JP2023012557A - Novel medicament for treating hepatic encephalopathy - Google Patents

Abstract

To provide a medicament for treating and/or preventing hepatic encephalopathy, comprising a quinolone compound as an active ingredient.SOLUTION: The present invention provides a medicament for treating and/or preventing hepatic encephalopathy, comprising 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or a pharmaceutically acceptable salt thereof or a metabolite thereof as an active ingredient.SELECTED DRAWING: None

Description

TECHNICAL FIELD The present invention relates to a therapeutic and/or preventive agent for hepatic encephalopathy, and more particularly to a therapeutic and/or preventive agent for hepatic encephalopathy containing a quinolone compound as an active ingredient.

In hepatic encephalopathy, neurological symptoms are caused by hyperammonemia associated with decreased ammonia metabolism, etc., and encephalopathy is considered to develop.

For the treatment of hepatic encephalopathy, synthetic disaccharides (such as lactulose) and low-absorbing antibacterial drugs (such as rifaximin) are used as therapeutic agents for hyperammonemia (Non-Patent Document 1). Rifaximin, an antibacterial agent, has a mechanism of action that reduces intestinal bacteria, including ammonia-producing bacteria, in the intestine (Non-Patent Documents 2 and 3), and is indicated for hyperammonemia in hepatic encephalopathy. However, even with these agents, hyperammonemia has not been cured completely, and therapeutic agents with stronger efficacy than existing drugs are desired.

Patent Document 1 discloses specific quinolone antibacterial agents, and that these antibacterial agents exhibit antibacterial activity against Clostridioides difficile living in the intestinal tract.

WO2013/029548

Montagnese S, et al., Dig Liver Dis. 2019; 51: 190-205. Finegold SM, et al., Antimicrob Agents Chemother. 2009; 53: 281-6. J. M. Sierra, et al., Antimicrob Agents Chemother. 2001; 45: 643-644.

An object of the present invention is to provide a new drug that is more effective than existing drugs for treating and/or preventing hepatic encephalopathy.

As a result of intensive studies, the present inventors found that 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5, a known quinolone antibacterial agent -Pyridyl)-4-oxo-3-quinolinecarboxylic acid can reduce ammonia concentration in portal vein blood more than existing drugs recognized as therapeutic agents for hyperammonemia in hepatic encephalopathy, The present inventors have completed the present invention based on the finding that it can be effective in the treatment of encephalopathy.

That is, the present invention is as follows.
[Item 1] 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or its A drug for treating and/or preventing hepatic encephalopathy, containing a pharmaceutically acceptable salt or a metabolite thereof as an active ingredient.

[Item 2] 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-carbamoylpyridine- 3-yl)-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, or 7-(6-amino-5-cyanopyridin-3-yl )-ethyl-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate.

[Item 3] The drug according to Item 1 or 2, which is an oral formulation.

[Item 4] The drug according to any one of Items 1 to 3, wherein the daily dose of the active ingredient is 0.5 mg to 6000 mg.

[Item 5] A therapeutically effective amount of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3 - A method of treating and/or preventing hepatic encephalopathy, which comprises administering a quinolinecarboxylic acid or a pharmaceutically acceptable salt thereof or a metabolite thereof to a patient in need thereof.

[Claim 6] 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3) for manufacturing a drug for treating and/or preventing hepatic encephalopathy -cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or a pharmaceutically acceptable salt or metabolite thereof.

[Claim 7] 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5 used for the treatment and/or prevention of hepatic encephalopathy -pyridyl)-4-oxo-3-quinolinecarboxylic acid or a pharmaceutically acceptable salt or metabolite thereof.

The compound of the present invention can lower the ammonia concentration in the portal vein blood and has a stronger ammonia concentration lowering effect than rifaximin, an existing therapeutic drug for hyperammonemia in hepatic encephalopathy. It is expected as a therapeutic and/or prophylactic drug for hepatic encephalopathy.

The results of Test Example 1 are shown. The results of Test Example 2 are shown.

1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid of the compound of the present invention is as follows. and is disclosed as Compound No. 2-18 in Patent Document 1, and its production method and antibacterial activity against Clostridioides difficile are also disclosed. (2S,3S,4S,5R,6R)-6-((7-amino-5-cyanopyridin-3-yl)-1, whose metabolites have the structures of formulas (2) to (4), respectively. -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 7-(6 -amino-5-cyanopyridin-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate, which are also of the present invention. are included in the compounds of

Since the compounds of the present invention may exist in the form of hydrates and/or solvates, these hydrates and/or solvates are also included in the compounds of the present invention.
Also included in the compounds of the present invention are deuterium conversion products obtained by converting ¹ H in any one or more of the compounds of the present invention to ² H(D).
The compound of the present invention obtained as a crystal and its pharmaceutically acceptable salt may have crystal polymorphs, and such crystal polymorphs are also included in the present invention.

"Pharmaceutically acceptable salt" means acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, inorganic acid salts such as phosphate, oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluene organic acid salts such as sulfonates and trifluoromethanesulfonates; and amino acid salts such as glutamates and aspartates. Various bases and salts include alkali metal salts such as sodium salts and potassium salts; Examples thereof include alkaline earth metal salts such as salts, or ammonium salts.

In the present invention, "hepatic encephalopathy" is considered to be caused by neurological symptoms caused by hyperammonemia, resulting in the development of encephalopathy. Symptoms vary from those with no subjective symptoms to coma, and this disease causes reversal of sleep rhythm, disorientation, flapping tremor, agitation, delirium, loss of consciousness, and coma. . Causes of hyperammonemia include serious liver disorders such as fulminant hepatitis and cirrhosis, urinary circuit defects such as urea cycle disorders, portosystemic shunt formation, and urease-producing bacterial infections. or a combination of the factors listed above.

The administration route of the compound of the present invention may be oral administration, parenteral administration or rectal administration, and the daily dose varies depending on the type of compound, administration method, symptoms and age of the patient, and the like. For example, in the case of oral administration, it is usually about 0.01 mg to 100 mg, preferably about 0.05 mg to 50 mg, more preferably about 0.1 mg to 20 mg, still more preferably about 1 mg to 10 mg per 1 kg body weight of a human or mammal. can be administered in one to several divided doses, and specifically, the daily dose for humans is about 0.5 mg to 6000 mg, preferably about 3 mg to 3000 mg, more preferably about 6 mg to 1200 mg, more preferably About 60 mg to 600 mg.

Dosage forms include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, ointments, patches, inhalants and the like. These formulations can be prepared according to a conventional method. Liquid preparations may be dissolved or suspended in water, a suitable aqueous solution, or other suitable medium at the time of use. Tablets and granules may also be coated by well-known methods. Formulations are manufactured by known methods using pharmaceutically acceptable additives.
Additives include excipients, disintegrants, binders, fluidizers, lubricants, coating agents, coloring agents, solubilizers, solubilizers, thickeners, dispersants, and stabilizers, depending on the purpose. , sweeteners, flavors and the like can be used. Specifically, for example, lactose, mannitol, calcium hydrogen phosphate, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, crospovidone, sodium starch glycolate. , hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, ferric oxide, yellow ferric oxide, etc. mentioned.

When the compound of the invention is prepared in a single formulation, for example, but not limited to, the compound of the invention may comprise from 0.1 to 85% by weight of the total composition of the formulation. Preferably, the compound of the invention is 10-70% by weight of the total composition of the formulation.

Furthermore, the compounds of the present invention can be used in combination or in combination with other drugs for the purpose of enhancing their effects and/or reducing side effects. Other drugs that can be used in combination or combination are, for example, rifaximin, lactulose, lactitol.

EXAMPLES The present invention will be described in more detail with test examples below, but the present invention is not limited thereto.

The effects of the compounds of the present invention on portal blood ammonia levels were examined using rats. The compounds of the present invention (hereinafter referred to as "test substances") and control agents used here are obtained as follows.
Test substance [1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid]: Otsuka Obtained from Pharmaceutical Co., Ltd. Control drug (rifaximin): Obtained from Sigma-Aldrich

Test example 1. Effect of this test substance on portal vein blood ammonia concentration Hyperammonemia is considered to be one of the major factors of consciousness disturbance in hepatic encephalopathy. Ammonia produced from food by metabolism of intestinal bacteria is transported to the liver via the portal vein after being absorbed in the intestinal tract. In this study, the effect of the test substance on portal blood ammonia concentration in normal rats was investigated.

(Preparation of administration solution)
The test substance was suspended in 5% gum arabic, and three suspensions of 0.02 mg/mL, 0.2 mg/mL, and 2 mg/mL were prepared immediately before use.

(Test method)
Male normal SD rats were divided into the following groups based on body weight, and the following administration solutions were orally administered once a day in amounts corresponding to the doses of each administration group. The administration start date of the first administration was defined as day 0, and on days 1, 3, and 5, 8 rats from each group were taken out, and portal vein blood was collected from each of them, followed by dry chemistry. , measured the concentration of ammonia in the blood. It should be noted that portal vein blood must be collected from one animal at one point, and it is not possible to collect blood from the same individual over time. Therefore, the ammonia concentration was not measured on day 0 as the reference value for each group, and the portal vein blood ammonia concentration of each group before the start of administration on day 0 was equivalent according to the grouping using body weight as an index. The test was conducted assuming that

(result)
In each group, the mean concentration of ammonia in the portal vein blood of 8 animals on each measurement day was calculated, and the summarized results are shown in FIG. Compared to the control administration group, the test substance administration group showed a significant portal blood ammonia level lowering effect at 1 mg/kg or more.

Test example 2. Comparison between this test substance and a control drug on the effect on portal vein blood ammonia concentration Using the existing antibacterial agent rifaximin, which is known to have been known to be effective, the effects thereof were compared by the same method as in Test Example 1 above.

(Preparation of administration solution)
A test substance or rifaximin was suspended in 5% gum arabic, and a 2 mg/mL suspension was prepared immediately before use.

(Test method)
Male normal SD rats were divided into the following groups based on body weight, and the following administration solutions were orally administered once a day in amounts corresponding to the doses of each administration group. The administration start date of the first administration was defined as day 0, and on days 5, 7, and 10, 5 rats from each group were taken out, and portal vein blood was collected from each of the rats, followed by a dry chemistry method. , measured the concentration of ammonia in the blood. It should be noted that portal vein blood must be collected from one animal at one point, and it is not possible to collect blood from the same individual over time. Therefore, the ammonia concentration was not measured on day 0 as the reference value for each group, and the portal vein blood ammonia concentration of each group before the start of administration on day 0 was equivalent according to the grouping using body weight as an index. The test was conducted assuming that

(result)
In each group, the average concentration of ammonia in the portal vein blood of 5 mice on each measurement day was calculated, and the summarized results are shown in FIG. The test substance-administered group and the rifaximin-administered group showed significantly lower portal vein blood ammonia level than the control group. Furthermore, the test substance-administered group showed a significantly lower portal vein blood ammonia level than the rifaximin-administered group.

Claims (7)

1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid or pharmaceutically acceptable thereof A drug for treating and/or preventing hepatic encephalopathy, containing as an active ingredient a salt or a metabolite thereof. 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 7-(6-amino-5-cyanopyridin-3-yl)-1- The agent of claim 1, which is ethyl cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate. 3. The drug of claim 1 or 2, which is an oral drug. Medicament according to any one of claims 1 to 3, characterized in that the daily dose of active ingredient is between 0.5 mg and 6000 mg. A therapeutically effective amount of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinolinecarboxylic acid A method for treating and/or preventing hepatic encephalopathy, which comprises administering to a patient in need of such treatment, or a pharmaceutically acceptable salt thereof or a metabolite thereof. 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5 for the manufacture of a medicament for treating and/or preventing hepatic encephalopathy -pyridyl)-4-oxo-3-quinolinecarboxylic acid or a pharmaceutically acceptable salt or metabolite thereof. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)- for use in the treatment and/or prevention of hepatic encephalopathy 4-oxo-3-quinolinecarboxylic acid or a pharmaceutically acceptable salt or metabolite thereof.

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