CN114929224A

CN114929224A - Novel medicine for treating hepatic encephalopathy

Info

Publication number: CN114929224A
Application number: CN202180008299.3A
Authority: CN
Inventors: 涩谷功; 冈大辅; 藤井千之
Original assignee: Otsuka Pharmaceutical Co Ltd
Current assignee: Otsuka Pharmaceutical Co Ltd
Priority date: 2020-02-10
Filing date: 2021-02-09
Publication date: 2022-08-19
Also published as: TW202140006A; JP2023012557A; WO2021161981A1; KR20220140560A; AU2021220445A1

Abstract

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

Description

Medicine for treating hepatic encephalopathy

Technical Field

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

Background

In hepatic encephalopathy, neurological symptoms are considered to be caused by hyperammonemia caused by hypoactivity of ammonia metabolism, and then develop into encephalopathy.

For the treatment of hepatic encephalopathy, synthetic disaccharides (e.g., lactulose) or poorly absorbable antimicrobial agents (e.g., rifaximin) have been used as drugs for the treatment of hyperammonemia (non-patent document 1). The antimicrobial agent rifaximin has a mechanism of action to reduce intestinal bacteria including ammonia-producing bacteria (non-patent documents 2 and 3), and thus the antimicrobial agent has been approved as a therapy for hyperammonemia in hepatic encephalopathy. However, even with these drugs, it is not expected to give any radical treatment to hyperammonemia, and therefore, there is a need to develop a more effective drug than the existing drugs.

Patent document 1 discloses a specific quinolone antimicrobial agent exhibiting antibacterial activity against Clostridium difficile (Clostridium difficile) living in the intestinal tract.

CITATION LIST

Patent document

[ patent document 1] WO2013/029548

Non-patent document

[ non-patent document 1] Montagnese S et al, Dig Liver Dis.2019; 51:190-205.

[ non-patent document 2] Finegold SM et al, Antimicrob Agents Chemother.2009; 53:281-6.

[ non-patent document 3] J.M. Sierra et al, Antimicrob Agents Chemother.2001; 45:643-644.

Disclosure of Invention

Technical problem

The main object of the present invention is to provide a novel medicament for the treatment and/or prevention of hepatic encephalopathy, which is more effective than the existing medicaments.

Technical solution

The present inventors have conducted extensive studies and then found 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 is more capable of reducing portal blood ammonia concentration than existing drugs which have been approved as a treatment for hyperammonemia in hepatic encephalopathy, and is effective for treating hepatic encephalopathy. The present invention has been completed based on the new findings.

The present invention includes the following embodiments.

(item 1)

A medicament for the treatment and/or prevention of hepatic encephalopathy, which comprises 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 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 7- (6-amino-5-cyanopyridin-3- -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ethyl ester.

(item 3)

The medicament according to

item

1 or 2, which is for oral administration.

(item 4)

The medicament according to any one of items 1 to 3, wherein the daily dose of the active ingredient is 0.5mg to 6000 mg.

(item 5)

A method for treating and/or preventing hepatic encephalopathy, comprising administering 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 to a patient in need thereof.

(item 6)

Use 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 or metabolite thereof, in the manufacture of a medicament for the treatment and/or prevention of hepatic encephalopathy.

(item 7)

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 or metabolite thereof, for use in the treatment and/or prevention of hepatic encephalopathy.

Advantageous effects

The compounds of the invention can reduce portal blood ammonia concentration and, in addition, are more effective in reducing ammonia concentration than the existing drug rifaximin for treating hyperammonemia in hepatic encephalopathy. Therefore, it is expected to be a novel drug for treating and/or preventing hepatic encephalopathy. Further, the compound of the present invention is a poorly absorbable drug and therefore is distributed at a high concentration in the intestinal tract when orally administered, but has low blood transferability. Therefore, the compound of the present invention also has an advantage that the risk of systemic side effects is low, which is a problem with the existing quinolone antibacterial agents.

Drawings

Fig. 1 shows the results of test 1.

Fig. 2 shows the results of test 2.

Detailed Description

The compound 1-cyclopropyl-6-fluoro-1, 4-dihydro-8-methyl-7- (2-amino-3-cyano-5-pyridyl) -4-oxo-3-quinoline-carboxylic acid of the present invention has a structure of formula (1), which is disclosed as compound nos. 2 to 18 in patent document 1, and said patent document 1 also discloses a process thereof and antibacterial activity thereof against clostridium difficile. And the 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-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-cyclopropylic acid The group-6-fluoro-8-methyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ethyl ester, which has the following structures (2) to (4), respectively, are included in the compounds of the present invention.

[ chemical formula 1]

[ chemical formula 2]

[ chemical formula 3]

[ chemical formula 4]

The compounds of the invention may be in the form of hydrates and/or solvates and thus the compounds of the invention also encompass hydrates and/or solvates thereof.

In addition, any one or more of them ¹ H atom quilt ² Compounds of the present invention having H (D) atoms replaced are also within the scope of the present invention.

Polymorphs may exist in the crystals of the compound of the present invention or a pharmaceutically acceptable salt thereof, and such crystalline polymorphs are therefore also within the scope of the present invention.

"pharmaceutically acceptable salts" include: as acid addition salts, salts with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate and phosphate; salts with organic acids such as oxalates, malonates, maleates, fumarates, lactates, malates, citrates, tartrates, benzoates, trifluoroacetates, acetates, methanesulfonates, p-toluenesulfonates and trifluoromethanesulfonates; and salts with amino acids such as glutamate and aspartate; and as salts with bases, alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium salts; and ammonium salts.

In hepatic encephalopathy of the present invention, neurological symptoms are considered to be caused by hyperammonemia, and then develop into encephalopathy. Symptoms range widely from asymptomatic states to coma, including reversal of sleep rhythm, disorientation, tremor, excitement, delirium, confusion, and coma. Causes of hyperammonemia include severe liver dysfunction such as fulminant hepatitis and liver cirrhosis, urea cycle deficiencies such as urea cycle dysfunction, portosystemic shunts, urease producing bacterial infections and combinations thereof.

The compounds of the present invention may be administered via any route selected from oral, parenteral and rectal administration. The daily dose depends on the compound, the route of administration, the condition of the patient, the age of the patient, etc. For example, in the case of oral administration, it may be administered in a dose of from about 0.01mg to about 100mg, preferably from about 0.05mg to about 50mg, more preferably from about 0.1mg to about 20mg, even more preferably from about 1mg to about 10mg, per kg of body weight of the human or mammal, in parts to parts. For example, a daily dosage for humans comprises from about 0.5mg to about 6000mg, preferably from about 3mg to about 3000mg, more preferably from about 6mg to about 1200mg, even more preferably from about 60mg 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 formulations may be prepared in conventional manner. If the dosage form is a liquid dosage form, it may be formulated by mixing it with water, a suitable aqueous solution, or other suitable solvent to prepare a formulation using a solution or suspension. The tablets and the granules may be coated in a well-known manner. The dosage forms can be prepared in a known manner with pharmaceutically acceptable additives.

Additives useful herein include excipients, disintegrants, binders, fluidizers, lubricants, coating agents, colorants, co-solvents, solubilizers, thickeners, dispersants, stabilizers, sweeteners, and flavoring agents, depending on the intended use. For example, they include lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, calcium carboxymethyl cellulose, 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, and yellow iron oxide.

In the case where the compound of the present invention is formulated into a single dosage form, the dosage form may include the compound of the present invention in an amount of 0.1 to 85% (w/w) of the entire composition, but the present invention is not limited thereto. Preferably, it comprises 10-70% (w/w) of the total composition.

In addition, the compounds of the present invention may be used in combination with or as a combination with another drug to enhance the effect and/or alleviate side effects. Another drug that may be used in combination includes, for example, rifaximin, lactulose and lactitol.

Examples

The present invention is explained in more detail below by referring to tests, however, the scope of the present invention is not limited thereto.

The effect of the compounds of the present invention on portal blood ammonia concentration was studied in rats. The compound of the present invention (hereinafter referred to as "test substance") and the reference drug used herein 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 Tsukamur Pharmaceutical Co., Ltd (Otsuka Pharmaceutical Co., Ltd.)

Reference drug (rifaximin): obtained from Sigma-Aldrich.

Test 1 Effect of test substances on Portal vein blood Ammonia concentration

Hyperammonemia is considered to be one of the major factors leading to disturbance of consciousness in hepatic encephalopathy. Ammonia produced from food by the metabolic activity of intestinal bacteria is absorbed in the intestine and then transported to the liver via the portal vein. This test was conducted for the purpose of investigating the effect of the test substance on portal blood ammonia concentration in normal rats.

(preparation of administration sample)

The test substance was suspended in 5% gum arabic, and then the suspension was diluted before use to prepare each suspension at three concentrations (0.02mg/mL, 0.2mg/mL, and 2 mg/mL).

(test method)

Normal male SD rats were divided into groups based on their body weight as shown in the following table. Each of the administration samples shown in the following table was orally administered once a day to rats in each administration group. The date on which the first administration was performed was set as the initial day (day 0). On days 1, 3 and 5, 8 rats each were removed from each group, portal vein blood was collected from each rat, and the ammonia concentration in each collected blood was analyzed by dry chemical techniques. In portal vein blood collection, one analysis must be provided for each rat, and it is not possible to take more than one blood sample from the same rat throughout the test. Thus, the day 0 ammonia concentration assumed to be referenced for each group was not analyzed, but rather the day 0 portal blood ammonia concentration was assumed to be the same between groups, since the groupings were made based on their body weight, and the tests were conducted under this assumption.

Administration set	Drug administration sample
		Control group	5% Arabic Gum
0.1mg/kg group	0.02mg/mL suspension
		1mg/kg group	0.2mg/mL suspension
10mg/kg group	2mg/mL suspension

(results)

Portal blood ammonia concentrations for analysis of 8 rats were calculated to obtain an average value for each group and each analysis day, and the results are summarized as shown in fig. 1. Compared with the control group, the test substance administration group with the dosage of more than 1mg/kg shows a remarkable reduction effect on the portal blood ammonia concentration.

Test 2 comparison of the Effect of test substance and reference drug on Portal blood Ammonia concentration

The effect of the test substance of the present invention and rifaximin, an existing antibiotic that has been used for treating hyperammonemia in hepatic encephalopathy, on the reduction of portal blood ammonia concentration was evaluated by the method shown in test 1 above, and the effects were compared with each other.

(preparation of administration sample)

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

(test method)

Normal male SD rats were divided into groups shown in the following table based on their body weight. Each administration sample shown in the following table was administered once per day to each administration group. The date on which the first administration was performed was set as the initial day (day 0). On days 5, 7 and 10, 5 rats each were removed from each group, portal vein blood was collected from each rat, and the ammonia concentration in each collected blood was analyzed by dry chemical techniques. In portal vein blood collection, one analysis must be provided for each rat, and it is not possible to take more than one blood sample from the same rat throughout the test. Thus, the day 0 ammonia concentration assumed to be the reference for each group was not analyzed, but rather the day 0 portal blood ammonia concentration was assumed to be the same between groups, since the grouping was based on their body weight, and the test was conducted under this assumption.

Administration set	Drug administration sample
		Control group	5% Arabic Gum
Test substance administration group of 10mg/kg	2mg/mL test substance suspension
		Rifaximin administration group of 10mg/kg	Rifaximin suspension of 2mg/mL

(results)

The analyzed portal blood ammonia concentration of 5 rats was calculated to obtain an average value for each group and each measurement day, and the results are summarized as shown in fig. 2. The test substance-administered group and the rifaximin-administered group showed a significant reduction in portal blood ammonia concentration compared with the control group. Furthermore, the test substance-administered group showed a significant lowering effect on portal blood ammonia concentration as compared with the rifaximin-administered group.

Claims

1. A medicament for the treatment and/or prevention of hepatic encephalopathy, which comprises 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.

2. The medicament according to 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-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-cyanopyridine- 3-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ethyl ester.

3. The medicament of claim 1 or 2, which is for oral administration.

4. A medicament according to any one of claims 1 to 3, wherein the daily dose of the active ingredient is between 0.5mg and 6000 mg.

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.

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 for use in the treatment and/or prevention of hepatic encephalopathy.