JPH1017564A - New thiophene derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having a nitrogen-containing cycloalkyl group and a carbamoyl group, having a specific antiphencyclidine action and useful as a psychopharmaceutical, etc. SOLUTION: The compound of formula I the B ring is a four to ten- membered, nitrogen-containing cycloalkyl ring; A is a direct bond, a lower alkylene; R<1> is a group of formula II; R<2> is a group of formula III [R<3> , R<4> , R<6> , R<7> are each H, a (substituted) lower alkyl, a (substituted)aralkyl; (n), (m) are each 0, 1-6; X<1> , X<2> are each O, S, NR<10> (R<10> is H, a lower alkyl, etc.); R<5> , R<8> are each H, a (substituted) lower alkyl, a (substituted)cycloalkyl, etc.]}, e.g. 4-[5-[(hexahydro-1-azepinyl)methyl]-2-thenoyl]-1-piperazinecarboxaldeh yde. The compound of formula I is preferably obtained e.g. by aminating a carboxylic acid compound of formula IV in the presence of an organic base such as triethylamine and a dehydrating agent such as a carbodiimide in an organic solvent such as methylene dichloride in an ice-cooled state to in a thermally refluxed state.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel thiophene derivative having an anti-PCP (phencyclidine) action.

[0002]

2. Description of the Related Art It is known that PCP induces psychiatric symptoms very similar to those of schizophrenia including negative symptoms [Am. J. Psychiat. , 135,1081
(1987)]. On the other hand, administration of PCP to animals induces various abnormal behaviors. This suggests that drugs that specifically suppress PCP-induced abnormal behavior in animals (anti-PCP action) are useful as therapeutic agents for schizophrenia in humans. Further, since PCP has an NMDA receptor inhibitory action, these drugs having an anti-PCP action are:
It is also considered to be useful as a therapeutic drug for diseases considered to be caused by decreased NMDA receptor function, ie, memory / cognitive impairment in senile dementia and problematic behaviors such as delirium. Conventionally, dopamine receptor blockers have been mainly used as therapeutic agents for schizophrenia. However, these dopamine blockers are not only ineffective against negative symptoms, but also cause side effects such as extrapyramidal symptoms [T. I. P. S. , 13, 116 (19
92)]. On the other hand, specific anti-PCP drugs are also excellent in that they also improve the negative symptoms of schizophrenia in which dopamine blockers do not work, and do not have side effects like dopamine blockers. First, the present inventors have found that a novel thiophene derivative having a nitrogen-containing cycloalkyl lower alkyl group has an anti-PCP effect, and
225450 and WO 95/29910. On the other hand, thiophene derivatives having a nitrogen-containing cycloalkyl lower alkyl group include 2-amino-4- (5-
Piperidinomethyl-2-thienyl) thiazole (Japanese Patent Application Laid-Open No. 62-192379) is known, but it does not disclose any anti-PCP activity.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide an anti-P
An object of the present invention is to provide a novel thiophene derivative having a CP (phencyclidine) action or a salt thereof.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies on compounds having an excellent specific anti-PCP activity, and as a result, have found that nitrogen-containing cycloalkyl groups and chemical compounds whose chemical structures are completely different from those of conventional compounds. The present invention was completed by creating a thiophene derivative having a carbamoyl group or a salt thereof. That is, the present invention relates to a thiophene derivative represented by the general formula (I) or a salt thereof, and a pharmaceutical composition containing the compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0005]

Embedded image (The symbols in the formula have the following meanings. Ring B: 4- to 10-membered nitrogen-containing cycloalkyl ring A: bond or lower alkylene group R ³ , R ⁴ , R ⁶ and R ^{7 are the} same or different and are each a hydrogen atom or a lower alkyl group or an aralkyl group which may have a substituent n and m: the same or different and an integer of 0 or 1 to 6 R ⁵ , R ⁸ and R ^{9 are the} same or different and each include a hydrogen atom or a lower alkyl group, a cycloalkyl group, an aralkyl group, an aryl group or one or two nitrogen atoms which may have a substituent, or 5 or 6-membered heteroaryl group D-ring: a 5- to 7-membered cycloalkyl ring which may have a carbonyl group and contains 1 or 2 nitrogen atoms R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are combined with a hydrogen atom, a lower alkyl group or R ³ or R ⁶ to form 5 to 8
A member ring may be formed. )

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the compound (I) of the present invention will be described in detail. In the definition of the general formula in this specification,
Unless otherwise specified, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms. As the "lower alkyl group", specifically, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert group -Pentyl group, 1-methylbutyl group, 2-methylbutyl group,
Examples thereof include a 1,2-dimethylpropyl group, a hexyl group, and an isohexyl group, and are preferably a linear or branched alkyl group having 1 to 4 carbon atoms. The “lower alkylene group” is a linear or branched alkylene group having 1 to 6 carbon atoms, specifically, a methylene group, an ethylene group, an ethylidene group, a propylidene group, an isopropylidene group, a propylene group, Trimethylene group, tetramethylene group, 1,
Examples thereof include a 1-dimethylethylene group, a 1,2-dimethylethylene group, an ethylethylene group, a pentamethylene group, and a hexamethylene group, and are preferably a linear alkylene group having 1 to 3 carbon atoms.

"4- to 10-membered nitrogen-containing cycloalkyl ring"
Specific examples thereof include, for example, azetidine, pyrrolidine, piperidine, hexahydroazepine, octahydroazosin, octahydroazonin, and decahydroxyazecin, and hexahexaazepine is preferred. As the “5- to 7-membered cycloalkyl optionally having a carbonyl group and containing 1 or 2 nitrogen atoms”, specifically, for example, pyrrolidine, piperidine, piperazine, piperazinedione, hexahydroazepine, 2-pyrrolidinone, 2-pyrrolidinone -Piperidinone, ε-caprolactam or 7-heptane lactam, and the like, preferably 2-piperidinone. The phrase “may form a ring together with R ³ or R ⁶ ” means a 5- to 8-membered lactam ring or cyclic imide, specifically, for example, 2-pyrrolidinone, 2-pyrrolidinone,
Examples thereof include piperidinone, 2,6-piperidinedione, ε-caprolactam and 7-heptane lactam, and ε-caprolactam is preferred.

The "cycloalkyl group" is a ring atom having 3 to 8 ring atoms.
And monocyclic hydrocarbon ring groups, specifically, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclooctyl group, and a cyclohexyl group is preferable.
The “aralkyl group” is a group in which an arbitrary hydrogen atom of the above “lower alkyl group” is substituted with a phenyl group, a naphthyl group or the like, and specifically, for example, a benzyl group, a phenethyl group, a phenylpropyl group, a methylphenylethyl group , Phenylbutyl, methylphenylpropyl, ethylphenylethyl, dimethylphenylethyl, phenylpentyl, methylphenylbutyl, phenylhexyl, methylphenylpentyl, naphthylmethyl,
Examples thereof include a naphthylethyl group, a naphthylpropyl group, a naphthylbutyl group, a naphthylpentyl group and a naphthylhexyl group, and a benzyl group is preferable. The “aryl group” means a carbocyclic aryl, and specifically includes, for example, a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an anthryl group or a phenanthryl group, and is preferably a phenyl group. The "heteroaryl group" is a 5- or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms, and specifically includes, for example, pyrrole, imidazole, pyridine, pyridazine, pyrimidine or pyrazine, and preferably pyridine or pyrimidine. is there.

"Lower alkyl group or aralkyl group optionally having substituents" and "Lower alkyl group, cycloalkyl group, aralkyl group, aryl group or heteroaryl group optionally having substituents""Asa" substituent "includes a hydroxyl group, a lower alkoxy group, an amino group, a mono- or di-lower alkylamino group,
Examples thereof include a lower alkanoylamino group, a carboxyl group, a lower alkoxycarbonyl group, a cyano group, a halogen atom and a nitro group. The "lower alkoxy group" is a linear or branched alkoxy group having 1 to 6 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group and an isobutoxy group. , Sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group and the like, and preferably a methoxy group. The “mono- or di-lower alkylamino group” is an amino group having one or two lower alkyl groups, specifically, for example, a methylamino group,
Examples include an ethylamino group, a propylamino group, an isopropylamino group, a dimethylamino group, a diethylamino group, a dipropylamino group, and a diisopropylamino group.
The “lower alkanoylamino group” is an amino group having a lower alkanoyl group, and specific examples include a formylamino group, an acetylamino group, a propionylamino group, a butyrylamino group, an isobutyrylamino group, and the like. It is an amino group. The “lower alkoxycarbonyl group” is a straight-chain or branched alkoxycarbonyl group having 1 to 6 carbon atoms.
Methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec
-Butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, t
ert-pentyloxycarbonyl group and the like.

"Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom. The compound of the present invention may form a salt with an acid or a base in some cases. Salts with such acids include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, formic acid, acetic acid,
Acid addition with organic acids such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid or glutamic acid Salts may be mentioned. Examples of salts with bases include addition salts of inorganic bases such as lithium, sodium, potassium, magnesium, calcium and aluminum with organic bases such as methylamine, ethylamine and ethanolamine, and basic amino acids such as lysine and ornithine. And ammonium salts.

Further, the compound of the present invention may contain an asymmetric carbon atom, and there are optical isomers based on this. In addition, when it has more than one asymmetric carbon atom, diastereoisomers are present. The present invention includes a mixture of these isomers and an isolated one. Furthermore, the compound of the present invention also includes a hydrate or a solvate such as methanol or ethanol or a polymorph thereof. As described above, the compounds of the present invention have been described in detail, but all of them are included in the compounds of the present invention.

(Production method) The compound of the present invention can be produced by applying various synthetic methods. The typical production method is illustrated below.

(First manufacturing method)

Embedded image (In the formula, ring B, A, R ¹ and R ² are as described above.) The compound (I) of the present invention is produced by amidating a carboxylic acid compound represented by the general formula (II) by a conventional method. it can.
This reaction is carried out in an organic solvent such as methylene chloride, DMF, tetrahydrofuran, ether or dioxane, in the presence of an organic base such as triethylamine, diisopropylethylamine or the like, in a carbodiimide such as dicyclohexylcarbodiimide, diphenylphosphoryl azide, N, N'-disc. Using a dehydrating condensing agent such as cinimidinyl carbonate or the like under ice-cooling or heating under cooling, or by converting (II) into an acid halide or an acid anhydride by a conventional method, various amine compounds and methylene chloride, DMF, tetrahydrofuran, ether,
The reaction is carried out in an organic solvent such as dioxane in the presence of an organic base such as triethylamine and diisopropylethylamine under ice cooling or heating to reflux.

(Second production method)

Embedded image (Wherein B ring, A, R ¹ and R ² are as described above,
R ¹³ represents a lower alkyl group, and DIBAL represents diisobutylaluminum hydride. The compound (I) of the present invention can be produced by reacting an ester compound represented by the general formula (III) with an amine compound in the presence of DIBAL. This reaction can be carried out in an organic solvent such as toluene, benzene, tetrahydrofuran, ether or dioxane under ice-cooling or heating conditions. The compound of the present invention thus produced is isolated and purified as a salt, a hydrate, a solvate or a polymorphic substance as it is free. The salt of compound (I) can also be produced by subjecting the salt to a conventional salt formation reaction. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography. Various isomers can be separated by selecting an appropriate starting compound or by utilizing a difference in physical properties between the isomers. For example, optical isomers can be obtained by selecting appropriate raw materials or by a racemic resolution method of a racemic compound (for example, a method of optically resolving a diastereomer salt with a general optically active base). It can lead to scientifically pure isomers. Hereinafter, in addition to those described in the examples, the compounds can be synthesized using the above-mentioned production methods, the production methods of the examples, and modifications thereof which are known to those skilled in the art, and require special experiments. The following compound can be obtained without using:

N-ethyl 4- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] -1-piperazinecarboxamide N- (4-nitrophenyl) 4- [5-[(hexahydro-1- Azepinyl) methyl] -2-thenoyl] -1
-Piperazinecarboxamide N- (4-methylbenzyl) 4- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] -1
-Piperazinecarboxamido 4-benzoyl-1- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl]-[1,4] -diazepane N-benzyl 4- [5-[(hexahydro-1-azepinyl) ) Methyl] -2-thenoyl]-[1,4] -diazepan-1-carboxamide 2- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] -3,4-dihydro-1H-isoquinoline N- [1- [5-[(hexahydro-1-azepinyl)
Methyl] -2-thenoyl] piperidin-4-yl benzamide N- (2-pyridyl) 5-[(hexahydroazepinyl) methyl] -2-thiophenecarboxamide N- (3-pyridyl) 5-[(hexahydro Azepinyl) methyl] -2-thiophenecarboxamide N- (4-pyridyl) 5-[(hexahydroazepinyl) methyl] -2-thiophenecarboxamide 4-benzylidene-1- [5-[(hexahydro-1-
Azepinyl) methyl] -2-thenoyl] piperidine N-benzyl-3- [1- [5-[(hexahydro-1
-Azepinyl) methyl] -2-thenoyl] pyrrolidine-
3-yl] urea N- (2-oxo-2-phenyl) 5-[(hexahydro-1-azepinyl) methyl] -2-thiophencarboxamide 1- [5-[(hexahydro-1-azepinyl) methyl] -2 -Thenoyl] piperidin-4-one 4- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] morpholine 1- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl]- 4-phenoxypiperidine 1-benzenesulfonyl-4- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] piperazine 1- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] -4- (p-toluyl) piperazine N-benzyl 4- [4-[(hexahydro-1-azepinyl) methyl] -2-te Yl] -1-piperazinecarboxamide N-benzyl 3- [4-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] -1-piperazinecarboxamide N-benzyl 4- [5-[(1-pyrrolidyl) methyl ] -2-Thenoyl] -1-piperazinecarboxamide

[0016]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 4- [5-[(Hexahydro-1-azepinyl) methyl] -2-thenoyl] -1-piperazinecarboxaldehyde 1-piperazinecarboxaldehyde 600 mg of N, N
1.5 g of 5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate in 30 ml of -dimethylformaldehyde solution, 3.7 g of triethylamine.
After adding 1.2 ml of diphenylphosphoryl azide under ice cooling, the mixture was stirred at room temperature overnight. To the reaction solution was added 100 ml of saturated aqueous sodium hydrogen carbonate, and the precipitated crystals were filtered and recrystallized from isopropanol-diisopropyl ether to obtain 781 mg of the title compound. Melting point: 86-87 ° C. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.50-1.70 (8H, m), 2.65-2.
70 (4H, m), 3.45 (2H, t), 3.62
(2H, t), 3.75 (2H, t), 3.79 (2
H, t), 3.83 (2H, s), 6.85 (1H,
d), 7.19 (1H, d), 8.12 (1H, s)

EXAMPLE 2 Ethyl 2-[[5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] amino] acetate 5-[(hexahydro-1-azepinyl) methyl] thiophen-2-carboxylate 2.5 ml of triethylamine was added to 20 ml of a suspension of 900 mg of salt in acetonitrile, stirred for 10 minutes, 835 mg of N, N'-disuccinimidyl carbonate was added, and the mixture was stirred at room temperature for 2 hours. Next, 455 mg of glycine ethyl ester hydrochloride was added, the mixture was stirred at room temperature overnight, concentrated under reduced pressure, 50 ml of saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted three times with 50 ml of chloroform. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 400 mg of the title compound. Melting point: 63-64 ° C. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.29 (3H, t), 1.55 (8H, s),
1.60-1.70 (4H, m), 2.60-2.67
(2H, m), 3.82 (2H, s), 4.20 (2
H, d), 4.25 (2H, q), 6.38 (1H, b
r), 6.86 (1H, d), 6.44 (1H, d)

Example 3 N-benzyl-2-[[5 [(hexahydro-1-azepinyl) methyl] -2-thenoyl] amino] acetamide N-benzyl-2-aminoacetamide hydrochloride 534m
g, amidation was conducted using 800 mg of 5- [1-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate hydrochloride according to the method of Example 1 to give the title compound 6
00 mg was obtained. Melting point: 157-158 ° C Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.56 (8H, s), 2.55-2.60 (4
H, m), 3.79 (2H, s), 3.86 (2H,
d), 4.29 (2H, d), 6.95 (1H, d),
7.20-7.35 (5H, m), 7.61 (1H,
d), 8.40 (1H, t), 8.67 (1H, t)

Example 4 N-benzyl-3-[[5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] amino] propionamide N-benzyl-3-aminopropionamide hydrochloride 856
mg, 5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate hydrochloride (1.0 g) was amidated by the method of Example 1 to give the title compound 80
0 mg was obtained. Melting point: 152-153 ° C. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.56 (8H, s), 2.59 (4H, s),
3.10-3.20 (2H, m), 3.25-3.40
(2H, m), 3.78 (2H, s), 4.21 (2
H, d), 6.94 (1H, d), 7.15-7.30.
(5H, m), 7.55 (1H, d), 8.43 (1
H, t), 8.51 (1H, t)

Example 5 N- [3- (N-benzylcarbamoyl) propyl]-
5-[(hexahydro-1-azepinyl) methyl] -2
-Thiophenecarboxamide N-benzyl-4-aminobutyramide hydrochloride 1.2 g,
5-[(hexahydro-1-azepinyl) methyl] -2
Using 1.0 g of -thiophenecarboxylic acid hydrochloride, amidation was carried out by the method of Example 1 to obtain 720 mg of the title compound. Melting point: 137-138 ° C. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.56 (8H, s), 1.90-2.00 (2
H, m), 2.35 (2H, dd), 2.65 (4H,
dd), 3.40-3.50 (2H, m), 3.81
(2H, s), 4.42 (2H, d), 6.22 (1
H, br), 6.70 (1H, br), 6.84 (1
H, d), 7.31 (5H, s), 7.38 (1H,
d)

Example 6 1) t-Butyl (S) -4-benzylcarbamoyl-
To the solution of 2,2-dimethyl-3-oxazolidinecarboxylate 1N diisobutylaluminum hydride-toluene (10 ml) was added benzylamine (1.2 ml), and the mixture was stirred for about 1 hour until the exothermic reaction solution returned to room temperature. Methyl, (S) -2,2-dimethyl-3,4-
10 ml of a toluene solution of 2.6 g of oxazolidine dicarboxylate was added, and the mixture was stirred at 60 ° C. for 3 hours. Next, the reaction solution was ice-cooled, 10 ml of water was added, and the mixture was stirred for 30 minutes, filtered through celite, 100 ml of brine was added, and 100 ml of toluene was added.
1 was separated twice. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 2.5 g of the title compound. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.41 (9H, s), 1.52 (3H, s),
1.61 (3H, s), 3.90-4.60 (5H,
m), 7.32 (5H, s)

2) (S) -N-benzyl-2-amino-
3-hydroxypropionamide hydrochloride t-butyl (S) -4-benzylaminocarbonyl-
A 4N salt-ethyl acetate solution was added to 2.5 g of 2,2-dimethyl-3-oxazolidinecarboxylate, and the mixture was stirred at room temperature. The precipitated crystals were filtered to obtain 800 mg of the title compound. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 3.34 (1H, s), 3.60-4.00 (2
H, m), 4.35 (2H, d), 5.53 (1H,
t), 7.31 (5H, s), 8.91 (1H, t)

3) (S) -N- [1-[(N-benzylcarbamoyl) -2-hydroxyethyl] -5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxamide (S) -N Using 367 mg of -benzyl-2-amino-3-hydroxypropionamide hydrochloride and 243 mg of 5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate hydrochloride, amidation was carried out by the method of Example 2. 438 mg of the title compound were obtained. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.65 (8H, s), 2.50-2.70 (4
H, m), 3.60-3.70 (1H, m), 3.81
(2H, s), 4.22 (1H, d), 4.40-4.
60 (2H, m), 4.63 (1H, br), 6.85
(1H, d), 7.20-7.40 (5H, m), 7.
41 (1H, d)

Example 7 N, N-bis [(N-benzylcarbamoyl) methyl]
-5-[(hexahydro-1-azepinyl) methyl]-
2-thiophenecarboxamide N, N-bis [N-benzylcarbamoyl) methyl] amine 1.7 g, 5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate 1.5
Using g, amidation was carried out by the method of Example 1 to obtain 2.0 g of the title compound. Melting point: 147-148 ° C. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.56 (8H, s), 2.50-2.65 (4
H, m), 3.31 (4H, s), 3.79 (2H,
s), 6.88 (1H, d), 7.13 (1H, d),
7.20-7.40 (10H, m), 8.78 (1H,
br), 9.26 (1H, br)

Example 8 N-benzyl-2- [N- [5-[(hexahydro-1
-Azepinyl) methyl] -2-thenoyl] -N-methylamino] acetamidoethyl 2- [N- [5-[(hexahydro-1-azepinyl) methyl] -N-methylamino] acetate
Example 6 using 5 g and 0.6 ml of benzylamine
Amidation was carried out by the method of 1) to obtain 1.0 g of the title compound. Melting point: 105-106 ° C Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.56 (8H, s), 2.66 (4H, dd),
3.32 (3H, s), 3.82 (2H, s), 4.1
8 (2H, s), 4.48 (2H, d), 6.83 (1
H, d), 7.27 (5H, s), 7.32 (1H,
d)

Example 9 N-benzyl-2- [N-benzyl-N- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoylamino] acetamidoethyl 2- [N-benzyl-N- [5 Amidation was carried out by the method of Example 6-1) using 1.5 g of-[(hexahydro-1-azepinyl) methyl] -2-thenoylamino] acetate and 0.5 ml of benzylamine to obtain 1.0 g of the title compound. Melting point: 119-120 ° C Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.57 (8H, s), 1.60-1.70 (4
H, m), 2.60-2.70 (4H, m), 3.81
(2H, s), 4.61 (2H, d), 6.14 (1
H, br), 6.84 (1H, d), 7.20-7.4.
0 (6H, m)

Example 10 N- (2-benzyloxyethyl) -5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxamide (2-benzyloxyethyl) amine 439 mg, 5-
Example 2 using 800 mg of [(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate hydrochloride
The title compound was obtained by amidation according to the procedure described above in 800 mg. Melting point: 56-57 ° C. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.60-1.70 (8H, m), 2.60-2.
70 (4H, m), 3.64 (4H, s), 3.80
(2H, s), 4.55 (2H, s), 6.30 (1
H, br), 6.84 (1H, d), 7.20-7.4.
0 (6H, m)

Example 11 N-benzyl-4- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] -1-piperazinecarboxamide N-benzyl-1-piperazinecarboxamide 690 m
g, 5- [Hexahydro-1-azepinyl) methyl]-
Amidation was carried out using 875 mg of 2-thiophenecarboxylic acid hydrochloride according to the method of Example 1 to obtain 700 mg of the title compound. Melting point: 86-88 ° C. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.56 (8H, s), 2.66 (4H, dd),
3.40-3.50 (4H, m), 3.70-3.80
(4H, m), 3.81 (2H, s), 4.45 (2
H, d), 4.72 (1H, t), 6.84 (1H, b
r), 7.25-7.52 (6H, m)

Example 12 1-benzoyl-4- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] piperazine 740 mg of 1-benzoylpiperazine hydrochloride, 5-
Amidation was carried out using 900 mg of [(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate according to the method of Example 1 to obtain 800 mg of the title compound. Melting point: 103-105 ° C Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.50-1.70 (8H, m), 2.60-2.
70 (4H, m), 3.30-4.00 (10H,
m), 6.83 (1H, d), 7.18 (1H, d),
7.40-7.50 (4H, m)

Example 13 1- [5-[[4- (2-Pyrimidinyl) -1-piperazinyl] carbonyl] -2-thenyl] hexahydro-1
-Azepine 1- (2-pyrimidinyl) piperazine 893 mg, 5-
Amidation was performed by the method of Example 1 using 1.5 g of [(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate to obtain 1.2 g of the title compound. Melting point: 108-109 ° C. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.57 (8H, s), 2.62 (4H, dd),
3.73 (4H, s), 3.75-3.85 (6H,
m), 6.67 (1H, t), 6.95 (1H, d),
7.30 (1H, d), 8.39 (2H, d)

Example 14 1- [5-[[4- (2-pyridinyl) -1-piperazinyl] carbonyl] -2-thenyl] hexahydro-1-
Azepine 1- (2-pyridinyl) piperazine 1.0 ml, 5-
Amidation was conducted by the method of Example 1 using 1.5 g of [(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate to obtain 1.0 g of the title compound. Melting point: 84-85 ° C. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.57 (8H, s), 2.62 (4H, dd),
3.50-3.60 (4H, m), 3.70-3.80
(4H, m), 3.81 (2H, s), 6.67 (1
H, dd), 6.84 (1H, d), 6.95 (1H,
d), 7.30 (1H, d), 7.57 (1H, d
d), 8.13 (1H, d)

Example 15 1- [5-[(4-Phenyl-1-piperazinyl) carbonyl] -2-thenyl] -hexahydroazepine 0.8 ml of 1-phenylpiperazine, 5-[(hexahydro-1-azepinyl) Using 1.5 g of [methyl] -2-thiophenecarboxylate hydrochloride, amidation was carried out by the method of Example 1 to obtain 800 mg of the title compound. Melting point: 83-84 ° C. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.57 (8H, s), 2.62 (4H, dd),
3.20 (4H, t), 3.78 (4H, t), 3.8
1 (2H, s), 6.82 (1H, d), 6.40 −
7.00 (3H, m), 7.20-7.30 (3H,
m)

Example 16 1- [5-[(4-benzyl-1-piperazinyl) carbonyl] -2-thenyl] hexahydro-1-azepine 960 mg of 1-benzylpiperazine, 5-[(hexahydro-1-azepinyl) methyl Amidation was carried out according to the method of Example 1 using 1.5 g of 2-thiophenecarboxylic acid hydrochloride to obtain 1.9 g of the title compound. Melting point: 88-89 ° C. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.56 (8H, s), 2.40 (4H, dd),
2.60 (4H, t), 3.51 (2H, s), 3.6
3 (4H, t), 3.79 (2H, s), 6.91 (1
H, d), 7.21 (1H, d), 7.25-7.40.
(5H, m)

Example 17 1-benzyl-4- [5- [hexahydro-1-azepinyl) methyl] -2-thenoyl] -2-piperazinone 1-benzyl-2-piperazinone 415 mg, 5-
Amidation was carried out according to the method of Example 1 using 601 mg of [(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylic acid to obtain 600 mg of the title compound. Melting point: 98-99 ° C. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.50-1.70 (8H, m), 2.66 (4
H, dd), 3.35 (2H, t), 3.82 (2H,
s), 3.91 (2H, t), 4.52 (2H, s),
4.64 (2H, s), 6.84 (1H, d), 7.2
2 (1H, d), 7.30-7.40 (5H, m)

Example 18 Ethyl 4 [4- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoylpiperazine-1-carboxylate hydrochloride 0.8 ml of ethyl 1-piperazinecarboxylate,
5-[(hexahydro-1-azepinylmethyl) -2-
Example 1 Using 1.5 g of thiophenecarboxylate hydrochloride
Amidation was carried out by the method of 4
An ethyl acetate solution was added, and the precipitated crystals were filtered to obtain 1.1 g of the title compound. Melting point: 207-209 ° C. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.20 (3H, t), 1.50-1.90 (8
H, m), 3.00-3.10 (2H, m), 3.30
-3.40 (2H, m), 3.46 (4H, t), 3.
64 (4H, t), 4.07 (2H, q), 4.56
(2H, d), 7.42 (1H, d), 7.44 (1
H, d), 10.80 (1H, br)

Example 19 1- [5-[(Hexahydro-1-azepinyl) methyl] -2-thenoyl] -4- (4-methoxybenzoyl] piperazine hydrochloride 2.2 g of 1- (4-methoxybenzoyl) piperazine ,
5-[(hexahydro-1-azepinyl) methyl] -2
Using 2.8 g of thiophenecarboxylate hydrochloride, a 4N hydrochloric acid-ethyl acetate solution was added to the compound obtained by amidation according to the method of Example 1, and the precipitated crystals were filtered and recrystallized from methanol-isopropanol to give the title. Compound 2.
7 g were obtained. Melting point: 205-207 ° C. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.30-1.90 (8H, m), 3.00-3.
15 (2H, m), 3.30-3.40 (2H, m),
3.50-3.75 (8H, m), 3.80 (3H,
s), 4.59 (2H, d), 7.00 (2H, d),
7.38 (1H, d), 7.41 (2H, d), 7.4
4 (1H, d), 10.10 (1H, br)

Example 20 t-butyl 4- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] -1-piperazinecarboxylate 980 m of t-butyl 1-piperazinecarboxylate
g, 5-[(hexahydro-1-azepinyl) methyl]
Using 1.5 g of -2-thiophenecarboxylate hydrochloride, amidation was carried out by the method of Example 1 to obtain 1.1 g of the title compound. Melting point: 115-116 ° C. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.48 (9H, s), 1.62 (8H, br),
2.67 (4H, dd), 3.49 (4H, t), 3.
72 (4H, t), 3.82 (2H, s), 6.83
(1H, d), 7.16 (1H, d)

Example 21 4- (4-Fluorobenzoyl) -1- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl]
Piperazine 1- (4-Fluoropenzoyl) piperazine hydrochloride
Using 3 g of 1.5 g of 5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate hydrochloride, the title compound was obtained by amidation according to the method of Example 1.
6 g were obtained. Melting point: 107-108 ° C Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.50-1.70 (8H, m), 2.67 (4
H, t), 3.40-3.80 (8H, br), 3.8
2 (2H, s), 6.83 (1H, d), 7.10-
7.30 (4H, m), 7.45 (1H, d)

Example 22 1- [5-[(Hexahydroazepinyl) methyl] -2
-Thenoyl] -4- (4-nitrobenzoyl) piperazine 1- (4-nitrobenzoyl) piperazine hydrochloride 1.4
g, 5-[(hexahydro-1-azepinyl) methyl]
Example 1 using 1.5 g of -2-thiophenecarboxylic acid
Amidation was carried out by the method described above to obtain 960 mg of the title compound. Melting point: 121-122 ° C Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.50-1.70 (8H, m), 2.67 (4
H, t), 3.46 (2H, br), 3.74 (2H,
br), 3.82 (2H, s), 3.87 (4H, b
r), 6.84 (1H, d), 7.19 (1H, d),
7.60 (2H, d), 8.31 (2H, d)

Example 23 4-cyclohexylcarbonyl-1- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] piperazine 1.1 g, 5 of 1-cyclohexanecarbonylpiperazine
-[(Hexahydro-1-azepinyl) methyl] -2-
Example 1 Using 1.4 g of thiophenecarboxylate hydrochloride
Amidation was carried out by the method of to give 1.0 g of the title compound. Melting point: 96-97 ° C. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.20-1.30 (2H, m), 1.50-1.
90 (16H, m), 2.40-2.50 (1H,
m), 2.67 (4H, dd), 3.50-3.80.
(8H, m), 3.82 (2H, s), 6.83 (1
H, d), 7.17 (1H, d)

Example 24 1 [5-[(4-Acetyl-1-piperazinyl) carbonyl] -2-thenyl] hexahydro-1-azepine hydrochloride 1-acetylpiperazine 650 mg, 5-[(hexahydro-1-azepinyl) Using 1.4 g of [methyl] -2-thiophenecarboxylate hydrochloride, amidation was carried out by the method of Example 1 to obtain 900 mg of the title compound. Melting point: 195-197 ° C Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.50-1.70 (4H, br), 1.80-
1.90 (4H, br), 2.12 (3H, s), 2.
96 (2H, br), 3.55 (4H, t), 3.70
(4H, t), 3.79 (2H, t), 4.34 (2
H, s), 7.24 (1H, d), 7.60 (1H,
d), 12.73 (1H, br)

Example 25 1-benzyl-3-[[5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] amino] -1,
3,4,5,6,7-hexahydro-2H-azepine-
2-one monooxalate 2-amino-1-benzyl-1,3,4,5,6,7-
666 mg of hexahydro-2H-azepin-2-one,
5-[(hexahydro-1-azepinyl) methyl] -2
Compound 910m obtained by amidation using the method of Example 2 using 900 mg of thiophenecarboxylate hydrochloride
g of oxalic acid in methanol was added to and dissolved in methanol, and the mixture was concentrated under reduced pressure and recrystallized from acetonitrile to obtain 810 mg of the title compound. Melting point: 120-121 ° C. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.15 (1H, dd), 1.50-1.80 (1
1H, m), 1.80-1.90 (2H, dd), 2.
98 (4H, s), 3.27 (1H, dd), 3.59
(1H, dd), 4.28 (2H, s), 4.50 (2
H, d), 4.63 (2H, d), 4.81 (1H, d
d), 7.20 (1H, s), 7.25-7.35 (5
H, m), 7.80 (1H, d), 8.47 (1H,
d)

Example 26 N- (trans-4-methoxycyclohexyl) -5
[(Hexahydro-1-azepinyl) methyl] -2-thiophenecarboxamide trans-4-methoxycyclohexylamine hydrochloride 4
Using 80 mg, 5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate hydrochloride (800 mg) and amidation by the method of Example 2, the title compound 6 was obtained.
80 mg were obtained. Melting point: 130-131 ° C. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.20-1.30 (2H, m), 1.30-1.
40 (2H, m), 1.50-1.70 (8H, m),
2.00-2.20 (4H, m), 2.66 (4H, d
d), 3.10-3.20 (1H, m), 3.35 (3
H, s), 3.81 (2H, s), 3.90-4.00.
(1H, m), 5.64 (1H, d), 6.83 (1
H, d), 7.35 (1H, d)

Example 27 1- [5-[(Hexahydro-1-azepinyl) methyl] -2-thenoyl] -4-piperidinecarboxamide 0.7 g of 4-piperidinecarboxamide, 5-[(hexahydro-1-azepinyl) methyl Amidation was carried out according to the method of Example 1 using 1.5 g of 2-thiophenecarboxylic acid hydrochloride to obtain 1.2 g of the title compound. Melting point: 126-128 ° C. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.40-1.50 (2H, m), 1.56 (8
H, s), 1.70-1.80 (2H, m), 2.35
-2.45 (1H, m), 2.61 (4H, dd),
2.95-3.05 (2H, br), 3.20-3.4
0 (2H, br), 3.80 (2H, s), 4.23
(2H, d), 6.91 (1H, d), 7.20 (1
H, d)

Example 28 4-[[1- [5-[(Hexahydro-1-azepinyl) methyl] -2-thenoyl] -4-piperidyl] oxy] acetanilide 4-[(4-piperidyl) oxy] acetanilide 28
Using 0 mg, 330 mg of 5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate, the title compound 34 was obtained by amidation according to the method of Example 1.
0 mg was obtained. Melting point: 86-88 ° C Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.50-1.70 (12H, m), 1.85-
1.90 (2H, m), 1.90-2.05 (2H,
m), 2.16 (3H, s), 2.66 (4H, d
d), 3.70-3.80 (2H, m), 3.82 (2
H, s), 3.85-4.00 (2H, m), 4.50
-4.60 (1H, m), 6.82 (1H, d), 6.
89 (2H, d), 7.12 (1H, br), 7.16
(1H, d), 7.40 (2H, d)

Example 29 N-benzyl-N-alpha- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] -1-phenylalanamide 1.2 g of N-benzyl-1-phenylalanamide , 5-
Amidation was carried out using 1.2 g of [(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylic acid according to the method of Example 1 to obtain 620 mg of the title compound. Melting point: 86-87 ° C. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.50-1.70 (8H, m), 2.66 (4
H, t), 3.09 (1H, dd), 3.26 (1H,
dd), 3.81 (2H, s), 4.29 (1H,
d), 4.39 (1H, d), 4.78 (1H, m),
5.99 (1H, t), 6.84 (1H, d), 7.0
7 (2H, d), 7.20-7.60 (9H, m) The following table shows the chemical structural formulas of the compounds obtained in Examples 1 to 29.

[0048]

[Table 1]

[0049]

[Table 2]

[0050]

The compound (I) of the present invention is a specific anti-PCP
Psychotropic, anti-schizophrenic,
It is useful as an anti-dementia drug such as Alzheimer's disease, a drug for improving behavioral problems such as delirium associated with dementia, or a drug for treating mental retardation and autism in childhood. Anti-PC of compound (I) of the present invention
P action was confirmed by the following test method.

Anti-PCP Action Test Experimental Method Male Wistar rats (n = 8) (body weight 200-30)
0g) was administered subcutaneously with PCP (3 mg / kg) and 30 minutes later, placed in whole boat avalatas (HBA). The test compound (10 mg / kg) was administered subcutaneously 15 minutes before the administration of PCP. HBA has 16 holes of 4cm diameter on the floor and 40cm height and width with 20cm height wall around the floor.
[Psychopharm]
acology, 52, 271 (1977)]. HBA
The locomotor activity (number of times of movement of the floor section divided into 9 (Locommotion)) and exploratory behavior (number of times of putting a head in a hole (Dipping)) were measured over 5 minutes. Male Wistar rats (n = 8) to which PCP (3 mg / kg) was subcutaneously administered were used as a control group.
In this pharmacological test, the compound of the present invention statistically significantly (compared to the control group by the Mann-Whitney U test) antagonized the increase in locomotion and the decrease in exploratory behavior induced by PCP.

A preparation containing one or more of the compound (I) of the present invention or a salt thereof as an active ingredient can be prepared by using carriers, excipients and other additives for preparations which are usually used.
Tablets, buccal, powder, fine granules, granules, capsules,
Pills, oral solutions (including syrups), injections, inhalants, suppositories, transdermal solutions, ointments, transdermal patches, transmucosal patches (for example, oral patches), transmucosal It is prepared as a liquid (for example, a nasal solution) or the like and is orally or parenterally administered. Pharmaceutical carriers and excipients include solid or liquid non-toxic pharmaceuticals. These include, for example, lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol and the like and other commonly used ones.

The clinical dose of the compound (I) of the present invention to humans is appropriately determined depending on the individual case in consideration of the symptoms, body weight, age, sex, administration route and the like of the patient to which the compound (I) is applied. 0.1-1000 per adult per day
mg, preferably in the range of 1 to 200 mg, orally in one to several doses per day, or 1 per adult.
0.1 to 1000 mg per day, preferably 0.3 to 3
It is administered intravenously in the range of 0 mg once to several times a day, or continuously intravenously in the range of 1 hour to 24 hours a day. Of course, as described above, the dose varies under various conditions, so that a smaller dose than the above dose may be sufficient.

Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location C07D 409/12 213 C07D 409/12 213 223 223 239 239 241 241 241 413/12 333 413/12 333 (72) Invention Person Takuma Morita 1-1-1 Ninomiya, Tsukuba-shi, Ibaraki Ninomiya Arai Mansion 208 (72) Inventor Shinichi Tsukamoto 4-14 Onogawa, Tsukuba-shi, Ibaraki

Claims (2)

[Claims] 1. A thiophene derivative represented by the general formula (I) or a salt thereof. Embedded image (The symbols in the formula have the following meanings. Ring B: 4- to 10-membered nitrogen-containing cycloalkyl ring A: bond or lower alkylene group R ³ , R ⁴ , R ⁶ and R ^{7 are the} same or different and are each a hydrogen atom or a lower alkyl group or an aralkyl group which may have a substituent n and m: the same or different and an integer of 0 or 1 to 6 R ⁵ , R ⁸ and R ^{9 are the} same or different and each include a hydrogen atom or a lower alkyl group, a cycloalkyl group, an aralkyl group, an aryl group or one or two nitrogen atoms which may have a substituent, or 5 or 6-membered heteroaryl group D-ring: a 5- to 7-membered cycloalkyl ring which may have a carbonyl group and contains 1 or 2 nitrogen atoms R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are combined with a hydrogen atom, a lower alkyl group or R ³ or R ⁶ to form 5 to 8
A member ring may be formed. ) 2. A medicament comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.