JPH05950A - Diuretic - Google Patents

Abstract

PURPOSE:To obtain a useful diuretic exhibiting excellent diuretic action and low toxicity by using a specific benzazepine compound as an active component. CONSTITUTION:The objective diuretic agent contains 3-[1-carboxy-2-[2-(4- piperidyl) ethylthio] amino-2-oxo-2, 3, 4, 5-tetrahydro-IH-1-benzazepine-1-acetate, its pharmacologically permissively salt, ester compound or its optical isomer as an active component. The diuretic can be administered by oral or parenteral administration in the form of powder, granule, tablet, capsule, injection, etc., by mixing the active component with proper pharmacologically permissively carrier, excipient, diluent, etc. The daily dose for adult is usually about 1-100mg in the case of oral administration.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medicine, and more particularly to a diuretic containing as an active ingredient a certain benzazepine compound.

[0002]

2. Description of the Related Art As a compound having an angiotensin converting enzyme inhibitory action, JP-A-1-199962 discloses 3
-[1-Carboxy-2- {2- (4-piperidyl) ethylthio} ethyl] amino-2-oxo-2,3,4
5-Tetrahydro-1H-1-benzazepine-1-acetic acid, its optical isomers or pharmacologically acceptable salts are disclosed. On the other hand, an angiotensin converting enzyme inhibitory agent having a diuretic effect is disclosed in JP-A-55-49352, JP-A-58-113183, and Journal.
Of the Medicinal Chemistry (J. Med. Chem.
33, 1600 and 1606 (1990)
Year).

[0003]

The treatment of hypertension is usually carried out by combining an antihypertensive drug and a diuretic, but such multidrug combination causes new side effects. It is a considerable burden for the patient to use. In addition, an angiotensin converting enzyme inhibitor having a diuretic effect that has been reported so far is one in which the chemical structure of an existing thiazide diuretic is added to the molecule, and side effects derived from it cannot be avoided. I have a problem.

[0004]

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted extensive studies to solve such problems, and as a result, disclosed in Japanese Patent Application Laid-Open No. 1-11.
It was found that a certain kind of benzazepine compound described in Japanese Patent Publication No. 99962 has an excellent diuretic action and is useful as a medicine, and completed the present invention. That is,
The present invention is 3- [1-carboxy-2- {2- (4-piperidyl) ethylthio} ethyl] amino-2-oxo-
2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid (hereinafter, also referred to as compound I), a pharmacologically acceptable salt or ester compound or an optical isomer thereof as an active ingredient And diuretics.

Since Compound I has an asymmetric atom in its molecule, it includes any form of an optically pure antipode, diastereoisomer or a mixture thereof. Further, since it has an acidic group and a basic group in the molecule, it is possible to form a salt with a usual organic acid, an organic base, further an inorganic acid, and an inorganic base. Contains all salt. That is, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, methanesulfonic acid, organic acids such as p-toluenesulfonic acid, methylamine, diethylamine , Triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, trishydroxymethylaminomethane, lysine, ornithine, arginine, guanidine, quinine, cinchonine and other organic bases, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and other inorganic acids Furthermore, it is a salt with an inorganic base such as ammonia, sodium, potassium, calcium, magnesium or zinc. In addition, ester compounds include lower alkyl (methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl, etc.) esters or aralkyl (benzyl, 2-phenylethyl, phenylpropyl, phenylbutyl, diphenylmethyl, etc. , These may be substituted with halogen, nitro, lower alkyl, lower alkoxy, halo lower alkyl, etc.) and the like. Further, hydrates and solvates are also included.

The diuretic of the present invention is orally prepared in the form of powder, granules, tablets, capsules, injections, etc. by mixing the active ingredient with a pharmacologically acceptable carrier, excipient, diluent and the like. Or parenterally. The dose varies depending on the target disease and symptoms, but in the case of oral administration,
Usually, it is about 1 to 100 mg per day for an adult.

[0007]

[Examples] The formulation examples of the diuretics of the present invention are illustrated below. Example 1: Tablet Compound I 10 mg Lactose 150 mg Crystalline cellulose 50 mg Carboxymethyl cellulose calcium 7 mg Magnesium stearate 3 mg Total 220 mg This tablet can be coated with a film, which is usually used, and can be further sugar-coated. Example 2: Granules Compound I 10 mg Polyvinylpyrrolidone 25 mg Lactose 405 mg Hydroxyspropylcellulose 50 mg Talc 10 mg Total 500 mg Example 3: Powdered compound I 10 mg Lactose 600 mg Starch 360 mg Colloidal silica 30 mg Total 1000 mg Example 4: Capsule compound I Sugar 10 mg 122 mg Crystalline cellulose 56 mg Colloidal silica 2 mg Total 190 mg Example 5: Injectable compound 1 in 1 ml of an aqueous solution (pH 6.5 to 7.0) 1
~ 30 mg. The preparation process is performed aseptically.

[0008]

Experimental Example: Diuretic effect Compound I 3 mg / kg was orally administered to spontaneously hypertensive rats, and the rats were placed in metabolic cages one by one, and within 24 hours after drug administration with free water and food intake. The excreted urine was collected. Expressing the urine volume of the control group as 100%, (S) -3- [1 (R) -carboxy-2-
{2- (4-Piperidyl) ethylthio} ethyl] amino-2-oxo-2,3,4,5-tetrahydro-1H-
Urinary excretion rate of 1-benzazepine-1-acetic acid is 185%
(The risk rate was 1% or less and was significant). Toxicity test When the above compound (1000 mg / kg) was orally administered to male mice, no deaths were observed. The compound used in the present invention exhibits excellent diuretic action and low toxicity, and is therefore useful as a diuretic.

Claims (1)

Claims 1. 3- [1-carboxy-2- {2- (4
-Piperidyl) ethylthio} ethyl] amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid, a pharmaceutically acceptable salt or ester compound thereof, or an optical isomer thereof A diuretic characterized by comprising as an active ingredient.