，-R_e1-N-R_e2and-R_e-N(R_e1)-R_e2Wherein R is_e，R_e1And R_e2Are the same or different alkyl, cycloalkyl or heterocycloalkyl groups.

In the present invention, the term "alkylcarbonyl" refers to an alkyl, cycloalkyl or heterocycloalkyl group containing one or more carbonyl groups, unless otherwise specified. Examples of alkylcarbonyl groups include, but are not limited to, aldehyde groups (-R)_e-C (═ O) -H), keto (-R)_e-C(＝O)-R_e1) Carboxylic acid group (R)_e-C (═ O) OH), ester group (-R)_e-C(＝O)O-R_e1) Carboxamide, (-R)_e-C(＝O)O-N(R_e1)R_e2) (iii) an alkenoyl group (-R)_e-C(＝O)-C(R_e1)＝C(R_e2)R_e3) Acyl halide (-R)_e-C(＝O)-X_h) And acid anhydride group (-R)_e-C(＝O)-O-C(＝O)-R_e1) Wherein R is_e，R_e1，R_e2And R_e3Are the same or different alkyl, cycloalkyl or heterocycloalkyl groups; and X_hIs a halogen.

In the present invention, unless otherwise specified, the term "perfluoroalkyl" refers to an alkyl, cycloalkyl or heterocycloalkyl group containing one or more fluoro groups, including, but not limited to, perfluoromethyl, perfluoroethyl, perfluoropropyl.

In the present invention, unless otherwise specified, the term "aryl" refers to a chemical structure containing one or more aromatic rings. In certain embodiments, all of the ring atoms are carbon atoms. In certain embodiments, one or more of the ring atoms is a non-carbon atom, such as an oxygen, nitrogen, or sulfur atom ("heteroaryl"). Examples of aryl groups include, but are not limited to, phenyl, benzyl, naphthyl, anthracenyl, pyridyl, quinolinyl (quinolyl), isoquinolinyl (isoquinolyl), pyrazinyl, quinoxalinyl, acridinyl, pyrimidinyl, quinazolinyl, pyridazinyl, cinnolinyl, imidazolyl, benzimidazolyl, purinyl, indolyl, furyl, benzofuranyl, isobenzofuranyl, pyrrolyl, indolyl, isoindolyl, thienyl (thiophenyl), benzothienyl (benzothiophenyl), pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, thiazolyl (thiaxolyl), guanidino (quaternino) and benzothiazolyl.

In certain embodiments, the pharmaceutical composition comprises at least one HPP of a parent drug or related compound thereof useful for the treatment of parkinson's disease, and a pharmaceutically acceptable carrier.

In certain embodiments, the pharmaceutical composition may comprise more than one HPP of the same or different parent drug. The different parent drugs may belong to the same or different classes of drugs that may be used in the treatment of parkinson's disease. For example, the pharmaceutical composition may comprise an HPP of a parent drug or 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.

The pharmaceutical composition may further comprise water.

The pharmaceutical composition may further comprise an alcohol (e.g., ethanol, glycerol, isopropanol, octanol, etc.).

In certain embodiments, the pharmaceutical composition comprises an HPP of a parent drug or related compound thereof, wherein at least one parent drug is levodopa (e.g., an HPP comprising one or more of the structures Pro-L-dopa-1, Pro-L-dopa-2, Pro-L-dopa-3, Pro-L-dopa-4, and/or Pro-L-dopa-5); dopamine (e.g., HPP comprising one or more of the structures Pro-dopamine-1, Pro-dopamine-2, Pro-dopamine-3, Pro-dopamine-4, and/or Pro-dopamine-5); and at least one parent drug is aspirin or another anti-inflammatory drug (e.g., HPP comprising one or more structures selected from the group consisting of structural formula NSAID-1, structural formula NSAID-2, structural formula NSAID-3, structural formula NSAID-4, structural formula NSAID-5, structural formula NSAID-6, structural formula NSAID-7, structural formula NSAID-8, structural formula NSAID-9, structural formula NSAID-10, structural formula NSAID-11, structural formula NSAID-12, and structural formula NSAID-13).

In certain embodiments, the pharmaceutical composition comprises: 4- (2- (2- (methylamino) acetamido) ethyl-1, 2, -phenylene ester hydrochloride (4- (2- (2- (methylamino) acetamido) ethyl) -1,2, -phenylene dibenzoate hydrochloride), 4- (2- (2- (methylamino) acetamido) ethyl-1, 2, -phenylene acetate (4- (2- (2- (methylamino) acetamido) ethyl) -1,2, -phenylene dibenzate acetate), 4- (6-methyl-4, 8-dioxo-5, 7-dioxa-2, 9-diazaden-11-yl) -1,2, -phenylene hydrobromide (4- (6-methyl-4, 8-dioxo-5, 7-dioxa-2, 9-diazadecan-11-yl) -1,2, -phenylene dibenzoate hydrate, 4- (2- (2-amino-3-phenylpropionylamino) ethyl) -1,2-phenylene ester hydrochloride (4- (2- (2-amino-3-phenylpropionamido) ethyl) -1,2, -phenylene dibenzoate hydrochloride), 4- (2- (((1- ((pyrrolidine-2-carbonyl) oxy) ethoxy) amino) ethyl) -1, 2-diphenylcarboxylic acid, 4- (2- (((1- ((pyrrolidine-2-carbonyl) oxy) ethoxy) amino) ethyl) -1,2-phenylene ester hydrochloride (4- (2- (((1- ((pyrrolidine-2-carbonyl) oxy) amino) ethoxy) ethyl) -1, 2), -phenylene dibenzoate hydrochloride, bis (2-ethylbutyric acid) 4- (2-piperidine-4-carboxamido) ethyl) -1,2, -phenylene ester hydrochloride (4- (2-piperidine-4-carboxamide) ethyl) -1,2, -phenylene bis (2-ethylbutyric acid) 4- (2- (((((((((((((-octahydro-1H-quinolizin-3-yl) oxy) carbonyl) amino) ethyl) -1,2, -phenylene acetate (4- (2- ((((((((((-octahydro-1H-quinolizin-3-yl) oxy) carbonyl) amino) ethyl) -1,2, -phenylene bis (2-ethylidoate) acetate, 1- ((-2-aminoisobutyrate) amide), isobutyrate (2-aminoisobutyrate), 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxaoctatrien-8-yl) ethyl) carbamoyl) oxy ethyl ester hydrofluoride (1- (((2- (4-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacin-8-yl) ethyl) oxymethyl) ethyl isobutryate hydrofluoride), isobutyric acid 1- (((2- (3-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxaoctatrien-8-yl) ethyl) carbamoyl) oxy) ethyl ester hydrofluoride (1- (((2- (3-amino-2, 5-dio-2, 3, 4, 5-tetrahydrobenozo [ b ] [1, 4] dioxin-8-yl) ethyl) carbamoyl) oxy) ethyl isobutyrate hydrofluoride, benzoic acid (((2- ((ethoxycarbonyl) amino) ethyl) -2- (2-methylamino) acetoxy) phenyl ester hydrochloride (5- (2- ((ethoxycarbonyl) amino) ethyl) 2- (2-methylamino) acetoxy) phenyl ester hydrochloride) -2- (2-methyalamino) acetoxy) phenyl ester hydrochloride, dibenzoate 4- (2-aminoethyl) -1, 2-aminoethylidene) -phenyl ester hydrochloride (1- (2-methylamino) acetoxy) phenyl ester hydrochloride, 2-phenylene dibenzoate hydrochloride, dibenzoic acid (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylene ester hydrochloride ((S) -4- (2-amino-3-isoproxy-3-oxopropyl) -1,2-phenylene dibenzoate hydrochloride), dibenzoic acid (S) -4- (2-amino-3- (heptane-4-yloxy) -3-oxopropyl) -1,2-phenylene ester hydrochloride ((S) -4- (2-amino-3- (heptan-4-yloxy) -3-oxopropyl) -1,2-phenylene ester hydrochloride), divalproeic acid (S) -4- (2-amino-3- (heptan-4-yloxy) -3-oxopropyl) -1,2-phenylene dibenzoate hydrochloride), divaricatic acid (S) -4- (2-amino-3-isopropoxy-3- Oxopropyl) -1,2-phenylene ester hydrochloride ((S) -4- (2-amino-3-isopropyloxy-3-oxopropyl) -1,2-phenylene dipentanoate hydrochloride), (S) -4- (2-amino-3-ethoxy-3-oxopropyl) -1,2-phenylene diacetate hydrochloride), (S) -4- (2-amino-3-ethoxy-3-oxopropyl) -1,2-phenylene ester hydrochloride ((S) -4- (2-amino-3-oxo-3- (pentan-3-yloxy) propyl) -1,2-phenylene diacetate hydrochloride), (S) -4- (2-amino-3-oxo-propyl) -1,2-phenylene ester hydrobromide- (pentan-3-yloxy) propyl) -1,2-phenylene bis (2-methylproprione) hydrobromide), dibenzoic acid (S) -4- (2-aminoacetamido) -3-isopropoxy-3-oxopropyl) -1,2-phenylene ester hydrochloride ((S) -4- (2-aminoacetamido) -3-isoproxy-3-oxopropyl) -1,2-phenylene dibenzoate hydrochloride), dibenzoic acid 4- ((2S) -3-oxo-3- (pentan-3-yloxy) -2- (pyrrolidine-2-carboxamido) propyl) -1,2-phenylene ester hydrofluoride (4- ((2S) -3-oxo-3- (pentan-3-yloxy) -2- (pyrrolidine-2-carboxamido) propyl) -1,2-phenylene ester hydrofluoride) Carboxamid) propyl) -1,2-phenylene dibenzoate hydrochloride, (S) -4- (3-isopropoxy-3-oxo-2- (piperidine-4-carboxamido) propyl) -1,2-phenylene ester hydrochloride ((S) -4- (3-isopropoxy-3-oxo-2- (piperidine-4-carboxamido) propyl) -1,2-phenylene dibenzoate hydrochloride), bis (2-methylpropionic acid) 4- ((2S) -3-isopropoxy-3-2- (octahydro-1H-quinolizine-2-carboxamido) -3-oxopropyl) -1,2-phenylene ester hydrochloride (4- ((2S) -3-isopropoxy-3-2- (octahydro-1H-quinolizine-2-carboxamido) -3-oxopropyl) -1,2-phenylene ester hydrochloride -2-carboxamido) -3-oxoprophyl) -1,2-phenylene bis (2-methylproprionate) hydrochloride), (2S) -3- (3-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxaoctatrien-8-yl) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino) propionic acid isopropyl ester hydrobromide [ (2S) -isoproprion 3- (3-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenozo [ b ] [1, 4] dioxin-8-y 1) -2- (((1- (isobutyloxy) ethoxy) carboxy) propionic acid) hydrolyzate ] hydrate ], (2S) -3- (4-amino-2, isopropyl 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxaoctatrien-8-yl) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino) propanoate hydrobromide [ (2S) -isoproyl 3- (4-amino-2, 5-dioxol-2, 3, 4, 5-tetrahydroben-zo [ b ] [1, 4] dioxin-8-y 1) -2- (((1- (isobutyloxy) ethoxy) carbonyl) amino) propanoate hydrobromide ], benzoic acid 5- ((2S) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino-3-isopropoxy-3-oxopropyl) -2- (2- (methylamino) acetoxy) phenyl ester hydrochloride (5- ((2S) -2- ((1- (isobutyloxy) ethoxy) carbonyl) amino-3-isopropoxy-3-oxopropyl) -2- (2- (methy lamino) acetoxy) phenyl benzoate hydrochloride (4- ((2S) -2- (((1- (isobutyloxy) ethoxy) carbonyl) amino-3-isopropoxy-3-oxopropyl) -2- (2- (methylamino) acetoxy) phenyl ester hydrochloride) (4- ((2S) -2- (((1- (isobutyloxy) ethoxy) carbonyl) amino) -2- (2- (methy) acetoxy) phenyl ester hydrochloride), dibenzoic acid 4- ((2S) -3-isopropoxy-2- (((octahydroxy) carbonyl) -3-isopropoxy-3-oxopropyl) -2- (2- (methy lamino) acetoxy) phenyl benzoate hydrochloride), dibenzoic acid 4- ((2S) -3-isopropoxy-2- (((octahydroindolizine-1-oxocarbonyl) amino) 3-oxopropyl) phenyl ester hydrochloride) Phenyl) -1,2-phenylene acetate (4- ((2S) -3-isopropyloxy-2- (((octylindolizin-1-yl) oxy) carbonyl) amino) -3-oxopropy-l) -1,2-phenylene dibenzoate acetate), 2- [ (2, 6-dichloro-3-methylphenyl) amino ] benzoic acid 2- (diethylamino) ethyl ester acetate (2- (diethylamino-3-methylphenoxy) amino ] benzoate, Z) -2- (5-fluoro-2-methyl-1- (4-methylsulfinyl) benzylidene) -1H-inden-1-yl) acetic acid 2- (diethylaminoethyl) ethyl ester acetate ((Z) -2- (diethylamino) ethyl2- (5-fluoro-2-methyl-1- (5-methylsulfinyl) benzylidene-1-yl) acetic acid 2- (diethylaminoethyl) ethyl ester acetate 2-methyl-1- (4-methoxylsulfinyl) benzylidene) -1H-inden-1-yl) acetate. AcOH), 2- (dimethylamino) ethyl2- (3-phenoxyphenyl) propanoate hydrochloride (hydrochloride), 2- (dimethylamino) ethanethiol 2- (3-phenoxyphenyl) propanoate hydrochloride (hydrochloride of S-2- (3-phenoxyphenyl) propanoate), 4-acetoxy-2 ', 4 ' -difluoro- [1, 1 ' -biphenyl ] -3-carboxylic acid 2- (dipropylamino) ethyl ester hydrochloride (2- (dipropylamino) ethyl 4-acetoxy-2 ', 4 ' -diol- [1, 1' -biphenol ] -3-carboxylate hydrochloride, 2- (diethylamino) ethyl2- (4-isobutylphenyl) propionate hydrochloride (2- (diethylamino) ethyl2- (4-isobutylphenyl) propionate hydrochloride), and/or 2- (diethylamino) ethyl 2-acetoxybenzoate (2- (diethylamino) ethyl 2-acetoxybenzoate).

In certain embodiments, the pharmaceutical composition further comprises one or more catechol-O-methyltransferase inhibitors. In certain embodiments, the one or more catechol-O-methyltransferase inhibitors are administered orally.

catechol-O-methyltransferase (COMT) metabolises L-dopa peripherally to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD), which 3-OMD does not readily cross the Blood Brain Barrier (BBB). Entacapone and tolcapone are both catechol-O-methyltransferase inhibitors that prevent COMT from metabolizing L-dopa to 3-methoxy-4-hydroxy-L-phenylalanine at the periphery of the nerve to avoid the adverse effects of L-dopa. BERGE ET AL., 66j. phararm. sci.1-19 (1977).

For example, a pharmaceutical composition may comprise an HPP of a parent drug or related compound, wherein the parent drug is selected from levodopa, dopamine, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), and any combination thereof, in addition to an oral catechol-O-methyltransferase inhibitor (e.g., 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 administered orally. aromatic-L-amino acid decarboxylases (DOPA decarboxylase or DDC) are important enzymes in the biosynthesis of Dopamine (DA) from L-DOPA. DDC is present both within and outside the blood-brain barrier (periphery of the body). DDC inhibitors prevent DDC from converting levodopa to dopamine. However, exogenously supplied levodopa is metabolized peripherally to its active metabolite dopamine before reaching the blood brain barrier. Thus, a PD brain that lacks dopamine cannot receive enough of its prodrug precursor, levodopa, due to the destruction of the peripheral DDC. However, carbidopa and other DDC inhibitors that are peripheral DDC inhibitors can reduce the peripheral DDC conversion of levodopa before it crosses the blood-brain barrier. In other words, carbidopa and other DDC inhibitors have no effect on the conversion of levodopa to dopamine by DDC in brain tissue. Eventually, more exogenous levodopa reaches the brain.

Examples of DDC inhibitors include, but are not limited to, carbidopa, benserazide, difluoromethyl dopa, and α -methyldopa.

In certain embodiments, the pharmaceutical composition may comprise more than one HPP of different parent drugs. The different parent drugs may belong to the same or different classes of drugs useful for the treatment of parkinson's disease. For example, a pharmaceutical composition may comprise HPP of a parent drug or related compound (wherein the parent drug is selected from levodopa, dopamine, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), and any combination thereof), plus one or more DDC inhibitors (wherein the DDC inhibitors are selected from carbidopa, benserazide, difluoromethyl dopa, alpha-methyldopa, and any other aromatic-L-amino acid decarboxylase inhibitors).

In certain embodiments, the pharmaceutical composition comprises (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylene dibenzoate and 2- (diethylamino) ethyl 2-acetoxybenzoate.

In certain embodiments, the pharmaceutical composition comprises (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylene dibenzoate, 2- (diethylamino) ethyl 2-acetoxybenzoate, carbidopa and/or entacapone.

In certain embodiments, the pharmaceutical composition comprises (S) -4- (2-amino-3-oxo-3- (pentan-3-yloxy) propyl) -1,2-phenylene bis (2-methylpropionate) and 2- (diethylamino) ethyl2- (4-isobutylphenyl) propionate.

In certain embodiments, the pharmaceutical composition comprises 4- (2- (((1- ((pyrrolidine-2-carbonyl) oxy) ethoxy) amino) ethyl) -1,2, -phenylene dibenzoate and 4- (dimethylamino) butyl 2- (3-phenoxyphenyl) propionate.

In certain embodiments, the pharmaceutical composition comprises (S) -4- (2-amino-3-oxo-3- (pentan-3-yloxy) propyl) -1,2-phenylene bis (2-methylpropionate), 2- (diethylamino) ethyl2- (4-isobutylphenyl) propionate, carbidopa and/or entacapone.

In certain embodiments, the pharmaceutical composition comprises (S) -4- (2-amino-3- (heptan-4-yloxy) -3-oxopropyl) -1,2-phenylene dibenzoate, and 2- (dipropylamino) ethyl 4-acetoxy-2 ', 4 ' -difluoro- [1, 1 ' -biphenyl ] -3-carboxylate.

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" refers to an amount that results in an increase in the treatment, cure, prevention, or amelioration of a disease, disorder (disorder), or side effect, or a decrease in the rate of progression of a disease or disorder (disorder), as compared to a subject not obtaining such an amount.

This amount will vary depending on various factors including, but not limited to, the nature of the HPP or pharmaceutical composition disclosed herein (including activity, pharmacokinetics, pharmacodynamics, and bioavailability, etc.), the physiological condition of the subject (including age, sex, type and stage of disease, physical condition, sensitivity to the dose used, and type of drug) or the cell, the nature of the pharmaceutically acceptable carrier in the formulation, the route of administration. Furthermore, the effective or therapeutically effective amount depends on whether one or more HPPs or pharmaceutical compositions disclosed in the present invention are administered alone or in combination with other drugs, other treatments or other therapies or physical therapies. One skilled in the clinical and medical arts can determine an effective or therapeutically effective amount by routine experimentation, i.e., adjusting the dosage by monitoring the response of the cell or subject to administration of one or more HPPs disclosed herein or pharmaceutical compositions thereof. A typical dosage range may be from about 0.1mg/kg to about 100mg/kg or more, depending on the factors mentioned above. In certain embodiments, the dosage range may be from about 0.1mg/kg to about 100 mg/kg; or from about 1mg/kg to about 100 mg/kg; or from about 5mg/kg to about 100 mg/kg. For more guidance see Remington: the Science and Practice of Pharmacy, 21st Edition, Univ. of Sciences In Philadelphia (USIP), Lippincott Williams & Wilkins, Philadelphia, PA, 2005, which is incorporated herein by reference in its entirety to provide further guidance in determining a therapeutically effective amount.

In the present invention, the term "about" refers to ± 10%, ± 5%, or ± 1% of its numerical value.

In the present invention, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable raw material, composition or medium, such as a filler, diluent, excipient, solvent or encapsulating material, in liquid or solid form, involved in transporting or transporting HPP from 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 part of the body.

Each "pharmaceutically acceptable" carrier should be compatible with the other ingredients of the pharmaceutical formulation (e.g., HPP) and be suitable for contact with the tissues and organs of a biological subject without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, i.e., with a suitable benefit-risk ratio.

In certain embodiments, the pharmaceutically acceptable carrier is selected from the group consisting of alcohols, ketones, esters, cellulose, mannitol, croscarmellose sodium, vegetable oils, hydroxypropyl methylcellulose, water, and aqueous solutions.

Examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn flour and potato flour; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) sterilizing water; (17) isotonic saline solution; (18) ringer's solution; (19) alcohols such as ethanol and propanol; (20) phosphoric acid buffer solution; and (21) other compatible substances used in pharmaceutical preparations that are not toxic, such as acetone.

The pharmaceutical compositions may contain pharmaceutically acceptable auxiliary substances to approximate the physiological conditions of the pharmaceutical composition, such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.

In one embodiment, the pharmaceutically acceptable carrier is an aqueous carrier, such as a buffered saline solution and the like. In certain embodiments, the pharmaceutically acceptable carrier is a polar solvent, such as acetone or alcohols.

The concentration of the high penetration prodrug in these formulations can vary widely, depending on the volume of fluid, viscosity, body weight, etc., and the mode of administration and the desired amount of the biological subject. For example, the concentration (by weight) may be from about 0.0001% to about 100%, from about 0.001% to about 50%, from about 0.01% to about 30%, from about 0.1% to about 20%, and from about 1% to about 10%.

The compositions of the present invention may be used for prophylactic, therapeutic and/or hygienic purposes. The mode of administration may be topical, mucosal (e.g., oral, nasal, vaginal, rectal), parenteral, transdermal, subcutaneous, intramuscular, intravenous, inhalational, ocular, and other convenient routes of administration. The pharmaceutical compositions may take a wide variety of unit dosage forms depending on the mode of administration. For example, unit dosage forms suitable for oral administration include powders, tablets, pills, capsules and lozenges and unit dosage forms suitable for transdermal administration include solutions, suspensions and gels.

Thus, a typical pharmaceutical composition for transdermal, oral, or intravenous administration is used in an amount of about 10 daily per biological subject^-8g to about 100 g; about 10^-8g to about 10^-5g, about 10^-6g to about 1g, about 10^-6g to about 100g, about 0.001g to about 100g, about 0.01g to about 10g, or about 0.1g to about 1 g. The dosage that can be used per biological subject is from about 0.001mg up to about 100g per day. The actual method of formulating compositions for parenteral administration is consistent with or close to that known in the art and is described in several publications such as Remington: the Science and Practice of Pharmacy 21st ed., Lippincott Williams&Wilkins, (2005) is described in more detail.

Use of high penetration prodrugs

i) Method of crossing biological barriers

Another aspect of the invention pertains to methods of crossing one or more biological barriers of a biological subject using the compositions of the invention. The methods comprise administering a high penetration prodrug or a pharmaceutical composition thereof to a biological subject. In certain embodiments, the high penetration prodrug crosses one or more biological barriers at a rate of about 20-fold or more, about 50-fold or more, greater than about 100-fold or more, greater than about 200-fold or more, greater than about 300-fold or more, greater than about 500-fold or more, greater than about 1,000-fold or more, greater than the parent drug.

In the present invention, the term "biological barrier" refers to a biological layer that divides a biological environment into distinct spatial spaces or compartments that can regulate (e.g., prevent, limit, enhance or not affect) the passage, permeation, or transport of a chemical substance or substance from one space or location to another. Different spaces or compartments in the present invention may have the same or different chemical or biological environments. Biological layers in the present invention include, but are not limited to, a biofilm, a cellular layer, a biological structure, an inner surface of a biological object, organism, organ, or body cavity, an outer surface of a biological object, organism, organ, or body cavity, or any combination or complex thereof.

Examples of biological membranes include lipid bilayer structures, eukaryotic cell membranes, prokaryotic cell membranes, and intracellular membranes (e.g., nuclear or organelle membranes such as golgi membrane, rough and smooth Endoplasmic Reticulum (ER) membranes, ribosomal envelope, vacuolar membrane, vesicular membrane, liposomal membrane, mitochondrial membrane, lysosomal membrane, nuclear envelope, chloroplast membrane, phytochromosomal membrane, peroxisome membrane, and membranes of microsomes).

Lipid bilayers refer to bilayers of lipid-like molecules, including but not limited to: phospholipids and cholesterol. In certain particular embodiments, the liposome of the lipid bilayer is an amphiphilic molecule comprising a polar head group and a non-polar fatty acid tail group. Lipid bilayers are aqueous solutions with two layers of liposomes arranged with their fatty acid tails facing each other through hydrophobic interactions to form an oily core, and their charged head groups facing both sides of the biofilm. In some particular embodiments, the lipid bilayer may contain one or more embedded protein and/or carbohydrate molecules.

Cell layers include eukaryotic cell layers (such as epithelial cells, lamina propria, and smooth or mucosal muscularis (in the gastrointestinal tract)), prokaryotic cell layers (such as the surface layer or S-layer, the S-layer being a two-dimensional monolayer composed of identical proteins or glycoproteins, specifically the S-layer being part of the cell envelope found in bacteria and archaea), biofilms (biofilms are structural aggregates of microorganisms embedded in spontaneously formed polymeric matrices and attached to an active or inert surface), and plant cell layers (such as the epidermis). The cells can be normal cells or pathological cells (e.g., diseased cells, cancer cells).

Examples of biological structures include tightly or interlockingly linked closed barrier structures such as the blood-milk barrier and the blood-brain barrier (BBB) that prevent the entry of toxins, bacteria and viruses. In particular, the blood-brain barrier consists of an impenetrable endothelial cell layer, which is not only a physical barrier formed by the tight association of adjacent endothelial cells, but also a transport barrier containing influx and efflux transporters. The biological structure may also comprise a mixture of cells, proteins and sugars (e.g. thrombi).

Examples of the inner surface of a biological object, organism, organ or body cavity are buccal mucosa, esophageal mucosa, gastric mucosa, intestinal mucosa, olfactory mucosa, oral mucosa, bronchial mucosa, uterine mucosa and endometrium (mucosa of uterus, inner wall layer of pollen cell wall endometrium or spore), or a combination or complex thereof.

Examples of external surfaces of biological objects, organisms, organs or body cavities include capillaries (e.g., capillaries in heart tissue), mucous membranes associated with the skin (e.g., mucous membranes of the nostrils, lips, ears, reproductive organ regions, and anus), external surfaces of organs (e.g., liver, lungs, stomach, brain, kidneys, heart, ears, eyes, nose, mouth, tongue, colon, pancreas, gall bladder, duodenum, rectostomach, colorectal, intestinal, venous, respiratory, blood vessels, anorectum, and anus), skin, epidermis (e.g., dead layers of epidermal cells or stratum corneum of overlapping cells of keratinocytes or animal hair, multi-layered heat resistant structures of many invertebrate external epidermis, waxy and/or glue films of plant epidermis or polymers), pollen of the outer layers of plant walls or spores), and combinations or complexes thereof.

In addition, the biological barrier further comprises a carbohydrate layer, a protein layer or any other biological layer, or a combination or complex thereof. For example, skin is a complex of biological layers. The skin includes an epidermal layer (outer surface), a dermal layer and a subcutaneous layer. The epidermal layer contains several layers including a basal cell layer, an echinocyte layer, a granulocytic layer, and a stratum corneum layer. The cells in the epidermal layer are called keratin cells. The stratum corneum (stratum corneum) is the outermost layer of the epidermis, where the cell shape is flat and scaly (scaly). These cells on the skin surface contain many keratins and are arranged in an overlapping manner to have a strong and oil and water repellent character.

ii) methods of treating Parkinson's disease in a biological subject

Another aspect of the invention pertains to methods of treating a condition in a biological subject using the compositions of the invention, or pharmaceutical compositions thereof. The method comprises administering the pharmaceutical composition to a biological subject.

In the present invention, the term "treating" means curing, alleviating, inhibiting, or preventing. The term "treat" refers to cure, alleviate, inhibit, or prevent. The term "treatment" refers to curing, alleviating, inhibiting, or preventing.

In the present invention, the term "biological subject" or "experimental subject" refers to an organ, a group of organs, an organism, or a group of organisms that together perform a specific task. In the present invention, the term "organism" refers to a collection of molecules, such as animals, plants, fungi, or microorganisms, as a stable or less stable whole and having vital characteristics.

In the present invention, the term "animal" refers to a eukaryote that can move freely. Animals include, but are not limited to, vertebrata (e.g., humans, mammals, birds, reptiles, amphibians, fish, maripobranchiata and leptocardia), tunicates (e.g., haichow, urotheca, sorberacea and ascidioidea), arthropods (e.g., insects, polypoda, malacapoda, arachnida, acropoda, crustaceans and cyclosporins), gehyrea (anthropoda), and worms (e.g., rotifers).

The disease states treatable by the present methods include those treatable by the parent drug of the high penetration prodrug, Parkinson's disease and related conditions.

Methods of treating Parkinson's disease or disorders associated therewith in a biological subject with one or more HPPs or pharmaceutical compositions thereof

Another aspect of the invention pertains to methods of treating Parkinson's disease and related disorders in a biological subject or a subject using one or more HPPs or pharmaceutical compositions thereof. The method comprises administering one or more HPPs or a pharmaceutical composition thereof to a biological subject or a test subject.

In certain embodiments, the methods of treating parkinson's disease and its associated diseases in a subject comprise administering to the subject a therapeutically effective amount of a high penetration prodrug, or a pharmaceutical composition thereof.

The high penetration prodrug or pharmaceutical composition thereof may be administered to a biological subject by any route of administration known, including, but not limited to, oral, enteral, oral, nasal, topical, rectal, vaginal, spray, mucosal, epidermal, transdermal, dermal, ocular, pulmonary, subcutaneous, and/or injectable. The pharmaceutical compositions can be administered in a variety of unit dosage forms depending on the mode of administration.

The preferred methods of administration of the compounds are transdermal (transdermal), dermal (dermal), topical (topical administration).

In certain embodiments, the methods further comprise orally administering a therapeutically effective amount of one or more of the foregoing COMT inhibitors and/or one or more DDC inhibitors.

When multiple drugs (e.g., HPP, COMT inhibitor, and DDC inhibitor) are administered to a subject, several HPPs and/or other drugs may be administered at substantially the same time or at different times. The multiple agents may be mixed together prior to administration to a subject, or administered separately. In certain embodiments, some of the plurality of agents may be mixed prior to administration, while others are administered separately. Each drug may be administered in any possible order, and by any possible method.

In the present invention, the pharmaceutical composition may comprise a plurality of components for administration to a subject by different routes of administration. For example, a pharmaceutical composition as described above comprising one or more HPPs as described above and one or more COMT inhibitors and/or one or more DCC inhibitors, the one or more HPPs may be administered transdermally, topically, or transdermally, while the one or more COMT inhibitors and/or one or more DCC inhibitors as described above are administered orally. The components may be administered in any order or in any possible combination.

The high penetration prodrug or pharmaceutical composition thereof may be administered to a subject in the form of a formulation or recipe suitable for each route of administration. Formulations useful in the methods of the invention comprise one or more high penetration prodrugs, one or more pharmaceutically acceptable carriers, and other optional therapeutic ingredients. The formulations may conveniently be presented in unit dosage form and may be formulated according to any method of pharmacy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the subject and the particular mode of administration. Generally, the amount of high penetration prodrug that can be combined with a carrier material to produce a therapeutically effective amount is the amount of HPP that produces a therapeutic effect. Generally, the content varies from about 0.01% to about 99% HPP, preferably from about 0.1% to about 20%, by percentage.

Methods of formulating these formulations or compositions include the step of admixing the high penetration prodrug and one or more pharmaceutically acceptable carriers, optionally one or more accessory ingredients. In general, the high penetration prodrugs and liquid carriers, or finely divided solid carriers, or both, are combined to form a homogeneous, compact preparation which can be shaped, if desired.

Dosage forms suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or aqueous or nonaqueous solutions or suspensions, or an oil-in-water or water-in-oil liquid emulsion, or an elixir or syrup, or as lozenges (using an inert base such as gelatin and glycerin, or sucrose and acacia) and/or mouthwashes and the like, each containing a predetermined amount of the high penetration prodrug as the active ingredient. The compounds may also be administered as a bolus, ointment, or paste.

In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules and the like), the high penetration prodrug is admixed with one or more pharmaceutically acceptable carriers, such as sodium citrate and dicalcium phosphate, and/or any one or more of the following: (1) fillers or admixtures, for example starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; (3) humectants, such as glycerol; (4) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents, for example, acetol and glyceryl monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) a coloring agent. In the case of capsules, tablets and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using excipients (lactose or milk sugar and the like, high molecular weight polyethylene glycols and the like).

Tablets may be made by extrusion or molding with optionally one or more additional ingredients. Compressed tablets may be prepared using binders (for example, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrating agents (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active agents or dispersing agents. Molded tablets the high penetration prodrug powder or peptidomimetic moistened with an inert liquid diluent can be formed in a suitable machine. Tablets and other solid preparations, such as dragees, capsules, pills and granules, can optionally be scored or prepared with coatings and shells (e.g., enteric coatings or other coatings well known in the pharmaceutical formulation arts). For slow release or controlled release applications of the high penetration prodrugs, the agents may be prepared with, for example, hydroxypropylmethylcellulose, other polymer matrices, liposomes and/or microspheres in various proportions to achieve the desired release rate. Sterile solid compositions can also be prepared by filtration through, for example, a bacterial filter or sterilization by the addition of a sterilizing agent, and can be dissolved in sterilized water, or other sterile injectable medium prior to use. These compositions may also optionally contain a soothing agent and may optionally contain a composition that slowly and/or slowly releases the high penetration prodrug at a specific site in the gastrointestinal tract. Examples of embedding compositions include polymers and waxes. The high penetration prodrug can also be microencapsulated with one or more of the above excipients.

Liquid preparations for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the high penetration prodrugs, the liquid formulations may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents, emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, butylene glycol, oils (especially, cottonseed, peanut, corn, germ, olive oil, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the high penetration prodrugs, may contain suspending agents as, for example, oxiranylated isostearyl poly, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as a suppository by mixing one or more of the high penetration prodrugs with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature but liquid at body temperature and, therefore, will dissolve in the colon or vagina and release the active agent. Dosage forms suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

Dosage forms for topical or transdermal or epidermal or dermal administration of the high penetration prodrug compositions include powders, sprays, ointments, pastes, creams, paints, gels, solutions, patches and inhalants. The active ingredient may be mixed with a pharmaceutically acceptable carrier, and optionally a preservative, buffer, or propellant, under sterile conditions. Ointments, pastes, creams, and gels may contain, in addition to the high penetration prodrug composition, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyvinylidene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof. Powders or sprays can contain, in addition to the high penetration composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, for example chlorofluorohydrocarbons, and volatile, for example unsubstituted hydrocarbons, such as butane and pentane. The best dosage forms for topical and transdermal administration are pure water, aqueous solutions of solutions, ethanol, solutions of ethanol and water, and solutions of isopropanol and water.

The high penetration prodrug or pharmaceutical composition may optionally be administered by spraying. Sprays can be formulated as aqueous sprays, liposomal formulations or solid particles containing the high penetration prodrugs. Suspensions other than water (e.g., fluorocarbon propellants) may also be used. A sony nebulizer may also be used. Aqueous sprays are prepared by formulating an aqueous solution or suspension of the agent with conventional pharmaceutically acceptable carriers or stabilizers. The carrier and stabilizer vary with the needs of the particular compound, but typically include non-ionic surfactants (tweens, pluronics or polyethylene glycols), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

Transdermal patches may also be used to deliver the high penetration prodrug composition to the target site. These formulations may be prepared by dissolving or dispersing the agent in a suitable medium. Skin absorption enhancers may also be used in order to increase the flux of the peptidomimetic across the skin. The rate of flux can be controlled by adding a rate controlling membrane or dispersing a peptidomimetic into a polymeric medium or gel.

Formulations for ocular administration, ophthalmic ointments, powders, solutions, and the like are also within the scope of the invention.

Dosage forms suitable for parenteral administration include a high penetration prodrug and one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which can be reconstituted into sterile injectable solutions or dispersions prior to use, which can contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may be employed in formulations for parenteral administration include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be achieved, for example, by the use of a membrane material (e.g., a soft phospholipid), by the maintenance of the required particle size in a dispersion, and by the use of surfactants.

Formulations suitable for parenteral administration may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. The growth of microorganisms is inhibited by the addition of various antibiotic and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, such as sugars, sodium chloride, and the like may also be added to the composition. In addition, agents that delay absorption, such as aluminum monostearate and gelatin, can be added to prolong the absorption of the injectable pharmaceutical preparation.

The high penetration prodrug is made into microcapsule matrix or coated in biodegradable polymer such as polylactic-polyglycolide to make injectable precipitation type. The rate of release of the drug can be controlled depending on the ratio of high penetration prodrug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot forms can also be prepared by entrapping the high penetration prodrug in liposomes or microemulsions which are compatible with body tissues.

In certain embodiments, the high penetration prodrug or pharmaceutical composition is delivered to the site of action at a therapeutically effective dose. As is well known in pharmacology, the precise amount of the optimal effective dose of the high penetration prodrug to achieve the optimal therapeutic effect will depend, for example, on the activity, specific properties, pharmacokinetics, pharmacodynamics, and bioavailability of the high penetration prodrug, the physiological condition of the recipient (e.g., race, age, sex, body weight, diet, disease type and stage, general physical condition, responsiveness to the dose and type of drug administered), the nature of the pharmaceutically acceptable carrier in the formulation, the route and frequency of administration used, and the severity and susceptibility of the condition being treated. However, the guidelines set forth above may be used as a basis for fine-tuning treatment, e.g., determining the optimal dosage to be administered, and will only require routine experimentation involving testing the subject and adjusting the dosage. See, leimington: the Science and Practice of Pharmacy (Gennaro ed.20.sup.th edition, Williams & Wilkins PA, USA) (2000).

Advantages of

Levodopa can cause nausea, vomiting, gastrointestinal bleeding, motor aberrations at peak doses, and diminished efficacy at peak and trough doses. The above problems are solved by transdermal administration of a high penetration composition of L-dopa and dopamine which can be administered continuously at a therapeutically minimum effective dose to avoid nausea, vomiting, gastrointestinal bleeding, motor disturbances at peak doses, and a diminished therapeutic effect at trough and peak doses.

Recently, there has been increasing research in humans and animals with evidence that neuroinflammation plays a major role in neuronal loss in Parkinson's disease. In addition, the pro-inflammatory agent lipopolysaccharide itself or in combination with other environmental factors causes the degeneration of dopamine-containing neurons, such as the insecticide rotenone, exacerbating such neurodegenerative diseases. These effects provide strong evidence that inflammation is involved in the pathogenesis of parkinson's disease. Although dopamine substitutes may alleviate symptoms of the disorder, no effective therapy is available to prevent the progressive degeneration of dopamine-containing neurons. Transdermal administration of high penetration compositions of L-dopa and/or dopamine with aspirin and/or other non-steroidal anti-inflammatory drugs (NSAIDs) can not only ameliorate the symptoms of parkinson's disease, but can also stop the potential progressive degeneration of dopamine-related neurons.

When a high penetration composition of L-dopa and/or dopamine, and aspirin and/or other non-steroidal anti-inflammatory drugs (NSAIDs) is administered transdermally, simultaneous oral administration of carbidopa, benserazide, difluoromethyl-dopa, alfa-methyldopa, and/or other DDC inhibitors and/or entacapone, and tolcapone, and/or COMT inhibitors thereof can help a greater portion of exogenous levodopa or dopamine to reach the brain to reduce the side effects of L-dopa or dopamine.

V. examples

The following examples are to better illustrate the present invention and are not to be construed as limiting the scope of the present invention. All of the specific compositions, materials and methods described below, in whole or in part, are within the scope of the invention. These specific compositions, materials and methods are not intended to limit the scope of the invention in any way but are merely illustrative of specific embodiments within the scope of the invention. Those skilled in the art can develop equivalent compositions, materials and methods without exercise of inventive faculty and without departing from the scope of the invention. It will be apparent that many variations are possible in light of the procedure described herein without departing from the scope of the invention. It is the intention of the inventors to include such variations within the scope of the invention. Moreover, all references are incorporated herein in their entirety as if fully set forth herein.

EXAMPLE 1 preparation of 4- (2- (2- (methylamino) acetamido) ethyl) -1, 2-phenylene-ester hydrochloride Diphenyl formate

Diphenyl formate 4- (2- (2- (methylamino) acetamido) ethyl) -1,2-phenylene ester hydrochloride

In this example, dopamine hydrochloride (19g) was added to acetone (200ml) to give a dopamine hydrochloride solution. Water (200ml) and sodium bicarbonate (R0090, 50g) were added to the dopamine hydrochloride solution to give mixture 1. Boc-N-methylaminoacetic acid N-hydroxysuccinimide ester (Boc-Sar-OSu, 29g) was added to mixture 1 to give mixture 2. Mixture 2 was stirred at room temperature overnight and then extracted by the addition of ethyl acetate (R0061, 500 ml). The organic layer was separated and washed with water (2X100ml), 20% citric acid (2X200ml), and water (3X100ml), respectively, and dried over sodium sulfate to give solution 3. The sodium sulfate was then filtered off and washed with ethyl acetate to give mixture 4. Solution 3 and mixture 4 were mixed, followed by the addition of pyridine (R0081, 30ml) and then benzoyl chloride (R0488, 30g) dropwise to give mixture 5. Mixture 5 was stirred at room temperature for 2 hours, then washed with water (2X100m1), 5% sodium bicarbonate (2X100ml), water (100m1), 20% citric acid (2X200ml), and water (3X100ml), respectively, and dried over sodium sulfate to give solution 6. The sodium sulfate was filtered and washed with ethyl acetate to give solution 7. Solution 6 and solution 7 were mixed and concentrated to about 200ml (solution 8). Anisole (20g) was added to the solution 8, followed by hydrogen chloride gas (20g) to obtain a precipitate. The precipitated solid was collected and washed with ethyl acetate to give 4- (2- (2- (methylamino) acetylamino) ethyl) -1,2-phenylene dibenzoate hydrochloride.

EXAMPLE 2 preparation of 4- (2- (2- (methylamino) acetamido) ethyl) -1,2-phenylene dibenzoate acetate

In this example, 4- (2- (2- (methylamino) acetamido) ethyl) -1,2-phenylene dibenzoate hydrochloride (23g) was dissolved in isopropanol (300ml) to give mixture 1. Sodium acetate (4g) was added to mixture 1 to give mixture 2. Mixture 2 was stirred at room temperature for 2 hours and then filtered to remove the solids. The filtered solution was evaporated to dryness to obtain 4- (2- (2- (methylamino) acetamido) ethyl) -1,2-phenylene dibenzoate acetate.

Example 3 preparation of 4- (6-methyl-48-dioxo-5, 7-dioxa-2, 9-diazacyclodecan-11-yl) -1,2-phenylene dibenzoate hydrobromide

Dibenzoic acid 4- (6-methyl-4, 8-dioxo-5, 7-dioxa-2, 9-diazhendecan-11-yl) -1,2-phenylene ester hydrobromide

In this example, dopamine hydrochloride (19g) was added to acetone (200ml) to give a dopamine hydrochloride solution. Water (200ml) and sodium bicarbonate (R0090, 50g) were added to dopamine hydrochloride solution to give mixture 1. Di-tert-butyl dicarbonate (22g) was then added to mixture 1 to give mixture 2. The mixture 2 was stirred at room temperature overnight, followed by extraction with ethyl acetate (R0061, 500 ml). The organic layer was separated and washed with water (2x100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, then dried over sodium sulfate to give solution 3. The sodium sulfate was then filtered and washed with ethyl acetate to give mixture 4. Solution 3 and mixture 4 were mixed, followed by the addition of pyridine (R0081, 30ml) and then benzoyl chloride (R0488, 30g) dropwise to give mixture 5. Mixture 5 was stirred at room temperature for 2 hours then washed with water (2x100ml), 5% sodium bicarbonate (2x100ml), water (100ml), 20% citric acid (2x200ml) and water (3x100ml), respectively, and dried over sodium sulfate to give solution 6. The sodium sulfate was filtered and washed with ethyl acetate to give solution 7. Solution 6 and solution 7 were mixed and concentrated to about 200ml (solution 8). Anisole (20g) was added to the solution 8, followed by the introduction of hydrogen chloride gas (20g) to obtain a precipitate. The filtered solid was collected and washed with ethyl acetate, followed by suspending the solid in DCM (200ml) to give mixture 9. Sodium hydrogencarbonate (20g) and tetrabutylammonium hydrogensulfate (11g) were added to the mixture 9 to obtain a mixture 10. 1-chloroethyl chloroformate (16g) was then added to mixture 10 to give mixture 11. Mixture 11 was stirred at room temperature overnight. The organic layer of mixture 11 was then collected and washed with water (3x200ml) and dried over anhydrous sodium sulfate to give solution 12. The sodium sulfate was removed by filtration and washed with DCM to give solution 13. Solution 12 and solution 13 were combined and then evaporated to dryness. The residue was dissolved in acetonitrile (200ml) to obtain a mixture 14. Boc-sarcosine (36g) was added to mixture 14 to give mixture 15. A mixture of diisopropylethylamine (34ml) and Boc-sarcosine (36g) was first prepared, which was then added to mixture 15 to give mixture 16. The mixture 16 was stirred at 55 ℃ for 48 hours, then ethyl acetate (500m1) was added with stirring. The obtained organic layer was collected and washed with 5% sodium bicarbonate (3x100ml) and water (3x100ml), respectively, and then dried over anhydrous sodium sulfate to give solution 17. The sodium sulfate was filtered and washed with ethyl acetate to give solution 18. Combine solution 17 and solution 18 and concentrate to 300 ml. Anisole (20g) was added to the concentrated solution, followed by the introduction of hydrogen bromide gas (30g) to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give 4- (6-methyl-4, 8-dioxo-5, 7-dioxa-2, 9-diazaden-11-yl) -1,2-phenylene dibenzoate hydrobromide.

EXAMPLE 4 preparation of 4- (2- (2-amino-3-phenylpropionylamino) ethyl) -1,2-phenylene dibenzoate hydrochloride

Dibenzoic acid 4- (2- (2-amino-3-phenylpropionylamino) ethyl) -1,2-phenylene ester hydrochloride

In this example, dopamine hydrochloride (19g) was added to acetone (200ml) to give a dopamine hydrochloride solution. Water (200ml) and sodium bicarbonate (R0090, 50g) were added to dopamine hydrochloride solution to give mixture 1. Boc-phenylalanine N-hydroxysuccinimide ester (Boc-Phe-OSu, 36g) was added to mixture 1 to give mixture 2. The mixture 2 was stirred at room temperature overnight, followed by extraction with ethyl acetate (R0061, 500 ml). The organic layer was separated and washed with water (2x100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and dried over sodium sulfate to give solution 3. The sodium sulfate was then filtered and washed with ethyl acetate to give mixture 4. Solution 3 and mixture 4 were combined, followed by the addition of pyridine (R0081, 30ml) and then the dropwise addition of benzoyl chloride (R0488, 30g) to afford mixture 5. The mixture 5 was stirred at room temperature for 2 hours, then washed with water (2x100ml), 5% sodium bicarbonate (2x100ml), water (100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and the sodium sulfate was dried to give solution 6. After filtration of the sodium sulfate and washing with ethyl acetate, a solution 7 was obtained. The solution 6 and the solution 7 were combined and concentrated to about 200ml (to give a solution 8). Anisole (20g) was added to solution 8, followed by the introduction of hydrogen chloride gas (20g) to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give 4- (2- (2-amino-3-phenylpropionylamino) ethyl) -1,2-phenylene dibenzoate hydrochloride.

EXAMPLE 5 preparation of 4- (2- (((1- ((pyrrolidine-2-carbonyl) oxy) ethoxy) amino) ethyl) -1,2-phenylene dibenzoate hydrochloride

Diphenyl formate 4- (2- (((1- ((pyrrolidine-2-carbonyl) oxy) ethoxy) carbonyl) amino) ethyl) -1,2-phenylene ester hydrochloride

In this example, dopamine hydrochloride (19g) was added to acetone (200ml) to give a dopamine hydrochloride solution. Water (200ml) and sodium bicarbonate (R0090, 50g) were added to dopamine hydrochloride solution to give mixture 1. Di-tert-butyl dicarbonate (22g) is then added to mixture 1 to give mixture 2. The mixture 2 was stirred at room temperature overnight, and extracted with ethyl acetate (R0061, 500 ml). The organic layer was separated and washed with water (2x100ml), 20% citric acid (2x100ml), and water (3x100ml), respectively, and dried over sodium sulfate to give solution 3. The sodium sulfate was then filtered and washed with ethyl acetate to give mixture 4. After combining solution 3 and mixture 4, pyridine (R0081, 30ml) was added first, followed by the dropwise addition of benzoyl chloride (R0488, 30g) to give mixture 5. The mixture 5 was stirred at room temperature for 2 hours, then washed with water (2x100ml), 5% sodium bicarbonate (2x100ml), water (100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and dried over sodium sulfate to give solution 6. The sodium sulfate was filtered and washed with ethyl acetate to give solution 7. Solution 6 and solution 7 were combined and concentrated to about 200ml (solution 8). Anisole (20g) was added to the solution 8, followed by the introduction of hydrogen chloride gas (20g) to obtain a precipitate. The precipitated solid was collected and washed with ethyl acetate, followed by suspending the precipitated solid in DCM (200ml) to give a mixture 9. Sodium hydrogencarbonate (20g) and tetrabutylammonium hydrogensulfate (11g) were added to the mixture 9 to obtain a mixture 10. 1-chloroethyl chloroformate (16g) was then added to mixture 10 to give mixture 11. The mixture 11 was stirred at room temperature overnight. The organic layer of mixture 11 was then collected and washed with water (3x200ml) and dried over anhydrous sodium sulfate to give solution 12. After removal of the sodium sulfate by filtration and washing with DCM, solution 13 was obtained. The solution 12 and the solution 13 were combined and evaporated to dryness. The residue was dissolved in acetonitrile (200ml) to obtain a mixture 14. Boc-sarcosine (36g) was added to mixture 14 to give mixture 15. A mixture of diisopropylethylamine (34ml) and Boc-sarcosine (36g) was first prepared, which was then added to mixture 15 to give mixture 16. The mixture 16 was stirred at 55 ℃ for 48 hours, followed by the addition of ethyl acetate (500ml) with stirring. The organic layers obtained were collected and washed with 5% sodium bicarbonate (3x100ml) and water (3x100ml), respectively, to give solution 17 after drying over anhydrous sodium sulfate. The sodium sulfate was filtered and washed with ethyl acetate to give solution 18. Solution 17 and solution 18 were combined and concentrated to 300 ml. Anisole (20g) was added to the concentrated solution, followed by introduction of hydrogen chloride gas (30g) to obtain a precipitate. The precipitated solid was collected and washed with ethyl acetate to give 4- (2- (((1- ((pyrrolidine-2-carbonyl) oxy) ethoxy) amino) ethyl) -1,2-phenylene dibenzoate hydrochloride.

EXAMPLE 6 preparation of bis (2-ethylbutanoic acid) 4- (2-piperidine-4-carboxamido) ethyl) -1,2-phenylene ester hydrochloride

Bis (2-ethylbutanoic acid) 4- (2-piperidine-4-carboxamido) ethyl) -1,2-phenylene ester hydrochloride

In this example, dopamine hydrochloride (19g) was added to acetone (200ml) to give a dopamine hydrochloride solution. Water (200ml) and sodium bicarbonate (R0090, 50g) were added to dopamine hydrochloride solution to give mixture 1. Boc-piperidine-4-carboxylic acid N-hydroxysuccinimide ester (Boc-Inp-OSu, 33g) was added to mixture 1 to give mixture 2. The mixture 2 was stirred at room temperature overnight, followed by extraction with ethyl acetate (R0061, 500 ml). The organic layer was separated and washed with water (2x100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, then dried over sodium sulfate to give solution 3. The sodium sulfate was then filtered and washed with ethyl acetate to give mixture 4. Solution 3 and mixture 4 were combined, pyridine (R0081, 30ml) was added, and 2-ethylbutyryl chloride (28g) was added dropwise to give mixture 5. Mixture 5 was stirred at room temperature for 2 hours, then washed with water (2x100ml), 5% sodium bicarbonate (2x100ml), water (100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and dried over sodium sulfate to give solution 6. The sodium sulfate was filtered and washed with ethyl acetate to give solution 7. Solution 6 and solution 7 were combined and concentrated to about 200ml (solution 8). Anisole (20g) was added to solution 8, followed by the introduction of hydrogen chloride gas (20g) to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give bis (2-ethylbutyric acid) 4- (2-piperidine-4-carboxamido) ethyl) -1,2-phenylene ester hydrochloride.

EXAMPLE 7 preparation of bis (2-ethylbutanoic acid) 4- (2- (((((((-octahydro-1H-quinolizin 3-yl) oxy) carbonyl) amino) ethyl) -1,2-phenylene acetate

Bis (2-ethylbutanoic acid) 4- (2- (((((((-octahydro-IH-quinolizin-3-yl) oxy) carbonyl) amino) ethyl) -1,2-phenylene acetate

The solid was suspended in ethyl acetate (200ml) to give a mixture 9. Triethylamine (25ml) was first added to the mixture 9, and octahydro-1H-quinolizin-3-ylcarbonyl chloride hydrochloride (octahydro-1H-quinolizin-3-yl carbochlororide) (22g) dissolved in ethyl acetate (50ml) was added dropwise to the mixture 9 to give a mixture 10. The mixture 10 was stirred at room temperature for 2 hours, then washed with 5% sodium bicarbonate and water to give a mixture 11. Acetic acid (6g) was added to mixture 11, followed by hexane (200ml), to form a precipitate. The precipitated solid was collected by filtration and washed with ethyl acetate/hexane to give bis (2-ethylbutanoic acid) 4- (2- (((((((-octahydro-1H-quinolizin-3-yl) oxy) carbonyl) amino) ethyl) -1,2, -phenylene acetate.

EXAMPLE 8 preparation of 1- (((2- (4-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) ethyl) carbamoyl) oxy) ethyl ester hydrofluoride isobutyrate, and 1- (((2- (3-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) ethyl) carbamoyl) oxy) ethyl ester hydrofluoride isobutyrate

Isobutyric acid 1- (((2- (4-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) ethyl) carbamoyl) oxy) ethyl ester hydrofluoride

Isobutyric acid 1- (((2- (3-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) ethyl) carbamoyl) oxy) ethyl ester hydrofluoride

The residue was suspended in DCM (200ml) to give mixture 12. Sodium bicarbonate (20g) and tetrabutylammonium hydrogen sulfate (11g) were added to mixture 12 to form mixture 13. 1-chloroethyl chloroformate (16g) was then added to mixture 13 to give mixture 14. The mixture 14 was stirred at room temperature overnight. The organic layer of mixture 14 was then collected and washed with water (3x200ml) and dried over anhydrous sodium sulfate to give solution 15. The sodium sulfate was removed by filtration and washed with DCM to give solution 16. Solution 15 and solution 16 were combined and evaporated to dryness. The residue was dissolved in isobutyric acid (100ml) to form a mixture 17. A mixture of diisopropylethylamine (60ml) and isobutyric acid (36ml) was first prepared and then added to mixture 17 to give mixture 18. The mixture 18 was stirred at 55 ℃ for 48 hours, then ethyl acetate (500ml) was added with stirring. The resulting organic layers were collected and washed with 5% sodium bicarbonate (3x100ml) and water (3x100ml), respectively, and dried over anhydrous sodium sulfate to give solution 19. The sodium sulfate was filtered and washed with ethyl acetate to give a solution 20. Solution 19 and solution 20 were combined and concentrated to 300 ml. Anisole (20g) was added to the concentrated solution, followed by the introduction of hydrogen fluoride gas (20g), to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give isobutyric acid 1- (((2- (4-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) ethyl) carbamoyl) oxy) ethyl ester hydrofluoride and isobutyric acid 1- (((2- (3-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) ethyl) carbamoyl) oxy) ethyl ester hydrofluoride.

EXAMPLE 9 preparation of 4- (2- ((ethoxycarbonyl) amino) ethyl) -2- (2-methylamino) acetoxy) phenyl benzoate hydrochloride and 5- (2- ((ethoxycarbonyl) amino) ethyl) -2- (2-methylamino) acetoxy) phenyl benzoate hydrochloride

Benzoic acid 4- (2- ((ethoxycarbonyl) amino) ethyl) -2- (2-methylamino) acetoxy) phenyl ester hydrochloride

Benzoic acid 5- (2- ((ethoxycarbonyl) amino) ethyl) -2- (2-methylamino) acetoxy) phenyl ester hydrochloride

In this example, dopamine hydrochloride (19g) was added to acetone (200ml) to give a dopamine hydrochloride solution. 40ml of pyridine was added to the dopamine hydrochloride solution to give a mixture 1. N- (ethoxycarbonyloxy) succinimide (18g) was then added to mixture 1 to give mixture 2. The mixture 2 was stirred at room temperature overnight, and extracted with ethyl acetate (R0061, 500 ml). The organic layer was separated and washed with water (2x100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and dried over sodium sulfate to give solution 3. The sodium sulfate was then filtered and washed with ethyl acetate to give mixture 4. Solution 3 and mixture 4 were combined and evaporated to dryness. The obtained residue and Trt-sarcosine (Trt-sarcine) (36g) were dissolved in acetone (300ml), to obtain a mixture 5. 1-Ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (20g) and 4-dimethylaminopyridine (12g) were added to mixture 5 to give mixture 6. The mixture 6 was stirred at room temperature overnight and then evaporated to dryness. Ethyl acetate (500ml) was added to the residue to give mixture 7, which mixture 7 was washed with water (2x100ml), 5% sodium bicarbonate (3x100ml), water (100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and then dried over sodium sulfate to give solution 8. The sodium sulfate was filtered and washed with ethyl acetate to give solution 9. To the combined solution 8 and solution 9, pyridine (20ml) was added first, followed by dropwise addition of benzoyl chloride (15g) to give a mixture 10.

The mixture 10 was stirred at room temperature for 4 hours and washed with water (2x100ml), 5% sodium bicarbonate (2x100ml), water (100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, then dried over sodium sulfate to give solution 11. The sodium sulfate was filtered and washed with ethyl acetate to give solution 12.

Anisole (20g) was added to the combined solutions 11 and 12, followed by hydrogen chloride gas (20g) to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give 4- (2- ((ethoxycarbonyl) amino) ethyl) -2- (2-methylamino) acetoxy) phenyl benzoate hydrochloride and 5- (2- ((ethoxycarbonyl) amino) ethyl) -2- (2-methylamino) acetoxy) phenyl benzoate hydrochloride.

EXAMPLE 10 preparation of 4- (2-aminoethyl) -1,2-phenylene dibenzoate hydrochloride

Diphenyl formate 4- (2-aminoethyl) -1,2-phenylene ester hydrochloride

EXAMPLE 11 preparation of (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylene dibenzoate hydrochloride

Diphenyl carboxylic acid (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylene ester hydrochloride

In this example, (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionic acid (20g) was added to isopropanol (200ml) to give mixture 1. Hydrogen chloride gas (20g) was introduced into the mixture 1 to obtain a mixture 2. Mixture 2 was stirred at 60 ℃ for 2 days, then isopropyl acetate (200ml) was added to give a precipitate. The precipitated solid was collected and washed with isopropyl acetate to obtain isopropyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride.

Isopropyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride (28g) was added to acetone (200ml) to give mixture 3. To mixture 3 were added water (200ml) and sodium hydrogencarbonate (50g), followed by di-tert-butyl dicarbonate (22g), to give mixture 4. The mixture 4 was stirred at room temperature overnight, followed by addition of ethyl acetate (500 ml). The organic layer (mixture 5) was washed with water (2x100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and dried over anhydrous sodium sulfate to give solution 6. The sodium sulfate was then filtered and washed with ethyl acetate to give mixture 7. Solution 6 and mixture 7 were combined, pyridine (R0081, 30ml) was added first, followed by benzoyl chloride (R0488, 30g) dropwise to give mixture 8. The mixture 8 was stirred at room temperature for 2 hours, then washed with water (2x100ml), 5% sodium bicarbonate (3x100ml), water (100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and dried over sodium sulfate to give solution 9. The sodium sulfate was filtered and washed with ethyl acetate to give solution 10. Solution 9 and solution 10 were combined and concentrated to about 300ml (solution 11). Anisole (20g) was added to the solution 11, followed by the introduction of hydrogen chloride gas (20g), 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-phenylene dibenzoate hydrochloride.

EXAMPLE 12 preparation of (S) -4- (2-amino-3- (hept-4-yloxy) -3-oxopropyl) -1,2-phenylene dibenzoate hydrochloride

(S) -4- (2-amino-3- (hept-4-yloxy) -3-oxopropyl) -1,2-phenylene dibenzoate

In this example, (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionic acid (20g) was added to 4-heptanol (200ml), yielding mixture 1. Hydrogen chloride gas (20g) was introduced into the mixture l to obtain a mixture 2. Mixture 2 was stirred at 60 ℃ for 2 days, then isopropyl acetate (200ml) was added, forming a precipitate. The precipitated solid was collected and washed with isopropyl acetate to give 4-heptyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride.

4-heptyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propanoate hydrochloride (28g) was added to acetone (200ml), to give a mixture 3. To mixture 3 were added water (200ml) and sodium hydrogencarbonate (50g), followed by di-tert-butyl dicarbonate (22g), to give mixture 4. The mixture 4 was stirred at room temperature overnight, followed by addition of ethyl acetate (500 ml). The organic layer (mixture 5) was washed with water (2x100ml), 20% citric acid (2x200ml) and water (3x100ml), respectively, followed by drying over anhydrous sodium sulfate to give solution 6. The sodium sulfate was then filtered and washed with ethyl acetate to give mixture 7. Solution 6 and mixture 7 were combined and pyridine (R0081, 30ml) was added first, followed by the dropwise addition of benzoyl chloride (R0488, 30g) to give mixture 8. The mixture 8 was stirred at room temperature for 2 hours, then washed with water (2x100ml), 5% sodium bicarbonate (3x100ml), water (100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, then dried over sodium sulfate to give solution 9. The sodium sulfate was filtered and washed with ethyl acetate to give solution 10. Solution 9 and solution 10 were combined and concentrated to about 300ml (solution 11). Anisole (20g) was added to the solution 11, followed by the introduction of hydrogen chloride gas (20g), to obtain a precipitate. The precipitated solid was collected and washed with ethyl acetate to give (S) -4- (2-amino-3- (hept-4-yloxy) -3-oxopropyl) -1,2-phenylene dibenzoate hydrochloride.

EXAMPLE 13 preparation of (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1, 2-phenylene-dicarboxylate hydrochloride

Dipentanoic acid (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylene ester hydrochloride

In this example, (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionic acid (20g) was added to isopropanol (200ml) to give mixture 1. Hydrogen chloride gas (20g) was introduced into the mixture 1 to obtain a mixture 2. Mixture 2 was stirred at 60 ℃ for 2 days, then isopropyl acetate (200ml) 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) propionate hydrochloride.

Isopropyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride (28g) was added to acetone (200ml) to give a mixture 3. To mixture 3 were added water (200ml) and sodium hydrogencarbonate (50g), followed by di-tert-butyl dicarbonate (22g), to give mixture 4. The mixture 4 was stirred at room temperature overnight, followed by addition of ethyl acetate (500 ml). The organic layer was washed with water (2x100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and dried over anhydrous sodium sulfate to give solution 6. The sodium sulfate was then filtered and washed with ethyl acetate to give mixture 7. After combining solution 6 and mixture 7, pyridine (R0081, 30ml) was added followed by the dropwise addition of valeryl chloride (24g) to afford mixture 8. The mixture 8 was stirred at room temperature for 2 hours, then washed with water (2x100ml), 5% sodium bicarbonate (3x100ml), water (100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and dried over sodium sulfate to give solution 9. The sodium sulfate was filtered and washed with ethyl acetate to give solution 10. Solution 9 and solution 10 were combined and concentrated to about 300ml (solution 11). Anisole (20g) was added to the solution 11, followed by the introduction of hydrogen chloride gas (20g), 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-phenylene pivalate hydrochloride.

EXAMPLE 14 preparation of (S) -4- (2-amino-3-ethoxy-3-oxopropyl) -1,2-phenylene diacetate hydrochloride

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

In this example, (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionic acid (20g) was added to ethanol (200ml) to give a mixture 1. Hydrogen chloride gas (20g) was bubbled through mixture 1 to obtain mixture 2. Mixture 2 was stirred at 60 ℃ for 2 days, then isopropyl acetate (200ml) was added, forming a precipitate. The precipitated solid was collected and washed with isopropyl acetate to give ethyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride.

Ethyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride (26g) was added to acetone (200ml) to give a mixture 3. To mixture 3 were added water (200ml) and sodium hydrogencarbonate (50g), followed by di-tert-butyl dicarbonate (22g), to give mixture 4. The mixture 4 was stirred at room temperature overnight, followed by addition of ethyl acetate (500 ml). The organic layer (mixture 5) was washed with water (2x100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and dried over anhydrous sodium sulfate to give solution 6. The sodium sulfate was then filtered and washed with ethyl acetate to give mixture 7. Solution 6 and mixture 7 were combined and pyridine (R0081, 30ml) was added first, followed by 18 grams of acetyl chloride dropwise, to afford mixture 8. Mixture 8 was stirred at room temperature for 2 hours, then washed with water (2x100ml), 5% sodium bicarbonate (3x100ml), water (100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and dried over sodium sulfate to give solution 9. The sodium sulfate was filtered and washed with ethyl acetate to give solution 10. Solution 9 and solution 10 were combined and concentrated to about 300ml (solution 11). Anisole (20g) was added to the solution 11, followed by the introduction of hydrogen chloride gas (20g), to obtain a precipitate. The precipitated solid was collected and washed with ethyl acetate to give (S) -4- (2-amino-3-ethoxy-3-oxopropyl) -1,2-phenylene diacetate hydrochloride.

EXAMPLE 15 preparation of (S) -4- (2-amino-3-oxo-3- (pentan-3-yloxy) propyl) -1,2-phenylene bis (2-methylpropionate hydrobromide)

Bis (2-methylpropanoic acid) (S) -4- (2-amino-3-oxo-3- (pentan-3-yloxy) propyl) -1,2-phenylene ester hydrobromide

In this example (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionic acid (20g) was dissolved in 3-pentanol (200ml) to give mixture 1. Hydrogen chloride gas (20g) was bubbled through mixture 1 to obtain mixture 2. Mixture 2 was stirred at 60 ℃ for 2 days, then isopropyl acetate (200ml) was added, forming a precipitate. The precipitated solid was collected and washed with isopropyl acetate to obtain isopropyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride.

Amyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride (28g) was added to acetone (200ml) to give mixture 3. To mixture 3 were added water (200ml) and sodium hydrogencarbonate (50g), followed by di-tert-butyl dicarbonate (22g), to give mixture 4. The mixture 4 was stirred at room temperature overnight, followed by addition of ethyl acetate (500 ml). The organic layer (mixture 5) was washed with water (2x100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and then dried over anhydrous sodium sulfate to give solution 6. The sodium sulfate was then filtered and washed with ethyl acetate to give mixture 7. Solution 6 and mixture 7 were combined and pyridine (R0081, 30ml) was added first, followed by the dropwise addition of isobutyryl chloride (22g) to give mixture 8. Mixture 8 was stirred at room temperature for 2 hours, then washed with water (2x100ml), 5% sodium bicarbonate (3x100ml), water (100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and dried over sodium sulfate to give solution 9. The sodium sulfate was filtered and washed with ethyl acetate to give solution 10. Solution 9 and solution 10 were combined and concentrated to about 300ml (solution 11). Anisole (20g) was added to the solution 11, followed by the introduction of hydrogen chloride gas (20g), 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-phenylene diacetate hydrochloride.

EXAMPLE 16 preparation of (S) -4- (2-Aminoacetamido) -3-isopropoxy-3-oxopropyl) -1,2-phenylene dibenzoate hydrochloride

Diphenyl formate (S) -4- (2- (2-aminoacetamido) -3-isopropoxy-3-oxopropyl) -1,2-phenylene ester hydrochloride

In this example, (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionic acid (20g) was added to isopropanol (200ml) to give mixture 1. Hydrogen chloride gas (20g) was introduced into the mixture l to obtain a mixture 2. Mixture 2 was stirred at 60 ℃ for 2 days, then isopropyl acetate (200ml) was added, forming a precipitate. The precipitated solid was collected and washed with isopropyl acetate to obtain isopropyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride.

Isopropyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride (28g) was added to acetone (200ml) to give a mixture 3. To mixture 3 were added water (200ml) and sodium bicarbonate (50g) followed by N- (tert-butoxycarbonyl-glycine N-hydroxysuccinimide ester (27g) to give mixture 4. mixture 4 was stirred overnight at room temperature, then ethyl acetate (500ml) was added, the organic layer (mixture 5) was washed with water (2X100ml), 20% citric acid (2X200ml), and water (3X100ml), respectively, and dried over anhydrous sodium sulfate to give solution 6. then sodium sulfate was filtered and washed with ethyl acetate to give mixture 7. after combining solution 6 and mixture 7, pyridine (R0081, 30ml) was added first, then benzoyl chloride (30g) was added dropwise to give mixture 8. mixture 8 was stirred at room temperature for 2 hours, then water (2X100ml), 5% sodium bicarbonate (3X100ml), water (100ml), water, and mixtures, 20% citric acid (2x200ml), and water (3x100ml) were washed and dried over sodium sulfate to give solution 9. The sodium sulfate was filtered and washed with ethyl acetate to give solution 10. Solution 9 and solution 10 were combined and concentrated to about 300ml (solution 11). Anisole (20g) was added to the solution 11, followed by the introduction of hydrogen chloride gas (20g), to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give (S) -4- (2-aminoacetamido) -3-isopropoxy-3-oxopropyl) -1,2-phenylene dibenzoate hydrochloride.

Example 17 preparation of 4- ((2S) -3-oxo-3- (pentan-3-yloxy) -2- (pyrrolidine-2-carboxamido) propyl) -1,2-phenylene dibenzoate hydrofluoride

Diphenyl formate 4- ((2S) -3-oxo-3- (pentan-3-yloxy) -2- (pyrrolidine-2-carboxamido) propyl) -1,2-phenylene hydrofluoride salt

In this example, (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionic acid (20g) was added to 3-pentanol (200ml) to give a mixture 1. Hydrogen chloride gas (20g) was introduced into the mixture 1 to obtain a mixture 2. Mixture 2 was stirred at 60 ℃ for 2 days, then isopropyl acetate (200ml) was added, forming a precipitate. The precipitated solid was collected and washed with isopropyl acetate to obtain isopropyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride.

3-pentyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propanoate hydrochloride (28g) was added to acetone (200ml) to give mixture 3. To mixture 3 were added water (200ml) and sodium bicarbonate (50g) followed by N- (tert-butoxycarbonyl-proline N-hydroxysuccinimide ester (32g) to give mixture 4. mixture 4 was stirred at room temperature overnight and then ethyl acetate (500ml) was added, the organic layer (mixture 5) was washed with water (2X100ml), 20% citric acid (2X200ml), and water (3X100ml), respectively, and dried over anhydrous sodium sulfate to give solution 6. then sodium sulfate was filtered and washed with ethyl acetate to give mixture 7. after combining solution 6 and mixture 7, piperidine (R0081, 30ml) was added first, then 22g benzoyl chloride (22g) was added dropwise to give mixture 8. mixture 8 was stirred at room temperature for 2 hours, then water (2X100ml), 5% sodium bicarbonate (3X100ml), water (100ml), respectively, 20% citric acid (2x200ml), and water (3x100ml) were washed and dried over sodium sulfate to give solution 9. The sodium sulfate was filtered and washed with ethyl acetate to give solution 10. Solution 9 and solution 10 were combined and concentrated to about 300ml (solution 11). Anisole (20g) was added to the solution 11, followed by the introduction of hydrogen fluoride gas (20g), to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give 4- ((2S) -3-oxo-3- (pentan-3-yloxy) -2- (pyrrolidine-2-carboxamido) propyl) -1,2-phenylene dibenzoate hydrofluoride.

EXAMPLE 18 preparation of (S) -4- (3-isopropoxy-3-oxo-2- (piperidine-4-carboxamido) propyl) -1,2-phenylene dibenzoate hydrofluoride

(S) -4- (3-isopropoxy-3-oxo-2- (piperidine-4-carboxamido) propyl) -1,2-phenylene dibenzoate hydrofluoride

In this example, (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionic acid (20g) was added to isopropanol (200ml) to give mixture 1. Hydrogen chloride gas (20g) was introduced into the mixture 1 to obtain a mixture 2. Mixture 2 was stirred at 60 ℃ for 2 days, then isopropyl acetate (200ml) was added, forming a precipitate. The precipitated solid was collected and washed with isopropyl acetate to obtain isopropyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride.

Isopropyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride (28g) was added to acetone (200ml) to give mixture 3. To mixture 3 was added water (200ml) and sodium bicarbonate (50g), followed by Boc-piperidine-4-carboxylic acid N-hydroxysuccinimide ester (Boc-Inp-OSu, 33g) to give mixture 4. The mixture 4 was stirred at room temperature overnight, followed by addition of ethyl acetate (500 ml). The organic layer (mixture 5) was washed with water (2x100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and dried over anhydrous sodium sulfate to give solution 6. The sodium sulfate was filtered and washed with ethyl acetate to give mixture 7. After combining solution 6 and mixture 7, pyridine (R0081, 30ml) was added first, followed by the dropwise addition of 30g of benzoyl chloride to give mixture 8. The mixture 8 was stirred at room temperature for 2 hours, then washed with water (2x100ml), 5% sodium bicarbonate (3x100ml), water (100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and dried over sodium sulfate to give solution 9. The sodium sulfate was filtered and washed with ethyl acetate to give solution 10. Solution 9 and solution 10 were combined and concentrated to about 300ml (solution 11). Anisole (20g) was added to the solution 11, followed by the introduction of hydrogen fluoride gas (20g), to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give (S) -4- (3-isopropoxy-3-oxo-2- (piperidine-4-carboxamido) propyl) -1,2-phenylene dibenzoate hydrofluoride.

EXAMPLE 19 preparation of bis (2-methylpropionic acid) 4- ((2S) -3-isopropoxy-3-2- (octahydro-1H-quinolizine-2-carboxamido) -3-oxopropyl) -1,2-phenylene ester hydrochloride

Bis (2-methylpropionic acid) 4- ((2S) -3-isopropoxy-3-2- (octahydro-1H-quinolizine-2-carboxamido) -3-oxopropyl) -1,2 phenylene ester hydrochloride

In this example, (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionic acid (20g) was added to isopropanol (200ml) to give mixture 1. Hydrogen chloride gas (20g) was introduced into the mixture 1 to obtain a mixture 2. Mixture 2 was stirred at 60 ℃ for 2 days, then isopropyl acetate (200ml) was added, forming a precipitate. The precipitated solid was collected and washed with isopropyl acetate to obtain isopropyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride.

Isopropyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride (28g) was added to acetone (200ml) to give mixture 3. To mixture 3 were added water (200ml) and sodium bicarbonate (50g), followed by octahydro-1H-quinolizine-2-carboxylic acid N-hydroxysuccinimide ester (28g) to give mixture 4. The mixture 4 was stirred at room temperature overnight, followed by addition of ethyl acetate (500 ml). The organic layer (mixture 5) was washed with water (2x100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and dried over anhydrous sodium sulfate to give solution 6. The sodium sulfate was then filtered and washed with ethyl acetate to give mixture 7. After combining solution 6 and mixture 7, pyridine (R0081, 30ml) was added first, followed by 22 grams of isobutyryl chloride dropwise to give mixture 8. Mixture 8 was stirred at room temperature for 2 hours, then washed with water (2x100ml), 5% sodium bicarbonate (3x100ml), water (100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and dried over sodium sulfate to give solution 9. The sodium sulfate was filtered and washed with ethyl acetate to give solution 10. Solution 9 and solution 10 were combined and concentrated to about 100ml (solution 11). To solution 11 was added hexane (200ml) followed by acetic acid (6g) to form a precipitate. The precipitated solid was collected and washed with ethyl acetate/hexane to give 4- ((2S) -3-isopropoxy-3-2- (octahydro-1H-quinolizine-2-carboxamido) -3-oxopropyl) -1,2-phenylene ester hydrochloride bis (2-methylpropionic acid).

EXAMPLE 20 preparation of isopropyl (2S) -3- (3-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino) propanoate hydrobromide and isopropyl (2S) -3- (4-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino) propanoate hydrobromide

Isopropyl (2S) -3- (3-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino) propanoate hydrobromide

Isopropyl (2S) -3- (4-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino) propanoate hydrobromide

In this example, (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionic acid (20g) was added to isopropanol (200ml) to give mixture 1. Hydrogen chloride gas (20g) was introduced into the mixture 1 to obtain a mixture 2. Mixture 2 was stirred at 60 ℃ for 2 days, then isopropyl acetate (200ml) was added, forming a precipitate. The precipitated solid was collected and washed with isopropyl acetate to give (S) -2-amino-3- (3, 4-dihydroxyphenyl) propyl ester isopropyl hydrochloride.

Isopropyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride (28g) was added to acetone (200ml) to obtain an isopropyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride solution. Water (200ml) and sodium bicarbonate (R0090, 50g) were added to the dopamine hydrochloride solution to give mixture 3. Then, N α - (benzyloxycarbonyloxy) succinimide (25g) was added to the mixture 3 to obtain a mixture 4. The mixture 4 was stirred at room temperature overnight, then extracted by addition of ethyl acetate (R0061, 500 ml). The organic layer was separated and washed with water (2x100ml), 20% citric acid (2x200ml) and water (3x100ml), respectively, and dried over sodium sulfate to give solution 5. The sodium sulfate was then filtered and washed with ethyl acetate to give solution 6. Solution 5 and mixture 6 were combined and evaporated to dryness. The obtained residue and Boc-L-aspartic acid (24g) were dissolved in acetone (300ml) to give a mixture 7. To mixture 7 were added 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (40g) and 4-dimethylaminopyridine (22g) to give mixture 8. The mixture 8 was stirred at room temperature overnight and then evaporated to dryness. Ethyl acetate (500ml) was added to the residue to give mixture 9, which mixture 9 was washed with water (2x100ml), 5% sodium bicarbonate (3x100ml), water (100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and dried over sodium sulfate to give solution 10. The sodium sulfate was filtered and washed with ethyl acetate to give solution 11. Solution 10 and solution 11 were combined and evaporated to dryness. The residue was dissolved in methanol (R0084, 300ml) to give mixture 12. Palladium on carbon (10%, 10g) was first added to the mixture 12 under nitrogen and then hydrogen was bubbled in at room temperature to remove benzyloxycarbonyl. The mixture 13 was filtered to remove palladium on carbon and evaporated to dryness.

The residue was suspended in DCM (200ml) to give mixture 14. Sodium bicarbonate (15g) and tetrabutylammonium hydrogen sulfate (11g) were added to the mixture 14 to obtain a mixture 15. 1-chloroethyl chloroformate (16g) was then added to mixture 15 to give mixture 16. The mixture 16 was stirred at room temperature overnight. The organic layer of mixture 16 was then collected, washed with water (3x200ml) and dried over anhydrous sodium sulfate to give solution 17. The sodium sulfate was removed by filtration and washed with DCM to give solution 18. Solution 17 and solution 18 were combined and evaporated to dryness. The residue was dissolved in isobutyric acid (100ml) to give a mixture 19. A mixture of diisopropylethylamine (60ml) and isobutyric acid (36ml) was first prepared and then added to mixture 19 to give mixture 20. The mixture 20 was stirred at 55 ℃ for 48 hours, and then ethyl acetate (500ml) was added with stirring. The resulting organic layers were collected and washed with 5% sodium bicarbonate (3x100ml) and water (3x100ml), respectively, and then dried over anhydrous sodium sulfate to give solution 21. The sodium sulfate was filtered and washed with ethyl acetate to give solution 22. Solution 21 and solution 22 were combined and concentrated to 300 ml. Anisole (20g) was added to the concentrated solution, followed by the introduction of hydrogen bromide gas (30g), to form a precipitate. The precipitated solid was collected and washed with ethyl acetate to give isopropyl (2S) -3- (3-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino) propanoate hydrobromide and isopropyl (2S) -3- (4-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino) propanoate hydrobromide.

EXAMPLE 21 preparation of benzoic acid 5- ((2S) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino-3-isopropoxy-3-oxopropyl) -2- (2- (methylamino) acetoxy) phenyl ester hydrochloride and benzoic acid 4- ((2S) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino-3-isopropoxy-3-oxopropyl) -2- (2- (methylamino) acetoxy) phenyl ester hydrochloride

Benzoic acid 5- ((2S) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino-3-isopropoxy-3-oxopropyl) -2- (2- (methylamino) acetoxy) phenyl ester hydrochloride

Benzoic acid 4- ((2S) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino-3-isopropoxy-3-oxopropyl) -2- (2- (methylamino) acetoxy) phenyl ester hydrochloride

In this example, (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionic acid (20g) was added to isopropanol (200ml) to give a mixture 1. Hydrogen chloride gas (20g) was introduced into the mixture 1 to obtain a mixture 2. Mixture 2 was stirred at 60 ℃ for 2 days, then isopropyl acetate (200ml) was added, forming a precipitate. The precipitated solid was collected and washed with isopropyl acetate to obtain isopropyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride.

28g of isopropyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride was added to acetone (200ml) to obtain an isopropyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride solution. To the dopamine hydrochloride solution were added water (200ml) and sodium bicarbonate (R0090, 50g) to give mixture 3. Then N α - (benzyloxycarbonyloxy) succinimide (25g) was added to mixture 3 to give mixture 4. The mixture 4 was stirred at room temperature overnight, then extracted by addition of ethyl acetate (R0061, 500 ml). The organic layer was separated and washed with water (2x100ml), 20% citric acid (2x200ml) and water (3x100ml), respectively, and dried over sodium sulfate to give solution 5. The sodium sulfate was then filtered and washed with ethyl acetate to give solution 6. Solution 5 and mixture 6 were combined and evaporated to dryness.

The obtained residue and Trt-sarcosine (Trt-sarcine) (36g) were dissolved in acetone (300ml) to obtain a mixture 7. 1-Ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (20g) and 4-dimethylaminopyridine (12g) were added to mixture 7 to give mixture 8. The mixture 8 was stirred at room temperature overnight and then evaporated to dryness. Ethyl acetate (500ml) was added to the residue to give mixture 9, which mixture 9 was washed with water (2x100ml), 5% sodium bicarbonate (3x100ml), water (100ml), 20% citric acid (2x200ml) and water (3x100ml), respectively, and dried over sodium sulfate to give solution 10. The sodium sulfate was filtered and washed with ethyl acetate to give solution 11. Pyridine (20ml) was added to the solution 11 to obtain a mixture 12. Benzoyl chloride (15g) was added dropwise to the mixture 12 to obtain a mixture 13. The mixture 13 was stirred at room temperature for 4 hours, then washed with water (2x200ml), 5% sodium bicarbonate (3x100ml), water (100ml), 20% citric acid (2x200ml), and water (3x100ml), respectively, and dried over anhydrous sodium sulfate to give solution 14. The sodium sulfate was removed by filtration and washed with ethyl acetate to give a solution 15. The solution 14 and the solution 15 were combined and evaporated to dryness.

The obtained residue was dissolved in methanol (300ml) to obtain a mixture 16. 10% palladium on carbon (10%, 10g) was added to the mixture 16 under nitrogen, and then hydrogen was passed through the obtained mixture at room temperature until the benzyloxycarbonyl group was substantially completely removed. The palladium on carbon was removed by filtration, and the obtained solution was evaporated to dryness.

The residue obtained was suspended in DCM (200 ml). Sodium bicarbonate (15g) and tetrabutylammonium hydrogen sulfate (11g) were added to the DCM suspension. To the obtained reaction mixture was added 1-chloroethyl chloroformate (16 g). The reaction mixture was then stirred at room temperature overnight. The organic layer was collected and washed with water (3 × 200 ml). The solution was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration and washed with DCM. The DCM solution was evaporated to dryness.

The residue was dissolved in isobutyric acid (100 ml). To the reaction solution was added a mixture of diisopropylethylamine (60ml) and isobutyric acid (R0874, 36ml), the two components of the mixture being mixed prior to this addition. The mixture was stirred at 55 ℃ for 48 hours. To the reaction mixture was added ethyl acetate (500ml) with stirring. The organic solution was collected and washed with 5% sodium bicarbonate (3x100ml) and water (3x100 ml). The solution was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration and washed with ethyl acetate (3 ×). The solution was concentrated to 300 ml. Anisole (20g) was added to the ethyl acetate solution. Hydrogen chloride gas (30g) was then bubbled through the ethyl acetate solution. The solid was collected and washed with ethyl acetate.

EXAMPLE 22 preparation of 4- ((2S) -3-isopropoxy-2- ((((octahydroindolizine 1-yl) oxy) carbonyl) amino) -3-oxopropyl) -1,2-phenylene dibenzoate acetate

Diphenyl formate 4- ((2S) -3-isopropoxy-2- ((((octahydroindolizin-1-yl) oxy) carbonyl) amino) -3-oxopropyl-1, 2-phenylene acetate

In this example, (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionic acid (20g) was added to isopropanol (200 ml). Hydrogen chloride gas (20g) was bubbled through the mixture. The mixture was stirred at 60 ℃ for 2 days. Isopropyl acetate (200ml) was added to the mixture. The solid was collected and washed with isopropyl acetate.

Isopropyl (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionate hydrochloride (28g) was added to acetone (200 ml). Water (200ml) and sodium bicarbonate (50g) were added to the reaction mixture. Di-tert-butyl dicarbonate (22g) was added to the reaction mixture. The mixture was stirred at room temperature overnight. Ethyl acetate (500ml) was added to the mixture. The mixture was washed with water (2x100ml), 20% citric acid (2x200ml), and water (3x100 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration and washed with ethyl acetate. Pyridine (30ml) was added to the ethyl acetate solution. Benzoyl chloride (30g) was added dropwise to the reaction mixture. The solution was stirred at room temperature for 2 hours. The solution was washed with water (2x100ml), 5% sodium bicarbonate (2x100ml), water (100ml), 20% citric acid (2x200ml) and water (3x100 ml). The solution was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration and washed with ethyl acetate. The solution was concentrated to 200 ml. Anisole (20g) was added to the ethyl acetate solution. Hydrogen chloride gas (20g) was then bubbled through the ethyl acetate solution. The solid was collected and washed with ethyl acetate.

The solid was suspended in ethyl acetate (200ml) and 25ml triethylamine was added to the mixture. Octahydroindolizin-1-yl chlorocarbonate hydrochloride (22g) in ethyl acetate (50ml) was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 2 hours. The mixture was washed with 5% sodium bicarbonate and water (3 ×). Acetic acid (6g) was added to the mixture. 200ml of hexane were added to the mixture. The solid was collected by filtration and washed with ethyl acetate/hexane.

EXAMPLE 23 preparation of 2- (diethylamino) ethyl2- [ (2, 6-dichloro-3-methylphenyl) amino ] benzoate acetate

2- (diethylamino) ethyl2- ((2, 6-dichloro-3-methylphenyl) amino) benzoate acetate

29.6g (0.1mol) of 2- [ (2, 6-dichloro-3-methylphenyl) amino]Benzoic acid was dissolved in 300ml chloroform. 20.6g N, N' -dicyclohexylcarbodiimide was added to the reaction mixture. 11.7g of diethylaminoethylamine were added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. The solid was removed by filtration. The chloroform solution was treated with 5% NaHCO₃(2x100ml) and water (3x100 ml). The organic solution was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration. 6g of acetic acid are added to the reaction mixture with stirring. Hexane (200ml) was added. The solid product was collected by filtration.

EXAMPLE 24 preparation of 2- (diethylaminoethyl) ethyl (Z) -2- (5-fluoro-2-methyl-1- (4-methylsulfinyl) benzylidene) -1H-inden-1-yl) acetate

2- (diethylamino) ethyl (Z) -2- (5-fluoro-2-methyl-1- (4- (methylsulfinyl) benzylidene) -1H-inden-3-yl) acetate

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

EXAMPLE 25 preparation of 2- (3-phenoxyphenyl) propionic acid 2- (dimethylamino) ethyl ester hydrochloride

2- (3-Phenoxyphenyl) propionic acid 2- (dimethylamino) ethyl ester hydrochloride

26.1g (0.1mol) of 2- (3-phenoxyphenyl) propionyl chloride are dissolved in 300ml of ethyl acetate. The mixture was cooled to 0 ℃. 8.9g of dimethylaminoethanol were added to the reaction mixture. Sodium bicarbonate (30g) was added to the mixture. The mixture was stirred at room temperature for 5 hours. The mixture was washed with water (3 × 200 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Hydrogen chloride gas (5g) was bubbled through the mixture. The solid was collected by filtration and washed with ethyl acetate.

Example 26 preparation of 2- (dimethylamino) ethanethiol ester hydrochloride S-2- (3-phenoxyphenyl) propanoic acid

2- (dimethylamino) ethanethiol ester hydrochloride of S-2- (3-phenoxyphenyl) propionic acid

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

EXAMPLE 27 preparation of 2- (dipropylamino) ethyl 4-acetoxy-2 ', 4 ' -difluoro- [1, 1 ' -biphenyl ] -3-carboxylate hydrochloride [5- (2, 4-difluorophenyl) acetylsalicylic acid 2- (dipropylamino) ethyl ester hydrochloride ]

4-acetoxy-2 ', 4 ' -difluoro- [1, 1 ' -biphenyl ] -3-carboxylic acid 2- (dipropylamino) ethyl ester hydrochloride

31.1g (0.1mol) of 5- (2, 4-difluorophenyl) acetylsalicyloyl chloride are dissolved in 300ml of ethyl acetate. The mixture was cooled to 0 ℃. 11.7g (0.1mol) of diethylaminoethanol are added to the reaction mixture. Sodium bicarbonate (30g) was added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. Water (200ml) was then added to the mixture. The ethyl acetate layer was collected and washed with water (3 ×). The solution was dried over anhydrous sodium sulfate. Anhydrous hydrogen chloride gas was passed into the reaction mixture with stirring. The solid was collected and washed with ethyl acetate.

EXAMPLE 28 preparation of 2- (4-isobutylphenyl) propionic acid 2- (diethylamino) ethyl ester hydrochloride

2- (diethylamino) ethyl2- (4-isobutylphenyl) propionate hydrochloride

41g ibuprofen was dissolved in 200ml ethyl acetate. 16ml of thionyl chloride were added to the mixture. The mixture was refluxed for 2 hours. The mixture was completely evaporated to dryness. 500ml of ethyl acetate are added to the residue and evaporated off. 500ml of ethyl acetate were added to the reaction mixture. The solution was cooled to 5 ℃ with an ice water bath. 23g N, N-diethylaminoethanol was added dropwise to the reaction mixture. 40g of sodium carbonate were slowly added to the reaction mixture. The mixture was stirred at room temperature overnight. 200ml of water were added to the mixture. The ethyl acetate solution was collected, washed with water (3 × 200ml) and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration and washed with ethyl acetate (3 × 100 ml). Anhydrous hydrogen chloride gas (10g) was passed through the mixture. The solid was collected and washed with ethyl acetate.

EXAMPLE 29 preparation of 2- (diethylamino) ethyl 2-acetoxybenzoate (2- (diethylamino) ethyl acetylsalicylate hydrochloride)

2- (diethylamino) ethyl 2-acetoxybenzoate hydrochloride

36g of aspirin were dissolved in 100ml of ethyl acetate. 16ml of thionyl chloride were added to the mixture. The mixture was refluxed for 3 hours. The mixture was completely evaporated to dryness. 100ml of ethyl acetate are added to the residue and evaporated off. 500ml of ethyl acetate were added to the reaction mixture. The solution was cooled to 5 ℃ with an ice water bath. 23g N-diethylaminoethanol was added dropwise to the reaction mixture. To the reaction mixture was slowly added 40g NaHCO₃. The mixture was stirred at room temperature overnight. 200ml of water were added to the mixture. The ethyl acetate solution was collected and washed with water (3 × 100ml) and then dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration and washed with ethyl acetate (3 × 100 ml). Anhydrous hydrogen chloride gas (10g) was bubbled through the mixture. The solid was collected and washed with ethyl acetate.

EXAMPLE 30 determination of the penetration Rate of HPPs

4- (2- (2- (methylamino) acetamido) ethyl) -1,2-phenylene ester hydrochloride (Compound-1) (4- (2- (2- (methylamino) acetamido) ethyl) -1,2-phenylene dibenzoate hydrochloride), 4- (2- (2- (methylamino) acetamido) ethyl) -1, 2-diphenyl ester acetate (Compound-2) (4- (2- (2- (methylamino) acetamido) ethyl) -1,2-phenylene dibenzoate acid), 4- (6-methyl-4, 8-dioxo-5, 7-dioxa-2, 9-diaza-n-11-yl) -1-dibenzoate, 2-phenylene hydrobromide (Compound-3) (4- (6-methyl-4, 8-dioxo-5, 7-dioxa-2, 9-diazadecan-11-yl) -1,2-phenylene dibenzoate hydrate), 4- (2- (2-amino-3-phenylpropionylamino) ethyl) -1,2-phenylene dicarboxylate hydrochloride (Compound-4) (4- (2- (2-amino-3-phenylpropanamido) ethyl) -1,2-phenylene dibenzoate hydrochloride), 4- (2- (((1- ((pyrrolidine-2-carbonyl) oxy) ethoxy) amino) ethyl) -1,2-phenylene dicarboxylate hydrochloride (Compound-5) (4- (2- (((1- (((2-oxo) oxy) ethoxy) amino) ethyl) -1,2-phenylene dicarboxylate hydrochloride (Compound-5) (4- (2- (((1- ((2- (4- (2- (1 (L)) Pyrrolidine-2-carbonyl) oxy) ethoxy) amino) ethyl) -1,2-phenylene dibenzoate hydrochloride, bis (2-ethylbutyric acid) 4- (2-piperidine-4-carboxamido) ethyl) -1,2-phenylene ester hydrochloride (Compound-6) (4- (2-piperidine-4-carboxamide) ethyl) -1,2-phenylene bis (2-ethylbutyrate) hydrochloride), bis (2-ethylbutyric acid) 4- (2- (((((-octahydro-1H-quinolizin-3-yl) oxy) carbonyl) amino) ethyl) -1,2-phenylene acetate (Compound-7) (4- (2- ((((-octahydro-1H-quinolizin-3-yl) oxy) carbonyl) hydroxy) 1-1, 2-phenylenebis (2-ethylbutanoate) acetate), isobutyric acid 1- (((2- (4-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) ethyl) carbamoyl) oxy) ethyl ester hydrofluoride (Compound-8 a) (1- (((2- (4-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxin-8-yl) ethyl) methacrylate) carbamoyl) oxy) ethyl isobutylate hydrofluoride, isobutyric acid 1- (((2- (3-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) ethyl) carbamoyloxy) hydrofluoride (Compound-8 a) -8b) (1- (((2- (3-amino-2, 5-dioxol-2, 3, 4, 5-tetrahydrobenzol [ b ] [1, 4] dioxocin-8-yl) ethyl) carbayl) oxy) ethyl isobutyrate hydrofluoride), benzoic acid 5(- (2- ((ethoxycarbonyl) amino) ethyl) -2- (2-methylamino) acetoxy) phenyl ester hydrochloride (compound-9 a) (5- (2- ((ethoxycarbonyl) amino) ethyl) -2- (2-methy) phenoxy benzoate hydrochloride), benzoic acid 5- (2- ((ethoxycarbonyl) amino) ethyl) -2- (2-methylamino) acetoxy) phenyl ester hydrochloride (compound-9 b) (5- (2- ((ethoxycarbonyl) amino) ethyl) -2- (2-methylamino) acetoxy) phenyl ester hydrochloride), 4- (2-aminoethyl) -1,2-phenylene dibenzoate hydrochloride (Compound-10) (4- (2-aminoethyl) -1,2-phenylene dibenzoate hydrochloride), 4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylene dibenzoate hydrochloride (Compound-11) ((S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylene dibenzoate hydrochloride), 4- (2-amino-3- (hept-4-yloxy) -3-oxopropyl) -1,2-phenylene dibenzoate hydrochloride (Compound-12) ((S) -4- (2-amino-3- (hept-4-yloxy) -3-oxopropyl) -1,2-phenylene dibenzoate hydrochloride (Compound-10) - (heptan-4-yloxy) -3-oxopropyl) -1,2-phenylene dibenzoate hydrochloride, (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylene ester hydrochloride (Compound-13) ((S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylene dibenzoate hydrochloride), diacetic acid (S) -4- (2-amino-3-ethoxy-3-oxopropyl) -1,2-phenylene ester hydrochloride (Compound-14) ((S) -4- (2-amino-3-ethoxy-3-oxopropyl) -1,2-phenylene ester hydrochloride (Compound-14), 2-phenylenediacetate hydrochloride, bis (2-methylpropanoic acid) (S) -4- (2-amino-3-oxo-3- (pentan-3-yloxy) propyl) -1,2-phenylene hydrobromide (Compound-15) ((S) -4- (2-amino-3-oxo-3- (pentan-3-yloxy) propyl) -1, 2-phenylenebis (2-methylproprione) hydrobromide), dibenzoic acid (S) -4- (2-aminoacetylamino) -3-isopropoxy-3-oxopropyl) -1,2-phenylene dicarboxylate (Compound-16) ((S) -4- (2-aminoacetamido) -3-oxopropoxy-3-oxopropyl) -1,2-phenylene dicarboxylate (Compound-16), 2-phenylene dibenzoate hydrochloride), dibenzoic acid 4- ((2S) -3-oxo-3- (pentane-3-yloxy) -2- (pyrrolidine-2-carboxamido) propyl) -1,2-phenylene hydrofluoride (Compound-17) (4- ((2S) -3-oxo-3- (pentan-3-yloxy) -2- (pyrollidine-2-carboxamido) propyl) -1,2-phenylene dibenzoate hydrofluoride), dibenzoic acid (S) -4- (3-isopropoxy-3-oxo-2- (piperidine-4-carboxamido) propyl) -1,2-phenylene dibenzoate hydrochloride (Compound-18) ((S) -4- (3-isopropoxy-3-oxo-2-carboxamido) propyl) -1,2-phenylene hydrochloride (Compound-18) ((S) -4- (3-isopropoxy-3-oxo-2-carboxamido) hydrochloride - (piperidine-4-carboxamid) propyl) -1,2-phenylene dibenzoate hydrochloride, bis (2-methylpropionic acid) 4- ((2S) -3-isopropoxy-3-2- (octahydro-1H-quinolizine-2-carboxamido) -3-oxopropyl) -1,2-phenylene ester hydrochloride (Compound-19) (4- ((2S) -3-isopropoxy-3-2- (octahydro-1H-quinolizine-2-carboxamid) -3-oxopropyl) -1,2-phenylene ester hydrochloride), (2S) -3- (3-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzo [ b ] [1, 4] dioxacyclooctatrien-8-yl) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino) propionic acid isopropyl ester hydrobromide (compound-20 a) ((2S) -isoproyl 3- (3-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzol [ b ] [1, 4] dioxacin-8-yl) -2- (((1- (isobutryloxy) ethoxy) carbonyl) amino) propanoate hydrobromide), (2S) -3- (4-amino-2, 5-dioxo-2, 3, 4, 5-tetrahydrobenzol [ b ] [1, 4] dioxacyclooct-8-yl) -2- (((1- (isobutyryloxy) ethoxy) carbonyl) amino) propionic acid isopropyl ester hydrobromide (compound-20 b) ((2S) -isoproyl) propionic acid isopropyl ester hydrobromide (compound-20 b) 3- (4-amino-2, 5-dioxon-2, 3, 4, 5-tetrahydrobenzole [ b ] [1, 4] dioxocin-8-yl) -2- (((1- (isobutoxy) ethoxy) carbonyl) amino-3-isopropoxy-3-oxopropyl) -2- (2- (methylamino) acetoxy) phenyl ester hydrochloride (Compound-21 a) (5- ((2S) -2- (((1- (isobutoxy) ethoxy) carbonyl) amino-3-oxopropyl) -3-isopropoxy) -2- (2- (methylamino) acetoxy) phenyl ester hydrochloride), benzoic acid 4- (((2S) -2- (((1- (isobutoxy) ethoxy) carbonyl) amino-3-isoproxy) -2- (2- (Methalamino) acetoxy) phenoxy) phenyl ester) Ethoxy) carbonyl) amino-3-isopropoxy-3-oxopropyl) -2- (2- (methylamino) acetoxy) phenyl ester hydrochloride (Compound-21 b) (4- ((2S) -2- (((1- (isobutryloxy) ethoxy) carbonyl) amino-3-isopropoxy-3-oxopropyl) -2- (2- (methylamino) ethoxy) phenyl benzoate hydrochloride), dibenzoic acid 4- ((2S) -3-isopropoxy-2- ((((octahydroindolin-1-yl) oxy) carbonyl) amino) -3-oxopropyl) -1,2-phenylene ester acetate (Compound-22) (4- ((2S) -3-isopropoxy-2- (((octahydroindolizin-1-yl) oxy) carbonyl) amino) -3-oxopropyl) -1,2-phenylene ester acetate (Compound-22) (4- ((2S) -3-isopropoxy-2- (((octohydroindolizin-1-yl) oxy) carbonyl) amino) -3-oxo) amino) -3-propanoyl) oxypyr) -1,2-phenylene dibenzae acetate), 2- [ (2, 6-dichloro-3-methylphenyl) amino ] benzoic acid 2- (diethylamino) ethyl ester acetate (compound-23) (2- (diethylamino) ethyl2- [ (2, 6-dichloro-3-methylphenyl) amino ] benzoate acetate), (Z) -2- (5-fluoro-2-methyl-1- (4-methylsulfinyl) benzylidene) -1H-inden-1-yl) acetic acid 2- (diethylaminoethyl) ethyl ester acetate (compound-24) ((Z) -2- (diethylaminoethyl) benzyl) 2- (5-fluoro-2-methyl-1- (4-methylsulfinyl) benzyl) -1H-inden-1-yl) acetate. acetate, 2- (dimethylamino) ethyl2- (3-phenoxyphenyl) propanoate hydrochloride (compound-25) (2- (dimethylamino) ethyl2- (3-phenoxyphenyl) propionate hydrochloride), S-2- (3-phenoxyphenyl) propanoate (2- (dimethylamino) ethanethiol hydrochloride (compound-26) (S- (2- (dimethylamino) ethyl2- (3-phenoxyphenyl) propanoate hydrochloride), 4-acetoxy-2 ', 4' -difluoro- [1, 1 '-biphenyl ] -3-carboxylic acid 2- (dipropylamino) ethyl ester hydrochloride (compound-27) (2- (dipropylenephenyl) ethyl 4-acetoxy-2', 4 '-difluoro- [1, 1' -biphenyl ] -3-carboxalylate), 2- (diethylamino) ethyl2- (4-isobutylphenyl) propionate hydrochloride (compound-28) (2- (diethylamino) ethyl2- (4-isobutylphenyl) propionate hydrochloride), 2- (diethylamino) ethyl 2-acetoxybenzoate hydrochloride (compound-29) (2- (diethylamino) ethyl 2-acetoxybenzoate hydrochloride), 4- (2-aminoethyl) benzene-1, 2-diol hydrochloride (compound 30) (4- (2-aminoethyl) benzene-1, 2-diol hydrochloride), 2-amino-3- (3, 4-dihydroxyphenyl) propionic acid (L-dopa, compound 31) (2-amino-3- (3, 4-dihydroxyphenyl) propanoic acid), acetylsalicylic acid (compound 32) (acetylsalicylic acid), the speed of 2- (p-isobutylphenyl) propionic acid (ibuprofen, compound 33) (2- (p-isobutylphenyl) propionic acid), and 2- (3-phenoxyphenyl) propionic acid (compound 34) (2- (3-phenoxyphenyl) propionic acid) through human skin was measured in vitro in modified Franz cells. Wherein the human skin is separated from human skin tissue (360-400 μm thick) anterior or posterior to the thigh region. The receiving solution was made up of 10ml of phosphate buffered solution (0.2M) pH 7.4, and the results are shown in Table 1. The results indicate that the positive charge on the amino group is important for the drug to cross biological membranes and skin barriers.

TABLE 1 cumulative amount of dopamine, L-dopa, and NSAID prodrugs over 8 hours

Example 31 effects of (S) -4- (2-amino-3-isopropoxy-3-oxopropyl) -1,2-phenylene Diphenyl ester hydrochloride (drug A) and 2-acetoxybenzoic acid 2- (diethylamino) ethyl ester hydrochloride (drug B) on improvement of motor function disorders and reduction of Negro-striatal neurodegeneration in the HDB model of Parkinson' S disease (PD) induced by 6-hydroxypolyamine

Subjects (SD rats) were modeled, grouped and tested according to the following protocol:

200 Sprague-Dawley rats (male, 200- & 230g) received brain stereotactic surgery one week after acclimation.

1. After anaesthesia, a hole (about 1mm in diameter) was drilled in the rat left cranium with a hand-operated electric drill, the coordinates of which relative to the anterior fontanel were: AP +0.5mm, ML-2.8mm, DV 6.0 mm.

2.6-Hydroxydopamine (20. mu.g, 5mg/ml concentration) or sterile saline was injected into the rat left striatum using a micro-adjustment syringe fitted with a 26-gauge steel cannula. This compound can cause degenerative neurological deformation in the distal substantia nigra and impair dopamine transport in the nigro-striatal pathway, ultimately leading to motor dysfunction.

3. Animals were screened with dehydrated morphine and a classical spin assay after 3 consecutive weeks of 6-hydroxydopamine administration. Animals meeting the lesion criteria and dehydrated morphine-induced spin scores were randomly divided into 11 groups.

4. The rats were randomly divided into 11 groups (n-12) and each group was dosed with the drug as specified in table 2;

table 2: medicament and dose to a subject

5. Preparation

(1) L-DOPA (3mg/mL) was dissolved in water as a positive control solution for group 1 (group 1 orally, groups 2-11 transdermally) and administered in a volume of 2 mL/kg. The vehicle (negative control solution for group 2) was 30% ethanol (v/v) and the dosing volume was 1286. mu.L/kg. The test solutions of the other groups (groups 3-11) were freshly prepared daily.

(2) Test solution formulation methods for groups 3-5: 50.33mg of drug A dissolved in 10ml of 30% ethanol (v/v), this solution being the stock solution [ (2) a ];

a. test solution for drug a group 5 (high dose group): stock solution [ (2) a ] is the test solution of group 5, administered at a volume of 1286 μ L/kg;

b. test solution for drug a group 4 (medium dose group): 3.00mL stock solution [ (2) a ] diluted to 9.00mL with 30% ethanol (v/v), this solution was the test solution of group 4 administered at a volume of 1286. mu.L/kg;

c. test solution for drug a group 3 (low dose group): 1.00mL stock solution [ (2) a ] diluted to 9.00mL with 30% ethanol (v/v), this solution was the test solution of group 4 administered at a volume of 1286. mu.L/kg;

(3) group 6 test solution preparation method: 5.67mg drug A and 264mg drug B were dissolved in 10ml 30% ethanol (v/v), which was the test solution of group 6;

(4) group 7 test solution preparation method: 16.67mg drug A and 264mg drug B were dissolved in 10ml 30% ethanol (v/v), which was the test solution of group 7;

(5) group 8 test solution preparation method: 264mg of drug B was dissolved in 10ml of 30% ethanol (v/v), which was the test solution of group 8;

(6) group 9 test solution preparation method: 5.67mg drug A and 791mg drug B were dissolved in 10ml 30% ethanol (v/v), which was the test solution of group 9;

(7) set 10 test solution configuration method: 16.67mg drug A and 791mg drug B were dissolved in 10ml 30% ethanol (v/v), which was the test solution for group 10;

(8) group 11 test solution preparation method: 791mg of drug A dissolved in 10ml of 30% ethanol (v/v), this solution being the test solution of group 11;

7. the day prior to dosing, upper back hair (including a positive control group given L-dopa for double blind trial design) was shaved with small animal shaving scissors and shaved as needed to ensure that back skin was exposed in the trial study. An aliquot (643 uL/kg) of the formulation was applied to the animal (near the shoulder and neck) at 9 am on the day of administration to an area of about 3cmX3cm, which was repeated once more at 4 pm.

8. At week 4 post-molding, each group began receiving treatment.

9. The treatment was followed weekly by rotational testing.

Figure 1 is the residence time in the spin test after 1-3 weeks of treatment (n-12). Fig. 2 is the rotation rate at which the rats dropped in the spin test after 1-3 weeks of treatment (n-12).

Longer dwell times on the rotor and faster rotational speeds indicate that the mobility of the parkinsonian animal is better (if the test compound has no side effects).

The data for all batches (12/group) were pooled and the positive control group (group 1, L-dopa, 6mg/kg, oral) showed no efficacy after 3 weeks of treatment compared to the vehicle group. While all test solution groups (groups 2-11) showed a stronger effect after 3 weeks of treatment compared to the blank group. Levodopa contributes to the improvement of motor syndrome in parkinson's disease. Levodopa can cause nausea, vomiting, gastrointestinal bleeding, dyskinesia at peak dose, and functional deterioration at peak and trough doses, so the positive control group (group 1, L-dopa, 6mg/kg, oral) showed no effect compared to the vehicle group, while transdermal administration of prodrug of L-dopa (drug a) avoided dyskinesia at peak dose, and functional deterioration at peak and trough doses. Therefore, the positive control group (group 1, L-dopa, 6mg/kg, oral) had no effect compared to the vehicle group. Transdermal administration of the prodrug of L-dopa (drug a) avoids dyskinesia at peak doses and functional degradation at peak and trough doses. The low dose group of drug A (L-dopa prodrug, 0.67mg/kg, group 3) was more effective than the high dose group of drug A (2mg and 6mg/kg, groups 4 and 5). These results indicate that the dose of the L-dopa prodrug administered transdermally is much lower (9-fold lower) than the dose of L-dopa administered orally. After 3 weeks of treatment, 30mg and 90mg/kg of drug B (aspirin prodrug) had good efficacy compared to vehicle and positive control. Drug B at 30mg/kg (group 8) showed a therapeutic effect comparable to drug B at 90mg/kg (group 11). This result indicates that 30mg/Kg of drug B is sufficient, and higher doses are not required. Drug a in combination with drug B (groups 6 and 9) was much better in subjects than either drug B or drug a alone.

Where multiple drugs (e.g., one or more high penetration compositions or other drugs) are administered to a subject in combination, each drug may be administered separately, or one or more drugs may be administered as separate drugs at substantially the same time (e.g., two or more drugs are sprayed at substantially the same time without mixing prior to spraying), or one or more drugs may be mixed together prior to administration to a subject, or several of the above methods may be used together. The drugs may be administered in any possible order.

Example 32 drug a (transdermal), drug B (transdermal), and oral carbidopa have improved motor function deficits and reduced efficacy in nigromas-striatal neurodegeneration in the 6-hydroxypolydopamine-induced Parkinson's Disease (PD) HDB model.

The subjects (Sprague-Dawley rats) were modeled as described in example 31, grouped and tested according to the following protocol.

1. The rats were randomly divided into 11 groups (n-12) and each group was dosed with the drug as specified in table 3;

table 3: medicament and dose to a subject

2. Preparation

(1) L-dopa (3mg/mL) and carbidopa (1.5mg/mL) were dissolved in water as a positive control solution (oral) for group 1, administered at a volume of 2 mL/kg. Carbidopa dissolved in water (3mg/mL) was administered as an aromatic-L-amino acid decarboxylase inhibitor (oral) group 2-11 in a volume of 2 mL/kg. The vehicle (negative control solution for group 2) was a 30% ethanol solution (v/v) and the administration volume was 1,286. mu.L/kg. The other test solutions (transdermal, groups 3-11) were fresh daily.

(2) Methods for preparing the test solutions of groups 3-5: 50.33mg of drug A was dissolved in 10mL of 30% ethanol solution (v/v). This solution was stock solution (2).

(a) Stock solution (2) was the group 5 (high dose group) test solution. The administration volume was 1,286. mu.L/kg.

(b) Group 4 (medium dose group) test solution configuration: 3.00ml of stock solution (2) was diluted to 9.00ml with 30% ethanol solution. This solution was the test solution of group 4. The administration volume was 1,286. mu.L/kg.

(c) Group 3 (low dose group) test solution configuration: 1.00ml of stock solution (2) was diluted to 9.00ml with 30% ethanol solution. This solution was the test solution of group 3. The administration volume was 1,286. mu.L/kg.

(3) Group 6 test solution preparation method: 5.67mg drug A and 264mg drug B were dissolved in 10mL of 30% ethanol solution (v/v). This solution was the test solution of group 6.

(4) Group 7 test solution preparation method: 16.67mg drug A and 264mg drug B were dissolved in 10mL of 30% ethanol solution (v/v). This solution was the test solution of group 7.

(5) Group 8 test solution preparation method: 264mg of drug B was dissolved in 10mL of 30% ethanol solution (v/v). This solution was the test solution of group 8.

(6) Group 9 test solution preparation method: 5.67mg drug A and 791mg drug B were dissolved in 10mL of 30% ethanol solution (v/v). This solution was the test solution of group 9.

(7) Set 10 test solution configuration method: 16.67mg drug A and 791mg drug B were dissolved in 10mL of 30% ethanol solution (v/v). This solution was the test solution of group 10.

(8) Group 11 test solution preparation method: 791mg of drug B was dissolved in 10mL of 30% ethanol solution (v/v). This solution was the test solution of group 11.

3. The day before dosing, the upper back (near the neck and shoulders) of the mice were shaved with a small animal shaver (since double-blind experiments required all rats including the positive control group with L-dopa). In the experiment, the skin was shaved again as necessary to keep the back skin bare. On the day of administration, an aliquot (643 μ L/kg) of the formulation was applied to the exposed skin (between the neck and shoulders) of the animals for a 3cmx3cm square interval at 9 a.m. and repeated at 4 p.m.

4. At 4 weeks after molding, all groups of rats began to receive treatment.

5. After 4 weeks of treatment, rats were subjected to a spin test.

Figure 3 is the residence time in the rotational test after 4 weeks of treatment (n-12). Fig. 4 is the rotation rate at which the rats dropped in the rotation test after 4 weeks of treatment (n-12).

Carbidopa can reduce peripheral DDC transition before levodopa crosses the blood-brain barrier, thereby reducing the side effects of L-dopa. The results show that carbidopa increased the efficacy of all L-dopa and L-dopa prodrug (drug a) treatment groups (groups 1, 3, 4, 5, 6, 7, 9, 10), but did not alter the efficacy of the vehicle group and the aspirin prodrug group (drug B) (groups 2, 8 and 11).

Example 33 therapeutic efficacy of L-dopa and ibuprofen prodrugs on the 6-hydroxypolydopamine induced Parkinson's Disease (PD) HDB model for improving motor function deficits and reducing Neuglo-striatal neurodegeneration

The subjects (Sprague-Dawley rats) were modeled as described in example 31, grouped and tested according to the following protocol.

1. The rats were randomly divided into 11 groups (n-12) and each group was dosed with the drug as specified in table 4; drug C was (S) -4- (2-amino-3-oxo-3- (pent-3-yloxy) propyl) -1, 2-phenylene-ester hydrobromide bis (2-methylpropionate), and drug D was 2- (diethylamino) ethyl2- (4-isobutylphenyl) propionate acetate:

TABLE 4 drugs and dosages to subjects

2. Preparation

(1) L-dopa (3mg/mL) was dissolved in water as a positive control solution (oral) for group 1, administered in a volume of 2 mL/kg. The vehicle (negative control solution of group 2) was a 30% ethanol solution (v/v) and the administration volume was 1286. mu.L/kg. The other groups of test solutions (transdermal, groups 3-11) were fresh daily.

(2) Set 3-5 methods of preparation of test solutions: 50.33mg of drug C was dissolved in 10mL of 30% ethanol solution (v/v). This solution was stock solution (2).

a) Test solution for group 5 (high dose group) drug C: stock solution (2) was the test solution of group 5. The administration volume was 1286. mu.L/kg.

b) Test solution for group 4 (medium dose group) drug C: 3.00ml of stock solution (2) was diluted to 9.00ml with 30% ethanol solution. This solution was the test solution of group 4. The administration volume was 1286. mu.L/kg.

c) Test solution for group 3 (medium dose group) drug C: 1.00ml of stock solution (2) was diluted to 9.00ml with 30% ethanol solution. This solution was the test solution of group 3. The administration volume was 1286. mu.L/kg.

(3) Group 6 test solution preparation method: 5.67mg drug C and 132mg drug D were dissolved in 10mL of 30% ethanol solution (v/v). This solution was the test solution of group 6.

(4) Group 7 test solution preparation method: 16.67mg drug C and 132mg drug D were dissolved in 10mL of 30% ethanol solution (v/v). This solution was the test solution of group 7.

(5) Group 8 test solution preparation method: 132mg of drug D was dissolved in 10mL of 30% ethanol solution (v/v). This solution was the test solution of group 8.

(6) Group 9 test solution preparation method: 5.67mg drug C and 395.5mg drug D were dissolved in 10mL of 30% ethanol solution (v/v). This solution was the test solution of group 9.

(7) Set 10 test solution configuration method: 16.67mg drug C and 395.5mg drug D were dissolved in 10mL of 30% ethanol solution (v/v). This solution was the test solution of group 10.

(8) Group 11 test solution preparation method: 395.5mg of drug D was dissolved in 10mL of 30% ethanol solution (v/v). This solution was the test solution of group 11.

3. The day before dosing, mice were shaved on their upper back (in the neck and shoulders) using a small animal shaver (since double-blind experiments required all rats including the positive control group of L-dopa). Rats will be shaved again as necessary during the experiment to keep the skin bare. On the day of administration, an aliquot (643 μ L/kg) of the formulation was applied to the exposed skin (between the neck and shoulder) of the animals at 9 a.m. intervals of 3cmx3cm squares (between the neck and shoulder) and repeated at 4 p.m.

4. At 4 weeks after molding, all groups of rats began to receive treatment.

5. After 4 weeks of treatment, the rats received a spin test.

Fig. 5 is the residence time in the rotational test after 4 weeks of treatment (n-12). Fig. 6 is the rotation rate at which the rats dropped in the rotation test after 4 weeks of treatment (n-12).

The data for all batches (12/group) were combined and the positive control group (L-dopa, 6mg/kg, oral) showed no efficacy compared to the vehicle group after 4 weeks of treatment, while all the test drug treated groups showed stronger efficacy compared to the blank group after 4 weeks of treatment. Levodopa can cause nausea, vomiting, gastrointestinal bleeding, dyskinesia at peak dose, and functional deterioration at peak and trough dose, so the positive control group (L-dopa, 6mg/kg, oral) showed no effect compared to the blank group, while transdermal administration of prodrug of L-dopa (drug C) avoided dyskinesia at peak dose, and functional deterioration at peak and trough dose. The low dose group of drug C (L-dopa prodrug, 0.67mg/kg, group 3) was more efficacious than the medium and high dose groups (2mg & g and 6mg/kg, groups 4 and 5). This result indicates that the dose of the L-dopa prodrug administered transdermally should be much lower than the dose of oral L-dopa. After four weeks of treatment, 15mg and 45mg & g of drug D (ibuprofen prodrug) showed efficacy compared to the blank and positive control. 15mg/Kg of drug D (group 8) had similar efficacy as 45mg/Kg of drug D (group 11). Thus, a 15mg/Kg dose is sufficiently high that higher doses are not required. Drug C and drug D in combination (groups 6 and 9) were more effective than drug D (groups 8 and 11) or drug C (group 3) administered alone.

Example 34 efficacy of L-dopa and ibuprofen prodrugs and 1.5mg/kg carbidopa to improve motor function deficits and reduce Neugo-striatal neurodegeneration in the HDB model of Parkinson's Disease (PD) induced by 6-hydroxypolyamine.

The subjects (Sprague-Dawley rats) were modeled as described in example 31, grouped and tested according to the following protocol.

1. The rats were randomly divided into 11 groups (n-12) and each group was administered with the drug at the dose specified in table 5;

TABLE 5 drugs and dosages to subjects

2. Preparation

(1) L-dopa (3mg/mL) and carbidopa (1.5mg/mL) dissolved in water was the positive control solution for group 1 (oral) administered in a volume of 2 mL/kg. Carbidopa (1.5mg/mL) was dissolved in water and administered as an aromatic-L-amino acid decarboxylase inhibitor to groups 2-11 (oral) in a volume of 2 mL/kg. The vehicle (negative control solution for group 2) was 30% ethanol (v/v) and the dosing volume was 1,286 μ L/kg. The solutions of the other test groups (transdermal, groups 3-11) were fresh daily.

(2) Set 3-5 methods of preparation of test solutions: 50.33mg of drug C was dissolved in 10ml of 30% ethanol solution (v/v). This solution was stock solution (2).

a. Group 5 test solution drug C solution (high dose group) formulation method: stock solution (2) was the test solution of group 5. The administration volume is 1,286 uL/kg;

b. group 4 test solution drug C solution (high dose group) formulation method: 3.00ml of stock solution (2) was diluted to 9.00ml with 30% ethanol (v/v). This solution was the test solution of group 4. The administration volume is 1,286 uL/kg;

c. group 3 test solution drug C solution (high dose group) formulation method: 1.00ml of stock solution (2) was diluted to 9.00ml with 30% ethanol (v/v). This solution was the test solution of group 4. The administration volume is 1,286 uL/kg;

(3) group 6 test solution preparation method: 5.67mg of drug C and 132mg of drug D were dissolved in 10ml of 30% ethanol solution (v/v). This solution was the test solution of group 6.

(4) Group 7 test solution preparation method: 16.67mg of drug C and 132mg of drug D were dissolved in 10ml of 30% ethanol solution (v/v). This solution was the test solution of group 7.

(5) Group 8 test solution preparation method: 132mg of drug D was dissolved in 10ml of 30% ethanol solution (v/v). This solution was the test solution of group 8.

(6) Group 9 test solution preparation method: 5.67mg of drug C and 395.5mg of drug D were dissolved in 10ml of 30% ethanol solution (v/v). This solution was the test solution of group 9.

(7) Set 10 test solution configuration method: 16.67mg of drug C and 395.5mg of drug D were dissolved in 10ml of 30% ethanol solution (v/v). This solution was the test solution of group 10.

(8) Group 11 test solution preparation method: 395.5mg of drug D was dissolved in 10ml of 30% ethanol solution (v/v). This solution was the test solution of group 11.

3. The day before dosing, mice were shaved on their upper back (near the neck and shoulders) using a small animal shaver (positive control rats with L-dopa were included as required for double-blind experiments). Rats were shaved again as necessary during the experiment to keep the skin bare. On the day of administration, an aliquot (643 μ L/kg) of the formulation was applied to the exposed skin (between the neck and shoulders) of the animal in a 3cmx3cm square area at 9 am, and repeated at 4 pm.

4. Four weeks after surgery, all groups began to receive treatment.

5. After 4 weeks of treatment, the rats received a spin test.

Figure 7 is the residence time in the rotational test after 4 weeks of treatment (n-12). Fig. 8 is the rotation rate at which the rats dropped in the rotation test after 4 weeks of treatment (n-12).

Carbidopa can reduce peripheral DDC conversion before levodopa crosses the blood-brain barrier, thereby reducing the side effects of L-dopa. The results show that carbidopa increased the efficacy of all L-dopa and L-dopa prodrug treatment groups (groups 1, 3, 4, 5, 6, 7, 9, 10), but not the placebo and ibuprofen prodrug treatment groups (groups 2, 8, 11).

Example 35 efficacy of 4- (2- (((1- ((pyrrolidine-2-carbonyl) oxy) ethoxy) amino) ethyl) -1,2-phenylene ester hydrochloride (drug E) and 4- (dimethylamino) butyl 2- (3-phenoxyphenyl) propanoate hydrochloride (drug F) for improving motor function deficits and reducing Neuglo-striatal neurodegeneration in the HDB model of Parkinson's Disease (PD) induced by 6-hydroxypolyamine

The subjects (Sprague-Dawley rats) were modeled as described in example 31, grouped and tested according to the following protocol.

1. The rats were randomly divided into 11 groups (n-12) and each group was administered with the drug at the dose specified in table 6;

TABLE 6 drugs and dosages to subjects

2. Dosage forms

(1) L-dopa was dissolved in water (3mg/mL) as a positive control solution for group 1 (for oral administration in group 1) and the administration volume was 2 mL/kg. The vehicle (negative control solution for group 2) was 30% ethanol (v/v) and the dosing volume was 1286. mu.L/kg. The solutions of the other test groups (groups 3-11) were freshly prepared daily.

(2) Groups 3-5 methods of preparation of test solutions: 37.75mg of drug E was dissolved in 10mL of 30% ethanol (v/v). This solution served as storage solution (2).

a. Test solution of group 5 drug E (high dose group): stock solution (2) was the test solution of group 5. The administration volume was 1,286. mu.L/kg.

b. Test solution for group 4 drug E (medium dose group): 3.00ml of the stock solution (2) was diluted to 9.00ml with 30% ethanol (v/v). This solution was the test solution of group 4. The administration volume is 1286 muL/kg;

c. test solution of group 3 drug E (low dose group): 1.00ml of the stock solution (2) was diluted to 9.00ml with 30% ethanol (v/v). This solution was the test solution of group 3. The administration volume is 1286 muL/kg;

(3) method of formulation of test solutions of group 6: 4.25mg of drug E and 176mg of drug F were dissolved in 10mL of 30% ethanol (v/v). This solution served as the test solution for group 6.

(4) Method of formulation of test solutions for group 7: 12.5mg of drug E and 176mg of drug F were dissolved in 10mL of 30% ethanol (v/v). This solution served as the test solution for group 7.

(5) Method of formulation of test solutions for group 8: 176mg of drug F was dissolved in 10mL of 30% ethanol (v/v). This solution served as the test solution for group 8.

(6) Method of formulation of test solutions of group 9: 4.25mg of drug E and 527mg of drug F were dissolved in 10mL of 30% ethanol (v/v). This solution served as the test solution for group 9.

(7) Method of formulation of test solutions for group 10: 12.5mg drug E and 527mg drug F were dissolved in 10mL 30% ethanol (v/v). This solution served as the test solution for group 10.

(8) Method of formulation of test solutions for group 11: 527mg of drug F was dissolved in 10mL of 30% ethanol (v/v). This solution served as the test solution for group 11.

3. One day prior to dosing, mice (positive control rats with L-dopa, as required by double-blind experiments) were shaved on their backs (near the neck and shoulders) with a small animal shaver. Rats were shaved as needed during the experiment to keep the back skin bare. On the day of administration, an aliquot (643 μ L/kg) of the formulation was applied to the exposed skin (between the neck and shoulders) of the animals at 9 a.m. intervals of 3cmx3cm squares, and repeated at 4 p.m.

4. Four weeks after surgery, all groups of rats began to receive treatment.

5. After 4 weeks of treatment, the spin test was performed.

Figure 9 is the residence time in the rotational test after 4 weeks of treatment (n-12). Fig. 10 is the rotation rate at which the rats dropped in the rotation test after 4 weeks of treatment (n-12).

The data for all batches (12/group) were combined and the positive control group (L-dopa, 6mg/kg, oral) showed no efficacy compared to the blank after 4 weeks of treatment, whereas all drug test groups showed strong efficacy compared to the blank after 4 weeks of treatment. Levodopa and dopamine caused nausea, vomiting, gastrointestinal bleeding, dyskinesia at peak dose, and functional deterioration at peak and trough dose, so that the positive control group of L-dopa, 6mg/kg, orally administered) showed no efficacy compared to the blank group. The transdermal administration of dopamine prodrug then slowly enters the animal and avoids dyskinesia at peak doses and functional degradation at peak and trough doses. Drug E (dopamine prodrug, 0.5mg/kg, group 3) the low dose group was more effective than the medium and high dose groups of drug E (1.5mg/kg and 4.5mg/kg, groups 4, 5). Higher doses may therefore cause side effects like L-dopa. Treatment with 20mg and 60mg/kg of drug F showed efficacy after four weeks compared to the blank and positive control groups. The therapeutic effect of 20mg/Kg of drug F (group 8) was similar to that of 60mg/Kg of drug F (group 11). This result may indicate that a 20mg/Kg dose is sufficient and that higher doses are not required. Drug E and drug F in combination (groups 6 and 9) were more effective than drug F (groups 8 and 11) or drug E (group 3) alone.

Example 36 therapeutic efficacy of drug G (S) -4- (2-amino-3- (heptan-4-yloxy) -3-oxopropyl) -1,2-phenylene ester hydrochloride) and drug H (4-acetoxy-2 ', 4' -difluoro- [1, 1 '-biphenyl ] -3-carboxylic acid 2- (dipropylamino) ethyl ester hydrochloride) on improving motor function deficits and reducing Neuglo-striatal neurodegeneration in the HDB model of Parkinson' S disease (PD) induced by 6-hydroxypolyamine

The subjects (Sprague-Dawley rats) were modeled as described in example 31, grouped and tested according to the following protocol.

1. The rats were randomly divided into 11 groups (n-12) and each group was dosed with the drug as specified in table 7;

TABLE 7 drug and dose received by test animals

2. Preparation

(1) L-dopa was dissolved in water (3mg/mL) as a positive control solution (oral) for group 1 at a dose volume of 2 mL/kg. The vehicle (solution of group 2 negative control group) was a 30% ethanol solution and the administration volume was 1,286. mu.L/kg. The test solutions of the other test groups (groups 3-11) were fresh daily.

(2) Test solution preparation method of groups 3-5: 50.33mg of drug G was dissolved in 10ml of 30% ethanol solution (v/v). This solution was stock solution (2).

a. Test solution of group 5 (high dose group) drug G: stock solution (2) was the test solution of group 5. The administration volume is 1286 muL/kg;

b. group 4 (medium dose group) test solution of drug G. 3.00ml of stock solution (2) was diluted to 9.00ml with 30% ethanol solution. This solution was the test solution of group 4. The administration volume is 1286 muL/kg;

c. group 3 (low dose group) test solution of drug G. 1.00ml of stock solution (2) was diluted to 9.00ml with 30% ethanol solution. This solution was the test solution of group 4. The administration volume is 1286 muL/kg;

(3) group 6 test solution preparation method: 5.67mg of drug G and 132mg of drug H were dissolved in 10ml of 30% ethanol solution (v/v). This solution was the test solution of group 6.

(4) Group 7 test solution preparation method: 16.67mg of drug G and 132mg of drug H were dissolved in 10ml of 30% ethanol solution (v/v). This solution was the test solution of group 7.

(5) Group 8 test solution preparation method: 132mg of drug H was dissolved in 10ml of 30% ethanol solution (v/v). This solution was the test solution of group 8.

(6) Group 9 test solution preparation method: 5.67mg of drug G and 395.5mg of drug H were dissolved in 10ml of 30% ethanol solution (v/v). This solution was the test solution of group 9.

(7) Set 10 test solution configuration method: 16.67mg of drug G and 395.5mg of drug H were dissolved in 10ml of 30% ethanol solution (v/v). This solution was the test solution of group 10.

(8) Group 11 test solution preparation method: 395.5mg of drug H was dissolved in 10ml of 30% ethanol solution (v/v). This solution was the test solution of group 11.

3. The day before dosing, mice were shaved on their upper back (near the neck and shoulders) using a small animal shaver (rats in a positive control group with L-dopa were included as required for a double-blind experiment). Rats were shaved again as necessary during the experiment to keep the skin exposed at the site of administration. On the day of administration, an aliquot (643 μ L/kg) of the formulation was applied to the exposed skin (between the neck and shoulders) of the animal in a 3cmx3cm square area at 9 a.m. and repeated 4 p.m.

4. At week 4 post-surgery, all groups of rats began to receive treatment.

5. After 4 weeks of treatment, the patients received the spin test.

Figure 11 is the residence time in the rotational test after 4 weeks of treatment (n-12). Fig. 12 is the rotation rate at which the rat falls in the rotation test after 4 weeks of treatment (n-12).

The data for all batches (12/group) were combined and the positive control group (L-dopa, 6mg/kg, oral) showed no efficacy after 4 weeks of treatment compared to the blank group, whereas all the test drug-treated groups showed strong efficacy after 4 weeks of treatment compared to the blank group. Levodopa can cause nausea, vomiting, gastrointestinal bleeding, dyskinesia at peak doses, and functional deterioration at peak and trough doses, so the positive control group (L-dopa, 6mg/kg, oral) showed no therapeutic effect compared to the blank group, while transdermal administration of a prodrug of L-dopa avoided dyskinesia at peak doses, and functional deterioration at peak and trough doses. Drug G (L-dopa prodrug, 0.67mg/kg, group 3) was more efficacious in the low dose group than in the medium and high dose groups (2mg/kg and 6mg/kg, groups 4, 5). Higher doses may cause side effects like L-dopa. Compared with the blank group and the positive control group, the treatment effect is shown after 15mg and 45mg/kg of the drug H is received for four weeks. 15mg/Kg of drug H (group 8) was similar in therapeutic effect to 45mg/Kg of drug H (group 11). This result indicates that a 15mg/Kg dose is sufficient and that higher doses are not required. Drug G and drug H in combination (groups 6 and 9) were more effective than drug H (groups 8 and 11) or drug G (group 3) administered alone.

Where multiple drugs (one or more high penetration compositions or other drugs) are administered to a subject in combination, each drug may be administered separately, or one or more drugs may be administered as separate drugs at substantially the same time (e.g., two or more drugs sprayed at substantially the same time without mixing prior to spraying), or one or more drugs may be mixed together prior to administration to a subject, or several of the above methods may be used together. The drugs may be administered in any possible order.

Example 37 efficacy of drug A (transdermal), drug B (transdermal), and entacapone (oral) for improving motor function deficits and reducing Neugolo-striatal neurodegeneration in the HDB model of Parkinson's Disease (PD) induced by 6-hydroxypolyamine

The subjects (Sprague-Dawley rats) were modeled as described in example 31, grouped and tested according to the following protocol.

1. The rats were randomly divided into 11 groups (n-12) and each group was dosed with the drug as specified in table 8;

TABLE 8 drug and dose received by test animals

2. Preparation

(1) L-dopa (3mg/mL) and entacapone (12.5mg/mL) were dissolved in 0.5% CMC-Na (sodium carboxymethyl cellulose) as a positive control solution (oral) for group 1 at an administration volume of 2 mL/kg. Entacapone dissolved in 0.5% CMC-Na (12.5mg/mL) is a catechol-O-methyl-translocase inhibitor for groups 2-11 (oral administration) at a volume of 2 mL/kg. The vehicle (negative control solution for group 2) was a 30% ethanol solution (v/v) and the administration volume was 1,286. mu.L/kg. The test solutions of the other test groups (transdermal, groups 3-11) were fresh daily.

(2) Set 3-5 methods of preparation of test solutions: 50.33mg of drug A was dissolved in 10mL of 30% ethanol solution (v/v). This solution was stock solution (2).

a. The test solution for group 5 (high dose group) drug a is the stock solution (2). The administration volume is 1,286 uL/kg;

b. test solution for group 4 (medium dose group) drug a: 3.00ml of stock solution (2) was diluted to 9.00ml with 30% ethanol (v/v). This solution was the test solution of group 4. The administration volume is 1,286 uL/kg;

c. test solution for group 3 (low dose group) drug a: 1.00ml of stock solution (2) was diluted to 9.00ml with 30% ethanol (v/v). This solution was the test solution of group 4. The administration volume is 1286 muL/kg;

(3) group 6 test solution preparation method: 5.67mg drug A and 264mg drug B were dissolved in 10mL 30% ethanol (v/v). This solution was the test solution of group 6.

(4) Group 7 test solution preparation method: 16.67mg drug A and 264mg drug B were dissolved in 10mL 30% ethanol (v/v). This solution was the test solution of group 7.

(5) Group 8 test solution preparation method: 264mg of drug B was dissolved in 10mL of 30% ethanol (v/v). This solution was the test solution of group 8.

(6) Group 9 test solution preparation method: 5.67mg drug A and 791mg drug B were dissolved in 10mL 30% ethanol (v/v). This solution was the test solution of group 9.

(7) Set 10 test solution configuration method: 16.67mg drug A and 791mg drug B were dissolved in 10mL 30% ethanol (v/v). This solution was the test solution of group 10.

(8) Group 11 test solution preparation method: 791mg of drug B was dissolved in 10mL of 30% ethanol (v/v). This solution was the test solution of group 11.

3. The day before dosing, mice were shaved on their upper back (near the neck and shoulders) using a small animal shaver (rats in a positive control group with L-dopa were included as required for a double-blind experiment). Rats were shaved again as necessary during the experiment to keep the skin exposed at the site of administration. On the day of administration, an aliquot (643. mu.L/kg) of the formulation was applied to the exposed skin (between the neck and shoulders) of the animal in 3cmx3cm squares, repeated 4 pm.

4. After 4 weeks of surgery, all groups of rats began to receive treatment.

5. After 4 weeks of treatment, the rats received a spin test.

Fig. 13 is the residence time in the rotational test after 4 weeks of treatment (n-12). Fig. 14 is the rotation rate at which the rats dropped in the rotation test after 4 weeks of treatment (n-12).

Entacapone is a catechol-O-methyltransferase inhibitor that prevents COMT from metabolizing L-dopa peripherally to 3-methoxy-4-hydroxy-L-amphetamine to avoid adverse L-dopa reactions. The results show that entacapone increased the efficacy of all L-dopa and L-dopa prodrug treatment groups (groups 1, 3, 4, 5, 6, 7, 9, 10) without changing the efficacy of the vehicle group and the aspirin prodrug group (groups 2, 8, 11).

Example 38 therapeutic effects of drug A (transdermal), drug B (transdermal), entacapone (oral) and carbidopa (oral) improve motor function deficits and reduce Neugo-striatal neurodegeneration in the HDB model of Parkinson's Disease (PD) induced by 6-hydroxypolyamine

The subjects (Sprague-Dawley rats) were modeled as described in example 31, grouped and tested according to the following protocol.

1. The rats were randomly divided into 11 groups (n-12) and each group was dosed with the drug as specified in table 9;

TABLE 9 drug and dose received by test animals

2. Preparation

(1) L-dopa (3mg/mL), entacapone (12.5mg/mL), and carbidopa (1.5mg/mL) were dissolved in 0.5% CMC-Na as a positive control solution (oral) for group 1 in an administration volume of 2 mL/kg. Entacapone (12.5mg/mL) and carbidopa (1.5mg/mL) dissolved in 0.5% CMC-Na was a solution of groups 2-11 (oral) administered in a volume of 2 mL/kg. The vehicle (negative control solution for group 2) was a 30% ethanol solution (v/v) and the administration volume was 1,286. mu.L/kg. The solutions of the other test groups (transdermal, groups 3-11) were fresh daily.

(2) Set 3-5 methods of preparation of test solutions: 50.33mg of drug A was dissolved in 10mL of 30% ethanol (v/v). This solution was stock solution (2).

a. Stock solution (2) was a test solution for group 5 (high dose group) drug a. The administration volume was 1286. mu.L/kg.

b. Configuration of group 4 (medium dose group) drug a test solution: 3.00ml of stock solution (2) was diluted to 9.00ml with 30% ethanol solution. This solution was the test solution of group 4. The administration volume was 1286. mu.L/kg.

c. Group 3 (low dose group) formulation of drug a test solution. 1.00ml of stock solution (2) was diluted to 9.00ml with 30% ethanol solution. This solution was the test solution of group 4. The administration volume was 1286. mu.L/kg.

(3) Group 6 test solution preparation method: 5.67mg drug A and 264mg drug B were dissolved in 10mL 30% ethanol (v/v). This solution was the test solution of group 6.

(4) Group 7 test solution preparation method: 16.67mg drug A and 264mg drug B were dissolved in 10mL 30% ethanol (v/v). This solution was the test solution of group 7.

(5) Group 8 test solution preparation method: 264mg of drug B was dissolved in 10mL of 30% ethanol (v/v). This solution was the test solution of group 8.

(6) Group 9 test solution preparation method: 5.67mg drug A and 791mg drug B were dissolved in 10mL 30% ethanol (v/v). This solution was the test solution of group 9.

(7) Set 10 test solution configuration method: 16.67mg drug A and 791mg drug B were dissolved in 10mL 30% ethanol (v/v). This solution was the test solution of group 10.

(8) Group 11 test solution preparation method: 791mg of drug B was dissolved in 10mL of 30% ethanol (v/v). This solution was the test solution of group 11.

3. The day before dosing, mice were shaved on their upper back (near the neck and shoulders) using a small animal shaver (rats in the positive control group with L-dopa were included due to the double blind experimental requirements). Rats were shaved again as necessary during the experiment to keep the skin exposed at the site of administration. On the day of administration, an aliquot (643. mu.L/kg) of the formulation was applied to the exposed skin (between the neck and shoulders) of the animal in 3cmx3cm squares, repeated 4 pm.

4. All groups of rats began to receive treatment 4 weeks after surgery.

5. Treated 4 weeks rats received a spin test.

Figure 15 is the residence time in the rotational test after 4 weeks of treatment (n-12). Fig. 16 is the rotation rate (n-12) at which the rats dropped in the rotation test after 4 weeks of treatment.

The combination of carbidopa and entacapone is better than the single use of carbidopa or entacapone. The results show that the combination of carbidopa and entacapone can increase the efficacy of all L-dopa and L-dopa prodrug treatment groups ((groups 1, 3, 4, 5, 6, 7, 9, 10), but the efficacy of the vehicle group and the aspirin prodrug group (groups 2, 8 and 11) was unchanged.

Example 39 treatment of Parkinson's disease and related disorders

A solution of 15mg of drug A and 30mg of drug B in 0.5ml of water is applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject as needed every 3 to 10 hours.

EXAMPLE 40 treatment of Parkinson's disease and related disorders

Solutions of 10mg drug A and 20mg drug B in 0.5ml water were applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject as needed at 3-10 hour intervals.

EXAMPLE 41 treatment of Parkinson's disease and related disorders

Example 42 treatment of Parkinson's disease and related disorders

Solutions of 30mg drug A and 50mg drug B dissolved in 0.5ml water were applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject as needed at 3-10 hour intervals.

Example 43 treatment of Parkinson's disease and related disorders

Solutions of 15mg drug A and 30mg drug B dissolved in 0.5ml water were applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject as needed at 3-10 hour intervals. Before or after the above solution is administered, a tablet containing 10mg carbidopa and/or inactive ingredients, e.g., cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose is orally administered to improve the effectiveness of transdermal therapy.

Example 44 treatment of Parkinson's disease and related disorders

Solutions of 20mg drug A and 40mg drug B dissolved in 0.5ml water were applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject as needed at 3-10 hour intervals. Before or after the above solution is administered, a tablet containing 15mg of carbidopa and/or inactive ingredients, e.g., cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose is orally administered to improve the effectiveness of transdermal therapy.

Example 45 treatment of Parkinson's disease and related disorders

Solutions of 15mg drug a and 30mg drug B dissolved in 0.5ml water were applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject every 3-10 hours. Before or after administration of the above solution, a tablet containing 15mg of carbidopa, 70mg of entacapone and/or inactive ingredients, e.g., cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose is orally administered to improve the effectiveness of transdermal therapy.

EXAMPLE 46 treatment of Parkinson's disease and related disorders

Solutions of 20mg drug a and 40mg drug B dissolved in 0.5ml water were applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject every 3-10 hours. Before or after administration of the above solution, a tablet containing 15mg of carbidopa, 100mg of entacapone and/or inactive ingredients, e.g., cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose is orally administered to improve the effectiveness of transdermal therapy.

EXAMPLE 47 treatment of Parkinson's disease and related Compounds

Solutions of 10mg drug C and 15mg drug D dissolved in 0.5ml water were applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject every 3-10 hours.

Example 49 treatment of Parkinson's disease and related disorders

Solutions of 30mg of drug C and 30mg of drug D dissolved in 0.5ml of water were applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject every 3 to 10 hours.

EXAMPLE 50 treatment of Parkinson's disease and related disorders

Solutions of 20mg drug C and 15mg drug D dissolved in 0.5ml water were applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject every 3-10 hours. Before or after the above solution is administered, a tablet containing 15mg of carbidopa and/or inactive ingredients, e.g., cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose is orally administered to improve the effectiveness of transdermal therapy.

Example 51 treatment of Parkinson's disease and related disorders

Solutions of 10mg drug C and 10mg drug D dissolved in 0.5ml water were applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject every 3-10 hours. Before or after administration of the above solution, a tablet containing 15mg of carbidopa, 100mg of entacapone and/or inactive ingredients, e.g., cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose is orally administered to improve the effectiveness of transdermal therapy.

Example 52 treatment of Parkinson's disease and related disorders

Solutions of 30mg drug C and 20mg drug D dissolved in 0.5ml water were applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject every 3-10 hours. Before or after administration of the above solution, a tablet containing 15mg of carbidopa, 70mg of entacapone and/or inactive ingredients, e.g., cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose is orally administered to improve the effectiveness of transdermal therapy.

Example 53 treatment of Parkinson's disease and related disorders

30mg of drug C and 25mg of drug D are dissolved in 0.5ml of water to prepare a (transdermal) solution which is applied to the skin of the neck, chest, back and/or any other part of the biological subject every 3 to 10 hours (transdermally). Before or after administration of the above solution, a tablet containing 10mg of carbidopa, 50mg of entacapone and/or inactive ingredients, e.g., cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose is orally administered to improve the effectiveness of transdermal therapy.

Example 54 treatment of Parkinson's disease and related disorders

Solutions of 10mg of drug E and 10mg of drug F dissolved in 0.5ml of water were applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject every 3 to 10 hours.

Example 55 treatment of Parkinson's disease and related disorders

Solutions of 20mg of drug E and 20mg of drug F dissolved in 0.5ml of water were applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject every 3 to 10 hours.

Example 56 treatment of Parkinson's disease and related disorders

Solutions of 5mg drug E and 10mg drug F dissolved in 0.5ml water were applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject every 3-10 hours.

Example 57 treatment of Parkinson's disease and related disorders

A solution of 10mg of drug G and 10mg of drug H dissolved in 0.5ml of water was applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject every 3 to 10 hours.

EXAMPLE 58 treatment of Parkinson's disease and related disorders

Solutions of 15mg drug G and 15mg drug H dissolved in 0.5ml water were applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject every 3-10 hours.

Example 59 treatment of Parkinson's disease and related disorders

Solutions of 20mg drug G and 15mg drug H dissolved in 0.5ml water were applied (transdermally) to the skin of the neck, chest, back and/or any other part of a biological subject every 3-10 hours.

EXAMPLE 60 treatment of Parkinson's disease and related disorders

Solutions of 20mg drug G and 15mg drug H dissolved in 0.5ml water were applied (transdermally) to the skin of the neck, chest, back and/or any other part of the biological subject every 3-10 hours. Before or after administration of the above solution, a tablet containing 10mg of carbidopa, 70mg of entacapone and/or inactive ingredients, e.g., cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose is orally administered to improve the effectiveness of transdermal therapy.

Example 61 treatment of Parkinson's disease and related disorders

A solution of 10mg of drug G and 10mg of drug H dissolved in 0.5ml of water is administered (transdermally) to the neck, chest, back and/or any other part of a biological subject every 3 to 10 hours. Before or after transdermal administration, tablets containing 10mg of carbidopa, 50mg of entacapone and/or inactive ingredients, e.g., cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose are administered orally to increase the effectiveness of the transdermal treatment.

Example 62 treatment of Parkinson's disease and related disorders

Solutions of 20mg drug G and 15mg drug H dissolved in 0.5ml water were administered (transdermally) to the neck, chest, back and/or any other part of the biological subject every 3-10 hours. Tablets containing 15mg of carbidopa, 100mg of entacapone and/or other inactive ingredients such as cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose are administered orally either before or after administration of the above solutions to increase the effectiveness of transdermal therapy.

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Novel high-penetration medicine for treating Parkinson's disease and medicine composition thereof