JPH02233615A - Bronchial asthma remedy - Google Patents

Abstract

PURPOSE:To provide a bronchial asthma remedy having an excellent bronchodilator activity by containing a xanthine derivative and an alkali adduct salt thereof as an active ingredient. CONSTITUTION:A bronchial asthma remedy contains as an active ingredient a compound of the formula (R1 is H or methyl; R2 is ethyl, n-propyl, n-butyl or isopropyl) or a physiologically acceptable alkali adduct salt thereof, e.g. 3,7-dihydro-1,7-dimethyl-3-(2-methylpropyl)-1H-purine-2,6-dione. The cured examples using the bronchial asthma remedy exhibit that the remedy has a more excellent bronchodilator activity than a typical bronchial asthma remedy, theophylline. The compound is administered in a dose of 100-1200mg a day ordinarily for an adult on oral administration.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a therapeutic agent for bronchial asthma containing a xanthine derivative represented by the following general formula (!) and a pharmacologically acceptable alkali addition salt thereof as an active ingredient, Used in the medical field.

(In the formula, R1 represents a hydrogen atom or a methyl group, and R2 represents an ethyl, n-propyl, n-butyl, or isobutyl group.) As a therapeutic agent for bronchial asthma, there are various drugs including bronchodilators. These drugs are widely used in clinical practice.

Among them, xanthine compounds are also used as therapeutic agents for bronchial asthma, and theophylline (Theophylline
y l 1 1ne: Common name; The Nerck
Index 1 0 edition. Former l4; formula (■)) is a typical commercially available therapeutic agent for bronchial asthma.

For example, xanthine conductors such as those described in The Journal of American Chemical Society (The
Journal of American Ch.
(Emical Society), up 3653
(ls54) also has a diuretic effect, as disclosed in West German Patent Publication No. 3138397 and West German Patent Publication No. 352580.
Although it is a well-known compound whose production method has already been disclosed in No. 1, etc., its potential for application as a therapeutic agent for bronchial asthma has not been known at all.

Theophylline represented by the above formula (n) is a typical bronchial asthma treatment agent that is widely used clinically as described above, but the separation between the main action and side effects is small, and the side effects include central nervous excitement, diuresis, and heart disease. Excitement, increased gastric juice secretion, etc. are likely to occur, and the effective blood concentration range is very narrow, so drug concentration monitoring is necessary.Furthermore, it is necessary to be careful about interactions when used in combination with other drugs, etc. There are many points to keep in mind when using this method, and there are many problems in clinical use.

The present invention aims to improve these drawbacks of theophylline and develop a drug that has fewer side effects, a wide safety margin, and fewer interactions with other drugs.

The present inventors have conducted extensive research into xanthine compounds as drugs that overcome the drawbacks of theophylline in view of the above circumstances, and have found that the xanthine derivative represented by the general formula (I) has a completely unexpected bronchodilating effect The present inventors have discovered that the present invention has the following characteristics, and have completed the present invention.

Examples of the pharmacologically acceptable alkali addition salts of the compound represented by the general formula (I) of the present invention include inorganic alkali salts such as sodium, potassium, calcium, ammonium, etc., ethylenediamine, ethanolamine, etc. N. Examples include salts of organic bases such as N-dialkylethanolamine.

The therapeutic agent for bronchial asthma containing the xanthine derivative represented by the general formula (I) of the present invention (hereinafter referred to as the compound of the present invention) as an active ingredient can be administered either orally or parenterally. Examples of dosage forms for oral administration include tablets,
Examples include capsules, powders, fine granules, granules, and syrups. Examples of dosage forms for parenteral administration include injections, suppositories, inhalants, ointments, and patches.

In the preparation of these preparations, pharmacologically and pharmaceutically acceptable additives may be added as appropriate, including excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, and pigments. , a diluent, a base, a dispersant, an adhesive, a base cloth, a solubilizer or a solubilizer, an isotonizing agent, a pH adjuster, a stabilizer, etc. are used. For example, in oral preparations and mucosal injections, excipients include glucose, lactose, D-mannitol. Starch, crystalline cellulose, etc. are used as disintegrants and disintegration aids, such as carboxymethyl cellulose, starch, carboxymethyl cellulose calcium, etc., and as binders, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, etc. are used as lubricating agents. As a brightening agent, magnesium stearate, talc, etc. are used. As a coating agent, hydroxypropyl methylcellulose, Eudragift, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, glycerin fatty acid ester, white sugar, titanium oxide, etc. are used as a base. Glycol, hard fat, etc. are used as a dispersing agent, sorbitan trioleate, etc. are used as a dispersing agent, and in transdermal preparations, petrolatum, liquid paraffin, polyethylene glycol, etc. are used as a base, and polyacrylic acid is used as an adhesive. Sodium, polyvinyl alcohol, methyl cellulose, polybutene, etc. as the base fabric, formulation components such as cotton fabric, and in the case of injections, as a solubilizing agent or solubilizing agent that can constitute an aqueous or dissolution type injection, Distilled water for injection, physiological saline, propylene glycol, etc. are used as tonicity agents, glucose, sodium chloride, D-mannitol, glycerin, etc. are used as pill regulators, and preparations such as inorganic acids, organic acids, or inorganic bases are used as pill regulators. ingredients are used.

The dose of the compound of the present invention to be administered orally to a patient is usually 100 to 1200 mg per day for adults, but it can be adjusted as appropriate depending on age, symptoms, etc.

Example 1 The excellent effects of the compounds of the present invention will be explained below using test examples. At that time, theophylline was used as a comparison drug.

Table test example! [Removal of Guinea Pig Tracheal Relaxation Effect The trachea was removed from a Kohartle strain male guinea pig (weighing approximately 400 g), and a tracheal section chain specimen was prepared. There are 8 specimens
The specimen was suspended in a Lock-Ringer bath (37@) aerated with a mixed gas of 5% 02 and 5% CO2, and the resting tension was measured isotically. The drug is applied cumulatively in the bath, and the relaxation by isobroterenol 1μ threshold is taken as 100%;
This relaxation test revealed that the compound of the present invention has a superior tracheal relaxing effect compared to theophylline.

EXAMPLES Hereinafter, formulation examples will be explained with reference to examples of the manufacturing method of the compound of the present invention, but the present invention is not limited to the specific details of these examples.

Reference example 1 3,7-dihydro-1. 7-dimethyl-3-(2-
Methylprovir)-1H-purine-2.6-dione3.7-dihydro1-methyl-3-(2-methinoleprovir)-18-purine-2.8-dione2. OOg and potassium carbonate 1.24g N. Add 0 methyl iodide to 18 ml suspension of N-dimethylformamide under water cooling and stirring.
．． Add 87 ml and stir at room temperature for 3 hours. After neutralizing the reaction solution with dilute hydrochloric acid, the solvent was distilled off under reduced pressure. Add brine to the residue and extract with chloroform. The extract is dried and then evaporated under reduced pressure.

N-hexane is added to the residue, and the precipitated crystals are collected by filtration.

Ethyl acetate Recrystallized from n-hexane mixture, melting point 8
1.37 g of pale brown crystals with an angle of 8-100° are obtained.

Elemental analysis value ClIH16N4 0 2 theoretical value C,
55.92i H. 8.83; N. 23.71
Experimental value C. 55.71; H. 6.82; N
, 23.67 Compounds of Reference Examples 2 to 4 are obtained according to the shading method of Reference Example 1.

Reference example 2 3-butyl-3,7-dihydro 1,7-dihydro? Lou-I
H-purine-2.8-dionic crystal light brown crystal (AcOEt-n-Hexane) Melting point 82-83# Elemental analysis value C, H, N40■ Theoretical value C. 55.92; H. 6.83; N
, 23.71 experimental value C. 55.87; H.
8. F4; N. 23.59 Reference Example 3 3-ethyl-3,7-dihydro 1,7-dimethynole-
IH-purine-2,6-dione Properties Pale brown needle crystals (A
cOEt-n-Hexane) Melting point 127-130" Elemental analysis value C9H2N402 Theoretical value C.51.92; H, s.sl; N
．． 2G. 9t experimental value C, 51.81; H,
5. F2; N. 28.88 Reference Example 4 3.7-dihydro-1,7-dimethyl-3-probyl-
IH-purine-2,6-dione Properties Colorless needle crystals (Ac
OEt-n-11exane) Melting point 99-100 @ Elemental analysis value C10Hl4N 4 0 2 Theoretical value C
, 54.04; H. 8.35; N. 25.2
1 Experimental value C. 53.98; H, G. lG;
N, 25.05 Reference Example 5 3-ethyl-3,7-dihydro-7-methyl-IH-purine-2,6-dione 3-ethyl-3,7-dihydro IH-purine-2,6
- 3.75 g of dione and 288 g of potassium carbonate N,N
-To a suspension of 41.61 ml of dimethylformamide, 1.551 ml of methyl iodide is added while stirring while cooling with water, and the mixture is stirred at room temperature for 5 hours. After neutralizing the reaction solution with dilute hydrochloric acid, the solvent was distilled off under reduced pressure. Add a small amount of water to the residue and filter the crystals. Recrystallized from methanol to produce a colorless needle-shaped product 2 with a melting point of 260-262°
．． Obtain 50g.

Elemental analysis value C 8 } {10N4 0 2 Theoretical value C
, 49.48; H, 5.19; N, 28.
85 experimental value C, 49.38; H. 5.35;
N, 28.91 Compounds of Reference Examples 6 to 7 are obtained according to the production method of Reference Example 5.

Reference Example 6 3-Butyl-3,7-dihydro-7-methyl-IH-purine-2,6-dione Properties Pale yellow needle-like product (MeO11) Melting point 224-225 @ Elemental analysis value C10Hl4 N 4 02 Theoretical value C
．． 54.04i H, 8.35; N, 25.2
1 experimental value C, 53.96; H, li. 48;
N, 25.20 Reference Example 7 3.7-dihydro-7-methyl-3-(2-methylpropyl)-18-purine-2.8-dione Properties Colorless crystals (EtOH) Melting point 241-243° Elemental analysis value CIOH14N4 0 2 theoretical value C,
54.04; H, 8.35; N, 25.21
Experimental value C, 54.08; H, li. 31;
N, 25.18 Example 1 Tablets are prepared by the following method.

Compound of Reference Example 1 100 g lactose
Appropriate amount Corn starch 10 g Magnesium stearate 1 g Hydroxypropylene methylcellulose phthalate 7 mg Polyethylene glycol 8000 0.5s + g? Example 3 Capsules are prepared by the following method.

Compound of Reference Example 1 50mg lactose■
Appropriate amounts of 15 g of calcium carboxymethyl cellulose, 2 g of hydroxypropinoresenolelose, 120 mg of ammasium or more are mixed in a conventional manner and filled into hard capsules.

Example 2 An injection is prepared by the method below.

Compound of Reference Example 1 - 100 g Sodium chloride 35 g Example 4 Granules were prepared by the following method! 4l2.

Compound of Reference Example 1 200g lactose
Appropriate amount of crystalline cellulose
100mg Hydroxypropyl methylcellulose phthalate 90mg Glycerin fatty acid ester 81g Nore 1000mg Yunho! II. The preparation thus produced containing the xanthine derivative represented by the general formula (I) and its pharmacologically acceptable alkali addition salt as active ingredients has an excellent bronchodilating effect, It is extremely useful as a therapeutic agent for asthma.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 represents a hydrogen atom or a methyl group, R_
2 represents an ethyl, n-propyl, n-butyl or isobutyl group. ) A therapeutic agent for bronchial asthma comprising a xanthine derivative represented by the following and a pharmacologically acceptable alkali addition salt thereof as an active ingredient.