JPH0616663A - Tetrahydrobenzo(b)thiophene derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a new tetrahydrobenzo[b]thiophene derivative useful as a therapeutic agent for endotoxin shock developing in a patient with serious infectious disease of Gram-positive bacteria. CONSTITUTION:The compound of formula I [R<1> is lower alkyl or (substituted) phenyl; dotted line shows presence or absence of double bond] such as 2-[4,5- dihydropyridazin-3(2H)-on-6-yl]-5-[(2-methylphenyl)sulfonylamino]4,5,6,7- tetrahydrobenzo[b]thiophene. The compound of formula I is obtained by reacting compound of formula II with a compound of formula III (X is reactive residue). The raw material compound of formula II is a new compound and is obtained by starting a compound of formula IV (Y is H or Cl).

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel tetrahydrobenzo [b] thiophene derivative having an endotoxin shock-protecting action and a method for producing the same.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 3-223277 discloses 4-
[4- (4-chlorobenzenesulfonamidomethyl)-
It is disclosed that a benzothiophene derivative such as 4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl] -4-oxobutanoic acid ethyl ester exhibits a platelet aggregation inhibitory action. On the other hand, steroid hormones, aprotinin (protease inhibitor), dobutamine (cardiotonic drug) and the like have been conventionally used as therapeutic agents for endotoxin shock that develops in patients with severe infection with Gram-negative bacteria.

[0003]

DISCLOSURE OF THE INVENTION The present invention provides a novel compound having an excellent endotoxin shock protective action.

[0004]

The tetrahydrobenzo [b] thiophene derivative according to the present invention has the general formula [I]

[0005]

[Chemical 9]

(Wherein R ¹ represents a lower alkyl group or a phenyl group which may have a substituent, and the dotted line represents the presence or absence of a double bond).

Specific examples of the object [I] of the present invention include:
R ¹ is 1) lower alkyl group, or 2) lower alkyl group,
Examples thereof include compounds having a phenyl group which may be substituted with a group selected from a lower alkoxy group, halogen, nitro group, hydroxyl group, cyano group, amino group, mono-lower alkylamino group and di-lower alkylamino group.

In the object [I] of the present invention, specific examples of the lower alkyl group and the lower alkoxy group include an alkyl group and an alkoxy group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms.

Among the objects [I] of the present invention, a compound in which R ¹ is a phenyl group which may be substituted with a group selected from an amino group, a mono-lower alkylamino group and a di-lower alkylamino group is It can be in the form of a pharmaceutically acceptable salt. Examples of the pharmacologically acceptable salt include inorganic acid salts such as hydrochloride, sulfate and hydrobromide, and organic acid salts such as fumarate, oxalate and maleate. .

The object [I] of the present invention and a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and are mixed with an excipient suitable for oral or parenteral administration. However, it can be used as a pharmaceutical preparation. Further, the pharmaceutical preparation may be a solid preparation such as a tablet, a capsule or a powder, or a liquid preparation such as a solution, a suspension or an emulsion. Further, for parenteral administration, it can be used in the form of injection. The dose varies depending on the age, weight, condition of the patient or the degree of disease, but the daily dose is usually 1 to 200 mg / kg, especially 10 to 100 mg / kg, orally for parenteral administration. In the case of 0.1 to 30 mg / kg, especially 1 to 20 mg / kg
It is preferably kg.

According to the present invention, the target [I] is, for example, a compound of the general formula [II]

[0012]

[Chemical 10]

(Wherein the symbols have the same meanings as described above) or a salt thereof is represented by the general formula [III]

[0014]

[Chemical 11]

(In the formula, X represents a reactive residue, and other symbols have the same meanings as described above).

Further, among the target compounds [I], a compound in which a dotted line represents the absence of a double bond, that is, a compound of the general formula [IA]

[0017]

[Chemical 12]

(Wherein the symbols have the same meanings as above), the compounds represented by the general formula [IV]

[0019]

[Chemical 13]

It can be produced by reacting a compound represented by the formula (wherein the symbols have the same meanings as described above) with hydrazine. Further, in the target compound [I], a compound in which a dotted line represents the presence of a double bond, that is, a compound of the general formula [IB]

[0021]

[Chemical 14]

The compound represented by the formula (wherein the symbols have the same meanings as described above) can be produced by oxidizing the compound [IA].

In the above production method of the present invention, the compound [I
I] and the compound [III] are condensed in a suitable solvent,
It can be appropriately carried out in the presence or absence of a deoxidizing agent. The reactive residue (X) of the compound [III] is a nucleophilically leaving group such as a halogen atom or an alkoxy group, and when the compound [III] is a symmetrical sulfonic acid anhydride, a lower alkyl group. A sulfonyloxy group, a benzenesulfonyloxy group, a lower alkyl group-substituted benzenesulfonyloxy group and the like can be preferably used.

Examples of the deoxidizing agent include tri-lower alkylamine, N-lower alkylmorpholine, pyridine,
Organic bases such as 2,6-lutidine and inorganic bases such as alkali metal hydroxides, alkali metal hydrogencarbonates and alkali metal carbonates can be preferably used.

The solvent may be an inert solvent which does not adversely influence the reaction, and examples thereof include halogen solvents such as chloroform, dichloromethane and dichloroethane, toluene,
Aromatic hydrocarbons such as xylene, tetrahydrofuran, ethers such as dioxane, ketone solvents such as acetone and methyl ethyl ketone, esters such as ethyl acetate, acetonitrile, pyridine, 2,6-lutidine, dimethylformamide, dimethyl sulfoxide, 1, Examples thereof include 3-dimethyl-2-imidazolidine and the like, and combinations of these solvents and water. The present condensation reaction can be widely carried out at -78 ° C to the boiling point of the reaction mixture, for example, -10 ° C to 150 ° C.
Especially, it can be suitably carried out at -10 ° C to 60 ° C.

The reaction between compound [IV] and hydrazine is
It can be appropriately carried out in a suitable solvent or in the absence of a solvent. The solvent may be an inert solvent that does not adversely influence the reaction, for example, lower alcohol, acetic acid, lower fatty acids such as propionic acid, toluene, aromatic hydrocarbons such as xylene, tetrahydrofuran, ethers such as dioxane. can give. Hydrazine may be a hydrate. This reaction can be carried out over a wide range from room temperature to the boiling point of the reaction mixture, for example 10 ° C to 200 ° C, especially 20 ° C to
It can be suitably carried out at 150 ° C.

Oxidation of compound [IA] can be carried out according to a conventional method, for example, compound [IA] in a suitable solvent.
A] is treated with sodium 3-nitrobenzenesulfonate under basic conditions, or is reacted redox using dimethyl sulfoxide under acidic conditions, or
It can be suitably carried out by subjecting it to a dehydrogenation reaction with bromine-acetic acid or the like. As the solvent, water, acetic acid, trifluoroacetic acid, methanesulfonic acid, acetic acid solution of hydrobromic acid, or the like can be preferably used.

The starting material compound [II] of the present invention is a novel compound, for example, (1) the general formula [V]

[0029]

[Chemical 15]

After protecting the amino group of the compound represented by the formula (wherein Y represents a hydrogen atom or a chlorine atom),
(2) In a suitable solvent, a catalyst (anhydrous aluminum chloride, etc.,
In the presence of a Lewis acid catalyst, which is generally used in Friedel-Crafts reaction, or sulfuric acid or polyphosphoric acid type catalyst), succinic anhydride is reacted, and (3) when Y is a chloro atom, catalytic reduction is performed. It can be produced by removing the atom, (4) reacting the obtained compound with hydrazine in a suitable solvent, and (5) removing the protecting group according to a conventional method.

On the other hand, the starting compound [IV] of the present invention is also a novel compound. For example, (1) the above amino-substituted benzothiophene compound [V] is added to a deoxidizing agent (tri-lower alkylamine, etc. (2) The presence of a catalyst (a Friedel-Crafts reaction catalyst such as anhydrous aluminum chloride) in a suitable solvent by reacting with a sulfone compound [III] in the presence or absence of amines and an inorganic base). It can be produced by reacting with succinic anhydride under the following conditions and (3) when the symbol Y is a chlorine atom, catalytic reduction is performed to remove the chlorine atom.

[0032]

[Action]

Experimental Example (Protection against mouse lethality induced by endotoxin) Male ddy mice fasted for about 24 hours were orally administered with a specimen dissolved or suspended in a 0.25% sodium carboxymethylcellulose (CMC) aqueous solution (100 mg / kg). After 30 minutes, 100 mg / 10 ml / kg of E. coli-derived endotoxin (lipopolysaccharide) dissolved in physiological saline was intraperitoneally administered.
The survival rate of the sample-administered group was calculated when the survival rate of the control group to which the CMC aqueous solution was orally administered reached 20% (about 20 hours after the endotoxin administration). As a result, 2- [4,5
-Dihydropyridazin-3 (2H) -one-6-yl]
-5- (n-butylsulfonylamino) -4,5,6
The survival rate of 7-tetrahydrobenzo [b] thiophene is 9
It was 0%.

[0033]

【Example】

Example 1 (1) A suspension of 5-[(2-methylphenyl) sulfonylamino] -4,5,6,7-tetrahydrobenzo [b] thiophene (2.25 g) and succinic anhydride (1.61 g) in dichloroethane (25 ml) was used. Then, under cooling with ice, 4.39 g of anhydrous aluminum chloride is added, and then the mixture is stirred at room temperature for 3 hours.
The reaction solution is poured into ice water and extracted with ethyl acetate. By washing and drying the obtained organic layer, the solvent is distilled off,
2- (3-Carboxypropionyl) -5-[(2-methylphenyl) sulfonylamino] -4,5,6,7-
3.47 g of tetrahydrobenzo [b] thiophene are obtained.

(2) 3.47 g of the compound obtained above
Hydrazine monohydrate 2.1 in 30 ml of ethanol
Add 8 g and heat to reflux for 3 hours. After cooling, the precipitated crystals were collected by filtration to give 2- [4,5-dihydropyridazin-3 (2H) -on-6-yl] -5-[(2-
Methylphenyl) sulfonylamino] -4,5,6,7
2.31 g of tetrahydrobenzo [b] thiophene are obtained. m. p. : 204-206 ° C

Examples 2-6 The corresponding starting compound was treated in the same manner as in Example 1 to give the following first
The compounds listed are obtained.

[0036]

[Table 1]

Example 7 2- [4,5-Dihydropyridazin-3 (2H) -one-6-yl] -5-[(2-methylphenyl) sulfonylamino] -4,5,6,7-tetrahydro 1.41 g of benzo [b] thiophene was suspended in 8 ml of 25% hydrogen bromide-acetic acid solution, and 0.25 ml of dimethyl sulfoxide.
Is added and the mixture is stirred at room temperature for 2 hours. Then, diisopropyl ether was added to the reaction solution, and the precipitated crystals were collected by filtration to give 2- [pyridazin-3 (2H) -on-6-yl] -5-[(2-methylphenyl) sulfonylamino] -4. 1.00 g of 5,5,6,7-tetrahydrobenzo [b] thiophene are obtained. m. p. : 242-247 ° C

Examples 8-12 The corresponding starting compound was treated in the same manner as in Example 7 to give the following 2nd compound:
The compounds listed are obtained.

[0039]

[Table 2]

Example 13 2- [4,5-Dihydropyridazin-3 (2H) -one-6-yl] -5-amino-4,5,6,7-tetrahydrobenzo [b] thiophene hydrogen iodide Acid salt 1.34
g and 1.2 ml of triethylamine 1,3-dimethyl-
To 20 ml of 2-imidazolidine, 765 mg of benzenesulfonyl chloride is added, and the mixture is stirred at room temperature for 1 hour. The reaction solution is poured into ice water and extracted with ethyl acetate. After washing and drying the organic layer, the solvent is distilled off. By recrystallizing the obtained crystal from nitromethane, 2- [4,5-dihydropyridazin-3 (2H) -one-6-yl] -5-
1.22 g of (phenylsulfonylamino) -4,5,6,7-tetrahydrobenzo [b] thiophene are obtained. m. p. : 212-213 ° C

Example 14 (1) 2- [4,5-dihydropyridazine-3 (2)
H) -on-6-yl] -6-methoxycarbonylamino-4,5,6,7-tetrahydrobenzo [b] thiophene (1.01 g) was dissolved in methanol (10 ml), and potassium hydroxide (560 mg) in water (5 ml) was added. Stir at room temperature for 3 hours. Methanol was distilled off from the reaction solution, the residue was extracted with ethyl acetate, dried and the solvent was distilled off to give 2- [4,5-dihydropyridazine-3 (2H)-.
0.5 g of crystals of on-6-yl] -6-amino-4,5,6,7-tetrahydrobenzo [b] thiophene are obtained.

(2) 0.5 g of the compound obtained above is dissolved in 15 ml of ethyl acetate and 10 ml of tetrahydrofuran, and a solution of 1.54 g of potassium carbonate in 10 ml of water is added and stirred. Then, under ice cooling, 0.7 g of benzenesulfonic acid chloride is added, and the mixture is stirred at room temperature for 1.5 hours. The organic layer is separated, washed and dried, and then the solvent is distilled off. The obtained crystals were recrystallized from tetrahydrofuran-isopropyl ether to give 2- [4,5-dihydropyridazin-3 (2H) -one-6-yl] -6-phenylsulfonylamino-4,5,6,6. 0.52 g of 7-tetrahydrobenzo [b] thiophene is obtained. m. p. : 230-232 ° C

Examples 15 to 16 The corresponding starting compounds were treated in the same manner as in Example 13 to obtain the compounds shown in Table 3 below.

[0044]

[Table 3]

Reference Example 1 A solution of 5-amino-4,5,6,7-tetrahydrobenzo [b] thiophene hydrochloride 2.00 g and triethylamine 2.40 g in 15 ml of methylene chloride was cooled with ice.
A solution of 2.11 g of 2-methylbenzenesulfonic acid chloride in 5 ml of methylene chloride is added dropwise and stirred for 1 hour. After washing and drying the reaction solution, the solvent is distilled off. The obtained crystals were recrystallized from ethyl acetate-hexane to give 5-
[(2-methylphenyl) sulfonylamino] -4,
5,6,7-tetrahydrobenzo [b] thiophene 2.
58 g are obtained. m. p. : 130-132 ° C

Reference Example 2-6 The corresponding starting compound was treated in the same manner as in Reference Example 1 to give the following 4th component.
The compounds listed are obtained.

[0047]

[Table 4]

Reference Example 7 (1) 5-amino-4,5,6,7-tetrahydrobenzo [b] thiophene hydrochloride 3.79 g and triethylamine 4.04 g were added to a solution of 30 ml of methylene chloride in chloroform under ice cooling. 1.89 g of methyl carbonate is added dropwise, and the mixture is stirred at room temperature for 2 hours. Pour the reaction solution into ice water, separate the organic layer,
After drying, the solvent is distilled off. By recrystallizing the obtained crystals from isopropyl ether, 3.80 g of 5-methoxycarbonylamino-4,5,6,7-tetrahydrobenzo [b] thiophene is obtained. m. p. : 108-109 ° C

(2) 5.00 g of the compound obtained above
And succinic anhydride 5.92g dichloroethane 125ml
15.68 g of anhydrous aluminum chloride in the suspension under ice cooling
Is added with stirring, and the mixture is stirred at room temperature overnight. The reaction solution is poured into ice water and extracted with ethyl acetate. After washing and drying the obtained organic layer, the solvent is distilled off to give 2- (3
7.02 g of -carboxypropionyl) -5-methoxycarbonylamino-4,5,6,7-tetrahydrobenzo [b] thiophene are obtained.

(3) 7.02 g of the compound obtained above
5.95 g of hydrazine monohydrate is added to a 200 ml solution of ethanol in 1 above, and the mixture is heated under reflux for 1.5 hours. The solvent was distilled off from the reaction solution, and the obtained crystals were recrystallized from methanol to give 2- [4,5-dihydropyridazine-
3 (2H) -on-6-yl] -5-methoxycarbonylamino-4,5,6,7-tetrahydrobenzo [b]
5.87 g of thiophene are obtained. m. p. : 205-206 ° C

(4) 2.35 g of the compound obtained above
3.26 g of 97% trimethylsilane iodide was added dropwise to a 70 ml solution of chloroform in (1) and heated under reflux for 2 hours. After cooling, 7 ml of methanol is added to the reaction solution and the mixture is stirred. The precipitated crystals were collected by filtration to give 2- [4,5-dihydropyridazin-3 (2H) -one-6-yl] -5-
2.78 g of amino-4,5,6,7-tetrahydrobenzo [b] thiophene hydroiodide are obtained. m. p. :> 300 ℃

Reference Example 8 (1) Reference Example 7 was prepared using 2-chloro-5-amino-4,5,6,7-tetrahydrobenzo [b] thiophene hydrochloride.
Treated in the same manner as-(1), 2-chloro-5-methoxycarbonylamino-4,5,6,7-tetrahydrobenzo [b] thiophene was obtained. m. p. : 120-121 ° C

(2) 2.51 g of the compound obtained above
To a suspension of 2.56 g of succinic anhydride and 50 ml of dichloroethane, 6.80 g of anhydrous aluminum chloride is added with stirring under ice cooling, and the mixture is stirred at room temperature for 7 hours. The reaction solution is poured into ice water and extracted with ethyl acetate. After washing and drying the organic layer, the solvent is distilled off to give 2-chloro-3-
2.83 g of (3-carboxypropionyl) -5-methoxycarbonylamino-4,5,6,7-tetrahydrobenzo [b] thiophene are obtained. m. p. 178-179 ° C

(3) 2.83 g of the compound obtained above
To 10% palladium-carbon (160 mg) is added to a solution of triethylamine (3.5 ml) in methanol (50 ml), and catalytic reduction is performed at room temperature and atmospheric pressure for 2 hours. 10% Palladium-carbon is removed from the reaction solution, and the solvent is distilled off. The residue is neutralized with 5% hydrochloric acid and then extracted with ethyl acetate. Wash the organic layer,
After drying, the solvent was distilled off to give 3- (3-carboxypropionyl) -5-methoxycarbonylamino-
2.45 g of 4,5,6,7-tetrahydrobenzo [b] thiophene are obtained. m. p. 187-188 ° C

(4) 2.45 g of the compound obtained above
2.0 g of hydrazine monohydrate is added to a solution of 100 ml of ethanol in, and the mixture is heated under reflux for 1 hour. The solvent was distilled off from the reaction solution, and the obtained crystals were recrystallized from methanol to give 3- [4,5-dihydropyridazine-3 (2
H) -on-6-yl] -5-methoxycarbonylamino-4,5,6,7-tetrahydrobenzo [b] thiophene 2.18 g is obtained. m. p. : 223-224 ° C

(5) The compound obtained above was used as Reference Example 7.
Treated in the same manner as-(4), 3- [4,5-dihydropyridazin-3 (2H) -one-6-yl] -5-amino-4,5,6,7-tetrahydrobenzo [b] Obtain thiophene hydroiodide. m. p. :> 300 ℃

Reference Example 9 (1) 6-Amino-4,5,6,7-tetrahydrobenzo [b] thiophene hydrochloride was treated in the same manner as in Reference Example 7- (1) to give 6-methoxycarbonylamino. -4
5,6,7-Tetrahydrobenzo [b] thiophene is obtained. m. p. : 156-157 ° C

(2) 1.06 g of the compound obtained above
To a suspension of 1.26 g of succinic anhydride and 25 ml of dichloroethane, 3.32 g of anhydrous aluminum chloride was added with stirring under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, the organic layer was separated, washed and dried, and then the solvent was distilled off to recrystallize the resulting crystals to give 2 crystals.
1.10 g of-(3-carboxypropionyl) -6-methoxycarbonylamino-4,5,6,7-tetrahydrobenzo [b] thiophene are obtained. m. p. : 114-116 ° C

(3) 1.10 g of the compound obtained above
Hydrazine monohydrate (1.00 g) in 10 ml of acetic acid solution
Is added and heated under reflux for 1 hour. Pour the reaction solution into ice water,
Extract with ethyl acetate. After washing and drying the organic layer, the solvent was distilled off to give 2- [4,5-dihydropyridazin-3 (2H) -one-6-yl] -6-methoxycarbonylamino-4,5,6,6. 1.01 g of 7-tetrahydrobenzo [b] thiophene is obtained as a foam. 1R ^neat ν _max (cm ⁻¹ ): 3280,169
0.1660 Mass (m / z): 307 (M ⁺ ).

[0060]

INDUSTRIAL APPLICABILITY The tetrahydrobenzo [b] thiophene derivative [I] and its pharmacologically acceptable salts, which are the objects of the present invention, have an excellent endotoxin shock-protecting action, and therefore, for example, severe gram-negative bacteria It is useful as a therapeutic drug for endotoxin shock that develops in patients with infectious diseases.

 ─────────────────────────────────────────────────── --- Continuation of the front page (72) Inventor Koji Tamura 2-385 Kitabukuro, Omiya City, Saitama Prefecture Tanabe Pharmaceutical Omiya Dormitory (72) Inventor Yasuhiko Sasaki 85-1 Kanda, Urawa City, Saitama Prefecture 410 Urawa New Heights

Claims (5)

[Claims] 1. A compound represented by the general formula [I]: (In the formula, R ¹ represents a lower alkyl group or a phenyl group which may have a substituent, and the dotted line represents the presence or absence of a double bond.) Or a tetrahydrobenzo [b] thiophene derivative or A pharmacologically acceptable salt thereof. 2. R ¹ is selected from 1) lower alkyl group, or 2) lower alkyl group, lower alkoxy group, halogen, nitro group, hydroxyl group, cyano group, amino group, mono-lower alkylamino group and di-lower alkylamino group. The compound according to claim 1, which is a phenyl group which may be substituted with a selected group. 3. A compound represented by the general formula [II]: (In the formula, the dotted line represents the presence or absence of a double bond.) The compound represented by the formula [III] (In the formula, R ¹ is a lower alkyl group or a phenyl group which may have a substituent, and X represents a reactive residue.), And the product is optionally pharmacologically reacted. A compound of the general formula [I] wherein the salt is an acceptable salt (In the formula, symbols have the same meaning as described above.) A process for producing a tetrahydrobenzo [b] thiophene derivative or a pharmaceutically acceptable salt thereof. 4. A compound represented by the general formula [IV]: (Wherein R ¹ represents a lower alkyl group or a phenyl group which may have a substituent) is reacted with hydrazine, and the product is optionally treated with a pharmacologically acceptable salt thereof. The general formula [IA] is characterized by (In the formula, symbols have the same meaning as described above.) A process for producing a tetrahydrobenzo [b] thiophene derivative or a pharmaceutically acceptable salt thereof. 5. A compound represented by the general formula [IA]: (In the formula, R ¹ represents a lower alkyl group or a phenyl group which may have a substituent.) The compound represented by the general formula [IB] characterized by being oxidized. (In the formula, symbols have the same meaning as described above.) A process for producing a tetrahydrobenzo [b] thiophene derivative or a pharmaceutically acceptable salt thereof.