MXPA98009568A - Derivatives of amidinobenceno substitute and medical compositions of mis - Google Patents

Abstract

A substituted amidinobenzene derivative of the following general formula (I) or a salt thereof, and a pharmaceutical composition comprising the derivative or a salt thereof and a pharmaceutically acceptable carrier. (The symbols in the above formula have the following meanings: R1: a group which can be converted to an amidino group in vivo, R2 and R3: the same or different and each represents a carboxyl group or a group which can be convert into a carboxyl group in vivo, X1 and X2: the same or different and each represents a lower alkylene group, m: 0, 1 or 2, n: 0 or 1, provided that n = 1 when m = 0. These have GPIIb / IIIa receptor antagonist activity and are useful as medicines to improve cardiac, ischemic disorders, administer in operations of cardiac surgery or vascular surgery, medicine to improve cerebrovascular disorders and medicines to improve disorders of peripheral arteries. In addition, these are useful as an excellent prodrug in peroral absorbability and maintenance of the effec

Description

SPECIFICATION SUBSTITUTE AMIDINOBENZENE DERIVATIVES AND MEDICAL COMPOSITIONS THEREOF TECHNICAL FIELD The present invention relates to substituted amidinobenzene derivatives and their salts that are useful as medicines, especially as GPIIb / IIIa antagonists.

ANTECEDENT TECHNIQUE During a prolonged period of time after the discovery of Donne in 1842 (see C. R. Acad. Sci. (Paris), 1_4, 336-368, 1842), blood platelets have been considered as the component in the blood which is necessary for haemostasis. At present, it has been clarified that blood platelets not only play a major role in the hemostatic mechanism of blood, but are also multifunctional as participants in the creation of arteriosclerosis, disorders of the cardiovascular system including thrombotic disorders, metastasis of cancer, inflammations, rejections after transplantation, and also REF: 28525 immunoreactions, etc., which are clinically important. Thrombotic disorders and ischemic disorders are treated therapeutically by re-establishing blood circulation through the application of medicines or by physical means. However, a clinically problematic phenomenon has recently been found that, after re-establishment of blood circulation, activation, adhesion and aggregation of blood platelets are promoted on the basis of tissue damage of the blood vessel including endothelial cells and balance of systemic fibrinolysis-coagulation, unbalanced caused by the medicines themselves, and the like. For example, it has been clarified that, after the blood circulation has been re-established by thrombolytic therapy using a t-PA (Tissue Plasminogen Activator) or the like, the fibrinolytic activity and the coagulation activity are activated to break up the balance of systemic fibrinolysis / coagulation. Clinically, this causes re-occlusion and is therefore seriously problematic in therapy (see J. Am. Coil, Cardiol., 12, 616-623, 1988). On the other hand, a PTCA therapy (coronary, transluminal, percutaneous angioplasty) has rapidly become popular, with the production of good results to some extent, for the healing of disorders such as coronary stenosis and aortostenosis, such as stenocardia, infarction. to the myocardium, etc. However, this therapy involves serious problems in that it damages the tissue of blood vessels including endothelial cells to cause coronary obstruction, acute and even re-stenosis that occurs in approximately 30% of therapeutic cases. Blood platelets play a major role in various thrombotic disorders (for example, re-occlusion) after such therapy of re-establishment of blood circulation. Therefore, the effectiveness of anti-platelet agents for such disorders would be expected. However, it has not yet been verified that conventional antiplatelet agents are effective. GPIIb / IIIa is a glycoprotein of the platelet membrane, which is one of the integrin family (see Blood, 8_0, 1386-1404, 1992). This intangine binds to adhesive proteins such as fibrinogen, von Illebrand factor, etc., and they have an important function in the term in the aggregation of blood platelets. The monoclonal antibodies against GPIIb / IIIa, the peptides having a sequence of RGD and the like have potent inhibitory activity of platelet aggregation, and some of which have already been put on clinical examinations. GPIIb / IIIa, low molecular weight, non-peptide antagonists are known from Japanese published patent application (kokai) 4-288051 (sulfonamide fibrinogen receptor antagonists of the following representative compounds, and a Japanese patent application, published (koka i) 6-25227 (imino derivatives, cyclics of the following representative compound, and are described by Leo et al. (see Journal of Medication, Chemis try, 35_, 4393-4407, 1992) in which the following representative compound is described.

(Tyr: Tyrosine) The piperizine acetic acid derivatives of the following general formula are described in the PCT patent application, published O93 / 10091 (in which X1 and Y1, which may be the same or different, represent CH or N; X2 represents CH or, when X1 represents CH, it may also have N; Y2 represents N, when Y1 represents N, it can also represent CH; Z represents N or N + R5; R1 represents a hydrogen atom or a hydroxyl, alkyl of 1 to 4 carbon atoms or a 2,2,2-trifluoroethyl group; R2 represents a hydrogen atom or, when both X1 and X2 represent CH, can also represent a fluorine, chlorine or bromine atom or an alkyl group of 1 to 4 carbon atoms; R3 represents a hydrogen atom or, when both Y1 and Y2 represent N, can also represent an alkyl group of 1 to 4 carbon atoms or hydroxymethyl; R4 represents a hydrogen atom, when Z represents N, R4 can also represent an alkyl group of 1 to 4 carbon atoms; R5 represents an alkyl group of 1 to 4 carbon atoms or phenylalkyl of 1 to 4 carbon atoms; R6 represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms). However, the compounds of the above application are described as inhibitors of platelet aggregation. GPIIb / IIIa antagonists that have a wide range of safety and a defined effect through oral administration are highly desired.

DESCRIPTION OF THE INVENTION The present inventors created novel benzamidine derivatives of the following formula and found that the derivatives have excellent GPIIb / IIIa antagonist activity and filed a patent application (Japanese patent application No. Hei-8-333342 (kokai) (wherein R1 and R2 are the same or different and each has a hydrogen atom or an ester residue, X1 represents a lower alkylene group, X2 represents an individual bond or a lower alkylene group, m represents 0, 1 or 2; n represents O or 1, with the proviso that n = 1 when m = 0). As a result of further extensive studies, it was found that novel substituted amidinobenzene derivatives obtained by changing these amidinobenzene derivatives to prodrugs in the amidino group have extremely excellent peroral absorbability and sustaining effect, which results in the embodiment of the present invention. Thus, the present invention relates to the substituted amidinobenzene derivatives of the following general formula (I) and their salts, as well as also pharmaceutical compositions comprising such compounds together with pharmaceutically acceptable carriers. (the symbols in the above formula have the following meanings: R1: a group that can be converted to an amidino group in vivo; R2 and R3: the same or different and each represents a carboxyl group or a group that can be converted to a carboxyl group in vivo; X1 and X2: the same or different and each represents a lower alkylene group; m: 0, 1 or 2; n: 0 or 1, with the condition that n = 1 when m = 0. The same applies later in the present). The compounds of the present invention are structurally characterized in that the substituent R1 in benzene is a group that can be converted to an amidino group in vivo and in this way the compounds are prodrugs. As described below, such a change in prodrugs achieved extremely excellent peroral absorbability and accompaniment of sustained effects. The second feature is that (1) the compounds have two carboxyl groups or a group that can be converted to a carboxyl group in the piperidine ring and / or (2) the compounds have one or two oxo groups in the ring of piperazine. The compounds of the present invention have an excellent GPIIb / IIIa antagonist effect based on such a structure. Preferable compounds among the compounds of the present invention in the general formula (I) shown above are: the substituted amidinobenzene derivatives or salts thereof, wherein at least one of R2 and R3 is a group that can be converted to a carboxyl group in vivo (ie, the compounds that have been made into prodrugs in both the amidino group and the carboxyl group (commonly called prodrug compounds) double)); derivatives substituted aminobenzene or salts thereof, wherein the group which can be converted into an amidino group in vivo of R1 is a group selected from the group consisting of a hydroxyamidino group, a lower alcoxicarbonilamidino group, a lower alkoxyamidino group and a lower alkanoylamine group; derivatives substituted amidinobenceno or salts thereof, wherein the group can be converted into a carboxyl group in vivo of R2 and R3 is a group selected from the group consisting of a lower alkoxycarbonyl group, a lower alkoxycarbonyl-lower alkoxy group , a lower alkoxy group-lower alkoxy-lower alkoxycarbonyl group, a halogeno-lower alkoxycarbonyl, lower alkenyloxycarbonyl group, a lower alkanoyloxy-lower alkoxycarbonyl, a group alkenoyloxy-lower alkoxycarbonyl lower alkanoyl group lower-alkoxycarbonyl lower, a group lower-alkoxycarbonyl alkenoyl, a lower-alkoxycarbonyl-lower alkanoyloxy lower alkoxycarbonyloxy group lower-alkoxycarbonyl lower alkoxy group lower-lower alkoxycarbonyloxy-lower alkoxycarbonyl, dialkylamino lower alkoxy group-alkoxycarbonyl infer a group cycloalkyloxycarbonyloxy-lower alkoxycarbonyl, an alcox group lower ibenciloxicarbonilo a nitrobenzyloxycarbonyl group, a lower alcoxibenzhidriloxicarbonilo group, a benzhydryloxycarbonyl group, a benzyloxy-lower alkoxycarbonyl group, a 2-oxotetrahydrofuran-5-yloxycarbonyl, one-oxo-5-alkyl-l 2, 3-dioxolen-4 group -ylmethoxycarbonyl, a tetrahydrofranylcarbonyloxymethoxycarbonyl group, and a 3-phthaloxycarbonyl group; and the substituted amidinobenzene derivatives or salts thereof, wherein m = 1.

The still preferred compounds are the substituted amidinobenzene derivatives or salts thereof, wherein m = 1 and n = 0. Particularly preferred compounds are the compounds shown below or salts thereof. 4- [4- (4-hydroxyamidinophenyl) -3-oxo-l-piperazinyl] -1-piperidinacetate ethyl, 4- [4- (4-hydroxyamidinophenyl) -3-oxo-l-piperazinyl] -1-piperidinacetate of methyl, ethyl 4- [4- (4-methoxycarbonylamidoinophenyl) -3-oxo-l-piperazinyl] -1-piperidinacetate, 4- [4- (4-methoxycarbonylamidophenyl) -3-oxo-l-piperazinyl] -1- methyl piperidinacetate, and ethyl 4- [4- (4-ethoxycarbonylaminopinophenyl) -3-oxo-l-piperazinyl] -1-piperidinacetate. Among these compounds, the most preferred compound is ethyl 4- [4- (4-hydroxylamidoinophenyl) -3-oxo-l-piperazinyl] -1-piperidinacetate or salts thereof. Other preferred compounds include the substituted amidinobenzene derivatives or salts thereof, wherein m = 0 and n = 1, particularly the substituted amidinobenzene derivatives or salts thereof wherein both of R 2 and R 3 are a group that can be converted to a carboxyl group in vivo. Subsequently, the compounds (I) of the present invention are described in detail. Unless specifically indicated otherwise, the term "lower", as referred to herein for the definitions of the general formulas given herein, is directed to a linear or branched carbon chain having from 1 to 6. carbon atoms. Accordingly, the "lower alkylene group" represented by X1 and X2 in the general formula (I) is suitably a linear or branched alkylene group having from 1 to 6 carbon atoms, and its illustrative examples include a methylene group, a group ethylene, a methylmethylene group, a trimethylene group, a propylene group, a 2-propylene group, a dimethylmethylene group, a tetramethylene group, a 1-methyltrimethylene group, a 2-methyltrimethylene group, a 3-methyltrimethylene group, a group 1 ethylethylene, a 2-ethylethylene group, a 2, 2-dimethylethylene group, a 1, 1-dimethylethylene group, an ethylmethylmethylene group, a propylmethylene group, a pentamethylene group, a 1-methyltetramethylene group, a 2-methyltetramethylene group, a group 3-methyltetramethylene, a 4-methyltetramethylene group, a 1,1-dimethyltrimethylene group, a 2,2-dimethyltrimethylene group, a 3, 3-dimethyltrimethylene group, a 1,3-dimethyltrimethylene group, a 2,3-dimethyltrimethylene group, a 1, 2-dimethyltrime group ethylene, a 1-ethyltrimethylene group, a 1,1,2-trimethylethylene group, a diethylmethylene group, a 1-propylethylene group, a 2-propylethylene group, a butylmethylene group, a hexamethylene group, a 1-methylpentamethylene group, m group 1,1-dimethyltetramethylene, a 2,2-dimethyltetramethylene group, a 3,3-dimethyltetramethylene group, a 4,4-dimethyltetramethylene group, a 1, 1,3-trimethyltrimethylene group, in group 1, .1,2- trimethyltrimethylene, a 1-1, -1, 2,2-tetramethylethylene group, a 1-l-dimethyl-2-ethylethylene group, a 1, 1-diethylethylene group, a 1-propyltrimethylene group, a 2-propyltrimethylene group, a 3-propyltrimethylene group, 1-butylethylene group, 2-butylethylene group, 1-methyl-1-propylethylene group, 2-methyl-2-propylethylene group, 1-methyl-2-propylethylene group, 2 group -methyl-propylethylene, a pentylmethylene group, a butylmethylmethylene group, an ethylpropylmethylene group, and the like. Among these groups, straight alkylene groups of 1 to 3 carbon atoms are preferable, and a methylene group and an ethylene group are most preferable. The "group that can be converted to an amidino group in vivo" of RI and the "group that can be converted to a carboxyl group in vivo" of R2 and / or R3 are the groups that constitute the compound that can be an active body of the drugs, or a group that constitutes a prodrug of amidine that can be metabolized in vivo to become an amidine compound as an active body in the first case or a group that constitutes a prodrug of carboxylic acid that can be metabolized in vivo to form a carboxylic acid compound as an active body in the latter case. The "group that can be converted to an amidino group in vivo" and the "group that can be converted to a carboxyl group in vivo" can easily be determined by administering the compound of the present invention to a human or other animals and analyzing the product metabolized by analytical techniques, ordinary. That is, the former can be detected as a compound having an amidino group after in vivo metabolism and the latter can be detected as a compound having a carboxyl group after metabolism in vivo. Accordingly, the "group that can be converted to an amidino in vi vo group" of R 1 includes substituted amidino groups that can be hydrolyzed by in vivo metabolism, ie, those that substitute a prodrug based on the amidino group. The substituted amidino group includes a hydroxyamidino group, a lower idino alkoxycarbony group, a lower alkoxyamidino group and a lower alkanoylamido group. A hydroxyamidino group and a lower alkoxycarbonylamido group are preferable, and a hydroxyamidino group is particularly preferable. The "group that can be converted to a carboxyl group in vivo" of R2 and / or R3 includes substituted carboxyl groups that can be hydrolyzed by in vivo metabolism, ie, those that substitute a prodrug based on the carboxyl group. The substituted carboxyl group includes a lower, unsubstituted, alkoxycarbonyl group and lower, straight-chain substituted alkoxycarbonyl groups, for example, a lower alkoxy-lower alkoxycarbonyl group, a lower alkoxy-lower alkoxy-lower alkoxycarbonyl group, a halogen- lower alkoxycarbonyl, an alkenyloxycarbonyl group lower alkanoyloxy group lower-alkoxycarbonyl lower an alkenoyloxy group lower-alkoxycarbonyl lower alkanoyl group lower-alkoxycarbonyl lower alkenoyl group lower-alkoxycarbonyl lower alkoxy group lower-alkanoyloxy inferring-lower alkoxycarbonyl a lower alkoxycarbonyloxy group-lower alkoxycarbonyl, lower alkoxycarbonyl-lower alkoxycarbonyloxy-lower, and lower dialkylamino lower alkoxycarbonyl-alkoxy group, and an alkoxycarbonyl group cycloalkyloxycarbonyloxy-, a lower alcoxibenciloxicarbonilo group, a nitrobenzyloxycarbonyl group, one alcoxibenzhidriloxicarbonilo group lower a benzhydryloxycarbonyl group, a benzoyloxy-lower alkoxycarbonyl group, a 2-oxotetrahydrofuran-5-yloxycarbonyl, one-oxo-5-alkyl-l 2, 3-dioxolen-4-ylmethoxycarbonyl a tetrahidrofuranilcarboniloximetoxicarbonilo group group, and a 3-phthalidyloxycarbonyl group. Preferable groups are a lower alkoxycarbonyl group, unsubstituted and lower alkoxycarbonyl groups, substituted, straight chain, for example, an alkoxycarbonyl halogeno-lower alkoxy group-lower alkoxycarbonyl, alkoxy lower-alkoxy lower-alkoxycarbonyl lower, a group bottom, an alkenyloxycarbonyl group lower alkanoyloxy group lower-alkoxycarbonyl lower an alkenoyloxy group lower-alkoxycarbonyl lower alkanoyl group lower-alkoxycarbonyl lower alkenoyl group lower-alkoxycarbonyl lower alkoxy group lower-lower alkanoyloxy-lower alkoxycarbonyl, a group lower alkoxycarbonyloxy-lower alkoxycarbonyl, lower-alkoxycarbonyl-lower alkoxycarbonyloxy lower alkoxy group, and the di-lower alkylamino-lower alkoxycarbonyl and a group cycloalkyloxycarbonyloxy-lower alkoxycarbonyl group, a 2-oxo-5-alkyl-l, 3 -dioxolen-4-ylmethoxycarbonyl, and a 3-phtalidyloxy group arbonyl. A lower alkoxycarbonyl group is more preferable, and a methoxycarbonyl group and an ethoxycarbonyl group are particularly preferable. The "lower alkyl group" includes, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tertbutyl group, a pentyl group, an isopentyl group, a neopentyl group, a ter-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 1,2-dimethylpropyl group, a hexyl group, an isohexyl group, a 1-methylpentyl group, a 2 group -methylpentyl, a 3-methylpentyl group, a group 1, 1-dimethylbutyl, a 1,2-dimethylbutyl group, a 2, 2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, a 3, 3-dimethylbutyl group, a 1-ethylbutyl group , a 2-ethylbutyl group, a 1,1,2-trimethylpropyl group, a 1,2-trimethylpropyl group, a 1-ethyl-1-methylpropyl group, an l-ethyl-2-methylpropyl group, and the like. The "lower alkoxy group" corresponds to a hydroxyl group from which a hydrogen atom is replaced by the lower alkyl group described above, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group (amyloxy), an isopentyloxy group, a ter-pentyloxy group, a neopentyloxy group, a 2-methylbutoxy group, a 1,2-dimethylpropoxy group, a 1-ethylpropoxy group, a hexyloxy group, and the like, preferably a group methoxy, an ethoxy group, and a tert-butoxy group. The "lower alkanoyl group" is preferably those having 2 to 6 carbon atoms (eg, acetyl, propionyl, pivaloyl and the like); the "lower alkenoyl group" is preferably those having 3 to 6 carbon atoms (an acryloyl group, a crotonoyl group, a maleoyl group, and the like); the "cycloalkyl group" is preferably those having 3 to 8 carbon atoms, particularly those having 3 to 6 carbon atoms (eg, cyclopropyl, cyclopentyl, cyclohexyl and the like). The "lower alkenyl group" is preferably those having 2 to 6 carbon atoms (eg, a vinyl group, an allyl group, a 1-propenyl group, and the like). The "halogeno-lower alkyl group" corresponds to the lower alkyl group, mentioned above of which one or more hydrogen atoms is / are substituted by halogen atom (s) and includes a fluoromethyl group, a chloromethyl group, a bromomethyl group, a iodomethyl group, a 1-chloroethyl group, a 2-chloroethyl group, a dichloromethyl group, a trifluoromethyl group, a dichlorobromomethyl group and the like. In the basic skeleton of the compound (I) of the present invention, the portion represented by the formula - N- means a ring oxopiperazine or a dioxopiperazine ring. Illustrative examples of the oxopiperazine ring according to the present application are shown below.

Between these rings, the ring represented by is preferentially and the ring represented by dN- it is particularly preferable. The compounds (I) of the present invention have at least one asymmetric carbon atom, depending on the skeletal piperidinyl group and its substituent (a group of -X2-R3). Depending on the other substituents, the compounds (I) may have carbon atom (s), asymmetric (s), additional (s). The compounds of the present invention can exist in the form of optical isomers, depending on these asymmetric carbon atoms. In addition, these exist in the form of tautomeric isomers depending on the carbonyl groups or the amidino groups on the substituents and also on the shape of the geometric isomers depending on the double bonds. The present invention encompasses all isolated isomers of these optical isomers, tautomeric isomers, and geometric isomers as well as mixtures thereof. The compounds (I) of the present invention can be formed into salts. Examples of the preferred salts include alkali metal or alkaline earth metal salts such as sodium salts, potassium salts and calcium salts; hydrogen halides such as fluorohydrates, hydrochlorides, hydrobromides and iodides; salts with inorganic acids, such as carbonates, nitrates, perchlorates, sulfates and phosphates; lower alkylsulfonates such as methanesulfonates, trifluoromethanesulfonates and ethanesulfonates; arylsulfonates such as benzenesulfonates and p-toluenesulfonates; salts with organic acids, such as fumarates, succinates, citrates, tartrates, oxalates and maleates, salts with amino acids, such as glutamates and aspartates. In addition, the present invention encompasses pharmaceutically acceptable hydrates and solvates of the compounds (I) as well as polymorphic isomers of the compounds (I) of the present invention. In fact, the present invention is not limited to only the compounds of the Examples which are hereinafter mentioned herein but encompasses all the substituted amidinobenzene derivatives of the general formula (I) and their pharmaceutically acceptable salts.

(Production Methods) Some production methods, typical for the compounds of the present invention, are explained below. First Production Method (In the formula, R 2, R 3, X 1, X 2, m and n have the same meanings as before Rla means a hydroxyamidino group or a lower alididinoidino group). The compound (Ia) of the present invention can be produced by reacting the nitrile compound (II) with hydroxylamine hydrochloride or a lower alkoxyamide hydrochloride in a suitable solvent in the presence of a base. The appropriate solvent is preferably inert to the reaction and examples of such inert solvents include methanol, ethanol, dimethylformamide (DMF), dimethylacetamide, tetrachloroethane, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran (THF), dioxane, dimethoxymethane , diethoxymethane, ethyl acetate, benzene, toluene, acetonitrile, dimethyl sulfoxide (DMSO), etc., and mixed solvents thereof. The solvent is appropriately selected depending on the various reaction conditions. Examples of the base include sodium, sodium hydride, sodium methoxide, sodium ethoxide, potassium carbonate, triethylamide, pyridine and the like. Examples of the base which is preferably used in this reaction include triethylamine, sodium methoxide and sodium ethoxide. The reaction can be carried out usually under room temperature, with heating, or with heating under reflux, and preferably with heating under reflux.

Second Production Method (In the formula, R.sub.2, R.sub.3, X.sub.1, X.sub.2, M.sub.n have the same meanings as before, R.sub.4 represents a lower alkoxycarbonyl group or a lower alkanoyl group R.sub.l denotes a lower alkoxycarbonylamido group or a lower alkanoyl amidino group. releasable such as a halogen atom, a hydroxyl group, a lower alkoxy group, a phenoxy group, an imidazolyl group, an arylsulfonyloxy group and a leaving group of an active carboxylic acid derivative). The compound (Ib) of the present invention can be produced by reacting the amidino compound (III) with a compound (IV) in the presence of an appropriate base. Examples of the appropriate base include those described above, and preferably sodium hydroxide, potassium carbonate and triethylamine. Solvents can be used in this reaction and, examples of the solvents that are used include those described above. Examples of preferable solvents include stratified or layered solvent of water-dichloromethane, THF, DMF and the like. The active carboxylic acid derivative includes active esters which are obtained by reaction with a phenol compound such as p-nitrophenol or the like, or with an N-hydroxyamine compound such as N-hydroxysuccinimide, 1-hydroxy-benzotriazole or the like; mixed acid anhydrides which are obtained by reaction with a monoalkyl carbonate or an organic acid, and mixed phosphoryl anhydrides which are obtained by reaction with diphenylphosphoryl chloride and N-methylmorpholine; acid azides which are obtained by reacting an ester with hydrazine or an alkyl nitrile; acid halides such as acid chlorides, acid bromides, etc .; symmetric acid anhydrides, etc.

(Other Production Methods) Among the compounds (I) of the present invention, those having a carboxyl group such as R2 and / or R3 can be obtained by dissolving the corresponding compounds having a group that can be converted to a carboxyl group in live as R2 and / or R3, in an appropriate solvent followed by ordinary ester hydrolysis under basic conditions, acidic conditions or neutral conditions. Examples of the base that is used under basic conditions include sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide and the like. Examples of the acid that is used under acidic conditions include Lewis acids (eg, hydrochloric acid, sulfuric acid, boron trichloride), trifluoroacetic acid, p-toluenesulfonic acid. Under neutral conditions, halogen ions (for example lithium iodide and lithium bromide), alkali metal salts (for example thiol and selenol), iodotrimethylsilane and enzymes (for example, esterase) can be used. Examples of the solvent that is used in the reaction include water, alcohol (for example methanol and ethanol), acetone, dioxane, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, formic acid, acetic acid, pyridine, lutidine, collidine. and similar. The commonly used solvents described above can be used as a mixture with water. The reaction usually proceeds under ambient temperature but sometimes must be carried out under ice cooling or with heating, and in this way the reaction is carried out under the appropriately selected temperature. By appropriately selecting the conditions for hydrolysis, the substituted carboxylic acid compounds have only one carboxyl group. For example, an ester compound in which an ester residue is easily hydrolyzed under acidic conditions (for example, tert-butyl group or the like) and another ester residue is easily hydrolysed under basic conditions (e.g., methyl ester, ester ethyl or similar) is hydrolyzed under selected conditions (acidic or basic conditions), whereby only one of the two ester residues is selectively hydrolysed. If desired, the carboxylic acid compounds can also be esterified to give the desired esters. The esterification can be carried out in any ordinary manner under suitably selected conditions. The compounds of the present invention wherein R2 and / or R3 are / is the group that can be converted to a carboxyl group in vivo can also be obtained by interesterification with suitable alcohols. For example, a large amount in excess of an alcohol is used for the interesterification that is carried out in the presence of an acid or a base or any other catalyst (for example, titanium (IV) alkoxide) or the other alcohols that formed during the reaction are removed from the reaction system, thereby changing the equilibrium of the reaction towards the production system of the desired ester compound.

(Methods for Producing Compounds of the Start Compounds) Next, the methods for preparing the compounds that are used as start compounds are described below. Production Method A (In the formula, R3, R4, X1 and X2 have the same meanings as mentioned above). The compound (VII) can be obtained by dissolving a compound (VI) in an appropriate solvent followed by the reaction with a secondary amine, suitable to give an enamine, and then allowing the alkyl acrylate (e.g., methyl acrylate) or halogenated alkyl (e.g., ethyl bromoacetate) acts on the enamine. The enamine can be used after isolation or without isolation. Examples of the secondary amine include pyrrolidine, piperidine, morpholine, diethylamine and diisopropylamine. Examples of the solvent include toluene, benzene, chlorobenzene and the like. In addition to those commonly used solvents, the reaction can be carried out in any of the other organic solvents since the solvent does not cause a bad influence on the reaction.

The reaction is carried out with the elimination of water outside the system that forms when the enamine is formed, by adding water absorption agents such as potassium hydroxide, Molecular sieves, etc. or by using a Dean-Stark trap (azeotropic dehydration device). The temperature for the reaction is preferably adjusted to azeotropic or reflux temperature.

Production Method B (In the formula, R3, R4, X1, X2, m and n have the same meanings as before). The compound (II) is obtained by dissolving a compound (VIII) in a suitable solvent followed by reacting it with an amine compound (IX) to give a Schiff's base, which is then reduced after isolation or without isolation. The solvent is an organic solvent, inert to the reaction, including, for example, benzene, toluene, xylene, methanol, ethanol, isopropanol, methylene chloride, dichloroethane, chloroform, acetic acid, and the like. The reaction is conducted in a manner such that a compound (VIII) is reacted with an amount corresponding to the reaction of an amine compound (IX) or, alternatively, using one of these in a somewhat excessive amount, in the form of preferably in the presence of an acid catalyst such as p-toluenesulfonic acid, adipic acid, oxalic acid, pyridine hydrochloride, acetic acid or the like. Depending on the reaction conditions, the reaction is advantageously carried out with the removal of water outside the system, by adding water absorption agents such as potassium hydroxide, Molecular Sieve, or by using a Dean-Stark trap ( azeotropic dehydration apparatus). The temperature for the reaction is usually below room temperature but can be adjusted to azeotropic or reflux temperature depending on the reaction conditions. The reaction of the Schiff base is carried out by adding a reducing agent such as a metal hydride complex (eg, sodium borohydride, lithium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride), borane, or the like in a solution of the reaction of the previous step.

Production Method C NC £ NH-A 1-A * 2 * -NH-A 4-A "3-Y, 11 (X") (In the formula, A1 to A4 may be the same or different and each is a carbonyl group or a methylene group, Y1 represents the same releasable group as Y and Y2 represents the same leaving group as Y1 or a hydrogen atom) .

In this reaction, a compound (XI) is reacted with an amine compound (X) to produce a compound (XII). (1) When the above compound (XI) is an alkyl derivative wherein Y2 is a leaving group, and A4 is a methylene group. This reaction can be carried out in accordance with ordinary N-alkylation. The reaction is carried out by stirring an amine compound (X) and an amount corresponding to the reaction of a compound (XI) in an inert solvent with cooling or under heating. To promote the reaction, it is desirable to add a base (e.g., an inorganic base such as potassium carbonate, sodium carbonate, sodium hydride or the like, or an organic base such as triethylamine or the like) to the reaction system. (2) When the above compound (XI) is a carboxylic acid derivative wherein Y2 is a leaving group, and A4 is a carbonyl group. The amide compound (XII) is obtained by acylation of an amine (X) with a carboxylic acid or its active derivative (XI) in a suitable solvent.

The active carboxylic acid derivative includes active ethers described above in the Second Production Method and an amide compound (XII) is also obtained by acylation in a carboxylic acid (XI) and a condensing agent in a suitable solvent. The condensation agent used in the reaction is preferably N, N-dicyclohexylcarbodiimide (DCC), l-ethyl-3- (3- (N, N-dimethylamino) propyl) carbodiimide, carbonyldiimidazole, diphenylphosphoryl azide (DPPA), diethylphosphoryl azide or the like. The reaction is usually carried out in a solvent under cooling or at room temperature. The solvent used is an organic solvent not involved in the reaction, such as dimethylformamide, dimethylacetamide, dioxane, tetrahydrofuran, diethyl ether, dichloroethane, chloroform, carbon tetrachloride, dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, acetonitrile, sulfoxide. of dimethyl, etc., and mixed solvents thereof. These organic solvents can be appropriately selected depending on the method applied. Depending on the type of acylation, the reaction must sometimes be carried out under dehydrated conditions.

Furthermore, depending on the method that is applied, it is preferable for the uniform progress of the reaction to carry out the reaction in the presence of a base such as N-methylmorpholine, triethylamide, trimethylamine, pyridine, etc., or to use a base such as a solvent (3) When the above compound (XI) is an aldehyde wherein Y2 is a hydrogen atom and A4 is a carbonyl group. A compound (XII) is obtained by dissolving an aldehyde derivative (XI) in a suitable solvent, reacting it with an amine (X) and then reducing the imino ion, produced. The reaction solvent, the reducing agent and the reaction conditions in Production Method B, mentioned above, can be applied to this reaction.

Production Method D (In the formula, A1 to A4, Y1 and m have the same meanings as before). To obtain a (di) oxopiperazine (IX) ring compound by cyclization, the precursor (XII) is treated in a suitable solvent in the absence or presence of a suitable catalyst. This reaction is carried out with cooling with ice or at room temperature or under heating. Examples of the solvents used include dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrachloroethane, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, dimethoxymethane, dimethoxyethane, benzene, chlorobenzene, toluene, water, acetic anhydride, alcohols, etc. ., which are selected appropriately depending on the various reaction conditions. Examples of the catalyst used include bases (eg, sodium hydride, potassium hydride, n-butyllithium, sec-butyllithium, potassium tert-butoxide, potassium bis (trimethylsilyl) amide, lithium diisopropylamide, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, triethylamine, diisopropylethylamine, dimethylaminopyridine), salts (eg, sodium acetate and potassium acetate) , and acids (for example, sulfuric acid and hydrochloric acid). Production Method E (In the formula, A1 to A4, X1, X2, Y1, Y2, R2, R3, m and n have the same meanings as before). In the similar manner as described in Production Method B, the compound (X) and the compound (VII) are reacted to form a compound (XIII). The solvent, catalyst, and the reaction conditions, etc. they are the same with those of Production Method B described, described above. In a similar manner as described in Production Method C, the compound (XIV) is produced from the compound (XIII). The solvent, catalyst and the reaction conditions, etc. they are the same with those of Production Method C described above. Cyclization to form the (di) oxopiperazine ring can be carried out in the same manner as described in Production Method D. The solvent, catalyst and reaction conditions, etc. they are the same as those of Production Method D described above. Production Method F (In the formula, R2, R3, X1, X2, m and n have the same meanings as before). The compounds (III) having an amidino group can be produced according to any of the following methods (i), (ii) and (iii). (i) Method for converting a nitrile into an imidate followed by condensation with an amine: A nitrile (II) compound is reacted with an alcohol such as methanol, ethanol or the like in the presence of a hydrogen chloride gas at -40 ° C to 0 ° C to give an imidate, which is then reacted with ammonia or an amine or amine salt such as ammonium carbonate, ammonium chloride, ammonium acetate or the like. As the solvent for the reaction, methanol, ethanol, acetone, tetrahydrofuran, or the like are used, (ii) Method for converting a nitrile into a thioamide and then into a thioimidate followed by condensation with an amine: A nitrile compound (II) ) is reacted with hydrogen sulfide in the presence of an organic base such as methylamine, triethylamine, pyridine, picoline or the like to give a thioamide compound. The thioamide compound can also be obtained by reacting a nitrile compound (II) with 0.0-diethyl dithiophosphate in the presence of hydrogen chloride. The thioamide compound, obtained in this way, is then reacted with a lower alkyl halide such as methyl iodide, ethyl iodide or the like to give a thioimidate, which is then reacted with ammonia or an amine or salt of amine such as ammonium carbonate, ammonium chloride, ammonium acetate or the like. As the solvent for the reaction, methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate or the like are used. (iii) Method for directly adding an amine, amine salt, metal amide or Grignard reagent to a nitrile: A reagent such as ammonia, ammonium chloride with ammonia, ammonium thiocyanate, alkylammonium thiocyanate, MeAl (Cl) NH2, NaNH2, (CH3) 2NMgBr or the like is added to a nitrile compound (II) in an appropriate solvent or without a solvent. As the solvent, chloroform, methanol, ethanol, acetone, tetrahydrofuran, toluene, dimethylformamide, or the like are used. The addition of a catalyst of a base such as sodium hydride or the like or an acid such as aluminum chloride, p-toluenesulfonic acid or the like to the reaction system markedly accelerates the reaction in some cases. The reaction can be carried out with cooling, - or at room temperature, or under heating.

Production Method G llla) (In the formula, R2, R3, X1, X2 and n have the same meanings as before). Cyclization to form an oxopiperazine ring compound (lia) is carried out by reacting a precursor (Xllla) with glyoxal in an appropriate solvent. The reaction can be carried out with cooling with ice, under room temperature or under heating. Examples of the solvent that is used include mixed tetrahydrofuran-water solvent, dimethylformamide, dimethyl sulfoxide, l-methyl-2-pyrrolidine, dioxane, dimethoxymethane, alcohols, etc., which can be appropriately selected depending on the various reaction conditions.

Production Method H (In the formula, A1, A2, X1, X2, Y2, R2, R3 and n have the same meanings as before). This reaction process is to obtain the compound (XIII) by reacting the compound (XV) and the amine compound (XVI). 1) When Y2 is Y1 and A1 is a methylene group in the above compound (XV), the reaction is carried out in a similar manner as described in 1) of the Production Process C. 2) When Y2 is Y1 and A2 is a carbonyl group in the above compound (XV), the reaction is carried out in a similar manner as described in 2) of the Production Process C. 3) When Y2 is a hydrogen atom and A2 is a carbonyl group in the compound (XV) above, the reaction is carried out in a similar manner as described in 3) of the Production Process C.

The compounds of the present invention when produced in the manner mentioned above are isolated and purified by any ordinary chemical operation including, for example, extraction, precipitation, fractional chromatography, recrystallization and the like. In addition, the compounds of the present invention can be conducted in the desired salts by the ordinary salt formation reaction.

INDUSTRIAL APPLICABILITY The compounds of the present invention are useful as orally applicable GPIIIb / IIIa receptor antagonists, especially inhibitors of platelet aggregation, including, for example, drugs for the improvement of cardiac disorders, ischemic (stenocardia of anxiety, acute myocardial infarction), and also for the prevention of the following secondary complications, postoperative reobstruction and re-stenosis after coronary artery bypass or PTCA, as well as for the promotion of coronary thrombolysis and prophylaxis of the re-obstruction after coronary thrombolysis, etc.); how it administers in cardiac surgery operations or in vascular surgery operations; as medicines for the improvement of cerebrovascular disorders (transient ischemic attack (TIA), cerebral infarction, subarachnoid hemorrhage (spasmodic, vascular contraction), etc.); and as medicines for the improvement of disorders of peripheral arteries (arterial, chronic obstruction, etc.). Since the compounds of the present invention have been especially useful as a prodrug of the compounds in our prior application (a Japanese patent application, published, unexamined No. 8-333342) and therefore are useful as medicines for the improvement of the disorders mentioned above not only by parenteral administration such as, for example, intravascular injection but also by peroral administration. In addition, since the residence time in the plasma of Compound A is prolonged by the administration of the compounds of the present invention as a prodrug, the pharmaceutical effects of the compounds of the present invention act for a long time, and the clinical utility of the compounds is high. In addition, the toxicity of the compounds of the present invention is much lower than that of conventional compounds. The effect of inhibiting platelet aggregation of the compounds of the present invention and utility as the prodrug have been confirmed by the following test methods: Metabolic test of an active body (Compound A) in plasma The compound of Example 2 of the present invention was administered to three small dogs or hounds, orally in a dose of 10 mg / kg as an aqueous solution and then blood was withdrawn about 48 hours after administration. After centrifugation, the plasma was separated and then stored at -20 ° C until analysis. Compound A (compound name: 4- [4- (4-amidinophenyl) -3-oxo-l-piperazinyl] -1-piperidineacetic acid, Japanese Patent Application, published, unexamined No. 8-333342), which is an active body produced as a metabolite of the Compound of Example 2, was determined by the method of high performance liquid chromatography to obtain the pharmacokinetic parameters. Compound A was also administered to the same small dogs or hounds at a dose of 10 mg / kg, and then the concentration of Compound A in the plasma was measured. The pharmacokinetic parameters of Compound A after administration of the Compound of Example 2 and Compound A were compared with each other. Table 1 shows the pharmacokinetic parameters of Compound A in the plasta after oral administration, and in Figure 1 the time-concentration profile in the plasma of Compound A after oral administration is shown. Table 1 depicts pharmacokinetic parameters of Compound A in the plasma after oral administration of Compound of Example 2 and Compound A to small dogs or hounds at a dose of 10 mg / kg (average of three animals ± standard deviation) and Figure 1 represents the concentration-time profile in the plasma of Compound A.

Table 1 (where Cma? is the maximum concentration in the plasma, Tma? is the time to reach Cmax, AUC0- 8 is the area under the time-concentration curve in the plasma about 48 hours after the administration, t? / 2 is half the elimination time). The area under the time-concentration curve in the plasma of Compound A after administration of the Compound of Example 2 was about 3 times greater than that after administration of Compound A. The t? / 2 of Compound A is also mostly prolonged when administered orally as the Compound of Example 2. It is confirmed that not only the bioavailability but also the residence time in the plasma of Compound A is increased when administered as Compound of Example 2 which is designated for a double prodrug of the Compound A.

Inhibitory activity of platelet aggregation ex vivo in cynomolgus monkeys: The cynomolgus monkeys that had been lightly anaesthetized by intramuscular administration of ketamine hydrochloride were fixed in a workbench, and a sample compound of the present invention dissolved or was administered. suspended in a solution of methylcellulose in the stomach by means of a stomach probe in a dose of 1 mg / kg. Before administration and after administration in a predetermined period of time, 3 ml (containing 1/10 times by volume of sodium citrate) was collected from the animal's blood through the femoral vein. From the blood, platelet-rich plasma (PRP) was obtained according to the method of De Marco et al. (See J. Clin. Inves t., 11, 1272-1277, 1986). The PRP was adjusted to 3 x 108 / ml with an automatic blood cell counter (Model MEK-5158, produced by Nihon Koden Co.) before use. Then, 20 μM of ADP and 10 μg / ml of collagen derived from the bovine tendon (produced by Niko Bioscience Co.) as a trigger to cause the aggression of the platelets. The degree of platelet aggregation was measured with a platelet aggregation meter (NBS Hematracer 801, produced by Niko Bioscience Co.). The inhibitory activity of the platelet aggregation of the tested compound was represented by the percentage of inhibition (%) relative to the percentage of maximum aggregation of each animal before the addition of the test compound. The test results are shown in Table 2 together with the results of Compound A which is the active body of the compounds of the present invention.

Table 2 As shown in the above results, the compounds of the present invention showed excellent ratio of inhibition of platelet aggregation even in comparison with compound A of the active body. In addition, the inhibition ratio of platelet aggregation in the case of the prodrug compound of the present application was excellently maintained after 9, 12 and 24 hours after the administration, which confirmed that. the compound shows sufficient maintenance of the effect. Incidentally, as described in our previous application, the active body compound in the present application has an excellent effect in inhibiting the binding of GPIIb / IIIa to fibrinogen and thus per se has an inhibitory effect on platelet aggregation. Accordingly, it is clear that the compounds of the present invention, after in vivo absorption, are metabolized to become an active body compound shown above as the result of the metabolic test of an active body in the plasma and sample the inhibitory effect of platelet aggregation based on the effect to inhibit the binding of fibrinogen to GPIIb / IIIa. As shown in the above pharmacological test results, the compounds of the present invention are excellent in bioavailability and maintenance of the effect. Accordingly, it was confirmed that the compounds of the present invention are favorable compounds as a prodrug, especially as a double prodrug. Pharmaceutical compositions comprising one or more of the compounds and their salts of the present invention as the active ingredient can be formulated together with the carriers, excipients and other additives which are generally used in the ordinary formulation. The carriers and excipients that are used for the formulation can be pharmaceutically acceptable, non-toxic, solid or liquid substances. Examples of such carriers and excipients include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol and others that are ordinarily used in the art. The pharmaceutical composition can be administered either orally as tablets, pills, capsules, granules, powders, liquids, etc., or parenterally as intravenous or intramuscular injections, suppositories, transdermal preparations, inhalants, intracystic injection, etc. The dose of the composition is determined adequately for individual patients, depending on their conditions, ages, sexes, etc. However, in general, the oral dose for adults is approximately 0.1 mg / kg / day to 100 mg / kg / day, which is administered once in a while or in portions of 2 to 4. Where the composition is administered intravascularly depending on the conditions of the patients, the dose is, in general, approximately 0.001 mg / kg to 10 mg / kg and applied once to several times a day. The solid composition for use in oral administration according to the present invention is used in the form of tablets, powders, granules and the like. In such a solid composition, one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, metasilicic acid or magnesium aluminate. In the usual manner, the composition may contain additives other than inert diluent, such as a lubricant (e.g., magnesium stearate), a disintegrating agent (e.g., calcium cellulose glycolate), a stabilizing agent (e.g. lactose) and an agent of solubilization (for example, glutamic acid and aspartic acid). If necessary, the tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like. The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like and contains a commonly used inert diluent such as purified water or ethyl alcohol. In addition to the inert diluent, this composition may also contain auxiliary agents such as wetting agent, a suspending agent and the like, as well as sweetening, flavoring, flavoring and antiseptic substances. Injections for parenteral administration include aqueous or non-aqueous, aseptic solutions, suspensions and emulsions. Examples of the diluent for use in aqueous solutions and suspensions include distilled water for the use of injection and saline, physiological. Examples of the diluent for use in the non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, a plant oil (for example, olive oil), an alcohol (for example, ethyl alcohol), Polysorbate 80 and the like. Such a composition may further contain additive agents such as an antiseptic, a wetting agent, an emulsifying agent, a dispersing agent, a stabilizing agent (e.g., lactose) and a solubilizing assisting agent (e.g., glutamic acid and Aspartic acid) . These compositions are sterilized by filtering through a bacteria retention filter, a mixture of a germicide or irradiation. Alternatively, these can be used when making solid, sterile compositions and dissolving them in sterile water or a sterile solvent for injection before use.

BEST MODES FOR CARRYING OUT THE INVENTION The present invention is described in greater detail by means of the following Examples. However, the compounds of the present invention are not limited to only the compounds of the Examples, but include all the compounds of the general formula mentioned above (I), their salts, hydrates, solvates, tautomers, geometric and optical isomers and isomers polymorphic Reference Example 1 Methyl 4-oxo-3-piperidinecarboxylate hydrochloride (9.65 g), 21.0 g of ethyl bromoacetate and 24.0 g of potassium carbonate were dissolved in 200 ml of N, N-dimethylformamide and the solution was stirred at room temperature overnight. Then, 100 ml of water was added to the reaction liquid, and the mixture was extracted with 500 ml of ethyl acetate. The resulting extract was dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: chloroform) to give 9.0 g of ethyl 3-ethoxycarbonylmethyl-3-methoxycarbonyl-4-oxo-l-piperidineacetate as an oily substance. Mass spectrum (m / z): FAB (Pos) 330 (M + + 1) NMR spectrum (CDC13, internal TMS standard): d: 1.23-1.31 (6H, m), 2.46-2.51 (1H, m) , 2.71 (2H, dd), 2.91-2.96 (2H, m), 3.00- 3.08 (2H, m), 3.35-3.45 (2H, m), 3.79 (3H, s), 4.10-4.19 (4H, m) Reference Example 2 Ethyl 3-ethoxycarbonylmethyl-3-methoxycarbonyl-4-oxo-l-piperidineacetate (1.0 g) and 140 mg of lithium chloride were dissolved in 10 ml of N, N-dimethylformamide and the solution was heated to reflux for 48 hours. Then, 10 ml of water was added to the reaction liquid, and the mixture was extracted with 100 ml of ethyl acetate. The resulting extract was dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: chloroform) to give 400 mg of diethyl 4-oxo-1,3-piperidinediacetate as an oily substance. Mass spectrum (m / z): FAB (Pos) 272 (M + + 1) NMR spectrum (CDC13, internal standard of TMS): d: 1.23-1.30 (6H, m), 2.18 (1H, dd), 2.36 - 2.40 (1H, m), 2.50 (1H, t), 2.70-2.77 (3H, m), 3.13-3.26 (3H, m), 3.38 (2H, s), 4.09-4.22 (4H, m) Reference Example 3 Diethyl 4-oxo-l, 3-piperidinediacetate (28 g), 19 g of 4- (l-piperazinyl) benzonitrile and 6 g of acetic acid were dissolved in 250 ml of dichloromethane, 42 g were added. of sodium triacetoxyborohydride, and the mixture was stirred at room temperature for 24 hours. The reaction liquid was neutralized with an aqueous solution of 1 N sodium hydroxide and then the organic layer was separated. The organic layer was dried over sodium sulfate and concentrated, and the resulting residue was purified by chromatography on silica gel (eluent: hexane: ethyl acetate = 1: 1) to give 13 g of 4- [4- ( 4-cyanophenyl) -1-piperazinyl] -1,3-piperidinacetate diethyl ester.

Reference Example.4 4- [4- (4-Cyanophenyl) -1-piperazinyl] -1,3-piperidinacetate diethyl ester (8.2 g) was dissolved in 100 ml of ethanol, and the hydrogen chloride was made to the blown from -10 ° C to -20 ° C until saturation. The solution was warmed to room temperature and stirred overnight, and the solvent was removed by evaporation. The residue obtained in this way was dissolved in 100 ml of ethanol, 9.0 g of ammonium carbonate were added and the mixture was stirred at room temperature overnight. The solvent was removed from the reaction mixture by evaporation, and the resulting residue was purified by column chromatography on silica gel (eluent: chloroform: methanol = 10: 1) to give 4.4 g of 4- [4-hydrochloride]. - (4-amidinophenyl) -1-piperazinyl] -1,3-piperidinacetate diethyl ester. Mass spectrum (m / z): FAB (Pos) 460 (M + + 1) NMR spectrum (DMSO-d6, internal standard of TMS): d: 1.18 (6H, t), 1.69-1.83 (3H, m) , 2.01- 2.33 (5H, m), 2.66-2.87 (3H, m), 3.08- 3.23 (4H, m), 4.03-4.33 (4H, m), 7.06 (2H, d), 7.73 (2H, d) Reference Example 5 N- (tert-butoxycarbonyl) glycine (14.83 g) was dissolved in 50 ml of tetrahydrofuran, and 13.73 g of 1,1'-carbonylbis-1H-imidazole was gradually added, and the mixture was stirred at room temperature. environment for 3 hours. Then, 10 g of p-aminobenzonitrile was added and the mixture was stirred for 3 days. Then, the solvent was removed by evaporation under reduced pressure. Water was added to the resulting residue. The crystals formed in this manner were collected by filtration, washed with a small amount of ethanol, and then dried under reduced pressure to give 20.5 g of 2- (tert-butoxycarbonylamino) -N- (4-cyanophenyl) acetamide. Mass spectrum (m / z): FAB 276 (M + H) + NMR spectrum (CDC13, internal standard TMS): d: 1.49 (9H, s), 3.92 (2H, d), 5.18 (1H, s) broad), 7.61 (2H, d), 7.65 (2H, d), 8.59 (1H, broad s) Reference Example 6 A solution of ethyl acetate (45.5 ml) of 4N hydrogen chloride solution was added to 10 g of 2- (tert-butoxycarbonylamino) -N- (4-cyanophenyl) acetamide in a closed vessel and the mixture it was stirred for 18 hours. The crystals formed were collected by filtration, washed with ethyl acetate and then dried under reduced pressure to give 7.7 g of 2-amino-N- (4-cyanophenyl) acetamide hydrochloride. Then, 58.8 ml of an aqueous saturated sodium hydrogen carbonate solution and 20 ml of water were added to 3.7 g of the hydrochloride obtained in this manner, and the mixture was stirred for 1 hour. The crystals formed in this manner were collected by filtration and dried under reduced pressure to give 2.5 g of 2-amino-N- (4-cyanofenyl) acetamide. Mass spectrum (m / z): FAB 176 (M + H) + NMR spectrum (CDC13, internal TMS standard): d: 1.68 (2H, broad s), 3.50 (2H, s), 7.61 (2H, d), 7.74 (2H, d), 9.75 (1H, broad s) Reference Example 7 The 2-amino-N- (4-cyanophenyl) acetamide (1.83 g) was dissolved in 90 ml of methylene chloride, 3.10 g of ethyl 2- (4-oxo-l-piperidine) acetate, 4.4 of acetic acid and 8.88 g of sodium triacetoxyborohydride were added in that order, and the mixture was stirred for 1.5 hours. After the concentration of the mixture under reduced pressure, water and sodium carbonate were added to make the alkaline system. Then, the crystals formed were collected by filtration. The crude crystals were dissolved in chloroform and washed with brine. The resulting organic layer was dried over anhydrous sodium sulfate and filtered and the resulting filtrate was concentrated under reduced pressure. Ether was added to the resulting residue, and the solid formed was collected by filtration to give 2.82 g of ethyl 4- [N- (4-cyanophenyl) carbamoylmethylamino] -1-piperidinacetate. Mass spectrum (m / z): APCI * Q1MS: 345 NMR spectrum (CDC13, internal TMS standard): d: 1.27 (3H, t), 1.50-1.58 (2H, m), 1.67 (1H, broad s ), 1.88-1.90 (2H, m), 2.23-2.27 (2H, m), 2.49-2.54 (1H, m), 2.95 (2H, m), 3.22 (2H, s), 3.42 (2H, s), 4.18 (2H, q), 7.62 (2H, d), 7.72 (2H, d), 9.69 (1H, broad s) Reference Example 8 Sodium cyanoborohydride (0.48 g) and 0.57 g of acetic acid were added in that order to a mixed solution of 1.0 g of ethyl 4- [N- (4-cyanophenyl) carbamoylmethylamino] -1-piperidineacetate, 10 ml of methanol and 2.85 g of chloroacetaldehyde (40% aqueous solution), and the mixture was stirred overnight. The solvent was removed by evaporation, chloroform was added, and the mixture was washed with a saturated aqueous sodium carbonate aqueous solution. The resulting organic layer was separated and concentrated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel (eluent: chloroform: methanol = 100: 1, v / v) to give 1.15 g of 4- [N- (2-chloroethyl) -N- [N-] Ethyl (4-cyanophenyl) carbamoylmethyl] amino] -1-piperidinacetate. Mass spectrum (m / z): FAB 407 (M + H) + Reference Example 9 Ethyl 4- [N- (2-chloroethyl) -N- [N- (4-cyanophenyl) carbamoylmethyl] amino] -1-piperidineacetate (1.08 g) was dissolved in 30 ml of N, N- dimethylformamide, 0.18 g of sodium hydride (60% in oil) was gradually added and the mixture was stirred for 5 hours. An aqueous solution of saturated ammonium chloride was added and the solvent was removed by evaporation. Then, chloroform and a saturated aqueous sodium carbonate solution were added, the mixture was subjected to the. liquid-liquid separation and the resulting organic layer was concentrated under reduced pressure. Ether was added to the resulting residue, and the solid formed was collected by filtration to give 0.43 g of ethyl 4- [4- (4-cyanophenyl) -3-oxo-l-piperazinyl] -1-piperidinacetate. Mass spectrum (m / z): FAB 371 (M + H) + NMR spectrum (CDC13, internal standard TMS): d: 1.28 (3H, t), 1.65-1.71 (2H, m), 1.83- 1.85 (2H, m), 2.24-2.28 (2H, m), 2.35-2.39 (1H, m), 2.91-2.93 (2H, m), 3.01- 3.04 (2H, m), 3.22 (2H, s), 3.46 (2H, s), 3.71-3.73 (2H, m), 4.19 (2H, q, 7.49 (2H, d), 7.68 (2H, d) In the same manner as in Reference Example 4, the compound was obtained of the following Reference Example 10.

Reference Example 10 Ethyl 4- [4- (4-amidinophenyl) -3-oxo-1-piperazinyl] -1-piperidinacetate Hydrochloride Starting compound: 4- [4- (4-cyanophenyl) -3-oxo- 1-pipetranyl] -1-ethyl piperidinacetate Mass spectrum (m / z): FAB 388 (M + H) + NMR spectrum (DMSO-d6, internal standard TMS): d: 1.19 (3H, t), 1, .43-1.47 (3H, m), 1.77-1.80 (2H, m), 2.17-2.21 (2H, m), 2.29 (1H, m), 2.87-2.89 (4H, m), 3.19 (2H, s), 3.33 (2H, s), 3.70-3.72 (2H, d), 4.08 (2H, q), 7.65 (2H, d), 7.84 (2H, d), 9.01 (2H, broad s), 9.32 (2H, broad s) In the same manner as in Reference Example 9, the compound of the following Reference Example 11 was obtained.

Reference Example 11 4- [4- (4-cyanophenyl) -3-oxo-l-piperazinyl] -1-methyl piperidinacetate Starting compound: 4- [N- (2-chloroethyl) -N- [N- ( 4-cyanophenyl) carbamoylmethyl] amino] -1-methyl piperidinacetate Mass spectrum (m / z): FAB (Pos.) 357 (M + + 1) NMR spectrum (CDC13, internal TMS standard): d: 1.63- 1.73 (2H, m), 1.83-1.86 (2H,), 2.22-2.28 (2H, m), 2.33-2.41 (1H, m), 2.91-2.93 (2H, m), 3.00-3.03 (2H, m) , 3.24 (2H, s), 3.46 (2H, s), 3.71-3.74 (5H, m), 7.49 (2H, d), 7.68 (2H, d) In the same manner as in Reference Example 4, obtained the compound of the following Reference Example 12.

Reference Example 12 Methyl 4- [4- (4-amidinophenyl) -3-oxo-1-piperazinyl] -1-piperidinacetate hydrochloride Starting compound: 4- [4- (4-cyanophenyl) -3-oxo- Methyl 1-piperazinyl] -1-piperidinacetate Mass spectrum (m / z): FAB (Pos.) 374 (M + + 1) NMR spectrum (DMS0-d6, internal TMS standard): d: 1.47- (2H , m), 1.79-1.81 (2H, m), 2.21- 2.31 (3H, m), 2.89 (4H, m), 3.34 (4H, m), 3.62 (3H, s), 3.71-3.73 (2H, m ), 7.65 (2H, d), 7.88 (2H, d), 9.28 (2H, broad s), 9.43 (2H, broad s).

Reference Example 13 Ethyl 4 - [[2- (4-cyanoanilino) ethyl] amino] -1-piperidinacetate (1.0 g) was dissolved in a mixed solvent of 10 ml of tetrahydrofuran and 10 ml of water, 0.69 was added. my glyoxal (40%, aqueous), and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated and the residue was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium carbonate aqueous solution and brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting crude crystals were recrystallized with toluene-hexane to give 0.86 g of ethyl 4- [4- (4-cyanofenyl) -3-oxo-l-piperazinyl] -1-piperidinacetate. Mass spectrum (m / z): FAB 371 (M + H) + NMR spectrum (CDC13, internal standard of TMS): d: 1.28 (3H, t), 1.5-1.9 (4H,), 2.1-2.4 ( 3H, m), 2.9-3.1 (4H, m), 3.22 (2H, s), 3.46 (2H, s), 3.7-3.8 (2H, m), 4.19 (2H, q), 7.48 (2H, d) 7.69 (2H, d) Example 1 Hydroxylamine hydrochloride (700 mg) was dissolved in 100 ml of ethanol and 680 mg of sodium ethoxide was added at room temperature. After 5 minutes, 2.2 g of 4- [4- (4-cyanophenyl) -1-piperazinyl] -1,3-piperidineacetate were added. (±) -cis-diethyl, and the mixture was heated to reflux overnight. The reaction solution was concentrated, 200 ml of water were added, and the mixture was extracted with 300 ml of chloroform. The extract was dried over sodium sulfate, concentrated and then purified by column chromatography on silica gel (eluent: chloroform-methanol = 50: 1 to 20: 1) to give 1.5 g of 4- [4- ( 4-Hydroxyamidinophenyl) -1-piperazinyl] -1,3-piperidinacetate of (±) -cis-diethyl.

Mass spectrum (m / z): FAB (Pos.) 476 (M + + 1) NMR spectrum (CDC13, internal standard TMS): d: 1.24-1.28 (6H, m), 1.76-1.78 (1H, m ), 2.06-2.11 (1H, m), 2.21-2.30 (2H, m), 2.55-2.75 (7H, m), 4.06-4.22 (4H, m), 4.80 (2H, s), 6.88 (2H, d) ), 7.51 (2H, d) Example 2 Ethanol (38 ml), 0.90 g of hydroxylamine hydrochloride and 1.64 g of triethylamine were added to 3.0 of ethyl 4- [4- (4-cyanophenyl) -3-oxo-l-piperazinyl] -1-piperidinacetate and the mixture was heated under reflux for 3 hours. The crystals formed were collected by filtration at the temperature of about 30 ° C, and recrystallized with chloroform-methanol to give 2.27 g of 4- [4- (4-hydroxyamidinophenyl) -3-oxo-l-piperazinyl] -1 ethyl-piperidinacetate Elemental Analysis (for C2oH29N504) C (%) H (%) N (%) Calculated 59.54 7.2 17.36 Found 59.31 7.05 17.32 NMR spectrum (DMS0-d6, internal standard TMS): d: 1.19 (3H, t), 1.39-1.48 (2H, m), 1.77-1.80 (2H, m), 2.16-2.21 (2H, m), 2.24-2.27 (1H, m), 2.83-2.89 (4H, m), 3.19 ( 2H, s), 3.28 (2H, s), 3.62-3.65 (2H, m), 4.08 (2H, q), 5.81 (2H, s), 7.34 (2H, d), 7.67 (2H, d), 9.64 (1H, s) In the same manner as in Example 1, the compound of the following Example 3 was obtained.

Example 3 Methyl 4- [4- (4-hydroxyamidinofenyl) -3-oxo-l-piperazinyl] -1-piperidinacetate Starting compound: 4- [4- (4-cyanofenyl) -3-oxo-1- methyl piperazinyl] -1-piperidinacetate Elemental analysis (for C? 9H27N504 • 0.25 H20) C (%) H (%) N (%) Calculated 56.63 7.13 17.38 Found 56.81 6.79 17.26 NMR spectrum (CDC13, internal standard TMS) : d: 1.73-1.86 (4H, m), 2.22-2.28 (2H, m), 2.34-2.41 (1H, m), 2.87-2.89 (2H, m), 3.02-3.05 (2H, m), 3.25 ( 2H, s), 3.45 (2H, s), 3.62-3.65 (2H, m), 3.73 (3H, s), 4.83 (2H, broad s), 7.32 (2H, d), 7.62 (2H, d) Example 4 4- (4- (4-hydroxyamidinophenyl) -1-piperazinyl] -1,3-piperidinediacetate of (±) -cis-diethyl (1.5 g) was dissolved in 50 ml of 1N hydrochloric acid and the solution was heated to reflux during the night. The reaction liquid was concentrated and the concentrated product was purified by ODS column chromatography (eluent: water to water: methanol = 1: 1) to give 100 mg trichlorhydrate of (±) -cis-4- acid. [4- (4-hydroxyamidinophenyl) -1-piperazinyl] -1- [(ethoxycarbonyl) methyl] piperidin-3-acetic. Mass spectrum (m / z): FAB (Pos.) 448 (M + + 1) NMR spectrum (DMS0-d6, internal standard TMS): d: 1.18 (3H, t), 1.76 (1H, m), 1.98-2.01 (1H, m), 2.10-2.19 (2H, m), 4.06 (2H, q), 5.62 (2H, s), 6.89 (2H, d), 7.51 (2H, d), 9.33 (1H, s) Example 5 4- (4- (4-hydroxyamidinophenyl) -1-piperazinyl] -1,3-piperidinediacetate of (±) -cis-diethyl (1.5 g) was dissolved in 50 ml of 1N hydrochloric acid and the solution was heated reflux overnight. The reaction liquid was concentrated and the concentrated product was purified by ODS column chromatography (eluent: water) to give 450 mg of (±) -cis-4- [4- (4-hydroxyamidinophenyl) -1 trichlorohydrate. , 3-piperidindiacetic. Mass spectrum (m / z): FAB (Pos.) 420 (M + + 1) NMR spectrum (DMSO-de, internal standard of 'TMS): d: 7.15 (2H, d), 7.71 (2H, d) , 11.09 (1H, Example 6 4- [4- (4-amidinophenyl) -1-piperazinyl] -1 hydrochloride was dissolved, (±) -cis-diethyl 3-piperidinediacetate (1.5 g) in 150 ml of methylene chloride, 300 mg of methyl chloroformate and 30 ml of a 0.2 N aqueous sodium hydroxide solution were added, and the mixture was added. stirred at room temperature for 1 hour. The organic layer was separated, washed twice with water, dried over sodium sulfate and then concentrated. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol = 50: 1) to give 850 mg of 4- [4- (4-methoxycarbonylamidophenyl) -1-piperadinyl] -1, 3- (±) -cis-diethyl piperidinediacetate. Mass spectrum (m / z): FAB (Pos.) 518 (M + + 1) NMR spectrum (CDC13, internal standard of TMS): d: 1.24-1.28 (6H, m), 1.47-1.59 (3H, m ), 1.77 (1H, d), 2.06-2.11 (1H, m), 2.21-2.30 (2H, d), 2.54-2.60 (3H, m), 2.63- 2.71 (4H, m), 2.88-2.95 (2H , m), 3.17 (2H, q), 3.28 (4H, t), 3.78 (3H, s), 4.06-4.19 (4H, m), 6.87 (2H, d), 7.81 (2H, d) Of the same As in Example 6, the compound of the following Example 7 was obtained.

Example 7 Ethyl 4- [4- (-methoxycarbonylaminopinophenyl) -3-oxo-1-piperazinyl] -1-ethyl piperidinacetate Starting compound: 4- [4- (4-amidinophenyl) -3-oxo-l-piperazinyl] - Ethyl 1-piperidinacetate Elemental Analysis (for C22H3? N505) C (%) H (%) N (%) Calculated 59.31 7.01 15.72 Found 59.02 7.03 15.63 NMR spectrum (CDC13, internal standard of TMS): d: 1.28 (3H , t), 1.63-1.75 (2H, m), 1.83-1.86 (2H, m), 2.22-2.28 (2H, m), 2.33- 2.41 (1H, m), 2.90-2.92 (2H,), 3.01- 3.04 (2H, m), 3.23 (2H, s), 3.45 (2H, 's), 3.69-3.72 (2H, m), 3.78 (3H, s), 4.19 (2H, q), 7.40 (2H, d) ), 7.90 (2H, d) Example 8 Ethyl 4- [4- (4-hydroxyamidinophenyl) -3-oxo-l-piperazinyl] -1-piperidinacetate (0.8 g) was dissolved in 8 ml of water, and 0.21 g of hydroxide monohydrate was added. lithium with cooling with ice. The mixture was stirred for 30 minutes under ice-cooling, an aqueous solution of saturated ammonium chloride was added, and the mixture was concentrated. The crystals formed were collected by filtration to give 0.67 g of 4- [4- (4-hydroxyamidinophenyl) -3-oxo-1-piperazinyl] -1-piperidine acetic acid. Elemental Analysis (for C? 8H25N50 • H20) C (%) H (%) N (%) Calculated 54.95 6.92 17.80 Found 55.14 6.66 18.00 NMR spectrum (DMSO-d6 + CF3COOD, internal standard of TMS): d: 2.11- 2.14 (2H, m), 2.38 (2H, m), 3.17 (2H, m), 3.64-3.77 (5H, m), 4.04-4.07 (2H, m), 4.18 (4H, m), 7.65 (2H, d), 7.83 (2H, d) In the same manner as in Example 6, the compound of the following Examples 9 to 10 was obtained.

Example 9 Methyl 4- [4- (4-methoxycarbonylaminopinophenyl) -3-oxo-1-piperazinyl] -1-piperidinacetate Starting compound: 4- [4- (4-amidinophenyl) -3-oxo-l- hydrochloride methyl piperazinyl] -1-piperidinacetate Elemental Analysis (for C2? H29N505 • 0.25 H20) C (%) H (%) N (%) Calculated 57.85 6.82 16.06 Found 57.70 6.60 16.20 NMR spectrum (CDC13, internal standard of TMS) : d: 1.63-1.73 (2H, m), 1.83-1.86 (2H, m), 2.22-2.28 (2H, m), 2.34-2.40 (1H, m), 2.89-2.92 (2H, m), 3.00- 3.03 (2H, m), 3.24 (2H, s), 3.45 (2H, s), 3.70-3.72 (2H, m), 3.73 (3H, s), 3.78 (3H, s), 7.40 (2H, d) 7.90 (2H, d) Example 10 Ethyl 4- [4- (4-methoxycarbonylaminopinophenyl) -3-oxo-1-piperazinyl] -1-piperidinacetate Starting compound: 4- [4- (4-amidinophenyl) -3-oxo-l- hydrochloride ethyl piperazinyl] -1-piperidinacetate Elemental Analysis (for C23H33N505 • 0.25 H20) C (%) H (%) N (%) Calculated 59.53 7.28 15.09 Found 59.61 7.13 15.08 NMR spectrum (CDC13, internal standard of TMS): d : 1.28 (3H, t), 1.35 (3H, t), 1.63-1.73 (2H, m), 1.83-1.86 (2H, m), 2.23-2.28 (2H, m), 2.34-2.40 (1H, m) , 2.90-2.92 (2H, m), 3.01-3.04 (2H, m), 3.23 (2H, s), 3.45 (2H, s), 3.70-3.73 (2H, m), 4.17-4.25 (4H, m) , 7.43 (2H, d), 7.91 (2H, d) The chemical structures of the compounds obtained in the above Examples are set forth in the following Table 3 and Table 4 Table 3 Table 4 In addition to the compounds of the examples, described above, other compounds of the present invention are shown in the following Table 5 through Table 9. These compounds can be synthesized, without particular experiments, according to any of the Methods and Production Processes described above and the modified processes thereof, known to those of ordinary skill in the art.

Table Table 6 Table 7 Table 8 Table 9 BRIEF DESCRIPTION OF THE DRAWING Figure 1 depicts the concentration-time profile in the plasma of Compound A after oral administration of Compound of Example 2 and Compound A to small dogs or hounds at a dose of 10 mg / kg (average of three animals ± normal derivation).

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Having described the invention as above, property is claimed as contained in the following:

Claims (10)

- CLAIMS

1. A substituted amidinobenzene derivative of the following general formula (I) or a salt thereof: (characterized in that the symbols in the above formula have the following meanings: R1: a group which can be converted to an amidino group in vivo, R2 and R3 the same or different and each represents a carboxyl group or a group which is can convert to a carboxyl group in vivo, X1 and X1 the same or different and each represents a lower alkylene group, m: 0, 1 or 2, n: 0 or 1, provided that n = 1 when m = 0

2. The substituted amidinobenzene derivative or a salt thereof according to claim 1, characterized in that at least one of R2 and R3 is a group that can be converted to a carboxyl group in vivo.

3. The substituted amidinobenzene derivative or a salt thereof according to claim 1, characterized in that the group which can be converted to an in vivo amidino group of R1 is a group selected from the group consisting of a hydroxyamidino group, an alkoxycarbonylamido group , a lower alkoxyamidino group and a lower alkanoylamine group.

4. The substituted amidinobenzene derivative or a salt thereof according to claim 1, characterized in that the group which can be converted to an in vivo carboxyl group of R2 and R3 is a group selected from the group consisting of a lower alkoxycarbonyl group, a lower alkoxy group-lower alkoxycarbonyl, lower-alkoxycarbonyl-lower alkoxy lower a halogeno-lower alkoxycarbonyl, lower alkenyloxycarbonyl group, an alkanoyloxy group lower-alkoxycarbonyl lower an alkenoyloxy group lower-alkoxycarbonyl lower alkoxy group an alkanoyl lower-alkoxycarbonyl, a lower alkoxycarbonyl-lower alkenoyl group, a lower alkoxy-lower alkanoyloxy-lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-lower alkoxycarbonyl group, a lower alkoxy-lower alkoxycarbonyloxy-lower alkoxycarbonyl group, a di-lower alkoxycarbonyl lower , a cycloalkite group loxicarboniloxi-alkoxycarbonyl, a lower alcoxibenciloxicarbonilo group, a nitrobenzyloxycarbonyl group, a lower alcoxibenzhidriloxicarbonilo group, a benzhydryloxycarbonyl group, a benzoyloxy-lower alkoxycarbonyl group, a 2-oxotetrahydrofuran-5-yloxycarbonyl group, a 2-oxo-5-alkyl- 1, 3-dioxolen-4-ylmethoxycarbonyl, a tetrahydrofuranylcarbonyloxymethoxycarbonyl group and a 3-phthaloxycarbonyl group.

5. The substituted amidinobenzene derivative or a salt thereof according to any of claims 1 to 4, characterized in that m = 1.

6. The substituted amidinobenzene derivative or a salt thereof according to claim 1, characterized in that it is ethyl 4- [4- (4-hydroxylamidoinophenyl) -3-oxo-l-piperazinyl] -1-piperidinacetate, 4- [4 - (4-hidroxilamidinofenil) -3-oxo-l-piperazinyl] -1-piperidineacetate, methyl 4- [4- (4-metoxicarbonilamidinofenil) -3-oxo-l-piperazinyl] -1-piperidineacetate, 4- [4- (4-metoxicarbonilamidinofenil) -3-oxo-l-piperazinyl] -1-piperidineacetate, methyl 4- [4- (4-etoxicarbonilamidinofenil) -3-oxo-l-piperazinyl] -1-piperidineacetate.

7. The substituted amidinobenzene derivative or a salt thereof according to claim 1, characterized in that it is ethyl 4- [4- (4-hydroxylamidoinophenyl) -3-oxo-l-piperazinyl] -1-piperidinacetate.

8. A pharmaceutical composition, characterized in that it comprises a substituted amidinobenzene derivative of the following general formula (I) or a salt thereof, and a pharmaceutically acceptable carrier: (The symbols in the above formula have the following meanings: R1: a group which can be converted to an amidino group in vivo, R2 and R3: the same or different and each represents a carboxyl group or a group which can be convert into a carboxyl group in vivo, X1 and X2: the same or different and each represents a lower alkylene group, m: 0, 1 or 2, n: 0 or 1, provided that n = 1 when m = 0 .

9. The pharmaceutical composition according to claim 8, characterized in that it is an antagonist of the GPIIb / IIIa receptor.

10. The pharmaceutical composition according to claim 9, characterized in that it is an inhibitor of platelet aggregation. SUMMARY OF THE INVENTION A substituted amidinobenzene derivative of the following general formula (I) or a salt thereof, and a pharmaceutical composition comprising the derivative or a salt thereof and a pharmaceutically acceptable carrier. (The symbols in the above formula have the following meanings: RJ a group which can be converted into an amidino group in vivo, R2 and R3: the same or different and each represents a carboxyl group or a group which can be converted in a carboxyl group in vivo, X1 and X 'the same or different and each represents a lower alkylene group, m: 0, 1 or 2; n: O or 1, with the proviso that n = 1 when m = 0. These have GPIIb / IIIa receptor antagonist activity and are useful as medicines to improve cardiac, ischemic disorders, administer in cardiac surgery operations? or in operations of vascular surgery, medicine to improve cerebrovascular disorders and medicines to improve disorders of peripheral arteries. In addition, these are useful as an excellent prodrug in peroral absorbability and maintenance of the effect. .