JPH0768224B2 - Benzimidazole derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention has a strong selective leukotriene antagonism and is useful for the prevention and treatment of allergic diseases such as asthma, benzimidazole derivatives, intermediates thereof and It relates to their manufacturing method.

[Conventional technology]

Leukotrienes (leukotrienes C ₄ , D ₄ , and E ₄ ), which are metabolites of the 5-lipoxygenase system of arachidonic acid, are considered to be major causative agents of immediate-type allergic diseases such as bronchial asthma. reacting substance of
anaphylaxis) is a component.

Therefore, drugs that antagonize leukotrienes are expected as useful antiallergic agents, but few drugs are orally effective, and no practical examples have been reported so far.

In addition, the present inventors previously described the following general formula It was found that the compound represented by the formula (5) has a leukotriene antagonism and was disclosed as JP-A-61-186368.

[Problems to be Solved by the Invention and Means for Solving the Problems] As a result of further intensive studies, the present inventors have found that the compound represented by the general formula [I] is a potent and selective leukotriene antagonist. They found that they have an effect and completed the invention.

[Wherein R ¹ is a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms or a dimethylaminopropyl group, R ² is a hydrogen atom or a lower alkanoyl group having 1 to 3 carbon atoms, and R ³ is hydrogen base paper, carbon A lower alkyl group having 1 to 3 carbon atoms or 1 to 3 carbon atoms
, A lower alkanoyl group of X is a sulfur atom, a sulfinyl group, a sulfonyl group, an amino group or a methylene group,
Is an alkylene group having 1 to 12 carbon atoms which may be substituted with a hydroxyl group or a lower alkyl group having 1 to 3 carbon atoms,-(CH
R ') _n -CR "= CR"-(CHR') _m- , (Here, R ′ and R ″ are each independently a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms or a hydroxyl group, and n and m are 0 to 3
Represents an integer) and Y represents an oxygen atom or a sulfur atom. ] The benzimidazole derivative represented by these, its acid addition salt, alkali salt, and hydrate.

According to the present invention, the compound represented by the general formula [I] can be produced by the route described below.

(1) The compound of the general formula [I] in which X represents a sulfur atom and R ² represents a hydrogen atom is a compound represented by the general formula [III] or the general formula [III ′] in the compound of the general formula [II]. It is manufactured by acting. Typically, the presence of a base such as potassium carbonate, sodium carbonate or potassium hydroxide in the compound represented by the general formula [II] in a suitable solvent such as dimethylformamide, dimethylsulfoxide or alcohol. It is produced by reacting a compound represented by the general formula [III] or the general formula [III ′] below.

[In the formula, R ¹ and R ³ are as described above. ] [In the formula, A and Y are as described above, and Z represents a leaving group. (2) Further, the compound of the general formula [I] in which X represents a methylene group is produced by reacting the compound of the general formula [IV] with the compound of the general formula [V]. Typically, a compound of the general formula [IV] is reacted with a compound of the general formula [V] in a suitable solvent, for example, a polar solvent such as ethanol or methanol, and then, for example, potassium hydroxide, sodium hydroxide or the like. It is manufactured by adding an aqueous base solution and stirring with heating.

[In the formula, R ¹ is as described above. ] [In the formula, R ⁴ represents a lower alkyl group having 1 to ⁴ carbon atoms,
R ² , A and Y are as described above. (3) The compound of the general formula [I] in which X is a sulfinyl group is produced by oxidizing the compound of the general formula [I] in which X is a sulfur atom. Typically, the compound of the general formula [I]
By reacting a compound in which X is a sulfur atom with an equivalent or excess mild oxidant such as m-chloroperbenzoic acid or hydrogen peroxide in an appropriate amount of solvent such as methylene chloride or alcohol. Manufactured.

(4) The compound of the general formula [I] in which X is a sulfonyl group is produced by oxidizing the compound of the general formula [I] in which X is a sulfur atom. Typically, the compound of the general formula [I]
And a compound in which X is a sulfur atom is treated with a double amount or an excess of a mild oxidant similar to (3).

(5) the general formula [I] in R ² is prepared by compound esterified R ² is a hydrogen atom in the compound is a lower alkanoyl group having 1 to 3 carbon atoms general formula [I]. Typically, for the compound of the general formula [I] in which R ² is a hydrogen atom, in the presence of an excess base such as pyridine, triethylamine or 4-dimethylaminopyridine in an inert solvent such as methylene chloride or chloroform. Alternatively, it is prepared by reacting an alkanoic acid derivative such as an acid chloride or an acid anhydride in pyridine.

[Wherein R ¹ , R ² , R ³ , X, A and Y are as described above. Next, if desired, the compound represented by the general formula [I] can be converted into its salt according to a conventional method. Examples of the acid addition salts include salts with inorganic acids such as lead acid, sulfuric acid and phosphoric acid, salts with organic acids such as methanesulfonic acid, lactic acid, acetic acid, citric acid and tartaric acid. Examples of the alkali salt include alkali metal salts such as sodium and potassium.

Further, the compound represented by the general formula [V] is also novel and is produced from the compound represented by the general formula [VI]. Typically, it is produced by adding a suitable solvent such as ether and alcohol to the compound represented by the general formula [VI], and reacting with hydrogen chloride under cooling.

[In the formula, R ² , R ⁴ , A and Y are as described above. ] [In the formula, R ² , A and Y are as described above. EXAMPLES Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.

Example 1 2- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propylthio] benzimidazole-
Preparation of 5-carboxylic acid 2-mercaptobenzimidazole-5-carboxylic acid 3.
25 g (10.3 mmol), 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propyl bromide 2.00 g
(10.3 mmol) and 1.27 g (22.6 mmol) of potassium hydroxide were added to 30 ml of ethanol, and the mixture was heated under reflux for 4 hours. The reaction solution was poured into ice water, acidified with concentrated hydrochloric acid, extracted with ethyl acetate and concentrated. The residue was separated and purified by silica gel column chromatography (methylene chloride: ethyl acetate: methanol = 10: 2: 1), and recrystallized from n-hexane-ethyl acetate to obtain 3.00 g of the desired product as a pale yellow powdery crystal.

Yield 68.0%, melting point 106-108 ° C Elemental analysis value (%): Calculated value as C ₂₂ H ₂₄ N ₂ O ₅ S (actual value): C, 61.67 (61.76): H, 5.65 (5.89):
N, 6.54 (6.26) Example 2 2- [2- (4-acetyl-3-hydroxy-2-propylphenoxy) ethylthio] benzimidazole-5.
-Production Method of Carboxylic Acid 2- (4-Acetyl-3-hydroxy-2-propylphenoxy) ethyl bromide 2.71 g (9.00 mmol) and 2
-Ethyl mercaptobenzimidazole-5-carboxylate 2.00 g (9.00 mmol) 30 ml of N, N-dimethylformamide
, 1.49 g (10.78 mmol) of potassium carbonate (anhydrous) was added, and the mixture was stirred at 80 to 90 ° C for 30 minutes. The reaction solution was poured into ice water, acidified with concentrated hydrochloric acid, extracted with ethyl acetate and washed with water,
Anhydrous sodium sulfate dried and concentrated. The residue was separated and purified by silica gel column chromatography (methylene chloride: ethyl acetate = 10: 1) to obtain 2.33 g of a yellow oily ester compound (yield 58.5%). 2.20 g (4.97 mmol) of this ester form 1
The mixture was added to 20 ml of N sodium hydroxide aqueous solution and heated under reflux for 30 minutes. The reaction solution was poured into ice water, acidified with concentrated hydrochloric acid, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography (methylene chloride: methanol = 10: 1), and n-hexane-
The target product, 1.60, which is colorless powder crystal recrystallized from ethyl acetate
got g.

Yield 77.7%, melting point 108-110 ° C Elemental analysis value (%): Calculated value as C ₂₁ H ₂₂ N ₂ O ₅ S (actual value): C, 60.86 (60.65): H, 5.35 (5.35: N,
6.76 (6.61) Example 3 Preparation of 2- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropylthio] benzimidazole-5-carboxylic acid In the same manner as in Example 2, 3 Yellow oil from 1.91 g (7.63 mmol) of-(4-acetyl-3-hydroxy-2-propylphenoxy) -1,2-epoxypropane and 1.70 g (7.65 mmol) of ethyl 2-mercaptobenzimidazole-5-carboxylate. 2.10 g (yield 58.2%) of the ester compound was obtained. This was similarly hydrolyzed to obtain 870 mg of the target product, which was a light brown powder crystal.

Yield 44.0%, melting point 133-135 ° C Elemental analysis value (%): Calculated value as C ₂₂ H ₂₄ N ₂ O ₆ S (actual value): C, 59.45 (59.94): H, 5.44 (5.60):
N, 6.30 (6.23) Example 4 2- [3- (3-acetoxy-4-acetyl-2-propylphenoxy) propylthio] benzimidazole-
Preparation of 5-carboxylic acid 2- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propylthio] benzimidazole-
5-carboxylic acid 1.50 g (3.50 mmol), methylene chloride 50 ml,
A mixture of 4 ml of triethylamine, 4 ml of acetic anhydride and 100 mg of 4-dimethylaminopyridine was first cooled with ice and then returned to room temperature and stirred for 5 hours. After adding 4 ml of methanol to the reaction solution and stirring at room temperature for 30 minutes, the reaction solution was concentrated, the residue was washed with water, dissolved in ethanol and concentrated. The residue was separated and purified by silica gel column chromatography (methylene chloride: ethyl acetate: methanol = 10: 2: 1) and recrystallized from n-hexane-chloroform to obtain 970 mg of the desired product as a yellow powdery crystal.

Yield 58.2%, melting point 85-87 ° C Elemental analysis value (%): Calculated as C ₂₄ H ₂₆ N ₂ O ₆ S _1/3 H ₂ O (actual value): C, 60.49 (60.64): H, 5.64 (5.78):
N, 5.88 (5.72) Example 5 Preparation of 2- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propylsulfinyl] benzimidazole-5-carboxylic acid 2- [3- (4-acetyl- 3-Hydroxy-2-propylphenoxy) propylthio] benzimidazole-
5-carboxylic acid 1.00 g (2.33 mmol) was added to methylene chloride 30 ml,
Dissolve in a mixed solution of 3 ml of methanol, and 503 mg (2.33 mmo) of m-chloroperbenzoic acid (80%) with cooling and stirring at 0 ° C or lower.
l) was added little by little and the mixture was stirred at the same temperature for 15 minutes. The reaction solution was concentrated and the residue was subjected to silica gel column chromatography (methylene chloride: ethyl acetate: methanol = 10: 2: 1).
Was separated and purified by and recrystallized from ethanol-water to obtain 540 mg of the desired product as colorless powder crystals.

Yield 52.1%, melting point 173-175 ° C Elemental analysis value (%): Calculated value as C ₂₂ H ₂₄ N ₂ O ₆ S (actual value): C, 59.45 (59.61): H, 5.44 (5.46):
N, 6.30 (6.30) Example 6 Preparation of 2- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propylsulfonyl] benzimidazole-5-carboxylic acid 2- [3- (4- Acetyl-3-hydroxy-2-propylphenoxy) propylthio] benzimidazole-
5-carboxylic acid 1.08 g (2.52 mmol) was added to methylene chloride 30 ml,
Dissolve in a mixture of 3 ml of methanol and stir at 5-10 ° C with m-chloroperbenzoic acid (80%) 1.20 g (5.56 mmol)
Was added little by little, and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was concentrated, the residue was separated and purified by silica gel chromatography (methylene chloride: ethyl acetate: methanol = 10: 2: 1), and recrystallized from n-hexane-ethyl acetate to give the desired product as colorless powder crystals (890 mg). Got

76.7% yield, mp 212 to 215 ° C. (decomposition) Elemental analysis (%): Calculated _{C 22 H 24 N 2 O 7} S ( Found): C, 57.38 (57.50) : H, 5.25 (5.27) :
N, 6.08 (6.09) Examples 7 to 31 The compounds shown in Table 1 (Examples 7 to 31) were synthesized in the same manner as in Examples 1 to 6.

Example 32 Method for producing ethyl 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentanimidate hydrochloride 5- (4-acetyl-3-hydroxy-2-propylphenoxy) valeronitrile 5.5 g, ethanol 0.95 A mixture of 30 ml of ether and 30 ml of ether was cooled with a freezing agent (salt-ice), and hydrogen chloride was absorbed for 20 minutes at 0 ° C or lower. It was left at the same temperature for 30 minutes and then left in the refrigerator overnight. The solvent was distilled off under reduced pressure, and ether was added to the residue for crystallization to give colorless crystals of the desired product 4.0 g
Got

Yield 75.0%, melting point 104-105 ° C Elemental analysis value (%): Calculated as C ₁₈ H ₂₇ NO ₄ · HCl · 1 / 2H ₂ O (actual value): C, 58.93 (58.75): H, 7.97 ( 7.75):
N, 3.82 (4.02) Examples 33 to 35 Compounds shown in Table 2 in the same manner as in Example 32 (Examples 33 to 35)
35) was synthesized.

Example 36 2- [4- (4-Acetyl-3-hydroxy-2-propylphenoxy) butyl] benzimidazole-5-carboxylic acid 5- (4-Acetyl-3-hydroxy-2-propylphenoxy) pentanimidic acid A mixture of 3.0 g of ethyl hydrochloride, 1.4 g of ethyl 3,4-diaminobenzoate and 40 ml of ethanol was stirred at room temperature for 1 day. 1.6 g of sodium hydroxide in 30 ml of water
Was added to the above reaction solution, and the mixture was stirred under reflux for 40 minutes.
The solvent was evaporated under reduced pressure, diluted with ice water, diluted hydrochloric acid was added to acidify the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified by column chromatography (methylene chloride / ethanol = 9: 1, silica gel) to obtain 2.0 g of the desired product in an amorphous form.

Yield 62.7%, melting point 98-100 ° C Elemental analysis value (%): Calculated value as C ₂₃ H ₂₆ N ₂ O ₅ (actual value): C, 67.30 (67.14): H, 6.38 (6.40):
N, 6.82 (6.85) Examples 37 to 39 The compounds shown in Table 3 (Examples 37 to 39) in the same manner as in Example 36.
39) was synthesized.

Example 40 2- [4- (4-Acetyl-3-hydroxy-2-propylphenylthio) butylthio] benzimidazole-
5-carboxylic acid i) 4- (4-acetyl-3-hydroxy-2-propylphenylthio) butyl bromide 1,4-dibromobutane 32.9 g was dissolved in acetone 100 ml,
Add 5.25 g of potassium carbonate (anhydrous) and 1 g of potassium iodide,
Under heating under reflux 2'-hydroxy-4'-mercapto-3 '
-Propylacetophenone 8.00g in acetone (20m
l) was added dropwise over 1 hour, and the mixture was heated under reflux for 2 hours. The insoluble matter was separated, the liquid was concentrated, and the residue was separated and purified by silica gel column chromatography (benzene) to obtain 6.90 g (52.6%) of the desired product as a yellow oily substance.

_{NMRδH (CDCl 3) 0.99 (3H} , t, J = 7Hz, CH 3 CH 2 CH 2 -), 1.
62 (2H, m, CH ₃ CH ₂ CH ₂ −), 1.95 (4H, m, BrCH ₂ (CH ₂ ) ₂ CH ₂ S
−), 2.57 (3H, s, −COCH ₃ ), 2.74 (2H, t, J = 7Hz, CH ₃ CH ₂
CH ₂ −), 2.99 (2H, t, J = 6Hz, BrCH ₂ (CH ₂ ) ₂ CH ₂ S−), 3.43
(2H, t, J = 6Hz , BrCH 2 (CH 2) 2 CH 2 -), 6.70 (1H, d, J =) 9
Hz, 7.50 (1H, d, J = 9Hz, 12.74 (1H, s, -OH) ii) 2- [4- (4-acetyl-3-hydroxy-2)
-Propylphenylthio) butylthio] benzimidazole-5-carboxylate ethyl 2-mercaptobenzimidazole-5-carboxylate 1.29 g was dissolved in N, N-dimethylformamide 20 ml,
After adding 960 mg of potassium carbonate (anhydrous) and stirring at 60-70 ° C for 30 minutes, 4- (4-acetyl-3-hydroxy-2-propylphenylthio) butyl bromide was stirred at the same temperature.
A 2.00 g N, N-dimethylformamide solution (10 ml) was added dropwise over 10 minutes, and the mixture was further stirred at the same temperature for 30 minutes. The reaction solution was poured into ice water, acidified with concentrated hydrochloric acid, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography (methylene chloride: ethyl acetate = 10: 1) to give the desired product as a pale yellow oil 2.
Obtained 53 g (89.8%).

iii) 2- [4- (4-acetyl-3-hydroxy-
2-Propylphenylthio) butylthio] benzimidazole-5-carboxylic acid 2- [4- (4-acetyl-3-hydroxy-2-propylphenylthio) butylthio] benzimidazole-
2.50 g of ethyl 5-carboxylate was dissolved in 30 ml of 1,4-dioxane, 30 ml of an aqueous solution of 1.03 g of sodium hydroxide was added, and 60
The mixture was stirred at 0 ° C for 2 hours. The reaction solution was poured into ice water, acidified with concentrated hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to obtain 1.52 g (64.5%) of the desired product as yellow crystals. Melting point 90-95 ° C,
Elemental analysis: as _{C 23 H 26 N 2 O 4} S 2, Calculated (Found) C, 6
0.24 (60.01): H, 5.71 (5.86): N, 6.11 (5.93) [Effect of the Invention] The compound of the present invention shows a strong leukotriene D ₄ antagonistic action in the isolated ileum of the guinea pig or the tracheal smooth muscle specimen. Remarkably, the compound according to the present invention showed a remarkable inhibitory effect on the tracheal stenosis of guinea pigs caused by leukotriene D ₄ by oral administration, over the control compound.

Male Hartley guinea pigs weighing 450 g were anesthetized with pentobarbital sodium 30 mg / kg (intraperitoneal), and changes in airway pressure were modified by the Konzett-Rssler; J. Harvey et al., J. Pharmacol.M
ethod.9,147-155,1983). The airway narrowing reaction was induced by administering leukotriene D ₄ (3 μg / kg) from a cannula inserted into the left external jugular vein. Prior to administration of leukotriene D ₄ , animals were treated with indomethacin (10 mg / kg) and propranolol (1 mg / kg).
Was administered intravenously. The test compound was suspended in a 5% gum arabic solution and orally administered 2 hours before the administration of leukotriene D ₄ .

The experimental results are shown in Table 4.

As shown in Table 4, the compound of the present invention showed an airway stenosis suppressing effect by oral administration at a lower dose than the control compound.

On the other hand, it is well known that FPL55712, which is known as a typical leukotriene antagonist, does not show any effect by oral administration (P. Sheard et al., Monogr. Allergy, 244-248, S.
Karger, 1977).

7- [3- (4-Acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropoxy] -4-
Oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid sodium salt As is clear from the above results, the compound of the present invention is effective in treating diseases caused by leukotrienes such as bronchial asthma, eyes,
Nose and gastrointestinal allergic diseases and allergic dermatitis,
Further, it is useful for treating circulatory disorders and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location // A61K 31/415 ABF ACD

Claims (7)

[Claims] 1. A general formula [I] [Wherein R ¹ is a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms or a dimethylaminopropyl group, R ² is a hydrogen atom or a lower alkanoyl group having 1 to 3 carbon atoms, and R ³ is a hydrogen atom or a carbon atom] A lower alkyl group having 1 to 3 carbon atoms or 1 to 3 carbon atoms
, A lower alkanoyl group of X is a sulfur atom, a sulfinyl group, a sulfonyl group, an amino group or a methylene group,
Is an alkylene group having 1 to 12 carbon atoms which may be substituted with a hydroxyl group or a lower alkyl group having 1 to 3 carbon atoms,-(CH
R ') _n -CR "= CR"-(CHR') _m- , (Here, R ′ and R ″ are each independently a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms or a hydroxyl group, and n and m are 0 to 3
Represents an integer) and Y represents an oxygen atom or a sulfur atom. ] The benzimidazole derivative represented by these, its acid addition salt, alkali salt, and hydrate. 2. A general formula [II] [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms or a dimethylaminopropyl group, and R ³ represents a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms or a lower alkanoyl group having 1 to 3 carbon atoms. Represents a group. ] To the compound represented by the following general formula [III] Or the general formula [III ′] [Wherein A is a hydroxyl group or an alkylene group having 1 to 12 carbon atoms which may be substituted with a lower alkyl group having 1 to 3 carbon atoms,-(CHR ') _n -CR "= CR"-(CHR') _m −, (Here, R ′ and R ″ are each independently a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms or a hydroxyl group, and n and m are 0 to 3
Represents an integer of), Y is an oxygen atom or a sulfur atom,
Z represents a leaving group. ] The compound according to claim 1, wherein R ² represents a hydrogen atom and X represents a sulfur atom in the general formula [I], wherein an acid addition thereof is carried out. Method for producing salts, alkali salts and hydrates. 3. A general formula [IV] [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms or a dimethylaminopropyl group. ] The compound represented by the following general formula [V] [Wherein R ² represents a hydrogen atom or a lower alkanoyl group having 1 to 3 carbon atoms, R ⁴ represents a lower alkyl group having 1 to ⁴ carbon atoms, A
Is a hydroxyl group or an alkylene group having 1 to 12 carbon atoms which may be substituted with a lower alkyl group having 1 to 3 carbon atoms,-(CHR ') _n -CR "= CR"-(CHR') _m- , (Here, R ′ and R ″ are each independently a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms or a hydroxyl group, and n and m are 0 to 3
Represents an integer) and Y represents an oxygen atom or a sulfur atom. ] The compound according to claim 1, wherein R ³ represents a hydrogen atom and X represents a methylene group in the general formula [I], wherein the compound represented by the formula: Methods for producing salts, alkali salts and hydrates. 4. A general formula [I] [Wherein R ¹ is a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms or a dimethylaminopropyl group, R ² is a hydrogen atom or a lower alkanoyl group having 1 to 3 carbon atoms, and R ³ is a hydrogen atom or a carbon atom] A lower alkyl group having 1 to 3 carbon atoms or 1 to 3 carbon atoms
Is a lower alkanoyl group of A is a hydroxyl group or 1 to 1 carbon atoms.
1 to 3 carbon atoms which may be substituted with a lower alkyl group of 3
12 alkylene groups,-(CHR ') _n -CR "= CR"-(CHR') _m- , (Here, R ′ and R ″ are each independently a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms or a hydroxyl group, and n and m are 0 to 3
Represents the integer) of. ] In the general formula [I], X represents a sulfinyl group or a sulfonyl group, and Y represents an oxygen atom, wherein X is a sulfur atom and Y is an oxygen atom. A method for producing the compound according to claim 1, its acid addition salt, alkali salt and hydrate. 5. General formula [I] [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms or a dimethylaminopropyl group, and R ³ represents a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms or a lower alkanoyl group having 1 to 3 carbon atoms. A group, X is a sulfur atom, a sulfinyl group, a sulfonyl group, an amino group or a methylene group, and A is a hydroxyl group or an alkylene group having 1 to 12 carbon atoms which may be substituted with a lower alkyl group having 1 to 3 carbon atoms, − (CHR ′) _n −CR ″ = CR ″ − (CHR ′) _m −, (Here, R ′ and R ″ are each independently a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms or a hydroxyl group, and n and m are 0 to 3
Represents an integer) and Y represents an oxygen atom or a sulfur atom. ] In the general formula [I], the acid chloride or acid anhydride is allowed to act on the compound wherein R ² is a hydrogen atom,
A method for producing a compound, an acid addition salt thereof, an alkali salt or a hydrate thereof according to claim 1, wherein R ² represents a lower alkanoyl group having 1 to 3 carbon atoms. 6. A general formula [V] [In the formula, R ² , A and Y are as described above, and R ⁴ has 1 carbon atom.
4 represents a lower alkyl group. ] The compound shown by these, or its acid addition salt. 7. A general formula [VI] [Wherein A is a hydroxyl group or an alkylene group having 1 to 12 carbon atoms which may be substituted with a lower alkyl group having 1 to 3 carbon atoms,-(CHR ') _n -CR "= CR"-(CHR') _m −, (Here, R ′ and R ″ are each independently a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms or a hydroxyl group, and n and m are 0 to 3
Represents an integer) and Y represents an oxygen atom or a sulfur atom. ] The alkanolic hydrogen chloride is made to act on the compound shown by these, The manufacturing method of the compound shown by the general formula [V] of Claim 6, or its acid addition salt characterized by the above-mentioned.