CN1223648A - Novel thiophene derivatives and pharmaceutical compositions thereof - Google Patents

Abstract

The present invention relates to thiophene derivatives of general formula (I) and pharmaceutically acceptable salts thereof. These compounds act as an anti-PCP agonist, thus being useful as psychotropic or antischizophrenic agents and so on. In said formula R1 is -A1-X1-R3; R2 is -A2-X2-R4 or nil; B is a four- to ten-membered nitrogenous cycloalkyl or a five- or six-membered nitrogenous unsaturated heterocycle; Ar is aryl or heteroaryl; A1, A2 and A3 are each independently a bond or lower alkylene; X1 and X2 are each independently a bond, -O-, -S- or the like; and R3 and R4 are each independently hydrogen, cyclic imido, lower alkyl, cycloalkyl, aryl or aralkyl, with the provisos that when Ar is a thiazole ring, at least either of A1 and A2 is lower alkylene and that when Ar is a benzene ring, compounds wherein one of R1 and R2 is methyl or halogeno and the other thereof is hydrogen are excepted.

Description

Novel thiophene derivatives and pharmaceutical compositions thereof

technical field

The present invention relates to medicine, especially a novel thiophene derivative or its pharmaceutically acceptable salt with anti-PCR (phencyclidine) effect, and a drug with anti-PCR effect using the derivative as an active ingredient.

Background technique

It is well known that PCR can induce psychotic symptoms similar to each symptom of schizophrenia including recessive symptoms [Am.J.Psychiat., 135, 1081 (1987) Am.J.Phsychiat., 148, 1301 (1991) ]. On the other hand, if PCR is administered to animals, various abnormal behaviors are induced. From the above facts, it can be considered that the drug that can specifically inhibit the abnormal behavior (anti-PCR effect) of animals induced by PCR is also useful as a drug for the treatment of human schizophrenia [Neuropsychopharmacology, 15 (10), 651 (1993), Behav Brain Res , 74, 45 (1996)]. Moreover, since PCR has NMDA receptor blocking effect [J.Pharm.Exp.Thera., 238,938(1986), Br.J.Pharmacol.,79,565(1982)], the above-mentioned drugs with anti-PCR effect are used as the reason Alzheimer's memory, a disease caused by weakened NMDA receptor function. Therapeutic agents for abnormal behaviors such as cognitive impairment and delirium are also useful [J.Neurochem., 54(2), 526(1990), LifeScience, 55(25/26), 2147(1994)].

In the past, dopamine receptor blockers were mainly used as therapeutic drugs for schizophrenia. However, dopamine blockers not only have poor effects on hidden symptoms, but also have side effects such as extrapyramidal symptoms [T.I.P.S., 13, 116 (1992)].

Correspondingly, specific anti-PCR drugs can improve the hidden symptoms of schizophrenia that do not work with dopamine blockers, and it also has the advantage of not causing dopamine blocker-like side effects.

First, the present inventors discovered that novel thiophene derivatives having a nitrogen-containing cycloalkyl lower alkyl group have anti-PCR effects, which was reported in WO94/225450 or WO95/29910.

In addition, a compound represented by the following general formula is described in Japanese Patent Laid-Open Publication No. Sho 62-192379,

(Refer to the above bulletin for detailed definitions)

Depending on the substituent used, it may be a thiophene derivative having a nitrogen-containing cycloalkyl group and a thiazolyl group. Furthermore, the same compound is also described in Japanese Patent Laid-Open Publication No. Sho 61-18178. These two publications also report that the above-mentioned compounds have anti-hypoxic effects, anti-amnestic effects and anxiolytic effects, and are also useful as therapeutic agents for dementia or anxiolytic agents. However, the anti-PCR effect is not mentioned at all.

In addition, Journal of the Chemical Society, Perkin Transactions Pt.l: Organic Chemistry, 22, 2355 (1976) describes the synthesis method of the compound represented by the following general formula,

(Refer to the above literature for detailed definitions)

But there is also nothing to suggest or reveal an anti-PCR effect.

The novel thiophene derivative represented by the general formula (I) of the present invention does not include the compounds described in the above-mentioned Japanese Patent Laid-Open Publication and Documents, and its structure is also significantly different from the compounds disclosed by the inventors in previous International Laid-Open Gazettes.

disclosure of invention

The inventors of the present invention have carefully studied compounds that specifically have a good anti-PCR effect and found that thiophene with nitrogen-containing cycloalkyl lower alkyl (or nitrogen-containing unsaturated heterocycle) and aromatic ring or heteroaryl ring The derivative or its pharmaceutically acceptable salt has good anti-PCR effect, thus completing the present invention.

That is, the present invention is a novel thiophene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof.

(The symbols in the formula have the following meanings:

R ₁ : Formula-A ₁ -X ₁ -R ₃ ,

R ₂ : formula -A ₂ -X ₂ -R ₄ or absent,

Ring B: 1) 4-10 membered nitrogen-containing cycloalkyl ring or

2) 5-6 membered nitrogen-containing unsaturated heterocyclic rings,

Ar ring: an aromatic ring that may have substituents or a 5-6 membered heteroaromatic ring or an 8-10-membered bicyclic ring containing 1 to 4 heteroatoms of one or more than two kinds selected from nitrogen atoms, oxygen atoms, and sulfur atoms Heteroaromatic rings,

A ₁ , A ₂ and A ₃ : the same or different bonds or lower alkylene groups,

或-C≡C-,X ₁ and X ₂ : same or different bonds, formula -O-, -S-, -NR ₅ -,

or -C≡C-,

R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ : the same or different hydrogen atoms or lower alkyl groups,

R ₃ and R ₄ : the same or different hydrogen atoms, cyclic imino groups that may be condensed with a benzene ring that may have substituents, or lower alkyl, cycloalkyl, aryl or aryl that may each have substituents alkyl,

However, when the Ar ring is a thiazole ring, either one of _A1 and _A2 is a lower alkylene group, and when the Ar ring is a benzene ring, either one of _R1 and _R2 is methyl or halogen, and the other except for hydrogen atoms)

Another object of the present invention is to provide a pharmaceutical composition comprising the above-mentioned thiophene derivative (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Moreover, the pharmaceutical composition is a drug with anti-PCR effect.

Preferably, the above-mentioned drug with anti-PCR effect is psychotherapy drug or anti-schizophrenia drug. Furthermore, the above-mentioned anti-PCR drug is a therapeutic agent for diseases caused by weakened NMDA receptor function, that is, a therapeutic agent for dementia, a drug for improving abnormal behavior accompanied by dementia, a therapeutic agent for mental retardation in children and/or a therapeutic agent for autism. therapeutic agent.

The thiophene derivatives represented by the general formula (I) of the present invention or their pharmaceutically acceptable salts are characterized in chemical structure by lower alkyl substituted by nitrogen-containing cycloalkyl lower alkyl (or nitrogen-containing unsaturated heterocyclic group) base) and thiophene derivatives substituted by aromatic ring or heteroaryl ring, its pharmacological feature is that it can also improve the hidden symptoms of schizophrenia that do not work with dopamine receptor blockers.

The thiophene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof is not described in any of the aforementioned publications and documents, and is a novel compound having novel effects not described in the above publications or the like.

That is, the compound (I) of the present invention clearly excludes the compounds described in the aforementioned publications and documents in terms of the definitions of the Ar ring substituents R ₁ and R ₂ .

Hereinafter, the compound of the present invention will be described in detail.

The word "lower" used when defining the general formula of the present invention is not particularly limited, and represents a straight or branched carbon chain with 1 to 6 carbon atoms.

Therefore, "lower alkyl" specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-amyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl or isohexyl.

The "lower alkylene" represented by _A1 , _A2 and _A3 specifically includes methylene, ethylene, methylmethylene, propylene, methylethylene, butylene, methyl Propylene, pentylene or hexylene is preferably an alkylene group having 1 to 4 carbon atoms. The "lower alkylene" represented by _A3 includes the above-mentioned groups, among which methylene is most preferable.

The "cycloalkyl" represented by _R3 and _R4 refers to a 3-8 membered monocyclic hydrocarbon group, specifically including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, etc., preferably is cyclohexyl.

"Aryl" refers to a carbocyclic aryl group, specifically including benzene, biphenyl, naphthalene, anthracene or phenanthrene, etc., preferably phenyl.

"Aralkyl" refers to a group obtained by substituting any hydrogen atom of the aforementioned "lower alkyl" with phenyl or naphthyl, specifically including benzyl, phenethyl, phenylpropyl, methylphenethyl, Phenylbutyl, Methylphenylpropyl, Ethylphenethyl, Dimethylphenethyl, Phenylpentyl, Methylphenbutyl, Phenylhexyl, Methylphenpentyl, Naphthylmethyl, Naphthaleneethyl, Naphthalene propyl, naphthalene butyl, naphthyl pentyl or naphthyl hexyl, etc., preferably benzyl.

Of the "1) 4- to 10-membered nitrogen-containing cycloalkyl ring or 2) 5- to 6-membered nitrogen-containing unsaturated heterocyclic ring" represented by B ring, "4 to 10-membered nitrogen-containing cycloalkyl ring" is preferred. "4- to 10-membered nitrogen-containing cycloalkyl ring" specifically refers to azetidine, pyrrolidine, piperidine, hexahydroazepine, octahydroazocine, octahydroazonine or decahydroazepine etc., the best of which is hexahydroazepine. "5-6 membered nitrogen-containing unsaturated heterocyclic ring" refers to a 5-6 membered unsaturated ring containing 1 to 4 nitrogen atoms as heteroatoms, specifically including pyrrole, imidazole, triazole, pyrazole, pyridine, pyrazine, Pyrimidine, pyridazine, pyrazine, triazine, etc., preferably imidazole.

"A 5-6 membered heteroaryl ring or an 8-10-membered bicyclic heteroaryl ring containing 1 or more than 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms" specifically Including pyrrole, imidazole, triazole, furan, oxazole, isoxazole, oxadiazole, thiophene, thiazole, isothiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, indole, isoindole Indole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzisothiazole, benzothiadiazole , quinoline, isoquinoline, benzopyridazine, benzopyrimidine, benzopyrazine, benzotriazine, imidazopyridine, imidazopyrimidine, triazolopyridazine, etc., preferably triazole, oxa Oxadiazoles, thiazoles, thiadiazoles, imidazopyridines, imidazopyrimidines, triazolopyridazines, most preferably triazoles and oxadiazoles.

The "cyclic imino group that can be condensed with a benzene ring" represented by R ₃ and R ₄ specifically includes succinimidyl group, glutarimyl group, phthalimide group and the like.

The "cyclic imino group that may have a substituent that may be condensed with a benzene ring or a lower alkyl, cycloalkyl, aryl or aralkyl group that may have a substituent" represented by _R3 and _R4 ""Substituent" specifically includes halogen atom, hydroxyl, lower alkoxy, acyloxy, carbamoyloxy, one or two lower alkylcarbamoyloxy, amino, one or two lower alkylamino, amido, Carbamoylamino, one or two lower alkylcarbamoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, one or two lower alkylcarbamoyl, cyano, nitro, etc., preferably halogen atom, nitro, hydroxyl and lower alkoxy.

"Halogen atom" means fluorine atom, chlorine atom, bromine atom and iodine atom, preferably fluorine atom and chlorine atom.

"Lower alkoxy" refers to a straight-chain or branched alkoxy group with 1 to 6 carbon atoms, specifically including methoxy, ethoxy, propoxy, isopropoxy, butoxy, and isobutyl Oxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, etc., preferably methoxy.

"Acyl" in "acyloxy" or "acylamino" refers to lower alkanoyl or aroyl, specifically including formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, tri Methylacetyl, hexanoyl, tert-butylacetyl, benzoyl, toluoyl, methoxybenzoyl, and naphthylcarbonyl, etc.

The compound (I) of the present invention can also undergo an addition reaction with an acid to form a salt. Salts with acids include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, or phosphoric, or formic, acetic, propionic, oxalic, malonic, succinic, fumaric, maleic, lactic, malic , citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid or glutamic acid and other organic acids formed acid addition salts.

Salts can also be formed with bases, such as addition salts with inorganic bases such as lithium, sodium, potassium, magnesium, calcium or aluminum or organic bases such as methylamine, ethylamine, ethanolamine, or with lysine or ornithine, etc. Salts or ammonium salts of basic amino acids.

Furthermore, since the compounds of the present invention sometimes contain a chiral carbon atom, optical isomers based on this chiral carbon atom exist. Moreover, when there are two or more chiral carbon atoms, diastereoisomers also exist. The present invention includes mixtures and monomers of these isomers.

The compound (I) of the present invention or its salt can also be isolated in the form of various solvates or polymorphs such as hydrates and ethanolates, and the compounds of the present invention include these hydrates, solvates and polymorphs.

Among the compounds (I) of the present invention, preferably the ring B is a compound having a nitrogen-containing cycloalkyl ring of 4 to 10 members, and the particularly preferred compound is a compound whose ring B is hexahydroazepine and/or _A3 is methylene The compound of the base, the better compound is the compound whose Ar ring is triazole, oxadiazole, thiazole, thiadiazole, imidazopyridine, imidazopyrimidine or triazolopyridazine, and the best compound is that Ar is triazole or oxadiazole compounds.

A particularly desirable compound is 5-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-3-phthalimidoethyl-1,2 ,4-oxadiazole, 5-amino-3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-tri Azole or its pharmaceutically acceptable salt.

The compounds of the present invention in the present application have been described above, and all of them are included in the compounds of the present invention.

Preparation

Using the characteristics of the basic skeleton or substituent type based on the compound (I) of the present invention and its pharmaceutically acceptable salt, various suitable synthetic methods can be used to prepare the compound (I) of the present invention and its pharmaceutically acceptable salt . Here, what is effective in terms of production technology is to substitute, if necessary, the amino group and the like in the compound of the present invention with a functional group that can be easily converted into an amino group or the like with an appropriate protecting group. In addition to the above-mentioned amino protecting groups, these protecting groups include, for example, the protecting groups described in the second edition of "Protective Groups in Organic Syntheses" edited by Green and Wuts, which can be appropriately selected according to different reaction conditions. In addition, functional groups other than the above-mentioned protecting groups that can be easily converted into groups such as nitro groups and amino groups can also be used in the same manner as the protecting groups.

Hereinafter, typical production methods of the compounds of the present invention are listed.

(式中，B环和A₃如前所述，R₁₄为低级烷基，R₁₅为氨基或具有被保护的羟基的低级烷基。此时可使用的保护基包括苯甲基、二苯甲基、三苯甲基、芳酰基、低级烷酰基、叔丁基二甲基甲硅烷基等甲硅烷基、四氢吡喃基等缩醛基等。)Preparation method 1

(In the formula, Ring B and _A3 are as described above, _R14 is a lower alkyl group, and _R15 is an amino group or a lower alkyl group with a protected hydroxyl group. The protective groups that can be used at this time include benzyl, diphenyl methyl group, trityl group, aroyl group, lower alkanoyl group, silyl group such as tert-butyldimethylsilyl group, acetal group such as tetrahydropyranyl group, etc.)

The compound (Ia) of the present invention can be obtained by reacting an ester compound represented by the general formula (II) with an amidoxime compound.

This reaction can be carried out in organic solvents such as tetrahydrofuran, diethyl ether, and dioxane, in the presence of alkalis such as lithium diisopropylamide, bis(trimethylsilyl)amide, and sodium hydride, under cooling-heating reflux under conditions.

(式中，B环和A₃如前所述，X表示卤原子。)When R ₁₅ is a protected hydroxyl group, the deprotection reaction can be carried out according to common methods. For example, the benzyl protecting group can be removed by reduction, oxidation or hydrolysis under acidic conditions, and the acyl protecting group can be removed under acidic or basic conditions. It can be removed by hydrolysis under certain conditions, the silyl protecting group can be removed by fluoride ion, and the acetal protecting group can be removed by acidic conditions.

(In the formula, ring B and _A3 are as described above, and X represents a halogen atom.)

In addition, the compound of the present invention can also be obtained by reacting the haloacyl compound represented by the general formula (II') with the amidoxime compound instead of the ester compound represented by the general formula (II). In this case, the reaction can be carried out at room temperature in the presence of an organic base such as triethylamine or diisopropylethylamine in a solvent such as tetrahydrofuran, dioxane, chloroform, methylene chloride, benzene, or toluene.

(式中，B环和A₃如前所述，Y表示卤原子、对甲苯磺酰氧基、甲氧基、琥珀酰亚氨氧基等可离去基，R₁₆和R₁₈表示可带有相同或不同的被保护的氨基或羟基的低级烷基或芳烷基，R₁₇表示低级烷基。这里的保护基如前所述。)Preparation method 2

(In the formula, ring B and _A3 are as described above, Y represents a halogen atom, p-toluenesulfonyloxy, methoxy, succinimidyloxy and other leaving groups, _R16 and _R18 represent optional There are lower alkyl or aralkyl groups with the same or different protected amino or hydroxyl groups, and R ₁₇ represents a lower alkyl group. The protecting group here is as previously described.)

The nitrile compound represented by the general formula (Ⅲ) is reacted with sodium alkoxide, then reacted with cyanamide to obtain the cyanoamidine derivative (Ⅳ), and then (Ⅳ) is reacted with hydroxylamine hydrochloride; or (Ⅲ) is reacted with hydrazine and N , N-dimethylformamide reaction; or make (Ⅲ) react with hydroxylamine hydrochloride to obtain amidoxime derivative (Ⅴ), then make (Ⅴ) react with ester compound or acid anhydride; or make (Ⅲ) react with hydrogen sulfide to obtain The compounds (Ib-e) of the present invention can be obtained by reacting the thioamide derivative (VI) with a ketone derivative.

The reaction with sodium alkoxide can be carried out at room temperature to heating under reflux, and the reaction with cyanamide can be carried out in organic solvents such as tetrahydrofuran and dioxane or under solvent-free conditions. The reaction with hydroxylamine can use tetrahydrofuran, dioxane, methanol, ethanol and other solvents, in the presence of organic bases such as triethylamine and diisopropylethylamine or inorganic bases such as sodium hydroxide and potassium hydroxide, at room temperature to heating under reflux conditions. The reaction with hydrazine can be carried out under heating and reflux using solvents such as DMF, tetrahydrofuran, and dioxane. The reaction with ester, acid halide or acid anhydride can use tetrahydrofuran, dioxane, chloroform, dichloromethane, benzene, toluene and other solvents in the presence of organic bases such as triethylamine and diisopropylethylamine or inorganic bases such as sodium hydride Under low or neutral conditions, it is carried out under ice cooling to heating to reflux. The reaction with hydrogen sulfide can be carried out in the presence of organic bases such as triethylamine and diisopropylethylamine using solvents such as pyridine, tetrahydrofuran and dioxane. The reaction with a ketone compound can be carried out at room temperature to heating under reflux using a solvent such as methanol or ethanol.

(式中，B环和A₃如前所述，R₁₉和R₂₂相同或不同地表示低级烷基或芳烷基，R₂₀表示氢原子或低级烷基，R₂₁和R₂₃表示低级烷基。)Preparation method 3

(In the formula, ring B and _A3 are as described above, _R19 and _R22 represent lower alkyl or aralkyl either identically or differently, _R20 represents a hydrogen atom or a lower alkyl group, _R21 and _R23 represent a lower alkane base.)

Make the hydrazide compound represented by the general formula (VII) and sulfuric acid S-methylisothiourea, cyanamide, various isothiocyanates, tetrafluoroborate carbonyl lower alkoxy-2-methylmethanimine or imine The compound (If~j) of the present invention can be prepared by reacting the amino acid ester or imido ester compound, followed by cyclization; or reacting (VII) with bromcyanic acid.

The reaction with sulfuric acid S-methylthiourea or cyanamide can be carried out with methanol, ethanol, etc. as solvents at room temperature to heating under reflux conditions, and inorganic bases such as sodium hydroxide and potassium hydroxide can also be used in the reaction. For the reaction with isothiocyanate, solvents such as methanol, ethanol, THF, dioxane, ether, and dichloromethane can be used. Carried out at room temperature to heating to reflux. The reaction with tetrafluoroborate carbonyl lower alkoxy-2-methylformimine or imidate compound can use solvents such as THF, dioxane, ether, dichloromethane, etc., in triethylamine, diisopropyl Carried out in the presence of organic bases such as ethylamine. The cyclization reaction can use solvents such as methanol, ethanol or no solvent, under neutral conditions, or under acidic conditions such as concentrated sulfuric acid, acetic acid, toluenesulfonic acid, trifluoroacetic acid, ammonium chloride, or in sodium hydroxide, Under basic conditions such as potassium hydroxide, it is carried out at room temperature to heating under reflux.

Furthermore, the compound (If) of the present invention can also be produced by reacting the haloacyl compound represented by the aforementioned general formula (II') with aminoguanidine, using the compound of the general formula (VIII) as an intermediate.

(式中，B环和A₃如前所述。)Preparation method 4

(In the formula, B ring and A ₃ are as previously described.)

Compound (Ib) of the present invention can be obtained by activating a carboxylic acid compound represented by general formula (XII), reacting it with cyanamide to obtain compound (XIV), and then reacting (XIV) with hydroxylamine.

Activation can be converted to halides, anhydrides or succinimidyl esters according to common methods. The reaction of the activated acid derivative (ⅩⅢ) and cyanamide can use organic solvents such as tetrahydrofuran, dioxane, chloroform, dichloromethane, benzene, toluene, organic bases such as triethylamine, diisopropylethylamine or Carried out in the presence of inorganic bases such as sodium hydride. The reaction with hydroxylamine can be carried out according to the conditions of Preparation Method 2.

(式中，B环和A₃如前所述，R₂₃和R₂₄表示低级烷基。)Preparation method 5

(In the formula, Ring B and _A3 are as described above, and _R23 and _R24 represent lower alkyl groups.)

Make the amide derivative represented by general formula (XV) react with N,N-dimethylformamide dimethyl acetal and cyanamide to obtain compound (XVI), then make (XVI) and hydroxylamine-O-sulfonic acid or hydrazine compound reaction, the compounds (Ik and Ii) of the present invention can be prepared.

The reaction with N,N-dimethylformamide dimethyl acetal can be carried out under room temperature to heating conditions with DMF as solvent. The reaction with hydroxylamine-O-sulfonic acid can be carried out in organic solvents such as methanol and ethanol, in the presence of organic bases such as pyridine, triethylamine and diisopropylethylamine, at room temperature to heating and reflux conditions. The reaction with the hydrazine compound can be carried out at room temperature to heating under reflux conditions with an organic acid such as acetic acid as a solvent.

(式中，B环和A₃如前所述，R₂₅表示低级烷基或芳烷基。)Preparation method 6

(In the formula, ring B and _A3 are as described above, and _R25 represents a lower alkyl or aralkyl group.)

The acetyl derivative represented by the general formula (XVII) is reacted with aminotriazole, then reacted with tert-butoxybis(dimethylamino)methane, and then the resulting (XIX) is cyclized to obtain the present invention Compound (Im).

The dehydration reaction of aminotriazole can be carried out under acidic conditions such as acetic acid, toluenesulfonic acid, trifluoroacetic acid, etc., using solvents such as benzene or toluene, at room temperature to heating under reflux conditions. The cyclization reaction can be carried out according to the conditions of Preparation Method 3.

(式中，B环、A₃和Y如前所述，R₂₆表示低级烷基或芳烷基，Z表示CH或N，n表示3～9。)Preparation method 7

(In the formula, ring B, A ₃ and Y are as described above, R ₂₆ represents a lower alkyl or aralkyl group, Z represents CH or N, and n represents 3-9.)

The compound (In) of the present invention can be obtained by reacting a ketone compound represented by the general formula (XX) with 2-aminopyridine or 2-aminopyrimidine and removing the phthaloyl group to form a cyclic amine.

The reaction with 2-aminopyridine or 2-aminopyrimidine can be carried out at room temperature to heating under reflux using solvents such as methanol and ethanol. The deprotection reaction of the phthaloyl group can be carried out according to a usual method. For example, a method using pyridazine, methylamine, or the like is employed. The reaction to form cyclic amines can be carried out by alkylation of amines in a conventional manner. For example, it can be carried out with a dihaloalkylene at room temperature to heating under reflux in the presence of an inorganic base such as potassium carbonate using solvents such as propanol, butanol, tetrahydrofuran, and dioxane. In order to promote the progress of the reaction, potassium iodide or the like may be added.

Preparation method 8 (In the formula, Ring B, A ₃ , Ar, R ₁ , and R ₂ are as described above.)

The compound (Io) of the present invention can be obtained by metallating a thiophene compound represented by the general formula (XXIII) and then reacting it with iodide.

This reaction can use solvents such as hexane, tetrahydrofuran, ether and toluene, in the presence of bis(triphenylphosphine) nickel chloride, diisobutylaluminum hydride, n-butyl lithium and zinc chloride, at -80 ° C to room temperature next.

The compound (I) of the present invention produced by the production method 1 to the production method 8 has various substituents, and the compound of the present invention can also be produced by modifying them. For example, according to common methods, compounds with amino substituents can be modified by amidation, carbamate, urea, etc.; or according to common methods, compounds with ester or carboxyl substituents can be amidated and then reduced to Modifications such as alcohol. The hydroxyl group of the group having a hydroxyl group can be esterified, carbonated, carbaminated, etc. according to a usual method. Furthermore, a hydroxyl group can be converted into an amino group by subjecting a hydroxyl group to a phthalimide to undergo a Mitsunobu reaction, followed by removal of the phthaloyl group according to the conditions of Preparation Method 7.

The compound of the present invention obtained above can be isolated and refined in the form of free form, salt, hydrate, solvate or polymorph, and the salt of compound (I) can be prepared according to conventional salt-forming reactions.

Conventional chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography methods can be used for separation and purification.

The various isomers can be separated by selecting appropriate starting compounds or by taking advantage of the differences in physical properties between the isomers. For example, by selecting an appropriate starting material or using a racemic resolution method of a racemic compound (for example, an optical resolution method in which diastereomeric salts are generally formed with an optically active base, etc.) can be obtained. pure isomers.

Possibility of industrial use

Because the compound (I) of the present invention has specific anti-PCR effect, it can improve the weakening of NMDA receptor function, so, based on this, it can be used as a psychotherapeutic drug, anti-schizophrenia drug, and an anti-PCR drug for the treatment of Alzheimer's disease. Drugs for dementia, drugs to improve abnormal behaviors such as delirium accompanying dementia, and/or drugs for the treatment of mental retardation and autism in children are useful.

The anti-PCR effect of the compound (I) of the present invention was confirmed by the following test method.

Anti-PCR effect test

experimental method

Wistar male rats (n=8) (body weight 200-300 g) were subcutaneously injected with PCR (3 mg/kg), and 30 minutes later, they were put into a hole board apparatus (HBA, hole board apparatus). Test compounds (10 mg/kg) were injected subcutaneously within 15 minutes after PCR injection. HBA is an opening device with 16 holes with a diameter of 4 cm at the bottom, a wall with a height of 20 cm around, and an opening of 40 cm in both length and width [Psychopharmacology, 52, 271 (1977)].

After 5 minutes, the amount of movement (the number of movements at the bottom divided into 9 parts (Locomotion)) and the exploratory behavior (the number of times the head penetrates the hole (Dipping)) of the rats in the HBA were measured. In addition, Wistar male rats (n=8) subcutaneously injected with PCR (3 mg/kg) were used as the control group.

This pharmacological test shows that the compounds of the present invention have statistically significant antagonism (compared with the control group by Mann-Whitney U-test) to the increase in the amount of exercise and the decrease in inquiry behavior caused by PCR (the following table).

Table 1 Example 34 increased exercise 10mg/kg·sc (P<0.01) Decreased exploratory behavior 10mg/kg·sc (P<0.05)

Using the carriers, excipients and other additives commonly used in preparations, preparations containing one or more than two compounds (I) of the present invention or their salts as active ingredients can be made into tablets, buccal tablets, powders, granules, Granules, capsules, pills, oral solutions (including syrups), injections, inhalants, suppositories, transdermal solutions, ointments, transdermal patches, transmucosal patches (such as intraoral patches agent), transmucosal solution (such as nasal solution) and the like can be taken orally or parenterally.

The solid composition for oral administration of the present invention can be tablet, powder, granule and the like. These solid compositions are mixed with one or more active substances and at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, silicon Magnesium aluminate. According to conventional methods, the composition may also contain additives other than inert diluents, such as lubricants such as magnesium stearate and disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, glutamic acid or aspartic acid, etc. Solubilizers and co-solvents. If necessary, tablets or pills can also be coated with gastric or enteric films such as sucrose, gelatin, hydroxypropyl cellulose, and hydroxypropyl methylcellulose phthalate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, etc., which contain commonly used inert diluents such as purified water, ethanol and the like. In addition to inert diluents, such compositions may also contain auxiliary agents such as solubilizers and solubilizers, wetting agents, suspending agents, and sweeteners, flavoring agents, fragrances and preservatives.

Injections for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions, and emulsions. Diluents for aqueous solutions and suspensions include distilled water for injection and physiological saline. Diluents for water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Tween 80 (trade name) and the like. These compositions may also contain additives such as isotonic agents, preservatives, lubricants, emulsifiers, dispersants, stabilizers (such as lactose), solubilizers and solubilizers. They can be sterilized by filtration through bacterial filter membranes, combined with the use of antibacterial agents or by irradiation. They can also be made into sterile solid compositions and used after being dissolved in sterile water or sterile injectable solvents before use.

The clinical dosage of the compound of the present invention can be appropriately selected according to the patient's symptoms, body weight, age, sex and administration route. Oral administration is usually 0.1-1000 mg/kg per day for adults, preferably 1-200 mg, and intravenous injection is generally 0.1-100 mg per day for adults, preferably 0.3-30 mg. It can be administered once or divided into 2-4 times. .

The best state to implement the invention

Prescription examples and examples are disclosed below, and the present invention will be described in more detail. However, the present invention is not limited to these examples.

Prescription Case (Tablet)

Composition 20mg Tablet

The compound of the present invention 20mg

Lactose 75

                                                                                                  

Hydroxylcel cellulose 4.5

Carbarmethyl cellulose calcium 8.8

Magnesium stearate 0.7

Total 120mg

20mg tablet

100 g of the compound of the present invention, 375 g of lactose, and 80 g of cornstarch were evenly mixed with a flow granulation coating device, and then 225 g of 10% hydroxypropyl cellulose solution was sprayed therein for granulation. After drying, pass through a 20-mesh sieve, then add 19g of carboxymethylcellulose calcium and 3.5g of magnesium stearate, mix, and use a rotary tablet press to squeeze out 120mg per tablet with a punch of 7mm×8.4R tablet.

Example 1

1-[5-(3-Benzyl-1,2,4-oxadiazol-5-yl)-2-thienylmethyl]hexahydro-1H-azepine hydrochloride

Dissolve 535mg (2.0mmol) of 5-[(hexahydro-1H-azepine-1-yl)methyl-2-thienyl]-carboxylic acid ethyl ester and 360mg (2.4mmol) of 2-phenylacetamide In 20ml of tetrahydrofuran, add 120mg (3.0mmol) of sodium hydride at room temperature, and heat to reflux for 2 hours. After filtering the insoluble matter, the filtrate was concentrated under reduced pressure. Water was then added to the residue, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography eluting with chloroform-methanol (80:1) to obtain 343 mg of the free form of the title compound. 960mg (2.72mmol) of the free compound was dissolved in 30ml of ethyl acetate, then 0.7ml (2.8mmol) of 4N HCl/AcOEt was added dropwise, the precipitated crystals were collected by filtration, and recrystallized with acetonitrile to obtain 690mg of the title compound.

Melting point: 189～192℃

¹ H-NMR (δppm, DMSO-d ₆ )

1.53-1.59(2H,m),1.65-1.67(2H,m),1.82-1.85(4H,m),3.02-3.08(2H,m),3.41(1H,br),4.15(2H,s), 4.64(2H,d,J=5.5Hz),7.27(1H,m),7.34(4H,br),7.63(1H,d,J=3.7Hz),7.97(1H,d,J=3.7Hz), 11.36(1H,br)

Example 2

1-[5-(3-Phenylethyl-1,2,4-oxadiazol-5-yl)-2-thienylmethyl]hexahydro-1H-azepine hydrochloride

Starting materials were 1.34 g (5.0 mmol) ethyl 5-[(hexahydro-1H-azepine-1-yl)methyl-2-thienyl]-carboxylate and 985 mg (6.0 mmol) 3-phenylpropionyl Ammonium oxime was carried out in the same manner as in Example 1 to obtain 650 mg of the title compound.

Melting point: 180～182℃

¹ H-NMR (δppm, DMSO-d ₆ )

1.56-1.60(2H,m),1.66-1.68(2H,m),1.84(4H,br),3.03-3.09(6H,m),4.66(2H,d,J=4.9Hz),7.21(1H, m),7.26-7.30(4H,m),7.64(1H,d,J=3.7Hz),7.98(1H,d,J=3.7Hz),11.24(1H,br)

Example 3

1-[5-[3-(3-Phenylpropyl)-1,2,4-oxadiazol-5-yl]-2-thienylmethyl]hexahydro-1H-azepine hydrochloride

Starting materials were 1.34 g (5.0 mmol) ethyl 5-[(hexahydro-1H-azepine-1-yl)methyl-2-thienyl]-carboxylate and 1.07 g (6.0 mmol) 4-phenylbutyl For amidoxime, the same operation as in Example 1 was performed to obtain 560 mg of the title compound.

Melting point: 174～176°C (acetonitrile)

¹ H-NMR (δppm, DMSO-d ₆ )

1.55-1.60(2H,m),1.64-1.67(2H,m),1.83(4H,br),1.98-2.04(2H,m),2.66-2.69(2H,m),2.74-2.77(2H,m ),3.05-3.09(2H,m),4.66(2H,d,J=5.5Hz),7.18-7.31(5H,m),7.62(1H,d,J=3.7Hz),7.98(1H,d, J=3.7Hz),11.07(1H,br)

Example 4

1) 5-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-3-tetrahydropyranyloxymethyl-1,2,4-oxa Oxadiazole

Starting materials were 8.0 g (29.9 mmol) ethyl 5-[(hexahydro-1H-azepine-1-yl)methyl-2-thienyl]-carboxylate and 6.3 g (35.9 mmol) 2-(tetrahydro Pyranyloxy) acetamidoxime, the same operation as in Example 1 was carried out to obtain 4.4 g of the title compound.

¹ H-NMR (δppm, DMSO～d ₆ )

1.55-1.90(10H,m),2.60-2.70(4H,m),3.30-3.73(3H,m),3.85～4.23(4H,m),4.70(1H,d,J=13.4Hz),4.80- 4.96(3H,m),6.95(1H,d,J=3.7Hz),7.75(1H,d,J=3.7Hz)

2) 5-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazole-3-methanol

1N HCl75ml (75mmol) was added dropwise to 80ml of ethanol solution of 6.23g (16.74mmol) of the compound obtained in 1), and stirred at room temperature for 4 hours. Then, the reaction solution was concentrated under reduced pressure, 80 ml of 1N NaOH was added to the resulting residue, extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (75:1) to obtain 3.76 g of the title compound.

Melting point: 79～81℃ (isopropyl ether)

¹ H-NMR (δppm, DMSO-d ₆ )

1.58-1.78(9H,m),2.68-2.70(4H,m),3.88(2H,m),3.88(2H,s),4.83(2H,s),6.96(1H,d,J=3.7Hz) ,7.75(1H,d,J=3.7Hz)

Example 5

1-[5-(3-Benzyloxymethyl-1,2,4-oxadiazol-5-yl)-2-thienylmethyl]hexahydro-1H-azepine hydrochloride

In an argon flow at 0°C, 20 ml of a tetrahydrofuran solution of 820 mg (2.8 mmol) of the compound of Example 4-2) was added dropwise to 10 ml of a tetrahydrofuran suspension of 118 mg (2.94 mmol) of sodium hydride, and stirred for 15 minutes. Add 0.35ml (2.94mmol) of benzyl bromide and 10mg of tetrabutylammonium iodide, and stir at room temperature for 16 hours. Water was then added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, eluting with chloroform-methanol (80:1), to obtain 580 mg of the free form of the title compound. Then 0.3 ml of 4N HCl/AcOEt was added, the precipitated crystals were collected by filtration, and recrystallized from acetonitrile-ethyl acetate to obtain 467 mg of the title compound.

Melting point: 166～168℃

¹ H-NMR (δppm, DMSO-d ₆ )

1.55-1.60(2H,m),1.65-1.67(2H,m),1.84(4H,br),3.04-3.12(2H,m),4.63(2H,s),4.67-4.69(2H,m), 4.71(2H,s),7.33(1H,m),7.37(5H,m),7.65(1H,d,J=3.7Hz),8.03(1H,d,J=3.7Hz),11.21(1H,br )

Example 6

[5-[5-(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazol-3-yl]methyl benzoate 1.0 g salt

Dissolve 450mg (1.53mmol) of the compound of Example 4-2) in 30ml of dichloromethane, then add 0.32ml (2.3mmol) of triethylamine and 0.21ml (1.84mmol) of benzoyl chloride, and stir overnight at room temperature. After the reaction solution was washed with water, the organic layer was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was subjected to silica gel column chromatography eluting with chloroform-methanol (75:1) to obtain 550 mg of the title compound in free form. Dissolve 180mg (0.453mmol) of the above-mentioned free compound in 5ml of methanol, then add 5ml of a methanol solution of 40mg (0.44mmol) oxalic acid, stir at room temperature for 10 minutes, evaporate the solvent under reduced pressure, and then add a small amount of methanol to the resulting residue , Ether, to crystallize it. The crystals were collected by filtration and dried to obtain 166 mg of the title compound.

Melting point: 120～121℃

¹ H-NMR (δppm, DMSO-d ₆ )

8.03-8.01(2H,m),7.97(1H,d,J=3.7Hz),7.72(1H,m),7.59-7.56(2H,m),7.34(1H,d,J=3.7Hz),5.56 (2H,s),4.28(2H,s),2.93(4H,brs),1.70(4H,brs),1.59(4H,brs)

Example 7

N-Benzylcarbamate[5-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazol-3-yl] Methyl Ester 1.0 Oxalate

The compound of 480mg (1.64mmol) embodiment 4)-2 was dissolved in 10ml N, in the N-dimethylformamide, then added dropwise 162mg (1.64mmol) cuprous chloride and 229mg (1.72mmol) benzyl isocyanate Ester in N,N-dimethylformamide solution 5ml, stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform, washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 690 mg of the free form of the title compound. Take 520 mg of the above free compound and 104 mg of oxalic acid, perform the same operation as in Example 6, and perform a salt-forming reaction to obtain 398 mg of the title compound.

Melting point: 129～130℃

¹ H-NMR (δppm, DMSO-d ₆ )

8.05(1H,t),7.94(1H,d),7.32-7.22(6H,m),5.23(2H,s),4.26-4.22(4H,m),2.92(4H,br),1.70(4H, brs),1.59(4H,brs)

Example 8

1-[5-(3-Aminomethyl-1,2,4-oxadiazol-5-yl)-2-thienylmethyl]hexahydro-1H-azepine 2 hydrochloride

Under ice cooling, add 1.1g (7.5mmol) phthalimide, 1.97g (7.5mmol) triphenylphosphine and 1.31 g (7.5 mmol) of diethyl azodicarboxylate was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in 50 ml of ethanol, and 3.3 ml (68.2 mmol) of hydrazine monohydrate was added dropwise, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was acidified by adding 1N HCl, and washed with chloroform. Then, a 4N aqueous sodium hydroxide solution was added to the aqueous layer to make it alkaline, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography eluting with chloroform-methanol (30:1) to obtain 1.86 g of the free form of the title compound. Then 1N HCl was added to 400 mg of the free compound to form a salt, and recrystallized from isopropanol to obtain 362 mg of the title compound.

Melting point: 230～232℃

¹ H-NMR (δppm, DMSO-d ₆ )

1.59-1.66(4H,m),1.85(4H,m),3.08(2H,br),4.31(2H,s),4.67(2H,s),7.68(1H,d,J=3.7Hz),8.05 (1H,d,J=3.7Hz),8.92(3H,br),11.79(1H,br)

Example 9

1-Benzyl-3-[[5-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazole-3 -yl]methyl]urea

770mg (2.63mmol) of the free compound of Example 8 was dissolved in 20ml of DMF, 5ml of a DMF solution of 369mg (2.77mmol) benzyl isocyanate was added, and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography eluting with chloroform-methanol (50:1) to obtain 1.0 g of the title compound.

Melting point: 101～103℃

¹ H-NMR (δppm, CDCl ₃ )

7.70(1H,d,J=3.7Hz),7.31-7.26(5H,m),6.95(1H.d.J=3.7Hz),5.10(2H,m),4.57(2H,d,J=5.7Hz), 4.42(2H,d,J=7.5Hz),3.88(2H,s),2.71(4H,m),1.64(8H,brs)

Example 10

N-[[5-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazol-3-yl]methyl ] Benzamide 1.0 Fumarate

585mg (2.0mmol) of the free compound of Example 8 was dissolved in 20ml of dichloromethane, then 0.6ml (4.0mmol) of triethylamine, 0.28ml (2.4mmol) of benzoyl chloride and 4-DMAP (catalyst) were added, Stir at room temperature for 19 hours. The reaction solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography, eluting with chloroform-methanol (80:1), to obtain 510 mg of the title compound in free form. To 490 mg (1.24 mmol) of the free compound was added 140 mg (1.2 mmol) of fumaric acid to form a salt, thereby obtaining 348 mg of the title compound.

Melting point: 79～81℃

¹ H-NMR (δppm, DMSO-d ₆ )

9.22(1H,t),7.91-7.85(3H,m),7.58-7.48(3H,m),7.16(1H,d),6.92(2H,s),4.62(2H,d),3.91(2H, s),2.67-2.64(4H,m),1.57(8H,brs)

Example 11

a) N-benzyl-5-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazol-3-yl Methylamine 2 hydrochloride

b) N,N-dibenzyl-5-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazole- 3-Methylamine 2 hydrochloride

Add dropwise 0.53ml (5.2mmol) benzaldehyde in 1.52g (5.2mmol) 1,2-dichloroethane solution 55ml of the free compound of Example 8, after stirring at room temperature for 2.5 hours, add dropwise 31.44g ( 6.76mmol) NaBH(OAc) and 0.6ml acetic acid, stirred at room temperature for another 2 days. Then, concentrated ammonia water was added to the reaction solution, and the organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was eluted with chloroform-methanol (100:1 to 80:1) by silica gel column chromatography to obtain 359 mg of free form b) and 980 mg of free form a). Then it was salted with 4N HCl/AcOEt to obtain the title compound b) 330mg, a) 1036mg.

a) ¹ H-NMR (δppm, DMSO-d ₆ )

11.84(1H,br),10.42(2H,br),8.06(1H,d),7.70(1H,d),7.61-7.59(2H,m),7.45-7.25(3H,m),4.68(2H, brs),4.42(2H,brs),4.30(2H,brs),3.33(2H,br),3.08(2H,br),1.99-1.89(4H,m),1.67(4H,br),1.58(4H ,br)

MS(FAB,Pos,m/z)383(M ⁺⁺ 1)

b) ¹ H-NMR (δppm, DMSO-d ₆ )

11.64(1H,br),8.04(1H,d),7.70(1H,d),7.55(4H,br),7.43-7.39(6H,m),4.68(2H,d),4.11(4H,br) ,3.33(2H,m),3.11-3.05(2H,m),1.91-1.85(4H,m),1.69-1.65(4H,m),1.61-1.55(4H,m)

MS(FAB,Pos,m/z)473(M ⁺⁺ 1)

Example 12

1) 3-tert-butyldimethylsilyloxyethyl-5-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2 ,4-oxadiazole

Using 12.0g (44.9mmol) of 5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]carboxylic acid ethyl ester and 12.7g (58.3mmol) of 3-tert-butyldi Methylsilyloxypropionamide oxime was carried out in the same manner as in Example to obtain 9.62 g of the title compound.

¹ H-NMR (δppm, CDCl ₃ )

0.04(6H,s),0.86(9H,s),1.63-1.70(8H,m),2.69(4H,m),2.99(2H,t,J=6.8Hz),3.87(2H,s),4.04 (2H,t,J=6.8Hz),6.94(1H,d,J=3.9Hz),7.71(1H,d,J=3.9Hz)

2) 5-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazole-3-ethanol hydrochloride

Under ice cooling, 28.4 ml (28.4 mmol) of tetrabutylammonium fluoride (1.0 M, THF solution) was added dropwise to 250 ml of a tetrahydrofuran solution of 9.97 g (25.2 mmol) of the compound obtained in 1), and stirred at the same temperature for 1 hour. The reaction solution was concentrated, and the resulting residue was acidified by adding 1N HCl, and washed with chloroform. Then add 4N NaOH to the water layer to make the reaction solution alkaline, then extract it with ethyl acetate, wash the organic layer with saturated brine, dry it with anhydrous magnesium sulfate, and evaporate the solvent to obtain the free form title compound 7.27 g (quantitative), then 950 mg (3.09 mmol) of it was salified with 4N HCl/AcOEt, and recrystallized with acetonitrile to obtain 639 mg of the title compound.

Melting point: 229～231℃

¹ H-NMR (δppm, DMSO-d ₆ )

1.50-1.78(4H,m),1.83(4H,br),2.87-2.90(2H,m),3.05-3.09(2H,m),3.78-3.80(2H,m),4.66-4.68(2H,m ),7.62(1H,d,J=3.7Hz),7.98(1H,d,J=3.7Hz),11.06(1H,br)

Example 13

1-[5-[3-(2-Benzyloxyethyl)-1,2,4-oxadiazol-5-yl]-2-thienylmethyl]hexahydro-1H-azepine hydrochloride

Using 1.34g (5.0mmol) ethyl 5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]carboxylate and 1.8g (9.28mmol) 3-benzyloxypropane For amidoxime, the same operation as in Example 1 was performed to obtain 850 mg of the free form of the title compound.

Melting point: 145～147℃

¹ H-NMR (δppm, DMSO-d ₆ )

1.50-1.75(4H,m),1.84(4H,m),3.04-3.10(4H,m),3.82-3.85(2H,m),4.51(2H,s),4.66-4.68(2H,m), 7.20-7.38(5H,m),7.64(1H,d,J=3.7Hz),7.98(1H,d,J=3.7Hz),11.28(1H,br)

Example 14

1-[5-[3-(2-Ethoxyethyl)-1,2,4-oxadiazol-5-yl]-2-thienylmethyl]hexahydro-1H-azepine hydrochloride

Using 1.07g (4.0mmol) ethyl 5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]carboxylate and 0.8g (6.0mmol) 3-ethoxypropane For amidoxime, the same operation as in Example 1 was performed to obtain 507 mg of the title compound.

Melting point: 149～151℃

¹ H-NMR (δppm, DMSO-d ₆ )

11.1(1H,br),7.99(1H,d),7.63(1H,d),4.67(2H,s),3.77(2H,t),3.47-3.43(2H,m),3.38-3.35(4H, m), 2.99(2H,t), 1.84(4H,m), 1.67-1.64(2H,m), 1.60-1.55(2H,m), 1.08(3H,t)

Example 15

1-[5-(3-Venyl-1,2,4-oxadiazol-5-yl)-2-thienylmethyl]hexahydro-1H-azepine hydrochloride

Add 418mg (3.0mmol) 4-nitrophenol, 786mg (3.0mmol) triphenylphosphine and 0.48ml (3.0mmol) azo Diethyl dicarboxylate was stirred overnight at room temperature. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography to obtain 260 mg of the free form of the title compound. This was then salified with 4N HCl/AcOEt to afford 191 mg of the title compound.

Melting point: 173～174℃

¹ H-NMR (δppm, DMSO-d ₆ )

11.07(1H,br),8.03(1H,d,J=3.7Hz),7.64(1H,d,J=3.7Hz),6.85(1H,m),6.40(1H,m),5.94(1H,m ),4.68(2H,s),3.39-3.34(4H,br),1.84(4H,br),1.67-1.64(2H,m),1.61-1.57(2H,m)

Example 16

2-[5-[5-(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazol-3-yl]ethyl benzoate 1.0 Oxalate

In the same manner as in Example 6, 580 mg of the free form of the title compound was obtained from 450 mg (1.46 mmol) of the free form of the compound in Example 12-2). Of these, 541 mg (1.31 mmol) were salified with 112.5 mg (1.25 mmol) of oxalic acid to obtain 384 mg of the title compound.

Melting point: 121-123°C

¹ H-NMR (δppm, DMSO-d ₆ )

7.96-7.90(3H,m),7.60(1H,m),7.52(2H,t,J=7.9Hz),7.32(1H,br),4.65(2H,t,J=6.1Hz),4.25(2H ,br),3.26(2H,t,J=6.1Hz),2.92(4H,brs),1.69(4H,brs),1.59(4H,brs)

Example 17

4-Methoxybenzoic acid 2-[5-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazole-3 -yl]ethyl oxalate

In the same manner as in Example 6, 444 mg of the title compound was obtained from 307 mg (1.0 mmol) of the free compound of Example 12-2) and 205 mg (1.2 mmol) of 4-methoxybenzoyl chloride.

Melting point: 131～132℃

¹ H-NMR (δppm, DMSO-d ₆ )

7.91(1H,d),7.88-7.86(2H,m),7.31(1H,d),7.04-7.02(2H,m),4.60(2H,t),4.25(2H,br),3.82(3H, s), 3.24(2H,t), 2.92(4H,br), 1.69(4H,br), 1.59(4H,br)

Example 18

4-fluorobenzoic acid 2-[5-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazol-3-yl ] Ethyl oxalate

In the same manner as in Example 6, 438 mg of the title compound was obtained from 307 mg (1.0 mmol) of the free compound of Example 12-2) and 0.14 ml (1.2 mmol) of 4-fluorobenzoyl chloride.

Melting point: 96～97℃

¹ H-NMR (δppm, DMSO-d ₆ )

8.01-7.98(2H,m),7.91(1H,d),7.38-7.33(3H,m),4.64(2H,t),4.28(2H,br),3.26(2H,t),2.94(4H, br),1.70(4H,br),1.59(4H,br)

Example 19

4-Nitrobenzoic acid 2-[5-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazole-3- base] ethyl oxalate

In the same manner as in Example 6, 439 mg of the title compound were obtained from 307 mg (1.0 mmol) of the free compound of Example 12-2) and 4-nitrobenzoyl chloride.

Melting point: 67～69℃

¹ H-NMR (δppm, CDCl ₃ )

8.40-8.10(4H,m),7.72(1H,d,J=3.7Hz),6.96(1H,d,J=3.7Hz),4.79(2H,t,J=6.4Hz),3.80(2H,s ),3.27(2H,t,J=6.4Hz),2.70(4H,br),1.64(8H,br)

Example 20

Cyclohexanecarboxylic acid 2-[5-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazol-3-yl ] ethyl ester

In the same manner as in Example 6, 409 mg of the title compound was obtained from 307 mg (1.0 mmol) of the free compound of Example 12-2) and 0.16 ml (1.2 mmol) of cyclohexanecarbonyl chloride.

Melting point: 41～42℃

¹ H-NMR (δppm, CDCl ₃ )

7.72(1H,d),6.95(1H,d),4.48(2H,t),3.88(2H,s),3.10(2H,t),2.69(2H,t),2.70-2.68(4H,m) ,2.29(1H,m),1.90-1.86(2H,m),1.75-1.61(10H,m),1.47-1.37(2H,m),1.31-1.16(4H,m)

Example 21

2-[5-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazol-3-yl]ethyl acetate 1.0 Oxalate

In the same manner as in Example 6, 330 mg of the title compound was obtained from 615 mg (2.0 mmol) of the free compound of Example 12-2) and 0.38 ml (4.0 mmol) of acetic anhydride.

Melting point: 105～106℃

¹ H-NMR (δppm, DMSO-d ₆ )

7.85(1H,d,J=3.7Hz),7.16(1H,d,J=3.7Hz),6.62(2H,s),4.38(2H,t,J=6.1Hz),3.93(2H,s), 3.09(2H,t,J=6.1Hz),3.69-3.67(4H,m),1.99(3H,s),1.61-1.59(8H,m)

Example 22

1-[5-(3-Methyl-1,2,4-oxadiazol-5-yl]-2-thienylmethyl]hexahydro-1H-azepine

Operated in the same manner as in Example 1, by 570mg (7.70mmol) acetamidoxime and 1.03g (3.85mmol) 5-[(hexahydro-1H-azepine-1-yl) methyl]-2-thienyl] carboxyl ethyl ester to obtain 280 mg of the title compound.

Melting point: 45～46℃

¹ H-NMR (δppm, CDCl ₃ )

7.71(1H,d),6.95(1H,d),3.88(2H,s),2.70-2.64(4H,m),2.43(3H,s),1.64(8H,brs)

Example 23

N-Benzylcarbamate 2-[5-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazole-3- base] ethyl ester

In the same manner as in Example 7, 570 mg of the free form of the title compound was obtained from 610 mg (1.98 mmol) of the free form compound of Example 12-2) and 278 mg (2.08 mmol) of benzyl isocyanate. 560 mg of this was then salified with 141 mg of fumaric acid to obtain 366 mg of the title compound.

Melting point: 138～139℃

¹ H-NMR (δppm, DMSO-d ₆ )

7.84(1H,d,J=3.7Hz),7.72(1H,t),7.30-7.16(5H,m),6.62(2H,s),4.36(2H,t,J=6.1Hz),4.15(2H ,d,J=6.1Hz),3.93(2H,s),3.07(2H,t,J=6.1Hz),2.68-2.66(4H,m),1.61-1.58(8H,m)

Example 24

N-Ethylcarbamate 2-[5-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazole-3- Base] Ethyl Ester 1.0 Oxalate

In the same manner as in Example 7, 198 mg of the title compound was obtained from 330 mg (1.07 mmol) of the free compound of Example 12-2) and 82 mg (1.15 mmol) of ethyl isocyanate.

Melting point: 112～113℃

¹ H-NMR (δppm, DMSO-d ₆ )

7.92(1H,d),7.33(1H,d),7.12(1H,br),4.31(2H,t),4.27(2H,br),3.05(2H,t),3.00-2.93(6H,m) ,1.70(4H,br),1.59(4H,br),0.98(3H,t)

Example 25

N-(2-chloroethyl)carbamate 2-[5-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxa Oxadiazol-3-yl] ethyl ester 1.0 oxalate

In the same manner as in Example 7, 437 mg of the title compound was obtained from 462 mg (1.5 mmol) of the free compound of Example 12-2) and 0.15 ml (1.65 mmol) of 2-chloroethyl isocyanate.

Melting point: 71～72℃

¹ H-NMR (δppm, DMSO-d ₆ )

7.92(1H,d),7.45(1H,t),7.34(1H,d),4.35(2H,t),4.29(2H,br),3.56(2H,t),3.29-3.24(2H,m) ,3.07(2H,t),2.94(4H,br),1.71(4H,br),1.59(4H,br)

Example 26

N-butylcarbamate 2-[5-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazole-3- Base] Ethyl Ester 1.0 Oxalate

In the same manner as in Example 7, 573 mg of the title compound was obtained from 462 mg (1.5 mmol) of the free compound of Example 12-2) and 0.19 ml (1.65 mmol) of n-butyl isocyanate.

Melting point: 109～110℃

¹ H-NMR (δppm, DMSO-d ₆ )

7.93(1H,d),7.37(1H,d),7.13(1H,t),4.34-4.30(4H,m),3.06(2H,t),2.99(4H,m),2.94-2.91(2H, m),1.72(4H,br),1.59(4H,br),1.36-1.30(2H,m),1.26-1.20(2H,m),0.86(3H,t)

Example 27

N-tert-butylcarbamate 2-[5-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazole-3 -yl] ethyl ester 1.0 oxalate

In the same manner as in Example 7, 378 mg of the title compound was obtained from 462 mg (1.5 mmol) of the free compound of Example 12-2) and 0.19 ml (1.65 mmol) of tert-butyl isocyanate.

Melting point: 140～141℃

¹ H-NMR (δppm, DMSO-d ₆ )

7.92(1H,d),7.34(1H,d),6.90(1H,br),4.29-4.27(4H,m),3.04(2H,t),2.95(4H,br),1.71(4H,br) ,1.59(4H,br),1.18(9H,s)

Example 28

N-cyclohexylcarbamate 2-[5-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazole-3- Base] Ethyl Ester 1.0 Oxalate

In the same manner as in Example 7, 363 mg of the title compound was obtained from 462 mg (1.5 mmol) of the free compound of Example 12-2) and 0.25 ml (1.95 mmol) of cyclohexyl isocyanate.

Melting point: 78～79℃

¹ H-NMR (δppm, DMSO-d ₆ )

7.92(1H,d),7.35(1H,d),7.08(1H,d),4.31(2H,t),3.38(1H,m),3.21(1H,br),3.05(2H,t),2.96 (4H,br),1.71(6H,br),1.59(6H,br),1.22-1.06(6H,m)

Example 29

N-Phenylcarbamate 2-[5-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazole-3- base] ethyl ester

In the same manner as in Example 7, 515 mg of the title compound was obtained from 462 mg (1.5 mmol) of the free compound of Example 12-2) and 232 mg (1.95 mmol) of phenylisocyanate.

Melting point: 68～70℃

¹ H-NMR (δppm, DMSO-d ₆ )

7.73(1H,d),7.37-7.27(3H,m),7.05(1H,m),6.96(1H,d),6.66(1H,br),4.60(2H,t),3.88(2H,br) ,3.16(2H,t),2.70-2.68(4H,m),1.65(8H,m)

Example 30

N-(4-nitrophenyl)carbamate 2-[5-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4- Oxadiazol-3-yl] ethyl ester

In the same manner as in Example 7, 604 mg of the title compound was obtained from 462 mg (1.5 mmol) of the free compound of Example 12-2) and 320 mg (1.95 mmol) of 4-nitrophenyl isocyanate.

Melting point: 73～74℃

¹ H-NMR (δppm, DMSO-d ₆ )

8.29-8.26(2H,m),8.22-8.19(2H,m),7.54(1H,m),6.96(1H,d),4.79(2H,t),3.88(2H,br),3.28(2H, t),2.70-2.68(4H,m),1.66-1.63(8H,m)

Example 31

N-(4-methoxyphenyl)carbamate 2-[5-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4 -Oxadiazol-3-yl]ethyl ester

In the same manner as in Example 7, 652 mg of the title compound was obtained from 462 mg (1.5 mmol) of the free compound of Example 12-2) and 291 mg (1.95 mmol) of 4-methoxyphenyl isocyanate.

Melting point: 83～84℃

¹ H-NMR (δppm, DMSO-d ₆ )

9.45(1H,br),7.93(1H,d),7.36-7.33(3H,m),6.86-6.82(2H,m),4.45(2H,t),4.27(2H,br),3.69(3H, s), 3.15(2H,t), 2.93(4H,br), 1.70(4H,br), 1.59(4H,br)

Example 32

N-(4-fluorophenyl)carbamate 2-[5-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxa Oxadiazol-3-yl] ethyl ester 1.0 oxalate

In the same manner as in Example 7, 465 mg of the title compound was obtained from 462 mg (1.5 mmol) of the free compound of Example 12-2) and 267 mg (1.95 mmol) of 4-fluorophenyl isocyanate.

Melting point: 93～94℃

¹ H-NMR (δppm, DMSO-d ₆ )

9.70(1H,br),7.93(1H,d),7.46-7.42(2H,m),7.34(1H,d),7.10(2H,t),4.47(2H,t),4.30(2H,br) ,3.16(2H,t),2.96-2.94(4H,m),1.70(4H,br),1.59(4H,br)

Example 33

N-(2-nitrophenyl)carbamate 2-[5-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4- Oxadiazol-3-yl] ethyl ester 1.0 oxalate

In the same manner as in Example 7, 440 mg of the title compound was obtained from 462 mg (1.5 mmol) of the free compound of Example 12-2) and 271 mg (1.65 mmol) of 2-nitrophenyl isocyanate.

Melting point: 88～89℃

¹ H-NMR (δppm, DMSO-d ₆ )

9.87(1H,br),7.96-7.93(2H,m),7.69-7.61(2H,m),7.35-7.30(2H,m),4.47(2H,t),4.31(2H,br),2.96( 2H,br),1.71(4H,br),1.59(1H,br)

Example 34

N-[2-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazol-3-yl]ethyl] Phthalimide hydrochloride

At room temperature, add 3.59g (24.4mmol) phthalimide, 3.84ml (24.4mmol) azo Diethyl dicarboxylate and 6.39 g (24.4 mmol) of triphenylphosphine were stirred at room temperature for 10 hours. Then, the reaction solution was concentrated under reduced pressure, and the obtained residue was eluted with ethyl acetate-n-hexane (1:1) by silica gel column chromatography to obtain 8.9 g of a mixture containing the free form of the title compound. After pulverizing the solid, 1N HCl was added to make it acidic, ethyl acetate was added and stirred for 1 hour, and the precipitated crystal was collected by filtration to obtain 5.344 g of a crude product. Finally, 1.10 g of them were recrystallized from acetonitrile to obtain 724 mg of the title compound.

Melting point: 181～182℃

¹ H-NMR (δppm, DMSO-d ₆ )

11.13(1H,br),7.94(1H,d),7.90-7.83(4H,m),7.63(1H,d),6.66(2H,d),3.97(2H,t),3.36(4H,m) ,3.13(2H,t),1.84(4H,m),1.67-1.55(4H,m)

Example 35

1) Nα-cyano-2-(hexahydro-1H-azepine-1-yl)methylthiophene-5-carbonylamidine

Add 3.68g (68.08mmol) sodium methylate in 210ml of methanol solution of 7.5g (34.04mmol) 2-cyano group-[5-[(hexahydro-1H-azepine-1-yl) methyl] thiophene, in Under argon atmosphere, stir at room temperature for 24 hours. Then, 3.9ml (68.08mmol) of acetic acid and 2.15g (51.06mmol) of cyanamide were added to the reaction liquid, and stirred at room temperature for another 24 hours. The reaction liquid was concentrated, and chloroform-methanol (20:1) was added to the obtained residue, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography, eluting with chloroform-methanol (50:1 to 10:1), to obtain 2.62 g of the title compound.

¹ H-NMR (δppm, DMSO-d ₆ )

9.02(1H,br),8.49(1H,br),7.84(1H,d),7.01(1H,d),3.80(2H,s),2.59(4H,br),1.56(8H,brs)

2) 1-[5-(3-Amino-1,2,4-oxadiazol-5-yl)-2-thienylmethyl]hexahydro-1H-azepine

2.62g (9.99mmol) of the compound obtained in 1) was dissolved in 55ml of tetrahydrofuran and 11ml of methanol, then 1.41g (19.98mmol) of hydroxylamine hydrochloride and 4.23ml (29.97mmol) of triethylamine were added, and heated to reflux for 21 hours. The reaction solution was concentrated under reduced pressure, and chloroform-methanol (10:1) was added to the resulting residue, washed with water, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting residue was subjected to silica gel column chromatography eluting with chloroform-methanol (75:1) to obtain 2.58 g of the title compound.

Melting point: 135～136℃

¹ H-NMR (δppm, DMSO-d ₆ )

7.68(1H,d),7.09(1H,d),6.35(2H,s),3.87(2H,s),2.65-2.63(4H,brs),1.58(8H,brs)

Example 36

1-[5-(4-Amino-4H-1,2,4-triazol-3-yl)-2-thienylmethyl]hexahydro-1H-azepine

Dissolve 2.0g (9.08mmol) of 2-cyano-[5-[(hexahydro-1H-azepine-1-yl)methyl]thiophene in 13.5ml of N,N-dimethylformamide, then add 13.5ml of hydrazine-hydrate was heated to reflux for 5 hours. After cooling to room temperature, the reaction solution was poured into ice water, and the precipitated crystals were collected by filtration, washed with water, and dried overnight at 70°C under reduced pressure to obtain 1.97 g of the title compound. Finally, 560 mg of it was recrystallized from ethyl acetate to obtain 335 mg of the target product.

Melting point: 104～105℃

¹ H-NMR (δppm, DMSO-d ₆ )

8.44(1H,s),7.72(1H,d),7.00(1H,d),6.34(2H,s),3.83(2H,s),2.64-2.62(4H,m),1.57(8H,brs)

Example 37

1) 4-Benzylimino-3-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-triazole

0.31 ml (3.0 mmol) of benzaldehyde was added to 10 ml of methanol solution of 831 mg (3.0 mmol) of the compound of Example 36, and stirred at room temperature for 4 hours. Then, under ice-cooling, 827 mg (3.9 mmol) NaBH(OAc)3 and 0.35 ml acetic acid were added to the reaction liquid, and stirred at room temperature for another 9 days. The reaction solution was washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting residue was subjected to silica gel column chromatography eluting with chloroform-methanol (25:1) to obtain 600 mg of the title compound.

¹ H-NMR (δppm, CDCl ₃ )

8.63(2H,d),7.95(2H,d),7.84(1H,d),7.61-7.53(3H,m),6.95(1H,d),3.89(2H,s),2.71-2.69(4H, m),1.68-1.62(8H,m)

2) 1-[5-(4-Benzylamino-4H-1,2,4-triazol-3-yl)-2-thienylmethyl]hexahydro-1H-azepine

Under ice-cooling, 58 mg (1.5 mmol) of sodium borohydride was added to 20 ml of an ethanol solution of 354 mg (0.969 mmol) of the compound obtained in 1), and the mixture was stirred at room temperature for 24 hours. After concentrating the reaction solution, chloroform and aqueous ammonia were added to the residue, and the organic layer was separated and dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting residue was subjected to silica gel column chromatography and eluted with chloroform-methanol-ammonia (100:10:1) to obtain 353 mg of the title compound.

Melting point: 79～81℃

¹ H-NMR (δppm, DMSO-d ₆ )

8.61(1H,s),7.67(1H,d),7.37-7.27(5H,m),7.19(1H,t),6.99(1H,d),4.22(2H,d),3.84(2H,s) ,2.65-2.62(4H,m),1.59(8H,brs)

Example 38

1) 2-(hexahydro-1H-azepine-1-yl)methylthiophene-5-carboxylic acid amidinohydrazide

Add 6.07g (21.7mmol) sulfuric acid S-methylisothiourea and 43.5ml (43.5mmol) of 1N NaOH, methanol (about 130ml) was added to the reaction mixture until it became a homogeneous solution, then stirred at room temperature for 10 days, after filtering off the insoluble matter, the solvent was concentrated, and the resulting residue was directly washed with silica gel Column chromatography eluting with chloroform-methanol-ammonia (40:10:1) afforded 7.32 g of the title compound.

¹ H-NMR (δppm, DMSO-d ₆ )

10.37(1H,br),7.13(1H,d),6.76(1H,d),6.73(4H,br),3.71(2H,s),2.59-2.57(4H,m),1.56(8H,brs)

2) 1-[5-(5-Amino-1H-1,2,4-triazol-3-yl)-2-thienylmethyl]hexahydro-1H-azepine

80 ml of ethanol solution of 7.32 g (24.8 mmol) of the compound obtained in 1) was heated to reflux for 8 days. The reaction solution was concentrated, and the resulting residue was subjected to silica gel column chromatography and eluted with chloroform-methanol-ammonia water (100:10:1 to 40:10:1) to obtain 5.98 g of the title compound. 1.5 g of them were recrystallized with 25 ml of acetonitrile to obtain 1.26 g of the target product.

Melting point: 160～161℃

¹ H-NMR (δppm, DMSO-d ₆ )

11.95(1H,brs),7.20(1H,brs),6.86(1H,brs),6.04(2H,brs),3.76(2H,s),2.61-2.59(4H,m),1.56(8H,brs)

Example 39

5-amino-N-benzyl-3-[5-[(hexahydro-1H-azepine-1-yl)methyl-2-thienyl]-1H-1,2,4-triazole-1 -Formamide

Add 331 mg (2.49 mmol) of benzyl isocyanate in 75 ml of N,N-dimethylformamide solution of 690 mg (2.49 mmol) of the compound of Example 38, and stir at room temperature 2 hours. The reaction solution was concentrated, and the resulting residue was dissolved in chloroform, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography eluting with chloroform-methanol (75:1) to obtain 1.07 g of the title compound. An appropriate amount of diethyl ether was added therein for crystallization, and then recrystallized from ethyl acetate-n-hexane to obtain 564 mg of the target compound.

Melting point: 130～131℃

¹ H-NMR (δppm, DMSO-d ₆ )

7.45(1H,d,J=3.7Hz),7.40-7.31(5H,m),7.24(1H,t),6.84(1H,d,J=3.7Hz),6.27(2H,brs),4.57(2H ,d,J=6.1Hz),3.83(2H,s),2.68-2.66(4H,m),1.65-1.60(8H,m)

Example 40

1) Ethyl-N ¹ -[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienonyl]-N ² -Oxamidrase-to

カルボェトキシ-S-メチルチオホルムイミウテテトラフルオロボレ-ト (30.86 mmol) and 6.33 g (25.0 mmol) of 2-(hexahydro-1H-azepine-1-yl)methylthiophene-5-carboxylic acid hydrazide Add 7.4ml (52.5mmol) triethylamine to 150ml of anhydrous dichloromethane solution, and heat to reflux for 36 hours. After the reaction solution was washed with water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain 5.70 g of the title compound.

¹ H-NMR (δppm, CDCl ₃ )

11.45(1H,br),8.10(1H,d),6.94(1H,d),6.12(2H,br),4.38(2H,m),3.87(2H,s),2.66(4H,m),1.62 (8H,br),1.45(3H,t)

2) 3-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole-5-carboxylic acid ethyl ester

352 mg (1.0 mmol) of the compound obtained in 1) was dissolved in 5 ml of acetic acid, and heated to reflux for 3 hours. The reaction solution was concentrated under reduced pressure, ammonia water and chloroform were added to the resulting residue, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Finally, the residue was purified by silica gel column chromatography to obtain 248 mg of the title compound.

¹ H-NMR (δppm, CDCl ₃ )

7.51(1H,d),6.85(1H,d),4.45-4.29(2H,m),3.96(2H,brs),2.81(4H,br),1.61(8H,br),1.33(3H,t)

MS(FAB,Pos,m/z)335(M ⁺⁺ 1)

Example 41

5-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole-3-methanol

Under ice cooling, 502 mg (1.5 mmol) of the compound of Example 40 in 20 ml of anhydrous tetrahydrofuran was added dropwise to 5 ml of a suspension of 85.4 mg (2.25 mmol) of lithium aluminum hydride in anhydrous tetrahydrofuran, and stirred at the same temperature for 4 hours. Sodium sulfate·decahydrate was then added to the reaction mixture, and the insoluble matter was filtered off. The solvent was distilled off, and the resulting residue was eluted with silica gel column chromatography with chloroform-methanol (10:1) to obtain 312 mg of the title compound.

Melting point: 159～161℃

¹ H-NMR (δppm, DMSO-d ₆ )

13.89(1H,br),7.37(1H,d),6.93(1H,d),5.62(1H,br),4.57(2H,d),3.81(2H,s),2.63-2.60(4H,m) ,1.57(8H,brs)

Example 42

1-[5-(5-Methyl-1H-1,2,4-triazol-3-yl)-2-thienylmethyl]hexahydro-1H-azepine 2 hydrochloride

Add 2.8ml (20mmol) triethylamine and 2.48g (20 mmol) ethyl acetylimidate hydrochloride, stirred at room temperature for 21 hours. 1.2 g of ammonium chloride was added to this solution, followed by stirring at 80° C. for 4 hours. The reaction solution was concentrated, 28% ammonia water and chloroform were added to the obtained residue, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography eluting with chloroform-methanol (80:1) to obtain 814 mg of the title compound in free form. Final salification with 4N HCl/ethyl acetate afforded 593 mg of the title compound.

Melting point: 161～163℃

¹ H-NMR (δppm, DMSO-d ₆ )

11.06(1H,br),7.59(1H,d),7.45(1H,d),4.56-4.55(2H,d),3.38-3.33(2H,m),3.10-3.02(2H,m),2.39( 3H,s),1.85-1.83(4H,m),1.68-1.63(2H,m),1.60-1.54(2H,m)

Example 43

1-[5-(5-Amino-1,3,4-oxadiazol-2-yl)-2-thienylmethyl]hexahydro-1H-azepine

Add 2.5g (23.57mmol) cyanobromide in 250ml of ethanol solution of 5.43g (21.43mmol) 2-(hexahydro-1H-azepine-1-yl) methylthiophene-5-carboxylic acid hydrazide, room temperature After stirring at low temperature for 2 hours, it was stirred at 50°C for 7 hours. Concentrate the reaction solution under reduced pressure, add saturated aqueous sodium bicarbonate solution and chloroform to the obtained residue, separate the organic layer, wash with saturated brine, then dry with anhydrous magnesium sulfate, evaporate the solvent, and reconstitute the obtained residue with ethyl acetate. Crystallization gave 2.43 g of the title compound.

Melting point: 232-234°C

¹ H-NMR (δppm, DMSO-d ₆ )

7.33(1H,d),7.23(2H,s),7.00(1H,d),3.83(2H,s),2.63-2.61(4H,m),1.57(8H,brs)

Example 44

1-Benzyl-3-[5-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,3,4-oxadiazole-2- base] urea

0.14 ml (1.1 mmol) of benzyl isocyanate was added to 20 ml of a pyridine solution of 278 mg (1.0 mmol) of the compound of Example 43, and stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (50:1) to obtain 406 mg of the title compound.

Melting point: 184～185℃

¹ H-NMR (δppm, DMSO-d ₆ )

10.96(1H,br),7.97(1H,t),7.48(1H,d,J=3.7Hz),7.37-7.24(5H,m),7.07(1H,d,J=3.7Hz),4.41(2H ,d,J=5.7Hz),3.86(2H,s),2.64(4H,brs),1.58(8H,brs)

Example 45

1) 4-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1-benzylthiosemicarbazide

Add 928mg (6.22mol) benzyl isothiocyanate dropwise in 15ml of ethanol solution of 1.5g (5.92mmol) 2-(hexahydro-1H-azepine-1-yl) methylthiophene-5-carboxylic acid hydrazide Ethanol solution of ester in 5ml was stirred at room temperature for 2 hours, and then heated to reflux for 1 hour. The reaction solution was cooled with ice water, and the precipitated crystals were collected by filtration, washed well with cold ethanol, and dried under reduced pressure to obtain 2.19 g of the title compound.

¹ H-NMR (δppm, DMSO-d ₆ )

8.06(1H,t),7.94(1H,d),7.32-7.22(6H,m),5.23(2H,s),4.26-4.22(4H,m),2.92(4H,brs),1.70(4H, brs),1.59(4H,brs)

2) 1-[5-(5-amino-1,3,4-thiadiazol-2-yl)-2-thienylmethyl]hexahydro-1H-azepine

Under ice cooling, 6 ml of concentrated sulfuric acid was added to 806 mg (2.0 mmol) of the compound obtained in 1), and the mixture was stirred at this temperature for 1 hour and then at room temperature for 3 hours. Then the reaction solution was poured into ice, and 5N aqueous sodium hydroxide solution was added to make it alkaline, and extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was recrystallized from ethyl acetate-n-hexane to obtain 482 mg of the title compound.

Melting point: 156～157℃

¹ H-NMR (δppm, CDCl ₃ )

7.17(1H,d,J=3.9Hz),6.83(1H,d,J=3.9Hz),5.44(2H,brs),3.83(2H,s),2.69-2.66(4H,m),1.65-1.62 (8H,m)

Example 46

1-Benzyl-3-[5-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,3,4-thiadiazole-2- base] urea

Add dropwise 132 mg (1.16 mmol) of benzyl isocyanate in N, N-dimethylformamide solution of 342 mg (1.16 mmol) of the compound of Example 45-2) in 25 ml of N, N-dimethylformamide solution 5ml, stirred at room temperature for 22 hours. Then the reaction solution was concentrated under reduced pressure, chloroform and water were added to the obtained residue, the organic layer was separated, dried with anhydrous magnesium sulfate, the solvent was evaporated, and the obtained residue was separated by silica gel column chromatography with chloroform-methanol (40:1～25: 1) was eluted to obtain 399 mg of the title compound.

Melting point: 232-233°C

¹ H-NMR (δppm, DMSO-d ₆ )

11.13(1H,br),7.41(1H,d,J=3.7Hz),7.36-7.25(5H,m),7.16(1H,brs),6.98(1H,d,J=3.7Hz),4.37(2H ,d,J=6.1Hz),3.82(2H,s),2.64-2.62(4H,m),1.58(8H,br)

Example 47

N-[5-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,3,4-thiadiazol-2-yl]benzamide

Use 350mg (1.19mmol) of the compound of Example 45-2), 0.33ml (2.38mmol) of triethylamine and 0.18mg (1.55mol) of benzoyl chloride, and 4-N,N-dimethylaminopyridine in a catalytic amount , the same operation as in Example 10, to obtain 396 mg of the title compound.

Melting point: 219～221℃

¹ H-NMR (δppm, DMSO-d ₆ )

13.04(1H,br),8.14(2H,d),7.66(1H,d),7.59-7.56(3H,m),7.04(1H,d),3.88(2H,s),2.68-2.66(4H, m),1.60(8H,m)

Example 48

1-[5-(5-Benzylamino-1,3,4-thiadiazol-2-yl)-2thienylmethyl]hexahydro-1H-azepine

0.37ml (3.67mmol) benzaldehyde was added dropwise in 100ml of 1,2-dichloroethane solution of the compound of 1.08g (3.67mmol) Example 45-2), and after stirring at room temperature for 90 minutes, 1.02g (7.34 mmol) NaBH(OAC) ₃ and 0.42 ml (7.34 mmol) acetic acid, stirred at room temperature for another 51 hours. Then, it was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 270 mg of the title compound.

Melting point: 165～166℃

¹ H-NMR (δppm, DMSO-d ₆ )

8.40(1H,t),7.38-7.26(5H,m),7.22(1H,d,J=3.7Hz),6.93(1H,d,J=3.7Hz),4.52(2H,d,J=5.5Hz ),3.79(2H,s),2.62-2.60(4H,m),1.57(8H,br)

Example 49

1-[5-(5-Ethylamino-1,3,4-thiadiazol-2-yl)-2-thienylmethyl]hexahydro-1H-azepine

Operated in the same manner as in Example 45, by 760mg (3.0mmol) 2-(hexahydro-1H-azepine-1-yl) methylthiophene-5-carboxylic acid hydrazide and 288mg (3.3mmol) ethyl isothiocyanate ester to obtain 820 mg of the title compound.

Melting point: 112～114℃

¹ H-NMR (δppm, DMSO-d ₆ )

7.88(1H,t),7.22(1H,d),6.93(1H,d),3.80(2H,s),3.34-3.29(2H,s),2.63-2.61(4H,m),1.57(8H, br),1.20(3H,t)

Example 50

1-ethyl-3-[5-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,3,4-thiadiazole-2- base] urea

In the same manner as in Example 46, 220 mg of the title compound was obtained from 200 mg (0.68 mmol) of the compound of Example 45-2) and 51 mg (0.72 mmol) of ethyl isocyanate.

Melting point: 203～204℃

¹ H-NMR (δppm, DMSO-d ₆ )

10.99(1H,brs),7.41(1H,d,J=3.7Hz).6.98(1H,d,J=3.7Hz),6.62(1H,brs),3.82(2H,s),3.21-3.15(2H ,m),2.64-2.62(4H,m),1.58(8H,brs),1.08(3H,t,J=6.7Hz)

Example 51

N-[5-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,3,4-thiadiazol-2-yl]acetamide

In the same manner as in Example 47, 380 mg of the title compound was obtained from 350 mg (1.19 mmol) of the compound of Example 45-2) and 0.15 ml of acetic anhydride.

Melting point: 248～249℃

¹ H-NMR (δppm, DMSO-d ₆ )

12.61(1H,br),7.52(1H,d,J=3.7Hz),7.0(1H,d,J=3.7Hz),3.83(2H,s),3.64-3.62(4H,m),2.21(3H ,s),1.58(8H,brs)

Example 52

1) 5-[(Hexahydro-1H-azepine-1-yl)methyl]-thiophene-5-N-methoxy-N-methylformamide

8.0 g (29.0 mmol) of 2-(hexahydro-1H-azepine-1-yl) hydrochloride of methylthiophene-5-carboxylic acid was suspended in 300 ml of tetrahydrofuran, and then 10.1 ml (72.5 mmol) triethylamine, 4.12 g (30.46 mmol) hydroxybenzotriazole and 8.34 g (43.5 mmol) WSCD·HCl, stirred for 1 hour. Add 3.51g (36.0mmol) of N,O-dimethylhydroxylamine hydrochloride and 8.36ml (60.0mmol) of triethylamine, and stir overnight. Next, ethyl acetate and water were added to the reaction solution, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography eluting with chloroform-methanol (80:1) to obtain 7.51 g of the title compound.

¹ H-NMR (δppm, CDCl ₃ )

1.63(8H,brs),2.68(4H,m),3.35(3H,s),3.84(3H,s),3.85(2H,s),6.89(1H,d,J=3.7Hz),7.80(1H ,d,J=3.7Hz)

2) 2-Acetyl-5-[(hexahydro-1H-azepine-1-yl)methyl]-thiophene

Under argon flow, 39.0ml (40.4mmol) methyllithium (1.04M ether solution) was added dropwise in 70ml of anhydrous tetrahydrofuran solution of 9.51g (33.86mmol) of the compound obtained in 1) at 0°C, and at the same temperature After stirring for 30 minutes, it was stirred for a further 3 hours at room temperature. Water and ethyl acetate were then added to the reaction solution, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography eluting with chloroform-methanol (80:1) to obtain 7.10 g of the title compound.

¹ H-NMR (δppm, CDCl ₃ )

7.55(1H,d),6.91(1H,d),3.83(2H,d),2.67-2.55(4H,m),2.52(3H,s),1.62(8H,br)

3) (E)-N-[1-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]ethylene]-4H-1,2,4 -Triazol-4-amine

2) Add 1.93g (22.95mmol) of 4-amino-1,2,4-triazole and catalytic amount of p-toluenesulfonic acid to 50ml of toluene solution of 1.19g (5.0mmol) of the obtained compound, and load it into Dean Stark The tube was heated to reflux for 1 week, and then the reaction liquid was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.28 g of the title compound.

¹ H-NMR (δppm, CDCl ₃ )

8.21(2H,s),7.48(1H,d,J=4.0Hz),7.94(1H,d,J=4.0Hz),3.85(2H,s),2.69-2.65(4H,m),2.35(3H ,s),1.64(8H,br)

4) (E,E)-N-[3-Dimethylamino-1-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-2- Propylene-4H-1,2,4-triazol-4-amine

2.76ml (13.38mmol) of tert-butylbis(dimethylamino)methane (Bradereck's reagent) was added dropwise in 50ml of tetrahydrofuran solution of the compound obtained in 1.23g (4.05mmol), and then in an argon atmosphere, Stir at room temperature for 48 hours. The reaction solution was concentrated under reduced pressure to obtain 1.38 g of the title compound.

¹ H-NMR (δppm, CDCl ₃ )

8.23(2H,s),7.3-6.90(3H,m),4.74(1H,d),3.86(2H,s),2.89(6H,s),2.70-2.64(4H,m),1.63(8H, b)

5) 6-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-triazolo[4,3-b]pyridazine

717 mg (2.0 mmol) of the compound obtained in 4) was dissolved in 20 ml of acetic acid, and heated to reflux for 4 hours. Then, the reaction solution was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution and chloroform were added to the obtained residue, and the organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. Next, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography eluting with acetone-toluene (2:1) to obtain 690 mg of the title compound. It was recrystallized from ethyl acetate-isopropyl ether to obtain 174-purpose product.

Melting point: 101～102℃

¹ H-NMR (δppm, CDCl ₃ )

9.06(1H,s),8.09(1H,d),7.54(1H,d),7.49(1H,d),6.96(1H,d),3.88(2H,s),2.73-2.70(4H,m) ,1.68-1.59(8H,m)

Example 53

1) N,N-Dimethyl-N'-[5-(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]formamidine

3.72g (15.65mmol) 5-[(hexahydro-1H-azepine-1-yl) methyl]thiophene-2-formamide was dissolved in 30mlN,N-dimethylformamide, then added 3.4ml( 25.6 mmol) N,N-dimethylformamide dimethyl acetal, stirred at 80°C for 4 hours. Next, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 3.82 g of the title compound.

¹ H-NMR (δppm, CDCl ₃ )

8.58(1H,s),7.73(1H,d),6.88(1H,d),3.85(2H,s),3.19(6H,s),2.71-2.62(4H,s),1.62(8H,brs)

2) 1-[5-(1,2,4-oxadiazol-5-yl)-2-thienylmethyl]hexahydro-1H-azepine 1.0 oxalate

0.9 ml (11.0 mmol) of pyridine and 1.64 g (14.5 mmol) of hydroxylamine O-sulfonate were added to 20 ml of methanol solution of 1.91 g (7.25 mmol) of the compound obtained in 1), and stirred overnight at room temperature. Then, the reaction liquid was concentrated under reduced pressure, 10% K ₂ CO ₃ was added to the resulting residue under ice cooling, followed by extraction with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography eluting with chloroform-methanol (100:1 to 80:1) to obtain 42 mg of the free form of the title compound. 40 mg of the above free compound was dissolved in 5 ml of methanol and 2 ml of chloroform, then a methanol solution containing 13 mg of oxalic acid was added, concentrated under reduced pressure, and finally the resulting residue was crystallized with methanol and ether to obtain 33 mg of the title compound.

Melting point: 131～132℃

¹ H-NMR (δppm, DMSO-d ₆ )

9.48(1H,br),7.37(1H,d),7.19(1H,d),4.51(2H,s),3.14(1H,br),3.10(1H,br),1.80(2H,m),1.60 (4H,m)

Example 54

1-[5-(1H-1,2,4-triazol-3-yl)-2-thienylmethyl]hexahydro-1H-azepine

0.15 ml (3.0 mmol) of hydrazine monohydrate was added dropwise to 3.5 ml of an acetic acid solution of 440 mg (1.5 mmol) of the compound obtained in Example 53-1), stirred at room temperature for 120 hours, and then continued to stir at 80° C. for 4 hours. Next, the reaction solution was concentrated under reduced pressure, 28% ammonia water and chloroform were added to the resulting residue, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from ethyl acetate to obtain 99 mg of the title compound.

Melting point: 129～130℃

¹ H-NMR (δppm, DMSO-d ₆ )

9.11(1H,s),7.42(1H,d),6.95(1H,d),3.80(2H,s),2.63-2.61(4H,m),1.57(8H,brs)

Example 55

1) 5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thiophene amidoxime

Add 19g of hydroxylamine hydrochloride in 500ml of ethanol solution of 70g 2-cyano-[5-(hexahydro-1H-azepine-1-yl)methyl]thiophene, heat at 80°C and stir for 5 hours. After concentrating the reaction solution, 500 ml of saturated aqueous sodium bicarbonate solution was added, followed by extraction three times with 300 ml of chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue dried under reduced pressure was purified by silica gel column chromatography to obtain 51 g of the title compound.

¹ H-NMR (δppm, CDCl ₃ )

1.61(8H,s),2.50-2.80(4H,m),3.82(2H,s),4.56(2H,br),6.82(1H,d),7.10(1H,d),7.27(1H,br)

2) 3-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazole-5-carboxylic acid ethyl ester hydrochloride Salt

Under ice cooling, 0.5 ml of triethylamine and 0.4 ml of ethyl chloroglyoxylate were added to 20 ml of a chloroform solution of 831 mg of the compound of Example 55-1), heated to 40° C., and stirred for 3 hours. Then add 50ml of saturated aqueous sodium bicarbonate solution to the reaction solution for extraction, dry the organic layer with anhydrous sodium sulfate, concentrate under reduced pressure, then use silica gel column chromatography to refine the resulting residue, and then add 4N hydrochloric acid-ethyl acetate solution , and the precipitated crystals were filtered to obtain 370 mg of the title compound.

Melting point: 178～179℃

¹ H-NMR (δppm, DMSO-d ₆ )

1.37(3H,t),1.50-1.90(8H,m),3.05-3.20(2H,m),3.35-3.50(2H,m),4.46(2H,q),4.67(2H,d),7.53( 1H,d),7.91(1H,d),10.05(1H,br)

Example 56

1) 1-[5-(5-tert-butyldimethylsilyloxymethyl-1,2,4-oxadiazol-3-yl)-2-thienylmethyl]hexahydro-1H-nitrogen Miscellaneous

Add 220 mg of sodium hydride to 50 ml of the tetrahydrofuran solution of the compound of 2.1 g of Example 55-1), stir at room temperature for 1 hour, then add 1.8 g of ethyl 2-tert-butyldimethylsilyloxyacetate, and heat to 60 °C and stirred for 3 hours. Then add 200ml of saturated brine to the reaction solution, then extract 3 times with 100ml of ethyl acetate, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and finally use silica gel column chromatography The residue was purified to obtain 1.1 g of the title compound.

¹ H-NMR (δppm, CDCl ₃ )

0.03(6H,s),0.78(9H,s),1.04-1.60(8H,m),2.40-2.60(4H,m),3.70(2H,s),4.78(2H,s),6.75(1H, d),7.46(1H,d)

2) 1-[5-(5-Hydroxymethyl-1,2,4-oxadiazol-3-yl)-2-thienylmethyl]hexahydro-1H-azepine hydrochloride

In 1.1 g of 1-[5-(5-tert-butyldimethylsilyloxymethyl-1,2,4-oxadiazol-3-yl)-2-thienylmethyl-1-hexahydro-1H-nitrogen Add 4.0 ml of a 1.0 N tetrabutylammonium fluoride-tetrahydrofuran solution to 10 ml of a tetrahydrofuran solution of zepine, and stir at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, 4N hydrochloric acid-ethyl acetate solution was added, and the precipitated crystals were filtered to obtain 680 mg of the title compound.

Melting point: 171～172℃

¹ H-NMR (δppm, DMSO-d ₆ )

1.50-1.75(4H,m),1.75-1.90(4H,s),3.00-3.20(2H,m),3.30-3.45(2H,m),4.63(2H,d),4.79(2H,s), 6.11(1H,br),7.55(1H,d),7.79(1H,d),10.74(1H,br)

Example 57

1) 1-[5-(5-tert-butoxycarbonylaminomethyl-1,2,4-oxadiazol-3-yl)-2-thienylmethyl]hexahydro-1H-azepine

Use 1.7g 5-(hexahydro-1H-azepine-1-yl)methyl]-2-thiophene amidoxime and 2.0g N-tert-butoxycarbonyl glycine ethyl ester, adopt the same method as in Example 56-1) method to obtain 1.1 g of the title compound.

¹ H-NMR (δppm, CDCl ₃ )

1.47(9H,s),1.63(8H,br),2.50-2.80(4H,s),3.86(2H,d),4.58(2H,d),5.20(1H,br),6.91(1H,d) ,7.61(1H,d)

2) 1-[5-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-2-thienylmethyl]hexahydro-1H-azepine 2 hydrochloride 1/2 Hydrate

Dissolve 1.1g of 1-[5-(5-tert-butoxycarbonylaminomethyl-1,2,4-oxadiazol-3-yl)-2-thienylmethyl]hexahydro-1H-azepine in In 30 ml of 4N hydrochloric acid-1,4-dioxane solution, stirred at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 966 mg of the title compound.

Melting point: 203～204℃

¹ H-NMR (δppm, DMSO-d ₆ )

1.50-1.75(4H,br),1.85(4H,s),3.00-3.20(2H,br),3.30-3.50(2H,br),4.58(2H,s),4.63(2H,s),7.58( 1H,d),7.81(1H,d),8.94(3H,br),11.22(1H,br)

Example 58

2-[3-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxazol-5-yl]acetic acid ethyl ester salt salt

Add 3.6 g of diethyl malonate to 100 ml of toluene solution of 2.0 g of 5-[(hexahydro-1H-azepine-1-yl) methyl]-thiophene-2-aminoxime, heat to 100 ° C, stir one night. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, 4N hydrochloric acid-ethyl acetate solution was added, and the resulting precipitate was recrystallized from ethanol-ether to obtain 1.6 g of the title compound. (Yield 53%)

Melting point: 122～123℃

¹ H-NMR (δppm, CDCl ₃ )

1.22(3H,t),1.50-1.70(4H,m),1.75-1.90(4H,m),3.00-3.15(2H,m),3.30-3.45(2H,m),4.17(2H,q), 4.37(2H,s),4.65(2H,d),7.53(1H,d),7.81(1H,d),10.34(1H,br)

Example 59

1-[5-(5-Hydroxyethyl-1,2,4-oxadiazol-3-yl)-2-thienylmethyl]hexahydro-1H-azepine hydrochloride

Under ice cooling, in 1.5g 2-[3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxazole-5 - Base] Add 650 mg of sodium borohydride to 40 ml of THF solution of ethyl acetate free base, add 27 ml of methanol while stirring for about 1 hour, and stir for another 1 hour. Still under ice-cooling, 1N hydrochloric acid was added to the reaction solution until the solution did not bubble, then 100 ml of saturated aqueous sodium bicarbonate solution was added, and extracted three times with 50 ml of chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by silica gel column chromatography, followed by adding 4N hydrochloric acid-ethyl acetate solution, filtering the precipitated crystals, and using Recrystallization from ethanol-ethyl acetate gave 725 mg of the title compound.

Melting point: 186～187℃

¹ H-NMR (δppm, DMSO-d ₆ )

1.50-1.70(4H,m),1.75-1.90(4H,m),3.00-3.20(4H,m),3.30-3.40(2H,m),3.85(2H,t),4.65(2H,d), 7.51(1H,d),7.78(1H,d),10.27(1H,br)

Example 60

1) 1-[5-(5-tert-butoxycarbonylaminoethyl-1,2,4-oxadiazol-3-yl)-2-thienylmethyl]hexahydro-1H-azepine 2 salt salt

Using 2.9g of 5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thiophene amidoxime and 2.0g of N-tert-butoxycarbonyl-β-alanine methyl ester, adoption and implementation In the same manner as in Example 56, 1.2 g of the title compound was obtained.

¹ H-NMR (δppm, CDCl ₃ )

1.44(9H,s),1.63(8H,s),2.55-2.80(4H,m),3.11(2H,t),3.60(2H,t),3.86(2H,s),5.15(1H,br) ,6.91(1H,d),7.61(1H,d)

2) 1-[5-(5-Aminoethyl-1,2,4-oxadiazol-3-yl)-2-thienylmethyl]hexahydro-1H-azepine

Using 1.1g of 1-[5-(5-tert-butoxycarbonylaminoethyl-1,2,4-oxadiazol-3-yl)-2-thienylmethyl]hexahydro-1H-azepine, using The protecting group was removed in the same manner as in Example 57-2), to obtain 1.1 g of the title compound.

Melting point: 210～211℃

¹ H-NMR (δppm, DMSO-d ₆ )

1.50-1.75(4H,m),1.84(4H,s),2.40-2.60(2H,t),3.10-3.20(2H,t),3.40-3.50(4H,m),4.63(2H,d), 7.56(1H,d),7.80(1H,d),8.15(3H,br),11.00(1H,br)

Example 61

1) 5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thiophenethioamide

Add 3ml of triethylamine to 50ml of 4.6g of 1-(5-cyano-2-thiophenemethyl)hexahydro-1H-azepine pyridine solution, introduce hydrogen sulfide gas while stirring at room temperature, a small amount each time, last 2 Hour. The reaction solution was concentrated under reduced pressure, 50 ml of saturated aqueous sodium bicarbonate solution was added to the residue, and extraction was performed three times with 50 ml of chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 4.3 g of the title compound.

¹ H-NMR (δppm, DMSO-d ₆ )

1.56(8H,s),2.45-2.75(4H,m),3.74(2H,s),6.94(1H,d),7.54(1H,d),9.30(1H,br),9.47(1H,br)

2) 1-[5-(4-methylthiazol-2-yl)-2-thienylmethyl]hexahydro-1H-azepine 2 hydrochloride

Add 730 mg of chloroacetone to 30 ml of ethanol solution of 2.0 g of 5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thiophenethioamide, and heat and stir at 80° C. overnight. After cooling the reaction solution with ice, hydrochloric acid was added dropwise to adjust the pH to 1, and then concentrated under reduced pressure. The residue was recrystallized from acetonitrile to obtain 1.6 g of the title compound.

Melting point: 187～190℃

¹ H-NMR (δppm, DMSO-d ₆ )

1.50-2.00(8H,m),2.38(3H,s),3.00-3.20(2H,m),3.35-3.45(2H,m),4.54(2H,s),7.32(1H,s),7.46( 1H,d),7.58(1H,d),7.70(1H,br),11.36(1H,br)

Example 62

1) 2-[5-phthalimidomethyl-2-thienyl]imidazo[1,2-a]pyridine

5-Bromoacetyl-2-(phthalimidomethyl)thiophene (0.80 g) and 2-aminopyridine (0.23 g) were dissolved in absolute ethanol (50 ml), and heated to reflux for 6 hours. The resulting crystals were collected by filtration and purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain 0.38 g of the title compound.

¹ H-NMR (δppm, DMSO-d ₆ )

8.48(1H,d),8.24(1H,s),7.90(4H,s),6.79-7.56(5H,s),4.95(2H,s)

2) 2-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]imidazo[1,2-a]pyridine hydrochloride

2-[5-phthalimidomethyl-2-thienyl]imidazo[1,2-a]pyridine (0.38g) and hydrazine hydrate (0.058g) were dissolved in methanol (10ml) and chloroform (5ml) of the mixed solution, heated to reflux overnight. The reaction solution was filtered, the filtrate was concentrated, and purified by silica gel column chromatography (chloroform:methanol=4:1) to obtain 0.14 g of an aminomethylthiophene intermediate. Then, the above-mentioned intermediate (0.14g), 1,6-dibromohexane (0.16g), potassium carbonate (0.19g) and potassium iodide (0.05g) were added to n-butanol (10ml), and heated to reflux for 6 hours. The reaction liquid was filtered, the filtrate was concentrated, purified by silica gel column chromatography (chloroform:methanol=10:1), and salt-forming reaction was carried out with 4N hydrochloric acid-ethyl hydrochloric acid solution in diethyl ether to obtain 0.061 g of the title compound.

Melting point: 214～216℃

MS(FAB,Pos,m/z)312(M ⁺⁺ 1)

Example 63

1) 2-[5-phthalimidomethyl-2-thienyl]imidazo[1,2-a]pyrimidine

Using 2-aminopyrimidine, the title compound was synthesized in the same manner as in Example 62-1).

¹ H-NMR (δppm, DMSO-d ₆ )

8.91(1H,dd),8.50(1H,dd),8.22(1H,s),7.90(4H,d),7.44(1H,d),7.00-7.13(2H,m),4.97(2H,s)

2) 2-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]imidazo[1,2-a]pyrimidine fumarate

Using 2-[5-phthalimidomethyl-2-thienyl]imidazo[1,2-a]pyrimidine as the starting material, fumaric acid was used to carry out the salt-forming reaction, using the method described in Example 62 -2) The title compound was synthesized by the same method.

Melting point: 188～191℃

¹ H-NMR (δppm, DMSO-d ₆ )

8.92(1H,dd),8.51(1H,dd),8.21(1H,s),7.43(1H,d),7.05(1H,dd),6.99(1H,d),6.59(2H,s),3.88 (2H,s),2.50(4H,brd),1.59-1.66(8H,br)

Example 64

4-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]benzoic acid ethyl ester

Under ice cooling, add 3.8ml (1N) diisobutylaluminum hydride-toluene solution to 100ml of anhydrous tetrahydrofuran suspension of 2.5g di(triphenylphosphine)nickel chloride, stir for 10 minutes, then add 4.3g 4- Iodide ethyl benzoate, and then use intubation and argon pressure to inject 3.0g1-(2-thienyl)hexahydro-1-azepine, 60ml anhydrous tetrahydrofuran, 9.6ml (1.6N) A solution prepared by n-butyllithium-hexane solution and 5.4 ml (1N) dichloride ether solution (Jismicrolide-Tel) was then stirred overnight at room temperature. The reaction solution was filtered with diatomaceous earth, and after concentrating the filtrate under reduced pressure, 100ml of saturated sodium bicarbonate was added to the residue, extracted three times with 100ml of chloroform, the organic layers were combined, washed with saturated brine, concentrated under reduced pressure, and then washed with silica gel After purification by column chromatography, 4N hydrochloric acid-ethyl acetate was added, and the precipitated crystals were filtered to obtain 290 mg of the title compound (4%).

Melting point: 194～197℃

¹ H-NMR (δppm, DMSO-d ₆ )

1.34(3H,t),1.55-1.90(8H,m),3.10-3.20(2H,m),3.30-3.50(2H,m),4.33(2H,q),4.62(2H,d),7.92( 1H,d),7.70(1H,d),7.82(2H,d),8.01(2H,d),9.85(1H,br)

Example 65

3-Amino-5-[5-[(pyrrolidin-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole

In the same manner as in Example 38, 580 mg of the title compound were obtained from 1.8 g (7.99 mmol) of 2-(1-pyrrolidinyl)methylthiophene-5-carboxylic acid hydrazide.

Melting point: 180～181℃

¹ H-NMR (δppm, DMSO-d ₆ )

11.96(1H,brs),7.21(1H,brs),6.87(1H,brs),6.05(2H,brs),3.70(2H,s),2.51-2.48(4H,m),1.73-1.66(4H, m)

Example 66

1-[5-(5-Amino-1H-1,2,4-triazol-3-yl)-3-thienylmethyl]hexahydro-1H-azepine

In the same manner as in Example 38, 2.03 g of the title compound were obtained from 3.32 g (13.1 mmol) of 4-(hexahydro-1H-azepin-1-yl)methylthiophene-2-carboxylic acid hydrazide.

Melting point: 167～168℃

¹ H-NMR (δppm, DMSO-d ₆ )

12.02(1H,br),7.33(1H,s),7.18(1H,s),6.03(2H,br),3.56(2H,s),2.56-2.51(4H,m),1.55(8H,s)

Example 67

1-[2-[5-(5-Amino-1H-1,2,4-triazol-3-yl)-2-thienyl]ethyl]hexahydro-1H-azepine

In the same manner as in Example 38, 2.39 g of the title compound were obtained from 3.70 g (13.84 mmol) of 5-[2-(hexahydro-1H-azepine-1-yl)ethyl]thiophene-2-carboxylic acid hydrazide.

Melting point: 109～110℃

¹ H-NMR (δppm, DMSO-d ₆ )

11.94(1H,br),7.18(1H,s),6.79(1H,s),6.00(2H,br),2.90-2.86(2H,m),2.70-2.62(6H,m),1.59-1.56( 8H,m)

Example 68

3-Amino-5-[5-(1H-imidazol-1-ylmethyl)-2-thienyl]-1H-1,2,4-triazole

In the same manner as in Example 38, 177 mg of the title compound was obtained from 360 mg (1.36 mmol) of 2-(1H-imidazol-1-yl)methylthiophene-5-carboxylic acid hydrazide.

Melting point: 178～180℃

¹ H-NMR (δppm, DMSO-d ₆ )

12.03(1H,brs),7.75(1H,brs),7.24(1H,d),7.22(1H,brs),7.03(1H,d),6.91(1H,brs),6.09(2H,brs),5.38 (2H,brs)

Example 69

2-Amino-5-[5-(1H-imidazol-1-ylmethyl)-2-thienyl]-1H-1,3,4-oxadiazole hydrobromide

In the same manner as in Example 43, 866 mg of the title compound were obtained from 1.11 g (5.0 mmol) of 2-(1H-imidazol-1-yl)methylthiophene-5-carboxylic acid hydrazide.

Melting point: 261～262℃

¹ H-NMR (δppm, DMSO-d ₆ )

9.28(1H,s),7.86(1H,s),7.71(1H,s),7.43(1H,s),7.37-7.34(3H,m),5.77(2H,brs)

Example 70

N-[5-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,3,4-oxadiazol-2-yl]benzamide Hydrochloride

Add 1.8 ml (15.0 mmol) of benzoyl chloride to 15 ml of a pyridine solution of 278 mg (1.0 mmol) of the compound of Example 43, and stir at 80° C. for 10 days. Then, the reaction liquid was concentrated under reduced pressure, chloroform was added to the resulting residue, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography, and the obtained crude crystals were recrystallized from ethanol-diisopropyl ether to obtain 241 mg of the title compound.

Melting point: 182～184℃

¹ H-NMR (δppm, DMSO-d ₆ )

12.23(1H,br),10.96(1H,br),8.04(2H,d),7.75(1H,d),7.68(1H,t),7.61-7.54(3H,m),4.65(2H,s) ,3.45-3.43(2H,br),3.10(2H,br),1.85(4H,brs),1.65(4H,br)

Example 71

1-[5-(5-Benzylamino-1,3,4-oxadiazol-2-yl)-2-thienylmethyl]hexahydro-1H-azepine

Add 0.13ml (1.05mmol) benzyl isocyanate in 25ml of acetonitrile solution of 253mg (1.0mmol) 2-(hexahydro-1H-azepine-1-yl) methylthiophene-5-carboxylic acid hydrazide, After stirring at room temperature for 40 hours, 718 mg (2.2 mmol) of 1,2-dibromo-1,1,2,2-tetrachloroethane, 1.22 ml of triethylamine and 1.16 g of triphenylphosphine were added, followed by stirring at room temperature for 9 hours. The reaction liquid was concentrated, and chloroform was added to the resulting residue, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography to obtain 122 mg of the free form of the title compound. Finally, 117 mg of this was salified with 27 mg of oxalic acid to obtain 122 mg of the title compound.

Melting point: 104～105℃

¹ H-NMR (δppm, DMSO-d ₆ )

8.42(1H,t),7.45(1H,d),7.38 7.26(7H,m),4.43(2H,d),4.32(2H,br),3.00(4H,brs),1.72(4H,brs), 1.59(4H,brs)

Example 72

1-[5-(5-Hydroxy-1,3,4-oxadiazol-2-yl)-2-thienylmethyl]hexahydro-1H-azepine

760mg (3.0mmol) of 2-(hexahydro-1H-azepine-1-yl)methylthiophene-5-carboxylic acid hydrazide was dissolved in 30ml of tetrahydrofuran and 3ml of N,N-dimethylformamide, and then Add 583 mg (3.6 mmol) of 1,1′-carbonyldiimidazole and 0.84 ml (6.0 mmol) of triethylamine, and heat to reflux for 3 hours. Next, the reaction liquid was concentrated, and chloroform was added to the obtained residue, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain 793 mg of the title compound.

Melting point: 117～119℃

¹ H-NMR (δppm, CDCl ₃ )

8.84(1H,br),7.44(1H,d),6.91(1H,d),3.89(2H,brs),2.74-2.71(4H,m),1.74-1.58(8H,m)

Example 73

1-[5-[5-(2-pyridyl)-1,3,4-oxadiazol-2-yl]-2-thienylmethyl]hexahydro-1H-azepine oxalate

In 50ml of dichloromethane solution of 1010mg (4.0mmol) 2-(hexahydro-1H-azepine-1-yl)methylthiophene-5-carboxylic acid hydrazide, add 8ml pyridine and 1.28g picolinoyl chloride hydrochloride salt, and stirred overnight at room temperature. After washing the reaction solution with water, it was dried over anhydrous magnesium sulfate. After distilling off the solvent, it was azeotroped four times with 50 ml of toluene to obtain 1.5 g of crystals. Next, under ice cooling, 0.23 ml of triethylamine and 140 mg (0.83 mol) of 1,2-chloro-1,3-dimethylimidazolium chloride were added to 30 ml of a dichloromethane solution of 268 mg (0.75 mmol) of the above crystals , stirred at room temperature for 4 days. After washing the reaction solution with water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain 87 mg of the free form of the title compound. Finally, 75 mg of this was salified with 19 mg of oxalic acid to obtain 76 mg of the title compound.

Melting point: 217～218℃

¹ H-NMR (δppm, DMSO-d ₆ )

8.80(1H,d),8.25(1H,d),8.08(1H,m),7.86(1H,d),7.66(1H,m),7.33(1H,brs),4.29(2H,brs),1.72 (4H,brs),1.61(4H,brs)

Example 74

1-[5-(5-Methyl-1,3,4-oxadiazol-2-yl)-2-thienylmethyl]hexahydro-1H-azepine oxalate

In the same manner as in Example 73, 81 mg was obtained with 507 mg (2.0 mmol) of 2-(hexahydro-1H-azepine-1-yl) methylthiophene-5-carboxylic acid hydrazide and 0.23 ml (2.4 mmol) of acetic anhydride title compound.

Melting point: 91～92℃

¹ H-NMR (δppm, DMSO-d ₆ )

7.68(1H,d),7.28(1H,d),4.28(2H,s),2.56(3H,s),1.71(4H,brs),1.59(6Hbrs)

Example 75

1-[5-(5-Phenyl-1,3,4-oxadiazol-2-yl)-2-thienylmethyl]hexahydro-1H-azepine

Add 687mg (4.0mmol) methyl benzoimidate in 7ml of pyridine solution of 507mg (2.0mmol) 2-(hexahydro-1H-azepine-1-yl) methylthiophene-5-carboxylic acid hydrazide Hydrochloride, heated to reflux for 4 hours. The reaction liquid was concentrated, and chloroform was added to the resulting residue, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography. 110 mg of the title compound were obtained.

Melting point: 95～97℃

¹ H-NMR (δppm, CDCl ₃ )

8.13-8.10(2H,m),7.68(1H,d),7.56-7.50(4H,m),3.89(2H,s),2.72-2.70(4H,m),1.73-1.60(8H,m)

Example 76

N-Benzyl-5-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole-3-carboxamide

1.0 g (3.0 mmol) of the compound of Example 40 was dissolved in 3.3 ml (30.0 mmol) of benzylamine, and stirred at 80° C. for 4 hours. Chloroform was added to the reaction solution, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography, and the obtained crystals were washed with hot isopropyl ether, and finally recrystallized from ethyl acetate-n-hexane to obtain 997 mg of the title compound.

Melting point: 137～139℃

¹ H-NMR (δppm, DMSO-d ₆ )

9.20(1H,br),7.53(1H,d),7.34(5H,br),7.25(1H,t),6.99(1H,d),4.48(2H,d),3.82(2H,s),2.61 (4H,brs),1.54(8H,brs)

Example 77

N-Benzyl-5-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazol-3-ylmethyl Amine 3/2 Fumarate

594 mg (1.5 mmol) of the compound of Example 76 in 10 ml of anhydrous tetrahydrofuran solution was added dropwise to 5 ml of a suspension of 230 mg (6.0 mmol) of lithium aluminum hydride in anhydrous tetrahydrofuran, and heated to reflux for 11 hours. Then add 460 mg (12.0 mmol) of lithium aluminum hydride and heat to reflux for 3 days. Then, sodium sulfate·decahydrate was added to the reaction mixture, and the insoluble matter was filtered off, then the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain 104 mg of the free form of the title compound. Further, 74 mg of this was salified with 33 mg of fumaric acid and recrystallized from methanol to obtain 63 mg of the title compound.

Melting point: 155～157℃

¹ H-NMR (δppm, DMSO-d ₆ )

7.42-7.32(5H,m),7.26(1H,m),6.97(1H,brs),6.60(3H,s),3.86-3.84(4H,m),3.80(2H,brs),2.68-2.66( 4H,m),1.58(8H,brs)

Example 78

[5-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazol-3-yl]methyl benzoate

In the same manner as in Example 6, 351 mg of the title compound was obtained from 292 mg (1.0 mmol) of the compound of Example 41.

FABMS(Pos,m/z)397(M ⁺⁺ 1)

¹ H-NMR (δppm, CDCl ₃ )

8.04(2H,d),7.56(1H,t),7.50(1H,d),7.41(3H,t),6.87(1H,d),5.49(2H,s),3.87(2H,s),2.74 -2.66(4H,m),1.70-1.54(8H,m)

Example 79

1-[5-[5-(2-pyridyl)-1H-1,2,4-triazol-3-yl]-2-thienylmethyl]hexahydro-1H-azepine

Add 81mg (1.5mmol) sodium methylate in 13.5ml of methanol solution of 1.56g (15.0mmol) 2-cyanopyridine, after stirring at room temperature for 3.5 hours, under ice-cooling, add 0.085ml (1.5mmol) acetic acid and 1.52g ( 6.0 mmol) of 2-(hexahydro-1H-azepine-1-yl)methylthiophene-5-carboxylic acid hydrazide, stirred at room temperature for 24 hours. The precipitated crystals were collected by filtration to obtain 1.97 g of crystals. Then 894mg (2.5mmol) of it was dissolved in 13ml of acetic acid, and heated to reflux for 6.5 hours. The solvent was distilled off, 28% ammonia water and chloroform were added to the obtained residue, the layers were separated, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain 715 mg of the title compound.

Melting point: 160～162℃

¹ H-NMR (δppm, DMSO-d ₆ )

14.74(1H,br),8.72(1H,d),8.12(1H,d),8.01(1H,dt),7.54(1H,m),7.50(1H,d),6.98(1H,d),3.83 (2H,s),2.68-2.60(4H,m),1.58(8H,brs)

Example 80

1-[5-(2-Methyl-2H-1,2,4-triazol-3-yl]-2-thienylmethyl]hexahydro-1H-azepine hydrochloride

Add 0.3ml (5.59mmol) methylhydrazine dropwise in 5ml of the acetic acid solution of the compound obtained in 820mg (2.8mmol) Example 53-1), after heating to reflux for 5 days, add 0.6ml (11.18mmol) methylhydrazine again, and heat Reflux for 2 days. The solvent was distilled off, 28% ammonia water and chloroform were added to the obtained residue, and the layers were separated. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography, then salted with 0.7 ml of 4N HCl/ethyl acetate, and recrystallized from acetonitrile to obtain 204 mg of the title compound.

Melting point: 232～233℃

¹ H-NMR (δppm, DMSO-d ₆ )

10.61(1H,br),8.00(1H,d),7.69(1H,d),7.54(1H,d),4.61(2H,brs),4.07(3H,s),3.40-3.34(2H,M) ,3.13-3.05(2H,m),1.83(4H,brs),1.66-1.58(4H,m)

Example 81

1-[5-[3-(2-pyridyl)-1H-1,2,4-oxadiazol-5-yl]-2-thienylmethyl]hexahydro-1H-azepine oxalate

The same operation as in Example 1, with 1.07g (4.0mmol) 5-[(hexahydro-1H-azepine-1-yl) methyl-2-thienyl] ethyl carboxylate and 823mg (6.0mmol) 2 -pyridylaminoxime, 149 mg of the free form of the title compound were obtained. Finally, 72 mg of this was salified with 18 mg of oxalic acid to obtain 57 mg of the title compound.

Melting point: 164～166℃

¹ H-NMR (δppm, DMSO-d ₆ )

8.79(1H,d),8.14(1H,d),8.08-8.03(2H,m),7.64(1H,m),7.40(1H,d),4.34(2H,s),2.98(4H,br) ,1.73(4H,brs),1.61(4H,brs)

Example 82

1) O-[5-(hexahydro-1H-azepine-1-yl)methyl-2-thienyl]-3-phthalimidopropionamide oxime

Dissolve 9.59g (93.0mmol) of 3-aminopropionamide oxime in 288ml of 1,3-dimethyl-2-imidazolidinone, then add 14.46g (97.65mM) of phthalic anhydride, and stir at room temperature for 1 hour Then, it was stirred at 140° C. for 2 hours. The reaction solution was cooled to room temperature, and 15.6ml (111.6mM) of triethylamine, 16.4g (55.8 mmol), after stirring at room temperature for one night, add 720ml saturated brine, filter the precipitated crystals, and wash with distilled water to obtain 19.96g O-[5-(hexahydro-1H-azepine-1-yl) methyl Base-2-thiophenoyl]-3-phthalimidopropionamide oxime (from (hexahydro-1H-azepine-1-yl)methyl-2-thiophene carbonyl chloride hydrochloride The calculated yield was 79%).

¹ H-NMR (δppm, DMSO-d ₆ )

7.85(4H,s),7.00(1H,d),6.57(1H,d),3.82(2H,s),2.51(4H,br),1.56(8H,brs)

2) N-[2-[5-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1,2,4-oxadiazole-3- Base]ethyl]phthalimide hydrochloride

Add 100ml xylene in 2.57g O-[5-(hexahydro-1H-azepine-1-yl)methyl-2-thiophenoyl]-3-phthalimidopropionamide oxime , heated to reflux for 8 hours. After cooling the reaction solution to room temperature, it was filtered, 2 ml of 4N hydrochloric acid-ethyl acetate was added under ice cooling, and the precipitated crystals were collected by filtration to obtain 2.2 g of the title compound (yield 82%).

Example 83

1-[5-(5-Amino-1H-1,2,4-triazol-3-yl)-2-thienylmethyl]hexahydro-1H-azepine

Add 500ml of 1,3-dimethyl-2-imidazoline in 24.0g (81.6mmol) of 5-(hexahydro-1H-azepine-1-yl)methyl-2-thiophene carbonyl chloride hydrochloride Ketone and 18.0g (163.2mM) of aminoguanidine hydrochloride were stirred at room temperature for 1 hour, then 16.3g (60% oily, 408mM) of sodium hydride was added, and stirred overnight at 130°C. The reaction solution was cooled to room temperature, and 50 ml of water and 500 ml of n-hexane were added to separate the layers. After adding 1000 ml of saturated brine to the lower layer, it was extracted 7 times with 500 ml of ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, then 1000 ml of acetonitrile was added, and 150 ml of 4N hydrochloric acid/ethyl acetate was added under ice cooling, and the precipitated crystals were collected by filtration. Add 200 ml of 1N sodium hydroxide to the obtained crystals, extract 3 times with 200 ml of ethyl acetate, dry with anhydrous sodium sulfate, concentrate under reduced pressure to 1/10 amount, and collect the precipitated crystals by filtration to obtain 10.4 g of the title compound ( Yield 51%).

The chemical structural formulas of the compounds obtained in the above-mentioned Examples 1 to 83 are listed in the following tables.

In addition to the above-listed compounds, according to the aforementioned preparation methods, the methods described in the examples and their slightly modified methods, or the preparation methods known to those of ordinary skill in the art and their slightly modified methods, no special preparation is required. The following compounds can be synthesized experimentally.

5-Benzylamino-3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole

5-amino-3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-thiadiazole

5-Benzylureido-3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-thiadiazole

5-Benzamido-3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-thiadiazole

5-Benzylamino-3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-thiadiazole

5-aminomethyl-3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole

5-phthalimidomethyl-3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4- Triazole

3-Benzylureido-5-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-oxadiazole

3-Benzamido-5-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-oxadiazole

2-Benzoylamino-5-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,3,4-oxadiazole

2-Benzylamino-5-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,3,4-oxadiazole

4-Benzylureido-3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole

4-Benzamido-3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole

5-Benzylureido-3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole

5-Benzamido-3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole

1-Benzyl-3-[[3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole- 5-yl]methyl]urea

5-Benzamidomethyl-3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole

5-Benzyloxymethyl-3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole

5-Benzyloxymethyl-3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole

5-Benzoylmethyl-3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole

N-Benzylcarbamate[3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole-5- base] methyl ester

5-amino-3-[5-[(pyrrolidin-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole

5-amino-3-[4-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole

1-[5-(2-pyridyl)-2-thienylmethyl]hexahydro-1H-azepine

1-[5-(2-furyl)-2-thienylmethyl]hexahydro-1H-azepine

1-[5-(2-pyrimidinyl)-2-thienylmethyl]hexahydro-1H-azepine

1-[5-(4-Amino-2-pyridyl)-2-thienylmethyl]hexahydro-1H-azepine

1-[5-(4-Aminophenyl)-2-thienylmethyl]hexahydro-1H-azepine

5-amino-3-[5-(hexahydro-1H-azepine-1-yl)methyl-2-thienyl]-1,2,4-oxadiazole

2-Amino-4-[5-(hexahydroazepinyl)methyl-2-thienyl]imidazole

Claims (11)

1. A thiophene derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof,

(The symbols in the formula have the following meanings: R ₁ : Formula-A ₁ -X ₁ -R ₃ , R ₂ : formula -A ₂ -X ₂ -R ₄ or absent, Ring B: 1) 4-10 membered nitrogen-containing cycloalkyl ring or 2) 5-6 membered nitrogen-containing unsaturated heterocyclic rings, Ar ring: an aromatic ring that may have substituents or a 5-6 membered heteroaromatic ring or an 8-10-membered bicyclic ring containing 1 to 4 heteroatoms of one or more than two kinds selected from nitrogen atoms, oxygen atoms, and sulfur atoms Heteroaromatic rings, A ₁ , A ₂ and A ₃ : the same or different bonds or lower alkylene groups, X ₁ and X ₂ : same or different bonds, formula -O-, -S-, -NR ₅ -,

or -C≡C-, R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ : the same or different hydrogen atoms or lower alkyl groups, R ₃ and R ₄ : the same or different hydrogen atoms, cyclic imino groups that may be condensed with a benzene ring that may have substituents, or lower alkyl, cycloalkyl, aryl or aromatic groups that may have substituents respectively alkyl), However, when the Ar ring is a thiazole ring, either one of _A1 and _A2 is a lower alkylene group, and when the Ar ring is a benzene ring, either one of _R1 and _R2 is methyl or halogen, and the other except for hydrogen atoms). 2. The thiophene derivative or the pharmaceutically acceptable salt thereof as claimed in claim 1, wherein ring B is a 4-10 membered nitrogen-containing cycloalkyl ring. 3. The thiophene derivative or the pharmaceutically acceptable salt thereof as claimed in claim 1 or 2, wherein ring B is a hexahydroazepine ring. 4. The thiophene derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein A ₃ is methylene. 5. The thiophene derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the Ar ring is 2 or more compounds selected from nitrogen atom, oxygen atom and sulfur atom. A 5-membered heteroaromatic ring with 3 heteroatoms, or a 9-membered heteroaromatic ring with 2 to 4 heteroatoms containing one or more kinds selected from nitrogen atoms, oxygen atoms and sulfur atoms. 6. The thiophene derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the Ar ring is triazole, oxadiazole, thiazole, thiadiazole, imidazopyridine, imidazopyrimidine , Triazolopyridazine. 7. 5-[5-[(Hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-3-phthalimidoethyl-1,2,4- Oxadiazole, 5-amino-3-[5-[(hexahydro-1H-azepine-1-yl)methyl]-2-thienyl]-1H-1,2,4-triazole or Pharmaceutically acceptable salts. 8. A pharmaceutical composition characterized by comprising the thiophene derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, and a pharmaceutically acceptable carrier. 9. The pharmaceutical composition according to claim 8, further characterized in that it is an anti-PCR drug. 10. The pharmaceutical composition according to claim 9, further characterized in that the anti-PCR drugs are psychotherapeutic drugs and anti-schizophrenia drugs. 11. The pharmaceutical composition according to claim 9, wherein the anti-PCR drug is a drug for treating dementia, a drug for improving abnormal behaviors associated with dementia, a therapeutic agent for mental retardation in children and/or a drug for autism. therapeutic agent.