PHOSPHONIC ACID DIESTER DERIVATIVES

Abstract: Novel phosphonic diester derivatives represented by general formula (1) or pharmacologically acceptable salts thereof which are useful as drugs, wherein R 1 represents amino, N-(lower alkyl)amino, N-(lower alkenyl)amino, etc.; R 2 and R 3 represent each hydrogen, lower alkyl, halogeno, lower alkoxy etc.; R 4 represents hydrogen, lower alkyl or phenyl(lower alkyl); R 5 and R 6 represent each lower alkyl; X, Y and Z are all carbon atoms, or one of X, Y and Z is a nitrogen atom while other two are carbon atoms; and Q represents a single bond or alkylene.

Description: TECHNICAL FIELD OF THE INVENTION The present invention relates to novel phosphonic acid diester derivatives and agents for the prophylaxis or treatment of diabetes containing the same. BACKGROUND OF THE INVENTION The derivatives of the present invention are novel compounds which have not been so far described in the literature. JP 05-170653, for example, discloses e.g. 4-diethoxyphosphinoylmethyl-N-(4-chloro phenyl) benzamide as an active ingredient in treating diabetes mellitus and diabetic complication. DISCLOSURE OF THE INVENTION The present invention provides novel derivatives represented by the following general formula (1): wherein R 1 represents amino group, N-lower alkylamino group, N-lower alkenylamino group, N-phenylamino group whose benzene. ring may be substituted with 1 or 2 groups being selected from halogen atom and lower alkoxy group, N-phenyl(lower)alkylamino group, N,N-di(lower)alkylamino group or 4-lower alkylpiperazinyl group; R 2 and R 3 represent, identically or differently, hydrogen atom, lower alkyl group, halogen atom, lower alkoxy group, nitro group, amino group, N-lower alkylsulfonylamino group or N-lower alkanoylamino group; R 4 represents hydrogen atom, lower alkyl group or phenyl(lower)alkyl group; R 5 and R 6 represent, identically or differently, lower alkyl group; X, Y and Z represent that all of them are carbon atoms or one of them is nitrogen atom and the other two are carbon atoms; Q represents a single bond or alkylene group; or pharmacologically acceptable salts thereof. The phosphonic acid diester derivative or the pharmacologically acceptable salts thereof of the present invention have blood glucose-lowering activities and are typically useful, for example, as agents for the prophylaxis or treatment of diabetes. That is to say, the present invention relates to (1) Phosphonic acid diester derivative represented by the general formula: wherein R 1 represents amino group, N-lower alkylamino group, N-lower alkenylamino group, N-phenylamino group whose benzene ring may be substituted with 1 or 2 groups being selected from halogen atom and lower alkoxy group, N-phenyl(lower)alkylamino group, N,N-di-(lower)alkylamino group or 4-lower alkylpiperazinyl group; R 2 and R 3 represent, identically or differently, hydrogen atom, lower alkyl group, halogen atom, lower alkoxy group, nitro group, amino group, N-lower alkylsulfonylamino group or N-lower alkanoylamino group; R 4 represents hydrogen atom, lower alkyl group or phenyl(lower)alkyl group; R 5 and R 6 represent, identically or differently, lower alkyl group; X, Y and Z represent that all of them are carbon atoms or one of them is nitrogen atom and the other two are carbon atoms; Q represents a single bond or alkylene group; or the pharmacologically acceptable salts thereof, (2) The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof described in the aforesaid (1), wherein X, Y and Z are all carbon atoms, or X is nitrogen atom and both Y and Z are carbon atoms, (3) The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof described in the aforesaid (2), wherein X, Y and Z are all carbon atoms, (4) The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof described in the aforesaid (3), wherein the derivative is represented by the general formula: wherein R 1 , R 2 , R 3 , R 5 , R 6 and Q have the same meanings as mentioned above, (5) The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof described in the aforesaid (4), wherein R 2 and/or R 3 is lower alkyl group, halogen atom or nitro group, (6) The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof described in the aforesaid (5), wherein Q is trimethylene group, (7) The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof described in the aforesaid (6), wherein R 2 is halogen atom and R 3 is hydrogen atom or halogen atom, (8) The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof described in the aforesaid (7), wherein the derivative is one selected from diethyl 3-[N-[3,5-dichloro-2-(N-methylcarbamoyl)phenyl]carbamoyl]propylphosphonate, diethyl 3-[N-[4,6-dichloro-2-(N-methylcarbamoyl)phenyl]carbamoyl]propylphosphonate and diethyl 3-[N-[3-chloro-2-(N-phenylcarbamoyl)phenyl]carbamoyl]-propylphosphonate, (9) An agent for the prophylaxis or treatment of diabetes containing at least one compound described in any of the aforesaid (1) to (8) as active ingredient together with nontoxic carrier, (10) Use of the compound described in any of the aforesaid (1) to (8) for manufacturing a medicament for the prophylaxis or treatment of diabetes, (11) The compound described in any of the aforesaid (1) to (8) used for manufacturing a medicament for the prophylaxis or treatment of diabetes, (12) A pharmaceutical composition comprising the compound described in any of.the aforesaid (1) to (8) and the pharmacologically acceptable carrier, (13) The method of preventing or treating diabetes which comprises administering the compound described in any of the aforesaid (1) to (8) to a diabetic patient, and (14) Blood glucose-lowering agent comprising the compound described in any of the aforesaid (1) to (8). Each group defined in the aforesaid general formula (1), representing phosphonic acid diester derivatives, is illustrated as follows. In the following description of this specification explaining the present invention, the term "phosphonic acid diester derivative or the pharmacologically acceptable salt thereof" is hereinafter referred to merely as "phosphonic acid diester derivative". That is, N-lower alkylamino group includes, for example, N-methylamino, N-ethylamino, N-propylamino, N-butylamino, N-pentylamino, N-hexylamino, and the like, wherein the lower alkyl moiety is straight- or branched-chain alkyl of C1 to C6. N-lower alkenylamino group includes, for example, N-vinylamino, N-allylamino, N-isopropenylamino, N-(3-butenyl)amino, N-(4-pentenyl)-amino, N-(5-hexenyl)amino, and the like, wherein the lower alkenyl moiety is straight- or branched-chain alkenyl of C2 to C6. Halogen atom includes, for example, fluorine atom, chlorine atom, bromine atom, iodine atom, and the like. Lower alkoxy group includes a straight- or branched-chain alkoxy group of C1 to C6, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like. N-phenyl(lower)alkylamino group includes, for example, N-benzylamino, N-(1-phenylethyl)amino, N-(2-phenylethyl)amino, N- N-(3-phenylpropyl)amino, N-(4-phenylbutyl)amino, N-(5phenylpentyl)-amino, N-(6-phenylhexyl)amino, and the like, wherein the lower alkyl moiety is straight- or branched-chain alkyl of C1 to C6. N,N-di(lower)alkylamino group includes, for example, N,N-dimethylamino, N.N-diethylamino, N,N-dipropylamino, N,N-dibutylamino, N,N-dipentylamino, N,N-dihexylamino, N-ethylN-methylamino, N N-methyl-N-propylamino, and the like, wherein the lower alkyl moiety is straight- or branched-chain alkyl of C1 to C6. 4-Lower alkylpiperazinyl group includes, for example, 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-propylpiperazinyl, 4-butylpiperazinyl, 4-pentylpiperazinyl, 4-hexylpiperazinyl, and the like, wherein the lower alkyl moiety is straight- or branched-chain alkyl of C1 to C6. Lower alkyl group includes a straight- or branched-chain alkyl group of C1 to C6, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like. N-lower alkylsulfonylamino group includes, for example, NN-methylsulfonylamino, N-ethylsulfonylamino, N-propylsulfonylamino, N-butylsulfonylamino, N-pentylsulfonylamino, N-hexylsulfonylamino, and the like, wherein the lower alkyl moiety is straight- or branched-chain alkyl of C1 to C6. N-lower alkanoylamino group includes, for example, N-acetylamino, N-propionylamino, N-butyrylamino, N-valerylamino, N-pivaloylamino, N-hexanoylamino, N-heptanoylamino, and the like, wherein the lower alkanoyl moiety is straight- or branched-chain alkanoyl of C2 to C7. Phenyl(lower)alkyl group includes, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, and the like, wherein the lower alkyl moiety is straight- or branched-chain alkyl of C1 to C6. Alkylene group refers to a straight- or branched-chain alkylene group of approximately C1 to C8, for example, methylene, ethylene, ethylidene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, and the like. Examples of N-phenylamino group whose benzene ring may be substituted with 1 or 2 groups being selected from halogen atom and lower alkoxy group include N-phenylamino, N-(2-fluorophenyl)amino, N-(3-fluorophenyl)amino, N-(4-fluorophenyl)amino, N-(2-chlorophenyl)amino, N-(3-chlorophenyl)amino, N-(4-chlorophenyl)amino, N- N-(2-bromophenyl)amino, )amino, N-(3-bromophenyl)amino, N-(4-bromophenyl)amino, N-(4-iodophenyl)amino, N-(3,5·dichlorophenyl)amino, N-(2,3-dichlorophenyl)amino, N-(2,4-dichlorophenyl)amino, N-(2-methoxyphenyl)amino, N-(3-methoxyphenyl)amino, N-(4-methoxyphenyl)amino, N-(4-ethoxyphenyl)aminb, N-(4-propoxyphenyl)amino, N-(4-butoxyphenyl)amino, N-(4-pentyloxyphenyl)amino, N-(4-hexyloxyphenyl)amino, N-(2,3-dimethoxyphenyl)amino, N-(2,4-dimethoxyphenyl)amino, N-(2,5-dimethoxyphenyl)amino, N-(2,6-dimethoxyphenyl)amino, N- (3,4-dimethoxyphenyl)amino, N-(3,5-dimethoxyphenyl)amino, and the like. Halogen atom and lower alkoxy group as substituents have the aforesaid significance. The pharmacologically acceptable salts of phosphonic acid diester derivatives of the present invention include, for example, salts with inorganic acids such as hydrochloric acid, nitric acid and phosphoric acid, and salts with organic acids such as oxalic acid and fumaric acid. In the general formula (1) described above, the examples of compounds suitable for medicines, especially agents for the treatment of diabetes, include each compound belonging to any of groups (a) to (g). (a) The phosphonic acid diester derivatives of the general formula (1), wherein X, Y and Z are all carbon atoms, or X is nitrogen atom and both Y and Z are carbon atoms. (b) The phosphonic acid diester derivatives of the aforesaid item (a), wherein X, Y and Z are all carbon atoms. (c) The phosphonic acid diester derivatives of the aforesaid item (b) which are represented by the following general formula: wherein R 1 , R 2 , R 3 , R 5 , R 6 and Q have the same meanings as mentioned above; are preferable. (d) The phosphonic acid diester derivatives of the aforesaid item (c), wherein R 2 and/or R 3 is lower alkyl group, halogen atom or nitro group, are more preferable. (e) The phosphonic acid diester derivatives of the aforesaid item (d), wherein Q is trimethylene group, are more preferable. (f) The phosphonic acid diester derivatives of the aforesaid item (e), wherein R 2 is halogen atom and R 3 is hydrogen atom or halogen atom, are more preferable. (g) More preferred phosphonic acid diester derivative of the aforesaid item (f) is one selected from diethyl 3-[N-[3,5-dichloro-2-(N-methylcarbamoyl)phenyl]carbamoyl]propylphosphonate, diethyl 3-[N-[4,6-dichloro-2-(N-methylcarbamoyl)phenyl]-carbamoyl]propylphosphonate and diethyl 3-[N-[3-chloro-2-(N-phenylcarbamoyl)phenyl]carbamoyl]propylphosphonate. The derivative of the present invention can be prepared by various kinds of methods. The examples are described in detail with the following reaction schemes. wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y and Z have the same meanings as mentioned above, Q' represents alkylene group, W represents halogen atom. According to the procedure shown in Reaction scheme-1, a compound (1a) of the present invention can be obtained by reacting a compound (2) with an acid halide (3) in an inert solvent, in the presence of an acid acceptor. Both compounds (2) and (3) are known compounds. The inert solvent described above includes, for example, aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene and petroleum ether, chain or cyclic ethers such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran (THF) and 1,4-dioxane, ketones such as acetone, methyl ethyl ketone and acetophenone, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane. The preferable examples of the acid acceptor include tertiary amines such as triethylamine, pyridine, 4-dimethylaminopyridine, and the like. The ratio between compound (2) and acid halide (3) employed in the above reaction is not limited specifically to, but preferably from about an equimolecular amount to a small excess of the latter based on the former. It is preferable to employ usually an equimolecular amount to an excess of acid acceptor based on acid halide. The reaction proceeds either under cooling, at room temperature or under heating. It is preferable to carry out the reaction usually in the range of from 0°C to the reflux temperature of a solvent and the reaction may generally be completed in about 0.5 to 10 hours. wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 . X, Y, Z and Q' have the same meanings as mentioned above. According to the procedure shown in Reaction scheme-2, a compound (1a) of the present invention can be obtained by reacting a compound (2) with a compound (4) in an inert solvent, in the presence of a condensing agent. Compound (4) is a known compound. The inert solvent used in this reaction may be any of known aprotic solvents, for example, N,N-dimethylformamide (DMF), or the like, preferably. The condensing agent includes, for example, N,N-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole, NN-hydroxysuccinimide, diethylphosphoryl cyanide, diphenylphosphoryl azide, and the like. The combined use of diethylphosphoryl cyanide and triethylamine is especially favorable. The ratio between compound (2) and compound (4) for the use in the above reaction is, not limited in any way and may vary with a wide range, usually an equimolecular quantity to a small excess, preferably about equimolecular quantity of the latter based on the former. It is suitable to employ an equimolecular amount to an excess, preferably a small excess of condensing agent based on compound (4). The reaction is carried out under the conditions ranging from cooling to near room temperature and is usually completed in about 0.5 to 2 hours. wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, Y and Z have the same meanings as mentioned above. R 6a is the same as R 5 . According to the procedure shown in Reaction scheme-3, a compound (1b) of the present invention can be obtained by reacting p-nitrophenyl chloroformate (5) with trialkyl phosphite (6) in an inert solvent to yield a compound (7), which is not isolated, followed by reacting with a compound (2) in the same reaction mixture. The inert solvent used in this reaction includes, for example, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like. The ratio of each compound used in the above reaction is not limited in any way and may vary with a wide range. It is preferable to use 1 to 1.2-fold molar quantities of p-nitrophenyl chloroformate (5) and trialkyl phosphite (6) based on compound (2), respectively. The reaction between p-nitrophenyl chloroformate (5) and trialkyl phosphite (6) described above is carried out at room temperature to the reflux temperature of a solvent, preferably at the reflux temperature of a solvent, usually for 0.5 to 5 hours. The reaction between compound (7) and compound (2) is carried out at room temperature to the reflux temperature of a solvent, preferably at near room temperature, usually for about 1 to 30 hours. In the reaction between compound (7) and compound (2), an acid acceptor (for example, triethylamine, pyridine, N,N-dimethylaniline, N-methylmorpholine, or the like) may be added at 1 to a small excessive molar quantities based on compound (2), if necessary. The objective compound or the compound of the present invention obtained by the procedures shown in the aforesaid reaction schemes may readily be isolated and purified by the conventional separation technique, and the examples of the technique include adsorption chromatography, preparative thin-layer chromatography, recrystallization, solvent extraction, or/and the like. Compounds capable of forming salts such as the aforesaid starting compounds (1) and (4) may be used in the form of salts, and the examples of the salts include the aforesaid pharmacologically acceptable salts. Starting compounds (2), (3), (4), (5) and (6) may readily be prepared by the known methods or by known methods per se. Agents for the prophylaxis or treatment of diabetes of the present invention may be utilized in the form of general pharmaceutical preparations by the use of the compounds represented by the above general formula (1) or the pharmacologically acceptable salts thereof as active ingredients, together with suitable nontoxic pharmaceutical carriers. The aforesaid pharmaceutical carriers utilized in agents for the prophylaxis or treatment of diabetes of the present invention may be illustrated according to the usage form of the pharmaceutical preparations, for example, diluents or excipients such as commonly used bulking agents, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, and the like, which may appropriately be selected in accordance with the dosage unit forms of the desired pharmaceutical preparations. As the aforesaid dosage unit forms of the pharmaceutical preparations, various forms may be selected in accordance with the object of treatment, and the typical examples of the forms include tablets, pills, powder, liquid preparations, suspensions, emulsions, granules, capsules, suppositories, injectable preparations (liquids, suspensions, or the like), ointments, and the like. In case of formulating in the form of tablets, the above usable pharmaceutical carriers include, for example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and potassium phosphate, binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropyl cellulose, methylcellulose and polyvinylpyrrolidone, disintegrants such as carboxymethylcellulose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropyl cellulose, dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate and calcium carbonate, surfactants such as polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate and stearic acid monoglyceride, disintegration inhibitors such as sucrose, stearin, cocoa butter and hydrogenated oil, absorption promoters such as quaternary ammonium base and sodium lauryl sulfate, moisturizers such as glycerol and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silica, lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol, and the like. Further, tablets may be coated with usual coating materials, if necessary, for example, may be sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film coating tablets, or double-layer tablets, multiple-layer tablets. In case of formulating in the form of pills, the usable pharmaceutical carriers include, for example, excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oil, kaolin and talc, binders such as gum arabic powder, gum tragacanth powder, gelatin and ethanol, disintegrants such as laminaran and agar, and the like. In case of formulating in the form of suppositories, the usable pharmaceutical carriers include, for example, polyethylene glycol, cocoa butter, higher alcohol, higher alcohol esters, gelatin, semisynthetic glyceride, and the like. Capsules may be prepared according to the conventional method, by mixing the compounds of the present invention with a variety of pharmaceutical carriers illustrated above, followed by filling hard gelatin capsules, soft gelatin capsules, or the like, with the mixture. When prepared in the form of injectable preparations such as liquid preparations, emulsions and suspensions, these preparations are preferably sterile and isotonic to blood. In case of formulating into these forms, the usable diluents include, for example, water, ethanol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, and the like. The pharmaceutical preparations may contain enough sodium chloride, glucose or glycerol to prepare an isotonic solution and further usual solubilizing agents, buffer, soothing agents, and the like, may be added. Further, the pharmaceutical preparations may contain coloring agents, preservatives, perfume, flavoring, sweetening agents, and the like, and other medicines, if necessary. When prepared in the form of ointment such as paste, cream and gel, the usable diluents include, for example, white petrolatum, paraffin, glycerol, cellulose derivatives, polyethylene glycol, silicone, bentonite, and the like. The amount of the compounds of the present invention (active ingredients) contained in the aforesaid pharmaceutical preparations, is not limited in any way and may be appropriately selected from a wide range, preferably about 1 to 70 weight % of the pharmaceutical preparations. The mode of administration of the aforesaid pharmaceutical preparations is not limited and may be determined according to a variety of pharmaceutical forms, the age, sex and other conditions of the patient, the degree of disease, and the like. For example, tablets, pills, liquid preparations, suspensions, emulsions, granules and capsules are administered orally, injectable preparations are administered intravenously, or intramuscularlly, intracutaneously, subcutaneously or intraperitoneally, soley or in combination with common replenishers such as glucose and amino acid, and suppositories are administered intrarectally. The dosage of the aforesaid pharmaceutical preparations may be appropriately selected in accordance with the mode of administration, the age, sex and other conditions of the patient, the degree of disease, and the like. The compounds of the present invention (active ingredients) may generally be administered at a daily dose of from about 0.5 to 20mg, preferably 1 to 10mg per kg of body weight for an adult human, given in a single dose or in divided doses 2 to 4 times a day. In the following section, preparation examples of compounds of the present invention are provided as examples in order to illustrate the present invention in more detail. Then the pharmacological tests on the compounds of the present invention and the pharmaceutical formulations of the compounds of the present invention are also provided. The 1 H-NMR spectrum data of the compounds of the present invention (in the case of oily substances) which were obtained according to each production process, were measured by using CDCl 3 as a solvent and tetramethylsilane (TMS) as an internal standard. [Best Mode for Carrying Out the Invention] Example 1 Diethyl 3 [N- [5 -chloro- 2 - (N-methylcarbamoyl)p henyl] carbamoyl]-propylphosphonate was prepared as follows. 4-(Diethoxyphosphoryl)butyric acid (12.13g) was dissolved in dichloromethane (100ml), to which a catalytic amount of DMF and thionyl chloride (6.44g) were added successively at room temperature and the mixture was heated under reflux for 3 hours. Then, the reaction mixture was cooled to 0°C, to which a solution of 4-chloro-N-methylanthranilamide (9.99g) in dichloromethane (50ml) and pyridine (19.6ml) was dropwise added at 0°C and the mixture was stirred overnight at room temperature. The reaction mixture was washed successively with dilute hydrochloric acid and saturated saline solution, dried over anhydrous MgSO 4 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to give a brown oily compound (14.81g). The structure and melting point of the obtained compound are given in Table 1. Examples 2 to 50 Each compound shown in Table 1 was obtained in the similar manner as Example 1. The structures and physical properties (melting points or NMR data) of those compounds are given in Table 1. Example 51 Diethyl N-[5-chloro-2-(N-methylcarbamoyl)phenyl]carbamoyl phosphonate was prepared as follows. p-Nitrophenyl chloroformate (4.30g) and triethyl phosphite (3.66g) were dissolved in dry dichloromethane (20ml) and the mixture was heated under reflux for 30 minutes. Next the above reaction mixture was cooled to room temperature, to which NN-methyl-2-amino-4-chlorobenzamide (3.69g) and triethylamine (2.22g) were added and the mixture was stirred at room temperature for 20 hours. Water (50ml) was added and the reaction mixture was extracted with chloroform. The chloroform layer was washed successively with saturated sodium bicarbonate aqueous solution (50ml) and water (50ml), then dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; chloroform:ethyl acetate=1:1) and thus obtained crude crystals were recrystallized from ethyl acetate-n-hexane to give the desired compound (3.70g) . as colorless crystals. The structure and melting point of the obtained compound is given in Table 1. Examples 52 to 56 Further, each compound shown in Table 1 was obtained in the similar manner as Example 1. The structures and physical properties (melting points or NMR data) of those compounds are given in Table 1. In the following Table 1, Me, Et, i-Pr, Ph, Bn and Bu represent methyl, ethyl, isopropyl, phenyl, benzyl and n-butyl, respectively. Formulation Example 1 Preparation of tablets Tablets (2000 tablets) containing a compound of the present invention obtained in Example 31 as an active ingredient (300mg per tablet) were prepared according to the following recipe. a compound of the present invention obtained in Example 31 600g, lactose (Japanese Pharmacopoeia) 67g, corn starch (Japanese Pharmacopoeia) 33g, carboxymethylcellulose calcium (Japanese Pharmacopoeia) 25g, methylcellulose (Japanese Pharmacopoeia) 12g, magnesium stearate (Japanese Pharmacopoeia) 3g. That is, according to the above recipe, the compound of the present invention obtained in Example 31 was fully mixed with lactose, corn starch and carboxymethylcellulose calcium. The mixture was granulated with methylcellulose aqueous solution and passed through a 24-mesh screen. The granules were mixed with magnesium stearate and the mixture was compressed to give the desired tablets. Formulation Example 2 Preparation of Capsules Hard gelatin capsules (2000 capsules) containing a compound of the present invention obtained in Example 8 as an active ingredient (200mg per capsule) were prepared according to the following recipe. a compound of the present invention obtained in Example 8 400g, crystalline cellulose (Japanese Pharmacopoeia) 60g, corn starch (Japanese Pharmacopoeia) 34g, talc (Japanese Pharmacopoeia) 4g, magnesium stearate (Japanese Pharmacopoeia) 2g. That is, according to the above recipe, each of the components was ground to a powder and they were mixed together to give a uniform mixture. Oral gelatin capsules of appropriate size were filled with the mixture to obtain the desired capsules. Pharmacological Test Example The compounds of the present invention were tested for blood glucose-lowering activities in rats in the following manner. That is, Dexamethasone (Decadron S injectable solution:made by Banyu Pharmaceutical Co.,Ltd.) was administered intraperitoneally to a group (test group) of 5 male Wister rats (6 weeks old) at a daily dose of 0.5mg/kg, once a day for 4 days. Immediately after the administration of dexamethasone, a test compound (100mg/kg) dissolved in 5% gum arabic solution was administered orally to rats daily. On day 4, the rats were decapitated 4 hours after the administration of dexamethasone. Blood was collected and centrifuged (3000rpm, 4°C, 15 minutes), then the glucose level in the obtained serum was measured by the use of Glucose cII Test Wako (made by Wako Pure Chemical Industries, Ltd.). The rats were maintained on a diet ad libitum and then fasted 24 hours before the collection of blood. Animals which were given 5% gum arabic solution instead of a test compound were served as a control group and those which were maintained merely on a diet ad libitum were served as a normal group. The serum glucose levels of them were measured according to the same manner as above. The decrease rate of blood glucose level was determined by the value (mean value) of each group from the following equation. Decrease Rate (%) in Blood Glucose Level = (the value of control group) - (the value of test group) (the value of control group) - (the value of normal group) × 100 Results obtained were shown in the following Table 2. Test compound (Example No.) Decrease rate (%) in blood glucose level Test compound (Example No.) Decrease rate (%) in blood glucose level 4 20 25 17 5 31 31 59 7 30 32 16 8 39 36 12 9 30 38 18 12 15 40 14 14 44 44 21 15 50 51 17 16 22 54 13 19 24 - - In the same manner as Example 1, the compounds shown in the following Table 3 may be obtained. INDUSTRIAL UTILIZATION OF THE INVENTION Phosphonic acid diester derivatives of the present invention are effective for the prophylaxis or treatment of diabetes and are useful as medicines for human or animal.

Claims: A phosphonic acid diester derivative represented by the general formula: wherein R 1 represents amino group, N-lower alkylamino group, N-lower alkenylamino group, N-phenylamino group whose benzene ring may be substituted with 1 or 2 groups being selected from halogen atom and lower alkoxy group, N-phenyl(lower)alkylamino group, N,N-di(lower)alkylamino group or 4-lower alkylpiperazinyl group; R 2 and R 3 represent, identically or differently, hydrogen atom, lower alkyl group, halogen atom, lower alkoxy group, nitro group, amino group, N-lower alkylsulfonylamino group or N-lower alkanoylamino group; R 4 represents hydrogen atom, lower alkyl group or phenyl(lower)alkyl group; R 5 and R 6 represent, identically or differently, lower alkyl group; X, Y and Z represent that all of them are carbon atoms or one of them is nitrogen atom and the other two are carbon atoms; Q represents a single bond or alkylene group; or a pharmacologically acceptable salt thereof. The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof of Claim 1, wherein X, Y and Z are simultaneously carbon atoms; or X is nitrogen atom and both Y and Z are carbon atoms. The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof of Claim 2, wherein X, Y and Z are simultaneously carbon atoms. The phosphonic acid diester derivative of Claim 3, which is represented by the general formula: wherein R 1 , R 2 , R 3 , R 5 , R 6 and Q have the same meanings as mentioned hereinbefore, or the pharmacologically acceptable salt thereof. The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof of Claim 4, wherein R 2 and/or R 3 is lower alkyl group, halogen atom or nitro group. The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof of Claim 5, wherein Q is trimethylene group. The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof of Claim 6, wherein R 2 is halogen atom and R 3 is hydrogen atom or halogen atom. The phosphonic. acid diester derivative of Claim 7, which is one selected from diethyl 3-[N-[3,5-dichloro-2-(N-methylcarbamoyI)-phenyllcarbamoyljpropylphosphonate, diethyl 3-[N-[4,6-dichloro-2-(N-methylcarbamoyl)phenyl)carbamoyl]propylphosphonate and diethyl 3-[N-[3-chloro-2-(N-phenylcarbamoyl)phenyl]carbamoyl]propylphosphonate, or the pharmacologically acceptable salt thereof. An agent for the prophylaxis or treatment of diabetes containing at least one compound claimed in any of Claims 1 to 8 as an active ingredient together with a nontoxic carrier. Use of the compound claimed in any of Claims 1 to 8 for manufacturing a medicament for the prophylaxis or treatment of diabetes. A pharmaceutical composition comprising the compound claimed in any of Claims 1 to 8 and a pharmacologically acceptable carrier.

Inventors: INOUE YASUHIDE, KAWAMURA KENICHI, MIYATA KAZUYOSHI, SAKAI YASUHIRO, TSUDA YOSHIHIKO, INOUE, YASUHIDE, KAWAMURA, KENICHI, MIYATA, KAZUYOSHI, SAKAI, YASUHIRO, TSUDA, YOSHIHIKO
Applicants: OTSUKA PHARMA CO LTD, OTSUKA PHARMACEUTICAL FACTORY, INC.
Application year: 1999
Main classification: C07F9
IPC codes: C07F9, A61P31, A61P3, A61K31