WO1999009018A1 - BENZOTHIAZOLONE DERIVATIVES HAVING SELECTIVE β2 RECEPTOR AGONIST ACTIVITY - Google Patents

Abstract

Compounds which selectively stimulate a β2 receptor present in the airway smooth muscle in a short time. The compounds are benzothiazolone derivatives represented by general formula (I) or pharmacologically acceptable salts or solvates thereof. The compounds represented by formula (I) are useful for the treatment of respiratory diseases, inflammatory diseases, and allergic diseases.

Description

 Description Benzothiazone Derivatives Having Selective β2 Receptor Agonist Activity Background of the Invention

 Field of the invention

 The present invention relates to a benzothiazolone derivative which is present in airway smooth muscle) and stimulates a 52 receptor, and a medicament containing the same as an active ingredient. More specifically, the present invention relates to a therapeutic agent for respiratory diseases, allergic diseases The present invention relates to a therapeutic agent and an inflammatory disease therapeutic agent. In recent years, asthma has been described as a disorder characterized by reversible airway obstruction, nonspecific airway hyperresponsiveness, and chronic airway inflammation (Dish LBI / WHO Workshop Report: Global Strategy ior Asthma Management and Preventation. National Institute of Health) , National Heart, Lung, and Blood Institute Publication Number 95-3659 (1995)). Most of the chronic airway inflammation in bronchial asthma is considered to be allergic inflammation, but the mechanism of the inflammation is unknown.

Drugs having an anti-inflammatory effect have been regarded as important as these therapeutic agents, and treatment using steroids has been performed. Steroids have side effects (diagnosis and treatment, 81, 1185-1118, 1993). On the other hand, allergic rhinitis is classified as type I allergic and is thought to play an important role in the transmission of histamine and other danigaku transmitters from mast cells. Although anti-histamine drugs have been used as these therapeutic agents, no satisfactory therapeutic agents have been found (Recent Medicine, Vol. 49, 576--591, 1994). Year). Allergic dermatitis can be broadly divided into atopic dermatitis and allergic contact dermatitis, and no satisfactory therapeutic agent has been found. Bronchial asthma is a disease characterized by reversible airway obstruction.Airway obstruction is caused by three factors: 1) airway smooth muscle spasm, 2) mucosal edema, and 3) excessive airway mucus secretion. It is thought to be composed. Among them, it is known that a receptor stimulant which is a bronchodilator is effective for spasm of airway smooth muscle. However, since these) 9 receptor stimulants also act on the cardiovascular system, there are problems such as limited use in patients with ischemic heart disease, arrhythmias, and hypertension (diagnosis and treatment, 81, 1 195-1 204 page). In order to solve this problem, a compound having a relatively greater stimulating activity on the 2 receptors present on the airway smooth muscle than on the β1 receptor present on the muscle, that is, selective yS 2 Receptor stimulants are expected to be effective as excellent bronchodilators with few side effects.

 In addition, the National Cardiopulmonary and Blood Research Institute of the United States and the Global Initiative for Asthma of the World Health Organization (supervised by Sohei Makino: International Guidelines for Asthma Management, Global Strategy for Asthma Management 'Prevention, NHLBI ZWH 0 Workshop on Asthma Treatment Guidelines) International Medical Publishing, 1995) reported the use of a short-acting inhaled drug, Ishiyaku Iyaku, as a palliative remedy for the treatment of transient subjective symptoms in the treatment of asthma. Is recommended. In view of the above, a short-acting selective β 2 receptor stimulant having a relatively large activity at the S 2 receptor (as opposed to the 1 receptor) is desired.

 On the other hand, for bronchial asthma, peak flow monitoring is used as an index in non-seizure (chronic asthma) treatment, and the severity before treatment (classified as steps 1 to 4 and increasing in severity in order). The gradual treatment power has been done. In the treatment of seizures (acute asthma), treatments based on seizure intensity are used.

Specifically, as a treatment method during non-seizure (chronic asthma), inhalation of short-acting S2 receptor stimulant in Step 1 is appropriate, and inhalation anti-inflammatory drug or oral in Steps 2 to 4) In addition to the use of 3 2 receptor stimulants, short-acting ^ 2 receptor stimulation It is strongly recommended that inhalation of the intense agent be performed 3 to 4 times in Z days or less. In addition, inhalation therapy of j82 receptor stimulants and subcutaneous injection of epinephrine are used as treatment for seizures.

 However, there is a problem that epinephrine cannot be used when there is a disorder of the cardiovascular system to stimulate not only the 32 receptor stimulating effect but also the entire sympathetic nerve. Furthermore, since it stimulates not only the 32 receptor but also the ^ 1 receptor similarly, there is a possibility that side effects may occur when administered to patients with heart disease. In view of the above, a short-acting and highly selective; 52 receptor stimulant is expected.

 However, a selective / 52 receptor stimulant characterized by the above-mentioned short-acting action has not been reported as far as the present inventors know.

 For example, among the active ingredients of typical existing drugs on the market, isoproterenol (4- [hydroxy-2-[(1-isopropyl) amino] ethyl] 1,1,2-dihydroxybenzene) is used for a short time. ) 3 receptor stimulant, but low selectivity for yS 2 receptor (Euro. J. Pharmacol., Vol. 227, 403-409 (1992); Life

Science, vol. 52, 2145-2160 (1993)). Sarbu Even Malle (2-t-butylamino-1- (4-hydroxy-13-hydroxymethylphenyl) ethanol hemisulfate has high selectivity for the; 82 receptor but is not short-acting ( Euro. J. Pharmacol., Vol. 227, 403-409 (1992); Life Science, vol. 52, 2145-2160 (1993)) o Formoterol (N— [2-hydroxy-15-[(RS)) — 1-Hydrochloride 2— [(RS) -2- (4-methoxyphenyl) 1-1-methylethylamino] ethyl] phenyl] formamide hemi-fumarate monohydrate) has a selectivity for β 2 receptor Compared to salbutamol, it has a longer working time (Life Science, vol. 52, 2145-2160 (1993)).

Also, Jounal of Medical Chemistry, vol. 30, No. 7, 1166-1176 (1987), U.S. Pat.No. 4,554,284, WO92Z0870, WO932 3 3 8 5, W 09 3/2447 3-. Benzothiazolone derivatives are disclosed in WO 95/04047, WO 95/25 104, W 097/10227, WO 97/23470, and US Patent No. 5648370. Have been.

 Summary of the Invention

 The present inventors have searched for a compound having selective β 2 receptor stimulating activity and having a short action time. As a result, certain benzothiazolone derivatives having an ethanolamine structure substituted by a lower alkyl group at the 7-position selectively stimulate / S 2 receptors in airway smooth muscle and have a short action time. Suppresses degranulation reaction from human mast cells, suppresses TNF-α production from human mast cells, relaxes bronchi in mice and guinea pigs in vivo, and passively in mice and rats It was found that the skin reaction caused by cutaneous anaphylaxis and hissamine was suppressed. The present invention is based on this finding. Accordingly, an object of the present invention is to provide a novel compound which selectively and rapidly stimulates the 62 receptor. Another object of the present invention is to provide a pharmaceutical composition containing the novel compound.

 The benzothiazolone derivative according to the present invention is a compound represented by the following formula (I) and a pharmacologically acceptable salt and solvate thereof:

(In the above formula, R ¹ is a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms which may be substituted by one or more halogen atoms, a hydroxyl group, a cyano group, a nitro group, or an amino group, Represents an alkenyl group of 4 or an alkynyl group having 2 to 4 carbon atoms, and R ² and R ³ may be the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group Or one or more halogen atoms, a hydroxyl group, a cyano group, a nitro group, or an alkoxy group having 1 to 4 carbon atoms which may be substituted by an amino group, and R ⁴ is a hydrogen atom, or one or more A hydrogen atom, a hydroxyl group, a cyano group, a nitro group, or an alkyl group having 1 to 4 carbon atoms which may be substituted with an amino group, provided that R ⁴ represents a hydrogen atom, and R ³ But water Atoms, when referring to 4 hydroxyl groups, or 4-menu butoxy group, when R ¹ represents a methyl group, and R ⁴ represents a hydrogen atom, and R ³ represents a 4 Ichimizusan group, and R ¹ is represents an n-propyl group and R ² , R "and R ⁴ represent a hydrogen atom).

 Also, the pharmaceutical composition according to the present invention comprises a compound of the formula (I) or a pharmacologically acceptable salt or solvate thereof.

 The compound according to the present invention has excellent medicinal effects as compared with conventional drugs, furthermore, has no fear of side effects on patients with heart disease, and is also excellent in quick action. Therefore, according to the present invention, there is provided a therapeutic agent for respiratory diseases, inflammatory diseases, and / or allergic diseases that is safe for the human body.

 BRIEF DESCRIPTION OF THE FIGURES

 Figure 1 shows the proton magnetism of 4-hydroxy-17- [1- (1-hydroxy-12-methylamino) ethyl] -1,3-benzothiazol-2 (3H) -one (Example 1) derived from sponge. Indicates resonance spectrum (500 MHz, in heavy water).

Figure 2 shows 4-hydroxy-1- 7- [1- (1-hydroxy-2-methylamino) ethyl] sponge-derived 1,1-benzothiazo-l-2 (3H) -one (Example 1) ¹¹³ C magnetic resonance scan Bae spectrum (5 0 0 MHz, heavy water) of showing the.

 FIG. 3 shows the broncholytic activity of the isolated guinea pig by the compound of the present invention. Hata: the compound of Example 2, Δ: sultopamol, □: formoterol, 〇: isoproterenol.

 FIG. 4 shows the duration of the isolated guinea pig bronchodilator action of the compound of the present invention. ·: Compound of Example 2, Δ: salbutamol, mouth: formoterol, Δ: isoproterenol.

 FIG. 5 shows the effect of the compound of the present invention on the bronchoconstriction effect of acetylcholine in anesthetized mice. Violence: control (no administration), □: compound of Example 2 (1 g / kg), Δ: compound of Example 2 (10 g / kg), Δ: compound of Example 2: (30 gZkg )

 FIG. 6 shows the effect of the compound of the present invention (Example 2) on the degranulation reaction from human mast cells.

 FIG. 7 shows the effect of the present conjugate on the production of TNF-α from human mast cells. Figure 8 shows the outline of the synthesis route of 4-hydroxy-17- [1- (1-hydroxy-2-methylamino) ethyl] -1,3-benzothiazo-l-2 (3H) one.

 Detailed description of the invention

 Compounds of formula (I)

 As used herein, an alkyl group, an alkenyl group, an alkynyl group, and an alkoxy group can be straight-chain or branched.

In the present specification, examples of the alkyl group having 1 to 4 carbon atoms representing ¹ , ⁴ and R ⁴ "include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t- Butyl, and s-butyl.

In the present specification, examples of the alkenyl group having 2 to 4 carbon atoms represented by R ¹ include Nyl (ethenyl), 1-propenyl, aryl (2-propenyl), isopropyl, 2-butenyl, and 1,3-butenyl groups.

In the present specification, examples of the alkynyl group having 2 to 4 carbon atoms represented by R ¹ include ethynyl, 1-propynyl, and 2-propynyl.

In the present specification, examples of the alkoxy group having 1 to 4 carbon atoms represented by R ² and R ³ include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-type Butoxy, and s-butoxy groups.

 One or more hydrogen atoms of the alkyl, alkenyl, alkynisole, and alkoxy groups may be substituted by a halogen atom, a hydroxyl group, a cyano group, a nitro group, or an amino group (preferably, a halogen atom). Often, examples of substituted alkyl, alkenyl, alkynyl, and alkoxy groups include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and trifluoromethoxy.

 In this specification, a halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

 In the formula (I), R preferably represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which may be substituted by one or more halogen atoms, a hydroxyl group, a cyano group, a nitro group, or an amino group. And more preferably, the number of carbon atoms which may be substituted by a hydrogen atom or one or more halogen atoms:! Represents an alkyl group (particularly, a methyl group) of 1 to 4.

In the general formula (I), R ² preferably represents a hydroxyl group.

R in the formula (I). Preferably represents a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms which may be substituted by one or more halogen atoms, and more preferably represents a hydroxyl group or a methoxy group. R ³ can preferably be located at position 4 of the benzothiazolone ring. In the formula (I), R ⁴ preferably represents a hydrogen atom or an alkyl group having 14 carbon atoms, which may be substituted with one or more halogen atoms, and more preferably a hydrogen atom.

 Optical isomers may exist in the compounds according to the present invention, and any isomers and mixtures thereof are also included in the present invention.

Preferred compounds of the compounds according to the present invention include R ¹ hydrogen atom, or an alkyl group having 14 carbon atoms which may be substituted by one or more halogen atoms, a hydroxyl group, a cyano group, a nitro group, or an amino group. R represents a hydroxyl group, represents a hydrogen atom, a halogen atom, a hydroxyl group, or an alkoxy group having 14 carbon atoms which may be substituted by one or more halogen atoms, and R ⁴ represents a hydrogen atom, or 1 or more And a compound of the formula (I) representing an alkyl group having 14 carbon atoms which may be substituted by a halogen atom.

 Further preferred compounds of the present invention include compounds of formula (Ia):

(

(In the above formula, R ^la represents a hydrogen atom or an alkyl group having 14 carbon atoms which may be substituted by one or more halogen atoms, a hydroxyl group, a cyano group, a nitro group, or an amino group.)

In the formula (Ia), R "is preferably a hydrogen atom or at least one halogen Represents an alkyl group having 1 to 4 carbon atoms (particularly a methyl group) which may be substituted by an atom.

 The most preferred compound according to the present invention is 4-hydroxy-7-

[1-(1-hydroxy-1-methylamino) ethyl]-1, 3-benzothiazol-1-2 (3 H) thiol.

 The compound according to the present invention can be a pharmacologically acceptable salt thereof. Such salts include pharmacologically acceptable non-toxic salts. Preferred examples are salts of alkali metal or alkaline earth metal such as sodium salt, potassium salt or calcium salt, hydrofluoride, hydrochloride, hydrobromide, hydroiodide. Inorganic salts such as hydrohalides, nitrates, perchlorates, sulfates, and phosphates; lower alkyl sulfones such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate Arylsulfonate, fumarate, succinate, citrate, tartrate, oxalate, maleate, acetic acid, apple such as benzenesulfonate, benzenesulfonate, p-toluenesulfonate Organic acid salts such as acid, lactic acid and ascorbic acid, and amino acid salts such as glutamate and aspartate are exemplified.

 The compounds according to the present invention can also be solvates (eg hydrates).

 Preparation of compounds of formula (I)

The compound of the formula (la), which is a typical compound of the formula (I), can be isolated and purified from sponges living in the sea by an extraction operation. Specifically, sponges are crushed using a blender or the like, and the crushed products are freeze-dried and extracted with methanol, ethanol, acetone, or a mixed solvent of methanol and black-mouthed form. The freeze-drying operation may be omitted, and the crushed sponge may be directly subjected to the extraction operation. In the extraction operation, a countercurrent distribution method using a suitable solvent may be performed. Then, The extract is applied to a suitable adsorbent (eg, alumina, silica gel, activated carbon, ion-exchange resin, "Diaion HP20" (manufactured by Mitsubishi Chemical Corporation)), etc., and the target compound is adsorbed and eluted with a suitable solvent. Then, by concentrating this under reduced pressure to dryness, the compound according to the present invention can be obtained.

 In order to further purify the compound according to the present invention, gel filtration, high-performance liquid chromatography, or the like may be combined as necessary for the above-mentioned extraction and adsorption operations. Specifically, column chromatography using an adsorbent such as silica gel, a gel filtration agent such as “Sephadex LH-20” (manufactured by Pharmacia), and high-performance liquid using a “YMC Pack” (manufactured by Yamamura Science). Chromatography can be further combined with countercurrent distribution.

 The compound of the formula (la), which is a representative compound of the compound of the formula (I), can also be synthesized according to the scheme shown in FIG.

 The compound of the formula (Π) in the scheme can be synthesized, for example, starting from commercially available 2-methoxy-5-methylphenylthiodiprea. Further, the compound of the formula (II) can be prepared according to the method described in, for example, Journal of Medicinal Chemistry, vol. 30, ppll 66-1176 (1987) and Japanese Patent Application Laid-Open No. 61-68746. —Methoxy 5—Methylaniline can also be synthesized (these references are incorporated herein by reference).

 Step (i) in the scheme is a step of oxidizing the compound represented by the formula (II). The compound represented by the formula (II) is mixed with cerium ammonium nitrate in a suitable solvent (for example, a polar solvent such as acetonitrile, methanol, and ethanol, preferably methanol). (The reaction is carried out at a temperature of 100 ° C., preferably 40 ° C. to 60 ° C. for 5 minutes to 6 hours, preferably 15 minutes to 1 hour to obtain a compound represented by the formula (ΙΠ).

Here, in the formula (II), R ⁵ and R ⁶ represent a hydroxyl-protecting group, and R ⁷ is Represents an alkyl group having a prime number of 1 to 4. Examples of the hydroxyl-protecting group include ester-protecting groups (for example, acetyl, trifluoroacetyl, benzoyl, pivaloyl, methoxycarbonyl, etc.), ether-based protecting groups (for example, benzyl, A paramethoxybenzizole group, a methoxymethyl group, an alkyl group having 1 to 4 carbon atoms, etc.) and a silyl-based protecting group (for example, t-butyldimethylsilizole group, triisopropylsilyl group, etc.).

 Step (ii) is a step of converting the formyl group of the compound represented by the formula (III) to cyanohydrin. The compound represented by the formula (III) is dissolved in an inert solvent (for example, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, preferably dichloromethane), and trimethylsilyl cyanide, a suitable Lewis. By reacting with an acid, preferably zinc iodide, at 0 ° C. to 100 ° C., preferably at room temperature, for 5 minutes to 6 hours, preferably 10 minutes to 15 minutes, the compound of formula (IV) The compound shown is obtained. Step (iii) is a step of reducing the cyano group of the compound represented by the formula (IV). The compound represented by the formula (IV) is dissolved in a suitable solvent (for example, ethers such as tetrahydrofuran and dioxane) with a suitable reducing agent, preferably lithium aluminum hydride, diisobutylaluminum hydride, etc. The compound represented by the formula (V) is obtained by reacting at 100 ° C., preferably 110 ° C. to 10 ° C., for 5 minutes to 12 hours, preferably 10 minutes to 15 minutes. .

Step (iv) is a step of protecting the hydroxyl group of the compound represented by the formula (V). For example, when X is a t-butyldimethylsilyl group, the compound represented by the formula (V) is converted into a suitable inert solvent (for example, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride). Together with t-butyldimethylsilyl trifluoromethanesulfonate and a base (for example, pyridine, dimethylaminopyridine, lutidine, etc., preferably lutidine), at 10 ° C. to 50 ° C., preferably 0 ° C. By reacting at 5 ° C for 10 minutes to 12 hours, preferably 0.5 hours to 1.5 hours, the compound of formula (VI) Is obtained.

 Step (V) is a step of protecting the amino group of the compound represented by the formula (VI). For example, in the case of an acyl group such as a Y-force, an acetyl group, a trifluoroacetyl group, or a benzoyl group, the compound represented by the formula (VI) can be prepared by adding a compound represented by the formula (VI) in a suitable inert solvent or without a solvent to a base, preferably In the presence of a carboxylic acid and a suitable binder (eg,

DDC), carboxylic acid chloride, carboxylic anhydride, etc., at 10 ° C to 60 ° C, preferably 0 ° C to 5 for 5 minutes to 12 hours, preferably 10 minutes to 3 hours. The reaction is carried out for 0 minutes to obtain the compound of formula (VII).

Step (vi) is a step of introducing R ^1a (representing a group having the same content as described above) into the compound represented by the formula (VII). When R ^1a is an alkyl group, the compound represented by the formula (VII) is dissolved in a suitable solvent (eg, N, N-dimethylformamide) in a salt group (eg, sodium hydride, hydrogenating power). , Carbon dioxide, sodium carbonate, etc., preferably sodium hydride), together with an alkyl halide, at −20 ° C. to 100 ° C., preferably at −10 ° C. to 10 ° C., By reacting for 5 minutes to 12 hours, preferably for 10 minutes to 20 minutes, a compound represented by the formula (VIII) is obtained. It will be apparent to those skilled in the art that the compound of formula (VIII), which is a group other than the R ^la alkyl group, can be synthesized according to the above method.

Step (vii) is a step of deprotecting the compound represented by the formula (VIII). For example, when t-butyldimethylsilyl group and Y is a trifluoroacetyl group, the compound represented by the formula (VIII) is dissolved in a suitable solvent (ethers such as tetrahydrofuran and dioxane) with a suitable acid or fluorine. -10 ° C to 60 ° C, preferably -10 ° C to 10 ° C, for 10 minutes to 12 hours, together with tetrabutylammonium fluoride, preferably tetrabutylammonium fluoride The reaction is preferably performed for 10 minutes to 1 hour to remove the t-butyldimethylsilyl group. Then, in alcohols such as methanol and ethanol, preferably methanol, sodium alkoxy 0 ° C. to 100 ° C., preferably together with potassium alkoxide, preferably sodium methoxide. 5 ° (: up to 40 ° C., for 10 minutes to 12 hours, preferably for 10 minutes By reacting for up to 30 minutes, a compound represented by the formula (IX) is obtained.

 Step (viii) is a step of deprotecting the compound represented by the formula (IX). A compound represented by the formula (IX) is converted into a suitable solvent that does not inhibit the reaction (for example, halogenated carbon such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, etc., acetonitrile, and preferably acetonitrile). In a suitable acid, Lewis acid, sodium thiomethoxide, preferably with boron tribromide, at a temperature of 20 ° (~ 100 ° (preferably 5 ° C ~ 40 ° C, 1 hour ~ 72 hours) The reaction is carried out for preferably 12 hours to 40 hours to obtain the compound represented by the formula (I).

 In the above synthesis method, the order of synthesis is determined so that side reactions do not occur in the functional groups that do not participate in the reaction, and even if the functional groups are protected with appropriate protecting groups so that the preferable L reaction does not proceed. The good will be apparent to those skilled in the art. It will also be apparent to those skilled in the art that compounds of formula (I) that are not included in formula (Ia) can be obtained by modifying the starting materials and the like.

 The acid addition salt of the compound of the formula (I) can be prepared by a known method, for example, by dissolving an equivalent or excess amount of acid in a solvent solution of the compound dissolved in a suitable organic solvent such as methanol, ethanol, 2-propanol and the like. It can be produced by adding.

 In the scheme of FIG. 8, the intermediates of formulas (III) and (V) are novel compounds. C Therefore, according to the present invention, compounds of the following formulas (IIIa) and (Va) are provided. Is:

(Ilia)

(In the above formula, ⁵ & 1 and ¹⁶ 3 may be the same or different, and represent a hydrogen atom,

An alkyl group having 1 to 4 carbon atoms which may be substituted by one or more halogen atoms, an acetyl group, a trifluoroacetyl group, a benzoyl group, a bivaloyl group, a methoxycarbonyl group, a benzyl group, a paramethoxybenzyl group, Represents a toxicoxymethyl group, a t-butyldimethylsilyl group, or a triisopropylsilyl group).

 The compounds of the above formulas (IIIa) and (Va) are useful as intermediates for producing the compounds of the formula (Ia).

 Compound Uses Z Pharmaceutical Composition

 The compounds according to the invention have relatively much greater activity on the ^ 2 receptor than on the; 91 receptor. That is, the compounds according to the present invention have selective ^ 2 receptor stimulating activity. The compounds according to the invention also relax the isolated guinea pig bronchial tissue at very low concentrations. Furthermore, when the compounds according to the invention are actually administered to mice, a very strong bronchodilator effect is observed.

Accordingly, the compounds according to the present invention are useful in the treatment of respiratory diseases such as bronchial asthma (eg, acute bronchial asthma, chronic bronchial asthma), asthmatic bronchitis, emphysema, bronchitis, acute bronchitis. Since the compound according to the present invention has a very strong selective 2-receptor stimulating activity, it is expected to be a therapeutic agent for respiratory diseases without side effects such as a heart rate enhancing action. As used herein, reversible diseases include reversible Airway obstruction shall be included, and drugs for treating respiratory diseases shall include airway dilators and bronchodilators.

 The compounds according to the invention also have a (very short duration) 52 receptor stimulating activity. Therefore, the compounds according to the present invention are useful for the treatment of respiratory diseases, particularly those requiring acute rescue (for example, acute bronchial asthma).

 The compounds according to the invention also inhibit the degranulation reaction from human mast cells, ie the release of chemical mediators (chemical mediators) from fl. The release of chemical messengers includes allergic asthma (including bronchial asthma), allergic rhinitis, allergic dermatitis (eg, atopic dermatitis and allergic contact inflammation), juniper measles, pruritus, allergic conjunctivitis, anaphylaxis It is known to cause allergic diseases such as bronchitis, acute bronchitis, and allergic diseases such as bronchitis (Bird and Circulation, Vol. 44, No. 12, 1240-1247 and 1255-1260 (1996 The latest medicine, volume 49 (extra number), pp. 102-122 (1994)). The compounds according to the invention also suppress the production of TNF-α from human mast cells. TNF-α is allergic to sexual asthma (including bronchial asthma), allergic rhinitis, allergic ^ t inflammation (eg, atopic dermatitis and allergic contact dermatitis), juniper, pruritus, allergic It is known to cause allergic diseases such as conjunctivitis and inflammatory diseases such as bronchitis and acute bronchitis (ibid.). Furthermore, the compounds according to the present invention suppressed passive cutaneous anaphylaxis and histamine-induced allergic reactions in mice and rats.

 Therefore, the compounds according to the present invention are useful for treating allergic diseases and inflammatory diseases. In addition, allergic diseases may mean part of inflammatory diseases, and inflammatory diseases may mean part of allergic diseases.

 According to the present invention, there is provided a pharmaceutical composition used for treating the above-mentioned diseases.

The compounds according to the invention may be administered by any suitable route of administration, in particular by non-human For animals, methods such as intraperitoneal administration, subcutaneous administration, intravenous administration to veins or arteries, and local administration by injection, and for humans, intravenous administration, intraarterial administration, local administration by injection, intraperitoneal administration, It can be administered by thoracic cavity, oral administration, inhalation administration, subcutaneous administration, intramuscular administration, sublingual administration, transdermal absorption, or rectal administration. L, preferred for intravenous or inhaled administration.

 Inhalation devices used for the inhalation method include, for example, a jet nebulizer, an ultrasonic nebulizer, HFV (high frequency vibration), an IPB (intermittent positive pressure breathing) metered dose inhaler, and a spin spatula. From the viewpoint of its immediate effect, portability, and simplicity, a metered dose inhaler is preferably used. (Refer to Chiba Prefectural Inhalation Therapy Society for Pediatric Bronchial Inhalation Therapy, Inhalation Therapy Manual, pp. 18-23, 1992).

 The compound according to the present invention may be administered as it is, but is preferably administered as a pharmaceutical composition together with a pharmacologically acceptable carrier. The formulation of the pharmaceutical composition may be appropriately determined in consideration of the administration method and the purpose of administration. Examples thereof include powders (powder for inhalation), injections, suspensions, tablets, granules, powders, and capsules. , Ointments, creams and the like. Injections or inhalants are preferred.

As a solvent, for example, water, physiological saline, etc., as a solubilizer, for example, ethanol, a polysorbate, as an excipient, for example, lactose, starch, crystalline cellulose, mannitol, maltose, calcium hydrogen phosphate, light Gay anhydride, calcium carbonate, etc., as binders, for example, starch, polyvinylpyrrolidone, hydroxypropylcellulose, ethylcellulose, carboxymethylcellulose, arabia gum, etc., as disintegrants, for example, magnesium stearate, talc, As a stabilizer, for example, lactose, mannitol, maltose, polysorbates, macrogol, polyoxyethylene castor oil and the like can be used as a stabilizer. You. If necessary, glycerin, dimethylacetamide, 70% sodium lactate, surfactants, and basic substances (eg, ethylenediamine, ethanolamine, sodium carbonate, arginine, meglumine, trisaminomethane) Can also be added. These components can be used to produce injections, tablets, granules, inhalants or aerosols, capsules and other dosage forms.

 For metered dose inhalers, the agents of the present invention can be formulated and administered as aqueous solutions or suspensions. For example, a propellant, for example, an aerosol spray formulation in which the drug is suspended in compressed air, compressed carbon dioxide or CFC-based propellerone, optionally with one or more stabilizers, may also be used. be able to. Examples of CFC-based probratons include chlorofluorocarbon (CFC-11, CFC-12 and CFC-114), hydrochlorofluorocarbon (HCFC-123, HCFC-124 and HCFC-141), hydrofluorocarbon (HCFC — 125 and HFC — 134 a). Also, for administration by inhalation or insufflation, the agents of the present invention may take the form of a dry powder composition, for example a powder mix of the active ingredient and a suitable carrier such as lactose. The powder composition may be presented in unit dosage form, for example, in capsules, cartridges or blister packs. From these forms, the powder can be supplied with the aid of an inhaler, such as a Rotahaler inhaler (Glaxo Group trade name) or, in the case of prestar packaging, a desk healer (Mskhaler) inhaler (Glaxo Group trade name). In addition, in the case of administration using a nebulizer or an inhalation device, the particle size of the drug or powder composition should be 100 / m or less, and it should be sprayed from 0.5 / zm to 25 zm. Is desirable o

The dose of the compound is determined in consideration of various situations so that the total dose does not exceed a certain amount when administered continuously or intermittently. Specifically, one day for an adult Between 0.01 and 50 Omg. For metered dose inhalers, the dose is adjusted to be 0.01 to 0.5 ml per spray, and is about 0.001 to 10 mg per spray. The precise dose to be used will depend on the route of administration, the mode of administration, and the age, weight and condition of the patient, and will be determined by the clinician or veterinarian.

 In the present specification, “treatment” is used in a sense including prophylaxis. According to the present invention, an effective amount of a compound of formula (I) or a pharmacologically acceptable salt or solvate thereof is administered to a human or human suffering from a respiratory disease, an inflammatory disease, and / or an allergic disease. There is provided a method for treating these diseases, including administration to animals other than the above. The method of administering the compound of the formula (I) can be carried out according to the above description.

 Example

 Power for explaining the present invention in more detail by the following examples The present invention is not limited to these.

 Example 1 Isolation and purification of 4-hydroxy-1-7- [1- (1-hydroxy-2-substitutedamino) ethyl] -1,3-benzothiazol-12 (3H) -one

8 kg of sponge (Dysidea sp.) Collected around April to June in the sea near Okijima prefecture was ground using a blender and freeze-dried. The freeze-dried sponge was further used with a blender to obtain 935 g of powder. The powdered sponge was extracted three times using a mixed solvent of dichloromethane-methanol (1: 1). The extract was concentrated, dissolved in 3 liters of ethyl acetate, and subjected to distribution chromatography twice using 1.5 volumes of distilled water. The obtained water fraction of a total of 8 liters was concentrated to obtain about 200 g of a concentrate. The concentrate was adsorbed to a column (7 cm0x50 cm) of a silica gel column (manufactured by Mesolek, silica gel 60) equilibrated with dichloromethane-methanol (15: 1), and dichloromethane-methanol (15: 1) was added. 2 liters, then 4 liters of dichloromethane-methanol-water (3: 1: 0.1), and then dichloromethane-methanol The eluent (1: 1: 0.1) was eluted at 3 liters. The active fraction was concentrated to obtain 80 g of a concentrate.

 40 g of the obtained concentrate was dissolved in 20% methanol, and the concentrate was adsorbed on a column (100 ml) of activated carbon. After washing with 300 ml of 20% methanol, 70% acetone was eluted with 300 ml, and then with 70% acetone (0.4% trifluoroacetic acid) 600 ml. After the active fraction was concentrated to dryness, the resulting concentrate was used as eluent, 20% methanol-80% 20 mM potassium phosphate buffer (pH 7.0), and an ODS column (Yemushi I., SH- 343-7) by liquid high performance chromatography.

 After the active fraction was concentrated to dryness, it was further fractionated by the same high-performance liquid chromatography using 10% methanol-90% 20 mM potassium phosphate buffer (pH 7.0) as an eluent. The active fraction was concentrated to dryness, and then pre-equilibrated with dichloromethane-methanol-water (3: 1: 0.1) on a silica gel column (manufactured by Merck, silica gel 60) (1.2 cm0x2 Ocm ) Was adsorbed with this concentrate and eluted with the same solvent used for equilibration.

 After the active fraction was concentrated to dryness, the crude product obtained was pre-equilibrated with dichloromethane-methanol-water (6: 1: 0.1, 2% acetic acid). The column was eluted with the same solvent used for equilibration, and then eluted with the same solvent used for equilibration.

(1-Hydroxy-2-methylamino) ethyl] -1,3-benzothiazoluyl 2 (3H) -one acetate (4.8 mg) was obtained. Proton (Figure 1) and

1 ³ C (FIG. 2) Nuclear magnetic resonance scan Bae-vector results, and, from the results of high-resolution Masusu Bae-vector, the compound 4-hydroxy-one 7 _ [1 - (1-hydroxy-one 2- main Thiamino) ethyl] -1,3-benzothiazole-2 (3H) one. ¹ H-certificate (D ₂₀ )

2.71 (s, 3H, NHCH ₃ ), 3.26 (m, 2H, CH ₂ NHCHg), 5.03 (dd, J = 4.3Hz, 8.5Hz, 1H, CH OHNHCHg), 6.8 (d, J = 8.5Hz, 1H, ArH-5), 7.0 (d, J = 8.5Hz, 1H, ArH-6)

MS; fight = 241, [a] d ²⁶ = -l 0.0 °

 Example 2 Synthesis of 4-hydroxy-1-7- [1- (1-hydroxy-1-methylamino) ethyl] -1,3-benzothiazol-2 (3H) one

 The outline of the synthesis of the title compound is as shown in FIG.

 (1) Synthesis of 2,4-dimethoxy-17-methyl-1,3-benzothiazole (II)

 2-Methoxy-5-methylphenylthiourea (Lancaster; # 12101) (3.0 g) was dissolved in chloroform (70 ml), and bromine (4.9 g) was dissolved in ice under ice-cooling. The solution (10 ml) was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes and then heated and refluxed for another 40 minutes. After cooling to room temperature, the precipitated crystals were collected by filtration and washed with acetone. The obtained white crystals were dissolved in hot water (180 ml), cooled, and adjusted to pH 10 with aqueous ammonia to precipitate white crystals. The crystals were collected by filtration and dried under reduced pressure.

The obtained crystals were dissolved in phosphoric acid (80 ml), and an aqueous solution of sodium nitrite (2.22 g) (8 ml) was added dropwise under cooling to -15 ° C. After completion of the dropwise addition, the mixture was further stirred at −15 ° C. for 90 minutes to obtain a purple suspension. An aqueous solution (60 ml) of copper sulfate pentahydrate (11.6 g) and sodium chloride (14.3 g) was ice-cooled, and the purple suspension was added dropwise. After completion of the dropwise addition, the mixture was further stirred at room temperature for 3 hours. The reaction solution was extracted with ethyl ether, the ethyl ester layer was neutralized with a saturated aqueous sodium hydrogen carbonate solution, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. , 2-Methoxy-1-methyl-1,3-benzothiazole (2.16 g) was obtained. Next, 2-methyl-4--1-methoxy-1,7-methyl-1,3-benzothiazole (2.16 g) was dissolved in methanol (50 ml), and sodium methoxide (5.48 g) was added. The mixture was refluxed for 2 hours. The solvent was distilled off under reduced pressure, and the obtained oil was suspended in water and adjusted to pH 4 with acetic acid. The suspension was extracted with getyl ether, the getyl ether layer was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2,4-dimethoxy-17-methyl-1,3-benzothiazole (1.72 g).

1 H-NM (CDC1 ₃₎

2.37 (s, 3H, ArCH3-7) , 3.98 (s, 3H, OCH 3), 4.24 (s, 3H, ArOCHg), 6.78 (d, J = 7.9H z, 1H, ArH-5), 6.96 (d , J = 7.9Hz, 1H, ArH-6)

MS; [M +] = 209

 (2) Synthesis of 2,4-dimethoxy-1,3-benzothiazole-17-carbaldehyde (III)

 2,4-Dimethoxy-7-methyl-1,3-benzothiazol (1.72 g) and cerium ammonium nitrate (20.8 g) synthesized in (1) above were combined with methanol (80 ml). ) And stirred at 60 ° C. for 5 minutes. The solvent was distilled off, water was added to the resulting oil, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was purified by silica gel column chromatography, and 2,4-dimethoxy-1,3-benzothiazolyl was purified. 7-Carboxaldehyde (1.0 g) was obtained.

1 H-NMR (CDC1 ₃₎

4.11 (s, 3H, OCH ₃ ), 4.27 (s, 3H, ArOCH ^), 7.02 (d, J = 9Hz, 1H, ArH-5), 7.74 (d, J = 9Hz, 1H, ArH-6), 9.98 (s, 1H, CH0)

MS; [M ⁺ ] = 223 (3) Synthesis of 2-amino-1- (2,4-dimethoxy-1,3-benzothiazole-17-yl) 1-1-ethanol (V)

 Dissolve 2,4-dimethoxy-1,3-benzothiazo-l-u7-carbaldehyde (1.0 g) synthesized in (2) above in dichloromethane (30 ml) and add trimethylsilyl cyanide (2.4 ml). ) And zinc iodide (29 Omg) were added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained oily substance is tetrahydrofuran

(30 ml) and cooled to 0 ° C. This was added dropwise to a suspension of lithium aluminum hydride (51 mg) in tetrahydrofuran (30 ml). After stirring at 0 ° C for 10 minutes, sodium sulfate decahydrate was added. After the reaction solution was filtered through celite, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give 2-amino-1- (2,4-dimethoxy-1,3-benzothiazole-17-yl) -1. 1 ー Even knol (95 Omg) was obtained.

_{1 H-NMR (CD 3 0D} )

3.07 (dd, J = 9.7Hz, 12Hz, 1H, CH ₀ NH ₂ ), 3.14 (dd, J = 3.9Hz, 12Hz, 1H, CH ₂ NH ₀ ), 3.98 (s, 3H, OCH ₃ ), 4.19 ( s, 3H, ArOCHg), 5.07 (dd, J = 9.7Hz, 3.9Hz, 1H, ArCHOH), 7.06 (d, J = 8.5Hz, 1H, ArH-5), 7.22 (d, J = 8.5Hz, 1H , ArH-6)

 MS; [M +] = 254

 (4) 2 — {[1— (t—butyl) -1,1-dimethylsilyl] oxy} -2- (2,4 dimethyl 1,3-benzothiazolyl 7— ^ T) 1—1-ethylamine ( VI) Synthesis

2-Amino-1- (2,4-dimethoxy-1,3-benzothiazoyl-17-yl) 1-1-ethanol (85 mg) synthesized in (3) above was suspended in dichloromethane (3 ml). It became cloudy, and lutidine (0.12 ml) and t-butyldimethylsilyl trifluoromethanesulfonate (0.23 ml) were added, and the mixture was stirred at room temperature for 1 hour. 0 ° C To the mixture was added 1 hydrochloric acid under cooling, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2-{[1- (t-butyl) -1, 1-Dimethylsilyl] oxy} —2— (2,4-dimethoxy-1,3-benzobenzothiazole-1-yl) -11-ethylamine (62 mg) was obtained.

1 H- anonymous (CDC1 ₃₎

-0.11 (s, 3H, Si CH ₃ ), 0.07 (s, 3H, Si CHg), 0.90 (s, 9H, SiC (CHg)), 2.85

(dd, J = 4.9Hz, 13Hz, 1H, CH ₂ NH2), 2.93 (dd, J = 6.7Hz, 13Hz, 1H, CH ₂ NH ₉ ), 3.99 (s,

3H, 0CH _o ), 4.23 (s, 3H, ArOCH), 4.69 (dd, J = 4.9Hz, 6.7Hz, 1H, ArCHOTBS), 6.81 oo ——

 (d, J = 7.9Hz, 1H, ArH-5), 7.04 (d, J = 7.9Hz, 1H, ArH-6)

 (5) Nl- [2-{[1-t-butyl) -1,1,1-dimethylsilyl] oxy} -2- (2,4-dimethoxy-1,3-benzothiazol-1-ethyl) ethyl ] —Synthesis of 2,2,2-trifluoroacetamide (VII)

2 — {[1— (t-butyl) -1,1,1-dimethylsilyl] oxy} synthesized in (4) above—2— (2,4-dimethoxy-1,3-benzothiazoyl 7 T) — 1-Ethylamine (62 mg) was dissolved in pyridine (3 ml), trifluoroacetic anhydride (72 μl) was added, and the mixture was stirred at 0 ° C for 10 minutes. 1% Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and N1- [2-[[1- (t-butyl) ) 1, 1-dimethylsilyl] oxy}-2-(2,4-dimethoxy-1, 3-benzothiazo-1-71-ethyl) ethyl]-2,2, 2-trifluoroacetamide ( 8 lmg).丄H-NMR (CDC1 ₃₎

-0.12 (s, 3H, Si CH _n ) ₍ 0.06 (s, 3H, Si CH ₃ ), 0.91 (s, 9H, SiC (CH ₃ ) „), 3.46 (m, lH, CH ₂ NHTFA), 3.69 ( m, 1H, CHg NHTFA), 4.00 (s, 3H, OCH ₃ ), 4.24 (s, 3H, ArOCH ₃ ), 4.90 (dd, J = 4.3 Hz, 8.6 Hz, 1H, ArCHOTBS), 6.83 (d, J = 7.9 Hz, 1H, ArH-5), 7.06 (d, J = 7.9 Hz, 1H, ArH- 6)

MS; [M +] = 464

 (6) Nl- [2-{[1- (t-butyl) -1,1,1-dimethylsilyl] oxy} —2 -— (2,4-dimethoxy-1,3-benzothiazol-1-ethyl) ethyl] Synthesis of N-methyl-1,2,2,2-trifluoroacetamide (VIII)

 N1- [2-{[1- (t-butyl) -11,1-dimethylylsilyl] oxy} synthesized in (5) above} -2-(2,4-dimethyl-1--1,3-benzothiazolu-l7 —Yl) ethyl] —2,2,2-trifluoroacetamide (8 lmg) dissolved in N, N-dimethylformamide (3 ml), sodium hydride (15 mg), methyl iodide (251) was added, and the mixture was stirred at 0 ° C for 1 hour. Water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. N1- [2-{[1- (t-butyl) 1), 1-Dimethylsilyl] oxy} —2— (2,4-Dimethoxy-1,3-benzothiazolyl 7-yl) ethyl] —N1-Methyl-1,2,2,2-trifluoro Acetamide (7 lmg) was obtained.

¹ H-NMR (CDC1 ₃₎

-0.13 (s, 3H, Si CH ₃ ), 0.05 (s, 3H, Si CH ₃ ), 0.88 (s, 9H, SiC (CH ₃ ) ₃ ), 2.99 (s, 3H, N (CH ₃ ) TFA) , 3.51 (dd, J = 7.9Hz , 13Hz, 1H, CH 2 n (CH n) TFA), 3.58 (dd, J = 5.5, 13Hz, 1H, CH 2 n (CH 0) TFA), 4.01 (s, 3H, 0CH ₃ ), 4.25 (s, 3H, ArOCHg), 5.15 (dd, J = 5.5Hz, 7.9Hz, 1H, ArCHOTBS), 6.82 (d, J = 8.6Hz, 1H, ArH-5), 7.05 ( d, J = 8.6Hz, 1H, ArH-6)

MS; [M ⁺ ] = 478 (7) Synthesis of 1- (2,4-dimethoxy-1,3, -benzothiazole-17-yl) -1- (methylamino) -11-ethanol (IX)

 N1- [2-{[1- (t-butyl) -11,1-dimethylylsilyl] oxy} synthesized in (6) above -2-(2,4-Dimethoxy-1,1,3-benzothiazoyl) 7 —Yl) ethyl] — N1-methyl-1,2,2,2-trifluoroacetamide

(337 mg) was dissolved in tetrahydrofuran (10 ml), a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran (1.1 ml) was added, and the mixture was stirred at 0 ° C for 20 minutes. Water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and N1- [2- (2,4 dimethoxy 1,1 3-Benzothiazole-1-yl) -2-hydroxyethyl] —N1-methyl-1,2,2,2-trifluoroacetamide (238 mg) was obtained.

 N1- [2- (2,4-Dimethoxy-1,1,3-benzothiazolu-1-yl) -12-hydroxyethyl] synthesized above. N1-Methyl-1,2,2,2-trifluoroacetamide (45 mg) was dissolved in methanol (5 ml), sodium methoxide (70 mg) was added, and the mixture was stirred at room temperature for 40 minutes. After the solvent was distilled off, the residue was purified by alumina column chromatography, and 1- (2,4-dimethoxy-1, 3-benzothiazol-1-7-yl) -12- (methylamino) 1-1-etano- (23 mg).

丄H- negation R (CD ₃ 0D)

2.41 (s, 3H, NHCH) , 2.72 (dd, J = 4.3Hz, 12Hz, 1H, CH 2 HCH 3), 2.83 (dd, J = 9.2Hz, 12Hz, 1H, CH 0 NHCH.), 3.96 (s , 3H, 0CH ₃ ), 4.18 (s, 3H, ArOCHg), 4.90 (dd, J = 4.3Hz, 9.2Hz, 1H, Ar CH0HCH _o ), 6.93 (d, J = 7.9Hz, 1H, ArH-5 ), 7.12 (d, J = 7.9Hz, 1H, A

 —— L

rH-6) (8) Synthesis of 4-hydroxy-1-7- [1-hydroxy-1-methylamino) ethyl] -1,3-benzothiazo-l-2 (3H) -one (I)

 11- (2,4-Dimethoxy-11,3-benzothiazole-7%)-12- (methylamino) -11-ethanol (23 mg) synthesized in (7) above was suspended in dichloromethane, and triodor was added. A solution of boron chloride in dichloromethane (1.2 ml) was added, and the mixture was stirred at room temperature for 36 hours. After adding sodium bicarbonate to neutralize and concentrate, the resulting concentrate is used as eluent, 10% methanol-90% 20 mM potassium phosphate buffer (pH 7.0), and ODS column (Yemushi Ichisha, It was fractionated by liquid high performance chromatography using SH-343-7). The active fraction was lyophilized, extracted with dichloromethane-methanol (1: 1), and extracted with 4-hydroxy-17- [1-hydroxy-2-methylamino) ethyl] -1,3-benzothiazolulu-2 (3H) —On-phosphate 1.66 mg was obtained.

1 H-NME (D ₂₀ )

2.57 (s, 3H, NHCflg) , 3.09 (dd, J = 4.3Hz, 13Hz, 1H, CHg NHCHg), 3.15 (dd, J = 9.2Hz, 13Hz, 1H, CH 2 NHCH 3), 4.8 (dd, J = 4.3Hz, 9.2Hz, 1H, CHOHNHCH ^), 6.5 (d, J = 8.6Hz, 1H, ArH-5), 6.8 (d, J = 8.6Hz, 1H, ArH-6)

Melting point: approx. 180 ° C (decomposition)

 Pharmacological test example 1 Isolated guinea pig bronchodilator

Guinea pig bronchial specimens were prepared according to the method of Ak ε asu (Akeasu, J. Pharma. Pharmacol, vol. 4, pp671 (1962)). The neck and muscles of the guinea pig were incised along the midline, and the cervical trachea from the lower end of the epiglottis to the chest was removed and immersed in Tyrode-1 HEPES buffer (nutrient solution). A filter paper sufficiently moistened with a nutrient solution was spread in a petri dish, and after removing the loose connective tissue of the outer membrane, a ring having a width of 2 to 3 mm with the cartilage still attached was formed. Open the cartilage opposite the muscle with scissors, it respectively using three adhesive, and ligated to the specimen to each _{other, 37 ° (:, C0 9} 5%, 0 2 It was suspended in a Magnus apparatus under 95% conditions. The lower end of the specimen is fixed, and the upper end is connected to a tension measuring transducer 1 (Nihon Kohden, TB-611T), and the tension (relaxation) is measured using a strain pressure amplifier (Nihon Kohden, AP-621G). Recorded isometrically.

 The compound of Example 2 and the control compound were administered cumulatively from the lower concentration at the concentrations shown in FIG. 3, and a concentration-dependent curve of the tension (relaxation) of the sample with respect to the drug was drawn. The concentration (molar concentration) of the test compound corresponding to 50% tension (relaxation) was determined from the concentration-dependent curve, and the negative logarithm of this value was used as the pD2 value.

The results were as shown in FIG. In guinea pig bronchi, 4-hydro carboxymethyl one 7- [1- (1-hydroxy-one 2- Mechiruamino) Echiru] -1, 3-base Nzochiazo - Lu ₂ 3H) one on, salves evening mall known compound It had an extremely strong bronchodilator effect of about 1800 times and about 4000 times that of isoproterenol.

 Pharmacological test example 2; 82 receptor selectivity test

 The neck and muscle of the guinea pig were incised along the midline, the heart was excised, and the left atrium was excised. As in pharmacological test example 1, the lower end of the specimen was fixed, and the upper end was connected to a tension transducer (Nihon Kohden, TB-611T) for measuring the heart rate. (Nihon Kohden Kogyo, AT-601G). First, the maximum heart rate of isoproterenol was determined and set to 100%. The compound of Example 2 and the control compound were cumulatively administered from a low concentration, and a concentration-dependent curve of the heart rate of the sample with respect to the drug was drawn. The concentration (molar concentration) of the test compound corresponding to 50% enhancement was determined from the concentration-dependent curve, and the negative logarithmic value of this value was used as the pD2 value. In addition, the selectivity of the test drug for the S 2 receptor was determined by the following formula in combination with the results of Pharmacological Test Example 1.

Selectivity-10 (PD 2 for bronchorelaxation—p D 2 for left atrial heart rate enhancement) The results were as shown in Table 1.

4-Hydroxy-7- [1- (1-hydroxy-l-methylamino) ethyl] -l, 3-benzothiazolu-l-2 (3H) -one had a very weak heart rate-enhancing effect.

 In addition, 4-hydroxy-1- 7- [1- (1-hydroxy-1-methylamino) ethyl] -1,3-benzothiazol-12 (3H) -one is about 2000 times that of the known compound Salbu Yumole, formoterol. Approximately 30 times as high as that of the selective yS 2 receptor.

 Pharmacological test example 3 Duration test of isolated guinea pig bronchorelaxation

The duration test of bronchodilator activity in guinea pig bronchi was performed according to the method of Voss et al. (Voss et al., Euro. J. Pharmacol. Vol.227, p403-409 (1992)) _c

 -5 According to the method of pharmacological test example 1, the guinea pig bronchi was suspended in the apparatus. 3X10

Maximum contraction was induced using M-mesacolin, which was defined as a relaxation rate of 0%. Of I匕合compounds and Fuorumoteroru such that 1 X 10- ⁸ M Example 2, so that the salbutamol Contact and isoproterenol a 3 X 10- ⁷ M, and administered to induce maximal relaxation, which Was set to a relaxation rate of 100%. Guinea pig trachea immediately after maximal relaxation is induced The struts were washed with Tyrode-HEPES buffer, and this time was used as the reaction start time to measure shrinkage over time.

 The results were as shown in FIG. The 4-hydroxy-7- [1- (1-hydroxy-12-methylamino) ethyl] —2,3-dihydro-1,3-benzothiazol-2-one of the present invention is compared with the half-life of the activity. It is about 0.58 times that of the known compound isoproterenol, about 0.12 times that of salbutamol, and about 0.09 times that of formoterol, and has a very short action time; it has a 32 receptor stimulating action.

 Pharmacological test example 4 Inhibitory effect of acetylcholine on bronchoconstriction in anesthetized mice (1)

 The airway contraction was measured by measuring the change in airway resistance using an airway resistance measuring device according to the Konzet-Rossler method. Anesthetized by injecting pentobarbitone sodium 10 OmgZkg into the abdominal cavity of the mouse, tracheostomy, intubation of a tracheal forceps made of glass, and a closed animal ventilator (Harvard Apparatus, type 683) The artificial ventilation was performed 60 times a minute with an air volume of 0.6 ml. After the operation was completed, 0.1 mg of pancuronium bromide was injected intravenously to stop spontaneous breathing. The pressure of the air overflowing from the side branch of the tracheal force neura was measured with a pressure transducer (ゥ go << Basil, type 7020), and this was used as an index of the airway contraction response. The compound of Example 2, formoterol and salbutamol were administered intravenously immediately before acetylcholine was administered intravenously.

The results were as shown in FIG. 4-Hydroxy-1 7- [1- (1-Hydroxyl-2-methylamino) ethyl] 1,1,3-benzothiazol-2 (3H) -one had an extremely strong L-bronchodilator effect. Pharmacological test example 5 Degranulation inhibition test from human mast cells

The inhibitory effect on the degranulation reaction from human mast cells was measured. Human mast cells were obtained from human umbilical cord blood by a culture method according to the method of Yanagida et al. (Yanagida et al., Blood, 86, 3705, 1995). Human IgE was added to the cell culture solution to a final concentration of 1 βg / m 1, and cultured for 1 hour or more to sensitize. After washing the cells, they were suspended in a yellow HE PES buffer in the evening, and dispensed to a plate so that 2 × 10 ⁴ Zwe 11 cells were obtained. Further, the compound of Example 2 was added so as to have the final concentration indicated by the concentration, and the cells were cultured for 30 minutes. Next, an anti-human IgE antibody was added to a final concentration of 3 g Zm1, and the mixture was cultured for 30 minutes, and then the culture supernatant was recovered. The degranulation rate was determined using the tryptase activity contained in the supernatant as an index. That is, 100 ^ 1 substrate solution (0.8 mM benzoyl-DL-arginine-p-nitroanilide) was added to 50 wl of the supernatant, the mixture was allowed to stand at 37 ° C, and the absorbance at 405 nm was measured. Was. The cells were disrupted with 0.2% Triton X-100, the supernatant was serially diluted, and the tryptase activity of each dilution was measured to prepare a standard curve. Using the tryptase activity in the supernatant obtained from the cells reacted with the test drug, the degranulation rate was calculated from a standard curve.

 The results were as shown in FIG. 4-Hydroxy-7- [1- (1-Hydroxymethyl 2-methylamino) ethyl] -1,3-benzothiazol-1-2 (3H) -one has an excellent inhibitory effect on human mast cell degranulation. Was.

 Pharmacological test example 6 TNF-α production suppression test from human mast cells

The inhibitory effect on TNF-α production from human mast cells was measured. Human obese cells were obtained from human umbilical cord blood by a culture method according to the method of Yanagida et al. (Yanagida et al., Blood, 86, 3705, 1995). Human IgE was added to the cell culture solution to a final concentration of 1 β / m 1 and cultured for 1 hour or more to sensitize. After washing the cells, resuspend them in the culture medium and dispense them on the plate so that 4 x 10 " Was. Further, the compound of Example 2 was added so as to have the final concentration indicated by the concentration, and the cells were cultured for 30 minutes. Next, an anti-human IgE antibody was added to a final concentration of 3 ^ g / ml, and the cells were cultured for 6 hours. Thereafter, the culture supernatant was recovered. The amount of TNF- in the supernatant was measured by the ELISA method (Biosource, Cytoscreen Immunoassay Kit). The results were as shown in FIG. 4-Hydroxy-7- [1- (1-hydroxy-2-methylamino) ethyl] 1-1,3-benzothiazol-12 (3H) -one has an excellent inhibitory effect on TNF-α production. Was.

The test results of pharmacological test examples 1 to 6 are as shown in Table 2.

Table 2

Test compound

 Pharmacological test

 O

 Example II Compound of Example 2 Formoterol Salbutamol Isoproterenol

 o

 (1) Guinea pig bronchodilator PD2 = 10.77 PD2 = 10.60 PD2 = 7.50 PD2 = 7.17 00

(2) / 92ZSl selectivity (fold) 10471 380 5.25 0.16

 (3) Duration of guinea pig tracheal relaxation 4 (min) 48 (min) 37 (min) 7

 (4) Broncho-relaxing action in mice (in vivo) 2 / g / kg or less 1-: L 0 ^ g / k 10-100 zg / kg male

(ED ₅₀ )

 (5) Inhibition of mast cell degranulation (cultured cells) I C50 = O. 52 (nM) Not performed Not performed Not male

(6) Inhibition of mast cell TNF-α production

Pharmacological test example 7 For suppression of bronchoconstrictive response by acetylcholine in anesthetized mice (2)

 The measurement of airway constriction was performed in the same manner as in Pharmacological Test Example 4. The compound and formoterol synthesized in the same manner as in Example 2 were administered intravenously immediately before the first intravenous administration of acetylcholine. Acetylcholine, which was double-fold diluted, was administered from a low concentration, and a concentration-dependent curve for acetylcholine was drawn to determine the area under the curve.

 The results were as shown in Table 3. 4-Hydroxy-7— [1- (1-Hydroxyl-2-methylamino) ethyl] 1,1,3-Venzothiazol-1 2 (3H) -one has a stronger bronchodilator effect than formoterol Had. Table 3

 *: Ρ <0.05, η: Ρ <0.01 indicates a significant difference from the control group. C Pharmacological Test Example 8 Passive cutaneous anaphylaxis in mice.

The passive skin anaphylaxis of mice and the skin reaction with histamine were performed according to the method of Inagaki et al. (Inagaki et al., Int. Arch. Allergy Appl. Immunol. Vol. 87, p. p254-259 (1988)). Under ether anesthesia, 20 β g / ml of mouse anti-dinitrophenyl monoclonal IgE antibody 101 was injected into the right ear of the mouse. Forty-eight hours later, the mice were again injected with 2 × 10 ⁴ g / m 1 of Hismin 10 10 in the left ear under Ethesore anesthesia. Immediately thereafter, 0.25 ml of physiological saline containing 0.25 mg of dinitrophenylated bovine serum albumin and 1.25 mg of Evans blue dye was intravenously injected to elicit the reaction. After 30 minutes, separate the reaction site, incubate with 1N potassium hydroxide 0.35m1 at 37 ° C, then mix with acetone / phosphoric acid mixture (13: 5) 4.65m1 The dye was extracted by the method described above, and the absorbance at a wavelength of 62 Onm was measured. The compound synthesized in the same manner as in Example 2 and salbutamol were administered intravenously immediately before histamine intradermal injection.

 The results for the ^ ^ response to passive ^ t anaphylaxis and hissumin were as shown in Tables 4 and 5, respectively. 4-Hydroxy-7- [1- (1-Hydroxy-1-methylamino) ethyl] -1,3-benzothiazolu-2 (3H) one is an extremely potent inhibitor of increased vascular permeability compared to the known compound salbutamol. Had an effect.

 Table 4

 Test compound n dose suppression rate

 β / kg (g)

 mean S.E. (%) Control group 6 10.0 Sat 1.4

Compound of Example 2 6 0.3 9.1 ± 0.6 9 Compound of Example 2 6 1 6.2 ± 0.2 tree 38 Compound of Example 2 6 3 4.2 Sat 0.4 58 Suleptamol 6 0.3 10.0 ± 1.3 0 Salbutamol 6 1 12.4 ± 1.0 -24 Salbutamol 6 3 11.2 ± 1.4 -12 *: P <0.05, **: P <0.01 indicates a significant difference from the control group c Table 5

 *: P <0.05 indicates a significant difference from the control group c Pharmacological Test Example 9 Inhibitory effect of passive cutaneous anaphylaxis in rats and skin response by chemical mediator

 The passive skin anaphylaxis of the rat and the skin reaction by the chemical mediator were performed according to the method of Eda et al. (Eda et al., Int. Arch. Allergy Appl. Immunol. Vol. 92,

PP209-216Q990)). Under ether anesthesia, a total of 6 reaction sites were set on the left skin of the shaved rat, with the median line interposed between the left and right 3 sites. The first point is 0.1 ml of physiological saline as a control site for passive anaphylaxis and the second point is 0.1 ml of mouse anti-dinitrophenyl-monoclonal IgE antibody of 20 OngZml. Injection. Forty-eight hours later, again under ether anesthesia, 0.1 ml of saline was added as a control site for skin reactions caused by chemical mediators, and 2 X was added at the fourth point.

1 0 ^u g / 1 of a hiss evening Min 0. lm 1, the fifth point of 5 X 1 0- ⁷ gZm 1 0.1 ml of serotonin and, on the sixth point, 3 × 10 ¹⁷ gZml of platelet activating factor 0.1 lm 1 were injected intradermally. Next, 1 ml of dinitrophenylated bovine serum albumin (DNP-BSA) and 5 ml of Evans blue dye in saline were injected intravenously to elicit the reaction. After 30 minutes, the reaction site is separated, and the mixture is incubated at 37 ° C with 1N potassium hydroxide and lm 1 at 37 ° C, and then mixed with 8.3 ml of an acetate / phosphoric acid mixture (13: 5). The dye was extracted by, and the absorbance at a wavelength of 620 nm was measured. The compound synthesized in the same manner as in Example 2 and sultamol were administered intravenously immediately before the intradermal injection of the chemical mediator.

The results were as shown in Table 6. 4-Hydroxy 7— [1- (1-Hydroxyl-methyl-2-amino) ethyl] -1,3-benzothiazol-2 (3H) -one has a very strong inhibitory effect on vascular hyperpermeability compared to suleptamol Had.

Table 6

CO

*: P <0.05, **: P <0.01 indicates a significant difference from the control group.

Pharmacological test example 10 Inhibitory effect of awake guinea pig on airway contraction by inhalation of ascaris extract

 The airway contraction reaction by inhalation of Ascaris extract was performed according to the method of Inoue et al. (Inoue et al., ASTHMA Vol 4, pp. 74-79 (1991)). Guinea pigs were sensitized by injecting 20 g of Ascaris extract and 20 mg of silica gel intraperitoneally twice at 2-week intervals.

 Inhalation of 0.1% ascaris extract using an ultrasonic nebulizer (OMRON, NE-U07 type) for 1 minute twice a week after the final sensitization at 1-week intervals. Was triggered. In the normal group, physiological saline was inhaled instead of the Ascaris extract. Airway contraction was measured using a respiratory resistance / airway hypersensitivity measurement system for small animals (Chest, Animalast ™ C-210). With the head out, a guinea pig was placed in the body chamber, the oral and nasal passages were covered with a conical mask, connected to an amplifier via a differential pressure transducer, and the respiratory flow was determined. Also, a sine wave of 30 Hz was given to the body surface using a speaker and a generator, and the air pressure inside the body chamber was connected to the amplifier via a differential pressure transducer, and the pressure change inside the chamber was determined. . Respiratory resistance was automatically calculated by computer analysis from the pressure change and the minute airflow change of 30 Hz superimposed on ventilation by using the calculation formula of Hyatt. The compound synthesized in the same manner as in Example 2 and salbutamol were inhaled for 1 minute using a 10-line nebulizer (chest, Animalast ™ C-210) two minutes before inhaling the Ascaris extract. The rate of decrease in respiratory flow after inhalation of Ascaris extract and the rate of increase in respiratory resistance after inhalation of Ascaris extract were determined by the following equations.

Reduction rate of respiratory flow (%) = [(A-B) / A] X 1 0 0

 A: Respiratory flow before inhalation of test compound

 B: Respiratory flow 3 minutes after inhalation of Ascaris extract

Rate of increase in respiratory resistance (%) = [(Β '— A') ΖΑ '] X 1 0 0 A ': Respiratory resistance before inhalation of test compound

Β ': Respiratory resistance 3 minutes after inhalation of Ascaris extract

 The results were as shown in Tables 7 and 8. 4-Hydroxy-7- [1- (1-Hydroxy-1-methylamino) ethyl] -1,3_benzothiazo-l-lu2 (3Η) -one has a stronger bronchodilator effect than Sarpu Even Mall. I was.

 Table Ί

*: P <0.05,: P <0.01 indicates a significant difference from the control group _c Pharmacological test example 1 1 Inhibitory effect of awake guinea pig on airway constriction response by acetylcholine inhalation

 Airway constriction was induced by inhaling 0.5% acetylcholine in normal guinea pigs for 1 minute using a 10-piece nebulizer (Tisto, Amalmarast TMC-2100). The measurement of airway constriction was performed in the same manner as in Pharmacological Test Example 10. Airway constriction with acetylcholine was performed twice at intervals of about 3 hours, and the compound synthesized in the same manner as in Example 2 and salbutamol were used immediately before the second inhalation of acetylcholine.

(Chest, Animalast TMC-2100) for 1 minute. The inhibitory activity of the test compound on the airway constriction response to acetylcholine inhalation was determined by the following formula.

Saccharide inhibitory activity by acetylcholine ¾λ (%) = [(A-B) ZA] x 100 A: Reduction rate of respiratory flow after first inhalation of acetylcholine

B: Decrease in respiratory flow after the second inhalation of acetylcholine

The results were as shown in Table 9. 4-hydroxy-1- 7- [1- (1-Hydrox-l- 2-methylamino) ethyl]-1,3-benzothiazo-l-2 (3H) 1-one has a very strong bronchodilator effect compared to salbutamol. Had.

Four

Table 9

 *: P <0.05 5 **: P <0.01 indicates a significant difference from the control group c

Claims

1. a compound of the following formula (I) or a pharmacologically acceptable salt or solvate thereof:

a

(In the above formula, R ¹ is a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms which may be substituted with one or more halogen atoms, a hydroxyl group, a cyano group, a nitro group, or an amino group, Represents an alkenyl group of 4 or an alkynyl group having 2 to 4 carbon atoms, and R ² and R ³ may be the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group Or represents an alkoxy group having 1 to 4 carbon atoms which may be substituted by one or more halogen atoms, a hydroxyl group, a cyano group, a nitro group or an amino group, and R ⁴ represents a hydrogen atom or one or more halogen atoms A carbon which may be substituted by an atom, a hydroxyl group, a cyano group, a nitro group, or an amino group

Represents a ~ 4 alkyl group, provided that, ^1, R ² and R ⁴ are tables hydrogen atom, when a force, one R ³ represents a hydrogen atom, 4-hydroxyl group or 4 main butoxy group,, R丄Represents a methyl group, R ² and R ⁴ represent a hydrogen atom, and R represents a ^4- monohydroxyl group, and R ¹ represents an n-propyl group, and R, R ³ and R ⁴ represent a hydrogen atom. Unless otherwise indicated).

2. R ¹ force hydrogen atom, or one or more halogen atoms, hydroxyl group, cyano group, Represents an alkyl group having 1 to 4 carbon atoms which may be substituted by a nitro group or an amino group, R ² represents a hydroxyl group, R ³ hydrogen atom, a halogen atom, a hydroxyl group, or one or more halogen atoms Represents an alkoxy group having 1 to 4 carbon atoms which may be substituted by, and R ⁴ represents an alkyl group having 1 to 4 carbon atoms which may be substituted by a hydrogen atom or at least one halogen atom. A compound according to claim 1.

 3. A compound of the following formula (Ia) or a pharmacologically acceptable salt or solvate thereof:

(Represented in the above formula, R ^{1 a} is hydrogen atom or one or more halogen atoms, a hydroxyl group, a Shiano group, a nitro group or a § alkyl group which 1 carbon atoms which may be 1-4 substituted amino group).

4. The compound according to claim 3, wherein R ^1a is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which may be substituted with one or more halogen atoms.

 5. 4-Hydroxy-7- [1- (1-hydroxy-12-methylamino) ethyl] -1,3-benzothiazole-12 (3H) one or a pharmacologically acceptable salt or solvate thereof .

 6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5, or a pharmacologically acceptable salt or solvate thereof.

7. Bronchial asthma, asthmatic bronchitis, emphysema, bronchitis, and acute bronchitis The pharmaceutical composition according to claim 6, which is used for treating a respiratory disease selected from the group consisting of:

8. The pharmaceutical composition according to claim 6, which is used for treating acute bronchial asthma.

9. The pharmaceutical composition according to claim 6, which is in the form of a powder for inhalation.

 10. The medicament according to claim 6, which is used for treatment of an allergic disease selected from allergic asthma, allergic rhinitis, allergic dermatitis, bronchial asthma, rash, pruritus, allergic conjunctivitis, and anaphylaxis. Composition.

 1 1. The pharmaceutical composition according to claim 6, which is used for treating an inflammatory disease selected from bronchitis and acute bronchitis.

 1 2. An airway or bronchodilator comprising the compound according to any one of claims 1 to 5 or a pharmacologically acceptable salt or solvate thereof.

 1 3. Compound of formula (IIIa):

(In the formula, R ^"a and R ^{6 a} may be the same or different, a hydrogen atom, 1 or more substituents on these alkyl groups having 1 to 4 carbon atoms by halogen atom, Asechiru group, triflic O-acetyl, benzoyl, bivaloyl, methoxycarbonyl, benzyl, para-methoxybenzyl, methoxymethyl, t-butyldimethylsilyl, or triisopropylsilyl).

1 4. Compound of formula (V a):

(In the above formula, && 1 to ³ may be the same or different, and may be a hydrogen atom, an alkyl group having 1 to 4 carbon atoms which may be substituted by one or more halogen atoms, an acetyl group, a trifluoromethyl group. O-acetyl, benzoyl, bivaloyl, methoxycarbonyl, benzyl, para-methoxybenzyl, methoxymethyl, t-butyldimethylsilyl, or triisopropylsilyl).

 1 5. Any one of claims 1 to 5 for the manufacture of a medicament for the treatment of a respiratory disease selected from the group consisting of bronchial asthma, asthmatic bronchitis, emphysema, bronchitis, and acute bronchitis. Use of the compound described in the item.

 1 6. For the manufacture of a medicament for the treatment of allergic diseases selected from the group consisting of allergic asthma, allergic rhinitis, allergic dermatitis, bronchial asthma, juniper, pruritus, allergic conjunctivitis, and anaphylaxis Use of the compound according to any one of claims 1 to 5.

 1 7. Use of a compound according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment of an inflammatory disease selected from the group consisting of bronchitis and acute bronchitis.

1 8. comprising administering to a mammal an effective amount of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable carrier. Bronchial asthma, asthmatic bronchitis, lungs ^, bronchitis, and sudden A method for treating a respiratory disease selected from the group consisting of respiratory bronchitis.

 1 9. comprising administering to a mammal an effective amount of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier. A method for treating an allergic disease selected from the group consisting of allergic asthma, allergic rhinitis, allergic ^ inflammation, bronchial asthma, juniper, pruritus, allergic conjunctivitis, and anaphylaxis.

 20. comprising administering to a mammal an effective amount of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier. A method for treating an inflammatory disease selected from the group consisting of bronchitis and acute bronchitis.