TWI874582B - Novel medicament for treating hepatic encephalopathy - Google Patents

Abstract

The present invention relates to a medicament for treating and/or preventing hepatic encephalopathy, comprising a quinolone compound as an active ingredient.

Description

New drugs for the treatment of hepatic encephalopathy

The present invention relates to a drug for treating and/or preventing hepatic encephalopathy, and more specifically, to a drug for treating and/or preventing hepatic encephalopathy, comprising a quinolone compound as an active ingredient.

In hepatic encephalopathy, the neurological symptoms are thought to result from hyperammonemia resulting from decreased amino metabolic activity, and then the encephalopathy develops.

In order to treat hepatic encephalopathy, synthetic disaccharides (e.g., lactulose, etc.) have been used as drugs for treating hyperammonemia or low-absorption antimicrobial agents (e.g., rifaximin, etc.) (Non-patent Document 1). The antimicrobial agent rifaximin has a mechanism of action of reducing intestinal bacteria (including ammonia-producing bacteria) (Non-patent Documents 2 and 3), and thus the antimicrobial agent has been approved as a treatment for hyperammonemia in hepatic encephalopathy. However, even if these drugs are used, it is not expected to be any complete treatment for hyperammonemia, and therefore it is desired to develop drugs that are more potent than existing drugs.

Patent document 1 discloses a specific quinolone antimicrobial agent that exhibits antibacterial activity against Clostridium difficile living in the intestine. [Citation list] [Patent document]

[PL 1] WO2013/029548 [Non-patent document]

[NPL 1] Montagnese S et al., Dig Liver Dis. 2019; 51: 190-205. [NPL 2] Finegold SM et al., Antimicrob Agents Chemother. 2009; 53: 281-6. [NPL 3] J. M. Sierra et al., Antimicrob Agents Chemother. 2001; 45: 643-644.

[Technical issues]

The main purpose of the present invention is to provide a novel drug for treating and/or preventing hepatic encephalopathy, which is more effective than existing drugs. [Solution to the problem]

The inventors have extensively studied and then discovered that the known quinolone antimicrobial agent 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinoline-carboxylic acid can reduce the ammonia concentration in portal venous blood beyond the existing drugs approved as a treatment for hyperammonemia in hepatic encephalopathy, and that it can be used to treat hepatic encephalopathy. Based on this new discovery, the present invention has been completed.

The present invention includes the following embodiments. (Clause 1) A drug for treating and/or preventing hepatic encephalopathy, comprising 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridinyl)-4-oxo-3-quinoline-carboxylic acid or a pharmaceutically acceptable salt thereof or a metabolite thereof as an active ingredient.

(Item 2) The drug of 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-aminoformylpyridin-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-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester.

(Article 3) A medicine as defined in Article 1 or 2, which is for oral administration.

(Article 4) A drug as defined in any one of Articles 1 to 3, wherein the daily dose of the active ingredient is 0.5 mg to 6000 mg.

(Article 5) A method for treating and/or preventing hepatic encephalopathy, comprising administering to a patient in need thereof a therapeutically effective amount of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridinyl)-4-oxo-3-quinoline-carboxylic acid or a pharmaceutically acceptable salt thereof or a metabolite thereof as an active ingredient.

(Article 6) The 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 its pharmaceutically acceptable salt or its metabolite in the manufacture of a medicament for the treatment and/or prevention of hepatic encephalopathy.

(Article 7) A 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 or a metabolite thereof, which is used for treating and/or preventing hepatic encephalopathy. [Effects of the present invention]

The compounds of the present invention can reduce the ammonia concentration in portal venous blood, and further have a potent reducing effect on ammonia concentration that exceeds that of rifaximin, a drug currently used to treat hyperammonemia in hepatic encephalopathy. Therefore, it is expected to be a novel drug for treating and/or preventing hepatic encephalopathy. In addition, the compounds of the present invention are poorly absorbed drugs, and therefore when they are orally administered, they are distributed in high concentrations in the intestines, but they have low blood transferability. Therefore, the compounds of the present invention also have the advantage of low risk of systemic side effects, which are a problem of existing quinolone antibacterial agents.

The compound of the present invention, 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinoline-carboxylic acid, has a structure of formula (1) and is disclosed as compound numbers 2 to 18 in patent document 1. The document also discloses its method and its antibacterial activity against Clostridium difficile. Moreover, its metabolites are (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-aminoformylpyridin-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-carboxylic acid ethyl ester, each of which has the following structure of formula (2) to (4), and they are included in the compounds of the present invention. [Chemical 1] [Chemistry 2] [Chemistry 3] [Chemistry 4]

The compounds of the present invention may be in the form of hydrates and/or solvates, and thus the compounds of the present invention also include their hydrates and/or solvates. In addition, the compounds of the present invention (in which any one or more ¹ H atoms are replaced by ² H(D) atoms) are also within the scope of the present invention. There may be polymorphic crystals of the compounds of the present invention or their pharmaceutically acceptable salts, and thus such crystalline polymorphic crystals are also within the scope of the present invention.

"Pharmaceutically acceptable salts" include acid addition salts, salts of inorganic acids such as hydrochlorides, hydrobromides, hydroiodates, sulfates, perchlorates and phosphates; and salts of organic acids such as oxalates, malonates, maleates, fumarates, lactates, malates and citrates. , tartrates, benzoates, trifluoroacetates, acetates, methanesulfonates, p-toluenesulfonates and trifluoromethanesulfonates; and salts with amino acids, such as glutamine and aspartate; and salts with bases, alkaline metal salts, such as sodium and potassium; alkaline earth metal salts, such as calcium; and ammonium salts.

In the hepatic encephalopathy of the present invention, it is believed that the neurological symptoms are caused by hyperammonemia, and then the encephalopathy develops. The symptoms range from asymptomatic state to coma state, which includes sleep rhythm reversal, disorientation, flapping tremors, agitation state, delirium, unconsciousness and coma. Causes of hyperammonemia include severe liver dysfunction (such as fulminant hepatitis and cirrhosis), urea cycle defects (such as urea cycle disorders), portosystemic shunts, urease-producing bacterial infections and combinations thereof.

The compounds of the present invention can be administered by any route selected from oral administration, parenteral administration, and rectal administration. The daily dose depends on the compound, the route of administration, the patient's condition, the patient's age, etc. In the case of oral administration, for example, it can generally be administered in one or more portions in an amount of about 0.01 mg to about 100 mg, preferably about 0.05 mg to about 50 mg, more preferably about 0.1 mg to about 20 mg, and even more preferably about 1 mg to about 10 mg/kg of body weight of a human or mammal. For example, the daily dose for humans includes about 0.5 mg to about 6000 mg, preferably about 3 mg to about 3000 mg, more preferably about 6 mg to about 1200 mg, and even more preferably about 60 mg to about 600 mg.

The dosage forms of the present invention include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, wipes, patches and inhalants. These dosage forms can be prepared in a known manner. If the dosage form is a liquid, it can be formulated to prepare a solution or suspension by mixing it with water, a suitable aqueous solution or other suitable solvent. Tablets and granules can be coated in a well-known manner. The dosage form can be prepared in a known manner using pharmaceutically acceptable additives. The additives used herein include excipients, disintegrants, binders, fluidizers, lubricants, coating agents, colorants, solubilizers, solubilizing agents, thickeners, dispersants, stabilizers, sweeteners and flavoring agents, depending on the intended use. For example, it includes lactose, mannitol, calcium hydrogen phosphate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, calcium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, starch sodium hydroxyacetate, 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 and yellow ferric oxide.

When the compound of the present invention is formulated into a single dosage form, the dosage form may contain 0.1 to 85% (w/w) of the compound of the present invention in the overall composition, but the present invention is not limited thereto. Preferably, it is 10 to 70% (w/w) in the overall composition.

In addition, in order to enhance the effect and/or reduce the side effects, the compound of the present invention can be used in combination with another drug or as a combination with another drug. Other drugs that can be used in combination include (for example) rifaximin, lactulose and lactitol. [Example]

The present invention is explained in more detail by the experiments mentioned below, however, the scope of the present invention is not limited thereto.

Hereinafter, the effect of the compound of the present invention on the ammonia concentration in portal vein blood was studied using rats. The compound of the present invention (hereinafter referred to as "test substance") and the reference drug used in this article were obtained as shown below. Test substance [1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridinyl)-4-oxo-3-quinoline-carboxylic acid]: obtained from Otsuka Pharmaceutical Co., Ltd. Reference drug (rifaximin): obtained from Sigma-Aldrich.

Test 1. Effect of the test substance on the ammonia concentration in the portal vein Hyperammonemia is considered to be one of the main factors causing mental impairment in hepatic encephalopathy. Ammonia produced by the metabolic activity of intestinal bacteria is absorbed in the intestine and then transported to the liver through the portal vein. This test was conducted to study the effect of the test substance on the ammonia concentration in the portal vein of normal rats.

(Preparation of administration samples) The test substance was suspended in 5% gum arabic and then the suspension was diluted before use. Three concentrations of each suspension were prepared (0.02 mg/mL, 0.2 mg/mL, and 2 mg/mL).

(Test method) Normal male SD rats were divided into the groups shown in the table below according to their body weight. Each administration sample shown in the table below was orally administered to the rats in each administration group once a day. The day of the first administration was set as the starting day (day 0). On the 1st day, the 3rd day and the 5th day, 8 rats were taken from each group, portal blood was collected from each rat, and the ammonia concentration in each collected blood was analyzed by dry chemical technology. When collecting portal blood, one rat must be used for one analysis, and blood cannot be collected from the same rat more than once throughout the experiment. Therefore, the ammonia concentration on day 0 was not analyzed, which was considered as a reference for each group, and it was assumed that the ammonia concentration in the portal blood of each group on day 0 was the same, because the groups were grouped based on their body weight, and the experiment was carried out under this assumption. Administration group Sample administration Control group 5% Gum Arabic 0.1 mg/kg group 0.02 mg/mL suspension 1 mg/kg group 0.2 mg/mL suspension 10 mg/kg group 2 mg/mL suspension

(Results) The ammonia concentration in the portal venous blood of 8 rats was calculated to obtain the average value thereof for each group and each analytical day, and the summary of the results is shown in Figure 1. The test substance administration group of 1 mg/kg or more showed a significant lowering effect on the ammonia concentration in the portal venous blood compared with the control group.

Study 2. Comparison of the effects of the test substance and the reference drug on portal venous ammonia concentrations The test substance and the existing antibiotic rifaximin, which has been used to treat hyperammonemia in hepatic encephalopathy, were evaluated and compared with each other regarding their effects on portal venous ammonia concentrations by the method described in Study 1 above.

(Preparation of administration samples) The test substance or rifaximin was suspended in 5% gum arabic, and then the suspension was diluted to prepare 2 mg/mL of each suspension before use.

(Test method) Normal male SD rats were divided into the groups shown in the table below based on their body weight. Each administration sample shown in the table below was administered to each administration group once a day. The day of the first administration was set as the starting day (day 0). On the 5th day, the 7th day and the 10th day, 5 rats were taken from each group, portal venous blood was collected from each rat, and the ammonia concentration in each collected blood was analyzed by dry chemical technology. When collecting portal venous blood, it is necessary to use one rat for one analysis, and blood cannot be collected from the same rat more than once during the entire experiment. Therefore, the ammonia concentration on day 0, which was considered as a reference for each group, was not analyzed, but instead, it was assumed that the ammonia concentration in portal venous blood on day 0 was the same in each group because the groups were divided based on their body weight, and the experiment was performed under this assumption. Administration group Sample administration Control group 5% Gum Arabic 10 mg/kg test substance administration group 2 mg/mL test substance suspension 10 mg/kg rifaximin group 2 mg/mL Rifaximin suspension

(Results) The ammonia concentration in the portal vein of 5 rats was calculated to obtain the average value for each group and each measurement day, and the summary results are shown in Figure 2. The test substance administration group and the rifaximin administration group showed a significant decrease in the ammonia concentration in the portal vein compared with the control group. In addition, the test substance administration group showed a significant decrease in the ammonia concentration in the portal vein compared with the rifaximin administration group.

Figure 1 shows the results of Test 1. Figure 2 shows the results of Test 2.

Claims (4)

A 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 thereof for the manufacture of a drug for treating and/or preventing hepatic encephalopathy. For use as claimed in claim 1, wherein the drug is for oral administration. For use as claimed in claim 1 or 2, wherein the 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 thereof is administered to a patient in need thereof in a therapeutically effective amount as an active ingredient. For use as claimed in claim 3, the daily dose of the active ingredient is 0.5 mg to 6000 mg.