JPH05286922A - Guanidinophenol derivative - Google Patents

Abstract

PURPOSE:To provide the subject new compound exhibiting an inhibitory effect on phospholipase A2 or trypsin and useful for preventing or improving various inflammatory diseases, allergic diseases, disseminated intravascular coagulation, pancreatitis, its advancement into a serious state and disorder of plural organs. CONSTITUTION:A compound of formula I (R is a 1 to 4C alkyl, a 1 to 4C alkoxy, COOR<1>, COR<2>, OACOOR<3>, NR<4>R<5>, BNR6R<7>, formula II or formula III; R<1>, R<4>, R<12>, R<12> and R<13> are each H or a 1 to 4C alkyl; R<2> is a 1 to 4C alkyl or phenyl; R<6> and R<7> are each H, a 1 to 4C alkyl, phenyl., a 7 to 10C phenylalkyl, etc.; R<11> is H, a 1 to 7C alkyl, a 4 to 14-membered mono- to poly- cyclic cycloalkyl; A and E are each a 1 to 4C alkylene; B is SO2 or CO) or its acid adduct salt, e.g. p-(N-methyl-N-phenylcarbamoyl)benzoic acid p- guanidinophenyl ester hydrochloric acid salt represented by formula IV. This compound can be obtained by an esterification reaction between a compound of formula V and a compound of formula VI.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a guanidinophenol derivative. More specifically, phospholipase A ₂
(PLA ₂ ) having inhibitory activity, i) General formula

[Chemical 6] (Wherein all symbols have the same meanings as described below), guanidinophenol derivatives, and acid addition salts thereof, ii) methods for producing them, and iii) agents containing them.

[0002]

BACKGROUND OF THE INVENTION Phospholipase A ₂ (PLA ₂ ) is an enzyme that hydrolyzes an ester bond at the 2-position of cell membrane phospholipids and is known to exist in two types, membrane-bound PLA ₂ and pancreatic PLA ₂ . .. First, membrane-bound PLA ₂ liberates arachidonic acid (AA) from phospholipids. This AA
From these, physiologically active substances that cause various inflammatory diseases and allergic diseases, prostaglandins, thromboxanes, and leukotrienes are produced.

On the other hand, pancreatic PLA ₂ decomposes phospholipids, destroys cell membranes, and produces lysolecithin having strong cytotoxicity. Recently, pancreatitis due to the cell membrane damage action, its severity and multi-organ damage have been emphasized.
There is also a report that membrane-bound PLA ₂ is also involved in these diseases. Therefore, by inhibiting PLA ₂ , release of AA, which is a precursor of various physiologically active substances, can be suppressed, and thus it is considered to be useful for the prevention and / or treatment of various inflammatory diseases and allergic diseases. .. In addition, because it can suppress the cell membrane damage effect, pancreatitis,
It is considered to be useful for prevention and / or treatment of the severity and multi-organ disorder.

[0004]

Many compounds having a PLA ₂ inhibitory action are known. Among them, as those containing a guanidino group, for example, those having the formula

[Chemical 7] Camostat mesylate represented by or formula

[Chemical 8] Examples include guanidinobenzoic acid derivatives such as nafamostat mesylate shown in (Nippon Rinji, 48 (1), 165-17).
2, 1990).

Further, the compound having a structure similar to that of the compound of the present invention is represented by the formula:

[Chemical 9] Compound shown by (Chem.Pharm.Bull., 32 (11), 4466-
4477, 1 84). It is disclosed that this compound has an inhibitory action against proteolytic enzymes such as trypsin and plasmin and an anti-complement action, but it is not known at all to have a PLA ₂ inhibitory action.

[0006]

OBJECTS OF THE INVENTION The present inventors have conducted research to find a novel guanidino derivative having a PLA ₂ inhibitory action,
It was found that the guanidinophenol derivative represented by the general formula (I) achieves the object. Further, it was found that the compound of the present invention also has a strong trypsin inhibitory action.

[0007]

Comparison with Prior Art The guanidinophenol derivative of the present invention is a novel compound which has never been known. Further, conventionally, it was known that some guanidinobenzoic acid derivatives (the compounds represented by the formulas (A) and (B) described above) have a PLA ₂ inhibitory action. It was not known that the compound represented by C)) has this action.
Therefore, it cannot be predicted from these conventional techniques that the guanidinophenol derivative of the present invention has a PLA ₂ inhibitory action.

[0008]

DISCLOSURE OF THE INVENTION The present invention includes 1) general formula (I)

[Chemical 10] (In the formula, R is (i) an alkyl group having 1 to 4 carbon atoms, (ii) an alkoxy group having 1 to 4 carbon atoms, (iii) —COOR ¹ (in the formula, R ¹ is a hydrogen atom or a carbon number 1) To (4) alkyl group), (iv) -COR ² (in the formula, R ² represents an alkyl group having 1 to 4 carbon atoms or a phenyl group), (v) -OA-COOR ³ ( In the formula, A represents an alkylene group having 1 to 4 carbon atoms, and R
³ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. ), (Vi) -NR ⁴ R ⁵ (in the formula, R ⁴ and R ⁵ each independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), (vii) -B-NR ⁶ R ⁷

(Wherein B represents a sulfonyl group or a carbonyl group, R ⁶ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group or a phenylalkyl group having 7 to 10 carbon atoms, and R ⁷ represents A hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, a phenylalkyl group having 7 to 10 carbon atoms or -D-COOR ⁸ (wherein, D is 1 to 4 carbon atoms)
Represents an alkylene group of R ⁸ is a hydrogen atom and has 1 to 1 carbon atoms.
7 represents an alkyl group having 7 or a phenylalkyl group having 7 to 10 carbon atoms. ), Or R ⁶ and R ⁷ together with the adjacent nitrogen atom

[Chemical 11] (In the formula,

[Chemical 12] Represents a 4- to 7-membered saturated monocyclic heterocycle or a condensed heterocycle in which a benzene ring is condensed therewith, R ⁹ is a hydrogen atom, or —COOR ¹⁰ (wherein R ¹⁰ is a hydrogen atom, and has 1 to ¹⁰ carbon atoms).
4 represents an alkyl group having 4 to 10 carbon atoms or a phenylalkyl group having 7 to 10 carbon atoms. ) Is represented. ) Is represented. ),

(Viii)

[Chemical 13] (In the formula, R ¹¹ represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms or a 4- to 14-membered monocyclic or polycyclic cycloalkyl group.), Or (ix)

[Chemical 14] (In the formula, E represents an alkylene group having 1 to 4 carbon atoms, and R is
¹² and R ¹³ each independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. ) Is represented. ) Compounds represented by the above) or acid addition salts thereof, 2) a method for producing them, and 3) a drug containing them as an active ingredient.

In the present invention, isomers include all isomers unless otherwise specified. For example, the alkyl group, alkoxy group and alkylene group include straight-chain and branched-chain ones. Also included are isomers formed by the presence of asymmetric carbon atoms, such as when branched-chain alkyl groups, alkoxy groups and alkylene groups are present.

In the general formula (I), R, R ¹ , R ² , R ³ ,
R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³
The alkyl group having 1 to 4 carbon atoms in the group represented by is a methyl group, an ethyl group, a propyl group, a butyl group and isomers thereof. In the group represented by R in the general formula (I), the alkoxy group having 1 to 4 carbon atoms is a methoxy group, an ethoxy group, a propoxy group, a butoxy group and isomers thereof.

In the group represented by R ⁸ in the general formula (I), the alkyl group having 1 to 7 carbon atoms is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl group and isomers thereof. .. In the general formula (I),
The phenylalkyl group having 7 to 10 carbon atoms in the groups represented by R ⁶ , R ⁷ and R ⁸ is methyl, ethyl, propyl, butyl and isomers thereof substituted by one phenyl group. .. The alkylene group having 1 to 4 carbon atoms represented by A, D and E is methylene, ethylene, trimethylene, tetramethylene and isomers thereof.

In the general formula (I),

[Chemical 15] The 4- to 7-membered saturated monocyclic heterocycle represented by or a condensed heterocycle in which a benzene ring is condensed therewith are pyrrolidine,
Piperidine, perhydroazepine, indoline, 1,
2,3,4-tetrahydroquinoline ring and the like can be mentioned.
Examples of the 4- to 14-membered monocyclic or polycyclic cycloalkyl represented by R ¹¹ in the general formula (I) include cyclopentyl, cyclohexyl, decahydronaphthyl, tetradecahydroanthratyl, adamantyl and the like.

Specific compounds of the present invention include: p- (N-carboxymethyl-N-phenylsulfamoyl) benzoic acid p-guanidinophenyl ester, p- (N-ethoxycarbonylmethyl-N-phenylsulfur) Famoyl) benzoic acid p-guanidinophenyl ester, p- (N-benzyloxycarbonylmethyl-N-phenylsulfamoyl) benzoic acid p-guanidinophenyl ester, p- (N-benzyl-N-ethoxycarbonyl) Methylsulfamoyl) benzoic acid p-guanidinophenyl ester, p- (N-benzyl-Nt-butoxycarbonylmethylsulfamoyl) benzoic acid p-guanidinophenyl ester, p- (N-benzyl-N- Benzyloxycarbonylmethylsulfamoyl) benzoic acid p- Ani amidinophenyl ester,

P- (N-benzyl-N-ethoxycarbonylpropylsulfamoyl) benzoic acid p-guanidinophenyl ester, p- (N-benzyl-Nt-butoxycarbonylpropylsulfamoyl) benzoic acid p -Guanidinophenyl ester, -p- (N-benzyl-N-benzyloxycarbonylpropylsulfamoyl) benzoic acid p-guanidinophenyl ester, -p- (N-carboxyethyl-N-phenylcarbamoyl) benzoic acid p-guanidino Phenyl ester, p- (N-ethoxycarbonylethyl-N-phenylcarbamoyl) benzoic acid p-guanidinophenyl ester, p- (N-benzyloxycarbonylethyl-N-phenylcarbamoyl) benzoic acid p-guanidinophenyl ester,・- (N-benzyl -N- ethoxycarbonylmethylcarbamoyl) benzoic acid p- guanidino phenyl ester,

P- (N-benzyl-Nt-butoxycarbonylmethylcarbamoyl) benzoic acid p-guanidinophenyl ester, p- (N-benzyl-N-benzyloxycarbonylmethylcarbamoyl) benzoic acid p-guanidinophenyl Ester, p- (N-benzyl-N-ethoxycarbonylpropylcarbamoyl) benzoic acid p-guanidinophenyl ester, p- (N-benzyl-Nt-butoxycarbonylpropylcarbamoyl) benzoic acid p-guanidinophenyl ester, -P- (N-benzyl-N-benzyloxycarbonylpropylcarbamoyl) benzoic acid p-guanidinophenyl ester, and the compounds described in Examples and the like.

[0018]

[Acid Addition Salt] The compound of the present invention represented by the general formula (I) is
It is converted into the corresponding acid addition salt by a known method. The salt is preferably non-toxic and water-soluble. Suitable acid addition salts include inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, or acetates, trifluoroacetates, lactates, tartrates, oxalates. , Fumarate, maleate, citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate,
Organic acid salts such as gluconate can be mentioned.

[0019]

PROCESS FOR PRODUCING THE COMPOUND OF THE INVENTION The compound of the present invention represented by the general formula (I) has the general formula (II)

[Chemical 16] (Wherein R represents the same meaning as described above) and a compound of formula (III)

[Chemical 17] It is produced by subjecting p-guanidinophenol represented by

Of the compounds of the present invention represented by the general formula (I), carboxylic acid compounds, that is, the general formula

[Chemical 18] (Wherein, R ^a is (i) -COOH, in (ii) -O-A-COOH ( wherein, A are as defined above.), (Iii) -B- NR 6a R 7a ( wherein , B represents the same meaning as described above, and R ^6a represents the above R ⁶
R ^7a has the same meaning as above, and R ^7a is —D—COOH (wherein D ⁷
Represents the same meaning as described above. ) Or R
^6a and R ^7a together with the adjacent nitrogen atom

[Chemical 19] Represents. ), Or

(Iv)

[Chemical 20] Represents. ) Is a corresponding ester, that is, a compound represented by the general formula

[Chemical 21] (In the formula, R ^b is (i) —COOR ^1b , (wherein, R ^1b represents an alkyl group having 1 to 4 carbon atoms), (ii) —OA—COOR ^3b (In the formula, A is It has the same meaning as described above and R ^3b has 1 carbon atom.
Represents an alkyl group of ~ 4. ), (Iii) -B-NR 6b R 7b ( wherein, B represents the same meaning as above, R ^6b is the R ⁶
And R ^7b has the same meaning as

[Chemical formula 22]

(In the formula, D has the same meaning as described above.)
Or R ^6b and R ^7b together with the adjacent nitrogen atom

[Chemical formula 23] (In the formula,

[Chemical formula 24] Represents the same meaning as described above, and R ^10b represents an alkyl group having 1 to 4 carbon atoms or a benzyl group. ) Is represented. ),
Or (iv)

[Chemical 25] (In the formula, R ^11b represents an alkyl group having 1 to 4 carbon atoms). ) Is hydrolyzed under acidic conditions to remove a t-butyl group, or dealkylated with boron tribromide to remove an alkyl group having 1 to 4 carbon atoms or a benzyl group, or It is prepared by catalytic reduction to remove the benzyl group.

The compound represented by the general formula (II) is known per se or can be produced by a known method. The compound represented by the formula (III) has the formula:

[Chemical formula 26] It can be produced by subjecting p-aminophenol represented by and the cyanamide represented by the formula H ₂ NCN to a guanidylation reaction.

The esterification reaction, hydrolysis under acidic conditions, dealkylation, catalytic reduction and guanidylation reaction can be carried out by known methods. In each reaction in the present specification, the reaction product is an ordinary purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or column chromatography. It can be purified by a method such as chromatography, washing, recrystallization and the like. Purification may be carried out for each reaction, or after completion of some reactions. Other starting materials and respective reagents in the present invention are known per se or can be produced by known methods.

[0025]

[Pharmacological activity] The compound of the present invention represented by the general formula (I) is P
It has been confirmed by various experiments that it has LA ₂ inhibitory activity and trypsin inhibitory activity. For example, in a laboratory experiment, the following results were obtained.

[Experimental Method] (1) PLA ₂ Inhibitory Activity 50 mM Tris / HCl buffer (pH 7.5, 874 μm)
1; contains 100 mM sodium chloride and 1 mM EDTA. ), 1 M calcium chloride (6 μl), 1% bovine serum albumin (10 μl) and 2.5 mM 10P
A reaction solution containing Y-PC (10 μl) was prepared. Various concentrations of test compounds or water (50 μl) were added to the reaction solution.
Then, 10 mU / ml PLA ₂ solution (50 μl) was added, and the fluorescence intensity was measured at Ex = 345 nm and Em = 396 nm. Fluorescence intensity in the absence of test compound is 100
% To obtain the percentage (%) in the presence of the test compound,
The _C50 value was calculated. The results are shown in Table I.

[0027]

[Table 1]

(2) Trypsin inhibitory activity 0.2 M HEPES / sodium hydroxide buffer (pH 8.
0, 100 μl) and distilled water (640 μl), and various concentrations of the test compound or water (10 μl)
Add mU / ml trypsin solution (50 μl) and add 3
Pre-incubated for 1 minute at 0 ° C. 2.5 mM BAPNA (200 μl) was added to the reaction solution, and the temperature was 30 °
The cells were incubated at room temperature, and the absorbance at 405 nm was measured. Taking the absorbance in the absence of the test compound as 100%, the percentage (%) in the presence of the test compound was determined, and the IC ₅₀ was calculated.
The value was calculated. The results are shown in Table II.

In the above experimental method, 10PY-PC was 3'-palmitoyl-2- (1-pyrenedecanoyl)-.
L-α-phosphatidylcholine and HEPES are 4- (2
-Hydroxyethyl) -1-piperazineethanesulfonic acid, and BAPNA represent α-N-benzoyl-DL-arginine-p-nitroanilide hydrochloride.

[0030]

[Table 2]

[0031]

[Toxicity] On the other hand, the toxicity of the compound of the present invention is very low, and it can be judged that it is sufficiently safe for use as a medicine.

[0032]

[Application to pharmaceuticals] By inhibiting PLA ₂ and trypsin in animals including humans, especially humans, various inflammatory diseases, allergic diseases, generalized intravascular coagulation, pancreatitis, its seriousness and Prevention of multi-organ disorders and /
Or it is useful for treatment. In order to use the compound of the present invention represented by the general formula (I), a non-toxic acid addition salt thereof, or a hydrate thereof for the above purpose, it is usually systemically or topically, orally or parenterally. Is administered. Although the dose varies depending on age, symptoms, therapeutic effect, administration method, treatment time, etc., usually, it is orally administered once per adult in the range of 1 mg to 1000 mg once a day. , Or, per adult, in a range of 1 mg to 100 mg once a day, once or several times a day, parenterally (preferably intravenously), or in a range of 1 hour to 24 hours a day It is continuously administered intravenously.

Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient in some cases, or a dose exceeding the range may be necessary. When the compound of the present invention is administered, it is used as solid compositions, liquid compositions and other compositions for oral administration, injections for parenteral administration, external preparations, suppositories and the like. Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents (water, ethanol). Etc.) may be included.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Other compositions for parenteral administration include external preparations containing one or more active substances and prepared by a conventional method, such as external preparations such as ointments and ointments, and suppositories for rectal administration. Agents and pessaries are included.

[0035]

Reference Examples and Examples The present invention will be described in detail below with reference to Reference Examples and Examples, but the present invention is not limited thereto. The solvent in the parentheses shown at the place of separation by chromatography indicates the elution solvent or developing solvent used, and the ratio represents the volume ratio. IR is measured by KBr tablet method and NMR is measured in deuterated methanol unless otherwise specified.

Reference Example 1 p- (N-methyl-N-phenylcarbamoyl) benzoic acid methyl ester

[Chemical 27] A suspension of terephthalic acid monomethyl ester (7.0 g) in thionyl chloride (15 ml) was refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure and dissolved in methylene chloride. The solution was added dropwise to a methylene chloride-pyridine (15 ml-7 ml) solution of N-methylaniline (4.2 g) under ice cooling, and the mixture was allowed to stand at room temperature for 1 hour.
Stir for hours. The reaction solution was poured into diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (10.6 g) having the following physical data. TLC: Rf = 0.56 (hexane: ethyl acetate = 1: 1
1).

Reference Examples 1 (a) and 1 (b) Using the corresponding compounds instead of N-methylaniline, the procedure of Reference Example 1 was repeated to obtain the compounds of the present invention shown in Table III. Reference Example 1 (c), 1 (d) Using terephthalic acid monobenzyl ester in place of terephthalic acid monomethyl ester, and the corresponding compound in place of N-methylaniline, and operating in the same manner as in Reference Example 1, The compounds of the present invention shown in Table III were obtained.

[0038]Reference Examples 1 (e), 1 (f)  Terephthalate instead of terephthalic acid monomethyl ester
Acid mono-t-butyl ester, and N-methylaniline
In the same manner as in Reference Example 1 using the corresponding compound instead of
By operation, the compounds of the present invention shown in Table III were obtained.

[0039]

[Table 3]

Reference Example 2 p- (Nt-butoxycarbonylmethyl-N-phenylcarbamoyl) benzoic acid methyl ester

[Chemical 28] To a dimethylformamide (DMF; 100 ml) solution of the compound (12.4 g) produced in Reference Example 1 (b), 60% sodium hydride (2.2 g) was added under ice cooling. The mixture was stirred at room temperature for 1 hour. T-Butyl bromoacetate (8.9 ml) was slowly added dropwise to the reaction solution, and the mixture was stirred at room temperature for 24 hours.

The reaction solution was diluted with diethyl ether, the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (17.0 g) having the following physical data. TLC: Rf = 0.38 (hexane: ethyl acetate = 2:
1). Reference Example 2 (a) to (c) Using the compounds prepared in Reference Examples 1 (d) and 1 (f) and the corresponding compound instead of t-butyl bromoacetate, the same operation as in Reference Example 2 was performed. Then, the compounds of the present invention shown in Table IV were obtained.

[0042]

[Table 4]

Reference Example 3 p- [p- (N, N-dimethylcarbamoylmethoxycarbonyl) phenyl] benzoic acid t-butyl ester

[Chemical 29] 4,4'-Biphenyldicarboxylic acid mono-t-butyl ester (756 mg) was added to an ethanol solution of potassium hydroxide (167 mg). After distilling off the solvent, azeotropic distillation was carried out with benzene. The residual potassium salt was dissolved in dimethyl sulfoxide, 2-chloro-N, N-dimethylacetamide (369 mg) was added thereto, and the mixture was stirred at 100 ° C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (814 mg) having the following physical data.
Got TLC: Rf = 0.26 (hexane: ethyl acetate = 1: 1
2).

Reference Example 4 p- [p- (t-butoxycarbonyl) phenyl] benzoic acid 2-adamantyl ester

[Chemical 30] 4,4'-biphenyldicarboxylic acid mono-t-butyl ester (894 mg), 2,2'-dipyridyl disulfide (991 mg) and triphenylphosphine (1.18)
The acetonitrile solution of g) was refluxed for 30 minutes. The solvent was distilled off, 2-adamantanol (1.37 g) and triethylamine (1 drop) were added to the residue, and the mixture was heated at 100 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.1 g) having the following physical data. TLC: Rf = 0.77 (hexane: ethyl acetate = 4:
1).

Reference Example 5 p- (N-methyl-N-phenylcarbamoyl) benzoic acid

[Chemical 31] 1N sodium hydroxide (60 ml) was slowly added to a solution of the compound (10.6 g) produced in Reference Example 1 in dioxane-methanol (50 ml-20 ml) at room temperature, and the mixture was stirred for 3 hours. The reaction solution was neutralized with 2N hydrochloric acid, and the solvent was evaporated. The residue was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (10.0 g) having the following physical data. TLC: Rf = 0.11 (hexane: ethyl acetate = 1: 1
1).

Reference Examples 5 (a), 5 (b) Instead of the compound prepared in Reference Example 1, Reference Example 1 (a)
Alternatively, the compound produced in Reference Example 2 was used for the same operation as in Reference Example 5 to obtain the compounds of the present invention shown in Table V.

[0047]

[Table 5]

Reference Example 6 p-[(2-ethoxycarbonyl-1-indolyl) carbonyl] benzoic acid

[Chemical 32] Compound (2.86 g) produced in Reference Example 1 (c) and 10% palladium-carbon (200 mg) in methanol (50 ml)
The suspension was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give the title compound (2.34 g) having the following physical data. TLC: Rf = 0.31 (chloroform: methanol = 9:
1).

[0049]Reference examples 6 (a) and 6 (b)  Instead of the compound produced in Reference Example 1 (c),
Using the compound produced in Reference Example 2 (a) or 2 (b)
Then, the same operation as in Reference Example 6 was carried out to carry out the present invention shown in Table VI.
I got a compound.

[0050]

[Table 6]

Reference Example 7 p- [p- (N, N-dimethylcarbamoylmethoxycarbonyl) phenyl] benzoic acid

[Chemical 33] The compound (814 mg) produced in Reference Example 3 was suspended in anisole (2 ml). The suspension was cooled to 0 ° C., trifluoroacetic acid (TFA; 4 ml) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, and the residue was azeotropically distilled with toluene. The residue was washed with ether to give the title compound (529) having the following physical data.
mg) was obtained. TLC: Rf = 0.64 (ethyl acetate: acetic acid = 9: 1).

Reference Examples 7 (a) to (c) Instead of the compound prepared in Reference Example 3, the compounds prepared in Reference Example 1 (e), 2 (c) or 4 were used, respectively. By the same operation, the compounds of the present invention shown in Table VII were obtained.

[0053]

[Table 7]

Reference Example 8 p- (1H-hexahydroazepin-1-yl-sulfonyl) benzoic acid

[Chemical 34] A solution of hexamethyleneimine (4.56 mg) in pyridine-methylene chloride (10 ml-50 ml) was cooled to 0 ° C, and
-(Chlorosulfonyl) benzoic acid (4.40 g) was added in small portions. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (1.81 g) having the following physical data. TLC: Rf = 0.37 (chloroform: methanol: triethylamine = 20: 1: 1).

Reference Example 8 (a) Using aniline instead of hexameilenimine, the same procedure as in Reference Example 8 was carried out to obtain the compound of the present invention shown below.

[Chemical 35] TLC: Rf = 0.66 (chloroform: methanol: triethylamine = 7: 3: 2).

Reference Example 9 p- (ethoxycarbonylmethoxy) benzoic acid

[Chemical 36] DMF of p-hydroxybenzaldehyde (10 g)
Sodium hydride (2.0 g) was added to the (100 ml) solution under ice cooling. The mixture was stirred at room temperature for 1 hour. Ethyl chloroacetate (10 g) was added to the reaction mixture, and the temperature was 60 ° C.
It was stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 3: 1) to obtain p- (ethoxycarbonylmethoxy) benzaldehyde. This was dissolved in acetone (200 ml), and the Jones (Jone's) reagent was added under ice cooling. Excess reagent was treated with isopropanol. The reaction mixture was poured into water and extracted with ether. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the obtained solid was washed with diisopropanol to obtain the title compound (14 g) having the following physical properties. TLC: Rf = 0.45 (chloroform: methanol: triethylamine = 20: 1: 1).

Reference Example 10 p-guanidinophenol hydrochloride

[Chemical 37] An ethanol solution of p-aminophenol hydrochloride (39 g) and an aqueous cyanamide solution (16.8 g / 34 ml of water) was refluxed for 2 days. The reaction mixture was concentrated under reduced pressure, and the obtained solid was washed with isopropanol to give the title compound (35 g) having the following physical data. TLC: Rf = 0.43 (ethyl acetate: acetic acid: water = 3: 1:
1).

Example 1 p- (N-methyl-N-phenylcarbamoyl) benzoic acid p-guanidinophenyl ester hydrochloride

[Chemical 38] The compound (1.50 g) produced in Reference Example 5 and the compound (0.94 g) produced in Reference Example 10 were dissolved in pyridine (8 ml). Dicyclohexylcarbodiimide (1.50
g) was added and the mixture was stirred for 24 hours. The reaction mixture is filtered,
White powder was removed. The solvent was distilled off, and the residue was washed with ethyl acetate. The residue was dissolved in water and freeze-dried to give a powder. The crystals were washed with ethyl acetate and dried to give the title compound (1.44 g) as a white powder having the following physical data. TLC: Rf = 0.47 (chloroform: methanol: acetic acid = 5: 1: 1); IR: ν 3350, 1737, 1672, 1631, 1591, 1507, 12
66, 1206, 1074, 1015, 865, 701 cm ^-1 ; NMR: δ 8.00 (2H, d, J = 8.4Hz), 7.47 (2H, d, J = 8.4H)
z), 7.30 (11H, m), 3.50 (3H, s).

Examples 1 (a) -1 (t) Instead of the compound prepared in Reference Example 5, Reference Example 5
(A), 5 (b), 6, 6 (a), 6 (b), 7, 7
Using (a), 7 (b), 7 (c), 8, 8 (a), 9 and the corresponding compounds, the same procedure as in Example 1 was performed, and
The compound of the present invention shown in VIII was obtained.

[0060]

[Table 8]

[0061]

[Table 9]

[0062]

[Table 10]

[0063]

[Table 11]

[0064]

[Table 12]

Example 2 p- (N-carboxymethyl-N-phenylcarbamoyl) benzoic acid p-guanidinophenyl ester trifluoroacetate

[Chemical Formula 39] The compound (0.75 g) produced in Example 1 (b) was suspended in anisole (3 ml). TFA (4
ml) was added and the mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 1 hour. The solvent was distilled off, and the residue was azeotropically distilled with toluene. The obtained solid was washed with diethyl ether-ethyl acetate and dried to give the title compound (0.43) as a brown powder having the following physical data.
g) was obtained. TLC: Rf = 0.45 (chloroform: methanol: acetic acid = 3: 1: 1); IR: ν 3392, 1737, 1684, 1626, 1594, 1508, 14
36, 1303, 1269, 1204, 1139, 1076, 802, 724, 701 c
m ^-1 ; NMR: δ 7.98 (2H, d, J = 8.6Hz), 7.46 (2H, d, J = 8.6H)
z), 7.25 (9H, m), 7.43 (2H, s).

[0066]

[Formulation Example] Formulation Example 1 The following components were admixed in a conventional manner and punched out to give 100 tablets each containing 50 mg of the active ingredient.・ P- (N-methyl-N-phenylcarbamoyl) benzoic acid p-guanidinophenyl ester ・ hydrochloride ・ ・ ・ 5.0 g ・ Carboxymethylcellulose calcium (disintegrant) ・ ・ ・ 0.2 g ・ Magnesium stearate (lubricant) ・ ・ ・ 0.1 g ・ Microcrystalline cellulose …… 4.7 g

Formulation Example 2 The following components were mixed by a conventional method, the solution was sterilized by a conventional method, 5 ml each was filled in an ampoule, and freeze-dried by a conventional method, and 20 mg of the active ingredient was contained in 1 ampoule. I got 100 ampoules. -P- (N-methyl-N-phenylcarbamoyl) benzoic acid p-guanidinophenyl ester-hydrochloride ... 2 g-citric anhydride ... 200 mg-distilled water-500 ml

Claims (1)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R is (i) an alkyl group having 1 to 4 carbon atoms, (ii) an alkoxy group having 1 to 4 carbon atoms, (iii) —COOR ¹ (in the formula, R ¹ is a hydrogen atom or a carbon number 1) To (4) alkyl group), (iv) -COR ² (in the formula, R ² represents an alkyl group having 1 to 4 carbon atoms or a phenyl group), (v) -OA-COOR ³ ( In the formula, A represents an alkylene group having 1 to 4 carbon atoms, and R
³ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. ), (Vi) -NR ⁴ R ⁵ (in the formula, R ⁴ and R ⁵ each independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), (vii) -B-NR ⁶ R ⁷ (In the formula, B represents a sulfonyl group or a carbonyl group, R ⁶ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group or a phenylalkyl group having 7 to 10 carbon atoms, and R ⁷ is hydrogen. Atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, a phenylalkyl group having 7 to 10 carbon atoms or -D-COOR ⁸ (in the formula, D represents an alkylene group having 1 to 4 carbon atoms, and R ⁸ is hydrogen. Atom, an alkyl group having 1 to 7 carbon atoms or a phenylalkyl group having 7 to 10 carbon atoms), or R ⁶ and R ⁷ together with an adjacent nitrogen atom are (In the formula, Represents a 4- to 7-membered saturated monocyclic heterocycle or a condensed heterocycle in which a benzene ring is condensed, R ⁹ is a hydrogen atom, or —COOR ¹⁰ (wherein R ¹⁰ is a hydrogen atom, and has 1 to ¹⁰ carbon atoms).
4 represents an alkyl group having 4 to 10 carbon atoms or a phenylalkyl group having 7 to 10 carbon atoms. ) Is represented. ) Is represented. ), (Viii) (In the formula, R ¹¹ represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, or a 4- to 14-membered monocyclic or polycyclic cycloalkyl group), or (ix) (In the formula, E represents an alkylene group having 1 to 4 carbon atoms, and R
¹² and R ¹³ each independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. ) Is represented. ) Or the acid addition salt thereof.