JPS6335626B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention is applicable to pharmaceuticals, particularly SRS-A (Slow Reacting Substance of Anaphylaxis).
The present invention relates to a novel heterocyclic compound represented by the following general formula () useful as an antagonist, a salt thereof, and a method for producing the same. [The symbols in the formula have the following meanings. R ¹ : lower acyl group, R ² : lower alkyl group, A: lower alkylene group optionally substituted with hydroxyl group, Y: oxygen atom, sulfur atom, or carbonylimino group (-CONH-),

[Formula]: 6-membered ring with 1 oxygen atom; 5- or 6-membered ring with 2 nitrogen atoms; 5-membered ring with 3 nitrogen atoms; 5-membered ring with 1 sulfur atom and 1 or 2 nitrogen atoms A heterocycle selected from member rings, which may be fused with a benzene ring R ³ , R ⁴ and R ⁵ : the same or different, a hydrogen atom,
Lower alkyl group, group represented by the formula -A ¹ -R ⁶ , hydroxyl group, mercapto group, lower alkoxy group, lower alkylthio group, formula -Y ¹ -A ²
- Group represented by R ⁷ , oxo group (=O), thioxo group (=S), amino group, formula -NH-
A group represented by CO-R ₉ , a carboxy group, or a group represented by the formula -CO-R ¹⁰ , (However, when R ³ , R ⁴ and R ⁵ are substituted on a benzene ring fused with a hetero ring, ,
R ³ , R ⁴ and R ⁵ are a hydrogen atom, an amino group, or a group represented by the formula -NHCO-R ⁹ ) A ¹ : lower alkylene group, R ⁶ : hydroxyl group, mercapto group, Y ¹ : oxygen atom or sulfur atom, A ² : Lower alkylene group, R ⁷ : Carboxy group, lower alkoxycarbonyl group, or N-lower alkyl-hydroxyaminocarbonyl group, R ⁹ : Carboxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxyphenyl lower alkoxy Carbonyl lower alkyl group, carboxy group, or lower alkoxycarbonyl group, R ¹⁰ : lower alkoxy group. however,

When [Formula] is a heterocycle fused with a benzene ring, Y is bonded to the heterocycle moiety. (Background of the Invention) In allergic asthma and other atopic diseases in humans, or in anaphylactic shock in animals, various chemical mediators are released from the lungs and other tissues, causing damage to the smoothness of bronchial muscles, pulmonary blood vessels, etc. It is thought to cause damage to living organisms by contracting muscles and increasing the permeability of skin blood vessels.
Such chemical messengers include histamine and
SRS-A can be cited. Although histamine plays an important role in anaphylactic shock in guinea pigs, it is a less important chemical mediator in human allergic asthma [Eiser; Pharmacology and Therapeutics]. .Ther.), 17 , 239
-250 (1982)]. On the other hand, there is considerable evidence suggesting that SRS-A is the most important chemical messenger in human allergic asthma [Brocklehurst; Journal of Physiology (J.physiol.), 151 , 416―435
(1960): Austen and Orange; American Review of Respiratory Diseases (Am.Rev.Reop.
Dis.), 12 , 423-436 (1975): Adams and Lichtenstein; Journal of Immunol., 122 , 555-562 (1979)]. The development of drugs for preventing, eliminating, or alleviating the symptoms of allergic reactions has been aimed at inhibiting the production and release of such chemical mediators, or antagonizing their effects. Disodium cromoglycate is a drug that suppresses the release of histamine.
is well known, and many antihistamines are commercially available as drugs that antagonize histamine. On the other hand, while histamine is a fast-acting and short-lasting chemical mediator, SRS-A was known to be a slow-acting chemical mediator with a long duration, but recently Samuelsson (Samuelson) It was found to be a mixture of the determined leukotrienes C ₄ , D ₄ and E ₄ . SRS-A, or leukotriens, is a metabolite of polyunsaturated fatty acids (particularly arachidonic acid) by lipoxygenase, and in addition to acting as a chemical mediator in the allergic reaction, it also has the effect of increasing mucus secretion, reducing ciliary movement, It has been revealed that it has effects such as coronary vasoconstriction and cardiac contractile force reduction. Therefore, it is desired to develop a drug that suppresses the production and release of SRS-A or antagonizes these effects. (Specific Description of the Invention) The present inventors have been searching for a drug that suppresses the production and release of SRS-A or a drug that antagonizes these effects. As a result, the head compound of the present invention ()
The present invention was completed based on the discovery that the compound and its salt strongly antagonize SRS-A. (1) Compound In this specification, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified. Therefore, specific examples of the lower alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, and sec-
Butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group,
1-methylbutyl group, 2-methylbutyl group, 1,
2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2
-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group,
Examples include 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, and 1-ethyl-2-methylpropyl group. In addition, as the lower acyl group, formyl group,
Examples include acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, and the like. Furthermore, the lower alkylene group specifically includes a methylene group, an ethylene group, and a methylmethylene group.

[Formula] trimethylene group, 1-methylethyl Ren group

[Formula] 2-methylethylene group

[Formula] Tetramethylene group, 1-methyltrimethylene group, 2-methyltrimethylene group, 3
-Methyltrimethylene group, 1-ethylethylene group, 2-ethylethylene group, pentamethylene group,
1-methyltetramethylene group, 2-methyltetramethylene group, 3-methyltetramethylene group, 4-
Specific examples of lower alkylene groups in which a linear or branched alkylene group having 1 to 6 carbon atoms, such as a methyltetramethylene group or a hexamethylene group, is substituted with a hydroxy group include a hydroxymethylene group,
1-hydroxyethylene group, 2-hydroxyethylene group, 1-hydroxytrimethylene group, 2-hydroxytrimethylene group, 3-hydroxytrimethylene group, 1-hydroxy-2-methylethylene group, 2-hydroxy-1-methyl ethylene group, 1
-Hydroxytetramethylene group, 2-hydroxytetramethylene group, 3-hydroxytetramethylene group, 4-hydroxytetramethylene group, 2-hydroxy-1-methyltrimethylene group, 2-hydroxy-3-methyltetramethylene group, 2 -Hydroxypentamethylene group, 4-hydroxypentamethylene group, 2-hydroxyhexamethylene group,
Examples include hydroxy lower alkylene groups such as 5-hydroxyhexamethylene groups in which hydrogen atoms at arbitrary positions of the above lower alkylene group are substituted with hydroxyl groups. In addition, lower alkoxy groups include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyl group. oxy group,
Examples include straight-chain or branched alkoxy groups having 1 to 6 carbon atoms such as tert-pentyloxy group and hexyloxy group. 〓Lower alkylthio group〓 is a linear or branched alkylthio group having 1 to 6 carbon atoms, and specific examples include methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, sec-butylthio group,
These include tert-butylthio group, pentylthio group, isopentylthio group, neopentylthio group, tert-pentylthio group, and hexylthio group. Examples of the lower alkoxycarbonyl group include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-
A linear or branched alcohol having 1 to 6 carbon atoms, such as a butoxycarbonyl group, a pentyloxycarbonyl group, an isopentyloxycarbonyl group, a neopentyloxycarbonyl group, a tert-pentyloxycarbonyl group, a hexyloxycarbonyl group, and a carboxy Examples include groups formed with esters. 〓N-lower alkyl-hydroxyaminocarbonyl group〓 is a hydroxyaminocarbonyl group

It means a group in which the hydrogen atom bonded to the nitrogen atom in [Formula] is substituted with the above lower alkyl group, and specifically, for example, N-methylhydroxyaminocarbonyl group, N-ethylhydroxyaminocarbonyl group, N- Propylhydroxyaminocarbonyl group, N-isopropylhydroxyaminocarbonyl group, N-butylhydroxyaminocarbonyl group, N-isobutylhydroxyaminocarbonyl group, N-pentylhydroxyaminocarbonyl group, N-isopentylhydroxyaminocarbonyl group, N-hexyl Examples include hydroxyaminocarbonyl group. 〓carboxy lower alkyl group〓, 〓lower alkoxycarbonyl lower alkyl group〓, 〓lower alkoxyphenyl lower alkoxycarbonyl lower alkyl group〓, when any hydrogen atom of the above 〓lower alkyl group〓 is 〓carboxy group〓, 〓lower alkoxy group〓, respectively. Carbonyl group means a group substituted with lower alkoxyphenyl or lower alkoxycarbonyl group.
In addition, "lower alkoxyphenyl lower alkoxycarbonyl group" means a group in which any hydrogen atom of the above "lower alkoxycarbonyl group" is substituted with a phenyl group which is ortho-, meta-, or para-substituted with the above "lower alkoxy group". do.

The heterocycle represented by [Formula] is a 6-membered ring having 1 oxygen atom; a 5- to 6-membered ring having 2 nitrogen atoms; a 5-membered ring having 3 nitrogen atoms; 1 sulfur atom and 1 to 1 nitrogen atom. A heterocycle selected from two five-membered rings, which may be fused with a benzene ring, or may be saturated or unsaturated. Examples of suitable ones include:
1,3-thiazole ring

[Formula] 4,5-di Hydro-1,3-thiazole ring

[Formula] A sothiazole ring

[Formula] 1,2,3-thia diazole ring

[Formula] 1,2,4-thiazi azole ring

[Formula] Imidazole ring

[Formula] Pyrazole ring

[Formula] 1H- 1,2,3-triazole ring

[Formula] 1H -1,2,4-triazole ring

【formula】 2H-plan ring

[Formula] 4H-pyran ring

[Formula] Pyrimidine ring

[Formula] etc. A typical example of these heterocycles fused with a benzene ring is a benzothiazole ring.

[Formula] Benzimidazole ring

Examples include [Formula]. This heterocycle may have 1 to 3 substituents as R ³ , R ⁴ , and R ⁵ , and when the heterocycle is fused with a benzene ring, R ³ , R ⁴ .
The substituent for R ⁵ may be bonded to either the benzene ring or the heterocyclic moiety. More specifically, the substituents for the hydrogen atom of the heterocycle, R ³ , R ⁴ , and R ⁵ are lower alkyl groups;
A ¹ - Hydroxy, mercapto, substituted lower alkyl group represented by R ⁶ ; hydroxyl group; mercapto group; lower alkoxy group; lower alkylthio group; formula - Y ¹ -
Carboxy-, lower alkoxycarbonyl-, N-lower alkylhydroxyaminocarbonyl-substituted lower alkoxy group or lower alkylthio group represented by A ² - R ⁷ ; oxo group; thioxo group;
Amino group; carboxy lower alkanoylamino group, lower alkoxycarbonyl lower alkanoylamino group, lower alkoxyphenyl lower alkoxycarbonyl lower alkanoylamino group, oxaloamino group, or lower alkoxyoxarylamino group represented by the formula -NH-CO-R ⁹ group; carboxy group; or lower alkoxycarbonyl group represented by the formula -CO-R ¹⁰ . In addition, the "lower alkanoyl group" in the above "carboxy lower alkanoylamino group", "lower alkoxycarbonyl lower alkanoylamino group" and "lower alkoxyphenyl lower alkoxycarbonyl lower alkanoylamino group" is an acetyl group,
propionyl group, butyryl group, isobutyryl group,
It means a linear or branched alkylcarbonyl group having 2 to 6 carbon atoms, such as a valeryl group, an isovaleryl group, a pivaloyl group, or a hexanoyl group. The compounds of the present invention represented by the above general formula () include optical isomers based on the presence of an asymmetric carbon atom, tautomers based on the type of heterocycle, and the presence of an oxo group, hydroxy group, thioxo group, or mercapto group; This includes those in which cis and trans geometric isomers exist based on the conformation of the two substituents bonded to a saturated or partially saturated heterocycle. The compounds of the present invention include separated isomers and mixtures thereof. Furthermore, some of the compounds of the present invention form salts. The present invention also includes salts of the compound represented by the above general formula (), and examples of such salts include salts with inorganic bases such as sodium and potassium, ethylamine, propylamine, diethylamine, triethylamine, morpholine, piperidine, etc. , salts with organic bases such as N-ethylpiperidine, diethanolamine, and cyclohexylamine, salts with basic amino acids such as lysine and ornithine, ammonium salts, and mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid. Salts, salts with organic acids such as acetic acid, oxalic acid, succinic acid, citric acid, maleic acid, malic acid, fumaric acid, tartaric acid, and methanesulfonic acid, and salts with acidic amino acids such as glutamic acid and aspartic acid. (2) Production method The compound of the present invention can be synthesized by various methods. Typical manufacturing methods are illustrated below. [In the formula, R ¹ , R ² , A, Y,

[Formula], R ³ , R ⁴ , R ⁵ , Y ¹ , A ² , R ⁷ and R ⁹ have the above meanings, and other symbols have the following meanings. X: halogen atom, M: hydrogen atom or alkali metal atom, Y ² : oxygen atom or sulfur atom, R ¹¹ : hydrogen atom or lower alkyl group, R ¹² : lower alkyl group or hydroxy group, Y ³ : single bond, Oxygen atom, sulfur atom, or imino group (-NH-), R ¹³ : Lower alkyl group, A ³ : Single bond, lower alkylene group, or when Y ³ is an imino group, carbonyl group or carbonyl lower alkylene group, A ⁴ : single bond or lower alkylene group having 1 to 4 carbon atoms, R ³ ′, R ⁴ ′ and R ⁵ ′: the same or different, hydrogen atom,
Lower alkyl group, hydroxyl group, lower alkoxy group, lower alkylthio group, formula - Y ¹ - A ² -
A group represented by ^R7 ', an oxo group (=O), an amino group, a group represented by the formula -NH-CO- ^R9 ',
Carboxy group, or a group represented by the formula -CO-R ¹⁰ (where A ¹ , Y ¹ , A ² and R ¹⁰ have the above meanings, and R ⁷ ' is a lower alkoxycarbonyl group, or a N-lower an alkyl-hydroxyaminocarbonyl group, and ^R9 ' means a lower alkoxycarbonyl lower alkyl group, a lower alkoxyphenyl lower alkoxycarbonyl lower alkyl group, or a lower alkoxycarbonyl group.) Specifically, the halogen atom is Examples of the alkali metal atoms include iodine, bromine, and chlorine atoms, and examples of alkali metal atoms include sodium and potassium. Method A Among the compounds of the present invention, the compound in which Y is an oxygen atom or a sulfur atom is obtained by reacting a halogen compound represented by the general formula () with a hydroxy or mercapto compound represented by the general formula () or an alkali metal substituted product thereof. Manufactured by The reaction is carried out using dimethylformamide, dimethyl sulfoxide, methanol, ethanol, propanol, acetone, and dimethylformamide, dimethyl sulfoxide, methanol, ethanol, propanol, acetone,
It is carried out in an organic solvent such as methyl ethyl ketone, tetrahydrofuran, chloroform, dioxane, water, or a mixed solvent thereof. When a hydroxy- or mercapto-substituted heterocyclic compound is used as the compound (), it is usually carried out in the presence of a base, such as potassium carbonate, Triton B, potassium hydroxide, sodium hydroxide, sodium hydride, etc. is suitable. The reaction temperature is not particularly limited, but is usually set at room temperature or under heating. Method B In the compound of the present invention, Y is a carbonylimino group (-
Compound (b), which is CONH-), is produced by reacting a carboxylic acid represented by the general formula () or a reactive derivative thereof with an amino compound represented by the general formula (). Reactive derivatives of compound () include acid halides such as acid chlorides and acid bromides; acid azides; N-hydroxybenzotriazole and N-
Active ester with hydroxysuccinimide; Symmetrical acid anhydride; Alkyl carbonic acid mixed acid anhydride, p-
Mixed acid anhydrides with toluenesulfonic acid; and the like. When reacting compound () with a male carboxylic acid, dicyclohexylcarbodiimide or 1,
It is advantageous to carry out in the presence of a condensing agent such as 1'-carbonyldiimidazole. The reaction is carried out using Compound () or its reactive derivative and Compound () in approximately equimolar amounts or in a slightly excess molar amount of one of them, and an organic solvent inert to the reaction, such as pyridine, tetrahydrofuran, dioxane, ether, benzene, toluene, xylene. ,,
It is carried out in a solvent such as methylene chloride, dichloroethane, chloroform, dimethylformamide, ethyl acetate, or acetonitrile. Depending on the type of reactive derivative, triethylamine, pyridine, picoline, lutidine,
It may be advantageous to add a base such as N,N-dimethylaniline, potassium carbonate, or sodium hydroxide in order to make the reaction proceed smoothly. Pyridine can also serve as a solvent. The reaction temperature varies depending on the type of reactive derivative and is not particularly limited. Method D In the heterocycle represented by the general formula (d), a lower alkoxy group, a lower alkylthio group, a lower alkoxycarbonyl lower alkoxy group, a lower alkoxycarbonyl lower alkylthio group, a carboxy lower alkoxy group, a carboxy lower alkylthio group,
A compound substituted with a lower alkoxycarbonyl lower alkoxy group or a lower alkoxycarbonyl lower alkylthio group is a compound of the present invention in which a hydroxy group or a mercapto group is substituted on the heterocycle represented by the general formula (), or an alkali metal substituted product thereof, as a raw material, It can also be produced by reacting this with a halogen compound (). The reaction is carried out in substantially the same manner as in Method A. When a compound in which a plurality of hydroxy groups or mercapto groups are present in the heterocycle or an alkali metal-substituted product thereof is used as a raw material, all or selectively thereof can be reacted to form the target product. Method E Compounds of the present invention in which the heterocycle is substituted with a carboxy lower alkanoylamino group, a lower alkoxycarbonyl lower alkanoylamino group, a lower alkoxyphenyl lower alkoxycarbonyl lower alkanoylamino group, an oxaloamino group, or a lower alkoxyoxarylamino group. can be produced by reacting a compound represented by the general formula (e) in which a heterocycle is substituted with an amino group with a carboxylic acid represented by the general formula () or a reactive derivative thereof. The reaction conditions etc. are almost the same as method B. When a compound in which a plurality of amino groups are present in the heterocycle is used as a raw material, it is also possible to produce a compound in which all of the amino groups have reacted. F Method A compound in which a (N-lower alkyl)hydroxyaminocarbonyl-lower alkoxy group or -lower alkylthio group is bonded to the heterocycle in the compound of the present invention is a carboxylic acid represented by the general formula (g) or a reactive derivative thereof, It is produced by reacting with amines represented by general formula (XI). The reaction is carried out in the same manner as in Methods B and E. When a compound in which a plurality of carboxyl groups are bonded to a heterocyclic ring is used as a raw material, all or a part thereof can be selectively reacted to obtain the target product. G Method The free carboxylic acid compound represented by general formula (j) can be easily produced by ester hydrolysis of the corresponding ester compound (i). In this reaction, a conventional method of hydrolysis in the presence of a base such as sodium carbonate or sodium hydroxide or an acid such as trifluoroacetic acid or hydrochloric acid can be applied. When a compound in which a plurality of esters are present in the heterocycle is used as a raw material, it is also possible to derive a compound in which all the esters are hydrolyzed. H method A compound (k) that does not have a free mercapto group, a carboxy group, or a reactive hydroxyl group among the compounds of the present invention
is produced by reacting a dihydroxybenzene derivative represented by general formula (XII) or an alkali metal substituted derivative thereof with a halogen compound represented by general formula (XII). The reaction is carried out in the same manner as in methods A and D, especially for compounds in which Y ¹ or Y ² is an oxygen atom. Method I Among the compounds of the present invention, the compound in which A is a 2-hydroxy lower alkylene group is an epoxy compound represented by the general formula (XI) and a hydroxy- or mercapto-compound represented by the general formula () or an alkali metal substituted product thereof It can be produced by reacting with. The reaction is essentially the same as the A, D, H method,
Using equal moles of compound (XI) and compound () or an excess mole of one of them, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, propanol, acetone, methyl ethyl ketone, tetrahydrofuran, chloroform,
In an organic solvent inert to the reaction such as dioxane, in the presence of a base such as potassium carbonate, Triton B, potassium hydroxide, sodium hydroxide, sodium hydride, etc. when using a free hydroxy- or mercapto compound as the compound (). , preferably under anhydrous conditions. Method J Contrary to method G, the ester compound represented by the general formula (i) is a combination of a carboxylic acid represented by the general formula (j) or a reactive derivative thereof, and a lower alcohol or lower alkyl represented by the general formula (). It is synthesized by reacting with a reactive derivative of an alcohol component such as a halide. The reaction can be easily accomplished according to conventional methods. The compounds of the present invention produced by these various methods are isolated and purified by applying chemical operations commonly used in this field, such as extraction, recrystallization, and column chromatography. (Effect of the invention) As mentioned above, the compound of the present invention () has SRS-A
Because it strongly antagonizes the It is useful for In addition, the compounds of the present invention include compounds that have SRS-A production and release suppressing effects and bronchodilating effects in addition to SRS-A antagonistic effects. Furthermore, the compounds of the present invention are useful as anti-ulcer agents. Inhibition of contraction of guinea pig ileum and trachea by SRS-A and LTD ₄ Method: Male Hartley guinea pigs weighing 500-700 g were killed by head contusion. ileum and
Tracheal segments prepared by the method of Constantine (1965) were suspended under a tension of 1.0 g in a Magnus bath containing 10 ml of Tyrode's solution at 37° C. and aerated with a mixed gas of 95% O ₂ +5% CO ₂ . Tissues were allowed to equilibrate for 60 minutes. During this time, change the Tyrode solution every 15 minutes, each time.
The tension was adjusted to 1.0 g. The tension generated by the tissue is
Measurements were made isometrically with a Sleton gauge transducer. Ileum and 10 ^-8 MLTD ₄ for submaximal concentrations of SRS-A (from guinea pig lungs)
The constrictive response of the trachea to the trachea was measured in the absence of drug and subsequently in the presence of various concentrations of the test compound. Drug incubation time was 20 minutes.

【table】

[Table] Inhibition of anaphylactic asthma via SRS-A in unanesthetized guinea pigs Method: Male Hartley guinea pigs weighing 370-410 g were treated with rabbit anti-bovine serum albumin serum (PHA).
Passive sensitization was performed by intravenously administering 1 ml/Kg of antibody (antibody titer: 20480). 24 hours after sensitization,
indomethacin (2mg/Kg), mepyramine (2mg/Kg)
Kg) and propranolol (0.3 mg/Kg) were administered into the saphenous vein 20, 5, and 5 minutes before antigen challenge, respectively. The animal was then placed in a chamber with an internal volume of 11 fitted with a glass nebulizer, and a 1% solution of bovine serum albumin was sprayed into the chamber for 30 seconds. Animals were allowed to inhale the antigen aerosol for 2 minutes and observed for 15 minutes after exposure. The time from the start of inhalation to onset of cough and mortality were recorded. Test compounds were orally administered 30 minutes before antigen challenge. Results: At 3 mg/Kgp.o., the compound of Example 21 showed a tendency to inhibit SRS-A-mediated anaphylactic asthma in unanesthetized guinea pigs, but this effect was not significant (Table 3). At doses of 10 mg/Kg or higher, the compound of Example 21
mediated anaphylactic asthma was significantly suppressed.

[Table] Toxicity When the compound of Example 21 was orally administered to mice and rats, the minimum lethal dose was 1000 mg/Kg or more. The compound of the present invention () or a salt thereof can be used as it is or in a pharmaceutical composition mixed with a known pharmaceutically acceptable carrier, excipient, etc. [e.g., tablets, capsules, powders, granules, pills, ointments, etc.] It can be safely administered orally or parenterally as a tablet, syrup, injection, inhaler, or suppository. The dosage varies depending on the subject, administration route, symptoms, etc., but is usually 0.1 to 500 mg per day for adults, preferably 1 to 200 mg, and this is administered orally or parenterally in 2 to 3 divided doses a day. . (Example) The present invention will be described in detail with reference to Examples below. In addition, a manufacturing example of the raw material compound is shown in Reference Example. In the description, nPr stands for normal (n)-propyl group, DCC stands for dicyclohexylcarbodiimide,
P-TsOH means para-toluenesulfonic acid. Reference example 1 2,5-dimercapto-1,3,4-thiadiazole 60g, potassium hydroxide 25g, ethanol
After stirring 750 ml of the mixture at 70°C for 1 hour, α-
Add 68 g of ethyl bromoacetate and heat under reflux for 2 hours. After cooling, insoluble matter was removed and the liquid was concentrated under reduced pressure.
Add 600ml of 10% sodium hydroxide to the residue,
Stir for 1 hour at °C. After cooling, concentrated hydrochloric acid was added to the reaction solution to make it acidic (PH1 or less), and the resulting crystals were collected, washed with water, and recrystallized from acetone [(5-mercapto-1,3,4-thiadiazol-2-yl)thio]. 60g of acetic acid was obtained. Melting point 170℃ Reference example 2 2,5-dimercapto-1,3,4-thiadiazole 3g, anhydrous potassium carbonate 2.76g, N,N-
Ethyl 4- to a mixture of 10 ml of dimethylformamide
Add 1 g of bromobutyrate and stir at room temperature overnight. The reaction solution was added to dilute hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (using 200 ml of silica gel) and eluted with a mixture of toluene and ethyl acetate (9:1) to obtain ethyl 4-[(5-mercapto-1,3,
0.95 g of 4-thiadiazol-2-yl)thio]butyrate was obtained. Melting point 107-108℃ Reference example 3 2,4-dihydroxy-3-propylacetophenone 1.42g, ethyl 4-bromobutyrate 2
A mixture of 1.5 g of anhydrous potassium carbonate and 10 ml of N,N-dimethylformamide was stirred at room temperature overnight. 100 ml of water was added to the reaction solution, and the mixture was extracted with 30 ml of toluene. After washing the extract with water and drying over anhydrous magnesium sulfate, the solvent was distilled off and the resulting residue was subjected to silica gel column chromatography and eluted with toluene to obtain ethyl 4-(4-acetyl-3-hydroxy-2). -Propylphenoxy)butyrate
1.5 g was obtained as an oil. 1.3g of this oily substance
g of potassium hydroxide was dissolved in 40 ml of 80% methanol and allowed to stand for 1 hour. water in reaction solution
20 ml was added, and methanol was distilled off under reduced pressure. The aqueous solution was made acidic with 5% hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give 1.1 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyric acid.
I got it. Melting point 138-139℃ Reference example 4 2.5-dimercapto-1,3,4 in a mixture of 9.66 g of sodium hydroxide, 14.6 ml of water, and 122 ml of methanol.
-Add and dissolve 36.3g of thiadiazole. Cool the mixture, add a mixture of 24.1 ml of ethyl bromoacetate and 24 ml of methanol at below 10°C, stir at room temperature for 3 hours, and then cool to below 10°C. When 43.5 ml of water and 400 ml of 50% methanol are added sequentially, crystals will precipitate, so leave it in an ice room overnight. Take the crystals and add water, 50%
After washing with methanol and drying, ethyl [(5-
Mercapto-1,3,4-thiadiazole-2-
42.5 g of yl)thio]acetate were obtained. Melting point 67-68℃ Reference example 5 Add a solution of 2.6 g of sodium hydroxide and 5 ml of water to a mixture of 10 g of 2,5-dimercapto-1,3,4-thiadiazole and 100 ml of methanol. 9 g of ethyl 5-bromovalerate was gradually added to this mixed solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, 100 ml of water was added, and the mixture was extracted with ethyl acetate.
The extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of toluene and ethyl acetate (9:1).
10 g of [(5-mercapto-1,3,4-thiadiazol-2-yl)thio]valerate was obtained. Melting point 53℃ Reference example 6 Add 7.4 g of ethyl 6-bromohexanoate to a mixture of 7.6 g of 2,5-dimercapto-1,3,4-thiadiazole, 1.5 ml of water, 15 ml of methanol, and 2.0 g of sodium hydroxide, and stir at room temperature for 2 hours.
After making the reaction solution acidic with dilute hydrochloric acid, add 150 ml of water. Extract the mixed solution with toluene, wash the extract with water,
Dry over anhydrous magnesium sulfate and concentrate under reduced pressure. The residue was recrystallized from toluene-n-hexane to obtain ethyl 6-[(5-mercapto-1,3,4-thiadiazol-2-yl)thio]hexanoate. Melting point 79-80℃ Reference example 7 6.9 g of 2,5-dimercapto-1,3,4-thiadiazole and 5.8 g of ethyl 4-chlorovalerate
g was used as the starting material and treated in the same manner as in Reference Example 5,
Ethyl 4-[(5-mercapto-1,3,4-thiadiazol-2-yl)thio]valerate 1.5
I got g. Oil nuclear magnetic resonance spectrum (CDCl ₃ , TMS, internal standard, ppm.) 1.25 (t, 3H), 1.45 (d, 3H), 2.08 (t,
2H), 2.52 (t, 2H), 3.70 (q, 1H), 4.15
(q, 2H) Reference example 8 7.5 g of 2,5-dimercapto-1,3,4-thiadiazole and 5.8 g of ethyl 2-bromopropionate were treated in the same manner as in Reference Example 5 to obtain ethyl 2-[(5-mercapto-1,3 ,4
6.1 g of -thiadiazol-2-yl)thio]propionate was obtained. Oil nuclear magnetic resonance spectrum (CDCl ₃ , TMS, internal standard, ppm.) 1.28 (t, 3H), 1.64 (d, 3H), 4.0-4.80
(m, 3H) Reference example 9 2,5-dimercapto-1,3,4-thiadiazole 1.5g, anhydrous potassium carbonate 1.3g, N,N-
Add 1.6 g of 3-bromopropionic acid to a mixture of 20 ml of dimethylformamide. The initially red reaction solution gradually fades and turns yellow. Pour the reaction solution into 100 ml of ice water and extract three times with 30 ml of ethyl acetate. The extract was washed with water and extracted twice with 20 ml of 5% aqueous sodium bicarbonate solution. Wash the extract with ethyl acetate and acidify with dilute hydrochloric acid. Extracted 3 times with 30 ml of ethyl acetate,
The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3-[(5-mercapto-1,3,4-
Thiadiazol-2-yl)thio]propionic acid
0.76g was obtained. Melting point 105-108℃ Reference example 10 2,4-dihydroxy-3-propylacetophenone 3g, ethyl bromoacetate 2.5g,
2.3g of anhydrous potassium carbonate and methyl ethyl ketone
30 ml of the mixture was heated under reflux for 5 hours. The solvent was removed under reduced pressure, 50 ml of toluene was added, washed with water, washed with dilute aqueous sodium hydroxide solution, washed again with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was recrystallized from toluene-n-hexane. ethyl (4
2.8 g of -acetyl-3-hydroxy-2-propylphenoxy) acetate was obtained (melting point 66-66.5).
℃). A mixture of this material, 20 ml of methanol, and 8 ml of 2N aqueous sodium hydroxide solution was stirred at 50°C for 2 hours. Concentrate under reduced pressure, add 30 ml of water, and wash with toluene. Acidify with dilute hydrochloric acid and extract with ethyl acetate, wash the extract with water, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. The residue was recrystallized from isopropyl alcohol to obtain 2.3 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid. Melting point 140-141℃ Reference example 11 2,4-dihydroxy-3-propylacetophenone 1g, 1-bromo-2-chloroethane 1.1
A mixture of 0.75 g of anhydrous potassium carbonate, 0.05 g of tetra-n-butylammonium bromide, and 5 ml of methyl ethyl ketone was heated under reflux for 3 hours with vigorous stirring. After cooling, add 30 ml of toluene to the reaction solution, wash with dilute aqueous sodium hydroxide solution, wash with water, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. The residue was recrystallized from isopropyl alcohol to obtain 0.46 g of 4-(2-chloroethoxy)-2-hydroxy-3-propylacetophenone. Melting point 73-74℃ Elemental analysis value (as C ₁₃ H ₁₇ O ₃ Cl) C (%) H (%) Cl (%) Theoretical value 60.82 6.67 13.81 Experimental value 60.67 6.72 13.76 Reference example 12 Using 1 g of 2,4-dihydroxy-3-propylacetophenone and 4.5 g of 1,4-dibromobutane as raw materials, it was treated in the same manner as in Reference Example 11, and then purified by silica gel column chromatography (elution solvent: toluene). 4-bromobutoxy)-
2-Hydroxy-3-propylacetophenone
1.3g was obtained. Oily substance. Nuclear magnetic resonance spectrum ( _CDCl3 , TMS internal standard, ppm) 0.95 (t, 3H), 1.10~1.80 (m, 2H), 1.80~
2.20 (m, 4H), 2.58 (s, 3H), 2.64 (t,
2H), 3.52 (t, 2H), 4.08 (t, 2H), 6.42
(d, 1H), 7.58 (d, 1H), 12.7 (s, 1H). Reference example 13 1 g of 2,4-dihydroxy-3-propylacetophenone and 4.7 g of 1,5-dibromopentane were treated in the same manner as in Reference Example 12 to obtain 4-(5
-Bromopentyloxy)-2-hydroxy-3
-1.3g of propylacetophenone was obtained. Oily substance. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard, ppm) 0.94 (t, 3H), 1.30-2.10 (m, 8H), 2.56
(s, 3H), 2.64 (t, 2H), 3.46 (t, 2H),
4.40 (t, 2H), 6.42 (d, 1H), 7.58 (d,
1H), 12.72 (s, 1H) Reference example 14 3 g of ethyl [(5-mercapto-1,3,4-thiadiazol-2-yl)thio]acetate,
A mixed solution of 9 g of 1,3-dibromopropane, 2.02 g of anhydrous potassium carbonate, 0.01 g of tetra-n-butylammonium bromide, and methyl ethyl ketone,
Stir vigorously for 3 hours at 60°C. After cooling, toluene is added to the reaction mixture, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of toluene and ethyl acetate (9:1).
-(3-bromopropyl)thio-1,3,4-thiadiazol-2-yl]thio]acetate 1.35
I got g. Melting point 118-120℃ Example 1 Add 250 mg of 4-(2,3-epoxy)propoxy-2-hydroxy-3-propylacetophenone to a mixture of 600 mg of 2,5-dimercapto-1,3,4-thiadiazole, 560 mg of anhydrous potassium carbonate, and 10 ml of dimethylformamide. Stir overnight at room temperature.
The reaction solution was added to dilute hydrochloric acid and extracted with toluene. The extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using toluene-ethyl acetate (4:1).
Elute with a mixture of 2-hydroxy-4-[2-hydroxy-3-[(5-mercapto-1,3,4
260 mg of -thiadiazol-2-yl)thio]propoxy]-3-propylacetophenone was obtained.
Oily substance. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard, ppm) 0.92 (t, 3H), 1.2-1.8 (m, 2H), 2.56 (s,
3H), 2.63 (t, 2H), 3.48 (dd, 2H), 4.0~
4.2 (m, 2H), 4,2~4,6 (m, 1H),
6.42 (d, 1H), 7.61 (d, 1H), 12.7 (s,
1H) Example 2 2 g of 4-(3-bromopropoxy)-2-hydroxy-3-propylacetophenone, 1.6 g of 2-amino-5-mercapto-1,3,4-thiadiazole, 1.6 g of anhydrous potassium carbonate and N,N-dimethyl 20ml of formamide mixture at 20-30℃
After stirring for an hour, 100 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with toluene to give 4-[3-[(5-amino-1,
2.3 g of 3,4-thiadiazol-2-yl)thio]propoxy]-2-hydroxy-3-propylacetophenone was obtained. Melting point 144-145℃ Elemental analysis value (as C ₁₆ H ₂₁ N ₃ O ₃ S ₂ ) C (%) H (%) N (%) S (%) Theoretical value 52.29 5.76 11.43 17.45 Experimental value 52.09 5.71 11.58 17.61 Implementation Examples 3 to 13 The following compounds were obtained in the same manner as in Example 2.

【table】

【table】

【table】

[Table] Example 14 21.87 g of 4-(3-chloropropoxy)-2-hydroxy-3-propylacetophenone, 18.18 g of ethyl [(5-mercapto-1,3,4-thiadiazol-2-yl)thio]acetate, anhydrous potassium carbonate A mixture of 12.7 g methyl ethyl ketone (80 ml) is heated under reflux for 2.5 hours with vigorous stirring.
After cooling, insoluble materials are separated and the liquid is concentrated under reduced pressure.
Add 200 ml of ethyl acetate and 150 ml of toluene, wash with dilute aqueous sodium hydroxide solution, wash with water, dry anhydrous magnesium sulfate, and concentrate under reduced pressure. The residue was subjected to silica gel column chromatography, and toluene-
Elute with a mixture of ethyl acetate (10:1) to obtain ethyl [[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-
1,3,4-thiadiazol-2-yl]thio]
33 g of acetate was obtained. Melting point 71-72.5℃ Elemental analysis value (as C ₂₀ H ₂₆ N ₂ O ₅ S ₃ ) C (%) H (%) N (%) S (%) Theoretical value 51.04 5.57 5.95 20.44 Experimental value 51.07 5.49 5.79 20.17 Implementation Examples 15-18 The following were synthesized in the same manner as in Example 14.

【table】

[Table] Example 19 2,4-dihydroxy-3-propylacetophenone 0.45 g, ethyl [[5-(3-bromopropyl)thio-1,3,4-thiadiazole-2-
Using 0.75 g of ethyl[5-[[3-
(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiadiazol-2-yl]thio]acetate 0.2
I got g. The physical properties of the obtained compound were consistent with those of the compound obtained in Example 14. Example 20 4-(3-bromopropoxy)-2-hydroxy-3-propylacetophenone 596 mg, ethyl [(5-mercapto-1,3,4-thiadiazol-2-yl)thio]acetate 372.4 mg, anhydrous potassium carbonate 326 mg A mixture of 5 ml of N,N-dimethylformamide was stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure, added with chloroform, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography,
Elute with a mixture of toluene and ethyl acetate (10:1) to obtain ethyl [[5-[[3-(acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiadiazole. -2-il]
663.3 mg of thio]acetate was obtained. The physical properties of the obtained compound were consistent with those of the compound obtained in Example 14. Example 21 4-(3-bromopropoxy)-2-hydroxy-3-propylacetophenone 3.1g, [(5-
Mercapto-1,3,4-thiadiazole-2-
A mixture of 2.4 g of yl)thio]acetic acid, 3 g of potassium carbonate, and 30 ml of N,N-dimethylformamide was stirred at room temperature for 3 hours. After adding 150 ml of water to the reaction solution, the mixture was extracted with ethyl acetate. The aqueous layer was separated, acidified with 10% hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a solid. The solid was recrystallized from ethanol to give [[5-[[3-(4-acetyl-3-
Hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiadiazole-2-
2.5 g of yl]thio]acetic acid was obtained. Melting point 129-130℃ Elemental analysis value (as C ₁₈ H ₂₂ N ₂ O ₅ S ₃ ) C (%) H (%) N (%) S (%) Theoretical value 48.85 5.01 6.33 21.74 Experimental value 48.78 5.13 6.29 21.49 Implementation Example 22 2-hydroxy-4-[3 obtained in Example 7
-(5-mercapto-1,3,4-thiadiazol-2-yl)thio]propoxy]-3-propylacetophenone and promoacetic acid were treated in the same manner as in Example 21 to obtain [[5-[ [3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiadiazol-2-yl]thio]acetic acid was obtained. The physical properties of the obtained compound were consistent with those of the compound obtained in Example 21. Example 23 1.3 g of 4-(4-bromobutoxy)-2-hydroxy-3-propylacetophenone obtained in Reference Example 12, [[5-mercapto-1,3,4-thiadiazol-2-yl)thio]acetic acid A mixture of 1.0 g of potassium carbonate, 1.0 g of anhydrous potassium carbonate, and N,N-dimethylformamide was stirred at 50°C for 3 hours. Add 30 ml of water to the reaction solution, wash with toluene, acidify with dilute hydrochloric acid, and extract with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue is recrystallized from ethyl acetate. 1.15 g of -[[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyl]thio]-1,3,4-thiadiazol-2-yl]thio]acetic acid was obtained. Melting point 123-124.5℃ Elemental analysis value (as C ₁₉ H ₂₄ N ₂ O ₅ S ₃ ) C (%) H (%) N (%) S (%) Theoretical value 49.98 5.30 6.14 21.07 Experimental value 49.76 5.29 6.07 21.13 Implementation Examples 24-27 The following compounds were synthesized in the same manner as in Example 23.

【table】

[Table] Example 28 4-[3-[(5-amino-1,
Add 0.28 g of mono-p-methoxybenzyl malonate to a solution of 0.28 g of 3,4-thiadiazol-2-yl)thio]propoxy]-2-hydroxy-3-propylacetophenone dissolved in 5 ml of pyridine.
g, 0.20 g of dicyclohexylcarbodiimide and 10 mg of p-toluenesulfonic acid were added, and the mixture was stirred at room temperature for 3 hours. After separating the insoluble matter, concentrate the liquid under reduced pressure. Add 30 ml of water to the resulting residue, and add 20 ml of toluene.
Extracted in ml. After washing the extract with water and drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a solid. The solid was washed with methanol and dried to give p-methoxybenzyl 3-[[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3 ,4-thiadiazole-
2-yl]amino]-3-oxopropionate
0.25g was obtained. Melting point 133-135℃. Elemental analysis value (as C ₁₇ H ₃₁ N ₃ O ₇ S ₂ ) C (%) H (%) N (%) S (%) Theoretical value 56.53 5.45 7.32 11.18 Experimental value 56.81 5.46 7.19 10.96 Examples 29-32 Implementation The following compound was obtained in the same manner as in Example 28.

【table】

[Table] Example 33 p-methoxybenzyl ester obtained in Example 28
0.9g potassium hydroxide 1.5g 90% methanol 30
ml of the solution, and after standing at room temperature for 30 minutes, 30 ml of water was added to the reaction solution. The aqueous solution obtained by distilling off the methanol in the reaction solution under reduced pressure was diluted with ethyl acetate.
After washing with 30ml and acidifying the aqueous solution with 10% hydrochloric acid,
Extracted with 30 ml of ethyl acetate. After washing the extract with water and drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a solid. The solid was washed with chloroform and dried to give 3-[[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]
0.5 g of thio]-1,3,4-thiadiazol-2-yl]amino]-3-oxopropionic acid was obtained. Melting point 172-174℃ Elemental analysis value (as C ₁₉ H ₂₃ N ₃ O ₆ S ₂ ) C (%) H (%) N (%) S (%) Theoretical value 50.32 5.11 9.26 14.14 Experimental value 50.05 5.01 9.29 13.93 Implementation Examples 34-39 The following compounds were obtained in the same manner as in Example 33.

【table】

【table】

[Table] Example 40 Ethyl [[5-[[3-(4
-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiadiazol-2-yl]thio]acetate 4.2 g,
Add 20 ml of 5% aqueous sodium hydroxide solution to a mixture of 30 ml of methanol and stir for 30 minutes. Add 30 ml of water and remove methanol under reduced pressure. The residual solution is washed with ethyl acetate, acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from 90% ethanol to give [[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiadiazole-
3.07 g of 2-yl]thio]acetic acid was obtained. The physical properties of the obtained compound were consistent with those of the compound obtained in Example 21. Examples 41 to 45 The following compounds were obtained in the same manner as in Example 40.

【table】

[Table] Example 46 4-[3-[(5-amino-1,
Ethyloxalyl chloride was added to a solution of 0.4 g of 3,4-thiadiazol-2-yl)thio]propoxy]-2-hydroxy-3-propylacetophenone dissolved in 10 ml of pyridine while cooling to below -10°C.
After adding a mixture of 0.2 g and 1 ml of toluene, stir at room temperature for 30 minutes.
Stir for a minute. After the reaction, 50 ml of water was added, and the mixture was extracted with 30 ml of ethyl acetate. The extract was washed successively with water, 5% hydrochloric acid, and water, and after drying, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with toluene-ethyl acetate (3:2) to give ethyl N-[5-[[3-(4-acetyl-3-)].
0.3 g of hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiazol-2-yl]oxamate was obtained. Melting point 146-147℃ Elemental analysis value (as C ₁₈ H ₂₁ O ₆ N ₃ S ₂ ) C (%) H (%) N (%) S (%) Theoretical value 49.19 4.82 9.56 14.59 Experimental value 49.28 4.80 9.43 14.56 Implementation Example 47 2-hydroxy-4-[2 obtained in Example 1
-Hydroxy-3-[(5-mercapto-1,3,
[[5-
[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropyl]
Thio]-1,3,4-thiadiazol-2-yl]thio]acetic acid was obtained. Melting point 72-75℃ Nuclear magnetic resonance spectrum ( _CDCl3 , TMS internal standard, ppm) 0.92 (t, 3H), 1.3-1.8 (m, 2H), 2.54 (s,
3H), 2.60 (t, 2H), 3.60 (t, 2H), 4.04
(s, 2H), 4.0~4.2 (m, 2H), 4.2~4.6 (m,
1H), 6.42 (d, 1H), 7.60 (d, 1H), 12.7
(s, 1H) Example 48 4-(4-acetyl-3-
Hydroxy-2-propylphenoxy)butyric acid 0.42
Methyl [[5
0.31 g of -amino-1,3,4-thiadiazol-2-yl)thio]acetate, 0.4 g of dicyclohexylcarbodiimide, and 3 mg of p-toluenesulfonic acid were added and stirred at room temperature for 3 hours. Separate the insoluble matter and concentrate. Dissolve 1 g of potassium hydroxide in 20 ml of 90% methanol without purifying the residual solids, and after separating the insoluble materials, cool the solution at room temperature.
It was left for 30 minutes. 20 ml of water was added to the reaction solution, methanol was distilled off under reduced pressure, and the resulting aqueous solution was washed with 20 ml of ethyl acetate. The aqueous solution was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give [[5-[[4
-(4-acetyl-3-hydroxy-2-propylphenoxy)butyrylamide]-1,3,4-
0.3 g of thiadiazol-2-yl]thio]acetic acid was obtained. Nuclear magnetic resonance spectra (CDCl ₃ , DMSO-d ₆ ,
TMS internal standard, ppm) 0.87 (3H, t), 1.1~1.7 (2H), 2.57 (3H,
s), 1.9-3.0 (6H), 4.07 (2H, s), 4.11
(2H, t), 6.61 (1H, d), 7.78 (1H, d),
12.80 (1H, s) Example 49 p-methoxybenzyl 3- obtained in Example 31
[[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-
100 mg of 1H-1,2,4-triazol-3-yl]amino]-3-oxopropionate was added to a mixture of 1.5 ml of trifluoroacetic acid and 0.1 ml of anisole.
After dissolving at ~20°C and stirring for 30 minutes, trifluoroacetic acid was distilled off under reduced pressure. 20 ml of water was added to the residue and extracted with 20 ml of ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a solid. The solid was washed with methylene chloride and dried to give 3-[[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1H-1,2,4- 50 mg of triazol-3-yl]amino]-3-oxopropionic acid was obtained. Melting point 163-165℃ Nuclear magnetic resonance spectrum (CDCl ₃ -DMSO-d ₆
(10:1), TMS, ppm) 0.90 (3H, t), 1.2~1.8 (2H), 2.0~2.8
(4H), 2.55 (3H, s), 3.25 (3H, t), 3.48
(2H, s), 4.17 (2H, t), 6.44 (1H, d),
7.61 (1H, d), 12.68 (1H, s) Example 50 0.7 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid obtained in Reference Example 10,
Add 0.57 g of dicyclohexylcarbodiimide to a mixture of 0.6 g of ethyl [[5-amino-1,3,4-thiadiazol-2-yl)thio]acetate, 10 ml of pyridine, and 1 mg of p-toluenesulfonic acid.
Stirred at room temperature for 1 hour. Insoluble matter was separated, the liquid was concentrated under reduced pressure, ethyl acetate was added to the residue, washed with dilute hydrochloric acid, washed with dilute aqueous sodium bicarbonate solution, washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was - Recrystallize from methoxyethanol to obtain ethyl [[5-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)acetamide]-1,3,4-thiadiazol-2-yl]
0.8 g of thio]acetic acid was obtained. Melting point 183-184℃ Elemental analysis value (as C ₁₉ H ₂₃ N ₃ O ₆ S ₂ ) C (%) H (%) N (%) S (%) Theoretical value 50.32 5.11 9.26 14.14 Experimental value 50.47 5.14 9.24 14.38 Implementation Example 51 [[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]
-1,3,4-thiadiazol-2-yl]thio]acetic acid 0.5g, dicyclohexylcarbodiimide 0.23g, 1-hydroxybenzotriazole
Add N- to a mixture of 0.14g and 50ml of tetrahydrofuran.
A mixture of methylhydroxylamine, 0.27 g of hydrochloride, 0.3 g of triethylamine, and 5 ml of N,N-dimethylformamide is added, and the mixture is stirred at room temperature overnight. Separate the insoluble matter, concentrate the liquid under reduced pressure, and add 100% ethyl acetate.
ml, washed with water, washed with dilute concentrated aqueous sodium bicarbonate solution, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate was added to the residue, insoluble matter was separated, and the liquid was concentrated. Triene residue
Recrystallized from n-hexane mixture to give 2-[[5-[[3
-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-
0.18 g of thiadiazol-2-yl]thio]-N-hydroxy-N-methylacetamide was obtained. Melting point 97-99°C Elemental analysis value (as C ₁₉ H ₂₅ N ₃ O ₅ S ₃ ) N (%) Theoretical value 8.91 Experimental value 9.06 Next, a recipe example is shown. Formulation Example 1 (Tablet) Compound of Example 21 30 mg Lactose 104 mg Corn starch 57 mg Hydroxypropylcellulose 4 mg Carboxymethylcellulose calcium 4 mg Magnesium stearate 1 mg Total 200 mg 30 g of the compound of Example 21, 104 g of lactose and 57 g of cornstarch were uniformly mixed. Hydroxypropyl cellulose 10% (w/v) aqueous solution in the mixture
40 ml was added and granules were prepared by wet granulation.
4 g of calcium carboxymethyl cellulose and 1 g of magnesium stearate were added to the granules, mixed, and compressed into tablets (1 tablet).
200mg). Formulation example 2 (capsules) Compound of Example 21 30mg Crystalline cellulose 40mg Crystalline lactose 129mg Magnesium stearate 1mg Total 200mg Take 1000 times the amount of each of the above ingredients, mix them in a conventional manner, fill them into gelatin capsules, and prepare capsules (1 capsules (200 mg). Formulation Example 3 (Inhaler) Dissolve 0.1 g of the compound of Example 21 in approximately 90 ml of a mixture of ethanol, propylene glycol, and purified water (weight ratio: 30:10:60), and add the same mixture to bring the total volume up.
After reducing the volume to 100 ml, each 10 ml was filled into a designated container and sealed to obtain an inhalant.

Claims (1)

[Claims] 1. General formula [The symbols in the formula have the following meanings. R ¹ : Lower acyl group, R ² : Lower alkyl group, A: Lower alkylene group optionally substituted with a hydroxyl group, Y: Oxygen atom, sulfur atom, or carbonylimino group (-CONH-), [Formula]: Selected from 6-membered ring having 1 oxygen atom; 5- to 6-membered ring having 2 nitrogen atoms; 5-membered ring having 3 nitrogen atoms; 5-membered ring having 1 sulfur atom and 1 to 2 nitrogen atoms R ₃ , R ₄ and R ₅ are the same or different, and the heterocycle may be fused with a benzene ring;
Lower alkyl group, group represented by the formula -A ¹ -R ⁶ , hydroxyl group, mercapto group, lower alkoxy group, lower alkylthio group, formula -Y ¹ -A ²
- Group represented by R ⁷ , oxo group (=O), thioxo group (=S), amino group, formula -NH-
A group represented by CO-R ⁹ , a carboxy group, or a group represented by the formula -CO-R ¹⁰ , (however,
When R ³ , R ⁴ and R ⁵ are substituted with a benzene ring condensed with a heterocycle, R ³ , R ⁴ and R ⁵ are hydrogen atoms, amino groups or formulas -NH-
CO—R ⁹ ) A ¹ : Lower alkylene group, R ⁶ : Hydroxyl group or mercapto group, Y ¹ : Oxygen atom or sulfur atom, A ² : Lower alkylene group, R ⁷ : Carboxy group, lower alkoxycarbonyl group, or N-lower alkyl-hydroxyaminocarbonyl group, R ⁹ : carboxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxyphenyl lower alkoxycarbonyl lower alkyl group, carboxy group, or lower alkoxycarbonyl group, R ¹⁰ : Lower alkoxy group. However, when [Formula] is a heterocycle condensed with a benzene ring, Y is bonded to the heterocycle. ] A heterocyclic compound or a salt thereof. 2 General formula () [The symbols in the formula have the following meanings. ^R1 : lower acyl group, ^R2 : lower alkyl group, A: lower alkylene group optionally substituted with a hydroxyl group, X: halogen atom. ] A halogen compound represented by the general formula () [The symbols in the formula have the following meanings. M: hydrogen atom or alkali metal atom, Y ² : oxygen atom is a sulfur atom, [Formula]: 6-membered ring with 1 oxygen atom; 5- to 6-membered ring with 2 nitrogen atoms; has 3 nitrogen atoms 5-membered ring: a heterocycle selected from 5-membered rings having 1 sulfur atom and 1 to 2 nitrogen atoms, which heterocycle may be fused with a benzene ring, R ³ , R ⁴ and R ⁵ : Same or different, hydrogen atom,
Lower alkyl group, group represented by the formula -A ¹ -R ⁶ , hydroxyl group, mercapto group, lower alkoxy group, lower alkylthio group, formula -Y ¹ -A ²
- Group represented by R ⁷ , oxo group (=O), thioxo group (=S), amino group, formula -NH-
A group represented by CO-R ⁹ , a carboxy group, or a group represented by the formula -CO-R ¹⁰ , (however,
When R ³ , R ⁴ and R ⁵ are substituted with a benzene ring condensed with a heterocycle, R ³ , R ⁴ and R ⁵ are hydrogen atoms, amino groups or formulas -NH-
CO—R ⁹ ) A ¹ : Lower alkylene group, R ⁶ : Hydroxyl group or mercapto group, Y ¹ : Oxygen atom is sulfur atom, A ² : Lower alkylene group, R ⁷ : Carboxy group, lower alkoxycarbonyl group, or N-lower alkyl-hydroxyaminocarbonyl group, R ⁹ : carboxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxyphenyl lower alkoxycarbonyl lower alkyl group, carboxy group, or lower alkoxycarbonyl group, R ¹⁰ : Lower alkoxy group. However, when [Formula] is a heterocycle condensed with a benzene ring, Y ² is bonded to the heterocycle moiety. ] General formula (a) characterized by reacting with a hydroxy- or mercapto-compound or an alkali metal substituted product thereof [In the formula, R ¹ , R ² , A, Y ² , [Formula], R ³ , R ⁴ and R ⁵ have the above meanings. ] A method for producing a heterocyclic compound represented by: 3 General formula () [The symbols in the formula have the following meanings. R ¹ : lower acyl group, R ² : lower alkyl group, A: lower alkylene group optionally substituted with a hydroxyl group, and a carboxylic acid or a reactive derivative thereof;
General formula () [The symbols in the formula have the following meanings. [Formula]: 6-membered ring with 1 oxygen atom; 5- or 6-membered ring with 2 nitrogen atoms; 5-membered ring with 3 nitrogen atoms; 5-membered ring with 1 sulfur atom and 1 or 2 nitrogen atoms A heterocycle selected from member rings, which may be fused with a benzene ring, R ³ , R ⁴ and R ⁵ : the same or different, a hydrogen atom,
Lower alkyl group, group represented by the formula -A ¹ -R ⁶ , hydroxyl group, mercapto group, lower alkoxy group, lower alkylthio group, formula -Y ¹ -A ²
- Group represented by R ⁷ , oxo group (=O), thioxo group (=S), amino group, formula -NH-
A group represented by CO-R ⁹ , a carboxy group, or a group represented by the formula -CO-R ¹⁰ , (however,
When R ³ , R ⁴ and R ⁵ are substituted with a benzene ring condensed with a hetero ring, R ³ , R ⁴ and R ⁵ are hydrogen atoms, amino groups or -NH-
CO—R ⁹ ) A ¹ : Lower alkylene group, R ⁶ : Hydroxyl group or mercapto group, Y ¹ : Oxygen atom or sulfur atom, A ² : Lower alkylene group, R ⁷ : Carboxy group, lower alkoxycarbonyl group, or N-lower alkyl-hydroxyaminocarbonyl group, R ⁹ : carboxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxyphenyl lower alkoxycarbonyl lower alkyl group, carboxy group, or lower alkoxycarbonyl group, R ¹⁰ : Lower alkoxy group. However, when [Formula] is a heterocycle condensed with a benzene ring, the amino group is bonded to the heterocycle moiety. ] General formula (b) characterized by reacting with an amino compound represented by [In the formula, R ¹ , R ² , A, [Formula], R ³ , R ⁴ and R ⁵ have the above meanings. ] A method for producing a heterocyclic compound represented by: 4 General formula () [The symbols in the formula have the following meanings. R ¹ : Lower acyl group, R ² : Lower alkyl group, A: Lower alkylene group optionally substituted with a hydroxyl group, Y: Oxygen atom, sulfur atom, or carbonylimino group (-CONH-), [Formula]: 6-membered ring having an oxygen atom; 5- to 6-membered ring having 2 nitrogen atoms; 5-membered ring having 3 nitrogen atoms; 5-membered ring having 1 sulfur atom and 1 to 2 nitrogen atoms A heterocycle, the heterocycle may be fused with a benzene ring, R ⁴ and R ⁵ are the same or different, a hydrogen atom, a lower alkyl group, a group represented by the formula -A ¹ -R ⁶ ,
Hydroxyl group, mercapto group, lower alkoxy group, lower alkylthio group, formula -Y ¹ -A ² -
Group represented by R ⁷ , oxo group (=O), thioxo group (=S), amino group, formula -NH-CO
- A group represented by R ⁹ , a carboxy group, or a group represented by the formula -CO-R ¹⁰ (However, when R ⁴ and R ⁵ are substituted with a benzene ring condensed with a heterocycle, R ⁴ and R ⁵ is a hydrogen atom, an amino group or a group represented by -NH-CO-R ⁹ ), A ¹ : Lower alkylene group, R ⁶ : Hydroxyl group or mercapto group, Y ¹ : Oxygen atom or sulfur atom, A ² : Lower alkylene group, R ⁷ : Carboxy group, lower alkoxycarbonyl group, or N-lower alkyl-hydroxyaminocarbonyl group, R ⁹ : Carboxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxyphenyl lower alkoxycarbonyl lower Alkyl group, carboxy group, or lower alkoxycarbonyl group, R ¹⁰ : lower alkoxy group, M: hydrogen atom or alkali metal atom. However, when [Formula] is a heterocycle condensed with a benzene ring, Y is bonded to the heterocycle moiety. ] ^{Hydroxy- or} mercapto-compounds or ^their alkali metal-substituted products and ^the general formula () means. ] General formula (d) characterized by reacting with a halogen compound represented by [In the formula, R ¹ , R ² , A, Y, [Formula], R ⁴ , R ⁵ , Y ¹ , A ² and R ⁷ have the above meanings. ] A method for producing a heterocyclic compound represented by: 5 General formula (e) [The symbols in the formula have the following meanings. R ¹ : Lower acyl group, R ² : Lower alkyl group, A: Lower alkylene group optionally substituted with a hydroxyl group, Y: Oxygen atom, sulfur atom, or carbonylimino group (-CONH-), [Formula]: Selected from 6-membered ring having 1 oxygen atom; 5- to 6-membered ring having 2 nitrogen atoms; 5-membered ring having 3 nitrogen atoms; 5-membered ring having 1 sulfur atom and 1 to 2 nitrogen atoms R ⁴ and R ⁵ are the same or different, a hydrogen atom, a lower alkyl group, a group represented by the formula -A ¹ -R ⁶ ; ,
Hydroxyl group, mercapto group, lower alkoxy group, lower alkylthio group, formula -Y ¹ -A ² -
Group represented by R ⁷ , oxo group (=O), thioxo group (=S), amino group, formula -NH-CO
- A group represented by R ⁹ , a carboxy group, or a group represented by the formula -CO-R ¹⁰ (However, when R ⁴ and R ⁵ are substituted with a benzene ring condensed with a heterocycle, R ⁴ and R ⁵ is a hydrogen atom, an amino group, or a group represented by the formula -NH-CO-R ⁹ ), A ¹ : Lower alkylene group, R ⁶ : Hydroxyl group, or mercapto group, Y ¹ : Oxygen atom or sulfur atom, A ² : Lower alkylene group, R ⁷ : Carboxy group, lower alkoxycarbonyl group, or N-lower alkyl-hydroxyaminocarbonyl group, R ⁹ : Carboxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxyphenyl lower alkoxycarbonyl lower Alkyl group, carboxy group, or lower alkoxycarbonyl group, R ¹⁰ : lower alkoxy group. However, when [Formula] is a heterocycle condensed with a benzene ring, Y is bonded to the heterocycle moiety. ] An amino compound represented by the general formula () HOOC-R ⁹ () [wherein R ⁹ represents the above-mentioned meaning. ] General formula (f) characterized by reacting with a carboxylic acid represented by or a reactive derivative thereof [In the formula, R ¹ , R ² , A, Y, [Formula], R ⁴ , R ⁵ , and R ⁹ have the above meanings. ] A method for producing a heterocyclic compound represented by: 6 General formula (g) [The symbols in the formula have the following meanings. R ¹ : Lower acyl group, R ² : Lower alkyl group, A: Lower alkylene group optionally substituted with a hydroxyl group, Y: Oxygen atom, sulfur atom, or carbonylimino group (-CONH-), [Formula]: Selected from 6-membered ring having 1 oxygen atom; 5- to 6-membered ring having 2 nitrogen atoms; 5-membered ring having 3 nitrogen atoms; 5-membered ring having 1 sulfur atom and 1 to 2 nitrogen atoms R ⁴ and R ⁵ are the same or different, a hydrogen atom, a lower alkyl group, a group represented by the formula -A ¹ -R ⁶ , which may be fused with a benzene ring. ,
Hydroxyl group, mercapto group, lower alkoxy group, lower alkylthio group, formula -Y ¹ -A ² -
Group represented by R ⁷ , oxo group (=O), thioxo group (=S), amino group, formula -NH-CO
- A group represented by R ⁹ , a carboxy group, or a group represented by the formula -CO-R ¹⁰ (However, when R ⁴ and R ⁵ are substituted with a benzene ring condensed with a heterocycle, R ⁴ and R ⁵ is a hydrogen atom, an amino group, or a group represented by the formula -NH-CO-R ⁹ ), A ¹ : Lower alkylene group, R ⁶ : Hydroxyl group, or mercapto group, Y ¹ : Oxygen atom or sulfur atom, A ² : Lower alkylene group, R ⁷ : Carboxy group, lower alkoxycarbonyl group, or N-lower alkyl-hydroxyaminocarbonyl group, R ⁹ : Carboxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxyphenyl lower alkoxycarbonyl lower Alkyl group, carboxy group, or lower alkoxycarbonyl group, R ¹⁰ : lower alkoxy group. However, when [Formula] is a heterocycle condensed with a benzene ring, Y is bonded to the heterocycle moiety. ] A carboxylic acid or a reactive derivative thereof, and
General formula (XI) [In the formula, R ¹¹ means a lower alkyl group, and R ¹² means a hydroxy group. ] General formula (h) characterized by reacting with an amine represented by [In the formula, R ¹ , R ² , A, Y, [Formula], R ⁴ , R ⁵ , Y ¹ , A ² , R ¹¹ and R ¹² have the above meanings. ] A method for producing a heterocyclic compound represented by: 7 General formula (i) [The symbols in the formula have the following meanings. R ¹ : Lower acyl group, R ² : Lower alkyl group, A: Lower alkylene group optionally substituted with a hydroxyl group, Y: Oxygen atom, sulfur atom, or carbonylimino group (-CONH-), [Formula]: Selected from 6-membered ring having 1 oxygen atom; 5- to 6-membered ring having 2 nitrogen atoms; 5-membered ring having 3 nitrogen atoms; 5-membered ring having 1 sulfur atom and 1 to 2 nitrogen atoms It is a heterocycle with
The heterocycle may be fused with a benzene ring, R ⁴ and R ⁵ are the same or different, a hydrogen atom, a lower alkyl group, a group represented by the formula -A ¹ -R ⁶ ,
Hydroxyl group, mercapto group, lower alkoxy group, lower alkylthio group, formula -Y ¹ -A ² -
Group represented by R ⁷ , oxo group (=O), thioxo group (=S), amino group, formula -NH-CO
- A group represented by R ⁹ , a carboxy group, or a group represented by the formula -CO-R ¹⁰ , (However, when R ³ , R ⁴ and R ⁵ are substituted with a benzene ring condensed with a hetero ring,
R ⁴ and R ⁵ are hydrogen atoms, amino groups or formulas -
NH—CO—R ⁹ ) A ¹ : Lower alkylene group, R ⁶ : Hydroxyl group or mercapto group, Y ¹ : Oxygen atom or sulfur atom, A ² : Lower alkylene group, R ⁷ : Carboxy group, lower Alkoxycarbonyl group, or N-lower alkyl-hydroxyaminocarbonyl group, R ⁹ : carboxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxyphenyl lower alkoxycarbonyl lower alkyl group, carboxy group, or lower alkoxycarbonyl group, R ¹⁰ : Lower alkoxy group, Y ³ : Single bond, oxygen atom, sulfur atom, or imino group (-NH-), A ³ : Single bond, lower alkylene group, or carbonyl group or carbonyl when Y ³ is an imino group. Lower alkylene group, R ¹³ : lower alkyl group or lower alkoxyphenyl lower alkyl group. However, when [Formula] is a heterocycle condensed with a benzene ring, Y is bonded to the heterocycle moiety. ] General formula (j) characterized by hydrolyzing the ester represented by [In the formula, R ¹ , R ² , A, Y, [Formula], R ⁴ , R ⁵ , Y ³ and A ³ have the above meanings. ] A method for producing a heterocyclic compound represented by: 8 General formula (XII) [The symbols in the formula have the following meanings. ^R1 : lower acyl group, ^R2 : lower alkyl group, M: hydrogen atom or alkali metal atom. ] Dihydroxybenzene derivative or its alkali metal substituted product and general formula () [The symbols in the formula have the following meanings. X: halogen atom, A: lower alkylene group optionally substituted with a hydroxyl group, Y: oxygen atom, sulfur atom, or carbonylimino group (-CONH-), [Formula]: 6-membered ring having one oxygen atom ; 5- to 6-membered ring having 2 nitrogen atoms; 5-membered ring having 3 nitrogen atoms; 5-membered ring having 1 sulfur atom and 1 to 2 nitrogen atoms; The ring may be fused with a benzene ring, R ³ ′, R ⁴ ′, and R ⁵ ′: the same or different, hydrogen atom, lower alkyl group, hydroxyl group, lower alkoxy group, lower alkylthio group, formula -Y ¹ -
A group represented by A ² - R ⁷ ', oxo group (=O),
An amino group, a group represented by the formula -NH-CO-R ⁹ ', or a group represented by the formula -CO-R ¹⁰ (However, benzene in which R ³ ', R ⁴ ' and R ⁵ ' are fused with a heterocycle) When substituted on a ring, R ³ ′, R ⁴ ′, and R ⁵ ′ are a hydrogen atom, an amino group, or a group represented by -NHCO-R ⁹ ′) A ¹ : Lower alkylene group, Y ¹ : Oxygen atom or a sulfur atom, A ² : lower alkylene group, R ⁷ ′: lower alkoxycarbonyl group, or N-
lower alkyl-hydroxyaminocarbonyl group, R ⁹ ′ : lower alkoxycarbonyl lower alkyl group,
Lower alkoxyphenyl lower alkoxycarbonyl lower alkyl group or lower alkoxycarbonyl group, R ¹⁰ : lower alkoxy group. However, when [Formula] is a heterocycle condensed with a benzene ring, Y is bonded to the heterocycle moiety. ] General formula (k) characterized by reacting with a halogen compound represented by [In the formula, R ¹ , R ² , A, Y, [Formula], R ³ ′, R ⁴ ′ and R ⁵ ′ have the above meanings. ] A method for producing a heterocyclic compound represented by: 9 General formula () [The symbols in the formula have the following meanings. R ¹ : lower acyl group, R ² : lower alkyl group, A ⁴ : single bond or lower alkylene group having 1 to 4 carbon atoms. ] Epoxy compound shown by and general formula () [The symbols in the formula have the following meanings. M: hydrogen atom or alkali metal atom, Y ² : oxygen atom or sulfur atom, [Formula]: 6-membered ring with 1 oxygen atom; 5- to 6-membered ring with 2 nitrogen atoms; 3 nitrogen atoms 5-membered ring; a heterocycle selected from 5-membered rings having 1 sulfur atom and 1 to 2 nitrogen atoms,
The heterocycle may be fused with a benzene ring R ³ , R ⁴ , R ⁵ : the same or different, a hydrogen atom, a lower alkyl group, a group represented by the formula -A ¹ -R ⁶ ,
Hydroxyl group, mercapto group, lower alkoxy group, lower alkylthio group, formula -Y ¹ -A ² -
A group represented by ^R7 , an oxo group (=O), an amino group, a group represented by the formula -NH-CO- ^R9 ,
A carboxy group or a group represented by the formula -CO-R ¹⁰ (However, when R ³ , R ⁴ and R ⁵ are substituted with a benzene ring fused with a hetero ring,
R ³ , R ⁴ and R ⁵ are a hydrogen atom, an amino group, or a group represented by the formula -NHCO-R ⁹ ) A ¹ : Lower alkylene group, R ⁶ : Hydroxyl group or mercapto group, Y ¹ : Oxygen atom or sulfur atom , ^A2 : Lower alkylene group, ^R7 : Carboxy group, lower alkoxycarbonyl group, or N-lower alkyl-hydroxyaminocarbonyl group, ^R9 : Carboxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxyphenyl lower Alkoxycarbonyl lower alkyl group, carboxy group, or lower alkoxycarbonyl group, R ¹⁰ : lower alkoxy group. However, [Formula] is bonded to the heterocyclic part condensed with the benzene ring. ] General formula (l) characterized by reacting with a hydroxy- or mercapto-compound represented by or an alkali metal substituted product thereof [In the formula, R ¹ , R ² , R ⁴ , Y ² , [Formula], R ³ , R ⁴ and R ⁵ have the above meanings. ] A method for producing a heterocyclic compound represented by: