Pharmaceutical composition for irritable bowel syndrome containing a quinolone compound

Abstract

The present invention relates to a pharmaceutical composition containing a quinolone compound for irritable bowel syndrome, and specifically to the use of a quinolone compound, particularly 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinoline-carboxylic acid or a pharmacologically acceptable salt, hydrate, solvate, or deuteride thereof, for preventing or treating irritable bowel syndrome in humans or animals.

Description

Technical Field

[0001] The present invention belongs to the medical field, and particularly relates to a drug for the prevention or treatment of irritable bowel syndrome containing a low-absorption quinolone compound or a pharmacologically acceptable salt thereof as an active ingredient.

Background Art

[0002] IBS (irritable bowel syndrome) is a functional gastrointestinal disorder accompanied by symptoms such as abdominal pain accompanied by changes in the form and frequency of stools, but is not associated with structural or biochemical abnormalities detectable by current ordinary diagnostic tools. This condition affects 5% - 10% of people who are healthy at a certain point in time, and most people repeat recurrence and remission. According to the Rome classification, IBS can be classified into four categories: diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), mixed (IBS-M), and unclassified (IBS-U). In China, the IBS population is in the range of 1.4 - 11.5%, and the majority is mainly diarrhea-predominant (IBS-D). Only 25% of patients visited the hospital seeking treatment.

[0003] Currently, there is no treatment method for IBS. The main treatment methods include patient education about symptoms, improvement of diet, water-soluble dietary fiber, and antispasmodics. Other treatment methods tend to be limited to people with severe symptoms, and include central nervous system regulators, intestinal secretion promoters, drugs acting on opioid or 5-HT receptors, or antibiotics with low absorption, as well as psychotherapy. For example, tricyclic antidepressants are effective in the treatment of IBS-D, but have many side effects such as sleep, constipation, and thirst in the throat. Similarly, 5HT antagonists are applied in this area (Non-Patent Document 1). However, even when using these drugs, complete treatment of IBS-D cannot be expected, and therefore the development of drugs more powerful than existing drugs is desired.

[0004] Patent Document 1 discloses a specific quinolone antibacterial agent that exhibits antibacterial activity against Clostridioides (Clostridium) difficile, which inhabits the intestinal tract.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Non-Patent Documents

[0006]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] The main object of the present invention is to provide a novel medicament for treating and / or preventing irritable bowel syndrome (IBS), particularly IBS-D, which is more effective than existing drugs.

Means for Solving the Problems

[0008] As a result of intensive studies, the present inventors have found that 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinoline-carboxylic acid, a known quinolone antibacterial agent, improves the fecal output of restrained rats, which is a characteristic of irritable bowel syndrome, and is effective for the treatment of irritable bowel syndrome, thus completing the present invention.

[0009] The present invention provides the use of a quinolone compound for preventing or treating IBS, particularly IBS-D, as described in Items 1 to 11 below.

[0010] [Item 1] A medicament for treating and / or preventing IBS, comprising, as an active ingredient, 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinoline-carboxylic acid, or a pharmaceutically acceptable salt, precursor or metabolite, hydrate, solvate or deuterated form thereof.

[0011] [Item 2] The medicament according to Item 1, wherein the metabolite is (2S,3S,4S,5R,6R)-6-((7-amino-5-cyanopyridin-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carbonyl)oxo)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid, 7-(6-amino-5-carbamoylpyridin-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, or ethyl 7-(6-amino-5-cyanopyridin-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate.

[0012] [Item 3] The medicament according to Item 1 or 2, which is for oral administration.

[0013] [Item 4] The medicament according to any one of Items 1 to 3, wherein the daily dose of the active ingredient is 7.5 mg to 24,000 mg.

[0014] [Item 5] The medicament according to any one of Items 1 to 4, wherein the IBS is IBS-D.

[0015] [Item 6] A method for the treatment and / or prevention of IBS, characterized by administering to a patient in need a therapeutically effective amount of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinoline-carboxylic acid, or a pharmaceutically acceptable salt, precursor or metabolite, hydrate, solvate or deuterated form thereof.

[0016] [Item 7] The method of item 6, wherein the IBS is IBS-D.

[0017] [Item 8] Use of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinoline-carboxylic acid, or a pharmaceutically acceptable salt, precursor or metabolite, hydrate, solvate or deuterated form thereof, in the manufacture of a medicament for the treatment and / or prevention of IBS.

[0018] [Item 9] The use of item 8, wherein the IBS is IBS-D.

[0019] [Item 10] 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinoline-carboxylic acid, or a pharmaceutically acceptable salt, precursor or metabolite, hydrate, solvate or deuterated form thereof, for use in the treatment and / or prevention of IBS.

[0020] [Item 11] 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinoline-carboxylic acid, or a pharmaceutically acceptable salt, precursor or metabolite, hydrate, solvate or deuterated form thereof, of item 10, wherein the IBS is IBS-D.

Brief Description of the Drawings

[0021]

Figure 1

Figure 2

Figure 3

Figure 4

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Figure 6

Mode for Carrying Out the Invention

[0022] The compound of the present invention having the structure of formula (1), 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinoline-carboxylic acid, is disclosed as compound 2-18 in WO2013 / 029548 and can be synthesized according to WO2013 / 029548.

Chemical formula

[0023] The compound of the present invention may include a precursor or metabolite of the compound, for example, (2S,3S,4S,5R,6R)-6-((7-amino-5-cyanopyridin-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carbonyl)oxo)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid, 7-(6-amino-5-carbamoylpyridin-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, and ethyl 7-(6-amino-5-cyanopyridin-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate, each having the structure of the following formula (2)-(4).

Chemical formula

Chemical formula

Chemical formula

[0024] The compound of the present invention may form a hydrate and / or a solvate, and thus the hydrate and / or solvate of the compound of the present invention are also included. Also, the compound of the present invention in which one or more arbitrary 1 H atoms are 2 substituted with H(D) atoms is also within the scope of the present invention. There may be polymorphs in the crystals of the compound of the present invention or its pharmaceutically acceptable salts, and such crystal polymorphs are also within the scope of the present invention.

[0025] Examples of "pharmaceutically acceptable salts" include acid addition salts such as salts with inorganic acids like hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate, etc.; salts with organic acids such as oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, etc.; and salts with amino acids such as glutamate, aspartate, etc.; and salts with bases such as alkali metal salts like sodium salt, potassium salt, etc.; alkaline earth metal salts like calcium salt, etc.; and ammonium salts.

[0026] The compounds of the present invention and their pharmaceutical compositions are usually used in the form of ordinary pharmaceutical preparations. The pharmaceutical preparations can be prepared by mixing with conventional pharmaceutically acceptable diluents or carriers such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and lubricants. Examples of the pharmaceutical preparations include various preparations suitable for the treatment of diseases, such as tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections such as solutions and suspensions. In the manufacture of tablets, conventional carriers such as excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicate, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and other disintegrants, sucrose, stearin, cocoa butter, hardened oil and other disintegration inhibitors, quaternary ammonium salts, sodium lauryl sulfate and other absorption promoters, glycerin, starch and other wetting agents, starch, lactose, kaolin, bentonite, colloidal silicate and other adsorbents, purified talc, stearate, boric acid powder and polyethylene glycol and other lubricants can be used. Tablets may also be coated with conventional coating agents, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or in the form of two-layer or multi-layer tablets. In the preparation of pills, conventional carriers such as excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oil, kaolin, talc, gum arabic powder, tragacanth powder, gelatin, ethanol and other binders, laminaran, agar and other disintegrants can be used. In the preparation of suppositories, for example, conventional carriers such as polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides can be used. In the preparation of injections, the solutions, emulsions or suspensions of the compounds are sterilized and preferably made isotonic with body fluids.These solutions, emulsions and suspensions are prepared by mixing the active compound with conventional diluents such as water, aqueous lactic acid, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol or polyoxyethylene sorbitan fatty acid esters. The formulations can also contain an amount of sodium chloride, glucose, or glycerin sufficient to make them isotonic with body fluids. The formulations can also contain conventional solubilizers, buffers, anesthetics, and also coloring agents, preservatives, fragrances, flavors, sweeteners, and other agents. Paste, cream, and gel formulations can be prepared using white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite, etc. as diluents. If the compound of the active ingredient precipitates in the injection, acids such as methanesulfonic acid, propionic acid, hydrochloric acid, succinic acid, lactic acid, etc. may be added to the injection as necessary to store the injection as a stable solution.

[0027] The compounds of the present invention may be contained in any amount in the formulation, but are usually contained in an amount of 1 to 70% by weight based on the total weight of the formulation.

[0028] The pharmaceutical composition of the present invention can be administered by any method. An appropriate administration method may be selected according to the formulation form, the age, sex, and severity of the disease of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are administered via the oral route. In the case of injections, they are administered intravenously alone or together with adjuvant solutions such as glucose or amino solutions. Injections may also be administered via intramuscular, intradermal, subcutaneous, or intraperitoneal routes. Suppositories are administered via the rectal route. The pharmaceutical composition may be in the form of ophthalmic, ointment, patch, or inhalant.

[0029] The dosage of the composition of the present invention may vary depending on the administration method, the age and gender of the patient, the severity of the disease, etc. For example, in the case of oral administration, usually, per 1 kg of the body weight of a human or a mammal, it can be administered in divided doses of about 0.125 mg to about 400 mg, preferably about 0.25 mg to about 200 mg, more preferably about 0.5 mg to about 100 mg, and even more preferably about 1 mg to about 50 mg, 1 to several times. For example, as the daily dosage for a human, it can be about 7.5 mg to about 24000 mg, preferably about 15 mg to about 12000 mg, more preferably about 30 mg to about 6000 mg, and even more preferably about 60 mg to about 3000 mg.

Examples

[0030] The present invention will be described by the following examples, experimental examples, and production examples. It should be noted that the present invention is not limited to these examples, experimental examples, and preparation examples, and various changes and modifications can be made without departing from the scope and gist of the present invention.

[0031] The restraint stress (RS) model used in the following examples is a common model used when testing the efficacy of drugs against IBS and was first proposed by Williams et al., Gastroenterology 1988, 94: 611. The RS model is thought to mimic IBS, an intestinal disorder that shows no structural or biochemical abnormalities, as it shows inhibition of intestinal transport and an increase in the number of defecations without forming ulcers. Currently, an improved restraint stress model, as previously described by Wang et al., Int. J. Gastroenterol. Disord. Ther. 2017, 4: 131., is widely used. References regarding visceral hypersensitivity and histamine are, for example, Christine West, Karen-Anne McVey Neufeld, "Animal models of visceral pain and the role of the microbiome. Neurobiology of Pain" 10 (2021) 100064; Giada De PalmaChiko ShimboriDavid E. ReedYang YuVirginia RabbiaJun LuNestor Jimenez-VargasJessica SessenweinCintya Lopez-LopezMarc PigrauJosue Jaramillo-PolancoYong ZhangLauren BaergAhmad ManzarJulien PujoXiaopeng BaiMaria Ines Pinto-SanchezAlberto CamineroKaren MadsenMichael G. SuretteMichael BeyakAlan E. LomaxElena F. VerduStephen M. CollinsStephen J. VannerPremysl Bercik. Histamine production by the gut microbiota induces visceral hypersensitivity via histamine 4 receptor signaling in mice (Sci. Transl. Med., 14 (655), eabj1895).

[0032] Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto. The compounds of the present invention (hereinafter referred to as "test substances") and reference drugs used herein were obtained as follows.

[0033] Test substance 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinoline-carboxylic acid, shown as OPS-2071, was synthesized by Otsuka Pharmaceutical Co., Ltd.

[0034] Experimental Example 1: Influence of the test substance on fecal volume in a restraint stress (RS) rat model (Animals) Male Sprague-Dawley (SD) rats weighing 200 - 250 g were purchased from Charles River Laboratories Beijing and housed three per cage in individually ventilated cages (IVCs) in the SPF-grade animal facility of OSRI. All animals were maintained on a 12-hour light-dark cycle, and rodent feed and water were available ad libitum. All animal research procedures were in accordance with the animal welfare regulations and approved by the Institutional Animal Care and Use Committee (IACUC) of OSRI.

[0035] (Reagents) Arabic gum (AG) was purchased from Sigma (CAT#: G9752-500G).

[0036] (Establishment of the restraint stress rat model) As shown in Table 1, SD rats were randomly assigned to three groups based on body weight, with six rats assigned to each group. Rats (Groups 2 and 3) were restrained daily in plastic cylinders for 2 hours in the afternoon for 10 consecutive days (from D1 to D10). Rats in the control group (Group 1) remained in their respective cages without interference during the experimental period. After repeating RS modeling three times from D4 to D10 for 3 days, rats in Groups 2 and 3 were treated with vehicle (5% AG) and test substance (2.5 mg / kg) respectively in the morning (4 hours before afternoon restraint) for 7 consecutive days. The fecal pellet output was used to estimate the motility of the distal colon as a validated index (Hong S et al., Gut 2009, 58: 202-210). During the 2-hour restraint period, the fecal output of rats was collected and counted as in the control group of rats during the same 2-hour simulated observation period. TIFF2025522052000006.tif46169

[0037] (Results) The behavior of the rats was observed daily, and all indicators were normal. As shown in Figures 1 and 2, treatment with OPS-2071 improved the weight loss due to restraint stress. When RS modeling was performed for 2 hours a day for 7 days, the weight gain observed in non-RS control rats was delayed (Group 2 vs. Group 1). However, when treated with OPS-2071 at 2.5 mg / kg for 7 days, the effect was alleviated to some extent (Group 3 vs. Group 2). Food intake was monitored starting from the 3rd day after treatment initiation (6th day after RS application). Treatment with OPS-2071 showed a protective effect against the decreased appetite observed in the RS control group (Group 3 vs. Group 2). Changes in defecation volume were observed upon application of restraint stress. Stress increased the fecal volume in the RS group (Group 2 vs. Group 1). On the 4th day, the test group was treated with 2.5 mg / kg of OPS-2071, and a decrease in fecal pellet output was observed as shown in Figure 3 (Group 3 vs. Group 2).

[0038] Experimental Example 2: Evaluation of the efficacy of OPS-2071 on visceral hypersensitivity and histamine levels in a restraint stress (RS) model (Establishment of the restraint stress rat RS model) As described above, Sprague Dawley rats were continuously restrained in plastic cylinders for 2 hours every day for 7 days. In the control group, the rats were placed in individual cages without being disturbed during the experimental period.

[0039] (Visceral motor responses to colorectal distension on days 3 and 7) A colon dilation - polyethylene balloon (length 3 cm, maximum diameter 1.5 cm) was fixed to a tube attached to a sphygmomanometer and used for colon dilation. The balloon was coated with lubricating oil and inserted into the distal colon of the rat such that the tip of the balloon was 2 cm proximal to the anus. The rat was restrained in a plastic containment device using the sphygmomanometer dilation apparatus and acclimated for 10 minutes prior to the test. The rat was given stepwise dilation of the colon (0 - 100 mmHg, increasing by 5 mmHg each time) until the first contraction of the testis, tail, or abdominal muscle tissue occurred. This visualization was performed by three independent observers. The visceral pain threshold index was defined as the first nociceptive response as described above (T. J. Ness; G. F. Gebhart, 「Colorectal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudaffective reflexes in the rat」, Brain Research, Vol. 450, Issues 1 - 2, pages 153 - 169, May 21, 1988; Wesselmann, U.; Lai, J., 「Mechanisums of referred viiceral pain: uterine inflammation in the adult virgin rat results in neurogenic plasma extravasation in the skin」, Pain Vol. 73, Issue 3, pages 309 - 317, 1997). In the rapid inflation protocol used in this study, the compliance of the colon was not measured. The colon dilation was repeated three times at a 5 - minute stimulation interval, and the mean pressure at the nociceptive threshold was recorded for each rat.

[0040] (Treatment) OPS-2071(2071): Prepared once a week with 5% AG (gum arabic), the gum arabic was gum arabic derived from Acacia trees purchased from Sigma (CAT#: G9752-500G). As shown in Table 2, the treatment was started from the 4th day to the 7th day. TIFF2025522052000007.tif56162

[0041] Sampling Urine collection on the 7th day: Urine samples were collected daily after restraint. A plastic dish was placed under the restraint tube and urine samples were collected. It was immediately transferred to a tube and stored at -80°C until further analysis. Histamine was measured as follows according to the manufacturer's instructions using a histamine ELISA kit (CAT#: D751012, BBI).

[0042] Procedure: 1. Calculate the required number of slats in advance, take out the kit 30 minutes before the test, and let it return to room temperature. 2. Add 50 μL each of the standard solution and the specimen to each reaction well. The standard solution needs to be punctured again. Immediately add 50 μL of the biotin-labeled histamine antibody detection solution to each reaction well, seal the plate, and incubate at 37°C for 45 minutes. 3. Washing: Discard the liquid and shake to dry. Add 350 μL of the washing solution to each reaction well, immerse for 1 - 2 minutes, and repeat shaking to dry 4 times. 4. Add 100 μL of the HRP-labeled streptavidin detection solution to each reaction well, seal the plate, and incubate at 37°C for 30 minutes. 5. Washing: Add 300 μL of the washing solution to each reaction well and dry at 30-second intervals. Repeat this 4 times. 6. Add 90 μL of the color development solution (light-blocking solution) to each reaction well, and after sealing the plate, develop color at 37°C for 15 minutes. 7. Add 50 μL of the reaction termination solution to each reaction well and immediately measure the OD value at a wavelength of 450 nm using an enzyme-labeling device (within 5 minutes). 8. The OD value was measured at a wavelength of 450 nm using an enzyme labeling device. 9. A standard curve was plotted with the concentration of the standard substance on the horizontal axis and the absorbance on the vertical axis. 10. Statistical significance was calculated by one-way ANOVA using a two-sided T-test (visceral sensitivity on day 3) or Dunnett's multiple comparison. A P < 0.05 was considered statistically significant.

[0043] (Results) Figures 4 and 5 show the visceral motor responses (mmHg) to colorectal distension. Figure 4 shows the visceral motor responses on day 3, which was 1 day before compound treatment was recorded between the control group and the RS group. Figure 5 shows the visceral motor responses on day 7. As shown in Figure 4, on day 3, the visceral sensitivity of rats in the RS group increased compared to the control group (the visceral sensitivity level showed a significant difference (p < 0.01) - control group vs. RS group). In the treatment group administered 2.5 mg / kg of OPS-2071, as shown in Figure 5, a decrease in visceral sensitivity was observed on day 7 (that is, 4 days after OPS-2071 administration, the visceral sensitivity level showed a significant difference (p < 0.05) - treatment group (2.5 mg / kg) vs. RS group). Figure 6 shows the histamine levels in urine quantified by ELISA on day 7, which was 4 days after OPS-2071 compound treatment. On day 7, as shown in Figure 6, the urinary histamine concentration in rats in the RS group was higher than that in the control group, but the urinary histamine value observed in the 2.5 mg / kg compound treatment group decreased (the urinary histamine value showed a highly significant difference (p < 0.01) between the control group and the RS group, and the urinary histamine level showed a highly significant difference (p < 0.01) between the treatment group (2.5 mg / kg) and the RS group).

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