Prevention or treatment of Parkinson's disease

Abstract

Disclosed is a prophylactic or therapeutic drug for Parkinson's disease, which comprises a trisulfide compound and is characterized by being administered in combination with a drug that is used for a dopamine supplementation therapy.

Description

[Technical Field]

[0001] This invention relates to the prevention or treatment of Parkinson's disease. [Background technology]

[0002] Parkinson's disease is a neurodegenerative disease characterized by motor symptoms such as bradykinesia, tremor, and muscle rigidity, caused by selective damage to dopamine-producing neurons in the substantia nigra. The basic treatment for Parkinson's disease is dopamine replacement therapy. However, there are therapeutic challenges, such as the need to gradually increase the amount of medication administered to achieve therapeutic effects and the occurrence of side effects from dopamine replacement therapy, and the development of new therapeutic drugs is highly anticipated.

[0003] In recent years, it has been reported that an imbalance in intracellular iron ion concentration leads to mitochondrial dysfunction and increased production of reactive oxygen species, resulting in abnormal cellular function (Non-Patent Literature 1). Furthermore, ferroptosis, a phenomenon in which lipid oxidation reactions involving iron ions are enhanced when the intracellular redox balance is disrupted, ultimately leading to cell death due to the breakdown of cell membrane function, has attracted attention.

[0004] On the other hand, there is growing concern that infectious diseases may exacerbate health and social impairments originating from other illnesses. In Parkinson's disease, it has been reported that infection with the novel coronavirus (SARS-CoV-2) can intensify oxidative stress and worsen damage to dopamine-expressing neurons (Non-Patent Literature 2).

[0005] It has been reported that oxidation reactions accelerated in the presence of iron ions are deeply involved in the pathogenesis and progression of Parkinson's disease. Dopamine, a neurotransmitter, has a catechol structure and is inherently prone to oxidation, but it has been pointed out that oxidation is further accelerated in the presence of iron ions. Oxidation of dopamine is a cause of dopamine deficiency, and it has also been suggested that oxidized dopamine produced in the body polymerizes to form insoluble neuromelamine, which may be involved in the pathogenesis. Furthermore, it has been pointed out that oxidized dopamine leads to the degeneration of α-synuclein and the formation of its aggregates, which is involved in the pathogenesis and exacerbation of Parkinson's disease (Non-Patent Literature 3).

[0006] Polysulfides such as glutathione trisulfide (GSSSG) are converted in vivo to active sulfur species such as glutathione persulfide (GSSH). These active sulfur species have been reported to possess potent antioxidant properties and potentially have physiological functions such as anti-aging (e.g., Non-Patent Documents 4 and 5). Furthermore, methods for producing GSSG are known, such as the method described in Patent Document 1.

[0007] Drugs used for Parkinson's disease are ideally delivered to the dopamine neurons in the substantia nigra and striatum of the brain with high efficiency. Nasal administration is attracting attention as a method of administration that relatively increases the concentration in the brain because it can avoid so-called first-pass metabolism and deliver the drug directly to the brain (Non-Patent Literature 6). On the other hand, since the drug concentration that can be administered via nasal administration is limited, it is desirable that the drug used for nasal administration be administered as a solution and is non-irritating, considering the reduction of the burden on the patient taking medication. For example, compounds that are highly water-soluble and do not have ionizable functional groups, or are ionically neutral, are presumed to be suitable drugs. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2018 / 117186

Patent document 2

Patent Document 3

Patent document 4

Non-licensed literature

[0009] [Non-licensed document 1] Gille and Reichmann, "Iron-dependent functions of mitochondria--relation to neurodegeneration", J Neural Transm (Vienna), 2011, 118(3):349-59. [Non-licensed document 2] Smeyne et al., “COVID-19 infection enhances susceptibility to oxidative-stress induced parkinsonism” Mov Disord. 2022 May 17. doi: 10.1002 / mds.29116. Online ahead of print. [Non-licensed document 3] Burbulla et al., "Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease", Science, 2017, 22;357(6357):1255-1261.

Non-licensed Document 4

Non-licensed Document 5

[0010] No drugs are known that can suppress the oxidation of dopamine accelerated in the presence of iron ions, thereby suppressing dopamine deficiency. The inventors of this invention hypothesize that combining a compound with such an effect with dopamine replacement therapy may enhance the therapeutic effect of dopamine replacement therapy, reduce the dosage of drugs used in dopamine replacement therapy, and improve the patient's quality of life by reducing side effects. In other words, the objective of this invention is to search for a compound with such an effect and provide a preventive or therapeutic agent for Parkinson's disease. [Means for solving the problem]

[0011] The inventors have discovered that glutathione trisulfide, lipoic acid trisulfide, pantethine trisulfide, and N,N'-diacetyl-L-cysteine ​​trisulfide inhibit the oxidation reaction of dopamine, which is accelerated in the presence of iron ions, and have completed the present invention. The present invention provides the following [1] to

[64] . [1] A prophylactic or therapeutic agent for Parkinson's disease containing a trisulfide compound, characterized by being administered in combination with a drug used in dopamine replacement therapy, wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof, formula (1) [ka] Compound represented by the formula [wherein X is -OR 1 or -NR 2 R 3 Show, R 1 R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. 2 and R 3 Each of these independently represents a hydrogen atom or a C1-C6 alkyl group, and the alkyl group may have one or more substituents selected from the group consisting of an amino group and a carboxyl group. ] (hereinafter also referred to as compound (1)), a pharmaceutically acceptable salt thereof or a cyclodextrin inclusion complex thereof, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof, which are prophylactic or therapeutic agents. [2] A prophylactic or therapeutic agent comprising a drug used in dopamine replacement therapy, characterized by being administered in combination with a trisulfide compound, wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof, compound (1), a pharmaceutically acceptable salt thereof or a cyclodextrin inclusion complex thereof, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof. [3] The preventive or therapeutic agent according to [1] or [2], wherein the trisulfide compound and the drug used for dopamine replacement therapy are administered simultaneously or separately. [4] A prophylactic or therapeutic agent for Parkinson's disease comprising a trisulfide compound and a drug used in dopamine replacement therapy, wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof, compound (1), a pharmaceutically acceptable salt thereof or a cyclodextrin inclusion complex thereof, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof. [5] The prophylactic or therapeutic agent according to any one of [1] to [4], wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof. [6] The prophylactic or therapeutic agent according to [5], wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, amino acid salts of glutathione trisulfide, and alkali metal salts of glutathione trisulfide. [7] The prophylactic or therapeutic agent according to [5], wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, arginine salt of glutathione trisulfide, and sodium salt of glutathione trisulfide. [8] The prophylactic or therapeutic agent according to any one of [1] to [4], wherein the trisulfide compound is lipoic acid trisulfide or a pharmaceutically acceptable salt thereof. [8-2] The prophylactic or therapeutic agent according to any one of [1] to [4], wherein the trisulfide compound is pantethine trisulfide or a pharmaceutically acceptable salt thereof. [8-3] The prophylactic or therapeutic agent according to any one of [1] to [4], wherein the trisulfide compound is N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof. [9] The preventive or therapeutic agent according to any one of [1] to [8-4], wherein the drug used in the dopamine replacement therapy above comprises at least one selected from the group consisting of dopamine precursors, dopa decarboxylase inhibitors, catechol-O-methyltransferase inhibitors, monoamine oxidase inhibitors, dopamine release enhancers, and dopamine agonists.

[10] A kit for the prevention or treatment of Parkinson's disease, comprising a preparation containing a trisulfide compound and a preparation containing a drug used in dopamine replacement therapy, wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof, compound (1), a pharmaceutically acceptable salt thereof or a cyclodextrin inclusion complex thereof, or pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof.

[11] The kit according to

[10] , wherein a preparation containing the above trisulfide compound and a preparation containing the drug used for dopamine replacement therapy are administered simultaneously or separately.

[12] The kit according to

[10] or

[11] , wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof.

[13] The kit according to

[12] , wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, amino acid salts of glutathione trisulfide, and alkali metal salts of glutathione trisulfide.

[14] The kit according to

[12] , wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, arginine salt of glutathione trisulfide, and sodium salt of glutathione trisulfide.

[15] The kit according to

[10] or

[11] , wherein the trisulfide compound is lipoic acid trisulfide or a pharmaceutically acceptable salt thereof. [15-2] The kit according to

[10] or

[11] , wherein the trisulfide compound is pantethine trisulfide or a pharmaceutically acceptable salt thereof. [15-3] The kit according to

[10] or

[11] , wherein the trisulfide compound is N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof.

[16] A kit according to any one of

[10] to [15-3], wherein the drug used in the dopamine replacement therapy is selected from the group consisting of dopamine precursors, dopa decarboxylase inhibitors, catechol-O-methyltransferase inhibitors, monoamine oxidase inhibitors, dopamine release enhancers, and dopamine agonists.

[17] A method for the prevention or treatment of Parkinson's disease, comprising administering a trisulfide compound and a drug used in dopamine replacement therapy or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof, compound (1), a pharmaceutically acceptable salt thereof or a cyclodextrin inclusion complex thereof, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof.

[18] The method according to

[17] , wherein the trisulfide compound and a drug used in dopamine replacement therapy are administered simultaneously or separately.

[19] The method according to

[17] or

[18] , wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof.

[20] The method according to

[19] , wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, amino acid salts of glutathione trisulfide, and alkali metal salts of glutathione trisulfide.

[21] The method according to

[19] , wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, arginine salts of glutathione trisulfide, and sodium salts of glutathione trisulfide.

[22] The method according to

[17] or

[18] , wherein the trisulfide compound is lipoic acid trisulfide or a pharmaceutically acceptable salt thereof. [22-2] The method according to

[17] or

[18] , wherein the trisulfide compound is pantethine trisulfide or a pharmaceutically acceptable salt thereof. [22-3] The method according to

[17] or

[18] , wherein the trisulfide compound is N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof.

[23] The method according to any one of

[17] to [22-3], wherein the drug used in the dopamine replacement therapy is selected from the group consisting of dopamine precursors, dopa decarboxylase inhibitors, catechol-O-methyltransferase inhibitors, monoamine oxidase inhibitors, dopamine release enhancers, and dopamine agonists.

[24] A drug used in dopamine replacement therapy for the prevention or treatment of Parkinson's disease, characterized by being administered in combination with a trisulfide compound, wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof, compound (1), a pharmaceutically acceptable salt thereof or a cyclodextrin inclusion complex thereof, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof.

[25] The drug used for dopamine replacement therapy according to

[24] , wherein the trisulfide compound and the drug used for dopamine replacement therapy are administered simultaneously or separately.

[26] A drug used for dopamine replacement therapy for use according to

[24] or

[25] , wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof.

[27] The drug used for dopamine replacement therapy for use according to

[26] , wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, amino acid salts of glutathione trisulfide, and alkali metal salts of glutathione trisulfide.

[28] The drug used for dopamine replacement therapy for use according to

[26] , wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, arginine salt of glutathione trisulfide, and sodium salt of glutathione trisulfide.

[29] A drug used for dopamine replacement therapy for use according to

[24] or

[25] , wherein the trisulfide compound is lipoic acid trisulfide or a pharmaceutically acceptable salt thereof. [29-2] A drug used for dopamine replacement therapy for use according to

[24] or

[25] , wherein the trisulfide compound is pantethine trisulfide or a pharmaceutically acceptable salt thereof. [29-3] A drug used for dopamine replacement therapy for use according to

[24] or

[25] , wherein the trisulfide compound is N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof.

[30] A drug used in dopamine replacement therapy according to any one of

[24] to [29-3], wherein the drug used in the dopamine replacement therapy comprises at least one selected from the group consisting of dopamine precursors, dopa decarboxylase inhibitors, catechol-O-methyltransferase inhibitors, monoamine oxidase inhibitors, dopamine release enhancers, and dopamine agonists.

[31] A trisulfide compound for use in the prevention or treatment of Parkinson's disease, characterized by being administered in combination with a drug used in dopamine replacement therapy, wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof, compound (1), a pharmaceutically acceptable salt thereof or a cyclodextrin inclusion complex thereof, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof.

[32] The trisulfide compound for use according to

[31] , wherein the preparation containing the above trisulfide compound and the preparation containing the drug used for dopamine replacement therapy are administered simultaneously or separately.

[33] The trisulfide compound for use according to

[31] or

[32] , wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof.

[34] The trisulfide compound for use according to

[33] , wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, amino acid salts of glutathione trisulfide, and alkali metal salts of glutathione trisulfide.

[35] The trisulfide compound for use according to

[33] , wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, arginine salt of glutathione trisulfide, and sodium salt of glutathione trisulfide.

[36] The trisulfide compound for use according to

[31] or

[32] , wherein the trisulfide compound is lipoic acid trisulfide or a pharmaceutically acceptable salt thereof. [36-2] The trisulfide compound for use according to

[31] or

[32] , wherein the trisulfide compound is pantethine trisulfide or a pharmaceutically acceptable salt thereof. [36-3] The trisulfide compound for use according to

[31] or

[32] , wherein the trisulfide compound is N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof.

[37] A trisulfide compound for use according to any one of

[31] to [36-3], wherein the drug used in the dopamine replacement therapy is selected from the group consisting of dopamine precursors, dopa decarboxylase inhibitors, catechol-O-methyltransferase inhibitors, monoamine oxidase inhibitors, dopamine release enhancers, and dopamine agonists.

[38] A combination of a trisulfide compound and a drug used in dopamine replacement therapy for use in the prevention or treatment of Parkinson's disease, wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof, compound (1), a pharmaceutically acceptable salt thereof or a cyclodextrin inclusion complex thereof, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof.

[39] The combination according to

[38] , wherein a preparation containing the above trisulfide compound and a preparation containing the drug used for dopamine replacement therapy are administered simultaneously or separately.

[40] The combination according to

[38] or

[39] , wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof.

[41] The combination according to

[40] , wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, amino acid salts of glutathione trisulfide, and alkali metal salts of glutathione trisulfide.

[42] The combination according to

[40] , wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, arginine salt of glutathione trisulfide, and sodium salt of glutathione trisulfide.

[43] The combination according to

[38] or

[39] , wherein the trisulfide compound is lipoic acid trisulfide or a pharmaceutically acceptable salt thereof. [43-2] The combination according to

[38] or

[39] , wherein the trisulfide compound is pantethine trisulfide or a pharmaceutically acceptable salt thereof. [43-3] The combination according to

[38] or

[39] , wherein the trisulfide compound is N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof.

[44] A combination of any of the following

[38] to [43-3] in which the drugs used in the dopamine replacement therapy include at least one selected from the group consisting of dopamine precursors, dopa decarboxylase inhibitors, catechol-O-methyltransferase inhibitors, monoamine oxidase inhibitors, dopamine release enhancers, and dopamine agonists.

[45] Use of a drug used in dopamine replacement therapy for the manufacture of a drug for the prevention or treatment of Parkinson's disease, characterized by being administered in combination with a trisulfide compound, wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof, compound (1), a pharmaceutically acceptable salt thereof or a cyclodextrin inclusion complex thereof, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof.

[46] The use according to

[45] , wherein the preparation containing the trisulfide compound and the preparation containing the drug used for dopamine replacement therapy are administered simultaneously or separately.

[47] The use according to

[45] or

[46] , wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof.

[48] ​​The use according to

[47] , wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, amino acid salts of glutathione trisulfide, and alkali metal salts of glutathione trisulfide.

[49] The use according to

[47] , wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, arginine salt of glutathione trisulfide, and sodium salt of glutathione trisulfide.

[50] The use according to

[45] or

[46] , wherein the trisulfide compound is lipoic acid trisulfide or a pharmaceutically acceptable salt thereof. [50-2] The use according to

[45] or

[46] , wherein the trisulfide compound is pantethine trisulfide or a pharmaceutically acceptable salt thereof. [50-3] The use according to

[45] or

[46] , wherein the trisulfide compound is N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof.

[51] The use according to any one of

[45] to [50-3], wherein the drug used in the dopamine replacement therapy comprises at least one selected from the group consisting of dopamine precursors, dopa decarboxylase inhibitors, catechol-O-methyltransferase inhibitors, monoamine oxidase inhibitors, dopamine release enhancers, and dopamine agonists.

[52] Use of a trisulfide compound for the manufacture of a drug for the prevention or treatment of Parkinson's disease, characterized by being administered in combination with a drug used in dopamine replacement therapy, wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof, compound (1), a pharmaceutically acceptable salt thereof or a cyclodextrin inclusion complex thereof, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof.

[53] The use according to

[52] , wherein the preparation containing the trisulfide compound and the preparation containing the drug used for dopamine replacement therapy are administered simultaneously or separately.

[54] The use according to

[52] or

[53] , wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof.

[55] The use according to

[54] , wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, amino acid salts of glutathione trisulfide, and alkali metal salts of glutathione trisulfide.

[56] The use according to

[54] , wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, arginine salt of glutathione trisulfide, and sodium salt of glutathione trisulfide.

[57] The use according to

[52] or

[53] , wherein the trisulfide compound is lipoic acid trisulfide or a pharmaceutically acceptable salt thereof. [57-2] The use according to

[52] or

[53] , wherein the trisulfide compound is pantethine trisulfide or a pharmaceutically acceptable salt thereof. [57-3] The use according to

[52] or

[53] , wherein the trisulfide compound is N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof.

[58] Use according to any one of

[52] to [57-3], wherein the drug used in the dopamine replacement therapy above comprises at least one selected from the group consisting of dopamine precursors, dopa decarboxylase inhibitors, catechol-O-methyltransferase inhibitors, monoamine oxidase inhibitors, dopamine release enhancers, and dopamine agonists.

[59] Use of a combination of a drug used in dopamine replacement therapy and a trisulfide compound for the manufacture of a drug for the prevention or treatment of Parkinson's disease, wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt or compound (1), a pharmaceutically acceptable salt thereof or a cyclodextrin inclusion complex thereof, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof.

[60] The use according to

[59] , wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof.

[61] The use according to

[60] , wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, amino acid salts of glutathione trisulfide, and alkali metal salts of glutathione trisulfide.

[62] The use according to

[60] , wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, arginine salt of glutathione trisulfide, and sodium salt of glutathione trisulfide.

[63] The use according to

[59] , wherein the trisulfide compound is lipoic acid trisulfide or a pharmaceutically acceptable salt thereof. [63-2] The use according to

[59] , wherein the trisulfide compound is pantethine trisulfide or a pharmaceutically acceptable salt thereof. [63-3] The use according to

[59] , wherein the trisulfide compound is N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof.

[64] Use according to any one of

[59] to [63-3], wherein the drug used in the dopamine replacement therapy above comprises at least one selected from the group consisting of dopamine precursors, dopa decarboxylase inhibitors, catechol-O-methyltransferase inhibitors, monoamine oxidase inhibitors, dopamine release enhancers, and dopamine agonists. [Effects of the Invention]

[0012] According to the present invention, it may be possible to enhance the therapeutic effect of dopamine replacement therapy and reduce the dosage of drugs used in dopamine replacement therapy, thereby improving the patient's quality of life by reducing side effects. [Brief explanation of the drawing]

[0013] [Figure 1] Figure 1 is a graph showing that the oxidation of dopamine, which is accelerated in the presence of iron ions, is suppressed by glutathione trisulfide. [Figure 2]Figure 2 is a graph showing that the oxidation of dopamine, which is accelerated in the presence of iron ions, is suppressed by lipoic acid trisulfide. [Figure 3] Figure 3 is a graph showing that the oxidation of dopamine, which is accelerated in the presence of iron ions, is suppressed by pantethine trisulfide. [Figure 4] Figure 4 is a graph showing that the oxidation of dopamine, which is accelerated in the presence of iron ions, is suppressed by N,N'-diacetyl-L-cysteine ​​trisulfide. [Modes for carrying out the invention]

[0014] The present invention will be described in detail below, but the present invention is not limited to the following embodiments.

[0015] The preventive or therapeutic agent and the preventive or therapeutic method of the present invention may be administered to or applied to humans.

[0016] The trisulfide compounds used in the preventive or therapeutic agents of the present invention are glutathione trisulfide or a pharmaceutically acceptable salt thereof, compound (1), a pharmaceutically acceptable salt thereof, or cyclodextrin inclusion complexes thereof, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof. Glutathione trisulfide is represented by formula (2). Pantethine trisulfide is represented by formula (2A). N,N'-diacetyl-L-cysteine ​​trisulfide is represented by formula (2B). [ka]

[0017] In the present invention, examples of pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; salts with organic acids such as acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid; salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with amino acids such as arginine.

[0018] Pharmaceutically acceptable salts of glutathione trisulfide and pantethine trisulfide are preferably amino acid salts or alkali metal salts, and more preferably arginine salts or sodium salts. Pharmaceutically acceptable salts of compound (1) are preferably salts with alkali metals, and more preferably sodium salts.

[0019] Glutathione trisulfide or a pharmaceutically acceptable salt thereof, compound (1) or a pharmaceutically acceptable salt thereof, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine trisulfide or a pharmaceutically acceptable salt thereof may have polymorphic crystal forms, but is not limited to any crystal form, and may be a single substance in any crystal form or a mixture thereof. In addition, glutathione trisulfide or a pharmaceutically acceptable salt thereof, compound (1) or a pharmaceutically acceptable salt thereof, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine trisulfide or a pharmaceutically acceptable salt thereof also includes amorphous forms. Glutathione trisulfide or a pharmaceutically acceptable salt thereof, compound (1) or a pharmaceutically acceptable salt thereof, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine trisulfide or a pharmaceutically acceptable salt thereof includes anhydrates and solvates (particularly hydrates). Glutathione trisulfide or a pharmaceutically acceptable salt thereof, compound (1) or a pharmaceutically acceptable salt thereof, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or N,N'-diacetyl-L-cysteine trisulfide or a pharmaceutically acceptable salt thereof may be a co-crystal with an amino acid (e.g., arginine).

[0020] In one embodiment, compound (1) is represented by formula (3)

Chemical Formula

Chemical Formula

[0021] Compound (1) is, in another embodiment, formula (5) [ka] A compound represented by the formula [wherein R 2 and R 3 Each of these independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group may have one or more substituents selected from the group consisting of an amino group and a carboxyl group. 1 and R 2 R may be a hydrogen atom, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or an alkyl group. These alkyl groups may have substituents on one or both of an amino group and a carboxyl group. 1 and R 2 R may be, for example, a group represented by formula (6) (where * indicates a bond). A specific example of a compound represented by formula (5) is, for example, R 2 and R 3 Both are compounds with hydrogen atoms, R 2 is a hydrogen atom and R 3 Examples of compounds in which the group is represented by formula (6) include those in which the group is represented by formula (6). [ka]

[0022] The compound represented by formula (5) can be produced by a step (1) of oxidizing the compound represented by formula (5a) with an oxidizing agent to obtain a sulfoxide compound, and a step (2) of reacting the obtained sulfoxide compound with a sulfur source. [ka] [In the formula, R 1 and R 2Each of these is independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group may have one or more substituents selected from the group consisting of amino groups and carboxyl groups.

[0023] The above manufacturing method may also involve carrying out steps 1 and 2 in a one-pot reaction without isolating the sulfoxide compound.

[0024] The solvent used in step 1 is not particularly limited, as long as it dissolves the compound represented by formula (5a) and the oxidizing agent and does not inhibit the oxidation reaction. Examples of such solvents include water, aqueous sulfuric acid solution, aqueous ethanol solution, and aqueous acetonitrile solution, with water being preferred. The amount of solvent used in step 1 can be 1 mL to 500 mL per 1 g of the compound represented by formula (5a), and is preferably 10 mL to 20 mL.

[0025] Examples of oxidizing agents used in step 1 include potassium peroxymonosulfate (sold under trade names such as Oxone®), peracetic acid, hydrogen peroxide, and sodium periodate. Hydrogen peroxide may be used together with a catalytic amount of methyltrioxorenium. From the viewpoint of safety and cost, potassium peroxymonosulfate is a preferred oxidizing agent. The amount of oxidizing agent used can be 0.8 to 2.0 equivalents, preferably 1.0 to 1.3 equivalents, per equivalent of the compound represented by formula (5a).

[0026] The reaction temperature in step 1 can be -20°C to 30°C, preferably -5°C to 5°C.

[0027] The reaction time in step 1 can be 5 minutes to 24 hours, preferably 0.5 hours to 2 hours.

[0028] The solvent used in step 2 is not particularly limited, as long as it dissolves the sulfoxide compound and the sulfur source and does not inhibit the subsequent reaction. Examples of such solvents include water, aqueous sulfuric acid solution, aqueous ethanol solution, and aqueous acetonitrile solution, with water being preferred. The amount of solvent used in step 2 can be 1 mL to 500 mL per 1 g of sulfoxide compound, and is preferably 10 mL to 20 mL.

[0029] Examples of sulfur sources used in step 2 include sodium sulfide, potassium sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide, and hydrogen sulfide. The amount of sulfur source used can be 0.5 to 4.0 equivalents per equivalent of the sulfoxide compound, preferably 0.9 to 1.2 equivalents.

[0030] The reaction temperature in step 2 can be -20°C to 30°C, preferably -5°C to 25°C.

[0031] The reaction time in step 2 can be 10 minutes to 2 days, preferably 0.5 hours to 2 hours.

[0032] When steps 1 and 2 are carried out in a one-pot reaction, examples of reaction solvents include water, aqueous sulfuric acid solution, aqueous ethanol solution, and aqueous acetonitrile solution, preferably water, and the amount of solvent can be 1 mL to 500 mL per 1 g of the compound represented by formula (5a), preferably 10 mL to 20 mL. Examples of oxidizing agents used include potassium peroxymonosulfate, peracetic acid, hydrogen peroxide (which may be used together with a catalytic amount of methyltrioxorenium), and sodium periodate, preferably potassium peroxymonosulfate, and the amount of oxidizing agent used can be 0.8 equivalents to 2.0 equivalents per 1 equivalent of the compound represented by formula (5a), preferably 1.0 equivalent to 1.3 equivalents. Examples of sulfur sources that can be used include sodium sulfide, potassium sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide, and hydrogen sulfide. The amount of sulfur source used can be 0.5 to 4.0 equivalents, preferably 0.9 to 1.2 equivalents, per equivalent of the compound represented by formula (5a). The reaction temperature can be -20°C to 30°C, preferably -5°C to 25°C. The reaction time can be 15 minutes to 2 days, preferably 1 to 4 hours.

[0033] In addition to steps 1 and 2, the process may optionally include steps to protect functional groups such as hydroxyl groups, carbonyl groups, amino groups, and carboxyl groups, and steps to deprotect the protected functional groups. Protecting groups and protection / deprotection reactions for these functional groups are well known to those skilled in the art, and appropriate protecting groups and protection / deprotection reactions can be selected by referring to "Greene's Protective Groups in Organic Synthesis," etc.

[0034] The compound represented by formula (5a) is lipoic acid and NHR 2 R 3It can be produced by condensation. Examples of solvents for the condensation reaction include dichloromethane, chloroform, and tetrahydrofuran, with tetrahydrofuran being preferred. The amount of solvent can be 1 mL to 200 mL per 1 g of the compound represented by formula (5a), preferably 3 mL to 35 mL. Examples of condensing agents to be used include 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and its salts, N,N'-dicyclohexylcarbodiimide (DCC), and diisopropylcarbodiimide (DIC) (N-hydroxysuccinimide (NHS) and 1-hydroxybenzotriazole (HOBt) may be used as additives). The amount of condensing agent used can be 0.8 equivalents to 2.0 equivalents per 1 equivalent of the compound represented by formula (5a), preferably 1.0 equivalent to 1.5 equivalents. The reaction temperature can be -10°C to 40°C, preferably 15°C to 25°C. The reaction time can be 1 hour to 3 days, preferably 1 hour to 24 hours.

[0035] The compound represented by formula (5) is lipoic acid trisulfide and NHR 2 R 3 It can also be manufactured by condensation. The condensation conditions are the same as described above.

[0036] R 1 The compound represented by formula (3), in which the alkyl group has 1 to 6 carbon atoms, can be produced by a step (1) of oxidizing the compound represented by formula (3a) with an oxidizing agent to obtain a sulfoxide compound, and a step (2) of reacting the obtained sulfoxide compound with a sulfur source. The reaction conditions are the same as described above. [ka] [In the formula, R 1 This represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

[0037] The compound represented by formula (3a) is lipoic acid and R 1It can be manufactured by condensing OH groups. The process is the same as described above.

[0038] R 1 Compounds represented by formula (3), in which is an alkyl group having 1 to 6 carbon atoms, include lipoic acid trisulfide and R 1 It can also be manufactured by condensing OH groups. The condensation conditions are the same as described above.

[0039] Cyclodextrin may be α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or derivatives thereof. Here, "derivative" means that at least one hydrogen atom of the hydroxyl group of each cyclodextrin is substituted with an alkyl group or sugar which may have substituents. Examples of cyclodextrin derivatives that can be used include methyl-α-cyclodextrin, methyl-β-cyclodextrin, methyl-γ-cyclodextrin, dimethyl-α-cyclodextrin, dimethyl-β-cyclodextrin, dimethyl-γ-cyclodextrin, hydroxyethyl-α-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, glucosyl-γ-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and the like.

[0040] A cyclodextrin inclusion complex can be produced by the following steps: dissolving cyclodextrin in a solvent (step a), adding compound (1) or a pharmaceutically acceptable salt thereof to the resulting solution and stirring (step b), and filtering the stirred solution, washing it with the same solvent used in step a, freezing the filtrate, and freeze-drying it (step c). The filtration and washing steps in step c may be omitted.

[0041] The solvent used in step a is preferably water.

[0042] The amount of solvent used in step a can be 1 to 350 ml per 1 g of cyclodextrin, preferably 1 to 80 ml.

[0043] In step b, the mass ratio of cyclodextrin to compound (1) or a pharmaceutically acceptable salt thereof can be 2 to 20, preferably 5 to 16.5.

[0044] The stirring temperature in step b can be 20-50°C, and may be room temperature.

[0045] The stirring time in step b can be 0.25 to 40 hours, preferably 2 to 35 hours.

[0046] In step b, after adding compound (1) or a pharmaceutically acceptable salt thereof, the same solvent used in step a may be added before stirring. In this case, the amount of solvent can be 0 to 30 ml per 1 g of cyclodextrin, preferably 0 to 20 ml.

[0047] The amount of solvent used in step c can be 0 to 150 ml per 1 g of cyclodextrin, preferably 0 to 20 ml.

[0048] The freezing temperature in step c can be -30 to -20°C, preferably -20°C.

[0049] The freezing time in step c can be 10 to 50 hours.

[0050] The freeze-drying in step c can be carried out at an absolute pressure of 20 to 100 Pa and an ambient temperature of 10 to 40°C, preferably 20°C.

[0051] The freeze-drying period in step c can be 1 to 5 days.

[0052] Pantethine trisulfide or a pharmaceutically acceptable salt thereof can be produced by the method described in Patent Document 3.

[0053] N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof can be produced by the method described in Patent Document 4.

[0054] Regarding drugs used in dopamine replacement therapy, for example, the "Parkinson's Disease Treatment Guidelines 2018" (Igaku-Shoin), supervised by the Japanese Society of Neurology, can be consulted. In one embodiment, the drugs used in dopamine replacement therapy include at least one selected from the group consisting of dopamine precursors, dopa decarboxylase inhibitors, catechol-O-methyltransferase (COMT) inhibitors, monoamine oxidase (MAOB) inhibitors, dopamine release enhancers, and dopamine agonists. Examples of dopamine precursors include levodopa (L-dopa). Examples of dopa decarboxylase inhibitors include carbidopa and benserazide. Examples of COMT inhibitors include entacapone. Examples of MAOB inhibitors include safinamide, selegiline, and rasagiline. Examples of dopamine release enhancers include amantadine. Examples of dopamine agonists include cabergoline, bromocriptine, pergolide, talipexole, pramipexole, ropinirole, rotigotine, and apomorphine. These drugs may also be in the form of pharmaceutically acceptable salts, and these drugs or their pharmaceutically acceptable salts may be crystalline or amorphous, and may be anhydrous or solvate (especially hydrate).

[0055] Specific examples of combinations of two or more drugs used in dopamine replacement therapy include the combination of a dopamine precursor and a dopa decarboxylase inhibitor (e.g., levodopa and carbidopa, levodopa and benserazide), the combination of a dopamine precursor, a dopa decarboxylase inhibitor, and a COMT inhibitor (e.g., levodopa, carbidopa, and entacapone), the combination of a dopamine precursor and a dopamine agonist (e.g., levodopa and talipexole, levodopa and cabergoline, levodopa and ropinirole), and the combination of a dopamine precursor and a MAOB inhibitor (e.g., levodopa and selegiline).

[0056] In the present invention, "administered in combination" or "combined use" means using active ingredients in combination, and includes (1) an embodiment in which the drug used in dopamine replacement therapy and the trisulfide compound are administered as a single formulation, and (2) an embodiment in which the drug used in dopamine replacement therapy and the trisulfide compound are administered simultaneously or separately with a time difference as separate formulations. In the case of (2), the drug used in dopamine replacement therapy may be administered first, or the trisulfide compound may be administered first. Furthermore, in the case of (2), any of the following may be used: (i) the drug used in dopamine replacement therapy and the trisulfide compound are formulated separately and administered simultaneously via the same route of administration; (ii) the drug used in dopamine replacement therapy and the trisulfide compound are formulated separately and administered separately with a time difference via the same route of administration; (iii) the drug used in dopamine replacement therapy and the trisulfide compound are formulated separately and administered simultaneously via different routes of administration (administered from different sites in the same patient); or (iv) the drug used in dopamine replacement therapy and the trisulfide compound are formulated separately and administered separately with a time difference via different routes of administration. In the case of (i), the two formulations may be mixed immediately before administration.

[0057] In other words, "combined administration" or "combined use" in the present invention can be described as a mode of use in which one drug is administered while the action or effect of one drug is manifesting in the patient's body. That is, in the present invention, it is preferable that the drugs used in dopamine replacement therapy and trisulfide compounds are administered simultaneously in the patient's body, for example, in the blood, and it is preferable that the other drug is administered to the patient within 24 hours after the administration of one drug.

[0058] The dosage of drugs used in dopamine replacement therapy (or the dosage of each drug if two or more drugs are used in combination) is preferably 0.1 to 50 mg per kg of body weight per day (0.1 to 50 mg / kg / day), more preferably 0.5 to 20 mg / kg / day, and even more preferably 1 to 10 mg / kg / day.

[0059] The dosage of the trisulfide compound is preferably 0.5 to 800 mg per kg of body weight per day (0.5 to 800 mg / kg / day), more preferably 1 to 400 mg / kg / day, and even more preferably 2 to 200 mg / kg / day.

[0060] It is preferable that the dosage of the drug used in dopamine replacement therapy is 0.1 to 50 mg / kg / day and the dosage of the trisulfide compound is 0.5 to 800 mg / kg / day; more preferably, the dosage of the drug used in dopamine replacement therapy is 0.5 to 20 mg / kg / day and the dosage of the trisulfide compound is 1 to 400 mg / kg / day; and even more preferably, the dosage of the drug used in dopamine replacement therapy is 1 to 10 mg / kg / day and the dosage of the trisulfide compound is 2 to 200 mg / kg / day. When the dosages of the drug and trisulfide compound used in dopamine replacement therapy are within this range, it is thought that a higher preventive effect against Parkinson's disease will be achieved, and a higher therapeutic effect will be demonstrated. In addition, it is also expected that side effects will be further reduced.

[0061] The number of times drugs and trisulfide compounds used in dopamine replacement therapy are administered can be 1 to 8 times a day or 1 to 4 times a day. Such a frequency of administration is expected to reduce the burden on patients and improve medication compliance. As a result, the preventive or therapeutic effects and side effect reduction effects of the present invention are expected to be further improved. When discontinuing drug administration, the dosage may be gradually reduced. For example, one method is to administer one drug during a drug-free period from the other.

[0062] The Parkinson's disease preventive or therapeutic agent of the present invention can be administered orally, for example, as tablets, capsules, powders, granules, liquids, or syrups, or parenterally as nasal sprays, injections, infusions, or suppositories. These dosage forms can be formulated using known pharmaceutical techniques. In the case of solid dosage forms, pharmacologically acceptable excipients such as starch, lactose, refined sucrose, glucose, crystalline cellulose, carboxycellulose, carboxymethylcellulose, carboxyethylcellulose, calcium phosphate, magnesium stearate, and gum arabic can be added during formulation, and if necessary, lubricants, binders, disintegrants, coatings, and colorants can be added. In the case of liquid dosage forms, stabilizers, solubilizers, suspending agents, emulsifiers, buffers, and preservatives can be added. [Examples]

[0063] The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto.

[0064] Example 1: Inhibition test of dopamine oxidation accelerated in the presence of iron ions The test included dopamine hydrochloride (DA·HCl) and Fe 3+ Iron(III) nitrate nonahydrate (Fe(NO3)3·9H2O) was used as the source, hydrogen peroxide as the oxidizing agent, and glutathione trisulfide dihydrate, lipoic acid trisulfide, pantethine trisulfide, or N,N'-diacetyl-L-cysteine ​​trisulfide were used as the trisulfide compounds.

[0065] The preparation methods for each substance are as follows: • 10 mM DA·HCl aqueous solution: Prepared by dissolving DA·HCl in purified water. 20mM Fe 3+ Solution: Prepared by dissolving Fe(NO3)3·9H2O in 5 mmol / L H2SO4. • 40 mM glutathione trisulfide solution: Prepared by dissolving glutathione trisulfide dihydrate in 0.2 mol / L phosphate buffer (pH=6.5). • 40 mM lipoic acid trisulfide solution: Prepared by dissolving lipoic acid trisulfide in 0.2 mol / L phosphate buffer (pH=6.5). • 400 mM pantethine trisulfide solution: Prepared by dissolving pantethine trisulfide in 0.2 mol / L phosphate buffer (pH=6.5). • 40 mM N,N'-diacetyl-L-cysteine ​​trisulfide: Prepared by dissolving N,N'-diacetyl-L-cysteine ​​trisulfide in 0.2 mol / L phosphate buffer (pH=6.5).

[0066] Each substance was mixed in 50 mL or 5 mL test tubes with the pre-prepared solutions of each substance (listed above) and 0.2 M phosphate buffer (pH=6.5) to obtain 20 mL or 2 mL of reaction solution, so that each substance was at the following concentrations in the reaction solution. Dopamine: 2 mmol / L Fe 3+ :2 mmol / L Hydrogen peroxide: 1 mol / L Glutathione trisulfide: 3 concentrations (5, 10, or 20 mmol / L) Trisulfide lipoate: 2 concentrations (10 or 20 mmol / L) Pantethine trisulfide: 3 concentrations (100, 150, or 200 mmol / L) N,N'-diacetyl-L-cysteine ​​trisulfide: 3 concentrations (5, 10, or 20 mmol / L)

[0067] The reaction mixture was stirred at 25°C at 500 rpm for 6 to 9 hours. The dopamine concentration in the reaction mixture was quantified using high-performance liquid chromatography (HPLC).

[0068] The HPLC conditions are as follows: Detector: UV absorbance spectrophotometer (measurement wavelength: 280 nm) Column: Inertsil ODS-2 (4.6 mm I.D. × 150 mm, 5 μm) Column temperature: Constant temperature around 35°C Mobile phase: A 0.2 mol / L aqueous solution of disodium hydrogen phosphate was mixed with a 0.2 mol / L aqueous solution of citric acid to adjust the pH to 3.0. Flow rate: 0.7mL / min Injection volume: 20μL Area measurement range: 30 minutes after sample solution injection Preparation of sample solution: 100 μL of reaction solution was diluted 10-fold with water to prepare the sample solution. Retention time: Dopamine (DA) approximately 7 minutes

[0069] As shown in Figure 1, Fe 3+ In the presence of Fe, the oxidation of dopamine was accelerated, and the concentration of dopamine decreased rapidly. Glutathione trisulfide is Fe 3+ It inhibited the oxidation of dopamine in the presence of Fe. Similarly, as shown in Figure 2, lipoic acid trisulfide also inhibited Fe 3+ It inhibited the oxidation of dopamine in the presence of Fe. Similarly, as shown in Figure 3, pantethine trisulfide also inhibited Fe 3+ It inhibited the oxidation of dopamine in the presence of Fe. Similarly, as shown in Figure 4, N,N'-diacetyl-L-cysteine ​​trisulfide also inhibited Fe 3+ It suppressed the oxidation of dopamine in the presence of [the substance].

[0070] Glutathione trisulfide, lipoic acid trisulfide, pantethine trisulfide, and N,N'-diacetyl-L-cysteine ​​trisulfide are Fe 3+Because it effectively suppresses the dopamine oxidation reaction accelerated in the presence of this substance, it is expected that combining it with conventional dopamine replacement therapy can effectively address the challenges of conventional dopamine replacement therapy, such as failure to improve symptoms (wearing-off), sudden wear-off of drug effects (on-off phenomenon), and drug side effects (such as dyskinesia).

[0071] Reference example 1 <(R)-Lipoic Acid Trisulfide Manufacturing> [ka] 24.38 g (118.17 mmol) of (R)-α-lipoic acid and 488 mL (20.0 v / w) of 75% ethanol aqueous solution were charged into a 200 mL square flask. After confirming that the contents of the flask had dissolved, the flask was cooled to an internal temperature of 0°C. Oxone® (41.40 g, 124.20 mmol, 1.05 equivalents) was added in two equal parts, and the mixture was reacted for approximately 50 minutes. After filtering off insoluble matter from the reaction mixture, it was washed with 65 mL (2.67 v / w) of ethanol. To the filtration wash, 400 mL (206.93 mmol, 1.75 equivalents) of an aqueous Na2S solution (70.70 g of Na2S·9H2O dissolved in 569 mL of water) was added dropwise over approximately 2.5 hours at an internal temperature of 2-6°C (during addition and reaction, a 3 mol / L aqueous sulfuric acid solution was used to control the pH to 6-7, with a total volume of 14 mL used). After reacting at an internal temperature of 3°C and pH 7 for approximately 50 minutes, 41 mL (1.7 v / w) of an aqueous 3 mol / L aqueous sulfuric acid solution was added dropwise to adjust the pH to 1.3. Next, 320 mL (13.1 v / w) of water and 320 mL (13.1 v / w) of ethyl acetate were added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted four times with 160 mL (6.6 v / w) of ethyl acetate, and the organic layers were combined and concentrated under reduced pressure at an external temperature of 30°C. After dissolving the concentrate in ethanol, it was purified by column chromatography using ODS. The fraction was concentrated under reduced pressure at ambient temperature of 30°C, then dried with an oil pump to obtain 10.69 g of (R)-lipoic acid trisulfide (44.84 mmol, yield 38%, HPLC purity 99.7%, white solid).

[0072] <(R)-Lipoamidotrisulfide Manufacturing> [ka] 2.00 g (8.39 mmol) of (R)-lipoic acid trisulfide and 65 mL (32.5 v / w) of methylene chloride were charged into a 200 mL square flask. After confirming that the contents of the flask had dissolved, 2.07 g (10.77 mmol, 1.28 equivalents) of 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride (EDC·HCl) and 1.42 g (12.33 mmol, 1.47 equivalents) of N-hydroxysuccinimide (NHS) were added. After replacing the air in the flask with nitrogen, the reaction was allowed to proceed at room temperature for approximately 8 hours. Next, 2.28 mL (33.74 mmol, 4.02 equivalents) of 28% aqueous ammonia was added dropwise over 5 minutes at room temperature, and the reaction was allowed to proceed overnight. Subsequently, at room temperature, 60 mL of water (30.0 v / w) was added and the mixture was separated. The organic layer was then washed three times with 60 mL of 2.5% sodium bicarbonate aqueous solution (30.0 v / w), and then four times with 60 mL of water (30.0 v / w). After washing, the organic layer was concentrated under reduced pressure at an ambient temperature of 25°C, and then dried using an oil pump to obtain 1.93 g of (R)-lipoamide trisulfide (8.13 mmol, yield 97%, HPLC purity 99.6%, white solid). 1 H-NMR: (CDCl3,400MHz)δ(ppm)=5.36(bs,2H),3.33(m,1H),3.13(m,2H),2.22(m,3H),1.89(m,1H),1.74-1.42(m,6H). HR-ESI-TOF-MS:m / z 236.0238 ([MH] - ),calcd for[C8H 14 NOS3]-236.0243.

[0073] Reference example 2 <Manufacturing of lipoamido trisulfide (racemic mixture)> [ka] 1.00 g (4.87 mmol) of lipoamide (racemic) and 182 mL (182.0 v / w) of 85% dimethylformamide aqueous solution were placed in a 500 mL square flask. After confirming that the contents of the flask had dissolved, the flask was cooled to an internal temperature of 4°C. 1.63 g (4.89 mmol, 1.00 equivalent) of Oxone® was added to the same flask in three separate portions every 10 minutes, and the reaction was allowed to proceed for approximately 1 hour. Using a 3 mol / L sulfuric acid aqueous solution, 1.24 g (5.16 mmol, 1.06 equivalent) of sodium sulfide nonahydrate was added in separate portions at an internal temperature of 5°C, while controlling the pH of the reaction solution between 5 and 11, and the reaction was allowed to proceed for approximately 1.5 hours. 180 mL of water (180.0 v / w) and 50 mL of methylene chloride (50.0 v / w) were added, and the mixture was extracted with methylene chloride. The aqueous layer was then extracted twice with 50 mL of methylene chloride (50.0 v / w), and the organic layers were combined and concentrated under reduced pressure at an ambient temperature of 30°C or below. 80 mL of water (80.0 v / w) was added dropwise to the concentrated residue over 30 minutes at room temperature to induce crystallization. The slurry was filtered and washed with 50 mL of water (50.0 v / w). The wet crystals were dried under reduced pressure at 25°C to obtain 510 mg of lipoamide trisulfide (racemic mixture) (2.15 mmol, yield 44%, HPLC purity 92%, white solid).

[0074] <Purity test of lipoamide trisulfide (HPLC)> Detector: UV absorbance spectrophotometer (measurement wavelength: 220 nm) Column: LiChrosorb RP-18 (Kanto Chemical, 4.0mm I.D. × 250mm, 5μm) Column temperature: Constant temperature around 40°C Mobile phase A: Phosphate aqueous solution (pH 3) Mobile phase B: methanol Mobile phase delivery: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows.

[0075] [Table 1] Flow rate: 1mL / min Injection volume: 10μL Area measurement range: 35 minutes after sample solution injection Retention time: Lipoamido sulfoxide (12-13 minutes), Lipoamide (approx. 17 minutes), Lipoamido trisulfide (approx. 19 minutes)

[0076] Reference examples 3~9 In the following, "HP" is an abbreviation for "hydroxypropyl," "Me" is an abbreviation for "methyl," and "Mal" is an abbreviation for "maltosyl."

[0077] <Manufacturing of Trisulfide Lipoate> [ka]

[0078] 2.0 g (9.02 mmol) of lipoic acid and 40 mL of 75% ethanol aqueous solution were placed in a reaction vessel and cooled to 0°C. 3.4 g (10.20 mmol) of Oxone® was added, and the mixture was reacted for approximately 2 hours. After filtering out the inorganic salts from the reaction solution, the mixture was washed with 7 mL of ethanol. 5.8 g (24.1 mmol) of sodium sulfide notahydrate was added to the filtrate, and the mixture was reacted for approximately 1 hour. 7 mL of 3 mol / L sulfuric acid aqueous solution was added dropwise to this reaction solution, followed by the addition of 20 mL of water and 45 mL of ethyl acetate (AcOEt), and the mixture was extracted with AcOEt. The aqueous layer was extracted twice with 20 mL of AcOEt, and the organic layers were combined and concentrated under reduced pressure. After dissolving the concentrate in 3 mL of ethanol, the solution was purified using an ODS column (YMC Dispo PackAT, mobile phase: aqueous acetonitrile solution) to obtain 0.7 g (2.39 mmol, HPLC purity: 100%) of lipoic acid trisulfide.

[0079] <Manufacturing of CD inclusion complex of lipoic acid trisulfide> Reference Example 3: β-CD inclusion complex of lipoic acid trisulfide (racemic mixture) 20.0 mg (0.899 mmol) of β-CD10 and 80 mL of water were placed in a 100 mL round-bottom flask. After confirming that the contents of the flask had dissolved, 99.8 mg (0.419 mmol) of trisulfide lipoate was added, and the flask was rinsed with 20 mL of water. After stirring at 45°C for 15 minutes, the mixture was filtered, and the flask and crystals were washed with 10 mL of water. The resulting filtrate was frozen in a -20°C freezer for 23 hours. Freeze-drying was performed at an ambient temperature of 20°C for approximately 4.5 days to obtain 980.0 mg of inclusion complex (white solid).

[0080] Reference Example 4: HP-β-CD inclusion complex of lipoic acid trisulfide (racemic mixture) 1291.0 mg of HP-β-CD and 16 mL of water were placed in a 50 mL round-bottom flask. After confirming that the contents of the flask had dissolved, 100.0 mg (0.419 mmol) of lipoic acid trisulfide was added. After stirring at room temperature for approximately 28 hours, the mixture was filtered, and the flask and crystals were washed with 10 mL of water. The resulting filtrate was frozen in a -20°C freezer for approximately 2 days. Freeze-drying was performed at an ambient temperature of 20°C for approximately 2 days to obtain 1330.0 mg of inclusion complex (white solid).

[0081] Reference Example 5: HP-β-CD inclusion complex of (R)-lipoic acid trisulfide 969.9 mg of HP-β-CD and 10 mL of water were placed in a 50 mL round-bottom flask. After confirming that the contents of the flask had dissolved, 100.3 mg (0.421 mmol) of (R)-lipoic acid trisulfide was added, and the flask was washed with 4 mL of water. After stirring at room temperature for approximately 25 hours, the mixture was filtered, and the flask and crystals were washed with 12 mL of water. The resulting filtrate was frozen in a -20°C freezer for 15 hours. Freeze-drying was performed at an ambient temperature of 20°C for approximately 2 days to obtain 1040.0 mg of inclusion complex (white solid).

[0082] Reference Example 6: Me-β-CD inclusion complex of lipoic acid trisulfide (racemic mixture) 1616.0 mg of Me-β-CD (a mixture of several methylated compounds) and 12 mL of water were placed in a 50 mL round-bottom flask. After confirming that the contents of the flask had dissolved, 101.0 mg (0.424 mmol) of lipoic acid trisulfide was added, and the flask was washed with 4 mL of water. After stirring for 21 hours, the mixture was filtered, and the flask and crystals were washed with 12 mL of water. The resulting filtrate was frozen in a -20°C freezer for 20 hours. Freeze-drying was performed at an ambient temperature of 20°C for approximately 4 days to obtain 1665.2 mg of inclusion complex (white solid).

[0083] Reference Example 7: Me-β-CD inclusion complex of (R)-lipoic acid trisulfide 1616.0 mg of Me-β-CD (a mixture of several methylated compounds) and 16 mL of water were placed in a 50 mL round-bottom flask. After confirming that the contents of the flask had dissolved, 99.9 mg (0.420 mmol) of (R)-lipoic acid trisulfide was added, and the flask was washed with 4 mL of water. After stirring at room temperature for 6 hours, the mixture was filtered, and the flask and crystals were washed with 13 mL of water. The resulting filtrate was frozen in a -20°C freezer for 28 hours. Freeze-drying was performed at an ambient temperature of 20°C for approximately 3 days to obtain 1610.9 mg of inclusion complex (white solid).

[0084] Reference Example 8: Mal-β-CD inclusion complex of lipoic acid trisulfide (racemic mixture) Mal-β-CD 1224.2 mg (0.839 mmol) and 14 mL of water were placed in a 50 mL round-bottom flask. After confirming that the contents of the flask had dissolved, 100.4 mg (0.421 mmol) of lipoic acid trisulfide was added, and the flask was washed with 2 mL of water. After stirring at room temperature for 31 hours, the mixture was filtered, and the flask and crystals were washed with 10 mL of water. The resulting filtrate was frozen in a -20°C freezer for 22 hours. Freeze-drying was performed at an ambient temperature of 20°C for approximately 46 hours to obtain 1180.0 mg of inclusion complex (white solid).

[0085] Reference Example 9: Mal-β-CD inclusion of (R)-lipoic acid trisulfide Mal-β-CD 1224.2 mg (0.839 mmol) and 10 mL of water were placed in a 50 mL round-bottom flask. After confirming that the contents of the flask had dissolved, 100.1 mg (0.420 mmol) of (R)-lipoic acid trisulfide was added, and the flask was washed with 5 mL of water. After stirring at room temperature for 4.5 hours, the mixture was filtered, and the flask and crystals were washed with 11 mL of water. The resulting filtrate was frozen in a -20°C freezer for 24 hours. Freeze-drying was performed at an ambient temperature of 20°C for approximately 41 hours to obtain 1319.6 mg of inclusion complex (white solid).

[0086] Table 2 shows the yield and solubility of the inclusion complexes obtained in Reference Examples 3-9.

[0087] [Table 2]

[0088] Reference Example 10: Production of Pantethine Trisulfide [ka] In a 1 L square flask, 18.75 g of 80% pantethine aqueous solution (27.04 mmol, equivalent to 15.00 g of pantethine) and 180 mL of water (12.0 v / w) were charged, and the mixture was cooled to an internal temperature of 1°C. To this, 10.34 g of Oxone® (31.02 mmol, 1.15 equivalents, calculated assuming 4.8% available oxygen) was added in four portions every 10 minutes, after which the flask was rinsed with 8 mL of water, and the reaction was allowed to proceed for approximately 3 hours. At an internal temperature of 0-1°C, 45 mL of 0.67 mol / L sodium sulfide aqueous solution (29.98 mmol, equivalent to 1.11 equivalents) was added dropwise over 45 minutes, while 1.6 mL of 3 mol / L sulfuric acid aqueous solution was used to control the pH to below 7 during the addition. The mixture was reacted at an internal temperature of 1°C and pH 4 for 40 minutes. Then, 500 mL of ethanol (33.3 v / w) was added at an internal temperature of 1-5°C to precipitate the inorganic salt, and the mixture was stirred at an internal temperature of 1-5°C for 30 minutes. After filtering the inorganic salt, it was washed with 50 mL of ethanol (3.3 v / w), and the filtrate was concentrated under reduced pressure at an external temperature of 23°C to obtain 34 g of crude pantethine trisulfide. 6 mL of water was then added and dissolved to prepare 40 g (2.7 w / w) of column stock solution. The solution was purified by ODS column, and fractions with an LC purity of 95% or higher were separated. The fractions were concentrated under reduced pressure at an external temperature of 30°C, and then dried using an oil pump to obtain 9.57 g of pantethine trisulfide (16.31 mmol, yield 60%, white solid). 1 H NMR:(D2O,400MHz)δ(ppm)=3.97(s,2H),3.44-3.58(m,10H),3.37(d,J=11.4H z,2H),3.04(t,J=6.2Hz,4H),2.50(t,J=6.2Hz,4H),0.91(s,6H),0.87(s,6H). HR-ESI-TOF-MS:m / z 585.2086([MH] - ), calcd for[C 22 H 41 N4O8S3]-585.2092.

[0089] <Purity test of pantethine trisulfide> Detector: UV absorbance spectrophotometer (measurement wavelength: 220 nm) Column: LiChrosorb RP-18 (Kanto Chemical, 4.0mm ID x 250mm, 5μm) Column temperature: Constant temperature around 40°C Mobile phase A: Phosphate aqueous solution (pH 3) Mobile phase B: methanol Mobile phase delivery: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows.

[0090] [Table 3] Flow rate: 0.6mL / min Injection volume: 5μL Area measurement range: 40 minutes after sample solution injection Retention time: Pantethine sulfoxide (approx. 20 minutes), Pantethine (approx. 22 minutes), Pantethine trisulfide (approx. 23 minutes)

[0091] Reference Example 11: Pantethine trisulfide nasal spray (10%) A nasal spray formulation containing pantethine trisulfide was manufactured by mixing and stirring pantethine trisulfide (10% by mass), benzalkonium (0.01% by mass), carboxyvinyl polymer (0.5% by mass), L-arginine (1% by mass), and physiological saline (88.49% by mass) in a vacuum stirring device under light shielding, followed by filtration sterilization in a sterile environment, and aseptic filling into a sterilized container.

[0092] Reference Example 12: Production of N,N'-diacetyl-L-cysteine ​​trisulfide [ka]

[0093] 1.0 g (3.08 mmol) of N,N'-diacetyl-L-cystine and 10 mL of water were placed in a reaction vessel and cooled to an internal temperature of 1°C. 1.25 g (3.72 mmol) of Oxone® was added, and the mixture was reacted for approximately 3 hours. Subsequently, 8.5 mL (3.71 mmol) of 0.44 mol / L aqueous sodium sulfide solution was added dropwise, and the mixture was reacted for approximately 3 hours. After adding 33 mL of acetonitrile to the reaction mixture, the inorganic salt was filtered, and the mixture was washed with 5 mL of acetonitrile. The filtrate was concentrated under reduced pressure using an evaporator, and the concentrate was purified by an ODS column (mobile phase: aqueous acetonitrile solution) to obtain 0.2 g (0.56 mmol) of N,N'-diacetyl-L-cysteine ​​trisulfide.

[0094] The HPLC conditions are as follows: Detector: UV absorbance spectrophotometer (measurement wavelength: 220 nm) Column: LiChrosorb RP-18 (Kanto Chemical, 4.0 x 250 mm, 5 μm) Column temperature: Constant temperature around 40°C Mobile phase: 40% (v / v) acetonitrile aqueous solution Flow rate: 0.5mL / min

[0095] Reference Example 13: Production of N,N'-diacetyl-L-cysteine ​​trisulfide [ka]

[0096] 1.0 g (6.13 mmol) of N-acetyl-L-cysteine ​​and 40 mL of 20% acetonitrile aqueous solution were placed in a reaction vessel and cooled to an internal temperature of 5°C. 3.4 g (10.14 mmol) of Oxone® was added, and the reaction was allowed to proceed for approximately 2.5 hours. Subsequently, 1.5 g (6.12 mmol) of sodium sulfide nonahydrate was added, and the reaction was allowed to proceed for approximately 1 hour. After adding 33 mL of acetonitrile, the inorganic salt was filtered and washed with 3 mL of acetonitrile. The filtrate was concentrated under reduced pressure using an evaporator, and the concentrate was purified by an ODS column (mobile phase: acetonitrile aqueous solution) to obtain 0.1 g (0.28 mmol) of N,N'-diacetyl-L-cysteine ​​trisulfide.

[0097] The HPLC conditions are the same as those described in Reference Example 12.

Claims

1. A prophylactic or therapeutic agent for Parkinson's disease containing a trisulfide compound, characterized by being administered in combination with a drug used in dopamine replacement therapy, The aforementioned trisulfide compound is Glutathione trisulfide or a pharmaceutically acceptable salt thereof; Formula (1) 【Chemistry 1】 Compound represented by the formula [wherein X is -OR １ or -NR ２ R ３ R １ R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ２ and R ３ Each independently represents a hydrogen atom or a C1-C6 alkyl group, and the alkyl group may have one or more substituents selected from the group consisting of amino groups and carboxyl groups. ], pharmaceutically acceptable salts thereof or cyclodextrin inclusion complexes thereof; Pantethine trisulfide or a pharmaceutically acceptable salt thereof; or N,N'-diacetyl-L-cysteine ​​trisulfide or its pharmaceutically acceptable salts It is a preventative or therapeutic agent.

2. A preventive or therapeutic agent for Parkinson's disease, comprising a drug used in dopamine replacement therapy, characterized by being administered in combination with a trisulfide compound, The aforementioned trisulfide compound is Glutathione trisulfide or a pharmaceutically acceptable salt thereof; Formula (1) 【Chemistry 2】 a compound represented by [wherein X is -OR １ or -NR ２ R ３ , R １ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ２ and R ３ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and said alkyl group may have one or more substituents selected from the group consisting of an amino group and a carboxy group.], a pharmaceutically acceptable salt thereof or a cyclodextrin inclusion complex thereof; Pantethine trisulfide or a pharmaceutically acceptable salt thereof; or N,N'-diacetyl-L-cysteine ​​trisulfide or its pharmaceutically acceptable salts It is a preventative or therapeutic agent.

3. The preventive or therapeutic agent according to claim 1 or 2, wherein the trisulfide compound and the drug used in the dopamine replacement therapy are administered simultaneously or separately.

4. A preventive or therapeutic agent for Parkinson's disease, comprising a trisulfide compound and a drug used in dopamine replacement therapy, The aforementioned trisulfide compound is Glutathione trisulfide or a pharmaceutically acceptable salt thereof; Formula (1) 【Transformation 3】 Compound represented by the formula [wherein X is -OR １ or -NR ２ R ３ R １ R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ２ and R ３ Each independently represents a hydrogen atom or a C1-C6 alkyl group, and the alkyl group may have one or more substituents selected from the group consisting of amino groups and carboxyl groups. ], pharmaceutically acceptable salts thereof or cyclodextrin inclusion complexes thereof; Pantethine trisulfide or a pharmaceutically acceptable salt thereof; or N,N'-diacetyl-L-cysteine ​​trisulfide or its pharmaceutically acceptable salts It is a preventative or therapeutic agent.

5. The preventive or therapeutic agent according to claim 1, 2, or 4, wherein the trisulfide compound is glutathione trisulfide or a pharmaceutically acceptable salt thereof.

6. The preventive or therapeutic agent according to claim 5, wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, amino acid salts of glutathione trisulfide, and alkali metal salts of glutathione trisulfide.

7. The preventive or therapeutic agent according to claim 5, wherein the glutathione trisulfide or a pharmaceutically acceptable salt thereof comprises at least one selected from the group consisting of glutathione trisulfide, arginine salt of glutathione trisulfide, and sodium salt of glutathione trisulfide.

8. The preventive or therapeutic agent according to claim 1, 2, or 4, wherein the trisulfide compound is lipoic acid trisulfide or a pharmaceutically acceptable salt thereof.

9. The preventive or therapeutic agent according to claim 1, 2, or 4, wherein the trisulfide compound is pantethine trisulfide or a pharmaceutically acceptable salt thereof.

10. The preventive or therapeutic agent according to claim 1, 2, or 4, wherein the trisulfide compound is N,N'-diacetyl-L-cysteine ​​trisulfide or a pharmaceutically acceptable salt thereof.

11. The preventive or therapeutic agent according to claim 1, 2, or 4, wherein the drug used in the dopamine replacement therapy comprises at least one selected from the group consisting of dopamine precursors, dopa decarboxylase inhibitors, catechol-O-methyltransferase inhibitors, monoamine oxidase inhibitors, dopamine release enhancers, and dopamine agonists.

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