JPS644509B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an aminocarboxylic acid derivative, a method for producing the same, and an antiulcer agent containing the same as an active ingredient. More specifically, the present invention has an excellent anti-ulcer effect,
The present invention also relates to an aminocarboxylic acid derivative having a specific pharmacological action, a method for producing the same, and an antiulcer agent containing the same as an active ingredient. However, according to the present invention, the following formula (), [In the formula, R ₁ and R ₂ represent an oxo group together, or R ₁ represents _a hydrogen atom and _{R 2 represents} a hydroxyl group. R ₃ represents a hydrogen atom or a lower alkyl group. ] An aminocarboxylic acid derivative or an acid addition salt thereof is provided. Many drugs have been known to treat peptic ulcers.These drugs include (a) drugs that suppress aggressive factors such as hydrochloric acid, pepsin, and gastrin and histamine that promote their secretion; and (b) Drugs are divided into two categories: drugs that enhance so-called protective factors that improve mucosal resistance, including renal mucosal blood flow and mucin production, and promote repair of defective mucosa. Drugs that suppress aggressive factors include antacids, anticholinergic agents, antipepsin agents, and antigastrin drugs, and drugs that enhance defensive factors include agents that protect or regenerate mucous membranes. Furthermore, as a drug that acts on both of the above factors, cetraxate hydrochloride (Japanese Unexamined Patent Publication No. 101134/1982) is known. Compared to these drugs, the novel aminocarboxylic acid derivative represented by the above formula () or its acid addition salt provided by the present invention has a structure not found in conventional antiulcer agents, and Surprisingly, it was confirmed that it has a very strong anti-ulcer effect on serotonin ulcers, which are thought to be caused by impaired gastric mucosal blood flow and hypermotility. Furthermore, the compounds of the present invention have almost no proteolytic enzyme inhibitory effects, such as antithrompin and antitrypsin effects, as seen in cetraxate hydrochloride, and are therefore thought to have fewer side effects. Therefore, the aminocarboxylic acid derivative or acid addition salt thereof of the present invention is fully expected to be a drug having excellent anti-ulcer effects with few side effects. In the aminocarboxylic acid derivative or acid addition salt thereof represented by the above formula () of the present invention, R ₁ , R ₂
and R ₃ are defined as follows. That is, R ₁ and R ₂ together represent an oxo group, or R ₁ is a hydrogen atom and R ₂ is a hydroxyl group. Accordingly, the aminocarboxylic acid derivative represented by the above formula () according to the definitions of R ₁ and R ₂ may specifically include the following compounds. That is, (i) the following formula (-a), [In the formula, R ₃ represents a hydrogen atom or a lower alkyl group. ] An aminocarboxylic acid derivative or its acid addition salt represented by (ii) the following formula (-b) [In the formula, R ₃ represents a hydrogen atom or a lower alkyl group. ] An aminocarboxylic acid derivative or an acid addition salt thereof. In the above formula (), (-a) or (-b), R ₃ is a hydrogen atom or a lower alkyl group. Such lower alkyl groups are not particularly limited, but are preferably alkyl groups having 1 to 10 carbon atoms,
Particularly preferred are methyl, ethyl, propyl, and butyl groups, with methyl and ethyl groups being particularly preferred. Further, in the present invention, the above formulas (), (-a), (
The acid addition salts of the aminocarboxylic acid derivatives represented by -b) are also included, and such acid addition salts may be any pharmaceutically acceptable salts, such as hydrochloride, hydrobromic acid mineral acid salts such as salts, sulfates, and phosphates; or organic acid salts such as formates, acetates, monochloroacetates, trichloroacetates, trifluoroacetates, oxalates, and citrates; or paratoluene Examples include acid addition salts such as sulfonates and organic sulfonates such as benzenesulfonates. Among them, hydrochloride is particularly preferably used from the viewpoint of ease of storage and stability. Preferred specific examples of the aminocarboxylic acid derivatives or acid addition salts thereof of the present invention as described above are as follows. (i) Those represented by the above formula (-a), (1) p-(4-aminomethylbenzoyl)-phenylpropionic acid, (2) methyl p-(4-aminomethylbenzoyl)-phenylpropionate ester, (3) p-(4-aminomethylbenzoyl)-phenylpropionate ethyl ester, (4) p-(4-aminomethylbenzoyl)-phenylpropionate propyl ester, (5) p-(4- (aminomethylbenzoyl)-phenylpropionate isopropyl ester, (6) hydrochloride of the compound of (1) to (5), especially (1) to (3), or (1) to (3)
(ii) those represented by the above formula (-b), (1) α-(4-aminomethylphenyl)-p-
(2-carboxyethyl)-benzyl alcohol, (2) α-(4-aminomethylphenyl)-p-
(2-methoxycarbonylethyl)-benzyl alcohol, (3) α-(4-aminomethylphenyl)-p-
(2-ethoxycarbonylethyl)-benzyl alcohol, (4) α-(4-aminomethylphenyl)-p-
(2-Propoxycarbonylethyl)-benzyl alcohol, (5) Hydrochloride of the compounds of (1) to (4), especially the hydrochloride of (1), (2) or (1), (2) is preferred. Thus, the aminocarboxylic acid derivative or acid addition salt thereof of the present invention is produced as follows. (i) Synthesis of a compound (formula (-a) above) in which R ₁ and R ₂ together represent an oxo group in the above formula (); [In the formula, X represents a halogen atom. ] An acid addition salt or an amino group-protected derivative of an aminocarboxylic acid halide represented by the following formula (), [In the formula, R ₄ represents a lower alkyl group. ] by reacting phenylpropionate represented by the following formula (- a) [In the formula, R ₃ represents a hydrogen atom or a lower alkyl group. ] The aminocarboxylic acid derivative or its acid addition salt represented by these is produced. (ii) In the above formula (), R ₁ is a hydrogen atom, R ₂
represents a hydroxyl group (the above formula (-
Synthesis of b)); The following formula (-a) obtained by the above method [In the formula, R ₃ represents a hydrogen atom or a lower alkyl group. ] The following formula (-b) is obtained by reducing the aminocarboxylic acid derivative represented by the formula (-b) or its acid addition salt, and then, if necessary, performing a hydrolysis and/or esterification reaction that is known per se. [In the formula, R ₃ is the same as the above definition. ] The aminocarboxylic acid derivative or its acid addition salt represented by these is produced. In the acid addition salt or amino group-protected derivative of the aminocarboxylic acid halide represented by the above formula (), which is a raw material for the above-described production method, X is a halogen atom, and a chlorine atom is particularly preferred. As acid addition salts of such aminocarboxylic acid halides, hydrochlorides and sulfates are particularly preferred. In addition, in the case of amino group-protected derivatives of aminocarboxylic acid halides, the protecting group for the amino group is a normal amino acid or a protecting group used in peptide synthesis, which promotes side reactions in the condensation reaction described below. It is not particularly limited as long as it is not present and can be easily eliminated by acid or alkali, etc., and the following can be mentioned. That is, formyl group, acetyl group, trifluoroacetyl group, chloroacetyl group, etc. as acyl type protecting group; tertiary-type as urethane type protecting group.
Examples include a butoxycarbonyl group, a tertiary-amyloxycarbonyl group, a diisopropylmethyloxycarbonyl group, and a phthalyl group. Among these, acetyl groups, trifluoroacetyl groups, phthalyl groups, etc. are preferred because they are inexpensive and easy to handle. Among these, the amino group-protected derivative of the aminocarboxylic acid halide of formula () can be obtained by a known method than the amino group-protected aminocarboxylic acid, for example, by reacting the amino group-protected aminocarboxylic acid with thionyl chloride, phosphorus pentachloride, etc. It can be easily manufactured by The other raw material for the production method of the present invention is phenylpropionic acid ester represented by the above formula (), where R ₄ represents a lower alkyl group,
Alkyl groups having 1 to 10 carbon atoms are preferred, and specific examples of such lower alkyl groups include methyl,
ethyl, n-propyl, isopropyl, butyl,
Examples include pentyl and isopentyl groups. Among these, methyl and ethyl groups are industrially preferred. The condensing agent used when condensing the acid addition salt or amino group-protected derivative of the aminocarboxylic acid halide of the above formula () with the phenylpropionate ester of the above formula () is a general acid halide and an aromatic compound. A Lewis acid catalyst used in the reaction is preferred. Specific examples of such condensing agents include aluminum chloride, aluminum bromide, ferric chloride, zinc chloride, stannic chloride, titanium chloride, and preferably aluminum chloride and aluminum bromide. . The condensing agent is preferably used in an amount equal to or more than the equivalent molar amount of the acid addition salt of the aminocarboxylic acid halide or the amino group-protected derivative of the formula (), and is usually used in an equivalent molar amount to 10 times the molar amount. As the solvent used in the reaction, halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, dichloroethane, and tetrachloroethane, and inert solvents such as nitrobenzene and carbon disulfide are preferably used. The reaction is generally preferably carried out by adding the phenylpropionate ester of the formula () to a mixed solution of the acid addition salt or amino group-protected derivative of the aminocarboxylic acid halide of the formula () and the condensing agent. Further, the condensing agent may be added little by little to a solution of an acid addition salt of an aminocarboxylic acid halide or an amino group-protected derivative and a phenylpropionate, or an aminocarboxylic acid halide may be added to a mixed solution of a phenylpropionate and a condensing agent. Acid addition salts or amino group-protected derivatives of acid halides may also be added. The reaction temperature can be generally carried out at a temperature ranging from 0°C to the boiling point of the solvent used, but preferably from room temperature to 70°C. After the reaction is completed, when starting from the acid addition salt of the aminocarboxylic acid halide represented by the above formula (), the solvent is usually removed by means such as decantation or distillation, water is added to the residue, and excess condensing agent is removed. After decomposition and making the solution alkaline, a decomposition operation such as an extraction operation is performed to obtain an aminocarboxylic acid derivative of the above formula (-a) in which R ₃ is a lower alkyl group. Then, if necessary, hydrolysis using an acid or an alkali as a catalyst in a manner known per se can be carried out to obtain an aminocarboxylic acid derivative or an acid addition salt thereof in which R ₃ is a hydrogen atom in the above formula (-a). . When an acid is used as a catalyst for hydrolysis, the desired product can be obtained as an acid addition salt. The acid catalyst used here includes mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid; organic acids such as formic acid, acetic acid, monochloroacetic acid, trichloroacetic acid, trifluoroacetic acid, oxalic acid, and citric acid; Examples include organic sulfonic acids such as toluenesulfonic acid and benzenesulfonic acid. Furthermore, conversion to an acid addition salt other than the acid addition salt of the acid used as a catalyst can be easily carried out by neutralizing the compound with an alkali and then treating it with the desired acid. Further, when the above-mentioned hydrolysis is carried out using an alkali, an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, etc. is usually used as the alkali catalyst. In this case, the product is obtained as an alkali metal salt of the aminocarboxylic acid derivative represented by the above formula (-a), but by neutralizing this with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., the product is obtained by the above formula (-a). −
In a), an aminocarboxylic acid derivative in which R ₃ is a hydrogen atom is obtained. Such compounds can also be converted into their acid addition salts by contacting them with acids. The aminocarboxylic acid derivative or its oxidized salt obtained as described above is subjected to a normal esterification reaction,
For example, the formula ( -a) can also be converted into an aminocarboxylic acid derivative or an acid addition salt thereof in which R ₃ is a lower alkyl group. On the other hand, when starting from an amino group-protected derivative of an aminocarboxylic acid halide represented by the above formula (), after the reaction is completed, the solvent is usually removed by means such as decantation or distillation, and water is added to the residue to remove excess condensation. In the formula (-a), R ₃ is a lower alkyl group,
Products whose amino groups are protected can be obtained. The resulting product is then subjected to a known deprotection reaction using an acid or an alkali as a catalyst.
When an acid is used as a reaction catalyst, the hydrolysis reaction of the ester occurs simultaneously, and the product in which R ₃ is a hydrogen atom in formula (-a) is often obtained as an acid addition salt of the acid used. , convenient.
The acid catalyst used here includes mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid; organic acids such as formic acid, acetic acid, monochloroacetic acid, trichloroacetic acid, trifluoroacetic acid, oxalic acid, and citric acid; Examples include organic sulfonic acids such as toluenesulfonic acid and benzenesulfonic acid. Further, when the above deprotection reaction is carried out using an alkali, an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, etc. is usually used as the alkali catalyst. In this case, the product is obtained as an alkali metal salt of a carboxylic acid, and by neutralizing this with the above-mentioned acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, R ₃ can be easily converted into the above formula (-a). Aminocarboxylic acid derivatives which are hydrogen atoms can be obtained. The aminocarboxylic acid derivative or acid addition salt thereof obtained as described above is subjected to a conventional esterification reaction, for example, using an acid catalyst such as mineral acids such as sulfuric acid and hydrochloric acid, and organic acids such as para-toluenesulfonic acid and benzenesulfonic acid. By reacting with alcohols such as methanol, ethanol, propanol, and isopropanol in the presence of alcohols, the lower alkyl esters, i.e., aminocarboxylic acid derivatives in which R ₃ is a lower alkyl group in formula (-a), or acid addition salts thereof It can be converted to . As described above, in the above formula (), R ₁
The aminocarboxylic acid derivative of the present invention or its acid addition salt (formula (-a) above) of the present invention, in which R 2 and R ₂ together represent an oxo group, is obtained. The compound of formula (-a) thus obtained is reduced, and then, if necessary, hydrolysis and/or esterification reactions known per se are carried out to obtain the compound of formula (-b), that is, the formula ( )
A compound in which R ₁ is a hydrogen atom and R ₂ is a hydroxyl group is obtained. Preferably, the reduction is carried out using sodium borohydride or a derivative thereof, or catalytic reduction using a palladium catalyst such as palladium-carbon. Examples of the derivatives of sodium borohydride used here include lithium borohydride, lithium triethylborohydride, sodium trimethoxyborohydride, potassium triisopropoxyborohydride, and the like. The amount of sodium borohydride or its derivative to be used is determined based on the aminocarboxylic acid derivative represented by the above formula (-a) or its acid addition salt 1 which is the raw material compound.
It is preferable to use 1.5 to 15 times the mole.
As the organic solvent used in the reaction, for example, alcohols such as methyl alcohol, ethyl alcohol, and isopropyl alcohol, and ethers such as diethyl ether and tetrahydrofuran are preferably used. The reaction temperature is preferably cooled in the initial stage to suppress heat generation, and the reaction temperature is usually preferably 5°C to 50°C. Further, in order to carry out the above-mentioned catalytic reduction using a palladium-carbon catalyst, 5% palladium-carbon or the like is particularly preferably used. The amount of such catalyst used is, for example, 50 mg to 1 g of raw material.
100 g, preferably 50 mg to 1 g is sufficient. The solvent used is the same as that used for sodium borohydride or its derivatives. The reaction usually proceeds at room temperature, but if desired, it may be heated or carried out under pressure. The aminocarboxylic acid derivative or acid addition salt thereof obtained as described above can be purified by recrystallization, ion exchange, chromatography, etc. In addition, if necessary, it can be converted into other compounds by performing the per se known hydrolysis reaction and/or esterification reaction as described above. In this way, the above formula (-b), that is, the aminocarboxylic acid derivative or its acid addition salt in which R ₁ is a hydrogen atom and R ₂ is a hydroxyl group in the above formula () is obtained. Therefore, according to the present invention, the aminocarboxylic acid derivative represented by the above formula () or its acid addition salt provided by the present invention has an excellent antiulcer effect. An antiulcer agent containing a carboxylic acid derivative or an acid addition salt thereof as an active ingredient is provided. The aminocarboxylic acid derivatives or acid addition salts thereof of the present invention can usually be administered orally or parenterally, such as intrarectally, subcutaneously, or intramuscularly; however, oral administration is preferred; Administration is also convenient for patients. For oral administration, solid preparations or liquid preparations include, for example, tablets,
There are pills, powders, and granules. In such solid preparations, one or more active substances, aminocarboxylic acid derivatives or acid addition salts thereof, and inert diluents such as calcium carbonate, potato starch, alginic acid, lactose, etc. are mixed. Ru.
Formulation is carried out in accordance with conventional methods, but additives other than diluents, for example lubricants such as magnesium stearate, may be included. Liquid preparations for oral administration include, for example, emulsions, solutions, suspensions, syrups or elixirs, which may be prepared using commonly used inert diluents such as water or liquid paraffin. may contain. In addition to inert diluents, liquid preparations may also contain adjuvants such as wetting agents, suspending agents, sweeteners, fragrances, or preservatives. The liquid preparation may also be in the form of capsules of easily absorbed material such as gelatin. Solid preparations for rectal administration include suppositories prepared by conventional methods containing one or more active substances. For preparations for parenteral administration such as subcutaneous and intramuscular administration,
Examples include sterile aqueous or non-aqueous solutions, suspensions, emulsions, and the like. Examples of non-aqueous solutions or suspensions include those made of propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable organic esters such as ethyl oleate, and the like. Such formulations for parenteral administration may contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, and the like. These preparations are sterilized by filtration through bacteria-retaining filters, incorporation of disinfectants, or irradiation. It can also be obtained by producing a sterile solid preparation and dissolving it in sterile water or a sterile injection solvent immediately before use. When the active compound of the present invention, an aminocarboxylic acid derivative or an acid addition salt thereof, is administered as an anti-ulcer agent, the dosage is usually preferably 50 to 1000 mg per day. These dosages depend on the patient's medical condition, weight, age, or route of administration. As detailed above, the aminocarboxylic acid derivatives or acid addition salts thereof of the present invention have excellent anti-ulcer effects and are fully expected to be used as drugs with few side effects. Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 1.0 g of N-acetyl-4-aminomethylbenzoic acid chloride (produced by reacting N-acetyl-4-aminomethylbenzoic acid with thionyl chloride) was suspended in 30 ml of carbon disulfide and stirred vigorously. After adding 1.9 g of aluminum chloride while cooling on ice,
A solution of 776 mg of phenylpropionate methyl ester and 10 ml of carbon disulfide was added and stirred under reflux for 4 hours. After the reaction is complete, the carbon disulfide layer is separated by decantation, and a small amount of ice water is carefully added to the residue to decompose excess aluminum chloride. It was then extracted three times with ethyl acetate. The ethyl acetate layer was washed with a 1N aqueous sodium hydroxide solution, then water, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure to obtain 1122 mg of a yellow oil. This product had the following physical properties and was identified as p-(N-acetyl-4-aminomethylbenzoyl)-phenylpropionic acid methyl ester. NMR ( _CDCl3 ), δ (ppm): 7.2-7.8 (8H, m, benzene ring Hs), 4.4 (2H, d, J=6Hz, -NH- _CH2- ), 3.6 (3H, s,

[Formula]), 2.4-3.2 (4H, m, -CH ₂ -), 2.0 (3H, s,

[Formula]) Then, 100 c.c. of 12N hydrochloric acid was added to the product and stirred under reflux for 8 hours. After distilling off the hydrochloric acid under reduced pressure, it was reconsolidated from acetone-water to give p-(4-aminomethylbenzoyl)phenylpropionate hydrochloride.
938 mg (62% from phenylpropionate methyl ester) was obtained. This product has the following physical properties and supports the structure of p-(4-aminomethylbenzoyl)-phenylpropionic hydrochloride. NMR (MeOH- _d4 ), δ (ppm): 7.3-8.0 (8H, m, benzene ring Hs), 4.25 (2H, s, _{H2N- CH2-} ), 2.5-3.2 (4H, m, - CH ₂ −), elemental analysis: C ₁₇ H ₁₈ NO ₃ Cl (molecular weight 319.79) Calculated value (%): C: 63.9 H: 5.7 N: 4.4 Experimental value (%): C: 63.6 H: 5.6 N: 4.4 Melting point :214~220℃ IR (KBr) (cm ^-1 ): 3000, 2940, 1740, 1700, 1650, 1610, 1520,
1415, 1390, 1310, 1280, 1230, 1180, 1145,
1110, 930, 850, 830, 760. Example 2 1 g of N-acetyl-4-aminomethylbenzoic acid chloride was suspended in 40 ml of carbon disulfide, and 2.8 g of aluminum bromide was added under ice cooling with vigorous stirring. Thereafter, a solution of 720 mg of phenylpropionate methyl ester and 15 ml of carbon disulfide was added, and the mixture was stirred under reflux for 3 hours. Thereafter, the same process as in Example 1 was carried out to obtain the desired p-
718 mg of (4-aminomethylbenzoyl)phenylpropionic hydrochloride was obtained. Example 3 500 mg of N-acetyl-4-aminomethylbenzoic acid chloride was suspended in 20 ml of carbon disulfide, and 1 g of aluminum chloride was added under ice cooling with vigorous stirring, followed by phenylpropionate ethyl ester.
A solution of 421 mg of carbon disulfide and 10 ml of carbon disulfide was added and reacted under reflux for 3 hours. Thereafter, the same process as in Example 1 was carried out to obtain the desired p-
416 mg of (4-aminomethylbenzoyl)-phenylpropionic acid hydrochloride was obtained. Example 4 500 mg of N-acetyl-4-aminomethylbenzoic acid chloride was suspended in 15 ml of 1,2-dichloroethane, 0.8 g of aluminum chloride was added under ice cooling with vigorous stirring, and then 388 mg of phenylpropionate methyl ester was added. 1,2-dichloroethane 7
ml of solution was added and stirred at 60°C for 2 hours. After the reaction was completed, 1,2-dichloroethane was distilled off, and ice water was carefully added to the residue to decompose excess aluminum chloride. The following treatment and hydrolysis were performed in the same manner as in Example 1 to obtain the desired p-(4-aminomethylbenzoyl).
-476 mg of phenylpropionic hydrochloride were obtained. Example 5 500 mg of p-(4-aminomethylbenzoyl)-phenylpropionic hydrochloride was dissolved in 50 ml of ethanol, 100 mg of concentrated hydrochloric acid was added, and the mixture was refluxed with ethanol for 30 minutes.
Allowed time to react. During this time, about 25 ml of ethanol was distilled off. After the reaction, the solvent was distilled off under reduced pressure and the residue was recrystallized from ethanol-acetone to obtain the desired p-(4
-aminomethylbenzoyl)-phenylpropionic acid ethyl ester hydrochloride 451 mg (83%) were obtained. This material has the following physical properties and supports the structure. NMR (MeOH- _d4 ), δ (ppm): 7.3-8.0 (8H, m, benzene ring), 4.3 (2H, s, _NH2 - _CH2- ), 3.95-4.35 (2H, q, J=7Hz ,

[Formula]), 2.5 to 3.2 (4H, m, -CH ₂ -), 1.25 (3H, t, J = 7Hz,

[Formula]) Melting point: 186-192℃ Elemental analysis: C ₁₉ H ₂₂ NO ₃ Cl (molecular weight 347.84) Calculated value (%): C: 65.6, H: 6.4, N: 4.0 Experimental value (%): C: 65.9 , H: 6.2, N: 3.9 IR (KBr) (cm ^-1 ): 3000, 2950, 1730, 1650, 1610, 1415, 1370,
1315, 1205, 1150, 1045, 930. Example 6 45 g of thionyl chloride was added to 3 g of p-aminomethylbenzoic acid 1/2 sulfate and reacted at 50° C. for 6 hours to synthesize acid chloride. 150ml of 1,2-dichlorothane
6 g of aluminum chloride was added to the suspension while stirring vigorously under ice cooling. Furthermore, a solution of 2.5 g of phenylpropionate methyl ester and 20 ml of 1,2-dichloroethane was added to the solution, and the mixture was reacted at 55 DEG C. for 3 hours. After the reaction was completed, 1,2-dichloroethane was distilled off, and a small amount of 6N caustic soda aqueous solution and anhydrous sodium carbonate were added to the resulting residue under ice cooling. It was then extracted with about 50 ml of ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, and then evaporated under reduced pressure to obtain a syrup-like substance. This product was purified by silica gel column chromatography to obtain 2.0 g (45%) of the desired p-(4-aminomethylbenzoyl)-phenylpropionic acid methyl ester. This material has the following physical properties and supports the structure well. NMR ( _CDCl3 ), δ (ppm): 7.2-7.9 (8H, m, benzene ring), 3.95 (2H, s, _NH2 - _CH2- ), 3.65 (3H, s, -COOC _H3 ), 2.4-3.3 (4H, m, methylene) Elemental analysis: C ₁₈ N ₁₉ NO ₃ (molecular weight 297.35) Calculated value (%): C: 72.7, H: 6.4, N: 4.7 Experimental value (%): C: 72.3, H: 6.2, N: 4.3 Then this p-(4-aminomethylbenzoyl)
-Phenylpropionate methyl ester 1.0g
30 ml of 2N hydrochloric acid was added and hydrolyzed at 60°C for 2 hours. After the reaction, hydrochloric acid was distilled off under reduced pressure, and the resulting residue was recrystallized from an acetone-water system to obtain the desired p-(4
946 mg (88%) of -aminomethylbenzoyl)-phenylpropionic hydrochloride were obtained. This material has physical properties similar to those obtained in Example 1. Example 7 Dissolve 500 mg of p-(4-aminomethylbenzoyl)-phenylpropionic acid hydrochloride in 40 ml of methanol and add 500 mg of sodium borohydride under ice cooling.
was added slowly. After reacting at room temperature for 1 hour, add concentrated sulfuric acid to adjust the pH to 3 for the esterification reaction.
It was left for 12 hours. After the reaction is complete, add 1NKOH− under ice cooling.
MeOH solution was slowly added to bring the pH to 8 and the resulting solid was separated. The liquid was distilled to dryness under reduced pressure, and 50 ml of chloroform was added to the resulting residue to extract the target product. After washing the chloroform layer with water and drying it over anhydrous sodium sulfate, the chloroform layer is distilled off under reduced pressure to obtain an oily substance. The product is then purified by column chromatography using silica gel as an adsorbent (elution solvent: methanol-chloroform mixed solvent) to obtain the desired oily α.
-(4-aminomethylphenyl)-p-(2-methoxycarbonylethyl)-benzyl alcohol 257
mg (55%). This material has the following physical properties and supports the structure. NMR ( _CDCl3 ): δ (ppm) 7.3 (8H, s, benzene ring Hs), 5.75 (1H, s, -CH (OH)-), 3.6 (3H, s, -COOC _H3 ), 4.0~ 2.5 (8H, m, methylene and N H ₂ ) Elemental analysis: C ₁₈ H ₂₁ NO ₃ (molecular weight, 299.37) Calculated value (%): C: 72.2, H: 7.1, N: 4.1 Experimental value (%): C :71.9, H:6.9, N:4.8 Then the above α-(4-aminomethylphenyl)
Add 10 ml of 1N hydrochloric acid to 200 mg of -p-(2-methoxycarbonylethyl)-benzyl alcohol at room temperature.
The hydrolysis reaction was carried out for 24 hours. After the reaction was completed, hydrochloric acid was distilled off under reduced pressure to obtain a white solid.
This product was recrystallized from acetone-water and the desired α-(4-aminomethylphenyl)-p(2-carboxyethyl)-benzyl alcohol hydrochloride 87mg
(40%). This material has the following physical properties and supports the structure well. NMR (MeOH-d ₄ ), δ (ppm) 7.3-7.5 (8H, m, benzene ring), 5.4 (1H, s, -CH (OH)-), 4.2 (2H, m, NH ² -CH _2- ), 3.2-2.4 (4H, m, _-CH2- ), Elemental analysis: _C17H20NO3Cl (molecular weight _321.80 ) Calculated value (%): C: 63.5, H: 6.3 _, N: 4.4 Experimental values (%): C: 63.5, H: 6.1, N: 4.1 IR (KBr), (cm ^-1 ) 3450, 3000, 1720, 1600, 1510, 1480, 1420,
1380, 1300, 1210, 1110, 810. Example 8 [Serotonin ulcer test] Seven-week-old SD rats (body weight 200 g to 220 g) were
After 24 hours of fasting, 5% p-(4-aminomethylbenzoyl)-phenylpropionic hydrochloride was administered.
It was suspended in gum arabic and administered orally, and 30 minutes later, 20 mg/Kg of serotonin was administered subcutaneously. After 4 hours, the abdomen was opened, the stomach was removed, the stomach body was observed using a stereomicroscope, the area of the ulcer site was measured, and the sum total was taken as the ulcer index. The results are shown in Table 1. The control group was administered with 5% gum arabic and serotonin.

[Table] Based on the above results, p-(4
It was confirmed that -aminomethylbenzoyl)-phenylpropionate hydrochloride has a strong anti-ulcer effect. In the same manner as above, α-(4-aminomethylphenyl) was used instead of p-(4-aminomethylbenzoyl)-phenylpropionic hydrochloride as the drug.
Table 2 shows the results obtained using -p-(2-carboxyethyl)-benzyl alcohol hydrochloride.

[Table] From Table 2, it was confirmed that α-(4-aminomethylphenyl)-p-(2-carboxyethyl)-benzyl alcohol hydrochloride provided by the present invention also has an anti-ulcer effect. Example 9 Antithrompinic and antitrypsinic effects were expressed by p-
(4-Aminomethylbenzoyl)-phenylpropionate hydrochloride and cetraxate hydrochloride were measured by the following method. [Measurement of calcium re-addition time (antithrombin effect)] Cetraxate hydrochloride, p-(4-aminomethylbenzoyl)-phenylpropionic hydrochloride,
Dissolve in phosphate-buffered saline (PH=24) to a concentration of 10 ^-2 M.
Dilute with 7.4) and use. Separately, white native male domestic rabbit (weight 3-3.5Kg)
Therefore, 9/10 volume of blood was collected using 1/10 volume of 3.8% sodium citrate as an anticoagulant.
Centrifuge at 2800 rpm for 10 minutes to obtain the upper plasma.
Dispense the obtained plasma in 0.1 ml portions into small test tubes,
After pre-incubation with 0.1 ml of the above specimen at various concentrations or phosphate buffered saline (= control) at 37°C for 5 minutes, 0.2 ml of 0.02M calcium chloride was added, and incubation was carried out from time to time in an incubator. While stirring, measure the time until solidification using a stopwatch. Such a measurement method is described in the literature, Tohoku J.exp.
References are made to 1972, 106, 233-248. [Measurement of antitrypsin effect] 35 mm negative color film (Fujicolor)
Cut N100 or Agfa color) to an appropriate length,
Attach it to the fixing plate with the emulsion side facing up. Trypsin (10500 BAEEunit/mg Sigma) is dissolved in phosphate buffered saline to make a 200 BAEEunit/ml solution. The above samples were added to 10 ^-2 M phosphate buffered saline.
Dissolve and dilute with phosphate buffered saline (PH = 7.4) before use. Next, the trypsin solution prepared as described above was spotted on the film surface at regular intervals, 5 microns each, and then 5 microns of the above sample or physiological saline (= control) was added on top of it, and then placed in a thermostat at 37°C. Leave it inside for 30 minutes. After 30 minutes, remove from the incubator and score the degree of discoloration of the spotted area. As a result of the above test, the p-
(4-Aminomethylbenzoyl)-phenylpropionic hydrochloride does not exhibit antithrompinic or antitrypsinic effects even at 10 ^-4 molar concentrations. On the other hand, it was confirmed that cetraxate hydrochloride exhibits strong effects even at concentrations below 10 ^-5 mol. Example 10 Production of Capsules Hard gelatin capsules suitable for oral administration containing the following ingredients were produced in a conventional manner. p-(4-Aminomethylbenzoyl)-phenylpropionate hydrochloride 50mg Lactose 39mg Corn starch 10mg Talc 0.5mg Magnesium stearate 0.5mg 100mg Example 11 [Manufacture of tablets] Contains the following ingredients suitable for oral administration: Tablets were manufactured in the usual manner. p-(4-Aminomethylbenzoyl)-phenylpropionate hydrochloride 50mg Crystalline cellulose 50mg Lactose 40mg Corn starch 10mg Magnesium stearate 1mg Talc 1mg 152mg Example 12 [Manufacture of injection] Using the following ingredients, the usual method An injection was produced. p-(4-aminomethylbenzoyl)-phenylpropionate hydrochloride 20 mg Solubilizing agent 100 mg Acetate buffer 5 ml Example 13 [Manufacture of suppositories] Suppositories were manufactured using the following ingredients in a conventional manner. p-(4-Aminomethylbenzoyl)-phenylpropionate hydrochloride 50 mg Glycerin fatty acid ester 50 mg Cocoa butter 1.4 g 1.5 g Example 14 [Manufacture of powder] A powder was manufactured using the following ingredients in a conventional manner. p-(4-Aminomethylbenzoyl)-phenylpropionate hydrochloride 50mg Lactose 100mg Corn starch 100mg Hydroxypropyl cellulose 10mg 260mg

Claims (1)

[Claims] 1. The following formula (), [In the formula, R ₁ and R ₂ represent an oxo group together, or R ₁ represents _a hydrogen atom and _{R 2 represents} a hydroxyl group. R ₃ represents a hydrogen atom or a lower alkyl group. ] An aminocarboxylic acid derivative or an acid addition salt thereof. 2 The aminocarboxylic acid derivative represented by the above formula () or its acid addition salt has the following formula (-a), [In the formula, R ₃ is the same as defined above. ] The aminocarboxylic acid derivative or the acid addition salt thereof according to claim 1, which is the aminocarboxylic acid derivative or the acid addition salt thereof. 3 In the above formula (-a), R ₃ is a hydrogen atom,
Claim 2 which is a methyl group or an ethyl group
Aminocarboxylic acid derivatives or acid addition salts thereof as described in 2. 4 The aminocarboxylic acid derivative represented by the above formula () or its acid addition salt is represented by the following formula (-b) [In the formula, R ₃ is the same as defined above. ] The aminocarboxylic acid derivative or the acid addition salt thereof according to claim 1, which is the aminocarboxylic acid derivative or the acid addition salt thereof. 5. The aminocarboxylic acid derivative or acid addition salt thereof according to claim 4, wherein in the above formula (-b), R ₃ is a hydrogen atom or a methyl group. 6 The following formula (), [In the formula, X represents a halogen atom. ] An acid addition salt or an amino group-protected derivative of an aminocarboxylic acid halide represented by the following formula (), [In the formula, R ₄ represents a lower alkyl group. ] is reacted with a phenylpropionate ester represented by the following in the presence of a condensing agent, and then, if necessary, deprotection and/or hydrolysis and/or
Or the following formula (-a) characterized by carrying out an esterification reaction [In the formula, R ₃ represents a hydrogen atom or a lower alkyl group. ] A method for producing an aminocarboxylic acid derivative or an acid addition salt thereof. 7 The following formula (-a) [In the formula, R ₃ represents a hydrogen atom or a lower alkyl group. ] The following formula (-b) is characterized in that the aminocarboxylic acid derivative represented by the formula (-b) or its acid addition salt is reduced, and then, if necessary, hydrolysis and/or esterification reactions known per se are performed. [In the formula, R ₃ is the same as defined above. ] A method for producing an aminocarboxylic acid derivative or an acid addition salt thereof. 8 The following formula (), [In the formula, R ₁ and R ₂ represent an oxo group together, or R ₁ represents _a hydrogen atom and _{R 2 represents} a hydroxyl group. R ₃ represents a hydrogen atom or a lower alkyl group. ] An anti-ulcer agent containing an aminocarboxylic acid derivative represented by the following or its acid addition salt as an anti-ulcer active ingredient.