JP2003063990A - Agent for preventing or curing adipohepatitis containing angiotensin converting enzyme inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicine containing useful angiotensin converting enzyme inhibitor as to an agent for preventing or curing adipohepatitis which possesses an excellent effect for improving the adipohepatitis. SOLUTION: The agent contains the angiotensin converting enzyme inhibitor as the effective ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a fatty liver preventive or therapeutic agent containing as an active ingredient one or more agents selected from the group of angiotensin converting enzyme inhibitors.

[0002]

BACKGROUND OF THE INVENTION Angiotensin converting enzyme (ACE) inhibitors that suppress the renin-angiotensin system are well known as therapeutic agents for hypertension (for example, JP-A-61-267).
579, JP-A-52-116457, US Pat. No. 4,374,829, etc.), and its effectiveness against diabetic nephropathy has been clarified [eg, New England Journal of Medicine]. , Volume 313,
1617 to 1620 (1985): Ne
w. Eng. J. Med. , 313 , 1617-162
0 (1985)]. However, it is not known to be effective in improving fatty liver.

[0003]

DISCLOSURE OF THE INVENTION The present inventor has conducted various studies on the drug efficacy of angiotensin-converting enzyme inhibitors, and as a result, the angiotensin-converting enzyme inhibitor has an excellent effect of improving fatty liver and a fatty liver preventive agent. Further, they have found that they are useful as therapeutic agents (particularly therapeutic agents), and have completed the present invention.

The present invention provides a preventive or therapeutic agent for fatty liver (in particular, a therapeutic agent) containing as an active ingredient one or more agents selected from the group of angiotensin converting enzyme inhibitors.

[0005]

The angiotensin converting enzyme inhibitor, which is the active ingredient compound of the present invention, comprises one or more drugs selected from the drug group.

Representative examples of the angiotensin converting enzyme inhibitor which is the active ingredient compound of the present invention include, for example, JP-A-61-267579 and JP-A-52-1.
16457, U.S. Pat. No. 4,374,829, JP-A-58-126851, JP-A-58-2.
06591, JP-A-57-77651, JP-A-55-9058, and JP-A-58-206591.
JP-A-63-258459 and the like, tetrahydrothiazepine compounds, proline compounds, pyridazinodiazepine compounds, glycine compounds,
It may be an imidazolidine compound or an isoquinoline compound, preferably temocapril, captopril, enalapril, silinopril, cilazapril, delapril, alacepril, imidapril or quinapril, more preferably temocapril, captopril or enalapril, particularly preferably. Is temocapril.

The plane structural formulas of typical angiotensin converting enzyme inhibitors are shown below.

[Chemical 1]

[0008]

[Chemical 2]

Temocapril is disclosed in JP-A-61-267757.
9 and US Pat. No. 4,699,905, etc.,
Its chemical name is (+)-(2S, 6R)-[6- (1
S) -1-Ethoxycarbonyl-3-phenylpropylamino] -5-oxo-2- (2-thienyl) perhydro-1,4-thiazepin-4-ylacetic acid, a dicarboxylic acid derivative thereof (temocaprylate). Alternatively, it includes a pharmacologically acceptable salt thereof, a pharmacologically acceptable monoester thereof or a pharmacologically acceptable salt thereof (temocapril hydrochloride and the like).

Captopril is disclosed in JP-A-52-11645.
No. 7, Japanese Patent No. 4,046,889, etc.,
Its chemical name is 1-[(2S) -3-mercapto-2-
Methylpropionyl] -L-proline, including a pharmacologically acceptable ester thereof or a pharmacologically acceptable salt thereof.

Enalapril is described in US Pat. No. 4,374,829, and its chemical name is N-[(S) -1-
Ethoxycarbonyl-3-phenylpropyl] -L-alanyl-L-proline, including its pharmacologically acceptable ester or its pharmacologically acceptable salt (enalapril maleate, etc.).

Lisinopril is disclosed in JP-A-58-12685.
1 and U.S. Pat. No. 4,555,502.
Its chemical name is (S) -1- [N2- (1-carboxy-3-phenylpropyl) -L-lysyl] -L-proline, its pharmacologically acceptable ester or its pharmacologically acceptable. Includes salt.

Cilazapril is disclosed in JP-A-58-20659.
No. 1 and US Pat. No. 4,512,924, etc.,
Its chemical name is (1S, 9S) -9-[(S) -1-ethoxycarbonyl-3-phenylpropylamino] octahydro-10-oxo-6H-pyridazino [1,2-
[alpha]] [1,2] diazepine-1-carboxylic acid, including its pharmacologically acceptable ester or its pharmacologically acceptable salt.

Delapril is described in JP-A-57-77651, US Pat. No. 4,385,051 and the like, and its chemical name is (S) -N- (2,3-dihydro-1H-indene-2- Yl) -N- [N- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanyl] glycine, and includes a pharmacologically acceptable ester thereof or a pharmacologically acceptable salt thereof.

Alacepril is described in JP-A-55-9058, US Pat. No. 4,248,883 and the like, and its chemical name is 1- (D-3-acetylthio-2-methylpropanoyl) -L-prolyl. -L-phenylalanine, which includes a pharmacologically acceptable ester thereof or a pharmacologically acceptable salt thereof.

Imidapril is disclosed in JP-A-58-20397.
No. 1 and US Pat. No. 4,508,727.
Its chemical name is (4S) -3-[(2S) -2-[(1
S) -1-Ethoxycarbonyl-3-phenylpropylamino] propionyl] -1-methyl-2-oxoimidazolidine-4-carboxylic acid, which is a pharmacologically acceptable ester or a pharmacologically acceptable salt thereof. Include.

Quinapril is described in JP-A-63-258459.
No. 4,761,479 and the like, and their chemical names are (S) -2-[(2S) -2- (1S)-
1-ethoxycarbonyl-3-phenylpropylamino) propionyl] -1,2,3,4-tetrahydro-
3-isoquinolinecarboxylic acid, which includes a pharmacologically acceptable ester thereof or a pharmacologically acceptable salt thereof.

When the above compound has an asymmetric carbon atom, the angiotensin converting enzyme inhibitor of the present invention includes optical isomers and isomers thereof. further,
A hydrate of the above compound is also included.

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION The angiotensin-converting enzyme inhibitor, which is the active ingredient of the present invention, is a known compound or can be easily produced by a known method (for example, JP-A-61).
-267579, JP-A-52-116457, US Pat. No. 4,374,829, JP-A-58.
-126851, JP-A-58-206591, JP-A-57-77651, JP-A-55-90.
58, JP-A-58-206591, JP-A-63-258459).

The angiotensin-converting enzyme inhibitor, which is the active ingredient of the present invention, has an excellent effect of improving fatty liver and has low toxicity, and is therefore useful as a preventive or therapeutic drug (particularly, therapeutic drug) for fatty liver. . The prophylactic or therapeutic agent is preferably for warm-blooded animals, more preferably for humans.

When the angiotensin-converting enzyme inhibitor which is the active ingredient of the present invention is used as a prophylactic or therapeutic agent for fatty liver, itself or an appropriate pharmacologically acceptable excipient or diluent. Etc., and can be administered orally by tablets, capsules, granules, powders, syrups, etc. or parenterally by injections, suppositories, etc.

These formulations include excipients such as lactose,
Sugar derivatives such as white sugar, glucose, mannitol, sorbitol; corn starch, potato starch,
Starch derivatives such as α-starch and dextrin; Cellulose derivatives such as crystalline cellulose; Gum arabic; Dextran; Organic excipients such as pullulan; and light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and aluminometasilicate. Inorganic excipients such as silicate derivatives such as magnesium; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate. ), Lubricants (for example, stearic acid metal salts such as stearic acid, calcium stearate, magnesium stearate; talc; waxes such as bees wax and gay wax; boric acid; adipic acid; sulfate salts such as sodium sulfate) Glycol; fumaric acid; sodium benzoate; DL leucine; sodium lauryl sulfate, lauryl sulfate such as magnesium lauryl sulfate; silicic anhydride, silicic acid hydrates and the like;
Also, the above starch derivative can be mentioned. ), A binder (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone,
Mention may be made of macrogol and compounds similar to the excipients mentioned above. ), Disintegrants (eg, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as internally crosslinked sodium carboxymethylcellulose; chemically modified such as carboxymethylstarch, sodium carboxymethylstarch, crosslinked polyvinylpyrrolidone) Starch / celluloses; the above starch derivatives can be mentioned), emulsifiers (for example, colloidal clays such as bentonite and bee gum; metal hydroxides such as magnesium hydroxide and aluminum hydroxide; sodium lauryl sulfate, Anionic surfactants such as calcium stearate; cationic surfactants such as benzalkonium chloride; and polyoxyethylene alkyl ethers, polyoxyethylene Rubitan fatty esters and nonionic surfactants such as sucrose fatty acid ester.), Stabilizers (e.g.,
Paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbin Mention may be made of acids. ), Flavoring agents (for example, commonly used sweeteners, acidulants, flavors, etc.) and diluents and the like can be used to produce the compound by a known method.

The amount used depends on symptoms, age, etc., but in the case of oral administration, the lower limit is 0.1 mg (preferably 1 mg) and the upper limit is 500 mg (preferably 50 mg) per dose.
In the case of intravenous administration, the lower limit is 0.01 mg (preferably 0.1 mg) and the upper limit is 100 mg (preferably 25 mg) per dose.
Can be administered to an adult 1 to 7 times per day depending on the symptoms.

[0024]

EXAMPLES The present invention will be described in more detail below by showing Examples and Formulation Examples, but the scope of the present invention is not limited thereto. Example 1 Six-week-old male KK- ^Ay mice (purchased from CLEA Japan, Inc.) were kept in the animal breeding room in the laboratory for about 2 weeks until the time of experimental use. Animal breeding room is kept at 25 ± 1 ℃, 6
A 12-hour light-dark cycle was performed from time to 18:00. One KK-A ^y mouse was divided into one cage, and the mice were bred in an environment where they could freely take water and research diet.

The osmotik minipump (os) was used to release temocaprylate at a concentration of 5 mg / kg / day.
motic mini pump: model 1002
Alza) was prepared and placed in the abdominal cavity of 8-week-old KK-A ^y mice.

2 weeks after administration of temocaprylate, KK-A
^y mouse orbital sinus
inus), blood was collected, the abdomen was opened, and the liver was observed. The concentration of temocaprylate used did not affect systolic blood pressure (112.8 ± 2.03 m
mHg vs. 110.4 ± 1.91 mmHg).

After separating the blood sample into plasma, plasma triglyceride (TG) and plasma free fatty acid (FFA), which are indicators of lipid metabolism, were respectively treated with triglyceride E.
-Test (Wako Pure Chemical) and NEFA C-Test (Wako Pure Chemical) were used for measurement. The results are shown in Table 1.

Images of the liver were taken with a digital camera. The result is shown in FIG.

[0029]

[Table 1] Plasma triglyceride (TG) and plasma free fatty acid (FFA) experiment Test compound Dose Number of animals TG FFA number (mg / kg / day) (mg / dl) ¹ (mEq / l) ² ─── ───────────────────────────────── 1 Temocaprylate 5 8 426.49 ± 48.63 0.59 ± 0.02 −−−−− −−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Control group-8 532.62 ± 42.46 0.98 ± 0.15 ────────── ────────────────────────── 1) P〉 0.05 2) P〉 0.05

In the liver of the 10-week-old KK-A ^y mouse control group, spots due to fat were observed and discolored to yellow, and fatty liver was exhibited, but in the temocaprylate administration group, this tendency was observed. Was alleviated, and the progression of fatty liver was clearly prevented. Formulation Example 1 Film-coated tablets Temocapril hydrochloride 8.0 g, lactose 94.3 g, low-substituted hydroxypropylcellulose 12 g and 4.5 g
Of hydroxypropyl cellulose was added and mixed.
An appropriate amount of water was added to the obtained mixed powder and kneaded, and then condyles were dried, dried, and granulated to obtain granules. 1.2 g of magnesium stearate was added to the obtained granules and mixed. The obtained mixed granules were tabletted by a tableting machine so that each tablet had a weight of 120 mg, and tablets (the weight of one tablet was 120 m).
g: The amount of temocapril hydrochloride per tablet is 8.0 mg)
Got The obtained tablets were coated with 5 mg of each film to give film-coated tablets each weighing 125 mg.

[0031]

EFFECTS OF THE INVENTION The angiotensin-converting enzyme inhibitor, which is the active ingredient of the present invention, has an excellent effect of improving fatty liver and has low toxicity, and therefore is useful as a preventive or therapeutic drug (particularly, therapeutic drug) for fatty liver. Is.

[Brief description of drawings]

FIG. 1 shows the effect of improving fatty liver in the liver.

Continued front page    F-term (reference) 4C069 AA18 BD02                 4C084 AA02 AA17 BA01 BA14 BA23                       BA32 CA59 DC40 NA14 ZA75                       ZC20                 4C086 AA01 AA02 BC04 MA01 MA04                       NA14 ZA75 ZC20

Claims (5)

[Claims] 1. A prophylactic or therapeutic agent for fatty liver which comprises, as an active ingredient, one or more drugs selected from the group of angiotensin converting enzyme inhibitors. 2. A group of angiotensin converting enzyme inhibitors is temocapril, captopril, enalapril, lisinopril, cilazapril, delapril, alacepril,
The preventive or therapeutic agent according to claim 1, which is imidapril or quinapril. 3. The preventive or therapeutic agent according to claim 1, wherein the drug group of angiotensin converting enzyme inhibitors is one or more drugs selected from the group consisting of temocapril, captopril and enalapril. 4. The preventive or therapeutic agent according to claim 1, wherein the drug group of angiotensin converting enzyme inhibitors is temocapril. 5. A therapeutic agent for fatty liver, which comprises the angiotensin-converting enzyme inhibitor drug group according to any one of claims 1 to 4 as an active ingredient.