JP2001151779A - 4,5,6,7-TETRAHYDROTHIENO[2,3-c]PYRIDINE COMPOUND - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new 4,5,6,7-tetrahydrothieno[2,3-c]pyridine compound. SOLUTION: The objective 4,5,6,7-tetrahydrothieno[2,3-c]pyridine compound is expressed by formula (I) [R is H, methyl or a halogen atom; R1 is a lower alkyl group, a cycloalkyl group, a mono or di(lower alkyl)amino group, an aryl group, a heterocyclic group or a lower alkyl group substituted with an aryl group or a heterocyclic group; R2 is H or a 1-3C alkyl; R3 is a lower alkyl, a lower alkanoyl, a cycloalkylcarbonyl or a di(lower alkyl)amino group which may have an aryl substituent].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to 4,5,6,7-tetrahydrothieno [2,3-c] pyridine compounds, and more particularly to TNF (tumor necrosis factor).
The present invention relates to a 4,5,6,7-tetrahydrothieno [2,3-c] pyridine compound having an inhibitory action on α production.

[0002]

2. Description of the Related Art TNF (tumor necrosis factor) -α is a kind of cytokine produced by activated macrophages and was discovered in 1975 as a factor that induces hemorrhagic necrosis at a tumor site. It is widely recognized as a mediator involved in the mechanism. However,
It is conceivable that disruption of the TNF-α production regulation mechanism, for example, sustained and excessive production may cause various diseases such as tissue damage or cause exacerbation. Therefore, preventing or impairing the overproduction or action of TNF-α may be a useful therapeutic agent for many inflammatory, infectious, immune or malignant diseases. Such diseases include allergies, bronchial asthma, sepsis,
Arthritis (rheumatoid arthritis / osteoarthritis, etc.), diabetes, psoriasis, Crohn's disease, ulcerative colitis and the like.

[0003] Under such technical background, there have been many reports of compounds having an inhibitory action on TNF-α production.
However, there is no disclosure of a 4,5,6,7-tetrahydrothieno [2,3-c] pyridine-based compound, and no description suggesting this is found. Also, JP-A-49-15
No. 93 or DD272078 describes 4,5,6,7-tetrahydrothieno [2,3-c] pyridine-based compounds having the same skeleton as the present invention. In addition to the structure different from the compound of the present invention, none of the compounds suggests a TNF-α production inhibitory action.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a TN
An object of the present invention is to provide a TNF-α production inhibitor useful as a prophylactic or therapeutic agent for a disease induced by F-α.

[0005]

The present inventors have conducted intensive studies in view of the above-mentioned problems, and as a result, have found that 4,5,6,7-tetrahydrothieno [2,3-c] pyridine-based compounds have excellent TNF. It has been found that the compound has an inhibitory effect on -α production, and the present invention has been completed. That is, the present invention provides a compound represented by the general formula (I):

[0006]

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Wherein R represents a hydrogen atom, a methyl group or a halogen atom, and R ₁ represents a lower alkyl group, a cycloalkyl group, a mono- or di-lower alkylamino group, an aryl group, a heterocyclic group, an aryl group or A lower alkyl group substituted by a heterocyclic group, wherein R ₂ is a hydrogen atom or C ₁
To C ₃ alkyl groups, and R ₃ represents a lower alkyl group, a lower alkanoyl group, a cycloalkylcarbonyl group or a di-lower alkylamino group which may be substituted by an aryl group. 4,5,6,7-tetrahydrothieno [2,3-c] pyridine compound represented by the formula: Also,
The present invention relates to a medicament comprising the compound or a hydrate thereof or a pharmacologically acceptable salt thereof as an active ingredient, particularly TNF-
It relates to an α production inhibitor.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The substituents of the compound represented by formula (I) will be described in more detail. R represents a hydrogen atom, a methyl group or a halogen atom. Halogen atom means, for example, fluorine, chlorine, bromine and iodine. In the present invention, R is preferably a hydrogen atom or a chlorine atom, especially a chlorine atom.

R ₁ is a lower alkyl group, a cycloalkyl group, a mono- or di-lower alkylamino group, an aryl group,
A heterocyclic group, or a lower alkyl group substituted by an aryl group or a heterocyclic group. The lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, include linear or branched alkyl group of C ₁ -C _6, such as a tert- butyl group, preferably C ₁ -C ₄ And an alkyl group. The cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, be a cycloalkyl group C ₃ -C ₇ such as cycloheptyl group, in particular cyclopropyl or cyclobutyl group is preferred. The mono- or di-lower alkylamino group means a mono- or di-substituted amino group with the lower alkyl group described above. Specific examples include a methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino group and the like, and a diethylamino group is preferred. The aryl group includes, for example, a phenyl, naphthyl, biphenyl group and the like which may be substituted by a halogen atom, methyl, ethyl, formyl, nitro group and the like. As the heterocyclic group, an oxygen atom, a sulfur atom, and a nitrogen atom other than a carbon atom as a ring-constituting atom are 1 to 2 or less.
Means a 5- to 6-membered monocyclic heterocyclic group having two or more rings. Specifically, there are pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, piperidyl, piperazinyl, morpholinyl group and the like, and preferably a pyridyl group. These heterocyclic groups may be substituted with, for example, a halogen atom, methyl, ethyl, formyl, nitro group or the like, similarly to the aryl group. Examples of the lower alkyl group substituted by an aryl group or a heterocyclic group include the above-mentioned lower alkyl group substituted by an aryl group or a heterocyclic group, preferably a C _{1 to} C ₃ alkyl group. Specifically, benzyl, phenethyl, 1- (4-
A formyl-1-piperazinyl) ethyl group.

R ₂ represents a hydrogen atom or a C ₁ -C ₃ alkyl group, preferably a hydrogen atom, a methyl group or an ethyl group. R ₃ represents a C ₁ -C ₄ alkyl group optionally substituted by an aryl group, a lower alkanoyl group, a cycloalkylcarbonyl group or a di-lower alkylamino group. Examples of the C ₁ -C ₄ alkyl group which may be substituted by the aryl group include methyl, ethyl, propyl, benzyl, phenethyl and the like, preferably methyl, ethyl and benzyl. The lower alkanoyl group means a C ₂ -C ₅ alkanoyl group, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl group and the like, and an acetyl group is particularly preferable. Examples of the cycloalkylcarbonyl group include a cycloalkyl group represented by R ₁ and a carbonyl group bonded thereto, such as cyclopropylcarbonyl and cyclobutylcarbonyl groups.
Preferably, a cyclopropylcarbonyl group is used.
Examples of the di-lower alkylamino group include the same groups as those described for R ₁ , and preferably include dimethylamino, diethylamino, and dipropylamino groups.

Preferred specific examples of the compound represented by the formula (I) used as an active ingredient in the TNF-α production inhibitor of the present invention include the following compounds or salts thereof. 6-acetyl-2-acetylamino-3- (2-chlorobenzoyl) -4,5,6,7-tetrahydrothieno [2,3-c] pyridine 6-acetyl-3- (2-chlorobenzoyl) -2 -Cyclobutylcarbonylamino-4,5,6,7-tetrahydrothieno [2,3-c] pyridine 6-acetyl-3- (2-chlorobenzoyl) -2-cyclopropylcarbonylamino-4,5,6, 7-tetrahydrothieno [2,3-c] pyridine 6-acetyl-3- (2-chlorobenzoyl) -2-isobutyrylamino-4,5,6,7-tetrahydrothieno [2,3-c] pyridine 6-acetyl-3- (2-chlorobenzoyl) -2-pivaloylamino-4,5,6,7-tetrahydrothieno [2,3-c] pyridine 6-acetyl-3-benzoi 2-cyclopropyl-carbonyl-amino-4,5,6,7-tetrahydrothieno [2,3-c] pyridine

6-acetyl-3-benzoyl-2-isobutyrylamino-4,5,6,7-tetrahydrothieno [2,3-c] pyridine 6-benzyl-3- (2-chlorobenzoyl) -2 -Isobutyrylamino-4,5,6,7-tetrahydrothieno [2,3-c] pyridine 6-benzyl-3- (2-chlorobenzoyl) -2-cyclopropylcarbonylamino-4,5,6, 7-tetrahydrothieno [2,3-c] pyridine 6-benzyl-3- (2-chlorobenzoyl) -2-nicotinoylamino-4,5,6,7-tetrahydrothieno [2,3-c] pyridine 3 -(2-chlorobenzoyl) -2-cyclopropylcarbonylamino-6-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine 3- (2-chlorobenzo ) -2-isobutyryl-6-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine

3- (2-chlorobenzoyl) -6-cyclopropylcarbonyl-2-isobutyrylamino-4,
5,6,7-tetrahydrothieno [2,3-c] pyridine 3- (2-chlorobenzoyl) -6-cyclopropylcarbonyl-2-cyclopropylcarbonylamino-4,
5,6,7-tetrahydrothieno [2,3-c] pyridine 3- (2-chlorobenzoyl) -6-cyclopropylcarbonyl-2-nicotinoylamino-4,5,6,7-
Tetrahydrothieno [2,3-c] pyridine 6-acetyl-2-cyclopropylcarbonylamino-
3- (2-methylbenzoyl) -4,5,6,7-tetrahydrothieno [2,3-c] pyridine 6-acetyl-3- (3-chlorobenzoyl) -2-isobutyrylamino-4,5 , 6,7-Tetrahydrothieno [2,3-c] pyridine 6-acetyl-2-isobutyrylamino-3- (2-methylbenzoyl) -4,5,6,7-tetrahydrothieno [2,3- c] pyridine

3- (2-chlorobenzoyl) -6-ethyl-2-isobutyrylamino-4,5,6,7-tetrahydrothieno [2,3-c] pyridine 3- (2-chlorobenzoyl)- 6-ethyl-2- (N
-Ethyl-N-isobutyryl) amino-4,5,6,7
-Tetrahydrothieno [2,3-c] pyridine 6-acetyl-3- (2-chlorobenzoyl) -2-diethylaminocarbonylamino-4,5,6,7-tetrahydrothieno [2,3-c] pyridine N, N-diethyl-N'-methyl-N '-[6-acetyl-3- (2-chlorobenzoyl) -4,5,6,7-
Tetrahydrothieno [2,3-c] pyridin-2-yl] urea 2-acetylamino-3- (2-chlorobenzoyl)-
6-dimethylamino-4,5,6,7-tetrahydrothieno [2,3-c] pyridine 6-acetyl-3- (2-chlorobenzoyl) -2-
(4-Formyl-1-piperazinyl) propionylamino-4,5,6,7-tetrahydrothieno [2,3-
c] pyridine

The compounds of the present invention optionally form hydrates, which are of course included in the present invention. The compound of the present invention is produced by a conventional method,
The typical methods are as follows.

(Production method 1)

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(Wherein R, R ₁ , R ₂ and R ₃ have the above-mentioned meanings). That is, the compound represented by the formula (II) is reacted with an acid halide such as acid chloride or acid bromide. The compound of formula (I ′) is obtained by obtaining a compound of formula (I ′), optionally further metallating the formula (I ′) with an appropriate base, and then reacting the corresponding alkyl halide R ₂ X. Can be obtained.

In each reaction step, for example, a solvent not involved in the reaction such as toluene, xylene, chloroform, dichloromethane, tetrahydrofuran, dimethylformamide or the like is used under an atmosphere of a dry inert gas (nitrogen gas, argon gas, etc.). Is also good. The reaction temperature is usually in the range of room temperature to 200 ° C, preferably 25 ° C to 1 ° C.
It is in the range of 00 ° C. The reaction time is 30 minutes to 48 hours,
Usually, it is completed in 30 minutes to 2 hours.

The reaction is carried out in the presence of inorganic salts such as sodium hydrogencarbonate, sodium carbonate and sodium hydroxide, alkali metal hydrides such as sodium hydride and potassium hydride, or organic salts such as triethylamine, pyridine and piperazine. Preferred results are obtained by performing a halogenation reaction or the like. The compound of formula (I) obtained by these methods can be used as it is or in the form of a salt thereof by known treatment means (eg, extraction, concentration, distillation, crystallization, filtration, recrystallization, various types of chromatography, etc.). And can be purified.

(Production method 2) In the compound represented by the formula (I '), the compound wherein R ₁ is a mono- or di-lower alkylamino group is prepared by the following formula (II) in addition to the above-mentioned production method (1).
Can also be produced as follows using

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(Wherein R and R ₃ have the same meanings as described above). That is, the compound represented by the formula (II) can be added to, for example, tetrahydrofuran, in a dry inert gas (nitrogen gas, argon gas, etc.) atmosphere. After reacting phosgene in a solvent such as dimethoxyethane, diglyme, toluene and benzene,
By subjecting the corresponding amine compound to a condensation reaction, the formula (I ′) can be obtained. The reaction can be easily and safely performed by using bis (trichloromethyl) carbonate instead of phosgene.

The compounds according to the present invention have an inhibitory effect on TNF-α production and are therefore effective for, for example, allergic diseases, rheumatoid arthritis, ulcerative colitis and the like. When the compound according to the present invention is used as an anti-inflammatory drug and an anti-allergic drug, it can be administered by an appropriate administration method such as oral or parenteral. Forms for oral administration include, for example, tablets, granules, capsules, pills, powders and the like, and forms for parenteral administration include, for example, injections,
Inhalants, suppositories, liquid preparations and the like can be mentioned. When formulating these compositions for pharmaceutical administration, they can be prepared according to a conventional method using the compound of the present invention or a salt thereof.

For example, in the case of an oral preparation, lactose, glucose,
Corn starch, excipients such as sucrose, carboxymethylcellulose calcium, disintegrants such as hydroxypropylcellulose, calcium stearate, magnesium stearate, talc, polyethylene glycol, lubricants such as hardened oil, hydroxypropylcellulose, hydroxypropylmethylcellulose, Carboxymethylcellulose, polyvinyl alcohol, gelatin, gum arabic and other binders, glycerin, wetting agents such as ethylene glycol, and other surfactants, if necessary, can be used to prepare a desired dosage form using a flavoring agent and the like. it can. In the case of parenteral preparations, water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, and a diluent such as gum tragarant, if necessary, dissolution aids, buffers, preservatives, flavors, A coloring agent or the like can be used.

When the compound of the present invention is formulated as an antiallergic agent, the dosage unit of the compound of the present invention is 1 to 300 mg / day, preferably 1 to 100 mg / day, and preferably 1 to 100 mg / day for an adult per adult. 0.1 to 10 per day
0 mg, preferably in the range of 0.5 to 30 mg, and a desired therapeutic effect can be expected by divided administration of 1 to 3 times a day each.

[0025]

EXAMPLES Next, synthesis examples and preparation examples of the compounds according to the present invention,
Test examples are shown as examples. Hereinafter, typical examples of the present invention will be described, but it is needless to say that the present invention is not limited thereto. In addition, the production method of the starting material is shown as a production example. The ¹ H-NMR data in the text indicates a chemical shift value using TMS as an internal standard.

Production Example 1 1-Cyclopropylcarbonyl-4-hydroxypiperi
Preparation of gin 10 g of 4-hydroxypiperidine was added to dichloromethane 20
The solution was dissolved in 0 ml, and 16.5 ml of triethylamine was added. In an argon stream, a solution of 8.9 ml of cyclopropylcarbonyl chloride in 50 ml of dichloromethane was added at -60 ° C. The mixture was stirred and reacted at the same temperature for 1 hour. After completion of the reaction, brine and chloroform were added for extraction. By dehydrating the organic layer with magnesium sulfate and concentrating under reduced pressure,
16 g of the target substance was obtained.

Preparation Example 2 Preparation of 1-cyclopropylcarbonyl-4-piperidone 8.1 ml of oxalyl chloride was added to 60 ml of dichloromethane.
and dimethylsulfoxide (10 ml) was slowly added dropwise at -67 ° C in an argon stream. 1-cyclopropylcarbonyl-4-hydroxypiperidine 8.0
g was dissolved in 40 ml of dichloromethane and added dropwise to the above solution at −67 ° C., and the mixture was stirred and reacted for 1 hour. Further, 33 ml of triethylamine was added at the same temperature, and the temperature was returned to room temperature.
After completion of the reaction, brine and chloroform were added for extraction.
The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (elution solvent; ethyl acetate: n-hexane = 3: 1) to obtain 5.7 g of the target substance.

Production Example 3 Production of 2-chloro-cyanoacetophenone 200 ml of THF containing 30 ml of diisopropylamine
132 ml of a 1.6 M hexane solution of n-butyllithium is added dropwise to the solution at 0 ° C. in an argon stream. After stirring for 1 hour, the mixture was cooled to -70 ° C, and 12 ml of acetonitrile was added, and the mixture was stirred and reacted for 1 hour. To this was added a 100 ml THF solution containing 20 g of 2-chlorobenzonitrile, and 2.5
The mixture was stirred and reacted for hours. After completion of the reaction, the reaction was quenched by adding a saturated ammonium chloride solution, extracted with ethyl acetate, washed with brine, and then the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (300 ml), concentrated hydrochloric acid (60 ml) was added at room temperature, and the mixture was stirred and reacted for 2.5 hours.
After the completion of the reaction, brine and dichloromethane were added for extraction. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure,
n-Hexane was added for crystallization. The obtained crystals were filtered and washed with n-hexane to obtain 23.8 g of the target substance.

Production Example 4 2-amino-3- (2-chlorobenzoyl) -6-cycl
Lopropylcarbonyl-4,5,6,7-tetrahydro
Preparation of thieno [2,3-c] pyridine 1-cyclopropylcarbonyl 4-piperidone 4.0
g, sulfur 767 mg, 2-chloro-cyanoacetophenone 4.4 g in N, N-dimethylformamide 40 ml
And triethylamine (3.4 ml) was added at 60 ° C. After completion of the reaction, water and ethyl acetate were added for extraction. The organic layer was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and crystallized by adding methanol. The obtained crystals were filtered and washed with methanol to obtain 5.6 g of the target substance.

Production Example 5 6-acetyl-2-amino-3- (2-chlorobenzoy
) -4,5,6,7-tetrahydrothieno [2,3-
c] Preparation of pyridine 4.0 g of 1-acetyl-4-piperidone, sulfur 767
mg, 2-chloro-cyanoacetophenone (4.4 g) was dissolved in N, N-dimethylformamide (40 ml).
At 37 ° C., 3.4 ml of triethylamine were added. After completion of the reaction, water and ethyl acetate were added for extraction. The organic layer was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and crystallized by adding methanol. The obtained crystals were filtered and washed with methanol to obtain 5.6 g of the target substance.

Production Example 6 2-amino-3- (2-chlorobenzoyl) -6-methyl
-4,5,6,7-tetrahydrothieno [2,3-
c] Preparation of pyridine 4.0 g of 1-methyl-4-piperidone, 1.4 of sulfur
g, 2-chloro-cyanoacetophenone 6.5 g to N,
The resultant was dissolved in N-dimethylformamide (40 ml), and triethylamine (5.0 ml) was added at 60 ° C. After the reaction,
Water and ethyl acetate were added for extraction. The organic layer was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (elution solvent: chloroform: methanol = 70: 1) to obtain 4.8 g of the target substance.

Example 1 6-acetyl-2-acetylamino-3- (2-chloro
Benzoyl) -4,5,6,7-tetrahydrothieno
Synthesis of [2,3-c] pyridine 6-acetyl-2-amino-3- (2-chlorobenzoyl) -4,5,6,7-tetrahydrothieno [2,3-
c] To a solution of 250 mg of pyridine in 2.5 ml of pyridine,
In an argon stream, 70 μl of acetyl chloride was added under ice-cooling, and the mixture was stirred and reacted at the same temperature for 1.5 hours. After completion of the reaction, water and ethyl acetate were added for extraction. The organic layer was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane = 5: 1) to give
273 mg of the desired compound were obtained.

Example 11 6-Acetyl-3- (2-chlorobenzoyl) -2-
(N-isobutyryl-N-methyl) amino-4,5
6,7-tetrahydrothieno [2,3-c] pyridine
Synthetic 6-acetyl-3- (2-chlorobenzoyl) -2-isobutyrylamino-4,5,6,7-tetrahydrothieno [2,3-c] pyridine (200 mg) was dissolved in dimethylformamide (2 ml) and the mixture was cooled to 0 ° C. Then 24 mg of 60% sodium hydride was added. After stirring for 10 minutes in an argon stream, 0.04 ml of methyl iodide was added, and the mixture was returned to room temperature and stirred and reacted overnight. After completion of the reaction, water and ethyl acetate were added for extraction. The organic layer was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and silica gel column chromatography (elution solvent: ethyl acetate: n-hexane = 4:
By purifying in 1), 186 mg of the target compound was obtained.

A method similar to that of Embodiment 1 (however, Embodiment 9
And Example 25 employs the same method as in Example 11) for the compound and ¹ H-NMR data shown in Table 1 below.
1 to Table 3-5.

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[0035]

[Table 1]

[0036]

[Table 2]

[0037]

[Table 3]

[0038]

[Table 4]

[0039]

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[0040]

[Table 5]

[0041]

[Table 6]

[0042]

[Table 7]

[0043]

[Table 8]

[0044]

[Table 9]

[0045]

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[0046]

[Table 10]

[0047]

[Table 11]

[0048]

[Table 12]

[0049]

[Table 13]

[0050]

[Table 14]

Formulation Example 1 (Preparation of Tablet) Compound of the present invention (Compound 1) 250 g Lactose 620 g Corn starch 400 g Hydroxypropylcellulose 20 g Magnesium stearate 10 g After mixing the above compound of the present invention, lactose and corn starch until uniform, hydroxy A 5 W / V% ethanol solution of propylcellulose is added and kneaded and granulated.
After passing through a 16-mesh sieve and sieving, the tablets were compressed in a conventional manner to give tablets each having a weight of 130 mg, a diameter of 7 mm, and a main drug content of 25 mg.

Test Example 1 (TNF-α Production Inhibition Test) Rats were subjected to heparin-treated test tubes under pentobarbital anesthesia to collect blood. RPM equal to blood collected
I-1640 was added, and the mixture was dispensed into a 24-well plate, a solvent (DMSO) or a test drug dissolved in the solvent was added, and preincubation was performed at 37 ° C., 5% CO ₂ for 30 minutes. The reaction was started by the addition of LPS (lipopolysaccharide) and for 4 hours at 37 ° C., 5% CO _2.
And the reaction was stopped in an ice bath. After stopping the reaction, the mixture was centrifuged at 3000 rpm at 4 ° C. for 15 minutes, and TNF-α in the supernatant was measured by ELISA. The activity of the test drug was determined by determining the production inhibition rate with respect to the solvent control group, and determining the concentration of the test drug that inhibited TNF-α production by 50%. The test results are shown in Table 4.

[0053]

[Table 15]

[0054]

The compound of the present invention has an excellent TNF-α production inhibitory action. Therefore, inhibiting the production of TNF-α has a very effective effect on many diseases, especially inflammatory diseases, autoimmune diseases such as rheumatoid arthritis, allergic diseases, etc. Or it is useful as a therapeutic.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) A61P 37/08 A61P 37/08 43/00 111 43/00 111 (72) Inventor Takeji Seki Central Tokyo 5-4-1, Tsukiji-ku, Tokyo F-term (reference) in Niken Kagaku Co., Ltd.

Claims (8)

[Claims] 1. A compound of the general formula (I) [In the formula, R represents a hydrogen atom, a methyl group or a halogen atom, and R ₁ represents a lower alkyl group, a cycloalkyl group, a mono- or di-lower alkylamino group, an aryl group, a heterocyclic group, or an aryl group or a heterocyclic group. Represents a substituted lower alkyl group; R ₂ represents a hydrogen atom or a C ₁ -C ₃ alkyl group; R ₃ represents a lower alkyl group, a lower alkanoyl group, or a cycloalkylcarbonyl which may be substituted by an aryl group; Group or a di-lower alkylamino group. 4,5,6,7-tetrahydrothieno [2,3-c] pyridine compound represented by the formula: During wherein formulas, R represents a hydrogen atom or a halogen atom, R ₁ is showed alkyl group C ₁ -C _4, a cyclopropyl group, a cyclobutyl group, a diethylamino group, a phenyl group or a pyridyl group, R ₂ is a hydrogen atom, a methyl group or an ethyl group, R ₃ is 4,5,6,7 according to claim 1, wherein represents a methyl group, an ethyl group, an acetyl group, a cyclopropyl group, a benzyl group or a dimethylamino group
A tetrahydrothieno [2,3-c] pyridine compound; 3. The 4,5,6,7-tetrahydrothieno [2, according to claim 1, wherein R represents a chlorine atom.
3-c] Pyridine compounds. 4. The 4,5,6,7-tetrahydrothieno [2] according to claim 1 or 2, wherein R ₁ represents a methyl group, an ethyl group, an isopropyl group or a diethylamino group.
3-c] Pyridine compounds. 5. The 4,5,6,7-tetrahydrothieno [2,3-c] pyridine compound according to claim 1, wherein R ₂ represents a hydrogen atom. 6. The method according to claim 1, wherein R ₃ represents an ethyl group, an acetyl group or a cyclopropylcarbonyl group.
4,5,6,7-tetrahydrothieno [2,3-
c] A pyridine compound. 7. The method according to claim 1, wherein
A pharmaceutical composition comprising a 7-tetrahydrothieno [2,3-c] pyridine compound or a hydrate thereof, or a pharmacologically acceptable salt thereof, and a carrier. 8. The method according to claim 1, wherein the first, second, third, fourth, fifth, sixth, fifth, and sixth aspects of the present invention are used.
A TNF-α production inhibitor comprising, as an active ingredient, a 7-tetrahydrothieno [2,3-c] pyridine compound, a hydrate thereof, or a pharmacologically acceptable salt thereof.