JPH10101556A - Factor d-inhibiting medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine containing a compound selected from among a guanidino fatty acid derivative, a guanidinobenzoic acid derivative, etc., and enabling to prevent and treat diseases caused by factor D. SOLUTION: This factor D-inhibiting medicine contains a guanidinofatty acid derivative of formula I [R<1> is H, a halogen, nitro, an alkyl, an alkoxy, carboxy, an alkoxycarbonyl; (n) is 3-6], a guanidinobenzoic acid derivative of formula II (R<2> , R<3> are each a substituent; E is O, S), a guanidinophenol derivative of formula III (R<4> , R<5> are each a substituent), and an amidinophenol derivative of formula IV (R<6> , R<7> are each a substituent) as an active ingredient. The medicine is useful for preventing and treating systemic erythematosus, glomerulonephrits, pulmonary obstruction after the dialysis of kindney, adult respiratory impending syndromes, rejection reaction on organ transplantation, arthritis, etc. The active ingredient is orally administered at a dose of 1-1000mg/ time once to several times a day for an adult or parenterally administered at a dose of 1-100mg/time once to several times a day.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a guanidino fatty acid derivative, a guanidino benzoic acid derivative, a guanidino phenol derivative, an amidino phenol derivative and their non-toxic salts, acid addition salts and hydrates thereof. The present invention relates to a factor D inhibitor containing the above substances as active ingredients. More specifically, the general formulas (I), (II), (III) and (IV)

Embedded image (In the formula, all symbols have the same meaning as described below.) A guanidino fatty acid derivative, a guanidino benzoic acid derivative, a guanidino phenol derivative, an amidino phenol derivative and their non-toxic salts, acid addition salts or hydration thereof The present invention relates to a Factor D inhibitor containing, as an active ingredient, one or more substances selected from substances.

[0002]

BACKGROUND OF THE INVENTION Factor D is described in PHLesavra et al., 1979 (see J. Immunology, 123 , 529 (1979)) and AEDavi, 1980.
(Biochem. J., 187 , 863 (1980)) is a complement system activator isolated and purified from plasma. Factor D is a trypsin-like serine protease that always exists in the blood as an active form of a single-chain structure, and its amino acid sequence has already been determined (Biochemistry, 23 , 2482).
(1984)). Factor D is the rate-limiting enzyme involved in the alternative mechanism of activation of the complement system. That is, C
When Factor B binds to Factor 3b to form a C3 convertase precursor C3b, B, Factor D decomposes the Arg-Lys portion of the C3b, B complex to a limited extent, and Ba and C3b, B
Produce b (C3 convertase), causing activation of the complement system. Factor D has a molecular weight of 24,000 and is 3% less than other proteases such as plasmin and trypsin.
It is a completely different enzyme in that it has only 5 to 40% equivalence and the above-mentioned effects.

The following are reported as studies on the involvement of factor D in disease states. (1) Serum factor D concentration in patients with systemic lupus erythematosus (SLE) is elevated. (2) Factor D passes through the glomerular membrane, is catabolized in the proximal tubule and is rapidly removed, but increases in factor D in renal failure, serum of renal dialysis patients and urine, and accumulation of factor D As a result, the ability to solubilize the immune complex is reduced. (3) Complement components including C3 are rapidly decreasing in adult respiratory distress syndrome (ARDS) patients. In addition, neutrophil adhesion, aggregation, activation, and subsequent damage to peripheral endothelium
5a plays an important role. (4) In organ transplant rejection, DAF (Decay Accelerating Factor), one of the complement activation control proteins
Is involved in the activation of the alternative pathway complement system.

[0004] Factor D inhibitors are believed to be useful in the prevention and / or treatment of various diseases caused by Factor D. Considering the involvement of Factor D in the pathology, for example, systemic lupus erythematosus (SL
E), glomerulonephritis, pulmonary embolism after renal dialysis, adult respiratory distress syndrome (ARDS), organ transplant rejection, arthritis and the like.

[0005] It has been reported that FUT-175 having a guanidino group has a factor D inhibitory activity [N. Ikari,
et. al., Immunology, 49 , 685 (1983).

Embedded image

Further, the compound of the present invention has an antitrypsin action,
It is known to have LTB ₄ antagonism (Japanese Patent Application Laid-Open No.
89640, JP-A-8-109164, JP-A-7-206801 and JP-A-8-143529).

[0007]

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies to find an inhibitor of factor D from the above viewpoints. As a result, a guanidino fatty acid derivative represented by the general formula (I):
A guanidinobenzoic acid derivative represented by the general formula (II), a guanidinophenol derivative represented by the general formula (III),
The present inventors have found that the amidinophenol derivative represented by the general formula (IV) has a strong factor D inhibitory activity and completed the present invention.

[0008]

It has never been known that the compounds of the present invention have a potent factor D inhibitory activity. More specifically, the above-mentioned FUT-175 is a guanidinobenzoic acid derivative, a guanidino fatty acid derivative represented by the general formula (I), a guanidinophenol derivative represented by the general formula (III), and a guanidinophenol derivative represented by the general formula (IV) of the present invention. The compound is structurally completely different from the amidinophenol derivative shown. In the above-mentioned FUT-175, guanidinobenzoic acid is substituted by a substituted naphthyl group. However, the guanidinobenzoic acid derivative represented by the general formula (II) of the present invention is obtained by substituting guanidinobenzoic acid with a phenyl group or a substituted phenyl group. And are structurally different compounds in this respect. Therefore, the guanidino fatty acid derivative, guanidinobenzoic acid derivative, guanidinophenol derivative of the present invention,
It is completely unexpected from the prior art that amidinophenol derivatives have potent factor D inhibitory activity. The fact that these compounds have potent Factor D inhibitory activity has now been confirmed for the first time by the present inventors through experiments.

[0009]

The present invention relates to (1) a compound represented by the general formula (I):

Embedded image (Wherein, R ¹ represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group, an alkoxy group, a carboxy group or an alkoxycarbonyl group, and n represents an integer of 3 to 6). A factor D inhibitor comprising, as an active ingredient, a non-toxic salt, an acid addition salt or a hydrate thereof, (2)

Embedded image (Wherein, R ² and R ³ represent various substituents, and E represents an oxygen atom or a sulfur atom), a guanidinobenzoic acid derivative, a nontoxic salt thereof, an acid addition salt thereof or a hydration thereof. D containing a substance as an active ingredient
Inhibitor, (3) general formula (III)

Embedded image (Wherein R ⁴ and R ⁵ represent various substituents.) A factor D inhibitor containing, as an active ingredient, a guanidinophenol derivative represented by the following formula, a non-toxic salt thereof, an acid addition salt or a hydrate thereof: , (4) general formula (IV)

Embedded image (Wherein R ⁶ and R ⁷ represent various substituents), a non-toxic salt thereof,
The present invention relates to a Factor D inhibitor containing an acid addition salt or a hydrate thereof as an active ingredient.

In the present invention, all isomers are included unless otherwise indicated. For example, alkyl, alkoxy, alkylene, alkenylene and alkynylene include straight and branched ones, and the double bond in the alkenylene is a mixture of E, Z and EZ. Things included. Also included are isomers resulting from the presence of asymmetric carbon atoms, such as when branched alkyl, alkoxy, alkylene, alkenylene, and alkynylene groups are present.

Each substance used as an active ingredient in the present invention is well known, and will be described in detail below. Preferably, the compound represented by the general formula (I)

Embedded image (Wherein R ¹ represents a hydrogen atom, halogen, nitro, alkyl, alkoxy, carboxy or alkoxycarbonyl group, and n represents an integer of 3 to 6), a guanidino fatty acid derivative represented by the formula: Acid addition salts or hydrates thereof.

Examples of the guanidino fatty acid derivative represented by the general formula (I) included in the present invention include JP-B-47-21977.
No. 50-2494, No. 45-33175, No. 49-2107, JP-A-48-29732, No. 49-24917, No. 51-75042, No. 5
The compounds described in 4-76532 are included.

As a more preferred compound, the following formula (1)
And 6-guanidinohexanoic acid / p-ethoxycarbonylphenyl ester, non-toxic salts, acid addition salts and hydrates thereof.

Embedded image

Preferably, the compound represented by the general formula (II)

Embedded image (Wherein, R ² and R ³ represent various substituents, and E represents an oxygen atom or a sulfur atom), a guanidinobenzoic acid derivative, a nontoxic salt thereof, an acid addition salt thereof or a hydration thereof. Things.

Examples of the guanidinobenzoic acid derivative represented by the general formula (II) included in the present invention include JP-A-48-297.
Nos. 32 and 49-24917 (U.S. Pat.No. 3,824,267);
49-11842, 50-5038, 50-69035, 51-16
Nos. 631, 52-89640 (U.S. Pat.
15412, 53-147044, 54-70241 and 55-
55154 (U.S. Pat.No. 4,224,342), U.S. Pat. Nos. 55-115865, and 55-115863 (U.S. Pat.No. 4,283,418), 56-346
No. 62 (U.S. Pat.No. 4,310,533), No. 62-111963 and No. 63-165357 (European Patent Publication No. 222608), No. 55-10
0356, 56-110664, 57-142956, 57-1429
No. 57, No. 58-41855, No. 58-49358, No. 62-103058 and No. 62-155253.

More preferred compounds include N, N-dimethylcarbamoylmethyl p- (p-guanidinobenzoyloxy) phenylacetate represented by the following formula (2):

Embedded image Equation (3):

Embedded image And p- (p-guanidinobenzoyloxy) phenylacetic acid and their non-toxic salts, acid addition salts or hydrates thereof.

Preferably, the compound represented by the general formula (III)

Embedded image (Wherein R ⁴ and R ⁵ represent various substituents), a non-toxic salt thereof, an acid addition salt thereof or a hydrate thereof.

Examples of the guanidinophenol derivative represented by the general formula (III) included in the present invention are described in
No. 286922, Chem. Pharm. Bull., 32 , 4466-4477 (1984) and Japanese Patent Application No. 8-113159.

More preferred compounds include those represented by formula (4):

Embedded image P- (p-guanidinophenoxycarbonyl) -α-methylcinnamic acid N-allyl-N-ethoxycarbonylmethylamide represented by

Equation (5):

Embedded image And m- (p-guanidinophenoxycarbonyl) benzenesulfonic acid amide and their non-toxic salts, acid addition salts or hydrates thereof.

Preferably, the compound represented by the general formula (IV)

Embedded image (Wherein R ⁶ and R ⁷ represent various substituents), a non-toxic salt thereof,
Acid addition salts or hydrates thereof.

Examples of the amidinophenol derivative represented by the general formula (IV) included in the present invention include JP-A-58-418.
No. 55, JP-A-8-109164 (European Patent Publication No. 588655),
JP-A-7-206801 (European Patent Publication No.656349),
8-143529 (European Patent Publication No. 703216).

More preferred compounds include those represented by formula (6):

Embedded image P- (p-amidinophenoxycarbonyl) represented by
-Α-methylcinnamic acid N-allyl-N-ethoxycarbonylmethylamide,

Equation (7):

Embedded image P- (p-amidinophenoxycarbonyl) represented by
-Α-methylcinnamic acid N-allyl-N-carboxymethylamide,

Equation (8):

Embedded image P- (p-amidinophenoxycarbonyl) represented by
-Α-methylcinnamic acid N-propargyl-N-ethoxycarbonylmethylamide,

Equation (9):

Embedded image P- (p-amidinophenoxycarbonyl) represented by
Cinnamic acid N- (4-phenylmethyl) piperazinylamide;

Equation (10):

Embedded image P- (p-amidinophenoxycarbonyl) represented by
Phenylpropionic acid N-allyl-N-ethoxycarbonylmethylamide,

Equation (11):

Embedded image P- (p-amidinophenoxycarbonyl) represented by
-Α-methylcinnamic acid N- (1- (S) -ethoxycarbonyl-2-ethoxycarbonylethylthio) ethylamide,

Equation (12):

Embedded image P- (p-amidinophenoxycarbonyl) represented by
-Α-methylcinnamic acid N-ethoxycarbonylmethyl-
N-hexylamide,

Equation (13):

Embedded image P- (4-amidino-2-methoxycarbonylphenoxycarbonyl) -α-methylcinnamic acid N-allyl-N-ethoxycarbonylmethylamide represented by

Equation (14):

Embedded image P- (p-amidinophenoxycarbonyl) represented by
-Α-methylcinnamic acid N- (1,1-bis (ethoxycarbonylmethyl) methyl-N-cyclohexylamide,

Equation (15):

Embedded image P- (p-amidinophenoxycarbonyl) represented by
-Α-methylcinnamic acid N-2-ethoxycarbonylethyl-N-3-methoxypropylamide and non-toxic salts, acid addition salts or hydrates thereof.

In the present invention, each active ingredient may be used alone, but two or more active ingredients may be blended to form a single preparation.

The compounds described herein can be converted to non-toxic salts or acid addition salts by known methods. The salt is preferably a non-toxic, water-soluble salt. Suitable salts include
Salts of alkali metals (such as potassium and sodium), salts of alkaline earth metals (such as calcium and magnesium), ammonium salts, and pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine,
Dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, N-methyl-
D-glucamine).

The acid addition salt is preferably non-toxic and water-soluble. Suitable acid addition salts include, for example, inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, benzoate Acid salts, citrates, methanesulphonates, ethanesulphonates, benzenesulphonates, toluenesulphonates, isethionates, glucuronates, organic salts such as gluconates, but preferably Is a methanesulfonate. The compound described herein or a non-toxic salt or acid addition salt thereof may be converted into a hydrate by a known method.

[0036]

[Production method of the compound of the present invention] Among the compounds according to the present invention, a guanidino fatty acid derivative represented by the general formula (I), a guanidinobenzoic acid derivative represented by the general formula (II), and a guanidinophenol represented by the general formula (III) The derivative and the amidinophenol derivative represented by the general formula (IV) can be produced by the method described in the above specification or a method analogous thereto.

[0037]

[Effects] As mentioned above, Factor D inhibitors are systemic lupus erythematosus (SLE), glomerulonephritis, pulmonary embolism after renal dialysis, adult respiratory distress syndrome (ARDS), organ transplant rejection, arthritis, etc. It is considered useful for the prevention and / or treatment of Therefore, general formulas (I), (II), and (II) having Factor D inhibitory activity
The compounds of the present invention represented by I) and the general formula (IV) are useful in animals including humans, especially humans, particularly systemic lupus erythematosus (SLE), glomerulonephritis, pulmonary embolism after renal dialysis, adult respiratory distress syndrome ( ARDS), organ transplant rejection, arthritis and the like can be used as a prophylactic and / or therapeutic agent.

[0038]

[Toxicity] It has been confirmed that the toxicity of each active ingredient and their non-toxic salts, their non-toxic acid addition salts and their hydrates contained in the present invention is very low. For example, when the methanesulfonate of compound 6 was intravenously administered to a male mouse, the LD ₅₀ value was 117 mg / kg. Therefore, any of the active substances included in the present invention can be judged to be sufficiently safe and suitable for use as a medicament.

In order to use the substance according to the present invention for the above purpose, it is usually administered systemically or locally, in an oral or parenteral form. The dosage varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., and is usually orally administered once to several times a day per adult in the range of 1 mg to 1000 mg per administration. Or parenterally (preferably intravenously) once to several times daily, in the range of 1 mg to 100 mg per adult, or 1 hour to 24 hours daily. It is continuously administered intravenously in a range. Of course, as mentioned above,
Since the dose varies depending on various conditions, a dose smaller than the above-mentioned dose may be sufficient, or may be required outside the range.

When the compound of the present invention is administered, it is used as a solid composition, a liquid composition and other compositions for oral administration and an injection, an external preparation, a suppository and the like for parenteral administration. Can be Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules. In such solid compositions, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, It is mixed with magnesium metasilicate aluminate.
The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate,
A disintegrating agent such as calcium cellulose glycolate and a solubilizing agent such as glutamic acid or aspartic acid may be contained. The tablet or pill may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or may be coated with two or more layers, if necessary. . Also included are capsules of absorbable materials such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs and the like. In such liquid compositions, one or more active substances are contained in commonly used inert diluents (eg, purified water, ethanol).
The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, and preservatives. Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se. The composition contains, in addition to the inert diluent, a stabilizing agent such as sodium bisulfite to render it isotonic and an isotonic agent such as sodium chloride, sodium citrate or citric acid. You may. The method of manufacturing the spray is
For example, it is described in detail in U.S. Patent Nos. 2,868,691 and 3,095,355.

The injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (registered trademark). Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing, and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used in the manufacture of sterile solid compositions which are sterilized or dissolved in sterile distilled water for injection or other solvents before use. Other compositions for parenteral administration include external solutions, ointments, liniments, suppositories for rectal administration, and vaginal administration containing one or more active substances and formulated in a conventional manner. Pessaries etc. are included.

[0043]

EXAMPLES The present invention will now be described in detail with reference to Examples and Examples, but the present invention is not limited thereto. The solvent in parentheses shown at the point of separation by chromatography indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio.

Example 1 (1): Factor D inhibitory activity 20 mM Tris buffer (pH 7.4, containing 100 mM magnesium chloride, 100 μl), 2.5 mM Boc-G
In-Ala-Arg-MCA (20 μl), aqueous solutions or water (20 μl) of various concentrations of the test compound, and distilled water (40 μl) were added to make a total volume of 180 μl.
To this solution was added 12.5 μg / ml Factor D enzyme solution (20 μl) and the mixture was incubated at 37 ° C. for 30 minutes. Ex = 370 nm and E
The fluorescence was measured at m = 460 nm. Assuming that the increase in fluorescence in the absence of the test compound was 100%, the percentage (%) in the presence of the test compound was determined, and the IC50 value was calculated. Table 1 shows the results.

[0045]

[Table 1]

In the above experimental method, Boc-Gln-
Ala-Arg-MCA stands for t-butoxycarbonyl-glutamine-alanine-arginine-methylcoumarinamide.

[0047]

[Formulation example]

Formulation Example 1 The following components were mixed in a conventional manner and then tableted to obtain 100 tablets each containing 50 mg of the active ingredient. P- (p-amidinophenoxycarbonyl) -α-methyl-cinnamate N-ethoxycarbonylmethyl-N-allylamide methanesulfonate (methanesulfonate of compound 6) 5.0 g carboxymethylcellulose calcium ( Disintegrant) 0.2 g • Magnesium stearate (lubricant) 0.1 g Microcrystalline cellulose 4.7 g

Formulation Example 2 After mixing the following components by a conventional method, the solution is sterilized by a conventional method, filled into ampoules in 5 ml portions, freeze-dried by a conventional method, and contains 20 mg of the active ingredient in one ampule. 100 ampoules were obtained. P- (p-amidinophenoxycarbonyl) -α-methyl-cinnamic acid N-ethoxycarbonylmethyl-N-allylamide methanesulfonate (methanesulfonate of compound 6) 2 g citric anhydride … 200 mg ・ Distilled water …… 500 ml

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/495 A61K 31/495 C07C 279/18 C07C 279/18 // C07D 295/18 C07D 295/18 Z

Claims (8)

[Claims] 1. A compound of the general formula (I) (Wherein, R ¹ represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group, an alkoxy group, a carboxy group or an alkoxycarbonyl group, and n represents an integer of 3 to 6). A factor D inhibitor comprising, as an active ingredient, a non-toxic salt, acid addition salt or hydrate thereof. 2. A compound of the general formula (II) (Wherein R ² and R ³ represent a substituent and E represents an oxygen atom or a sulfur atom), a guanidinobenzoic acid derivative, a non-toxic salt thereof, an acid addition salt or a hydrate thereof. Factor D inhibitor contained as an active ingredient. 3. A compound of the general formula (III) (Wherein, R ⁴ and R ⁵ represent a substituent.) A factor D inhibitor comprising, as an active ingredient, a guanidinophenol derivative represented by the following formula, a non-toxic salt thereof, an acid addition salt or a hydrate thereof. 4. A compound of the general formula (IV) (Wherein, R ⁶ and R ⁷ represent a substituent.) A factor D inhibitor comprising, as an active ingredient, an amidinophenol derivative represented by the following formula, a nontoxic salt thereof, an acid addition salt or a hydrate thereof. 5. The method according to claim 5, wherein the active ingredient is 6-guanidinohexanoic acid.
2. The inhibitor according to claim 1, which is p-ethoxycarbonylphenyl ester, a non-toxic salt thereof, an acid addition salt thereof or a hydrate thereof. 6. The active ingredient is p- (p-guanidinobenzoyloxy) phenylacetic acid N, N-dimethylcarbamoylmethyl ester, p- (p-guanidinobenzoyloxy) phenylacetic acid, their non-toxic salts, acid addition salts and 3. The inhibitor according to claim 2, which is one or more substances selected from hydrates thereof. 7. The active ingredient is p- (p-guanidinophenoxycarbonyl) -α-methylcinnamic acid N-allyl-N-ethoxycarbonylmethylamide, m- (p-guanidinophenoxycarbonyl) benzenesulfonic acid amide, and the like. The inhibitor according to claim 3, which is one or more substances selected from non-toxic salts, acid addition salts and hydrates thereof. 8. The active ingredient is p- (p-amidinophenoxycarbonyl) -α-methylcinnamic acid N-allyl-N-ethoxycarbonylmethylamide, p- (p-amidinophenoxycarbonyl) -α-methylcinnamic acid N-allyl-N-carboxymethylamide, p- (p-amidinophenoxycarbonyl) -α-methylcinnamic acid N-propargyl-N-ethoxycarbonylmethylamide, p- (p-amidinophenoxycarbonyl) cinnamic acid N
-(4-phenylmethyl) piperazinylamide, p- (p-amidinophenoxycarbonyl) phenylpropionic acid N-allyl-N-ethoxycarbonylmethylamide, p- (p-amidinophenoxycarbonyl) -α-methylcinnamic acid N- (1- (S) -ethoxycarbonyl-2
-Ethoxycarbonylethylthio) ethylamide, p- (p-amidinophenoxycarbonyl) -α-methylcinnamic acid N-ethoxycarbonylmethyl-N-hexylamide, p- (4-amidino-2-methoxycarbonylphenoxycarbonyl) -α -Methylcinnamic acid N-allyl-N-
Ethoxycarbonylmethylamide, p- (p-amidinophenoxycarbonyl) -α-methylcinnamic acid N- (1,1-bis (ethoxycarbonylmethyl) methyl-N-cyclohexylamide, p- (p-amidinophenoxycarbonyl)- α-Methylcinnamic acid N-2-ethoxycarbonylethyl-N-3
The inhibitor according to claim 4, which is one or more substances selected from -methoxypropylamide, a non-toxic salt thereof, an acid addition salt thereof and a hydrate thereof.