WO2022075780A1 - Composition pharmaceutique pour la prévention ou le traitement d'une vessie hyperactive - Google Patents

Composition pharmaceutique pour la prévention ou le traitement d'une vessie hyperactive Download PDF

Info

Publication number
WO2022075780A1
WO2022075780A1 PCT/KR2021/013819 KR2021013819W WO2022075780A1 WO 2022075780 A1 WO2022075780 A1 WO 2022075780A1 KR 2021013819 W KR2021013819 W KR 2021013819W WO 2022075780 A1 WO2022075780 A1 WO 2022075780A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
overactive bladder
ctibd
preventing
compound
Prior art date
Application number
PCT/KR2021/013819
Other languages
English (en)
Korean (ko)
Inventor
박철승
안진희
이나라샘
파기레수바나하우샤바우
파기레하우샤바우시바지
Original Assignee
광주과학기술원
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 광주과학기술원 filed Critical 광주과학기술원
Publication of WO2022075780A1 publication Critical patent/WO2022075780A1/fr

Links

Images

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/30—Other Organic compounds

Definitions

  • the present invention relates to the treatment of overactive bladder, and specifically, a pharmaceutical composition for preventing or treating overactive bladder using a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; Health functional food composition for preventing or improving overactive bladder; And it relates to a method for preventing or treating overactive bladder. In addition, it relates to a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • overactive bladder is a chronic condition in which detrusor overactivity is observed in a urodynamic study, and involuntary bladder contractions are characteristically in the filling phase of the micturition cycle. Introduced by the International Continence Society in 1988 to name symptoms. Since then, the International Continence Society has redefined overactive bladder as symptomatic syndrome, which includes urinary incontinence, urgency urinary incontinence, increased daytime frequency, and nocturia. there is
  • detrusor overactivity uncontrollable detrusor contraction that occurs spontaneously or induced when the bladder is full in a urodynamic test
  • detrusor overactivity is observed in urodynamic examination in more than 50% of diagnosed patients, so it is considered to be an important pathophysiological change that causes overactive bladder symptoms.
  • bladder outlet obstruction occurs due to an enlarged prostate or the like, bladder hypertrophy is induced secondarily. It is said to be sensitive.
  • the Cleveland Clinic recommends that overactive bladder patients avoid several foods. Considering this, it is possible that the detrusor bladder in overactive bladder patients have increased excitability even under normal circumstances.
  • nocturia causes sleep disturbance, increasing fatigue in the patient.
  • overactive bladder symptoms the risk of depression is increased in overactive bladder patients.
  • the risk of falling in patients with urge incontinence was 30% higher than in the group without urge incontinence, and the risk of fracture was also higher by 3%.
  • the goals of treatment for overactive bladder are to reduce bladder contractility, increase bladder capacity, and dull the sense of urination to facilitate bladder filling, that is, urine storage.
  • the primary treatment for overactive bladder is behavioral therapy and drug therapy.
  • antimuscarinic drugs have the highest level of evidence. The efficacy of the individual drugs is said to be almost the same.
  • Bladder muscle contraction occurs when acetylcholine secreted from nerve endings acts on muscarinic receptors in the bladder muscle.
  • Antimuscarinic agents inhibit involuntary detrusor contraction by competitively inhibiting the action of acetylcholine on muscarinic receptors.
  • Antimuscarinic agents decrease urgency and increase bladder capacity during the fullness of the voiding cycle.
  • antimuscarinic drugs do not affect detrusor contraction during urination.
  • recommended antimuscarinic agents include Darifenacin, Fesoterodine, Oxybutynin, Propiverine, Solifenacin, Tolterodine, and Tolterodine.
  • drugs such as Trospium, which have similar efficacy in alleviating overactive bladder symptoms.
  • those of greater than or equal to severity include gastrointestinal pain, gastritis, nausea, vomiting, blurred vision, urinary retention, voiding difficulty, and dysuria.
  • Dysuria urinary tract infection, fatigue, somnolence, sedation, insomnia, confusion, cognitive impairment, depression, headache
  • headache include headache, palpitation, tachycardia, hypertension, orthostatic disturbance, and a fall.
  • Korean Patent No. 10-1513800 discloses the prevention or treatment efficacy of overactive bladder using ginger extract as an active ingredient
  • Korean Patent No. 10-1362539 discloses pumpkin seed oil or pumpkin seed extract, soybean extract and magnesium as main components.
  • the present inventors have less adverse reactions and side effects, and as a result of intensive research to develop a safe therapeutic agent for treating overactive bladder symptoms, the compound of the present invention activates BKca channels to prevent or treat overactive bladder through relaxation of bladder muscles By confirming that there is an effect to complete the present invention.
  • One object of the present invention is to provide a pharmaceutical composition for preventing or treating overactive bladder comprising a compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • Another object of the present invention is to provide a health functional food composition for preventing or improving overactive bladder comprising a compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • Another object of the present invention is to prevent or treat overactive bladder comprising administering a pharmaceutical composition comprising the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient to an individual other than a human. is to provide
  • Another object of the present invention is to provide a compound represented by Formula 1, or a pharmaceutically acceptable salt thereof.
  • the compound represented by Formula 1 of the present invention has excellent efficacy in activating BKca channels, inhibits bladder smooth muscle contraction due to inactivation of BKca channels, and can treat or improve overactive bladder, so it is widely used as a therapeutic agent for overactive bladder can be used
  • 1A is a graph showing the screening of a library of 8,364 compounds through a cell-based fluorescence assay.
  • 1B is a graph showing the fluorescence values of 8 representative compounds and vehicle (DMSO, 1%) through RFU values.
  • 1C is a graph showing the fluorescence values of representative 8 compounds and vehicle (DMSO, 1%) through fold increase values.
  • 2A is a schematic diagram showing compound 1 and its derivatives.
  • FIG. 2B is a graph showing the results of fluorescence values of compound 1 and its derivatives through RFU values.
  • 2C is a graph showing the fluorescence value results of compound 1 and its derivatives through fold increase values.
  • 3A is a graph showing the results of fluorescence values as RFU values through cell-based fluorescence assay in order to confirm the effect of compound 1, compound 4, and compound 7 on BKca channel enhancement.
  • 3B is a graph showing the fluorescence value results of compound 1, compound 4, and compound 7 through fold increase values.
  • 4A is a graph showing the fluorescence values of AD-293 cells expressing an overactive mutant BKca channel through RFU after treatment with various concentrations of CTIBD.
  • FIG. 4B is a graph showing the fluorescence value of AD-293 cells expressing the hyperactive mutant BKca channel through fold increase after treatment with various concentrations of CTIBD.
  • 5 is a graph showing the reverse reinforcement induction of the external current of the BKca channel by CTIBD through an electrophysiological test
  • 6A is a graph showing the current value of the BKca channel after CTIBD and vehicle treatment
  • 6B is a graph showing the efficacy of CTIBD on the G-V relationship.
  • 6C is a graph showing the efficacy of CTIBD on V 1/2 .
  • 7A is a graph showing the current value of the activation state of the BKca channel when CTIBD or vehicle is processed.
  • 7B is a graph showing the current value of the inactive state of the BKca channel when CTIBD or vehicle is processed.
  • 7C is a graph showing the activation time-conductivity value of the BKca channel when CTIBD or vehicle is treated.
  • 7D is a graph showing the inactivation time-conductivity value of the BKca channel when CTIBD or vehicle is treated.
  • 8A is a graph showing the effect of CTIBD on ACh-induced contraction of isolated rat bladder tendon.
  • 8B is a graph showing the Ach-induced contraction relaxation effect of CTIBD according to the peak of the Ach-induced contraction.
  • 9A is a graph showing the intravesical pressure curve in the rat by distilled water, acetic acid, and CTIBD.
  • 9B is a graph showing the basal pressure in rats by distilled water, acetic acid, and CTIBD.
  • 9C is a graph showing the maximum pressure of voiding contraction in rats by distilled water, acetic acid, and CTIBD.
  • 9D is a graph showing the mutual contraction interval of rats by distilled water, acetic acid, and CTIBD.
  • 9E is a graph showing the amount of urination in rats by distilled water, acetic acid, and CTIBD.
  • FIG. 10 is a graph showing the fluorescence value results of a cell-based fluorescence assay using the compound at a concentration of 3 uM as RFU values in order to examine the effect of CTIBD and its derivatives on the BKca channel.
  • 11 is a graph showing the fluorescence value results of a cell-based fluorescence assay using the compound at a concentration of 1 uM as RFU values to examine the effect of CTIBD and its derivatives on the BKca channel.
  • FIG. 12 is a graph showing the fluorescence value results of a cell-based fluorescence assay using the compound at a concentration of 5 uM as RFU values in order to examine the effect of CTIBD and its derivatives on the BKca channel.
  • FIG. 13 is a graph showing the fluorescence value results of a cell-based fluorescence assay using the compound at a concentration of 2 uM as RFU values to examine the effect of CTIBD and its derivatives on the BKca channel.
  • One aspect for achieving the above object provides a pharmaceutical composition for preventing or treating overactive bladder comprising a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • the prevention or treatment of overactive bladder may be achieved by relaxation of bladder smooth muscle, activation of BKca channels, or an increase in the maximum open-possibility state due to a decrease in the voltage threshold for activation of BKca channels. It may be made by stable maintenance, but is not limited thereto.
  • the BKca channel activation efficacy of compound 4 was confirmed through a cell-based fluorescence assay ( FIGS. 2 to 4 ) and an electrophysiological test ( FIG. 5 ), and this was confirmed by bladder smooth muscle After pretreatment with ACh, the contraction was inhibited compared to the control group even when contraction was induced, and the effect of smooth muscle relaxation was confirmed (Fig. 8). 9), overactive bladder improvement or treatment was confirmed.
  • the compound that achieves prevention or treatment of overactive bladder may be one represented by the following formula (1):
  • R 1 to R 5 are each independently hydrogen, halogen, carboxymethylphenyl, or methoxypyridinyl;
  • R 6 is hydrogen or halogen.
  • halogen of R 1 to R 5 may be fluoro, chloro, or bromo, and more specifically, chloro.
  • halogen of R 6 may be fluoro, chloro, or bromo, and more specifically, chloro or bromo.
  • R 1 to R 5 may each independently be hydrogen or chloro (Cl), and at least one or more of R 1 to R 5 may be chloro. Specifically, it may have one or more Cl substituents among R 1 to R 5 , and more specifically, it may have one, two, or two or more Cl.
  • the compound of Formula 1 may be represented by Formulas 2 to 7:
  • the compound represented by Formula 2 is 4-(4-(4-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzyl-1,3-diol (4-(4- (4-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol), and preferably may be one synthesized by the present inventors, but is not limited thereto.
  • it was named CTIBD, and excellent efficacy in treating or preventing overactive bladder by bladder smooth muscle relaxation induced by BKca channel activation of the compound was confirmed, which was discovered for the first time by the present inventors.
  • the compound represented by Formula 3 is 4-(4-(3,4-dichlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzyl-1,3-diol (4- (4-(3,4-dichlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol), and preferably may be synthesized by the present inventors, but is not limited thereto .
  • it was named GM 90178, and excellent efficacy for treating or preventing overactive bladder by bladder smooth muscle relaxation induced by BKca channel activation of the compound was confirmed, which was discovered for the first time by the present inventors.
  • the compound represented by Formula 4 is 4-(4-(2,3-dichlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzyl-1,3-diol (4- (4-(2,3-dichlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol), and preferably one synthesized by the present inventors, but is not limited thereto .
  • it was named GM 90174, and excellent efficacy in treating or preventing overactive bladder by bladder smooth muscle relaxation induced by BKca channel activation of the compound was confirmed, which was discovered for the first time by the present inventors.
  • the compound represented by Formula 5 is 4-(4-(3-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzyl-1,3-diol (4-(4- (3-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol), and preferably may be one synthesized by the present inventors, but is not limited thereto.
  • it was named GM 90172, and excellent efficacy in treating or preventing overactive bladder by bladder smooth muscle relaxation induced by BKca channel activation of the compound was confirmed, which was discovered for the first time by the present inventors.
  • the compound represented by Formula 6 is 4-(4-(2,4-dichlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzyl-1,3-diol (4- (4-(2,4-dichlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol), and preferably one synthesized by the present inventors, but is not limited thereto .
  • it was named GM 90170, and excellent efficacy in treating or preventing overactive bladder by bladder smooth muscle relaxation induced by BKca channel activation of the compound was confirmed, which was discovered for the first time by the present inventors.
  • the compound represented by Formula 7 is 4-(4-(2-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzyl-1,3-diol (4-(4- (2-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol), and preferably may be one synthesized by the present inventors, but is not limited thereto.
  • it was named GM 90181, and excellent efficacy in treating or preventing overactive bladder by bladder smooth muscle relaxation induced by BKca channel activation of the compound was confirmed, which was discovered for the first time by the present inventors.
  • R 1 , R 2 , R 4 and R 5 may be hydrogen, and R 3 may be fluoro, chloro, bromo, carboxymethylphenyl, or methoxypyridinyl.
  • the compound of Formula 1 may be represented by the following Formulas 8 to 15:
  • the compound represented by Formula 8 is 4-(4-(4-fluorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol (4-(4 -(4-fluorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol), and preferably may be one synthesized by the present inventors, but is not limited thereto.
  • it was named GM 90113, and excellent efficacy for treating or preventing overactive bladder by bladder smooth muscle relaxation induced by BKca channel activation of the compound was confirmed, which was discovered for the first time by the present inventors.
  • the compound represented by Formula 9 is 4-(4-(4-bromophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol (4-(4 -(4-bromophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol), and preferably may be one synthesized by the present inventors, but is not limited thereto.
  • it was named GM 90114, and excellent efficacy in treating or preventing overactive bladder by bladder smooth muscle relaxation induced by BKca channel activation of the compound was confirmed, which was discovered for the first time by the present inventors.
  • the compound represented by Formula 10 is 2-(4'-(5-(2,4-dihydroxyphenyl)-3-(trifluoromethyl)isoxazol-4-yl)-[1,1' -Biphenyl]-4-yl)acetic acid (2-(4'-(5-(2,4-dihydroxyphenyl)-3-(trifluoromethyl)isoxazol-4-yl)-[1,1'-biphenyl]-4 -yl)acetic acid), and preferably may be one synthesized by the present inventors, but is not limited thereto.
  • it was named GM 90116, and excellent efficacy in treating or preventing overactive bladder by bladder smooth muscle relaxation induced by BKca channel activation of the compound was confirmed, which was discovered for the first time by the present inventors.
  • the compound represented by Formula 11 is 4-(4-(4-(6-methoxypyridin-3-yl)phenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1, 3-diol (4-(4-(4-(6-methoxypyridin-3-yl)phenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol), preferably this It may be synthesized by the inventor, but is not limited thereto. In the present invention, it was named GM 90120, and excellent efficacy in treating or preventing overactive bladder by bladder smooth muscle relaxation induced by BKca channel activation of the compound was confirmed, which was discovered for the first time by the present inventors.
  • the compound represented by Formula 12 is 4-chloro-6-(4-(4-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol (4 -chloro-6-(4-(4-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol), and preferably one synthesized by the present inventors, but limited thereto it is not going to be In the present invention, it was named GM 90163, and excellent efficacy for treating or preventing overactive bladder by bladder smooth muscle relaxation induced by BKca channel activation of the compound was confirmed, which was discovered for the first time by the present inventors.
  • the compound represented by Formula 13 is 4-chloro-6-(4-(4-fluorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol ( 4-chloro-6-(4-(4-fluorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol), and preferably one synthesized by the present inventors, but It is not limited. In the present invention, it was named GM 90164, and excellent efficacy in treating or preventing overactive bladder by bladder smooth muscle relaxation induced by BKca channel activation of the compound was confirmed, which was discovered for the first time by the present inventors.
  • the compound represented by Formula 14 is 4-(4-(4-bromophenyl)-3-(trifluoromethyl)isoxazol-5-yl)-6-chlorobenzene-1,3-diol ( 4-(4-(4-bromophenyl)-3-(trifluoromethyl)isoxazol-5-yl)-6-chlorobenzene-1,3-diol), and preferably one synthesized by the present inventors, but limited thereto it is not going to be In the present invention, it was named GM 90165, and excellent efficacy in treating or preventing overactive bladder by bladder smooth muscle relaxation induced by BKca channel activation of the compound was confirmed, which was discovered for the first time by the present inventors.
  • the compound represented by Formula 15 is 4-bromo-6-(4-(4-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol ( 4-bromo-6-(4-(4-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol), which may be preferably synthesized by the present inventors, but It is not limited. In the present invention, it was named GM 90176, and excellent efficacy in treating or preventing overactive bladder by bladder smooth muscle relaxation induced by BKca channel activation of the compound was confirmed, which was discovered for the first time by the present inventors.
  • FIG. 1 screening was conducted to discover the compounds (FIG. 1), and after confirming that compound 1 had an effect on BKca channel activation, the structure-activity correlation of its derivatives was investigated in the same way. As a result, it was confirmed through cell-based fluorescence assays ( FIGS. 2 to 4 ) and electrophysiological tests ( FIG. 5 ) that compound 4 (CTIBD) had superior BKca channel activation efficacy, and the derivatives of the CTIBD compound were Through the same method, a number of compounds having excellent efficacy above a certain level were identified ( FIGS. 10 to 13 ), and a number of compounds having an overactive bladder treatment and improvement efficacy including CTIBD were discovered.
  • CTIBD cell-based fluorescence assays
  • FIG. 5 electrophysiological tests
  • the term "pharmaceutically acceptable salt” refers to a salt in a form that can be used pharmaceutically among salts, which are substances in which cations and anions are coupled by electrostatic attraction, and are usually metal salts, organic bases It may be a salt with, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like.
  • the metal salt may be an alkali metal salt (sodium salt, potassium salt, etc.), alkaline earth metal salt (calcium salt, magnesium salt, barium salt, etc.), an aluminum salt or the like;
  • Salts with organic bases include triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine salts with, etc.
  • salts with inorganic acids may be salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like;
  • Salts with organic acids may be salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic
  • active ingredient refers to a component capable of exhibiting the desired activity alone or in combination with a carrier having no activity by itself.
  • overactive bladder refers to detrusor overactivity observed in a urodynamic study, and characteristically involuntary in the filling phase of the micturition cycle. Introduced by the International Continence Society in 1988 to name chronic symptoms of chronic bladder contraction, the symptoms included include urinary incontinence, urgency urinary incontinence, and increased daytime frequency. daytime frequency) and nocturia.
  • prevention refers to any action that inhibits or delays the onset of a disease by the pharmaceutical composition according to the present invention.
  • treatment refers to any action in which the symptoms of the disease-causing individual are improved or beneficially changed by the pharmaceutical composition.
  • composition may further include a pharmaceutically acceptable carrier, excipient or diluent, which may include a non-naturally occurring carrier.
  • pharmaceutically acceptable carrier refers to a carrier or diluent that does not irritate the organism and does not impair the preventive or therapeutic activity and properties of the composition of the present invention for preventing or treating hyperpigmentation disease symptoms.
  • acceptable pharmaceutical carriers for compositions formulated as liquid solutions are sterile and biocompatible, and include saline, sterile water, Ringer's solution, buffered saline, albumin injection, dextrose solution, maltodextrin solution, glycerol, ethanol. And one or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers, and bacteriostats may be added as needed.
  • the pharmaceutically acceptable carrier of the present invention may include a non-natural carrier.
  • carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate , calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, polycaprolactone, polylactic acid (Poly Lactic Acid), poly-L-lactic acid (poly-L-lactic acid), mineral oil, and the like.
  • the pharmaceutical composition may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories and sterile injection solutions according to conventional methods, respectively.
  • the carrier may include various amorphous carriers, microspheres, nanofibers, and the like.
  • a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc. commonly used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the extract and its fractions, for example, starch, calcium carbonate, It may be prepared by mixing sucrose or lactose, gelatin, or the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.
  • Liquid formulations for oral administration include suspensions, solutions, emulsions, syrups, etc.
  • various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is.
  • Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.
  • Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • the pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount, and the term, “pharmaceutically effective amount” is sufficient to treat or prevent a disease at a reasonable benefit/risk ratio applicable to medical treatment or prevention.
  • the amount, and the effective dose level is the severity of the disease, the drug activity, the patient's age, weight, health, sex, the patient's sensitivity to the drug, the administration time of the composition of the present invention used, the route of administration and the rate of excretion Treatment period , may be determined according to factors including drugs used in combination with or concurrently with the composition of the present invention and other factors well known in the medical field.
  • the pharmaceutical composition of the present invention may be administered alone or in combination with a known therapeutic agent for pterygium. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects.
  • screening was performed to discover a compound for activating BKca channel that treats overactive bladder symptoms caused by bladder smooth muscle contraction and relaxes bladder smooth muscle ( FIG. 1 ), and compound 1 is a BKca channel
  • CTIBD compound 4
  • BKca channel activation of the CTIBD derivatives in the same method was identified through a cell-based fluorescence assay to identify a number of compounds with excellent efficacy above a certain level (Figs. 13), the efficacy of treatment and improvement of overactive bladder of a number of compounds including CTIBD was confirmed.
  • Another aspect for achieving the above object provides a health functional food for preventing or improving overactive bladder comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the term “improvement” refers to any action that at least reduces a parameter related to a condition to be treated by administration of the composition of the present invention, for example, the severity of symptoms.
  • health functional food refers to a food manufactured and processed using raw materials or ingredients useful for the human body according to Act No. 6727 of the Health Functional Food Act, and 'functionality' refers to the It refers to obtaining useful effects for health purposes such as regulating nutrients with respect to structure and function or physiological actions.
  • health food means food that has an active health maintenance or promotion effect compared to general food
  • health supplement means food for the purpose of health supplementation.
  • the terms health functional food, health food and health supplement food can be mixed.
  • the compound of the present invention may be added as it is or used together with other foods or food ingredients, and may be appropriately used according to a conventional method.
  • the food of the present invention can be prepared by a method commonly used in the art, and at the time of manufacture, it can be prepared by adding raw materials and components commonly added in the art.
  • the food composition may further include a physiologically acceptable carrier, the type of carrier is not particularly limited and any carrier commonly used in the art may be used.
  • the food composition contains food additives such as preservatives, disinfectants, antioxidants, colorants, coloring agents, bleaching agents, seasonings, sweeteners, flavoring agents, expanding agents, strengthening agents, emulsifying agents, thickeners, filming agents, gum base agents, foam inhibitors, solvents, and improving agents. may include The additive may be selected according to the type of food and used in an appropriate amount.
  • the formulation of the food may be prepared without limitation as long as it is a formulation recognized as a food.
  • the composition for food of the present invention can be prepared in various forms, and unlike general drugs, it has the advantage of not having side effects that may occur when taking the drug for a long period of time using food as a raw material, and has excellent portability, so overactive bladder It can be ingested as an adjuvant to enhance the effectiveness of prevention or improvement.
  • Another aspect for achieving the above object is to prevent or treat overactive bladder comprising administering to an individual a pharmaceutical composition comprising the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient provide a way
  • the term "individual” refers to all animals, such as rats, mice, livestock, including humans, that have or may develop wrinkles or skin aging.
  • the term "administration” means introducing the composition of the present invention to a patient by any suitable method, and the administration route of the composition may be administered through any general route as long as it can reach the target tissue.
  • Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration may be administered intranasally, but is not limited thereto.
  • composition of the present invention may be administered daily or intermittently, and the number of administrations per day may be administered once or divided into two to three times.
  • composition of the present invention may be used alone or in combination with other drug treatments to improve overactive bladder. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, and can be easily determined by those skilled in the art.
  • Another aspect for achieving the above object provides the use of the compound represented by Formula 1 for preventing or treating overactive bladder:
  • R 1 to R 5 are each independently hydrogen, halogen, carboxymethylphenyl, or methoxypyridinyl;
  • R 6 is hydrogen or halogen.
  • Another aspect for achieving the above object provides a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof:
  • R 1 to R 5 are each independently hydrogen, halogen, carboxymethylphenyl, ethoxycarbonylmethylphenyl, trifluoromethylphenyl or methoxypyridinyl;
  • R 6 is hydrogen or halogen.
  • R 1 to R 5 may each independently be hydrogen, halogen, carboxymethylphenyl, ethoxycarbonylmethylphenyl, trifluoromethylphenyl or methoxypyridinyl. there is.
  • the compound represented by Chemical Formula 1 may be one represented by any one of Chemical Formulas 3 to 17.
  • Chemical Formulas 3 to 15 are as described above, and Chemical Formulas 16 and 17 are as follows.
  • pharmaceutically acceptable salt is the same as described above.
  • the compound represented by Formula 16 is ethyl 2-(4'-(5-(2,4-dihydroxyphenyl)-3-(trifluoromethyl)isoxazol-4-yl)-[1,1 '-Biphenyl]-4-yl)acetate (ethyl 2-(4'-(5-(2,4-dihydroxyphenyl)-3-(trifluoromethyl)isoxazol-4-yl)-[1,1'-biphenyl] -4-yl)acetate), and preferably one synthesized by the present inventors, but is not limited thereto.
  • the compound represented by Formula 17 is 4-(3-(trifluoromethyl)-4-(4'-trifluoromethyl)-[1,1'-biphenyl]-4-yl)isoxazole- 5-yl)benzene-1,3-diol (4-(3-(trifluoromethyl)-4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)isoxazol-5-yl ) benzene-1,3-diol), which may be preferably synthesized by the present inventors, but is not limited thereto.
  • the compound library for screening was obtained from the Korea Research Institute of Chemical Technology (KRICT, Daejon, South Korea; www.chembank.org), a KRICT diversity library containing 8,364 unique compounds.
  • CTIBD 4-(4-(4-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol
  • CTIBD 4-(4-(4-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol
  • CTIBD 4-(4-(4-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol
  • CTIBD Stock solutions and derivatives thereof were prepared by dissolving in dimethyl sulfoxide (DMSO; Sigma-Aldrich, St. Louis, MO).
  • modified human embryonic kidney cells (AD-293 cells) stably expressing the mutant BKca channel (G803D/N806K) were used.
  • the cells were cultured in Dulbecco's modified Eagle's medium (High glucose) containing 10% fetal bovine serum (Hyclone) and antibiotics (1 mg/ml geneticin; Gibco/Life Technologies, Waltham, Mass.).
  • Dulbecco's modified Eagle's medium High glucose
  • fetal bovine serum Hyclone
  • antibiotics 1 mg/ml geneticin; Gibco/Life Technologies, Waltham, Mass.
  • the cells were then seeded and cultured in 96-well clear-bottomed black-wall plates (Corning Incorporated, Corning, NY) coated with poly-d-lysine (Sigma-Aldrich, St. Louis, MO).
  • the growth medium was removed from the plate in which the cells were being cultured, 80 ⁇ l of a loading buffer containing FluxOR fluorescent dye was added to each well of the plate, and then reacted in the dark for 1 hour. After the reaction, the loading buffer was removed, and 100 ⁇ l of assay buffer containing various concentrations of the test compound in the compound library was added to each well of the plate, followed by reaction for 20 to 30 minutes.
  • DMSO DMSO (1%) was used as a vehicle group
  • CTBIC an activator of BKca channels
  • the fluorescent dye was measured using a FlexStation 3 multimode microplate reader (Molecular Devices, Sunnyvale, CA) and SoftMax Pro software.
  • the fluorescence excitation-wavelength was 485 nm and the emission-wavelength was 528 nm.
  • the fluorescence signal was measured every 2 seconds, and depolarization of the cell membrane was chemically induced by adding a stimulation buffer containing a high concentration of TI+. Specifically, 20 ⁇ l of stimulation buffer was treated in each well after 20 seconds from the start of the measurement.
  • a relative fluorescence unit (RFU or F/F0, F0: minimum value of fluorescence signals of each well) was used to analyze the brightness of fluorescence.
  • the rat BKca channel ⁇ (Slo1) subunit was expressed in Xenopus oocytes. Specifically, for subcloning and functional expression of rat BKca, an oocyte expression vector (pNBC1.0 or pNBC2.0) was used, and cDNA sequence information of the rat BKca channel ⁇ subunit was obtained from GenBank, and its accession number was AF135265. am.
  • Oocytes were surgically extracted from ovaries of V-VI stage X. laevis (Nasco, Fort Atkinson, Wis.). After extraction, the oocytes were prepared in a Ca2+-free oocyte Ringer's (OR) culture (86 mM NaCl, 1.5 mM KCl, 2 mM MgCl2, and 10 mM HEPES, pH 7.6), and reacted at room temperature for 1.5 to 2 hours to remove the follicular cell layer of the oocyte.
  • OR oocyte Ringer's
  • oocytes were washed several times with Ca2+-free OR cultures and ND-96 cultures (96 mM NaCl, 2 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 5 mM HEPES, and 50 g/ml gentamicin, pH 7.6). rinsed Thereafter, in order to stabilize the oocytes, they were cultured in an ND-96 medium at 18° C. for at least 24 hours. Thereafter, nuclease-free distilled water containing approximately 50 ng of synthetic Slo1 cRNA was injected into each oocyte for electrophysiological testing. After injection, oocytes were cultured in ND-96 medium for 1 to 3 days at 18°C.
  • a borosilicate glass-pipette (WPI, Sarasota, FL) was prepared by pulling and fire-polishing, and at this time, the resistance of the hot-polished pipette was 3-5 M ⁇ .
  • the channel current was amplified through an Axopatch 200B amplifier (Molecular Devices, San Jose, CA), and a four-pole Bessel filter was used for the 1kHz low-pass filter. Channel currents were digitized at a rate of 10 or 20 points/ms using a Digidata 1200A (Molecular Devices).
  • the BK Ca channel potential was activated through voltage-clamp pulses in increments of 10 mV in the range of -80 to 200 mV.
  • the resting potential was fixed at -100 mV.
  • the test solution was composed of 120 mM potassium gluconate, 10 mm HEPES, 4 mM KCl, and 5 mM EGTA under pH 7.2 conditions.
  • bladder tendons were isolated (approximately 2 x 8 mm) from male Sprague-Dawley rats (300-350 g), and Krebs solution (118.4 mM NaCl, 4.7 mM KCl, 1.2 mM KH2PO 4 , 1.2 mM MgSO 4 , 25.0 mM NaHCO 3 , 2.5 mM CaCl2, and 12.2 mM glucose, pH 7.4, mixture of 95 % O2 and 5% CO2 (37° C.)) of 10 ml were mounted in a tissue bath (organ bath).
  • All experimental animals were anesthetized and maintained at 37°C using a heat pad.
  • the bladder was injected with distilled water or distilled water containing 0.5% acetic acid (AA) at a rate of 0.05 mL/min at room temperature. Specifically, in the normal group, distilled water was continuously injected for at least 1 hour, or 0.5% AA was injected until bladder contraction occurred.
  • CTIBD was injected through the peritoneal cavity at a single dose of 20 mg/kg 40 minutes after AA administration. Intravesical pressure was measured 90 minutes after administration.
  • Baseline pressure BP, mmHg
  • maximal pressure of voiding contraction MPVC; mmHg
  • intercontraction interval ICI, sec
  • voiding volume VV, ml
  • Example 1-1 primary screening
  • a novel BKca channel activator was identified by screening compounds of a chemical library containing a total of 8,364 substances through a cell-based fluorescence assay, and experiments were performed through the methods of Experimental Examples 1 to 3.
  • compound 1(4-(4-phenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol) was a compound having excellent efficacy in BKca channel activity.
  • Example 1-2 secondary screening
  • CTIBD compound 4
  • the efficacy of the selected CTIBD on the BKca channel was evaluated through an electrophysiological test.
  • the ⁇ -subunit of the BKca channel of wild-type rats was expressed in Xenopus oocytes, and the current in the cell membrane was measured through the extracted oocytes. More specifically, the intracellular Ca 2+ concentration of the explanted cells was fixed at 3 ⁇ M, and 3 ⁇ M CTIBD was applied to the outer part of the cell membrane for 30 seconds from the start of the potential measurement.
  • CTIBD increased the current from the reference value in a time-dependent manner.
  • the channel potential decreased and returned to the reference value.
  • CTIBD regulates two states of BKca channel, strengthening and weakening.
  • CTIBD moved the G-V curve to a negative current in a concentration-dependent manner, and increased the maximum conductivity (Gmax).
  • V 1/2 decreased by about 50 m V 1/2 from 155.8 ⁇ 2.3 mV to 105.2 ⁇ 3.6 mV.
  • CTIBD lowered the voltage threshold for activation and increased the maximum open-probability of the BKca channel.
  • FIGS. 7A to 7B representative current values of activation (opening) and inactivation (closing) of the BKca channel in the presence or absence of 10 ⁇ M CTIBD were confirmed ( FIGS. 7A to 7B ).
  • the activation time - the conduction ( ⁇ activation ) value was obtained by substituting a single exponential (single-exponential) at each voltage.
  • FIGS. 7C to 7D when 10 ⁇ M CTIBD was present, it was confirmed that the activation ratio significantly increased at all voltages ( FIG. 7C ), and the time-conduction value in inactivation was also significantly increased. was confirmed (FIG. 7D).
  • CTIBD can be utilized as a potential BKca channel activator because it does not significantly affect the opening of the BKca channel, and it slows the channel closing and stably maintains the activation state.
  • CTIBD enhances the activation of the BKca channel. Accordingly, it was confirmed through the rat bladder tendon whether the CTIBD had a relaxation effect in the bladder through activation of the BKca channel.
  • CTIBD induces relaxation of bladder smooth muscle by inhibiting ACh-induced contraction of bladder smooth muscle in a concentration-dependent manner.
  • Example 5 Since it was confirmed that the bladder smooth muscle was relaxed in Example 5, the effect on urination according to the actual bladder muscle relaxation was confirmed. Specifically, in order to measure the pharmacological effect of CTIBD on the urinary function, CTIBD was intraperitoneally injected into the AA-induced OAB rat model.
  • baseline pressure BP, mmHg
  • maximal pressure of voiding contraction MPVC; mmHg
  • intercontraction interval ICI, sec
  • voiding volume VV, ml
  • the CTIBD of the present invention has therapeutic efficacy for overactive bladder by relaxing the bladder/voiding muscles.
  • Example 7-1 Primary comparison of BKca channel activity efficacy of CTIBD derivatives through structure-activity correlation investigation
  • the CTIBD compound had significantly better BKca channel activity at a low concentration of 1 uM than its derivatives having other functional groups.
  • Example 7-2 Secondary comparison of BKca channel activity efficacy of CTIBD derivatives through structure-activity correlation investigation
  • GM 90169 confirmed that the RFU value was lower than that of the CTIBD selected in the above example, but the following five CTIBD derivative compounds except for this had an RFU value superior to that of CTIBD.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Urology & Nephrology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Nutrition Science (AREA)
  • Mycology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Polymers & Plastics (AREA)
  • Food Science & Technology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un traitement pour une vessie hyperactive et, en particulier : une composition pharmaceutique, pour prévenir ou traiter une vessie hyperactive, à l'aide d'un composé représenté par la formule chimique 1 ou des sels pharmaceutiquement acceptables de celui-ci ; une composition fonctionnelle d'aliment de santé pour prévenir ou traiter une vessie hyperactive ; et une méthode pour prévenir ou traiter une vessie hyperactive. La présente invention concerne également un composé représenté par la formule chimique 1 ou des sels pharmaceutiquement acceptables de celui-ci. Le composé représenté par la formule chimique 1 selon la présente invention présente un excellent effet d'activation des canaux BKca et inhibe ainsi la contraction des muscles lisses de la vessie due à la désactivation du canal BKca et peut traiter ou soulager une vessie hyperactive due à la contraction des muscles lisses de la vessie. Par conséquent, le composé peut être largement utilisé comme agent thérapeutique pour la vessie hyperactive.
PCT/KR2021/013819 2020-10-07 2021-10-07 Composition pharmaceutique pour la prévention ou le traitement d'une vessie hyperactive WO2022075780A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20200129572 2020-10-07
KR10-2020-0129572 2020-10-07

Publications (1)

Publication Number Publication Date
WO2022075780A1 true WO2022075780A1 (fr) 2022-04-14

Family

ID=81125883

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2021/013819 WO2022075780A1 (fr) 2020-10-07 2021-10-07 Composition pharmaceutique pour la prévention ou le traitement d'une vessie hyperactive

Country Status (2)

Country Link
KR (1) KR20220046505A (fr)
WO (1) WO2022075780A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102653689B1 (ko) 2023-12-28 2024-04-02 주식회사 상상바이오 방광염 및 요실금과 같은 방광의 배뇨기능을 개선하기 위한 식품 조성물

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020061914A1 (en) * 1999-05-12 2002-05-23 Jensen Bo Skaaning Ion channel modulating agents
JP2009530238A (ja) * 2006-03-14 2009-08-27 ノイロサーチ アクティーゼルスカブ ジフェニル尿素誘導体及び塩化物チャネル遮断薬又はＢＫＣａチャネル調節薬としてのその使用
KR20170108514A (ko) * 2016-03-18 2017-09-27 광주과학기술원 BKCa 채널 활성화용 조성물

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020061914A1 (en) * 1999-05-12 2002-05-23 Jensen Bo Skaaning Ion channel modulating agents
JP2009530238A (ja) * 2006-03-14 2009-08-27 ノイロサーチ アクティーゼルスカブ ジフェニル尿素誘導体及び塩化物チャネル遮断薬又はＢＫＣａチャネル調節薬としてのその使用
KR20170108514A (ko) * 2016-03-18 2017-09-27 광주과학기술원 BKCa 채널 활성화용 조성물

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LEE NARASAEM, LIM BONG HEE, LEE KYU-SUNG, SHIN JIMIN, PAGIRE HAUSHABHAU S., PAGIRE SUVARNA H., AHN JIN HEE, LEE SUNG WON, KANG TON: "Identification and Characterization of a Novel Large-Conductance Calcium-Activated Potassium Channel Activator, CTIBD, and Its Relaxation Effect on Urinary Bladder Smooth Muscle", MOLECULAR PHARMACOLOGY, vol. 99, no. 2, 1 February 2021 (2021-02-01), US , pages 114 - 124, XP055919538, ISSN: 0026-895X, DOI: 10.1124/molpharm.120.000106 *
SOJUNG LEE, MEE REE CHAE, BYOUNG-CHEOL LEE, YONG-CHUL KIM, JAE SUE CHOI, SUNG WON LEE, JAE HOON CHEONG, CHUL-SEUNG PARK: "Urinary Bladder-Relaxant Effect of Kurarinone Depending on Potentiation of Large-Conductance Ca2+-Activated K+ Channels", MOLECULAR PHARMACOLOGY, vol. 90, no. 2, 1 August 2016 (2016-08-01), pages 140 - 150, XP055414124, DOI: 10.1124/mol.115.102939 *

Also Published As

Publication number Publication date
KR20220046505A (ko) 2022-04-14

Similar Documents

Publication Publication Date Title
AU2020377805B2 (en) Melanocortin-4 receptor agonists
WO2011083999A2 (fr) Dérivé de biguanide, son procédé de préparation, et composition pharmaceutique contenant ce dérivé en tant que principe actif
WO2015099392A1 (fr) Dérivé de pyranochroményl phénol, et composition pharmaceutique pour le traitement d'un syndrome métabolique ou d'une maladie inflammatoire
WO2019168237A1 (fr) Nouveau composé et composition pour la prévention, l'amélioration ou le traitement de la fibrose ou de la stéatohépatite non alcoolique le comprenant en tant que principe actif
WO2011159137A2 (fr) Nouvelle thio-urée ou nouveau dérivé d'urée, procédé permettant leur préparation, et composition pharmaceutique destinée à prévenir ou à traiter le sida, les contenant en tant que principe actif
WO2021118318A2 (fr) Nouveau dérivé d'indole et son utilisation
WO2020106119A1 (fr) Composition pharmaceutique comprenant des inhibiteurs de l'histone-désacétylase 6
WO2022075780A1 (fr) Composition pharmaceutique pour la prévention ou le traitement d'une vessie hyperactive
WO2012053768A2 (fr) Composé à base d'aryloxyphénoxyacétyl présentant une activité inhibitrice du hif-1, son procédé de préparation, et composition pharmaceutique le contenant en tant que principe actif
WO2018004065A1 (fr) Nouveau dérivé d'aryléthane et composition pharmaceutique contenant ce dérivé comme principe actif
WO2018004263A1 (fr) Dérivé de pyranochroményl phénol optiquement actif et composition pharmaceutique comprenant ledit dérivé de pyranochroményl phénol optiquement actif
WO2011049274A1 (fr) Dérivés d'imidazole et compositions pour le traitement d'un mélanome
WO2009096667A2 (fr) Nouveau dérivé de quinazoline-2,4-dione et compositions médicales pour la prophylaxie et le traitement de la maladie du nerf crânien contenant ledit dérivé
WO2012148140A2 (fr) Dérivés d'alcaloïdes à base d'imidazole ayant des effets d'inhibition de l'angiogenèse et antioxydants et leur procédé de préparation
WO2021149900A1 (fr) Dérivé d'adamantyle disubstitué ou son sel pharmaceutiquement acceptable, et composition pharmaceutique pour empêcher la croissance du cancer le contenant comme principe actif
WO2022149925A1 (fr) Nouvel inhibiteur de tryptophane hydroxylase et son utilisation
WO2019231262A1 (fr) Nouveau composé dérivé de biphényle et son utilisation
WO2021100897A1 (fr) Composition pharmaceutique pour la prévention ou le traitement du cancer, comprenant un composé à base de biguanide et du ferrocène ou un dérivé de ferrocène en tant que principes actifs
WO2017119570A1 (fr) Dérivé de thiazolidinedione et son utilisation
WO2014185561A1 (fr) Nouveau composé ou son sel pharmaceutiquement acceptable et composition pharmaceutique pour la prévention ou le traitement de maladies associées à uch-l1, le contenant en tant que principe actif
WO2018030840A1 (fr) Composition pour le durcissement de tissu mou
WO2018004066A1 (fr) Nouveau dérivé d'aryléthane et composition pharmaceutique contenant ce dérivé comme principe actif
WO2015111967A1 (fr) Dérivé phénoxy-acryle et son utilisation
WO2021091358A1 (fr) Analogues de la prostaglandine et leurs utilisations
WO2023068852A1 (fr) Composé dérivé de benzothiophène-1,1-dioxyde utilisé en tant qu'inhibiteur de stat3 et son utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21878030

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 03.08.2023)

122 Ep: pct application non-entry in european phase

Ref document number: 21878030

Country of ref document: EP

Kind code of ref document: A1