WO2022196614A1 - Agent de traitement ou de prévention de la maladie de chagas - Google Patents

Agent de traitement ou de prévention de la maladie de chagas Download PDF

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WO2022196614A1
WO2022196614A1 PCT/JP2022/011217 JP2022011217W WO2022196614A1 WO 2022196614 A1 WO2022196614 A1 WO 2022196614A1 JP 2022011217 W JP2022011217 W JP 2022011217W WO 2022196614 A1 WO2022196614 A1 WO 2022196614A1
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group
coptisine
compound
chagas disease
same
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PCT/JP2022/011217
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English (en)
Japanese (ja)
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謙二 平山
雄基 田山
修作 水上
かつ子 小松
一文 當銘
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国立大学法人 長崎大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis

Definitions

  • the present invention relates to a compound effective in treating or preventing Chagas disease, preferably a compound effective in treating or preventing acute and/or chronic Chagas disease. Furthermore, it relates to a therapeutic or prophylactic agent for Chagas disease containing the compound.
  • Chagas disease caused by the protozoan Trypanosoma cruzi, is a tropical disease (infectious disease) transmitted by the triatomine bug, which is widespread in Latin America and the Caribbean.
  • the disease stage is roughly divided into an acute stage and a chronic stage.
  • An object of the present invention is to provide a therapeutic or preventive agent for Chagas disease containing a compound effective for the treatment or prevention of Chagas disease.
  • the compound is one or more selected from the group consisting of coptisine and dehydrocorridarin or a salt thereof, or a compound represented by general formula (I) or a salt thereof, [1] or [ 2].
  • the agent according to any one of [1] to [5] which is further characterized by being effective for the treatment or prevention of acute and chronic Chagas disease.
  • a compound effective for the treatment or prevention of Chagas disease and an agent for the treatment or prevention of Chagas disease containing the compound can be provided.
  • FIG. 2 is a diagram showing the results of evaluation of antitrypanosomal activity (crude drug extract/crude drug-derived compound), which is primary screening.
  • FIG. 2 is a diagram showing the results of a cytotoxicity test (herbal drug extract and herbal drug-derived compound), which is a secondary screening.
  • FIG. 2 shows the results of measuring the antitrypanosomal activity of the compounds of the present invention.
  • FIG. 3 shows the results of IC 50 measurements on intracellular amastigotes for the compounds of the present invention.
  • FIG. 2 shows the results of measurement of cytotoxicity against NBMH cells for compounds of the present invention.
  • FIG. 2 shows the results of measuring the cytotoxicity of the compounds of the present invention against HuH28 cells.
  • A Images of in vivo luminescence intensity after intraperitoneal administration of coptisine to mice.
  • Chaagas disease is a tropical disease (infectious disease) caused by Trypanosoma cruzi protozoa and transmitted by an insect called assassin bug.
  • acute phase Chagas disease usually refers to a period of several weeks to several months immediately after infection, and refers to asymptomatic symptoms or symptoms such as fever, fatigue, itching, headache, and diarrhea.
  • red swelling and lumps appearing on the skin where the protozoa have invaded chagoma
  • Romagna sign due to bites by kissing bugs or contact with the feces of kissing bugs.
  • This symptom usually disappears spontaneously within a few weeks, but the protozoa may remain in the body and enter a long incubation period.
  • the state in which trypomastigotes are present in the blood and the state in which amastigotes are present in the cells may be referred to as the "acute phase” or a state simulating the "acute phase.” .
  • the “chronic phase” of Chagas disease refers to cardiac complications (cardiac hypertrophy, heart failure, changes in heart rate, arrhythmia, apical artery aneurysm/thrombosis, cardiopulmonary arrest (sudden death), etc.), intestinal complications (enlargement of the esophagus or colon (megaesophagus/megacolon), difficulty eating or excretion due to these) refers to the state. These symptoms may be seen in about 10 to 30% of infected people.
  • the state in which amastigotes proliferate in cells may be referred to as a "chronic phase” or a state simulating a "chronic phase.”
  • the therapeutic or preventive agent (composition) for Chagas disease of the present invention is described in detail below.
  • the therapeutic or preventive agent (composition) for Chagas disease of the present invention is a compound or a salt thereof selected from the group consisting of coptisine, berberine, palmatine, epiberberine, berberrubine and ditetrahydrocoptisine, or the following general formula:
  • Compound represented by (I) in this specification, may be referred to as "analogous compound” or a salt thereof (wherein R 1 , R 2 , R 3 and R 4 may be the same or different, hydrogen atom, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1 -6 haloalkyl group, C 3-6 cycloalkyl group, preferably hydrogen atom, C 1-6 alkyl group or C 3-6 cycloalkyl group, more preferably hydrogen atom or C 1-6 is an alkyl group.
  • R 1 may form a 5- or 6-membered ring together with R 2 and the adjacent oxygen atom
  • R 3 may form a 5- or 6-membered ring together with R 4 and the adjacent oxygen atom
  • R 5 , R 6 , R 7 and R 8 may be the same or different and are C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, halogen atom, C 1-6 haloalkyl group , a C 3-6 cycloalkyl group, a C 1 -C 6 alkoxy group, a carboxyl group or an amino group, preferably a C 1-6 alkyl group, a halogen atom or a C 3-6 cycloalkyl group.
  • the nitrogen atom is a C 1-6 alkyl group or a halogen atom.
  • the therapeutic or preventive agent (composition) for Chagas disease of the present invention is a compound or a salt thereof selected from the group consisting of coptisine, berberine, palmatine, epiberberine, berberrubine and ditetrahydrocoptisine, or the above
  • the compound represented by general formula (I) or a salt thereof is contained as an active ingredient.
  • the "C 1 -C 6 alkyl group” includes, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, secondary butyl group, tertiary butyl group, pentyl group and isopentyl group. , a tertiary pentyl group, a neopentyl group, a 2,3-dimethylpropyl group, and other linear or branched alkyl groups, but are not limited thereto.
  • the "C 2 -C 6 alkenyl group” includes, for example, linear groups such as vinyl group, allyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 2-methyl-2-propenyl group, and the like. or branched alkenyl groups, but are not limited thereto.
  • the "C 2 -C 6 alkynyl group” includes, for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 3-methyl- Linear or branched alkynyl groups such as 1-propynyl group and phenylethynyl group may be mentioned, but not limited thereto.
  • halo means "halogen atom"
  • the halogen atom indicates a chlorine atom, a bromine atom, an iodine atom or a fluorine atom.
  • C 3 -C 6 cycloalkyl group includes, but is not limited to, cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
  • the "C 1 -C 6 alkoxy group” includes, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, secondary butoxy group, tertiary butoxy group, pentyloxy group, isopentyloxy linear or branched alkoxy groups such as neopentyloxy groups, etc., but are not limited thereto.
  • Preferred salts for use in the present invention include, for example, inorganic acid salts such as hydrochlorides, sulfates, nitrates and phosphates, acetates, fumarates, maleates, oxalates, methanesulfonates, and benzenesulfones.
  • Salts, organic acid salts such as p-toluenesulfonate, and salts with inorganic or organic bases such as sodium ion, potassium ion, calcium ion, and trimethylammonium can be exemplified, but are not limited to these.
  • the agent for treating or preventing Chagas disease of the present invention contains a compound or a salt thereof selected from the group consisting of coptisine, berberine and palmatine, or a compound represented by the general formula (I) or a salt thereof. More preferably, the agent for treating or preventing Chagas disease of the present invention contains coptisine or a salt thereof, more preferably coptisine hydrochloride, but is not limited thereto.
  • the therapeutic or prophylactic agent for Chagas disease of the present invention includes, but is not limited to, dehydrocorridarin nitrate or palmatine hydrochloride.
  • Another preferred embodiment of the agent for treating or preventing Chagas disease of the present invention includes, but is not limited to, one or more selected from the following six compounds or salts thereof.
  • a compound or a salt thereof selected from the group consisting of coptisine, berberine, palmatine, epiberberine, berberrubine and ditetrahydrocoptisine, or the general formula (I)
  • a plurality of represented compounds or salts thereof eg, 1 or more, 2 or more, 3 or more, 1 to 5, or 2 to 4, etc. may be included.
  • the agent for treating or preventing Chagas disease of the present invention is useful not only for the treatment or prevention of acute phase Chagas disease, but also for the treatment or prevention of chronic phase Chagas disease.
  • the agent of the present invention is effective in treating or preventing acute phase symptoms of Chagas disease, and more preferably, the agent of the present invention is effective in treating or preventing acute phase symptoms and chronic phase symptoms.
  • the content of the above compound in the agent or composition for treating or preventing Chagas disease of the present invention is not particularly limited, but in 100% by mass of the agent or composition, for example, in the range of about 50% to about 100% by mass. It may be present, preferably in the range of about 75% to about 100% by weight, more preferably about 90% to about 100% by weight.
  • the agent or composition of the present invention can be formulated by appropriately blending the above-described compound of the present invention or a salt thereof and, if desired, pharmaceutically acceptable carriers, additives and the like.
  • Formulation methods and techniques for this purpose have been well established in the past, and may be followed.
  • pharmaceuticals specifically oral agents such as tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, injections, infusions, suppositories, ointments
  • Parenteral agents such as patches can be used, but are not limited to these.
  • the mixing ratio of the carrier or additive may be set as appropriate based on the range normally employed in the field of pharmaceuticals and the like.
  • Pharmaceutically acceptable carriers or additives are not particularly limited, but examples of carriers include various carriers such as aqueous or oily bases, and examples of aqueous carriers include water, physiological saline, and ethanol. , glycerin, polyethylene glycol, propylene glycol, methyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyacrylic acid, polysaccharide gum-based natural polymers, etc.
  • oily carriers include vaseline, squalane, Examples include, but are not limited to, oils such as paraffin and waxes.
  • additives examples include enzymes, pH adjusters, preservatives, bactericides, excipients, binders, disintegrants, lubricants, antioxidants, brighteners, flavors, sweeteners, acidulants, seasonings. , bittering agents, emulsifiers, thickeners, stabilizers, gelling agents, coloring agents, flavoring agents, flavoring agents, and the like. Techniques for these additives are well established in the prior art, and may be followed in the present invention. Furthermore, the composition of the present invention may contain any ingredient known in the fields of medicine, pharmacy, veterinary medicine, food, etc., as long as the effects of the present invention are not lost.
  • the compound of the present invention can be administered orally or parenterally.
  • the administration form include oral administration, topical administration to the eye, intravenous administration, transdermal administration, etc., and if necessary, pharmaceutically acceptable additives are appropriately selected and used, and a dosage form suitable for the administration form is used.
  • can be formulated into For example, when the compound of the present invention or a salt thereof is administered orally or by injection, it can be determined depending on the age and body weight of the ingestor, symptoms, administration time, dosage form, administration method, drug combination, and the like.
  • the intake is preferably about 60 to 600 mg/mL per adult (about 60 kg) per day. If administered by injection, it is preferably set to inject up to about 60 mg/mL.
  • the amount of the compound or its salt to be applied can be appropriately selected according to the skin area to be applied. is preferably about 0.01-5 mg, more preferably about 0.05-1 mg. It is preferable to administer or apply the above administration dose once or in several divided doses per day.
  • the compound of the present invention e.g., a compound or a salt thereof selected from the group consisting of coptisine, berberine, palmatine, epiberberine, berberrubine and ditetrahydrocoptisine, or the above Compounds represented by general formula (I), etc.
  • the compound of the present invention e.g., a compound or a salt thereof selected from the group consisting of coptisine, berberine, palmatine, epiberberine, berberrubine and ditetrahydrocoptisine, or the above Compounds represented by general formula (I), etc.
  • Methods for encapsulating compounds are well established in the art and may be followed.
  • Cukabit[n]uril (usually n is 5 to 10) is a barrel-shaped compound (see below) with n glycourils, which are structural units, arranged in a ring and having a hydrophobic vacancy inside. be.
  • Cukabit [n] uril is known to selectively show a very high interaction with compounds having a naphthalene structure, a cholesterol structure, etc. compounds selected from the group consisting of epiberberine, berberrubine and ditetrahydrocoptisine or salts thereof).
  • a method for producing such a cukabit[n]uril is described, for example, in JP-A-2012-246239, and the method may be followed. Alternatively, a commercially available product (Merck) may be used.
  • n is preferably 6-9, more preferably 7-8.
  • Cucurbit[n]uril is synthesized by the method described in JP-A-2012-246239.
  • the compounds of the present invention can be incorporated into cukabit[n]urils by mixing, for example, 2:1 to 1:2 in a solvent suitable for inclusion (such as an organic solvent). . Water solubility is improved by inclusion of the compound of the present invention.
  • Cukabit is sometimes written as cucurbit, but it is the same thing.
  • Another embodiment of the compound preferably encompassing the compound of the present invention includes dextrins such as ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, and cluster dextrin, as well as crown ethers (e.g., 12-crown -4, 15-crown-5, 18-crown-6, etc.), fullerene (e.g., C60 fullerene, C70 fullerene, etc.), calix[m]arene (m: 3 to 20, preferably n: 4 to 8 ), pillar arenes (eg, 1,4-dimethoxy pillar[5]arene), and the like, but are not limited thereto.
  • the effect of the present invention treatment of acute and / or chronic Chagas disease or preventive effect, etc.
  • the effect of the present invention treatment of acute and / or chronic Chagas disease or preventive effect, etc.
  • ⁇ Compound, Reagent> Crude drug-derived compounds and crude drug extracts: those provided by the Institute of Japanese and Chinese Medicine, University of Toyama as a Japanese and Chinese drug library were used.
  • New Born Mouse Heart (NBMH) cells those provided by Nekken Bioresource Center, Nagasaki University were used.
  • HuH28 cells those provided by Chulabhorn International School of Medicine, Thammasat University were used.
  • D-luciferin (MB000102-R70170-2) Syd Labs
  • Coptisine chloride (C685500) Toronto Research Chemicals
  • Isoflurane (095-06573) Wako Pure Chemical
  • Cyclophosphamide monohydrate (C0768) SIGMA-ALDRICH.
  • Example 1 Primary screening using antitrypanosomal activity as an index 1-1 Experimental method Trypomastigotes ( 3 x 104 cells/well) in which luciferase gene was incorporated in a 96-well white plate and fibers isolated from mouse heart Blast cells (NBMH cells) (5 ⁇ 10 4 cells/well) were seeded. Either the herbal drug-derived compound (20 ⁇ M) or herbal drug extract (20 ⁇ g/mL) described in Tables 1 and 2 above was added to each well and cultured for 72 hours. NP40 was added as a positive control, and only the solvent in which the drug was dissolved was added to the negative control. In addition, wells were provided to add benznidazole, an existing drug. The volume per well was 100 ⁇ l.
  • Example 1 After culturing for 72 hours, 100 ⁇ l of 0.6% NP40 was added to disrupt the cells. The disrupted cells and medium were transferred to a 1.5 mL tube and centrifuged (12,000 rpm, 15 minutes). After centrifugation, 100 ⁇ l of luciferin (Picagene) was added to 50 ⁇ l of the supernatant, and the luminescence intensity (544 nm/590 nm) was measured with a plate reader (measurement time: 1 second). Taking the luminescence suppression rate of the negative control as 0% and the luminescence suppression rate of the positive control as 100%, the luminescence suppression rate of each compound or extract was calculated. The experimental method of Example 1 was based on the method described in Bettiol et al. (PLoS Neglected Tropical Diseases, 2009, 3(2): e384.) effect on amastigotes can be confirmed.
  • Example 2 Secondary Screening Using Cytotoxicity as Index 2-1 Experimental Method NBMH cells (1 ⁇ 10 4 /well) and HuH28 cells (1 ⁇ 10 4 /well) were seeded in a 96-well black plate. Either a crude drug-derived compound (20 ⁇ M) or a crude drug extract (20 ⁇ g/mL) was added to each well and cultured for 72 hours. As a positive control, NP40 was added, and as a negative control, only solvent in which the drug was dissolved was added. In addition, wells were provided to add benznidazole, an existing drug. The volume per well was 100 ⁇ l. After culturing for 72 hours, 10 ⁇ l of Alamar Blue reagent was added, and the cells were further incubated for 4 hours. After that, the fluorescence intensity was measured with a plate reader (measurement time 0.1 sec).
  • FIG. (A) is the result of the crude drug extract
  • (B) is the result of the crude drug-derived compound.
  • the compounds or extracts that showed a decrease in luminescence intensity of 80% or more in the primary screening three of them, Coptisine Chloride, Dehydrocorydaline Nitrate, and Palmatine Chloride, showed fluorescence. No decrease in strength was observed, indicating no cytotoxicity. Since these three compounds had a common structure, three more analogues (berberrubine, epiberberine, and di-tetrahydrocoptisine) were added. Six compounds were tested for activity against trypanosomes.
  • Example 3 Measurement of IC50 of Antitrypanosoma Activity 3-1 Experimental Method The antitrypanosoma activity of the above six compounds was measured by the same experimental method as in Example 1.
  • the concentrations of coptisine, dehydrocorridarin and palmatine were 40 ⁇ M, 33 ⁇ M, 20 ⁇ M, 16.5 ⁇ M, 10 ⁇ M, 8.25 ⁇ M, 5.0 ⁇ M, 4.13 ⁇ M, 2.5 ⁇ M, 2.06 ⁇ M and 1.25 ⁇ M.
  • Berberrubine, epiberberine and ditetrahydrocoptisine concentrations were 50 ⁇ M, 25 ⁇ M, 12.5 ⁇ M, 6.25 ⁇ M, 3.125 ⁇ M and 1.6 ⁇ M.
  • Example 4 Measurement of IC50 of Activity against Intracellular Amastigote 4-1 Experimental Method Trypomastigotes expressing luciferase gene and NBMH cells were seeded in a 25 cm 2 flask at a ratio of 2:1. The medium was MEM+1% NBCS to enhance intracellular infection. After 24 hours, the cells were washed twice with PBS, added with MEM+10% NBCS, and further cultured in an incubator for 24 hours. After that, trypsin treatment was performed to detach NBMH cells containing Trypanosoma cruzi (T. cruzi). NBMH cells (5 ⁇ 10 4 /well) containing T. cruzi were seeded in a 96-well white plate.
  • T. cruzi Trypanosoma cruzi
  • One of the above six compounds was added to each well and cultured for 72 hours.
  • the concentrations of coptisine, dehydrocorridarin and palmatine were 40 ⁇ M, 33 ⁇ M, 20 ⁇ M, 16.5 ⁇ M, 10 ⁇ M, 8.25 ⁇ M, 5.0 ⁇ M, 4.13 ⁇ M, 2.5 ⁇ M, 2.06 ⁇ M and 1.25 ⁇ M.
  • Berberrubine, epiberberine and ditetrahydrocoptisine concentrations were 50 ⁇ M, 25 ⁇ M, 12.5 ⁇ M, 6.25 ⁇ M, 3.125 ⁇ M and 1.6 ⁇ M.
  • NP40 was added, and as a negative control, only solvent in which the drug was dissolved was added.
  • Benznidazole an existing drug.
  • the volume per well was 100 ⁇ l.
  • the concentrations of coptisine hydrochloride, dehydrocorridarin nitrate and palmatine hydrochloride are the same as in Example 3.
  • the concentrations of epiberberine, berberrubine and ditetrahydrocoptisine were 100 ⁇ M, 50 ⁇ M, 25 ⁇ M, 12.5 ⁇ M, 6.25 ⁇ M and 3.125 ⁇ M.
  • 100 ⁇ l of 0.6% NP40 was added to disrupt the cells. The disrupted cells and medium were transferred to a 1.5 ml tube and centrifuged (12,000 rpm, 15 minutes).
  • Example 4 100 ⁇ l of luciferin (Picagene) was added to 50 ⁇ l of the supernatant, and the luminescence intensity (544 nm/590 nm) was measured with a plate reader (measurement time: 1 second). Taking the luminescence suppression rate of the negative control as 0% and the luminescence suppression rate of the positive control as 100%, the luminescence suppression rate of each compound or extract was calculated.
  • the experimental method of Example 4 was described by Rycker et al. (PLoS Negl Trop Dis. 2016 Apr 15;10(4):e0004584) and Alonso-Padilla et al. ) was used as a reference. This experimental system can confirm the effect of trypanosome-infected cells on proliferating amastigotes.
  • Example 5 Evaluation of cytotoxicity against NBMH cells 5-1 Experimental method For the above six compounds, the same experimental method as in Example 2 except that the cells used in the experimental method of Example 2 were changed to one type of NBMH cells. was evaluated for cytotoxicity against NBMH cells. The concentration of each compound is the same as in Example 4.
  • Example 6 Evaluation of cytotoxicity against HuH28 cells 6-1 Experimental method For the above six compounds, the same experimental method as in Example 2 except that the cells used in the experimental method of Example 2 were changed to one type of HuH28 cells. was evaluated for cytotoxicity against HuH28 cells. The concentration of each compound is the same as in Example 4.
  • Example 7 Effect of coptisine on mice 7-1
  • Experimental method 1 ⁇ 10 4 cells of T. cruzi (trypomastigotes type, Tulahuen strain) were intraperitoneally administered to 7- to 8-week-old female BALB/c mice. The drug was administered for 5 consecutive days from day 4 to day 8 of infection.
  • Coptisine was administered intraperitoneally twice daily at a dose of 30 mg/kg. Thereafter, immunosuppression was performed by intraperitoneal administration of 200 mg/kg of cyclophosphamide monohydrate on days 31, 34, and 37 of infection.
  • Benznidazole 100 mg/kg was orally administered once a day as a positive control.
  • As a negative control 1% PBS was orally administered once a day.
  • Luminescence intensity was measured on day 14 of infection, day 28 of infection, and day 40 of infection after immunosuppression, including the day before the start of drug administration (day 3 of infection) and the day after the end of drug administration (day 9 of infection). I went there a total of 5 times. Luminescence intensity was measured by intraperitoneally administering D-luciferin at 150 mg/kg, inhaling isoflurane for 10 minutes, and using the luminescence in vivo imaging system IVIS Lumina II.
  • FIG. Figure 7-1 is an image of the in vivo luminescence intensity of each group of mice
  • Figure 7-2 is the result of quantification of the luminescence intensity.
  • Intraperitoneal administration of coptisine to trypanosome-infected mice decreased the luminescence intensity.
  • coptisine attenuated the fluorescence intensity to the same level as or more than that of benznidazole on day 40 of infection after immunosuppression, which is a chronic phase model. This result indicates that coptisine is effective in the acute and chronic stages of trypanosomal infection.
  • Example 8 (improvement of water solubility by inclusion of compound) Copticine hydrochloride or berberine hydrochloride was added to cukabit[7]uril by mixing cukabit[7]uril and coptisine hydrochloride or berberine hydrochloride purchased from Merck & Co. 1:1 in water. subsumed. Inclusion improved the water solubility of coptisine hydrochloride or berberine hydrochloride. Coptisine hydrochloride or berberine hydrochloride with such improved water solubility is suitable for, for example, in vivo administration (oral administration, injection administration), and thus is useful.

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Abstract

La présente invention concerne un agent de traitement ou de prévention de la maladie de Chagas, caractérisé en ce qu'il contient un ou plusieurs composés sélectionnés dans le groupe constitué de coptisine, de berbérine, de palmatine, d'épiberbérine, de berberrubine, et de ditétrahydrocoptisine, ou un sel de ces dernières, ou un composé représenté par la formule générale (I) ou un sel de ce dernier.
PCT/JP2022/011217 2021-03-17 2022-03-14 Agent de traitement ou de prévention de la maladie de chagas WO2022196614A1 (fr)

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JPH07330623A (ja) * 1994-06-10 1995-12-19 Tsumura & Co 神経細胞死抑制剤
JP2005281284A (ja) * 2004-03-26 2005-10-13 Ivy Cosmetics Corp コラーゲン合成促進皮膚外用剤
JP2018177733A (ja) * 2017-04-19 2018-11-15 国立大学法人帯広畜産大学 抗原虫作用を持つ生薬由来化合物と生薬エキス

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Publication number Priority date Publication date Assignee Title
JPH07330623A (ja) * 1994-06-10 1995-12-19 Tsumura & Co 神経細胞死抑制剤
JP2005281284A (ja) * 2004-03-26 2005-10-13 Ivy Cosmetics Corp コラーゲン合成促進皮膚外用剤
JP2018177733A (ja) * 2017-04-19 2018-11-15 国立大学法人帯広畜産大学 抗原虫作用を持つ生薬由来化合物と生薬エキス

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