TW202140006A - 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

Novel drugs for the treatment of hepatic encephalopathy

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

In hepatic encephalopathy, it is believed that the neurological symptoms are caused by hyperammonemia resulting from decreased ammonia metabolism, and then the development of encephalopathy.

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

Patent Document 1 discloses a specific quinolone antimicrobial agent, which exhibits antibacterial activity against Clostridium difficile living in the intestinal tract. [Citation List] [Patent Literature]

[PL 1] WO2013/029548 [Non-Patent Literature]

[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 problem]

The main purpose of the present invention is to provide a novel drug for the treatment and/or prevention of 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-formic acid can reduce the ammonia concentration in portal vein blood exceeding the existing drugs that have been approved as the treatment of hyperammonemia in hepatic encephalopathy, and It can be used to treat hepatic encephalopathy. Based on this new discovery result, the present invention has been completed.

The present invention includes the following examples. (Article 1) A medicine for treating and/or preventing hepatic encephalopathy, which comprises 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyanide (5-pyridyl)-4-oxo-3-quinoline-carboxylic acid or a pharmaceutically acceptable salt or metabolite thereof as the active ingredient.

(Article 2) Such as the drug of Clause 1, wherein the metabolite is (2S, 3S, 4S, 5R, 6R)-6-((7-amino-5-cyanopyridin-3-yl)-1-cyclopropyl- 6-fluoro-8-methyl-4- pendant oxy-1,4-dihydroquinoline-3-carbonyl) pendant oxy)-3,4,5-trihydroxytetrahydro-2H-piperan-2 -Formic acid, 7-(6-amino-5-aminomethylpyridin-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-di Hydroquinoline-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) Such as the drugs of Clause 1 or 2, which are for oral administration.

(Article 4) The drug of any one of clauses 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, which comprises administering a therapeutically effective amount of 1-cyclopropyl-6-fluoro-1,4-dihydro-8 as an active ingredient to a patient in need -Methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinoline-carboxylic acid or a pharmaceutically acceptable salt or metabolite thereof.

(Article 6) A kind of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3- The use of quinoline-formic acid or a pharmaceutically acceptable salt or metabolite thereof in the manufacture of drugs for the treatment and/or prevention of hepatic encephalopathy.

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

The compound of the present invention can reduce the ammonia concentration in portal blood, and its further potent reduction effect on ammonia concentration exceeds the current drug rifaximin used for the treatment of hyperammonemia in hepatic encephalopathy. Therefore, it is expected to be a novel drug for the treatment and/or prevention of hepatic encephalopathy. In addition, the compound of the present invention is a poorly absorbed drug, and therefore when it is orally administered, it will be distributed in a high concentration in the intestinal tract, but it has low blood transferability. Therefore, the compounds of the present invention also have advantages, namely, low risk of systemic side effects, which is a problem with existing quinolone antibacterial agents.

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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), which is disclosed as compound numbers 2 to 18 in Patent Document 1, which also discloses its method and its antibacterial activity against Clostridium difficile. And, its metabolite is (2S, 3S, 4S, 5R, 6R)-6-((7-amino-5-cyanopyridin-3-yl)-1-cyclopropyl-6-fluoro-8- Methyl-4- pendant oxy-1,4-dihydroquinoline-3-carbonyl) pendant oxy)-3,4,5-trihydroxytetrahydro-2H-piperan-2-carboxylic acid, 7-( 6-Amino-5-aminomethylpyridin-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3- Formic acid and 7-(6-amino-5-cyanopyridin-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline Ethyl -3-formate, each of which has the structure of the following formulas (2) to (4), and the like are included in the compound of the present invention. [化1]

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The compounds of the present invention may be in the form of hydrates and/or solvates, and therefore, 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 polymorphism in the crystals of the compound of the present invention or a pharmaceutically acceptable salt thereof, and therefore such polymorphism is also within the scope of the present invention.

"Pharmaceutically acceptable salts" include acid addition salts, salts with inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate and phosphate; and organic acids Salts, such as oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, formate Sulfonate, p-toluenesulfonate and trifluoromethanesulfonate; and salts with amino acids, such as glutamate and aspartate; and salts with bases, alkali metal salts, such as sodium salt And potassium salt; alkaline earth metal salt, such as calcium salt; and ammonium salt.

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, and include sleep rhythm reversal, disorientation, flapping tremor, excitement, delirium, unconsciousness, and coma. The causes of hyperammonemia include severe liver dysfunction (such as violent hepatitis and cirrhosis), urea cycle defects (such as urea cycle disorders), portosystemic shunt, urease-producing bacterial infection, and combinations thereof.

The compound 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 may generally be 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, even more preferably about 1 mg A dose of up to about 10 mg/kg of the body weight of a human or mammal is administered in one to several portions. 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, 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, liniments, patches and inhalants. These dosage forms can be prepared in a conventional manner. If the dosage form is liquid, it can be a formulation to prepare a solution or suspension by mixing it with water, a suitable aqueous solution or other suitable solvents for use. Tablets and granules can be coated in a well-known manner. The dosage form can be prepared using pharmaceutically acceptable additives in a known manner. According to the intended use, the additives used herein include excipients, disintegrating agents, binders, fluidizing agents, lubricants, coating agents, coloring agents, solubilizers, solubilizing agents, and thickening agents. Agents, dispersants, stabilizers, sweeteners and flavoring agents. 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 carboxymethyl cellulose Sodium, crospovidone, sodium starch glycolate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, calcium stearate, stearin Sodium fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, iron trioxide and yellow iron oxide.

In the case of formulating the compound of the present invention into a single dosage form, the dosage form may contain 0.1 to 85% (w/w) of the compound of the present invention based on the overall composition, but the present invention is not limited thereto. Preferably, it is 10 to 70% (w/w) of 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 to this.

Hereinafter, rats are used to study the effect of the compound of the present invention on the ammonia concentration in portal blood. The compounds of the present invention (hereinafter referred to as "test substances") and reference drugs used herein are obtained as shown below. Test substance [1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo- 3-quinoline-formic acid]: available from Otsuka Pharmaceutical Co., Ltd. Reference drug (rifaximin): obtained from Sigma-Aldrich.

Test 1. The effect of the test substance on the ammonia concentration in portal vein blood. Hyperammonemia is considered to be one of the main factors causing consciousness impairment in hepatic encephalopathy. The ammonia produced by the metabolic activities of intestinal bacteria is absorbed in the intestine and then transported to the liver via the portal vein. This test is based on the purpose of studying the effect of the test substance on the ammonia concentration in the portal blood of normal rats.

(Preparation of samples for administration) The test substance was suspended in 5% gum arabic, and then the suspension was diluted before use. Each suspension was prepared at three concentrations (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 rats in each administration group once a day. Set the day of the first vote as the starting day (day 0). On Day 1, Day 3, and Day 5, 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 technique. When collecting portal vein 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 is not analyzed. It is considered as the reference for each group. Instead, it is assumed that the ammonia concentration in the portal blood of each group on day 0 is the same, because the grouping is based on their body weight, and under this assumption Carry out the test. Investment group Sample delivery 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

(result) The analyzed ammonia concentration in the portal blood of 8 rats was calculated to obtain the average value for each group and each analysis day, and the summarized results are shown in Figure 1. Compared with the control group, the test substance administration group of 1 mg/kg or more showed a significant reduction effect on the ammonia concentration in the portal vein blood.

Test 2. Comparison of the effect of the test substance and the reference drug on the ammonia concentration in portal vein blood. The test substance was evaluated by the method shown in Test 1 above and it has been used in the treatment of hyperammonemia in hepatic encephalopathy. The existing antibiotic rifaximin has the effect of reducing the ammonia concentration in portal blood, and comparing these effects with each other.

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

(Test method) Normal male SD rats were divided into the groups shown in the following table based on their body weight. Each administration sample shown in the following table was administered to each administration group once a day. Set the day of the first vote as the starting day (day 0). On the 5th, 7th, and 10th days, 5 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 technique. When collecting portal vein blood, it is necessary to use one rat 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 is not analyzed, and it is considered as the reference for each group. Instead, it is assumed that the ammonia concentration in the portal blood on day 0 is the same in each group, because the grouping is based on their body weight. And implement the test under this assumption. Investment group Sample delivery Control group 5% gum arabic 10 mg/kg test substance administration group 2 mg/mL test substance suspension 10 mg/kg rifaximin administration group 2 mg/mL Rifaximin suspension

(result) The analyzed ammonia concentration in the portal blood of 5 rats was calculated to obtain the average value for each group and each measurement day, and the summarized results are shown in FIG. 2. Compared with the control group, the test substance administration group and the rifaximin administration group showed a significant reduction effect on the ammonia concentration in the portal vein blood. In addition, compared with the rifaximin administration group, the test substance administration group showed a significant reduction effect on the ammonia concentration in portal blood.

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

Claims (7)

A medicine for treating and/or preventing hepatic encephalopathy, which comprises 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 metabolite thereof as the active ingredient. Such as the drug of claim 1, wherein the metabolite is (2S, 3S, 4S, 5R, 6R)-6-((7-amino-5-cyanopyridin-3-yl)-1-cyclopropyl- 6-fluoro-8-methyl-4- pendant oxy-1,4-dihydroquinoline-3-carbonyl) pendant oxy)-3,4,5-trihydroxytetrahydro-2H-piperan-2 -Formic acid, 7-(6-amino-5-aminomethylpyridin-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-di Hydroquinoline-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. Such as the medicine of claim 1 or 2, which is for oral administration. The medicine according to any one of claims 1 to 3, wherein the daily dose of the active ingredient is 0.5 mg to 6000 mg. A method for treating and/or preventing hepatic encephalopathy, which comprises administering a therapeutically effective amount of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl as an active ingredient to a patient in need Group-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3-quinoline-carboxylic acid or a pharmaceutically acceptable salt or metabolite thereof. A kind of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3- The use of quinoline-formic acid or a pharmaceutically acceptable salt or metabolite thereof for the manufacture of drugs for the treatment and/or prevention of hepatic encephalopathy. A kind of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(2-amino-3-cyano-5-pyridyl)-4-oxo-3- Quinoline-formic acid or a pharmaceutically acceptable salt or metabolite thereof is used for the treatment and/or prevention of hepatic encephalopathy.

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