JPH0717647B2 - Tetrahydropyridine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention has effects on the central nervous system of mammals, anxiolytic effect,
The present invention relates to a tetrahydropyridine derivative represented by the following general formula (I) and a salt thereof which are useful as a psychotropic drug having a learning improving effect.

(In the formula, A is a sulfur atom or an oxygen atom, R ₁ is a carbon atom 1
~ 10 alkoxy groups, benzyloxy group, amino group,
Cyclohexylamino group, amino; di-lower alkylamino; amino group substituted with an alkyl group having 1 to 3 carbon atoms which may be substituted with carboxy or lower alkoxycarbonyl group, hexahydro-1H-1,4-diazepino group , A morpholino group, a 4-pyrimidinylpiperazino group,
Morpholinoamino group or N, N-dicyclohexylureido group, R ₂ and R ₃ are halogen atoms, lower alkyl groups,
Lower alkenyl group, phenyl group, aliphatic acyl group optionally having amino group, benzoyl group optionally substituted with halogen atom or lower alkoxy group, or optionally substituted with lower alkoxy group or nitro group Represents a benzyl group, m and n are integers of 0 to 4, and when m and n are 2 or more, R ₂ and R ₃ may be the same or different, and R ₁ has ₁ to 10 carbon atoms. When it is an alkoxy group, at least one of R ₂ and R ₃ is not a hydrogen atom. (Prior Art) It is known that a β-carboline-3-carboxylic acid derivative represented by the following general formula is useful as a psychotic drug having an anti-aggressive action (JP-A-56-43283).

Further, it is known that a 1,2,3,4-tetrahydrobenzothieno [2,3-c] pyridine derivative represented by the following general formula is useful as a central nervous system depressant and a tranquilizer ( Japanese Examined Patent Publication No. 50-2519)

Further, it is known that the pyridine derivative represented by the following general formula has a psychotropic action (Japanese Patent Laid-Open No. 61-23677).
9).

In addition, 1,2,3,4-tetrahydrobenzo [b] thieno [2,3
-C] Synthetic studies on pyridine or its derivatives and biochemical studies on the brain were carried out by Gerhard Wolf and Felix Zymalkowski, arc.
h.Pharm.), 279, 309 (1976), and Kleine Schmidt Bradley Buoy, Wraith Duane Earl,
Pettibone Douglas J., Robinson Janet El, Journal of Pharmacology and Experimental Zerapeutics (Brandley
V Clineschmidt, Duane R. Reiss, Douglas J. Petti
bone and Janet L. Robinson, J.Pharmacol.Exp.The
r.), 696-708, 235 (3) (1985) and the like. However, the tetrahydropyridine derivative represented by the general formula (I) has not been known, nor has its medicinal effect been known.

(Problems to be Solved by the Invention) The present inventors have diligently studied the production and usefulness of a tetrahydropyridine derivative represented by the general formula (I), and are useful as a drug having an anxiolytic action and a learning improving action. It is intended to provide a novel tetrahydropyridine derivative.

(Means for Solving the Problems) The present invention provides the following general formula (I): The present invention provides a tetrahydropyridine derivative represented by and a salt thereof.

In the above general formula (1), A is a sulfur atom or an oxygen atom. R ₁ is an alkoxy group having 1 to 10 carbon atoms, benzyloxy group, amino group, cyclohexylamino group, amino; di-lower alkylamino; 1 to 3 carbon atoms optionally substituted by carboxy or lower alkoxycarbonyl group An amino group substituted with an alkyl group, hexahydro-1H-1,4-diazepino group, morpholino group, 4-pyrimidinylpiperazino group, morpholinoamino group or N,
Examples thereof include N-dicyclohexylureido group. Specific examples of R ₁ include R ₁ , methoxy group, ethoxy group, propyloxy group, hexyloxy group, benzyloxy group, amino group, methylamino group, ethylamino group, and 2-aminoethylamino group. , 3-aminopropylamino group, N-dimethylaminoethylamino group, hexahydro-1H-1,4-diazepino group, morpholino group, 4-pyrimidinylpiperazino group, N, N-dicyclohexylureido group, cyclohexylamino group, A morpholino amino group, a butyric acid ethyl ester group, and a butyric acid group. R ₂ and R ₃
Is a halogen atom, a lower alkyl group, a lower alkenyl group, a phenyl group, an aliphatic acyl group which may have an amino group, a benzoyl group or a lower alkoxy group which may be substituted with a halogen atom or a lower alkoxy group, or Examples thereof include a benzyl group which may be substituted with a nitro group. Specific R ₂ and R ₃ include R ₂ and R ₃
Examples of chlorine atom, 2-chlorobenzoyl group, acetyl group, 4-aminobutyroyl group, 4-methoxybenzyl group, methyl group, allyl group, benzyl group, 4-
It is a nitrobenzyl group. m and n are integers of 0-4. When m and n are 2 or more, R ₂ and R ₃ may be the same or different.

An example of the tetrahydropyridine derivative of the present invention is shown below.

(1) 2- (2-chlorobenzoyl) -1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-
3-Carboxylic acid ethyl ester (2) 2-acetyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester (3) 2- (4 -Methoxybenzoyl) -1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester (4) 2- (4-aminobutyroyl) -1, 2,3,4-Tetrahydro-benzo [b] thieno [2,3-c] pyridine-
3-Carboxylic acid ethyl ester (5) 2- (4-methoxybenzyl) -1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-
3-Carboxylic acid ethyl ester (6) 2-methyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester (7) 2-allyl- 1,2,3,4-Tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester (8) 2-benzyl-1,2,3,4-tetrahydro-benzo [b ] Thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester (9) 2- (4-nitrobenzyl) -1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c ] Pyridine-3
-Carboxylic acid ethyl ester (10) 1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester (11) 1-methyl-1,2,3 , 4-Tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester (12) 4-methyl-1,2,3,4-tetrahydro-benzo [b] thieno [2, 3-c] pyridine-3-carboxylic acid ethyl ester (13) 6-chloro-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester ( 14) Hexahydro-1- (1,2,3,4-tetrahydro-
Benzo [b] thieno [2,3-c] pyridine-3-carbonyl) -1H-1,4-diazepine (15) N- (2-aminoethyl) -1,2,3,4-tetrahydro-benzo [ b] thieno [2,3-c] pyridine-3-
Carboxamide (16) Hexahydro-1- (4-methyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carbonyl) -1H-1,4-diabipine ( 17) Hexahydro-1- (1-phenyl-1,2,3,4-
Tetrahydro-benzo [b] thieno [2,3-c] pyridine-carbonyl) -1H-1,4-diazepine (18) Hexahydro-1- (6-chloro-1,2,3,4-tetrahydro-benzo [ b] thieno [2,3-c] pyridine-3-carbonyl) -1H-1,4-diazepine (19) N-methyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3 -C] pyridine-3-carbamide (20) N-ethyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carbamide (21) 4- (1, 2,3,4-Tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carbonyl) -morpholine (22) N- (4-morpholino) -1,2,3,4-tetrahydro-benzo [B] Thieno [2,3-c] pyridine-3-carboxamide (23) 1- (1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyc Lysine-3-carbonyl) -4-pyrimidinylpiperazine (24) 4- (1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carbamino) butyric acid ethyl ester (25 ) 4- (1,2,3,4-Tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboamino) butyric acid (26) 4- (2-methyl-1,2,3,4 -Tetrahydro-benzo [b] thieno [2,3-c] pyridine-carbonyl)
-Morpholine (27) N- (1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carbonyl) -N, N'-
Dicyclohexylurea (28) N-cyclohexyl-1,2,3,4-tetrahydro-
Benzo [b] thieno [2,3-c] pyridine-3-carboxamide The compound represented by the general formula (I) of the present invention can be obtained by the following synthetic method.

1) Method 1 In the formula, A, R ₁ , R ₂ , R ₃ , m and n have the same meanings as described above,
R ₄ and R ₄ ′ are H or R ₂ , R ₄ ″ is R ₂ , and X ₁ and X ₂ are a hydrogen atom such as a halogen atom, a methanesulfone group, or a 4,6-dimethylpyrimidinylmercapto group. It represents a compound that binds to an acid, or a compound that is excellent as a leaving group.

The method for obtaining the compound (III) from the compound (II) is described in Etch Earl Sinyder, Donald S. Matterson,
Journal of American Chemistry Society (HRSnyder and Donald S. Matteson, J.Am.C
hem, Soc.), 79 , 2217 (1957).

The solvent used in the method of synthesizing compound (III) from compound (II) is a mixed solvent of a polar solvent such as acetic acid and dimethylformamide and a nonpolar solvent such as benzene and toluene, and preferably compound (II) is converted into acetic acid. It is advisable to add a benzene solution of alkyldenisopropylamine dropwise to the solution dissolved in. The alkyldenisopropylisopropylamine is generally used in 1 to 3 equivalents, preferably 1.1 to 1.5 equivalents. In addition, alkyl denternary butyl amine or the like may be used instead of alkyl den isopropyl amine. Hydrochloric acid, sulfuric acid or the like may be added as a reaction catalyst.
The reaction temperature is −20 to 50 ° C., preferably 0 to 10 ° C. It usually takes 10 to 70 hours.

The method for obtaining the compounds (IV) and (V) from the compound (III) is described in DA Little and DI Weissblate, Journal of American Chemistry Society (DALittle and DIWesblat, JA
m.Chem.Soc.), 69 , 2118 (1947).

The solvent used in the method of synthesizing compound (IV) from compound (III) is xylene, toluene or the like, preferably xylene. The reaction temperature is 50 to 150 ° C, preferably 90 to 100 ° C. Generally 1-12
Finish in time. Alkyl nitroacetate is used in 1 to 3 equivalents.

The solvent used in the method of synthesizing compound (V) from compound (IV) is preferably a mixed solvent of water and a polar solvent such as methyl alcohol or ethyl alcohol. This reaction temperature is
It is carried out at 10 to 120 ° C, preferably 60 to 80 ° C. Generally, it takes 10 to 120 minutes. Use 1 to 10 equivalents of iron powder,
Use 1 to 20 equivalents of hydrogen chloride. Further, a metal such as zinc may be used in place of the iron powder, or reduction with hydrogen in the presence of a catalyst such as Raney nickel or palladium-activated carbon may be performed.

The method of synthesizing the compounds (VI) and (VII) from the compound (V) is described by Gerhard W. Wolf, Felix Timorkowski, and Archib Bear Pharmazi.
olf and Felix Zymalkowski, arch.Pharm.), 279, 309
(1976) was referred to.

The solvent used in the method of synthesizing compound (VI) from compound (V) is an organic solvent such as ethanol or benzene. The reaction temperature is 50 to 150 ° C. and is generally completed in 1 to 12 hours.

The solvent used in the method for synthesizing compound (VII) from compound (VI) is methanol, ethanol, water or the like, and preferably water. The reaction temperature is 50-12
It is performed at 0 ° C. and is generally completed in 10 minutes to 2 hours. As the reaction catalyst, 10 to 100 equivalents of an acid such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, etc. is used.

The method for obtaining the compound (I) from the compound (VII) is
Boatonick et al., Journal of American Chemistry Society (B.Bortnick, et.al, J.Am.Ch
em.Soc.), 78 , 4039 (1956).

The solvent used in the method of synthesizing compound (I) from compound (VII) is an organic solvent such as chloroform and ethanol, preferably chloroform. The reaction temperature is 0 to 100 ° C, preferably 30 to 60 ° C. Generally, it takes 1 to 12 hours. H of compound (VII)
To neutralize X ₁ , tertiary amines such as triethylamine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene are used. When no substituent is introduced into the nitrogen at the 2-position, R ₄ ″ X ₂ is not added in this reaction, and only the neutralization reaction is performed on the charcoal.

2) Method 2 When R ₁ is an amino group, it may be carried out by the following method using as a starting material a substance in which R ₁ is an alkoxy group in the above formula (VII).

In the formula, A, R ₁ , R ₂ , R ₃ , R ₄ , R ₄ ′ and R ₄ ″ have the same meanings as described above, and R ′ is a methyl group, an ethyl group or the like having 1 to 6 carbon atoms. R ₁₁ and R ₁₂ are each a hydrogen atom, amino, di-lower alkylamino, an alkyl group having 1 to 3 carbon atoms which may be substituted with a carboxy or lower alkoxycarbonyl group, or R ₁₁ and R 12. ₁₂ jointly cyclohexylamino group, hexahydro-1H-
It forms a 1,4-diazepino group, a morpholino group, a 4-pyrimidinylpiperazino group, a morpholinoamino group, or an N, N-dicyclohexylureido group. Boc is a tertiary butoxycarbonyl group, and X ₁ , X ₂ , X ₃ , X ₄ are halogen atoms, methanesulfone group, 4,6-dimethylpyrimidinylmercapto group, etc. Or represents an excellent leaving group.

The method for obtaining the compound (VIII) from the compound (VII) is as follows: T. Nakagawa, K. Kroiwa, K. Narita, W.
Isowa, Bulletin of the Chemical Society of Japan (T.Nakagawa, K.Kuroiwa, K.Narita,
Y. Isowa, Bull, Chem. Soc. Japan), 1269, 46 (1973). The solvent used in the method of synthesizing compound (VIII) from compound (VII) is an organic solvent such as chloroform, methylene chloride, tetrahydrofuran, dimethylformamide and the like. This reaction is carried out at 0-100 ° C,
Generally, it is completed in 1 to 48 hours. A tertiary amine such as triethylamine or N-methylmorpholine is used for neutralizing HX ₁ of the compound (VII). In addition, as a method for introducing a tertiary butoxycarbonyl group (Boc group), a Boc agent such as Boc-azide may be used. Or
Instead of the Boc group, another protecting group for amino group such as benzyloxycarbonyl may be used.

The method for obtaining compound (IX) from compound (VIII) is
Brand, BF Langer, Etch Sachs, J. Poratonic, Journal of American Chemistry Society (E.Brand, BFErla
nger, H.Sacks, J.Polathick, J.Am.Chem.Soc.), 73 , 3510
(1951) was referred to. From compound (VIII) to compound (I
The solvent used in the method for synthesizing X) is water such as alcohol such as methanol and ethanol. The reaction is carried out at 0 to 80 ° C and is generally completed in 1 to 48 hours.
Sodium hydroxide is used in 1 to 3 equivalents. Further, potassium hydroxide or the like may be used instead of sodium hydroxide. Citric acid and acetic acid are used as the acid that neutralizes the alkali.

The method for obtaining the compound (XI) from the compound (X) is
W. Anderson, AC McGregor,
Journal of American Chemistry Society (GWAnderson, ACMcgregor, J.Am.Chem.So
c.), 79 , 6180 (1957). The solvent used in the method of synthesizing compound (XI) from compound (X) is ethyl acetate, dioxane or the like. This reaction is -20
It is performed at -100 ° C and is generally completed in 10 minutes to 5 hours.
The hydrochloric acid used is for 1 to 20 equivalents. Further, instead of hydrochloric acid, trifluoroacetic acid, hydrogen bromide, hydrogen fluoride, methanesulfonic acid or the like may be used.

The solvent used in the method of synthesizing compound (I) from compound (XI) is an organic solvent such as chloroform, dioxane, ethanol and the like, preferably chloroform. The reaction temperature is 0 to 150 ° C., preferably 30
~ 60 ° C. Generally, it is completed in 1 to 24 hours. General formula
R ₄ ″ X ₄ is methyl bromide, acetyl chloride or the like, and is usually used in 1 to 3 equivalents. To neutralize HX ₄ produced as a by-product, triethylamine, N-methylmorpholine, 1,8
A tertiary amine such as diazabicyclo [5,4,0] -7-undecene is used.

3) Method 3 In the formula (V), a substance in which R ₁ is an alkoxy group may be used as a starting material and followed by the route of the following formula.

4) Method 4 As another amidation method, an amide may be directly converted from an ester as shown in the following formula. In this case, a catalyst such as phenyllithium may be used.

The compound represented by the general formula (I) can be in the form of a pharmaceutically acceptable acid or base addition salt.
Examples of the pharmaceutically acceptable acid addition salt include acid addition salts with inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, or organic acids such as acetic acid, p-toluenesulfonic acid and maleic acid. Examples of the base addition salt include base addition salts with inorganic bases such as sodium hydroxide and calcium hydroxide, or organic bases such as ammonia and triethylamine.

When the compound of the present invention is administered to a human, in the case of central nervous system diseases, it is administered by an oral agent or an intravenous injection. The dose is 10 to 300 mg per day for an adult, 1 to 3
Administer in divided doses. The administration time may be several days to 6 months for continuous administration, or the daily dose and administration period may vary depending on the patient's condition.

In addition, the compound of the present invention may be used in combination with other agents depending on the patient's condition. For example, in central nervous system diseases, it is used in combination with anxiolytic agents, antidepressants, cerebral metabolism activating agents, cerebral circulation improving agents and the like.

(Examples) Hereinafter, the present invention will be described in more detail with reference to Examples.
The present invention is not limited to this.

Reference Example 1,2,3,4-tetrahydro-benzo [b] thieno [2,3-
c] Pyridine-3-carboxylic acid ethyl ester was obtained by the following method.

Dissolve 33.6 g of benzo [b] thiophene in 150 ml of glacial acetic acid,
Methylidene isopropylamine 19.6g benzene 5 under ice cooling
A 0 ml solution was added dropwise. After returning to room temperature and stirring for 2 days, 5
The reaction solution was added to 00 ml of water and washed with 100 ml of ether three times. The aqueous layer was adjusted to pH 10.0 with 5N sodium hydroxide and extracted 4 times with 100 ml of ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, dried under reduced pressure, and subjected to silica gel column chromatography (benzo [b] thiophen-3-ylmethyl) isopropylamine 30.8 g.
(Yield 60%) was obtained.

IR (νmax, cm ^-1 ): 3300,2960,2870,1550,1440,760,740 NMR (δ, CDCl ₃ ): 1.10 (d, J = 6Hz, 6H), 2.50 to 2.90 (m,
1H), 3.80 (s, 2H), 7.20 ~ 7.50 (m, 3H), 7.60 ~ 7.90
(M, 2H) (Benzo [b] thiophen-3-ylmethyl) isopropylamine 10.97 g and ethyl nitroacetate 13.3 g were dissolved in dry xylene 50 ml and stirred under nitrogen stream.
The temperature was raised to 100 ° C. After 5 hours, the insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. Dissolve the residue in 500 ml of ethyl acetate and add 5%
The extract was washed 3 times with 100 ml of an aqueous citric acid solution, 3 times with 100 ml of a 5% aqueous sodium hydrogen carbonate solution, and twice with 100 ml of a saturated saline solution, dried over sodium sulfate, and then the ethyl acetate was distilled off under reduced pressure. After removing the excess ethyl nitroacetate by a vacuum pump, 11.17 g (yield 80%) of (benzo [b] thiophen-3-yl) -2-nitropropionic acid ethyl ester was obtained by silica gel column chromatography.

IR (νmax, cm ^-1 ): 2960,2870,1730,1550,1370,1250,76
0,740 NMR (δ, CDCl ₃ ): 1.10 (T, J = 6Hz, 3H), 3.15 (dd, 2H),
3.50 ~ 3.80 (m, 1H), 4.00 (q, 2H), 7.10 ~ 7.50 (m, 3
H), 7.50 to 7.90 (m, 2H) (benzo [b] thiophen-3-yl) -2-nitropropionic acid ethyl ester 2.79 g and iron powder 3.5 g, water 7.5 m
It was put in a mixed solution of 1, 7.5 ml of ethanol and 10 ml of 12N hydrochloric acid. The reaction was carried out at room temperature for 1 hour. After filtering the excess iron powder, add 200 ml of water to the filtrate and adjust the pH to 9 with sodium hydrogen carbonate.
Adjusted to ~ 10 and extracted 3 times with 50 ml chloroform. The chloroform layer was washed twice with 200 ml of water and twice with 100 ml of saturated saline and then dried over magnesium sulfate, and chloroform was distilled off under reduced pressure. Dissolve the residue in ethyl acetate and add 1N hydrochloric acid /
Add 10 ml of ethyl acetate solution, collect the precipitated crystals by filtration, and
-Amino- (benzo [b] thiophen-3-yl) -propionic acid ethyl ester / hydrochloride 1.14 g (yield 40%)
Got

IR (νmax, cm ^-1 ): 3420,3050,2970,1740,1570,1480,124
0,760,740 NMR (δ, CDCl ₃ ) (free form): 1.10 (t, J = 6Hz, 3H), 1.50
(S, 2H), 3.15 (dd, 2H), 3.50 to 3.80 (m, 1H), 4.00 (q,
2H), 7.10 to 7.50 (m, 3H), 7.50 to 7.90 (m, 2H) 2-amino- (benzo [b] thiophen-3-yl)-
23.24 g of propionic acid ethyl ester hydrochloride and 10.2 ml of formalin were dissolved in a mixed solution of 200 ml of ethanol and 200 ml of water and refluxed for 3 hours while stirring. After concentrating the reaction solution to about half and adjusting the pH of sodium hydrogen carbonate to 9-10,
It was extracted three times with 300 ml of chloroform. The chloroform layer was washed twice with 100 ml of saturated saline and then dried over magnesium sulfate, and chloroform was distilled off under reduced pressure. The residue was recrystallized from chloroform / ether to obtain 14.84 g (yield 69%) of 1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester. It was

IR (νmax, cm ^-1 ): 2970,2900,1720,1430,1195,760,740 NMR (δ, CDCl ₃ ): 1.35 (t, J = 6Hz, 3H), 2.25 (s, 2H),
3.10 (dd, 2H), 3.70 ~ 4.00 (m, 1H), 4.30 (q, 2H), 7.30
~ 8.00 (m, 4H) Example 1 2- (2-chlorobenzoyl) -1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester Was obtained by the following method.

Chloroform of 1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester 0.60 g, triethylamine 0.64 ml, and 2-chlorobenzoyl chloride 523 mg synthesized in Reference Example It was added to 30 ml and stirred for 1 hour at room temperature. The reaction solution was washed with 30 ml of water, then with 30 ml of sodium bicarbonate water having a pH of 9.0, and further with 30 ml of water. The chloroform layer was dried over Glauber's salt and evaporated under reduced pressure to give 2- (2-chlorobenzoyl) -1,2,
614 mg of 3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester (yield 67
%) Was obtained.

IR (νmax, cm ^-1 ): 1712,1638,1420,1200,1025, NMR (δ, CDCl ₃ ): 1.17 (t, J = 6Hz, 3H), 3.52 (m, 2H),
4.11 (m, 3H), 4.50 (bs, 2H), 7.46 (m, 8H) Mass (m / e): 401,399,260,196,141,139,115,111 Example 2 2-acetyl-1,2,3,4-tetrahydro-benzo [b]
Thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester and 2-4-methoxybenzoyl) -1,2,3,4
-Tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester is 1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3. -Using carboxylic acid ethyl ester as a starting material, 324 mg of acetic anhydride and 510 of 4-methoxybenzochloride were used instead of 614 mg of 2-chlorobenzoyl chloride of Example 1.
It could be synthesized in exactly the same manner as in Example 1 except that mg was used. The results are shown in Table 1-1 and the analysis results are shown in Table 1-2.

Example 3 2- (4-aminobutyroyl) -1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester-hydrochloride Could be synthesized by the method.

1,2,3,4-tetrahydro-benzo [b] thieno [2,3-
c] Pyridine-3-carboxylic acid ethyl ester 392 mg,
441 mg of p-methoxybenzyloxycarbonylaminobutyric acid was added to 5 ml of dimethylformamide, and 269 mg of diethyl cyanophosphate and 251 of triethylamine were added.
μ was added, and the mixture was stirred at 50 ° C. for 2 hours. 100 ml of ethyl acetate
Was added after the reaction was completed, and the mixture was washed 3 times with 100 ml of water. The ethyl acetate layer was reduced in thickness and concentrated, followed by silica gel column chromatography (developing solvent chloroform: methanol = 50: 1) to
[4- (p-Methoxybenzyl) oxycarbonylaminobutyroyl] -1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester was obtained, followed by To this product, 5 ml of 1N hydrochloric acid / ethyl acetate was added, and the mixture was stirred at 50 ° C for 1 hour, cooled, and then 2
-(4-aminobutyroyl) -1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester-hydrochloride 315 mg yield 54
%).

IR (νmax, cm ^-1 ): 1735,1620,1435,1200,1025 NMR (δ, CDCl ₃ ): 1.07 (t, J = 6Hz, 3H), 1.90 (m, 2H),
2.83 (m, 4H), 3.37 (m, 1H), 4.03 (m, 4H), 5.20 (m, 2
H), 7.53 (m, 6H) Mass (m / e): 346,329,260,188,186,160 Example 4 2- (4-methoxybenzyl) -1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c ] Pyridine-3-carboxylic acid ethyl ester, 2-methyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-
3-carboxylic acid ethyl ester, 2-allyl-1,2,3,4
-Tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester, 2-benzyl-
1,2,3,4-tetrahydro-benzo [b] thieno [2,3-
c] Pyridine-3-carboxylic acid ethyl ester and 2
-(4-Nitrobenzyl) -1,2,3,4-tetrahydro-
Benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester is 1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid. Using ethyl ester as a starting material, 4-methoxybenzyl chloride 468 mg, methyl iodide 798 mg, allyl bromide 361 mg, benzyl bromide 511 mg and 4-nitrobenzyl bromide 646 mg, instead of 2-chlorobenzoyl chloride 614 mg of Example 1, triethylamine. 0.6
Synthesis was possible in exactly the same manner as in Example 1 except that 700 mg of 1,8-diazabicyclo [5,4,0] 7-undecene was used instead of 4 ml. The results are shown in Table-1 and the analysis results are shown in Table 2-2.

Example 5 1,2,3,4-Tetrahydro-benzo [b] thieno [2,3-
c] Pyridine-3-carboxylic acid benzyl ester is an intermediate 1,2,3,4 except that 19.5 g of benzyl nitroacetate is used instead of 13.3 g of ethyl nitroacetate of Reference Example.
-Tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid was prepared in exactly the same manner as ethyl ester.

The results are shown in Table 3-1 and Analysis results Table 3-2.

Example 6 1-Methyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester was prepared by using acetaldehyde 19.5 instead of formalin 10.2 ml in the reference example. It could be synthesized in exactly the same manner as the synthesis of 1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester except that g was used.

The results are shown in Table 4-1 and the analysis results are shown in Table 4-2.

Example 7 4-Methyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester was prepared by using 19.6 g of methylidene isopropylamine as a reference example.
In the same manner as in the synthesis of 1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester except that 23.7 g of ethylidene isopropylamine was used in place of I was able to synthesize it.

The results are shown in Table 5-1 and the analysis results are shown in Table 5-2.

Example 8 6-Chloro-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester was replaced by 5% instead of 33.6 g of benzothiophene of Reference Example.
1, except that 42.3 g of -chloro-benzothiophene was used,
2,3,4-Tetrahydro-benzo [b] thieno [2,3-c]
It could be synthesized in exactly the same manner as the synthesis of pyridine-3-carboxylic acid ethyl ester.

The results are shown in Table 6-1 and the analysis results are shown in Table 6-2.

Example 9 Hexahydro-1- (1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-carbonyl) -1H
-1,4-diazepine hydrochloride was obtained by the following method.

1,2,3,4-tetrahydro-synthesized in the same manner as in Reference Example
6 g of ethyl benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid and 6.63 g of 2- (tert-butoxycarbonylthio) -4,6-dimethylpyrimidine were dissolved in 20 ml of dry chloroform and then for 30 minutes. Refluxed. After the chloroform was distilled off under reduced pressure, the residue was dissolved in 300 ml of ethyl acetate, washed 3 times with 50 ml of 5% aqueous sodium hydrogen carbonate solution, twice with 5% aqueous citric acid solution, and twice with saturated saline solution, and then with sodium sulfate. Dried. Ethyl acetate was evaporated under reduced pressure, the residue was recrystallized from chloroform-petroleum ether, and 2-tert.
6.1 g of ethyl butoxidecarbonyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid were obtained. (Yield 76%) IR (νmax, cm ⁻¹ ): 2970,1720,1695,1400,760,640 NMR (δ, CDCl ₃ ): 1.10 (t, J = 6Hz, 3H), 1.50 (s, 9H),
3.40 (m, 2H), 4.05 (q, J = 6Hz, 2H), 4.70 (d, J = 9Hz, 2
H), 5.10 to 5.50 (m, 1H), 7.10 to 7.70 (m, 4H) 2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine 6 g of ethyl-3-carboxylic acid ester was dissolved in a mixed solution of 30 ml of methanol and 20 ml of chloroform, 4 ml of 5N sodium hydroxide aqueous solution was added, and the mixture was refluxed for 5 hours. The solvent was evaporated under reduced pressure, 5% citric acid (300 ml) and chloroform (300 ml) were added, the chloroform layer was washed with saturated brine, and dried over sodium sulfate. The chloroform layer was distilled off under reduced pressure and the residue was recrystallized from chloroform-hexane to give 2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3. -4.15 g of carboxylic acid was obtained.
(Yield 75%) IR (νmax, cm ^-1 ): 2970,2860,1700,1695,1400,760,740 NMR (δ, CDCl ₃ ): 1.50 (s, 9H), 3.40 (s, 2H), 4.60 ( d,
J = 9Hz, 2H), 5.10 to 5.50 (m, 1H), 7.10 to 7.70 (m, 4H) 2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3 -C] Pyridine-3-carboxylic acid 0.32 g and hexahydro-1H-1,4-diazepine.
2 g was dissolved in 5 ml of dimethylformamide, a solution of 0.33 g of diphenylphosphoryl azide in 3 ml of dimethylformamide was added, and the mixture was stirred overnight. Add 50 ml of ethyl acetate to the reaction mixture,
2 times with 5% aqueous sodium hydrogen carbonate solution and 2 times with saturated saline solution.
After washing twice, it was dried over sodium sulfate. Sodium sulfate was filtered, 5 ml of 1N hydrochloric acid-ethyl acetate solution was added, and the mixture was heated at 50 ° C. for 1 hour. After the ethyl acetate was distilled off under reduced pressure, the residue was dissolved in 30 ml of water and washed 3 times with 10 ml of ethyl ether. Adjust the pH of the aqueous layer to 12 with 5N sodium hydroxide.
Was prepared, and 1 g of sodium chloride was added, followed by extraction with chloroform three times. After drying the chloroform layer with magnesium sulfate,
The residue was purified by silica gel thin layer chromatography (solvent: ethyl acetate: methanol = 10: 1), 1N hydrochloric acid-ethyl acetate (2 ml) was added, and the precipitated crystals were collected by filtration, and hexahydro-1- (1,2,3 , 4-Tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carbonyl) -1H-1,4
-0.24 g of diazepine hydrochloride was obtained. (Yield 62%) (Table 7-1, Table 8-1) By the same method, -tert-butoxycarbonyl-1,2,3,
4-Tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid 0.32 g and ethylenediamine as starting materials, N- (2-aminoethyl) -1,2,3,4-tetrahydro- 0.19 g of benzo [b] thieno [2,3-c] pyridine-3-carboxamide dihydrochloride was obtained. (Yield 54
%) (Table 9-1, Table 10-1) Hexahydro-1- (1,2,3,4-tetrahydro-benzo [b] was obtained by the same method, using ethylideneisopropylamine instead of methylideneisopropylamine. ] Thieno [2,3-c] pyridine-3-carbonyl)
-1H-1,4-diazepine dihydrochloride 0.26 g was obtained. (yield
65%) (Table 7-1, Table 8-1) In addition, benzaldehyde and 50 equivalents of hydrogen chloride were used in place of formalin, and hexahydro-1 was obtained by the same method.
-(1,2,3,4-Tetrahydro-1-phenyl-benzo [b] thieno [2,3-c] pyridine-3-carbonyl)
0.33 g of -1H-1,4-diazepine dihydrochloride was obtained. (yield
71%) (Table 9-1, Table 10-1) Hexahydro-1- (1,2,3,4) was obtained by the same method using 5-chlorobenzo [b] thiophene instead of benzo [b] thiophene. -Tetrahydro-6-chloro-
0.22 g of benzo [b] thieno [2,3-c] pyridine-3-carbonyl) -1H-1,4-diazepine dihydrochloride was obtained.
(Yield 53%) (Table 9-1, Table 10-1) Example 10 N-methyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carbonamide hydrochloride can be obtained by the following method. 2-tert-
Butoxycarbonyl-1,2,3,4-tetrohydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid 0.3
2g and methylamine hydrochloride 0.08g and triethylamine 0.1
Dissolve 7 ml in 5 ml of dimethylformamide, and under ice cooling, diphenylphosphoryl azide 0.33 g of dimethylformamide 5 ml
The solution was added dropwise, and a solution of 0.17 ml of triethylamine in 2 ml of dimethylformamide was added dropwise, followed by stirring at room temperature for 2 hours. 50 ml of ethyl acetate was added to the reaction solution, which was washed 3 times with 10 ml of 5% aqueous citric acid solution, 3 times with 5% aqueous sodium hydrogen carbonate solution and 2 times with saturated saline solution, and then dried over sodium sulfate. Sodium sulfate was filtered, 5 ml of 1N hydrochloric acid-ethyl acetate solution was added, and the mixture was heated at 50 ° C. for 1 hour. overnight,
After standing in the refrigerator, the precipitated crystals were collected by filtration and N-methyl-1,2,3,4-tetrohydro-benzo [b] thieno [2,3-
c] Pyridine-3-carbamide hydrochloride (0.23 g) was obtained. (Yield 65%) IR (νmax, cm ⁻¹ ): 3300,3210,3060,2920,1650 2-tert-butoxycarbonyl-1,2,
Starting from 3,4-tetrohydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid as a starting material, N-ethyl-1,2,3,4-tetrohydro-benzo [b] thieno [2] , 3-
c] Pyridine-3-carboxamide hydrochloride, 4- (1,2,
3,4-Tetrohydro-benzo [b] thieno [2,3-c] pyridine-3-carbonyl) morpholine hydrochloride, N-
(4-morpholino) -1,2,3,4-tetrohydro-benzo [b] thieno [2,3-c] pyridine-3-carboxamide hydrochloride, 1- (1,2,3,4-tetrohydro- Benzo [b] thieno [2,3-c] pyridine-3-carbonyl)
Pyrimidinylpiperazine hydrochloride, 4- (1,2,3,4-tetrohydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylicamino) -butyric acid ethyl ester hydrochloride was obtained. (Table 9, Table 10) Example 11 4- (1,2,3,4-Tetrohydro-benzo [b] thieno [2,3-c] pyridine-3-carbamino) -butyric acid
Obtained by the following method. 400 mg of 4- (1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboamino) -butyric acid ethyl ester was dissolved in 2 ml of ethanol, and 1N aqueous sodium hydroxide solution 1.5 was added. ml was added, and the mixture was stirred at room temperature for 5 hours. Ethanol was distilled off under reduced pressure and 100 ml of water was added.
Was charged, the pH was adjusted to 5 with 1N hydrochloric acid, and the mixture was stirred overnight. The precipitate was collected by filtration, and 4- (1,2,3,4-tetrohydro-
305 mg of benzo [b] thieno [2,3-c] pyridine-3-carbamino) -butyric acid were obtained. (Yield 82%) IR (νmax, cm ^-1 ): 3430,3250,3100,2920,1660,1570,143
0 NMR (δ, CDCl ₃ ): 1.50 to 2.00 (br, 2H), 2.00 to 2.60 (b
r, 2H), 4.00 (s, 2H), 5.80 ~ 6.50 (br, 2H), 7.20 ~ 7.50
(M, 2H), 7.50 to 8.00 (m, 2H) Example 12 4- (2-Methyl-1,2,3,4-tetrohydro-benzo [b] thieno [2,3-c] pyridine-3- Carbonyl)
-Morpholine hydrochloride was synthesized by the following method.

4- (1,2,3,4-Tetrohydro-benzo [b] thieno [2,3-c] pyridine-3-carbonyl) -morpholine hydrochloride 0.34 g, triethylamine 0.31 ml and methyl bromide 0.11 g chloroform 5 ml And was refluxed for 30 minutes.
Chloroform was distilled off under reduced pressure, 20 ml of 5% aqueous sodium hydrogen carbonate solution and 50 ml of ethyl acetate were added, and the ethyl acetate layer was washed with saturated brine and dried over sodium sulfate. Ethyl acetate was evaporated under reduced pressure, the residue was purified by silica gel thin layer chromatography, 1N hydrochloric acid-ethyl acetate (1 ml) was added, and the precipitated crystals were collected by filtration to give 4- (2-methyl-1,2,3,
0.29 g of 4-tetrohydro-benzo [b] thieno [2,3-c] pyridine-3-carbonyl) -morpholine hydrochloride was obtained. (Yield 82%) IR (νmax, cm ^-1 ): 3400,2970,2900,1655,1420,1110,76
0,740 NMR (δ, CDCl ₃ , free form): 2.80 (d, J = 7Hz, 2H), 2.90
(S, 8H), 3.60 (s, 8H), 3.70 to 3.90 (m, 1H), 4.05 (s, 1
H), 7.0 to 7.70 (m, 4H) Example 13 1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester synthesized in Example 1 6 g and 2- (tert-butoxycarbonylthio) -4,6-dimethylpyrimidine 6.63 g were dissolved in 20 ml of dry chloroform and refluxed for 30 minutes. After the chloroform was distilled off under reduced pressure, the residue was dissolved in 300 ml of ethyl acetate and
% Aqueous sodium hydrogen carbonate solution (3 times), 5% aqueous citric acid solution (2 times), saturated saline solution (2 times), and dried over sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was recrystallized from 100 ml of chloroform-petroleum-ether (1: 1), 6.
18 g of product was obtained. The NMR and IR data of this product are
As shown below, the product is 2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid ethyl ester. I confirmed that there is. (Yield 76%) IR (νmax, cm ⁻¹ ): 2970,1720,1695,1400,760,740 NMR (δ, CDCl ₃ ): 1.10 (t, J = 6Hz, 3H), 1.50 (s, 9H),
3.40 (m, 2H), 4.05 (q, J = 6Hz, 2H), 4.70 (d, J = 9Hz, 2
H), 5.10 to 5.50 (m, 1H), 7.10 to 7.70 (m, 4H) 2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine 6 g of ethyl-3-carboxylic acid ester was dissolved in a mixed solution of 30 ml of methanol and 20 ml of chloroform, 4 ml of 5N sodium hydroxide aqueous solution was added, and the mixture was refluxed for 5 hours. The solvent was evaporated under reduced pressure, 5% citric acid (300 ml) and chloroform (300 ml) were added, the chloroform layer was washed with saturated brine, and dried over sodium sulfate. The chloroform layer was distilled off under reduced pressure, and the residue was recrystallized from chloroform-hexane to obtain 4.15 g of a product.
The NMR and IR data of this product are as shown below, and this product is 2-tert-butoxycarbonyl-1,
2,3,4-Tetrahydro-benzo [b] thieno [2,3-c]
It was confirmed to be pyridine-3-carboxylic acid (yield 75
%).

IR (νmax, cm ^-1 ): 2970,2860,1700,1695,1400,760,740 NMR (δ, CDCl ₃ ): 1.50 (s, 9H), 3.40 (s, 2H), 4.60 (d,
J = 9Hz, 2H), 5.10 ~ 5.50 (m, 1H), 7.10 ~ 7.70 (m, 4H) Dissolve 7.23 g of dicyclohexylcarbodiimide in 100 ml of dimethylamide and keep at 80 ° C, 10 g of 3,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carboxylic acid and 50 ml of dimethylformamide were added and stirred for 30 minutes. Then, 500 ml of ethyl acetate and 300 ml of water were added to separate the layers. Furthermore, ice water 200m
The ethyl acetate layer was washed twice with 1 times and twice with 200 ml of saturated saline. A small amount of N, N'-dicyclohexylurea formed was collected by filtration, ethyl acetate was distilled off under reduced pressure, and 200 ml of petroleum ether was added for precipitation to obtain 12.22 g of a product. NMR of this product,
IR data are shown below, and this product is N- [2-tert-butoxycarbonyl-1,2,3,4-
It was confirmed to be tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carbonyl] -N, N'-dicyclohexylurea (yield 75%).

NMR (δ, CD ₃ OD): 0.83 to 2.33 (m, 31H), 3.00 to 4.00 (m,
3H), 4.17 (s, 2H), 4.87 (s, 1H), 7.20 to 8.03 (m, 4H) N- [2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-
3-Carbonyl] -N, N'-dicyclohexylurea 12.
22 g was added to 50 ml of ethyl acetate and 10 ml of chloroform, and 14 ml of 5N hydrochloric acid / ethyl acetate was added and stirred at 50 ° C. for 3 hours to precipitate crystals, which were collected by filtration and washed with 30 ml of ether to obtain 6.5 g of a product. It was The NMR and IR data of this product are shown below, and this product is N- (1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-
3-Carbonyl] -N, N'-dicyclohexylurea
It was confirmed to be the hydrochloride salt (yield 60%).

IR (νmax, cm ^-1 ): 2940,1715,1665,1430,750,730 NMR (δ, d ₄ -DMSO): 0.80-2.26 (m, 22H), 3.00-4.37
(M, 5H), 4.53 (s, 2H), 7.20 to 8.70 (m, 4H) Mass (m / e): 340, 314, 188, 172, 161 Example 14 2-tert-butoxycarbonyl-1, synthesized in Example 13
2,3,4-Tetrahydro-benzo [b] thieno [2,3-c]
Pyridine-3-carboxylic acid (12.3 g) was dissolved in dry dimethylformamide (50 ml), cyclohexylamine (4.02 g) was further added, and the mixture was stirred for 30 minutes. Diphenylphosphothryl azide 12.17 g / dry dimethylformamide 10 ml solution and triethylamine 6.7 ml were further added, and the mixture was stirred at room temperature for 1 day. After distilling off dimethylformamide under reduced pressure, the residue was dissolved in 300 ml of ethyl acetate, washed 3 times with 50 ml of 5% aqueous sodium hydrogen carbonate solution, twice with 5% aqueous citric acid solution, and twice with saturated saline solution, and then sodium sulfate. Dried in. Ethyl acetate was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent chloroform).
g product was obtained. The NMR and IR data of this product are shown below, and this product is N-cyclohexyl-2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-benzo [b] thieno [2 , 3-c] Pyridine-3
-Confirmed to be carboxamide (60% yield).

IR (νmax, cm ^-1 ): 2970,1720,1620,1400,760,740 NMR (δ, CCl ₄ ): 1.47 (m, 19H), 1.47 to 3.10 (m, 1H), 3.
16 ~ 3.80 (m, 2H), 4.63 (d, J = 16Hz, 2H), 4.87 ~ 5.20
(M, 1H), 69.16 (d, J = 8Hz, 1H), 7.00 to 7.83 (m, 4H) N-cyclohexyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c ] Pyridine-carbamide 9.17 g
Was added to 30 ml of ethyl acetate, and 5N hydrochloric acid / ethyl acetate 1 was added to this.
After adding 3.3 ml and stirring at 50 ° C. for 2 hours, N-cyclohexyl-2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-carbamide hydrochloride Salt precipitated, and after filtration, 30 ml of ether
Washed with to give 6.37 g of product. NMR, IR of this product
The data are shown below, and the product is
It was confirmed to be N-cyclohexyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-carbamide hydrochloride (yield 82%).

IR (νmax, cm ^-1 ): 2935,1720,1660,1430,750,730 NMR (δ, d ₄ -DMSO): 0.81 to 2.25 (m, 10H), 2.98 to 4.35
m, 5H), 4.54 (s, 2H), 7.20 to 8.72 (m, 4H) Mass (m / e): 314,188,172,161 (Effect of the invention) The compound according to the present invention has the following specific anxiolytic effect and learning improvement. Shows the action.

Using Wistar male rats (6 weeks old),
J.R., Bear Bee, Claudee Dee
E, Psycho Pharmacologia (Vogel JR, Beer
B., and Clody DE, Psychopharmacologia), 1−7, 2
1 , (1971) was used to investigate the anxiolytic effect and learning improving effect of this compound using the Waterlick conflict test.

This test uses rats that have been deprived of water, so that each time they drink water, they are subjected to an electric shock, and the rats are in a state of conflict (anxiety), and the effects of drugs on them are investigated.

(1) Anxiolytic effect Rats that have been dehydrated for 24 hours before the test are allowed to drink water. 4-5
The drug was administered after an hour, and the test was started after a treatment time of 15 minutes. The number of shocked shocks is the number of electric shocks that rats receive in 5 minutes after starting to drink water, and indicates whether or not to suppress the conflict (anxiety) of receiving electric shocks when drinking water. That is, an increase in the number of shocks means that the anxiolytic effect is enhanced.
Table 11 shows the values when the drug-non-administered rats were set to 100. (N = 5) (2) Learning improvement effect This test system was carried out simultaneously with the measurement of the anxiolytic effect of (1), and it measures the latency time until the starved rat first starts drinking water.

It is judged that the learning improvement effect was enhanced as the latency time was longer. Table 12 shows the values when the average value of drug-untreated rats was 100. (N = 5) It was shown that this compound prolongs the latency significantly and has a learning improving effect. This suggested that the compound of the present invention was obtained by an anxiolytic drug and an anti-dementia drug.

(3) Utility of the present invention A comparison was made with the prior art. Β-carboline-3-ethyl ester (β-carboline-3-ethyl ester, which is a representative compound of JP-A-56-43283
(Abbreviated as CCE), which is a representative compound of Japanese Patent Publication No. 50-2510 6-
Chloro-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine (abbreviated as C-1), JP-A-61-236
Benzothieno [2,3-c] pyridine-3-carboxylic acid ethyl ester (abbreviated as A-1), which is a representative compound of 779,
N-ethyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine- which is a representative compound of the present invention
3-Carboxamide hydrochloride (abbreviated as A-2), N-cyclohexyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carbamide hydrochloride (A- 3), and N- (1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carbonyl) -N, N'-dicyclohexylurea hydrochloride (A- A comparative test of the anxiolytic effect of 4) was carried out. The test method was exactly the same as the method of (1) anxiolytic action.
The test results are shown in Table 13.

From the results of the test of anxiolytic action in Table 13, N-ethyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-
c] pyridine-3-carbamide hydrochloride, N-cyclohexyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carbamide hydrochloride, and N- (1, 2,3,4-Tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carbonyl) -N, N'-dicyclohexylurea hydrochloride is significantly different from the prior art, The utility seems to be sufficient.

Also, β-CCE, C-1, A-1, A-3 and 4-A
A comparative test of mental stimulating effect was carried out.

The test method is S. Nomura et al. European Journal
Pharmacologie (S.Nomura et.al.Eur.J.Pharmaco
l.) 1982, 83 , 171-175. The test method is described below.

The effect of each drug on immobility observed during forced swimming in mice was examined by the water wheel rotation method. The meaning of this test method is described below. The immobility that is observed when mice are forced to swim in water is considered to indicate an information-depleted state that gives up to escape after learning that it is impossible to escape from a narrow environment (device). It is known that kinetics are shortened by drugs having a psychostimulating action such as antidepressants and MAO inhibitors. That is, in the test method, 40 minutes after the prophylactic administration of each drug, the mouse was placed in a water layer with a water wheel at a water temperature of 25 ° C., and the rotation speed of the water wheel observed by the mouse during the 6-minute observation period was measured. (However, β-CCE is performed 15 minutes after subcutaneous administration).

As a result, as is clear from Table 14, the compounds of the present invention, A-3 and A-4, showed a significant increase in the rotational speed of the turbine as compared with the other drugs. From these results, the compounds of the present invention, A-3 and A-4, were confirmed to be antidepressant and MA
It was suggested that it has a psychostimulatory effect similar to that of O inhibitors.
From the results of the psychostimulation test in Table 16, N-cyclohexyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carbamide hydrochloride, which is the compound of the present invention, is shown. , N- (1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carbonyl)
-N, N'-dicyclohexylurea hydrochloride and the like are significantly different from the prior art and are also useful as psychoactive agents.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location A61K 31/55 AAE 9454-4C (56) Reference JP-A-63-96188 (JP, A)

Claims (1)

[Claims] 1. The following general formula (I): (In the formula, A is a sulfur atom or an oxygen atom, R ₁ is a carbon atom 1
~ 10 alkoxy groups, benzyloxy group, amino group,
Cyclohexylamino group, amino; di-lower alkylamino; amino group substituted with an alkyl group having 1 to 3 carbon atoms which may be substituted with carboxy or lower alkoxycarbonyl group, hexahydro-1H-1,4-diazepino group , A morpholino group, a 4-pyrimidinylpiperazino group,
Morpholinoamino group or N, N-dicyclohexylureido group, R ₂ and R ₃ are halogen atoms, lower alkyl groups,
Lower alkenyl group, phenyl group, aliphatic acyl group optionally having amino group, benzoyl group optionally substituted with halogen atom or lower alkoxy group, or optionally substituted with lower alkoxy group or nitro group Represents a benzyl group, m and n are integers of 0 to 4, and when m and n are 2 or more, R ₂ and R ₃ may be the same or different, and R ₁ has ₁ to 10 carbon atoms. When it is an alkoxy group, at least one of R ₂ and R ₃ is not a hydrogen atom. ) The tetrahydropyridine derivative and its salt shown by these.