JPH06192096A - Therapeutic agent for nephritis - Google Patents

Abstract

PURPOSE:To prepare a therapeutic agent for nephritis such as chronic nephritic, acute nephritic and nephrotic syndromes or pyelonephritis, comprising a specific carbostyril derivative (salt) as an active ingredient and having suppressing action on urinary proteins and high therapeutic effects with hardly any side effects. CONSTITUTION:This therapeutic agent for nephritis is obtained by using a carbostyril derivative of the formula (R is benzoyl which may have a lower alkoxy group on the phenyl ring; the bond between the carbon atoms at the 3-and 4-positions of the carbostyril skeleton denotes single or double bond) {e.g. 6-[4-(3,4--dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril} and/or salt as an active ingredient, adding an additive such as an excipient (e.g. starch), a lubricant (e.g. magnesium stearate) and a disintegrating agent (e.g. lactose) thereto and forming the resultant blend into a tablet. This medicine has suppressing effects on urinary proteins such as chronic nephritic and nephrotic syndromes with hardly any side effects.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a therapeutic agent for nephritis containing a pharmaceutically useful carbostyril derivative represented by the following general formula (1) and / or a salt thereof as an active ingredient.

[0002]

2. Description of the Related Art Typical diseases as renal dysfunction associated with urinary proteins include renal diseases such as chronic nephritis syndrome, subclinical proteinuria / acute nephritis syndrome, nephrotic syndrome, IgA nephropathy and pyelonephritis. There is a therapeutic agent such as a diuretic, a vasodilator, a platelet aggregation inhibitor and a steroid, which is used in combination with a dietary therapy in view of the accompanying autonomic and other findings. In addition, platelet aggregation inhibitors and steroids are used for urinary protein treatment of the above diseases,
At present, it is difficult to treat nephritis because a sufficient efficacy rate cannot be obtained, and further, a headache caused by a platelet aggregation inhibitor, a severe headache, or a side effect caused by long-term administration of a steroid drug. Therefore, in the above nephritis treatment method, there is a demand for development of a nephritis therapeutic agent for the above diseases, which has a more reliable therapeutic effect and fewer side effects.

[0003]

DISCLOSURE OF THE INVENTION It is an object of the present invention to provide a therapeutic agent for nephritis with a higher efficacy rate in the above-mentioned method for treating nephritis.

The inventors of the present invention have made extensive studies on the development of the above-mentioned therapeutic agent for nephritis. As a result, the carbostyril derivative represented by the general formula (1) described below is, for example, Japanese Patent Publication No. 1-43.
As described in JP 747, it is already known that it is useful as a cardiotonic agent, but it was found that the derivative has an inhibitory effect on urinary protein which is difficult to predict from the cardiotonic effect, and based on this finding. The invention was completed here.

[0005]

That is, the present invention provides a nephritis therapeutic agent containing a carbostyril derivative represented by the following general formula (1) and / or a salt thereof as an active ingredient, particularly a carbostyril derivative of 6- The present invention provides the above nephritis therapeutic agent, which is [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril.

[0006]

[Chemical 2]

[In the formula, R represents a benzoyl group which may have a lower alkoxy group on the phenyl ring. The carbon-carbon bond between the 3-position and 4-position of the carbostyril skeleton represents a single bond or a double bond. More specifically, each group represented by the general formula (1) is as shown below.

That is, the lower alkoxy group is, for example, a straight or branched chain alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy group. Can be illustrated.

Examples of the benzoyl group which may have a lower alkoxy group as a substituent on the phenyl ring include benzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2-ethoxybenzoyl and 3-ethoxybenzoyl. , 4-ethoxybenzoyl, 3-isopropoxybenzoyl, 4-butoxybenzoyl, 2-pentyloxybenzoyl, 3-hexyloxybenzoyl, 3,4-dimethoxybenzoyl,
It may have 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms as a substituent on the phenyl ring such as 2,5-dimethoxybenzoyl and 3,4,5-trimethoxybenzoyl groups. A benzoyl group can be illustrated.

The salts of the carbostyril derivative represented by the above general formula (1) include pharmaceutically acceptable acid addition salts. Specific examples of the acidic compound that forms the salt include inorganic acids such as sulfuric acid, phosphoric acid, nitric acid, hydrochloric acid and hydrobromic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid. An organic acid such as an acid can be exemplified.

The carbostyril derivative represented by the general formula (1) and / or its salt, which is the active ingredient of the therapeutic agent for nephritis of the present invention, is usually used in the form of a general pharmaceutical preparation. Such a preparation is prepared using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant which are usually used. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections. (Solutions, suspensions, etc.) and the like.

In the case of molding into tablets, those conventionally known in this field can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid. Excipients such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose,
Binders such as potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc. Disintegrants, sucrose, stearin, cocoa butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, glycerin, moisturizers such as starch, starch, lactose, kaolin,
Examples thereof include adsorbents such as bentonite and colloidal silicic acid, refined talc, stearates, boric acid powders, and lubricants such as polyethylene glycol. Further, the tablet may be a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet. In the case of molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, excipients such as kaolin and talc, gum arabic powder, Examples thereof include tragacanth powder, a binder such as gelatin and ethanol, and a disintegrating agent such as laminaranthantene.

In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. it can.

When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood. When the solution, emulsion and suspension are formed into a form, they are diluted. As the agent, all agents commonly used in this field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. May be.

If necessary, coloring agents, preservatives, fragrances,
Flavors, sweeteners, and other pharmaceuticals may be included in the pharmaceutical preparation.

The amount of the compound of the general formula (1) contained in the above-mentioned pharmaceutical preparation is not particularly limited and can be appropriately selected within a wide range, but it is usually 1 to 70% by weight, preferably 1 to 3% by weight in the whole composition.
It is 0% by weight.

The administration method of the above pharmaceutical preparation is not particularly limited, and various preparation forms, patient's age, sex, other conditions,
It is determined according to the degree of the disease. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of an injection, it is intravenously administered alone or mixed with a usual replacement fluid of glucose or amino acid sugar, and further, if necessary, it is intramuscularly, intradermally, subcutaneously or intraperitoneally administered alone. In the case of suppositories, it will be administered rectally.

The dose of the above-mentioned pharmaceutical preparation is appropriately selected according to the usage, the age and sex of the patient, other conditions, the degree of disease, etc., but the amount of the compound of the general formula (1) which is an active ingredient is usually the body weight per day. About 0.5 to 30 mg per Kg is recommended. In addition, the active ingredient in the dosage unit form is about 1-10.
It is recommended to contain 00 mg. Furthermore, the active ingredient combination of the present invention can be administered once a day or divided into 3 to 4 times a day.

[0019]

INDUSTRIAL APPLICABILITY According to the present invention, there is provided a therapeutic agent for nephritis containing a carbostyril derivative represented by the general formula (1) and / or a salt thereof as an active ingredient. According to the nephritis therapeutic agent,
An inhibitory effect on urinary proteins such as chronic nephritis and nephrotic syndrome is obtained, and as a result, it is effective as a therapeutic agent for the above nephritis.

[0020]

EXAMPLES In order to explain the present invention in more detail, formulation examples and pharmacological test examples of the drug of the present invention will be given below.

Formulation Example 1 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg In one tablet, the above composition Tablets were produced.

Formulation Example 2 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril 150 g Azehiru (trademark, manufactured by Asahi Kasei Corporation) 40 g Corn starch 30 g Magnesium stearate 2g Hydroxypropyl methylcellulose 10g Polyethylene glycol-6000 3g Castor oil 40g Methanol 40g After mixing and polishing the above active ingredient compounds, azehill, corn starch and magnesium stearate, sugar coating R10mm
Tablet with the key. The obtained tablets are hydroxypropylmethyl cellulose, polyethylene glycol-600.
A film-coated tablet is prepared by coating with a film-coating consisting of 0, castor oil and methanol.

Formulation Example 3 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril 150.0 g Citric acid 1.0 g Lactose 33.5 g Dicalcium phosphate 70. 0 g Pluronic F-68 30.0 g Sodium lauryl sulfate 15.0 g Polyvinylpyrrolidone 15.0 g Polyethylene glycol (Carbowax 1500) 4.5 g Polyethylene glycol (Carbowax 6000) 45.0 g Corn starch 30.0 g Dry sodium lauryl sulfate 3.0 g Dry magnesium stearate 3.0 g Ethanol Appropriate amount The above active ingredient compound, citric acid, lactone, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulfate are mixed.

The above mixture was added to No. Sifted with 60 screen, polyvinylpyrrolidone, carbowax 1500
And wet granulation with an alcoholic solution containing Carbowax 6000. Alcohol is added as needed to make the powder a pasty mass. Add corn starch and continue mixing until uniform particles are formed. No. Pass through 10 screens, place in trays and dry in oven at 100 ° C for 12-14 hours. The dried particles were Sieve through a 16 screen, add dry sodium lauryl sulfate and dry magnesium stearate, mix and compression mold to desired shape in tablet press.

The core is treated with a varnish and talc is sprinkled to prevent moisture absorption. The undercoat layer is coated around the core. Apply varnish a sufficient number of times for internal use. Further subbing layers and smooth coatings are applied in order to make the tablets completely round and smooth. Color coating is applied until the desired shade is obtained. After drying, the coated tablets are polished to prepare tablets of uniform gloss.

[0026]

[Pharmacological test] 6- [4- (3,4-
Dimethoxybenzoyl) -1-piperazinyl] -3,4
-Dihydrocarbostyril (hereinafter referred to as "Compound 1")
The following pharmacological tests were carried out using

Female B / WF1 mouse [NZB × NZW
Fl mouse; B / W Fl mouse] is a model of autoimmune disease (SLE) that spontaneously develops nephritis [BS.
Andrews, et al., J. Exp. Med., 148, 1198-1215 (1978)],
Characteristic findings of this model include development of nephritis with aging, increase in autoantibody titers of anti-DNA antibody, antinuclear antibody, anti-erythrocyte antibody and the like in serum. With regard to nephritis in particular, lesions such as proliferative glomerulonephritis, membranous glomerulonephritis, lupus nephritis, and sclerosing glomerulonephritis appearing in human SLE nephritis appear with age, and immune complexes become glomerular basal. It is known to show the same pathological condition as human autoimmune nephritis, such as being observed in the membrane.

The model was used from the age of 25 weeks (purchased from Charles River Japan). 10 groups per experiment
The above model mice were used. The mice in each of the above groups were fed with a feed (manufactured by Oriental Yeast Co., Ltd.) and water, which are usually used for mice of this type.

The compound 1 was suspended in a 0.5% carboxymethyl cellulose (CMC: Carboxy Methyl Cellulose; manufactured by Serogen) solution and used for the experiment. Administration of Compound 1 was started at 25 weeks of age per mouse body weight of 1 kg at 25 weeks of age, and was orally administered by gavage for 5 weeks and 2 days until 43 weeks of age (Compound 1 administration group). As a control, a control group (solvent-administered group) in which only a 0.5% CMC solution containing no compound 1 was similarly administered was provided.

At the age of 39 weeks and 43 weeks of age from the start of the above administration, the amount of urinary protein in each group of mice was measured by Combistics (made by Miles Sankyo).

The results are shown in Table 1.

[0032]

[Table 1]

From the table, the compound 1 is compared with the vehicle administration group.
It was confirmed that the administration group reduced the appearance amount of urinary protein at both 39 and 43 weeks of age. From these results, Compound 1 of the present invention reduces the amount of urinary protein in nephritis-induced mice, and is therefore effective as a therapeutic agent for nephritis.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Shoichi Adachi 9349-3, Ishihara-cho, Takasaki-shi Gunma 9 (72) Inventor Hiroyuki Ichikawa 3-11 Nakadori-cho, Tokushima-shi, Tokushima (72) Inventor Seiji Akamatsu 223-1 Kawasaki, Omamachi, Naruto City, Tokushima Prefecture (72) Inventor Shiro Saito 2294-80 Yamanamachi, Takasaki City, Gunma Prefecture

Claims (2)

[Claims] 1. A general formula: [In the formula, R represents a benzoyl group which may have a lower alkoxy group on the phenyl ring. Carbostyryl skeleton 3
The carbon-carbon bond between the 4-position and the 4-position represents a single bond or a double bond. ] A therapeutic agent for nephritis, which comprises a carbostyril derivative represented by the following formula and / or a salt thereof as an active ingredient. 2. The carbostyril derivative is 6- [4-
(3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl.
The therapeutic agent for nephritis according to.