MXPA00008146A

MXPA00008146A - Cyclic amide compounds

Info

Publication number: MXPA00008146A
Application number: MXPA/A/2000/008146A
Authority: MX
Inventors: Hiroyuki Ishiwata; Seiichi Sato; Mototsugu Kabeya; Soichi Oda; Yukio Hattori; Makoto Suda; Manabu Shibasaki; Hiroshi Nakao; Takao Nagoya
Original assignee: Kowa Co Ltd
Priority date: 1998-02-19
Filing date: 2000-08-18
Publication date: 2001-07-09

Abstract

Compounds represented by general formula (1) and drugs containing the same, wherein A represents an optionally substituted aromatic compound, etc.;B represents nitrogen or CH;X represents optionally substituted lower alkylene, etc.;Y represents a single bond;Z represents an optionally substituted divalent residue of benzene, etc.;and m and n are each an integer of 1 to 4. Because of having an excellent IgE antibody production inhibitory effect, these compounds are useful as antiallergic agents, etc.

Description

COMPOSITE OF CYCLIC AMID TECHNICAL FIELD The present invention relates to novel cyclic amide compounds and to medicaments useful for preventing and treating allergic immunological diseases or the like, which comprise said compound as an active ingredient.

PREVIOUS TECHNIQUE IgE, which is a type of immunoglobulin (Ig), is a specific allergen molecule produced by an IgE-producing cell differentiated from a B cell. This process is activated by the contact of an immunocyte with an allergen in vivo. IgE is produced in a target organ by an allergy and binds to a receptor on the surface of a barley cell, which is a central effector cell in an allergic reaction, or a basophil (sensitized state). After sensitization, allergic chemical mediators such as histamine, leukotrienes, prostaglandins and PAF, and injury enzymes such as tryptase are released from the barley cell stimulated by the reaction of the specific IgE and an allergen that invades the living body, so that immediate responses develop such as acceleration of vascular permeability, constriction of smooth muscle and vasodilation. In addition, cytokines such as IL-4, which directly activate other cells of the immune system, are also secreted from the stimulated barley cell. As a result, eosinophils, basophils and the like infiltrate a tissue, and allergic chemical mediators and tissue injury proteins such as MBP, which are secreted by these inflammatory cells, induce a delayed response, so the allergic symptom is prolonged. and it is taken as seriously ill. From this, IgE is considered a substance that is primarily involved in the attack of an allergic immune disease. Therefore, several compounds that have an inhibitory effect on the production of an IgE antibody with a view to developing antiallergic agents have been found and reported to date. [Pharmacology and Therapy, 1994, 22 (3), 1369; Japanese patent application open to the public No. 106818/1989; Japanese Patent Application No. 17506/1995; Japanese patent applications open to the public Nos. 92216/1996 and 109177/1996; and WO 96/1 1682]. However, the objective has not always been sufficiently achieved under the circumstances. Accordingly, an object of the present invention is to find a compound that has a strong inhibitory effect on the production of an IgE antibody to provide in this manner an effective medicament for allergic immunological diseases, comprising this compound as an active ingredient.

BRIEF DESCRIPTION OF THE INVENTION With the above circumstances in view, the present inventors have carried out an extensive investigation. As a result, it has been found that the novel cyclic amide compounds represented by the general formula (1), which will be described below, salts thereof or solvates thereof have an excellent inhibitory effect on the production of an IgE antibody. and they are useful as medicaments such as antiallergic agents, thus leading to complete the present invention. According to the present invention, a compound represented by the following general formula (1) is then provided: (1) wherein A is a residue of an alicyclic compound that can be substituted, an aromatic compound that can be substituted, or a heterocyclic compound that can be substituted; X is an individual link; a lower alkylene group which can be substituted; a divalent residue in an alicyclic compound that can be substituted, an aromatic compound that can be substituted, or a heterocyclic compound that can be substituted; an imino group that can be substituted; or a sulfur atom or an oxygen atom; And it is an individual bond, or a lower alkylene, imino or lower alkylimino group; Z is a group of -CH = CH-, -C = C-, - (CH = CH) 2-, -C = C-CH = CH- or -CH = CH-C = C, or a divalent residue of benzene, pyridine, pyrimidine or pyrazine that can be substituted; B is a nitrogen atom or = CH-; and m and n are the same or different from each other and are independently an integer from 1 to 4, a salt thereof, or a solvate thereof. In accordance with the present invention, a medicament comprising the above compound (1) is also provided as an active ingredient. In accordance with the present invention, there is further provided a medicinal composition comprising the above compound (1) and a pharmaceutically acceptable carrier. In accordance with the present invention, the use of the above compound (1) for a medicament is also provided. In accordance with the present invention, there is also provided a method for treating an allergic immune disease, which comprises administering the above compound (1).

DETAILED DESCRIPTION OF THE INVENTION In the present invention, examples of the alicyclic compound represented by A or X include saturated or unsaturated alicyclic compounds having 3 to 14 carbon atoms, for example, cycloalkanes such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane; cycloalkenes such as cyclopentene and cyclohexene; and bicyclic fused cycloalkenes such as indene, indane, dihydronaphthalene and tetrahydronaphthalene. Examples of the aromatic compound include aromatic compounds having 5 to 14 carbon atoms, such as benzene and naphthalene. Examples of the heterocyclic compound include 5- to 7-membered heterocyclic compounds containing 1 to 3 nitrogen atoms, such as pyrrolidine, pyridine, piperidine, piperazine and homopiperazine. Examples of the lower alkylene group represented by X or Y include linear or branched alkylene groups having 1 to 8 carbon atoms, and specifically, methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethyl, hexamethylene, heptamethylene and octamethylene groups. In the formula (1), it is particularly preferred that A is a phenyl, naphthyl, dihydronaphthyl, indenyl, pyridyl, indolyl, isoindolyl, quinolyl or isoquinolyl group. These groups may have 1 to 3 substituents. Here, examples of the substituents in these groups include a hydroxyl group, halogen atoms, lower alkyl groups which may be substituted by 1 to 3 halogen atoms, lower alkoxy groups, an amino group, monoalkylamino groups, dialkylamino groups and alkylthio groups lower. As A, a phenyl group substituted by 1 to 3 substituents selected from lower alkyl and lower alkoxy groups is particularly preferred. The lower alkylene group represented by X is preferably a linear or branched alkylene group having 1 to 8 carbon atoms. More preferred is a linear alkylene group having 2 to 4 carbon atoms. These groups may have substituents such as halogen atoms, or hydroxyl, lower alkoxy, amino, monoalkylamino, dialkylamino, carboxyl or lower alkoxycarbonyl groups. Of these, a lower alkylene group which can be substituted by an amino, monoalkylamino, dialkylamino, carboxyl or lower alkoxycarbonyl group is particularly preferred. The divalent residue of the alicyclic compound, which is represented by X, is preferably a divalent residue of a cycloalkane having 5 to 8 carbon atoms. Examples of the divalent residue of the aromatic compound, which is represented by X, including phenylene and naphthylene groups, the phenylene group being particularly preferred. Here, the phenylene group may be any of the groups 1, 2-phenylene, 1,3-phenylene and 1,4-phenylene, with the group 1, 2-phenylene or 1,4-phenylene being particularly preferred. Preferable examples of the divalent residue of the heterocyclic compound, which is represented by X, include divalent residues of pyridine, pyrrolidine, piperidine, piperazine and homopiperazine. The divalent residue of the alicyclic compound, aromatic compound or heterocyclic compound, or the imino group, which is represented by X, can be substituted by a halogen atom, a hydroxyl group, a lower alkyl group which can be substituted by a group amino, monoalkylamino or dialkylamino, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, an amino group, an alkylamino group, a dialkylamino group, a nitro group, a cyano group, an aralkyl group, or the like. Here, examples of the alkylamino and dialkylamino groups include lower alkylamino groups and lower diacylamino groups, respectively. It is preferred that X is the alkylene group having from 1 to 8 carbon atoms, the divalent residue of the aromatic compound that can be substituted, or the divalent residue of the heterocyclic compound that can be substituted. And it is preferably an individual bond or an alkylene group having 1 to 8 carbon atoms. Examples of groups that can be substituted in the benzene divalent residue, pyridine, pyrimidine or pyrazine represented by Z include halogen atoms, and lower alkyl, lower alkoxy, amino and nitro groups. Z is preferably a divalent benzene residue that can be substituted. is particularly preferably a 1,4-piperazinyl, 1,4-hocmHo 2p? perazinyl or 1,4-piperidinyl group In the different substituent groups described above or similar, "alkyl" in the alkyl groups, alkylamino groups, dialkaryl groups , alkylthio groups and the like generally includes linear or branched alkyl having 1 to 12 carbon atoms. Of these, lower alkyl groups are preferred. Lower alkyl groups include linear or branched alkyl groups having 1 to 8 carbon atoms. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl groups. Of these, those having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n- groups are particularly preferred. hexyl. "Alkoxy" in alkoxy groups, alkoxycarbonyl groups and the like generally includes linear or branched alkoxy having 1 to 12 carbon atoms. Of these, lower alkoxy groups are preferred. Lower alkoxy groups include linear or branched alkoxy groups having 1 to 8 carbon atoms. Specific examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy groups. Of these alkoxy groups, those having 1 to 6 carbon atoms are preferred. Examples of the aralkyl group include Cß-C ar-alkyl aryl groups of C?-8 such as benzyl, phenylethyl and naphthylmethyl groups. Examples of the lower alkylthio group include alkylthio groups having 1 to 8 carbon atoms.

Halogen atoms include fluorine, chlorine, bromine and iodine atoms. No particular limitation is imposed on the salts of the cyclic amide compounds (1) according to the present invention, provided they are pharmaceutically acceptable salts. In case the cyclic amide compounds (1) are basic compounds, however, examples of the salts include salts of mineral acids such as hydrochlorides, sulfates and nitrates; and salts of organic acids such as methanesulfonates, acetates, oxalates and citrates. On the other hand, in case the cyclic amide compounds (1) are acidic compounds, examples of the salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and salts of organic bases such as pyridine salts, picoline salts and triethylamine salts. The cyclic amide compounds (1) may be present in the form of solvates such as hydrates. The cyclic amide compounds (1) according to the present invention can be prepared according to, for example, the following reaction formula: (1) where A, X, Y, Z, B, m and n have the same meanings as defined above. More specifically, the compounds (1) according to the present invention are obtained by the reaction of N-acylation of a carboxylic acid (2) with a diamine (3). The N-acylation reaction can be carried out using any N-acylation reaction known per se in the art. It is preferred to apply, for example, (a) a method in which the carboxylic acid (2) and the diamine (3) are reacted in the presence of a condensation reagent, preferably in the presence of a condensation reagent and a base, in a solvent, or (b) a method in which a reactive derivative of the carboxylic acid and the diamine (3) are reacted in a solvent, preferably in the presence of a base. Examples of the solvents used in these reactions may include dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, methylene chloride and dichloroethane. As the base, an organic base such as pyridine, triethylamine or diisopropylethylamine, or an inorganic base such as sodium carbonate or sodium acid carbonate can be used. Examples of condensation reagents that can be used include 1,3-dicyclohexylcarbodumide, 1-cyclohexyl-3-morpholinoethylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1,1'-carbonyldiimidazole, diethyl phosphorocyanidate, azide. of diphenylphosphoryl, bis (2-oxo-3-oxazolidinyl) -phosphinic chloride and 2-chloro-1-methylpyridinium iodide. Examples of useful carboxylic acid derivatives include acid halides such as acid chloride, acid azides, symmetrical acid anhydrides, mixed anhydrides with pivalic acid or the like, and active esters such as cyanomethyl esters and p-nitrophenyl esters. In each of method (a) and method (b), the N-acylation reaction is completed by reacting the carboxylic acid (2) or the reactive derivative thereof with the diamine (3) at the reaction temperature of 0. ° C at 100 ° C for 30 minutes at 30 hours. The isolation and purification of compound (1) from the reaction mixture can be carried out using any method known per se in the art, for example, filtration, extraction, washing, drying, concentration, recrystallization and various types of chromatographies. The compound (1) obtained in this way can be converted into an acid addition salt or a base salt in a method known per se in the art. The compound (1) can also be converted into a solvate with a reaction solvent, solvent for recrystallization or the like, and in particular, a hydrate. Since the cyclic amide compounds (1) according to the present invention have an excellent inhibitory effect on the production of an IgE antibody as demonstrated in the test example, which will be described later, and inhibitory effects on the production of IL-4 and IL-5, are useful as medicaments for the prevention and treatment of various allergic immunological diseases, for example, asthma, atopic dermatitis, allergic rhinitis, disease Irritable bowel, contact dermatitis, allergic ophthalmopathy and the like. The cyclic amide compounds (1) or the salts thereof according to the present invention can be formulated into a medicinal composition, for example, several oral and parenteral preparations in the form of a solid, semi-solid or liquid by adding a pharmaceutically acceptable carrier, inorganic or organic according to a method known per se in the art. Examples of the oral preparations include tablets, pills, granules, soft and hard capsules, powders, grains, triturations, emulsions, syrups, pellets and elixirs. Examples of parenteral preparations include injections, drops, infusions, ointments, lotions, tonics, nebulizers, suspensions, oils, emulsions, suppositories and eye drops. The active ingredients according to the present invention can be formulated into various preparations according to a method known per se in the art. In these preparations, surfactants, excipients, colorants, odor correctors, preservatives, stabilizers, pH regulators, suspension stabilizers, isotonic agents and the like, may be suitably used as required. The dose of the cyclic amide compound (1) or the salt thereof varies according to the type of the compound, the type of a disease to be treated or prevented, a method of administration, the age, sex, and weight of a patient who will be administered, treatment time and the like. However, the compound can be administered in a dose of 0.01 to 1,000 mg / kg of weight / day. The compound can be administered in one or several portions, for example, 2 to 6 portions per day.

EXAMPLES The present invention will be described hereinafter in greater detail by means of the following examples. However, the present invention is not limited to these examples.

REFERENCE EXAMPLE 1 Preparation of 1,3-bis (1-p-piperazine Dpropane tetrahydrochloride (D 1,3-Dibromopropane (1.0 ml, 9.9 mmol) and potassium carbonate (2.0 g, 15 mmol) were added to a solution of 1-formylpiperazine (2.5 g, 22 mmol) in dimethylformamide (5 ml), and the mixture was mixed. stirred for 20 hours in a controlled bath at 60 ° C. Then water was added to the reaction mixture to carry out the extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 2.13 g (yield: 81%) of 1,3-bis (4-formyl-1-piperazinyl) propane as a colorless oil. Concentrated hydrochloric acid (6.0 ml, 72 mmol) was then added to a solution in methanol (18 ml) of 1,3-bis (4-formyl-1-piperazinyl) propane (950 mg, 3.5 mmol) synthesized by the procedure above, and the mixture was stirred for 6 hours in a controlled bath at 65 ° C. The reaction mixture was concentrated under reduced pressure, and the resulting crude crystals were washed with ethanol and diethyl ether, thereby obtaining 960 mg (yield: 76%) of the title compound as a colorless crystalline powder [melting point: 260 ° C (decomposition)]. (1) GB 840358 1957.

REFERENCE EXAMPLE 2 Preparation of 1,4-bis (1-piperazinyl) benzene 1-Benzylpiperazine (2.8 ml, 16 mmol) and potassium carbonate (2.3 g, 17 mmol) were added to a solution of 1-chloro-4-nitrobenzene (2.0 g; 13 mmol) in dimethylformamide (0.5 ml), and the mixture was stirred for 7 hours in a controlled bath at 100 ° C. Water was added to the reaction mixture to carry out extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 2.9 g (yield: 76%) of 4- (4-benzyl-1-piperazinyl) -1-nitrobenzene as a colorless oil. 4- (4-Benzyl-1-piperazinyl) -1-nitrobenzene (2.6 g, 8.9 mmol) synthesized by the above procedure and zinc powder (3.2 g, 48 mmol) were added to a solution of calcium chloride (665 mg. 6.0 mmole) in water-ethanol-acetic acid (12 ml-55 ml-1.2 ml), and the mixture was stirred under reflux for 15 minutes in a controlled bath at 10 ° C. Insoluble substances were removed from the reaction mixture by suction filtration through Celite, and the filtrate was concentrated under reduced pressure. A saturated aqueous solution of sodium acid carbonate was added to the resulting concentrated residue to carry out extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The crude crystals obtained in this manner were recrystallized from benzene-n-hexane to obtain 2.3 g (yield: 96%) of 4- (4-benzyl-1-piperazinyl) aniline as light brown needles (melting point: 137-138). ° C). Bis (2-chloroethyl) amine hydrochloride (534 mg, 3.0 mmol) and sodium iodide (3.0 g, 20 mmol) were added to a solution in methanol (20 ml) of 4- (4-benzyl-1-piperazinyl). -aniline (1.1 g, 4.1 mmol) synthesized by the above procedure, and the mixture was stirred for 13 hours in a controlled bath at 70 ° C. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous solution of sodium acid carbonate was added to the resulting concentrated residue to carry out extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude oil was purified by silica gel column chromatography, thereby obtaining 775 mg of 4- (4-benzyl-1-piperazinyl) -1- (1-piperazinyl) benzene containing impurities as a oil. Trimethylamine (0.3 ml) was added; 2.2 mmol) and di-tert-butyl dicarbonate (450 mg, 2.1 mmol) to a solution of this oil (775 mg) in methylene chloride (5 ml) under ice-cooling, and the mixture was stirred for 30 minutes. A saturated aqueous solution of sodium acid carbonate was added to the reaction mixture to carry out extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining crude crystals (738 mg, yield: 42%) of 4- (4-benzyl-1-piperazinyl) -1- (4-ter- butoxycarbonyl-1-piperazinyl) -benzene. The crude crystals were recrystallized from chloroform-diethyl ether-n-hexane to obtain colorless flakes (melting point: 132-133 ° C). 10% palladium on carbon (104 mg) and concentrated hydrochloric acid (0.60 ml, 7.2 mmol) were added to a solution in methanol (10 ml) of 4- (4-benzyl-1-piperazinyl) -1- (4- tert-butoxycarbonyl-1-piperazinyl) benzene (354 mg, 0.81 mmol) synthesized by the above procedure. After the mixture was stirred for 12 hours in a controlled bath at 55 ° C under hydrogen, the catalyst was removed from the reaction mixture by filtration. Once the filtrate was concentrated under reduced pressure, a procedure of adding ethanol (10 ml) to the residue twice and concentrating the mixture under reduced pressure was carried out twice. The resulting concentrated residue was dissolved in water (5 ml), and potassium carbonate (400 mg, 2.9 mmol) and di-tert-butyl dicarbonate (1.0 g, 4.6 mmol) were added to this solution under cooling with ice. After the mixture was stirred for 30 minutes, the reaction mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 1,4-bis (4-tert-butoxycarbonyl-1-piperazinyl) benzene (59 ml, yield: 16%) as a colorless oil. Trifluoroacetic acid (1 m) was added to a methylene chloride solution (1 ml) of 1,4-bis (4-tert-butoxycarbonyl-1-piperazinyl) benzene (59 mg, 0.13 mmol) synthesized by the above procedure under ice cooling, and the mixture was stirred for 30 minutes. The reaction mixture was then concentrated under reduced pressure, and the resulting concentrated residue (81 mg) was dissolved in methanol-chloroform (1: 2). The solution was applied to a column packed with alumina (3 g), and the column was eluted with methanol-chloroform (1: 2). The eluted material was concentrated under reduced pressure, then obtaining 31 mg (yield: 88%) of the title compound as a colorless oil.

REFERENCE EXAMPLE 3 Preparation of methyl 2,2-bis (4-piperidinyl) -methacrylate dihydrochloride A 50% dispersion of sodium hydride in a mineral oil (6.6 g, 140 mmol) was added to a solution of di-tert-butyl malonate (10 g, 46 mmol) in dimethylformamide (100 ml) under ice cooling , and the mixture was stirred for 30 minutes. Then (4-chloromethyl) pyridine (1.6 g, 90 mmol) was added to this solution and the mixture was stirred for 30 minutes in a controlled bath at 70 ° C. The reaction mixture was poured into ice water and extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure, thereby obtaining crude crystals (17.1 g) of 2,2-bis [(4-pyridyl) methyl] di-tert-butyl malonate. The crude crystals (17.1 g) of di-tert-butyl 2,2-bis [(4-pyridyl) methyl] malonate synthesized by the above procedure were dissolved in trifluoroacetic acid (90 ml), and the solution was stirred at room temperature. environment for 30 minutes. The reaction mixture was concentrated under reduced pressure and the resulting concentrate was heated for 20 minutes in a controlled bath at 200 ° C and then dissolved in methanol (170 ml). 4N Hydrogen chloride in ethyl acetate (100 ml, 400 mmol) was added to the solution, and the mixture was stirred for 2 hours and then concentrated under reduced pressure. The resulting concentrated residue was made basic by the addition of 2.5 N aqueous sodium hydroxide and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 6.0 g (yield: 51%) of methyl 2,2-bis [(4-pyridyl) methyl] acetate as a colorless oil. Platinum oxide (1.2 g) was added to a solution in acetic acid (20 ml) of methyl 2,2-bis [(4-pyridyl) methyl] acetate (1.8 g, 7.1 mmol) synthesized by the above procedure, and the mixture was stirred for 12 hours in a controlled bath at 70 ° C under hydrogen. The catalyst was removed from the reaction mixture by filtration and the filtrate was concentrated under reduced pressure. The resulting concentrated residue was dissolved in methanol (20 ml). Then trimethylamine (10 ml, 72 mmol) and di-tert-butyl dicarbonate (8.4 g, 39 mmol) were added to this solution and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting concentrated residue was dissolved in ethyl acetate. The solution was washed successively with 3N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 3.1 g (yield: 95%) of methyl 2,2-bis [(1-tert-butoxycarbonyl-4-piperidinyl) methyl] acetate. as a colorless oil. 4N Hydrogen chloride in ethyl acetate (1.0 mL, 4.0 mmol) was added to a solution in ethyl acetate (0.5 mL) of 2,2-bis [(1-tert-butoxycarbonyl-4-piperidinyl) methyl] Methyl acetate (210 mg, 0.45 mmol) synthesized by the above procedure, and the mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The concentrated residue was suspended in diethyl ether and collected by filtration to obtain 16 mg (yield: 76%) of the title compound as a colorless crystalline powder (melting point: 269-271 ° C).

REFERENCE EXAMPLE 4 Preparation of 1,3-bis (1-tert-butoxycarbonyl-4-piperidinyl) -2- (dimethylamino) propane An aqueous solution of 5N sodium hydroxide (5 ml, 25 mmol) was added to a methanol solution (5 ml) of methyl 2,2-bis [(1-tert-butoxycarbonyl-4-piperidinyl) methyl] acetate ( 906 mg; 1.9 mmol) synthesized by the procedure described in reference example 3, and the mixture was stirred for 30 minutes in a controlled bath at 100 ° C. The reaction mixture was made acidic by the addition of 6N hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 861 mg (yield: 98%) of 2,2-bis [(1-tert-butoxycarbonyl-4-piperidinyl) methyl] acetic acid as a colorless oil. Triethylamine (0.39 ml, 2.8 mmol), diphenylphosphoryl azide (0.61 ml, 2.8 mmol) and benzyl alcohol (0.39 ml, 3.8 mmol) were added to a solution in toluene (10 ml) of 2,2-bis [(1) acid. -ter-butoxycarbonyl-4-piperidinyl) methy1] acetic acid (855 mg, 1.9 mmol) synthesized by the above procedure, and the mixture was stirred for 12 hours in a controlled bath at 100 ° C. The reaction mixture was concentrated under reduced pressure, and the resulting concentrated residue was dissolved in ethyl acetate. This solution was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 639 mg (yield: 61%) of 2-benzyloxycarbonylamino-1,3-bis (1-tert-butoxycarbonyl-4-piperidinyl) propane as a colorless oil. % palladium on carbon (125 mg) was added to an ethanol solution (10 ml) of 2-benzyloxycarbonylamino-1,3-bis [(tert-butoxycarbonyl-4-piperidinyl) propane (639 mg, 1.1 mmol) synthesized. by the above procedure, and the mixture was stirred for 3 hours in a controlled bath at 50 ° C under hydrogen. The catalyst was removed from the reaction mixture by filtration and the filtrate was concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 403 mg (yield: 83%) of 2-amino-1,3-bis (1-tert-butoxycarbonyl-4-piperidinyl). Propane as a colorless oil. An aqueous solution of 37% formaldehyde (0.75 ml, 10 mmol) and sodium cyanoborohydride (194 mg, 3.0 mmol) were added to a solution in acetonitrile (15 ml) of 2-amino-1,3-bis (1-). tert-butoxycarbonyl-4-piperidinyl) propane (373 mg, 0.88 mmol) synthesized by the above procedure, and the mixture was stirred at room temperature for 30 minutes. Then acetic acid was added to the solution to adjust the pH to about 5, and the mixture was stirred for an additional 30 minutes at room temperature. The reaction mixture was brought to a pH of about 10 by the addition of 2.5N aqueous sodium hydroxide and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 388 mg (yield: 98%) of the title compound as a colorless oil.

REFERENCE EXAMPLE S Preparation of 1,3-bis (1-tert-butoxycarbonyl-4-piperidinyl) -2- r (dimethylamino) methynpropane Under ice-cooling, calcium chloride (968 mg, 8.8 mmol) and sodium borohydride (668 mg, 17 mmol) were added to a solution in tetrahydrofuran-ethanol (9 ml-14 ml) of 2,2-bis (1 Methyl tert-butoxycarbonyl-4-piperidinyl] -methyl] acetate (1.0 g, 2.1 mmol) synthesized by the procedure described in Reference Example 3, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting concentrated residue was dissolved in chloroform. The solution was washed successively with 3N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 900 mg (yield: 96%) of 2,2-bis (1-tert-butoxycarbonyl-4-piperidinyl) -methyl alcohol] Ethyl as a colorless oil. Then pyridine (0.090 ml, 1.1 mmol), carbon tetrabromide (716 mg, 2.2 mmol) and triphenylphosphine (567 mg, 2.2 mmol) were added to a solution in diethyl ether (5 ml) of 2,2-bis (1) alcohol. -ter-butoxycarbonyl-4-piperidinyl) -methyl] ethyl (476 mg, 1.1 mmol) synthesized by the above procedure under ice-cooling, the ice bath was removed and the mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 465 mg (yield: 86%) of 1,3-bis (1-tert-butoxycarbonyl-4-piperidinyl) -2- (bromoethyl) Propane as a colorless oil. Dimethylamine hydrochloride (638 mg, 7.8 mmol), potassium carbonate (1.2 g, 8.7 mmol) and potassium iodide (144 mg, 0.87 mmol) were added to a solution in dimethylformamide (10 ml) of 1,3-bis ( 1-tert-butoxycarbonyl-4-piperidinyl) -2- (bromoethyl) propane (437 mg, 0.87 mmol) synthesized by the above procedure, and the mixture was stirred for 4 hours in a controlled bath at 60 ° C. A 0.1 N aqueous solution of sodium hydroxide was added to the reaction mixture to carry out the extraction with diethyl ether. The organic layer was washed is saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 243 mg (yield: 60%) of the title compound as a colorless oil.

REFERENCE EXAMPLE 6 Preparation of N, N-bisr (4-piperdinediDmethylmethylamine trichlorohydrate Sodium cyanoborohydride (440 mg, 7.0 mmol) was added to a solution of [(1-tert-butoxycarbonyl-4-piperidinyl) -methyl] amine (1.5 g, 7.0 mmol) in methanol (30 mL) under ice-cooling, and the mixture was stirred for 15 minutes. A solution of 1-tert-butoxycarbonyl-4-piperidinocarbaldehyde (1.4 g, 9.1 mmol) in methanol (5 ml) and acetic acid (0.40 ml, 7.0 mmol) was added to the resulting solution and the mixture was stirred for 4 hours. hours. After removing the ice bath, the mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the resulting concentrated residue was added to a saturated aqueous solution of sodium acid carbonate to carry out extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 1.83 g (yield: 63%) of N, N-bis [(1-tert-butoxycarbonyl-4-piperidinyl) methyl] amine as a colorless oil. Aqueous solution of 37% formaldehyde (5 ml, 67 mmol) and sodium cyanoborohydride (314 mg, 5.0 mmol) were added to a solution in acetonitrile (20 ml) of N, N-bis [(1-tert-butoxycarbonyl) -4-piperidinyl) -methyl] amine (1.0 g, 2.4 mmol) synthesized by the above procedure, and the mixture was stirred at room temperature for 15 minutes. Then acetic acid was added to the solution to adjust the pH to about 5, and the mixture was further stirred for 48 hours at room temperature. The reaction mixture was brought to a pH of about 10 by the addition of 2.5N aqueous sodium hydroxide and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 989 mg (yield: 95%) of N, N-bis [(1-tert-butoxycarbonyl-4-piperidinyl) methyl] - methylamine as a colorless oil. It was then added to a solution of 4N hydrogen chloride in ethyl acetate (5 ml, 20 mmol) in a methylene chloride solution (3 ml) of N, N-bis [(1-tert-butoxycarbonyl-4-p) Peridinyl) -methyl] methylamine (640 mg, 1.5 mmol) synthesized by the above procedure under ice-cooling. The ice bath was removed, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crude crystals were recrystallized from methanol-diethyl ether, thereby obtaining 412 mg (yield: 82%) of the title compound as colorless needles (melting point: 280 ° C or more).

REFERENCE EXAMPLE 7 Preparation of N, N'-bis (4-piperidinyl) -N, N'-dimethyl-ethylenediamine tetrahydrochloride Then 1-benzyl-4-piperidone (5.00 g, 26 mmol) and sodium cyanoborohydride (1.25 g, 20 mmol) were added to a solution of N, N'-dimethylethylenediamine (785 mg, 8.9 mmol) in methanol (20 ml. ) under cooling with ice. The ice bath was removed, acetic acid (2.5 ml, 44 mmol) was added to the solution, and the mixture was stirred for 15 minutes. Then potassium carbonate (3 g, 22 mmol) and a saturated aqueous solution of sodium acid carbonate were added to the reaction mixture to carry out the reaction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 955 mg (yield: 25%) of N, N'-bis (1-benzyl-4-piperidinyl) -N, N'-dimethylethylenediamine. as a colorless oil. 10% palladium on carbon (125 mg) and concentrated hydrochloric acid (1.2 ml, 14 mmol) were added to a solution in water-methanol (4 ml-8 ml) of N, N'-bis (1-benzyl-4). -peridinyl) -N, N'-dimethylethylenediamine (757 mg; 1. 7 mmoles) synthesized by the above procedure, and the mixture was stirred for 6 hours in a controlled bath at 55 ° C under hydrogen. The catalyst was removed from the reaction mixture by filtration, and the filtrate was concentrated under reduced pressure. The resulting crude crystals were washed with ethanol, thereby obtaining 497 mg (yield: 71%) of the title compound as a colorless crystalline powder [melting point: 275 ° C (decomposition)].

REFERENCE EXAMPLE 8 Preparation of 1,4-bis (4-p-pentydinyl) methy-piperazine tetrahydrochloride Then a solution of methanesulfonyl chloride (0.17 ml, 2.2 mmol) in methylene chloride (1 ml) was added to a solution in methylene chloride (3 ml) of alcohol (1-tert-butoxy-carbonyl-4-piperazinyl) methyl (400 mg, 1.9 mmol) and N, N-diisopropylethylamine (0.45 ml, 2.6 mmol) were cooled under ice, and the mixture was stirred for 2 hours. The ice bath was removed and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture to carry out extraction with ethyl acetate. The organic layer was washed successively with 0.1N hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure, thereby obtaining crude crystals (645 mg) of (1-tert-butoxycarbonyl-4-piperazinyl) methyl methanesulfonate. Piperazine (86 mg, 1.0 mmol), potassium carbonate (415 mg, 3.0 mmol) and potassium iodide (366 mg, 2.2 mmol) were added to a solution in dimethylformamide (7 ml) of the crude methanesulfonate crystals of (1 mg). -ter-butoxycarbonyl-4-piperazinyl) -methyl (645 mg, approximately 2.2 mmol) synthesized by the above procedure, and the mixture was stirred for 2 hours in a controlled bath at 80 ° C. Water was added to the reaction mixture to carry out the reaction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sulfate and then concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 205 mg (yield: 41%) of 1,4-bis [(1-tert-butoxycarbonyl-4-piperidinyl) methyl] piperaz. Like a colorless oil. 4N hydrogen chloride in ethyl acetate (4 mL, 16 mmol) was added to a methylene chloride solution (2 mL) of 1,4-bis [(1-tert-butoxycarbonyl-4-piperidinyl) methyl] -piperazine. (195 mg, 0.40 mmol) synthesized by the above procedure under cooling with ice, and the mixture was stirred for 30 minutes. The ice bath was removed and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting crude crystals were recrystallized from methylene chloride-methanol-diethyl ether, thereby obtaining 154 mg (yield: 84%) of the title compound as a colorless crystalline powder ( fusion, 280 ° C or higher).

EXAMPLE 1 Preparation of 1,2-bisr4-r (E, E) -5- (3,4,5-trimethoxyphenyl) -2,4-pentadienoyl-1-piperazinenethane dihydrochloride Oxalyl chloride (0.055 ml, 0.63 mmol) was then added to a solution of (E, E) -5- (3,4,5-trimethoxyphenyl) -2,4-pentadienoic acid (16 mg, 0.44 mmol) in dimethylformamide-methylene chloride (0.1 ml-5 ml) under ice-cooling. The ice bath was removed, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain crude crystals of (E, E) -5- (3,4,5-trimethoxyphenyl) -2,4-pentadienoyl chloride. N, N-diisopropylethylamine (0.12 ml, 0.69 mmol) was added to a methylene chloride solution (3 ml) of 1,2-bis (1-piperazinyl) ethane tetrahydrochloride (69 mg, 0.20 mmol) synthesized by the same procedure than that of reference example 1 under cooling with ice. A solution in methylene chloride (3 ml) of (E, E) -5- (3,4,5-trimethoxyphenyl) -2,4-pentadienoyl was synthesized by the above procedure was added dropwise to this solution under cooling with ice.

After concluding the addition, the mixture was stirred for 1 hour. A 5% aqueous solution of sodium acid carbonate was added to the reaction mixture to carry out extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 133 mg (yield: 99%) of 1,2-bis [4 - [(E, E) -5- (3,4, 5-trimethoxyphenyl) -2,4-pentadienoyl] -1-piperazinyl] ethane as a colorless oil. Concentrated hydrochloric acid (0.050 ml, 0.60 mmol) was added to an ethanol solution (5 ml) of 1,2-bis [4 - [(E; E) -5- (3,4,5-trimethoxyphenyl) -2 , 4-pentadienoyl] -1-pyrrazinyl] ethane (128 mg, 0.19 mmoles) synthesized in the manner described in the above procedure, and the reaction mixture was concentrated under reduced pressure. A process of adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure was then carried out twice, and the resulting concentrated residue was recrystallized from methanol-diethyl ether to obtain the title compound as a yellow crystalline powder. Clear. Melting point: 265-267 ° C. H-NMR (data of the free base of the title compound) (DMSO-dβ> 120 ° C) d: 2.80-2.90 (m, 12H), 3.54 (dd, J = 5.0, 5.0 Hz, 8H), 3.72. (s, 6G), 3.82 (s, 12H), 6.62 (d, J = 14.7 Hz, 2H), 6.80 (s, 4H), 6.81 (d, J = 15.4 Hz, 2H), 6.96 (dd, J = 15.4, 10.7 Hz, 2H), 7.19 (d, J = 14.7, 10.3 Hz, 2H).

EXAMPLE 2 Preparation of 1,2-bisr4-r4- (3,4,5-trimethoxy-phenyl) -benzoyl-1-piperazinyl-methane dihydrochloride According to the same procedure as that of example 1, 1,2-bis [4- [4- (3,4,5-trimethoxypheni) benzoyl] -1-piperazinyl] ethane (84 mg, yield: 71%) was obtained ) as a colorless oil of 4- (3,4,5-trimethoxyphenyl) benzoic acid (97 mg, 0.34 mmol) and 1,2-bis (1-piperazinyl) ethane tetrahydrochloride (55 mg, 0.16 mmol) synthesized by the same procedure used in reference example 1. Concentrated hydrochloric acid (0.028 ml, 0.34 mmol) was added to a solution of 1,2-bis [4- [4- (3,4,5-trimethoxyphenyl) benzoyl] -1-piperazinyl] ethane (84 mg, 0.1 1 mmol) in ethanol (5 ml), and the reaction mixture was concentrated under reduced pressure. A procedure consisting of adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure was carried out twice. The resulting crude crystals were suspended in methanol, and collected by filtration to obtain the title compound as a colorless crystalline powder. Melting point: 282-285 ° C. ^ -NMR (data from the free base of the title compound) (DMSO-de, 120 ° C) d: 2.40-2.70 (m, 12H), 3.40-3.60 (m, 4H), 3.70-3.90 (m, 4H) ), 3.74 (s, 6H), 3.90 (s, 12H), 6.77 (s, 4H), 7.47 (d, J = 8.3 Hz, 4H), 7.59 (d, J = 8.3Hz, 4H).

EXAMPLE 3 Preparation of 1,3-bis-4-di (E, E) -5- (3,4,5-trimethoxyphenyl) -2,4-pentadienoin-1-piperazinepropane dihydrochloride According to the same procedure used in example 1, 1,3-bis [4 - [(E, E) -5- (3,4,5-trimethoxyphenyl) -2,4-pentadienoyl] -1- was obtained piperazinyl] propane 135 mg; yield: 86%) as a pale yellow oil from (E, E) -5- (3,4,5-trimethoxyphenyl) pentadienoic acid (130 mg, 0.49 mmole) and 1,3-bis (1-, 1-tetrahydrochloride) piperazinyl) propa or (80 mg, 0.22 mmol) synthesized by the procedure described in reference example 1. Concentrated hydrochloric acid (0.040 ml, 0.48 mmol) was added to a solution of 1,3-bis [4 - [(E) , E) -5- (3,4,5-trimethoxyphenyl) -2,4-pentadienoyl] -1-piperazinyljpropane (130 mg, 0.19 mmol) in ethanol (5 ml), and the reaction mixture was concentrated under reduced pressure . After a procedure consisting of adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure was carried out twice, the resulting concentrated residue was recrystallized from methanol-diethyl ether to obtain the title compound as a pale yellow crystalline powder. Melting point: 263-265 ° C. 1 H-NMR (DMSO-de, 120 ° C) (no NH + proton of the ammonium salt was observed) d: 2.15-2.30 (m, 2H), 2.80-3.30 (m, 16H), 3.73 (s, 6H) , 3.82 (s, 12H), 3.85-4.00 (m, 4H), 6.65 (d, J = 14.7 Hz, 2H), 6.81 (s, 4H), 6.87 (d, J = 15.4 Hz, 2H), 6.97 ( dd, J = 15.4, 9.7 Hz, 2H), 7.27 (dd, J = 14.7, 9.7 Hz, 2H).

EXAMPLE 4 Preparation of 1,3-bisr4-ITE.E) -5- (4-ter) -butyl-2-methoxyphenyl) -2,4-pentadienoiH-1-piperazinepropropane dihydrochloride According to the same procedure used in example 1, 1,3-bis [4 - [(E, E) -5- (4-tert-butyl-2-methoxyphenyl) -2,4-pentadienoyl] -1- was obtained piperazinyljpropane (52 mg, yield: 75%) as a pale yellow oil from (E, E) -5- (4-tert-butyl-2-methoxyphenyl) -2,4-pentadienoic acid (57 mg, 0.22 mmol) and 1,3-bis (1-piperazinyl) propane tetrachlorohydrate (35 mg, 0.10 mmol) synthesized by the procedure described in reference example 1. Concentrated hydrochloric acid (0.025 ml, 0.30 mmol) was added to a solution of 1, 3-bis [4 - [(E, E) -5- (4-tert-butyl-2-methoxyphenyl) -2,4-pentadienoyl] -1-piperazinyl] propane (49 mg, 0.070 mmol) in ethanol (5 ml) , and the reaction mixture was concentrated under reduced pressure. A procedure was carried out twice which consisted in adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure, to obtain the title compound as a pale yellow amorphous powder. 1 H-NMR (data of the free base of the title compound) (DMSO-de, 120 ° C) d: 1.30 (s, 18H), 1.58-1.67 (m, 2H), 2.33-2.43 (m, 12H), 3.49-3.59 (m, 8H), 3.85 (s, 6H), 6.57 (d, J = 14.6 Hz, 2H), 6.90-7.01 (m, 6H), 7.04 (d, J = 15.6 Hz, 2H), 7.20 (dd, J = 14.6, 10.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H).

EXAMPLE 5 Preparation of 1,3-bisr4-r4- (3,4,5-trimethoxyphenyl) benzop-1-piperazinylpropane dihydrochloride According to the same procedure used in Example 1, 1,3-bis [4- [4- (3,4,5-trimethoxyphenyl) benzoyl] -1-piperazinyl] propane (43 mg, yield: 57%) was obtained ) as a colorless oil from 4- (3,4,5-trimethoxyphenyl) benzoic acid (64 mg, 0.21 mmol) and 1,3-bis (1-piperazinyl) propane tetrahydrochloride (35 mg, 0.10 mmol) synthesized by the procedure described in reference example 1. Concentrated hydrochloric acid (0.015 ml, 0.18 mmole) was added to a solution of 1,3-bis [4- [4- (3,4,5-trimethoxypheni) benzo] 1-piperazinyl] propane (43 mg, 0.050 mmol) in ethanol (5 ml), and the reaction mixture was concentrated under reduced pressure. After a procedure consisting of adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure was carried out twice, the resulting concentrated residue was recrystallized from methanol-diethyl ether to obtain the title compound as a colorless crystalline powder. Melting point: 262-265 ° C. 1 H-NMR (DMSO-d 6, 120 ° C) (no NH + proton of the ammonium salt was observed) d: 2.05-2.20 (m, 2H), 2.60-3.40 (m, 12H), 3.75 (s, 6H) , 3.72-3.84 (m, 8H), 3.87 (s, 12H), 6.92 (s, 4H), 7.49 (d, J = 8.0Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H).

EXAMPLE 6 Preparation of 1,3-bis-4-lTE) -5- (3,4,5-trimethoxyphenyl) -2- penten-4-inoip-1-piperazinepropane dihydrochloride In accordance with the same procedure used in example 1, 1,3-bis [4 - [(E) -5- (3,4,5-trimethoxyphenyl) -2-penten-4-yno] - 1-piperazinyl] propane (14mg, yield: 81%) as a pale yellow oil from (E) -5- (3,4,5-trimethoxyphenyl) -2-penten-4-ylco ( 1 10 mg, 0.42 mmol) and 1,3-bis (1-piperazinyl) propane tetrachlorohydrate (72 mg, 0.2 mmol) synthesized by the procedure described in reference example 1. Concentrated hydrochloric acid (0.060 ml; mmoles) to a solution of 1,3-bis [4 - [(E) -5- (3,4,5-trimethoxyphenyl) -2-penten-4-ynyl] -1-piperazinyl] propane (114 mg, 0.15 mmoles) in ethanol (5 ml), and the reaction mixture was concentrated under reduced pressure. After a procedure consisting of adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure was carried out twice, the resulting concentrated residue was recrystallized from ethanol-diethyl ether to obtain the title compound as a pale yellow crystalline powder. Melting point: 235-237 ° C. 1 H-NMR (DMSO-d 6, 120 ° C) (no NH 4 proton of the ammonium salt was observed) d: 2.11-2.23 (m, 2H), 2.70-3.25 (m, 12H), 3.74 (s, 6H) , 3.80 (s, 12H), 3.82-4.01 (m, 8H), 6.77 (s, 4H), 6.80 (d, J = 15.3Hz, 2H), 7.01 (d, J = 15.3Hz, 2H).

EXAMPLE 7 Preparation of 1,3-bis-4-f3-3,4,5-trirnetoxyphenyl) -2-propinoin-1-piperazinylpropane 1,3-Bis (1-piperazinyl) propane tetrahydrochloride (57 mg, 0.16 mmol) synthesized by the procedure described in Reference Example 1 and N, N-diisopropylethylamine (0.28 mL, 1.6 mmol) was added to a solution of (3- (3,4,5-trimethoxyphenyl) -2-propynoic acid (80 mg, 0.34 mmol) in tetrahydrofuran (3 ml) Diethyl phosphocyanurate (0.055 ml, 0.37 mmol) was added gradually to the mixture under cooling in The ice bath was stirred, the mixture was stirred at room temperature for 1 hour, and water was added to the reaction mixture to carry out extraction with chloroform.The organic layer was washed with saturated brine, dried over Anhydrous sodium sulfate was then concentrated under reduced pressure.The resulting crude oil was purified by column chromatography on silica gel to obtain crude crystals.The crude crystals obtained in this way were recrystallized from chloroform-acetone-diethyl ether Oth to obtain 75 mg (yield: 72%) of the title compound as colorless needles. Melting point: 214-215 ° C. 1 H-NMR (DMSO-de, 120 ° C) d: 1.66 (tt, J = 7.1, 7.1 Hz, 2H), 2.40-2.53 (m, 4H), 3.50-3.88 (m, 16H), 3.77 (s, 6H), 3.82 (s, 12H), 6.84 (s, 4H).

EXAMPLE 8 Preparation of 1,3-bis-4-r5-nitro-2- (3,4,5-trimethoxyphenyl) benzoin-1-piperazinepropane dihydrochloride According to the same procedure used in Example 7, 1,3-bis [4- [5-nitro-2- (3,4,5-trimethoxyphenyl) benzoyl] -1-piperazinyl] propane (234 mg; yield: 69%) as a pale yellow oil from 5-nitro-2- (3,4,5-trimethoxyphenyl) -benzoic acid (280 mg, 0.84 mmol) and 1,3-bis (1-piperazinyl) tetrachlorohydrate propane (143 mg, 0.40 mmol) synthesized by the procedure described in reference example 1. Concentrated hydrochloric acid (0.090 ml, 1.1 mmol) was added to a solution of 1,3-bis [4- [5-nitro] 2- (3,4,5-Tr.methoxyphenyl) benzoyl] -1-piperazinylpropane (230 mg, 0.27 mmol) in ethanol (5 mL), and the reaction mixture was concentrated under reduced pressure. A procedure was carried out twice which consisted in adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure, to obtain the title compound as a pale yellow amorphous powder. 1 H-NMR (DMSO-de, 120 ° C) (no NH + proton of the ammonium salt was observed) d: 1.80-1.95 (m, 2H), 2.70-2.80 (m, 4H), 2.60-3.50 (m, 16H), 3.74 (s, 6H), 3.81 (s, 12H), 6.75 (s, 4H), 7.77 (d, J = 8.5Hz, 2H), 8.19 (d, J = 2.4Hz, 2H), 8.28 ( dd, J = 8.5, 2.4Hz, 2H).

EMPLO 9 Preparation of 1, 3-bisr4-r5-amino-2 - (3,4,5-trimethoxypheni-benzoip-1-piperazinylpropane dihydrochloride % Palladium on carbon (50 mg) was added to a solution in acetic acid-methanol (1 ml-1 ml) of 1,3-bis [4- [5-nitro-2- (3,4) dihydrochloride] 5-trimethoxyphenyl) benzoyl] -1-piperazinyl] -propane (91 mg, 0.10 mmol) synthesized by the procedure described in Example 8. After the mixture was stirred at room temperature for 3 hours under hydrogen, the catalyst it was removed from the reaction mixture by filtration. The filtrate was concentrated under reduced pressure, and a saturated aqueous solution of sodium acid carbonate was added to the resulting concentrated residue to carry out extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 29 mg (yield: 37%) of 1,3-bis [4- [5-amino-2- (3,4,5- trimethoxyphenyl) benzoyl] -1-piperazinyl] propane as a colorless oil. Concentrated hydrochloric acid (0.020 ml, 0.24 mmol) was added to a solution of 1,3-bis [4- [5-amino-2- (3,4,5-trimethoxyphenyl) benzoyl] -1-piperazinyl. ] propane (29 mg, 0.030 mmol) in ethanol (5 ml), and the reaction mixture was concentrated under reduced pressure. After a procedure was carried out twice consisting of adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure, the resulting concentrated residue was recrystallized from methylene chloride-diethyl ether to obtain the title compound as a pale yellow crystalline powder. Melting point: 230 ° C (decomposition). 1 H-NMR (DMSO-de, 120 ° C) (no NH + proton of the ammonium salt was observed) d: 1.90-2.15 (m, 2H), 2.60-3.01 (m, 4H), 3.20-4.50 (m, 16H), 3.73(s, 6H), 3.78 (s, 12H), 6.60 (s, 4H), 6.72 (br s, 2H), 6.86 (br d, J = 8.2 Hz, 2H), 7.23 (br d, J = 8.2 Hz , 2H).

EXAMPLE 10 Preparation of 1,3-bstr4-r (E, E) -5- (4-trifluoromethylphenyl) -2,4-pentadienoin-1-piperazine-propane dihydrochloride According to the same procedure used in example 7, 1,3-bis [4 - [(E, E) -5- (4-trifluoromethylphenyl) -2,4-pentadienoyl] -1-piperazinyl] propane ( 11 1 mg, yield: 84%) as a colorless amorphous powder from (E, E) -5- (4-trifluoromethylphenyl) -2,4-pentadienoic acid (107 mg, 0.44 mmol) and tetrachlorohydrate from 1.3 bis (1-piperazinyl) propane (72 mg, 0.20 mmol) synthesized by the procedure described in reference example 1. Concentrated hydrochloric acid (0.040 ml, 0.48 mmol) was added to a solution of 1.3-bs [4 - [(E, E) -5- (4-trifluoromethylphenyl) -2,4-pentadienoyl] -1-piperazinyl] propane (11.1 mg, 0.16 mmol) in ethanol (5 ml), and the mixture of The reaction was concentrated under reduced pressure. After a procedure consisting of adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure was carried out twice, the resulting concentrated residue was recrystallized from ethanol-diethyl ether to obtain the title compound as a colorless crystalline powder. Melting point: 241 ° C (decomposition). 1 H-NMR (DMSO-de, 120 ° C) (NH + proton of the ammonium salt was not observed) d: 2.20 (t, J = 7.3 Hz, 2H), 2.55-3.65 (m, 12H), 3.75-4.20 (m, 8H), 6.76 (d, J = 14.6 Hz, 2H), 7.03 (d, J = 15.6 Hz, 2H), 7.15 (dd, J = 15.6, 10.4 Hz, 2H), 7.30 (dd, J = 14.6, 10.4 Hz, 2H), 7.65-7.73 (m, 8H).

EXAMPLE 11 Preparation of dimethanesulfonate of 1,4-bisr4-r4- (3,4,5-trimethoxyfen-di-benzoyl-1-piperazinipbutane According to the same procedure used in Example 7, 1,4-bis [4- [4- (3,4,5-trimethoxyphenyl) benzoyl] -1-piperazinyl] butane (110 mg, yield: 84%) was obtained ) as a colorless oil from 4- (3,4,5-trimethoxyphenyl) benzoic acid (103 mg, 0.36 mmol) and 1,4-bis (1-piperazinyl) butane tetrahydrochloride (63 mg, 0.17 mmol) synthesized by the same procedure used in Reference Example 1. An aqueous solution of 0.1 M methanesulfonic acid (3.0 mL, 0.30 mmol) was added to a solution of 1,4-bis [4- [4- (3,4, 5-trimethoxyphenyl) benzoyl] -1-piperazinyl] butane (110 mg, 0.14 mmol) in ethanol (15 ml), and the reaction mixture was concentrated under reduced pressure. After a procedure was carried out 3 times which consisted in adding ethanol (15 ml) to the residue and concentrating the mixture under reduced pressure, the resulting concentrated residue was recrystallized from methanol-diethyl ether to obtain the title compound as colorless prisms. Melting point: 166-169 ° C (decomposition). 1 H-NMR (DMSO-de, 120 ° C) (no NH + proton of the ammonium salt was observed) d: 1.70-1.80 (m, 4H), 2.38 (s, 6H), 2.90-3.20 (m, 16H) , 3.76 (s, 6H), 3.87 (s, 12H), 3.70-3.90 (m, 4H), 6.92 (s, 4H), 7.50 (d, J = 8.3 Hz, 4H), 7.72 (d, J = 8.3 Hz, 4H).

EXAMPLE 12 Preparation of 1,8-bisr4-r (E.E) -5- (4-tert-butylphenyl) -2,4-pentadienoin-1-piperazininoctane dihydrochloride According to the same procedure used in Example 7, 1 s, 8-bis [4 - [(E, E) -5- (4-tert-butylphenyl) -2,4-pentadienoyl] -1-piperazinyl-octane (105 mg) was obtained. Yield: 72%) as a colorless oil from (E, E) -5- (4-tert-butylphenyl) -2,4-pentadienoic acid (101 mg, 0.40 mmol) and 1,8-bis (1-tetrahydrochloride) -piperazinyl] octane (86 mg, 0.20 mmol) synthesized by a procedure similar to the procedure described in reference example 1. Concentrated hydrochloric acid (0.050 ml, 0.60 mmol) was added to a solution of 1,8-bis [4-]. [(E, E) -5- (4-tert-butylphenyl) -2,4-pentadienoyl] -1-piperazinyl-octane (105 mg, 0.14 mmol) in ethanol (5 ml), and the reaction mixture was concentrated under reduced pressure. After a procedure was carried out twice consisting of adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure, the resulting concentrated residue was recrystallized from methanol-diethyl ether to obtain the title compound as a colorless crystalline powder. Melting point: 288-290 ° C. 1 H-NMR (DMSO-de, 120 ° C) (no NH + proton of the ammonium salt was observed) d: 1.27 (s, 18H), 1.28-1.32 (m, 8H), 1.43-1.46 (m, 4H) , 2.30-2.34 (m, 4H), 2.38 (dd, J = 5.1, 5.1 Hz, 8H), 3.54 (dd, J = 5.1, 5.1 Hz, 8H), 6.60 (d, J = 14.6Hz, 2H), 6.86 (d, J = 15.6Hz, 2H), 6.95 (dd, J = 15.6, 10.2Hz, 2H), 7.21 (dd, J = 14.6, 10.2Hz, 2H), 7.36 (d, J = 8.5Hz, 4H ), 7.41 (d, J = 8.5Hz, 4H).

EXAMPLE 13 Preparation of 1, 8-bisr4-f (E, E) -5- (2-methylthio-3-pyridyl) -2,4-pentadienoyl-1-piperazinipoctane dihydrochloride According to the same procedure used in Example 7, a pale yellow oil containing 1,8-bis [4 - [(E, E) -5- (2-methylthio-3-pyridyl) -2.4 was obtained. -pentadienoyl] -1-piperazinyl] -octane from (E, E) -5- (2-methylthio-3-pyridyl) -2,4-pentadienoic acid (114 mg, 0.44 mmol) and tetrahydrochloride of 1 , 8-bis (1-piperazinyl) octane (86 mg, 0.20 mmol) synthesized by a procedure similar to the procedure described in reference example 1. Concentrated hydrochloric acid (0.085 ml, 1.0 mmol) was added to a solution of this oil pale yellow in ethanol (5 ml), and the reaction mixture was concentrated under reduced pressure. After a procedure consisting of adding ethanol (10 ml) to the residue twice and concentrating the mixture under reduced pressure was carried out twice, the resulting concentrated residue was recrystallized from ethanol-diethyl ether to obtain 71 mg (yield: 47%) of the title compound as a pale yellow crystalline powder. Melting point: 190 ° C (decomposition). 1 H-NMR (data for the free base of the title compound) (CDCl 3) d: 1.20-1.40 (m, 8H), 1.40-1.60 (m, 4H), 2.30-2.40 (m, 4H), 2.40-2.50 ( m, 8H), 2.59 (s, 6H), 3.50-3.80 (m, 8H), 6.48 (d, J = 14.9Hz, 2H), 6.83 (dd, J = 15.3, 10.0Hz, 2H), 7.00 (dd) , J = 7.6, 4.8Hz, 2H), 7.08 (d, J = 15.3Hz, 2H), 7.47 (dd, J = 14.9, 10.0Hz, 2H), 7.64 (dd, J = 7.6, 1.7Hz, 2H) , 8.37 (dd, J = 4.8, 1.7Hz, 2H).

EXAMPLE 14 Preparation of 1,4-bislT4-r4- (3,4,5-trimethoxyphenyl) benzoyl-1-piperazinylmethylcyclohexane dihydrochloride According to the same procedure used in Example 7, crude crystals (118 mg) of 1,4-bis [[4- [4- (3,4,5-trimethoxy-phenyl) benzoyl] -1 were obtained. -piperazinyl] methyl] cyclohexane from 4- (3,4,5-trimethoxyphenyl) benzoic acid (122 mg, 0.44 mmol) and 1,4-bis [(1-piperazinyl) methyl] -cyclohexane tetrachlorohydrate (85 mg, 0.20 mmol) synthesized by a procedure similar to the procedure described in reference example 1. Concentrated hydrochloric acid (0.050 ml, 0.60 mmol) was added to a solution of the crude crystals of 1,4-bis [[4] - [4- (3,4,5-trimethoxyphenyl) benzoyl] -1-piperazinyl] -methyl] cyclohexane (118 mg, 0.14 mmol) in ethanol (5 ml), and the reaction mixture was concentrated under reduced pressure. After a procedure consisting of adding ethanol (10 ml) to the residue twice and concentrating the mixture under reduced pressure was carried out twice, the resulting concentrated residue was recrystallized from chloroform-methanol-diethyl ether to obtain 105 mg (yield: 58%) of the title compound as a pale yellow crystalline powder. Melting point: 280 ° C or more. 1 H-NMR (data for the free base of the title compound) (CDCl 3) d: 0.80-0.90 (m, 4H), 1.85-2.05 (m, 2H), 1.80-1.90 (m, 4H), 2.16 (d, J = 7.0Hz, 4H), 2.25-2.60 (m, 8H), 3.40-3.80 (m, 8H), 3.89 (s, 6H), 3.93 (s, 12H), 6.77 (s, 4H), 7.47 (d , J = 8.2Hz, 4H), 7.58 (d, J = 8.2Hz, 4H).

EXAMPLE 15 Preparation of 1,4-bislT4-r (E, E) -5- (4-chloropheni0-2.4-pentadienoip-l-piperazine methylcyclohexane dihydrochloride According to the same procedure used in Example 7, crude crystals (72 mg) of 1,4-bis [[4 - [(E, E) -5- (4-chlorophenyl) -2,4-pentadienoyl were obtained. ] -1-piperazinyl] methyl] cyclohexane from (E, E) -5- (4-chlorophenyl) -2,4-pentadienoic acid (92 mg, 0.44 mmol) and 1,4-bis-tetrahydrochloride [(1)] piperazinyl) methyl] cyclohexane (85 mg, 0.20 mmol) synthesized by a procedure similar to the procedure described in reference example 1. Concentrated hydrochloric acid (0.030 ml, 0.36 mmol) was added to a solution in ethanol (5 ml) of the crude crystals (72 mg, 0.090 mmol) of 1,4-bis [[4 - [(EE) -5- (4-chlorophenyl) -2,4-pentadienoyl] -1-piperazinyljmethyl] -cyclohexane, and the mixture of reaction was concentrated under reduced pressure. After a procedure was carried out twice consisting of adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure, the resulting concentrated residue was recrystallized from methanol-diethyl ether to obtain 66 mg (yield: 50%) of the title compound as a colorless crystalline powder. Melting point: 284 ° C (decomposition). 1 H-NMR (data for the free base of the title compound) (CDCl 3) d: 0.80-1.00 (m, 4H), 1.40-1.50 (m, 2H), 1.75-1.95 (m, 4H), 2.15 (d, J = 7.3Hz, 4H), 2.30-2.51 (m, 8H), 3.50-3.80 (m, 8H), 6.46 (d, J = 14.6Hz, 2H), 6.79 (d, J = 15.6Hz, 2H), 6.87 (d, J = 15.6, 10.0Hz, 2H), 7.29-7.39 (m, 8H), 7.42 (dd, J = 14.6, 10.0Hz, 2H).

EXAMPLE 16 Preparation of 1,4-bis-T4-r4- (3,4,5-trimethoxyphenyl) benzo-p-1-piperazinylmethylbenzene dihydrochloride According to the same procedure used in example 7, 1,4-bis [[4- [4- (3,4,5-trimethoxyphenyl) benzoyl] -1-piperazinyl] methyl] benzene was obtained (157 mg, yield: 96%) as a colorless oil from 4- (3,4,5-trimethoxyphenyl) benzoic acid (122 mg, 0.44 mmol) and 1,4-bis [(1-piperazine) tetrachlorohydrate] methyl] benzene (84 mg, 0.20 mmol) synthesized by a procedure similar to the procedure described in reference example 1. Concentrated hydrochloric acid (0.065 ml, 0.78 mmol) was added to a solution of 1,4-bis [4- [4- (3,4,5-trimethoxyphenyl) benzoyl] -1-piperazinyl] methyl] benzene (157 mg, 0.19 mmol) in ethanol (5 ml), and the reaction mixture was concentrated under reduced pressure. After a procedure consisting of adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure was carried out twice, the resulting concentrated residue was recrystallized from chloroform-methanol-diethyl ether to obtain the compound of title as a colorless crystalline powder. Melting point: 264 ° C (decomposition). 1 H-NMR (DMSO-de, 120 ° C) (NH + proton of the ammonium salt was not observed) d: 2.65-3.10 (m, 8H), 3.75 (s, 6H), 3.82-3.86 (m, 8H) , 3.86 (s, 12H), 4.15-4.30 (m, 4H), 6.91 (s, 4H), 7.46 (d, J = 8.2Hz, 4H), 7.63 (s, 4H), 7.69 (d, J = 8.2 , 4H).

EXAMPLE 17 Preparation of 1,4-bis | T4-r (E) -5- (3A5-trimethoxyphenyl) -2- penten-4-inoly1-1-piperazinylmethoxybenzene dihydrochloride According to the same procedure used in Example 7, 1,4-bis [[4 - [(E) -5- (3,4,5-trimethoxyphenyl) -2-penten-4-ynyl] -1 was obtained. -piperazinyl] methyl] benzene (127 mg, yield: 83%) as a pale yellow oil from (E) -5- (3,4,5-trimethoxyphenyl) -2-penten-4-ynoic acid (15) mg, 0.44 mmol) and 1,4-bis [(1-piperazinyl) methyl] benzene tetrahydrochloride (84 mg, 0.20 mmol) synthesized by a procedure similar to the procedure described in Reference Example 1. Concentrated hydrochloric acid ( 0.055 mL; 0.66 mmol) to a solution of 1,4-bis [[4 - [(E) -5- (3,4,5-trimethoxyphenyl-2-penten-4-ynyl] -1-piperazinyl] methyl] benzene (127 mg, 0.16 mmol) in ethanol (5 ml), and the reaction mixture was concentrated under reduced pressure, after which a procedure consisting of adding ethanol (10 ml) to the residue and concentrating twice was carried out. the mixture under reduced pressure, the resulting concentrated residue was recrystallized from chloride of methylene-methanol-diethyl ether to obtain the title compound as a pale yellow crystalline powder. Melting point: 268 ° C (decomposition). 1 H-NMR (DMSO-de, 120 ° C) (no NH + proton of the ammonium salt was observed) d: 1.70-3.40 (m, 12H), 3.65-3.90 (m, 4H), 3.74 (s, 6H) , 3.79 (s, 12H), 4.00-4.25 (m, 4H), 6.77 (s, 4H), 6.78 (d, J = 15.3Hz, 2H), 6.98 (d, J = 15.3Hz, 2H), 7.58 ( s, 4H).

EXAMPLE 18 Preparation of 1,4-bisrr4-r (E.E) -5- (3,4,5-Trimethylphenin-2,4-pentadiene-H-1-piperazinophenyl) benzene dihydrochloride According to the same procedure used in example 7, 1,4-bis [[4 - [(E, E) -5- (3,4,5-trimethylphenyl) -2,4-pentadienol] -1 was obtained piperazinyl] methyl] benzene (100 mg) as a colorless crystalline powder from (E, E) -5- (3,4,5-trimethylphenyl) -2,4-pentadienoic acid (95 mg, 0.44 mmol) and (1,4-bis [(1-piperazinyl) methyl] benzene tetrahydrochloride (84 mg, 0.20 mmol) synthesized by a procedure similar to the procedure described in reference example 1. Concentrated hydrochloric acid (0.050 ml, 0.60 mmol) was added. ) to a solution of 1,4-bis [[4 - [(E, E) -5- (3,4,5-trimethylphenyl) -2,4-pentadienoyl] -1-piperazinyl] methyl] benzene ( 100 mg, 0.14 mmol) in ethanol (5 ml), and the reaction mixture was concentrated under reduced pressure, after which a procedure consisting of adding ethanol (10 ml) to the residue and concentrating the mixture was carried out twice. under reduced pressure, the resulting concentrated residue was recrystallized from methanol-diethyl ether NaHCO3 to obtain 69 mg (yield: 47%) of the title compound as a colorless crystalline powder. Melting point: 278 ° C (decomposition). 1 H-NMR (data from the free base of the title compound) (DMSO-de, 120 ° C) d: 2.13 (s, 6H), 2.24 (s, 12H), 2.38-2.44 (m, 8H), 3.51 (s, 4H), 3.52-3.60 (m, 8H), 6.58 (d, J = 14.6 Hz, 2H), 6.78 (d, J = 15.6 Hz, 2H), 6.91 (dd, J = 15.6, 10.7 Hz, 2H), 7.10 (s, 4H), 7.19 (dd, J = 14.6, 10.7 Hz, 2H), 7.26 (s, 4H).

EXAMPLE 19 Preparation of 2,6-bislT4-r4-3.4,5-trimethoxyphenyl) benzoyl-1-piperazine-U-methylpyridine dihydrochloride According to the same procedure used in Example 7, 2,6-bis [[4- [4- (3,4,5-trimethoxyphenyl) benzoyl] -1-piperazinyl] methyl] pyridine was obtained (157 mg, yield: 96%) as a colorless oil from 4- (3,4,5-trimethoxyphenyl) benzoic acid (126 mg, 0.44 mmol) and 2,6-bis [(1-piperazinyl) tetrahydrochloride] methyl] pyridine (84 mg, 0.20 mmol) synthesized by a procedure similar to the procedure described in reference example 1. Concentrated hydrochloric acid (0.080 ml, 0.96 mmol) was added to a solution of 2,6-bis [[4-] [4- (3,4,5-trimethoxyphenyl) benzoyl] -1-piperazinyl] methyl] pyridine (157 mg, 0.19 mmol) in ethanol (5 ml), and the reaction mixture was concentrated under reduced pressure. After a procedure consisting of adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure was carried out twice, the resulting concentrated residue was recrystallized from methanol-diethyl ether to obtain the title compound as a colorless crystalline powder. Melting point: 224-226 ° C. 1 H-NMR (DMSO-de, 120 ° C) (no NH + proton of the ammonium salt was observed) d: 1.70-3.60 (m, 8H), 3.75 (s, 6H), 3.86 (s, 12H), 3.86 -4.01 (m, 8H), 4.35-4.50 (m, 4H), 6.91 (s, 4H), 7.48 (d, J = 8.2Hz, 4H), 7.54 (d, J = 7.8 Hz, 2H), 7.70 ( d, J = 8.2 Hz, 4H), 7.92 (t, J = 7.8 Hz, 1 H).

EXAMPLE 20 Preparation of 2,6-bislT4-r (E) -3- (2-naphthyl) -2-propenoiri-1-piperazinylmethylpyridine According to the same procedure used in example 7, crude crystals were obtained from (E) -3- (2-naphthyl) -2-propenoic acid (87 mg, 0.44 mmol) and 2,6-bis tetrahydrochloride [(1-piperazinyl) methyl] pyridine (92 mg, 0.22 mmol) synthesized by a procedure similar to the procedure described in reference example 1. The crude crystals obtained in this manner were recrystallized from chloroform-n-hexane to obtain 121 mg (yield: 95%) of the title compound as a colorless crystalline powder. Melting point: 200-202 ° C. 1 H-NMR (DMSO-de, 120 ° C) d: 2.50-2.55 (m, 8H), 3.56-3.66 (m, 12H), 7.20 (d, J = 15.6 Hz, 2H), 7.33 (d, J = 7.6Hz, 2H), 7.46-7.52 (m, 4H), 7.60 (d, J = 15.6 Hz, 2H), 7.72 (t, J = 7.6 Hz, 1 H), 7.75-7.90 (m, 8H), 8.06 (s, 2H).

EXAMPLE 21 Preparation of 1,4-bis-4-r4- (3,4,5-trimethoxyphenyl) benzoip-1-piperazinylbenzene According to the same procedure used in Example 1, crude crystals (35 mg, yield: 72%) were obtained from 4- (3,4,5-trimethoxyphenol) benzoic acid (70 mg, 0.24). mmoles) and 1,4-bis (1-piperazinyl) benzene (15 mg, 0.061 mmol) synthesized by the procedure described in reference example 2. The crude crystals obtained in this manner were recrystallized from chloroform-diethyl ether obtain the title compound as a colorless crystalline powder. Melting point: 218-219 ° C. 1 H-NMR (CDCl 3) d: 2.90-3.30 (m, 8H), 3.50-3.70 (m, 8H), 3.90 (s, 6H), 3.94 (s, 12H), 6.78 (s, 4H), 6.92 (s) , 4H), 7.50 (d, J = 8.3 Hz, 4H), 7.61 (d, J = 8.3 Hz, 4H).

EXAMPLE 22 Preparation of 1,1 '-ethylene-4-r (E, E) -5- (3,5-dimethoxy-4-isopropoxyphenyl) -2,4-pentadiene-phexahydro-1,4-diazepine Potassium carbonate (0.50 g, 3.6 mmol) was added to a solution in water (1 mL) of 1,1'-ethylene dihydrochloride (hexahydro-1,4-diazepine) (385 mg, 1.0 mmol) synthesized in accordance with the same procedure used in reference example 1. The mixture was stirred at room temperature for 15 minutes and concentrated under reduced pressure. A procedure consisting of adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure was carried out twice. The resulting concentrated residue was purified by column chromatography on silica gel, thereby obtaining 236 mg (yield: 69%) of 1,1'-ethylene (hexahydro-1,4-diazepine) as a colorless oil. According to the same procedure used in example 1, the title compound (15 mg) was obtained; yield: 70%) as a colorless amorphous powder from (E, E) -5- (3,5-dimethoxy-4-iopropoxyphenyl) -2,4-pentadienoic acid (147 mg, 0.51 mmol) and 1 , 1'-ethylene (hexahydro-1,4-diazepine) (48 mg, 0.21 mmol) synthesized by the above procedure. 1 H-NMR (DMSO-de, 120 ° C) d: 1.20 (d, J = 6.2 Hz, 12H), 1.76 (br dddd, J = 5.9, 5.9, 5.9, 5.9 Hz, 4H), 2.59 (s, 4H ), 2.61-2.67 (m, 4H), 2.70-2.76 (m, 4H), 3.52-3.61 (m, 8H), 3.79 (s, 12H), 4.33 (qq, J = 6.2, 6.2 Hz, 2H), 6.58 (d, J = 14.6 Hz, 2H), 6.80 (s, 4H), 6.81 (d, J = 15.4 Hz, 2H), 6.96 (dd, J = 15.4, 10.7 Hz, 2H), 7.21 (dd, J = 14. 6, 10.7 Hz, 2H).

EXAMPLE 23 Preparation of 1.1 '-trimetlendr4-r4- (3,4,5-trimethoxyphenyl) benzoylhexahydro-1,4-diazepine dihydrochloride Potassium carbonate (0.50 g, 3.6 mmol) was added to a solution in water (1 ml) of 1, -trimethylenedi (hexahydro-1,4-diazepine) tetrachlorohydrate (540 mg, 1.4 mmol) synthesized in accordance with same procedure used in reference example 1. The mixture was stirred at room temperature for 15 minutes, and concentrated under reduced pressure. A procedure consisting of adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure was carried out twice. The resulting concentrated residue was purified by column chromatography on silica gel, thereby obtaining 323 mg (yield: 96%) of 1,1 '-trimethylene (hexahydro-1,4-diazepine) as a colorless oil. According to the same procedure used in Example 1, 1, 1 '-trimethylendi [4- [4- (3,4,5-trimethoxyphenyl) benzoyl] -hexahydro-1,4-diazepine] (105 mg; yield: 78%) as a colorless oil from 4- (3,4,5-trimethoxyphenyl) benzoic acid (1 18 mg, 0.41 mmol) and 1,1 '-trimethylene (hexahydro-1,4-diazepine) ( 42 mg, 0.17 mmoles) synthesized by the above procedure. Concentrated hydrochloric acid (0.025 ml, 0.30 mmol) was added to a solution of 1,1 '-trimethylendi [4- [4- (3,4,5-trimethoxyphenyl) benzoyl] hexahydro-1,4-diazepine] (46 mg 0.060 mmole) in ethanol (5 ml), and the reaction mixture was concentrated under reduced pressure. The concentrated residue was suspended in diethyl ether, and collected by filtration to obtain the title compound as a colorless crystalline powder. Melting point: 259 ° C (decomposition). 1 H-NMR (data from the free base of the title compound) (DMSO-de, 120 ° C) d: 1.57 (tt, J = 6.8, 6.8 Hz, 2H), 1.70-1.82 (m, 4H), 2.52 ( t, J = 6.8 Hz, 4H), 2.16-2.75 (m, 8H), 3.48-3.61 (m, 8H), 3.76 (s, 6H), 3.87 (s, 12H), 6.92 (s, 4H), 7.40 (d, J = 8.3 Hz, 4H), 7.67 (d, J = 8.3 Hz, 4H).

EXAMPLE 24 Preparation of 1,1'-octamethylenedir-4-dihydrochloride (E, E) -5- (3,4,5-trimethoxypheni0-2,4-pentadienoylhexahydro-1,4-diazepine) According to the same procedure used in Example 7, 1,1 '-octamethylenedi [4 - [(E, E) -5- (3,4,5-trimethoxyphenyl) -2,4-pentadienoyl] hexahydro- was obtained. 1,4-diazepine] (96 mg, yield: 60%) as a colorless oil from (E, E) -5- (3,4,5-trimethoxypheni) -2,4-pentadienoic acid (116 mg; 0.44 mmol) and 1,1 '-octamethylene (hexahydro-1,4-diazepine) (91 mg, 0.20 mmol) synthesized by a procedure similar to the procedure used in reference example 1. Concentrated hydrochloric acid (0.030 ml; 0.36 mmol) to a solution of 1,1 '-octamethylenedi [4 - [(E, E) -5- (3,4,5-trimethoxyphenyl) -2,4-pentadienoyl] hexahydro-1,4-diazepine] ( 76 mg, 0.095 mmol) in ethanol (5 ml), and the reaction mixture was concentrated under reduced pressure. A procedure was carried out twice which consisted in adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure, to obtain the title compound as a pale yellow amorphous powder. 1 H-NMR (DMSO-d 6, 120 ° C) (no NH 4 proton of the ammonium salt was observed) d: 1.20-1.45 (m, 8H), 1.60-1.80 (m, 4H), 1.95-2.40 (m, 8H), 2.95-3.10 (m, 4H), 2.10-3.60 (m, 4H), 3.60-3.75 (m, 4H), 3.72 (s, 6H), 3.80-3.82 (m, 4H), 3.82 (s, 12H), 6.61 (d, J = 14.6 Hz, 2H), 6.81 (s, 4H), 6.86 (d, J = 15.6 Hz, 2H), 6.98 (dd, J = 15.6, 10.4 Hz, 2H), 7.26 ( dd, J = 14.6, 10.4 Hz, 2H).

EXAMPLE 25 Preparation of 1.1 '-bisr (E -3- (3,4-dihydro-6,7,8-trimethoxy-2-naphthyl) -2-propenop-4,4'-bipiperidine According to the same procedure used in Example 7, crude crystals were obtained from (E) -3- (3,4-dihydro-6,7,8-trimethoxy-2-naphthyl) -2-propenoic acid ( 160 mg, 0.55 mmoles) and 4,4'-bipiperidine dihydrochloride (60 mg, 0.25 mmoles). The crude crystals obtained in this way were recrystallized from chloroform-diethyl ether to obtain 99 mg (yield: 56%) of the title compound as a pale yellow crystalline powder. Melting point: 253-256 ° C. 1 H-NMR (DMSO-de, 120 ° C) d: 1.00-1.20 (m, 4H), 1.40-1.50 (m, 2H), 1.60-1.75 (m, 4H), 2.50-3.00 (m, 8H), 3.74 (s, 6H), 3.81 (s, 12H), 4.25-4.35 (m, 8H), 6.51 (d, J = 15.0 Hz, 2H), 6.63 (s, 2H), 6.86 (s, 2H), 7.24 (d, J = 15.0, Hz, 2H).

EXAMPLE 26 Preparation of 1,1 '-bisr (E) -3- (3-quinolyl) -2-propenop-4,4'-bipiperidine According to the same procedure used in Example 1, crude crystals (92 mg, yield: 46%) were obtained from (E) -3- (3-quinolyl) -2-propenoic acid hydrochloride (194 mg; 0.82 mmole) and 4,4'-bipiperidine dihydrochloride (91 mg, 038 mmole). The crude crystals obtained in this manner were suspended in chloroform-diethyl ether and collected by filtration to obtain the title compound as a colorless crystalline powder. Melting point: 270 ° C or more. 1 H-NMR [CD 3 OD-CDCl 3 (1: 5)] d: 1.22-1.41 (m, 4H), 1.44-1.58 (m, 2H), 1.83-2.00 (m, 4H), 2.73 (br dd, J = 12.5 , 12.5Hz, 2H), 3.20 (br dd, J = 12.5, 12.5Hz, 2H), 4.30 (br d, J = 12.5Hz, 2H), 4.77 (br d, J = 12.5Hz, 2H), 7.24 ( d, J = 15.6Hz, 2H), 7.64 (br dd, J = 8.4, 6.7Hz, 2H), 7.77 (d, J = 15.6Hz, 2H), 7.79 (br dd, J = 8.4, 6.7Hz, 2H ), 7.92 (br d, J = 8.4 Hz, 2 H), 8.08 (br d, J = 8.4 Hz, 2 H), 8.36 (s, 2 H), 9.08 (s, 2 H).

EXAMPLE 27 Preparation of 1,3-bisH -r (E) -3- (5,6-dimethoxy-1,1-dimethyl-2-indenyl) -2- propenoip-4-piperidinepropropane According to the same procedure used in example 7, crude crystals were obtained from (E) -3- (5,6-dimethoxy-1,1-dimethyl-2-indenyl) -2-propionic acid (33 mg 0.12 mmole) and 1,3-bis (4-piperidinyl) propane (1 mg, 0.053 mmole). The crude crystals obtained in this way were recrystallized from chloroform-diethyl ether to obtain 16 mg (yield: 42%) of the title compound as a pale yellow crystalline powder. Melting point: 192-194 ° C. 1 H-NMR (DMSO-de, 120 ° C) d: 1.05-1.15 (m, 4H), 1.20-1.30 (m, 6H), 1.31 (s, 12H), 1.45-1.60 (m, 2H), 1.70- 1.80 (m, 4H), 2.80-3.00 (m, 4H), 3.76 (s, 6H), 3.82 (s, 6H), 4.15-4.25 (m, 4H), 6.67 (d, J = 15.9Hz, 2H) , 6.99 (s, 4H), 7.06 (s, 2H), 7.27 (d, J = 15.9Hz, 2H).

EXAMPLE 28 Preparation of 1,3-bisM -5- (3,4,5-tr.methoxyphenol) -3-pyridylcarbonyl! 1-4-piperidinylpropane According to the same procedure used in example 7, the title compound (28 mg, yield: 68%) was obtained as a colorless crystalline powder from 5- (3,4,5-trimethoxyphenyl) -3- pyridinecarboxylic acid (34 mg, 0.12 mmole) and 1,3-bis (4-piperidinyl) propane (12 mg, 0.055 mmole). 1 H-NMR (DMSO-de, 120 ° C) d: 1.10-1.40 (m, 10H), 1.49-1.64 (m, 2H), 1.65-1.75 (m, 4H), 2.93-3.02 (m, 4H), 3.76 (s, 6H), 3.88 (s, 12H), 3.92-4.08 (m, 4H), 6.97 (s, 4H), 7.97 (dd, J = 2.1, 2.1 Hz, 2H), 8.49 (d, J = 2.1 Hz, 2H), 8.89 (d, J = 2.1 Hz, 2H).

EXAMPLE 29 Preparation of 1,3-bisH-r4- (3,4,5-trimethoxyphenyl) benzoyl-4-piperidinyl-2- (dimethylamino) propane hydrochloride Hydrogen chloride was added at 4N in ethyl acetate (1 mL, 4 mmol) to a solution in ethyl acetate (0.5 mL) of 1,3-bis (1-tert-butoxycarbonyl-4-piperidinyl) -2- (dimethylamino) propane (132 mg, 029 mmol) synthesized by the procedure described in reference example 4, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain crude crystals of 1,3-bis (4-piperidinyl) -2- (dimethylamino) propane trichlorohydrate. According to the same procedure used in example 7, 1,3-bis [1- [4- (3,4,5-trimethoxyphenyl) benzoyl] -4-piperidinyl-2- (dimethylamino) propane (189 mg Yield: 82%) as a colorless oil from 4- (3,4,5-trimethoxyphenol) benzoic acid (167 mg, 058 mmol) and crude crystals of 1,3-bs trichlorohydrate ( 4-piperidinyl) -2- (dimethylamino) -propane synthesized by the above procedure. Concentrated hydrochloric acid (0.060 ml, 0.72 mmol) was added to a solution of 1,3-bs [1- [4- (3,4,5-trimethoxyphenyl) benzoyl] -4-piperidinyl] -2- (dimethylamino) propane (189 mg, 0.24 mmol) in ethanol (5 ml), and the mixture was concentrated under reduced pressure. A procedure of adding ethanol (10 ml) to the residue and the concentration of the mixture under reduced pressure was carried out twice to obtain the title compound as a pale yellow amorphous powder. 1 H NMR (DMSO-de, 120 ° C) (no NH + proton of the ammonium salt was observed) d: 1.15-1.25 (m, 4H), 1.40-1.50 (m, 2H), 1.70-1.85 (m , 8H), 2.69 (s, 6H), 2.70-3.10 (m, 4H), 3.20 (m, 1 H), 3.76 (s, 6H), 3.87 (s, 12H), 4.00-4.10 (m, 4H) , 6.92 (s, 4H), 7.41 (d, J = 8.3Hz, 4H), 7.68 (d, J = 8.3Hz, 4H), EXAMPLE 30 Preparation of 1,3-bis-4-methyl-3- (3,4,5-trimethoxyphenyl) benzoin-4-piperidinyl-2- (dimethylamino) propane hydrochloride 4N Hydrogen chloride in ethyl acetate (1 mL, 4 mmol) was added to a solution in ethyl acetate (0.5 mL) of 1,3-bis (1-tert-butoxycarbonyl-4-pperidinium) -2- (dimethylamino) propane (84 mg, 0.19 mmoles) synthesized by the procedure described in reference example 4, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the crude crystals of 1,3-bis (4-piperidinyl) -2- (dimethylamino) propane trichlorohydrate. In accordance with the same procedure as that followed in Example 7, 1,3-bis [1- [4-methyl-3- (3,4,5-trimethoxyphenyl) benzoyl] -4-piperidinyl] -2- was obtained (dimethylamino) propane (53 mg, yield: 35%) as a colorless oil from 4-methyl-3- (3,4,5-trimethoxyphenyl) benzoic acid (12 mg, 0.37 mmol) and the crystals Crude 1,3-bis (4-piperidinyl) -2- (dimethylamino) -propane trichlorohydrate were synthesized by the above procedure. Concentrated hydrochloric acid (0.020 mL, 0.24 mmol) was added to a solution of 1,3-bis [1- [4-methyl-3- (3,4,5-trimethoxyphenyl) benzoyl] -4-piperidinyl] -2- (dimethylamino) propane (53 mg, 0.064 mmol) in ethanol (5 ml) and the reaction mixture was concentrated under reduced pressure. A procedure of adding ethanol (10 ml) to the residue was carried out twice and the mixture was concentrated under reduced pressure to obtain the title compound as a pale yellow amorphous powder. 1 H NMR (DMSO-de, 120 ° C) (no NH + proton of the ammonium salt was observed) d: 1.10-1.25 (m, 4H), 1.41-1.45 (m, 2H), 1.65-1.80 (m , 8H), 2.28 (s, 6H), 2.67 (br s, 6H), 2.80-3.00 (m, 4H), 3.25 (m, 1 H), 3.76 (s, 6H), 3.80 (s, 12H), 4.00-4.10 (m, 4H), 6.57 (s, 4H), 7.18 (d, J = 1.7Hz, 2H), 7.23 (dd, J = 7.8, 1.7Hz, 2H), 7.31 (d, J = 7.8Hz , 2H).

EXAMPLE 31 Preparation of 1,3-bislTl- (E) -5- (3,4,5-trimethoxyphenyl) -2- penten-4-inoyl-1-4-piperidinyl-1-2- (dimethylamino) propane hydrochloride 4N Hydrogen chloride in ethyl acetate (1 mL, 4 mmol) was added to a solution in ethyl acetate (0.5 mL) of 1,3-bis (1-tert-butoxycarbonyl-4-piperidinyl) -2- (dimethylamino) ) propane (135 mg, 0.30 mmol) synthesized by the procedure described in reference example 4, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the crude crystals of 1,3-bis (4-piperidinyl) -2- (dimethylamino) propane trichlorohydrate. In accordance with the same procedure as described in Example 7, 1,3-bis [1 - [(E) -5- (3,4,5-trimethoxyphenyl) -2-penten-4-ynyl] - was obtained. 4-piperidinyl] -2- (dimethylamino) propane (104 mg, yield: 47%) as a colorless oil from (E) -5- (3,4,5-trimethoxyphenyl) -2-penten-4- (4) acid inoculum (157 mg, 0.60 mmole) and crude crystals of 1,3-bis (4-piperidinyl) -2- (d-methalamino) -propane trichlorohydrate were synthesized by the above procedure. Concentrated hydrochloric acid (0.035 ml, 0.42 mmol) was added to a solution of 1,3-bis [1 - [(E) -5- (3,4,5-trimethoxypheni) -2-penten-4-inoyl] - 4- piperidinyl] -2- (dimethylamino) propane (104 mg, 0.14 mmol) in ethanol (5 ml) and the reaction mixture was concentrated under reduced pressure. A procedure of adding ethanol (10 ml) to the residue and concentration of the mixture under reduced pressure was carried out twice to obtain the title compound as a pale yellow amorphous powder. 1 H NMR (DMSO-de, 120 ° C) (no NH + proton of the ammonium salt was observed) d: 1.00-1.20 (m, 4H), 1.40-1.50 (m, 2H), 1.70-1.80 (m , 8H), 2.68 (s, 6H), 2.80-3.00 (m, 4H), 3.25 (m, 1 H), 3.74 (s, 6H), 3.80 (s, 12H), 4.15-4.25 (m, 4H) , 6.73 (d, J = 15.4Hz, 2H), 6.77 (s, 4H), 6.99 (d, J = 15.4Hz, 2H).

EXAMPLE 32 Preparation of 1,3-bis-4-hydroxyfluoride (3,4,5-trimethoxy-phenyl) benzoyl-1-4-piperidinin-2-r (dimethylamino) methylene propane 4N hydrogen chloride in ethyl acetate (1 ml; 4 mmole) was added to a solution in ethyl acetate (0.5 ml) of 1,3-bis (1-tert-butoxycarbonyl-4-pperidinyl) -2 - [(dimethylamine) methylene] propane (67 mg, 0.14 mmol) synthesized by the procedure described in reference example 5, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain crude crystals of 1,3-bis (4-piperidinyl) -2 - [(dimethylamino) methyl] propane trichlorohydrate. In accordance with the same procedure as described in example 7, 1,3-bs [1- [4- (3,4,5-tr ~ methoxyphenyl) benzoyl] -4-p-per Dinyl] -2 - [(dimethylamino) methyl] propane (62 mg, yield: 54%) as a colorless oil from 4- (3,4,5-trimethoxyphenyl) benzoic acid (157 mg, 0.60 mmol) and Crude crystals of 1,3-bis (4-piperidinyl) -2 - [(dimethylamino) methyl] propane trichlorohydrate were synthesized by the above procedure. Concentrated hydrochloric acid (0.020 mL, 0.24 mmol) was added to a solution of 1,3-bis [1- [4- (3,4,5-trimethoxyphenyl) benzoyl] -4-piperidinyl] -2 - [(dimethylamino) methyl] propane (62 mg) in ethanol (5 ml) and the reaction mixture was concentrated under reduced pressure. A procedure of adding ethanol (10 ml) to the residue and concentration of the mixture under reduced pressure was carried out twice to obtain the title compound as a pale yellow amorphous powder. 1 H NMR (DMSO-de, 120 ° C) (no NH + proton of the ammonium salt was observed) d: 1.00-1.45 (m, 8H), 1.65-1.75 (m, 7H), 2.74 (s, 6H ), 2.80-3.00 (m, 6H), 3.75 (s, 6H), 3.87 (s, 12H), 4.00-4.10 (m, 4H), 6.92 (s, 4H), 7.41 (d, J = 8.3Hz, 4H), 7.68 (d, J = 8.3Hz, 4H).

EXAMPLE 33 Preparation of 1,3-bis hydrochloride | -f (E) -5- (3,4,5-trimethoxypheni-2-penten-4-inoin-4-piperidinin-2-r (dimethylamino-1-methylpropane hlc 4N Hydrogen chloride in ethyl acetate (1 ml, 4 mmol) was added to a solution in ethyl acetate (0.5 ml) of 1,3-bis (1-tert-butoxycarbonyl-4-piperidinyl) -2- ( dimethylamino) propane (92 mg, 0.20 mmol) synthesized by the procedure described in reference example 5, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the crude crystals of 1,3-bis (4-piperidinyl) -2 - [(dimethylamino) methyl] propane trichlorohydrate. In accordance with the same procedure as described in example 7, 1,3-bs [1 - [(E) -5- (3,4,5-trimethoxyphenyl) -2-penten-4-ynyl was obtained ] -4-piperidinyl] -2 - [(dimethylamino) methyl] propane (46 mg, yield: 31%) as a pale yellow oil from (E) -5- (3,4,5-trimethoxyphenyl) - 2-penten-4-ynoic (105 mg, 0.40 mmol) and the crude crystals of 1,3-bis (4-piperidinyl) -2 - [(dimethylamino) methyl] propane trichlorohydrate were synthesized by the above procedure. Concentrated hydrochloric acid (0.020 mL, 0.24 mmol) was added to a solution of 1,3-bis [1 - [(E) -5- (3,4,5-trimethoxyphenyl) -2-penten-4-ynyl] - 4- piperidinyl] -2 - [(dimethylamine) methyl] propane (46 mg, 0.061 mmol) in ethanol (5 ml) and the reaction mixture was concentrated under reduced pressure. A procedure of adding ethanol (10 ml) to the residue and concentration of the mixture under reduced pressure was carried out twice to obtain the title compound as a pale yellow amorphous powder. 1 H NMR (DMSO-de, 120 ° C) (no NH + proton of the ammonium salt was observed) d: 1.20-1.40 (m, 8H), 1.60-1.80 (m, 7H), 2.75 (s, 6H ), 2.80-3.00 (m, 6H), 3.74 (s, 6H), 3.80 (s, 12H), 4.10-4.20 (m, 4H), 6.72 (d, J = 15.4Hz, 2H), 6.77 (s, 4H), 6.98 (d, J = 15.4Hz, 2H).

EXAMPLE 34 Preparation of 1,3-Bis-i-E) -5- (3,4,5-trimethoxyphenyl) -2-penten-4-yl-4-piperidinip-2-propane-carboxylic acid In accordance with the same procedure as described in Example 7, 1,3-bis [1 - [(E) -5- (3,4,5-trimethoxyphenyl) -2-penten-4-ynyl] - was obtained. Methyl 4-piperidinyl] -2-propanecarboxylate (136 mg, yield: 88%) as a colorless oil from (E) -5- (3,4,5-trimethoxyphenyl) -2-penten-4 -inoic acid (16 mg, 0.44 mmol) and methyl 2,2-bis [(4-piperidinyl) methyl] acetate dihydrochloride (70 mg, 0.21 mmol) synthesized by the procedure described in reference example 3. 5N aqueous sodium hydroxide (2 ml, 10 mmol) was added to a solution in methanol (2 ml) of 1,3-bis [1 - [(E) -5- (3,4,5-trimethoxyphenyl) -2- methyl penten-4-ynyl] -4-piperidinyl] -2-propanedicarboxylate (136 mg, 0.18 mmol) was synthesized by the procedure described above, and the mixture was stirred for 1 hour in a controlled bath at 65 ° C. The reaction mixture was made acidic by the addition of 1 N hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and subsequently concentrated under reduced pressure. The resulting crude oil was purified by column chromatography on silica gel, thereby obtaining 46 mg (yield: 35%) of the title compound as a pale yellow amorphous powder. 1 H-NMR (DMSO-de, 120 ° C) (no OH proton of the carboxyl group was observed) d: 1.00-1.90 (m, 14H), 2.40-3.00 (m, 5H), 3.74 (s, 6H) , 3.80 (s, 12H), 4.10-4.20 (m, 4H), 6.71 (d, J = 15.4Hz, 2H), 6.78 (s, 4H), 6.97 (d, J = 15.4Hz, 2H).

EXAMPLE 35 Preparation of N, N-bisrH-r4- (3,4,5-trimethoxy-phenoxybenzoyl-4-piperidinemethoxymethamino) hydrochloride In accordance with the same procedure explained in example 7, N, N-bis [[1- [4- (3,4,5-trimethoxyphenyl) benzoyl] -4-piperidinyl] methyl] methylamine (144 mg; : 94%) as a colorless oil from 4- (3,4,5-trimethoxy-phenyl) benzoic acid (126 mg, 0.44 mmol) and N, N-bis [(4-piperidinyl) methyl] methylamino trichlorohydrate (67 mg; 0.20 mmoles) were synthesized by the procedure described in reference example 6. Concentrated hydrochloric acid (0.045 ml, 0.54 mmole) was added to a solution of N, N-bis [[1- [4- (3,4,5 -trimethoxyphenyl) benzoyl] -4-piperidinyl] methyl] methylamino (142 mg, 0.18 mmol) in ethanol (5 ml) and the reaction mixture was concentrated under reduced pressure. A procedure of adding ethanoi (10 ml) to the residue and concentration of the mixture under reduced pressure was performed twice to obtain the title compound as a colorless amorphous powder. 1 H-NMR (DMSO-de, 120 ° C) (no NH + proton of the aluminum salt was observed) d: 1.35-1.40 (m, 4H), 1.80-2.00 (m, 4H), 2.10-2.20 ( m, 2H), 2.70-3.30 (m, 1 1 H), 3.75 (s, 6H), 3.86 (s, 12H), 4.00-4.15 (m, 4H), 6.91 (s, 4H), 7.41 (d, J = 8.2Hz, 4H), 7.67 (d, J = 2.8Hz, 4H).

EXAMPLE 36 Preparation of N.N-bislT1-r (E) -3- (6,7,8-Tritymethoxy-2-naphthiD-2-propenoyl-4-piperidinimethyl-dimethylamino) hydrochloride In accordance with the same procedure explained in Example 7, Preparation of N, N-bis [[1 - [(E) -3- (6,7,8-trimethoxy-2-naphthyl) -2-propenoyl hydrochloride] l] -4-piperidinyl] methyl] methylamine (57 mg, yield: 87%) was obtained as a colorless oil from (E) -3- (6,7,8-trimethoxy-2-naphthyl) -2 acid -propenoic acid (50 mg, 0.17 mmol) and N, N-bis [(4-piperidinyl) methyl] methylamino trichlorohydrate (29 mg, 0.086 mmol) were synthesized by the procedure described in reference example 6. Concentrated hydrochloric acid ( 0.020 ml, 0.24 mmol) were added to a solution of N, Nb \ s [[1 - [(E) -3- (6,7,8-trimethoxy-2-naphthyl) -2-propenoyl] -4 -piperidinyl] methyl] methylamine (57 mg, 0.074 mmol) in ethanol (5 ml) and the reaction mixture was concentrated under reduced pressure. A procedure of adding ethanol (10 ml) to the residue and concentrating the mixture under reduced pressure was performed twice to obtain the title compound as a pale yellow amorphous powder. 1 H-NMR (DMSO-de, 120 ° C) (no NH + proton of the aluminum salt was observed) d: 1.20-1.32 (m, 4H), 1.80-2.15 (m, 6H), 2.70-3.10 ( m, 8H), 2.78 (br s, 3H), 3.88 (s, 6H), 3.93 (s, 6H), 4.00 (s, 6H), 4.25-4.37 (m, 4H), 7.13 (d, J = 15.4 Hz, 2H), 7.14 (s, 2H), 7.58 (d, J = 15.4Hz, 2H), 7.71 (dd, J = 8.5, 1.5Hz, 2H), 7.74 (d, J = 8.5Hz, 2H), 8.04 (br s, 2H).

EXAMPLE 37 Preparation of N, N'-Bisri-R4- (3A5-trimethoxyphenyl) benzoin-4-piperidinin-N, N'-dimethylethylenediamine dihydrochloride In accordance with the same procedure explained in example 1, N, N'-bis [1- [4- (3,4,5-trimethoxyphenyl) benzoyl] -4-piperidinyl] -N, N'-dimethylethylenediamine ( 159 mg; yield: 87%) as a colorless oil from 4- (3,4,5-trimethoxy-phenyl) benzoic acid (173 mg, 0.60 mmol) and N, N'-bis (4-piperidinyl) tetrachlorohydrate ) -N, N'-dimethylethylenediamine (92 mg, 0.23 mmol) were synthesized by the procedure described in reference example 7. Concentrated hydrochloric acid (0.030 ml, 0.36 mmol) was added to a solution of N, N'-bis [1- [4- (3,4,5-Tr! Methoxy-phenyl) -benzoyl] -4-piperidinyl] -N, N'-dimethylethylenediamine (60 mg, 0.076 mmol) in ethanol (5 ml) and the mixture of The reaction was concentrated under reduced pressure. The concentrated residue was suspended in diethyl ether and collected by filtration to obtain the title compound as a colorless crystalline powder. Melting point: 263 ° (decomposition). 1 H NMR (free base data of the title compound) (DMSO-d 6, 120 ° C) d: 1.37-1.50 (m, 4H), 1.72-1.80 (m, 4H), 2.26 (s, 6H), 2.55 ( s, 4H), 2.59-2.69 (m, 2H), 2.85-2.99 (m, 4H), 3.77 (s, 6H), 3.88 (s, 12H), 4.04-4.15 (m, 4H), 6.93 (s, 4H), 7.43 (s, J = 8.5Hz, 4H), 7.68 (d, J = 8.5Hz, 4H).

EXAMPLE 38 Preparation of N, N'-bisH-r4-fluoro-3- (3,4,5-trimethoxyphenyl) benzoin-4-piperidinyl-N, N'-dimethylethylenediamine In accordance with the same procedure described in example 1, the title compound (49 mg, yield: 83%) was obtained as a colorless amorphous powder from 4-fluoro-3- (3,4,5-trimethoxyphenyl) ) benzoic acid (59 mg, 0.18 mmoles) and N, N'-bis (4-piperidinyl) -N, N'-dimethylethylenediamine tetrahydrochloride (29 mg, 0.072 mmoles) were synthesized by the procedure described in reference example 7. 1 H NMR (DMSO-de, 120 ° C) d: 1.36-1.49 (m, 4H), 1.69-1.78 (m, 4H), 2.31 (s, 6H), 2.52 (s, 4H), 2.57-2.66 (m , 2H), 2.86-2.99 (m, 4H), 3.76 (s, 6H), 3.83 (s, 12H), 4.00-4.13 (m, 4H), 6.82 (s, 4H), 7.27 (dd, J = 8.5 , 3JHF = 10.9Hz, 2H), 7.35 (ddd, J = 8.5, 2.3, 4JHF = 4.9Hz, 2H), 7.50 (dd, J = 2.3, 4JHF = 7.6HZ, 2H).

EXAMPLE 39 Preparation of 1,4-bislT1-r4- (3A5-trimethoxyphenyl) benzoyl-4-piperidinylmethylpiperazine dihydrochloride In accordance with the procedure described in Example 7, 1,4-bis [[1-4- (3,4,5-trimethoxyphenyl) benzoyl] -4-piperidinyl] methyl] piperazine was obtained (101 mg, yield: 82%) as a colorless oil from 4- (3,4,5-trimethoxyphenyl) benzoic acid (91 mg); 0.31 mmole) and 1,4-bis [(4-pperidinium] methyl] piperazine tetrahydrochloride (64 mg, 0.15 mmole) were synthesized by the procedure described in the example by reference 8. Concentrated hydrochloric acid (0.050 ml 0.60 mmole) was added to a solution of 1,4-bis [[1-4- (3,4,5-trimethoxy-phenyl) -benzoyl] -4-piperidinyl] methyl] piperazine (100 mg, 0.12 moles). ) in ethanol (5 ml) and the reaction mixture was concentrated under reduced pressure, then a process of addition of ethanol (10 ml) to the residue and concentration of the mixture under reduced pressure was performed twice, the resulting concentrated residue turned to recrystallize from methanol-diethyl ether to obtain the title compound as colorless needles Melting point: 261-263 ° C 1 H NMR (DMSO-120 ° C): (no NH 4 proton was observed from the ammonium salt) d: 1.15-1.35 (m, 4H), 1.80-1.90 (m, 4H), 1.97-2.10 (m, 2H), 2.70-2.80 (m, 4H), 2.80-3.40 (m, 12H) , 3.75 (s, 6H), 3.86 (s, 12H), 3.95-4.1 0 (m, 4H), 6.92 (s, 4H), 7.41 (d, J = 8.2 Hz, 4H), 7.68 (d, J = 8.2 Hz, 4H).

EXAMPLE 40 Preparation of 1,4-bislTl-4-methoxy-3- (3,4,5-trimethoxy-phenyl) -benzoyl-4-piperidinyl-1-piperazine dichlorohydrate In accordance with the procedure described in example 7, 1, 4-bis [[1- [4-methoxy-3- (3,4,5-trimethoxyphenyl) benzoyl] -4-piperidinyl] methyl] piperazine (81 mg; yield: 61%) was obtained as a colorless oil from 4-methoxy-3- (3,4,5-trimethoxyphenyl) benzoic acid (100 mg, 0.35 mmol) and 1,4-bis-tetrahydrochloride [4- piperidinyl] methyl] piperazine (63 mg, 0.15 mmol) were synthesized by the procedure described in reference example 8. Concentrated hydrochloric acid (0.040 ml, 0.48 mmol) was added to a solution of 1,4-bis [[1- [4-methoxy-3- (3,4,5-trimethoxyphenyl) benzoyl] -4-piperidinyl] methyl] piperazine (80 mg, 0.090 mol) in ethanol (5 ml) and the reaction mixture was concentrated under reduced pressure. After a procedure of addition of ethanol (10 ml) to the residue and concentration of the mixture under reduced pressure was performed twice, the resulting concentrated residue was recrystallized from methanol-diethyl ether to obtain the compound of the same. Title as colorless needles. Melting point: 251-253 ° C. 1 H NMR (DMSO-120 ° C): (no NH + proton of the ammonium salt was observed) d: 1 .10-1.30 (m, 4H), 1.75-1.85 (m, 4H), 1.95-2.05 (m, 2H), 2.55-3.40 (m, 16H), 3.75 (s, 6H), 3.81 (s, 12H), 3.82 (s, 6H), 4.00-4.15 (m, 4H), 6.75 (s, 4H), 7.1 1 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 2.1 Hz, 2H), 7.33 (dd, J = 8.2, 2.1 Hz, 2H ). The compounds obtained in this manner with the present invention are shown in tables 1 to 10.

TABLE 1 TABLE 2 TABLE 3 TABLE 4 TABLE 6 TABLE 7 TABLE 8 03 TABLE 9 EXAMPLE OF TEST 1 Evaluation of the effect of inhibition on the production of IqE antibody The spleen of a mouse (Balb / C, 8-week-old male) was excised and triturated in 0.3% BSA / HBSS to prepare individual cells by means of a 200 mesh filter. Additionally, the individual cells were hemolyzed by a 17 mM Tris solution of 0.75% ammonium chloride to prepare a splenocyte suspension (1 x 107 / ml) using RPM medium I 1640/25 mM HEPES / O.3% BSA . Then, the suspension was reacted with a rat anti-mouse monoclonal antibody Thy-1, 2 (product of Cedarlane Co.) at 4 ° C for 1 hour, the reaction mixture was centrifuged, and the pellet cells were suspended. again (1 x 107 / ml, RPMI / HEPES / BSA). Subsequently, after the suspension was reacted with a rabbit complement of low toxicity (product of Cedarlane Co.) at 37 ° C for 1 hour, the removed cells were removed by specific gravity centrifugation using lypholith M (product of Cedarlane). Co.) to obtain the B cell fraction as viable cells. After the B cells (105 / 0.2 ml / well) were cultured for one day with LPS (E. coli 026: B6, product of DIFCO Co.) using a 96-well plate, mouse IL-4 was added ( product of Genzyme Co.) to perform the culture for 7 more days. Each test agent was added on the first day of culture, and the amount of IgE in culture supernatant was measured by ELISA after culture, thus calculating the effect of inhibition of the agent on the production of IgE antibody. The inhibition activities of the test agents in the 10"6 M concentrations are shown in Table 11.

TABLE 11 Industrial Application The cyclic amide compounds (1) according to the present invention have an inhibitory effect on the production of an IgE antibody and are therefore useful as medicaments for preventing and treating immunological diseases wherein IgE participates, for example, various allergic immunological diseases, such as asthma.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound represented by the following general formula (1 ): (1) wherein A is a residue of an alicyclic compound that can be substituted, an aromatic compound that can be substituted, or a heterocyclic compound that can be substituted; X is a simple link; a lower alkylene group which can be substituted; a divalent residue of an alicyclic compound that can be substituted, an aromatic compound that can be substituted, or a heterocyclic compound that can be substituted; an imino group that can be substituted; or a sulfur atom or an oxygen atom; Y is a single bond, or a lower alkylene, lower alkyl imino group or imino; Z is a group of -CH = CH-, -C = C-, - (CH = CH) 2-, -C = C-CH = CH- or -CH = CH-C = C-, or a divalent residue of benzene, pyridine, pyrimidine or pyrazine which can be substituted; B is a nitrogen atom or = CH-; ymyn are equal or different from each other and independently an integer from 1 to 4, provided that - YXY- is a lower alkylene group which is unsubstituted and Z is -CH = CH-, A is not a phenyl group which is not substituted neither 3,4-methylenedioxyphenyl, a salt thereof or a solvate thereof.

2. The compound, the salt thereof or the solvate thereof according to claim 1, further characterized in that A is an indenyl, phenyl, naphthyl, dihydronaphthyl, indolyl, isoindolyl, pyridyl, quinolyl or isoquinolyl group which may be substituted by 1 to 3 substituents selected from a hydroxyl group, halogen atoms, lower alkyl groups which may be substituted by 1 to 3 halogen atoms, lower alkoxy groups, an amino group, monoalkylamino groups, dialkylamino groups, and lower alkylthio groups .

3. The compound, the salt thereof, or the solvate thereof according to claim 1, further characterized by X is a lower alkylene group which may be substituted by one or more substituents selected from halogen atoms, a hydroxyl group , lower alkyl groups which may be substituted by an amino group, monoalkylamino group or dialkylamino group, lower alkoxy groups, a carboxyl group, lower alkoxycarbonyl groups, an amino group, alkylamino groups, dialkylamino groups, a nitro group, cyano group and aralkyl groups; or an imino group which may be substituted by a lower alkyl group.

4. The compound, the salt thereof, or the solvate thereof according to claim 1, further characterized in that X is a divalent residue of a cycloalkane having from 5 to 8 carbon atoms, which may be substituted by one or more substituents selected from halogen atoms, a hydroxyl group, lower alkyl groups which may be substituted by an amino group, monoalkylamino group or dialkylamino group, lower alkoxy groups, a carboxyl group, lower alkoxycarbonyl groups, an amino group, alkylamino groups, dialkylamino groups, a nitro group, a cyano group and aralkyl groups.

5. The compound, the salt thereof, or the solvate thereof according to claim 1, further characterized in that X is a phenylene group which may be substituted by one or more substituents selected from halogen atoms, a hydroxyl group, lower alkyl groups which may be substituted by an amino group, monoalkylamino group or dialkylamino group, lower alkoxy groups, a carboxyl group, alkoxycarbonyl groups, an amino group, alkylamino groups, dialkylamino groups, a nitro group, a cyano group and aralkyl groups.

6. The compound, the salt thereof, or the solvate thereof according to claim 1, further characterized in that X is a divalent residue of pyridine, pyrrolidine, piperidine, piperazine or homopiperazine which may be substituted by one or more substituents selected from halogen atoms, a hydroxyl group, lower alkyl groups which may be substituted by an amino group, monoalkylamino group or dialkylamino group, lower alkoxy groups, a carboxyl group, lower alkoxycarbonyl groups, an amino group, alkylamino groups, dialkylamino groups, a nitro group, a cyano group and groups aralkyl.

7. A medicament comprising the compound, the salt thereof, or the solvate thereof according to any one of claims 1 to 6, as an active ingredient.

8. The medicament according to claim 7, which is an agent for inhibiting the production of an IgE antibody.

9. The medicament according to claim 7 or 8, which is an agent for preventing and treating an allergic immunological disease.

10. The medicament according to any of claims 7 to 9, which is an agent for preventing and treating asthma, atopic dermatitis, allergic rhinitis, inflammatory bowel disease, contact dermatitis or allergic ophthalmopathy.

11. A medicinal composition comprising the compound, the salt thereof or the solvate thereof according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

12. The use of a compound, the salt thereof or the solvate thereof as claimed in any of claims 1 to 6 for the manufacture of a medicament for preventing and treating an allergic immune disease.

13. The use as claimed in claim 12, wherein the disease is also asthma, atopic dermatitis, allergic rhinitis, inflammatory bowel disease, contact dermatitis or allergic ophthalmopathy.