JPH0114223B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel compound included in lower alkanoic acid derivatives and a method for producing the same. This invention shows that certain lower alkanoic acid derivatives are very potent inhibitors of aldose reductase (reductase) and are therefore associated with various diabetic complications (e.g., diabetic cataracts, neuropathies, retinopathy). and kidney disease). In this regard, spirohydantoin compounds and 5,6-dihydro-4H-pyrrolo[3,2,1
-ij] Quinoline-1,2-dione is an aldose
It is known to be a reductase inhibitor [US Pat. No. 4,117,230 (1978) and US Pat. No. 4,151,282]
(1979)]. However, the aldose of this invention
Reductase inhibitors are structurally different from these conventional compounds. The purpose of this invention is to provide novel lower alkanoic acid derivatives. Another object of this invention is to provide a novel method for producing lower alkanoic acid derivatives. The compound of this invention is a compound represented by the following general formula (Ia) and a pharmaceutically acceptable salt thereof. [In the formula, R ¹ _a is hydroxy, halogen, nitro,
aryloxy optionally substituted with amino, _C3 - _C8 cycloalkyl, aryl or halogen, ^R2 is hydrogen, halogen or lower alkyl, ^R3 is carboxy or lower alkoxycarbonyl, Y _a is -S-, -O- or -CH ₂ -,
A is lower alkylene. However, when R ² is hydrogen and Y _a is -S- or -O-, R ¹ _a is a group other than halogen] This new compound (Ia) can be produced by the following method. can. Method 1 Method 2 Method 3 Method 4 Method 5 Method 6 [In the formula, R ¹ _a , R ² , R ³ , Y _a and A are each as defined above, R ¹ _b is halogen, R ¹ _c is lower alkoxy, and R ³ _a is protected and X is an acid residue] Among the starting compounds (), the new compound can be produced by the following production methods (A), (B) and (C), and other compounds can also be produced using similar methods. It can be manufactured by a method. Manufacturing method (A) Manufacturing method (B) Manufacturing method (C) [In the formula, R ¹ _a , R ² and Y _a are as defined above, and R ¹ _a is hydroxy, halogen, nitro, C ₃ to _{C 8}
cycloalkyl, aryl, or aryloxy which may be substituted with halogen, R ⁴ is hydrogen or acyl, and X ² and X ³ are each halogen] Next, in the description of this specification, the present invention Definitions of various terms to be included within the scope are detailed. "Lower" means 1 carbon unless otherwise specified.
~6 means. Preferred "lower alkoxy" includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and the like. Preferred "halogens" include fluorine, chlorine,
Mention may be made of bromine or iodine. Suitable "lower alkyls" include methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, and the like. Suitable "lower alkoxycarbonyl" includes methoxycarbonyl, ethoxycarbonyl,
Examples include propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and the like. Suitable "protected carboxy groups" include:
Esterified carboxy groups such as lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.) are mentioned. Suitable "lower alkylene" includes methylene, ethylene, ethylidene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, and the like. Suitable "acid residues" include halogen, azide, and acyloxy (e.g.,
benzenesulfonyloxy, tosyloxy, etc.)
Examples include. Suitable "C ₃ - C ₈ cycloalkyl" includes:
Examples include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Examples of suitable "aryl moieties" in the terms "aryl" and "aryloxy optionally substituted with halogen" include phenyl,
Examples include tolyl, xylyl, naphthyl, etc. Suitable "acyl" includes aliphatic acyl groups and acyl groups containing aromatic or heterocycles. Preferred examples of this acyl include lower alkanoyl (e.g., formyl, acetyl, etc.), lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), lower alkanesulfonyl (e.g.,
mesyl, ethanesulfonyl, etc.), arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.), aroyl (e.g., benzoyl, toluoyl, etc.), phenyl lower alkanoyl (e.g.,
(phenylacetyl, phenylpropionyl, etc.),
Examples include phenoxy lower alkanoyl (eg, phenoxyacetyl, etc.). Pharmaceutically acceptable salts of compounds () and (Ia) include salts with inorganic or organic bases, such as metal salts (e.g., sodium, potassium, magnesium, calcium, etc.), ammonium salts, amine salts. (eg, ethanolamine salt, trimethylamine salt, triethylamine salt, dicyclohexylamine salt, etc.), amino acid salts (eg, arginine salt, etc.), and inorganic or organic acid addition salts (eg, hydrochloride, sulfate, etc.). The details of the preferred method for producing the novel compound (Ia) of the present invention will be explained below. Method 1 The target compound (Ia) or its salt can be produced by reacting the compound () or its salt with the compound () or its salt. Suitable salts of compound () include metal salts and acid addition salts as exemplified for compound (Ia). Suitable salts of compound () include salts with inorganic or organic bases such as those exemplified for compound (Ia). This reaction is typically carried out using, for example, acetone, chloroform, benzene, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide,
The reaction is carried out in any other solvent that does not adversely affect the reaction. This reaction is preferably carried out in the presence of an inorganic or organic base. Suitable bases include alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.),
Alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonates (e.g., sodium carbonate, etc.), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, etc.), alkali metal hydrogen carbonates. (e.g., sodium bicarbonate, potassium bicarbonate, etc.), trialkylamines (e.g., trimethylamine, triethylamine, etc.), pyridine, picoline, diazabicyclo compounds (e.g., 1,5
-Diazabicyclo[4,3,0]nonene-5;
1,5-diazabicyclo[5,4,0]undecene-5; 1,4-diazabicyclo[2,2,2]
octane, etc.), alkali metal acetates (eg, sodium acetate, potassium acetate, etc.), alkali metal lower alkoxides (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.). Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature or under heating. Method 2 Compound (I ² _a ) or a salt thereof can be produced by reducing compound (I ¹ _a ) or a salt thereof. Suitable salts _of compound ( ^1a ) include salts with inorganic or organic bases as exemplified for compound (1a). This reduction can be carried out using, for example, water, methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid,
This reaction is usually carried out in any other solvent that does not adversely affect the reaction. Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature or under heating. Method 3 Compound (I ³ _a ) or a salt thereof can be produced by reacting compound (I ² _a ) or a salt thereof with a diazotizing agent, and then reacting the obtained compound with benzene. Suitable salts for compound (I ² _a ) include those exemplified for compound (Ia). Suitable examples of diazotizing agents include lower alkyl nitrites (e.g., methyl nitrite, ethyl nitrite, propyl nitrite, butyl nitrite, t-butyl nitrite, etc.), alkali metal nitrites (e.g., sodium nitrite), etc.) etc. This diazotization reaction is usually carried out in water or any other solvent that does not adversely affect the reaction. This diazotization reaction is preferably carried out in the presence of a mineral acid such as hydrochloric acid or sulfuric acid. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or at room temperature. The reaction mixture thus obtained can be used as it is in the next reaction step. The following reactions with benzene include inorganic or organic bases, such as alkali or alkaline earth metal hydroxides (e.g., sodium hydroxide), alkali metal acetates (e.g., sodium acetate, etc.)
It is usually carried out in the presence of Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or at room temperature. Method 4 Compound (I ⁴ _a ) or a salt thereof can be produced by reacting compound (I 4 a ) or a salt thereof with a halogenating agent. Suitable salts of compound () include salts with inorganic and organic bases as exemplified for compound (I _a ). Suitable examples of the halogenating agent include chlorine, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-bromophthalimide, and the like. This reaction is usually carried out in methanol, ethanol, chloroform, dioxane, or any other solvent that does not adversely affect the reaction. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating. Method 5 Compound (I ⁶ _a ) or a salt thereof can be produced by subjecting compound (I ⁵ _a ) or a salt thereof to a carboxy-protecting group elimination reaction. Suitable salts of compound (I ⁵ _a ) include acid addition salts such as those exemplified for compound (I _a ). This elimination reaction can be performed using all conventional methods used for the elimination reaction of protected carboxy groups, e.g.
Hydrolysis, reduction, etc. can be applied. When the protecting group is an ester, it can be removed by hydrolysis, reduction, or the use of a Lewis acid, and these methods are appropriately selected depending on the type of carboxy protecting group. Hydrolysis is performed in the presence of a base as exemplified in Method 1 above, or an inorganic or organic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, trifluoroacetic acid, benzenesulfonic acid, P-toluenesulfonic acid, etc.) It is preferable to do this at the bottom. Suitable reduction methods include those exemplified in Method 2 above. Suitable Lewis acids include aluminum trichloride and the like. This elimination reaction is usually carried out in water, methanol, ethanol, acetic acid, or other solvents that do not adversely affect the reaction. Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature or under heating. Method 6 Compound (I ⁷ _a ) or a salt thereof can be produced by subjecting compound (I 7 a ) or a salt thereof to an elimination reaction of the lower alkyl moiety of the lower alkoxy group. Suitable salts of compound () include salts with inorganic or organic bases as exemplified for compound (I _a ). This reaction can be performed using hydrohalic acids (e.g., hydroiodic acid, hydrobromic acid, etc.), Lewis acids (e.g.,
It is preferable to carry out the reaction in the presence of aluminum trichloride (aluminum trichloride, etc.). This reaction is usually carried out in water, acetic anhydride, acetic acid, or other solvents that do not adversely affect the reaction. Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature or under heating. In this reaction, the protected carboxy group may be converted to a free carboxy group during the reaction, and such cases are also included within the scope of the present invention. The method for producing the raw material compounds ( _a ), ( _b ) and ( _c ) of this invention will be described in detail below. Production method A (a) Production of compound () Compound () can be produced by reacting compound (XI) or a salt thereof with compound (). Suitable salts of compound (XI) include acid addition salts (eg, hydrochloride, sulfate, etc.). This reaction is usually carried out in the presence of acetone, methanol, tetrahydrofuran, chloroform, benzene, or other solvents that do not adversely affect the reaction. Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature or under heating. The obtained compound () can be used in the next step without isolation. (b) Production of Compound () Compound () can be produced by subjecting a compound () in which R ⁴ is an acyl group to a deacylation reaction. This deacylation reaction can be carried out by conventional methods such as hydrolysis. This hydrolysis can be carried out in a manner similar to that described in Method 5 above. (c) Production of compound () Compound () or a salt thereof can be produced by reacting compound () with an oxidizing agent. Suitable examples of oxidizing agents include halogens (e.g.
(chlorine, bromine, iodine, etc.), sodium ferricyanide, etc. This reaction is usually carried out in dichloromethane, chloroform, benzene, or other solvents that do not adversely affect the reaction. Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature or under heating. (d) Production of compound () Compound () can be produced by reacting compound () or a salt thereof with a diazotizing agent and then reacting the obtained compound with cupric halide. Suitable salts of compound () include those exemplified for compound (XI). Suitable examples of the diazotizing agent include those exemplified in Method 3 above. Examples of cupric halides include cupric chloride and cupric bromide. This reaction is normally carried out in acetonitrile, benzene, chloroform, or any other solvent that does not adversely affect the reaction. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or at room temperature. (e) Production of compound ( _a ) Compound ( _a ) can be produced by hydrolyzing compound (). This hydrolysis is carried out in the same manner as described in Method 5 above. Production method (B) (a) Production of compound (XII) Compound (XII) or a salt thereof can be produced by reacting compound () or a salt thereof with a polysulfide metal. Suitable salts of compound (XII) and () are the same as those exemplified for compound (XI). Suitable examples of metal polysulfides include alkali metal disulfides (eg, sodium disulfide, potassium disulfide, etc.). This reaction typically involves water, acetone, methanol,
The reaction is carried out in ethanol, methanol water, acetone water, or other solvents that do not adversely affect the reaction. Although the reaction temperature is not particularly limited, the reaction is usually carried out under heating. (b) Production of compound ( _a ) Compound ( _a ) can be produced by reacting compound (XII) or its salt with metal sulfide and then reacting the obtained compound with phosgene. First step In this case, compound (XII) or a salt thereof is reacted with a metal sulfide. Suitable examples of the metal sulfide include alkali metal sulfides (e.g., sodium sulfide, potassium sulfide, etc.). This reaction is usually carried out in water, methanol, ethanol,
The reaction is carried out in acetone, methanol water, acetone water, or other solvents that do not adversely affect the reaction. Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature or under heating. The obtained compound can be used in the next step without isolation. In the second step, the generated compound is reacted with phosgene to generate the compound ( _a ). This reaction usually involves water, acetone, methanol,
The reaction is carried out in ethanol, toluene, or other solvents that do not adversely affect the reaction. This reaction is preferably carried out in the presence of an inorganic or organic base as exemplified in Method 1 above. Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature or under cooling. Production method C (a) Production of compound ( _b ) Compound ( _b ) can be produced by reacting compound (XI) with a nitrating agent. Suitable examples of nitrating agents include nitric acid, fuming nitric acid,
Examples include a mixture of nitric acid and concentrated sulfuric acid. This reaction can be carried out in the presence or absence of water or other solvents that do not adversely affect the reaction. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or at room temperature. (b) Production of compound ( _c ) Compound ( _c ) or a salt thereof can be produced by reducing compound ( _b ). Suitable salts of compound ( _c ) are the same as those exemplified for compound (XI). This reduction is carried out in substantially the same manner as described in Method 2 above. Compound (I _a ) of this invention and its pharmaceutically acceptable salts are very potent aldose reductase inhibitors. This will be explained using the following test example. Test example (inhibitory effect on rabbit lens aldose reductase) () Test compound (1) 2-oxo-5-chloro-6-phenoxy-
3-benzothiazolineacetic acid (2) 2-oxo-5-chloro-6-phenyl-3
-Benzothiazolineacetic acid (3) 2-oxo-6-phenoxy-3-benzothiazolineacetic acid (4) 2-oxo-6-(2-chlorophenoxy)
-3-benzothiazolineacetic acid (5) 2-oxo-6-phenyl-7-chloro-3
-Benzothiazolineacetic acid (6) 2-oxo-5-chloro-6-cyclohexyl-3-benzothiazolineacetic acid (7) 2-oxo-5-chloro-6-phenyl-3
-Benzoxazolineacetic acid (8) 2-oxo-5-chloro-6-bromo-3-
Benzothiazolineacetic acid (9) 2-oxo-6-chloro-1-indolineacetic acid (10) 2-oxo-5-chloro-3-benzothiazolineacetic acid (11) 2-oxo-5-chloro-3-benzoxazolineacetic acid (12) 2-oxo-6-chloro-3-benzothiazolineacetic acid (13) 2-oxo-5-methyl-6-phenyl-
3-Benzothiazolineacetic acid (14) 2-oxo-5,6-dichloro-3-benzothiazolineacetic acid (15) 2-oxo-5-chloro-6-nitro-3
-Benzothiazolineacetic acid (16) 2-oxo-5-chloro-6-amino-3
-Benzothiazolineacetic acid () Test method: Journal of Biological Chemistry (J.Bio.Chem.) except that the enzyme prepared from rabbit lens was used instead of aldose reductase prepared from calf lens. ) No. 240
The inhibitory effect (%) of the test compound at various concentrations was determined by a method substantially similar to that described in Vol. 877 (1965). The 50% inhibitory concentration (IC ₅₀ ) of each sample was calculated from the thus obtained data on the inhibitory effect using a graph. () Test results The test results are shown in the table below.

[Table] For the prevention and treatment of diabetic complications in mammals, compound (I _a ) or a pharmaceutically acceptable salt thereof can be mixed with a pharmaceutically acceptable carrier,
It can be administered in the form of a pharmaceutical composition. The pharmaceutical composition of this invention includes capsules, tablets, granules,
It can be formulated into dosage forms such as powders, injections, and ophthalmic preparations (eg, eye drops, ointments). Pharmaceutically acceptable carriers include a variety of organic or inorganic carrier materials commonly used in pharmaceutical applications, including excipients such as sucrose, starch, mannitrate, sorbitol, lactose,
glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.), binders (e.g., cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, starch, etc.), disintegrants (e.g., starch, carboxymethylcellulose, calcium salts of carboxymethylcellulose, hydroxypropyl starch, sodium glycol-starch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), lubricants (such as magnesium stearate, aerosil, talc, sodium lauryl sulfate, etc.), Flavoring agents (e.g. citric acid, menthol, ammonium salt of glycyrrhizin, glycine, orange powder, etc.), preservatives (e.g. sodium benzoate, sodium bisulfite,
methylparaben, propylparaben, etc.), stabilizers (e.g., citric acid, sodium citrate, acetic acid, etc.), suspending agents (e.g., methylcellulose,
polyvinylpyrrolidone, aluminum stearate, etc.), dispersants [e.g. polysorbate 80,
Emulgen 408, Emazol (both are surfactants)], aqueous diluents (e.g. water), wax bases (e.g. cocoa butter, polyethylene glycol,
Uitepsol, white petrolatum, etc.). The dosage of the active compound in the pharmaceutical compositions of this invention will vary depending on various factors such as the condition, weight and/or age of the patient, as well as the route of administration, but the dose of compound (I _a ) or the pharmaceutically acceptable The preferred dosage of the salt is usually about 0.1-100 mg/
It is selected from within the range of Kg/day, but is not limited thereto. Next, the present invention will be explained with reference to manufacturing examples and examples. Production Example 1 (a) Benzoyl chloride (47.6 g) was added dropwise to a solution of ammonium thiocyanate (30.2 g) in anhydrous acetone (660 ml) with stirring at 50°C. After refluxing for 1.5 hours, the mixture was cooled to room temperature. A solution of 2-phenoxyaniline (47.6 g) in anhydrous acetone (300 ml) was added dropwise to this mixture containing benzoyl isothiocyanate. While stirring the reaction mixture
After refluxing for 1.5 hours, the mixture is concentrated under reduced pressure to precipitate crystals. This was taken, washed twice with water, and then dried to obtain crystalline 1-(2-phenoxyphenyl)-3-benzoylthiourea. (b) 1-(2-phenoxyphenyl) obtained above
3-benzoylthiourea was dissolved in a mixture of 10% aqueous sodium hydroxide (660 ml) and methanol (530 ml) at 50°C. reaction mixture 50
After stirring at ℃ for 30 minutes, it was cooled on ice to precipitate crystals, which were separated, washed with water, dried, and 1-
(2-phenoxyphenyl)thiourea was obtained. Melting point 120-124℃. Production Example 2 The following compounds were produced in substantially the same manner as in Production Examples 1(a) and (b), respectively. (1) (a) 1-(4-phenoxyphenyl)-3-
Benzoylthiourea, melting point 123-126℃ (b) 1-(4-phenoxyphenyl)thiourea, melting point 180-184℃ (2) (a) 1-(3-chloro-4-phenoxyphenyl) -3-benzoylthiourea (b) 1-(3-chloro-4-phenoxyphenyl)thiourea, melting point 116-120℃ (3) (a) 1-[4-(2-chlorophenoxy)phenyl ]-3-benzoylthiourea, melting point
116-119℃ (b) 1-[4-(2-chlorophenoxy)phenyl]thiourea, melting point 131-132℃ (4) (a) 1-(2-chloro-4-biphenylyl)
-3-benzoylthiourea, melting point 123-125℃ (b) 1-(2-chloro-4-biphenylyl)thiourea, melting point 155-158℃ Production example 3 1-(2-phenoxyphenyl)thiourea ( A solution of bromine (35.0 g) in chloroform (50 ml) was added dropwise to a mixture of bromine (53.4 g) and chloroform (100 ml) over 40 minutes while stirring under ice cooling. After heating at reflux for 1 hour and 40 minutes, the mixture was cooled to room temperature. Water was added to the resulting mixture and then the mixture was made alkaline with 5% aqueous sodium hydroxide solution. The chloroform layer was separated, washed with water, dried over magnesium sulfate, concentrated under reduced pressure to obtain crystals, which were recrystallized twice from isopropyl alcohol to give 2-amino-4-phenoxybenzo Thiazole (25.8g) was obtained. Melting point 135-137℃. Production Example 4 The following compound was produced in substantially the same manner as Production Example 3. (1) 2-amino-6-phenoxybenzothiazole, melting point 167-169℃ (2) 2-amino-5-chloro-6-phenoxybenzothiazole (3) 2-amino-6-(2- chlorophenoxy)
Benzothiazole, melting point 161-167℃ Production Example 5 (a) To a solution of 1-(2-chloro-4-biphenylyl)thiourea (5.3 g) in chloroform (150 ml), add bromine (3.2 g) in chloroform ( 10 ml) solution was added dropwise over 15 minutes while stirring at room temperature. After continued stirring at room temperature for 30 minutes, the reaction mixture was heated under reflux for 5 hours and 15 minutes, then cooled to room temperature to precipitate crystals, which were separated.
Sodium bisulfite and an aqueous sodium hydroxide solution were added to the crystals, the mixture was extracted with ethyl acetate, the extract was washed with water, dried over magnesium sulfate, concentrated under reduced pressure, and 2-amino-5-chloro-6- A mixture (4.1 g) of phenylbenzothiazole and 2-amino-6-phenyl-7-chlorobenzothiazole was obtained. (b) To a mixture of anhydrous cupric bromide (4.2 g) and anhydrous acetonitrile (80 ml), t-butyl nitrite (2.6 g) was added dropwise with stirring under ice cooling. A mixture (4.1 g) of 2-amino-5-chloro-6-phenylbenzothiazole and 2-amino-6-phenyl-7-chlorobenzothiazole was added to this mixture for 10 minutes while stirring under ice cooling. dripped. After stirring for 1 hour and 40 minutes under ice cooling, the reaction mixture was concentrated under reduced pressure, and dilute hydrochloric acid was added to the resulting residue. This mixture was extracted with chloroform. The organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give an oily residue. This was chromatographed on silica gel using a benzene-hexane mixture (1:2) as an eluent to obtain a first fraction (A) and a second fraction (B). Fraction (A) yielded crystalline 2-bromo-5-chloro-6-phenylbenzothiazole (1.0 g).
was gotten. Melting point 105-108℃. NMR δppm (DMSO―d ₆ ): 7.53 (5H, S),
8.25 (1H, S), 8.28 (1H, S). In addition, from fraction (B), crystalline 2-bromo-6-
Phenyl-7-chlorobenzothiazole (1.5g)
was gotten. Melting point 105-109℃. NMR δppm (DMSO-d ₆ ): 7.57 (5H, S),
7.67 and 8.08 (2H, ABg, J=9Hz). Production Example 6 To a mixture of anhydrous cupric bromide (22.1 g) and anhydrous acetonitrile (320 ml), t-butyl nitrite (12.8 g) was added dropwise while stirring under ice cooling. Add 2-amino-4-phenoxybenzothiazole (20.0g) to this mixture while stirring under ice-cooling.
Added over 25 minutes. After stirring under ice cooling for 1.5 hours, acetonitrile was removed from the resulting mixture under reduced pressure, and the resulting residue was dissolved in a small amount of diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated in vacuo to give an oily residue. This was chromatographed on silica gel using a benzene/n-hexane mixture (1:1) as eluent. Fractions containing the target compound are collected and crystallized to obtain 2-bromo-
4-Phenoxybenzothiazole (9.9g) was obtained. Melting point 117-121℃. Production Example 7 The following compound was produced in substantially the same manner as Production Example 6. (1) 2-bromo-6-phenoxybenzothiazole; Oil IR (liquid film): 1605, 1590, 1560 cm ^-1 (2) 2-bromo-5-chloro-6-phenoxybenzothiazole, melting point 153-154℃ (3) 2-bromo-6-(2-chlorophenoxy)
Benzothiazole; Oil IR (liquid film): 1600, 1580, 1560 cm ^-1 Production example 8 Add 2-bromo-4-phenoxy to a sodium ethoxide solution prepared from metallic sodium (460 mg) and absolute ethanol (50 ml). Benzothiazole (3.0g) was added. The mixture was refluxed for 45 minutes with stirring. After removing the solvent under reduced pressure,
10% hydrochloric acid (30 ml) and acetone (50 ml) were added to the residue. The resulting mixture was refluxed for 2 hours with stirring. The solvent was removed under reduced pressure and the resulting residue was recrystallized from a mixture of ethanol and n-hexane to obtain crystalline 2-oxo-4-phenoxybenzothiazoline (2.0 g). Melting point 153-155℃. Production Example 9 The following compound was produced in substantially the same manner as Production Example 8. (1) 2-oxo-6-phenoxybenzothiazoline, melting point 140-145℃ (2) 2-oxo-5-chloro-6-phenoxybenzothiazoline, melting point 237-241℃ (3) 2-oxo -6-(2-chlorophenoxy)
Benzothiazoline, melting point 132-133°C (4) 2-oxo-5-chloro-6-phenylbenzothiazoline, melting point 245-259°C (5) 2-oxo-6-phenyl-7-chlorobenzothiazoline, melting point 256 -257℃ Production Example 10 A mixture of sodium sulfide nonahydrate (14.7g) and sulfur (1.76g) in water (50ml) was heated to 60℃.
The mixture was stirred for 1 hour. The obtained sodium disulfide aqueous solution was added dropwise to a solution of 3-nitro-4-chlorodiphenyl ether (24.9 g) in acetone (50 ml) over 30 minutes while stirring at 60°C. The reaction mixture was refluxed for 45 minutes with stirring and then cooled to room temperature. The acetone was removed under reduced pressure, and the precipitated crystals were separated and washed with a small amount of acetone to obtain yellowish crystalline bis(2-nitro-4-phenoxyphenyl) disulfide (13.2 g). Obtained. melting point
118-121℃. Production Example 11 (a) Anhydrous aluminum chloride (16.0 g) was added to a solution of 1,4-dichlorobenzene (294 g) in anhydrous carbon disulfide (400 ml). Chlorocyclohexane (96 g) was added dropwise to this mixture over 3 hours while stirring at room temperature. After continued stirring at room temperature for 3 hours, the reaction mixture was left at room temperature overnight. Dilute hydrochloric acid was added to the reaction mixture with stirring. The organic layer was separated, washed with water, dried over magnesium sulfate, concentrated under reduced pressure and left at room temperature for a while to form a precipitate. This precipitate was removed. The liquid was distilled under reduced pressure to obtain 1,4-dichloro-2-cyclohexylbenzene (47.0 g). boiling point
138℃/5mmHg. (b) A mixture of nitric acid (d=1.42, 4 ml) and concentrated sulfuric acid (6 ml) was stirred in a solution of 1,4-dichloro-2-cyclohexylbenzene (12.0 g) in concentrated sulfuric acid (15 ml) under ice cooling. It dripped. Stir 10
After continuing for a minute, ice water was added to the reaction mixture to produce an oily residue, which was extracted with ether and
The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained oily residue was distilled under reduced pressure to obtain 1,4-dichloro-2-cyclohexyl-5-nitrobenzene (10.0 g).
Boiling point 170℃/2mmHg (c) 1,4-dichloro-2-cyclohexyl-5
- Bis(2-nitro-4-chloro-5-cyclohexylphenyl) disulfide was produced from nitrobenzene in substantially the same manner as in Production Example 10. Melting point 183-184℃. Production example 12 Bis(2-nitro-4-phenoxyphenyl)
A mixture of disulfide (13.2 g) and sodium sulfide nonahydrate (36.7 g) in water was refluxed with stirring for 3 hours and then cooled to room temperature. A 10% aqueous sodium hydroxide solution (50 ml) was added to the resulting mixture. Phosgene was passed through the reaction mixture with stirring under ice cooling until it was neutralized. The resulting mixture was acidified with hydrochloric acid, extracted with ethyl acetate, washed with water, dried over magnesium sulfide and concentrated under reduced pressure to give a residue using benzene and a mixture of benzene and ethyl acetate (10:1) as eluent. Chromatographed on silica gel. The fraction containing the target compound was concentrated under reduced pressure to obtain crystals, which were recrystallized from a mixture of benzene and n-hexane to obtain crystalline 2-oxo-5-phenoxybenzothiazoline (4.0 g). I got it. Melting point 145-150℃. Production Example 13 The following compound was produced in substantially the same manner as Production Example 12. (1) 2-oxo-5-chloro-6-cyclohexylbenzothiazoline, melting point 230-231℃ Production example 14 Add nitric acid ( d = 1.42, 275 g) in concentrated sulfuric acid (500 ml).
The mixture was added dropwise over 1 hour while stirring at °C. After stirring for 1 hour under ice-cooling, the reaction mixture was poured with ice water (10
) to precipitate crystals, which were separated, washed with water, and dried to give 2-oxo-5-chloro-6-
Nitrobenzothiazoline (539g) was obtained. melting point
235℃ (decomposition). Production Example 15 The following compound was produced in substantially the same manner as Production Example 14. (1) 2-oxo-5-chloro-6-nitrobenzoxazoline, melting point 196-203℃ (2) 2-oxo-5-nitro-6-chloroindoline, crystalline IR (Nudiyol): 1710, 1620, 1520, 1340,
1330cm ^- NMR (DMSO-d ₆ ) δ (ppm): 3.55 (2H, S),
6.95 (1H, S), 7.93 (1H, S) (3) 2-oxo-5-methyl-6-nitrobenzothiazoline, melting point > 250°C Production example 16 Chloride in a mixture of ethanol (200 ml) and water (40 ml) Ammonium (2.2g) and metallic iron (19.7g)
added. 2-oxo-5-nitro-6-chloroindoline (12.5 g) was added to this mixture at 60°C. After refluxing for 45 minutes, the reaction mixture was filtered under warm conditions. The slag was washed with ethanol. The liquid and washing liquid were combined and evaporated to dryness under reduced pressure to give 2-oxo-5-amino-6-chloroindoline (10.0
g) was obtained. Example 1 A mixture of 2-oxo-4-phenoxybenzothiazoline (2.0 g), ethyl bromoacetate (1.7 g) and potassium carbonate (1.4 g) in acetone (30 ml) was refluxed with stirring for 1 hour. . The resulting mixture was filtered, the liquid was concentrated under reduced pressure, and the residue was recrystallized from a mixture of ethanol and n-hexane to obtain crystalline 2-oxo-4-phenoxy-3-
Ethyl benzothiazoline acetate (2.0 g) was obtained.
Melting point 96-99℃. Example 2 The following compound was produced in substantially the same manner as in Example 1. (1) Ethyl 2-oxo-5-phenoxy-3-benzothiazoline acetate, melting point 120-122℃ (2) Ethyl 2-oxo-6-phenoxy-3-benzothiazoline acetate, melting point 79-81℃ (3) 2 -Oxo-5-chloro-6-phenoxy-
3-Benzothiazoline ethyl acetate, melting point 109-
111℃ (4) 2-oxo-6-(2-chlorophenoxy)
-3-Benzothiazoline ethyl acetate, oil (5) 2-oxo-5-chloro-6-phenyl-3
-Benzothiazoline ethyl acetate, melting point 130-131
℃ (6) 2-oxo-6-phenyl-7-chloro-3
-Benzothiazoline ethyl acetate, melting point 147-148
°C (7) Methyl 2-oxo-5-chloro-6-cyclohexyl-3-benzothiazoline acetate, melting point
133-134℃ (8) 2-oxo-6-chloro-1-indoline ethyl acetate, melting point 135-136℃ (9) 2-oxo-5-chloro-6-nitro-3-
Benzothiazoline ethyl acetate, melting point 170-171℃ (10) 2-oxo-5-chloro-6-nitro-3-
Benzoxazoline ethyl acetate, melting point 126.5-
128℃ (11) Ethyl 2-(2-oxo-5-chloro-6-nitro-3-benzothiazoline)propionate, melting point 112-114℃ (12) 2-oxo-5-methyl-6-nitro-3 ―
Benzothiazoline ethyl acetate, melting point 159-160℃ (13) 2-oxo-6,7-dichloro-3-benzothiazoline methyl acetate, melting point 158-159℃ (14) 2-oxo-4,7-dichloro-3- Methyl benzothiazoline acetate, melting point 104-106°C (15) 2-oxo-4,5-dichloro-3-benzothiazoline methyl acetate, melting point 136-138°C (16) 2-oxo-5-fluoro-6-chloro-
3-Benzothiazoline ethyl acetate, melting point 111-
113°C Example 3 A mixture of 2-oxo-5-chloro-6-amino-3-benzothiazoline ethyl acetate (347.8 g) and concentrated hydrochloric acid (1040 ml) was stirred at room temperature for 30 minutes.
After the resulting mixture was cooled to 2°C, a solution of sodium nitrite (88.3 g) in water (120 ml) was added dropwise thereto over 40 minutes at a temperature lower than 5°C. Mixture at 0℃
After stirring for 20 minutes, this mixture was treated with benzene (5.2
) was added dropwise over 30 minutes. After stirring the reaction mixture for 1 hour and 40 minutes under ice-cooling, a solution of sodium acetate trihydrate (1.56Kg) in water (3.6) was added to the reaction mixture for 1 hour and 40 minutes under ice-cooling.
It dripped over time. This mixture was stirred at room temperature overnight. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue was recrystallized from ethanol to give 2-oxo-5-
Ethyl chloro-6-phenyl-3-benzothiazoline acetate (311.5 g) was obtained. Melting point: 130-131°C Example 4 The following compound was produced in substantially the same manner as in Example 3. (1) 2-oxo-5-chloro-6-phenyl-3
-Benzoxazoline ethyl acetate, melting point 99-
101℃ (2) Ethyl 2-(2-oxo-5-chloro-6-phenyl-3-benzothiazoline)propionate, oil IR (liquid film): 1740, 1680cm ^-1 NMR (DMSO-d ₆ ) δ (ppm): 1.13 (3H, t,
J = 7Hz), 1.58 (3H, d, J = 6Hz),
4.13 (2H, q, J = 7Hz), 5.45 (1H, q,
J=6Hz), 7.2-7.7 (7H, m) (3) 2-oxo-5-phenyl-6-chloro-1
-Indoline ethyl acetate, melting point 132-133℃ (4) 2-oxo-5-methyl-6-phenyl-3
-Benzothiazoline ethyl acetate, melting point 138-141
°C Example 5 2-oxo-5-chloro-6-phenoxy-3
-To a solution of benzothiazoline ethyl acetate (2.5 g) in methanol (100 ml), add sodium hydroxide (360
mg) in water (10 ml) was added. The reaction mixture was heated to 50°C for 15 minutes, concentrated under reduced pressure, and the resulting residue was acidified with dilute hydrochloric acid to obtain crystals, which were washed with water, dried, and recrystallized from ethanol water. -Oxo-5-chloro-6-phenoxy-
3-Benzothiazolineacetic acid (2.2g) was obtained. Melting point 190-194℃. Example 6 2-oxo-5-chloro-6-phenyl-3-
A solution of sodium hydroxide (40.3 g) in water (540 ml) was added dropwise to a solution of benzothiazoline ethyl acetate (269.6 g) in ethanol (5.4 g) at 50° C. over 5 minutes. After stirring at 50 °C for 15 minutes, the mixture was cooled to room temperature to precipitate crystals, which were separated.
After washing with ethanol and acetone, the crystalline 2-
Oxo-5-chloro-6-phenyl-3-benzothiazoline acetic acid sodium salt (217.3 g) was obtained.
The crystals were dissolved in water and acidified with dilute hydrochloric acid to obtain crude crystals, which were recrystallized from ethanol water to give crystalline 2-oxo-5-chloro-6-phenyl-3-benzothiazolineacetic acid ( 131.9g) was obtained. Melting point: 262-266°C Example 7 The following compound was produced in substantially the same manner as in Examples 5 and 6. (1) 2-oxo-4-phenoxy-3-benzothiazolineacetic acid, melting point 148-151℃ (2) 2-oxo-5-phenoxy-3-benzothiazolineacetic acid, melting point 179-181℃ (3) 2-oxo -6-phenoxy-3-benzothiazolineacetic acid, melting point 150-152℃ (4) 2-oxo-6-(2-chlorophenoxy)
-3-Benzothiazolineacetic acid, melting point 162-164℃ (5) 2-oxo-6-phenyl-7-chloro-3
-Benzothiazolineacetic acid, melting point 254-257℃ (6) 2-oxo-5-chloro-6-cyclohexyl-3-benzothiazolineacetic acid, melting point 222-226
℃ (7) 2-(2-oxo-5-chloro-6-phenyl-3-benzothiazoline)propionic acid, melting point 202-203℃ (8) 2-oxo-5-methyl-6-phenyl-3
-Benzothiazolineacetic acid, melting point 245-250℃ (9) 2-oxo-6-chloro-1-indolineacetic acid, melting point 215℃ (decomposed) (10) 2-oxo-5-chloro-6-amino-3-
Benzothiazolineacetic acid, melting point 246-249℃ (11) 2-oxo-6,7-dichloro-3-benzothiazolineacetic acid, melting point 244-246℃ (12) 2-oxo-4,7-dichloro-3-benzothiazoline Acetic acid, melting point 259-261℃ (13) 2-oxo-4,5-dichloro-3-benzothiazolineacetic acid, melting point 223-225℃ (14) 2-oxo-5-fluoro-6-chloro-
3-benzothiazolineacetic acid, melting point 251-255°C Example 8 2-oxo-5-chloro-6-phenyl-3-
Concentrated hydrochloric acid (5 ml) was added to a solution of benzoxazoline ethyl acetate (1.5 g) in acetic acid (10 ml). The reaction mixture was stirred at 60°C for 1.5 hours and then cooled to room temperature. The resulting mixture was diluted with water to precipitate crystals, which were separated, washed with water, dried, and recrystallized from a mixture of chloroform and acetone to give 2-oxo-5-chloro-6-phenyl-3. - Benzoxazoline acetic acid was obtained. Melting point 200-203℃. Example 9 The following compound was produced in substantially the same manner as in Example 8. (1) 2-oxo-5-phenyl-6-chloro-1
-Indolineacetic acid, melting point 260-262℃ (2) 2-oxo-5-chloro-6-nitro-3-
Benzothiazolineacetic acid, melting point 240-243°C (decomposition) Example 10 57% hydroiodic acid (50ml) and acetic anhydride (15ml)
2-oxo-5-methoxy-3-
A solution of benzothiazoline ethyl acetate (2.67 g) in acetic acid (15 ml) was added. The reaction mixture was refluxed for 1.5 hours with stirring and then cooled to room temperature. Ice water and a small amount of sodium bisulfite were added to the resulting mixture. The mixture was extracted with ethyl acetate, the extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain crystalline 2-oxo-5-hydroxy-
3-Benzothiazolineacetic acid (1.7g) was obtained. Melting point 217-221℃. Example 11 Bromine (2 ml) was added to a solution of 2-oxo-5-chloro-3-benzothiazoline methyl acetate (10 g) in dioxane (100 ml) at 25-30°C with stirring for 40 minutes.
It was added dropwise over a period of minutes. After continued stirring at room temperature for 4 hours, the precipitate in the resulting mixture was separated, washed with dioxane and diethyl ether, and dried to give crystalline 2-oxo-5-chloro-6-bromo-3-
Methyl benzothiazoline acetate (8.38 g) was obtained.
Melting point 209-210℃. (b) 2-oxo-5-chloro-6-bromo-3-
A mixture of methyl benzothiazoline acetate (2.0 g), methanol (250 ml) and 10% aqueous sodium hydroxide solution (2.5 ml) was stirred.
After refluxing for 1.5 hours, the mixture was cooled with ice water to precipitate crystals, which were separated. The liquid was concentrated under reduced pressure to obtain further crystals. Both crystals were combined and dissolved in water (80 ml) under heating to remove insoluble matter. Adjust the solution to PH2-3 with 10% hydrochloric acid,
Crystals were precipitated by cooling, separated, washed with water, and dried to obtain crystalline 2-oxo-5-chloro-6-bromo-3-benzothiazolineacetic acid (1.5 g). Melting point 249-252℃. Example 12 The following compounds were produced in substantially the same manner as in Examples 11(a) and (b). (a) Ethyl 2-oxo-5,6-dichloro-3-benzothiazoline acetate, melting point 147-149℃ (b) 2-oxo-5,6-dichloro-3-benzothiazolineacetic acid, melting point 256-258℃ Conducted Example 13 Ammonium chloride (25g) and iron (300g) were added to a mixture of ethanol (10) and water (1).
Add ethyl 2-oxo-5-chloro-6-nitro-3-benzothiazoline acetate (436.6 g) to this mixture.
was added under mild reflux. After refluxing for 4 hours with stirring, the resulting mixture was filtered warm.
The slag was washed with ethanol. The liquid and washing liquid were combined, concentrated under reduced pressure, cooled to room temperature to precipitate crystals, separated, and 2-oxo-5-chloro-
Ethyl 6-amino-3-benzothiazoline acetate (347.8 g) was obtained. Melting point 154-160℃. Example 14 The following compound was produced in substantially the same manner as in Example 13. (1) 2-oxo-5-chloro-6-amino-3-
Benzoxazoline ethyl acetate, melting point 137-141
℃ (2) Ethyl 2-(2-oxo-5-chloro-6-amino-3-benzothiazoline)propionate, melting point 105-106℃ (3) 2-oxo-5-methyl-6-amino-3-
Benzothiazoline ethyl acetate, melting point 140-142°C Example 15 Ethyl chloroacetate ( 3.2 g) was added dropwise at room temperature. The reaction mixture was refluxed for 4 hours with stirring and then filtered while heating. The slag was washed with acetone. The liquid and washing liquid were combined and concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel to obtain crystalline 2-oxo-5-amino-6-chloro-1.
-Ethyl indoline acetate (0.9g) was obtained. IR (Nujiyor): 3440, 3330, 3220, 1750,
1690, 1590cm ^-1 NMR (CDCl ₃ ) δppm: 6.64 (1H, S), 6.55 (1H,
S), 4.34 (2H, S), 4.19 (2H, q, J=
7Hz), 3.44 (2H, S), 1.27 (3H, t, J
=7Hz) Example 16 2-oxo-5-chloro-6-phenyl-3-
Benzothiazolineacetic acid 500g Starch 1987g Magnesium stearate 13g The above ingredients were mixed in a conventional manner and filled into 10,000 hard gelatin capsules, each containing the active ingredient 2-oxo-5-chloro-6-phenyl-3-benzothiazolineacetic acid. You will get 10.000 capsules containing 50 mg each. Example 17 2-oxo-5-chloro-3-benzothiazolineacetic acid 250g Starch 1980g Magnesium stearate 20g The above ingredients were mixed in a conventional manner and filled into 10,000 hard gelatin capsules to obtain the active ingredient 2-oxo-5. 10,000 capsules each containing 25 mg of -chloro-3-benzothiazolineacetic acid are obtained. Example 18 2-oxo-5-chloro-3-benzoxazolineacetic acid 20000g Lactose 10400g Starch 3600g Ethyl cellulose 1800g Magnesium stearate 200g The above ingredients were mixed in a conventional manner, and each tablet contained the active ingredient 2-oxo-5-chloro- 360 mg tablets containing 200 mg of 3-benzoxazoline acetic acid 100,000
tablet. The obtained tablets may be sugar coated if desired.
Cover with film coating or enteric coating.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ _a is hydroxy, halogen, nitro,
aryloxy optionally substituted with amino, _C3 - _C8 cycloalkyl, aryl or halogen, ^R2 is hydrogen, halogen or lower alkyl, ^R3 is carboxy or lower alkoxycarbonyl, Y _a is -S-, -O- or -CH ₂ -, A is lower alkylene, provided that R ² is hydrogen and Y _a is -S- or -O
-, R ¹ _a is a group other than halogen. ] A compound represented by: and a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 _, wherein ^R1a is phenoxy optionally substituted with hydroxy, halogen, nitro, amino, _C3 - _C8 cycloalkyl, phenyl or halogen. 3. Claim 2, wherein R ¹ _a is halogen, phenyl, or phenoxy, R ² is halogen or lower alkyl, R ³ is carboxy, and Y _a is -S- or -O- Compounds described in. 4. The compound according to claim 3, wherein Y _a is -S-. 5 2-oxo-5,6-dichloro-3-benzothiazolineacetic acid, 2-oxo-5-chloro-6-bromo-3-benzothiazolineacetic acid, 2-oxo-5-chloro-6-phenyl-3-
Benzothiazolineacetic acid, 2-oxo-5-methyl-6-phenyl-3-
Benzothiazolineacetic acid, 2-oxo-5-chloro-6-phenoxy-3
-benzothiazolineacetic acid, and pharmaceutically acceptable salts thereof. 6. The compound according to claim 3, wherein Y _a is -O-. 7 2-oxo-5-chloro-6-phenyl-3
- The compound according to claim 6, which is benzoxazoline acetic acid or a pharmaceutically acceptable salt thereof. 8 General formula [In the formula, R ¹ _a is hydroxy, halogen, nitro,
Amino, C ₃ - C ₈ cycloalkyl, aryl or aryloxy optionally substituted with halogen, R ² is hydrogen, halogen or lower alkyl, Y _a is -S-, -O- or -CH ₂ -, respectively means. However, R ² is hydrogen and Y _a is -S- or -O
-, R ¹ _a is a group other than halogen. ] ^A compound or ^a salt thereof represented by ^the general ^formula : ] or a salt thereof to form the general formula A method for producing a lower alkanoic acid derivative or a salt thereof, which comprises obtaining a compound represented by the formula [wherein R ¹ _a , R ² , R ³ , Y _a and A are each as defined above] or a salt thereof. 9 General formula [In the formula, R ¹ _a is hydroxy, halogen, nitro,
amino, _C3 - _C8 cycloalkyl, aryloxy or aryloxy optionally substituted with halogen, ^R2 is hydrogen, halogen, or lower alkyl, Y _a is -S-, -O- or _-CH2- , A means lower alkylene, and R ³ _a means a protected carboxy group. However, R ² is hydrogen and Y _a is -S- or -O
-, R ¹ _a is a group other than halogen. ] The carboxy-protecting group of the compound represented by or its salt is removed to form the general formula [In the formula, R ¹ _a , R ² , Y _a and A are each as defined above] A method for producing a lower alkanoic acid derivative or a salt thereof, which is characterized by obtaining a compound represented by the following formula or a salt thereof.