WO2023096258A1 - Composition pour la prévention ou le traitement d'une maladie intestinale inflammatoire, comprenant du riluzole ou un nouveau dérivé du riluzole comme principe actif - Google Patents

Composition pour la prévention ou le traitement d'une maladie intestinale inflammatoire, comprenant du riluzole ou un nouveau dérivé du riluzole comme principe actif Download PDF

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WO2023096258A1
WO2023096258A1 PCT/KR2022/018090 KR2022018090W WO2023096258A1 WO 2023096258 A1 WO2023096258 A1 WO 2023096258A1 KR 2022018090 W KR2022018090 W KR 2022018090W WO 2023096258 A1 WO2023096258 A1 WO 2023096258A1
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bowel disease
inflammatory bowel
colitis
riluzole
ibd
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PCT/KR2022/018090
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English (en)
Korean (ko)
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정연진
김재정
강찬규
박소희
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부산대학교 산학협력단
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Priority claimed from KR1020210163069A external-priority patent/KR102625977B1/ko
Priority claimed from KR1020220103818A external-priority patent/KR20240025777A/ko
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Publication of WO2023096258A1 publication Critical patent/WO2023096258A1/fr

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    • 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
    • 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
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/82—Nitrogen atoms

Definitions

  • the present invention provides a composition for preventing or treating inflammatory bowel diseases (IBD) comprising riluzol or a novel riluzol derivative as an active ingredient.
  • IBD inflammatory bowel diseases
  • IBD Inflammatory bowel disease
  • GI gastrointestinal tract
  • UC ulcerative colitis
  • CD Crohn's disease
  • ulcerative colitis occurs in the large intestine and the pathology is limited to the innermost mucosal layer
  • Crohn's disease can have pathology throughout the entire gastrointestinal tract, affecting the deeper barrier up to the muscle layer.
  • biologics including anti-TNF agents
  • current anti-inflammatory bowel disease agents aminosalicylates, glucocorticoids, and immunosuppressive agents
  • immunosuppressive agents Biological agents such as immunosuppressants
  • anti-TNF- ⁇ agents do not provide satisfactory clinical results in a significant number of patients with inflammatory bowel disease due to low anti-inflammatory activity, drug resistance, and serious side effects due to long-term use.
  • biologics form the mainstream of IBD drug development, but the high cost of biologics, low patient compliance due to parenteral administration, and a significant proportion of patients with tolerance and resistance to drugs are low molecular weight inflammatory bowel disease treatment. The unmet medical need for drug development remains high.
  • An object of the present invention is to provide a compound selected from a novel riluzol derivative compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory bowel disease (IBD) comprising riluzole or the novel riluzole derivative compound as an active ingredient.
  • IBD inflammatory bowel disease
  • Another object of the present invention is to provide a health functional food composition for preventing or improving inflammatory bowel disease (IBD) comprising riluzole or the novel riluzole derivative compound as an active ingredient.
  • IBD inflammatory bowel disease
  • the present invention provides a compound selected from a riluzol derivative compound represented by Formula 1 below, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the present invention provides a compound selected from a riluzol derivative compound represented by Formula 2, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • n 1 to 5
  • R may be hydrogen (H) or a divalent acid group.
  • the present invention relates to inflammatory bowel disease (IBD) comprising any one of riluzole, a riluzol derivative compound represented by Formula 1 and a riluzol derivative compound represented by Formula 2 as an active ingredient.
  • IBD inflammatory bowel disease
  • the present invention relates to inflammatory bowel disease (IBD) comprising any one of riluzole, a riluzol derivative compound represented by Formula 1 and a riluzol derivative compound represented by Formula 2 as an active ingredient.
  • IBD inflammatory bowel disease
  • the present invention relates to a pharmaceutical composition and a health functional food composition for preventing or treating inflammatory bowel disease (IBD) containing riluzole or a novel riluzole derivative as an active ingredient, which has been clinically Due to its low anti-inflammatory activity, it has a better therapeutic effect in suppressing inflammation and alleviating symptoms than sulfasalazine (SSZ), which is used only for mild to moderate inflammatory bowel disease (mild to moderate IBD), while also being used as a glucocorticoid, immunosuppressive agent ( Compared to immunosuppressants), it has a lower possibility of serious side effects, so it can be applied to severe inflammatory bowel disease and can be used more safely for a long period of time. Therefore, by using riluzol as an active ingredient in a pharmaceutical composition or health functional food composition, it is possible to safely and effectively prevent, improve, or treat inflammatory bowel disease.
  • IBD inflammatory bowel disease
  • SSZ sulfasala
  • Figure 2 shows experimental results regarding the effective dose of riluzole (RLZ) required for the treatment and improvement of colitis.
  • Figure 6 shows the experimental results of comparing the concentration of riluzol in the cecum and blood when riluzol and riluzol derivatives were administered, respectively.
  • prevention refers to any action that suppresses or delays the onset of inflammatory bowel disease or at least one symptom of the disease by administration of the pharmaceutical composition or health functional food composition according to the present invention. do. Also included is treatment of subjects in remission of the disease to prevent or prevent relapse.
  • treatment refers to all things that improve or beneficially change inflammatory bowel disease, or at least one symptom of the disease, such as alleviating, reducing, or disappearing, by administration of the pharmaceutical composition according to the present invention. means action.
  • “improvement” means improving or beneficially altering the symptoms of inflammatory bowel disease, such as alleviating, reducing, or disappearing at least one symptom of inflammatory bowel disease or the disease by ingestion of the health functional food composition according to the present invention. means all actions
  • pharmaceutical composition means a composition administered for a specific purpose, which is administered to prevent or treat inflammatory bowel disease, or at least one symptom of the disease for the purpose of the present invention.
  • health functional food is similar to food for specified health use (FoSHU), and is a food with high medical and medical effects processed to efficiently display bioregulatory functions in addition to nutritional supply. it means.
  • the present invention provides a compound selected from a riluzol derivative compound represented by Formula 1 below, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the present invention provides a compound selected from a riluzol derivative compound represented by Formula 2, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • n 1 to 5
  • R may be hydrogen (H) or a divalent acid group, preferably n is 1 or 2, and R may be hydrogen (H) or succinyl. .
  • the present invention relates to prevention of inflammatory bowel disease (IBD) comprising, as an active ingredient, any one of riluzole, a riluzol derivative compound represented by Formula 1, and a riluzol derivative compound represented by Formula 2 above. Or it provides a pharmaceutical composition for treatment.
  • IBD inflammatory bowel disease
  • any one of the riluzole, the riluzol derivative compound represented by Formula 1, and the riluzol derivative compound represented by Formula 2 may be preferably administered at 4 to 15 mg/kg per day, but more Preferably, 5 to 10 mg/kg may be administered.
  • any one of the riluzole, the riluzole derivative compound represented by Formula 1, and the riluzol derivative compound represented by Formula 2 blocks glutamatergic neurotransmission, enhances Wnt/beta-catenin signal, It can cause molecular actions such as inhibiting GSK3beta and inducing IL-10.
  • any one of the riluzole, the riluzol derivative compound represented by Formula 1, and the riluzol derivative compound represented by Formula 2 is one or more inflammatory mediators selected from the group consisting of CINC-3, iNOS, and COX-2. Expression of factors may be reduced, but is not limited thereto.
  • the inflammatory bowel disease may be selected from the group consisting of ulcerative colitis, Crohn's disease, collagenous colitis, lymphocytic colitis, ischemic colitis, converting colitis, and Behcet's syndrome, but is not limited thereto.
  • composition according to the present invention can be prepared according to conventional methods in the pharmaceutical field.
  • the pharmaceutical composition according to the present invention may be formulated with an appropriate pharmaceutically acceptable carrier according to the formulation, and, if necessary, further includes an excipient, a diluent, a dispersing agent, an emulsifier, a buffer, a stabilizer, a binder, a disintegrant, a solvent, and the like It can be manufactured by
  • the "pharmaceutically acceptable” means that it is not toxic to cells or humans exposed to the pharmaceutical composition, and the appropriate carrier inhibits the activity and characteristics of the compound according to the present invention or its pharmaceutically acceptable salt. It may be selected differently depending on the dosage form and dosage form.
  • the pharmaceutical composition according to the present invention can be applied in any dosage form, and more specifically, it can be formulated and used in parenteral dosage forms such as oral dosage forms, external preparations, suppositories and sterile injection solutions according to conventional methods.
  • the solid dosage form is in the form of tablets, pills, powders, granules, capsules, etc., preferably enteric preparations, sustained-release tablets, and delayed-release tablets, and includes at least one excipient, for example , Starch, calcium carbonate, sucrose, lactose, sorbitol, mannitol, cellulose, gelatin, etc. may be mixed and prepared, and lubricants such as magnesium stearate and talc may be included in addition to simple excipients.
  • a liquid carrier such as fatty oil may be further included in addition to the above-mentioned materials.
  • liquid formulations include suspensions, solutions for internal use, emulsions, syrups, etc.
  • various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. there is.
  • the parenteral formulation may include a sterilized aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a lyophilized formulation, and a suppository.
  • Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
  • As a base for the suppository witepsol, macrogol, Tween 61, cacao butter, laurin fat, glycerogeratin, and the like may be used. It is not limited thereto, and all suitable agents known in the art may be used.
  • calcium or vitamin D 3 may be further added to the pharmaceutical composition according to the present invention to enhance therapeutic efficacy.
  • the pharmaceutical composition may be administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount that is sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects.
  • the effective dosage level of the pharmaceutical composition depends on the purpose of use, the patient's age, sex, weight and health condition, disease type, severity, drug activity, drug sensitivity, administration method, administration time, administration route and excretion rate, treatment Duration, combination, or factors including drugs used concurrently and other factors well known in the medical arts may be determined differently.
  • the pharmaceutical composition according to the present invention may be administered to any animal that may develop inflammatory bowel disease, and the animal may include, for example, humans and primates as well as livestock such as cattle, pigs, horses, and dogs. there is.
  • the pharmaceutical composition according to the present invention may be administered by an appropriate administration route according to the formulation form, and may be administered through various oral or parenteral routes as long as it can reach the target tissue.
  • the method of administration is not particularly limited, and may be administered by conventional methods such as oral, rectal or intravenous, intramuscular or subcutaneous injection.
  • the pharmaceutical composition according to the present invention may be used alone for the prevention or treatment of inflammatory bowel disease, or may be used in combination with surgery or other drug treatment.
  • IBD inflammatory bowel disease
  • the inflammatory bowel disease may be selected from the group consisting of ulcerative colitis, Crohn's disease, collagenous colitis, lymphocytic colitis, ischemic colitis, converting colitis, and Behcet's syndrome, but is not limited thereto.
  • the health functional food may be made into a powder, granule, tablet, capsule, syrup or beverage, etc., and there is no limit to the form that the health functional food can take, and the conventional It can include all foods of meaning.
  • beverages and various drinks, fruits and their processed foods (canned fruit, jam, etc.), fish, meat and their processed foods (ham, bacon, etc.), breads and noodles, cookies and snacks, dairy products (butter, cheese, etc.) ), etc., and may include all functional foods in a conventional sense.
  • food used as feed for animals may also be included.
  • the health functional food composition according to the present invention may be prepared by further including acceptable food additives and other appropriate auxiliary ingredients commonly used in the art.
  • acceptable food additives for example, flavors, natural carbohydrates, sweeteners, vitamins, electrolytes, colorants, pectic acid, alginic acid, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonating agents, and the like may be further contained.
  • the natural carbohydrate monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol may be used.
  • natural sweeteners such as thaumatin and stevia extract or synthetic sweeteners such as saccharin and aspartame may be used.
  • the effective dose of riluzol contained in the health functional food according to the present invention can be used according to the effective dose of the pharmaceutical composition, but in the case of long-term intake for the purpose of health and hygiene or health control It may be less than the above range, and may be appropriately adjusted according to the purpose of use, such as prevention, health or therapeutic treatment.
  • Riluzole (hereinafter referred to as RLZ) was purchased from Tokyo Chemical Industry (Tokyo, Japan) and Ambeeds (Illinoi, AH, USA). Sulfasalazine (hereinafter referred to as SSZ) was manufactured by Sigma Chemical Co. Inc. (St. Louis, MO, USA).
  • Salicylic acid hereinafter referred to as SA
  • N- (tert-Butoxycarbonyl)-L-aspartic acid 4-benzyl ester N- (tert-Butoxycarbonyl)-L-aspartic acid 4-benzyl ester; , BOC-Asp-Obzl
  • CDI 1,1'-Carbonyldiimidazole
  • N- (tert-Butoxycarbonyl)-L-glutamic acid 5-benzyl ester N- (tert-Butoxycarbonyl)-L-glutamic acid 5-benzyl ester; hereinafter referred to as BOC-Glu-Obzl
  • BOC-Glu-Obzl is AK scientific ( Union City, AA, USA).
  • Succinic anhydride, sodium nitrite (NaNO 2 ), sulfamic acid and 2,4-dinitrobenzene sulfonic acid hydrate (DNBS) were purchased from Tokyo Chemical Industry (Tokyo, Japan).
  • Reaction solvents and high-performance liquid chromatography (HPLC) grade solvents were manufactured by Junsei Chemical Co.
  • Cytokine-induced neutrophil chemoattractan-3 enzyme-linked immunosorbent assay (CINC-3 ELISA) kit was purchased from R&D Systems (Minneapolis, MN, USA). Phosphate buffer (pH 7.4, PBS) was purchased from Thermo Fisher Scientific (Waltham, MA, USA). All other chemicals were reagent grade commercial products. Spots on thin layer chromatography (TLC) plates (Silica Gel F254s, Merck Millipore, Burlington, MA, USA) were detected using a UV lamp (254 nm).
  • TLC thin layer chromatography
  • IR and 1 H-NMR spectra were recorded using a Varian FT-IR spectrophotometer (Varian, Palo Alto, CA, USA) and a Varian AS 500 spectrometer (Varian), respectively. Chemical shifts of the NMR spectra are expressed in ppm downfield from tetramethylsilane.
  • Electrospray ionization mass spectrometry (ESI-MS) spectra were obtained using an Agilent 65360 Q-TOF (Agilent, Santa Clara, CA, USA).
  • RLZ-azo-SA RAS in the form of an azo bond between RLZ and SA (RLZ-azo-SA) was obtained in a yield of 38% by extraction with ethyl acetate (hereinafter referred to as EA).
  • the aqueous layer was discarded, and when the layers were separated by adding 10 mL of 5% sodium bicarbonate (hereinafter referred to as NaHCO 3 ) solution, the aqueous layer was removed and EA was evaporated. After evaporation, 550 ⁇ L of TFA (trifluoroacetic acid) and 450 ⁇ L of DCM (dichloromethane) were added and stirred for 45 minutes. After evaporating the reaction solution, 10 mL of ACN, 100 mg of succinic anhydride, and 1 mL of TEA were added, and the mixture was stirred at 40 °C for 4 hours.
  • TFA trifluoroacetic acid
  • DCM dichloromethane
  • reaction solution After evaporating the reaction solution, it was dissolved in 10 mL of 1 M NaOH and hydrolyzed for 3 hours. Put the reaction solution in a separatory funnel, add 10 mL of EA, and when the layers were separated, the aqueous layer was separated and stirred at 4 ° C. using 1 M HCl to adjust the pH to 1.0. Only the precipitate was obtained by centrifugation and washed with 10 mL of ethyl ether to obtain SAR and SGR in yields of 80% and 75%, respectively.
  • Human colon carcinoma cell line HCT116 cells and murine macrophage RAW 264.7 cells were treated with 10% fetal bovine serum (HyClone, Logan, UT, USA) and penicillin/streptomycin. were cultured in DMEM (Dulbecco's Modified Eagle's Medium; HyClone) containing (penicillin/streptomycin; HyClone).
  • DMEM Dulbecco's Modified Eagle's Medium
  • HyClone penicillin/streptomycin
  • the HPLC system consisted of a Gilson model 306 pump, a 151 variable UV detector and a model 234 autoinjector (Gilson, Middleton, WI, USA).
  • a Symmetry C 18 column Hector, Theale, Berkshire, UK; 250 x 4.6 mm, 5 ⁇ m was used for chromatographic separation. Samples from each experiment were filtered through a membrane filter (0.45 ⁇ m).
  • mobile phase A consisted of distilled water and ACN (4:6, v/v) and mobile phase B consisted of distilled water and ACN (7:3, v/v).
  • HPLC analysis was performed at a flow rate of 1 mL/min. Eluates were monitored at 263 nm using a UV detector measuring absorption with a sensitivity of AUFS 0.01. The retention time of RLZ in mobile phase A was 5.6 minutes, and the retention time of RAS in mobile phase B was 7.3 minutes.
  • RAS, SAR, SGR, AR, and GR (2 mM) dissolved in 5 mL of isotonic phosphate buffer were mixed with small intestine and cecal suspensions (5 mL), and incubated at 37 °C for 24 hours. Cecal contents were incubated under nitrogen. 0.5 mL of the mixture was collected at regular intervals and centrifuged at 10,000 x g for 10 minutes at 4° C., and the supernatant (0.2 mL) was extracted with EA (0.3 mL). The organic layer (0.2 mL) was transferred to a new microtube and after complete evaporation the mobile phase (0.2 mL) was added. The solution was filtered through a membrane filter (0.45 ⁇ m) and the concentration of drug in the filtrate (20 ⁇ L) was analyzed using HPLC.
  • GSK3beta inhibitory effect of RLZ were conducted on two cell lines of Preparation Example 3.
  • the two cell lines were treated with 10, 50, and 100 uM of RLZ for 24 hours, respectively, and the inhibition of glycogen synthase (hereinafter, referred to as GS) phosphorylation, a substrate of GSK3beta, was analyzed by Western blot to measure the inhibitory effect of GSK3beta.
  • GS glycogen synthase
  • mice [ Experimental example 5] DNBS (2,4- dinitrobenzene sulfonic colitis induced by acid hydrate) in mice
  • a rubber cannula (2 mm, OD) was inserted from the colon to the rectum, and the tip was placed at the splenic flexion site 8 cm from the anus. Then, DNBS (48.0 mg) dissolved in 0.4 mL of 50% aqueous ethanol was injected into the colon through a rubber cannula.
  • Group 1 oral administration of 1.0 mL of PBS
  • Group 2 (RLZ untreated DNBS group): PBS 1.0 mL orally administered;
  • Group 3 oral administration of RLZ (2 mg/kg) in 1.0 mL of PBS;
  • Group 4 oral administration of SSZ (5 mg/kg) in 1.0 mL of PBS;
  • Group 5 oral administration of RLZ (10 mg/kg) in 1.0 mL of PBS;
  • Group 1 oral administration of 1.0 mL of PBS
  • Group 2 (RLZ untreated DNBS group): PBS 1.0 mL orally administered;
  • Group 3 oral administration of RLZ (10 mg/kg) in 1.0 mL of PBS;
  • Group 4 oral administration of SSZ (30 mg/kg) in 1.0 mL of PBS;
  • CDS colonic damage score
  • MPO myeloperoxidase activity was measured in the large intestine (4 cm). Inflamed colon (0.2 g) was homogenized in a vial containing 2.0 mL of 5.0% hexadecyltrimethylammonium bromide (HTAB, pH 6.0) solution and incubated on ice for 20 minutes. The homogenates were centrifuged at 10,000 xg for 10 min at 4 °C, and 0.1 mL of the supernatant was o-dianisidine (16.7 mg) and 30.0% H 2 O 2 (1.7 mL).
  • HTAB hexadecyltrimethylammonium bromide
  • MPO activity was defined as dissolving 1.0 ⁇ mol of peroxide per minute at 25 °C.
  • the SD rats of Preparation Example 4 were starved for 24 hours under conditions where only water could be consumed, and then RLZ (10 mg/kg) or RAS (16.4 mg/kg; RLZ 10 mg). /kg) containing PBS (1.0 mL) was orally administered to the SD rats.
  • Plasma 0.3 mL was obtained by centrifuging the blood samples at 10,000 x g for 10 minutes at 4°C.
  • Plasma (0.25 mL) transferred to a centrifuge tube was extracted with EA (0.7 mL). The organic layer (0.5 mL) was evaporated and dissolved in a mobile phase (0.15 mL), filtered through a membrane filter (0.45 ⁇ m), and RLZ in the filtrate (20.0 ⁇ L) was analyzed by HPLC.
  • the contents of the cecum obtained at 4, 8 and 12 hours after oral administration were mixed in isotonic phosphate buffer (pH 6.8) to make a 10% suspension. After centrifugation at 10,000 x g for 10 min at 4 °C, the supernatant (0.2 mL) was extracted with EA (0.3 mL). The organic layer (0.2 mL) was transferred to a new microtube and after complete evaporation the mobile phase (0.2 mL) was added. The solution was filtered through a membrane filter (0.45 ⁇ m) and the concentration of RLZ in the filtrate (20 ⁇ L) was analyzed using HPLC.
  • Experiment 1 (5 groups) and Experiment 2 (4 groups) were conducted with the male SD rats of Preparation Example 4 as follows. The number of mice per group was 5.
  • Group 1 oral administration of 1.0 mL of PBS
  • Group 2 drug-untreated DNBS group: PBS 1.0 mL orally administered;
  • Group 3 oral administration of RLZ (10 mg/kg) in 1.0 mL of PBS;
  • RAS(L) treated DNBS group oral administration of RAS (8.2 mg/kg) in 1.0 mL of PBS;
  • RAS(H) treated DNBS group Oral administration of RAS (16.4 mg/kg) in 1.0 mL of PBS
  • Group 1 oral administration of 1.0 mL of PBS
  • Group 2 drug-untreated DNBS group: PBS 1.0 mL orally administered;
  • Group 3 oral administration of SSZ (30 mg/kg) in 1.0 mL of PBS;
  • Group 4 (RAS-treated DNBS group): Oral administration of RLZ (16.4 mg/kg) in 1.0 mL of PBS
  • CDS Colonic damage score
  • MPO myeloperoxidase activity was measured in the large intestine (4 cm). Inflamed colon (0.2 g) was homogenized in a vial containing 2.0 mL of 5.0% hexadecyltrimethylammonium bromide (HTAB, pH 6.0) solution and incubated on ice for 20 minutes. The homogenates were centrifuged at 10,000 xg for 10 min at 4 °C, and 0.1 mL of the supernatant was o-dianisidine (16.7 mg) and 30.0% H 2 O 2 (1.7 mL).
  • HTAB hexadecyltrimethylammonium bromide
  • MPO activity was defined as dissolving 1.0 ⁇ mol of peroxide per minute at 25 °C.
  • Levels of the inflammatory chemokine CINC-3 and the anti-inflammatory cytokine IL-10 were determined in the inflamed colon using ELISA kits.
  • the large intestine minced into small pieces in potassium phosphate buffer (pH 6.0) was homogenized and then centrifuged at 10,000 ⁇ g at 4 °C for 10 minutes.
  • ELISA was performed according to the manufacturer's instructions.
  • Results were expressed as mean ⁇ standard deviation (SD).
  • SD standard deviation
  • ANOVA analysis of variance
  • Tukey's HSD test or Mann-Whitney U test (for CDS) was used to test for differences between groups. Differences with ⁇ or P ⁇ 0.05 were considered statistically significant.
  • RLZ exerts molecular actions that block glutamatergic neurotransmission and enhance Wnt/beta-catenin signaling, suggesting that these molecular actions of RLZ have potential for treating colon inflammation.
  • RLZ was orally administered once a day at 2, 5 and 10 mg/kg, respectively, to the colitis rats induced by DNBS of Experimental Example 4. After 7 days, mice were euthanized, and colon damage and inflammation were assessed by measuring CDS, MPO activity, and levels of the chemoattractant CINC-3 and inflammatory mediators COX-2 and iNOS in the inflamed colon.
  • RLZ was able to alleviate colon damage and inflammation in a dose-dependent manner, and when RLZ was treated at 5 and 10 mg/kg, all anti-colitis indexes were significantly improved, When treated with 2 mg/kg, CINC-3 levels and MPO activity were significantly improved.
  • the DNBS-induced group showed severe colon damage and inflammation affecting neighboring organs. Both RLZ and SSZ healed the inflammatory damage of the colon, and overall, RLZ was more effective than SSZ. It was more effective. Except for CDS, RLZ was found to be more effective than SSZ in reducing the levels of MPO and the inflammatory mediator CINC-3.
  • RLZ is known as a neuroprotective drug clinically used for amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. RLZ blocks glutamatergic neurotransmission and Wnt/beta-catenin signaling ( It is known as a molecular mechanism that can enhance Wnt/beta-catenin signaling), but since RLZ shows a stronger anti-colitis effect at a higher dose than the RLZ dose (2 mg/kg) in which this molecular mechanism is thought to act, additional The anti-colitis molecular mechanism was investigated through cell experiments conducted in Experimental Examples 3 and 4 above.
  • ALS amyotrophic lateral sclerosis
  • RLZ inhibited phosphorylation of GS, a substrate of GSK3beta, an anti-colitis target kinase, in a concentration-dependent manner.
  • IL-10 an anti-inflammatory cytokine
  • RAS, SAR, SGR, AR, and GR are the large intestine-targeting riluzole precursors that are stable when passing through the small intestine after oral administration and can be converted to the parent drug, RLZ, upon reaching the large intestine. It was found to have a characteristic
  • RLZ (10 mg/kg) or RAS (16.4 mg/kg; equivalent to 10 mg/kg of RLZ) was orally administered to SD.
  • RLZ concentrations were measured in the blood and cecum at 4, 8, and 12 hours.
  • RLZ was detected in the cecum at a higher concentration when RAS was administered than when RLZ was administered.
  • the maximum amount of RLZ in 1 g of the cecum was 44.6 ⁇ g (12 h), and 6.5 ⁇ g (12 h) when RLZ was administered.
  • FIG. 6A the maximum amount of RLZ in 1 g of the cecum was 44.6 ⁇ g (12 h), and 6.5 ⁇ g (12 h) when RLZ was administered.
  • RLZ was detected in the blood at concentrations of 1.17 ⁇ M at 4 hours and 0.99 ⁇ M at 8 hours after oral administration of RLZ, and 0.04 ⁇ M at 4 hours and 0.19 ⁇ M at 8 hours after oral administration of RAS. It was detected and it was confirmed that the concentration of RLZ in the blood was reduced.
  • the DNBS-induced group showed severe colon damage and inflammation affecting neighboring organs. Both RAS and RLZ healed the inflammatory damage of the colon, and in particular, RAS was more effective than RLZ. found to be more effective.
  • the MPO activity of the inflamed colon was reduced by about 57% over the DNBS control by RLZ, whereas it was reduced by up to 72% over the DNBS control by RAS.
  • the level of CINC-3 was consistent with the results of CDS and MPO activity, and it was confirmed that RAS was more effective than RLZ in reducing the level of the inflammatory mediator CINC-3.
  • Fig. 7D administration of RAS and RLZ reduced the levels of COX-2 and iNOS, which are target gene products of NF ⁇ B.
  • DNBS-induced inflammation increased the level of phosphorylated glycogen synthase (p-GS), a substrate of beta-GSK, and RAS administration significantly reduced the level of p-GS in tissues.
  • RAS was more effective than RLZ at equimolar doses.
  • the group in which DNBS was induced showed severe colon damage and inflammation affecting neighboring organs. Both RAS and SSZ healed inflammatory damage of the colon, and RAS was more effective than SSZ.
  • MPO activity in the inflamed colon was reduced by SSZ to about 35% of the DNBS control group, whereas by RAS it was reduced by up to 71% of the DNBS control group.
  • RAS was more effective than SSZ in reducing the level of CINC-3, an inflammatory mediator, consistent with the results of CDS and MPO activities on the level of CINC-3.

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Abstract

La présente invention concerne une composition pharmaceutique et une composition alimentaire fonctionnelle pour la santé pour prévenir ou traiter une maladie intestinale inflammatoire, comprenant du riluzole et un nouveau dérivé du riluzole en tant que principe actif. Le riluzole est connu comme étant un médicament neuroprotecteur utilisé cliniquement pour la maladie de Charcot qui est une maladie neurodégénérative, mais le riluzole peut avoir un effet thérapeutique potentiel dans le traitement d'une maladie intestinale inflammatoire par des actions moléculaires telles que le blocage de la neurotransmission glutamatergique, l'amélioration des signaux Wnt/bêta-caténine, l'inhibition de GSK3bêta, et l'induction d'IL-10.
PCT/KR2022/018090 2021-11-24 2022-11-16 Composition pour la prévention ou le traitement d'une maladie intestinale inflammatoire, comprenant du riluzole ou un nouveau dérivé du riluzole comme principe actif WO2023096258A1 (fr)

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KR1020210163069A KR102625977B1 (ko) 2021-11-24 2021-11-24 리루졸을 유효성분으로 포함하는 염증성 장질환 예방 또는 치료용 조성물
KR10-2021-0163069 2021-11-24
KR1020220103818A KR20240025777A (ko) 2022-08-19 2022-08-19 리루졸 유도체 및 이를 유효성분으로 포함하는 대장 표적성 염증성 장질환 예방 또는 치료용 조성물
KR10-2022-0103818 2022-08-19

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010065491A2 (fr) * 2008-12-01 2010-06-10 Carolus Therapeutics, Inc. Procédés de traitement de troubles inflammatoires
WO2011008298A2 (fr) * 2009-07-16 2011-01-20 Nectid, Inc. Nouvelles formes pharmaceutiques de l’axomadol
US20150352082A1 (en) * 2013-01-22 2015-12-10 Consejo Superior De Investigaciones Científicas Substituted benzothiazoles and therapeutic uses thereof for the treatment of human diseases
US20170312334A1 (en) * 2014-04-02 2017-11-02 Rogne Bioscience Inc. Methods and compositions for treating inflammatory disorders

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010065491A2 (fr) * 2008-12-01 2010-06-10 Carolus Therapeutics, Inc. Procédés de traitement de troubles inflammatoires
WO2011008298A2 (fr) * 2009-07-16 2011-01-20 Nectid, Inc. Nouvelles formes pharmaceutiques de l’axomadol
US20150352082A1 (en) * 2013-01-22 2015-12-10 Consejo Superior De Investigaciones Científicas Substituted benzothiazoles and therapeutic uses thereof for the treatment of human diseases
US20170312334A1 (en) * 2014-04-02 2017-11-02 Rogne Bioscience Inc. Methods and compositions for treating inflammatory disorders

Non-Patent Citations (2)

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Title
MISHRA SURYA PRAKASH, SHUKLA SUNIT KUMAR, PANDEY BAJRANG LAL: "A preliminary evaluation of comparative effectiveness of riluzole in therapeutic regimen for irritable bowel syndrome", ASIAN PACIFIC JOURNAL OF TROPICAL BIOMEDICINE, ELSEVIER, CHINA, vol. 4, 1 May 2014 (2014-05-01), China , pages S335 - S340, XP093068972, ISSN: 2221-1691, DOI: 10.12980/APJTB.4.2014C205 *
PARK SOHEE, KANG CHANGYU, KIM JAEJEONG, JU SANGHYUN, YOO JIN-WOOK, YOON IN-SOO, KIM MIN-SOO, LEE JAEWON, JUNG YUNJIN: "A Colon-Targeted Prodrug of Riluzole Improves Therapeutic Effectiveness and Safety upon Drug Repositioning of Riluzole to an Anti-Colitic Drug", MOLECULAR PHARMACEUTICS, AMERICAN CHEMICAL SOCIETY, US, vol. 19, no. 11, 7 November 2022 (2022-11-07), US , pages 3784 - 3794, XP093068973, ISSN: 1543-8384, DOI: 10.1021/acs.molpharmaceut.2c00255 *

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