Butenoic acid derivatives

Abstract: A butenoic acid compound is defined by the following formula: in which Z is O,S, vinylene or azomethyne, A is an alkylene and J is phenyl or etc. It is useful to treat the heart disease.

Description: The present invention relates to a butenoic acid derivative having an excellent activity as a drug. [Background of the Invention and Prior Art] In Europe and America, cardiovascular diseases top the list of death causes. Meanwhile, although cerebrovascular diseases such as cerebral apoplexy rather ranked high in death causes in Japan, a tendency for ischemic heart diseases to increase rapidly has been recently seen as the life-style and diet have neared those of Europe and America. The term "ischemic heart disease" refers to a series of diseases generally caused when the supply of oxygen to the cardiac muscle does not meet the demand of the muscle for oxygen. Representative examples thereof include coronary arteriosclerosis, acute myocardial infarction and stenocardia. Although a nitro drug, calcium antagonist or β-blocker is now used for the treatment of the above diseases, no sufficiently effective drug has been found as yet. Accordingly, the development of a new drug superior to those of the prior art has been expected. EP-A-0 344 577 cited according to Article 54(3) EPC, reveals butenoic acid derivatives including vinyl groups being substituted by a heteroaryl group for the treatment of ischemic heart diseases. Journal of Medicinal Chemistry, vol. 29, pp. 19-25, 1986 refers to the antihypertensive activity of a series of 4-amino-6,7-dimethoxyquinazoline derivatives. [Constitution and Effect of the Invention] The inventors of the present invention have studied for a long time to obtain a new type of remedy for ischemic heart diseases and have found that the butenoic acid derivative which will be described below exhibits an excellent coronary vasodilating effect. Namely, the compound of the present invention is a butenoic acid derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof: wherein R¹ represents a group represented by the formula: {wherein R² and R 2' may be the same or different from each other and each represent a hydrogen atom or a straight-chain or branched C₁₋₆ alkyl, cycloalkyl or allyl group, or alternatively, R² and R 2' may together form a ring, X represents an oxygen or sulfur atom, a group represented by the formula: = N-R³ (wherein R³ represents carbamoyl group) or a group represented by the formula: (wherein R' and R'' may be the same or different from each other and each represent a hydrogen atom, or nitro group) Z represents a vinylene (-CH=CH-) group, R⁶ and R⁷ may be the same or different from each other and each represent a hydrogen atom or a straight-chain or branched C₁₋₆ alkyl, cycloalkyl or allyl group, A represents a C 1∼6 alkylene group which may have a straight-chain or branched C₁₋₆ alkyl or hydroxy-substituted, straight-chain or branched C₁₋₆ alkyl substituent bonded to any carbon of the group, J represents a group represented by the formula: {wherein R⁸, R⁹ and R¹⁰ may be the same or different from each other and each represent a hydrogen or halogen atom, a C₁₋₆ alkyl a C₁₋₆ alkoxy group, and n represents an integer of 1 to 6. In the above definition, when Z is a group represented by the formula: -CH=CH-, i.e., when the group represented by the formula: is a phenyl group, the compound of the present invention is a butenoic acid derivative represented by the following general formula (I'): wherein R¹, R⁶, A, R⁷, J and n are defined above. The straight-chain or branched C₁₋₆ alkyl group defined with respect to R², R 2' , R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² in the above definition of the compound (I) according to the present invention may be exemplified by methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, sec-butyl, n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl groups, among which methyl and ethyl groups are most preferred. The straight-chain or branched C₁₋₆ alkoxy group defined with respect to R⁸, R⁹ and R¹⁰ may be one derived from any of the alkyl groups described above. The straight-chain or branched C₁₋₆ alkoxycarbonyl group defined with respect to R³ and R⁵ may be one derived from any of the alkyl groups described above. A represents an alkylene group having 1 to 6 carbon atoms, preferably 3 or 4 carbon atoms. The alkylene group may be substituted with a straight-chain or branched C₁₋₆ alkyl group as described above or a hydroxy-substituted straight-chain or branched C₁₋₆ alkyl group (for example, a methyl or hydroxymethyl group) at any carbon of the alkylene group. J represents a group represented by the formula: (wherein R⁸, R⁹ and R¹⁰ are each as defined above). Particularly, it is preferred that 1 to 3 members out of R⁸, R⁹ and R¹⁰ are each a straight-chain or branched C₁₋₆ alkyl group, still preferably a methyl group. The compounds having the formulae (C) and (D) are preferable. All the substitutes of these formulae are defined before. In the formula (C), R2 and R2' are preferably hydrogen or a straight-chain or branched C₁₋₆ alkyl such as methyl. X is preferably sulfur and =N-R3, R3 being defined before. Z is preferably vinyl. A is preferably an alkylene having 3 or 4 carbon atoms. m is preferably 2. J is preferably 3,4-dimethoxyphenyl and 3,5-dimethoxyphenyl. The compound (D) is a preferable one of (C). In the formula (I'), it is preferred that R1 is R2R2'N-CX-NH- and A is an alkyl having 3 or 4 carbon atoms. J is preferably 3,4-dimethoxyphenyl or 3,5-dimethoxyphenyl. The following compounds are preferred. (E)-N-[3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N²-methylthioureido)phenyl)-3-butenamide (E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N²-methylureido)phenyl)3-butenamide (E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(N²-methylureido)phenyl)-3-butenamide (E)-N-[3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N²-methylthioureido)phenyl)-3-butenamide (E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-((1-methylamino-2-nitroethen-1-yl)amino)phenyl]-3-butenamide The invention provides a pharmacological composition which comprises a pharmacologically effective amount of the compound or salt as defined above and a pharmacologically acceptable carrier. It also provides the use of the compound or salt as defined above for preparing a medicament for treating, preventing, remitting or ameliorating ischemic heart diseases by administering the compound or salt defined above in a pharmacologically effective amount to a human being. The pharmacologically acceptable salt of the present invention includes inorganic acid salts such as hydrochloride, sulfate, hydrobromide and phosphate and organic acid salts such as formate, acetate, maleate, fumarate, tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate. Although optical isomers or tautomers are present depending upon the kind of the substituent of the compound according to the present invention, it is a matter of course that they fall within the scope of the present invention. Representative processes for the preparation of the compound according to the present invention will now be described. Preparation Process A butenoic acid derivative represented by the general formula (I) wherein the moiety represented by the formula: is a phenyl group, i.e., one represented by the following general formula: (wherein R¹, R⁶, R⁷, A, J and n are each as defined above) is prepared according to, for example, the following process: (wherein R¹, R⁶, R⁷, A, n and J are each as defined above.) Namely, the objective compound (I') can be prepared by reacting a carboxylic acid represented by the general formula (II) or a reactive derivative thereof with an amino compound represented by the general formula (III) to carry out amidation. The reactive derivative of the compound (II) includes acid halide thereof such as acid chloride thereof and acid bromide thereof; acid azide; active esters thereof with N-hydroxybenzotriazole or N-hydroxysuccinimide; symmetric acid anhydride thereof and mixed acid anhydride thereof with alkylcarbonic acid or p-toluenesulfonic acid. When the compound (II) to be used is of free acid type, the above reaction is preferably carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, ethyl chloroformate, diethyl azodicarboxylate or dipyridyl disulfide at a room temperature or under cooling at a temperature of -78°C or above or by heating under reflux. The reaction is carried out in water or an organic solvent which is inert to the reaction, for example, methanol, ethanol, pyridine, tetrahydrofuran, dioxane, ether, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform, dimethylformamide, methylene chloride, ethyl acetate or acetonitrile by using substantially equimolar amounts of a compound (II) or a reactive derivative thereof and a compound (III) or by using a slight excess of either of them. Depending upon the kind of the reactive derivative, it is sometimes, advantageous for smoothening the progress of the reaction that a base such as diisopropylethylamine, triethylamine, pyridine, picoline, lutidine, N,N-dimethylaniline, 4-dimethylaminopyridine, potassium carbonate or sodium hydroxide is used in the reaction. Although the reaction temperature is not particularly limited but varies depending upon the kind of the reactive derivative, the reaction is generally carried out at a temperature of from -20°C to the reflux temperature to obtain the objective compound. The compound represented by the general formula (II) to be used as a starting material according to the present invention can be prepared by, for example, the following process: (In the above series of formulas, R¹ is as defined above and Ph represents a phenyl group) (Step 1) In this step, a compound represented by the general formula (V) is reacted with a compound represented by the general formula (IV) in the presence of a copper catalyst such as powdered copper or copper oxide according to the Ullmann reaction to obtain a compound (VI). This reaction may be carried out in the absence of any solvent or in the presence of an organic solvent which is inert to the reaction, for example, nitrobenzene, dimethylformamide or pyridine, or water. Alternatively, a compound represented by the general formula (VI) can be also prepared by reacting a compound represented by the general formula (V) with a salt of a compound represented by the general formula (IV) with a metal such as lithium, sodium or potassium to carry out the replacement. This reaction may be carried out in the absence of any solvent or in the presence of an organic solvent which is inert to the reaction, for example, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, dioxane, ether or tetrahydrofuran. (Step 2) A compound (II) can be prepared by reacting a compound represented by the general formula (VI) with a compound represented by the general formula (VI') in a solvent such as ether, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide or dimethyl sulfoxide in the presence of t-butoxypotassium, caustic potash, caustic soda, sodium methoxide, sodium ethoxide or sodium hydride at a temperature of from -78°C to a room temperature according to an ordinary process. Alternatively, the compound represented by the above general formula (II) can be also prepared by, for example, the following process: [when R¹ is a group represented by the formula: wherein R² is as defined above, R² is a hydrogen atom and X is a group represented by the formula: = N - R³ (wherein R³ is as defined above)] (In the above series of formulas, R² and R³ are each as defined above) (Step 1) In this step, a compound represented by the general formula (VII) is prepared by hydrolyzing the alkanoylamino group of a compound represented by the general formula (II') under an acidic or basic condition according to a conventional process and esterifying the obtained product according to a conventional process. This hydrolysis is carried out in a solvent such as water, water-containing methanol, water-containing ethanol, water-containing tetrahydrofuran or water-containing dioxane in the presence of hydrochloric acid, sodium hydroxide, potassium hydroxide or lithium hydroxide at a room temperature or by heating under reflux. This esterification is carried out in a solvent such as methanol, ethanol or propanol in the presence of hydrogen chloride, concentrated sulfuric acid or p-toluenesulfonic acid at a room temperature or by heating under reflux. (Step 2) In this step, a compound represented by the general formula (VII) is reacted with a compound represented by the general formula (VIII) to obtain a compound represented by the general formula (IX). This reaction is preferably carried out in the absence of any solvent or in the presence of a solvent inert to the reaction, for example, chloroform, dichloromethane, dichloroethane, tetrahydrofuran, dioxane, benzene, toluene, xylene or dimethylformamide at a room temperature or by heating under reflux. (Step 3) In this step, a compound represented by the general formula (IX) is reacted with a compound represented by the general formula (X) in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide to obtain a compound represented by the general formula (XI). The reaction is preferably carried out in the absence of any solvent or in the presence of an organic solvent inert to the reaction, for example, chloroform, dichloromethane, dichloroethane, ether, tetrahydrofuran, dioxane, acetonitrile, benzene, toluene or xylene at a room temperature or by heating under reflux. Alternatively, a compound represented by the general formula (XI) can be prepared by reacting a compound represented by the general formula (IX) with dimethyl sulfate, trimethyloxonium tetrafluoroborate, triethyloxonium tetrafluoroborate, methyl iodide or ethyl iodide according to a conventional process to obtain an isourea or isothiourea derivative and reacting the isourea or isothiourea derivative with a compound represented by the general formula (X) or a salt thereof with lithium, sodium or potassium. This reaction is preferably carried out in the absence of any solvent or in the presence of an organic solvent inert to the reaction, for example, chloroform, dichloromethane, dichloroethane, ether, tetrahyrofuran, dioxane, acetonitrile, benzene, toluene or xylene at a room temperature or by heating under reflux. (Step 4) A compound represented by the general formula (XI) is hydrolyzed under an acidic or basic condition according to a conventional process to obtain a compound represented by the general formula (II''). This hydrolysis is carried out in a solvent such as water, water-containing methanol, water-containing ethanol, water-containing tetrahydrofuran or water-containing dioxane in the presence of hydrochloric acid, sodium hydroxide, potassium hydroxide or lithium hydroxide at a room temperature or by heating under reflux. When R¹ is a group represented by the formula: wherein R² is as defined above and X is an oxygen or sulfur atom (i.e., when R 2' is H), as will be described below, a compound represented by the general formula: can be easily prepared by hydrolyzing a compound represented by the general formula (IX) in a similar manner to that described in the above Step 4. Alternatively, a compound represented by the general formula (XI) can be prepared by the following process: (In the above series of formulas, R², R³ and R¹³ are each as defined above) Namely, a compound represented by the general formula (XI) can be prepared by reacting a compound represented by the general formula (VII) with a compound represented by the general formula (XIII) and reacting the obtained product with an amine represented by the general formula (XV) or a salt thereof with lithium, sodium or potassium or by reacting a compound represented by the general formula (VII) with a compound represented by the general formula (XII). These reactions are each preferably carried out in the absence of any solvent or in the presence of an organic solvent inert to the reaction, for example, chloroform, dichloromethane, dichloroethane, ether, tetrahydrofuran, dioxane, acetonitrile, benzene, toluene or xylene at a room temperature or by heating under reflux. Further, the compound represented by the general formula (II) can be also prepared by the following processes: (In the above series of formulas, R⁴, R⁵ and R¹³ are each as defined above) (Step 1) A compound represented by the general formula (XX) can be prepared by reacting a compound represented by the general formula (VII) with an ortho ester compound represented by the general formula (XVII) such as methyl orthoformate, ethyl orthoformate, methyl orthoacetate, ethyl orthoacetate, methyl orthopropionate or ethyl orthopropionate and reacting the obtained product with an amine represented by the general formula (XIX) or a salt thereof with lithium, sodium or potassium or by reacting a compound represented by the general formula (VII) with a compound represented by the general formula (XVI). These reactions are each preferably carried out in the absence of any solvent or in the presence of an organic solvent inert to the reaction, for example, chloroform, dichloromethane, dichloroethane, ether, tetrahydrofuran, dioxane, acetonitrile, benzene, toluene or xylene at a room temperature or by heating under reflux. (Step 2) A compound represented by the general formula (XX) is hydrolyzed under an acidic or basic condition to obtain a compound represented by the general formula (II'''') This hydrolysis is carried out in a solvent such as water, water-containing methanol, water-containing ethanol, water-containing tetrahydrofuran or water-containing dioxane in the presence of hydrochloric acid, sodium hydroxide, potassium hydroxide or lithium hydroxide at a room temperature or by heating under reflux. Further, a compound represented by the general formula (IX) wherein X' is a sulfur atom can be also prepared by the following process: (In the above series of formulas, R², R 2' and R¹³ are each as defined above) (Step 1) In this step, a compound represented by the general formula (VII) is reacted with thiophosgene in the presence or absence of a base to obtain a compound represented by the general formula (VII'). The base may be triethylamine, pyridine or 2,6-lutidine. This reaction is preferably carried out in the absence of any solvent or in the presence of an organic solvent inert to the reaction, for example, chloroform, dichloromethane, dichloroethane, tetrahydrofuran, dioxane, benzene, toluene, xylene or dimethylformamide at ordinary temperatures or under cooling with ice or by heating under reflux. (Step 2) In this step, a compound represented by the general formula (VII') is reacted with a compound represented by the general formula (XV') to obtain a compound represented by the general formula (IX'). This reaction is preferably carried out in the absence of any solvent or in the presence of an organic solvent inert to the reaction, for example, chloroform, dichloromethane, dichloroethane, ether, tetrahydrofuran, dioxane, acetonitrile, benzene, toluene or xylene at ordinary temperatures or under cooling with ice or by heating under reflux. On the other hand, another starting material, i.e., the compound (III) can be prepared by, for example, the following processes: (Preparation process 1) (In the above series of formulas, R⁶, R⁷, n, A and J are each as defined above) (Step 1) In this step, a compound represented by the general formula (XXI) is reacted with a compound represented by the general formula (XXII) according to a conventional process to obtain a compound (XXIII). More paricularly, the reaction between the both is carried out in a solvent such as benzene, toluene, xylene, dimethylformamide, acetonitrile, dimethyl sulfoxide, dioxane or tetrahydrofuran in the presence of a base such as potassium carbonate, sodium carbonate, triethylamine or diisopropylethylamine under heating to obtain a compound (XXIII). (Step 2) A compound represented by the general formula (XXIII) wherein Y' is a leaving group such as a halogen atom or a methanesulfonyloxy group is converted into a compound (XXV) by the reaction thereof with an alkali metal salt of phthalimide (XXIV) such as potassium or sodium salt thereof in the presence of a base such as potassium carbonate or sodium carbonate. On the other hand, a compound represented by the general formula (XXIII) wherein Y' is a protected hydroxyl group such as a trityloxy or tert-butyldimethylsiloxy group is converted into a compound (XXV) by removing the protective group from the compound according to a conventional process and subjecting the obtained product to the reaction with phthalimide, triphenylphosphine and diethyl azodicarboxylate. In this reaction, a solvent which is inert to the reaction is used and examples thereof include dimethyl sulfoxide, dimethylacetamide, dimethylacetamide, acetonitrile and tetrahydrofuran. (Step 3) A compound (III') (corresponding to the compound represented by the formula (III) wherein R⁶ is H) can be prepared by heating a compound represented by the general formula (XXV) together with, for example, hydrazine monohydrate under reflux in the presence of an organic solvent such as methanol or ethanol. (Step 4) A compound represented by the general formula (III) can be prepared by reacting a compound represented by the general formula (III') (corresponding to a compound represented by the general formula (III) wherein R⁶ is H) with an aldehyde or ketone in the presence of a catalyst such as palladium/carbon, platinum oxide or Raney nickel in an atmosphere of hydrogen to carry out reductive amination. The aldehyde or ketone to be used in this step may be acetone, cyclobutanone, cyclopentanone or benzaldehyde. Further, a solvent such as methanol, ethanol, benzene, toluene, xylene, dimethylformamide, tetrahydrofuran, dioxane or ethyl acetate may be used in this step. Alternatively, a compound represented by the general formula (III) can be prepared by conventing a compound represented by the general formula (III') into an acid amide or carbamate, such as N-formyl, N-acetyl, N-methoxycarbonyl or N-ethoxycarbonyl derivative according to a conventional process and reducing the obtained acid amide or carbamate with a metal hydride complex such as lithium aluminum hydride or borane. This reduction is carried out in a solvent such as ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane or diethylene glycol dimethyl ether at a room temperature or by heating under refulux. Alternatively, the compound (XXV) can be prepared by the following process: (In the above series of formulas, R⁷, n, A and J are each as defined above) Namely, a compound (XXV) can be prepared by reacting a compound represented by the general formula (XXI) with a compound (XXVI) in the presence of a base such as potassium carbonate, sodium carbonate, triethylamine or diisopropylethylamine at a room temperature or by heating under reflux. In this reaction, a solvent such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide or acetonitrile may be used. (Preparation process 2) (In the above series of formulas, R⁷, n and J are each as defined above) (Step 1) A compound represented by the general formula (XXI) is reacted with a compound represented by the general formula (XXVII) in the absence of any solvent or in the presence of a solvent such as dichloromethane, chloroform, acetonitrile, dimethylformamide, dimethyl sulfoxide, ether, tetrahydrofuran, methanol or ethanol by heating under reflux to obtain a compound (XXVIII). (Step 2) A compound represented by the general formula (XXVIII) is hydrogenated in the presence of a catalyst such as palladium/carbon, platinum oxide or Raney nickel to obtain a compound represented by the formula (III''). This hydrogenation is carried out in a solvent such as methanol, ethanol, dimethylformamide or ethyl acetate under a normal or elevated pressure at an ordinary or higher temperature. (Preparation process 3) (In the above series of formulas, R⁶, R⁷, n and J are each as defined above) (Step 1) A lactam represented by the general formula (XXIX) is hydrolyzed under an acidic or basic condition according to a conventional process to obtain a compound represented by the general formula (XXX). This hydrolysis is carried out in a solvent such as water, water-containing methanol, water-containing ethanol, water-containing tetrahydrofuran or water-containing dioxane in the presence of hydrochloric acid, sodium hydroxide, potassium hydroxide or lithium hydroxide at a room temperature or by heating under reflux. (Step 2) A compound represented by the general formula (XXXII) can be prepared by reacting a compound represented by the general formula (XXX) with a compound represented by the general formula (XXXI) to carry out the acylation and methylating the obtained product with diazomethane. This acylation is carried out in an organic solvent such as dichloromethane, choloroform, acetonitrile, dimethylformamide, ether, tetrahydrofuran, dioxane, benzene, toluene or xylene in the presence of a base such as triethylamine, pyridine, potassium carbonate or sodium carbonate at an ordinary temperatures or under cooling with ice or by heating under reflux. (Step 3) A compound represented by the general formula (XXXIV) can be prepared by reacting a compound represented by the general formula (XXXII) with a compound represented by the general formula (XXXIII) to carry out amidation. This reaction is carried out in the absence of any solvent or in the presence of an organic solvent inert to the reaction, for example, methanol, ethanol, dichloromethane, chloroform, tetrahydrofuran, ether, dioxane, benzene, toluene, xylene or dimethyl sulfoxide at a room temperature or by heating under reflux. (Step 4) A compound represented by the general formula (XXXIV) is reduced with a metal hydride such as lithium aluminum hydride or borane to obtain a compound represented by the general formula (III'''). This reduction is carried out in an organic solvent such as tetrahydrofuran, ether, dioxane, 1,2-dimethoxyethane or diethylene glycol dimethyl ether at a room temperature or by heating under reflux. Objective compounds of the present invention other than those represented by the following general formula: (wherein R¹, R⁶, R⁷, n, A and J are each as defined above), i.e., compounds represented by the general formula (I') wherein the moiety represented by the formula: is replaced by the group represented by the formula: wherein Z' represents an oxygen or sulfur atom or an azomethyne group) can be prepared by the same processes as those described above. (Production process 4) (R⁶ in the formula (III) represents H). In the above formulae, R⁷, n and J are as defined above. (1st step) A compound (XXXVI) can be obtained by reacting a compound of formula (XXI) with a compound of formula (XXXV) without using any solvent or in a solvent such as dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, methanol or ethanol at room temperature or by heating under reflux. (2nd step) A compound of formula (III'') can be obtained by hydrogenating a compound of formula (XXXVI) in the presence of a catalyst such as palladium-carbon, platinum oxide or Raney nickel. The reaction solvents usable in this step include metahnol, ethanol, etc. The reaction is conducted at ambient or elevated temperature under atmospheric or elevated pressure. The compound of the present invention is effective in the therapy, prophylaxis, remission and amelioration of ischemic heart diseases such as coronary arteriosclerosis, various angina pectorises and myocardial infraction. When the compound of the present invention is to be used as a drug, it is administered orally or parenterally. Although the dose of the compound is not particularly limited but varies depending upon the degree of symptom, the age, sexuality, weight or sensitivity of a patient, the method, timing or interval of administration, the properties, prescription or kind of pharmaceutical preparation or the kind of an active ingredient, it is about 1 to 1000 mg, preferably about 5 to 500 mg, still preferably about 20 to 100 mg, per adult a day, which may be administered generally at once or in 2 to 4 portions. A solid medicine for oral administration containing the compound of the present invention as a principal agent is prepared by adding a filler and, if necessary, a binder, disintegrator, lubricant, coloring agent or corrigent to the compound and shaping the mixture into a tablet, coated tablet, granule, powder or capsule. Examples of the filler include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide and those of the binder include polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, acacia, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin and pectin. Examples of the lubricant include magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oils. The coloring agent may be any one which is permitted for use in drugs. Examples of the corrigent include powdered cocoa, mentha herb, aromatic powder, mentha oil, borneol and powdered cinnamon bark. Of course, the tablet or granule may be suitably coated with sugar, gelatin or the like. An injection containing the compound of the present invention as a principal agent is prepared by, if necessary, mixing the compound with a pH regulator, buffer agent, suspending agent, solubilizing agent, stabilizer, tonicity agent and/or preservative and converting the mixture into an intravenous, subcutaneous or intramuscular injection according to a conventional method. If necessary, the injection may be freeze-dried by a conventional process. Examples of the suspending agent include methylcellulose, polysorbate 80, hydroxyethylcellulose, acacia, powdered tragacanth, carboxymethylcellulose sodium and polyoxyethylene sorbitan monolaurate. Examples of the solubilizing agent include polyoxyethylene hardened castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol and ethyl ester of castor oil fatty acid. Further, the stabilizer includes sodium sulfite, sodium metasulfite and ether, while the preservative includes methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol. [Example] Examples of the present invention will now be described, though it is a matter of course that the present invention is not limited to them. Prior to the description of the Examples, processes for the preparation of the starting compounds (raw materials) to be used in the preparation of the compound according to the present invention will first be described. Preparative Example 1 Methyl (E)-4-(4-aminophenyl)-3-butenoate 7.5 g of (E)-4-(4-(acetylamino)phenyl)-3-butenoic acid was dissolved in a 1N aqueous solution of potassium hydroxide. The obtained solution was heated under reflux for 4 hours and cooled by allowing to stand. After the pH of the solution had been adjusted to about 3 by the addition of concentrated hydrochloric acid, the resulting solution was concentrated under a reduced pressure, followed by the addition of benzene. The obtained mixture was concentrated and freed from the water by azeotropic distillation to obtain a solid. 300 ml of methanol and 1 ml of concentrated sulfuric acid were added to the solid. The obtained mixture was heated under reflux for 3 hours, cooled by allowing to stand and concentrated under a reduced pressure. An aqueous solution of potassium carbonate was added to the residue and the obtained mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of common salt successively and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography [solvent: n-hexane/ethyl acetate (2 : 1)] to obtain 5.38 g of the title compound as a lightly orange-colored oil (yield: 82%). NMR(CDCl₃) δ ; 3.20(2H, d, J=6.2Hz), 3.6(2H, br), 3.70 (3H, s), 6.00(1H, dt, J=6.2Hz, 15.8Hz), 6.44(1H, d, J=15.8Hz), 6.5∼6.7(2H, m), 7.0 ∼7.2(2H, m) Preparative Example 2 Methyl (E)-4-(4-(N²-methylthioureido)phenyl)-3-butenoate 6.00 g of methyl (E)-4-(4-aminophenyl)-3-butenoate was dissolved in 60 ml of dioxane, followed by the addition of 2.75 g of methyl isothiocyanate. The obtained mixture was kept at 100°C for 5 hours to carry out a reaction. After the removal of the solvent from the reaction mixture, ethyl acetate was added to the residue to carry out crystallization. The insoluble matter thus formed was recovered by filtration to obtain 4.28 g of the title compound as a pale yellow powder. Further, the filtrate was concentrated and purified by silica gel column chromatography [solvent: n-hexane/ethyl acetate (1 : 1)] to obtain 0.95 g of the title compound (total: 5.23 g) (yield: 63%). melting point (°C): 129.5 to 130.5 elemental analysis as C₁₃H₁₆N₂O₂S: C H N S calculated (%) 59.06 6.10 10.60 12.13 found (%) 59.26 6.15 10.54 11.99 NMR(CDCl₃) δ ; 3.16(3H, d, J=4.7Hz), 3.26(2H, d, J=5.8Hz), 3.72(3H, s), 6.10(1H, br), 6.24(1H, dt, J= 5.8Hz, 16.2Hz), 6.51(1H, d, J=16.2Hz), 7.1 ∼7.3(2H, m), 7.3∼7.5(2H, m), 8.16 (1H,br s) Preparative Example 3 (E)-4-(4-(N²-Methylthioureido)phenyl)-3-butenoic acid The same procedure as that of Example 6 was repeated except that methyl (E)-4-(4-(N²-methylthioureido)phenyl)-3-butenoate was used. The title compound was obtained as a pale yellow powder (yield: 54%). melting point (°C): 150 to 152 elemental analysis as C₁₂H₁₄N₂O₂S: C H N S calculated (%) 57.78 5.64 11.19 12.81 found (%) 57.74 5.63 11.02 12.55 NMR(DMSO-d₆) δ ; 2.91(3H, d, J=4.4Hz), 3.16(2H, d, J=6.2Hz), 6.19(1H, dt, J=6.2Hz, 15.8Hz), 6.41(1H, d, J=15.8Hz), 7.34(4H, s), 7.67(1H, br d, J≅4Hz), 9.49(1H, br s) Preparative Example 4 Methyl (E)-4-(4-(N²-methylureido)phenyl-3-butenoate 3.00 g of methyl (E)-4-(4-aminophenyl)-3-butenoate was dissolved in 30 ml of 1,4-dioxane, followed by the addition of 1.11 ml of methyl isocyanate. The obtained mixture was heated under reflux for 3 hours and distilled under a reduced pressure to remove the solvent. Ether was added to the residue. The insoluble matter thus formed was recovered by filtration to obtain 0.87 g of the title compound as a pale yellow powder. The filtrate wsa concentrated and purified by silica gel column chromatography [solvent: dichloromethane/methanol (40 : 1)] to obtain 0.98 g of the title compound as a yellow solid (total: 1.85 g, yield: 48%). melting point (°C) : 146 to 148 elemental analysis as C₁₃H₁₆N₂O₃: C H N calculated (%) 62.89 6.50 11.28 found (%) 62.89 6.44 11.37 NMR(CDCl₃) δ ; 2.73(3H, d, J=4.8Hz), 3.22(2H, d, J=6.2Hz), 3.70(3H, s), 5.25∼5.54(1H, m), 6.12 (1H, dt, J=6.2Hz, 15.8Hz), 6.42(1H, d, J= 15.8Hz), 6.86 ∼7.39(5H, m) Preparative Example 5 (E)-4-(4-(N²-Methylureido)phenyl-3-butenoic acid The same procedure as that of Preparative Example 6 was repeated except that methyl (E)-4-(4-(N²-methylureido)phenyl)-3-butenoate was used. The title compound was obtained as a lightly orange-colored powder (yield: 74%). melting point (°C): 188.5 to 200.5 elemental analysis as C₁₂H₁₄N₂O₃: C H N calculated (%) 61.52 6.02 11.96 found (%) 61.60 6.06 11.81 NMR(DMSO-d₆) δ ; 2.63(3H, d, J=4.4Hz), 3.14(2H, d, J=7.2Hz), 5.95∼6.05(1H, m), 6.12(1H, dt, J=7.2Hz, 16.0Hz), 6.38(1H, d, J=10.0Hz), 7.25(2H, d, J=8.8Hz), 7.35(2H, d, J=8.8Hz), 8.52 (1H, s) Preparative Example 6 Methyl (E)-4-{4-((1-methylthio-2-nitroethen-1-yl)amino)phenyl}-3-butenoate 7.00 g of methyl (E)-4-(4-aminophenyl)-3-butenoate was dissolved in 120 ml of n-propanol, followed by the addition of 30.28 g of 1,1-bis-(methylthio)-2-nitroethylene. The obtained mixture was heated under reflux for 3 hours and distilled ro remove the solvent. The residue was purified by silica gel column chromatography (solvent: dichloromethane). The obtained solid was washed with ethyl ether to obtain 9.65 g of the title compound as a yellow powder (yield: 86%). melting point (°C): 136 to 138.5 elemental analysis as C₁₄H₁₆N₂O₄S: C H N S calculated (%) 54.53 5.23 9.09 10.40 found (%) 54.51 5.24 8.66 10.22 NMR(CDCl₃) δ ; 2.38(3H, s), 3.27(2H, d, J=5.7Hz), 3.72 (3H, s), 6.29(1H, dt, J=5.7Hz, 15.8Hz), 6.53(1H, d, J=15.8Hz), 6.68(1H, s), 7.22 (2H, d like, J=8Hz), 7.41(2H, d like, J=8 Hz), 11.79(1H, s) Preparative Example 7 Methyl (E)-4-{4-((1-methylamino-2-nitroethen-1-yl)amino)phenyl}-3-butenoate 1.00 g of methyl (E)-4-{4-((1-methylthio-2-nitroethen-1-yl)amino)phenyl}-3-butenoate was suspended in 5 ml of methanol, followed by the addition of 1.25 ml of a 40% solution of methylamine in methanol. The obtained mixture was stirred at a room temperature for 4 hours and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (30 : 1)] to obtain 0.5 g of the title compound as a pale yellow solid (yield: 54%). NMR(CDCl₃) δ ; 2.91(3H, br), 3.23(2H, d, J=5.8Hz), 3.68(3H, s), 6.19(1H, dt, J=5.8Hz, 16.2Hz), 6.43(1H, d, J=16.2Hz), 6.45(1H, br s), 6.96∼7.20(3H, m), 7.32(2H, d, J=7.9Hz), 11.50(1H, br) Preparative Example 8 (E)-4-{4-((1-Methylamino-2-nitroethen-1-yl)amino)phenyl}-3-butenoic acid The same procedure as that of Preparative Example 6 was repeated except that methyl (E)-4-{4-((1-methylamino-2-nitroethen-1-yl)amino)phenyl}-3-butenoate was used. The title compound was obtained as a lightly orange-colored powder (yield: 63%). NMR(DMSO-d₆) δ ; 2.94(3H, d, J=4.3Hz), 3.16(2H, d, J=5.4Hz), 6.12(1H, br s), 6.24(1H, dt, J=5.4Hz, 15.5Hz), 6.48(1H, d, J=15.5Hz), 7.12(2H, d, J=7.9Hz), 7.41(2H, d, J=7.9Hz) Preparative Example 9 N-Methyl-N-(2-(3,5-dimethoxyphenyl)ethyl)-1,4-diaminobutane 10.0 g of N-methyl-(2-(3,5-dimethoxyphenyl)ethyl)amine was dissolved in 130 ml of N,N-dimethylformamide, followed by the addition of 10.63 g of anhydrous potassium carbonate and 6.12 ml of 4-bromobutyronitrile. The reaction was carried out at a room temperature for 12 hours. Water was added to the reaction mixture. The obtained mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with water and a saturated aqueous solution of common salt successively, dried over anhydrous potassium carbonate and distilled to remove the solvent. 150 ml of ethanol, 11 ml of concentrated hydrochloric acid and 1 g of platinum oxide were added to the obtained residue to carry out hydrogenation at a room temperature under 3 kg/cm² for 12 hours. The catalyst was filtered out and the filtrate was concentrated under a reduced pressure, followed by the addition of concentrated aqueous ammonia. The obtained mixture was extracted with chloroform. The chloroform phase was dried over anhydrous potassium carbonate. After the solvent had been distilled off, the residue was distilled under a reduced pressure to obtain 10.85 g of the title compound as a colorless oil (yield: 80%). boiling point (°C): 165 ∼168 (0.5∼0.9mmHg) NMR(CDCl₃) δ ; 1.3 ∼1.9(6H, m), 2.2∼2.8(11H, m), 3.75 (6H, s), 6.2 ∼6.4(3H, m) Preparative Example 10 The following compounds were prepared in a similar manner to that of Preparative Example 21. · N-Methyl-N-(2-phenylethyl)-1,4-diaminobutane colorless oil boiling point (°C): 108∼114 (∼ 1 mmHg) NMR(CDCl₃) δ ; 1.15(2H, s), 1.25∼1.73(4H,m), 2.06∼ 2.92(11H, m), 7.02 ∼7.36(5H, m) · N-Methyl-N-(2-(4-methoxyphenyl)ethyl)-1,4 diaminobutane colorless oil boiling point (°C): 147∼155 (∼ 1 mmHg) NMR(CDCl₃) δ ; 1.27(2H,s), 1.34∼1.68(4H, m), 2.07∼ 2.85(11H, m), 3.76(3H, s), 6.69 ∼6.88 (2H, m), 6.97∼7.17(2H, m) · N-Methyl-N-(2-(3-methoxyphenyl)ethyl)-1,4-diaminobutane colorless oil boiling point (°C): 144∼150 (∼ 1 mmHg) NMR(CDCl₃) δ ; 1.40∼1.74(6H, m), 2.30(3H, s), 2.40 (2H t, J=7.2Hz), 2.57∼2.63(2H, m), 2.67∼2.78(4H, m), 3.80(3H, s), 6.72∼ 6.76(1H, m), 6.77∼6.81(1H, m), 7.17∼ 7.23(1H, m), 7.25∼7.27(1H, m) · N-Methyl-N-(2-(4-methylphenyl)ethyl)-1,4-diaminobutane colorless oil boiling point (°C): 128∼132 (0.5mmHg) NMR(CDCl₃) δ ; 1.40∼1.56(6H, m), 2.29(3H, s), 2.31 (3H, s), 2.40(2H, dt, J=0.8Hz, 7.6Hz), 2.55∼2.61(2H, m), 2.67∼2.76(4H, m), 7.09(4H, s) · N-Methyl-N-(2-(4-methoxy-3-methylphenyl)-ethyl)-1,4-diaminobutane coloress oil boiling point (°C): 148∼153 (∼ 1 mmHg) NMR(CDCl₃) δ ; 1.20(2H, s), 1.30∼1.62(4H, m), 2.20∼ 2.82(11H, m), 3.76(3H, s) 6.66(1H, d, J=9Hz), 6.80∼7.00(2H, m) Preparative Example 11 N-Methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-1,5-diaminopentane 2.5 g of N-methyl-(2-(3,4-dimethoxyphenyl)ethyl)amine was dissolved in 25 ml of N,N-dimethylformamide, followed by the addition of 1.95 g of anhydrous potassium carbonate and 1.65 ml of 4-bromovaleronitrile. The obtained mixture was reacted at a room temperature for 16 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated aqueous solution of common salt, dried over anhydrous potassium carbonate and distilled to remove the solvent. 40 ml of ethanol, 3.2 ml of concentrated hydrochloric acid and 0.3 g of platinum oxide were added to the obtained residue to carry out hydrogenation at a room temperature under 3 kg/cm² for 6 hours. The catalyst was filtered out and the filtrate was concentrated under a reduced pressure, followed by the addition of concentrated aqueous ammonia. The obtained mixture was extracted with chloroform. The chloroform phase was dried over anhydrous potassium carbonate and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol/concentrated aqueous ammonia (100 : 10 : 1)] to obtain 1.95 g of the title compound as a yellow oil (yield: 55%). NMR(CDCl₃), δ ; 1.2 ∼1.9(8H, m), 2.2∼2.9(11H, m), 3.83 (3H, s), 3.86(3H, s), 6.8 ∼6.9(3H, m) Preparative Example 12 3-((N-Methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino)-2-methylpropyl chloride 8.0 g of N-methyl-(2-(3,4-dimethoxyphenyl)ethyl)amine was dissolved in 120 ml of N,N-dimethylformamide, followed by the addition of 6.8 g of anhydrous potassium carbonate and 14.4 ml of 1-bromo-3-chloro-2-methylpropane. The obtained mixture was reacted at a room temperature for 12 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous potassium carbonate and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (50 : 1)] to obtain 4.67 g of the title compound as a pale yellow oil (yield : 40%). NMR(CDCl₃) δ ; 0.98(3H, d, J=6.8Hz), 1.6 ∼2.8(10H, m), 3.3 ∼3.5(2H, m), 3.83(3H, s), 3.85(3H, s), 6.6 ∼6.8(3H, m) Preparation Example 13 4-((N-Methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino)-3-methylpropionitrile 4.67 g of 3-((N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-amino)-2-methylpropyl chloride was dissolved in 40 ml of acetonitrile, followed by the addition of 2.13 g of potassium cyanide and 0.1 g of 18-crown-6. The obtained mixture was heated under reflux for 40 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: n-hexane/ethyl acetate (1 : 1)] to obtain 3.93 g of the title compound as a pale yellow oil (yield: 87%). NMR(CDCl₃) δ ; 1.02(3H, d, J=6.5Hz), 1.7 ∼2.8(12H, m), 3.82(3H, s), 3.84(3H, s), 6.6 ∼6.9(3H, m) Preparative Example 14 4-((N-Methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino-3-methylbutylamine 3.93 g of 4-((N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino)-3-methylpropionitrile was dissolved in 40 ml of ethanol to obtain a solution. 3.6 ml of concentrated hydrochloric acid and 0.3 g of platinum oxide were added to the solution to carry out hydrogenation at a room temperature under 3 kg/cm² for 7 hours. The catalyst was filtered out and the filtrate was concentrated under a reduced pressure, followed by the addition of concentrated aqueous ammonia. The obtained mixture was extracted with chloroform. The extract was dried over anhydrous potassium carbonate and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol/concentrated aqueous ammonia (100 : 10 : 1)] to obtain 2.98 g of the title compound as a pale yellow oil (yield: 75%). NMR(CDCl₃) δ ; 0.88(3H, d, J=6.5Hz), 1.0 ∼2.0(5H, m), 2.1 ∼2.3(5H, m), 2.4∼2.8(6H, m), 3.82 (3H, s), 3.84(3H, s), 6.6 ∼6.9(3H, m) Preparative Example 15 Methyl 4-((N-methyl-N-(3,4-dimethoxyphenylacetyl))amino)pentanoate 4.5 g of 1,5-dimethyl-2-pyrrolidinone was dissolved in 120 ml of 1N hydrochloric acid to obtain a solution. This solution was heated under reflux for 4 hours, cooled and distilled under a reduced pressure to remove the water. The obtained residue was passed through a Dowex ion-exchange column to obtain an amino carboxylic acid. This amino carboxylic acid was dissolved in 100 ml of water-containing acetone (water content: 50%), followed by the addition of 3.02 g of potassium carbonate. The obtained mixture was cooled to 0°C, followed by the slow dropwise addition of a solution of 8.54 g of 3,4-dimethoxyphenylacetyl chloride in 10 ml of acetone. The obtained mixture was stirred at a room temperature overnight and distilled under a reduced pressure to remove the acetone. The obtained aqueous phase was washed with ethyl acetate and the pH of the aqueous phase was adjusted to 2 to 3 with 2N hydrochloric acid. The resulting aqueous phase was extracted with chloroform thrice. The chloroform phase was distilled under a reduced pressure to remove the chloroform. 50 ml of ether was added to the residue. The obtained mixture was cooled to 0°C, followed by the gradual addition of a solution of diazomethane in ether. The obtained mixture was stirred at a room temperature for one hour. Excessive diazomethane was decomposed with acetic acid. The resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography [solvent: chloroform/methanol (100 : 1)] to obtain 2.05 g of the tile compound as a pale yellow oil (yield: 16%). NMR(CDCl₃) δ ; 1.09, 1.22(total 3H, d, J=7Hz), 1.54 ∼ 1.90(2H, m), 2.00∼2.46(2H, m), 2.72,2.74 (total 3H, s), 3.41∼3.74(5H,m), 3.82 (6H, s), 3.94∼4.20, 4.60∼4.87(total 1H, m), 6.71∼6.85(3H, m) Preparative Example 16 4-((N-Methyl-N-(3,4-dimethoxyphenylacetyl))amino)pentanamide 2.05 g of methyl 4-((N-methyl-N-(3,4-dimethoxyphenylacetyl))amino)pentanoate was dissolved in 20 ml of concentrated aqueous ammonia, followed by the addition of 3.3 g of ammonium chloride. The obtained mixture was stirred at a room temperature overnight and extracted with chloroform. The chloroform phase was dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: chloroform/methanol (50 : 1)] to obtain 1.20 g of the title compound as a pale yellow oil (yield: 63%). NMR(CDCl₃) δ ; 0.97, 1.10(total 3H, each t, J=7Hz), 1.53 ∼1.88(2H, m), 1.88∼2.10(2H, m), 2.72, 2.77(total 3H, each s), 3.56 ∼3.72(2H, m), 3.84(6H, s), 3.90∼4.19, 4.50∼4.88 (total 1H, each m), 6.68 ∼6.88(3H, m) Preparative Example 17 4-(N-Methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino)pentylamine 0.2 g of lithium aluminum hydride was suspended in 10 ml of tetrahydrofuran to obtain a suspension. 10 ml of a solution of 0.4 g of 4-((N-methyl-N-(3,4-dimethoxyphenylacetyl))amino)pentanamide in tetrahydrofuran was dropwise added to the suspension at a room temperature. The obtained mixture was heated under reflux for 4 hours and cooled. 1 ml of a 6N aqueous solution of sodium hydroxide and 1 ml of water were successively added to the resulting mixture, followed by stirring. The insoluble matter thus precipitated was filtered out and the filtrate was distilled under a reduced pressure. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol/concentrated aqueous ammonia (1000 : 100 : 1)] to obtain 0.2 g of the title compound as a pale yellow oil (yield: 55%). NMR(CDCl₃) δ ; 0.95(3H, d, J=7Hz), 1.48∼1.85(4H, m), 2.15(3H, s), 2.47∼2.92(6H, m), 3.84 (6H, s), 6.70∼6.90(3H, m) Preparative Example 18 N-(4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)-2-butyl)phthalimide 58.5 g of N-methyl-2-(3,4-dimethoxyphenyl)ethylamine was slowly dropwise added to 23.1 g of methyl vinyl ketone under cooling with ice. The obtained mixture was allowed to stand at a room temperature overnight and dissolved in 500 ml of methanol to obtain a solution. 14 g of sodium borohydride was added to the solution in portions under cooling with ice. The obtained mixture was stirred at a room temperature for 2 hours and excessive reagent was decomposed with acetone. The methanol was distilled off under a reduced pressure and the residue was extracted with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate, freed from the solvent and purified by silica gel column chromatography [solvent: chloroform/methanol (100 : 1)] to obtain 70 g of 4-((N-(2-(3,4-dimethoxyphenyl)ethyl)-N-methyl)amino)-2-butanol (yield: 87%). 4.74 g of 4-((N-(2-(3,4-dimethoxyphenyl)ethyl)-N-methyl)amino)-2-butanol, 4.65 g of triphenylphosphine and 2.61 g of phthalimide were dissolved in 50 ml of tetrahydrofuran. The obtained solution was cooled to 0°C, followed by the dropwise addition of 3.09 g of diethyl azodicarboxylate. The obtained mixture was stirred at a room temperature overnight and filtered. The filtrate was concentrated under a reduced pressure. The residue was made acidic by the addition of 1N hydrochloric acid and washed with ethyl acetate. The aqueous phase was made basic with lithium hydroxide and extracted with chloroform. The chloroform phase was dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: chloroform/methanol (100 : 1)] to obtain 4.2 g of the title compound as a pale yellow oil (yield: 60%). NMR(CDCl₃) δ ; 1.50(3H, d, J=7Hz) 2.02(3H, s), 2.24(3H, s), 2.14∼2.68(8H, m), 3.86(3H, s), 3.89 (3H, s), 4.34∼4.61(1H, m), 6.62∼6.88 (3H, m), 7.64∼7.96(4H, m) Preparative Example 19 4-((N-Methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino)-2-butylamine 4.8 g of N-(4-((N'-(2-(3,4-dimethoxyphenyl)ethyl)-N'-methyl)amino)-2-butyl)phthalimide was dissolved in 50 ml of ethanol, followed by the addition of 0.73 g of hydrazine monohydrate. The obtained mixture was heated under reflux for 2 hours and cooled. The formed precipitate was filtered out and the filtrare was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography [solvent: chloroform/methanol/concentrated aqueous ammonia (250 : 25 : 1)] to obtain 2.58 g of the title compound as a pale yellow oil (yield: 80%). NMR(CDCl₃) δ ; 1.07(3H, d, J=6Hz), 1.32∼1.89(4H, m), 2.28(3H, s), 2.32∼3.07(7H, m), 3.81(3H, s), 3.84(3H, s), 6.55∼6.85(3H, m) Preparative Example 20 N-Methyl-N-(4-(tert-butyldimethylsiloxy)-butan-2-yl)-[2-(3,5-dimethoxyphenyl)ethyl]amine 2.16 g of methanesulfonyl chloride was slowly added to 30 ml of a solution of 3.50 g of 4-(tert-butyldimethylsiloxy)butan-2-ol and 1.90 g of triethylamine in ether under cooling with ice. After 30 minutes, water was added to the obtained mixture, followed by the extraction with ether. The ether phase was dried over anhydrous sodium sulfate and filtered. The filtrate was distilled to remove the ether. The residue was dissolved in 30 ml of acetonitrile, followed by the addition of 3.37 g of N-methyl-[2-(3,5-dimethyoxypheny)ethyl]amine and 3.48 g of potassium carbonate. The obtained mixture was heated under reflux for 12 hours and cooled to precipitate a crystal. The crystal was filtered out and the filtrate was concentrated under a reduced pressure and extracted with ether thrice. The ether phase was washed with an aqueous solution of common salt, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under a reduced pressure and purified by silica gel column chromatography [solvent: chloroform/methanol (100 : 1)] to obtain 3.33 g of the title compound as a yellow oil (yield: 56%). NMR(CDCl₃) δ ; 0.04(6H, s), 0.89(9H, s), 0.95(3H, d, J=6.6 Hz), 1.38 ∼1.92(2H, m), 2.25(3H, s), 2.40∼2.96(5H, m), 3.58(2H, t, J=6.6Hz), 3.77(6H, s), 6.20∼6.39(3H, m) Preparative Example 21 3-(N-Methyl-N-(2-(3,5-dimethoxyphenyl)ethyl)amino)butylamine 3.33 g of N-methyl-N-(4-(tert-butyldimethylsiloxy)-butan-2-yl)-[2-(3,5-dimethoxyphenyl)ethyl]amine was dissolved in 13 ml of tetrahydrofuran to obtain a solution. 13 ml of a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1 mmol/ml) was slowly dropwise added to the solution. The obtained mixture was stirred at a room remperature for 3 hours and distilled to remove the solvent. The residue was extracted with ether thrice and the ether phase was dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The residue was dissolved in 25 ml of tetrahydrofuran, followed by the addition of 1.29 g of phthalimide and 2.29 g of triphenylphosphine. 1.52 g of diethyl azodicarboxylate was slowly added to the obtained mixture at a room temperature. The obtained mixture was stirred overnight and distilled to remove the solvent. The residue was made acidic with 0.5 N hydrochloric acid and washed with ether. The aqueous phase was made basic with lithium hydroxide and extracted with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate and the filtrate was concentrated under a reduced pressure to obtain a residue. This resiude was dissolved in 20 ml of ethanol, followed by the addition of 200 mg of hydrazine monohydrate. The obtained mixture was heated under reflux for 2 hours and cooled. The white precipitate thus formed was filtered out and the filtrate was concentrated under a reduced pressure, followed by the addition of 20 ml of a 10% solution of sodium hydroxide. The obtained mixrure was extracted with chloroform thrice. The chloroform phase was washed with a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate and concentrated under a reduced pressure to obtain 830 mg of the title compound as a yellow oil (yield: 36%). NMR(CDCl₃) δ ; 0.92(3H, d, J=6.3Hz), 1.18∼2.08(4H, m), 2.24(3H, s), 2.52∼2.92(7H, m), 3.77(6H, s), 6.20∼6.36(3H, m) Preparative Example 22 N-Methyl-N-(2-(3-chloro-4-methoxyphenyl)ethyl)-1,4-diaminobutane A mixture comprising 5.00 g of N-methyl-(2-(3-chloro-4-methoxyphenyl)ethylamine, 9.49 g of N-(4-bromobutyl)phthalimide, 4.16 g of anhydrous potassium carbonate and 50 ml of N,N-dimethylformamide was stirred at a room temperature for 14 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate and the ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated, followed by the addition of 50 ml of ethanol and 1.5 ml of hydrazine monohydrate. The obtained mixture was heated under reflux for 2 hours, cooled by allowing to stand and filtered to remove insoluble matter. The filtrate was distilled to obtain 3.16 g of the title compound as a colorless oil (yield: 47%). boiling point (°C): 167∼172 (∼ 1 mmHg) NMR(CDCl₃) δ ; 1.20(2H, s), 1.30∼1.64(4H, m), 2.20∼ 2.84(11H, m), 3.82(3H, s), 6.77(1H, d, J=8.6Hz), 6.98(1H, dd, J=2.2Hz, 8.6Hz), 8.15(1H, d, J=2.2Hz) Preparative Example 23 The following compounds were prepared in a similar manner to that of Preparative Example 34. · N-Methyl-N-(2-(4-chlorophenyl)ethyl)-1,4-diaminobutane colorless oil boiling point (°C): 143∼147 (∼ 1 mmHg) NMR(CDCl₃) δ ; 1.25∼1.72(6H, m), 2.28(3H, s), 2.39 (2H, t, J=7.6Hz), 2.54∼2.60(2H, m), 2.66∼2.76(4H, m), 7.12(2H, d, J=8.8Hz), 7.24(2H, d, J=8.8Hz) · N-Methyl-N-(2-(3,4-dichlorophenyl)ethyl)-1,4-diaminobutane colorless oil boiling point (°C): 163∼165 (∼ 1 mmHg) NMR(CDCl₃) δ ; 1.36∼1.68(6H, m), 2.27(3H, s), 2.38 (2H, t, J=7.6Hz), 2.54∼2.59(2H, m), 2.67∼2.74(4H, m), 7.03(1H, dd, J=2.4Hz, 8.4Hz), 7.24(1H, d, J=2.4Hz), 7.33(1H, d, J=8.4Hz) The compounds of the following examples were prepared according to the methods described before. Example 1 (E)-[N-(3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N²-methylthioureido)phenyl)-3-butenamide pale yellow oil NMR(CDCl₃) δ ; 1.5 ∼1.9(2H, m), 2.24(3H, s), 2.3∼2.7 (6H, m), 3.00(3H, d, J=6.2Hz), 3.09(2H, d, J=4.8Hz), 3.2 ∼3.5(2H, m), 3.83(6H, s), 6.08(1H, dt, J=4.8Hz, 15.1Hz), 6.2 ∼6.5 (2H, m), 6.5 ∼6.8(3H, m), 7.0∼7.4(5H, m), 8.34(1H, br s) Example 2 (E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N²-methylureido)phenyl)-3-butenamide pale yellow oil NMR(CDCl₃) δ ; 1.40∼1.84(2H, m), 2.20(3H, s), 2.32∼ 2.84(9H, m), 2.96(2H, d, J=6.2Hz), 3.14 ∼3.28(2H, m), 3.81(3H, s), 3.83(3H, s), 5.75∼6.14(2H, m), 6.32(1H, d, J=15.8Hz), 6.52∼6.81(3H, m), 7.04(2H, d, J=8.8Hz), 7.23(2H, d, J=8.8Hz), 7.57(1H, t, J=5Hz), 8.06(1H, s) Example 3 (E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl-N'-methyl)amino)butyl]-4-(4-(N²-methylureido)phenyl)-3-butenamide white solid NMR(CDCl₃) δ ; 1.40∼1.76(4H, m), 2.12∼2.86(12H, m), 2.96∼3.35(4H, m), 3.75(6H, s), 5.76∼ 6.45(6H, m), 6.78∼7.29(5H, m), 7.92(1H, s) Example 4 (E)-N-[3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N²-methylthioureido)phenyl)-3-butenamide white amorphous product NMR(CDCl₃) δ ; 1.48∼1.85(2H, m), 2.24(3H, s), 2.38∼ 2.76(6H, m), 2.99(2H, d, J=6.2Hz), 3.09 (3H, d, J=4.4Hz), 3.18∼3.45(2H, m), 3.83 (6H, s), 5.83∼6.51(3H, m), 6.55∼6.83 (3H, m), 7.06∼7.38(5H, m), 8.32(1H, br s) Example 5 (E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-[4-((1-methylamino-2-nitroethen-1-yl)amino)phenyl]-3-butenamide lightly orange-colored amorphous product NMR(CDCl₃) δ ; 1.44∼1.80(2H, m), 2.21(3H, s), 2.30∼ 3.06(11H, m), 3.15 ∼3.20(2H, m), 3.81 (3H, s), 3.82(3H, s), 6.08(1H, dt, J=6.2Hz, 15.8Hz), 6.39(1H, d, J=15.8Hz), 6.40(1H, br), 6.52 ∼6.80(4H, m), 7.05(2H, d, J= 8.6Hz), 7.12∼7.36(3H, m) Production Example 24 5-Bromo-2-thiophenecarboxaldehyde dimethyl acetal: 50 g of 5-bromo-2-thiophenecarboxaldehyde was dissolved in 200 mℓ of methylene chloride. A suspension of 50 g of montmorillonite K-10 in about 50 mℓ of trimethyl o-formate was added to the solution and the solution was stirred at room temperature for about 30 min. Montmorillonite K-10 was filtered off and the methylene chloride layer was washed with a saturated aqueous sodium hydrogencarbonate solution and then with a saturated aqueous common salt solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure to give 55.9 g of the intended compound in the form of a light yellow oil. NMR(CDCl₃, 400MHz) δ ; 3.35(6H, s), 5.54(1H, s), 6.82(1H, d, J= 3.5Hz), 6.95(1H, d, J=3.5Hz) Production Example 25 Methyl (E)-4-(4-(N²-ethylthioureido)phenyl)-3-butenoate: 2.00 g of methyl (E)-4-(4-aminophenyl)-3-butenoate was dissolved in 20 mℓ of dioxane. 1.1 mℓ of ethyl isothiocyanate was added to the solution and a reaction was conducted at 100°C for 10 h. The solvent was distilled off and benzene was added to the residue. An insoluble matter was filtered off and the residue was concentrated again. The product was purified according to silica gel column chromatography (solvent: n-hexane/ethyl acetate = 2/1) to give 1.65 g of the intended compound in the form of a light yellow solid (yield: 57%). m.p. (°C): 88 to 89 (recrystallized from n-hexane/ethyl acetate) EMA for C₁₄H₁₈N₂O₂S: C H N S calcd (%) 60.41 6.52 10.06 11.52 found (%) 60.45 6.48 10.03 11.57 NMR(CDCl₃, 400MHz) δ ; 1.19(3H, t, J=7.2Hz), 3.27(2H, d, J=6.8Hz), 3.67(2H, m), 3.73(3H, s), 5.95(1H, br), 6.31(1H, dt, J=6.8Hz, 16Hz), 6.48(1H, d, J=16Hz), 7.14(2H, d, J=8.4Hz), 7.42(2H, d, J=8.4Hz), 7.64(1H, br s) The following compound was produced in the same manner as that described above: Methyl (E)-4-(4-(N²-n-propylthioureido)phenyl)-3-butenoate: light yellow solid (yield: 69%) m.p. (°C): 76.5 to 78 (recrystallized from n-hexane/ethyl acetate) EMA for C₁₅H₂₀N₂O₂S: C H N S calcd (%) 61.61 6.89 9.58 10.97 found (%) 61.66 6.80 9.67 10.86 NMR(CDCl₃, 400MHz) δ ; 0.92(3H, t, J=7.2Hz), 1.60(2H, sextet, J=7.2Hz), 3.27(2H, d, J=6.8Hz), 3.60 (2H, q, J=7.2Hz), 3.73(3H, s), 6.00(1H, br), 6.32(1H, dt, J=6.8Hz, 15.6Hz), 6.48 (1H, d, J=15.6Hz), 7.14(2H, d, J=8.4Hz), 7.43(2H, d, J=8.4Hz), 7.61(1H, s) Production Example 26 Methyl (E)-4-(4-N²-isopropylthioureido)phenyl)-3-butenoate: 2.00 g of (E)-4-(4-aminophenyl)-3-butenoate and 3.21 mℓ of triethylamine were dissolved in 35 mℓ of chloroform and the solution was stirred under cooling with ice. 0.88 mℓ of thiophosgene was dropped thereinto and the mixture was heated under reflux for 30 min. The reaction mixture was cooled again with ice. 0.98 mℓ of isopropylamine was dropped thereinto and the mixture was heated under reflux for 30 min. After leaving to cool, 1N hydrochloric acid was added thereto. The product was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was distilled off. The product was purified according to silica gel column chromatography (solvent: n-hexane/ethyl acetate = 3/1) to give 1.75 g of the intended compound in the form of a yellow powder (yield: 57%). m.p. (°C): 123 to 124.5 (recrystallized from n-hexane/ethyl acetate) EMA for C₁₅H₂₀N₂O₂S: C H N S calcd (%) 61.61 6.89 9.58 10.97 found (%) 61.53 6.83 9.60 10.95 NMR(CDCl₃, 400MHz) δ ; 1.21(6H, d, J=6.4Hz), 3.27(2H, d, J=7.2Hz), 3.73(3H, s), 4.58(1H, m), 5.79(1H, d, J=8.8 Hz), 6.32(1H, dt, J=7.2Hz, 15.6Hz), 6.49 (1H, d, J=15.6Hz), 7.13(2H d, J=8.4Hz), 7.42(2H, d, J=8.4Hz), 7.68(1H, s) Production Example 27 3-((2-(3,4-Dimethoxyphenyl)ethyl)amino)butyronitrile: A mixture of 10.0 g of 2-(3,4-dimethoxyphenyl)ethylamine with 14 mℓ of crotononitrile was stirred at 100°C for 30 h. The mixture was concentrated under reduced pressure and the product was purified according to silica gel column chromatography (solvent: ethyl acetate) to give 7.57 g of the intended compound in the form of a light brown oil (yield: 55%). NMR (CDCl₃, 400 MHz) δ; 1.22 (3H, d, J = 6.4 Hz), 1.38 (1H, br), 2.43 (2H, d, J = 5.6 Hz), 2.70 - 2.80 (2H, m), 2.81 - 2.92 (2H, m), 3.04 (1H, m), 3.87 (3H, s), 3.88 (3H, s), 6.74 (1H, d, J = 2 Hz), 6.75 (1H, dd, J = 2, 8 Hz), 6.81 (1H, d, J = 8 Hz) Production Example 49 3-(N-(2-(3,4-Dimethoxyphenyl)ethyl-N-methyl)amino)butyronitrile: A mixture of 20.0 g of N-methyl-N-(2-(3,4-dimethoxyphenyl)ethylamine with 50 mℓ of crotononitrile was heated under reflux for 30 h. The mixture was concentrated under reduced pressure and the product was purified according to silica gel chromatography (solvent: n-hexane/ethyl acetate = 3/2) to give 9.49 g of the intended compound in the form of a yellow solid (yield: 35%). NMR (CDCl₃, 400 MHz) δ; 1.17 (3H, d, J = 6.8 Hz), 2.30 (1H, dd, J = 7.6, 16.8 Hz), 2.31 (3H, s), 2.47 (1H, dd, J = 6, 16.8 Hz), 2.56 - 2.74 (4H, m), 3.15 (1H, m), 3.86 (3H, s), 3.88 (3H, s), 6.73 (1H, d, J = 2 Hz), 6.74 (1H, dd, J = 2, 8.4 Hz), 6.80 (1H, d, J = 8.4 Hz) Production Example 28 3-((2-(3,4-Dimethoxyphenyl)ethyl)amino)butylamine: 7.57 g of 3-((2-(3,4-dimethoxyphenyl)ethyl)amino)butyronitrile was dissolved in 60 mℓ of a solvent . 0.5 g of platinum oxide and 5 mℓ of concentrated hydrochloric acid were added to the solution and hydrogenation was conducted at room temperature under 3 kg/cm² for 4 h. The catalyst was filtered off and the product was thoroughly washed with methanol and concentrated under reduced pressure. Dilute aqueous ammonia was added thereto. After extraction with chloroform followed by drying over anhydrous potassium carbonate, the solvent was distilled off. After distillation under reduced pressure, 5.23 g of the intended compound was obtained in the form of a colorless oil (yield: 68%). bp (°C); 154 ∼ 159 (∼ 1 mmHg) NMR (CDCl₃, 400 MHz) δ; 1.05 (3H, d, J = 6 Hz), 1.1 - 1.4 (3H, br), 1.45 (1H, m), 1.55 (1H, m), 2.65 - 2.85 (6H, m), 2.91 (1H, m), 3.86 (3H, s), 3.87 (3H, s), 6.74 (1H, d, J = 2 Hz), 6.75 (1H, dd, J = 2, 8.8 Hz), 6.81 (1H, d, J = 8.8 Hz) The following compound was produced in the same manner as that described above: 3-(N-((2-(3,4-dimethoxyphenyl)ethyl)-N-methyl)amino)butylamine: colorless oil b.p. (°C); 151 ∼ 155 (∼ 1 mmHg) NMR (CDCl₃, 90 MHz) δ; 0.93 (3H, d, J = 6.3 Hz), 0.93 - 1.82 (4H, m), 2.12 (3H, s), 2.24 - 2.93 (7H, m), 3.78 (3H, s), 3.83 (3H, s), 6.54 - 6.84 (3H, m) Example 6 (E)-[N-(3-(N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-[4-(N³-methyl-N²-carbamoylguanidino)phenyl]-3-butenamide: 1.00 g of (E)-[N-(3-(N'-(2-(3,5-dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-[4-(N³-methyl-N²-cyanoguanidino)phenyl]-3-butenamide was dissolved in a mixed solvent comprising 10 mℓ of methanol and 5 mℓ of chloroform and the solution was cooled with ice. 2.2 mℓ of a 4.6 M solution of hydrogen chloride in methanol was added thereto and stirred at room temperature for 14 h. The solvent was distilled off under reduced pressure. Dilute aqueous ammonia was added to the residue. The product was extracted with chloroform and dried over anhydrous potassium carbonate. The solvent was distilled off under reduced pressure. The product was purified according to silica gel column chromatography (solvent: dichloromethane/methanol/concentrated aqueous ammonia = 1000/100/3) to give 0.82 g of the intended compound in the form of a yellow oil. (Yield: 80%) NMR(CDCl₃, 400MHz) δ ; 1.05∼1.65(4H, m), 2.17(3H, s), 2.42∼ 2.65(6H, m), 2.83(3H d, J=4.4Hz), 3.01 (2H, d, J=8Hz), 3.29∼3.38(2H, m), 3.77 (6H, s), 4.78(1H, br), 6.19(1H, dt, J=8Hz, 16Hz), 6.26(2H, d, J=2.4Hz), 6.31(1H, t, J=2.4Hz), 6.41(1H, d, J=16Hz), 7.12(2H, d, J=8.4Hz), 7.21(1H, br), 7.28(1H, br), 7.33(1H, d, J=8.4Hz)

Claims: Claims for the following Contracting States : DE, GB, FR, IT, NL, SE, LI, CH, BE, AT, LU, DK A butenoic acid compound having the formula (I) or a pharmacologically acceptable salt thereof: wherein R¹ represents a group represented by the formula (wherein R² and R 2' may be the same or different from each other and each represent a hydrogen atom or a straight-chain or branched C₁₋₆ alkyl, cycloalkyl or allyl group, or alternatively R² and R 2' may together form a ring, X represents an oxygen or sulfur atom, a group represented by the formula: = N-R³ (wherein R³ represents a carbamoyl group), or a group represented by the formula: (wherein R' and R'' may be the same or different from each other and each represent a hydrogen atom or nitro group), Z represents a vinylene (-CH=CH-) group, R⁶ and R⁷ may be the same or different from each other and each represent a hydrogen atom or a straight-chain or branched C₁₋₆ alkyl, cycloalkyl or allyl group, A represents a C₁₋₆ alkylene group which may have a straight-chain or branched C₁₋₆ alkyl or hydroxy substituted, straight-chain or branched C₁₋₆ alkyl substituent bonded to any carbon of the group, J represents a group represented by the formula: (wherein R⁸, R⁹ and R¹⁰ may be the same or different from each other and each represent a hydrogen or halogen atom, a C₁₋₆ alkyl or C₁₋₆ alkoxy group, and n represents an integer of 1 to 6 The compound or salt as claimed in Claim 1, in which the compound has the formula (C): wherein R2 and R2' are hydrogen or a C₁₋₆ alkyl, X is sulfur or =N-R3, R3 being defined before, Z is vinyl, A is an alkylene having 3 or 4 carbon atoms, m is 2, J is as defined above. The compound or salt as claimed in Claim 1, in which the compound has the formula (D): wherein R², R 2' , R⁶, A, R⁷, R⁸, R⁹, R¹⁰ and n are as defined in claim 1. The compound or salt as claimed in Claim 1, which is selected from the group consisting of: (E)-N-[3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N²-methylthioureido)phenyl)-3-butenamide (E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N²-methylureido)phenyl)3-butenamide (E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(N²-methylureido)phenyl)-3-butenamide (E)-N-[3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N²-methylthioureido)phenyl)-3-butenamide (E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-((1-methylamino-2-nitroethen-1-yl)amino)phenyl]-3-butenamide. A pharmacological composition which comprises a pharmacologically effective amount of the compound or salt as defined in Claim 1 and a pharmacologically acceptable carrier. The use of the compound of claim 1 for preparing a medicament effective in treating, preventing, remitting or ameliorating ischemic heart diseases. Claims for the following Contracting States : ES, GR A process for preparing a butenoic acid compound having the formula (I) or a pharmacologically acceptable salt thereof: wherein R¹ represents a group represented by the formula (wherein R² and R 2' may be the same or different from each other and each represent a hydrogen atom or a straight-chain or branched C₁₋₆ alkyl, cycloalkyl or allyl group, or alternatively R² and R 2' may together form a ring, X represents an oxygen or sulfur atom, a group represented by the formula: = N-R³ (wherein R³ represents a carbamoyl group), or a group represented by the formula: (wherein R' and R'' may be the same or different from each other and each represent a hydrogen atom or nitro group), Z represents a vinylene (-CH=CH-) group, R⁶ and R⁷ may be the same or different from each other and each represent a hydrogen atom or a straight-chain or branched C₁₋₆ alkyl, cycloalkyl or allyl group, A represents a C₁₋₆ alkylene group which may have a straight-chain or branched C₁₋₆ alkyl or hydroxy substituted, straight-chain or branched C₁₋₆ alkyl substituent bonded to any carbon of the group, J represents a group represented by the formula: (wherein R⁸, R⁹ and R¹⁰ may be the same or different from each other and each represent a hydrogen or halogen atom, a C₁₋₆ alkyl or C₁₋₆ alkoxy group, and n represents an integer of 1 to 6, which process comprises reacting a carboxylic acid represented by the general formula or a reactive derivative thereof with an amino compound represented by the general formula to obtain the butenoic acid compound having the formula (I), wherein R¹, R⁶, R⁷, A, n and J are each as defined above, and optionally converting the compound into a pharmacologically acceptable salt thereof. Process as claimed in Claim 1, in which the compound of the formula (I) is represented by the formula (C): wherein R2 and R2' are hydrogen or a C₁₋₆ alkyl, X is sulfur or =N-R3, R3 being defined before, Z is vinyl, A is an alkylene having 3 or 4 carbon atoms, m is 2, J is as defined above. Process as claimed in Claim 1, in which the compound of the formula (I) has the formula (D): wherein R², R 2' , R⁶, A, R⁷, R⁸, R⁹, R¹⁰ and n are as defined in claim 1. Process as claimed in Claim 1, in which a compound of the formula (I) is selected from the group consisting of: (E)-N-[3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N²-methylthioureido)phenyl)-3-butenamide (E)-N-[3-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N²-methylureido)phenyl)3-butenamide (E)-N-[4-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)butyl]-4-(4-(N²-methylureido)phenyl)-3-butenamide (E)-N-[3-((N'-(2-(3,5-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-(N²-methylthioureido)phenyl)-3-butenamide (E)-N-[4-((N'-(2-(3,4-Dimethoxyphenyl)ethyl)-N'-methyl)amino)propyl]-4-(4-((1-methylamino-2-nitroethen-1-yl)amino)phenyl]-3-butenamide. Process for preparing a pharmacological composition, which process comprises the step of adding a pharmacologically effective amount of the compound or salt as defined in Claim 1 to a pharmacologically acceptable carrier. The use of a compound as defined in Claim 1 for preparing a medicament effective in treating, preventing, remitting or ameliorating ischemic heart diseases.

Inventors: ADACHI HIDEYUKI, ISHIBASHI KEIJI, KABASAWA YASUHIRO, KAWAMURA TAKANORI, MINAMI NORIO, OGAWA TOSHIAKI, OZAKI FUMIHIRO, ADACHI, HIDEYUKI, ISHIBASHI, KEIJI, KABASAWA, YASUHIRO, KAWAMURA, TAKANORI, MINAMI, NORIO, OGAWA, TOSHIAKI, OZAKI, FUMIHIRO
Applicants: EISAI CO LTD, EISAI CO., LTD.
Application year: 1990
Main classification: C07D211
IPC codes: C07C275, C07C257, A61K31, C07D213, C07D405, C07D333, C07D521, C07D233, C07C279, C07D239, C07C235, C07C323, C07C335, C07D307, A61P9, C07C237, C07D209, C07D409