JP2002047206A - Accelerator for gdnf production, therapeutic agent for parkinson's disease and therapeutic agent for als - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an accelerator for the glial cell line-derived neurotrophic factor(GDNF) production usable as a therapeutic agent for Parkinson's diseases and a therapeutic agent for amyotrophic lateral sclerosis(ALS). SOLUTION: A compound having an activity for inhibiting a V type ATPase, its pharmaceutically acceptable salt or prodrug is used as the accelerator for the GDNF production.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a V-type ATPase.
A GDNF (glial cell line-derived neurotrophic factor) production promoter comprising, as an active ingredient, a compound having an activity of inhibiting (adenosine triphosphatase), a pharmaceutically acceptable salt or a prodrug thereof (eg, conkanamycin A); And a therapeutic agent for Parkinson's disease and ALS (amyotrophic lateral sclerosis).

[0002]

2. Description of the Related Art Parkinson's disease is a neurodegenerative disease whose main symptoms are dyskinesias such as tremor, muscle rigidity, immobility / sloppy motion, and postural dysfunction. In the Parkinson's disease patient's brain, dopamine neurons projecting from the dense part of the midbrain to the striatum are observed to be highly deficient, and a decrease in the function of the substantia nigra-striatal dopamine nervous system is observed. Is the cause.

[0003] Currently, pharmacotherapy for Parkinson's disease is limited to symptomatic treatment to compensate for dopamine neuronal dysfunction. In this symptomatic treatment, dopamine prodrugs L-dopa and dopamine D2 receptor are used. Agonists, dopamine release promoters, anticholinergics, and the like have been used. However, these drugs also tend to produce serious side effects such as gastrointestinal disorders (nausea, vomiting), cardiovascular disorders (orthostatic hypotension), and psychiatric symptoms (hallucinations, delusions). In the use of L-dopa, which is the most effective among these symptomatic treatment drugs, the effect of long-term administration may be disturbed (wear).
(ing-off phenomena, on-off phenomena), reduced efficacy, sudden death, etc.

On the other hand, amyotrophic lateral sclerosis (ALS)
It is a neurodegenerative disease caused by the loss of motor nerve, and its main symptom is muscle atrophy and muscle weakness. Anticholinesterase drugs may be administered as symptomatic treatment, but there is no effective treatment. ALS has a progressive course, eventually leading to quadriplegia and respiratory distress. ALS
The average course from onset to death is 3-4 years.

[0005] In view of the above background, there is a need for the development of drugs based on causative therapy for suppressing neurodegeneration (not symptomatic therapy) for neurodegenerative diseases such as Parkinson's disease and ALS. At present, neurotrophic factors have been attracting attention as causal treatments to replace these conventional symptomatic treatments for these neurodegenerative diseases. This neurotrophic factor is a protein that is produced from nerve cells or glial cells and plays an important role in regulating the differentiation, growth and survival of nerves, and in promoting repair and regeneration processes after nerve damage. In recent years, many neurotrophic factors have been discovered, and their application to disease treatment has been studied.

[0006] Among various neurotrophic factors, glial cell line-derived neurotrophic factor (GDNF) is a novel neurotrophic factor purified from the culture supernatant of rat glial B49 cells by a bioassay using cultured cerebral nerve cells. It is a neurotrophic factor (Science, 260, 1130, 1993). From the study using primary cultured cerebral nerve cells, GDNF was GAB
A (γ-aminobutyric acid) and serotonin neuronal activity were not affected and were shown to be selective neurotrophic factors for dopamine neurons.

[0007] It has been reported that GDNF suppresses the neuronal damage in primary culture during cerebral neurons induced by 1-methyl-4-phenyl pyridinium (MPP +), a dopamine neurotoxin (J. Neurochem., 66, 74, 1996). . Furthermore, administration of dopamine neurotoxin MPTP (MPP + precursor) (Nature, 373, 335, 1995) and administration of 6-hydroxy-dopamine (Proc. Natl. Acad. Sci., 9)
2, 8935, 1995) and medial forebrain bundle transection (Natu
re, 373, 339, 1995) was reported to be suppressed by GDNF. MPT
Not only does GDNF suppress the dyskinesias of mice due to P administration and significantly reduce the decrease in dopamine content in the striatum, but these effects were also observed in post-administration of GDNF (Nature, 373, 335, 1995). As shown in the above literature, the action of GDNF in vivo surpassed that of brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF).

GDNF has also been reported to be effective in rhesus monkeys (Nature, 380, 252, 199).
6) Clinical effects are also expected. In this report, rhesus monkeys were infused with MPTP and administered GDNF 3 months later intraventricularly, which suppressed dopamine neuron loss in the substantia nigra and simultaneously improved Parkinson's symptoms. The effect of GDNF outweighed the effect of cinemet, which was used as a control, in persistence and potency. In addition, dystonia and dyskinesia as seen in Sinemet
Side effects such as vomiting and vomiting were not observed in GDNF.

On the other hand, subsequent studies have revealed that GDNF has potent neurotrophic factor activity not only on dopamine nerves but also on motor nerves (Science,
266, 1062, 1994). Furthermore, GDNF was reported to have a strong inhibitory effect on motor nerve cell death induced by facial nerve transection in neonatal rats (Na
ture, 373, 341, 1995). Also, GDNF
Inhibits motor nerve apoptosis (Nature, 373, 344, 199).
5).

[0010]

From the above results, neurodegenerative diseases such as Parkinson's disease which is a dopamine neurodegenerative disease and ALS which is a motor neurodegenerative disease,
Although DNF is expected to be effective, its use is severely restricted when used in the clinic, as the route of administration of GDNF must be intraventricular.

An object of the present invention is to provide a remedy for Parkinson's disease and a remedy for ALS which have solved the above-mentioned disadvantages of the prior art. Still another object of the present invention is to provide a G drug that can be used as a therapeutic agent for Parkinson's disease and ALS
An object of the present invention is to provide a DNF production promoter.

[0012]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that V-type ATPase (adenosine triphosphatase)
Compounds (eg, macrolides such as conkanamycin A and bafilomycin) have inhibitory activity on GDN in various human and rat-derived glioma cells.
It has been found that such a low-molecular compound is extremely effective as an agent for promoting F production, that is, as an agent for GDNF production that can be used in place of GDNF itself as a therapeutic agent for Parkinson's disease and ALS.

That is, the present invention relates to a compound having an activity of inhibiting V-type ATPase, a GDNF production promoter containing a pharmaceutically acceptable salt or a prodrug thereof.
The present invention further relates to a therapeutic agent for Parkinson's disease containing the above-mentioned GDNF production promoter. The present invention further provides the aforementioned GDN
The present invention relates to an ALS therapeutic agent containing an F production promoter.

The present invention further relates to the use of a GDNF production promoter for producing a therapeutic agent for Parkinson's disease or ALS.

[0015]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described more specifically with reference to the drawings as necessary. In the following description, “parts” and “%” representing the quantitative ratios are based on mass unless otherwise specified. (GDNF Production Promoter) The GDNF production promoter of the present invention contains an active ingredient based on a GDNF production promoting action (for example, based on V-type ATPase inhibitory activity).

From the viewpoint of GDNF production efficiency, the GDNF production promoting effect (S) when the test drug is used at a concentration of 100 ng / ml and the control ( The ratio (S / C) to the GDNF production amount (C) in the case of (concentration of the test drug = 0) is preferably 2 or more, more preferably 5 or more (particularly 10 or more). <Measurement method of GDNF production promoting property> A test drug whose GDNF production promoting property is to be measured under the same conditions as in "Example 1" described below, instead of "Conkanamycin A" used in Example 1. Used and as glioma cells T98G,
GDNF production promotion is measured using U87MG or C6 glioma. (V-type ATPase) ATPase is a type of ion pump found in cells. Many ion pumps
Ions are transported using the energy generated during ATP degradation, and these ATPases are known to be widely distributed in cell membranes and organelle membranes. ATPa
se is classified into P-type, F-type, V-type, and the like based on their ion permeation mechanism, molecular structure, and the like.

Of these ATPases, V-type ATPase
(Vacuolar ATPase) is a complex molecule composed of multiple subunits found in eukaryotic cells.
And functions as a proton pump that transports protons (H ⁺ ) into cells. V type ATPase is
It is thought that acidification of cells and organelles controls the activities and processing processes of various functional proteins and consequently regulates cell functions (for details of this V-type ATPase, see, for example,
Annals. New York Academy of Sciences, 600-6
See the article by Keeling et al. On page 08, "Vacuolar H ⁺ -ATPases
Can be referred to.) (Compound having V-type ATPase inhibitory activity) V-type AT
The compound having Pase inhibitory activity is the above-mentioned V type AT
A compound that binds to a specific site of Pase and reduces the rate of a reaction based on V-type ATPase. In the present invention, a compound having a V-type ATPase inhibitory activity has an activity measured by the following inhibitory activity measurement method,
Preferably, ₅₀ exhibits an activity of 10 μM or less, more preferably 10 nM or less. <Method for measuring inhibitory activity> V-type ATPase activity was measured using Bowman
Natl. Acad. Sci. USA 85, 7972 (198
8)) can be measured. That is, the transfer of H ⁺ into cells can be measured by a fluorescence method as a change in intracellular pH. V-type ATPase inhibitory activity is measured by comparing the fluorescence intensity in the presence of the inhibitor with the fluorescence intensity in the absence of the inhibitor.

V-type ATPase usable in the present invention
The compound having an inhibitory activity is not particularly limited as long as it has the ATPase inhibitory activity as described above, but its molecular weight (in the case of a mixture, its weight average molecular weight) is 1000.
Or less (more preferably 500 or less). The compound having the V-type ATPase inhibitory activity is a compound having the V-type ATPase inhibitory activity.

[0019]

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Where Y is

[0021]

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Wherein W ¹ is hydrogen or C ₂ -C ₆ alkanoyl, and Z is

[0023]

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Wherein W ² is hydrogen, hydroxy, or C ₁ -C ₆ alkoxy, W ³ is C ₁ -C ₆ alkyl or C ₂ -C ₈ alkenyl, and W ⁴ is hydroxy, C ₁ -C ₆ -C ₆ alkoxy, C ₂ -C ₆ alkanoyloxy,

[0025]

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(Where W ⁵ is hydroxy, C ₁ -C ₆
Alkoxy, amino,

[0027]

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Wherein W ⁶ is hydroxy or C ₂ -C
_{6 is} alkanoyloxy, W ⁷ is hydroxy or C ₂ -C ₆ alkanoyloxy), R ¹ is hydroxy or C ₂ -C ₆ alkanoyloxy, and R ² is C ₁ -C ₆ It is preferably a compound represented by｝ which is alkyl. Here, regarding the macrolide compound, and each active ingredient described below,
Unless otherwise indicated, pharmaceutically acceptable salts of the individual active ingredients and / or prodrugs are also intended to be included.

Such a macrolide compound is more preferably a conkanamycin A, a bafilomycin A
1, bafilomycin B1, bafilomycin C1, and bafilomycin D. (Pharmaceutically acceptable salt or prodrug) In the present invention, the compound having the V-type ATPase inhibitory activity can be used in the form of a pharmaceutically acceptable salt or prodrug, if necessary. . For details of such salts or prodrugs, reference can be made, for example, to page 7, line 58 to page 9, line 38 of the aforementioned European Patent Publication No. 0689839A2. (Therapeutic agent for Parkinson's disease) In the therapeutic agent for Parkinson's disease of the present invention, the GDNF production promoter itself can be used as a therapeutic agent for Parkinson's disease, but from the viewpoint of administration convenience (handling, safety, etc.). Preferably, the GDNF production promoter is usually formulated and used as a therapeutic agent for Parkinson's disease. In an embodiment of the present invention in which a GDNF production promoter is formulated, the Parkinson's disease therapeutic agent of the present invention comprises a GDNF production promoter effective in improving Parkinson's disease, and a pharmaceutically acceptable formulation auxiliary. It is preferable to include

As will be described later, for example, the production of GDNF is promoted in various glioma cells, and as a result, G
A GDNF production promoter (for example, a low molecular weight compound such as a V-type ATPase inhibitor) having the same action as DNF is
It can be a useful therapeutic agent for neurodegenerative diseases such as Parkinson's disease. As for the therapeutic agent for Parkinson's disease related to GDNF, the above-mentioned GDNF-related literature (particularly, Nature, 380, 252 (1996)) can be referred to as needed. (Therapeutic agent for ALS) In the ALS therapeutic agent of the present invention, G
Although the DNF production promoter itself can be used as an ALS therapeutic agent, from the viewpoint of administration convenience (handling, safety, etc.), the GDNF production promoter is usually formulated into A
It is preferably used as an LS therapeutic. In an embodiment of the present invention in which a GDNF production promoter is formulated, the ALS therapeutic agent of the present invention comprises an effective amount of GDNF for improving ALS.
It is preferable to include a production accelerator and a pharmaceutically acceptable auxiliary for pharmaceutical preparation.

As will be described later, for example, it promotes the production of GDNF in various glioma cells, and as a result,
A GDNF production promoter (for example, a low molecular weight compound such as a V-type ATPase inhibitor) having the same action as DNF is
It can be a useful therapeutic agent for neurodegenerative diseases such as ALS. Regarding this ALS therapeutic agent related to GDNF,
If necessary, refer to the above-mentioned GDNF-related documents (especially, Na
, 377, 341 (1995)). (Formulation) The GDNF production promoter of the present invention (or a pharmaceutically acceptable salt or prodrug thereof) is
Based on the F production promoting effect, it is useful as a therapeutic agent for Parkinson's disease or ALS.

The GDNF production promoter (for example, V
Compound having type ATPase inhibitory activity) or a pharmaceutically acceptable salt or prodrug thereof can be used as it is, or in the form of various preparations. The preparation containing the GDNF production promoter used as an active ingredient in the present invention contains an effective amount of GDN as an active ingredient.
An F production promoter or a pharmaceutically acceptable salt or prodrug thereof may be added to a pharmaceutically acceptable additive (eg, a carrier or excipient which is a formulation auxiliary usually used in the formulation of pharmaceuticals) , And other additives).

The administration of the GDNF production promoter of the present invention or a preparation thereof may be performed in the form of tablets, pills, capsules, granules, powders,
It may be in any form of oral administration by liquid or the like, or parenteral administration by injection such as intravenous injection or intramuscular injection, suppository, transdermal or the like. In preparing the compositions in oral dosage form, any useful pharmaceutically acceptable carrier can be used. For example, oral liquid preparations such as suspensions and syrups include water, sugars such as sucrose, sorbitol, and fructose; glycols such as polyethylene glycol and propylene glycol; oils such as sesame oil, olive oil, and soybean oil; It can be produced using preservatives such as hydroxybenzoic esters and flavors such as strawberry flavor and peppermint. Powders, pills, capsules and tablets are excipients such as lactose, glucose, sucrose, mannitol, starch, disintegrants such as sodium alginate, lubricants such as magnesium stearate, talc, polyvinyl alcohol, hydroxypropyl It can be produced using a binder such as cellulose and gelatin, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin. From the viewpoint of easy administration, tablets or capsules are preferred for oral administration.

The injection can be prepared using a carrier comprising distilled water, salt solution, glucose solution or a mixture of salt water and glucose solution. At this time, it can be prepared as a solution, suspension or dispersion using a suitable auxiliary according to a conventional method. The dose of the GDNF production promoter or a pharmaceutically acceptable salt or prodrug thereof (active ingredient) can be appropriately determined depending on the individual case in consideration of symptoms, age, sex, and the like of the administration subject. . The dose of the active ingredient is generally 1 to 1,000 mg per adult per day for oral administration, preferably 5 to 1,000 mg per day.
In the case of parenteral administration, 1 to 500 mg per adult per day, in the range of 1 to 500 mg per day.
It can be administered subcutaneously or intravenously in one to several doses, or can be continuously administered intravenously in the range of 1 hour to 24 hours a day. As described above, since the dose may fluctuate under various conditions, a sufficient effect may be obtained with an amount smaller than the above dose range.

Hereinafter, the present invention will be further described with reference to examples.

[0036]

EXAMPLES Example 1 GDN of Conkanamycin A in Glioma Cells
F production promoting action) Concanamicin A (purchased from Wako Pure Chemical Industries, Ltd., Tokyo, Japan) was used as a compound having V-type ATPase inhibitory activity, and all were ATCC; American Type Culture Collection as glioma cells.
Using two types of human glioma cells (U87MG, T98G) and one type of rat glioma cells (C6) obtained from the United States (Maryland, USA), concanamicin A promotes GDNF production in glioma cells. Verity et al. (J. Neurochem. 70. 531
(1998)).

Two of the above three types of glioma cells (T98G and C6 cells) were suspended in Dulbecco's modified Eagle medium (manufactured by Gibco, trade name: Dulbecco's modified Eagle medium) containing 10% calf serum. 7 cells
× 10 ⁵ cells / well (about 1 ml per well)
To a 12-well plate (IWAKI Glass Co., Ltd., Chiba, Japan). A U-plate was used in the same manner except that a collagen type I coated plate (manufactured by IWAKI Glass Co., Chiba, Japan) was used as a 12-well plate.
87MG cells were seeded.

The next day after seeding (about 20 hours after seeding), the above Dulbecco's modified Eagle medium was suctioned off using a suction machine, and the remaining cells were phosphate-buffered saline (pH 7.0).
2; Dainippon Pharmaceutical Co., Ltd.). After washing, Opti- containing 0.5% bovine serum albumin was added to the cells.
MEM (manufactured by Gibco) was added at 1 ml / well. A 12-well plate containing cells after the above treatment in a well is
After subjecting to culture in an O ₂ incubator (CO ₂ concentration 5%, 37 ° C.) for 24 hours, a test drug (concanamycin A, concentration: 1 to 100) dissolved in dimethyl sulfoxide
1 μl (0 μg / ml) was added to the medium in the wells.
After reacting the test drug with the cells by further culturing the cells in the CO ₂ incubator under the same conditions for 24 hours, the culture supernatant was collected and stored frozen at -80 ° C.

The amount of GDNF was measured using an ELISA kit (manufactured by Promega, trade name: GDNF Emax Immunoassay).
System, Wisconsin, USA) according to the protocol attached to the kit. That is, the culture supernatant that had been cryopreserved was reacted with an anti-GDNF monoclonal antibody coated on a 96-well plate for 6 hours. After washing the plate, the plate was reacted overnight with an anti-GDNF polyclonal antibody. After washing the plate, the plate was reacted with a secondary antibody labeled with HRP (Horse Radish Peroxidase) and developed with a TMB (3,3 ', 5,5'-tetramethylbenzidine) solution. The absorbance was measured at A _450.

The results are shown in the graphs of FIGS. The numerical value in each graph is the GDNF when the test drug was not added (concentration = 0).
When the amount of production is defined as a reference (100%), the ratio of the amount of GDNF produced when the test drug concanamicin A is added (increase rate%) is shown. As shown in the graphs of FIGS. 1 to 3, conkanamycin A was obtained from human glioma cells (U87MG, T9
8G) and rat glioma cells (C6) promoted GDNF production in a concentration-dependent manner from a relatively low concentration (1 to 10 ng / ml). Example 2 One type of human glioma cell (T98) was prepared in the same manner as in Example 1 except that bafilomycin A ₁ (Wako Pure Chemical Industries, Ltd.) was used as a compound having V-type ATPase inhibitory activity.
With total 2 kinds of G) and one rat glioma cells (C6), it was measured GDNF production promoting action of Bafilomycin A ₁ in glioma cells.

The results are shown in the graphs of FIGS. The numerical value in each graph is the GD when no test drug was added (concentration = 0).
When the amount of NF production was defined as a reference (100%), the ratio of the amount of GDNF produced when the test drug (bafilomycin) was added (increase rate%) was shown. As shown in the graphs of FIGS. 4 and 5, bafilomycin was converted to human glioma cells (T9
8G) and rat glioma cells (C6) promoted GDNF production in a concentration-dependent manner from a relatively low concentration (1 to 100 ng / ml).

[0042]

As described above, according to the present invention, a compound having an activity of inhibiting V-type ATPase, or a GDNF production promoter containing a pharmaceutically acceptable salt, solvate or prodrug thereof is provided. Provided. As described above, GDNF production promoters (for example, low-molecular compounds such as V-type ATPase inhibitors) that promote the production of GDNF and consequently have the same action as GDNF are used in neuronal diseases such as Parkinson's disease and ALS. It can be a useful therapeutic agent for degenerative diseases.

[Brief description of the drawings]

FIG. 1. Using human glioma cells (U87MG)
It is a graph which shows the example which measured the GDNF production promotion effect of the compound which has V type ATPase inhibitory activity (conkanamycin A).

FIG. 2 shows the expression of V using human glioma cells (T98G).
It is a graph which shows the example which measured the GDNF production promotion effect of the compound (conkanamycin A) which has a type ATPase inhibitory activity.

FIG. 3 is a graph showing an example of measuring the GDNF production promoting effect of a compound having a V-type ATPase inhibitory activity (concanamycin A) using rat glioma cells (C6).

FIG. 4 shows the expression of V using human glioma cells (T98G).
Compounds with type ATPase inhibitory activity is a graph showing an example of measurement of GDNF production promoting action of (Bafilomycin A _1).

FIG. 5 is a graph showing an example of measuring the GDNF production promoting effect of a compound having a V-type ATPase inhibitory activity (bafilomycin A ₁ ) using rat glioma cells (C6).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 43/00 111 A61P 43/00 111 C12N 9/99 C12N 9/99 // C07D 313/00 C07D 313 / 00 407/06 407/06 407/14 407/14 C12P 21/02 C12P 21/02 K (72) Inventor Mariko Nishiguchi 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Invention Person Kimiko Tokugawa 3-24-1, Takada, Toshima-ku, Tokyo F-term in Taisho Yakuhin Co., Ltd. EA15 GA02 MA01 MA02 MA03 MA04 MA05 NA14 NA15 ZA02 ZB22 ZC20

Claims (10)

[Claims] GDNF comprising a compound having an activity of inhibiting V-type ATPase (adenosine triphosphatase), a pharmaceutically acceptable salt thereof, or a prodrug thereof
(Glial cell line-derived neurotrophic factor) production promoter. 2. The GDNF according to claim 1, wherein the compound having V-type ATPase inhibitory activity is a macrolide compound, a pharmaceutically acceptable salt thereof, or a prodrug.
Production promoter. 3. The compound having V-type ATPase inhibitory activity has the formula: Ｙwhere Y is Wherein W ¹ is hydrogen or C ₂ -C ₆ alkanoyl, and Z is Wherein W ² is hydrogen, hydroxy, or C ₁ -C ₆ alkoxy, W ³ is C ₁ -C ₆ alkyl or C ₂ -C ₈ alkenyl, and W ⁴ is hydroxy, C ₁ -C ₆ Alkoxy, C ₂ -C ₆
Alkanoyloxy, (Where W ⁵ is hydroxy, C ₁ -C ₆ alkoxy,
Amino, embedded image W ⁶ is hydroxy or C ₂ -C ₆ alkanoyloxy; W ⁷ is hydroxy or C ₂ -C ₆ alkanoyloxy); and R ¹ is hydroxy or C ₂ -C ₆ alkanoyloxy. The GDNF production promoter according to claim 2, wherein the agent is oxy, and R ² is C ₁ -C ₆ alkyl, a macrolide compound represented by｝, a pharmaceutically acceptable salt thereof, or a prodrug. 4. The GDNF production promoter according to claim 2, wherein the macrolide compound is concanamycin A, a pharmaceutically acceptable salt thereof, or a prodrug. 5. The GDNF production promoter according to claim 2, wherein the macrolide compound is bafilomycin, a pharmaceutically acceptable salt thereof, or a prodrug. 6. The method according to claim 1, which is a therapeutic agent for Parkinson's disease.
5. The GDNF production promoter according to any one of 5. 7. The GDNF production promoter according to claim 6, further comprising a pharmaceutically acceptable auxiliary for pharmaceutical preparation. 8. The GDNF production promoter according to any one of claims 1 to 5, which is a therapeutic agent for ALS (amyotrophic lateral sclerosis). 9. The GDNF production promoter according to claim 8, further comprising a pharmaceutically acceptable auxiliary for pharmaceutical preparation. 10. Use of a compound having an activity of inhibiting V-type ATPase, a pharmaceutically acceptable salt or a prodrug thereof for producing a therapeutic agent for Parkinson's disease or ALS.