WO1999009018A1 - DERIVES DE BENZOTHIAZOLONE PRESENTANT UNE ACTIVITE SELECTIVE D'AGONISTE DU RECEPTEUR β2 - Google Patents

DERIVES DE BENZOTHIAZOLONE PRESENTANT UNE ACTIVITE SELECTIVE D'AGONISTE DU RECEPTEUR β2 Download PDF

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WO1999009018A1
WO1999009018A1 PCT/JP1998/003628 JP9803628W WO9909018A1 WO 1999009018 A1 WO1999009018 A1 WO 1999009018A1 JP 9803628 W JP9803628 W JP 9803628W WO 9909018 A1 WO9909018 A1 WO 9909018A1
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group
hydrogen atom
compound
allergic
bronchitis
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PCT/JP1998/003628
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English (en)
Japanese (ja)
Inventor
Hidefumi Suzuki
Kazutoshi Shindo
Akihiro Ueno
Masao Takei
Hiromi Fukamachi
Tatsuo Higa
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Kirin Beer Kabushiki Kaisha
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2

Definitions

  • 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.
  • 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).
  • a compound having a relatively greater stimulating activity on the 2 receptors present on the airway smooth muscle than on the ⁇ 1 receptor present on the muscle that is, selective yS 2 Receptor stimulants are expected to be effective as excellent bronchodilators with few side effects.
  • 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.
  • seizures acute asthma
  • seizures based on seizure intensity are used.
  • inhalation of short-acting S2 receptor stimulant in Step 1 is appropriate, and inhalation anti-inflammatory drug or oral in Steps 2 to 4)
  • 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.
  • inhalation therapy of j82 receptor stimulants and subcutaneous injection of epinephrine are used as treatment for seizures.
  • 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
  • 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:
  • 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
  • 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
  • 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
  • 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.
  • 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, ⁇ : sultopamol, ⁇ : formoterol, ⁇ : isoproterenol.
  • FIG. 4 shows the duration of the isolated guinea pig bronchodilator action of the compound of the present invention.
  • ⁇ Compound of Example 2
  • ⁇ salbutamol
  • mouth formoterol
  • ⁇ 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)
  • ⁇ compound of Example 2 (10 g / kg)
  • ⁇ 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- ⁇ 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.
  • an alkyl group, an alkenyl group, an alkynyl group, and an alkoxy group can be straight-chain or branched.
  • 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.
  • 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.
  • examples of the alkynyl group having 2 to 4 carbon atoms represented by R 1 include ethynyl, 1-propynyl, and 2-propynyl.
  • 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).
  • substituted alkyl, alkenyl, alkynyl, and alkoxy groups include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and trifluoromethoxy.
  • a halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • 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.
  • 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.
  • 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
  • R 4 represents a hydrogen atom, or 1 or more
  • a compound of the formula (I) representing an alkyl group having 14 carbon atoms which may be substituted by a halogen atom.
  • 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.
  • 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-
  • 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).
  • 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.
  • 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.
  • a suitable adsorbent eg, alumina, silica gel, activated carbon, ion-exchange resin, "Diaion HP20" (manufactured by Mitsubishi Chemical Corporation)
  • gel filtration, high-performance liquid chromatography, or the like may be combined as necessary for the above-mentioned extraction and adsorption operations.
  • 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 ( ⁇ ) 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).
  • 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 ( ⁇ ).
  • R 5 and R 6 represent a hydroxyl-protecting group
  • R 7 is Represents an alkyl group having a prime number of 1 to 4.
  • 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.
  • an acid preferably zinc iodide
  • 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.
  • a suitable solvent for example, ethers such as tetrahydrofuran and dioxane
  • 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).
  • 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).
  • a suitable inert solvent for example, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride.
  • a base for example, pyridine, dimethylaminopyridine, lutidine, etc., preferably lutidine
  • Step (V) is a step of protecting the amino group of the compound represented by the formula (VI).
  • 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,
  • 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).
  • 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).
  • a suitable solvent eg, N, N-dimethylformamide
  • 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.
  • Step (vii) is a step of deprotecting the compound represented by the formula (VIII).
  • a suitable solvent ethers such as tetrahydrofuran and dioxane
  • reaction is preferably performed for 10 minutes to 1 hour to remove the t-butyldimethylsilyl group.
  • 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
  • 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).
  • 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).
  • 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.
  • 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 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.
  • 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.
  • respiratory diseases such as bronchial asthma (eg, acute bronchial asthma, chronic bronchial asthma), asthmatic bronchitis, emphysema, bronchitis, acute bronchitis.
  • respiratory diseases such as bronchial asthma (eg, acute bronchial asthma, chronic bronchial asthma), asthmatic bronchitis, emphysema, bronchitis, acute bronchitis.
  • 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.
  • chemical mediators chemical mediators
  • 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
  • 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- ⁇ from human mast cells.
  • TNF- ⁇ 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.).
  • the compounds according to the present invention suppressed passive cutaneous anaphylaxis and histamine-induced allergic reactions in mice and rats.
  • the compounds according to the present invention are useful for treating allergic diseases and inflammatory diseases.
  • allergic diseases may mean part of inflammatory diseases
  • inflammatory diseases may mean part of allergic diseases.
  • 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.
  • a solvent for example, water, physiological saline, etc.
  • 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.
  • binders for example, starch, polyvinylpyrrolidone, hydroxypropylcellulose, ethylcellulose, carboxymethylcellulose, arabia gum, etc., as disintegrants, for example, magnesium stearate, talc
  • a stabilizer for example, lactose, mannitol, maltose, polysorbates, macrogol, polyoxyethylene castor oil and the like can be used as a stabilizer.
  • glycerin, dimethylacetamide, 70% sodium lactate, surfactants, and basic substances eg, ethylenediamine, ethanolamine, sodium carbonate, arginine, meglumine, trisaminomethane
  • surfactants eg, ethylenediamine, ethanolamine, sodium carbonate, arginine, meglumine, trisaminomethane
  • basic substances eg, ethylenediamine, ethanolamine, sodium carbonate, arginine, meglumine, trisaminomethane
  • the agents of the present invention can be formulated and administered as aqueous solutions or suspensions.
  • 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.
  • 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).
  • 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).
  • 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.
  • treatment is used in a sense including prophylaxis.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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.
  • Guinea pig bronchial specimens were prepared according to the method of Ak ⁇ 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).
  • 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.
  • Example 2 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.
  • 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 neck and muscle of the guinea pig were incised along the midline, the heart was excised, and the left atrium was excised.
  • 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).
  • a tension transducer Nihon Kohden, TB-611T
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ( ⁇ 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.
  • 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 ⁇ g / 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.
  • 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.
  • 100 ⁇ 1 substrate solution 0.8 mM benzoyl-DL-arginine-p-nitroanilide
  • 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.
  • 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 ⁇ / 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.
  • test results of pharmacological test examples 1 to 6 are as shown in Table 2.
  • mice in vivo 2 / g / kg or less 1-: L 0 ⁇ g / k 10-100 zg / kg male
  • 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.
  • 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 ⁇ 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.
  • 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.
  • 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 TM 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
  • Rate of increase in respiratory resistance [( ⁇ '— A') ⁇ '] X 1 0 0 A ': Respiratory resistance before inhalation of test compound
  • 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.
  • Saccharide inhibitory activity by acetylcholine 3 ⁇ 4 ⁇ (%) [(A-B) ZA] x 100

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Abstract

La présente invention concerne des composés stimulant sélectivement un récepteur β2 brièvement présent dans le muscle lisse des voies aériennes. Ces composés sont des dérivés de benzothiazoline représentés par la formule générale suivante (I), l'un de ses sels pharmaceutiquement admis, ou l'un de ses solvates. Les composés représentés par la formule (I) conviennent particulièrement au traitement des affections respiratoires, des affections inflammatoires et des affections allergiques.
PCT/JP1998/003628 1997-08-14 1998-08-14 DERIVES DE BENZOTHIAZOLONE PRESENTANT UNE ACTIVITE SELECTIVE D'AGONISTE DU RECEPTEUR β2 WO1999009018A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005074924A1 (fr) * 2004-02-09 2005-08-18 Novartis Ag Combinaison d'agonistes de l'adrenorecepteur beta2 de la benzothiazol-2-one et de corticosteroides dans le traitement des maladies respiratoires
JP2005539027A (ja) * 2002-08-09 2005-12-22 ノバルティス アクチエンゲゼルシャフト ベータ−２−アドレノレセプターアゴニスト活性を有するベンゾチアゾール誘導体
WO2006056471A1 (fr) 2004-11-29 2006-06-01 Novartis Ag Derives de 5-hydroxy-benzothiazole presentant une activite agoniste de l'adrenorecepteur beta-2
US7345060B2 (en) 2003-11-21 2008-03-18 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US8933108B2 (en) 2011-09-06 2015-01-13 Novartis Ag Benzothiazolone compound

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WO1995025104A1 (fr) * 1994-03-15 1995-09-21 Smithkline Beecham P.L.C. Nouveaux derives heterocycliques d'ethanolamine presentant une activite agoniste du beta-adrenorecepteur
WO1997023470A1 (fr) * 1995-12-23 1997-07-03 Astra Pharmaceuticals Ltd. Ethanamines de benzothiazolone biologiquement actives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995025104A1 (fr) * 1994-03-15 1995-09-21 Smithkline Beecham P.L.C. Nouveaux derives heterocycliques d'ethanolamine presentant une activite agoniste du beta-adrenorecepteur
WO1997023470A1 (fr) * 1995-12-23 1997-07-03 Astra Pharmaceuticals Ltd. Ethanamines de benzothiazolone biologiquement actives

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005539027A (ja) * 2002-08-09 2005-12-22 ノバルティス アクチエンゲゼルシャフト ベータ−２−アドレノレセプターアゴニスト活性を有するベンゾチアゾール誘導体
US7838535B2 (en) 2003-11-21 2010-11-23 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US7842704B2 (en) 2003-11-21 2010-11-30 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US8247564B2 (en) 2003-11-21 2012-08-21 Theravance, Inc. Compounds having BETA2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US7345060B2 (en) 2003-11-21 2008-03-18 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
WO2005074924A1 (fr) * 2004-02-09 2005-08-18 Novartis Ag Combinaison d'agonistes de l'adrenorecepteur beta2 de la benzothiazol-2-one et de corticosteroides dans le traitement des maladies respiratoires
JP2007522141A (ja) * 2004-02-09 2007-08-09 ノバルティス アクチエンゲゼルシャフト 呼吸器疾患の処置のためのベンゾチアゾール−２−オンベータ２アドレナリン受容体アゴニストとコルチコステロイドの組合せ剤
KR100891415B1 (ko) * 2004-11-29 2009-04-02 노파르티스 아게 베타-2-아드레날린 수용체 효능제 활성을 갖는5-히드록시-벤조티아졸 유도체
AU2005308909B2 (en) * 2004-11-29 2009-08-27 Novartis Ag 5-hydroxy-benzothiazole derivatives having beta-2-adrenoreceptor agonist activity
WO2006056471A1 (fr) 2004-11-29 2006-06-01 Novartis Ag Derives de 5-hydroxy-benzothiazole presentant une activite agoniste de l'adrenorecepteur beta-2
JP2008520618A (ja) * 2004-11-29 2008-06-19 ノバルティス アクチエンゲゼルシャフト 有機化合物
US8076489B2 (en) 2004-11-29 2011-12-13 Novartis Ag 5-hydroxy-benzothiazole derivatives having beta-2-adrenoreceptor agonist activity
EP2305659A1 (fr) * 2004-11-29 2011-04-06 Novartis AG Derives de 5-hydroxy-benzothiazole presentant une activite agoniste de l'adrenorecepteur beta-2
CN101065370B (zh) * 2004-11-29 2012-11-14 诺瓦提斯公司 具有β-2-肾上腺素受体激动剂活性的5-羟基-苯并噻唑衍生物
AU2005308909C1 (en) * 2004-11-29 2014-11-27 Novartis Ag 5-hydroxy-benzothiazole derivatives having beta-2-adrenoreceptor agonist activity
JP4648950B2 (ja) * 2004-11-29 2011-03-09 ノバルティス アーゲー 有機化合物
US10251868B2 (en) 2011-09-06 2019-04-09 Novartis Ag Benzothiazolone compound
US8933108B2 (en) 2011-09-06 2015-01-13 Novartis Ag Benzothiazolone compound
US9913828B2 (en) 2011-09-06 2018-03-13 Novartis Ag Benzothiazolone compound

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