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    • 专利摘要:
    An N-acylpiperazine derivative or a salt thereof expressed by the followingformula 1:wherein R1 represents a pyridylcarbonyloxy lower alkyl group, a benzoylamino loweralkyl group, benzyl group, carbamoyl group, pyridyl group, or diphenylmethyl group; R2 represents a lower alkyl group or a lower alkoxy group; n represents an integer of 0 to 2; R3 represents a hydrogen atom, an alkenyl group, or benzyl group; and m represents an integer of 1 to 3. The N- acylpiperazine derivative or a salt thereof has an anti- ulcer effect,an antibacterial activity against Helicobacter pyroli, and high safety to be available forprevention or cure of various ulcers.
    公开号:EP0832887A1
    申请号:EP97307709
    申请日:1997-09-30
    公开日:1998-04-01
    发明作者:Chikao Nishino；Fumitaka Sato；Hirotada Fukunishi
    申请人:Shiseido Co Ltd；
    IPC主号:C07D295-00
    专利说明:
    FIELD OF THE INVENTION
    The present invention relates to an N-acylpiperazine derivative and, inparticular, to an N-acylpiperazine derivative having an antibacterial activity againstHelicobacter pyroli or an anti- ulcer effect.BACKGROUND OF THE INVENTION
    Various theories have been proposed with respect to a cause of ulcer inhuman. In particular, it has been elucidated that stress, taking of non-steroidalanti-inflammatory drugs for curing rheumatic diseases, and the like are closelyrelated to ulcer formation, mainly due to relatively excess gastric acid secretion.Accordingly, it is important to suppress the acid secretion in order to prevent ulcerformation and to cure it.
    On the other hand, it has been considered that Helicobacter pyroli, which is arod normally existing in stomach, generates ammonia due to its strong urease activity,thereby inducing ulcer and persistence of itself. Since it persistently lives withinmucus and mucosa, it becomes the greatest cause for recurrence of ulcer.Accordingly, it has been considered that the recurrence of ulcer can be prevented ifthis bacterium is sterilized.
    Though various kinds of medicaments for curing ulcer have beenconventionally developed, few medicaments have been known to have an effect forpreventing stress ulcers from generating and an antibacterial activity againstHelicobacter pyroli.DISCLOSURE OF THE INVENTION
    In view of the problems of the above- mentioned prior art, the object of thepresent invention is to provide a compound which is excellent in preventing ulcer from generating and to provide antibacterial drug against Helicobacter pyroli andanti- ulcer drug including such a compound as a main component.
    As a result of the diligent studies conducted by the inventors, it has beenfound that a specific N-acylpiperazine derivative is effective against various kinds ofulcer due to its antibacterial property against Helicobacter pyroli or its acid secretioninhibition as a main action mechanism. Thus, the present invention has beenaccomplished.
    Namely, an N- acylpiperazine derivative or a salt thereof in accordance withthe present invention is expressed by the following formula 1:
    wherein R1 represents a pyridylcarbonyloxy lower alkyl group, a benzoylamino loweralkyl group, benzyl group, carbamoyl group, pyridyl group, or diphenylmethyl group; R2 represents a lower alkyl group or a lower alkoxy group; n represents an integer of 0 to 2; R3 represents a hydrogen atom, an alkenyl group, or benzyl group; and m represents an integer of 1 to 3.

    An antibacterial drug against Helicobacter pyroli in accordance with thepresent invention comprises, as an effective ingredient, said N-acylpiperazinederivative or the pharmacologically acceptable salt thereof, together with apharmaceutically acceptable carrier and/or adjuvant.
    An anti-ulcer drug in accordance with the present invention comprises, asan effective ingredient, said N-acylpiperazine derivative or the pharmacologicallyacceptable salt thereof, together with a pharmaceutically acceptable carrier and/oradjuvant.
    A method for the treatment of peptic ulcers in man or mammals inaccordance with the present invention comprises administering an effective amount ofsaid N- acylpiperazine derivative or the pharmacologically acceptable salt thereof to ahost.
    A method for the inhibition of acid secretion in stomach of man or mammalsin accordance with the present invention comprises administering an effective amountof said N- acylpiperazine derivative or the pharmacologically acceptable salt thereof toa host.
    A method for the inhibition of growth of Helicobacter pyroli in stomach ofman or mammals in accordance with the present invention comprises administeringan effective amount of said N-acylpiperazine derivative or the pharmacologicallyacceptable salt thereof to a host.
    A method for the prevention of peptic ulcers in man or mammals inaccordance with the present invention comprises administering an effective amount ofsaid N- acylpiperazine derivative or the pharmacologically acceptable salt thereof to ahost.BRIEF DESCRIPTION OF THE DRAWINGS
    Figs. 1 to 5 show examples of steps for manufacturing the N- acylpiperazinederivative in accordance with the present invention andFigs. 6 to 9 show examples of steps for manufacturing material compoundsfor the N- acylpiperazine derivative in accordance with the present invention.
    EXAMPLES
    In the compound in accordance with the present invention, the"pyridylcarbonyloxy lower alkyl group" found at R1 represents a group expressed bythe following formula a:
    wherein p represents an integer of 1 to 4 and, preferably, 2.
    The "benzoylamino lower alkyl group" found at R1 represents a groupexpressed by the following formula b:
    wherein Y represents a substituted or an unsubstituted phenyl group; and qrepresents an integer of 1 to 4 . Y is preferably 3,4-methylenedioxyphenyl groupand q is preferably 2.
    Benzyl group found at R1 can have a substituted group on its aromatic ring.For such benzyl group having a substituted group, piperonyl group can be cited, forexample.
    Carbamoyl group at R1 can have a substituted group on its nitrogen atom.For such a substituted group, a lower alkyl group can be introduced. Here, the loweralkyl group can be exemplified by that of R2 mentioned below. Preferably, it is abranched alkyl group and, particularly preferably, isopropyl group.
    Pyridyl group at R1 can have a substituted group on its pyridine ring and,preferably, unsubstituted pyridyl group.
    In the present invention, the lower alkyl group found at R2 is a straight orbranched alkyl group having 1 to 6 carbon atoms. Examples thereof include methyl,ethyl, n-propyl, n- butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n- pentyl,1-ethylpropyl, isoamyl, and n- hexyl group. Preferably it is a branched lower alkyl group and, particularly preferably, isobutyl group.
    The lower alkoxy group found at R2 represents an alkoxy group derivedfrom the above-mentioned lower alkyl group. A preferable example thereof ismethoxy group.
    An alkenyl group at R3 refers to a straight or branched alkenyl group whichhas at least one double bond and has 2 to 20 carbon atoms. While the double bondhas two kinds of configurations, namely, cis and trans, each double bond in alkenylgroup may have either configurations. Among such a alkenyl group, a branchedalkenyl group is preferable. Further, prenyl, geranyl, neryl or farnesyl group ispreferable. Furthermore, prenyl or geranyl group is preferable.
    Benzyl group found at R3 can have a substituted group on its aromatic ring.A preferable example of such a substituted group is a halogen atom includingchlorine, bromine, iodine, and fluorine atom. The most preferable example thereof isfluorine atom. Also, the fluorine atom is bonded to para- position, preferably.
    A preferable compound of the present invention may be a compound inwhich R3 is an alkenyl group in the above-mentioned formula 1. Particularlyprefelably, it may be expressed by the following formula 2:
    wherein Ra represents methyl group or prenyl group; R1 represents a pyridylcarbonyloxy lower alkyl group, a benzoylamino loweralkyl group, or benzyl group; and R2, m, and n are same as those in the above- mentioned formula 1.

    In the compound in which R3 is an alkenyl group in formula 1, it ispreferable that n is 1 or 2 and R2 is isobutyl or methoxy group.
    Also, in the compound in which R3 is an alkenyl group in formula 1, it is preferable that n is 0.
    A preferable compound of the present invention may be a compound inwhich R3 is benzyl group, R2 is a lower alkyl group, and both of n and m are 1 inthe above- mentioned formula 1. Particularly preferably, it may be expressed by thefollowing formula 3:
    wherein R1 represents carbamoyl, benzyl, or pyridyl group; R2 represents a lower alkyl group; Rb represents a halogen atom; and I represents 0 or 1.

    In the formula 3, it is preferable that I is 1 and Rb is fluorine atom bondedto para-position.
    In the compound in which R3 is benzyl group, R2 is a lower alkyl group,and both of n and m are 1 in the above- mentioned formula 1, it is preferable that R2is isobutyl group.
    A preferable compound of the present invention may be expressed by thefollowing formula 4:
    wherein R1 represents benzyl or diphenylmethyl group, and R2 represents a loweralkyl group.
    In formula 4, R2 is isobutyl group, preferably.
    In the following, while an example of the method for manufacturing thecompound of the present invention will be explained, it should not be restrictedthereto.
    Among the compounds (I) of the present invention expressed by formula 1,the compound (I-a) in which R3 is an alkenyl or benzyl group can be manufacturedby reaction formula A shown in Fig. 1.
    In reaction formula A, from a carboxylic acid (II) and a substituted piperazine(III), by using a known amide-bond forming reaction such as mixed anhydridemethod, acid chloride method, DCC method, or azide method, the N-acylpiperazinederivative (I-a) of the present invention can be obtained. Here, R1 in the compound(III) and R2, m, and n in the compound (II) are defined as formula 1 mentioned above,while R3 in the compound (III) represents an alkenyl group or benzyl group.
    In the mixed anhydride method, by using an activator such as diphenylphosphinic chloride, ethyl chloroformate, isobutyl chloroformate, or pivaloyl chloride,the carboxylic acid (II) is converted into its corresponding anhydride and then reactedwith the compound (III). As an additive, for example, an organic base such as triethylamine, pyridine, or N- methylmorpholine can be used. As a solvent, for example, ahalogenated hydrocarbon such as dichloromethane or chloroform; an aromatichydrocarbon such as benzene, toluene, or xylene; an ether such as tetrahydrofuran ordioxane; or an amide such as N,N-dimethylformamide or N,N-dimethylacetamidecan be used. While the reaction temperature and reaction time may be changedaccording to the material compounds used, the reaction is usually effected at atemperature within the range of - 15°C to the reflux temperature of the solvent.
    In the acid chloride method, as an activator, for example, phosphoruspentachloride, phosphorus trichloride, or thionyl chloride is used to convert thecarboxylic acid (II) into the corresponding acid chloride and then the latter is reactedwith the compound (III). As an additive, for example, an organic base such as triethylamine, pyridine, or N- methylmorpholine can be used. As a solvent, for example, a halogenated hydrocarbon such as dichloromethane or chloroform; an aromatichydrocarbon such as benzene, toluene, or xylene; or an amide such asN,N- dimethylformamide or N'N- dimethylacetamide can be used. While thereaction temperature and reaction time may be changed according to the materialcompounds used, the reaction is usually effected at a temperature within the range of0°C to the reflux temperature of the solvent.
    In the DCC method, as a condensing agent, for example, N,N'- dicyclohexylcarbodiimide (DCC) or 1- ethyl-3- (3- dimethylaminopropyl)carbodiimidehydrochloride (WSCI) can be used. As a solvent, for example, a halogenatedhydrocarbon such as dichloromethane or chloroform; an aromatic hydrocarbon such asbenzene, toluene, or xylene; an ether such as tetrahydrofuran or dioxane; or an amidesuch as N,N-dimethylformamide or N,N- dimethylacetamide can be used. Ifnecessary, this reaction may be effected while 1-hydroxybenzotriazole (HOBt) orN-hydroxy succinimide (HOSu) is added thereto. While the reaction temperatureand reaction time may be changed according to the material compounds used, thereaction is usually effected at a temperature within the range of 0°C to the refluxtemperature of the solvent.
    In the azide method, as an activator, for example, diphenylphosphorylazide isused to convert the carboxylic acid (II) into the corresponding azide and then thelatter is reacted with the compound (III). As an additive, for example, an organicbase such as triethylamine, pyridine, or N-methylmorpholine can be used. As asolvent, for example, a halogenated hydrocarbon such as dichloromethane orchloroform; an aromatic hydrocarbon such as benzene, toluene, or xylene; or an amidesuch as N,N-dimethylformamide or N,N-dimethylacetamide can be used. While thereaction temperature and reaction time may be changed according to the materialcompounds used, the reaction is usually effected at a temperature within the range of0°C to the reflux temperature of the solvent.
    Specifically, for example, diphenylphosphinic chloride or pivaloyl chloride isused as an activator for the mixed anhydride method, while triethylamine is used as an additive to effect the reaction in a solvent such as chloroform or N,N-dimethylformamide at a temperature within the range of -15°C to room temperature, therebyattaining the aimed object.
    Also, the compound (I-a) in which R3 is an alkenyl or benzyl group informula 1 can be synthesized by reaction formula B shown in Fig. 2.
    At the first step of reaction formula B, from a carboxylic acid (II) and aprotected piperazine (IV), by using the condensation methods described in reactionformula A, a compound (V) can be obtained. In the compound (II), R2, m, and n aredefined as formula 1 mentioned above, while R3 is an alkenyl or benzyl group, R4in the compound (IV) represents an amino- protecting group which can be a urethanetype protecting group such as benzyloxycarbonyl group or tert-butyloxycarbonylgroup, an acyl type protecting group such as formyl group or tosyl group, or an alkyltype protecting group such as trityl group as long as no problem occurs in thesubsequent reaction.
    At the second step of reaction formula B, the compound (V) is subjected toa deprotecting reaction so as to obtain a compound (VI).
    For this deprotecting reaction, various kinds of known methods can be usedaccording to the kind of the amino-protecting group R4. For example, hydrazine,hydrochloric acid, hydrogen peroxide, or the like can be used as the deprotectingagent when R4 is formyl group. Specifically, for example, hydrochloric acid withinthe range of 1N to 6N is used to effect the reaction in methanol at a temperatureWithin 0°C to room temperature, thereby attaining the aimed object.
    At the third step of reaction formula B, the compound (VI) is reacted with ahalogenated compound (VII) in the presence of a base so as to obtain theN-acylpiperazine derivative (I-a) of the present invention. In the compound (VII),X represents a halogen atom, while R1 is defined as formula 1 mentioned above.
    As a base, for example, an inorganic base such as potassium carbonate,potassium hydroxide, sodium hydroxide, or sodium hydride; or an organic base suchas triethylamine or pyridine can be used. Specifically, for example, potassium carbonate is used as a base, and the reaction is effected in a solvent such as acetone,N,N-dimethylformamide, dichloromethane, or benzene at a temperature within therange of 0 °C to the reflux temperature of the solvent, thereby attaining the aimedobject.
    Among the compounds (I) of the present invention, a compound in which R1is a benzoylamino lower alkyl group, for example, a compound (I-b) can besynthesized by reaction formula C shown in Fig. 3.
    At the first step of the reaction formula C, the compound (V), which can besynthesized by the first step of reaction formula B mentioned above, is subjected to areduction so as to obtain an amine (XVIII). Here, R4' represents a cyanoalkyl group.
    In reduction of the cyano group at this reaction, a known method can beused For example, Birch reduction method, a reduction method by metal hydridecomplex compound, a method using Raney nickel, or the like can be used. In Birchreduction, while sodium or lithium is used mainly as a catalyst, the reaction can beeffected in the mixed solvent of liquid ammonia and alcohol such as methanol orethanol. When the metal hydride complex compound is used, as a reagent, lithiumaluminum hydride, aluminum hydride, sodium borohydride, or the like can be used.As a solvent, for example, an ether such as diethylether, tetrahydrofuran or dioxane;or an alcohol such as methanol, ethanol, or butanol can be used. When sodiumborohydride is used, Raney nickel, aluminium chloride, cobalt chloride, or the like canbe used as a catalyst. When Raney nickel is used, methanol saturated by ammonia isused as a solvent and hydrogenation is effected under a pressure, thereby attainingthe aimed object. While the reaction temperature and reaction time may be changedaccording to the material compounds used in all cases, the reaction is usually effectedat a temperature within the range of 0°C to the reflux temperature of the solvent.
    Specifically, for example, lithium aluminum hydride is suspended intetrahydrofuran while being cooled with ice and, after the compound (XIII) is droppedthereto, the reaction is effected at a temperature within the range of 0°C to the refluxtemperature of the solvent. Then, the reaction solution is treated with water, aqueous sodium hydroxide solution, or the like, thereby attaining the aimed object.
    At the second step of the reaction formula C, by amidation of the compound(XVII) with A-CO-Y, the compound (I-b) of the present invention can be obtained.Here, Y is defined as that of formula b mentioned above, while A represents hydroxygroup, a halogen atom, or -OCOY. This amidation can be effected under a reactioncondition similar to that of reaction formula A.
    Among the compound (I) of the present invention, a compound in which R3is benzyl group, for example, a compound expressed by the above- mentioned formula3 can be synthesized by reaction formula D shown in Fig. 4.
    At the first step of reaction formula D, from a carboxylic acid (VIII) and thesubstituted piperazine (III), by using the condensation method described in reactionformula A, a compound (IX) can be obtained R1 in the compound (III) and R2 inthe compound (VIII) are defined as those of formula 1. R6 in the compound (VIII)represents a protecting group for a phenolic hydroxy group. As long as no problemoccurs in the subsequent reaction, benzyl group, various kinds of substituted benzylgroups, benzyloxycarbonyl group, tert-butyloxycarbonyl group, and the like can beused therefor.
    At the second step of reaction formula D, the compound (IX) is subjected toa deprotecting reaction so as to obtain the compound (XIX) in which R5 is hydrogenatom.
    For this deprotecting reaction, various kinds of known methods can be usedaccording to the kind of the protecting group R5. For example, when R5 is benzylgroup, reductive elimination method or acid-treated elimination method can be used.Specifically, for example, under a catalytic reduction condition, by using palladium-carbon as a catalyst, a reaction is effected in a solvent such as ethanol under ahydrogen gas atmosphere at a temperature within the range of room temperature tothe reflux temperature of the solvent, thereby attaining the aimed object.
    At the third step of reaction formula D, the compound (XIX) is reacted withthe appropriately substituted benzyl halide (X) in the presence of a base so as to obtain the compound (I-c) of the present invention in which R3 is benzyl group. Inthe compound (X), Rb and 1 are defined as those of formula 3, while X represents ahalogen atom.
    As a base in this reaction, for example, an inorganic base such as potassiumcarbonate, potassium hydroxide, sodium hydroxide, and sodium hydride; or an organicbase such as triethylamine and pyridine can be used. Specifically, for example,potassium carbonate is used as a base so as to effect a reaction in a solvent such asacetone and N,N-dimethylformamide at a temperature within the range of roomtemperature to the reflux temperature of the solvent, thereby attaining the aimedobject.
    Here, as in the case of reaction formula D, a compound in which R3 ishydrogen atom or benzyl group and neither of n nor m is 1 in the compound (I) of thepresent invention can be synthesized.
    Among the compound (I) of the present invention, the compound in whichR3 is hydrogen atom and R1 is benzyl group or diphenylmethyl group, for example, acompound expressed by formula 4 mentioned above can be synthesized by reactionformula E shown in Fig. 5.
    At the first step of reaction formula E, the compound (VIII) is subjected to adeprotecting reaction so as to obtain a compound (XX). This reaction can be effectedunder the condition similar to that of the second step of reaction formula D.
    At the second step of reaction formula E, from the carboxylic acid (XX) andthe substituted piperazine (III), by using the condensation method described inreaction formula A, a compound (I-d) of the present invention can be obtained. R1in the compound (III) and R2 in the compound (VIII) are defined as those of formula4.
    In the following, a manufacturing method of each material compound will beexplained
    The material compound (II) in reaction formula A and B may becommercially available or can be synthesized by a known method. For example, the material compound (II-a) in which R3 is benzyl group and both of n and m are 1 inthe material compound (II) can be manufactured by reaction formula F shown in Fig.6.
    At the first step of reaction formula F, the compound (XI) is reacted withthe substituted benzyl halide (X) in the presence of a base to obtain the compound(XII). R2 in the compound (XI) is defined as that of formula 1, while Rb and 1 in thecompound are defined as those of formula 3. X in the compound (X) represents ahalogen atom. R6 in the compound (XI) represents a carboxyl-protecting groupwhich may be a lower alkyl group such as methyl group, ethyl group, or tert-butylgroup, phenacyl group, or trichloroethyl group as long as no problem occurs in thesubsequent reaction.
    As a base in this reaction, for example, an inorganic base such as potassiumcarbonate, potassium hydroxide, sodium hydroxide, and sodium hydride; or an organicbase such as triethylamine and pyridine can be used. Specifically, for example,potassium carbonate is used as a base so as to effect a reaction in a solvent such asacetone and N,N-dimethylformamide at a temperature within the range of roomtemperature to the reflux temperature of the solvent, thereby attaining the aimedobject.
    At the second step of reaction formula F, the compound (XII) is subjected toa deprotecting reaction so as to obtain the carboxylic acid(II-a).
    For this deprotecting reaction, various kinds of known methods can be usedaccording to the kind of the protecting group R5. For example, when R6 is methylor ethyl group, known ester hydrolysis method can be used for deprotection.Specifically, for example, an inorganic base such as sodium hydroxide and potassiumhydroxide is used so as to effect a reaction in a solvent such as water, methanol, andethanol at a temperature within the range of room temperature to the refluxtemperature of the solvent, thereby attaining the aimed object.
    Among the material compound (II) in reaction formula A and B, for example,a compound (II-b) in which R3 is an alkenyl group can be synthesized by reaction formula G shown in Fig. 7.
    In reaction formula G, R2, m, and n in the compound (XIII) are defined asthose of formula 1. R7 represents a carboxyl-protecting group which may be alower alkyl group such as methyl group, ethyl group, and tert-butyl group; phenacylgroup; or trichloroethyl group as long as no problem occurs in the subsequentreaction. R3 in the compound (XIV) represents an alkenyl group, while X representsa halogen atom.
    In reaction formula G, an alkenyl halide (XIV) is reacted with a compound(XIII) in the presence of a base and then hydrolyzed so as to synthesize thecarboxylic acid (II-b).
    The first step of this reaction can be effected in the presence of a base.Sodium amide, triethylamine, sodium hydride, sodium hydroxide, potassium carbonate,barium oxide, silver oxide, or the like can be used therefor. Also, a catalytic amountof potassium iodide can be added thereto. As a solvent, for example, an alcohol suchas methanol, ethanol, and butanol; an aromatic compound such as benzene, toluene,xylene, and pyridine; an ether such as diethylether, tetrahydrofuran, and dioxane; anamide such as N,N-dimethylformamide and N,N-dimethylacetamide; or a ketonesuch as dimethylsulfoxide and acetone can be used. While the reaction temperatureand reaction time may be changed according to the material compounds used, thereaction is usually effected at a temperature within the range of 0°C to the refluxtemperature of the solvent.
    Specifically, for example, the compound (XIII) is dissolved in tetrahydrofuranor N,N- dimethylformamide and, after sodium hydride as a base is added and stirredtherein, the alkenyl halide is added thereto so as to effect a reaction at a temperaturewithin the range of room temperature to the reflux temperature of the solvent,thereby attaining the aimed object.
    In the reaction of the second step, the ester compound (XV) is hydrolyzedin the presence of an acid or a base so as to synthesize the carboxylic acid (II-b).Hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, or the like can be used as the acid, while sodium hydroxide, potassium hydroxide, potassium t- butoxide, or the likecan be used as a base. As a solvent, a carboxylic acid such as formic acid and aceticacid; an alcohol such as methanol and ethanol; water; or a mixed solvent thereof canbe used. While the reaction temperature and reaction time can be changed accordingto the material compounds used, the reaction is usually effected at a temperaturewithin the range of 0°C to the reflux temperature of the solvent.
    Specifically, for example, the ester compound (XV) is dissolved in an alcoholsuch as methanol and ethanol and then an aqueous sodium hydroxide or potassiumhydroxide solution is added thereto so as to effect a reaction at a temperature withinthe range of room temperature to the reflux temperature of the solvent, therebyattaining the aimed object.
    The material compound (XIV) used in reaction formula G can besynthesized by reaction formula H in Fig. 8.
    In reaction formula H, X and R3 are defined as those of reaction formula G.In this reaction, by halogenation of an alcohol (XVI), an alkenyl halide (XIV) can beobtained.
    For this reaction, a general method known as halogenation of hydroxy groupcan be used. As a reagent of halogenation, for example, a strong acid such ashydrochloric acid or hydrobromic acid; a phosphorus compound such as phosphorustribromide, phosphorus trichloride, or phosphorus pentachloride; thionyl chloride;N-halogenosuccinimide and methyl sulfide; triphenylphosphine and a halogenatedhydrocarbon; or methanesulfonyl chloride and lithium halide is used to effect thereaction. As a solvent, for example, a halogenated hydrocarbon such asdichloromethane and chloroform; an aromatic compound such as benzene, toluene,xylene, and pyridine; an ether such as diethylether, tetrahydrofuran and dioxane; oran amide such as N,N-dimethylformamide or N,N-dimethylacetamide can be usedWhile the reaction temperature and reaction time may be changed according to thematerial compounds used, the reaction is usually effected at a temperature within therange of 0°C to the reflux temperature of the solvent.
    Specifically, for example, in the presence of lithium chloride andtriethylamine, methanesulfonyl chloride is used so as to effect a reaction in a solventsuch as acetone at a temperature within the range of 0°C to room temperature,thereby attaining the aimed object.
    The material compound (III) in reaction formula A and D may becommercially available or can be synthesized by reaction formula I in Fig. 9.
    At the first step of reaction formula I, the protected piperazine (IV) isreacted with the appropriate halide (VII) in the presence of a base so as to obtain thecompound (XVII). R4 in the compound (IV) represents an amino-protecting groupwhich can be a urethane type protecting group such as benzyloxycarbonyl group andtert-butyloxycarbonyl group; an acyl type protecting group such as formyl group andtosyl group; or an alkyl type protecting group such as trityl group as long as noproblem occurs in the subsequent reaction. X in the compound (VII) represents ahalogen atom.
    As a base, for example, an inorganic base such as potassium carbonate,potassium hydroxide, sodium hydroxide, and sodium hydride; or an organic base suchas triethylamine and pyridine can be used. Specifically, for example, potassiumcarbonate is used as a base so as to effect a reaction in a solvent such as acetone,N,N-dimethylformamide, dichloromethane, and benzene at a temperature within therange of 0 °C to the reflux temperature of the solvent, thereby attaining the aimedobject.
    At the second step of reaction formula I, the compound (XVII) is subjectedto a deprotecting reaction so as to obtain the compound (III).
    For this deprotecting reaction, various kinds of known methods can be usedaccording to the kind of the amino-protecting group R4. For example, hydrazine,hydrochloric acid, hydrogen peroxide, or the like can be used as the deprotectingagent when R4 is formyl group. Specifically, for example, hydrochloric acid withinthe range of 1N to 6N is used to effect the reaction in methanol at a temperaturewithin the range 0 °C to room temperature, thereby attaining the aimed object.
    Among the material compounds used in the above-mentioned reactionformulas, those with no preparation methods described, for example, compound (IV),(VII), (VIII), and (X), may be commercially available or easiiy synthesized by using aknown method.
    Also, examples of salts of the N- acylpiperazine derivative (I) of the presentinvention with an acid include salts with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, and phosphoric acid and salts with organic acids suchas acetic acid, propionic acid, citric acid, lactic acid, oxalic acid, maleic acid, furnaricacid, succinic acid, tartaric acid, and methane sulfonic acid. These salts can be easilymanufactured by a normal method.
    The N-acylpiperazine derivative in accordance with the present inventionhas a strong effect against stress ulcer and an excellent effect for suppressing gastricacid secretion. Further, it has an antibacterial activity against Helicobacter pyroliwhich is supposed to be a cause for recurrence of ulcer. Furthermore, it has a highsafety. Accordingly, it is useful as a medicament for curing and preventing pepticulcer in man or mammals and, particularly, gastric ulcer in man. Conventionally,there has hardly been known such a compound which has both effect for suppressinggastric acid secretion and antibacterial activity against Helicobacter pyroli.Accordingly, it is indicated that the compound of the present invention is not onlyeffective in preventing and curing ulcer but also in preventing the recurrence thereof.
    When the compound of the present invention is administered as amedicament for curing and preventing peptic ulcer, it may be administered orally astablet, powder, granule, capsule, syrup, or the like as well as parenterally assuppository, injection, external drug, instillation or the like. While the amount ofadministration may be outside of the range mentioned below according to the degreeof symptom, personal difference, age, kind of ulcer, or the like, it should of course beadjusted so as to fit the individual circumstances in specific cases. Usually 0.01 to200 mg/kg or, preferably, 0.05 to 50 mg/kg or, more preferably, 0.1 to 10 mg/kg isadministered per day for an adult in a single dose or several doses.
    When formulating the medicament, a normal manufacturing method is usedwith a normal formulation carrier. If necessary, pharmacologically andpharmaceutically acceptable additives may be added thereto.
    Namely, when preparing an oral solid formulation, after an excipient and, ifnecessary, a binder, a decaying agent, a luster, a coloring agent, a correctives, and thelike are added to the main medicament, a normal method is used to form tablet,coated tablet, granule, powder, capsule, or the like.
    Examples of the excipient include lactose, corn starch, sucrose, glucose,sorbitol, crystalline cellulose, and silicon dioxide. Examples of the binder includepolyvinylalcohol, polyvinylether, ethyl cellulose, methyl cellulose, gum arabic,tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch, andpolyvinylpyrrolidone. Examples of the decaying agent include starch, agar, gelatinpowder, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, calciumcitrate, dextrin, and pectin. Examples of the luster include magnesium stearate, talc,polyethyleneglycol, silica, and hardened vegetable oil. As the coloring agent, thosepermitted to be added to medicines are used. Examples of the correctives includecocoa powder, menthol, aromatic acid, mentha oil, borneol, and cinnamon powder. Ifnecessary, these tablet and granule can be coated with sugar-coating,gelatin-coating, and the like.
    When preparing an injection, if necessary, a pH-adjusting agent, a buffer, astabilizer, a solubilizer, and the like are added to the main medicament and then anormal method is used to form subcutaneous, intramuscular, and intravenous injectiondrugs.
    In the following, the present invention will be explained in further detail byspecifically examples. However, the present invention should not be restricted tothese examples.
    First, test methods used for evaluating these examples will be explained. WIS: Restraint and Water Immersion Stress- Induced Ulcer Inhibition Testi) Meaning
    The degree of inhibition of the stress ulcer formation is tested.ii) Method
    Male Crj:SD or Slc:SD rats (6 to 7- week- old) were fasted overnight, butallowed free access to water. Each group has 5 to 8 of these rats. The samplecompound was dissolved or suspended in an aqueous solution of 03% sodiumcarboxymethylcellulose or 0.05% Tween 80 and then was orally administered (100mg/10 ml/kg). To a control group, the vehicle was administered. 10 minutes later,the rats were placed in a stress cage and immersed to the level of xipfoid process in awater bath (21°C) for 7 hours. At the end of the stress, the rats were sacrificed byinhalation of ether or carbon dioxide. Then, the stomach of each was removed,inflated by injecting 10 ml of 5% formalin neutral buffer solution, and immersed in 1%formalin neutral buffer solution for 30 minutes or more to be fixed. The stomach wasincised along the greater curvature and then the length of each erosion in theglandular portion was determined under dissecting microscope. The sum of thelength of erosions per stomach was defined as ulcer index (UI).iii) Judgment Standard
    The effect obtained when 100 mg/kg of the sample compound had beenadministered was expressed as ulcer formation inhibitory rate (%) as follows:ulcer formation inhibitory rate (%) = (1- (UI in sample group/UI in control group)) × 100 CAP: Acid Secretion Inhibition Test In Vitroi)Meaning
    The acid secretion inhibitory activity in a cell level is studied. It can alsobe used for studying the mechanism of the effect.ii)Methodii- a) Preparation of isolated gastric fundus gland suspension
    First, an isolated gastric fundic gland sample was prepared. Namely, a maleJapanese White rabbit (2.5 to 3 kg) was anesthetized to death with Nembutal™ andthen the abdomen was incised. Immediately thereafter, the stomach was removedand, after its pyloric and cardiac antrum were severed, incised along its greatercurvature into two sheets. The gastric contents adhering to the mucosal surface waswashed out with ice-cooled PBS (-) and then carefully washed therein. The gastricwall was spread on a cork board with its mucosal surface facing up and the feed andmucus thereon were completely removed with sterile gauze. The mucosa wasseparated therefrom by a spatula and then collected in ice-cooled PBS (-). Afterbeing washed twice with PBS (-), the mucosa was minced into 2-3mm3 pieces byscissors. These pieces were further washed twice with a nutrient solution. Thenutrient solution comprises 132.4 mM of NaCl, 5.4 mM of KCI, 5 mM of Na2HPO4.12H2O, 1 mM of NaH2PO4 · 2H2O, 1.2 mM of MgSO4, 1 mM of CaCl2, 25 mM ofHEPES, 2 mg/ml of glucose, and 1 mg/ml of BSA. Into 70 ml of the nutrient solutioncontaining 1 mg/ml of collagenase, minced mucosal pieces were dispersed andintensely stirred in a conical flask with a stirrer at 37°C for 40 to 60 minutes.During this period, 100% O2 was sprayed on the nutrient solution surface and the pHwas appropriately measured such that it was immediately adjusted to pH 7.4, whenthe value was therebelow, with a base. The nutrient solution was added to thereaction solution so as to attain the total amount of about 200 ml. After being filteredthrough a mesh, the suspension was divisionally introduced into 50 ml centrifugetubes and left for 15 minutes such that gastric fundic gland was deposited. Thesupernatant was repeatedly removed by an aspirator, dispersed in the nutrientsolution, and then left such that the gastric fundic gland was washed three times. Atthis time, without using a pipette, the suspension was alternately introduced into twocentrifuge tubes so as to effect dispersion. The number of cells was counted undermicroscope and adjusted to 1.6 × 106 cells/ml.ii- b) [14C]- aminopyrine uptake test
    Then, [14 C]- aminopyrine uptake test was performed. After an Eppendorf tube was weighed, 10 µl (final concentration: 10-5M) of histamine dissolved in theabove- mentioned nutrient solution, 10 µl (final concentration: 10-5M) of the testcompound dissolved in DMSO, and 10 µl (final concentration: 0.05 µ Ci/ml) of [14C]-aminopyrine diluted with the nutrient solution were introduced therein and then970 µl of the isolated gastric fundic gland suspension prepared above was addedthereto. Subsequently, this mixture was shaken at 37°C for 40 minutes at 125cycles/minute. After being centrifuged for 30 minutes, 200 µl of its supernatant wascollected into a mini-vial, while the rest was removed by an aspirator. The glandpellet was completely dried as the tube with its lid being opened was kept for onenight in a drying oven at 80°C and then the lid was closed and the weight wasdetermined at room temperature. Then 100 µl of 1N KOH was added thereto andthe tube with its lid being closed was treated at 60°C for 1 to 2 hours so as todissolve the pellet. Then, the contents thereof were transferred to a mini-vial. Intothe mini-vial containing the supernatant or gland pellet, 4 ml of Atomlite™ wasadded and then the radioactivity was measured by a liquid scintillation counter. Here,after the radioactivity of the gland pellet was corrected by using a sample in which 20mM of NaSCN was added so as to cancel the hydrogen ion concentration gradient, theintegration ratio of aminopyrine specifically trapped by the gland pellet was calculatedThis experiment was performed in duplicate.ii-c) Calculation of the accumulation rate of aminopyrine
    Here, its principle will be briefly explained. In the isolated gastric fundicgland, acid is accumulated in a space between its secretory tubule and intraglandularcavity. Aminopyrine is weak base (pKa=5.0) and nonionic in a neutral solution so asto freely pass through the cell membrane, whereas it is ionized in an acidic solutionand thus cannot pass through the cell membrane due to its electric charge.Therefore, aminopyrine is accumulated in a closed acidic space within the isolatedgastric fundic gland. In view of this characteristic, the accumulation rate (R) ofaminopyrine is calculated by the following equation:R = ((corrected radioactivity of precipitate)/(radioactivity of supernatant)) × (200/(mg dry weight of gland pellet)) iii) Judgment Standard
    The effect of the sample compound at the final concentration of 10-5 M wasexpressed by acid secretion inhibitory rate (%) as follows:acid secretion inhibitory rate (%) =(1- (R in sample group/R in control group)) x 100 uAHP: Antibacterial Activity Test Against Helicobacter pyrolii) Meaning
    The minimum inhibitory concentration (MIC) against Helicobacter pyroli(microaerophilic gram-negative bacterium which is supposed to deeply involve inpathogenesis, relapse, and recrudescence of ulcer, referred to as "HP" in thefollowing) is measured so as to find out compounds which have antimicrobial activityagainst Helicobacter pyroli. ii)Method
    MICs were determined by the agar dilution method. The stock culture(-80°C) of HP NCTC 11637 was thawed and cultured on tripticase soy agarsupplemented with 5% sheep blood at 37°C in an atmosphere of 5% O2, 10% CO2,and 85%N2. Grown colonies were transferred to the same plate and precultured for3 days under the same condition.
    A 1,000 µg/ml solution of the sample compound containing DMSO notmore than 25% was serieslly diluted to be various concentrations 2- fold in sterilepurified water. 100 µl volume from each dilution was mixed thoroughly with 900 µlof brucella agar supplemented with 5% horse blood and solidified in a 24 well microplate, thereby yielding an MIC measurement plate.
    An appropriate amount of the colony grown on the plate by preculturing wassuspended in Mueller Hinton broth till turbidness was recognizable by naked eyes (abacterial suspension containing about 107 cfu/ml of the bacteria), and diluted 100-foldin the same broth; this resulted in a bacterial suspension for inoculation containing about 105 cfu/ml of the bacteria.
    10 µl of the bacterial suspension for inoculation (about 103 cfu) wasinoculated on this plate and cultured for 7 days under the same condition as that ofpreculture. Thereafter, it was judged whether there had been bacteria growth or not.iii) Judgment Standard
    The minimum concentration of the sample compound when there were novisible colonies or, if any, 5 or less colonies of HP was defined as MIC (µg/ml).
    Here, when the MIC value was 100 µg/ml or more, in a manner similar tothe above-mentioned method, both of a MIC measurement plate with a 250mMsolution of the sample compound and a MIC measurement plate for control without asample compound were prepared and then the bacteria was inoculated thereon in amanner similar to the above-mentioned method. As the result of the comparison ofthese plates, when the number of the colony on the plate containing the samplecompound was less than 90% with respect to that on the control plate, it wasrepresented by "+". Contrary to this, when there was 90% or more, it wasrepresented by "-". AT: Single Dose Toxicity Pretesti) Method
    Male Slc:ICR mice (5-week-old) were used. Each group has 3 to 5 miceand each mouse was fasted, but allowed free access to water, for 4 to 5 hours from 9a.m. in the test day. Then, 2,000 mg/10 ml/kg of the sample compound dissolved orsuspended in an aqueous solution of 0.5% sodium carboxymethyl cellulose was orallyadministered thereto. To a control, only the vehicle was administered. Thebehavior and symptom were observed at each of 15 minutes, 30 minutes, 1 hour, 2hours, and 3 hours after the administration and then daily till one week thereafter.The body weight was measured before and after the fasting as well as at the sametime everyday. The dead animals were immediately subjected to autopsy and theirorgans were observed microscopically. Also, the living animals were sacrificed with ether or carbon dioxide one week after the administration and then their organs wereobserved microscopically.ii)Judgment Standard
    The toxicity at the single dose of 2,000 mg/kg of the sample compound wasexpressed as being classified into 5 levels.
    5: Mortality rate is 0%; no toxicity is found at all both in behavior andorgans.
    4: Mortality rate is 0%; while no toxicity is found in organs, slight toxicity isobserved in behavior and body weight increase.
    3: While there is a dead animal (though not all the animals are dead), notoxicity is found in organs.
    2: Regardless of whether there is a dead animal or not, toxicity is found inorgans.
    1: All the animals are dead. MTT: Cell Damaging and Protecting Effect Testi) Meaning
    It is confirmed that there is no toxicity in cell level. Those having atoxicity in cell level are inappropriate as an anti-ulcer drug. Also, it can beconfirmed that the effects of the sample compounds in other cell level tests do notresult from their toxicity.ii) Method
    A male Japanese White rabbit (2.5 to 3 kg) was anesthetized to death byNembutal™ and, immediately thereafter, its stomach was removed. The greatercurvature of the stomach was incised so as to remove the stomach contentstherefrom. After the mucosal surface was washed with HBSS (Hanks' Balanced SaltSolution), the stomach in ice-cooled HBSS was transferred to a laboratory. Then,after the pyloric antrum was removed, the gastric corpus mucosa was separated by aspatula and then minced into 2 to 3 mm3 pieces in BME (Basal Medium Eagle). Thereafter, these pieces were shaken at 120 to 130 cycles/minute for 15 minutes at37°C in BME 60ml containing 280 U/ml of dispase and 30 to 50 U/ml of collagenase.Here, the concentration of collagenase was appropriately changed for each lot inview of the state of cells. The pieces were washed twice with EBSS (Earle'sBalanced Salt Solution) containing 1 mM of EDTA and then shaken in MEM(Minimum Essential Medium) containing 1 mM of EDTA at 37°C for 5 minutes.Subsequently, they were shaken in the dispase and collagenase having the sameconcentrations as those mentioned above for 15 minutes so as to remove thesupernatant and then further shaken at 37°C for 50 to 60 minutes at 120 to 130cycles/minute. Then, after being washed twice with HBSS, Ham F12 containing 2%of Ultrocer G™ was used to attain the concentration of 1 × 106 cells/ml. Thusformed suspension was dispensed in each well of a 96- well plate by 200 µl. Theplate was incubated in the atmosphere composed of 5% CO2 and 95% air at 37°C forthree days so as to attain a confluent state and then subjected to MTT assay.
    The sample compound was dissolved in DMSO so as to attain aconcentration of 10-2 M and then diluted with HBSS containing 2% of Ultrocer G™so as to attain a final concentration of 10-4 M. To each group, which 8 wells wereused for, 10 µl of MTT reagent was added immediately after 100 µl of the mediumin each well was exchanged for same volume of the resulting solution of the samplecompound. After being incubated in an atmosphere composed of 5% CO2 and 95%air at 37°C for 4 hours, thus formed solution was centrifuged and then its supernatantwas discarded. Subsequently, 100 µl of 100% ethanol was added to the residue soas to dissolve MTT formazan. Then, the absorbance (OD: 570 to 630) was measuredby a microplate reader. This method utilizes a phenomenon in which MTT ischanged to MTT formazan only by mitochondria of living cells so as to change color.iii)Judgment Standard
    The cell damaging or cell protecting effect of the sample compound at thefinal concentration of 10-4 M was expressed as cell damaging rate (%) as follows:cell damaging rate (%) = (1- (absorbance in sample group/absorbance in control group)) × 100
    Accordingly, the smaller rate value is better in the cell damage.
    Based on the foregoing effect tests and safety tests, anti-ulcer effect,anti-bacterial effect against Helicobacter pyroli, and safety of the example compoundsof the present invention were studied. Compound Group 1
    The N-acylpiperazine derivative in this compound group 1 is a compound inwhich R3 is an alkenyl group in formula 1. As the N-acylpiperazine derivativescorresponding to this compound group 1, the following example compounds weretested.Example 1:
    Example 2:
    Example 3:
    Example 4:
    Example 5:
    Example 6:
    Example 7:
    ExampleAnti- ulcer TestsAnti- HP TestSafety WISCAPAHPMTT181100.53.13 µg/ml >212 99.4 223 101.1 -24443 +-295 99.2+-506 99.5 -167 99.6 -44
    As clearly from TABLE 1, the compounds in this compound group 1 havehigh antibacterial activity against Helicobacter pyroli as well as excellent anti-ulcereffect and acid secretion inhibition effect. Also, it is understood that thesecompounds have high safety. Compound Group 2
    The N- acylpiperazine derivative in this compound group 2 is a compound inwhich R3 is benzyl group, R2 is a lower alkyl group, and both of n and m are 1 informula 1. As the N-acylpiperazine derivatives corresponding to this compoundgroup 2, the following example compounds were tested.Example 8:
    Example 9:
    Example 10:
    ExampleAnti-ulcer TestsAnti-HP TestSafety CAPAHPMTTAT836.93.13 µg/ml >-93994.6+-321096.0 -345
    As clearly from TABLE 2, the N-acylpiperazine derivatives in thiscompound group 2 having benzyl group at R3 and an alkyl group at the neighboringposition have high anti-ulcer effect, acid secretion inhibition effect, and antibacterialactivity against Helicobacter pyroli. Also, it is understood that these compounds havevery high safety. Compound Group 3
    The N- acylpiperazine derivative in this compound group 3 is a compound inwhich R3 is hydrogen atom, R2 is a lower alkyl group, and both of n and m are 1 informula 1. As the N-acylpiperazine derivatives corresponding to this compoundgroup 3, the following example compounds were tested.Example 11:
    Example 12:
    ExampleAnti-ulcer TestsAnti-HP TestSafety CAPAHPMTT1193.13.13 µg/ml>51241.9+-12
    As clearly from TABLE 3, N- acylpiperazine derivatives in this compoundgroup 3 have high anti- ulcer effect, acid secretion inhibition effect, and antibacterialactivity against Helicobacter pyroli. Also, it is understood that these compounds havehigh safety.
    In the following, the manufacturing method of the example compounds ofthe present invention will be shown. Example 1Synthesis of 1- (4- geranyloxy)benzoyl- 4- [2- (piperonyloylamino)ethyl]piperazine
    In a manner similar to Example 8, 4-geranyloxybenzoic acid (5.49g) wassubjected to a condensation reaction with cyanomethylpiperazine (2.75g), therebyyielding an amide (7.19g). This amide (2.29g) was dissolved in methanol and cobaltchloride (2.86g) and sodium borohydride (2.27g) were added thereto while beingcooled with ice. After being stirred at room temperature for 20 minutes, the reactionmixture was concentrated. The residue was dissolved in chloroform and thenfiltrated. the filtrate was concentrated, thereby yielding an amine (1.12g).
    The amine (1.12g) was dissolved in methylene chloride and triethylamine(0.45g) was added thereto. While being cooled with ice, the mixture, withpiperonyloyl chloride (0.41g) added thereto, was stirred at 0 °C to for 1 hour. Thereaction mixture was washed with sodium hydrogencarbonate aqueous solution andbrine successively, dried over sodium sulfate anhydride, and then filtrated. Thefiltrate was concentrated and the resulting residue was purified by silica gel columnchromatography (chloroform : methanol = 50:1), thereby yielding 0.27g(23%) of theaimed compound as pale yellow oil.1H-NMR (CDCl3) δ : 7.37(2H, d, J=8.8Hz), 7.31-7.24(2H, m), 6.91(2H, d,J=8.8Hz), 6.84(1H, d, J=8.8Hz), 6.57(1H, s), 6.03(2H, s), 5.48(1H, t, J=6.4Hz),5.09(1H, t, J=6.8Hz), 4.56(2H, d, J=6.4Hz), 3.80-3.50(4H, bs), 3.53(2H, q, J=5.4Hz),2.62(2H, t, J=5.9Hz), 2.17-2.03(4H, m), 1.74(3H, s), 1.68(3H, s), 1.61(3H,s). Example 2Synthesis of 1-(4-geranyloxy-3-isobutyl)benzoyl-4-[2-(piperonyloylamino)ethyl]piperazine
    In a manner similar to Example 8, 4-geranyloxy-3-isobutylbenzoic acid (1.51g) was subjected to a condensation reaction with N-hydroxyethylpiperazine(0.65g), thereby yielding an amide (1.95g, 94%). This amide (1.95g) was reacted withpiperonyloyl chloride (0.93g), thereby yielding 1.92g(68%) of the aimed compound aspale yellow oiL1H-NMR (CDCl3) δ : 7.63(1H, d, J=8.3Hz), 7.45(1H, s), 7.25(1H, d, J=8.3Hz),7.15(1H, s), 6.84(1H, d, J=8.8Hz), 6.82(1H, d, J=8.3Hz), 6.04(1H, s), 5.45(1H, t,J=6.8Hz), 5.10(1H, t, J=6.4Hz), 4.55(2H, d, J=5.8Hz), 4.42(2H, t, J=5.8Hz),3.82-3.40(4H, bs), 2.79(2H, t, J=5.8Hz), 2.58(4H, s), 2.49(2H, d, J=6.8Hz),2.18-2.04(4H, m), 1.91(1H, n, J=6.4), 1.72(3H, s), 1.68(3H,s), 1.61(3H, s), 0.88(6H, d,J=6.4Hz). Example 3Synthesis of 1-(4-geranyloxy)benzoyl-4-(2-isonicotinoyloxyethyl)piperazine
    In a manner similar to Example 8, 4-geranyloxybenzoic acid (8.23g) wassubjected to a condensation reaction with N- hydroxyethylpiperazine (3.91g), therebyyielding an amide (11.6g). This amide (1.93g) was reacted with isonicotinoyl chloride(0.89g), thereby yielding 1.13g(46%) of the aimed compound.m.p. 52.5-55.0°C1H-NMR (CDCl3)δ : 8.79(2H, d, J=5.8Hz), 7.84(2H, d, J=5.4Hz), 7.36(2H, d,J=8.8Hz), 6.91(2H, d, J=8.8Hz), 5.47(1H, t, J=6.8Hz), 5.09(1H, t, J=6.8Hz), 4.56(2H,d, J=6.4Hz), 4.50(2H, t, J=5.4Hz), 3.85-3.40(4H, bs), 2.81(2H, t, J=5.4) 2,58(4H, s),2.19-2.06(4H, m), 1.74(3H, s), 1.68(3H, s), 1.61(3H, s). Example 4Synthesis of 1- (4-geranyloxy)benzoyl-4-piperonylpiperazine
    In a manner similar to Example 8, 4-geranyloxybenzoic acid (1.01g) wassubjected to a condensation reaction with N-piperonylpiperazine (0.97g), therebyyielding 1.85g(96%) of the aimed compound. Example 5Synthesis of 1-benzyl- 4- (3,5- dimethoxy-4- geranyloxy)benzoylpiperazine
    In a manner similar to Example 8, 3,5- dimethoxy- 4- geranyloxybenzoicacid was subjected to a condensation reaction with N-benzylpiperazine, therebyyielding the aimed compound. Example 6Synthesis of -benzyl-4-(3,4,5-triprenyloxy)benzoylpiperazine
    In a manner similar to Example 8, 3,4,5-triprenyloxybenzoic acid(1.12g)was subjected to a condensation reaction with N-benzylpiperazine (0.57g), therebyyielding 1.14g(72%) of the aimed compound.1H-NMR (CDCl3) δ : 7.27-7.32(2H,s), 6.60(2H, s), 5.52-5.60(1H, m), 5.44-5.52(2H, m), 4.54(4H, d, J=6.3Hz), 4.50(-2H, d, J=63Hz), 3.50- 3.77(4H, m), 3.53(2H, s),2.41-2.55(4H, m), 1.71- 1.76(18H, m). Example 7Synthesis of 1-benzyl-4-(3,4-dimethoxy-5-geranyloxy)benzoylpiperazine
    In a manner similar to Example 8, 3,4-dimethoxy-5-geranyloxybenzoicacid (1.00g) was subjected to a condensation reaction with N-benzylpiperazine(0.56g), thereby yielding 1.29g(87%) of the aimed compound.1H-NMR (CDCl3) δ : 7.26-7.32(5H, m), 6.62(2H, s), 5.45- 5.53(1H, m), 5.04-5.12(1H, m), 4.58(2H, d, J=6.4Hz), 3.85(6H, s), 3.45-3.90(4H, m); 3.54(2H ,s),2.35-2.59(4H, m), 2.05-2.10(4H, m), 1.72(3H, s), 1.67(3H, s), 1.60(3H, s). Example 8Synthesis of 1- [4- (4- fluorobenzyloxy)-3- isobutyllbenzoyl- 4- (N- isopropylcarbamoyl)piperazine
    [4-(4-fluorobenzyloxy)-3-isobutyl]benzoic acid (1.51g) was dissolved in amixture of chloroform (25ml) and triethylamine (1.39ml), and then diphenylphosphinic chloride(0.96ml) was added thereto while being cooled with ice. After being stirredfor 40 minutes, the mixture, with 1- isopropylcarbamoylpyridine(0.89g) added thereto,was stirred for 1.5 hours at room temperature. The reaction mixture was washedwith 1N sodium hydroxide aqueous solution and brine successively, dried over sodiumsulfate anhydride, and then filtrated. The filtrate was concentrated under a vacuum.The residue was recrystallized from n-hexane/ethyl acetate, thereby yielding1.66g(73%) of the aimed compound as white crystals.mp 166.8-167.9 °C1H-NMR (CDCl3)δ : 739(2H, dd, J=8.8, 5.4Hz), 7.28-7.22(1H, m), 7.18(1H,s),7.09(1H, t, J=8.8Hz), 6.89(1H, d, J=8.3Hz), 5.06(2H, s), 4.23(1H, d, J=73Hz),3.98(1H, d, J=6.8Hz), 3.75-3.50(4H, bs), 3.39(4H, t, J=5.4Hz), 2.53(2H, d, J=7.3Hz),2.02-1.85(1H, m), 1.17(6H, d, J=6.8Hz), 0.89(6H, d, J=6.4Hz). Example 9Synthesis of 1-(4-benzyloxy-3-isobutyl)benzoyl-4-benzylpiperazine
    In a manner similar to Example 8, 4-benzyloxy-3-isobutylbenzoic acidwas subjected to a condensation reaction with N-benzylpiperazine, thereby yieldingthe aimed compound. Example 10Synthesis of 1-[4-(4-fluorobenzyloxy)-3-isobutyl]benzoyl-4-(2-pyridyl)piperazine
    In a manner similar to Example 8, [4-(4-fluorobenzyloxy)-3-isobutyl]benzoic acid was subjected to a condensation reaction with N-(2-pyridyl)piperazine,thereby yielding the aimed compound. Example 11Synthesis of 1-(2-hydroxy-3-isobutyl)benzoyl-4-piperonyloylpiperazine
    In a manner similar to Example 8, 2-hydroxy-3-isobutylbenzoic acid (0.50g) was subjected to a condensation reaction with N- piperonylpiperazine (0.62g),thereby yielding 0.64g(62.7%) of the aimed compound.1H-NMR (CDCl3)δ : 9.76(1H, s), 7.14(1H, d, J=7.4Hz), 7.07(1H, d, J=7.8Hz),6.85(1H, s), 6.71-6.77(3H, m), 5.95(2H, s), 3.73(4H, brt, J=5.0Hz), 3.45(2H, s),2.52(2H, d, J=72Hz), 2.48(4H, brt, J=5.0Hz), 1.92-2.04(1H, m), 0.92(6H, d,J=6.6Hz). Example 12Synthesis of 1-diphenylmethyl-4-(3-hydroxy-4-isobutyl)benzoylpiperazine
    In a manner similar to Example 8, 3- hydroxy- 4- isobutylbenzoic acid wassubjected to a condensation reaction with N- diphenylmethylpiperazine (0.62g),thereby yielding the aimed compound.
    权利要求:
    Claims (12)
    [1] An N-acylpiperazine derivative or a salt thereof expressed by thefollowing formula 1:
    [2] An N-acylpiperazine derivative or a salt thereof according to claim 1,wherein R3 is an alkenyl group.
    [3] An N-acylpiperazine derivative or a salt thereof according to claim 2,which is expressed by the following formula 2.
    [4] An N-acylpiperazine derivative or a salt thereof according to claim 2 or3, wherein n is 1 or 2 and R2 is isobutyl or methoxy group.
    [5] An N-acylpiperazine derivative or a salt thereof according to claim 2 or3, wherein n is 0.
    [6] An N-acylpiperazine derivative or a salt thereof according to claim 1,wherein R3 is benzyl group, R2 is a lower alkyl group, and both of n and m are 1.
    [7] An N-acylpiperazine derivative or a salt thereof according to claim 6,which is expressed by the following formula 3:
    [8] An N-acylpiperazine derivative or a salt thereof according to claim 7,wherein 1 is 1 and Rb is fluorine atom bonded to para- position.
    [9] An N-acylpiperazine derivative or a salt thereofaccording to claim 1, which is expressed by the followingformula 4:
    [10] An N-acylpiperazine derivative or a salt thereofaccording to any of claims 6 to 9, wherein R2 is isobutyl.
    [11] A pharmaceutical composition for therapeutic use,comprising, as an active ingredient, an N-acylpiperazinederivative or a pharmacologically-acceptable salt thereofaccording to any of claims 1 to 10, together with apharmaceutically-acceptable carrier and/or adjuvant.
    [12] Use of an N-acylpiperazine derivative or apharmacologically-acceptable salt thereof according to anyof claims 1 to 10, for the manufacture of a medicament forthe treatment of Helicobacter pylori, acid secretion orpeptic ulcers, in mammals, e.g. gastric ulcers in man.
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    AT203989T|2001-08-15|
    AU717312B2|2000-03-23|
    JPH10152487A|1998-06-09|
    KR19980025185A|1998-07-06|
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    优先权:
    申请号 | 申请日 | 专利标题
    JP27887296||1996-09-30||
    JP278872/96||1996-09-30||
    JP27887296||1996-09-30||
    JP85937/97||1997-03-18||
    JP08593797A|JP4189043B2|1996-09-30|1997-03-18|N-acyl piperazine derivatives, antibacterial agents, anti-ulcer agents|
    JP8593797||1997-03-18||
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