JPH0784423B2 - 3-Amino-2-substituted benzoyl acrylic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is a 3-amino-2-substituted benzoyl acrylic acid derivative, which is a useful intermediate for synthesizing 8-alkoxyquinolonecarboxylic acid derivatives showing strong antibacterial activity. Regarding

Composition of the Invention The 3-amino-2-substituted benzoylacrylic acid derivative of the present invention has the general formula Is a novel compound represented by.

In the above formula, R ¹ represents a lower alkyl group, R ² and R ³ represent the same or different lower alkyl groups, and A represents a nitrile group or a lower alkoxycarbonyl group.

In the above general formula (I), R ¹ is preferably a linear or branched alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl and isopropyl. ² and R ³ are the same or different and are linear or branched having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl. Represents a lower alkyl group, A is a nitrile group or, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,
Isopropoxycarbonyl, n-butoxycarbonyl,
An alkoxycarbonyl group having 2 to 5 carbon atoms such as isobutoxycarbonyl is shown.

Particularly preferable compounds in the general formula (I) are:
R ¹ represents a methyl group and has the formula Are dimethylamino groups and diethylamino groups, and A is a nitrile group, a methoxycarbonyl group or an ethoxycarbonyl group.

The 3-amino-2-substituted benzoyl acrylic acid derivative having the general formula (I) of the present invention has the general formula (In the formula, X represents a halogen atom such as chlorine or bromine,
R ¹ has the same meaning as described above. ) A substituted benzoyl halide compound represented by the general formula (In the formula, R ² , R ³ and A have the same meanings as described above), and are produced by reacting a 3-aminoacrylic acid derivative represented by the formula ( ³ ) in an inert solvent in the presence of chlorine. be able to.

As the solvent that can be used in this reaction, ether compounds such as tetrahydrofuran, diethyl ether, dioxane and dimethoxyethane, aromatic compounds such as benzene, toluene and xylene, or chlorine compounds such as methylene chloride and chloroform can be used, and particularly ethers. System solvents are preferred.
The reaction temperature is -30 to 170 ° C, preferably 0 to 80 ° C. Usually, the reaction proceeds rapidly near room temperature, but it is preferable to heat it to 50 to 80 ° C. to complete the reaction thereafter. The reaction time depends on the reaction temperature, but is in the range of 1 to 15 hours.

Examples of the base that can be used include tertiary amines such as pyridine, triethylamine and N-methylpiperidine, but triethylamine is preferable.

The concentration of reaction substrates (II) and (III) is 0.1-10, respectively.
Although it is possible in the range of M, it is usually better to carry out in the range of 0.5 to 1.2M.

Further, (II) and (III) have a stoichiometric amount (molar ratio) of 1: 1.
It is preferable that the base is used in an amount of 0.8 to 3.0 equivalents, preferably 1.0 to 1.5 equivalents with respect to the acid halide (II).

As a method for obtaining the product after completion of the reaction, a general method can be used in which the reaction mixture is concentrated or added to water without concentration to remove the formed salt and then extracted with a non-water-soluble organic solvent. The target product can be obtained with high purity by removing the solvent from the extract, but in the case of further purification, it can be isolated as a pure product by column chromatography or recrystallization.

The substituted benzol halide (II) and the corresponding carboxylic acid used in the above reaction are novel compounds, and the production method thereof is described in JP-A-63-198664, Will be described in detail as a reference example.

The compound (I) of the present invention is a useful intermediate for producing an antibacterial agent, and is a novel intermediate having a cyclopropyl group at the 1-position and an alkoxy group at the 8-position, for example according to the reaction route shown below. It can lead to a quinolonecarboxylic acid type antibacterial agent.

In the above formula, R ¹ , R ² and R ³ have the same meanings as described above, R represents a lower alkyl group, The amine compound (V) having is a pyrrolidine or piperazine derivative which may have a lower alkyl group, a lower alkoxy group, a hydroxyl group or an amino group as a substituent.

The reaction of the first step is a reaction of reacting compound (I) with cyclopropylamine in an inert solvent to obtain compound (III).

The solvent that can be used in this reaction is diethyl ether,
Tetrahydrofuran, ether compounds such as dioxane, hexane, aliphatic compounds such as cyclohexane, aromatic compounds such as benzene, toluene, xylene, chlorine compounds such as methylene chloride, chloroform, carbon tetrachloride or methyl acetate, ethyl acetate, etc. Ester compounds can be used. The reaction temperature is −20 to 100 ° C., preferably 0 to 50 ° C. Although the reaction time varies depending on the reaction temperature, it is several minutes to 10 hours, usually 2 hours or less.

The reaction of the second step is a reaction of treating compound (III) with a deoxidizing agent in the presence of a solvent to obtain compound (IV).

The solvent that can be used in this reaction is diethyl ether,
Ether-based compounds such as tetrahydrofuran and dioxane, or N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, sulfolane, N-
An aprotic polar solvent such as methylpyrrolidone can be used. Examples of the deoxidizing agent that can be used include sodium hydride, butyllithium, sodium methoxide, potassium t-butoxide, metallic sodium, sodium carbonate, potassium carbonate and potassium fluoride, with sodium hydride being preferred. The reaction temperature varies depending on the type of deoxidizing agent used, but is room temperature to 300 ° C, preferably room temperature to 1
It is performed in the range of 00 ℃. The reaction time varies depending on the reaction temperature, but it is 1 to 20 hours, usually 2 to 6 hours.

In the reaction of the third step, a) compound (IV) is heated with borofluoric acid to prepare the boron fluoride chelate compound. (In the formula, R ¹ has the same meaning as described above.),
b) A reaction for obtaining the compound (VI) by reacting the resulting compound (IV ′) with the amine compound (V) in the presence or absence of a deoxidizing agent in a solvent as the case requires.

As the solvent used in this reaction, dimethylsulfoxide, N, N-dimethylformamide, hexamethylphosphoric triamide, aprotic polar solvents such as dimethylacetamide are preferred, but also acetone, ketones such as methyl ethyl ketone, It is also possible to use ethers such as diethyl ether, tetrahydrofuran, dioxane, esters such as ethyl acetate, alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol, and nitriles such as acetonitrile. Examples of the deoxidizing agent include tertiary amines such as triethylamine, tributylamine, pyridine, picoline, lutidine and collidine, and inorganic bases such as sodium carbonate and potassium carbonate. The amount of the deoxidizing agent used is preferably equimolar to 5 times the molar amount of the compound (IV ′), but in the case of the amines, a large excess can be used as a solvent. Further, since the excess amine (V) is used as a deoxidizing agent, the reaction proceeds smoothly even if no other deoxidizing agent is added. The reaction is carried out at room temperature to 200 ° C.

In the reaction of the step b), a chelate compound of an object is first obtained, which is treated with a hydrous alcohol or a basic hydrous alcohol to give a compound (VI) / BF ₃ adduct or (VI), respectively. ) Can be guided to. The compound (VI) / BF ₃ adduct is easily induced to the target compound (VI) by treatment with a base.

As the base used in this treatment operation, alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, or triethylamine, and tertiary amines such as 4-dimethylaminopyridine Can be raised.

Compound (IV) or (VI) · BF thus obtained
_{The 3} adduct is converted into a desired salt, if necessary, according to a conventional method.

The quinolonecarboxylic acid derivative having the general formula (VI) and its pharmacologically acceptable salt exhibit excellent antibacterial action. When its antibacterial activity was measured by the agar plate dilution method, for example, Staphylococcus aureus, Gram-positive bacteria such as enterococci and Escherichia coli, Shigella, Klebsiella pneumoniae, mutated bacterium, Serratia, Enterobacter, Salmonella, Pseudomonas aeruginosa, etc. It showed strong antibacterial activity against a wide range of pathogens including Gram-negative bacteria and their resistant bacteria. The test results are shown in Table 1 using norfloxacin as a control compound.

Next, the present invention will be described more specifically with reference to Examples and Reference Examples.

Example 1 3-Dimethylamino-2- (3-methoxy-2,4,5-trifluorobenzoyl) acrylic acid methyl ester 3-methoxy-2,4,5-trifluorobenzoic acid chloride 2.0 g (8.91 mmol) Was dissolved in 10 ml of anhydrous tetrahydrofuran and cooled to 5 ° C or lower with ice water. To this solution, 1.15 g (8.91 mmo of 3-dimethylaminoacrylic acid methyl ester)
l) was dissolved in 3 ml of anhydrous tetrahydrofuran and added dropwise, and 0.94 g (9.31 mmol) of triethylamine was slowly added dropwise with cooling, and the mixture was stirred at room temperature for 5 hours and then heated at 60 ° C for 50 minutes. After concentrating the reaction solution, 20 ml of water was added and the mixture was extracted twice with 20 ml of dichloromethane, washed with water and dried. After concentration, 10 ml of methanol-water (6: 4) was added for recrystallization, and 3-dimethylamino-2- (3-methoxy-2,4,5
-Trifluorobenzoyl) acrylic acid methyl ester
1.36 g was obtained. Yield 48% mp 87 - 90 ° C. NMR spectrum _{(CDCl 3) δppm: 3.07 (} bs, 6H, N (CH 3) 2) 3.53 (s, 3H, COOCH 3) 3.99 (s, there is a coupling between the fluorine , 3H, ArOCH ₃ ) 7.07 (octet, 1H, aromatic proton) 7.71 (s, 1H, olefin proton) Mass spectrum: m / e 317 (M ⁺ ) Elemental analysis value% (as C ₁₄ H ₁₄ F ₃ NO ₄ ) Theoretical value: C, 53.00; H, 4.45; N, 4.41 Analytical value: C, 52.94; H, 4.43; N, 4.31 Example 2 3-Dimethylamino-2- (3-methoxy-2,4,5- Trifluorobenzoyl) acrylic acid ethyl ester 3.0 g (13.4 mmol) of 3-methoxy-2,4,5-trifluorobenzoic acid chloride was dissolved in 5 ml of anhydrous diethyl ether, cooled with ice water to 5 ° C or lower, and added to this solution. A solution prepared by dissolving 1.35 g (13.4 mmol) of ethylamine in 10 ml of anhydrous diethyl ether was added dropwise. Further, while cooling, 1.92 g (13.4 mmol) of 3-dimethylaminoacrylic acid ethyl ester was dissolved in 20 ml of anhydrous diethyl ether, and the mixture was slowly added dropwise and stirred at room temperature for 5 hours, and then left overnight. After concentrating the reaction solution, 20 ml of water was added and the mixture was extracted twice with 20 ml of dichloromethane, washed with water and dried. Column purification of this solution
3-Dimethylamino-2- (3-methoxy-2,4,5-trifluorobenzoyl) acrylic acid ethyl ester 1.30
got g. Yield 29%, oil.

NMR spectrum (CDCl ₃ ) δppm: 1.02 (t, 3H, CH ₃ CH ₂ O) 3.10 (bs, 6H, N (CH ₃ ) ₂ ) 4.02 (q, 2H, CH ₃ CH ₂ O) 4.04 (s, foot there is a coupling between the element, 3H, ArOCH ₃₎ 7.11 ^{(octet, m / e 331 (M +} ) example 3 3-dimethylamino-2- (3-methoxy-2,4,5-trifluorobenzoyl Robben benzoyl) acrylonitrile 2.0 g (8.91 mmol) of 3-methoxy-2,4,5-trifluorobenzoic acid chloride was dissolved in 10 ml of anhydrous tetrahydrofuran and cooled to 5 ° C. or lower with ice water, and 0.86 g of 3-dimethylaminoacrylniloryl was added to this solution. 8.91 mmol) was dissolved in anhydrous tetrahydrolane (3 ml) and added dropwise, and triethylamine 0.94 (9.31 mmol) was slowly added dropwise with cooling, and the mixture was stirred at room temperature for 4 hours and then heated at 65 ° C. for 3.5 hours. After concentration, add 20 ml of water and add 20 ml of chloroform.
Were extracted 3 times with water, washed with water and dried. Column purified to give 3-dimethylamino-2- (3-methoxy-2,4,5-
2.02 g of trifluorobenzoyl) acrylonitrile was obtained. Yield 80% Melting point 97-99 ° C NMR spectrum (CDCl ₃ ) δppm: 3.33 (bs, 3H) 3.47 (bs, 3H, NCH ₃ ) ₂ ) 4.05 (s, with coupling with fluorine, 3H, ArOCH ₃ ) 6.97 (Octet, 1H, aromatic proton) 7.90 (s, 1H, olefin proton) Mass spectrum: m / e 284 (M ⁺ ) Elemental analysis value% (as C ₁₃ H ₁₁ F ₃ N ₂ O ₂ ) Theoretical value : C, 54.93; H, 3.90; N, 9.86 Analytical value: C, 54.93; H, 3.90; N, 9.81 Reference Example 1 3-Cyclopropylamino-2- (3-methoxy-2,4,
5-Trifluorobenzoyl) acrylic acid methyl ester 5.64 g (17.8 mmol) of 3-dimethylamino-2- (3-methoxy-2,4,5-trifluorobenzoyl) acrylic acid methyl ester obtained in Example 1 was added to dichloromethane. Dissolve in 60 ml, under stirring with ice cooling, cyclopropylamine 1.22 g (21.4 m
mol) was slowly added dropwise, and the mixture was further stirred at room temperature for 10 minutes. The reaction solution was evaporated to dryness under reduced pressure, and methanol-water (5:
3) 8 ml was added and recrystallization was carried out to obtain 3.84 g of 3-cyclopropylamino-2- (3-methoxy-2,4,5-trifluorobenzoyl) acrylic acid methyl ester. By the same operation, 0.44 g of secondary crystals was obtained from the liquid.

Melting point 78-81 ° C Similarly, by using ethyl 3-dimethylaminoacrylate, 3-cyclopropylamino-2- (3
-Methoxy-2,4,5-trifluorobenzoyl) acrylic acid ethyl ester was obtained.

Reference Example 2 1-Cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester 3-cyclopropylamino-2- (3-methoxy-2, Four,
5-Trifluorobenzoyl) acrylic acid ethyl ester 1.20 g (3.5 mmol) was dissolved in anhydrous tetrahydrofuran 30 ml, 60% sodium hydride 150 mg (3.5 mmol) was added, and the mixture was stirred at room temperature for 30 minutes and acidified with 1N hydrochloric acid. , Extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated under reduced pressure to give 0.83 g of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester as a colorless needle. It was obtained as a crystal.

Melting point 180-182 ° C Mass spectrum: m / e 323 (M ⁺ ), 251 (M ⁺ -CO ₂ Et), 41
(C ₃ H ₅ ⁺ ) Reference Example 3 1-Cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid BF ₂ -chelate Obtained in Reference Example 2 1.0 g (3 mmol) of the obtained 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester was added to 4
After suspending in 20 ml of 2% hydrofluoric acid and stirring at 90-100 ° C for 3 hours, the mixture was poured into water and the precipitated crystals were collected to collect 1-cyclopropyl-6,7-difluoro-8-methoxy-1. , 4-Dihydro-4-oxoquinoline-3-carboxylic acid ・ BF ₂ −
1.1 g of the chelate was obtained as colorless powdery crystals.

Mp 224-226 ° C. Elemental analysis% (C ₁₄ H ₁₀ BF ₄ as NO ₄₎ theory: C, 49.10; H, 2.94 ; N, 4.08 Analytical values: C, 49.24; H, 3.01 ; N, 3.79 Reference Example 4 1-Cyclopropyl-6-fluoro-8-methoxy-7
-(1-Piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride 0.11 g (0.32 mmol) of the chelate compound obtained in Reference Example 3
Was dissolved in 0.5 ml of dimethyl sulfoxide, 0.11 g (1.2 mmol) of anhydrous piperazine was added, and the mixture was left at room temperature overnight. The reaction mixture was poured into 50 ml of diethyl ether, the precipitated yellow crystals of the chelate compound were collected, and this was dissolved in a mixed solution of 30 ml of 80% ethanol and 5 ml of triethylamine,
The mixture was heated under reflux for 4 hours. The reaction solution was heated to remove insoluble materials, the solution was concentrated under reduced pressure, and the obtained crystals were washed with ethanol to give 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-piperazinyl) -1. , 4-dihydro-4-
0.07 g of oxoquinoline-3-carboxylic acid was obtained as colorless powdery crystals.

Melting point 177-178 ° C. This crystal was suspended in 30 ml of ethanol, 1 ml of concentrated hydrochloric acid was added, the solvent was concentrated under reduced pressure, and the residue was washed with ethanol to obtain 0.06 g of the hydrochloride of the target compound as a colorless powder.

Mp 246-248 ° C. (decomposition) Elemental _{analysis% (C 18 H 20 FN 4} OCl · 1 / 2H 2 O as a) the theoretical value: C, 59.14; H, 5.45 ; N, 10.33 analysis: C, 53.31; H , 5.47; N, 10.36 The following compounds were synthesized in the same manner as in Reference Example 4.

Reference Example 10 3-Methoxy-2,4,5-trifluorobenzoic acid and its acid chloride 160.0 g (0.83 mol) of pentafluorobenzonitrile was dissolved in 2.5 of methanol, and 44.8 g (0.83 mol) of sodium methoxide was stirred at room temperature. 1.6 of a methanol solution of was added dropwise. After completion of the dropping, the mixture was left overnight at room temperature, the solvent was distilled off under reduced pressure, the residue was shaken with toluene-water, the toluene layer was washed with water, dried over anhydrous sodium sulfate, and then distilled under reduced pressure, and the remaining solid matter was removed by n.
After washing with -hexane, 160.7 g of 4-methoxy-2,3,5,6-tetrafluorobenzonitrile was obtained as colorless needle crystals.

Mass spectrum: m / e 205 (M ⁺ ), 190 (M ⁺ −CH ₃ ), 162 (M
⁺ -CH ₃ -CO) filled with liquid ammonia 150ml and above so obtained 4-methoxy-2,3,5,6-fluorobenzonitrile 100.0 g (0.49 mol) into the autoclave, and allowed to stand overnight at room temperature . After removing the ammonia, the remaining solid matter is washed with water, and 2
84.4 g of -amino-4-methoxy-3,5,6-trifluorobenzonitrile was obtained as a colorless powder.

Mass spectrum: m / e 202 (M ⁺ ), 172 (M ⁺ -CH ₂ = 0), 15
9 (M ⁺ —CH ₃ —CO) Then, to 84.4 g (0.42 mol) of 2-amino-4-methoxy-3,5,6-trifluorobenzonitrile, 50 ml of water and 200 ml of concentrated sulfuric acid were added, and the mixture was heated to 100 ° C. for 1 hour. After stirring for an hour, 150 ml of water was added, and the mixture was further stirred for 2 hours at 110-120 ° C. After allowing to cool to room temperature, ice water was added and neutralized with potassium carbonate. The precipitated crystals were extracted with ethyl acetate, the organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 3-methoxy-2,4,5-
57.6 g of trifluoroaniline was obtained as colorless needle crystals.

Melting point 45-47 ° C Mass spectrum: m / e 177 (M ⁺ ), 147 (M ⁺ -CH ₂ = 0) NMR spectrum (CDCl ₃ ) δppm: 3.65 (br, 2H, -NH ₂ ) 4.01 (s, 3H _{, -OCH 3) 6.22~6.36 (m,} 1H, aromH) thus obtained 3-methoxy-2,4,5-trifluoro-aniline 1.01 g (5.6 mmol) of acetic acid 3 ml, water 25 ml, concentrated sulfuric acid 1.68 It was dissolved in a mixed solution of g (16.8 mmol), cooled to 0 ° C,
1 ml of an aqueous solution containing 0.46 g (6.6 mmol) of sodium nitrite was added dropwise with stirring at 0-3 ° C. At the same temperature after dropping, 30
After stirring for a minute, a diazonium salt solution was obtained.

On the other hand, 1.80 g (7.2 mmol) of copper sulfate pentahydrate was dissolved in 10 ml of water, and 5 ml of an aqueous solution containing 1.95 g (30 mmol) of potassium cyanide was added dropwise under stirring at 20 ° C. or below to obtain a brown transparent solution. After adding 4.02 g (48 mmol) of sodium hydrogen carbonate,
30 ml of benzene was added.

The above-mentioned diazonium salt solution was added dropwise to this two-layer solution with vigorous stirring at 30 to 45 ° C, and after completion of the addition, the reaction mixture was heated to 65 ° C. After cooling to room temperature, the benzene layer was separated, washed with water, dried and evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: toluene),
3-methoxy-2,4,5-trifluorobenzonitrile 0.7
7 g was obtained as a red oil.

IR spectrum (film method, ν _max cm ^-1 ): 2250,1620,1500,1480,1120,1080 1.24 g (7 mmol) of 3-methoxy-2,4,5-trifluorobenzonitrile obtained as above. 5 ml concentrated sulfuric acid and 1.2
After adding ml, the mixture was heated at 100-140 ° C for 30 minutes, poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and dried under reduced pressure to give 3-methoxy-2,4,5-trifluorobenzamide (1,10 g) as a light brown powder.

Melting point 131-133 ° C Mass spectrum: m / e 250 (M ⁺ ), 189 (M ⁺ -NH ₂ ) Next, 46.4 g (0.226 mol) of this 3-methoxy-2,4,5-trifluorobenzamide was added to 900 ml of water. Suspended in 1N, 226 ml (0.226 mol) of 1N sodium hydroxide was added, and the mixture was heated under reflux with stirring for 2 hours. After allowing to cool to room temperature, the reaction mixture was extracted with ethyl acetate to remove unreacted substances, and the aqueous layer was acidified with hydrochloric acid. The precipitated crystals were extracted with ethyl acetate, the organic layer was washed with water, dried and evaporated under reduced pressure to give 3-methoxy-2,4,5-trifluorobenzoic acid 37.
1 g was obtained as colorless needle crystals.

Melting point 115-117 ° C Mass spectrum: m / e 206 (M ⁺ ), 189 (M ⁺ -OH), 161 (M ⁺
-COOH) NMR spectrum (CDCl ₃ ) δppm: 4.09 (s, 3H, OCH ₃ ) 7.50 to 7.62 (m, 1H, aromH) 8.0 to 10.0 (br, 1H, COOH) Then 3-methoxy-2,4, 5-trifluorobenzoic acid
1.14 g (5.5 mmol) was dissolved in 10 ml of dry benzene, 5 ml of thionyl chloride was added, and the mixture was heated under reflux for 1 hour. After the reaction, benzene and excess thionyl chloride were completely distilled off to obtain 3-methoxy-2,4,5-trifluorobenzoic acid chloride.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication location C07C 253/30 (72) Inventor Kiyoshi Omori 5 5 1987, Kogushi, Ube, Yamaguchi Prefecture Ube Institute of Industrial Research Co., Ltd. (72) Fumio Kimura, 5 1987, Kogushi, Ube City, Ube City, Yamaguchi Prefecture, Ube Laboratory, Ube Industries Ltd. (72) Masayuki Iwata, 1-2-2, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd.

Claims (1)

[Claims] 1. A general formula (In the formula, R ¹ represents a lower alkyl group, R ² and R ³ represent the same or different lower alkyl groups, and A represents a nitrile group or a lower alkoxycarbonyl group.) Substituted benzoyl acrylic acid derivative