Patent Application
20230364053
The present invention relates to a pharmaceutical composition for treating the prostate cancer or breast cancer. According to the present invention, refractory prostate cancer or breast cancer can be treated.
Prostate cancer and breast cancer are the most common cancers affecting men and women in Europe and the United States. In Japan, the number of patients with prostate cancer is increasing dramatically due to the Westernisation of the diet and the ageing of the population. The growth of prostate cancer is generally stimulated by androgen, which is a male hormone. On the other hand, estrogen, which is a female hormone, stimulates the growth of breast cancer. Therefore, hormone therapies that inhibit androgen and estrogen production and function are usually used for the treatment of prostate cancer and breast cancer. Although the effect of hormone therapy is initially excellent, prostate cancer relapses within a few years as castration-resistant prostate cancer (CRPC). In addition, the acquisition of resistance to hormone therapy is also a problem in breast cancer (PATENT LITERATURES 1 and 2). Thus, the control of treatment-resistant cancers that are resistant to hormone therapy is the most important problem to be solved.
Therefore, the object of the present invention is to provide a therapeutic agent for treating hormone therapy-resistant, treatment-resistant cancers, and a method of the treatment of hormone therapy-resistant, treatment-resistant cancers.
The inventors have studied intensively on therapeutic agents and methods for treating hormone therapy-resistant, treatment-resistant cancers. Surprisingly, they found that two groups of compounds with specific chemical structures can effectively treat hormone therapy-resistant, treatment-resistant cancers.
The present invention is based on these findings.
Therefore, the present invention relates to
[1] A pharmaceutical composition for treating prostate cancer comprising: a compound represented by a following formula (1):
the compound represented by the formula (2) is a compound selected from the group consisting of
[3] A pharmaceutical composition for treating breast cancer comprising:
the compound represented by the formula (2) is a compound selected from the group consisting of
According to the pharmaceutical composition of the present invention, hormone therapy-resistant prostate cancer or hormone therapy-resistant breast cancer can be effectively treated. Furthermore, the pharmaceutical composition of the present invention can effectively treat not only hormone therapy-resistant prostate cancer or breast cancer but also non-hormone therapy-resistant prostate or breast cancer and Castration-resistant prostate cancer or treatment-resistant breast cancer caused by other mechanisms.
The pharmaceutical composition for treating prostate cancer or the pharmaceutical composition for treating breast cancer of the present invention comprises: a compound (hereinafter referred to as compound A) represented by a following formula (1):
Specifically, the examples of an alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a normal butyl group, an isobutyl group, a secondary butyl group, a tertiary butyl group, a normal pentyl group, an isopentyl group, a neopentyl group, a tertiary pentyl group, a normal hexyl group, and an isohexyl group. An alkyl group having 1 to 3 carbon atoms is preferred.
Specifically, the examples of an alkoxy group having 1 to 6 carbon atoms include a methoxy group, an ethoxy group, a normal propoxy group, an isopropoxy group, a normal butoxy group, an isobutoxy group, a secondary butoxy group, a tertiary butoxy group, a normal pentyloxy group, an isopentyloxy group, a neopentyloxy group, a normalhexyloxy group, or an isohexyloxy group. An alkoxy group having 1 to 3 carbon atoms is preferred.
A heterocyclic alkyl group is a heterocycle group (a monovalent group formed by detaching one hydrogen atom attached to the ring of a heterocyclic compound) to which an alkylene group is attached. A heterocycle group is, but not limited to, preferably a saturated or unsaturated 5- or 6-membered ring, more preferably a saturated 5- or 6-membered ring, such as pyrrolidinyl group, piperidyl group, piperidino group, morpholinyl group, morpholino group, piperazinyl group, pyrrolyl group, imidazolyl group, or pyridyl group. The alkyl moiety (alkylene group) is, but not limited to, preferably an alkylene group having 1 to 6 carbon atoms, and more preferably an alkylene group having 1 to 3 carbon atoms. Specifically, the examples of a heterocycle group include a piperidinomethyl group, a pyrrolidinylmethyl group, a piperidylmethyl group, a morpholinylmethyl group, a morpholinomethyl group, a piperazinylmethyl group, a pyrrolylmethyl group, an imidazolylmethyl group, a pyridylmethyl group, a (1-pyrrolidinyl)butyl group, a morpholinopropyl group, a 1,1 dimethyl-2-(1-pyrrolidinyl)ethyl group, a 1,1-dimethyl-2-piperidinoethyl group, a 1,1-dimethyl-3-(imidazol-1-yl)propyl group, a (2,6-dimethylpiperidino)methyl group, a (2,6-dimethylpiperidino)ethyl group, a (2,6-dimethylpiperidino)propyl group, etc.
A 5 to 7 membered heterocyclic ring, which may have a substituent, is preferably a 5- or 6-membered heterocyclic ring, most preferably a 6-membered heterocyclic ring. The heterocyclic ring is, but not limited to, a saturated or unsaturated heterocyclic ring, preferably a saturated heterocyclic ring. The examples of 5- to 7-membered heterocyclic ring are morpholine (tetrahydro-1,4-oxazine), piperazine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, imidazole, pyridine, tetrahydro-1,3-oxazine, or tetrahydro-1,2-oxazine.
The examples of the substituent include a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a phenylalkyl group having 1 to 6 carbon atoms. A phenylalkyl group having 6 to 12 carbon atoms is an alkylene group bonded to a phenyl group. An alkyl moiety (alkylene group) is, but not limited to, preferably an alkylene group having 1 to 6 carbon atoms, and more preferably an alkylene group having 1 to 3 carbon atoms.
Aldehyde group is a group represented by —CHO. A hydroxy group is a group represented by —OH.
An alkyl ester group having 1 to 6 carbon atoms is a group in which an alkyl group having 1 to 6 carbon atoms is bonded to an ester group (—COO—). An alkyl group having 1 to 6 carbon atoms is as described above.
An alkyl ester alkylene group is a group in which an alkyl group having 1 to 6 carbon atoms is bonded to an ester group (—COO—) and further bonded to alkylene group having 1 to 6 carbon atoms. An alkyl group having 1 to 6 carbon atoms is as described above. The examples of an alkylene group having 1 to 6 carbon atoms include a methylene group, an ethylene group, a n-propylene group, an isopropylene group, a n-butylene group, an isobutylene group, a t-butylene group, a n-pentylene group, a 2-methylbutylene group, a 2,2-dimethylpropylene group, a n-hexylene group, or a heptylene group.
Compound A is a derivative of 4-phenylcoumarin. 4-Phenylcoumarin and a derivative thereof can be synthesized by various methods. Compound B is a derivative of indole or indoline. Indole or indoline and derivatives thereof can also be synthesized by various methods. For example, indole can be synthesized by a gas phase reaction of aniline and ethylene glycol in the presence of catalyst, using aniline as the starting material. These compounds can also be purchased commercially.
The examples of compound A include, but not limited to, compound 10-0, compound 10-1, compound 10-2, compound 10-3, compound 10-4, and compound 10-5 represented by the following formulae:
The examples of compound B include, but not limited to, compounds 14-0, 14-1, 14-2, 14-3, 14-4, 14-5, 14-6, and 14-7 represented by the following formulae:
The salts of compound A and compound B are pharmaceutically acceptable salts, which may be acid addition salts or salts with bases, depending on the type of substituent. Specifically, the examples of acid addition salts or salts with bases include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartrate, ditoloyl tartrate, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid, salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, and organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine, and ammonium salts, etc.
Furthermore, the active ingredients used in the present invention also include various hydrates, solvates, and crystalline polymorphs of compound A or compound B and salts thereof. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
Prostate cancer, which is the therapeutic target of the pharmaceutical composition of the present invention, is cancer that develops in the prostate gland and an antiandrogenic agent may be administered as hormone therapy. The type of prostate cancer to be treated is, but not limited to, androgen-independent prostate cancer (CRPC) that has acquired resistance to hormone therapy, which is a particularly effective target. As shown in the Examples described later, the pharmaceutical composition of the present invention can be effectively used for CRPC that has acquired resistance to hormone therapy, since the pharmaceutical composition shows remarkable anticancer effects on AR-positive CRPC and AR-negative CRPC. However, the pharmaceutical composition can also be used to treat prostate cancer that is not hormone therapy-resistant or CRPC by other mechanisms.
Breast cancer, which is the therapeutic target of the pharmaceutical composition of the present invention, is a carcinoma that develops in the breast tissue, and an anti-estrogen agent may be administered as hormone therapy. The type of breast cancer to be treated is, but not limited to, estrogen-independent breast cancer that has developed resistance to hormone therapy, which is a particularly effective target. However, the pharmaceutical composition can also be used to treat breast cancer that is not hormone therapy-resistant or resistant to treatment by other mechanisms.
The inventors of the present invention have found that RNA-binding protein PSF (PTB-associated Splicing Factor) regulates factors involved in the malignant transformation of cancer in prostate cancer or breast cancer that has acquired resistance to hormone therapy. For example, PSF upregulates the expression of AR or its spliced variant, AR-V7, which is increased in Castration-resistant prostate cancer (CRPC). PSF expression is also upregulated in breast cancer OHTR cells that have acquired resistance to hormone therapy compared with the parental MCF7 cells that is sensitive to hormone therapy.
Compounds A and B used in the present invention can bind to PSF. As shown in the Examples, the expression of AR, AR-V7, and SchLaP1, which are target genes of PSF at the RNA level, can be inhibited in 22Rv1 cells, a model cell for hormone-resistant prostate cancer. In addition, in OHT-TamR cells, a hormone-resistant model of breast cancer, the expression of ERα and SCFD2, which are downstream genes of PSF, can be inhibited.
That is to say, it is considered that compounds A and B are effective for the treatment of hormone therapy-resistant prostate cancer or breast cancer by binding to PSF and suppressing the function of PSF.
A pharmaceutical composition containing one or more of the above-mentioned compound A or compound B, or salts thereof as an active ingredient can be prepared by using excipients commonly used in the art, that is to say, excipients for pharmaceutical compositions and drug carriers, etc., by a method commonly used in the art.
Administration may be oral in pill, capsule, granule, powder, or liquid form, etc., or parenteral in injection such as intra-articular, intravenous, or intramuscular, suppository, eye drop, eye ointment, transdermal solution, ointment, transdermal patch, transmucosal solution, transmucosal patch, inhalation, etc.
The examples of solid composition for oral administration include tablets, dispersions, and granules. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and/or magnesium metasilicate. The composition may contain inert additives, such as lubricants e.g., magnesium stearate, disintegrants e.g., sodium carboxymethylstatinate, stabilizer, solubilizer, etc., according to conventional methods. Tablets or pills may be coated with a sugar coating or a film of a gastric or enteric soluble substance as needed. The examples of liquid composition for oral administration include pharmaceutically acceptable emulsion, solution, suspension, syrup, or elixir, which contain commonly used inert diluent, such as purified water or ethanol. In addition to the inert diluent, the liquid composition may contain auxiliary agents such as solubilizer, wetting agent, and suspending agent, sweetening agent, flavoring agent, aromatic agent, and preservative.
The examples of injectable drug for parenteral administration include sterile aqueous or non-aqueous solution, suspension or emulsion. The examples of aqueous solvent include, distilled water or saline solution for injection. The examples of nonaqueous solvent include, propylene glycol, polyethylene glycol or vegetable oils such as olive oil, alcohols such as ethanol, or polysorbate 80 (pharmacopeia name). Such composition may further contain isotonicity agent, preservative, wetting agent, emulsifier, dispersant, stabilizer, or solubilizer. These are sterilized, for example, by filtration through a bacteria-retaining filter, the addition of a bactericidal agent, or irradiation. These can also be produced as sterile solid composition and dissolved or suspended in sterile water or sterile injectable solvent, prior to use.
The examples of topical products include ointments, hard plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments, etc. The examples of topical products also include commonly used ointment bases, lotion bases, aqueous or non-aqueous liquids, suspensions, emulsions, etc. The examples of ointment or lotion bases include polyethylene glycol, propylene glycol, white vaseline, white beeswax, polyoxyethylene hardened castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sesquioleinic acid sorbitan, etc.
Transmucosal agents, such as inhalants and nasal spray, may be used in solid, liquid, or semi-solid form and can be manufactured according to conventionally known methods. For example, known excipients, pH adjusters, preservatives, surfactants, lubricants, stabilizers and thickeners may be added appropriately. Any suitable devices for inhalation or air delivery may be used for administration. For example, transmucosal agents may be administered using known devices such as metered dose inhalation devices or atomizers, as a compound alone or as a powder in a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier. Dry powder inhalers and the like may be used for single or multiple doses, and dry powder or powder-containing capsules may be used. Alternatively, transmucosal agents may be administered in the form of a pressurized aerosol spray using suitable ejection agents, such as preferred gases, for example, chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide, etc.
Dosage varies depending on the type of disease, symptom, age, and gender of patients. The usual dosage for oral administration is approximately 0.001 mg/kg-500 mg/kg per day for adults, which is administered once or divided into two to four doses. When administered by injection, injection is administered as a rapid intravenous infusion or intravenous drip at a dose of approximately 0.0001 mg/kg-10 mg/kg once or twice per day for adults. When administered by inhalation, a single or multiple doses of approximately 0.0001 mg/kg-10 mg/kg per adult per day is administered. When administered by transdermal drug, transdermal drug is applied once or twice per day at a dose of approximately 0.01 mg/kg-10 mg/kg per day for adults.
Compound A or compound B, or salts thereof, may be used in combination with various therapeutic or prophylactic agents for diseases for which compound A or compound B, or salts thereof is considered to be effective. The combination use may be simultaneous, or separate and consecutive, or at desired time intervals. The simultaneous administration formulation may be a compounding agent or a separate formulation.
<<Method for Treating Prostate Cancer or Breast Cancer>>
The compound A or compound B may be used for the treatment of prostate cancer or breast cancer. That is to say, this specification discloses a method for treating prostate cancer or breast cancer comprising the step of administering a therapeutically effective amount of a compound represented by the formula (1) or a salt thereof, or a compound represented by the formula (2) or (3) or a salt thereof, to a patient having prostate cancer or breast cancer patient.
<<Compound A or Compound B for Use in the Treatment of Prostate or Breast Cancer>>
The compound A or compound B may be used for the treatment of prostate cancer or breast cancer. That is to say, this specification discloses a compound represented by the formula (1) or a salt thereof, or a compound represented by the formula (2) or (3) or a salt thereof for use in the treatment of prostate or breast cancer.
<<Use of Compound A or Compound B in the Manufacture of Pharmaceutical Composition>>
The compound A or compound B may be used for the manufacture of a pharmaceutical composition for the treatment of prostate cancer or breast cancer.
That is to say, this specification discloses use of a compound represented by the formula (1) or a salt thereof, or a compound represented by the formula (2) or (3) or a salt thereof, in the manufacture of a pharmaceutical composition for the treatment of prostate cancer or breast cancer.
<<Function>>
The mechanism by which compound A or compound B is effective in the treatment of prostate cancer or breast cancer has not been analyzed in detail, but can be estimated as follows. A compound A is a derivative of 4-phenylcoumarin. The skeleton of 4-phenylcoumarin is considered to be important for binding to PSF (anticancer effect). Furthermore, the presence of an oxygen atom at the 7-position of coumarin is considered to enhance the anticancer effect. A compound B is a derivative of indole or indoline. The skeleton of indole or indoline is considered to be important for the binding to PSF (anticancer effect).
The present invention will now be further illustrated by, but is by no means limited to, the following Examples.
In this Example, the effects of compound A and compound B on the proliferative ability of 22Rv1, a model cell line of hormone therapy-resistant prostate cancer, and LTAD (long time androgen deprived) cells, a model of hormone therapy resistance, were examined.
Cells were seeded in a 96-well plate (3×103 cells/well), and compound 10-0 and compound 14-0 were added at the concentration of 30 μM. After 3 days, cell proliferative ability was evaluated by MTS assay. The MTS assay was performed as follows:
The reaction was carried out using Cell titer 96 (Promega). The MTS assay is an assay to measure the number of viable cells that based on the reduction reaction of tetrazolium salt [MTS; 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] to the formazan product that is a chromogenic substance. After 1 hour incubation, the absorbance is measured using a microplate reader at 490 nm to evaluate cell proliferative ability.
Furthermore, the MST assay was performed in the same manner using LTAD and VCaP cells by adding 1 μM or 10 μM of compound 10-0, 10-1, 10-3, 14-0, or 14-5.
The results showed that all the compounds 10-0, 10-1, 10-3, 14-0, and 14-5 significantly suppressed cell proliferation (
In this Example, the inhibitory ability of compounds 10-0, 10-1, 10-2, 10-3, 10-4, 14-0, and 14-5 to the interaction of PSF with its target RNA was examined by RNA pull-down method.
A biotin-labeled probe for CTBP1-AS was prepared using Biotin RNA Labeling Mix (Roche). The RNA probe was prepared by T7 RNA polymerase using a DNA strand in which 1.5 kb of CTBP1-AS was incorporated into T7 promoter as a template. RNA was mixed with nuclear extracts extracted from cells with RIP buffer and rotated at 4° C. for 8 hours for binding. Avidin beads were added and the mixture was rotated for 2 hours to collect biotinylated RNA probes. The beads were collected by centrifugation, washed with buffer three times, and then SDS sample buffer was added to the beads, and the bound proteins were examined by Western blotting. 22Rv1 cells were used to prepare nuclear extracts in the same manner as in Example 1, except the concentrations of the added compounds were varied.
As shown in
In this Example, the effects of compounds 10-0, 10-1, 10-3, 14-0, and 14-5 on cell proliferation were examined using a model cell line of hormone therapy-resistant prostate cancer 22Rv1, breast cancer cell MCF7, and a model of hormone therapy-resistant OHTR cells established from MCF7 cells. The MTS assay was performed as in Example 1.
As shown in
In this Example, the expression levels of PSF target genes at the RNA level, AR, AR-V7, SchLaP1, and downstream signals of AR, FKBPS and ACSL3, were examined by adding compounds 10-0, 10-1, and 10-3 to 22Rv1 cells.
22Rv1 cells were treated with compounds 10-0, 10-1, and 10-3. After 48 hours incubation, total RNA was collected to examine changes in mRNA expression of the target genes. This analysis was performed by quantitative real-time PCR as follows
Total RNA was collected from cells using ISOGEN (NIPPON Gene). cDNA was synthesized using Prime script RT reagent kit (TaKaRa Bio). Step one real-time PCR (Applied biosystem) and KAPA SYBR Fast PCR kit (NIPPON Genetics) were used to measure the mRNA expression levels of each gene and the internal control, GAPDH. The expression levels for GAPDH were calculated from the number of cycles using the ΔΔCt method.
It was confirmed that the mRNA expression of AR, AR-V7, SchLaP1, FKBPS, and ACSL3 was suppressed by the administration of compound 10, 10-1, or 10-3 (10 μM) (
In this Example, compounds 10-0, 10-1, and 10-3 were added to hormone therapy resistant breast cancer model OHT-TamR cells. After 48 hours of cultivation, the cells were collected, lysed, and immunoprecipitated with PSF antibody. Then total RNA binding to PSF protein was extracted. Quantitative PCR was used to quantify the amount of RNA bound to PSF for ERα, SCFD2, and TRA2B, which are target genes of PSF at the RNA level. As a control, GAPDH-bound RNA was also quantified.
OHT-TamR cells were treated with compounds 10-0, 10-1, and 10-3 for 48 hours. Total RNA binding to PSF protein was collected from immunoprecipitated beads, and the amount of each target gene and GAPDH as a control was measured. Quantitative real-time PCR was performed as in Example 4.
It was confirmed that the binding of ERα, SCFD2, and TRA2B to PSF protein was significantly inhibited by the administration of compound 10-3 (10 μM) compared to GAPDH, and binding of ERα and SCFD2 was significantly inhibited by the administration of 10-1 (
In this Example, anticancer effect of compound 10-3 in vivo was examined using a xenograft mouse model.
For tumor transplantation, 22Rv1 cells were adjusted to 1×107, mixed with Matrigel at 1:1, and injected subcutaneously into 6-week-old male nude mice (BALB/cAJcl-nu/nu). Five to eight days after subcutaneous injection, testes were removed when the tumor volume reached about 100-200 mm3, to prepare a model of hormone therapy refractory CRPC tumors. Six mice were injected intraperitoneally with compound 10-3 at a concentration of 1 mg/kg. Vehicle (DMSO) was administered as a control. The treatment was repeated 5 times/week for 2 weeks, and the tumor diameter was measured (
As shown in
In addition, administration of compound 10-3 reduced the number of cells expressing Ki67 and AR in tumor tissues (
In this Example, the effects of compounds 10-1 and 10-3 on cell proliferation were examined using an AR-negative CRPC model DU145 cells. The MTS assay was performed as in Example 1.
As shown in
In this Example, anticancer effect of compound 10-3 in vivo was examined using an AR-negative CRPC tumor xenograft model, in which DU145 cells were subcutaneously transplanted to mice.
For tumor transplantation, DU145 cells were adjusted to 1×107, mixed with Matrigel at 1:1, and injected subcutaneously into 6-week-old male nude mice (BALB/cAJcl-nu/nu). Five to eight weeks after subcutaneous injection, when the tumor volume reached about 100-200 mm3, compound 10-3 was injected intraperitoneally at a concentration of 5 mg/kg into 8 mice (the photo shows 4-5 mice). Controls were injected with Vehicle (DMSO). The treatment was repeated 5 times/week for 3 weeks, and the tumor diameter was measured (
As shown in
In this Example, the binding site of compound 10-3 to PSF, which is the target protein of the present invention, was examined by docking assay. Furthermore, mutations were introduced into the amino acids of PSF that are predicted to interact with compound 10-3, and the inhibitory effect of compound 10-3 on the interaction of PSF with its target RNA was examined.
The crystal structure of human PSF (276-535 amino acids) was downloaded from the Protein Data Bank (PDB). The volume and shape of the binding cavities were analyzed using the SiteFinder module of the Molecular Operation Environment (MOE) program. As a result, compound 10-3 was estimated to bind to the Coild-Coil site from the NOPS of PSF, as shown in
The following combinations of mutations were introduced into the above-mentioned presumed site at position 490, tyrosine (Y), position 516, lysine (K), and position 517, aspartic acid (D).
The binding of mut #1, mut #2, mut #1+2, or wild-type PSF to the RNA strand of CTBP1-AS was examined by RNA pull-down method. The inhibitory effect for binding of compound 10-3 was measured by adding compound 10-3. Compared to the wild type, mut #1, mut #2, or mut #1+2s mutant showed the decreased inhibitory effect on the PSF binding to the RNA probe by the addition of compound 10-3. Therefore, it is likely that compound 10-3 binds to tyrosine (Y) at position 490, lysine (K) at position 516, and aspartate (D) at position 517 in the region spanning from NOPS to Coild-Coil of PSF.
The pharmaceutical composition of the present invention can be effectively used for the treatment of prostate cancer and breast cancer.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2020-165745 | Sep 2020 | JP | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/JP2021/015982 | 4/20/2021 | WO |
