JPH06298730A - Guanidinobenzoic acid ester derivative - Google Patents

Abstract

PURPOSE:To obtain the subject compound having strong inhibiting action on enzymes such as trypsin, plasmin or thrombin and useful as an antitrypsin agent effective against pancreatitis, an antiplasmin agent effective against hemorrhagic diseases and an antithrombin agent effective against thrombosis. CONSTITUTION:The guanidinobenzoic acid ester derivative is expressed by formula I [X is formula II {Y is (CH2)3, formula III, TV, V, VI, VII, VIII or IX]; (n) is an integer of 1-5}, e.g. 4-(2-hydroxyethylthio)phenyl guanidinobenzoate. The compound expressed by formula I is obtained by subjecting guanidinobenzoic acid or its reactive derivative to esterifying reaction with a compound expressed by formula X. This compound expressed by formula I includes 4-(2-ethoxyethylthio)phenyl 4-guanidinobenzoate, 4-(2- phthalimidoethylthio)phenyl 4-guanidinobenzodte, etc., besides the exemplified compound.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a guanidinobenzoic acid ester derivative having an excellent action as a medicine, a method for producing the same, and a medicine containing the same.

[0002]

BACKGROUND ART Pancreatitis is clinically classified into acute pancreatitis and chronic pancreatitis. Acute pancreatitis normalizes the pancreas both clinically and biologically when the causative factors or factors are eliminated, but in chronic pancreatitis, histological or functional changes occur even if the causative factors or factors disappear. Is said to remain. Although the etiology of pancreatitis is not always clear, alcoholism is the most common in Japan, followed by unknown cause (idiopathic) and gallstone. The process from the onset to the development of pancreatitis is complicated and is not yet fully understood.
At present, anti-enzyme therapy is widely used as a drug therapy, but the development of a more safe and superior pancreatic enzyme inhibitor is awaited.

[0003]

OBJECT OF THE INVENTION One of the objects of the present invention is to provide a novel guanidinobenzoic acid ester derivative, and further to provide a process for producing the guanidinobenzoic acid ester derivative, and further to provide the guanidinobenzoic acid ester derivative. It is intended to provide a medicine containing a derivative as an active ingredient.

[0004]

The object compound of the present invention is a guanidinobenzoic acid ester derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[0005]

[Chemical 20]

{Where X is

[Chemical 21] Or formula-OR (wherein R represents a hydrogen atom or a lower alkyl group, and n represents an integer of 1 to 5).

In the above definition, the lower alkyl group found in the definition of R is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, isobutyl, 1-methyl. Propyl, ter
It means t-butyl, n-pentyl, 1-ethylpropyl, isoamyl, n-hexyl and the like. The pharmacologically acceptable salt specifically means an addition salt of an inorganic acid such as hydrochloride, sulfate, hydrobromide, perchlorate or hydroiodide, oxalate or maleate. And organic acid addition salts such as fumarate, succinate, and methanesulfonate.

The compound (I) of the present invention or a pharmacologically acceptable salt thereof has a strong inhibitory action on enzymes such as trypsin, plasmin and thrombin, and therefore is an antitrypsin agent effective for the treatment of pancreatitis, It is useful as an antiplasmin agent effective for treating hemorrhagic diseases and an antithrombin agent effective for treating thrombus.

[0009]

[Manufacturing Method] Although various methods for manufacturing the compound (I) of the present invention can be considered, a typical method is as follows. That is, the following general formula (II)

And a guanidinobenzoic acid represented by the following general formula (III)

[Chemical formula 23] The target substance of the present invention can be obtained by stellizing a compound represented by the formula (wherein X and n have the above-mentioned meanings) by a conventional method. As the most typical method, the guanidinobenzoic acid represented by (II) or its reactive derivative is esterified with the compound represented by (III). Specifically, (I
An acid halide of guanidinobenzoic acid represented by I), that is, a compound represented by the following (II ′) [for example, easily obtained by heating compound (II) with thionyl chloride]

The object of the present invention is to react ## STR23 ## in which Hal means a halogen atom such as chlorine and bromine with a compound (III) in the presence of a deoxidizing agent such as pyridine and triethylamine. Material (I) is obtained. Examples of the organic solvent used in this method include tetrahydrofuran, ether, benzene, toluene, dimethylformamide, pyridine, and dimethylsulfoxide. Of these, pyridine is most preferred, but when an organic solvent other than pyridine is used, triethylamine, triptylamine, dimethylamine, organic amines such as pyridine, calcium carbonate, sodium carbonate, sodium hydroxide and the like can be used as deoxidizing agents. Inorganic bases can be used. As another method, the guanidinobenzoic acid represented by (II) and the compound represented by the formula (III) are directly condensed in the presence of a dehydrating agent such as DCC (1,3-dicyclohexylcarbodiimide). You can also In any of the methods, in the formula (I), when X represents the formula —OH, the compound (III) has the following general formula:

[Chemical 25] In the reaction, the hydroxyl group bonded to the alkylene is protected by a protecting group usually used in the chemical reaction,
After completion of the reaction, the protective group for the hydroxyl group is removed. Typical examples of the protecting group include a benzyl group, a paramethoxybenzyl group, a 3,4-dimethoxybenzyl group, a triphenylmethyl group, a methoxymethyl group, a methylthiomethyl group, a 2-methoxyethoxymethyl group, and a tetramethoxy group. Examples thereof include a hydrotopyranyl group and a tetrahydrothiopyranyl group.

The compound (I) obtained by such a method is appropriately converted into a pharmaceutically acceptable acid addition salt by a conventional method. To give a concrete example, the obtained compound (I) is treated with an aqueous solution of sodium hydrogen carbonate to form a carbonate, which may be converted into an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or nitric acid, if necessary. It can be easily converted into a salt or an organic acid salt such as formic acid, acetic acid, lactic acid, tartaric acid, oxalic acid, citric acid, succinic acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

In the illustrated production method, the starting material (III) can be produced, for example, by the following method. I) In the formula (I), X is

[Chemical formula 26] (Wherein Y has the above-mentioned meaning), and when n = 2 to 5, Step 1

[0012]

[Chemical 27] (In the formula, Hal means a halogen atom, and n and Y have the above-mentioned meanings.) That is, 1, ω-dihalogenoalkane (IV) represented by the formula (IV) (as halogen, bromine, chlorine and the like are included. Is preferred) and an imide compound represented by the formula (V) is subjected to a condensation reaction in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide to give a compound of the formula (VI)
A compound represented by can be produced. On this occasion,
Examples of the organic solvent include acetone, methyl ethyl ketone, methyl isoptyl ketone, methanol, ethanol, propanol, isopropanol, butanol, dimethylformamide (DMF), dimethyl sulfoxide (DMS).
O) or the like can be used. Process 2

[0013]

[Chemical 28] (Wherein n and Y have the above-mentioned meanings), that is, to the compound (VI) prepared by Step 1,
The 4-hydroxythiophenol represented by I) is subjected to a condensation reaction preferably in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide to obtain compound (III ″). Examples of the organic solvent used at this time include methanol, ethanol, propanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isoptyl ketone, dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

II) In the formula (I), when X represents a group represented by the formula --OR (wherein R represents a lower alkyl group), the starting material is the following general formula:

[0015]

[Chemical 29] This compound is represented by, for example, Japanese Examined Patent Publication No.
It can be produced by the method described in No. 79.

III) When n = 1 in the formula (I), the following method is also possible.

[0017]

[Chemical 30]

Next, typical compounds of the present invention will be listed, but the purpose thereof is to facilitate understanding of the present invention, and the present invention is not limited thereto. There is no end.・ 4- (3-phthalimidopropylthio) phenyl 4
-Guanidinobenzoate 4- (4-phthalimidobutylthio) phenyl 4-
Guanidinobenzoate 4- (5-phthalimidobenzylthio) phenyl 4
4-guanidinobenzoate 4- [3- (cis-1,2-cyclohexanedicarboximide) propylthio] phenyl 4-guanidinobenzoate 4- [4- (cis-1,2-cyclohexanedicarboximide) butylthio] phenyl 4 -Guanidinobenzoate 4- [5- (cis-1,2-cyclohexanedicarboximide) benzylthio] phenyl 4-guanidinobenzoate 4- [3- (5,5-dimethyl-2,4-dioxooxazolidine-3 -Yl) propylthio] phenyl 4
-Guanidinobenzoate 4- [4- (5,5-dimethyl-2,4-dioxooxazolidin-3-yl) butylthio] phenyl 4-
Guanidinobenzoate 4- [5- (5,5-dimethyl-2,4-dioxooxazolidin-3-yl) ventilthio] phenyl 4
-Guanidinobenzoate 4- (2-hydroxyethylthio) phenyl 4-guanidinobenzoate 4- (3-hydroxypropylthio) phenyl 4-
Guanidinobenzoate 4- (4-hydroxybutylthio) phenyl 4-guanidinobenzoate 4- (5-hydroxypentylthio) phenyl 4-
Guanidinobenzoate 4- (2-ethoxyethylthio) phenyl 4-guanidinobenzoate 4- (3-ethoxypropylthio) phenyl 4-guanidinobenzoate 4- (4-ethoxybutylthio) phenyl 4-guanidinobenzoate 4- (5-Ethoxypentylthio) phenyl 4-guanidinobenzoate 4- (2-methoxyethylthio) phenyl 4-guanidinobenzoate 4- (3-methoxypropylthio) phenyl 4-guanidinobenzoate 4- (4-methoxybutyl) Thio) phenyl 4-guanidinobenzoate * 4- (5-methoxypentylthio) phenyl 4-guanidinobenzoate * 4- (2-isopropoxyethylthio) phenyl 4
-Guanidinobenzoate 4- (3-isopropoxypropylthio) phenyl
4-guanidinobenzoate 4- (4-isopropoxybutylthio) phenyl 4
-Guanidinobenzoate 4- (5-isopropoxypentylthio) phenyl
4-guanidinobenzoate 4- (phthalimidomethylthio) phenyl 4-guanidinobenzoate 4-[(cis-1,2-cyclohexanedicarboximido) methylthio] phenyl 4-guanidinobenzoate 4-[(5,5-dimethyl- 2,4-Dioxo-oxazolidin-3-yl) methylthio] phenyl 4-guanidinobenzoate 4- (glutarimidomethylthio) phenyl 4-guanidinobenzoate 4- (2-glutarimidoethylthio) phenyl 4
-Guanidinobenzoate 4- (3-glutarimidopropylthio) phenyl
4-guanidinobenzoate 4- (4-glutarimidobutylthio) phenyl 4
-Guanidinobenzoate 4- (5-glutarimidobenzilthio) phenyl
4-guanidinobenzoate 4- (2-phthalimidoethylthio) phenyl 4-
Guanidinobenzoate 4- [2- (cis-1,2-cyclohexanedicarboximide) ethylthio] phenyl 4-guanidinobenzoate 4- [2- (5,5-dimethyl-2,4-dioxooxazolidine-3- Il) ethylthio] phenyl 4-
Guanidinobenzoate 4- [2- (cis-bicyclo [2.2.1] heptane-endo-2,3-dicarboximido) ethylthio]
Phenyl 4-guanidinobenzoate 4- [2- (cis-bicyclo [2.2.2] octane-2,3-dicarboximido) ethylthio] phenyl 4-guanidinobenzoate 4- [2- (cis-bicyclo [ 2.2.1] Hepter
5-ene-endo-2,3-dicarboximido) ethylthio] phenyl 4-guanidinobenzoate.4- [2- (cis-cyclohex-4-ene-1,2.
-Dicarboximido) ethylthio] phenyl 4-guanidinobenzoate

Next, the pharmacological action of the compound of the present invention will be shown by experimental examples.

[Pharmacological Experimental Example] Regarding typical compounds of the present invention,
In vitro trypsin, plasmin and thrombin inhibitory effects were measured. That is, the trypsin inhibitory action is a concentration (IC ₅₀ ) at which the trypsin 0.5 μg / ml inhibits 50% of the ability of trypsin to hydrolyze benzoyl-D and L-arginine-p-nitroanilide hydrochloride at 25 ° C. The molar concentration (M) is shown. For plasmin, HD-Val-Leu-L-Lys-p is used.
-Nitroanilide dihydrochloride, for thrombin HD-Phe-L-pipecolyl-LA
50% inhibitory concentration was measured using rg-p-nitroanilide dihydrochloride as a substrate.

The results are shown in Table 1.

[Table 1] Compound A: 4- (2-hydroxyethylthio) phenyl 4-guanidinobenzoate methanesulfonate Compound B: 4- (2-ethoxyethylthio) phenyl
4-guanidinobenzoate methanesulfonate compound C: 4- [2- (cis-1,2-cyclohexanedicarboximide) ethylthio] phenyl 4-guanidinobenzoate methanesulfonate compound D: 4- (2-phthalimide Ethylthio) phenyl 4-guanidinobenzoate methanesulfonate Compound E: 4- [2- (5,5-dimethyl-2,4-dioxooxazolidin-3-yl) ethylthio] phenyl 4-guanidinobenzoate methanesulfone Acid salt It was revealed from the above experimental examples that the compound of the present invention has a strong inhibitory effect on excellent enzymes such as trypsin, plasmin and thrombin.

Further, the compounds A to E used in the above experimental examples
For, by using ICR mouse was subjected to acute toxicity test by intravenous administration, these compounds LD ₅₀
All values were 50 mg / kg to 200 mg / kg. Therefore, the compound of the present invention has an extremely excellent inhibitory action on enzymes such as trypsin, plasmin and thrombin, and therefore, based on the trypsin inhibitory activity, a therapeutic agent for chronic and acute pancreatitis, and further plasmin and thrombin inhibitory activity. Therefore, it is useful as a therapeutic agent for bleeding disorders and thrombosis.

When the compound of the present invention is administered to the above-mentioned patients as a therapeutic agent for these diseases, the type of disease; the degree of symptoms; the age of the patient; the state of health; the weight; Treatment frequency; it varies depending on the desired effect and the like, but is not particularly limited, but is about 5 mg to 1,000 mg, preferably about 10 mg to 500 mg per day for an adult, orally or parenterally administered once or more times a day. It In particular, when used as a therapeutic agent for pancreatitis, the dose falls within the above range, but typical preferred examples are about 10 mg to 500 mg per adult day, more preferably about 30 mg to about 30 mg per day.
It is 300 mg.

Examples of dosage forms include powders, fine granules,
Granules, tablets, capsules, suppositories, injections and the like can be mentioned. In the case of formulation, it is produced by a conventional method using a usual formulation carrier. That is, when preparing a solid preparation for oral use, an excipient and, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, etc. are added to the main drug, and then tablets and coatings are carried out by a conventional method. Tablets, granules, powders, capsules, etc.

Examples of excipients include lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose,
Silicon dioxide and the like, as the binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose,
Hydroxypropyl starch, polyvinylpyrrolidone and the like are, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin and the like as a disintegrating agent, and stearic acid as a lubricant. Magnesium, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc. are permitted to be added to pharmaceuticals as coloring agents, but as flavoring agents, cocoa powder, mint brain, aromatic acid, peppermint oil, dragon brain , Cinnamon powder, etc. are used. Needless to say, these tablets and granules may be coated with sugar, gelatin or the like, if necessary. When preparing an injectable preparation, a pH adjusting agent, a buffering agent, a stabilizing agent, a solubilizing agent and the like are added to the main drug as necessary, and an intravenous injection is prepared by a conventional method.

[0025]

EXAMPLES Examples of the present invention will be described below, but it goes without saying that the present invention is not limited thereto. Reference Example 4- (2-succinimidoethylthio) phenol 4
-Guanidinobenzoate methanesulfonate

[0026]

[Chemical 31]

(1) 1-Bromo-2-succinimide
Synthesis of tan 49.5 g of succinimide was dissolved in 750 ml of 2-butanone under heating, 187.9 g of dipromoethane and 138 g of anhydrous potassium carbonate were added, and the mixture was heated under reflux for 9.5 hours. Then, the inorganic substances were filtered off, the filtrate was evaporated, 2 l of chloroform was added to the residue, washed with water, and the organic layer was dried over anhydrous magnesium sulfate. The title compound having a boiling point of 127 ° C./2.5 mmHg is obtained by filtering this, distilling the filtrate off, and purifying.
67.37 g (yield 65%) was obtained. (2) 4-hydroxyphenyl 2-succinimide
175.92 g of 1-bromo-2-succinimidoethane and 107.6 g of 4-hydroxythiophenol obtained by the method of the synthesis (1) of tyl sulfide were dissolved in 860 ml of ethanol, and 141.42 g of anhydrous potassium carbonate was further added to the solution. Heated to reflux for hours. After completion of the reaction, the inorganic substances were filtered off, the solvent was distilled off, water was added, the pH was adjusted to 1 with hydrochloric acid, the mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with water, and dried over anhydrous magnesium sulfate. did. This was filtered, the filtrate was distilled off, and ethyl acetate was added to the residue for recrystallization to obtain 42.67 g (yield 20%) of the title compound having the following physical properties. ^. Melting point (° C): 114-122.5 ^. Nuclear magnetic resonance spectrum δ (DMSO-d ₆ ): 2.52 (s,
4H), 2.91 (t, J = 8.0Hz, 2H), 3.50 (t, J = 8.0Hz, 2H),
6.73 (d, J = 9.6Hz, 2H), 7.24 (d, J = 9.6Hz, 2H), 9.57 (b
s, 1H) (3) 4- (2-succinimidoethylthio) phenyl
Of 4-guanidinobenzoate methanesulfonate
32.04 g of 4-hydroxyphenyl 2-succinimidoethyl sulfide obtained by the method of synthesis (2) was dissolved in 260 ml of pyridine, 4-guanidinobenzoic acid chloride was added thereto under ice cooling, and the mixture was stirred at room temperature for 16.5 hours. . After completion of the reaction, 5 l of saturated aqueous sodium hydrogen carbonate under ice cooling
Was added, and the precipitate was collected by filtration, washed with water and acetone, and dried to obtain 45.5 g of 4- (2-succinimidoethylthio) phenyl 4-guanidinobenzoate-carbonate.
(Yield 75%) was obtained. Then, this was suspended in 910 ml of methanol, 12.0 g of methanesulfonic acid was added, and dissolved under heating. Crystals were precipitated by concentrating methanol, and this was filtered to obtain 37.6 g (total yield 58%) of the title compound having the following physical properties. ^. Melting point (° C): 201.6 ^. Nuclear magnetic resonance spectrum δ (DMSO-d ₆ ): 2.36 (s,
3H), 2.53 (s, 4H), 3.15 (t, J = 6.8Hz, 2H), 3.61 (t, J
= 6.8Hz, 2H), 7.27 (d, J = 8.8Hz, 2H), 7.43 (d, J = 8.8Hz,
2H), 7.47 (d, J = 8.8Hz, 2H), 7.7 (bs, 4H), 8.16 (d, J
= 8.8Hz, 2H), 10.10 (bs, 1H)

Example 1 4- (2-phthalimidoethylthio) phenyl 4-g
Anidinobenzoate / methanesulfonate

[0029]

[Chemical 32]

(1) 1-Bromo-2-phthalimidoethane
The title compound (yield 66%) having the following physical properties was synthesized by silica gel column chromatography for purification. ^. Melting point (° C): 81.5 to 82.5 (2) 4-hydroxyphenyl 2-phthalimidoethyl
Synthesis of sulfide According to the method of Reference Example (2), silica gel column chromatography was used for purification to synthesize the title compound having the following physical properties (yield 92%). ^. Melting point (° C): 125-126.5 ^. Nuclear magnetic resonance spectrum δ (DMSO-d ₆ ): 3.03 (t,
J = 7.6Hz, 2H), 3.69 (t, J = 7.6Hz, 2H), 6.62 (d, J = 9.2
Hz, 2H), 7.18 (d, J = 9.2Hz, 2H), 7.75 (s, 4H), 9.45 (s,
1H) (3) 4- (2-phthalimidoethylthio) phenyl
4-guanidinobenzoate methanesulfonate
The title compound having the following physical properties was synthesized according to the method of (4) in Synthesis Reference Example. ^. Nuclear magnetic resonance spectrum δ (DMSO-d ₆ ): 2.39 (s,
3H), 3.24 (t, J = 6.8Hz, 2H), 3.79 (t, J = 6.8Hz, 2H),
7.12 (d, J = 9.6Hz, 2H), 7.35 (d, J = 9.6Hz, 2H), 7.40 (d,
J = 9.6Hz, 2H), 7.7 (bs, 4H), 7.76 (s, 4H), 8.06 (d, J
= 9.6Hz, 2H), 10.03 (s, 1H)

In accordance with the method of Reference Example, Examples 2, 3 and
Compound 4 was synthesized. Example 2 4- [2- (cis-1,2-cyclohexanedicarboxy
Cyimido) ethylthio] phenyl 4-guanidinoben
Zoate methanesulfonate

[0032]

[Chemical 33]

^.. Nuclear magnetic resonance spectrum δ (DMSO-d ₆
): 1.2 ~ 1.85 (m, 8H), 2.38 (s, 3H), 2.76 ~ 2.97 (m,
2H), 3.17 (bt, J = 7.2Hz, 2H), 3.61 (bt, J = 7.2Hz, 2
H), 7.25 (d, J = 10.0Hz, 2H), 7.43 (d, J = 10.0Hz, 2H),
7.48 (d, J = 10.0Hz, 2H), 7.76 (bs, 4H), 8.16 (d, J = 10.
0Hz, 2H), 10.11 (s, 1H)

Example 3 4- [2- (5,5-dimethyl-2,4-dioxooxy)
Sazolidin-3-yl) ethylthio] phenyl 4-g
Anidinobenzoate / methanesulfonate

[0035]

[Chemical 34]

^.. Nuclear magnetic resonance spectrum δ (DMSO-d ₆
): 1.46 (s, 6H), 2.32 (s, 3H), 3.24 (t, J = 6.8Hz, 2
H), 3.60 (t, J = 6.8Hz, 2H), 7.18 (d, J = 10.0Hz, 2H),
7.35 (d, J = 10.0Hz, 2H), 7.42 (d, J = 10.0Hz, 2H), 7.66
(bs, 4H), 8.07 (d, J = 10.0Hz, 2H), 9.96 (bs, 1H)

Example 4 4- (2-hydroxyethylthio) phenyl 4-gua
Nidinobenzoate methanesulfonate

[0038]

[Chemical 35]

(1) 2-hydroxyethyl 4-hydr
Synthesis of Roxyphenyl Sulfide To 50 g of 4-hydroxythiophenol and 54.56 g of ethylene bromohydrin, 280 ml of 28% ammonia water was added and stirred vigorously at room temperature for 2 hours. Add 225 ml of concentrated hydrochloric acid under ice cooling,
After adjusting the pH of the aqueous layer to 1, the mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated saline and dried over anhydrous magnesium sulfate. This was filtered, and the filtrate was concentrated and subjected to silica gel column chromatography to obtain 44.77 g (yield 66%) of the title compound having the following physical properties. ^. Melting point (° C): 70-71 ^. Nuclear magnetic resonance spectrum δ (DMSO-d ₆ ): 2.89 (t,
J = 7.2Hz, 2H), 3.60 (tt, J = 7.2, 6.4Hz, 2H), 4.08 (t,
J = 6.4Hz, 1H), 6.73 (d, J = 8.4Hz, 2H), 7.23 (d, J = 8.4
Hz, 2H), 9.00 (s, 1H) (2) 4-hydroxyphenyl 2- (tetrahydro
Synthesis of pyran-2-yloxy) ethyl sulfide 2-hydroxyethyl 4 synthesized by the method of (1)
-Hydroxyphenyl sulfide 17.91 g was dissolved in tetrahydrofuran 280 ml and p-toluenesulfonic acid 0.18 was added.
Add g. 17.69 g of 3,4-dihydro-2H-pyran dissolved in 140 ml of tetrahydrofuran was added dropwise thereto under ice cooling, and the mixture was stirred at room temperature for 4 hours. After distilling off the solvent, it was extracted with diethyl ether and washed with an aqueous sodium hydrogen carbonate solution,
It was dried over anhydrous magnesium sulfate. This was filtered, the filtrate was evaporated, and subjected to silica gel column chromatography to obtain 15.38 g (yield 58%) of the title compound having the following physical properties. ^. Nuclear magnetic resonance spectrum δ (DMSO-d ₆ ): 1.1-
1.85 (m, 6H), 2.96 (t, J = 7.6Hz, 2H), 3.1 ~ 3.9 (m, 4
H), 4.53 (bs, 1H), 6.74 (d, J = 9.6Hz, 2H), 7.24 (d, J =
9.6Hz, 2H), 9.52 (bs, 1H) (3) 4- (2-hydroxyethylthio) phenyl
Synthesis of 4-guanidinobenzoate / methanesulfonic acid 4-hydroxyphenyl synthesized by the method (2)
2- (tetrahydropyran-2-yloxy) ethyl
96.08 g of sulfide was dissolved in 800 ml of pyridine, 4-guanidinobenzoic acid chloride was added under ice cooling, and the mixture was stirred at room temperature for 24 hours or more. Under ice-cooling, saturated sodium hydrogen carbonate was added, the precipitate was collected by filtration, and this was washed with water, then with acetone,
The organic layer was washed with ethyl acetate in that order and dried to obtain 104 g of 4-[(2-tetrahydropyran-2-yloxy) ethylthio] phenyl 4-guanidinobenzoate / carbonate. This was suspended in 1033 ml of methanol, 37.9 g of methanesulfonic acid was added, and when almost completely dissolved, 31 g of activated carbon was added.
Was added, and after stirring for 30 minutes, activated carbon was filtered. The filtrate was dissolved in 1.2 l of ether under cooling with heating, treated with activated carbon and filtered to remove activated carbon, 2.5 l of diethyl ether was added, the mixture was allowed to stand for 30 minutes, and the precipitated crystals were collected by filtration to give the title compound having the following physical properties. 35.44 g (yield 22%) was obtained. ^. Melting point (° C): 141-143 ^. Nuclear magnetic resonance spectrum δ (DMSO-d ₆ ): 2.36 (s,
3H), 3.06 (t, J = 6.8Hz, 2H), 3.58 (t, J = 6.8Hz, 2H),
7.23 (d, J = 8.8Hz, 2H), 7.4 ~ 7.47 (m, 4H), 7.77 (bs, 3
H), 8.15 (d, J = 8.4Hz, 2H), 10.09 (bs, 1H)

Example 5 4- (2-Ethoxyethylthio) phenyl 4-guani
Dinobenzoate / methanesulfonate

[0041]

[Chemical 36]

3.4 g of 2-ethoxyethyl 4-hydroxyphenyl sulfide was dissolved in 50 ml of pyridine, and
-Guanidinobenzoyl chloride was added under ice cooling, and the mixture was stirred at room temperature for 27 hours. Saturated aqueous sodium hydrogencarbonate was added under ice cooling, and the precipitate was collected by filtration to obtain 2.86 g (yield 40%) of 4- (2-ethoxyethylthio) phenyl 4-guanidinobenzoate / carbonate. This was suspended in 100 ml of methanol, 0.78 g of methanesulfonic acid was added, dissolved under heating, and then concentrated. This was cooled, diethyl ether was added to precipitate an oil, and this oil was washed twice with diethyl ether. Next, the residue was dissolved in methanol, ethyl acetate was added, and the precipitate was collected by filtration to obtain 1.94 g of the title compound having the following physical properties. ^. Melting point (° C): 129-130 ^. Nuclear magnetic resonance spectrum δ (DMSO-d ₆ ): 1.10 (t,
J = 7.6Hz, 3H), 2.38 (s, 3H), 3.15 (t, J = 6.4Hz, 2H),
3.44 (q, J = 7.6Hz, 2H), 3.56 (t, J = 6.4Hz, 2H), 7.21 (d,
J = 9.6Hz, 2H), 7.41 (d, J = 9.6Hz, 2H), 7.45 (d, J = 9.6
Hz, 2H), 7.76 (bs, 4H), 8.15 (d, J = 9.6Hz, 2H), 10.10
(s, 1H)

[Chemical formula 22]

[Chemical formula 22]

Continuation of front page (51) Int.Cl. ⁵ Identification number Office reference number FI Technical display location A61K 31/40 AED 7431-4C 31/42 7431-4C C07D 209/48 263/44 (72) Inventor Shuhei Miyazawa 4-18-4 Kasuga, Yatabe-cho, Tsukuba-gun, Ibaraki Market Apartment 403 (72) Inventor Kanji Yamanaka 725-25 Shimohirooka, Shimura Hirooka, Shinji-gun, Ibaraki (72) Inventor, Miyamoto 2-8 Sengen Sakuramura, Niiji-gun, Ibaraki -9 Oyoshi Appart No.3 (72) Inventor Hishinuma Uharu 3-10-20 Kashiwa Stone Heights, Kashiwa City, Chiba Prefecture 305 (72) Inventor Junichi Nagakawa 2-15-3, Umezono, Sakura Village, Shinji District, Ibaraki Prefecture (72) ) Inventor Naoko Nagaoka 29-4 Higashiarai, Yatabe-cho, Tsukuba-gun, Ibaraki Arai Mansion 2B (72) Inventor Hidetoshi Kawashima 126-30 Yonei, Toride City, Ibaraki Prefecture (72) Inventor Tsuyoshi Kawada 2-Chuo, Tsuchiura City, Ibaraki Prefecture 16-23 Kamejo Heights 25 (72) Inventor Junsaku Nagaoka 29-4 Higashiarai, Yatabe-cho, Tsukuba-gun, Ibaraki Arai Mansion 2B (72) Inventor Wakabayashi Husband Mito, Ibaraki Prefecture Motoyoshida-cho, 368

Claims (18)

[Claims] 1. A general formula: [Where X is the formula: Or a group represented by formula -OR (wherein R represents a hydrogen atom or a lower alkyl group).
n represents an integer of 1 to 5] or a guanidinobenzoic acid ester derivative or a pharmaceutically acceptable salt thereof. 2. A guanidinobenzoic acid ester derivative or a pharmacological agent thereof according to claim 1, wherein X is a group represented by the formula —OR (wherein R represents a hydrogen atom or a lower alkyl group). Acceptable salt. 3. X is of the formula: The guanidinobenzoic acid ester derivative or the pharmaceutically acceptable salt thereof according to claim 1, which is a group represented by: 4. The guanidinobenzoic acid ester derivative according to claim 1, wherein n is 2 to 5, or a pharmaceutically acceptable salt thereof. 5. n is 2-5 and X is of the formula: The guanidinobenzoic acid ester derivative or the pharmaceutically acceptable salt thereof according to claim 1, which is a group represented by: 6. A guanidinobenzoic acid ester derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein n = 2. 7. n = 2 and X is of the formula: The guanidinobenzoic acid ester derivative or the pharmaceutically acceptable salt thereof according to claim 1, which is a group represented by: 8. The guanidinobenzoic acid ester derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is 4- (2-hydroxyethylthio) phenyl 4-guanidinobenzoate. 9. The guanidinobenzoic acid ester derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is 4- (2-ethoxyethylthio) phenyl 4-guanidinobenzoate. 10. The guanidinobenzoic acid ester derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is 4- (2-phthalimidoethylthio) phenyl 4-guanidinobenzoate. 11. The compound is 4- [2- (cis-1,2-
A guanidinobenzoic acid ester derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is cyclohexanedicarboximido) ethylthio] phenyl 4-guanidinobenzoate. 12. A guanidino according to claim 1, wherein the compound is 4- [2- (5,5-dimethyl-2,4-dioxooxazolidin-3-yl) ethylthio] phenyl 4-guanidinobenzoate. A benzoic acid ester derivative or a pharmaceutically acceptable salt thereof. 13. A guanidinobenzoic acid represented by the following general formula: embedded image and the following general formula: embedded image (wherein X represents the formula: Means a group represented by. n represents an integer of 1 to 5} and is subjected to an esterification reaction with a compound represented by the following formula: A guanidinobenzoate derivative represented by the formula (wherein n and X have the above-mentioned meanings) and, if necessary, a pharmaceutically acceptable salt of the guanidinobenzoate derivative or a drug thereof. A method of producing a salt that is physically acceptable. 14. A general formula: {Where X is the formula Means a group represented by. n represents an integer of 1 to 5}, and a therapeutic agent for a disease having an effective trypsin inhibitory activity, which comprises a guanidinobenzoate derivative represented by the formula: or a pharmacologically acceptable salt thereof as an active ingredient. 15. A general formula: {Where X is the formula Means a group represented by. n means an integer of 1 to 5}, and a therapeutic agent for a disease having an effective plasmin inhibitory activity, which comprises a guanidinobenzoic acid ester derivative represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient. 16. A general formula: {Where X is the formula Means a group represented by. n represents an integer of 1 to 5}, and a therapeutic agent for a disease having an effective thrombin inhibitory activity, which comprises a guanidinobenzoic acid ester derivative or a pharmacologically acceptable salt thereof as an active ingredient. 17. A general formula: {Where X is the formula Means a group represented by. n means an integer of 1 to 5}, and a therapeutic agent for chronic or acute pancreatitis containing a guanidinobenzoate derivative represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient. 18. A general formula: {Where X is the formula Means a group represented by. n means an integer of 1 to 5}, and a therapeutic agent for chronic or acute pancreatitis containing a guanidinobenzoate derivative represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient.